This account examines double asymmetric induction from theoretical and practical viewpoints. In the context of four major organic reactions-the aldol, Diels-Alder, catalytic hydrogenation, and epoxidation-it is shown that a double asymmetric induction can be analyzed in terms of the single asymmetric reactions of each of the two chiral reactants. A rule which qualitatively relates the results of these single asymmetric reactions with the outcome of the double asymmetric reaction is proposed. A powerful new strategy based on this rule for the predictable creation of new chiral centers is discussed and the use of this strategy for the synthesis of sugars and macrolides is presented.

Double Asymmetric Synthesis and a New Strategy for Stereochemical Control in Organic Synthesis

Asymmetric catalysts, either chemical or biological, effect the reactions of enantiomeric substrates at unequal rates, allowing for the kinetic resolution of racemates. The asymmetric reaction of chirally labile compounds capable of undergoing in situ racemization can, in principle, afford a single stereoisomer in 100% ee and in 100% yield. The second-order reaction provides a powerful tool for the stereoselective synthesis of chiral compounds, as exemplified by, among others, the biochemical hydrolysis of hydantoins or oxazolinones and microbial reductions or BINAP–Ru(II) catalyzed hydrogenation of certain α-substituted β-keto esters. Such transformations are characterized by the presence of parallel reactions interrelated by the stereoinversion of the enantiomeric substrates. The efficiency is decisively affected by the kinetic parameters, particularly the relative rates of the stereoinversion and reaction as well as the intrinsic stereochemical parameters of the catalyst and substrate. Such stereoselec...

Stereoselective Organic Synthesis via Dynamic Kinetic Resolution

Stereocontrol in the synthesis of acyclic systems: applications to natural product synthesis

uous specification of the steric course and the product configuration of diastereoselective reactions. The reflection-invariant relative topicity of approach of reactants is defined as like {Ik) and unlike (ul) if the corresponding descriptor pairs are Re*,Re*. or R*,Re*, and Re*,Si* or R*,Si*, respectively. The descriptor pair notations (Ik and uc) of reactants disclose related steric courses of reactions more often than do the relative configurations of their products, for which the configurational notation I= R*,R* and u= R*,S* is proposed. The advantage of specifying the relative topicity is demonstrated by means of a series of recent examples of importance to the synthetic organic chemist taken from the literature and from our own work. 1. Introduction-The Problem Complex natural products such as macrolides, ionophores, and related compounds have recently become target molecules for synthetic organic chemists[’]. The often formidable array of asymmetric carbon atoms in the structures of these compounds[21 has stimulated the development of highly stereoselective asymmetric syntheses. Foremost amongst these are the ald~l[~-~], nitr~aldoF“~], and Michael additions[81. In all these reactions two planar trigonal carbon atoms are linked together to create a pair of asymmetric tetrahedral carbon atoms [route (a) in Scheme 11. Stereoselective additions to 01efins[~] and to trigonal carbon atoms a to an asymmetric carbon [routes (b) and (c), respectively, in Scheme 11, give the same type of products 1L7.9-121

The Unambiguous Specification of the Steric Course of Asymmetric Syntheses

Synthesis of optically active pheromones

About the Stereospecific α-Alkylation of β-Hydroxyesters



It was found, that dianions derived from β-hydroxyesters with lithium diisopropylamide (LDA) at −50 to −20° were alkylated stereospecifically (Scheme 1). The stereospecificity was 95–98%, the threo-compound (threo-2, -3 and -4) being the main product. This was proved for threo-2 and -3 by preparing the β-lactones 7 and 8, respectively, which were pyrolyzed to trans-1, 4-hexadiene (9) and trans-1-phenyl-2-butene (10), respectively (Scheme 2). Moreover, the acid threo-6 from threo-3 was converted by dimethylformamide-dimethylacetal to cis-1-phenyl-2-butene (11) (s. footnote 6).



The alkylation of α-monosubstituted β-hydroxyesters also turned out to be stereospecific. Reduction of 16 and 18 with actively fermenting yeast furnished (+)-17 and (+)-2. respectively (Scheme 4), which were each mixtures of the (2R, 3S)- and the (2S, 3S)-isomers. Alkylation of (+)-17 with allyl bromide yielded after chromatography (2S, 3S)-19 and of (+)-2 with methyl iodide (2R, 3S)-19, the oxidation of which finally gave (S)-(−)-20 and (R)-(+)-20, respectively.

