First total synthesis of (+)-crassalactone A

Article abstract of DOI:10.1016/j.tetlet.2009.12.038

A simple and highly efficient first total synthesis of cytotoxic (+)-crassalactone A starting from (R)-mandelic acid is described. The strategy involves the osmium tetroxide-catalyzed cis-hydroxylation and the stereoselective addition of ethyl lithiopropi

Full text of DOI:10.1016/j.tetlet.2009.12.038

Tetrahedron Letters 51 (2010) 946–948
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Tetrahedron Letters
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First total synthesis of (+)-crassalactone A
*
V. Shekhar, D. Kumar Reddy, V. Suresh, D. Chanti Babu, Y. Venkateswarlu
Organic Chemistry Division-I, Natural Products Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and highly efficient first total synthesis of cytotoxic (+)-crassalactone A starting from (R)-man-
delic acid is described. The strategy involves the osmium tetroxide-catalyzed cis-hydroxylation and the
stereoselective addition of ethyl lithiopropiolate to a chiral aldehyde intermediate as key steps.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 18 November 2009
Revised 6 December 2009
Accepted 9 December 2009
Available online 16 December 2009
Dedicated to Professor N. S. Sarma, Andhra
University, Visakhapatnam on his 60th birth
day and his excellent contributions in
marine natural products
Keywords:
Goniothalamus
Polyalthia crassa
Styrllactones
(+)-Crassalactone A
Lactonization
Cis-hydroxylation
1. Introduction
sis of biologically active natural products8a–c we report here the
first total synthesis of (+)-crassalactone A (1).
O
Plants of the genus Goniothalamus (family; Annonaceae) in
South East Asia have been known for a long time for their proven
use in folk medicine. The extract of the seeds of Goniothalamus
amuyon is reported to be employed for the treatment of edema
and rheumatism.1 The other applications include its use as paink-
illers2 and mosquito repellents. In view of the medicinal properties,
these plants are considered as a potential source of biologically ac-
tive compounds. Styryl lactones, a group of important secondary
metabolites is known for their significant cytotoxicity against sev-
eral human cancer cell lines,3 are widely present in the genus
Goniothalamus.4,5 Among which goniotriol is an important member
of this family occurring in two enantiomeric forms6 with a signif-
icant cytotoxicity in the potato disc and the brine shrimp tests.
More recently (+)-crassalactone A (1) a 5-O-cinnamoyl derivative
of (+)-goniotriol was isolated from the ethyl acetate extract of
the leaves and twigs of Polyalthia crassa.7 The new compound 1
shows cytotoxic activity against a panel of mammalian cancer cell
lines. The structure was determined on the basis of spectroscopic
methods. In continuation of our interest towards the total synthe-
1
O
2
3
OH
8
10
9
7
4
11
12
6
OH O5
14
Ph
13
O
1
The retro-synthesis analysis of compound 1 is shown Scheme 1.
It was envisioned that (+)-crassalactone A (1) could be synthesized
from 2 by cis hydrogenation, functional group transformations,
elaboration, and lactonization. While in turn 2 could be originated
from a,b-dihydroxy ester 3 which could be derived from the com-
mercially available (R)-mandelic acid 4 (Scheme 1).
The journey of the synthesis was started from the commercially
available chiral source (R)-mandelic acid 4. Since the C8 chiral center
is matched with compound 4 it was chosen as the starting compound
for the synthesis. The other C6, C7, and C5 chiral centers were
achieved via osmium tetroxide cis-dihydroxylation and anionic
additionof ethyl lithiopropiolateto the chiral intermediate aldehyde.
2. Results and discussion
* Corresponding author. Tel.: +91 40 27193167; fax: +91 40 27160512.
E-mail addresses: luchem@yahoo.com, luchem@iict.res.in, padalu@gmail.com
(Y. Venkateswarlu).
