《有机化学》课程教学资源（文献资料）Asymmetric Addition of Alkylzinc Reagents to Cyclic αβ-Unsaturated Ketones

JACIS COMMUNICATIONS Sang-Jin Jeon and Patrick J.Walsh Received May 23,2003:E-mall:pwalsh@sa penn.edu We recently reported the asymmetric addition of alkylzin Table1.Asymmetric Addition of Alkyl Groups to Cyclic Enones rcaesoketonstusineancaslyprepaKredconsirainetdeome entry substrates ZnR2 time (h)yield (%ee (% R=Me 40 84 ctoaditonrea 2 R=Et 40 76 98 3 R=Me 3 0 55 98 R-E 3T 65 96 ective additic 5 R=Me 40 62 99 6 we of on into the effic t and hi R-E 50 7 R=Me 40 54 95 5 nediiesthalnelhercaboraeladetedpoidtei R-Et 95 9 R=Me 99 10 m。 R=Et 38 32 99 one-pot protocol for thee 11 1 R=Et 19 75 52 is complete 12 50 61 Se Supporting mationforcedctcminationprotocol MeOH 1 HO Me asymmetri addition of alkylzine reagents to aldehydes,it ha and not i ZnR2 +TI(OP0)4 1 (1) 3 1.q)tmp. in 5%and 65%viel nd s shou nEt Aryl-substitute silica gel. Likewis eofZne identical co natedadnylcaDS t山0na conjugate addition.In con enan oselectivity in each id of alkyl substituen 9544■J.AM.CHEM.s0C.2003.1259544-9545 10.1021/la036302t CCC:$25.00 2003 Amgrcan Chomical societ

Asymmetric Addition of Alkylzinc Reagents to Cyclic r,â-Unsaturated Ketones and a Tandem Enantioselective Addition/Diastereoselective Epoxidation with Dioxygen Sang-Jin Jeon and Patrick J. Walsh* P. Roy and Diane T. Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323 Received May 23, 2003; E-mail: pwalsh@sas.upenn.edu We recently reported the asymmetric addition of alkylzinc reagents to ketones using an easily prepared constrained-geometry catalyst.1 A noteworthy aspect of this study is that it offers a solution to a long-standing problem in synthetic organic chemistry: the catalytic synthesis of tertiary alcohols from acetophenone derivatives with high enantioselectivity. In contrast to related addition reactions with aldehyde substrates, which are promoted by hundreds of catalysts,2,3 only a handful of systems will promote additions to ketones,1,4-7 and most of these require high catalyst loadings and long reaction times.5-7 Despite significant effort in this area, we are not aware of successful reports of the enantioselective addition of alkyl groups to conjugated cyclic enones. In this Communication, we report the results of an investigation into the efficient and highly enantioselective 1,2-addition reactions of cyclic R,â-unsaturated ketones. The resulting tertiary allylic alcohols are valuable inter￾mediates that can be further elaborated via directed epoxidation reactions with excellent diastereoselectivities. The resulting epoxy alcohols undergo Lewis acid promoted semipinacol rearrangement to give â-hydroxy-R,R-disubstituted ketones. Furthermore, we have developed a tandem, one-pot protocol for the enantioselective addition/diastereoselective epoxidation simply by capping the reaction with a balloon of dioxygen when the asymmetric addition is complete. Initial evaluation of ligand 1 in the asymmetric addition reaction (eq 1) with ZnMe2 and ZnEt2 indicated that 2-substituted enones are excellent substrates. Thus, as shown in Table 1, treatment of enone 2 with 10 mol % ligand 1, 3 equiv of ZnMe2, and 1.2 equiv of Ti(Oi Pr)4 at room temperature leads to the tertiary allylic alcohol in 84% yield and 99% enantioselectivity after chromatography on silica gel. Likewise, use of ZnEt2 under identical conditions provided the allylic alcohol in 76% yield and 98% enantioselectivity (entry 2). It is significant that the titanium catalyst is chemoselective, giving only carbonyl addition and no conjugate addition. In contrast, copper-catalyzed additions of dialkylzinc reagents to enones give conjugate addition products.8 In a related titanium-BINOL-catalyzed asymmetric addition of alkylzinc reagents to aldehydes, it has recently been definitively demonstrated that the alkyl group is transferred from titanium, and not zinc.9 Thus, the oxophilic Ti￾alkyl adds in a 1,2-fashion, and the soft Cu-alkyl adds in a 1,4- fashion. The scope of the asymmetric ketone alkylation is illustrated in Table 1. Addition of ZnMe2 and ZnEt2 to 2-methyl cyclopentenone exhibits 98% and 96% enantioselectivity in 55% and 65% yield, respectively. Increasing the length of the 2-substituent to pentyl led to an increase in the enantioselectivities to 99% for both ZnMe2 and ZnEt2. Aryl-substituted substrates also underwent alkylation with high enantioselectivity, but with diminished yields due to aldol/ dehydration side reactions. Reactions of 2-phenyl cyclohexenone with ZnMe2 and ZnEt2 both generated allylic alcohol products with 95% enantioselectivity, albeit in 54% and 40% yield. Decreased yields were observed with the exocyclic enone 6, which gave 20% and 32% yield with 99% enantioselectivity in each case. Enones devoid of alkyl substituents R to the carbonyl group are not particularly good substrates, giving 52% and 61% enantioselectivity (entries 11 and 12). Because of Table 1. Asymmetric Addition of Alkyl Groups to Cyclic Enones a See Supporting Information for ee determination protocol. Published on Web 07/22/2003 9544 9 J. AM. CHEM. SOC. 2003, 125, 9544-9545 10.1021/ja036302t CCC: $25.00 © 2003 American Chemical Society

