Sulfone directed alkylative bridge cleavage of oxabicyclic vinyl sulfones with organolithium reagents (1)

Sul one di ec ed alkyla i e b idge clea age o oxabicyclic inyl sul ones wi h o ganoli hium eagen s (1) Oxabic ic1 o inil sul onas: Ro u a alquilan e di ec a del puen e con eac i os o ganolí icos ARJONA, O. and PLUMET. J. Depa amen o de Química O gánica 1, Facul ad de Química, Uni e sidad Complu ense, 28040 Mad id, Spain. ABSTRACT An e icien egio-and s e eocon olled me hodology o he alkyla i e b idge clea age o oxabicyclic inyl sul ones is desc ibed. A ange o 7 -oxabicyclic[2.2.1. ]hep enyl and 8-oxabicyclic [3.2.1.]oc enyl sul ones has been ound o unde go an o e all syn S~' opening when ea ed wi h a wide a ie y o o ganoli hium eagen s and li hium aluminum hyd ide. In his manne , higWy unc ionalized cyclohexenyl and cyclohep enyl sul ones, e sa ile syn he ic in e media es, a e now a ailable in high yields. The comple e s e eoselec i i y encoun e ed in he exo conjuga e addi ion may be explained by chela ion o he o ganome allic eagen wi h he oxygen b idge and s e ic ac o s. Fu he mo e, less-s ained subs a es allow o comple e con ol o he addi ion and elimina ion s ages. Key wo ds: Oxabicyclic compounds. Syn S~' . Exo conjuga e addi ion. RESUMEN Se desc ibe una in e esan e o u a alquilan e egio-y es e eocon olada del puen e de oxabiciclo inil sul onas. Las 7-oxabiciclo[2.2. 1] hep enil y 8-oxabiciclo [3.2. 1.] oc enil sul onas su en ape u as syn S~' cuando se a an con una amplia a iedad de eac i os o ganolí icos e hidu o de li io y aluminio. De es a o ma, se ob ienen ciclohexenil y ciclohep enil sul onas, al amen e uncionalizadas, que son in e medios sin é icos e sá iles. La comple a es e eoselec i idad encon ada en la adición conjugada exo puede explica se en base a la quelación del eac i o o ganome álico con el oxígeno puen e. Palab as cla e: Compues os oxabiciclicos. Syn S~ ' . Adición conjugada exo. Recibido: 5-4-1995. Acep ado: 28-4-1 995. BIBLID [0004-2927(1995) 36:3; 417-432] A s Pha maceu ica, 36:3; 417-432, 1995 418 ARJONA, O. and PLUMET. J. INTRODUCTION Oxabicyclic compounds a e aluable in e media es (2) o he syn hesis o a a ie y o molecules o biological in e es (3). Recen ad ances in asymme ic Diels-Alde p ocesses (4), enzyma ic (5) and chemical (6) esolu ions should ende hese in e media es e en mo e a ac i e o o ganic chemis s and encou age he sea ch o new egio- and s e eocon olled unc ionaliza ions o hese subs a es. A c ucial ans o ma ion in many syn heses employing oxabicyclic in e me- dia es A (Scheme 1) has been he clea age o he oxygen b idge o p oduce unc ionalized cyclohexane o cyclohep ane de i a i es B. To his end, many g oups ha e de eloped di e en solu ions including [3-elimina ions o sui able de i a i es (7), ea men wi h s ong acids (8), educ i e elimina ion o endo unc ionali ies such as Cl o S02Ph (9), agmen a ion (10) and hyd oly ic condi ions (11). Howe e , all hese me hods ha e ailed in se e al cases (9, 12) and none o he aboye p o ocols allow o he