A Concise and Versatile Total Synthesis of All Stereoisomers of Tarchonanthuslactone

Article abstract of DOI:10.1055/s-0034-1378784

We describe the versatile and concise total synthesis of all stereoisomers of tarchonanthuslactone from (R)- or (S)-3-hydroxybutyrate via eight steps. The key steps of the synthesis include a highly diastereoselective chelation-controlled Mukaiyama aldol

Full text of DOI:10.1055/s-0034-1378784

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2019–2023
letter
2019
S. Huang et al.
Letter
Synlett
A Concise and Versatile Total Synthesis of All Stereoisomers of
Tarchonanthuslactone
Shuangping Huanga,1
Dongwang Liua,1
Linjun Tangb
Feifei Huanga
Wei Yangc
Xiaoji Wang*a
O
O
O
HO
O
O
2 steps
O
HO
6 steps
(+)-tarchonanthuslactone
OH
O
HO
O
O
OMe
HO
HO
a School of Pharmacy, Jiangxi Science and Technology Normal
University, 330013 Nanchang, Jiangxi, P. R. of China
2012207455@tju.edu.cn
b School of Life Science, Jiangxi Science and Technology Normal
University, 330013 Nanchang, Jiangxi, P. R. of China
c Laboratory of Chemical Genomics, School of Chemical Biology
and Biotechnology, Peking University Shenzhen Graduate
School, 518055 Shenzhen, Guangdong, P. R. of China
O
O
2 steps
(+)-7-epi-tarchonanthuslactone
Received: 25.03.2015
Accepted after revision: 10.06.2015
Published online: 30.07.2015
O
O
HO
HO
O
O
DOI: 10.1055/s-0034-1378784; Art ID: st-2015-w0208-l
Abstract We describe the versatile and concise total synthesis of all
stereoisomers of tarchonanthuslactone from (R)- or (S)-3-hydroxybu-
tyrate via eight steps. The key steps of the synthesis include a highly
diastereoselective chelation-controlled Mukaiyama aldol reaction of a
p-methoxybenzyl-protected aldehyde and a Yamaguchi lactonization of
a δ-hydroxy-trans-α,β-unsaturated carboxylic acid.
(+)-tarchonanthuslactone
O
O
HO
HO
O
O
Key words total synthesis, tarchonanthuslactone, chelation-con-
trolled Mukaiyama aldol reaction, δ-hydroxy-trans-α,β-unsaturated car-
boxylic acid, Yamaguchi lactonization
(+)-7-epi-tarchonanthuslactone
Figure 1 Structures of (+)-tarchonanthuslactone and its 7-epimer
Many natural products containing syn/anti-6,8-diol/5,6-
dihydro-2H-pyran-2-one unit have captured the interest of
chemical scientists because of their varied and novel bio-
logical activities, such as anticancer, antibacterial, and anti-
fungal activities.2 Their α,β-unsaturated unit is assumed to
play an important role in their pharmacological properties.
One related natural product is tarchonanthuslactone, which
was first isolated by Bohlmann in 1979 from the leaves of
the tree Tarchonanthus trilobus.3 A previous biological
study discovered that caffeic acid could lower the plasma
glucose levels in diabetic rats.4 Tarchonanthuslactone has a
3,4-dihydroxyhydrocinnamic acid and a 1,3-diol unit with
one hydroxyl group embedded in an α,β-unsaturated δ-lac-
tone (Figure 1). This property makes it an ideal target for
the total synthesis of tarchonanthuslactones.
ies on its synthesis have been published within six years
thereafter. The novel bioactivity of tarchonanthuslactone
compelled us to develop approaches that are more efficient
at producing tarchonanthuslactones. Here, we describe our
short, efficient, and versatile total synthesis of all stereoiso-
mers of tarchonanthuslactone.
