Synthesis of (+)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, a diastereoselective approach

Article abstract of DOI:10.1002/ejoc.201403218

The diastereoselective synthesis of (+)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (90% ee) was accomplished by employing a combination of two synthetic methods, that is, the Petasis synthesis of amino acids and the Pomeranz-Fritsch-Bobbitt synthesis of tetrahydroisoquinoline derivatives. The stereochemical outcome of the synthesis was controlled by chiral aminoacetaldehyde acetals, which were used as the amine component of the Petasis step to yield the Pomeranz-Fritsch-Bobbitt substrate for the tetrahydroisoquinoline ring formation in one simple operation.

Full text of DOI:10.1002/ejoc.201403218

FULL PAPER
DOI: 10.1002/ejoc.201403218
Synthesis of (+)-6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic
Acid, a Diastereoselective Approach
Ilona Bułyszko,[a] Maria Chrzanowska,[a] Agnieszka Grajewska,[a] and
Maria D. Rozwadowska*[a]
Keywords: Total synthesis / Asymmetric synthesis / Multicomponent reactions / Diastereoselectivity / Cyclization /
Nitrogen heterocycles
The diastereoselective synthesis of (+)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (90%ee)
was accomplished by employing a combination of two syn-
thetic methods, that is, the Petasis synthesis of amino acids
synthesis was controlled by chiral aminoacetaldehyde acet-
als, which were used as the amine component of the Petasis
step to yield the Pomeranz–Fritsch–Bobbitt substrate for the
tetrahydroisoquinoline ring formation in one simple opera-
and the Pomeranz–Fritsch–Bobbitt synthesis of tetrahydroiso- tion.
quinoline derivatives. The stereochemical outcome of the
amine component and thus prepared the key intermediate
Introduction
for the Pomeranz–Fritch–Bobbitt cyclization in one step. By
employing this approach, we have performed the racemic
syntheses of several tetrahydroisoquinoline-1-carboxylic
acids[1] and simple isoquinoline alkaloids[2] in satisfactory
overall yields. To further develop this procedure, we have
undertaken experiments to adapt our approach to asym-
metric synthesis. Herein, we present the diastereoselective
synthesis of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-
1-carboxylic acid (1), which is related to simple isoquinoline
alkaloids[4] and important arylglycine derivatives[5] and was
selected to demonstrate the effectiveness of our approach.
In 2008 Fülöp and co-workers[6] reported the first prepa-
ration of both enantiomers of 6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline-1-carboxylic acid [(–)-1 and (+)-1] in
high yield and high enantiomeric purity. Their method was
based on the chemoenzymatic kinetic resolution of the race-
mic ethyl ester of 1 by using CAL-B (Candida antarctica
lipase B) to prepare (–)-1 and alcalase for (+)-1. The retro-
synthetic analysis of the total diastereoselective synthesis of
(+)-1 as reported herein is shown in Scheme 2.
We have recently reported[1,2] a new and practical method
for the synthesis of tetrahydroisoquinoline derivatives that
are functionalized at C-1 by using a combination of
two synthetic methods, that is, a multicomponent Petasis
reaction and a Pomeranz–Fritsch–Bobbitt cyclization. In
Scheme 1, the three-component Petasis reaction, which in-
volves boronic acid, a carbonyl derivative, and an amine,[3]
for the preparation of an amino acid and the Pomeranz–
Fritsch–Bobbitt cyclization of amino acetals[4] are shown.
Results and Discussion
Scheme 1.
The diastereoselectivity of our synthesis was ac-
complished by using chiral aminoacetaldehyde acetals 2a–
2d as the amine components of the Petasis reaction to yield
the diastereomeric amino acetals for the Pomeranz–Fritsch–
Bobbitt cyclization (see Scheme 3). Acetals 2a–2d were pre-
pared in high yield by heating at reflux a benzene solution
(Dean–Stark apparatus) of dimethoxyacetaldehyde with
readily cleavable chiral amines such as (S)-(–)-α-phenyleth-
Our method[1,2] involves a substantial modification to the
Petasis reaction. We used aminoacetaldehyde acetals as the
[a] Faculty of Chemistry, A. Mickiewicz University,
ul. Umultowska 89b, 61-614 Poznan´, Poland
E-mail: mdroz@amu.edu.pl
http://www.chemia.amu.edu.pl
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403218.
Eur. J. Org. Chem. 2015, 383–388
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
383

I. Bułyszko, M. Chrzanowska, A. Grajewska, M. D. Rozwadowska
FULL PAPER
Scheme 2. Retrosynthetic presentation of the synthesis of (+)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid.
