Stereoselective synthesis of cis-1,3-dimethyltetrahydroisoquinolines: Formal synthesis of naphthylisoquinoline alkaloids

Article abstract of DOI:10.1002/ejoc.201200798

A synthetic route to enantiopure cis-1,3-dimethyltetrahydroisoquinolines, synthetic precursors of naphthylisoquinoline alkaloids, has been developed. The synthesis relies on the use of a phenylglycinol-derived lactam as the starting enantiopure scaffold. After stereoselective opening of the oxazolidine ring, the C-3 methyl substituent was installed, taking advantage of the lactam carbonyl group by stereoselective hydrogenation of an α-methylenamide generated via a vinyl triflate.

Full text of DOI:10.1002/ejoc.201200798

Job/Unit: O20798
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Date: 14-08-12 16:34:01
Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201200798
Stereoselective Synthesis of cis-1,3-Dimethyltetrahydroisoquinolines:
Formal Synthesis of Naphthylisoquinoline Alkaloids
Mercedes Amat,*[a] Fabiana Subrizi,[a] Viviane Elias,[a] Núria Llor,[a] Elies Molins,[b] and
Joan Bosch[a]
Dedicated to Professor Miguel A. Miranda on the occasion of his 60th birthday
Keywords: Asymmetric synthesis / Total synthesis / Nitrogen heterocycles / Lactams / Alkaloids
A
synthetic route to enantiopure cis-1,3-dimethyltetra- azolidine ring, the C-3 methyl substituent was installed, tak-
hydroisoquinolines, synthetic precursors of naphthylisoquin-
oline alkaloids, has been developed. The synthesis relies on
the use of a phenylglycinol-derived lactam as the starting
enantiopure scaffold. After stereoselective opening of the ox-
ing advantage of the lactam carbonyl group by stereoselec-
tive hydrogenation of an α-methylenamide generated via a
vinyl triflate.
Introduction
The naphthylisoquinoline alkaloids[1] constitute a re-
markable group of structurally diverse natural products
with an unprecedented origin,[2] arising from acetate and
malonate units rather than aromatic amino acids. Their
characteristic substitution pattern includes a stereogenic bi-
aryl axis and an unusual methyl substituent at the 3-posi-
tion of the isoquinoline ring. They exhibit a broad spectrum
of important biological activities, among them antimalarial,
antileishmanial, antitrypanosomal, antitumor, and anti-
HIV. Many of these alkaloids incorporate a 6,8-dioxygen-
ated 1,3-dimethyltetrahydroisoquinoline moiety, in some
cases with a 1,3-cis relative configuration, for example, anci-
strocline, ancistrobrevines A and D, korupensamine D, and
ancistrotectorine (Figure 1). A few naphthalene-devoid 1,3-
dimethyltetrahydroisoquinolines also occur in nature,[3]
such as gentrymine A, which is the free heterocyclic half of
ancistrobrevine D.
Figure 1. Naphthylisoquinoline alkaloids.
these heterocyclic building blocks has received considerable
attention. However, all previous synthetic approaches to
cis-1,3-dimethyltetrahydroisoquinolines 9 involve the re-
duction (NaBH4 or H2, Pd/C) of the corresponding 3,4-
dihydro derivatives,[4] usually prepared by Bischler–Napier-
alski cyclization.[4a–4d,4f,4g]
These alkaloids are usually assembled through bond for-
mation between naphthalene and tetrahydroisoquinoline
rings in the key synthetic step, so the development of ef-
ficient procedures for the stereocontrolled construction of
Results and Discussion
We herein report a practical procedure for the synthesis
of enantiopure cis-1,3-dimethyltetrahydroisoquinolines 9.
From the stereochemical standpoint, the synthesis involves
two crucial steps: (1) the stereoselective preparation of an
enantiopure 1-methyl-3-oxotetrahydroisoquinoline deriva-
tive 4 by cyclocondensation of δ-keto acid 1 with (R)-phen-
ylglycinol,[5] followed by removal of the chiral inductor
from the resulting tricyclic lactam; and (2) the stereoselec-
tive introduction of the C-3 methyl substituent, taking ad-
vantage of the lactam carbonyl group (Scheme 1).
[a] Laboratory of Organic Chemistry, Faculty of Pharmacy, and
Institute of Biomedicine (IBUB), University of Barcelona,
Av. Joan XXIII s/n, 08028 Barcelona, Spain
Fax: +34-934-024-539
E-mail: amat@ub.edu
Homepage: http://www.ub.edu/sintefarma/
[b] Institut de Ciència de Materials de Barcelona (CSIC),
Campus UAB, 08193 Cerdanyola, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200798.
Eur. J. Org. Chem. 0000, 0–0
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M. Amat, F. Subrizi, V. Elias, N. Llor, E. Molins, J. Bosch
FULL PAPER
Scheme 3. Lactamization step.
sodium in liquid ammonia brought about the cleavage of
the exocyclic C–N bond to give the key tetrahydroisoquin-
olone intermediate 4a. Further reduction of 4a with
NaBH4/I2, followed by treatment with Pd/C in MeOH to
cleave[10] the resulting N-epimeric mixture of amino–borane
complexes, led to amine 6, which was also prepared by
LiAlH4 reduction of 3 followed by debenzylation of the re-
sulting tertiary amine 5.
The stereoselective introduction of the C-3 substituent
from lactam 4a was accomplished by hydrogenation of an
α-substituted enamide generated by alkylation of the lactam
carbonyl, activated as a vinyl triflate.[11] To this end, lactam
4a was converted into the N-protected derivatives 4b and
4c (Scheme 4). The N-acyl substituent not only acts as a
protecting group, but also increases the facial selectivity of
hydrogen uptake. The conversion of lactams 4b and 4c into
the corresponding vinyl triflates 7b and 7c was satisfactorily
accomplished with LiHMDS and Comins’ triflating rea-
Scheme 1. Synthetic strategy for the preparation of enantiopure cis-
1,3-dimethyltetrahydroisoquinolines 9.
In the reaction with 1,5-dicarbonyl derivative 1,[6] (R)-
phenylglycinol acts as a chiral latent form of ammonia in
a process that mimics the presumed biosynthetic origin of
acetogenin isoquinoline alkaloids.[7] The cyclocondensation
reaction gave a single tricyclic lactam 2 (Scheme 2), the ab-
solute configuration of which was unambiguously estab-
lished by X-ray crystallographic analysis.[8]
Scheme 2. Preparation of the key 1-methyl-3-oxotetrahydroisoquin-
oline intermediate 4a.
A tentative explanation for the 3-H/10b-Me relative trans
configuration is that the initially formed imine is in equilib-
rium with two diastereoisomeric oxazolidines and that the
irreversible final lactamization occurs faster from the ox-
azolidine that allows a less hindered approach of the ester
group to the nitrogen, as depicted in Scheme 3.
