A facile total synthesis of all stereoisomers of tarchonanthuslactone and euscapholide from chiral epichlorohydrin

Article abstract of DOI:10.1055/s-0028-1087524

A versatile and facile synthetic route to all the stereoisomers of tarchonanthuslactone and euscapholide was developed using epichlorohydrin as the source of all the chiral centers. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087524

LETTER
249
A Facile Total Synthesis of All Stereoisomers of Tarchonanthuslactone and
Euscapholide from Chiral Epichlorohydrin
Synthesis of
T
arch
e
onanthusla
c
e
tone and E
-
uscapho
Y
lide oon Lee,* Vasu Sampath, Yeokwon Yoon
School of Molecular Science (BK21) and Department of Chemistry, Korea Advanced Institute of Science & Technology (KAIST), Daejon,
305-701, Korea
Fax +82(42)8698370; E-mail: leehy@kaist.ac.kr
Received 10 October 2008
O
O
Abstract: A versatile and facile synthetic route to all the stereoiso-
mers of tarchonanthuslactone and euscapholide was developed us-
ing epichlorohydrin as the source of all the chiral centers.
O
OH
O
OH
O
Key words: tarchnanthuslactone, euscapholide, epichlorohydrin,
diversity, total synthesis
1d (euscapholide)
2 (kurzilactone)
O
O
O
OH
OH
O
AcO
O
O
Natural products that contain a,b-unsaturated d-lactone
moiety possess a wide range of biological activities pre-
sumably due in part their electrophilic nature as Michael
acceptors.1 While euscapholide (1d)2 that was isolated
along with its glucoside from leaves of Euscaphis japoni-
ca shows the anti-inflammatory activity, its analogue 3,7-
dihydroxy-5-octenolide that lacks the Michael acceptor
does not show any anti-inflammatory activity.3 A related
natural product, tarchonanthulactone (4a)4 that was isolat-
ed from Tarchonanthustrilobus compositae shows the an-
tidiabetic activity.5 Structurally related compounds shown
in Figure 1 have interesting biological activities such as
anticancer (kurzilactone),6 antimicobacterial (passiflori-
cin A),7 and antigerminating activity (cryptocarya diace-
tate).8
n
4a (tarchonanth uslactone)
3 (cryptocarya acetates)
O
O
OH OH
14
5 (passifloricin A)
OH
Figure 1
natural products, only a few versatile approaches to these
natural products and analogues were reported.12 Related
diversity-oriented synthesis focused on the solid-support-
ed synthesis rather than versatile synthesis. We became
interested in devising a practical, versatile, and yet stereo-
selective route to these natural products and their stereo-
isomers and decided to utilize epichlorohydrin as the
source of chiral alcohols.
Due to these interesting biological activities and subtleties
in stereostructures, there have been many reports on the
total synthesis of these natural products.9 The stereoselec-
tive syntheses either confirmed or revised initially as-
signed structures.10 Diversity-oriented synthesis was also
devised to confirm the structures of natural products and
to study biological activities of analogues of the natural
products.11 While most synthetic approaches focused on
stereoselective synthesis of the natural isomers of these
Epichlorohydrin could be a versatile source for the syn-
thesis of various polyhydroxylated natural products and
their diastereomers since a single stereoisomer of epichlo-
rohydrin can be utilized to generate either isomer of a
chiral carbinol center. Depending on the order of nucleo-
philic addition to epichlorohydrin both R- and S-isomeric
OH
OH
i) R2
i) R1
O
Cl
O
R2
R1
R2
R1
ii) R2
ii) R1
R1
O
R1
O
Cl
OH
O
OH
R2
R1
R2
O
O
R2
Cl
Scheme 1 Versatility of epichlorohydrin
SYNLETT 2009, No. 2, pp 0249–0252
x
x.
x
x.
