Alkylidenebutenolides

Regio- and stereoselective synthesis of y-alkylidenebutenolides and related compounds 97T6707. 

Finally, the outstanding functional group tolerance of the Stille reaction was exploited to prepare a series of alkylidenebutenolids. y-(Dibromomethylene)butenolide (6.42.) was sequentially coupled with phenyltributylstannane and styryltributylstannane to result in the selective exchange of the two bromine atoms. In the first intermediate it is always the Z-olefin that is formed.62... 

Negishi, E.-E Kotora, M. Regio- and Stereoselective Synthesis of y-Alkylidenebutenolides and Related Compounds, Tetrahedron 1997, 53, 6707-6738. 

Among the classic examples is the coupling-cyclization of alkynes with Z-y6-bromo acrylic acid derivatives invented by Negishi and Kotora [110] as a sequential access to the y-alkylidenebutenolide 140 in excellent yield (Scheme 53). The constitutional isomeric cY-pyranone 141 is only formed in 4% yield. 

The terminal alkyne, 3-(4-methoxyphenyl)-1-propyne (1.2 moles) and 4-iodotoluene in benzene containing 2 moles triethylamine, catalytic amounts of palladium(ll) acetate and triphenylphosphine when heated in an autoclave at 119 C for 4 hours under pressure with carbon monoxide (300psi.) afforded an 85% yield of the alkylidenebutenolide, 3-(4-methoxybenzylidene)-5-(4-methylphenyl)furan-2(3H)-one (ref. 134). 

Table 1. List of conjugated alkylidenebutenolides that have been synthesized by the sulphone method...

Stereoselective preparation of ( )-5-stannyl-)/-alkylidenebutenolide 100 was achieved by the reaction of tin acetylide with tributylstaimyl 3-iodopropenoate derivative 99, and the arylbutenolide 101 was obtained by the Migita-Kosugi-Stille reaction of 100 [53]. 

The tricyclic core of brownin F was prepared in eight synthetic operations via a diastereo-, chemo-, and regioselective intramolecular [3 + 2] cycloaddition between a cyclic carbonyl ylide and a y-alkylidenebutenolide (130BC4178). 

Another important class of oxypalladation reactions involves carboxypalladation of aUcynoic acids to produce lactones. Depending on the strnctnre of the aUcynoic acids and the type of group that displaces Pd from the putative aUcenylpalladium intermediate, this carboxypalladation-reductive elimination tandem process can give stereoselectively either (E)- or (Z)- y-alkylidenebutenolides and possibly higher homologues as well (Scheme 7). 

Since then, extensive studies to further improve both tandem and cascade versions shown in Schemes 7 and 8 have been conducted to alleviate several undesirable side reactions for optimizing the product yields, and a number of naturally occurring (Z)-y-alkylidenebutenolides have been synthesized, as summarized in Table 2 and Schemes 10 and 11A similar but less efficient synthesis of lissoclinolide has also been reportedP" The currently available data suggest that the Pd- or Ag-catalyzed lactonization of appropriate alkynoic acids and their precursors provides by far the most efficient and satisfactory method for the synthesis of y-alkylidenebutenolides, which represent a large number of biologically and medicinally important compounds. 

TABLE 2. Synthesis of Naturally Occurring (Z)-y-Alkylidenebutenolides Via Oxypalladation... 

During the development of a Pd-catalyzed procedure for benzoquinone synthesis, the formation of y-alkylidenebutenolides was unexpectedly observed, when Pd(OAc)2-PPh3 was used as a catalyst in conjunction with an excess of NEts (Scheme 2). In sharp contrast, the use of 5 mol % of phosphine-free Pd(dba>2 and 1 equiv of NEts produced the desired benzoquinone in 93% yield. The lactone formation must have taken place via base-induced trapping of the acylpalladium intermediate with an essentially 1 1 mixture of in situ generated E- and Z-enolates (Scheme 2). 

Regio- and Stereoselective Synthesis of y-Alkylidenebutenolides and Related Compounds. 

A total of three 1, co-bis(trialkylstannylated) monoene and diene building blocks was known in the mid-1990s (Fig. 4). At that time we began to explore the synthetic chemistry of polyunsaturated y-alkylidenebutenolides. We were intrigued to learn that the mentioned distannanes acted as molecular linchpins under Stille-coupling conditions in the Nicolaou, Danishefsky, and Mullen groups. These transformations are shown in Schemes 1-3. 

The utility of y-alkylidenebutenolides is demonstrated in both intra- and inter-molecular [Rh2(OAc)4l-catalysed 1,3-dipolar cycloaddition reactions in CH2CI2 affording spiro[6,4]lactone moieties with the concomitant constmction of quaternary Spiro stereocentres. Furthermore, a convergent and versatile route for the formation of the (5,7) skeleton of molecules, isolated from the Schisandra genus, is reported. Computational studies provided the mechanism of the intermolecular [3 + 2]-cycloaddition between 2-diazo-l,3-ketoester and protoanemonin and rationalized the empirical observations. " ... 

Photochemical [4+1] cycloaddition of allenyl ketones and aldehydes with carbon monoxide provides a-alkylidenebutenolides (Scheme 4-304). The reaction is catalyzed by pentacarbonyliron. With methyl and tert-butyl substituents at the allene unit a good... 

Schmidt-Leithoff, J. and Bruckner, R. (2005) Synthesis of the 2-alkenyl-4-alkylidenebut-2-eno4-lactone (= a-alkenyl-y-alkylidenebutenolide) core structure of the carotenoid pyrrhoxanthin via the regioselective dihydroxylation of hepta-2,4-diene-5-ynoic acid esters. Helv. Chim. Acta, 88, 1943-1959. 

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