First stereoselective total synthesis of stagonolide G

Article abstract of DOI:10.1016/j.tetlet.2010.03.102

First stereoselective total synthesis of nonenolide stagonolide G involving a convergent strategy is described. The key reactions include Keck allylation and Grubbs ring closing metathesis reaction.

Full text of DOI:10.1016/j.tetlet.2010.03.102

Tetrahedron Letters 51 (2010) 2903–2905
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First stereoselective total synthesis of stagonolide G
*
*
P. Srihari , B. Kumaraswamy, Dinesh C. Bhunia, J. S. Yadav
Organic Division-I, Indian Institute of Chemical Technology, CSIR, 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:
First stereoselective total synthesis of nonenolide stagonolide G involving a convergent strategy is
described. The key reactions include Keck allylation and Grubbs ring closing metathesis reaction.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 10 March 2010
Revised 22 March 2010
Accepted 24 March 2010
Available online 28 March 2010
During recent years secondary metabolites are attaining signif-
icant interest due to their potent biological properties.1 Ten-mem-
bered ring containing macrolide nonenolides, stagonolides A-I, and
modiolides A and B (Fig. 1)2 are the recent examples which have
been isolated very frequently in both liquid and solid cultures of
Stagonospora cirsii Davis, a fungal pathogen isolated from Cisium
arvense. As these natural products are available in scarce amounts,
only a few compounds have been investigated for the biological
activities. While stagonolide A was found to be phytotoxic2a stag-
onolide F was found to display both anti-fungal and anti bacterial
activities.2b Intrigued by the biological properties of these macro-
lides, we became interested in taking up the total synthesis of
these nonenolides. In continuation to our work on the synthesis
of lactone containing natural products,3 recently we have accom-
plished the total synthesis of stagonolide A3a and stagonolide B.3b
Herein, we report the first stereoselective total synthesis of stagon-
olide G using a convergent approach.
OH
O
OH
O
OH
O
O
HO
HO
HO
O
O
O
O
O
HO
Me
Me
O
Stagonolide D 4
Stagonolide B 2
Stagonolide C 3
Stagonolide A 1
OH
OH
OH
OH
O
O
O
O
OH
Me
O
O
O
Me
Stagonolide H 8
Me
O
Me
O
Stagonolide G 7
Stagonolide E 5 Stagonolide F 6
HO
OH
HO
OH
HO
O
O
Me
O
Me
O
O
Me
O
*
Stagonolide I 9
Modiolide A 10
Modiolide B 11
Retrosynthetically, we envisaged that the target molecule can
be obtained from the ester 12 with two terminal olefin moieties
by a ring closing metathesis followed by di-debenzylation. The es-
ter 12 in turn is obtained by a coupling/esterification of two key
fragments, alcohol 13 and an acid 14 (Scheme 1). While the acid
is obtained from commercially available 1,4-butanediol, the alco-
Figure 1.
OH
O
O
hol 13 with two stereocenters can be obtained from
D-glucose
diacetonide involving a chiron pool approach.
O
O
OH
OBn
Accordingly, we began our synthesis with the protection of the
-glucose diacetonide with benzyl bromide and NaH to provide the
D
OBn
12
Stagonolide G 7
corresponding benzyl ether 15. Compound 15 on selective aceto-
nide deprotection gave the diol 16. Sequential oxidative cleavage
of the diol with NaIO4 followed by reduction with NaBH4 provided
alcohol 17. The primary alcohol was converted to tosylate and re-
duced with LiAlH4 to give compound 18. The compound 18 was
treated with catalytic amount of con.H2SO4 to result in lactol 19,
O
OH
OBn
O
O
+
OH
HOOC
HO
O
OBn
13
14
OH
O
Glucose diacetonide
1,4-butanediol
* Corresponding authors. Tel.: +91 4027191490; fax: +91 4027160512 (P.S.).
E-mail addresses: srihari@iict.res.in, sriharipabbaraja@yahoo.com (P. Srihari),
yadavpub@iict.res.in (J.S. Yadav).
Scheme 1. Retrosynthesis.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.102

