Asymmetric synthesis of tetrabenazine and dihydrotetrabenazine

Article abstract of DOI:10.1021/jo900480n

(Chemical Equation Presented) The enantioselective synthesis of (+)-tetrabenazine (TBZ) and (+)-dihydrotetrabenazine (DTBZ), agents of significant interest for therapeutic and molecular imaging applications, has been completed in 21% (TBZ) and 16% (DTBZ)

Full text of DOI:10.1021/jo900480n

disorders such as schizophrenia,7 Tourette’s syndrome,8 Par-
kinson’s,9 Huntington’s,10 and Alzheimer’s diseases,11 as well
as the mechanism of narcotics and addiction.12 Recently, (+)-
[11C]DTBZ has been used to detect the loss of pancreas ꢀ-cell
mass/function in rodent models of diabetes.13 VMAT-2 has been
identified as a potential ꢀ-cell selective biomarker via gene
expression profiling.14 Type II diabetes represents a growing
worldwide economic challenge.15 Detection of ꢀ-cell dysfunc-
tion prior to hyperglycemia might enable interventions that delay
or even prevent the onset of hyperglycemia and the debilitating
health issues associated with it.16
The (+)-(2R,3R,11bR)-DTBZ enantiomer binds more tightly
to rat VMAT-2 (Ki ) 0.97 nM) than does the corresponding
(-) enantiomer (Ki ) 2.2 µM).17 Consistent with this observa-
tion, biodistribution of (+)-[11C]DTBZ correlated with VMAT-2
distribution in vivo, whereas the (-) isomer did not.6b The
literature presents examples of enantiomerically pure 11C8–13,17,18
and 18F19 DTBZ analogs for imaging VMAT-2. In all cases,
the synthesis of these agents required resolution of a racemic
mixture. To our knowledge, no asymmetric synthesis of DTBZ
Asymmetric Synthesis of Tetrabenazine and
Dihydrotetrabenazine
Michael J. Rishel,* Kande K. D. Amarasinghe,
Sean R. Dinn, and Bruce F. Johnson
GE Global Research, One Research Circle,
Niskayuna, New York 12309
rishel@research.ge.com
ReceiVed March 3, 2009
The enantioselective synthesis of (+)-tetrabenazine (TBZ)
and (+)-dihydrotetrabenazine (DTBZ), agents of significant
interest for therapeutic and molecular imaging applications,
has been completed in 21% (TBZ) and 16% (DTBZ) overall
yield and in >97% ee from the starting dihydroisoquinoline.
The synthesis utilizes Sodeoka’s palladium-catalyzed asym-
metric malonate addition to set the initial stereocenter
followed by a number of diastereoselective transformations
to incorporate the remaining asymmetric centers.
(6) (a) Koeppe, R. A.; Frey, K. A.; Vander Borght, T. M.; Karlamangla, A.;
Jewett, D. M.; Lee, L. C.; Kilbourn, M. R.; Kuhl, D. E. J. Cereb. Blood Flow
Metab. 1996, 16, 1288. (b) Koeppe, R. A.; Frey, K. A.; Kuhl, D. E.; Kilbourn,
M. R. J. Cereb. Blood Flow Metab. 1999, 19 (12), 1376.
(7) Taylor, S. F.; Koeppe, R. A.; Tandon, R.; Zubieta, J.-K.; Frey, K. A.
Neuropsychopharmacology 2000, 23 (6), 667.
(8) Meyer, P.; Bohnen, N. I.; Minoshima, S.; Koeppe, R. A.; Wernette, K.;
Kilbourn, M. R.; Kuhl, D. E.; Frey, K. A.; Albin, R. L. Neurology 1999, 53 (2),
371.
(9) (a) Bohnen, N. I.; Albin, R. L.; Koeppe, R. A.; Wernette, K. A.; Kilbourn,
Michael R.; Minoshima, S.; Frey, K. A. J. Cereb. Blood Flow Metab. 2006, 26
(9), 1198. (b) Sossi, V.; Holden, J. E.; Topping, G. J.; Camborde, M.-L.;
Kornelsen, R. A.; McCormick, S. E.; Greene, J.; Studenov, A. R.; Ruth, T. J.;
Doudet, D. J. J. Cereb. Blood Flow Metab. 2007, 27 (7), 1407.