Initially (R)-mandelic acid 4 was converted into its methyl ester
derivative 5 using the reported literature procedure with 93%
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.038

V. Shekhar et al. / Tetrahedron Letters 51 (2010) 946–948
947
the ratio of (E/Z = 93:7). After chromatographic separation of the
two geometrical isomers, the E-isomer (7a) [E-configuration in 7a
supported by 1H NMR coupling constant (J = 15.3 Hz) was reacted
with a catalytic amount of OsO4 in the presence of excess N-methyl-
O
O
O
Ph
O
TBDMS O
OH
O
OEt
morpholine N-oxide in acetone–water (5:1) system to afford
a,b-
O
O
OH
dihydroxy ester 3. The reaction afforded high anti-selectivity
(90:10 ratio of anti: syn)9 with respect to the existing C8 chiral cen-
ter, and the anti isomer 3 was separated chromatographically in 85%
yield. The formation of compound 3 was established by its 1H NMR
spectral data due to the presence of two hydroxy methine protons at
d 3.83 (1H, td, J = 8.3, 1.1 Hz, CHOH-CHOSi) and 4.52 (1H, dd, J = 5.6,
0.94 Hz, CHOH-CO2Et). The dihydroxy ester 3 masked by acetonide
protection using 2,2-dimethoxypropane in the presence of catalytic
amount of p-TSA to give compound 8 in 87% yield, which was re-
duced with DIBAL-H, furnished alcohol 9 in an excellent yield. Pri-
O
Ph
O
2
1
OH
TBDMS
O
OH
OH
OEt
O
OH
O
mary alcohol
9
upon oxidation with Dess–Martin reagent10
4
3
afforded the intermediate chiral aldehyde, which on treatment with
ethyl lithiopropiolate11 at ꢀ78 oC in the presence of LDA generated
10 as the almost single isomer12 along with the negligible amount
of other diastereomer (recognized by 1H NMR) in good yield (75%).
The formation of compound 10 was confirmed by its 1H NMR spec-
tral data due to hydroxyl methine proton vicinal to alkyne at d 3.96
(1H, d, J = 9.9 Hz, CHOH). Compound 10 was esterified with cin-
namic acid in the presence of standard DCC and DMAP procedure
to give compound 2 in 65% yield. The triple bond in compound 2
on partial hydrogenation into cis-alkene using Lindlar’s catalyst
(5 w/w% Pd on CaCO3/Pb, 70 w/w%) in hexane afforded 11 in 90%
Scheme 1.
yield.8d The hydroxyl group in the methyl-(R)-mandelate was
protected with TBDMS group using tert-butyldimethylsilyl chloride
in an anhydrous DCM afforded compound 6. Ester 6 was reduced
with DIBAL-H at ꢀ78 oC to give good yield the corresponding
aldehyde, which was treated with (ethoxycarbonylmethylene)trip-
henylphosphoranecarbonyl in an anhydrous DCM to furnish the
Wittig product a,b-unsaturated esters 7a and 7b in 87% yield with
OTBDMS
OH
OH
c
OMe
OH
b
OMe
a
O
O
O
6
5
4
OTBDMS
OH
TBDMSO
OEt
OEt
d
e
(Z)-isomer
7b
+
O
OH
O
7a
3
TBDMSO
O
TBDMS
OH
TBDMS
O
O
f
g
OH
OEt
OEt
O
O
O
O
O
8
O
O
9
10
O
O
Ph
Ph
COOEt
TBDMSO
O
TBDMS
O
O
h
i
OEt
O
O
O
O
O
O
2
11
O
OH
j
OH
O
Ph
O
1
Scheme 2. Reagents and Conditions: (a) MeOH, cat P-TSA, reflux 4 h, 93%; (b) TBSCl, Imidazole, dry DCM, 3 h, rt, 95%; (c) i). DIBAL-H, dry DCM, ꢀ78 oC, 1 h; (ii)
P(Ph)3CHCO2Et.DCM, 6 h, rt, 70% (for two steps); (d) OSO4, NMO, Acetone–H2O (5:1), rt, 8 h, 85%; (e) 2,2-DMP, p-TSA (cat), Dry acetone, 6hr, rt, 87%; (f) 1) DIBAL-H, dry DCM,
0
oC, 1 h, 90%; (g) i) Dess–Martin Periodinane, dry DCM, 1 h; ii) CHCCO2Et, ꢀ78 oC, LDA, THF, 12 h, 62% (for two steps); (h) DCC, Cinnamic acid, DMAP, dry DCM, rt, 3 h, 65%; (i)
H2 (1bar), Lindlar’s catalyst.(70 w/w%), quinoline, hexane, rt, 90%; (j) 3% MeOH/HCl,0 oC to rt, 5 h; 65%.

948
V. Shekhar et al. / Tetrahedron Letters 51 (2010) 946–948
7. Tuchindra, P.; Munyoo, B.; Pohmakor, M.; Thinapong, P.; Sophasan, S.; Santisuk,
T.; Reutrakul, V. J. Nat. Prod. 2006, 69, 1728.
yield. Finally the deprotection of TBS and acetonide groups followed
by cyclization of compound 11 was achieved on treating with 3%
methanolic HCl, which afforded (+)-crassalactone A (1) in a single
step with 65% yield. The formation of compound 1 was established
by 1H NMR spectral data in which the double bond signals in the lac-
tone appeared at d 6.19 (1H, d, J = 9.6 Hz) and 7.0 (1H, dd, J = 9.5,
6.0 Hz) and the lactonic methane proton appeared at 4.75 (dd,
J = 5.8, 2.6 Hz). Compound 1 also characterized by 13C NMR spectral
data due to the carbonyl in d-lactone appeared at d 162.4, carbonyl in
a cinnamate group at d 165.7 and the carbons C-3, C-4, C-5, C-6, C-7,
and C-8 appeared at d 123.5, 140.4, 62.5, 77.5, 73.3, and 73.5, respec-
tively. The double bond carbons in cinnamate group appeared at d
8. (a) Selvam, J. J. P.; Rajesh, K.; Suresh, V.; Chanti Babu, D.; Venkateswarlu, Y.