To the best of our knowledge, most of the published
synthetic routes for tarchonanthuslactones involved scis-
sion of the unsaturated bond via either an intramolecular
ring-closing metathesis (RCM) reaction5d,g–i,k or a modified
Horner–Wadsworth–Emmons (HWE) reaction5c,l because
the cis-α,β-unsaturated carboxylic acid or ester is more fa-
vorable to the formation of the α,β-unsaturated δ-lactone
due to the steric factor. In 2007, Hiroyuki reported δ-lac-
tone formation from a series of δ-hydroxy-trans-α,β-unsat-
urated carboxylic acids accompanied by trans–cis isomeri-
zation.6 As shown in Scheme 1, they proposed the possible
route was the activation (intermediate I) of the carboxylic
acid group by using 2,4,6-trichlorobenzoyl chloride fol-
lowed by consecutive Michael addition (intermediate II) of
pyridine, formation of the cis isomer (intermediate III)
along with the elimination of pyridine and δ-lactonization.
Since Takata first reported its total synthesis in 1987,
several approaches to prepare tarchonanthuslactone and its
isomers have been reported.5 The reported dissimilar ele-
gant disconnection of synthetic approaches seemed to have
prevented developments in total synthesis of this syn/anti-
6,8-diol/5,6-dihydro-2H-pyran-2-one compound; no stud-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2019–2023

2020
S. Huang et al.
Letter
Synlett
R2
N
R2
R2
–
+
R1
O
Cl
R1
OH
R1
O
OH N+
O
OH
O
OH
O
I
II
R1 = H or Me
R2
N
R
2 = H or OBn
R2
R1
–
R1
O
Cl
OH
O
=
O
O
O
Cl
Cl
III
Scheme 1 Proposed mechanism of δ-lactone formation from δ-hydroxy-trans-α,β-unsaturated carboxylic acids by Hiroyuki
Curiously, there are almost no applications using this proto-
col. In addition, alkoxyl groups such as PMB ether group are
commonly used in the chelation-controlled Mukaiyama al-
dol addition to give highly diastereoselective diol adducts,7
which could be used to construct the syn/anti-diol struc-
ture of tarchonanthuslactones. Based on the above consid-
erations, our retrosynthetic analysis is outlined in Scheme
2. We surmise that tarchonanthuslactone and 7-epi-tar-
chonanthuslactone could be formed from 3,4-dihydroxyhy-
drocinnamic 5 and lactone 4. Compound 4 could be pre-
pared from δ-hydroxy-trans-α,β-unsaturated ester 3 ac-
cording Hiroyuki’s protocol. Compound 3 could be obtained
via chelation-controlled Mukaiyama aldol reaction be-
tween 1 and silyl enol ether 2.8
Thus, the synthesis of tarchonanthuslactones, as shown
in Scheme 3, was initiated by using commercially available
methyl (R)-3-hydroxybutyrate. According to the retrosyn-
thetic strategy for constructing the 1,3-anti-diol via a chela-
tion-controlled Mukaiyama aldol reaction, we first protect-
ed the hydroxyl group of the starting material with a PMB
group. Treatment of (R)-3-hydroxybutyrate with 4-me-
thoxybenzyl 2,2,2-trichloroacetimidate (8)9 and catalytic
10-camphorsulfonic acid (CSA) produced compound 6 in
94% yield,10 which was then reduced with DIBAL-H to afford
aldehyde 1. Aldehyde 1 was designed to react with silyl enol
ether 2 to give Mukaiyama aldol adduct 3.
