Stereoselective total synthesis of stagonolide C and formal total synthesis of modiolide A

Article abstract of DOI:10.1055/s-0029-1217556

The influence of protecting groups at C4 and C7 on a ring-closing metathesis reaction was investigated. Matched induction led to the total synthesis of stagonolide C and the formal total synthesis of modiolide A. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217556

LETTER
2129
Stereoselective Total Synthesis of Stagonolide C and Formal Total Synthesis of
Modiolide A
Debendra K. Mohapatra,* Uttam Dash, P. Ramesh Naidu, J. S. Yadav*
Organic Chemistry Division-I, Indian Institute of Chemical Technology (CSIR), Uppal Road, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: mohapatra@iict.res.in
Received 6 May 2009
This paper is dedicated to Dr. A. V. Rama Rao on the occasion of his 74th birthday.
R5
O
Me
O
Me
OH
O
Abstract: The influence of protecting groups at C4 and C7 on a
ring-closing metathesis reaction was investigated. Matched induc-
tion led to the total synthesis of stagonolide C and the formal total
synthesis of modiolide A.
H
R4
R3
O
O
O
O
H
R2
R1
OH
Key words: decanolide, stagonolide C, modiolide A, ring-closing
metathesis, Sharpless asymmetric epoxidation
5
1–3
4
1. R1 = H, R2 + R3 = O, R4 = OH, R5 = propyl
2. R1 = β-OH, R2 = H, R3 = OH, R4 = OH, R5 = propyl
3. R1 = α-OH, R2 = OH, R3 = H, R4 = H, R5 = Me
Many naturally occurring ten-membered lactones isolated
from fungal metabolites, commonly known as decano-
lides, have attracted considerable attention from synthetic
organic chemists as well as bioorganic chemists, because
of their interesting structural features and various biolog-
ical activities such as plant growth inhibition and anti-
feedant, anti-fungal and anti-bacterial activities.1 The
main phytotoxic metabolite produced by S. Cirsii in liquid
culture, named stagonolide (1) was isolated and character-
ized as a new nonenolide.2 Other metabolites include
eight new stagonolides, named stagonolide B to I (2–9),
which were isolated and chemically characterized includ-
ing their biological properties.3a,b These stagonolides were
structurally similar to stagonolide (1) and were isolated
from the same fungus. Another structurally similar ten-
membered lactone known as modiolide A (10) was isolat-
ed by Kobayashi and co-workers3c from marine-origin mi-
croorganisms and shown to be active against both bacteria
and fungi.
OH
OH
OH
H
O
O
O
O
OH
OH
Me
OH
H
O
O
O
Me
Me
O
6
7
8
HO
OH
O
O
O
HO
O
Me
O
O
Me
O
9
10
11
Me
Me
O
Me
O
O
O
OH
OH
OH
OH
OH
OH
12
13
14
Figure 1 Stagonolide (1), stagonolide B–I (2–9), modiolide A (10),
herbarumin III (11), nonenolide (12), and decarestrictine C1 and C2
(13 and 14)
Construction of lactones through the formation of a C–C
bond and, particularly, by intramolecular ring-closing
metathesis4 reactions remains as a promising tool for the
synthesis of decanolides. Recently, Murty et al. reported
the total synthesis of stagonolide F following a ring-clos-
ing metathesis approach.5 The influence of the protecting
groups on the geometrical outcome of the ring-closing
metathesis reaction has been reported previously.6 During
our studies on the total synthesis of nonenolide6c (12) and
decarestrictine6a C1 and C2 (13 and 14, Figure 1), we ob-
served that complete control of the double bond geometry
formed during the ring-closing metathesis reaction was
possible through the selection of protecting groups.
izing its substrate and protecting group based selectivity,
we have investigated the outcome of such ring-closing
metathesis reactions on substrates with protecting groups
at chiral centers adjacent to both the reacting sites. In this
way we hoped to achieve the total synthesis of stagonolide
C and the formal total synthesis of modiolide A.
According to our retrosynthetic analysis (Scheme 1), con-
struction of the ten-membered lactone would arise from
the formation of the C5–C6 olefinic linkage from the bis-
alkene which, in turn, would be prepared via esterification
of alcohol 17 and acid 18; the fragments would be pre-
pared from L-malic acid and butane-1,4-diol, respectively.
As part of an ongoing program aimed at exploring ring-
closing metathesis for macrolide synthesis and at general-
The synthesis of fragment 17 began with the known com-
pound 21,7 which was subjected to reduction with
DIBAL-H at –15 °C in dichloromethane to afford allyl al-
cohol 22 in 81% yield. Sharpless asymmetric epoxidation8
SYNLETT 2009, No. 13, pp 2129–2132
Advanced online publication: 15.07.2009
DOI: 10.1055/s-0029-1217556; Art ID: G10809ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