Über die Stereospezifität der α‐Alkylierung von β‐Hydroxycarbonsäureestern. Vorläufige Mitteilung

Stereospecific Synthesis of (+)-(3R, 4R)-4-Methyl-3-heptanol, the Enantiomer of a Pheromone of the Smaller European Elm Bark Beetle (Scolytus multistriatus)



Reduction of 2 with actively fermenting baker's yeast gave (−)-3. Stereospecific alkylation [3] of (−)-3 with propyl iodide furnished ethyl (+)-(2R, 3R)-2-propyl-3-hydroxypentanoate ((+)-4, 58%) which was converted to the tetrahydropyranyl ether (−)-5, then the alcohol 6, the p-toluenesulfonate 7 and the thiophenyl ether 8 to give the title compound (+)-1. The latter consisted of 97% of the threo- and 3% of the erythro-isomer. The above synthesis also correlates the absolute configuration of (−)-(R)-3 with that of (+)-(R)-citronellic acid (see [2]).

Stereospezifische Synthese von (+)-(3R, 4R)-4-Methyl-3-heptanol, das Enantiomere eines Pheromons des kleinen Ulmensplintkäfers (Scolytus multistriatus)

The Stereoselectivity of the α-Alkylation of (+)-(1R, 2S)-cis-Ethyl-2-hydroxy-cyclohexanecarboxylate



In continuation of our work on the stereoselectivity of the α-alkylation of β-hydroxyesters [1] [2], we studied this reaction with the title compound (+)-2. The latter was prepared through reduction of 1 with baker's yeast. Alkylation of the dianion of (+)-2 furnished (−)-4 in 72% chemical yield (Scheme 1) and with a stereoselectivity of 95%. Analogously, (−)-7 was prepared with similar yields. Oxidation of (−)-4 and (−)-7 respectively furnished the ketones (−)-6(Scheme 3) and (−)-8(Scheme 4) respectively, each with about 76% enantiomeric excess (NMR.). It is noteworthy that yeast reduction of rac-6(Scheme 3) is completely enantioselective with respect to substrate and product and gives optically pure (−)-4 in 10% yield, which was converted into optically pure (−)-6(Scheme 3).



The alkylation of the dianionic intermediate shows a higher stereoselectivity (95%) from the pseudoequatorial side than that of 1-acetyl- or 1-cyano-4-t-butyl-cyclohexane (71% and 85%) [9] or that of ethyl 2-methyl-cyclohexanecarboxylate (82%). The stereochemical outcome of the above alkylation is comparable with that found in open chain examples [1] [2].



Finally (+)-(1R, 2S)-2 was also alkylated with Wichterle's reagent to give (−)-(1S, 2S)-9 in 64% yield. The latter was transformed into (−)-(S)-10 and further into (−)-(S)-11(Scheme 5). (−)-(S)-10 and (−)-(S)-11 showed an e.e. of 76–78% (see also [11]). Comparison of these results with those in [11] confirmed our former stereochemical assignment concerning the alkylation step.

Über die Stereoselektivität der α‐Alkylierung von (1R, 2S) (+)‐cis‐2‐hydroxy‐cyclohexancarbonsäureäthylester

On the stereoselectivity of the α-alkylation of β-hydroxy esters. Enantioselective synthesis of 4,4- and 6,6-disubstituted cyclohex-2-en-1-ones.

Through sequential Claisen- and Cope rearrangements the chainlengthening of allylic alcohols by one isoprene unit was achieved. Treatment of (E)-1a first with lithium N-cyclohexyl-N-isopropylamide at −70°, followed by trimethylsilylchloride and warming up to room temperature yielded after work-up 3a (R = H), which rearranged at 156° in high yield to (E/Z)-4a. An analogous reaction sequence transformed 6 to 8. Choosing lithium N-methylanilide as a base (E/Z)-9 was selectively rearranged to 12, which was converted to the Cecropia juvenile hormone precursor (E/Z)-4b.

György Fráter

Papers

Über die Stereospezifität der α‐Alkylierung von β‐Hydroxycarbonsäureestern. Vorläufige Mitteilung

Stereospezifische Synthese von (+)-(3R, 4R)-4-Methyl-3-heptanol, das Enantiomere eines Pheromons des kleinen Ulmensplintkäfers (Scolytus multistriatus)

Über die Stereoselektivität der α‐Alkylierung von (1R, 2S) (+)‐cis‐2‐hydroxy‐cyclohexancarbonsäureäthylester

On the stereoselectivity of the α-alkylation of β-hydroxy esters. Enantioselective synthesis of 4,4- and 6,6-disubstituted cyclohex-2-en-1-ones.

Synthese yon 2,6‐Diencarbonsäuren Vorläufige Mitteilung