(10) Bohnen, N. I.; Koeppe, R. A.; Meyer, P.; Ficaro, E.; Wernette, K.;
Kilbourn, M. R.; Kuhl, D. E.; Frey, K. A.; Albin, R. L. Neurology 2000, 54 (9),
1753.
(11) Koeppe, R. A.; Gilman, S.; Joshi, A.; Liu, S.; Little, R.; Junck, L.;
Heumann, M.; Frey, K. A.; Albin, R. L. J. Nucl. Med. 2005, 46 (6), 936.
(12) (a) Brown, J. M.; Hanson, G. R.; Fleckenstein, A. E. J. Pharmacol.
Exp. Ther. 2001, 296 (3), 762. (b) Schwartz, K.; Weizman, A.; Rehavi, M. Eur.
Neuropsychopharm. 2005, 15 (2), 235. (c) Partilla, J. S.; Dempsey, A. G.; Nagpal,
A. S.; Blough, B. E.; Bauman, M. H.; Rothman, R. B. J. Pharmacol. Exp. Ther.
2006, 319 (1), 237. (d) Schwartz, K.; Herman, I.; Peer, G.; Weizman, A.; Rehavi,
M. J. Neural Trans. 2007, 114 (2), 281.
(13) Souza, F.; Simpson, N.; Raffo, A.; Saxena, C.; Maffei, A.; Hardy, M.;
Kilbourn, M. R.; Goland, R.; Leibel, R.; Mann, J. J.; Van Heertum, R.; Harris,
P. E. J. Clin. InVest. 2006, 116 (6), 1506.
(14) Maffei, A.; Liu, Z.; Witkowski, P.; Moschella, F.; Del Pozzo, G.; Liu,
E.; Herold, K.; Winchester, R. J.; Hardy, M. A.; Harris, P. E. Endocrinology
2004, 145, 4513.
(15) (a) Yach, D.; Stuckler, D.; Brownell, K. D. Nat. Med. 2006, 12 (1), 62.
(b) Dall, T.; Edge-Mann, S.; Zhang, Y.; Martin, J.; Chen, Y.; Hogan, P. Diabetes
Care 2008, 31, 1.
(16) (a) Simpson, N. R.; Souza, F.; Witowski, P.; Maffei, A.; Raffo, A.;
Herron, A.; Kilbourn, M. R.; Jurewicz, A.; Herold, K.; Liu, E.; Hardy, M. A.;
Van Heertum, R.; Harris, P. E. Nucl. Med. Biol. 2006, 33 (7), 855. (b) Harris,
P.; Maffei, A. PCT Int. Appl.WO 2006-US24049, 2007. (c) Scheen, A. J. Diabetes
Metab. 2007, 33, 3.
Dihydrotetrabenazine (DTBZ) and tetrabenazine (TBZ),
synthetic analogs of the ipecac alkaloid emetine, were first
reported as racemic mixtures in the 1950s.1 They are potent
inhibitors of vesicular monoamine transporter-2 (VMAT-2),
binding with affinities of 6 and 8 nM, respectively, for the
racemic compounds in in vitro assays.2 Inhibition of VMAT-2
by TBZ and DTBZ results in monoamine depletion via
metabolism of cytoplasmic monoamines by the monoamine
oxidase enzymes.3
In August 2008, racemic TBZ (Xenazine) was approved for
use in the U.S. for the treatment of chorea associated with
Huntington’s disease.4 DTBZ is the major metabolite of TBZ
in vivo.5 Enantiomerically pure (+)-DTBZ radiolabeled with
11C has been widely used to image VMAT-2 in the brain6 for
the purpose of understanding neurological and psychiatric
(1) (a) Pletscher, A. Science 1957, 126, 507. (b) Brossi, A.; Chopard-dit-
Jean, L. H.; Schnider, O. HelV. Chim. Acta 1958, 16 (193), 1793. (c) Brossi, A.;
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(77), 583. (d) Beke, D.; Sza´ntay, C. Chem. Ber. 1962, 95, 2132.
