The stereoselective total synthesis of (-)-dihydrotetrabenazine

Article abstract of DOI:10.1016/j.tetlet.2012.10.017

A highly stereoselective synthesis of (-)-dihydrotetrabenazine has been accomplished using (R)-tert-butanesulfinamide as a chiral source. The synthesis involves the allylation of chiral N-sulfinyl imine followed by ring closure of the resulting secondary amide with a tethered halide and the Evans-Aldol reaction as key steps.

Full text of DOI:10.1016/j.tetlet.2012.10.017

Tetrahedron Letters 53 (2012) 6916–6918
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Tetrahedron Letters
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The stereoselective total synthesis of (ꢀ)-dihydrotetrabenazine
⇑
N. Siva Senkar Reddy, A. Srinivas Reddy, J. S. Yadav, B. V. Subba Reddy
Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly stereoselective synthesis of (ꢀ)-dihydrotetrabenazine has been accomplished using (R)-tert-
butanesulfinamide as a chiral source. The synthesis involves the allylation of chiral N-sulfinyl imine
followed by ring closure of the resulting secondary amide with a tethered halide and the Evans-Aldol
reaction as key steps.
Received 16 August 2012
Revised 2 October 2012
Accepted 4 October 2012
Available online 12 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric synthesis
(R)-tert-Butanesulfinamide
Allylation of N-sulfinyl imine
Asymmetric syn-Aldol reaction
Natural product synthesis
In 1950s, the ipecac alkaloids such as emetine, dihydrotetraben-
azine (1, DTBZ), and tetrabenazine (2, TBZ) were first isolated as
racemic mixtures (Fig. 1)1 Of these, dihydrotetrabenazine is an ac-
tive metabolite of tetrabenazine. The racemic tetrabenazine has re-
cently been approved as a drug candidate by FDA for the treatment
of Chorea, which represents a major advancement of Huntington’s
disease (HD).2 The clinical research test reveals that TBZ dramati-
cally decreases the Chorea when compared to the patients treated
with placebo.3 TBZ and DTBZ are useful as vesicular monoamine
transporter 2 (VMAT2) inhibitors. The radio labeled TBZ and DTBZ
are used as radiotracers in Positron Emission Tomography (PET) for
imaging the dopamine neuron degeneration diseases and recently
the beta-cell mass related to diabetes.4
we attempted the total synthesis of dihydrotetrabenazine using
N-tert-butanesulfinamide as a source of chirality.
Herein, we report a highly efficient total synthesis of (ꢀ)-dihy-
drotetrabenazine (1) via the allylation of an enantiopure
sulfinimine. Our retrosynthetic approach for the synthesis of
(ꢀ)-dihydrotetrabenazine (1) is outlined in Scheme 1. Accordingly,
we envisioned that (ꢀ)-dihydrotetrabenazine could be accessed
from lactam 15 which in turn could be prepared by an intramolec-
ular amidation of ester 14. The compound 13 was proposed to be
obtained from enantiopure N-sulfinyl imine 5 by two consecutive
reactions viz allylation and Evans aldol reaction. The aldimine 5
could be prepared by the condensation of (R)-tert-butanesulfina-
mide with an aldehyde 4 which was prepared by a known proce-
dure from 2-(3,4-dimethoxyphenyl)ethanol 3.
Due to its promising biological activity, DTBZ has attracted
many synthetic chemists to take up its total synthesis. As a result,
various approaches have appeared in the literature.5
The construction of fragment 9 of dihydrotetrabenazine is out-
lined in Scheme 2. Accordingly, we began the synthesis of 9 from a
commercially available 2-(3,4-dimethoxyphenyl)ethanol 3, which
was converted into the corresponding aldehyde 4 in 70% yield
using a known procedure.8 The condensation of an aldehyde 4 with
(R)-tert-butanesulfinamide in the presence of CuSO4 afforded the
The chiral N-tert-butanesulfinamide is a versatile chiral auxil-
iary for the asymmetric induction in the preparation of syntheti-
cally useful chiral amines.6 Addition of an organometallic reagent
to C@N bond of an enantiopure sulfinimine is one of the most ele-
gant methods for the synthesis of chiral amines. The electron-with-
drawing sulfinyl group is highly stereodirecting and activates the
C@N bond effectively in nucleophilic addition reactions, and can
easily be removed to provide the enantiopure amine derivatives.7
However, the use of this useful chiral auxiliary in the total synthe-
sis of complex natural products is still unexplored to a great extent.
