Saturated and unsaturated lactones T. LADUWAHETTY Merck Sharp and Dohme, Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR - Arq:x Reviewing the literature published between 1 January 1993 and 31 July 1994 1 Introduction 3 Macrolides Pyr, CHCI3 'H ...O (i) EtOH, reflux (ii) H,. (R)-BINAP-Run 2 /3-Lactones 0 4 Medium-ring lactones 5 &Lactones 6 Spirolactones 7 y-Lactones 8 But-2-enolides and tetronic acids OH 0 A r a O E 1 1 (9696%) 9 a-Methylene butyrolactones 10 References go eHg(= A r d s e OH 0 Ar\/ N- 3 (52430%; 95% e.e.) 2 (90%) but 10 References Hg(W3Me)Z Ar&se Ar\/ MeCN Scheme 1 1 Introduction This review surveys the literature relating to saturated and unsaturated lactones, and includes macrolides, tetronic acids, and a-methylene lactones.The chemistries associated with carboxylic acids and esters are covered in separate articles in Contemporary Organic Synthesis. 2 /?-Lactones Few lactonization methods are suitable for /3-lactone formation due to the inherent lability of this moiety. In fact, hitherto, no practical methods exist for the preparation of enantiopure B-lactones. Combining Noyori's efficient protocol for the synthesis of #?-hydroxy esters and a variant of the Corey/Nicolaou lactonization methodology, large-scale syntheses of /3-lactones such as 3 are now possible (Scheme 1 ).I It was found that cyclization of the 2-pyridylthiol ester 2 is superior to the benzenethiol analogue since the latter gives the cyclized product in only 60% yield, making chromatography necessary.The use of Masamune's mercury( 11) methanesulfonate catalyst together with the 2-pyridylthiol ester ensures that lactone formation occurs quickly ( 10 min.), without resorting to prolonged heating so that decomposition is avoided. It should be noted that only one of the six steps in the synthesis (the formation of 1) requires chromatography, thus making it a viable synthesis on multigram-scale, to obtain /3-substituted B-lactones of either absolute configuration. An interesting variation of the classical Reformatsky reaction involves treating the a-bromoester 4 with ketones in the presence of indium (Scheme 2).2 Aliphatic ketones (with the exception of acetone) and aromatic ketones are transformed into #?-lactones instead of the /3-hydroxy esters. It is noteworthy that even aromatic ketones give /3-lactones with zinc in DMF, instead of the traditional non-polar solvents used for the Reformatsky reaction. Formation of /3-lactones using this methodology is entirely restricted to the synthesis of a,a * ,/3,/3'-tetrasubstituted #I-lactones, since cyclization is facilitated by the gem-dialkyl effect.Polar solvents such as DMF also facilitate elimination of the intermediate metal alkoxide, hence favouring #I-lactone formation. r 1 M In 95 Zn 2 Scheme 2 5 (84%) 98 (76%) Ladu wahetty: Saturated and unsaturated lactones 133H0YC6H13 3 Macrolides A novel macrolactonization procedure involves the in situ generation of a conjugated ketene, viz. 6, from the l-butoxy-1,3-diyne 5.3 Addition of 5 to a refluxing benzene solution of triethylamine then gives the highly functionalized lactone 7 in 45% yield. The neutral reaction conditions make this strategy ideal for acid/base sensitive compounds such as 8 (Scheme 3).The ethoxy alkyne intermediates, which are readily available from the corresponding aldehydes, have not only been used to construct macrolides, but also five-, six-, and seven-membered ring lactones! PhS 5 Et3N, A benzene 1 L 7 (45%) 6 (i) Liz-OEt (ii) TBDMSCI (iii) deprotection I OTBDMS H e Y H 0 0 (49%) Scheme 3 1 , 1 , 1-Trifluoroethyl-o-hydroxy-carboxylates give macrolactones ( 16-membered or higher) in good yields5 under tin( IV ) catalysis (Scheme 4). The thermodynamic impetus for the formation of the lactone is the formation of R,SnOCH,CF,, which in turn dissociates to form the tin alkoxide 9 and trifluoroethanol which boils off under the reaction conditions.Smaller ring lactones (ten-membered and less) do not form due to competing dimerization. L 9 41 % Scheme 4 Large ring lactones can be synthesized by cyclizing hydroxy acids under Lewis acidic conditions via an activated anh~dride.6.~ This method can also be used for the synthesis of seven-membered lactones (Scheme 5). Hydrous zirconium( IV ) oxide8 modified with TMSCl and zeolites' has also been used to synthesize medium to large ring lactones. 0 0 5 mol% TiCI, + I d (92%) (R)-ricindeic acid lactone (n= 1-9) \ I n Scheme 5 Several macrolactonization methods involving acyl activation have proved to be unsuccessful for the synthesis of the macrolides 10 and 1 1.The presence of the 174-diene and the p, y-unsaturated ester functionality makes these pheromones unstable to heat, acid, and base. The use of the Steglich modification of the Mitsunobu cyclization, however, has enabled the efficient cyclization of the hydroxyacid precursors of 10 and 11 in very acceptable yields.'