C O M M U N I C A T I O N S
Scheme 2 a
a Reagents and conditions: (a) Ac2O, cat. DMAP, Py, 95%; (b) 1. MeMgBr, CuBr‚DMS, THF/DMS (2:1) at -20 °C, then 9 in THF at -45 °C; 2. Cat.
PTSA, DCM, 85%; (c) 1. NaOH, EtOH/H2O (1:1), 80 °C; 2. CO2, then KI3, H2O, 95%; (d) Raney Ni, DCM/EtOH, 71%; (e) SEM-Cl, i-Pr2NEt, TBAF,
DCM, 97%; (f) NaH, HCO2Et, Et2O, 96%; (g) 5, NMP, K2CO3, 95%; (h) MgBr2, n-BuSH, Et2O, 75%; (i) Hg(OCOCF3)2, THF; (l) NaBH4, THF, aq NaOH
5%, 50% over two steps; (m) AcOEt/MeOH, (2:1), cat. Pd(C), H2 1 atm, 95%.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
The absolute configuration at the C-3 and C-4 stereocenters of
the so formed iridoid 15 would then ensue from addition of the
primary hydroxyl groups across the si-face of the (E) double bond,
followed by 1,3 migration of the mercury atom from oxygen to
carbon on the less encumbered side of the tricyclic system and free
radical displacement of the mercury atom (Scheme 2).15 In the event,
References
(1) (a) Jensen, S. R.; Kirk, O.; Nielsen, B. J.; Norrestam, R. Phytochemistry
1987, 6, 1725-1731. (b) Boros, C. A.; Stermitz, F. R. J. Nat. Prod. 1990,
53, 1055-1147. (c) Tietze, L. F.; Fischer, R.; Remberg, G. Liebigs Ann.
Chem. 1987, 971-975. (d) Santangelo, E. M.; Roticci, D.; Liblikas, I.;
Norin, T.; Unelius, C. R. J. Org. Chem. 2001, 66, 5384-5387 and
references therein.
treatment of glucoside 4 with Hg(OCOCF3)2 in THF, followed by
reduction of the intermediate organomercurial with basic NaBH4,
smoothly provided protected semperoside A 15 as a single
stereoisomer in 50% yield. Subsequent Pd(0)-mediated hydro-
genolysis (H2, 5% Pd/C in AcOEt/MeOH) of the four benzyl groups
(2) Ghisalberti, E. L. Phytomedicine 1998, 5, 147-163.
(3) Zanoni, G.; Agnelli, F.; Meriggi, A.; Vidari, G. Tetrahedron: Asymmetry
2001, 12, 1779-1784.
(4) (a) Curran, D. P.; Chen, M.-H.; Leszczweski, D.; Elliot, R. L.; Rakiewicz,
D. M. J. Org. Chem. 1986, 51, 1612-1614. (b) Grieco, P. A.; Srinivasan,
C. V. J. Org. Chem. 1981, 46, 2591-2593.
1
delivered compound 1 in 95% isolated yield. H and 13C spectra,
and IR spectroscopic data of 1 were identical to those described
for semperoside A.1a The melting point and optical rotation of 1
finely matched those of a repurified sample of natural semperoside
[natural semperoside A: mp ) 181-183 °C, [R]20D +65.7 (c 0.2,
(5) Corey, E. J.; Weinshenker, N. M.; Shaaf, T. K.; Huber, W. J. Am. Chem.
Soc. 1969, 91, 5675-5677.
(6) Kamano, Y.; Pettit, G. R. J. Org. Chem. 1973, 38, 2202-2204.
(7) The 13C NMR spectrum of 6 revealed a mixture of (E)- and (Z)-enol olefins
and traces of the corresponding aldehyde.
MeOH);16 synthetic 1: mp ) 182-184 °C; [R]20 +67.2 (c 0.3,
(8) (a) Miller, B.; Margulies, H.; Drabb, T., Jr.; Wayne, R. Tetrahedron Lett.
1970, 11, 3801-3804. (b) MacAlpine, G. A.; Raphael, R. A.; Shaw, A.;
Taylor, A. W.; Wild, H.-J. J. Chem. Soc., Perkin Trans. 1 1976, 411-
417.
(9) Spohr, U.; Bach, M.; Spiro, R. G. Can. J. Chem. 1993, 71, 1928-1942.
(10) Cassady, J.; Howie, G. A. J. Chem. Soc., Perkin Trans. 1 1974, 512-
513.
D
MeOH)]. In addition, CD spectra of the natural and the synthetic
samples showed an identical Cotton effect at 215 nm (∆ꢀ ) -1.3).
Thus, the sterecontrolled synthesis of glucoside 1 from (3aR,4R,-
6aS)-lactone 8 proved the absolute configuration of semperoside
A unequivocally. This stereostructure corresponds to the stereo-
chemistry originally suggested by Jensen and co-workers.1a In
summary, a versatile and concise strategy for the total synthesis of
semperoside A 1, an iridoid endowed with an unusual glycosidation
pattern, has been developed. This inaugural total synthesis of
semperoside A was achieved in 10 steps and 17% overall yield
from the enantiomerically pure lactone 8, which is now available
in multigram amount.17
(11) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293-297.
(12) Green, T. W.; Wuts, P. M. ProtectiVe Groups in Organic Synthesis; Wiley-
Interscience, New York, 1999; pp 45-48.
(13) (a) Takahashi, M.; Suzuki, H.; Moro-Oka, Y.; Ikawa, T. Tetrahedron Lett.
1982, 23, 1079-1082. (b) Tietze, L. F.; Lo¨gers, M. Liebigs Ann. Chem.
1990, 261-265. (c) Deslongchamps, P.; Dory, Y. L.; Li, S. HelV. Chim.
Acta 1996, 79, 41-50.
(14) Paquette, L. A.; Bolin, D. G.; Stepanin, M.; Branan, B. M.; Mallavadhani,
U. V.; Tae, J.; Eisemberg, S. W. E.; Rogers, R. D. J. Am. Chem. Soc.
1998, 120, 11603-11615.
(15) (a) Hill, C. L.; Whitesedes, G. M. J. Am. Chem. Soc. 1974, 96, 870-876.
(b) Kang, S. H.; Lee, J. H.; Lee, S. B. Tetrahedron Lett. 1998, 39, 59-
62.
(16) Published data of semperoside A are slightly different,1a probably due to
an impurity we detected (TLC) in the original natural material.
(17) Zanoni, G.; Porta, A.; Meriggi, A.; Franzini, M.; Vidari, G. J. Org. Chem.
2002, 67, 6064-6069.
Acknowledgment. This research was supported by Italian
MIUR (funds COFIN and FIRB). We thank Professor S. R. Jensen
(Technical University of Denmark) for an authentic sample of
natural semperoside A 1.
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