Stereoselective total synthesis of polyrhacitide A

Article abstract of DOI:10.1016/j.tetlet.2010.02.059

Stereoselective total synthesis of polyketide lactone isolated from Chinese medicinal ant Polyrhacis lamellidens is described. Ring-closing metathesis followed by stereoselective intramolecular oxa-Michael addition reactions were used to construct the bic

Full text of DOI:10.1016/j.tetlet.2010.02.059

Tetrahedron Letters 51 (2010) 2052–2054
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Stereoselective total synthesis of polyrhacitide A
*
Subhash Ghosh , Ch. Nageswara Rao
Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective total synthesis of polyketide lactone isolated from Chinese medicinal ant Polyrhacis lam-
ellidens is described. Ring-closing metathesis followed by stereoselective intramolecular oxa-Michael
Received 13 January 2010
Revised 9 February 2010
Accepted 11 February 2010
Available online 16 February 2010
addition reactions were used to construct the bicyclic lactone moiety in the molecule and
was used as a chiral pool material
L-malic acid
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Polyrhacitide A
Ring-closing metathesis
L-Malic acid
Ants from different parts of the world produce a wide range of
Our synthesis (Scheme 2) started from compound 5, which was
prepared from 6 according to the reported procedure.6a,b Protec-
tion of the secondary hydroxyl group of 5 as its benzyl ether
followed by acetonide deprotection under acidic conditions
furnished diol 86c in 90% yield over two steps. Chemoselective
tosylation of the primary alcohol followed by tosyl displacement
with the vicinal hydroxyl group under basic conditions furnished
epoxide 96c in 70%. Crucial opening of the epoxide 9 at the less
substituted carbon atom with the anion generated from dithiane
9a using n-butyllithium in THF under argon atmosphere gave
compound 10 in 80% yield.7 Deprotection of the dithioacetal group
with AgNO3 in aqueous ethanol at 60 °C furnished keto compound
11 in 78% yield.8
Hydroxyl directed stereoselective reduction of the keto group
using NaBH4 and Et2BOMe9 in THF/MeOH (4:1) at ꢀ78 °C gave
1,3-syn diol 12 in 83% (dr 95:5). Acetonide protection of the 1,3-
diol using 2,2-dimethoxy propane in the presence of catalytic
amount CSA yielded compound 13 in 95% yield. We planned to
introduce the C4-OH center via asymmetric allylation, but when
the aldehyde obtained from the olefinic compound 13 was sub-
jected to asymmetric allylation,10 using Brown’s10a as well as
Keck10b protocols gave poor yields (ꢁ5%). This unexpected result
forced us to do the substrate-controlled allylation.11 Thus the alde-
hyde on treatment with allylmagnesium bromide in ether gave
compound 14 (2.5:1) as inseparable diastereomeric mixtures. On
acylation with acryloyl chloride compound 14 gave the separable
diastereomers 4 (major) and 4a (minor). To establish the stereo-
chemistry at C4 compound 4a was converted to compound 15a
in three steps. In the 13C NMR spectrum of compound 15a, the
methyls of the C4:C6-O-isopropylidene group resonating at d
24.6 and 24.8 and the ketal carbon at d 100.1 confirmed their anti
relationship according to the reports of Rychnovsky12a and
interesting natural products having important biological functions
and of considerable pharmacological interest.1 Very recently Jiang
and co-workers have isolated two new bicyclic lactones polyrhaci-
tides A (1) and B (2)2 (Fig. 1) from the Chinese medicinal ants Poly-
rhacis lamellidens, which have been used widely in China as
traditional folk medicine for the treatment of rheumatoid arthritis
and hepatitis.3 The structure and absolute configuration of the
molecules were determined by detailed spectroscopic studies.
Although significant biological activities of polyrhacitides A (1)
and B (2) remain unknown, extract of p. lamellidens showed signif-
icant analgesic and anti-inflammatory activities.4 Therefore one
might expect similar bioactivity of polyrhacitides A (1) and B (2).
