Asymmetric Acylation of sec-Alcohols with Twisted Amides Possessing Axial Chirality Induced by the Adjacent Asymmetric Center

Abstract

This paper reports that axially chiral twisted amides serve as asymmetric acylating agents for sec-alcohols under neutral conditions. Kinetic resolution of various racemic sec-alcohols and desymmetrization of 1,2-, 1,3-, and 1,4-meso-diols were performed by using the twisted amides. The utility of this desymmetrization method was shown by the preparation of the synthetic intermediate 28 for macrolide antibiotic nodusmicin and 18-deoxynargenicin. The stereoselectivity of the acylation reactions is significantly dependent on the bulkiness of both the acyl group and the C-4 substituent of the chiral auxiliary. When an amide possessing an imidazolyl group at C-4 was employed, the stereoselectivity was reversed to give R esters. A possible working model of the acylation reaction is also described on the basis of the structural studies of the twisted amides by IR and 1 H and 13 C NMR spectroscopies and AM1 calculations. These studies suggested that rotamer II is thermodynamically more stable than the others. The rotamer II has an axial chirality about its C(O)-N linkage that is induced by the adjacent chiral center. This would enable discrimination of the two enantiomeric hydroxy groups of the racemic alcohols or meso-diols.

Asymmetric Synthesis of Bicyclic Diol Derivatives through Metal and Enzyme Catalysis: Application to the Formal Synthesis of Sertraline

“…(For yields see Table 1): An analytical sample of (R,R)- .0 ppm; the analytical data for 7 b was in accordance with those previously reported. [27] Procedure for the DYKAT of diol 1 c: Base tBuOK (0.5 m, 0.02 mmol) in THF (40 mL) was added to a flame-dried Schlenk flask under argon. THF was removed under vacuum and the flask refilled with argon.…”

Chemistry of Bridged Lactams and Related Heterocycles

“…67–69 The effect of amide distortion has been leveraged to control chemical transformations 132–140 including hydrolysis, 61–66 acylation, 132–134 desymmetrization 135 and kinetic resolution 136,137 of alcohols. Bridged lactams have been applied as intermediates in the synthesis of bioactive natural products 141–192 and are even present in the structures of several alkaloids.…”

6.08 Acylation-Type Reactions: Synthesis of Esters via Acyl Transfer

“…33,34,46 They proposed a reaction model that could be confirmed by 1 H-NMR measurements, X-ray analysis, and DFT computations. 47 It has been suggested that the selectivities in the KRs of secondary alcohols are because of self-complexation of the acylated catalyst.…”