A concise total synthesis of triptolide

Full text of DOI:10.1021/jo981362g

6446
J . Org. Chem. 1998, 63, 6446-6447
A Con cise Tota l Syn th esis of Tr ip tolid e
Dan Yang,* Xiang-Yang Ye, Ming Xu, Kwan-Wah Pang,
Ning Zou, and Roy M. Letcher
Department of Chemistry, The University of Hong Kong,
Pokfulam Road, Hong Kong
F igu r e 1.
Received J uly 14, 1998
Here, the radical cyclization was highly stereoselective, as
four stereocenters were set up in one step. Construction of
R,â-unsaturated γ-lactone 8 was carried out in three steps
following the method developed by Crisp.10 Vinyl triflate
formation from â-keto ester 6 was followed by DIBAL-H
reduction. Subsequent Pd-catalyzed carbonylation of the
hydroxy vinyl triflate provided lactone 8.
Acetonide deprotection of 8 gave a 1:1 mixture of diols 9
and 10, the latter being formed as a result of epimerization
under the hydrolysis condition. Diol 9 was converted to
monoepoxide 11 using the Adler reaction.11 A one-pot
process involving acetonide removal and Adler reaction was
found to give a moderate yield of monoepoxide 11 directly
from 8. When methyl(trifluoromethyl)dioxirane generated
in situ was used,12 the second epoxide was introduced as a
single diastereomer. Further epoxidation with basic H2O2
provided triptonide 12, another potent immunosuppressant
isolated from Lei Gong Teng. Here the two epoxidation
processes offered complete stereocontrol and high efficiency.
Finally, reduction of triptonide 12 with NaBH4 in MeOH in
the presence of Eu(fod)3 furnished triptolide 1 (47%) together
with its R-hydroxyl epimer 13 (47%).13
Triptolide 1, a diterpenoid with a triepoxide structure, was
isolated by Kupchan from the Chinese medicinal herb
Tripterygium wilfordii Hook F (Lei Gong Teng) and found
to have potent antileukemic and antitumor activities.1
Subsequent studies showed that triptolide also inhibits
lymphocyte proliferation and interleukin-2 production, which
may account for the effectiveness of Lei Gong Teng crude
extracts in the treatment of a number of immune disorders
such as rheumatoid arthritis and systemic lupus erythema-
tosus.2 While epoxide alkylation was proposed to be the
mode of action, triptolide’s actions on cells remain
unknown.1b,3 To unravel triptolide’s structural features that
are responsible for its immnosuppressive activities, we have
developed a concise total synthesis of triptolide and its
analogues, which is reported herein.4
Our synthetic strategy for triptolide 1 is shown in Figure
1. The key steps involve (1) radical cyclization of an acyclic
5
precursor mediated by Mn(OAc)3 and (2) triepoxide con-
struction using our previously reported method.6
As shown in Scheme 1, compound 2 was readily synthe-
sized from commercially available 2-isopropylphenol in three
steps.7 Benzylic deprotonation of 2 and coupling of the
derived higher order mixed cuprate with 2-methyl-2-viny-
loxirane using the Lipshutz method8 generated 3 in 72%
yield. Allylic alcohol 3 was converted to bromide 4, which
upon treatment with methyl acetoacetate dianion furnished
the acyclic precursor 5.9 Radical cyclization of compound 5
using the Snider method5 gave two major products: 6 of
trans ring juncture (40%) and 7 of cis ring juncture (8%).
Despite high stereoselectivity, radical cyclization of 5
suffered from side reactions such as hydrolysis of the
acetonide group and benzylic elimination. Therefore, an
alternative preparation of 9 was developed (Scheme 2).
Ortho-directed metalation of MOM ether 14 with n-BuLi and
alkylation with MeI was followed by another lithiation with
s-BuLi and quenching with 4-bromo-2-methyl-2-butene to
furnish olefin 15.14 Compound 15 was converted to its
methyl ether, which was then oxidized to allylic alcohol 16.15
Acyclic precursor 17 was prepared in two steps from 16 by
bromination and dianion displacement. Radical cyclization
of 17 gave two major products 19a (55%) and 20 (20%). In
comparison, radical cyclization of R-chlorinated precusor 18
gave the desired trans product 21 in excellent yield (90%),
and dechlorination of 21 afforded compound 19b quantita-
tively.16,17 19a and 19b were converted to the known lactone
22 following the Crisp method.10 Deprotection of 22 with
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5424. (b) Garver, L. C.; van Tamelen, E. E. J . Am. Chem. Soc. 1982, 104,
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Tokoroyama, T.; Koike, H.; Hirotsu, K.; Ezaki, Y. Tetrahedron 1982, 38,
2559.
18
BBr3 furnished racemic triptophenolide 23, an antiinflam-
matory agent also isolated from Lei Gong Teng.19 Benzylic
oxidation of 22 and subsequent demethylation and reduction
provided â-alcohol 9.4f
(10) Crisp, G. T.; Meyer A. G. J . Org. Chem. 1992, 57, 6972.
(11) (a) Adler, E.; Brasen, S.; Miyake, H. Acta Chem. Scand. 1971, 25,
2055. (b) Becker, H. D.; Bremholt, T.; Adler, E. Tetrahedron Lett. 1972, 41,
4205.
(12) Yang, D.; Wong, M.-K.; Yip, Y.-C. J . Org. Chem. 1995, 60, 3887.
(13) NaBH4 reduction in the absence of Eu(fod)3 gave a 1:3 mixture in
favor of the wrong isomer (13). See ref 4d.
(14) (a) For a recent review on ortho-directed metalation, see: Snieckus,
V. Chem. Rev. 1990, 90, 879. (b) Winkle, M. R.; Ronald, R. C. J . Org. Chem.
1982, 47, 2101.
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cyclizations, see: Snider, B. B. Chem. Rev. 1996, 96, 339. (b) Snider, B. B.;
Mohan, R.; Kates, S. A. J . Org. Chem. 1985, 50, 3659. (c) Snider, B. B.;
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Chem. Soc., Perkin Trans. 1 1980, 1862.
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1986, 42, 2873. (c) Lipshutz, B. H.; Ellsworth, E. L.; Behling, J . R.; Campbell,
A. L. Tetrahedron Lett. 1988, 29, 893.
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S0022-3263(98)01362-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/01/1998

