Temporary Generation of a Cyclopropyl Oxocarbenium Ion Enables Highly Diastereoselective Donor–Acceptor Cyclopropane Cycloaddition

Abstract

A novel formal [3+2] cycloaddition of cyclopropylacetals and aldehydes was developed, and the resulting trisubstituted tetrahydrofurans display three new chiral centers formed with highly diastereoselectivity. This method is stereocomplementary to most previously reported cycloadditions of malonate diesters, relies on the transient generation of cyclopropyl oxocarbenium ions, proceeds under mild conditions, and is based on the concept of temporary activation of an otherwise inert protecting group.

Total Synthesis, Stereochemical Assignment, and Divergent Enantioselective Enzymatic Recognition of Larreatricin

“…Given our prior interest in the stereoselective synthesis of tetrahydrofuran derivatives and in the chemistry and biology of PPOs from a variety of plants, our collaborative interest was piqued by the enantiospecificity of larreatricin hydroxylase and the possibility that other tyrosinases might exhibit similar behavior. Here, we report a concise, efficient and scalable enantioselective synthesis of 1 and an unambiguous structural assignment of its (+) and (−) enantiomeric forms.…”

“…Additionally,a nu nambiguous assignment of the absolutec onfigurationo fn aturally occurring (À)-larreatricin is still missing after nearly three decades of researcho nt his family of metabolites. [14] Given our prior interest in the stereoselective synthesis of tetrahydrofuran derivatives [15] and in the chemistry and biology of PPOs [6] from av ariety of plants, [16][17][18] our collaborative inter-est was piqued by the enantiospecificity of larreatricin hydroxylase and the possibility that other tyrosinases might exhibit similar behavior.H ere, we report ac oncise, efficient and scalable enantioselective synthesis of 1 and an unambiguous structural assignment of its (+ +)a nd (À)e nantiomeric forms. We also report detailed kinetic studies of its divergent enantiospecific uptake by three different tyrosinases from two kingdoms (Scheme 1C"T able 1), including (+ +)-larreatricin hydroxylase, which we were able to produce recombinantly for the first time.…”

Visible‐Light Photocatalytic Intramolecular Cyclopropane Ring Expansion

“…Therefore, in the presence of a Lewis acid, 1,3‐zwitterions can be generated and trapped by different double bonds, that is C=C, C=N, C=O. Brilliant examples of intermolecular cycloadditions (Scheme a) from the groups of Maulide, Trushkov, Tang, Doyle, Tomilov, and Werz– have been reported recently, while the group of Wang and others have developed related intramolecular cross‐cycloadditions (IMCC; Scheme b)…”

Convergent Synthesis of Trisubstituted Tetrahydrofurans via Bis-Thermally Reactive 1,5-Diene-Tert-Butyl Carbonates.

“…Considering the relevance of tetrahydrofurans to drug discovery, a variety of strategies have been developed to access them in efficient ways. [13] Synthesis strategies fall into one of two subcategories: (a) constructive synthesis, where the THF scaffold is assembled [14][15][16][17][18][19][20][21][22][23] or (b) by an approach that functionalizes a preexisting THF core (e.g C-H functionalization, cross-coupling reactions. [24][25][26][27][28][29][30][31] The former category is of particular relevance to this report.…”

“…Specifically, it was proposed that 1,5-dienes 1 derived from alkylidenemalononitrile and a cis-buten-1,4-diol derivative could undergo polythermal transformation involving Cope rearrangement, Boc-deprotection, and intramolecular oxy-Michael addition. Reviews of furan synthesis literature [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] and "domino reactions [38,39] " in general reveal that this proposal is unique and would access novel trisubstituted THFs. The most relevant prior art is summarized in Scheme 1, which demonstrates the likelihood of oxy-Michael additions to alkylidenemalonic acid derivatives.…”