(' 10 (71%) 11 (68%) 134 Contemporary Organic SynthesisThermolysis of 1,2,4-trioxane derivatives is an attractive possibility to access large ring systems." The synthetic utility of this methodology (Scheme 6) is limited, however, since the rules governing ring-opening have yet to be fully understood. n = 4 25% n=12 - Scheme 6 4 Medium-ring lactones A useful method for the preparation of nine-membered unsaturated lactones involves using the Malherbe-Bellus variant of the Claisen rearrangement.I Thus 2-vinyltetrahydrofurans (12-14) (Scheme 7) react with dichloroketene, generated in situ, to give the trans-lactones ( 15- 17) in good yields. The reaction is stereospecific with regard to the stereochemistry of the initial alkene double bond. Thus a mixture of transfcis (85 : 15) 14 gives a mixture of 2-methyl conformers of 17 (85: 15). The tri-n-butyltinhydride mediated dechlorination of 14 results in the formation of the cis-lactone, indicating 18 to be the thermodynamically favoured product. Tetrahydrofuranyl trifluroacetic anhydrides undergo a similar ring-expansion, via an acyloxonium ion 19,13 to give functionalized ten-membered lactones. Attack of a nucleophile at the bridge-head carbon in 19 then gives the major product 20, whilst regioselective elimination leads to 2 1 (Scheme 8).R' 12 R'=H 15 R' =H,s% 13 R' = CH2OTBDMS 16 R' = CH,OTBDMS, 60% 14 R'=Me 17 R' =Me, 55% 1Bun3SnH R' b 18 Scheme 7 Laduwahetty: Saturated and unsaturated lactones n TiCI, 19 1 CI I OCOCF3 I 1 ; 85% 4 20 21 Scheme 8 While iodolactonizations, to form medium-ring lactones, are not favourable processes, due to gauche interactions in the transition state, replacing one of the carbons with an oxygen, as in 22, gives the seven-membered lactone product without resorting to high dilution ~0nditions.l~ e 0 - C O 2 H 22 I bis(simcd1idine)iodine-hexafluorophosphate 0 59% The methodology developed by Holmes et al. for the synthesis of medium-ring ethers has been extended to the corresponding lactones.lS Thus the homochiral diol24, which is readily available from the oxazolidinone 23, can be converted into a selenoxide 2 5, which then undergoes a stereoselective Claisen rearrangement to provide the eight-membered lactone 26.The seven-membered lactone 27 is also accessible using this methodology (Scheme 9). Medium-ring and macrocyclic acetylenic lactones can be accessed by treating bicyclic tosyl-hydrazones with N-bromosuccinimide (Scheme 1 0).l6 An interesting diastereoselective synthesis of medium-ring lactones 29 involves treating the trichloroacetate 28 with Cu(bpy)Cl (Scheme 1 l ) . 1 7 Although similar cyclizations of dichloroacetates have been reported previously, the dichloroacetate analogue of 28 did not cyclize. Simple alkenyl trichloroacetates (30,3 1 ) do cyclize to give eight- and nine-membered rings as well, although terminal substitution of the alkene reduces the rate of the reaction.Except in the cyclization of 28, dichloroacetates generally give higher yields than trichloroacetates in these cyclizations. 5 &Lactones Radical-mediated endocyclic cleavage of the tetrahydrofuranyl hydroxy ester 32 provides the keto 1350 OBn Dmannose - \ CHO - oiN+ LiBH4, q, OBn Bn 23 24 O X 0 l(0 PhSe-zE (ii) NaI04 26 (73%, > 95% e.e.) 25 ,%Ph 29 Scheme 9 n = 1,3,7 Scheme 10 O)TBDMS 27 (45%, > 95% e.8.) 0 n = 0,65% n = 1.3,7, -90% ester 33, which then cyclizes the corresponding d-lactone under basic conditions (Scheme 12).’* The corresponding tetrahydropyranyl analogue also undergoes exclusive endocyclic cleavage although re-cyclization to the seven-membered ring only occurs when constrained in a bicyclic system (Scheme 13).ci.s-4,5-disubstituted d-lactones involves the heterolytic cleavage of vicinal donor-acceptor substituted cyclobutanes (Scheme 14).” The 1,4-zwitterionic species produced from the cyclobutane under Lewis acidic conditions forms the (E)-enolate intermediate 34 which then reacts with aldehydes. The resulting hydroxy esters are cyclized under acidic conditions. The chelated chair transition state explains the formation of the cis-lactone 35 as the major product. The reactions with methyl ketones are less selective, although dehydration of the anti-hydroxy ester, in preference to the syn, during the lactonization conditions ensures that the cis-lactone emerges as the major product.The diastereoselectivity in the analogous reaction of a-monosubstituted cyclobutanes 36 with symmetrical ketones (Scheme 15) to provide cis-2,4-d-lactones is diminished. This is attributed to the fact that the chiral centre in the zwitterionic species 37 formed from 36 is A diastereoselective synthesis of - 02cc13 30 Scheme 11 0 0 + +OLi OR - q o 0 II 0 Q 33 (45%) Scheme 12 #? to the reaction centre and therefore less likely to influence the reaction. A novel cyclization strategy for the synthesis of homochiral2,4-disubstituted #?