Stereoselective total synthesis of stagonolide E

Article abstract of DOI:10.1016/j.tetlet.2010.09.072

The first total synthesis of a 10-membered macrolide, stagonolide E is described from readily available 4-penten-1-ol. The synthetic strategy involves Jacobsen's kinetic resolution, Sharpless epoxidation, Stille-Gennari, and Yamaguchi lactonization as key reactions.

Full text of DOI:10.1016/j.tetlet.2010.09.072

Tetrahedron Letters 51 (2010) 6166–6168
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Stereoselective total synthesis of stagonolide E
⇑
Gowravaram Sabitha , P. Padmaja, P. Narayana Reddy, Surender Singh Jadav, J. S. Yadav
Organic Division I, 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:
Received 22 July 2010
Revised 14 September 2010
Accepted 18 September 2010
Available online 24 September 2010
The first total synthesis of a 10-membered macrolide, stagonolide E is described from readily available 4-
penten-1-ol. The synthetic strategy involves Jacobsen’s kinetic resolution, Sharpless epoxidation, Stille–
Gennari, and Yamaguchi lactonization as key reactions.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Macrolide
Jacobsen’s kinetic resolution
Sharpless epoxidation
Stille–Gennari
Yamaguchi lactonization
Ten-membered macrolides such as aspinolide A,1 putaminoxin,2
and nonenolide3 have been isolated from fungal sources and are
known to possess potent biological properties. Stagonolides A–I4
(Fig. 1) represent a family of novel 10-membered ring lactones pro-
duced recently from Stagonospora cirsii, a fungal pathogen of Cir-
sium arvense causing necrotic lesions on leaves. Among them
stagonolide A was found to be phytotoxic and stagonolide B exhib-
ited potent antifungal, antibacterial, and cytotoxic activities. The
scarce availability of these macrolides coupled with their interest-
ing biological profile continued to attract the attention of synthetic
chemists. However, syntheses of some members of this class of
compounds have been reported.5 To the best of our knowledge,
so far no synthesis has been reported for 8. Our continued interest
on the synthesis of 10-membered lactones6 led us to take up the
synthesis of stagonolide E. Herein we report a simple route to
the total synthesis of stagonolide E starting from readily available
4-penten-1-ol.
Retrosynthetically (Scheme 1), we envisaged that the target
molecule 8 can be obtained from seco acid 13 by Yamaguchi lact-
onization followed by MOM deprotection. The seco acid 13 in turn
can be made from aldehyde 14 using Stille–Gennari reaction. Com-
pound 14 can be obtained from 15 by dihydroxylation and cleav-
age of the diol, while the allylic alcohol 15 is readily obtained
from 4-penten-1-ol by standard transformations.
(Scheme 2). Removal of benzyl ether using Li in liq NH3 provided
primary alcohol 19 in 75% yield, which was oxidized to the
corresponding aldehyde under Swern oxidation conditions. The
aldehyde was homologated by a two-carbon Wittig ylide (etoxy-
carbonylmethylene)triphenyl phosphorane in benzene at reflux
for 3 h to furnish a,b-unsaturated ester 20. The ester group in com-
pound 20 was reduced to alcohol 21 in 85% yield using DIBAL-H in
dry CH2Cl2 at °C to rt for 2 h. Sharpless asymmetric epoxidation7 of
21 ((ꢀ)-DET, Ti(OiPr)4, cumene hydroperoxide) afforded epoxy
alcohol 22 in 75% yield (95% ee). The epoxy alcohol 22 was
converted to the corresponding epoxy iodide 23 by treating with
iodine, triphenylphosphine, and imidazole in a mixture of diethyl-
ether and acetonitrile in 3:1 ratio at 0 °C to rt in 90% yield. Com-
pound 23 was converted to a secondary allylic alcohol 24 in 80%
yield by refluxing with activated zinc8 in ethanol. The resulting
alcohol 24 was protected as its MOM ether using MOMCl,
N,N-diisopropylethyl amine in CH2Cl2 to afford 15 in 80% yield.
The terminal olefin in 15 was subjected to dihydroxylation with
OsO4 to give vicinal diol, which on oxidative cleavage with NaIO4
provided an aldehyde. A two-carbon extension of the aldehyde
using triphenylphosphoranylideneacetaldehyde (Ph3P@CHCHO)
afforded 14 in 73% yield. Applying the Stille–Gennari9 reaction to
compound 14 provided ester 27 using methyl P,P0-bis(2,2,2-trifluo-
roethyl)phosphonoacetate in the presence of NaH at ꢀ78 °C with
excellent stereoselectivity (Z,E/E,E 95:5) in 80% yield. Cleavage of
the TBS ether in 27 using TBAF in THF afforded 28 in 70% yield.
