Vanadium‐Catalyzed Enantioselective Desymmetrization of meso Secondary Allylic Alcohols and Homoallylic Alcohols

Kinetic resolution of secondary allylic or homoallylic alcohols is one of the most important synthetic protocols to provide enantiomerically enriched epoxides, especially those carrying several continuous chiral centers. These chiral building blocks could be very useful for the asymmetric synthesis of natural products and biologically active substances. Many efficient protocols have been developed to satisfactorily mediate the kinetic resolution of allylic alcohols.[1] Recently, we reported a new bis-hydroxamic acid (BHA) ligand for the enantioselective vanadium catalyzed asymmetric epoxidation as well as kinetic resolution of allylic and homoallylic alcohols (Scheme 1).[2,3] Scheme 1 Asymmetric Epoxidation and Kinetic Resolution of Allylic and Homo-allylic Alcohols Catalyzed by Vanadium-BHA Complexes However, the intrinsic problem of kinetic resolution is that the maximum yield is 50%. Half of the starting material is considered undesired compound after the reaction. On the other hand, desymmetrization of meso-secondary allylic and homoallylic alcohols, which shares the same principle of facial discrimination of olefins with kinetic resolution, does not have this limitation because in theory all the starting material can participate in the reaction. Therefore, it should be more efficient than kinetic resolution in providing optically pure epoxy alcohols bearing at least two stereo centers. Several meso-secondary allylic alcohols have been successfully desymmetrized by Sharpless Asymmetric Epoxidation reaction,[1b, 4] and applied in stereo-selective natural product synthesis.[5] However, cis-substituted meso-secondary allylic alcohol substrates could not provide satisfactory enantioselectivities. Additionally, catalyst loading for Sharpless system catalyzed desymmetrization was usually high, even higher than stoichiometric.[1b] Our vanadium-BHA system has several features that would facilitate this reaction, such as low catalyst loading, tolerance of aqueous peroxy oxidants, mild reaction conditions and easy work-up procedures. Using our vanadium-BHA catalytic asymmetric epoxidation system, several typical meso-secondary allylic alcohols: such as trans-, cis-, unsym-, and un-substituted divinyl carbinols, were all desymmetrized into corresponding epoxy allylic alcohols in high stereoselectivities and good yields (Table 1). Table 1 Desymmetrization of meso-Secondary Allylic Alcohols Since we had modified reaction conditions for the vanadium catalyzed asymmetric epoxidation in our previous study, we then applied ligands 1a–1c to the desymmetrization reactions under the optimal conditions. 1.0 mol% catalyst loading was used. As we found in our previous study, ligand 1a provided trans-substituted and unsym-substituted substrates with excellent enantioselectivities, while 1b was suitable for cis-substituted substrates. The reactions also provided high diastereoselectivities and good yields. The simplest product in this category, 1,2-epoxy-4-penten-3-ol (3e) was generated with 95% ee when more bulky ligand, 1c, was used. CHP was better than aqueous TBHP in facilitating the transformation for 3e. The absolute configuration of epoxy alcohol 3e was determined as (2S, 3R), by comparison with literature NMR data and optical rotation.[6] Absolute configurations of epoxy alcohols 3a–d were concluded from that of 3e and kinetic resolution results of secondary allylic alcohols.[2] With these successful results in hand, we applied this catalyst system in the asymmetric epoxidation of meso-secondary homoallylic alcohols, which had been an unsolved problem of asymmetric synthesis (Table 2). Substrates bearing cis-substituents at the double bonds provided excellent yield and ee, while trans-counterparts did not proceed as satisfactorily. Table 2 Desymmetrization of meso-Secondary Homo-allylic Alcohols Although our previous study showed that temperature does not significantly affect the enantioselectivity of homoallylic alcohol epoxidation,[3] here a lower temperature (0°C) is necessary to achieve excellent ee values. As a result, the reaction time required was lengthened (Table 2, entries 5 and 6). These substrates are typical examples of ‘combination of enantiotopic groups and diastereotopic faces’.[4b] Studies from Schreiber proved that these reactions could provide higher stereoselectivities but lower yields in longer reaction time.[4b, 8] This is applicable in our reaction as well. Enantiotopic groups are the two double bonds, while diastereotopic faces are two faces of each double bond. Given longer reaction time, substrate 4a underwent desymmetrization with constantly increasing ee% and diastereomeric ratio, while the yield had a peak value at about 200hrs. (Table 2, entries 1–3) In order to decrease the reaction time while retaining high enantioselectivity and acceptable yield of product 5a, we attempted to apply 2 mol% catalyst loading to the system. The combination of lower temperature and higher catalyst loading provided the best result of this study. (Table 2, entry 4). Stereospecific base-catalyzed epoxide ring hydrolysis of epoxy alcohol 5a provided a 1, 2, 4-triol of which the absolute configuration has been established (Scheme 2).[7] Therefore, the absolute configuration of 5a was determined as (2R, 4R). These results further supported our previous mechanism hypothesis on the vanadium-BHA catalyzed epoxidation.[3] Scheme 2 Absolute Configuration Determination of 5a To the best of our knowledge, our highly stereoselective synthesis of compound 5a is the first time this very promising synthetic intermediate has been accessed.[9] Existing direct epoxidation methods of 4a can only provide poor conversion.[10–13] Indirect approaches include either compromising with its racemic mixture obtained by iodo-lactonization,[14, 15] synthesizing via multiple steps from chiral pool compounds such as (−)-(S)-malic acid,[16] or use of Jacobsen’s hydrolytic kinetic resolution of the racemic mixture.[9] This is true even though 5a has been used in several academic and industrial syntheses, including the racemic mixture of the crucial intermediate of the famous cholesterol control medicine atorvastatin, i.e. Lipitor®.[9, 14–16] Now that we have developed a highly stereoselective desymmetrical synthesis of compound 5a, all those procedures can be circumvented. Thus, we believe more syntheses based on our progress will soon become available. In conclusion, we have successfully applied our vanadium-BHA catalyst system to the highly enantioselective desymmetrization of meso-secondary allylic and homoallylic alcohols. Further studies focusing on improvements of the catalytic conditions are in progress.