Communications
J . Org. Chem., Vol. 63, No. 19, 1998 6447
Sch em e 1a
Sch em e 2a
a
Reagents and conditions: (a) MOMCl, NaH, THF, 65 °C, 2.5 h,
a
Reagents and conditions: (a) (CH2O)n, SnCl4, 2,6-lutidine, toluene,
100 °C, 10 h, 82%; (b) NaBH4, MeOH, 0 °C, 1 h, 96%; (c) (CH3)2C(OCH3)2,
TsOH (cat.), CH2Cl2, reflux, 1 h, 80%; (d) s-BuLi, THF, -78 °C, 0.5 h;
99%; (b) n-BuLi, THF, -40 to +20 °C, 2 h, then MeI, -78 °C, 1 h,
98%; (c) s-BuLi, THF, -78 to -30 °C, 2 h, then (CH3)2CdCHCH2Br,
-78 °C, 1 h, 98%; (d) TMSCl, LiBF4, CH3CN, -10 to +25 °C, 4 h, 97%;
(e) Me2SO4, K2CO3, acetone, reflux, 2.5 h, 100%; (f) SeO2, t-BuOOH
(4.0 equiv), CH2Cl2, 0 °C, 8 h, then NaBH4, MeOH, 73%; (g) MsCl,
Et3N, CH2Cl2, -40 to -20 °C, 1 h, then LiBr, THF, -20 to +25 °C, 2
h, 96%; (h) CH3COCH2CO2CH3, NaH, n-BuLi, THF, 0 °C, 1 h, 85% of
17; or CH3COCHClCO2Et, NaH, n-BuLi, THF, -10 °C, 1 h, 84% of
18; (i) HOAc, Mn(OAc)3‚2H2O, 70 °C, 1 h, 55% of 19a and 20% of 20;
(j) HOAc, Mn(OAc)3‚2H2O, rt, 6 h, 90%; (k) Zn/HOAc, rt, 2 h, 100%; (l)
KHMDS, PhNTf2, THF, -78 to +25 °C, 14 h; (m) DIBAL-H, THF, -78
to +25 °C, 8 h; (n) LiCl, n-Bu3N, Pd(PPh3)4, CO (1 atm), THF, 65 °C,
12 h, overall 64% (from 19a or 19b); (o) BBr3, CH2Cl2, -40 to +25 °C,
12 h, 99%; (p) CrO3, HOAc/H2O (9:1), 6 h; (q) BBr3, CH2Cl2, -40 °C to
+25 °C, 12 h; (r) NaBH4, MeOH, 0 °C, 2 h, 44% from 22. Abbrevia-
tions: MOM, methoxymethyl.
CuCN, 2-thienylithium, THF, -78 to +25 °C,
1 h; 2-methyl-2-
vinyloxirane, -78 to 0 °C, 4 h, 72%; (e) PPh3, CBr4, CH2Cl2, 25 °C, 0.5
h, 88%; (f) CH3COCH2COOCH3, NaH, n-BuLi, THF, 0 °C, 1 h, 84%;
(g) Mn(OAc)3‚2H2O, HOAc, 70 °C, 1 h, 40% of 6 and 8% of 7; (h)
KHMDS, PhNTf2, THF, -78 to +25 °C, 14 h, 98%; (i) DIBAL-H, THF,
-78 to +25 °C, 8 h, 72%; (j) LiCl, n-Bu3N, Pd(PPh3)4, CO (1 atm), THF,
65 °C, 12 h, 97%; (k) PPTS, CH3CN/H2O (1:1), 70 °C, 10 h, 40% of 11
and 40% of 12; (l) NaIO4, TsOH, CH3CN/H2O (3:1), 25 °C, 4 h, 52%
(50% conversion); (m) NaIO4, MeOH/H2O (3:1), 0-25 °C, 1 h, 96%; (n)
CF3COCH3, Oxone, NaHCO3, CH3CN/H2O (3:2), 25 °C, 4 h, 70%; (o)
H2O2, NaOH, MeOH, 25 °C, 3 h, 96%; (p) Eu(fod)3, NaBH4, MeOH,
-40 °C, 0.5 h, 47% of 1 and 47% of 16. Abbreviations: KHMDS,
potassium hexamethyldisilazide; PPTS, pyridinium p-toluenesulfonate.
The above scheme can be adapted to an enantioselective
total synthesis by using acyclic precursors bearing chiral
auxiliaries in the radical cyclization step.20 More impor-
tantly, it will allow rapid access to various triptolide
analogues designed to probe the cellular processes that
triptolide interferes with.
Ack n ow led gm en t . This work was supported by the
University of Hong Kong and the Hong Kong Research
Grants Council. We thank Dr. K.-K. Cheung for X-ray
analysis.
Su p p or tin g In for m a tion Ava ila ble: Determination of ster-
eochemistry for compounds 6 and 7 (34 pages).
(20) Zhang, Q.; Mohan, R. M.; Cook, L.; Kazanis, S.; Peisach, D.; Foxman,
B. M.; Snider, B. B. J . Org. Chem. 1993, 58, 7640.
J O981362G