Patent Application: US-50842800-A

Abstract:
2 , 3 - dioxabicyclononane derivatives , carrying , at position 4 , a sulfur - containing functionality selected from the group consisting of sulfonyl , sulfinyl and sulfenyl , adhered to c vie methylene group , represented by structural formula wherein : x is hydrogen , hydroxy , alkoxy , optionally substituted by alkoxy or acyloxy , aralkoxy optionally substituted by alkoxy or aryloxy , and m is hydrogen , hydroxy , alkoxy , alkenyloxy , acyloxy , optionally substituted by acyl or acyloxy , aralokoxy , arylalkenyloxy , oxalyloxy substituted by alkoxy , diamino or alkylamino , diamino or carbonyloxy substituted by arloxy , diamino , diamino and alkylamino ; or x and m together represent a carbon - carbon bond or an oxygen atom ; l is hydrogen or l and m together represent a carbon - carbon bond ; and either z is a radical r -- s n -- and y is hydrogen , or y is r -- s n -- and z is hydrogen , wherein r is alkyl optionally substituted by alkoxy or alkoxycarbonyl , cycloalkyl , or aryl or araklkyl optionally substituted by alkyl , halogen or cf 3 ; and n is 0 , 1 , or 2 , are useful for the prevention and / or treatment of malaria .

Description:
______________________________________abbreviations______________________________________ac acetyl bn benzyl br . broad ( in nmr spectroscopy ) bz benzoyl ci chemical ionization ( in mass - spectroscopy ) dbpo di - tert - butyl peroxalate dci desorption chemical ionization ( in mass - spectroscopy ) dmap ( 4 - dimethylamino ) pyridine dp direct phase ( in chromatography ) hplc high - performance liquid chromatography hrms high - resolution mass spectrum mcpba m - chloroperoxybenzoic acid mplc medium - pressure liquid chromatography r . sub . f retention factor ( in chromatography ) rp reverse phase ( in chromatography ) rt room temperature tf trifluoromethanesulfonyl ( triflyl ) tlc thin layer chromatography tms trimethylsilyl toco thiol - oxygen cooxidation v . s . very strong ( in ir - spectroscopy ) τ . sub . r retention time ( in hplc ) ______________________________________ the methodology applied for the synthesis of the novel antimalarial 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonanes of type a involves one or more of the following processes : ( 1 ) submission of monoterpenes like r -(+)- limonene 1 , s -(-)- limonene ) 1 &# 39 ; and carveol derivatives 3 to thiol oxygen cooxidation reactions ( toco reactions ), followed by treatment with a reducing agent , such as triphenylphosphine . this process is suitable for the preparation of compounds of type a ( r represents an alkyl -, aralkyl - or aryl group , m represents hydroxyl , n = 0 ) as described in general procedure 1 . ( 2 ) oxidation of the sulfide group in compounds of type a ( r represents an alkyl , aralkyl - or aryl group , n = 0 ) to the corresponding sulfones of type a ( r represent an alkyl -, aralkyl - or aryl group , n = 2 ) as described in general procedure 2 . ( 3 ) oxidation of the sulfide group in compounds a ( r represents an alkyl -, aralkyl - or aryl group ; n = 0 ) to sulfoxides of type a ( r represents an alkyl -, aralkyl - or aryl group ; n = 1 ), as described in general procedure 3 . ( 4 ) manipulations of functional groups in compounds of type a ( r represents an alkyl -, aralkyl - or aryl group , n = 0 or n = 2 ) as described in general procedures 4 - 8 . ## str5 ## general procedure 1 synthesis of 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane - 8 - ols a ( r represents alkyl , aralkyl - and aryl ; n = 0 ; m = oh ). through a stirred solution of monoterpene ( 1 , 1 &# 39 ; or 3 ) ( ca . 3 equivalents , 0 . 02 - 0 . 10 m ) and di - tert - butyl peroxalate ( dbpo ) ( 0 . 02 - 0 . 04 equivalents ) in n - heptane - benzene mixture ( ca . 2 : 1 ) oxygen gas is gently bubbled with simultaneous addition of a solution of thiol ( 1 equivalent ) in benzene or heptane ( 5 - 20 ml ) over a period 12 h ( syringe pump ). after the addition of thiol is completed the mixture is kept under oxygen for additional 12 - 14 h . it is then diluted with ch 2 cl 2 , cooled to 0 - 5 ° c . and powdered ph 3 p ( 1 equivalent ) is added . the mixture is stirred for an additional 2 h at 0 - 5 ° c . and for 1 h at rt , solvents are evaporated at rt flash chromatography affords the title compounds , which can be used for the preparation of additional antimalarial agents of type a as described in general procedures 2 - 7 . preparation of sulfones a ( n = 2 ). a solution of a sulfide a ( r represents alkyl , aralkyl or aryl ; n = 0 ) ( 1 equivalent , ca . 0 . 2 m ) and mcpba ( ca . 2 . 2 - 2 . 5 equivalents ) in etoac is stirred at rt for 4 - 10 h . after consumption of the intermediate sulfoxide ( tlc monitoring ) the mixture is poured into a saturated solution of nahco 3 , extracted with an organic solvent , dried ( na 2 so 4 and nahco 3 ) and evaporated . chromatography of the residue affords the title compounds . preparation of sulfoxides a ( n = 1 ). to a solution of a sulfide a ( r represents alkyl , aralkyl or aryl ; n = 0 ) ( 1 equivalent , ca . 0 . 05 m ) in etoac at - 30 ÷- 50 ° c ., a solution of mcpba ( ca . 1 . 05 equivalents , ca . 0 . 06 m solution ) in etoac is added and the mixture is stirred at - 30 ÷- 40 ° c . until the starting material is consumed ( monitoring by tlc ). the mixture is poured into a saturated solution of nahco 3 , extracted with an organic solvent , dried ( na 2 so 4 and nahco 3 ) and evaporated . chromatography of the residue affords the title compounds . synthesis of 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] non - 7 - enes a ( m and x together represent a carbon - carbon bond ; n = 0 or n = 2 ) and 8 - methylene - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonanes a ( l and m together represent a carbon - carbon bond ; n = 0 or n = 2 ). to a mixture of socl 2 ( ca . 4 equivalents ) and pyridine ( 10 equivalents ) in dry ch 2 cl 2 ( ca . 40 ml / mmol substrate ) at - 30 -- 40 ° c . is added during 1 . 5 h , a solution of a 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan - 8 - ol a ( m = oh , x = h , n = 0 or n = 2 ) ( 1 equivalent , ca . 1 mmol / 10 ml ) in ch 2 cl 2 . the temperature is raised to 25 ° c . and after stirring for 5 h , the reaction mixture is poured into ice - cold 0 . 1 m hcl ( ca . 25 ml / mmol of substrate ), extracted with hexane / etoac , washed with saturated nahco 3 , dried ( na 2 so 4 + nahco 3 ) and evaporated . chromatography of the residue affords a mixture of the two title compounds . synthesis of 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonanes a ( m represents a hydrogen atom ; n = 0 or n = 2 ). to a mixture of a 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] non - 7 - enes of type a ( m and x together represent a carbon - carbon bond ; n = 0 or n = 2 ) and / or 8 - methylene - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonanes a ( l and m together represent a carbon - carbon bond ; n = 0 or n = 2 ) ( 1 equivalent , ca . 0 . 01 m solution ), and potassium azodicarboxylate ( 10 - 15 equivalents ) in meoh / ch 2 cl 2 at 0 ° c . is added during ca . 1 h , a solution of acoh ( 20 - 30 equivalents ) in ch 2 cl 2 . the mixture is stirred for 2 days at rt , diluted with ether , filtered through celite ® and evaporated . chromatography of the residue affords the title compounds . synthesis of 8 - acyloxy - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonanes a ( m represents an acyloxy function ; n = 0 or n = 2 ). to a solution of a 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan - 8 - ol a ( m represents a hydroxyl group , n = 0 or n = 2 ) ( 1 equivalent , ca . 0 . 5 m solution ) and 2 , 6 - lutidine ( ca . 3 equivalents ) in ch 2 cl 2 at 0 ° c . is added tmsotf ( ca . 2 equivalent ). the mixture is stirred for 30 min at 0 ° c . and then at rt until the starting material is consumed . the reaction mixture is poured into cold water , extracted with an organic solvent , dried ( na 2 so 4 + nahco 3 ) and evaporated to give a ( m represents the otms group ; n = 0 or n = 2 ) in practically quantitative yield . a mixture of the crude tms - derivative ( 1 equivalent ), acyl chloride ( 5 - 8 equivalents ) and oven - dried csf ( 3 - 5 equivalents ) in acetonitrile ( ca . 10 ml / mmol ) is stirred for 5 - 10 days at rt the mixture is poured into a saturated nahco 3 solution , extracted with organic solvent , dried ( na 2 so 4 + nahco 3 ) and evaporated . chromatography of the residue affords the title compounds . synthesis of 8 - alkoxy - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonanes a ( m represents an aralkoxy or alkenyloxy function ; n = 2 ). to a suspension of a 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan - 8 - ol of type a ( m represents a hydroxyl group ; n = 2 ) ( 1 equivalent , ca . 0 . 3 m solution ) in dry ether , at 0 ° c . is added a concentrated solution of ccl 3 c (= nh ) or ( r represents an alkenyl or an ( aryl ) alkyl group ) ( 3 - 4 equivalents ) in ch 2 cl 2 . following formation of a homogeneous mixture , a solution of tfoh ( ca . 0 . 03 equivalents , ca . 0 . 1 m ) in dry ether is added . the reaction mixture is stirred for ca . 5 h at 0 ° c . addition of solutions of trichloroacetimidate and tfoh is repeated until the starting hydroxysulfone is consumed . the mixture is then diluted with an organic solvent , excess of ( na 2 so 4 + nahco 3 ) is added and the mixture is stirred overnight . concentration in vacuo , followed by chromatography affords the title compounds . synthesis of 7 , 8 - epoxy - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonanes a ( m and x together represent an oxygen atom ; n = 2 ). a mixture of a 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] non - 7 - ene a ( m and x together represent a carbon - carbon bond ; n = 2 ) ( 1 equivalent , ca . 0 . 05 m solution ) and mcpba ( ca . 1 . 1 equivalents ) in ch 2 cl 2 is stirred at rt for 12 h , diluted with hexane / etoac , washed with saturated nahco 3 , dried ( na 2 so 4 + nahco 3 ) and evaporated . chromatography of the residue affords the title compounds . the compounds in the following examples were prepared according to schemes 1 - 15 , presented hereinafter . ## str6 ## to a stirred solution of r -(+)- limonene 1 ( 6 . 13 g , 45 mmol ) in a mixture of n - heptane ( 500 ml ) and benzene ( 200 ml ) was added in one portion di - tert - butyl peroxalate ( dbpo ) ( 105 mg , 0 . 45 mmol ). oxygen gas was bubbled through the mixture at rt , with simultaneous addition of a solution of thiophenol ( phsh ) ( 1 . 653 g , 15 mmol ) in benzene ( 20 ml ) ( syringe pump ) over a period of 12 h . after the addition of phsh was completed the mixture was exposed to oxygen for an additional 14 h . after addition of ch 2 cl 2 ( 100 ml ) the mixture was cooled to 0 - 5 ° c . and powdered ph 3 p ( 3 . 93 g , 15 mmol ) was added in one portion . the mixture was then stirred for 2 h at 0 - 5 ° c . and for 1 h at rt , solvents were evaporated at rt flash chromatography ( silica gel 60 , 230 - 400 mesh from merck , gradient elution , etoac - hexane , from 1 : 49 to 3 : 7 ) followed by additional flash chromatography ( etoac - hexane , 3 : 7 ) afforded a mixture of ( 1r , 4r , 5r , 8r )- 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan - 8 - ol ( 2a ) and ( 1r , 4s , 5r , 8r )- 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan - 8 - ol ( 2b ) ( 2a / 2b ca . ( 55 : 45 ), 2 . 41 g ( 8 . 19 mmol , 54 . 6 % yield ), as a colorless or pale yellow oil , r f 0 . 29 ( etoac - hexane 3 : 7 ), ir ( neat ): 690 , 740 , 1015 , 1055 , 1373 , 1440 , 1454 , 1480 , 1584 , 2921 , 2928 , 2964 , 3420 cm - 1 . 1 h nmr ( cdcl 3 , 400 mhz ) ( δ ): 1 . 25 ( br . s , me 11 , 2a ), 1 . 56 ( d , 4 j 11 , 12 = 0 . 6 hz , me 11 , 2b ), total 3 h ; 1 . 39 ( s , me 10 , 2b ), 1 . 40 ( s , me 10 , 2a ), total 3 h ; 1 . 58 ( m , 1 h , h e 7 , 2a + 2b ); 1 . 76 - 1 . 85 ( m , 2 h , h e 6 + h a 6 , 2a + 2b ); 1 . 81 ( m , h e 5 , 2b ), 1 . 91 ( dddd , 3 j 5e6e = 3 j 5e9a = 3 j 5e6a = 3 j 5e9a = 3 . 2 hz , h e 5 , 2a ), total 1 h ; 1 . 98 ( ddd , 2 j 9a9e = 13 . 6 hz , 3 j 9a5e = 3 . 2 hz , 3 j 9a1e = 2 . 0 hz , h a 9 , 2a ), 2 . 01 ( ddd , 2 j 9a9e = 14 . 2 hz , 3 j 9a5e = 3 . 2 hz , 3 j 9a1e = 1 . 9 hz , h a 9 , 2b ), total 1 h ; 2 . 10 ( ddd , 2 j 9e9a = 13 . 6 hz , 3 j 9e1e = 5 . 5 hz , 3 j 9e5e = 3 . 2 hz , h e 9 , 2a ), 2 . 26 ( ddd , 2 j 9e9a = 14 . 2 hz , j 9e1e = 4 . 4 hz , 3 j 9e5e = 3 . 0 hz , h e 9 , 2b ), total 1 h ; 2 . 31 - 2 . 41 ( m , 1 h , h a 7 , 2a + 2b ); 2 . 96 ( d , 2 j = 12 . 0 hz , h 12 , 2b ), 3 . 35 ( d , 2 j = 12 . 8 hz , h 12 , 2a ), total 1 h ; 3 . 03 ( dd , 2 j = 12 . 0 hz , 4 j 12 , 11 = 0 . 6 hz , h &# 39 ; 12 , 2b ), 3 . 71 ( dd , 2 j = 12 . 8 hz , 4 j 12 , 11 = 0 . 5 hz , h 12 , 2a ), total 1 h ; 3 . 68 ( m , h 1 , 2a ), 3 . 71 ( m , h 1 , 2b ), total 1 h ; 7 . 17 - 7 . 23 ( m , 1 h , h 16 , 2a + 2b ); 7 . 27 - 7 . 33 ( m , 2 h , h 15 , 2a + 2b ); 7 . 36 - 7 . 43 ( m , 2 h , h 14 , 2a + 2b ). 13 c nmr ( cdcl 3 , 100 mhz ) ( δ ): isomer 2a : 21 . 89 ( me 11 ), 23 . 58 ( c 6 h 2 ), 24 . 17 ( c 9 h 2 ), 28 . 04 ( me 10 ), 29 . 23 ( c 5 h ), 35 . 51 ( c 7 h 2 ), 40 . 68 ( c 12 h 2 ), 71 . 40 ( c 8 ), 81 . 57 ( c 1 h ), 83 . 77 ( c 4 ), 126 . 14 ( c 16 h ), 128 . 87 ( 2c 14 h ), 129 . 63 ( 2c 15 h ), 136 . 84 ( c 13 ); isomer 2b : 21 . 76 ( me 11 ), 23 . 30 ( c 6 h 2 ), 24 . 26 ( c 9 h 2 ), 28 . 04 ( me 10 ), 30 . 50 ( c 5 h ), 35 . 84 ( c 7 h 2 ), 40 . 73 ( c 12 h 2 ), 71 . 35 ( c 8 ), 82 . 02 ( c 1 h ), 83 . 83 ( c 4 ), 126 . 33 ( c 16 h ), 128 . 93 ( 2c 14 h ), 129 . 63 ( 2c 15 h , 136 . 42 ( c 13 ). r -(+)- limonene 1 ( 2 . 73 g , 20 . 0 mmol , 66 . 8 %) was recovered in the first chromatography the title compounds were obtained in 53 . 7 % yield ( 8 . 0 mmol ) from s (-)- limonene 1 &# 39 ; using the procedure for the preparation of compounds 2a , b from r (+)- limonene . 1 h nmr and ir spectra are consistent with those described for ( 1r , 4r , 5r , 8r )- and ( 1r , 4s , 5r , 8r )- diastereomers 2a , b . oxygen was bubbled through a solution of the β - benzoate 3a ( 350 mg , 1 . 36 mmol ) and dbpo ( 4 . 3 mg , 0 . 018 mmol ) in benezene - n - heptane ( 20 ml , 1 : 1 ) for 10 h with simultaneous addition of a solution of phsh ( 50 mg , 0 . 45 mmol ) in heptane ( 10 ml ) ( syringe pump ). after completion of the thiol addition , the mixture was kept under oxygen for an addition 15 h , diluted with ch 2 cl 2 ( 10 ml ), cooled to 4 ° c . and ph 3 p ( 118 mg , 0 . 45 mmol ) was added in 4 portions . the mixture was stirred at 4 ° c . for 1 h and at rt for an additional 1 h , the solvents were evaporated , and flash chromatography ( hexane - etoa , 3 : 1 ) afforded a mixture ( 42 mg , 22 . 3 % yield ) of ( 1r , 4s , 5s , 7s , 8s )- 7 - benzoyloxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan - 8 - ol 4a ( less polar isomer ) and ( 1r , 4r , 5s , 7s , 8s )- 7 - benzoyloxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan - 8 - ol 4b ( more polar isomer , ( 4a / 4b ca . 50 : 50 ), r f 0 . 26 ( etoac - hexane , 1 : 3 ), colorless semisolid . ir ( neat ): 3547 , 1713 , 1271 , 711 cm - 1 . additional flash chromatography afforded a sample of crystalline 4a ( less polar isomer ), mp 139 - 140 ° c . 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 37 ( br . s , 3 h , me 11 ), 1 . 44 ( s , 3 h , me 10 ), 1 . 83 ( ddd , 1 h , 2 j = 13 . 1 hz , 3 j 6a7a = 11 . 6 hz , 3 j 6a5e = 3 . 3 hz , h a 6 ), 2 . 08 ( m , 2 h , h a 9 + h e 9 ), 2 . 20 ( m , 1 h , h e 5 ), 2 . 37 ( m , 1 h , h e 6 ), 3 . 35 ( d , 1 h , 2 j = 12 . 9 hz , h 12 ), 3 . 73 ( br . d , 1 h , 2 j = 12 . 9 hz , h &# 39 ; 12 ), 3 . 96 ( dd , 1 h , 3 j 1e9e = 3 j 1e9a = 2 . 4 hz , h e 1 ), 5 . 76 ( dd , 1 h , 3 j 7a6a = 11 . 6 hz , 3 j 7a6e = 6 . 3 hz , h a 7 ), 7 . 20 ( m , 1 h , h 16 ), 7 . 30 ( m , 2 h , h 15 , 15 &# 39 ;), 7 . 42 ( m , 2 h , h 14 , 14 &# 39 ;), 7 . 48 ( m , 2 h , h meta - benz . ), 7 . 60 ( m , 1 h , h para - benz . ), 8 . 03 ( m , 1 h , h ortho - benz .). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 30 ( me 11 ), 23 . 68 ( c 9 h 2 ), 24 . 46 ( me 10 ), 29 . 23 ( c 6 h 2 ), 31 . 31 ( c 5 h ), 40 . 54 ( c 12 h 2 ), 72 . 81 ( c 8 ), 74 . 75 ( c 6 h ), 82 . 75 ( c 1 h ), 83 . 79 ( c 4 ), 126 . 43 ( c 16 h ), 128 . 54 ( 2ch ), 129 . 03 ( 2ch ), 129 . 48 ( 2ch ), 129 . 94 ( 2ch ), 130 . 07 ( c 1 - benz . ), 133 . 24 ( c p - benz . h ), 136 . 56 ( c 13 ), 165 . 59 ( c ═ o ). more polar isomer 4b : 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 43 ( s , 3h , me 10 ), 1 . 58 ( br . s , 3 h , me 11 ), 1 . 77 ( ddd , 1 h , 2 j = 12 . 8 hz , 3 j 6a7a = 11 . 2 hz , 3 j 6a5e = 3 . 4 hz , h a 6 ), 2 . 07 - 2 . 36 ( m , 4 h , h e 5 + h e 6 + h e , a 9 ), 3 . 03 ( d , 1 h , 2 j = 12 . 3 hz , h 12 ), 3 . 24 ( br . d , 1 h , 2 j = 12 . 