Natural products Nozaki-Hiyama-Kishi reaction

The unique features of the Nozaki-Hiyama Kishi reaction make this an attractive methodology in the application to natural products synthesis, particularly the pronounced chemoselectivity and remarkable compatability with an array of functional groups. However, there are very few reports published of the application of enantioselective NHK reactions in the total synthesis of natural products. This section is divided into three parts 1) preparation of fragments with the NHK reaction in the synthesis of a portion of a natural product 2) the NHK reaction in the final or second last step of a natural product 3) the NHK reaction utilized anywhere in the total synthesis of a natural product. The next several pages show natural products where the NHK reaction have been employed in the syntheses of natural products since Fiirstner s review published in 1999. ... 

This chapter will review the literature up to the end of 2011 on the stereoselective Nozaki-Hiyama-Kishi reaction and applications in natural product synthesis. The transformation of the NHK reaction from using stoichiometric to catalytic amounts of chromium will be addressed initially then the diastereoselective NHK, followed by the enantioselective version (with an emphasis on the different classes of chiral ligands that have been employed in a wide variety of carbon-carbon bond forming processes), and finally, selected examples of the application of the NHK reaction to natural product synthesis will be described. 

Considering the unique features that the Nozaki-Hiyama-Kishi reaction possesses and its undoubted potential in the synthesis of complex natural products, the development of an efficient enantioselective version to control the absolute stereochemical outcome for a range of processes was highly desirable. However, because of the difficulties such as ligand coordination and specificity combined with the tendency of chromium(II) to form dimers or clusters with polydentate ligands, considerable effort has been devoted to the development of enantioselective variants. These studies have resulted in the expansion of the NHK to now include an impressive array of carbon-carbon, bond-forming processes (Scheme 12.6). 

Solandelactones A, B, E, and F have been synthesized by White et al., in which the diene side chain was installed using a Nozaki-Hiyama-Kishi reaction. Aldehydes 48 and 49 were prepared by tetrapropylammonium perruthenate oxidation of the corresponding alcohols and were immediately treated with CrCla and NiCl2 to afford the natural products solandelactone A, B, E, and F (Scheme 12.36). ... 

We selected the natural product thyrsiferol as an ideal target to test our ideas. Its total synthesis was envisioned to proceed as illustrated in the Scheme 28. The successful coupling between aldehyde 84 and vinyl iodide 82 via a Nozaki-Hiyama-Kishi (NHK) reaction [66] had been demonstrated previously [29]. We therefore sought to model our final steps after precedence presented by Forsyth for the union of these two fragments. The focus of our synthetic strategy centered around the stereoselective synthesis of the ABC framework (84) of thyrsiferol (1) as a scaffold to validate the scope of the Cp2TiCl reaction with epoxides toward the assembly of Q-C-glycosides and cyclic ethers. 

The one-pot Barbier-type addition of alkenyl, aryl, allyl, vinyl, propargyl, alkynyl, or allenylchromium compounds to aldehydes or ketones is known as the Nozaki-Hiyama-Kishi (NHK) reaction. An excellent review by Furstner published in 1999 detailed the exhaustive literature on the carbon-carbon bond formations involving organochromium(III) reagents. This chapter will present major developments and examples of recent carbon-carbon bond formation methodology and improvements as well as their use in natural products synthesis since 1999. 

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