Synthesis of 4-oxo- and 4-anti-formyl-8,10,12,13-tetraoxapentacyclo[5.5.1.0(2,6).0(3,11).0(5,9)]tridecanes

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Synthesis of 4-Oxo- and 4-anti-Formyl-8,10,12,13-tetraoxapentacyclo-

[5.6.1.02~~.0~J~.O~~~]tridecanes

Hsien-Jen Wu’ and Jyh-Haur Chern

Department of applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan, China

Abstract:

The synthesis of 4-0x0- and 4-anti-formyl-8,10,12,13- tetraoxapentacyclo[5.5.1.02~6.03~11.05~9]tridecanes has been accomplished. Ozonolysis of compounds lOa,b and 12a-c in dichloromethane at -78 “C followed by reduction with dimethyl sulfide gave the title compounds, 4- oxo-tetraoxa-cages lla,b and 14a-q in moderate yields. Ozonolysis of the endo-syn isomers 15a,b and 18a,b under the same reaction conditions gave 4-anti-formyl-tetraoxa-cages 17a,b and 20a,b, respectively.

0 1997 Published by Elsevier Science Ltd. Introduction

The synthesis and chemistry of polycyclic cage compounds have attracted considerable attention in recent years.1 The vast majority of the work reported in this area has dealt with carbocyclic cage compounds, such as triprismane ,2 tetraprismane (cubane),x pentaprismane,4 homopentaprismane,5 hexaprismane,G dodecahedrane,T heptacyclotetradecane (HCTD),* pogodane,g and fullerenes.10 On the other hand, the synthesis and chemistry of heterocyclic cage compounds have received less attention. However, there are some reports regarding the chemistry11 and synthesislz-17 of oxa-cage compounds in the literature. This class of heterocyclic cage compounds is synthesized by intramolecular alkene-oxirane (20-271) photocycloaddition,‘z by transannular cyclization of suitable compounds,13 by tandem cyclization,l4 by dehydration of diols having the proper stereochemistry, 15 by base-promoted rearrangement,16 and by intramolecular etherification of an alkene bond with organoselenium reagents.”

Recently, we developed new methods for the synthesis of a series of oxa-cage compounds, such as diacetal trioxa-cages,18 triacetal trioxa-cages, lg tetraacetal tetraoxa-cages,20 tetraacetal pentaoxa-cages,21 and pentaacetal pentaoxa-cages (the pentaoxa[5]peristylanes).22 We also

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17654 H.-J. WV and J.-H. CHERN

investigated the chemical nature of the acetal groups of tetraoxa-cages and discovered a novel hydride rearrangement and one-pot conversion from oxa-cages to aza-cages.23 As part of a program that involves the synthesis, chemistry, and applications of new heterocyclic cages, we report here the synthesis of 4-0x0- and 4-anti-formyl-8,10,12,13tetraoxapentacyclo-

[5.5.1.02~6.03~ii.O5~s]tridecanes. 4-0xo-8,10,12,13-tetraoxapentacyclo[5.5.1.0~~~.03~~~.0~~9]tridecane is a new system for the facial selectivity study on carbonyl group. We have investigated the facial selectivity of a series of oxa-cages, and the results will be reported soon.

Results and Discussion

Reaction of 6,8dimethylfulvene 1 (commercially available) with (Z)-3-hexene-2,5-dione 2azoa in dichloromethane at 25 “C for 24 h gave the endo adduct 3 (10%) and compound 4 (50%) (Scheme 1). When the reaction time was prolonged at 25 “C for 72 h, compound 4 was obtained in 70% yield. Refluxing the adduct 3 in dichloromethane for 24 h gave 4 in 80% yield. NO detectable amount of the other regioisomer 5 was obtained. The regiochemistry of 4 was determined by iH-lH correlated two-dimensional NMR spectral analysis. Proton HI (6 6.53) showed strong coupling to proton HZ (6 5.74), which, in turn, displayed coupling to proton H3 (6 5.30). ‘Proton H3 exhibited strong coupling to proton H4 (6 3.69), which, in turn, showed coupling to H5 (S 3.03), and Ha displayed coupling to Hs (6 4.87). The stereochemistry of 4 was determined on the basis of NOE experiments. Irradiating the H4 proton gives 4.8% enhancement for the H3 proton absorptions and 4.2% enhancement for the H5 proton absorptions. Reaction of 1 with (Z)-y-oxo-a&unsaturated thioesters 6a-c209 in CHzC12 at 25 “C for 24 h gave compounds 8a-c in 60-65% yields. The amount of the endo adducts 7a-c was too small to be isolated. We proposed that compounds 4 and 8 were obtained by a [3,3] sigmatropic rearrangement from 3 and 7, respectively.

To improve the yields of the endo adducts, 6-acetoxyfulvene 9 was prepared for the Diels- Alder reaction as a diene. Reaction of 9 with the ene-diones 2a,b in dichloromethane at 25 “C for 48 h gave the endo adducts lOa,b in 50-55% yields, with unreacted starting compounds. Ozonolysis of lOa,b in dichloromethane at -78 “C followed by reduction with dimethyl sulfide gave I-oxo-tetraoxa-cage compounds lla,b in 60-66% yields (Scheme 2). Ownolysis of 3 under the same reaction conditions gave lla in 65% yield. Thus, we have accomplished the synthesis of new tetraoxa-cages with a carbonyl group on the apex carbon, 4-0x0-8,10,12,13- tetraoxapentacyclo[5.5.1.02~6.03~~~.0~~9]tridecanes, in a short sequence.

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Synthesis of oxa-cage compounds Scheme 1 17655 l+Za- 4 CH2C12 25 ‘C 12 h l+oyoF[ &zcH]-q: 3 b R= i-C3H7 7 c R = n-C4Hs Scheme 2

03

CHzClz -18 oc MQS - 03 I&# 3 - - lla CH2C12 -78 OC bR=H

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Reaction of 9 with 6a-c in dichloromethane at 25 “C for 48 h gave the endo adducts 12ac (30%) and compounds 13a-c (35%) (Scheme 3). Both compounds 12 and 13 contained two regioisomers in each case from their 1H and W NMR spectra. Ozonolysis of 12a-c in dichloromethane at -78 “C followed by reduction with dimethyl sulfide gave 4-oxo-tetraoxa-cage compounds 14a-c in 60-65O4 yields.

