Alcohols, from addition organometallics

Lactonization of alcohols derived by organometallic addition to 2-formyl amides, lactol formation from 2-formyl amides themselves and lactam formation from their nitrogen counterparts are also useful synthetically. 

M. Tramontini, Synthesis 1982, 605-644 . .Stereoselective Synthesis of Diastereomeric Amino Alcohols from Chiral Aminocarbonyl Compounds by Reduction or by Addition of Organometallic Reagents". 

The formation of chiral alcohols from carbonyl compounds has been fairly widely studied by reactions of aldehydes or ketones with organometallic reagents in the presence of chiral ligands. Mukaiyama et al. 1081 obtained excellent results (up to 94% e.e.) in at least stoichiometric addition of the chiral auxiliary to the carbonyl substrate and the organometallic reagent. 

Acetylide (RC=CNa) and alkynide (RC=CMgX and RC=CLi) are good nucleophiles. They react with carhonyl group to from alkoxide, which under acidic work-up gives alcohol. The addition of acelylides and alkynides produces similar alcohols to organometallic reagents. 

Enantiomerically-pure sulfoxides are readily available. Ilan Marek of Technion-Israel Institute of Technology reports (1. Am. Chem. Soc. 125 11776, 2003) that alkyne-derived sulfoxides such as 8 can be used to direct the addition of an allylic organometallic, prepared in situ, to an aldehyde 9. Both the secondary alcohol, from the aldehyde, and the adjacent quaternary center of 10 are formed with >99% stereocontrol. 

Direct attack on oxygen was postulated in the reaction of Grignard and lithium reagents with [E]-2-benzenesulfonyl-3-phenyloxaziridine 55. The principal organic products were alcohols and phenols (50-95% yields), derived from the organometallic reagent, and amines derived from addition of the organometallic to the intermediate A -sulfonyl imine (60-95%). 

We need carbonyl groups to do conjugate addition so the tertiary alcohols will have to be made from them. In Chapter 9 (p. 222) we saw how to make such tertiary alcohols from esters and organometallic compounds and in Problem 1 of this set we saw how to do double conjugate additions on unsaturated esters - all the pieces fit together. 

The use of inorganic supramolecular compounds in catalysis has also been successful in recent years. Hupp etal. incorporated a Mn (III)-porphyrin see Porphyrin) epoxidation catalyst inside a molecular square, a system that shows enhanced catalyst stability and substrate selectivity as compared to the free catalyst. In another example, chiral metallocyclophanes were constructed from Pt(PEt3)2 units and enantiopure atropoisomeric l,E-binapthyT6,6 -bis-(acetylenes) and used in enantioselective diethyl zinc addition to aldehydes to afford chiral secondary alcohols. The first organometallic triangle based on Pt(II) and alkyne-di-substituted-binaphthyl system was reported and found to effect asymmetric catalysis reactions of aldehydes to alcohols with excellent conversion rates and enantiomeric excess/ ... 

The preparation of the optical antipodes of a-aminopropiophenone from norephedrine and an improved large-scale resolution of norephedrine have been described. The stereoselective synthesis of diastereomeric amino-alcohols from chiral aminocarbonyl compounds by reduction or by addition of organometallic reagents has been reviewed, and syntheses of a-allenic amines and allenic amino-alcohols have been reported. 

A one-pot synthesis of unsymmetrical tertiary alcohols from the N-methyl-aminopyridine amides (2) by successive addition of two metallo-nucleophiles (Grignard reagents or organolithiums) has been developed (Scheme 3). Substitution of LiAlH4 for the second organometallic reagent leads to secondary alcohols. 

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