The effects of the nature of catalyst and of the solvent on the stereoselectivity in amine-catalyzed asymmetric synthesis of substituted cyclohexa-1,3-dienes from prenal and monoesters of ylidenemalonic acids

Abstract

In the amine-catalyzed reactions of prenal with (Z)-5-methyl-2-(methoxycarbonyl)hexa-2,4-dienoic or (Z%3-phenyl-2-(ethoxycarbonyl)prop-2-enoic acid chiral 13-amino alcohols provide for higher enantiomeric purity of the resulting alkyl 4-methyl-6-(2-methylprop-1-enyl)-and 4-methyl-6-phenylcyclohexa-l,3-dienoates than that provided by related chiral amines without hydroxy group. The vatues of ee attained in nonpolar solvents are higher than those observed in the polar ones. Substituting stoichiometric amounts of a chiral 1-amino-3-methylbuta-l,3-diene for a combination of prenal with 0.1 equiv, of the corresponding chirat amine results in the products of much lower enantiomeric purity.Key words: 3-methylbut-2-enal, chiral secondary amines and hydroxy amines; chiral dienamines; monoalkyl ylidenemalonates; net enantioselectivity.Employing homochiral 2-amino-1,3-dienes in asymmetric Diels--Alder cycloaddition reactions 1,2 involves preparing them preliminarily. On the other hand, chiral six-membered carbocycles can be obtained following the same pattern, but in a single step, by generating a chiral l-amino-l,3-diene from a branched ct,13-enal A and a chiral secondary amine in the presence of an atkyl hydrogen ylidenemalonate as the dienopile. 3 Then the nascent dieneamine B eycloadds to the dienophile C to give unstable 13-amino acids D which readily release CO 2 (this makes the whole process irreversible) and leave a chiral cyclohexadiene E and the starting chiral amine which re-enters the catalytic cycle (Scheme 1).Here we report on the effects of the structure and absolute configuration of chiral amines on the net enantioselectivity (NES) and its trend in the aminecatalyzed asymmetric synthesis of methyl 4-methyl-6-(2-methylprop-1 -enyl)cyclohexa-1,3-dienecarboxylate (1) or ethyl 4-methyl-6-phenylcyclohexa-l,3-dienecarboxylate (2) from prenal (3) and 5-methyl-2-(methoxycarbonyl)hexa-2,4-dienoic (4) or 5-methyl-2-(ethoxycarbonyl)prop-2-enoie acid (5), respectively.* All experiments were carried out using crystalline monoesters 4 and 5 consisting entirely of the Z isomers (according to 1H NMR data, cf Ref. 4), which makes * In fact, the formation of compounds I and 2 involves two diastereoselective steps, that is, the formation and fragmentation of the corresponding cycloadducts of the type D. Hence, as a matter of convenience, the stereochemical outcome of the whole process should be termed net enantioselectivity.

Old tricks, new dogs: organocatalytic dienamine activation of α,β-unsaturated aldehydes

“…The first Diels–Alder reaction takes place by a [4+2]-cycloaddition pathway involving a cis -configured dienamine intermediate ( AB ), and it was proposed that the expulsion of CO 2 promotes the cycloaddition process ( AB′ intermediate) to form 111 in line with Serebryakov's original postulation in the 90's. 10 The reaction proceeded quite well for a large variety of cases (19 examples) in good yields and enantioselectivities.…”

“…The early example of in situ generation of dienamine intermediates demonstrated by Serebryakov et al 10 has inspired others to make use of these intermediates for the α-functionalisation of α,β-unsaturated aldehydes in a wide variety of reactions.…”

“…After this early example from the 70's, in 1993, Serebryakov and colleagues were the first to study the stoichiometric and organocatalytic dienamine activation of α,β-unsaturated aldehydes ( Scheme 2 ). 10 In these works, the authors described the synthesis of different polysubstituted cyclohexadienes, using the HOMO-raising activation of the dienamine system. The authors reported that after the formation of the chiral dienamine, a subsequent cycloaddition from its sterically less hindered face to a dienophile ( exo or endo approach) can take place to give the final cycloadducts which, after hydrolysis and release of the catalyst, could give the polysubstituted cyclohexadienes.…”

The effect of pressure on the diastereoselectivity of the reaction of prenal with monoalkyl ylidenemalonates catalysed by homochiral secondary amines

“…Recently, the catalytic synthesis of optically active cyclohexa-1,3-dienes from β-branched α,β-alkenals and various monoalkyl ylidenemalonates was described, 1 and factors affecting the apparent (net) enantioselectivity of this process were studied. 2 The reaction mechanism (Scheme 1) 1-3 involves the transient formation of a dienamine followed by two consecutive, inherently diastereoselective reactions. One of them, intermolecular [4+2] cycloaddition, is strongly accelerated by pressure, 4 whereas the other is believed to proceed via a six-membered transition state, 5 which can also be affected by pressure.…”

“…Since the net enantioselectivity of cyclohexadiene formation diminishes with temperature, 1,2 we used a high-pressure technique as an alternative to heating for accelerating the process without damaging the ee of its products. Scheme 2 demonstrates two examples examined.…”