Total Synthesis of the C‐1027 Chromophore Core: Extremely Facile Enediyne Formation through SmI₂‐Mediated 1,2‐Elimination

Abstract

The spontaneous aromatization of the enediyne chromophore of the potent antitumor agent C‐1027 generates a p‐benzyne biradical, which cleaves double‐stranded DNA. The title reaction was developed for the construction of nine‐membered‐ring enediynes and applied as the final step in the synthesis of the exceptionally unstable core structure of the C‐1027 chromophore (see scheme; Boc, MOM, MPM, and TES are protecting groups; Ms=methanesulfonyl).

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

“…100,101) This approach enabled the first synthesis of the exceedingly unstable core structure ( 125 ) of the chromophore ( 97 ) (Scheme 13) 141–149) and the labile protected aglycon ( 131 ) (Scheme 15; in preparation for publication). 16) …”

“…The final feature is an extremely facile SmI 2 -mediated reductive 1,2-elimination of 124 using p -trifluoromethylbenzoate as an electron acceptor for chemoselective olefination in the presence of potentially reactive functionalities such as the doubly allylic OTES group at C9 and the propargylic OAr moiety at C8. 16) However, when the benzoxazine ester was attached, its α,β-unsaturated carbonyl group was reduced preferentially and rapidly to afford 128 (Scheme 14). Therefore, this functionality was masked in the hydrate form as 129 for the SmI 2 –reduction, then dehydrated to complete the total synthesis of the labile aglycon ( 131 ), a more stable compound than the core structure ( 125 ) (in preparation for publication).…”

“…167) These 3-chlorocyclopenta[a]indene derivatives were isolated from marine Norcardiopsis species, whereas no C6-chlorinated fijiolides were isolated. New unstable 9-membered enediyne 172 with a TES group on C13-OH has the same structure as the core of C-1027 chromophore ( 97 ) 16) and was synthesized from 123 (Scheme 13). Enediyne 172 was treated with LiCl in DMSO to determine if the C6-chlorinated product 174 (R 1 =H, R 2 =Cl) was formed as expected, given the results of 161 (Scheme 19).…”

“…This review focuses on describing our synthetic studies and related studies of two families of bioactive natural products: the ciguatoxins, which are large 3 nm-long molecules that exhibit extremely potent neurotoxicity, 4–12) and the nine-membered enediyne chromoprotein antitumor antibiotics, which have delicate architectures that include the chromophores of neocarzinostatin, 13) N1999-A2, 14) maduropeptin, 15) C-1027, 16) and kedarcidin. 17) In addition, the innovative syntheses of other structurally complex bioactive natural products such as avermectin 18) and milbemycin, 19) which are potent anthelmintic macrolides, are outlined.…”

Biomimetic Total Synthesis of Cyanosporaside Aglycons from a Single Enediyne Precursor through Site‐Selective p‐Benzyne Hydrochlorination

“…Immediate esterification with an electrondeficient functionality solved this issue. After an improved [16] Ce III -mediated cyclization between the acetylide and aldehyde moieties of 12 (R = TES), the TFBz [17] ester at C8 of 13 was thus formed and could be isolated as a single diastereoisomer (70 % yield, two steps). Notably, the methoxymethyl ether 12 (R = MOM) failed to cyclize, presumably because of unfavorable Ce III chelation modes enforced between the neighboring MOM and aldehyde groups.…”