Stereoselective preparation of cyclobutanes with four different substituents: total synthesis and structural revision of pipercyclobutanamide A and piperchabamide G

Abstract

A general strategy was developed for the diastereo- and enantioselective synthesis of cyclobutanes with four different substituents. It consists of three transition metal-catalyzed reactions — a Rh^II-catalyzed cyclopropanation, a Ag^I-catalyzed regioselective and stereospecific ring expansion, and a Rh^I-catalyzed addition reaction. Structures of pipercyclobutanamide A and piperchabamide G were synthesized and revised.

Figure 1

Selected Four-membered Ring Natural Products

Scheme 1

Proposed Strategy for Stereoselective Synthesis of Pipercyclobutanamide A and Piperchabamide G

Scheme 2

Stereoselective Synthesis of Cyclobutenoate Conditions: a) bromoacetyl bromide then TsNHNHTs, DBU; b) 1.0 mol % Rh₂(5S-MEPY)₄, CH₂Cl₂, reflux; c) piperidine, AlMe₃, CH₂Cl₂; d) DMSO, (COCl)₂, Et₃N; e) NaCN, HOAc, MeOH then EtOH/HCl, 0°C 2 days; f) Dess Martin periodinane; g) TsNHNH₂, toluene, 80°C, then DBU, rt; h) 10 mol % AgOTf, CH₂Cl₂

Scheme 3

Stereoselective Synthesis of Proposed Structures of Pipercyclobutanamide A and Piperchabamide G Conditions: a) 5.0 mol % [Rh(COD)Cl]₂, dioxane/H₂O (10:1), 3,4-(methylenedioxy) phenylboronic acid; b) EtONa, EtOH; (c) Pd/C, H₂, EtOH; d) Dess Martin periodinane; e) KHMDS, reagent A, DMF/HMPA; f) DIBALH, Tol; g) KHMDS, reagent B, THF; h) Pd/C, H₂, MeOH.