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M. R. J. Med. Chem. 1996, 39, 191.
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K. Eur. J. Pharmacol. 1995, 278, 249.
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275. (b) Saner, A.; Pletscher, A. J. Pharmacol. Exp. Ther. 1977, 203, 556.
(4) Hayden, M. R.; Leavitt, B. R.; Yasothan, U.; Kirkpatrick, P. Nat. ReV.
Drug DiscoVery 2009, 8, 17.
(5) (a) Schwarz, D. E.; Bruderer, H.; Reider, J.; Brossi, A. Biochem.
Pharmacol. 1966, 15, 645. (b) Kilbourn, M. R.; Lee, L. C.; Heeg, M. J.; Jewett,
D. M. Chirality 1997, 9, 59.
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Kung, H. F. Nucl. Med. Biol. 2006, 22, 685. (b) Kilbourn, M. R.; Hockley, B.;
Lee, L.; Hou, C.; Goswami, R.; Ponde, D. E.; Kung, M.-P.; Kung, H. F. Nucl.
Med. Biol. 2007, 34, 233. (c) Kung, M.-P.; Hou, C.; Goswami, R.; Ponde, D.;
Kilbourn, M. R.; Kung, H. F. Nucl. Med. Biol. 2007, 34, 239. (d) Kung, M.-P.;
Hou, C.; Lieberman, B. P.; Oya, S.; Ponde, D. E.; Blankemeyer, E. B.;
Skovronsky, D.; Kilbourn, M. R.; Kung, H. F. Nucl. Med. Biol. 2008, 49, 1171.
10.1021/jo900480n CCC: $40.75
Published on Web 04/17/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4001–4004 4001

SCHEME 1. Synthesis of (+)-DTBZ
has been reported to date.20 A facile asymmetric synthesis would
allow access to large quantities of enantiomerically pure material
that may be useful for further studies involving this class of
compounds.
D has also been reported.23 After careful consideration we
eventually decided to pursue the asymmetric malonate addition
approach (E to D) in favor of the asymmetric allylation route
based on reported yields, ee’s, and catalyst stoichiometry.
The asymmetric synthesis of (+)-DTBZ is described in
Scheme 1. Starting from the commercially available dihydroiso-
quinoline, we were able to incorporate the desired malonate
according to the published procedure23 to provide 1 in excellent
yield and enantiomeric excess. We found that the palladium
catalyst derived from (S)-DM-binap was quite suitable for
mediating the asymmetric transformation. Our initial attempts
to convert the malonate 1 directly to the monoester 2 using
Krapcho’s method24 invariably left us with a complex mixture
of products. We discovered that partial hydrolysis under
carefully controlled conditions followed by thermally catalyzed
decarboxylation in the presence of triethylamine25 provided the
desired monoester 2 in 79% yield. Reduction of the monoester
to provide the key intermediate 3 was effected cleanly by
treatment with DIBALH in a mixture of toluene and hexanes.
With 3 in hand we were ready to install the desired aliphatic
side chain through the application of a Nozaki-Hiyama-Kishi
coupling reaction.26 The requisite vinyl iodide for this trans-
formation was prepared from the commercially available
terminal alkyne with a modification to the standard procedure
using B-iodo-9-BBN (see Supporting Information). With the
necessary precursors 3 and 4 in hand we were able to medi-
ate the desired coupling reaction in excellent yield to provide
the desired allylic alcohol as a nearly 1:1 mixture of diastere-
omers. Direct oxidation of this mixture using Dess-Martin
periodinane cleanly yielded the desired R,ꢀ-unsaturated ketone
5. Conversion of 5 to (+)-TBZ was achieved under the mildly
acidic conditions required for Boc deprotection. The cyclization
routinely yielded a 5:1 mixture of diastereomers unsurprisingly
favoring the isomer in which the aliphatic side chain resided in
the equatorial position. Final reduction of 6 to (+)-DTBZ (7a)
was accomplished according to conventional procedures using
sodium borohydride in ethanol.1b,5a,27 The reduction typically
Our retrosynthetic approach is outlined in Figure 1. We
envisioned that (+)-DTBZ could be accessed from A via a
selective 6-endo-trig cyclization21 followed by reduction of the
resultant ketone with a sterically unencumbered hydride source.
