Enantioselective aldol condensation

Several examples exist of the application of chiral natural N-compounds in base-catalyzed reactions. Thus, L-proline and cinchona alkaloids have been applied [35] in enantioselective aldol condensations and Michael addition. Techniques are available to heterogenize natural N-bases, such as ephedrine, by covalent binding to mesoporous ordered silica materials [36]. 

The ultimate goal of designing highly enantioselective aldol condensations demands that all stereochemical aspects of the bond construction process be kinetically controlled. Over the past 5 years, this objective has stimulated a great deal of research, and a wealth of new information is now becoming available on the important kinetic stereochemical control elements and possible transition state geometries for this reaction. 

Finally, another possibility is to design enantioselective syntheses by using external chiral auxiliaries either in catalytic or in stoichiometric quantities [21], Since these strategies are nowadays of great interest in organic synthesis, we will consider here some of the most recent results achieved in enantioselective aldol condensations, as well as in the asymmetric epoxidation and hydroxylation of olefmic double bonds. 

Enantioselective aldol condensations Chiral enolates. "Simple asymmetric induction"... 

Scope and limitations of enantioselective aldol condensations. Recent advances... 

The preceding reactions illustrate control of stereochemistry by aldehyde substituents. Substantial effort has also been devoted to use of chiral auxiliaries and chiral catalysts to effect enantioselective aldol reactions.71 72 Avery useful approach for enantioselective aldol condensations has been based on the oxazolidinones 1-3, which are readily available in enantiomerically pure form. 

Enantioselective aldol condensation. Masamtinc et al. have prepared optically pure /Miydroxy-a-methyl carboxylic acids by aldol condensation with the (S)- and (RHsomers of the ethyl ketone I, prepared in three steps from commercially available (S)- and (R>mandelic acid. For example, (SH is converted into the (Z)-boron cnolatc (2), which condenses with propionaldehyde to form a single aldol... 

Evans DA, Bartroli J et al (1981) Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates. J Am Chem Soc 103 2127-2129... 

Benaglia M, Celentano G, Cozzi F (2001) enantioselective aldol condensation catalyzed by poly(ethylene glicol)-supported prohne. Adv Synth Catal 343 171-173... 

Aldol reactions of methyl ketones. The optically active 1,3-oxazolidine (1) formed from a methyl ketone and ( — (-norephedrine aftir conversion to the tin(ll) enolate undergoes enantioselective aldol condensation with aldehydes. The enantioselectivity is partic-... 

Recently, a lot of attention has been focused on enantioselective aldol condensations using organoboron compounds. But in this review, only related literature has been cited, as the major purpose of the review is to present synthetic applications of organoboranes obtained by the hydroboration reaction of carbon-carbon multiple bonds. 

The synthesis began, as shown in Scheme 2.16, with the alkylation and subsequent hydrolysis of compounds 160 and 161 to afford aldol precursor 162. An enantioselective aldol condensation, using D-proline as a catalyst, gave a 70% yield of 163 and 164 in a 1 1 ratio, both diastereomers being formed in 36% ee. Isolation of the desired 164 followed by dehydration and recrystallization then gave optically pure (-I-) 165 in 10-12% yield from the racemates 160 and 161. A stereospecific sequence involving ketone reduction and protection as the MOM ether followed by bishydroxylation of the olefin and subsequent acetonide formation gave the key intermediate 166 (74%). 

Masamune has also completed a synthesis of tylonide hemiacetal (291) based on the creative use of enantioselective aldol condensations, as shown in Scheme 2.26. The aldol condensation of 328, derived from (/f)-hexahydromandelic acid and prop anal, was found to be >100 1 diastereoselective, affording the 2,3 syn compound 329 in 97% yield. Transformation to the p,7-unsaturated ester 330 occurred via selenoxide elimination and periodate cleavage followed by esterification. Formation of the silyl ether, reduction, and protection of the ester followed by ozonolysis of the terminal olefin gave the diol-protected aldehyde 331. The C-11 to C-15 segment 332 was then completed via chain elongation and a subsequent reduction-oxidation sequence in 34% overall yield from 330. 