Inspired by its potential application in natural products synthesis,
respective N-sulfinyl imine
5
in 81% yield.9 Addition of
MeO
MeO
N
N
MeO
H
MeO
H
OH
O
(-)-Dihydrotetrabenazine (1)
(-)-Tetrabenazine (2)
Figure 1. Examples of tetrahydroisoquinoline alkaloids, (-)-dihydrotetrabenazine
(1) and (-)-tetrabenazine (2).
⇑
Corresponding author.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.017

N. Siva Senkar Reddy et al. / Tetrahedron Letters 53 (2012) 6916–6918
6917
MeO
MeO
Ph
O
O
O
MeO
MeO
Ph
a
NH
b
N
N
O
HO
+
N
H
O
H
O
O
10
11
1
15
12
OH
OH
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
Cl
c
NBoc
NBoc
OH
NBoc
OH
N
O
H
S
O
H
O
5
O
Ph
14
N
OH
14
13
O
O
O
O
MeO
MeO
OH
MeO
MeO
MeO
MeO
e
d
N
O
3
N
H
H
Scheme 1. Retrosynthetic approach of (ꢀ)-dihydrotetrabenazine.
1
15
OH
OH
Scheme 3. Coupling of aldehyde 9 with 12. Reagents and conditions: (a) Et3N,
pivalolyl chloride, LiCl, THF, 0 °C; 78% (b) (R)-4-benzyl-3-(4-methylpentanoyl)
oxazolidin-2-one, Bu2BOTf, Et3N, CH2Cl2, ꢀ78 °C–0 °C; 80% (c) NaOMe, MeOH/
CH2Cl2, ꢀ25 °C, 1 h, 63%; (d) (i) TMSOTf, CH2Cl2, rt, 5 h; (ii) K2CO3, 18-crown-6,
MeOH, rt, 1d, 80%; (over two steps); (e) LAH, THF, 70 °C, 2 h, 76%.
MeO
MeO
OH
MeO
MeO
Cl
Ref. 7
a
H
3
5
4
O
MeO
MeO
Cl
methanol (63%) to afford the ester 14.16 Removal of the Boc group
from compound 14 with TMSOTf in CH2Cl2 followed by cyclization
of the resulting secondary amine with a tethered ester in the pres-
ence of K2CO3 and 18-crown-6 in methanol gave the lactam 15 in
80% yield (over two steps).17 The reduction of lactam 15 with LAH
in THF afforded the (ꢀ)-dihydrotetrabenazine (1) in 76% yield
MeO
MeO
Cl
b
c
H
N
N
S
O
S
O
6
MeO
MeO
MeO
MeO
d
[a
D = ꢀ54.5, c = 0.6, MeOH] (Scheme 3).18 The optical rotation
N
N
S
O
Boc
and spectral data of the (ꢀ)-dihydrotetrabenazine (1) are in good
agreement with the data reported in the literature.19,20
In summary, we have demonstrated a highly efficient total syn-
thesis of (ꢀ)-dihydrotetrabenazine using (R)-tert-butanesulfina-
mide as a chiral source. The use of asymmetric Evans-Aldol
reaction establishes the stereochemistry of another two chiral cen-
ters which makes this synthesis more simple, quite efficient, and
attractive.