Scheme 3. The synthesis of acid 1 from acetal 2, boronic acid 3, and glyoxylic acid (4) and through addition product 5 and the cyclization
of N-dealkylated compound 6 (DCM = dichloromethane).
ylamine, (S)-(–)-α-naphthylethylamine, (S)-(+)-tetrahydro- various degrees of diastereoselectivity (0–99%de), which
naphthyl-1-amine, and (R)-(–)-1-indanamine, respectively, depended on the type of boronic acid and amine that were
followed by a NaBH4 reduction and a bulb-to-bulb distil- employed. α-(1-Naphthyl)ethylamine also found application
lation. Because of the low value of the specific rotation of in the reaction.[9]
acetal 2c {[α]2D0 = +2.97 (c = 1.16, CHCl3)}, enantiomer ent-
When we performed the Petasis reaction between amino
2c {[α]2D0 = –2.26 (c = 1.23, CHCl3)} was prepared to com- acetal 2a, 3,4-dimethoxyphenylboronic acid (3), and glyox-
pare the HPLC analyses and prove the enantiomeric purity ylic acid (4) in dichloromethane at room temp. for 72 h,
of 2c.
amino acid 5a was formed in approximately a 70:30 dia-
In the first series of experiments, amino acetal 2a, which stereomeric ratio (see Scheme 3). After trituration of the
contained (S)-(–)-α-phenylethylamine as the auxiliary and crude product with hexane, 5a was isolated as a sticky solid
building block, was chosen as the amine component be- in 90% yield, which was pure enough to be used in the
cause of its well-recognized utility of both enantiomers in next step. Attempts to isolate 5a as a pure compound by
the synthesis of enantioenriched compounds.[7] Chiral α- crystallization or chromatographic separation were unsuc-
phenylethylamines have also been tested in a few Petasis cessful. In the latter case, substantial decomposition of the
reactions[8] to afford products in fair to good yields with compound was observed during chromatography. Such a
384
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Synthesis of 1,2,3,4-Tetrahydroisoquinoline-1-carboxylic Acid
situation was also observed during the syntheses of amino acid 1. Moreover, compound 6 was a crystalline compound,
acids 5b–5d.
which could be purified and enantiomerically enriched by
The diastereomeric composition of amino acid 5a was crystallization of the crude products from 96% ethanol.
established by both 1H NMR spectroscopic and chiral When amino acid 5a was used in this reaction, crystalline
HPLC analysis of the crude product (after derivatization N-debenzylated product (+)-6 was obtained in 85% yield
with diazomethane). Thus, the diastereomeric ratio of ap- with an er (enantiomeric ratio) of approximately 72:28. The
proximately 70:30 for compound 5a could be deduced from crystallization of the crude product from 96% ethanol af-
1
the H NMR spectroscopic data by comparing the integra- forded an almost racemic first crop of crystals, which were
tion values of the doublet resonances at δ = 1.47 and isolated in 33% yield. The second crop of crystals supplied
1.58 ppm, which represent the methyl group protons of the a sample of 6 in 48% yield with 80:20 er. Enantiomerically
nitrogen substituent. A similar diastereomeric composition pure (+)-6 {[α]2D0 = +85 (c = 1.15, MeOH); m.p. 141–
(approximately 72:28) was also established by HPLC analy- 142 °C} was prepared by a series of recrystallizations of the
sis. The latter method was used for the determination of enriched fractions from 96% ethanol.
the diastereomeric compositions of amino acids 5b–5d (see
N-Dealkylated product (+)-6 was then subjected to the
Scheme 3).
Pomeranz–Fritsch–Bobbitt cyclization/hydrogenolysis pro-
To improve the diastereoselectivity of the Petasis step, we cedure.[10] In the course of experiments, we noticed that the
investigated the influence of several parameters on the de- steric outcome of this step strongly depended on the reac-
gree of diastereoselectivity in the synthesis of 5a. Of the tion conditions and the workup procedure. The results were
solvents examined, only a moderate increase in dr (dia- in accordance with the well-known configurational instabil-
stereomeric ratio, 77:23) was observed when the reaction ity of aryl glycine derivatives,[11] which included tetrahydro-
was carried out in toluene. However, this reaction resulted isoquinoline-1-carboxylic acids.[12] After many control ex-
in lower conversion value because of the poor solubility of periments, reproducible results were obtained when the cy-
amino acids in this solvent. In addition, the reaction did clization step was carried out in 20% hydrochloric acid at
not progress in either ethanol or water at room temp. after room temperature for 72 h under argon in darkness. This
72 h, whereas a mixture of products, which consisted of mixture was then hydrogenated for 24 h in the presence of
polymeric substances, were formed at an elevated tempera- 10% Pd/C catalyst (20% w/w) by using hydrogen from a
ture (80 °C). An increase in the dr could not be achieved at balloon. When a sample of amino acid (+)-6 {80:20 er;
a lower temperature (e.g., –20, –10, and 0 °C). In this case, [α]2D0 = +60.8 (c = 1.08, MeOH); m.p. 140–142 °C} was sub-
the progress of the reaction was very slow, and when the jected to the Pomeranz–Fritsch–Bobbitt sequence of trans-
reaction was conducted at either –20 or –10 °C, only ap- formations under the above reaction conditions, the hydro-
proximately a 30% conversion was observed after 10 d. chloride salt of the tetrahydroisoquinoline carboxylic acid,
Thus, the typical Petasis reaction conditions, that is, DCM (+)-1·HCl, was isolated in 66% yield {[α]2D0 = +43.7 (c =
as the solvent at room temperature for 72 h of reaction time, 1.1, MeOH)} as a hygroscopic foam after evaporation of
were employed for the synthesis of amino acids 5b–5d.
