Enolates trans-Boron enolate generation

Whereas carboxylic esters had been considered to be inert under the conditions of boron enolate formation by enolization [2c], Corey s group elaborated protocols that allowed for the generation of boron enolates from esters. Thus, trans-boron enolates 100 result from simple carboxylic esters by deprotonation, while 5-phenyl thiopropionate formed cis-enolate 101 - in accordance with Masamune s observation. In both cases, the C2-symmetric diazaborolidine 99 served as the Lewis acid for enolization (Scheme 2.28) [112]. The stereochemical divergence of ester and thioester has been rationalized by postulating an E2-type elimination mechanism starting from the complex 102 that loses bromide in a... 

Scheme 2.26 Controlled generation of as- and trans-boron enolates from ketones.

The generation of cis-boron enolates from ketones with dialkylboron chlorides and hindered tertiary amines had been known for some time, from the work of Mukaiyama and Evans [13, 48, 87]. However, the synthesis of the corresponding trans-boron enolates remained problematic. Brown addressed this issue, reporting enolization conditions that provide access to either eno-late diastereomer [88]. The stereochemical outcome of ketone enolization was shown to be dependent both on the electronegative group on boron and on the nature of the alkyl substituents. In this regard, the combination of bulky boron ligands (cyclohexyl), a boron chloride derivative, and an unhindered base (EtjN) proved optimal for the stereoselective synthesis of trans-enolates (166) from a variety of ketones (Scheme 4.16). 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

Scheme 5 details the asymmetric synthesis of dimethylhydrazone 14. The synthesis of this fragment commences with an Evans asymmetric aldol condensation between the boron enolate derived from 21 and trans-2-pentenal (20). Syn aldol adduct 29 is obtained in diastereomerically pure form through a process which defines both the relative and absolute stereochemistry of the newly generated stereogenic centers at carbons 29 and 30 (92 % yield). After reductive removal of the chiral auxiliary, selective silylation of the primary alcohol furnishes 30 in 71 % overall yield. The method employed to achieve the reduction of the C-28 carbonyl is interesting and worthy of comment. The reaction between tri-n-butylbor-... 

Having discussed a qualitative picture for how configurationally pure enolates can be synthesized (with a mnemonic for the trends discussed above in the boxed sections of Scheme 1), we can finally discuss their reaction with aldehydes in aldol reactions. In theory, up to four different reaction products can be generated in any given aldol reaction since two new stereocenters can be created by the process. In reality, because boron enolates react in tight tran-... 

Thioesters give trans-hoion enolates 96 when treated with dicyclopentylboron triflate in the presence of Hiinig s base, as shown in Scheme 2.27 for t-butyl propanethioate [109] — a protocol that has been applied for the generation of the chiral boron enolate 97 featuring a C2-symmetric borolane moiety [110]. However, the stereoselectivity in enolate formation can be reversed by starting from phenyl (rather than from alkyl) propanethioate so that cis-enolate 98 forms exclusively [111] - a result that might originate from thermodynamic control [100]. 

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