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

Sulfone directed alkylative bridge cleavage of oxabicyclic vinyl sulfones with organolithium reagents (1) Oxabic ic1 o vinil sulfonas: Rotura alquilante directa del puente con reactivos organolíticos ARJONA, O. and PLUMET. J. Departamento de Química Orgánica 1, Facultad de Química, Universidad Complutense, 28040 Madrid, Spain. ABSTRACT An efficient regio-and stereocontrolled methodology for the alkylative bridge cleavage of oxabicyclic vinyl sulfones is described. A range of 7 -oxabicyclic[2.2.1. ]heptenyl and 8-oxabicyclic [3.2.1.]octenyl sulfones has been found to undergo an overall syn S~' opening when treated with a wide variety of organolithium reagents and lithium aluminum hydride. In this manner, higWy functionalized cyclohexenyl and cycloheptenyl sulfones, versatile synthetic intermediates, are now available in high yields. The complete stereoselectivity encountered in the exo conjugate addition may be explained by chelation of the organometallic reagent with the oxygen bridge and steric factors. Furthermore, less-strained substrates allow for complete control of the addition and elimination stages. Key words: Oxabicyclic compounds. Syn S~' . Exo conjugate addition. RESUMEN Se describe una interesante rotura alquilante regio-y estereocontrolada del puente de oxabiciclo vinil sulfonas. Las 7-oxabiciclo[2.2. 1] heptenil y 8-oxabiciclo [3.2. 1.] octenil sulfonas sufren aperturas syn S~' cuando se tratan con una amplia variedad de reactivos organolíticos e hiduro de litio y aluminio. De esta forma, se obtienen ciclohexenil y cicloheptenil sulfonas, altamente funcionalizadas, que son intermedios sintéticos versátiles. La completa estereoselectividad encontrada en la adición conjugada exo puede explicarse en base a la quelación del reactivo organometálico con el oxígeno puente. Palabras clave: Compuestos oxabiciclicos. Syn S~ ' . Adición conjugada exo. Recibido: 5-4-1995. Aceptado: 28-4-1 995. BIBLID [0004-2927(1995) 36:3; 417-432] Ars Pharmaceutica, 36:3; 417-432, 1995 418 ARJONA, O. and PLUMET. J. INTRODUCTION Oxabicyclic compounds are valuable intermediates (2) for the synthesis of a variety of molecules of biological interest (3). Recent advances in asymmetric Diels-Alder processes (4), enzymatic (5) and chemical (6) resolutions should render these intermediates even more attractive to organic chemists and encourage the search for new regioand stereocontrolled functionalizations of these substrates. A crucial transformation in many syntheses employing oxabicyclic intermediates A (Scheme 1) has been the cleavage of the oxygen bridge to produce functionalized cyclohexane or cycloheptane derivatives B. To this end, many groups have developed different solutions including [3-eliminations of suitable derivatives (7), treatment with strong acids (8), reductive elimination of endo functionalities such as Cl or S02Ph (9), fragmentation (10) and hydrolytic conditions (11). However, all these methods have failed in several cases (9, 12) and none of the aboye protocols allow for the construction of carbon-carbon bonds throughout the bridge cleavage step. Thus, the rigid bicyclic structures, powerful elements for stereoand regiocontrol, are not utilized for this crucial transformation. Several years ago we reported a new regioand stereoselective cleavage of the oxygen bridge of simple oxanorbomenic aleohols 4 and 5 with organolithium reagents to produce cyclohexenediols 10 (13) (Scheme 1). While this methodology, coupled with our procedures to prepare endo 4 or exo 5 substrates (14) was later found to be quite general (15), the inherent lack