cons uc ion o ca bon-ca bon bonds h oughou he b idge clea age s ep. Thus, he igid bicyclic s uc u es, powe ul elemen s o s e eo- and egiocon ol, a e no u ilized o his c ucial ans o ma ion. Se e al yea s ago we epo ed a new egio- and s e eoselec i e clea age o he oxygen b idge o simple oxano bomenic aleohols 4 and 5 wi h o ganoli hium eagen s o p oduce cyclohexenediols 10 (13) (Scheme 1). While his me hodology, coupled wi h ou p ocedu es o p epa e endo 4 o exo 5 subs a es (14) was la e ound o be qui e gene al (15), he inhe en lack o egiocon ol became appa en a an ea ly s age; namely, egiocon olled condi ions o p epa e isome ic cyclohexenols 14 could no be ound. In ac , ei he p o ec ion o he ee aleohol, 7, o sepa a ion o he ee aleohol om he eac i e cen e by a me hylene b idge, 9, esul ed in d ama ic losses o egioselec i i y. The same beha io was obse ed in he case o 8-oxabicyclo[3.2.1.]oc enyl ca binols 6 and 8 (16a). Thus, he eac ion o 6 wi h -BuLi a o ds compound 11 egioselec i ely whe eas in he case o 8, a ca. equimolecula mix u e o egioisome ic hyd oxycyclohep enes 13 and 15 was ob ained. These limi a ions and ou in e es in he de elopmen o egiospeci ic me hodology o achie e he alkyla i e b idge clea age owa ds ei he isome (12-13 o 14-15) was a ma e o in ensi e esea ch in ou labo a o y. The in oduc ion o an elec on wi hd awing subs i uen on he double bond was en isaged o be an appealing and s aigh o wa d solu ion o his p oblem. In his manne , he egiochemis y o he p ocess should be eadily con olled and u he mo e he syn he ic po en ial o he opening p oduc s would be inc eased subs an ially. A phenylsul onyl unc ionali y (Scheme JI) appea ed pa icula ly a ac i e a his s age since he equi ed subs a es e and E should be eadily a ailable om a a ie y o oxabicyclic compounds (17) (see below) and he syn he ic e sa ili y o inyl sul ones is well documen ed (18, 19). I was A s Pha maceu ica, 36:3; 417-432, 1995 SULFONE DIRECTED ALKYLATIVE BRIDGE CLEAVAGE OF OXABICYCLIC VINYL... 419 Scheme 1 , ( E , O n1 , ' , , A ~x y 1 X= CN, y= OAc, n= 1 2 X=Y=O ,n= 1 3 X=Y=O,n=2 n= 1,2 4 X= H, alkyl, inyl, a yl, Y= OH , n= 1 5 X= OH, Y= alkyl, inyI, a yl, n= 1 6 X= Me, Y = OH, n= 2 7 X= Me, Y= OBn, n= 1 8 X=Me, Y=OBn,n=2 9 X= H, Y= CH2 0H , n= 1 • OH ó: n1 I ' I I " , , I , , B OH ~)n VX y 10 X= H, alkyl, inyl, a yl, Y= OH, R= Me, n-Bu, Ph, e c., n= 1 11 X= Me, Y= OH, R= -Bu, n= 2 12 X= Me, Y= OBn, R= n-Bu, n= 1 13 X= Me, Y= OBn, R= -Bu, n= 2 ~x OH 14 X= Me, Y= OBn R= n-BuLi, n= 1 15 X= Me, Y=OBn, R= -BuLi, n= 2 expec ed ha conjuga e addi ion o an o ganoli hium eagen (R 3 Li) o inyl sul ones e and E would gene a e an a-sul onyl ca banion which would unde go B-eli nina ion gi ing ise o adduc s D and F espec i ely. In his pape we epo a ull accoun o ou e o s in his ield (16) which ha e esul ed in an e icien egio- and s e eocon olled me hodology o achie e he alkyla i e b idge clea age o oxabicyclic inyl sul ones o p oduce subs i u ed hyd oxycyclohexenyl o cyclohep enyl inyl sul ones. A s Pha maceu ica, 36:3; 417-432, 19 95 SULFONE DIRECTED ALKYLA TIVE BRIDGE CLEA V AGE OF OXAB TC YCLIC VTNYL... 