With aldehyde 1 in hand, we then performed the
Mukaiyama aldol reaction with silyl enol ether 2 using 1
and different Lewis acids, such as BF3·OEt2, SnCl4, and TiCl4,
O
TBSO
TBSO
OH
5
+
O
O
O
O
O
HO
HO
HO
HO
OH
O
O
O
O
O
4
(+)-tarchonanthuslactone
(+)-7-epi-tarchonanthuslactone
PMBO
OH
O
OMe
3
PMBO
O
OTMS
OMe
+
H
1
2
Scheme 2 Retrosynthetic analysis of (+)-tarchonanthuslactone and (+)-7-epi-tarchonanthuslactone
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2019–2023

2021
S. Huang et al.
Letter
Synlett
OTMS
OMe
PMBO
OH
O
a
PMBO
O
b
OMe
OMe
O
2
(R)-3-hydroxy-
butyrate
6
1
H
PMB
Cl
H
PMBO
OH
O
O
O
i-PrO
i-PrO
OTMS
OMe
PMBO
PMBO
OH
O
O
Ti
OMe
3
H
OMe
OMe
Cl
3
Me
2
complex A
OH
Mukaiyama aldol
syn-3
Scheme 4 Proposed mechanism of chelation-controlled Mukaiyama
aldol reaction
Scheme 3 Reagents and conditions: a) 4-methoxybenzyl 2,2,2-trichlo-
roacetimidate (8), CSA (cat.), CH2Cl2, 0 °C to r.t., overnight, 94%; b)
DIBAL-H, CH2Cl2, –78 °C, 1 h, 83%.
into (+)-7-epi-tarchonanthuslactone14 in 71% overall yield
over two steps through a well-established esterification
procedure.5 The procedure utilized the acid 5, which was
prepared from 3,4-dihydroxyhydrocinnamic acid and sub-
sequently deprotected using tetrabutyl ammonium fluo-
ride (TBAF) in the presence of benzoic acid. In contrast to
(+)-7-epi-tarchonanthuslactone, (+)-tarchonanthuslactone
requires inversion of its chiral center at the C-7 position. Af-
ter screening some esterification conditions, tert-butyldi-
methylsilyl (TBS)-protected (+)-tarchonanthuslactone (10)
was produced in 62% yield by using diethyl azodicarboxyl-
ate (DEAD) and Ph3P in the solvent of THF at 0 °C. To the
best of our knowledge, this classic protocol was first used in
the synthesis of tarchonanthuslactones. Compound 10 was
subsequently deprotected, following the same procedure as
above, to give (+)-tarchonanthuslactone.15 Thus, we pre-
pared (+)-tarchonanthuslactone and (+)-7-epi-tarchonan-
thuslactone from (R)-3-hydroxybutyrate. Similarly, we
could easily obtain the other two isomers of tarchonan-
thuslactones if we changed the starting material to (S)-3-
hydroxybutyrate and used the same sequence of the above
reactions. Consequently, we could obtain all four diastereo-
mers of tarchonanthuslactone.
as shown in Table 1. However, we obtained low yields and
moderate diastereoselectivity of the desired product when
using the above Lewis acids, which was in accordance with
the literature.7c,11 Fortunately, we found Lewis acid Ti(Oi-
Pr)2Cl2 efficiently promote this vinylogous Mukaiyama al-
dol reaction. Consequently, aldehyde 1 reacted with silyl
enol ether 2 upon treatment with Ti(Oi-Pr)2Cl2 at –78 °C,
delivering a high-yielding, stereoselective reaction (82%
yield, 3/syn-3 = 5:1).12
Table 1 Screening of Lewis Acids of Mukaiyama Aldol Reaction with
Aldehyde 1 and Silyl Enol Ether 2
Entry
Lewis acids
Solvent
Yield (%)
3/syn-3
1
2
3
4
BF3·OEt2
SnCl4
CH2Cl2
CH2Cl2
CH2Cl2
toluene
32
8
2:1
n.d.a
2:1
TiCl4
29
82
Ti2Cl2(Oi-Pr)2
5:1
a Not determined.