2130
D. K. Mohapatra et al.
LETTER
O
O
O
OH
ref. 12
OH
HO
TBDPSO
9
6
1
2
8
O
O
20
27
5
7
3
4
HO
RO
i) TPP, imidazole, I2
THF, 0 °C, 15 min
OH
OR
NaH, PMBBr
3
15. R = PMB
16. R = TBS
TBDPSO
THF, 0 °C to r.t.
4 h, 84%
ii) Zn dust, NaI, MeOH
reflux, 4 h
OH
O
OH
28
OPMB
76% for 2 steps
HO
TBAF, THF
+
HO
17
TBDPSO
OPMB
OH
18
0 °C to r.t., 7 h
94%
OPMB
OPMB
29
30
i) IBX, THF, DMSO, r.t., 3 h
O
OH
ii) NaClO2, NaH2PO4⋅2H2O
COOH
HO
HO
2-methyl-2-butene, t-BuOH–H2O
0 °C to r.t., 2 h, 84% over 2 steps
HOOC
OPMB
20
19
18
Scheme 1 Retrosynthetic analysis of stagonolide C
Scheme 3 Synthesis of fragment 18
of 22 with (+)-DIPT produced 2,3-epoxy alcohol 23 in
85% yield in a 95:5 ratio with the required isomer as the
major product (based on 1H and 13C NMR). Conversion of
the hydroxy group in 23 into the iodo-derivative with
triphenylphosphine, I2 and imidazole in THF, followed by
activated zinc dust mediated elimination,9 furnished allyl-
ic alcohol 24, which was protected as its p-methoxybenzyl
ether to afford 25 in 84% yield (Scheme 2). Deprotection
of the isopropylidene group with p-toluenesulfonic acid in
methanol,10 followed by selective protection of the prima-
ry hydroxy group with tosyl chloride and triethylamine
and further reduction of the tosyl derivative with lithium
aluminum hydride, gave the required alcohol fragment
1711 in 76% yield over two steps.
tion in THF afforded 30 in 94% yield (Scheme 3). The pri-
mary hydroxy group was then oxidized with IBX13 to
afford the corresponding aldehyde; further oxidation14
with NaClO2 in the presence of NaH2PO4 and 2-methyl-2-
butene as a scavenger, furnished acid 1815 in 84% yield
over two steps.
Our next task was to couple the two fragments and inves-
tigate the critical ring-closing metathesis reaction. Ac-
cordingly, condensation of fragments 17 and 18 was
achieved using N-(3-dimethylaminopropyl)-N¢-ethylcar-
bodiimide hydrochloride (EDC hydrochloride) and 4-
(dimethylamino)pyridine (DMAP) to afford the bis-ole-
finic ester 15 in 85% yield (Scheme 4). As per our earlier
report, a 0.001 M solution of 1516 and 10 mol% of Grubbs’
second-generation catalyst failed to provide the required
ten-membered lactone when heated under reflux even up
to 48 hours in anhydrous, degassed dichloromethane. The
crucial ring-closing metathesis reaction also failed in an-
hydrous benzene under reflux conditions and by using
The synthesis of fragment 18 started from the known in-
termediate 27,12 which was prepared from commercially
available 1,4-butane diol (20), followed by the same se-
quence of reactions as performed during the preparation
of 25. Treatment of compound 29 with 1 M TBAF solu-
OH
O
ref. 7
COOH
DIBAL-H
HOOC
O
COOEt
CH2Cl2, –15 °C
15 min, 81%
19
21
O
(+) DIPT, Ti(Oi-Pr)4
O
O
O
O
TBHP, CH2Cl2, –20 °C
4 Å MS, 10 h, 85%
OH
OH
22
23
i) TPP, Imidazole, I2
THF, 0 °C, 10 min
ii) Zn dust, NaI
MeOH, reflux, 3 h
68% for 2 steps
OPMB
O
OH
O
NaH, PMBBr
O
O
THF, 0 °C to r.t.
4 h, 84%
24
25
PMBBr = p-methoxybenzyl bromide
i) TsCl, CH2Cl2
OH
OPMB
OH OPMB
TsOH, MeOH
Et3N, 0 °C to r.t., 6 h
HO
ii) LAH, THF
0 °C to r.t., 2 h
76% for 2 steps
0 °C to r.t., 3 h, 90%
26
17
Scheme 2 Synthesis of fragment 17
Synlett 2009, No. 13, 2129–2132 © Thieme Stuttgart · New York