Due to their potential biological activities and unique structural
features, as well as limited availability from the natural source
(56.2 mg of A and 19.2 mg of B from 2 kg of ants) prompted us to
develop an efficient strategy for their syntheses. While we were
preparing this Letter, the first total synthesis of polyrhacitides A
and B has appeared in the literature, where the catalytic asymmet-
ric Overman esterification was utilized to install all the stereogenic
centers.5 In this Letter, we report the second stereoselective total
synthesis of polyrhacitide A starting from L-malic acid.
Retrosynthetic analysis of polyrhacitide A revealed that the
bicyclic lactone in the molecule could be constructed from com-
pound 3 via an intramolecular oxa-Michael addition. The Michael
acceptor that is, the
a,b-unsaturated six-membered d-lactone in
3 could be synthesized from the bis-olefinic compound 4, which
in turn could be obtained from the known compound 5 derived
from L-malic acid (Scheme 1).
* Corresponding author. Fax: +91 40 27193108.
E-mail addresses: subhash@iict.res.in, subhashbolorg3@yahoo.com (S. Ghosh).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.059

S. Ghosh, Ch. Nageswara Rao / Tetrahedron Letters 51 (2010) 2052–2054
2053
O
1
2
O
OH OH
8
H
O
OH OH OH
H
O
7
O
O
3
4
Polyrhacitide A (1)
Polyrhacitide B (2)
Figure 1. Structure of polyrhacitides A and B.
Evans.12b Therefore in the major isomer 4, the C4-OH and C6-OH
had 1,3-syn relationship. Next, the bis-olefinic compound 4 was
subjected to RCM reaction using Grubbs 2nd generation catalyst13
in CH2Cl2 to give compound 1515a in 80% yield. Global deprotection
of the compound 15 with TiCl4 in CH2Cl2 at 0 °C gave compound 3,
which on treatment with DBU14 in THF at 0 °C afforded polyrhaci-
O
OH OH
H
O
Oxa-Michael
OH OH OH
O
O
1
3
-
O
HOOC
O
COOH
O
OH
OH
5
O
O
OBn O
4
L−malic acid (6)
O
Scheme 1. Retrosynthetic analysis of polyrhacitide A.
i
ii
ref. 6a,b
O
L−malic acid
O
O
OH
6
5
9
O
OBn
7
iv
S
HO
iii
O
OH OBn
S
S
OBn
vi
8
C7H15
OH OBn
10
S
9a
C7H15
vii
v
C7H15
O
OH OBn
OH OH OBn
12
11
ix
viii
C7H15
C7H15
O
O
OBn
6
O
O
OBn OH
x
14
13
1
1
C7H15
C7H15
8
4
C7H15
O
O
OBn O
4
O
O
OBn O
15
xi
O
O
OBn O
4a
O
O
O
O
xiii
xii
OH OH
H
O
6
Polyrhacitide A (1)
8
4
C7H15
O
O
O
O
HO
3
15a
Scheme 2. Reagents and conditions. (i) NaH, BnBr, TBAI (cat), DMF, 0 °C to rt, 24 h, 95%; (ii) AcOH, EtOH/H2O, (2.5:1.), 0 °C to rt, 24 h, 95%; (iii) (a) TsCl, Et3N, CH2Cl2, DMAP,
0 °C to rt, 1 h; (b) K2CO3, MeOH, 0 °C to rt, 1 h, 70% over two steps; (iv) 9a, nBuLi, THF, rt, 80%; (v) AgNO3, EtOH/H2O (10:1), 60 °C, 45 min, 78%; (vi) Et2BOMe, NaBH4, THF/
MeOH (4:1), ꢀ78 °C, 3 h, 83%, dr 95:5; (vii) 2,2-DMP, CSA (cat), CH2Cl2, 0 °C to rt, 4 h, 95%; (viii) OsO4, NMO, acetone/H2O (1:1), 12 h; (b) NaIO4, THF/H2O (1:1), 0 °C to rt, 1 h;
(c) allylmagnesium bromide, Et2O, 0 °C, 1 h; 60% over three steps, dr = 2.5:1; (ix) acryloyl chloride, Et3N, CH2Cl2, 0 °C to rt, 30 min, 68% 4 and 27% 4a; (x) Grubbs 2nd
generation catalyst, CH2Cl2, 50 °C, 12 h, 80%; (xi) TiCl4, CH2Cl2, 0 °C to rt, 30 min, 75%; (xii) DBU, THF, 0 °C to rt, 36 h, 90%; (xiii) (a) K2CO3, MeOH, rt, 1 h; (b) H2, Pd/C, MeOH;
(c) 2,2-DMP, CSA (cat), CH2Cl2, 0 °C to rt, 4 h, 75%.