Scheme 4. Access to enantiopure cis-1,3-dimethyltetrahydroiso-
quinolines. Formal synthesis of the naphthylisoquinoline alkaloids
10[17] and 11.[18] LiHMDS = lithium bis(trimethylsilyl)amide, Boc
= tert-butyloxycarbonyl, TMSOTf = trifluoromethanesulfonic acid
The reductive opening of the oxazolidine ring was per-
formed with Red-Al and also took place in excellent yield
with complete stereoselectivity (retention of configura-
tion)[9] to give bicyclic lactam 3. Subsequent treatment with trimethylsilyl ester.
2
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Stereoselective Synthesis of cis-1,3-Dimethyltetrahydroisoquinolines
gent.[12] Subsequent alkylation with lithium methylcuprate
Given that a variety of enantiopure 1-substituted 3-oxo-
(generated in situ from MeLi and CuI), with final quench- tetrahydroisoquinolines are easily available by cycloconden-
ing with methyl iodide,[11] afforded the methylated enamides sation of 2-formylphenylacetic esters with phenylglycinol
8b and 8c in 72 and 81% overall yield, respectively, from followed by α-amidoalkylation of the resulting tricyclic lac-
4a.
tams,[19] the methodology developed herein opens a general
Finally, catalytic hydrogenation of 8b and 8c under synthetic route to enantiopure cis-1,3-disubstituted tetra-
slightly acidic conditions (MeOH, 1.5 equiv. of aq. HCl, hydroisoquinolines.
room temp., 1 atm) using Pd/C as the catalyst took place
with complete facial selectivity, leading to the respective N-
acyl-1,3-cis-dimethyltetrahydroisoquinolines 9b and 9c in
Experimental Section
high yield.[13,14]
(3R,10bS)-8,10-Dimethoxy-10b-methyl-5-oxo-3-phenyl-2,3,6,10b-
Unexpectedly, deprotection of the N-Boc derivative 9b
with trifluoroacetic acid (TFA) led to a 4:6 epimeric mix-
ture of cis and trans derivatives 9a and 1-epi-9a, presumably
tetrahydro-5H-oxazolo[2,3-a]isoquinoline (2): A solution of com-
pound 1 (1.15 g, 4.81 mmol) and (R)-phenylglycinol (790 mg,
2.26 mmol) in toluene (40 mL) was heated at reflux for 22 h in a
Dean–Stark system. The solvent was removed under reduced pres-
through a retro-Michael ring-opening process favored by
the methoxy groups, as outlined in Scheme 5.[15]
sure and the residue was purified by flash chromatography under
silica (hexane to 7:3 hexane/EtOAc) to afford compound 2 (1.06 g,
65%) as a brown solid. [α]2D2 = –211.1 (c = 1.0, CHCl3). H NMR
1
(400 MHz, CDCl3, COSY, HETCOR, 25 °C): δ = 1.72 (s, 3 H,
CH3), 3.71 (d, J = 19.0 Hz, 1 H, 6-H), 3.77 (d, J = 19.0 Hz, 1 H,
6-H), 3.81 (s, 3 H, CH3O), 3.89 (s, 3 H, CH3O), 4.11 (dd, J = 9.2,
8.0 Hz, 1 H, 2-H), 4.59 (t, J = 8.4 Hz, 1 H, 2-H), 5.33 (t, J =
8.0 Hz, 1 H, 3-H), 6.30 (d, J = 2.4 Hz, 1 H, 9-H), 6.45 (d, J =
2.4 Hz, 1 H, 7-H), 7.30 (m, 5 H, ArH) ppm. 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ = 24.9 (CH3), 37.9 (C-6), 55.3 (CH3O), 56.0 (C-
3), 58.2 (CH3O), 70.4 (C-2), 95.1 (C-10b), 98.4 (C-9), 103.1 (C-7),
118.3 (C-6a), 125.6 (C-m), 127.2 (C-p), 128.6 (C-o), 132.3 (C-10a),
139.4 (C-i), 157.4 and 160.6 (C-i), 166.2 (CO) ppm. IR (KBr): ν =
˜
1514, 1610, 1660, 2256, 2977 cm–1. HRMS (ESI-TOF): calcd. for
C20H21NO4 [M + H]+ 340.1549; found 340.1543.
(1R)-2-[(R)-2-Hydroxy-1-phenylethyl]-6,8-dimethoxy-1-methyl-3-
oxo-1,2,3,4-tetrahydroisoquinoline (3): Red-Al (2 mL of a 65% solu-
tion in toluene, 6.5 mmol) was slowly added (10 min) to a cooled
solution (–78 °C) of lactam 2 (220 mg, 0.65 mmol) in anhydrous
CH2Cl2 (2 mL). The resulting solution was stirred at 0 °C for 1 h
and poured into crushed ice. The aqueous layer was extracted with
CH2Cl2, and the combined organic extracts were dried, filtered,
and concentrated. Flash chromatography (2:8 Et2O-EtOAc) af-
forded compound 3 (212 mg, 96%) as a white solid. [α]2D2 = +13.9
Scheme 5. Epimerization of 6,8-dioxygenated cis-1,3-disubstituted
tetrahydroisoquinolines.
This problem was overcome by using TMSOTf/2,6-lutid-
ine[16] (see Scheme 4), which allowed removal of the N-Boc
to be achieved in high yield, leading to the N-unsubstituted
1,3-cis derivative 9a; an early intermediate in a previous
synthesis of korupensamine D.[4c,4d] On the other hand,
LiAlH4 reduction of the N-methoxycarbonyl derivative 9c
led to the N-methyl-cis-tetrahydroisoquinoline 9d. Com-
parison of the sign of the [α] value of 9d with that pre-
viously reported for this compound[17] confirmed the 1R,3S
absolute configuration of our synthetic material. Taking
into account previous transformations, the synthesis of teta-
hydroisoquinoline 9d constitutes a formal synthesis of O-
methylancistrocline (10)[17] and 5-epi-4Ј-O-demethyl-ancis-
trobertsonine C (11).[18]
1
(c = 1.0, CHCl3). H NMR (400 MHz, CDCl3, COSY, HETCOR,
25 °C): δ = 1.10 (d, J = 6.4 Hz, 3 H, CH3), 3.56 (d, J = 18.8 Hz, 1
H, 4-H), 3.73 (s, 3 H, CH3O), 3.75 (d, J = 18.8 Hz, 1 H, 4-H), 3.77
(s, 3 H, CH3O), 4.10 (dd, J = 12.0, 4.4 Hz, 1 H, CH2OH), 4.28 (dd,
J = 12.0, 7.6 Hz, 1 H, CH2OH), 4.71 (q, J = 6.4 Hz, 1 H, 1-H),
5.15 (dd, J = 7.6, 4.4 Hz, 1 H, CHAr), 6.25 (d, J = 2.0 Hz, 1 H, 7-
H), 6.30 (d, J = 2.0 Hz, 1 H, 5-H), 7.24–7.34 (m, 5 H, ArH) ppm.