2904
P. Srihari et al. / Tetrahedron Letters 51 (2010) 2903–2905
O
O
O
O
OH
O
O
O
NaH, BnBr
0.8%H2SO4
MeOH, 0 ºC - rt
6 h, 89%
HO
O
O
O
DMF, 0 ºC - rt
O
HO
O
15
6 h, 92%
O
BnO
TsCl, Et3N,
DCM, DMAP(cat)
BnO
16
O
NaIO4,DCM
O
O
O
5%H2SO4,THF
HO
BnO
NaBH4,MeOH
overall yield 75%
O
LAH,THF, reflux
5 h, 78%
40 ºC, 10 h, 80%
O
18
BnO
17
CH3PPh3I,
t-BuOK, THF
OH
OH
O
OH
H5IO6,
O
0 ºC - rt, 2 h,
EtOAC:H2O (1:1)
rt, 2 h
BnO
OH
19
OBn
20
OBn
two steps 72%
13
Scheme 2. Synthesis of alcohol.
which was treated with periodic acid to yield the aldehyde 20. The
aldehyde was subjected to one carbon Wittig reaction with meth-
yltriphenylphosphonium iodide in the presence of potassium tert-
butoxide to yield the key fragment olefinic alcohol 13 (Scheme 2).
The other key fragment acid 14 was synthesized starting from
1,4-butanediol. Accordingly, 1,4-butanediol was selectively mono-
protected as the corresponding TBS ether 21 and the free primary
alcohol was converted to aldehyde 22 by PCC oxidation. The alde-
hyde on Keck allylation4 provided chiral homoallyl alcohol 23 in
93% yield with 97%ee. The resulting chiral secondary alcohol was
protected as the corresponding benzyl ether 24 with NaH and ben-
zyl bromide and then treated with TBAF to yield the free primary
alcohol 25 (Scheme 3). Oxidation of the primary alcohol with BAIB
and TEMPO yielded the corresponding acid 14.5
coupled together using DCC and DMAP to yield the correspond-
ing ester 12. When the compound 12 was exposed to Grubbs’
2nd generation catalyst for 3 h at 40 °C in dichloromethane, we
were gratified to observe the formation of the desired Z isomer
exclusively as a single product 26 (Scheme 4).6 Finally, deprotec-
tion of the two benzyl moieties with TiCl4 afforded the target
molecule stagonolide G.7 The spectroscopic data were compared
with those of the natural product reported earlier and were
found to be similar2c in all respects but with a variation in opti-
cal rotation.
In conclusion, we have accomplished the total synthesis of
stagonolide G following a convergent approach involving chiron
pool synthesis. Keck allylation and Grubbs’ olefin metathesis reac-
tions are the other key steps utilized for the target synthesis. The
synthesis of other stagonolide members and their analogues is
currently being investigated for their utility toward biological
evaluation.
With the two intermediates in hand, the stages were set for
coupling them together and proceed further for ring closing
metathesis reaction. Thus, the acid 14 and the alcohol 13 were
NaH,TBSCl,
OH
PCC, DCM
OH
TBSO
CHO
TBSO
HO
0 ºC to rt,
2 h, 75%
THF, rt, 8 h, 92%
21
22
(R)-BINOL-Ti(OiPr)
(5 mol%)
NaH, BnBr
TBAI, THF
OH
4 Ao MS,-15 ºC
OBn
TBAF,THF
TBSO
TBSO
SnBu3
0 ºC, rt, 3 h
91%
0 ºC, 3 h, 93%
23
24
DCM, 40 h, 93%
OBn
HO
OBn
TEMPO, BAIB
CH3CN:H2O (4:1)
rt, 2 h, 84%
HOOC
25
14
Scheme 3. Synthesis of acid.
OBn
O
Grubbs 2nd generation
(20 mol%),
DCC, DMAP
O
A
+ B
O
DCM, 40 ºC, 3 h, 92%
DCM, 0 ºC,
OBn
OBn
12 h, 82%
O
12
OBn
26
OH
O
TiCl4, DCM
O
0 ºC, 2 h, 72%
OH
Stagonolide G
Scheme 4. Synthesis of stagonolide G.

