Diastereoselective formal total synthesis of (±)-triptolide via a novel cationic cyclization of 2-alkenyl-1,3-dithiolane

Article abstract of DOI:10.1039/c0cc00250j

A concise and diastereoselective formal total synthesis of triptolide, a natural product with a wide range of biological properties, is described. The key reaction is an unprecedented 6-endo-Trig cationic cyclization of a 2-alkenyl-1,3-dithiolane precursor induced by TMSOTf as Lewis acid.

Full text of DOI:10.1039/c0cc00250j

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Diastereoselective formal total synthesis of (Æ)-triptolide via a novel
cationic cyclization of 2-alkenyl-1,3-dithiolanew
Sylvie Goncalves,a Paul Hellier,b Marc Nicolas,b Alain Wagnera and Rachid Baati*a
Received 5th March 2010, Accepted 9th June 2010
DOI: 10.1039/c0cc00250j
A concise and diastereoselective formal total synthesis of tripto-
lide, a natural product with a wide range of biological properties, is
described. The key reaction is an unprecedented 6-endo-Trig
cationic cyclization of a 2-alkenyl-1,3-dithiolane precursor induced
by TMSOTf as Lewis acid.
to describe an expedient synthesis of (Æ)-triptophenolide (2),
and the shortest formal synthesis of (Æ)-triptolide (1), through a
novel highly diastereoselective cationic cyclization using
TMSOTf as Lewis acid and a 2-alkenyl-1,3-dithiolane substrate
as initiator, a transformation with no literature precedent.
Fig. 2 depicts our initial retrosynthetic analysis of 1 and 2,
deriving from 3. The tetracycle 3 would arise from the tricyclic
ketone 4 after construction of the butenolide moiety. As the
key step, we identified a 6-endo-Trig cationic cyclization of
enone 5 to obtain diastereoselectively trans-4. This reaction is
usually promoted by protic and Lewis acids9 such as phosphoric
acid, BF3ÁEt2O, TiCl4, AlCl3 and SnCl4. However, although
many successes have been achieved, cationic cyclizations with
high diastereoselectivities and high efficiency are still challenging
tasks. The precursor monocyclic enone 5 would be obtained
from the readily available iodide 610 and commercial methyl
acetoacetate.
(À)-Triptolide (1) was first isolated by Kupchan et al. in 19721
from the extracts of Tripterygium Wilfordii Hook F., a plant
from southern China (Fig. 1). This diterpene triepoxide
exhibits impressive biological properties such as antitumor,
immunosupressive, anti-inflammatory, and anti-fertility activities.2
(+)-Triptophenolide (2), which lacks the triepoxide units and
is isolated from the same extract,3 is also a powerful anti-
inflammatory and immunosuppressive agent.4
The challenging and unique structure of 1 combined with its
impressive array of biological activities have attracted the
attention of several synthetic groups.5–8 Many studies have
been reported including total syntheses by Berchtold,5 Van
Tamelen,6 Yang7 and, more recently, a formal synthesis by
Sherburn.8 To date, all the synthetic strategies based on
biomimetic cationic or radical cyclizations have focused on
the construction of the tetracycle 3 (Fig. 1), which was
accomplished in 13–20 steps.5–7 Most of the reported syntheses
remain lengthy, and some of them are plagued with limitations
such as the low diastereoselectivity for the fashioning of
the trans-decalin unit 3.5 Due to the structural challenges
presented by 1, the difficulties to access 1 and 2 from natural
sources, and their promising biological profiles, a short syn-
thesis of these products and an avenue to analogue construc-
tion were deemed important. In this communication, we wish
The synthesis began with the three step preparation of the
key 3-methylcyclohexenone derivative 5 (Scheme 1). C-alkyla-
tion of the lithium dianion of methyl acetoacetate, formed
upon treatment with 2 equiv. of LDA at 0 1C, with 6 afforded
b-ketoester 7 in 76% yield. Subsequent Michael addition of 7
onto MVK in the presence of K2CO3 delivered 8, which was
engaged in a one-pot decarboxylative aldol reaction, yielding 5
in satisfactory 66% overall yield.
