{"paper_id":"e7d9003a-39ae-4e58-943d-6eefc4590798","body_text":"Breast cancer is a major health threat\nto women of all age groups\nand a prime contributor to cancer deaths in women. About two-thirds\nof cases when first diagnosed are classified as hormone-dependent\n(ER + ), in which to grow and develop the tumors need estrogens,\nwhich act via the estrogen receptor (ER). 1  Endocrine therapy administered by the oral route is an effective\nform of treatment for this type of cancer. 2  Although newer targeted agents such as mTOR and CDK4/6 inhibitors,\ne.g., everolimus and palbociclib, are now gaining recognition in treatment,\nthey are expensive and are administered in conjunction with endocrine\ntherapy. 3 , 4  Currently, the first-line treatment for\npatients with hormone-dependent breast cancer (HDBC) includes either\na selective estrogen-receptor modulator, such as tamoxifen, which\nblocks the action of estrogens at the ER or an ER downregulator (SERD), 5  or a “third-generation” aromatase\ninhibitor (AI) such as letrozole, anastrozole, and exemestane. This\nstrategy leads to a reduction in the biosynthesis of estrogens and\nhas been found to be superior to tamoxifen alone. 6  Also, in one study, anastrozole has shown significant preventative\nactivity in high-risk postmenopausal women with undiagnosed breast\ncancer. 7  However, resistance will inevitably\noccur and blocking the action of estrogens at the ER and inhibiting\nthe aromatase enzyme are not the only strategies available for endocrine\ntherapy. There is now evidence that inhibition of steroid sulfatase\n(STS), 8  the enzyme that converts the biologically\ninactive estrone sulfate to estrone, as well as dehydroepiandrosterone\nsulfate to dehydroepiandrosterone, may render significant estrogen\ndeprivation in patients treated with an STS inhibitor. This strategy\nworks in an intracrine fashion because in the postmenopausal setting\ntumor cells can convert the large reservoir of circulating estrone\nsulfates, imported through organic anion transporters, to active estrogen\nin situ. Moreover, STS inhibition also decreases levels of androstenediol,\nan estrogenic androgen, 9  levels of which\nare unaffected by AI inhbition. Chronic AI treatment leads to compensatory\nincreases in both STS and 17β-HSD1 levels. 10  Moreover, the contribution of both STS and organic anion\ntransporters to AI resistance was recently established and could be\novercome by an STS inhibitor. 11  These ideas\nhave led to STS inhibitors reaching phase II clinical trials for several\nindications in oncology including breast cancer and endometrial cancer\nand a phase I trial in prostate cancer. 12\nThe first STS inhibitor discovered with a remarkable potency\nwas\nthe steroidal sulfamate ester estrone-3- O -sulfamate\n(EMATE,  1 ,  Figure  1 ). 13  This agent is orally active\nand inhibits STS in an irreversible manner. However, EMATE was subsequently\nshown to be highly estrogenic in rats and this undesirable property\neffectively precluded its further development for use in the treatment\nof HDBC, although the estradiol variant (E2MATE, PGL2001,  1a ) has nevertheless proceeded to clinical trials in the hormone-dependent\nnononcology setting of endometriosis. 12a , 12b , 14\nStructures of STS inhibitors:  1  (EMATE),  1a  (E2MATE), and  2  (Irosustat, STX64, 667COUMATE,\nBN83495).\nIn an attempt to search for a\nnonestrogenic alternative to  1  with a comparable or even\nsuperior STS inhibitory profile,\nmany structurally diverse inhibitors that contain the pharmacophore\nfor irreversible inhibition of STS, i.e., an aryl sulfamate ester,\nhave been developed, 8 , 12 , 15  leading to the clinical inhibitor Irosustat  2  ( Figure  1 ). 16  Initial work focused on designing A/B ring mimics of  1  such as derivatives of indanone, tetralone, and tetrahydronaphthol, 15  and this yielded a series of bicyclic coumarin\nsulfamates 17  ( 3 – 8 ,  Figure  2 ) that were promising leads, showed a significant improvement over\nthe first lead nonsteroidal candidate 5,6,7,8-tetrahydronaphthalene\n7- O -sulfamate, and, more significantly, possessed\nin vivo activity. A main lead was the two-ring 4-methylcoumarin-7- O -sulfamate ( 3 ) that was orally active in vivo\nand, like EMATE, was a highly potent time- and concentration-dependent\nSTS inhibitor, but importantly with no rodent estrogenic activity. 18 , 19  The related 3,4-dimethylcoumarin-7- O -sulfamate\n( 6 ) inhibited STS in MCF-7 cells with IC 50  = 30 nM, and a series of derived tricyclic compounds was subsequently\nsynthesized that proved even more potent. 16 , 17  Further development of this series of nonsteroidal inhibitors led\nto the discovery of the tricyclic coumarin sulfamate ( 2 ) (Irosustat, STX64, 667COUMATE, BN83495,  Figure  1 ) which has proven to be the most successful\nSTS inhibitor to date. 12 , 16  Recently, other examples of both\nmono- 20 , 21  and two-ring sulfamate-based STS inhibitors 22  have been published, but these compounds are\ngenerally still of relatively modest inhibitory activity. Irosustat\nwas the first STS inhibitor to enter clinical trials for postmenopausal\npatients with advanced HDBC and has shown encouraging results. 12 , 23 − 26  Irosustat has just completed CRUK sponsored phase II trials in both\nearly breast cancer and in advanced breast cancer in combination with\nan AI, with positive indications of efficacy. 27 , 28\nStructures\nof bicyclic coumarin sulfamates  3 – 8 , including COUMATE  3 . X = OSO 2 NH 2 .\nHowever, despite the significant\nprogress made in developing irreversible\ninhibitors of STS and although  1a  and  2  have\nreached clinical trials, their mechanism of action remains unresolved.\nThe crystal structure of human STS has been solved, 29 , 30  and several hypotheses have been postulated to suggest how a sulfamate-based\nSTS inhibitor might inhibit STS irreversibly. The currently favored\nhypothesis is a transfer of the sulfamoyl group (or as sulfonylamine)\nto a hydrated or unhydrated STS active site formylglycine residue,\nand this leads to inactivation of the active site machinery. 12b  Although multiple mechanisms have been proposed\nfor this, e.g. ref. ( 12e ), see ref. ( 12b ) for\na full up-to-date discussion.\nBecause of the unique role that\na coumarin ring system plays in\nthe design of potent STS inhibitors, we further expand here the bicyclic\ncoumarin sulfamate series exemplified by  3 – 8  to give derivatives that bear various substituents at the\n3- and/or 4-position(s), following on from preliminary encouraging\ndata. 17  The inhibitory activities of most\nnew candidates against STS were evaluated in MCF-7 cells and in placental\nmicrosomes. This study, in conjunction with other studies carried\nout on  2 , 16 , 17  provides a more comprehensive\nstructure–activity relationship (SAR) for coumarin sulfamates\nand has also produced highly active inhibitors of picomolar potency\nin vitro. The activity of two of the best bicyclic compounds is supported\nby molecular modeling and by comparing binding poses with those of\nthe benchmark compounds EMATE and Irosustat.\n\nThe\ncompounds synthesized in this work fall into two different\nseries: (i) those with an alkyl group of increasing carbon chain length\nor other functionalities at the C-4 position of the coumarin ring\n( A ,  Figure  3 ) and (ii) those with an alkyl group of increasing carbon chain length\nor other functionalities at the C-3 position and with a methyl group\nat the C-4 position of the coumarin ring ( B ,  Figure  3 ).\nGeneral structures of\nbicyclic coumarin sulfamates:  A : 4-substituted series,  B : 3,4-disubstituted series.\nWe employed β-keto esters as starting materials for\nsynthesizing\ncoumarins with a substituent at the 3-position, and this also leads\nto a 4-methyl substituent. Because 4-methylcoumarin 7- O -sulfamate (COUMATE) is more active as an STS inhibitor than unsubstituted\ncoumarin 7- O -sulfamate, we retained this 4-substituted\ngroup, which imbues good activity. 18 , 19  Thus, to study\nfurther the SAR of COUMATE, we ideally needed to keep this 4-methyl\ngroup for comparison while we explored different substituents at the\n3-position. Apart from coumarin  46a , the bicyclic ring\nof other parent coumarins was constructed by the Pechmann synthesis\nof hydroxyl coumarins. For our purposes, this route was preferred\nbecause the target structures can be prepared with relative ease by\ncondensing resorcinol with an appropriate β-keto ester. The\nonly synthetic hurdle to overcome is the synthesis of the various\nβ-keto esters required because most of them are not available\ncommercially. The 7-hydroxycoumarins synthesized are subsequently\nsulfamoylated with freshly prepared sulfamoyl chloride to form the\ncorresponding coumarin sulfamates.\nThe alkanoyl acetate esters\nrequired as starting material for the\ncoumarins in the 4-alkyl series ( A ,  Figure  3 ) were synthesized by treating\nthe inexpensive ethyl potassium malonate with the corresponding acid\nchloride in the presence of magnesium chloride (MgCl 2 ),\ntriethylamine (Et 3 N), and acetonitrile (CH 3 CN)\nas the solvent ( Scheme  1 ). 31  This method has the advantage of\nbeing relatively safe, clean, economical, and suitable for scaling\nup with the product produced in high yield and purity, which is free\nfrom any unnecessary side products. Rathke and Cowan 32  have shown that the combination of anhydrous MgCl 2  and Et 3 N provides a system with enough basicity for metallating\nethyl potassium malonate and that the reactions failed when MgCl 2  was replaced with other metal chlorides such as ZnCl 2 , CuCl 2 , FeCl 3 , TiCl 4 , LiCl,\nand AlCl 3 . 32  The number of equivalents\nof reagents used in the reaction determines the yield of the product\nobtained. For aromatic acid chlorides which have electron-withdrawing\nsubstituents such as fluoro, chloro, or nitro groups, 2.1 equiv of\npotassium ethyl malonate, 2.5 equiv of MgCl 2 , and 2.2 equiv\nof Et 3 N are optimal, and the yield is around 90%. On the\nother hand, aliphatic acid chlorides or aromatic acid chlorides containing\nelectron-donating substituents generate side products, which are minimized\nby employing extra equivalent of Et 3 N to obtain the alkanoyl\nacetate in high yield.\n(i) SOCl 2 /tetrahydrofuran\n(THF), reflux; (ii) (a) MeCN, MgCl 2 , Et 3 N, 10–25\n°C, 2.5 h, (b) RCOCl, Et 3 N, 0 °C, 0.5 h, room\ntemperature (rt), 12 h; (iii) RCHO, SnCl 2 , CH 2 Cl 2 , rt, 3 h.\nβ-Ketoesters\nwere also prepared efficiently by reacting the\ncorresponding aldehyde with ethyl diazoacetate in the presence of\na catalytic amount of tin(II) chloride (SnCl 2 ) ( Scheme  1 ). The mechanism\nof the reaction is likely to proceed via a betaine intermediate, followed\nby a preferential migration of the aldehyde hydrogen to the β-carbon\ni.e., a 1,2-hydride shift producing the required β-keto ester\nand N 2  as products. The two most noteworthy aspects of\nthis method are its selectivity and the mild conditions involved.\nThe reaction is insensitive to atmosphere, is complete between 1 and\n2 h at room temperature, and can be catalyzed by various Lewis acids,\nsuch as BF 3 , ZnCl 2 , ZnBr 2 , AlCl 3 , SnCl 2 , GeCl 2 , and SnCl 4 , but the highest yield is obtained with SnCl 2 . 33  Although other common organic solvents can be\nused, CH 2 Cl 2  is often employed because it gives\nthe best results and can be easily removed.\nThe α-alkylacetoacetates\nrequired for the synthesis of coumarins\nin the 3-substituted-4-methyl series were prepared conveniently by\ntreating a solution of ethyl acetoacetate in CH 2 Cl 2  with the corresponding alkyl bromide in the presence of potassium\ncarbonate (K 2 CO 3 ) and tetrabutylammonium chloride\n(Bu 4 NCl) ( Scheme  2 ). 34\n(i) RBr, K 2 CO 3 , H 2 O, Bu 4 NCl, CH 2 Cl 2 , reflux, 40 h.\nPechmann synthesis of coumarins\nwith a β-keto ester and resorcinol\nwas carried out in the presence of an equimolar mixture of trifluoroacetic\nacid (CF 3 COOH) and concentrated sulfuric acid (H 2 SO 4 ) warmed from ice-water temperature to room temperature\n( Schemes  3  and  4 ). The use of a 1:1 mixture\nof conc. H 2 SO 4  and conc. CF 3 COOH\nas the condensing agent for the Pechmann synthesis of coumarins was\nfirst described by Hua et al., 35  and, in\nour hands, such a mixture has been found to be as effective as using\nconc. H 2 SO 4  alone, which is playing a role as\na catalyst. The role of conc. CF 3 COOH in this reaction\nis not entirely clear, although it might be acting as an organic solvent\nand lowering the viscosity of the reaction mixture, rendering the\nstirring process more efficient.\n(i)\nConc. H 2 SO 4 /conc. CF 3 COOH, 3 h, 0\n°C to rt, (ii) anhydrous\ndimethylformamide (DMF), NaH, N 2 , 0 °C and H 2 NSO 2 Cl (∼5 equiv), 0 °C to rt.\n(i) Conc. H 2 SO 4 /conc. CF 3 COOH, 3 h, 0 °C to rt; (ii) (Bu) 4 N + HSO 4 – , CH 2 Cl 2 , rt; (iii) anhydrous DMF, NaH, N 2 , 0 °C\nand H 2 NSO 2 Cl (∼5 equiv), 0 °C to\nrt.\nThe sulfamoylation reaction was performed\nby reacting the hydroxyl\ncoumarins with an excess of (∼5 equiv) sulfamoyl chloride after\ntreating with 1 equiv of NaH as described previously by Woo et al. 36\n\nThe in vitro inhibition of STS activity by most of the sulfamates\nsynthesized in this work was measured in two assay systems: (i) a\npreparation of an intact monolayer of MCF-7 cells, which assesses\nthe ability of compounds to cross the cell membrane and inhibit STS\nunder conditions that closely resemble the tissue/physiological situation\nand (ii) a placental microsomes preparation where a higher concentration\nof substrate is employed, with which a compound has to compete for\nbinding to the enzyme active site. For the placental microsome STS\nassay, a saturating substrate concentration of 20 μM was used\nand inhibitors were tested under initial rate conditions. The MCF-7\nSTS assay is meant to mimic/reflect physiological conditions (intact,\nliving cells). Hence, a physiological concentration of 3 nM of E1S\nwas used. The results are reported as % inhibition at various concentrations,\nand IC 50  values are determined for several compounds ( Tables  1 – 4 ). Although time- and concentration-dependence studies\nhave not been carried out to confirm the nature of inhibition for\nthose compounds tested, it is anticipated that they act mechanistically\nin a similar manner to other aryl sulfamates like  1  and  2 , which have been shown to be active-site-directed inhibitors\nUnless stated otherwise, errors\nare <5% of the reported value (from triplicate experiments).\nRef ( 15 ).\n*:\nResults not determined; cf. EMATE\n(IC 50  = 65 pM). 13b\nFor 4- n -alkyl derivatives  9 – 15 ,  17 , and  18 , all derivatives\ninhibit STS activity >90% at 1 μM. Based\non the % inhibition observed at 0.1 and 0.01 μM, the inhibitory\nactivity of the compounds increases slightly as the chain length of\nthe alkyl group increases, and it peaks at the nonyl ( 14 , 90% at 0.01 μM) and decyl ( 15 , 86% at 0.01 μM)\nderivatives. This may be attributed to the increase in lipophilicity\nof the compounds as their alkyl group becomes longer until steric\nhindrance potentially becomes a limiting factor. A similar observation\nwas reported in studies of ( p - O -sulfamoyl)- N -alkanoyl tyramines. 37 , 38  We and others have\nalso noted the existence of a hydrophobic pocket at the end of the\nsteroid binding pocket 39  that might also\nbe accessed by the present compound series to improve binding, although\nseeking the right compromise between hydrophobicity and steric hindrance\nis important. 40  For other substituents\nat the 4-position of the coumarin ring, their inhibitory activities\nvary with the phenethyl derivative  24  (39% at 0.01 μM,\nIC 50  = 18 nM) and the cyclohexyl derivative  26  (37% at 0.01 μM, IC 50  = 24 nM) being the most active.\nHowever, both  24  and  26  are less potent\nas STS inhibitors than the 4- n -alkyl derivatives.\nOne possibility is that the active site of STS, like many other enzymes\nwith steroids as substrate in general, has limited accommodation for\nsubstituents at the C1/C11/C12 edge of the steroid scaffold. Hence,\nthe more flexible aliphatic alkyl chains may be better tolerated by\nthe enzyme active site than the bulkier and more rigid substituents\nsuch as phenyl, benzyl, phenethyl, 4-ethylphenyl, and cyclohexyl when\nthese substituents are placed at the 4-position of the coumarin ring\nsystem, which mimics the A/B ring of the steroidal STS inhibitor  1 .