A concise synthesis of tetrabenazine: An intramolecular aza-prins-type cyclization via oxidative c-h activation

Article abstract of DOI:10.1021/ol202792q

A concise synthesis of tetrabenazine and dihydrotetrabenazine is described. The key feature of this synthesis is the intramolecular aza-Prins-type cyclization of an amino allylsilane via oxidative C-H activation. 2011 American Chemical Society.

Full text of DOI:10.1021/ol202792q

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6500–6503
A Concise Synthesis of Tetrabenazine: An
Intramolecular Aza-Prins-Type Cyclization
via Oxidative CꢀH Activation
Young Wook Son,† Tae Hui Kwon,† Jae Kyun Lee,‡ Ae Nim Pae,‡,§ Jae Yeol Lee,†
Yong Seo Cho,*,‡,§ and Sun-Joon Min*,‡,§
Department of Chemistry, College of Sciences, Kyung Hee University, 1 Hoegi-Dong,
Seoul 130-701, Republic of Korea, Center for Neuro-Medicine, Korea Institute of
Science and Technology (KIST), Seoul, 136-791, Republic of Korea, and School of
Science, University of Science and Technology (UST), Daejeon, 305-333,
Republic of Korea
ys4049@kist.re.kr; sjmin@kist.re.kr
Received October 18, 2011
ABSTRACT
A concise synthesis of tetrabenazine and dihydrotetrabenazine is described. The key feature of this synthesis is the intramolecular aza-Prins-type
cyclization of an amino allylsilane via oxidative CꢀH activation.
Huntington’s disease (HD) is a hereditary neurodegen-
erative disorder characterized by progressive motor dys-
function, cognitive decline, and psychiatric interruption.1
Recent studies suggest that the dopamine signaling path-
way plays an important role in HD neuropathology. In
fact, it has been reported that a high concentration of
dopamine causes toxic effects on striatal neurons in mouse
models.2 Therefore, regulation of dopaminergic neuro-
transmission in HD constitutes a potential therapeutic
target for treatment of HD.
for treatment of chorea associated with HD (Figure 1).4
TBZ and its metabolite dihydrotetrabenazine (DTBZ, 2)
reversibly inhibit the vesicular monoamine transporter-2
(VMAT2).5 Because this transporter is responsible for
translocation of dopamine from the cytoplasm into the
synaptic vesicle for reuptake, TBZ can decrease the dopa-
mine level in the brain by blocking VMAT2, which exerts
antichorea effects in HD patients.6
Tetrabenazine (TBZ, xenazine, 1), first introduced as an
antipsychotic in the 1950s,3 was approved by the FDA
† Kyung Hee University.
‡ Korea Institute of Science and Technology.
§ University of Science and Technology.
Dedicated to Professor Michael E. Jung on the occasion of his 65th
birthday.
(1) Vonsattel, J. P.; DiFiglia, M. J. Neuropathol. Exp. Neurol. 1998,
57, 369.
Figure 1. Structures of tetrabenazine and dihydrotetrabenazine.
(2) (a) Zhuang, X.; Oosting, R. S.; Jones, S. R.; Gainetdinov, P. R.;
Miller, G. W.; Caron, M. G.; Hen, R. Proc. Natl. Acad. Sci. U.S.A. 2001,
98, 1982. (b) Jakel, R. J.; Maragos, W. F. Trends Neurosci. 2000, 23, 239.
(3) Quinn, G. P.; Shore, P. A.; Brodie, B. B. J. Pharmacol. Exp. Ther.
1959, 127, 103.
The resolution and biological evaluation studies of the
DTBZ enantiomers indicated that the (þ)-enantiomer of
(5) Henry, J. P.; Scherman, D. Biochem. Pharmacol. 1989, 38, 2395.
(6) Kenney, C.; Jankovic, J. Expert Rev. Neurother. 2006, 6, 7.
(4) Hayden, M. R.; Leavitt, B. R.; Yasothan, U.; Kirkpatrick, P. Nat.
Rev. Drug Disc. 2009, 8, 17.
r
10.1021/ol202792q
Published on Web 11/21/2011
2011 American Chemical Society

