Total Synthesis of two isoflavone C-glycosides (6-tert-butyl puerarin and
6-tert-butyl-4'-methoxypuerarin) through the deoxybenzoin pathway
Yunpeng Zou a, b, #, Shouguo Zhang b, #, Xiaoxue Wen b, Gang wang b, Yunbo sun b, Shuchen
Liu b, Tao Peng b, *, Yue Gao a, b, * and Lin Wang a, b,
*
a College of Life Science and Bio-engineering, Beijing University of Technology, Beijing 100124, P. R. China
b Beijing Institute of Radiation Medicine, Beijing 100850, P. R. China
ABSTRACT
The total synthesis of two isoflavone C-glycosides (6-tert-butylpuerarin and
6-tert-butyl-4'-methoxypuerarin) was achieved through the deoxybenzoin pathway with overall
yields of 14.6% and 14.2%. The key intermediate 12 was obtained by de-tert-butylation of 10 with
trifluoroacetic acid and Friedel-Crafts acetylation of 2-C-β-D-glucopyranoside 11. The ring
closure of 12 with the POCl3/DMF reagent resulted glucosyl isoflavone formation 13, which was
debenzylated and demethylated by BBr3 to obtain 14 and 15. This pathway represents a novel
synthetic pathway based on Friedel–Crafts acetylation and Vilsmeier-Haack cyclization to achieve
isoflavone C-glycosides in high yields.
KEYWORDS: C-glycoside; Isoflavone; 6-tert-butylpuerarin; deoxybenzoin pathway;
6-tert-butyl-4'-methoxypuerarin
Isoflavone C-glycosides, in which the sugar moiety is attached by a C–C bond
directly to the isoflavone ring, are not easily hydrolyzed in acidic gastric juices
compared with O-glycosides and aglycone. These glycosides exhibit various
biological activities such as radioprotective,1 anti-myocardial ischemic,2 mitogenic,
and colony-stimulating,3 and antidiabetic4 activities. Among these compounds,
puerarin, which is found mainly in Pueraria radix, show strong anti-myocardial
ischemic effects;5 it expands the coronary artery and cerebrovascular system,6
significantly reduces myocardial oxygen consumption,7 and improves cardiac systolic
function. To improve the efficacy of puerarin and enhance its concentration in the
blood, 6-tert-butylpuerarin and 6-tert-butyl-4'-methoxypuerarin were totally
synthesized to prevent the 7-O-β-D-glucuronide and 4'-O-sulfate formation of the
compound in the liver.8
Numerous active C-glucosylflavonoids, such as vicenin-1,9 flavocommelin,10
saponarin,11 and orientin,12 were synthesized starting from C-glucosyl acetophenones.
The condensation of C-glucosyl acetophenone 1 with
3,4-bis(benzyloxy)benzaldehyde led to the production of C-glucosylchalcone 2, which
yielded orientin (Scheme 1)12 after I2–dimethyl sulfoxide promoted intramolecular
cyclodehydrogenation and a final debenzylation by hydrogenolysis. The synthetic
pathway of C-glucosylisoflavonoids was highly similar to that of
C-glucosylflavonoids. 8-β-D-glucopyranosylgenistein was synthesized via
C-glucosylchalcone 3 formation by aldol condensation of C-glucosyl acetophenone 1
with 4-(benzyloxy)benzaldehyde. The oxidative rearrangement of chalcone 3 with
thallium(III) nitrate yielded a dimethyl acetal 5, which was then cyclizated by
refluxing in 10% HCl and de-O-benzylated by hydrogenolysis to give the desired 8-β-