Asymmetric synthesis of arylglycines and their use as chiral templates for the stereocontrolled synthesis of 7,8-disubstituted 3-Aryl-1,2,3,4-tetrahydroisoquinolin-4-ols

Article abstract of DOI:10.1002/1099-0690(200111)2001:22<4343::AID-EJOC4343>3.0.CO;2-D

A synthetic technique for the asymmetric synthesis of arylglycines has been optimized, reaching the target amino acids in only four steps with good yields and with enantiomeric excesses higher than 99%. The key step consisted of a stereocontrolled electrophilic amination reaction of (S,S)-(+)-pseudoephedrine-based arylacetamide enolates with di-tertbutylazodicarboxylate. The arylglycines thus obtained turned out to be excellent chiral templates for the production of chiral, nonracemic 7,8-disubstituted 3-aryl-1,2,3,4-tetrahydroisoquinolines, through use of a synthetic sequence involving: (1) reduction of the arylglycines to the parent arylglycinols, (2) N-benzylation with appropriately substituted aromatic aldehydes and (3) Swern oxidation followed by acid catalysed cyclization of the obtained a-amino aldehydes.

Full text of DOI:10.1002/1099-0690(200111)2001:22<4343::AID-EJOC4343>3.0.CO;2-D

FULL PAPER
Asymmetric Synthesis of Arylglycines and Their Use as Chiral Templates for
the Stereocontrolled Synthesis of 7,8-Disubstituted
3-Aryl-1,2,3,4-tetrahydroisoquinolin-4-ols
[a]
[a]
[a]
[a]
´
Eneritz Anakabe, Jose L. Vicario, Dolores Badıa,* Luisa Carrillo, and
Victoria Yoldi[a]
Keywords: Aminations / Amino acids / Asymmetric synthesis / Heterocycles
A synthetic technique for the asymmetric synthesis of aryl- turned out to be excellent chiral templates for the production
glycines has been optimized, reaching the target amino acids of chiral, nonracemic 7,8-disubstituted 3-aryl-1,2,3,4-tetrahy-
in only four steps with good yields and with enantiomeric droisoquinolines, through use of a synthetic sequence invol-
excesses higher than 99%. The key step consisted of a ster-
eocontrolled electrophilic amination reaction of (S,S)-(+)-
pseudoephedrine-based arylacetamide enolates with di-tert-
butylazodicarboxylate. The arylglycines thus obtained
ving: (1) reduction of the arylglycines to the parent arylglyci-
nols, (2) N-benzylation with appropriately substituted aro-
matic aldehydes and (3) Swern oxidation followed by acid-
catalysed cyclization of the obtained α-amino aldehydes.
Introduction
ation procedure using either PictetϪSpengler[11] or
BischlerϪNapieralsky[12] cyclizations. 3-Phenyl-1,2,3,4-
tetrahydroisoquinolin-4-ols have therefore been obtained in
enantiopure form by starting from chiral, nonracemic 1,2-
diarylaminoethanols.[7] The use of these cyclization proce-
dures as key steps in the construction of the heterocyclic
system has a severe limitation, however, which is that the
substitution pattern in the aromatic ring of the isoquinoline
skeleton is dictated by the electronic requirements of the
cyclization step. Thus, these methodologies are more diffi-
cult to apply for the synthesis of 7,8-disubstituted deriva-
tives,[13] and this is the substitution pattern most commonly
found in nature (see Figure 1). In this context, we recently
developed a procedure for the asymmetric synthesis of 6,7-
dimethoxy-4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol us-
ing (S)-(ϩ)-phenylglycine as the starting chiral source
(Scheme 1).[8] This would, in principle, allow access to en-
antiopure isoquinolin-4-ols with any kind of substitution
pattern at the heterocyclic aromatic ring. However, this
methodology is limited to the production of 3-phenyl iso-
quinolines because of the lack of commercially available
chiral, nonracemic arylglycines. Development of a general
procedure for the stereocontrolled synthesis of 3-aryl-
1,2,3,4-tetrahydroisoquinolin-4-ols with any desired substi-
tution pattern would therefore require a straightforward
method for the synthesis of arylglycines in enantiopure
form.
The stereoselective synthesis of isoquinoline alkaloids is
a field of growing interest in synthetic organic chemistry.[1]
As a consequence, many methods have already been pub-
lished for the stereoselective syntheses of 1-substituted
tetrahydroisoquinolines,[1,2] which are very useful interme-
diates for the preparation of a wide range of enantiopure
alkaloids.[3] Although chiral, nonracemic tetrahydroisoqui-
nolin-4-ol derivatives are of considerable interest, due to
their biological activity and as naturally occurring alkal-
oids,[4] research into their stereoselective synthesis is not as
fully developed as that of the 1-substituted derivatives.