Hydrolysis of ester 28 using LiOH provided seco acid 13 in 90%
yield followed by Yamaguchi lactonization (2,4,6-trichlorobenzoyl-
chloride in refluxing toluene) to provide macrolactone 29 (ee
>95%). Finally, removal of MOM group under neutral conditions
completed the synthesis of the target molecule, stagonolide E 8
Accordingly, the synthesis began with the known secondary
alcohol 176b prepared from 4-penten-1-ol 16. The secondary alco-
hol 17 was protected as TBS ether using t-butyldimethylsilyl chlo-
ride and imidazole in CH2Cl2 at rt to afford product 18 in 95% yield
⇑
Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512.
E-mail address: gowravaramsr@yahoo.com (G. Sabitha).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.072

G. Sabitha et al. / Tetrahedron Letters 51 (2010) 6166–6168
6167
OH
O
O
O
O
O
O
O
OH
OH
O
OH
OH
O
stagonolide A 4
aspinolide A 1
putaminoxin 2
nonenolide 3
OH
OH
OH
OH
4
5
OH
OH
OH
6
9
3
2
O
O
O
O
O
O
O
O
10
O
stagonolide C 6
stagonolide E 8
stagonolide B 5
stagonolide D 7
OH
OH
OH
HO
OH
O
O
O
O
O
O
O
OH
O
O
stagonolide F 9
stagonolide H 11
stagonolide G 10
stagonolide I 12
Figure 1. Stagonolides A–I.
OH
OH
OTBS
O
OH
O
O
H
OMOM
OMOM
O
14
13
stagonolide E 8
OTBS
OH
16
OMOM
15
Scheme 1. Retrosynthesis.
in 60% yield. The IR, 1H NMR, 13C NMR, and mass data of the syn-
thetic 8 was in good accordance with those of the natural product.
In the DQFCOSY-(600 MHz, CDCl3, 27 °C) spectrum of stagono-
lide E (Fig 1, structure 8), couplings between H-2 with H-3 and
H-4 with H-5 and a weak coupling between H-3 and H-4 were ob-
served. In addition to this, a coupling was observed between H-5
and a proton of HO–CH-6 carbon. In the HSQC-(600 MHz, CDCl3)
spectrum, the four protons of dienyl system and adjacent HO–C-
6 coupled with the signals observed at 140.2, 139.4, 126.5, 125.6,
(C-5, C-3, C-4, and C-2), and 73.5 (C-6). The observed values of
the synthetic compound 8 were matched with the reported values
of the natural product.4b
2930, 2858, 1465, 1252, 834, 774 cmꢀ1; HRMS: m/z [M+1]+ calcd
for C13H28O3Si: 261.1936; found: 261.1932.
(3R, 6R)-6-(tert-butyldimethylsilyloxy)hept-1-en-3-ol (24). ½a D25
ꢁ
:
ꢀ5.6 (c = 1.85, CHCl3); 1H NMR (300 MHz, CDCl3): 0.05 (d, 6H,
J = 6.8 Hz), 0.90 (s, 9H), 1.15 (d, 3H, J = 6.0 Hz), 1.44–1.66 (m, 4H),
3.80–3.92 (m, 1H), 4.00–4.14 (m, 1H), 5.04–5.28 (dd, 2H, J = 10.6,
17.3 Hz), 5.77–5.93 (m, 1H); 13C NMR (75 MHz, CDCl3): ꢀ4.8,
ꢀ4.5, 21.6, 23.3, 33.0, 35.4, 68.5, 73.2, 114.3, 141.2; IR (neat):
3411, 2930, 2858, 1253, 1096, 835, 774 cmꢀ1
; HRMS: m/z
[M+Na]+ calcd for C13H28O2SiNa: 267.2879; found: 267.2883.