13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 19.9 (CH3), 38.2 (C-4),
51.0 (C-1), 55.3 (2CH3O), 63.2 (CH2OH), 63.7 (CHAr), 96.7 (C-
7), 102.8 (C-5), 118.5 (C-4a), 127.5 (C-p), 127.8 (C-o), 128.4 (C-m),
133.4 (C-8a), 136.9 (C-i), 155.1 and 160.0 (C-i), 170.6 (CO) ppm.
IR (KBr): ν = 1513, 1629, 2240, 3400 cm–1. HRMS (ESI-TOF):
˜
calcd. for C20H23NO4 [M + H]+ 342.1699; found 342.1703.
Conclusions
(R)-6,8-Dimethoxy-1-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline
(4a): NH3 (35 mL) was condensed at –78 °C in a three-necked
round-bottomed flask equipped with a cold-finger condenser
charged with dry ice/acetone. The temperature was raised to –33 °C
and a solution of lactam 3 (322 mg, 0.94 mmol) in THF (3 mL)
was added. Then, sodium metal was added in small portions until
a blue color persisted. The mixture was stirred at –33 °C for 1 min.
The reaction was quenched by the addition of solid NH4Cl until
the blue color disappeared. The mixture was stirred at room tem-
We have reported a new strategy for the synthesis of
enantiopure cis-1,3-dimethyltetrahydroisoquinolines
9
based on the use of phenylglycinol-derived tricyclic lactam
2 as the starting enantiopure scaffold. After stereoselective
opening of the oxazolidine ring, the cis-1,3 relative configu-
ration was installed by stereoselective hydrogenation of an
α-methylenamide generated via a vinyl triflate.
Eur. J. Org. Chem. 0000, 0–0
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M. Amat, F. Subrizi, V. Elias, N. Llor, E. Molins, J. Bosch
FULL PAPER
perature for 4 h, poured into water, and extracted with CH2Cl2.
The combined organic extracts were dried and concentrated to give
a clear residue, which was purified by chromatography (EtOAc) to
ture was heated at reflux for 20 h and cooled to 0 °C. MeOH
(5 mL) was slowly added and the stirring was continued at room
temp. for 30 min. The solvent was evaporated and the resulting
solid was digested with 2 n aqueous KOH (30 min). The resulting
afford 4a (201 mg, 97%) as a white solid; m.p. 168–171 °C. [α]2D2
=
–31.5 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3, COSY, suspension was extracted with CH2Cl2 and the combined organic
HETCOR, 25 °C): δ = 1.38 (d, J = 6.9 Hz, 3 H, CH3), 3.45 (d, J
= 20.0 Hz, 1 H, 4-H), 3.65 (d, J = 20.0 Hz, 1 H, 4-H), 3.79 (s, 3
extracts were dried and concentrated. The resulting residue was
dissolved in MeOH (2 mL) and stirred for 12 h in the presence of
H, CH3O), 3.81 (s, 3 H, CH3O), 4.75–4.82 (m, 1 H, 1-H), 6.25 (d, 5% Pd/C (15 mg, 55% wet). The suspension was filtered, and the
J = 2.2 Hz, 1 H, 7-H), 6.34 (d, J = 2.2 Hz, 1 H, 5-H), 7.44 (br. s, filtrate was concentrated. Column chromatography (SiO2 pre-
NH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 23.4 (CH3), viously washed with TEA; 95:5 CH2Cl2/MeOH to, 90:5:5 CH2Cl2/
35.8 (C-4), 47.2 (C-1), 55.2 (CH3O), 55.3 (CH3O), 96.8 (C-7), 103.1 MeOH/TEA as eluent) of the residue afforded an oil (61 mg),
(C-5), 117.4 (C-4a), 132.9 (C-8a), 156.0 and 159.8 (C-i), 171.3 (CO) which was dissolved in CH2Cl2 (8 mL). The solution was washed
ppm. IR (KBr): ν = 1517, 1668, 2966, 3217 cm–1. HRMS (ESI-
with a saturated aqueous solution of NaHCO3, dried, filtered, and
evaporated to afford 6 as a yellow oil (40 mg, 43%).
˜
TOF): calcd. for C12H15NO3 [M + H]+ 222.1124; found 222.1121.
Method B: LiAlH4 (90 mg, 2.4 mmol) was added to a solution of
lactam 3 (200 mg, 0.6 mmol) in THF (5 mL) at 0 °C. The mixture
was stirred at room temp. for 2.5 h, cooled to 0 °C, and quenched
with MeOH, water, and 10% aqueous NaOH. The aqueous layer
was extracted with CH2Cl2, and the combined organic extracts
were dried and concentrated. Column chromatography (15:85 hex-
ane/EtOAc) of the residue afforded (1R)-2-[(R)-2-hydroxy-1-phen-
ylethyl]-6,8-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline (5;
110 mg, 56%) as a dark yellow oil. [α]2D2 = –39.2 (c = 0.5, CHCl3).
1H NMR (400 MHz, CDCl3, COSY, HETCOR, 25 °C): δ = 1.36
(d, J = 6.8 Hz, 3 H, CH3), 2.58 (m, 2 H, 4-H), 2.65 (m, 1 H, 3-H),
3.10 (m, 1 H, 3-H), 3.75 (s, 3 H, CH3O), 3.76 (s, 3 H, CH3O), 3.84
(m, 2 H, CH2OH), 3.88 (m, 1 H, CHAr), 4.23 (q, J = 6.4 Hz, 1 H,
1-H), 6.19 (s, 1 H, 7-H), 6.27 (s, 1 H, 5-H), 7.24–7.34 (m, 5 H,
ArH) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 20.3 (CH3),
27.9 (C-4), 39.7 (C-3), 49.0 (C-1), 55.1 (CH3O), 55.2 (CH3O), 62.0
(CH2OH), 64.7 (CHAr), 96.4 (C-5), 103.9 (C-7), 120.9 (C-8a),
127.6 (C-p), 128.2 (C-o), 128.7 (C-m), 136.5 (C-4a), 138.7 (C-i),
(R)-2-(tert-Butoxycarbonyl)-6,8-dimethoxy-1-methyl-3-oxo-1,2,3,4-
tetrahydroisoquinoline (4b): nBuLi (1.6 m in hexane, 0.28 mL,
0.45 mmol) was added to a solution of lactam 4a (100 mg,
0.45 mmol) in THF (5 mL) at –78 °C. After stirring for 20 min, the
mixture was transferred by cannula into a cooled (–78 °C) solution
of di-tert-butyl dicarbonate (142 mg, 0.68 mmol) in THF (2 mL).