The compound A could be disconnected to the key chiral
aldehyde B through removal of the vinylogous group that would
ultimately become the aliphatic side chain of (+)-DTBZ. We
initially considered two possible routes to the key intermediate
B. The first route originated from manipulation of the chiral
allyltetrahydroisoquinoline C to provide B. Access to the chiral
intermediate C was enabled by a few recent reports on the
asymmetric allylation of dihydroisoquinoline (E).22 Alterna-
tively, the catalytic asymmetric addition of malonates to
dihydroisoquinolines (E) to provide intermediates resembling
(20) We have published patent applications around this process: (a) Rishel,
M. J.; Amarasinghe, K. K. D.; Dinn, S. R.; Johnson, B. F. US 20080306267
A1. (b) Rishel, M. J.; Amarasinghe, K. K. D.; Dinn, S. R.; Johnson, B. F. US
20080306269 A1. (c) Rishel, M. J.; Amarasinghe, K. K. D.; Dinn, S. R.; Johnson,
B. F. WO 2008154243.
FIGURE 1. Retrosynthetic analysis of (+)-DTBZ.
4002 J. Org. Chem. Vol. 74, No. 10, 2009

(R)-tert-Butyl 6,7-Dimethoxy-1-(5-methyl-3-methylene-2-oxohexyl)-
3,4-dihydroisoquinoline-2(1H)-carboxylate (5). To a neat mixture
of 1.2 g (5.6 mmol) of the vinyl iodide 4 (1.7 equiv) and 3.2 g (9.5
mmol) of the aldehyde 3 (1.0 equiv) at room temperature was added
3.0 equiv of chromium chloride (2.1 g, 16.9 mmol) doped with
0.5% NiCl2 (w/w). The mixture was vortexed for about 2 min to
provide a homogeneous, green/gray paste and then stirred under
nitrogen for an additional 10 min, after which time 20 mL of
anhydrous DMF was added to bring the final reaction concentration
to 0.34 M. The reaction mixture was deep green in color and was
permitted to continue stirring at room temperature for 14 h.
Following the allotted time, the reaction mixture was diluted with
1:1 EtOAc-hexanes, an aqueous 0.5 M EDTA solution (pH 9)
was added, and the entire mixture was allowed to stir for 1.5 h.
The aqueous layer was extracted with three portions of EtOAc,
dried (MgSO4), and filtered, and the filtrate was concentrated under
reduced pressure to provide a green oil. The crude material was
subjected to column chromatography on SiO2 (35% EtOAc-hexanes;
elution was observed at 285nm and 228 nm). The product was a
pale yellow oil (2.3 g, 5.5 mmol) isolated in 98% yield. The
diastereomeric mixture of products was taken up in 50 mL of
dichloromethane to provide a 0.1 M solution and was then cooled
to 0 °C. To the mixture was then added 1.1 equiv of the
Dess-Martin reagent (2.6 g, 6.2 mmol). The reaction mixture was
allowed to stir, slowly warming to room temperature over 2.5 h.
The reaction was quenched by the addition of saturated aqueous
sodium bicarbonate solution and diluted with ethyl acetate. The
organic and aqueous layers were partitioned and separated, and the
aqueous layer was extracted with three additional portions of ethyl
acetate. The combined organic extracts were washed with brine,
dried (MgSO4), filtered, and concentrated under reduced pressure.
