Synthetic approaches to butenolides D. W. KNIGHT Chemistry Department, University Park, Nottingham, NG7 2RD, UK Reviewing the literature published between 1976 and 1992 1 2 3 4 4.1 4.2 4.3 4.4 4.5 5 5.1 5.2 5.2.1 5.2.2 6 7 8 9 10 11 Introduction a-Substituted butenolides #?-Substituted butenolides y-Substituted butenolides Simple derivatives Methods using carbanions From maleic anhydride/furan Diels-Alder adduc t s From furans Other methods Hydroxy- and alkoxy-substituted butenolides a-Hydroxy- and alkoxy-butenolides y-Hydroxy- and alkoxy-butenolides From furans Other methods Butenolides substituted with alkoxycarbonyl groups Y lidenebutenolides Ring-fused butenolides S piro-butenolides Multi-substituted butenolides References 1 Introduction Butenolides occupy a literally central position between butyrolactone and furan structures, both in terms of synthetic chemistry and biosynthesis.These compounds also form an important and diverse group of natural products in their own right, encompassing both fatty acid and terpenoidal biosynthetic origins, and they display a wide range of biological activities. Very simple examples include the buttercup metabolite protoanemonin, the butter flavour component bovolide, and the related component of mushroom flavour, long-chain butenolides represented by acarenoic acid and methyl lichensterinate, and the highly unsaturated ylidenebutenolide lissoclinolide. However, the bulk of natural butenolides are terpenoid in origin. These range from the simple monoterpenoid mintlactones to numerous sesquiterpenes, representing most of the major biosynthetic classes and exemplified by confertifolin, aristolactone, and furodysinin lactone.Other examples include the paniculides and the highly oxidized metabolites freelingyne and the piscicidal vallapin. protoanemonin . HT 0 mushroom component C02Me n-c’3H27* 0 methyl lichensterinate mintlactones aristolactone -+ 0 bovolide acarenoic acid OH 0 lissoclindide confertifolin Wo f urodysinin hctone paniculide A freelingyne Me0 vallapin Knight: Synthetic approaches to butenolides 287Butenolide diterpenes are represented amongst the labdanes and the related jolkinolide E, while sesterterpene representatives include the PLA, inhibitor manoalide and the unusual and cytotoxic carotenoid metabolite luffariolide A. Digitoxin and related cardenolides are perhaps the most widely known members of the butenolide family.Two final and unique examples are the seed germination stimulant strigol and members of the securinine alkaloids, such as 4-epiphyllanthine. labdadienolide A jolkinolide E manoalide Qo luff aridide A digitoxin referred to as indicated in formula 1. The literature has been surveyed from 1976, the year of publication of the last extensive review of this topic,' up to 1992 inclusively. An attempt has been made to be reasonably comprehensive, but complete coverage is not claimed. The material has been arranged primarily on the basis of structural types, in order to facilitate access. Thus, monosubstituted and polysubstituted examples are grouped in separate sections. Clearly, in many cases, the same methodology can be applied to syntheses of members of the different groups.Where this has been reported, every effort has been made to provide cross references; the imagination of the reader will be required when this is not the case. Applications of many of the methods to natural product synthesis have been included in order to emphasize the utility of the strategy concerned. The parent butenolide 1, which is commercially available, can be prepared by Baeyer-Villiger oxidation of furan-2-carbo~aldehyde,~ using hydrogen peroxide/formic acid or from furan itself, in 62-7 1% yield by treatment with bromine in acetic acid/acetic anh~dride.~ 2 a-Substituted butenolides A neat method for the conversion of the parent butenolide 1 into the a-substituted homologues 3 consists of sequential Michael addition of thiophenolate and aldol condensation of the resulting enolate to give intermediates 2 ,4 Conventional oxidative elimination of sulfur completes the sequence, which unfortunately fails when ketones are used as electrophiles.The isomeric enolate 4 can be generated from the corresponding a,a-bis-( pheny1thio)- butyrolactone by treatment with ethylmagnesium bromide; similar condensation and elimination steps then lead to the same a-substituted butenolides 3.5 1 2 I 4 3 In general, a-alkoxy- and silyloxy-furans react with .-..& N , . ' the exception other a-position is the stannyl of the triflate furan 5 , n u c l e ~ s . ~ ~ - ~ ~ which reacts An largely at the /?-position of the furan, thus providing a non-anionic route to the a-hydroxyalkyl-butenolides 3.6 R-0 electrophiles, usually under the influence of a Lewis acid, to give y-substituted butenolides by reaction at &g&o - OH Stflgol 4-epiphyllanthine For the purpose of this review, the term 'butenolide' specifically refers to the conjugated or A*-butenolides; other, more systematic, names include but-2-en-4-olides and 2( 5H)-furanones.The - 3 a O S m T f substituent positions in butenolide structures are 5 288 Contemporary Organic SynthesisAn alternative strategy, which allows the indirect generation of an anionic centre at the a position of a butenolide, begins with the easily prepared Diels-Alder adduct 6, which can be readily converted into the monoester 7. Enolization and alkylation under standard conditions, lactonization, and finally a retro-Diels-Alder reaction delivers the monosubstituted butenolides 8.7 Limiting factors are the restriction to allylic and benzylic halides as electrophiles, as is usual with ester enolates, and in some cases the high temperature [200-280"C] required in the last step.This idea has been employed el~ewhere,~'-~~> 233, 234 as the adduct 6 and relatives thereof also effectively prevent competition from Michael additions which could interfere in reactions between butenolides themselves and nucleophiles. Another way of generating a /3-carbanion in a butenolide precursor involves the use of a diaminophosphate group to direct deprotonation to the 6-position of a furan, rather than to the much more usual a'-site.The resulting anion 9 reacts with aldehydes, ketones, and benzylic bromides, but not with other alkylating agents, to provide the butenolides 8, together with some of the deconjugated isomers, in ca. 50% yield, following brief exposure to formic acid.8 0 6 7 (if LDA-RX (i9 200-280 "c 'I 9 8 The fact that A2-butenolides contain an endocyclic, conjugated double bond suggests that alkene positional isomerization should provide a number of approaches to them. The above examples6> * already attest to the ease of isomerization of A3-butenolides; a-alkylidenebutyrolactones similarly are useful as precursors to A2-butenolides. For example, the a-allenylbutyrolactones 10 are converted into butenolides 11 upon exposure to dicobalt octacarbonyl, by a formal [ 1.33-hydride shift;Y of more general use is the finding that many rhodium( I ) hydride complexes, of the type which are well known to induce alkene migrations, readily catalyse the isomerization of aklylidene lactones 12 into the butenolides 13,33.35.171,172+202,227 in generally good yields.'" R 10 11 An alternative way of achieving this type of isomerization, and at the same time incorporating an additional functional group, is to employ an ene reaction; for example, by using 2-phenyltriazoline- 3,5-dione as the enophile, the alkylidene lactones 12 can be converted into the butenolides 14, in generally excellent yields.' Using this strategy, the ancistrofuran precursor 16 has been prepared by cyclization of the initial ene product 15.A rather elegant alternative to this method features cation-driven cyclizations of the dienoate 17 [X = PhSe, Br, or 0 (from peracid)]; the natural compound itself is accessed by a related but stepwise process.' 15 H 16 axx+ /J C02Me 17 In general, a-silylfurans are converted into butenolides when oxidized by buffered per acid^'^ and using the hydroxyalkyl functions in the furans ( 18; n = 1 or 2) to direct metallation to the adjacent a-position, regioselective introduction of a trimethylsilyl group can be achieved; subsequent peracid oxidation then leads to the synthetically useful butenolides 19.13 into y-hydroxybutenolides by singlet oxygen.' 1 6 , ' l 7 B Y i a 19 20 The isomeric hydroxyalkyl lactones 20" can be obtained via the same strategy, after first blocking the more reactive a-position by using a phenylthio group.One use of this type of silylated furan is as a precursor to the Grignard reagent 2 1 .I4 Coupling the latter with alkyl iodides, using dilithium tetrachlorocuprate as the catalyst, followed by oxidation constitutes an alternative route to the a-substituted butenolides 13. The corresponding B-substituted butenolides can be similarly obtained. Knight: Synthetic approaches to butenolides 28921 An extra degree of synthetic flexibility is offered by the a-stannylbutenolide 22, prepared from the corresponding phenylthiobutenolide by a desulfurylative-stannylation reaction, which undergoes smooth palladium( 0)-catalysed couplings with aryl iodides and presumably many related Stille-type coupling reactions.' SnBu3 CXo 22 3 b-Substituted butenolides The /%isomer 23 of the foregoing stannylbutenolide 22 similarly provides a wide range of opportunities for the preparation of B-substituted butenolide~.'