C-3- and C-4-Substituted Bicyclic Coumarin Sulfamates as Potent Steroid Sulfatase Inhibitors.

The compounds synthesized in this work fall into two different series: (i) those with an alkyl group of increasing carbon chain length or other functionalities at the C-4 position of the coumarin ring ( A , Figure 3 ) and (ii) those with an alkyl group of increasing carbon chain length or other functionalities at the C-3 position and with a methyl group at the C-4 position of the coumarin ring ( B , Figure 3 ). General structures of bicyclic coumarin sulfamates: A : 4-substituted series, B : 3,4-disubstituted series. We employed β-keto esters as starting materials for synthesizing coumarins with a substituent at the 3-position, and this also leads to a 4-methyl substituent. Because 4-methylcoumarin 7- O -sulfamate (COUMATE) is more active as an STS inhibitor than unsubstituted coumarin 7- O -sulfamate, we retained this 4-substituted group, which imbues good activity. 18 , 19 Thus, to study further the SAR of COUMATE, we ideally needed to keep this 4-methyl group for comparison while we explored different substituents at the 3-position. Apart from coumarin 46a , the bicyclic ring of other parent coumarins was constructed by the Pechmann synthesis of hydroxyl coumarins. For our purposes, this route was preferred because the target structures can be prepared with relative ease by condensing resorcinol with an appropriate β-keto ester. The only synthetic hurdle to overcome is the synthesis of the various β-keto esters required because most of them are not available commercially. The 7-hydroxycoumarins synthesized are subsequently sulfamoylated with freshly prepared sulfamoyl chloride to form the corresponding coumarin sulfamates. The alkanoyl acetate esters required as starting material for the coumarins in the 4-alkyl series ( A , Figure 3 ) were synthesized by treating the inexpensive ethyl potassium malonate with the corresponding acid chloride in the presence of magnesium chloride (MgCl 2 ), triethylamine (Et 3 N), and acetonitrile (CH 3 CN) as the solvent ( Scheme 1 ). 31 This method has the advantage of being relatively safe, clean, economical, and suitable for scaling up with the product produced in high yield and purity, which is free from 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 ethyl 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, and AlCl 3 . 32 The number of equivalents of reagents used in the reaction determines the yield of the product obtained. For aromatic acid chlorides which have electron-withdrawing substituents such as fluoro, chloro, or nitro groups, 2.1 equiv of potassium ethyl malonate, 2.5 equiv of MgCl 2 , and 2.2 equiv of Et 3 N are optimal, and the yield is around 90%. On the other hand, aliphatic acid chlorides or aromatic acid chlorides containing electron-donating substituents generate side products, which are minimized by employing extra equivalent of Et 3 N to obtain the alkanoyl acetate in high yield. (i) SOCl 2 /tetrahydrofuran (THF), reflux; (ii) (a) MeCN, MgCl 2 , Et 3 N, 10–25 °C, 2.5 h, (b) RCOCl, Et 3 N, 0 °C, 0.5 h, room temperature (rt), 12 h; (iii) RCHO, SnCl 2 , CH 2 Cl 2 , rt, 3 h. β-Ketoesters were also prepared efficiently by reacting the corresponding aldehyde with ethyl diazoacetate in the presence of a catalytic amount of tin(II) chloride (SnCl 2 ) ( Scheme 1 ). The mechanism of the reaction is likely to proceed via a betaine intermediate, followed by a preferential migration of the aldehyde hydrogen to the β-carbon i.e., a 1,2-hydride shift producing the required β-keto ester and N 2 as products. The two most noteworthy aspects of this method are its selectivity and the mild conditions involved. The reaction is insensitive to atmosphere, is complete between 1 and 2 h at room temperature, and can be catalyzed by various Lewis acids, such 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 used, CH 2 Cl 2 is often employed because it gives the best results and can be easily removed. The α-alkylacetoacetates required for the synthesis of coumarins in the 3-substituted-4-methyl series were prepared conveniently by treating a solution of ethyl acetoacetate in CH 2 Cl 2 with the corresponding alkyl bromide in the presence of potassium carbonate (K 2 CO 3 ) and tetrabutylammonium chloride (Bu 4 NCl) ( Scheme 2 ). 34 (i) RBr, K 2 CO 3 , H 2 O, Bu 4 NCl, CH 2 Cl 2 , reflux, 40 h. Pechmann synthesis of coumarins with a β-keto ester and resorcinol was carried out in the presence of an equimolar mixture of trifluoroacetic acid (CF 3 COOH) and concentrated sulfuric acid (H 2 SO 4 ) warmed from ice-water temperature to room temperature ( Schemes 3 and 4 ). The use of a 1:1 mixture of conc. H 2 SO 4 and conc. CF 3 COOH as the condensing agent for the Pechmann synthesis of coumarins was first described by Hua et al., 35 and, in our hands, such a mixture has been found to be as effective as using conc. H 2 SO 4 alone, which is playing a role as a catalyst. The role of conc. CF 3 COOH in this reaction is not entirely clear, although it might be acting as an organic solvent and lowering the viscosity of the reaction mixture, rendering the stirring process more efficient. (i) Conc. H 2 SO 4 /conc. CF 3 COOH, 3 h, 0 °C to rt, (ii) anhydrous dimethylformamide (DMF), NaH, N 2 , 0 °C and H 2 NSO 2 Cl (∼5 equiv), 0 °C to rt. (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 and H 2 NSO 2 Cl (∼5 equiv), 0 °C to rt. The sulfamoylation reaction was performed by reacting the hydroxyl coumarins with an excess of (∼5 equiv) sulfamoyl chloride after treating with 1 equiv of NaH as described previously by Woo et al. 36

Docking studies were conducted to explore potential interactions between the substituted bicyclic coumarin derivatives and the STS active site, in a similar fashion to those carried out for STX64/Irosustat and related series members. 16 They show that the two most active compounds 29 and 41 are placed in a very similar fashion to the irreversible STS inhibitor Irosustat, with the sulfamoyl group in close proximity and opposite to the catalytic FGly 75 ( Figure 5 ), suggesting that a putative sulfamoyl group transfer could also readily occur that might lead to similar irreversible inhibition (although note that no experiments were conducted to explore the reversibility/irreversibility of 29 and 41 against STS). Residue V486 on one side and residues L103 and V177 on the other sandwich the bicyclic ring system. Both compounds possibly form a hydrogen bond (N···O = ∼3.2 Å) from their chromen-2-one oxygen to the NH of G100 in the same manner as Irosustat ( Figure 5 ). These more potent compounds have fairly small hydrophobic pendant groups attached to the 3-position of the chromen-2-one ring. These hydrophobic moieties lie between the hydrophobic sidechains of L103, F178, and F488. Those compounds with larger pendant groups may be less active due to the hydrophobic nature of the group making the compound less soluble. Alternatively, because STS is a membrane-bound protein and any substrate or inhibitor has to pass through the membrane to access the active site, it may be that larger hydrophobic tails result in the inhibitor failing to fully transit through the membrane: the hydrophobic tail stays, preferentially, embedded in the membrane. Left: docking of EMATE (cyan) and 29 (brown) into the crystal structure of human STS. Right: docking of Irosustat (cyan) and 41 (brown) into the crystal structure of human STS. In both figures, the Ca 2+ ion is depicted as a yellow sphere and FG75 is the gem -diol form of FGly 75 aldehyde. The dotted yellow lines are potential hydrogen bonds. On examining the data in Table 5 , where the best compounds are benchmarked against the steroidal EMATE and the nonsteroidal Irosustat and, more particularly, against the known two-ring coumarin sulfamate COUMATE, it is readily apparent that highly potent compounds have been designed through the targeted 3- and 4-substitutions undertaken in this work. Some of these ( 29 , 32 , 41 , and 42 ) have a potency approaching the clinical drug Irosustat in the more definitive intact MCF-7 cell assay, and of these, 29 is highly 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 Irosustat in the more challenging placental microsomal STS assay. It has an attractive 3-benzyl substituent that, as for the highly active homolog 42 , could potentially be substituted to further refine activity. Moreover, 41 and 42 are structurally distinct from the fully saturated C-ring surrogate of Irosustat and, as more versatile compounds, could form the basis of an attractive series for further optimization and eventual preclinical development. In any case, if we sensibly take COUMATE 3 for comparison, the best compounds are gratifyingly some 100–500 times more potent in the MCF-7 assay.

The in vitro inhibition of STS activity by most of the sulfamates synthesized in this work was measured in two assay systems: (i) a preparation of an intact monolayer of MCF-7 cells, which assesses the ability of compounds to cross the cell membrane and inhibit STS under conditions that closely resemble the tissue/physiological situation and (ii) a placental microsomes preparation where a higher concentration of substrate is employed, with which a compound has to compete for binding to the enzyme active site. For the placental microsome STS assay, a saturating substrate concentration of 20 μM was used and inhibitors were tested under initial rate conditions. The MCF-7 STS assay is meant to mimic/reflect physiological conditions (intact, living cells). Hence, a physiological concentration of 3 nM of E1S was used. The results are reported as % inhibition at various concentrations, and IC 50 values are determined for several compounds ( Tables 1 – 4 ). Although time- and concentration-dependence studies have not been carried out to confirm the nature of inhibition for those compounds tested, it is anticipated that they act mechanistically in a similar manner to other aryl sulfamates like 1 and 2 , which have been shown to be active-site-directed inhibitors Unless stated otherwise, errors are <5% of the reported value (from triplicate experiments). Ref ( 15 ). *: Results not determined; cf. EMATE (IC 50 = 65 pM). 13b For 4- n -alkyl derivatives 9 – 15 , 17 , and 18 , all derivatives inhibit STS activity >90% at 1 μM. Based on the % inhibition observed at 0.1 and 0.01 μM, the inhibitory activity of the compounds increases slightly as the chain length of the alkyl group increases, and it peaks at the nonyl ( 14 , 90% at 0.01 μM) and decyl ( 15 , 86% at 0.01 μM) derivatives. This may be attributed to the increase in lipophilicity of the compounds as their alkyl group becomes longer until steric hindrance potentially becomes a limiting factor. A similar observation was reported in studies of ( p - O -sulfamoyl)- N -alkanoyl tyramines. 37 , 38 We and others have also noted the existence of a hydrophobic pocket at the end of the steroid binding pocket 39 that might also be accessed by the present compound series to improve binding, although seeking the right compromise between hydrophobicity and steric hindrance is important. 40 For other substituents at the 4-position of the coumarin ring, their inhibitory activities vary with the phenethyl derivative 24 (39% at 0.01 μM, IC 50 = 18 nM) and the cyclohexyl derivative 26 (37% at 0.01 μM, IC 50 = 24 nM) being the most active. However, both 24 and 26 are less potent as STS inhibitors than the 4- n -alkyl derivatives. One possibility is that the active site of STS, like many other enzymes with steroids as substrate in general, has limited accommodation for substituents at the C1/C11/C12 edge of the steroid scaffold. Hence, the more flexible aliphatic alkyl chains may be better tolerated by the enzyme active site than the bulkier and more rigid substituents such as phenyl, benzyl, phenethyl, 4-ethylphenyl, and cyclohexyl when these substituents are placed at the 4-position of the coumarin ring system, which mimics the A/B ring of the steroidal STS inhibitor 1 . Apart from the two lower members 3 and 4 and the two higher members 17 and 18 , other 4- n -alkyl derivatives ( 5 – 16 ) tested show >90% inhibition at 1 μM. However, the SAR between chain length and inhibitory activity is not clear because all derivatives evaluated show the same order of magnitude in regard to % inhibition at 0.01 μM and IC 50 values. Nonetheless, the n -pentyl ( 10 , IC 50 = 40 nM) and n -dodecyl ( 17 , IC 50 = 45 nM) derivatives appear to be the most active inhibitors in this group. For those derivatives that have bulkier substituents at the 4-position, they are significantly less potent than their n -alkyl derivatives with the exception of 23 (benzyl, IC 50 = 64 nM), 24 (phenethyl, IC 50 = 82 nM), and 26 (cyclohexyl, IC 50 = 42 nM), the IC 50 values of 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 from the cell-free placental microsomes assay ( Tables 2 and 3 ). A similar phenomenon was observed in previous work. 41 Unless stated otherwise, errors are <5% of the reported value (from triplicate experiments). Ref ( 15 ). Ref ( 17 ). *: Results not determined; cf. EMATE (IC 50 = 25 nM), 17 2 (IC 50 = 8 nM). 17 Unless stated otherwise, errors are <5% of the reported value (from triplicate experiments). Ref ( 15 ). *: Results not determined. A relatively smaller number of synthesized compounds in this series compared to their 4-substituted relatives were tested for their inhibitory activities. From the results available, 3-alkylated-4-methyl compounds 28 – 33 show >97% inhibition at 0.1 μM, whereas compounds 39 – 43 , which have other substituents at the 3-position, inhibit STS between 29 and 98% at 0.1 μM. Of those five compounds that have IC 50 values determined, 29 is the most potent (0.68 nM), closely followed by 41 and 42 (1 and 1.1 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, IC 50 = 1.1 nM), there is 1 order of magnitude difference between the potency of the two pairs of compounds. This finding suggests that placing either a benzyl or a phenethyl group at the 3-position of the coumarin ring produces a more potent STS inhibitor. It is anticipated that on binding of 41 and 43 into the active site of STS, the coumarin ring of which is designed to mimic the A/B ring of 1 , their substituents at the 3-position extend into the same area where the C/D ring of 1 resides. On the basis of the IC 50 values available, it appears that compounds with shorter alkyl chains at 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 those with longer alkyl chains ( 32 – 34 , 37 ; IC 50 > 300 nM). This contrasts with those compounds in the 4-alkylated series ( Table 2 ) the IC 50 values (40–102 nM) of which are tighter and fall within the same order of magnitude. This finding suggests that a long alkyl chain placed at the 4-position of the coumarin ring may interact better with the enzyme active site than its counterpart placed at the 3-position of the coumarin ring. To this effect, the sulfamate group of 4-alkylated compounds may be better positioned within the catalytic site of the enzyme for inactivation. For compounds 40 – 43 , the inhibitory activity observed at 0.1 μM starts from 65% for 40 (phenyl) and rises to 94% for 41 (benzyl) before it falls to 91 and 47% for 42 (phenethyl) and 43 (phenylpropyl), respectively. A similar pattern is observed when the IC 50 values of 40 (54 nM), 41 (8 nM), and 42 (33 nM) are compared. In regard to potency, the benzyl group is therefore the optimal substituent for this group of 3-substituted-4-methyl coumarin sulfamates. It is possible that the phenyl, phenethyl, and phenylpropyl groups interact less favorably with or are less well accommodated by the enzyme active site ( Table 4 ). Unless stated otherwise, errors are <5% of the reported value (from triplicate experiments). Ref ( 15 ). Ref ( 17 ). *: Results not determined. When the benzyl group of 41 is replaced by a cyclohexylmethyl group to give 44 , a reduction in potency is observed (at 0.1 μM, 94% for 41 vs 74% for 44 ). The same pattern, but to a greater extent, is observed when the phenethyl group is replaced by a cyclohexylethyl group as shown by the 91% inhibition of the STS observed for 42 at 0.1 μM compared to the 37% inhibition for 45 at the same concentration. This finding suggests that the more rigid and electron-rich phenyl group may interact better with the enzyme active site (such as through π-interactions with neighboring amino acids) than the more flexible aliphatic cyclohexyl group. The best inhibitors are illustrated in Figure 4 , with an attempt to illustrate the mimicry of the steroidal C and D rings and also with some comparative activities shown in Table 5 . Diagrammatic comparison 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 ( 1 ), Irosustat ( 2 ), and COUMATE ( 3 ). Solid lines denote similarity to steroid C and D rings.