2054
S. Ghosh, Ch. Nageswara Rao / Tetrahedron Letters 51 (2010) 2052–2054
tide A (1) in 72% over two steps, whose analytical data, (1H and
1998, 54, 5869–5882; (c) Sharma, G. V. M.; Kumar, K. R. Tetrahedron:
Asymmetry 2004, 15, 2323–2326.
7. Ide, M.; Nakata, M. Bull. Chem. Soc. Jpn. 1999, 72, 2491–2499.
8. Reece, C. A.; Rodin, J. O.; Brownlee, R. G.; Duncan, W. G.; Silverstein, R. M.
Tetrahedron 1968, 24, 4249–4256.
13C)15b and the specific rotation (synthetic ½a 2D5
ꢂ
= +5.5, c 0.09,
= +8.3, c 0.6, MeOH) were in good agreement
MeOH, reported ½a D25
ꢂ
with the literature values.
ˇ
9. Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J. Tetrahedron
In conclusion, we have achieved the stereoselective total syn-
thesis of polyrhacitide A (1) from L-malic acid. Currently we are
working on the total synthesis of polyrhacitide B, with a little mod-
ification of the above strategy, which will be reported in due
course.
Lett. 1987, 28, 155–158.
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Acknowledgments
We are thankful to DST, New Delhi, India for financial support
(S.G.) and CSIR, New Delhi, India, (C.N.R.) for research fellowships.
We are also thankful to Dr. J. S. Yadav Director of IICT, Dr. A. C. Kun-
war, Dr. T. K. Chakraborty Director of CDRI for their support and
encouragement and Professor Zhi-Hong Jiang for providing the
copies of NMR (1H and 13C) of natural polyrhacitide A.
14. (a) Umarye, J. D.; Le mann, T.; García, A. B.; Mamane, V.; Sommer, S.;
Waldmann, H. Chem. Eur. J. 2007, 13, 3305–3319; (b) Prasad, K. R.; Gholap, S. L.
J. Org. Chem. 2008, 73, 2–11.
15. (a) Analytical data of compound 15: Rf = 0.5 (silica gel, 20% EtOAc in hexane);
½
a 2D8
ꢂ
ꢀ46.31 (c 0.19, CHCl3); IR (neat):
mmax 2924, 2855, 1728, 1460, 1383, 1249,
1109, 741, 701 cmꢀ1 1H NMR (600 MHz, CDCl3): d 7.39–7.27 (m, 5H), 6.79
;
(ddd, J = 9.0, 6.5, 2.4 Hz, 1H), 6.0 (dd, J = 9.5, 2.4 Hz, 1H), 4.58 (m, 1H), 4.53 &
4.45 (two d, J = 11.8 Hz, 2H), 3.98 (m, 1H), 3.77 (pent, J = 5.9 Hz, 1H), 3.73 (m,
1H), 2.35 (t, J = 7.5 Hz, 2H), 2.14 (m, 1H), 1.88 (m, 1H), 1.63 (m, 1H), 1.4 (s, 3H),
1.36 (s, 3H), 1.26–1.24 (m, 15H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (150 MHz,
CDCl3): d 164.5, 145.1, 138.3, 128.4, 128.1, 127.7, 121.3, 98.3, 75.3, 71.3, 70.3,
69.0, 65.6, 39.5, 38.8, 37.1, 36.4, 33.7, 32.0, 30.1, 29.7, 29.3, 29.2, 29.0, 24.9,
22.6, 14.1; MS (ESI): m/z (%) 459 (50) [M+H]+, 481 (100) [M+Na]+; HRMS (ESI):
calcd for C28H42O5 Na [M+Na]+ 481.2909, found 481.2929.