2
0
0
9
Advanced online publication: 15.01.2009
DOI: 10.1055/s-0028-1087524; Art ID: U11208ST
© Georg Thieme Verlag Stuttgart · New York

250
H.-Y. Lee et al.
LETTER
O
O
O
O
O
O
O
O
R
R
O
O
OH
OH
O
OH
O
4a
1a
1b
O
O
O
6a
Li
Li
4b
O
+
O
O
O
O
O
+
Cl
O
O
O
R
R
O
O
OH
OH
O
OMe
O
OH
O
4c
1c
1d
O
O
O
6b
4d
R = 3,4-dihydroxyphenethyl
Scheme 2 Synthetic analysis for all diastereomers of tarchonanthuslactone and euscapholide
alcohols can be prepared. A carbonyl dianion equivalent Reaction of (R)-epichlorohydrin (7a) with lithium salt of
like dithiane anion can connect two epichlorohydrin to- TMS-acetylene in the presence of BF3·OEt2 produced the
gether to produce 1,3,5-triols stereoselectively halohydrin in 91% yield.15 The halohydrin was isolated to
(Scheme 1) and again depending on the reaction order and ensure the stereochemistry of the corresponding epoxide
subsequent reactions,13c all the diastereomers of 1,3,5-tri- 8a, since direct conversion of epichlorohydrin into 8a
ols can be synthesized. Even with this clear advantage of could lead to ambiguity of stereochemical purity of the
epichlorohydrin in stereoselective synthesis, epichlorohy- epoxide 8a; that is, a possible direct substitution of chlo-
drins have not been used widely in total synthesis presum- ride by acetylide anion as the outcome of direct substitu-
ably due to scarcity of enantiomerically pure tion would produce the enantiomer of 8a.13a After the
epichlorohydrin.13 That situation changed recently as epoxide 8a was obtained from halohydrin, the second
enantiomerically pure epichlorohydrin became readily acetylide anion, the anion of propynoate was added to 8a
available as Jacobsen’s kinetic resolution provided an ef- using Yamaguchi conditions16 to furnish the bisalkynyl
ficient route to both enantiomers of epichlorohydrin.14 We ester 9a in 67% yield.17
envisioned that the polyhydroxylated compounds repre-
At this stage we anticipated that the mercury-mediated hy-
sented in Figure 1 and their stereoisomers can be synthe-
dration of the terminal alkyne would be kinetically favor-
sized from epichlorohydrin and acyl anion equivalents.
able to conjugated internal alkyne ,though conjugated
As the first example of our synthetic strategy utilizing epi- internal alkyne was reported to be hydrated to the corre-
chlorohydrin, we devised a synthetic route to tarchonan- sponding b-ketoester.18 Initially, the silyl group of 9a was
thuslactone and all diastereomers via euscapholide and deprotected before mercury-mediated hydration reaction
its diastereomers. Tarchonanthuslactone and eus- to facilitate the selective hydration of the terminal alkyne.
capholide have an interesting relationship as they exhibit To our delight, selective hydration of the terminal alkyne
opposite stereostructures at the chiral centers. To make was achieved though the yield was moderate. When the
both natural products efficiently, a versatile asymmetric intermediate 9a was subjected directly to the hydration re-
synthetic route is necessary and epichlorohydrin appeared action without deprotection of the silyl group,19 still the
to be the good starting material for that purpose. The un- methyl ketone 6a was obtained selectively in 85% yield.
saturated lactone ring can be assembled through stereose- The silyl group of the alkyne might have facilitated the
lective partial reduction of propynoate, and another hydration reaction as it would stablilize cationic interme-
alcohol can be prepared from corresponding terminal diate.20 The ketone of 6a was reduced under chelation
alkyne. This bisalkynyl intermediate 9a (or 9b) can be control using diethylmethoxyborane and NaBH4 to fur-
prepared stereoselectively from the chiral epichlorohydrin nish syn-1,3-diol 10a as a single diastereomer.21 The par-
and two acetylide anions (Scheme 2).
tial reduction of alkynoate 10a using Lindlar catalyst
provided the Z-olefin in 81% yield.22 Lactone formation
was accomplished using catalytic amount of PTSA in ben-
zene to afford (–)-euscapholide (1a)2 in 86% yield. The
spectral data and optical rotation of 1a matched well with
the reported ones. Finally, tarchonanthuslactone was pre-
pared from 1a in a well-established, two-step sequence.
