Enantioselective Synthesis of Allenes by Catalytic Traceless Petasis Reactions

Abstract

Allenes are useful functional groups in synthesis as a result of their inherent chemical properties and established reactivity patterns. One property of chemical bonding renders 1,3-substituted allenes chiral, making them attractive targets for asymmetric synthesis. While there are many enantioselective methods to synthesize chiral allenes from chiral starting materials, fewer methods exist to directly synthesize enantioenriched chiral allenes from achiral precursors. We report here an asymmetric boronate addition to sulfonyl hydrazones catalyzed by chiral biphenols to access enantioenriched allenes in a traceless Petasis reaction. The resulting Mannich product from nucleophilic addition eliminates sulfinic acid, yielding a propargylic diazene that performs an alkyne walk to afford the allene. Two enantioselective approaches have been developed; alkynyl boronates add to glycolaldehyde imine to afford allylic hydroxyl allenes, and allyl boronates add to alkynyl imines to form 1,3-alkenyl allenes. In both cases, the products are obtained in high yields and enantioselectivities.

Figure 1

Development of an enantioselective allene synthesis reaction. Asymmetric routes to chiral allenes from (A) alkynyl boronate addition to glycolaldehyde imine and (B) allylation of alkynyl hydrazones.

Figure 2

Isolation of hydrazide intermediate 3a.

Figure 3

Utility of the chiral allene products prepared from traceless Petasis reactions. (a) Stereospecific cycloetherifications yield substituted dihydrofurans. (b) An efficient synthesis of laballenic acid (35), a major constituent of Leonotis nepetaefolia seed oil. (c) A formal total synthesis of 39, an odor-active lactone component of oranges and wasabi, intercepting Ma’s intermediate (i.e., 38).