The first stereoselective and the total synthesis of Leiocarpin C and total synthesis of (+)-Goniodiol

Article abstract of DOI:10.1016/j.tetlet.2008.08.078

The synthesis of the styryl lactone Leiocarpin C has been achieved in a highly stereoselective manner using Jacobsen's kinetic resolution, Sharpless asymmetric epoxidation and Sharpless asymmetric dihydroxylation as key steps. This is the first total synthesis of Leiocarpin C, and thus establishes for the first time the absolute stereochemistry of this natural product.

Full text of DOI:10.1016/j.tetlet.2008.08.078

Tetrahedron Letters 49 (2008) 6765–6767
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The first stereoselective and the total synthesis of Leiocarpin C
and total synthesis of (+)-Goniodiol
*
J. S. Yadav , K. Premalatha, S. J. Harshavardhan, B. V. Subba Reddy
Division of Organic Chemistry, 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:
The synthesis of the styryl lactone Leiocarpin C has been achieved in a highly stereoselective manner
using Jacobsen’s kinetic resolution, Sharpless asymmetric epoxidation and Sharpless asymmetric dihydr-
oxylation as key steps. This is the first total synthesis of Leiocarpin C, and thus establishes for the first
time the absolute stereochemistry of this natural product.
Received 19 July 2008
Revised 21 August 2008
Accepted 25 August 2008
Available online 28 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Styryl lactones
Jacobsen’s kinetic resolution
Sharpless asymmetric epoxidation
Sharpless asymmetric dihydroxylation
The genus Goniothalamus (Annonaceae) consists of 115 species,
spread over the entire tropics and subtropics.1 Most of the known
styryl lactones are isolated from the genus Goniothalamus.2 Styryl
lactones are natural heterocyclic compounds with potential cyto-
toxicity including antitumor, antifungal, and antibiotic properties.3
Leiocarpin C (1) was isolated from the seeds of Goniothalamus leio-
carpus (Annonaceae), a tropical plant found in the south of Yunnan
Province in China.4 Leiocarpins are found to possess cytotoxic
activities against several human tumor cell lines.5 (+)-Goniodiol
(2) was isolated from the leaves and twigs of Goniothalamus sesqui-
pedalis (Annonaceae) and from the stem bark of Goniothalamus
gigantus (Annonaceae). It is a potent and a selective cytotoxic com-
O
O
O
OH
O
OH
OH
Ph
Ph
Ph
1
OH
OH
2
OH
+
OH
OH
OH
Ph
OBn
3
4
12
Scheme 1. Retrosynthetic analysis of 1 and 2.
pound against human lung carcinoma A-549 (ED50 = 0.12
l )
g mLꢀ1
g mLꢀ1).6 Conse-
epoxychloride 6 was converted into chiral propargylic alcohol13
7
and p-388 murine leukemia cells (IC50 = 4.56
l
quently, a large number of reports have appeared on the total syn-
thesis of (+)-Goniodiol.7–9 However, there are no reports on the
total synthesis of Leiocarpin C.
in 72% yield via base-induced ring opening with n-BuLi in dry
THF. Protection of 7 with TBSCl in the presence of imidazole gave
TBS ether 8 in 92% yield.
In continuation of our program on the total synthesis of bioac-
tive lactones,10 herein, we report a flexible, stereoselective route
for the first total synthesis of Leiocarpin C (1) and also for the syn-
thesis of (+)-Goniodiol (2). The retrosynthesis of Leiocarpin C is de-
picted in Scheme 1.