3 hz , h &# 39 ; 12 ), 3 . 99 ( m , 1 h , h e 1 ), 5 . 78 ( dd , 1 h , 3 j 7a6a = 11 . 2 hz , 3 j 7a6e = 6 . 3 hz , h a 7 ), 7 . 21 ( m , 1 h , h 16 ), 7 . 30 ( m , 2 h , h 15 , 15 &# 39 ;), 7 . 42 ( m , 2 h , h 14 , 14 &# 39 ;), 7 . 48 ( m , 2 h , h meta - benz . ), 7 . 59 ( m , 1 h , h para - benz . ), 8 . 03 ( m , 1 h , h ortho - benz . ), 13 c nmr ( 100 mhz , cdcl 3 , δ ): 21 . 40 ( me 11 ), 23 . 80 ( c 9 h 2 ), 24 . 46 ( me 10 ), 28 . 99 ( c 6 h 2 ), 32 . 53 ( c 5 h ), 40 . 70 ( c 12 h 2 ), 72 . 83 ( c 8 ), 74 . 81 ( c 7 h ), 83 . 23 ( c 1 h ), 83 . 88 ( c 4 ), 126 . 51 ( c 16 h ), 128 . 52 ( 2ch ), 129 . 03 ( 2ch ), 129 . 48 ( 2ch ), 129 . 90 ( 2ch ), 130 . 08 ( c 1 - benz . ), 133 . 20 ( c p - benz . h ), 135 . 99 ( c 13 ), 165 . 52 ( c ═ o ). oxygen was bubbled through a solution of the β - benzoate 3a ( 993 mg , 3 . 87 mmol ) and dbpo ( 23 mg , 0 . 1 mmol ) in hexane - benzene ( 50 ml , 4 : 1 ) with simultaneous addition ( syringe pump ) during 10 h a solution of n - bush ( 180 mg , 2 . 0 mmol ) in hexane ( 20 ml ). after completion of the addition the mixture was kept under oxygen for an additional 14 h , cooled to 5 ° c ., and ph 3 p ( 526 mg , 2 . 0 mmol ) was added . the reaction mixture was stirred for 2 h at 5 ° c ., for additional 1 h at rt and then evaporated . flash chromatography ( hexane - etoac , 9 : 1 → 7 : 3 ) afforded a mixture of diastereomeric ( 1s , 4s , 5s , 7s , 8s )- 7 - benzoyloxy - 4 - n - butylthiomethyl - 4 , 8 - dimethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan - 8 - ol 5a and ( 1s , 4r , 5s , 7s , 8s )- 7 - benzoyloxy - 4 - n - butylthiomethyl - 4 , 8 - dimethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan - 8 - ol 5b ( 59 mg of ˜ 85 % purity , ca . 6 . 5 % yield ; 5a / 5b ca . 55 : 45 ) as a pale yellow viscous liquid , r f 0 . 26 ( hexane - etoac , 4 : 1 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 0 . 91 ( t , 3 j = 7 . 3 hz , me 16 ch 2 , 5b ), 0 . 92 ( t , 3 j = 7 . 3 hz , me 16 ch 2 , 5a ), total 3 h ; 1 . 36 ( br . s , me 11 , 5a ), 1 . 58 ( br . s , me 11 , 5b ), total 3 h , 1 . 42 ( m , 2 h , mec 15 h 2 ), 1 . 43 ( s , me 10 , 5b ), 1 . 44 ( s , me 10 , 5a ), total 3 h ; 1 . 60 ( m , 2 h , c 14 h 2 ch 2 s ), 1 . 78 ( ddd , 2 j = 13 . 3 hz , 3 j 6a7a = 11 . 6 hz , 3 j 6a5e = 3 . 4 hz , h a 6 , 5b ), 1 . 82 ( ddd , 2 j = 13 . 2 hz , 3 j 6a7a = 11 . 8 hz , 3 j 6a5e = 3 . 5 hz , h a 6 , 5a ), 1 h total ; 1 . 96 - 2 . 52 ( m , total 4 h , h e 5 + h e 6 + h e , a 9 , 5a + 5b ), 2 . 59 ( br . t , 3 j = 7 . 3 hz , ch 2 s , 5a ), 2 . 61 ( br . t , 3 j = 7 . 3 hz , c 13 h 2 s , 5b ), total 2 h ; 2 . 60 ( br . d , 2 j = 12 . 2 hz , h 12 , 5b ), 2 . 80 ( br . d , 2 j = 12 . 2 hz , h &# 39 ; 12 , 5b ), 2 . 96 ( br . d , 2 j = 13 . 2 hz , h 12 , 5a ), 3 . 20 ( br . d , 2 j = 13 . 2 hz , h &# 39 ; 12 , 5a ), total 2 h ; 3 . 97 ( br . s , 1 h , h e 1 , 5a + 5b ), 5 . 76 ( m , 1 h , h a 7 , 5a + 5b ), 7 . 46 ( m , 2 h , h m - benz ., 5a + 5b ), 7 . 59 ( m , 1 h , h p - benz ., 5a + 5b ), 8 . 03 ( m , 2 h , h 0 - benz ., 5a + 5b ); 13 c nmr ( 100 mhz , cdcl 3 , δ ): isomer 5a : 13 . 67 ( me 16 ), 21 . 89 ( c 15 h 2 ), 22 . 09 ( me 11 ), 23 . 79 ( c 9 h 2 ), 24 . 44 ( me 10 ), 29 . 33 ( c 6 h 2 ), 31 . 58 ( c 5 h ), 31 . 82 ( c 14 h 2 ), 33 . 47 ( c 13 h 2 ), 38 . 16 ( c 12 h 2 ), 72 . 81 ( c 8 ), 74 . 79 ( c 7 h ), 82 . 73 ( c 1 h ), 83 . 81 ( c 4 ), 128 . 50 ( 2c m - benz . h ), 129 . 46 ( 2c o - benz . h ), 130 . 05 ( c 1 - benz . ), 133 . 20 ( c p - benz . h ), 165 . 58 ( c ═ o ); isomer 5b : 13 . 62 ( me 16 ), 20 . 66 ( me 11 ), 21 . 85 ( c 15 h 2 ), 23 . 89 ( c 9 h 2 ), 24 . 44 ( me 10 ), 28 . 99 ( c 6 h 2 ), 31 . 54 ( c 14 h 2 ), 32 . 59 ( c 5 h ), 33 . 67 ( c 13 h 2 ), 38 . 88 ( c 12 h 2 ), 72 . 80 ( c 8 ), 74 . 96 ( c 7 h ), 83 . 15 ( c 1 h ), 83 . 92 ( c 4 ), 128 . 50 ( 2c m - benz . h ), 129 . 46 ( 2c o - benz . h ), 130 . 09 ( c 1 - benz . ), 133 . 17 ( c p - benz . h ), 165 . 58 ( c ═ o ). oxygen was bubbled through a solution of the α - benzoate 3b ( 690 mg , 2 . 70 mmol ) and dbpo ( 8 . 5 mg , 0 . 036 mmol ) in hexane - benzene ( 50 ml , 7 : 3 ) with simultaneous addition ( syringe pump ) of a solution of phsh ( 99 mg , 2 . 0 mmol ) in hexane ( 20 ml ) during 10 h . after completion of the thiol addition , the mixture was kept under oxygen for an additional 14 h , cooled to 4 ° c ., and ph 3 p ( 236 mg , 0 . 90 mmol ) was added . the reaction mixture was stirred for 2 h at 5 ° c . and at rt for additional 1 h . the solvents were then evaporated , and flash chromatography ( hexane - etoac , 9 : 1 → 1 : 1 ) afforded a mixture of diastereomeric ( 1s , 4s , 5s , 7r , 8s )- 7 - benzoyloxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan - 8 - ol 6a and ( 1s , 4r , 5s , 7r , 8r )- 7 - benzoyloxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan - 8 - ol 6b ( 24 mg of ca . 94 % purity , 6 % yield , 6a / 6b ca . 65 : 35 ), r f 0 . 42 ( etoac - heaxane , 35 : 65 ) as a pale yellow oil . 1 h nmr ( 400 ) mhz , cdcl 3 , δ ): 1 . 23 ( br . s , me 11 , 6a ), 1 . 59 ( br . s , me 11 , 6b ), total 3 h ; 1 . 41 ( s , me 10 , 6b ), 1 . 42 ( s , me 10 , 6a ), total 3 h ; 1 . 91 - 2 . 37 ( m , total 5 h , h 3 5 + h a , e 6 + h a , e 9 , 6a + 6b ); 3 . 00 ( d , 2 j = 12 . 1 hz , h 12 , 6b ), 3 . 14 ( br . d , 2 j = 12 . 1 hz , h &# 39 ; 12 , 6b ), 3 . 39 ( d , 2 j = 12 . 8 hz , h 12 , 6a ), 3 . 80 ( br . d , 2 j = 12 . 8 hz , h &# 39 ; 12 , 6a ), total 2 h ; 3 . 82 ( m , h e 1 , 6a ), 3 . 88 ( dd , 3 j 1e9e = 4 . 1 hz , 3 j 1e9a = 1 . 5 hz , h e 1 , 6b ), total 1 h ; 5 . 26 ( dd , 1 h , 3 j 7e6e = 5 . 0 hz , 3 j 7e6a = 1 . 7 hz , h e 7 , 6b ), 5 . 27 ( dd , 1 h , 1 j 7e6e = 5 . 0 hz , 3 j 7e6a = 1 . 5 hz , h e 7 , 6a ), total 1 h ; 7 . 09 ( m , 1 h ), 7 . 22 ( m , 6 b ), 7 . 29 ( m , 6a ), total 2 h ; 7 . 41 - 7 . 47 ( m ,), 7 . 54 - 7 . 58 ( m ,), total 5 h ; 8 . 13 ( m , 2 h ), 13 c nmr ( 100 mhz , cdcl 3 , δ ): isomer 6a : 22 . 30 ( me 11 ), 23 . 42 ( c 9 h 2 ), 23 . 47 ( me 10 ), 28 . 81 ( c 6 h 2 ), 29 . 36 ( c 5 h ), 40 . 78 ( c 12 h 2 ), 73 . 83 ( c 8 ), 74 . 36 ( c 7 h ), 80 . 85 ( c 1 h ), 82 . 74 ( c 4 ), 126 . 36 ( c 16 h ), 128 . 48 ( 2ch ), 129 . 00 ( 2ch ), 129 . 81 ( 2ch ), 129 . 90 ( 2ch ), 130 . 15 ( c 1 - benz . ), 133 . 11 ( c p - benz . h ), 136 . 71 ( c 13 ), 166 . 33 ( c ═ o ); isomer 6b : 21 . 68 ( me 11 ), 23 . 35 ( me 10 ), 23 . 56 ( c 9 h 2 ), 28 . 68 ( c 6 h 2 ), 30 . 86 ( c 5 h ), 40 . 37 ( c 12 h 2 ), 73 . 68 ( c 8 ), 74 . 51 ( c 7 h ), 81 . 38 ( c 1 h ), 82 , 83 ( c 4 ), 126 . 12 ( c 16 h ), 128 . 52 ( 2ch ), 128 . 88 ( 2ch ), 129 . 06 ( 2ch ), 129 . 81 ( c 1 - benz . ), 129 . 90 ( 2ch ), 133 . 18 ( c p - benz . h ), 136 . 25 ( c 13 ), 166 . 25 ( c ═ o ). oxygen was bubbled through a solutionof α - carveol 3c ( 2 . 284 g , 15 mmol ) and dbpo ( 47 mg , 0 . 2 mmol ) in benzene - n - hexane ( 250 ml , 1 : 1 ) with simultaneous addition ( syringe pump ) of a solution of phsh ( 550 mg , 5 . 0 mmol ) in hexane ( 20 ml ) during 12 h . after completion of the thiol addition , the mixture was kept under oxygen for an additional 12 h , cooled to 5 ° c . and ph 3 p ( 1 . 31 g , 5 . 0 mmol ) was added in 3 portions . the mixture was stirred at 5 ° c . for 2 h and for an additional 2 hr at rt , the solvents were evaporated , and flash chromatography ( hexane - etoac , 3 : 1 → 1 : 1 ) afforded ( 1r , 4s , 5r , 8r )- 7 - benzoyloxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan - 8 - ol monohydrate 7a ( 194 mg , 11 . 8 % yield ) as colorless needles , mp 108 - 109 ° c . ( hexane - etoac , 5 : 1 ), r f 0 . 20 ( etoac - hexane , 50 : 50 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ); 1 . 36 ( br . s , 3 h , me 11 ), 1 . 45 ( s , 3 h , me 10 ), 1 . 96 - 2 . 06 ( m , total 3 h , h e 5 + h a , e 9 ), 2 . 09 ( ddd , 1 h , 2 j = 16 . 0 hz , 3 j 6a5e = 3 . 7 hz , 3 j 6a7e = 1 . 4 hz , h a 6 ), 2 . 18 ( ddd , 1 h , 2 j = 16 . 0 hz , 3 j 6e7e = 5 . 5 hz , 3 j 6e5e = 4 . 4 hz h e 6 ), 3 . 37 ( d , 1 h , 2 j = 12 . 9 hz , h 12 ), 3 . 55 ( br . dd , 1 h , 3 j 7e , oh = 13 . 2 hz , 3 j 7e6e = 5 . 5 hz , h e 7 ), 3 . 76 ( dd , 1 h , 2 j = 12 . 9 hz , 4 j 12 &# 39 ; , 11 = 0 . 6 hz , h &# 39 ; 12 ), 3 . 76 ( m , 1 h , h e 1 ), 4 . 09 ( d , 1 h , 3 j ho , 7e = 13 . 2 hz , oh , exch . with cd 3 cood ), 7 . 22 ( m , 1 h , h 16 ), 7 . 32 ( m , 2 h , 2h 15 ), 7 . 42 ( m , 2 h , 2 h 14 ). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 22 ( me 11 ), 22 . 91 ( c 9 h 2 ), 24 . 57 ( me 10 ), 29 . 95 ( c 5 h ), 30 . 92 ( c 6 h 2 ), 40 . 55 ( c 12 h 2 ), 72 . 98 ( c 7 h ), 74 . 21 ( c 8 ), 82 . 19 ( c 1 h ), 83 . 86 ( c 4 ), 126 . 56 ( c 16 h ), 129 . 03 ( 2c 15 h ), 130 . 07 ( 2c 14 h ), 136 . 35 ( c 13 ). anal . calcd for c 16 h 22 o 4 s × h 2 o : c , 58 . 51 ; h 7 . 36 ; s , 9 . 76 . found : c , 58 . 48 ; h 7 . 34 ; s , 9 . 27 . preparation of ( 1r , 4r , 5r )- 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan - 7 - ene ( 9a ), ( 1r , 4s , 5r )- 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan - 7 - ene ( 9b ), ( 1r , 4r , 5r )- 4 , 8 - dimethyl - 8 - methylidene - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan ( 10a ) and ( 1r , 4s , 5r )- 4 - methyl - 8 - methylidene - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonan ( 10b ) ( scheme 3 ). to a mixture of socl 2 ( 1 . 90 g , 16 . 0 mmol ) and pyridine ( 3 . 165 g , 40 . 0 mmol ) in ch 2 cl 2 ( 150 ml ) at - 30 ÷- 40 ° c . was added during 1 . 5 h a solution of hydroxysulfides 2a , b ( 1 . 10 g , 3 . 74 mmol , ratio 2a / 2b ca . 55 : 45 ) in ch 2 cl 2 ( 30 ml ). the temperature raised to 25 ° c . and the mixture was stirred for additional 4 h . the resulting mixture was poured into ice - cold 0 . 1 m hcl ( 100 ml ), extracted with hexane - etoac ( 9 : 1 , 2 × 300 ml ), the organic layer was washed with saturated nahco 3 ( 2 × 80 ml ), dried ( na 2 so 4 + nahco 3 ) and evaporated . the residue was purified by flash chromatography ( hexane - etoac , 95 : 5 ) to give a mixture of unsaturated sulfides 9a , b and 10a , b ( 798 mg , total 80 %, consisting of 9a , ca . 47 %, 9b , 39 %, 10a ; 8 %; and 10b , 6 % according the integration of the c 1 h peaks in 400 mhz 1 h nmr spectrum ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 20 ( d , 4 j = 0 . 7 hz , me 11 9a ), 1 . 29 ( d , 4 j = 0 . 6 hz , me 11 10a ), 1 . 57 ( d , 4 j = 0 . 5 hz , me 11 10b ), 1 . 58 ( d , 4 j = 0 . 8 hz , me 11 9b ), total 3 h ; 1 . 55 ( ddd , 2 j = 13 . 1 hz , 3 j 9a5e = 3 . 0 hz , 3 j 9a1e = 2 . 0 hz , h a 9 9a ), 1 . 63 ( dddd , 2 j = 13 . 0 hz , 3 j 9a5e = 2 . 9 hz , 3 j 9a1e = 2 . 4 hz , 4 j = 0 . 5 hz , h a 9 9b ), 1 h ; 1 . 79 - 1 . 81 ( m , ca . 3 h , me 10 9a , b ), 1 . 93 ( m , h e 5 9b ), 2 . 04 ( m , h e 5 9a ), total ca . 1 h ; 2 . 15 - 2 . 37 ( m ), 2 . 48 ( dddd , 2 j = 13 . 0 hz , 3 j 9e5e = 3 j 9e1e = 3 . 6 hz , 4 j 9e6e = 1 . 6 hz , h e 9 9b ), total 3 h ; 2 . 90 ( d , 2 j = 11 . 8 hz , h 12 9b ) and 2 . 99 ( dd , 2 j = 11 . 8 hz , 4 j 12 , 11 = 0 . 8 hz , h &# 39 ; 12 9b ), 3 . 00 ( d , 2 j = 12 . 0 hz , h 12 10b ) and 3 . 10 ( dd , 2 j = 12 . 0 hz , 4 j 12 , 11 = 0 . 5 hz , h &# 39 ; 12 10b ), 3 . 30 ( d , 2 j = 12 . 2 hz , h 12 10a ), 3 . 33 ( d , 2 j = 12 . 7 hz , h 12 9a ) and 3 . 79 ( dd , 2 j = 12 . 7 hz , 4 j 12 , 11 = 0 . 7 hz , h 12 9a ), total 2 h ; 4 . 10 ( m , 3 j 1e9e = 3 . 6 hz , 3 j 1e9a = 2 . 0 hz , h e 1 , 9a ), 4 . 13 ( br . dd , 3 j 1e9e = 3 . 6 hz , 3 j 1e9a = 2 . 4 hz , h e 1 9b ), 4 . 34 ( br . dd , 3 j 1e9e = 4 . 0 hz , 3 j 1e9a = 1 . 4 hz , h e 1 , 10a ), 4 . 40 ( br . dd , 3 j 1e9e = 4 . 3 hz , 3 j 1e9a = 1 . 7 hz , h e 1 10b ), total 1 h ; 4 . 89 - 4 . 93 ( m , hh &# 39 ; c 10 = 10a , b ), 5 . 73 ( m , h 7 9b ), 5 . 75 ( m , h 7 9a ), total ca . 1 h ; 7 . 18 - 7 . 46 ( m , 5 h ). by an additional preparative rp hplc ( column lichrosorb ® rp - 8 ( 7 μm ) 250 - 25 ; eluent - mecn - h 2 o , 60 : 40 ) single diastereomer ( 1r , 4r , 5r )- 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] non - 7 - ene 9a ( ca . 97 % purity ) was isolated : a colorles waxy substance , mp 60 - 63 ° c . 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 20 ( d , 3 h , 4 j = 0 . 6 hz , me 11 ), 1 . 55 ( ddd , 1 h , 2 j = 13 . 1 hz , 3 j 9a5e = 3 . 0 hz , 3 j 9a1e = 2 . 0 hz , h a 9 ), 1 . 80 ( ddd , 3 h , 5 j 10 , 6a = 2 . 7 hz , 5 j 10 , 6e = 4 j 10 , 7 = 1 . 6 mz , me 10 ), 2 . 04 ( m , 1 h , h e 5 ), 2 . 21 ( dddq , 1 h , 2 j = 19 . 0 hz , 3 j 6a7 = 5 . 4 hz , 3 j 6a5e = 5 j 6a10 = 2 . 7 hz , h a 6 ), 2 . 30 ( dddd , 1 h , 2 j = 13 . 1 hz , 3 j 9e5e = 3 j 9e1e = 3 . 6 hz , 4 j 9e6e = 1 . 6 hz , h e 9 ), 2 . 33 ( dddq , 1 h , 2 j = 19 . 0 hz , 3 j 6e7 = 6 . 4 hz , 3 j 6e5e = 5 j 6e10 = 1 . 6 hz , h e 6 ), 3 . 34 ( d , 1 h , 2 j = 12 . 7 hz , h 12 ), 3 . 79 ( br . dd , 2 j = 12 . 7 hz , 4 j 12 &# 39 ; , 11 = 0 . 7 hz , h 12 ), 4 . 10 ( m , 1 h , 3 j 1e9e = 3 . 6 hz , 3 j 1e9a = 2 . 0 hz , h e 1 ), 5 . 76 ( m , 1 h , h 7 ), 7 . 19 ( m , 1 h , h 16 ), 7 . 29 ( m , 2 h , h 15 , 15 &# 39 ;), 7 . 42 ( m , 2 h , h 14 , 14 &# 39 ;). 13 c nmr ( 100 mhz , cdcl 3 , δ ); 21 . 17 me 10 ), 22 . 72 ( me 11 ), 26 . 38 ( c 9 h 2 ), 27 . 56 ( c 6 h 2 ), 28 . 52 ( c 5 h ), 40 . 73 ( c 12 h 2 ), 76 . 21 ( c 1 h ), 83 . 37 ( c 4 ), 126 . 15 ( c 16 h ), 126 . 82 ( c 7 h ), 128 . 90 ( 2c 15 h ), 129 . 69 ( 2c 14 h ), 131 . 26 ( c 8 ═), 136 . 96 ( c 13 ). preparation of ( 1r , 4r , 5r , 8s )- 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] non - 7 - ene ( 11a ), ( 1r , 4r , 5r )- 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane ( 11b ), ( 1r , 4s , 5r , 8s )- 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane ( 12a ) and ( 1r , 4s , 5r , 8r )- 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane ( 12b ) ( scheme 4 ). to a mixture of unsaturated sulfides 9a , b and 10a , b ( total 120 mg , 0 . 43 mmol ; ratio 9a : 9b : 10a : 10b ca . 54 : 34 : 6 . 5 : 5 . 5 ) and potassium azodicarboxilate ( 1 . 00 g , 5 . 15 mmol ) in meoh ( 3 ml ) and ch 2 cl 2 ( 2 ml ) at 0 ° c . for 45 min was added a solution of acoh ( 620 mg , 10 . 32 mmol ) in ch 2 cl 2 ( 2 ml ). temperature was slowly raised to 25 ° c . ( 2 h ) and the reaction mixture was stirred for an additional 48 h . the mixture was diluted with ether ( 50 ml ), filtered through celite ® and evaporated . the residue was separated by several consecutive mplc ( hexane - etoac , 98 : 2 ) to give starting material 9a , b ( 70 mg , 0 . 25 mmol ; 9a / 9b ca . 61 : 39 ), sulfides 12a ( 4 mg ), 12b ( 3 mg ), and two fractions consisted of mixtures of 11a , b with different ratio of isomers : ( 4 mg , 11a / 11b 83 : 17 ) and ( 19 mg , 11a / 11b 53 : 47 ). 11a , b : 1 h nmr ( cdcl 3 , 400 mhz ) ( δ ): 1 . 09 ( d , 3 j = 6 . 7 hz , me 10 , 11b ), 1 . 10 ( d , 3 j = 6 . 7 hz , me 10 , 11a ), total 3 h ; 1 . 24 ( br . s , me 11 , 11a ), 1 . 55 ( d , 4 j 11 , 12 = 0 . 7 hz , me 11 , 11b ), total 3 h ; 1 . 41 ( ddd , 3 j = 13 . 3 hz , 3 j 9a5e = 3 . 0 hz , 3 j 9a1e = 1 . 7 hz , h a 9 11a ), 1 . 48 ( ddd , 2 j = 13 . 1 hz , 3 j 9a5e = 3 . 2 hz , 3 j 9a1e = 1 . 7 hz , h a 9 11b ), total 1 h ; 1 . 58 - 1 . 69 ( m , 2 h , h e 6 + h a 6 , 11a + 11b ); 1 . 75 - 1 . 85 ( m , 1 h , h a 8 , 11a + 11b ); 1 . 90 - 1 . 94 ( m , 1 h , h e 5 , 11a + 11b ); 1 . 94 - 2 . 05 ( m , 2 h , h e 7 + h a 7 , s11a + 11b ); 2 . 28 ( dddd , 3 j 9e9a = 13 . 3 hz , 3 j 9e1e = 3 j 9e5e = 4 . 0 hz , 4 j 9e6e = 2 . 6 hz , h e 9 , 11a ), 2 . 45 ( dddd , 2 j 9e9a = 13 . 1 hz , 3 j 9e1e = 3 j 9e5e = 3 . 8 hz , 4 j 9e6e = 2 . 9 hz , h e 9 , 11b ), total 1 h ; 2 . 94 ( d , 2 j = 11 . 9 hz , h 12 , 11b ) and 3 . 05 ( dd , 2 j = 11 . 9 hz , 4 j 12 , 11 = 0 . 7 hz , h &# 39 ; 12 , 11b ), 3 . 31 ( d , 2 j = 12 . 7 hz , h 12 , 11a ), and 3 . 73 ( dd , 2 j = 12 . 7 hz , 4 j 12 , 11 = 0 . 7 hz , h 12 , 11a ), total 2 h ; 3 . 83 ( m , 3 j 1e9e = 4 . 0 hz , 3 j 1e9a = 1 . 7 hz , h e 1 , 11a ), 3 . 86 ( m , 3 j 1e9e = 3 . 8 hz , 3 j 1e9a = 1 . 7 hz , h e 1 , 11b ), total 1 h ; 7 . 17 - 7 . 43 ( m , 5 h , 11a + 11b ). isomer 11a : 13 c nmr ( cdcl 3 , 100 mhz ) ( δ ): 18 . 56 ( me 10 ), 22 . 05 ( me 11 ), 27 . 06 ( ch 2 ), 29 . 19 ( c 5 h ), 29 . 56 ( ch 2 ), 29 . 59 ( ch 2 ), 35 . 62 ( c 8 h ), 40 . 91 ( c 12 h 2 ), 79 . 23 ( c 1 h ), 83 . 36 ( c 4 ), 126 . 07 ( c 16 h ), 128 . 90 ( 2c 15 h ), 129 . 59 ( 2c 14 h ), 136 . 90 ( c 13 ). isomer 12a : 1 h nmr ( cdcl 3 , 400 mhz ) ( δ ): 1 . 02 ( d , 3 h , 3 j = 7 . 4 hz , me 10 ), 1 . 25 ( d , 3h , 4 j 11 , 12 = 0 . 6 hz , me 11 ), 1 . 29 ( br . dd , 1h , 2 j = 14 . 0 hz , 3 j 7e6e = 5 . 8 hz , h e 7 ), 1 . 62 ( ddd , 1h , 2 j = 13 . 6 hz , 3 j 9a5e = 3 . 1 hz , 3 j 9a1e = 1 . 8 hz , h a 9 ), 1 . 74 ( dddd , 2 j = 3 j 6a7a = 14 . 0 hz , 3 j 6a5e = 6 . 2 hz , 3 j 6a7e = 3 . 4 hz , h a 6 ), 1 . 84 ( m , 1h , 2 j = 14 . 0 hz , h e 6 ), 1 . 87 ( m , 1h , h e 5 ); 2 . 02 ( dddd , 1h , 2 j 9e9a - 13 . 6 hz , 3 j 9e5e = 6 . 2 hz , 3 j 9e1e = 3 . 6 hz , 4 j 9e6e = 1 . 3 hz , h e 9 ), 2 . 39 ( br . dq , 1h , 3 j 8e , 10 = 7 . 