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Monday, February 18, 2013
Tristan H. Lambert
Columbia University

Asymmetric C-C Bond Formation

Andrew G. Myers at Harvard reported (Angew. Chem. Int. Ed. 2012, 51, 4568. DOI: 10.1002/anie.201200370) the alkylation of the pseudophenamine amide 1 selectively setting the quaternary stereogenic center of 2. This is an effective replacement for his previously-reported pseudoephedrine, now a controlled substance.

Amine catalysis has enabled numerous methods for the asymmetric α-functionalization of aldehydes, although α-alkylation remains a significant challenge. David W. C. MacMillan at Princeton developed (J. Am. Chem. Soc. 2012, 134, 9090. DOI: 10.1021/ja303116v) an α-vinylation of aldehydes 3 with vinyliodoniums 5, which relied on the "synergistic combination" of the amine catalyst 4 and copper(I) bromide. The stability of the β,γ-unsaturated aldehyde products under the reaction conditions is notable.

A procedure for the asymmetric β-vinylation of α,β-unsaturated aldehydes such as 7 was developed (Eur. J. Org. Chem. 2012, 2774. DOI: 10.1002/ejoc.201200150) by Claudio Palomo at the Universidad del Pais Vasco in Spain. Amine 8 catalyzed enantioselective Michael addition of β-nitroethyl sulfone 9 to 7, followed by acetalization and elimination of HNO2 and SO2Ph, furnished products such as 10 in high enantiomeric excess. In a conceptually related reaction, a surrogate for acetate as a nucleophile was reported (Chem. Commun. 2012, 48, 148. DOI: 10.1039/C1CC15714K) by Wei Wang at the University of New Mexico and Jian Li of the East China University of Science and Technology. In this case, amine 13-catalyzed Michael addition of pyridyl sulfone 11 to unsaturated aldehydes 12, followed by acetalization and reductive removal of the sulfone gave rise to the ester product 14 with very high ee.

Asymmetric hydroformylation offers a powerful approach for the synthesis of carbon stereocenters, but controlling the regioselectivity of the reaction remains a challenge with many substrate classes. Christopher J. Cobley of Chirotech Technology Ltd. (UK) and Matthew L. Clarke at the University of St. Andrews showed (Angew. Chem. Int. Ed. 2012, 51, 2477. DOI: 10.1002/anie.201108203) that the mixed phosphine-phosphite ligand "bobphos" (16) (bobphos = best of both phosphorus ligands) provided significant selectivities for the branched hydroformylation products, up to 10:1 b:l in the case of 15. Another major challenge for hydroformylation is to control the regioselectivity of internal olefin substrates. Joost N. H. Reek at the University of Amsterdam utilized (J. Am. Chem. Soc. 2012, 134, 2860. DOI: 10.1021/ja211455j) a supramolecular ligand to override the inherent preference for hydroformylation of alkenes such as 2-octene (18).

Chiral 4-alkyl-4-aryl butanoic acids have proven useful as a building block for a wide range of synthetic applications. The enantioselective synthesis of these building blocks via asymmetric hydrogenation was reported (Angew. Chem. Int. Ed. 2012, 51, 2708. DOI: 10.1002/anie.201107802) by Qi-Lin Zhou at Nankai University. Readily available tri-substituted alkene substrates such as 20 were reduced in the presence of the iridium complex 21 to furnish products 22 with high enantiomeric excess.

Much progress has been made of late in the area of cross-coupling to form Csp3 stereocenters; however the majority of these methods have employed alkyl halide electrophiles. Gregory C. Fu at MIT (currently Caltech) demonstrated (J. Am. Chem. Soc. 2012, 134, 2966. DOI: 10.1021/ja300031w) that propargylic carbonates 23 may be enantioselectively cross-coupled via nickel catalysis with arylzinc reagents to generate adducts 25 with high ee.

Finally, Ben L. Feringa at the University of Groningen in the Netherlands developed (J. Am. Chem. Soc. 2012, 134, 4108. DOI: 10.1021/ja300743t) a Z-selective asymmetric allylic alkylation (AAA) of allylic gem-dichlorides 26 to produce vinyl chlorides 27. This copper(I) catalyzed procedure utilizes the phosphoramidite ligand 30 to product Z-vinyl chloride products with good to high E/Z selectivities and enantioselectivities. Notably, the Z-vinyl chlorides could be cross-coupled without isomerization of the olefin geometry or racemization, allowing access to complex products such as 29.

T. H. Lambert, Org. Chem. Highlights 2013, February 18.