The commercially available homoallyl alcohol 4 was protected
as its benzyl ether, and then treated with m-CPBA to afford the
racemic epoxide 9 in 86% yield. Kinetic resolution14 of epoxide 9
with (S,S)-Jacobsen’s catalyst gave the chiral epoxide 10 in 43%
yield along with the chiral diol 11 in 43% yield. Regioselective ring
opening15 of chiral epoxide 10 with alkynyl borane prepared in situ
at ꢀ78 °C in dry THF by reaction of the lithium acetylide of 8 with
BF3ꢁOEt2 followed by deprotection of the TBS group using TBAF
gave propargylic alcohol 12 in 82% yield. Reduction of propargylic
alcohol 1216 with LiAlH4 in refluxing THF gave allylic alcohol 13 in
90% yield. Protection of diol 13 as its TBS ether using TBSCl and
imidazole in dichloromethane followed by Sharpless asymmetric
dihydroxylation17 using AD mix-b afforded diol in only 20% yield
Sharpless asymmetric epoxidation11 of cinnamyl alcohol 3 in
the presence of
D
(ꢀ)-DET, TBHP, and Ti(OiPr)4 in dichloromethane
gave the desired epoxyalcohol 5 in 82% yield. The epoxyalcohol 5
was converted into epoxychloride12 6 in 88% yield using Ph3P
and a catalytic amount of NaHCO3 in refluxing CCl4. Subsequently,
* Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J. S. Yadav).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.078

6766
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 6765–6767
OTBS
OH
O
O
a
d
c
b
Ph
OH
Ph
OH
Ph
Cl
Ph
OH
11
Ph
5
9
3
6
7
8
OBn
OBn
OBn
O
e
O
f
+
OH
HO
4
10
OMOM
OMOM
OH
OH
OH
g
i
OH
h
Ph
OBn
8+10
Ph
Ph
OBn
14
OBn
13
12
OH OMOM
MOMO
Ph
OMOM
MOMO
Ph
OMOM
O
O
O
MOM
Ph
j
l
k
OBn
OH
OBn
OH
O
O
15
16
17
O
MOMO
Ph
O
OMOM
COOH
MOM
Ph
OMOM
CO2CH3
O
O
m
n
o
OH
O
OH
Ph
O
O
19
OH
Leiocarpin C
18
Scheme 2. Reagents and conditions: (a)
D
(ꢀ)-DET, Ti(OiPr)4, TBHP, CH2Cl2, ꢀ30 °C, 82%; (b) Ph3P, CCl4, NaHCO3 reflux, 88%; (c) n-BuLi, THF, 72% (d) TBSCl, Imidazole, CH2Cl2,
0 °C to rt 92%; (e) (i) NaH/BnBr, TBAI, THF, 0 °C to rt 92%; (ii) m-CPBA, CH2Cl2, 0 °C, 86%; (f) (S,S)-Jacobsen’s catalyst, H2O, rt 43%; (g) (i) n-BuLi, BF3ꢁOEt2, THF; (ii) TBAF, THF,
0 °C to rt 82%; (h) LiAlH4, THF, reflux, 90%; (i) MOMCl, Hunig’s base, CH2Cl2, 0 °C to rt 92%; (j) AD mix-b, CH3SO2NH2, t-BuOH/H2O (1:1), 0 °C; (k) 2,2-DMP, p-TSA, CH2Cl2, 90%;
(l) DDQ:H2O (9:1), 85%; (m) (i) IBX/DMSO, CH2Cl2, 0 °C to rt 70%; (ii) NaH2PO4, NaClO2, DMSO, H2O, 0 °C to rt 85%; (n) CH2N2 in ether, 0 °C, 85%; (o) MeOH/p-TSA, reflux, 78%.
O
O
O
O
O
OH
O
a
O
O
c
b
2
OH
Ph
OMs
Ph
Ph
O
OH
O
20
21
1
Scheme 3. Reagents and conditions: (a) (i) 2,2-DMP, p-TSA, 85%; (ii) MsCl, Et3N, CH2Cl2, 79%; (b) DBU, CH2Cl2, 80%; (c) MeOH/p-TSA, rt 75%.
even at 0 °C for 4 days. This maybe due to the steric hindrance of
the TBS groups. Therefore, the diol 13 was protected as its MOM
ether 14 in 92% yield using Hunig’s base and MOMCl in dry dichlo-
romethane, which was then subjected to Sharpless asymmetric
dihydroxylation to afford diol 15 in 80% yield (see Scheme 2).
The diol 15 was protected as the corresponding acetonide using
2,2-DMP and a catalytic amount of p-TSA to afford 16. Debenzyla-
tion of 16 using DDQ:H2O18 gave the primary alcohol 17, which
was oxidized to the corresponding acid 18 by a two-step process.
