An enantioselective synthetic strategy toward the polyhydroxylated agarofuran

Article abstract of DOI:10.1016/S0040-4039(01)00377-X

This paper describes a new approach for the enantioselective syntheses of naturally occurring polyhydroxylated dihydroagarofuran sesquiterpenoids starting from (-)-carvone. Through utilizing asymmetric Robinson annulation and acetoxylation as key steps, the agarofuran skeleton was enantioselectively constructed and an oxyfunctionalized group was introduced into the C-1 position. The important intermediate 23 to dihydroagarofuran was obtained in eleven steps.

Full text of DOI:10.1016/S0040-4039(01)00377-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3101–3103
An enantioselective synthetic strategy toward the
polyhydroxylated agarofuran
Gang Zhou, Xiaolei Gao, Weidong Z. Li and Yulin Li*
National Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University, Lanzhou,
Gansu 730000, PR China
Received 9 August 2000; revised 1 March 2001; accepted 2 March 2001
Abstract—This paper describes a new approach for the enantioselective syntheses of naturally occurring polyhydroxylated
dihydroagarofuran sesquiterpenoids starting from (−)-carvone. Through utilizing asymmetric Robinson annulation and acetoxyla-
tion as key steps, the agarofuran skeleton was enantioselectively constructed and an oxyfunctionalized group was introduced into
the C-1 position. The important intermediate 23 to dihydroagarofuran was obtained in eleven steps. © 2001 Elsevier Science Ltd.
All rights reserved.
In the sesquiterpenic family, a large number of b-dihy-
droagarofuran polyol esters based on dihydroagaro-
furan skeleton 1 have been isolated1,2 from the species
Celastraceae. These kind of compounds have been
demonstrated to exhibit a wide spectrum of biological
properties, including significant cytotoxic,3 immunosup-
pressive,4 anticancer,5 insect antifeedant6 and potent
anti-HIV activity.7 Their classic derivatives range from
the least structurally complex diol 2,8 and the triol
isocelorbicol 3,9 to complex polyols such as 4 (Fig. 1).10
ested in developing a facile and general approach for
the total synthesis of a polyhydroxylated agarofuran.
Reported herein is an efficient approach for the enan-
tioselective construction of a carbon skeleton and the
introduction of an oxyfunctionalized group at the C-1
position.
In our earlier efforts, research interest was mainly
focused on the introduction of an oxygenated group at
the C-1 position. Our initial synthetic strategy was to
employ ( )-9-keto-a-agarofuran 5 as a key intermedi-
ate, which was readily prepared from carvone in seven
steps.13 After considerable endeavor, several intermedi-
ates 6–12 have been obtained in several steps (Fig. 2).
Unfortunately, attempted allylic oxidation or enone’s
a%-position oxidation of these compounds failed under
various conditions, including PCC, SeO2, CrO3–SiO2,
PDC, CrO3–tBuOOH, Pb(OAc)4 and Mn(OAc)3.
Employing oxidative agents mentioned above only
resulted in undesired products, complex mixtures or
recovered substrates.
Their highly oxygenated tricyclic frameworks, compris-
ing a number of contiguous stereocenters, pose a
formidable synthetic challenge and have attracted
immense interest from synthetic chemists. Several
racemic total syntheses of polyhydroxylated agaro-
furans have been reported since 1984.11,12 However,
there is no report on the total synthesis of optically
active polyhydroxylated agarofuran to our knowledge.
In our own quest for an enantioselective avenue toward
a bioactive polyhydroxylated agarofuran, we are inter-
OH OH
OH OH
OH OH
HO
HO
HO
9
6
1
4
8
7
2
3
5
12
13
O
O
O
O
HO
11
4
2
3
1
Figure 1.
Keywords: dihydroagarofuran; sesquiterpenoid; enantioselective synthesis.
* Corresponding author. E-mail: liyl@lzu.edu.cn
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00377-X