4 hz , 3 j 8e7a = 7 . 2 hz , h e 8 ), 2 . 55 ( dddd , 1h , 2 j ˜ 3 j 7a6a = 14 . 0 hz , 3 j 7a8e ˜ 3 j 7a6e = 7 . 2 hz , h a 7 ), 3 . 29 ( d , 1h , 2 j = 12 . 8 hz , h 12 ), 3 . 75 ( br . dd , 2 j = 12 . 8 hz , 4 j 12 &# 39 ; , 11 = 0 . 7 hz , h 12 ), 3 . 79 ( m , 1h , 3 j 1e9e = 3 . 6 hz , 3 j 1e9a = 3 j 1e8e = 1 . 8 hz , h e 1 ), 7 . 18 ( m , 1h , h 16 ), 7 . 28 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 41 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( cdcl 3 , 100 mhz ) ( δ ): 19 . 18 ( me 10 ), 22 . 06 ( me 11 ), 23 . 38 ( c 6 h 2 ), 24 . 02 ( c 9 h 2 ), 27 . 17 ( c 7 h 2 ), 29 . 61 ( c 5 h ), 32 . 98 ( c 8 h ), 40 . 83 ( c 12 h 2 ), 80 . 32 ( c 1 h ), 83 . 66 ( c 4 ), 126 . 11 ( c 16 h ), 128 . 90 ( 2c 15 h ), 129 . 66 ( 2c 14 h ), 136 . 92 ( c 13 ). isomer 12b : 1 h nmr ( cdcl 3 , 400 mhz ) ( δ ): 1 . 025 ( d , 3h , 3 j = 7 . 4 hz , me 10 ), 1 . 29 ( br . dd , 1h , 2 j = 13 . 6 hz , 3 j 7e6e ˜ 6 . 0 hz , h e 7 ), 1 . 54 ( d , 3h , 4 j 11 , 12 = 0 . 7 hz , me 11 ), 1 . 64 - 1 . 82 ( m , 4h , h e 5 + h e 6 + h a 6 + h a 9 ), 2 . 20 ( dddd , 1h , 2 j 9e9a = 13 . 4 hz , 3 j 9e5e = 6 . 6 hz , 3 j 9e1e = 3 . 9 hz , 4 j 9e6e = 1 . 3 hz , h e 9 ), 2 . 37 ( br . dq , 1h , 3 j 8e , 10 = 7 . 4 hz , 3 j 8e7a = 6 . 8 hz , h 3 8 ), 2 . 53 ( dddd , 1h , 2 j ˜ 3 j 7a6a = 13 . 6 hz , 3 j 7a8e ˜ 3 j 7a6e = 6 . 8 hz , h a 7 ), 2 . 97 ( d , 1h , 2 j = 12 . 0 hz , h 12 ), 3 . 09 ( br . dd , 2 j = 12 . 0 hz , 4 j 12 &# 39 ; , 11 = 0 . 7 hz , h 12 ), 3 . 84 ( ddd , 1h , 3 j 1e9e = 3 . 9 hz , 3 j 1e9a = 3 j 1e8e = 1 . 8 hz , h e 1 ), 7 . 19 ( m , 1h , h 16 ), 7 . 28 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 37 ( m , 2h , h 14 , 14 &# 39 ;). 13 c nmr ( cdcl 3 , 100 mhz ) ( δ ): 19 . 02 ( me 10 ), 21 . 96 ( me 11 ), 23 . 05 ( c 6 h 2 ), 24 . 05 ( c 9 h 2 ), 27 . 51 ( c 7 h 2 ), 31 . 14 ( c 5 h ), 32 . 89 ( c 8 h ), 40 . 78 ( c 12 h 2 ), 80 . 76 ( c 1 h ), 83 . 65 ( c 4 ), 126 . 29 ( c 16 h ), 128 . 97 ( 2c 15 h ), 129 . 62 ( 2c 14 h ), 136 . 86 ( c 13 ). synthesis of ( 1r , 4r , 5r , 8r )- 8 - acetoxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane ( 13a ), ( 1r , 4s , 5r , 8r )- 8 - acetoxy - 4 , 8 - dimethyl - 4 - phenylthio - methyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane ( 13b ), ( 1r , 4r , 5r , 8r )- 8 - acetylacetoxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane ( 14a ) and ( 1r , 4s , 5r , 8r )- 8 - acetylacetoxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane ( 14b ) ( scheme 5 ). to a solution of sulfides 2a and 2b ( 1 . 15 g , 3 . 91 mmol , 2a / 2b 55 : 45 ), pyridine ( 1 . 54 g , 19 . 5 mmol ) and dmap ( 49 mg , 0 . 4 mmol ) in dry ch 2 cl 2 ( 30 ml ) at 0 ° c . was added a solution of accl ( 1 . 22 g , 15 . 6 mmol ) in ch 2 cl 2 ( 5 ml ). the mixture was stirred for 1 h at 0 ° c . and for 12 h at rt the dark reaction mixture was poured into water ( 100 ml ), extracted with hexane - etoac ( 7 : 3 mixture , 3 × 100 ml ), dried ( na 2 so 4 + nahco 3 ) and evaporated . the residue was separated by flash chromatography ( gradient elution , hexane - etoac , 9 : 1 → 7 : 3 ) to give : ( i ) unreacted hydroxysulfides 2a and 2b ( 292 mg , 0 . 99 mmol , 25 . 4 %); ( ii ) a mixture of diastereomers ( 1r , 4r , 5r , 8r )- 8 - acetoxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicylo [ 3 . 3 . 1 ] nonane 13a and ( 1r , 4s , 5r , 8r )- 8 - acetoxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane 13b ( 518 mg , 1 . 54 mmol , 52 . 9 % yield , 13a / 13b ca . 55 : 45 ) as a colorless viscous liquid , r f 0 . 67 ( hexane - etoac 7 : 3 ); ( iii ) a mixture of diastereomers ( 1r , 4r , 5r8r )- 8 - acetylacetoxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane 14a and ( 1r , 4s , 5r , 8r )- 8 - acetylacetoxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane 14b ( 152 mg , 12 . 6 % yield , 14a / 14b ca . 54 : 46 ; keto / enol ca . 91 : 9 ) as a colorless oil , r f 0 . 40 ( hexane - etoac 7 : 3 ); ( iv ) a mixture of diastereomers of e - enolacetates e - 15a , b ( 48 mg , 0 . 105 mmol , 3 . 6 % yield , e - 15a / e - 15b ca . 54 : 46 ) as a yellowish viscous oil , r f 0 . 61 ( hexane - etoac 7 : 3 ); ( v ) a mixture of diastereomers of z - enolacetates z - 15a , b ( 41 mg , 0 . 090 mmol , 3 . 1 % yield , z - 15a / z - 15b ca . 52 : 48 ) as a yellowish viscous oil , r f 0 . 50 ( hexane - etoac 7 : 3 ). spectral data for 13a , b : ir ( neat ); 692 , 742 , 1022 v . s , 1054 , 1204 , 1223 , 1254 v . s , 1371 v . s , 1453 , 1732 v . s , 2935 cm - 1 . 1 h nmr ( cdcl 3 , 400 mhz ) ( δ ): 1 . 24 ( br . s , me 11 , 13a ), 1 . 56 ( br . s , me 11 , 13b ), total 3h ; 1 . 65 ( s , me 10 , 13b ), 1 . 66 ( s , me 10 , 13a ), total 3h ; 1 . 67 - 1 . 89 ( m , 3h , h e 6 + h a 6 + h a 9 , 13a + 13b ); 1 . 74 ( m , h e 5 , 13b ), 1 . 90 ( dddd , 3 j 5e6e = 3 j 5e9e = 6 . 6 hz , 3 j 5e6a = 3 j 5e9a = 3 . 3 hz , h e 5 , 13a ), total 1h ; 2 . 07 ( ddd , 2 j 9e9a = 14 . 1 hz , 3 j 9e5e = 6 . 6 hz , 3 j 9e1e = 3 . 4 hz , h e 9 , 13a ), 2 . 27 ( m , h e 9 , 13b ), total 1h , 2 . 12 - 2 . 20 ( m , 1h , h e 7 , 13a + 13b ); 2 . 25 ( ddd , 2 j 7a7e = 15 . 0 hz , j 7a6a = 13 . 2 hz , 3 j 7a6e = 6 . 0 hz , h a 7 , 13b ), 2 . 28 ( ddd , 2 j 7a7e = 14 . 3 hz , j 7a6a = 13 . 3 hz , 3 j 7a6e = 6 . 0 hz , h a 7 , 13a ), total 1h ; 2 . 95 ( h 12 , 13b )) and 3 . 02 ( 4 j 12 , 11 = 0 . 4 hz , h &# 39 ; 12 , 13b ), ( abq , 2 j = 12 . 0 hz ), 3 . 30 ( d , 2 j = 12 . 8 hz , h 12 , 13a ) and 3 . 72 ( dd , 2 j = 12 . 8 hz , 4 j 12 , 11 = 0 . 5 hz , h 12 , 13a ), total 2h ; 4 . 40 ( dd , 3 j 1e9e = 3 . 4 hz , 3 j 1e9a = 1 . 0 hz , h 1 , 13a ), 4 . 44 ( dd , 3 j 1e9e = 3 . 4 hz , 3 j 1e9a = 0 . 8 hz , h 1 , 13b ), total 1h ; 7 . 17 - 7 . 23 ( m , 1h , h 16 , 13a + 13b ); 7 . 29 ( m , 2h , h 15 , 13a + 13b ); 7 . 37 ( m , 2h , h 14 , 13a + 13b ). 13 c nmr ( cdcl 3 , 100 mhz ) ( δ ): isomer 13a : 22 . 03 ( me 11 ), 22 . 42 ( me 10 ), 22 . 55 ( me 17 c = o ), 23 . 50 ( c 6 h 2 ), 23 . 97 ( c 9 h 2 ), 28 . 52 ( c 5 h ), 32 . 88 ( c 7 h 2 ), 40 . 71 ( c 12 h 2 ), 77 . 46 ( c 1 h ), 82 . 76 ( c 8 ), 83 . 85 ( c 4 ), 126 . 24 ( c 16 h ), 128 . 91 ( 2c 14 h ), 129 . 76 ( 2c 15 h ), 136 . 73 ( c 13 ), 170 . 13 ( c = o ); isomer 13b : 21 . 77 ( me 11 ), 22 . 53 ( me 10 ), 22 . 55 ( me 17 c = o ) 23 . 22 ( c 6 h 2 ), 24 . 09 ( c 9 h 2 ), 29 . 89 ( c 5 h ), 33 . 20 ( c 7 h 2 ), 40 . 81 ( c 12 h 2 ), 77 . 91 ( c 1 h ), 82 . 67 ( c 8 ), 83 . 73 ( c 4 ), 126 . 43 ( c 16 h ), 128 . 96 ( 2c 14 h ), 129 . 73 ( 2c 15 h ), 136 . 29 ( c 13 ), 170 . 13 ( c = o ). spectral data for 14a , b : 1 h nmr ( cdcl 3 , 400 mhz ) ( δ ): 1 . 23 ( br . s , me 11 , 14a ), 1 . 55 ( br . s , me 11 , 14b ), total 3h ; 1 . 68 ( s , me 10 , 14b ), 1 . 69 ( s , me 10 , 14a ), total 3h ; 1 . 70 - 1 . 93 ( m , 4h ); 2 . 08 ( ddd , 2 j 9e9a = 14 . 0 hz , 3 j 9e5e = 6 . 5 hz , 3 j 9e1e = 3 . 5 hz , h e 9 , 14 ), 2 . 15 - 2 . 33 ( m ), total 3h ; 2 . 25 ( s , me 18 c = o , 14a ), 2 . 26 ( s , me 18 c = o , 14b ), total 3h ; 2 . 95 ( h 12 , 14b ) and 3 . 00 ( br ., h &# 39 ; 12 , 14b ), ( abq , 2 j = 12 . 6 hz ), 3 . 31 ( d , 2 j = 12 . 8 hz , h 12 , 14a ) and 3 . 69 ( br . d , 2 j = 12 . 8 hz , h 12 , 14a ), total 2h ; 3 . 40 ( s , c 17 h 2 c = o , 14a ), 3 . 41 ( s , c 17 h 2 c = o , 14b ), total 2h ; 4 . 37 ( br . d , 3 j 1e9e = 3 . 5 hz , h e 1 , 14a keto ), 4 . 41 ( br . d , 3 j 1e9e = 3 . 6 hz , h e 1 , 14b keto ), 4 . 45 ( br . d , 3 j 1e9e = 3 . 5 hz , h e 1 , 14a enol ), 4 . 49 ( br . d , 3 j 1e9e = 3 . 5 hz , h e 1 , 14b enol ), total 1h ; 4 . 92 ( br . s , hc =, 14a enol ), 4 . 94 ( br . s , hc =, 14b enol ); 7 . 26 - 7 . 42 ( m , 5h arom ., 14a + 14b ); 1 . 205 ( br . s , ho enol , 14a + 14b ). 13 c nmr ( cdcl 3 , 100 mhz ) ( δ ): isomer 14a : 21 . 89 ( me 11 ), 22 . 48 ( me 10 ), 23 . 28 ( c 6 h 2 ), 23 . 74 ( c 9 h 2 ), 28 . 43 ( c 5 h ), 30 . 15 ( me 18 c = o ), 32 . 67 ( c 7 h 2 ), 40 . 59 ( c 12 h 2 ), 51 . 18 ( c 17 h 2 ), 77 . 30 ( c 1 h ), 83 . 76 ( c 4 ), 84 . 25 ( c 8 ), 90 . 60 ( hc 17 = enol ), 126 . 16 ( 16 h ), 128 . 83 ( 2c 14 h ), 129 . 65 ( 2c 15 h ), 136 . 62 ( c 13 ), 165 . 83 ( oc 20 = o ), 200 . 57 ( c 19 = o ); isomer 14b : 21 . 64 ( me 11 ), 22 . 49 ( me 10 ), 22 . 98 ( c 6 h 2 ), 23 . 85 ( c 9 h 2 ), 29 . 74 ( c 5 h ), 30 . 15 ( me 18 c = o ), 33 . 02 ( c 7 h 2 ), 40 . 75 ( c 12 h 2 ), 51 . 18 ( c 17 h 2 ), 77 . 72 ( c 1 h ), 83 . 82 ( c 4 ), 84 . 17 ( c 8 ), 90 . 60 ( hc 17 = enol ), 126 . 37 ( c 16 h ), 128 . 88 ( 2c 14 h ), 129 . 68 ( 2c 15 h ), 136 . 18 ( c 13 ), 165 . 84 ( oc 20 = o ), 200 . 57 ( c 19 = o ). preparation of ( 1r , 4r , 5r , 8r )- 8 - ethoxyoxalyloxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane ( 18a ) and ( 1r , 4s , 5r , 8r )- 8 - ethoxyoxalyloxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane ( 18b ) ( scheme 6 ). ( a ) to a solution of hydroxysulfides 2a , b ( 153 mg , 0 . 52 mmol ) and 2 , 6 - lutidine ( 155 mg , 1 . 45 mmol ) in ch 2 cl 2 ( 3ml ) at 0 ° c . was added neat tfotms ( 260 mg , 1 . 10 mmol ) and the reaction mixture was stirred at 0 ° c . for 30 min , the temperature was raised to 20 ° c . after 30 min the reaction mixture was poured into the cold water ( 4 ° c ., 30 ml ) and extracted with etoac - hexane ( 1 : 4 , 2 × 30 ml ), washed with cold saturated nahco 3 ( 15 ml ), dried ( na 2 so 4 ), and evaporated to give the crude tms - derivative 16a , 6 ( 16a / 16b ca . 56 : 44 ) ( 204 mg , ca . quant . yield ) as a mobile pale yellow liquid . ir ( neat ): 2954 , 2928 , 1453 , 1446 , 1372 , 1250 v . s ., 1125 , 1060 v . s , 1040 v . s , 858 v . s , 840 v . s , 748 , 739 , 690 cm - 1 . 1 h nmr ( cdcl 3 , 400 mhz ): 0 . 108 and 0 . 111 ( s , me 3 si ), total 9h ; 1 . 22 ( br . s , me 11 16a ) and 1 . 53 ( d , me 11 , 4 j = 0 . 5 hz , 16b ), total 3h ; 1 . 38 ( s , me 10 16b ) and 1 . 39 ( s , me 10 16a ), total 3h ; 1 . 60 - 1 . 65 ( m , 1h , h e 7 16a + 16b ), 1 . 67 - 1 . 82 ( m , 3h ), 1 . 84 ( dddd , 3 j 5e9e = 3 j 5e6e = 6 . 0 hz , 3 j 5e9a = 3 j 5e6a = 3 . 0 hz , h e 5 16a ), 1 . 97 - 1 . 99 ( m , 1h ), 2 . 06 ( ddd , 2 j = 13 . 0 hz , 3 j 9a5e = 3 . 0 hz , 3 j 9a1e = 2 . 5 hz , h a 9 16a ), 2 . 13 - 2 . 25 ( m ), total 2h ; 2 . 945 and 3 . 015 ( 4 j 12 , 11 = 0 . 5 hz ) ( abq , 2 j = 12 . 0 hz , h 12 + h 12 + h &# 39 ; 12 16b ), 3 . 32 ( d , 2 j = 12 . 0 hz , h 12 16a ) and 3 . 68 ( dd , 2 j = 12 . 7 hz , 4 j 12 &# 39 ; , 11 = 0 . 6 hz , h &# 39 ; 12 16a ), total 12h ; 3 . 59 ( br . dd , 3 j 1e9e = 3 j 1e9a = 2 . 5 hz , h e 1 16a ), 3 . 63 ( m , h e 1 16b ), total 1h ; 7 . 26 - 7 . 42 ( m , 5h ). ( b ) the mixture of tms - derivative 16a , b ( 202 mg , ca . 0 . 52 mmol ) and oxalyl chloride ( 3ml ) was stirred at rt for 18 h , evaporated under vacuum for 3 h ( 0 . 2 mm hg ) to afford the crude chloride 17a , b ( 17a / 17bca . 56 : 44 ) as a viscous pale brown oil . ir ( neat ): 2965 , 2937 , 1796 v . s , 1754 v . s , 1481 , 1452 , 1441 , 1376 , 1275 v . s , 1224 , 1118 , 1053 , 1015 v . s , 977 v . s , 954 , 823 v . s , 808 , 741 v . s , and 692 cm - 1 . 1 h nmr ( cdcl 3 , 250 mhz , δ ): 1 . 26 ( br . s , me 11 17a ) and 1 . 58 ( br . s , me 11 17b ), total 3h ; 1 . 78 ( s , me 10 17b ) and 1 . 79 ( s , me 10 17a ), total 3h ; 1 . 68 - 2 . 02 ( m , 4h ), 2 . 15 ( ddd , 2 j = 13 . 8 hz , 3 j 9e5e = 6 . 6 hz , 3 j 9e1e = 3 . 4 hz , h e 9 17a ), 2 . 30 - 2 . 44 ( m ), total 3h ; 2 . 965 and 3 . 00 ( br .) ( abq , 2 j = 12 . 1 hz , h 12 + h &# 39 ; 12 17b ), 3 . 33 ( d , 2 j = 13 . 0 hz , h 12 17a ) and 3 . 70 ( dd , 2 j = 13 . 0 hz , 4 j 12 &# 39 ; , 11 = 0 . 5 hz , h &# 39 ; 12 17a ), total 2h ; 4 . 28 ( br . dd , 3 j 1e9e = 3 . 4 hz , 3 j 1e9a = 1 . 0 hz , h e 1 17a ), 4 . 32 ( br . dd , 3 j 1e9e = 3 . 4 hz , 3 j 1e9a = 1 . 0 hz , h e 1 17b ), total 1h ; 7 . 18 - 7 . 45 ( m , 5h ). ( c ) to a solution of crude chloride 17a , b in ch 2 cl 2 ( 3 ml ) at 0 ° c . was added a solution of etoh ( 79 mg , 1 . 7 mmol ) and 2 , 6 - lutidine ( 214 mg , 2 . 0 mmol ) in ch 2 cl 2 ( 2 ml ) and the reaction mixture was stirred overnight at 4 ° c . the mixture was poured into cold water ( 50 ml ), extracted with etoac - hexane ( 1 : 4 , 2 × 50 ml ), dried ( na 2 so 4 ) and evaporated . flash chromatography ( hexane - etoac , 85 : 15 ) of the residue gave the esters 18a , b ( 18a / 18b ca . 57 : 43 ) ( 140 mg , 0 . 355 mmol , 68 % yield ) as a viscous pale yellow liquid , r f 0 . 41 ( hexane - etoac , 4 : 1 ). ir ( neat ): 29 . 84 , 2938 , 1765 v . s , 1742 v . s , 1451 , 1441 , 1374 , 1320 v . s , 1185 v . s , 1090 , 1053 , 1013 v . s , 741 v . s , 692 cm - 1 . 1 h nmr ( cdcl 3 , 250 mhz , δ ): 1 . 26 ( br . s , me 11 18a ) and 1 . 57 ( br . s , me 11 18b ), total 3h ; 1 . 373 ( t , 3 j = 7 . 1 hz , me 18 ch 2 18a ), 1 . 378 ( t , 3 j = 7 . 1 hz , me 18 ch 2 18b ), total 3h ; 1 . 75 ( s , me 10 18b ) and 1 . 76 ( s , me 10 18a ), total 3h ; 1 . 68 - 1 . 96 ( m , 4h ), 2 . 11 ( ddd , 2 j = 13 . 6 hz , 3 j 9e5e = 6 . 2 hz , 3 j 9e1e = 3 . 4 hz , h e 9 18a ), 2 . 27 - 2 . 39 ( m ), total 3h ; 2 . 96 and 3 . 015 ( br .) ( abq , 2 j = 12 . 1 hz , h 12 + h &# 39 ; 12 18b ), 3 . 32 ( d , 2 j = 12 . 9 hz , h 12 18a ) and 3 . 71 ( br . d , 2 j = 12 .. 9 hz , h &# 39 ; 12 18a ), total 2h ; 4 . 325 ( q , 3 j = 7 . 1 hz , c 17 h 2 o 18a ), 4 . 331 ( q , 3 j = 7 . 1 hz , c 17 h 2 o 18b ), total 2h ; 4 . 34 ( m , h e 1 18a ), 4 . 38 ( m , h e 1 18b ), total 1h ; 7 . 17 - 7 . 44 ( m , 5h ). to a solution of chloride 17 a , b , prepared from hydroxysulfides 2a , b ( 112 mg , 0 . 38 mmol ) as described above , in ch 2 cl 2 ( 3 ml ) at 0 ° c . was added a solution of dibenzylamine ( 156 mg , 0 . 8 mmol ) and 2 , 6 - lutidine ( 160 mg , 1 . 5 mmol ) in ch 2 cl 2 ( 2 ml ). the mixture was stirred for 8 h at 0 ° c ., poured into cold water ( 50 ml ), extracted with hexane - etoac ( 3 : 1 , 2 × 50 ml ), organic layer was washed with saturated khso 4 ( 15 ml ) and nahco 3 ( 15 ml ), dried ( na 2 so 4 ) and evaporated . flash chromatography ( hexane - etoac , 85 : 15 ) of the residue gave the amides 19a , b ( 19a / 19b ca . 59 : 41 ) ( 160 mg , 0 . 293 mmol , 77 % yield based on the alcohols 2a , b ) as a colorless oil , r f 0 . 38 ( hexane - etoac , 4 : 1 ). ir ( neat ): 1728 v . s , 1661 v . s , 1452 v . s , 1440 v . s , 1374 , 1287 , 1265 , 1170 v . s , 1081 , 1053 , 1014 v . s , 738 v . s , 694 v . s . cm - 1 . 1 h nmr ( cdcl 3 , 250 mhz , δ ): 1 . 24 ( br . s , me 11 19a ) and 1 . 57 ( br . s , me 11 19b ), total 3h ; 1 . 71 ( br . s , 3h , me 10 19a + 19b ), 1 . 62 - 1 . 90 ( m , 4h ), 2 . 06 ( ddd , 2 j = 13 . 4 hz , 3 j 9e5e = 6 . 2 hz , 3 j 9e1e = 3 . 5 hz , h e 9 19a ), 2 . 18 - 2 . 42 ( m ), total 3h ; 2 . 95 and 3 . 00 ( br .) ( abq , 2 j = 12 . 1 hz , h 12 + h &# 39 ; 12 19b ), 3 . 32 ( d , 2 j = 13 . 0 hz , h 12 19a ) and 3 . 68 ( br . d , 2 j = 13 . 0 hz , h &# 39 ; 12 19a ), total 2h ; 4 . 33 ( br . d , 3 j 1e9e = 3 . 4 hz , h e 1 19a ) and 4 . 39 ( m , h e 1 19b ), total 1h ; 4 . 38 ( br . s , 2h , nc 17 h 2 ), 4 . 52 ( br . s , 2h , nc 18 h 2 ), 7 . 22 - 7 . 41 ( m , 15h ). preparation of ( 1s , 4s , 5s , 8s )- 8 - acetoxy - 4 , 8 - dimethyl - 4 phenylthio - methyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane ( 13 &# 39 ; a ) and ( 1s , 4r , 5s , 8s )- 8 - acetoxy - 4 , 8 - dimethyl - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane ( 13 &# 39 ; b ) ( scheme 7 ). to a neat tms - derivative 16 &# 39 ; a , b , prepared from 2 &# 39 ; a , b ( 0 . 854 mmol , 252 mg ) and tmsotf as described in example 9 , was added accl ( 2 . 0 ml ) and the mixture was stirred at rt for 50 h . the mixture was evaporated to give the crude acetoxysulfide 13 &# 39 ; a , b ( 293 mg , 0 . 841 mmol , practically quantitative yield ) as a pale yellow oil . 1 h nmr spectrum of 13 &# 39 ; a , b is consistent with that of 13a , b . to a solution of sulfides 2a and 2b ( 55 / 45 ) ( 2 . 10 g , 7 . 13 mmol ) in etoac ( 40 ml ) at rt was added a solution of mcpba ( 5 . 12 g of ca . 60 %, 17 . 8 mmol ) in etoac ( 100 ml ) and the reaction mixture was stirred for 8 h . then it was diluted with hexane ( 140 ml ), washed with saturated nahco 3 ( 2 × 100 ml ), the combined water washings were extracted with etoac - hexane ( 1 : 1 , 200 ml ). the organic extract was dried ( na 2 so 4 and nahco 3 ), evaporated and the residue was chromatographed ( hexane - etoac , 1 : 1 ) to afford a mixture of diastereomers 21a and 21b ( 2 . 129 g , 91 % yield ; 21a / 21b ca . 55 : 45 ). the diastereomers were separated by mplc ( hexane - etoac , 1 : 1 ). less polar isomer 21a , mp 112 - 113 ° c . ( hexane - etoac , 5 : 1 ), r f 0 . 38 ( etoac - hexane , 1 : 1 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 33 ( s , 3h , me 10 ), 1 . 49 ( br . s , 3h , me 11 ), 1 . 58 ( ddd , 1h , 2 j = 14 . 2 hz , 3 j 7e6e = 5 . 4 hz , 3 j 7e6a = 0 . 9 hz , h e 7 ), 1 . 80 - 1 . 93 ( m , 2h , h e 6 + h a 6 ), 2 . 10 ( ddd , 1h , 2 j = 13 . 9 hz , 3 j 9a5e = 3 . 0 hz , 3 j 9a1e = 2 . 0 hz , h a 9 ), 2 . 21 ( ddd , 1h , 2 j = 13 . 