The first total synthesis of putaminoxin and determination of its absolute configuration

Article abstract of DOI:10.1016/j.tetlet.2009.07.055

Asymmetric synthesis of putaminoxin, a phytotoxic macrolide from the cultured dinoflagellate Amphidinium sp., has been accomplished. Absolute configuration of putaminoxin was concluded to be 1 from comparison of the NMR data and [α]_D values of synthetic and natural putaminoxin.

Full text of DOI:10.1016/j.tetlet.2009.07.055

Tetrahedron Letters 50 (2009) 5417–5419
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The first total synthesis of putaminoxin and determination
of its absolute configuration
*
Gowravaram Sabitha , K. Yadagiri, R. Swapna, J. S. Yadav
Organic Division I, 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:
Asymmetric synthesis of putaminoxin, a phytotoxic macrolide from the cultured dinoflagellate Amphid-
inium sp., has been accomplished. Absolute configuration of putaminoxin was concluded to be 1 from
Received 4 June 2009
Revised 9 July 2009
Accepted 11 July 2009
Available online 15 July 2009
comparison of the NMR data and [a] values of synthetic and natural putaminoxin.
D
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
10-Membered lactone
Putaminoxin
Fungus
RCM
Putaminoxin 1,1 a phytotoxic lactone, was isolated from the
culture of Phoma putaminum fungus. This fungal pathogen is
responsible for a necrotic leaf disease of Erigeron annuus (L), a
weed widely found in fields and pastures all over Europe, includ-
ing Italy. Related 10-membered lactones2 such as putaminoxin B
and putaminoxin E have also been isolated from fungi with phy-
totoxic activity (Fig. 1). The structure of 1 was characterized
using spectroscopic and chemical methods as (5S) 5-hydroxy-9-
propyl-6-nonen-9-olide. However, the relative and absolute ste-
reochemistry at C9 remained unresolved. Considering that the
new phytotoxic lactones could be directly used as herbicides
or as leads for the preparation of analogues, research was carried
out to isolate and characterize the toxic macrolides produced by
P. Putaminum.
In view of its interesting phytotoxic activity and in order to
determine the absolute stereochemistry at C9 of putaminoxin,
we planned an asymmetric total synthesis of 1 as shown in Scheme
1. Putaminoxin 1 could be obtained by ring-closing metathesis
(RCM) of 2 through esterification of the segment 3 and the segment
4. In this Letter, we describe the first total synthesis of putaminox-
in 1 and its absolute configuration to be 1.
The synthesis of the other fragment began with the epoxy alco-
hol 6 prepared as reported by us earlier.4 The alcohol 6 was con-
verted to the corresponding epoxy iodide in 78% yield by treating
with triphenylphosphine, iodine, and imidazole in a mixture of
dry ether and acetonitrile. The compound was converted into a
secondary allylic alcohol 8 in 85% yield by refluxing with activated
zinc in dry ethanol. After protecting the secondary hydroxyl group
as its 4-methoxybenzyl ether using sodium hydride and 4-
methoxybenzyl bromide, the compound 9 was subjected to depro-
tection of the tetrahydropyran to give alcohol 10. The alcohol 10
was oxidized to aldehyde by using 2-iodoxybenzoic acid followed
by subsequent oxidation using NaClO2 to give the required acid
fragment 3 in 80% yield (Scheme 3).
Next the union of the two fragments 3 and 4 was achieved by
using N,N0-dicyclohexylcarbodiimide and 4-dimethylaminopyri-
dine in dichloromethane to furnish the diene ester 2. Treatment
of 2 with the Grubbs’ first generation catalyst (20% mol) under
high dilution furnished a 9:1 E:Z mixture of macrocyclic lactones,
from which the (E)-isomer 11 was isolated in 60% yield by silica
gel column chromatography. Oxidative removal of 4-methoxy-
benzyl ether in compound 11 gave the target molecule 1 (Scheme
4).
We commenced the synthesis from the commercially available
n-butyraldehyde 5, which was subjected to an enantioselective
Keck allylation3 using (S)-Binol and allyl-tri-n-butyltin to furnish
the homoallylic alcohol 4 with the known stereochemistry in 75%
yield with excellent enantioselectivity of 95% ee (determined by
chiral HPLC) (Scheme 2).
The prepared synthetic putaminoxin is identical (IR, 1H and 13
NMR) with the natural product and also has an optical rotation
ꢁ25.2 (c 1, CHCl3) which is in good agreement with the liter-
ature value [lit.1
C
½ ꢀ
a 2D5
½
a 2D5
ꢀ
ꢁ23.1 (c 1.6, CHCl3)]. Thus, the absolute ste-
reochemistry of putaminoxin 1 was established as 5S and 9R.
In summary, this Letter describes the first total synthesis of
(5S,9R)-(ꢁ)-putaminoxin and its absolute configuration has been
fixed.
* Corresponding author. Tel./fax: +91 40 27160512.
E-mail address: gowravaramsr@yahoo.com (G. Sabitha).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.055

