Full details of the development of a direct coupling of catharanthine with vindoline to provide vinblastine are described along with key mechanistic and labeling studies. Following an Fe(III)-promoted coupling reaction initiated by generation of a presumed catharanthine radical cation that undergoes a subsequent oxidative fragmentation and diastereoselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)-NaBH 4 /air solution leads to oxidation of the C15′-C20′ double bond and reduction of the intermediate iminium ion directly providing vinblastine (40-43%) and leurosidine (20-23%), its naturally occurring C20′ alcohol isomer. The yield of coupled products, which exclusively possess the natural C16′ stereochemistry, approaches or exceeds 80% and the combined yield of the isomeric C20′ alcohols is >60%. Preliminary studies of Fe(III)-NaBH 4 /air oxidation reaction illustrate a generalizable trisubstituted olefin scope, identified alternatives to O 2 trap at the oxidized carbon, provides a unique entry into C20′ functionalized vinblastines, and affords initial insights into the observed C20′ diastereoselectivity. The first disclosure of the use of exo-catharanthine proceeding through Δ 19′,20′ -anhydrovinblastine in such coupling reactions is also detailed with identical stereochemical consequences. Incorporating either a catharanthine N-methyl group or a vindoline N-formyl group precludes Fe(III)-promoted coupling, whereas the removal of the potentially key C16 methoxy group of vindoline does not adversely impact the coupling efficiency. Extension of these studies provided a total synthesis of vincristine (2) via N-desmethylvinblastine (36, also a natural product), 16-desmethoxyvinblastine (44) and 4-desacetoxy-16-desmethoxyvinblastine (47) both of which we can now suggest are likely natural products produced by C. roseus, desacetylvinblastine (62) and 4-desacetoxyvinblastine (59), as well as a series of key analogues bearing systematic modifications in the vindoline subunit. Their biological evaluation provided additional insights into the key functionality within the vindoline subunit contributing to the activity and sets the foundation on which further, more deep-seated changes in the structures of 1 and 2 will be explored in future studies.

The catalytic asymmetric epoxidation of alpha,beta-unsaturated amides using Sm-BINOL-Ph3As=O complex was succeeded. Using 5-10 mol % of the asymmetric catalyst, a variety of amides were epoxidized efficiently, yielding the corresponding alpha,beta-epoxy amides in up to 99% yield and in more than 99% ee. Moreover, the novel one-pot tandem process, one-pot tandem catalytic asymmetric epoxidation-Pd-catalyzed epoxide opening process, was developed. This method was successfully utilized for the efficient synthesis of beta-aryl alpha-hydroxy amides, including beta-aryllactyl-leucine methyl esters. Interestingly, it was found that beneficial modifications on the Pd catalyst were achieved by the constituents of the first epoxidation, producing a more suitable catalyst for the Pd-catalyzed epoxide opening reaction in terms of chemoselectivity.

Catalytic asymmetric cyclopropanation of enones with dimethyloxosulfonium methylide using a La−Li3−(biphenyldiolate)3 + NaI complex is described. The present method is complementary to the previously reported catalytic enantioselective methods in terms of ylides used, and trans products were exclusively obtained in good yield (96−73%) and high enantioselectivity (99−84% ee). Use of biphenyldiol 1b-H2 and NaI additive was essential to achieve high enantioselectivity.

No abstract

Chiral a-and b-hydroxy amides are useful building blocks for the synthesis of biologically active compounds.[1] The synthesis of these intermediates in both a regio-and stereoselective manner, however, is difficult. There are only a few methods for the synthesis of such chiral units, and their substrate scope and selectivity remain unsatisfactory.[2] The regioselective epoxide-opening reaction of optically active a,b-epoxy amides is one of the most attractive approaches to this problem. We [3] and Aggarwal's group [4] recently succeeded in developing efficient strategies to obtain a,b-epoxy amides in a highly enantioselective manner. There are no reports, however, on regioselective epoxide-opening reactions of a,b-epoxy amides, [3,5] in contrast to the success with a,b-epoxy ketones.[6] We report herein a new synthesis of nearly enantiomerically pure a-and b-hydroxy amides with high substrate generality, which consists of a novel highly regioselective epoxide opening of both b-alkyl-and b-arylsubstituted a,b-epoxy amides (Scheme 1). An efficient enantioselective synthesis of (R)-fluoxetine, using the newly developed method, is also described.To realize the highly regioselective epoxide-opening reactions of a,b-epoxy amides, it is important to control the relative reactivity of the a-and b-positions, which depends on the b-substituent. Thus, we discuss the reactions of the b-arylsubstituted amide (paths A and B) and of the b-alkylsubstituted amide (paths C and D).We recently described the highly enantio-and regioselective synthesis of b-aryl a-hydroxy amides using a one-pot, tandem process consisting of catalytic asymmetric epoxidation and a Pd-catalyzed epoxide opening (path A). The selectivity was based on the higher reactivity of the b-position (benzyl position) over that of the a-position.[3] The higher reactivity of the b-position, however, make it difficult to obtain b-hydroxy amides through cleavage of the C a ÀO bond (path B). Indeed, the general conditions for selective cleavage of the C a ÀO bond in a,b-epoxy ketones, such as SmI 2 and [Cp 2 TiCl 2 ]/Zn, [6,7] gave unsatisfactory results (trace amounts) with a,b-unsaturated and -saturated amides as the major products. To overcome this difficulty, we examined a so-called intramolecular hydride transfer using Red-Al (sodium bis(2-methoxyethoxy)aluminum hydride), [1c, 8] which might react with NÀH first to produce a NÀAl species; the remaining hydride attacks the a-position of the epoxy amide (see Figure 1). As we expected, the reduction of 2 a with Red-Al gave b-hydroxy amide 5 a [7] as the major product in moderate yield (Table 1, entry 1). This result prompted us to optimize the reaction conditions.To gain insight into the reaction mechanism, especially for the counterion effects, calculations were performed by means of the hybrid density functional method (B3LYP [9] ) using a 6-31G(d) basis set. As shown in Figure 1, the coordination of a sodium ion to the epoxide and carbonyl oxygen atoms should weaken the C b ÀO bond (D b = 0.0315 ) more effectively ...