After stirring for 40 min, a saturated aqueous solution of NH4Cl
was added. The aqueous layer was extracted with EtOAc. The com-
bined organic layers were dried, filtered, and concentrated under
vacuum. The residue was purified by flash chromatography (hexane
to 7:3 hexane/EtOAc) to afford compound 4b (112 mg, 78%) as a
white oil. [α]2D2 = –55.4 (c = 1.02, CHCl3). 1H NMR (400 MHz,
CDCl3, COSY, HETCOR, 25 °C): δ = 1.41 (d, J = 6.6 Hz, 3 H,
CH3), 1.56 [s, 9 H, C(CH3)3], 3.58 (d, J = 19.5 Hz, 1 H, 4-H), 3.79
(s, 3 H, CH3O), 3.80 (d, J = 19.5 Hz, 1 H, 4-H), 3.83 (s, 3 H,
CH3O), 5.64 (q, J = 6.6 Hz, 1 H, 1-H), 6.25 (d, J = 1.8 Hz, 1 H,
7-H), 6.36 (d, J = 1.8 Hz, 1 H, 5-H) ppm. 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ = 20.3 (CH3), 27.9 [C(CH3)3], 39.7 (C-4), 49.3 (C-
1), 55.3 (2CH3O), 82.9 [C(CH3)3], 96.7 (C-5), 102.6 (C-7), 117.9 (C-
8a), 132.6 (C-4a), 152.0 (C-i), 155.5 (NCO), 160.1 (C-i), 169.4 (CO)
157.3 and 158.5 (C-i) ppm. IR (KBr): ν = 3417, 2936 cm–1. HRMS
˜
(ESI-TOF): calcd. for C20H25NO3 [M + H]+ 328.1907; found
328.1904. A solution of the above amine (110 mg, 0.34 mmol) in
EtOH (7.4 mL), 1 n aqueous HCl (739 μL), and 5% Pd/C (226 mg,
55% wet) was hydrogenated at room temperature and atmospheric
pressure for 6 h. The catalyst was removed by filtration, the solvent
was evaporated, and the resulting residue was washed with 1 n
aqueous HCl and extracted with Et2O. The aqueous phase was
basified with saturated aqueous NaHCO3 and extracted with
CH2Cl2. The combined organic extracts were dried and concen-
trated to give a residue, which was purified by column chromatog-
raphy (SiO2 previously washed with TEA; 95:5 CH2Cl2/MeOH to,
90:5:5 CH2Cl2/MeOH/TEA as eluent) to afford 6 (66 mg, 94%) as
a dark yellow oil. [α]2D2 = +10.3 (c = 1.95, CHCl3). 1H NMR
(300 MHz, CDCl3, COSY, HETCOR, 25 °C): δ = 1.39 (d, J =
6.6 Hz, 3 H, CH3), 2.40 (br. s, 1 H, NH), 2.66 (dt, J = 16.5, 3.9 Hz,
1 H, 4-H), 2.80 (dq, J = 16.5, 10.2, 6.3 Hz, 1 H, 4-H), 3.03 (dq, J
= 13.2, 5.7, 3.3 Hz, 1 H, 3-H), 3.21 (dq, J = 13.2, 9.9, 5.1 Hz, 1 H,
3-H), 3.77 (s, 3 H, CH3O), 3.78 (s, 3 H, CH3O), 4.24 (q, J = 6.6 Hz,
1 H, 1-H), 6.22 (d, J = 2.4 Hz, 1 H, 7-H), 6.29 (d, J = 2.4 Hz, 1
H, 5-H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 20.8
(CH3), 29.7 (C-4), 37.9 (C-3), 46.3 (C-1), 55.0 (CH3O), 55.1
(CH3O), 96.3 (C-5), 104.3 (C-7), 121.7 (C-8a), 136.0 (C-4a), 157.1
ppm. IR (KBr): ν = 1441, 1502, 1606, 1710, 1776, 2957 cm–1
.
˜
HRMS (ESI-TOF): calcd. for C17H23NO5 [M + H]+ 322.1653;
found 322.1649.
(R)-6,8-Dimethoxy-2-(methoxycarbonyl)-1-methyl-3-oxo-1,2,3,4-
tetrahydroisoquinoline (4c): Operating as in the above preparation
of 4b, from lactam 4a (285 mg, 1.29 mmol) in THF (10 mL), nBuLi
(1.6 m in hexane, 0.81 mL, 1.29 mmol), and dimethyl dicarbonate
(210 mg, 1.55 mmol) in THF (7 mL), tetrahydroisoquinoline 4c
(335 mg, 93%) was obtained as a white oil after flash chromatog-
raphy (7:3 hexane/EtOAc). [α]2D2 = –65.4 (c = 1.03, CHCl3). 1H
NMR (400 MHz, CDCl3, COSY, HETCOR, 25 °C): δ = 1.42 (d, J
= 6.4 Hz, 3 H, CH3), 3.62 (d, J = 19.2 Hz, 1 H, 4-H), 3.79 (s, 3 H,
CH3O), 3.82 (d, J = 19.2 Hz, 1 H, 4-H), 3.83 (s, 3 H, CH3O), 3.91
(s, 3 H, CH3O), 5.73 (q, J = 6.4 Hz, 1 H, 1-H), 6.26 (d, J = 1.6 Hz,
1 H, 7-H), 6.36 (d, J = 1.6 Hz, 1 H, 5-H) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 20.3 (CH3), 39.7 (C-4), 50.5 (C-
1), 53.9 (CO2CH3), 55.4 (2CH3O), 96.9 (C-5), 102.7 (C-7), 117.7
(C-8a), 132.4 (C-4a), 154.4 (NCO), 155.6 and 160.4 (C-i), 169.6
(CO) ppm. IR (KBr): ν = 1439, 1503, 1606, 1710, 1776, 2843,
˜
2956 cm–1. HRMS (ESI-TOF): calcd. for C14H17NO5 [M + H]+
280.1177; found 280.1179.
and 158.5 (C-i) ppm. IR (KBr): ν = 2935, 1606 cm–1. HRMS (ESI-
˜
TOF): calcd. for C12H17NO2 [M + H]+ 208.1332; found 208.1332.
(1R)-6,8-Dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline (6).