~ CO2Et Eto40 - ____c OEt 26 27 OEt 1, t 28 is found in the fungus Psathyrella scobinacea, and an E/Z mixture of which has been isolated from Senecio cZeveZandii.20 However, these reports suggest that a better route to the salt 30 is from 3,3-dimethylacrylic acid, as outlined below.205 SnBu3 I 23 29 30 31 E-Scobinolide Formally, the 'inverse' approach to this method of producing B-substituted butenolides 25 features palladium( 0)-catalysed coupling reactions between dialkylzincs and the B-bromobutenolide 24.16 Such butenolides can also be obtained from the bromide 24 by an alternative, if somewhat capricious combination of Michael addition and elimination reactions, usually using lithium dialkylcuprates as the nuc1eophiles.l Br R 24 25 A more convoluted approach to this type of butenolide begins with the keto-ester 26, which is first alkylated using an allylic chloride then saponified and finally decarboxylated and homologated to the unsaturated esters 27 by a Wadsworth-Emmons condensation. Acid-catalysed ring closure and borohydride reduction of the resulting y-ethoxybutenolides (Section 5.2) completes this synthesis of butenolides 28, which are useful precursors of the furanoterpenes perillene and dendrolasin.18 diacetoxyacetone, was the key step in a preparation of B-hydroxymethylbutenolide 29." (See also reference 14.) This compound occurs naturally as a metabolite of Siphonodon australe and is also useful as a precursor of the phosphonium salt 30 [ cf.reference 1951. One application of the latter is in a non-stereoselective synthesis of Scobinolide 3 1, which A similar olefination reaction, but of A different approach to the unsaturated esters 27 in general features a Peterson olefination as the key step.21 Another example of the way in which a Wadsworth-Emmons reaction can be employed in this area is illustrated in the synthesis of (S)-manoalide diol33b .22 Starting from 2-deoxy-~-ribose, the butenolide 32 was prepared to form the alkene linkage, as in the foregoing examples. A second Wadsworth-Emmons condensation was then used to obtain the central trisubstituted olefinic bond; the synthesis' 17, l8 was completed by selectively reducing the carboxylate function of ester 33a by mixed anhydride formation and treatment with sodium borohydride.32 0 33a; R=C02Bn b; R=CHzOH 290 Contemporary Organic Synthesis/I-Substituted butenolides, e.g. 35, can also be prepared by PDC oxidations of TMS cyanohydrins derived from #?,/?-disubstituted-a,/3-unsaturated aldehydes, e.g. 34.23 Yields are variable (40-75%) and the method is rather limited in that mixtures are obtained when both positions y- to the aldehyde carry hydrogens and are thus open to oxidation. This method has been used to prepare the labdadienolide 36 starting from manool, but the isolated yield from the oxidation step was only 16°h.24 Ar 34 35 36 Esters corresponding to the aldehydes 34 can be oxidized to butenolides using the allylic oxidant selenium dioxide; yields are increased by adding a little perchloric acid which apparently increases the reactivity of the oxidant by protonation of the Se = 0 bond.25 The method is limited to substituents lacking an a-photon (aryl; tert-alkyl).An alternative access to /I-arylbutenolides 35 is provided by an application of the Heck reaction in which aryl iodides are coupled with the unsaturated ester 37 under solid-liquid phase transfer conditions using palladium( 11) chloride as the catalyst.26 Yields are in the range of 48-71%; extensions of the method to more highly substituted examples have not been reported. 37 This approach has been applied to the elaboration of the /I-substituted butenolide unit in the cardenolides 39 by coupling between an enol triflate 38, derived from a steroidal 17-one, and the ester 37, followed by lactonization induced by an acidic ion exchange resin.27 Completion of the synthesis involves a regiospecific hydrogenation using conventional conditions to give the final product 40.The /?-substituted butenolide function present in the cardenolides has been prepared in a number of different ways involving construction of the lactone ring using anionic chemistry. For example, a Reformatsky reaction has been used to obtain the hydroxyester 4 1 from the corresponding a -met hylthio ketone; subsequent acid- and base-treatments lead to the desired products 40.28 A more extended but nevertheless efficient approach also begins with a steroidal 17-one, Knoevenagel condensation of which with ethyl cyanoacetate followed by borohydride reduction leads to the cyan0 alcohol 42.Alcohol protection, Dibal-H reduction, and treatment with cyanide then affords the protected cyanohydrin 43. Brief exposure to acid gives the corresponding /I-hydroxybutyrolactone and thence the butenolide 40, following chlorination and thermal elimination.29 38 37 Pd(OAC), ByN. PPh3 - then H30+ 42 39 H2 Pd-C,EtOAc I The Bestmann ketenylidene phosphorane method155 has been used in a much shorter approach to the 17-hydroxy-cardenolides 45 from the hydroxy ketones 44.30 This procedure was also found to be the best of a number of alternatives for the elaboration of the butenolide function in the insect antifeedant ajugarin IV 46.31 Ph#=C=C=O 44 45 46 Other Wittig-based methods leading to /I-substituted butenolides 48 include an intramolecular version in which the likely intermediate 47 in the Bestmann method is prepared in stepwise manner by ester formation between an a-bromo-acid and an a-bromoketone followed by quaternization Knight: Synthetic approaches to butenolides 291and elimination of hydrogen bromide.32 Overall yields are generally high in both models and in cardenolide synthesis, but the methodology is not appropriate for the elaboration of ring-fused butenolides, starting with cyclic a-bromoketones.tXPPh3 47 49 48 The phosphorane 49, derived from maleic anhydride, undergoes smooth Wittig reactions with aldehydes; subsequent selective reduction of the ester function using sodium diethylaluminium hydride leads to the corresponding p-alkylidenebutyrolactones, isomerization'" of which completes the sequence.33 During a synthesis of digitoxigenin, the butenolide function was introduced by a palladium-induced rearrangement of the allylic epoxide 50, with concomitant ~yclization.~~ Oxidative elimination of the sulfenyl function from the resulting butyrolactone 5 1 then completed the sequence.A contribution to butenolide synthesis from the burgeoning area of radical chemistry is the finding that the acetylenic mixed acetals 52 undergo smooth cyclization when treated with tributyltin radicals;35 the resulting acetals 53 are readily converted into examples of the butenolides 48, following oxidation and isomerization.'O* 35 52 53 A tandem version starting with the acetal54 can be used for the preparation of the cardenolide fragment 55.Sequential alkylation of the sulfone dianion 5641,206,225 by an alkyl halide and iodoacetate leads to the hydroxy-acids 57 and thence to the butenolides 48.36 The method can also be used to prepare y-substituted butenolides. 54 55 ArS02 KR-48 0- -0 c02- 56 57 A more direct but unfortunately less efficient approach to the lactones 48, developed during synthesis of the insect antifeedant ajugarin 1, ( cf reference 3 1 ) features Michael addition236, 245 of a sulfone 58 to the acetylenic ester 59.37 Overall yields are - 45% after completion of the route by lactonization and reductive removal of the sulfur function. 59 The potentially useful alkynyl butenolide 6 1 is available from an unusual reaction in which the ester 60 is subjected to gas-phase pyrolysis; the mechanism probably consists of a tandem ene/[ 1.51-hydride shift sequence.38 60 550 "c 61 4 y-Substituted butenolides 4.1 Simple derivatives A number of approaches to enantiomers of the simplest y-substituted butenolide, Angelicalactone 64 [( S)-enantiomer shown], have been developed which may be more generally useful.For example, the tetronic acid 62 is available in two steps from ethyl L-lactate; reduction of the alkene function1o5, 258 using the borane-ammonia complex and dehydration of the resulting, largely trans-hydroxy-butyrolactone 63 completes the sequence.39 OH OH 62 63 64 292 Contemporary Organic SynthesisOther precursors include y-hydroxymethyl-butenolide derivatives (see below)40 and the hydroxy-sulfone 65, obtained by yeast reduction of the corresponding keto-sulfone.4'.In contrast to the related #?