Boger, Ishikawa, Elliott, Velcicky and Choi. JACS, 2006,
ASAP. DOI: 10.1021/ja061256t.
More outstanding cyclisation action, this time from the Boger labs at Scripps. Working towards a whole class of bisindole alkaloid structures, including Vinblastine and vincristine (known for their potent anti-tumour action), they have completed
the total synthesis of vindoline (not a window cleaner). This structure, also found in nature, is a synthetic and biosynthetic precursor to the former targets. Along with an accompanying methodology paper, this work describes their forays into the synthesis of this interesting motif.
The work hinges upon an immense [4+2] / N2 elimination / [3+2] sequence that creates three rings and sets six stereocentres in one pot. In the first case, they completed the synthesis of the related structure, minovine. The cyclisation
sequence went particularly well (in 74%); they then had to remove an extraneous carbonyl group, which they completed using Lawesson’s reagent to convert to the thiolactam, and then reduction with Raney nickel. For those who can’t remember (or can’t be bother looking), here’s that reagent:
They then opened the ether bridge and used Burgess’ reagent to provide a good leaving group for the liberated alcohol, which allowed then to eliminate, but unfortunately as a mixture of natural product and the undesired alkene isomer. Again, here’s that funky named reagent.
They were then able to showcase this methodology and strategy further, with short syntheses of vindorosine, 4-desacetoxyvindorosine, N-methylaspidospermidine, and finally, vindoline, which itself was completed in a remarkable eleven steps! Using relatively familiar methodology to get to the cyclisation precursor, they produced both cis- and trans- material, and cyclised. Both gave the expected products, with the trans- cyclising faster, and the enantiomers separated
using HPLC. Then, reducing-off the carbonyl as before, along with ether-bridge opening retuned the target.