-keto- d-lactones (Scheme 16) involves treating the halo diester 38 with Zn and trimethylchlorosilane?O Simple trituration of the crude product with hexanes then gives 39 in 70% yield. The presence of TMSCl is crucial to the reaction as the lack of it produces large amounts of the diester 40 due to protonation of the zinc enolate.Since the proton source is the product lactone, TMSCl silylates the intermediate ketal until work-up. 136 Contemporary Organic Synthesis' U O R R OH I NaH R=(CH,), I Qco2. 65% Scheme 13 0 H13C6J0 40 38 (1:4, ether/TMSCI) 1'" 1 H20 0 C6H 13 OH 39 (70%) Scheme 16 The radical-mediated cyclization of 4 1 in the presence of Bu,SnH to produce the corresponding d-lactone is dramatically concentration dependent (Entries a and b).,' Under the concentrated conditions Tris( trimethylsilyl)silane, on the other hand, undergoes the desired exo-trig mode of cyclization to produce the d-lactone, independent of concentration.shown only the reduced product 42 is obtained. + 0 34 cat. pTsOH toluene, 90°C OHRs C02Et RS 35 cisltrans : 92 : 8 41 42 Concentration Bu",SnH (TMS),SiH (ratio d volume of entry a x loo 0% 82% entry b x lo00 92% 90% Scheme 14 solvent/gram substrate) Acyloxypalladation and subsequent room temperature elimination of palladium hydride under mild conditions constitutes an efficient synthesis of bicyclic p and y-lactones. Larock et a(." have improved upon the present methodology by employing Pd( OAc), in DMSO. A variety of ring systems, including fused, bridged bicyclic, and spirocyclic, involving the formation of five- and six-membered + 36 - UZM (i) T~(OP~~CI, (ii) H20, pTsOH TMSO P f 0 cisltrans : 65/35 pfYpf 0 37 Scheme 15 Laduwahetty: Saturated and unsaturated lactones rings are produced efficiently.Four-, seven- and twelve-membered rings, however, are not. The product composition in the Pd( OAc), catalysed reaction 43 -, 44/45 can be different from that obtained from iodolactonization or selenolactonization (Scheme 17). Even cyclization reactions involving different palladium catalysts can make a difference to the outcome of the reaction. Thus, Hegedus et al. have cyclized the alkenoic acid 46 to the 3-methyl coumarin 48 using PdC1,. The (Z)-phthalide 47 is the only 137product formed under the Larock conditions. It is likely that 47 is produced through a n-ally1 intermediate which undergoes an intramolecular displacement by the carboxylate group followed by subsequent double bond isomerization. n = I , 81% n = 2 , 68% 43 44 45 3 1 46 47 (71%) \% PdCI+?IkCN 48 (41%) Scheme 17 DDQ in aqueous acetone is an extremely mild method for the selective deprotection of an orthoester to a d-lactone23 even in the presence of an acetal (Scheme 18).This selectivity can be attributed to the orthoester being a more electron-rich species than the acetal, and hence forming a charge-transfer complex with the DDQ. The reaction of DDQ in benzene only effects the oxidation of the allylic hydroxyl group. 6 Spirolactones Sequential reaction of the metallocycle 49 with an epoxide and carbon dioxide provides a direct, one-step synthesis of spiro d-la~tones.~~ This approach can be used to prepare both bicyclic and tricyclic spiro- 6-lactones. Whilst good regioselectivity is observed with unsymmetrical epoxides, this methodology also provides a direct method for the synthesis of d-lactones with a p-quaternary centre.Radical cyclizations of 1,3-diones 50 or of /3-keto esters 51 and alkenes either directly25 or via a selenide26 intermediate provide novel routes to spiro lactones (Scheme 19). OMe ?Me ( - - - A 0 --0 0 : H I 99% yield 34% Scheme 18 63% (1:l mixture of diastereorners) 0 0 50 64% 0 0 0 0 (i) LDA, PhSeCl (ii) hv, C6H, 254 nM SePh 51 Scheme 19 64% 138 Contemporary Organic Synthesis7 y-Lactones A highly enantioselective reduction of bicyclic Osmium tetroxide mediated dihydroxylations of p-amino-( E)-crotylsilanes provide a route for the asymmetric synthesis of a-amino- y-lactones (Scheme 20).27 The diastereoselectivity arises from the approach of the osmium reagent anti-to the silyl group.Whereas the anti-diastereomer gives the 3'4-cis-lactone 52 in good yield and selectivity, the syn-diasteromer provides the 3,4-trans-lactone. Even basic amines are tolerated under the reaction conditions. d C 0 2 M e SiMe2Ph ,SiMe2Ph R, ,SiMqPh 0 H OH H OH 52 trans cis R=N3 15 1 05% R = NHCO~BU' 40 1 95% R = NMe2 23 1 54% Scheme 20 The xanthate 53 derived from a sugar cyclizes in the presence of Bu,SnH to give a mixture of bicyclic lactones in 47% yield.28 Although there clearly needs to be an improvement in terms of selectivity, this route is a simple and elegant method of obtaining these homochiral intermediates which are precursors in prostaglandin syntheses (Scheme 2 1 ). 