Method A: A solution of iodine (114 mg, 0.45 mmol) in THF
(2 mL) was slowly added to a cooled (0 °C) suspension of NaBH4
(42.7 mg, 1.13 mmol) in anhydrous THF (2.5 mL), and the mixture
was stirred at this temperature for 5 min (until the solution became
colorless). Then, a solution of lactam 4a (100 mg, 0.45 mmol) in
THF (2 mL) was added to the solution (0 °C). The resulting mix-
(R)-2-(tert-Butoxycarbonyl)-6,8-dimethoxy-1,3-dimethyl-1,2-dihy-
droisoquinoline (8b): LiHMDS (1 m in THF, 0.47 mL, 0.47 mmol)
was slowly added to a solution of lactam 4b (100 mg, 0.31 mmol)
in THF (1 mL) at –78 °C. After stirring for 3.5 h, a cooled solution
(–78 °C) of 2-[bis(trifluoromethylsulfonyl)amino]-5-chloropyridine
(183 mg, 0.47 mmol) in THF (4 mL) was added by cannula, and
4
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Stereoselective Synthesis of cis-1,3-Dimethyltetrahydroisoquinolines
the mixture was stirred at room temp. for 16 h. EtOAc (35 mL) was
added and the organic layer was washed with water, dried, filtered,
and concentrated. The resulting residue was purified by column
chromatography (95:5 hexane/EtOAc) to give (R)-2-(tert-butoxy-
carbonyl)-6,8-dimethoxy-1-methyl-3-(trifluoromethylsulfonyloxy)-
chromatography (CH2Cl2). [α]2D2 = –327.7 (c = 1.25, CHCl3). 1H
NMR (400 MHz, CDCl3, COSY, HETCOR, 25 °C): δ = 1.18 (d, J
= 6.4 Hz, 3 H, CH3), 2.24 (s, 3 H, CCH3), 3.75 (s, 3 H, CH3O),
3.77 (s, 3 H, CH3O), 3.79 (s, 3 H, CH3O), 5.71 (q, J = 6.4 Hz, 1
H, 1-H), 5.89 (d, J = 1.2 Hz, 1 H, 4-H), 6.18 (d, J = 2.4 Hz, 1 H,
7-H), 6.29 (d, J = 2.4 Hz, 1 H, 5-H) ppm. 13C NMR (100.6 MHz,
1,2-dihydroisoquinoline (7b; 130 mg, 94%) as a yellow oil. [α]2D2
=
–30.3 (c = 1.85, CHCl3). 1H NMR (400 MHz, CDCl3, COSY, CDCl3, 25 °C): δ = 18.3 (CH3), 21.8 (CCH3), 47.2 (C-1), 52.7
HETCOR, 25 °C): δ = 1.24 (d, J = 7.0 Hz, 3 H, CH3), 1.50 [s, 9 (CO2CH3), 55.3 (2CH3O), 96.8 (C-5), 100.4 (C-7), 113.6 (C-4),
H, C(CH3)3], 3.80 (s, 3 H, CH3O), 3.82 (s, 3 H, CH3O), 5.80 (q, J 116.5 (C-8a), 132.1 (C-3), 135.1 (C-4a), 154.2 (NCO), 155.1 (C-6),
= 7.0 Hz, 1 H, 1-H), 6.10 (s, 1 H, 4-H), 6.32 (d, J = 2.4 Hz, 1 H, 159.6 (C-8) ppm. IR (KBr): ν = 1321, 1442, 1603, 1643, 1713, 2842,
˜
7-H), 6.40 (d, J = 2.4 Hz, 1 H, 5-H) ppm. 13C NMR (100.6 MHz, 2957 cm–1. HRMS (ESI-TOF): calcd. for C15H19NO4 [M + H]+
CDCl3, 25 °C): δ = 18.3 (CH3), 27.9 [C(CH3)3], 49.7 (C-1), 55.4 278.1388; found 278.1387.
(CH3O), 55.5 (CH3O), 83.3 [C(CH3)3], 98.6 (C-7), 102.1 (C-5),
(1R,3S)-2-(tert-Butoxycarbonyl)-6,8-dimethoxy-1,3-dimethyl-
106.3 (C-4), 117.3 (C-8a), 116.8 (CF3), 118.4 (q, J = 320.9 Hz,
1,2,3,4-tetrahydroisoquinoline (9b): A solution of 8b (43 mg,
CF3), 129.7 (C-3), 139.1 (C-4a), 151.4 (NCO), 155.4 and 160.0 (C-
0.14 mmol) in MeOH (8 mL), 2 n aqueous HCl (105 μL), and 5%
i) ppm. IR (KBr): ν = 1459, 1501, 1607, 1718, 1770, 2976 cm–1.
˜
Pd/C (21 mg, 55% wet) was hydrogenated at room temp. and atmo-
spheric pressure for 6 h. The catalyst was removed by filtration and
the solvent was evaporated. The resulting residue was diluted in
CH2Cl2 (15 mL) and the solution was washed with water. The or-
ganic layer was dried and concentrated to give 9b (44 mg, 97%).
[α]2D2 = –29.9 (c = 0.5, CHCl3). 1H NMR (400 MHz, CDCl3, COSY,
HETCOR, 25 °C): δ = 1.33 (d, J = 6.6 Hz, 3 H, CH2CHCH3), 1.40
(d, J = 6.6 Hz, 3 H, CHCH3), 1.48 [s, 9 H, C(CH3)3], 2.68 (dd, J
= 15.9, 6.9 Hz, 1 H, 4-H), 2.94 (dd, J = 15.9, 6.9 Hz, 1 H, 4-H),
3.78 (s, 3 H, CH3O), 3.79 (s, 3 H, CH3O), 3.80 (br. s, 1 H, 3-H),
5.68 (q, J = 6.6 Hz, 1 H, 1-H), 6.26 (d, J = 2.4 Hz, 1 H, 7-H), 6.32
(d, J = 2.4 Hz, 1 H, 5-H) ppm. 13C NMR (100.6 MHz, CDCl3,
25 °C): δ = 14.1 (CH2CHCH3), 22.6 (CHCH3), 28.5 [C(CH3)3], 31.9
(C-4), 35.4 (C-1), 46.8 (C-3), 55.2 (CH3O), 55.3 (CH3O), 79.2
[C(CH3)3], 96.6 (C-7), 112.8 (C-5), 132.3 (C-8a), 154.8 (C-4a), 156.3
HRMS (ESI-TOF): calcd. for C18H22F3NO7 S [M + H]+ 454.1147;
found 454.1142. MeLi (1.6 m in THF, 47 μL, 0.76 mmol) was added
to a suspension of CuI (102.8 mg, 0.54 mmol) in THF (2.3 mL) at
0 °C. After stirring for 20 min, the mixture was transferred by can-
nula into a cooled (0 °C) solution of the above triflate (70 mg,
0.15 mmol) in THF (1.2 mL). The mixture was stirred for 3.5 h,
quenched with MeI (29 μL, 0.462 mmol), and stirred at room temp.
for 40 min. The solvent was evaporated, the residue was taken up
with EtOAc (30 mL) and washed with a saturated aqueous solution
of NH4Cl. The organic layer was dried, filtered, and concentrated.
