Stereoselective Simmons–Smith Cyclopropanation of Chiral Enamides

Abstract

Efficient and practical access to chiral aminocyclopropanes is secured by the title reaction (see example). Both E and Z enamides undergo the cyclopropanation with high diastereoselectivity (d.r. up to >95:5). The application of this methodology to the synthesis of biologically significant aminocyclopropanes illustrates the potential of chiral enamides as useful building blocks for stereoselective organic synthesis.

Isomerization of N-Allyl Amides To Form Geometrically Defined Di-, Tri-, and Tetrasubstituted Enamides

“…This supports the proposed mechanism, since both substitutions would lead to additional A 1,3 -strain in the proposed π-allyl intermediate. The importance of both coordination of the amide and double activation of the C-H (allylic and α to the amide) is supported by competition experiments between allyl benzamide 3a and either 16 or 17 .…”

“…39 However, we were surprised to find that, under traditional hydroboration conditions, we instead formed the product from α addition to give the α-borylamido complex 14b . Mechanistically the reversal in selectivity may arise from the increased A 1,3 strain experienced for tetrasubstituted enamides. 40 To minimize strain, rotation of the C vinyl -N bond could lead to intramolecular delivery of borane through coordination with the amide oxygen becoming faster than intermolecular addition of the borane to the tetrasubstituted enamide.…”

Synthesis of amido-spiro[2.2]pentanes via Simmons–Smith cyclopropanation of allenamides

“…We had previously examined Simmons-Smith cyclopropanations of chiral enamides and achieved a much greater success in stereochemical control 17. As shown in Scheme 4, chiral E -enamides such as 18 and E - 19 gave amido-cyclopropanes 20 and trans - 21 with diastereomeric ratios of 95:5 and 83:17, respectively, while chiral Z -enamides such as 22 and Z - 19 led to even higher diastereomeric ratios of ≥95:5 in each case.…”

“…To the best of our knowledge, preparation of amino-spiro[2.2]pentanes directly through bis-cyclopropanations of 1-amino-allenes is not known 2,10–13,16. Our recent interest17,18 in cyclopropanations of enamides13,19,20 en route to optically enriched amino-cyclopropanes21,22 coupled with our decade long efforts in developing the chemistry of allenamides23–26 allowed us to envision the possibility of developing a direct construction of amido-spiro[2.2]pentanes via Simmons-Smith cyclopropanation of allenamides 1 [Scheme 1]. Based on our previous work on a number of different stereoselective cycloaddition manifolds employing allenamides,27 we anticipated that this cyclopropanation could proceed stereoselectively in which the zinc carbenoid can approach the bottom π-face of the more favored conformer 1a [Scheme 1].…”

A Highly Regio- and Stereoselective Synthesis of α-Fluorinated Imides via Fluorination of Chiral Enamides

“…We had calculated that the most stable conformation of these chiral enamides being that the chiral oxazolidinone ring is essentially coplanar with alkene to maximize the delocalization of nitrogen lone pair into the olefin. 24 With this conformational preference, the chiral oxazolidinone auxiliary plays a distinct role in providing a key facial bias for the fluorine to approach from the Si -face as represented in ent - 3d . Subsequent trapping of the N -acyl iminium ion A with water can in principle be stereoselective, but this stereochemical information is lost in the ensuing oxidation.…”