When the ketone of 6a was reduced by NaBH(OAc)3
through intramolecular delivery of a hydride, anti-1,3-
Though all the isomers of euscapholide or tarchonanthus-
lactone could be synthesized from either isomer of ep-
ichlorohydrin, synthesis of tarchonanthuslactone (4a) and
4b started from (R)-epichlorohydrin via 1a and 1b, re-
spectively, and the synthesis of the other diastereomers of
tarchnanthuslactone 4c and 4d started from (S)-epichloro-
hydrin via 1c and euscapholide (1d).
Synlett 2009, No. 2, 249–252 © Thieme Stuttgart · New York

LETTER
Synthesis of Tarchonanthuslactone and Euscapholide
251
O
O
TMS
O
b
c
O
OH
TMS
Cl
OTBS
OTBS
MeO
72%
67%
HO
8a
9a
7a
11
d
85%
O
O
O
O
O
O
e
f
g, h
g, h
OH OH
OH
OH OH
O
OH
O
OH
MeO
MeO
MeO
76%
92%
70%
75%
1a
10a
6a
10b
1b
i, j
k
i, j
O
69%
70%
O
85%
O
O
O
O
O
O
OH
OH
OH
OH
O
O
O
12
4b
4a
O
O
O
O
O
OH
OH
OH
OH
O
O
O
4c
4d
72%
i, j
i, j
70%
O
O
O
O
O
g, h
e
f
72%
OH OH
OH
O
OH OH
g, h
O
OH
O
OH
MeO
MeO
MeO
72%
89%
75%
1d
10d
6b
10c
1c
72%
d
O
TMS
O
c
b
O
OH
TMS
Cl
MeO
79%
83%
7b
8b
9b
Scheme 3 Reagents and conditions: (a) TMSCCLi, BF3·Et2O, THF; (b) NaOH, CH2Cl2; (c) LiCCCOOMe, BF3·Et2O, THF; (d) HgSO4,
H2SO4, THF, r.t.; (e) NaBH4, Et2BOMe, THF–MeOH, –78 °C (f) NaBH(OAc)3, MeCN–AcOH (2:1), –40 °C; (g) H2, Pd/CaCO3, quinoline,
benzene, r.t.; (h) PTSA, benzene; (i) 11, DCC, DMAP, CH2Cl2; (j) TBAF, PhCOOH, THF; (k) DBU, CH2Cl2.
diol 10b was obtained selectively in 76% yield. The anti- of all four diastereomers of tarchonanthuslactone and
diol 10b was converted into a diastereomer of tarchnan- euscapholide.
thuslactone (4b) via a diastereomer of euscapholide 1b. A
In conclusion, we demonstrated that an efficient total syn-
thesis of tarchonanthuslactone and euscapholide along
with all of their diastereomers in a nine-step sequence and
seven-step sequences, respectively, from enantiomerical-
tetraketide 1223 was also synthesized using DBU in
dichloromethane. The natural euscapholide (1d) and other
isomers of tarchonanthuslactone were synthesized from
(S)-epichlorohydrin following the same synthetic se-
ly pure epichlorohydrins. The current total synthesis is not
quence. While these compounds could have been synthe-
only the shortest total synthesis of the natural product
sized from (R)-epichlorohydrin by simply altering the
among the reported synthesis but so versatile that tarcho-
nanthuslactone and euscapholide with opposite stereo-
chemistry at the chiral centers were synthesized through
reaction sequence in the first two epoxide opening steps,
we decided to use (S)-epichlorohydrin as the starting ma-
terial to avoid a possible complication with ester group
the same reaction sequence. Since the synthetic scheme
during the second epoxide-opening reaction with lithium
was simple, straightforward, and versatile, the current
acetylide (Scheme 3). Thus, we completed the synthesis
synthetic strategy using chiral epichlorohydrin would
Synlett 2009, No. 2, 249–252 © Thieme Stuttgart · New York

252
H.-Y. Lee et al.