Some reports have described the asymmetric synthesis of
tetrahydroisoquinoline derivatives in which the substituent
at C(4) bears a hydroxy function,[5] but only a few reports
can be found in which, in addition, the substituent at the
3-position is an aryl moiety,[6,7,8] a pattern found quite often
in nature, as in the protoberberine alkaloids ophiocarpine[9]
or papaverberine (Figure 1), among others.[10]
Although many of the reported methods for the ster-
eocontrolled synthesis of arylglycines[14] are quite effective,
Figure 1. Natural 13-hydroxyprotoberberine alkaloids
One of the most widely employed method for the con-
struction of the isoquinoline core involves a heterocycliz-
[a]
´
´
Departamento de Quımica Organica II. Facultad de Ciencias.
Universidad del Pais Vasco,
P. O. Box 644, 48080 Bilbao, Spain
Fax: (internat.) ϩ 34-94/464-8500
E-mail: qopbaurm@lg.ehu.es
Scheme 1
Eur. J. Org. Chem. 2001, 4343Ϫ4352
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/1122Ϫ4343 $ 17.50ϩ.50/0
4343

´
E. Anakabe, J. L. Vicario, D. Badıa, L. Carrillo, V. Yoldi
FULL PAPER
some of them require multistep syntheses, the use of highly
toxic reagents, laborious separation of diastereoisomers or
harsh reaction conditions, while some lack the required
high chemo- and diastereoselectivities for subsequent syn-
thetic purposes. We have thus been engaged in the develop-
ment of a suitable, high-yielding procedure for the ste-
reocontrolled synthesis of this particular kind of racemi-
zation-prone amino acids.[15] One possible route to these
derivatives might be a stereocontrolled amination[16,17] of
arylacetamide enolates using (S,S)-(ϩ)-pseudoephedrine as
chiral auxiliary,[18] as shown in Scheme 2. Subsequent hy-
drolysis of the obtained adducts would afford the wanted
amino acids in enantiopure form, provided that no racemiz-
ation at the newly created chiral centre occurred during
these processes.
Scheme 3
rine-derived enolates with other electrophiles required the
aid of LiCl salts to accelerate the reaction.[18,20]
The adducts 2aϪd were treated with trifluoroacetic acid,
followed by hydrogenation of the resulting solution over Ni/
Raney catalyst to yield the target arylglycine-based (S,S)-
(ϩ)-pseudoephedrine amides 3aϪd. These, upon acid hy-
drolysis (9  H2SO4/dioxane), afforded the corresponding
amino acids 4aϪd in good yields after ion exchange chro-
matography. In addition, the chiral auxiliary (S,S)-(ϩ)-
pseudoephedrine could be recovered from the reaction mix-
ture in ca. 88% yield and with no racemization, as indicated
by the [α]2D0 value (Table 1). In order to calculate the ee with
which the arylglycines 4aϪd had been obtained, they were
converted into the corresponding methyl ester derivatives
5aϪd by treatment with 2,2-dimethoxypropane/HCl;[21]
chiral HPLC analysis then showed that they were of
Scheme 2
In this paper we wish to report a detailed description of
this procedure for the stereocontrolled synthesis of arylgly-
cines and their use as precursors of chiral, nonracemic 7,8-
disubstituted 3-aryl-1,2,3,4-tetrahydroisoquinolin-4-ols.
Results and Discussion
1. Asymmetric Synthesis of Arylglycines
As shown in Scheme 3, the arylacetic acid-derived (S,S)- Ͼ99% ee. This confirmed that all of the transformations
(ϩ)-pseudoephedrine amides 1aϪd, prepared as previously performed on the adducts 2aϪd had proceeded without ra-
reported,[19] were deprotonated under kinetic conditions, cemization in any of the steps. It should also be pointed out
and subjected to amination reaction at Ϫ105 °C, using di- that arylglycine 4d has been employed as a key precursor in
tert-butyl azodicarboxylate (DTBAD) as a source of elec- the total synthesis of vancomycin-like antibiotics.[22]
trophilic nitrogen.[16] The resulting adducts 2aϪd were ob-
The absolute configuration of the obtained arylglycines
tained in Ͼ95% de, determined by H NMR spectroscopy was assigned as S by comparison of the [α]2D0 value meas-
by comparison of the spectra of the obtained adducts with ured for arylglycine 4c ([α]2D0 ϭ ϩ120.8, c ϭ 0.4, H2O) with
those of the corresponding mixtures of epimers at the newly that reported in the literature ([α]2D0 ϭ Ϫ119.7 (c ϭ 0.8,
created chiral centre. The amination reaction proved to be H2O) for the R isomer).[14k] The stereochemistry of the
fast, and was complete within a few minutes, in contrast newly created chiral centre during the amination reaction
with other reports[18,19] in which reactions of pseudoephed- of amides 1aϪd is hence in agreement with a previously
1
Table 1. Stereocontrolled synthesis of arylglycines
R1
R2
R3
Prod.
