Total synthesis of 6-deoxyclitoriacetal isolated from Stemona collinsae Craib.

Article abstract of DOI:10.1016/j.tetlet.2006.05.188

A total synthesis of the rotenoid, 6-deoxyclitoriacetal, a cytotoxic natural product, was successfully achieved by using platinum-catalysed hydroarylation, Sharpless asymmetric dihydroxylation, regioselective IBX diol oxidation and stereoselective intramo

Full text of DOI:10.1016/j.tetlet.2006.05.188

Tetrahedron Letters 47 (2006) 5989–5991
Total synthesis of 6-deoxyclitoriacetal isolated
from Stemona collinsae Craib.
Prapas Khorphueng,a Jumreang Tummatorn,a Amorn Petsom,a
Richard J. K. Taylorb and Sophon Roengsumrana,*
aResearch Centre for Bioorganic Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University,
Bangkok 10330, Thailand
bDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 25 April 2006; revised 10 May 2006; accepted 18 May 2006
Abstract—A total synthesis of the rotenoid, 6-deoxyclitoriacetal, a cytotoxic natural product, was successfully achieved by using
platinum-catalysed hydroarylation, Sharpless asymmetric dihydroxylation, regioselective IBX diol oxidation and stereoselective
intramolecular keto-aldehyde pinacol coupling as the key steps.
Ó 2006 Elsevier Ltd. All rights reserved.
Stemona collinsae Craib. (Stemonaceae) has been used
as a traditional Thai medicine with a wide range of
applications (liver cancer, skin infections, anti-parasitic
agent, etc.).1 In a previous paper, we reported the isola-
tion and X-ray crystal structure of 6-deoxyclitoriacetal
(1) from Stemona collinsae, and described its potent
cytotoxic activity against human breast carcinoma (BT
479), lung carcinoma (CHAGO), hepato-carcinoma
(Hep-G2), gastric carcinoma (KATO3) and colon
carcinoma (SW620).2 Moreover, 6-deoxyclitoriacetal
obtained from the roots of Clitoria macrophylla has been
shown to exhibit strong cytotoxic activity against P388
lymphocytic leukaemia cell lines.3 Since 6-deoxyclitori-
acetal (1) possesses such strong cytotoxic activity against
a variety of cancer cell lines, we initiated a synthetic
programme in this area. In this letter, we report the total
synthesis of 6-deoxyclitoriacetal (1).
The retrosynthetic approach we adopted for compound 1
is outlined in Scheme 1. The synthetic strategy is based on
8
H
6
MeO
OH
O
HO
O
O
MeO
O
O
6a
+
12
10
4
OH
OH
OH
O
1
OMe
OMe
OMe
OMe
O
OMe
1
2
3
O
OMe
OMe
5
OMe
4
Scheme 1. Retrosynthesis of 1.
Keywords: Rotenoid; Samarium diiodide; Pinacol coupling.
*
Corresponding author. Tel.: +66 19173955; fax: +66 22541309; e-mail addresses: prapas@mut.ac.th; mr_big2545@yahoo.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.188