-hydroxy-esters, the derived Frater-type diani0ns~~7 225 do not couple to ally1 bromide with any significant degree of stereoselectivity. Conversion of the separable epimers 66 into lactone 64 then proceeds along conventional lines. The ( + )-( S)-enantiomer 64 has also been prepared from ( L )-tartaric acid by a relatively lengthy route.42 Similarly, a number of routes are available for the elaboration of the useful (S)-hydroxymethyl butenolide 67. Starting with 66 67 ( R )-isopropylideneglyceraldehyde derived from D-mannitol, the necessary homologation can be achieved either by condensation with lithi~acetate~~ or through a cis-selective Wittig reaction.44 The latter route appears to be the more practical.Alternatives include overall oxidative removal of the two secondary functions from the D-ribono- 1,4-lactone derivative 68 by an apparently unprecedented elimination to give a mixture of the acetoxy and bromo derivatives 6945 and the more conventional deoxygenations of D-ribono- 1 $-lactone by pyrolysis of a derived cyclic orth~formate.~'*~~ OAc 68 69 These reports also outline approaches to ( - )-umbelactone206-208 and to lactone 67, starting from the corresponding butyrola~tone,~~ and to the natural butenolide glycoside ranunculin 70, by coupling lactone 6 7 to glucopyranosyl bromide.47 Further methods for effecting this type of bis-deoxygenation, but of ascorbic acid derivatives have been detailed;48 using these methods, useful y-substituted butenolides such as either enantiomer of the epoxides 7 1 can be prepared.49 70 71 Almost inevitably, butenolide 67 has also been prepared by a route which utilizes an asymmetric Sharpless epoxidation as the source of chirality.5o Thus, the epoxy-alcohol72 so obtained reacts with cyanide via a prior Payne rearrangement to give the homologue 73 and thence the target, as its O-benzyl ether.72 73 Closely similar chemistry has been used to obtain the y, y-disubstituted butenolides 74.51 Various methods for preparing the derivatives (75; X = OR, Br, SPh, NR,) have also been described, starting either with the hydroxymethyl lactone 6752 or by condensation of an appropriate epoxide with the dianion of phenylselenoacetic acid.53. 57 74 75 Almost complete stereocontrol is observed in condensations between y-hydroxy-butenofides and chiral N-acetyl thiazolidine thiones, leading to the useful butenolides 76.54 a R 76 4.2 Methods using carbanions Formation of the 2,3-bond using carbanion chemistry is the least common of the three possibilities described in this section.An intramolecular version features cyclization of the readily prepared sulfinyl carbonates 77 using LDA as the base, followed by pyrolytic elimination of the sulfur function, leading to generally excellent yields of the butenolides 78.55 Alternatively, the chloroacrylate 79, available in three steps from propargyl alcohol, reacts sequentially with two equivalents of a Grignard reagent and then lithium metal to give the intermediate vinyl carbanion 80, carboxylation of which leads to the y, y-disubstituted butenolides 8 1 .56 79 80 81 Methods involving formation of the 3,4 bond constitute some of the most generally applicable and useful approaches to butenolides.For example, Knight: Synthetic approaches to butenolides 293condensations between the dianion 82 and an epoxide, which can be homochiral as shown, followed by lactonization [DCC-DMAP] and a facile oxidative elimination of the selenide group lead to the lactones 83 in 70-75% overall yields.57 The analogous sulfur version of this approach was reported some ten years previously and continues to find application^.^^ The same chiral butenolides can also be accessed by yeast reductions of the chloro-keto esters 84; optical purities can be e~cellent.~~ 0 C02Me - u 82 83 84 A rather different way in which the homochiral butenolides 86 can be constructed from an epoxide starts with the epoxy-sulfone 85, also prepared using yeast reduction (but of the corresponding keto-sulfone) to generate the chiral centre,41, 206 and consists of sequential copper-catalysed attack by a Grignard reagent and homologation using i~doacetate,~ as shown.60 A weakness in this approach is the poor returns from the last two steps. 85 86 The sulfoxide analogues 87 of the first formed intermediates in the foregoing method can be generated by reduction of the corresponding keto-sulfoxides.61 Either epimer at the secondary alcohol position can be obtained, depending on the reducing agent and the final products 86 have enantiomeric enrichments in excess of 90%; however, similarly poor yields are obtained in the later, closely related homologation and elimination steps.A rather more efficient sulfur-based procedure is to subject the hydroxy-sulfoxides 87 to a Pummerer rearrangement and then homologate the resulting hydroxy-aldehydes using nucleophilic acetate.62 A sulfoxide rearrangement is also featured in an approach to the disubstituted butenolides 90 by condensations of the aldehydes 88 with sulfinylacetate which lead to the unsaturated esters 89.h3 The sequence is completed by Michael addition of thiophenolate, which allows formation of the corresponding butyrolactone, and elimination. ?- ,S 'Ar a7 88 89 I I 90 A very different approach to the chiral butenolides 83 features attack of a Grignard reagent onto the C,-symmetric imide 91, derived from tartrate, followed by stereoselective borohydride reduction and acidification to give the dihydroxy lactones 92 and finally reductive removal of the two hydroxyl groups (triiodoimidazole, P h,P, Zn); final enantiomeric enrichments can be 2 98°/0.64 Of the many possibilities for constructing a butenolide 78, by formation of the 4,5 bond, perhaps the simplest approach is by condensation of an aldehyde 93 with the acetylide 94, followed by Lindlar hydrogenation.Although conceptually straightforward, the experimental details require close attenti0n.6~ Reduction of 1 -trimethylsilylpropargylic alcohols using Bu'MgBr-Cp,TiCl,( cat.) leads smoothly to the dianionic intermediate 95; subsequent carboxylation and desilylation (TBAF ) provides an alternative.66 The availability of chiral, non-racemic starting alcohols means this approach should be well suited to the asymmetric preparation of y-substituted butenolides 83.R-0 + L i \ _L 78 CO2Et 93 94 +YSiMe3 - - ent -83 BrMgO MgBr 95 The /3-lithio acrolein derivative 96 represents a more reactive example of the same principle; the resulting /3-bromobutenolides 97, obtained following mild acidic hydrolysis and manganese dioxide oxidation, can be debrominated using tin hydride to give the final products 90.",'06 The related dianionic species 98 condenses smoothly with aldehydes leading to /3-sulfonyl butenolides 99; removal of the sulfur function is not described>* 96 97 98 99 A widely used method for preparing butenolides 90 involves condensations between a three carbon unit 294 Contemporary Organic Synthesis100, having a (masked) carboxylic acid function [XI at the distal position, and an aldehyde or ketone, followed by lactonization and oxidative elimination of the sulfur group.- - 90 \X 100 Examples of this include the acid derivative itself 101,6y the 0rthoester102,~~ the related amide dianion 103,71 the ally1 sulfone 104,72 the sulfoxide analogues 10573 and 106,74 and the tris-sulfenyl-propene 107.753 *06 Overall yields using the sulfones 102 and 103 are generally high. 104 PhS L i t PhS SPh 107 ' 3 O M e OMe 102 Lisa 105 R--20 PhS02 108 PhFO2 103 PhSO Li>R 106 Eto2c-o 109 Attempts to achieve asymmetric induction using analogues of the sulfone 103 derived from ( R )-a-methylbenzylamine were not successful but at least the chiral ligand could be used to allow separation of the resulting diastereomers.Much the same is true of the generally less useful chiral sulfoxides 105 and derivatives of sulfoxides 106 where asymmetry is incorporated either at sulfur or the carbonyl position. can be homologated by enolization and reaction with an electrophile. For example, such intermediates derived from y-sulfonyl-butenolides react with allylic or benzylic halides, but not saturated alkyl halides, to give the lactones cleanly removed using tin hydride. Similarly, the lithium enolate of angelica lactone 64 reacts with ethyl acrylate to give the ester 109.77 Unfortunately, in examples both of other electrophiles and isomeric methyl-substituted butenolides, mixtures of products arising from attack at the a- and y-positions are usually obtained.The 'reverse' disconnection is also possible. Thus, ethoxybutenolides (Section 5.2) react with two equivalents of an alkyl lithium in tetrahydrofuran to give the disubstituted butenolides 8 1, after Jones oxidation of the resulting lactol. In favourable circumstances, preformed butenolides The sulfonyl group can be y-Substituted butenolides 78 can be similarly prepared from the corresponding y- hydroxybuten~lide.