Morita-Baylis-Hillman adduct derivatives

Some additional examples, where the stereochemical outcome of the cycloaddition to chiral alkenes has been explained in terms of the Honk—Jager model, should also be mentioned. The diastereomer ratio found in the reaction of y-oxy-a,p-unsamrated sulfones (166), with Morita-Baylis-Hillman adducts [i.e., ot-(a -hydro-xyalkyl)-acrylates (167)] (Scheme 6.27), with dispiroketal-protected 3-butene-l,2-diol (168), and with a,p-unsamrated carbonyl sugar and sugar nitroolefin (169) derivatives, all agree well with this model. 

A new route to 6-substituted pyrrolo[2,l-b]thiazoles 58 takes advantage of an intramolecular thermal cyclization of acetates 56 <07S3037>. These acetates are easily derived from the Morita-Baylis-Hillman adducts of thiazole-2-carboxaldehyde. This strategy has also been extended to the synthesis of the tricyclic analogs 60. 

Morita-Baylis—Hillman Adducts or Derivatives for the Construction of Cyclic Frameworks... 

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. 

As an extension of this work, the same authors have used polystyrene-supported proline as a recyclable catalyst in the Morita-Baylis-Hillman reaction of a range of aryl aldehydes with methyl or ethyl vinyl ketone. These reactions were performed in the presence of imidazole and provided a series of Morita-Baylis-Hillman adducts in moderate to high yields (17 88%) combined with high enantioselectivities of up to 95% ee (Scheme 2.55). This study represented the first example of supported proline as heterogeneous catalyst for the Morita-Baylis-Hillman reaction. In addition, Zhou et al. reported that these reactions could be eatalysed by combinations of L-proline with chiral tertiary amines derived from various readily available chiral sources, such as L-proline or (5)-a-phenylethylamine. In these conditions, the Morita-Baylis-Hillman adducts were obtained in reasonable chemical yields (34-97%) and low to good enantioselectivities (12 83% ee). In this study, it was demonstrated that the proline stereochemistry was the sole factor to determine the eonfiguration of the newly formed chiral centre. 

Wang and co-workers also developed the first catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with readily accessible Morita-Baylis-Hillman adduct as the dipolarophUe catalyzed by Cu(l)/TF-BiphamPhos complex, which provides a facile access to a new kind of highly substituted pyrrolidine derivatives bearing a unique quaternary and two tertiary stereogenic centers in excellent diastereoselectivity and up to 97% ee (Scheme 6) [16]. Recently, the asymmetric [3+2] cycloaddition employing dimethyl itaconate and 2-methyleneglutarate as dipolarophiles was also realized with this catalytic system (Scheme 6) [17]. 

The Morita-Baylis-Hillman reaction of chiral glyoxylic acid derivatives with cyclic a,/ -unsaturated ketones proceeded under the catalytic influence of dimethyl sulfide in the presence of titanium tetrachloride [27]. The adducts were obtained with high diastereomeric excess (>95% de) and typical yields around 80%. 

Chen and coworkers published a formal [3 + 3]-type reaction to give highly substituted cyclohexenes 8. This domino process consists of an allylic-allylic alkylation of an a,a-dicyanoalkene derived from 1-indanone and Morita-Baylis-Hillman carbonates, following an intramolecular Michael addition, by employing dual orga-nocatalysis of commercially available modified cinchona alkaloid (DHQD)2AQN If (hydroquinidine (anthraquinone-l,4-diyl) diether) and (S)-BINOL. The cyclic adducts... 

The Baylis-Hillman (also called Morita-Baylis-Hillman) (MBH) reaction (see Sect. 10.2.4 and Scheme 10.17) is the base-catalyzed addition of keto compounds to acrylic derivatives. The catalyst is a cyclic tertiary amine such as 1,4-diazabicyclo[2.2.2]octane (DABCO). Due to the generally poor yields observed, the reaction has not received sufficient attention despite the great synthetic value of the polyfunctional adducts. Among the various methods proposed to activate the reaction, pressure 107] and hydrophobic effects [70] have been used. Table 10.31 presents the results obtained in some Baylis-Hillman reactions carried out under pressure in aqueous solution [108]. 

Acetates of Morita-Baylis-Hillman (MBH) adduct 2 can be stereoselectively prepared by the reaction of acetyl chloride in the presence of a base or, alternatively, acetic anhydride in cone. H2S04. However, acetates 2 derived from aromatic aldehydes (R = Ar) prefer to undergo isomerization to generate the thermodynamically more stable acetate 3, either by intramolecular rearrangement... 

Highly functionalized MBH adducts and their derivatives have afforded access to structurally complex and diverse molecules. The synthetic applications of these compounds have clearly established the Morita-Baylis-Hillman (MBH) reaction as a standard synthetic methodology in the arsenal of organic chemists. This chapter describes the general application of the MBH reaction in the synthesis of a series of natural products and their analogues. 

Cinchona alkaloid derivatives can also serve as useful Lewis basic catalysts, as very well exemplified by their successful employment in the Morita-Baylis-Hillman (MBH) reaction and its aza variant (aza-MBH), which provide a convenient access to functionalised allylie aleohols and amines. As early as 1999 Hatakeyama and coworkers reported the use of p-isocupreidine (P-ICPD) as a catalyst for the reaction of aliphatic and aromatic aldehydes with 1,1,1,3,3,3-hexafluoroisopropyl acrylate, affording the desired adducts with very high enantioselectivities (Scheme 14.19). The concomitant formation of the dioxanone derivatives lowered the yield in the MBH adducts and caused difficulties in the experimental proeedure. Interestingly, the dioxanone derivatives had the opposite eonfiguration at the alcoholic stereocentre compared to the MBH produet, highlighting an intriguing mechanistic feature of this Lewis-base catalysed reaction. ... 

The same research group also developed an enantioselective catalytic Mannich reaction using a phosphoglycine benzophenone imine as a Man-nich donor, promoted by the 2-picolyl N-oxide PTC catalyst 48h/ The new reaction represented an efficient method for the preparation of ot,p-diami-nophosphonic acids (94). Furthermore, they synthesised ot-alkylidene-p-amino carbonyl derivatives, usually named as aza-Morita-Baylis-Hillman (aza-MBH) adducts (95), by an asymmetric Mannich reaction using the N-(2-methoxybenzyl) quininium catalyst 48g followed by Horner olefination (Scheme 16.31). ... 

In 2006, Berkessel and coworkers reported a new and improved iso-phoronediamine-derived bisthiourea organocatalyst for the asymmetric Morita-Baylis-Hillman reaction. Employing 20 mol% of catalyst 67 and N,iV,iV, iV -tetramethylisophoronediamine (TMIPDA) as base under neat reaction conditions, the adduct of 2-cyclohexen-l-one with cyclohex-anecarbaldehyde was obtained in 75% yield and 96% enantiomeric excess... 

Shibasaki et al. also developed chiral barium catalysts prepared from barium alkoxide and optically active BINOL 3 or aryloxide 4 derivatives. These catalysts were applied to asymmetric Mannich reactions of p,y-unsaturated esters (Table 27) [101]. In this reaction, the initially formed Mannich adducts isomerized to afford aza-Morita-Baylis-Hillman-type products in moderate to good yields with good enantioselectivities. For four substrate examples, ayloxide 4 ligand worked well (entries 2—4). 

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