References and notes
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Int. Ed. Engl. 1997, 36, 77–80; (b) Schröder, F.; Sinnwell, V.; Baumann, H.; Kaib,
M. Chem. Commun. 1996, 2139–2140; (c) Schröder, F.; Franke, S.; Francke, W.;
Baumann, H.; Kaib, M. Tetrahedron 1996, 52, 13539–13546; (d) Mackintosh, J.
A.; Veal, D. A.; Beattie, A. J.; Gooley, A. A. J. Biol. Chem. 1998, 273, 6139–6143.
2. Jiang, Z. H.; Yang, Q. X.; Tanaka, T.; Kouno, I. J. Nat. Prod. 2008, 71, 724–727.
3. (a) Zhang, J. H.; Ma, A. H.; Xie, X. F.; Li, S. L. Jiangsu J. TCM 1996, 17, 43–45; (b)
Zhang, R. W.; Shao, S. H. J. Jiangxi. College TCM 1996, 8, 47–48; (c) Li, S. L.; Ren, Y.
J.; Cui, X.; Qian, Z. Z.; Dong, Q. Chin. Tradit. Pat. Med. 1994, 17, 47–49.
4. Kou, J.; Ni, Y.; Li, N.; Wang, J.; Liu, L.; Jiang, Z.-H. Biol. Pharm. Bull. 2005, 28, 176–
180.
(b) Analytical data for polyrhacitide A: Mp: 65 °C. Rf = 0.5 (silica gel, 80% EtOAc in
hexane); ½a 2D8
ꢂ
+5.5 (c 0.09, MeOH); IR (neat): mmax 3421, 3315, 2923, 2854,
1729, 1454, 1340, 1201, 1087 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d 4.88 (m, 1H),
4.40 (br s, 1H), 4.11–4.01 (m, 2H), 3.83 (m, 1H), 2.90 (dt, J = 19.3, 1.6 Hz, 1H),
2.81 (dd, J = 19.3, 5.2 Hz, 1H), 2.05 (m, 1H), 2.02 (m, 1H), 1.94 (ddd, J = 14.0, 4.0,
2.0 Hz, 1H), 1.71 (dt, J = 14.7, 9.5 Hz, 1H), 1.67–1.61 (m, 2H), 1.59 (dt, J = 14.4,
2.7 Hz, 1H), 1.54–1.44 (m, 3H), 1.41–1.36 (m, 2H), 1.32–1.20 (m, 10H), 0.88 (t,
J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3): d 169.3, 72.7, 72.5, 72.1, 67.0, 66.0,
43.2, 42.8, 37.7, 37.2, 36.4, 31.8, 29.6, 29.4, 29.3, 25.4, 22.6, 14.1; MS (ESI): m/z
(%) 329 (30) [M+H]+, 351 (100) [M+Na]+; HRMS (ESI): calcd for C18H32O5 Na
[M+Na]+ 351.2154, found 351.2147.
5. Menz, H.; Kirsch, S. F. Org. Lett. 2009, 11, 5634–5637.
6. (a) Barth, M.; Bellamy, F. D.; Renaut, P.; Samreth, S.; Schuber, F. Tetrahedron
1990, 46, 6731–6740; (b) Ishikawa, T.; Ikeda, S.; Ibe, M.; Saito, S. Tetrahedron