03- I 6 steps - rq C02Me ] 1 23 20 : 57 Scheme 21 meso- 1,2-dicarboxylic anhydrides using Noyori's (R)-BINAL-H provides an efficient route into a variety of y-lactones.29 The lactones 55 and 57, which are used as building blocks in the synthesis of prostanoids, are obtained in good yield with 8349% enantiomeric excess. The fused lactone 59 which is a key intermediate in the synthesis of ( + )-biotin can be obtained from 58 in 95% e.e.after one recrystallization from benzene. The reaction is governed by the steric bulk on the concave and convex faces of the bicyclic system. Thus an increase in bulk on the convex face reduces enantioselectivity, whereas an increase in bulk on the concave face improves selectivity. The chirality of the product cannot be predicted u priori: for instance, ( R )-BINAL-H reduces the carbonyl attached to the group with the (R)-configuration in 56, whilst reducing the carbonyl attached to the carbon with the (S)-configuration in 54.But since both enantiomers of l,l,-bi-2-naphthol are commercially available, the lactone of desired configuration can be obtained. (R)-BI NAL-H 0 54 55 (99%) 56 57 (84%) 0 0 PhANKNAPh (R)-BINAL-H PhANKNAPh 58 59 (76%, 95% e.e.) Additions of silyl ketene acetals to lactones occur only under forcing conditions. Using tris( dimethyl-amido)sulfonium trimethyl silicate (TAST ) as catalyst, however, enables their smooth reaction at low temperature.,' The greater reactivity of ketones under forcing conditions is still observed with TAST (Scheme 22). Homochiral truns-3,4-disubstituted lactones can be synthesized from the thermodynamically stable truns-cyclobutanone 6 1,' which is in turn obtained by asymmetric deprotonation of 3-phenylcyclobutanone (Scheme 23).The direct alkylation of the enol silyl ether 60 was unsuccessful and the 2-alkylated products are obtained by sequential acylation, elimination, and hydrogenation. Vicinal donor-acceptor substituted cyclopropanes have been used as an innovative entry to 2,3,4-trisubstituted y-lactones. The cyclopropanes are obtained from the corresponding ketene acetal and the diazoacetic ester to give the trans-isomer of 62 as the Ladu wahetty: Saturated and unsaturated lactones 139R' + OSiMe HOMe TASF THF -25 "C - 63% Scheme 22 Me Me Ph '4, PhANXPh ti c 'n Ph' Phh -0 L\ OSiEt3 60 (92% e.e.) (i) C4H&H0 (ii) AqO, DBU 1 Scheme 23 major product.Reactions of 62 with symmetrical ketones under Lewis acid conditions provides the cis-2,3-disubstituted lactones with excellent selectivity and in high yield.32 This selectivity arises from the approach of the ketone anti-to the cationic substituent (Scheme 24). Shimada et al. have extended this reaction to the synthesis of cis-2,3-trans- 3,4-trisubstituted y-lactones by employing an aldehyde as the ele~trophile.~~ Reaction of 63 with 62 0 R' = Et 99 1 , 95% Scheme 24 cyclohexanaldehyde, for instance, gives the cis-trans product 64 with moderate selectivity (Scheme 25). A variety of aldehydes can be utilized, although selectivity increases with increasing bulkiness. Using ZrCl,, in which the metal-oxygen bond is longer, results in a higher trans-3,4 selectivity (85: 15).Optically active alcohols obtained by the well established reaction of chiral boron reagents with aldehydes can be converted into y-lactones in a two step procedure (Scheme 26).34 Taking advantage of the fact that aromatic esters are less likely to be reduced by borane than an alkyl ester, due to their lower basicity, the alkene 65 can be reacted with a borane reagent and oxidized in situ to obtain the lactone directly in good yield. The corresponding acetate protected alcohol only forms the lactone in 17% yield. For acid-sensitive lactones such as 66 thexylborane can be employed, thus avoiding the presence of HC1 in the oxidizing step, since the original conditions only gives 66 in 80% e.e. (Scheme 27). The selectivity of disiamylborane for terminal alkenes, on the other hand, can be taken into account for the synthesis of useful intermediates such as 67.butyrolactones, such as those present in ( - )-cis-whiskey lactone, can be achieved by the samarium diodide promoted fragmentation of 68 (Scheme 28).3s N-oxidations of b- y-unsaturated carboxylic acids3h followed by iodolactonizations provide a route to trans, trans-2,3,4-trisubstituted lactones (Scheme 29). The stereoselectivity of the reaction is governed by the transition state 69 and involves a 5-endu-tet type cyclization. The alternative transition state 70, where the electronegative substituent allows for maximum n-o* interaction, leads to