Stereoselective synthesis of (+)-secosyrin 1

Article abstract of DOI:10.1016/j.tetlet.2009.01.106

A Chiron approach for the synthesis of (+)-secosyrin 1 from d-mannitol has been described. The key steps are a stereoselective Wittig reaction and an intramolecular Michael addition on the disubstituted butenolide, leading to a highly stereoselective form

Full text of DOI:10.1016/j.tetlet.2009.01.106

Tetrahedron Letters 50 (2009) 1693–1695
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Stereoselective synthesis of (+)-secosyrin 1
*
D. Gautam, B. Venkateswara Rao
Organic Division III, Indian Institute of Chemical Technology, Habsiguda, Tarnaka, Hyderabad, Andhrapradesh 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A Chiron approach for the synthesis of (+)-secosyrin 1 from D-mannitol has been described. The key steps
Received 13 November 2008
Revised 9 January 2009
Accepted 18 January 2009
Available online 23 January 2009
are a stereoselective Wittig reaction and an intramolecular Michael addition on the disubstituted bute-
nolide, leading to a highly stereoselective formation of the tertiary chiral centre of (+)-secosyrin 1.
Ó 2009 Elsevier Ltd. All rights reserved.
Some plant pathogens produce signal molecules (elicitors)
which are recognized specifically by resistant plants and enable
the plants to initiate active defense responses against these patho-
gens.1 In 1993, Sims and co-workers2 isolated Syringolides 1 and 2
(1 and 2, Fig. 1) from Pseudomonas syringae Pv. Tomato, which are
the first known nonproteinaceous metabolites found to elicit
hypersensitive responses on soybean plants carrying the resistance
gene Rpg4.3 Two years later, Sims and co-workers4 reported the
isolation of four structurally related metabolites from the same
source, syributins 1 and 2 (5 and 6) and secosyrins 1 and 2 (3
and 4). Although these compounds are not active elicitors, they
certainly display biosynthetic interest as they are co-produced
with syringolides, and may provide a clue to the nature of the
genes involved in the hypersensitive response.
The retrosynthetic analysis (Scheme 1) showed that 3 could be
obtained from the oxidation, lactonization and deprotection of ole-
fin compound 7. Olefin 7 could be obtained from bicyclic lactone 8,
which could be obtained from intramolecular Michael addition on
disubstituted butenolide 9. The stereoselective formation of a cis-
fused bicyclic lactone was predicted10 since it is obvious that the
alternative trans ring junction between the two five-membered
rings has a highly unfavourable ring strain leading to the highly
stereoselective formation of the tertiary chiral centre of 8. Com-
pound 9 can be obtained from olefin 10, which could be conve-
niently prepared from D-mannitol.
The synthesis of 3 commenced from 11 which was readily ob-
tained by following the procedure mentioned in the literature.11
The primary hydroxy of 11 was protected as its TBDPS ether to give
12. The TEMPO-mediated oxidation of 12 gave 13. A two-carbon
extension of 13 was performed in a stereoselective manner by
using the Wittig reaction to yield 14. The bulky TBDPS group might
have directed the formation of only the Z-isomer.12 The removal of
TBDPS in 14 with TBAF gave 15, which on reaction with benzyl bro-
mide yielded 16. The selective isopropylidene deprotection of 16
The interesting properties of syringolides triggered extensive
work regarding their biochemical evaluation in plant research.5
Their interesting biological activity coupled with important struc-
tural features of 1 and 2 such as the spiro system with a tertiary
chiral centre has attracted the attention of many synthetic organic
chemists.6 Syributins6d,k,7 and secosyrins7a,b,8 were also targeted by
different research groups. In continuation of our interest in the
synthesis of oxygenated heterocycles,9,10 we undertook the stereo-
selective synthesis of (+)-secosyrin 1(3).
O
OH
O
O
H
Both racemic8c and enantioselective approaches have been
developed for secosyrins. The enantioselective approaches have
Me(H2C)n
Me(H2C)n
HO
O
O
H
O
O
utilized isopropylidene
D
-glyceraldehydes,7a diisopropyl
D
D
-tar-
O
O
trate,7b,8a -xylulose,8b and
D
-arabinose8d as the chiral starting
HO
materials. Different strategies have been adopted for the construc-
tion of the tetrahydrofuran unit of compound 3. Two of these syn-
theses7a,8d utilized Michael addition as a key step for the formation
of the tetrahydrofuran unit with a stereoselectivity of not more
than 5:1. Herein, we wish to present a novel approach for the
(+)-secosyrin 1 (3) starting from D-mannitol and utilizing a highly
stereoselective intramolecular Michael addition on disubstituted
butenolide.
