Acyclic Stereocontrol in the Ireland–Claisen Rearrangement of α‐Branched Esters

Abstract

The Ireland-Claisen rearrangement is a powerful synthetic method that has found extensive application in chemical synthesis. [1,2] The substrates for this reaction can be prepared readily and convergently by the coupling of an allylic alcohol with a carboxylic acid, and the chirality of the allylic alcohol is relayed efficiently to the carbon-carbon bond formed in the rearrangement. The absolute configuration of the two stereocenters created in the Ireland-Claisen reaction can be predicted reliably on the basis of a chairlike-transition-state model. The reaction can even be used to assemble two contiguous quaternary stereogenic centers under mild conditions. One of the current deficiencies of the method, however, is the low diastereoselectivity observed in the rearrangement of a-branched esters (Scheme 1). This shortcoming became apparent to us when we chose the IrelandClaisen rearrangement as an underlying strategy for the synthesis of the spiroimine core of gymnodimine and related natural products: [3,4] We envisaged the efficient formation of the sterically congested C7 and C22 stereocenters through the rearrangement of ester 3 (Scheme 1).For efficient chirality transfer to each of the two stereocenters that form upon the rearrangement of abranched esters such as 3, E/Z-selective enolization is required. Herein, we describe the only method developed to date that enables this type of stereoselective enolization, [5] as well as the application of this method to the Ireland-Claisen rearrangement and the enantioselective synthesis of the cyclohexene ring of gymnodimine.Our initial experiments focused on the selective production of E or Z enolates from esters in which the difference in the steric and electronic properties of the a substituents R 1 and R 2 is minimal. The chirality of lithium amides 4-6 was used to control the stereoselectivity of deprotonation (Scheme 2).[6] The starting amines were selected for their ready availability. OBrien and co-workers had described a particularly efficient synthesis of amines such as 7, which can be prepared from inexpensive styrene oxide on a large scale with no chromatographic separation. [7] Importantly, the chiral amines are not consumed in the deprotonation reaction and can be recovered in high yield by simple extraction with aqueous acid.Although the stereogenic center at the a position of the ester is destroyed upon deprotonation, it is reintroduced as a quaternary stereogenic center through the [3,3] sigmatropic shift. Ester 8 a derived from commercially available (S)-2-methylbutyric acid served as the model substrate for a preliminary study of the deprotonation step (Table 1). In a control experiment, the treatment of 8 a with LDA followed by Me 3 SiCl gave the E and Z isomers of the corresponding enolate with low selectivity (Z/E 2:1), as expected (Table 1, Scheme 1. The Ireland-Claisen rearrangement of a-branched esters as a strategy for the synthesis of the spiroimine core of gymnodimine and related natural products. PMB = p-methoxybenzyl, Pv = pivaloyl, TBDPS ...

Stereoselective total synthesis of (+)-licochalcone E

“…Hydrolysis of the Evans' oxazolidinone in 7 with LiOH and H 2 O 2 in THF-H 2 O provided (S)-2-arylpropionic acid 3 in 71% yield (Qin et al, 2007). The acid 3 was converted to (R)-2-aryl-3-methyl-3-butene 10 in 3 steps.…”

[3,3]-Sigmatropic rearrangements: recent applications in the total synthesis of natural products

“…22 Upon warming to room temperature, the Claisen rearrangement takes place and delivers carboxylic acid 145 in a 94% yield, completing the highly stereoselective installation of the congested stereocenters at C5 and C31.…”

Synthesis and biology of cyclic imine toxins, an emerging class of potent, globally distributed marine toxins

“…Several groups have reported synthetic studies toward the total synthesis of gymnodimine, 88 of which only the Romo group disclosed success in completing the total synthesis. 89 The Romo synthesis adopted a convergent strategy that separated the oxolane and spiroimine subunits within the macrocyclic structure of gymnodimine (Scheme 7).…”