7
8
e
MeO
MeO
N
O
Boc
9
Acknowledgement
Scheme 2. Synthesis of aldehyde 9. Reagents and conditions: (a) (R)-tert-butane-
sulfinamide, CuSO4, CH2Cl2, 25 °C, 24 h, 81%; (b) AllylMgBr, CH2Cl2, ꢀ78 °C, 1 h, 80%;
(c) NaH, DMF, 0 °C to rt, 6 h, 76%; (d) (i) EtOH/HCl, 1,4-dioxane, 5 h, 0 °C; (ii) Boc2O,
Et3N, CH2Cl2, rt, 1 h, 75% (over two steps); (e) OsO4, 2,6-lutidine, NaIO4, 1,4-dioxane,
2 h, 78%.
A.S.R. thanks CSIR, New Delhi, India for the financial support in
the form of fellowship.
Supplementary data
allylmagnesium bromide onto aldimine 5 at ꢀ78 °C in dichloro-
methane gave the homoallylic sulfinamide 6 in 80% yield with
9:1 ratio of diastereomers.10 The diastereomeric mixtures could
easily be separated by column chromatography. An intramolecular
cyclization of a major isomer 6 in the presence of NaH in DMF at
room temperature gave the cyclized product 7 in 76% yield.11 Re-
moval of the sulfinyl group with ethanolic HCl gave the tetrahydro-
isoquinoline in 85% yield.12 The resulting free amine was then
protected as a Boc derivative 8 in 80% yield by treatment with an
excess of TEA in dichloromethane followed by the addition of
Boc anhydride.9 Oxidative cleavage of the terminal olefin of 8 using
OsO4, 2,6-lutidine, and NaIO4 gave the aldehyde 9 in 78% yield in a
single step (Scheme 2).13
Next we attempted the preparation of (R)-acyloxazolidinone 12
by acylation of the (R)-oxazolidinone 10 with 4-methyl-pentanoic
acid 11 using a known experimental procedure.14 Asymmetric
aldol reaction of boron enolate, derived from acyloxazolidinone
12 with an aldehyde 9 gave the syn aldol adduct 13 in 80% yield.15
The chiral auxiliary was then removed using sodium methoxide in
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.10.
017.
References and notes
1. (a) Pletscher, A. Science 1957, 126, 507; (b) Brossi, A.; Chopard-dit-Jean, L. H.;
Schnider, O. Helv. Chim. Acta 1958, 16, 1793; (c) Brossi, A.; Chopard-dit-Jean, L.
H.; Wursch, J.; Schnider, O. Helv. Chim. Acta 1960, 18, 583; (d) Beke, D.; Szantay,
C. Chem. Ber. 1962, 95, 2132.
2. (a) Bernhardt, C.; Schwan, A.-M.; Kraus, P.; Epplen, J. T.; Kunstmann, E. Eur. J.
Hum. Genet. 2008, 16, 1; (b) Walker, F. O. Lancet 2007, 369, 218.
3. (a) Kenney, C.; Jankovic, J. Expert Rev. Neurother. 2006, 6, 7; (b) Huntington
study group Neurology 2006, 66, 366.
4. (a) Toomey, J. S.; Bhatia, S.; Moon, L. T.; Orchard, E. A.; Tainter, K. H.; Lokitz, S. J.;
Terry, T.; Mathis, J. M.; Penman, A. D. PLoS ONE 2012, 7, e39041; (b) Normandin,
M. D.; Petersen, K. F.; Ding, Y. S.; Lin, S. F.; Naik, S.; Fowles, K.; Skovronsky, D.
M.; Herold, K. C.; McCarthy, T. J.; Calle, R. A.; Carson, R. E.; Treadway, J. L.; Cline,
G. W. J. Nucl. Med. 2012, 53, 908.
5. (a) Rishel, M. J.; Amarasinghe, K. D.; Dinn, S. R.; Johnson, B. F. J. Org. Chem. 2009,
74, 4001; (b) Son, Y. W.; Kwon, T. H.; Lee, J. K.; Pae, A. N.; Lee, J. Y.; Cho, Y. S.;
Min, S. Org. Lett. 2011, 13, 6500; (c) Johannes, M.; Altmann, K. Org. Lett. 2012,
14, 3752.

