Total synthesis of (-)-Englerin A

Article abstract of DOI:10.1016/j.tetlet.2014.01.012

A novel and efficient total synthesis of Englerin A is reported. The synthesis featured an intramolecular olefin metathesis ring closure reaction and a highly stereoselective oxygen bridge formation induced by an iodonium ion. This strategy can be used fo

Full text of DOI:10.1016/j.tetlet.2014.01.012

Tetrahedron Letters 55 (2014) 1339–1341
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of (À)-Englerin A
Jinghua Zhang a, , Shuyan Zheng b, , Wei Peng b, Zhengwu Shen a,b,
⇑
a School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
b Basilea Pharmaceutical China Ltd, Haimen, Jiangsu 226100, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient total synthesis of Englerin A is reported. The synthesis featured an intramolecular
olefin metathesis ring closure reaction and a highly stereoselective oxygen bridge formation induced
by an iodonium ion. This strategy can be used for the synthesis of natural products Englerin A and Engl-
erin B and can provide flexibility in the preparation of various 9-substituted analogues of Englerin A for
further structure–activity relationship studies.
Received 22 October 2013
Revised 3 January 2014
Accepted 6 January 2014
Available online 10 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Natural products
(À)-Englerin A
Stereoselective
Englerin A1 (Fig. 1) is a sesquiterpene isolated from the bark of
euphorbiaceae Phyllanthus engleri. This compound, which pos-
sesses a novel 5-6-5 oxa-tricyclo ring moiety, exhibits significant
anti-cancer activity, especially for renal cell carcinoma with GI50
(growth inhibition of 50%) levels that are 1–2 orders lower than
that of taxol. Due to its novel structure and biological properties,
Englerin A has been a synthetic target of many research laborato-
ries around the world. Thus far, nine research groups have com-
pleted the total synthesis or formal synthesis of Englerin A.2a–j In
addition, there are three noteworthy synthetic strategies
reported.2k,l,3 Herein, we report a new total synthesis approach of
Englerin A and Englerin B from a commercially available starting
material (i.e., R-(À)-carvone).
HO
H
HO
H
O
OH
(-)-Englerin A
OH
H
H
1
2
O
O
HO
H
OH
H
Our retrosynthetic analysis is illustrated in Scheme 1. To estab-
lish the seven chiral centers of Englerin A, a basic sesquiterpene
skeleton and an oxygen bridge moiety are key to the synthesis. Dis-
connection of the cinnamate and glycolate substitutions of Engler-
in A revealed the guainane sesquiterpene core 1. Compound 1 was
envisioned to be formed by intramolecular etherification of com-
pound 2. The seven member ring of compound 2 was envisaged
to be constructed by olefin metathesis from 3, which can be ob-
tained by pinacol coupling or similar manipulations from 4. Inter-
mediate 4, which is a known compound, can be conveniently
prepared from commercially available R-(À)-carvone according to
a previously reported protocol.3
H
-(-)-carvone
3
4
R
Scheme 1. Retrosynthetic disconnection of (À)-Englerin A.
easily synthesized by modifying the known procedure.3 To obtain
dihydroxyl intermediate 3 in the most efficient way, the pinacol
coupling4 between compound 4 and 13 was attempted (Scheme 3).
Although the model reaction between aldehyde 4 and compound
11 yielded coupling products 12 in approximately 50% yield, the
same reaction condition is not applicable to the reaction between
13 and 4 despite the various reaction conditions tested. We specu-
lated that the failure of the pinacol coupling between 4 and 13 may
be due to the steric hindrance of the isopropyl group near the car-
bonyl moiety. The unexpected difficulty with the pinacol coupling
between 4 and 13 led us to modify our original approach. An
The successful implementation of the above synthetic strategy
is shown in Scheme 2 starting from chiral aldehyde 4, which was
⇑
Corresponding author. Tel.: +86 513 8219 8001; fax: +86 513 8219 8003.
E-mail address: jeff_shen_1999@yahoo.com (Z. Shen).
These authors contributed equally to this Letter.
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.012

