Abstract

The 1,4-O , O' -dicarbamate 5 , derived from ( S )-2-(dibenzylamino)butane-1,4-diol, is prepared from L -aspartic acid in three synthetic steps. Deprotonation with sec -butyllithium removes the 1-pro-S proton with essentially complete substratecontrolled diastereoselectivity. The resulting chiral lithium compound 7 is configurationally stable and reacts stereospecifically with retention of the configuration at C-1 with a large number of electrophiles. A good level of enantiofacial selectivity is observed in the addition reaction of 7 with achiral aldehydes. Medium kinetic resolution was observed with racemic 2-alkylcyclohexanones. Quite generally, the reagent 7 achieves the nucleophilic introduction of the (protected) stereohomogeneous 2-amino-1,4-dihydroxybutanide fragment. Decarbamoylation is best achieved by reduction with LiAlH 4 . Deuteration of the 1-pro-S position provides efficient protection against deprotonation in the 1-position owing to a large kinetic H/D-isotope effect. The (-)-sparteinemediated deprotonation therein removes the 4-pro-S -H, which also was achieved for the 1-methylthio-and the 1-phenylthio derivative. The combined strategy makes possible the stereocontrolled chain-elongation of the 2-amino-1,4-dihydroxybutane unit at both termini by C -electrophiles.

A flexible system of building blocks can be used for the synthesis of the potential enzyme inhibitors 1 and 2 (n = 1, 2) in high enantiomeric purity. The regiochemistry of the deprotonation is determined by the reaction conditions. 1, ω‐Alkanediols 1 and 2 are available from (S)‐aspartic and (S)‐glutamic acid, respectively; a variety of electrophiles El can be added at C‐1 or C‐ω.

Abstract

Differentially protected 1-O -and 4-O -monocarbamates, derived from ( S )-2-(dibenzylamino)butane-1,4 -diol are prepared and investigated with respect to their capability of being deprotonated and forming the corresponding lithium carbanions. In the 1-O -trityl and methyl 4-O -monocarbamates 6a and 6b the pro -S -4-H is removed by sec -butyllithium/(-)-sparteine with high diastereoselectivity. The 1-O -(2-methoxyethyl) 4-O -monocarbamate (23e) undergoes a highly selective, substrate-controlled abstraction of the pro -S -4-H without addition of any diamine. On the other hand, the 4-O -methyl 1-O -monocarbamate 7a reacts with sec -butyllithium in diethyl ether with essentially complete stereoselectivity and forms the bicyclic chelate 33 complex with ( S )-configuration at the lithiated C-1 atom. Trapping by means of iodomethane, CO 2 , and other electrophiles proceed with complete stereoretention. The method is applied for the synthesis of Boletus toxin (2 S ,4 S )-γ -hydroxy-norvaline in the form of the lactone hydrochloride. Further, evidence was found that the 2-(dimethylamino) group in the 1-O -TBDMS 4-O -monocarbamate 16 induces a highly substrate-controlled deprotonation in the (4 S )-position.Several methods have been developed in order to differentiate the two carbonyl groups in ( S )-aspartic acid. 5 Fur- Monocarbamates, Derived from ( S )-2-(Dibenzylamino)butane-1,4-diol, and the Influence of the Second O -Protecting Group on the Regioselectivity of Deprotonation -Application to the Synthesis of the Boletus Toxin (2 S ,4 S )-γ -Hydroxy-norvalinether approaches utilize different ( S )-amino acids with a four-carbon backbone such as ( S )-methionine, 5g, 6 ( S )asparagine 7 or the expensive 8 ( S )-homoserine for starting materials. Scheme 1Downloaded by: University of Illinois at Chicago. Copyrighted material.