9 hz , 3 j 9e5e = 6 . 1 hz , 3 j 9e1e = 3 . 5 hz , h e 9 ), 2 . 27 ( m , 1h , h e 5 ), 2 . 27 ( ddd , 1h , 2 j = 14 . 2 hz , 3 j 7a6a = 13 . 8 hz , 3 j 7a6e = 6 . 6 hz , h a 7 ), 3 . 26 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 3 . 66 ( dd , 1h , 3 j 1e9e = 3 . 5 hz , 3 j 1e9a = 2 . 0 hz , h e 1 ), 4 . 21 ( br . d , 1h , 2 j = 14 . 3 hz , h &# 39 ; 12 ), 7 . 57 ( dddd , 2h , 3 j 15 , 14 = 3 j 15 , 16 = 7 . 4 hz , 4 j 1514 &# 39 ; = 4 j 15 &# 39 ; 14 = 1 . 3 hz , h 15 , 15 &# 39 ;), 7 . 65 ( dddd , 1h , 3 j 16 , 15 = 3 j 16 , 15 &# 39 ; = 7 . 4 hz , 4 j 1614 = 4 j 1614 &# 39 ; = 1 . 3 hz , h 16 ), 7 . 93 ( ddd , 2h , 3 j 14 , 15 = 3 j 14 , 15 = 7 . 4 hz , 4 j 14 , 16 = 1 . 3 hz , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 87 ( me 11 ), 23 . 45 ( c 6 h 2 ), 24 . 64 ( c 9 h 2 ), 27 . 97 ( me 10 ), 30 . 05 ( c 5 h ), 35 . 70 ( c 7 h 2 ), 61 . 02 ( c 12 h 2 ), 71 . 30 ( c 8 ), 81 . 96 ( c 1 h ), 82 . 71 ( c 4 ), 127 . 51 ( 2c 14 &# 39 ; h ), 129 . 33 ( 2c 15 h ), 133 . 71 ( c 16 h ), 141 . 08 ( c 13 ). anal . calcd for c 16 h 22 o 5 s : c , 58 . 87 ; h , 6 . 79 ; s , 9 . 82 . found : c , 58 . 87 ; h , 6 . 84 ; s , 9 . 73 . more polar isomer 21b : a colorless oil r f 0 . 34 ( etoac - hexane , 1 : 1 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 28 ( s , 3h , me 1 ), 1 . 58 ( br . dd , 1h , 2 j = 14 . 0 hz , 3 j 7e6e = 5 . 2 hz , h e 7 ), 1 . 70 ( br . s , 1h , oh ), 1 . 79 ( br . s , 3h , me 11 ), 1 . 85 - 1 . 99 ( m , 2h , h e 6 + h a 6 ), 2 . 03 ( ddd , 1h , 2 j = 13 . 4 hz , 3 j 9a5e = 3 . 2 hz , 3 j 9a1e = 1 . 7 hz , h a 9 ), 2 . 08 ( dddd , 1h , 3 j 5e6e = 3 j 5e9e = 6 . 2 hz , 3 j 5e6a = 3 j 5e9a = 3 . 2 hz , h e 5 ), 2 . 12 ( ddd , 1h , 2 j = 3 j 7a6a = 14 . 0 hz , 3 j 7a6e = 6 . 7 hz , h a 7 ), 2 . 26 ( ddd , 1h , 2 j = 13 . 4 hz , 3 j 9e5e = 6 . 2 hz , 3 j 9e1e = 3 . 3 hz , h e 9 ), 3 . 14 ( d , 1h , 2 j = 14 . 0 hz , h 12 ), 3 . 33 ( br . d , 1h , 2 j = 14 . 0 hz , h &# 39 ; 12 ), 3 . 68 ( dd , 1h , 3 j 1e9e = 3 . 3 hz , 3 j 1e9a = 1 . 7 hz , h e 1 ), 7 . 56 ( dddd , 2h , 3 j 15 , 14 = 3 j 15 , 16 = 7 . 4 hz , 4 j 1515 &# 39 ; = 4 j 15 &# 39 ; 14 = 1 . 4 hz , h 15 , 15 &# 39 ;), 7 . 66 ( dddd , 1h , 3 j 16 , 15 = 3 j 16 , 15 &# 39 ; = 7 . 4 hz , 4 j 1614 = 4 j 1614 &# 39 ; = 1 . 4 hz , h 16 ), 7 . 92 ( ddd , 2h , 3 j 14 , 15 = 3 j 14 , 15 = 3 j 14 &# 39 ; , 15 &# 39 ; = 7 . 4 hz , 4 j 14 , 16 = 1 . 3 hz , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 21 . 84 ( me 11 ), 23 . 57 ( c 9 h 2 ), 23 . 85 ( c 6 h 2 ), 28 . 01 ( me 10 ), 31 . 53 ( c 5 h ), 35 . 54 ( c 7 h 2 ), 60 . 55 ( c 12 h 2 ), 71 . 19 ( c 8 ), 82 . 45 ( c 1 h ), 82 . 94 ( c 4 ), 127 . 62 ( 2c 14 h ), 129 . 33 ( 2c 15 h ), 133 . 83 ( c 16 h ), 141 . 21 ( c 13 ). to a solution of sulfides 11 a , b ( 18 . 0 mg , 0 . 065 mmol , 11a / 11b 54 : 46 ) in etoac ( 0 . 5 ml ) was added mcpba ( 52 mg of ca . 60 %, 0 . 18 mmol ) and the mixture was stirred for 8 h at rt the mixture was poured into saturated nahco 3 ( 10 ml ), extracted with hexane - etoac ( 7 : 3 , 40 ml ), organic extract was washed with saturated nahco 3 ( 10 ml0 and the water washings were extracted with hexane - etoac ( 7 : 3 , 30 ml ). the combined organic layer was dried ( na 2 so 4 + nahco 3 ) and evaporated . flash chromatography ( hexane - etoac , 80 : 20 ) afforded a mixture of diastereomeric sulfones 22 a , b ( 18 . 0 mg , 90 % yield , ratio 22a / 22b ca . 55 : 45 ). the sulfones were separated by semi - preparative dp hplc ( column - lichrospher ® si 60 ( 10 μm ) 250 - 10 ; eluent i - proh - hexane 2 : 98 ). less polar isomer 22 a , colorless semisolid , τ r 16 . 7 min ( column - lichrospher ® si 60 ( 5 μm ) 250 - 4 ; eluent etoac - hexane 12 : 88 ). 1 h nmr ( cdcl 3 , 250 mhz ) ( δ ): 1 . 09 ( d , 3h , 3 j = 6 . 4 hz , me 10 ), 1 . 53 ( br . s , 3h , me 11 ), 1 . 58 ( ddd , 1h , 2 j = 13 . 4 hz , 3 j 9a5e = 3 . 0 hz , 3 j 9a1e = 1 . 7 hz , h a 9 ), 1 . 64 - 2 . 13 ( m , 5h , h e 6 + h a 6 + h e 7 + h a 8 ), 2 . 36 ( br . dddd , 1h , 3 j 5e9e = 3 j 5e6e = 6 . 0 hz , 3 j 5e9a = 3 j 5e6a = 3 . 0 hz , h e 5 ), 2 . 48 ( br . ddd , 1h , 2 j 9e9a = 13 . 4 hz , 3 j 9e5e = 6 . 0 hz , 3 j 9e1e = 3 . 6 hz , h e 9 ), 3 . 25 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 3 . 86 ( br . dd , 1h , 3 j 1e9e = 3 . 6 hz , 3 j 1e9a = 1 . 7 hz , h e 1 ), 4 . 31 ( br . dd , 1h , 2 j = 14 . 3 hz , 4 j = 0 . 6 hz , h &# 39 ; 12 ), 7 . 60 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 66 ( m , 1h , h 16 ), 7 . 97 ( m , 2h , h 14 , 14 &# 39 ;); dci hrms obsd 311 . 12940 , calcd for c 16 h 23 o 4 s ( m + h ) 311 . 13171 . more polar isomer 22b , colorless solid , mp 129 - 130 ° c ., τ r 17 . 7 min . ( column - lichrospher ® si 60 ( 5μm ) 250 - 4 ; eluent etoac - hexane 12 : 88 ). 1 h nmr ( cdcl 3 , 400 mhz ) ( δ ): 1 . 01 ( d , 3h , 3 j = 6 . 4 hz , me 10 ), 1 . 46 ( ddd , 1h , 2 j = 13 . 3 hz , 3 j 9a5e = 3 . 1 hz , 3 j 9a1e = 2 . 0 hz , h a 9 ), 1 . 65 ( m , 1h ), 1 . 68 - 1 . 82 ( m , 3h , h e 6 + h a 6 + h e 7 + h a 7 ); 1 . 80 ( d , 3h , 4 j 11 , 12 &# 39 ; = 0 . 5 hz , me 11 ), 2 . 07 - 2 . 14 ( m , 2h , h e 5 + h a 8 ), 2 . 47 ( dddd , 1h , 2 j 9e9a = 13 . 3 hz , 3 j 9e1e = 4 . 4 hz , 3 j 9e5e = 4 j 9e6e = 3 . 2 hz , h e 9 ), 3 . 14 ( d , 1h , 2 j = 14 . 0 hz , h 12 ), 3 . 37 ( br . dd , 1h , 2 j = 14 . 0 hz , 4 j 12 &# 39 ; 11 = 0 . 5 hz , h &# 39 ; 12 ), 3 . 85 ( br . dd , 1h , 3 j 1e9e = 4 . 4 hz , 3 j 1e9a = 2 . 0 hz , h e 1 ), 7 . 57 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 66 ( m , 1h , h 16 ), 7 . 93 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 18 . 49 ( me 10 ), 22 . 06 ( me 11 ), 27 . 33 ( ch 2 ), 28 . 96 ( ch 2 ), 29 . 61 ( c 7 h 2 ), 31 . 56 ( c 5 h ), 35 . 53 ( c 8 h ), 60 . 60 ( c 12 h 2 ), 80 . 06 ( c 1 h ), 82 . 53 ( c 4 ), 127 . 64 ( 2c 14 h ), 129 . 32 ( 2c 15 h ), 133 . 76 ( c 16 h ), 141 . 37 ( c 13 ). ci hrms ( ch 4 ) obsd 311 . 12650 , calcd for c 16 h 23 o 4 s ( m + h ) 311 . 13171 . to a solution of sulfides 13a and 13b ( 55 / 45 ) ( 55 mg , 0 . 163 mmol ) in etoac ( 1 ml ) at 0 ° c . was added a solution of mcpba ( 103 mg of ˜ 60 %, 0 . 35 mmol ) in etoac ( 1 . 5 ml ) and the reaction mixture was stirred for 4 h at rt the reaction mixture was poured into saturated nahco 3 ( 10 ml ), extracted with etoac - hexane ( 1 : 2 , 2 × 30 ml ). the organic extract was dried ( na s so 4 and nahco 3 ), evaporated and the residue was separated by mplc ( hexane - etoac , 7 : 3 ) to give the sulfones 23a ( 31 mg ) and 23b ( 26 mg ) ( total yield 97 %). less polar isomer 23a , mp 96 - 98 ° c ., r f 0 . 37 ( hexane - benzene - etoac 11 : 6 : 3 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 51 ( br . s , 3h , me 11 ), 1 . 62 ( s , 3h , me 10 ), 1 . 78 ( dddd , 1h , 2 j = 14 . 5 hz , 3 j 6a7a = 13 . 4 hz , 3 j 6a7e = 6 . 8 hz , 3 j 6a5e = 3 . 4 hz , h a 6 ), 1 . 88 ( ddd , 1h , 2 j = 14 . 0 hz , 3 j 9a5e = 3 . 4 hz , 3 j 9a1e = 1 . 2 hz , h a 9 ), 1 . 90 ( dddd , 1h , 2 j = 14 . 5 hz , 3 j 6e5e 6 . 8 hz , 3 j 6e7e = 3 j 6e7a = 2 . 8 hz , h e 6 ), 2 . 01 ( s , 3h , me 17 co ), 2 . 14 ( m , 1h , h e 7 ), 2 . 19 ( m , 1h , h a 7 ), 2 . 26 ( ddd , 1h , 2 j = 14 . 0 hz , 3 j 9e5e = 6 . 5 hz , 3 j 9e1e = 3 . 2 hz , h e 9 ), 2 . 30 ( br . dddd , 1h , 3 j 5e9e = 3 j 5e6e = 6 . 8 hz , 3 j 5e9a 3 j 5e6a = 3 . 4 hz , h e 5 ), 3 . 25 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 4 . 22 ( dd , 1h , 2 j = 14 . 3 hz , 4 j 12 &# 39 ; , 11 = 0 . 4 hz , h &# 39 ; 12 ), 4 . 45 ( br . dd , 3 j 1e9e = 3 . 2 hz , j 1e9a = 1 . 2 hz , h e 1 ), 7 . 58 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 66 ( m , 1h , h 16 ), 7 . 94 ( m , 2h , h 14 , 14 &# 39 ;). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 42 ( me 17 co ), 22 . 49 ( me 10 ), 23 . 09 ( me 11 ), 23 . 39 ( c 6 h 2 ), 24 . 52 ( c 9 h 2 ), 29 . 42 ( c 5 h ), 33 . 26 ( c 7 h 2 ), 60 . 98 ( c 12 h 2 ), 77 . 80 ( c 1 h ), 82 . 54 ( c 8 ), 8 . 272 ( c 4 ), 127 . 52 ( 2c 14 h ), 129 . 35 ( 2c 15 h ), 133 . 75 ( c 16 h ), 141 . 08 ( c 13 ), 170 . 20 ( c = o ). hrms ( ci , ch 4 ): obsd 369 . 13300 , calcd for c 18 h 25 o 6 s ( m + 1 ) 369 . 13719 . anal . calcd for c 18 h 24 o 6 s : c , 58 . 68 ; h , 6 . 56 ; s , 8 . 70 . found : c , 58 . 64 ; h , 6 . 55 ; s , 8 . 34 . more polar isomer 23b , a colorless solid , mp 101 - 102 ° c ., r f 0 . 31 ( hexane - benzene - etoac 11 : 6 : 3 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 56 ( s , 3h , me 10 ), 1 . 79 ( ddd , 1h , 2 j = 13 . 6 hz , 3 j 9a5e = 3 . 4 hz , 3 j 9a1e = 1 . 4 hz , h a 9 ), 1 . 80 ( br . s , 3h , me 11 ), 1 . 84 ( dddd , 1h , 2 j = 14 . 0 hz , 3 j 6a7a = 14 . 0 hz , 3 j 6a7e = 6 . 0 hz , 3 j 6a5e = 3 . 4 hz , h a 6 ), 1 . 96 ( m , 1h , h e 6 ), 2 . 00 ( s , 3h , me 17 co ), 2 . 04 ( m , 1h , h a 7 ), 2 . 10 ( dddd , 1h , 3 j 5e9e = 3 j 5e6e = 6 . 8 hz , 3 j 5e9a = 3 j 5e6a = 3 . 4 hz , h e 5 ), 2 . 16 ( br . dd , 1h , 2 j = 14 . 5 hz , 3 j 7e6e = 6 . 0 hz , h e 7 ), 2 . 29 ( ddd , 1h , 2 j = 13 . 6 hz , 3 j 9e5e = 6 . 8 hz , 3 j 9e1e = 3 . 6 hz , h e 9 ), 3 . 12 ( d , 1h , 2 j = 14 . 0 hz , h 12 ), 3 . 32 ( br . d , 1h , 2 j = 14 . 0 hz , h &# 39 ; 12 ), 4 . 42 ( br . d , 3 j 1e9e = 3 . 6 hz , j 1e9a = 1 . 4 hz , h e 1 ), 7 . 57 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 66 ( m , 1h , h 16 ), 7 . 92 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 21 . 94 ( me 11 ), 22 . 43 ( me 17 co ), 22 . 53 ( me 10 ), 23 . 40 ( c 9 h 2 ), 23 . 78 ( c 6 h 2 ), 30 . 92 ( c 5 h ), 32 . 92 ( c 7 h 2 ), 60 . 50 ( c 12 h 2 ), 78 . 45 ( c 1 h ), 82 . 35 ( c 8 ), 82 . 97 ( c 4 ), 127 . 61 ( 2c 14 h ), 129 . 37 ( 2c 15 h ), 133 . 89 ( c 16 h ), 141 . 15 ( c 13 ), 170 . 16 ( c = o ). anal . calcd for c 18 h 24 o 6 s : c , 58 . 68 ; h , 6 . 56 ; s , 8 . 70 found : c , 58 . 72 ; h , 6 . 57 ; s , 8 . 51 . to a solution of sulfides 14a and 14b ( 55 / 45 ) ( 130 mg , 0 . 34 mmol ) in etoac ( 6 ml ) at 0 ° c . was added mcpba ( 276 mg of ca . 60 %, 0 . 96 mmol ) and the mixture was stirred for 6 hr at rt the reaction mixture was poured into saturated nahco 3 ( 20 ml ), extracted with etoac - hexane ( 2 : 3 , 3 × 25 ml ). the organic extract was dried ( na 2 so 4 and nahco 3 ), evaporated and the residue was purified by flash chromatography ( hexane - etoac , 3 : 2 ) to afford a mixture of diastereomeric 24a and 24b ( 94 mg , total yield 66 . 7 %, 24a / 24b ca . 55 : 45 ). the sulfones were separated by mplc ( hexane - etoac , 3 : 2 ). less polar isomer 24a , colorless oil . 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 52 ( br . s , 3h , me 11 ), 1 . 66 ( s , 3h , me 10 ), 1 . 80 ( dddd , 1h , 2 j = 14 . 0 hz , 3 j 6a7a = 13 . 7 hz , 3 j 6a7e = 6 . 5 hz , 3 j 6a5e = 3 . 4 hz , h a 6 ), 1 . 91 ( m , 1h , h a 9 ), 1 . 93 ( m , 1h , h e 6 ), 2 . 15 - 2 . 25 ( m , 2h , h e 7 + h a 7 ), 2 . 26 ( s , 3h , me 18 c = o ), 2 . 28 ( ddd , 1h , 2 j = 13 . 0 hz , 3 j 9e5e = 6 . 4 hz , 3 j 9e1e = 3 . 6 hz , h e 9 ), 2 . 31 ( dddd , 1h , 3 j 5e9e = 6 . 4 hz , 3 j 5e9a = 3 j 5e6a = 3 . 2 hz , h e 5 ), 3 . 27 ( d , 1h , 2 j = 14 . 4hz , h 12 ), 3 . 242 ( s , ca . 2h , c 17 h 2 co keto form ), 4 . 20 ( br . d , ca . 1h , 2 j = 14 . 4 hz , h &# 39 ; 12 keto ), 4 . 23 ( br . d , 2 j = 14 . 0 hz , h &# 39 ; 12 enol ), total 1h ; 4 . 43 ( br . d , ca . 1h , 3 j 1e9e = 3 . 6 hz , h e 9 keto ), 4 . 50 ( br . d , 3 j 1e9e = 4 . 0 hz , h e 9 enol ), total 1h ; 4 . 94 ( br . s , hc = enol ), 7 . 58 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 67 ( m , 1h , h 16 ), 7 . 94 ( m , 2h , h 14 , 14 &# 39 ;), 12 . 05 ( br . s , ho enol ) ( ratio keto / enol ca . 93 : 7 in ca . 2 % solution in cdcl 3 ). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 53 ( me 10 ), 23 . 01 ( me 11 ), 23 . 27 ( c 6 h 2 ), 24 . 39 ( c 9 h 2 ), 29 . 39 ( c 5 h ), 30 . 28 ( me 18 co ), 33 . 13 ( c 7 h 2 ), 51 . 29 ( c 17 h 2 ), 60 . 95 ( c 12 h 2 ), 77 . 73 ( c 1 h ), 82 . 75 ( c 4 ), 84 . 17 ( c 8 ), 127 . 53 ( 2c 14 h ), 129 . 36 ( 2c 15 h ), 133 . 76 ( c 16 h ), 141 . 05 ( c 13 ), 165 . 99 ( oc 20 = o ), 200 . 48 ( mec 19 = o ). hrms ( ci , ch 4 ): obsd 411 . 15100 , calcd for c 20 h 27 o 7 s ( m + 1 ) 411 . 14775 ; obsd 439 . 17800 , calcd for c 22 h 31 o 7 s ( m + 29 ) 439 . 17905 . more polar isomer 24b , colorless oil . 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 60 ( s , 3h , me 10 ), 1 . 80 ( br . s , 3h , me 11 ), 1 . 81 - 1 . 88 ( m , 2h , h a 6 + h a 9 ), 1 . 93 ( d , 4 j = 0 . 4 hz , me 18 c = enol ), 1 . 95 ( m , 1h , h e 6 ), 2 . 07 ( ddd , 1h , 2 j = 3 j 7a6a = 14 . 5 hz , 3 j 7a6e = 6 . 0 hz , h a 7 ), 2 . 10 ( dddd , 1h , 3 j 5e9e = 3 j 5e6e = 6 . 8 hz , 3 j 5e9a = 3 j 5e6a = 3 . 4 hz , h e 5 ), 2 . 18 ( ddd , 1h , 2 j = 14 . 5 hz , 3 j 7e6e = 6 . 0 hz , h e 7 ), 2 . 25 ( s , 3h , me 18 c = o ), 2 . 30 ( br . ddd , 1h , 2 j = 13 . 8 hz , 3 j 9e5e = 6 . 8 hz , 3 j 9e1e = 3 . 6 hz , h e 9 ), 3 . 13 ( d , 1h , 2 j = 14 . 0 hz , h 12 ), 3 . 32 ( dd , ca . 1h , 2 j = 14 . 0 hz , 4 j 12 &# 39 ; , 11 = 0 . 3 hz , h &# 39 ; 12 keto ), 3 . 33 ( br . d , 2 j = 14 . 0 hz , h &# 39 ; 12 enol ), total 1h ; 3 . 41 ( s , ca . 2h , c 17 h 2 co keto form ), 4 . 39 ( br . d , ca . 1h , 3 j 1e9e = 3 . 6 hz , h e 9 keto ), 4 . 49 ( br . d , 3 j 1e9e = 3 . 8 hz , h e 9 enol ), total 1h ; 4 . 93 ( br . s , hc = enol ), 7 . 58 ( m , 2h , 2h 15 ), 7 . 66 ( m , 1h , h 16 ), 7 . 92 ( m , 2h , 2h 14 ), 12 . 04 ( br . s , ho enol ) ( ratio keto / enol ca . 95 : 5 in ca . 2 % solution in cdcl 3 ). 13 c nmr ( 63 mhz , cdcl 3 , δ ): 21 . 89 ( me 11 ), 22 . 56 ( me 10 ), 23 . 25 ( c 9 h 2 ), 23 . 65 ( c 6 h 2 ), 30 . 30 ( me 18 co ), 30 . 84 ( c 5 h ), 32 . 82 ( c 7 h 2 ), 51 . 29 ( c 17 h 2 ), 60 . 51 ( c 12 h 2 ), 78 . 35 ( c 1 h ), 83 . 03 ( c 4 ), 83 . 97 ( c 8 ), 127 . 62 ( 2c 14 h ), 129 . 38 ( 2c 15 h ), 133 . 91 ( c 16 h ), 141 . 12 ( c 13 ), 165 . 95 ( oc 20 = o ), 200 . 58 ( mec 19 = o ). dci hrms : obsd 411 . 14210 , calcd for c 20 h 27 o 7 s ( m + 1 ) 411 . 14775 . to a solution of sulfides 18a , b ( 118 mg , 0 . 30 mmol ) in etoac ( 4 ml ) at 5 ° c . was added a solution of mcpba ( 216 mg of ca . 60 %, 0 . 75 mmol ) in etoac ( 3 ml ). the mixture was stirred for 5 h at rt , poured into saturated na hco 3 ( 30 ml ) and extracted with hexane - etoac ( 3 : 1 , 3 × 40 ml ). organic extract was dried ( na 2 so 4 ) and evaporated . flash chromatography ( hexane - etoac , 75 : 25 ) of the residue gave a mixture of diastereomeric sulfones 25a , b ( 120 mg , 94 % yield , 25a / 25b ca . 57 : 43 ) as a colorless oil . the sulfones were separated by mplc ( hexane - etoac 75 : 25 ). less polar isomer 25a , a colorless oil . ir ( neat ): 2987 , 2940 , 1767 v . s , 1737 v . s , 1448 v . s , 13 . 76 v . s , 1310 , 1187 v . s , 1152 v . s , 1095 v . s , 1086 v . s , 1013 v . s , 751 , 724 v . s , 690 cm - 1 . 1 h nmr ( cdcl 3 , 400 mhz , δ ): 1 . 37 ( t , 3h , 3 j = 7 . 1 hz , me 18 ch 2 ), 1 . 53 ( br . s , 3h , me 11 ), 1 . 72 ( s , 3h , me 10 ), 1 . 82 ( dddd , 1h , 2 j = 14 . 2 hz , 3 j 6a7a = 13 . 2 hz , 3 j 6a7e = 6 . 8 hz , 3 j 6a5e = 3 . 5 hz , h a 6 ), 1 . 94 ( ddddd , 1h , 2 j = 14 . 2 hz , 3 j 6e7e = 5 . 2 hz , 3 j 6e7a = 3 j 6e5e = 4 j 6e9e = 2 . 6 hz , h e 6 ), 1 . 97 ( ddd , 1h , 2 j = 14 . 0 hz , 3 j 9a5e = 2 . 6 hz , 3 j 9a1e = 1 . 4 hz , h a 9 ), 2 . 24 - 2 . 37 ( m , 4h , h e 5 + h e 7 + h a 7 + h 3 9 ), 3 . 27 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 4 . 21 ( br . d , 1h , 2 j = 14 . 3 hz , h &# 39 ; 12 ), 4 . 33 ( q , 2h , 3 j = 7 . 1 hz , c 17 h 2 o ), 4 . 36 ( br . dd , 1h , e j 1e9e = 3 . 6 hz , 3 j 1e9a = 1 . 4 hz , h e 1 ), 7 . 59 ( m , 2h , 2h 15 ), 7 . 67 ( m , 1h , h 16 ), 7 . 94 ( m , 2h , 2h 14 ). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 13 . 92 ( me 18 ch 2 ), 22 . 34 ( me 10 ), 23 . 05 ( me 11 ), 23 . 23 ( c 6 h 2 ), 24 . 46 ( c 9 h 2 ), 29 . 32 ( c 5 h ), 32 . 49 ( c 7 h 2 ), 60 . 96 ( c 12 h 2 ), 63 . 03 ( c 17 h 2 ), 77 . 74 ( c 1 h ), 82 . 91 ( c 4 ), 86 . 58 ( c 8 ), 127 . 57 ( 2c 14 h ), 129 . 41 ( 2c 15 h ), 133 . 83 ( c 16 h ), 141 . 03 ( c 13 ), 156 . 66 ( c = o ), 158 . 08 ( c = o ). anal . calcd for c 20 h 26 o 8 s : s , 7 . 52 . found : s , 7 . 13 . more polar isomer 25b , a colorless oil . ir ( neat ): 1763 v . s , 1740 v . s , 1448 , 1376 , 1322 v . s , 1197 v . s , 1181 v . s , 1154 v . s , 1087 , 1014 v . s , 734 v . s , 690 cm - 1 . 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 36 ( t , 3h , 3 j = 7 . 1 hz , me 18 ch 2 ), 1 . 66 ( s , 3h , me 10 ), 1 . 80 - 1 . 89 ( m , 1h , h a 6 ), 1 . 82 ( br . s , 3h , me 11 ), 1 . 88 ( ddd , 1h , 2 j = 14 . 2 hz , 3 j 9a5e = 3 . 4 hz , 3 j 9a1e = 1 . 8 hz , h a 9 ), 1 . 99 ( m , 1h , h e 6 ), 2 . 13 ( m , 1h , h e 5 ), 2 . 14 ( ddd , 1h , 2 j = 3 j 7a6a = 14 . 6 hz , 3 j 7a6e = 2 . 0 hz , h a 7 ), 2 . 33 ( br . dd , 1h , 2 j = 14 . 6 hz , 3 j 7e6e = 6 . 2 hz , h e 7 ), 2 . 34 ( ddd , 1h , 2 j = 14 . 2 hz , 3 j 9e5e = 6 . 4 hz , 3 j 9e1e = 3 . 6 hz , h e 9 ), 3 . 12 ( d , 1h , 2 j = 14 . 0 hz , h 12 ), 3 . 32 ( br . d , 1h , 2 j = 14 . 