LETTER
Synthesis of Stagonolide C and Modiolide A
2131
protecting groups such as PMB ethers and TBS ethers. Fi-
nally, reaction with diol 31 (0.001 M in CH2Cl2) and 10
mol% Grubbs’ second-generation catalyst afforded the re-
quired ten-membered lactone 317 (stagonolide C) as the
sole product in 68% yield. The geometry of the newly
formed double bond was unequivocally assigned by de-
tection of the olefinic Jtrans coupling constant (15.6 Hz be-
tween the protons at d = 5.41 and 5.58 ppm, respectively).
The constitution and configuration of the assigned struc-
ture was unambiguous since the spectral and analytical
data were in excellent accord with the proposed structure
and perfectly matched with those reported in the litera-
ture.3a In addition, computational analysis of both isomers
showed the E-isomer to be 6 kcal/mol less in energy than
the Z-isomer, signifying that the E-isomer in this case is
more stable than the Z-isomer (Figure 2).
O
OH
OPMB
EDC, DMAP, CH2Cl2
0 °C, 14 h, 85%
+
HO
OPMB
17
18
O
O
O
DDQ, CH2Cl2/H2O
O
0 °C to r.t.
40 min, 85%
RO
HO
OR
OH
31
15 R = PMB
16 R = TBS
Grubbs catalyst
2
Grubbs catalyst
2
nd generation
nd generation
Figure 2 Minimum energy conformers calculated for the E- and Z-
isomers of stagonolide C
CH2Cl2, reflux
30 h, 68%
CH2Cl2, reflux
48 h
O
O
In conclusion, the first stereoselective total synthesis of
stagonolide C and the formal total synthesis of modiolide
A were achieved starting from commercially available L-
malic acid and 1,4-butane diol. The key reactions in-
volved were Sharpless asymmetric epoxidation, activated
zinc dust mediated reductive elimination and ring-closing
metathesis.
O
O
HO
RO
OH
OR
31 R = PMB
32 R = TBS
stagonolide C (3)
TBSOTf, CH2Cl2
–15 °C, 1 h, 82%
O
O
Acknowledgment
O
ref. 6h
U.D. and P.R.N. thank CSIR, New Delhi, India, for the financial as-
sistance in the form of fellowships.
O
TBSO
HO
OH
OTBS
References and Notes
33
modiolide A (10)
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Mugishima, T.; Komatsu, K.; Sone, T.; Tanaka, M.;
Scheme 4 Total synthesis of stagonolide C (3) and formal total syn-
thesis of modiolide A (10)
As the RCM reaction failed with both the TBS-protected
and PMB-protected bis-olefins, we proceeded with the ad-
vanced intermediate for the total synthesis of modiolide
A. The free hydroxy groups present at C4 and C7 in 3
were protected as their TBS ethers with TBSOTf in
dichloromethane at –15 °C, to afford the bis-TBS com-
pound 33,18 whose spectral and analytical data were in
good agreement with the reported values.6h
Synlett 2009, No. 13, 2129–2132 © Thieme Stuttgart · New York

