Bromide, epoxide opening

The industrial production of Crixivan (9 H2S04) took advantage of the chirality of (IS,2R)-aminoindanol to set the two central chiral centers of 9 by an efficient diastereoselective alkylation-epoxidation sequence.17 The lithium enolate of 12 reacted with allyl bromide to give 13 in 94% yield and 96 4 diastereoselective ratio. Treatment of a mixture of olefin 13 and V-chlorosuccinimide in isopropyl acetate-aqueous sodium carbonate with an aqueous solution of sodium iodide led to the desired iodohydrin in 92% yield and 97 3 diastereoselectivity. The resulting compound was converted to the epoxide 14 in quantitative yield. Epoxide opening with piperazine 15 in refluxing methanol followed by Boc-removal gave 16 in 94% yield. Finally, treatment of piperazine derivative 16 with 3-picolyl chloride in sulfuric acid afforded Indinavir sulfate in 75% yield from epoxide 14 and 56% yield for the overall process (Scheme 24.1).17-22... 

Epoxides 159 were converted to allylic alcohols 161 in high yields in acetonitrile in a one-pot procedure. The reaction involved triphenylphos-phine-catalyzed epoxide opening with trimethylsilyl bromide, followed by elimination of the trimethylsilyl bromohydrin from 160 with DBU at reflux temperature (84JA7854). 

A synthesis of cyclopropanols exploiting C-C bond cleavage has been reported with a-halo epoxides as starting materials (Scheme 16). The diradical formed by reduction of the bromide and by direct epoxide opening via electron transfer (see below) has been postulated as the crucial intermediate [30]. 

Cleavage of Epoxides. Epoxide opening with TMS-Br occurs to provide the primary alkyl bromide at —60 °C (eq 7). ... 

A phase-transfer catalyst such as tetra-n-butyl ammonium bromide has been used to chemoselectively epoxidize 1,4-units rather than 1,2-units in PBD [127] or HTPB [128] in a biphasic system. The degree of conversion accessible with peracids was up to 90% before the epoxidation of 1,2-vinyl groups was possible. Side reactions such as epoxide opening or oxidatimi of terminal hydroxyl groups have not been observed [128]. Modified clays (e.g., Closite 30B, a montmorillonite modified with ammonium salts) were also found to be favorable for epoxidation of cis-l,4-PBD because no phase-transfer agents need to be separated and phase transfer was not the rate-determining step [129,130]. 

Medroxyprogesterone acetate (74) is stmcturaHy related to and has been prepared from hydroxyprogesterone (39) (Fig. 10). Formation of the bis-ketal accomplishes the protection of the ketones and the required migration of the double bond. Epoxidation with peracetic acid produces a mixture of epoxides (75), with a predominating. Treatment of the a-epoxide with methyl magnesium bromide results in diaxial opening of the epoxide. Deprotection of the ketones provides (76), which is dehydrated to (77) by treatment with dilute sodium hydroxide in pyridine. Upon treatment with gaseous hydrochloric... 

Alkylation of orgatiomatigatiese reagaits witli alkyl bromides can also be improved by adrlition of CuCl f3 mol96). Hie reactions proceed at room temperature and are complete witliin a few bouts [123, 130], Hie opening of epoxides is also improved under tliese conditions. Hie reaction also features good clienioselectivity, tolerating tlie presence of sensitive functions sucli as ketones t Sclieme 2.59) [130]. 

A synthetically useful diastereoselectivity (90% dc) was observed with the addition of methyl-magnesium bromide to a-epoxy aldehyde 25 in the presence of titanium(IV) chloride60. After treatment of the crude product with sodium hydride, the yy -epoxy alcohol 26 was obtained in 40% yield. The yyn-product corresponds to a chelation-controlled attack of 25 by the nucleophile. Isolation of compound 28, however, reveals that the addition reaction proceeds via a regioselective ring-opening of the epoxide, which affords the titanium-complexed chloro-hydrin 27. Chelation-controlled attack of 27 by the nucleophile leads to the -syn-diastereomer 28, which is converted to the epoxy alcohol 26 by treatment with sodium hydride. 

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