COMMUNICATIONS 器 OH e&OnePolsynmtnesctEpoyANeohalPoatuaswm entry products yield (%) entry substrates 2nR yield (%ee (% 70 R=Me 8299 2 丫2 R-El 8099 89 3 R=Me 5098 4 3 REt 60 97 , 75 0 98 5 R-Me 6 R=Et 609的 73 R=EL 3496 the similar steric eofld afer centers the asvmmetric addition and the epoxidation reaction. The ketone productsare formed as single with References (entries1,2,and 4). ibility of perfo 尚 )mmey2002,13 29 (9)0Carroll,P.J:Walsh.P.Chem.So dioxygen (1am)resulted in complete conversion to the ce of 2 aded reaction is co (16)K T.In Eoo PoeCodoomhatour 51 (7)2.94-5776 JA036302T .AM.cHEM.s0C.V0L.125,N0.32,20039545

the similar steric environments of the oxygen lone pairs, discrimina￾tion of the enantiotopic carbonyl faces of these substrates is quite challenging. The allylic alcohols in eq 1 are valuable chiral building blocks that contain chiral quaternary centers. Such centers are difficult to access, and, therefore, methods to synthesize them have attracted considerable attention.10,11 The Lewis acid-promoted semipinacol rearrangement of R-hydroxy epoxides is another useful method to establish chiral quaternary centers.12,13 Thus, diastereoselective epoxidation of selected allylic alcohols was examined using m-CPBA. The desired syn-epoxy alcohols were obtained in >90% yield. Treatment of the epoxy alcohols with BF3‚OEt2, as shown in eq 2, resulted in semipinacol rearrangement cleanly providing new â-hydroxy-R,R-disubstituted ketones in good yields (Table 2). The ketone products are formed as single diastereomers with no loss of ee in the epoxidation/rearrangement sequence. These densely functionalized products contain chiral all-carbon stereocenters (entries 1, 2, and 4). We next investigated the possibility of performing a tandem one￾pot enantioselective ketone alkylation/diastereoselective epoxidation sequence. Dialkylzinc reagents readily react with dioxygen to provide metal peroxides.14,15 In the presence of titanium tetraiso￾propoxide, hydroperoxides are known to catalyze olefin epoxidation with high diastereoselectivity.16 Performing the addition reaction with ZnEt2 followed by exposure of the reaction mixture to dioxygen (1 atm) resulted in complete conversion to the syn-epoxy alcohol in under 4 h. Epoxidations in the presence of ZnMe2 were very slow. In these reactions, 2 equiv of ZnEt2 was added before exposure to dioxygen. The yields and enantioselectivities of the epoxy alcohols (Table 3) are essentially identical to those of the addition reactions reported in Table 1. Interestingly, the epoxidation reaction outlined here is very different than the Sharpless asym￾metric epoxidation in that our reaction is conducted under basic, aprotic conditions.17 An effective protocol for the enantioselective addition of alkyl groups to cyclic conjugated enones is disclosed. This transformation can be coupled with a diastereoselective epoxidation in which the ultimate oxidant is generated from dioxygen. Rearrangement of the resulting epoxy alcohols provides highly functionalized aldol type products with excellent ee that are not accessible through traditional aldol chemistry. We are currently investigating the mechanism of the asymmetric addition and the epoxidation reaction. Acknowledgment. This work was supported by the NIH (GM58101). Supporting Information Available: Procedures and full charac￾terization of new compounds (PDF). This material is available free of charge via the Internet at http://pubs.acs.org. References (1) Garcı´a, C.; LaRochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10970-10971. (2) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833-856. (3) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824. (4) Yus, M.; Ramo´n, D. J.; Prieto, O. Tetrahedron: Asymmetry 2002, 13, 2291-2293. (5) Ramo´n, D. J.; Yus, M. Tetrahedron Lett. 1998, 39, 1239-1242. (6) Ramo´n, D. J.; Yus, M. Tetrahedron 1998, 54, 5651-5666. (7) Yus, M.; Ramon, D. J.; Prieto, O. Tetrahedron: Asymmetry 2003, 14, 1103-1114. (8) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755-756. (9) Balsells, J.; Davis, T. J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10336-10348. (10) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591-4597. (11) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388- 401. (12) Shimazaki, M.; Hara, H.; Suzuki, K.; Tsuchihashi, G.-i. Tetrahedron Lett. 1987, 28, 5891-5894. (13) Tu, Y. Q.; Fan, C. A.; Ren, S. K.; Chan, A. S. C. J. Chem. Soc., Perkin Trans. 1 2000, 3791-3794. (14) Yamamoto, K.; Yamamoto, N. Chem. Lett. 1989, 1149-1152. (15) Enders, D.; Zhu, J.; Raabe, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 1725-1728. (16) Katsuki, T. In Epoxidation of Allylic Alcohols; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Comprehensive Asymmetric Catalysis; Springer: Berlin, 1999; Vol. 2, pp 621-648. (17) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-5776. JA036302T Table 2. Semipinacol Rearrangement Products Table 3. One-Pot Synthesis of Epoxy Alcohol Products with Oxygen a For reactions with ZnMe2, 1.5-2 equiv of ZnEt2 was added after complete ketone consumption. COMMUNICATIONS J. AM. CHEM. SOC. 9 VOL. 125, NO. 32, 2003 9545