2132
D. K. Mohapatra et al.
LETTER
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C14H20O3Na: 259.1310; found: 259.1318.
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CHCl3); IR (KBr): 3426, 2929, 2865, 1709, 1610, 1513,
1455, 1250 cm–1; 1H NMR (300 MHz, CDCl3): d = 7.16 (d,
J = 8.7 Hz, 2 H), 6.8 (d, J = 8.7 Hz, 2 H), 5.77–5.65 (m, 1 H),
5.25–5.2 (m, 2 H), 4.51 (d, J = 11.4 Hz, 1 H), 4.25 (d,
J = 11.4 Hz, 1 H), 3.77 (s, 3 H), 3.77–3.70 (m, 1 H), 2.41 (t,
J = 7.3 Hz, 2 H), 1.91–1.78 (m, 2 H); 13C NMR (75 MHz,
CDCl3): d = 179.4, 159.0, 138.0, 130.2, 129.3, 117.6, 113.6,
78.7, 69.7, 55.1, 30.0, 29.9; MS (ESI): m/z = 273 [M + Na]+;
HRMS (ESI): m/z [M + H]+ calcd for C14H18O4Na:
273.1102; found: 273.1101.
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(16) Analytical and spectral data of 15: [a]D27 –55.3 (c 1.9,
CHCl3); IR (KBr): 2923, 2853, 1729,1613, 1513, 1377, 1248
cm–1; 1H NMR (300 MHz, CDCl3): d = 7.28–7.24 (m, 4 H),
6.91–6.85 (m, 4 H), 5.80–5.68 (m, 2 H), 5.29–5.13 (m, 5 H),
4.54 (d, J = 11.5 Hz, 1 H), 4.51 (d, J = 11.3 Hz, 1 H), 4.27
(d, J = 11.3 Hz, 1 H), 4.21 (d, J = 11.5 Hz, 1 H), 3.82 (s, 3
H), 3.80 (s, 3 H), 3.80–3.72 (m, 2 H), 2.41–2.18 (m, 2 H),
1.96–1.67 (m, 4 H), 1.21 (d, J = 6.2 Hz, 3 H); 13C NMR (75
MHz, CDCl3): d = 172.8, 159.0, 138.5, 138.3, 130.5, 130.3,
129.6, 129.3, 117.5, 117.0, 113.7, 79.1, 76.3, 69.9, 69.8,
67.6, 55.2, 42.2, 30.5, 30.4, 20.5; MS (ESI): m/z = 491 [M +
Na]+; HRMS (ESI): m/z [M + H]+ calcd for C28H36O6Na:
491.2409; found: 491.2413.
(17) Analytical and spectral data of 3: [a]D27 +46.2 (c 1.0,
CHCl3); IR (KBr): 3443, 2923, 2855, 1717, 1647, 1448,
1368, 1243 cm–1; 1H NMR (300 MHz, CDCl3): d = 5.58 (dd,
J = 15.6, 9.2 Hz, 1 H), 5.41 (dd, J = 15.6, 9.0 Hz, 1 H), 5.14
(dq, J = 11.1, 6.4 Hz, 1 H), 4.15–4.05 (m, 2 H), 2.32–2.25
(m, 1 H), 2.04 (m, 3 H), 1.92–1.71 (m, 2 H), 1.22 (d, J = 6.4
Hz, 3 H); 13C NMR (75 MHz, CDCl3): d = 174.6, 135.8,
132.8, 74.3, 71.8, 67.8, 43.2, 34.3, 31.5, 21.3; MS (ESI):
m/z = 223 [M + Na]+.
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(18) Analytical and spectral data of 33: [a]D27 +14.7 (c 1.4,
EtOH); IR (KBr): 2931, 2859, 1731, 1645, 1461, 1370, 1248
cm–1; 1H NMR (300 MHz, CDCl3): d = 5.45 (dd, J = 15.8,
9.0 Hz, 1 H), 5.30 (dd, J = 15.8, 8.6 Hz, 1 H), 5.14–5.03 (m,
1 H), 4.08–3.97 (m, 2 H), 2.26–2.20 (m, 1 H), 2.05–1.96 (m,
2 H), 1.95–1.84 (m, 1 H), 1.78–1.71 (m, 2 H), 1.18 (d,
J = 6.6 Hz, 3 H), 0.86 (s, 9 H), 0.85 (s, 9 H), 0.04 (s, 6 H),
0.02 (s, 6 H); 13C NMR (75 MHz, CDCl3): d = 174.4, 135.1,
132.4, 75.3, 73.0, 67.5, 44.8, 35.5, 31.5, 25.7, 21.4, 18.1,
–4.3, –4.4, –4.7; MS (ESI): m/z = 429 [M + H]+; HRMS
(ESI): m/z [M + H]+ calcd for C22H44O4NaSi2: 451.2675;
found: 451.2675.
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(11) Analytical and spectral data of 17: [a]D27 –30.4 (c 1.8,
CHCl3); IR (KBr): 3456, 2922, 2853, 1616, 1513, 1247
cm–1; 1H NMR (300 MHz, CDCl3): d = 7.16 (d, J = 9.0 Hz,
2 H), 6.73 (d, J = 9.0 Hz, 2 H), 5.80–5.68 (m, 1 H), 5.23–
5.14 (m, 2 H), 4.51–4.48 (m, 1 H), 4.48 (d, J = 11.3 Hz, 1 H),
4.19 (d, J = 11.3 Hz, 1 H), 4.01–3.94 (m, 1 H), 3.73 (s, 3 H),
1.67–1.50 (m, 2 H), 1.07 (d, J = 6.8 Hz, 3 H); 13C NMR (75
MHz, CDCl3): d = 159.2, 138.1, 129.4, 128.6, 117.1, 113.8,
Synlett 2009, No. 13, 2129–2132 © Thieme Stuttgart · New York

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