6918
N. Siva Senkar Reddy et al. / Tetrahedron Letters 53 (2012) 6916–6918
6. (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984; (b) Sun,
X. W.; Xu, M. H.; Lin, G. Q. Org. Lett. 2006, 8, 4979; (c) Lin, G. Q.; Xu, M. H.;
Zhong, Y. W.; Sun, X. W. Acc. Chem. Res. 2008, 41, 831.
7. (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600; (b)
Davis, F. A.; Yang, B.; Deng, J.; Zhang, J. ARKIVOC 2006, 7, 120; (c) Bosque, I.;
Gonza´lez-Go´mez, J. C.; Foubelo, F.; Yus, M. J. Org. Chem. 2012, 77, 4190.
8. (a) Yamato, M.; Washigaki, K.; Qais, N.; Ishikawa, S. Tetrahedron 1990, 46, 5909;
(b) Coldham, I.; Jana, S.; Watson, L.; Martin, N. G. Org. Biomol. Chem. 2009, 7,
1674.
9. (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999,
64, 1278; (b) Harried, S. S.; Croghan, M. D.; Kaller, M. R.; Lopez, P.; Zhong, W.;
Hungate, R.; Reider, P. J. J. Org. Chem. 2009, 74, 5975.
10. (a) Nishikawa, Y.; Kitajima, M.; Kogure, N.; Takayama, H. Tetrahedron 2009, 65,
1608; (b) Lin, S.; Zhao, G. Eur. J. Org. Chem. 2010, 1660.
11. (a) Natsume, M.; Wada, M. Chem. Pharm. Bull. 1972, 20, 1589; (b) Reddy, L. R.;
Das, S. G.; Liu, Y.; Prashad, M. J. Org. Chem. 2010, 75, 2236.
12. (a) Liu, M.; Sun, X.; Xu, M.; Lin, G. Chem. Eur. J. 2009, 15, 10217; (b) Sun, X.; Liu,
M.; Xu, M.; Lin, G. Org. Lett. 2008, 10, 1259.
13. Chandrasekhar, S.; Mahipal, M.; Kavitha, M. J. Org. Chem. 2009, 74, 9531.
14. Peddie, V.; Butcher, R. J.; Robinson, W. T.; Wilce, M. C. J.; Traore, D. A. K.; Abell,
A. D. Chem. Eur. J. 2012, 18, 6655.
20. Spectral data for selected compounds
(ꢀ)-Dihydrotetrabenazine (1):
½
a 2D8
ꢁ
ꢀ54 (c = 0.6, MeOH); 1H NMR (CDCl3,
500 MHz): d 6.67 (1H, s), 6.58 (1H, s), 3.84 (6H, s), 3.45–3.32 (1H, m), 3.20–
2.97 (4H, m), 2.69–2.53 (2H, m), 2.51–2.39 (1H, m), 2.04–1.95 (1H,m), 1.80–
1.65 (2H, m), 1.63–1.47 (2H, m), 1.11–1.01 (1H, m), 0.96–0.70 (6H, m); 13C
NMR (75 MHz, CDCl3): d 147.6, 147.3, 129.1, 126.3, 111.6, 108.1, 74.5, 60.9,
59.9, 56.0, 55.9, 51.7, 41.4, 40.4, 39.7, 29.0, 25.4, 24.1, 21.7. IR (KBr): mmax 3396,
2925, 1566, 1409, 1259, 760 cmꢀ1; ESIMS: m/z 320 [M+H]+. Compound (15):
½
a 2D8
ꢁ
ꢀ102 (c = 0.5, CHCl3); 1H NMR (300 MHz, CDCl3): d 6.66 (1H, s), 6.61 (1H,
s), 4.81–4.73 (1H, m), 4.60 (1H, dd, J = 4.0, 11.3 Hz), 3.87–3.85 (6H, m), 2.94–
2.58 (4H, m), 2.36–2.26 (1H, m), 2.11–1.95 (2H, m), 1.93–1.69 (2H, m), 1.67–
1.55 (1H, m), 0.98 (3H, d, J = 6.6 Hz), 0.92 (3H, d, J = 6.4 Hz); 13C NMR (75 MHz,
CDCl3): d 171.2, 147.7, 128.2, 127.1, 111.4, 107.9, 68.9, 55.9, 55.8, 53.2, 48.6,
39.9, 39.8, 38.8, 29.6, 28.3, 26.5, 23.1, 22.3; IR(KBr): vmax 3410, 2924, 2854,
1616, 1515, 1460, 1256, 1222, 1078, 757, 701 cmꢀ1; ESIMS: m/z 334 [M+H]+.
