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Totally Synthetic by Paul H. Docherty, 11 July 2010

Total Synthesis of GB 13 & GB 16


W. Zi, S. Yu, D. Ma, Angew. Chem. Int. Ed. 2010, 49, 5887-5890.

DOI: 10.1002/anie.201002299

Why make one natural product when you can make two just as easily? Or three in this case, but the headline syntheses are the Galbulimima Alkaloids GB-13 and GB-16 - notable members of a family that is getting some serious attention in pharma - one analogue is currently in phase III trials. With all that potential, it’s not surprising that these molecules have received a lot of synthetic attention; indeed, GB-13 was one of the first syntheses I have described! Another popular member is himgaline, with two (1, 2) previous descriptions here.

Ma’s approach was to work towards these targets from a common, late-stage precursor, and to build complexity as non-linearly as possible. One thing I really appreciate about his work and this paper is his synthesis of the smaller fragments, as he describes the synthesis from the commercial precursors rather than literature intermediates. Perhaps he has done this as the routes are really quite neat. Starting with 3-aminobutan-1-ol, a condensation with 1,3-cyclohexanedione gave the bicyclic intermediate after a displacement-cyclisation. Reduction of the enone under fairly forcing conditions gave the cis-decalin-type structure, generating a pair of stereocenters and allowing completion of a complex, key intermediate in only five steps.

A second intermediate was called into existance using only one more step. A literature intramolecular asymmetric conjugate addition was able to build a fairly busy cyclohexane, which, after a selective reduction, could be esterified to give the desired lactone with ease.

Unifying these two fragments wasn’t without its problems - stereoselectivity being the major issue, as the group could only acheive a 3.5:1 d.r. However, this was actually irrelevant, as the two diastereomers were taken through a fairly busy elimination / epimerisation / reduction sequence to get to their final goal.

A few steps later, they were ready to make that ring-system even more complex! Working with a ketone and an enone, treatment with samarium diiodide did a reaction I wasn’t too surprised to learn. I’d seen the SmI2 mediate coupling of ketone before, so it’s not really much of a stretch to see this happen in a ‘conjugate’ sense when working with an enone. The process was completed by a quick DMP oxidation to complete the majority of GB-13 (two more steps required).

Harking back to one of my earlier posts (the Evans’ total synthesis of Himgaline), Ma also sees that GB-13 was isolated along with an equibrilating isomer, 16-oxo-Himgaline, in which the piperidine nitrogen adds into the enone. The reversible process can be fixed by reducing the resulting ketone - something both the groups completed by addition of triacetoxysodium borohydride. No yield is given by Ma, so I presume his result concorded with Evans.

Very nice stuff, and a well-written paper!