Iodo-lactonization

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. 

A number of enantiomerically pure chiral building-blocks, such as 292-294, have been prepared (270,271) by zinc-copper cleavage of 5-bromo-5-deoxy-2,3-0-isopropylidene-D-ribono-1,4-lactone, followed by reduction. Similarly, from the 5-iodo lactone analogue the enoic acid 295 was obtained by reaction with zinc/silver-graphite (272). 

Scheme 50 Allylation of a-iodo lactones Al-BINOL and Al-sulfonamide ligands as single...

This reaction has been used mostly to prepare iodo lactones, but bromo lactones and, to a lesser extent, chloro lactones, have also been prepared. In the case of -y.S-unsaturated acids, 5-membered rings (y-lactones) are predominantly formed (as shown above note that Mar-kovnikov s rule is followed), but 6-membered and even 4-membered lactones have also been made by this procedure. Thallium reagents, along with the halogen, have also been used.653 For a method of iodoacetyl addition, see 5-35. 

Medium-sized lactones A new method for synthesis of lactones that is particularly useful in the case of medium sized ones involves the hypoiodite reaction with a catacondensed lactol such as 1, which results in cleavage to the ten-membered isomeric iodo lactone 2. Phoracantholide I (3) is obtained on reductive removal of iodine. 

In the event, iodolactonization of the carboxylate salt derived from the ester 458 afforded 459, and subsequent warming of the iodo lactone 459 with aqueous alkali generated an intermediate epoxy acid salt, which suffered sequential nucleophilic opening of the epoxide moiety followed by relactonization on treatment with methanol and boron trifluoride to deliver the methoxy lactone 460. Saponification of the lactone function in 460 followed by esterification of the resulting carboxylate salt with p-bromophenacylbromide in DMF and subsequent mesylation with methanesulfonyl chloride in pyridine provided 461. The diazoketone 462 was prepared from 461 by careful saponification of the ester moiety using powdered potassium hydroxide in THF followed by reaction with thionyl chloride and then excess diazomethane. Completion of the D ring by cyclization of 462 to the keto lactam 463 occurred spontaneously on treatment of 462 with dry hydrogen chloride. 

Treatment of a-iodo lactone (45) with triethylborane under oxygen atmosphere gives the corresponding a-hydroxy lactone (46), via a-lactone radical species. This reaction comprises of SH2 reaction by Ef on the iodine atom of a-iodo lactones, reaction of the formed a-lactone radical with molecular oxygen, and subsequent hydrogen-atom abstraction from the solvent to form alkyl hydroperoxide (ROOH). Finally, by the addition of dimethyl sulfide for the reduction of the peroxide, the corresponding a-hydroxy lactone is obtained (eq. 2.24) [58]. 

In another lactonisation reaction, a cyclic hemiacetal or its opened ketone-alcohol equivalent (see Scheme VII/33, structures VII/172 and VII/173), is transformed to an iodo lactone VII/175 (12-iodopentadecan-15-olide) and the isomeric VII/174 (2-iodo-2-(3 -hydroxypropyl)cyclododecanone) by irradiation with high pressure mercury arc in the presence of HgO-I2 in benzene solution [114] as outlined in Scheme VII/33. 

Oxonane-2,9-dione reacts with amines, producing monoanilide in 94% yield <20010PP391>. Hydrostannylation of oxathionine 80 gave vinyl tin lactone 81 in 80% yield. Formation of the corresponding iodo lactone 82 was achieved in 87% yield by a Sn/I-exchange (Scheme 13) <2002JOC4565>. 

Synthesis of ester 83a and amide 83b was performed by palladium-catalyzed carbonylation starting from iodo lactone 98 to afford products in good yields (Scheme 13, Section 14.10.5.4) <2002JOC4565>. 

When 2,2-dimethy]-3-butenoic acid (1, R = CH,) is treated under the standard iodolactonization conditions, the corresponding /1-lactone 2 (R = C H3) is immediately formed. This compound is converted in 24 hours into the thermodynamically more stable y-lactone 3 (R = CH3)3. When a short reaction time is employed, in the absence of potassium iodide, the iodo-/ -lactone 2 is obtained, showing that the formation of a four-membered ring (rlmo 1827 cm-1) rather than a five-membered ring (vmax 1780 cm-1) is favored under kinetic control. 

The cyclization of 1-cyclohexeneacetic acid (1) has been studied under a variety of conditions. Treatment of the thallium salt with iodine affords a mixture of the y-iodo-/ -lactone 3 and a /J-iodo-y-lactone 29. (47 , 55 )-5-Iodo-l-oxaspiro[3.5]nonan-2-one (3), which predominates in the mixture, rearranges to the thermodynamically more stable /i-iodo-y-lactone. nV-hexahydro-3a-iodobenzofuran-2(3/7)-one (2). 

