Solid-Phase Baylis-Hillman Reaction

Follotving the quite recent discovery of the broad range of biological activities exhibited by members of the sesquiterpene-based drimane family, namely mnio-petals, kuehneromycins, and marasmanes, a solid-phase approach towards a common key intermediate has recently been disclosed [408]. This supported synthesis offers the additional advantage of potential access to libraries of compounds with the same sesquiterpenoid skeleton. 

Oxidation of the secondary alcohol in the Baylis-Hillman adduct (593) proved essential to allow the subsequent intramolecular Diels-Alder reaction to proceed at a lower temperature due to activation of the dienophile. 

In order to access isoxazole-based potential antithrombotic agents [409], acrylic acid was loaded onto 2-chlorotrityl resin and then subjected to Baylis-Hillman reaction -with a variety of 3-substituted phenyl-5-isoxazolecarboxaldehydes (pre- 

Binding of acrylic acid To 2-chlorotrityl resin (100 mg, 1.30 mmol g No-vabiochem) in DMF/CH2CI2 (1 mb 1 1, v/v) was added 6 equiv. of EtsN followed by 4 equiv. of acrylic acid. The resulting mixture was spun at 600 rpm for 4 h. Thereafter, MeOH (1 mL) was added and the reaction was allowed to continue for a further 30 min. The resin was subsequently washed as follows  

Baylis-Hillman reaction The aforementioned resin was treated with DMSO (700 (b) followed by DABCO (3 equiv.), and the mixture was shaken for 30 min. A solution of a 3-substituted phenyl-5-isoxazolecarboxaldehyde 

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In the solid-phase Baylis-Hillman reaction developed in our group [19] resin-bound acrylic ester reacted with aldehydes to form 3-hydroxy-2-methylidene-propionic acids, or with aldehydes and sulfonamides in a three-component reaction to form 3-aminoaryl-2-methylidene sulfonylpropionic acids [20] (Fig. 6.4). 

In this subsection, we describe a couple of examples taken from the recent literature, in which the Baylis-Hillman reaction has been employed for the construction of new carbon-carbon bonds. The Baylis-Hillman reaction proceeds in a catalytic cycle propagated by a nucleophilic catalyst (584). The nucleophilic catalyst initiates the cycle by Michael addition to a double bond bearing an EWG (586 or 590). The carbon a to the EWG is acidic and may react with an electrophile. Finally, the nucleophilic catalyst is eliminated, completing the cycle (Scheme 122). The most frequently used catalysts are quinuclidine, DABCO, phosphines, thiopheno-lates, and selenophenolates. The reaction rate of a catalytic Baylis-Hillman reaction approaches a maximum at a certain temperature and declines upon further heating, as the equilibrium concentration of (587) becomes very small. In the first example, the electrophilic component of the reaction was immobilized on a solid phase and the nucleophile was in solution, while in the other example the situation was reversed (Scheme 122). 

Solid-phase synthesis by the cyclization of polymer-bound hydrazones of [1-keto esters. Jung and co-workers (99JOC1362) (Scheme 24) have reported the synthesis of pyrazol-3-one 102 from polymer-bound /1-keto ester 100 and phenyl hydrazine. In the first step, polymer-bound 3-hydroxy-2-methylidenepropionic acid 99 is derived from a Baylis-Hillman reaction between polymer-bound allylic alcohol... 

A number of combinatorial-based syntheses have been reported. Andrus et al. prepared a solution-phase indexed combinatorial library of nonnatural polyenes such as 291 for multidrug resistance reversal.298 This library was formed by modification of R and R. Ellman and co-workers reported a combinatorial library of synthetic receptors targeting vancomycin-resistant bacteria,209 and Paterson et al. prepared polyketide-type libraries by iterative asymmetric aldol reactions on solid support.2l0 Rieser et al. used combinatorial liquid-phase synthesis to prepare [1,4]-oxazepine-7-ones by the Baylis-Hillman reaction (see sec. 9.7.B).2H Schreiber and co-workers reported the synthesis and evaluation of a library of polycyclic small molecules for use in chemical genetic assays.2 2 Bauer et al. reported a library of N-substituted 2-pyrazoline compounds... 

Kulkarni, B.A. and Ganesan, A. (1999) Solid-phase s5uithesis of 8-keto esters via sequential Baylis-Hillman and Heck reactions. J. Comb. Chem., 1, 373-8. 

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