LETTER
(m, 2 H), 2.07 (br, 1 H), 2.02–1.95 (m, 1 H), 1.76–1.71 (dt,
J = 12.6, 4.2 Hz, 1 H), 1.23 (d, J = 6.2 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): d = 164.0, 145.2, 121.2, 76.8, 65.2, 43.5,
29.4, 23.7.
readily be applicable to the total synthesis of other natural
products along with their stereoisomers.
Compound 4a: [a]D –76.2 (c 0.22, CHCl3), [a]25 –76
(c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3): d = 6.81–6.78
(ddd, J = 10.0, 5.0, 2.4 Hz, 1 H), 6.73–6.70 (m, 2 H), 6.59–
6.56 (dd, J = 8.1, 2.0 Hz, 1 H), 5.99–5.96 (ddd, J = 10.0, 3.0,
1.0 Hz, 1 H), 5.05–5.01 (m, 1 H), 4.16 (m, 1 H), 2.81 (t,
J = 6.5 Hz, 2 H), 2.58 (t, J = 7.2 Hz, 2 H), 2.29 (m, 1 H), 2.20
(m, 1 H), 2.04–2.01 (m, 1 H), 1.76–1.70 (m, 1 H), 1.23 (d,
J = 6.3 Hz, 3 H), 0.95 (s, 9 H), 0.94 (s, 9 H), 0.15 (s, 6 H),
0.14 (s, 6 H). 13C NMR (100 MHz, CDCl3): d = 172.7, 165.0,
145.4, 143.9, 142.2, 132.8, 120.9, 120.4, 115.4, 115.2, 75.2,
67.0, 41.0, 35.8, 30.1, 29.0, 20.5.
Acknowledgment
This research was supported by a grant from Marine Biotechnology
Project funded by Ministry of Land, Transport and Maritime Affair,
Republic of Korea.
References and Notes
(1) Harris, J. M.; Li, M.; Scott, J. G.; O’Doherty, G. A. In
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Compound 4b: [a]D –9.5 (c 0.2, CHCl3). 1H NMR (400
MHz, CDCl3): d = 6.85–6.81 (m, 1 H), 6.72 (d, J = 8.1 Hz,
1 H), 6.66 (d, J = 2.0 Hz, 1 H), 6.57–6.55 (dd, J = 8.1, 2.1
Hz, 1 H), 6.01–5.97 (ddd, J = 11.6, 5.8, 1.9 Hz, 1 H), 5.13–
5.09 (m, 1 H), 4.22–4.18 (m, 1 H), 2.84–2.77 (m, 2 H), 2.55
(t, J = 6.9 Hz, 2 H), 2.26–2.22 (m, 2 H), 1.89–1.86 (dd,
J = 9.4, 3.2 Hz, 1 H), 1.81–1.77 (dd, J = 9.7, 3.2 Hz, 1 H),
1.22 (d, J = 6.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d =
172.4, 164.8, 145.3, 143.6, 142.6, 132.6, 121.1, 120.4,
115.29, 74.3, 66.9, 41.2, 36.2, 30.3, 29.5, 20.4.