the filtrate. An additional amount of (+)-1·HCl was reco-
Next, we examined aminoacetaldehyde acetals 2b–2d, vered in 33% yield by washing the catalyst with 20% hydro-
which were derived from the chiral amines (S)-(–)-α- chloric acid and water, but the sample showed a low the
naphthylethylamine (for 2b), (S)-(+)-tetrahydronaphthyl-1- specific rotation value {[α]2D0 = +11.2 (c = 1.00, MeOH)}.
amine (for 2c), and (R)-(–)-1-indanamine (for 2d), in the The treatment of (+)-1·HCl {[α]2D0 = +43.7 (c = 1.1,
Petasis reaction. Amino acids 5b–5d were prepared with MeOH)} with dilute ammonium hydroxide to pH ≈ 6 de-
high conversion but still only with a moderate diastereo- posited (+)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-
selectivity (see Scheme 3). The highest asymmetric induc- 1-carboxylic acid (1). Recrystallization of the crude product
tion (87:13 dr), but the opposite configuration at C-1 for from ethanol/water (50:50) afforded 1 as a crystalline com-
the major isomer, was achieved in the reaction with amino pound in 41% yield with 95:5 er {[α]2D0 = +53.4 (c = 0.305,
acetal 2d. In the reaction with amino acetal 2c, practically H2O); m.p. 234.5–235 °C}.
no induction was observed.
A sample of the dextrorotatory enantiomer (93%ee), as
The final step of the synthesis, the construction of the described by Fülöp and co-workers,[6] was characterized by
tetrahydroisoquinoline ring system, employed the Pomer- [α]2D5 = +62 (c = 0.30, H2O), m.p. 265–267 °C, and spectro-
anz–Fritsch–Bobbitt cyclization/hydrogenolysis process.[10] scopic data. These data were in full accordance with that of
The procedure for this step involved the treatment of the our product (+)-1.
Pomeranz–Fritsch–Bobbitt amino acetal with 20% hydro-
chloric acid followed by a catalytic hydrogenation with a
Pd/C catalyst. When this was applied to Petasis product 5a,
a sluggish reaction occurred, which led to a mixture of com-
Conclusions
pounds.
The diastereoselective total synthesis of (+)-6,7-dimeth-
Fortunately, the N-deprotected amino acid (+)-6 which oxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1,
was easily prepared from compounds 5a and 5b by 90%ee) was achieved by using a combination of two syn-
hydrogenolysis in methanol in the presence of Pearlman’s thetic methods, that is, the Petasis synthesis of amino acids
catalyst, could be efficiently cyclized to give isoquinoline and the Pomeranz–Fritsch–Bobbitt synthesis of tetrahydro-
Eur. J. Org. Chem. 2015, 383–388
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385

I. Bułyszko, M. Chrzanowska, A. Grajewska, M. D. Rozwadowska
FULL PAPER
J = 5.4 Hz, 1 H), 4.64 (q, J = 6.6 Hz, 1 H), 7.45–7.53 (m, 3 H),
7.66 (d, J = 6.5 Hz, 1 H), 7.74 (d, J = 8.2 Hz, 1 H), 7.85–7.88 (m,
1 H), 8.18 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 23.6, 49.2, 53.5, 53.6, 54.0, 104.0, 122.7, 122.9, 125.3, 125.7,
125.7, 127.2, 128.9, 131.3, 133.9, 140.8 ppm. MS (EI): m/z (%) =
259 (7) [M]+, 244 (11), 184 (16), 155 (100), 75 (18). HRMS: calcd.
