A Bidirectional Approach to the Synthesis of Polypropionates: Synthesis of C1–C13 Fragment of Zincophorin and Related Isomers

Abstract

The structure-activity study of a bioactive natural product containing polypropionate subunits requires that its stereoisomers also be evaluated. Therefore, a general approach to synthesize these motifs is necessary. We describe herein the synthesis of the C1-C13 polypropionate subunit of zincophorin and isomers thereof using a two-reaction sequence: an aldol reaction using a mixture of tetrasubstituted enoxysilanes and a hydrogen-transfer reaction, both under Lewis acid control. Selection of the appropriate Lewis acid dictates the stereochemical outcome of these reactions. From a tactical standpoint, this study shows how a polypropionate sequence can be read and constructed in two directions, either the east-west or the west-east approaches. The choice of the optimal route is influenced by the number of complexation sites that can interfere in the aldol step under bidentate Lewis acid control.

Diastereoselective Hydrogen‐Transfer Reactions: An Experimental and DFT Study

“…The stereochemistry of the radical precursor at C2 was demonstrated experimentally to be unrelated to the stereochemical outcome of radical reduction reaction 4a. c, d, f It was thus reasonable to consider the same radical intermediates generated from both halide isomers at the C2 position at the transition state.…”

“…(4) and Eq. (5)] 4f. 8f Aluminum and magnesium Lewis acids, which were demonstrated to allow the formation of endocyclic radical intermediates by complexation of the ester and the C3alcohol group, afforded selectively the complementary 2,3‐ syn inductions [Eq.…”

“…8f Aluminum and magnesium Lewis acids, which were demonstrated to allow the formation of endocyclic radical intermediates by complexation of the ester and the C3alcohol group, afforded selectively the complementary 2,3‐ syn inductions [Eq. (6)] 4a,f. 10 The stereocontrol brought by these radical reduction strategies proved to be highly reliable.…”

“…10 The stereocontrol brought by these radical reduction strategies proved to be highly reliable. By combining them with anionic Mukaiyama aldol reactions, a comprehensive approach to the preparation of polypropionates4f was elaborated for the synthesis of all possible 16 polypropionate stereopentads as single diastereoisomers from α‐chiral β‐hydroxyaldehydes 4d, , , …”

Chemische Synthesen und chemische Biologie von Carboxylpolyether‐Ionophoren: Aktuelle Entwicklungen

“…[47] Um maximale Stereodivergenz in der Synthese der C 3 -Einheit aus gängigen Aldol-Reaktionspartnern zu erreichen, entwickelten 2011 Guindon und Mitarbeiter einen Prozess aus Mukaiyama-Aldol-Reaktion und diastereoselektivem Wasserstofftransfer. [56] Ause in-und demselben Aldehyd 23 und dem vom a-Brompropionat abgeleiteten Silylenolether 24 kçnnen alle der vier mçglichen Diastereomere effizient und mit hoher Selektivitäti nz wei Stufen durch unterschiedliche Kombinationen zwischen A/B (fürStufe 1) und C/D (für Stufe 2) (Schema 4a)h ergestelllt werden. Durch Verwendung dieser Strategie in der Totalsynthese von Zincophorin [48] wurden die vier Chiralitätszentren über zwei iterative Anwendungen von Bedingungen, die die anti-Konfiguration bevorzugen, aufgebaut (Schema 4b).…”