Reactions iodolactonization

Keywords A(1,2) strain A(1,3) strain Enamine Epimerization [2,3] and [3,3] sigmatropic shifts Intramolecular SN2 reaction Iodolactonization Hydroboration Conjugate addition 1,3-oxazolidinones Diastereoselectivity... 

Because the Corey synthesis has been extensively used in prostaglandin research, improvements on the various steps in the procedure have been made. These variations include improved procedures for the preparation of norbomenone (24), alternative methods for the resolution of acid (26), stereoselective preparations of (26), improved procedures for the deiodination of iodolactone (27), alternative methods for the synthesis of Corey aldehyde (29) or its equivalent, and improved procedures for the stereoselective reduction of enone (30) (108—168). For example, a catalytic enantioselective Diels-Alder reaction has been used in a highly efficient synthesis of key intermediate (24) in 92% ee (169). 

Intermediate 8, the projected electrophile in a coupling reaction with intermediate 7, could conceivably be derived from iodolactone 16. In the synthetic direction, cleavage of the acetonide protecting group in 16 with concomitant intramolecular etherification could result in the formation of the functionalized tetrahydrofuran ring of... 

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. 

In contrast, the reaction of 147 with 1, in the absence of catalyst, affords traces of adduct after 3 days. The activation by I2 is due to the formation of cationic iodolactonization intermediate 148 (Scheme 4.28) which reacts easily with the diene, affording the dihydrooxazole 149 which is then treated with Bu N to give the final adduct. With some substrates, this method of activation was proved to be more effective than the use of Lewis acids. 

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... 

On page 313, the effect of methyl substitution on the stereoselectivity of a,a-diallylcarboxylic acids under iodolactonization conditions was discussed. Consider the two compounds shown and construct a reaction energy profile for... 

SCHEME 2. The stereoselective Diels-Alder reaction leading to an important iodolactone prosta-glandine precursor... 

Lewis acid catalysis is not limited to cases in which increased yields or enhanced selectivities are desired. Lewis acids offer also the possibility to induce chiral information leading to enantioselective product formation. The enantioselective induction by chiral Lewis acids found widespread application in organic synthesis, especially in the synthesis of natural products with many chiral centres. An enantioselective Diels-Alder reaction is the key step in the synthesis of an iodolactone prostaglandine precursor (Scheme 6).88... 

Typical procedure A solution of 4-pentenoic acid (0.0500 g, 0.500 mmol), bis(p-chlorophenyl)tellurium diiodide (0.302 g, 0.500 mmol) and pyridine (0.040 g, 0.500 mmol) was heated at reflux in 20 mL of chloroform for 5 days. The reaction mixture was concentrated in vacuo, and the residue was purified via chromatography on silica gel eluted with 1 1 hexane/ethyl acetate to give 0.073 g (66%) of the iodolactone and 0.140 mg (80%) of diaryl telluride. 

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). 

Reaction of the unsaturated acid A and I2 in acetonitrile (no base) gives rise in 89% yield to a 20 1 mixture of two stereoisomeric iodolactones. Formulate the complete stereochemistry of both the major and the minor product to be expected under these conditions. 

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). 

The solution is allowed to cool, and 19.7 g (0.35 mol) of potassium hydroxide 1n 25 mL of water and 75 mL of methanol is added. The mixture is heated under reflux for 1 hr under nitrogen. After the alkaline solution is allowed to cool to room temperature, It is washed with ether and acidified with coned HC1. The acidic solution is extracted with three 50-mL portions of ether, and the organic layer is dried over MgS04, filtered, and concentrated under reduced pressure. The yield of crude 3-phenyl-4-pentenoic acid is 38-39 g (86-88%). This material is essentially pure by NNR analysis and can be used directly as starting material for the following iodolactonization reactions. The acid can be further purified by crystallization from hexane (86% recovery in two crops) to give product melting at 44-46°C. 

Iodolactonization has become a useful reaction for the stereocontrol led introduction of chiral centers in both cyclic and acyclic3" systems. Depending upon the reaction conditions, the cyclizatlon can be carried out... 

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). 

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