Asymmetric Baylis-Hillman

Apart from tertiary amines, the reaction may be catalyzed by phosphines, e.g. tri- -butylphosphine or by diethylaluminium iodide." When a chiral catalyst, such as quinuclidin-3-ol 8 is used in enantiomerically enriched form, an asymmetric Baylis-Hillman reaction is possible. In the reaction of ethyl vinyl ketone with an aromatic aldehyde in the presence of one enantiomer of a chiral 3-(hydroxybenzyl)-pyrrolizidine as base, the coupling product has been obtained in enantiomeric excess of up to 70%, e.g. 11 from 9 - -10 ... 

The asymmetric Baylis-Hillman reaction of sugar-derived aldehydes as chiral electrophiles with an activated olefin in dioxane water (1 1) proceeded with 36-86% de and in good yields of the corresponding glycosides (Eq. 10.47).104 The use of chiral /V-mcthylprolinol as a chiral base catalyst for the Baylis-Hillman reaction of aromatic aldehydes with ethyl acrylate or methyl vinyl ketone gave the adducts in good yields with moderate-to-good enantioselectivities in l,4-dioxane water (1 1, vol/vol) under ambient conditions.105... 

Scheme 4.57 Chiral allenes by an asymmetric Baylis—Hillman type reaction.

A chiral pyrrolizidine (53) catalyses asymmetric Baylis-Hillman reactions. Important structural features include an accessible nitrogen lone pair and a strategically placed hydroxy group the latter may also interact with alkali metal cations, which catalyse the reaction. 

For a brief review of recent developments in the asymmetric Baylis-Hillman reaction, see P. Langer, Angew. Chem. 2000, 112, 3177-3180 Angew. Chem. Int. Ed. 

Asymmetric Baylis-Hillman-Reactions of Chiral Substrates 1167... 

Asymmetric Baylis-Hillman reactions using sugar acrylates have been reported to proceed with moderate diastereoselectivity (5-40% ee) [23]. The reaction of camphor-based chiral acryloylhydrazides with aldehydes in the presence of DABCO afforded /1-hydroxy-a-methylene carbonyl derivatives in 68-92% yield with high diastereoselectivity (up to 98% de) [24]. Both diastereomers could be selectively obtained simply by changing the solvent. 

Aggarwal and coworkers have studied the electrophilic behavior of enantiomerically pure N-p-toluenesulfinimines and N-tert-butanesulfinimines in the asymmetric Baylis-Hillman reaction with methyl acrylate with and without Lewis acids [26], In the presence of In(OTf)3 good yields and high diastereoselectivities have been achieved providing an effective route to /i-amino-a-methylene esters. 

Bicyclic azetidines 6 have been obtained by reduction of the corresponding fused P-lactams, or alternatively by reduction of the appropriate bicyclic thiono-y-lactams <02T7303>. These fused azetidines have been used as catalysts for the asymmetric Baylis-Hillman reaction. However, significant difficulties in the preparation of the 1-azabicyclo[3.2.0]heptanes 6 precluded further investigations and reduced the attractiveness of these azacycles as catalysts. 

Genisson et al. also prepared two diastereomers of 2 -hydroxymethyl analogs through an asymmetric Baylis-Hillman reaction-like sequence to prepare a A-substimted 2 -methylene C-13 side chain (Scheme 3-3). After incorporation of the side chain to C-13 of 7,10-ii/-Troc-10-DAB, the product was then subjected to osmylation to yield 2 (R)- and 2 (5)-hydroxymethyl docetaxel 7a-b analogs stereoselectively. Both taxoids displayed less tubulin polymerization abilities than did paclitaxel, but the major product 2 / -isomer 7a is more active than the minor one 2 5-isomer 7b. ... 

Genisson, Y Massardier, C. Gautier-Luneau, I. Greene, A. E. Effective enantiose-lective approach to a-aminoalkylacrylic acid derivatives via a synthetic equivalent of an asymmetric Baylis-Hillman reaction application to the synthesis of two C-2 hydroxymethyl analogs of docetaxel. J. Chem. Soc. Perkin Trans. 1, 1996, 2869-2872. 