1: syringolide 1 (n=4)
2: syringolide 2 (n=6)
3: secosyrin 1 (n=4)
4: secosyrin 2 (n=6)
O
O
HO
5: syributin 1 (n=4)
6: syributin 2 (n=6)
O
(CH2)nMe
HO
O
* Corresponding author. Tel./fax: +91 40 27193003.
E-mail address: venky@iict.res.in (B. Venkateswara Rao).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.106

1694
D. Gautam, B. Venkateswara Rao / Tetrahedron Letters 50 (2009) 1693–1695
O
O
O
O
Me(H2C)4
O
Me(H2C)4
HO
O
O
O
O
OR
OR
OH
RO
HO
O
O
O
3
7
8
O
O
EtO
O
OH
OH
HO
HO
OR
HO
OR
HO
OH
-Mannitol
O
OH
9
D
10
Scheme 1.
was performed using aq H2SO4 in EtOH to afford 17, which on
treatment with NaIO4 followed by reduction of the resulting alde-
hyde using NaBH4 gave 18. Compound 18 was treated with PTSA in
aq acetone to cleave the isopropylidene, and the crude concen-
trated reaction mixture was treated with excess NaHCO3 in ethyl
acetate for 2 days. Stereoselective intramolecular Michael addition
O
OH
O
OH
a
b
OTBDPS
ref 11
OH
O
D-Mannitol
O
O
O
O
O
11
12
O
O
EtO
EtO
O
O
O
O
e
c
OTBDPS
OR
OBn
O
O
O
O
O
O
d
O
O
O
14; R= TBDPS
15; R= H
16
13
O
O
O
EtO
O
EtO
O
h
g
f
O
HO
HO
OBn
OBn
HO
HO
OBn
HO
O
O
17
18
19
O
O
OH
O
O
i
l
k
OTBS
OBn
OR
TBSO
O
HO
RO
O
O
23
21; R= H
20
j
22; R= TBS
O
O
OH
O
Me(H2C)4
O
Me(H2C)4
O
m
n
3
OTBS
OTBS
TBSO
TBSO
O
O
24
25
Scheme 2. Reagents and conditions: (a) TBDPSCl, Imidazole, CH2Cl2, 0 °C to rt, 12 h, 90%; (b) NaOCl, TEMPO free radical, TBAI (cat. amount), NaBr, EtOAc, toluene, H2O,
NaHCO3, 0 °C, 2 h, 94%; (c) PPh3CHCO2C2H5, toluene, reflux, 5 h, 78%; (d) TBAF, THF, 0 °C to rt, 12 h, 70%; (e) BnBr, Ag2O, 4 Å molecular sieves, CH2Cl2, rt, 24 h, 80%; (f) aq
H2SO4, EtOH, rt, 10 h, 70%; (g) (i) NaIO4, CH2Cl2, 0 °C to rt 3 h; (ii) NaBH4, MeOH, 0 °C to rt, 2 h, 86% for two steps; (h) PTSA, acetone/water (3:2), rt, 5 h, then NaHCO3, EtOAc, rt,
2 days, 70%; (i) H2, 10% Pd/C, EtOAc, rt, 12 h, 95%, (j) TBSOTf, 2,6-lutidine, THF, ꢀ78 °C to rt, 4 h, 86%; (k) (i) DIBAL-H, CH2Cl2, ꢀ78 °C, 2 h, 97%; (ii) PPh3CH3I, KOtBu, THF, 0 °C to
rt, 15 min, 80%; (l) hexanoic anhydride, Et3N, DMAP, CH2Cl2, 0 °C to rt, 1 h, 98%; (m) NaIO4, RuCl3. H2O (cat. amount), Na2HPO4. 2H2O, H2O, CCl4, MeCN, rt, 18 h, 62%; (n) TFA,
TFAA, rt, 1 h then TBAF, rt, 2 days, 73%.

D. Gautam, B. Venkateswara Rao / Tetrahedron Letters 50 (2009) 1693–1695
1695
Tetrahedron Lett. 1998, 39, 8895; (c) Donohoe, T. J.; Fisher, J. W.; Edwards, P.
