Metal-mediate reactions based formal synthesis of triptonide and triptolide

Article abstract of DOI:10.1016/j.tetlet.2014.11.010

A formal synthesis of triptolide and triptonide has been achieved based on metal-mediate reactions. Specially, Noyori's ruthenium catalyzed enantioselective transfer hydrogenation, indium(III) catalyzed cationic polyene cyclization, palladium catalyzed ca

Full text of DOI:10.1016/j.tetlet.2014.11.010

Tetrahedron Letters 55 (2014) 7118–7120
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal-mediate reactions based formal synthesis of triptonide
and triptolide
⇑
Hongtao Xu, Huanyu Tang, Huijin Feng, Yuanchao Li
Department of Medical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A formal synthesis of triptolide and triptonide has been achieved based on metal-mediate reactions.
Specially, Noyori’s ruthenium catalyzed enantioselective transfer hydrogenation, indium(III) catalyzed
cationic polyene cyclization, palladium catalyzed carbonylation, rhodium catalyzed double bond migra-
tion, and palladium catalyzed ortho sp2 C–H bond oxygenation reactions served as convenient entry
points for the preparation of the tetracyclic building blocks and the C14 hydroxyl group.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 9 September 2014
Revised 25 October 2014
Accepted 3 November 2014
Available online 6 November 2014
Keywords:
Diterpenoid
Triptolide
Triptonide
Metal
Synthesis
Triptolide (1) and triptonide (2) are two closely related diter-
17
15
O
pene natural products, isolated by Kupchan et al. from extracts of
12
1
11
9
Tripterygium wilfordii Hook. f. (TWHF) in 1972 (Scheme 1). From
20
13 16
O
1
R2
4
C
2
a structural point of view, key features of these compounds include
three successive epoxide groups, the trans-fused A/B-ring and an
unsaturated five-membered lactone ring. Two of the primary bio-
logically active ingredients of TWHF, triptolide, and triptonide have
attracted particular attention owing to their extensive biological
activities, like antitumor, anti-inflammatory and immunosuppres-
1
OH
1
0
8
R
1
A
4
B
O
3
5
18
O
7
O
O
6
H
D
H
O
O
19
3
1. Triptolide: R
=OH, R
2
=H
1
1
2
. Triptonide: R ,R =O
2
2
sive. Due to their unique structure and impressive biological
activity, there is considerable interest in their total synthesis and
structure modifications have been carried out in many research
groups worldwide and yielded a lot of important structure–activity
Rh
Pd
3
relationship information (SARs). Furthermore, some analogues of
Pd
Ce
triptolide have already entered human clinical trials for rheuma-
4
O
toid arthritis and cancer.
TBSO
H
H
5
Metal mediate reactions, especially the late transition metals
O
5
4
mediate reactions, have made great contributions to the formation
of carbon–oxygen, carbon–halogen, carbon–nitrogen, carbon–sul-
fur, and carbon–carbon bonds in the synthetic organic chemistry.
Moreover, recently metal catalyzed functionalization of unreactive
C–H bonds has brought a revolution in the synthesis of structurally
complex and delicate natural products, and pharmaceuticals. It will
form a new ally for the powerful synthetic strategies that we use
In
Ru
O
TBSO
6
7
⇑
Corresponding author. Tel.: +86 21 50806600x3502; fax: +86 21 50807288.
E-mail address: ycli@mail.shcnc.ac.cn (Y. Li).
Scheme 1. Triptolide, triptonide, and retrosynthetic analysis.
http://dx.doi.org/10.1016/j.tetlet.2014.11.010
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0