Synthetic routes to two-ring coumarin 7- O -sulfamate derivatives possessing 3- and 4-modified substitutions were devised, generally using an α-alkylacetoacetate strategy and the Pechman hydroxycoumain synthesis. 15 , 17 Compounds were shown to inhibit, often highly potently, the emerging clinical drug target STS 8 now validated for hormone-dependent diseases 12 using an intact MCF-7 cell assay and an assay against placental microsomal STS activity. The best compounds were benchmarked for activity against the steroidal sulfamate drug EMATE, 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, highly potent compounds were designed. In intact MCF-7 cells, compounds 29 , 32 , 41 , and 42 had a 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 STS. With COUMATE 3 taken as the most relevant comparative structural benchmark for non-tricyclic derivatives, the best compounds were ca. 100–500 times more potent in the MCF-7 assay. Both 41 and 42 possess motifs structurally distinct from the fully saturated cyclic C-ring of Irosustat with attractive pendant 3-benzyl and 3-phenethyl substituents, respectively, that could potentially be further optimized through aromatic substitution. Compounds 29 and 41 were modeled into STS in comparison to benchmarks and dock well into the active site, placing the aryl sulfamate moiety opposite the catalytic FGly, as for Irosustat 16 and with their pendant side chains occupying a hydrophobic pocket noted previously. 39 The expectation is that, in a similar fashion to Irosustat and EMATE, such compounds will act as irreversible inhibitors by transfer of their sulfamoyl group to the STS enzyme, 12b , 13b although this has not been formally explored here. Thus, the versatile 3-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 are potent STS inhibitors and could represent new leads for potential preclinical development.

STS inhibitory assays were performed essentially as previously described. 13b , 43 The ability of the compounds synthesized to inhibit E1S was tested in vitro using MCF-7 cells and a placental microsomal preparation from a sulfatase-positive human placenta from a normal term pregnancy and compared with that of EMATE. For the placental microsome STS assay, a saturating substrate concentration of 20 μM was used and inhibitors were tested under initial rate conditions. For the MCF-7 STS assay, a physiological concentration of 3 nM E1S was used. Thus, for the placental microsome assay: [E1S] = 20 μM, [I] = 0.1 nM to 10 μM; MCF-7: [E1S] = 3 nM, [I] = 0.1 nM to 10 μM (NB for highly potent compounds, this was changed to 0.1 pM to 10 nM). All reagents were purchased commercially either from Aldrich Chemicals Co. (Gillingham, Dorset, U.K.) or Lancaster synthesis (Morecambe, Lancashire, U.K.). All organic solvents used were of general purpose or analytical grade and were obtained from Fisons Plc. (Loughborough, U.K.) and stored over 4 Å molecular sieves. Anhydrous dimethylformamide (DMF) used for all sulfamoylation reactions was purchased from Aldrich and was stored under a positive pressure of N 2 after use. Sulfamoyl chloride was prepared by adapting a method originally reported by Appel and Berger 44 and was stored as a standard solution in purified sulfur-free dry toluene. 36 Thin-layer chromatography (TLC) was carried out using precoated plates (Merck TLC aluminum sheets silica gel 60 F254, art. no. 5554). Product(s) and starting material were detected by treating plates with a methanolic solution of phosphomolybdic acid followed by heating or simply by viewing directly under UV light. Flash column chromatography was carried out by gradient elution (solvents used are indicated in the text) on wet-packed silica gel (Sorbsil C60). IR spectra were recorded using a PerkinElmer 782 spectrophotometer with peak positions expressed in cm –1 . 1 H and 13 C NMR spectra were recorded using either a Jeol Delta 270 MHz or Varian Mercury VX 400 MHz spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) using an internal standard of tetramethylsilane. Coupling constants ( J ) are quoted to the nearest 0.1 Hz. Mass spectra were acquired at the Mass Spectrometry Service Centre, Bath and FAB mass spectra used m -nitrobenzyl alcohol as matrix. Elemental analyses were carried out by the Microanalysis Service, Bath. Melting points are uncorrected and were determined using a Reichert-Jung Thermo Galen Kofler block. High-performance liquid chromatography (HPLC) was performed using a Waters 660E instrument equipped with an autosampler and photo diode array detector. A Waters Radialpak column (RP18, 8 mm × 100 mm) was used. The conditions of elution and analytical data are as indicated for each compound analyzed. Schrödinger software (running under Maestro 9.0) was used to build and minimize all of the ligands. The ALS75 residue in PDB crystal structure 1P49 (human placental estrone/dehydroepiandrosterone sulfatase) was mutated to the gem -diol form using the Schrödinger software editing tools. Minimization of the resulting structure, with the position of the backbone atoms fixed, allowed the atoms of the gem -diol and surrounding side chains to adopt low-energy conformations. Ligands were docked into the rigid protein using GOLD. A 10 Å sphere centered on the ALS75 sulfate was defined as the binding site. The GOLDScore fitness function was used to score the docked poses (25 for each ligand). To ethyl potassium malonate (2.1 equiv) in MeCN (100 mL/5 g of acid chloride) at 10–15 °C and under N 2 was added Et 3 N (3.2 equiv), followed by MgCl 2 (2.5 equiv). The mixture was stirred at 20–25 °C for 2.5 h and then at 0 °C for 0.5 h before the corresponding acid chloride (1 equiv) was added dropwise during 25 min. The mixture was further treated with Et 3 N (5 mL) and stirred overnight at 20 °C. The evaporation residue was dissolved in toluene and re-concentrated. More toluene was added, stirred, and cooled to 10–15 °C before aq HCl (1 M, 50 mL) was added cautiously while keeping the temperature <25 °C. The organic layer was washed with 1 M aq HCl (50 mL) and water. Drying, evaporation, and distillation or chromatography (CHCl 3 or CHCl 3 /acetone, 10:1) gave the corresponding ethyl α-alkanoylacetate. To anhydrous SnCl 2 (0.1 equiv) was added CH 2 Cl 2 (∼100 mL/5 g of aldehyde), followed by ethyl diazoacetate (1.05 equiv). The reaction was initiated by adding a few drops of the corresponding aldehyde in CH 2 Cl 2 . When N 2 evolution began, the remaining solution of aldehyde (1 equiv) was added dropwise over 30 min. After the evolution of N 2 had stopped (∼1–3 h), the mixture was washed with brine (50 mL) and extracted twice (Et 2 O). Drying, evaporation, and chromatography (CHCl 3 or CHCl 3 /acetone, 10:1) or distillation gave the corresponding ethyl alkanoylacetate. K 2 CO 3 (2.4 equiv), water (50 mL), alkyl bromide (1 equiv), ethyl acetoacetate (1 equiv), CH 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 cooling, the separated organic layer was washed with 5 M aq HCl (30 mL). The mixture was extracted twice with Et 2 O. The combined ethereal extracts were dried, filtered, and concentrated in vacuo. Chromatography (CHCl 3 or CHCl 3 /acetone 10:1) or distillation gave the corresponding ethyl α-alkylacetoacetate. Resorcinol (1 equiv) was dissolved in the corresponding hot β-keto ester (1 equiv). The resulting syrup was cooled to 0 °C and treated dropwise with a mixture of CF 3 COOH (2 equiv) and conc. H 2 SO 4 (2 equiv) while keeping the temperature <10 °C. After stirring for 3 h at room temperature, the mixture was cautiously quenched with ice-water. The brightly colored gluey mass formed was stirred for further 1 h. The bright yellow/brown precipitate resulted was collected by suction filtration, washed exhaustively with water, and re-dissolved in acetone. The yellow/brown solid obtained upon evaporation was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient) and/or recrystallized from hot absolute ethanol, acetone/hexane (4:1), or THF/hexane (2:0.5) to give the corresponding coumarin as a crystalline solid. To a solution of the compound (1 equiv) in anhydrous DMF (5 mL) at 0 °C under N 2 was added NaH (1 equiv). When the evolution of H 2 had ceased, previously prepared sulfamoyl chloride (∼3–5 equiv) was introduced. After stirring at room temperature under N 2 overnight, the mixture was quenched with ice-water. The organic fractions were extracted into ethyl acetate (∼150 mL) and washed with brine (4 × 100 mL). Drying, evaporation, chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and/or recrystallization with either ethyl acetate/hexane (5:2) or THF/hexane (2:1) gave the corresponding crystalline sulfamate. This was prepared by 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 mmol). The crude oily residue was purified by flash chromatography (CHCl 3 ) to give 9a as a pale yellow oil (4.65 g, 78%): R f = 0.92 (CHCl 3 /acetone, 10:1); 1 H NMR (400 MHz, CDCl 3 ): δ = 0.91 (t, J = 7.3 Hz, 3H, C7–H 3 ), 1.28 (t, J = 7.0 Hz, 3H, CH 2 C H 3 ), 1.29–1.37 (m, 2H, CH 2 ), 1.54–1.62 (m, 2H, CH 2 ), 2.55 (t, J = 7.3 Hz, 2H, C4–H 2 ), 3.44 (s, 2H, C2–H 2 ) and 4.19 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 – H] − ; HRMS-FAB + : m / z [M + H] + ; Anal. calcd for C 9 H 17 O 3 : 173.1099, found: 173.1089. This was prepared with resorcinol (2.0 g, 18 mmol), 9a (3.13 g, 18.2 mmol), and a mixture of CF 3 COOH (2.77 mL, 36.3 mmol) and conc. H 2 SO 4 (1.83 mL, 36.3 mmol). The crude yellow/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 (Lit. 45 mp 139–140 °C, ethanol); IR (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, 2H, CH 2 ), 2.73 (t, J = 7.6 Hz, 2H, C1′–H 2 ), 6.08 (s, 1H, C3–H), 6.71 (d, J = 2.4 Hz, 1H, C8–H), 6.80 (dd, J = 8.6 and 2.4 Hz, 1H, C6–H), 7.6 (d, J = 8.5 Hz, 1H, C5–H) and 10.53 ppm (s, 1H, OH); MS (FAB + ): m / z (%) 437.2 (15) [2M + H] + , 219.2 (100) [M + H] + ; MS (FAB – ): m / z (%) 435.3 (20) [2M – H] − , 217.2 (100) [M – H] − ; HRMS-FAB + : m / z [M + H] + calcd for C 13 H 15 O 3 : 219.1021, found: 219.1034; Anal. calcd for C 13 H 14 O 3 : C 71.54, H 6.47, found: C 71.40, H 6.49. Upon sulfamoylation, 9b (700 mg, 3.21 mmol) gave a crude white solid, which was fractionated by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated 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 °C; IR (KBr) ṽ = 3400–3100, 1750, 1450–1300, 1100–1150 cm –1 ; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.93 (t, J = 7.3 Hz, 3H, CH 3 ), 1.36–1.45 (m, 2H, CH 2 ), 1.57–1.64 (m, 2H, CH 2 ), 2.82 (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 = 2.4 Hz, 1H, C8–H), 7.94 (d, J = 8.8 Hz, 1H, C5–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 – HNSO 2 ] + ; MS (FAB – ): m / z (%) 593.2 (15) [2M – H] − , 296.2 (100) [M – H] − , 217.2 (60) [M – H 2 NSO 2 ] − ; HRMS-FAB + : m / z [M + H] + calcd for C 13 H 16 NO 5 S: 298.0749, found: 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. This was prepared by 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 mmol). The crude oily residue was purified by flash chromatography (CHCl 3 ) to give 10a as a pale yellow oil (6.58 g, 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 (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 (%) 187.2 (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. This was prepared with resorcinol (2.0 g, 18 mmol), 10a (3.4 g, 18 mmol), and a mixture of CF 3 COOH (2.8 mL, 36 mmol) and conc. H 2 SO 4 (1.8 mL, 36 mmol). The crude yellow/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 °C (Lit. 46 mp 145–146 °C); 1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.87 (t, J = 7.1 Hz, 3H, C5′–H 3 ), 1.33–1.34 (m, 4H, CH 2 CH 2 ), 1.58–1.61 (m, 2H, CH 2 ), 2.72 (t, J = 7.6 Hz, 2H, C1′–H 2 ), 6.08 (s, 1H, C3–H), 6.71 (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 – H] − , 231.2 (100) [M – H] − ; HRMS-FAB + : m / z [M + 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. Upon sulfamoylation, 10b (700 mg, 3.01 mmol) gave a crude white sold (893 mg), which was fractionated by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated was recrystallized from ethyl acetate/hexane to give 10 as white crystals (251 mg, 27%): R f = 0.36 (CHCl 3 /ethyl acetate, 4:1); mp 128–132 °C; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.88 (t, J = 7.1 Hz, 3H, C5′–H 3 ), 1.31–1.39 (m, 4H, CH 2 CH 2 ), 1.59–1.64 (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 = 1.5 and 8.5 Hz, 1H, C6–H), 7.33 (d, J = 1.5 Hz, 1H, C8–H), 7.93 (d, J = 8.5 Hz, 1H, C5–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 – HNSO 2 ] + ; MS (FAB – ): m / z (%) 621.2 (20) [2M – H] − , 310.2 (100) [M – H] − , 231.2 (100) [M – H 2 NSO 2 ] − ; HRMS-FAB + : m / z [M + 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, H 5.56, N 4.50. This was prepared by 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). The 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 (400 MHz, CDCl 3 ): δ = 0.88 (t, J = 7.3 Hz, 3H, C9–H 3 ), 1.26–1.32 (m, 9H, CH 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: 201.1492. This was prepared with resorcinol (2.20 g, 19.9 mmol), 11a (4.0 g, 20 mmol), and a mixture of CF 3 COOH (3.1 mL, 40 mmol) and conc. H 2 SO 4 (2.04 mL, 39.9 mmol). The crude orange 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 °C; 1 H NMR (400 MHz, DMSO- d ): δ = 0.86 (t, J = 7.1 Hz, 3H, C6′–H 3 ), 1.27–1.37 (m, 6H, 3 × CH 2 ), 1.55–1.63 (m, 2H, CH 2 ), 2.72 (t, J = 7.6 Hz, 2H, C1′–H 2 ), 6.08 (s, 1H, C3–H), 6.71 (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 (%) 493.4 (10) [2M + H] + , 247.2 (100) [M + H] + ; MS (FAB – ): m / z (%) 491.3 (15) [2M – H] − , 245.2 (100) [M – H] − ; HRMS-FAB + : m / z [M + 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. Upon sulfamoylation, 11b (700 mg, 2.84 mmol) gave a crude white solid, which was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated 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 °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 (m, 2H, CH 2 ), 2.81 (t, J = 7.9 Hz, 2H, C1′–H 2 ), 6.37 (s, 1H, C3–H), 7.29 (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 (FAB + ): m / z (%) 651.3 (10) [2M + H] + , 326.2 (100) [M + H] + , 247.2 (10), [M + H – HNSO 2 ] + ; MS (FAB – ): m / z (%) 649.3 (15) [2M – H] − , 324.2 (100) [M – H] − , 245.2 (60), [M – H 2 NSO 2 ] − ; HRMS-FAB + : m / z [M + 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, H 5.88, N 4.25. This was prepared by 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). The 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 (400 MHz, CDCl 3 ): δ = 0.88 (t, J = 7.3 Hz, 3H, C10–H 3 ), 1.26–1.29 (m, 11H, CH 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 (100) [M – H] − ; HRMS-FAB + : m / z [M + H] + calcd for C 12 H 23 O 3 : 215.1647, found: 215.1652. This was prepared with resorcinol (1.8 g, 16 mmol), 12a (3.5 g, 16 mmol), and a mixture of CF 3 COOH (2.52 mL, 32.7 mmol) and conc. H 2 SO 4 (1.67 mL, 32.7 mmol). The crude yellow 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 °C; 1 H NMR (400 MHz, DMSO- d ): δ = 0.86 (t, J = 7.1 Hz, 3H, C7′–H 3 ), 1.24–1.36 (m, 8H, 4 × CH 2 ), 1.55–1.63 (m, 2H, CH 2 ), 2.72 (t, J = 7.6 Hz, 2H, C1′–H 2 ), 6.08 (s, 1H, C3–H), 6.71 (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 (%) 261.2 (100) [M + H] + ; MS (FAB – ): m / z (%) 519.3 (60) [2M – H] − , 259.2 (100) [M – H] − ; HRMS-FAB + : m / z [M + H] + calcd for C 16 H 21 O 3 : 261.1491, found: 261.1501; Anal. calcd for C 16 H 20 O 3 : C 73.82, H 7.74, found: C 73.60, H 7.82. Upon sulfamoylation, 12b (700 mg, 2.69 mmol) gave a crude white solid, which was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated 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 °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 (m, 2H, CH 2 ), 2.81 (t, J = 7.3 Hz, 2H, C1′–H 2 ), 6.37 (s, 1H, C3–H), 7.27–7.33 (m, 2H, C6–H and C8–H), 7.39 (d, J = 8.8 Hz, 1H, C5–H) and 8.22 (s, 2H, NH 2 ); MS (FAB + ): m / z (%) 679.3 (60) [2M + H] + , 340.1 (100) [M + H] + , 261.1 (10) [M + H – HNSO 2 ] + ; MS (FAB – ): m / z (%) 677.1 (20) [2M – H] − , 338.1 (100) [M – H] − , 259.1 (60) [M – H 2 NSO 2 ] − ; HRMS-FAB + : m / z [M + 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, H 6.31, N 4.15. This was prepared by method A using ethyl potassium malonate (13.0 g, 76.4 mmol), CH 3 CN (120 mL), Et 3 N (16.2 mL, 116 mmol), MgCl 2 (8.7 g, 91 mmol), and nonanoyl chloride (6.69 mL, 37.8 mmol). The crude oily residue was purified by flash chromatography (CHCl 3 ) to give 13a as a pale yellow oil (6.73 g, 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 (m, 15H, CH 2 C H 3 and 6 × CH 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 (%) 229.2 (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. This was prepared with resorcinol (1.93 g, 17.5 mmol), 13a (4.0 g, 18 mmol) and a mixture of CF 3 COOH (2.7 mL, 35 mmol) and conc. H 2 SO 4 (1.8 mL, 35 mmol). The crude yellow 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 °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 (m, 2H, CH 2 ), 2.51 (t, J = 7.3 Hz, 2H, C1′–H 2 ), 6.08 (s, 1H, C3–H), 6.71 (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 (%) 549.5 (80) [2M + H] + , 275.2 (100) [M + H] + ; MS (FAB – ): m / z (%) 547.4 (75) [2M – H] − , 273.2 (100) [M – H] − ; HRMS-FAB + : m / z [M + 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. Upon sulfamoylation, 13b (400 mg, 1.46 mmol) gave a crude white solid which was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated 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 °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 (m, 2H, CH 2 ), 2.81 (t, J = 7.3 Hz, 2H, C1′–H 2 ), 6.37 (s, 1H, C3–H), 7.28 (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 (FAB + ): m / z (%) 707.0 (80) [2M + H] + , 354.0 (100) [M + H] + , 275.0 (20) [M + H – HNSO 2 ] + ; MS (FAB – ): m / z (%) 705.2 (20) [2M – H] − , 352.1 (100) [M – H] − , 273.1 (70) [M – H 2 NSO 2 ] − ; HRMS-FAB + : m / z [M + 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, H 6.50, N 3.75. This was prepared by method A using ethyl potassium malonate (13.0 g, 76.4 mmol), CH 3 CN (120 mL), Et 3 N (16.2 mL, 116 mmol), MgCl 2 (8.7 g, 91 mmol), and decanoyl chloride (7.5 mL, 36 mol). The crude oily residue was purified by flash chromatography (CHCl 3 ) to give 14a as a pale yellow oil (7.79 g, 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 (m, 17H, CH 2 C H 3 and 7 × CH 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 (%) 243.1 (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. This was prepared with resorcinol (1.14 g, 10.3 mmol), 14a (2.5 g, 10 mmol), and a mixture of CF 3 COOH (1.6 mL, 21 mmol) and conc. H 2 SO 4 (1.05 mL; 20.6 mmol). The crude yellow solid was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow solid isolated was recrystallized from acetone/hexane to give 14b as off-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 (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 = 2.4 Hz, 1H, C8–H), 7.52 (d, J = 8.8 Hz, 1H, C5–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: 289.1807; Anal. calcd for C 18 H 24 O 3 : C 74.97, H 8.39, found: C 75.10, H 8.39. Upon sulfamoylation, 14b (400 mg, 1.39 mmol) gave a crude white solid, which was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated 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 °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 (m, 2H, CH 2 ), 2.81 (t, J = 7.3 Hz, 2H, C1′–H 2 ), 6.37 (s, 1H, C3–H), 7.28 (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 (FAB + ): m / z (%) 735.3 (90) [2M + H] + , 368.1 (100) [M + H] + ; MS (FAB – ): m / z (%) 733.1 (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: C 59.05, H 6.91, N 3.74. This was prepared by method B using CH 2 Cl 2 (80 mL), ethyl diazoacetate (3.52 g, 30.8 mmol), SnCl 2 (556 mg, 2.9 mmol), and undecanal (5.0 g, 29 mmol) in CH 2 Cl 2 . The crude oily residue was purified by fractional distillation under reduced pressure 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, CDCl 3 ) δ = 0.88 (t, J = 6.9 Hz, 3H, C13–H 3 ), 1.26–1.61 (m, 19H, CH 2 C H 3 and 8 × CH 2 ), 2.53 (t, J = 7.2 Hz, 2H, C4–H 2 ), 3.43 (s, 2H, C2–H 2 ) and 4.19 (q, J = 7.2 Hz, 2H, C H 2 CH 3 ); MS (FAB + ): m / z (%) 257.2 (100) [M + 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: 257.2129. This was prepared with resorcinol (1.07 g, 9.76 mmol), 15a (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 chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow solid isolated was recrystallized from acetone/hexane to give 15b as off-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 (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 = 2.4 Hz, 1H, C8–H), 7.52 (d, J = 8.8 Hz, 1H, C5–H) and 8.19 (s, 1H, OH); MS (FAB + ): m / z (%) 303.1 (100) [M + H] + ; MS (FAB – ): m / z (%) 301.1 (100) [M – H] − ; HRMS-FAB + : m / z [M + H] + calcd for C 19 H 27 O 3 : 303.1960, found: 303.1973; Anal. calcd for C 19 H 26 O 3 : C 75.46, H 8.67, found: C 75.10, H 8.72. Upon sulfamoylation, compound 15b (400 mg, 1.32 mmol) gave a crude white solid, which was fractionated by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated was recrystallized from ethyl acetate/hexane to give 15 as white fine needles (288 mg, 57%): R f = 0.55 (CHCl 3 /ethyl acetate, 4:1); mp 112–115 °C; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.85 (t, J = 7.1 Hz, 3H, C10′–H 3 ), 1.16–1.38 (m, 14H, 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 = 2.1 Hz, 1H, C8–H), 7.93 (d, J = 8.8 Hz, 1H, C5–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 – HNSO 2 ] + ; MS (FAB – ): m / z (%) 761.0 (80) [2M – H] − , 380.0 (100) [M – H] − , 301.1 (90) [M – H 2 NSO 2 ] − ; HRMS-FAB + : m / z [M + H] + calcd for C 19 H 28 NO 5 S: 382.1688, found: 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. This was prepared by method B using CH 2 Cl 2 (80 mL), ethyl diazoacetate (3.25 g, 28.5 mmol), SnCl 2 (514 mg, 2.7 mmol), and dodecyl aldehyde (5.0 g, 27 mmol) in CH 2 Cl 2 (20 mL). The crude oily residue was purified by fractional distillation under reduced pressure to give 16a as a colorless oil (5.3 g, 72%): R f = 0.74 (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 (m, 21H, CH 2 C H 3 and 9 × 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 (%) 271.1 (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. This was 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 mmol) and conc. H 2 SO 4 (2.0 mL, 22 mmol). The crude yellow solid was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow solid isolated was recrystallized from acetone/hexane to give 16b as white crystals (1.92 g, 55%): R f = 0.86 (CHCl 3 /acetone, 3:1); mp 102–105 °C; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.85 (t, J = 6.2 Hz, 3H, C11′–H 3 ), 1.23–1.36 (m, 16H, 8 × CH 2 ), 1.54–1.60 (m, 2H, CH 2 ), 2.72 (t, J = 7.6 Hz, 2H, C1′–H 2 ), 6.07 (s, 1H, C3–H), 6.71 (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 – H] − ; HRMS-FAB + : m / z [M + H] + calcd for C 20 H 29 O 3 : 317.2117, found: 317.2121; Anal. calcd for C 20 H 28 O 3 : C 75.91, H 8.92, found: C 75.50, H 8.97. Upon sulfamoylation, compound 16b (400 mg, 1.27 mmol) gave a crude white solid, which was fractionated by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated was recrystallized from ethyl acetate/hexane to give 16 as white fine fluffy crystals (88 mg, 18%): R f = 0.54 (CHCl 3 /ethyl acetate, 4:1); mp 114–116 °C; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.85 (t, J = 7.0 Hz, 3H, C11′–H 3 ), 1.24–1.38 (m, 16H, 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 Hz, 1H, C8–H), 7.93 (d, J = 8.6 Hz, 1H, C5–H) and 8.24 (s, 2H, NH 2 ); MS (FAB + ): m / z (%) 396.1 (100) [M + H] + , 317.2 (20) [M + H – HNSO 2 ] − ; MS (FAB + ): m / z (%) 394.3 (100) [M – 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; Anal. calcd for C 20 H 29 NO 5 S: C 60.74, H 7.39, N 3.54, found: C 61.00, H 7.44, N 3.52. This was prepared by method B using CH 2 Cl 2 (80 mL), ethyl diazoacetate (3.02 g, 26.5 mmol), SnCl 2 (478 mg, 2.5 mmol), and tridecanal (5.0 g, 25 mmol) in CH 2 Cl 2 (20 mL). The crude oily residue was purified by flash chromatography (CHCl 3 ) to give 17a as a colorless oil, which solidified 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 MHz, CDCl 3 ) δ = 0.88 (t, J = 6.4 Hz, 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 (FAB + ): m / z (%) 285.2 (100) [M + H] + , MS (FAB – ): m / z (%) 283.2 (100) [M – H] − ; HRMS-FAB + : m / z [M + H] + calcd for C 17 H 33 O 3 : 285.2429, found: 285.2426. This was 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 mmol) and conc. H 2 SO 4 (1.5 mL, 21 mmol). The crude brown solid was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the yellow solid isolated was recrystallized from acetone/hexane to give 17b as fine yellow crystals (747 mg, 22%): R f = 0.77 (CHCl 3 /acetone, 3:1); mp 101–103 °C; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 0.85 (t, J = 7.0 Hz, 3H, C12′–H 3 ), 1.17–1.36 (m, 18H, 9 × CH 2 ), 1.55–1.60 (m, 2H, CH 2 ), 2.72 (t, J = 7.4 Hz, 2H, C1′–H 2 ), 6.08 (s, 1H, C3–H), 6.71 (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: 331.2279; Anal. calcd for C 21 H 30 O 3 : C 76.33, H 9.15, found C 76.80, H 8.80. Upon sulfamoylation, compound 17b (400 mg; 1.21 mmol) gave a crude white solid, which was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated 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 °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 (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 = 2.3 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 (FAB + ): m / z (%) 410.2 (100) [M + H] + , 331.2 (20) [M + H – HNSO 2 ] + ; MS (FAB – ): m / z (%) 817.3 (20) [2M – H] − , 408.3 (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; Anal. calcd for C 21 H 31 NO 5 S: C 61.59, H 7.63, N 3.42, found: C 61.90, H 7.65, N, 3.34. This was prepared by method B using CH 2 Cl 2 (80 mL), ethyl diazoacetate (2.82 g, 24.7 mmol), SnCl 2 (446 mg, 2.35 mmol), and tetradecanal (5.0 g, 24 mmol) in CH 2 Cl 2 (20 mL). The crude oily residue was purified by flash chromatography (CHCl 3 ) to give 18a as a colorless oil, which solidified to an off-white soft solid on standing (5.45 g, 78%): R f = 0.71 (CHCl 3 ); mp 45–47 °C (Lit. 49 mp 41–42 °C); MS (FAB + ) m / z : 299.2 [100, (M + H) + ]; 1 H NMR (400 MHz, CDCl 3 ) δ = 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 (100) [M – H] − ; HRMS-FAB + : m / z [M + H] + calcd for C 18 H 35 O 3 : 299.2586, found: 299.2599. This was 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 mmol) and conc. H 2 SO 4 (1.5 mL, 20 mmol). The crude brown solid was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the beige solid isolated was recrystallized from acetone/hexane to give 18b as fine cream-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 = 0.85 (t, J = 7.0 Hz, 3H, C13′–H 3 ), 1.19–1.36 (m, 20H, 10 × CH 2 ), 1.54–1.62 (m, 2H, CH 2 ), 2.72 (t, J = 7.4 Hz, 2H, C1′–H 2 ), 6.08 (s, 1H, C3–H), 6.71 (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: 345.2438; Anal. calcd for C 22 H 32 O 3 : C 76.70, H 9.36, found: C 76.85, H 9.31. Upon sulfamoylation, compound 18b (350 mg, 1.01 mmol) gave a crude white solid, which was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated 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 °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 (m, 2H, CH 2 ), 2.81 (t, J = 7.8 Hz, 2H, C1′–H 2 ), 6.38 (s, 1H, C3–H), 7.29 (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 (FAB + ): m / z (%) 424.3 (100) [M + H] + , 345.3 (25) [M + H – HNSO 2 ] + ; MS (FAB – ): m / z (%) 422.3 (60) [M – H] − , 343.3 (100) [M – H 2 NSO 2 ] − ; HRMS-FAB + : m / z [M + 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, H 7.90, N 3.46. This was prepared with resorcinol (1.21 g, 11.1 mmol), ethyl 4-methyl-3-oxopentanoate (1.6 g, 10 mmol), and a mixture of CF 3 COOH (1.7 mL, 22 mmol) and conc. H 2 SO 4 (2.2 mL, 22 mmol). The crude yellow solid was purified by recrystallization from acetone/hexane to give 19a as pale white fine crystals (420 mg, 21%): R f = 0.42 (CHCl 3 /acetone 3:1); mp 120–122 °C (Lit. 50 mp 62–64 °C—NB we are unable to explain this discrepancy) 1 H NMR (400 MHz, DMSO- d 6 ): δ = 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 = 8.8 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 – H] − , 203.1 (100) [M – H] − ; HRMS-FAB + : m / z [M + 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. Upon sulfamoylation, compound 19a (400 mg, 1.96 mmol) gave a crude white solid, which was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated was recrystallized from ethyl acetate/hexane to give 19 as white fine crystals (150 mg, 30%): R f = 0.22 (CHCl 3 /ethyl acetate, 4:1); mp 164–167 °C; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 1.26 (d, J = 6.7 Hz, 6H, CH(C H 3 ) 2 ), 3.31–3.34 (m, 1H, C H (CH 3 ) 2 ), 6.35 (s, 1H, C3–H), 7.29 (dd, J = 2.4 and 8.8 Hz, 1H, C6–H), 7.33 (d, J = 2.4 Hz, 1H, C8–H), 7.99 (d, J = 8.8 Hz, 1H, C5–H) and 8.23 (s, 2H, NH 2 ); MS (FAB + ): m / z (%) 567.1 (70) [2M + H] + , 284.1 (100) [M + H] + ; MS (FAB – ): m / z (%) 565.2 (30) [2M – H] − , 282.1 (100) [M – H] − , 203.1 (60) [M – H 2 NSO 2 ] − ; HRMS-FAB + : m / z [M + H] + calcd for C 12 H 14 NO 5 S: 284.0593, found: 284.0599; 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. This was prepared with resorcinol (7.0 g, 63 mmol), methyl 4,4-dimethyl-3-oxopentanoate (10.0 g, 63.2 mmol), and a 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 by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow solid isolated was recrystallized from THF/hexane to give 20a as pale yellow crystals (380 mg, 0.03%): R f = 0.61 (CHCl 3 /acetone, 3:1); mp 159–161 °C; 1 H NMR (400 MHz, CDCl 3 ) δ = 1.49 (s, 9H, C(CH 3 ) 3 ), 6.28 (s, 1H, C3–H), 6.85 (dd, J = 2.7 and 8.9 Hz, 1H, C6–H), 7.11 (d, J = 2.7 Hz, 1H, C8–H), 7.13 (s, 1H, OH) and 7.91 (d, J 6,5 = 8.9 Hz, 1H, C5–H); MS (FAB + ): m / z (%) 219.1 (100) [M + H] + ; MS (FAB – ): m / z (%) 217.1 (100) [M – H] − ; 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 6.49; HPLC: MeOH/H 2 O (90:10), flow rate = 2 mL min –1 , λ max = 321 nm, t R = 1.91 min. Upon sulfamoylation, compound 20a (310 mg, 1.43 mmol) gave a crude white solid, which was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated was recrystallized from ethyl THF/hexane to give 20 as white fine crystals (43 mg, 10%): R f = 0.48 (CHCl 3 /ethyl acetate, 4:1); mp 187–189 °C; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 1.45 (s, 9H, C(CH 3 ) 3 ), 6.33 (s, 1H, C3–H), 7.27 (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 (FAB + ): m / z (%) 298.0 (100) [M + H] + , 219.1 (15) [M + H – HNSO 2 ] + ; MS (FAB – ): m / z (%) 296.0 (100) [M – H] − , 217.0 (40) [M – H 2 NSO 2 ] − ; HRMS-FAB + : m / z [M + H] + calcd for C 13 H 16 NO 5 S: 298.0749, found: 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; HPLC: 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. This was prepared with resorcinol (2.93 g, 29.6 mmol), methyl 4-chloro-3-oxo-butanoate (4.0 g, 29 mmol), and a mixture of CF 3 COOH (4.1 mL, 53 mmol) and conc. H 2 SO 4 (2.7 mL, 53 mmol). The crude orange solid was purified by recrystallization from acetone/hexane to give 21a as off-white fine crystals (1.31 g, 23%): R f = 0.73 (CHCl 3 /acetone, 3:1); mp 183–185 °C (Lit. 51 mp 181 °C); 1 H NMR (400 MHz, DMSO- d 6 ): δ = 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 = 8.8 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 (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: 213.0127; Anal. calcd for C 10 H 7 ClO 3 : C 57.03, H 3.35%, found: C 57.00, H 3.20. Upon sulfamoylation, compound 21a (400 mg, 1.9 mmol) gave a crude yellow solid, which was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated was recrystallized from ethyl acetate/hexane to give 21 as pale green fine crystals (59 mg, 11%): R f = 0.44 (CHCl 3 /ethyl acetate, 4:1); mp 172–175 °C; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 5.05 (s, 2H, 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, 1H, 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 ) – H] − , 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: 289.9893; 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. This was prepared with resorcinol (2.0 g, 18 mmol), ethyl 3-oxo-3-phenylpropanoate (2.0 g, 18 mmol), and a mixture of CF 3 COOH (2.8 mL, 36 mmol) and conc. H 2 SO 4 (1.85 mL, 36.3 mmol). The crude orange solid was purified by recrystallization from hot absolute ethanol to give 22a as yellow crystals (1.85 g, 43%): R f = 0.71 (CHCl 3 /acetone, 3:1); 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 (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) and 10.67 (s, 1H, OH); MS (FAB + ): m / z (%) 239.1 (100) [M + H] + ; MS (FAB – ): m / z (%) 237.1 (100) [M – H] − ; 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. Upon sulfamoylation, compound 22a (700 mg, 2.94 mmol) gave a crude white solid, which was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated 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 185–190 °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, 1H, C5–H) and 7.59–7.62 (m, 7H, Ph–H and NH 2 —reduced to 5H when exchanged with D 2 O); MS (FAB + ): m / z (%) 318.1 (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 + 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, H 3.53, N 4.48. This was prepared by method B using CH 2 Cl 2 (80 mL), ethyl diazoacetate (4.99 g, 43.7 mmol), SnCl 2 (790 mg, 3.73 mmol), and phenylacetaldehyde (5.0 g, 42 mmol) in CH 2 Cl 2 . The crude oily residue was purified by distillation under reduced pressure to give 23a as a pale yellow oil (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 unable to explain this discrepancy) 1 H NMR (400 MHz, DMSO- d 6 ): δ = 2.16 (t, J = 7.3 Hz, 3H, CH 2 C H 3 ), 3.45 (s, 2H, 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 (FAB + ): m / z (%) 207.1 (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: 207.1014. This was prepared with resorcinol (1.6 g, 15 mmol), 23a (3.0 g, 15 mmol), and a mixture of CF 3 COOH (2.5 mL, 29 mmol) and conc. H 2 SO 4 (1.5 mL, 29 mmol). The crude yellow solid was purified by recrystallization from hot absolute ethanol to give 23b as pale yellow crystals (2.19 g, 60%): R f = 0.80 (CHCl 3 /acetone, 3:1), mp 209–212 °C (Lit. 54 mp 214–215 °C); 1 H NMR (400 MHz, CDCl 3 ) δ = 4.38 (s, 2H, C H 2 Ph), 5.98 (s, 1H, C3–H), 6.71 (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, 5H, PhH), 7.67 (d, J = 8.6 Hz, 1H, C5–H) and 10.57 (s, 1H, OH); MS (FAB + ): m / z (%) 505.1 (10) [2M + H] + , 253.1 (100) [M + H] + ; MS (FAB – ): m / z (%) 503.2 (15) [2M – H] − , 251.2 (100) [M – H] − ; HRMS-FAB + : m / z [M + H] + calcd for C 16 H 13 O 3 : 253.0865, found: 253.0863; Anal. calcd for C 16 H 12 O 3 : C 76.18, H 4.79, found: C 75.60, H 