Yield (%)
dr (%)[a]
Prod.
Yield (%)
Prod.
Yield (%)
Prod.
Yield (%)
ee (%)[b]
OMe
OCH2O
OMe
OMe
H
H
OMe
OBn
2a
2b
2c
2d
89
91
90
86
Ͼ95:5
Ͼ95:5
Ͼ95:5
Ͼ95:5
3a
3b
3c
3d
78
79
78
75
4a
4b
4c
4d
86
89
91
88
5a
5b
5c
5d
88
79
90
87
Ͼ99
Ͼ99
Ͼ99
Ͼ99
OMe
OMe
OBn
[a]
1
[b]
Determined by H NMR. Ϫ
Determined by chiral HPLC analysis (Chiralcel OD, UV detector, Hexanes/2-propanol 50:50. Flow
rate 0.60 mL/min).
4344
Eur. J. Org. Chem. 2001, 4343Ϫ4352

Asymmetric Synthesis of Arylglycines and Their Use as Chiral Templates
FULL PAPER
proposed mechanism[18] in which the high level of diastereo- followed by reduction with NaBH4 (Scheme 4, Table 2).
control observed in the reaction was attributed to exclusive The next step consisted of the methylation of the secondary
formation of the Z enolate, followed by the attack of the amine functionality, which was performed by treatment of
nitrogen electrophile on a reactive open intermediate, held amino alcohols 8aϪd with aqueous formaldehyde in the
in a staggered, rigid conformation through the action of presence of NaBH3CN. The reaction proceeds through ini-
bridging solvent or iPrNH (from LDA) molecules (Fig- tial formation of oxazolidine intermediates (which could be
ure 2).
isolated and identified) that, in the presence of excess of
reducing agent, underwent ring-opening to yield the target
N-methyl derivatives 9aϪd in good yields.
In order to complete the projected synthesis, amino alco-
hols 9aϪd were submitted to Swern oxidation reactions[24]
under modified conditions as previously reported by us.[25]
Thus, when amino alcohols 9aϪd were treated with oxalyl
chloride, dimethyl sulfoxide and diisopropylethylamine, α-
1
amino aldehydes 10aϪd could be detected in the H NMR
spectra of the crude mixtures and were isolated as colour-
less oils, prone to decomposition.[26] Finally, with the
freshly prepared aldehydes 10aϪd in hand, acid-catalysed
aromatic electrophilic reactions[8,27] were performed with a
nondehydrating reagent, affording the desired 3-aryl-
1,2,3,4-tetrahydroisoquinolin-4-ols 11aϪd as single diaster-
Figure 2. Proposed mechanism for the electrophilic amination of
(S,S)-(ϩ)-pseudoephedrine arylacetamide enolates
2. Asymmetric Synthesis of 7,8-Disubstituted
3-Aryl-1,2,3,4-tetrahydroisoquinolin-4-ols
With the focus now on the stereocontrolled synthesis
of 3-aryl-1,2,3,4-tetrahydroisoquinolin-4-ols, arylglycines
4aϪb and the simple phenylglycine were reduced with
LiBH4/TMSCl,[23] yielding the corresponding β-amino al-
cohols in good yields. Afterwards, these were easily trans-
formed into the corresponding N-benzyl derivatives 8aϪd
by initial formation of an imine intermediate 7aϪd with
an aromatic aldehyde with the desired substitution pattern,
1
eoisomers (de Ͼ 95%). The H NMR spectra of the crude
reaction mixtures each showed only one resonance for H(4),
with a coupling constant (JH3/H4 ϭ 2.4Ϫ2.8 Hz) typical of a
cis relationship between the substituents at the two adjacent
stereogenic carbons. Moreover, the observation of strong
nuclear Overhauser effects between protons H(3) and H(4)
was consistent with the proposed cis relative relationships
between these protons and so allowed (3S,4S) absolute con-
figurations to be assigned to isoquinolines 11aϪd. In addi-
tion, the enantiomeric excesses in which these heterocycles
11aϪd had been obtained were determined by chiral
HPLC, showing that little or no racemization had occurred
during the process from arylglycines 4aϪb or phenylglycine
to isoquinolines 11aϪd (ee: 81Ϫ90%, Scheme 5 and
Table 3).
Table 3. Synthesis of the tetrahydroisoquinolin-4-ols 11aϪd
Prod.