0 hz , h &# 39 ; 12 ), 4 . 32 ( q , 2h , 3 j = 7 . 1 hz , c 17 h 2 o ), 4 . 34 ( m , 1h , h e 1 ), 7 . 57 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 67 ( m , 1h , h 16 ), 7 . 92 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 63 mhz , cdcl 3 , δ ): 13 . 87 ( me 18 ), 21 . 87 ( me 11 ), 22 . 29 ( me 10 ), 23 . 30 ( c 9 h 2 ), 23 . 53 ( c 6 h 2 ), 30 . 70 ( c 5 h ), 32 . 14 ( c 7 h 2 ), 60 . 41 ( c 12 h 2 ), 63 . 01 ( c 17 h 2 o ), 78 . 26 ( c 1 h ), 83 . 12 ( c 4 ), 86 . 31 ( c 8 ), 127 . 58 ( 2c 14 h ), 129 . 37 ( 2c 15 h ), 133 . 92 ( c 16 h ), 141 . 02 ( c 13 ), 156 . 56 ( c ═ o ), 158 . 00 ( c ═ o ). to a solution of sulfides 19 a , b ( 137 mg , 0 . 25 mmol ) in etoac ( 5 ml ) was added a solution of mcpba ( 201 mg of ca . 60 %, 0 . 7 mmol ) in etoac ( 2 ml ). the mixture was stirred for 5 h at rt , poured into saturated nahco 3 ( 30 ml ) and extracted with hexane - etoac ( 1 : 1 , 3 × 50 ml ). the organic extract was dried ( na 2 so 4 ) and evaporated . flash chromatography ( hexane - etoac , 75 : 25 ) of the residue afforded the diastereomers 26a , b ( 143 . 5 mg , 99 % yield , 26a / 26b ca . 60 : 40 ) as a colorliess oil . the sulfones were separated by mplc ( hexane - etoac , 70 : 30 ). less polar isomer 26a , a colorless glass ; ir ( neat ): 1736 v . s , 1670 v . s , 1653 v . s , 1496 , 1453 v . s , 1377 , 1318 v . s , 1272 , 1181 v . s , 1171 v . s , 1150 v . s , 1083 v . s , 1013 , 912 , 723 v . s , 700 v . s , 690 v . s . cm - 1 . 1 h nmr ( cdcl 3 , 400 mhz , δ ): 1 . 50 ( br . s , 3h , me 11 ), 1 . 67 ( s , 3h , me 10 ), 1 . 72 ( m , 1h , h a 6 ), 1 . 82 - 1 . 92 ( m , 2h , h e 6 + h a 9 ), 2 . 18 - 2 . 28 ( m , 4h , h e 5 + h e 7 + h a 7 + h e 9 ), 3 . 27 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 4 . 17 ( br . d , 1h , 2 j = 14 . 3 hz , h &# 39 ; 12 ), 4 . 35 ( br . s , 2h , nc 17 h 2 ), 4 . 36 ( m , 1h , h e 1 ), 4 . 50 ( br . s , 2h , nc 18 h 2 ), 7 . 19 - 7 . 26 ( m , 4h ), 7 . 31 - 7 . 41 ( m , 6h ), 7 . 59 ( m , 2h , 2h 15 ), 7 . 67 ( m , 1h , h 16 ), 7 . 94 ( m , 2h , 2h 14 ). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 46 ( me 10 ), 22 . 93 ( me 11 ), 23 . 12 ( c 6 h 2 ), 24 . 33 ( c 9 h 2 ), 29 . 25 ( c 5 h ), 32 . 90 ( c 7 h 2 ), 46 . 22 ( nc 17 h 2 ), 50 . 02 ( nc 18 h 2 ), 60 . 89 ( c 12 h 2 ), 77 . 60 ( c 1 h ), 82 . 78 ( c 4 ), 86 . 51 ( c 8 ), 127 . 38 ( 2ch ), 127 . 53 ( 2c 14 h ), 127 . 87 ( ch ), 128 . 25 ( ch ), 128 . 46 ( 2ch ), 128 . 78 ( 2ch ), 128 . 93 ( 2ch ), 129 . 36 ( 2c 15 h ), 133 . 79 ( c 16 h ), 134 . 81 ( cq ), 135 . 34 ( cq ), 140 . 98 ( c 13 ), 162 . 14 ( c ═ o ), 162 . 18 ( c ═ o ). anal . calcd for c 32 h 35 no 7 s : c , 66 . 53 ; h , 6 . 11 ; n , 2 . 42 ; s , 5 . 55 . found : c , 65 . 36 ; h , 6 . 09 ; n , 2 . 10 , s , 5 . 28 . more polar isomer 26b , a colorless glass . ir ( neat ): 2982 , 2935 v . s , 1733 v . s , 1663 v . s , 1654 v . s , 1450 v . s , 1379 , 1322 v . s , 1312 v . s , 1176 v . s , 1153 v . s , 1084 , 1015 , 913 , 734 v . s , 700 cm - 1 . 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 61 ( s , 3h , me 10 ), 1 . 76 ( m , 1h , h a 9 ), 1 . 77 ( m , 1h , h a 9 ), 1 . 79 ( s , 3h , me 11 ), 1 . 92 ( m , 1h , h e 6 ), 2 . 03 ( dddd , 1h , 3 j 5e6e = 3 j 5e9e = 6 . 4 hz , 3 j 5e6a = 3 j 5e9a = 3 . 2 hz , h e 5 ), 2 . 09 ( ddd , 1h , 2 j = 3 j 7a6a = 14 . 2 hz , 3 j 7a6e = 6 . 0 hz , h a 7 ), 2 . 23 ( br . dd , 1h , 2 j = 14 . 6 hz , 3 j 7e6e = 5 . 8 hz , h e 7 ), 2 . 27 ( ddd , 1h , 2 j = 13 . 8 hz , 3 j 9e5e = 6 . 4 hz , 3 j 9e1e = 3 . 3 hz , h e 9 ), 3 . 11 ( d , 1h , 2 j = 14 . 0 hz , h 12 ), 3 . 29 ( br . d , 1h , 2 j = 14 . 0 hz , h &# 39 ; 12 ), 4 . 34 ( m , 1h , h e 1 ), 4 . 35 ( br . s , 2h , nc 17 h 2 ), 4 . 485 and 4 . 51 ( abq , 2h , 2 j = 14 . 7 hz , nc 18 h 2 ), 7 . 19 - 7 . 24 ( m , 4h ), 7 . 30 - 7 . 40 ( m , 6h ), 7 . 57 ( m , 2h , 2h 15 ), 7 . 66 ( m , 1h , h 16 ), 7 . 92 ( m , 2h , 2h 14 ). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 21 . 84 ( me 11 ), 22 . 49 ( me 10 ), 23 . 24 ( c 9 h 2 ), 23 . 50 ( c 6 h 2 ), 30 . 71 ( c 5 h ), 32 . 71 ( c 7 h 2 ), 46 . 27 ( nc 17 h 2 ), 50 . 04 ( nc 18 h 2 ), 60 . 49 ( c 12 h 2 ), 78 . 19 ( c 1 h ), 83 . 11 ( c 4 ), 86 . 30 ( c 8 ), 127 . 36 ( 2ch ), 127 . 63 ( 2c 15 h ), 127 . 90 ( ch ), 128 . 26 ( ch ), 128 . 48 ( 2ch ), 128 . 80 ( 2ch ), 128 . 95 ( 2ch ), 129 . 38 ( 2c 14 h ), 133 . 93 ( c 16 h ), 134 . 84 ( cq ), 135 . 35 ( cq ), 141 . 09 ( c 13 ), 162 . 10 ( c ═ o ), 162 . 21 ( c ═ o ). the mixture of diastereomeric ( 1r , 4r , 5r , 8r )- 4 , 8 - dimethyl - 8 - phenoxycarbonyloxy - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane 20a and ( 1r , 4s , 5r , 8r )- 4 , 8 - dimethyl - 8 - phenoxycarbonyloxy - 4 - phenylthiomethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonane 20b ( 75 mg , 0 . 181 mmol , 25 % yield , ratio 20a / 20b ca . 56 : 44 ) was prepared by phenoxycarbonylation of hydroxysulfides 2a , b . the sulfides 20a , b , a colorless solid , mp 64 - 67 ° c . 1 h nmr ( cdcl 3 , 250 mhz , δ ): 1 . 29 ( br . s , me 11 20a ) and 1 . 61 ( br . s , me 11 20b ), total 3h ; 1 . 777 ( br . s , me 10 20b ) and 1 . 784 ( br . s , me 10 20a ), total 3h ; 1 . 80 - 2 . 05 ( m , 4h ); 2 . 18 ( ddd , 2 j = 13 . 8 hz , 3 j 9e5e = 5 . 8 hz , 3 j 9e1e = 3 . 5 hz , h e 9 20a ), 2 . 29 - 2 . 48 ( m ), totla 3h ; 3 . 00 and 3 . 06 ( br .) ( abq , 2 j = 12 . 1 hz , h 12 + h &# 39 ; 12 20b ), 3 . 36 ( d , 2 j = 12 . 9 hz , h 12 20a ) and 3 . 75 ( br . d , 2 j = 12 . 9 hz , h &# 39 ; 12 20a ), total 2h ; 4 . 41 ( dd , 3 j 1e9e = 3 . 5 hz , 3 j 1e9a = 1 . 1 hz , h e 1 20a ) and 4 . 44 ( dd , 3 j 1e9e = 3 . 9 hz , 3 j 1e9a = 1 . 4 hz , h e 1 20b ), total 1h ; 7 . 16 - 7 . 48 ( m , 10h ). 13 c nmr ( cdcl 3 , 63 mhz ) ( δ ): isomer 20a : 22 . 01 ( me 11 ), 22 . 28 ( me 10 ), 23 . 37 ( c 6 h 2 ), 23 . 95 ( c 9 h 2 ), 28 . 47 ( c 5 h ), 32 . 38 ( c 7 h 2 ), 40 . 73 ( c 12 h 2 ), 77 . 50 ( c 1 h ), 84 . 03 ( c 4 ), 85 . 36 ( c 8 ), 121 . 07 ( 2c o - phen . h ), 125 . 90 ( c p - phen . h ), 126 . 33 ( c 16 h ), 128 . 95 ( 2c 14 h ), 129 . 39 ( 2c m - phen . h ), 129 . 84 ( 2c 15 h ), 136 . 66 ( c 13 ), 150 . 88 ( c 1 - phen . ), 151 . 37 ( c ═ o ); isomer 20b : 21 . 78 ( me 11 ), 22 . 28 ( me 10 ), 23 . 08 ( c 6 h 2 ), 24 . 08 ( c 9 h 2 ), 29 . 80 ( c 5 h ), 32 . 70 ( c 7 h 2 ), 40 . 83 ( c 12 h 2 ), 77 . 95 ( c 1 h ), 84 . 03 ( c 4 ), 85 . 29 ( c 8 ), 121 . 07 ( 2c o - phen . h ), 125 . 90 ( c p - phen . h ), 126 . 52 ( c 16 h ), 129 . 00 ( 2c 14 h ), 129 . 39 ( 2c m - phen . h ), 129 . 84 ( 2c 15 h ), 136 . 22 ( c 13 ), 150 . 88 ( c 1 - phen . ), 151 . 37 ( c ═ o ). to a solution of sulfides 20a , b ( 60 mg , 0 . 145 mmol ) in etoac ( 1 . 2 ml ) was added mcpba ( 108 mg of ca . 60 %, 0 . 38 mmol ). the mixture was stirred for 6 h at rt , diluted with hexane - etoac ( 3 : 1 , 50 ml ), washed with saturated nahco 3 ( 2 × 10 ml ) and the water washings were extracted with hexane - etoac ( 3 : 1 , 50 ml ). the combined organic extract was dried ( na 2 so 4 + nahco 3 ) and evaporated . mplc ( hexane - etoac , 80 : 20 ) of the residue afforded the diastereomeric sulfones 27a ( 31 . 7 mg ) and 27b ( 24 . 5 mg ) ( total 60 . 2 mg , 93 % yield ). less polar isomer 27a , a colorless solid , mp 99 - 100 ° c ., r f = 0 . 30 ( hexane - etoac , 75 : 25 ). 1 h nmr ( cdcl 3 , 400 mhz , δ ): 1 . 54 ( br . s , 3h , me 11 ), 1 . 72 ( s , 3h , me 10 ), 1 . 83 - 1 . 99 ( m , 2h , h e 6 + h a 6 ), 2 . 02 ( ddd , 1h , 2 j = 13 . 8 hz , 3 j 9a5e = 2 . 8 hz , 3 j 9a1e = 1 . 6 hz , h a 9 ), 2 . 28 - 2 . 39 ( m , 4h , h e 5 + h e 7 + h a 7 + h e 9 ), 3 . 28 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 4 . 23 ( br . d , 1h , 2 j = 14 . 3 hz , h &# 39 ; 12 ), 4 . 42 ( br . dd , 1h , 3 j 1e9e = 4 . 0 hz , 3 j 1e9a = 1 . 6 hz , h e 1 ), 7 . 15 ( m , 2h , 2h o - phen . ), 7 . 24 ( m , 1h , h p - phen . ), 7 . 39 ( m , 2h , 2h m - phen . ), 7 . 59 ( m , 2h , 2h 15 ), 7 . 67 ( m , 1h , h 16 ), 7 . 94 ( m , 2h , 2h 14 ). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 25 ( me 10 ), 23 . 08 ( me 11 ), 23 . 27 ( c 6 h 2 ), 24 . 51 ( c 9 h 2 ), 29 . 38 ( c 5 h ), 32 . 75 ( c 7 h 2 ), 60 . 99 ( c 12 h 2 ), 77 . 86 ( c 1 h ), 82 . 84 ( c 4 ), 85 . 12 ( c 8 ), 121 . 10 ( 2c o - phen . h ), 126 . 00 ( c p - phen . h ), 127 . 57 ( 2c 14 h ), 129 . 40 ( 2c 15 h ), 129 . 39 ( 2c m - phen . h ), 133 . 81 ( c 16 h ), 141 . 05 ( c 13 ), 150 . 89 ( c 1 - phen . ), 151 . 43 ( c ═ o ). anal . calcd for c 23 h 26 o 7 s : c , 61 . 87 ; h , 5 . 87 ; s , 7 . 18 . found : c , 62 . 21 ; h , 5 . 76 ; s , 6 . 95 . more polar isomer 27b , a colorless solid , mp 109 - 111 ° c ., r f = 0 . 26 ( hexane - etoac , 75 : 25 ). 1 h nmr ( cdcl 3 , 400 mhz , δ ): 1 . 66 ( s , 3h , me 10 ), 1 . 84 ( br . s , 3h , me 11 ), 1 . 87 - 1 . 97 ( m , 2h , h e 6 + h a 9 ), 2 . 02 ( m , 1h , h e 6 ), 2 . 15 ( ddd , 1h , 2 j = 3 j 7a6a = 15 . 0 hz , 3 j 7a6e = 6 . 0 hz , h a 7 ), 2 . 18 - 2 . 39 ( m , 1h , h e 5 ), 2 . 31 ( br . dd , 1h , 2 j = 15 . 0 hz , 3 j 7e6e = 6 . 0 hz , h e 7 ), 2 . 37 ( ddd , 1h , 2 j = 13 . 8 hz , 3 j 9e5e = 6 . 4 hz , 3 j 9e1e = 3 . 5 hz , h e 9 ), 3 . 14 ( d , 1h , 2 j = 14 . 0 hz , h 12 ), 3 . 34 ( br . d , 1h , 2 j = 14 . 0 hz , h &# 39 ; 12 ), 4 . 40 ( br . dd , 1h , 3 j 1e9e = 3 . 5 hz , h e 1 ), 7 . 15 ( m , 2h , 2h o - phen . ), 7 . 24 ( m , 1h , h p - phen . ), 7 . 38 ( m , 2h , 2h m - phen . ), 7 . 59 ( m , 2h , 2h 15 ), 7 . 68 ( m , 1h , h 16 ), 7 . 94 ( m , 2h , 2h 14 ). 13 c nmr ( 63 mhz , cdcl 3 , δ ): 21 . 94 ( me 11 ), 22 . 28 ( me 10 ), 23 . 41 ( c 9 h 2 ), 23 . 67 ( c 6 h 2 ), 30 . 83 ( c 5 h ), 32 . 49 ( c 7 h 2 ), 60 . 50 ( c 12 h 2 ), 78 . 47 ( c 1 h ), 83 . 17 ( c 4 ), 84 . 93 ( c 8 ), 121 . 09 ( 2c o - phen . h ), 126 . 01 ( c p - phen . h ), 127 . 65 ( 2c 14 h ), 129 . 42 ( 2c 15 h ), 129 . 47 ( 2c m - phen . h ), 133 . 95 ( c 16 h ), 141 . 15 ( c 13 ), 150 . 89 ( c 1 - phen . ), 151 . 42 ( c ═ o ). anal . calcd . for c 23 h 26 o 7 s : c , 61 . 87 ; h , 5 . 87 ; s , 7 . 18 . found : c , 61 . 78 ; h , 5 . 98 ; s , 7 . 19 . the title compounds were prepared by oxidation of sulfides 2 &# 39 ; a , b as described in example 13 for the corresponding ( 1r , 5r , 8r )- epimers 21a , b . 1 h nmr spectra in cdcl 3 of individual diastereomers 21 &# 39 ; a , b and 21a , b ( example 13 ) are identical . 21 &# 39 ; a is a colorless solid , mp 112 - 113 ° c . ( hexane - etoac ), 21 &# 39 ; b is a colorless oil , total yield of 21 &# 39 ; a , b 90 %. to tms - derivative 16 &# 39 ; a , b , prepared from 2 &# 39 ; a , b ( 0 . 854 mmol , 252 mg ) and tmsotf as described in example 10 , was added accl ( 2 . 0 ml ) and the mixture was stirred at rt for 50 h . the mixture was evaporated and the crude acetyloxysulfide 13 &# 39 ; a , b was dissolved in etoac ( 8 ml ) and oxidized by mcpba ( 526 mg of ca . 70 %, 2 . 135 mmol ) at rt for 6 h . workup as in example 15 followed by flash chromatography ( silica gel , hexane - etoac 3 : 1 ) afforded a mixture of sulfones 23 &# 39 ; a , b ( 265 mg , 84 %). the mixture was separated by mplc ( hexane - etoac , 3 : 1 ) to give the individual epimers 23 &# 39 ; a as a colorless solid , mp 96 - 98 ° c . and 23 &# 39 ; b , as a colorless solid , mp 101 - 102 ° c . nmr spectra are consistent with those described above for ( 1r , 5r , 8r )- epimers 23a and 23b ( example 15 ). to a solution of sulfides 4a , and 4b ( 80 mg , 0 . 193 mmol ) in etoac ( 2 ml ) at 0 ° c . was added a solution of mcpba ( 94 mg of ca . 85 %, 0 . 46 mmol ) in etoac ( 2 ml ). the mixture was stirred for 2 h at 0 - 5 ° c . and for 4 h at rt , diluted with etoac ( 10 ml ) and washed with saturated nahco 3 ( 3 × 5 ml ). water washings were extracted with etoac ( 2 × 10 ml ), the combined organic extract was dried ( na 2 so 4 ) and evaporated . flash chromatography ( hexane - etoac , 65 : 35 ) of the residue gave a mixture of diastereomeric sulfones 29a and 29b ( 80 . 5 mg , 93 % yield ) as colorless oil . the diastereomers were separated by mplc ( hexane - etoac , 60 : 40 ). less polar isomer 29b , a colorless solid , mp 132 - 133 ° c ., r f 0 . 42 ( hexane - etoac , 60 : 40 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 36 ( s , 3h , me 10 ), 1 . 90 ( br . s , 3h , me 11 ), 1 . 93 ( ddd , 1h , 2 j = 13 . 8 hz , 3 j 6a7a = 12 . 0 hz , 3 j 6a5e = 3 . 5 hz , h a 6 ), 2 . 16 ( ddd , 1h , 2 j = 13 . 8 hz , 3 j 9a5e = 3 . 3 hz , 3 j 9a1e = 2 . 0 hz , h a 9 ), 2 . 30 ( dddd , 1h , 2 j = 13 . 8 hz , 3 j 9e1e = 3 j 9e5e = 3 . 6 hz , 4 j 9e6e = 2 . 9 hz , h e 9 ), 2 . 34 ( br . s ., 1h , oh ), 2 . 43 ( ddddd , 1h , 3 j 5e9e = 3 . 6 hz , 3 j 5e6a = 3 . 5 hz , 3 j 5e9a = 3 . 3 hz , 3 j 5e6e = 2 . 9 hz , 4 j 5e1e = 1 . 5 hz , h e 5 ), 2 . 57 ( dddd , 1h , 2 j = 13 . 8 hz , 3 j 6e7a = 6 . 1 hz , 3 j 6e5e = 4 j 6e9e = 2 . 9 hz , h e 6 ), 3 . 16 ( d , 1h , 2 j = 13 . 9 hz , h 12 ), 3 . 58 ( br . d , 1h , 2 j = 13 . 9 hz , h &# 39 ; 12 ), 3 . 97 ( ddd , 1h , 3 j 1e9e = 3 . 6 hz , 3 j 1e9a = 2 . 0 hz , 4 j 1e5e = 1 . 5 hz , h e 1 ), 5 . 57 ( dd , 1h 3 j 7a6a = 12 . 0 hz , 3 j 7a6e = 6 . 1 hz , h a 7 ), 7 . 50 ( m , 2h ), 7 . 58 - 7 . 63 ( m , 3h ), 7 . 67 ( m , 1h ), 7 . 97 - 8 . 05 ( m , 4h ). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 21 . 71 ( me 11 ), 23 . 27 ( c 9 h 2 ), 24 . 31 ( me 10 ), 29 . 49 ( c 6 h 2 ), 33 . 61 ( c 5 h ), 60 . 24 ( c 12 h 2 ), 72 . 70 ( c 8 ), 74 . 58 ( c 7 h ), 82 . 91 ( c 4 ), 83 . 80 ( c 1 h ), 127 . 79 ( 2c 14 h ), 128 . 55 ( 2ch m - benz . ), 129 . 39 ( 2c 15 h ), 129 . 49 ( 2ch o - benz . ), 129 . 97 ( c 1 - benz . ), 133 . 30 ( ch p - benz . ), 133 . 91 ( c 16 h ), 141 . 02 ( c 13 ), 165 . 69 ( c ═ o ). anal . calcd . for c 23 h 26 o 7 s : c , 61 . 87 ; h , 5 . 87 ; s 7 . 18 . found : c , 61 . 60 ; h 5 . 91 ; s 7 . 43 . more polar isomer 29a , a colorless solid , mp 182 - 183 ° c ., r f 0 . 36 ( hexane - etoac , 60 : 40 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 41 ( s , 3h , me 10 ), 1 . 64 ( br . s , 3h , me 11 ), 1 . 88 ( ddd , 1h , 2 j = 13 . 3 hz , 3 j 6a7a = 11 . 8 hz , 3 j 6a5e = 3 . 6 hz , h a 6 ), 2 . 25 ( ddd , 1h , 2 j = 14 . 0 hz , 3 j 9a1e = 3 j 9a5e = 2 . 8 hz , h a 9 ), 2 . 28 ( dddd , 1h , 2 j = 14 . 0 hz , 3 j 9e5e = 3 . 2 hz , 3 j 9e1e = 2 . 8 hz , 4 j 9e6e = 2 . 2 hz , h e 9 ), 2 . 38 ( br . s ., 1h , oh ), 2 . 39 ( dddd , 1h , 2 j = 13 . 3 hz , 3 j 6e7a = 6 . 2 hz , 3 j 6e5e = 3 . 2 hz , 4 j 6e9e = 2 . 2 hz , h e 6 ), 2 . 61 ( br . dddd , 1h , 3 j 5e6a = 3 . 6 hz , 3 j 5e9e = 3 j 5e9a = 3 j 5e6e = 3 . 2 hz , h e 5 ), 3 . 31 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 4 . 23 ( br . d , 1h , 2 j = 14 . 3 hz , h &# 39 ; 12 ), 3 . 97 ( br . dd , 1h , 3 j 1e9e = 3 j 1e9a = 2 . 8 hz , h e 1 ), 5 . 71 ( dd , 1h , 3 j 7a6a = 11 . 8 hz , 3 j 7a6e = 6 . 2 hz , h a 7 ), 7 . 48 ( m , 2h ), 7 . 58 - 7 . 62 ( m , 3h ), 7 . 68 ( m , 1h ), 7 . 96 ( m , 2h ), 8 . 04 ( m , 2h ). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 23 . 28 ( me 11 ), 24 . 19 ( c 9 h 2 ), 24 . 41 ( me 10 ), 29 . 13 ( c 6 h 2 ), 32 . 10 ( c 5 h ), 60 . 87 ( c 12 h 2 ), 72 . 71 ( c 8 ), 74 . 51 ( c 7 h ), 82 . 51 ( c 4 ), 83 . 14 ( c 1 h ), 127 . 59 ( 2c 14 h ), 128 . 56 ( 2ch m - benz . ), 129 . 42 ( 2c 15 h ), 129 . 51 ( 2ch o - benz . ), 129 . 93 ( c 1 - benz . ), 133 . 31 ch p - benz . ), 133 . 87 ( c 16 h ), 140 . 96 ( c 13 ), 165 . 61 ( c ═ o ). anal . calcd for c 23 h 26 o 7 s : c , 61 . 87 ; h , 5 . 87 ; s 7 . 18 . found : c , 61 . 60 ; h 5 . 81 ; s 6 . 87 . to a solution of sulfides 5a and 5b ( 37 . 5 mg , 0 . 095 mmol , 5a / 5b ˜ 55 : 45 ) in etoac ( 1 ml ) at 0 ° c . was added a solution of mcpba ( 49 mg of ca . 85 %, 0 . 24 mmol ) in etoac ( 1 . 5 ml ). the mixture was stirred for 3 h at 0 - 5 ° c . and for additional 3 h at rt , diluted with etoac ( 10 ml ) and washed with saturated nahco 3 ( 2 × 10 ml ). water washings were extracted with etoac ( 15 ml , organic extract was dried ( na 2 so 4 , nahco 3 ) and evaporated . flash chromatography ( hexane - etoac , 70 : 30 ) of the residue afforded the separated diastereomeric sulfones 30a ( 19 . 5 mg ) and 30b ( 17 . 2 mg ) ( total 36 . 7 mg , 91 % yield ). less polar isomer 30b , a colorless oil , r f 0 . 36 ( hexane - etoac , 60 : 40 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 0 . 99 ( t , 3h , 3 j = 7 . 4 hz , me 16 ch 2 ), 1 . 44 ( s , 3h , me 10 ), 1 . 50 ( tq , 2h , 3 j = 3 j = 7 . 4 hz , mec 15 h 2 ch 2 ), 1 . 86 - 1 . 95 ( m , 3h , h a 6 + ch 2 c 14 h 2 ch 2 s ), 1 . 88 ( s , 3h , me 11 ), 2 . 16 ( ddd , 1h , 2 j = 13 . 0 hz , 3 j 9a1e = 2 . 5 hz , 3 j 9a5e = 1 . 9 hz , h a 9 ), 2 . 28 ( ddddd , 1h , 3 j 5e9e = 3 . 5 hz , 3 j 5e6e = 2 . 9 hz , 3 j 5e6a = 2 . 5 hz , 3 j 5e9a = 1 . 9 hz , 4 j 5e1e = 1 . 8 hz , h e 5 ), 2 . 31 ( dddd , 1h , 2 j = 13 . 0 hz , 3 j 9e5e = 3 . 5 hz , 3 j 9e1e = 3 . 3 hz , 4 j 9e6e = 2 . 9 hz , h e 9 ), 2 . 32 ( br . s ., 1h , oh ), 2 . 42 ( dddd , 1h , 2 j = 13 . 8 hz , 3 j 6e7a = 6 . 1 hz , 3 j 6e5e = 4 j 6e9e = 2 . 9 hz , h e 6 ), 3 . 