In the first step, the alcohol was oxidized to an aldehyde using
IBX and in the second step, the aldehyde was oxidized to acid19 18
using NaClO2/NaH2PO4. The resulting acid 18 was converted into
ester 19 in 85% yield using diazomethane in ether. Cyclization of
19 was achieved using p-TSA in refluxing methanol to afford the
target lactone, Leiocarpin C (1) in 78% yield. Thus, obtained Leio-
carpin C (1) was treated with 2,2-DMP in the presence of a catalytic
amount of p-TSA followed by mesylation of the secondary hydroxyl
group using mesyl chloride and triethylamine to afford product 20.
The compound 20 was treated with DBU to furnish 21. Deprotec-
tion of the acetonide in compound 21 using p-TSA in MeOH gave
(+)-Goniodiol 2 (Scheme 3).
In conclusion, the first total synthesis of Leiocarpin C has been
achieved in a highly stereoselective manner involving Jacobsen’s
kinetic resolution, Sharpless asymmetric epoxidation, regioselec-
tive ring opening of a chiral epoxide by an alkynyl borane and
Sharpless asymmetric dihydroxylation. This synthetic sequence
provides an easy access to the preparation of styryl lactones of bio-
logical importance.
Acknowledgment
K.P. and S.J.H.V. thank CSIR, New Delhi for the award of research
fellowships.
References and notes
1. Bermejo, A.; Lora, M. J.; Blázquez, M. A.; Rao, K. S.; Cortes, D.; Zafrapolo, M. C.
Nat. Prod. Lett. 1995, 7, 117.
2. Mereyala, H. B.; Joe, M. Curr. Med. Chem. Anti-Cancer Agents 2001, 1, 293.
3. (a) Mu, Q.; Tang, W. D.; Liu, R. Y.; Li, C. M.; Lou, L. G.; Sun, H. D. Planta Med.
2003, 69, 826; (b) Pihie, A. H.; Stanslas, J.; Din, L. B. Anticancer Res. 1998, 18,
1739.
4. Mu, Q.; Tang, W.; Li, C.; Lu, Y.; Sun, H.; Zheng, H.; Hoa, X.; Zheng, Q.; Wu, N.;
Lou, L.; Xu, B. Heterocycles 1999, 51, 2969.
5. Mu, Q.; Li, C. M.; He, Y. N.; Sun, H. D.; Zheng, H. L.; Lu, Y.; Zheng, Q. T.; Jiang, R.
W. Chin. Chem. Lett. 1999, 10, 135.
Leiocarpin C (1) exist as colorless needles, optical rotation ½a D20
ꢂ
ꢀ63.2 (c 0.5, CH3OH). (+)-Goniodiol 2 is a colorless liquid, optical
6. (a) Collett, L. A.; Davies-Coleman, M. T.; Rivett, D. E. A. Progress in the
Chemistry of Organic Natural Products. In Herz, W., Folk, H., Kirby, G. H., Moore,
R. E., Tamm, C., Eds.; Springer: Wien, 1997; p 181; (b) Talapatra, S. K.; Basu, D.;
Deb, T.; Goswami, S.; Talapatra, B. Indian J. Chem., Sect. B 1985, 24, 29; (c)
rotation ½a 2D0
ꢂ
+72.2 (c 0.68, CHCl3). The spectroscopic analyses
and optical rotation values were in accordance with the data re-
ported in the literature.20

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 6765–6767
6767
Alkofahi, A.; Ma, W. W.; Mckenzie, A. T.; Byrn, S. R.; Mclaughlin, J. L. J. Nat. Prod.
1989, 52, 1371; (d) Tsubuki, M.; Kanai, K.; Honda, T. J. Chem. Soc., Chem.
Commun. 1992, 1640; (e) Tsubuki, M.; Kanai, K.; Nagase, H.; Honda, T.
Tetrahedron 1999, 55, 2493.
1079, 689 cmꢀ1 1H NMR (400 MHz, CDCl3): d 7.52–7.48 (m, 2H) 7.38–7.25 (m,
.