J. Org. Lett. 2004, 6, 465; (d) Koumbis, A. E.; Varvogli, A.-A. C. Synlett 2006, 19,
3340.
on intermediate 19 had taken place to give syn-bicyclic lactone 20
in 70% yield.13,14 The deprotection of the benzyl group in 20 using
H2, Pd/C gave 21, which was converted to its disilyl ether 22. The
bicyclic lactone formation helped not only in creating the tertiary
chiral centre, but also in selectively protecting the hyroxyls. The
reduction of 22 with DIBAL-H and one carbon homologation
yielded 23. The acylation of 23 with hexanoic anhydride gave ester
24. The RuO4-mediated oxidative cleavage of a double bond in 24
gave acid 25. Finally, the lactonization of 25 with trifluoroacetic
anhydride/trifluoroacetic acid and the subsequent deprotection of
more robust secondary OTBS with TBAF have been carried out in
one pot to give compound 3. The spectral and physical properties
9. (a) Ramu, E.; Rao, B. V. Tetrahedron: Asymmetry 2008, 19, 1820; (b) Gautam, D.;
Kumar, D. N.; Rao, B. V. Tetrahedron: Asymmetry 2006, 17, 819; (c) Ramu, E.;
Bhaskar, G.; Rao, B. V.; Ramanjaneyulu, G. S. Tetrahedron Lett. 2006, 47, 3401;
(d) Naveen Kumar, D.; Sudhakar, N.; Rao, B. V.; Kishore, K. H.; Murty, U. S.
Tetrahedron Lett. 2006, 47, 771; (e) Kumar, A. R.; Sudhakar, N.; Rao, B. V.;
Raghunandhan, N.; Venkatesh, A.; Sarangapani, M. Bioorg. Med. Chem. Lett.
2005, 15, 2085; (f) Sudhakar, N.; Kumar, A. R.; Prabhakar, A.; Jagadeesh, B.; Rao,
B. V. Tetrahedron Lett. 2005, 46, 325; (g) Naveen Kumar, D.; Rao, B. V.;
Ramajaneyulu, G. S. Tetrahedron: Asymmetry 2005, 16, 1611; (h) Naveen Kumar,
D.; Rao, B. V. Tetrahedron Lett. 2004, 45, 2227.
10. (a) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008, 73, 2; (b) Bhaket, P.; Morris, K.;
Stauffer, C. S.; Datta, A. Org. Lett. 2005, 7, 875–876; (c) Prakash, K. R. C.; Rao, S.
P. Tetrahedron Lett. 1991, 32, 7473.
11. Naveen Kumar, D.; Rao, B. V. Tetrahedron Lett. 2004, 45, 7713.
12. The 1H NMR of the column-filtered product showed exclusive formation of Z-
isomer. Generally, the E-isomer of 14 undergoes spontaneous lactonization
upon deprotection of the TBDPS group. No lactonization of 14 was observed
upon deprotection of the TBDPS group, thus confirming the Z-isomer. Z-isomer
was further confirmed by the isolation of intermediate lactone 19 in 88% yield
prior to base-induced Michael addition.
of 3 are in good agreement with the reported values.7a
(c 0.275, CHCl3) lit.7a
+40.2 (c 1.1, CHCl3) (Scheme 2).
In conclusion, we have demonstrated the total synthesis of (+)-
secosyrin 1 (3) through a chiral pool strategy using -mannitol in a
½
a 2D6
+42.7
ꢁ
½ ꢁ
a 2D0
D
highly stereoselective fashion. The above-mentioned strategy is
useful in making related skeletons and analogues.
NMR data of compound 14: 1H NMR(300 MHz, CDCl3) d 1.09 (s, 9H), 1.16 (s, 3H),
1.27–1.37 (m, 12H), 3.65 (dd, J = 4.5 Hz, 9.1 Hz, 1H), 3.86–3.96 (m, 1H) 4.03–
4.23 (m, 4H), 4.25(d, J = 17.4 Hz, 1H), 4.46 (dd, J = 1.9 Hz, 17.4 Hz, 1H), 5.61 (d,
J = 9.1 Hz, 1H), 6.36 (s, 1H), 7.32–7.45 (m, 6H), 7.59–7.66 (m, 4H).