for C16H21NO2 [M]+ 259.15723; found 259.15711. HPLC (n-hex-
ane/iPrOH, 80:20): tR = 10.50 min.
isoquinoline derivatives. The stereoselectivity of the synthe-
sis was directed by chiral aminoacetaldehyde acetals 2a–2d,
which were used as the amine components of the Petasis
reaction. Acetals 2a–2d, which contained chiral N-substitu-
ents (i.e., α-phenylethyl, α-naphthylethyl, 1-tetrahydronaph-
thyl, and 1-indanyl groups), were transformed into aryl-
glycine derivatives 5a–5d, which were precursors for the
Pomeranz–Fritsch–Bobbitt step of the synthesis. After re-
moval of the nitrogen substituent, the N-dealkylated deriva-
tive (+)-6 was subjected to the cyclization/hydrogenolysis
procedure to afford the target (+)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline-1-carboxylic acid (1) in two simple
operations.
(S)-(+)-[1-(1,2,3,4-Tetrahydronaphthylamino)]acetaldehyde Dimeth-
yl Acetal (2c): Preparation on a 5 mmol scale afforded compound
2c (0.85 g, 72% yield) as an unstable oil; [α]2D0 = +2.97 (c = 1.16,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.42 (br. s, which disap-
peared upon treatment with D2O, 1 H), 1.71–1.75 (m, 1 H), 1.84–
1.88 (m, 2 H), 1.95–1.99 (m, 1 H), 2.72–2.88 (m, 4 H), 3.38 (s, 6
H), 3.78 (t, J = 5.0 Hz, 1 H), 4.50 (t, J = 5.5 Hz, 1 H), 7.06–7.18
(m, 3 H), 7.32–7.36 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 18.9, 28.3, 29.3, 48.5, 53.7, 53.9, 55.3, 104.2, 125.7, 126.6, 128.7,
129.0, 137.4, 138.9 ppm. MS (EI): m/z (%) = 235 (7) [M]+, 203 (5),
160 (19), 132 (14), 131 (100), 106 (18), 91 (20), 75 (21). HRMS:
calcd. for C14H19NO2 [M]+ 235.15723; found 235.15632. HPLC (n-
hexane/iPrOH, 90:10): tR = 12.00 min.
Experimental Section
General Methods: Melting points were measured with a Kofler
block. IR spectra were recorded with a Bruker FT-IR IFS 113V
spectrometer. The NMR spectroscopic data were recorded with a
Varian Gemini 300 spectrometer, and TMS was used as the internal
standard. Mass spectra were recorded with an AMD402 mass spec-
trometer. Optical rotation data were measured with a Perkin–Elmer
polarimeter 242B at 20 °C. Elemental analyses were carried out
with a Vario EL III elemental analyzer. Analytical HPLC data were
recorded with a Waters HPLC system with a Chiralcel OD-H col-
umn and using a flow rate of 0.5 mL/min. Merck DC-Alufolien
Kieselgel 60254 was used for the TLC analysis, and Kieselgel 60
(70–230 mesh ASTM) was employed for column chromatography.
All compounds were purchased from Aldrich Chemical Co. and
used as received.
ent-2c: [α]2D0 = –2.26 (c = 1.23, CHCl3). HPLC (n-hexane/iPrOH,
90:10): tR = 11.22 min.
(R)-(–)-(1-Indanamino)acetaldehyde Dimethyl Acetal (2d): Prepara-
tion on a 5 mmol scale afforded compoound 2d (0.83 g, 75.5%
yield); [α]2D0 = –23 (c = 1.00, CHCl ). IR (film): ν = 3320, 2940,
˜
3
2832 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.52 (br. s, which
disappeared upon treatment with D2O, 1 H), 1.79–1.88 (m, 1 H),
2.34–2.42 (m, 1 H), 2.77–2.85 (m, 3 H), 2.96–3.04 (m, 1 H), 3.38
(s, 3 H), 3.39 (s, 3 H), 4.26 (t, J = 6.6 Hz, 1 H), 4.50 (t, J = 5.6 Hz,
1 H), 7.17–7.25 (m, 3 H), 7.32–7.35 (m, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 30.3, 33.3, 48.5, 53.7, 54.1, 63.0, 104.2,
124.1, 124.7, 126.1, 127.3, 143.5, 144.8 ppm. MS (EI): m/z (%) =
221 (4) [M]+, 146 (19), 117 (100), 115 (14), 75 (28). HRMS: calcd.
for C13H19NO2 [M]+ 221.14159; found 221.14231. HPLC (n-hex-
ane/iPrOH, 90:10): tR = 11.11 min.