2 showed high affinity with Ki = 0.97 ( 0.48 nM for
VMAT2 in rat brains, whereas the (ꢀ)-enantiomer was
much less effective with Ki = 2.2 ( 0.3 μM.7 Furthermore,
radioactive (þ)-DTBZ was specifically distributed in re-
gions of the striatum in mice. These results indicated that
the binding of TBZ as well as that of DTBZ to VMAT2 is
stereospecific.
Due to the pharmaceutical significance of TBZ and
DTBZ, several reports8 have been published to date
including two recent excellent syntheses achieved by
Jonhson and Suh.9 As depicted in Scheme 1, these syn-
theses involved initial asymmetric installation at the C-1
position of the dihydroisoquinoline 3. The enantiomeri-
cally enriched 5 and 7 were then subjected to crucial
cyclization reactions, such as an intramolecular conjugate
addition and an aza-Claisen rearrangement/transannula-
tion, to produce tetrabenazine (1) effectively.
oxidative cyclizations is challenging because termination
of Prins cyclization by allylsilane has not been studied
intensively.11 The amino allylsilane 8 could arise from the
allylsilane 10, prepared by radical conjugate addition12
to R-hydroxymethyl acrylate 1113 and a Peterson type
olefination.14
Herein, we report the total synthesis of the tetrabenazine
alkaloids through an intramolecular aza-Prins-type cycli-
zation of an amino allylsilane using an oxidative CꢀH
activation.15
Scheme 2. Retrosynthetic Analysis
Scheme 1. Reported Syntheses of TBZ
To examine the viability of our cyclization strategy, we
first optimized the reaction conditions using the simple
amino allylsilane 13 as the substrate. The allylsilane 13 was
prepared from 3-(trimethylsilylmethyl)-but-3-en-1-ol16 by
tosylation and subsequent N-alkylation with tetrahydro-
isoquinoline (Scheme 3). Although several reports have
highlighted metal catalyzed CꢀH activation in benzylic or
allylic amine systems,17 we chose organic oxidizing agents
such as phenyliodine diacetate (PIDA), phenyliodine bis-
(trifluoroacetate) (PIFA), and dichlorodicyanoquinone
(DDQ) since they are stable solids that permit more prac-
tical as well as mild reaction conditions.18 To our delight,
treatment of the substrate 13 with PIDA in CH3CN at
Retrosynthetically, we envisioned the piperidinone ring
of TBZ being formed by an aza-Prins-type cyclization of
the amino allylsilane 8 followed by oxidative cleavage of
exomethylene (Scheme 2). We postulated that direct CꢀH
activation of the tetrahydroisoquinoline derivative 8 by a
single-electron oxidative agent would lead to an iminium
intermediate, which would undergo Prins-type cyclization
to give a benzo[a]quinolizidine ring system.10 In this trans-
formation, we expected a 2,5-trans piperidine would be
formed via the more favorable chairlike transition state
(TS) in which the isobutyl substituent is in an equatorial
position. On the other hand, the use of allylsilanes in
(12) Sibi, M. P.; Patil, K. Org. Lett. 2005, 7, 1453.
(13) Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001, 66, 5413.
(14) Bunnelle, W. H.; Narayanan, B. A. Org. Synth. 1990, 69, 89.
(15) For syntheses of oxacycles via Prins cyclization using organic
oxidants, see: (a) Tu, W.; Liu, L.; Floreancig, P. E. Angew. Chem., Int.
Ed. 2008, 47, 4184. (b) Tu, W.; Floreancig, P. E. Angew. Chem., Int. Ed.
2009, 48, 4567. (c) Yu, B.; Jiang, T.; Li, J.; Su, Y.; Pan, X.; She, X. Org.
Lett. 2009, 11, 3442.
(16) Hydroxy allylsilane 12 was prepared by silylation of the dianion
of 3-methyl-3-buten-1-ol followed by desilylation of the silyl ether. For a
detailed procedure, see: Trost, B. M.; Chan, D. M. T.; Nanninga, N.
Org. Synth. 1984, 62, 58.
(17) (a) Li, C.-J.; Li, Z. J. Am. Chem. Soc. 2005, 127, 3672. (b) Li, Z.;
Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928.
(c) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (d)Murahashi, S.-I.; Nakae, T.;
Terai, H.; Komiya, N. J. Am. Chem. Soc. 2008, 130, 11005. (e) Catino, A.;
Nichols, J. M.; Nettles, B. J.; Doyle, M. P. J. Am. Chem. Soc. 2006, 128,
5648.
(18) For examples of activation of CꢀH bonds adjacent to nitrogen
using PIDA, PIFA, or DDQ, see: (a) Shu, X.-Z.; Xia, X.-F.; Yang,
Y.-F.; Ji, K.-G.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2009, 74, 7464.
(b) Tsang, A. S.-K.; Todd, M. H. Tetrahedron Lett. 2009, 50, 1199.
(7) Kilbourn, M. R.;Lee, L.;VanderBorght, T.;Jewett, D. M.;Frey, K.
Eur. J. Pharmacol. 1995, 278, 249.
(8) (a) Yu, Q.; Luo, W.; Deschamps, J.; Holloway, H. W.; Kopajtic,
T.; Katz, J. L.; Brossi, A.; Greig, N. H. ACS Med. Chem. Lett. 2010, 1,
105. (b) Boldt, K. G.; Biggers, M. S.; Phifer, S. S.; Brine, G. A.; Rehder,
K. S. Synth. Commun. 2009, 39, 3574. (c) Kilbourn, M. R.; Lee, L. C.;
Heeg, M. J.; Jewett, D. M. Chirality 1997, 9, 59.
(9) (a) Rishel, M. J.; Amarasinghe, K. K. D.; Dinn, S. R.; Johnson,
B. F. J. Org. Chem. 2009, 74, 4001. (b) Paek, S.-M.; Kim, N.-J.; Shin, D.;
Jung, J.-K.; Jung, J.-W.; Chang, D.-J.; Moon, H.; Suh, Y.-G. Chem.;
Eur. J. 2010, 16, 4623.
(10) For iminium cyclization reactions using SET-photosensitiztion
or CAN, see: (a) Zhang, X.; Jung, Y. S.; Mariano, P. S.; Fox, M. A.;
Martin, P. S.; Merkert, J. Tetrahedron Lett. 1993, 34, 5239. (b) Yoon,
U. C.; Kim, K. T.; Oh, S. W.; Cho, D. W.; Mariano, P. S. Bull. Korean
Chem. Soc. 2001, 22, 1267.
(11) (a) Ghosh, A. K.; Cheng, X. Org. Lett. 2011, 13, 4108. (b)
Brizgys, G. J.; Jung, H. H.; Floreancig, P. E. Chem. Sci., DOI: 10.1039/
c1sc00670c.
Org. Lett., Vol. 13, No. 24, 2011
6501