In conclusion, we have developed an efficient and versa-
tile synthetic approach for the total synthesis of tarchonan-
thuslactone and all of its stereoisomers using the commer-
cially available compounds. The process involves eight
steps, which is the shortest synthetic route compared with
all other total syntheses that had been published. The cur-
rent approach was performed through a PMB chelation-
controlled Mukaiyama aldol reaction and a Yamaguchi lac-
tonization of δ-hydroxy-trans-α,β-unsaturated carboxylic
acid. Further studies on the application of this approach to
natural products containing syn/anti-6,8-diol/5,6-dihydro-
2H-pyran-2-one units are in progress and will be disclosed
in due course.
Suggested by Munro’s work,7d we proposed the mecha-
nism of chelation-controlled Mukaiyama aldol reaction,
which was described in Scheme 4. The high anti-selectivity
would arise from the β-chelation of titanium cation with
the aldehyde and the ether oxygen of PMB to form the com-
plex A, in which the methyl group occupied an axial posi-
tion. Subsequent attack of silyl enol ether 2 attacked from
the less hindered side, resulting in the formation of the
anti-diol product 3.
With 3 in hand, our next step was to build the α,β-un-
saturated lactone 4. As shown in Scheme 5, through Hiroyu-
ki’s protocol, we first subjected the methyl ester to hydroly-
sis with LiOH. The resulting unpurified δ-hydroxy-trans-
α,β-unsaturated carboxylic acid intermediate smoothly
formed the δ-lactone 7 in 87% overall yield in the presence
of 2,4,6-trichlorobenzoyl chloride and pyridine.13 The PMB
group was then removed to afford the corresponding inter-
mediate 4 in 80% yield. Finally, lactone 4 could be converted
Acknowledgment
We thank the National Natural Science Foundation of China (No.
21362012), Science and Technology Research Projects of the Educa-
tion Department of Jiangxi Province (No. GJJ14579), Scientific Re-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2019–2023

2022
S. Huang et al.
Letter
Synlett
O
O
HO
HO
TBSO
TBSO
ref. 5m
OH
OH
PMBO
OH
a
O
O
5
O
O
O
O
e
c
HO
3
TBSO
TBSO
O
O
O
O
HO
O
O
9
(+)-7-epi-tarchonanthuslactone
b
PMBO
O
HO
O
4
7
O
O
O
O
f
HO
HO
TBSO
TBSO
d
O
O
O
O
10
(+)-tarchonanthuslactone
Scheme 5 Reagents and conditions: (a) i) LiOH, THF–MeOH–H2O = 2:1:1, r.t., 1 h; ii) 2,4,6-trichlorobenzoyl chloride, pyridine, CH2Cl2, 0 °C, 1 h, 87%
overall; (b) DDQ, CH2Cl2–H2O (12:1), 0 °C, 1 h, 80%; (c) 5, DCC, DMAP, CH2Cl2, r.t., overnight, 81%; (d) 5, DEAD, Ph3P, THF, 0 °C, 3 h, 62%; (e) TBAF,
benzoic acid, THF, r.t., 1 h, 88%; (f) TBAF, benzoic acid, THF, r.t., 1 h, 88%.
search Fund of Jiangxi Provincial Education Department (No.
KJLD12036), Training Fund for Excellent young scientist of JiangXi
Province (No. [2013]138) for the funding support. We also thank pro-
fessor Chi-sing Lee of Peking University Shenzhen Graduate School for
his support of HRMS measurement.
Asymmetry 2007, 18, 975. (m) Lee, H.-Y.; Sampath, V.; Yoon, Y.
Synlett 2009, 249. (n) Huang, S. P.; Liu, D. W.; Tang, L. J.; Huang,
F. F.; Zhang, J. T.; Wang, X. J. Synth. Commun. 2015, 1240.
(6) Ono, M.; Zhao, X. Y.; Shida, Y.; Akita, H. Tetrahedron 2007, 63,
10140.
(7) See for example, see: (a) Peuchmaur, M.; Wong, Y.-S. J. Org.