R1
R2
R4
R5
Yield (%)
ee (%)[a]
11a
11b
11c
11d
OMe
OCH2O
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OBn
80
85
78
83
81
90
87
90
H
H
H
[a]
Determined by chiral HPLC analysis (Chiralcel OD, UV de-
tector, hexanes/2-propanol 75:25. Flow rate 0.50 mL/min)
Scheme 4
Table 2. Synthesis of N-methylamino alcohols 9aϪd
R1
R2
R4
R5
Prod.
Yield (%)
Prod.
Yield (%)[a]
Prod.
Yield (%)
Prod.
Yield (%)
OMe
OCH2O
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OBn
6a
6b
6c
6c
70
72
86
86
7a
7b
7c
7d
81
90
87
90
8a
8b
8c
8d
88
91
98
98
9a
9b
9c
9d
78
78
75
73
H
H
H
[a]
Yield of crude product.
Eur. J. Org. Chem. 2001, 4343Ϫ4352
4345

´
E. Anakabe, J. L. Vicario, D. Badıa, L. Carrillo, V. Yoldi
FULL PAPER
(2S,1ЈS,2ЈS)-(؉)-2-(3,4-Dimethoxyphenyl)-2-[N,NЈ-bis(1,1-di-
methylethoxycarbonyl)hydrazino]-N-(2Ј-hydroxy-1Ј-methyl-2Ј-
phenylethyl)N-methylacetamide (2a): nBuLi (3.87 mL of a 1.5  so-
lution in hexane, 5.8 mmol) was added to a cooled (Ϫ78 °C) solu-
tion of diisopropylamide (0.81 mL, 5.8 mmol) in dry THF (2 mL).
The reaction mixture was stirred for 20 min at this temperature,
and allowed to come to room temp. and stirred for additional
10 min. The mixture was cooled again to Ϫ78 °C and a THF
(15 mL) solution of 1a (1.00 g, 2.9 mmol) was added dropwise over
5 min. The reaction mixture was stirred for 1 h at this temperature,
for 15 min. at 0 °C and for 5 min. at room temp., after which it
was cooled again to Ϫ105 °C, at which temperature a solution of
DTBAD (0.67 g, 2.9 mmol) in dry THF (10 mL) was added drop-
wise over 10 min. The resulting solution was stirred for 1 h at Ϫ105
°C, allowed to come to room temp. and quenched with a saturated
NH4Cl solution (30 mL). The mixture was extracted with CH2Cl2
(3 ϫ 50 mL) and the combined organic fractions were collected,
dried over Na2SO4 and filtered. The solvent was removed in vacuo
to afford a yellowish oil, which was purified by flash column chro-
matography (hexanes/ethyl acetate, 2:8). Yield: 1.48 g, 89%. Mp:
89Ϫ92 °C (Et2O). Ϫ [α]2D0 ϭ ϩ110.7 (c ϭ 0.9, CH2Cl2). Ϫ IR
(KBr): ν˜ ϭ ν˜ ϭ 3401, 1701 cmϪ1. Ϫ 1H NMR (CDCl3) (5:1 rotamer
ratio; *indicates minor rotamer resonances): δ ϭ 0.55* (d, J ϭ
6.7 Hz, 3 H), 0.99 (d, J ϭ 6.7 Hz, 3 H), 1.18* (s, 18 H), 1.44 (s, 18
H), 2.28 (br. s, 1 H), 2.56* (s, 3 H), 2.67 (s, 3 H), 3.79 (s, 3 H), 3.81
(s, 3 H), 4.01 (m, 1 H), 4.45 (m, 2 H), 6.03 (s, 1 H), 6.45Ϫ6.95 (m, 3
H), 7.04Ϫ7.29 (m, 5 H). Ϫ 13C NMR (CDCl3) (5:1 rotamer ratio; *
indicates minor rotamer resonances): δ ϭ 13.6, 13.9*, 26.4, 27.1*,
27.4, 27.5, 27.7*, 55.2, 55.3*, 61.8, 65.2, 75.0*, 76.5, 79.1, 80.7*,
80.9, 81.2*, 110.3, 110.5*, 112.3, 121.7*, 124.2, 124.8*, 126.3,
127.1*, 127.5*, 127.8, 127.9*, 130.2, 148.0, 148.2*, 148.3, 148.5*,
151.0*, 151.2, 152.0*, 152.3, 153.6, 154.2*, 155.0*, 155.6, 171.4,
172.0*. Ϫ MS (EI): m/z (rel. int.): 573 (1) [Mϩ], 58 (100). Ϫ
C30H43N3O8: calcd. C 62.81, H 7.56, N 7.32; found C 62.85, H
7.51, N 7.41.