Having established the reaction condtions for aza-Prins-
type cyclizations using DDQ oxidation, we commenced
with the synthesis of tetrabenazine as illustrated in Scheme
4. Following the protocol developed by Sibi, we were able
to incorporate the isopropyl group into the acrylate 11
to provide 15 in 78% yield. After THP protection, we
attempted the direct conversion of the correponding
ester to the allylsilane using TMSCH2MgCl (Peterson type
olefination)20 suggested in Scheme 2; however, it was
unsuccessful presumably because of steric hindrance due
to the isopropyl group. Alternatively, we transformed
15 to the methyl ketone 16 through the Weinreb amide
intermediate.21 The ketone 16 was then treated with the
Comins reagent22 and KHMDS at ꢀ78 °C to afford
the vinyl triflate, which was subjected to hydrolysis to give
the alcohol 17 in 74% yield (2 steps). At this point, we
could effectively introduce the trimethylsilyl methyl group
into 17 using a palladium-catalyzed coupling reaction23 to
obtainthe desiredallylsilane, which was easilyconvertedto
the correspoding tosylate 10. Finally, the amino allylsilane
8 was prepared according to the same reaction conditions
as those for the synthesis of 13.
Scheme 3. Initial Attempt of the Aza-Prins-Type Cyclization
room temperature afforded the desired tricyclic ring al-
though the yield was only 33%. Encouraged by this result,
we attempted a number of reaction conditions to improve
the yield (Table 1). In fact, it turned out that PIDA was
a better oxidant than PIFA, which was not effective.
WhenweusedDDQ asthe oxidant, the reaction proceeded
rapidly at ambient temperature to give the corresponding
product 14 within 20 min. Moreover, we found that the
addition of LiClO4 is crucial for improving the effi-
ciency.19 Presumably, the counteranionofthe intermediate
(iminiumþꢀDDQHꢀ complex) generated by DDQ oxi-
ꢀ
dation is exchanged by ClO4 to form a new ion pair
(iminiumþꢀClO4ꢀ), which serves as a better electrophile.
On the basis of these findings, we selected the DDQ/
LiClO4/CH2Cl2 system as the optimal reaction conditions
for our synthesis.
Scheme 4. Synthesis of 8
Table 1. Optimization of the Aza-Prins-Type Cyclization of an
Amino Allylsilane through Oxidatve CꢀH Activationa
t
time
(h)
yield
(%)b
entry
reagent
PIDA
solvent
(°C)
1
2
CH3CN
CH2Cl2
THF
60
rt
rt
rt
rt
rt
rt
rt
rt
rt
24
6
19
PIDA
PIDA
PIDA
PIFA
NRc
20
3
6
With precursor 8 in hand, we applied the aza-Prins-type
cyclization for the construction of the piperidinone ring of
tetrabenazine (Scheme 5). Indeed, the amino allylsilane 8
was stereoselectively converted to the desired benzoisoqui-
nolizidine18underthebestconditionsidentifiedinTable1.
The relative stereochemistry of 18 was tentatively assigned
by analysis of the spectral data resulting from the NMR
4
DMF
6
54
5
CH2Cl2
CH3CN
DMF
24
24
6
NRc
12
6
PIFA
d
7
PIFA
ꢀ
8
DDQ
CH3CN
CH2Cl2
CH2Cl2
6
39
40
63
9
DDQ
0.25
0.25
10
DDQ/LiClO4
1
1
experiments including H, 13C, H COSY and HMQC.
a
˚
All reactions were peformed in the presence of 4 A molecular sieves.
b Isolated yield. c No reaction. d The starting material was decomposed.
(20) (a) Lee, T. V.; Channon, J. A.; Cregg, C.; Porter, J. R.; Roden,
F. S.; Yeoh, H. T.-L. Tetrahedron 1989, 45, 5877. (b) Narayanan, B. A.;
Bunnelle, W. H. Tetrahedron Lett. 1987, 28, 6261.
(21) Willians, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 31, 5461.
(22) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(23) Zhou, X.-T.; Lu, L.; Furkert, D. P.; Wells, C. E.; Carter, R. G.
Angew. Chem., Int. Ed. 2006, 45, 7622.
(19) (a) Mukaiyama, T.; Kobayashi, S.; Murakami, M. Chem. Lett.
1984, 1759. (b) Hayashi, Y.; Mukaiyama, T. Chem. Lett. 1987, 1811.
(c) Ying, B.-P.; Trogden, B. G.; Kohlman, D. T.; Liang, S. X.; Xu, Y.-C.
Org. Lett. 2004, 6, 1523.
6502
Org. Lett., Vol. 13, No. 24, 2011