08 ( m , 2h , ch 2 c 13 h 2 s ), 3 . 17 ( d , 1h , 2 j = 13 . 8 hz , h 12 ), 3 . 37 ( br . d , 1h , 2 j = 13 . 8 hz , h &# 39 ; 12 ), 4 . 00 ( ddd , 1h , 3 j 1e9e = 3 . 5 hz , 3 j 1e9a = 2 . 5 hz , 4 j 1e5e = 1 . 8 hz , h e 1 ), 5 . 68 ( dd , 1h , 3 j 7a6a = 12 . 0 hz , 3 j 7a6a = 6 . 1 hz , h a 7 ), 7 . 48 ( m , 2h , 2hc m - benz . ), 7 . 61 ( m , 1h , hc p - benz . ), 8 . 02 ( m , 2h , 2hc o - benz .). 13 c nmr ( 63 mhz , cdcl 3 , δ ): 13 . 52 ( me 16 ), 21 . 16 ( me 11 ), 21 . 68 ( c 15 h 2 ), 23 . 23 ( c 9 h 2 ), 24 . 13 ( c 14 h 2 ), 24 . 36 ( me 10 ), 29 . 33 ( c 6 h 2 ), 33 . 79 ( c 5 h ), 56 . 19 ( c 13 h 2 ), 56 . 57 ( c 12 h 2 ), 72 . 71 ( c 8 ), 74 . 44 ( c 7 h ), 82 . 53 ( c 4 ), 83 . 73 ( c 1 h ), 128 . 60 ( 2ch m - benz . ), 129 . 49 ( 2ch o - benz . ), 129 . 87 ( c 1 - benz . ), 133 . 36 ( ch p - benz . ), 165 . 79 ( c ═ o ). more polar isomer 30a , a colorless solid , mp 140 - 142 ° c ., r f 0 . 25 ( hexane - etoac , 60 : 40 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 0 . 98 ( t , 3h , 3 j = 7 . 4 hz , me 16 ch 2 ), 1 . 43 ( s , 3h , me 10 ), 1 . 49 ( tq , 2h , 3 j = 3 j = 7 . 4 hz , mec 15 h 2 ch 2 ), 1 . 64 ( s , 3h , me 11 ), 1 . 83 - 1 . 91 ( m , 2h , ch 2 c 14 h 2 ch 2 s ), 1 . 85 ( ddd , 2 j = 13 . 5 hz , 3 j 6a7a = 11 . 7 hz , 3 j 6a5e = 3 . 5 hz , h a 6 ), 2 . 25 ( m , 2h , h a 9 + h e 9 ), 2 . 31 ( m , 1h , 3 j 5e6a = 3 j 5e9e = 3 . 5 hz , 3 j 5e6e = 3 j 5e9a = 2 . 5 hz , h e 5 ), 2 . 40 ( br . s ., 1h , oh ), 2 . 38 ( ddddd , 1h , 2 j = 13 . 5 hz , 3 j 6e7a = 6 . 1 hz , 3 j 6e5e ≈ 2 . 5 hz , 4 j 6e9e ≈ j ≈ 1 . 6 hz , h e 6 ), 3 . 08 ( m , 2h , ch 2 c 13 h 2 s ), 3 . 50 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 3 . 76 ( br . d , 1h , 2 j = 13 . 8 hz , h &# 39 ; 12 ), 4 . 01 ( br . dd , 1h , 3 j 1e9e = 3 j 1e9a = 2 . 5 hz , h e 1 ), 5 . 72 ( dd , 1h , 3 j 7a6a = 11 . 7 hz , 3 j 7a6e = 6 . 2 hz , h a 7 ), 7 . 48 ( m , 2h , 2hc m - benz . ), 7 . 60 ( m , 1h , hc p - benz . ), 8 . 03 ( m , 2h , 2hc 0 - benz .). 13 c nmr ( 63 mhz , cdcl 3 , δ ): 13 . 55 ( me 16 ), 21 . 70 ( c 15 h 2 ), 22 . 46 ( me 11 ), 23 . 86 ( c 14 h 2 ), 24 . 12 ( c 9 h 2 ), 24 . 40 me 10 ), 29 . 06 ( c 6 h 2 ), 32 . 84 ( c 5 h ), 55 . 41 ( c 13 h 2 ), 56 . 64 ( c 12 h 2 ), 72 . 71 ( c 8 ), 74 . 36 ( c 7 h ), 81 . 95 ( c 4 ), 83 . 12 ( c 1 h ), 128 . 57 ( 2ch m - benz . ), 129 . 51 ( 2ch o - benz . ), 129 . 90 ( c 1 - benz . ), 133 . 33 ( ch p - benz ), 165 . 58 ( c ═ o ). anal . calcd for c 21 h 30 o 7 s : c , 59 . 14 ; h , 7 . 09 ; s , 7 . 52 . found : c , 59 . 34 ; h , 7 . 17 ; s , 7 . 22 . to a solution of sulfides 6a and 6b ( 19 . 5 mg of ca . 94 % purity , 0 . 0435 mmol , ca . 65 : 35 ) in etoac ( 1 . 2 ml ) at rt was added mcpba ( 32 mg of ca . 60 %, 0 . 108 mmol ) in etoac ( 2 ml ). the mixture was stirred for 5 h at rt , poured into satruated nahco 3 ( 10 ml ), extracted with hexane - etoac ( 30 ml , 3 : 2 ). the organic extract was dried ( na 2 so 4 , nahco 3 ), evaporated and mplc ( hexane - etoac , 60 : 40 ) of the residue afforded the diastereomeric sulfones 31a ( 11 . 0 mg ) and 31b ( 6 . 3 mg ) ( total 89 % yield ). less polar isomer 31b , a colorless solid , mp 160 - 162 ° c . ( dec .). 1 h nmr 400 mhz , cdcl 3 , δ ): 1 . 37 ( s , 3h , me 10 ), 1 . 86 ( s , 3h , me 11 ), 1 . 97 ( br . s ., 1h , oh ), 2 . 08 ( ddd , 1h , 2 j = 13 . 6 hz , 3 j 9a5e = 3 . 0 hz , 3 j 9a1e = 1 . 6 hz , h a 9 ), 2 . 21 ( ddd , 1h , 2 j = 16 . 0 hz , 3 j 6a5e = 4 . 4 hz , 3 j 6a7e = 2 . 0 hz , h a 6 ), 2 . 32 ( m , 1h , h e 5 ), 2 . 34 - 2 . 42 ( m , 2h , h e 6 + h e 9 ), 3 . 11 ( d , 1h , 2 j = 14 . 0 hz , h 12 ), 3 . 58 ( br . d , 1h , 2 j = 14 . 0 hz , h &# 39 ; 12 ), 3 . 94 ( dd , 1h , 3 j 1e9e = 3 . 6 hz , 3 j 1e9a = 1 . 6 hz , h e 1 ), 5 . 27 ( dd , 1h , 3 j 7e6e = 6 . 3 hz , 3 j 7e6a = 2 . 0 hz , h e 7 ), 7 . 34 ( m , 4h ), 7 . 49 ( m , 2h ), 7 . 68 ( m , 1h ), 7 . 64 ( m , 2h ), 7 . 97 ( m , 2h ). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 21 . 89 ( me 11 ), 22 . 83 ( c 9 h 2 ), 23 . 33 ( me 10 ), 29 . 32 ( c 6 h 2 ), 32 . 20 ( c 5 h ), 60 . 85 ( c 12 h 2 ), 73 . 33 ( c 8 ), 74 . 80 ( c 7 h ), 81 . 87 ( c 1 h ), 82 . 04 ( c 4 ), 127 . 02 ( 2c 14 h ), 128 . 48 ( 2ch m - benz . ), 129 . 17 ( 2c 15 h ), 129 . 65 ( 2ch o - benz . ), 129 . 83 ( c 1 - benz . ), 133 . 18 ( ch p - benz . ), 133 . 55 ( c 16 h ), 140 . 88 ( c 13 ), 166 . 08 ( c ═ o ). more polar isomer 31a , a colorless solid , mp 71 - 73 ° c . 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 39 ( s , 3h , me 10 ), 1 . 51 ( s , 3h , me 11 ), 1 . 94 ( br . s ., 1h , oh ), 2 . 14 ( ddd , 1h , 2 j = 14 . 0 hz , 3 j 9a5e = 5 . 0 hz , 3 j 9a1e = 2 . 4 hz , h a 9 ), 2 . 15 ( ddd , 1h , 2 j = 16 . 0 hz , 3 j 6a5e = 4 . 7 hz , 3 j 6a7e = 1 . 6 hz , h a 6 ), 2 . 35 ( ddd , 1h , 2 j = 16 . 0 hz , 3 j 6e5e = 6 . 5 hz , 3 j 6a7e = 5 . 0 hz , h e 6 ), 2 . 36 ( m , 1h , h e 9 ), 2 . 50 ( m , 1h , h e 5 ), 3 . 36 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 3 . 83 ( dd , 1h , 3 j 1e9e = 3 . 6 hz , 3 j 1e9a = 1 . 6 hz , h e 1 ), 4 . 34 ( br . d , 1h , 2 j = 14 . 3 hz , h &# 39 ; 12 ), 5 . 29 ( dd , 1h , 3 j 7e6e = 6 . 5 hz , 3 j 7e6a = 1 . 6 hz , h e 7 ), 7 . 44 ( m , 2h ), 7 . 55 - 7 . 62 ( m , 3h ), 7 . 68 ( m , 1h ), 7 . 97 ( m , 2h ), 8 . 10 ( m , 2h ). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 23 . 23 ( me 11 ), 23 . 41 ( me 10 ) 23 . 97 ( c 9 h 2 ), 28 . 71 ( c 6 h 2 ), 30 . 15 ( c 5 h ), 60 . 89 ( c 12 h 2 ), 73 . 35 ( c 8 ), 74 . 14 ( c 7 h ), 81 . 21 ( c 1 h ), 81 . 71 ( c 4 ), 127 . 58 ( 2c 14 h ), 128 . 48 ( 2ch m - benz . ), 129 . 42 ( 2c 15 h ), 129 . 90 ( 2ch o - benz . ), 130 . 11 ( c 1 - benz . ), 133 . 15 ( ch p - benz . ), 133 . 83 ( c 16 h ), 141 . 10 ( c 13 ), 166 . 20 ( c ═ o ). dci hrms : obsd 447 . 15100 , calcd for c 23 h 27 o 7 s ( m + 1 ) 447 . 14775 . to a solution of hydroxysulfone 21a ( 230 mg , 0 . 705 mmol ) and 2 , 6 - lutidine ( 193 mg , 1 . 80 mmol ) in ch 2 cl 2 ( 5 ml ) at - 30 ° c . was added tfotms ( 354 mg , 1 . 50 mmol ). temperature was slowly raised to 0 ° c . ( 30 min ) and the mixture was stirred at 0 ° c . for 1 . 5 h . the resulting solution was poured into ice - cold saturated nahco 3 ( 30 ml ), extracted with hexane - etoac ( 9 : 1 , 150 ml ), dried ( na 2 so 4 ) and evaporated to give the crude tms - derivative 32a , containing 2 , 6 - lutidine as an impurity ( 305 mg , 1 : 0 . 35 ), a colorless oil , r f 0 . 36 ( hexane - etoac 85 : 15 ). 1 h nmr ( 250 mhz , cdcl 3 , δ ): 0 . 12 ( s , 9h , me 3 s ), 1 . 37 ( s , 3h , me 10 ), 1 . 51 ( br . s , 3h , me 11 ), 1 . 66 ( ddd , 1h , 2 j = 13 . 6 hz , 3 j 9a5e = 3 j 9a1e = 3 . 4 hz , h a 9 ), 1 . 79 - 1 . 90 ( m , 1h , h a 6 + h e 6 ), 2 . 11 - 2 . 22 ( m , 3h , h e 7 + h a 7 + h e 9 ) 2 . 25 ( m , 1h , h e 5 ), 3 . 27 ( d , 1h , 2 j = 14 . 2 hz , h 12 ), 3 . 61 ( dd , 3 j 1e9e = j 1e9a = 3 . 4 hz , h e 1 ), 4 . 24 ( br . d , 1h , 2 j = 14 . 2 hz , h &# 39 ; 12 ), 7 . 59 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 68 ( m , 1h , h 16 ), 7 . 96 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 63 mhz , cdcl 3 , δ ): 2 . 46 ( me 3 si ), 22 . 93 ( me 11 ), 23 . 49 ( c 6 h 2 ), 24 . 33 ( c 9 h 2 ), 27 . 15 ( me 10 ), 30 . 03 ( c 5 h ), 35 . 97 ( c 7 h 2 ), 61 . 09 ( c 12 h 2 ), 74 . 40 ( c 8 ), 82 . 45 ( c 1 h ), 82 . 65 ( c 4 ), 127 . 54 ( 2c 14 h ), 129 . 31 ( 2c 15 h ), 133 . 65 ( c 16 h ), 141 . 22 ( c 13 ). the mixture of crude tms - derivative 32a ( 285 mg ) and accl ( 3 ml ) was stirred at rt for 45 h , evaporated in vacuo , the residue was dissolved in etoac ( 20 ml ) and poured into saturated nahco 3 ( 30 ml ). after addition of hexane ( 40 ml ) the organic layer was separated and the water layer was extracted with hexane - etoac ( 7 : 3 , 60 ml ). the combined organic extract was dried ( na 2 so 4 ), evaporated and purified by flash chromatography ( hexane - etoac , 80 : 20 ) to give the sulfone 23a ( 230 mg , 95 %), mp 98 - 99 ° c . the nmr spectrum of the sulfone 23a is identical to that of sulfone 23a prepared as described in example 15 . a mixture of tms - derivative 32a ( prepared from 0 . 22 mmol of hydroxysulfone 21a as described in example 25 ), phenoxyacetyl chloride ( 1 . 1 ml ) and freshly oven - dried csf ( 152 mg , 1 . 0 mmol ) in acetonitrile ( 2 . 4 ml ) was stirred at rt for a week . the mixture was poured into saturated nahco 3 ( 40 ml ) and stirred for 1 h at rt . hexane - etoac ( 75 : 25 , 100 ml ) was added , the organic layer was separated and washed with saturated nahco 3 ( 25 ml ). the combined water washings were extracted with hexane - etoac ( 2 : 1 , 75 ml ). the combined organic extract was dried ( na 2 so 4 + nahco 3 ) and evaporated . mplc ( hexane - etoac , 80 : 20 ) of the residue gave the sulfone 33a ( 57 mg , 56 % yield ) as an oil . 1 h nmr ( cdcl 3 , 400 mhz , δ ): 1 . 50 ( br . s , 3h , me 11 ), 1 . 60 ( m , 1h , h a 6 ), 1 . 67 ( s , 3h , me 10 ), 1 . 74 ( m , 1h , h a 9 ), 1 . 86 ( m , 1h , h e 6 ), 2 . 16 - 2 . 27 ( m , 4h , h e 5 + h e 7 + h a 7 + h e 9 ), 3 . 24 ( d , 1h , 2 j = 14 . 4 hz , h 12 ), 4 . 19 ( br . d , 1h , 2 j = 14 . 4 hz , h &# 39 ; 12 ), 4 . 36 ( br . d , 1h , 3 j 1e9e = 3 . 2 hz , h e 1 ), 4 . 57 ( s , 2h , c 17 h 2 o ), 6 . 89 ( m , 2h , 2h o - phen . ), 7 . 00 ( m , 1h , h p - phen . ), 7 . 30 ( m , 2h , 2h m - phen . ), 7 . 58 ( m , 2h , 2h 15 ), 7 . 66 ( m , 1h , h 16 ), 7 . 94 ( m , 2h , 2h 14 ). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 60 ( me 10 ), 23 . 02 ( me 11 ), 23 . 18 ( c 6 h 2 ), 24 . 36 ( c 9 h 2 ), 29 . 29 ( c 5 h ), 32 . 97 ( c 7 h 2 ), 60 . 93 ( c 12 h 2 ), 65 . 52 ( c 17 h 2 o ), 77 . 84 ( c 1 h ), 82 . 76 ( c 4 ), 84 . 47 ( c 8 ), 114 . 36 ( 2c o - phen . h ), 121 . 73 ( c p - phen . h ), 127 . 53 ( 2c 14 h ), 129 . 37 ( 2c 15 h ), 129 . 58 ( 2c m - phen . h ), 133 . 78 ( c 16 h ), 141 . 02 ( c 13 ), 157 . 65 ( c 1 - phen . ), 167 . 93 ( c ═ o ). dci hrms : obsd 461 . 16000 , calcd for c 24 h 29 o 7 s ( m + 1 ) 461 . 16340 . to a suspension of hydroxysulfone 21a ( 280 mg , 0 . 858 mmol ) in ether ( 3 ml ) at 0 ° c . was added a solution of o -( p - methoxybenzyl ) trichloroacetimidate 44 ( 1 . 287 g of ca . 93 %, 4 . 19 mmol ) in ch 2 cl 2 ( 1 . 5 ml ), the mixture was stirred for 10 min until homogeneous solution was formed . then at 0 ° c . a solution of tfoh in ether ( 0 . 43 ml of 0 . 1m tfoh solution in abs . ether , 0 . 043 mmol ) was added and the green - yellow mixture was stirred for 1 . 5 h at 0 ° c . and for 10 h at rt a second portion of tfoh solution ( 0 . 25 ml , 0 . 025 mmol ) was added and the mixture was stirred for 12 h and then additional portions of imidate 44 ( 772 mg , 2 . 51 mmol ) and tfoh solution ( 0 . 25 ml , 0 . 025 mmol ) were added and the mixture was stirred for additional 8 h until consumption of 21a ( tlc monitoring ). the mixture was diluted with ether ( 15 ml ) and hexane ( 15 ml ), nahco 3 ( 0 . 6 g ) and na 2 so 4 ( 2 g ) were added . after being stirred overnight the mixture was filtered , evaporated , fractionated by flash chromatography ( hexane - etoac 75 : 25 ) and purified by a number of mplc ( hexane - etoac 78 : 22 ) to afford 34a ( 175 mg , 45 . 7 %) as a pale yellowish oil , r f 0 . 40 ( hexane - etoac 75 : 25 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 38 ( s , 3h , me 10 ), 1 . 53 ( br . s , 3h , me 11 ), 1 . 81 ( dddd , 1h , 2 j = 3 j 6a7a 14 . 0 hz , 3 j 6a5e = 6 . 4 hz , 3 j 6a7e = 3 . 3 hz , h a 6 ), 1 . 85 ( m , 1h , h e 6 ), 1 . 94 ( br . dd , 1h , 2 j = 14 . 6 hz , 3 j 7e6e = 5 . 0 hz , h e 7 ), 2 . 11 ( ddd , 1h , 2 j = 3 j 7a6a = 14 . 0 hz , 3 j 7a6e = 6 . 4 hz , h a 7 ), 2 . 17 ( m , 2h , h e 9 + ha 9 ), 2 . 27 ( br . dddd , 1h , 3 j 5e6e ≈ 3 j 5e6a = 6 . 4 hz , 3 j 5e9e ≈ 3 j 5e9a = 3 . 2 hz , h e 5 ), 3 . 29 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 3 . 81 ( s , 3h , meo ), 3 . 825 ( br . dd , 1h , 3 j 1e9e = 3 j 1e9a = 3 . 0 hz , h e 1 ), 4 . 24 ( br . d , 1h , 2 j = 14 . 3 hz , h &# 39 ; 12 ), 4 . 29 and 4 . 41 ( abq , 2h , 2 j = 10 . 7 hz , ch 17 h 17 &# 39 ; o ), 6 . 88 ( ddd , 2h , 3 j = 8 . 7 hz , 4 j 1 = 4 j 2 = 2 . 0 hz , 2h m - benz . ), 7 . 24 ( br . d , 3 j = 8 . 7 hz , 2h o - benz . ), 7 . 58 ( dddd , 2h , 3 j 15 , 14 = 3 j 15 , 16 = 7 . 3 hz , 4 j 1514 &# 39 ; = 4 j 15 &# 39 ; 14 = 1 . 4 hz , h 15 , 15 &# 39 ;), 7 . 66 ( dddd , 1h , 3 j 16 , 15 = 3 j 16 , 15 &# 39 ; = 7 . 3 hz , 4 j 1614 = 4 j 1614 &# 39 ; = 1 . 4 hz , h 16 ), 7 . 95 ( br . d , 2h , 3 j 14 , 15 = 7 . 3 hz , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 16 ( me 10 ), 22 . 92 ( me 11 ), 23 . 53 ( c 6 h 2 ), 24 . 57 ( c 9 h 2 ), 19 . 86 ( c 5 h ), 30 . 76 ( c 7 h 2 ), 61 . 10 ( c 12 h 2 ), 62 . 91 ( c 17 h 2 o ), 75 . 94 ( c 8 ), 80 . 84 ( c 1 h ), 82 . 71 ( c 4 ), 113 . 78 ( 2c m - benz . h ), 127 . 55 ( 2c 14 h ), 128 . 72 ( 2c o - benz . h ), 129 . 33 ( 2c 15 h ), 131 . 26 ( c 1 - benz . ), 133 . 68 ( c 16 h ), 141 . 17 ( c 13 ), 158 . 92 ( c p - benz .). dci hrms : obsd 447 . 18690 , calcd for c 24 h 31 o 6 s ( m + 1 ) 447 . 18414 . to a suspension of hydroxysulfone 21a ( 95 mg , 0 . 32 mmol ) in ether ( 1 ml ) at 0 ° c . was added a solution of o -( γ , γ - dimethylallyl ) trichloroacetimidate 45 ( 240 mg of ca . 96 %, 1 . 0 mmol ) in ch 2 cl 2 ( 0 . 5 ml ), the mixture was stirred for 10 min to form a clear solution . a solution of tfoh in ether ( 0 . 1 ml of 0 . 1m tfoh solution in abs . ether , 0 . 01 mmol ) at 0 ° c . was added and the green - yellow mixture was stirred for 4 h at 0 ° c . subsequently additional portions of imidate 45 ( 240 mg , 1 . 0 mmol ) and tfoh solution ( 0 . 1 ml , 0 . 01 mmol ) were added and the mixture was stirred for 2 h , and then additional imidate 45 ( 240 mg , 1 . 0 mmol ) and tfoh solution ( 0 . 1 ml , 0 . 01 mmol ) were added . after being stirred for additional 2 h at 0 ° c . the mixture was diluted with etoac ( 15 ml ) and hexane ( 60 ml ), nahco 3 ( 2 g ) and na 2 so 4 ( 10 g ) were added and the mixture was stirred overnight . the mixture was filtered , evaporated , the residue was fractionated by flash chromatography ( hexane - etoac 84 : 16 ) and purified by mplc ( hexane - etoac 84 : 16 ) to give 35a ( 58 mg , 50 . 5 %) as a colorless oil , r f 0 . 42 ( hexane - etoac 80 : 20 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 29 ( s , 3h , me 10 ), 1 . 50 ( br . s , 3h , me 11 ), 1 . 65 ( m , 3h , me 20 ), 1 . 73 ( m , 3h , me 21 ), 1 . 78 ( dddd , 1h , 2 j = 3 j 6a7a 14 . 0 hz , 3 j 6a5e = 6 . 0 hz , 3 j 6a7e = 3 . 5 hz , h a 6 ), 1 . 82 ( m , 1h , h e 6 ), 1 . 85 ( br . dd , 1h , 2 j = 14 . 0 hz , 3 j 7e6e = 5 . 5 hz , h e 7 ), 2 . 06 ( ddd , 1h , 2 j ≈ 3 j 7a6a = 14 . 0 hz , 3 j 7a6e = 6 . 1 hz , h a 7 ), 2 . 10 - 2 . 18 ( m , 2h , h e 9 + ha 9 ), 2 . 27 ( dddd , 1h , 3 j 5e6e ≈ 3 j 5e9e = 6 . 0 hz , 3 j 5e6a ≈ 3 j 5e9a = 3 . 0 hz , h e 5 ), 3 . 27 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 3 . 77 ( br . s , 1h , h e 1 ), 3 . 80 and 3 . 90 ( dabq , 2h , 2 j = 10 . 8 hz , 3 j 17 , 18 = 3 j 17 &# 39 ; , 18 = 6 . 8 hz , h 17 and h &# 39 ; 17 ), 4 . 22 ( d . d , 1h , 2 j = 14 . 3 hz , 4 j = 0 . 3 hz , h &# 39 ; 12 ), 5 . 27 ( ddqq , 3 j 18 , 17 = 3 j 18 , 17 &# 39 ; = 6 . 8 hz , 3 j 18 , 20 = 3 j 18 , 20 = 1 . 4 hz , hc 18 =), 7 . 56 ( dddd , 2h , 3 j 15 , 14 = 3 j 15 , 16 = 7 . 5 hz , 4 j 1514 &# 39 ; = 4 j 15 &# 39 ; 14 = 1 . 4 hz , h 15 , 15 &# 39 ;), 7 . 65 ( dddd , 1h , 3 j 16 , 15 = 3 j 16 , 15 &# 39 ; = 7 . 5 hz , 4 j 1614 = 4 j 1614 &# 39 ; = 1 . 4 hz , h 16 ), 7 . 94 ( ddd , 2h , 3 j 14 , 15 = 7 . 4 hz , 4 j 14 , 16 = 4 j 14 &# 39 ; 16 = 1 . 4 hz , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 17 . 94 ( me 20 c =), 22 . 04 ( me 10 ), 22 , 87 ( me 11 ), 23 . 49 ( c 6 h 2 ), 24 . 48 ( c 9 h 2 ), 29 . 84 ( c 5 h ), 30 . 97 ( c 7 h 2 ), 57 . 78 ( c 17 h 2 o ), 61 . 09 ( c 12 h 2 ), 75 . 47 ( c 8 ), 80 . 70 ( c 1 h ), 82 . 63 ( c 4 ), 121 . 78 ( hc 18 =), 127 . 53 ( 2c 14 h ), 129 . 29 ( 2c 15 h ), 133 . 64 ( c 16 h ), 135 . 90 ( c 19 =), 141 . 17 ( c 13 ). dci hrms : obsd 395 . 18590 , calcd for c 21 h 31 o 5 s ( m + 1 ) 395 . 18922 ; obsd 377 . 17500 , calcd for c 21 h 29 o 4 s ( m + 1 - h 2 o ) 377 . 17866 . to a suspension of hydroxysulfone 21a ( 113 mg , 0 . 345 mmol ) in ether ( 1 . 2 ml ) at 0 ° c . a solution of iminoester 46 ( 406 mg of ca . 97 %, 1 . 41 mmol ) in ch 2 cl 2 ( 0 . 7 ml ) was added , the mixture was stirred for 10 min and a clear solution was formed . then at 0 ° c . a solution of tfoh in ether ( 0 . 15 ml of 0 . 1m tfoh solution in abs . ether , 0 . 015 mmol ) was added and the green - yellow mixture was stirred for 1 h at 0 ° c . and for 6 h at rt a second portion of iminoester 46 ( 406 mg , 1 . 41 mmol , neat ) and a solution of tfoh ( 0 . 15 ml , 0 . 015 mmol ) were added and the mixture was stirred for 12 h . a third portion of imidate 46 ( 406 mg , 1 . 41 mmol ) and tfoh solution ( 0 . 15 ml , 0 . 