Formal synthesis of semiaquilegin A

Article abstract of DOI:10.1016/j.tetlet.2009.12.118

A formal synthesis of semiaquilegin A is achieved starting from readily available oridonin in 19 linear steps. The absolute configuration of the natural product has been established. A variety of useful analogues were prepared through this synthetic route.

Full text of DOI:10.1016/j.tetlet.2009.12.118

Tetrahedron Letters 51 (2010) 1121–1123
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Formal synthesis of semiaquilegin A
a,
Jing Li a, Yong Jiang a, Qingjiang Li a, Qiang Xiao b, Yanxing Jia a, , Pengfei Tu
*
*
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China
b Institute of Organic Chemistry, Jiangxi Science & Technology Normal University, Nanchang 330013, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A formal synthesis of semiaquilegin A is achieved starting from readily available oridonin in 19 linear
steps. The absolute configuration of the natural product has been established. A variety of useful ana-
logues were prepared through this synthetic route.
Received 6 November 2009
Revised 15 December 2009
Accepted 21 December 2009
Available online 28 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Semiaquilegin A
Oridonin
Barton deoxygenation
Formal synthesis
Semiaquilegin A (1) (Fig. 1) was isolated by Tu and co-workers
from the roots of Semiaquilegia adoxoides (DC.) Makino., which has
been used for treating inflammation, snakebite, bruises, and so on
in Traditional Chinese Medicines (TCM).1 The structure of semi-
OH
HO
OH
OH
aquilegin A is 16
E-cinnamoyl) ester. It exhibits potent cytotoxic activity against
many cancer cell lines, such as Bel-7402 (IC50 = 5.61 M), BGC-803
(IC50 = 10.88 M), Hela (IC50 = 4.36 M), HL-60 (IC50 = 4.65 M),
and MCF-7 (IC50 = 6.38
M).2 The lack of availability from natural
a-hydroxy-ent-kaurane-17,20-di-(3,4-dihydroxy-
12
11
13
17
O
16
HO
20
l
O
H
H14
O
H
OH
H
O
9
l
l
l
1
4
8
OH
2
3
10
O
5
O
15
l
6
7
OH
sources has severely hampered its further development. The
complexity of its structure makes it difficult to provide a solution
to this supply problem by total synthesis of this formidable target.3
A semisynthesis of 1 from the readily available natural products is
possibly the simplest approach since it can provide rapid access
not only to 1 but also to other natural members of the ent-kaurane
diterpenoids and a variety of natural product analogues.4 In fact,
there are numerous successful examples of this semisynthetic
approach including taxanes,5 camptothecins,6 and ecteinascidins.7
Oridonin (2),8 an ent-kaurane diterpenoid, would be an appro-
priate candidate, which has various pharmacological and physio-
logical effects and has been used for the treatment of human
cancers, especially for esophageal carcinoma.9 The most relevant
structural difference of the core of 1 with 2 is the presence of many
hydroxy and ketone groups in 2 (Fig. 1). Thus, the conversion of 2
to 1 must involve appropriate deoxygenations at C-1, C-6, C-7,
C-14, and C-15 of the ent-kaurane diterpenoid skeleton. Herein,
we wish to report the formal synthesis of semiaquilegin A from
oridonin.
H
H
OH
18 19
Semiaquilegin A (1)
Oridonin (2)
ent-kaurane
Figure 1. Structures of semiaquilegin A and oridonin.
The successful conversion of oridonin (2) to the semiaquilegin A
(1) is outlined in Scheme 1. Protection of 7,14-dihydroxy in 2 with
2,2-dimethoxypropane in the presence of a catalytic amount of
PTSA provided 3 in 91% yield.10 The olefin of
a,b-unsaturated ke-
tone was first masked due to unsaturated ketone which resulted
in a side reaction during Barton deoxygenation. Thus, epoxidation
of 3 with 30% H2O2 and 6 N NaOH gave 4 in 88% yield (2:1 dr),
which could be separated by careful flash column chromatography.
However, the two diastereoisomers were not separated at this
stage because there was no selectivity in the following radical
epoxide-opening step. Reaction of 4 with NaH, CS2, MeI, and
imidazole in THF gave the thiocarbamate 5 in 88% yield.11 Treat-
ment of 5 with nBu3SnH in the presence of AIBN under refluxing
in toluene for 1 h gave 6a and 6b in 85% overall yield in a ratio
of 2:1 with simultaneous deoxygenation and epoxide-opening.12
The diastereomeric products could be separated and their relative
* Corresponding authors. Tel./fax: +86 10 8280 5166.
E-mail addresses: yxjia@bjmu.edu.cn (Y. Jia), pengfeitu@bjmu.edu.cn (P. Tu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.118

