General [4 + 1] Cyclization Approach To Access 2,2-Disubstituted Tetrahydrofurans Enabled by Electrophilic Bifunctional Peroxides

Abstract

A general [4 + 1] cyclization reaction of carbonyl nucleophiles with 2-iodomethylallyl peroxides, which function as unique electrophilic oxygen synthons, for the synthesis of a broad range of 2,2-disubstituted tetrahydrofurans is achieved under operationally simple conditions. The unprecedented asymmetric version of such reaction is also realized via chiral auxiliary-assisted cyclization, thus providing a distinct approach to access chiral tetrahydrofurans with high diastereoselectivities. The new method can be applied to the synthesis of core structure of posaconazole drug.

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

“…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.…”

“…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.…”

Phase-Transfer Catalyzed Asymmetric [4 + 1] Annulations for the Synthesis of Chiral 2,2-Disubstituted Tetrahydrothiophenes

“…Recently, our group reported a tandem C−C and umpolung C−O bond-forming reaction of bifunctional peroxides, a formal [4 + 1] process, for the synthesis of 2,2-disubstituted tetrahydrofurans under mild basic conditions. 8 Based on these findings, we questioned if such [4 + 1] annulation strategy could be extended to the construction of chiral 2,2-disubstituted tetrahydrothiophenes by devising appropriate bifunctional [S1−C4] synthons containing an electrophilic sulfur and an enoate termini in the presence of chiral phase-transfer catalysts. 9 Conceivably, such design not only allows the diversified synthesis of 2,2disubstituted tetrahydrothiophenes by flexibly changing the structures of one-carbon nucleophiles, but also enables to install versatile carbonyl functional groups into the resulting products for further derivatization.…”

Diastereoselective Synthesis of 2,3,4-Trisubstituted Tetrahydrofurans via Thermally Reactive 1,5-Diene-tert-butyl Carbonates

“…Considering the relevance of tetrahydrofurans to drug discovery (Figure ), a variety of strategies have been developed to access them in efficient ways . Synthetic strategies fall into one of two subcategories: (a) constructive synthesis, in which the THF scaffold is assembled, − or (b) an approach that functionalizes a preexisting THF core (e.g., C–H functionalization and cross-coupling reactions). − The former category is particularly relevant to this report. We have been advancing the classic Cope rearrangement (that of 3,3-dicyano-1,5-dienes) for application in modern chemical synthesis. − Considering that Cope rearrangement results in allylic transposition and an electrophilic alkylidenemalononitrile, we hypothesized that “trapping” with tethered nucleophiles could result in additional bond formation and structural complexity.…”