4.88. Upon sulfamoylation, 23b (400 mg, 1.6 mmol) gave a crude white solid, which was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated 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 °C; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 4.23 (s, 2H, C H 2 Ph), 6.32 (s, 1H, C3–H), 7.23–7.26 (m, 2H, C8–H and C6–H), 7.26–7.37 (m, 5H, PhH), 7.92 (d, J = 8.9 Hz, 1H, 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 – H] − , 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 C 16 H 13 NO 5 S: C 58.00, H 3.95, N 4.23%, found: C 57.70, H 3.97, N, 4.21. This was prepared by method B using CH 2 Cl 2 (80 mL), ethyl diazoacetate (4.5 g, 39 mmol), SnCl 2 (700 mg, 3.73 mmol), and hydrocinnam-aldehyde (5.0 g, 37 mmol) in CH 2 Cl 2 . The crude oily residue was purified by flash chromatography (CHCl 3 ) to give 24a as a pale yellow oil (5.38 g, 66%): R f = 0.63 (CHCl 3 ); 1 H NMR (400 MHz, DMSO- d 6 ): δ = 1.17 (t, J = 7.3 Hz, 3H, CH 2 C H 3 ), 2.79 (t, J = 7.5 Hz, 2H, C4–H 2 ), 2.87 (t, J = 7.5 Hz, 2H, C5–H 2 ), 3.60 (s, 2H, C2–H 2 ), 4.08 (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 – H] − ; HRMS-FAB + : m / z [M + H] + calcd for C 13 H 17 O 3 : 221.1178, found: 221.1181. This was prepared with resorcinol (1.25 g, 11.4 mmol), 24a (2.5 g, 11 mmol), and a mixture of CF 3 COOH (1.75 mL, 22.7 mmol) and conc. H 2 SO 4 (1.16 mL, 22.7 mmol). The crude yellow solid was purified by recrystallization from hot absolute ethanol to give 24b as pale white crystals (1.06 g, 35%): R f = 0.65 (CHCl 3 /acetone, 3:1); 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 (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 (100) [M – H] − ; HRMS-FAB + : m / z [M + H] + calcd for C 17 H 15 O 3 : 267.1021, found: 267.1018; Anal. calcd for C 17 H 14 O 3 : C 76.68, H 5.30, found: C 76.70, H 5.20. Upon sulfamoylation, 24b (400 mg, 1.5 mmol) gave a crude white solid, which was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated 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 = 2.96 (t, J = 8.8 Hz, 2H, C H 2 CH 2 Ph), 3.14 (t, J = 8.5 Hz, 2H, C H 2 Ph), 6.36 (s, 1H, C3–H), 7.22–7.34 (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 (FAB + ): m / z (%) 346.0 (100) [M + H] + , 91.0 (50) [CH 2 Ph] + ; MS (FAB – ): m / z (%) 344.0 (100) [M – H] − , 265.0 (60) [M – H 2 NSO 2 ] − ; HRMS-FAB + : m / z [M + H] + calcd for C 17 H 16 NO 5 S: 346.0749, found: 346.0754; 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. This was prepared by method A using ethyl potassium malonate (6.07 g, 35.7 mmol), CH 3 CN (120 mL), Et 3 N (7.58 mL, 54.4 mmol), MgCl 2 (4.05 g, 42.5 mmol), and 4-ethylbenzoyl chloride (2.5 mL, 17 mmol). The crude oily residue was purified by distillation under reduced pressure to give 25a as a colorless oil (3.74 g, 78%): R f = 0.64 (CH 2 Cl 2 ); bp 0.23 131–135 °C (Lit. 56 bp 0.004 105–112 °C); 1 H NMR (400 MHz, CDCl 3 ) δ = 1.22–1.33 (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 (s, 2H, C2–H 2 ), 4.21 (q, J = 6.8 Hz, 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 (100) [M – H] − ; HRMS-FAB + : m / z [M + H] + calcd for C 13 H 17 O 3 : 221.1178, found: 221.1177. This was prepared with resorcinol (1.5 g, 14 mmol), 25a (3.0 g, 14 mmol), and a mixture of CF 3 COOH (2.5 mL, 27 mmol) and conc. H 2 SO 4 (1.5 mL, 27 mmol). The crude orange solid was purified by recrystallization from hot ethanol to give 25b as white needles (1.66 g, 46%): R f = 0.72 (CHCl 3 /acetone, 4:1); mp 176–180 °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, 2H, CH 3 C H 2 ), 6.13 (s, 1H, C3–H), 6.77 (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 (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 – H] − ; HRMS-FAB + : m / z [M + H] + calcd for C 17 H 15 O 3 : 267.1021, found: 267.1018; Anal. calcd for C 17 H 14 O 3 : C 76.68, H 5.30, found: C 76.30, H, 5.30. Upon sulfamoylation, compound 25b (400 mg, 1.5 mmol) gave a crude white solid, which was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated was recrystallized from THF/hexane to give 25 as white fine crystals (114 mg, 22%): R f = 0.35 (CHCl 3 /ethyl acetate, 4:1); mp 170–173 °C; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 1.25 (t, J = 7.4 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 and 8.9 Hz, 1H, C6–H), 7.42–7.49 (m, 5H, PhH and C8–H), 7.57 (d, J = 8.6 Hz, 1H, C5–H) and 8.28 (s, 2H, NH 2 ); MS (FAB + ): m / z (%) 691.0 (30) [2M + H] + , 346.1 (100) [M + H] + ; MS (FAB – ): m / z (%) 689.3 (10) [2M – H] − , 344.2 (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; Anal. calcd for C 17 H 15 NO 5 S: C 59.12, H 4.38, N 4.06, found: C 59.00, H 4.36, N 4.03. This was prepared by method B using CH 2 Cl 2 (80 mL), ethyl diazoacetate (5.34 g, 46.8 mmol), SnCl 2 (85 mg, 4.5 mmol), and cyclohexanecarboxaldehyde (5.0 g, 45 mmol) in CH 2 Cl 2 (20 mL). The crude oily residue was purified by 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 (Lit. 53 bp 18 146–150 °C); 1 H NMR (400 MHz, CDCl 3 ) δ = 1.28 (t, J = 7.2 Hz, 3H, CH 2 C H 3 ), 1.39–2.49 (m, 11H, cyclohexyl-H), 3.48 (s, 2H, C2–H 2 ) and 4.19 (q, J = 7.2 Hz, 2H, C H 2 CH 3 ); MS (FAB + ): m / z (%) 199.0 (100) [M + 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: 199.1341. This was 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, 30.3 mmol) and conc. H 2 SO 4 (1.5 mL, 30 mmol). The crude yellow solid was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow solid isolated was recrystallized from hot acetone to give 26b as white crystals (1.45 g, 39%): R f = 0.80 (CHCl 3 /acetone, 4:1); mp 191–192 °C (Lit. 57 mp 176–178 °C); 1 H NMR (400 MHz, DMSO- d 6 ): δ = 1.38–1.87 (m, 11H, cyclohexyl-H), 6.04 (s, 1H, C3–H), 6.71 (d, J = J = 2.3 Hz, 1H, C8–H), 6.81 (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 + H] + , 245.1 (100) [M + H] + ; MS (FAB – ): m / z (%) 487.3 (15) [2M – H] − , 243.2 (100) [M – H] − ; HRMS-FAB + : m / z [M + 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. Upon sulfamoylation, compound 26a (400 mg, 1.6 mmol) gave a crude white solid, which was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient). The white solid isolated 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 °C; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 1.23–2.06 (m, 11H, cyclohexyl-H), 6.32 (s, 1H, C3–H), 7.32 (dd, J = 2.3 and 8.6 Hz, 1H, C6–H), 7.36 (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 (%) 324.1 (100) [M + H] + , 245.1 (15) [M + H – HNSO 2 ] + ; MS (FAB): m / z (%) 323.2 (100) [M – H] − , 243.2 (50) [M – H 2 NSO 2 ] − ; HRMS-FAB + : m / z [M + H] + calcd for C 15 H 18 NO 5 S: 324.0906, found: 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. 1-Adamantane acetic acid (5.0 g; 25.7 mmol) in an excess of thionyl chloride (20 mL; 77.2 mmol) and THF (5 mL) was boiled under reflux overnight under N 2 . Thionyl chloride was removed under vacuum to get the crude 27a as a brown oil (5.5 g; 101% crude), which was used 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 (400 MHz; CDCl 3 ) δ H : 1.11–1.76 (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) – H) − ]; 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. This was prepared by method A using ethyl potassium malonate (8.4 g; 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). The 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 (FAB + ) m / z : 265.2 [100, (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, (M – H) − ]; Acc. MS (FAB + ): 265.1697, C 16 H 25 O 3 requires 265.1705. This was prepared by general method using resorcinol (834 mg; 7.6 mmol), 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 from THF/hexane to give 27c as yellow crystals (1.82 g; 77%). R f : 0.72 (CHCl 3 /acetone, 4:1); mp 211–214 °C; 1 H NMR (400 MHz; CDCl 3 ) δ H : 1.52–2.09 (m, 15H, adamantane H), 1.90 (s, 2H, CH 2 ), 5.95 (s, 1H, C 3 –H), 6.69 (d, 1H, C 8 –H, J = 2.3 Hz), 6.78 (dd, 1H, C 6 –H, J = 2.3, 8.6 Hz), 7.75 (d, 1H, C 5 –H, J = 8.9 Hz) 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 + H) + ]; MS (FAB – ) m / z : 309.2 [100, (M – H) − ]; Acc. MS (FAB + ): 311.1568, C 20 H 23 O 3 requires 311.1569. Compound 27c (400 mg; 1.3 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid isolated was recrystallized from THF/hexane to give 27 as white fine crystals (88 mg; 18%). R f : 0.57 (CHCl 3 /ethyl acetate, 4:1); mp 218–221 °C; 1 H NMR (400 MHz; DMSO- d 6 ) δ H : 1.54–1.64 (m, 15H, adamantane H), 1.91 (s, 2H, CH 2 ), 6.24 (s, 1H, C 3 –H), 7.24–7.31 (m, 2H, C 6 –H and 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 + H) + ]; MS (FAB – ) m / z : 388.1 [100, (M – H) − ]; Acc. MS (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; N, 3.60%. This was prepared by general method using K 2 CO 3 (11.09 g; 79.2 mmol), water (50 mL), 1-bromopentane (4.09 mL; 33 mmol), ethyl 3-oxo-butanoate (4.29 mL; 33 mmol), CH 2 Cl 2 (50 mL), and Bu 4 NCl (∼10 g; 33 mmol). The crude oily residue (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 (400 MHz; DMSO- d 6 ) δ H : 0.85 (t, 3H, CH 3 , J = 7.3 Hz), 1.19 (t, 3H, CH 2 C H 3 , J = 7.3 Hz), 1.23–1.27 (m, 6H, 3 × CH 2 ), 1.68–1.72 (q, 2H, 3-CH 2 , J = 6.1 Hz), 2.17 (s, 3H, CH 3 CO), 3.57 (t, 1H, 2H, J = 7.3 Hz) and 4.12 (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. This was prepared by general method using resorcinol (2.2 g; 20 mmol), 28a (4.0 g; 20 mmol), and a mixture of CF 3 COOH (3.08 mL; 40 mmol) and conc. H 2 SO 4 (2.04 mL; 40 mmol). The crude pale yellow solid was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow solid 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 °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 (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, OH); found C, 72.90; H, 7.29; MS (FAB + ) m / z : 493.4 [15, (2M + H) + ], 247.3 [100, (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 247.1334; C 15 H 18 O 3 requires C, 73.15; H, 7.37%. Compound 28b (700 mg; 2.84 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid 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 °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, 1′-CH 2 , J = 8.2 Hz), 7.26–7.29 (m, 2H, C 6 –H and C 8 –H), 7.88 (d, 1H, C 5 –H, J = 7.9 Hz) and 8.19 (s, 2H, NH 2 ); MS (FAB + ) m / z : 326.2 [100, (M + H) + ], 245.2 [50, (M + H – HNSO 2 ) + ]; MS (FAB – ) m / z : 326.2 [100, (M – H) − ]; Acc. MS (FAB + ): Acc. MS (FAB + ): 326.1076, C 15 H 20 NO 5 S requires 326.1062; found C, 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%. This was prepared by general method using K 2 CO 3 (11.1 g; 79.2 mmol), water (50 mL), 1-bromohexane (4.63 mL; 33 mmol), ethyl 3-oxo-butanoate (4.29 mL; 33 mmol), CH 2 Cl 2 (50 mL), and Bu 4 NCl (∼10 g; 33 mmol). The crude oily residue was purified by flash chromatography (CHCl 3 ) to give 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 (400 MHz; DMSO- d 6 ) δ H : 0.85 (t, 3H, CH 3 , J = 6.7 Hz), 1.18 (t, 3H, CH 2 C H 3 , J = 7.1 Hz), 1.22–1.36 (m, 8H, 4 × CH 2 ), 1.71 (q, 2H, 3-CH 2 , J = 6.4 Hz), 2.17 (s, 3H, CH 3 CO), 3.57 (t, 1H, 2H, J = 6.7 Hz) and 4.12 (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 – H) − ]; Acc. MS (FAB + ): 215.1600, C 12 H 23 O 3 requires 215.1639. This was prepared by general method using resorcinol (1.28 g; 11.7 mmol), 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 from acetone/hexane to give 29b as white fine crystals (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) + ], 261.2 [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 × CH 2 ), 2.39 (s, 3H, C 4 –CH 3 ), 2.63 (t, 2H, 1′-CH 2 , J = 7.6 Hz), 6.83 (dd, 1H, C 6 –H, J = 2.4, 8.8 Hz), 6.96 (d, 1H, C 8 –H, J = 2.4 Hz), 7.49 (d, 1H, C 5 –H, J = 8.8 