NMR data of compound 19: 1H NMR(400 MHz, CDCl3) d = 2.34 (br s, 1H), 2.77 (br
s, 1H), 3.81 (m, 2H), 4.03 (br s, 1H), 4.37, 4.43 (AB-q, J = 14.9 Hz, 2H), 4.59, 4.63
(AB-q, J = 11.8 Hz, 2H), 5.09 (s, 1H), 6.08 (d, J = 1.5 Hz, 1H), 7.28–7.43 (m, 5H).
Acknowledgements
D. Gautam thanks the CSIR, New Delhi, for a research fellow-
ship. The authors also thank Dr. J. S. Yadav, Dr. A. C. Kunwar and
Dr. T. K. Chakraborty for their help and encouragement.
13. Analytical data of compound 20: Colourless liquid, ½a D28
ꢁ
+8.4 (c 2.2, CHCl3);
IR(Neat) 3423, 2924, 2858, 1781, 1452, 1037 cmꢀ1 1H NMR(300 MHz, CDCl3) d
;
2.58 (s, 2H), 3.56, 3.74 (AB-q, J = 9.8 Hz, 2H), 3.63 (d, J = 10.9 Hz, 1H) 3.95–4.04
(m, 2H), 4.31 (d, J = 10.9 Hz, 1H), 4.56, 4.70 (AB-q, J = 11.7 Hz, 2H), 4.69 (s, 1H),
7.26–7.4 (m, 5H); 13C NMR(75 MHz, CDCl3): d 37.4, 71.1, 73.7, 74.1, 74.6, 87.2,
88.8, 127.8, 128.2, 128.5, 136.3, 174.2; ESIMS: 287 [M+Na]+; ESI-HRMS: calcd
for C14H16O5Na [M+Na]+ = 287.0895, found: 287.0899.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.106.
14. (a) In batches of around 1 g (2.9 mmol) of 18, about 4% of diastereomeric 26
was also isolated and its structure was confirmed by its 1H NMR coupling
constants and NOE experiment. Compound 26 showed a coupling constant of
4.9 Hz for H4 and H5 protons (due to syn orientation), which was further
confirmed by the NOE between H4 and H7 protons and H4 and H5 protons
(due to the syn orientation of protons), thus confirming the compound 26. No
compound with trans ring junction was isolated.
References and notes
1. Schroder, F. Angew. Chem., Int. Ed. 1998, 37, 1213.
2. (a) Smith, M. J.; Mazzola, E. P.; Sims, J. J.; Midland, S. L.; Keen, N. T.; Burton, V.;
Stayton, M. M. Tetrahedron Lett. 1993, 34, 223; (b) Midland, S. L.; Keen, N. T.;
Sims, J. J.; Midland, M. M.; Stayton, M. M.; Burton, V.; Smith, M. J.; Mazzola, E.
P.; Graham, K. J.; Clardy, J. J. Org. Chem. 1993, 58, 2940.
3. (a) Keen, N. T.; Tamaki, S.; Kobayashi, D.; Gerhold, D.; Stayton, M. M.; Shen, H.;
Gold, S.; Lorang, J.; Thordal-Christensen, H.; Dahlbeck, D.; Staskawicz, B. Mol.
Plant Microbe Interact. 1990, 3, 112; (b) Keen, N. T.; Buzzell, R. I. Theor. Appl.
Genet. 1991, 81, 133.
O
O
1
NOE
O
O
2
4
H4
H5
HO
NOE
OBn
H7
H7
3
5
7
HO
O
O
4. Midland, S. L.; Keen, N. T.; Sims, J. J. J. Org. Chem. 1995, 60, 1118.
5. Selected publications: (a) Atkinson, M. M.; Midland, S. L.; Sims, J. J.; Keen, N. T.
Plant Physiol. 1996, 112, 297; (b) Tsurushima, T.; Midland, S. L.; Zeng, C.-M.; Ji,
C.; Sims, J. J.; Keen, N. T. Phytochemistry 1996, 43, 1219; (c) Ji, C.; Okinaka, Y.;
Takeuchi, Y.; Tsurushima, T.; Buzzell, R. I.; Sims, J. J.; Midland, S. L.; Slaymaker,
D.; Yoshikawa, M.; Yamaoka, N.; Keen, N. T. Plant Cell 1997, 9, 1425; (d) Ji, C.;
Boyd, C.; Slaymaker, D.; Okinaka, Y.; Takeuchi, Y.; Midland, S. L.; Sims, J. J.;
Herman, E.; Keen, N. T. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 3306; (e)
Tsurushima, T.; Ji, C.; Okinaka, Y.; Takeuchi, Y.; Sims, J. J.; Midland, S. L.;
Yoshikawa, M.; Yamaoka, N.; Keen, N. T. Dev. Plant Pathol. 1998, 13, 139; (f)
Slaymaker, D. H.; Keen, N. T. Plant Sci. 2004, 166, 387.