Scheme 3

c R = n-C4Hg R

Hydrolysis of the endo adducts lOa,b with a catalytic amount of sodium carbonate in aqueous methanol (1:l) at 25 “C gave the endo-syn isomers lSa,b in 80-90% yields (Scheme 4). The amount of the endo-anti isomers 16a,b was too small to be isolated. The stereochemistry of the formyl group on the apical carbon of 15 was determined by the following chemical transformation. Ozonolysis of 15a,b in dichloromethane at -78 “C followed by reduction with dimethyl sulfide gave the tetraaectal tetraoxa-cages 17a,b in 75-85% yields.

Scheme 4 NazC03 lOn,b - MeOH-H20 25 Oc 03 lSa,b - - CH2C12

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Synthesis of oxa-cage compounds 17657

Hydrolysis of the mixtures of the two regioisomers of 12a,b with a catalytic amount of sodium carbonate in aqueous methanol (1:l) at 25 “C gave the endo-syn isomers 18a,b and the

endo-anti isomers 19a,b in ratios of 7-8:l in 80-85% yields (Scheme 5). The stereochemistry of

the formyl group on the apical carbon of 18 and 19 was determined by the following chemical transformation. Ozonolysis of the endo-syn isomers 18a,b in dichloromethane at -78 “C followed by reduction with dimethyl sulfide gave the methylthio group substituted tetraacetal tetraoxa-cages 20a,b in 80-85% yields. As expected, the thioester group of 18a,b participated the cyclization process.2”

Scheme 5 Na$OJ 12a,b - MeOH-Hz0 03 lSa,b - - CH2C12 -78 ‘C Conclusion 20 aR=CH3 b R = i-C3H7

We have accomplished the synthesis of 4-0x0- and 4-anti-formyl-8,10,12,13- tetraoxapentacyclo[5.5.l.O~~~.O~~~~.O~~~]tridecanes in a short sequence. Ozonolysis of compounds lOa,b and 12a-c in dichloromethane at -78 “C followed by reduction with dimethyl sulfide gave the title compounds, 4-oxo-tetraoxa-cages lla,b and 14a-c, in moderate yields. Ozonolysis of the endo-syn isomers lSa,b and lSa,b under the same reaction conditions gave I-anti-formyl- tetraoxa-cages 17a,b and 20a,b, respectively. The formation of tetraoxa-cages can aslo be used as a probe for determining the stereochemistry of the formyl group on the apical carbon.

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17658 H.-J. WV arid J.-H. CHERN

Experimental Section

General. Melting points were determined in capillary tubes with a Laboratory Devices melting point apparatus and uncorrected. Infrared spectra were recorded in CHCl, solutions or

on neat thin films between NaCl disks. ‘H NMR spectra were determined at 300 MHz, and i3C NMR were determined at 75 MHz on Fourier transform spectrometers. Chemical shifts are

reported in ppm relative to TMS in the solvents specified. The multiplicities of 13C signals were determined by DEPT techniques. High resolution mass values were obtained with a high resolution mass spectrometer at the Department of Chemistry, National Tsing Hua University. Elemental analyses were performed at the microanalysis laboratory of National Taiwan University. For thin-layer chromatography (TLC) analysis, precoated TLC plates (Kieselgel60 F254) were used, and column chromatography was done by using KieseIgeI 60 (70-230 mesh) as the stationary phase. THF was distilled immediately prior to use from sodium benzophenone ketyl under nitrogen. CH,Cl, was distilled from CaH, under nitrogen.

Reaction of 6,6-Dimethylfulvene with (Z)-3-Hexene-t,&dione 2a.

To a solution of (Z)-3-hexene-2,5-dione 2a 20a (1.1 g, 9.5 mmol) in dichloromethane (20 mL) was added 6,6-dimethylfulvene (1.0 g, 9.4 mmol) at 25 “C. The reaction mixture was stirred at 25 “C for 24 h. The solvent was evaporated and the crude product was purified by column chromatography to give the endo adduct 3 (0.21 g, 10%) and compound 4 (1.02 g, 50%). Spectral data for 3: pale yellow oil; IR (neat) 2980, 1710, 1380 cm.l,iH NMR (300 MHz, CDC13)

6 6.33 (brs, 2H), 3.62 (brs, 2H), 3.35 (brs, 2H), 2.10 (s, 6H), 1.57 (s, 61-I); 1X! NMR (75 MHz, CDC13, DEPT) 6 206.43 (2CO), 144.34 (C), 137.89 (C), 134.55 (2CH), 57.08 (2CH), 46.41 (2CI-Q 29.97 (2CH3), 19.44 (2CH3); LRMS m/z (rel inten) 218 (M+, 36), 203 (40), 112 (100); HRMS (EI) calcd for Ci4HisC2 218.1307, found 218.1301.

Spectral data for 4: pale yellow oil; IR (neat) 2980, 1705, 1360 cm-l; 1H NMR (300 MHz, CDCl3) 6 6.53 (d, J= 6.0 Hz, lH), 5.74 (dd, J= 6.0, 1.5 Hz, III), 5.30 (dd, J= 8.1, 1.5 Hz, lH), 4.87 (d, J

= 4.5 Hz, lH), 3.69 (dd, J= 6.6, 4.5 Hz, lH), 3.03 (dd, J= 8.1, 6.6 Hz, 1H) , 2.16 (s, 3H), 1.74 (s,

3I-Q 1.70 (s, 3H), 1.65 (s, 3H), ‘3C NMR (75 MHz, CDCl3, DEPT) 6 206.57 (CO), 151.91 (C), 140.43 (C), 133.67 (CH), 132.36 (CH), 123.01 (C), 96.64 (CI-I) 81.55 (CH), 49.26 (CH), 40.06 (CH), 27.18 (CH3), 20.56 (CH3), 20.24 (CH3), 20.13 (CH3); LRMS m/z (rel inten) 218 @I+, 21) 203 (100); HRMS (EI) calcd for C14HisC2 218.1307, found 218.1312.

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Synthesis of oxa-cage compounds 17659

in dichloromethane (50 mL) was refluxed at 45 “C for 48 h. After cooling, the solvent was evaporated and crude product was purified by column chromatography to give 3a (0.80 g, 80%).

