A concise total synthesis of (+)-tetrabenazine and (+)-α- dihydrotetrabenazine

Article abstract of DOI:10.1002/chem.200902591

Highly concise asymmetric total syntheses of (+)-tetrabenazine (1), a drug for the treatment of chorea associated with Huntington's disease, and of (+)α-dihydrotetrabenazine (2), an active metabolite of 1, have been accomplished. Our synthetic route features a trans-selective enol etherification, followed by an unprecedented cation-dependent aza-Claisen rearrangement to establish the carbon framework and two stereogenic centers of tetrabenazine. The syntheses consist of seven steps (34% overall yield) for (+)-2 and eight steps (22% overall yield) for (+)-l.

Full text of DOI:10.1002/chem.200902591

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FULL PAPER
DOI: 10.1002/chem.200902591
A Concise Total Synthesis of (+)-Tetrabenazine and
(+)-a-Dihydrotetrabenazine
Seung-Mann Paek,[a] Nam-Jung Kim,[a] Dongyun Shin,[b] Jae-Kyung Jung,[c]
Jong-Wha Jung,[a] Dong-Jo Chang,[a] Hyunyoung Moon,[a] and Young-Ger Suh*[a]
Abstract: Highly concise asymmetric total syntheses of (+)-tetrabenazine (1), a
drug for the treatment of chorea associated with Huntingtonꢀs disease, and of (+)-
a-dihydrotetrabenazine (2), an active metabolite of 1, have been accomplished.
Our synthetic route features a trans-selective enol etherification, followed by an
unprecedented cation-dependent aza-Claisen rearrangement to establish the
carbon framework and two stereogenic centers of tetrabenazine. The syntheses
consist of seven steps (34% overall yield) for (+)-2 and eight steps (22% overall
yield) for (+)-1.
Keywords: bentazines
·
Claisen
rearrangement
total synthesis
·
rearrangement ·
Introduction
Chorea is one of the most common and debilitating motor
symptoms associated with Huntingtonꢀs disease (HD) and
afflicts the lives of the HD patients and caregivers.[1] HD
Figure 1. Structures of TBZ (1) and a-DHTBZ (2).
can affect people of all ethnic groups, but is more common
in most western countries. In particular, about 30000 people
in North America have HD and another 200000 are consid-
ered at risk of developing the condition.[2] Tetrabenazine
(TBZ, Xenazine, (Æ)-1, Figure 1), the first and only drug
approved by the US FDA as a racemate for the treatment
of chorea (15th August 2008), represents a major advance-
ment for HD patients.[3] In recent clinical tests in Europe
and Australia, the majority (69–80%) of TBZ-treated pa-
tients showed dramatically decreased chorea, in contrast to
patients treated with placebo.[4] With this pharmacological
activity, TBZ (as the racemate) is now taken by HD pa-
tients.
TBZ (1), in the form of the racemic, binds to vesicular
monoamine transporter type 2 (VMAT2) and depletes cere-
bral monoamines in neuronal synapses with a Ki value of
3 nm.[5] In addition, a-dihydrotetrabenazine (a-DHTBZ, 2),
an active metabolite of TBZ, also showed high specific bind-
ing affinity to VMAT2.[6] More importantly, enzymatic reso-
lution of racemic a-DHTBZ showed that its binding to
VMAT2 is highly stereoselective [Ki =0.97 nm for the (+)
enantiomer of 2 but Ki =2.2 mm for the (À) enantiomer].[7]
In view of the high-affinity stereospecific binding of 2, as
well as the frequent occurrence of side effects caused by the
undesired stereoisomers of racemic drugs, such as (R)-thali-
domide,[8] intensive and prompt studies on optically pure 1
and 2 as chiral switches were necessary for the development
of drugs with improved efficacy and fewer adverse drug re-
actions. In spite of the urgent demand for optically pure 1 or
2, however, only one asymmetric synthetic route to these
TBZ alkaloids—not including resolution of racemic 2 with
the aid of HPLC, enzymes, or chemicals—has been devel-
oped.[7–9] With this in mind, we took on the challenge and
[a] Dr. S.-M. Paek, N.-J. Kim, Dr. J.-W. Jung, Dr. D.-J. Chang, H. Moon,
Prof. Y.-G. Suh
College of Pharmacy, Seoul National University
Seoul 151-742 (Korea)
Fax : (+82)2-888-0649
E-mail: ygsuh@snu.ac.kr
[b] Dr. D. Shin
Life Sciences Research Division
Korea Institute of Science and Technology, Seoul 130-650 (Korea)
[c] Prof. J.-K. Jung
College of Pharmacy, Chungbuk National University
Cheongju 361-763 (Korea)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902591.
