Epoxide Reductive cyclization

The formation of THF derivatives through SH2 reaction with mono- and disubstituted olefins was also investigated to define the overall scope of the transformation. Some of our results are summarized in Table 8. Not surprisingly, the monosubstituted alkene 53 gave essentially none of the desired 54 (5%). It is well known that the primary radicals produced during the 5-exo cyclization are rapidly trapped by Cp2TiCl to yield the products of a reductive cyclization [17-20,65,66,73,74]. Epoxides containing disubstituted... 

Cyclic enol ethers such as 8 are also easily epoxidized. R. Daniel Little of the University of California, Santa Barbara has found (J. Org. Chem. 2005, 70, 5249) that such an epoxide is reduced with Tifffl) regioselectively to the radical, that adds with remarkable diastereocontrol to enones such as 7 to give the adduct 9. Reductive cyclization converted 9 to the tricyclic ether 10. The C-Br bond of 10 was stable both to the Et,SiH conditions, and to the free radical removal of the xanthate derived from the alcohol. 

Since the introduction of the titanocene chloride dimer 67a to radical chemistry, much attention has been paid to render these reactions catalytic. This field was reviewed especially thoroughly for epoxides as substrates [123, 124, 142-145] so only catalyzed reactions using non-epoxide precursors and a few very recent examples of titanium-catalyzed epoxide-based cyclization reactions, which illustrate the principle, will be discussed here. A very useful feature of these reactions is that their rate constants were determined very recently [146], The reductive catalytic radical generation using 67a is not limited to epoxides. Oxetanes can also act as suitable precursors as demonstrated by pinacol couplings and reductive dimerizations [147]. Moreover, 5 mol% of 67a can serve as a catalyst for the 1,4-reduction of a, p-un saturated carbonyl compounds to ketones using zinc in the presence of triethylamine hydrochloride to regenerate the catalyst [148]. 

The reductive cyclization of epoxides with alkenes and alkynes provides a very useful method for the synthesis of complex carbocyclic ring systems. Several interesting applications of this methodology have been reported in the past year. Two examples report the cyclization of an epoxide with an acrylate as the terminating group <07T 11341 ... 

Most of the reductive cyclizations of epoxides use Ti(III) species to reduce the epoxide and generate the reactive radical species. Nickel can also be used to effect this type of reductive cyclization <07JOC7451>. The reaction of epoxide 35 with Ni(cod)2 provides pumiliotoxin 209F in good yield. 

Synthesis of P-Keto Sulfoxides. Optically active p-keto sulfoxides are very useful building blocks (eq 4) because they can be stereoselectively reduced to afford either diastereomer of the corresponding p-hydroxy sulfoxide under appropriate conditions (Diisobutylaluminum Hydride or Zinc ChloridefDlBALf and thus give access to a wide variety of compounds chiral carbinols by desulfurization with Raney Nickel or LithiumJethyhmme ini the case of allylic alcohols epoxides via cyclization of the derived sulfonium salt butenolides by alkylation of the hydroxy sulfoxide 1,2-diols via a Pummerer rearrangement followed by reduction of the intermediate. ... 

Nickel-catalyzed reductive cyclizations and couplings in the syntheses of heterocycles including coupling of alkynes with epoxides and syntheses of indole and indolizidine alkaloids 04AG(E)3890. 

Reductive cyclization. Epoxides substituted with a carbon chain terminated (at a proper length) in an allenyl group are converted into cyclic products containing vicinal hydroxymethyl and vinyl substituents. 

With internal nucleophilic ring-opening, cyclization may occur thus the epox-idation of (125) by 3-CIC6H4CO3H produces an epoxide which cyclizes and, after oxidation in situ, gives (126). Reduction of (127 R = H or Me, R = H or OMe, R = H or OMe) with LiAlH4 and AICI3 (1 7) leads, via cyclization, to... 

Scheme 1.4 Epoxide opening/reductive cyclization cascade.

The former synthesis proceeds via epoxide 278 which was ring opened by azide, the resulting alcohol was protected and full reduction of the lactone and mesylation gave 279. Reductive cyclization and deprotection then provided 280 (Scheme 23). The 6-epi analogue 111 was prepared by converting 275 to pyrrolidine 276. Selective acetal removal and primary hydroxyl mesylation then allowed reductive cyclization followed by deprotection to give 277. Similar chemistry was also used to convert 281, closely related to 275, to (2R)-2-hydroxy-6-e/ /-castanospermine 282. ... 

Strategic exploitation of the molecular shape of lactone 309 was next utilized to install the desired stereogenicity at all positions on tricychc compound 311, a key intermediate targeted as the substrate for a reductive cyclization cascade. The quaternary center at the lactone a-position was first addressed. Deprotonation with hthium diisopropylamide in THF and addition of 1-cyanobenzotriazole (BtCN) yielded an a-cyanolactone, which was then alkylated from the convex face of the molecule employing ethyl iodide in a mixture of warm acetonitrile and potassium carbonate to furnish lactone 310. The scaffold curvature was then exploited to epoxidize stereoselec-tively the double bond from the convex face to provide oxirane 311 following a Prilezhaev oxidation protocol. 

Researchers at Lexicon Pharmaceuticals found that limonene aziridines could be efficiently prepared from the corresponding limonene oxides using the Blum aziridine synthesis. Epoxide 32 was opened with sodium azide to produce the regioisomeric azido-alcohols 33 and 34 in an approximate 1 1 ratio. The secondary azide was reductively cyclized with triphenylphosphine at ambient temperature, whereas the tertiary azide required heating to effect the same transformation. In this way, the desired aziridines 35 and 36 were prepared in good yield on multigram scale. 

A recent publication described a short enantioselective synthesis of (+)-L-733,060, a selective and potent nonpeptide neurokinin substance P receptor antagonist. The key chirality-inducing step involved a Shi epoxidation of homoallylic carboxylate 89. Subsequent intramolecular reductive cyclization of azidolactone constructed the piperidine ring. 

Richard C. Hartley of the University of Glasgow established Tetrahedron Lett. 2008, 49, 4771) what promises to be a powerful strategy for the convergent assembly of Spiro ketals, based on the condensation of the Ti alkyhdene derived from a thioacetal such as 19 with a lactone such as 18. James A. Marshall of the University of Virgina nicely reduced to practice J. Org. Chem. 2008, 73, 6753) the preparation and reductive cyclization of poly epoxides such as 22. Hiroki Oguri and Hideaki Oikawa of Hokkaido University demonstrated J. Am. Chem. Soc. 2008, 130, 12230) that overexpressed enzyme Lsdl9 converted 24 to lasolacid A 26. With acid, 24 cychzed to 25. 

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