Scheme 5
Conclusion
In summary, a simple and highly efficient route for the
stereoselective preparation of arylglycines has been de-
veloped, using a stereocontrolled amination procedure of
(S,S)-(ϩ)-pseudoephedrine arylacetamide enolates as a key
step. This affords access to the arylglycine skeleton in only
four steps, with easily performed and high-yielding reac-
tions. These arylglycines proved to be excellent chiral tem-
plates for the stereocontrolled synthesis of 3-aryl-1,2,3,4-
tetrahydroisoquinolin-4-ols with a 7,8-disubstitution pat-
tern in the aromatic ring of the isoquinoline core, a pattern
commonly found in nature and not accessible by conven-
tional heterocyclization routes such as PictetϪSpengler or
BischlerϪNapieralsky cyclization. The most advantageous
feature of the synthesis reported here is the fact that the
target heterocycle can be obtained with any desired substi-
tution pattern, provided that this substitution pattern can
be introduced in the starting arylglycine and aromatic alde-
hyde.
[2S,1ЈS,2ЈS]-(؉)-2-[N,NЈ-Bis(1,1-dimethylethoxycarbonyl)-
hydrazino]-N-(2Ј-hydroxy-1Ј-methyl-2Ј-phenylethyl)-N-methyl-2-
(3,4-methylenedioxyphenyl)acetamide (2b): Amide 2b was prepared
by the same procedure as employed for 2a, using amide 1b (1.00 g,
3.0 mmol) and DTBAD (0.70 g, 3.0 mmol). Yield: 1.54 g, 91%.
Mp: 150Ϫ153 °C (Et2O). [α]2D0 ϭ ϩ74.5 (c ϭ 1.2, CH2Cl2). Ϫ IR
Experimental Section
(KBr): ν ϭ 3400, 1710 cmϪ1. Ϫ 1H NMR (CDCl3) (7:1 rotamer
General Remarks: Melting points were determined in unsealed ca-
pillary tubes and are uncorrected. Ϫ IR spectra were obtained on
KBr pellets (solids) or CHCl3 solution (oils). NMR spectra were
˜
ratio; *indicates minor rotamer resonances): δ ϭ 0.59* (d, J ϭ
6.6 Hz, 3 H), 1.02 (d, J ϭ 6.6 Hz, 3 H), 1.23* (s, 18 H), 1.54 (s, 18
H), 2.59* (s, 3 H), 2.69 (s, 3 H), 4.12 (m, 1 H), 4.57 (m, 2 H), 6.09
(s, 1 H), 6.22 (s, 2 H), 6.31* (s, 2 H), 6.54Ϫ7.11 (m, 3 H), 7.22Ϫ7.35
(m, 5 H). Ϫ 13C NMR (CDCl3) (7:1 rotamer ratio, *indicates minor
rotamer resonances): δ ϭ 13.9, 14.2*, 25.1, 27.6, 27.7*, 27.8*, 28.0,
61.6, 61.9, 75.6*, 76.5, 79.6*, 79.7, 80.7, 81.0*, 95.9, 110.2,
110.6*, 123.6, 126.0*, 126.3, 126.4*, 126.7, 127.5*, 127.9, 128.2*,
128.4*, 128.9, 141.0, 141.7*, 147.2, 147.4*, 151.2*, 151.4, 152.1*,
152.3, 153.7, 154.4*, 155.4*, 155.7, 171.8*, 172.2. Ϫ MS (EI): m/z
(rel. int.): 557 (1) [Mϩ], 237 (100). Ϫ C29H39N3O8: calcd. C 62.46,
H 7.05, N 7.54; found C 62.39, H 7.11, N 7.50.
recorded at 20Ϫ25 °C, at 250 MHz for H and 62.8 MHz for 13C,
1
and resonances are reported in ppm relative to tetramethylsilane
unless otherwise stated. Assignment of individual 13C resonances
were supported by DEPT experiments. 1H-{1H} NOE experiments
were carried out in the difference mode by irradiation of all the
lines of a multiplet.[28] Ϫ Mass spectra were recorded by electron
impact at 70 eV. Ϫ TLC was carried out with 0.2 mm. thick silica
gel plates (Merck Kieselgel GF254). Viewing was by UV light or by
spraying with Dragendorff’s reagent.[29] Ϫ Flash column chroma-
tography[30] on silica gel was performed with Merck Kieselgel 60
(230Ϫ400 mesh). Determination of enantiomeric excesses was per-
formed by chiral HPLC analysis of noncrystallized samples using
[2S,1ЈS,2ЈS]-(؉)-2-[N,NЈ-Bis(1,1-dimethylethoxycarbonyl)-
a Chiracel OD column with a UV detector, with eluents and flow hydrazino]N-(2Ј-hydroxy-1Ј-methyl-2Ј-phenylethyl)-N-methyl-2-
rates as indicated in each case. Ϫ All solvents used in reactions
(3,4,5-trimethoxyphenyl)acetamide (2c): Amide 2c was prepared by
the same procedure as employed for 2a, using amide 1c (1.00 g,
were dried and purified according to standard procedures.[31] nBuLi
was titrated with diphenylacetic acid periodically prior to use. All 2.6 mmol) and DTBAD (0.61 g, 2.67 mmol). Yield: 1.45 g, 90%.
air- or moisture-sensitive reactions were performed under argon.