Chem. Eur. J. 2010, 16, 4623 – 4628
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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report here our success in the efficient asymmetric syntheses
of (+)-1 and (+)-2, based on a highly stereospecific ring-ex-
pansion through a cation-dependent amide-enolate-induced
aza-Claisen rearrangement (ACR),[10–12] to create the two
stereogenic centers of (+)-1, and a subsequent diastereose-
lective transannulation. Obviously, our strategies provide
rapid access to a variety of medicinally important benzoqui-
nolizidine alkaloids, including TBZ analogues.
Results and Discussion
Retrosynthetic analysis: Envisaging an efficient and unified
synthetic procedure, we pursued a concise procedure for
ready access to the key ten-membered lactam[13] intermedi-
ate 3 (Scheme 1), potentially effectively transformable into
(+)-1 and (+)-2 by electrophile-catalyzed transannulation
followed by amide reduction.[14]
Scheme 2. a) 4-Methylvaleric acid, EDCI, HOBt, CH2Cl2, 08C to RT,
86% for two steps; b) OsO4, NMO then NaIO4, acetone/H2O, 88%.
chelating, bulky base such as DBU in the presence of
TBSCl in CH2Cl2 at reflux could lead to the exclusive for-
mation of the desired E-enol ether 4 (E/Z 34:1, isolated;
Scheme 3) in 94% yield. The mechanism underlying the
high selectivity is not entirely clear. One plausible explana-
tion, however, could include initial generation of enolates
from 5 followed by a preferred silylation of the sterically
less encumbered E-enolate.[18,19]
Scheme 1. Retrosynthetic analysis of (+)-TBZ (1) and (+)-a-DHTBZ
(2).
The lactam 3 appeared obtainable by our lactam ring-ex-
pansion strategy,[12] with establishment of two of the requi-
site stereogenic centers of (+)-2 through 1,4 and 1,5 chirality
transfers. The E olefin geometry in the enol ether 4, crucial
for stereocontrol of the hydroxy group, was to be estab-
lished from the corresponding aldehyde 5 through a selec-
tive enol etherification.[15] Finally, asymmetric allylation of
Scheme 3. a) TBSCl, DBU, CH2Cl2, 408C, 5 h, 94%.
With enol ether 4 available in multigram quantities, we
first tested the feasibility of the pivotal ACR with regard to
the stereochemical course of the rearrangement under stan-
dard conditions (Table 1).
the commercially available synthon
8
by Nakamuraꢀs
At first, enol ether 4 was treated with LHMDS (in hexane
solution) in toluene at reflux. Unfortunately, these standard
conditions afforded only a small amount of the desired ring-
expanded product 3 (25%), along with a significant amount
of unidentified side and degradation products. Because of
the disappointing yield of 3, we examined a variety of rear-
rangement conditions including solvent, base, temperature,
and the enolate trapping reagent (entries 1–6). Reaction
under most of the conditions resulted in substrate recovery
or degradation. TMSOTf or TBSCl trapping of the amide
enolate derived from 4 followed by ACR afforded the de-
sired macrolactam 3 in 5~10% yield with the substrate
intact.
method[16] and subsequent olefin cleavage appeared likely to
afford the aldehyde 5. It is noteworthy that the stereochemi-
cal outcome addressed by utilization of the conformational
preference (substrate control) would render this approach
to (+)-1 and (+)-2 practical.
Synthesis: Our synthesis commenced with asymmetric allyla-
tion of the commercially available 8 to afford the enantio-
merically enriched homoallylic amine 7 (Scheme 2).[16] The
amine 7 was coupled with 4-methylvaleric acid, and subse-
quent olefin dihydroxylation followed by NaIO4-mediated
diol cleavage[17] gave the aldehyde 5.
We next set out to address the formidable task of stereo-
selective enol ether formation. Our extensive studies re-
vealed that treatment of the b-aminoaldehyde 5 with a non-
However, after intensive examination of a variety of bases
(entries 7–11), we finally observed that treatment of the E-
enol ether 4 with iPrMgCl (2.0m in THF solution) in ben-
4624
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Chem. Eur. J. 2010, 16, 4623 – 4628

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(+)-Tetrabenazine and (+)-a-Dihydrotetrabenazine
FULL PAPER
Table 1. Aza-Claisen rearrangement under various reaction conditions.