In initial attempts to execute the plan outlined above, we
focused on the cyclization of substrate 5. A series of acidic
activation conditions (BF3ÁEt2O, TiCl4, SnCl4 and TMSOTf)
were initially tried at room temperature in DCM, in order to
cyclize diastereoselectively 5 to the trans-decalin 4. While we
had anticipated the nucleophilic attack of the aromatic ring on
the activated enone, reactions were sluggish and resulted
mainly in the recovery of the starting material 5. The use
of H3PO4 in xylene under reflux resulted in the formation
Fig. 1 Structure of (À)-triptolide (1), (+)-triptophenolide (2) and
(+)-O-methyl triptophenolide (3).
a University of Strasbourg, Faculty of Pharmacy,
Laboratory of Functional ChemoSystems CNRS/UMR 7199,
74 route du Rhin BP60024, 67400 Illkirch, France.
E-mail: baati@bioorga.u-strasbg.fr; Fax: +33-368-854-306;
Tel: +33-368-854-301
Les Laboratoires Pierre Fabre Centre de Developpement Chimique
b
´
Industriel, 16 rue Jean Rostand, 81600 Gaillac, France
w Electronic supplementary information (ESI) available: Experimental
details. CCDC 753095. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0cc00250j
Fig. 2 Retrosynthetic analysis of 1 and 2.
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and the stereoselectivity of the reaction, 2-alkenyl-1,3-dithiane
11 was also evaluated. We found that the cyclization of 11
under the optimized conditions gave only 23% of trans-13,
42% of enone 5 along with 23% of the starting material 11
(Entry 8). In this case, the rate of the competitive deprotection
of the 1,3-dithiane was kinetically faster than the cycliza-
tion. These results demonstrated the unique and exceptional
reactivity and selectivity of the 2-alkenyl-1,3-dithiolane in the
cationic 6-endo-Trig cyclization.
To date, the reported TMSOTf catalyzed reactions15 are
mostly initiated through silicon–carbonyl, silicon–epoxide or
silicon–acetal activation. Our cyclization differs significantly
by the use of an unprecedented 2-alkenyl-1,3-dithiolane initiator.16
In the proposed rational mechanism, the activation mode
might involve the interaction of one sulfur atom of 10 with
the electrophilic silicon reagent, leading temporarily to the
opening of the 1,3-dithiolane moiety (Fig. 3).17
Scheme 1 Synthesis of the enone 5.
of the undesired cis-decalin 9, as the major product
(ratio cis-9/trans-4: 75/25), in contrast to previous reports11
(Table 1, Entry 1). Reasoning that this stereochemical out-
come was dictated by electronic rather than steric effects,
we thought to replace the conjugated enone initiator 5 by
1,3-dithiolane 10. We chose 1,3-dithiolane instead of dioxolane
because of their ease of preparation and greater stability
towards Lewis acids, to prevent in situ deprotection during
cyclization back to enone 5.12 Interestingly, the activation
conditions tried in DCM as solvent with 10 (BF3ÁEt2O, TiCl4,
SnCl4, TMSOTf, TMSNTf2) afforded trans-12 in moderate to
good yields (Entries 2–6). Indeed, while we could eventually
anticipate an initial rupture of the cyclic thioketal back to 5
under Lewis acid conditions,13 we found that TMSOTf was
the most efficient reagent (64% of trans-12) (Entry 5). It was
also found, through a screening of diverse solvents, that
performing the reaction with TMSOTf in dichloroethane
(DCE) furnished the desired trans-decalin 12 as the sole
reaction product, via a highly diastereoselective 6-endo-Trig
This event delivers a highly electrophilic cation intermediate
15 which can be stabilized by mesomeric effect with the
conjugated vinyl thionium ion 16 and the allylic carbenium
ion 17. After electrophilic substitution of the aromatic ring
and aromatization, thioenol 18 is formed, whose protonation
by TfOH leads to sulfonium ion 19. The subsequent cyclization
reinstalls the dithiolane unit affording (Æ)-12.17 The control of
the major trans stereochemistry of the decalin (Æ)-12 might be
fixed during the protonation step of 18 because of the steric
hindrance imposed by the methyl and the TMS groups on the
b face of 18. The delivery from the proton source arises
therefore from the opposite a face. Having optimized and
rationalized the synthesis of key intermediate trans-12, the
construction of the target 2 was achieved as follows.