General Procedure for Reaction of 6,6_Dimethylfulvene with (Z)- 7 -0x0- a , B -

unsaturated Thioesters 6a-c. To a solution of (Z)-methyl- r -oxo-2-pententhioate 6a (1.36 g, 9.4 mmol) in dichloromethane (20 mL) was added 6,6_dimethylfulvene (1.0 g, 9.4 mmol) at 25 “C. The reaction mixture was stirred at 25 “C for 48 h. The solvent was evaporated and the crude product was purified by column chromatography to give 8a in 65% yield with unreacted starting compounds. Spectral data for 8a: pale yellow oil; IR (neat) 2960, 2880, 1685, 1380 cm-l, 1H NMR (300 MHz, CDC13) c? 6.52 (d, J= 5.7 Hz, lH), 5.78 (dd, J= 5.7, 1.5 Hz, lH), 5.29 (dd, J= 7.2, 1.5 Hz, lH), 4.83 (d, J= 4.5 Hz, lH), 3.66 (dd, J= 6.9, 4.5 Hz, lH), 3.16 (dd, J= 7.2, 6.9 Hz, 1H) , 2.28 (s, 3H), 1.76 (s, 3I-I) 1.75 (s, 3H), 1.70 (s, 3H); W NMR (75 MHz, CDC13, DEPT) 6 202.26 (COS), 153.34 (C), 139.96 (C), 133.76 (CH), 133.06 (CH), 124.81 (C), 96.78 (CH), 81.66 (CH), 49.87 (CH), 42.36 (CH), 21.20 (CH3), 20.88 (CH3), 20.59 (CH3), 12.08 (SCH3); LRMS m/z (rel inten) 250 @I+, 18), 203 (100); HRMS (EI) calcd for Cl4H1802S 250.1028, found 250.1024.

Spectral data for 8b: pale yellow oil; yield 63% IR (neat) 2960, 1685, 1380 cm-l; 1H NMR (300 MHz, CDC13) 6 6.53 (d, J= 5.7 Hz, lH), 5.72 (dd, J= 5.7, 1.5 Hz, lH), 5.32 (dd, J= 7.2, 1.5 Hz, lH), 4.90 (d, J= 4.8 Hz, lH), 3.77 (dd, J= 6.9, 4.8 Hz, lH), 3.14 (dd, J= 7.2, 6.9 Hz, 1H) , 2.26 (s, 3H), 2.24-2.17 (m, lH), 1.75 (s, 3H), 1.74 (s, 3H), 1.04 (d, J= 6.6 Hz, 3H), 1.03 (d, J= 6.6 Hz, 3H); l3C NMR (75 MHz, CDC13, DEPT) 6 202.64 (COS), 161.76 (C), 140.29 (C), 134.14 (CH), 132.83 (CH), 124.43 (C), 95.04 (CH), 81.84 (CH), 49.58 (CH), 43.35 (CH), 32.57 (CH), 21.03 (CH3), 20.85 (CH3), 19.63 (CH3), 19.34 (CH3), 12.11 (SCH3); LRMS m/z (rel inten) 278 (M’, 8), 231 (100); HRMS (EI) calcd for CisH2202S 278.1341, found 278.1338.

Spectral data for 8c: pale yellow oil; IR (neat) 2970, 1685, 1370 cm-l; iH NMR (300 MHz, CDC13) 6 6.52 (d, J= 6.0 Hz, lH), 5.75 (dd, J= 6.0, 1.5 Hz, lH), 5.29 (dd, J= 7.2, 1.5 Hz, lH), 4.85 (d, J = 4.5 Hz, lH), 3.70 (dd, J= 6.9, 4.5 Hz, lH), 3.14 (dd, J= 7.2, 6.9 Hz, 1H) , 2.27 (s, 3H), 2.05-1.98 (m, 2H), 1.75 (s, 3I-I) 1.72 (s, 3H), 1.48-1.25 (m, 4H), 0.89 (t, J= 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3, DEPT) 6 202.35 (COS), 156.95 (C), 140.17 (C), 133.90 (CH), 133.06 (CH), 124.58 (C), 96.52 (CH), 81.69 (CH), 49.79 (CH), 42.79 (CH), 34.14 (CH2), 28.25 (CH2), 22.22 (CH2), 21.15 (CHJ), , 20.83 (CH3), 13.80 (CH3), 12.08 (SCH3); LRMS m/z (rel inten) 292 &I+, 11) 245 (100); HRMS (EI) calcd for C17H2402S 292.1497, found 292.1489.

General Procedure for Reaction of 6-Acetoxyfulvene with (Z)-2-Ene-l,l-diones 2a,b.

To a solution of 2a (0.82 g, 7.4 mmol) in dichloromethane (20 mL) was added 6-acetoxyfulvene (1.0 g, 7.3 mmol) at 25 “C. The reaction mixture was stirred at 25 “C for 48 h. The solvent was

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17650 H.-J. WV and J.-H. CHENN

evaporated and the crude product was purified by column chromatography to give the endc adduct 10a (0.98 g, 55%). In the case of lob, the product contained two regioisomers. Spectral data for 10a: pale yellow oil; IR (neat) 2980, 2880, 1755, 1710, 1225 cm-i; iH NMR (300 MHz, CDCls) 6 6.60 (s, lH), 6.32 -6.29 (m, 2H), 3.87 (brs, lH), 3.50-3.42 (m, 3H), 2.13 (s, 31-1) 2.11 (8, 3H) 2.10 (8, 3H); i3C NMR (75 MHz, CDCl3, DEPT) 6 205.41 (CO), 205.35 (CO) , 168.17 (CO), 136.76 (C), 134.49 (CI-I), 133.50 (CH), 116.45 (CH), 57.33 (CH), 56.14 (CH), 46.70 (CH), 44.75 (CH), 29.97 (CH3), 29.89 (CH3), 20.59 (CH3); LRMS m/z (rel inten) 248 (M+, 26), 233 (100); HRMS (RI) calcd for C14&604 248.1049, found 248.1044.