The glassware was oven-dried (140 °C) overnight and purged with
argon.
M.p. 130Ϫ133 °C (Et2O). [α]2D0 ϭ ϩ118.2 (c ϭ 0.9, CH2Cl2). Ϫ IR
(KBr): ν˜ ϭ 3400, 1750 cmϪ1. Ϫ 1H NMR (CDCl3) (5:2 rotamer
ratio; *indicates minor rotamer resonances): δ ϭ 0.56* (d, J ϭ
4346
Eur. J. Org. Chem. 2001, 4343Ϫ4352

Asymmetric Synthesis of Arylglycines and Their Use as Chiral Templates
Ϫ1. Ϫ H NMR (CDCl3) (3:1 rotamer ratio; *
˜ ϭ 3330, 1622 cm
FULL PAPER
1
6.7 Hz, 3 H), 0.85 (d, J ϭ 6.7 Hz, 3 H), 1.12* (s, 18 H), 1.31 (s, 18
ν
H), 2.28 (sa, 1 H), 2.49* (s, 3 H), 2.55 (s, 3 H), 3.63 (s, 3 H), 3.82 indicates minor rotamer resonances): δ ϭ 0.50 (d, J ϭ 6.7 Hz, 3
(s, 6 H), 3.98 (m, 1 H), 4.43 (m, 2 H), 6.00 (s, 1 H), 6.58 (s, 2 H), H), 0.80* (d, J ϭ 6.7 Hz, 3 H), 2.64* (s, 3 H), 2.87 (s, 3 H), 3.0Ϫ3.4
6.62* (s, 2 H), 7.00Ϫ7.23 (m, 5 H). Ϫ 13C NMR (CDCl3) (5:2
(sa, 3 H), 3.58 (m, 1 H), 4.49 (m, 1 H), 4.94 (s, 1 H), 5.86 (s, 2 H),
rotamer ratio, *indicates minor rotamer resonances): δ ϭ 13.5, 5.89* (s, 2 H), 6.63Ϫ6.73 (m, 3 H), 7.24Ϫ7.35 (m, 5 H). Ϫ 13C
13.9*, 26.3, 27.2, 27.7, 27.9, 28.2*, 55.1, 55.4*, 61.7, 64.6, 75.1*, NMR (CDCl3) (3:1 rotamer ratio; *indicates minor rotamer reso-
76.3, 79.0*, 80.2, 80.7, 81.0*, 110.2, 110.4*, 124.2, 124.6*, 126.1,
nances): δ ϭ13.8, 14.2*, 27.3, 55.9, 57.7, 74.4*, 75.0, 101.0, 107.2,
127.1*, 127.4, 127.9*, 148.1,, 148.3*, 148.5, 148.7*, 151.0*, 151.4, 107.3*, 107.5, 108.4*, 120.4, 120.5*, 120.7, 120.9*, 126.4, 126.7*,
152.2*, 152.4, 153.5, 154.3*, 155.0*, 155.5, 170.2*, 172.6. Ϫ MS 127.5*, 127.7, 134.1, 134.8*, 141.7, 141.8*, 146.9, 147.0*, 147.9*,
(EI): m/z (rel. int.): 603 (1) [Mϩ], 58 (100). Ϫ C31H45N3O9: calcd. 149.1, 173.6*, 173.8. Ϫ MS (EI): m/z (rel. int.): 342 (1) [Mϩ], 162
C 61.67, H 7.51, N 6.96; found C 61.70, H 7.53, N 7.00.
(100). Ϫ C19H22N2O4: calcd. C 66.65, H 6.48, N 8.18; found C
66.60, H 8.12, N 8.22.
[2S,1ЈS,2ЈS]-(؉)-2-[N,NЈ-Bis(1,1-dimethylethoxycarbonyl)-
hydrazino]-2-(3,5-dibenzyloxy-4-methoxyphenyl)-N-(2Ј-hydroxy-1Ј-
methyl-2Ј-phenylethyl)-N-methylacetamide (2d): Amide 2d was pre-
pared by the same procedure as employed for 2a, using amide 1d
(2S,1ЈS,2ЈS)-(؉)-2-Amino-N-(2Ј-hydroxy-1Ј-methyl-2Ј-phenylethyl)-
N-methyl-2-(3,4,5-trimethoxyphenyl)acetamide (3c): Amide 3c was
prepared by the same procedure as employed for 3a, using 2c
(1.00 g, 1.9 mmol) and DTBAD (0.44 g, 1.9 mmol). Yield: 1.22 g, (0.73 g, 1.2 mmol) as starting material. Yield: 0.34 g, 78%. M.p.