(4R, 7R, E)-7-(tert-butyldimethylsilyloxy)-4-(methoxymethoxy)-
oct-2-enal (14). ½a D25
ꢁ
: +22.5 (c = 1.55, CHCl3); 1H NMR (300 MHz,
In conclusion, a simple route to the first total synthesis of stag-
onolide E is reported utilizing Jacobsen’s kinetic resolution, Sharp-
less epoxidation, Stille–Gennari, and Yamaguchi lactonization as
key steps. Selected spectral data
CDCl3): 0.05 (d, 6H, J = 2.0 Hz), 0.90 (s, 9H), 1.14 (d, 3H,
J = 6.0 Hz), 1.35–1.83 (m, 4H), 3.36 (s, 3H), 3.74–3.84 (m, 1H),
4.24–4.35 (m, 1H), 4.6 (m, 2H), 6.16–6.28 (dd, 1H, J = 7.1, 7.7 Hz),
6.60–6.71 (dd, 1H, J = 6.0, 5.8 Hz), 9.8 (d, 1H, J = 7.7 Hz); 13C NMR
(75 MHz, CDCl3): ꢀ4.8, ꢀ4.4, 23.8, 25.8, 30.8, 34.8, 55.7, 68.2,
75.5, 95.0, 132.0, 156.7, 193.3; IR (neat): 2954, 2931, 2889, 2857,
((2R, 3R)-3-((R)-3-(tert-butyl dimethylsilyloxy)butyl)oxiran-2-
yl)methanol (22). ½a D25
ꢁ
: +12.0 (c = 1.35, CHCl3); 1H NMR (300 MHz,
CDCl3): 0.04 (d, 6H, J = 2.2 Hz), 0.89 (s, 9H), 1.14 (d, 3H,
J = 6.0 Hz), 1.41–1.70 (m, 4H), 2.86 (m, 1H), 2.92 (m, 1H), 3.61
(m, 1H), 3.78–3.92 (m, 2H); 13C NMR (75 MHz, CDCl3): ꢀ4.7,
ꢀ4.3, 22.3, 23.8, 28.0, 35.7, 56.1, 58.5, 61.7, 68.1; IR (neat): 3442,
1696, 1042, 835, 774 cmꢀ1
16H32O4SiNa: 339.1305; found: 339.1298.
(2Z, 4E, 6R, 9R)-methyl 9-(tert-butyldimethylsilyloxy)-6-(methoxy-
methoxy)deca-2,4-dienoate (27).
+46.1 (c = 1, CHCl3); 1H
;
HRMS: m/z [M+Na]+ calcd for
C
½
a 2D5
:
ꢁ

6168
G. Sabitha et al. / Tetrahedron Letters 51 (2010) 6166–6168
OTBS
OH
a
ref 6c
b
OH
R
OBn
16
18 R=OBn
19 R=OH
17
OTBS
OTBS
OTBS
c
R
d
R
O
20 R=COOEt
21 R=CH2OH
22 R=OH
23 R=I
OR
24 R=H
15 R=MOM
OTBS
OTBS
O
f
e
g
OMe
O
H
OMOM
OMOM
14
27
OH
O
OMOM
O
OH
i
h
R
OMOM
O
O
28 R=COOMe
13 R=COOH
stagnolide E 8
29
Scheme 2. Reagents and conditions: (a) (i) TBDMSCl, imidazole, DMAP, CH2Cl2, rt, 30 min, 95%; (ii) Li, liq NH3, dry THF, 10 min, rt, 75%; (b) (i) (COCl)2, DMSO, Et3N, CH2Cl2,
ꢀ78 °C, 2 h; (ii) Ph3P@CHCOOEt, benzene, reflux, 3 h, 90% (over two-steps); (iii) DIBAL-H, CH2Cl2, 0 °C to rt, 2 h, 85%; (c) (i) (ꢀ)-DET, Ti(OiPr)4, cumene hydroperoxide, 4°A MS,
CH2Cl2, ꢀ20 °C, 5 h, 75%; (ii) I2, Ph3P, imidazole, ether:acetonitrile (3:1), 0 °C to rt, 1 h, 90%; (d) (i) activated Zn, EtOH, reflux, 1–2 h 80%; (ii) MOMCl, N,N-diisopropylethyl
amine, dry CH2Cl2, 0 °C, 4 h, 80%; (e) (i) OsO4 (0.1 M solution in toluene), NMO, acetone/H2O (4:1), overnight; (ii) NaIO4, THF/H2O (2:1), 15 min 85%; (iii) Ph3P@CHCHO, CH2Cl2,
rt, 8 h, 73%; (f) (CF3CH2O)P(O)CH2CO2Me, NaH, dry THF, ꢀ78 °C, 2 h, 80%; (g) (i) TBAF, THF, 0 °C, 1 h, 70%; (ii) LiOHꢂH2O, THF/MeOH/H2O (3:1:1), 0 °C–rt overnight, 90%; (h)
2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, toluene, reflux, 9 h, 70%; (i) CeCl3ꢂ7H2O, CH3CN/MeOH (2:1), 48 h, reflux, 60%.