The crude material was purified by column chromatography on SiO2
(10-30% EtOAc-hexanes, elution was observed at 285 and 228
nm). The product was a colorless, foul-smelling oil (2.0 g, 4.7
mmol) that existed at 26 °C as a 60:40 mixture of rotamers in
solution (84%): 1H NMR (CDCl3) δ 0.82 (apparent t, J ) 7.6 Hz,
6H), 1.42 (s, 9H), 1.70 (apparent sept, J ) 6.62 Hz, 1H), 2.08-2.15
(m, 1H), 2.15-2.24 (m, 1H), 2.62-2.70 (m, 1H), 2.75-2.91 (m,
1H), 2.93-3.07 (m, 1H), 3.07-3.29 (m, 1.6H), 3.30-3.43 (m,
0.4H), 3.79 (s, 3H), 3.81 (s, 3.4H), 4.04-4.16 (m, 0.6H), 5.52-5.62
(m, 1H), 5.69 (s, 1H), 5.90 (s, 0.6H), 6.04 (s, 0.4H), 6.57 (s, 1H),
6.63 (s, 1H); 13C NMR (CDCl3) δ 22.5, 27.0, 27.3, 28.1, 28.4, 38.0,
39.3, 40.4, 45.2, 45.9, 51.6, 55.9, 56.0, 79.8, 80.2, 109.9, 110.3,
110.3, 111.4, 125.7, 125.7, 126.3, 129.3, 147.6, 147.9, 148.2, 148.3,
148.4, 154.4, 154.5, 199.5; HRMS-(ESI+) calcd for (C24H35NO5)
+ H) [M + H]+ 418.2594, found 418.2590.
yielded a 5:1 mixture of diastereomers favoring the product of
axial hydride addition to the (+)-TBZ core. The product of
equatorial hydride addition (7b not shown, see Experimental
Section) was also characterized. The diastereomers were easily
separated by flash chromatography on silica gel.
In conclusion, we have demonstrated a simple asymmetric
synthesis of (+)-DTBZ, a compound currently of significant
interest for use as an imaging agent for the prediction and
therapeutic monitoring of type I and type II diabetes and for
use as a neurological imaging agent. The product was prepared
in 16% overall yield and in 9 steps from the starting dihy-
droisoquinoline.
Experimental Section
(R)-tert-Butyl-1-(2-isopropoxy-2-oxoethyl)-6,7-dimethoxy-3,4-di-
hydroisoquinoline-2(1H)-carboxylate (2). The starting material (9.8
g, 20.4 mmol) was taken up in 100 mL of isopropyl alcohol to
provide a 0.2 M solution of 1. To this solution was added 100 mL
of a 1 M aqueous NaOH solution, bringing the final concentration
of the reaction mixture to 0.1 M with respect to the malonate. The
reaction mixture was heated to and maintained at 70 °C for 22 min
(timing was started when the temperature of the reaction mixture
exceeded 65 °C). Following the allotted time the reaction mixture
was quickly cooled to 0 °C by immersion in an ice-water bath.
The reaction mixture carefully acidified with 2 M aqueous HCl
and extracted with three portions of dichloromethane. The combined
organic extracts were dried (Na2SO4), filtered, and concentrated
under reduced pressure. The isolated material was taken up in 200
mL of THF to provide a 0.1 M solution (based on the original
quantity of 1 used in the reaction mixture), and 2.8 mL (20.4 mmol)
of triethylamine (1.0 equiv) was added to the reaction mixture at
room temperature. The reaction mixture was heated to 80 °C and
maintained at this temperature for 90 min. The reaction mixture
was cooled, concentrated under reduced pressure, dissolved in a
minimal quantity of CH2Cl2, and immediately purified by column
chromatography on SiO2 (15-40% EtOAc-hexanes; the eluant was
monitored at 284 nm). The product existed as a mixture of rotamers
at room temperature (variable temperature NMR analysis of this
product provided in the Supporting Information (Figure S1) clearly
indicated a rotameric mixture). The product was a colorless foam
79%: [R]26 -82 (c 0.24, CH2Cl2); IR (film) 2977, 2934, 1732,
D
1695, 1519, 1419, 1365, 1257, 1164, 1102 cm-1; 1H NMR (CDCl3)
δ 1.19-1.25 (m, 6H), 1.43-1.49 (m, 9H), 2.58-2.69 (m, 2H),
2.70-2.77 (m, 1H), 2.78-2.92 (m, 1H), 3.13-3.43 (m, 1H),
3.81-3.85 (m, 6H), 3.86-4.01 (m, 1H), 4.91-5.05 (m, 1H),
5.38-5.61 (m, 1H), 6.56-6.61 (m, 1H), 6.64-6.70 (s, 1H); 13C
NMR (CDCl3) δ 21.8, 21.90, 27.93, 28.1, 28.4, 37.5, 38.8, 42.2,
42.8, 51.1, 51.9, 55.9, 56.0, 68.1, 79.7, 80.2, 109.6, 110.0, 111.4,
111.5, 126.3, 126.5, 128.5, 128.8, 147.5, 148.0, 154.4, 154.5, 170.4,
170.6; LRMS-(ESI+) calcd for (C21H31NO6 + H) ([M + H]+
394.22, found 394.16; HRMS-(ESI+) calcd for (C21H31NO6) +
H) [M + H]+ 394.2224, found 394.2225.