85%. [α]2D0 ϭ ϩ121.4 (c ϭ 0.9, CH2Cl2). Ϫ IR (CHCl3): ν ϭ 3388,
172Ϫ175 °C (Et2O). [α]2D0 ϭ ϩ112.6 (c ϭ 0.2, CH2Cl2). Ϫ IR (KBr):
˜
˜
1
1698 cmϪ1. Ϫ H NMR (CDCl3) (5:1 rotamer ratio; *indicates mi-
ν ϭ 3350, 1660 cmϪ1. Ϫ 1H NMR (CDCl3) (3:2 rotamer ratio;
nor rotamer resonances): δ ϭ 0.53* (d, J ϭ 7.2 Hz, 3 H), 1.02 (d, *indicates minor rotamer resonances): δ ϭ 0.36 (d, J ϭ 6.7 Hz, 3
J ϭ 6.6 Hz, 3 H), 1.17* (s, 18 H), 1.46 (s, 18 H), 2.23 (sa, 1 H), H), 0.94* (d, J ϭ 6.7 Hz, 3 H), 2.56* (s, 3 H), 2.81 (s, 3 H), 3.0Ϫ3.5
2.51* (s, 3 H), 2.57 (s, 3 H), 3.65 (m, 1 H), 3.74 (s, 3 H), 3.78* (s, (sa, 3 H), 2.53 (s, 3 H), 2.56* (s, 3 H), 2.61* (s, 6 H), 2.83 (s, 6 H),
3 H), 4.45 (m, 2 H), 4.97* (s, 4 H), 5.01 (s, 4 H), 6.48 (s, 2 H), 4.01 (m, 1 H), 4.42 (m, 1 H), 4.86 (s, 1 H), 6.58 (s, 2 H), 7.11Ϫ7.19
7.23Ϫ7.47 (m, 15 H). Ϫ 13C NMR (CDCl3) (5:1 rotamer ratio, (m, 5 H). Ϫ 13C NMR (CDCl3) (3:2 rotamer ratio; *indicates minor
*indicates minor rotamer resonances): δ ϭ 13.4, 14.1*, 26.1, 26.8,
rotamer resonances): δ ϭ 13.5, 14.4*, 27.2, 55.3, 55.4*, 56.1,
27.2*, 27.4, 27.9*, 57.3, 57.8*, 60.1, 60.3*, 70.3*, 70.4, 74.4*, 75.3, 56.6*, 57.2, 59.0, 74.5*, 75.4, 109.9, 110.2*, 126.2, 126.5*, 126.7,
80.1*, 80.9, 81.3, 81.4*, 124.3, 124.6*, 125.2, 125.5*, 126.2, 126.4*, 127.0*, 127.5, 127.7*, 141.9, 142.2*, 147.8, 148.1*, 153.4, 154.1*,
126.7, 127.1*, 127.4, 127.8*, 127.9, 128.1*, 128.6, 130.1, 130.5*, 155.3*, 155.6, 173.2*, 173.5. Ϫ MS (EI): m/z (rel. int.): 358 (1)
136.5, 136.8*, 137.2, 137., 151.2*, 151.4, 152.0*, 152.2, 153.4, [Mϩ], 164 (100). Ϫ C21H28N2O5: calcd. C 64.93, H 7.27, N 7.21;
153.5*, 154.8, 171.6*, 172.3. Ϫ MS (EI): m/z (rel. int.): 412 (12), found C 64.90, H 7.30, N 7.18.
91 (100). Ϫ C43H53N3O9: calcd. C 68.32, H 7.07, N 5.56; found C
68.39, H 7.01, N 5.47.
