Stereoselective reactions of chiral α-amino aldehydes

Abstract

Optically active α-amino acids can be converted into the corresponding doubly protected N,N-dibenzyl α-amino aldehydes. These react diastereoselectively with Grignard reagents, lithium enolates and Me 3 SiCN/ZnX 2 to provide the nonchelation-controlled adducts. Molecular modelling explains some of the results. The sense of stereoselectivity can be reversed if Lewis acidic chelating reagents are used. Undesired racemization does not occur.

Synthesis and Diastereoselective Reactions of N,N-Dibenzylamino Aldehydes and Related Compounds

“…Convincing models have been proposed to account for these trends. Upon reacting aldehyde ( R )- 10a (prepared from D -alanine) with reagent 105 , a 10:90 mixture of 106 / 107 was obtained,113a which is similar to the reaction of ( S )- 10a with the titanium reagent 103 (note that this is the enantiomeric series). ,, However, the Z -boronate 108 afforded a 1:1 mixture of 109 / 110 . This means complete simple diastereoselectivity but essentially no diastereofacial selectivity (formally chelation or nonchelation control).…”

“…A different way to obtain the same epoxides with considerably higher degrees of diastereoselectivity is based on the reaction of the reagent PhSCH 2 Li (Table , entry 23) followed by treatment with Meerwein reagent . A third approach was described independently by several groups. ,,,, Accordingly, lithium carbenoids XCH 2 Li (X = Cl, Br, I) were reacted with aldehydes 10 , nucleophilic addition occurring at low temperatures with the expected nonchelation control followed by in situ intramolecular S N 2 reaction of the intermediate β -haloalkoxides at higher temperatures.…”

“…An application is the aldol reaction of isoleucinal 10e which affords adduct 64 exclusively. , This compound has the correct absolute and relative configuration to qualify as a building block in the synthesis of dolastatin-10 ( 65 ), a marine natural product with unusually high antineoplastic activity .…”

“…Upon reacting 10a with crotylmagnesium chloride (which is a mixture of E - and Z -isomers and the regioisomer), a totally unselective reaction was observed . However, prior in situ titanation 18 with Ti(O i- Pr) 4 (which generates reagent 103 selectively) 112 results in essentially only one diastereomer 104 . ,, This implies the usual nonchelation control as well as a high level of simple diastereoselectivity (anti selectivity) expected for E -configurated crotyltitanium reagents.

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