(3R,11bR)-3-Isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-py-
rido[2,1-a]isoquinolin-2(11bH)-one (6). The starting material 5 (2.0
g, 4.7 mmol, 1.0 equiv) was dissolved in 60 mL of 20% Me2S-
dichloromethane to provide an 81 mM solution of the starting
material. The solution was cooled to 0 °C, and 1.1 mL (5.2 mmol)
of triisopropylsilane (1.1 equiv) followed by 58 mL (0.75 mol) of
TFA (precooled to 0 °C) was added to the reaction mixture to
provide a final concentration of 41 mM. The reaction mixture was
permitted to stir at 0 °C for 1 h. Following the allotted time the
reaction mixture was quenched at 0 °C by the addition of saturated
aqueous potassium carbonate solution and then concentrated under
reduced pressure to remove the majority of the dimethylsulfide.
The mixture was extracted with five portions of dichloromethane,
and the combined organic extracts were washed with brine, dried
(MgSO4), filtered, and concentrated under reduced pressure to
provide the crude product as a yellow solid. The crude product
was recrystallized from 3.5% dimethoxyethane in hexanes. The
resulting colorless crystals were washed with hexanes to provide
pure (+)-tetrabenazine (6) 46%: mp 126.0 °C (3.5% DME-hexanes)
(21) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(22) (a) Takashi, T.; Miyazaki, M.; Fukuoka, H.; Nagata, K.; Ohsawa, A.
Org. Lett. 2006, 8, 1295. (b) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2006,
128, 9646.
(23) Sasamoto, N.; Dubs, C.; Hamashima, Y.; Sodeoka, M. J. Am. Chem.
Soc. 2006, 128, 14010.
(24) Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G. E.,
Jr.; Lovey, A. J.; Stephens, W. P. J. Org. Chem. 1978, 43, 138.
(25) Chang, Y. M.; Park, Y. S.; Lee, S. H.; Yoon, C. M. Tetrahedron Lett.
2004, 45, 9049.
(26) (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 5281. (b) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi,
Y. J. Am. Chem. Soc. 1986, 108, 5644. (c) Wipf, P.; Lim, S. J. Chem. Soc.,
Chem. Commun. 1993, 1664.
(a crystal polymorph was observed at 116 °C); [R]26 +37.2 (c
D
0.41, CH2Cl2); IR (film) 2952, 2920, 1712, 1517, 1465, 1368, 1326,
1263, 1230, 1206, 1155, 1144, 1107, 1009 cm-1; 1H NMR (CD2Cl2)
δ 0.89 (apparent t, J ) 7.2 Hz, 6H), 0.98 (ddd, J ) 12, 6.0, 4.0
(27) Dasilva, J. N.; Carey, J. E.; Sherman, P. S.; Pisani, T. J.; Kilbourn,
M. R. Nucl. Med. Biol. 1994, 21, 151.
J. Org. Chem. Vol. 74, No. 10, 2009 4003

Hz, 1H), 1.59-1.68 (m, 1H), 1.74 (ddd, J ) 12, 5.9, 5.7 Hz, 1H),
2.32 (apparent t, J ) 11.7 Hz, 1H), 2.46 (apparent t, J ) 12.3 Hz,
1H), 2.55 (ddd, J ) 12, 10.0, 3.8 Hz, 1H), 2.65-2.73 (m, 2H),
2.83 (dd, J ) 5.5, 2.8 Hz, 1H), 2.97-3.07 (m, 1H), 3.07-3.14 (m,
1H), 3.25 (dd, J ) 9.7, 6.3 Hz, 1H), 3.47 (apparent d, J ) 12 Hz,
1H), 3.75 (s, 3H), 3.77 (s, 3H), 6.55 (s, 1H), 6.60 (s, 1H) 13C NMR
(CD2Cl2) δ 22.0, 23.0, 25.5, 29.5, 35.2, 47.5, 47.6, 50.5, 55.9, 56.0,
61.5, 62.5, 108.5, 111.7, 126.4, 129.0, 147.7, 148.0, 209.7; HRMS-
(ESI+) calcd for (C19H27NO3 + H) ([M + H]+ 318.2069, found
318.2082.
