Iodolactonization alcohols

Birch reduction-alkylation of 5 with 2-bromoethyl acetate was carried out with complete facial selectivity to give 57. This tetrafunctional intermediate was converted to the bicyclic iodolactone 58 ( > 99% ee) from which the radical cyclization substrate 59 was prepared. The key radical cyclization occurred with complete regio- and facial-selectivity and subsequent stereoselective reduction of the resulting tertiary radical gave 60 with the required trans BC ring fusion.The allylic alcohol rmit of (+)-lycorine was obtained by a photochemical radical decarboxylation, 62 63. 

Iodolactonization of y, o-unsaturated alcohols results in preferential formation of tram-2, 5-disubstituted tetrahydrofuranes. However, the corresponding benzyl ethers cyclize preferentially to the cis-isomers. The alkyl group must be bulky enough to exert a steric effect, but not to prevent cyclization. Substituted benzyl ethers are particularly useful. Examples of this steric control are illustrated for the preparation of tram- and c/s-linalyl oxide (equations I and II).10... 

Pancratistatln. The first total synthesis of ( )-pancratistatin (94) (Scheme 14), the structurally most complex of narciclasine alkaloids, was achieved by Danishefsky [27]. The requisite starting material, the substituted benzaldehyde 95 prepared from pyrogallol in six steps in 18% overall yield, was converted via the homoallylic alcohol 96 into the diene 97. Reaction of 97 with 2-nitrovinylsulphone yielded the cycloadduct 98, which on treatment with tributyltinhydride and 2,2 -azobisisobutyronitrile furnished the cyclohexadiene 99. Whilst the cyclisation of the silylether 99 or the derived phenol, under the influence of iodine, could not be accomplished, the more nucleophilic stannylether did participate in the desired ring closure and provided via the iminium salt, the iodolactone 100 on aqueous work-up. 

There are also several reports of enantioselective transesterification involving primary alcohols possessing stereogenic centers by similar acylation procedures, such as 2,3-epoxy alcohols (eq 7), norbomene-derived iodolactones, and 1,3-propanediols. ... 

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],... 

The remaining segment, C-3 to C-8, was constructed by a similar route. Optically active allylic alcohol 229, produced from lithio ethylacetate and methacrolein followed by a second Sharpless kinetic resolution, was hydrolized to the corresponding hydroxy acid. Neutralization followed by iodolactonization then gave 230 in 85% yield. This highly stereoselective cyclization produced a cis-trans ratio of 20 1 via a one-pot procedure. Deprotonation and methylation afforded the expected anti a-methyl compound, contaminated with about 10% of the syn compound but none of the methyl ether. Formation of the silyl ether then produced 231 in 66% yield. Dibal reduction to the aldehyde concomitant... 

Yet another synthesis of the aldehydo-acid 430 by Takano s group (277) constitutes a further formal synthesis of ( )-quebrachamine. Here, butyro-nitrile was bisalkylated by allyl bromide, and the product converted into the iodolactone 441 by reaction with iodine in mild aqueous alkali. Hydrolysis then gave the corresponding alcohol, which on further hydrolysis and... 

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. 

Marshall JA, Yanik MM (1999) Synthesis of nonracemic p-hydroxy ketones and carbonate derivatives from homopropargylic alcohols through iodolactonization. J Org Chem 64 3798-3799... 

Alternatively reaction of an olefinic alcohol or acid can furnish a dimer through interaction of the bromonium ion with a second molecule of reactant acting as nucleophile. Methoxy bromo adducts are easily made by reaction of the alkene with t-butoxy bromide in methanol solution. Another interesting reaction of this kind is the selective iodination of arachidonic acid and docosahexaenoic acid by iodine and hydrogen peroxide in the presence of lactoperoxidase to give iodolactones. 

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). ... 

A special type of iodolactonization is the iodocarbonate cydization of homoallylic alcohols 927 [663]. Iodocarbonate cydization is an efficient and moderately erythro-stereoselective method for the functionalization of homoallylic alcohols with relative 1,3-asymmetric induction. 

An iodolactonization reaction of the iodocarbonate cyclizationtyTpe [670], as described in the last example of Section 4.3.3.5, has been performed with homopropargylic alcohols 944 and B0C2O, to afford non-racemic j8-hydroxy ketones 947 [671]. The ferf-butyloxycarbonylation reaction with B0C2O furnishes 945 in 98% yield. 

Scheme 3 shows the flexibility of this approach in more detail. Possible electrophiles for addition to metalated intermediate 4 include iodine to give the halogenated aromatic ring 6, Weinreb amides (e.g., 9) to access the aromatic ketone 10, DMF to give aldehyde 11, or various aldehydes, e.g., 8, 12, 15, or 16, to give differently substituted benzylic alcohols, e.g., 7, 13, 14, and 17, with diverse additional functional handles for further homologation. All these products may be readily further elaborated. Possible transformations include reductions, iodolactonizations, aldol reactions, allylation, epoxidation, or direct lactonization reactions. 

Ganem has described a novel allylic alcohol to haloepoxide transformation (26) (28) using t-butylhypochlorite as the oxidant. This is the first known case where anchimeric participation by the hydroxyhalonium ion, as in (27), is invoked. The reaction, which has an analogy with iodolactonization, is susceptible to conformational and stereochemical requirements, since the octalin (29) gave a low yield of (30). Mild conditions for the preparation of (mostly steroidal) oxirans... 

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). 

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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