P. Srihari et al. / Tetrahedron Letters 51 (2010) 2903–2905
2905
S.; Kumar, V. N.; Rao, R. S.; Srihari, P. Synthesis 2008, 1938–1942; (f) Srihari, P.;
Kumar, B. P.; Subbarayudu, K.; Yadav, J. S. Tetrahedron Lett. 2007, 48, 6977–6981;
(g) Srihari, P.; Bhasker, E. V.; Harshavardhan, S. J.; Yadav, J. S. Synthesis 2006,
4041–4045.
Acknowledgment
B.K. and D.C.B. thanks CSIR, New Delhi for financial assistance.
References and notes
4. Kurosu, M.; Miguel, L. Synlett 2005, 1109–1112.
5. Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293–295.
6. LCMS analysis of the crude reaction mixture showed the presence of single
isomer. 1H NMR analysis revealed the presence of cis isomer with the coupling
constant value of 11.3 Hz for olefinic protons.
1. (a) Arif, T.; Bhosale, J. D.; Kumar, N.; Mandal, T. K.; Bendre, R. S.; Lavekar, G. S.;
Dabur, R. J. Asian Nat. Prod. 2009, 11, 621–638; (b) Piel, J. Nat. Prod. Rep. 2009, 26,
338–362; (c) Nicolaou, K. C.; Chen, J. S.; Dalby, S. M. Bioorg. Med. Chem. 2009, 17,
2290–2303; (d) Lu, X.-L.; Xu, Q.-Z.; Liu, X.-Y.; Cao, X.; Ni, K.-Y.; Jiao, B.-H. Chem.
Biodiversity 2008, 5, 1669–1674; (e) Itokawa, H.; Morris-Natschke, S. L.;
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Yucheng, G. Curr. Med. Chem. 2006, 43, 303–332; (g) Croteau, R.; Kutchan, T. M.;
Lewis, N. G. Natural Products (Secondary Metabolites); Biochemistry and Molecular
Biology of Plants; Rockville: Maryland, 2000. pp 1250–1318; (h) Pietra, F. Nat.
Prod. Rep. 1997, 453–464.
7. Spectroscopic data for representative examples: Compound 13: Yellowish liquid;
½
a 2D5
ꢀ
= ꢁ48.5 (c 1.6, CHCl3); IR (neat): 3448, 2929, 1731, 1453, 1250, 1065,
3029 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.10 (d, J = 6.8 Hz, 3H), 2.65 (br s, 1H),
;
3.48 (t, J = 7.5 Hz, 1H), 3.65 (m, 1H), 4.47 (ABq, J = 12.1 Hz, 2H), 5.28–5.38 (m,
2H), 5.63–5.76 (m, 1H) 7.21–7.35 (m, 5H); 13C NMR (75 MHz, CDCl3): d 18.1,
69.5, 70.3, 85.9, 120.2, 127.6, 127.8, 128.3, 135.1, 137.9; ESIMS: m/z 215
(M+Na)+; HRMS for C12H17O2: calcd, 193.1223, found: 193.1214. Compound 14:
Yellowish liquid; ½a D25
ꢀ
= ꢁ28 (c 2.2, CHCl3); IR (neat): 3069, 3031, 2926, 2860,
1705, 1445, 1415, 1208, 737 cmꢁ1
;
1H NMR (500 MHz, CDCl3); d 1.74–1.83 (m,
2. For isolation of stagonolides: (a) Oleg, Y.; Galin, M.; Alexander, B. J. Agric. Food
Chem. 2007, 55, 7707–7711; (b) Antonio, E.; Alessio, C.; Alexander, B.; Galina,
M.; Anna, A.; Andera, M. J. Nat. Prod. 2008, 71, 31–34; (c) Antonio, E.; Alessio, C.;
Alexander, B.; Galina, M.; Anna, A.; Andera, M. J. Nat. Prod. 2008, 71, 1897–1901;
For isolation of modiolides: (d) Tsuda, M.; Mugishima, T.; Komatsu, K.; Sone, T.;
Tanaka, M.; Mikami, Y.; Kobayashi, J. J. Nat. Prod. 2003, 66, 412–415.
3. For our recent contributions on lactone containing molecules see: (a) Srihari, P.;
Kumaraswamy, B.; Maheswara Rao, G.; Yadav, J. S. Tetrahedron: Asymmetry
2010, 21, 106–111; (b) Srihari, P.; Kumaraswamy, B.; Somaiah, R.; Yadav, J. S.
Synthesis 2010, 1039–1045; (c) Srihari, P.; Vijaya Bhasker, E.; Bal Reddy, A.;
Yadav, J. S. Tetrahedron Lett. 2009, 50, 2420–2424; (d) Srihari, P.; Rajendar, G.;
Srinivasa Rao, R.; Yadav, J. S. Tetrahedron Lett. 2008, 49, 5590–5592; (e) Yadav, J.
1H), 1.84–1.95 (m, 1H), 2.24–2.34 (m, 1H), 2.34–2.48 (m, 3H), 3.45–3.54 (m, 1H),
4.51 (ABq, J = 11.1 Hz, 2H), 5.04–5.12 (m, 2H), 5.75–5.86 (m, 1H), 7.2–7.33 (m,
5H); 13C NMR (75 MHz, CDCl3): d 28.5, 30.0, 37.9, 70.9, 77.1, 117.4, 127.5, 127.7,
128.2, 134.1, 138.2, 179.7; ESIMS: m/z 257 (M+Na)+; HRMS for C14H18O3: calcd
257.1153; found: 257.1156. Stagonolide G 7: Sticky liquid; ½a D28
ꢀ
= +7 (c 0.3,
CHCl3), Lit.2c a 2D5
½ ꢀ = +96 (c 0.1, CHCl3); IR (neat): 3399, 2924, 2855, 1761, 1422,
1180, 1019 cmꢁ1 1H NMR (300 MHz, CDCl3); d 1.15 (d, J = 6.0 Hz, 3H), 1.90–2.10
;
(m, 1H), 2.29–2.71 (m, 5H), 3.67–3.72 (m, 1H), 4.07–4.15 (m, 1H), 4.50–4.61 (m,
1H), 5.56–5.73 (m, 2H); 13C NMR (75 MHz, CDCl3): d 18.6, 27.5, 28.7, 33.7, 70.8,
72.2, 79.6, 127.8, 132.5, 177.0; ESIMS: m/z 223 (M+Na)+; HRMS for C10H16NaO4:
calcd 223.0970; found: 223.0962.