1452, 1366, 1334, 1258, 1247, 1231, 1208, 1149, 1084, 1036, 1009
cm-1; 1H NMR (CD2Cl2) δ 0.93 (d, J ) 6.6 Hz, 3H), 0.95 (d, J )
6.6 Hz, 3H), 1.04 (ddd, J ) 14.6, 8.7, 4.3 Hz, 1H), 1.42 (dd, J )
20.2, 11.4 Hz, 1H), 1.59 (ddd, J ) 13.7, 9.6, 3.3 Hz, 1H), 1.64-1.78
(m, 2H), 1.96 (apparent t, J ) 11.4 Hz, 1H), 2.27 (br s, 1H),
2.40-2.48 (m, 1H), 2.54 (ddd, J ) 12.3, 3.7, 2.3 Hz, 1H),
2.60-2.67 (m, 1H), 2.95-3.09 (m, 3H), 3.11 (apparent d, J ) 11.1
Hz, 1H), 3.35 (ddd, J ) 10.4, 10.4, 4.5 Hz, 1H), 3.80-3.81 (m,
6H), 6.60 (s, 1H), 6.69 (s, 1H); 13C NMR (CD2Cl2) δ 21.6, 24.0,
25.3, 29.3, 39.7, 40.8, 41.6, 51.8, 55.7, 55.9, 60.0, 60.9, 74.3, 108.4,
111.7, 126.7, 129.8, 147.4, 147.6; HRMS-(ESI+) calcd for
(C19H29NO3 + H) ([M + H]+ 320.2226, found 320.2242.
(2R,3R,11bR)-3-Isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahy-
dro-1H-pyrido[2,1-a]isoquinolin-2-ol (7a) and (2S,3R,11bR)-3-
Isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-
a]isoquinolin-2-ol (7b). To a 0.11 M solution of 100 mg (0.32 mmol)
of (+)-TBZ (6) in 3 mL of ethanol at 0 °C was added 34 mg (0.90
mmol) of NaBH4 (2.85 equiv). The reaction mixture was allowed
to stir for 60 min at room temperature. The excess solvent was
carefully removed under reduced pressure, and the residue was taken
up in dichloromethane and washed with three portions of saturated
aqueous K2CO3. The aqueous washings were back extracted with
two portions of dichloromethane. The combined organic extracts
were dried (MgSO4), filtered, and concentrated under reduced
pressure to provide a colorless oil. Purification of the crude product
was achieved by chromatography on SiO2 (2.5-5% MeOH-
CH2Cl2, elution was observed at 285nm) UV active fractions were
reanalyzed by TLC. Two products, 7a and 7b (see Supporting
Information), were isolated from this procedure. The major product
Acknowledgment. We would like to thank Hans Grade for
aid in obtaining high resolution mass spectral data and Tracy
Zhang, Tom Early, and Paul Donahue for aid in obtaining and
interpreting NMR spectra. Additionally, the authors would like
to thank our colleagues at GE Healthcare Medical Diagnostics
for their generous support and counsel.
Supporting Information Available: General experimental
procedures along with detailed procedures for the preparation
of compounds 1, 3, and 4, spectral data for compound 7b and
copies of 1H and 13C NMR spectra of all reported compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
7a was a colorless solid 74 mg (0.23 mmol) 74%: [R]26 +48 (c
D
0.30, CH2Cl2); IR (film) 3381, 2951, 2920, 2866, 1611, 1532, 1465,
JO900480N
4004 J. Org. Chem. Vol. 74, No. 10, 2009