Flash chromatography (CH2Cl2) of the residue afforded 8b
(48.4 mg, 97%) as a green oil. [α]2D2 = –331.1 (c = 0.75, CHCl3). 1H
NMR (400 MHz, CDCl3, COSY, HETCOR, 25 °C): δ = 1.15 (d, J
= 6.8 Hz, 3 H, CH3), 1.49 [s, 9 H, C(CH3)3], 2.21 (s, 3 H, CCH3),
3.77 (s, 3 H, CH3O), 3.79 (s, 3 H, CH3O), 5.68 (q, J = 6.8 Hz, 1
H, 1-H), 5.83 (s, 1 H, 4-H), 6.18 (d, J = 2.4 Hz, 1 H, 7-H), 6.29 (d,
J = 2.4 Hz, 1 H, 5-H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C):
δ = 18.3 (CH3), 22.4 (CCH3), 28.3 [C(CH3)3], 46.8 (C-1), 55.3
(CH3O), 55.4 (CH3O), 80.8 [C(CH3)3], 96.6 (C-7), 100.1 (C-5),
112.8 (C-4), 116.8 (C-8a), 132.3 (C-3), 135.4 (C-4a), 152.8 (NCO),
(NCO), 159.1 (2C-i) ppm. IR (KBr): ν = 1458, 1609, 1690, 2853,
˜
2925, 2940 cm–1. EM (IQ+): m/z (%) = 306 (11), 265 (6), 264 (35),
251 (15), 250 (100), 220 (10), 207 (5), 206 (39), 191(4), 190 (9), 176
(4), 57 (11). HRMS (ESI-TOF): calcd. for C18H28NO4 [M + H]+
322.2013; found 322.1999.
155.2 and 159.5 (C-8) ppm. IR (KBr): ν = 1441, 1603, 1640, 1712,
˜
(1R,3S)-6,8-Dimethoxy-2-(methoxycarbonyl)-1,3-dimethyl-1,2,3,4-
tetrahydroisoquinoline (9c): Operating as described in the prepara-
tion of 9b, from 8c (100 mg, 0.36 mmol) in MeOH (10 mL), 2 n
aqueous HCl (270 μL), 5% of Pd/C (35 mg, 55% wet), compound
2956 cm–1. HRMS (ESI-TOF): calcd. for C18H25NO4 [M + H]+
320.1862; found 320.1856.
(R)-6,8-Dimethoxy-2-(methoxycarbonyl)-1,3-dimethyl-1,2-dihydro-
isoquinoline (8c): Operating as in the above preparation of 7b, from
a solution of lactam 4c (300 mg, 1.07 mmol) in THF (3.5 mL),
LiHMDS (1 m in THF, 1.61 mL, 1.61 mmol) and 2-[bis(trifluoro-
methylsulfonyl)amino]-5-chloropyridine in THF (12.5 mL), (R)-
6,8-dimethoxy-2-(methoxycarbonyl)-1-methyl-3-(trifluoromethyl-
sulfonyloxy)-1,2-dihydroisoquinoline (7c; 375 mg, 85 %) was ob-
tained as a yellow oil after flash chromatography (hexane to 85:15
hexane/EtOAc). [α]2D2 = –157.6 (c = 1.18, CHCl3). 1H NMR
(400 MHz, CDCl3, COSY, HETCOR, 25 °C): δ = 1.28 (d, J =
6.4 Hz, 3 H, CH3), 3.79 (s, 3 H, CO2CH3), 3.82 (s, 6 H, 2CH3O),
5.84 (q, J = 6.4 Hz, 1 H, 1-H), 6.17 (s, 1 H, 4-H), 6.33 (d, J =
2.0 Hz, 1 H, 7-H), 6.41 (d, J = 2.0 Hz, 1 H, 5-H) ppm. 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ = 18.2 (CH3), 50.2 (C-1), 53.6
1
9c (90 mg, 90%) was obtained. [α]2D2 = +13.0 (c = 1.0, CHCl3). H
NMR (400 MHz, CDCl3, COSY, HETCOR, 25 °C): δ = 1.27 (d, J
= 6.8 Hz, 3 H, CH2CHCH3), 1.34 (d, J = 6.8 Hz, 3 H, CHCH3),
2.62 (dd, J = 16.0, 6.4 Hz, 1 H, 4-H), 2.87 (dd, J = 16.0, 6.8 Hz, 1
H, 4-H), 3.65 (s, 3 H, CO2CH3), 3.71 (s, 3 H, CH3O), 3.72 (s, 3 H,
CH3O), 4.31 (br. s, 1 H, 3-H), 5.31 (br. s, 1 H, 1-H), 6.19 (d, J =
2.4 Hz, 1 H, 7-H), 6.25 (d, J = 2.4 Hz, 1 H, 5-H) ppm. 13C NMR
( 1 00 . 6 M H z , C D Cl3 , 25 °C ): δ = 20 . 6 (C HCH3 ), 21.7
(CH2CHCH3), 35.2 (C-4), 45.9 (C-1), 46.3 (C-3), 52.4 (CO2CH3),
55.2 (2CH3O), 96.4 (C-5), 104.1 (C-7), 118.9 (C-8a), 134.7 (C-4a),
156.2 (NCO), 159.2 (2C-i) ppm. HRMS (ESI-TOF): calcd. for
C15H21NO4 [M + H]+ 280.1543; found 280.1548.