419 Scheme 1 OH I I I ( : ,On I I I I I I .. cJ: ni I I A 1 X= CN, Y= OAc, n= 1 2 x= Y= O, n= 1 3 X=Y=0,n=2 n= 1,2 I 4 X= H, alkyI, inyI, a yI, Y = OH, n= 1 5 X= OH, y = alkyI, inyI, a yI, n= 1 6 X=Me, Y=OH,n=2 7 X= Me, Y= OBn, n= 1 8 X= Me, Y= OBo, n= 2 9 X= H, Y= CH2 0H , n= 1 I I " I , I B OH ~)n Vx y 10 X= H, alkyI, inyI, a yI, Y= OH , R= Me, n-Bu, Ph, e c., n= 1 11 X= Me, Y= OH , R= -Bu, 0= 2 12 X= Me, Y= OBn, R= n-Bu, n= 1 13 X= Me, Y= OBn, R= -Bu, n= 2 ~x OH 14 X= Me, Y= OBn R= n-BuLi, n= 1 15 X= Me, Y=OBn, R= -BuLi, n= 2 expec ed ha conjuga e addi ion o an o ganoli hium eagen (R3Li) o inyl sul ones e and E would gene a e an a- sul onyl ca banion which would unde go B-eli nina ion gi ing ise o adduc s D and F espec i ely. In his pape we epo a ull accoun o ou e o s in his ield (16) which ha e esul ed in an e icien egio- and s e eocon olled me hodology o achie e he alkyla i e b idge clea age o oxabicyclic inyl sul ones o p oduce subs i u ed hyd oxycyclohexenyl o cyclohep enyl inyl sul ones. A s P ha maceu ic a, 36:3; 417-432, 19 95 420 ARJONA, O. and PL UMET. J. Scheme 11 OH 0=0,1 e D 0=0,1 E F RESULTS AND DISCUSSION P epa a ion o subs a es. Scheme III ou lines he syn he ic ou es o ob ain inyl sul ones 26-28 as well as hei egioisome s 37-39. The key s ep o hese syn heses is he egioselec i e addi ion o sul enyl halides unde kine ic con ol o bicyc1ic subs a es, such as 1 and 2, con olled by emo e subs i u ion on C- 2 (17). Thus, addi ion o phenylsul enyl chlo ide o ke ones 2 and 3 ollowed by unc ional g oup manipula ions a o ds chlo osul ides 20, 21 and 22 (20). Al ema i ely, cyanoace oxy de i a i e 1 and he endo-benzyl e he s ( esul ing om eac ion o MeMgB wi h 2 and 3 (14, 16a) and subsequen benzyla ion) gi e ise o egioisome ic chlo osul ides 31, 32 and 33, p esumably unde s e ic con ol (17). Subsequen oxida ion and elimina ion comple e he sequence (21). In o de o ex end he scope o he me hodology, we p epa ed subs a es 45, 49 and 55 as shown in Scheme IV (see expe imen al sec ion). Oxano bomene me hanol 9 was benzoyla ed and PhSCI was' added wi h comple e s e ic con ol (22). Remo al o he benzoa e g oup and ea men wi h sodium hyd ide, in e es ingly, esul ed in smoo h o ma ion o inyl sul ide 43 (23). S anda d benzyla ion and oxida ion a o ded 45. Al ema i ely, icyc1ic sul ide 46 (22) was ea ed wi h an excess o n-BuLi in an e o o es he applicabili y o ou s ain-di ec ed A s Pha maceu ica, 36:3; 417-432, 1995 SULFONE DIRECTED ALKYLA TIVE BRIDGE CLEA V AGE OF OXA BI CYCLIC VINYL... 421 2,3 2 2,3 1 a, b, e • a, g Scheme lIJ a PhS~ O n el"" ~ x y 20 X= Me, Y= OBn, n= 1 21 X= Me, Y= OBn, n= 2 d,e --------<.