Preparation of Aminoacetaldehyde Acetals 2a–2d. General Pro-
cedure: The chiral amine (10 mmol) and dimethoxyacetaldehyde
(60 wt.-% solution in water, 3 mL, 20 mmol) were dissolved in
benzene (50 mL), and the solution was heated at reflux (Dean–
Stark trap) for 3 h. After that time, benzene was evaporated, and
the residue was dissolved in methanol (10 mL). The resulting solu-
tion was cooled to 0 °C and then treated with NaBH4 (15 mmol).
The reaction mixture was stirred at room temperature for 18 h and
then treated with water (5 mL) and 20% HCl (5 mL). The resulting
mixture was stirred for 1 h. Then, the pH of the solution was ad-
justed to alkaline by the addition of 20% NaOH. After extraction
with diethyl ether, drying over Na2SO4 and evaporation of the sol-
vent, product 2 was obtained as a colorless oil, which was purified
by bulb-to-bulb distillation.
Synthesis of Petasis Reaction Products 5a–5d. General Procedure:
In a round-bottomed flask, a suspension of 3,4-dimethoxyphenyl-
boronic acid (3) and glyoxylic acid monohydrate (4) in 1:1 molar
ratio in DCM (5 mL/mmol) was stirred at room temperature for 7–
10 min under argon, and then aminoacetaldehyde acetal 2 (1 molar
equiv.) was added. The clear solution was stirred at room tempera-
ture for 72 h. After that time, the inorganic solid precipitate was
removed by filtration, and the solvent was removed under reduced
pressure. The crude reaction product was triturated with hexane
to give amino acids 5 as an inseparable mixture of diastereomers.
Attempts to prepare 5 in crystalline form by crystallization or chro-
matographic purification and separation failed, and the latter re-
sulted in a substantial loss of yield. However, crude compound 5
was pure enough to be used in the next step of the synthesis with-
out further purification. Analytical samples for characterization
were prepared by chromatographic purification (silica gel column;
DCM/methanol, 100:1 to 100:5).
(S)-(–)-(1-Phenylethylamino)acetaldehyde Dimethyl Acetal (2a):
(1.96 g, 93% yield). [α]2D0 = –33 (c = 1.20, CHCl3); ref.[13] [α]2D0
=
–31 (c = 2.09, CHCl ). IR (film): ν = 3331, 2960, 2831 cm–1. 1H
˜
3
NMR (300 MHz, CDCl3): δ = 1.36 (d, J = 6.7 Hz, 3 H), 2.59
(dABq, J = 12.1, 5.4 Hz, 2 H), 3.31 (s, 3 H), 3.35 (s, 3 H), 3.75 (q,
J = 6.7 Hz, 1 H), 4.43 (t, J = 5.4 Hz, 1 H), 7.21–7.34 (m, 5 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 24.3, 49.0, 53.5, 54.0, 58.3, 103.9,
126.5, 126.9, 128.4, 145.3 ppm. MS (EI): m/z (%) = 209 (5) [M]+,
194 (26), 178 (13), 134 (85), 105 (90), 75 (100). HRMS: calcd. for
C12H19NO2 [M]+ 209.14159; found 209.14114. HPLC (n-hexane/
iPrOH, 98:2): tR = 11.1 min.
N-2,2-Dimethoxyethyl-N-methylbenzyl-2-(3,4-dimethoxyphenyl)-
glycine (5a): Following the general procedure, boronic acid 3, glyox-
ylic acid monohydrate (4), and aminoacetaldehyde dimethyl acetal
2a were employed on a 10 mmol scale to afford 5a (1.90 g, 90%
(S)-(–)-(1-Naphthylethylamino)acetaldehyde Dimethyl Acetal (2b):
yield, approximately 70:30 dr) as a foam. IR (film): ν = 3412 (br.),
˜
(1.95 g, 75% yield); [α]2D0 = –33 (c = 0.99, CHCl ). IR (film): ν =
2916, 2848, 1738 cm–1. 1H NMR (300 MHz, CDCl3, major isomer,
˜
3
3336, 2959, 2831 cm–1. H NMR (300 MHz, CDCl3): δ = 1.50 (d, diagnostic area): δ = 1.47 (d, J = 6.9 Hz), 3.24 (s), 3.27 (s), 3.78
1
J = 6.6 Hz, 3 H), 1.66 (s, which disappeared upon treatment with
D2O, 1 H), 2.66–2.74 (m, 2 H), 3.32 (s, 3 H), 3.36 (s, 3 H), 4.49 (t,
(s), 3.85 (s), 4.26 (q, J = 6.9 Hz), 4.72 (s) ppm. 1H NMR (300 MHz,
CDCl3, minor isomer, diagnostic area): δ = 1.58 (d, J = 6.9 Hz),
386
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Synthesis of 1,2,3,4-Tetrahydroisoquinoline-1-carboxylic Acid
3.17 (s), 3.26 (s), 3.66 (s), 3.82 (s), 4.39 (q, J = 6.9 Hz), 4.84 (s) ppm.