ofregiocontrol became apparent at an early stage; namely, regiocontrolled conditions to prepare isomeric cyclohexenols 14 could not be found. In fact, either protection of the free aleohol, 7, or separation of the free aleohol from the reactive center by a methylene bridge, 9, resulted in dramatic losses of regioselectivity. The same behavior was observed in the case of 8-oxabicyclo[3.2.1.]octenyl carbinols 6 and 8 (16a). Thus, the reaction of 6 with t-BuLi affords compound 11 regioselectively whereas in the case of 8, a ca. equimolecular mixture of regioisomeric hydroxycycloheptenes 13 and 15 was obtained. These limitations and our interest in the development of regiospecific methodology to achieve the alkylative bridge cleavage towards either isomer (12-13 or 14-15) was a matter ofintensive research in our laboratory. The introduction of an electron withdrawing substituent on the double bond was envisaged to be an appealing and straightforward solution to this problem. In this manner, the regiochemistry of the process should be readily controlled and furthermore the synthetic potential of the opening products would be increased substantially. A phenylsulfonyl functionality (Scheme JI) appeared particularly attractive at this stage since the required substrates e and E should be readily available from a variety of oxabicyclic compounds (17) (see below) and the synthetic versatility of vinyl sulfones is well documented (18, 19). It was Ars Pharmaceutica, 36:3; 417-432, 1995 SULFONE DIRECTED ALKYLATIVE BRIDGE CLEAVAGE OF OXABICYCLIC VINYL... 419 Scheme 1 , (tE , 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, vinyl, aryl, Y= OH , n= 1 5 X= OH, Y= alkyl, vinyI, aryl, 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, vinyl, aryl, Y= OH, R= Me, n-Bu, Ph, etc., n= 1 11 X= Me, Y= OH, R= t-Bu, n= 2 12 X= Me, Y= OBn, R= n-Bu, n= 1 13 X= Me, Y= OBn, R= t-Bu, n= 2 ~x OH 14 X= Me, Y= OBn R= n-BuLi, n= 1 15 X= Me, Y=OBn, R= t-BuLi, n= 2 expected that conjugate addition of an organolithium reagent (R 3 Li) to vinyl sulfones e and E would generate an a-sulfonyl carbanion which would undergo B-elirnination giving rise to adducts D and F respectively. In this paper we report a full account of our efforts in this field (16) which have resulted in an efficient regioand stereocontrolled methodology to achieve the alkylative bridge cleavage of oxabicyclic vinyl sulfones to produce substituted hydroxycyclohexenyl or cycloheptenyl vinyl sulfones. Ars Pharmaceutica, 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 (tt : ,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, vinyI, aryI, Y = OH, n= 1 5 X= OH, y = alkyI, vinyI, aryI, 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, vinyI, aryI, Y= OH , R= Me, n-Bu, Ph, etc., n= 1 11 X= Me, Y= OH , R= t-Bu, 0= 2 12 X= Me, Y= OBn, R= n-Bu, n= 1 13 X= Me, Y= OBn, R= t-Bu, n= 2 ~x OH 14 X= Me, Y= OBn R= n-BuLi, n= 1 15 X= Me, Y=OBn, R= t-BuLi, n= 2 expected that conjugate addition of an organolithium reagent (R3Li) to vinyl sulfones e and E would generate an asulfonyl carbanion which would undergo B-elirnination giving rise to adducts D and F respectively. In this paper we report a full account of our efforts in this field (16) which have resulted in an efficient regioand stereocontrolled methodology to achieve the alkylative bridge cleavage of oxabicyclic vinyl sulfones to produce substituted hydroxycyclohexenyl or cycloheptenyl vinyl sulfones. Ars P ha rmaceutic 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 Preparation of substrates. Scheme III outlines the synthetic routes to obtain vinyl sulfones 26-28 as well as their regioisomers 37-39. The