Generation and Rearrangement of N,O‐Dialkenylhydroxylamines for the Synthesis of 2‐Aminotetrahydrofurans

Abstract

A new diastereoselective route to 2-aminotetrahydrofurans has been developed from N,O-dialkenylhydroxylamines. These intermediates undergo a spontaneous C-C bond-forming [3,3]-sigmatropic rearrangement followed by a C-O bond-forming cyclization. A copper-catalyzed N-alkenylation of an N-Boc-hydroxylamine with alkenyl iodides, and a base-promoted addition of the resulting N-hydroxyenamines to an electron-deficient allene, provide modular access to these novel rearrangement precursors. The scope of this de novo synthesis of simple nucleoside analogues has been explored to reveal trends in diastereoselectivity and reactivity. In addition, a base-promoted ring-opening and Mannich reaction has been discovered to covert 2-aminotetrahydrofurans to cyclopentyl β-aminoacid derivatives or cyclopentenones.

Generation and Rearrangement of N,O‐Dialkenylhydroxylamines for the Synthesis of 2‐Aminotetrahydrofurans

“…[17] In contrast, we anticipated that mild basic conditions might cleave the tetrahydrofuran C À Ob ond and convert 8 to highly-substituted cyclopentanone products via af ormal aza-Petasis-Ferrier rearrangement. [12] This transformation was consistent for other 2-aminotetrahydrofurans as shown for 9b and 9d,a s well as other electrophiles as shown for 9c. The preferred conformation of this product was confirmed by Xray crystallography.…”

Nitrone and Alkyne Cascade Reactions for Regio‐ and Diastereoselective 1‐Pyrroline Synthesis

“…Ther egioselectivity observed for 12 f-12 i is consistent with the torsion-distortion regiochemical model proposed by Garg and Houk but does not rule out an alternative stepwise addition, rearrangement, and cyclization mechanism (Scheme 5B). [19,29,30] Ther egioselectivity observed for the cascade synthesis of 1-pyrrolines 14 is consistent with as terically controlled dipolar cycloaddition (Scheme 4a nd Scheme 5A). To determine if electronically activated alkynes could reverse this selectivity or indicate an alternative operative mechanism such as the one shown in Scheme 5B,p ropiolate 13 k was subjected to reaction con-ditions with nitrone 7a.A ss hown in Scheme 5C,p yrroline 14 o was observed as the major product and supports am echanistic pathway that proceeds through ad ipolar cycloaddition instead of ac onjugate addition.…”

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.…”