Ring-expanded analogs

Two approaches that have been validated for HIV inhibitors, nucleoside 5 -phosphonates [48] and 1,3-dioxolane analogs [49] have proven unsuccessful when applied to HCV inhibitors. Phosphonodiphosphates have been synthesized and are incorporated by NS5B RdRp, but Vmax/Km for these chain terminators is 10-100-fold less than for ATP, and potency must be greatly improved for analogs of this type to have utility [50]. A small series of 1,3-dioxolanes also failed to afford active inhibitors of HCV, or HIV, despite the addition of a 5-methyl substituent to impose the desired conformational preference [51]. Ring expanded nucleobases [52,53] and AICAR analogs have also been synthesized as HCV inhibitors which provide only weak replicon activity [54]. 

Indoles with dibromocarbene are ring-expanded to 3-bromoquinolines (162) and benzofurans behave analogously (Section 3.3.1.7.1). Isatins (163) with CH2N2 form 3-hydroxy-2-quinolones (164). 

The reaction of a cyclic sulfonium ylide such as dimethylsulfonium-2-oxocyclohexylide (411) with DMAD gives rise to a ring-expanded product, namely, dimethylsulfonium-2,3-dicarbomethoxy-4-oxo-2-cyclooctenylide (414), probably through the intermediates 412 and 413 (Scheme 65).249 By carrying out the reaction in benzene, it was possible to isolate a compound assumed to be 413, which was subsequently transformed in polar solvents to 414. The reaction of an analogous ylide... 

Reactions of carbocyclic P-keto esters, sulfonium ylides and enamines with activated alkynes such as DMAD are known to result in formation of (n + 2) ring expanded products. In a study of the analogous reactions of carbocyclic p-keto phosphonates, it was found that in the cases of the simple cyclic P-keto phosphonates 1, ring expansion occurred to give 2 in reasonable yield. Extension of the method to the tetralone 3, however, led to formation of two products, the "expected" (n + 2) ring expansion product analogous to 2 (37%), and the lactone 4 (29%). 

Thermal isomerization of alkenes to carbenes via a 1,2-silyl shift was examined both experimentally and theoretically (Scheme 3). 2,4-Dimethylene-l,3-disilacyclobutane undergoes thermal ring expansion to a 2-methylene-1,3-disilacyclopentene. The analogous all-carbon system failed to ring expand. Ab initio calculations revealed that this was... 

Using the same boratabenzene 68, Bazan and co-workers have formed titanium complex 70 and then studied its further reactions with acetylenes. Treatment of 70 with acetylene itself resulted in 71 as well as two ring-expanded products, 72 and 73 (Scheme 1) <2003AGE4510>. Formation of 72 was favored at low concentrations of acetylene in toluene solution whereas 73 becomes prevalent at high concentrations a mechanism involving initial coordination of acetylene to titanium was proposed. Similar reaction of 70 with (trimethylsilyl)acetylene gave a 79% yield of the product analogous to 72, the structure of which was determined by X-ray diffraction (see Section 7.14.3). 

The photochemical transformations of a series of 2-isopropylidenecyclobutanones in alcoholic media have been reported (15b,36). Irradiation of 2-isopropylidene-cyclobutanone [79a] in methanol afforded a quantitative yield of ring-expanded acetal [80a] with a quantum efficiency (at 313 nm) of 0.11. When irradiations were carried out in methanol-O-d, the acetal [80a] isolated contained >95% deuterium incorporation (nmr) at the indicated position. Completely analogous results were obtained with the 4,4-dimethyl derivative [79b] and 3,3,-... 

Bourchard et al. attempted to reduce the 7,19-cyclopropane docetaxel analog 92a electrochemically. Besides the major 10-deoxy product 92b, C-ring expanded 19-nor analog 93 was obtained as a minor product. Taxoid 93 did not exhibit any activity in both cytotoxicity and tubulin binding assays, although its conformation is analogous to that of docetaxel. 

Riiedi et al. discovered a novel and efficient two-carbon ring expansion of vinylcycloalkanones 148 (Scheme 32). Precursors with n = 9 to 15 were ther-molysed at 600-630 °C to generate diradical intermediates, which took part in intramolecular recombinations to yield ring-expanded y,8-imsaturated cy-cloalkanones 149 [120]. In each case a mixture of E and Z isomers was obtained. Thermolysis of the 12-membered-ring ethynyl-substituted cycloalka-none 149 yielded a novel 14-membered-ring allenyl-cycloalkanone 150 via an analogous mechanism. 

Cyclization to the benzo[c]phenanthridine (127) competes with rearrangement to the ring-expanded product (128) on irradiation of the amine oxide (129). A practical synthesis of the chlorin macrocycle (130) has been developed by irradiation of the seco-compound (131) in tetrahydrofuran containing TFA and Hiinig s base this is thought to take place by photocyc-lization of the ISrr-tautomer (132), followed by elimination of methanol. Analogous approaches have been employed in the syntheses of ( )-bonellin dimethyl ester and 20-methyl- and 20-cyano-isobacteriochlorins. " ... 

Analogous compounds 8 a —c with more than one sulfur atom in the ring have also been prepared by Akabori [26] and the synthesis led to ring-expanded products 9 and 10, probably by the route illustrated in Scheme 6-3. All the polyoxathiaferro-cenophanes showed little or no ability to extract hard alkali or alkaline earth cations... 

The alkylcarbene complex (14) has been produced by photolysis of (15). The reactive intermediate Pe(DMPE)2 (DMPE -Me2PCH2CH2PMe2) generated by photolysis of FeH2(DMPE)2 has been shown to be sufficiently reactive to add intermolecularly to the H bonds in pentane at -90 C to form la-(1-pentyl)PeH(DMPE)2 At -30 C the analogous reaction leads to E- and Z- ia-(pent-l-enyl)PeH(DMPE)2- The ring-expanded complexes (16) are formed on photolysis of the (aminocyclobutyl)iron complexes (17) (R Me, CHMe2). ... 

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