Direct and highly regioselective and enantioselective allylation of β-diketones

Abstract

The enantioselective allylation of ketones represents both a problem of fundamental importance in asymmetric reaction design and one of only a very small number of available methods to access valuable tertiary carbinols. Despite the vast amount of attention from chemists that this problem has elicited,1-8 however, success has generally been limited to just a few simple ketone types thus limiting the utility of these methods. A method for the selective allylation of functionally complex ketones would be expected to increase the utility of ketone allylation methods in the chemical synthesis of important targets. Here we describe the operationally simple, direct, regioselective, and enantioselective allylation of β-diketones. The strong tendency of β-diketones to act as nucleophilic species was overcome by the co-optation of their enol form to provide the necessary Brønsted acid activation. This unprecedented reaction thus not only significantly expands the pool of enantiomerically enriched and functionally complex tertiary carbinols that may be easily accessed, but also overturns more than a century of received wisdom regarding the reactivity of β-diketones.

Extremely Active Organocatalysts Enable a Highly Enantioselective Addition of Allyltrimethylsilane to Aldehydes

“…[3] In 1978, the first enantioselective allylation of aldehydes 2 was reported by Hoffmann et al,e mploying ac amphor-derived allylboronic ester as the nucleophile. [5] Such chiral reagents [6][7][8] have proven to be of considerable synthetic value,although the intrinsic need for wasteful stoichiometric, and usually non-recoverable amounts of enantiopure auxiliaries affect atom economy,c ost, environmental impact, and the overall synthetic appeal of the methodology. [5] Such chiral reagents [6][7][8] have proven to be of considerable synthetic value,although the intrinsic need for wasteful stoichiometric, and usually non-recoverable amounts of enantiopure auxiliaries affect atom economy,c ost, environmental impact, and the overall synthetic appeal of the methodology.…”

“…[4] Af ew years later,B rown et al introduced B-allyldiisopinocampheylborane,w hich has been the most popular chiral allylating agent until today. [5] Such chiral reagents [6][7][8] have proven to be of considerable synthetic value,although the intrinsic need for wasteful stoichiometric, and usually non-recoverable amounts of enantiopure auxiliaries affect atom economy,c ost, environmental impact, and the overall synthetic appeal of the methodology. [3] To this end, several effective catalytic variants with achiral allylboron reagents, [9,10] allylstannanes, [11][12][13] allyl halides, [14,15] and allyl acetates [16] have been developed.…”

Toward a more step-economical and scalable synthesis of spongistatin 1 to facilitate cancer drug development efforts

“…The synthesis of ketone 6 began with an application of our recently reported direct and enantioselective allylation of β-diketones, 17 in this case acetylacetone (Scheme 1b). Allyl-silane ( S , S )- 12 (commercially available, and easily prepared on tens of grams scale from ( S , S )- 13 and allyltrichlorosilane) reacts smoothly with acetylacetone to provide 14 .…”

Complex fragment coupling by crotylation: a powerful tool for polyketide natural product synthesis

“…27 When applied in concert with the silylformylation and Tamao oxidation chemistry described in Scheme 3, the fragment coupling crotylation methodology can deliver complex polyketide arrays from simple building blocks in an experimentally straightforward, step-economical, and relatively practical fashion. The application of this and other 28 new methodology to a step-economical and scalable synthesis and coupling of a diene-bearing AB spiroketal fragment such as 6 is being successfully pursued, and will be reported shortly.…”