Allylic enantiospecificity

The carbanions of 1-alkenyl sulphoxides 400 also react with carbonyl compounds to give the corresponding condensation products384 (equation 237). Solladie and Moine have used this type of reaction in their enantiospecific synthesis of the chroman ring of a-tocopherol 401. Addition of the lithio reagent 402 to the aldehyde 403 affords the allylic alcohol 404 in 75% yield as a sole diastereoisomer481 (equation 238). 

Diastereoselective syntheses of dihydrobenzo[f>]furans have been accomplished by a rhodium-catalyzed regioselective and enantiospecific intermolecular allylic etherification of o-iodophenols as a key step, providing the corresponding aryl ally ether 122, which leads to a dihydrobenzo[b]furan by treatment of the intermediate aryl iodide with tris(trimethylsilyl)silane and triethylborane at room temperature in the presence of air <00JA5012>. 

Tab. 10.1 Regioselective and enantiospecific rhodium-catalyzed allylic alkylation of enantiomerically enriched allylic carbonates.

In light of these significant challenges, Evans and Leahy reexamined the rhodium-catalyzed allylic alkylation using copper(I) enolates, which should be softer and less basic nucleophiles [23]. The copper(I) enolates were expected to circumvent the problems typically associated with enolate nucleophiles in metal-allyl chemistry, namely ehmina-tion of the metal-aUyl intermediate and polyalkylation as well as poor regio- and stereocontrol. Hence, the transmetallation of the lithium enolate derived from acetophenone with a copper(I) hahde salt affords the requisite copper] I) enolate, which permits the efficient regio- and enantiospecific rhodium-catalyzed allylic alkylation reaction of a variety of unsymmetrical acychc alcohol derivatives (Tab. 10.3). 

Scheme 10.8 outlines the application of rhodium-catalyzed allyhc amination to the preparation of (il)-homophenylalanine (J )-38, a component of numerous biologically active agents [36]. The enantiospecific rhodium-catalyzed allylic amination of (l )-35 with the lithium anion of N-benzyl-2-nitrobenzenesulfonamide furmshed aUylamine (R)-36 in 87% yield (2° 1° = 55 1 >99% cee) [37]. The N-2-nitrobenzenesulfonamide was employed to facilitate its removal under mild reaction conditions. Hence, oxidative cleavage of the alkene (R)-36 followed by deprotection furnished the amino ester R)-37 [37, 38]. Hydrogenation of the hydrochloride salt of (l )-37 followed by acid-catalyzed hydrolysis of the ester afforded (i )-homophenylalanine (R)-3S in 97% overall yield. 

Examination of the stereospecificity of the etherification indicated that the reaction was subject to a dramatic halide effect (Tab. 10.9). Treatment of enantiomerically enriched allylic carbonate (R)-53 (94% ee) under optimized conditions furnished the allyl ether (R)-54 in 84% yield (2° 1° >99 1), although with poor enantiospecificity (41% cee ... 

The synthesis in Scheme 13.40 uses stereospecific ring opening of the epoxide to establish the stereochemistry of the C-4 methyl group. The starting material can be made by enantiospecific epoxidation of the corresponding allylic alcohol.137... 

Johnson and co-workers (92) have recently reported the cyclization of the D-allylic alcohol 242 (optical purity of 91%). When the substrate 242 was treated with trifluoroacetic acid in 1,1-difluoroethane containing ethylene carbonate, a 65% yield of a- -5b-pregnen-20-one (243) was obtained with an optical purity of 91%. In a similar fashion, the enantiomer of 242 gave the enantiomer of 243 with an optical purity of 92%. Very little racemiza-tion has occurred and the cyclization step is essentially enantiospecific. Again, the A/B ring junction is cis and the process involves essentially total asymmetric synthesis due to the C-6 chiral center in 242. 

The regioselective and enantiospecific allylic substitution of alkyl-substituted allyl benzoates and carbamates with (Me2PhSi)2Zn and Cul has been shown to occur by an oxidative addition - reduction elimination mechanism rather than an SN2 mechanism.16... 

An enantiospecific synthesis of negstatin I (52) was accomplished efficiently with a sequence involving two C-imidazolide anion transformations. The first was coupling of a suitably protected carbohydrate intermediate with N-tritylimidazole. Direct monobromination of imidazole (51a, X = Y = H) was not feasible, except by selective halogen-metal exchange and reprotonation of dibromo intermediate (51b, X = Y = Br) [95TL6721], Introduction of the pendant acetic acid function was accomplished by C-allylation of 51c. 

R,5,S)-l-Allyl-2,5-dimethylpiperazine has been prepared by direct enantiospecific synthesis [29,39] and via classical resolution of the racemic piperazine [23,29]. Kilo-scale batches of (-)-(2R,55)-l-allyl-2,5-dimethylpi-perazine have been prepared from tra s-2,5-dimethylpiperazine by the three-step monoallylation shown in Scheme 5, followed by a resolution using di-p-toluoyl-D-tartaric acid. This resolution has also been achieved in a two-stage process using (—)-camphoric acid followed by di-p-toluoyl-D-tartaric acid, giving (—)-(22 ,5S)-l-allyl-2,5-dimethylpiperazine in >99% optical purity. 

Enantiospecific syntheses have utilized the chirality available in D-alanine and L-alanine. For instance, coupling and cyclization (after the necessary deprotection) of N-allyl-N-BOC-D-alanine with L-alanine methyl ester, followed by lithium aluminum hydride reduction of the diketopiperazine provided (—)-(2R,5S)-l-allyl-2,5-dimethylpiperazine (Scheme 6) [27,39], Ra-cemization was not observed during the synthesis. 

In a more impressive polyene cyclization, reaction of the optically active allylic alcohol 147 with trifluoroacetic acid and ethylene carbonate followed by workup with K2CO3 in aqueous methanol furnished the optically active product 150. The reaction is initiated by a yyn-selective SN2 reaction with allylic rearrangement (Sn2 ) and proceeds through the carbonate-trapped intermediate 149. Likewise, the reaction of the enantiomer of 147 furnished the enantiomer of 150. The cyclization step was essentially enantiospecific. The process involves total asymmetric synthesis due to a single chiral center in the starting allyl alcohol [24]. 

Sequential Rh-catalysed etherification of the allylic carbonate using the Cu(I) alkoxide derived from the enantiomers of the alkenyl alcohols followed by a RCM occur with excellent regio- and enantiospecificity and lead to cis- and traws-disubstituted dihydropyrans <04AG(E)4788>. 

Oxidative unmasking, enantiospecific reduction" of the enone (55), and stereoselective cix-hydroxylation on the allylic acetates (56a and 56b) paved the way for the first report on the synthesis of the spiro-C-linked disaccharides (57a and 57b). Extension of the same strategy to the uloses derived from d- and L-arabinose expectedly offered the enantiomeric spiro-C-linked disaccharides (58a and 58b and 59a and 59b, respectively Scheme 22.13). 

The enantiospecific synthesis of anhydromacrosalhine-methine (344) commenced with the tetracyclic ketone 343 which was converted into alstonerine (347) as described previously (227). Reduction of alstonerine, followed by dehydration of the resultant allylic alcohol, provided (—)-anhydromacrosalhine-methine (344), identical with material prepared from natural (+ )-ajmaline (Scheme 25) 228,230). In the context of a synthesis of talpinine and talcarpine, an improved synthesis of (—)-anhydromacrosalhine-methine was also achieved from improved routes to the tetracyclic ketones 348 and the enol ether 349, key intermediates in the talpinine/talcarpine synthesis (233). 

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