Since the enzyme reaction is reversible, conditions for the synthesis of Neu5Ac and natural or synthetic derivatives in high yield as well as of Kdn with the aid of bacterial lyase were elaborated (see section 6.1). The recombinant and overexpressed sialate-pyruvate lyase from E. coli is now in wide use as a speeific chiral catalyst which mediates highly enantioselective aldol condensation reactions leading to a variety of sialic acids. 

Enantioselective aldol condensation by means of an oxazolidone chiral auxiliary and boron enolate (see 1 st edition). 

Enantioselective aldol condensation (cyclization) using (S)-proline as catalyst, with high optical yield. 

In contrast, reaction of diethyl propionylphosphonate with lithium bis-(trimethylsilyl)amide (LiHMDS) at -78 °C gave the expected enolate as evidenced by its highly diastereoselective condensation with benzaldehyde, leading to the formation of 3-hydroxy-2-methyl-3-phenylpropionic acid (equation 91) " . An attempt was made to develop this concept to enantioselective aldol condensation. However, condensation of a cyclic chiral propionylphosphonamidate (31), synthesized from ( S)-A-isopropyl-4-aminobutan-2-ol, with benzaldehyde yielded 3-hydroxy-2-methyl-3-phenylpropionic acid in disappointingly low 47% e.e. (equation 92)... 

Mandelic acid and its derivatives are utilized as convenient precursors for the introduction of a chiral center, and they possess the extra advantage of bearing a useful functional group. Many mandelic acid derivatives also act as chiral auxiliaries for the induction of a chiral center in stereoselective transformations. Numerous natural products, such as macrolides and ionophore antibiotics, possess a carbon framework that may be viewed synthetically as arising from a sequence of highly stereo- and enantioselective aldol condensations. Boron enolates, chiral auxiliaries derived from mandelic acids 1 or 2, provide remarkably high aldol stereoselectivity. 

Orlandi, S., BenagUa, M. and Cozzi, F. (2004) Cu(II)-catalysed enantioselective aldol condensation between maloiuc acid bemitbioesters and aldehydes. Tetrahedron Letters, 45, 1747-1749. 

Highly enantioselective aldol condensation of the chiral A-acyl-oxazolidone via its dibutylboryl enolate with the appropriate aldehyde ... 

Figure 14 The enantioselective aldol condensation of 4-nitrobenzaldehyde, 45, with acetone catalyzed by 44 to give the aldol /f-49 in 97% enantiomeric excess. The loss of hydroxide from 46 and the loss of a proton from 47 are likely to be highly synchronized.

High e/y/firo-selectivity has been obtained using optically active zirconium enolates (18) derived from prolinol in an enantioselective aldol condensation (Scheme 14). Much lower selectivity was obtained using the corresponding lithium enolate. 

One of the most active areas of organoborane chemistry this year has been the application of boron enolates to enantioselective aldol condensations. Thus the enolate (82), derived from (5)-valinol, reacts with aldehydes R CHO to give, after cleavage of the oxazolidinone residue with R OH, the alcohols (83) with an erythro threo selectivity greater than 140 1, whereas the enolate (84), obtained from (IS, 2/ )-norephedrine, gives alcohols (85) with a selectivity of at least 500 1. Somewhat lower levels of selectivity are observed with the azaenolates (86) and (87) which give predominantly threo- and erythro-alcohols (88) and (89), respectively. ... 

Chiral boron enolates are effective in enantioselective aldol condensations, a transition-state model being proposed for the moderate chirality transfer exhibited (Scheme 57). ° Diastereoselection with chiral lithium enolates has also been demonstrated by a highly stereoselective synthesis of the Prelog-Djerassi lactonic acid. ... 

A very useful approach for enantioselective aldol condensations has been based on the oxazolidinones 1 and 2. Both compounds are readily available in enantiomeri-cally pure form. 

Paterson 1, Lister MA, McClure CK. Enantioselective aldol condensations the use of ketone boron enolates with chiral... 

Evans DA, Taber TR. Enantioselective aldol condensations via boron enolates. A steric model for asymmetric induction. Tetrahedron Lett. 1980 21 4675-4678. 

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