Spectral data for lob: pale yellow oil; yield 55% IR (neat) 2980, 1755, 1720, 1710, 1225 cm-i; iH NMR (300 MHz, CDCl3) 6 9.55 and 9.54 (d, J= 3.0 Hz, lH), 6.66 and 6.62 (s, lH), 6.56-6.48 (m, lH), 6.23-6.16 (m, lH), 4.02 and 3.90 (brs, lH), 3.77-3.71 (m, lH), 3.64 and 3.50 (brs, 1I-I) 3.10. 3.03 (m, lI$), 2.23 and 2.20 (s, 3H), 2.16 and 2.13 (s, 3H); i3C NMR (75 MHz, CDCL, DEPT) 6 205.43 (CO), 205.39 (CO), 200.64 (CHO), 200.60 (CHO), 168.06 (2CO), 136.98 (CH), 136.73 (C), 136.51 (C), 135.80 (CH), 133.51 (CH), 132.41 (CH), 116.82 (CH), 116.80 (CH), 59.85 (CH), 58.76 (CH), 55.93 (CH), 54.80 (CH), 47.12 (CH), 45.41 (CH), 45.14 (CH), 43.59 (CH), 28.88 (CH3), 28.83 (CH3), 20.66 (CH3) , 20.62 (CH3); LRMS m/z (rel inten) 234 @I+, 12), 219 (100); HRMS (El) calcd for C13H1404 234.0892, found 234.0896.

Synthesis of Tetraoxa-Cages lla,b from Ozonolysis of lOa,b. A solution of 10a (1.0 g, 4.0 mmol) in dichloromethane (30 mL) was cooled to -78 “C, and ozone was bubbled through it at -78 “C until the solution turned light blue. To this solution was added dimethyl sulfide (0.56 g, 9.0 mmol) at -78 “C. Then, the reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated, and the crude product was purified by column chromatography to give the tetraacetal oxa-cage compound lla (0.59 g, 66%).

1,7-Dimethyl-4-oxo-8,10,12,13-tetraoxapentacyclo[5.5.1.0~~~.0~~~~.0~~~]tridecanes lla: white waxy solid; mp 122-123 “C; IR (CHCb) 2880, 1765, 1380, 1070 cm-i; iH NMR (300 MHz, CDCb) 6 5.87 (d,

J =

5.7 Hz, 2H), 3.28-3.16 (m, 4H), 1.64 (s, 6H); i3C NMR (75 MHz, CDCL, DEPT) 6 204.97 (CO), 121.00 (2C) , 107.27 (2CH), 55.09 (2CH), 50.40 (2CH), 24.90 (2CH3); LRMS m/z (rel inten) 224 (M+, 23), 196 (100); HRMS (EI) calcd for Cd%205 224.0685, found 224.0689; Anal, calcd for CliH1205: C, 58.91; H,5.40, found: C, 58.82; H, 5.45.

l-Methyl-4-oxo-4,8,10,13-tetraoxapentacyclo[5.5.1.0 2s a~ii.Os~S]tridecane llb: white waxy 1 .O solid; mp 94.95’C; yield 60%; IR (CHCls) 2980,2880,1765,1070 cm-i; iH NMR (300 Hz, CDCb) 6 6.15 (d,

J=

5.1 Hz, lH), 5.87 (d,

J=

6.6 Hz, 2H), 3.62-3.56 (m, lH), 3.22-3.10 (m, 3H), 1.65 (8, 3H); ‘SC NMR (75 MHz, CDCl3, DEPT) 6 205.00 (CO), 121.35 (C), 112.52 (CH), 107.54 (CH),

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107.39 (CH), 55.06 (CH), 54.59 (CH), 49.20 (CH), 47.08 (CH), 24.53 (CH3); LRMS m/z (rel inten) 210 &I+, 37), 182 (100); HRMS (RI) calcd for CioHioO~ 210.0528, found 210.0531; Anal. calcd for CioHioOs: C, 57.13; H, 4.80, found: C, 57.01; H, 4.88.

Synthesis of Tetraacetal Tetraoxa-Cage lla from Ozonolysis of 3. The same reaction conditions and procedure as for the ozonolysis of lOa,b were applied for the ozonolysis of 3 to give the tetraoxa-cage lla in 65% yield.

General Procedure for the Reactions of 6-Acetoxyfulvene with (Z)- 7 -0x0- a, B - unsaturated Thioesters 6a-c. To a solution of 6a (1.1 g, 7.4 mmol) in dichloromethane (30 mL) was added 6-acetoxyfulvene (1.0 g, 7.3 mmol) at 25 “C. The reaction mixture was stirred at 25 “C for 48 h. The solvent was evaporated, and the crude product was purified by column chromatography to give the endo adduct 12a (0.60 g, 30%) and compound 13a (0.70 g, 35%). In each case, both the enab adducts 12a-c and compounds 13a-o contained two regioisoaers, and their spectral data were taken as mixtures of two regioisomers. Spectral data for 12a: pale yellow oil; IR (neat) 2980, 1755, 1710, 1690, 1220 cm-l; iH NMR (300 MHz, CDCl3) 6 6.62 and 6.59 (s, ZH), 6.58-6.53 (m, lH), 6.16-6.09 (m, lH), 3.93 and 3.83 (bra, lH), 3.81-3.76 (m, lH), 3.57 and 3.42 (bra, lH), 3.31-3.25 (m, lH), 2.30 and 2.29 (a, 3H), 2.15 and 2.12 (a, 3H), 2.05 and 2.04 (a, 3H); 13C NMR (75 MHz, CDC13, DEPT) B 205.27 (2CO), 197.24 (2COS), 168.14 (CO), 168.16 (CC), 137.10 (CH), 136.48 (C), 136.13 (C), 135.99 (CH), 132.52 (CH), 131.47 (CH), 116.71 (CH), 116.69 (CH), 58.05 (CH), 57.11 (CH), 56.85 (CH), 56.09 (CH), 48.59 (CH), 46.56 (CH), 46.01 (CH), 44.16 (CH), 30.65 (CH3), 30.62 (CH3), 20.65 (CH3), 20.60 (CH3), 11.76 (SCH3), 11.73 (SCH3); LAMS m/z (rel inten) 280 @I+, 21), 233 (100); HRMS (EI) calcd for C14HicO& 280.0769, found 208.0761.