electron withdrawal from the olefinic system, thus making it less reactive to the electrophile.The 4-hydroxy butenolide 71 may be readily converted into the menthyl ether 72, which is a useful homochiral synthon for conjugate addition reactions.37 The menthyl group can be removed later by reduction with NaBH, (Scheme 30). alkynoic acid 73 and a 2-alkynyl acetate in the Enantioselective syntheses of 3,4-disubstituted Allenol y-lactones can be synthesized from an 140 Contemporary Organic Synthesis63 Scheme 25 64 TCI, 2 10 61 27 ZrC14 4 4 81 11 R3 = cyclohexyl =/"i, ether, -lOO°C RCHO R > 99% e.e. 1PC2B- R Go R = Me. (i) BHflI.SMe2, CHfl12 (ii) CrO3, AcOH (iii) NaOH (iv) HCI - 0 -No2 78%. > 99% 8.e. 65 Scheme 26 0 II .o OAAr (i) thexylborane ~~~~ ' Ph R (N) HCI 66 ( W h , > 98% e.e.) 0 il I disiamylborane OCAr - \ 67 (a%, 98% e.e.) Scheme 27 OSiEt3 (+)-cawone ------ CO,Me CI 68 J SmI2 0 one diastereomer R = Me, 50% R = Bn, 70% Scheme 29 69 70 OMenth OMenth oeoH 120°C-130"C, (-)-men! hol 3 d' 7; +g 71 0 0 Q OMe OMe Scheme 30 OSiEt3 intramolecular nucleophilic attack of the carboxylate anion on the triple bond to generate 74 (Scheme 31).esters such as 75, followed by acid-catalysed fb ~~~~~ mo2& The addition of Me,A1 to a$-unsaturated sulfone 91 % Scheme 28 cyclization, provides a stereoselective route to cis-p- y-substituted lac tone^.^^ Lithium and magnesium reagents give mixtures of 1,2- and l,LC-adducts, whilst Bu,CuLi gives 1,4-addition without stereoselectivity. The coordination of the Me,Al to the MOM-ether prior to addition is the origin of the diastereoselectivity in this reaction. This methodology can be used to obtain homochiral lactones by enzymatic resolution of the alcohols obtained by condensing ( S)-( phenylsulfony1)-p-tolysulfinyl methane with an aldehyde (Scheme 32).The sulfoxide is then presence of Pd0.3* This methodology is an extension of an earlier report by the same research group, involving the coupling of alkynoic acids and 1-haloalkynes. The mechanism involves the generation of a a-allenyl palladium species which in turn activates the Ladu wahetty: Saturated and unsaturated lactones 141R' Ph02S e R 3 R2 - Pdo Ri + &C02H OAc R3 Pd(0Ac) 73 O O R 76 n (93 : 7) (30) : I OAC Scheme 33 R' = R2 = H, R3 = Ph, 50% R' = R2 = Me, R3 = Ph, 62% Scheme 31 Medl PhO2S MeO2C OMOM PM2sYYR - Me02C OMOM 75 1:1.6 mixture at a-position p o 4 Ph02S, 0 &CR R = Me, 82% Ph02S,,ioMe - + RCH2CH0 I (i) piperidine (ii) Lipase PS 1 FAG Ph02S d R + Ph02S+R (56%, > 98% e.e.) (41 %.> 95% e.e.) Scheme 32 eliminated and the resulting vinyl sulfone alkylated to provide the substrate for the addition of the organometallic reagent. Products with > 90% e.e. can be obtained in this manner. The addition of Me,A1 to the butenolide 76 results directly in the trans-lactone 77 as the major product. Et,AlCN, on the other hand, gives the cis-lactone 78 as the major product although with reduced selectivity (Scheme 33). This difference in stereoselectivity is attributed to the constraints imposed by the phenylsulfonyl group and its sensitivity to different reagents. The exploitation of molecular symmetry in synthesis has been extended to the halolactonization reaction by Kurth et al.(Scheme 34).,O The dienoic acids 79 and 80, prepared by an iterative Claisen rearrangement can be cyclized with I, to obtain the lactones 85 and 86 with excellent selectivity. The diastereoselectivities in the reactions of 79 and 80 arise from the fact that the nucleophilic carboxylate is confronted by two diastereoselective olefins which experience different ground-state conformations relative to the carboxylate. The conformational energy differences in the transition state favour cyclization towards the side where the carboxy and allylic substituents are anti; thus olefin selectivity can be anticipated when the C,-C,/C, - CBf differ in stereochemistry (8 1 versus 82). The C,-C, stereochemistry is determined by the face selectivity in the iodination (83 versus 84).The subtlety in these cyclizations can be illustrated (Scheme 34) by the dienoic acid 87, where both allylic substituents are syn and only differ from each other by a single methylene. The acid 87 cyclizes to give the lactone 88 with CY1 selectivity (22: 1) and excellent cis/trans selectivity. Having had success with the transition metal catalysed tandem cyclization/cycloaddition reactions of diazoketones, Padwa et al. have now explored the analogues reactions with diaz~esters.