A concise total synthesis of (-)-dehydroclausenamide utilizing the novel formation of cis-epoxide as the key step

Article abstract of DOI:10.1016/j.tetlet.2003.09.229

The asymmetric total synthesis of (-)-dehydroclausenamide 1 was accomplished through a concise and efficient synthetic route employing as the key step the novel formation of cis-epoxy amide 7, which was resulted from the reaction of starting material 4 bearing an optically pure erythro vicinal diol unit with 5H-3-oxa-octafluoro pentanesulfonyl fluoride (HCF₂CF ₂OCF₂CF₂SO₂F) in the presence of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU).

Full text of DOI:10.1016/j.tetlet.2003.09.229

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9383–9384
A concise total synthesis of (−)-dehydroclausenamide utilizing the
novel formation of cis-epoxide as the key step
Zhaohua Yan, Jianqiang Wang and Weisheng Tian*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai, 200032, PR China
Received 18 April 2003; revised 29 August 2003; accepted 16 September 2003
Abstract—The asymmetric total synthesis of (−)-dehydroclausenamide 1 was accomplished through a concise and efficient
synthetic route employing as the key step the novel formation of cis-epoxy amide 7, which was resulted from the reaction of
starting material 4 bearing an optically pure erythro vicinal diol unit with 5H-3-oxa-octafluoro pentanesulfonyl fluoride
(HCF2CF2OCF2CF2SO2F) in the presence of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU).
© 2003 Elsevier Ltd. All rights reserved.
Dehydroclausenamide 1, neoclausenamide 2 and clausen-
amide 3 are three major biologically active lactams
isolated from aqueous extract of dry leaves of Chinese
folk medicine Clausena lansium.1,2 These naturally
occurring molecules exhibit a remarkable hepatoprotec-
tive effect against chemical toxins, such as carbon tetra-
chloride and thioacetamide in preliminary animal tests;
further investigation showed they have potent anti-
amnaesic activity.2 Their interesting bio-activity and
poor availability led to active synthetic activities. In
1987, Hartwig3 first achieved the total synthesis of
(+)-3. Since then, Huang,4 Ikeda5 and Roberts6 and our
group,7 respectively, reported the asymmetric total syn-
theses of (−)-1, (+)-2, (−)-3 and (+)-3.
In our continued research program concerting
fluoroalkanosulfonyl fluoride induced reactions and
their application in organic synthesis,8 we found that
fluoro alkanosulfonyl fluorides can conveniently con-
vert some vicinal diols into the corresponding epox-
ides.9 When this reaction was applied to optically pure
erythro vicinal diol unit of amide 4, a smoothly trans-
formation to the corresponding 7 with the structural
feature of cis-epoxy amide was achieved in 82.5% yield,
while another free hydroxyl group remained intact
(Scheme 2).
In the course of our synthetic studies toward (+)-2, we
used amide 4 as an intermediate which can be easily
prepared starting from mandelic acid and methyl cinna-
mate. However, the direct transformation of 4 to trans-
epoxy amide 5 only resulted in a low yield (30%)
(Scheme 1), which led us to devise a longer synthetic
route including protection and deprotection steps.
Thus, after five consecutive steps, the oxidation product
ketone 6 was obtained in 49% overall yield.7
Scheme 1.
Scheme 2. Reagents and conditions: (i) HCF2CF2OCF2CF2-
* Corresponding author. Tel.: +86-021-64163300-3225; fax: +86-021-
SO2F, DBU, CH2Cl2, 0°C, 82.5%.
64166128; e-mail: wstian@pub.sioc.ac.cn
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.229