13C NMR (75 MHz, CDCl3): δ = 15.7, 16.6, 48.6, 48.7, 53.9, 54.9,
55.1, 55.73, 55.75, 55.79, 55.8, 61.3, 61.4, 66.6, 68.7, 103.2, 103.5,
110.7, 110.9, 112.6, 112.9, 122.0, 122.6, 126.7, 126.8, 127.5, 128.1,
128.2, 128.3, 128.6, 128.7, 140.4, 148.8, 148.9, 149.0, 149.2, 173.0,
tic area): δ = 3.19 (s), 3.24 (s), 3.82 (s), 3.86 (s), 4.53 (t, J = 5.6 Hz),
4.78 (dd, J = 6.1, 8.2 Hz), 4.70 (s) ppm. 13C NMR (75 MHz,
CDCl3): δ = 26.3, 30.6, 49.2, 54.7, 55.4, 55.8, 55.9, 66.5, 69.6, 103.9,
111.1, 113.1, 123.0, 124.9, 125.0, 126.9, 128.5, 141.3, 143.6, 149.0,
149.3, 172.9 ppm. MS: m/z (%) = 415 (1) [M]+, 340 (14), 339 (12),
173.9 ppm. MS (EI): m/z (%) = 403 (0.7) [M]+, 328 (26), 327 (16), 281 (28), 195 (33), 178 (11), 118 (12), 117 (100), 115 (14), 75 (14).
269 (31), 268 (13), 254 (21), 195 (86), 178 (15), 151 (14), 105.0 (100), HRMS: calcd. for C23H29NO6 [M]+ 415.19949; found 415.19746.
79 (13), 77 (13), 75 (20). HRMS: calcd. for C22 H2 9NO6 HPLC (after derivatization with diazomethane; n-hexane/iPrOH,
[M]+ 403.19949; found 403.19837. HPLC (after derivatization with
diazomethane; n-hexane/iPrOH, 98:2): tR = 32.64 (minor isomer)
and 36.70 min (major isomer).
98:2): tR = 28.72 (minor isomer) and 36.93 min (major isomer).
(+)-N-2,2-Dimethoxyethyl-2-(3,4-dimethoxyphenyl)glycine (6):
Petasis amino acid 5a (70:30 dr) was dissolved in absolute methanol
(6 mL/mmol), and the solution was hydrogenated (hydrogen from
a balloon) in the presence of the Pearlman’s catalyst (20% w/w)
at room temperature for 24 h. Then, the catalyst was removed by
filtration, and the solvent was evaporated. The crude crystalline
product was triturated with hexane to deposit (+)-6 (85% yield,
average value of several experiments; approximately 72:28 er).
Crystallization of the crude product (2.0 g/22 mL of 96% ethanol)
afforded the first crop of almost racemic crystals of 6 (33%), and
the second crop contained enantiomerically enriched (+)-6 (48%
yield, approximately 80:20 er). HPLC (after derivatization with di-
azomethane to give O,N-dimethylated derivative, n-hexane/iPrOH,
90:10): tR = 17.96 (major isomer) and 20.49 min (minor isomer).
An enantiomerically pure sample of 6 was prepared by repeated
crystallizations of enantiomerically enriched fractions by using
96% ethanol; m.p. 141–142 °C. [α]2D0 = +85 (c = 1.15, MeOH),
Ͼ99%ee. 1H NMR (300 MHz, [D6]DMSO): δ = 2.53 (dd, J = 12.3,
5.1 Hz, 1 H), 2.66 (dd, J = 12.5, 6.0 Hz, 1 H), 3.24 (s, 3 H), 3.26
(s, 3 H), 3.73 (s, 3 H), 3.74 (s, 3 H), 4.22 (s, 1 H), 4.48 (t, J ≈ 5.4 Hz,
1 H), 6.87–6.98 (m, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO/
[D4]CH3OH, 10:1 v/v ): δ = 47.4, 53.5, 53.8, 55.5, 55.55, 64.7, 101.9,
111.5, 111.6, 120.6, 129.7, 148.55, 148.6, 171.5 ppm. MS (EI): m/z
(%) = 255 (21) [M – CO2]+, 254 (63), 195 (85), 166 (50), 75 (100).