1122
J. Li et al. / Tetrahedron Letters 51 (2010) 1121–1123
O
O
HO
OH
OH
2,2-dimethoxypropane
PTSA, Acetone, 40 ºC
30% H2O2, 6N NaOH
MeOH, 0 ºC
H
H
NaH, CS2, MeI
imidazole, THF
H
O
OH
O
O
O
O
O
O
88%
91%
88%
OH
O
H
O
OH
OH
OH
2
3
4
S
O
OH
OH
MeS
O
H
AIBN, n-Bu3SnH
toluene, 110 oC
H
H
O
+
O
O
O
O
O
O
O
O
85%
O
O
O
O
S
SMe
6a
(2 : 1)
H
6b
5
OAc
OAc
OAc
NaBH4
MeOH
5% HCl
PhOC(S)Cl
Py., CH2Cl2
H
H
Ac2O, Py.
90%
CH2Cl2/MeOH (3:1)
6a
O
OH
OH
OH
O
O
O
83%
0
oC
75%
45%
O
O
O
OH
OH
7
8
9
OAc
S
OAc
O
n-Bu3SnH, AIBN
toluene, 110 oC
PTSA, toluene
1. AcCl, MeOH
85%
110 oC
H
H
O
H
O
O
O
2. TEMPO, NCS
TBACl, CH2Cl2
76%
61%
65%
OH
OMe
OH
OH
OH
O
OH
Ph
10
11
12
O
O
O
H
H
H
O
Pd/C, H2, MeOH
85 %
+
O
O
OH
13
OH
14a
OH
14b
1. NaBH4, MeOH, 0 o
81%
C
OH
OH
OH
OH
H
OH
OH
1. TsCl, Py., CH2Cl2, 90%
2. NaI, acetone, 85%
OsO4, Py.
Et2O, rt
H
H
14a
2. NH2NH2•H2O, glycol
180 - 220 ºC
61%
67%
3. DBU, DMF, 40 oC, 81%
15
16
17
Scheme 1. Synthesis of the core moiety of semiaquilegin A.
configurations were deduced by the NOESY spectrum. It is note-
worthy that the epoxide was opened without stereoselectivity in
this case, and both diastereoisomers of 5 gave the same result.
Protection of 17-hydroxy in 6a with Ac2O in pyridine provided
7 in 90% yield. At this stage, initial attempt for reduction of the
15-carbonyl group in 7 with NaBH4 failed possibly due to the ste-
ric hindrance of acetonide protecting group. Removal of acetonide
group with 5% HCl gave 8 in 83% yield. An attempt to remove the
14-hydroxy of 8 was unsuccessful due to the competitive retro-
aldol reaction under basic conditions. Thus, reduction of 15-car-
bonyl group of 8 with NaBH4 gave 9 smoothly in 75% yield. Reac-
tion of 9 with CS2 and MeI in the presence of a strong base such
as NaH in THF did not give the corresponding thiocarbamate, in-
stead, it resulted in a complicated product. To our delight, treat-
ment of 9 with PhOC(S)Cl and pyridine resulted in selective
reaction of 14-hydroxy to give phenylthionocarbonate 10, which
was reacted with AIBN and nBu3SnH to provide the desired prod-
uct 11.13
Thus, treatment of 11 with acetyl chloride in MeOH followed by
selective oxidation of the primary 17-hydroxy with TEMPO and
NCS provided aldehyde 12.14 Elimination of 15-hydroxy with PTSA
gave the
a,b-unsaturated aldehyde 13 in 65% yield. Reduction of
unsaturated aldehyde 13 (Pd/C, 1 atm H2 balloon) gave 14a and
14b in a ratio of 2:1, which could be separated by flash column
chromatography. Reduction of 14a with NaBH4 followed by
Wolff–Kishner–Huang reaction with NH2NH2ꢀH2O gave 15 success-
fully in a one-pot manner. Selective protection of primary 17-hy-
droxy with TsCl, followed by
a treatment with NaI, then
elimination of 17-iodine with DBU in DMF smoothly afforded the
exocyclic double bond product 16. Finally, treatment of 16 with
OsO4/Py directly gave the desired product 17 in a single diastereo-
isomer through substrate control.15,3
Hydrolysis of natural semiaquilegin A with NaOH in MeOH
provided 17 in 90% yield (Scheme 2). Spectroscopic data for the
synthetic 17 matched that of degradation from natural product.
Its optical rotation {½a D25
ꢂ102 (c 0.98, CHCl3)} was essentially
ꢁ
The removal of 15-hydroxy was the most difficult. After the fail-
ure of various direct strategies, we took another indirect tactic.
identical to that of the degradative product {½a D25
ꢂ105 (c 0.38,
ꢁ
CHCl3)}.

