Practical Asymmetric Synthesis of a Non-Peptidic α_vβ₃ Antagonist

Abstract

The development of a practical and highly convergent synthesis of an alpha(v)beta3 antagonist is described. The two key fragments present in this compound, a tetrahydropyrido[2,3-b]azepine ring system and a chiral 3-aryl-5-oxopentanoic acid, were constructed independently and then coupled at a late stage using a Wittig reaction. The pyridoazepine moiety was prepared from N-Boc 6-chloro-2-aminopyridine via directed ortho-metalation/alkylation followed by in situ cyclization. A Suzuki reaction was then used to attach the propionaldehyde side-chain required for Wittig coupling. The coupling partner was prepared from asymmetric methanolysis of a 3-substituted glutaric anhydride followed by elaboration of the acid moiety to the requisite beta-keto phosphorane. Using this route, kilogram quantities of the desired drug candidate were prepared.

Recent applications of Cinchona alkaloids and their derivatives as catalysts in metal-free asymmetric synthesis

“…Another example of desymmetrization of a cyclic meso-anhydride with (DHQD) 2 AQN as catalyst, showed a high enantioselectivity but too slow a reaction speed at low temperature. 173 …”

Boron Reagents in Process Chemistry: Excellent Tools for Selective Reductions

“…Gratifyingly, the cross-coupling of trialkylborane with chloride 44 cleanly afforded desired acetal 45 in 98% yield. 33 Danishefsky and co-workers effectively used a similar reaction sequence to synthesize one of the intermediates for the synthesis of an epothilone analogue, 12,13-desoxyepothilone F, which is active against tumor cells. The unprecedented coupling of 9-BBN intermediate with iodotrisubstituted alkene 46 proceeded smoothly to the desired diketone 48 in 60% yield (Scheme 19).…”

Transition metals in organic synthesis: Highlights for the year 2005

“…Synthetic targets included, prodigiosines [198], chartelline alkaloids [199], eupomatilone-3 [200], 9,10-deoxytridachione [201], hamigeran B [202], leprapinic acid and calycin [203], dehydrocoelenterazine analogs [204], gymnocin A (Eq. (11)) [205], murrastifoline A [206], styelsamine C and norsegoline [207], trispheridine [208], dragmacin F [209], ningalin D [210], eupomatilones [211], lucilactaene [47], epoxyquinols A-C and epoxytwinol A [212], mukonine [213], cepharanone [214], ␣ v ␤ 3 antagonist [215], alternariol [216], core of roseophilin [21], (−)-callystatin A [217], dibenzo[c,p]chrysene [218], GABA agonist [219,220], diazonamide A [221], dityrosine, trityrosine, pulcherosine [222], lamellarin D [223], integramycin [224], (+)-discodermolide and analogues [225,226], AB-ring system of hexacyclinic acid [227], ␦-trans-tocotrienoloic acid [135], spirofungins [228], kwakhurin [229], toward (+)-and (−)-deplanchein [230], combretastatin analogs [231], diazonamide A [75], cadiolide B [232], pukeleimide A [233], toward apoptolidin [234], polycitone A and B …”

“…The intermolecular Heck reaction was used in organic synthesis of, for example, glycocinnasperimicin D [426], cribrostatin IV [427], novel pyrimidine nucleosides [428], ␣ v ␤ 3 antagonist [215], KDR kinase inhibitors [376], selaginoidine [429], pancracine [430], pyrrolidino pseudoisocytidine [431], (+)-and (−)-deplanchein [230], rhizoxin D [432], 2-acetonylinosine [433] and 10-deoxyartemisinins [434]. A combination of an intermolecular and intramolecular Heck reaction of iodoarylalkenes was used to prepare macrocycles [435].…”