~~ 4.3 From maleic anhydride/furan Diels-Alder adducts Generally excellent yields of the y, y-disubstituted butenolides 8 1 can be secured by reaction between the half-ester 1 1 1, obtained by methanolysis of the Diels-Alder adduct 110, and an excess of a Grignard reagent followed by cycloreversion at 150 - 1 80"C.7y 0 110 11 1 Prior methanolysis is not necessary as it was later found that the initial anhydride 1 1 077 233, 234 reacts equally well with Grignard reagents.s0 Secondary Grignard reagents tend to add only once, leading to y-monosubstituted butenolides.81 As the dimethyl ester derived from the anhydride 1 10 is a meso-isomer, it is amenable to resolution by selective hydrolysis using porcine liver esterase [PLE]; subsequent regioselective reduction of the resulting half-ester (cf 11 1) affords the chiral butyrolactone 112.Sequential reduction to the corresponding lactol using Dibal-H, reaction with an organometallic nucleophile, Jones oxidation, and cycloreversion gives the chiral y-substituted butenolides 113 in good overall yield and with generally excellent enantiomeric enrichments .8 * 0 112 113 4.4 From furans Homologations of simple butenolides by enolization are not in general particularly productive.76, 77 A much more effective tactic is to begin with a 2-oxyfuran derivative 114 as these often react smoothly and regiospecifically with electrophiles to give good yields of the y-substituted butenolides 11 5 , although a-selective exceptions are known.6 Lewis acids usually feature as catalysts in such reactions and an appropriate choice is important.Illustrative of the method is the rearrangement of the acyloxyfurans 1 16 to the butenolides 1 17 (40-65'74 upon exposure to boron trifluoride etherate.83 114 115 Knight: Synthetic approaches to butenolides 295More generally useful is the finding that the acetyloxyfuran 1 18, produced by anodic oxidation of furan itself, undergoes efficient condensations with aldehydes in the presence of titanium( IV ) chloride to give the y-substituted butenolides 1 19.84 116 117 118 119 In contrast, a similar condensation with acetyl chloride leads to the ylidenebutenolide 120.The corresponding 2-silyloxyfuran 12 1 reacts similarly with orthoesters to give good yields of the acetals 122 and with diethyl acetals to give the corresponding ethers 123.85 OAc 120 EtO OEt OEt 121 122 123 More extensive studies of the synthetic potential of furan 12 1 have revealed that alkylations by allylic halides are best performed using silver trifluoroacetate as the trigger, neatly illustrated by a total synthesis of the natural butenolide freelignite 1 24,*6 but that reactions with aldehydes are best catalysed by triethylsilyl t ~ i f l a t e .~ ~ By a judicious choice of condition~,'~' the latter condensations can be highly stereoselective, leading to either the erythro or the threo (shown) isomers 125, and can be used to obtain y- C-glycosylated butenolides by highly stereoselective condensations with sugar-derived aldehydes or imines.88 Subsequent results suggest that silver triflate is one of the best reagents for effecting alkylations by primary alkyl iodides.*' Being relatively soft nucleophiles, these intermediates are good participants in Michael additions. An example is the preparation of the butenolide 128, an early intermediate in an approach to the mitomycins, by the addition of furan 127 to the enone 126; however, the transformation may not involve a simple Michael addition, but rather a Diels-Alder cycloaddition followed by an acid-catalysed rearrangement.'O Nonetheless, an example of such a Michael addition has been reported in the reaction of 2-methoxyfuran with a cyclic enone, induced by trimethylsilyl iodide?' fl 0 1 24 Ph 125 + 126 127 Ph 128 A variety of furans 129 carrying heteroatomic substituents in an a-position can be oxidized, using hydrogen peroxide or various peracids, to the corresponding butenolides 130.These include borates [ 129; X = B (OMe),],'* selenides ( 129; X = SePh),93 and silanes (129; X = SiMe3).13* 1 4 y 0 4 Often some, or all, of the initial product is the A3-butenolide and so an additional isomerization step is required to reach the final product 130.129 130 A different way in which a furan can be converted into a butenolide is by low temperature photo-oxygenation which leads to the cis-enediones 131; further oxidation with PCC in the presence of trimethylsilyl cyanide leads to the y-cyan0 butenolides 132.95 131 132 Diols 133 which correspond to the foregoing diones, are regioselectively oxidized to y-substituted butenolides 130 by treatment with Fetizon's reagent.Y6 133 4.5 Other methods A somewhat inefficient addition of mercury( 11) chloride to propargylic alcohols leads to the vinyl mercurals 134; a subsequent palladium-catalysed carbonylation step236-243 leading to the chlorobutenolides 135 is, 296 Contemporary Organic Synthesishowever, very efficient.97 Closely related tellurium chemistry can be used to prepare the parent butenolides 90 directly, although only in moderate overall yieldsg8 dianion 14 1, which condenses with aldehydes, leading to the a-methoxy-butenolides 142.Io6 As is often, but not always, the case with this type of chemistry, the rapidity and simplicity compensate for the rather poor yields.67,75, 133,139,16l,170,208-210 134 135 141 142 Chiral y-substituted butenolides 83 can be obtained by acid-catalysed ring closure of chiral 2,3-allenylcarboxylic acids; a limitation with this method is the availability of the starting materials.99 The a-fluoro-butenolides 136 can be obtained by a related process.lo0 136 An overall 5-endo-trig cyclization of methyl 2,3-allenecarboxylates to give the bromobutenolides ( 137; X = Br) can be effected in essentially quantitative yield by using molecular bromine.101 Such cyclizations can also be carried out using many of the other electrophiles usually associatedywith this type of reaction, to give the lactones ( 137; X = HgOAc, I, PhS, PhSe) in variable yields.lo2 This type of cy~lization,~~~? 204, 232 in this case induced by acid, may well be the last step in the formation of the diary1 butenolides 139 from the hydroxy-butenolide 138, using Friedel-Crafts conditions followed by thermolysis in DMF.lo3 Simple y-aryl butenolides can be obtained directly from y-hydroxy-butenolide, but only in moderate yields.lo4 x CI R* Ho*c’ (ii) (I) Ar-H.125 ‘c.AK&- DMF “a: Ar 0 0 137 138 139 During the development of iterative approaches to polypropionates, some potentially useful butenolide chemistry has been exploited, such as the preparation of the y-substituted butenolide 140 from the corresponding tetronic acid by reduction and subsequent eliminati~n.~’. 258 The report also contains some useful preparations of alkoxy-substituted butenolides, the topic of the next section.Ios 140 5 Hydroxy- and alkoxy-substituted butenolides 5.1 a-Hydroxy- and alkoxy-butenolides Direct lithiation of a-methoxyacrylic acid (or derived secondary amides) using t-butyl lithium gives the The related dianion 143 gives rather better returns of the corresponding a-benzyloxy-butenolides; this method was the most successful of a number tried for the synthesis and hence structural proof of the natural acetylamino-butenolide Leptosphaerin 144, carried out by White and his colleagues.1o7 Another dianionic species, the oxazolidinedione 145, is useful as a general precursor to the a-hydroxy- butenolides 147, following condensation with an a-chloro-ketone and hydrolysis of the intermediate 146.1°8 The latter is presumably formed by base-triggered rearrangement of the initial Darzens product.0 145 146 R’ I R2eoH 0 147 An alternative approach to a-methoxy-butenolides 149 is by acid-catalysed cyclization of the acetylacetone derivatives 148; the mechanism appears to involve a [ 1.3)-hydride shift.Io9 A double carbonylation of styrene, using dicobalt octacarbonyl as the catalyst under phase transfer conditions, leads to the a-hydroxy-butenolide 150 in 65% yield; further studies are needed to fully define the utility of this reaction.A more general approach to this type of /?-substituted hydroxy-butenolide 152 consists of condensation of the a-oxodiesters 15 1 with formaldehyde, palladium( 0)-catalysed cleavage of the ally1 esters, and decarboxylation. Knight: Synthetic approaches to butenolides 297298 9' R' 148 149 kOH 150 R a Pd" &OH HCOflH, \' 0 151 152 No discussion of P-hydroxy- or alkoxy-butenolides is given here as these are the tetronic acids and derivatives, a separate class of compound which is beyond the scope of this review. 