A total synthesis of (+/-)-Diospongin A

Brazilian Chemical Society (SBQ). Division of Medicinal Chemistry. 4th Brazilian Symposium on Medicinal Chemistry
A total synthesis of (+/-)-Diospongin A (a potent anti-osteoporotic
agent) assisted by Prins-ciclization on solvent-free conditions
Brito, G. A. J.; Camillo, J. R.; Bele, T. G. A. ; Dos Santos A. A.*
Department of Chemistry, Federal University of São Carlos, São Carlos, SP, Brazil.
* e-mail: [email protected]
Keywords: Diospongin A, anti-osteoporotic, Prins-cyclization, tetrahydropyran ring
O
Ph
Prins-cyclization is one of the most simple and
straightforward approaches for the construction of
1
tetrahydropyran ring systems. Diospongins A and B
possess a six-membered cyclic ether core with two
aromatic side chains (Figure 1). Diospongins A and
B were first isolated, by Yin et al, from the rhizomes
2
of Dioscorea spongiosa. They are known to exhibit
a potent anti-osteoporotic activity.
OH
OH
O
O
Diospongin A
Diospongin B
O
O
Figure 1
Recently we developed a Prins-cyclization protocol
4
in total absence of organic solvents. In this way
compound 3 was converted in the single
5
diastereoisomer 4 (60% isolated yield) by reaction
with benzaldehyde in the presence of catalytic
.
amount of FeCl3 SiO2. To complete the total
synthesis, compound 4 will be submitted to a
6
Mitsunobu reaction followed by a Wacker oxidation
(Scheme 3).
OH
Ph
O
(4)
Ph
O
OH
H
Ph
Ph
benzaldehyde
SiO2.FeCl3
SOLVENT-FREE
2h, 60%
O
O
(3)
Scheme 2
(3)
OH
Ph
Ph
a: Allyl bromide, Zn, THF (2h) 96%
b: Allyl bromide, Zn-Cu couple, solvent-free (20 min) 42%
In Scheme 1 is presented the retrosynthesis of (+/-)Diospongin A. By our proposal, two sequential
reactions can be conducted on solvent-free
conditions, namely allylation and Prins-cyclization
reactions.
Ph
O
Ph
(+/-)-Diospongin A
H
(2)
Results and Discussion
OH
OH
a or b
Introduction
Ph
Scheme 3
Conclusions
In summary, for the synthesis of (+/-)-Diospongin A,
two sequential solvent-free reactions were
performed. The next two necessary steps for
1
completion of the synthesis are known and present
good yields.
H
Compound 3, it was produced by two routes. When
the reaction was conducted by conventional
protocol, i.e. in THF solution, 3 was formed in 96%
isolated yield. Aiming a more eco-friendly protocol
we performed this reaction in absence of organic
solvents by simple mixing the reagents with a Zn-Cu
3
couple. By this methodology the homoallylic alcohol
(3) was isolated only in 42% yield (Scheme 2).
O
(+/-)-(4)
(+/-)-Diospongin A
Acknowledgements
(3)
Scheme 1
Ph
The authors are grateful to CAPES, CNPq and
FAPESP.
___________________
1
Yadav, J. S. Padmavani, B.; Reddy, B. V. S.; Venugopal, C.; Bhaskar,
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2
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Chen, Y.; Kadota, S. Planta Med. 2004, 70, 54.
3
Yan, W.; Wang, J.; Wang, K. Synlett. 2008, 1, 137.
4
Zukerman-Schpetcor, J.; Dos Santos, A. A.; Macedo, A.; Wendler, A.;
Brito, G. A. J.; Tiekink, E. R. Z. Kristallog. 2008, 223, 471; Canedo, E.
M.; Wendler, E.; Macedo, A.; Brito, G. A. J.; Dos Santos, A. A. BMOS,
Itapema – SC, 2007.
5
Vasconcellos, M. L. A.; Miranda, L. S. M. Quim. Nova 2006, 29, 834.
6
Keinan, E.; Seth, K.; Lamed, R. J. Am. Chem. Soc. 1986, 108, 3474.
4th Brazilian Symposium on Medicinal Chemistry – BrazMedChem2008