Asymmetric Synthesis of 2,3,4‐Trisubstituted Functionalised Tetrahydrofurans via an Organocatalytic Michael Addition as Key Step

Abstract

Abstract:The organocatalytic Michael addition of various aldehydes to (2E,4E)-ethyl 5-nitropenta-2,4-dienoate has been achieved under the catalysis of diphenylprolinol trimethylsilyl ether furnishing the products in good to excellent yields (61-94%) and high stereoselectivities (dr up to > 98:2, ee = 97 to > 99%). Starting from these Michael adducts, 2,3,4-trisubstituted functionalized tetrahydrofurans are available in two steps by reduction of the aldehyde followed by an intramolecular oxa-Michael addition in good yields (54-76%) and stereoselectivities (dr up to > 95:5, ee = 97 to > 99%).Keywords: asymmetric synthesis; Michael addition; nitroalkenes; organocatalysis; tetrahydrofurans After intensive investigations and tremendous progress in the last decade, organocatalysis has been developed to one of the main branches of asymmetric synthesis.[1] Within the field of organocatalysis, the amine-catalysed Michael addition of aldehydes and ketones to nitroalkenes via an enamine intermediate, which was independently discovered by List et al., Barbas et al. and our group, [2] has attracted great interest in recent years, since the resulting g-nitroaldehydes or ketones are precursors of many important compounds such as g-amino acids. Many efforts have been made to develop new efficient organocatalysts to expand the substrate spectrum of this Michael reaction or to involve it as a key step in domino reactions. [3][4][5] Our attention was drawn to (2E,4E)-ethyl 5-nitropenta-2,4-dienoate (B) as a Michael acceptor, because the 1,4-adducts (C) may be converted into 2,3,4-trisubstituted tetrahydrofurans (E) in two steps by reduction of the aldehyde followed by an intramolecular oxa-Michael addition (Scheme 1). Polysubstituted tetrahydrofurans are frequently found as sub-A C H T U N G T R E N N U N G units in many natural products such as Annonaceous acetogenins, [6] lignans, [7] polyether ionophores [8] and macrodiolides, [9] which possess various biological activities including antitumour, antihelmic, antimalarial, antimicrobial and antiprotozoal activity. Due to these important biological activities, many efforts have been made for the stereoselective synthesis of polysubstituted tetrahydrofurans. [10,11] Initially we performed the reaction with (2E,4E)-ethyl 5-nitropenta-2,4-dienoate (2) and 3 equivalents of propanal (1a) in dichloromethane at room temperature. The catalyst diphenylprolinol silyl ether 4 [12,13] (5 mol%) was used, which shows good catalytic activity and excellent asymmetric induction in enaminemediated Michael additions. Encouragingly, the reaction was complete within an hour affording the nitroaldehyde 3a in excellent yield (89%) and enantioselectivities (98% ee syn, 94% ee anti). However, only a moderate diastereoselectivity (syn:anti = 77:23) was achieved (Table 1, entry 1). A brief solvent screen was undertaken and it was found that excellent enantiomeric excesses were obtained in every solvent used Scheme 1. Asymmetric synthesis of 2,3,4-trisubstituted tetrahydrofurans -retrosynthetic analysis.

Organocatalytic Asymmetric Synthesis of Tetrahydrofuran and 1,2‐Dihydrobenzofuran Scaffolds

“…In 2010, Enders and co‐worker synthesized highly functionalized 2,3,4‐trisubstituted tetrahydrofurans in three steps using diphenylprolinol trimethylsilyl ether catalyst 9 . The key step involved in this synthesis is organocatalytic Michael addition between aldehyde 7 and compound 8 to achieve chiral nitroaldehydes 11 in enantiomerically enriched form.…”

Asymmetric Organocatalysis and the Nitro Group Functionality

“…Finally, the groups of both Alexakis 43 and Enders 44 have demonstrated the addition of aldehydes to nitrodienes using the Jørgensen-Hayashi catalyst 2 (Scheme 29).…”

Heteroatom methods

“…The initial nitro-Michael reaction could be performed with high enantio-and diastereo-selectvity through the use of pyrrolidinebased organocatalyst 1 making this an efficient method for the preparation of chiral functionalised tetrahydrofurans. 30 A Michael-oxa-Michael sequence was also used in the synthesis of a range of pyranochromenes, again employing an organocatalyst in order to achieve asymmetric induction. The reaction tolerated a range of aryl and alkyl groups possessing different functional groups and gave high yields and enantioselectivities.…”