Iodolactonization removal

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""" ... 

A very effective method for removal of the chiral auxiliary from cyclohexenones 34 involves treatment with I2 in THF-H2O to give the iodolactones 35 (Scheme 9). These highly functionalized chiral cyclohexanones have figured prominently in the asymmetric synthesis of natural products e.g. Scheme 15. Furthermore, selective cleavage of the cyclohexanone ring in 35... 

The 4-hydroxy-(S)-proline-derived acid (232) was subjected to electrophilic lactoni-zation either with J2-KJ-NaHC03 to yield the iodolactone (233a), or benzeneselenyl chloride to give the phenylselenolactone (23b). Reductive removal of X from these products was achieved with tri-n-butyl- or triphenyltin hydride, followed by hydro-genolysis to yield (234) with at least 99% optical purity 231 j). 

Boron trifluoride etherate (0.37 ml, 3 mmol) was added to a benzene (33 ml) solution of 4-pentenyl iodoacetate (1.0 mmol) under a nitrogen atmosphere at room temperature. Z Lv(tributyltin) (0.1 mmol) was added and the mixture was irradiated with a 300 W sun lamp at 20 °C. After 6 h, the solvent was removed and the residue was chromatographed on silica gel (hexane /ethyl acetate = 2/1) to produce the iodolactone in 80% yield [234]. 

A mixture of 10 g (0.057 mol) of 3-phenyl-4-pentenoic acid (3), 9.1 g (0.11 mol) of NaHCOj and 200 mL of H,0 is stirred until a homogeneous solution is obtained. 200 mL of CHC13 arc added, the mixture is cooled in an ice bath, and 28.4 g (0.112 mol) of iodine are added. The mixture is stirred at OX for 6 h, and the organic phase is washed with 10% aq sodium thiosulfate until colorless, then with H,0 and brine. The organic layer is dried and the solvent is removed under reduced pressure. The crude cw-iodolactone is obtained as a semisolid yield 15.5-16.3 g (91-95%) d.r. (cis/trans) 77 23 (determined by H NMR) mp 75-90X. Direct recrystallization of this material (diisopropyl ether) affords 9.0-9.5 g (52-55%) of material with a cis/trans ratio of 98 2 mp 103-104X. Further recrystallization from diisopropyl ether gives (in two crops) 8.3-8.9 g (48-52%) of product with a purity of 98% mp 104 105 X. Additional product can be obtained from the mother liquors. 

The C27-C38 segment 208 was prepared from D-galactal 227 (O Scheme 26). The silyl ether, prepared from 227, was selectively benzylated, and the resulting C3-alcohol was desilylated and propanoylated to afford 228. After the Ireland-Claisen rearrangement of 228, carboxylic acid 229 was subjected to iodolactonization followed by reductive removal of iodine to give y-lactone 230. This was converted to the C27-C38 segment 208. 

Unfortunately the optical purity was very low in these reactions. Nevertheless, the iodolactones were converted to the epoxides 255, and these were cyclized to 251 (R = Me) and 252 with lithium hexamethyldisilazane. The methyl ester 251 (R = Me) has also been made by copper-activated addition of methyl diazoacetate to the tricarbonyliron compound 256. The product, 257, was converted to 251 (R = Me) by a reaction sequence including ozonolysis to remove the side chain. 

Use of the enantiomerically pure alcohol 211 revealed a surprising stereospecificity. One enantiomer 215 gave (mostly) the required diastereoisomer 216 and hence the iodolactone 217 having the right stereochemistry at the spiro centre and at the lactone centre in the new ring. Removal of iodine, selective oxidation and addition of a d1 reagent gave (—) -cinatrin B. 

An interesting version of iodolactonisation is used to remove the chiral auxiliary from 220. Iodine attacks the alkene with participation of the amide oxygen atom 221 to give a salt 222 that hydrolyses to the iodolactone 223 with recovery of the auxiliary 26 if required. 

The hydroxy ketone B was converted to C, whose hydrolysis and iodolactonization followed by removal of the THP protective group yielded a separable mixture of two iodolactones D and E. The former (D) furnished ( -dihydroactinidiolide (89 ), while the latter (E) afforded (R)-89. Bioassay of our synthetic 89 and 89 by Dr. Tumlinson proved (7 )-89 as the bioactive pheromone component, and (.S )-89 was biologically inactive. 

FAB-MS and ESI-MS have proved to be useful in the direct detection of intermediates formed in a number of solution reactions. As such, these techniques nicely complement P NMR studies on the same systems. For example, the iodine-induced cyclization reaction of the unsaturated phosphoamidate 51a, phosphonates 51b and c and phosphate 51d (illustrated in Scheme 7) was monitored by removing aliquots of the reaction mixture and analysing them via FAB-MS"". The FAB mass spectra revealed the presence of the reactant 51 (observed as an [M + H] ion), the initial diiodo addition product 52 (observed as an [M + H] ion) and the quasiphosphonium ion 53 (observed as the intact quasiphos-phonium ion) and the iodolactone 54 (observed as an [M + H] ion). 

The bicarbonate (NaHCOs) is a strong enough base to remove the proton from the carboxyic add. Iodine attacks the alkene reversibly to give a mixture of diastereoisomers of the iodonium ion. If the T and Me groups are on the same side of the chain, the carboxylate group can attack the iodonium ion from the back and set up a tram iodolactone. The iodolactone is cleaved by methoxide and the oxyanion displaces iodide to give the epoxide. 

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... 

The aldol reaction with the lactate derivative was applied to the synthesis of citreoviral 78 (Scheme 8.12). The enolate of 72 was reacted with unsaturated aldehyde 73 to yield a,(3-dihydroxy-7,8-unsaturated imide 74 in a stereoselective manner. Adduct 74 was subjected to iodolactonization to accompany the removal of the chiral auxiliary to give 75 as a single isomer. Debenzylation was followed by etherification with the tertiary alcohol to provide the highly substituted furan 77 having all the chiral centers of the target molecule. The additional four-step sequence afforded citreoviral 78. 

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