Article

Enantioselective Rhodium-Catalyzed [2+2+2] Cycloadditions of Terminal Alkynes and Alkenyl Isocyanates: Mechanistic Insights Lead to a Unified Model that Rationalizes Product Selectivity

Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA.
Journal of the American Chemical Society (Impact Factor: 11.44). 10/2009; 131(43):15717-28. DOI: 10.1021/ja905065j
Source: PubMed

ABSTRACT This manuscript describes the development and scope of the asymmetric rhodium-catalyzed [2 + 2 + 2] cycloaddition of terminal alkynes and alkenyl isocyanates leading to the formation of indolizidine and quinolizidine scaffolds. The use of phosphoramidite ligands proved crucial for avoiding competitive terminal alkyne dimerization. Both aliphatic and aromatic terminal alkynes participate well, with product selectivity a function of both the steric and electronic character of the alkyne. Manipulation of the phosphoramidite ligand leads to tuning of enantio- and product selectivity, with a complete turnover in product selectivity seen with aliphatic alkynes when moving from Taddol-based to biphenol-based phosphoramidites. Terminal and 1,1-disubstituted olefins are tolerated with nearly equal efficacy. Examination of a series of competition experiments in combination with analysis of reaction outcome shed considerable light on the operative catalytic cycle. Through a detailed study of a series of X-ray structures of rhodium(cod)chloride/phosphoramidite complexes, we have formulated a mechanistic hypothesis that rationalizes the observed product selectivity.

Download full-text

Full-text

Available from: Kevin M Oberg, May 09, 2014
0 Followers
 · 
80 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The discovery and development of the asymmetric rhodium-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and exogenous alkynes to form indolizinone and quinolizinone scaffolds is described. This methodology has been expanded to include substituted alkenes and dienes, a variety of sterically and electronically diverse alkynes, and carbodiimides in place of the isocyanate. Through X-ray analysis of Rh(cod)/phosphoramidite complexes, additives that modify the enantio-determining step, and other experimental data, a mechanism has been proposed that explains lactam, vinylogous amide, and pyridone products and the factors governing their formation. Finally, we have applied this methodology to the synthesis of (+)-lasubine-II and (-)-209D.
    Pure and Applied Chemistry 07/2009; 82(7):1353-1364. DOI:10.1351/PAC-CON-09-12-09 · 3.11 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Excess substrate has been identified as an unintended spectator ligand affecting enantioselectivity in the [2 + 2 + 2] cycloaddition of alkenyl isocyanates with tolanes. Replacement of excess substrate with an exogenous additive affords products with consistent and higher ee's. The increase in enantioselectivity is the result of a change in composition of a proposed rhodium(III) intermediate on the catalytic cycle. The net result is a rational probe of a short-lived rhodium(III) intermediate and gives insight that may have applications in many rhodium-catalyzed reactions.
    Organic Letters 10/2009; 11(21):4934-7. DOI:10.1021/ol9020805 · 6.32 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cycloaddition reactions are attractive strategies for the rapid formation of molecular complexity in organic synthesis, as multiple bonds are formed in a single process. To this end, several research groups have been actively involved in the development of catalytic methods to activate readily accessible pi-components to achieve cycloadditions. However, the use of C-N pi-components for the formation of heterocycles by these processes is less well developed. It has been previously demonstrated that the combination of different isocyanates with two alkynes yields pyridones of several types by metal-catalyzed [2 + 2 + 2] cycloadditions. The potential of this chemistry has been extended to alkenes as C-C pi-components, allowing the formation of sp(3)-stereocenters. In this tutorial review directed towards [n + 2 + 2] cycloadditions of heterocumulenes, alkynes and alkenes, the recent advances in the catalytic asymmetric synthesis of indolizidine, quinolizidine and azocine skeletons are discussed.
    Chemical Society Reviews 11/2009; 38(11):3149-59. DOI:10.1039/b816702h · 30.43 Impact Factor