Spectral data for 13a: pale yellow oil; IR (neat) 2980, 1760, 1685, 1215, 1070 cm-i; iH NMR (300 MHZ, CDC13) 6 7.29 and 7.03 (a, lH), 6.68 and 6.29 (d, J= 5.7 Hz, lH), 6.08 and 5.95 (dd, J= 5.7, 2.1 Hz, lH), 5.20 and 5.11 (dd, J= 8.1, 2.1 Hz, lH), 4.84 and 4.72 (d, J= 5.1 Hz, lH), 3.84- 3.80 (m, lH), 3.53-3.46 (m, lH), 2.32 and 2.31 (a, 3H), 2.16 and 2.15 (a, 3H), 1.75 and 1.74 (a, 31-I); i3C NMR (75 MHz, CDC13, DEPT) 6 201.21 (COS), 201.14 (COS), 167.40 (CO), 167.27 (CO), 153.63 (2C), 135.36 (CH), 134.88 (CH), 133.17 (CI-I), 132.06 (C), 130.76 (CH), 130.35 (C), 129.00 (CH), 127.21 (U-I), 96.30 (CH), 93.94 (CH), 80.80 (CH), 79.34 (CH), 48.43 (CH), 47.46 (CH), 40.41 (U-I), 39.52 (CH), 20.58 (2CH3), 20.47 (2CH3), 11.85 (2SCHs); LRMS m/z (rel inten) 280 @I+, 8), 233 (100); HRMS (EI) calcd for Ci4Hic04S 280.0769, found 280.0756.

Spectral data for 12b: pale yellow oil; IR (neat) 2980, 1755, 1710, 1690, 1220 cm-i; iH NhIR (300 MHz, CDCL) cY 6.63 and 6.59 (a, lH), 6.60-6.54 (m, lH), 6.15-6.09 (m, lH), 3.93 and 3.80 (bra,

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II-I), 3.79-3.72 (m, U-I), 3.55 and 3.37 (brs, 1I-I) 3.52-3.45 (m, lH), 2.48-2.38 (m, 1I-b 2.28 and 2.27 (s, 3I-Q 2.15 and 2.12 (s, 3H), 1.09 and 1.07 (d, J = 6.6 Hz, 3H), 1.04 and 1.02 (d, J= 6.6 Hz,

3H); 13C NMR (75 MHz, CDCl3, DEPT) 6 211.87 (2CO), 197.18 (2COS), 168.22 (2C0), 137.41 (CH), 136.61 (C), 136.39 (C), 136.35 (CH), 132.09 (CH), 131.03 (CH), 116.58 (CH), 116.52 (CH), 57.39 (CH), 56.45 (CH), 54.63 (CH), 53.51 (CH), 48.46 (CH), 46.38 (CH), 46.26 (CH), 44.39 (CH), 41.40 (2CH), 20.66 (2CH3), 19.80 (CH3), 19.71 (CH3), 17.28 (2CH3), 11.73 (SCH3), 11.70 (SCH3); LRMS m/z (rel inten) 308 (M+, 12), 261 (100); HRMS (EI) calcd for C16H2004S 308.1082, found 308.1078.

Spectral data for 13b: pale yellow oil; yield 33 %; IR (neat) 2980, 1760, 1685, 1215, 1070 cm-l; 1H NMR (300 MHz, CDCl3) 6 7.28 and 7.02 (a, lH), 6.66 and 6.28 (d, J= 6.0 Hz, IH), 6.02 and 5.91

(dd, J=6.0,2.1Hz, lH),5.23and5.14(dd, J=7.2,2.1Hz, lI-I),4.91and4.81(d, J=4.8Hz, lH), 3.95-3.91 and 3.74-3.69 (m, lH), 3.63-3.60 and 3.53-3.50 (m, lH), 2.34 and 2.31 (a, 3H), 2.30-2.20 (m, lH), 2.17 and 2.16 (s, 3I-Q 1.02 and 1.00 (d, J = 6.6 Hz, 6H); 13C NMR (75 MHz, CDCb,

DEPT) 6 201.60 (2COS), 167.45 (CO), 167.37 (CO), 162.32 (BC), 135.36 (CH), 134.92 (CH), 133.37 (CH), 132.31 (C), 130.89 (CH), 130.80 (C), 128.80 (CH), 127.14 (CH), 94.95 (CH), 93.23 (CH), 81.32 (CH), 80.19 (CH), 48.30 (CH), 47.26 (CH), 41.51 (CH), 40.56 (CH), 32.55 (CH), 32.48 (0, 19.73 (CH3), 19.69 (CH3), 19.53 (CH3), 19.41 (CH3), 11.96 (CH3), 11.94 (CH3),11.69 (CH3). 11.44 (CH3); LRMS m/z (rel inten) 308 &I+, 14), 261 (100); HRMS (EI) calcd for C16H2004S

308.1082, found 308.1088.

Spectral data for 12~: pale yellow oil; yield 31%; IR (neat) 2980, 1755, 1710, 1690, 1220 cm-l;lH NMR (300 MHZ, CDCL) 6 6.61 and 6.58 (s, lH), 6.57-6.50 (m, lH), 6.17-6.10 (m, lH), 3.92 and 3.79 (brs, lH), 3.78-3.71 (m, lH), 3.53 and 3.40 (brs, 1H) 3.35-3.25 (m, lH), 2.28 and 2.26 (a, 3I-Q 2.28-2.20 (m, 2H), 2.15 and 2.12 (s, 3H), 1.60-1.20 (m, 4H), 0.88 (t, J= 7.2 Hz, 3H); 13C NMR (75

MHz, CDCL, DEPT) 6 207.74 (2CO), 197.25 (ZCOS), 168.22 (2CO), 137.04 (CH), 136.61 (C), 136.33 (C), 135.96 (CH), 132.53 (CH), 131.49 (CH), 116.62 (CH), 116.59 (CH), 57.21 (CH), 57.07 (CH), 56.21 (CH), 55.90 (CH), 48.46 (CH), 46.40 (CH), 46.17 (CH), 44.30 (CH), 43.27 (2CH2), 25.85 (2CH2), 22.27 (2CH2), 20.68 (CH3), 20.64 (CH3), 13.82 (2CH3), 11.79 (SCH3), 11.76 (SCH3); LRMS m/t (reI inten) 322 (M+, 16), 275 (100); HRMS (EI) calcd for C17H2204S 322.1239, found 322.1235.