1340
J. Zhang et al. / Tetrahedron Letters 55 (2014) 1339–1341
O
O
8
O
H
O
11
HO
H
O
OR
OH
9
5
TiCl4,LiAlH4,THF
11
1
H
3
4
4
12
H OH
(-)-Englerin A: R=COC
(-)-Englerin B: R=H
2
O
O
Figure 1. Structures of (À)-Englerin A and (À)-Englerin B.
O
13
HO
H
OH
Pinacol Coupling
O
3
HO
H
a , b
H
O
+
S
S
O
H
H
O
13
O
H
4
5
6
Grubb's II catalyst
Metathesis reaction
HO
d
c
HO
H
4
14
OH
H
H
OH
Scheme 3. Exploration of pinacol coupling and metathesis.
H
3
2
afforded intermediate 6 exclusively in 88% overall yield. However,
the stereoselectivity of this reaction was not satisfactory (i.e., the
ratio of the 6R and 6S isomer is approximately 3:1). Both Mitsun-
obu inversion6 and keto–enol tautomerization of 6R-ketone 6
failed to achieve the desired conversion from 6R-ketone 6 to 6S-ke-
tone 6. Fortunately, these two isomers can be separated by silica
gel column chromatography. Interestingly, the subsequent nucleo-
philic addition of allylmagnesium bromide to 6S-ketone 6 stereo-
specifically yielded compound 3 in 92% yield.
O
e
f
HO
H
O
H
O
O
I
I
Ph
H
H
7
8
O
O
g
h
O
H
O
H
Ph
Ph
The subsequent intramolecular olefin metathesis reaction7 of
intermediate 3 proceeded smoothly, and key intermediate bicyclic
2 was constructed in 94% yield providing the guainane sesquiter-
pene core of Englerin A.
O
O
OAc
OH
H
H
(-)-Englerin B acetate(9)
(-)-Englerin B
The next stage of the synthesis involved the stereoselective
installation of the furan oxygen bridge ring. The epoxidation8,9 of
O
O
compound 2 primarily yielded the b-epoxide, and the desired
a-
i
j
(-)-Englerin A
O
O
H
O
epoxide was obtained as a by-product. The reaction mixture was
Ph
OTBS
OTBS
HO
18
O
H
10
Scheme 2. Total synthesis of (À)-Englerin A. Reagents and conditions: (a) n-BuLi
(1.1 equiv), 5 (1.0 equiv), THF, À20 °C, 1 h; (b) HgCl2 (2.5 equiv), CdCO3 (3.0 equiv),
acetone, water, 0 °C, 1 h, 88% (two steps 3:1 dr). (c) allylmagnesium bromide (1 M in
ether, 2.3 equiv), THF, À20 °C, 1 h, 92%. (d) Grubbs II catalyst (0.05 equiv),
dichloromethane, 40 °C, 1 h, 94%. (e) NaIO4 (1.2 equiv), saturated aqueous NaHSO3
solution (2.4 equiv), CH3CN, H2O, 50 °C, 0.5 h, 94%. (f) trans-cinnamoyl chloride
(3.0 equiv), triethylamine (3.0 equiv), 4-DMAP (0.5 equiv), Toluene, 80 °C, 4 h, 96%.
(g) AgOAc (2.0 equiv), AcOH, 100 °C, 4 h, 87%. (h) K2CO3 (3.0 equiv), methanol, 20 °C,
3 h, 93%. (i) 18 (2.0 equiv), 2, 4, 6-trichlorobenzoyl chloride (2.2 equiv), triethyl-
amine (4.0 equiv), 4-DMAP (0.5 equiv), toluene, 80 °C, 1 h, 87%. (j) TBAF (1 M in THF,
2.0 equiv), THF, 0 °C, 10 min, 88%.
+
H
HO
H
HO
H
HO
H
+
OH
OH
O
OH
O
O
H
H
H
15
16
1
a
intramolecular pinacol coupling was designed to overcome the ste-
ric hindrance of the isopropyl group via intramolecular cyclization.
In this new approach, the cross-metathesis reaction between 4
and 13 was attempted to synthesize compound 14. However, poly-
merization of compound 13 was found to be the main reaction un-
der the various reaction conditions used. Finally, dihydroxyl
intermediate 3 was successfully obtained in three steps from alde-
hyde 4. The nucleophilic addition reaction between 1,3-dithiane
b
HO
H
HO
7
OH
OH
H
H
+
I
H
2
17
Scheme 4. Construction of the oxygen bridge. Reagents and conditions: (a) mCPBA
(1.2 equiv), CH2Cl2, 0 °C, 1 h, alcohol 1, 12%; isomer 15, 84%. (b) NaIO4 (1.2 equiv),
saturated aqueous NaHSO3 solution (2.4 equiv), CH3CN, H2O, 50 °C, 0.5 h, 94%.
anion
5
and aldehyde 4 with the subsequent deprotection5

J. Zhang et al. / Tetrahedron Letters 55 (2014) 1339–1341
1341
cancer cell 786-O and prostate cancer cell PC-3.12 The GI50 of
(À)-Englerin A against the 786-O cancer cell line and the PC-3
cancer cell line are 6.57 and 7.53 lM, respectively, and the GI50
C14
for taxol against both cell lines was less than 20 nM.
In summary, a novel and efficient total synthesis of Englerin A
was achieved from aldehyde 4 in 11% overall yield. The synthesis
featured an intramolecular olefin metathesis ring closure reaction
and a highly stereoselective oxygen bridge formation induced by
the iodonium ion. Key intermediate 7 can be used for the synthesis
of natural product Englerin A and Englerin B as well as for the prep-
aration of various 9-substituted analogues of Englerin A for further
structure–activity relationship studies.
C13
C1
C15
C4
C2
l1
O2
O1
Acknowledgment
This work was supported by the ADT program of Basilea
Pharmaceutica China Ltd.
C12
C5
C3
C6
Supplementary data
C7
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
01.012.
C8
C10
C11
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treated with acid without work-up, and compound 1 was obtained
in 12% yield while b-epoxide 15 was isolated in 84% of yield
(Scheme 4). It should be noted that compound 1 has been used
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