Enantioselective Alkyne Additions

Jiang has subsequently reported the use of amino alcohol 319 in Zn-cata-lyzed enantioselective alkyne additions to aldehydes [192]. In an important development of the method, the substrate scope was expanded also to include non-enolizable a-ketoesters, such as 318 (Equation 22) [193]. 

Numerous methods have been developed for the addition of Zn-acetylides that are preformed from terminal acetylenes with stoichiometric quantities of Et2Zn. Most notable of these is Pu s work, in which BINOL/Ti(IV) complexes are shown to be efficient catalysts in highly enantioselective additions 

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Enantioselective conjugate addition can also be carried out with cyclic enones. Shuichi Oi and Yoshio Inoue of Tohoku University in Sendai report (Tetrahedron Lett. 2004, 45, 5051) that a BINAP complex of Rh catalyzes the enantioselective conjugate addition of alkenyl Zr species such as 5, to give 7 in high enantiomeric excess. Alkenyl Zr species such as 5 are readily prepared by hydridozirconation of alkynes. It is particularly important that addition of TMS-C1 to the reaction mixture at the end of the conjugate addition leads cleanly to the enol ether 6. 

A copper-catalysed, enantioselective, conjugate addition of a terminal alkyne, which undergoes an in situ metallation, has been reported. The addition of phenylacetylene to Meldrum s acid-derived acceptors (196) takes place in aqueous medium, without recourse to an inert atmosphere. The success of the enantioselective reaction was made possible by the use of PINAP (198), a new class of P,IV-ligands (cf. QUINAP), which have the advantage of easier resolution. Furthermore, these modular ligands are responsive to numerous electronic and steric modifications that permit optimization of the reaction. The products (197) were obtained in good yields and with 82-97% ee.235... 

The enantioselective alkyne-imine addition has been achieved using a copper(i)-bis(oxazoline) compound in [G4GiIm]N(GF3S02)2 (Scheme 46). ... 

Scheme 2.26 Enantioselective conjugate addition of terminal alkynes to a,p-unsaturated thioamides with the use of chiral Cu(i) complex, Li(OC6H4- 3-OMe), and chiral phosphoric acid.

A new enantioselective Rh-catalyzed domino transformation of boronic acids with a cyclohexadienone-tethered alkyne gave access to fused heterocycles by desymmetrization of alkyne-tethered cyclohexadienones via the formation of two new C-C bonds and two new stereocenters with good enantioselectivities, syn-addition of the rhodium-aryl species onto the alkyne (130L1148). 

C. Wei, C.-J. Li, J. Am. Chem. Soc. 2002, 124, 5638-5639. Enantioselective direct-addition of terminal alkynes to imines catalyzed by copper(I)pybox complex in water and in toluene. 

The spiroketal (+)-spiroxaliiie methyl ether 31 contains three secondary oxygenated ste-reogenic centers. In a showcase of current chiral technology, Barry M. Trost of Stanford University constructed (Angew. Chetn. Int. Ed. 2007, 46, 7664) the first two of the three alcohols by the enantioselective addition of an aUsyne to an aldehyde. The chiral catalyst 25 that directed the alkyne additions was derived from a commercial Hgand. The last alcohol center was derived from / -(+)-epoxypropane. Note that the spiroketal was not prepared in the usual way, by acid-catalyzed cyclization of a dihydroxy ketone, but by Pd-catalyzed cyclization of the alkyne diol 30. 

Hydroboration of terminal alkynes followed by the B/Zn exchange and enantioselective catalytic addition to aldehydes serves as a simple and efficient method for the preparation of chiral nonracemic allylic alcohols. 

In the context of a practical synthesis of the HIV reverse transcriptase inhibitor efavirenz (300), the enantioselective addition of metalated terminal acetylenes to ketones was studied and developed at Merck (Scheme 2.37) [184], The key enantioselective addition of the lithium acetylide prepared from 298 to ketone 296 in the presence of amino alcohol 297 proceeded with impressive enantioselectivity additionally, the process can be conducted on multi-kilogram scale. Careful mechanistic studies including spectroscopic work by Collum suggested that the alkyne addition proceeds via the cubic lithium tetramer 301 [185],... 

In 2002, Braga el al. employed a chiral C2-symmetric oxazolidine disulfide as a ligand for the enantioselective synthesis of propargylic alcohols by direct addition of alkynes to aldehydes (Scheme 3.64). Good yields but moderate enantioselectivities (<58% ee) were obtained for the enantioselective alkyny-lation of aldehydes in the presence of ZnEt2. 

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