\nApart from\nthe two lower members  3  and  4  and the two\nhigher members  17  and  18 , other 4- n -alkyl derivatives\n( 5 – 16 ) tested show >90% inhibition\nat 1 μM. However, the SAR between chain length and inhibitory\nactivity is not clear because all derivatives evaluated show the same\norder of magnitude in regard to % inhibition at 0.01 μM and\nIC 50  values. Nonetheless, the  n -pentyl\n( 10 , IC 50  = 40 nM) and  n -dodecyl\n( 17 , IC 50  = 45 nM) derivatives appear to be\nthe most active inhibitors in this group. For those derivatives that\nhave bulkier substituents at the 4-position, they are significantly\nless potent than their  n -alkyl derivatives with the\nexception of  23  (benzyl, IC 50  = 64 nM),  24  (phenethyl, IC 50  = 82 nM), and  26  (cyclohexyl, IC 50  = 42 nM), the IC 50  values\nof which are of the same order of magnitude as those of  n -alkyl derivatives. As expected for a cell-based assay, the IC 50  values against STS obtained for compounds in  Table  1  are much lower than those obtained\nfrom the cell-free placental microsomes assay ( Tables  2  and  3 ). A similar\nphenomenon was observed in previous work. 41\nUnless stated otherwise, errors\nare <5% of the reported value (from triplicate experiments).\nRef ( 15 ).\nRef ( 17 ).\n*: Results not determined; cf. EMATE\n(IC 50  = 25 nM), 17 2  (IC 50  = 8 nM). 17\nUnless stated otherwise, errors\nare <5% of the reported value (from triplicate experiments).\nRef ( 15 ).\n*:\nResults not determined.\nA relatively\nsmaller number of synthesized compounds\nin this series compared to their 4-substituted relatives were tested\nfor their inhibitory activities. From the results available, 3-alkylated-4-methyl\ncompounds  28 – 33  show >97% inhibition\nat 0.1 μM, whereas compounds  39 – 43 , which have other substituents at the 3-position, inhibit STS between\n29 and 98% at 0.1 μM. Of those five compounds that have IC 50  values determined,  29  is the most potent (0.68\nnM), closely followed by  41  and  42  (1 and\n1.1 nM, respectively). On comparing  23  (4-benzyl, IC 50  = 75 nM,  Table  1 ) and  24  (4-phenethyl, IC 50  = 18 nM,  Table  1 ) with  41  (3-benzyl-4-methyl, IC 50  = 1 nM) and  42  (3-phenethyl-4-methyl,\nIC 50  = 1.1 nM), there is 1 order of magnitude difference\nbetween the potency of the two pairs of compounds. This finding suggests\nthat placing either a benzyl or a phenethyl group at the 3-position\nof the coumarin ring produces a more potent STS inhibitor. It is anticipated\nthat on binding of  41  and  43  into the active\nsite of STS, the coumarin ring of which is designed to mimic the A/B\nring of  1 , their substituents at the 3-position extend\ninto the same area where the C/D ring of  1  resides.\nOn the basis of the IC 50  values available, it appears that compounds with shorter alkyl chains\nat the 3-position of the coumarin ring ( 28 ,  n -pentyl, IC 50  = 12 nM and  29 ,  n -hexyl, IC 50  = 32 nM) are more potent STS inhibitors than\nthose with longer alkyl chains ( 32 – 34 ,  37 ; IC 50  > 300 nM). This contrasts with\nthose compounds in the 4-alkylated series ( Table  2 ) the IC 50  values (40–102\nnM) of which are tighter and fall within the same order of magnitude.\nThis finding suggests that a long alkyl chain placed at the 4-position\nof the coumarin ring may interact better with the enzyme active site\nthan its counterpart placed at the 3-position of the coumarin ring.\nTo this effect, the sulfamate group of 4-alkylated compounds may be\nbetter positioned within the catalytic site of the enzyme for inactivation.\nFor compounds  40 – 43 , the inhibitory\nactivity observed at 0.1 μM starts from 65% for  40  (phenyl) and rises to 94% for  41  (benzyl) before it\nfalls to 91 and 47% for  42  (phenethyl) and  43  (phenylpropyl), respectively. A similar pattern is observed when\nthe IC 50  values of  40  (54 nM),  41  (8 nM), and  42  (33 nM) are compared. In regard to potency,\nthe benzyl group is therefore the optimal substituent for this group\nof 3-substituted-4-methyl coumarin sulfamates. It is possible that\nthe phenyl, phenethyl, and phenylpropyl groups interact less favorably\nwith or are less well accommodated by the enzyme active site ( Table  4 ).\nUnless stated otherwise, errors\nare <5% of the reported value (from triplicate experiments).\nRef ( 15 ).\nRef ( 17 ).\n*: Results not determined.\nWhen the benzyl group of  41  is replaced\nby a cyclohexylmethyl\ngroup to give  44 , a reduction in potency is observed\n(at 0.1 μM, 94% for  41  vs 74% for  44 ). The same pattern, but to a greater extent, is observed when the\nphenethyl group is replaced by a cyclohexylethyl group as shown by\nthe 91% inhibition of the STS observed for  42  at 0.1\nμM compared to the 37% inhibition for  45  at the\nsame concentration. This finding suggests that the more rigid and\nelectron-rich phenyl group may interact better with the enzyme active\nsite (such as through π-interactions with neighboring amino\nacids) than the more flexible aliphatic cyclohexyl group. The best\ninhibitors are illustrated in  Figure  4 , with an attempt to illustrate the mimicry of the\nsteroidal C and D rings and also with some comparative activities\nshown in  Table  5 .\nDiagrammatic\ncomparison of some potent inhibitors evaluated: 4-pentylcoumarin-7- O -sulfamate ( 10 ), 4-nonylcoumarin-7- O -sulfamate ( 14 ), 4-tridecylcoumarin-7- O -sulfamate ( 18 ), 3-hexyl-4-methylcoumarin-7- O -sulfamate ( 29 ), 3-nonyl-4-methylcoumarin-7- O -sulfamate ( 32 ), 3-benzyl-4-methylcoumarin-7- O -sulfamate ( 41 ), 3-phenethyl-4-methylcoumarin-7- O -sulfamate ( 42 ), in comparison with EMATE\n( 1 ), Irosustat ( 2 ), and COUMATE ( 3 ). Solid lines denote similarity to steroid C and D rings.\n\nDocking studies\nwere conducted to explore potential interactions\nbetween the substituted bicyclic coumarin derivatives and the STS\nactive site, in a similar fashion to those carried out for STX64/Irosustat\nand related series members. 16  They show\nthat the two most active compounds  29  and  41  are placed in a very similar fashion to the irreversible STS inhibitor\nIrosustat, with the sulfamoyl group in close proximity and opposite\nto the catalytic FGly 75 ( Figure  5 ), suggesting that a putative sulfamoyl group transfer\ncould also readily occur that might lead to similar irreversible inhibition\n(although note that no experiments were conducted to explore the reversibility/irreversibility\nof  29  and  41  against STS). Residue V486\non one side and residues L103 and V177 on the other sandwich the bicyclic\nring system. Both compounds possibly form a hydrogen bond (N···O\n= ∼3.2 Å) from their chromen-2-one oxygen to the NH of\nG100 in the same manner as Irosustat ( Figure  5 ). These more potent compounds have fairly\nsmall hydrophobic pendant groups attached to the 3-position of the\nchromen-2-one ring. These hydrophobic moieties lie between the hydrophobic\nsidechains of L103, F178, and F488. Those compounds with larger pendant\ngroups may be less active due to the hydrophobic nature of the group\nmaking the compound less soluble. Alternatively, because STS is a\nmembrane-bound protein and any substrate or inhibitor has to pass\nthrough the membrane to access the active site, it may be that larger\nhydrophobic tails result in the inhibitor failing to fully transit\nthrough the membrane: the hydrophobic tail stays, preferentially,\nembedded in the membrane.\nLeft: docking of EMATE (cyan) and  29  (brown) into\nthe crystal structure of human STS. Right: docking of Irosustat (cyan)\nand  41  (brown) into the crystal structure of human STS.\nIn both figures, the Ca 2+  ion is depicted as a yellow sphere\nand FG75 is the  gem -diol form of FGly 75 aldehyde.\nThe dotted yellow lines are potential hydrogen bonds.\nOn examining the data in  Table  5 , where the best compounds are benchmarked\nagainst\nthe steroidal EMATE and the nonsteroidal Irosustat and, more particularly,\nagainst the known two-ring coumarin sulfamate COUMATE, it is readily\napparent that highly potent compounds have been designed through the\ntargeted 3- and 4-substitutions undertaken in this work. Some of these\n( 29 ,  32 ,  41 , and  42 ) have a potency approaching the clinical drug Irosustat in the more\ndefinitive intact MCF-7 cell assay, and of these,  29  is\nhighly significant with a similar picomolar IC 50 . Compound  41  is perhaps of the widest interest with an IC 50  of 1 nM but also with an inhibitory activity better than that of\nIrosustat in the more challenging placental microsomal STS assay.\nIt has an attractive 3-benzyl substituent that, as for the highly\nactive homolog  42 , could potentially be substituted to\nfurther refine activity. Moreover,  41  and  42  are structurally distinct from the fully saturated C-ring surrogate\nof Irosustat and, as more versatile compounds, could form the basis\nof an attractive series for further optimization and eventual preclinical\ndevelopment. In any case, if we sensibly take COUMATE  3  for comparison, the best compounds are gratifyingly some 100–500\ntimes more potent in the MCF-7 assay.\n\nSynthetic\nroutes to two-ring coumarin 7- O -sulfamate\nderivatives possessing 3- and 4-modified substitutions were devised,\ngenerally using an α-alkylacetoacetate strategy and the Pechman\nhydroxycoumain synthesis. 15 , 17  Compounds were shown\nto inhibit, often highly potently, the emerging clinical drug target\nSTS 8  now validated for hormone-dependent\ndiseases 12  using an intact MCF-7 cell assay\nand an assay against placental microsomal STS activity. The best compounds\nwere benchmarked for activity against the steroidal sulfamate drug\nEMATE, 13  the nonsteroidal Irosustat, 12 , 16  and the known two-ring parent coumarin sulfamate COUMATE. 18 , 19  Through the targeted 3- and 4-substitution strategy undertaken,\nhighly potent compounds were designed. In intact MCF-7 cells, compounds  29 ,  32 ,  41 , and  42  had\na potency approaching Irosustat with  29  having an IC 50  of 680 pM.  41  had a similar IC 50  of 1 nM but was also better than Irosustat against placental microsomal\nSTS. With COUMATE  3  taken as the most relevant comparative\nstructural benchmark for non-tricyclic derivatives, the best compounds\nwere ca. 100–500 times more potent in the MCF-7 assay. Both  41  and  42  possess motifs structurally distinct\nfrom the fully saturated cyclic C-ring of Irosustat with attractive\npendant 3-benzyl and 3-phenethyl substituents, respectively, that\ncould potentially be further optimized through aromatic substitution.\nCompounds  29  and  41  were modeled into STS\nin comparison to benchmarks and dock well into the active site, placing\nthe aryl sulfamate moiety opposite the catalytic FGly, as for Irosustat 16  and with their pendant side chains occupying\na hydrophobic pocket noted previously. 39  The expectation is that, in a similar fashion to Irosustat and EMATE,\nsuch compounds will act as irreversible inhibitors by transfer of\ntheir sulfamoyl group to the STS enzyme, 12b , 13b  although this has not been formally explored here. Thus, the versatile\n3-benzyl-4-methyl- and 3-phenethyl-4-methyl-derivatives  41  and  42 , respectively, and possibly also the 3- n -hexyl-4-methyl-derivative  29  from this study\nare potent STS inhibitors and could represent new leads for potential\npreclinical development.\n\nSTS inhibitory assays\nwere performed essentially as previously described. 13b , 43  The ability of the compounds synthesized to inhibit E1S was tested\nin vitro using MCF-7 cells and a placental microsomal preparation\nfrom a sulfatase-positive human placenta from a normal term pregnancy\nand compared with that of EMATE. For the placental microsome STS assay,\na saturating substrate concentration of 20 μM was used and inhibitors\nwere tested under initial rate conditions. For the MCF-7 STS assay,\na physiological concentration of 3 nM E1S was used. Thus, for the\nplacental microsome assay: [E1S] = 20 μM, [I] = 0.1 nM to 10\nμM; MCF-7: [E1S] = 3 nM, [I] = 0.1 nM to 10 μM (NB for\nhighly potent compounds, this was changed to 0.1 pM to 10 nM).\nAll reagents were purchased\ncommercially either from Aldrich Chemicals Co. (Gillingham, Dorset,\nU.K.) or Lancaster synthesis (Morecambe, Lancashire, U.K.). All organic\nsolvents used were of general purpose or analytical grade and were\nobtained from Fisons Plc. (Loughborough, U.K.) and stored over 4 Å\nmolecular sieves. Anhydrous dimethylformamide (DMF) used for all sulfamoylation\nreactions was purchased from Aldrich and was stored under a positive\npressure of N 2  after use. Sulfamoyl chloride was prepared\nby adapting a method originally reported by Appel and Berger 44  and was stored as a standard solution in purified\nsulfur-free dry toluene. 36\nThin-layer\nchromatography (TLC) was carried out using precoated plates (Merck\nTLC aluminum sheets silica gel 60 F254, art. no. 5554). Product(s)\nand starting material were detected by treating plates with a methanolic\nsolution of phosphomolybdic acid followed by heating or simply by\nviewing directly under UV light. Flash column chromatography was carried\nout by gradient elution (solvents used are indicated in the text)\non wet-packed silica gel (Sorbsil C60). IR spectra were recorded using\na PerkinElmer 782 spectrophotometer with peak positions expressed\nin cm –1 .  1 H and  13 C NMR spectra\nwere recorded using either a Jeol Delta 270 MHz or Varian Mercury\nVX 400 MHz spectrometer. Chemical shifts (δ) are reported in\nparts per million (ppm) using an internal standard of tetramethylsilane.\nCoupling constants ( J ) are quoted to the nearest\n0.1 Hz. Mass spectra were acquired at the Mass Spectrometry Service\nCentre, Bath and FAB mass spectra used  m -nitrobenzyl\nalcohol as matrix. Elemental analyses were carried out by the Microanalysis\nService, Bath. Melting points are uncorrected and were determined\nusing a Reichert-Jung Thermo Galen Kofler block. High-performance\nliquid chromatography (HPLC) was performed using a Waters 660E instrument\nequipped with an autosampler and photo diode array detector. A Waters\nRadialpak column (RP18, 8 mm × 100 mm) was used. The conditions\nof elution and analytical data are as indicated for each compound\nanalyzed.\nSchrödinger software (running\nunder Maestro 9.0) was used to build and minimize all of the ligands.\nThe ALS75 residue in PDB crystal structure 1P49 (human placental estrone/dehydroepiandrosterone\nsulfatase) was mutated to the  gem -diol form using\nthe Schrödinger software editing tools. Minimization of the\nresulting structure, with the position of the backbone atoms fixed,\nallowed the atoms of the  gem -diol and surrounding\nside chains to adopt low-energy conformations. Ligands were docked\ninto the rigid protein using GOLD. A 10 Å sphere centered on\nthe ALS75 sulfate was defined as the binding site. The GOLDScore fitness\nfunction was used to score the docked poses (25 for each ligand).\nTo ethyl potassium\nmalonate (2.1 equiv) in MeCN (100 mL/5 g of acid chloride) at 10–15\n°C and under N 2  was added Et 3 N (3.2 equiv),\nfollowed by MgCl 2  (2.5 equiv). The mixture was stirred\nat 20–25 °C for 2.5 h and then at 0 °C for 0.5 h\nbefore the corresponding acid chloride (1 equiv) was added dropwise\nduring 25 min. The mixture was further treated with Et 3 N (5 mL) and stirred overnight at 20 °C. The evaporation residue\nwas dissolved in toluene and re-concentrated. More toluene was added,\nstirred, and cooled to 10–15 °C before aq HCl (1 M, 50\nmL) was added cautiously while keeping the temperature <25 °C.\nThe organic layer was washed with 1 M aq HCl (50 mL) and water. Drying,\nevaporation, and distillation or chromatography (CHCl 3  or\nCHCl 3 /acetone, 10:1) gave the corresponding ethyl α-alkanoylacetate.\nTo anhydrous\nSnCl 2  (0.1 equiv) was added CH 2 Cl 2  (∼100 mL/5 g of aldehyde), followed by ethyl diazoacetate\n(1.05 equiv). The reaction was initiated by adding a few drops of\nthe corresponding aldehyde in CH 2 Cl 2 . When N 2  evolution began, the remaining solution of aldehyde (1 equiv)\nwas added dropwise over 30 min. After the evolution of N 2  had stopped (∼1–3 h), the mixture was washed with\nbrine (50 mL) and extracted twice (Et 2 O). Drying, evaporation,\nand chromatography (CHCl 3  or CHCl 3 /acetone,\n10:1) or distillation gave the corresponding ethyl alkanoylacetate.\nK 2 CO 3  (2.4 equiv),\nwater (50 mL), alkyl bromide (1 equiv), ethyl acetoacetate (1 equiv),\nCH 2 Cl 2  (50 mL/5 g of alkyl bromide), and Bu 4 NCl (1 or 2 equiv) were boiled under reflux for 3 days. After\ncooling, the separated organic layer was washed with 5 M aq HCl (30\nmL). The mixture was extracted twice with Et 2 O. The combined\nethereal extracts were dried, filtered, and concentrated in vacuo.