015 mmol ) were added and the mixture was stirred for 12 h followed by a fourth addition of tfoh solution ( 0 . 15 ml , 0 . 015 mmol ) and stirring for additional 30 h . the mixture was diluted with hexand - etoac ( 3 : 1 , 100 ml ), nahco 3 ( 2 g ) and na 2 so 4 ( 5 g ) were added . after being stirred overnight the mixture was filtered , evaporated , fractionated by flash chromatography ( hexane - etoac , 75 : 25 ) and further purified by mplc ( hexane - etoac 80 : 20 ) to give 36a ( 49 mg , 32 %) as a pale yellowish gum , r f 0 . 46 ( hexane - etoac 75 : 25 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 34 ( s , 3h , me 10 ), 1 . 53 ( br . s , 3h , me 11 ), 1 . 84 ( dddd , 1h , 2 j = 3 j 6a7a 14 . 0 hz , 3 j 6a5a = 5 . 6 hz , 3 j 6a7a = 3 . 6 hz , h a 6 ), 1 . 84 - 1 . 93 ( m , 2h , h e 6 + h e 7 ), 2 . 10 ( ddd , 1h , 2 j = 3 j 7a6a = 14 . 0 hz , 3 j 7a6e = 6 . 4 hz , h a 7 ), 2 . 15 - 2 . 22 ( m , 2h , h e 9 + ha 9 ), 2 . 27 ( dddd , 1h , 3 j 5e6e = 3 j 5e6a = 5 . 6 hz , 3 j 5e9e = 3 j 5e9a = 3 . 0 hz , h e 5 ), 3 . 29 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 3 . 82 ( br . s , 1h , h e 1 ), 3 . 80 and 3 . 90 ( ddabq , 2h , 2 j = 12 . 6 hz , 3 j 17 , 18 = 3 j 17 &# 39 ; , 18 = 5 . 8 hz , 4 j 17 , 19 = 4 j 17 &# 39 ; , 19 = 1 . 5 hz , h 17 and h &# 39 ; 17 ), 4 . 24 ( br . d , 1h , 2 j = 14 . 3 hz , h &# 39 ; 12 ), 6 . 25 ( ddd , 3 j 18 , 19 = 15 . 9 hz , 3 j 18 , 17 = 3 j 18 , 17 &# 39 ; = 5 . 8 hz , hc 18 =), 6 . 60 ( br . d , 3 j 19 , 18 = 15 . 9 hz , hc 19 =), 7 . 22 - 7 . 40 ( m , 5h , phch =), 7 . 58 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 66 ( m , 1h , h 16 ), 7 . 96 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 11 ( me 10 ), 22 . 93 ( me 11 ), 23 . 53 ( c 6 h 2 ), 24 . 58 ( c 9 h 2 ), 29 . 90 ( c 5 h ), 31 . 00 ( c 7 h 2 ), 61 . 15 ( c 12 h 2 ), 61 . 94 ( c 17 h 2 o ), 75 . 96 ( c 8 ), 80 . 78 ( c 1 h ), 82 . 75 ( c 4 ), 126 . 40 ( 2c o - phen . h ), 127 . 12 ( hc 18 =), 127 . 52 ( c p - phen . h ), 127 . 59 ( 2c 14 h ), 128 . 52 ( 2c m - phen . h ), 129 . 34 ( 2c 15 h ), 130 . 99 ( hc 19 =), 133 . 69 ( c 16 h ), 136 . 85 ( c 1 - phen . ), 141 . 24 ( c 13 ). dci hrms : obsd 443 . 19150 , calcd for c 25 h 31 o 5 s ( m + 1 ) 443 : 18922 . to a mixture of socl 2 ( 395 mg , 3 . 32 mmol ) and pyridine ( 656 mg , 8 . 30 mmol ) in ch 2 cl 2 ( 40 ml ) at 0 ° c . for 30 min a solution of hydroxysulfone 21a ( 270 mg , 0 . 827 mmol ) in ch 2 cl 2 ( 15 ml ) was added . the mixture was stirred at 0 ° c . for 2 h and for additional 4 h at rt , poured into ice - cold 0 . 2 n hcl ( 100 ml ) and extracted with hexane - etoac ( 3 : 1 , 2 × 200 ml ). the combined organic extract was washed with saturated nahco 3 ( 30 ml ), dried ( na 2 so 4 ), filtered and evaporated . flash chromatogaphy ( hexane - etoac , 80 : 20 ) afforded a colorless solid mixture of 37a and 38a ( 243 mg , 95 . 5 %, 37a / 38a ca . 86 : 14 ). more polar isomer 37a of ca . 97 . 5 % purity was obtained by several sequential mplc ( hexane - etoac , 85 : 15 ) as a colorless solid , mp 111 - 112 ° c . 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 47 ( d , 3h , 4 j = 0 . 6 hz , me 11 ), 1 . 72 ( ddd , 1h , 2 j = 13 . 3 hz , 3 j 9a5e = 2 . 8 hz , 3 = j 9a1e = 2 . 0 hz , h a 9 ), 1 . 78 ( ddd , 3h , 4 j 10 , 7 = 2 . 7 hz , 5 j 10 , 6a ≈ 5 j 10 , 6e = 1 . 7 hz , me 10 ), 2 . 26 ( dddq , 1h , 2 j = 19 . 1 hz , 3 j 6a7 = 5 . 4 hz , 3 j 6a5e ≈ 5 j 6a10 = 1 . 7 hz , h a 6 ), 2 . 39 ( dddq , 1h , 2 j = 19 . 1 hz , 3 j 6e7 = 3 . 2 hz , 3 j 6e5e ≈ 5 j 6e10 = 1 . 7 hz , h e 6 ), 2 . 46 ( m , 1h , h e 5 ), 2 . 50 ( dddd , 1h , 2 j = 13 . 3 hz , 3 j 9e5e = 3 j 9e1e = 3 . 5 hz , 4 or 5 j = 1 . 6 hz , h e 9 ), 3 . 29 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 4 . 12 ( m , 1h , h e 1 ), 4 . 31 ( dd , 1h , 2 j = 14 . 3 hz , 4 j = 0 . 6 hz , h &# 39 ; 12 ), 5 . 77 ( m , 1h , h 7 ), 7 . 58 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 66 ( m , 1h , h 16 ), 7 . 95 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 21 . 16 ( me 10 ), 23 . 62 ( me 11 ), 26 . 83 ( c 9 h 2 ), 27 . 48 ( c 6 h 2 ), 29 . 54 ( c 5 h ), 61 . 23 ( c 12 h 2 ), 76 . 70 ( c 1 h ), 82 . 35 ( c 4 ), 127 . 28 ( c 7 h ), 127 . 55 ( 2c 14 h ), 129 . 35 ( 2c 15 h ), 131 . 15 ( c 8 =), 133 . 71 ( c 16 h ), 141 . 20 ( c 13 ). anal . calcd . for c 16 h 20 o 4 s : c , 62 , 31 ; h , 6 . 54 ; s , 10 . 40 . found : c , 62 . 17 ; h , 6 . 57 ; s , 10 . 47 . less polar isomer 38a ( ca . 95 % purity ) was isolated as a colorless semi - solid by semi - preparative dp hpls ( column -- lichrospher ® si 60 ( 10 μm ) 250 - 10 ; eluent i - proh - hexane 2 : 98 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 57 ( d , 3h , 4 j = 0 . 6 hz , me 11 ), 1 . 65 ( ddd , 1h , 2 j = 13 . 7 hz , 3 j 9a5e = 3 . 2 hz , 3 j 9a1e = 1 . 7 hz , h a 9 ), 1 . 73 ( dddd , 1h , 2 j ≈ 3 j 6a7a = 14 . 2 hz , 3 j 6a5e = 6 . 4 hz , 3 j 6a7e = 3 . 8 hz , h a 6 ), 2 . 15 ( br . ddd , 1h , 2 j = 14 . 2 hz , 3 j 6e7e = 6 . 6 hz , 3 j 6e5e = 3 . 2 hz , h e 6 ), 2 . 39 ( br . dd , 1h , 2 j = 14 . 2 hz , 3 j 7e6e = 6 . 6 hz , h e 7 ), 2 . 46 ( dddd , 1h , 3 j 5e6a ≈ 3 j 5e9e = 6 . 4 hz , 3 j 5e6e ≈ 3 j 5e9a = 3 . 2 hz , h e 5 ), 2 . 57 ( ddd , 1h , 2 j = 13 . 7 hz , 3 j 9e5e = 6 . 4 hz , 3 j 9e1e = 3 . 6 hz , h e 9 ), 2 . 99 ( m , 1h , 2 j ≈ 3 j 6a7a = 14 . 2 hz , h e 7 ), 3 . 29 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 4 . 30 ( br . dd , 1h , 2 j = 14 . 3 hz , 4 j = 0 . 6 hz , h &# 39 ; 12 ), 4 . 36 ( br . dd , 1h , 3 j 1e9e = 3 . 6 hz , 3 j 1e9a = 1 . 7 hz , h e 1 ), 4 . 92 ( br . dd , 1h , 2 j ≈ 4 j 10 , 7a = 2 . 2 hz , h 10 ), 4 . 95 ( br . ddd , 1h , 2 j ≈ 4 j 10 &# 39 ; , 7a = 2 . 2 hz , 4 j = 0 . 6 hz , h &# 39 ; 10 ), 7 . 59 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 67 ( m , 1h , h 16 ), 7 . 96 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 23 . 32 ( me 11 ), 27 . 02 ( c 6 h 2 ), 30 . 39 ( c 5 h ), 30 . 50 ( c 9 h 2 ), 30 . 52 ( c 7 h 2 ), 61 . 27 ( c 12 h 2 ), 80 . 77 ( c 1 h ), 82 . 96 ( c 4 ), 113 . 59 (═ c 10 h 2 ), 127 . 57 ( 2c 14 h ), 129 . 36 ( 2c 15 h ), 131 . 15 ( c 8 =), 133 . 74 ( c 16 h ), 141 . 18 , ( c 13 ), 146 . 21 ( c 8 ). dci hrms obsd 309 . 11930 , calcd for c 16 h 21 o 4 s (+ h ) 309 . 11606 . to a solution of unsaturated sulfone 37a ( 36 . 0 mg of ca . 97 . 5 % purity , 0 . 114 mmol ) in ch 2 cl 2 ( 0 . 5 ml ) at 0 ° c . a suspension of mcpba ( 38 . 0 mg of ca . 60 %, 0 . 13 mmol ) in ch 2 cl 2 ( 1 . 5 ml ) was added . the mixture was stirred at rt for 12 h , diluted with hexane - etoac ( 40 ml , 3 : 1 ), washed with saturated nahco 3 ( 2 × 5 ml ), the water washings were extracted with hexane - etoac ( 20 ml , 3 : 1 ). the combined organic extract was dried ( na 2 so 4 + nahco 3 ) and evaporated . the residue was purified by flash chromatography ( hexane - etoac , 4 : 1 ) to afford the epoxide 39a ( 35 . 5 mg . 96 %) as a colorless solid , mp 130 - 131 ° c . 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 44 ( s , 3h , me 10 ), 1 . 50 ( d , 3h , 4 j = 0 . 5 hz , me 11 ), 1 . 91 ( ddd , 1h , 2 j = 14 . 0 hz , 3 j 9a5e = 2 . 3 hz , 3 j 9a1e = 1 . 8 hz , h a 9 ), 2 . 01 ( dd , 1h , 2 j = 16 . 5 hz , 3 j 6a5e = 2 . 3 hz , h a 6 ), 2 . 15 ( ddd , 1h , 2 j = 14 . 0 hz , 3 j 9e5e = 6 . 6 hz , 3 j 9e1e = 3 . 8 hz , h e 9 ), 2 . 21 - 2 . 32 ( m , 2h , h e 5 + h e 6 ), 3 . 19 ( br . d , 1h , 3 j 7e6e = 5 . 5 hz , h e 7 ), 3 . 29 ( d , 1h , 2 j = 14 . 3 hz , h 12 ), 4 . 18 ( br . dd , 1h , 3 j 1e9e = 3 . 8 hz , 3 j 1e9a = 1 . 8 hz , h e 1 ), 4 . 22 ( d . d , 1h , 2 j = 14 . 3 hz , 4 j = 0 . 5 hz , h &# 39 ; 12 ), 7 . 59 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 68 ( m , 1h , h 16 ), 7 . 94 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 63 mhz , cdcl 3 , δ ): 18 . 64 ( me 10 ), 22 . 57 ( c 9 h 2 ), 23 . 38 ( me 11 ), 25 . 27 ( c 6 h 2 ), 28 . 74 ( c 5 h ), 57 . 10 ( c 8 ), 59 . 00 ( c 7 h ), 60 . 93 ( c 12 h 2 ), 78 . 29 ( c 1 h ), 82 . 15 ( c 4 ), 127 . 50 ( 2c 14 h ), 129 . 36 ( 2c 15 h ), 133 . 79 ( c 16 h ), 140 . 99 ( c 13 ). anal . calcd for c 16 h 20 o 5 s : c , 59 . 74 ; h , 6 . 21 ; s , 9 . 88 . found : c , 59 . 54 ; h , 6 . 21 ; s , 9 . 46 . to a solution of sulfides 2a , b ( 468 mg , 1 . 59 mmol , ratio 2a / 2b ca . 55 : 45 ) in etoac ( 25 ml ) at - 50 ° c . was added a solution of mcpba ( 478 mg of ca . 60 %, ca . 1 . 65 mmol ) in etoac ( 20 ml ). the mixture was stirred at - 30 ÷- 40 ° c . for 1 h , poured into saturated nahco 3 ( 75 ml ), extracted with etoac ( 33 × 60 ml ), dried ( na 2 so 4 + nahco 3 ) and evaporated . flash chromatography on silica gel ( eluent hexane - etoac , 1 : 4 ) afforded the mixture of diastereomeric sulfoxides 40a , a &# 39 ;, b , b &# 39 ; ( 438 mg , total yield 89 %, ratio a : a &# 39 ;: b : b &# 39 ;˜ 21 : 31 . 5 : 20 : 27 . 5 according to the integration in 400 mhz 1 h nmr spectrum ). the sulfoxides were separated by mplc ( hexane - etoac , 22 : 78 ) to obtain the individual diastereomers ( listed below according the order of polarity ). isomer 40b , colorless solid , r f 0 . 38 ( hexane - etoac 1 : 4 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 36 ( s , 3h , me 10 ), 1 . 62 ( br . dd , 1h , 2 j = 13 . 9 hz , 3 j 7e6e = 5 . 8 hz , h e 7 ), 1 . 79 ( br . s , 3h , me 11 ), 1 . 81 ( m , 1h , h e 6 ), 1 . 96 ( dddd , 1h , 2 j ≈ 3 j 6a7a = 13 . 9 hz , 3 j 6a5e = 6 . 0 hz , 3 j 6a7e = 3 . 5 hz , h a 6 ), 2 . 00 ( m , 1h , h e 5 ), 2 . 13 ( ddd , 1h , 2 j = 13 . 5 hz , 3 j 9a5e = 2 . 9 hz , 3 j 9a1e = 2 . 0 hz , h a 9 ), 2 . 29 ( ddd , 1h , 2 j ≈ 3 j 7a6a = 13 . 9 hz , 3 j 7a6e = 6 . 2 hz , h a 7 ), 2 . 35 ( br . ddd , 1h , 2 j = 13 . 5 hz , 3 j 9e5e = 6 . 4 hz , 3 j 9e1e = 3 . 6 hz , h e 9 ), 2 . 77 ( dd , 1h , 2 j = 13 . 5 hz , 4 j = 0 . 6 hz , h &# 39 ; 12 ), 2 . 91 ( d , 1h , 2 j = 13 . 5 hz , h 12 ), 3 . 73 ( m , 3 j 1e9e = 3 . 6 hz , j 1e9a = 2 . 0 hz , h e 1 ), 7 . 50 - 7 . 56 ( m , 3h , h 15 , 15 &# 39 ; + h 16 ), 7 . 63 - 7 . 66 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 93 ( me 11 ), 23 . 70 ( c 6 h 2 ), 24 . 00 ( c 9 h 2 ), 28 . 04 ( me 10 ), 31 . 20 ( c 5 h ), 35 . 47 ( c 7 h 2 ), 65 . 57 ( c 12 h 2 ), 71 . 32 ( c 8 ), 82 . 20 ( c 1 h ), 82 . 61 ( c 4 ), 123 . 77 ( 2c 14 h ), 129 . 49 ( 2c 15 h ), 131 . 34 ( c 16 h ), 144 . 73 ( c 13 ). isomer 40a , colorless solid , r f 0 . 35 ( hexane - etoac 1 : 4 ). 1 h nmr ( 250 mhz , ( cdcl 3 , δ ): 1 . 41 ( s , 3h , me 10 ), 1 . 47 ( br . s , ( me 10 ), 32 . 16 ( c 5 h ), 35 . 46 ( c 7 h 2 ), 65 . 94 ( c 12 h 2 ), 71 . 38 ( c 8 ), 82 . 35 ( c 1 h ), 82 . 73 ( c 4 ), 3h , me 11 ), 1 . 60 - 1 . 73 ( m , 1h ), 1 . 92 - 2 . 04 ( m , 2h ), 2 . 17 - 2 . 24 ( m , 3h , h e 5 + h e 7 + h e 9 ), 2 . 41 ( ddd , 1h , 2 j = 14 . 2 hz , 3 j 7a6a = 12 . 6 hz , 3 j 7a6e = 7 . 6 hz , h a 7 ), 3 . 13 ( d , 1h , 2 j = 13 . 9 hz , h 12 ), 3 . 61 ( dd , 1h , 2 j = 13 . 9 hz , 4 j 12 &# 39 ; , 11 = 0 . 4 hz , h &# 39 ; 12 ), 3 . 75 ( m , 1h , h e 1 ), 7 . 52 - 7 . 58 ( m , 3h , h 15 , 15 &# 39 ; + h 16 ), 7 . 67 - 7 . 71 ( m , 2h , h 14 , 14 &# 39 ;). isomer 40b &# 39 ;, colorless solid , mp 138 - 140 ° c . ( dec . ), r f 0 . 34 ( hexane - etoac 1 : 4 ). 1 h nmr ( 250 mhz , cdcl 3 , δ ): 1 . 36 ( s , 3h , me 10 ), 1 . 57 ( br . dd , 1h , 2 j 7e7a = 13 . 4 hz , 3 j 7e6e = 5 . 5 hz , h e 7 ), 1 . 83 ( m , 1h , h a 6 ), 1 . 88 - 1 . 99 ( m , 2h , h e 5 + h e 6 ), 1 . 89 ( br . s , 3h , me 11 ), 2 . 08 ( ddd , 1h , 2 j = 13 . 4 hz , 3 j 9a5e = 2 . 9 hz , 3 j 9a1e = 2 . 0 hz , h a 9 ), 2 . 17 ( br . ddd , 1h , 2 j 7a7e ≈ 3 j 7a6a = 14 . 8 hz , 3 j 7a6e = 5 . 6 hz , h a 7 ), 2 . 35 ( br . ddd , 1h , 2 j = 13 . 4 hz , 3 j 9e5e = 6 . 1 hz , 3 j 9e1e = 3 . 6 hz , h e 9 ), 2 . 72 ( d , 1h , 2 j = 13 . 7 hz , h 12 ), 3 . 11 ( d , 1h , 2 j = 13 . 7 hz , h &# 39 ; 12 ), 3 . 75 ( m , 3 j 1e9e = 3 . 6 hz , 3 j 1e9a = 2 . 0 hz , h e 1 ), 7 . 52 - 7 . 57 ( m , 3h , h 15 , 15 &# 39 ; + h 16 ), 7 . 65 - 7 . 69 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 63 mhz , cdcl 3 , δ ): 21 . 97 ( me 11 ), 23 . 48 ( c 6 h 2 ), 23 . 94 ( c 9 h 2 ), 28 . 04 123 . 82 ( 2c 14 h ), 129 . 39 ( 2c 15 h ), 131 . 12 ( c 16 h ), 144 . 85 ( c 13 ). isomer 40a &# 39 ;, a colorless solid , mp 153 - 155 ° c ., r f 0 . 32 ( hexane - etoac 1 : 4 ). 1 h nmr ( 400 mhz , ( cdcl 3 , δ ): 1 . 40 ( s , 3h , me 10 ), 1 . 55 ( br . s , 3h , me 11 ), 1 . 63 ( br . dd , 1h , 2 j = 14 . 0 hz , 3 j 7e6e = 5 . 6 hz , h e 7 ), 1 . 83 ( m , 1h , h e 5 ), 1 . 86 ( dddd , 1h , 2 j = 3 j 6a7a = 14 . 0 hz , 3 j 6a5e = 5 . 9 hz , 3 j 6a7e = 3 . 4 hz , h a 6 ), 1 . 96 ( m , 1h , 2 j ≈ 14 . 0 hz , h e 6 ), 2 . 06 ( ddd , 1h , 2 j = 13 . 8 hz , 3 j 9a5e = 2 . 8 hz , 3 j 9a1e = 2 . 0 hz , h a 9 ), 2 . 18 ( ddd , 1h , 2 j = 13 . 8 hz , 3 j 9e5e = 6 . 4 hz , 3 j 9a1e = 3 . 6 hz , h e 9 ), 2 . 37 ( br . ddd , 1h , 2 j ≈ 3 j 7a6a = 14 . 0 hz , 3 j 7a6e = 6 . 5 hz , h a 7 ), 3 . 31 and 3 . 35 ( abq , 2h , 2 j = 14 . 0 hz , h 12 + h &# 39 ; 12 ), 3 . 70 ( m , 1h , 3 j 1e9e = 3 . 6 hz , 3 j 1e9a = 2 . 0 hz , h e 1 ), 7 . 47 - 7 . 56 ( m , 3h , h 15 , 15 &# 39 ; + h 16 ), 7 . 64 - 7 . 69 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 08 ( me 11 ), 23 . 47 ( c 6 h 2 ), 24 . 37 ( c 9 h 2 ), 28 . 06 ( me 10 ), 31 . 56 ( c 5 h ), 35 . 77 ( c 7 h 2 ), 66 . 08 ( c 12 h 2 ), 71 . 42 ( c 8 ), 81 . 94 ( c 1 h ), 82 . 25 ( c 4 ), 123 . 83 ( 2c 14 h ), 129 . 32 ( 2c 15 h ), 130 . 87 ( c 16 h ), 144 . 91 ( c 13 ). to a solution of sulfides 13a , b ( 376 mg , 1 . 12 mmol , ratio 13a / 13b ca . 55 : 45 ) in etoac ( 25 ml ) at - 50 ° c . was added a solution of mcpba ( 330 mg of ca . 60 % , ca . 1 . 15 mmol ) in etoac ( 15 ml ). the mixture was stirred at - 30 ÷ 40 ° c . for 3 h , poured into saturated nahco 3 ( 50 ml ), extracted with hexane - etoac ( 4 : 6 , 3 × 60 ml ), dried ( na 2 so 4 + nahco 3 ) and evaporated . the sulfoxides were separated by mplc ( hexane - etoac , 1 : 1 ), total yield 364 mg ( 1 . 02 mmol , 91 %). the least polar isomer 41b , 68 mg ( 0 . 193 mmol ), a colorless solid , mp 116 - 118 ° c ., r f 0 . 41 ( hexane - etoac 1 : 1 ). ir ( neat ): 2980 , 2929 , 1734 v . s , 1445 , 1372 v . s , 1257 v . s , 1232 v . s , 1186 , 1153 , 1086 v . s , 1056 , 1022 v . s , 933 , 826 , 753 , 735 , 694 cm - 1 . 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 65 ( s , 3h , me 10 ), 1 . 80 ( d , 3h , 4 j = 0 . 65 hz , me 11 ), 1 . 82 - 1 . 89 ( m , 2h , h e 6 + h a 6 ), 1 . 89 ( ddd , 1h , 2 j = 13 . 6 hz , 3 j 9a5e = 3 . 2 hz , 3 j 9a1e = 1 . 8 hz , h a 9 ), 2 . 02 ( m , 1h , h e 5 ), 2 . 03 ( s , 3h , me 17 co ), 2 . 18 - 2 . 29 ( m , 2h , h a 7 + h e 7 ), 2 . 39 ( br . ddd , 1h , 2 j = 13 . 6 hz , 3 j 9e5e = 5 . 7 hz , 3 j 9e1e = 3 . 8 hz , h e 9 ), 2 . 77 ( dd , 1h , 2 j = 13 . 4 hz , 4 j = 0 . 65 hz , h &# 39 ; 12 ), 2 . 92 ( d , 1h , 2 j = 13 . 4 hz , h 12 ), 4 . 47 ( br . dd , 3 j 1e9e = 3 . 8 hz , j 1e9a = 1 . 8 hz , h e 1 ), 7 . 52 - 7 . 57 ( m , 3h , h 15 , 15 &# 39 ; + h 16 ), 7 . 64 - 7 . 67 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 38 ( me 17 co ), 22 . 45 ( me 10 ), 22 . 88 ( me 11 ), 23 . 52 ( c 6 h 2 ), 23 . 76 ( c 9 h 2 ), 30 . 55 ( c 5 h ), 32 . 77 ( c 7 h 2 ), 65 . 45 ( c 12 h 2 ), 78 . 02 ( c 1 h ), 82 . 50 ( c 8 ), 82 . 57 ( c 4 ), 123 . 69 ( 2c 14 h ), 129 . 45 ( 2c 15 h ), 131 . 33 ( c 16 h ), 144 . 57 ( c 13 ), 170 . 08 ( c ═ o ). isomer 41a ( 78 mg , 0 . 221 mmol ), a colorless oil , r f 0 . 40 ( hexane - etoac 1 : 1 ). 1 h nmr ( 400 mhz , ( cdcl 3 , δ ): 1 . 44 ( br . s , 3h , me 11 ), 1 . 65 ( s , 3h , me 10 ), 1 . 86 ( dddd , 1h , 2 j ≈ 3 j 6a7a = 14 . 0 hz , 3 j 6a5e = 6 . 0 hz , 3 j 6a7e = 3 . 5 hz , h a 6 ), 1 . 95 - 2 . 00 ( m , 1h , h e 6 ), 1 . 96 ( ddd , 1h , 2 j = 14 . 0 hz , 3 j 9a5e = 4 . 0 hz , 3 j 9a1e = 1 . 7 hz , h a 9 ), 2 . 01 ( s , 3h , me 17 co ), 2 . 18 - 2 . 25 ( m , 3h , h e 5 + h e 7 + h e 9 ), 2 . 31 ( ddd , 1h , 2 j ≈ 3 j 7a6a = 14 . 0 hz , 3 j 7a6e = 6 . 0 hz , h a 7 ), 3 . 08 ( d , 1h , 2 j = 13 . 8 hz , h 12 ), 3 . 61 ( dd , 1h , 2 j = 13 . 8 hz , 4 j 12 &# 39 ; , 11 = 0 . 6 hz , h &# 39 ; 12 ), 4 . 52 ( m , 1h , h e 1 ), 7 . 50 - 7 . 58 ( m , 3h , h 15 , 15 &# 39 ; + h 16 ), 7 . 66 - 7 . 68 ( m , 2h , h 14 , 14 &# 39 ;). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 36 ( me 17 co ), 22 . 43 ( me 10 ), 23 . 36 ( c 6 h 2 ), 23 . 55 ( me 11 ), 24 . 16 ( c 9 h 2 ), 29 . 09 ( c 5 h ), 32 . 98 ( c 7 h 2 ), 64 . 54 ( c 12 h 2 ), 77 . 58 ( c 1 h ), 82 . 37 ( c 8 ), 82 . 53 ( c 4 ), 123 . 65 ( 2c 14 h ), 129 . 35 ( 2c 15 h ), 131 . 10 ( c 16 h ), 144 . 38 ( c 13 ), 170 . 10 ( c ═ o ). isomer 41b &# 39 ; ( 96 mg , 0 . 272 mmol ), a colorless solid , mp 105 - 107 ° c ., r f 0 . 36 ( hexane - etoac 1 : 1 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 62 ( s , 3h , me 10 ), 1 . 76 ( dddd , 1h , 3 j 6a7a = 14 . 2 hz , 2 j 6a6e = 12 . 5 hz , 3 j 6a5e = 7 . 2 hz , 3 j 6a7e = 3 . 3 hz , h a 6 ), 1 . 83 ( ddd , 1h , 2 j = 13 . 6 hz , 3 j 9a5e = 3 . 3 hz , 3 j 9a1e = 1 . 8 hz , h a 9 ), 1 . 89 ( br . s , 3h , me 11 ), 1 . 90 ( m , 1h , h e 5 ), 1 . 93 - 2 . 02 ( m , 1h , 2 j 6e6a ≈ 12 . 