Tetrahedron: Asymmetry 2009, 20, 1115; (b) Narasimhulu, M.; Krishna, A. S.;
Rao, J. V.; Venkateswarlu, Y. Tetrahedron 2009, 65, 2989; (c) Suresh, V.; Selvam,
J. J. P.; Rajesh, K.; Venkateswarlu, Y. Tetrahedron: Asymmetry 2008, 19, 1509; (d)
Kotora, M.; Negishi, E. I. Tetrahedron Lett. 1996, 37, 9041.
9. Examples of osmaylation on similarly constituted compounds see: (a) Cha, J. K.;
Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247; (b) Oishi, T.; Iida, K. Y.;
Hirama, M. Tetrahedron Lett. 1993, 34, 3573; (c) Surivet, J. P.; Volle, J. N.; Vatele,
J. M. Tetrahedron: Asymmetry 1996, 7, 3305.
10. Dess, D.; Martin, J. J. Org. Chem. 1983, 48, 4155.
11. (a) Bachmann, W. E.; Raunio, E. K. J. Am. Chem. Soc. 1950, 72, 2533; (b)
Herrmann, J. L.; Berger, M. H.; Schlessinger, R. H. J. Am. Chem. Soc. 1979, 101,
1544; (c) Midland, M. M.; Tramontano, A.; Cable, J. R. J. Org. Chem. 1980, 50, 28.
12. Su, Y. L.; Yang, C. S.; Teng, S. J.; Zhao, G.; Ding, Y. Tetrahedron 2001, 57, 2147.
13. Spectral data for selected compounds:
116.4 and 146.6. The physical {white solid, mp 132 oC; ½a D25
ꢁ
+319
Compound 3: ½a 2D5
ꢀ32.9 (c 2.5, CHCl3); IR (neat): 3488, 2995, 2942, 2860,
ꢁ
(c 0.1, CHCl3)} and spectral data13 of the synthesized compound 1
were found to be in good agreement with the reported literature
data7 (Scheme 2).
1735 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.28–7.42 (m, 5H), 4.68 (d, 1H,
;
J = 8.3 Hz), 4.52 (dd, 1H, J = 5.6, 0.94 Hz), 4.22–4.31 (m, 2H), 3.83 (td, 1H, J = 8.3,
1.1 Hz), 3.05 (d, 1H, J = 5.4 Hz), 1.62 (d, 1H, J = 7.6 Hz), 1.32 (t, 3H, J = 7.1 Hz),
0.9 (s, 9H), 0.1 (s, 3H), -0.2 (s, 3H); 13C NMR (75 MHz, CDCl3): d 173.5, 141.5,
128.3, 127.9, 127.1, 77.3, 76.4, 75.1, 70.0, 61.8, 25.7, 18.0, 14.1, ꢀ4.7, ꢀ5.3; MS-
ESIMS: m/z 377 [M+Na]+; HRMS calcd for C18H30NaO5Si 377.1755, found
In conclusion, we have accomplished the first total synthesis of
the cytotoxic of (+)-crassalactone A (1) in 10 steps with an overall
yield of 11% from (R)-mandelic acid.
377.1754; Compound 10: ½a D25
ꢁ
ꢀ5.2 (c 0.3, CHCl3); IR (neat): 3445, 2929, 2859,
2239, 1713, 1459, 1375, 1248, 1075, 840, 771, 701 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): d 7.26–7.35 (m, 5H), 4.81 (d, 1H, J = 5.6 Hz), 4.20–4.30 (m, 3H), 4.12
(dd, 1H, J = 7.6, 5.6 Hz), 3.96 (d, 1H J = 9.9 Hz), 1.46 (s, 3H), 1.40 (s, 3H), 1.29 (t,
3H, J = 6.8 Hz), 0.90 (s, 9H), 0.07 (s, 3H), ꢀ0.14 (s, 3H); 13C NMR (75MHz,
CDCl3): d 152.6, 138.6, 128.5, 128.2, 126.5, 109.8, 80.9, 79.6, 77.2, 75.3, 74.1,
71.5, 61.8, 61.3, 127.7, 27.2, 26.1, 19.0, 14.2, ꢀ4.4, ꢀ4.6; MS-ESIMS: m/z 466
[M+NH4]+; HRMS calcd for C24H40NO6Si 466.2619, found 466.2618; Compound
Acknowledgments
The authors V.S., D.K.R., V.S., D.C.B. are thankful to CSIR, New
Delhi, for the financial support and Dr. J. S. Yadav Director, Indian
Institute of Chemical Technology (IICT), for his encouragement.
