Synthesis of stagonolide C from Mulzer epoxide

Article abstract of DOI:10.1016/j.tetlet.2011.12.102

Total synthesis of stagonolide C using chiral pool strategy is described. The two key intermediates were prepared from l-glutamic acid and d-glucono-1,5-lactone, followed by Julia-Lythgoe olefination and Yamaguchi esterification to afford the target compo

Full text of DOI:10.1016/j.tetlet.2011.12.102

Tetrahedron Letters 53 (2012) 1153–1155
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of stagonolide C from Mulzer epoxide
⇑
Jian-Zhong Wu, Zhixia Wang, Chunhua Qiao
College of Pharmaceutical Science, Soochow University, Suzhou 215123, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Total synthesis of stagonolide C using chiral pool strategy is described. The two key intermediates were
Received 3 November 2011
Revised 20 December 2011
Accepted 23 December 2011
Available online 30 December 2011
prepared from
L-glutamic acid and D-glucono-1,5-lactone, followed by Julia–Lythgoe olefination and
Yamaguchi esterification to afford the target compound in an efficient way.
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
Stagonolide C
Mulzer epoxide
Julia–Lythgoe olefination
Yamaguchi esterification
Total synthesis
Naturally occurring macrolides, particularly 10-membered lac-
tones (noneolides) have continued to attract synthetic chemists
as well as biologists during recent years, because of their interest-
ing structural features and various biological activities like plant
growth inhibition, anti-feedant, anti-fungal and anti-bacterial
activities.1 For example, modiolide A and B have been shown to
have anti-bacterial and anti-fungal activities.2 Stagonolide C3 rep-
resents another novel 10-membered ring lactone, and was the
main phytotoxic metabolite of a fungal pathogen Stagonospora
cirsii, S. cirsii was isolated from Cirsium arvense, and was proposed
as a potential mycoherbicide by causing necrotic lesions on leaves.
Other metabolites, namely stagonolide B–I4 were structurally sim-
ilar to stagonolide C, and were isolated from the same fungus.
All noneolides shown in Figure 1 possess some common interest-
ing structural features, the olefinic moiety with well-defined geom-
etry as well as stereochemically pure hydroxyl appendages make
them very challenging synthetic targets. In 2009, Yadav and
co-workers5 reported the first total synthesis of stagonolide C. The
key steps include the intramolecular ring-closing metathesis to
construct the macrolide trans double bond. Sharpless asymmetric
epoxidation was employed to control the hydroxyl stereochemistry.
Later on, Nanda and co-workers6 independently reported an alter-
native total synthesis route, which also involved the ring-closing
metathesis reaction, while the hydroxyl stereo center was achieved
by enzyme-catalyzed reaction.
building blocks was exemplified to construct the stereochemically
defined 1,3-diol motif of verbalactone and exophilin A.8 Recently,
the same chiral epoxide building blocks were employed to success-
fully achieve other naturally occurring products which contain the
1,3-diol fragments.9,10 Herein, we wish to report our effort to
OH
OH
O
OH
OH
O
O
O
HO
O
O
Stagonolide C,1
Modiolide A
Herbarumin III
Me
O
Me
O
Me
O
O
O
O
OH
OH
OH
OH
OH
Decarestrictine C1
OH
Nonenolide
Decarestrictine C2
Figure 1. The structure of stagonolide C, modiolide A, herbarumin III, nonenolide,
and decarestrictine C1 and C2.
OH
H
In a previous study, a convenient route has been developed to
achieve the chiral building blocks 2 and 3 from the commercially
OH
H
O
O
Ο
Ο
inexpensive
D
-glucolactone (Fig. 2).8 Application of these chiral
Ο
Ο
2
3
⇑
Corresponding author.
E-mail address: qiaochunhua@suda.edu.cn (C. Qiao).
Figure 2. The structure of chiral building blocks Mulzer epoxide7 2 and 3.
0040-4039/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.102

