Baylis-Hillman reaction enantioselective

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... 

The Baylis-Hillman reaction (Scheme 3) of ethyl vinyl ketone with electron-deficient aromatic aldehydes (e.g. where R = 0-NO2C6H4), in MeCN or EtCN solution, has been found to proceed enantioselectively in presence of catalytic base (32) derived from proline. The Michael adduct formed between the catalyst and the vinyl... 

To date, hydrogen bond catalysis has been successfully utilized to facilitate enantioselective Michael additions, Baylis-Hillman reactions, Diels-Alder cycloadditions, and additions of 7i-nucleophiles to imines. 

The highly enantioselective Morita-Baylis-Hillman reaction of cyclohexenone with aldehydes is catalyzed by a chiral BlNOL-derived Brpnsted acid 8 in the presence of triethylphosphine as the nucleophilic promoter (Scheme 12.6). ... 

Scheme 81 Enantioselective Baylis-Hillman reaction in chiral ionic liquid 73...

Recently the group of Leitner was able to achieve high enantioselectivities in the aza-Baylis-Hillman reaction by the application of enantiopure ionic liquid with a chiral anion (Scheme 82) [208]. 

Scheme 82 Enantioselective aza-Baylis-Hillman reaction in a chiral anion based ionic liquid...

Chiral solvents rarely induce significant enantioselectivity, but ees up to 84% have been achieved in an aza-Baylis-Hillman reaction.161 Using an ionic liquid (IL), the anion of which is a dimalatoborate (54), it is suggested that the high enantioselectivity arises from strong ion-pair and hydrogen bond interactions with the zwitterionic intermediate of the reaction, i.e. IL-B- R3P+-CH2-CH=C(Me)-0 HO-IL. 

The aza-Baylis-Hillman reaction of 4-X-C6H4CH=NTs with CH2=CHCOMe, catalysed by PI13P in the newly designed chiral ionic liquid (121), derived from l-(—)-malic acid, gave products with up to 84% ee. This example represents the first highly enantioselective asymmetric reaction in which a chiral medium is the sole source of chirality.176... 

A series of A - / - n i trobe nzenesul fony 1 imincs have been reported to undergo asymmetric aza-Morita-Baylis-Hillman reactions with methyl acrylate mediated by DABCO in the presence of chiral thiourea organocatalysts with unprecedented levels of enantioselectivity (87-99% ee), albeit only in modest yields (25 19%). Isolation of a DABCO-acrylate-imine adduct as a key intermediate, kinetic investigation, and isotopic labelling, have been employed to determine the mechanism.177... 

Balan and Adolfsson [28] reported a direct catalytic enantioselective three-component aza Baylis-Hillman reaction between arylaldehydes, tosylamides, and Michael acceptors using the quinidine-based Hatekayama catalyst 96 [29] together with titanium isopropoxide as a Lewis acid cocatalyst (Scheme 9.18). High chemical yields and stereoselectivity ranging between 49 and 74% ee were obtained using various substituted arylaldehydes. 

Scheme 9.18. Catalytic enantioselective three-component aza Baylis-Hillman reaction.

An NMR kinetic study of a phosphine-catalysed aza-Baylis-Hillman reaction of but-3-enone with arylidene-tosylamides showed rate-limiting proton transfer in the absence of added protic species, but no autocatalysis.175 Brpnsted acids accelerate the elimination step. Study of the effects of BINOL-phosphinoyl catalysts sheds light not only on the potential for enantioselection with such bifunctional catalysis, but also on their scope for catalysing racemization. 

A highly enantioselective proline-catalysed intramolecular Morita-Baylis-Hillman reaction of hept-2-enedial (111) has been reported. Addition of imidazole to the mixture resulted in an unusual inversion of enantioselectivity.149 The first example of a TiCU-mediated Morita-Baylis-Hillman-type reaction of cy-acetyl cyclic ketene dithioacetals with arylaldehydes has been described.150... 

Another class of bifunctional organocatalysts for the enantioselective aza-Morita-Baylis-Hillman reaction of imines (112) with enones (113) (Scheme 6) is based on BINOL (115). The efficiency of the catalysts proved to be mainly influenced by the position of the Lewis basic moiety attached to the BINOL scaffold. The activation of the substrate by acid-base functionalities and the fixing of conformation of the catalyst (115) are apparently harmonized to maximize the enantiocontrol (<95% ee) 52... 

Much work related to the development of a catalytic, enantioselective version of the Baylis-Hillman-Reaction by the use of chiral bases has been published. Only low enantiomeric excesses were obtained when brucin, N-methylprolinol, N-methyl-ephedrine and nicotine... 

Scheme 5. Enantioselective Baylis-Hillman reaction using a chiral hydroxy-pyrrolizidine-catalyst (Barrett et al.).

Scheme 6. Enantioselective Baylis-Hillman reaction using modified Cinchona-alkaloids (Hatakeyama et a .).

Organocatalytic Enantioselective Morita-Baylis-Hillman Reactions... 

Organocata lytic Enantioselective Morita-Baylis-Hillman Reactions Table 5.4 MBH reaction of aryl aldehydes and MVK catalyzed by /MCD. 

Baylis-Hillman Reaction. Intramolecular cyclization of MeC0(CH2)2CH=CHC02Et using (-P)-CAMP produced the cy-clopentene in 40% isolated yield. A 3 1 equilibrium mixture which favored the product cyclopentene was formed after 10 days at 25 °C. CAMP was found to be superior to other phosphines, such as PBU3. DABCO and other nitrogen bases were ineffective for the cyclization reaction. However, the enantioselectivity of the product using CAMP was only 14%. 

The Baylis-Hillman reaction is rendered enantioselective in the presence of a chiral pyrrolizidine base 51. ... 

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