Diastereoselective halogenations

Diastereoselective halogenations using removable chiral auxiliaries have been the purpose of recent significant developments. a-Halo aldehydes, a-halo ketones and a-halo carboxylic acid derivatives are very useful precursors involved for total syntheses of pharmaceutical drugs and phytochemicals. In most cases, the biological activity is associated with one of the two enantiomers. So, diastereoselective halogenation of carbonyl compounds and carboxylic acid derivatives has attracted considerable attention in recent years, as a tool for the production of enantiomerically pure substances. The numerous examples of diastereoselective halogenation of compounds with non removable chiral adjuvants are outside the scope of this review. 

Halogen-lithium exchange of iodide 71 and subsequent addition of 2-acetyl-furan (72) to the resultant organolithium intermediate yielded two diastereomeric tertiary alcohols (dr=l l), which were converted to (E)-olefin 73 with complete diastereoselectivity upon brief exposure to catalytic amounts of concentrated aqueous hydrogen chloride (Scheme 11) [18]. Diastereoselective hydroboration/oxidation of 73 gave largely the desired stereoisomer 74 due to... 

Whereas the halogen-lithium exchange is of limited importance for the generation of a-lithiated ethers, the reductive lithiation of 0/S-acetals has been applied more frequently, the versatility being enhanced by remarkable diastereoselective variants. Thus, a single diastereomer of the lithium carbenoid 52 results from the diastereomeric mixture 51 (equation 34) . Representative examples of a-lithiated ethers generated by this method and their reactions with electrophiles are given in Table 4. 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

The addition of an allyl metal to a-amino aldehydes has been used by Vara Prasad and Rich (Scheme 12)J23l After the addition step, the allyl group is oxidized to a carboxylic acid and lactonized. Then, the a-carbon of the lactone is alkylated stereoselectively. These investigators also systematically examined the addition reaction to determine its diastereo-selectivity. The highest diastereoselectivity was obtained when allyltrimethylsilane was used in the presence of tin(IV) chloride. An increase in the steric bulk of the protecting group and of the side chain also resulted in a better diastereoselection. Alternatively, Taddei and co-workers 24-26 used a 2-(halomethyl)allylsilane and the side chains were introduced by nucleophilic substitution of the halogen (Scheme 13). 

Examples of radical-mediated C-alkylations are listed in Table 5.4. In these examples, radicals are formed by halogen abstraction with tin radicals (Entries 1 and 2), by photolysis of Barton esters (Entry 3), and by the reduction of organomercury compounds (Entry 4). Carbohydrate-derived, polystyrene-bound a-haloesters undergo radical allylation with allyltributyltin with high diastereoselectivity (97% de [41]). Cleavage from supports by homolytic bond fission with simultaneous formation of C-H or C-C bonds is considered in Section 3.16. 

The Lewis acid catalyzed conjugate addition of allylsilanes (140) to (142) and allylstannanes (154) and (155) to ot,0-enones, described by Sakurai,68a,68b is highly efficient and experimentally simple in contrast to the allylcuprate additions. Various substituents can be incorporated into the allylsilanes (allylstannanes), e.g. alkoxy, alkoxycarbonyl and halogen, some of which are incompatible with cuprate reagents 69 In addition, Heathcock and Yamamoto report that diastereoselectivity is correlated to the alkene geometry of both the allylmetals and the acceptor units for example, allylation of ( )-enones (143) and (146) affords predominantly the syn adducts (144) and (147), while (Z)-enone (149) gives predominantly the anti adduct (150 Scheme 25).680 On the other hand, with cyclohexen-2-one the (Z)-silane (141) affords predominantly the threo adduct (152), while (142) affords erythro adduct (ISS).686 The more reactive allylstannanes (154) and (155) also afford similar diastereoselectivity.68e,f... 

Application of the halogenation of y-aminoolefins preceding intramolecular cyclization has been applied to the synthesis of fused piperidines (Equation 33) <2003CC1918>. The presence of chiral substituents (e.g., via the nitrogen protecting group) generates a diastereoselective reaction (Equation 34). 

The halogen-metal exchange of one of a geminal pair of bromine atoms is readily achieved -a carbenoid is formed which may have sufficient stability to react as an organolithium before decomposing to a carbene by a-elimination.. m in cyclic systems, diastereoselectivity in this process has long been known,114116 though the outcome of reactions such as that of 137 is under a mixture of kinetic and thermodynamic control.117... 

Of similar nature are chiral halogenations using auxiliary groups. Typical examples are the conversion of esters to enantiomerically pure halohydrins (precursors to chiral epoxides) using camphor-10-sulfonic acid derivatives583 and the chiral synthesis of a-amino acid synthons via diastereoselective bromination of TV-acyl oxazolidone derivatives584. 

An interesting diastereoselectivity pattern was observed when a-halogen-sub stituted allylboronates were added to aldehydes. In this reaction, (Z)-alkenes were obtained as the major products7 (Scheme 3.VII). Hoffmann and Landmann explained the results by examining two competing six-membered chairlike transition states (Scheme 3.VIII). Among the possible factors that favor the transition state A, they pointed out that dipole-dipole interactions could play a dominant... 

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