Carbonates, asymmetric Baylis-Hillman

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. 

Kissel, Ramsden, and other researchers at Pfizer and Chirotech jointly published a novel chiral synthesis of pregabalin (2) in 2003 based on asymmetric hydrogenation (Burk et al., 2001, 2003). Their synthesis started with the condensation of isobutyralde-hyde with acrylonitrile under Baylis-Hillman conditions to give allylic alcohol 65. This alcohol was activated as the carbonate 66 and subjected to palladium-catalyzed car-bonylation conditions to give cyanoester 67. The ester 67 was hydrolyzed and converted to... 

Trost and coworkers have shown that Baylis-Hillman adducts can be efficiently derace-mized by Pd2dba3-CHCl3 catalyzed reaction of the corresponding carbonates 55 with phenols 56 in the presence of chiral C2-symmetric P,N-ligands (Scheme 11) [44], The strategy follows a dynamic kinetic asymmetric transformation process via jr-allyl palladium chemis-... 

This methodology has been expanded to geranyl methyl carbonate for the synthesis of the vitamin E nucleus, and to tiglyl methyl carbonate for the synthesis of (—)-calanolide A and B. In the latter example, the anthracenyldiamine -based ligand was required for optimum selectivity. The synthesis of (—)-aflatoxin B lactone utilizes a dynamic kinetic asymmetric transformation, whereby a suitably functionalized phenol reacts with a racemic 5-acyloxy-2-(5//)-furanone to provide a single product in 89% yield. One final example of phenol as a nucleophile is for the deracemization of Baylis-Hillman adducts." ... 

Chen and coworkers employed the cinchona alkaloid-derived catalyst 26 to direct Mannich additions of 3-methyloxindole 24 to the A-tosylimine 25 to afford the all-carbon quaternary center of oxindole 27 with good enantioselectivity (84% ee) [22]. The outcome of this Mannich reaction is notable in that it provided very good selectivity for the anti diastereomer (anti/syn 94 6). The mechanism of asymmetric induction has been suggested to involve a hydrogen bonding network between the cinchona alkaloid 26, the oxindole enolate of 24, and the imine electrophile 25 (Scheme 7). Asymmetric allylic alkylation of oxindoles with Morita-Baylis-Hillman carbonates has been reported by the same group [23]. 

ORGANOCATALYTIC ASYMMETRIC TRANSFORMATIONS OF BAYLIS-HILLMAN CARBONATE... 

Baylis-Hillman carbonate is a good substrate for asymmetric allylic substitution reaction, and various nucleophiles have been involved in this transformation. As shown in Scheme 9.36, the intermediate 72 (mechanistically formed by Michael... 

Morita-Baylis-Hillman carbonates undergo an hydrolysis in the presence of the asymmetric organocatalyst, hydroquinidine[anthraquinone-l,4-diyl] diether, and Cap2 in aqueous iV,iV-dimethylacetamide, yielding the allylic alcohol Tracer studies using showed that water is the nucleophile in the hydrolysis reaction. It is... 

A Lewis base-assisted Brpnsted base catalysis strategy has been used for direct asymmetric vinylogous alkylation of allylic sulfones with Morita-Baylis-Hillman (MBH) carbonates, in which a strong Brpnsted base, f-butoxy anion, generated in situ from a tertiary amine catalyst and MBH carbonate, is crucial in activating unstabilized nucleophiles. The y-regio-selective alkylation products were obtained with good to excellent enantiomeric excess (up to 98% ee) values when catalysed by a modified cinchona alkaloid. 

An asymmetric allylic alkylation of Morita-Baylis-Hillman carbonates and )0-keto sul-fones by modified cinchona alkaloids as catalysts gives products that undergo a Smiles rearrangement-sulfinate addition cascade to functionalized five-membered cyclic sul-fones (Scheme 172) ... 

The phosphine (127)-catalysed asymmetric 4 +1-cycloaddition reaction of Morita-Baylis-Hillman carbonates with dicyano-2-methylenebut-3-enoates formed highly functionalized cyclopentenes in high yields and excellent ee% The [RuCl(CO)2]2-catalysed 4 + 1-cycloaddition reaction of alkenyl propargyl acetates, RCH(OAc)C=CC(Me)=CH2, with CO in CH2CI2 produced highly functionalized cyclopentenones in high yields (96%). The chiral copper/Tol-BINAP complex... 

The introduction of the activated allylic bromides and Morita-Baylis-Hillman acetates and carbonates pioneered the development of a number of phosphine-catalyzed reactions in subsequent years [45]. Interestingly, the asymmetric variant of this type of transformation only appeared in the literature seven years later. In 2010, Tang, Zhou, and coworkers disclosed a highly enantioselective intramolecular ylide [3-f2] annulation using spirobiindane-based phosphine catalyst 31 (Scheme 20.27). BINAP was found inactive in this reaction even at an elevated temperature (70°C). Notably, both optically active benzobicyclo[4.3.0] compounds 32 and 32 with three continuous stereogenic centers could be obtained as major products in high yields and stereoselectivities just by a choice of an additive [Ti(OPr )4], which can block the isomerization of the double bond [46]. 

The asymmetric allylic substitution reaction of Morita-Baylis-Hillman carbonates (226) with diphenyl phosphite in the presence of chiral multifunctional thiourea-phosphine catalyst (228) provided allylic phosphites (227) in high yields and with excellent enantioselectivities (Scheme 76). 

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