(1R,3S)-6,8-Dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline
(CO2CH3), 55.4 (CH3O), 55.5 (CH3O), 98.8 (C-7), 102.3 (C-5), (9a): 2,6-Lutidine (56 mg, 0.48 mmol) and TMSOTf (65 μL,
106.9 (C-4), 116.8 (C-8a), 116.9 (CF3), 118.4 (q, J = 320.1 Hz, 0.36 mmol) were sequentially added to a solution of tetrahydroiso-
CF3), 129.5 (C-3), 138.4 (C-4a), 153.3 (NCO), 155.3 and 160.0 (C- quinoline 9b (37 mg, 0.12 mmol) in dry CH2Cl2 (308 μL), and the
8) ppm. IR (KBr): ν = 1439, 1502, 1612, 1729, 1776, 2850, 2927,
mixture was stirred at 0 °C for 1.5 h. The reaction was quenched
with a saturated aqueous solution of NH4Cl, and the resulting mix-
ture was extracted with CH2Cl2. The combined extracts were
washed with a saturated aqueous solution of NaHCO3, dried, and
concentrated to give 9a as yellow oil (27 mg, 98%). [α]2D2 = +73.0
(c = 0.44, CHCl3). 1H NMR (400 MHz, CDCl3, COSY, HETCOR,
25 °C): δ = 1.23 (d, J = 6.4 Hz, 3 H, CH2CHCH3), 1.44 (d, J =
˜
2956 cm–1. HRMS (ESI-TOF): calcd. for C15H16F3NO7 S [M +
H]+ 412.0677; found 412.0672. Following the procedure reported
for the preparation of 8b, from the above vinyl triflate (270 mg,
0.66 mmol) in THF (5 mL), MeLi (1.6 m in THF, 2 mL, 3.2 mmol),
CuI (438 mg, 2.3 mmol) in THF (10 mL), and MeI (0.12 mL,
1.97 mmol), compound 8c (180 mg, 99%) was obtained after flash
Eur. J. Org. Chem. 0000, 0–0
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M. Amat, F. Subrizi, V. Elias, N. Llor, E. Molins, J. Bosch
FULL PAPER
[3] Y. F. Hallock, K. P. Manfredi, J. W. Blunt, J. H. Cardellina II,
M. Schäffer, K.-P. Gulden, G. Bringmann, A. Y. Lee, J. Clardy,
G. François, M. R. Boyd, J. Org. Chem. 1994, 59, 6349–6355.
[4] a) M. A. Rizzacasa, M. V. Sargent, B. W. Skelton, A. H. White,
Aust. J. Chem. 1990, 43, 79–86 (racemic series) b) G.
Bringmann, R. Weirich, H. Reuscher, J. R. Jansen, L. Kinz-
inger, T. Ortmann, Liebigs Ann. Chem. 1993, 877–888; c) T. R.
Hoye, M. Chen, Tetrahedron Lett. 1996, 37, 3099–3100; d)
T. R. Hoye, M. Chen, B. Hoang, L. Mi, O. P. Priest, J. Org.
Chem. 1999, 64, 7184–7201; e) F. A. Davis, P. K. Mohanty,
D. M. Burns, Y. W. Andemichael, Org. Lett. 2000, 2, 3901–
3903; f) C. J. Bungard, J. C. Morris, J. Org. Chem. 2006, 71,
7354–7363. See also: g) G. L. Grunewald, T. M. Caldwell, Q.
Li, K. R. Criscione, Bioorg. Med. Chem. 1999, 7, 869–880; for
the synthesis of cis-1,3-disubstituted tetrahydroisoquinolines
by 1,3-cis-selective Pictet–Spengler reactions, see: h) Y.-C. Wu,
M. Liron, J. Zhu, J. Am. Chem. Soc. 2008, 130, 7148–7152, and
references therein.
[5] a) For a similar cyclocondensation reaction, see: M. J. Munch-
hof, A. I. Meyers, J. Org. Chem. 1995, 60, 7086–7087; for re-
views on the use of phenylglycinol-derived lactams as enantio-
meric scaffolds in alkaloid synthesis, see: b) G. P. Brengel, A. I.
Meyers, Chem. Commun. 1997, 1–8; c) M. D. Groaning, A. I.
Meyers, Tetrahedron 2000, 56, 9843–9873; d) C. Escolano, M.
Amat, J. Bosch, Chem. Eur. J. 2006, 12, 8198–8207; e) M.
Amat, M. Pérez, J. Bosch, Synlett 2011, 143–160; f) M. Amat,
N. Llor, R. Griera, M. Pérez, J. Bosch, Nat. Prod. Commun.
2011, 6, 515–526; g) M. Amat, M. Pérez, J. Bosch, Chem. Eur.
J. 2011, 17, 7724–7732.
6.4 Hz, 3 H, CHCH3), 1.70 (br. s, 1 H, NH), 2.46 (dd, J = 15.2,
11.2 Hz, 1 H, 4-H), 2.63 (dd, J = 15.6, 2.4 Hz, 1 H, 4-H), 2.88 (m,
1 H, 3-H), 3.78 (s, 6 H, 2CH3O), 4.24 (q, J = 6.4 Hz, 1 H, 1-H),
6.21 (d, J = 2.0 Hz, 1 H, 7-H), 6.32 (d, J = 2.4 Hz, 1 H, 5-H) ppm.
13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 22.2 (CH2CHCH3),
22.7 (CHCH3), 39.7 (C-4), 48.3 (C-1), 49.4 (C-3), 55.0 (CH3O),
55.2 (CH3O), 96.7 (C-5), 104.4 (C-7), 121.1 (C-8a), 137.9 (C-4a),
157.9 and 158.5 (C-i) ppm. HRMS (ESI-TOF): calcd. for
C13H19NO2 [M + H]+ 222.1489; found 222.1489.
(1R,3S)-6,8-Dimethoxy-1,2,3-trimethyl-1,2,3,4-tetrahydroisoquino-
line (9d): LiAlH4 (20 mg, 0.53 mmol) was added to a solution of
the carbamate 9c (35 mg, 0.13 mmol) in THF (1.3 mL) at 0 °C. The
mixture was stirred at room temp. for 1 h and then heated to reflux.
After 3.5 h, it was cooled to 0 °C and quenched with water. After
evaporation of the volatile components, the residue was diluted
with CH2Cl2 and washed with brine. The organic extract was dried,
filtered, and concentrated to give 9d (26 mg, 85%) as a pale yellow
oil. [α]2D2 = +123 (c = 1.0, CHCl3) [Lit[17] [α]1D9 = +120 (c = 1.08,
1
CHCl3)]. H NMR (400 MHz, CDCl3, COSY, HETCOR, 25 °C):
δ = 1.21 (d, J = 6.4 Hz, 3 H, CH2CHCH3), 1.36 (d, J = 6.4 Hz, 3
H, CHCH3), 2.42 (masked m, 1 H, 3-H), 2.45 (s, 3 H, NCH3), 2.53
(dd, J = 15.2, 10.4, 0.8 Hz, 1 H, 4-H), 2.68 (ddd, J = 15.2, 2.0 Hz,
1 H, 4-H), 3.62 (q, J = 6.4 Hz, 1 H, 1-H),3.78 (s, 3 H, CH3O), 3.79
(s, 3 H, CH3O), 6.22 (d, J = 2.4 Hz, 1 H, 7-H), 6.31 (d, J = 2.4 Hz,
1 H, 5-H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 21.2
(CH3), 22.5 (CH3), 39.1 (CH3), 41.1 (C-4), 55.0 (CH3O), 55.1
(CH3O), 55.2 (C-1), 56.9 (C-3), 96.5 (C-5), 103.5 (C-7), 121.2 (C-
8a), 137.6 (C-4a), 157.0 and 158.4 (C-i) ppm. HRMS (ESI-TOF):
calcd. for C14H21NO2 [M + H]+ 236.1645; found 236.1639.
