Enantioselective Synthesis of Cyclobutanes via Sequential Rh-catalyzed Bicyclobutanation/Cu-catalyzed Homoconjugate Addition

Abstract

Enantiomerically enriched cyclobutanes are constructed by a three-component process in which t-butyl (E)-2-diazo-5-arylpent-4-enoates are treated with Rh2(S-NTTL)4 to provide enantiomerically enriched bicyclobutanes, which can subsequently engage in homoconjugate addition/enolate trapping sequence to give densely functionalized cyclobutanes with high diastereoselectivity. This three-component, two-catalyst procedure can be carried out in a single flask. Rh2(S-NTTL)4–catalyzed reaction of t-butyl (Z)-2-diazo-5-phenylpent-4-enoate gives the Buchner cyclization product in excellent enantioselectivity.

Rh-Catalyzed Intermolecular Reactions of α-Alkyl-α-Diazo Carbonyl Compounds with Selectivity over β-Hydride Migration

“…40 We developed a complementary approach that gives access to tert -butyl bicyclobutane-1-carboxylates —substrates compatible with subsequent homoconjugate addition reactions. 41 Rh 2 ( S -NTTL) 4 was highly effective in bicyclobutanation reactions of tert -butyl ( E )-2-diazo-5-arylpent-4-enoates, giving bicyclobutane products in 65 – 88% yield and with 71 – 95% ee (Scheme 26). Interestingly, the ( E )- and ( Z )-olefin isomers of the diazoester both provided the identical diastereomer of the bicyclobutane, supporting a stepwise mechanism involving a zwitterionic intermediate.…”

“…However, the diastereomeric ratio was vastly improved upon epimerization with t- BuOK (up to 30:1 dr), providing the complementary diastereomer relative to that from kinetic protonation by BHT. 41 …”

Enzymatic construction of highly strained carbocycles

“…An alternative route relies on the double transfer of a carbene to alkynes, but the few examples in the literature are mostly limited to methylene carbene (11–13). Asymmetric bicyclobutane construction is particularly challenging, with multiple chiral centers generated at the same time (14, 15) (Figure S2). Cyclopropene synthesis through enantioselective single carbene addition to alkynes also requires chiral transition metal catalysts based on rhodium (16, 17), iridium (18) and cobalt (19).…”

A Mixed‐Ligand Chiral Rhodium(II) Catalyst Enables the Enantioselective Total Synthesis of Piperarborenine B

“…[22, 23] Inspired by the unique bioactivities of a number of cyclobutane-containing natural products, we sought to demonstrate the power of our strategy for enantioselective synthesis of unsymmetrical cyclobutanes. Additionally, we realized this would potentially enable rapid diversification of complex cyclobutanes for SAR studies.…”