3102
G. Zhou et al. / Tetrahedron Letters 42 (2001) 3101–3103
O
OH
OBz
OBz
O
O
O
O
O
HO
8
7
5
6
OBz
OBz
OH
OBz
O
O
HO
HO
O
O
O
O
11
12
9
10
Figure 2.
On the assumption that failure to introduce an oxy-
functionalized group at the C-1 position was due to the
steric hindrance of a rigid tetrahydrofuran ring, com-
bined with a consideration of the enantioselective syn-
thesis at the same time, we then turned our attention to
an alternative synthetic approach. The detailed path-
way of synthesis is summarized in Scheme 1.
(R)-O-acetylmandelic acid.16 Tosyl hydrazone forma-
tion followed by treatment with excess n-BuLi (6
equiv.) in anhydrous THF gave the conjugated diene 19
in 86% total yield.17 Diels–Alder cycloaddition of
diene18 19 to singlet oxygen generated from the adducts
between triphenylphosphite and ozone19 afforded the
desired endo-peroxide 20 as a single product in 81%
yield, in which the peroxide bridge was assigned as the
b-configuration based on the consideration that the
steric hindrance of the angular methyl group restricts
the approach of oxygen from the site undergoing reac-
tion. Rearrangement of peroxide 20 on K2CO3 in THF
gave the hydroxyl ketone 21 in 78% yield. The b-
configuration of the C-5 hydroxyl group in 21 was
further confirmed by the latter’s easy cyclization.
Regioselective acetoxylation with Mn(OAc)3 at the C-1
of enone 21 ultimately furnished the less polar acetate
22 in 53% yield.20 The stereochemistry of the acetate 22
was confirmed via an NOE experiment. According to
By the published method,14 an inseparable trione mix-
ture 15 could be readily prepared from commercially
available (−)-carvone 13 by epoxidation, cleavage of
epoxide and condensation with ethyl vinyl ketone.
D
-(+)-Phenylalanine-catalyzed asymmetric Robinson
annulation15 of trione 15 afforded the (−)-9-oxo-10-epi-
a-cyperone 16 (54% e.e.; [h]1D0 −25.5, c 2.54, CHCl3) in
51% yield by Hagiwara’s method. Selective reduction of
the keto group of 16 by sodium borohydride in MeOH
provided the hydroxyl enone 17. The enantiomeric
excess of 16 was determined by esterification of 17 with
OH
O
O
c
a, b
d
51%
85%
25%
O
O
O
O
O
13
15
16
14
e
75%
OH
OH
OH
OH
g
f
h
81%
O
O
90%
TsHNN
95%
O
19
18
17
20
78%
OH
i
OAc
OH
OAc
OH
O
O
O
j
K
53%
95%
O
OH
OH
22
21
23
Scheme 1. (a) 30% H2O2, KOH, MeOH–H2O, 0°C, 2.5 h; (b) 1N NaOH, H2O, reflux, 1 h; (c) EVK, KOH, MeOH, reflux, 6 h;
(d) -(+)-phenylalanine, -(+)-CSA, 30–70°C, 6 days; (e) NaBH4, MeOH, 0°C, 3 h; (f) TsNHNH2, BF3·Et2O, rt, 2 h; (g) n-BuLi,
D
D
THF, −78°C to 0°C, 10 h; (h) O3, P(OPh)3, CH2Cl2, −78°C to 0°C, 2.5 h; (i) K2CO3, THF, 40°C, 24 h; (j) Mn(OAc)3, benzene,
reflux, 10 h; (k) TfOH, THF, rt, 5 min.