Compound 4c: [a]D +9.7 (c 0.3, CHCl3). 1H NMR (300
MHz, CDCl3): d = 6.85–6.82 (m, 1 H), 6.74–6.65 (m, 2 H),
6.58–6.54 (dd, J = 8.0, 2.0 Hz, 1 H), 6.01–5.97 (ddd, J =
11.6, 5.8, 1.8 Hz, 1 H), 5.15–5.08 (m, 1 H), 4.21–4.18 (m,
1 H), 2.82–2.77 (m, 2 H), 2.55 (t, J = 6.8 Hz, 2 H), 2.25–2.21
(m, 2 H), 1.89–1.85 (dd, J = 9.3, 3.3 Hz, 1 H), 1.81–1.77 (dd,
J = 9.5, 3.4 Hz, 1 H), 1.22 (d, J = 6.3 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): d = 172.5, 164.9, 145.4, 143.6, 142.5,
132.6, 121.0, 120.4, 115.2, 74.4, 66.9, 41.2, 36.1, 30.3, 29.5,
20.4.
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728.
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(17) All new compounds showed satisfactory analytical data for
the assigned structure and purity. Spectroscopic Data for
Selected Compounds
Compound 4d: [a]D +91.5 (c 0.5, CHCl3). 1H NMR (400
MHz, CDCl3): d = 6.82–6.79 (ddd, J = 10.3, 5.4, 2.5 Hz,
1 H), 6.73–6.70 (m, 2 H), 6.58–6.55 (dd, J = 8.0, 2.0 Hz, 1
H), 5.99–5.96 (m, 1 H), 5.05–5.01 (m, 1 H), 4.16 (m, 1 H),
2.81 (m, 2 H), 2.58 (t, J = 7.2 Hz, 2 H), 2.28 (m, 1 H), 2.20
(m, 1 H), 2.04–2.01 (m, 1 H), 1.76–1.71 (m, 1 H), 1.23 (d,
J = 6.43 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 172.7,
165.0, 145.5, 143.9, 142.2, 132.8, 120.9, 120.3, 115.4, 75.2,
67.1, 40.9, 35.8, 30.1, 28.9, 20.4. Compound 12: 1H NMR
(400 MHz, C6D6–CDCl3, 1:1): d = 4.36–4.34 (m, 1 H), 3.84
(m, 1 H), 3.63–3.58 (m, 1 H), 2.55–2.51 (br d, J = 19.0 Hz,
1 H), 2.30–2.23 (dd, J = 19.1, 5.4 Hz, 1 H), 1.64–1.60 (br d,
J = 13.9 Hz, 1 H), 1.46–1.42 (m, 1 H), 1.31 (m, 1 H), 1.10–
1.03 (m, 1 H), 0.91 (d, J = 6.0 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): d = 169.4, 72.9, 65.9, 61.9, 38.6, 36.5, 29.4, 21.4.
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2002, 67, 2682.
Compound 1d: [a]D +142.8 (c 0.55, CHCl3), lit.2 [a]30
+115.5 (c 1.52, MeOH). 1H NMR (400 MHz, CDCl3): d =
6.88–6.84 (dt, J = 10.1, 3.4 Hz, 1 H), 6.01–5.98 (dt, J = 9.8,
1.8 Hz, 1 H), 4.65–4.58 (m, 1 H), 4.09–4.04 (m, 1 H), 2.40–
2.37 (m, 2 H), 2.02–1.95 (m, 1 H), 1.77–1.72 (dt, J = 12.6,
4.1 Hz, 1 H), 1.23 (d, J = 6.3 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): d = 163.9, 145.1, 121.2, 76.8, 65.2, 43.6, 29.5, 23.7.
Compound 1a: [a]D –115.5 (c 0.17, CHCl3), lit.22 [a]25 –111
(c 1, CHCl3). 1H NMR (400 MHz, CDCl3): d = 6.89–6.84
(ddd, J = 13.9, 6.7, 4.6 Hz, 1 H), 6.01–5.97 (dt, J = 9.7, 1.7
Hz, 1 H), 4.65–4.58 (m, 1 H), 4.08–4.03 (m, 2 H), 2.40–2.36
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48, 752.
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