Iodolactones allylation

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 the allylic carbonate 143 has been found to proceed with high stereo- and regio-selectivity to produce iodocarbonate 144. Steering by Ph (i.e. the primary coordination of the electrophile to Ph) has been suggested to account for this result231. 

The heading substitution reactions has been used to describe the conversion of a stereogenic center to another. Of course, this means that the substrate stereogenic center has had to be obtained by one of the reaction types outlined earlier, from the chiral pool, or by resolution. Reactions that fall into this category include epoxide and cyclic sulfate openings and iodolactonizations (Chapter 22). Perhaps the most important reaction of this type for asymmetric synthesis is allylic substitution in the presence of a transition metal catalyst. 

Other Enantioselective Transformations Mediated by Ti-TADDOLates. The iodolactonization of 2-allyl-2-hydroxy-4-pentenoic acid shown in eq 8 gives (21) in a 67% yield (after cyclization of some iodo isopropyl ester formed as a side product), the iodolactone is a single (—)-diastereoisomer with a 5 1 (S,S)I(R,R) ratio. The TADDOLate generated in situ was employed in stoichiometric amount. The two enantiomers of 2-pyridyl 2-phenylthiobutyrate react with a rate difference of 39 1 with excess isopropanol in the presence of 0.1 equiv of a Ti-TADDOLate under the conditions specified in eq 9. This leads to the isopropyl ester (22) containing 96% of the (/ )-enantiomer... 

The formation of a quaternary carbon center by the radical-mediated allylation of an a-iodolactone was examined for substrate 341 by Murakata, Jono, and Hos-hino [71]. Lewis acids for this reaction were prepared from a bis-sulfonamide and tri-methylaluminum in dichloromethane. Other aluminum compounds were employed in the preparation of the catalyst but all resulted in similar or lower asymmetric induction. The Lewis acid was complexed with the lactone and then the allylation procedure in Sch. 44 was performed. It was found that superior asymmetric induction could be achieved if the Lewis acid was prepared from the ligand with two equivalents of trimethylaluminum. It was also interesting that some turnover could be achieved, as indicated by the data obtained from use of 50 mol % catalyst. 

Radical reactions are also valuable strategies for the formation of quaternary carbon centers. An enantioselective variant of this has recently come to light utilizing aluminum as a Lewis acid complexed to a chiral binol ligand (103) in the allylation of -iodolactones 101 (Eq. (13.31), Table 13-6) [43]. It was established that diethyl ether as an additive in these reactions dramatically increases product enantioselectivities (compare entries 1 and 2, Table 13-6). Catalytic reactions were also demonstrated (entry 3) with no appreciable loss of selectivity. A proposed model for how diethyl ether functions to enhance selectivity in the enantioselective formation of these quaternary chiral centers is shown in 104. 

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... 

Asymmetric iodolactonization on solid support was carried out using a C2-sym-metric chiral auxiliary 35 [13, 22], The prolinol derived precursor was allylated, followed by treatment with iodine and H 20. The resulting lactone (36) was obtained with exclusive trans selectivity and 87% ee (Scheme 12.16). 

In comparison, the iodolactonization of 49 proceeds with very high diastereos-electivity and a 95 5 mixture of the products 50 and 51 is obtained [27, 28]. The diastereoselectivity is tightly controlled by A(1,3) strain between the methyl group on the terminal olefinic carbon and the other methyl group on the allylic carbon so much so that it allows the reaction to proceed primarily through the transition state 50a. 

Radical reactions are also valuable strategies for the formation of quaternary carbon-based centers. An enantioselective variant of this has recently come to light utilizing aluminum as a Lewis acid complexed to chiral BINOL ligand 26 in the allylation of a-iodolactones 24 (Eq. 9, Table 1) [13]. 

Figure 11.2 (a) The mechanism of the iodolactonization of diastereomeric allylic fluorides via the most stable rotamers of the l -alkene x-complexes. (b) definition for the inside, outside, and anti positions and relative energies for the corresponding rotamers of fluoromethyl-substituted iodonium ion. 

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... 

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... 

On the other hand, a-iodolactone was found as a nice substrate to realize the practical enantioselectivity [205]. In the presence of stoichiometric amount of chiral Lewis acid prepared by the 1 1 reaction of (S,S)-(157a) and Me3Al, the quaternary carbon formation through radical allylation with allyltributyltin resulted in the... 

The Keck radical allylation is a representative example of a radical fragmentation reaction employing the reagent allyltributyltin in the allylation process. " The first synthesis of the Stemona alkaloid stenine by Hart in 1990 established an iodolactonization/Keck allylation (93 —> 94) sequence (Scheme 25.44) as a solution to the problem of stereoselective ethyl group installation. ... 

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