1154
J.-Z. Wu et al. / Tetrahedron Letters 53 (2012) 1153–1155
OR''
OR
HO
O
OHC
OH
OR
O
OH
OR
OH
O
5. R = PMB, R' = TBS
O
OH
Mulzer' epoxide, 3
Ph
O
O
OR
O
N
N
N
NH2
SO2
Stagonolide C, 1
4. R = PMB
N
HO2C
CO2H
OR''
L-Glu
6. R = PMB, R'' = Me
Scheme 1. Retrosynthetic analysis of stagonolide C.
exploit one molecular architecture as an excellent precursor for the
total synthesis of stagonolide C.
the formation of 1417 in moderate yield. Next, the TBS protecting
group was cleaved with CSA/MeOH in a 90% yield. Subsequent
treatment with LiOH/MeOH–H2O afforded the seco acid 4. The
crucial ring-closing Yamaguchi esterification reaction failed in
THF at 100 °C using 8 equiv Yamaguchi reagent 16, finally, 20 equiv
of 16 successfully furnished 17 as the sole product in a 63% yield
(Scheme 4). Cleavage of PMB protecting groups using CAN18
achieved the target molecule 1,19 with the spectroscopic data con-
sistent with those reported in the literature.4a
In conclusion, we have described an efficient synthesis route to
construct stagonolide C. This protocol involved the utilization of
previously developed chiral epoxide intermediate, Julia–Lythgoe
coupling of two fragments and Yamaguchi esterification for intra-
molecular cyclization to achieve total synthesis of the target
compound. This synthesis exemplified the usage of Mulzer epoxide
Retrosynthetic analysis of the target molecule stagonolide C is
shown in Scheme 1. The target molecule can be achieved from seco
acid 4, the crucial ester linkage is planned to be constructed
through Yamaguchi esterification,11 The trans double bond can be
formed from aldehyde 5 and sulfone 6 via Julia–Lythgoe olefin-
ation.12 Fragments 5 and 6 would be prepared from the Mulzer
epoxide and
The synthesis of fragment 5 began with the Mulzer’ epoxide,
which was prepared from -glucono-1,5-lactone according to the
L-glutamic acid, respectively.
D
reported procedure.8 As shown in Scheme 2, the hydroxyl group
in epoxide 3 was protected as PMB ether 7 as reported previously.13
Treatment of this intermediate with LiAlH4 afforded the epoxy ring
opening product 8 in a 96% yield. The newly-formed hydroxyl group
was converted into a TBS ether 9 with TBSOTf/2,6-lutidine/CH2Cl2.14
The acetonide was carefully hydrolyzed using15 50% aq F3CCO2H in
CH2Cl2 to give 10. Subsequent treatment of diol 10 with NaIO4/H2O–
THF led to the required aldehyde 5 (Scheme 2).
OH
OPMB
Br
Br
PMBO-(C=NH)-CCl3
PPTS,CH2Cl2, 70%
The synthesis of fragment 6 started from intermediate 11,16
which was prepared from commercially available L-glutamic acid
ref 13
L-glutamic acid
1-phenyl-5-
OMe
OMe
O
in five steps. Protection of the hydroxyl group with PMBOC
(@NH)CCl3 in mild condition afforded 12, subsequent thianation
with N-phenyl-5-mercaptotetrazole/K2CO3 gave 13, which was then
subjected to m-CPBA oxidation to give fragment 6 in an 82% yield
(Scheme 3).
With 5 and 6 in hand, our next task was to couple the two frag-
ments. A careful survey of the critical Julia–Lythgoe olefination
reaction condition was conducted. Accordingly, condensation of
fragments 5 and 6 was achieved using sodium bis(trimethyl-
silyl)amide (NaHMDS) as base with hexamethylphosphoramide
(HMPA) as additive in THF. In this reaction, prolonged deprotona-
tion time by NaHMDS and slow addition of aldehyde would favor
O
O
12
11
PMBO
Ph
O
OPMB
Ph
S
N
S
N
mercapto-tetrazole
m-CPBA
N
N
OMe N
K2CO3,acetone, 84%
OMe N
N
CH2Cl2, 82%
N
O
O
13
6
Scheme 3. Synthesis of fragment 6.
OPMB
PMBO
O
S
Ph
O
OPMB
OTBS
NaHMDS,
HMPA
PMBO
O
OTBS
N
N
OMe
O
−78°C, 60%
OMe N
N
O
5
O
O
14
6
O
O
O
TBSOTf
O
LiAlH4
OPMB
OH
OPMB
OPMB
OPMB
PMBCl
2,6-lutidine
OH
CH2Cl2, 100%
OPMB
OH
OPMB
OH
96%
NaH
86%
MeOH
LiOH
98%
OMe
OH
O
CSA,90%
O
Mulzer' epoxide
8
O
O
7
15
4
3
Cl
HO
HO
O
O
OH
OPMB
O
O
Cl
COCl
NaIO4
50% TFA
CH2Cl2, 50%
OPMB
OTBS
OH
OPMB
CAN
MeCN:H2O=
10:1, 100%
OPMB
OPMB
16
THF/H2O
quant.
Cl
O
OTBS
Et3N, THF, then DMAP,
benzene, 63%
OTBS
O
O
10
1
5
9
17
Scheme 2. Synthesis of fragment 5.
Scheme 4. Total synthesis of stagonolide C.