5418
G. Sabitha et al. / Tetrahedron Letters 50 (2009) 5417–5419
OH
OH
OH
7
5
1
9
3
O
O
O
O
O
O
putaminoxin B
putaminoxin 1
putaminoxin E
Figure 1.
OPMB
OPMB
HOOC
OH
1
+
O
O
2
4
3
Scheme 1. Retrosynthesis
OH
a
CHO
5
4
Scheme 2. Reagents and conditions: (a)
SnBu3, Ti(OiPr)4, (S)-binol, dry DCM, ꢁ78 to ꢁ20 °C, 72 h, 75%, 95% ee.
a
O
O
b
THPO
I
THPO
THPO
OH
6
7
OPMB
OH
c
e
RO
8
9;
R = THP
R = H
d
10 ;
OPMB
HOOC
3
Scheme 3. Reagents and conditions: (a) imidazole, TPP, iodine, ether/acetonitrile (3:1), 0 °C to rt, 2 h, 78%; (b) Zn, dry ethanol, reflux, 4 h, 85%; (c) NaH, PMBBr, dry THF, 0 °C
to rt, 4 h, 86%; (d) PPTS, MeOH, 0 °C to rt, 6 h, 72%; (e) (i) IBX, dry DMSO, dry DCM, rt, 2 h; (ii) NaClO2, NaH2PO4ꢂ2H2O, 0 °C to rt, 1 h, 80%.
OH
5
OPMB
7
c
a
b
2
3
4
1
+
9
3
O
O
O
O
1
11
Scheme 4. Reagents and conditions: (a) DCC, DMAP, DCM, 0 °C to rt, 18 h, 73%; (b) (PCy3)2RuCH@Ph (20 mol %), DCM, reflux, 28 h, 60%; (c) DDQ, H2O/DCM (1:9), 0 °C to rt,
1 h, 80%.

