Alkenes as Chelating Groups in Diastereoselective Additions of Organometallics to Ketones.

Alkenes have been discovered to be chelating groups to Zn(II), enforcing highly stereoselective additions of organozincs to ß,γ-unsaturated ketones. 1H NMR studies and DFT calculations provide support for this surprising chelation mode. The results expand the range of coordinating groups for chelation-controlled carbonyl additions from heteroatom Lewis bases to simple C-C double bonds, broadening the 60 year old paradigm.

Asymmetric allylation of ketones and subsequent tandem reactions catalyzed by a novel polymer-supported titanium-BINOLate complex.

By using a novel, simple, and convenient synthetic route, enantiopure 6-ethynyl-BINOL (BINOL = 1,1-binaphthol) was synthesized and anchored to an azidomethylpolystyrene resin through a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. The polystyrene (PS)-supported BINOL ligand was converted into its diisopropoxytitanium derivative in situ and used as a heterogeneous catalyst in the asymmetric allylation of ketones. The catalyst showed good activity and excellent enantioselectivity, typically matching the results obtained in the corresponding homogeneous reaction. The allylation reaction mixture could be submitted to epoxidation by simple treatment with tert-butyl hydroperoxide (TBHP), and the tandem asymmetric allylation epoxidation process led to a highly enantioenriched epoxy alcohol with two adjacent quaternary centers as a single diastereomer. A tandem asymmetric allylation/Pauson-Khand reaction was also performed, involving simple treatment of the allylation reaction mixture with Co2(CO)8/N-methyl morpholine N-oxide. This cascade process resulted in the formation of two diastereomeric tricyclic enones in high yields and enantioselectivities.

Chelation-controlled additions to α-silyloxy aldehydes: an autocatalytic approach.

The Felkin-Anh model has been widely accepted to describe stereochemical outcomes in nucleophilic additions to α-silyloxy carbonyl compounds. Herein, it is demonstrated that chelation-controlled additions can be performed using dialkylzinc reagents in the presence of chlorotrimethylsilane with good to excellent diastereoselectivities. Ethyl zinc chloride, the Lewis acid responsible for promoting chelation, is generated in situ in an autocatalytic fashion. This approach circumvents its use in stoichiometric amounts.

Chelation-controlled addition of organozincs to α-chloro aldimines.

Nucleophilic additions to α-chiral α-halo carbonyl derivatives are well-known to generate Cornforth-Evans products via a nonchelation pathway. What was unprecedented before this report is C-X bonds reversing the diastereoselectivity through coordination to metals during C-C bond-forming reactions (chelation control). Herein we describe chelation control involving C-X bonds in highly diastereoselective additions of organozinc reagents to a variety of α-chloro aldimines. The unique ability of alkylzinc halide Lewis acids to coordinate to the Cl, N, and O of α-chloro sulfonyl imine substrates is supported by computational studies.

Diastereoselective chelation-controlled additions to ß-silyloxy aldehydes.

A general diastereoselective method for the addition of dialkylzincs and (E)-di- and (E)-trisubstituted vinylzinc reagents to ß-silyloxy aldehydes is presented. This method employs alkyl zinc triflate and nonaflate Lewis acids and affords chelation-controlled products (6:1 to > 20:1 dr).

Highly diastereoselective chelation-controlled additions to α-silyloxy ketones.

The polar Felkin-Anh, Cornforth-Evans, and Cram-chelation models predict that the addition of organometallic reagents to silyl-protected α-hydroxy ketones proceeds via a nonchelation pathway to give anti-diol addition products. This prediction has held true for the vast majority of additions reported in the literature, and few methods for chelation-controlled additions of organometallic reagents to silyl-protected α-hydroxy ketones have been introduced. Herein, we present a general and highly diastereoselective method for the addition of dialkylzincs and (E)-di-, (E)-tri-, and (Z)-disubstituted vinylzinc reagents to α-silyloxy ketones using alkyl zinc halide Lewis acids, RZnX, to give chelation-controlled products (dr ≥18:1). The compatibility of organozinc reagents with other functional groups makes this method potentially very useful in complex molecule synthesis.

Overriding Felkin control: a general method for highly diastereoselective chelation-controlled additions to alpha-silyloxy aldehydes.

According to the Felkin-Anh and Cram-chelation models, nucleophilic additions to alpha-silyloxy aldehydes proceed through a nonchelation pathway due to the steric and electronic properties of the silyl group, giving rise to Felkin addition products. Herein we describe a general method to promote chelation-control in additions to alpha-silyloxy aldehydes. Dialkylzincs, functionalized dialkylzincs, and (E)-disubstituted, (E)-trisubstituted, and (Z)-disubstituted vinylzinc reagents add to silyl-protected alpha-hydroxy aldehydes with high selectivity for chelation-controlled products (dr of 10:1 to >20:1) in the presence of alkylzinc halides or triflates, RZnX. With the high functional group tolerance of organozinc reagents, the mild Lewis acidity of RZnX, and the excellent diastereoselectivities favoring the chelation-controlled products, this method will be useful in the synthesis of natural products. A mechanism involving chelation is supported by (1) NMR studies of a model substrate, (2) a dramatic increase in reaction rate in the presence of an alkylzinc halide, and (3) higher diastereoselectivity with larger alkyl substituents on the alpha-carbon of the aldehyde. This method provides access to chelation-controlled addition products with high diastereoselectivity previously unavailable using achiral organometallic reagents.