Enantiospecific Total Synthesis of N‐Methylwelwitindolinone D Isonitrile

Abstract

We report the enantiospecific total synthesis of N-methylwelwitindolinone D isonitrile. Our route features a double C-H functionalization event involving a keto oxindole substrate to introduce the tetrahydrofuran ring of the natural product.

Identification and Characterization of a Welwitindolinone Alkaloid Biosynthetic Gene Cluster in the Stigonematalean Cyanobacterium Hapalosiphon welwitschii

“…[2] Except welwitindolinone A ( 4 ), all welwitindolinones isolated to date are 3,4-disubstituted oxindoles with a signature bicyclo[4.3.1]decane core motif, [1, 3] which has captivated considerable interest from the synthetic chemistry community worldwide that resulted in several total chemical syntheses of this family of molecules. [4] …”

“…[1] More recently, Baran and coworkers demonstrated that 4 could be readily obtained by a XeF 2 -mediated oxidative ring contraction of 12- epi -fischerindole I ( 7 ), [4c] which is implicated as the direct biosynthetic precursor to 4 . However, no genes or proteins associated with welwitindolinone biosynthesis have been identified and characterized to date.…”

“…This stereochemical discrepency at C-12 was suggested to be derived from a pair of diastereomeric monoterpene precursors, namely ( E ) and ( Z )-β-ocimenes ( 9 ), according to the original biosynthetic proposal formulated by Moore and others (Figure 1D). [1, 4d, 6] Since the study of the amb pathway has ruled out the involvement of ( Z )- 9 in the biogenesis of hapalindoles G/U, questions remain open on what is nature’s underlying principle to generate these structural diversities. To this end, we resorted to the identification of a biosynthetic gene cluster for welwitindolinones and related hapalindoles/fischerindoles to gain additional insights on the biogenesis of hapalindole-type natural products.…”

Modern Methods for Total Synthesis of Important Oxindole Alkaloids

“…Nonetheless, hydrolysis of 282, followed by IBX oxidation, generated the oxindole intermediate amino- et al (see above) made possible the synthesis of (+)-N-methylwelwitindolinone D isonitrile 296. 48,55 The important intermediate indole 275 (Scheme 49) was at this point converted to oxindole 286 using a one-pot oxidation/hydrolysis sequence (Scheme 52). Since the acidic conditions led to desilylation, reprotection of the alcohol was necessary to provide TBS-protected indole 287.…”

“…Related (C-3)-peroxy compounds were observed in previous studies by the Garg and Wood research groups. 55 In order to complete the total synthesis, it remained to elaborate the cyclic carbamate to the ketone and isonitrile functional groups present in the target molecule 296 (Scheme 54). To this end, ketone 292 was reduced to the corresponding alcohol 293 with LiAlH 4 .…”