Phenylmenthyl acrylate has been used as a component in an asymmetric Baylis-Hillman reaction. Treatment of the acrylate with 1,4-Diazabicyclo[2.2.2]octane and benzaldehyde at 8 kbar of pressure delivers the a-(hydroxyalkyl)acrylate (eq 8). The product obtained has an 86% de. Menthyl acrylate is superior to the phenylmenthyl acrylate in this particular application. In a radical-mediated addition, phenylmenthyl acrylate gives rise to the a-pyridyl sulfide in 68% yield (eq 9). The final product is isolated with a 56% de. 

A clean, high-yielding asymmetric Baylis-Hillman reaction has been reported employing Oppolzer s sultam, it couples acrylates with a variety of aldehydes at 0 °C, with >99% ee in all cases described. Another new, practical variant of the reaction employs a phosphine catalyst, and here the temperature effect is critical the rate increases in either direction from room temperature, with a dramatic improvement observed at 0 °C. This imusual observation is explained in terms of a temperatiue-dependent equthbrium between efficient and inefficient intermediates. 

Langer, P. The asymmetric Baylis-Hillman-reaction. in Organic Synthesis Highlights V165-177 (VCH, Weinheim, New York, 2003). 

Asymmetric Baylis-Hillman reactions catalyzed by CAMP 9 [21] and BINAP 10 [22] have also been studied but in this case the products were isolated in low... 

Catalysed asymmetric Baylis-Hillman reactions Catalysed Asymmetric Diels-Alder Reactions... 

The Baylis-Hillman reaction has become a very powerful carbon-carbon bond forming reaction in the past 20 years. A typical reaction involves an activated olefin (i.e., an acrylate) and an aldehyde in the presence of a tertiary amine such as diazobicyclo-[2.2.2]octane (DABCO) to form an a-methylhydroxyacrylate. A host of activated olefins have been utilized including acrylates, acroleins, a, 3-unsaturated ketones, vinylsulfones, vinylphosphonates, vinyl nitriles, etc. The Baylis-Hillman has been successfully applied inter- and intramolecularly. In addition, there are numerous examples of asymmetric Baylis-Hillman reactions. Reviews (a) Ciganek, E. Org. React. 1997, 51, 201-478. (b) Basavaiah, D. Rao, P. D. Hyma, R. S. Tetrahedron 1996, 52, 8001-8062. (c) Fort, Y. Berthe, M. C. Caubere, P. Tetrahedron 1992, 48, 6371-6384. 

A remarkable increase in enantioselectivity achieved by applying high pressure was observed by Hirama et al. [81] for an asymmetric Baylis-Hillman reaction, in addition an enhancement of the reaction rate was also found. The Baylis-Hillman reaction refers to the condensation of acrylates and aldehydes catalyzed by tertiary amines. Using various enantiopure 2,3-disubstituted l,4-diazabicyclo[2.2.2]octanes (DABCOs) as chiral amine bases the influence of high pressure on the reaction... 

Chiral 2,3-disubstituted DABCOs promote asymmetric Baylis-Hillman reactions under high pressure. While the yields are acceptable, the enantioselectivity is dismal. 

Iwabuchi Y, Furukawa M, Esumi T, Hatakeyama S (2001) An Enantio- and Stereocontrolled Synthesis of (-)-Mycestericin E via Cinchona Alkaloid-Catalyzed Asymmetric Baylis-Hillman Reaction. Chem Commun 2030... 

An asymmetric Baylis-Hillman reaction has been reported to give >90% ee using an activated acrylate [H2C=CHC02CH(CF3)2] and a chiral phenolamine " another approach uses a chiral pyrrolizidine base with a pendant alcohol. Diastereoselective pinacol coupling of aldehydes has been achieved using a complex of titanium(IV) and a chiral Schiff base. ... 

In 1995 Hirama and coworkers [16] reported an asymmetric Baylis-Hillman reaction catalyzed by chiral 2,3-disubstituted DABCO derivatives under increased pressure (Scheme 21.2a). Hirama observed an enhancement of both reaction rate and enantioselectivity for the reaction of 4-nitrobenzaldehyde with MVK under 5 kbar. At atmospheric pressure the reaction proceed very slowly (3 weeks) with low enantioselectivity (12-15% ee). The best results in terms of yield and enantioselectivity (up to 47%) were obtained with chiral DABCO catalyst bearing benzyl or 1-naphthyl groups. This is the first example of an organocatalytic reaction demonstrating that an increase in pressure can significantly enhance the enantioselectivity (e.g., from 12% to 47%). 

Scheme 21.2 Asymmetric Baylis-Hillman reactions with MVK and aldehydes.

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