A total synthesis of (±)-α-cyclopiazonic acid using a cationic cascade

Abstract

The indolic terpene alkaloid alpha-cyclopiazonic acid has been prepared in 11 steps from indole-4-methanol; the key step is a carbocationic cascade, terminated by a 4-nitrosulfonamide group and initiated by benzylic carbocation formation directly from the intermediate , which gives the tetracyclic product in 74% yield.

Clustered genes involved in cyclopiazonic acid production are next to the aflatoxin biosynthesis gene cluster in Aspergillus flavus

“…A. parasiticus strains differ from CPA-producing A. flavus isolates in region A to E. The sequence of the PCR fragment (0.9 kb) only amplified from location C of A. parasiticus SU-1 has only 88% DNA sequence identity plus 1% gap to that of A. flavus NRRL 3357 instead of the 98-99% identity known for other genes (Ehrlich et al, 2005). Chemical synthesis of CPA has been achieved (Haskins and Knight, 2005), but the biosynthetic steps have not yet been fully elucidated. The enzyme that catalyzes the conversion of cycloacetoacetyl-L-tryptophanyl (cAATrp) and dimethylallyl pyrophosphate to b-cyclopiazonic acid in P. cyclopium has been purified (McGrath et al, 1977).…”

α‐Cyclopiazonic Acid from Synthesis Perspective

“…In 2005, Knight published an interesting total synthesis of α-CPA using a cationic cascade strategy. [26] The beauty of the approach was that both the cyclohexene and pyrrolidine rings were formed in the same step from tryptophan derivative 22, obtainable in several steps from indole 21 (Scheme 5). Apart from a good yield (74 %), the cyclization offered the desired diastereoselectivity of the key stereotriad (just 8 % of the undesired epimer at C*).…”

“…After the two early publications, there has been a long break in CPA syntheses. In 2005, Knight published an interesting total synthesis of α‐CPA using a cationic cascade strategy [26] . The beauty of the approach was that both the cyclohexene and pyrrolidine rings were formed in the same step from tryptophan derivative 22 , obtainable in several steps from indole 21 (Scheme 5).…”

Enantioselective Synthesis of the Cyclopiazonic Acid Family Using Sulfur Ylides

“…Kozikowski and Natsume constructed the C–D rings in a stepwise manner, but with low diastereoselectivity. Knight developed an elegant cationic cascade, in which acyclic precursor 9 was converted into indole 6 with high stereocontrol,, although Scherkenbeck found that the same substrate cyclized to give a 1:1 mixture of diastereomers across the CD ring junction under slightly different conditions ,…”