6. (a) Kuwahara, S.; Moriguchi, M.; Miyagawa, K.; Konno, M.; Kodama, O.
Tetrahedron Lett. 1995, 36, 3201; (b) Kuwahara, S.; Moriguchi, M.; Miyagawa,
K.; Konno, M.; Kodama, O. Tetrahedron 1995, 51, 8809; (c) Wood, J. L.; Jeong, S.;
Salcedo, A.; Jenkins, J. J. Org. Chem. 1995, 60, 286; (d) Honda, T.; Mizutani, H.;
Kanai, K. J. Org. Chem. 1996, 61, 9374; (e) Henschke, J. P.; Rickards, R. W.
Tetrahedron Lett. 1996, 37, 3557; (f) Ishihara, J.; Ugimoto, T.; Murai, A. Synlett
1996, 335; (g) Zeng, C.-M.; Midland, S. L.; Keen, N. T.; Sims, J. J. J. Org. Chem.
1997, 62, 4780; (h) Yoda, H.; Kawauchi, M.; Takabe, K.; Ken, H. Heterocycles
1997, 45, 1895; (i) Ishihara, J.; Sugimoto, T.; Murai, A. Tetrahedron 1997, 53,
16029; (j) Yu, P.; Wang, Q.-G.; Mak, T. C. W.; Wong, H. N. C. Tetrahedron 1998,
54, 1783; (k) Di Florio, R.; Rizzacasa, M. A. Austr. J. Chem. 2000, 53, 327; (l)
Chenevert, R.; Dasser, M. Can. J. Chem. 2000, 78, 275; (m) Chenevert, R.; Dasser,
M. J. Org. Chem. 2000, 65, 4529.
6
OBn
26
26
Compound 26 formation can be explained by the epimerization of intermediate 19 to
28 via oxy-furan intermediate 27 followed by Michael addition of 28.
O-
O
O
H
O
h
HO
HO
18
HO
HO
H+
OBn
O
OBn
19
27
Michael
addition
O
HO
HO
26
OBn
7. (a) Yu, P.; Yang, Y.; Zhang, Z. Y.; Mak, T. C. W.; Wong, H. N. C. J. Org. Chem. 1997,
62, 6359; (b) Mukai, C.; Moharram, S. M.; Azukizawa, S.; Hanaoka, M. J. Org.
Chem. 1997, 62, 8095; (c) Yoda, H.; Kawauchi, M.; Takabe, K.; Hosoya, K.
Heterocycles 1997, 45, 1903; (d) Krishna, P. R.; Narsingam, M.; Kannan, V.
Tetrahedron Lett. 2004, 45, 4773; (e) Wong, H. N. C. Pure Appl. Chem. 1996, 68,
335.
28
(b) Analytical data of compound 26: White solid, mp 85 °C, ½a D28
ꢀ1.5 (c 0.65, CHCl3);
ꢁ
IR(Neat) 3446, 1776, 1636, 1075 cmꢀ1 1H NMR(300 MHz, CDCl3) d 2.69, 2.82 (AB-q,
;
J = 18.5 Hz, 2H) 3.50, 3.54 (AB-q, J = 10.2 Hz, 2H), 3.70 (dd, J = 7.2 Hz, 9.4 Hz, 1H),
4.12 (dd, J = 6.0 Hz, 9.4 Hz, 1H), 4.41–4.50 (m, 1H) 4.54, 4.60 (AB-q, J = 11.7 Hz, 2H),
4.81 (d, J = 4.9 Hz), 7.27–7.41 (m, 5H); 13C NMR(75 MHz, CDCl3): d 38.5, 71.2, 71.6,
71.6, 73.6, 83.6, 86.5, 127.7, 128.1, 128.6, 137.2, 174.8; ESIMS: 287 [M+Na]+.
8. (a) Mukai, C.; Moharram, S. M.; Hanaoka, M. Tetrahedron Lett. 1997, 38, 2511;
(b) Carda, M.; Castillo, E.; Rodriguez, S.; Falomir, E.; Alberto Marco, J.