Butenolides, asymmetric synthesi

One of the earliest and most important discoveries in metal-catalyzed asymmetric synthesis is Sharpless s Ti-catalyzed epoxidation of allylic alcohols. A mere mention of all the total syntheses that have used this technology would require a separate review article Here, we select Trost s masterful total synthesis of solamin (100, Scheme 14), for its beautiful and multiple use of Sharpless s asymmetric epoxidation.1161 Optically pure epoxy alcohol 95 is converted to both epoxy iodide 96 and diol 97 The latter two intermediates are then united to give 98, which is oxidized and converted to dihydrofuran 99 by a Ramberg-Backlund transformation. The Re catalyzed butenolide annulation that is used to afford the requisite unsaturated lactone only adds to the efficiency of this beautiful total synthesis. 

For example, N-(2-hydroxyphenyl)imines 9 (R = alkyl, aryl) together with chiral zirconium catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [17], the diastereo- and/or enantioselective synthesis of homoallylic amines [18], the enantioselective synthesis of simple //-amino acid derivatives [19], the diastereo- and enantioselective preparation of a-hydroxy-//-amino acid derivatives [20] or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans, a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10)... 

Chiral butenolides are versatile intermediates in asymmetric synthesis. In particular, (S)-(+ )-jS-angelica lactone (260) is extremely useful for the synthesis of y-valerolactone natural products. It can be prepared in a straightforward manner by Wittig olefination of 606 with (ethoxycarbonylmethylene)triphenylphosphorane, which gives pentenoate 616 as an 82 18 mixture of Z and E isomers. After separation of the isomers by column chromatography, the desired (Z)-616 is simultaneously deprotected and lactonized by treatment with a catalytic amount of sulfuric acid to furnish 260 in nearly quantitative yield [191]. 

Lithiated a-amino nitriles derived from an enantiomerically pure secondary amine have been used to achieve the asymmetric synthesis of trfl 5-dibenzylbutyrolactones (scheme 10) [58]. Enantiomeric excesses of greater than 96% were obtained after removing the chiral auxiliary. When aromatic aldehydes were used as electrophiles the benzylic alcohols were obtained as a mixture of the two epimers with a diastereomeric excess of 60-75%. Addition of a chiral sulfoxide, prepared using a modified Sharpless oxidation, to butenolide has also been utilised as part of an expeditious synthesis of podophyllotoxin (scheme 11) [59]. 

The asymmetric synthesis of both enantiomers of various butenolides was reported by Solladie in 1986. based upon his diastereoselective p-ketosulfoxide reduction chemistry (Scheme 4.10) [13], Butenolides are widely found as subunits in many naturally occurring compounds [14-17]. 

Butenolides substituted with a chiral sulphoxide moiety are also good substrates, as shown by the short asymmetric synthesis of (-)-podorhizon (91), a lignan natural product.t35]... 

A chair-like transition state, with lithium coordination to carbonyl and sulfinyl oxygens, has been proposed to account for the facial selectivity observed in the coupling reaction which permits the asymmetric synthesis of y-butenolides (Scheme 6). ... 

Thus, 1.7-octadiene (79), which was subjected to monohydroboration followed by asymmetric dihydroxylation of the remaining double bond to give triol 80 with approximately 80% ee. Further transformations then afforded the desired butenolide 81. Double asymmetric dihydroxylation of diene 83 and subsequent protection gave hydroxy lactone 84 [98], which was then converted into acetylenic bis(hydroxy)bistetrahydrofuran 82 as the required intermediate for the (+)-asimicin synthesis. Mitsunobu inversion at C-24 gave rise to the diastereomeric (+)-bullatacin precursor. 

In 2006, Hoveyda and coworkers developed an asymmetric Mannich reaction of silyloxyfurans and aldimines using a similar catalyst system (Scheme 9.18).28 The diastereo- and enantioselective reaction between silyloxyfurans and aldimines in the presence of catalyst gave y-butenolides, which are useful building blocks for organic synthesis. They also reported a mechanistic study of this reaction.2811... 

The only report of 2-sulfinyl butenolides appeared in 1993 [50]. The synthesis of 5-ethoxy-3-p-tolylsulfinyl-2(5H)-furanones (42a and 42b) and their behavior as dienophiles in asymmetric Diels-Alder reactions with cyclopentadiene were studied. This paper evaluates the relative ability of the two chiral centers at the dienophile (sulfur and C-5) to control the stereochemical course of the reaction. From the results obtained it was concluded that both chiral centers have a... 

All of the routes described so far can be readily adapted to provide asymmetric syntheses of lignans. Thus, Koga et al. have synthesised (+)-yatein (36) and (+)-/rfl/j5-burseran (37) by conjugate addition to a chiral butenolide (35) (scheme 8) [54,55]. The more readily available menthyloxybutenolide (38) has been utilised by other groups [56,57]. The products (39) and (40) after desulfurisation, serve as precursors for the synthesis of dibenzocyclooctadienes, furofurans and aryltetralins (scheme... 

Diels Alder reactions have been used in several asymmetric syntheses of podophyllotoxin and its stereoisomers. Thus, Choy used the benzocyclobutene (120) as the diene precursor and a non-racemic butenolide as the dienophile in his synthesis of (-)-epiisopodophyllotoxin (106) (scheme 42) [101]. However, the unfortunate regioselectivity of the Diels Alder reaction makes the overall synthesis unnecessarily lengthy. In contrast, Charlton et al. used the aldehyde (105) as the diene precursor and a non-racemic fumarate as the dienophile in their synthesis of podophyllotoxin (113) (scheme 43) [102,103]. 

In some cases, using the silyl enol ethers form of nucleophiles in the asymmetric Michael reactions is necessary for ensuring high reactivity and selectivity. MacMillan and co-workers [113] developed the first enantioselective organocata-lytic Mukaiyama-Michael reaction for the synthesis of enantioenriched 7-butenolide architecture in 2003. In the presence of chiral imidazolidinone catalyst 120 with acid additive, the reactions of silyloxy furan 118 with simple a,(3-unsaturated aldehydes... 

In 2005, the same group reported the first total synthesis of eupomatilone-3, on the basis of a DKR of a a,/l-unsaturated butenolide submitted to an asymmetric... 

The Fukuyama synthesis commenced with the copper-catalyzed asymmetric reduction of butenolide 26 to give lactone 27 in 98% enantiomeric excess (Scheme 9). Sequential alkylation with CbzCl followed by methyl acrylate provided lactone 28 and installed both of the required contiguous stereocenters. The key Curtius rearrangement was performed by conversion of the benzyl ester to the acyl azide followed by heating. Subsequent treatment with aqueous HCI provided cyclized lactam 8. This compound was then dibromi-nated to lactam 29 using bromine, ZnCl2, and formic acid, which were the only conditions that were able to introduce the orf/to-bromine. The fully elaborated aromatic compound 29 was treated with methylamine followed by PDC to obtain cyclic A -methylimide 23. 

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