A robust six-step process for the synthesis of crizotinib, a novel c-Met/ALK inhibitor currently in phase III clinical trials, has been developed and used to deliver over 100 kg of API. The process includes a Mitsunobu reaction, a chemoselective reduction of an arylnitro group, and a Suzuki coupling, all of which required optimization to ensure successful scale-up. Conducting the Mitsunobu reaction in toluene and then crystallizing the product from ethanol efficiently purged the reaction byproduct. A chemoselective arylnitro reduction and subsequent bromination reaction afforded the key intermediate 6. A highly selective Suzuki reaction between 6 and pinacol boronate 8, followed by Boc deprotection, completed the synthesis of crizotinib 1.

Furans are common substructures in numerous natural products, such as the cembranolides lophotoxin, 1 kallolides, 2 and pukalide. 3 These heterocycles are also found in numerous commercial products, including pharmaceuticals, fragrances, and dyes. Accordingly, many strategies have been developed for the preparation of furans. 4 Marshall and coworkers utilized 3-alkynyl allylic alcohols in S N 2′ reactions to provide 2,3-disubstituted furans. 5 Another method for the formation of 2,3-disubstituted furans from the same laboratory employed Ag(I)-or Rh(I)-catalyzed cyclizations of allenyl ketones and aldehydes. 6 Palladium catalysis has also been used for the synthesis of furans. Coupling of terminal acetylenes and γ-hydroxyalkynoates followed by Pd(II)catalyzed cyclization produced 2,4-disubstituted furans. 7 Wakabayashi et al. have used Pd(II) to promote intramolecular cyclizations of 3-alkynyl-1,2-diols to give either 2,3disubstituted or 2,3,4-trisubstituted furans from ,γ-acetylenic ketones. 8 Numerous literature protocols for the formation of furans employ 1,3-dicarbonyl compounds. Paquette and co-workers used these starting materials to prepare a 2,3,5-trisubstituted furan as an intermediate in the total synthesis of gorgiacerone, a furanocembranolide. 9 Larock and Cacchi studied the Pd(0)-mediated cyclizations of 2-propargylic-1,3-dicarbonyl compounds, 10 and Tsuji et al. used Pd(0) catalysis for the formation of furans in the intramolecular annelation reaction of -keto esters and either propargylic carbonates or oxiranes. 11 Other strategies based on dicarbonyl substrates use the Feist-Benary condensation of 1,2-dibromoacetate with acetoacetate to provide 2,3-disubstituted furans or the cyclocondensation of acetone dicarboxylate with 1,4-dibromobut-2-yne to give 2-vinylidenehydrofurans. 12,13 As part of our approach toward the total synthesis of lophotoxin, we were interested in a general protocol for 2-alkenylfurans. In this paper, we present the first use of unstabilized monocarbonyl systems in the formation of substituted furans. Our methodology employs alkynyl ketone enolates which undergo a thermal S N 2′ O-alkylation to provide the desired heterocycles. Furthermore, we were able to extend this strategy toward novel syntheses of 1,3-oxazoles and -thiazoles. Supporting Information Available: Experimental details and characterization for all new compounds. Copies of 1 H and 13 C NMR spectra (78 pages). (17) Thionation of amide 15 with Lawesson's reagent led, in lower yield, to the identical vinylthiazoline, and no thioamide intermediate was observed in this reaction either. Scheme 3 Scheme 4 Scheme 5 Scheme 6 Communications

A ten-linear-step construction of C-aromatic taxane diene 14 from ethyl isopropyl ketone, acryloyl chloride, and commercially available 8 is reported. This sequence concludes with an intramolecular pinacol coupling carried out on 13. 14 is oxidized by m-chloroperbenzoic acid and dimethyldioxirane to give 17 through intermediate epoxide 20 and by VO(acac)2−t-BuOOH and Mo(CO)6−t-BuOOH to give 13. 17 is converted efficiently into 22 upon treatment with Mo(CO)6−t-BuOOH, apparently through an unusual equilibration with isomeric 20, which is converted irreversibly to 22. While these oxidative transformations highlight some of the peculiar reactivity patterns characteristic of taxane-related structures, the formation of 14 through an intramolecular pinacol coupling that joins C-1 and C-2 demonstrates the potential of this strategy for stereoselectively delivering advanced taxane synthesis intermediates.

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