~ 22 X= y = OCH2CH2 0, n= 1 b,c,a CI~x d,e • PhS = y 31 X= Me, Y= OBn, n= 1 32 X= Me, Y= OBn, n= 2 a, , g 33 X= y = OCH2 CH 2 0, n= 1 • • PhS02~))D ~x y 26 X= Me, Y= OBn, n= 1 27 X= Me, Y= OBn, n= 2 PhS02~X 37 X= Me, Y= OBn, n= 1 38 X= Me, Y= OBn, n= 2 39 X= y = OCH2CH2 0, n= 1 aKey: (a) PhSCl, CHCl3 o CH3CN, O o c. (b) MeMgB , E 20 O o c. (e) NaH, BnB , (ea . n-Bu4Nl o 21 and 32= THF, O oc o e lux. (d) mCPBA, K2 C0 3, O oc o . . o 26, 28, 37 and 39; MMPP; MeOH, O oC o . . o 27 and 38. (e) DBU, CR2 Cl 2, O oC . ( ) 1. NaOMe, MeOR. 2. aq CR2 0, O oC o . . (g) E hyleneglyeol, p- TsOR, CJI 6, e lux. O e all yields, 26: 26% om 2; 27: 54% om 3; 28: 62% om 2; 37 : 33% om 5; 38: 64% om 3; 39: see e e enee 21. B-elimina ions (24) o his case, o a o d an excellen yield o inyl sul ide 47. Vinyl sul one 49 was p epa ed as aboye. On he o he hand, diol 50 (25) was con e ed o he highly subs i u ed and di e en ially p o ec ed inyl sul one 55 using an analogous syn he ic ou e, i. e., o ma ion o he icyc1ic sul ide, s ained-di ec ed ing opening and unc ional g oup manipula ions. Alkyla i e B idge Clea age 7-0xabicyclo[2.2.1.}hep enes sys ems. In iew o p e ious e o s in ol ing SN2' addi ions o o ganome allic eagen s o cyclic inyl sul ones (26, 27), we selec ed G igna d, cup a e and o ganoli hium eagen s o ou s udy. P elimina y expe imen s wi h me hyl G igna d and cup a e eagen s did no A s Pha maceu ica, 36:3; 417-432,1995 422 ARJONA, O. and PLUMET. J. Scheme ¡ a Q:(-OH a, b, c,d e, -J1J -)]J PhS "" '-OH PhS0 2 ""' -08n 9 Z=H 43 43 50 Z=C H2O H_ I b o,9 b, h o 50 PhS u g PhS~ e, PhSo,,~ -I O ""' -OH • I O 0- ' ""' -08n 46 Z=H 47 Z=H 49 Z= H 52 Z= CH 2OMOM 53 Z= CH 2OMOM 55 Z= CH 2OMOM aKey: (a) PhCOC1, py , O oC. (b) PhSCl, CHCI3, O oC. (e) NaOMe, MeOH, O oC o . . (d) NaH, THF, O oC o . . (e) NaH, BnB , (ea . n-Bu4Nl o 55), THF, . . o e lux. ( ) MMPP; MeOH, O oC o . . (g) n-BuLi, THF, -78 oC . (h) CH2(OMe h, p-TsOH, CH2CI2, e lux. O e alI yields, 45: 61 % o o 9; 49: 58% o o 46; 55 : 37% o o 50. p oduce he desi ed ans o ma ion. Acco dingly, we examined he eac ion be ween 37 and an excess o MeLi (3 equi , -78 oC, THF, 10 min) and an excellen yield o 56a was ob ained. Encou aged by his smoo h ans o ma ion, we explo ed o he o ganoli hium eagen s and hese esul s a e ga he ed in Table 1. In clea con as o MeLi, he eac ion be ween 37 and n- BuLi (2 equi , THF) was ema kably slow, e en a O oC, and, mo e impo an ly, he isola ed yield o 56b we e e y low and a iable amoun s o o he by- p oduc s, en a i ely cha ac e ized as desul onyla ed 37 and 56b , we e also p oduced. A e conside able expe imen a ion, we ound ha he use o oluene, a less coo dina ing sol en (28) a o ded excellen yields o alkyla i e opening p oduc 56b (en y 2). Simila ly, PhLi and inylli hium (29) (2 equi ) ga e excellen yields o 56c and 56d espec i ely (en ies 3 and 4). While we do no ully unde s and he di e ences ound be ween MeLi and n-BuLi in THF, he c ucial e ec o he use o oluene o he la e is no ewo hy (30). A s Pha maceu ica, 36:3; 417-432,1995 SULFONE D1RE CTED ALKYLA TIVE BRIDGE CLEA V AGE OF OXABICYCLlC VINYL... 423 Table I. - SN2' Opening Reac ions o 7 -0 xano bomenic Vinyl Sul ones wi h O ganoli ium Reagen s and LiAllI4 En y lb 2C 3C 4C 5b 6c 7d 8d 9d JO b Il b 12b 13 b 14b 15 d, 16 d 17 b 4 OH RLi ~ 3 I O2 X R~ 6 ------~~~ 2 PhSO 6 = 2 1 Y 37 X=Me , Y=OBn 39 X= y = OCH2 aI 20 45 X= H, y = CH 2 0Bn 4 PhS0 2 1j 3 Z I O2 X 6 :. 