\nChromatography (CHCl 3  or CHCl 3 /acetone 10:1)\nor distillation gave the corresponding ethyl α-alkylacetoacetate.\nResorcinol (1 equiv) was dissolved\nin the corresponding hot β-keto ester (1 equiv). The resulting\nsyrup was cooled to 0 °C and treated dropwise with a mixture\nof CF 3 COOH (2 equiv) and conc. H 2 SO 4  (2 equiv) while keeping the temperature <10 °C. After stirring\nfor 3 h at room temperature, the mixture was cautiously quenched with\nice-water. The brightly colored gluey mass formed was stirred for\nfurther 1 h. The bright yellow/brown precipitate resulted was collected\nby suction filtration, washed exhaustively with water, and re-dissolved\nin acetone. The yellow/brown solid obtained upon evaporation was purified\nby flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient)\nand/or recrystallized from hot absolute ethanol, acetone/hexane (4:1),\nor THF/hexane (2:0.5) to give the corresponding coumarin as a crystalline\nsolid.\nTo a solution of the compound (1 equiv) in anhydrous\nDMF (5 mL) at 0 °C under N 2  was added NaH (1 equiv).\nWhen the evolution of H 2  had ceased, previously prepared\nsulfamoyl chloride (∼3–5 equiv) was introduced. After\nstirring at room temperature under N 2  overnight, the mixture\nwas quenched with ice-water. The organic fractions were extracted\ninto ethyl acetate (∼150 mL) and washed with brine (4 ×\n100 mL). Drying, evaporation, chromatography (CHCl 3 /ethyl\nacetate, 8:1 to 2:1 gradient), and/or recrystallization with either\nethyl acetate/hexane (5:2) or THF/hexane (2:1) gave the corresponding\ncrystalline sulfamate.\nThis was prepared\nby method A using ethyl potassium malonate (12.6 g, 74.0 mmol), CH 3 CN (110 mL), Et 3 N (11.6 g, 115 mmol), MgCl 2  (8.39 g, 88.1 mmol), and pentanoyl chloride (4.34 g, 36.0\nmmol). The crude oily residue was purified by flash chromatography\n(CHCl 3 ) to give  9a  as a pale yellow oil (4.65\ng, 78%):  R f  = 0.92 (CHCl 3 /acetone,\n10:1);  1 H NMR (400 MHz, CDCl 3 ): δ = 0.91\n(t,  J  = 7.3 Hz, 3H, C7–H 3 ), 1.28\n(t,  J  = 7.0 Hz, 3H, CH 2 C H 3 ), 1.29–1.37 (m, 2H, CH 2 ), 1.54–1.62\n(m, 2H, CH 2 ), 2.55 (t,  J  = 7.3 Hz, 2H,\nC4–H 2 ), 3.44 (s, 2H, C2–H 2 ) and\n4.19 ppm (q,  J  = 7.3 Hz, 2H, C H 2 CH 3 ). MS (FAB + ):  m / z  (%) 173.1 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 171.1 (100) [M –\nH] − ; HRMS-FAB + :  m / z  [M + H] + ; Anal. calcd for C 9 H 17 O 3 : 173.1099, found: 173.1089.\nThis was\nprepared with resorcinol (2.0 g, 18 mmol),  9a  (3.13 g,\n18.2 mmol), and a mixture of CF 3 COOH (2.77 mL, 36.3 mmol)\nand conc. H 2 SO 4  (1.83 mL, 36.3 mmol). The crude\nyellow/brown solid was recrystallized from acetone/hexane to give  9b  as cream crystals (1.87 g, 47%):  R f  = 0.63 (CHCl 3 /acetone, 3:1); mp 135–138 °C\n(Lit. 45  mp 139–140 °C, ethanol);\nIR (KBr)  ṽ  = 3440, 1650 cm –1 ;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.92 (t,  J  = 7.3 Hz, 3H, CH 3 ), 1.34–1.43 (m, 2H, CH 2 ), 1.54–1.62 (m,\n2H, CH 2 ), 2.73 (t,  J  = 7.6 Hz, 2H, C1′–H 2 ), 6.08 (s, 1H, C3–H), 6.71 (d,  J  =\n2.4 Hz, 1H, C8–H), 6.80 (dd,  J  = 8.6 and 2.4\nHz, 1H, C6–H), 7.6 (d,  J  = 8.5 Hz, 1H, C5–H)\nand 10.53 ppm (s, 1H, OH); MS (FAB + ):  m / z  (%) 437.2 (15) [2M + H] + , 219.2 (100)\n[M + H] + ; MS (FAB – ):  m / z  (%) 435.3 (20) [2M – H] − , 217.2 (100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd\nfor C 13 H 15 O 3 : 219.1021, found: 219.1034;\nAnal. calcd for C 13 H 14 O 3 : C 71.54,\nH 6.47, found: C 71.40, H 6.49.\nUpon sulfamoylation,  9b  (700 mg, 3.21 mmol)\ngave a crude white solid, which was fractionated by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid\nisolated was recrystallized from ethyl acetate/hexane to give  9  as white crystals (98 mg, 10%):  R f  = 0.36 (CHCl 3 /ethyl acetate, 4:1); mp 147–150\n°C; IR (KBr)  ṽ  = 3400–3100, 1750,\n1450–1300, 1100–1150 cm –1 ;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.93\n(t,  J  = 7.3 Hz, 3H, CH 3 ), 1.36–1.45\n(m, 2H, CH 2 ), 1.57–1.64 (m, 2H, CH 2 ),\n2.82 (t,  J  = 7.6 Hz, 2H, C1′–H 2 ), 6.38 (s, 1H, C3–H), 7.29 (dd,  J  = 2.4 and 8.8 Hz, 1H, C6–H), 7.33 (d,  J  =\n2.4 Hz, 1H, C8–H), 7.94 (d,  J  = 8.8 Hz, 1H,\nC5–H) and 8.24 (s, 2H, NH 2 ); MS (FAB + ):  m / z  (%) 595.2 (70) [2M + H] + , 298.1 (100) [M + H] + , 219.1 (10) [M + H –\nHNSO 2 ] + ; MS (FAB – ):  m / z  (%) 593.2 (15) [2M – H] − , 296.2 (100) [M – H] − , 217.2\n(60) [M – H 2 NSO 2 ] − ;\nHRMS-FAB + :  m / z  [M + H] +  calcd for C 13 H 16 NO 5 S: 298.0749,\nfound: 298.0742; Anal. calcd for C 13 H 15 NO 5 S: C 52.52, H 5.09, N 4.71%, found: C 52.00, H 5.00, N 4.61.\nThis was prepared\nby method A using ethyl potassium malonate (13.0 g, 74.4 mmol), CH 3 CN (120 mL), Et 3 N (16.2 mL, 116 mmol), MgCl 2  (8.66 g, 90.1 mmol), and hexanoyl chloride (5.31 g, 38.2\nmmol). The crude oily residue was purified by flash chromatography\n(CHCl 3 ) to give  10a  as a pale yellow oil (6.58\ng, 93%):  R f  = 0.88 (CHCl 3 );  1 H NMR (400 MHz, CDCl 3 ): δ = 0.89 (t,  J  = 7.1 Hz, 3H, CH 3 ), 1.29 (t,  J  = 7.3 Hz, 3H, OCH 2 C H 3 ), 1.31–1.37\n(m, 4H, CH 2 CH 2 ), 1.56–1.63 (m, 2H, CH 2 ), 2.54 (t,  J  = 7.3 Hz, 2H, C4–H 2 ), 3.43 (s, 2H, C2–H 2 ) and 4.19 (q,  J  = 7.3 Hz, 2H, OC H 2 CH 3 ); MS (FAB + ):  m / z  (%)\n187.2 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 185.2 (100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] + ; Anal. calcd for C 10 H 19 O 3 : 187.1334, found: 187.1342.\nThis\nwas prepared with resorcinol (2.0 g, 18 mmol),  10a  (3.4\ng, 18 mmol), and a mixture of CF 3 COOH (2.8 mL, 36 mmol)\nand conc. H 2 SO 4  (1.8 mL, 36 mmol). The crude\nyellow/brown solid was recrystallized from acetone/hexane to give  10b  as pale yellow crystals (2.32 g, 56%):  R f  = 0.86 (CHCl 3 /acetone, 3:1); mp 148–150\n°C (Lit. 46  mp 145–146 °C);  1 H NMR (400 MHz, DMSO- d 6 ): δ\n= 0.87 (t,  J  = 7.1 Hz, 3H, C5′–H 3 ), 1.33–1.34 (m, 4H, CH 2 CH 2 ),\n1.58–1.61 (m, 2H, CH 2 ), 2.72 (t,  J  = 7.6 Hz, 2H, C1′–H 2 ), 6.08 (s, 1H, C3–H),\n6.71 (d,  J  = 2.4 Hz, 1H, C8–H), 6.80 (dd,  J  = 2.4 and 8.8 Hz, 1H, C6–H), 7.64 (d,  J  = 8.8 Hz, 1H, C5–H) and 10.53 (s, 1H, OH); MS (FAB + ):  m / z  (%) 465.3 (15) [2M + H] + , 233.2 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 463.4 (10) [2M –\nH] − , 231.2 (100) [M – H] − ; HRMS-FAB + :  m / z  [M\n+ H] +  calcd for C 14 H 17 O 3 : 233.1178, found: 233.1181; Anal. calcd for C 14 H 16 O 3 : C 72.39, H, 6.94%, found: C 72.33, H, 6.96.\nUpon sulfamoylation,  10b  (700 mg, 3.01 mmol)\ngave a crude white sold (893 mg), which was fractionated by flash\nchromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient).\nThe white solid isolated was recrystallized from ethyl acetate/hexane\nto give  10  as white crystals (251 mg, 27%):  R f  = 0.36 (CHCl 3 /ethyl acetate, 4:1); mp\n128–132 °C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.88 (t,  J  = 7.1 Hz, 3H,\nC5′–H 3 ), 1.31–1.39 (m, 4H, CH 2 CH 2 ), 1.59–1.64 (m, 2H, CH 2 ),\n2.81 (t,  J  = 7.6 Hz, 2H, C1′–H 2 ), 6.37 (s, 1H, C3–H), 7.28 (dd,  J  = 1.5 and 8.5 Hz, 1H, C6–H), 7.33 (d,  J  =\n1.5 Hz, 1H, C8–H), 7.93 (d,  J  = 8.5 Hz, 1H,\nC5–H) and 8.23 (s, 2H, NH 2 ); MS (FAB + ):  m / z  (%) 623.2 (70) [2M + H] + , 312.1 (100) [M + H] + , 233.1 (20) [M + H –\nHNSO 2 ] + ; MS (FAB – ):  m / z  (%) 621.2 (20) [2M – H] − , 310.2 (100) [M – H] − , 231.2\n(100) [M – H 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M\n+ H] +  calcd for C 14 H 18 NO 5 S: 312.0906, found: 312.0908; Anal. calcd for C 14 H 17 NO 5 S: C 54.01, H 5.50, N 4.50, found: C 54.70,\nH 5.56, N 4.50.\nThis was prepared\nby method A using ethyl potassium malonate (13 g, 74 mmol), CH 3 CN (120 mL), Et 3 N (16.2 g, 116 mmol), MgCl 2  (8.7 g, 91 mmol), and heptanoyl chloride (5.91 g, 36.2 mmol).\nThe crude oily residue was purified by flash chromatography (CHCl 3 ) to give  11a  as a pale yellow oil (4.51 g, 62%):  R f  = 0.64 (CHCl 3 );  1 H NMR\n(400 MHz, CDCl 3 ): δ = 0.88 (t,  J  = 7.3 Hz, 3H, C9–H 3 ), 1.26–1.32 (m, 9H,\nCH 2 C H 3  and 3 × CH 2 ), 1.59 (m, 2H, 5-CH 2 ), 2.35 (t,  J  = 7.3 Hz, 2H, C4–H 2 ), 3.43 (s, 2H, C2–H 2 ) and 4.19 (q,  J  = 7.1 Hz, 2H, C H 2 CH 3 ); MS (FAB + ):  m / z  (%) 201.2 (100) [M + H] + ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 11 H 21 O 3 : 201.1491, found:\n201.1492.\nThis was\nprepared with resorcinol (2.20 g, 19.9 mmol),  11a  (4.0\ng, 20 mmol), and a mixture of CF 3 COOH (3.1 mL, 40 mmol)\nand conc. H 2 SO 4  (2.04 mL, 39.9 mmol). The crude\norange solid obtained was recrystallized from acetone/hexane to  11b  as off-white crystals (2.95 g, 60%):  R f  = 0.72 (CHCl 3 /acetone, 3:1); mp 124–126\n°C;  1 H NMR (400 MHz, DMSO- d ): δ\n= 0.86 (t,  J  = 7.1 Hz, 3H, C6′–H 3 ), 1.27–1.37 (m, 6H, 3 × CH 2 ), 1.55–1.63\n(m, 2H, CH 2 ), 2.72 (t,  J  = 7.6 Hz, 2H,\nC1′–H 2 ), 6.08 (s, 1H, C3–H), 6.71\n(d,  J  = 2.4 Hz, 1H, C8–H), 6.80 (dd,  J  = 2.4 and 8.8 Hz, 1H, C6–H), 7.64 (d,  J  = 8.8 Hz, 1H, C5–H) and 10.53 (s, 1H, OH); MS (FAB + ):  m / z  (%) 493.4 (10) [2M + H] + , 247.2 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 491.3 (15) [2M –\nH] − , 245.2 (100) [M – H] − ; HRMS-FAB + :  m / z  [M\n+ H] +  calcd for C 15 H 19 O 3 : 247.1334, found: 247.1334; Anal. calcd for C 15 H 18 O 3 : C 73.15, H 7.37, found: C 73.30, H 7.40.\nUpon sulfamoylation,  11b  (700 mg, 2.84 mmol)\ngave a crude white solid, which was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid\nisolated was recrystallized from ethyl acetate/hexane to give  11  as fine white crystals (441 mg, 48%):  R f  = 0.24 (CHCl 3 /ethyl acetate, 4:1); mp 126–128\n°C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.87 (t,  J  = 6.7 Hz, 3H, C6′–H 3 ), 1.29–1.39 (m, 6H, 3 × CH 2 ), 1.58–1.66\n(m, 2H, CH 2 ), 2.81 (t,  J  = 7.9 Hz, 2H,\nC1′–H 2 ), 6.37 (s, 1H, C3–H), 7.29\n(dd,  J  = 2.4 and 8.6 Hz, 1H, C6–H), 7.33 (d,  J  = 2.4 Hz, 1H, C8–H), 7.93 (d,  J  = 8.6 Hz, 1H, C5–H) and 8.24 (s, 2H, NH 2 ); MS\n(FAB + ):  m / z  (%) 651.3\n(10) [2M + H] + , 326.2 (100) [M + H] + , 247.2\n(10), [M + H – HNSO 2 ] + ; MS (FAB – ):  m / z  (%) 649.3 (15) [2M –\nH] − , 324.2 (100) [M – H] − , 245.2 (60), [M – H 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M\n+ H] +  calcd for C 15 H 20 NO 5 S: 326.1062, found: 326.1079; Anal. calcd for C 15 H 19 NO 5 S: C 55.37, H 5.89, N 4.30, found: C 55.20,\nH 5.88, N 4.25.\nThis was prepared\nby method A using ethyl potassium malonate (10.5 g, 61.5 mmol), CH 3 CN (120 mL), Et 3 N (13.1 mL, 93.8 mmol), MgCl 2  (7.0 g, 73 mmol), and octanoyl chloride (5.0 mL, 29 mmol).\nThe crude oily residue was purified by flash chromatography (CHCl 3 ) to give  12a  as a pale yellow oil (3.86 g, 61%):  R f  = 0.76 (CHCl 3 );  1 H NMR\n(400 MHz, CDCl 3 ): δ = 0.88 (t,  J  = 7.3 Hz, 3H, C10–H 3 ), 1.26–1.29 (m, 11H,\nCH 2 C H 3  and 4 × CH 2 ), 1.57–1.61 (m, 2H, CH 2 ), 2.53 (t,  J  = 6.8 Hz, 2H, C4–H 2 ), 3.43 (s, 2H, C2–H 2 ) and 4.19 (q,  J  = 7.3 Hz, 2H, C H 2 CH 3 ); MS (FAB + ):  m / z  (%) 215.2 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 213.2\n(100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 12 H 23 O 3 : 215.1647, found: 215.1652.\nThis\nwas prepared with resorcinol (1.8 g, 16 mmol),  12a  (3.5\ng, 16 mmol), and a mixture of CF 3 COOH (2.52 mL, 32.7 mmol)\nand conc. H 2 SO 4  (1.67 mL, 32.7 mmol). The crude\nyellow solid was recrystallized from acetone/hexane to give  12b  as yellow crystals (2.32 g, 55%):  R f  = 0.78 (CHCl 3 /acetone, 3:1); mp 106–107\n°C;  1 H NMR (400 MHz, DMSO- d ): δ\n= 0.86 (t,  J  = 7.1 Hz, 3H, C7′–H 3 ), 1.24–1.36 (m, 8H, 4 × CH 2 ), 1.55–1.63\n(m, 2H, CH 2 ), 2.72 (t,  J  = 7.6 Hz, 2H,\nC1′–H 2 ), 6.08 (s, 1H, C3–H), 6.71\n(d,  J  = 2.4 Hz, 1H, C8–H), 6.80 (dd,  J  = 2.4 and 8.8 Hz, 1H, C6–H), 7.64 (d,  J  = 8.8 Hz, 1H, C5–H) and 10.53 (s, 1H, OH); MS (FAB + ):  m / z  (%) 261.2 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 519.3 (60) [2M – H] − , 259.2\n(100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 16 H 21 O 3 : 261.1491, found: 261.1501; Anal.\ncalcd for C 16 H 20 O 3 : C 73.82, H 7.74,\nfound: C 73.60, H 7.82.\nUpon sulfamoylation,  12b  (700\nmg, 2.69 mmol)\ngave a crude white solid, which was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid\nisolated was recrystallized from ethyl acetate/hexane to give  12  as fine white crystals (503 mg, 55%):  R f  = 0.42 (CHCl 3 /ethyl acetate, 4:1); mp 137–139\n°C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.86 (t,  J  = 7.1 Hz, 3H, C7′–H 3 ), 1.27–1.39 (m, 8H, 4 × CH 2 ), 1.58–1.64\n(m, 2H, CH 2 ), 2.81 (t,  J  = 7.3 Hz, 2H,\nC1′–H 2 ), 6.37 (s, 1H, C3–H), 7.27–7.33\n(m, 2H, C6–H and C8–H), 7.39 (d,  J  =\n8.8 Hz, 1H, C5–H) and 8.22 (s, 2H, NH 2 ); MS (FAB + ):  m / z  (%) 679.3 (60) [2M\n+ H] + , 340.1 (100) [M + H] + , 261.1 (10) [M +\nH – HNSO 2 ] + ; MS (FAB – ):  m / z  (%) 677.1 (20) [2M –\nH] − , 338.1 (100) [M – H] − , 259.1 (60) [M – H 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M\n+ H] +  calcd for C 16 H 22 NO 5 S: 340.1218, found: 340.1215; Anal. calcd for C 16 H 21 NO 5 S: C 56.62, H 6.24, N 4.13, found: C 56.90,\nH 6.31, N 4.15.\nThis was\nprepared by method A using ethyl potassium malonate (13.0 g, 76.4\nmmol), CH 3 CN (120 mL), Et 3 N (16.2 mL, 116 mmol),\nMgCl 2  (8.7 g, 91 mmol), and nonanoyl chloride (6.69 mL,\n37.8 mmol). The crude oily residue was purified by flash chromatography\n(CHCl 3 ) to give  13a  as a pale yellow oil (6.73\ng, 78%):  R f  = 0.65 (CHCl 3 );  1 H NMR (400 MHz, CDCl 3 ) δ = 0.88 (t,  J  = 7.3 Hz, 3H, C11–H 3 ), 1.26–1.61\n(m, 15H, CH 2 C H 3  and 6 ×\nCH 2 ), 2.53 (t,  J  = 7.6 Hz, 2H, C4–H 2 ), 3.43 (s, 2H, C2–H 2 ) and 4.19 (q,  J  = 7.3 Hz, 2H, C H 2 CH 3 ); MS (FAB + ):  m / z  (%)\n229.2 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 227.2 (100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 13 H 25 O 3 : 229.1725, found: 229.1794.\nThis was\nprepared with resorcinol (1.93 g, 17.5 mmol),  13a  (4.0\ng, 18 mmol) and a mixture of CF 3 COOH (2.7 mL, 35 mmol)\nand conc. H 2 SO 4  (1.8 mL, 35 mmol). The crude\nyellow solid was recrystallized from acetone/hexane to give  13b  as yellow crystals (2.31 g, 48%):  R f  = 0.71 (CHCl 3 /acetone, 3:1); mp 90–92\n°C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.85 (t,  J  = 7.1 Hz, 3H, C8′–H 3 ), 1.25–1.36 (m, 10H, 5 × CH 2 ), 1.55–1.62\n(m, 2H, CH 2 ), 2.51 (t,  J  = 7.3 Hz, 2H,\nC1′–H 2 ), 6.08 (s, 1H, C3–H), 6.71\n(d,  J  = 2.4 Hz, 1H, C8–H), 6.80 (dd,  J  = 2.4 and 8.8 Hz, 1H, C6–H), 7.64 (d,  J  = 8.8 Hz, 1H, C5–H) and 10.53 (s, 1H, OH); MS (FAB + ):  m / z  (%) 549.5 (80) [2M + H] + , 275.2 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 547.4 (75) [2M –\nH] − , 273.2 (100) [M – H] − ; HRMS-FAB + :  m / z  [M\n+ H] +  calcd for C 17 H 23 O 3 : 275.1647, found: 275.1647; Anal. calcd for C 17 H 22 O 3 : C 74.42, H 8.08, found: C 74.70, H 8.18.\nUpon sulfamoylation,  13b  (400 mg, 1.46 mmol)\ngave a crude white solid which was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid\nisolated was recrystallized from ethyl acetate/hexane to give  13  as white fine crystals (279 mg, 53%):  R f  = 0.37 (CHCl 3 /ethyl acetate, 4:1); mp 124–125\n°C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.85 (t,  J  = 6.7 Hz, 3H, C8′–H 3 ), 1.25–1.39 (m, 10H, 5 × CH 2 ), 1.58–1.63\n(m, 2H, CH 2 ), 2.81 (t,  J  = 7.3 Hz, 2H,\nC1′–H 2 ), 6.37 (s, 1H, C3–H), 7.28\n(dd,  J  = 2.4 and 8.5 Hz, 1H, C6–H), 7.32 (d,  J  = 2.4 Hz, 1H, C8–H), 7.93 (d,  J  = 8.5 Hz, 1H, C5–H) and 8.24 (s, 2H, NH 2 ); MS\n(FAB + ):  m / z  (%) 707.0\n(80) [2M + H] + , 354.0 (100) [M + H] + , 275.0\n(20) [M + H – HNSO 2 ] + ; MS (FAB – ):  m / z  (%) 705.2 (20) [2M –\nH] − , 352.1 (100) [M – H] − , 273.1 (70) [M – H 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M\n+ H] +  calcd for C 17 H 24 NO 5 S: 354.1375, found: 354.1375; Anal. calcd for C 17 H 23 NO 5 S: C 57.77, H 6.56, N 3.96, found: C 58.00,\nH 6.50, N 3.75.\nThis was\nprepared by method A using ethyl potassium malonate (13.0 g, 76.4\nmmol), CH 3 CN (120 mL), Et 3 N (16.2 mL, 116 mmol),\nMgCl 2  (8.7 g, 91 mmol), and decanoyl chloride (7.5 mL,\n36 mol). The crude oily residue was purified by flash chromatography\n(CHCl 3 ) to give  14a  as a pale yellow oil (7.79\ng, 89%):  R f  = 0.75 (CHCl 3 );  1 H NMR (400 MHz, CDCl 3 ) δ = 0.82 (t,  J  = 5.5 Hz, 3H, C12–H 3 ), 1.19–1.55\n(m, 17H, CH 2 C H 3  and 7 ×\nCH 2 ), 2.48 (t,  J  = 7.3 Hz, 2H, C4–H 2 ), 3.37 (s, 2H, C2–H 2 ) and 4.13 (q,  J  = 7.3 Hz, 2H, C H 2 CH 3 ); MS (FAB + ):  m / z  (%)\n243.1 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 241.1 (100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 14 H 27 O 3 : 243.1960, found: 243.1959.