Scheme 1. Retrosynthetic analysis of Polyrhacitide A (1) and
epi-Cryptocaryolone (3a)
Figure 1. Structures of polyrhacitide A (1), polyrhacitide B (2),
cryptocaryolone (3), and cryptocaryolone diacetate (4).
investigation showed that they have significant biological
activities and medicinal properties, ranging from the treat-
ment of headaches and morning sickness to that of cancer,
pulmonary disease, and various bacterial and fungal infec-
tions.5 The absolute and relative configurations of crypto-
caryolone (3) and cryptocaryolone diacetate (4) was estab-
lishedbyitsfirst total synthesis.7a Thedistinctivebiological
activities and fascinating architectures have stimulated
synthetic efforts directed toward their total synthesis.6,7
In all previous reports, intramolecular Michael addition
reaction8 was the only route for the synthesis of the bicyclic
lactone core. To overcome these constraints, new synthetic
strategies are well desired, and this prompted us to develop
a concise, stereoselective synthetic pathway via an advanced
intermediate from which both polyrhacitide A (1) and epi-
cryptocaryolone (3a) could be obtained.
In recent years, the use of molecular iodine in organic
synthesis has received considerable attention as an inex-
pensive, nontoxic, readily available mild Lewis acid cata-
lyst for various organic synthesis and transformations.9
Recently, we have reported a highly stereoselective synth-
esis of trans-2,6-disubstituted dihydropyran using molecu-
lar iodine as a cheap and eco-friendly Lewis acid catalyst.10
As part of our ongoing research on iodo-cyclization reac-
tions and its applications toward complex natural product
synthesis, herein, we report a successful syntheses of poly-
rhacitide A (1) and epi-cryptocaryolone (3a) in a highly
stereoselective and concise manner.
From a retrosynthetic perspective, we envisioned that
the most challenging bicyclic lactone would be constructed
from the acid 5 via iodo-lactonization that in turn would
arise from the terminal epoxide 6 (Scheme 1). The epoxide
could be prepared from iodo-derivative 7, which serves as
an advanced common intermediate for the syntheses of 1
and 3a. Iodo-carbonate intermediate 7 could be obtained
from a known intermediate 8 which in turn could be
prepared following a recently reported protocol from our
lab.
The synthesis commenced from the known chiral ep-
oxide 9 which was converted to a trans-2,6-disubstituted
dihydropyran ring system 8 via recently reported highly
stereoselective iodine catalyzed allylation methodology.10
The homoallyl alcohol 10was obtainedby treatingepoxide
9 with vinylmagnesium bromide in thepresence of a cata-
lytic amount of CuI at -20 °C in 85% yield (Scheme 2). In
order to achieve the synthesis of R,β-unsaturated aldehyde
11, a cross-metathesis (CM) between homoallyl alcohol 10
and acrolein (6.0 equiv) was carried out using a Hoveyda-
Grubbs catalyst (10 mol %) in CH2Cl2 at room tempera-
ture for 2 h afforded δ-hydroxy R,β-unsaturated aldehyde
11 in 85% yield. Treatment of 11 with 10 mol % molecular
iodine in THF at room temperature furnished the trans-
2,6-disubstituted-3,4-dihydropyran 8 in 91% yield. Next,
following Jin’s one-step dihydroxylation-oxidation
protocol,11 terminal olefin was selectively oxidized
to aldehyde 12 in 84% yield. The resultant aldehyde was
subjected to a Maruoka asymmetric allylation12 reaction
using (R)-BINOL to furnish the homoallyl alcohol 13
as a single isomer. It was then treated with di-tert-butyl
(5) Sam, T. W.; Yeu, C. S.; Jodynis-Liebert, J.; Murias, M.; Bloszyk,
E. Planta Med. 2000, 66, 199.
(6) For previous syntheses of polyrhacitides, see: (a) Menz, H.;
Kirsch, S. F. Org. Lett. 2009, 11, 5634. (b) Ghosh, S.; Rao, C. N.
Tetrahedron Lett. 2010, 51, 2052. (c) Yadav, J. S.; Rajendar, G.; Ganganna,
B.; Srihari, P. Tetrahedron Lett. 2010, 51, 2154.
(7) For previous syntheses of cryptocaryolone and cryptocaryolone
diacetate, see: (a) Smith, C. M.; O’Doherty, G. A. Org. Lett. 2003, 5,
1959. (b) Wang, X.; Wang, W.; Zheng, H.; Su, Y.; Jiang, T.; He, Y.; She, X.
Org. Lett. 2009, 11, 3136.
(8) Nising, C. F.; Braese, S. Chem. Soc. Rev. 2008, 37, 1218.
(9) For recent reviews, see: (a) Stavbers, S.; Jereb, M.; Zupan, M.
Synthesis 2008, 1487. (b) Togo, H.; Lida, S. Synlett 2006, 2159. (c) Smith,
M. B. e-EROS Encyclopedia of Reagents for Organic Synthesis; John
Wiley & Sons, Ltd.: 2001. (d) French, A. N.; Bissrire, S.; Wirth, T. Chem.
Soc. Rev. 2004, 33, 354. (e) Das, S.; Borah, R.; Devi, R. R.; Thakur, A. J.
Synlett 2008, 2741. For some reaction using iodine as Lewis acid, see:
(f) Sun, J.; Dong, Y.; Cao, L.; Wang, X.; Wang, S.; Hu, Y. J. J. Org. Chem.
2004, 69, 8932. (g) Bosco, J. W. J.; Agrahari, A.; Saikia, A. K. Tetrahedron
Lett. 2006, 47, 4065.
(11) Yu, W.; Mei, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217.
(12) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc.
2003, 125, 1708.
(10) Mohaparta, D. K.; Das, P. P.; Pattanayak, M. R.; Yadav, J. S.
Chem.;Eur. J. 2010, 16, 2072.
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