Morita-Baylis-Hillman cyclization

Roush and coworkers developed a new one-pot sequence consisting of an intramolecular Diels-Alder- and an intramolecular vinylogous Morita-Baylis-Hillman-cyclization for the synthesis of spinosyns [31]. These compounds are poly-ketide natural products possessing extraordinary insecticidal activity. 

Methot, J. L., Roush, W. R. Synthetic Studies toward FR182877. Remarkable Solvent Effect in the Vinylogous Morita-Baylis-Hillman Cyclization. Org. Lett. 2003, 5,4223-4226. 

Scheme 4.27 Intramolecular Morita-Baylis-Hillman cyclization in the synthesis of...

The product of the previous reaction provides a Baylis-Hillman type product via an intermolecular addition of an allenoate to an epoxide. The first example of a true Morita-Baylis-Hillman reaction of an epoxide has recently been reported <06CC2977>. Treatment of enone 34 with Me3P provides a good yield of the epoxide-opened product 35. The reaction must be carried out at low concentrations in order to avoid the generation of a variety of side products. When the terminal end of the epoxide is substituted (e.g. 34) the exo-mode of cyclization is the only product observed. When the terminal end of the epoxide is unsubstituted (e.g. 36), the endo-mode of cyclization predominates providing 37. 

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... 

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

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. 

This chemistry can be used to initiate sequential (cascade) cyclizations. From a Morita-Baylis-Hillman reaction and protection of the resulting hydroxyl we have prepared the triene 12. Treatment of 12 with a catalytic amount of CpCr(CO)3H under H2 for 6d gave the cyclization product 16 in 23% isolated yield, presumably by the mechanism in Scheme 1.11 [53]. 

The practical value of DMP as a reagent has been extended to various other synthetically useful oxidative transformations, such as the dehydration of primary alcohols under extraordinarily mild conditions [1276], synthesis of various polycyclic heterocycles via the oxidative cascade cyclization of anilides with pendant double bonds [1277], one-pot oxidative allylation of Morita-Baylis-Hillman adducts with allyltrimethylsilane promoted by DMP/Bp3-OEt2 [1278], synthesis of 2-amino-l,4-benzoquinone-4-phenylimides from anilines via DMP oxidation [1279], a-tosyloxylation of ketones using DMP and p-toluenesulfonic acid [1280] and the DMP-mediated oxidative aromatization of 1,3,5-trisubstitutedpyrazolines [1281]. 

Phosphonium salts may be intermediates in different reactions. The Morita-Baylis-Hillman reaction follows such a protocol. In a typical reaction sequence, a,P-unsaturated carbonyl compounds react with aldehydes in the presence of nucleophiles, such as a trialkylphosphine, to afford aldol-like products (Scheme 75/1), while in another example, unsaturated carbonyl compounds with bromo atom at the end of the chain are cyclized to cycloalkene derivatives (Scheme 75/2). In both... 

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. 

The annulation between Morita-Baylis-Hillman (MBH) carbonates and enones takes place under PBU3 catalysis (Scheme 6.7). Cascade [3-f2] cyclization-allylic... 

---