dihydrotetrabenazine 2 since its spectroscopic data were
identical to those reported in the literature.9
Scheme 5. Complete Syntheis of TBZ and DTBZ
In summary, this study describes the concise syntheses of
TBZ (1) and DTBZ (2) using an intramolecular aza-Prins-
type cyclization of an amino allylsilane. In particular, we
have shown that a single electron oxidant such as DDQ
could generate an iminium intermediate and that subse-
quent nucleophilic addition of an allylsilane moiety could
efficiently construct the benzoisoquinolizidine ring system.
Furthermore, this transformation is highly stereoselective,
which allowed us to access a TBZ alkaloid with high dia-
stereomeric purity. Currently, an asymmetric synthesis of
TBZ and DTBZ and their application for neurological
disorders are under investigation.
Acknowledgment. This research was financially sup-
ported by the Korea Institute of Science and Technology
(KIST) and the National Research Foundation of Korea
(NRF, 2010-0022531).
Most importantly, the coupling constants of the axial
C1-proton (2.21 ppm, dd, J = 12.2, 12.2 Hz) and the axial
C4-proton (1.97 ppm, dd, J = 11.1, 11.1 Hz) indicated that
the major isomer had the 2,5-trans stereochemistry in the
piperidine ring system. Final oxidative cleavage of 18 using
OsO4, NMO, and NaIO4 cleanly yielded tetrabenazine 1
in 61% yield. Additionally, treatment of 1 with NaBH4
in EtOH afforded the alcohol 2, which was shown to be
Supporting Information Available. Experimental de-
tails and NMR spectra of all intermediates. These mate-
rials are available free of charge via the Internet at http://
pubs.acs.org.
Org. Lett., Vol. 13, No. 24, 2011
6503