key step of these syntheses is the regioselective addition of sulfenyl halides under kinetic control to bicyc1ic substrates, such as 1 and 2, controlled by remote substitution on C2 (17). Thus, addition of phenylsulfenyl chloride to ketones 2 and 3 followed by functional group manipulations affords chlorosulfides 20, 21 and 22 (20). Altematively, cyanoacetoxy derivative 1 and the endo-benzyl ethers (resulting from reaction of MeMgBr with 2 and 3 (14, 16a) and subsequent benzylation) give rise to regioisomeric chlorosulfides 31, 32 and 33, presumably under steric control (17). Subsequent oxidation and elimination complete the sequence (21). In order to extend the scope of the methodology, we prepared substrates 45, 49 and 55 as shown in Scheme IV (see experimental section). Oxanorbomene methanol 9 was benzoylated and PhSCI was' added with complete steric control (22). Removal ofthe benzoate group and treatment with sodium hydride, interestingly, resulted in smooth formation of vinyl sulfide 43 (23). Standard benzylation and oxidation afforded 45. Altematively, tricyc1ic sulfide 46 (22) was treated with an excess of n-BuLi in an effort to test the applicability of our strain-directed Ars Pharmaceutica, 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, f, 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 or CH3CN, O o c. (b) MeMgBr, Et20 O o c. (e) NaH, BnBr, (eat. n-Bu4Nl for 21 and 32= THF, O oc to reflux. (d) mCPBA, K2 C0 3, O oc to r.t. for 26, 28, 37 and 39; MMPP; MeOH, O oC to r. t. for 27 and 38. (e) DBU, CR2 Cl 2, O oC . (f) 1. NaOMe, MeOR. 2. aq CR2 0, O oC to r.t. (g) Ethyleneglyeol, pTsOR, CJI 6, reflux. Overall yields, 26: 26% from 2; 27: 54% from 3; 28: 62% from 2; 37 : 33% from 5; 38: 64% from 3; 39: see referenee 21. B-eliminations (24) to this case, to afford an excellent yield of vinyl sulfide 47. Vinyl sulfone 49 was prepared as aboye. On the other hand, diol 50 (25) was converted to the highly substituted and differentially protected vinyl sulfone 55 using an analogous synthetic route, i. e., formation of the tricyc1ic sulfide, strained-directed ring opening and functional group manipulations. Alkylative Bridge Cleavage 7-0xabicyclo[2.2.1.}heptenes systems. In view ofprevious efforts involving SN2' additions of organometallic reagents to cyclic vinyl sulfones (26, 27), we selected Grignard, cuprate and organolithium reagents for our study. Preliminary experiments with methyl Grignard and cuprate reagents did not Ar s Pharmaceutica, 36:3; 417-432,1995 422 ARJONA, O. and PLUMET. J. Scheme ¡va Q:(-OH a, b, c,d e, f -J1J -)]J PhS "" '-OH PhS0 2 ""' -08n 9 Z=H 43 43 50 Z=C H2O H_ I bfo,9 b, h for 50 PhS ur g PhS~ e,f 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, pyr, O oC. (b) PhSCl, CHCI3, O oC. (e) NaOMe, MeOH, O oC to r. t. (d) NaH, THF, O oC to r.t. (e) NaH, BnBr, (eat. n-Bu4Nl for 55), THF, r. t. to reflux. (f) MMPP; MeOH, O oC to r. t. (g) n-BuLi, THF, -78 oC . (h) CH2(OMe h, p-TsOH, CH2CI2, reflux. OveralI yields, 45: 61 % froro 9; 49: 58% froro 46; 55 : 37% froro 50. produce the desired transformation. Accordingly, we examined the reaction between 37 and an excess of MeLi (3 equiv, -78 oC, THF, 10 min) and an excellent yield of 56a was obtained. Encouraged by this smooth transformation, we explored other organolithium reagents and these results are gathered in Table 1. In clear contrast to MeLi, the reaction between 37 and nBuLi (2 equiv, THF) was remarkably slow, even at O oC, and, more importantly, the isolated yield of 56b were very low and variable amounts of other byproducts, tentatively characterized as desulfonylated 37 and 56b , were also produced. After