5990
OH
P. Khorphueng et al. / Tetrahedron Letters 47 (2006) 5989–5991
cantly improved (88%) by changing the solvent to ethyl
O
O
acetate.7
a
b
a-Hydroxyketone 3 was next converted into mesylate 8
and triflate 9 in yields of 82% and 88%, respectively,
using standard conditions. Coupling of mesylate 8 with
the known phenol 28 using 18-crown-6 and K2CO3 in
CH3CN generated keto-aldehyde 10 in 67% yield.9
However, treatment of compound 2 with triflate 9 under
the same conditions provided compound 10 in a higher
yield of 85%. Treatment of 10 with samarium diiodide in
THF/t-BuOH at ꢀ78 °C provided compound 11 in 65%
yield through a stereoselective intra-molecular keto-
aldehyde pinacol coupling.10 Finally, oxidation of 11
with MnO2 in dichloromethane gave 6-deoxyclitori-
acetal (1) in 80% yield11 (Scheme 3).
OMe
OMe
OMe
OMe
OMe
OMe
6
5
4
c
HO
O
HO
HO
O
d
O
OMe
OMe
OMe
OMe
7
3
Scheme 2. Synthetic route to 3. Reagents and conditions: (a) Prop-
argyl bromide, K2CO3, acetone, KI, rt, quantitative; (b) PtCl2, toluene,
55 °C, 75%; (c) AD-mix-a, t-BuOH/H2O, MeSO2NH2, 92%; (d) IBX,
EtOAc 70 °C, 88%.
1
The synthetic product 1 exhibited H and 13C NMR
spectral data (a small doublet at d 4.67 (d, J = 2.3 Hz),
assigned to H-6a and an AB quartet at d 4.33 (dd,
J1 = 12.3, J2 = 1.6 Hz, 1H), and
d
4.47 (dd,
J1 = 12.3 Hz, J2 = 2.3 Hz, 1H), attributed to H-6), mp
(131–132 °C; lit.3b mp 130–131 °C) and optical rotation
the pinacol-type coupling between aldehyde 2 and ketone
3. We envisaged preparing compound 3 by elaboration of
alkene 4, which we planned to obtain from propargyl aryl
ether 5 using hydroarylation methodology.4
25
{½aꢁD +219.9 (c 1.0, CHCl3), lit.3b [a]D +233 (c 0.1,
CHCl3)} closely matching those published for the natu-
ral product.
In conclusion, the total synthesis of 6-deoxyclitoriacetal
1, a cytotoxic agent, has been accomplished by utilizing
a convergent and efficient strategy which should be suit-
able for the preparation of novel analogues for biologi-
cal evaluation.
The synthesis of compound 5 was completed as pre-
sented in Scheme 2. The reaction of 3,4-dimethoxyphe-
nol 6 with propargyl bromide and K2CO3 in acetone
at room temperature gave compound 54a in quantitative
yield. We were delighted to find that cyclisation of com-
pound 5 could be accomplished by platinum-catalysed
hydroarylation using PtCl2 in toluene to give the re-
quired alkene 4 in reasonable yield (75%). Sharpless
asymmetric dihydroxylation was then effected by treat-
ment of alkene 4 with AD-mix-a in t-BuOH-H2O giving
diol 7 in 92% yield ([a]D ꢀ12.4 (c 0.95, CHCl3).5 Regio-
selective oxidation of diol 7 at the benzylic position with
IBX in DMSO6 provided the desired ketone 3 in 40%
yield. However, the yield of this oxidation was signifi-
Acknowledgements
We thank the Thailand Research Fund (RGJ-PhD pro-
gram to P.K.), the Graduate School and Department of
Chemistry, Faculty of Science, Chulalongkorn Univer-
sity, for financial support and also the Ratchadapisake-
sompote for partial financial support.
RO
O
MeO
O
HO
O
O
O
O
b
a
O
OH
O
OMe
OMe
OMe
OMe
OMe
OMe
10
8 R= Ms
9 R= Tf
3
c
H
H
O
MeO
O
MeO
d
O
O
OH
OH
OH OH
OH
O
OMe
OMe
OMe
OMe
1
11
Scheme 3. Synthetic route to 1. Reagents and conditions: (a) MsCl or Tf2O, CH2Cl2, DMAP, Py; R = Ms, 82%; R = Tf, 88%; (b) 2, K2CO3, 18-
crown-6, CH3CN, 67% for 8 and 85% for 9; (c) SmI2, THF/t-BuOH, ꢀ78 °C to rt, 65%; (d) MnO2, CH2Cl2, 80%.