J.-Z. Wu et al. / Tetrahedron Letters 53 (2012) 1153–1155
1155
9. Yan, X.; Zhang, S.-M.; Wu, Y.-K.; Gao, P. Org. Biomol. Chem. 2011, 9, 6797.
as chiral building blocks in efficient access to other 1,3-diols con-
taining naturally occurring products.
10. Jiang, P.; Zhang, S.-M.; He, L.; Wu, Y.-K.; Li, Yan Tetrahedron 2011, 67, 2651.
11. Yamaguchi, M.; Innaga, J.; Hirata, K., et al Bull. Chem. Soc. Jpn. 1979, 52, 1989.
12. (a) Julia, M.; Paris, J. M. Tetrahedron. Lett. 1973, 14, 4833; (b) Julia, M.; Launary,
J.; Verpeaux, S.; Verpeaux, J. Tetrahedron Lett. 1982, 23, 2465; (c) Blakemore, P.
R.; Cole, W. J.; Morely, A. Synlett 1998, 26.
Acknowledgements
13. (a) Takaku, H.; Kamaike, K. Chem. Lett. 1982, 11, 189; (b) Takaku, H.; Kamaike,
K.; Tsuchiya, H. J. Org. Chem. 1984, 49, 51.
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15. Smith, A. B., III; Doughty, V. A.; Sfouggatakis, C.; Bennett, C. S.; Koyanagi, J.;
Takeuchi, M. Org. Lett. 2002, 4, 783.
J.W. thanks Soochow University for financial assistance. This
project is also funded by the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions to Qiao, C.
16. (a) Figadere, B.; Franck, X.; Cave, A. Tetrahedron. Lett. 1995, 36, 1637; (b)
Kamenecka, T. M.; Danishefsky, S. J. Chem. Eur. J. 2001, 7, 41.
Supplementary data
17. Analytical and spectral data of 14:
½
a 2D6
ꢀ
ꢁ39.7 (c 0.33, CHCl3). 1H NMR
(400 MHz, CDCl3) d 7.25 (d, J = 8.40 Hz, 4H), 6.87 (dd, J = 8.40, 2.00 Hz, 4H), 5.59
(m, 2H), 4.54 (d, J = 8.40 Hz, 1H), 4.51 (d, J = 8.40 Hz, 1H), 4.29 (d, J = 4.00 Hz,
1H), 4.27 (d, J = 4.00 Hz, 1H), 4.08–4.00 (m, 2H), 3.90–3.80 (m, 1H), 3.80 (s, 6H),
3.63 (s, 3H), 2.42–2.37 (m, 2H), 2.00–1.78 (m, 2H), 1.72–1.67 (m, 1H), 1.59–
1.55 (m, 1H), 1.13 (d, J = 6.40 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H). 13C NMR
(100 MHz, CDCl3) d 173.8, 159.1 (2C), 134.9, 132.5, 130.8, 130.5, 129.3 (2C),
129.2 (2C), 113.9 (2C), 113.8 (2C), 78.0, 70.1, 69.9, 65.0, 55.26 (2C), 51.5, 46.5,
30.7, 30.1, 29.7, 25.9 (3C), 24.5, 18.0, ꢁ4.03, ꢁ4.70. ESI-MS: m/z 609.8
([M+Na]+). ESI-HRMS calcd for C33H50O7SiNa ([M+Na]+): 609.3218; found:
609.3222.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.102.
References and notes
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ꢀ
+50 (c 0.2, CHCl3). (lit.4a a 2D5
½ ꢀ +48 (c 0.2,
CHCl3).) 1H NMR (400 MHz, CDCl3): 5.59 (dd, J = 15.60, 9.20 Hz, 1H), 5.44 (dd,
J = 15.60, 9.20 Hz, 1H), 5.18–5.13 (dq, J = 11.10, 6.30 Hz, 1H), 4.15–4.10 (m, 2H),
2.31–2.28 (m, 1H), 2.07–2.02 (m, 3H), 1.92–1.87 (m, 1H), 1.82–1.73 (m, 1H),
1.22 (d, J = 6.50 Hz, 3H). 13C NMR: (100 MHz, CDCl3): 174.2, 135.8, 133.1, 74.6,
72.3, 67.6, 43.6, 34.6, 31.5, 21.3. ESI-MS: m/z 222.9 ([M+Na]+). ESI-HRMS calcd
for C10H16O4Na ([M+Na]+): 223.0941; found: 223.0948.