~' The ester 89 does not cyclize, possibly due to the reduced electrophilicity of the rhodium carbenoid. The presence of an additional stabilizing group, as in 90, however, promotes the cyclization, providing the lactone product in good yield.Conformational differences between the mono- and di-substituted carbenoids may also govern their reactivity. presence of potassium iodide and sodium persulfate (Scheme 35). Unlike the standard iodolactonization conditions which require substantial amounts of KI and I,, this new procedure, which is based on the in situ oxidation of iodide with persulfate, only requires a slight excess of KI.42 Cyclizations of the acids 9 1-93 using standard iodolactonization conditions always give lower yields and need longer reaction times than the KI/persulfate method. The successful iodolactonization of but-3-enoic acid to the corresponding @-lactone is particularly noteworthy. The acid-sensitive fused-ring lactones 94 and 95 can be synthesized efficiently from the cyclic enol ethers shown and the monomethyl ester of malonic acid using ceric ammonium nitrate in acetic acid.43 Addition of Cu( OAc), to the reaction mixtures, to oxidize any secondary radical intermediates to A variety of carboxylic acids afford y-lactones in the 142 Contemporary Organic Synthesis81 olefinselectivity [w vemm +I% 79 R=Me 80 R=Et - * [N~HCO, i2 / I 87 Scheme 34 65% * b: 0 & Et KI, sodium persulfate HO 91 I Et 92% (20 min.) 92 94% (20 min.) I HO 93 62% (50 rnin.) Scheme 35 carbocations, avoids large amounts of side-products that may otherwise be formed.Ultrasound further increases the yields in the reactions by ca. 10%. Simple olefins give low to moderate yields of lactones, although a variety of electron-rich olefins have been shown to work very efficiently.Mn( OAc),, on the other hand, is not suitable for the synthesis of acetals such as 95. 88 CyKy' 1 :22 cidtmns 12:l. 74% CAN, CU(OAC)~ 94 (84%) C0,Me Me0 MeO a0 95 (81%) Samarium iodide promoted cyclizations of acetals provide trans-2,4-disubstituted y-lactones in good yields (Scheme 36). Although similar to the analogous reactions with Bu,SnH, the samarium iodide conditions are milder and avoid the troublesome removal of tin residues. This methodology also paves the way to introduce functional groups through sequential intramolecular cyclization and electrophilic trapping. Preparations of chiral lactones from meso-diols can be accomplished in high yields and enantioselectivity with Norcardia corallina B-276.44 Using whole cell methods such as this is more economical since it avoids the need to recycle the expensive co-factors necessary for enzyme-based methods. Analogous to horse-liver alcohol dehydrogenase (HLD), the initial oxidation is of the pro-( S) hydroxymethylene (Scheme 37).In contrast to HLD, however, the whole cell system is selective only for diols. extremely useful method for obtaining optially pure ketones and lactones (Scheme 38).4s The whole cell methodology using Acinetobacter calcoaceticus (NCIMB 987) or Cuwularia lunata (NRRL 2380) has The bio-Baeyer-Villiger reaction promises to be an Laduwahetty: Saturated and unsaturated lactones 143R' X = Br, I 1H2CQ. R' 5249% tmndcis- 86:14- 94:6 1 PhSeCl L O B d Scheme 36 0 a::;:: - 50%. W h 8.8. 0 50%. > 90% 8.8.0 95%, 91% 8.8. Scheme 37 b Br L (+)-40% + Scheme 38 144 Contemporary Organic Synthesis some drawbacks, as the organisms are not readily available and the yields are rarely high due to overmetabolism. A recent development in the area is the use of an enzyme-based method using a monooxygenase from the micro-organism Pseudomonas putida. This monoxygenase is unusual in that it utilizes NADH as its co-factor. NADH is much easier to recycle compared to the more common NADPH, which makes the whole process much more economical. This enzyme can also be used together with a dehydrogenase to convert an alcohol into a lactone directly (Scheme 39). 0 0 80% 8.8. > 95% 8.8. 4 &hydrogene* mono-cacygena: +o OH 0 Scheme 39 A mild method for the synthesis of 5-ethenyl- y-lactones involves an initial Baylis-Hillman coupling to form the hydroxy ester 96, followed by cyclization (Scheme 40).4h t-butyl-acetate, in the presence of a Lewis acid such as The enolate generated from LHMDS and 96 H 0 0 0 Scheme 40Et2A1C1, reacts with ( R ) - or (S)-propylene oxide resulting in the formation of (S)-4-methylbutyrolactones with 98% e.e.(Scheme 4 1).47 98% 8.8. Scheme 41 Scheme 43 8 But-2-enolides and tetronic acids Annulated butenolides, viz. 98 and 99, can be formed in a regioselective manner from the same intermediate sulfoxide 97 by generating the corresponding sulfene under different condition^.^^ Under anhydrous Pummerer conditions a vinyl sulfide is formed which upon mercury-mediated hydrolysis forms the butenolide 98 exclusively (Scheme 42).In the presence of H,O, however, the thermally generated sulfene reacts via the hydrated aldehyde 100 to provide 99 as the sole product. Acfl, 110°C ?I Ph (d I p H 0 97 dioxane or I toluene, 98 L 100 Scheme 42 99 Bromolactonizations of a P, y-unsaturated carboxylic acid provides p-lactone 10 1 which when treated with AgNO, results in the generation of an exocyclic cation (Scheme 43). Ring expansions then provide a, y-disubstituted butenolides in good yield.jY ethanol to a-P-unsaturated carboxylic acids provides the sulfone 102, the dianion of which can be reacted with aldehydes and ketone^.