\nThis was\nprepared with resorcinol (1.14 g, 10.3 mmol),  14a  (2.5\ng, 10 mmol), and a mixture of CF 3 COOH (1.6 mL, 21 mmol)\nand conc. H 2 SO 4  (1.05 mL; 20.6 mmol). The crude\nyellow solid was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow solid isolated\nwas recrystallized from acetone/hexane to give  14b  as\noff-white fine crystals (532 mg, 18%):  R f  = 0.71 (CHCl 3 /acetone, 3:1); mp 91–93 °C;  1 H NMR (400 MHz, CDCl 3 ) δ = 0.88 (t,  J  = 7.1 Hz, 3H, C9′–H 3 ), 1.27–1.44\n(m, 12H, 6 × CH 2 ), 1.64–1.72 (m, 2H, CH 2 ), 2.73 (t,  J  = 7.3 Hz, 2H, C1′–H 2 ), 6.14 (s, 1H, C3–H), 6.88 (dd,  J  = 2.4 and 8.8 Hz, 1H, C6–H), 7.08 (d,  J  =\n2.4 Hz, 1H, C8–H), 7.52 (d,  J  = 8.8 Hz, 1H,\nC5–H) and 10.54 (s, 1H, OH); MS (FAB + ):  m / z  (%) 577.2 (80) [2M + H] + , 289.1 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 575.2 (20) [2M – H] − , 287.1 (100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 18 H 25 O 3 : 289.1804, found:\n289.1807; Anal. calcd for C 18 H 24 O 3 : C 74.97, H 8.39, found: C 75.10, H 8.39.\nUpon sulfamoylation,  14b  (400 mg, 1.39 mmol)\ngave a crude white solid, which was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid\nisolated was recrystallized from ethyl acetate/hexane to give  14  as white fine crystals (36 mg, 7%):  R f  = 0.40 (CHCl 3 /ethyl acetate, 4:1); mp 101–103\n°C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.85 (t,  J  = 7.1 Hz, 3H, C9′–H 3 ), 1.18–1.43 (m, 12H, 6 × CH 2 ), 1.57–1.65\n(m, 2H, CH 2 ), 2.81 (t,  J  = 7.3 Hz, 2H,\nC1′–H 2 ), 6.37 (s, 1H, C3–H), 7.28\n(dd,  J  = 2.4 and 8.5 Hz, 1H, C6–H), 7.33 (d,  J  = 2.4 Hz, 1H, C8–H), 7.93 (d,  J  = 8.5 Hz, 1H, C5–H) and 8.24 (s, 2H, NH 2 ); MS\n(FAB + ):  m / z  (%) 735.3\n(90) [2M + H] + , 368.1 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 733.1\n(80) [2M – H] − , 366.0 (100) [M – H] − , 287.1 (90) [M – H 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 18 H 26 NO 5 S: 368.153, found: 2368.1539; Anal. calcd for C 18 H 25 NO 5 S: C 58.84, H 6.86, N 3.81, found:\nC 59.05, H 6.91, N 3.74.\nThis was\nprepared by method B using CH 2 Cl 2  (80 mL), ethyl\ndiazoacetate (3.52 g, 30.8 mmol), SnCl 2  (556 mg, 2.9 mmol),\nand undecanal (5.0 g, 29 mmol) in CH 2 Cl 2 . The\ncrude oily residue was purified by fractional distillation under reduced\npressure to give  15a  as a pale yellow oil (4.34 g, 58%):  R f  = 0.72 (CHCl 3 ); bp 0.15 : 135–139 °C (Lit. 47  bp 0.15 : 130–135 °C);  1 H NMR (400 MHz,\nCDCl 3 ) δ = 0.88 (t,  J  = 6.9 Hz,\n3H, C13–H 3 ), 1.26–1.61 (m, 19H, CH 2 C H 3  and 8 × CH 2 ), 2.53\n(t,  J  = 7.2 Hz, 2H, C4–H 2 ), 3.43\n(s, 2H, C2–H 2 ) and 4.19 (q,  J  =\n7.2 Hz, 2H, C H 2 CH 3 ); MS (FAB + ):  m / z  (%) 257.2 (100) [M\n+ H] + ; MS (FAB – ):  m / z  (%) 255.2 (100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 15 H 29 O 3 : 257.2117, found:\n257.2129.\nThis was\nprepared with resorcinol (1.07 g, 9.76 mmol),  15a  (2.5\ng, 9.8 mmol), and a mixture of CF 3 COOH (1.5 mL, 20 mmol)\nand conc. H 2 SO 4  (1.0 mL, 20 mmol). The crude\nyellow solid was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow solid isolated\nwas recrystallized from acetone/hexane to give  15b  as\noff-white fine crystals (1.66 g, 54%):  R f  = 0.73 (CHCl 3 /acetone, 3:1); mp 98–99 °C;  1 H NMR (400 MHz, CDCl 3 ) δ = 0.88 (t,  J  = 7.0 Hz, 3H, C10′–H 3 ), 1.27–1.42\n(m, 14H, 7 × CH 2 ), 1.64–1.72 (m, 2H, CH 2 ), 2.73 (t,  J  = 7.6 Hz, 2H, C1′–H 2 ), 6.14 (s, 1H, C3–H), 6.89 (dd,  J  = 2.4 and 8.8 Hz, 1H, C6–H), 7.11 (d,  J  =\n2.4 Hz, 1H, C8–H), 7.52 (d,  J  = 8.8 Hz, 1H,\nC5–H) and 8.19 (s, 1H, OH); MS (FAB + ):  m / z  (%) 303.1 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 301.1\n(100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 19 H 27 O 3 : 303.1960, found: 303.1973; Anal.\ncalcd for C 19 H 26 O 3 : C 75.46, H 8.67,\nfound: C 75.10, H 8.72.\nUpon sulfamoylation, compound  15b  (400 mg,\n1.32 mmol) gave a crude white solid, which was fractionated by flash\nchromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient).\nThe white solid isolated was recrystallized from ethyl acetate/hexane\nto give  15  as white fine needles (288 mg, 57%):  R f  = 0.55 (CHCl 3 /ethyl acetate, 4:1);\nmp 112–115 °C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.85 (t,  J  =\n7.1 Hz, 3H, C10′–H 3 ), 1.16–1.38 (m,\n14H, 7 × CH 2 ), 1.58–1.63 (m, 2H, CH 2 ), 2.81 (t,  J  = 7.6 Hz, 2H, C1′–H 2 ), 6.37 (s, 1H, C3–H), 7.28 (dd,  J  = 2.1 and 8.8 Hz, 1H, C6–H), 7.33 (d,  J  =\n2.1 Hz, 1H, C8–H), 7.93 (d,  J  = 8.8 Hz, 1H,\nC5–H) and 8.24 (s, 2H, NH 2 ); MS (FAB + ):  m / z  (%) 763.2 (65) [2M + H] + , 382.0 (100) [M + H] + , 303.1 (20) [M + H –\nHNSO 2 ] + ; MS (FAB – ):  m / z  (%) 761.0 (80) [2M – H] − , 380.0 (100) [M – H] − , 301.1\n(90) [M – H 2 NSO 2 ] − ;\nHRMS-FAB + :  m / z  [M + H] +  calcd for C 19 H 28 NO 5 S: 382.1688,\nfound: 382.1696; Anal. calcd for C 19 H 27 NO 5 S: C 59.82, H 7.13, N 3.67, found: C 60.15, H 7.12. N 3.54.\nThis\nwas prepared by method B using CH 2 Cl 2  (80 mL),\nethyl diazoacetate (3.25 g, 28.5 mmol), SnCl 2  (514 mg,\n2.7 mmol), and dodecyl aldehyde (5.0 g, 27 mmol) in CH 2 Cl 2  (20 mL). The crude oily residue was purified by fractional\ndistillation under reduced pressure to give  16a  as a\ncolorless oil (5.3 g, 72%):  R f  = 0.74\n(CHCl 3 ); bp 0.15 : 122–123 °C (Lit. 48  bp 0.1 : 123–125 °C);  1 H NMR (400 MHz, CDCl 3 ) δ = 0.88 (t,  J  = 7.0 Hz, 3H, C14–H 3 ), 1.25–1.61\n(m, 21H, CH 2 C H 3  and 9 ×\nCH 2 ), 2.53 (t,  J  = 7.3 Hz, 2H, C4–H 2 ), 3.43 (s, 2H, C2–H 2 ) and 4.19 (q,  J  = 7.3 Hz, 2H, C H 2 CH 3 ); MS (FAB + ):  m / z  (%)\n271.1 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 269.2 (100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 16 H 31 O 3 : 271.2273, found: 271.2285.\nThis\nwas prepared with resorcinol (1.22 g, 11.1 mmol),  16a  (3.0 g, 11 mmol), and a mixture of CF 3 COOH (2.0 mL, 22\nmmol) and conc. H 2 SO 4  (2.0 mL, 22 mmol). The\ncrude yellow solid was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow solid\nisolated was recrystallized from acetone/hexane to give  16b  as white crystals (1.92 g, 55%):  R f  =\n0.86 (CHCl 3 /acetone, 3:1); mp 102–105 °C;  1 H NMR (400 MHz, DMSO- d 6 ): δ\n= 0.85 (t,  J  = 6.2 Hz, 3H, C11′–H 3 ), 1.23–1.36 (m, 16H, 8 × CH 2 ), 1.54–1.60\n(m, 2H, CH 2 ), 2.72 (t,  J  = 7.6 Hz, 2H,\nC1′–H 2 ), 6.07 (s, 1H, C3–H), 6.71\n(d,  J  = 2.1 Hz, 1H, C8–H), 6.79 (dd,  J  = 2.1 and 8.5 Hz, 1H, C6–H), 7.63 (d,  J  = 8.5 Hz, 1H, C5–H) and 10.52 (s, 1H, OH); MS (FAB + ):  m / z  (%) 317.2 (100) [M + H] + ; MS (FAB + ):  m / z  (%) 631.4 (10) [2M – H] − , 315.3 (100) [M\n– H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 20 H 29 O 3 : 317.2117, found: 317.2121; Anal. calcd for\nC 20 H 28 O 3 : C 75.91, H 8.92, found:\nC 75.50, H 8.97.\nUpon sulfamoylation, compound  16b  (400 mg,\n1.27 mmol) gave a crude white solid, which was fractionated by flash\nchromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient).\nThe white solid isolated was recrystallized from ethyl acetate/hexane\nto give  16  as white fine fluffy crystals (88 mg, 18%):  R f  = 0.54 (CHCl 3 /ethyl acetate, 4:1);\nmp 114–116 °C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.85 (t,  J  =\n7.0 Hz, 3H, C11′–H 3 ), 1.24–1.38 (m,\n16H, 8 × CH 2 ), 1.58–1.65 (m, 2H, CH 2 ), 2.81 (t,  J  = 7.4 Hz, 2H, C1′–H 2 ), 6.37 (s, 1H, C3–H), 7.28 (dd, 1H,  J  = 2.3 and 8.9 Hz, C6–H), 7.33 (d,  J  = 2.3\nHz, 1H, C8–H), 7.93 (d,  J  = 8.6 Hz, 1H, C5–H)\nand 8.24 (s, 2H, NH 2 ); MS (FAB + ):  m / z  (%) 396.1 (100) [M + H] + , 317.2 (20)\n[M + H – HNSO 2 ] − ; MS (FAB + ):  m / z  (%) 394.3 (100) [M\n– H] − , 315.3 (70) [M – H 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 20 H 30 NO 5 S: 396.1845, found: 396.1843;\nAnal. calcd for C 20 H 29 NO 5 S: C 60.74,\nH 7.39, N 3.54, found: C 61.00, H 7.44, N 3.52.\nThis\nwas prepared by method B using CH 2 Cl 2  (80 mL),\nethyl diazoacetate (3.02 g, 26.5 mmol), SnCl 2  (478 mg,\n2.5 mmol), and tridecanal (5.0 g, 25 mmol) in CH 2 Cl 2  (20 mL). The crude oily residue was purified by flash chromatography\n(CHCl 3 ) to give  17a  as a colorless oil, which\nsolidified to a white soft solid on standing (6.98 g, 97%):  R f  = 0.65 (CHCl 3 ); mp 28 °C (Lit. 47  mp < 20 °C);  1 H NMR (400\nMHz, CDCl 3 ) δ = 0.88 (t,  J  = 6.4\nHz, 3H, C15–H 3 ), 1.25–1.64 (m, 23H, CH 2 C H 3  and 10 × CH 2 ), 2.53 (t,  J  = 7.3 Hz, 2H, C4–H 2 ), 3.43 (s, 2H, C2–H 2 ) and 4.19 (q,  J  = 7.3 Hz, 2H, C H 2 CH 3 ); MS\n(FAB + ):  m / z  (%) 285.2\n(100) [M + H] + , MS (FAB – ):  m / z  (%) 283.2 (100) [M – H] − ; HRMS-FAB + :  m / z  [M\n+ H] +  calcd for C 17 H 33 O 3 : 285.2429, found: 285.2426.\nThis\nwas prepared with resorcinol (1.16 g, 10.5 mmol),  17a  (3.0 g, 11 mmol), and a mixture of CF 3 COOH (2.0 mL, 21\nmmol) and conc. H 2 SO 4  (1.5 mL, 21 mmol). The\ncrude brown solid was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the yellow solid isolated was\nrecrystallized from acetone/hexane to give  17b  as fine\nyellow crystals (747 mg, 22%):  R f  = 0.77\n(CHCl 3 /acetone, 3:1); mp 101–103 °C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.85\n(t,  J  = 7.0 Hz, 3H, C12′–H 3 ), 1.17–1.36 (m, 18H, 9 × CH 2 ), 1.55–1.60\n(m, 2H, CH 2 ), 2.72 (t,  J  = 7.4 Hz, 2H,\nC1′–H 2 ), 6.08 (s, 1H, C3–H), 6.71\n(d,  J  = 2.3 Hz, 1H, C8–H), 6.79 (dd,  J  = 2.3 and 8.6 Hz, 1H, C6–H), 7.64 (d,  J  = 8.9 Hz, 1H, C5–H) and 10.54 (s, 1H, OH); MS (FAB + ):  m / z  (%) 331.2 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 329.3 (100) [M – H] + ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 21 H 31 O 3 : 330.2273, found:\n331.2279; Anal. calcd for C 21 H 30 O 3 : C 76.33, H 9.15, found C 76.80, H 8.80.\nUpon sulfamoylation,\ncompound  17b  (400 mg;\n1.21 mmol) gave a crude white solid, which was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid\nisolated was recrystallized from ethyl acetate/hexane to give  17  as white fine crystals (91 mg, 18%):  R f  = 0.55 (CHCl 3 /ethyl acetate, 4:1); mp 104–106\n°C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.85 (t,  J  = 7.0 Hz, 3H, C12′–H 3 ), 1.24–1.34 (m, 18H, 9 × CH 2 ), 1.58–1.63\n(m, 2H, CH 2 ), 2.81 (t,  J  = 7.6 Hz, 2H,\nC1′–H 2 ), 6.37 (s, 1H, C3–H), 7.28\n(dd,  J  = 2.3 and 8.9 Hz, 1H, C6–H), 7.33 (d,  J  = 2.3 Hz, 1H, C8–H), 7.93 (d,  J  = 8.6 Hz, 1H, C5–H) and 8.23 (s, 2H, NH 2 ); MS\n(FAB + ):  m / z  (%) 410.2\n(100) [M + H] + , 331.2 (20) [M + H – HNSO 2 ] + ; MS (FAB – ):  m / z  (%) 817.3 (20) [2M – H] − , 408.3\n(100) [M – H] − , 329.3 (70) [M – H 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 21 H 32 NO 5 S: 410.2001, found: 410.2006;\nAnal. calcd for C 21 H 31 NO 5 S: C 61.59,\nH 7.63, N 3.42, found: C 61.90, H 7.65, N, 3.34.\nThis was\nprepared by method B using CH 2 Cl 2  (80 mL), ethyl\ndiazoacetate (2.82 g, 24.7 mmol), SnCl 2  (446 mg, 2.35 mmol),\nand tetradecanal (5.0 g, 24 mmol) in CH 2 Cl 2  (20\nmL). The crude oily residue was purified by flash chromatography (CHCl 3 ) to give  18a  as a colorless oil, which solidified\nto an off-white soft solid on standing (5.45 g, 78%):  R f  = 0.71 (CHCl 3 ); mp 45–47 °C\n(Lit. 49  mp 41–42 °C); MS (FAB + )  m / z : 299.2 [100, (M +\nH) + ];  1 H NMR (400 MHz, CDCl 3 ) δ\n= 0.88 (t,  J  = 6.67 Hz, 3H, C16–H 3 ), 1.20–1.69 (m, 25H, CH 2 C H 3  and 11 × CH 2 ), 2.53 (t,  J  = 7.3 Hz, 2H, C4–H 2 ), 3.43 (s, 2H, C2–H 2 ) and 4.19 (q,  J  = 7.3 Hz, 2H, C H 2 CH 3 ); MS (FAB + ):  m / z  (%) 299.2 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 297.2\n(100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 18 H 35 O 3 : 299.2586, found: 299.2599.\nThis\nwas prepared with resorcinol (1.11 g, 10.1 mmol),  18a  (3.0 g, 10 mmol), and a mixture of CF 3 COOH (2.0 mL, 20\nmmol) and conc. H 2 SO 4  (1.5 mL, 20 mmol). The\ncrude brown solid was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the beige solid isolated was\nrecrystallized from acetone/hexane to give  18b  as fine\ncream-colored crystals (757 mg, 22%):  R f  = 0.72 (CHCl 3 /acetone, 3:1); mp 95–97 °C;  1 H NMR (400 MHz, DMSO- d 6 ): δ\n= 0.85 (t,  J  = 7.0 Hz, 3H, C13′–H 3 ), 1.19–1.36 (m, 20H, 10 × CH 2 ), 1.54–1.62\n(m, 2H, CH 2 ), 2.72 (t,  J  = 7.4 Hz, 2H,\nC1′–H 2 ), 6.08 (s, 1H, C3–H), 6.71\n(d,  J  = 2.3 Hz, 1H, C8–H), 6.79 (dd,  J  = 2.3 and 8.9 Hz, 1H, C6–H), 7.64 (d,  J  = 8.6 Hz, 1H, C5–H) and 10.54 (s, 1H, OH); MS (FAB + ):  m / z  (%) 345.2 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 343.3 (100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 22 H 33 O 3 : 345.2429, found:\n345.2438; Anal. calcd for C 22 H 32 O 3 : C 76.70, H 9.36, found: C 76.85, H 9.31.\nUpon sulfamoylation,\ncompound  18b  (350 mg,\n1.01 mmol) gave a crude white solid, which was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid\nisolated was recrystallized from ethyl acetate/hexane to give  18  as white crystals (101 mg, 23%):  R f  = 0.53 (CHCl 3 /ethyl acetate, 4:1); mp 120–121\n°C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.86 (t,  J  = 7.0 Hz, 3H, C13′–H 3 ), 1.20–1.39 (m, 20H, 10 × CH 2 ), 1.58–1.66\n(m, 2H, CH 2 ), 2.81 (t,  J  = 7.8 Hz, 2H,\nC1′–H 2 ), 6.38 (s, 1H, C3–H), 7.29\n(dd,  J  = 2.3 and 8.6 Hz, 1H, C6–H), 7.33 (d,  J  = 2.3 Hz, 1H, C8–H), 7.93 (d,  J  = 8.9 Hz, 1H, C5–H) and 8.24 (s, 2H, NH 2 ); MS\n(FAB + ):  m / z  (%) 424.3\n(100) [M + H] + , 345.3 (25) [M + H – HNSO 2 ] + ; MS (FAB – ):  m / z  (%) 422.3 (60) [M – H] − , 343.3\n(100) [M – H 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M\n+ H] +  calcd for C 22 H 34 NO 5 S: 424.2158, found: 424.2168; Anal. calcd for C 22 H 33 NO 5 S: C 62.38, H 7.85, N 3.31, found: C 62.60,\nH 7.90, N 3.46.\nThis was prepared with resorcinol (1.21 g, 11.1 mmol),\nethyl 4-methyl-3-oxopentanoate\n(1.6 g, 10 mmol), and a mixture of CF 3 COOH (1.7 mL, 22\nmmol) and conc. H 2 SO 4  (2.2 mL, 22 mmol). The\ncrude yellow solid was purified by recrystallization from acetone/hexane\nto give  19a  as pale white fine crystals (420 mg, 21%):  R f  = 0.42 (CHCl 3 /acetone 3:1); mp\n120–122 °C (Lit. 50  mp 62–64\n°C—NB we are unable to explain this discrepancy)  1 H NMR (400 MHz, DMSO- d 6 ): δ\n= 1.24 (d,  J  = 6.7 Hz, 6H, CH(C H 3 ) 2 ), 3.28–3.35 (m, 1H, C H (CH 3 ) 2 ), 6.08 (s, 1H, C3–H), 6.72 (d,  J  = 2.1 Hz, 1H, C8–H), 6.81 (dd,  J  = 2.1 and 8.8 Hz, 1H, C6–H), 7.71 (d,  J  =\n8.8 Hz, 1H, C5–H) and 10.54 (s, 1H, OH); MS (FAB + ):  m / z  (%) 409.2 (20) [2M + H] + , 205.2 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 407.2 (20) [2M –\nH] − , 203.1 (100) [M – H] − ; HRMS-FAB + :  m / z  [M\n+ H] +  calcd for C 12 H 13 O 3 : 205.0865, found: 205.0874; Anal. calcd for C 12 H 12 O 3 : C 70.57, H 5.92, found: C 70.60, H 6.00.\nUpon sulfamoylation, compound  19a  (400 mg,\n1.96 mmol) gave a crude white solid, which was purified\nby flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1\ngradient). The white solid isolated was recrystallized from ethyl\nacetate/hexane to give  19  as white fine crystals (150\nmg, 30%):  R f  = 0.22 (CHCl 3 /ethyl\nacetate, 4:1); mp 164–167 °C;  1 H NMR (400 MHz,\nDMSO- d 6 ): δ = 1.26 (d,  J  = 6.7 Hz, 6H, CH(C H 3 ) 2 ),\n3.31–3.34 (m, 1H, C H (CH 3 ) 2 ), 6.35 (s, 1H, C3–H), 7.29 (dd,  J  = 2.4\nand 8.8 Hz, 1H, C6–H), 7.33 (d,  J  = 2.4 Hz,\n1H, C8–H), 7.99 (d,  J  = 8.8 Hz, 1H, C5–H)\nand 8.23 (s, 2H, NH 2 ); MS (FAB + ):  m / z  (%) 567.1 (70) [2M + H] + , 284.1 (100)\n[M + H] + ; MS (FAB – ):  m / z  (%) 565.2 (30) [2M – H] − , 282.1 (100) [M – H] − , 203.1 (60) [M –\nH 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M + H] +  calcd\nfor C 12 H 14 NO 5 S: 284.0593, found:\n284.0599; Anal. calcd for C 12 H 13 NO 5 S: C 50.88, H 4.63, N 4.94, found: C 50.80, H 4.62, N 4.97.\nThis was prepared with resorcinol (7.0\ng, 63\nmmol), methyl 4,4-dimethyl-3-oxopentanoate (10.0 g, 63.2 mmol), and\na mixture of CF 3 COOH (10 mL, 0.2 mol) and conc. H 2 SO 4  (6.5 mL, 0.2 mol). The crude brown residue was purified\nby flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient),\nand the pale yellow solid isolated was recrystallized from THF/hexane\nto give  20a  as pale yellow crystals (380 mg, 0.03%):  R f  = 0.61 (CHCl 3 /acetone, 3:1); mp\n159–161 °C;  1 H NMR (400 MHz, CDCl 3 ) δ = 1.49 (s, 9H, C(CH 3 ) 3 ), 6.28 (s,\n1H, C3–H), 6.85 (dd,  J  = 2.7 and 8.9 Hz, 1H,\nC6–H), 7.11 (d,  J  = 2.7 Hz, 1H, C8–H),\n7.13 (s, 1H, OH) and 7.91 (d,  J 6,5  = 8.9\nHz, 1H, C5–H); MS (FAB + ):  m / z  (%) 219.1 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 217.1 (100) [M –\nH] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 13 H 15 O 3 : 219.1021, found: 219.1029; Anal. calcd for C 13 H 14 O 3 : C 71.54, H 6.47%, found: C 71.90, H\n6.49; HPLC: MeOH/H 2 O (90:10), flow rate = 2 mL min –1 , λ max  = 321 nm,  t R  = 1.91 min.