Organic Chemistry Portal
Organic Chemistry Highlights

Monday, May 9, 2016
Douglass F. Taber
University of Delaware

Alkaloid Synthesis: Ipalbidine (Clive), Hosieine A (Hong), Gephyrotoxin (You), Cylindricine A (Pandey), Martinellic Acid (Aponick), Lundurine A (Zhang/Qin)

(+)-Ipalbidine (3), isolated from Ipomoea harwickii Hemsl. and Ipomea muricata, has been reported to be a nonaddictive analgesic. En route to 3, Derrick L. J. Clive of the University of Alberta found (J. Org. Chem. 2015, 80, 10294. DOI: 10.1021/acs.joc.5b01890) that the 6-exo-trig free radical cyclization of 1 to 2 could be achieved by eight hour syringe pump addition of Bu3SnH and AIBN initiator to 1 in refluxing toluene.

(-)-Hoseine A (6), isolated from Ormosia hosier, binds to the α4β2 receptor with five times the potency of nicotine itself. Ran Hong of the Shanghai Institute of Organic Chemistry followed (Angew. Chem. Int. Ed. 2015, 54, 10940. DOI: 10.1002/anie.201505251) the Keck protocol to generate the nitroso compound 4 in situ, leading to 5 and thus to 6.

Shu-Li You, also of the Shanghai Institute of Organic Chemistry, effected (J. Am. Chem. Soc. 2015, 137, 15899. DOI: 10.1021/jacs.5b10440) the dearomatizing cyclization of 7 in high ee. The product 8 was carried on to an intermediate that intersected the classic Kishi total synthesis of (+)-Gephyrotoxin (9).

Ganesh Pandey of the Centre of Biomedical Research, Lucknow observed (Chem. Eur. J. 2015, 21, 13120. DOI: 10.1002/chem.201501859) that the addition of (R, R)-hydroanisoin 11 to the readily-prepared meso bis-sulfone 10 led to 12 with high diastereocontrol. This proved to be a versatile core for the elaboration of a variety of alkaloids, including (+)-Cylindricine (13). Note that the addition of 11 to N-Boc protected 10 led to ring opening, delivering a protected cyclohexenone (not illustrated) that will also be a valuable starting point for target-directed synthesis.

Aaron Aponick of the University of Florida devised (Angew. Chem. Int. Ed. 2015, 54, 15202, DOI: 10.1002/anie.201507848; 15827, DOI: 10.1002/anie.201507849) an elegant cascade dearomatization, preparing 16 by combining 14 with 15. The ketone 16 was carried on over several steps to (-)-Martinellic Acid (17).

Taking advantage of the recent observation (J. Org. Chem. 2008, 73, 9479. DOI: 10.1021/jo8017704) of the efficient in situ generation of unstabilized diazo alkanes from aldehydes and ketones, Dan Zhang and Yong Qin of Sichuan University prepared (Chem. Eur. J. 2015, 21, 13284. DOI: 10.1002/chem.201502011) the tosylhydrazone of the aldehyde 18. The diazo compound generated in situ by exposure to NaH was cyclized to 19 under Cu catalysis. Dehydration led to (-)-Lundurine A (20).

D. F. Taber, Org. Chem. Highlights 2016, May 9.