2: ½a 2D5
ꢁ
ꢀ13.4 (c 0.3, CHCl3); IR (neat): 3438, 2932, 2857, 2246, 1719, 1636,
1454, 1371, 1251, 1149, 1087, 1016, 840, 773, 702 cmꢀ1
;
1H NMR (300 Mz,
CDCl3): d 7.7 (d, 1H, J = 15.8 Hz), 7.22–7.55 (m, 10H), 6.38 (d, 1H, J = 15.8 Hz),
5.33 (d, 1H, J = 3.7 Hz), 4.77 (d, 1H, J = 5.2 Hz), 4.35 (dd, 1H, J = 6.7, 3.7 Hz),
4.17–4.25 (m, 2H), 4.08 (m, 1H), 1.43 (s, 3H), 1.38 (s, 3H), 1.32 (t, 3H, J = 6.7 Hz),
0.9 (s, 9H), 0.1 (s, 3H), ꢀ0.16 (s, 3H); 13C NMR (75 MHz, CDCl3): d 164.6, 152.5,
146.4, 140.7, 134.3, 128.9, 128.3, 128.2, 126.7, 126.5, 116.7, 110.8, 81.4, 78.4,
77.6, 75.2, 74.8, 63.0, 60.2, 27.9, 26.0, 18.4, 14.1, ꢀ4.5, ꢀ4.6; ESI-MS: m/z 596
[M+NH4]+; HRMS calcd for C33H46NO7Si; 596.3038, found 596.3039; Compound
References and notes
1. Wu, Y. C.; Duh, C. Y.; Chang, F. R.; Chang, G. Y.; Wang, S. K.; Chang, J. J.; McPhail,
D. R.; McPhail, A. T.; Lee, K. H. J. Nat. Prod. 1991, 54, 1077.
2. Sam, T. W.; Yeu, C. S.; Matsjeh, S.; Gan, E. K.; RaZak, D.; Mohamed, A. L.
Tetrahedron Lett. 1987, 28, 2541.
3. For recent review on cytotoxicity of styryl lactones and their analogues, see: (a)
De Fatima, A.; Modolo, L. V.; Conegero, L. S.; pilli, R. A.; Ferreia, C. V.; Kohn, L. K.;
de Carvalho, J. E. Curr. Med. Chem. 2006, 13, 3371; (b) Mereyala, H. B.; Joe, M.
Curr. Med. Chem. Anti-Cancer agents 2001, 1, 293; (c) Blazquez, M. A.; Bermejo,
A.; Zafra-Polo, M. C.; Cortes, D. Phytochem. Anal. 1999, 10, 161.
4. Fang, X. P.; Anderson, J. E.; Chang, C. J.; Fanwick, P. E.; McLaughlin, J. L. Chem.
Soc., Perkin Trans. 1 1990, 1655.
1: ½a 2D5
ꢁ
+319 (c 0.1, CHCl3); IR (neat): 3425, 2922, 1748, 1634, 1451, 1266,
1169, 1112, 1043, 939, 822, 763, 701, 554 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d
7.63 (d, 1H, J = 15.8 Hz), 7.29–7.50 (m, 10H), 7.0 (dd, 1H, J = 9.5, 6.0 Hz), 6.35 (d,
1H, J = 15.8 Hz), 6.19 (d, 1H, J = 9.6 Hz), 5.28 (dd, 1H, J = 6.0, 2.6 Hz), 4.90 (d, 1H,
J = 5.8 Hz), 4.75 (dd, J = 5.8, 2.6 Hz), 4.26 (m, 1H), 2.00 (br s, 2H); 13C NMR
(75 MHz, CDCl3): d 165.7 (C10), 162.4 (C2), 146.6 (C30), 140.4 (C4), 139.8 (C9),
133.6 (C40) 130.8 (C70), 128.9 (C60,C80), 128.7 (C11,C13), 128.3 (C12), 128.2
(C50,C90), 126.5 (C10,C14), 123.5 (C3), 116.4 (C20), 77.5 (C6), 73.5 (C8), 73.3
5. Fang, X. P.; Andreson, J. E.; Chang, C. J.; McLaughlin, J. L.; Fanwick, P. E. J. Nat.
Prod. 1991, 54, 103.
6. Talapatra, S. K.; Goswami, D.; Talapatra, B. Indian J. Chem., Sect. B 1985, 24, 29;
Wong, Y. S. Chem. Commun. 2002, 686.
(C7), 62.5 (C5); MS-ESIMS: m/z 398 [M+NH4]+; HRMS calcd for C22H24NO6
;
398.1598, found 398.1596.