Carboxylic acids iodolactonization

In addition, when we tuned the nucleophilicity of the side chain functionality by converting the alcohols to carboxylic acids, iodolactonization, when it occurred, appeared to be accompanied by the Friedel-Crafts alkylation (Scheme 16). 

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. 

A cursory inspection of key intermediate 8 (see Scheme 1) reveals that it possesses both vicinal and remote stereochemical relationships. To cope with the stereochemical challenge posed by this intermediate and to enhance overall efficiency, a convergent approach featuring the union of optically active intermediates 18 and 19 was adopted. Scheme 5a illustrates the synthesis of intermediate 18. Thus, oxidative cleavage of the trisubstituted olefin of (/ )-citronellic acid benzyl ester (28) with ozone, followed by oxidative workup with Jones reagent, affords a carboxylic acid which can be oxidatively decarboxylated to 29 with lead tetraacetate and copper(n) acetate. Saponification of the benzyl ester in 29 with potassium hydroxide provides an unsaturated carboxylic acid which undergoes smooth conversion to trans iodolactone 30 on treatment with iodine in acetonitrile at -15 °C (89% yield from 29).24 The diastereoselectivity of the thermodynamically controlled iodolacto-nization reaction is approximately 20 1 in favor of the more stable trans iodolactone 30. 

Unsaturated carboxylic acid 17 possesses the requisite structural features for an iodolactonization reaction.16 A source of electrophilic iodine could conceivably engage either diastereoface of the A20,21 double bond in 17. The diastereomeric iodonium ion inter-... 

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. 

Iodine is a very good electrophile for effecting intramolecular nucleophilic addition to alkenes, as exemplified by the iodolactonization reaction71 Reaction of iodine with carboxylic acids having carbon-carbon double bonds placed to permit intramolecular reaction results in formation of iodolactones. The reaction shows a preference for formation of five- over six-membered72 rings and is a stereospecific anti addition when carried out under basic conditions. 

Reactants with internal nucleophiles are also subject to cyclization by electrophilic sulfur reagents, a reaction known as sulfenylcyclization.92 As for iodolactonization, unsaturated carboxylic acids give products that result from anti addition.93... 

Diastereoselective iodolactonization of y, -unsaturated acids.2 Kinetic io-dolactonization of the meso-1,6-heptadien-4-carboxylic acid (1) results in two prod-... 

Iodolactonization of salts of unsaturated carboxylic acids, using potassium iodide, which has been oxidized by sodium persulfate in situ, gives rise to high product yields in very... 

Reaction of the ra-ene-5-yne carboxylic acid 977 with biscollidine iodine(l) hexafluorophosphate leads to exclusive formation of the C(6)-( )-iodovinyl tetrahydropyran-2-one 979. The product arises via attack of the acid onto the iodinium ion intermediate 978 (Scheme 258) <2004TL4503>. A similar iodolactonization of hex-5-enoic acid can be induced by Oxone -potassium iodide to furnish 6-(iodomethyl)tetrahydropyran-2-one in excellent yield (Equation 380) <2004SL368>. Similarly, treatment of 5-hexynoic acid with a polymer bound source of electrophilic iodide affords the tetrahydropyran-2-one 980 bearing a diiodo-substituted exocyclic double bond (Equation 381) <1999OL2101>. 

Intramolecular cohalogenation is a related process which leads to halogenation with cyclization. Recent examples are the polymer supported synthesis of 2,5-disubstituted tetrahydrofuran (equation 54)459 and the iodolactonization of co-unsaturated carboxylic acids (equation 55)460. 

The iodolactonization of 1,6-heptadiene-4-carboxylic acid derivatives23 25 is a reaction capable of differentiating between the two similar double bonds in the substrate and gives significant insight into (S,R) group and facial selectivity. 

The iodolactonization of a n, .vyn-3,5-dimethyl-l,6-heptadiene-4-carboxylic acid (9) under kinetic conditions in dichloromethane, saturated aqueous sodium hydrogen carbonate and iodine results in excellent alkene and facial selectivity. In fact, of the four possible isomeric iodolac-tones only three are isolated in a 96.5 3.1 0.4 ratio, i.c., there is >99 1 group selectivity and 97 3 distereofacial selectivity, as determined by capillary GLC and 300 MHz H-NMR analysis37. 