Spectral data for 13~: pale yellow oil; yield 31%; IR (neat) 2980, 1760, 1685, 1215, 1070 cm-l; 1H NMR (300 MHz, CDCl3) 6 7.28 and 7.03 (s, lH), 6.68 and 6.29 (d, J = 5.7 Hz, lH), 6.05 and

5.93(dd, J=5.7,2.1Hz, lH),5.22and5.12(dd, J=7.2,2.1Hz, lH),4.87and4.76(d, J=3.6Hz, lH), 3.90-3.86 and 3.70-3.65 (m, lH), 3.55-3.45 (m, lH), 2.33 and 2.31 (s, 3H), 2.18 and 2.16 (s, 3H), 2.05 -1.98 (m, 2H), 1.46-1.23 (m, 4H), 0.90 (t, J= 7.2 Hz, 3H); 13C NMR (75 MHz, CDCL,

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DEPT) 6 201.46 (COS), 201.40 (COS), 167.53 (CO), 167.43 (CO), 157.47 (2C), 135.47 (CH), 135.01 (CH), 133.32 (CH), 132.30 (C), 130.83 (CH), 130.70 (C), 128.96 (CH), 127.25 (CH), 96.34 (CH), 94.21 (CH), 81.07 (CH), 79.92 (CH), 48.80 (CH), 47.46 (CH), 41.03 (CH), 40.10 (0, 34.09 (CH2), 34.05 (CH2), 28.45 (CHz), 28.30 (CH2), 22.19 (2CH2), 20.68 (2CH3), 13.84 (2CH3), 11.96 (2SCH3); LRMS m/z (rel inten) 322 (M+, 13), 275 (100); HRMS (EI) calcd for C17H2204S

322.1239, found 322.1230.

Synthesis of Tetraoxa-Cages 14a-c from Ozonolysis of 12a-c. The same reaction conditions and procedure as for the synthesis of tetraoxa-cages lla,b from ozonolysis of lOa,b were applied for the synthesis of tetraoxa-cages 14a-c from ozonolysis of 12a-c.

l-Methylthio-7-methyl-4-oxo-8,lO,l2,13-tetraoxapentacyclo[6.5.1.0~~~.0~~~~.0~~~]tridecane

14a: white waxy solid; mp 88-89 “C; yield 62%; IR (CHC13) 2880, 1765, 1380, 1070 cm-l; ‘H NMR (300 Hz, CDCl3) 6 5.94 (d, J= 6.0 Hz, lH), 5.89 (d, J = 6.0 Hz, lH), 3.62 (dd, J = 9.9, 6.0 Hz, lH), 3.32 (dd, J = 9.9, 6.0 Hz, lH), 3.28-3.16 (m, 2H), 2.26 (6, 3H), 1.68 (s, 3H); W NMR (75 MHz, CDCl3, DEPT) 6 203.74 (CO), 125.63 (C), 122.06 (C), 107.98 (CH), 107.42 (CH), 55.01 (CH), 54.61 (CH), 52.79 (CH), 50.02 (CH), 24.58 (CH3), 12.94 (SCH3); LRMS m/z (rel inten) 256

@I+, 32), 209 (100); HRMS (EI) calcd for ClllH1205S 256.0405, Found 256.0411; Anal. calcd for ClllH1205S: C, 51.55; H 4.72, found: C,51.47; H, 4.77.

1-Methy1thio-7-isopropy1-4-oxo-8,10,12,13-tetraoxapentacyc1o[5.5.1.0~~~.0~~~~.0~~~]-

tridecane 14b: white waxy solid; mp 65-66 “C; yield 60%; IR (CHC13) 2880, 1765, 1380, 1070 cm-l; 1H NMR (300 Hz, CDCL) 6 5.94 (d, J= 6.6 Hz, lH), 5.91 (d, J= 6.6 Hz, lH), 3.56 (dd, J=

10.2, 6.6Hz, lH), 3.32 (dd, J= 10.2, 6.6 Hz, lH), 3.26 (dd, J= 7.2, 6.6 Hz, lH), 3.08 (dd, J= 7.2,

6.6 Hz, lH), 2.26 (s, 3H), 2.22-2.14 (m, lH), 1.03 (d, J= 6.6 Hz, 3H), 1.01 (d, J= 6.6 Hz, 3H); 13C NMR (75MHz, CDC13, DEPT) 6 203.96 (CO), 126.64 (C), 125.75 (C), 107.95 (CH), 107.44 (CH), 55.29 (CH), 54.66 (CH), 52.30 (CH), 46.49 (CH), 34.77 (CH), 17.14 (CH3), 17.07 (CH3), 13.01 (SCH3); LRMS m/z (rel inten) 284 @I+, 19), 237 (100); HRMS (EI) calcd for C13H1605S 284.0718,

found 284.0723; Anal. calcd for C13H1605S: C, 54.92; H, 5.68, found:C, 54.84; H, 5.74. l-Methylthi~7-butyl-4-oxo-8,10,12,13-Tetraoxapentacyclo[5.5.l.0~~~.0~~~~.0~~~]tridecane

14~: white waxy solid; mp 60-61 “C; yield 64%; IR (CHCls) 2980, 2880, 1765, 1070 cm-l; 1H NMR (300 Hz, CDCl3) 6 5.94 (d, J= 6.0 Hz, lH), 5.90 (d, J= 6.0 Hz, lH), 3.58 (dd, J= 10.2, 6.0 Hz, lH), 3.34-3.25 (m, 2H), 3.17 (dd, J= 7.2, 6.0 Hz, lH), 2.26 (s, 3H), 1.93-1.86 (m, 2H), 1.70-1.62 (m, 2H), 1.40-1.32 (m, 2I-I), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCls, DEPT) 6 203.89 (CO), 125.60 (C), 124.24 (C), 107.97 (CH), 107.38 (CH), 55.16 (CH), 54.61 (CH), 52.45 (CH), 48.33 (U-I), 37.09 (CH2), 26.07 (CH2), 22.53 (CH2),13.90 (CH3), 12.99 (SCH3); LRMS m/z

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Anal. calcd for CirHuOaS: C, 56.36; H, 6.09, found: C56.29; H, 6.14.

General Procedure for The Hydrolysis of lOa,b with NazCOs in Aqueous Methanol. To a solution of 10a (1.0 g, 4.0 mmol) in methanol (10 mL) and water (10 mL) was added NasCOs (0.040 g, 0.40 mmol) at 25 “C. The reaction mixture was stirred at 25 “C for 2 h. The solvent evaporated, and saturated NH&l solution (10 mL) was added. The reaction mixture was extracted with ether (5 x 30 mL). The organic layer was washed with brine, dried over MgS04, and evaporated, and the residue was purified by column chromatography to give the

endo-syn isomer 16a (0.74 g, 90%). The amount of the en&-anti isomer 16a was too small to be

isolated.