J. Li et al. / Tetrahedron Letters 51 (2010) 1121–1123
1123
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.12.118.
OH
HO
OH
OH
References and notes
O
H
1. Niu, F.; Chang, H.-T.; Jiang, Y.; Chen, F.-K.; Yuan, J.-Z.; Tu, P.-F. J. Asian Nat. Prod.
Res. 2006, 8, 87–91.
O
O
H
OH
OH
OH
HO
NaOH
MeOH
H
O
H
2. Bel-7402 (human hepatoma cell); BGC-803 (human gastric carcinoma cell);
Hela (human cervix epitheloid carcinoma cell); HL-60 (human promyelocytic
leukemia cell); MCF-7 (human breast adenocarcinoma cell).
3. (a) Corey, E. J.; Liu, K. J. Am. Chem. Soc. 1997, 119, 9929–9930; (b) Toyota, M.;
Wada, T.; Fukumoto, K.; Ihara, M. J. Am. Chem. Soc. 1998, 120, 4916–4925.
4. Cragg, G. M.; Grothaus, P. G.; Newman, D. J. Chem. Rev. 2009, 109, 3012–3043.
5. (a) Kingston, D. G. I. J. Org. Chem. 2008, 73, 3975–3984; (b) Potier, P. Acc. Chem.
Res. 1993, 26, 160–167.
90%
H
Semiaquilegin A (1)
17
Scheme 2. Hydrolysis of semiaquilegin A.
6. Rahier, N. J.; Thomas, C. J.; Hecht, S. M. In Anticancer Agents from Natural
Products; Cragg, G. M., Kingston, D. G. I., Newman, D. J., Eds.; CRC: LLC, Boca
Raton, FL, 2005; p 5.
7. (a) Cuevas, C.; Francesch, A. Nat. Prod. Res. 2009, 26, 322–337; (b) Menchaca, R.;
Martínez, V.; Rodríguez, A.; Rodríguez, N.; Flores, M.; Gallego, P.; Manzanares,
I.; Cuevas, C. J. Org. Chem. 2003, 68, 8859–8866; (c) Cuevas, C.; Pérez, M.;
Martín, M. J.; Chicharro, J. L.; Rivas, C. F.; Flores, M.; Francesch, A.; Gallego, P.;
Zarzuelo, M.; Calle, F.; García, J.; Polanco, C.; Rodríguez, I.; Manzanares, I. Org.
Lett. 2000, 2, 2545–2548.
In summary, we have achieved the formal synthesis of semi-
aquilegin A from a readily available oridonin. The present approach
demonstrates that the feasibility of the synthesis was not only
proved to rigorously define the full structures of a natural product
but also to provide a variety of useful analogues. Preparations of
analogues of 1 for detailed structure–activity relationship studies
are currently in progress in our laboratory and will be reported
in due course.
8. Oridonin can be purchased from chinese market (25$/g).
9. For an excellent review; see: Sun, H.-D.; Huang, S.-X.; Han, Q.-B. Nat. Prod. Res.
2006, 23, 673–698.
10. Zhou, W.-S.; Cheng, Y.-X. Acta Chim. Sinica 1990, 48, 1185–1190.
11. (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574–
1585; (b) Singh, V.; Prathap, S.; Porinchu, M. J. Org. Chem. 1998, 63, 4011–4017;
(c) Org. Synth. Coll. Vol. 2004, 10, 240.
12. (a) Anderson, D. W.; Black, R. M.; Leigh, D. A.; Stoddart, J. F.; Williams, N. E.
Tetrahedron Lett. 1987, 28, 2661–2664; (b) Bowman, W. R.; Brown, D. S.; Burns,
C. A.; Marples, B. A.; Zaidi, N. A. Tetrahedron 1992, 48, 6883–6896.
13. (a) Robins, M. J.; Wilson, J. S. J. Am. Chem. Soc. 1981, 103, 932–933; (b) Robins,
M. J.; Wilson, J. S.; Hansske, F. J. Am. Chem. Soc. 1983, 105, 4059–4065; (c)
Luzzlo, F. A.; Fitch, R. W. J. Org. Chem. 1999, 64, 5485–5493.
14. Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org. Chem. 1996, 61, 7452–
7454.
Acknowledgments
Financial supports from Peking University and National Natural
Science Foundation of China (No. 30600778) are greatly
appreciated.
Supplementary data
Supplementary data (detailed experimental procedures, com-
pound characterization, and copies of spectral data) associated
15. Kuraishi, T.; Taniguchi, T.; Murakami, T.; Tanaka, N.; Saiki, Y.; Cheng, C.-M.
Chem. Pharm. Bull. 1983, 31, 1494–1501.