C14H21NO6 (299.32): calcd. C 56.18, H 7.07, N 4.68; found C
55.89, H 6.64, N 4.63. HPLC (after derivatization with diazometh-
ane to give O,N-dimethylated derivative, n-hexane/iPrOH, 90:10):
tR = 17.09 min. The N-debenzylation of amino acids 5b and 5d was
carried out under the reaction conditions described above for 5a.
Amino acid 5b afforded (+)-6 in 83% yield and 79:21 er. Amino
acid 5d afforded (–)-6 in quantitative yield and 13:87 er.
N-2,2-Dimethoxyethyl-N-(1-naphthyl)ethyl-2-(3,4-dimethoxyphen-
yl)glycine (5b): Following the general procedure, boronic acid 3,
glyoxylic acid monohydrate (4), and aminoacetaldehyde dimethyl
acetal 2b were employed on a 0.75 mmol scale to afford 5b (0.28 g,
83% yield, 79:21 dr). IR (KBr): ν = 3548 (br.), 2936, 2838, 2590
˜
1
(br.), 1727, 1515 cm–1. H NMR (300 MHz, CDCl3, major isomer,
diagnostic area): δ = 1.64 (d, J = 6.8 Hz, 3 H), 2.76–3.01 (m, 2 H),
3.16 (s, 3 H), 3.25 (s, 3 H), 3.87 (s, 3 H), 3.88 (s, 3 H), 4.70 (s, 1
H), 5.02 (q, J = 6.7 Hz, 1 H), 6.79 (d, J = 1.6 Hz, 1 H), 6.85–6.91
(m, 2 H), 7.47–7.62 (m, 4 H), 7.85–7.90 (m, 2 H), 8.42 (d, J =
8.6 Hz, 1 H) ppm. 1H NMR (300 MHz, CDCl3, minor isomer,
diagnostic area): δ = 1.71 (d, J = 6.8 Hz, 3 H), 2.63–2.69 (m, 2 H),
3.00 (s, 3 H), 3.01 (s, 3 H), 3.82 (s, 3 H), 4.86 (s, 1 H) ppm. 13C
NMR (75 MHz, CDCl3, major isomer, diagnostic area): δ = 15.5,
50.4, 54.8, 54.8, 55.9, 57.5, 67.5, 103.7, 111.0, 113.1, 122.6, 123.7,
125.1, 125.3, 125.9, 126.3, 127.6, 129.0, 131.7, 134.1, 137.1, 148.9,
149.1, 173.4 ppm. MS (EI): m/z (%) = 422 (4) [M – 31]+, 377 (16),
304 (24), 178 (18), 155 (100), 75 (12). C26H31NO6·1/2H2O (462.5):
calcd. C 67.52, H 6.97, N 3.03; found C 67.28, H 6.67, N 2.94.
HPLC (after derivatization with diazomethane; n-hexane/iPrOH,
98:2): tR = 36.24 (minor isomer) and 37.82 min (major isomer).
N-2,2-Dimethoxyethyl-N-[1-(1,2,3,4-tetrahydro)naphthyl]-2-(3,4-di-
methoxyphenyl)glycine (5c): Following the general procedure, bo-
ronic acid 3, glyoxylic acid monohydrate (4), and amino acetal 2c
were employed on a 3.4 mmol scale to afford 5c (quantitative yield,
56:44 dr) as a foam. IR (film): ν = 3425 (br.), 2936, 2836, 2591
˜
1
(br.), 1727, 1516 cm–1. H NMR (300 MHz, CDCl3, major isomer,
diagnostic area): δ = 3.17 (s), 3.23 (s), 3.82 (t, J = 5.2 Hz), 3.84 (s),
3.87 (s), 4.44 (dd, J = 6.2, ~9.0 Hz), 4.72 (s), 7.58 (dd, J = 6.3,
(+)-6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic Acid
(1): Compound (+)-6 (80:20 er, 0.46 g, 1.5 mmol) was dissolved in
20% hydrochloric acid (15 mL), and the resulting solution was
stirred at room temperature for 72 h under argon in darkness. After
that time, the mixture was hydrogenated (hydrogen from a balloon)
in the presence of 10% Pd/C (20% w/w) for 24 h. The catalyst was
removed by filtration, and the filtrate was concentrated under high
vacuum to deposit the hydrochloride salt of the isoquinoline carb-
oxylic acid 1·HCl (0.28 g, 66% yield) as a hygroscopic foam; [α]2D0
= +43.7 (c = 1.1, MeOH). Washing the catalyst with 20% hydro-
chloric acid and water provided additional amounts of 1·HCl
(0.15 g, 33% yield) as creamy solid; [α]2D0 = +11.2 (c = 1.00,
MeOH). The 1·HCl {0.25 g, 0.9 mmol; [α]2D0 = +43.7 (c = 1.11,