[6] Prepared as reported in: A. Kamal, A. Sandhu, Tetrahedron
Lett. 1963, 4, 611–612.
[7] For an early biomimetic synthesis, see: G. Bringmann, J. R.
Jansen, Heterocycles 1986, 24, 2407–2410.
[8] CCDC-870255 (for 2) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[9] For the stereochemical outcome of related Red-Al reductions,
see: M. Amat, O. Bassas, N. Llor, M. Cantó, M. Pérez, E. Mol-
ins, J. Bosch, Chem. Eur. J. 2006, 12, 7872–7881, and references
therein.
[10] M. C. Couturier, J. L. Tucker, B. M. Andersen, P. Dubé, J. T.
Negri, Org. Lett. 2001, 3, 465–467.
[11] For the generation of vinyl triflates from 2-piperidone deriva-
tives, see: C. J. Foti, D. L. Comins, J. Org. Chem. 1995, 60,
2656–2657.
Methyl N-[2-(3,5-Dimethoxy-2-ethylphenyl)-1-methylethyl]carb-
amate (12): H NMR (CDCl3, 400 MHz, 25 °C): δ = 1.08 (t, J =
1
7.2 Hz, 3 H, CH3CH2); 1.14 (d, J = 6.4 Hz, 3 H, CHCH3); 2.59
(dd, J = 13.6, 8.4 Hz, 1 H, 2-H); 2.63 (q, J = 7.2 Hz, 2 H,
CH3CH2); 2.92 (dd, J = 13.6, 5.6 Hz, 1 H, 2-H); 3.65 (s, 3 H,
CO2CH3); 3.77 (s, 3 H, CH3O); 3.79 (s, 3 H, CH3O); 3.93 (br. a, 1
H, 1-H); 4.63 (br. s, 1 H, NH), 6.29 (d, J = 2.4 Hz, 1 H, 6Ј-H);
6.35 (d, J = 2.4 Hz, 1 H, 4Ј-H) ppm. 13C NMR (CDCl3,
100.6 MHz, 25 °C): δ = 14.6 (CH3CH2); 18.8 (CH3CH2); 20.4
(CHCH3); 40.1 (C-2); 48.0 (C-1); 51.8 (CO2CH3); 55.2 (CH3O);
55.3 (CH3O); 96.8 (C-4Ј); 106.3 (C-6Ј); 124.0 (C-2Ј); 137.3 (C-1Ј);
156.3 (NHCO); 158.0 (C-3Ј); 158.6 (C-5Ј) ppm. EM (IQ+) m/z (%):
283 (14), 282 (96), 280 (4), 253 (1), 250 (6).
[12] D. L. Comins, A. Dehghani, Tetrahedron Lett. 1992, 33, 6299–
6302.
[13] When the catalytic hydrogenation of 8b was performed in the
absence of HCl, a 6:4 cis/trans mixture of 9b and 3-epi-9b was
obtained.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of compounds 2–9
and 12, and X-ray crystallographic data for compound 2.
[14] Reduction of the double bond of enamides 8b and 8c with
Et3SiH/TFA (room temp., 3 h) was not satisfactory from the
stereochemical standpoint because it led to mixtures of
cis/trans isomers (with Boc deprotection from 8b). This was
initially attributed to a low facial selectivity in the generation
of the C-3 stereocenter. However, epimerization at C-1 can also
occur in the presence of TFA (see below in the main text). The
isolation (33%) of the ring-opening product 12 in the reduction
of 8c confirms this interpretation; for the stereoselective re-
duction of 1,2-dihydroisoquinolines to cis-1,3-substituted tetra-
hydroisoquinolines under ionic hydrogenation conditions, see:
P. Magnus, K. S. Matthews, V. Lynch, Org. Lett. 2003, 5, 2181–
2184.
Acknowledgments
Financial support from the Spanish Ministry of Science and Inno-
vation (MICINN), (project number CTQ2009-07021/BQU), and
the AGAUR, Generalitat de Catalunya (grant number 2009-SGR-
1111) is gratefully acknowledged. F. S. acknowledges the European
Union for a Short Term Scientific Mission in the context of the
COST Action CM0804.
[1] a) G. Bringmann, The Alkaloids (Ed.: A. Brossi), Academic
Press, New York, 1986, vol. 29, pp. 141–184; b) G. Bringmann,
F. Pokorny, The Alkaloids (Ed.: G. Cordell), Academic Press,
New York, 1995, vol. 46, pp. 127–271.
[2] G. Bringmann, A. Irmer, D. Feineis, T. A. M. Gulder, H.-P.
Fiedler, Phytochemistry 2009, 70, 1776–1786.
[15] For related epimerizations of 6,8-dioxygenated tetrahydroiso-
quinolines, see: Y. F. Hallock, J. H. Cardellina II, T. Kornek,
6
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Stereoselective Synthesis of cis-1,3-Dimethyltetrahydroisoquinolines
K.-P. Gulden, G. Bringmann, M. R. Boyd, Tetrahedron Lett.
1995, 36, 4753–4756; see also ref.[4d]
[16] M. M. Bastiaans, J. L. van der Baan, H. C. Ottenheijm, J. Org.
Chem. 1997, 62, 3880–3889.
[17] P. Chau, I. R. Czuba, M. A. Rizzacasa, J. Org. Chem. 1996,
61, 7101–7105.
[18] G. Bringmann, S. Rüdenauer, T. Bruhn, L. Benson, R. Brun,
Tetrahedron 2008, 64, 5563–5568.
[19] M. Amat, V. Elias, N. Llor, F. Subrizi, E. Molins, J. Bosch, Eur.
J. Org. Chem. 2010, 4017–4026.
Received: June 15, 2012
Published Online: ᭿
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Date: 14-08-12 16:34:01
Pages: 8
M. Amat, F. Subrizi, V. Elias, N. Llor, E. Molins, J. Bosch
FULL PAPER
Asymmetric Synthesis
M. Amat,* F. Subrizi, V. Elias, N. Llor,
E. Molins, J. Bosch ........................... 1–8
Stereoselective Synthesis of cis-1,3-Di-
An efficient stereoselective synthesis of en-
naphthylisoquinoline alkaloids, from an
easily accessible phenylglycinol-derived tri-
cyclic lactam 2 is reported.
methyltetrahydroisoquinolines:
Formal
antiopure
cis-1,3-dimethyltetrahydroiso-
Synthesis of Naphthylisoquinoline Alk-
aloids
quinolines 9, synthetic precursors of
Keywords: Asymmetric synthesis / Total
synthesis / Nitrogen heterocycles / Lact-
ams / Alkaloids
8
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