5.2 y-Hydroxy- and alkoxy-butenolides 5.2.1 From furans Photo-oxygenation of furan derivatives is one of the most popular ways of preparing y-hydroxy- butenolides.For example, such a reaction of the furfurals 153 l 2 or the corresponding furoic acids' l 3 leads to the lactones 154 in - 70% yields.' l 2 Rose bengal immobilized on Sephadex A25 is an especially useful sensitizer in these cases. Similarly, furfuryl alcohol can be converted into the parent y-hydroxy-butenolide in 97% yield.'12 153 154 Other unsaturated functions can be tolerated and when the oxidations are carried out in methanol, y-methoxybutenolides are produced, as illustrated by the conversion of furan 155 into the lactone 156.114 155 156 Problems of regioselectivity arise when 3-substituted or unsymmetrical 3,4-disubstituted furans are subjected to this type of oxidation; however, various carbonyl functions can act as effective control elements.' l 5 Undoubtedly, the major recent advance in this area has been the discovery that an a-trimethylsilyl group, when incorporated into the furan (e.g.157),'3314794 Contemporary Organic Synthesis facilitates each step of the sequence, especially the now regiospecific collapse of the intermediate endoperoxide, leading to the final producs 158.'16 (See also reference 123). This means that such silylfurans can serve as masked y-hydroxy-butenolides during a synthetic sequence; the final step of a total synthesis of manoalide 159 as well as of (E)-neomanoalide was just such a sequence.' l7 159 However, in some cases, it will no doubt be troublesome to incorporate the silicon function regioselectively. It is therefore interesting that a method has been developed for the regiospecific photo-oxygenation of 3-alkylfurans 160 to the lactones 16 1 .I l 8 The key is to induce decomposition of the intermediate endoperoxide using a highly hindered base which will only abstract the less sterically encumbered proton.This tactic has been successfully applied to syntheses of furodysinin lactone 162 and to relatives of manoalide 1 59.22 1 62 A number of other oxidative methods have also been used to convert furan derivatives into y-hydroxy-butenolides. These include treatment of the bromofurfuryl alcohols 163 with pyridinium chlorochromate (PCC), resulting in the formation of the y-hydroxy-butenolides 164 in 60-75% yields;' l9 Jones oxidation of the p-D-ribofuranosyl derivate 165 to give the C-nucleoside precursor 166 in 93% yield;'*O and oxidation of trimethylsilyloxyfurans 12 1 to y-acy10xy-l~~ and -sulfonyloxy-butenolides by treatment with iodosobenzene and the appropriate acid.'OH OH 1 63 164 BzO OBz BzO OBz 1 65 166 A rather different way in which such furans can be transformed into y-hydroxy-butenolides 164 is to use a version of the Lewis acid catalysed condensation reaction 1 14 -+ 11 5,85-89 but starting with the bis-( sily1oxy)furan 167, derived from a succinic anhydride.' 22 164 T E 4 OSi - I 167 A rather different approach to the hydroxy-butenolides 158 starts from the furan oxidation product 168 and involves sequential ozonolysis and Wittig homologation, leading to the dienes 169. Subsequent, rather brutal, acidolysis then gives the final products 158 in - 60% overall yields, along with the corresponding (E)-aldehyd~-acid.'~~ MeOQ OMe 168 5.2.2 Other methods COPE1 Me0 OMe 169 5m HCI dioxan 100 "c, 2h 1 158 Carbonylations of terminal alkynes which use dicobalt octacarbonyl as the catalyst in the presence of iodomethane to yield the y-hydroxy-butenolides 170 are best carried out using solid-liquid phase transfer conditions124 rather than those originally r e ~ 0 r t e d .l ~ ~ Attempts to use other alkylating agents have only been partially successful. Symmetrical alkynes can similarly be converted into the alkoxy-butenolides 17 1, but using a rhodium carbonyl ~ a t a l y s t ~ ~ ~ , ~ ~ * in the presence of an alcohol, R20H.126 R' R20 --&: 1 70 171 Methods for introducing the y-hydroxy-butenolide function into the naturally occurring germination stimulant strigol 172 all rely on enolate alkylation by the sodium salt of y-bromo-a-methyl-b~tenolide,~~~ the potassium salt in the presence of HMPA,128 or improvements of these.129 172 A variety of other heterosubstituted butenolides can be obtained from the parent y-hydroxy- or alkoxy-butenolides.Lewis acid catalysed exchange of the latter with ethanethiol leads to the thiol derivative 1 73130 whereas a Michael addition-elimination sequence can be used to prepare the p-amino- or thio-derivatives ( 174; X = R'N or S ) from the corresponding halobutenolides.' 31 A useful enolate can be generated from the thiol derivative 173, which reacts with differing regioselectivities depending upon the electrophile used.Thus, reactions with aldehydes give the a-substituted homologues 175 whereas additions to Michael acceptors lead to the y-substituted butenolides 1 76.132 RX OH '"q E t s e R 0 0 0 173 1 74 175 0 176 The natural y-hydroxy-butenolide lepichlorin 17 7 has been prepared by a route which features /3-lithioacrylate chemistry.133 As outlined above,lo6 such methodology while usually very brief is often rather ineffecient; this example is no exception. " H T 177 As both y-hydroxy- and y-alkyloxy-butenolides are readily reduced to the corresponding y-unsubstituted analogues using, for example, sodium borohydride, the foregoing methods could all in principle be of use in the preparation of butenolides in general. 6 Butenolides substituted with alkoxycarbonyl groups Starting from butyrolactone 178, the a-methoxycarbonyl butenolide 179 is best prepared Knight: Synthetic approaches to butenolides 299by sequential condensations with dimethyl carbonate and the relatively more reactive thiophenylation reagent S-phenyl benzenesulfonothioate, PhSSO,Ph, followed by oxidative elimination of the sulfur group.134 Alternatively, the ylidenemalonates 180 undergo smooth elimination of bromomethane upon thermolysis in xylene to provide y, y-disubstituted homologues of lactone 179.135 178 179 180 A more convoluted approach begins with addition of malonte to the allenic sulfoxides 18 1; subsequent [ 2.31-sigmatropic rearrangement of the resulting adduct 182 leads to the hydroxy diesters 183 and thence, upon lactonization and isomerization, to a-methoxycarbonyl butenolides.' 36 181 182 183 P-Alkoxycarbonyl butenolides 184 are readily obtained in general by starting with a P-keto-ester which is alkylated using an a-bromo-acid; subsequent dehydrative cyclization and isomerization completes this a ~ p r 0 a c h .l ~ ~ A natural product containing this structural feature is methyl lichensterinate 185; a synthesis has as a key step the Lewis acid catalysed condensation of methyl a-ketopalmitate with (diethylamino)propyne'91-'93 to give the amide 186. The synthesis is completed by allylic bromination and bicarbonate induced cyclization.' 3x The fumarate derived vinyl anions [ 187; R = NR2, OR' or SR']l''h condense with aldehydes to give /I-methoxycarbonyl butenolides directly in 30-83% yields.'39 184 185 Me02C C02Me M.'CH2h2+ Li+R CONE12 C02Me 186 187 7 Ylidenebutenolides The simplest member of this group, the naturally occurring protanemonin 188, can be obtained from 5-hydroxymethylfurfural by sequential photo-oxygenation, borohydride reduction,18 and deh~drati0n.l~~ The y-substituted butenolides 189 are easily prepared by tin( IV) chloride-catalysed condensations of the a-silyloxyfuran 12 1 with aldehydes;87 dehydration brought about by treatment with tosic acid in hot benzene leads to the ylidenebutenolides 190 in excellent overall ~ie1ds.l~~ OH 188 189 1 90 Ylidenebutenolides 190 can also be obtained in ca.70% yields from the alkoxyfurans ( 19 1; R = Me) by treatment with zinc bromide142 or from the corresponding methyl ethers using trimethylsilyl iodide.143 The latter method has been used to prepare bovolide 192, a butter flavour component.R% OR 191 1 92 As an alternative to the foregoing Lewis acid induced preparation of lactones 189, the related furans (191; R = But) can be obtained from the corresponding lithiofuran and an aldehyde or ketone; conversion to butenolides 190, in 44-81% overall yields, simply requires treatment with tosic acid in aqueous tetrah~dr0furan.l~~ a-Stannylfurans can be oxidized, via an intermediate y-acetoxybutenolide,121 to butenolides 190 using lead(1v ) acetate.145 In extreme cases, no substituents are necessary on the furan ring to facilitate oxidation; the tertiary carbinols 193 are converted directly into the corresponding ylidenebutenolides using PDC in DMF.14h Yields are only high, however, when both chain substituents are aryl groups.Related hydroxyalkylfurans can also be oxidized using phenylselenenyl chloride, apparently by a rather convoluted mechanism.147 193 Dehydrobromination is another way of generating an ylidenebutenolide, as in the case of the potentially useful bromo derivative 194; the intermediate butenolide was prepared by starting with an effectively 5-endo-trig bromolactonization9Y-102. lh4, 204, 232 of the corresponding 2,3-allenyl ester.14x 300 Contemporary Organic Synthesis194 Phosphonium salts derived from butenolides offer an alternative but often non-stereoselective entry into ylidenebutenolides. An example is the preparation of the retinoic acid analogue 196, using the ylide derived from the salt 195.14’ 195 196 The lactone double bond can also be prepared via an intramolecular Wittig reaction.Thus, addition of an enolizable a-diketone to the salt 198, followed by cyclization, leads to the useful ‘~emi-protected~~~’ ylidenebutenolides 197 in respectable yields.15o OEt P h $ y o E * R3 OEt 6Et 197 198 In the reverse sense, to the use of ylides from salt 195, ylidenebutenolides 199 are available from condensations between stabilized phosphorylides and maleic anhydrides. In the case of ( 199; R = OBu‘), the corresponding, relatively unstable, carboxylic acid can be obtained by treatment with mineral acid,151 while the thiolates ( 199; R = MeS), obtained in the same manner, can be desulfurized, using Raney nickel, to give the lactones 190 as isomeric mixtures.152 In examples of unsymmetrical anhydrides, attack usually occurs regioselectively to give the isomers 200.’53 ‘m R 0 2 C q R 0 0 1 99 200 A rather lengthy route to ylidenebutenolides 190 has, as a key intermediate, the phosphonate 201, obtained by a [ 1.31-dipolar addition reaction.Subsequent N-0 bond cleavage, hydrolysis, and olefination leads to the esters 202 and thence to the final products (after borohydride reduction, cyclization, and dehydration).’ 