1 y 26 X=Me , Y=OBn 28 X= Y= OCH2aI20 49 X= Z= H, Y = CH2 0Bn 5 X PhSO 3 ~ ~ 2 4 Y 56 RLi 4 PhS02Q~ 5 Z 2 6 X ~ 57 55 X =H , Y= CH 2 0Bn , Z= CH 2 0MOM Subs a e R P oduc 37 Me 56a 37 n- Bu 56b 37 Ph 56c 37 Vinyl 56d 39 Me 56e 45 Me 56 45 n-Bu 56g 45 AlIyl 56h 45 2-P openyl 56i 39 He 56j 26 He 57a 26 Me 57b 28 Me 57c 49 Me 57d 49 I- Hexynyl 57e 49 2-Fu yl 57 55 Me 57g Yi el d( %)" 87 78 86 95 85 81 78 64 67 62 65 80 75 82 74 69 88 NOTES: aUnop imized yields o pu e p od uc s. bIn THF, - 78 oc . cIn Toluene, -7 8 oC. dIn a mix u e ToU E p , 1:1, - 78 oC. eLiAlH4. O o c. A s Pha maceu ica, 36:3; 417-432, 1995 424 ARJONA, O. and PLUMET. J, To explo e he an icipa ed egiocon olled b idge opening, inyl sul one 26 was ea ed wi h MeLi, and adduc 57b esul ing om nucleophilic addi ion o C-6 and subsequen B-elimina ion was ob ained in good yield (en ies 11 and 12). Simila ly, ke als 28 and 39 smoo hly p oduced cyclohexenyl sul ones 57c and 56e (en ies 13 and 5) espec i ely. The me hodology was also applied o subs a es 45, 49 and 55 wi h simila esul s (en ies 6-9 and 14-17). O he syn he ically use ul o ganoli hium eagen s such as allylli hium (31 , 32), 2- u ylli hium (33) and l-hexynylli hium (34) we e also employed wi h simila esul s. In o de o ex end he scope o his me hodology, he eac ions be ween oxano bo nenic sul ones 26 and 39 and li hium aluminum hyd ide (4 mola equi , -78 oC) we e s udied. Thus, ai yields o cyclohexenyl sul ones 57a and 56j we e ealized in wha , o ou knowledge, is he s case o SN2' displacemen s o a hyd ide eagen on o a inyl sul one (en ies 10 and 11) (35). I should be men ioned ha he eac ion was e y dependen on he amoun o hyd ide used and on he eac ion empe a u e. Thus, sa u a ed sul one 59 (Scheme V) was ob ained a O oC (4 mola equi LAR); howe e , a -78 oC (1.5 mola equi LAR), bicyclic sul one 58 (49%) was he majo p oduc . 26 Scheme V PhSO Z Y1:'l ----------- ~Me THF LAH OBn 58 PhSOZ'Q, Me + ~ OBn UO 57a PhSOZI" 'Q Me + , OBn UO 59 The egio- and s e eochemis y o hese p oduc s we e eadily es ablished by spec oscopic echniques, pa icula ly by 'H NMR wi h he aid o selec i e decouplings and DNOE expe imen s. Fo ins ance, 56a and 57b p esen ed qui e di e en spli ing pa e ns o he inylic p o ons (56a, d, J = 1.3 Hz; 57b, ddd, J= 5.4,3.0 ,2.4 Hz). In addi ion, H-l exhibi s a ans diaxial coupling (12.6 Hz) in 56a and an equa o ial-axial coupling (3.7 Hz) in 57b. The la ge homoallylic coupling ound o 57b (J 25ax = 3.0 Hz) is also no ewo hy. 8-0xabicyclo[3.2.1.}oc enesys ems. The ex ension o his me hodology o 8- oxabicyclic[3.2.1.]oc ene sul ones 27 and 38 was explo ed in o de o assess he in luence o a less s ained oxygen b idge in he o e all SN 2' p ocess. Addi ionally, he syn he ic po en ial o he esul ing p oduc s (no easily a ailable highly unc ionalized cyclohep enes) was pa icula ly a ac i e (36). In his con ex , A s Pha maceu i ca. 36:3; 417-432, 1995