STORK Reductive cyclization

Reductive cyclization of y-ethynyl ketones to allylic alcohols. This reaction was first reported by Stork et al., who used an alkali metal and liquid ammonia.1 The main by-products, at least in cyclization to A-norsteroids, result from overreduction. This side reaction can be prevented by use of sodium naphthalenide in THF or DME.2... 

Barton and coworkers used free radical cyclization in the synthesis of tetracyclines (Scheme 105). Photolysis of 254 (X,Y = SR or OR) gives the corresponding radical, which cyclizes to the (Cy6) compound 255 in 80% yield when X,Y = SCH2CH2O. Quite remarkably, 255 is formed only in the cis form. Another completely stereoselective reaction toward the cis compound involving intramolecular addition to an acetylenic bond has been described by Pradhan and was discussed in Section IX.2 (Scheme 70). An analogous reductive cyclization (K, NH3) of ethynyl ketones has been used by Stork in the construction of a tricyclic intermediate for the synthesis of gibberellic acid. ... 

An efficient synthesis of ( )-yohimbine has been published by Stork and Guthikonda (222). Reaction of the pyrrolidine enamine of A-methylpiperidone with methyl 3-oxo-4-pentenoate gave 411 in good yield. Reduction of 411 with lithium in liquid ammonia furnished trans-TV-methyldecahydroisoquinolone 412. This building block was transformed in simple reaction steps to secoyohimbane 413 from which ( )-yohimbine could be obtained by oxidative cyclization with... 

Skrydstrup, Beau and co-workers122 have adapted Stork s method to the SmI2-reduction of glycosyl pyridyl sulfones bearing a silicon-tethered unsaturated group at HO-C(2). An example is shown with the synthesis of methyl a-C-zso-maltoside 172 from alkyne 170 via the 5-exo-dig radical cyclization of 171 (Scheme 56).144... 

G. Stork and M. J. Sofia, Stereospecific reductive methylation via a radical cyclization-desilylation process, J. Am. Chem. Soc. 708 6826 (1986). 

The 4-(chloromethyl)isoxazole 13, which is readily accessible from 3,5-dimethyloxazole, serves as a C4-building-block in annulations to cycloalkanones (isoxazole annelation according to Stork). The primary step is alkylation leading to product 14, a masked triketone. On hydrogenation, the isoxazole ring is reductively opened and cyclization via the enaminone 15 leads to the enamine 16. On treatment with sodium hydroxide, this is converted into the bicycloenone 17 by hydrolysis, acid fission of the y dicarbonyl system and an intramolecular aldol condensation (analogous to a Robinson annu-lation) ... 

Stork s methodology was employed by Fukumoto and co-workers in the enantioselective construction of the steroidal skeletons of (+)-cortisone and (+)-l l-deoxy-19-norcorticosterone, which contain nearly identical A, B, and C rings to ( )-adrenosterone (50). The dione 51 underwent reductive alkylation followed by hydrolysis and base-catalyzed cyclization to afford the tetracyclic compound 52, which contains the skeleton of (+)-coritsone. A similar protocol was followed in the construction of the core of (+)-ll-deoxy-19-norcorticosterone. 

Fukumoto and co-workers also used the Wichterle sequence to construct the A-ring in their total synthesis of 19-norcanrenone (55), constituting a formal total synthesis of the spiro steroid 19-norspironolactone. The enone 53 was reductively alkylated using the method developed by Stork to afford the enone 54 following a Pd-mediated dehydrogenation. Jones oxidation of 54 followed by hydrolysis and cyclization provides the pentacyclic diketone 55 in 22% overall yield over 5 steps. 

Wharton, P. S. Bohlen, D. H. Hydrazine Reduction of Epoxy Ketones to Allylic Alcohols /. Or. Chem. 1961, 26, 3615-3616. For a mechanistic study see Stork, G. Williard, P. G. Five- and Six-Membered-Ring Formation from Olefinic a,j8-Epoxy Ketones and Hydrazine /. Am. Chem. Soe. 1977, 99, 7067-7068. For a recent appUcation of the Wharton rearrangement see Liu, J. Hsung, R. P. Peters, S. D. Total Syntheses of (+)-Cylindricines C-E and (-)-Lepadiformine through a Common Intermediate Derived from an z -Prins Cyclization and Wharton s Rearrangement Oi. Lett. 2004, 6, 3989-3992. 

Stork and Livingston have also employed a Michael reaction methodology in a concise synthesis of alloyohimbone 247 (Scheme 3.37). In this sequence, the Schilf base 243, prepared from tryptamine and 4-methoxybenzaldehyde, underwent sequential Birch reduction and acylation to afford the cyclo-hexadiene 244. Hydrolysis provided the corresponding a, ) -unsaturated ketone. Under basic conditions, the key Michael addition took place to yield the cis-fused bicyclic lactam 245. Decarboxylation and ketalization afforded 246 which underwent Bischler-Napieralski cyclization and subsequent deke-talization to afford alloyohimbone 247. All in all. Stork has shown that Michael addition methodologies can be successfully employed to construct the pentacyclic yohimbine alkaloid skeleton in an eflBcient stereoselective manner. 

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