Chem. 2007, 72, 5374. (b) Evans, D. A.; Dart, M. J.; Duffy, J. L.;
Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322. (c) Evans, D. A.;
Carter, P. H.; Carreira, E. M.; Charete, A. B.; Prunet, J. A.; Lautens,
M. J. Am. Chem. Soc. 1999, 121, 7540. (d) Perry, N. B.; Blunt, J. W.;
McCombs, J. D. Munro M. H. G. J. Org. Chem. 1986, 51, 5478.
(8) Ratjen, L.; García-García, P.; Lay, F.; Beck, M. E.; List, B. Angew.
Chem. Int. Ed. 2011, 50, 754.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378784.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(9) Joly, G. D.; Jacobsen, E. N. Org. Lett. 2002, 4, 1795.
(10) Li, S. K.; Xu, R.; Bai, D. L. Tetrahedron Lett. 2000, 41, 3463.
(11) Christmann, M.; Kalesse, M. Tetrahedron Lett. 1999, 40, 7201.
(12) The stereochemistry of the new stereogenic center of 3 and its
syn isomer were determined by NOESY spectra after protection
of the diol with PMB group (Scheme 6).
(1) These two authors contributed equally to this work.
(2) (a) Jodynis-Liebert, J.; Murias, M.; Bloszyk, E. Planta Med. 2000,
66, 199. (b) Drewes, S. E.; Schlapelo, B. M.; Horn, M. M.; Scott-
Shaw, R.; Sandor, O. Phytochemistry 1995, 38, 1427.
(3) Bohlmann, F.; Suwita, A. Phytochemistry 1979, 18, 677.
(4) Hsu, F. L.; Chen, Y. C.; Cheng, J. T. Planta Med. 2000, 66, 228.
(5) (a) Nakata, T.; Hata, N.; Iida, K.; Oishi, T. Tetrahedron Lett. 1987,
(13) Experimental Procedure
To a solution of 3 (530 mg, 1.72 mmol) in THF–MeOH–H2O
(2:1:1, 40 mL) was added LiOH (824 mg, 34.4 mmol) at r.t. and
then kept the reaction stirring for 1 h. After that, the mixture
was acidified with a solution of 1 M aq HCl to pH 5–6. Then it
was extracted with CH2Cl2 (3 × 100 mL). The combined organic
layer was dried over anhydrous Na2SO4 and concentrated under
reduced pressure to afford the crude acid which was used for
the next reaction without further purification. Subsequently, to
the above crude acid in the solution of CH2Cl2 (0.5 mL) and pyri-
dine (4.4 mL) was added 2,4,6,-trichlorobenzoyl chloride (0.3
mL, 1.9 mmol) at 0 °C. The resulting mixture was stirred for 1 h
before being quenched with a solution of sat. NaHCO3 (15 mL).
The resulting mixture was extracted with CH2Cl2 (3 × 15 mL).
The combined organic layer was dried over anhydrous Na2SO4
and concentrated under reduced pressure. Purification by flash
chromatography (hexane–EtOAc, 1:1) offered the desired com-
28, 5661. (b) Mori, Y.; Suzuki, M. J. Chem. Soc., Perkin Trans.
1
1990, 1809. (c) Solladié, G.; Gressot-Kempf, L. Tetrahedron:
Asymmetry 1996, 7, 2371. (d) Reddy, M. V. R.; Yucel, A. J.;
Ramachandran, P. V. J. Org. Chem. 2001, 66, 2512. (e) Garaas, S.
D.; Hunter, T. J.; O’Doherty, G. A. J. Org. Chem. 2002, 67, 2682.
(f) Enders, D.; Steinbusch, D. Eur. J. Org. Chem. 2003, 4450.
(g) Sabitha, G.; Sudhakar, K.; Reddy, N. M.; Rajkumar, M.; Yadav,
J. S. Tetrahedron Lett. 2005, 46, 6567. (h) Gupta, P.; Naidu, S. V.;
Kumar, P. Tetrahedron Lett. 2005, 46, 6571. (i) Baktharaman, S.;
Selvakumar, S.; Singh, V. K. Tetrahedron Lett. 2005, 46, 7527.