\nUpon sulfamoylation,\ncompound  20a  (310 mg, 1.43 mmol) gave a crude white solid,\nwhich was\npurified by flash chromatography (CHCl 3 /ethyl acetate,\n8:1 to 2:1 gradient). The white solid isolated was recrystallized\nfrom ethyl THF/hexane to give  20  as white fine crystals\n(43 mg, 10%):  R f  = 0.48 (CHCl 3 /ethyl acetate, 4:1); mp 187–189 °C;  1 H NMR\n(400 MHz, DMSO- d 6 ): δ = 1.45 (s,\n9H, C(CH 3 ) 3 ), 6.33 (s, 1H, C3–H), 7.27\n(dd,  J  = 2.3 and 8.9 Hz, 1H, C6–H), 7.34 (d,  J  = 2.3 Hz, 1H, C8–H), 8.26 (s, 2H, NH 2 ) and 8.28 (d,  J  = 8.9 Hz, 1H, C5–H); MS\n(FAB + ):  m / z  (%) 298.0\n(100) [M + H] + , 219.1 (15) [M + H – HNSO 2 ] + ; MS (FAB – ):  m / z  (%) 296.0 (100) [M – H] − , 217.0\n(40) [M – H 2 NSO 2 ] − ;\nHRMS-FAB + :  m / z  [M + H] +  calcd for C 13 H 16 NO 5 S: 298.0749,\nfound: 298.0746; Anal. calcd for C 13 H 15 O 5 NS: C 52.51, H 5.08, N 4.71, found: C 52.40, H 4.91, N 4.76;\nHPLC: MeOH/H 2 O (70:30), flow rate = 2 mL min –1 , λ max  = 273.4 and 310.1 nm,  t R  = 1.6 min.\nThis was prepared with resorcinol (2.93 g, 29.6 mmol),\nmethyl 4-chloro-3-oxo-butanoate\n(4.0 g, 29 mmol), and a mixture of CF 3 COOH (4.1 mL, 53\nmmol) and conc. H 2 SO 4  (2.7 mL, 53 mmol). The\ncrude orange solid was purified by recrystallization from acetone/hexane\nto give  21a  as off-white fine crystals (1.31 g, 23%):  R f  = 0.73 (CHCl 3 /acetone, 3:1); mp\n183–185 °C (Lit. 51  mp 181 °C);  1 H NMR (400 MHz, DMSO- d 6 ): δ\n= 4.96 (s, 2H, CH 2 ), 6.42 (s, 1H, C3–H), 6.76 (d,  J  = 2.4 Hz, 1H, C8–H), 6.85 (dd,  J  = 2.4 and 8.7 Hz, 1H, C6–H), 7.69 (d,  J  =\n8.8 Hz, 1H, C5–H) and 10.69 (s, 1H, OH); MS (FAB + ):  m / z  (%) 421.2 (15) [2M + H] + , 211.1 (100) [M(Cl 35 ) + H] + ; MS (FAB – ):  m / z  (%) 419.1\n(15) [2M – H] − , 209.1 (100) [M(Cl 35 ) – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 10 H 8 37 ClO 3 : 213.0132 and 211.0151, C 10 H 8 35 ClO 3 : 211.0162, found:\n213.0127; Anal. calcd for C 10 H 7 ClO 3 : C 57.03, H 3.35%, found: C 57.00, H 3.20.\nUpon sulfamoylation,\ncompound  21a  (400 mg, 1.9 mmol) gave a crude yellow solid,\nwhich was purified\nby flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1\ngradient). The white solid isolated was recrystallized from ethyl\nacetate/hexane to give  21  as pale green fine crystals\n(59 mg, 11%):  R f  = 0.44 (CHCl 3 /ethyl acetate, 4:1); mp 172–175 °C;  1 H NMR\n(400 MHz, DMSO- d 6 ): δ = 5.05 (s,\n2H, CH 2 ), 6.72 (s, 1H, C3–H), 7.34 (dd,  J  = 2.4 and 8.8 Hz, 1H, C6–H), 7.38 (d,  J  = 2.4 Hz, 1H, C8–H), 7.96 (d,  J  = 8.8 Hz,\n1H, C5–H) and 8.28 (s, 2H, NH 2 ); MS (FAB + ):  m / z  (%) 289.9 (95) [M(Cl 35 ) + H] + , 210.9 (100) [M + H – HNSO 2 ] + ; MS (FAB – ):  m / z  (%) 287.9 (100) [M(Cl 35 ) –\nH] − , 208.9 (90) [M – H 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 10 H 9 35 ClNO 5 S: 289.9889 and 291.9862, C 10 H 9 37 ClNO 5 S: 291.9860, found:\n289.9893; Anal. calcd for C 10 H 8 ClNO 5 S: C 41.46, H 2.78, N 4.84, found: C 41.50, H 2.79, N 3.48.\nThis\nwas prepared with resorcinol (2.0 g, 18 mmol), ethyl 3-oxo-3-phenylpropanoate\n(2.0 g, 18 mmol), and a mixture of CF 3 COOH (2.8 mL, 36\nmmol) and conc. H 2 SO 4  (1.85 mL, 36.3 mmol).\nThe crude orange solid was purified by recrystallization from hot\nabsolute ethanol to give  22a  as yellow crystals (1.85\ng, 43%):  R f  = 0.71 (CHCl 3 /acetone,\n3:1); mp 248–252 °C (Lit. 52  mp 247–248 °C);  1 H NMR (400 MHz, DMSO- d 6 ): δ = 6.15 (s, 1H, C3–H), 6.79\n(dd,  J  = 1.2 and 8.8 Hz, 1H, C6–H), 6.81 (d,  J  = 1.2 Hz, 1H, C8–H), 7.27 (d,  J  = 8.8 Hz, 1H, C5–H), 7.51–7.57 (m, 5H, Ph–H)\nand 10.67 (s, 1H, OH); MS (FAB + ):  m / z  (%) 239.1 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 237.1 (100) [M –\nH] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 15 H 11 O 3 : 239.0629, found: 239.0634; Anal. calcd for C 15 H 10 O 3 : C 75.62, H 4.23. found: C 75.40, H 4.13.\nUpon sulfamoylation, compound  22a  (700 mg,\n2.94 mmol) gave a crude white solid, which was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid\nisolated was recrystallized from ethyl acetate/hexane to give  22  as white fine fluffy crystals (304 mg, 33%):  R f  = 0.60 (CHCl 3 /ethyl acetate, 4:1); mp\n185–190 °C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 6.36 (s, 1H, C3–H), 7.28 (dd,  J  = 2.1 and 8.7 Hz, 1H, C6–H), 7.39 (d,  J  = 2.1 Hz, 1H, C8–H), 7.58 (d,  J  = 8.7 Hz,\n1H, C5–H) and 7.59–7.62 (m, 7H, Ph–H and NH 2 —reduced to 5H when exchanged with D 2 O);\nMS (FAB + ):  m / z  (%) 318.1\n(100) [M + H] + ; MS (FAB – ):  m / z  (%) 316.2 (100) [M – H] − , 237.2 (65) [M – H 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M\n+ H] +  calcd for C 15 H 12 NO 5 S: 318.0357, found: 318.0379; Anal. calcd for C 15 H 11 NO 5 S: C 56.78, H 3.49, N 4.41, found: C 56.70,\nH 3.53, N 4.48.\nThis\nwas prepared by method B using CH 2 Cl 2  (80 mL),\nethyl diazoacetate (4.99 g, 43.7 mmol), SnCl 2  (790 mg,\n3.73 mmol), and phenylacetaldehyde (5.0 g, 42 mmol) in CH 2 Cl 2 . The crude oily residue was purified by distillation\nunder reduced pressure to give  23a  as a pale yellow oil\n(5.27 g, 61%):  R f  = 0.62 (CHCl 3 ); bp 0.3  185–189 °C (Lit. 53  bp 9  154–156 °C—NB we are\nunable to explain this discrepancy)  1 H NMR (400 MHz, DMSO- d 6 ): δ = 2.16 (t,  J  =\n7.3 Hz, 3H, CH 2 C H 3 ), 3.45 (s,\n2H, PhC H 2 ), 3.83 (s, 2H, C2–H 2 ), 4.17 (q,  J  = 7.3 Hz, 2H, C H 2 CH 3 ) and 7.20–7.36 (m, 5H, PhH); MS\n(FAB + ):  m / z  (%) 207.1\n(100) [M + H] + , 91.1 (40) [PhCH 2 ] + ; MS (FAB – ):  m / z  (%) 205.1 (100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 12 H 15 O 3 : 207.1021, found:\n207.1014.\nThis\nwas prepared with resorcinol (1.6 g, 15 mmol),  23a  (3.0\ng, 15 mmol), and a mixture of CF 3 COOH (2.5 mL, 29 mmol)\nand conc. H 2 SO 4  (1.5 mL, 29 mmol). The crude\nyellow solid was purified by recrystallization from hot absolute ethanol\nto give  23b  as pale yellow crystals (2.19 g, 60%):  R f  = 0.80 (CHCl 3 /acetone, 3:1), mp\n209–212 °C (Lit. 54  mp 214–215\n°C);  1 H NMR (400 MHz, CDCl 3 ) δ =\n4.38 (s, 2H, C H 2 Ph), 5.98 (s, 1H, C3–H),\n6.71 (d,  J  = 2.3 Hz, 1H, C8–H), 6.76 (dd,  J  = 2.3 and 8.6 Hz, 1H, C6–H), 7.23–7.36 (m,\n5H, PhH), 7.67 (d,  J  = 8.6 Hz, 1H, C5–H) and\n10.57 (s, 1H, OH); MS (FAB + ):  m / z  (%) 505.1 (10) [2M + H] + , 253.1 (100) [M +\nH] + ; MS (FAB – ):  m / z  (%) 503.2 (15) [2M – H] − , 251.2\n(100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 16 H 13 O 3 : 253.0865, found: 253.0863; Anal.\ncalcd for C 16 H 12 O 3 : C 76.18, H 4.79,\nfound: C 75.60, H 4.88.\nUpon sulfamoylation,  23b  (400\nmg, 1.6 mmol)\ngave a crude white solid, which was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid\nisolated was recrystallized from ethyl acetate/hexane to give  23  as white fine crystals (135 mg, 26%):  R f  = 0.39 (CHCl 3 /ethyl acetate, 4:1); mp 180–182\n°C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 4.23 (s, 2H, C H 2 Ph), 6.32\n(s, 1H, C3–H), 7.23–7.26 (m, 2H, C8–H and C6–H),\n7.26–7.37 (m, 5H, PhH), 7.92 (d,  J  = 8.9 Hz,\n1H, C5–H) and 8.22 (s, 2H, NH 2 ); MS (FAB + ):  m / z  (%) 663.4 (30) [2M + H] + , 332.1 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 330.2 (100) [M –\nH] − , 251.2 (50) [M – H 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 16 H 14 NO 5 S: 332.0593, found: 332.0590; Anal. calcd for\nC 16 H 13 NO 5 S: C 58.00, H 3.95, N 4.23%,\nfound: C 57.70, H 3.97, N, 4.21.\nThis\nwas prepared by method B using CH 2 Cl 2  (80 mL),\nethyl diazoacetate (4.5 g, 39 mmol), SnCl 2  (700 mg, 3.73\nmmol), and hydrocinnam-aldehyde (5.0 g, 37 mmol) in CH 2 Cl 2 . The crude oily residue was purified by flash chromatography\n(CHCl 3 ) to give  24a  as a pale yellow oil (5.38\ng, 66%):  R f  = 0.63 (CHCl 3 );  1 H NMR (400 MHz, DMSO- d 6 ): δ\n= 1.17 (t,  J  = 7.3 Hz, 3H, CH 2 C H 3 ), 2.79 (t,  J  = 7.5 Hz, 2H,\nC4–H 2 ), 2.87 (t,  J  = 7.5 Hz, 2H,\nC5–H 2 ), 3.60 (s, 2H, C2–H 2 ), 4.08\n(q,  J  = 7.3 Hz, 2H, C H 2 CH 3 ) and 7.13–7.29 (m, 5H, PhH); MS (FAB + ):  m / z  (%) 221.1 (100) [M + H] + , 91.0 (55) [PhCH 2 ] + ; MS (FAB – ):  m / z  (%) 219.1 (100) [M –\nH] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 13 H 17 O 3 : 221.1178, found: 221.1181.\nThis was prepared with resorcinol (1.25\ng, 11.4 mmol),  24a  (2.5 g, 11 mmol), and a mixture of\nCF 3 COOH (1.75 mL,\n22.7 mmol) and conc. H 2 SO 4  (1.16 mL, 22.7 mmol).\nThe crude yellow solid was purified by recrystallization from hot\nabsolute ethanol to give  24b  as pale white crystals (1.06\ng, 35%):  R f  = 0.65 (CHCl 3 /acetone,\n3:1); mp 175–177 °C (Lit. 55  mp 175–176 °C);  1 H NMR (400 MHz, CDCl 3 ) δ = 2.98–3.06 (m, 4H, CH 2 CH 2 ), 6.12 (s, 1H, C3–H), 6.59 (s, 1H, OH), 6.84 (dd,  J  = 2.4 and 8.8 Hz, 1H, C6–H), 7.11 (d,  J  = 2.4 Hz, 1H, C8–H), 7.20–7.34 (m, 5H, PhH) and 7.53\n(d,  J  = 8.8 Hz, 1H, C5–H); MS (FAB + ):  m / z  (%) 533.2 (40) [2M + H] + , 267.1 (100) [M + H] + , 91.1 (20) [CH 2 Ph] + ; MS (FAB – ):  m / z  (%) 531.2 (30) [2M – H] − , 265.0\n(100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 17 H 15 O 3 : 267.1021, found: 267.1018; Anal.\ncalcd for C 17 H 14 O 3 : C 76.68, H 5.30,\nfound: C 76.70, H 5.20.\nUpon sulfamoylation,  24b  (400 mg,\n1.5 mmol) gave a crude white solid, which was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid\nisolated was recrystallized from THF/hexane to give  24  as white fine crystals (395 mg, 76%):  R f  = 0.27 (CHCl 3 /ethyl acetate, 4:1); mp 89–93 °C;  1 H NMR (400 MHz, DMSO- d 6 ): δ\n= 2.96 (t,  J  = 8.8 Hz, 2H, C H 2 CH 2 Ph), 3.14 (t,  J  = 8.5 Hz, 2H,\nC H 2 Ph), 6.36 (s, 1H, C3–H), 7.22–7.34\n(m, 7H, PhH, C6–H and C8–H), 8.03 (d,  J  = 7.9 Hz, 1H, C5–H) and 8.25 (s, 2H, NH 2 ); MS\n(FAB + ):  m / z  (%) 346.0\n(100) [M + H] + , 91.0 (50) [CH 2 Ph] + ; MS (FAB – ):  m / z  (%) 344.0 (100) [M – H] − , 265.0 (60) [M\n– H 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 17 H 16 NO 5 S: 346.0749,\nfound: 346.0754; Anal. calcd for C 17 H 15 NO 5 S: C 59.12, H 4.38, N 4.06, found: C 59.30, H 4.89, N 3.86.\nThis was prepared by method A using ethyl potassium malonate (6.07\ng, 35.7 mmol), CH 3 CN (120 mL), Et 3 N (7.58 mL,\n54.4 mmol), MgCl 2  (4.05 g, 42.5 mmol), and 4-ethylbenzoyl\nchloride (2.5 mL, 17 mmol). The crude oily residue was purified by\ndistillation under reduced pressure to give  25a  as a\ncolorless oil (3.74 g, 78%):  R f  = 0.64\n(CH 2 Cl 2 ); bp 0.23  131–135 °C\n(Lit. 56  bp 0.004  105–112\n°C);  1 H NMR (400 MHz, CDCl 3 ) δ =\n1.22–1.33 (m, 6H, C H 3 CH 2 Ph and CH 2 C H 3 ), 2.70 (q,  J  = 7.8 Hz, 2H, C H 2 Ph), 3.97\n(s, 2H, C2–H 2 ), 4.21 (q,  J  = 6.8\nHz, 2H, C H 2 CH 3 ), 7.29 (d,  J  = 8.3 Hz, 2H, 2 × ArH) and 7.87 (d,  J  = 8.3 Hz, 2H, 2 × Ar-H); MS (FAB + ):  m / z  (%) 221.0 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 219.0\n(100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 13 H 17 O 3 : 221.1178, found: 221.1177.\nThis\nwas prepared with resorcinol (1.5 g, 14 mmol),  25a  (3.0\ng, 14 mmol), and a mixture of CF 3 COOH (2.5 mL, 27\nmmol) and conc. H 2 SO 4  (1.5 mL, 27 mmol). The\ncrude orange solid was purified by recrystallization from hot ethanol\nto give  25b  as white needles (1.66 g, 46%):  R f  = 0.72 (CHCl 3 /acetone, 4:1); mp 176–180\n°C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 1.23 (t,  J  = 7.6 Hz, 3H, C H 3 CH 2 ), 2.69 (q,  J  = 7.6 Hz,\n2H, CH 3 C H 2 ), 6.13 (s, 1H, C3–H),\n6.77 (m, 2H, C6–H and C8–H), 7.31 (d,  J  = 8.5 Hz, 1H, C5–H), 7.38–7.44 (m, 4H, PhH) and 10.64\n(s, 1H, OH); MS (FAB + ):  m / z  (%) 533.1 (10) [2M + H] + , 267.0 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 531.1 (20) [2M – H] − , 265.1 (100) [M\n– H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 17 H 15 O 3 : 267.1021, found: 267.1018; Anal. calcd for\nC 17 H 14 O 3 : C 76.68, H 5.30, found:\nC 76.30, H, 5.30.\nUpon sulfamoylation, compound  25b  (400 mg, 1.5 mmol) gave a crude white solid, which was\npurified\nby flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1\ngradient). The white solid isolated was recrystallized from THF/hexane\nto give  25  as white fine crystals (114 mg, 22%):  R f  = 0.35 (CHCl 3 /ethyl acetate, 4:1);\nmp 170–173 °C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 1.25 (t,  J  =\n7.4 Hz, 3H, C H 3 CH 2 ), 2.71 (q,  J  = 7.4 Hz, 2H, CH 3 C H 2 ), 6.44 (s, 1H, C3–H), 7.26 (dd,  J  = 2.3\nand 8.9 Hz, 1H, C6–H), 7.42–7.49 (m, 5H, PhH and C8–H),\n7.57 (d,  J  = 8.6 Hz, 1H, C5–H) and 8.28 (s,\n2H, NH 2 ); MS (FAB + ):  m / z  (%) 691.0 (30) [2M + H] + , 346.1 (100) [M +\nH] + ; MS (FAB – ):  m / z  (%) 689.3 (10) [2M – H] − , 344.2\n(100) [M – H] − , 265.2 (60) [M – H 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 17 H 16 NO 5 S: 346.0749, found: 346.0749;\nAnal. calcd for C 17 H 15 NO 5 S: C 59.12,\nH 4.38, N 4.06, found: C 59.00, H 4.36, N 4.03.\nThis was prepared by method B using CH 2 Cl 2  (80\nmL), ethyl diazoacetate (5.34 g, 46.8 mmol), SnCl 2  (85\nmg, 4.5 mmol), and cyclohexanecarboxaldehyde (5.0 g, 45 mmol) in CH 2 Cl 2  (20 mL). The crude oily residue was purified\nby fractional distillation under reduced pressure to give  26a  as a pale yellow oil (5.38 g, 66%):  R f  = 0.63 (CHCl 3 ); bp 0.3  135–139 °C\n(Lit. 53  bp 18  146–150\n°C);  1 H NMR (400 MHz, CDCl 3 ) δ =\n1.28 (t,  J  = 7.2 Hz, 3H, CH 2 C H 3 ), 1.39–2.49 (m, 11H, cyclohexyl-H), 3.48 (s,\n2H, C2–H 2 ) and 4.19 (q,  J  = 7.2\nHz, 2H, C H 2 CH 3 ); MS (FAB + ):  m / z  (%) 199.0 (100) [M\n+ H] + ; MS (FAB – ):  m / z  (%) 197.0 (100) [M – H] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 11 H 19 O 3 : 199.1334, found:\n199.1341.\nThis\nwas prepared with resorcinol (1.67 g, 15.1 mmol),  26a  (3.0 g, 15 mmol), and a mixture of CF 3 COOH (2.33 mL,\n30.3 mmol) and conc. H 2 SO 4  (1.5 mL, 30 mmol).\nThe crude yellow solid was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow solid\nisolated was recrystallized from hot acetone to give  26b  as white crystals (1.45 g, 39%):  R f  =\n0.80 (CHCl 3 /acetone, 4:1); mp 191–192 °C (Lit. 57  mp 176–178 °C);  1 H NMR\n(400 MHz, DMSO- d 6 ): δ = 1.38–1.87\n(m, 11H, cyclohexyl-H), 6.04 (s, 1H, C3–H), 6.71 (d,  J  =  J  = 2.3 Hz, 1H, C8–H), 6.81\n(dd,  J  = 2.4 and 8.8 Hz, 1H, C6–H), 7.70 (d,  J  = 8.8 Hz, 1H, C5–H) and 10.56 (s, 1H, OH); MS (FAB + ):  m / z  (%) 489.1 (15) [2M\n+ H] + , 245.1 (100) [M + H] + ; MS (FAB – ):  m / z  (%) 487.3 (15) [2M –\nH] − , 243.2 (100) [M – H] − ; HRMS-FAB + :  m / z  [M\n+ H] +  calcd for C 15 H 17 O 3 : 245.1178, found: 245.1179; Anal. calcd for C 15 H 16 O 3 : C 73.75, H 6.60, found: C 73.90, H 6.60.\nUpon sulfamoylation, compound  26a  (400 mg,\n1.6 mmol) gave a crude white solid, which was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid\nisolated was recrystallized from THF/hexane to give  26  as white fine crystals (192 mg, 36%):  R f  = 0.45 (CHCl 3 /ethyl acetate, 4:1); mp 187–190\n°C;  1 H NMR (400 MHz, DMSO- d 6 ): δ = 1.23–2.06 (m, 11H, cyclohexyl-H), 6.32 (s, 1H,\nC3–H), 7.32 (dd,  J  = 2.3 and 8.6 Hz, 1H, C6–H),\n7.36 (d,  J  = 2.3 Hz, 1H, C8–H), 8.01 (d,  J  = 8.9 Hz, 1H, C5–H) and 8.31 (s, 2H, NH 2 ); MS (FAB + ):  m / z  (%)\n324.1 (100) [M + H] + , 245.1 (15) [M + H – HNSO 2 ] + ; MS (FAB):  m / z  (%) 323.2 (100) [M – H] − , 243.2 (50) [M\n– H 2 NSO 2 ] − ; HRMS-FAB + :  m / z  [M + H] +  calcd for C 15 H 18 NO 5 S: 324.0906,\nfound: 324.0902; Anal. calcd for C 15 H 17 NO 5 S: C 55.72, H 5.30, N 4.33, found: C 55.70, H 5.28, N 4.17.\n1-Adamantane\nacetic acid (5.0 g; 25.7 mmol) in an excess of thionyl chloride (20\nmL; 77.2 mmol) and THF (5 mL) was boiled under reflux overnight under\nN 2 . Thionyl chloride was removed under vacuum to get the\ncrude  27a  as a brown oil (5.5 g; 101% crude), which was\nused for the next reaction without purification.  R f : 0.91 (CHCl 3 /MeOH, 8:1); (Lit. 58  bp 3  107–109 °C);  1 H NMR\n(400 MHz; CDCl 3 ) δ H : 1.11–1.76\n(m, 15H, adamantane H) and 2.69 (s, 2H, CH 2 CO); MS (FAB + )  m / z : 213.1 [100, (M( 35 Cl) + H) + ]; MS (FAB – )  m / z : 211.1 [100, (M( 35 Cl) –\nH) − ]; Acc. MS  m / z  (FAB + ): 213.1097, C 12 H 18 35 ClO requires 213.1081 and 215.1006, C 12 H 18 37 ClO requires 215.1012.\nThis was prepared by method A using ethyl\npotassium malonate (8.4\ng; 49 mmol), MeCN (150 mL), Et 3 N (11 mL; 75 mmol), MgCl 2  (5.6 g; 59 mmol), and  27a  (5.0 g; 24 mmol).\nThe crude oily residue was purified by flash chromatography (CHCl 3 ) to give  27b  as a brown oil (4.5 g; 72%).  R f : 0.77 (CHCl 3 /hexane, 9:1); (Lit. 58  bp 0.07  105–106 °C); MS\n(FAB + )  m / z : 265.2 [100,\n(M + H) + ], 135 [85, (C 10 H 15  + H) + ];  1 H NMR (400 MHz; CDCl 3 ) δ H : 1.24–1.58 (m, 15H, adamantane H), 1.28 (t, 3H, CH 2 C H 3 ), 2.28 (s, 2H, CH 2 CO), 3.41 (s, 2H, 2-CH 2 ) and 4.21 (q, 2H, C H 2 CH 3 ,  J  = 7.0 Hz); MS (FAB – )  m / z : 263.3 [100,\n(M – H) − ]; Acc. MS (FAB + ): 265.1697,\nC 16 H 25 O 3  requires 265.1705.