considerable experimentation, we found that the use of toluene, a less coordinating solvent (28) afforded excellent yields of alkylative opening product 56b (entry 2). Similarly, PhLi and vinyllithium (29) (2 equiv) gave excellent yields of 56c and 56d respectively (entries 3 and 4). While we do not fully understand the differences found between MeLi and n-BuLi in THF, the crucial effect of the use of toluene for the latter is noteworthy (30). Ars Pharmaceutica, 36:3; 417-432,1995 SULFONE D1RE CTED ALKYLA TIVE BRIDGE CLEA V AGE OF OXABICYCLlC VINYL... 423 Table I. - SN2' Opening Reactions of 7 -0 xanorbomenic Vinyl Sulfones with Organolitium Reagents and LiAllI4 Entry lb 2C 3C 4C 5b 6c 7d 8d 9d JO b Il b 12b 13 b 14b 15 d,f 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 1jt 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 Substrate R Product 37 Me 56a 37 nBu 56b 37 Ph 56c 37 Vinyl 56d 39 Me 56e 45 Me 56f 45 n-Bu 56g 45 AlIyl 56h 45 2-Propenyl 56i 39 He 56j 26 He 57a 26 Me 57b 28 Me 57c 49 Me 57d 49 IHexynyl 57e 49 2-Furyl 57f 55 Me 57g Yi el d( %)" 87 78 86 95 85 81 78 64 67 62 65 80 75 82 74 69 88 NOTES: aUnoptimized yields of pure prod ucts. bIn THF, - 78 oc . cIn Toluene, -7 8 oC. dIn a mixture ToU Etp , 1:1, - 78 oC. eLiAlH4. fO o c. Ars Pharmaceutica, 36:3; 417-432, 1995 424 ARJONA, O. and PLUMET. J, To explore the anticipated regiocontrolled bridge opening, vinyl sulfone 26 was treated with MeLi, and adduct 57b resulting from nucleophilic addition to C-6 and subsequent B-elimination was obtained in good yield (entries 11 and 12). Similarly, ketals 28 and 39 smoothly produced cyclohexenyl sulfones 57c and 56e (entries 13 and 5) respectively. The methodology was also applied to substrates 45, 49 and 55 with similar results (entries 6-9 and 14-17). Other synthetically useful organolithium reagents such as allyllithium (31 , 32), 2furyllithium (33) and l-hexynyllithium (34) were also employed with similar results. In order to extend the scope of this methodology, the reactions between oxanorbornenic sulfones 26 and 39 and lithium aluminum hydride (4 molar equiv, -78 oC) were studied. Thus, fair yields of cyclohexenyl sulfones 57a and 56j were realized in what, to our knowledge, is the frrst case of SN2' displacements of a hydride reagent onto a vinyl sulfone (entries 10 and 11) (35). It should be mentioned that the reaction was very dependent on the amount of hydride used and on the reaction temperature. Thus, saturated sulfone 59 (Scheme V) was obtained at O oC (4 molar equiv LAR); however, at -78 oC (1.5 molar equiv LAR), bicyclic sulfone 58 (49%) was the major product. 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 regioand stereochemistry of these products were readily established by spectroscopic techniques, particularly by 'H NMR with the aid of selective decouplings and DNOE experiments. For instance, 56a and 57b presented quite different splitting patterns for the vinylic protons (56a, d, J = 1.3 Hz; 57b, ddd, J= 5.4,3.0 ,2.4 Hz). In addition, H-l exhibits a trans diaxial coupling (12.6 Hz) in 56a and an equatorial-axial coupling (3.7 Hz) in 57b. The large homoallylic coupling found for 57b (J 25ax = 3.0 Hz) is also noteworthy. 8-0xabicyclo[3.2.1.}octenesystems. The extension of this methodology to 8oxabicyclic[3.2.1.]octene sulfones 27 and 38 was explored in order to assess the influence of a less strained oxygen bridge in the overall SN 2' process. Additionally, the synthetic potential of the resulting products (not easily available highly functionalized cycloheptenes) was particularly attractive (36). In this context, Ars Pharmaceuti ca. 36:3; 417-432, 1995