H. Xu et al. / Tetrahedron Letters 55 (2014) 7118–7120
7119
everyday and have the potential to streamline synthesis and pro-
vide novel approaches to complex architectures.6
rearrangement, and subsequently reduction with Lithium alumi-
num hydride (Scheme 2). Oxidation of alcohol 8 using Dess–
11
The research in our groups focused on the chemical synthesis
and biological evaluation of triptolide and its derivatives. As a
quintessential first step, we pursued the synthesis of triptolide
and triptonide as the most active members of the series. In the
quest for a practical solution, we saw an excellent opportunity to
scrutinize metal-mediate reactions, especially the metal catalyzed
functionalization of unreactive C–H bonds that have recently
developed. Our current synthesis focused on the advanced inter-
mediate 3, which was used in previous syntheses of 1 and 2
Martin periodinane yielded aldehyde 9. Reaction of 9 with lithium
trimethylsilyl acetylide gave a propanol intermediate, which with-
out purification upon oxidation with Dess–Martin periodinane suc-
cessfully afforded ketone 10. However, the enantioselective
reduction of 10 was unexpectedly difficult. Initially, subjection of
10 to an enantioselective transfer hydrogenation reaction using
Noyori’s Ru-catalyst (R,R)-12 in 2-propanol at room temperature,8
upon stirring for 24 h, unfortunately, did not allow any reaction to
occur. After several attempts, we were glad to find that upon treat-
ment of 10 with 2.5 mol % of (R,R)-12 in the presence of formic acid
and triethylamine in tetrahydrofuran at room temperature for
3
a,f,i
(
Scheme 1).
We envisaged the rapid assembly of the trans-fused
could be synthesized by indium(III)
A/B ring framework
5
2 h, alcohol 11 was obtained in 88% yield with 97% ee.7 During
workup with potassium carbonate, the acetylenic trimethylsilyl
group was cleaved off and the hydroxy group was protected as a
tert-butyldimethylsilyl ether afforded chiral silyl ether 6. The cru-
cial indium(III) catalyzed cationic cascade reaction of 6 was
12
catalyzed cationic polyene cyclization reaction of chiral propargy-
lic silyl ether 6 that was previously developed by Corey and
7
co-workers. Furthermore, chiral propargylic silyl ether 6 could
be synthesized from commercially available 3-phenylpropanal
aldehyde 7 through carbon chain extension and Noyori’s ruthe-
8
nium catalyzed enantioselective transfer hydrogenation reaction.
achieved by the slow addition of ether 6 to an intensely stirred
7
The construction of lactone 4 could be achieved via palladium cat-
suspension of InBr
3
in dichloromethane at À20 °C, Under this con-
alyzed carbonylation-lactone formation and rhodium catalyzed
dition, a key intermediate 5 was obtained in 75% yield, and was
completely stereoselective.
9
double bond migration reaction used 5 as the precursor. The syn-
thesis of advanced intermediate 3 could be achieved by cerium
With the trans-fused A/B ring framework 5 secured, our atten-
tion then was turned to the construction of the lactone D-ring
(Scheme 3). Hydroboration of 5 and subsequent oxidation with
alkaline hydrogen peroxide produced alcohol 13 as the single iso-
mer. Protection of the free hydroxyl group as pivaloyl ester followed
by treatment with p-toluenesulfonic acid monohydrate resulted in
the removal of the silyl protecting group to afford alcohol 14. Oxida-
tion of 14 with Jones reagent, followed by conversion of the result-
ing carbonyl group to the corresponding enolic triflate afforded
compound 15. Finally, removing the pivaloyl protection group of
ammonium nitrate mediate benzylic oxidation, palladium cata-
2
lyzed ortho sp C–H bond oxygenation and Friedel–Crafts isopropy-
1
0,3k
lation from 4.
Our investigation commenced with the carbon chain extension
of commercially available 3-phenylpropanal aldehyde 7 to get alco-
hol 8 by a modified known procedure, which involves reaction
of
7 with isopropenylmagnesium bromide, Johnson–Claisen
1
1
5 by using diisobutylaluminum hydride (DIBAL-H) yielded alcohol
6, which underwent palladium catalyzed carbonylation,9
a,9b
a
b
7
and in situ lactonization produced tetracyclic lactone 17. The
1
13
stereochemistry of 17 was established by H NMR, C NMR, and
assignments made with the help of 2D HSQC, COSY, and NOESY
experiments. Finally, after investigation into a variety of reported
double bond migration conditions, such as Rh(PPh
RhCl
glad to find that the reaction of 17 with catalytic amounts of tris(tri-
phenylphosphine)rhodium chloride and triethylsilane in refluxing
toluene afforded 4 in high yields.
At this juncture, all that remained for the synthesis of 3, was the
introduction of the C14 hydroxyl group and the C13 isopropyl
group (Scheme 4). Benzylic oxidation of compound 4 with ceric
nitrate produced ketone 18, which set a scaffold for the crucial pal-
OH
O
8
9
9c
3
3
) Cl,
1
3
14
15
3
Á3H
2
O, Grubbs II catalyst, Pd(OAc) , and DBU, we were
2
c
d
O
HO
TMS
TMS
1
0
1
1
2
ladium catalyzed ortho sp C–H bond oxygenation reaction. After
surveying of a variety of recently reported metal catalyzed ortho
sp C–H bond oxygenation conditions, we were glad to find that
upon reaction of 18 with Pd(OAc)
e
f
2
10
TBSO
TBSO
1
0a
H
, PhI(OTFA)
2
,
in dichloroeth-
2
ane at 80 °C for 3 h, phenol 19 could be obtained in moderate
yields. Finally, Friedel–Crafts alkylation of phenol 19 afforded the
6
5
1
13
advanced intermediate 3. ( H NMR and C NMR of compound 3
Ts
3f,k
25
were identical to that of Yang’s group and Li’s group.
[a]
D
Ph
Ph
N
3i
20
À41.3 (c 0.09, CH
2
Cl
2
); lit. , [a]
D
À43.5 (c 0.17, MeOH)). The remain-
Ru
ing steps toward triptolide 1 and triptonide 2 could be accomplished
N
3f,i
H
by following the literature procedure.
In summary, a formal synthesis of triptolide and triptonide has
been achieved based on the enantioselective synthesis of the
known advanced intermediate 3 (15 steps with 2.5% overall
yield). In our approach, Noyori’s ruthenium catalyzed enantiose-
lective transfer hydrogenation, indium(III) catalyzed cationic
polyene cyclization, palladium catalyzed carbonylation-lactone
formation, and rhodium catalyzed double bond migration reac-
tions served as convenient entry points for the preparation of
1
2
Scheme 2. Synthesis of 5. Reagents and conditions: (a) (1) isopropenylmagnesium
bromide, THF, 0 °C to rt, 1.5 h; (2) triethyl orthoacetate, propionic acid, reflux, 24 h;
(
(
3) LAH, THF, 0 °C, 30 min, 61% (3 steps); (b) DMP, NaHCO
c) (1) trimethyl silyl acetylene, n-BuLi, THF, À78 °C to À40 °C, 1 h; (2) DMP,
, DCM, 0 °C to rt, 4 h, 71% (2 steps); (d) 12, TEA, HCOOH, THF, rt, 2 h, 88%
yield, 97% ee; (e) (1) K CO , MeOH, rt, 2.5 h; (2) TBSCl, imidazole, DMF, 0 °C to rt,
overnight, 85% (2 steps); (f) InBr
, À20 °C, 5 h, 75%.
3
, DCM, 0 °C to rt, 6 h, 81%;
NaHCO
3
2
3
3