Entry Solvent Base [equiv]
T
Product
[%][a]
1
2
3
4
5
toluene LHMDS [3]
toluene LHMDS [1.1]
toluene LHMDS [2]
1208C
RT
RT
À788C to 08C
À788C to
1208C
RT to 1208C
1208C
1208C
808C
25%
n.d.[b]
n.d.
n.d.
5–10%
THF
LHMDS [2]
toluene LHMDS [2],
TMSOTf
6
7
8
9
10
11
12
toluene LHMDS [2], TBSCl
toluene KHMDS [2]
toluene iPrMgCl [2]
benzene iPrMgCl [5]
benzene iPrMgCl [2]
benzene iPrLi [2]
5–10%
n.d.
52%
76%
75%
n.d.
808C
808C
808C
Scheme 4. a) TsOH, benzene, 84%.
benzene tBuMgCl [2]
33%
[a] Isolated yield. Other diastereomers were not detected. [b] Not detect-
ed.
was furthermore confirmed by X-ray crystallography
(Scheme 5).[28]
zene at reflux exclusively provided the desired lactam 3 as a
detectable single diastereomer (76% yield). The superiority
of iPrMgCl over LHMDS is likely due to the gauche interac-
tion between the bulky MgCl complex and the OTBS group,
which forces the highly ordered chair-like transition state
(Figure 2). To the best of our knowledge, use of a Grignard
reagent such as iPrMgCl is the first example for ACR.[20–23]
Scheme 5. a) LAH, THF, 76%; b) TPAP, NMO, CH2Cl2, 64%.
Figure 2. Proposed transition state for the aza-Claisen rearrangement.
Conclusion
With the key ten-membered lactam 3 to hand, we ex-
plored an electrophile-assisted transannulation strategy[14,25]
for the construction of the desired benzoisoquinolizidine
scaffold of (+)-2 (Scheme 4). Fortunately, the transannula-
tion of lactam 3 to afford the benzoisoquinolizidine 9 could
be accomplished with the assistance of TsOH (RT, benzene,
24 h) with the concomitant cleavage of the TBS ether in a
highly diastereoselective fashion (36:1, 84% yield, isolat-
ed).[24,25] It is noteworthy that the ACR/transannulation se-
quence allowed the stereoselective construction of benzoiso-
quinolizidine skeleton through remote chiral communication
(Scheme 4).
Finally, LAH reduction of 9 afforded (+)-a-DHTBZ (2,
Scheme 5) and subsequent TPAP/NMO oxidation gave (+)-
TBZ (1); both compounds exhibited 1H NMR, 13C NMR,
HRMS, IR spectral data,[26] and optical rotations[27] identical
to those of the authentic products. The structure of (+)-1
In conclusion, we have achieved highly efficient and concise
asymmetric total syntheses of (+)-TBZ (1) and (+)-a-
DHTBZ (2) in seven and six steps from the known homoall-
yl amine 7 and in 22% and 34% overall yields, respectively.
The key features of our synthetic route include stereoselec-
tive elaboration of the E-enol ether unit from the corre-
sponding aldehyde, a subsequent amide-enolate-induced
ACR, which afforded almost perfect 1,4 and 1,5 remote
chiral transfer, and highly efficient construction of the ben-
zoisoquinolizidine skeleton by acid-catalyzed transannula-
tion. This highly stereoselective transformation allowed us
to acquire the biologically important TBZ alkaloids without
loss of enantiomeric purity; further studies of the clinical
uses of the TBZ analogues and mechanistic investigation of
the cation-dependent ACR are in progress.
Chem. Eur. J. 2010, 16, 4623 – 4628
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Y.-G. Suh et al.
AHCTUNGTRENNUNG
Experimental Section
General procedure: Unless noted otherwise, all starting materials and re-
agents were obtained from commercial suppliers and were used without
further purification. Tetrahydrofuran and Et2O were distilled from
sodium benzophenone ketyl. Dichloromethane, triethylamine, acetoni-
trile, and pyridine were freshly distilled from calcium hydride. All sol-
vents used for routine isolation of products and chromatography were re-
agent grade and glass-distilled. Reaction flasks were dried at 1008C. Air-
and moisture-sensitive reactions were performed under argon. Flash
column chromatography was performed on silica gel 60 (230–400 mesh)
with the solvents indicated. Thin-layer chromatography was performed
on silica gel plates (0.25 mm). Optical rotations were measured with
100 mm cells of 1–2 mL capacity. Chemical shifts are expressed in parts
per million (ppm, d) downfield from tetramethylsilane and are refer-
enced to the deuterated solvent (CDCl3). 1H NMR data are reported in
the order of chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet and/or multiple resonance), coupling constant in
hertz (Hz), and number of protons.