2,3-Bisendo-diacetyl-7-syn-formylbicyclo[2.2.l]d-heptene 15a: pale yellow oil; IR (neat) 2980, 2880, 1720, 1710 cm-l; iH NMR (300 MHz, CDCl3) 6 9.60 (s, lH), 6.26 (hrs, 2H), 3.46 (hrs, 2H), 3.32 (hres, 2H), 2.53 (hrs, lH), 2.10 (s,6H); *SC NMR (75 MHz, CDCb, DEPT) 6 205.61 (2C0), 200.10 (CHO), 134.66 (2CH), 68.00 (CH), 54.68 (2CH), 45.74 (2CH), 30.00 (2CH3); LRMS m/z (rel inten) 206 (M+, 17), 128 (100); HRMS (EI) calcd for C12Hl403 206.0943, found 206.0948. 2endo-Acetyl-3end~7-syn-diformylbicyclo[2.2.1]-5-heptene 15b: pale yellow oil; IR (neat) 2980, 2880, 1720, 1710 cm-‘; ‘H NMR (300 MHz, CDC13) 6 9.60 (s, lH), 9.54 (d, J= 2.1 Hz, lH), 6.47 (dd, J= 6.0, 3.0 Hz, lH), 6.13 (dd, J= 6.0, 3.0 Hz, lH), 3.71 (dd, J= 9.3, 3.6 Hz, 1H) 3.58 (hrs, lH), 3.51 (brs, lH), 2.96-2.91 (m, lH), 2.60 (s, lH), 2.19 (s, 3H); 13C NMR (75 MHz, CDCL, DEPT) ?i 205.83 (CO), 200.35 (CHO), 199.61 (CHO), 136.87 (CH), 133.55 (CH), 68.60 (CH), 56.78 (0, 53.51 (CH), 46.07 (CH), 44.55 (CH), 28.88 (CH3); LRMS m/z (rel inten) 192 (M+, 12), 114 (100); HRMS (EI) calcd for CllHl203 192.0786, found 192.0789.

Ozonolysis of lSa,b. Formation of Tetraoxa-Cages 17a,b. The same reaction conditions and procedure as for the ozonolysis of lOa,b were applied for the ozonolysis of lSa,b to give the tetraoxa-cages 17a,b.

1,7-Dimethy1-4-anti-formy1-8,10,12,13-tetraoxapentacyc1o[6.5.1.0~~~.0*~~~.0~~~]tridecane 17a: white waxy solid; mp 55-56 “C; yield 85%; IR (CHCL) 2970, 1720, 1070 cm-i; iH NMR (300 MHz, CDCl3) 6 9.73 (s, lH), 5.63 (d, J = 5.7 Hz, 2H), 3.22-3.18 (m, 5H), 1.54 (s, 6H); i3C NMR (75 MHz, CDCl3, DEPT) 6 199.52 (CHO), 117.65 (2C) , 102.79 (2CH), 56.20 (2CH), 55.44 (CH), 45.85 (2CH), 24.96 (2CH3); LRMS m/z (rel inten) 238 (M+, 41), 223 (100); HRMS (El) calcd for Cl2Hl406 238.0841, found 238.0835; Anal. calcd for Cl2Hl406; C, 60.48; H, 5.93, found ; C, 60.40; H, 5.97.

l-Methyl-kanti-formyl-8,10,12,13-tetraoxapentacyclo[5.5.1.0~~~.0~~~~.0~~~]tridecane 17b: highly viscous oil; yield 75%; IR (CHCl3) 2980, 1720, 1070 cm-i; iH NMR (300 Hz, CDC13) 6

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9.75 (8, lH), 5.85 (d, J= 5.4 Hz, lH), 5.63 (d, J= 6.0 Hz, lH), 5.62 (d, J= 6.0 Hz, lH), 3.51-3.46 (m, lH), 3.28-3.04 (m, 4H), 1.55 (8, 3I-I); 13C NMR (75MHz, CDCl3, DEPT) 6 199.43 (CHO), 118.02 (C), 109.60 (CH), 103.06 (CI-I), 102.63 (CH), 55.47 (CH), 55.08 (CH), 52.76 (CH), 45.82 (CH), 45.38 (U-I), 24.59 (CH3); LRMS m/z (rel inten) 224 (M+, 27), 209 (100); HRMS (EI) calcd for C11H1205 224.0685, found 224.0689; Anal. calcd for C11H1205: C, 58.91; H, 5.40, found: C, 58.80; H, 5.47.

General Procedure for The Hydrolysis of 12a,b with Na2CO3 in Aqueous Methanol. The same reaction conditions and procedure as for the hydrolysis of lOa,b were applied for the hydrolysis of 12a,b to give the endo-syn isomers lSa,b as the major products and the e&o-anti isomers 19a,b as the minor products.

Spectral data for 18a: pale yellow oil; yield 75%; IR (neat) 2980, 2880, 1720, 1710 , 1690 cm-1;1H NMR (300 MHz, CDCl3) 6 9.60 (s, lH), 6.54 (dd, J= 6.0, 3.0 Hz, lH), 6.06 (dd, J= 6.0, 3.0 Hz, lH), 3.75 (dd, J= 9.0, 3.6 Hz, lH), 3.51 (brs, lH), 3.41 (hrs, lH), 3.14 (dd, J = 9.0, 3.6 Hz, lH), 2.52 firs, lH), 2.28 (8, 3H) 2.02 (s, 3H); 1X! NMR (75 MHz, CDCL, DEPT) 6 205.34 (CO), 199.94 (CHO) , 197.59 (OS), 137.30 (CH), 132.64 (CH), 68.14 (CH), 55.56 (CH), 54.60 (CH), 47.61 (CH), 45.22 (CH), 30.78 (CH3), 11.81 (SCH3); LRMS m/z (rel inten) 238 (M+, 24), 191 (100);

HRMS (EI) calcd for C12H1403S 238.0664, found 238.0667.