54 0 N-0 0 OH 201 202 190 A further application of Bestmann’s ketenylidene phosphorane chemi~try~~-~* is in the direct formation of cyclic and acyclic butenolides 205 by condensations between enolizable 1,2-diones 203 and the phosphorane 204.155 Usually, good to excellent yields are obtained. 203 204 -0 205 A Wadsworth-Emmons homologation is a key step in the preparation of the epoxy-ester 206, the penultimate precursor of ( f )-8,9-dehydroasterolide 207.156 Related lithio-sulfone chemistry has proven suitable for the elaboration of the carotenoid-based ylidenebutenolides 208 (R = polyene chain) in which the vital alkene functions are generated by facile elimination of benzenesulfinic acid.157 206 207 “0- 208 The rather labile ylidenebutenolide 209 and related, ring-fused, structures are available from condensations between morpholine enamines and ketomalonates followed by cyclization of the resulting alcohols.158 Such products are often useful as Michael acceptors.Michael reactions are especially important for the preparation of examples of ring-fused butenolides in general, including ylidenebutenolides. Particularly useful in this respect is the P-vinylbutenolide 2 1 0,178 which condenses smoothly with /3-dicarbonyls to give, for example, the tricyclic system 2 1 1, following dehydration.’ 59 Another useful aspect of this type of product is that the corresponding sulfoxides readily rearrange to the transposed alcohols 212.A total synthesis of the phytoalexin lettucenin A featured as a central, but somewhat inefficient, step the radical-mediated rearrangement of the dibromomethyl dienone 213 to the hydroazulene 214, a ring expansion method developed some time ago by Barton’s group. 160 the synthesis of ylidenebutenolides by condensations of the weakly nucleophilic anion 2 15 with acid chlorides to give the lactones 216.161 Once again,lo6 yields are only moderate but the method is rapid and relatively simple.13-Lithioacrylate chemistrylo6 can also be applied to Knight: Synthetic approaches to butenolides 301302 \ kSPh 21 0 +co2Et 209 QSPh 0 21 1 (0 MCPBA (ii) NaHC03 I qH 0 0 21 2 Br \ Bu3SnH AIBN - I + Qio I 21 3 21 4 I C02Me 21 5 o--& 0 21 6 0 Cyclizations of acetylenic or allenic acids also constitute important approaches to ylidenebutenolides. For example, exposure of the enynoic acids 2 17 to mercuric oxide in hot DMF gives good yields of the corresponding lactones 2 21 7 21 8 Direct thermolysis in o-dichlorobenzene can also be used to effect such cyclizations when the substrates are ylidenemalonic acids.163 Ylidenebutenolides can be prepared from 3,4-allenecarboxylic acids by 5-exo-trig-iodolactonization,””02. ,04, 232 presumably followed by in situ e1iminati0n.l~~ The diary1 butenolides 220 can be obtained from the dienoic acids 2 19, prepared from an a-bromocinnamaldehyde and an arylacetic acid, by treatment with base.16s Contemporary Organic Synthesis __._c .-- I Br A? 0-6 0 21 9 220 A synthetic equivalent of the putative anion 22 1 is the dianion 222; following reaction with an electrophile (E), the resulting acid is subjected to iodolactonization and separate elimination steps to give the final products 223.166 These products could be useful as Michael acceptors in further syntheses.221 222 223 A final route to butenolides 190 is by reactions between trichloroacetic acid and 1 -alkenes, mediated by RuCl,(PPh,),; the initial products are a , a-dichlorobutyrolactones. 167 8 Ring-fused butenolides Cation-mediated cyclization of geranylphenyl sulfone leads to the cyclohexanol224; subsequent carboxylation, lactonization, and elimination completes this straightforward approach to the actinidiolide derivative 225.1b8 = p o S02Ph 224 225 Acid catalysis also plays a key role in a synthesis of 8,9-deoxyalliacol B 227 from the hydroxy-acid 226.169 More general approaches to ring-fused butenolides include a further application of /3-lithioacrylamide chemistrylo6 in which the vinyl anion 228 is condensed with carbonyls to give the adducts 229 directly,”O and a radical cyclization in which treatment of the acetylene 230 with the usual tributyltin hydride/AIBN combination leads to the butenolides 232 following oxidation and isomerization, for which rhodium trichloridelO is a particularly suitable catalyst,171 of the initially formed tetrahydrofuran 23 1.172 Both methods are generally efficient throughout, at least with these relatively simple examples.p C02H H30+* p OH OH 226 227 228 229230 231 232 An initial model established the viability of a novel approach to annulated butenolides and furans by intramolecular Diels-Alder cyclization of an acetylenic oxazole (e.g. 233) which leads to the furan 234, following expulsion of acetonitrile from the initial cycloadduct. In this particular example, acid-catalysed hydrolysis also results in rearrangement to the butenolide 235.174 233 234 lHi 0-d0 K 235 The potential of this methodology is demonstrated in syntheses of the norsecurinine precursor 237 from the initial cycloadduct 236, this time without rearrangement, and of the precursor 238 to paniculide A 239.175 As is often the case, the synthesis was completed only after some of the more obvious options failed.OMe 0 'Oki + I 'obi+ I 236 237 238 239 A key step in a different approach to the more highly oxygenated paniculides B and C relies on hydroxide-directed attack of dilithioacetate onto the epoxy alcohol 240, to give the butyrolactone 241.176 Subsequent, established chemistry then leads to the known precursor 24 2 MOMO MOMO 240 241 &i + / \ 242 The highly electrophilic Michael butenolide 2 has also been used as a precursor to the Paniculides 239 by condensation with the malonaldehyde 243 followed by rearrangementls9 of the initial adduct 244 to the later intermediate 245.'78 SPh DMSO Me02C OH Me02C DMF 243 244 OH M e O p C 245 The same idea, but using the alternative Michael acceptor 247, has been used to obtain the furoventalene precursor 248 from the malonaldehyde derivative 246.17y Similarly, the useful sesquiterpene precursors 249 have been prepared from /l-vinylbutenolide itself and Q -e t hoxy c arbon y lc y clo hexanone s .8o C02Me I 246 247 248 249 '0 Knight: Synthetic approaches to butenolides 303Generally, the foregoing Michael chemistry is not especially efficient, but relatively advanced precursors are produced from two much simpler reactants. A different type of Michael addition using the y-methylenebutenolide 250 as the acceptor has been used to prepare the elemane and eudesmane precursor 251.18' c02Me 250 TiCI, m o OH C02Me 251 A simple approach to annulated butenolides 253 is by Wadsworth-Emmons homologation of the corresponding epoxy-ketone 252;' 56 however, only the (2)-isomer of the intermediate mixture of alkenes cyclizes to the lactone.182 252 253 Less ambiguous is the intramolecular version exemplified in the conversion of the phosphonate 254 into jolkinolide E 255.183 The precursors 254 are best obtained from the corresponding a-hydroxyketones using a mixed anhydride formed from a phosphonoacetic acid and TFAA,lg4 although an alternative approach starts with a methyl vinyl ketone function; sequential oxidation by manganese( 111) acetate in the presence of chloroacetic acid leads to the key hydroxyketone derivatives.185 0 0 254 255 Sulfur chemistry plays a key role in a number of approaches to annulated butenolides.An unusual route to annulated butenolides (e.g. 257) features a vinylogous Pummerer rearrangement of a sulfinyl ester (e.g 256); extensions to more highly substituted systems could suffer from problems of regioselec tivity.186 q i i h A. H30+ Dioxan C02Me 256 257 A more general approach begins with the preparation of an a-thiomethylene ketone 258 which is homologated using phenylthiomethyl lithium. Pummerer rearrangement of the sulfoxide derived from the resulting thiomethyl aldehyde 259 leads to the corresponding furan 260 and thence to the butenolide 26 1 following slow acid hydr01ysis.l~~ Applications of this methodology include preparations of isodrimenin 262 and the coloratadienolide 263.BUS p - oBph 258 259 I1 t 261 260 0 0 %-? -0 262 263 An alternative method for the homologation of thiomethylene ketones 258 is to use dimethylsulfonium methylide; the resulting thiolactols are then easily converted into the corresponding furans (e.g. euryfuran, 264). Treatment of the latter with bromine in methanol leads largely to drimenin, while photo-oxygenation' occurs regioselectively to give valdiviolide 265 (R = OH).18s 264 Photo-oxygenation is the key step in a related approach to confertifolin 265 (R = H) from the diene 266; unfortunately, the yield is only 20°/~.189 The Diels-Alder adduct 267 is also a useful precursor to both Isodrimenin 262 and fragrolide 268.190 (diethylamino)propyne, catalysed by magnesium bromide, is a useful method for the preparation of unsaturated amides, which can be used as precursors to b~ten0lides.l~~ When 2,3-epoxycycloalkanones are the starting materials, the resulting amides (e.g.269) can be readily converted into a variety of butenolides The condensation of ketones with 270-272."' 