9384
Z. Yan et al. / Tetrahedron Letters 44 (2003) 9383–9384
1.2:1 mixture of 11a and 11b in a quantitive yield,
which can be easily separated through flash chromato-
graphy. Cyclization–etherification of 11a in the pres-
ence of potassium t-butoxide (KOBut) as base in anhy-
drous THF led to a clean formation of (−)-1 in 100%
yield, mp 198–200°C, [h]2D0 −92.5° (c, 0.18. MeOH).
Accordingly, 12, a C-7 epimer, was afforded under the
same conditions from 11b in 100% yield. The spectro-
scopic properties of the above obtained (−)-1 were in
good agreement with those previously reported.1,4
In conclusion, a concise and highly efficient total syn-
thesis of (−)-1 was completed in six linear steps and in
27.5% overall yield starting from amide 4. The key step
involved in this synthesis is novel, being mediated by
fluoroalkanosulfonyl fluoride transformation of vicinal
diols into the corresponding epoxides.
Scheme 3. Reagents and conditions: (i) PDC, CH2Cl2, rt, 82%;
(ii) 1% aq. Me4NOH, CH2Cl2, 40–45°C, 79%; (iii) MsCl,
Et3N, CH2Cl2, 0°C, 96%; (iv) NaBH4, THF, rt, for 11a, 54%,
for 11b, 46%; (v) KOBut, THF, rt, 100%; (vi) KOBut, THF,
rt, 100%.
References
1. (a) Yang, M. H.; Cao, Y. H.; Li, W. X.; Yang, Y. Q.;
Huang, L. Acta Pharm. Sinica 1987, 22, 33–40; (b) Yang,
M. H.; Chen, Y. Y.; Huang, L. Acta Chim. Sinica (English
Ed.) 1987, 267–270.
2. (a) Zhang, J. T. Acta Pharm. Sinica 1986, 21, 636–640; (b)
Duan, W. Z.; Zhang, J. T. Acta Chim. Sinica 1997, 32,
259–263.
3. Hartwig, W.; Born, L. J. Org. Chem. 1987, 52, 4352–4358.
4. Huang, D. F.; Huang, L. Tetrahedron 1990, 46, 3135–
3142.
Based on this novel result, we then carried out the total
synthesis of (−)-1 with a concise and efficient synthetic
route employing 7 as the key intermediate. Herein, we
would like to report the results of our study (Scheme 3).
5. Takura, T.; Matsumura, Y.; Ikeda, M. Synlett 1991, 343–
344.
6. Cappi, M. W.; Chen, W. P.; Robert, W. F.; Liao, Y. W.;
Roberts, S. M.; Skidmore, J.; Smith, J. A.; Williamson, N.
M. Chem. Commun. 1998, 1159–1160.
With the key intermediate 7 in hand, we then continued
our synthetic sequence (see Scheme 3). The reaction of
7 with pyridinium dichromate (PDC) in CH2Cl2 fur-
nished an oxidation product 8 in 82% yield. Subsequent
base-catalyzed cyclization of 8 in a biphasic medium
(CH2Cl2:H2O 1:1) provided cyclized lactam 9a as a
single product in 79% yield. No undesired C-5 isomer
9b was formed under this condition. Interestingly, when
this reaction was performed in a solution (THF:H2O
1:1) instead of a biphasic medium (CH2Cl2:H2O 1:1), a
mixture of 9a and 9b in a ratio of 1.6:1 was produced
in a nearly quantitive yield. Treatment of 9a with
methanesulfonyl chloride (MsCl) and Et3N in CH2Cl2
generated 10 in 96% yield. Next, our attention was
turned to the reduction of the ketone group at the C-5
side chain of 10. In the hope to obtian a higher ratio of
desired 11a to unwanted 11b in the product, bulky
reducing agents, such as diisobutylaluminum hydride
(DIBAL-H), potassium and lithium tri-sec-butylboro-
hydride (K and L-Selectride) were firstly investigated.
Unfortunately all attempts were unfruitful. Finally, the
reduction of 10 with sodium borohydride offered a
7. Wang, J. Q.; Tian, W. S. J. Chem. Soc., Perkin Trans. 1
1996, 209–212.
8. (a) Zhu, Z.; Tian, W. S.; Liao, Q. J. Tetrahedron Lett.
1996, 37, 8553–8556; (b) Zhen, Z.; Tian, W. S.; Liao, Q. J.;
Wu, Y. K. Bioorg. Med. Chem. Lett. 1998, 8, 1949–1952;
(c) Feng, X. S.; Tian, W. S.; Cheng, Q. Y. Bioorg. Med.
Chem. Lett. 1997, 7, 3113–3117; (d) Feng, X. S.; Tian, W.
S.; Cheng, Q. Y. J. Chem. Soc., Perkin Trans. 1 1998, 2,
1139–1147; (e) Tian, W. S.; Lei, Z.; Chen, L.; Huang, Y. J.
Fluorine Chem. 2000, 101, 305–308; (f) Chen, L.; Ding, K.;
Tian, W. S. Chem. Commun. 2003, 838–839.
9. (a) Tian, W. S.; Yan, Z. H.; Luo, Z. S.; Wang, J. Q. 16th
International Congress of Heterocyclic Chemistry (paper
abstract), Bozeman, 1997, OP-II-6; (b) Yan, Z. H. PhD
Thesis, Shanghai Institute of Organic Chemistry, the Chi-
nese Academy of Sciences, 1999. Ling, R.; Yoshida, M.;
Mariano, P. S. J. Org. Chem. 1996, 61, 4439–4449.