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%. Compound 29b (700 mg; 2.69 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid that was isolated was recrystallized from ethyl acetate/hexane to give 29 as white fine fluffy crystals (449 mg; 49%). R f : 0.41 (CHCl 3 /ethyl acetate, 4:1); mp 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 × CH 2 ), 2.43 (s, 3H, C 4 –H 3 ), 2.59 (t, 2H, 1′-CH 2 , J = 7.1 Hz), 7.26 (d, 1H, C 8 –H, J = 2.1 Hz), 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 [15, (2M + H) + ], 340.2 [100, (M + H) + ]; MS (FAB – ) m / z : 338.2 [100, (M – H) − ], 259.2 [45, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ): 340.1230, C 16 H 22 NO 5 S requires 340.1219; found 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%. This was prepared by general method using K 2 CO 3 (11.11 g; 80.39 mmol), water (50 mL), 1-bromoheptane (6 mL; 34 mmol), ethyl acetoacetate (4.27 mL; 33.5 mmol), CH 2 Cl 2 (50 mL), and Bu 4 NCl (∼10 g; 34 mmol). The crude oily residue was purified by flash chromatography (CHCl 3 ) to give 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 (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 (m, 12H, 6 × CH 2 ), 2.17 (s, 3H, CH 3 CO), 3.56 (t, 1H, 2H, J = 7.1 Hz) and 4.19 (q, 2H, C H 2 CH 3 , J = 7.1 Hz); MS (FAB + ) m / z : 229.2 [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. This was prepared by general method using resorcinol (965 mg; 8.76 mmol), 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 from acetone/hexane to give 30b as pale yellow crystals (730 mg; 30%). R f : 0.78 (CHCl 3 /acetone, 3:1); mp 96–98 °C; 1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 , J = 7.3 Hz), 1.26–1.53 (m, 10H, 5 × CH 2 ), 2.39 (s, 3H, C 4 –CH 3 ), 2.63 (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, OH); MS (FAB + ) m / z : 549.4 [15, (2M + H) + ], 275.2 [100, (M + H) + ]; MS (FAB – ) m / z : 547.4 [10, (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, 8.03; C 17 H 22 O 3 requires C, 74.42; H, 8.08%. Compound 64 (400 mg; 1.46 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid 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 °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 (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 – H) − ], 273.2 [90, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ): 354.1391, C 17 H 24 NO 5 S requires 354.1375; found 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%. This was prepared by general method using K 2 CO 3 (11.47 g; 82.98 mmol), water (50 mL), 1-bromooctane (6.0 mL; 35 mmol), ethyl 3-oxo-butanoate (4.41 mL; 34.6 mmol), CH 2 Cl 2 (50 mL), and Bu 4 NCl (∼10 g; 35 mmol). The crude oily residue was purified by flash chromatography (CHCl 3 /acetone) to give 31a as a pale yellow oil (3.1 g; 37%). (Lit. 63 bp 0.4 79–83 °C); R f : 0.68 (CHCl 3 ); 1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.86 (t, 3H, CH 3 , J = 6.7 Hz), 1.18 (t, 3H, CH 2 C H 3 , J = 7.3 Hz), 1.23–1.75 (m, 12H, 6 × CH 2 ), 2.06 (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) and 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 – H) − ]; Acc. MS (FAB + ): 243.1968, C 14 H 27 O 3 requires 243.1960. This was prepared by general method using resorcinol (910 mg; 8.26 mmol), 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 acetone/hexane to give 31b as white crystals (405 mg; 17%). R f : 0.72 (CHCl 3 /acetone, 3:1); 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, 6 × 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, (M + H) + ]; MS (FAB – ) m / z : 575.3 [35, (2M – H)], 287.2 [100, (M – H) − ]; Acc. MS (FAB + ): 289.1801, C 18 H 25 O 3 requires 289.1801; found C, 74.90; H, 8.40; C 18 H 24 O 3 requires C, 74.97; H, 8.39%. Compound 31b (400 mg; 1.39 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid 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 °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 (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, (M + H) + ]; MS (FAB – ) m / z : 733.3 [40, (2M – H) − ], 366.2 [100, (M – H) − ], 287.2 [60, (M – H 2 NSO 2 ) − ]; Acc. MS (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%. This was prepared by general method using K 2 CO 3 (7.4 g; 58 mmol), water (50 mL), 1-bromononane (5.0 mL; 24 mmol), ethyl 3-oxo-butanoate (3.1 mL; 24 mmol), CH 2 Cl 2 (50 mL), and Bu 4 NCl (∼10 g; 49 mmol). The crude oily residue was purified by flash chromatography (CHCl 3 ) to give 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 MHz; 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) + ]; MS (FAB – ) m / z : 255.2 [100, (M – H) − ]; Acc. MS (FAB + ): 257.2126, C 15 H 29 O 3 requires 257.2170. This was prepared by general method using resorcinol (1.07 g; 9.76 mmol), 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 chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow solid isolated was recrystallized from acetone/hexane to give 32b as white crystals (797 mg; 27%). R f : 0.69 (CHCl 3 /acetone, 3:1); mp 78–80 °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, 1′-CH 2 , J = 7.6 Hz), 6.86 (dd, 1H, C 6 –H, J = 2.4, 8.8 Hz), 7.05 (d, 1H, C 8 –H, J = 2.4 Hz), 7.49 (d, 1H, C 5 –H, J = 8.8 Hz) and 7.55 (s, 1H, OH); found C, 75.35; H, 8.65; MS (FAB + ) m / z : 605.3 [35, (2M + H) + ], 303.1 [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 303.1960; C 19 H 26 O 3 requires C, 75.46; H, 8.67%. Compound 32b (400 mg; 1.32 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid 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 °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 (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 – H) − ], 301.1 [75, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ): 382.1679, C 19 H 28 NO 5 S requires 382.1688; found 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%. This was prepared by general method using K 2 CO 3 (7.5 g; 54 mmol), water (50 mL), 1-bromodecane (5.0 mL; 23 mmol), ethyl 3-oxo-butanoate (2.88 mL; 22.6 mmol), CH 2 Cl 2 (50 mL), and Bu 4 NCl (∼10 g; 45 mmol). The crude oily 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 (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 , J = 7.3 Hz), 1.25–2.00 (m, 21H, CH 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. MS (FAB + ): 271.2275, C 16 H 31 O 3 requires 271.2273. This was prepared by general method using resorcinol (1.02 g; 9.25 mmol), 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 chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow solid isolated was recrystallized from acetone/hexane to give 33b as white crystals (807 mg; 28%). R f : 0.81 (CHCl 3 /acetone, 3:1); mp 96–100 °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 (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) and 7.49 (d, 1H, C 5 –H, J = 8.5 Hz); MS (FAB + ) m / z : 633.3 [50, (2M + H) + ], 317.1 [100, (M + H) + ]; MS (FAB – ) m / z : 631.2 [10, (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, 8.99 C 20 H 28 O 3 requires C, 75.91; H, 8.92%. Compound 33b (400 mg; 1.27 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid 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 °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 (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) + ], 396.1 [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 C 20 H 29 NO 5 S requires C, 60.74; H, 7.39; N, 3.54%. This was prepared by general method using K 2 CO 3 (7.1 g; 51 mmol), water (50 mL), 1-bromoundecane (5.0 mL; 21 mmol), ethyl 3-oxo-butanoate (2.71 mL; 21.3 mmol), CH 2 Cl 2 (50 mL), and Bu 4 NCl (∼10 g; 43 mmol). The crude oily residue was purified by flash chromatography (CHCl 3 /hexane, 8:1 to 2:1 gradient) to give 34a as a pale yellow 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, C H 2 CH 3 , J = 7.3 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. This was prepared by general method using resorcinol (968 mg; 8.8 mmol) 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 (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale brown solid 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 °C; 1 H NMR (400 MHz; CDCl 3 ) δ H : 0.85 (t, 3H, CH 3 , J = 7.0 Hz), 1.23–1.41 (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) + ], 331.1 [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 331.2273; found C, 76.10; H, 8.96 C 21 H 30 O 3 requires C, 76.33; H, 9.15%. Compound 34b (200 mg; 0.71 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid 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 °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 (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, C 21 H 31 NO 5 S requires C, 61.59; H, 7.63; N, 3.42%. This was prepared by general method using K 2 CO 3 (7.99 g; 57.8 mmol), water (60 mL), 1-bromododecane (6.0 mL; 24 mmol), ethyl 3-oxo-butanoate (3.1 mL; 24 mmol), CH 2 Cl 2 (60 mL), and Bu 4 NCl (∼10 g; 48 mmol). The crude oily residue 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 °C; (Lit. 67 bp 1.1 149–152 °C); 1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 , J = 7.0 Hz), 1.12–1.89 (m, 25H, CH 2 C H 3 and 11 × CH 2 ), 2.22 (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 : 299.2 [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. This was prepared by general method using resorcinol (553 mg; 5.02 mmol), 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 (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow solid 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 °C; 1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 , J = 7.0 Hz), 1.25–1.63 (m, 20H, 10 × CH 2 ), 2.38 (s, 3H, C 4 –CH 3 ), 2.63 (t, 2H, 1′-CH 2 , J = 7.4 Hz), 6.19 (s, 1H), 6.81 (dd, 1H, C 6 –H, J = 2.3, 8.6 Hz), 6.91 (d, 1H, C 8 –H, J = 2.3 Hz) and 7.48 (d, 1H, C 5 –H, J = 8.9 Hz); MS (FAB + ) m / z : 689.4 [20, (2M + H) + ], 345.4 [100, (M + H) + ]; MS (FAB – ) m / z : 343.3 [100, (M – H) − ]; Acc. MS (FAB + ): 345.2435, C 22 H 33 O 3 requires 345.2429; found C, 76.60; H, 9.22; C 22 H 32 O 3 requires C, 76.70; H, 9.36%. Compound 35b (100 mg; 0.29 mmol) was sulfamoylated, the crude white solid was purified by preparative TLC (CHCl 3 /ethyl acetate, 6:1), and the white solid isolated was 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), 1.24–1.48 (m, 20H, 10 × CH 2 ), 2.45 (s, 3H, C 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 (FAB – ) m / z : 422.1 [100, (M – H) − ], 343.2 [55, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ): 424.1246, C 22 H 34 NO 5 S requires 424.1241. This was prepared by general method using K 2 CO 3 (6.3 g; 46 mmol), water (60 mL), 1-bromotridecane (5.0 mL; 19 mmol), ethyl 3-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 residue 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 °C; 1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 , J = 7.0 Hz), 1.12–1.56 (m, 27H, CH 2 C H 3 and 12 × CH 2 ), 2.22 (s, 3H, CH 3 CO), 3.53 (t, 1H, 2H, J = 6.7 Hz) and 4.21 (q, 2H, C H 2 CH 3 , J = 7.0 Hz); MS (FAB + ) m / z : 313.3 [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. This was prepared by general method using resorcinol (705 mg; 6.4 mmol), 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 (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the pale yellow solid 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 °C; 1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 , J = 7.0 Hz), 1.26–1.84 (m, 22H, 11 × CH 2 ), 2.38 (s, 3H, C 4 –CH 3 ), 2.62 (t, 2H, 1′-CH 2 , J = 7.4 Hz), 5.87 (s, 1H, OH), 6.81 (dd, 1H, C 6 –H, J = 2.3, 8.7 Hz), 6.86 (d, 1H, C 8 –H, J = 2.3 Hz) and 7.48 (d, 1H, C 5 –H, J = 8.9 Hz); MS (FAB + ) m / z : 359.4 [100, (M + H) + ]; MS (FAB – ) m / z : 357.3 [100, (M – H) − ]; Acc. MS (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%. Compound 36b (400 mg; 1.12 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid 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 °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, 11 × 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 [30, (M – H 2 NSO 2 ) − ]; Acc. 