Hydroboration asymmetric synthesis using

As an alternative to the stoichiometric enantioselective hydroboration, catalytic hydroboration using chiral catalysts has been also developed for enantioselective hydroboration The catalytic hydroboration-amination methodology has been successfully applied as a one-pot reaction for the asymmetric synthesis of primary... 

Pyrrolidines are an important class of five-membered heterocycles with noteworthy biological properties [46]. In addition to pharmaceutical applications, the pyrrolidine moiety has also been widely used as a chiral auxiliary for asymmetric synthesis [47]. Although many elegant syntheses of chiral nonracemic pyrrolidines have been reported within the past decade or so [48-50], an alternative approach based on the intramolecular reaction of an azide and organoborane has been developed very recently [51-53], This approach utilizes the hydroboration-azide alkylation tandem reaction as a key sequence, taking advantage of the efficient stereocon-trolled steps. Scheme 20 shows an application of the synthesis of 3-substituted 5-(2-pyrrolidinyl)isoxazole which has been found to have nanomolar activity, comparable to (5)-nicotine, against whole rat brain [54]. 

Asymmetric hydroboration and conceptually similar reactions involving chiral reagents have been used with great success. Their principal shortcoming is that stoichiometric quantities of chiral compounds must be invested and only rarely can these compounds be recycled. An asymmetric reaction involving a catalyst that is chiral would be a superior way to accomplish an asymmetric synthesis since, with only a small amount of chiral material, large quantities of optically active product could, in principle, be obtained. 

Because it is often possible to control the stereochemical orientation of substituents on a cyclic array, Baeyer-Villiger cleavages of substituted cyclic ketones have been used extensively in the stereocon-trolled syntheses of substituted carbon chains. An asymmetric synthesis of L-daunosamine intermediate (30) from a noncarbohydrate precursor employed the cyclopentenol (28), prepared in optically pure form (95% ee) from 2-methylcyclopentadiene using asymmetric hydroboration (Scheme 8). Stereoselective epoxidation, conversion to Ae ketone and regioselective Baeyer-Villiger oxidation afforded lactone (29). 

The first substrate which was asymmetrically hydroborated using IPC2BH was c/s -2-butene, and the enantiomeric purity of the product 2-butanol (87% ee) obtained in this preliminary experiment was spectacular (eq 2), since Ipc2BH was made from a-pinene of low optical purity. This reaction represents the first nonenzymatic asymmetric synthesis for achieving high enantioselectivity. Its discovery marked the beginning of a new era of practical asymmetric synthesis obtained via reagent control. ... 

The asymmetric synthesis of Gliflumide is still underway. We are near the conq)le-tion of the synthesis, and thus far we have definitively shown that the hydroboration protocol can be used with more conqilicated aryl systems than simple monosubsti-tuted styrenes. 

The first enantioselective asymmetric synthesis with ee in the range of 90% was the asymmetric hydroboration of alkenes desoibed in 1961 by H. C. Brown et al. In this cl sic study (Rgure 3), (R)-(-)2 butanol of 90% ee was isolated using ccmunercial (+)-a-pinene of about 90% ee. More recently, the authors prepared enantiopure a-pin ie and wo e able to produce 2-butanol with 98% ee. Asynunetric hydroboration became an established and an important class of asymmetric syntheses with very high ee s. 

In addition to the enhanced rate of hydroalumination reactions in the presence of metal catalysts, tuning of the metal catalyst by the choice of appropriate ligands offers the possibility to influence the regio- and stereochemical outcome of the overall reaction. In particular, the use of chiral ligands has the potential to control the absolute stereochemistry of newly formed stereogenic centers. While asymmetric versions of other hydrometaUation reactions, in particular hydroboration and hydrosi-lylation, are already weU established in organic synthesis, the scope and synthetic utiHty of enantioselective hydroalumination reactions are only just emerging [72]. 

The typical technologies used for the preparation of amines have also been used for the synthesis of optically pure (R)- or (S)-l-aminoindane. For example, resolution approaches include the diastereoisomeric salt formation of racemic A-bcnzyl- l -aminoindane with (,S )-mandclic acid41 or (R,R) tartaric acid,42 which resulted in, after hydrogenation, (R)-l-aminoindane with >99% ee. Also, resolutions that use enzymatic acylation concepts have been described.43 44 The maximum theoretic yield of 50% is a clear limitation of these methods. Asymmetric synthetic approaches to chiral 1-aminoindanes have been described, including enantioselective hydrosilylation of l-indanoxime45 46 and hydroboration of indene 47 However, ee values were low to moderate. 

This possibility of intimate association of rhodium with the aromatic ring suggests further experiments. A logical extension of asymmetric syntheses involving prochir-al reactants is a kinetic resolution with related chiral reactants under similar conditions. In the one case of hydroboration-amination where this has been applied, it has proved to be very effective. The reactant was prepared directly by a Heck reaction on 1,2-dihydronaphthalene, and under the standard conditions of catalytic hydrobora-tion gave >45% of both enantiomerically pure recovered alkene with (after oxidative work-up) the alcohol of opposite hand, mainly as the trans-isomer. This procedure forms a simple and potentially useful route to pharmacologically active substances, demonstrated by the racemic synthesis shown [105] (Scheme 34). 

The ability of diisopinocampheylborane to hydroborate Z-alkencs with a high level of asymmetric induction has been used in the synthesis of natural products, e.g., loganin60, prostaglandins61,62 and carotenoids63. Deuterated alcohols have been obtained by the deu-teroboration of terminal and internal alkenes or by the hydroboration of deuterated alkenes55,56-64-66. 

Asymmetric hydroboration using IpC2BH was also applied in the stereocontrolled synthesis of a linearly fused triquinane, (+)-hirsutic acid (eq 1) ... 

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