\nThis was prepared by general method using\nresorcinol (834 mg; 7.6\nmmol),  27b  (2.0 g; 7.6 mmol), and a mixture of CF 3 COOH (1.2 mL; 15 mmol) and conc. H 2 SO 4  (1.5 mL; 15 mmol). The crude yellow solid was purified by recrystallization\nfrom THF/hexane to give  27c  as yellow crystals (1.82\ng; 77%).  R f : 0.72 (CHCl 3 /acetone,\n4:1); mp 211–214 °C;  1 H NMR (400 MHz; CDCl 3 ) δ H : 1.52–2.09 (m, 15H, adamantane\nH), 1.90 (s, 2H, CH 2 ), 5.95 (s, 1H, C 3 –H),\n6.69 (d, 1H, C 8 –H,  J  = 2.3 Hz),\n6.78 (dd, 1H, C 6 –H,  J  = 2.3, 8.6\nHz), 7.75 (d, 1H, C 5 –H,  J  = 8.9\nHz) and 10.54 (s, 1H, OH); found C, 77.42; H, 7.15; C 20 H 22 O 3  requires C, 77.39; H, 7.14%; MS (FAB + )  m / z : 311.1 [100, (M +\nH) + ]; MS (FAB – )  m / z : 309.2 [100, (M – H) − ]; Acc.\nMS (FAB + ): 311.1568, C 20 H 23 O 3  requires 311.1569.\nCompound  27c  (400 mg; 1.3\nmmol) was sulfamoylated, the crude white solid was purified by flash\nchromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient),\nand the white solid isolated was recrystallized from THF/hexane to\ngive  27  as white fine crystals (88 mg; 18%).  R f : 0.57 (CHCl 3 /ethyl acetate, 4:1);\nmp 218–221 °C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 1.54–1.64 (m,\n15H, adamantane H), 1.91 (s, 2H, CH 2 ), 6.24 (s, 1H, C 3 –H), 7.24–7.31 (m, 2H, C 6 –H\nand C 8 –H), 8.04 (d, 1H, C 5 –H,  J  = 8.9 Hz) and 8.25 (s, 2H, NH 2 ); MS (FAB + )  m / z : 390.0 [100, (M +\nH) + ]; MS (FAB – )  m / z : 388.1 [100, (M – H) − ]; Acc.\nMS (FAB + ): 390.1301, C 20 H 24 NO 5 S requires 390.1297; found C, 61.40; H, 5.75; N, 3.22; C 20 H 23 NO 5 S requires C, 61.68; H, 5.95;\nN, 3.60%.\nThis was\nprepared by general method using K 2 CO 3  (11.09\ng; 79.2 mmol), water (50 mL), 1-bromopentane (4.09 mL; 33 mmol), ethyl\n3-oxo-butanoate (4.29 mL; 33 mmol), CH 2 Cl 2  (50\nmL), and Bu 4 NCl (∼10 g; 33 mmol). The crude oily\nresidue (4.68 g) was purified by flash chromatography (CHCl 3 ) to give  28a  as a pale yellow oil (4.03 g; 61%). (Lit. 59  bp 8  101–105 °C);  R f : 0.69 (CHCl 3 );  1 H NMR\n(400 MHz; DMSO- d 6 ) δ H : 0.85 (t, 3H, CH 3 ,  J  = 7.3 Hz), 1.19\n(t, 3H, CH 2 C H 3 ,  J  = 7.3 Hz), 1.23–1.27 (m, 6H, 3 × CH 2 ), 1.68–1.72\n(q, 2H, 3-CH 2 ,  J  = 6.1 Hz), 2.17 (s, 3H,\nCH 3 CO), 3.57 (t, 1H, 2H,  J  = 7.3 Hz) and\n4.12 (q, 2H, C H 2 CH 3 ,  J  = 7.3 Hz); MS (FAB + )  m / z : 201.2 [100, (M + H) + ]; Acc. MS (FAB + ): 201.1492, C 11 H 21 O 3  requires 201.1491.\nThis\nwas prepared by general method using resorcinol (2.2 g; 20 mmol),  28a  (4.0 g; 20 mmol), and a mixture of CF 3 COOH\n(3.08 mL; 40 mmol) and conc. H 2 SO 4  (2.04 mL;\n40 mmol). The crude pale yellow solid was purified by flash chromatography\n(CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow\nsolid isolated was recrystallized from acetone/hexane to give  28b  as white crystals (2.03 g; 38%).  R f : 0.80 (CHCl 3 /acetone, 3:1); mp 101–102\n°C (Lit. 61  mp 111–113 °C);  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.87 (t, 3H, 5′-CH 3 ,  J  = 6.8 Hz), 1.29–1.44 (m, 6H, 3 × CH 2 ), 2.35\n(s, 3H, C 4 –CH 3 ), 2.51 (t, 2H, 1′-CH 2 ,  J  = 7.3 Hz), 6.71 (d, 1H, C 8 –H,  J  = 2.4 Hz), 6.78 (dd, 1H, C 6 –H,  J  = 2.4, 8.8 Hz), 7.59 (d, 1H, C 5 –H,  J  = 8.8 Hz) and 10.36 (s, 1H,\nOH); found C, 72.90; H, 7.29; MS (FAB + )  m / z : 493.4 [15, (2M + H) + ], 247.3 [100,\n(M + H) + ]; MS (FAB – )  m / z : 491.3 [10, (2M – H) − ], 245.2 [100, (M – H) − ]; Acc. MS (FAB + ): 247.1327, C 15 H 19 O 3  requires\n247.1334; C 15 H 18 O 3  requires C, 73.15;\nH, 7.37%.\nCompound  28b  (700\nmg; 2.84 mmol)\nwas sulfamoylated, the crude white solid was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white\nsolid isolated was recrystallized from ethyl acetate/hexane to give  28  as white fine crystals (479 mg; 52%).  R f : 0.82 (CHCl 3 /ethyl acetate, 4:1); mp 133–135\n°C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.87 (t, 3H, 5′-CH 3 ,  J  = 6.7 Hz), 1.31–1.49 (m, 6H, 3 × CH 2 ), 2.43 (s, 3H, C 4 –CH 3 ), 2.58 (t, 2H,\n1′-CH 2 ,  J  = 8.2 Hz), 7.26–7.29\n(m, 2H, C 6 –H and C 8 –H), 7.88 (d,\n1H, C 5 –H,  J  = 7.9 Hz) and 8.19\n(s, 2H, NH 2 ); MS (FAB + )  m / z : 326.2 [100, (M + H) + ], 245.2 [50, (M + H –\nHNSO 2 ) + ]; MS (FAB – )  m / z : 326.2 [100, (M – H) − ]; Acc. MS (FAB + ): Acc. MS (FAB + ): 326.1076,\nC 15 H 20 NO 5 S requires 326.1062; found\nC, 55.20; H, 5.88; N, 4.27; C 15 H 19 NO 5 S requires C, 55.37; H, 5.89; N, 4.30%.\nThis was\nprepared by general method using K 2 CO 3  (11.1\ng; 79.2 mmol), water (50 mL), 1-bromohexane (4.63 mL; 33 mmol), ethyl\n3-oxo-butanoate (4.29 mL; 33 mmol), CH 2 Cl 2  (50\nmL), and Bu 4 NCl (∼10 g; 33 mmol). The crude oily\nresidue was purified by flash chromatography (CHCl 3 ) to\ngive  29a  as a pale yellow oil (3.05 g; 43%). (Lit. 60  bp 10  127–129 °C);  R f : 0.66 (CHCl 3 );  1 H NMR\n(400 MHz; DMSO- d 6 ) δ H : 0.85 (t, 3H, CH 3 ,  J  = 6.7 Hz), 1.18\n(t, 3H, CH 2 C H 3 ,  J  = 7.1 Hz), 1.22–1.36 (m, 8H, 4 × CH 2 ), 1.71\n(q, 2H, 3-CH 2 ,  J  = 6.4 Hz), 2.17 (s, 3H,\nCH 3 CO), 3.57 (t, 1H, 2H,  J  = 6.7 Hz) and\n4.12 (q, 2H, C H 2 CH 3 ,  J  = 7.3 Hz); MS (FAB + )  m / z : 215.2 [100, (M + H) + ]; MS (FAB – )  m / z : 213.1 [100, (M –\nH) − ]; Acc. MS (FAB + ): 215.1600, C 12 H 23 O 3  requires 215.1639.\nThis was prepared by general method using\nresorcinol (1.28 g; 11.7\nmmol),  29a  (2.5 g; 12 mmol), and a mixture of CF 3 COOH (1.8 mL; 23 mmol) and conc. H 2 SO 4  (1.19 mL; 23.3 mmol). The crude pale white solid was recrystallized\nfrom acetone/hexane to give  29b  as white fine crystals\n(2.12 g; 70%).  R f : 0.81 (CHCl 3 /acetone, 3:1); mp 112–114 °C (Lit. 61  mp 111–112 °C); MS (FAB + )  m / z : 521.1 [100, (2M + H) + ],\n261.2 [100, (M + H) + ];  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.88 (t, 3H, 6′-CH 3 ,  J  = 7.1 Hz), 1.25–1.55 (m, 8H, 4\n× CH 2 ), 2.39 (s, 3H, C 4 –CH 3 ), 2.63 (t, 2H, 1′-CH 2 ,  J  = 7.6\nHz), 6.83 (dd, 1H, C 6 –H,  J  = 2.4,\n8.8 Hz), 6.96 (d, 1H, C 8 –H,  J  =\n2.4 Hz), 7.49 (d, 1H, C 5 –H,  J  =\n8.8 Hz) and 10.41 (s, 1H, OH); MS (FAB – )  m / z : 259.2 [100, (M – H) − ]; Acc. MS (FAB + ): 261.1421, C 16 H 21 O 3  requires 261.1412; found C, 73.90; H, 7.78; C 16 H 20 O 3  requires C, 73.82; H, 7.74%.\nCompound  29b  (700 mg; 2.69 mmol)\nwas sulfamoylated, the crude white solid was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white\nsolid that was isolated was recrystallized from ethyl acetate/hexane\nto give  29  as white fine fluffy crystals (449 mg; 49%).  R f : 0.41 (CHCl 3 /ethyl acetate, 4:1);\nmp 132–133 °C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.86 (t, 3H, CH 3 ,  J  = 5.5 Hz), 1.25–1.48 (m, 8H, 4\n× CH 2 ), 2.43 (s, 3H, C 4 –H 3 ), 2.59 (t, 2H, 1′-CH 2 ,  J  = 7.1\nHz), 7.26 (d, 1H, C 8 –H,  J  = 2.1\nHz), 7.28 (m, 1H, C 6 –H), 7.88 (d, 1H, C 5 –H,  J  = 7.3 Hz) and 8.19 (s, 2H, NH 2 ); MS (FAB + )  m / z : 679.4\n[15, (2M + H) + ], 340.2 [100, (M + H) + ]; MS (FAB – )  m / z : 338.2 [100,\n(M – H) − ], 259.2 [45, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ):\n340.1230, C 16 H 22 NO 5 S requires 340.1219;\nfound C, 56.90; H, 6.22; N, 4.12; C 16 H 21 NO 5 S requires C, 56.62; H, 6.24; N, 4.13%.\nThis was\nprepared by general method using K 2 CO 3  (11.11\ng; 80.39 mmol), water (50 mL), 1-bromoheptane (6 mL; 34 mmol), ethyl\nacetoacetate (4.27 mL; 33.5 mmol), CH 2 Cl 2  (50\nmL), and Bu 4 NCl (∼10 g; 34 mmol). The crude oily\nresidue was purified by flash chromatography (CHCl 3 ) to\ngive  30a  as a pale yellow oil (2.45 g; 33%). (Lit. 62  bp 0.4  80–85 °C);  R f : 0.9 (CHCl 3 );  1 H NMR\n(400 MHz; CDCl 3 ) δ H : 0.85 (t, 3H, CH 3 ,  J  = 7.1 Hz), 1.18 (t, 3H, CH 2 C H 3 J  = 7.1 Hz), 1.23–1.73\n(m, 12H, 6 × CH 2 ), 2.17 (s, 3H, CH 3 CO),\n3.56 (t, 1H, 2H,  J  = 7.1 Hz) and 4.19 (q, 2H, C H 2 CH 3 ,  J  = 7.1 Hz);\nMS (FAB + )  m / z : 229.2\n[100, (M + H) + ]; MS (FAB – )  m / z : 227.2 [100, (M – H) − ]; Acc. MS (FAB + ): 229.1804, C 13 H 25 O 3  requires 229.1803.\nThis was prepared by general method using\nresorcinol (965 mg; 8.76\nmmol),  30a  (2.0 g; 8.8 mmol), and a mixture of CF 3 COOH (1.55 mL; 20.2 mmol) and conc. H 2 SO 4  (1.03 mL; 20.2 mmol). The crude pale yellow solid was recrystallized\nfrom acetone/hexane to give  30b  as pale yellow crystals\n(730 mg; 30%).  R f : 0.78 (CHCl 3 /acetone, 3:1); mp 96–98 °C;  1 H NMR (400 MHz;\nCDCl 3 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 7.3 Hz), 1.26–1.53 (m, 10H, 5 ×\nCH 2 ), 2.39 (s, 3H, C 4 –CH 3 ),\n2.63 (t, 2H, 1′-CH 2 ), 7.01 (d, 1H, C 8 –H,  J  = 2.4 Hz), 6.85 (dd, 1H, C 6 –H,  J  = 2.4, 8.7 Hz), 7.49 (d, 1H, C 5 –H,  J  = 8.85 Hz) and 10.37 (s, 1H,\nOH); MS (FAB + )  m / z : 549.4\n[15, (2M + H) + ], 275.2 [100, (M + H) + ]; MS (FAB – )  m / z : 547.4 [10,\n(2M – H) − ], 273.2 [100, (M – H) − ]; Acc. MS (FAB + ): 275.1641, C 17 H 23 O 3  requires 275.1647; found C, 74.08; H,\n8.03; C 17 H 22 O 3  requires C, 74.42;\nH, 8.08%.\nCompound  64  (400\nmg; 1.46 mmol)\nwas sulfamoylated, the crude white solid was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white\nsolid isolated was recrystallized from ethyl acetate/hexane to give  30  as white fine crystals (75 mg; 14%).  R f : 0.51 (CHCl 3 /ethyl acetate 4:1); mp 138–140\n°C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.86 (t, 3H, CH 3 ,  J  = 6.7 Hz), 1.26–1.49 (m, 10H, 5 × CH 2 ), 2.43\n(s, 3H, C 4 –CH 3 ), 2.58 (t, 2H, 1′-CH 2 ,  J  = 7.1 Hz), 7.25–7.29 (m, 2H, C 6 –H and C 8 –H), 7.88 (d, 1H, C 5 –H,  J  = 8.8 Hz) and 8.18 (s, 2H, NH 2 ); MS (FAB + )  m / z : 707.2 [40, (2M + H) + ], 354.1 [100, (M + H) + ]; MS (FAB – )  m / z : 705.2 [40, (2M – H) − ], 352.1 [100, (M\n– H) − ], 273.2 [90, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ):\n354.1391, C 17 H 24 NO 5 S requires 354.1375;\nfound C, 57.80; H, 6.58; N, 3.92; C 17 H 23 NO 5 S requires C, 57.77; H, 6.56; N, 3.96%.\nThis was\nprepared by general method using K 2 CO 3  (11.47\ng; 82.98 mmol), water (50 mL), 1-bromooctane (6.0 mL; 35 mmol), ethyl\n3-oxo-butanoate (4.41 mL; 34.6 mmol), CH 2 Cl 2  (50 mL), and Bu 4 NCl (∼10 g; 35 mmol). The crude\noily residue was purified by flash chromatography (CHCl 3 /acetone) to give  31a  as a pale yellow oil (3.1 g; 37%).\n(Lit. 63  bp 0.4  79–83 °C);  R f : 0.68 (CHCl 3 );  1 H NMR\n(400 MHz; DMSO- d 6 ) δ H : 0.86 (t, 3H, CH 3 ,  J  = 6.7 Hz), 1.18\n(t, 3H, CH 2 C H 3 ,  J  = 7.3 Hz), 1.23–1.75 (m, 12H, 6 × CH 2 ), 2.06\n(s, 3H, CH 3 CO), 2.39 (q, 2H, 3-CH 2 ,  J  = 7.3 Hz), 3.61 (t, 1H, 2H,  J  = 6.7 Hz)\nand 4.12 (q, 2H, C H 2 CH 3 ,  J  = 7.1 Hz); MS (FAB + )  m / z : 243.2 [100, (M + H) + ]; MS (FAB – )  m / z : 241.2 [100, (M –\nH) − ]; Acc. MS (FAB + ): 243.1968, C 14 H 27 O 3  requires 243.1960.\nThis was prepared by general method using\nresorcinol (910 mg; 8.26\nmmol),  31a  (2.0 g; 8.3 mmol), and a mixture of CF 3 COOH (1.27 mL; 16.3 mmol) and conc. H 2 SO 4  (0.84 mL; 16.3 mmol). The crude brown solid was recrystallized from\nacetone/hexane to give  31b  as white crystals (405 mg;\n17%).  R f : 0.72 (CHCl 3 /acetone,\n3:1); mp 98–100 °C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 7.3 Hz), 1.27–1.46 (m, 12H,\n6 × CH 2 ), 2.38 (s, 3H, C 4 –CH 3 ), 2.54 (t, 2H, 1′-CH 2 ,  J  = 6.4 Hz), 6.69 (d, 1H, C 8 –H,  J  = 2.1 Hz), 6.81 (dd, 1H, C 6 –H,  J  = 2.1, 8.8 Hz), 7.62 (d, 1H, C 5 –H,  J  = 8.8 Hz) and 10.52 (s, 1H, OH); MS (FAB + )  m / z : 577.4 [40, (2M + H) + ], 289.2 [100,\n(M + H) + ]; MS (FAB – )  m / z : 575.3 [35, (2M – H)], 287.2 [100, (M\n– H) − ]; Acc. MS (FAB + ): 289.1801,\nC 18 H 25 O 3  requires 289.1801; found\nC, 74.90; H, 8.40; C 18 H 24 O 3  requires\nC, 74.97; H, 8.39%.\nCompound  31b  (400\nmg; 1.39 mmol)\nwas sulfamoylated, the crude white solid was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white\nsolid isolated was recrystallized from ethyl acetate/hexane to give  31  as white fine crystals (69 mg; 15%).  R f : 0.43 (CHCl 3 /ethyl acetate, 4:1); mp 135–138\n°C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.86 (t, 3H, CH 3 ,  J  = 7.3 Hz), 1.25–1.49 (m, 12H, 6 × CH 2 ), 2.43\n(s, 3H, C 4 –CH 3 ), 2.58 (t, 2H, 1′-CH 2 ,  J  = 7.1 Hz), 7.26–7.29 (m, 2H, C 6 –H and C 8 –H), 7.88 (d, 1H, C 5 –H,  J  = 8.8 Hz) and 8.18 (s, 2H, NH 2 ); found C, 58.70; H, 6.72; MS (FAB + )  m / z : 735.2 [35, (2M + H) + ], 368.1 [100,\n(M + H) + ]; MS (FAB – )  m / z : 733.3 [40, (2M – H) − ], 366.2 [100, (M – H) − ], 287.2 [60, (M\n– H 2 NSO 2 ) − ]; Acc. MS\n(FAB + ): 368.1529, C 18 H 26 NO 5 S requires 368.1532; N, 3.68; C 18 H 25 NO 5 S requires C, 58.84; H, 6.86; N, 3.81%.\nThis was\nprepared by general method using K 2 CO 3  (7.4\ng; 58 mmol), water (50 mL), 1-bromononane (5.0 mL; 24 mmol), ethyl\n3-oxo-butanoate (3.1 mL; 24 mmol), CH 2 Cl 2  (50\nmL), and Bu 4 NCl (∼10 g; 49 mmol). The crude oily\nresidue was purified by flash chromatography (CHCl 3 ) to\ngive  32a  as a pale yellow oil (2.76 g; 45%). (Lit. 64  bp 4.2  191 °C);  R f : 0.65 (CHCl 3 );  1 H NMR (400\nMHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 6.8 Hz), 1.26–1.91 (m, 19H, CH 2 C H 3  and 8 × CH 2 ), 2.22 (s, 3H, CH 3 CO), 3.39 (t, 1H, 2H,  J  = 7.3 Hz) and 4.19 (q, 2H, C H 2 CH 3 ,  J  = 7.3 Hz); MS (FAB + )  m / z : 257.2 [100, (M + H) + ];\nMS (FAB – )  m / z :\n255.2 [100, (M – H) − ]; Acc. MS (FAB + ): 257.2126, C 15 H 29 O 3  requires 257.2170.\nThis\nwas prepared by general method using resorcinol (1.07 g; 9.76\nmmol),  32a  (2.5 g; 9.8 mmol), and a mixture of CF 3 COOH (1.5 mL; 20 mmol) and conc. H 2 SO 4  (1.0 mL; 20 mmol). The crude yellow solid was purified by flash\nchromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and\nthe pale yellow solid isolated was recrystallized from acetone/hexane\nto give  32b  as white crystals (797 mg; 27%).  R f : 0.69 (CHCl 3 /acetone, 3:1); mp\n78–80 °C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.87 (t, 3H, CH 3 ,  J  = 7.1 Hz), 1.26–1.55 (m, 14H, 7 × CH 2 ), 2.39 (s, 3H, C 4 –CH 3 ), 2.63 (t, 2H,\n1′-CH 2 ,  J  = 7.6 Hz), 6.86 (dd,\n1H, C 6 –H,  J  = 2.4, 8.8 Hz), 7.05\n(d, 1H, C 8 –H,  J  = 2.4 Hz), 7.49\n(d, 1H, C 5 –H,  J  = 8.8 Hz) and 7.55\n(s, 1H, OH); found C, 75.35; H, 8.65; MS (FAB + )  m / z : 605.3 [35, (2M + H) + ],\n303.1 [100, (M + H) + ]; MS (FAB – )  m / z : 603.1 [40, (2M – H) − ], 301.1 [100, (M – H) − ]; Acc. MS (FAB + ): 303.1964, C 19 H 27 O 3  requires\n303.1960; C 19 H 26 O 3  requires C, 75.46;\nH, 8.67%.\nCompound  32b  (400\nmg; 1.32 mmol)\nwas sulfamoylated, the crude white solid was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white\nsolid isolated was recrystallized from ethyl acetate/hexane to give  32  as white fine crystals (184 mg; 37%).  R f : 0.82 (CHCl 3 /ethyl acetate, 4:1); mp 125–129\n°C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.85 (t, 3H, CH 3 ,  J  = 6.7 Hz), 1.24–1.48 (m, 14H, 7 × CH 2 ), 2.42\n(s, 3H, C 4 –CH 3 ), 2.58 (t, 2H, 1′-CH 2 ,  J  = 7.3 Hz), 7.25 (d, 1H, C 8 –H,  J  = 2.4 Hz), 7.28 (dd, 1H, C 6 –H,  J  = 2.1, 8.5 Hz), 7.88 (d, 1H, C 5 –H,  J  = 8.5 Hz) and 8.19 (s, 2H, NH 2 ); MS (FAB + )  m / z : 763.3 [45, (2M + H) + ], 382.1 [100, (M + H) + ]; MS (FAB – )  m / z : 761.2 [45, (2M – H) − ], 380.1 [100, (M\n– H) − ], 301.1 [75, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ):\n382.1679, C 19 H 28 NO 5 S requires 382.1688;\nfound C, 59.50; H, 7.08; N, 3.59; C 19 H 27 NO 5 S requires C, 59.82; H, 7.13; N, 3.67%.\nThis was\nprepared by general method using K 2 CO 3  (7.5\ng; 54 mmol), water (50 mL), 1-bromodecane (5.0 mL; 23 mmol), ethyl\n3-oxo-butanoate (2.88 mL; 22.6 mmol), CH 2 Cl 2  (50 mL), and Bu 4 NCl (∼10 g; 45 mmol). The crude\noily residue was purified by flash chromatography (CHCl 3 ) to give  33a  as a pale yellow oil (2.95 g; 48%). (Lit. 65  bp 2  140–150 °C);  R f : 0.76 (CHCl 3 );  1 H NMR\n(400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 7.3 Hz), 1.25–2.00 (m, 21H,\nCH 2 C H 3  and 9 × CH 2 ), 2.22 (s, 3H, CH 3 CO), 3.39 (t, 1H, 2H,  J  = 7.3 Hz) and 4.19 (q, 2H, C H 2 CH 3 ,  J  = 7.3 Hz); MS (FAB + )  m / z : 271.2 [100, (M + H) + ]; MS (FAB – )  m / z : 269.2 [100, (M – H) − ]; Acc.\nMS (FAB + ): 271.2275, C 16 H 31 O 3  requires 271.2273.\nThis was prepared by general method using\nresorcinol (1.02 g; 9.25\nmmol),  33a  (2.5 g; 9.3 mmol), and a mixture of CF 3 COOH (1.42 mL; 18.5 mmol) and conc. H 2 SO 4  (0.94 mL; 18.5 mmol). The crude brown solid was purified by flash\nchromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and\nthe pale yellow solid isolated was recrystallized from acetone/hexane\nto give  33b  as white crystals (807 mg; 28%).  