Development of an Enantioselective Synthetic Route to Neocarzinostatin Chromophore and Its Use for Multiple Radioisotopic Incorporation

Abstract

A convergent, enantioselective synthetic route to the natural product neocarzinostatin chromophore (1) is described. Synthesis of the chromophore aglycon (2) was targeted initially. Chemistry previously developed for the synthesis of a neocarzinostatin core model (4) failed in the requisite 1,3-transposition of an allylic silyl ether when applied toward the preparation of 2 with use of the more highly oxygenated substrates 27 and 54. An alternative synthetic plan was therefore developed, based upon a proposed reduction of the epoxy alcohol 58 to form the aglycon 2, a transformation that was achieved in a novel manner, using a combination of the reagents triphenylphosphine, iodine, and imidazole. The successful route to 1 and 2 began with the convergent coupling of the epoxydiyne 15, obtained in 9 steps (43% overall yield) from D-glyceraldehyde acetonide, and the cyclopentenone (+)-14, prepared in one step (75-85% yield) from the prostaglandin intermediate (+)-16, affording the alcohol 22 in 80% yield and with > or =20:1 diastereoselectivity. The alcohol 22 was then converted into the epoxy alcohol 58 in 17 steps with an average yield of 92% and an overall yield of 22%. Key features of this sequence include the diastereoselective Sharpless asymmetric epoxidation of allylic alcohol 81 (98% yield); intramolecular acetylide addition within the epoxy aldehyde 82, using Masamune's lithium diphenyltetramethyldisilazide base (85% yield); selective esterification of the diol 84 with the naphthoic acid 13 followed by selective cleavage of the chloroacetate protective group in situ to furnish the naphthoic acid ester 85 in 80% yield; and elimination of the tertiary hydroxyl group within intermediate 88 using the Martin sulfurane reagent (79% yield). Reductive transposition of the product epoxy alcohol (58) then formed neocarzinostatin chromophore aglycon (2, 71% yield). Studies directed toward the glycosylation of 2 focused initially on the preparation of the N-methylamino --> hydroxyl replacement analogue 3, an alpha-D-fucose derivative of neocarzinostatin chromophore, formed in 42% yield by a two-step Schmidt glycosylation-deprotection sequence. For the synthesis of 1, an extensive search for a suitable 2'-N-methylfucosamine glycosyl donor led to the discovery that the reaction of 2 with the trichloroacetimidate 108, containing a free N-methylamino group, formed the alpha-glycoside 114 selectively in the presence of boron trifluoride diethyl etherate. Subsequent deprotection of 114 under mildly acidic conditions then furnished the labile chromophore (1). The synthetic route was readily modified for the preparation of singly and doubly (3)H- and (14)C-labeled 1, compounds unavailable by other means, for studies of the mechanism of action of neocarzinostatin in vivo.

Total Synthesis of (+)-Sieboldine A: Evolution of a Pinacol-Terminated Cyclization Strategy

“…Efforts to improve the ring-closure were made by evaluating a variety of bases, solvents, and reagent concentrations (DBU, K 2 CO 3 ; CH 2 Cl 2 , CH 3 CN), but no improvement in yield were realized. Although formation of a trichloroacetimidate in the presence of a basic secondary amine has been reported, 40 trichloroacetonitrile is known to readily react with primary and secondary amines in the absence of base to form amidines. 41 Competitive formation of an amidine by reaction of the secondary hydroxylamine and trichloroacetonitrile might well be occurring; however, this presumption was not confirmed by the isolation of amidine products.…”

Designed DNA probes from the neocarzinostatin family: Impact of glycosyl linkage stereochemistry on bulge base binding

“…Derivitization to form α-N-methyl fucosylated chimeras is easily accomplished through trichloroacetimidate coupling, stereochemical control is a function of neighboring group participation. 10 In order to access the corresponding β-N-methyl fucosylated analogs however necessitated preparation of Fmoc capped N-methyl trichloroacetimidate 6 from the precursor aminolactol (Scheme 1). Glycosylation efficiency and selectivity for beta glycosylation was examined under a variety of conditions (Table 1), the optimal promoter being boron trifluoride in the presence of molecular sieves at -30°C.…”

Total synthesis and related studies of large, strained, and bioactive natural products

“…This aglycon ( 117 ) was extremely unstable, but was nonetheless glycosylated by the Myers group to complete the total synthesis of labile neocarzinostatin chromophore ( 95 ). 137,138) …”

“…151) Finally, we developed an enantioselective synthetic route 152–156) to the unstable protected aglycon ( 142 ) of kedarcidin chromophore with the revised C10 stereochemistry ( 98b ), which underwent spontaneous cycloaromatization in 1,4-cyclohexadiene/benzene to give an aromatized chromophore ( 143 ) (Scheme 15). 17) Since the kedarcidin chromophore ( 98b ) has also an additional ansa-macrolide linkage to the strained nine-membered enediyne core, similar to the C-1027 chromophore ( 97 ), their total syntheses were more difficult than those of neocarzinostatin ( 95 ) 13,137,138) and N1999-A2 ( 96b ). 14,117) The key features of our synthesis of the aglycon ( 142 ) of the chromophore ( 98b ) are: 1) the efficient convergent assembly of four fragments ( 134 , 135 , 137 , and 139 ); 2) a novel strategy to synthesize the alkynyl epoxide ( 134 ) concisely from 132 and 133 ; 3) a cerium amide promoted nine-membered diyne ring cyclization between C5 and C6 of 140 in the presence of the ansa-bridge; and 4) a SmI 2 -mediated reductive 1,2-elimination for chemoselective olefination in the presence of the C8,C9 epoxide and the highly functionalized ansa-macrolide.…”

“…94) Although 99 is the methanol adduct of a structurally undefined labile chromophore, it showed DNA cleavage site selectivity similar to that of the holoprotein. The complex, highly unsaturated, and functionalized molecular architecture of 99 differs from those of the other enediyne chromophores ( 95 , 90,138) 97 , 88,140) and 98b 151) ) of related chromoprotein antitumor antibiotics and clearly presented a daunting challenge for chemical synthesis. In particular, controlling the stereoselectivity of both the C4,13-Z-olefin and non-biaryl atropselectivity within the macrocycle necessitated the development and application of new strategies.…”