Compound (13): ½a D28
ꢁ
+15 (c = 1.9, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.40–
7.16 (5H, m), 6.65 (1H, s), 6.58 (1H, s), 5.28–5.18 (1H, m), 4.76–4.64 (1H, m),
4.26–3.99 (3H, m), 3.87 (3H, s), 3.85 (3H, s), 3.82–3.70 (1H, m), 3.33 (1H, dd,
J = 3.2, 13.0 Hz), 3.18–3.05 (1H, m), 2.96–2.79 (1H, m), 2.75–2.52 (2H, m), 2.04–
1.70 (4H, m), 1.60–1.52 (2H, m), 1.47 (9H, s), 0.95 (3H, d, J = 2.4 Hz), 0.92 (3H, d,
J = 2.4 Hz); 13C NMR (75 MHz, CDCl3): d 175.0, 156.3, 153.1, 147.5, 135.2, 129.2,
128.7, 127.1, 125.6, 111.1, 109.7, 80.5, 68.8, 65.7, 56.0, 55.8, 55.5, 50.5, 45.5,
40.3, 38.0, 37.8, 37.2, 28.2, 26.3, 23.5, 22.0; IR (KBr): vmax 3421, 2958, 1780,
1692, 1659, 1517, 1254, 1006, 701 cmꢀ1; ESIMS: m/z 611 [M+H]+. Compound
15. (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127; (b)
Evans, D. A.; Ng, H. P.; Clark, J. S.; Rieger, D. L. Tetrahedron 1992, 48, 2127.
16. (a) Kanomata, N.; Maruyama, S.; Tomonoa, K.; Anadaa, S. Tetrahedron Lett.
2003, 44, 3599; (b) Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 47.
17. Miyazaki, M.; Ando, N.; Sugai, K.; Seito, Y.; Fukuoka, H.; Kanemitsu, T.; Nagata,
K.; Odanaka, Y.; Nakamura, K. T.; Itoh, T. J. Org. Chem. 2011, 76, 534.
18. Paek, S.; Kim, N.; Shin, D.; Jung, J.; Jung, J.; Chang, D.; Moon, H.; Suh, Y. Chem.
Eur. J. 2010, 16, 4623.
(6): ½a 2D8
ꢁ
ꢀ29 (c = 0.7, CHCl3); 1H NMR (500 MHz, CDCl3): d 6.8 (1H, s), 6.61 (1H,
s), 5.73–5.60 (1H, m), 5.19–5.06 (2H, m), 4.60–4.51 (1H, m), 3.81 (3H, s), 3.76
(3H, s), 3.73–3.66 (1H, m), 3.64–3.55 (1H, m), 3.10–2.99 (2H, m), 2.53–2.44
(1H, m), 2.43–2.32 (1H, m), 1.13 (9H, s); 13C NMR (75 MHz, CDCl3): d 148.2,
148.1 134.1, 131.2, 128.7, 119.2, 112.9, 110.3, 55.8, 55.4, 51.8, 44.6, 43.1, 35.7,
22.5; IR (KBr): vmax 3425, 2927, 1518, 1213, 1030 cmꢀ1; ESIMS: m/z 374
19. Yao, Z.; Wei, X.; Wu, X.; Katz, J. L.; Kopajtic, T.; Greig, N. H.; Sun, H. Eur. J. Med.
Chem. 1841, 2011, 46.
[M+H]+
.