Some studies directed at the synthesis of the b + c + d rings of gibberellic acid, and in particular the fragment (134), have been reported.The Diels-Alder addition of butadiene to the cyclopentenone (135) afforded (136), which was converted via its iodo-lactone (137) into the tricyclic compound (138). However, the synthesis broke down at the removal of the ring D substituents. l-Hydroxy-7-methylenebicyclo[3,2,l]octane (139) provides a model for the gibbane-steviol c/d ring system. A synthetic route involves the photoaddition of allene to 1-cyclopentene-l-aldehyde to give l-formyl-7-methylenebicyclo-... 

The treatment of iodo lactones 162 with DBU in refluxing tetrahydrofuran afforded lactones 163 in high yields (84JA7854). 

The synthon of the a-acrylate anion is available from a secondary a-keto carboxamide by the Shapiro reaction. The secondary a-ketoamide trisylhydrazones ate ptepar in a one-pot synthesis by reaction of the isocyanides with acid chloride, water and trisylhydrazine in sequence. In DME solvent, the hydra-zone (103) is smoothly metallated with BuLi to give Ae trianion (KH). Allylation of the trianion (104) gives the hydrazone (105). Alternatively, warming (104) up to room temperature yields the dianion (106) which can be intercepted with several electrophiles (Scheme 23). The adduct (107) is readily transformed into the rran -iodo lactone (108) stereospecifically (equation 56). This chemistry also has been applied to a new synthesis of -lactams (Scheme 24). ... 

Any adventitious water introduced during these operations results in a decreased yield of iodo lactam and the formation of iodo lactone as an undesired side product. 

Both these reactions are more or less diastereoselective and give more or less one diastereoi-somer of 70. To discover the stereochemistry of the major adduct, the silyl ester (R = SiMeZ-Bu) was hydrolysed to the free acid 71 (note the designer chemoselectivity) and this was treated with buffered iodine in MeCN to give a crystalline iodo-lactone 72. An X-ray of this compound revealed that the structure of 71 was as shown and that the [3,3]-sigmatropic rearrangement must have had a boat transition state. 

Four ring forming transforms have been considered at length by the LHASA development group - the Diels Alder addition, the Robinson Annelation, the Simmons-Smith reaction, and iodo-lactonization. The first three of these have been fully implemented in LHASA and the fourth is completely flow charted and awaits only coding into the chemistry data base language. 

In terms of newer chemistry, the sample sequence shown below was generated by the iodo-lactonization transform. 

Fleet s group have examined the utility of carbohydrate-derived 2-azido- and 2-iodo-lactones for synthesis of novel, highly functionalized cyclopentanes and cyclohexanes. The azido lactone 11 undergoes KF-catalysed intramolecular aldol reaction to give 12 (major) and 13 (minor). The minor isomer arises through epimerization at C5 prior to the aldol cyclization. Lactone hydrolysis of the major isomer leads to 15. Similar hydrolysis of the minor isomer yields 16, and thus epimerization via retro-aldol must precede lactone ring opening via the intermediacy of 14. 

Earlier methods of converting /3y-unsaturated carboxylic acid salts into y-lactones by treatment with iodine have now been shown to involve initial formation of /S-iodo-lactones (41), and a modified procedure has... 

The synthetic principle of the latter 1,3-cycloelimination was applied in a synthesis of optically active caron aldehyde precursors, involving the transfer of chirahty from an unsaturated acyl proline 167 (261) (Reaction scheme 106) to an iodo lactone 168 which is processed further to yield two diastereomerically related add derivatives 169, 170. 

Simonot B, Rousseau G (1993) Preparation of 7-membered and medium-ring lactones by iodo lactonization. J Org Chem 58 4—5... 

Dicyanocobyrinic acid heptamethyl ester (52) undergoes oxidation at the a-bridge by molecular oxygen in the presence of ascorbic acid to form the wew-hydroxy-lactone (53) the dicyanocobyrinic acid lactone (54a) can be transformed into a variety of /S-meso-substituted derivatives, e.g. (54b), and reduction of the bromo- and iodo-lactones (54b R = Br or I) led to dicyanocobyrinic acid heptamethyl ester (52)/ Nickel complexes of 5-methyl derivatives of 1,19-dimethyl-octadehydrocorrins have been prepared, and the synthesis of l,19-diethoxycarbonyl-octamethylplatinum(ll) tetradehydrocorrin bromide by oxidative ring closure of the corresponding 1,19-diethoxycarbonyl-bilatriene in the presence of platinum chloride has been reported. 

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