An enantioselective convergent route to pamamycin 621A.
An effective approach to the total synthesis of natural antibiotic pamamycin 621A is described, in which the stereogenic centers at the C-13 and C-15 were taken from a chiral building block derived from the inexpensive D-glucolactone while all others (except the C-10) were installed via chiral auxiliary-induced asymmetric Evans/Crimmins aldol reactions. In the synthesis of the smaller/lower fragment, an antiselective Evans aldol condensation was found to occur only if a stoichiometric (rather than catalytic as reported in the literature) amount of magnesium chloride was present. A previously unknown effect of the steric bulkiness of the pyridine base employed on the stereochemical outcome of the formation of the THF ring in the presence of a chiral auxiliary was also observed. The THF rings in the larger/upper fragment were similarly synthesized with a high level of stereoselectivity from a linear precursor carrying a chiral auxiliary via intramolecular O-alkylations, most notably even under acidic conditions. The basic dimethylamino functionality at the C-15 was installed at the final stage of the whole synthesis, with those otherwise unavoidable side reactions in the conversion of the azido group effectively circumvented through using a very mild yet largely forgotten tributyltin reduction protocol.
Ren
Guo-Bao
GB
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
Huang
Yi-Xian
YX
Sun
Ya-Ping
YP
Li
Zhong-Han
ZH
Wu
Yikang
Y
D003500:Cyclization; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism
D018942:Macrolides; C546656:pamamycin 621 A