CHIRAL COOPERATIVITY - THE NATURE OF THE DIASTEREOSELECTIVE AND ENANTIOSELECTIVE STEP IN THE GOLD(I)-CATALYZED ALDOL REACTION UTILIZING CHIRAL FERROCENYLAMINE LIGANDS

Mechanistic aspects of the gold(I)-catalyzed aldol reaction of aldehydes with a-isocyanoacetate esters in the presence of a chiral ferrocenylamine ligand possessing both planar and central chirality were investigated. The synthesis of (S)-N-[2-(N>N-dimethylammo)ethyl]-N-methyl-1-[(5)-T,2-bis(diphenylphosphino)ferrocenyl]ethylamine [(S)-(S)-4] is described. Analysis of the 1H and 31P{1H} NMR spectral data of (S)-(S)-4 and (R)-(S)-4 suggested that their preferred time-averaged conformations in solution are different. Similar observations were made for the N,N-dimethylamine-substituted precursors, (S)-(S)-11 and (R)-(S)-11, of 4. The 1H NMR spectral data of the phenylseleno- and phenylthio-substituted analogues, 8a,b, of (R)-(S)-4 suggested that their conformations were different from that of (R)-(S)-4 in solution and, furthermore, that the phenyl substituents on the ligand donor groups are important in the stereoselective step of the gold(I)-catalyzed aldol reaction. The preferred conformer of (R)-(S)-4 in solution proposed from the 1H NMR spectral data is similar to that of the X-ray crystal structure of the gold(I) complex of (±)-(R*)-(S*)-4. The reaction of benzaldehyde (1a) with methyl a-isocyanoacetate (2a) catalyzed by bis(cyclohexyl isocyanide)gold(I) tetrafluoroborate (3) in the presence of the chiral ferrocenylamine ligand (R)-(S)-4 gave a mixture of the trans- and cis-oxazolines 5a and 6a in which (4S,5R)-5a was the predominant diastereomer, formed in 91% enantiomeric excess. The use of (S)-(S)-4 as a ligand demonstrated that not only does a change in the absolute configuration of the stereogenic carbon atom (a change in central chirality) from R to S result in both a reduction of the product trans:cis ratio but also the opposite trans-oxazoline enantiomer is formed in enantiomeric excess. Furthermore, the ee of the cis-oxazoline increased upon changing the absolute configuration of the stereogenic carbon atom from R to S. These results indicate that the insensitivity of product stereochemistry to the central chirality of the stereogenic carbon atom in the ferrocenylamine side chain previously observed for Grignard cross-coupling reactions cannot be generalized to other reaction types involving chiral ferrocenylamine ligands. The highest diastereo- and enantioselectivity of the trans-oxazoline 5 is obtained when the central and planar chirality are opposite as defined by the Cahn-Ingold-Prelog sequence rules. This constitutes the first example in a chiral transition-metal ligand containing both central and planar chirality of internal cooperativity of chirality in the control of product diastereo- and enantioselectivity. Variable-temperature 31P{1H} NMR spectra, kinetic isotope, and linear free energy studies suggest that prior coordination of aldehyde is not involved in the stereoselective transition state as previously supposed, but rather the rate-determining step of the gold(I)-catalyzed aldol reaction is attack of the aldehyde upon a gold(I) complex of ferrocenylamine ligand and a-isocyanoacetate ester. A stereoselective transition-state model that correctly predicts the correct enantiomer of the dominant trans-oxazoline formed was developed. An electronic effect of the substrate upon product stereoselectivity was demonstrated for certain heteroaldehydes and trifluoromethyl-substituted benzaldehydes. © 1990, American Chemical Society. All rights reserved.