8H), 5.39 (s, 1H), 4.50 (s, 2H), 4.01–3.94 (m, 1H), 3.71–3.60 (m, 2H), 2.46 (d,
J = 2.5 Hz, 2H), 1.89–1.80 (m, 2H). 13C NMR (50 MHz, CDCl3): d 141.5, 137.8,
129.0, 128.5, 127.5, 127.2, 84.2, 82.6, 74.2, 70.5, 68.9, 64.5, 35.8, 28.2. HRMS
(ESI): m/z calcd for C20H22O3Na: 333.1466, Found: 333.1469. (1S,2E,5R)-7-
7. (a) Prasad, K. R.; Gholap, S. L. Tetrahedron Lett. 2007, 48, 4679; (b) Tate, E. W.;
Dixon, D. J.; Ley, S. V. Org. Biomol. Chem. 2006, 4, 1698; (c) Deligny, M.;
Carreaux, F.; Carboni, B. Synlett 2005, 1462.
(benzyloxy)-1,5-bis (methoxymethyl)-1-phenylhept-2-ene12 (14): ½a D20
ꢂ
ꢀ4.5 (c
1.02, CHCl3); IR (neat):
m
3095, 2850, 1630, 1250, 1100, 896 cmꢀ1
.
1H NMR
8. (a) Banwell, M. G.; Coster, M. J.; Edwards, A. J.; Karunaratne, O. P.; Smith, J. A.;
Welling, L. L.; Willis, A. C. Aust. J. Chem. 2003, 56, 585; (b) Ramachandran, P. V.;
Chandra, J. S.; Reddy, M. V. R. J. Org. Chem. 2002, 67, 8710.
9. (a) Mukai, C.; Hirai, S.; Hanaoka, M. J. Org. Chem. 1997, 2, 6619; (b) Surivet, J. P.;
Gore, J.; Vatele, J. M. Tetrahedron Lett. 1996, 37, 371.
10. (a) Yadav, J. S.; Rao, B. M.; Rao, K. S.; Reddy, B. V. S. Synlett 2008, 1039; (b)
Yadav, J. S.; Reddy, P. M. K.; Reddy, P. V. Tetrahedron Lett. 2007, 46, 1037; (c)
Yadav, J. S.; Rao, K. V.; Prasad, A. R. Tetrahedron Lett. 2006, 47, 3773; (d) Yadav, J.
S.; Srinivas, R.; Sathaiah, K. Tetrahedron Lett. 2006, 47, 1603; (e) Yadav, J. S.;
Raju, A. K.; Rao, P. P.; Rajaiah, G. Tetrahedron: Asymmetry 2005, 16, 3283.
11. (a) Katzuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5954; (b) Sharpless,
K. B.; Woodward, S. S.; Finn, M. G. Pure Appl. Chem. 1983, 55, 1823; (c) Melloni,
P. Tetrahedron 1985, 41, 1391; (d) Peter, A. J. Chem. Soc., Perkin Trans. 1 1990,
2775.
(300 MHz, CDCl3): d 7.30–7.21 (m, 10H), 5.83–5.52 (m, 2H), 5.01 (d, J = 7.0 Hz,
1H), 4.57–4.51 (m, 4H), 4.50 (s, 2H), 3.80–3.72 (m, 1H), 3.56–3.45 (m, 2H), 3.27
(d, J = 6.2 Hz, 6H) 2.22–2.19 (m, 2H), 1.89–1.80 (m, 2H). 13C NMR (50 MHz,
CDCl3): d 140.9, 138.2, 132.9, 129.0, 128.5, 127.5, 127.0, 95.2, 93.2, 78.1, 74.3,
73.0, 66.8, 55.5, 38.2, 34.6. HRMS (ESI): m/z calcd for C24H32O5Na: 423.2147,
Found: 423.2150. (4R,5R)-4-[(2S)-4-(benzyloxy)-2-methoxymethyl)butyl]-5-
[(R)methoxymethyl)-1-(phenyl)methyl]-2,2-dimethyl-1,3-dioxalane (16):
½ ꢂ
a 2D0
ꢀ49.6 (c 0.75, CHCl3); IR (neat):
m
2925, 2885, 1170, 1050, 915, 700 cmꢀ1
.
