Chiral Vinyl Anions for “Carbonyl Umpolung”. Highly Stereoselective Addition of a Novel Enantiomerically Pure Vinyllithium Reagent to Aldehydes

Abstract

The vinyllithium reagent 13 and its enantiomer are generated by a bromine/lithium exchange reaction starting from dibromoalkenes 11 and 12, both available from the corresponding enantiomer of alkyl lactate. When 13 is allowed to react with aldehydes or with acetophenone, a highly stereoselective addition to the Re face of the carbonyl compounds occurs to give predominantly the diastereomers 15. Alkenes 25a, c, accessible by another bromine/lithium exchange reaction of 15a, d and subsequent protonation, can be cleaved by ozonolysis followed by reduction to afford carbinols 27a, b in > 98% ee. The sequence corresponds to a stereoselective introduction of a methanol d1 synthon (QCH,OH) or, as shown by other examples, of acyl and formyl d1 synthons (OCRO and OCHO) into prochiral carbonyl compounds. As a consequence, 13 and its enantiomer may be regarded as highly stereoselective reagents for "carbonyl umpolung". A series of further vinyllithium reagents, 38a-g and 54/55, is treated with benzaldehyde, but none of those displays comparable enantiofacial selectivity. The prerequisites to the highly stereoselective reactions of 13 and its enantiomer are briefly discussed.The introduction of a nucleophilic aldehyde, formic acid, or methanol synthon la, b and 2 ("dl reactivity"2)) into aldehydes or unsymmetrical ketones leads to the formation of one chiral center. There is no doubt that a-hetero-substituted carbanions, which can be considered as equivalents of the synthons la, b and 2 are amongst the most important reagents for carbon -carbon bond formation. The plethora of methods for carbonyl-dipol inversion ("umpolung" 3J) suffers, however, from the drawback that racemic products 3a, b and 4 are obtained. Enantiomerically pure acyloins 3a, a-hydroxy carboxylic acids 3b, and diols 4 should be available, in principle, if either chiral reagents incorporating d' reactivity or their achiral analogs combined with chiral additives are used. According to the latter conception, only moderate enantioselectivity has been obtained with most of the chiral complexing agents applied so far4'. Proline-derived ligands, although rather promising, seem to be effective for special combinations of substrates and reagents only5). On the other hand, a-hetero-substituted carbanions with covalently bonded chiral auxiliary groups are rare. Some of the few examples described so far are plagued by the fact that the chiral information is not readily accessible and has to be destroyed in order to liberate the desired acyloin 3a6). Other synthetic equivalents of the synthons la, b and 2 suffer from insufficient stereoselection with respect to the enantiotopic faces of the aldehyde'). Synthetic chemists, being aware of this problem, have elaborated several alternatives which do not involve the direct stereoselective additon of chiral synthons la, b and 2 to aldehydes, but, nevertheless, afford nonracemic acyloins 3a, a-hydroxy acids 3b, and diols 4. Amongst these detours are the enantioselective chemical'' or microbial'' reduction of achiral a-0x0 est...

Small and Versatile – Formyl Anion and Dianion Equivalents

“…The aldehyde functionality is liberated after ozonolysis of the C=N double bond. [23] A chiral version of a lithiated vinyl species was disclosed by Braun and co-workers (Scheme 3) [24] that utilises anion 15 (prepared from MEM-protected lactic acid). The MEM group was chosen because of its chelating properties which helped to achieve high stereoselectivities in reactions with aldehydes or ketones.…”

Lithium Carbenoids

“…Obviously, a kinetically favored substitution of the more easily accessible trans bromine atom occurs. When, however, slightly less than one equivalent (0.95-0.98 equiv) of n-butyllithium is slowly added to a solution of 40 in diethyl ether at −105 • C, the E-configurated carbenoid 41 forms almost exclusively, and the carboxylic acids E-and Z-42 are obtained after reaction with dry ice in a ratio of over 99:1 (Scheme 9) 192,193 . …”

“…The former procedure has been applied preferentially in the case of lithiated vinyl ethers, whereas the latter has been used in particular for cleavage of the double bond in such products that result from the reaction of lithiated vinyl bromides with electrophiles (Scheme 17). It turned out that the requirements of such a chiral d 1 reagent are fulfilled by the 1-bromo-1-lithio-1-alkenes S-and R-41, which are available from the corresponding enantiomer of lactate 192,193 . When added to aldehydes or imines, significant diastereoselectivity will be displayed only by the E-diastereomer 41.…”

“…Thus, the selective exchange of the bromine atom in the Z-position of the dibromoalkene 40, outlined in Scheme 9, is prerequisite to the efficiency of this concept. 193 .…”

“…This reaction takes place under complete retention of the configuration, as proven by the protonation that yields the Z-alkenes 149 193 Aside from aldehydes, imines can be considered to be suitable substrates for the addition of reagents with umpoled carbonyl reactivity because useful building blocks and important compounds like α-amino acid and aldehydes will result from this conversion (Scheme 21) 382 Re face. Thus, bromoalkenes 155 are obtained with high diastereoselectivity.…”