Intramolecular Morita-Baylis-Hillman Reaction

A study of the effect of the Michael acceptor configuration on the efficiency of intramolecular Morita-Baylis-Hillman reactions has been performed. Enones containing a pendant aldehyde moiety attached at the -position of the alkene group were employed as substrates and the reactions were catalysed by a phosphine. In all cases examined, with Ph3P as the catalyst, cyclization of (Z)-alkene (117) gave 2.5-8.5 times higher yield than with the E-isomer (115) under identical reaction conditions, both affording the same product (116). Steric effects are believed to be the source of this difference in reactivity.172... 

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... 

There have been only a few reports on asymmetric versions of the intramolecular MBH reaction Scheme 1.105 shows one representative example. The intramolecular Morita Baylis Hillman reaction has been achieved with unprecedented levels of enantioselectivity by using a co-catalyst system involving pipecolinic acid and iV-methylimidazole cyclic MBH products 289 were... 

Construction of -Alkylidene-y- and S-Lactone and Lactam Rings via Intramolecular Morita-Baylis-Hillman Reaction... 

Intramolecular Morita-Baylis-Hillman reaction of suitably functionalized acrylic acid derivatives 99 constitutes a powerful means for the construction of P-hydroxy-a-aUcylidene-Y- and 8-lactones 98a and lactams 98b frameworks (Scheme 4.26). 

Scheme 4.28 Intramolecular Morita-Baylis-Hillman reaction in the synthesis of lactones and lactams.

Scheme 10.28 Enantioselective intramolecular Morita-Baylis-Hillman reaction.

Intramolecular versions of the Morita-Baylis-Hillman reaction have also met with success using a dual Lewis acid/Lewis base catalyst system. Miller has shown that a combination of A-methyl imidazole (132) (10 mol%) and... 

An interesting alternative intramolecular cyclisation was discovered by Jprgensen and co-workers [187]. Although not strictly exploiting an enamine intermediate, the transformation represents a secondary amine catalysed Morita-Baylis-Hillman reaction leading to a series of highly functionalised cyclohexene products. Reaction of the Nazarov reagent 137 with a,P-unsaturated aldehydes in the presence of the diarylprolinol ether 30 led to the cyclohexene products 138 (49-68% yield 86-96% ee) via a tandem Michael/Morita-Baylis-Hillman reaction (Scheme 54). 

An intramolecular vinylogous Morita-Baylis-Hillman reaction, followed by intramolecular aldol cyclization,129 is described under Intramolecular Aldols above. 

Furthermore, following an analogous methodology, combining the Morita-Baylis-Hillman reaction and the Trost-Tsuji reaction, Krische and co-workers have obtained allyl-substituted cyclopentenones 94 [84], Reaction was initiated by Michael addition of tributyl phosphine to an enone moiety 92, generating a latent enolate 93 which reacts intramolecularly with a jr-allylPd complex as the electrophile partner. A final -elimination step of trib-utylphosphine, favored by the presence of the methoxide ion, delivered the substituted cyclopentenones 94 (Scheme 36). 

Mergott, D. J., Frank, S. A., Roush, W. R. Application of the Intramolecular Vinylogous Morita-Baylis-Hillman Reaction toward the Synthesis of the Spinosyn ATricyclic Nucleus. Org. Lett. 2002, 4, 3157-3160. 

Mergott, D.J., Frank, S.A., and Roush, W.R., Application of the intramolecular vinylogous Morita-Baylis-Hillman reaction toward the synthesis of the spinosyn A tricyclic nucleus, Org. Lett., 4, 3157, 2002. 

The L-threonine-derived phosphine-sulfonamide (23) is one of the best catalysts for the enantioselective aza-Morita-Baylis-Hillman reaction. A DPT study has identified ( ) a key intramolecular N-H—O hydrogen-bonding interaction between the sulfonamide... 

Such a synthetic approach was employed by Corey et al. [58] for the synthesis of optically active a-methylene-y-lactam 101 (Scheme 4.27). The starting acrylamide 100 was prepared in six steps from the cheap and readily available N-4-methoxybenzoyl r-threonine methyl ester. The quinuclidine-catalyzed intramolecular asymmetric Morita-Baylis-Hillman reaction of 100 was followed by the conversion of the introduced alcohol moiety into a bromomethyldimethylsilyl ether 101. The a-methylene-y-lactam 101 with two adjacent quaternary stereogenic centers was formed in high yield as a mixture of two diastereoisomers in 9 1 dr. Interestingly, it was a key intermediate in the total synthesis of natural product salinosporamide A (102) that was accomplished in eight steps. 

In 2004, Krishna and coworkers [59] reported that optically active a-methylene-y- and S-lactones can be obtained via intramolecular asymmetric Morita-Baylis-Hillman reaction starting from enantiomerically pure starting materials (Scheme 4.28). Diastereoselective cyclizations of chiral acrylates 103 and 105 were realized using DABCO as nucleophilic promoter. P,y-Disubstituted-a-methylene-y-lactone 104 and bicyclic a-methylene-8-lactone 106 with hydroxyl substituent in the 3-position were readily accessed following such strategy. 

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... 

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... 

A related approach for the synthesis of spirocyclopenteneoxindoles was developed by Barbas and coworkers. Chiral diphosphines catalyzed the [3+2] cycloaddition between the A-protected methyleneindolin-2-ones 17b and the Morita-Baylis-Hillman (MBH) carbonates 37 [18]. This reaction was initiated by the displacement of the carbonate moiety by the phosphine VI, an addition-elimination mechanism, which was followed by the deprotonation to afford ylide 39. A regioselective nucleophilic addition on 17 by 39, followed by an intramolecular conjugate addition, afforded intermediate 40 that, after elimination of PR3, delivered the corresponding spirocycle 41 (Scheme 10.11). 

The Morita-Baylis-Hillman (MBH) reaction is a powerful carbon-carbon bondforming reaction that has found widespread application in organic synthesis. In 2005, Miller and Hong independently reported the highly enantioselective intramolecular MBH reaction. The Miller group applied a combination of (S)-pipecohc acid 79 and N-methylimidazole to catalyze the cychzation of heptenal derivatives 80 in aqueous THF (Scheme 36.21a) [27a]. In contrast, Hong and coworkers used simple L-proline and imidazole as the catalysts (Scheme 36.21b) [27b]. 

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