R f : 0.81 (CHCl 3 /acetone, 3:1); mp\n96–100 °C;  1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 7.3 Hz), 1.26–1.55 (m, 16H, 8 × CH 2 ), 2.39\n(s, 3H, C 4 –CH 3 ), 2.63 (t, 2H, 1′-CH 2 ,  J  = 7.6 Hz), 6.85 (dd, 1H, C 6 –H,  J  = 2.4, 8.7 Hz), 7.02 (d, 1H, C 8 –H,  J  = 2.4 Hz), 7.32 (s, 1H, OH)\nand 7.49 (d, 1H, C 5 –H,  J  = 8.5\nHz); MS (FAB + )  m / z : 633.3\n[50, (2M + H) + ], 317.1 [100, (M + H) + ]; MS (FAB – )  m / z : 631.2 [10,\n(2M – H) − ], 315.1 [100, (M – H) − ]; Acc. MS (FAB + ): 317.2117, C 20 H 29 O 3  requires 317.2117; found C, 75.65; H,\n8.99 C 20 H 28 O 3  requires C, 75.91;\nH, 8.92%.\nCompound  33b  (400\nmg; 1.27 mmol)\nwas sulfamoylated, the crude white solid was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white\nsolid isolated was recrystallized from ethyl acetate/hexane to give  33  as white fine crystals (101 mg; 27%).  R f : 0.55 (CHCl 3 /ethyl acetate, 4:1); mp 118–121\n°C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.85 (t, 3H, CH 3 ,  J  = 7.6 Hz), 1.24–1.47 (m, 16H, 8 × CH 2 ), 2.43\n(s, 3H, C 4 –CH 3 ), 2.58 (t, 2H, 1′-CH 2 ,  J  = 7.3 Hz), 7.25 (d, 1H, C 8 –H,  J  = 2.4 Hz), 7.27 (m, 1H, C 6 –H); 7.87 (d, 1H, C 5 –H,  J  = 8.5 Hz) and 8.13 (s, 2H, NH 2 ); MS (FAB + )  m / z : 791.3 [20, (2M + H) + ],\n396.1 [100, (M + H) + ], 317.1 [30, (M + H – HNSO 2 ) + ]; MS (FAB – )  m / z : 394.1 [100, (M – H) − ], 315.1 [60, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ): 396.1850, C 20 H 30 NO 5 S requires 396.1845; found C, 60.65; H, 7.42; N, 3.12\nC 20 H 29 NO 5 S requires C, 60.74; H,\n7.39; N, 3.54%.\nThis\nwas prepared by general method using K 2 CO 3  (7.1\ng; 51 mmol), water (50 mL), 1-bromoundecane (5.0 mL; 21 mmol), ethyl\n3-oxo-butanoate (2.71 mL; 21.3 mmol), CH 2 Cl 2  (50 mL), and Bu 4 NCl (∼10 g; 43 mmol). The crude\noily residue was purified by flash chromatography (CHCl 3 /hexane, 8:1 to 2:1 gradient) to give  34a  as a pale\nyellow oil (3.25 g; 54%).  R f : 0.69 (CHCl 3 /hexane, 2:1); (Lit. 66  bp 1  145–150 °C);  1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 7.3 Hz), 1.25–1.85 (m, 23H, CH 2 C H 3  and 10 × CH 2 ), 2.22 (s, 3H, CH 3 CO), 3.39 (t, 1H, 2H,  J  = 7.3 Hz) and 4.15 (q, 2H,\nC H 2 CH 3 ,  J  =\n7.3 Hz); MS (FAB + )  m / z : 285.2 [100, (M + H) + ]; MS (FAB – )  m / z : 283.2 [100, (M – H) − ]; Acc. MS (FAB + ): 285.2422, C 17 H 33 O 3  requires 285.2429.\nThis was prepared by general method using\nresorcinol (968 mg; 8.8\nmmol) and  34a  (2.5 g; 8.8 mmol) in the presence of CF 3 COOH (1.4 mL; 18 mmol) and conc. H 2 SO 4  (0.9 mL; 18 mmol). The crude brown solid was purified by flash chromatography\n(CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale brown\nsolid isolated was recrystallized from acetone/hexane to give  34b  as white crystals (722 mg; 29%).  R f : 0.88 (CHCl 3 /acetone, 3:1); mp 74–76\n°C;  1 H NMR (400 MHz; CDCl 3 ) δ H : 0.85 (t, 3H, CH 3 ,  J  = 7.0 Hz),\n1.23–1.41 (m, 18H, 9 × CH 2 ), 2.35 (s, 3H, C 4 -CH 3 ), 2.51 (t, 2H, 1′-CH 2 ,  J  = 7.4 Hz), 6.67 (d, 1H, C 8 –H,  J  = 2.3 Hz), 6.78 (dd, 1H, C 6 –H,  J  = 2.3, 8.6 Hz), 7.59 (d, 1H, C 5 –H,  J  = 8.9 Hz) and 10.39 (s, 1H, OH); MS (FAB + )  m / z : 660.9 [35, (2M + H) + ],\n331.1 [100, (M + H) + ]; MS (FAB – )  m / z : 659.0 [10, (2M – H) − ], 329.2 [100, (M – H) − ]; Acc. MS (FAB + ): 331.2268, C 21 H 31 O 3  requires\n331.2273; found C, 76.10; H, 8.96 C 21 H 30 O 3  requires C, 76.33; H, 9.15%.\nCompound  34b  (200 mg; 0.71 mmol)\nwas sulfamoylated, the crude white solid was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white\nsolid isolated was recrystallized from ethyl acetate/hexane to give  34  as white fine crystals (11 mg; 4%).  R f : 0.49 (CHCl 3 /ethyl acetate, 4:1); mp 117–119\n°C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.87 (t, 3H, CH 3 ,  J  = 7.2 Hz), 1.22–1.45 (m, 18H, 9 × CH 2 ), 2.34\n(s, 3H, C 4 –CH 3 ), 2.59 (t, 2H, 1′-CH 2 ,  J  = 7.3 Hz), 6.89 (d, 1H, C 8 –H,  J  = 2.3 Hz), 7.19 (dd, 1H, C 6 –H,  J  = 2.3, 8.8 Hz); 7.59 (d, 1H, C 5 –H,  J  = 8.9 Hz) and 8.18 (s, 2H, NH 2 ); MS (FAB + )  m / z : 410.3 [100, (M + H) + ]; MS (FAB – )  m / z : 408.3 [100, (M – H) − ]; Acc. MS (FAB + ): 410.1992, C 21 H 32 NO 5 S requires 410.2001; found C, 61.40; H, 7.75; N, 3.16,\nC 21 H 31 NO 5 S requires C, 61.59; H,\n7.63; N, 3.42%.\nThis\nwas prepared by general method using K 2 CO 3  (7.99\ng; 57.8 mmol), water (60 mL), 1-bromododecane (6.0 mL; 24 mmol), ethyl\n3-oxo-butanoate (3.1 mL; 24 mmol), CH 2 Cl 2  (60\nmL), and Bu 4 NCl (∼10 g; 48 mmol). The crude oily\nresidue was purified by distillation under reduced pressure to give  35a  as a pale yellow oil (3.65 g; 51%).  R f : 0.66 (CH 2 Cl 2 ); bp 0.3  159–160\n°C; (Lit. 67  bp 1.1  149–152\n°C);  1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 7.0 Hz),\n1.12–1.89 (m, 25H, CH 2 C H 3  and 11 × CH 2 ), 2.22 (s, 3H, CH 3 CO), 3.53\n(t, 1H, 2H,  J  = 7.0 Hz) and 4.19 (q, 2H, C H 2 CH 3 ,  J  = 7.0 Hz);\nMS (FAB + )  m / z : 299.2\n[100, (M + H) + ]; MS (FAB – )  m / z : 297.2 [100, (M – H) − ]; Acc. MS (FAB + ): 299.2594, C 18 H 35 O 3  requires 299.2586.\nThis was prepared by general method using\nresorcinol (553 mg; 5.02\nmmol),  35a  (1.5 g; 5.0 mmol), and a mixture of CF 3 COOH (0.8 mL; 10 mmol) and conc. H 2 SO 4  (0.6 mL; 10 mmol). The crude brown solid was purified by flash chromatography\n(CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow\nsolid isolated was recrystallized from acetone/hexane to give  35b  as off-white crystals (146 mg; 9%).  R f : 0.74 (CHCl 3 /acetone, 3:1); mp 94–96\n°C;  1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 7.0 Hz),\n1.25–1.63 (m, 20H, 10 × CH 2 ), 2.38 (s, 3H,\nC 4 –CH 3 ), 2.63 (t, 2H, 1′-CH 2 ,  J  = 7.4 Hz), 6.19 (s, 1H), 6.81 (dd, 1H,\nC 6 –H,  J  = 2.3, 8.6 Hz), 6.91 (d,\n1H, C 8 –H,  J  = 2.3 Hz) and 7.48\n(d, 1H, C 5 –H,  J  = 8.9 Hz); MS (FAB + )  m / z : 689.4 [20, (2M +\nH) + ], 345.4 [100, (M + H) + ]; MS (FAB – )  m / z : 343.3 [100, (M –\nH) − ]; Acc. MS (FAB + ): 345.2435, C 22 H 33 O 3  requires 345.2429; found C, 76.60;\nH, 9.22; C 22 H 32 O 3  requires C, 76.70;\nH, 9.36%.\nCompound  35b  (100\nmg; 0.29 mmol)\nwas sulfamoylated, the crude white solid was purified by preparative\nTLC (CHCl 3 /ethyl acetate, 6:1), and the white solid isolated\nwas recrystallized from ethyl acetate/hexane to give  35  as white fine crystals (15 mg; 12%).  R f : 0.36 (CHCl 3 /ethyl acetate, 6:1); mp 157–159 °C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 7.2 Hz),\n1.24–1.48 (m, 20H, 10 × CH 2 ), 2.45 (s, 3H,\nC 4 –CH 3 ), 2.61 (t, 2H, 1′-CH 2 ,  J  = 7.4 Hz), 7.23 (d, 1H, C 8 –H,  J  = 2.3 Hz), 7.27 (dd, 1H, C 6 –H,  J  = 2.3, 8.6 Hz); 7.89 (d, 1H, C 5 –H,  J  = 8.9 Hz) and 8.21 (s, 2H, NH 2 ); MS (FAB + )  m / z : 847.1 [15, (2M + H) + ], 424.1 [100, (M + H) + ], 245.1 [30, (M + H – HNSO 2 ) + ]; MS\n(FAB – )  m / z : 422.1\n[100, (M – H) − ], 343.2 [55, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ): 424.1246, C 22 H 34 NO 5 S requires\n424.1241.\nThis\nwas prepared by general method using K 2 CO 3  (6.3\ng; 46 mmol), water (60 mL), 1-bromotridecane (5.0 mL; 19 mmol), ethyl\n3-oxo-butanoate (2.42 mL; 18.9 mmol), CH 2 Cl 2  (60 mL), and Bu 4 NCl (11.0 g; 37.9 mmol). The crude oily\nresidue was purified by distillation under reduced pressure to give  36a  as a pale yellow oil (2.88 g; 49%).  R f : 0.77 (CHCl 3 ); bp 0.3  153–155\n°C;  1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 7.0 Hz),\n1.12–1.56 (m, 27H, CH 2 C H 3  and 12 × CH 2 ), 2.22 (s, 3H, CH 3 CO), 3.53\n(t, 1H, 2H,  J  = 6.7 Hz) and 4.21 (q, 2H, C H 2 CH 3 ,  J  = 7.0 Hz);\nMS (FAB + )  m / z : 313.3\n[100, (M + H) + ]; MS (FAB – )  m / z : 311.2 [100, (M – H) − ]; Acc. MS (FAB + ): 313.2756, C 19 H 37 O 3  requires 313.2743.\nThis was prepared by general method using\nresorcinol (705 mg; 6.4\nmmol),  36a  (2.0 g; 6.4 mmol), and a mixture of CF 3 COOH (1.0 mL; 13 mmol) and conc. H 2 SO 4  (0.7 mL; 13 mmol). The crude brown solid was purified by flash chromatography\n(CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow\nsolid isolated was recrystallized from acetone/hexane to give  36b  as white crystals (621 mg; 27%).  R f : 0.65 (CHCl 3 /acetone, 3:1); mp 71–72\n°C;  1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 7.0 Hz),\n1.26–1.84 (m, 22H, 11 × CH 2 ), 2.38 (s, 3H,\nC 4 –CH 3 ), 2.62 (t, 2H, 1′-CH 2 ,  J  = 7.4 Hz), 5.87 (s, 1H, OH), 6.81 (dd,\n1H, C 6 –H,  J  = 2.3, 8.7 Hz), 6.86\n(d, 1H, C 8 –H,  J  = 2.3 Hz) and 7.48\n(d, 1H, C 5 –H,  J  = 8.9 Hz); MS (FAB + )  m / z : 359.4 [100, (M +\nH) + ]; MS (FAB – )  m / z : 357.3 [100, (M – H) − ]; Acc.\nMS (FAB + ): 359.2599, C 23 H 35 O 3  requires 359.2586; found C, 77.20; H, 10.00; C 23 H 34 O 3  requires C, 77.05; H, 9.56%.\nCompound  36b  (400 mg; 1.12 mmol)\nwas sulfamoylated, the crude white solid was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white\nsolid isolated was recrystallized from ethyl acetate/hexane to give  36  as white fine crystals (35 mg; 7%).  R f : 0.67 (CHCl 3 /ethyl acetate, 6:1); mp 115–119\n°C; MS (FAB + )  m / z : 438.2 [100, (M + H) + ];  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.84 (t, 3H, CH 3 ,  J  = 7.0 Hz), 1.23–1.44 (m, 22H,\n11 × CH 2 ), 2.42 (s, 3H, C 4 –CH 3 ), 2.58 (t, 2H, 1′-CH 2 ,  J  = 7.8 Hz), 7.26 (d, 1H, C 8 –H,  J  = 2.3 Hz), 7.28 (m, 1H, C 6 –H), 7.88 (d, 1H, C 5 –H,  J  = 8.6 Hz) and 8.21 (s, 2H, NH 2 ); MS (FAB – )  m / z : 436.2 [100, (M – H) − ], 357.2\n[30, (M – H 2 NSO 2 ) − ];\nAcc. MS (FAB + ): 438.2291, C 23 H 36 NO 5 S requires 438.2272; found C, 63.60; H, 7.98; N, 3.17; C 23 H 35 NO 5 S requires C, 63.13; H, 8.06;\nN, 3.20%.\nThis\nwas prepared by general method using K 2 CO 3  (5.6\ng; 43 mmol), water (60 mL), 1-bromotetradecane (5.0 mL; 18 mmol),\nethyl 3-oxo-butanoate (2.3 mL; 18 mmol), CH 2 Cl 2  (60 mL), and Bu 4 NCl (11.0 g; 36.1 mmol). The crude oily\nresidue was purified by distillation under reduced pressure to give  37a  as a pale yellow oil (2.32 g; 23%).  R f : 0.65 (CHCl 3 ); bp 0.3  158–162\n°C; (Lit. 68  bp 0.5  162 °C);  1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88\n(t, 3H, CH 3 ,  J  = 7.0 Hz), 1.20–1.81\n(m, 29H, CH 2 C H 3  and 13 ×\nCH 2 ), 2.17 (s, 3H, CH 3 CO), 3.53 (t, 1H, 2H,  J  = 7.0 Hz) and 4.19 (q, 2H, C H 2 CH 3 ,  J  = 7.0 Hz); MS (FAB + )  m / z : 327.2 [100, (M + H) + ]; MS (FAB – )  m / z : 325.2 [100, (M – H) − ]; Acc.\nMS (FAB + ): 327.2900, C 20 H 39 O 3  requires 327.2899.\nThis was prepared by general method using\nresorcinol (337 mg; 3.1\nmmol),  37a  (1.0 g; 3.1 mmol), and a mixture of CF 3 COOH (0.5 mL; 6.2 mmol) and conc. H 2 SO 4  (0.4 mL; 6.2 mmol). The crude brown residue was purified by flash\nchromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient) to\ngive  37b  as pale yellow waxy solid (472 mg; 41%).  R f : 0.74 (CHCl 3 /acetone, 3:1); mp\n64–66 °C;  1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 7.0 Hz), 1.12–1.82 (m, 24H, 12 × CH 2 ),\n2.38 (s, 3H, C 4 –CH 3 ), 2.62 (t, 2H, 1′-CH 2 ,  J  = 7.4 Hz), 6.21 (s, 1H, OH), 6.79 (dd,\n1H, C 6 –H,  J  = 2.3, 8.6 Hz), 6.84\n(d, 1H, C 8 –H,  J  = 2.3 Hz) and 8.59\n(d, 1H, C 5 –H,  J  = 8.9 Hz); MS (FAB + )  m / z : 373.1 [100, (M +\nH) + ]; MS (FAB – )  m / z : 371.2 [100, (M – H) − ]; Acc.\nMS (FAB + ): 373.2754, C 24 H 37 O 3  requires 373.2743; found C, 77.11; H, 10.20; C 24 H 36 O 3  requires C, 77.38; H, 9.74%.\nCompound  37b  (300 mg; 0.81\nmmol) was sulfamoylated, the crude white solid was purified by flash\nchromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient),\nand the white solid isolated was recrystallized from ethyl acetate/hexane\nto give  37  as white fine crystals (3 mg; 0.8%).  R f : 0.62 (CHCl 3 /ethyl acetate, 4:1);\nmp 119–121 °C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 7.0 Hz), 1.22–1.47 (m, 24H,\n12 × CH 2 ), 2.41 (s, 3H, C 4 –CH 3 ), 2.57 (t, 2H, 1′-CH 2 ,  J  = 7.8 Hz), 7.22 (d, 1H, C 8 –H,  J  = 2.3 Hz), 7.26 (dd, 1H, C 6 –H,  J  = 2.3, 8.6 Hz), 7.79 (d, 1H, C 5 –H,  J  = 8.9 Hz) and 8.20 (s, 2H, NH 2 ); MS (FAB + )  m / z : 452.3 [100, (M + H) + ],\n373.3 [10, (M + H – HNSO 2 ) + ]; MS (FAB – )  m / z : 450.2 [100,\n(M – H)], 371.3 [40, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ): 452.2455, C 24 H 38 NO 5 S requires 452.2471; found C,\n63.74; H, 7.99; N, 3.36 C 24 H 37 NO 5 S requires C, 63.83; H, 8.26; N, 3.10%.\nThis\nwas prepared by general method using K 2 CO 3  (5.7\ng; 41 mmol), water (60 mL), 1-bromopentadecane (5.0 mL; 17 mmol),\nethyl 3-oxo-butanoate (2.2 mL; 17 mmol), CH 2 Cl 2  (60 mL), and Bu 4 NCl (∼10 g; 34 mmol). The crude\noily residue was purified by distillation under reduced pressure to\ngive  38a  as a pale yellow oil (1.78 g; 31%).  R f : 0.67 (CHCl 3 ); bp 0.4  198–202 °C;  1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 7.0 Hz), 1.26–1.79 (m, 29H, CH 2 C H 3  and 16 × CH 2 ), 2.22 (s, 3H, CH 3 CO), 3.53 (t, 2H, 3-H 2 ,  J  = 6.7 Hz),\n3.37 (t, 1H, 2H,  J  = 7.0 Hz) and 4.18 (q, 2H, C H 2 CH 3 ,  J  = 7.0 Hz);\nMS (FAB + )  m / z : 341.2\n[100, (M + H) + ]; MS (FAB – )  m / z : 339.2 [100, (M – H) − ]; Acc. MS (FAB + ): 341.3058, C 21 H 40 O 3  requires 341.3056.\nThis was prepared by general method using\nresorcinol (486 mg; 4.41\nmmol),  38a  (1.5 g; 4.5 mmol), and a mixture of CF 3 COOH (0.7 mL; 8.8 mmol) and conc. H 2 SO 4  (0.5 mL; 8.8 mmol). The crude brown sticky solid was purified by\nflash chromatography (CHCl 3 /acetone gradient, 8:1 to 4:1),\nand the off-white waxy solid isolated was recrystallized from acetone/hexane\nto give  38b  as a white soft solid (123 mg; 0.07%).  R f : 0.86 (CHCl 3 /acetone, 3:1); mp\n59–61 °C;  1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 ,  J  = 7.0 Hz), 1.11–1.80 (m, 26H, 13 × CH 2 ),\n2.38 (s, 3H, C 4 –CH 3 ), 2.53 (t, 2H, 1′-CH 2 ,  J  = 6.6 Hz), 5.75 (s, 1H, OH), 6.79 (dd,\n1H, C 6 –H,  J  = 2.3, 8.6 Hz), 6.84\n(d, 1H, C 8 –H,  J  = 2.3 Hz) and 7.48\n(d, 1H, C 5 –H,  J  = 8.6 Hz); MS (FAB + )  m / z : 387.3 [100, (M +\nH) + ]; MS (FAB – )  m / z : 385.3 [100, (M – H) − ]; Acc.\nMS (FAB + ): 387.2892, C 25 H 39 O 3  requires 387.2899.\nCompound  38b  (90 mg; 0.23\nmmol) was sulfamoylated, the crude white solid was purified by preparative\nTLC (CHCl 3 /ethyl acetate gradient, 6:1), and the white\nsolid isolated was recrstallized from ethyl acetate/hexane to give  38  as a white fine solid (21 mg; 19%).  R f : 0.64 (CHCl 3 /ethyl acetate, 4:1); mp 114–116\n°C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.85 (t, 3H, CH 3 ,  J  = 7.0 Hz), 1.14–1.44 (m, 26H, 13 × CH 2 ),\n2.43 (s, 3H, C 4 –CH 3 ), 2.58 (t, 2H, 1′-CH 2 ,  J  = 7.4 Hz), 7.25 (d, 1H, C 8 –H,  J  = 2.3 Hz), 7.27 (dd, 1H, C 6 –H,  J  = 2.3, 8.6 Hz), 7.87 (d, 1H, C 5 –H,  J  = 8.6 Hz) and 8.16 (s, 2H, NH 2 ); MS (FAB + )  m / z : 466.3 [100, (M + H) + ], 387.3 [10, (M + H – HNSO 2 ) + ]; MS (FAB – )  m / z : 464.2 [100, (M – H) − ], 385.3 [40, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ): 466.2617, C 25 H 40 NO 5 S requires 466.2626; found C, 64.00; H, 8.82; N, 3.26;\nC 25 H 39 NO 5 S requires C, 64.48; H,\n8.44; N, 3.01%.\nThis was prepared by general method using resorcinol\n(2.0 g; 18 mmol),\nethyl 2-chloro-3-oxo-butanoate (2.99 g; 18 mmol), and a mixture of\nCF 3 COOH (2.27 mL; 36.3 mmol) and conc. H 2 SO 4  (1.83 mL; 36.3 mmol). The crude brown solid was purified\nby flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient),\nand the yellow solid isolated was recrystallized from acetone/hexane\nto give  39a  as off-white crystals (692 mg; 18%).  R f : 0.72 (CHCl 3 /acetone, 3:1); mp\n250–253 °C (Lit. 69  mp 250 °C);  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 2.09 (s, 3H, CH 3 ), 6.76 (d, 1H, C 8 –H,  J  = 2.4 Hz), 6.86 (dd, 1H, C 6 –H,  J  = 2.4, 8.8 Hz), 7.69 (d, 1H, C 5 –H,  J  = 8.8 Hz) and 10.68 (s, 1H,\nOH); MS (FAB + )  m / z : 211.1\n[100, (M( 35 Cl) + H) + ]; MS (FAB – )  m / z : 209.1 [100, (M( 35 Cl) – H) − ]; Acc. MS (FAB + )  m / z : 211.0178 C 10 H 8 35 ClO 3  requires 211.0162 and 213.0152 C 10 H 8 37 ClO 3  requires 213.0132;\nfound C, 57.30; H, 3.39; C 10 H 7 ClO 3  requires C, 57.03; H, 3.35%.\nCompound  39a  (400 mg; 1.9 mmol)\nwas sulfamoylated, the crude white solid was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white\nsolid isolated was recrystallized from ethyl acetate/hexane to give  39  as white fine crystals (164 mg; 30%).  R f : 0.30 (CHCl 3 /ethyl acetate, 4:1); mp 182–186\n°C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 2.59 (s, 3H, CH 3 ), 7.35 (dd, 1H,\nC 6 –H,  J  = 2.1, 8.8 Hz), 7.39 (d,\n1H, C 8 –H,  J  = 2.1 Hz), 7.98 (d,\n1H, C 5 –H,  J  = 8.8 Hz) and 8.29\n(s, 2H, NH 2 ); MS (FAB + )  m / z : 290.0 [100, (M( 37 Cl) + H) + ]; MS\n(FAB – )  m / z : 288.1\n[100, (M( 35 Cl) – H) − ], 209.1 [50,\n(M – H 2 NSO 2 ) − ]; Acc.\nMS (FAB + )  m / z : 290.9860,\nC 10 H 9 37 ClNO 5 S requires\n290.9782 and 288.9814 C 10 H 9 35 ClNO 5 S requires 291.9813; found C, 41.50; H, 2.62; N, 4.64; C 10 H 8 ClNO 5 S requires C, 41.46; H, 2.78;\nN, 4.84%.