Iodolactonization lactone synthesis

Curran s synthesis of ( )-A9(l2)-capnellene [( )-2] is detailed in Schemes 30 and 31. This synthesis commences with the preparation of racemic bicyclic vinyl lactone 147 from ( )-norbomenone [( )-145] by a well-known route.61 Thus, Baeyer-Villiger oxidation of (+)-145 provides unsaturated bicyclic lactone 146, a compound that can be converted to the isomeric fused bicyclic lactone 147 by acid-catalyzed rearrangement. Reaction of 147 with methylmagne-sium bromide/CuBr SMe2 in THF at -20 °C takes the desired course and affords unsaturated carboxylic acid 148 in nearly quantitative yield. Iodolactonization of 148 to 149, followed by base-induced elimination, then provides the methyl-substituted bicyclic vinyl lactone 150 as a single regioisomer in 66% overall yield from 147. 

Chiral butenolides are valuable synthons towards y-butyrolactone natural products [37] and have also been successfully applied to the synthesis of paraconic acids. The lactone 91, readily available from the hydroxyamide (rac)-90 by enzymatic resolution [38] followed by iodolactonization, proved to be an especially versatile key intermediate. Copper(I)-catalyzed cross coupling reactions with Grignard reagents allowed the direct introduction of alkyl side chains, as depicted in 92a and 92b (Scheme 13) [39, 40]. Further... 

Cycloalkylation (7, 148).2 Cycloalkylation of 2 with (Z)-l was used as one step in a total synthesis of (+ )-sesbanine (6), a constituent of Seshania drummondii seeds with antileukemic activity. The hydroxyl group was introduced into the cyclopentene ring of 4 by iodolactonization followed by reduction to give 5. Final steps included aminolysis of the lactone ring, intramolecular addition of the amide anion to the CN group, and hydrolysis to give 6. 

Few applications of cyclizations to form fused ring 8-lactones or tetrahydropyrans are found. Two consecutive bromolactonizations were used to effect stereoselective dihydroxylation of a cyclohexadi-enone system in a total synthesis of erythronolide B (Scheme S).64 Iodolactonization of an NJV-di-ethylbenzamide derivative to form a ds-fused benzolactone was a key step in a recent synthesis of pancratistatin.641 A di-fused tetrahydropyran was produced in good yield by intramolecular oxymercura-tion as shown in equation (17),59 although attempts to cyclize a more highly functionalized system have been reported to fail.65 Formation of a fused ring tetrahydropyran via an anti-Markovnikov 6-endo sel-enoetherification has been reported in cases where steric and stereoelectronic factors disfavor a 5-exo cyclization to a spirocyclic structure.38... 

As mentioned earlier in the discussion of cyclizations leading to (3-lactones, the (3-lactones formed from halolactonization of 1,4-dihydrobenzoic acids readily rearrange to produce bridged ring y-lac-tones.19 In some cases, the substitution pattern favors formation of the y-lactone even under conditions of kinetic control (equation 23).20 Synthesis of a variety of y-lactones by iodolactonization of dihydroben-zoic acid derivatives has been reported recently by Hart (equation 24).91 Attempted iodolactonization of the acid in the case where R = H resulted primarily in an oxidative decarboxylation however, iodolactonization was effected using the amide derivative. 

A general problem in the synthesis of steroid compounds is the construction of a dikctone with 5/6 (raws-fused rings and a quaternary carbon atom at the ring junction. Tethering can solve this problem, and we will present two strategies—one using a lactone derived from an iodolactonization reaction, and one using a sulfur atom. 

Bromolactonization. A key step in a synthesis of ramulosin (4) requires halolac-tonization of the y,8-unsaturated acid 1, which can result in a 7- or a 5-lactone. Bromolactonization results mainly in the desired 5-lactone (2), which is converted in two steps into 4.1 Iodolactonization of 1 results mainly in the undesired y-lactone and a mixture of isomeric 8-lactones. 

A useful application of this reaction to a cyclic alkene 2 constitutes the key step in the total synthesis of thromboxane B216. Starting from methyl a-D-glucopyranoside (1), 3,6-dihydro-2-hydroxymethyT6-methoxy-ATV-dimethyl-2/y-pyran-3-acetamide (2) is obtained pure in six steps. Treatment of the amide with 3 equivalents of iodine in tetrahydrofuran/water at 0 °C for 1 hour gives the iodolactone 3 in 80% yield. Deiodination with tributyltin hydride quantitatively affords the hydroxy lactone 4. 

Miscellaneous. trani-2,5-Dimethylpyrrolidine has been utilized as a chiral auxiliary for an asymmetric iodolactonization in the total synthesis of ( )-pleurotin and ( )-dihydropleurotin. The reaction affords the desired lactone in 47% yield and only 30% enantiomeric excess. 

EUmimtion of iodohydrins. Treatment of the iodolactone (1) in dry pyridine with 1.3 eq. of mesyl chloride at -20° for 2 hr. and at 0° for 1.5 hr. affords the unsaturated lactone (2) in practically quantitative yield. The reaction provided a key step in the synthesis of A prostaglandins, which previously were available from the primary E prostaglandins by dehydration of the )S-kctol unit. 