G. Sabitha et al. / Tetrahedron Letters 50 (2009) 5417–5419
5419
J = 11.7 Hz), 3.78 (s, 3H), 3.68 (q, 1H, J = 12.4, 6.5 Hz), 2.30 (dt, 2H, J = 1.4, 7.3,
8.7 Hz), 1.74–1.61 (m, 4H); 13C NMR (CDCl3, 75 MHz): d 179.37, 159.09, 138.58,
129.64, 129.4, 117.26, 113.68, 79.66, 69.76, 55.17, 33.47, 33.89, 20.65; ESIMS:
265 (M++1).
Acknowledgment
K.Y.G. thanks UGC, New Delhi, for the award of fellowship.
References and notes
(1R)-1-Propyl-3-butenyl (5S)-5-[(4-methoxybenzyl)oxy]-6-heptenoate (2):
½ ꢀ
a 2D5
+4.5 (c 1, CHCl3); IR (neat): 2925, 2854, 1732, 1610, 1512, 1247, 1170 cmꢁ1
;
1H NMR (CDCl3, 300 MHz): d 7.19 (d, 2H, J = 8.6 Hz), 6.81(d, 2H, J = 8.6 Hz), 5.68
(m, 2H), 5.19 (m, 2H), 5.03 (m, 2H), 4.89 (p, 1H, J = 5.8, 12.4, 18.6 Hz), 4.49 (d, 1H,
J = 11.5 Hz), 4.23 (d 1H, J = 11.5 Hz), 3.79 (s, 3H), 3.67 (q, 1H, J = 6.4, 13.3 Hz),
2.25 (m, 2H), 1.64–1.23 (m, 10H), 0.91 (t, 3H, J = 7.3 Hz); 13C NMR (CDCl3,
75 MHz): d 173.33, 159.11, 138.75, 133.71, 130.71, 129.27, 177.55, 117.19,
113.75, 79.72, 73.04, 69.66, 55.21, 38.69, 34.87, 34.32, 33.54, 31.59, 24.94, 22.49,
21.04, 13.92; ESIMS: 283 (M++Na).
1. Evidente, A.; Lanzetta, R.; Capasso, R.; Andolfi, A.; Bottalico, A.; Vurro, M.; Zonno,
M. C. Phytochemistry 1995, 40, 1637–1641.
2. Evidente, A.; Capasso, R.; Andolfi, A.; Vurro, M.; Zonno, M. C. Nat. Toxins 1998, 6,
183–188.
3. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467–8468.
4. Sabitha, G.; Reddy, E.V.; Giri, K.Y. and Yadav, J. S. Synthesis 2006, 19, 3270–
3274.Spectral data: (4R)-1-hepten-4-ol (4): IR (neat); 3438, 2940, 2866,
(5S,9R)-(ꢁ)-Putaminoxin (1): ½a D25
ꢀ
ꢁ 25.2 (c 1, CHCl3); IR (neat): 3432, 2959,
2930, 2871, 1729, 1670, 1443, 1364, 1180, 1007 cmꢁ1
;
1H NMR (CDCl3,
1643 cmꢁ1 1H NMR (CDCl3, 400 MHz): d 5.80 (m, 1H), 5.11 (td, 2H, J = 1.5,
;
300 MHz):
d 5.55 (ddd, 1H, J = 4.9, 10.5, 15.2 Hz), 5.32 (dd, 1H, J = 9.2,
3.1, 13.5 Hz), 3.61 (m, 1H), 2.26 (m, 1H), 2.11 (m, 1H), 1.43 (m, 4H), 0.94 (t, 3H,
15.2 Hz), 5.03 (m, 1H), 4.01 (dt,1H, J = 3.9, 7.9, 14.9), 2.44 (ddd, 1H, J = 3.9, 7.9,
14.9 Hz), 2.36 (dt, 1H, J = 3.9, 4.9, 12.4 Hz), 2.06–1.97 (m, 2H), 1.95–1.87 (m, 4H),
1.64–1.24 (m, 4H), 0.93 (t, 3H, J = 7.3 Hz); 13C NMR (CDCl3, 75 MHz): d 175.63,
137.14, 131.66, 75.34, 74.13, 40.36, 38.72, 36.42, 35.69, 22.29, 19.14, 13.86.
ESIMS: 235 (M++Na).
J = 7.5 Hz).
(5S)-5-[(4-Methoxybenzyl)oxy]-6-heptenoic acid (3): ½a D25
ꢀ
+25.2 (c 1, CHCl3); IR
1H NMR (CDCl3,
(neat): 3412, 2930, 1709, 1609, 1513, 1249, 1172, 1033 cmꢁ1
;
400 MHz): d 7.18 (d, 2H, J = 8.7 Hz), 6.81(d, 2H, J = 8.7 Hz), 5.70 (m, 1H), 5.22 (d,
1H, J = 2.9 Hz), 5.19 (d, 1H, J = 10.2 Hz), 4.49 (d, 1H, J = 11.7 Hz), 4.23 (d, 1H,