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; N, 3.20%. This was prepared by general method using K 2 CO 3 (5.6 g; 43 mmol), water (60 mL), 1-bromotetradecane (5.0 mL; 18 mmol), ethyl 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 residue 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 °C; (Lit. 68 bp 0.5 162 °C); 1 H NMR (400 MHz; CDCl 3 ) δ H : 0.88 (t, 3H, CH 3 , J = 7.0 Hz), 1.20–1.81 (m, 29H, CH 2 C H 3 and 13 × CH 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. MS (FAB + ): 327.2900, C 20 H 39 O 3 requires 327.2899. This was prepared by general method using resorcinol (337 mg; 3.1 mmol), 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 chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient) to give 37b as pale yellow waxy solid (472 mg; 41%). R f : 0.74 (CHCl 3 /acetone, 3:1); mp 64–66 °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 ), 2.38 (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, 1H, C 6 –H, J = 2.3, 8.6 Hz), 6.84 (d, 1H, C 8 –H, J = 2.3 Hz) and 8.59 (d, 1H, C 5 –H, J = 8.9 Hz); MS (FAB + ) m / z : 373.1 [100, (M + H) + ]; MS (FAB – ) m / z : 371.2 [100, (M – H) − ]; Acc. MS (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%. Compound 37b (300 mg; 0.81 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid isolated was recrystallized from ethyl acetate/hexane to give 37 as white fine crystals (3 mg; 0.8%). R f : 0.62 (CHCl 3 /ethyl acetate, 4:1); mp 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, 12 × 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) + ], 373.3 [10, (M + H – HNSO 2 ) + ]; MS (FAB – ) m / z : 450.2 [100, (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, 63.74; H, 7.99; N, 3.36 C 24 H 37 NO 5 S requires C, 63.83; H, 8.26; N, 3.10%. This was prepared by general method using K 2 CO 3 (5.7 g; 41 mmol), water (60 mL), 1-bromopentadecane (5.0 mL; 17 mmol), ethyl 3-oxo-butanoate (2.2 mL; 17 mmol), CH 2 Cl 2 (60 mL), and Bu 4 NCl (∼10 g; 34 mmol). The crude oily residue was purified by distillation under reduced pressure to give 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), 3.37 (t, 1H, 2H, J = 7.0 Hz) and 4.18 (q, 2H, C H 2 CH 3 , J = 7.0 Hz); MS (FAB + ) m / z : 341.2 [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. This was prepared by general method using resorcinol (486 mg; 4.41 mmol), 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 flash chromatography (CHCl 3 /acetone gradient, 8:1 to 4:1), and the off-white waxy solid isolated was recrystallized from acetone/hexane to give 38b as a white soft solid (123 mg; 0.07%). R f : 0.86 (CHCl 3 /acetone, 3:1); mp 59–61 °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 ), 2.38 (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, 1H, C 6 –H, J = 2.3, 8.6 Hz), 6.84 (d, 1H, C 8 –H, J = 2.3 Hz) and 7.48 (d, 1H, C 5 –H, J = 8.6 Hz); MS (FAB + ) m / z : 387.3 [100, (M + H) + ]; MS (FAB – ) m / z : 385.3 [100, (M – H) − ]; Acc. MS (FAB + ): 387.2892, C 25 H 39 O 3 requires 387.2899. Compound 38b (90 mg; 0.23 mmol) was sulfamoylated, the crude white solid was purified by preparative TLC (CHCl 3 /ethyl acetate gradient, 6:1), and the white solid 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 °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 ), 2.43 (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; C 25 H 39 NO 5 S requires C, 64.48; H, 8.44; N, 3.01%. This was prepared by general method using resorcinol (2.0 g; 18 mmol), ethyl 2-chloro-3-oxo-butanoate (2.99 g; 18 mmol), and a mixture of CF 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 by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the yellow solid isolated was recrystallized from acetone/hexane to give 39a as off-white crystals (692 mg; 18%). R f : 0.72 (CHCl 3 /acetone, 3:1); mp 250–253 °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, OH); MS (FAB + ) m / z : 211.1 [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; found C, 57.30; H, 3.39; C 10 H 7 ClO 3 requires C, 57.03; H, 3.35%. Compound 39a (400 mg; 1.9 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid 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 °C; 1 H NMR (400 MHz; DMSO- d 6 ) δ H : 2.59 (s, 3H, CH 3 ), 7.35 (dd, 1H, C 6 –H, J = 2.1, 8.8 Hz), 7.39 (d, 1H, C 8 –H, J = 2.1 Hz), 7.98 (d, 1H, C 5 –H, J = 8.8 Hz) and 8.29 (s, 2H, NH 2 ); MS (FAB + ) m / z : 290.0 [100, (M( 37 Cl) + H) + ]; MS (FAB – ) m / z : 288.1 [100, (M( 35 Cl) – H) − ], 209.1 [50, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ) m / z : 290.9860, C 10 H 9 37 ClNO 5 S requires 290.9782 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; N, 4.84%. This was prepared by general method using resorcinol (2.13 g; 19.4 mmol), ethyl 3-oxo-2-phenylbutanoate (4.0 g; 19 mmol), and a mixture of 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 recrystallization from ethanol to give 40a as yellow needles (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 (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), 7.66 (d, 1H, C 5 –H, J = 8.8 Hz) and 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 [100, (M – H) − ]; Acc. MS (FAB + ): 253.0798, C 16 H 12 O 3 requires 253.0786; found C, 76.10; H, 4.84; C 16 H 12 O 3 requires C, 76.18; H, 4.79%. Compound 40a (400 mg; 1.6 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid 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 °C; 1 H NMR (400 MHz; DMSO- d 6 ) δ H : 2.28 (s, 3H, CH 3 ), 7.31–7.38 (m, 2H, C 6 –H and C 8 –H), 7.40–7.49 (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 + H) + ], 253.0 [15, (M + H – HNSO 2 ) + ]; MS (FAB – ) m / z : 330.1 [100, (M – H) − ], 251.1 [60, (M – H 2 NSO 2 ) − ]; Acc. 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; N, 4.23%. This was prepared by general method using resorcinol (1.99 g; 18.2 mmol), ethyl 2-benzyl-3-oxo-butanoate (4.0 g; 18 mmol), and a mixture of 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 recrystallization from ethanol to give 41a as white crystals (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; DMSO- d 6 ) δ H : 2.39 (s, 3H, CH 3 ), 3.92 (s, 2H, CH 2 Ph), 6.71 (d, 1H, C 8 –H, J = 2.4 Hz), 6.80 (dd, 1H, C 6 –H, J = 2.4, 8.8 Hz), 7.15–7.28 (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) + ], 267.1 [100, (M + H) + ]; MS (FAB – ) m / z : 265.1 [100, (M – H)]; Acc. MS (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%. Compound 41a (400 mg; 1.5 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid 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 Ph–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) + ]; MS (FAB – ) m / z : 344.1 [100, (M – H) − ], 265.1 [60, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ): 346.0755, C 17 H 16 NO 5 S requires 346.0749; 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%. This was prepared by general method using K 2 CO 3 (8.97 g; 64.85 mmol), water (50 mL), (2-bromoethyl)benzene (5.0 mL; 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). The crude oily residue was purified by flash chromatography (CHCl 3 ) to give 42a as a pale yellow oil (2.17 g; 34%). (Lit. 72 bp 1.4 167–168 °C); R f : 0.78 (CHCl 3 ); 1 H NMR (400 MHz; CDCl 3 ) δ H : 1.25 (t, 3H, CH 2 C H 3 , J = 6.7 Hz), 2.29 (s, 3H, CH 3 ), 3.02 (q, 2H, C H 2 CH 2 Ph, J = 7.1 Hz), 3.71 (t, 1H, CH 2 , J = 7.3 Hz), 3.95 (t, 2H, CH 2 Ph, J = 7.1 Hz), 4.11 (q, 2H, C H 2 CH 3 , J = 7.1 Hz) and 7.16–7.34 (m, 5H, Ph–H); MS (FAB + ) m / z : 235.0 [100, (M + H) + ]; Acc. MS (FAB + ): 235.1335, C 14 H 19 O 3 requires 235.1334. This was prepared by general method using resorcinol (705 mg; 6.4 mmol), 42a (1.5 g; 6.4 mmol), and a mixture of CF 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 (CHCl 3 /acetone gradient, 8:1 to 4:1), and the white solid isolated was recrystallized from acetone/hexane to give 42b as gray crystals (746 mg; 42%). R f : 0.80 (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 (t, 2H, PhC H 2 , J = 5.2 Hz), 6.69 (d, 1H, C 8 –H, J = 2.4 Hz), 6.78 (dd, 1H, C 6 –H, J = 2.4, 8.5 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, OH); MS (FAB + ) m / z : 561.1 [10, (2M + H) + ], 281.0 [100, (M + H) + ]; MS (FAB – ) m / z : 279.1 [100, (M – H)]; Acc. MS (FAB + ): 281.1182, C 18 H 17 O 3 requires 281.1178; found C, 77.35; H, 5.95; C 18 H 16 O 3 requires C, 77.12; H, 5.75%. Compound 42b (400 mg; 1.43 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid isolated was recrystallized from ethyl acetate/hexane to give 42 as white fine crystals (132 mg; 26%). R f : 0.54 (CHCl 3 /ethyl acetate, 4:1); mp 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, 7H, C 6 –H, C 8 –H, and Ph–H), 7.83 (d, 1H, C 5 –H, J = 8.8 Hz) and 8.19 (s, 2H, NH 2 ); MS (FAB + ) m / z : 360.0 [100, (M + H) + ]; MS (FAB – ) m / z : 358.0 [100, (M – H) − ], 279.1 [40, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ): 360.0917, C 18 H 18 NO 5 S requires 360.0906; found 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%. This was prepared by general method using K 2 CO 3 (16.7 g; 0.12 mol), water (60 mL), 1-bromo-3-phenylpropane (10.0 mL; 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). The crude oily residue was purified by flash chromatography (CHCl 3 /hexane, 10:1) to give 43a as a colorless oil (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 (m, 6H, CH 2 ), 2.64 (t, 1H, 2H, J = 7.8 Hz), 4.21 (q, 2H, C H 2 CH 3 , J = 7.0 Hz) and 7.15–7.29 (m, 5H, Ph–H); MS (FAB + ) m / z : 249.1 [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. This was prepared by general method using resorcinol (443 mg; 4.03 mmol), 43a (1.0 g; 4.0 mmol), and a mixture of 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 flash chromatography (CHCl 3 /acetone gradient, 8:1 to 4:1), and the white solid isolated was recrystallized from THF/hexane to give 43b as pale green crystals (275 mg; 22%). R f : 0.76 (CHCl 3 /acetone, 3:1); mp 189–191 °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. MS (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 = 7.8 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 (m, 6H, C 6 –H and Ph–H), 7.42 (d, 1H, C 5 –H, J = 8.8 Hz) and 10.25 (s, 1H, OH); found C, 77.13; H, 6.28; C 19 H 18 O 3 requires C, 77.53; H, 6.16%. Compound 43b (230 mg; 0.78 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate gradient, 8:1 to 2:1), and the white solid isolated was recrystallized from THF/hexane to give 43 as white crystals (62 mg; 21%). R f : 0.54 (CHCl 3 /ethyl acetate, 4:1); mp 154–156 °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 = 8.2 Hz), 2.67 (t, 2H, CH 2 CH 2 C H 2 Ph, J = 7.4 Hz), 7.15–7.39 (m, 7H, C 8 –H, C 6 –H and Ph–H), 7.87 (d, 1H, C 5 –H, J = 8.8 Hz) and 8.19 (s, 2H, NH 2 ); MS (FAB + ) m / z : 374.0 [100, (M + H) + ]; MS (FAB – ) m / z : 372.1 [100, (M – H) − ], 293.1 [40, (M – H 2 NSO 2 ) − ]; Acc. MS (FAB + ): 374.1060, C 19 H 20 NO 5 S requires 374.1062; found 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%. This was prepared by general method using K 2 CO 3 (7.5 g; 54 mmol), water (50 mL), cyclohexylmethyl bromide (4.0 mL; 23 mmol), ethyl 3-oxo-butanoate (2.9 mL; 23 mmol), CH 2 Cl 2 (50 mL) and Bu 4 NCl (∼10 g; 23 mol). The crude pale yellow oil was purified by flash chromatography (CHCl 3 ) to give 44a as a pale yellow oil (1.44 g; 28%). (Lit. 73 bp 19 166 °C); R f : 0.58 (CHCl 3 ); 1 H NMR (400 MHz; CDCl 3 ) δ H : 1.08–1.34 (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 (t, 1H, 2H, J = 7.4 Hz) and 4.21 (q, 2H, C H 2 CH 3 , J = 7.0 Hz); MS (FAB + ) m / z : 227.3 [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. This was prepared by general method using resorcinol (487 mg; 4.42 mmol), 44a (1.0 g; 4.4 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 orange solid was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the white solid isolated was recrystallized from THF/hexane to give 44b as fine white crystals (409 mg; 34%). R f : 0.74 (CHCl 3 /acetone, 3:1); mp 193–196 °C; 1 H NMR (400 MHz; DMSO- d 6 ) δ H : 1.11–1.91 (m, 11H, cyclohexyl-H), 2.35 (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) + ], 273.2 [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%. Compound 44b (300 mg; 1.10 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid isolated was recrystallized from ethyl acetate/hexane to give 44 as white crystals (46 mg; 12%). R f : 0.55 (CHCl 3 /ethyl acetate, 4:1); mp 170–171 °C; 1 H NMR (400 MHz; DMSO- d 6 ) δ H : 1.22–1.31 (m, 11H, cyclohexyl-H), 2.06 (s, 3H, CH 3 ), 2.58 (d, 2H, CH 2 , J = 7.0 Hz), 7.32–7.35 (m, 2H, C 8 –H and 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 + H) + ]; MS (FAB – ) m / z : 350.0 [100, (M – H) − ], 271.1 [45, (M – H 2 NSO 2 ) − ]; Acc. 