1H
NMR (400 MHz, CDCl3): d 7.31–7.25 (m, 10H), 4.62 (d, J = 6.0 Hz, 1H), 4.57 (s,
2H), 4.51 (s, 2H), 4.45 (s, 2H), 4.12 (t, J = 7.3 Hz, 1H), 3.89–3.83 (m, 1H), 3.77–
3.72 (m, 1H), 3.51–3.44 (m, 2H), 3.34 (s, 3H), 3.30 (s, 3H), 1.83–1.76 (m, 2H),
1.69–1.49 (m, 2H), 1.32 (s, 3H), 1.27 (s, 3H). 13C NMR (50 MHz, CDCl3): d 139.5,
138.2, 129.0, 128.5, 128.2, 127.5, 126.2, 109.2, 95.2, 93.0, 82.1, 74.5, 73.2, 71.5,
66.8, 62.8, 55.6, 38.2, 34.5, 30.5. HRMS (ESI-MS): calcd for C27H38O7Na:
497.2515. Found: 497.2526. (4S,6R)-6-[(1R,2R)-1,2-dihydroxy-2-phenylethyl]-4-
12. Lee, J. B.; Downie, I. M. Tetrahedron 1967, 25, 359.
13. (a) Takano, S.; Samizu, K.; Sugihara, T.; Ogasawara, K. Chern. Cornrnun 1989,
1344; (b) Yadav, J. S.; Deshpande, D. K.; Sharma, G. V. M. Tetrahedron 1990, 46,
7033; (c) Yadav, J. S.; Deshpande, D. K.; Sharma, G. V. M. Tetrahedron 1992, 48,
4465.
14. Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A.
E.; Kurrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307.
15. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
16. Grant, B.; Djerassi, C. J. Org. Chem. 1974, 39, 968.
hydroxy-tetrahydro-2H-2-pyranone (Leiocarpin C) (1):
½
a 2D0
ꢂ
ꢀ63.2 (c 0.5,
CH3OH); IR (KBr):
m
3450, 3180, 2885, 1720, 1460, 1150, 890 cmꢀ1
.
1H NMR
(200 MHz, CDCl3): d 7.38–7.21 (m, 5H), 5.42 (d, J = 5.8 Hz, 1H), 4.77 (dd, J = 5.8,
2.4 Hz, 1H), 4.45–4.40 (m, 1H), 4.35 (dt, J = 7.0, 3.2 Hz, 1H), 3.35 (dd, J = 14.8,
7.2 Hz, 2H), 2.38 (t, J = 4.1 Hz, 2H). 13C NMR (75 MHz, CDCl3): d 173.5, 141.2,
129.2, 128.4, 127.3, 74.5 70.05, 68.8, 67.9, 41.5, 38.1. HRMS (ESI): calcd for
C13H16O5Na: 275.0895, Found: 275.0895. (6R)-6-[(1R,2R)-1,2-dihydroxy-2-
phenylethyl]-5,6-dihydro-2H-pyran-2-one; [(+)-Goniodiol] (2):
0.68, CHCl3). IR (neat): 3451, 2986, 1730, 1645, 1440, 1375, 1210,
1058 cmꢀ1 1H NMR (300 MHz, CDCl3):
7.20–7.75 (m, 5H), 6.82 (ddd,
½ ꢂ +72.2 (c
a 2D0
17. Junttila, M. H.; Hormi, O. E. O. J. Org. Chem. 2004, 69, 4816.
18. Yadav, J. S.; Chandrashekar, S.; Sumitra, G.; Rajashekar, K. Tetrahedron Lett.
1996, 37, 6603.
m
.
d
J = 9.5, 5.9, 2.9 Hz, 1H), 5.86 (dd, J = 9.6, 2.7 Hz, 1H), 5.32 (d, J = 3.7 Hz, 1H),
4.70 (dd, J = 10.8, 5.4 Hz, 1H), 4.30 (dt, J = 12.5, 3.8 Hz, 1H), 2.18–2.60 (m, 2H).
13C NMR (75 MHz CDCl3): d 29.6, 75.1, 78.4, 120.8, 126.4, 128.1, 129.3, 140.3,
145.8, 164.0. HRMS (ESI): m/z: calcd for C13H14O4: 235.0970. Found: 235.0968.
19. Dalcanale, E. J. Org. Chem. 1986, 51, 567.
20. Spectral data of selected compounds: (1S,5R)-7-(benzyloxy)-1-phenylhept-2-yne-
1,5-diol (12): ½a D20
ꢂ
+2.9 (c 0.90, CHCl3); IR (neat): m 3421, 2923, 2180, 1453,