7
120
H. Xu et al. / Tetrahedron Letters 55 (2014) 7118–7120
b
a
c
TBSO
TBSO
HO
HO
PivO
TfO
PivO
H
H
H
H
5
13
14
15
d
e
f
TfO
HO
O
O
H
H
H
O
O
4
1
6
17
Scheme 3. Synthesis of 4. Reagents and conditions: (a) BH
overnight; (2) PTSA, MeOH, rt, 1.5 h, 81% (2 steps); (c) (1) Jones reagent (8 N), acetone, 0 °C, 20 min; (2) LiHMDS, Tf
3
ÁTHF, THF, 0 °C to rt, 5 h, then NaOH (3 N), H
2
O
2
(30%), 0 °C to rt, 2.5 h, 81%; (b) (1) PivCl, TEA, DMAP, 0 °C to rt,
NPh, À78 °C to rt, overnight, 75% (2 steps); (d) DIBAL-H,
3 4 3 3 3 3
) , Bu N, LiCl, 80 °C, 10 h, 80%; (f) Rh(PPh ) Cl, Et SiH, toluene, reflux, 8 h, 91%.
2
2
CH Cl
2
, À78 °C, 2 h, 86%; (e) CO, Pd(PPh
Supplementary data
Supplementary data (detailed experimental procedures, and
copies of H NMR, C NMR, H–H COSY, HMBC, NOESY spectra)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.11.010.
a
1
13
O
O
O
H
4
H
O
O
18
b
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4
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Ce(NO
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applicable to the synthesis of other structurally relevant natural
products or bioactive derivatives, such as 16-hydroxytriptolide
and C13 modified analogues of triptolide. Further synthetic and
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(
Number: 13431900403), the National Natural Science Foundation
of NFSC, China (Number: 81373479) and the Specific Research
Construction Project of National Clinical Research Base of TCM,
China (Number: JDZX2012010).
1