A superb example of the synthetic utility of the iodolactonization reaction in organic synthesis is the conversion of the bicyclo[2.2.1]heptenone below into the Corey lactone. The latter compound possesses four contiguous stereogenic centers and is an important precursor for the synthesis of prostaglandins. 

During the total synthesis of the pentacyclic sesquiterpene dilactone (+)-merrilactone A by S.J. Danishefsky et al., a two-carbon unit was introduced at C9 by a Johnson-Claisen rearrangement. This high yielding transformation was carried out in the presence of catalytic 2,2-dimethyl propanoic acid at 135 °C using mesitylene as the solvent. A mixture of diastereomeric esters were formed, which were later hydrolyzed and subjected to iodolactonization to form the second lactone ring present in merrilactone A. The natural product was synthesized in 20 steps with an overall yield of 10.7%. 

The second Matsuo synthesis (233) was initiated with methyl 3-(2,2-dimethoxyethyl)-4-methyl-4-pentenoate (357) prepared (234) from carvone (239). Hydrolysis with lithium hydroxide followed by iodolactonization (I2-KI-NaHC03) and reduction with tri-n-butyl tin hydride in the presence of azobisisobutyronitrile in benzene under reflux afforded 358. The carbo-methoxy group was introduced with methyl chloroformate and LDA in quantitative yield, and reductive animation of 359 with methylamine and sodium cyanoborohydride gave the lactone 360. Heating of 360 with 10% Pd/C in decalin gave cerpegin (118) in 81% yield (Scheme 42) (233). 

The ester enolate Claisen rearrangement of (Z)-crotyl /V-tm-Boc-glycinate has been applied to the synthesis of lactone hydrochloride 4, the hydrolysis product of the amanita mushroom toxins a- and / -amanitin487. The rearrangement and the iodolactonization of the A -phthaloyl derivative are the stereocontrolling steps in this reaction sequence. 

Readily available /3-hydroxy-esters (e.g. 49) can be converted into butyrolactones (e.g. 50) simply by treatment with concentrated sulphuric acid. Cyclic ether-lactones (52) are available from hydroxy-acids (51) by iodolactonization followed by dehalogenation with silver acetate. A stereoselective total synthesis of the antifungal mould metabolite (53) has been reported. ... 

Still and Schneider have described" a total synthesis of ( )-frullanolide (82) in which the lactone ring is constructed by an enolate Claisen rearrangement of the type developed by Ireland s group, followed by iodolactonization, viz. (83) - (84). 

The synthesis of both R)- and (5)-enantiomers of 4,4,4-trifluoro-3-methyl-1-butanol (19,20) by Jacobs et al. [54] as building blocks for leuko-triene antagonists Scheme 5.12), demonstrates how oxazolidinone auxiliaries (21) and (22), derived from L-valine and (lS,2/ )-norephedrine, respectively, impart complementary selectivity in alkylation of chelated (Z)-enolates. Similarly, Trova et al. [55] have utilized the iV-acyl oxazolidinone (23), from L-phenylalanine and 3-phenylpropanoyl chloride, for the construction of diastereomeric lactones (24) and (25) as synthons for HIV-1 protease inhibitors Scheme 5.12). Following allylation and hydrolytic removal of the auxiliary, stereocomplementary iodolactonization reactions of... 

Lactones, cyclic esters such as compound A, are prepared by halolactonization, an addition reaction to an aikene. For example, iodolactonization of B forms lactone C, a key Intermediate In the synthesis of prostaglandin PGp2a (Section 4.15). Draw a stepwise mechanism for this addition reaction. 

The use of iodolactonization in the synthesis of 5-lactones is demonstrated in routes to a prostaglandin endoperoxide analogue, and to the antibiotic malyngolide. The latter compound (164) has also been prepared as a mixture of C-2 epimers by lactonization of the epoxide (163). Stereoselective sul-phenyl-lactonization plays an important role in a synthesis of octahy-droleukotrienes, and cyclization of the cyclopropyl acid (165) leads to the lactone (166). A spirocyclic dilactone has been prepared and undergoes... 

A comparison between the acid-catalysed lactonization and iodolactonization of norbornenecarboxylic acids has appeared. The synthesis and properties of some enol lactones have been studied. ... 

Three syntheses of the pseudoguaianolide ( )-confertin have appeared. Schultz uses the oxidation of an a-trimethylsilylated furan intermediate followed by reduction to give a butyrolactone during his synthesis. In another, the lactone (216), prepared by iodolactonization of the appropriate dimethyl amide, is converted into (217), using Bredereck s reagent (Scheme 114). In the third... 

Synthesis of Valerolactones.—The remote chiral centres in the lactone (222) are produced in a controlled manner by conjugate addition to the macrolide (220) followed by hydrolysis of (221) and iodolactonization (Scheme 116). ... 

---