Deprotection of the dithiolane trans-12 under the influence
of PIFA in TFA afforded the envisioned trans-4 ketone
(Scheme 2). Ketone trans-4 was sequentially alkylated with
CS2 and MeI to afford the advanced intermediate (Æ)-20.18
Epoxidation of the latter under Corey conditions upon dimethyl-
sulfonium methylide treatment followed by subsequent
cyclization (trans/cis ratio
=
97/3)14 in excellent yield
(90%, Entry 7). To further determine whether the ring size
of the protected ketone substrate would influence the efficiency
Table 1 Exploring the 6-endo-Trig cyclization
Entry Alkene Acida
Solvent
xylene
Product Yieldb d.r. cis/trans
1
2
3
4
5
6
7
8
5
H3PO4
9
57% 75/25
44% 0/100
27% 0/100
31% 0/100
64% 0/100
52% 0/100
90% 3/97
23% 0/100
10
10
10
10
10
10
11
BF3ÁEt2O CH2Cl2
12
12
12
12
12
TiCl4
SnCl4
CH2Cl2
CH2Cl2
TMSOTf CH2Cl2
TMSNTf2 CH2Cl2
TMSOTf Cl(CH2)2Cl 12
TMSOTf Cl(CH2)2Cl 13
a
b
Alkene 0.035 M (1.0 equiv.), acid (1.1 equiv.), rt. Yields determined
by HPLC.
Fig. 3 Plausible mechanism for the cationic cyclization.
Chem. Commun., 2010, 46, 5778–5780 | 5779
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Scheme 2 Completion of the synthesis of (Æ)-triptophenolide.
one-pot acidic hydrolysis gave 3 in 53% yield.18 Finally,
demethylation of 3 using BBr3 delivered cleanly the target
(Æ)-triptophenolide (2) in 92% yield. (Æ)-Triptolide 1 can be
then obtained from 3 by using Yang protocol.7
As a conclusion, we describe the most concise total synthesis
of (Æ)-triptophenolide (2) in 9 steps starting from 6 with a
global yield of 17%. We also report the shortest formal total
synthesis of (Æ)-triptolide (1) via intermediate 3 which is
prepared in 8 steps with a global yield of 19%. These syntheses
were achieved through the unprecedented cationic cyclization
of a 2-alkenyl-1,3-dithiolane triggered by TMSOTf. The develop-
ment of an asymmetric version as well as the investigation of the
scope of the methodology is in progress in our laboratory and
will be reported in due course.
11 G. Stork and A. Burgstahler, J. Am. Chem. Soc., 1951, 73,
3544.
12 Many attempts to synthesize efficiently allylic dioxolane from 5 in
order to study and compare their reactivity with 10 failed.
13 T. Ravindranathan, S. P. Chavan, R. B. Tejwani and
J. P. Varghese, J. Chem. Soc., Chem. Commun., 1991, 1750.
14 The trans diastereoselectivity of 12 was determined after deprotection
of the dithiolane moiety leading to trans-4. The trans/cis ratio of 97/3
1
was determined by H NMR, and corroborated by X-ray crystallo-
graphy analysis.
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5780 | Chem. Commun., 2010, 46, 5778–5780