Construction of 1,5-Enynes by Stereospecific Pd-Catalyzed Allyl–Propargyl Cross-Couplings

Abstract

The palladium-catalyzed cross-coupling of chiral propargyl acetates and allyl boronates delivers chiral 1,5-enynes with excellent levels of chirality transfer and applied across a broad range of substrates.1,5-Enynes are important and versatile synthetic intermediates. In addition to offering differentiated π-systems for selective functionalization, 1,5-enynes can be transformed into a diverse array of cyclic structures. 1 A current challenge to reaction methodology surrounding 1,5-enynes lies in the preparation of these structures in an enantiomerically enriched fashion. Synthesis of 1,5-enynes is commonly accomplished by allylation of propargylic electrophiles, employing either stoichiometric or catalytic Lewis acid activation. 2 While high levels of regiocontrol have been observed in these processes, they appear to proceed through an achiral carbocation intermediate and this feature precludes the transfer of chirality from enantiomerically-enriched starting materials to 1,5-enyne products (Scheme 1, eq. 1). 3,4 Transition metal catalysis could provide a solution to this limitation: palladium undergoes stereospecific anti S N 2´ oxidative addition with propargylic electrophiles. 5 This reaction delivers an η 1 -(allenyl)palladium complex (A, Scheme 1) whose configuration reflects that of the starting material. While (allenyl)palladium complexes can undergo isomerization to η 1 -(propargyl)palladium species (A→B), this transformation is also stereospecific. 5,6 With appropriately substituted substrates, both the propargyl (B) and the allenyl (A) palladium complexes are chiral and the fact that they are configurationally stable enables stereospecific cross-couplings. 7 However, the Pd-catalyzed cross-coupling of organometallic reagents and branched propargylic electrophiles generally favors the allene as opposed to the 1,5 enyne product. 7,8 This regioselectivity likely arises from steric effects; complex A is less hindered than complex B and this leads to allene products on reductive elimination. This reaction manifold renders traditional palladium catalysis ineffective for construction of chiral alkyne-containing compounds from chiral propargylic electrophiles.In contrast to the cross-coupling of alkyl, aryl and vinyl metal reagents, cross-couplings of allyl metal reagents may occur with allyl migration. To exploit this feature, our lab has studied cross-couplings of allyl metal reagents and allylic electrophiles and has found that these reactions appear to occur by an inner sphere 3,3'-reductive elimination. 9,10,11 In the presence of appropriately selected ligands (bidentate, small bite-angle diphosphines), allylallyl cross-couplings occur with excellent levels of regio-and stereocontrol. Along these * Corresponding Authormorken@bc.edu. Supporting Information. Procedures, characterization and spectral data. This material is available free of charge via the Internet at http://pubs.acs.org.The authors declare no competing financial interest. lines, we considered that allyl-propargyl cross-couplings mi...

Enantioselective and Enantiospecific Transition-Metal-Catalyzed Cross-Coupling Reactions of Organometallic Reagents To Construct C–C Bonds

“…Subsequent 3,3′ reductive elimination affords enyne 462 with excellent es and selectivity for formation of the alkyne over the allene. 338 Consistent with this mechanism, the reaction proceeds with inversion of stereochemistry. The authors have also disclosed a related kinetic resolution, in which a chiral ligand enables the selective allylation of one enantiomer of the propargylic substrate, allowing recovery of enantioenriched starting material.…”

Palladium/N-heterocyclic carbene catalysed regio and diastereoselective reaction of ketones with allyl reagents via inner-sphere mechanism

“…Less commonly, the reaction can follow an inner-sphere mechanism; in this case, the nucleophilic attack is targeted at Pd, forming an intermediate at first, followed by reductive elimination 13 14 15 16 17 18 19 20 . Recently, several studies on Pd-catalysed allylic substitution/coupling reactions via inner-sphere mechanism have been reported 21 22 23 24 25 26 27 28 29 30 31 32 33 . The key C–C bond-forming step was proposed to occur via [3,3']-reductive elimination in an allyl-Pd-allyl or allyl-Pd-nucleophile intermediate.…”

“…Morken realized excellent regio- and enantio-selectivities in the cross-coupling of monosubstituted allyl reagents with allyl boronates under Pd catalysis ( Fig. 1b ) 28 29 30 31 32 . These results reveal the unique character of the inner-sphere mechanism; in particular, branched products can be formed as major products when monosubstituted allyl reagents are used 21 28 .…”

Palladium-catalyzed construction of quaternary carbon centers with propargylic electrophiles

“…11 Morken et al overcame this challenge by utilizing allyl boronic ester 28 as the nucleophile in the cross-coupling with propargylic acetate 27 for the synthesis of 1,5-enynes 29 (Scheme 4). 12 The success of this approach was based on the migration of the allyl group in the reductive elimination step from 31, giving rise to propargylated 29 as the major product. Although the authors focused on secondary propargylic acetates, it was shown that a quaternary all-carbon center can be introduced not only with high regioselectivity (29a), but also with complete conservation of enantiomeric enrichment (29b) when a chiral propargylic acetate was used.…”