Spectral data for 19a: pale yellow oil; yield 10%; IR (neat) 2980, 2880, 1720, 1710, 1690 cm-1; 1H NMR (300 MHz, CDC13) 6 9.59 (d, J = 2.1 Hz, lH), 6.50 (dd, J = 6.0, 3.0 Hz, lH), 6.05 (dd, J = 6.0, 3.0 HZ, lH), 3.83 (dd, J= 9.0, 3.6 Hz, lH), 3.60 (brs, lH), 3.49 (brs, lH), 3.31 (dd, J= 9.0, 3.6 Hz, lH), 2.38 firs, lH), 2.28 (s, 3H) 2.04 (s, 3I-Q; 13C NMR (75 MHz, CDC13, DEPT) 6 204.96 (Co), 203.01 (CHO) , 197.06 (COS), 135.48 (U-I), 130.80 (CH), 69.10 (CH), 57.60 (CH), 56.57 (CH), 49.85 (CH), 47.41 (CH), 30.66 (CH3), 11.81 (SCH3); LRMS m/z (rel inten) 238 @I+, 32), 191

(100); HRMS (EI) calcd for C12H1403S 238.0664, found 238.0670.

Spectral data for 18b: pale yellow oil; yield 70%; IR (neat) 2980, 2880, 1720, 1710 , 1690, 1380 cm.‘; 1H NMR (300 MHz, CDCL) 6 9.62 (s, lH), 6.54 (dd, J = 5.7, 3.0 Hz, lH), 6.06 (dd, J = 5.7, 3.0 Hz, lH), 3.72 (dd, J = 9.6, 3.6 Hz, lH), 3.51 (hrs, lH), 3.36-3.32 (m, 2H), 2.53 (brs, lH), 2.43-2.36 (m, IH), 2.26 (s, 3H), 1.06 (d, J = 6.0 Hz, 3H), 1.03 (d, J = 6.0 Hz, 3H); 13C NMR (75 MHz, CDCL, DEPT) 6 211.95 (CO), 200.04 (CHO) , 197.53 (COS), 137.53 (CH), 132.34 (0, 68.28 (CH), 54.93 (CH), 52.13 (CH), 47.38 (U-I), 45.44 (CH), 41.48 (CH), 19.86 (CH3), 17.32 (CH3), 11.75 (SCH3); LRMS m/z (rel inten) 266 (M+, 27). 219 (100); HRMS @I) calcd for C14H1aOsS 266.0977, found 266.0974.

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NMR (300 MHz, CDCl3) 6 9.60 (d, J= 2.1 Hz, lH), 6.50 (dd, J= 6.0, 3.0 Hz, HI), 6.06 (dd, J=

6.0, 3.0 Hz, lH), 3.80 (dd, J=10.2, 3.6 Hz, lH), 3.61 (brs, lH), 3.54 (dd, J= 10.2, 3.6 Hz, lH), 3.44

(bra, lH), 2.46-2.38 (m, 2H), 2.27 (s, 3H) 1.09 (d, J= 6.6 Hz, 3H), 1.06 (d, J= 6.6 Hz, 3H); 13C

NMR (75 MHz, CDCL, DEPT) 6 211.49 (CO), 203.12 (CHO) , 196.99 (COS), 135.66 (CH), 130.46 (CH), 69.18 (CH), 56.91 (CH), 54.11 (CH), 49.61 (CH), 47.65 (CH), 41.39 (CH), 19.75 (CH3), 17.27 (CH3), 11.72 (SCH3); LRMS m/z (rel inten) 266 (M+, 21) 219 (100); HRMS (EI)

calcd for C14Hle03S 266.0977, found 266.0985.

General Procedure for the Ozonolysis of 18a,b. Formation of Tetraoxa-Cages 20a,b.

The same reaction conditions and procedure as for the ozonolysis of lOa,b were applied for the ozonolysis of lSa,b to give the tetraoxa-cages 20a,b..

l-Methylthio-7-Methyl-4-anti-formyl-8,10,12,13-tetraoxapentacyclo[6.5.1.0~~s.0~~~~.0~~s]-

tridecane 20a: highly viscous oil; yield 85%; IR (CHCL) 2970, 1720, 1070 cm-l; iH NMR (300 Hz, CDCl3) 6 9.74 (s, lH), 5.71 (d, J= 6.0 Hz, lH), 5.65 (d, J= 6.0 Hz, lH), 3.58 (dd, J= 10.8,

5.4 Hz, lH), 3.34-3.18 (m, 4H), 2.20 (s, 3H), 1.57 (s, 3H); 13C NMR (75MHz, CDCl3, DEPT) 6 199.22 (CHO), 122.74 (C), 118.71 (C), 103.68 (CH), 102.95 (CH), 58.49 (CH), 55.63 (CH), 55.06 (CH), 45.82 (CH), 45.47 (CH), 24.53 (CH3), 12.87 (SCH3); LRMS m/z (rel inten) 270 (M+, 48), 223

(100); HRMS (EI) calcd for CisH1405S 270.0562, found 270.0567; Anal. calcd for C12H14CSS: C, 53.32; H, 5.22, found: C,53.24; H, 5.28.

l-Methylthio-7-isopropyl-4-anti-formyl-8,10,12,l3-tetraoxapentacyclo

[5.5.1.0s~s.Os~ii.O6~s]tridecane 20b: highly viscous oil; yield 80%; IR (CHCL) 2980, 1720, 1380, 1070 cm-l; iH NMR (300 Hz, CDCls) 6 9.75 (s, lH), 5.70 (d, J = 5.7 Hz, lH), 5.66 (d, J = 5.7 Hz, lH), 3.50 (dd, J= 10.5, 5.4 Hz, lH), 3.30-3.20 (m, 3H), 3.13-3.08 (m, lH), 2.21 (s, 3H), 2.08-2.01

(m, lH), 0.99 (d, J= 6.0 Hz, 3H), 0.96 (d, J= 6.0 Hz, 3H); 13C NMR (75 MHz, CDCla, DEPT) 6

199.33 (CHO), 123.24 (C), 122.82 (C), 103.62 (CH), 102.87 (CH), 57.99 (CH), 55.13 (CH), 51.89 (CH), 46.01 (CH), 45.55 (CH), 34.52 (CH), 17.10 (CHs), 17.00 (CH3), 12.94 (SCH3); LRMS m/z

(rel inten) 298 (M+, 24), 251 (100); HRMS (ED calcd for C14HisOsS 298.0875, found 298.0869; Anal. calcd for C14HisOaS: C, 56.36; H, 6.09, found: C, 56.24; H, 6.16.

Acknowledgment. We thank the National Science Council of the Republic of China for finanical support (Grant No. NSC 86-2113-M009-001).

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