C₂-Symmetric Copper(II) Complexes as Chiral Lewis Acids. Scope and Mechanism of Catalytic Enantioselective Aldol Additions of Enolsilanes to (Benzyloxy)acetaldehyde

Abstract

C 2-Symmetric bis(oxazolinyl)pyridine (pybox)−Cu(II) complexes have been shown to catalyze enantioselective Mukaiyama aldol reactions between (benzyloxy)acetaldehyde and a variety of silylketene acetals. The aldol products are generated in high yields and in 92−99% enantiomeric excess using as little as 0.5 mol % of chiral catalyst [Cu((S,S)-Ph-pybox)](SbF6)2. With substituted silylketene acetals, syn reaction diastereoselection ranging from 95:5 to 97:3 and enantioselectivities ≥95% are observed. Investigation into the reaction mechanism utilizing doubly labeled silylketene acetals indicates that the silyl-transfer step is intermolecular. Further mechanistic studies revealed a significant positive nonlinear effect, proposed to arise from the selective formation of the [Cu((S,S)-Ph-pybox)((R,R)-Ph-pybox)](SbF6)2 2:1 ligand:metal complex. A stereochemical model is presented in which chelation of (benzyloxy)acetaldehyde to the metal center to form a square pyramidal copper intermediate accounts for the observed sense of induction. Support for this proposal has been obtained from double stereodifferentiating reactions, EPR spectroscopy, ESI spectrometry, and, ultimately, the X-ray crystal structure of the aldehyde bound to the catalyst. The C 2-symmetric bis(oxazolinyl)−Cu(II) complex [Cu((S,S)-tert-Bu-box)](OTf)2 is also an efficient catalyst for the aldol reaction, but the scope with this system is not as broad.

Cu(I)-catalyzed direct addition and asymmetric addition of terminal alkynes to imines

“…However, it was both encouraging and disappointing to find that although the reactivity was indeed enhanced significantly, no enantioselectivity was observed with most of these chiral catalysts. On the other hand, numerous enantioselective addition reactions with chiral copperbis(oxazoline) box complexes have been described during the past two decades (59)(60)(61). Therefore, we decided to try chiral bis(oxazolinyl) ligands in our reaction and found that the desired enantioselective addition product was formed with a low enantioselectivity by using bidentate box 1 and 2 with CuBr complex as catalysts in water (Fig.…”

Detection of the Heterochirality of a 1:2 Metal/Ph-pybox Complex Ion by ESIMS

“…3,4 Williams has reported that heterochiral [Co(Sub-pybox) 2 ] was formed selectively when Sub was Ph; however, mixtures of homo-and heterochiral complexes were formed when Sub was Me and Bz.…”

“…Evans and Jørgensen have both observed that, even using a M:1 ratio of 1:1, racemic 1 gave the near insoluble, catalytically inactive complex [M(1R)(1S)] 2+ . 3,4 Williams has reported that heterochiral [Co(Sub-pybox) 2 ] was formed selectively when Sub was Ph; however, mixtures of homo-and heterochiral complexes were formed when Sub was Me and Bz. 5 This diastereoselectivity was explained by the avoidance of steric interference between Ph-substituents on different ligands in the heterochiral complex and the possibility of favorable ³-stacking interactions between the Ph-substituents of one pybox ligand with the pyridine ring of another pybox ligand.…”

Total synthesis of zaragozic acid C by an aldol-based strategy

“…Although the hydrolysis-prone silyl ketene acetal derived from ester 13 could not be obtained in synthetically useful levels of purity in our hands, silyl ketene thioacetal 20 (Z:E=99:1), derived from thioester 14 in 95% yield, was more stable than the corresponding ester derivative, 26 and could be purified on Florisil. The stereochemistry of the major isomer was verified by 1 H NOE correlation (0.3%) between Si(CH 3 ) 3 and the methine proton in 20.…”