^" The resulting The addition of sodium p-toluenesulfinate in 101 R' 1Bu"i-i 25% Ts OH 102 Scheme 44 hydroxyfulfone can then be converted into the butenolide in modest overall yield (Scheme 44).The reactivity of bicyclic tetronates has been explored by Bertucco et al. and interesting differences between the monocyclic- and bicyclic-tetronates have been found.52 Unlike the methyl tetronate 103, which is completely inert to 174-addition by nucleophiles, the bicyclic tetronate 104 reacts with even poor nucleophiles such as trifluoroacetate to provide the 174-adduct 105 in 95% yield. Some other nucleophiles give interesting ring-opened butenolides. The addition of TMSI to bicyclic tetronates, a reagent previously used by Pattenden et al. for the de-esterification of methyl tetronates, results in rapid formation of the corresponding silyl enolate 106. Further reaction with excess reagent then leads to the ring-opened iodide 107 which can be hydrolysed to the tetronate 108 (Scheme 45).The hydrolysis of the methyl tetronate itself with TMSI does not, of course, involve the initial 1,4-addition. MeO bo 1 03 104 105 (95%) Ladu wahetty: Saturated and unsaturated lactones 145c -. 106 TMSI, MeCN or Ac@, MgBr2 1 X ~ O H - X ~ O T M S 0 0 108 107 X = I, Br Scheme 45 The first example of a conjugate addition of a carbon nucleophile to a tetronate has also been reported by these same research workers (Scheme 46). The bicyclic tetronate 109 was found to react with dialkyl cuprates in the presence of TMSCI to give a mixture of the ring-opened and bicyclic products 110 and 11 1, which on exposure to DBU are converted into 1 1 1 exclusively. The substituted tetronate 1 12 reacts with dialkylcuprates even without TMSCI, with the strain relief in the bicyclic structure being the driving force for the reaction.Methyl tetronate is, once more, inert to these conditions. ($yo =Hop + I DBU 111 110 t 109 111 112 Scheme 46 R = Me, 75% R = Bu, 70% 4-Fluoroalkylbut-2-en-4-olides can be synthesized by reaction of 2-silyloxy furans with perfluoroalkyl peroxides (Scheme 47).s2 The mechanism involves the oxidation of the furan to a radical cation and the simultaneous reduction of the resulting peroxide to a radical anion which in turn dissociates to a perfluoroalkyl radical. Addition of the radical to the furan radical cation, followed by rearrangement then provides the butenolide. Due to the strong electron-withdrawing effect of the trifluoromethyl group the anion 113 can react with various acrylates under weakly basic conditions (Scheme 48).Defluorination, a common problem with perfluoroalkyl anions, does not occur due to delocalization into the ring. n R(=CF3, 63% = C2F2, 78% Scheme 47 F3C [ Me02C%o] 113 1 82% Scheme 48 The titanium-catalysed additions of enol silanes to squaric acid 114, and heating of the resulting a-hydroxy ketones in the presence of pyridine, results in the exclusive formation of the (2)-butenolide 1 17 in 64% yield (Scheme 49).s3 The mechanism of this reaction involves a thermally allowed electrocyclic ring-opening to give 1 15 which recyclizes to the CI MeO K: 114 +OSiMe3 R CI MeO % 0 tl A R 116 0 0 R Scheme 49 R 117 146 Contemporary Organic Synthesisbutenolide. The observed (Z)-geometry of the methylene is due to the H-bonded enol form in the intermediate 1 16.A concise synthesis of (2)-isomers of y-alkylidenebutenolides can be achieved under mild conditions by reaction of acetylenes with bromoalkenoic acids under Pd ~atalysis.'~ This reaction provides an interesting interplay between the in situ generated Pd" species, which catalyses the coupling of 118 and 119, and the Pd" species which assists in the cyclization. Prolonged reaction times result in a lower E/Z ratio. PdC12(Ph3P)Z, CUI C02H E3N, MeCN, r.t. * R+H + Br u 118 119 d R = Ph, 80% ZIE: 97:3 R = THPOCH,, 62% ZIE : 9713 Cycloaddition reactions between the nitrile oxides 120 and propene afford mixtures of isoxazolidines (55-68% yield).55 Conversion of the latter into their corresponding salts, followed by hydrogenolysis and elimination then provides a useful route to disubstituted butenolides (Scheme 50)." CO2Et 120 I TfOMe R PPBA 0 a M e Scheme 50 9 a-Methylene butyrolactones The electroreduction of a catalytic amount of ZnBr, in acetonitrile provides an active Zn species which reacts with 12 1 and aldehydes or ketones to provide a-methylene- y-butyrolactones in one step (Scheme 5 1 ).sh The reaction