2(1H)-yl]-4-methylpentan-1-one (4’):
A mixture of the aldehyde 5
(82 mg, 0.25 mmol), TBSCl (70 mg, 0.46 mmol), and DBU (50 mL,
0.40 mmol) in CH2Cl2 (10 mL) was stirred at 408C for 5 h. The reaction
mixture was quenched with aqueous NaHCO3 and extracted with
CH2Cl2. The organic layer was dried over Na2SO4, filtered, and concen-
trated in vacuo. The residue was purified by flash column chromatogra-
phy on silica gel (EtOAc/hexane/Et3N 5:15:1) to afford the E-enol ether
4 (103 mg, 94%) as the major isomer and the undesired Z-enol ether 4’
(3 mg, 2.7%) as a colorless oil.
Compound 4: [a]2D0 =À114.1 (c=1.46, MeOH); 1H NMR (300 MHz,
CD3OD, mixture of rotamers): d=6.58 (s, 1H), 6.51 (s, 1H), 6.42 (d, J=
11.5 Hz), 6.34 (d, J=11.7 Hz, 1H), 5.72 (d, J=8.2 Hz), 5.25 (d, J=7.6 Hz,
1H), 5.09 (dd, J=7.6, 11.9 Hz), 4.98 (dd, J=8.0, 11.7 Hz, 1H), 4.40–4.36
(m), 3.85–3.81 (m, 1H), 3.66 (s, 3H), 3.65 (s, 3H), 3.39–3.29 (m), 2.97–
2.87 (m, 1H), 2.79–2.52 (m, 2H), 2.38–2.24 (m, 2H), 1.50–1.34 (m, 3H),
0.79–0.77 (m, 15H), 0.00 ppm (m, 6H); 13C NMR (75 MHz, CD3OD, mix-
ture of rotamers): d=183.6, 175.2, 174.8, 150.4, 150.2, 149.9, 146.9, 145.9,
129.8, 128.5, 128.9, 128.2, 127.0, 113.6, 113.5, 113.4, 113.2, 113.0, 60.8,
59.3, 59.2, 56.9, 52.9, 44.7, 41.9, 38.1, 36.4, 36.3, 33.5, 33.2, 30.6, 29.8, 29.6,
27.1, 26.9, 23.6, 23.5, 20.2, À4.3 ppm; IR (neat): n˜ =2954, 1647, 1515,
1462, 1256, 1180, 1119 cmÀ1; MS (EI+): m/z: 447 [M]+; HRMS (EI+): m/
z: calcd for C25H41O4NSi: 447.2805 [M]+; found: 447.2781.
Compound 4’: [a]2D0 =À218.4 (c=0.18, MeOH); 1H NMR (300 MHz,
CD3OD, mixture of rotamers): d=6.45 (s, 1H), 6.43 (s, 1H), 6.20 (d, J=
9.3 Hz, 1H), 5.68 (d, J=9.3 Hz, 1H), 4.59 (m, 1H), 4.47–4.27 (m, 1H),
3.53 (m, 1H), 3.53 (s, 3H), 3.49 (s, 3H), 2.80–2.70 (m, 1H), 2.67–2.14 (m,
5H), 1.37–1.03 (m, 4H), 0.77 (s, 9H), 0.66 (d, J=2.1 Hz, 3H), 0.64 (d, J=
2.4 Hz, 3H), 0.02 (s, 3H), 0.00 ppm (s, 3H); 13C NMR (75 MHz, CD3OD,
mixture of rotamers): d=174.3, 150.3, 150.1, 141.3, 140.8, 130.7, 128.7,
113.7, 113.5, 112.6, 112.2, 112.0, 111.8, 57.4, 57.2, 52.7, 38.5, 36.4, 36.3,
33.5, 33.0, 31.5, 30.7, 29.7, 27.0, 23.9, 23.6, 23.5, 19.9, À4.1, À4.3 ppm; IR
(neat): n˜ =2929, 1644, 1515, 1461, 1256, 1109 cmÀ1; MS (FAB+): m/z: 448
[M+H]+; HRMS (FAB+): m/z: calcd for C25H42O4NSi: 448.2883
[M+H]+; found: 448.2882.
