Total synthesis of CC-1065. I. Diels-Alder reactions of heterocyclic azadienes. II. Total synthesis of PDE-I and PDE-II. III. Total synthesis of N-benzenesulfonyl CPI, PDE-I dimer, and (+)- and (-)-CC-1065. IV. Total synthesis of (+)- and (-)-deoxy CC-1065

Robert Samuel Coleman, Purdue University

Abstract

The total synthesis of the naturally occurring antitumor-antibiotic agent CC-1065 (1) and the related, naturally occurring $c$-AMP phosphodiesterase inhibitors PDE-I (2) and PDE-II (3) are described and were based on the sequential implementation of two azadiene Diels-Alder reactions: an inverse electron-demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (103) with the electron-rich olefin 4,4-dimethoxybut-3-en-2-one (111) was utilized for construction of 1,2-diazine-3,6-dicarboxylate 104g, which was subsequently incorporated into an intramolecular Diels-Alder reaction of 3-(3-alkynylamino)-1,2-diazine 135 for construction of the BC-indoline ring system of the 1,2-dihydro-3$H$-pyrrolo(3,2-$e$) indole structure characteristic of PDE-I, PDE-II, and the central and right-hand segments of CC-1065. Implementation of the Hemetsberger-Rees styrylazide thermolysis for pyrrole-2-carboxylate A-ring formation to afford 144 was followed by use of a newly developed Lewis acid-catalyzed benzylic hydroperoxide rearrangement for C-4 phenolic hydroxyl introduction, and completed the total synthesis of PDE-I (2) and PDE-II (3). Direct coupling of the two 1,2-dihydro-3$H$-pyrrolo(3,2-$e$) indole-7-carboxylate subunits 223 and 2, constituting the central and right-hand segments of CC-1065, afforded PDE-I dimer (225). The synthetic approach to the cyclopropa($c$) pyrrolo (3,2-$e$) indol-4(5$H$)-one (CPI, 4) left-hand segment of CC-1065 was based on the regioselective addition of 1-piperidino-1-propene to the selectively activated 2-benzyloxy-$p$-quinonediimide 181 for direct introduction of the 3-methylpyrrole A-ring of CPI, and was followed by implementation of a 5-exo-dig aryl radical-alkyne cyclization of 199 for construction of the 3-substituted pyrroline C-ring. Ar-3$\sp\prime$ cyclization of 227 using Mitsunobu reaction conditions afforded $N\sp2$-benzenesulfonyl CPI (208). The CPI precursor 227 was resolved by chromatographic separation of the corresponding $R$-($-$)-$O$-acetylmandelate esters 228, and was followed by conversion to the corresponding chlorides 1$S$-234 and 1$R$-234 and direct coupling of 1$S$-236 and 1$R$-236 with PDE-I dimer (225). Subsequent base-promoted Ar-3$\sp\prime$ cyclization of 1$S$-237 and 1$R$-237 afforded natural (+)-CC-1065 ((+)-1) and enantiomeric ($-$)-CC-1065 (($-$)-1). In addition, optically active chlorides 1$S$-234 and 1$R$-234 were incorporated into the total synthesis of (+)- and ($-$)-CPI-CDPI$\sb2$ ((+)- and ($-$)-deoxy CC-1065, 239), which represent the optimal structural entities that embody the precise structural and functional features of CC-1065 that are responsible for the potent cytotoxic activity of the natural product. The in vitro cytotoxic evaluation of CC-1065 and CPI-CDPI$\sb2$ is presented.

Degree

Ph.D.

Advisors

Boger, Purdue University.

Subject Area

Organic chemistry

COinS