is, however, sensitive to the steric hindrance around the carbonyl group. The allylic carbanion equivalent 12 1 also reacts with aldehydes and ketones in the presence of SnCl, to provide a-methylene- y-butyrolactones (Scheme 5 1 ).57 The allyltrihalostannane intermediate in this sequence not only enhances the nucleophilicity of the anion, but also activates the carbonyl group towards nucleophilic attack. The resulting alkoxystannane 122 is reactive enough to form the lactone in situ.Due to the sensitivity of the organostannane to substitution around the carbonyl, diketones such as 123 can be utilized to give only the mono-alkylated product. =cBr CO2Et 121 + (i) Zn(CH3CN), (cat.), Zn rod (ii) H&+ R' EtO EtO <lr ____) SnCI2 qr - E t o B 1 2 B r R2 R' \' SnCI,Br 122 I 121 R g R' 0 &' R2 1 23 51% Scheme 51 Sodium dithionite initiated cyclizations of acyclic alkynoates give fluorinated a-alkylidine y-butyrolactones in good yield and selectivity (Scheme 52).s8 The reaction works best when R # H, although propynoates do give modest yields (44%). The reaction is initiated by the generation of a perfluoroalkyl radical by the dithionite which, due to its electrophilic nature, adds to the more electron-rich double bond.Cyclization to the triple bond is followed by iodine transfer to the vinyl radical. Good E/Z selectivities ( > 95:5) are obtained under the reaction conditions. This is due to the iodine transfer being slow, allowing the vinyl radical to invert to form the more stable ( E ) isomer. R 1 Scheme 52 A comprehensive study of the synthesis of iodoacetylenic esters and their radical mediated cyclization to ( E)-iodoalkylidine butyrolactones has been conducted by Weavers et aLS9 Whereas the exo-dig ring-closures of propargyl ethers and acetals have been successful, thereby making subsequent oxidation a necessity, the cyclization of the ester gives direct entry to the desired product.A variety of iodo esters have been synthesized by the iodonium ion Ladu wahetty: Saturated and unsaturated lactones 147mediated addition of a carboxylic acid to an alkene. Although several radical cyclization methods were attempted [ e.g. AIBN; Bu,SnH; Bu,SnCl, NaBH,; cobalt( I)] only one, the heating of a benzene solution of the iodoesters with dibenzoyl peroxide, proved 90% successful. A number of cyclic, bicyclic, and spirocyclic lactones were formed in modest (33%) to excellent yields (Scheme 53). With a few exceptions, Scheme 54 the cyclizations were stereospecific giving only the esters (E)-isomer. cyclized The to cyclopentyl give the more and stable cyclohexyl cis-ring iodo junction, g - Tz q regardless of the stereochemistry of the initial iodo ester.As expected, larger rings give significant proportions of the trans-isomer. SiMe, 0 CO2 Et 124 125 + 'O)+,H 0 B~;NF/ H 0 0 1 27 + H H 126 1 28 117a wo H O 33% Scheme 55 cis-lactones 125 and 126, whereas fluoride promoted cyclizations provide only the trans isomers 127 and 128. The five-membered ring is essential to allow for the folded conformation of 124 in order for the reaction to proceed. air-oxidation of vinyl phosphates, undergo Horner-Wadsworth-Emmons reactions to give ( E ) - or (Z)-a-methylene lactones depending on the conditions (Scheme 56)F4 The y-lactone gives exclusively the a-Phosphonolactones, which are prepared by 77% Ph - 0 / Scheme 53 Although direct photolysis of the iodoesters has proved unsuccessful, the (E)-alkylidine lactones can be photoisomerized to give E/Z mixtures, and the less accessible (2)-isomer can then be separated by chromatography.60 These lactones have the capacity to undergo nucleophilic displacement/elimination 75% KHMDS, / 18-Crown-6 reactions.The degree of stereospecificity is dependent R on the nucleophile.h' An interesting difference in OP(0Et)z outcome dimethylcuprate, is seen between where a the mixture reaction of isomers with lithium are O' 3 - [O] &n.,, KZc030 0 18crown-6 Y" obtained, and trifluoromethylcopper (Scheme 54) where the geometry of the reacting double bond is op Intramolecular cyclizations of o-formyl-a-trimethylsilylmethyl a,P-unsaturated esters 124 pave the way for carbocyclization, lactonization, and a-methylenation in one step, albeit in low yield (Scheme 55).63 The Lewis acid promoted cyclization of the (2)-isomer 124 gives only the 87% Scheme 56 148 Contemporary Organic Synthesis(25)-propylidine lactone with KHMDS in the presence of 18-crown-6, whilst giving a high proportion of the (2)-isomer with K,CO, and 18-crown-6.A survey of the examples cited, however, reveals that the conditions for ( E ) - or (2)-alkene formation vary with the structure of the starting phosphonolactone. 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 References G. 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