304 Contemporary Organic Synthesisrp R 265 266 & O 2 k @ 0 0 267 268 270 I 269 272 271 I ,,e methodology has been useb to synthesize ( + )-eremophilenolide 2731q2 and can be extended to include the conversion of a-silyloxyketones (e.g. 274) into annulated butenolides 275.1q3 273 274 275 A somewhat related route has been used to obtain the mintlactone isomers 278 by sequential deconjugative methylation of the unsaturated ester 2 76, epoxidation, and base-induced rearrangement of the resulting epoxy ester 277.1q4 276 (I) LDA, Me1 (ii) MCPBA 277 LDA, HMPA 1 278 During the early stages of a total synthesis of marasmic acid, the ring system 280 was established by an intramolecular Diels-Alder reaction of the B-alkenylbutenolide 2 79, followed by base-catalysed i~omerization.'~~ The precursor was prepared using the phosphonate 28 1, which will be of value in other syntheses as well as complementing the corresponding Wittig method using salt 30.1q.20 279 O= P(OEt)2 ko 0 281 AcO 280 A much more unusual Diels-Alder cyclization in which a phenyl group acts as the diene has been used to obtain the annulated butenolides 283 by heating the allenic esters 282 in xylene.lY6 A2 282 ;12 283 A photochemical [2 + 21 cycloaddition between cyclobutene- 1 -carboxylic acid and ( + )-isopiperitenone is a key feature of a neat synthesis of the isoaristolactone isomer 286.Reduction of the initial photoadduct 284 leads to the lactone 285 which undergoes a thermal electrocyclic ring-opening to give the final product in 26% overall yield.197 Knight: Synthetic approaches to butenolides 305I I _ . NaCNBH- r-w 284 285 0 Q 286 ( k )-arktolactone itself (290) has been obtained by a clever application of a [ 2.31-Wittig rearrangement in which the cyclic ether 287 is converted into the cyclic enyne 288. Subsequent Mitsunobu inversion, alkyne reduction using Red-Al, and trapping of the resulting vinylalane using N-iodosuccinimide leads to the penultimate precursor 289, ~arbonylation~~~ of which completes the synthesis.lY8 287 288 290 289 Thus, authentic isoaristolactone differs from aristolactone 290 in the configuration of the alkene function; the latter can be transformed into the former by exposure to dilute acid.lY7 Routes to spiro-butenolides are detailed below; lower homologues can serve as precursors to ring-fused butenolides as in the Lewis acid catalysed rearrangement of the spiro-B-lactones 291 to the a-chlorobutenolides 292 .IY9 291 292 9 Spiro-butenolides Clearly, many of the foregoing methods could be adapted to the elaboration of spiro-butenolides; the following are approaches specifically designed to produce this type of lactone.The useful lithio-propynoate 946s condenses smoothly with cycloalkanones to provide the adducts 293; a subsequent Michael addition/trapping sequence leads to the spiro-lactones ( e g 294) in good yields .200 293 294 Unsubstituted spiro-butenolides can be similarly prepared from cycloalkenones by reaction with the dianion of 3-phenylsulfinyl-propionic acid followed by elimination, but not in especially good overall yields.*"l Radical cycli~ations~~~ 72, 227, 228 can also be used to access such butenolides, as illustrated by a synthesis of ( k )-andirolactone 297 from the mixed acetal295; Jones oxidation of the intermediate acetal296, obtained in ca.70% yield, and isomerization'O by silica gel completes the sequence.202 295 296 297 Essentially the same cyclization can be carried out using the corresponding bromo ester, mediated either phot~chemically~~~ or by tin h~dride/AIBN.~~~ An isolated example (298 + 299) indicates that iodocyclizations of allenecarboxamidesYY-102~ 14*9 1643 232 could be a useful route to functionalized spiro-buten~lides.~~~ 298 299 10 Multi-substituted butenolides As is the case in the foregoing section, many of the methods outlined above could be extended to include examples of polysubstituted butenolides.The following are procedures which have largely only been or can only be applied to such targets. Some synthetically useful bromobutenolides can be prepared by allylic bromination of the corresponding methylbutenolides; these include the y-bromo 306 Contemporary Organic Synthesisderivative 300 and the a-methyl isomer, together with the bromomethyl derivatives 301 and 3O2,l9y2O the Aldol reactions between a lithio- or O-silyl-enolate and an a-keto-acetal lead to the adducts 312; latter being best prepared from methyl ~enecioate.~~~ The yeast reduction product 303,41 obtained, essentially optically pure, successfully undergoes sequential, but non-stereoselective, a l k y l a t i ~ n s ~ ~ , ~ ~ by iodomethane and sodium iodoacetate to give ( R )-umbelactone 304,46 following lactonization and elimination, in 30% overall yield.206 Other approaches to the latter, as the racemate, include acid-induced rearrangement of the corresponding epo~y-enoate,~~~ and a relatively efficient condensation of the p-lithioacrylate 305 (R' = H; R2 = Me)lo6 with benzyloxyethanal.208 I f Br BfQ 0 Y p 0 Qo 300 30 1 302 303 304 305 Approaches based on the intermediacy of the corresponding /3-bromo dianion 306 followed by Michael addition/elimination to introduce the P-methyl substituent are less attractive due to the poor yields obtained in the last step.The foregoing is but a single example of a much more general approach in which dianions 305 are reacted with aldehydes or ketones to give polysubstituted butenolides 307 in 40-60% isolated yields.209 The related B-lithioamide 308 is similarly useful in butenolide synthesis;lo6 perhaps surprisingly, this intermediate is generated directly from the parent amide using lithium tetramethylpiperidide (LTMP) without competition from deprotonation at the a-site of the furan.210 306 307 308 A different way to construct an a,y-disubstituted butenolide 31 1 has the chlorosulfone 309 as the starting material.Michael additions of lithiostannane and condensation with an aldehyde, R2CH0, leads, after elimination, to the vinylstannane 310, carboxylation of which, by tin-lithium exchange,239 completes the sequence.21 309 31 0 31 1 subsequent acid-cat alysed reorganization provides another approach to the butenolides 3 1 1. Both steps proceed in - 70% yield.212 A related but slightly less efficient route has the alkylation of an acid enolate using an a-chloro acetal as the key step.213 31 2 Related to this are condensations between the dianion derived from the bis-sulfenyl species 3 13 and ketones; methanolysis aided by silver nitrate completes this efficient preparation of the potentially useful butenolides 3 14.214 31 3 31 4 Formation of the butenolide alkene linkage by an aldol-type condensation has been further exploited in a synthesis of the hydroxyethyl butenolide 3 15 from 2-deoxy-~-ribose,~'~ and in a preparation of the a-thiobutenolides 3 16 from an a-acetoxy aldehyde and the lithium enolate of ethyl phenylthioacetate.2 l6 31 5 31 6 Intramolecular variants are also useful, as in the synthesis of the a-arylbutenolides 3 18 from the esters 3 17, the latter being available from the corresponding arylacetic acid by esterification using an a-halo ketone.21 A similar intramolecular aldol condensation provides the useful phosphonates 3 19 from the corresponding propionates.218 31 7 31 8 31 9 Palladium (0)-induced cyclizations of the a-mercurio esters 320 lead to good yields of the butenolides 32 1; unfortunately, a stoichiometric quantity of the palladium reagent Li2PdC14 is required.219 A similar disconnection, but featuring an intramolecular Michael addition, can be used to obtain the butenolide precursors 322.220 Knight: Synthetic approaches to butenolides 307320 321 322 Another viable method for formation of the alkene bond in a butenolide is by reactions between an a-seleno- or a-sulfenyl-carboxylate enolate (e.g.82) and an e p o ~ i d e . ~ ~ + ~ ~ This method can be extended to include most types of substituted butenolides, starting from the initial adducts 323.221 For example, simple oxidative elimination of sulfur provides a , y-disubstituted butenolides whereas, when R2 = H, Pummerer rearrangement of the derived sulfoxide leads to the useful Michael acceptor 324, allowing the preparation of both /3,y-326 and a,#?, y-substituted analogues.R2 R'Tph "'-QSPh 0 323 324 More highly substituted homologues of the a-sulfenyl butenolides 324 can be obtained