Lactone iodolactones

Cyclopentene derivatives with carboxylic acid side-chains can be stereoselectively hydroxy-lated by the iodolactonization procedure (E.J. Corey, 1969, 1970). To the trisubstituted cyclopentene described on p. 210 a large iodine cation is added stereoselectively to the less hindered -side of the 9,10 double bond. Lactone formation occurs on the intermediate iod-onium ion specifically at C-9ot. Later the iodine is reductively removed with tri-n-butyltin hydride. The cyclopentane ring now bears all oxygen and carbon substituents in the right stereochemistry, and the carbon chains can be built starting from the C-8 and C-12 substit""" ... 

PGF2a- The cyclopentane ring of the Corey lactone (9) is the host of four contiguous stereogenic centers. Retrosynthetic simplification of 9 provides 10, a construct which is more complex than 9 Nevertheless, intermediate 10 possesses structural features that satisfy the requirement for the iodolactonization transform. The iodolactone in 10 constitutes the retron for the iodolactonization transform.11 Cleavage of the indicated bonds in 10 sacrifices two of the five stereocenters and provides unsaturated carboxylic acid... 

The adjacent iodine and lactone groupings in 16 constitute the structural prerequisite, or retron, for the iodolactonization transform.15 It was anticipated that the action of iodine on unsaturated carboxylic acid 17 would induce iodolactonization16 to give iodo-lactone 16. The cis C20-C21 double bond in 17 provides a convenient opportunity for molecular simplification. In the synthetic direction, a Wittig reaction17 between the nonstabilized phosphorous ylide derived from 19 and aldehyde 18 could result in the formation of cis alkene 17. Enantiomerically pure (/ )-citronellic acid (20) and (+)-/ -hydroxyisobutyric acid (11) are readily available sources of chirality that could be converted in a straightforward manner into optically active building blocks 18 and 19, respectively. 

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. 

Entries 15 to 18 are examples of use of iodocyclization in multistep syntheses. In Entry 15, iodolactonization was followed by elimination of HI from the bicyclic lactone. In Entry 16, a cyclic peroxide group remained unaffected by the standard iodolactonization and subsequent Bu3SnH reductive deiodination. (See Section 5.5 for... 

Iodolactonization of anti,syn-1 could result in four iodolactones, two resulting from face selectivity, and two resulting from diastereotopic olefin selectivity. In practice only three lactones are formed in a 142 4.7 1 ratio, with 4 being essentially the only product. In fact this kinetic iodolactonization proceeds with 147 1 olefin selectivity and 30 1 face selectivity, considerably higher than the selectivity observed in previous iodolactonization of 3-methyl-4-pentenoic acid (8, 257). Lac-tonization of 1 also shows cis-C4,C5 selectivity. 

A different mode of fragmentation of the lactone ring in 35 occurred to give butyrolactone 38 when anhydrous lithium alkoxides were used in place of metal hydroxides under aqueous conditions (Scheme 10). It is noteworthy that 36, 37 and 38 (R = H) are all formed without racemization. Although we are only in the early stages of development of the chemistry of iodolactones 35, it is already clear that there is considerable potential for utilization of the butenolides derived from 35 as scaffolds for construction of carbocyclic and heterocyclic ring... 

Birch reduction-methylation of the 2,3-dialkyl substituted benzamide 85 (Scheme 19) provided the cyclohexa-1,4-diene 86 with diastereoselectivity comparable to that observed with the 2-alkylbenzamides illustrated in Scheme 4. Cyclohexadiene 86 was converted to iodolactone 87 and reduction of 87 with BusSnH occurred with exclusive equatorial delivery of hydrogen to give the axial methoxyethyl derivative 88. Lactone 88 was converted to the Caribbean fruit fly pheromone (+)-epia-nastrephin 90 (> 98% ee) in 9.5% overall yield from the chiral benzamide 85. °... 

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... 

Bis(5> m-collidine)iodine(I) tetrafluoroborate in DMSO has been found to be a convenient reagent for the conversion of alkanes to a-iodocarbonyl compounds. When dihydrofuran (305a) and dihydropyran (305b) are the substrates, this reaction affords the corresponding a-iodolactones 306 (Scheme 77). This method converts certain glycals such as 307 to their corresponding a-iodo-a,/3-unsaturated lactones 309, presumably because of elimination of a molecule of acetic acid from the initially formed lactone 308 (86S727) (Scheme 78). 

When iodolactonization is carried out under nonbasic conditions, the addition step becomes reversible and the product is then the thermodynamically favored one.52 53 This usually results in the formation of the stereoisomeric lactone which has adjacent substituents Ira ns with respect to one another. 

The iodolactonization of bicyclic lactone 143 provides a mixture of iodolactones (Equation 48) in excellent overall yield <2002JA2080>. 

Homochiral lactones are also generated by iodolactonization reactions of cyclic alkenes in the presence of iodine in good yield (Equation 113) <1997TL3817>. 

Iodolactonization of /3,-y-unsaturated acids can also be achieved by the reaction of iodine with the thallium(I) carboxylates in ether solution. This reaction also has the possibility of giving /3- or -y-lactones, with the substitution on the double bond having the major influence. Thus thallium 3-butenoate gave the /3-lactone, while thallium 4-methyl-3-pentenoate gave the y-lactone, both in high yields (74JCS(Pl)l864). 

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. 

In addition to the procedures listed in Table 3.38, further reactions have been used to generate halides upon cleavage. In Section 3.5.2, iodolactonization is presented as a method for the preparation of iodomethyl lactones from resin-bound pentenoic or hexenoic acid derivatives. Closely related to the iodolactonization is the iodine-mediated formation of 2-(iodomethyl)tetrahydrofurans from resin-bound isoxazoli-dines (Entry 9, Table 3.38 for the mechanism, see Figure 15.5). Nitriles can also be prepared by cleavage and simultaneous dehydration of amides RCONH2 from the Rink or Sieber linkers with TFA anhydride (Entry 10, Table 3.38). 

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. 

Examples of 1,3-asymmetric induction in cyclizations to 8-lactones have been observed. Iodolactonization of 3-methyl-5-hexenoic acid to a 8-lactone under equilibrating conditions showed reasonable stereoselectivity (6 1 cis trans).l20b Recent studies have examined the formation of 8-lactones from cyclization of 5-hexenoic acids with a homoallylic oxygen substituent at C-3.135 Selenolactonization of 3-hydroxy-5-hexenoic acid under conditions of kinetic control provided the trans lactone in modest yield (40%) and high stereoselectivity.13515 Equilibrating conditions led to a slight preponderance of the cis... 

The illustrative preparative example is the conversion of cyclohex-1 -en-l-yl-acetic acid into the y-iodolactone (12) (cis-l-iodo-7-oxabicyclo[4.3.0]nona-8-one,188 Expt 5.172). In general the simpler iodolactones tend to be unstable the preparative sequence therefore recommends conversion into the unsaturated lactone by a dehydrohalogenation reaction. 

Dehydrohalogenation of y-iodolactone. A solution of the foregoing lactone in pyridine (10 ml) (CAUTION) is kept at room temperature for 2 days. Etha-... 

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