MeOH)} was treated with ammonium hydroxide (25%) that was
diluted with chloroform/methanol (NH4OH/CHCl3/CH3OH,
0.5:45:4.5 v/v/v) to pH ≈ 6 at room temp. for 30 min. Evaporation
of solvents and crystallization of the crude product from ethanol/
water (50:50) afforded pure, crystalline (S)-(+)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1, 0.1 g, 41%
1
8.9 Hz) ppm. H NMR (300 MHz, CDCl3, minor isomer, diagnos-
tic area): δ = 3.29 (s), 3.38 (s), 3.86 (s), 3.87 (s), 4.17 (dd, J = 4.3,
6.2 Hz), 4.25 (dd, J = 6.1, 8.6 Hz), 4.69 (s), 7.51 (d, J =
7.5 Hz) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.6, 22.0, 25.4,
26.2, 29.6, 29.7, 49.0, 50.4, 53.7, 54.8, 54.86, 54.91, 55.82, 55.84,
55.9, 60.2, 62.6, 67.7, 69.2, 103.4, 103.5, 110.7, 111.0, 112.6, 113.1,
122.3, 122.5, 125.9, 126.2, 127.2, 127.5, 128.0, 128.3, 128.8, 129.26,
129.29, 135.6, 135.8, 138.8, 139.4, 148.9, 149.1, 149.2, 173.7,
174.6 ppm. MS (EI): m/z (%) = 429 (1) [M]+, 354 (16), 353 (17),
295 (12), 195 (29), 178 (14), 166 (30), 151 (11), 132 (14), 131 (100),
130 (37), 91 (15), 75 (15). HRMS: calcd. for C24H31NO6 [M]+
429.21515; found 429.21274. HPLC (after derivatization with di-
azomethane, n-hexane/iPrOH, 98:2): tR = 25.57 (major isomer) and
28.45 min (minor isomer).
N-2,2-Dimethoxyethyl-N-(1-indanyl)-1-(3,4-dimethoxyphenyl)gly-
cine (5d): Following the general procedure, boronic acid 3, glyoxylic
acid monohydrate (4), and amino acetal 2d were employed on a
2 mmol scale to give 5d (quantitative yield, 13:87 dr). IR (KBr): ν
˜
= 3437 (br.), 2938, 2836, 2594 (br.), 1727, 1515 cm–1. 1H NMR yield, 95:5 er); [α]2D0 = +53.4 (c = 0.305, H2O), m.p. 234.4–235 °C.
(300 MHz, CDCl3, major isomer, diagnostic area): δ = 3.27 (s), 3.34
1H NMR (300 MHz, D2O): δ = 2.99 (t, J = 6.3 Hz, 2 H), 3.44 (td,
(s), 3.87 (s), 3.89 (s), 4.22 (t, J = 5.0 Hz), 4.67 (dd, J = 6.1, 7.8 Hz), J = 6.4, 12.7 Hz, 1 H), 3.58 (td, J = 6.3, 12.9 Hz, 1 H), 3.84 (s, 3
4.89 (s) ppm. H NMR (300 MHz, CDCl3, minor isomer, diagnos- H), 3.87 (s, 3 H), 4.86 (s, 1 H), 6.85 (s, 1 H), 7.15 (s, 1 H) ppm. 13
C
1
Eur. J. Org. Chem. 2015, 383–388
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
387

I. Bułyszko, M. Chrzanowska, A. Grajewska, M. D. Rozwadowska
FULL PAPER
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NMR (75 MHz, D2O): δ = 27.0, 42.7, 58.5, 58.6, 61.1, 113.4, 114.3,
123.1, 127.3, 149.8, 150.9, 175.0 ppm. MS (EI): m/z (%) = 237 (1.4)
[M]+, 236 (4), 193 (36), 192 (100), 191 (11), 190 (10), 177 (19), 176
(31), 148 (17), 147 (11), 146 (10), 134 (12), 131 (12), 118 (12), 77
(12). HRMS: calcd. for C12H15NO4 [M]+ 237.10011; found
237.09911. HPLC (after derivatization with diazomethane to give
O,N-dimethylated derivative, n-hexane/iPrOH, 80:20): tR
=
29.17 min.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra of all compounds and
HPLC data.
Acknowledgments
This work was supported by a research grant from the National
Science Centre, Poland (NCN 2011/01/D/ST5/06627).
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Received: September 16, 2014
Published Online: November 27, 2014
388
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Eur. J. Org. Chem. 2015, 383–388