The iodolactonization of anti,anti-3,5-dimethyl-l,6-heptadiene-4-carboxylic acid (9) is informative for diastereofacial selectivity, in this (anti,anti)-meso form the two alkenes are enan-tiotopic, and the kinetic iodolactonization affords the corresponding lactones in a 93 7 ratio. 

The regioselectivity of the iodolactonization of l,6-hcptadicnc-4-carboxylic acid derivatives24 is strongly affected by electronic factors. In fact, the electronic control, as a consequence of the differential alkene substitution, was proven in the iodolactonization of 2-methyl-l,6-heptadi-ene-4-carboxylic acid and 2-methyl-l,6-octadiene-4-earboxylie acid. The conditions employed play an important role in the selectivity low temperature, tetrahydrofuran as solvent and butyllithium as base strongly increase the trans/cis selectivity in favor of the methallyl moiety. 

To determine which control element is dominant in the kinetic iodolactonization of 1,6-hepta-diene-4-carboxylic acid, both anti- and, sy -3,4-dimethyl-2-(2-propenyl)-4-pentenoic acid were iodolactonized under kinetic conditions. 

The enantioselective iodolactonization of a-hydroxy carboxylic acid derivatives is achieved by using a stoichiometric amount of the chiral titanium reagent (8) (eq 18). ... 

The concept of using an ester auxiliary which also contains a handle suitable for chelation was first disclosed in 1984/1985. Thus TiCU-promoted addition of cyclopentadiene to the acrylate of ethyl (S)-lactate (379) proceeded readily at -63 C to give (with a 39 1 endolexo preference) a 93 7 mixture of norbomenes (381a) and (382a), from which the major product (381a) was isolated by MPLC (Scheme 93, Table 23, entry 1). Mild saponification of adduct (381a) with LiOH in aqueous THF and purification via iodolactonization/elimination provided pure (l/ ,2/ )-5-norbomene-2-carboxylic acid. 

The bicarbonate (NaHC03) is a strong enough base to produce the anion of the carboxylic acid. Iodine attacks the alkene reversibly to give a mixture of diastereoisomers of the iodonium ion. If the and Me groups are on the same side of the chain, the COj group can attack the iodonium ion from the back and set up a trans iodolactone. The iodolactone is cleaved by methoxide and the oxyanion displaces iodide to give the epoxide. 

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. 

Intramolecular cyclization is a useful method for the preparation of lactones and cyclic ethers [34], The most common examples are iodolactonization and iodoetherification, the former using a carboxylic acid derivative as the nucleophile and the latter relying on a hydroxy group. Thus, butyrolactones are available from Y, -unsaturated carboxylic acid derivatives [1,35,36], while unsaturated alcohols lead to cyclic ethers [37-40], Lactones are also available from a wide variety of nucleophiles such as carbonates [41], orthoesters [42], or carbamates [43,44], which can all be used in place of a carboxylate anion [44,45],... 

Bicyclo[2.2.1]hept-5-ene-2-e rfo-carboxylic acid is especially well suited to the iodolactonization reaction, which has been used for the determination of the optical purity of stereoselective steps leading to the bicyclic system166. This application demonstrates the confidence in the stereoselectivity of the halolactonization reaction. 

Explanation. The HI liberated from NaOH/l2 is added onto the prevailing double bond of cyclohexen-3-ene carboxylic acid (I), thereby affording an intramolecular addition, usually termed as iodolactonization. 

Although the iodolactonization of norborn-5-en-2-en o-ylacetic acid proceeds analogously to that of norborn-5-en-2-endo-carboxylic acid except that a 6-lactone, of course, is formed, the next higher homologue, 3-(norborn-5-en-2-endo-yl)propionic acid, does not conform to this pattern, and instead the rearrangement product (411) is obtained mechanisms are discussed. The cyclic acetals (412 n = 1 or 2) are formed on reaction of the enwith sodium ethoxide in ethanol by way of the intermediates (415) and (413). ... 

---