(j) Scott, M. S.; Luckhurst, C. A.; Dixon, D. J. A. Org. Lett. 2005, 7,
5813. (k) Yadav, J. S.; Kumar, N. N. Reddy M. S.; Prasad, A. R. Tet-
rahedron 2007, 63, 2689. (l) George, S.; Sudalai, A. Tetrahedron:
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2019–2023

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S. Huang et al.
Letter
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O
OMe
OMe
no NOE
H
H
PMBO
OH
O
DDQ
no NOE
NOE
H
4Å MS, CH2Cl2
OMe
O
O
O
O
O
3
OMe
11
OMe
OMe
NOE
NOE
O
H
H
H
NOE
PMBO
OH
O
DDQ
OMe
4Å MS, CH2Cl2
OMe
O
O
O
O
O
syn-3
OMe
12
OMe
Scheme 6
pound 7 (414 mg, 87% yield) as a yellow oil.
1.76 (m, 2 H), 1.20 (d, J = 6.4 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 173.0, 165.3, 145.9, 143.8, 142.5, 132.4, 120.7, 120.1,
115.2, 74.5, 67.1, 41.1, 36.1, 30.2, 29.4, 20.4. ESI-HRMS: m/z
calcd for C17H20O6Na [M + Na]+: 343.1152; found: 343.1149.
[α]D25 –79.3 (c 0.44, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.11
(d, J = 8.4 Hz, 2 H), 6.73–6.70 (m, 3 H), 5.87 (d, J = 10.0 Hz, 1 H),
4.54–4.47 (m, 1 H), 4.42 (d, J = 10.8 Hz, 1 H), 4.21 (d, J = 10.8 Hz,
1 H), 3.83–3.74 (m, 1 H), 3.65 (s, 3 H), 2.21–2.10 (m, 2 H), 1.75–
1.69 (m, 1 H), 1.61–1.55 (m, 1 H), 1.08 (d, J = 6.0 Hz, 3 H). 13C
NMR (100 MHz, CDCl3): δ = 164.3, 159.1, 145.2, 130.6, 129.3,
121.2, 113.7, 74.8, 70.7, 70.4, 55.2, 42.9, 29.8, 19.8. ESI-HRMS:
m/z calcd for C16H20O4Na [M + Na]+: 299.1254; found: 299.1252.
(14) (+)-7-epi-Tarchonanthuslactone
(15) (+)-Tarchonanthuslactone
[α]D25 56.8 (c 0.41, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 6.84–
6.72 (m, 3 H), 6.57 (d, J = 8.0 Hz, 2 H), 6.00 (d, J = 10.0 Hz, 1 H),
5.07–5.05 (m, 1 H), 4.19–4.10 (m, 1 H), 2.82 (t, J = 6.8 Hz, 2 H),
2.60 (t, J = 7.2 Hz, 2 H), 2.26–2.05 (m, 3 H), 1.77–1.72 (m, 1 H),
1.24 (d, J = 6.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 172.9,
165.2, 145.7, 144.0, 142.4, 132.6, 120.8, 120.3, 115.4, 75.2, 67.2,
40.8, 35.9, 30.1, 29.0, 20.4. ESI-HRMS: m/z calcd for C17H20O6Na
[M + Na]+: 343.1152; found: 343.1152.
[α]D25 26.5(c 0.78, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 6.87–
6.84(m, 1 H), 6.73–6.68 (m, 2 H), 6.53 (d, J = 8.0 Hz, 1 H), 5.99 (d,
J = 10.0 Hz, 1 H), 5.14–5.11 (m, 1 H), 4.14–4.08 (m, 1 H), 2.79 (t,
J = 6.8 Hz, 2 H), 2.57 (t, J = 6.8 Hz, 2 H), 2.22–2.20 (m, 2 H), 1.85–
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2019–2023