G. Zhou et al. / Tetrahedron Letters 42 (2001) 3101–3103
3103
the literature method,11a treatment of 22 with trifl-
uoromethanesulfonic acid smoothly afforded pure
agarofuran 23 (60% e.e.;16 [h]D21 −12.9, c 0.78, CHCl3)
after chromatographic purification of the crude product
on silica gel, which has shown identical spectral data
with its structure.21 The downfield 13C NMR signals at
l 83.62 and 83.43 for two oxygen-linked quaternary
carbons indicated the successful cyclization of the tetra-
hydrofuran ring.
In summary, we have presented a new enantioselective
synthetic strategy to construct the skeleton and intro-
duce an oxyfunctionalized group into the C-1 position
as anticipated, which allows us to obtain the optically
active important intermediate 23 to polyhydroxylated
agarofuran starting from (−)-carvone in eleven steps.
Application of the established method to the further
syntheses of a number of naturally occurring polyhy-
droxylated agarofurans is under active investigation.
25, 513; (b) Gonzalez, A. G.; Jimenez, I. A.; Ravelo, A.
G.; Bazzocchi, I. L. Tetrahedron 1993, 49, 6637.
7. Duan, H.; Takaishi, Y.; Bando, M.; Kido, M.; Imakura,
Y.; Lee, K. Tetrahedron Lett. 1999, 40, 2969.
8. Tu, Y. Q.; Wu, D. G.; Zhou, J.; Chen, Y. Z. Phytochem-
istry 1990, 29, 2923.
9. Smith, C. R.; Miller, R. W.; Weisleder, D.; Rohweder,
W. K.; Eickman, N.; Clardy, J. J. Org. Chem. 1976, 41,
3264.
10. Gonzalez, A. G.; Luis, J. G.; Grillo, T. A.; Vazquez, J. T.
J. Nat. Prod. 1991, 54, 579.
11. (a) White, J. D.; Shin, H.; Kim, T.-S.; Cutshall, N. S. J.
Am. Chem. Soc. 1997, 119, 2404; (b) White, J. D.; Cut-
shall, N. S.; Kim, T.-S.; Shin, H. J. Am. Chem. Soc. 1995,
117, 9780.
12. (a) Huffman, J. W.; Raveendranath, P. C. Tetrahedron
1987, 43, 5557; (b) Huffman, J. W.; Desai, R. C.; Hillen-
brand, G. F. J. Org. Chem. 1984, 49, 982; (c) Huffman, J.
W.; Raveendranath, P. C. J. Org. Chem. 1986, 51, 2148.
13. Huffman, J. W.; Hillenbrand, G. F. Tetrahedron Suppl.
1981, 9, 269.
Acknowledgements
14. Li, Y.; Chen, X.; Shao, S.; Li, T. Indian J. Chem. 1993,
32, 356.
We are grateful for the financial support from the
National Natural Science Foundation of China (Grant
No. 29732060), the National Outstanding Youth Fund
(No. 29925204) and the Foundation for University Key
Teacher by the Ministry of Education of China.
15. Hagiwara, H.; Uda, H. J. Org. Chem. 1988, 53, 2308.
16. Parker, D. J. Chem. Soc., Perkin Trans. 2, 1983, 83. The
enantiomeric excess of compounds 16 and 23 was deter-
mined by 1H NMR integration of the esters of com-
pounds 17 and 23 with (R)-O-acetylmandelic acid.
17. Shapiro, R. H. Org. React. (N.Y.) 1976, 23, 405.
18. For Diels–Alder cycloaddition using singlet oxygen with
diene, see: (a) Adam, W.; Prein, M. Acc. Chem. Res.
1996, 29, 275; (b) Wasserman, H. H.; Ives, J. L. Tetra-
hedron 1981, 37, 1825.
References
1. (a) Munoz, O.; Penazola, A.; Gonzales, A. G.; Ravelo, A.
G.; Bazzocchi, I. L.; Alvarenga, N. L. In Studies in
Natural Products Chemistry; Atta-ur-Rahman, Ed.;
Elsevier Science: Amsterdam, 1996; Vol. 18, pp. 739–783;
(b) Crombie, L.; Crombie, W. M. L.; Whiting, D. A. The
Alkaloids 1990, 39, 139–164.
2. Gonzalez, A. G.; Gonzalez, C. M.; Ravelo, A. G.; Fraga,
B. M.; Dominguez, X. A. Phytochemistry 1988, 27, 473.
3. Kuo, Y.-H.; King, M. L.; Chen, C.-F.; Chen, H.-Y.;
Chen, C.-H.; Chen, K.; Lee, K.-H. J. Nat. Prod. 1994, 57,
263.
4. Zhen, Y. L.; Xu, Y.; Lin, J. F. Acta Pharm. Sin. 1989, 24,
568.
5. Takaishi, Y.; Ujita, K.; Tokuda, H.; Nishino, H.;
Iwashima, A.; Fujita, T. Cancer Lett. 1992, 65, 19.
6. (a) Gonzalez, A. G.; Jimenez, I. A.; Ravelo, A. G.; Coll,
J.; Gonzalez, J. A.; Lloria, J. Biochem. Syst. Ecol. 1997,
19. Murray, R. W.; Kaplan, M. L. J. Am. Chem. Soc. 1969,
91, 5358.
20. For general reviews on the Manganese(III) mediated
acetylation of a,b-unsaturated systems, see: (a) Melikyan,
G. G. Synthesis 1993, 833; (b) Demir, A. S.; Jeganathan,
A. Synthesis 1992, 235.
1
21. Spectral data for 23: H NMR (400 MHz, CDCl3) l 0.90
(s, 3H), 1.23 (s, 3H), 1.33 (s, 3H), 2.00 (s, 3H), 2.10 (s,
3H), 2.77 (d, J=4.4 Hz, 1H), 3.98 (m, 1H), 4.88 (s, 1H),
6.01 (s, 1H); 13C NMR (100 MHz, CDCl3) l 192.6, 172.3,
158.5, 127.7, 83.6, 83.4, 75.5, 65.2, 46.3, 42.7, 34.2, 30.7,
29.9, 22.5, 21.0, 20.2, 17.5. EIMS (70 eV) m/z 308 (M+,
3%), 293 (15%), 291 (50%), 290 (5%), 240 (13%), 149, 75
(100); IR (film): 3486, 2976, 2934, 1729, 1680 cm−1
;
FAB-HRMS: found 331.1510, C17H22O5+Na+ requires:
331.1521.
.
.