\nThis was prepared by general method using resorcinol\n(2.13 g; 19.4\nmmol), ethyl 3-oxo-2-phenylbutanoate (4.0 g; 19 mmol), and a mixture\nof CF 3 COOH (3.0 mL; 39 mmol) and conc. H 2 SO 4  (2.0 mL; 39 mmol). The crude yellow solid was purified by\nrecrystallization from ethanol to give  40a  as yellow\nneedles (4.1 g; 83%).  R f : 0.59 (CHCl 3 /acetone, 3:1); mp 226–228 °C; (Lit. 70  mp 226–228 °C);  1 H NMR\n(400 MHz; DMSO- d 6 ) δ H : 2.21 (s, 3H, CH 3 ), 6.75 (d, 1H, C 8 –H,  J  = 2.4 Hz), 6.84 (dd, 1H, C 6 –H,  J  = 2.4, 8.6 Hz), 7.27–7.47 (m, 5H, Ph–H),\n7.66 (d, 1H, C 5 –H,  J  = 8.8 Hz)\nand 10.67 (s, 1H, OH); MS (FAB + )  m / z : 505.1 [10, (2M + H) + ], 253.0 [100, (M + H) + ]; MS (FAB – )  m / z : 503.1 [10, (2M – H) − ], 251.1\n[100, (M – H) − ]; Acc. MS (FAB + ): 253.0798, C 16 H 12 O 3  requires 253.0786;\nfound C, 76.10; H, 4.84; C 16 H 12 O 3  requires C, 76.18; H, 4.79%.\nCompound  40a  (400 mg; 1.6 mmol)\nwas sulfamoylated, the crude white solid was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white\nsolid isolated was recrystallized from ethyl acetate/hexane to give  40  as white fine crystals (246 mg; 52%).  R f : 0.36 (CHCl 3 /ethyl acetate, 4:1); mp 184–187\n°C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 2.28 (s, 3H, CH 3 ), 7.31–7.38\n(m, 2H, C 6 –H and C 8 –H), 7.40–7.49\n(m, 5H, Ph–H), 7.95 (d, 1H, C 5 –H,  J  = 8.8 Hz) and 8.27 (s, 2H, NH 2 ); MS (FAB + )  m / z : 332.0 [100, (M +\nH) + ], 253.0 [15, (M + H – HNSO 2 ) + ]; MS (FAB – )  m / z : 330.1 [100, (M – H) − ], 251.1\n[60, (M – H 2 NSO 2 ) − ];\nAcc. MS (FAB + ): 332.0589, C 16 H 14 NO 5 S requires 332.0593; found C, 58.00; H, 3.94; N, 4.21; C 16 H 13 NO 5 S requires C, 58.00; H, 3.95;\nN, 4.23%.\nThis was prepared by general method using resorcinol\n(1.99 g; 18.2\nmmol), ethyl 2-benzyl-3-oxo-butanoate (4.0 g; 18 mmol), and a mixture\nof CF 3 COOH (2.8 mL; 36 mmol) and conc. H 2 SO 4  (1.8 mL; 36 mmol). The crude brown solid was purified by\nrecrystallization from ethanol to give  41a  as white crystals\n(4.35 g; 90%).  R f : 0.79 (CHCl 3 /acetone, 3:1); mp 230–232 °C (Lit. 71  mp 226–227 °C);  1 H NMR (400 MHz;\nDMSO- d 6 ) δ H : 2.39 (s,\n3H, CH 3 ), 3.92 (s, 2H, CH 2 Ph), 6.71 (d, 1H,\nC 8 –H,  J  = 2.4 Hz), 6.80 (dd, 1H,\nC 6 –H,  J  = 2.4, 8.8 Hz), 7.15–7.28\n(m, 5H, Ph–H), 7.64 (d, 1H, C 5 –H,  J  = 8.8 Hz) and 10.48 (s, 1H, OH); MS (FAB + )  m / z : 532.9 [10, (2M + H) + ],\n267.1 [100, (M + H) + ]; MS (FAB – )  m / z : 265.1 [100, (M – H)]; Acc.\nMS (FAB + ): 267.1026, C 17 H 15 O 3  requires 267.1012; found C, 76.60; H, 5.34; C 17 H 14 O 3  requires C, 76.68; H, 5.30%.\nCompound  41a  (400 mg; 1.5 mmol)\nwas sulfamoylated, the crude white solid was purified by flash chromatography\n(CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white\nsolid isolated was recrystallized from THF/hexane to give  41  as white fine crystals (279 mg; 54%).  R f : 0.57 (CHCl 3 /ethyl acetate, 4:1); mp 168–170 °C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 2.39 (s, 3H, CH 3 ), 3.99 (s, 2H, PhC H 2 ), 7.17–7.31 (m, 6H, C 6 –H and\nPh–H), 7.32 (d, 1H, C 8 –H,  J  = 2.0 Hz), 7.92 (d, 1H, C 5 –H,  J  = 8.6 Hz) and 8.22 (s, 2H, NH 2 ); MS (FAB + )  m / z : 346.1 [100, (M + H) + ];\nMS (FAB – )  m / z :\n344.1 [100, (M – H) − ], 265.1 [60, (M –\nH 2 NSO 2 ) − ]; Acc. MS (FAB + ): 346.0755, C 17 H 16 NO 5 S requires\n346.0749; found C, 59.10; H, 4.39; N, 4.04; C 17 H 15 NO 5 S requires C, 59.12; H, 4.38; N, 4.06%.\nThis was prepared by general method using\nK 2 CO 3  (8.97 g; 64.85 mmol), water (50 mL), (2-bromoethyl)benzene\n(5.0\nmL; 27 mmol), ethyl 3-oxo-butanoate (3.44 mL; 27 mmol), CH 2 Cl 2  (50 mL), and Bu 4 NCl (∼10 g; 27 mmol).\nThe crude oily residue was purified by flash chromatography (CHCl 3 ) to give  42a  as a pale yellow oil (2.17 g; 34%).\n(Lit. 72  bp 1.4  167–168\n°C);  R f : 0.78 (CHCl 3 );  1 H NMR (400 MHz; CDCl 3 ) δ H : 1.25\n(t, 3H, CH 2 C H 3 ,  J  = 6.7 Hz), 2.29 (s, 3H, CH 3 ), 3.02 (q, 2H,\nC H 2 CH 2 Ph,  J  = 7.1 Hz), 3.71 (t, 1H, CH 2 ,  J  = 7.3\nHz), 3.95 (t, 2H, CH 2 Ph,  J  = 7.1 Hz),\n4.11 (q, 2H, C H 2 CH 3 ,  J  = 7.1 Hz) and 7.16–7.34 (m, 5H, Ph–H); MS\n(FAB + )  m / z : 235.0 [100,\n(M + H) + ]; Acc. MS (FAB + ): 235.1335, C 14 H 19 O 3  requires 235.1334.\nThis was prepared by general method using\nresorcinol (705\nmg; 6.4 mmol),  42a  (1.5 g; 6.4 mmol), and a mixture of\nCF 3 COOH (1 mL; 13 mmol) and conc. H 2 SO 4  (0.7 mL; 13 mmol). The crude brown solid was purified by flash chromatography\n(CHCl 3 /acetone gradient, 8:1 to 4:1), and the white solid\nisolated was recrystallized from acetone/hexane to give  42b  as gray crystals (746 mg; 42%).  R f :\n0.80 (CHCl 3 /acetone, 3:1); mp 175–178 °C  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 2.16 (s, 3H, CH 3 ), 2.73 (t, 2H, C H 2 CH 2 Ph,  J  = 5.5 Hz), 2.79\n(t, 2H, PhC H 2 ,  J  = 5.2\nHz), 6.69 (d, 1H, C 8 –H,  J  = 2.4\nHz), 6.78 (dd, 1H, C 6 –H,  J  = 2.4,\n8.5 Hz), 7.16–7.29 (m, 5H, Ph–H), 7.56 (d, 1H, C 5 –H,  J  = 8.8 Hz) and 10.42 (s, 1H,\nOH); MS (FAB + )  m / z : 561.1\n[10, (2M + H) + ], 281.0 [100, (M + H) + ]; MS (FAB – )  m / z : 279.1 [100,\n(M – H)]; Acc. MS (FAB + ): 281.1182, C 18 H 17 O 3  requires 281.1178; found C, 77.35; H,\n5.95; C 18 H 16 O 3  requires C, 77.12;\nH, 5.75%.\nCompound  42b  (400 mg; 1.43\nmmol) was sulfamoylated, the crude white solid was purified by flash\nchromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient),\nand the white solid isolated was recrystallized from ethyl acetate/hexane\nto give  42  as white fine crystals (132 mg; 26%).  R f : 0.54 (CHCl 3 /ethyl acetate, 4:1);\nmp 196–198 °C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 2.21 (s, 3H, CH 3 ), 2.76 (t, 2H, C H 2 CH 2 Ph,  J  = 7.3 Hz), 2.87 (t, 2H, PhC H 2 ,  J  = 7.9 Hz), 7.17–7.27 (m,\n7H, C 6 –H, C 8 –H, and Ph–H),\n7.83 (d, 1H, C 5 –H,  J  = 8.8 Hz)\nand 8.19 (s, 2H, NH 2 ); MS (FAB + )  m / z : 360.0 [100, (M + H) + ]; MS (FAB – )  m / z : 358.0 [100,\n(M – H) − ], 279.1 [40, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ):\n360.0917, C 18 H 18 NO 5 S requires 360.0906;\nfound C, 60.00; H, 4.81; N, 3.89; C 18 H 17 NO 5 S requires C, 60.16; H, 4.77; N, 3.90%.\nThis was prepared by general method using\nK 2 CO 3  (16.7 g; 0.12 mol), water (60 mL), 1-bromo-3-phenylpropane\n(10.0\nmL; 50.2 mmol), ethyl 3-oxo-butanoate (6.5 mL; 50.2 mmol), CH 2 Cl 2  (60 mL), and Bu 4 NCl (28 g; 0.1 mol).\nThe crude oily residue was purified by flash chromatography (CHCl 3 /hexane, 10:1) to give  43a  as a colorless oil\n(4.92 g; 39%).  R f : 0.61 (CHCl 3 /hexane, 10:1);  1 H NMR (400 MHz; CDCl 3 ) δ H : 1.26 (t, 3H, CH 2 C H 3 ,  J  = 7.0 Hz), 2.19 (s, 3H, CH 3 ), 1.85–2.61\n(m, 6H, CH 2 ), 2.64 (t, 1H, 2H,  J  = 7.8\nHz), 4.21 (q, 2H, C H 2 CH 3 ,  J  = 7.0 Hz) and 7.15–7.29 (m, 5H, Ph–H);\nMS (FAB + )  m / z : 249.1\n[100, (M + H) + ]; MS (FAB – )  m / z : 247.1 [100, (M – H) − ]; Acc. MS (FAB + ): 249.1491, C 15 H 21 O 3  requires 249.1491.\nThis was prepared by general method using\nresorcinol (443\nmg; 4.03 mmol),  43a  (1.0 g; 4.0 mmol), and a mixture\nof CF 3 COOH (0.6 mL; 8.1 mmol) and conc. H 2 SO 4  (0.4 mL; 8.1 mmol). The crude orange solid was purified by\nflash chromatography (CHCl 3 /acetone gradient, 8:1 to 4:1),\nand the white solid isolated was recrystallized from THF/hexane to\ngive  43b  as pale green crystals (275 mg; 22%).  R f : 0.76 (CHCl 3 /acetone, 3:1); mp\n189–191 °C; MS (FAB + )  m / z : 589.2 [10, (2M + H) + ], 295.1 [100, (M + H) + ]; MS (FAB – )  m / z : 293.1 [100, (M – H) − ]; Acc.\nMS (FAB + ): 295.1675, C 19 H 19 O 3  requires 295.1680;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 1.71 (quintet, 2H, CH 2 C H 2 CH 2 Ph,  J  = 7.8 Hz), 2.13 (s, 3H, CH 3 ), 2.54 (t, 2H, C H 2 CH 2 CH 2 Ph,  J  =\n7.8 Hz), 2.63 (t, 2H, CH 2 CH 2 C H 2 Ph,  J  = 7.4 Hz), 6.82 (d, 1H, C 8 –H,  J  = 2.4 Hz), 7.13–7.27\n(m, 6H, C 6 –H and Ph–H), 7.42 (d, 1H, C 5 –H,  J  = 8.8 Hz) and 10.25 (s, 1H,\nOH); found C, 77.13; H, 6.28; C 19 H 18 O 3  requires C, 77.53; H, 6.16%.\nCompound  43b  (230 mg; 0.78\nmmol) was sulfamoylated, the crude white solid was purified by flash\nchromatography (CHCl 3 /ethyl acetate gradient, 8:1 to 2:1),\nand the white solid isolated was recrystallized from THF/hexane to\ngive  43  as white crystals (62 mg; 21%).  R f : 0.54 (CHCl 3 /ethyl acetate, 4:1); mp\n154–156 °C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 1.76 (pentet, 2H, CH 2 C H 2 CH 2 Ph,  J  = 8.2 Hz), 2.49 (s, 3H, CH 3 ), 2.62 (t, 2H, C H 2 CH 2 CH 2 Ph,  J  =\n8.2 Hz), 2.67 (t, 2H, CH 2 CH 2 C H 2 Ph,  J  = 7.4 Hz), 7.15–7.39 (m,\n7H, C 8 –H, C 6 –H and Ph–H),\n7.87 (d, 1H, C 5 –H,  J  = 8.8 Hz)\nand 8.19 (s, 2H, NH 2 ); MS (FAB + )  m / z : 374.0 [100, (M + H) + ]; MS (FAB – )  m / z : 372.1 [100,\n(M – H) − ], 293.1 [40, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ):\n374.1060, C 19 H 20 NO 5 S requires 374.1062;\nfound C, 61.30; H, 4.94; N, 3.49; C 19 H 19 NO 5 S requires C, 61.11; H, 5.13; N, 3.75%.\nThis was prepared by general method using\nK 2 CO 3  (7.5 g; 54 mmol), water (50 mL), cyclohexylmethyl\nbromide (4.0 mL; 23 mmol), ethyl 3-oxo-butanoate (2.9 mL; 23 mmol),\nCH 2 Cl 2  (50 mL) and Bu 4 NCl (∼10\ng; 23 mol). The crude pale yellow oil was purified by flash chromatography\n(CHCl 3 ) to give  44a  as a pale yellow oil (1.44\ng; 28%). (Lit. 73  bp 19  166 °C);  R f : 0.58 (CHCl 3 );  1 H NMR\n(400 MHz; CDCl 3 ) δ H : 1.08–1.34\n(m, 11H, cyclohexyl-H), 1.27 (t, 3H, CH 2 C H 3 ,  J  = 7.0 Hz), 1.69 (t, 2H, CH 2 ,  J  = 7.0 Hz), 2.22 (s, 3H, CH 3 ), 3.53\n(t, 1H, 2H,  J  = 7.4 Hz) and 4.21 (q, 2H, C H 2 CH 3 ,  J  = 7.0 Hz);\nMS (FAB + )  m / z : 227.3\n[100, (M + H) + ]; MS (FAB – )  m / z : 225.3 [100, (M – H) − ]; Acc. MS (FAB + ): 227.1632, C 13 H 23 O 3  requires 227.1647.\nThis was prepared by general method using\nresorcinol (487\nmg; 4.42 mmol),  44a  (1.0 g; 4.4 mmol), and a mixture\nof CF 3 COOH (0.7 mL; 8.8 mmol) and conc. H 2 SO 4  (0.5 mL; 8.8 mmol). The crude orange solid was purified by\nflash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient),\nand the white solid isolated was recrystallized from THF/hexane to\ngive  44b  as fine white crystals (409 mg; 34%).  R f : 0.74 (CHCl 3 /acetone, 3:1); mp\n193–196 °C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 1.11–1.91 (m, 11H, cyclohexyl-H),\n2.35 (s, 3H, CH 3 ), 2.43 (d, 2H, CH 2 ,  J  = 7.0 Hz), 6.68 (d, 1H, C 8 –H,  J  = 2.3 Hz), 6.79 (dd, 1H, C 6 –H,  J  = 2.3, 8.6 Hz), 7.59 (d, 1H, C 5 –H,  J  = 8.6 Hz) and 10.21 (s, 1H, OH); MS (FAB + )  m / z : 545.3 [15, (2M + H) + ],\n273.2 [100, (M + H) + ]; MS (FAB – )  m / z : 271.2 [100, (M – H) − ]; Acc. MS (FAB + ): 273.1491, C 17 H 21 O 3  requires 273.1492; found C, 74.80; H, 7.47; C 17 H 20 O 3  requires C, 74.97; H, 7.40%.\nCompound  44b  (300 mg; 1.10\nmmol) was sulfamoylated, the crude white solid was purified by flash\nchromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient),\nand the white solid isolated was recrystallized from ethyl acetate/hexane\nto give  44  as white crystals (46 mg; 12%).  R f : 0.55 (CHCl 3 /ethyl acetate, 4:1); mp\n170–171 °C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 1.22–1.31 (m, 11H, cyclohexyl-H),\n2.06 (s, 3H, CH 3 ), 2.58 (d, 2H, CH 2 ,  J  = 7.0 Hz), 7.32–7.35 (m, 2H, C 8 –H\nand C 6 –H), 7.93 (d, 1H, C 5 –H,  J  = 8.6 Hz) and 8.39 (s, 2H, NH 2 ); MS (FAB + )  m / z : 352.0 [100, (M +\nH) + ]; MS (FAB – )  m / z : 350.0 [100, (M – H) − ], 271.1\n[45, (M – H 2 NSO 2 ) − ];\nAcc. MS (FAB + ): 352.1214, C 17 H 22 NO 5 S requires 352.1218; found C, 58.30; H, 5.86; N, 3.79; C 17 H 21 NO 5 S requires C, 58.10; H, 6.02;\nN, 3.99%.\nThis was prepared by general method using K 2 CO 3  (8.68 g; 62.8 mmol), water (60 mL), 1-bromo-2-cyclohexylethane\n(5.0\nmL; 26.2 mmol), ethyl 3-oxo-butanoate (3.34 mL; 26.2 mmol), CH 2 Cl 2  (50 mL), and Bu 4 NCl (7.3 g; 26 mmol).\nThe crude orange oily residue was purified by flash chromatography\n(CHCl 3 ) to give  45a  as a pale yellow oil (850\nmg; 14%). (Lit. 73  bp 19  175 °C);  R f : 0.72 (CHCl 3 );  1 H NMR\n(400 MHz; CDCl 3 ) δ H : 1.19–1.66\n(m, 13H, cyclohexyl-H and CH 2 ), 1.27 (t, 3H, CH 2 C H 3 ,  J  = 7.0 Hz), 1.80–1.87\n(m, 2H, CH 2 ), 2.22 (s, 3H, CH 3 ), 3.35 (t, 1H,\n2H,  J  = 7.4 Hz) and 4.19 (q, 2H, C H 2 CH 3 ,  J  = 7.0 Hz); MS (FAB + )  m / z : 241.3 [100, (M +\nH) + ]; MS (FAB – )  m / z : 239.3 [100, (M – H) − ]; Acc.\nMS (FAB + ): 241.1804, C 14 H 25 O 3  requires 241.1804.\nThis was prepared by general method using\nresorcinol (343\nmg; 3.12 mmol),  45a  (750 mg; 3.12 mmol), and a mixture\nof CF 3 COOH (0.5 mL; 6.2 mmol) and conc. H 2 SO 4  (0.4 mL; 6.2 mmol). The crude orange solid was purified by\nflash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient),\nand the white solid isolated was recrystallized from THF/hexane to\ngive  45b  as white crystals (352 mg; 39%).  R f : 0.79 (CHCl 3 /acetone, 3:1); mp 148–151\n°C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 1.11–1.73 (m, 11H, cyclohexyl-H), 2.34\n(s, 3H, CH 3 ), 2.51–2.53 (m, 4H, CH 2 CH 2 ), 6.67 (d, 1H, C 8 –H,  J  = 2.3 Hz), 6.78 (dd, 1H, C 6 –H,  J  = 2.3, 8.6 Hz), 7.59 (d, 1H, C 5 –H,  J  = 8.9 Hz) and 10.38 (s, 1H, OH); MS (FAB + )  m / z : 572.9 [10, (2M + H) + ], 287.1 [100,\n(M + H) + ]; MS (FAB – )  m / z : 571.1 [10, (2M – H) − ], 285.2 [100, (M – H) − ]; Acc. MS (FAB + ): 287.1639, C 18 H 23 O 3  requires\n287.1647; found C, 75.50; H, 7.67; C 18 H 22 O 3  requires C, 75.50; H, 7.74%.\nCompound  45b  (250 mg; 0.87\nmmol) was sulfamoylated, the crude white solid was purified by flash\nchromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient),\nand the white solid isolated was recrystallized from ethyl acetate/hexane\nto give  45  as white fine crystals (155 mg; 49%).  R f : 0.47 (CHCl 3 /ethyl acetate, 4:1);\nmp 179–181 °C;  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 1.19–1.78 (m,\n11H, cyclohexyl-H), 2.41 (s, 3H, CH 3 ), 2.49–2.59\n(m, 4H, CH 2 CH 2 ), 7.25–7.28 (m, 2H, C 8 –H and C 6 –H), 7.87 (d, 1H, C 5 –H,  J  = 8.6 Hz) and 8.20 (s, 2H, NH 2 ); MS (FAB + )  m / z : 366.0 [100, (M + H) + ]; MS (FAB – )  m / z : 364.0 [100, (M – H) − ], 285.1 [40, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ): 366.1319, C 18 H 24 NO 5 S requires 366.1297; found C, 59.10; H, 6.31; N, 3.62;\nC 18 H 23 NO 5 S requires C, 59.16; H,\n6.34; N, 3.83%.\nTo a CH 2 Cl 2  (100\nmL) solution of\n2,4-dihydroxyacetophenone (5.0 g; 33 mmol; 1 equiv), tetrabutylammonium\nhydrogensulphate (300 mg; 0.88 mmol; 0.03 equiv), and 20% aq K 2 CO 3  (100 mL) was added 4-methoxyphenylacetyl chloride\n(6.7 g; 36 mmol; 1.1 equiv) CH 2 Cl 2  (30 mL) dropwise\nover 30 min and stirred for 4 h at rt. The organic layer was separated,\nwashed with water (3 × 200 mL), dried, and concentrated. The\ncrude pale brown syrup was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 4:1 gradient), and the pale yellow\nsolid isolated was recrystallized from THF/hexane to give  46a  as white crystals (1.2 g; 13%).  R f :\n0.68 (UV visible and fluorescent) (ethyl acetate/hexane, 1:1); mp\n230–232 °C (Lit. 74  mp 233–234\n°C);  1 H NMR (400 MHz; DMSO- d 6 ) δ H : 2.60 (s, 3H, CH 3 ), 3.81\n(s, 3H, OCH 3 ), 6.63 (dd, 1H, C 6 –H,  J  = 2.3, 8.9 Hz), 6.71 (d, 1H, C 8 –H,  J  = 2.3 Hz), 6.90 (d, 2H, Ph-2,6-H 2 ,  J  = 8.6 Hz), 7.29 (d, 2H, Ph-3,5-H 2 ,  J  = 8.6 Hz), 7.72 (d, 1H, C 5 –H,  J  = 8.9 Hz) and 12.42 (s, 1H, OH); MS (FAB + )  m / z : 283.2 [100, (M + H) + ];\nMS (FAB – )  m / z :\n281.2 [100, (M – H) − ]; Acc. MS (FAB + ): 283.0898, C 17 H 15 O 4  requires 283.0892;\nfound C, 71.98; H, 5.36; C 17 H 14 O 4  requires C, 72.33; H, 5.00%.\nUpon sulfamoylation, compound  46a  (500 mg; 1.77 mmol) gave a crude white solid, which was fractionated\nby flash chromatography (CHCl 3 /ethyl acetate 8:1 to 2:1\ngradient). The white solid isolated was recrystallized from ethyl\nacetate/hexane to give  46  as white fine leaves (331 mg;\n52%).  R f : 0.86 (CHCl 3 /ethyl\nacetate, 4:1); mp 129–132 °C;  1 H NMR (400 MHz;\nDMSO- d 6 ) δ H : 2.77 (s,\n3H, CH 3 ), 3.75 (s, 3H, OCH 3 ), 6.93 (d, 2H, Ph-2,6-H 2 ,  J  = 8.6 Hz), 7.31 (d, 2H, Ph-3,5-H 2 ,  J  = 8.6 Hz), 7.35 (dd, 1H, C 6 –H,  J  = 1.9, 8.9 Hz), 7.48 (d, 1H, C 8 –H,  J  = 1.9 Hz), 8.21 (d, 1H, C 5 –H,  J  = 8.9 Hz), 8.24 (s, 2H, NH 2 ); MS (FAB + )  m / z : 362.1 [100, (M + H) + ]; MS (FAB – )  m / z : 361.2 [100, (M – H) − ]; Acc. MS (FAB + ): 362.0705, C 17 H 16 NO 6 S requires 362.0698; found C, 56.30; H, 4.21; N, 3.78;\nC 17 H 15 NO 6 S requires C, 56.50; H,\n4.18; N, 3.88%. ref. ( 45 )","source_license":"CC-BY-4.0","license_restricted":false}