by intramolecular Wadsworth-Emmons condensations.222 Closely related to this is the extremely efficient Lewis acid catalysed thioalkylation of ketene bis-( trimethylsilyl)acetals.223 The sulfmyl analogues of a-sulfenyl butenolides 324 have also been prepared but by a rather different sequence which proceeds by way of a vinyl sulfoxide.224 A reverse way to construct the same bond is by homologation of the a-phenylthioketone anions 325 using iod~acetate;~~~ 41, 206 subsequent borohydride reduction and, again, oxidative elimination of the thiol group completes this efficient approach to B,y-substituted butenolides 326.22s phsf-o R2ao R' R2 325 326 Manganese( 111) acetate can be used to induce the addition of a variety of esters to unactivated alkenes; when a-chloro esters are used, a-halobutyrolactones are obtained and thence butenolides following elimination from the corresponding iodolactone.226 Unfortunately, the yields are not spectacular, especially from the initial addition (33-53%).What are now regarded as more standard radical processes are generally more productive. For example, the usual combination of tributyltin hydride and AIBN is highly suited to the transformation of the a-bromo-esters 327 into the /3-methylene-lactones 328,2039 227 which can easily be isomerized'" to the corresponding butenolides. Under similar conditions, the acetals 329 cyclize to give the alternative butenolide precursors 330.228 Anodic oxidation of the /3, y-unsaturated esters 33 1 is effective as a route to the polysubstituted butenolides 332 only when the /3-substituent is an aryl group.22Y 329 330 Ar A: 331 332 Bromolactonization of the readily available vinylmalonates 333 leads smoothly to the #?-bromobutyrolactones 334; degradation to the corresponding a , y-disubstituted butenolides 3 1 1 occurs slowly upon exposure to sodium iodide in hot 3-pentan0ne.~~" The method has been exemplified by a preparation of the natural butenolide acarenoic acid 335.A detailed study has been performed on related eliminations from a-bromobutyrolactones.23 Cyclizationyy-'02~ 1649 204 of the phenyl substituted allene carboxylic acids 336 requires only an acid catalyst to give good yields of the butenolides 337 although with hydrogen bromide the potentially useful /3-bromo derivatives 338 are obtained.232 336 337 338 A combination of methods7.7y-81 for homologation of the Diels-Alder adduct 6 represents an efficient approach to the trisubstituted butenolides 339233 and also, to the chiral y-methyl derivatives 340.234 308 Contemporary Organic Synthesis0 6 339 H*QR 0 340 The dimethyl derivative 340 (R= Me) is a component of mushroom flavour while the butyl analogue is one of the volatile Streptomyces lactones. A general approach to these, as racemates rac-340, features homologation of the methylene dioxane 34 1 by sequential deprotonation, using BusLi, and reaction with acetaldehyde and an alkyl halide to give the alcohols 342.235 Overall, this sequence can be summarized by the hypothetical dianion 343.341 342 -Y- '0 343 As already described, various acetylenes are the starting materials in many viable approaches to butenolides. A further example is a very simple route to disubstituted butenolides 345 by the addition of Grignard reagents to propargylic alcohols 344, followed by carb~xylation.~~~ Y1 9' 344 345 An attractive alternative consists of hydride reduction of a secondary propargylic alcohol 346 and iodination of the resulting vinylalane which leads to the (2)-iodo-alcohols 347 and thence to the a, y-disubstituted butenolides 3 1 1 lY8 following palladium( 0)-cataly sed ~arbonylation.~~~ 346 347 Propargylic alcohols can also be converted into butenolides 3 1 1 by regioselective hydrozirconation and carbonylation in 50-70% overall yields,238 or by formation of an intermediate vinylstannane.21 ' 9 239 Reaction between a disubstituted alkyne 348, an acid chloride, and NaCo( CO), followed by acidolysis of the resulting cobalt complex leads directly to the butenolides 349.240 Regioselection is clearly a problem with unsymmetrical alkynes although both phenyl and t-butyl groups are placed largely in the a-position of the final butenolide when in competition with methyl substituents in the acetylenic substrate.348 v 349 A remarkable triple carbonylation occurs in the conversion of the epoxy alcohol 350 into the butenolide 35 1 under phase transfer conditions.241 Unfortunately, a similar yield ( - 35%) of the product of single carbonylation 352 is obtained.HO 350 1 351 352 A neat way to exploit the power of palladium( 0)-catalysed carbonylation reactions is in the conversion of the vinyl triflates 353 into a,@-disubstituted butenolides 354.242 An especially attractive feature is that the triflates 353 are derived from the corresponding B-keto esters in two steps. 353 354 The vinyl manganese species 355, formed by sequential insertion of carbon monoxide and a 1-alkyne into an alkylmanganese pentacarbonyl complex, are similarly The same overall transformation can be carried out using an acylpentacarbonyl chromate and a l-alk~ne.~~, A significant feature of many of these methods, especially the latter, is the non-acidic nature of the required conditions.*lmR2 0 Mn(CO), 355 Knight: Synthetic approaches to butenolides 309Michael additions of Grignard reagents or lithium divinylcuprates to the ynoates 356, (cf reference 37) obtained using lithiopropynoate 94,(j5 constitutes a general approach to the B, y-disubstituted butenolides 357,245 while palladium-catalysed a-arylation of these intermediates gives variable yields (32-93%) of the a-arylbutenolides 3 1 1 ( R1 = Ar).246 356 357 A direct conversion of internal alkynes into a,B-disubstituted butenolides using the water gas shift reaction will probably only be useful for the elaboration of symmetrically substituted species.247 More highly substituted analogues can be prepared by a related method in which the carbonylation126 is carried out in the presence of a 1-alkene and with similar limitations.248 The foregoing drawbacks also apply to a very simple method for the conversion of aldehydes (RCH,CHO) into a,P-disubstituted butenolides 345 ( R1 = R2) by exposure to carbon monoxide in sulfuric acid; the first step is presumably an aldol conden~ation.~~' The readily available ketene dithioacetals 358 can be epoxidized using dimethylsulfonium methylide188 leading, after rearrangement, to the potentially useful and partly protected150 forms, 359, of the corresponding a,P-disubstituted butenolides 360.250 Mild acid treatment of the intermediates 359 generates the corresponding f ~ r a n ' * ~ which can be alkylated at the remaining free a-position, allowing the preparation of a$, y-trisubstituted homologues.R2 F2 358 359 360 Epoxides also feature in other routes to butenolides. For example, exposure of the diepoxy-ester 361 to HCl or HBr in DMF leads to the dihalo-butenolides 362251 while a related acid-catalysed rearrangement of the /3-lactams 363 results in formation of the aminomethyl-lactones 364.252 R2 F2 361 362 R' R' $%Nph R 2 q N H P h 0 363 364 1,l -Disubstituted alkenes 365 participate in reactions with a-oxocarboxylic acids 366 under (Lewis) acidic conditions, leading eventually to a , y, y-trisubstituted butenolides 367 in moderate yields which are somewhat offset by the simplicity of the method.253 R' R2 R' +o H02C k + R' PqR2 367 Baeyer-Villiger oxidation is effective for the conversion of the cyclobutenones 368 into the corresponding butenolides 369.254 The enones 368 are obtained from cycloadditions of alkynes to keteniminium salts derived from tertiary amides.368 369 Although somewhat limited in its scope, a mechanistically interesting butenolide synthesis is the conversion of diphenylcyclopropenone 370 into the a,B-diphenyl butenolides 37 1 by condensation with the sodium salt of an a~etoacetate.~~~ Pt qrn M=J* Y - O Me02C 370 371 Similar reactions with sodiomalonate lead to ylidenebutenolides. A useful but again somewhat restricted photochemical rearrangement is illustrated by the transformation of the a , y, y-trisubstituted butenolide 372 into the corresponding a$, y-isomer 373.256 At At P h q p h - hv ph%ph 372 373 Finally, two methods which approach butenolides from opposite ends of the oxidation scale: the silyl enol ether 374 can be converted into the butenolide 375 in an example of a more general reaction whereby unsaturation can be introduced into such 310 Contemporary Organic Synthesisintermediates by treatment with an ally1 carbonate and a palladium catalyst, while sequential hydrogenat ion and dehydration3Y! lo5 of the tetronic acid 376 is an efficient way to obtain the butenolide 377.258 374 375 ?H (i) Raney Ni (ii) TsCl Et3N OSiMe3 OMW 376 377 The tetronic acid was prepared using an intramolecular Grignard reaction; however, discussion of this class of hydroxy-butenolides is beyond the scope of this present review! 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 References Y.S.Rao, Chem. 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