5 hz , h e 6 ), 2 . 02 ( s , 3h , me 17 co ), 2 . 07 ( m , 1h , 2 j 7a7e = 14 . 8 hz , 3 j 7a6a = 14 . 2 hz , 3 j 7a6e = 5 . 6 hz , h a 7 ), 2 . 14 ( m , 1h , 2 j 7e7a ≈ 14 . 8 hz , 3 j 7e6e ≈ 6 . 6 hz , h e 7 ), 2 . 35 ( br . ddd , 1h , 2 j = 13 . 6 hz , 3 j 9e5e = 6 . 8 hz , 3 j 9e1e = 3 . 3 hz , h e 9 ), 2 . 67 ( br . d , 1h , 2 j = 13 . 6 hz , h 12 ), 3 . 10 ( d , 1h , 2 j = 13 . 6 hz , h &# 39 ; 12 ), 4 . 49 ( br . d , 3 j 1e9e = 3 . 3 hz , h e 1 ), 7 . 49 - 7 . 57 ( m , 3h , h 15 , 15 &# 39 ; + h 16 ), 7 . 63 - 7 . 67 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 05 ( me 10 ), 22 . 47 ( me 17 co ), 22 . 59 ( me 11 ), 23 . 46 ( c 6 h 2 ), 23 . 80 ( c 9 h 2 ), 31 . 60 ( c 5 h ), 32 . 92 ( c 7 h 2 ), 65 . 82 ( c 12 h 2 ), 78 . 34 ( c 1 h ), 82 . 64 ( c 8 ), 82 . 81 ( c 4 ), 123 . 81 ( 2c 14 h ), 129 . 42 ( 2c 15 h ), 131 . 16 ( c 16 h ), 144 . 90 ( c 13 ), 170 . 22 ( c ═ o ). the most polar isomer 41a &# 39 ; ( 122 mg , 0 . 346 mmol ), a colorless solid , mp 98 - 100 ° c ., r f 0 . 29 ( hexane - etoac 1 : 1 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 56 ( br . s , 3h , me 11 ), 1 . 68 ( s , 3h , me 10 ), 1 . 78 ( dddd , 1h , 2 j ≈ 3 j 6a7a = 14 . 0 hz , 3 j 6a5e = 6 . 0 hz , 3 j 6a7e = 3 . 2 hz , h a 6 ), 1 . 80 - 1 . 88 ( m , 2h , h e 5 + h a 9 ), 1 . 95 ( m , 1h , 2 j ≈ 14 . 0 hz , h e 6 ), 2 . 01 ( s , 3h , me 17 co ), 2 . 20 ( br . dd , 1h , 2 j ≈ 14 . 8 hz , 3 j 7e6e = 6 . 2 hz , h e 7 ), 2 . 30 ( ddd , 1h , 2 j = 14 . 8 hz , 3 j 7a6e = 5 . 9 hz , h a 7 ), 3 . 31 and 3 . 355 ( abq , 2h , 2 j = 14 . 0 hz , h 12 + h &# 39 ; 12 ), 4 . 47 ( br . d , 1h , 3 j 1e9e = 3 . 6 hz , h e 1 ), 7 . 48 - 7 . 57 ( m , 3h , h 15 , 15 &# 39 ; + h 16 ), 7 . 66 - 7 . 69 ( m , 2h , h 14 , 14 &# 39 ;). 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 23 ( me 11 ), 22 . 48 ( me 17 co ), 22 . 53 ( me 10 ), 23 . 42 ( c 6 h 2 ), 24 . 17 ( c 9 h 2 ), 30 . 90 ( c 5 h ), 33 . 20 ( c 7 h 2 ), 66 . 04 ( c 12 h 2 ), 77 . 75 c 1 h ), 82 . 25 ( c 8 ), 82 . 67 ( c 4 ), 123 . 82 ( 2c 14 h ), 129 . 35 ( 2c 15 h ), 130 . 92 ( c 16 h ), 144 . 86 ( c 13 ), 170 . 22 ( c ═ o ). preparation of ( 1r , 4r , 5r )- 4 , 8 - dimethyl - 4 - phenylsulfinylmethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] non - 7 - enes ( 42a , a &# 39 ;), ( 1r , 4s , 5r )- 4 , 8 - dimethyl - 4 - phenylsulfinylmethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] non - 7 - enes ( 42b , b &# 39 ;), ( 1r , 4r , 5r )- 4 - methyl - 8 - methylidene - 4 - phenylsulfinylmethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonanes ( 43a , a &# 39 ;) and ( 1r , 4s , 5r )- 4 - methyl - 8 - methylidene - 4 - phenylsulfinylmethyl - 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonanes ( 43b , b &# 39 ;) ( scheme 15 ). to a solution of sulfides 9a , b and 10a , b ( 138 mg , 0 . 50 mmol ) in etoac ( 10 ml ) at - 30 ÷- 35 ° c . was added a solution of mcpba ( 128 mg of ca . 70 %, ca . 0 . 52 mmol ) in etoac ( 8 ml ). the mixture was stirred at - 30 ÷- 40 ° c . for 1 h , poured into saturated nahco 3 ( 50 ml ), extracted with etoac ( 3 × 30 ml ), dried ( na 2 so 4 + nahco 3 ) and evaporated . the mixture of eight sulfoxides was fractionated by mplc ( hexane - etoac , from 1 : 4 to 1 : 1 ) to give 3 fractions of sulfoxides , total yield 135 mg ( 0 . 462 mmol , 92 . 3 %). ( i ) the least polar fraction , separated 18 mg ( total 0 . 061 mmol ), a colorless solid , mp 136 - 139 ° c ., r f 0 . 49 ( hexane - etoac 1 : 1 ), consisted of 42b and 43b ( 42b / 43b ca . 85 : 15 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 625 ( ddd , 2 j = 13 . 4 hz , 3 j 9a5e = 3 . 1 hz , 3 j 9a1e = 1 . 9 hz , h a 9 42b ) and 1 . 70 ( ddd , 2 j = 13 . 1 hz , 3 j 9a5e = 3 . 0 hz , 3 j 9a1e = 2 . 2 hz , h a 9 43b ), total 1h ; 1 . 79 ( br . dd , ca . 2 . 5h , 4 j 10 , 7 = 2 . 8 hz , 5 j 10 , 6e = 2 . 0 hz , me 10 42b ); 1 . 810 ( br . d , 4 j = 0 . 55 hz , me 11 43b ), 1 . 816 ( br . d , 4 j = 0 . 65 hz , me 11 42b ), total 3h ; 2 . 08 ( m , ca . 0 . 15h , h e 6 43b ); 2 . 16 ( m , h e 5 43b ) and 2 . 19 ( m , h e 5 42b ), total 1h ; 2 . 27 - 2 . 42 ( m , total ca . 2 . 3h ); 2 . 60 ( dddd , ca . 0 . 85h , 2 j = 13 . 2 hz , 3 j 9e5e = 3 j 9e1e = 3 . 5 hz , 4 j 9e6e = 1 . 2 hz , h e 9 42b ); 2 . 67 ( m , ca . 0 . 15h , h 7 43b ); 2 . 77 ( dd , 2 j = 13 . 5 hz , 4 j = 0 . 65 hz , h &# 39 ; 12 42b ) and 2 . 855 ( dd , 2 j = 13 . 4 hz , 4 j = 0 . 55 hz , h &# 39 ; 12 43b ), total 1h ; 2 . 88 ( d , 2 j = 13 . 5 hz , h 12 42b ) and 2 . 97 ( d , 2 j = 13 . 4 hz , h 12 43b ), total 1h ; 4 . 17 ( br . dd , 3 j 1e9e = 3 . 5 hz , 3 j 1e9a = 1 . 9 hz , h e 1 42b ) and 4 . 44 ( br . dd , 3 j 1e9e = 3 . 5 hz , 3 j 1e9a = 1 . 5 hz , h e 1 43b ), total 1h ; 4 . 930 ( br . s , h 10 43b ) and 4 . 936 ( br . s , h &# 39 ; 10 43b ), total ca . 0 . 3h ; 5 . 73 ( m , ca . 0 . 85h , h 7 42b ); 7 . 47 - 7 . 56 ( m , total 3h , h 15 , 15 &# 39 ; + h 16 ), 7 . 62 - 7 . 68 ( m , total 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 21 . 15 ( me 10 42b ), 23 . 17 ( me 11 43b ), 43b ), 26 . 29 ( c 9 h 2 42b ), 27 . 20 ( c 6 h 2 43b ), 27 . 94 ( c 6 h 2 42b ), 29 . 80 ( c 9 h 2 42b ), 30 . 28 ( c 7 h 2 43b ), 30 . 35 ( c 5 h 42b ), 31 . 58 ( c 5 h 43b ), 65 . 47 ( c 12 h 2 43b ), 65 . 50 ( c 12 h 2 42b ), 76 . 83 ( c 1 h 42b ), 80 . 77 ( c 1 h 43b ), 82 . 19 ( c 4 42b ), 113 . 31 (═ c 10 h 2 43b ), 123 . 74 ( 2c 14 h ) 42b ), 123 . 80 ( 2c 14 h 43b ), 126 . 00 (═ c 7 h 42b ), 129 . 44 ( 2c 15 h 42b ), 129 . 51 ( 2c 15 h 43b ), 131 . 29 ( c 16 h 42b ), 131 . 35 ( c 16 h 43b ), 131 . 80 ( c 8 = 42b ), 144 . 68 ( c 13 42b ), 146 . 1 ( c 13 43b ). the following fraction , separated 61 mg ( total 0 . 209 mmol ), colorless oil , r f 0 . 43 ( hexane - etoac 1 : 1 ). the fraction consisted of 42a , 43a , 42b &# 39 ; and 43b &# 39 ; ( 42 / 43 ca . 94 : 6 ; 42a / 42b &# 39 ; ca . 55 : 45 ). 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 39 ( br . d , 4 j = 0 . 7 hz , me 11 42a ); 1 . 875 ( br . s , me 11 43b &# 39 ;), 1 . 895 ( br . s , me 11 42b &# 39 ;), total 3h ; 1 . 56 ( m , h a 9 43b &# 39 ;), 1 . 63 ( ddd , 2 j = 13 . 1 hz , 3 j 9a5e = 3 . 2 hz , 3 j 9a1e = 2 . 1 hz , h a 9 42b &# 39 ;) and 1 . 75 ( ddd , 2 j = 13 . 4 hz , 3 j 9a5e ≈ 3 j 9a1e = 2 . 4 hz , h a 9 42a ), total ca . 1h ; 1 . 765 ( m , me 10 42b &# 39 ;) and 1 . 79 ( m , me 10 42a ), total ca . 3h ; 1 . 99 ( m , ca . 0 . 5h , h e 5 42a ); 2 . 20 ( m , ca . 0 . 5h , h a 6 42a ); 2 . 26 - 2 . 34 ( m , total ca . 1h , h e 5 + h a 6 42b &# 39 ;); 2 . 36 - 2 . 48 ( m , total ca . 2h ); 2 . 53 - 2 . 59 ( m , total ca . 0 . 5h , h e 9 42b &# 39 ;, 43b &# 39 ;); 2 . 55 ( d , 2 j = 13 . 8 hz , h 12 42b &# 39 ;) and 3 . 13 ( d , 2 j = 13 . 9 hz , h 12 42a ), total 1h ; 3 . 08 ( br . d , 2 j = 13 . 8 hz , h &# 39 ; 12 42b &# 39 ;), 3 . 13 ( br . d , 2 j = 13 . 8 hz , h &# 39 ; 12 43b &# 39 ;) and 3 . 66 ( dd , 2 j = 13 . 9 hz , 4 j = 0 . 7 hz , h &# 39 ; 12 42a ), total 1h ; 4 . 15 ( m , h e 1 42a , 42b &# 39 ;) and 4 . 43 ( br . d , h e 1 43a , 43b &# 39 ;), total 1h ; 4 . 895 ( br . s , h 10 43a , b &# 39 ;) and 4 . 90 ( br . s , h &# 39 ; 10 43a , b &# 39 ;), total ca . 0 . 12h ; 5 . 68 ( m , h 7 42b &# 39 ;) and 5 . 78 ( m , h 7 42a ), total ca . 0 . 95h ; 7 . 46 - 7 . 56 ( m , total 3h , h 15 , 15 &# 39 ; + h 16 ), 7 . 61 - 7 . 68 ( m , total 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 21 . 08 ( me 10 42a , 42b &# 39 ;), 21 . 87 ( me 11 42b &# 39 ;), 22 . 10 ( me 11 43b &# 39 ;), 24 . 09 ( me 11 42a ), 26 . 20 ( c 9 h 2 42b &# 39 ;), 26 . 50 ( c 9 h 2 42a ) 27 . 38 ( c 6 h 2 42a ), 27 . 78 ( c 6 h 2 42b &# 39 ;), 29 . 21 ( c 5 h 42b &# 39 ;), 31 . 53 ( c 5 h 42a ), 64 . 83 ( c 12 h 2 42a ), 66 . 19 ( c 12 h 2 42b &# 39 ;), 76 . 42 ( c 1 h 42a ), 77 . 05 ( c 1 h 42b &# 39 ;), 80 . 94 ( c 1 h 43a , b &# 39 ;), 81 . 94 ( c 4 42a ), 82 . 11 ( c 4 42b &# 39 ;), 113 . 10 (═ c 10 h 2 43a , b &# 39 ;), 123 . 72 ( 2c 14 h 42a ), 123 . 76 ( 2c 14 h 42b &# 39 ;), 126 . 60 (= c 7 h 42b &# 39 ;), 126 . 93 (= c 7 h 42a ), 129 . 29 ( 2c 15 h 42b &# 39 ;), 129 . 34 ( 2c 15 h 42a ), 130 . 99 ( c 8 = 42b &# 39 ;), 131 . 01 ( c 16 h 42b &# 39 ;), 131 . 06 ( c 16 h 42a ), 131 . 09 ( c 8 = 42a ), 144 . 60 ( c 13 42a ), 144 . 77 ( c 13 42b &# 39 ;), 146 . 28 ( c 13 43a , b &# 39 ;). the most polar fraction , 56 mg ( total 0 . 192 mmol ), a colorless oil , r f 0 . 35 ( hexane - etoac 1 : 1 ). the fraction consisted of 42a &# 39 ; and 43a &# 39 ; ( 42a &# 39 ;/ 43a &# 39 ; ca . 91 : 9 ). the isomers 42a &# 39 ; and 43a &# 39 ; were separated by additional mplc ( hexane - etoac 2 : 3 ) of the last fraction . less polar isomer 43a &# 39 ; ( ca . 95 % purity ) was isolated as a colorless waxy solid , mp 78 - 82 ° c . 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 58 ( m , 1h , h a 9 ), 1 . 61 ( br . s , 3h , me 11 ), 1 . 72 ( dddd , 1h , 2 j = 3 j 6a7a = 13 . 8 hz , 3 j 6a5e = 6 . 4 hz , 3 j 6a7e = 3 . 7 hz , h a 6 ), 2 . 04 ( dddd , 1h , 3 j 5e6a = 3 j 5e9e = 6 . 4 hz , 3 j 5e6e = 3 j 5e9a = 3 . 2 hz , h e 5 ), 2 . 18 ( m , 1h , 2 j = 13 . 8 hz , h e 6 ), 2 . 41 ( br . dd , 1h , 2 j = 15 . 2 hz , 3 j 7e6e = 6 . 0 hz , h e 7 ), 2 . 51 ( br . ddd , 1h , 2 j = 13 . 6 hz , 3 j 9e5e = 6 . 4 hz , 3 j 9e1e = 3 . 5 hz , h e 9 ), 3 . 06 ( m , 1h , h a 7 ), 3 . 28 ( br . d , 1h , 2 j = 14 . 0 hz , h 12 ), 3 . 50 ( br . d , 1h , 2 j = 14 . 0 hz , h &# 39 ; 12 ), 4 . 37 ( br . dd , 1h , 3 j 1e9e = 3 . 5 hz , 3 j 1e9a = 1 . 5 hz , h e 1 ), 4 . 93 ( br . dd , 1h , 2 j = 4 j 10 , 7a = 2 . 2 hz , h 10 ), 4 . 96 ( m , 1h , h &# 39 ; 10 ), 7 . 52 ( m , 1h , h 16 ), 7 . 55 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 69 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 22 . 48 ( me 11 ), 27 . 00 ( c 6 h 2 ), 30 . 05 ( c 9 h 2 ), 30 . 47 ( c 7 h 2 ), 31 . 69 ( c 5 h ), 66 . 24 ( c 12 h 2 ), 80 . 61 ( c 1 h ), 82 . 49 ( c 4 ), 113 . 64 (= c 10 h 2 ), 123 . 85 ( 2c 14 h ), 129 . 33 ( 2c 15 h ), 130 . 91 ( c 16 h ), 146 . 22 ( c 13 ), 154 . 64 ( c 8 ). more polar isomer 42a &# 39 ;, a colorless solid , mp 90 - 92 ° c . 1 h nmr ( 400 mhz , cdcl 3 , δ ): 1 . 51 ( br . s , 3h , me 11 ), 1 . 64 ( ddd , 1h , 2 j = 13 . 3 hz , 3 j 9a5e = 3 . 0 hz , 3 j 9a1e = 2 . 2 hz , h a 9 ), 1 . 79 ( ddd , 3h , 4 j 10 , 7 = 2 . 7 hz , 5 j 10 , 6a = 5 j 10 , 6e = 1 . 6 hz , me 10 ), 1 . 99 ( m , 1h , h e 5 ), 2 . 23 ( dddq , 1h , 2 j = 19 . 2 hz , 3 j 6a7 = 5 . 4 hz , 3 j 6a5e = 5 j 6a10 = 1 . 6 hz , h a 6 ), 2 . 37 - 2 . 47 ( m , 2h , h e 6 + h e 9 ), 3 . 30 ( d , 1h , 2 j = 14 . 0 hz , h 12 ), 3 . 44 ( dd , 1h , 2 j = 14 . 0 hz , 4 j = 0 . 35 hz , h &# 39 ; 12 ), 4 . 12 ( m , 1h , 3 j 1e9a = 3 j 1e9a = 2 . 2 hz , h e 1 ), 5 . 78 ( m , 1h , h 7 ), 7 . 50 ( m , 1h , h 16 ), 7 . 53 ( m , 2h , h 15 , 15 &# 39 ;), 7 . 68 ( m , 2h , h 14 , 14 &# 39 ;); 13 c nmr ( 100 mhz , cdcl 3 , δ ): 21 . 10 ( me 10 ), 22 . 70 ( me 11 ), 26 . 47 ( c 9 h 2 ), 27 . 35 ( c 6 h 2 ), 30 . 95 ( c 5 h ), 66 . 09 ( c 12 h 2 ), 76 . 54 ( c 1 h ), 81 . 77 ( c 4 ), 123 . 79 ( 2c 14 h ), 126 . 98 ( c 7 h ), 129 . 27 ( 2c 15 h ), 130 . 82 ( c 16 h ), 131 . 56 ( c 8 =), 144 . 93 ( c 13 ). the protozoan plasmodium falciparum is a causative agent of malaria . the antimalarial activity of 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonanes of type a was determined by measuring the incorporation of [ 3 h ] hypoxanthine , by the methods of desjardins 9 and milhous , 10 into chloroquinone - sensitive plasmodium falciparum ( nf54 ) 11 in the presence of varying drug concentrations . dose - response response curves that were fit to the experimental data by means of the marquardt algorithm 12 were solved for the drug concentration that kills 50 % of parasites ( ic 50 ), and were analyzed for accuracy of fit ( r 2 value , typically ≧ 0 . 99 ). provisional ic 50 values were obtained in a survey of seven 5 - fold dilutions ( in triplicate ) of stock solutions of chromatographically - purified or recrystalized test compound . assay were later expanded to include ten concentrations ( in quadruplicate ) of ˜ 1 . 8 - fold dilutions , which flank the provisional ic 50 . tables 1 - 3 present tabulations of a number of compounds that have been synthesized along with the ic 50 ( in nm ). table 1__________________________________________________________________________in vitro antimalarial activity of ( 1r , 5r )- 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonanesagainst chloroquine - sensitive p . falciparum ( nf 54 ) - # str7 ## - compound absolute no . configuration m y z ic . sub . 50 ( nm ) __________________________________________________________________________21a 1r , 4r , 5r , 8r oh phso . sub . 2 h 55 . sup . e 21b 1r , 4s , 5r , 8r oh h phso . sub . 2 89 . sup . e 40a &# 39 ; 1r , 4r , 5r , 8r oh phso h 150 . sup . e 23a 1r , 4r , 5r , 8r oac phso . sub . 2 h 17 . sup . e 23b 1r , 4s , 5r , 8r oac h phso . sub . 2 17 . sup . e 41a 1r , 4r , 5r , 8r oac phso h 40 . sup . e 41a &# 39 ; 1r , 4r , 5r , 8r oac phso h 14 . sup . e 41b 1r , 4s , 5r , 8r oac h phso 71 . sup . e 24a 1r , 4r , 5r , 8r oco ) ch . sub . 2 ac phso . sub . 2 h 46 . sup . e 24b 1r , 4s , 5r , 8r oc ( o ) ch . sub . 2 ac h phso . sub . 2 73 . sup . e 25a 1r , 4r , sr , 8r oc ( o ) c ( o ) oet phso . sub . 2 h 170 . sup . e 25b 1r , 4s , 5r , 8r oc ( o ) c ( o ) oet h phso . sub . 2 140 . sup . e 26a 1r , 4r , 5r , 8r oc ( o ) c ( o ) nbn . sub . 2 phso . sub . 2 h 21 . sup . 3 26b 1r , 4s , 5r , 8r oc ( o ) c ( o ) nbn . sub . 2 h phso . sub . 2 81 . sup . e 27a 1r , 4r , 5r , 8r oc ( o ) oph phso . sub . 2 h 47 . sup . e 27b 1r , 4s , 5r , 8r oc ( o ) oph h phso . sub . 2 150 . sup . e 34a 1r , 4r , 5r , 8r och . sub . 2 c . sub . 6 h . sub . 4 ome - p phso . sub . 2 h 14 . sup . e 35a 1r , 4r 5r , 8r och . sub . 2 ch ═ cme . sub . 2 phso . sub . 2 h 35 . sup . e 36a 1r , 4r , 5r , 8r och . sub . 2 ch ═ chph - phso . sub . 2 h 32 . sup . e trans 22a 1r , 4r , 5r , 8s h phso . sub . 2 h 17 . sup . e 22b 1r , 4s , 5r , 8s h h phso . sub . 2 24 . sup . e__________________________________________________________________________ notes : . sup . e expansion data . table 2______________________________________in vitro antimalarial activity of ( 1s , 5s )- 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonanes against chloroquine - sensitive p . falciparum ( nf 54 ) - # str8 ## - compound absolute ic . sub . 50 no . configuration y z ( nm ) ______________________________________ 4a 1s , 4s , 5s , 7s , 8s phs h 110 . sup . s 29a 1s , 4s , 5s , 7s , 8s phso . sub . 2 h 250 . sup . s 30a 1s , 4s , 5s , 7s , 8s n - buso . sub . 2 h 300 . sup . s______________________________________ notes : . sup . s survey data . table 3__________________________________________________________________________in vitro antimalarial activity of unsaturated and 7 , 8 - epoxy2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonanes against chloroquine - sensitive p . falciparum ( nf 54 ) __________________________________________________________________________ # str9 ## # str10 ## # str11 ## - 37a y = phso . sub . 2 43a &# 39 ; 39a 42a &# 39 ; y = phso compound absolute ic . sub . 50 no . configuration ( nm ) __________________________________________________________________________ 37a 1r , 4r , 5r 490 . sup . s 42a &# 39 ; 1r , 4r , 5r 350 . sup . e 43a &# 39 ; 1r , 4r , 5r 340 . sup . e 39a 1r , 4r , 5r , 7r , 8r 92 . sup . e__________________________________________________________________________ notes : . sup . 3 expansion data . . sup . s survey data . the results summarized in tables 1 - 3 indicate that several of these compounds exhibit in vitro antimalarial activity of the same order of magnitude as that recorded under the same conditions for artemisin ( ic 50 = 11 nm ). 13 based on the in vitro antimalarial activity of compounds of type a , the in vivo antimalarial activity of two representatives , namely of compounds 23a and 34a , were tested . the results are described in table 4 . table 4______________________________________in vivo antimalarial activity of ( 1r , 4r , 5r , 8r )- 2 , 3 - dioxabicyclo [ 3 . 3 . 1 ] nonanes 23a and 34a against chloroquine - sensitive parasites plasmodium berghei ( n strain ) and chloquine - resistant parasites plasmodium yoelii ( ssp . ns ) in mg / kg ). * - # str12 ## - p . berghei p . yoelii compound ( n strain ) ( ssp . ns ) no . m ed . sub . 50 ed . sub . 90 ed . sub . 50 ed . sub . 90______________________________________23a oac 3 . 7 7 . 3 12 . 5 28 . 0 34a opmb 1 . 3 2 . 3 4 . 8 8 . 3______________________________________ * ed . sub . 50 and ed . sub . 90 are given as the daily dose in mg / kg , repeated every 4 days . substances were administered to mice subcutaneously and tested by the fourday test .. sup . 14 , 15 in vivo antimalarial activity of compounds 23a and 34a is similar to that of artemisinin ( ed 50 = 0 . 95 ; 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