(R)-1-(1-Allyl-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-methyl-
pentan-1-one (6): EDCI (1.7 g, 8.8 mmol) and HOBt (1.2 g, 8.8 mmol)
were added at ambient temperature to a solution of amine 7 (1.0 g,
4.3 mmol) and 4-methylvaleric acid (0.89 mL, 7.0 mmol) in CH2Cl2
(20 mL). The reaction mixture was stirred for 12 h, quenched with aque-
ous NH4Cl, and extracted with CH2Cl2. The organic layer was dried over
MgSO4 and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (EtOAc/hexane/CH2Cl2 1:4:1 to
1:2:1) to afford the homoallylic amide 6 (1.2 g, 86%) as a colorless oil.
The enantioselectivity was determined as 89% ee [chiral HPLC analysis
(DAICEL chiralpak AD-H, hexane/propan-2-ol 75:25), flow rate=
1.0 mLminÀ1, 238C, l =254 nm, retention time, major (9 min), minor
(17 min), 89% ee]: [a]2D0 =À115.9 (c=1.9, MeOH); 1H NMR (300 MHz,
CD3OD, mixture of rotamers): d=6.79 (s), 6.74 (s, 1H), 6.69 (s, 1H),
5.95–5.74 (m, 1H), 5.54 (dd, J=5.3, 8.8 Hz, 1H), 5.14–4.95 (m, 2H), 4.54
(dd, J=3.5, 13.0 Hz), 3.91 (ddd, J=2.9, 5.3, 13.5 Hz, 1H), 3.80 (s), 3.78
(s, 6H), 3.53 (ddd, J=4.95, 10.0, 13.7 Hz), 3.10 (ddd, J=4.95, 11.3,
12.9 Hz, 1H), 2.91–2.24 (m, 6H), 1.67–1.39 (m, 3H), 0.94–0.87 ppm (m,
6H); 13C NMR (100 MHz, CD3OD, mixture of rotamers): d=175.6,
175.4, 150.3, 150.1, 149.8, 137.2, 136.6, 130.9, 130.7, 128.4, 127.9, 119.6,
118.2, 113.9, 113.7, 112.6, 112.3, 58.2, 57.3, 57.2, 53.7, 43.0, 42.9, 41.9, 37.2,
36.5, 36.3, 33.4, 30.4, 29.8, 29.7, 29.3, 23.5 ppm; IR (neat): n˜ =2953, 1639,
1516, 1435, 1359, 1258, 1121, 1027 cmÀ1; MS (EI+): m/z: 331 [M]+;
HRMS (EI+): m/z: calcd for C20H29O3N: 331.2147 [M]+; found: 331.2135.
AHCTUNGTERG(NNUN 5S,6R,E)-6-(tert-Butyldimethylsilyloxy)-5-isobutyl-10,11-dimethoxy-
2,3,5,6-tetrahydrobenzo[d]azecin-4(1H)-one (3): iPrMgCl (0.51 mL of a
2.0m solution in THF, 1.0 mmol) was added dropwise at 808C to a solu-
tion of the enol ether 4 (230 mg, 0.51 mmol) in benzene (10 mL) and the
resulting solution was heated at reflux for 5 h. The reaction mixture was
quenched with H2O and extracted with EtOAc. The combined organic
layers were dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(EtOAc/hexane 1:3 with 5% MeOH) to afford the g,d-unsaturated
lactam 3 (175 mg, 76%) as a white solid: m.p. 1728C; [a]2D0 =À171.1 (c=
0.22, MeOH); 1H NMR (300 MHz, CD3OD): d=7.68 (t, J=6.2 Hz, 1H),
6.67 (s, 1H), 6.61 (s, 1H), 6.34 (d, J=16.2 Hz, 1H), 5.31 (dd, J=8.2,
16.4 Hz, 1H), 3.98 (t, J=8.8 Hz, 1H), 3.72–3.60 (m, 1H), 3.67 (s, 3H),
3.65 (s, 3H), 3.20 (dt, J=3.5, 12.8 Hz, 1H), 2.64 (ddt, J=2.5, 4.7, 10.8 Hz,
1H), 2.13 (td, J=2.6, 11.3 Hz, 1H), 2.00 (dt, J=2.1, 9.5 Hz, 1H), 1.59
(dd, J=8.9, 11.3 Hz, 1H), 1.39–1.30 (m, 2H), 0.80 (s, 9H), 0.75 (d, J=
