Conversion of Natural Narciclasine to Its C-1 and C-6 Derivatives and Their Antitumor Activity Evaluation: Some Unusual Chemistry of Narciclasine

Abstract

During the search for a general, efficient route toward the synthesis of C-1 analogues of narciclasine, natural narciclasine was protected and converted to its C-1 enol derivative using a novel semi-synthetic route. Attempted conversion of this material to its triflate in order to conduct cross-coupling at C-1 resulted in a triflate at C-6 that was successfully coupled with several functionalities. Four novel compounds were fully deprotected after seven steps and subjected to evaluation for cytotoxic activity against three cancer cell lines. Only one derivative showed moderate activity compared to that of narciclasine. Spectral and physical data are provided for all new compounds.

Design and Synthesis of C-1 Methoxycarbonyl Derivative of Narciclasine and Its Biological Activity

“…Scheme 2. Synthesis of the A-ring acid chloride (14) from ortho-vanillin (15). Reagents and conditions: i. Br2, NaOAc, AcOH, rt; ii.…”

“…The number of unnatural derivatives of narciclasine reported in the literature is very small compared with those derived from pancratistatin. Thus, our group previously published efforts towards the total syntheses of narciclasine analogs, namely compounds 5-9 shown in Figure 1 [11][12][13][14]. 10-Aza-narciclasine (7) is the only derivative of narciclasine synthesized by our group that displayed activity comparable to that of the natural product [12].…”

“…Recently, we began pursuing the synthesis of C-1 narciclasine analogs based on a convergent synthesis wherein the A-and C-ring precursors are synthesized separately and later combined to form the B-ring, thus producing the full narciclasine backbone (Scheme 1). The synthesis of the A-ring precursor (14) begins from ortho-vanillin (15) and is based on previous work [15][16][17][18], while the C-ring synthesis begins with ortho-dibromobenzene (13). Enzymatic dihydroxylation of the latter compound installs the syn-diol moiety at C-3 and C-4 in the correct configuration (12, Scheme 1) [19].…”