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; N, 3.99%. This was prepared by general method using K 2 CO 3 (8.68 g; 62.8 mmol), water (60 mL), 1-bromo-2-cyclohexylethane (5.0 mL; 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). The crude orange oily residue was purified by flash chromatography (CHCl 3 ) to give 45a as a pale yellow oil (850 mg; 14%). (Lit. 73 bp 19 175 °C); R f : 0.72 (CHCl 3 ); 1 H NMR (400 MHz; CDCl 3 ) δ H : 1.19–1.66 (m, 13H, cyclohexyl-H and CH 2 ), 1.27 (t, 3H, CH 2 C H 3 , J = 7.0 Hz), 1.80–1.87 (m, 2H, CH 2 ), 2.22 (s, 3H, CH 3 ), 3.35 (t, 1H, 2H, 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 + H) + ]; MS (FAB – ) m / z : 239.3 [100, (M – H) − ]; Acc. MS (FAB + ): 241.1804, C 14 H 25 O 3 requires 241.1804. This was prepared by general method using resorcinol (343 mg; 3.12 mmol), 45a (750 mg; 3.12 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 orange solid was purified by flash chromatography (CHCl 3 /acetone, 8:1 to 4:1 gradient), and the white solid isolated was recrystallized from THF/hexane to give 45b as white crystals (352 mg; 39%). R f : 0.79 (CHCl 3 /acetone, 3:1); mp 148–151 °C; 1 H NMR (400 MHz; DMSO- d 6 ) δ H : 1.11–1.73 (m, 11H, cyclohexyl-H), 2.34 (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, (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 287.1647; found C, 75.50; H, 7.67; C 18 H 22 O 3 requires C, 75.50; H, 7.74%. Compound 45b (250 mg; 0.87 mmol) was sulfamoylated, the crude white solid was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 2:1 gradient), and the white solid isolated was recrystallized from ethyl acetate/hexane to give 45 as white fine crystals (155 mg; 49%). R f : 0.47 (CHCl 3 /ethyl acetate, 4:1); mp 179–181 °C; 1 H NMR (400 MHz; DMSO- d 6 ) δ H : 1.19–1.78 (m, 11H, cyclohexyl-H), 2.41 (s, 3H, CH 3 ), 2.49–2.59 (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; C 18 H 23 NO 5 S requires C, 59.16; H, 6.34; N, 3.83%. To a CH 2 Cl 2 (100 mL) solution of 2,4-dihydroxyacetophenone (5.0 g; 33 mmol; 1 equiv), tetrabutylammonium hydrogensulphate (300 mg; 0.88 mmol; 0.03 equiv), and 20% aq K 2 CO 3 (100 mL) was added 4-methoxyphenylacetyl chloride (6.7 g; 36 mmol; 1.1 equiv) CH 2 Cl 2 (30 mL) dropwise over 30 min and stirred for 4 h at rt. The organic layer was separated, washed with water (3 × 200 mL), dried, and concentrated. The crude pale brown syrup was purified by flash chromatography (CHCl 3 /ethyl acetate, 8:1 to 4:1 gradient), and the pale yellow solid isolated was recrystallized from THF/hexane to give 46a as white crystals (1.2 g; 13%). R f : 0.68 (UV visible and fluorescent) (ethyl acetate/hexane, 1:1); mp 230–232 °C (Lit. 74 mp 233–234 °C); 1 H NMR (400 MHz; DMSO- d 6 ) δ H : 2.60 (s, 3H, CH 3 ), 3.81 (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) + ]; MS (FAB – ) m / z : 281.2 [100, (M – H) − ]; Acc. MS (FAB + ): 283.0898, C 17 H 15 O 4 requires 283.0892; found C, 71.98; H, 5.36; C 17 H 14 O 4 requires C, 72.33; H, 5.00%. Upon sulfamoylation, compound 46a (500 mg; 1.77 mmol) gave a crude white solid, which was fractionated by flash chromatography (CHCl 3 /ethyl acetate 8:1 to 2:1 gradient). The white solid isolated was recrystallized from ethyl acetate/hexane to give 46 as white fine leaves (331 mg; 52%). R f : 0.86 (CHCl 3 /ethyl acetate, 4:1); mp 129–132 °C; 1 H NMR (400 MHz; DMSO- d 6 ) δ H : 2.77 (s, 3H, 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; C 17 H 15 NO 6 S requires C, 56.50; H, 4.18; N, 3.88%. ref. ( 45 )

Breast cancer is a major health threat to women of all age groups and a prime contributor to cancer deaths in women. About two-thirds of cases when first diagnosed are classified as hormone-dependent (ER + ), in which to grow and develop the tumors need estrogens, which act via the estrogen receptor (ER). 1 Endocrine therapy administered by the oral route is an effective form of treatment for this type of cancer. 2 Although newer targeted agents such as mTOR and CDK4/6 inhibitors, e.g., everolimus and palbociclib, are now gaining recognition in treatment, they are expensive and are administered in conjunction with endocrine therapy. 3 , 4 Currently, the first-line treatment for patients with hormone-dependent breast cancer (HDBC) includes either a selective estrogen-receptor modulator, such as tamoxifen, which blocks the action of estrogens at the ER or an ER downregulator (SERD), 5 or a “third-generation” aromatase inhibitor (AI) such as letrozole, anastrozole, and exemestane. This strategy leads to a reduction in the biosynthesis of estrogens and has been found to be superior to tamoxifen alone. 6 Also, in one study, anastrozole has shown significant preventative activity in high-risk postmenopausal women with undiagnosed breast cancer. 7 However, resistance will inevitably occur and blocking the action of estrogens at the ER and inhibiting the aromatase enzyme are not the only strategies available for endocrine therapy. There is now evidence that inhibition of steroid sulfatase (STS), 8 the enzyme that converts the biologically inactive estrone sulfate to estrone, as well as dehydroepiandrosterone sulfate to dehydroepiandrosterone, may render significant estrogen deprivation in patients treated with an STS inhibitor. This strategy works in an intracrine fashion because in the postmenopausal setting tumor cells can convert the large reservoir of circulating estrone sulfates, imported through organic anion transporters, to active estrogen in situ. Moreover, STS inhibition also decreases levels of androstenediol, an estrogenic androgen, 9 levels of which are unaffected by AI inhbition. Chronic AI treatment leads to compensatory increases in both STS and 17β-HSD1 levels. 10 Moreover, the contribution of both STS and organic anion transporters to AI resistance was recently established and could be overcome by an STS inhibitor. 11 These ideas have led to STS inhibitors reaching phase II clinical trials for several indications in oncology including breast cancer and endometrial cancer and a phase I trial in prostate cancer. 12 The first STS inhibitor discovered with a remarkable potency was the steroidal sulfamate ester estrone-3- O -sulfamate (EMATE, 1 , Figure 1 ). 13 This agent is orally active and inhibits STS in an irreversible manner. However, EMATE was subsequently shown to be highly estrogenic in rats and this undesirable property effectively precluded its further development for use in the treatment of HDBC, although the estradiol variant (E2MATE, PGL2001, 1a ) has nevertheless proceeded to clinical trials in the hormone-dependent nononcology setting of endometriosis. 12a , 12b , 14 Structures of STS inhibitors: 1 (EMATE), 1a (E2MATE), and 2 (Irosustat, STX64, 667COUMATE, BN83495). In an attempt to search for a nonestrogenic alternative to 1 with a comparable or even superior STS inhibitory profile, many structurally diverse inhibitors that contain the pharmacophore for irreversible inhibition of STS, i.e., an aryl sulfamate ester, have 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 sulfamates 17 ( 3 – 8 , Figure 2 ) that were promising leads, showed a significant improvement over the first lead nonsteroidal candidate 5,6,7,8-tetrahydronaphthalene 7- O -sulfamate, and, more significantly, possessed in vivo activity. A main lead was the two-ring 4-methylcoumarin-7- O -sulfamate ( 3 ) that was orally active in vivo and, like EMATE, was a highly potent time- and concentration-dependent STS inhibitor, but importantly with no rodent estrogenic activity. 18 , 19 The related 3,4-dimethylcoumarin-7- O -sulfamate ( 6 ) inhibited STS in MCF-7 cells with IC 50 = 30 nM, and a series of derived tricyclic compounds was subsequently synthesized that proved even more potent. 16 , 17 Further development of this series of nonsteroidal inhibitors led to the discovery of the tricyclic coumarin sulfamate ( 2 ) (Irosustat, STX64, 667COUMATE, BN83495, Figure 1 ) which has proven to be the most successful STS inhibitor to date. 12 , 16 Recently, other examples of both mono- 20 , 21 and two-ring sulfamate-based STS inhibitors 22 have been published, but these compounds are generally still of relatively modest inhibitory activity. Irosustat was the first STS inhibitor to enter clinical trials for postmenopausal patients with advanced HDBC and has shown encouraging results. 12 , 23 − 26 Irosustat has just completed CRUK sponsored phase II trials in both early breast cancer and in advanced breast cancer in combination with an AI, with positive indications of efficacy. 27 , 28 Structures of bicyclic coumarin sulfamates 3 – 8 , including COUMATE 3 . X = OSO 2 NH 2 . However, despite the significant progress made in developing irreversible inhibitors of STS and although 1a and 2 have reached clinical trials, their mechanism of action remains unresolved. The crystal structure of human STS has been solved, 29 , 30 and several hypotheses have been postulated to suggest how a sulfamate-based STS inhibitor might inhibit STS irreversibly. The currently favored hypothesis is a transfer of the sulfamoyl group (or as sulfonylamine) to a hydrated or unhydrated STS active site formylglycine residue, and this leads to inactivation of the active site machinery. 12b Although multiple mechanisms have been proposed for this, e.g. ref. ( 12e ), see ref. ( 12b ) for a full up-to-date discussion. Because of the unique role that a coumarin ring system plays in the design of potent STS inhibitors, we further expand here the bicyclic coumarin sulfamate series exemplified by 3 – 8 to give derivatives that bear various substituents at the 3- and/or 4-position(s), following on from preliminary encouraging data. 17 The inhibitory activities of most new candidates against STS were evaluated in MCF-7 cells and in placental microsomes. This study, in conjunction with other studies carried out on 2 , 16 , 17 provides a more comprehensive structure–activity relationship (SAR) for coumarin sulfamates and has also produced highly active inhibitors of picomolar potency in vitro. The activity of two of the best bicyclic compounds is supported by molecular modeling and by comparing binding poses with those of the benchmark compounds EMATE and Irosustat.