Aldehydes reductive metallation

Hoffmaim-La Roche has produced -carotene since the 1950s and has rehed on core knowledge of vitamin A chemistry for the synthesis of this target. In this approach, a five-carbon homologation of vitamin A aldehyde (19) is accompHshed by successive acetalizations and enol ether condensations to prepare the aldehyde (46). Metal acetyUde coupling with two molecules of aldehyde (46) completes constmction of the C q carbon framework. Selective reduction of the internal triple bond of (47) is followed by dehydration and thermal isomerization to yield -carotene (21) (Fig. 10). 

It is not clear whether the silyl iodide causes activation of only one of the benzyloxy groups, or if a substitution by iodine takes place before reductive metalation. These reagents exhibit a high preference for aldehyde over ketone addition13. 

The catalyst derived from Rh6(CO)i6 is the most active catalyst for aldehyde reduction of all the group 8 metals we have studied (12,13). 

Catalysts and Catalyst Concentration. The most active catalyst for benzaldehyde reduction appears to be rhodium [Rh6(C0)i6 precursor], but iron [as Fe3(C0)i2] and ruthenium [as Ru3(C0)12] were also examined. The results of these experiments are shown in Table 1. Consistent with earlier results (12), the rhodium catalyst is by far the most active of the metals investigated and the ruthenium catalyst has almost zero activity. The latter is consistent with the fact that ruthenium produces only aldehydes during hydroformylation. Note that a synergistic effect of mixed metals does not appear to be present in aldehyde reduction as contrasted with the noticeable effects observed for the water-gas shift reaction (WGSR) and related reactions (13). 

The effect of cryptands on the reduction of ketones and aldehydes by metal hydrides has also been studied by Loupy et al. (1976). Their results showed that, whereas cryptating the lithium cation in LiAlH4 completely inhibited the reduction of isobutyraldehyde, it merely reduced the rate of reduction of aromatic aldehydes and ketones. The authors rationalized the difference between the results obtained with aliphatic and aromatic compounds in terms of frontier orbital theory, which gave the following reactivity sequence Li+-co-ordinated aliphatic C=0 x Li+-co-ordinated aromatic C=0 > non-co-ordinated aromatic C=0 > non-co-ordinated aliphatic C=0. By increasing the reaction time, Loupy and Seyden-Penne (1978) showed that cyclohexenone [197] was reduced by LiAlH4 and LiBH4, even in the presence of [2.1.1]-cryptand, albeit much more slowly. In diethyl ether in the absence of... 

Reductive metallation of aldehydes (but not ketones) by tri-n-butyl-(trimethyisilyl)stannane to yield a-hydroxystannanes is catalysed by tetra-n-butylammonium cyanide [15]. Other phase-transfer catalysts are not as effective and solvents, other than tetrahydrofuran, generally give poorer conversions. Use of a chiral catalyst induced 24% ee with 3-phenylpropanal. 

R. A. W. Johnstone, Reduction of Carboxylic Acids to Aldehydes by Metal Hydrides, in Comprehensive Organic Synthesis (B. M. Trost, I. Fleming, Eds.), Vol. 8, 259, Pergamon Press, Oxford, 1991. 

Reductive metallation must now be performed at room temperature for the electron transfer to proceed at a reasonable rate and under Barbier conditions. At this temperature, the intermediate reagent is stable enough for a carbon-carbon bond formation in the presence of the carbonyl compound (Barbier conditions) because without the latter, it would -eliminate or protonate. This simple procedure is mild enough to be extended to the synthesis of a carbon-linked disaccharide, as shown in Figure 17, for the preparation of the derivative of the C-linked mimic 24 of the a-D-marmopyranosyl(l->2)-D-glucopyra-noside from sulfone 22 and aldehyde 23. ... 

Reduction of Carboxylic Acids to Aldehydes by Metal Hydrides... 

The procedure is remarkably effective for the coupling with cyclic ketones and provides a fast access to a-C-ketosides of Neu5Ac. The coupling efficiency is however moderate in the synthesis of C-disaccharides, as shown with the D-galactose-derived aldehyde 198 (O Scheme 44). Acetates 213 provide the expected compound 215 but much less efficiently than sulfide 204 (30 versus 82% yield, respectively). The moderate yield using acetates 213 is due to the competitive pinacol coupling of aldehyde 198 because the rate of the reductive metallation of the anomeric acetates is too slow. 

The use of InCls for Lewis acid activation of aldehyde substrates leads to rapid transmetalation of the allylic stannane, followed by carbonyl addition reactions of an allyl indium reagent. Premixing of InCb and the allylic stannane in the absence of aldehyde often produces precipitation and poor results. On the other hand, allyl indium reagents have been independently prepared by several procedures, including reductive metalations. Several important reviews describe the methods of preparation and the reactivity of allyl indium compounds. This discussion will be limited to key factors regarding the transmetalation of allylic stannanes in the presence of aldehydes. Stereochemical events leading to the production of anti adducts as major products are illustrated in Scheme 5.2.55. 

Zinc ion is essential for the catalytic activities of both yeast and liver alcohol dehydrogenase. Until recently, model systems have been notably unsuccessful in accounting for the participation of Zn(II) in the enzyme-catalyzed oxidoreductive interconversion of aldehyde and alcohol. The studies of Creighton and Sigman (20) and of Shinkai and Bruice (21, 22) conclusively demonstrate that Lewis (general) acid catalysis by Zn + (and other divalent metal ions) can effectively promote aldehyde reduction by the reduced 1,4-dihydropyridine moiety. 

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