Asymmetric allylation, Baylis-Hillman

It is also possible to carry out a substrate-controlled reaction with aldehydes in an asymmetric way by starting with an acetylene bearing an optically active ester group, as shown in Eq. 9.8 [22]. The titanium—acetylene complexes derived from silyl propiolates having a camphor-derived auxiliary react with aldehydes with excellent diastereoselectivity. The reaction thus offers a convenient entry to optically active Baylis—Hillman-type allyl alcohols bearing a substituent (3 to the acrylate group, which have hitherto proved difficult to prepare by the Baylis—Hillman reaction itself. 

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... 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

Sato and coworkers have reported an asymmetric synthesis of Baylis-Hillman-type allylic alcohols 48, 49 via a chiral acetylenic ester titanium alkoxide complex (Scheme 9) [41]. These reactions rely on the use of the novel acetylenic ester titanium alkoxide complex 44 with a camphor-derived chiral auxiliary. Optically active, stereodefined hydroxy acrylates 46, 47 were obtained in high yields and with excellent regio- and diastereoselectivities. The chiral auxiliary was subsequently cleaved off by alcoholysis. 

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-... 

The Morita-Baylis-Hillman (MBH) reaction is an important 100% atom economic transformation that allows the formation in one step of a flexible allylic alcohol motif. Efforts in this field have been directed recently to the solution of two problems to enhance the generally sluggish reaction rate and to achieve asymmetric catalytic versions. Scheme 1.15 gives the catalytic cycle of the MBH reaction. The catalyst is a highly nucleophilic tertiary amine, generally DABCO, or a tertiary phosphine, which adds to the oc,P-unsaturated electrophile in a 1,4 fashion to deliver an enolate that, in turn, adds to the aldehyde. A critical step is the proton transfer from the enolizable position to the oxygen atom this process is catalysed by an alcohol that plays the role of a proton shuttle between the two positions. Water has also been reported to strongly speed up the reaction at a well-defined concentration. Moreover, the... 

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]. 

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 series of quinidine-derived organocatalysts, solvents, and temperatures for the asymmetric allylic 5 2 reaction between 0-Boc-protected Morita-Baylis-Hillman adducts and carbamates or tosylcarbamates were tested. The best results were 0 obtained using the catalyst (2) in THF at 20 C. Most of the yields obtained using a variety of substrates were >80%, with >80% ee. 

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 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). 

---