NMR (300 MHz, CDCl3): 0.04 (s, 6H), 0.88 (s, 9H), 1.12 (d, 3H,
J = 6.2 Hz), 1.39–1.78 (m, 4H), 3.33 (s, 3H), 3.70 (s, 3H), 3.73–3.81
(m, 1H), 4.06–4.14 (m, 1H), 4.56 (d, 1H, J = 7.1 Hz), 4.66 (d, 1H,
J = 7.1 Hz), 5.68 (d, 1H, J = 11.5 Hz), 5.88 (dd, 1H, J = 8.0, 15.0 Hz),
6.57 (t, 1H, J = 11.5 Hz), 7.47 (dd, 1H, J = 11.5, 15.0 Hz); 13C NMR
(75 MHz, CDCl3): ꢀ4.7, ꢀ4.4, 24.0, 26.0, 31.6, 35.2, 51.2, 55.5,
68.4, 76.2, 94.2, 117.5, 128.0, 143.5, 144.0, 166.5; IR (neat): 3426,
73.2, 73.5, 125.6, 126.5, 139.4, 140.2, 168.1; IR (neat): 3447,
2924, 2853, 1704, 1257 cmꢀ1; HRMS: m/z [M+Na]+ calcd for
C10H14O3Na: 205.0851; found: 205.0845.
Acknowledgments
P.P. thanks theUGC and P.N.R. thanks the CSIR, New Delhi, for
the award of fellowships.
2930, 2857, 1720, 1176, 1037, 833, 773 cmꢀ1
; HRMS: m/z
[M+Na]+ calcd for C19H36O5SiNa: 395.1041; found: 395.1048.
(2Z, 4E, 6R, 9R)-methyl 9-hydroxy-6-(methoxymethoxy)deca-2,4-
dienoate (28). ½a D25
ꢁ
: +43.2 (c = 0.7, CHCl3); 1H NMR (300 MHz,
References and notes
CDCl3): 1.20 (d, 3H, J = 6.2 Hz), 1.46–1.80 (m, 4H), 3.38 (s, 3H),
3.73 (s, 3H), 3.78–3.89 (m, 1H), 4.14–4.26 (m, 1H), 4.57 (d, 1H,
J = 6.8 Hz), 4.68 (d, 1H, J = 6.8 Hz), 5.70 (d, 1H, J = 11.3 Hz), 5.91
(dd, 1H, J = 6.8, 15.5 Hz), 6.57 (t, 1H, J = 11.3 Hz), 7.50 (dd, 1H,
J = 11.5, 15.5 Hz); 13C NMR (75 MHz, CDCl3): 23.5, 31.6, 34.7,
51.2, 55.6, 67.7, 76.2, 94.3, 117.7, 128.0, 143.1, 144.0, 166.6; IR
(neat): 3432, 2932, 1716, 1200, 1035 cmꢀ1; HRMS: m/z [M+Na]+
calcd for C13H22O5Na: 281.2781; found: 281.2774.
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(3Z, 5E, 7R, 10R)-7-(methoxymethoxy)-10-methyl-7,8,9,10-tetra-
hydrooxecin-2-one (29).
½
a 2D5 +47.4 (c = 0.8, CHCl3); 1H NMR
:
ꢁ
(300 MHz, CDCl3): 1.22 (d, 3H, J = 6.2 Hz), 1.57–1.94 (m, 4H), 3.35
(s, 3H), 4.15 (td, 1H, J = 4.0, 9.0 Hz), 4.53 (d, 1H, J = 6.8 Hz), 4.70
(d, 1H, J = 6.6 Hz), 5.00 (m, 1H), 5.64 (dd, 1H, J = 9.6, 15.4 Hz),
5.85 (d, 1H, J = 10.5 Hz), 6.16 (d, 1H, J = 15.1 Hz), 6.62 (d, 1H,
J = 10.3 Hz); 13C NMR (75 MHz, CDCl3): 21.4, 29.7, 39.0, 55.5,
73.1, 73.2, 95.0, 124.1, 128.1, 138.5, 140.6, 168.0; IR (neat): 3456,
2931, 1710, 1253, 1045 cmꢀ1; HRMS: m/z [M+Na]+ calcd for
C12H18O4Na: 249.1041; found: 249.1048.
(3Z, 5E, 7R, 10R)-7-hydroxy-10-methyl-7,8,9,10-tetrahydrooxecin-
2-one (stagonolide E) (8). ½a D25
ꢁ
: ꢀ181 (c = 0.2, CHCl3); 1H NMR
(300 MHz, CDCl3): 1.22 (d, 3H, J = 6.6 Hz), 1.57–1.94 (m, 4H), 4.25
(td, 1H, J = 4.0, 9.0 Hz), 4.98 (m, 1H), 5.74 (dd, 1H, J = 9.4,
15.3 Hz), 5.85 (d, 1H, J = 11.6 Hz), 6.12 (br d, 1H, J = 15.4 Hz), 6.62
(br d, 1H, J = 11.6 Hz); 13C NMR (75 MHz, CDCl3): 21.3, 30.3, 37.4,