P. Khorphueng et al. / Tetrahedron Letters 47 (2006) 5989–5991
5991
6. Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong,
Y.-L. J. Am. Chem. Soc. 2002, 124, 2245–2258.
7. More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001–
3003.
8. Lau, C. K.; Belanger, P. C.; Dufresne, C.; Scheigetz, J.
J. Org. Chem. 1987, 52, 1670–1673.
9. (a) Li, K.; Helm, R. F. J. Chem. Soc., Perkin Trans. 1
1996, 2425–2426; (b) Lee, A.-L.; Ley, S. V. Org. Biomol.
Chem. 2003, 1, 3957–3966.
10. (a) Swindell, C. S.; Fan, W. Tetrahedron Lett. 1996, 37,
2321–2324; (b) Ohmori, K.; Kitamura, M.; Suzuki, K.
Angew. Chem., Int. Ed. 1999, 38, 1226–1228.
References and notes
1. Shiengthong, D.; Donavanik, T.; Uaprasert, V.; Roeng-
sumran, S.; Massy-Westropp, R. A. Tetrahedron Lett.
1974, 2015–2018.
2. Roengsumran, S.; Khorphueng, P.; Chaichit, N.; Jaiboon-
Muangsin, N.; Petsom, A. Z. Kristallogr. NCS 2003, 105–
106.
3. (a) Fang, N. B.; Casida, J. E. Proc. Natl. Acad. Sci. U.S.A.
1998, 95, 3380–3384; (b) Lin, L. J.; Ruangrungsi, N.;
Cordell, G. A.; Shieh, H. L.; Min, Y.; Pezzuto, J. M.
Phytochemistry 1992, 31, 4329–4331; (c) Li, L.; Wang, H.
K.; Chang, J. J.; McPhail, A. T.; McPhail, D. R.; Terada,
H.; Konoshima, T.; Kokumai, M.; Kozuka, M.; Estes, J.
R.; Lee, K. H. J. Nat. Prod. 1993, 56, 690–698.
4. (a) Pastine, S. J.; Sames, D. Org. Lett. 2003, 5, 4053–4055;
(b) Liu, C.; Han, X.; Wang, X.; Widenhoefer, R. A. J. Am.
Chem. Soc. 2004, 126, 3700–3701.
11. Data for compound 1: Pale yellow solid, mp 131–132 °C
25
(lit.3b mp 130–131 °C); ½aꢁD +219.9 (c 1.0, CHCl3), {lit.3b
[a]D +233 (c 0.1, CHCl3)}; IR (chloroform): mmax, 3444,
2939, 2842, 1670, 1610, 1574, 1509, 1461, 1336, 1263, 1206,
1160, 1120, 1044, 1025, 822, 735 cmꢀ1
;
1H NMR
(400 MHz, DMSO-d6): d 3.57 (s, 3H), 3.70 (s, 3H) 3.74
(s, 3H), 4.33 (dd, J1 = 12.3, J2 = 1.6 Hz, 1H), 4.47 (dd,
J1 = 12.3 Hz, J2 = 2.3 Hz, 1H), 4.67 (d, J = 2.3 Hz, 1H),
6.01 (d, J = 2.3 Hz, 1H), 6.06 (d, J= 2.3 Hz, 1H), 6.68 (s,
1H), 6.71 (s, 1H), 11.95 (s, 1H); 13C NMR (100 MHz,
CDCl3): d 55.8, 55.9, 56.3, 63.6, 66.9, 75.5, 94.5, 95.6,
100.1, 101.1, 108.2, 109.2, 143.9, 148.3, 151.3, 161.6, 164.3,
169.0, 195.0; HRMS (FAB) m/z calcd for C19H19O8
(MH+) 375.1080; found 375.1074.
25
5. Data for compound 7: mp 98–99 °C; ½aꢁD ꢀ12.4 (c 0.95,
CHCl3); IR (chloroform) mmax: 3378, 2938, 1662, 1621,
1541, 1512, 1449, 1403, 1265, 1224, 1200, 1162, 1127, 1057,
938 cmꢀ1; H NMR d 3.85 (s, 3H), 3.86 (s, 3H), 4.09 (m,
1
3H), 4.71 (s, 1H), 6.41 (s, 1H), 6.88 (s, 1H); 13C NMR d
55.9, 56.4, 65.8, 65.9, 66.1, 100.2, 111.8, 113.1, 144.0,
147.9, 150.3; HRMS (ESI-TOF) (M++Na) m/z calcd for
C11H14O5Na 249.0739: found 249.0740.