Nickel-catalyzed reductive coupling reactions of 1,3-enynes and aromatic aldehydes efficiently afford conjugated dienols in excellent regioselectivity and modest enantioselectivity when conducted in the presence of catalytic amounts of a monodentate, P-chiral ferrocenyl phosphine ligand. 1-(Trimethylsilyl)-substituted enynes are shown to be effective coupling partners in these reactions, and the dienol products thus formed readily undergo protiodesilylation under mild conditions.
A nickel-catalyzed method for the three-component coupling of alkenes(ethylene and alpha olefins), aldehydes, and silyl triflates is described, and this process represents the first catalytic method for coupling aldehydes and alkenes to give allylic alcohol derivatives. Conceptually, the alkene functions as a replacement for an alkenylmetal reagent.
Several stereoselective routes to the synthesis of (1S,3R)-t-butyldimethyl-(1-methyl-3-oxiranyl-propoxy)-silane (13a) were explored, and the use of Jacobsen's hydrolytic kinetic resolution to separate a mixture of diastereomeric epoxides was a key step in the shortest of these. As part of an approach to the total synthesis of amphidinolide T2 (2), this epoxide, corresponding to C17–C22 of the natural product, was successfully joined with an alkyne (C13–C16) by way of a nickel-catalyzed reductive coupling reaction.
Highly regioselective, catalytic asymmetric reductive coupling reactions of 1,3-enynes and ketones have been achieved using catalytic amounts of Ni(cod)2 and a P-chiral, monodentate ferrocenyl phosphine ligand. These couplings represent the first examples of catalytic, intermolecular reductive coupling of alkynes and ketones, enantioselective or otherwise, and afford synthetically useful 1,3-dienes possessing a quaternary carbinol stereogenic center in up to 70% ee.
Ni-catalyzed reductive coupling of aryl alkynes (1) and enantiomerically enriched α-oxyaldehydes (2) afford differentiated anti-1,2-diols (3) with high diastereoselectivity and regioselectivity, despite the fact that the methoxymethyl (MOM) and para-methoxybenzyl (PMB) protective groups typically favor syn-1,2-diol formation in carbonyl addition reactions of this family of aldehydes.
A complex derived from Ni(cod)2 and NHC−IPr catalyzes a three-component coupling reaction involving allenes, aldehydes, and organosilanes and transfers the axial chirality of the allene to a stereogenic center in the product with very high fidelity. An unexpected regioselectivity is observed; favored are allylic rather than homoallylic alcohol derivatives, corresponding to the unusual process of coupling two electrophilic atoms: the allene sp and aldehyde carbon atoms. In all cases, high enantioselectivity, high Z/E selectivity, and, with differentially substituted allenes, high site selectivity are observed. This transformation represents the first enantioselective multicomponent coupling process of allenes.
A complex derived from Ni(cod)2 and NHC−IPr catalyzes a three-component coupling reaction involving allenes, aldehydes, and organosilanes and transfers the axial chirality of the allene to a stereogenic center in the product with very high fidelity. An unexpected regioselectivity is observed; favored are allylic rather than homoallylic alcohol derivatives, corresponding to the unusual process of coupling two electrophilic atoms: the allene sp and aldehyde carbon atoms. In all cases, high enantioselectivity, high Z/E selectivity, and, with differentially substituted allenes, high site selectivity are observed. This transformation represents the first enantioselective multicomponent coupling process of allenes.
Described in this work are total syntheses of amphidinolides T1 and T4 using two nickel-catalyzed reductive coupling reactions of alkynes, with an epoxide in one case (intermolecular) and with an aldehyde in another (intramolecular). The latter was used to effect a macrocyclization, form a C−C bond, and install a stereogenic center with 10:1 selectivity in both natural product syntheses. Alternative approaches in which intermolecular alkyne−aldehyde reductive coupling reactions would serve to join key fragments were investigated and are also discussed; it was found that macrocyclization (i.e. intramolecular alkyne−aldehyde coupling) was superior in several respects (diastereoselectivity, yield, and length of syntheses). Alkyne−epoxide reductive couplings were instrumental in the construction of key fragments corresponding to approximately half of the molecule of both natural products. In one case (T4 series), the alkyne−epoxide coupling exhibited very high site selectivity in a coupling of a diyne. A model for the stereoselectivity observed in the macrocyclizations is also proposed.
Nickel-catalyzed reductive couplings of aldehydes with alkynes that contain tethered olefins are described, in which the degree and sense of regioselectivity are controlled by the length of the tether and the presence or absence of an additive. When the alkyne and alkene are separated by four bonds, very high (95:5) regioselectivities are observed. Use of a monodentate phosphine as an additive leads to formation of the opposite regioisomer in equal and opposite selectivity (5: 95). These results provide strong evidence for an interaction between the remote alkene and the metal center during the regioselectivity-determining step and suggest that reactions with and without an additive proceed via fundamentally distinct mechanisms.
The aryl substituent on the catalyst is central to the success of the title reaction (see scheme) which affords allylic amines in up to 89 % ee and 91 % yield with a catalyst derived from [Ni(cod)2] and a P-chiral ferrocenyl phosphane (e.g. 1). The coupling products are easily deprotected to enantiomerically enriched, tetrasubstituted primary allylic amines, which can be recrystallized to optical purity.