6.2 Hz, 3H), 0.68 (d, J=6.0 Hz, 3H), 0.00 ppm (s, 6H); 13C NMR
(75 MHz, CD3OD): d=178.3, 150.4, 150.1, 139.7, 134.4, 133.0, 131.6,
116.0, 111.7, 79.0, 57.4, 56.6, 45.1, 45.0, 38.4, 32.2, 28.8, 27.1, 25.0, 22.9,
(R)-2-[6,7-Dimethoxy-2-(4-methylpentanoyl)-1,2,3,4-tetrahydroisoquino-
lin-1-yl]acetaldehyde (5): OsO4 (0.05m in toluene, 1.0 mL, 0.05 mmol)
was added to
a solution of N-methylmorpholine N-oxide (330 mg,
2.8 mmol) in acetone (2 mL) and H2O (2 mL). After the system had been
stirred for 10 min, the homoallylic amide 6 (310 mg, 0.93 mmol) in ace-
tone (2 mL) was added and the reaction mixture was stirred for an addi-
tional 12 h. NaIO4 (590 mg, 2.8 mmol) was added and the reaction mix-
ture was stirred for 30 min. The reaction mixture was quenched with
Na2SO3 at 08C and filtered, and the combined layers were extracted with
EtOAc. The combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/hexane 2:1) to afford the aldehyde
5 (275 mg, 88%) as colorless crystals. [a]2D0 =À114.0 (c=0.86, CHCl3);
1H NMR (300 MHz, CDCl3, mixture of rotamers): d=9.81–9.76 (m, 1H),
6.62 (s, 1H), 6.57 (s, 1H), 6.00 (q, J=4.6 Hz, 1H), 3.91–3.76 (m, 1H),
3.81 (s, 6H), 3.47 (ddd, J=4.5, 10.2, 13.3 Hz, 1H), 3.13–2.66 (m, 4H),
2.46–2.23 (m, 1H), 2.33 (q, J=8.2 Hz, 1H), 1.61–1.44 (m, 2H), 0.88 (d,
J=2.4 Hz, 3H), 0.86 ppm (d, J=2.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3, mixture of rotamers): d=200.0, 199.2, 172.5, 172.2, 148.2, 148.0,
147.9, 147.6, 127.8, 127.7, 126.4, 125.5, 111.6, 111.1, 109.6, 108.9, 55.9,
55.8, 51.8, 51.1, 49.9, 47.7, 40.1, 35.8, 34.0, 33.8, 33.5, 31.7, 31.6, 31.3, 28.6,
27.7, 27.5, 27.3, 22.4, 22.3, 22.2, 22.1 ppm; IR (neat): n˜ =2954, 1720, 1637,
1516, 1460, 1360, 1258, 1122 cmÀ1; MS (EI+): m/z: 333 [M]+; HRMS
(EI+): m/z: calcd for C19H27O4N: 333.1940 [M]+; found: 333.1976.
19.8, À3.0, À3.8 ppm; IR (neat): n˜ =2924, 1631, 1458, 1257, 1099 cmÀ1
;
MS (EI+): m/z: 447 [M]+; HRMS (EI+): m/z: calcd for C25H41O4NSi:
447.2805; found: 447.2825 [M]+.
(2R,3S,11bR)-2-Hydroxy-3-isobutyl-9,10-dimethoxy-2,3,6,7-tetrahydro-
1H-pyrido
droxy-3-isobutyl-9,10-dimethoxy-2,3,6,7-tetrahydro-1H-pyrido
quinolin-4(11bH)-one (9’): pTSA·H2O (23 mg, 0.12 mmol) was added to
ACHUTGTNRENN[GU 2,1-a]isoquinolin-4ACTHUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
a solution of the lactam 3 (40 mg, 89 mmol) in benzene (5 mL). The mix-
ture was stirred for 12 h at ambient temperature and additional
pTSA·H2O (23 mg, 0.12 mmol) was added. The reaction mixture was
stirred for an additional 12 h, quenched with H2O, and extracted with
EtOAc. The combined organic layers were dried over MgSO4 and con-
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Chem. Eur. J. 2010, 16, 4623 – 4628