(2S,1ЈS,2ЈS)-(؉)-2-Amino-2-(3,5-dibenzyloxy-4-methoxyphenyl)-N-
(2Ј-hydroxy-1Ј-methyl-2Ј-phenylethyl)-N-methylacetamide
(3d):
[2S,1ЈS,2ЈS]-(؉)-2-Amino-2-(3,4-dimethoxyphenyl)-N-(2Ј-hydroxy- Amide 3d was prepared by the same procedure as employed for 3a,
1Ј-methyl-2Ј-phenylethyl)-N-methylacetamide (3a): Trifluoroacetic
acid (15 mL) was added in one portion to a cooled (0 °C) solution
using 2d (0.86 g, 1.16 mmol) as starting material. Yield: 0.51 g,
82%. [α]2D0 ϭ ϩ116.7 (c ϭ 0.2, CH2Cl2). Ϫ IR (CHCl3): ν˜ ϭ 3355,
of 2a (0.67 g, 1.2 mmol) in CH2Cl2 (10 mL). The mixture was 1628 cmϪ1. Ϫ 1HϪNMR (CDCl3) (3:2 rotamer ratio; *indicates
stirred for 30 min. at room temp. and transferred to a hydrogena-
minor rotamer resonances): δ ϭ 0.41 (d, J ϭ 7.2 Hz, 3 H), 0.96*
tion vessel. Ni/Raney was added and the mixture was shaken under (d, J ϭ 6.5 Hz, 3 H), 2.53* (s, 3 H), 2.78 (s, 3 H), 3.0Ϫ3.5 (sa, 3
H2 pressure (150 psi) for 48 h. The catalyst was filtered and the H), 3.72 (m, 1 H), 3.77* (s, 3 H), 3.82 (s, 3 H), 4.44 (m, 1 H), 5.02*
resulting solution was basified with NaOH (aq) and extracted with
CH2Cl2 (3 ϫ 40 mL). The combined organic fractions were col- NMR (CDCl3) (3:2 rotamer ratio; *indicates minor rotamer reson-
lected, dried over Na2SO4 and filtered, and the solvent was re- ances): δ ϭ 13.5, 14.4*, 27.2, 57.2, 57.9, 62.3*, 62.6, 70.1*, 70.4,
moved in vacuo to afford a yellowish oil, which was purified by 74.1*, 75.5, 124.2, 124.4*, 125.6, 125.8*, 126.1, 126.3*, 126.6,
(s, 4 H), 5.06 (s, 4 H), 6.54 (s, 2 H), 7.28Ϫ7.52 (m, 15 H). Ϫ 13C
normal pressure column chromatography (methanol/ethyl acetate
127.2*, 127.5, 127.9*, 127.9, 128.4*, 128.5 (Ar{CH}), 130.3,
130.6*, 136.2, 136.9*, 137.1, 137.6*, 151.3, 151.5*, 151.9, 171.2*,
172.4. Ϫ MS (EI): m/z (rel. int.): 540 (1) [Mϩ], 91 (100). Ϫ
1:1). Yield: 0.32 g, 78%. M.p. 137Ϫ139 °C (Et2O). [α]2D0ϭ ϩ105.2
(c ϭ 0.2, CH2Cl2). Ϫ IR (KBr): ν ϭ 3354, 1631 cmϪ1. Ϫ 1H NMR
˜
(CDCl3) (3:2 rotamer ratio; *indicates minor rotamer resonances): C33H36N2O5: calcd. C 73.31, H 6.71, N 5.18; found C 73.28, H
0.38 (d, J ϭ 6.7 Hz, 3 H), 0.92* (d, J ϭ 6.7 Hz, 3 H), 2.54* (s, 3 6.65, N 5.12.
H), 2.80 (s, 3 H), 3.0Ϫ3.5 (sa, 3 H), 2.51 (s, 3 H), 2.57* (s, 3 H),
(2S)-(؉)-3,4-Dimethoxyphenylglycine (4a): A solution of the α-ami-
noamide 3a (0.53 g, 1.5 mmol) in dioxane (10 mL) was added to a
cooled (0 °C) 9  H2SO4 solution and the mixture was refluxed for
6 h. Water (20 mL) was added, and the mixture was carefully bas-
ified to pH 12 and extracted with CH2Cl2 (3 ϫ 20 mL) (from which
(S,S)-(ϩ)-pseudoephedrine could be recovered in ca. 88% yield).
The aqueous layer was then basified with HCl to pH 3 and was
2.60* (s, 3 H), 2.80 (s, 3 H), 4.02 (m, 1 H), 4.44 (m, 1 H), 4.88 (s,
1 H), 6.64Ϫ6.71 (m, 3 H), 7.14Ϫ7.21 (m, 5 H). Ϫ 13C NMR
(CDCl3) (3:2 rotamer ratio; *indicates minor rotamer resonances):
δ ϭ 13.6, 14.2*, 27.0, 55.4, 55.5*, 55.9, 56.0*, 57.5, 59.2, 74.0*,
75.1, 109.7, 110.8*, 118.9, 119.3*, 126.2, 126.4*, 126.5, 127.1*,
127.5, 127.9*, 128.1*, 128.5, 141.8, 141.9*, 147.9, 148.1*, 153.6,
154.1*, 155.7*, 155.9, 173.6*, 173.8. Ϫ MS (EI)m/z (Int. rel.): 358
washed with CH2Cl2 (3 ϫ 30 mL). After reduction of the volume
(1) [Mϩ], 165 (100). Ϫ C20H26N2O4: calcd. C 67.02, H 7.31, N 7.82;
of the aqueous layer in vacuo to approx. 10 mL, it was loaded onto
found C 67.09, H 7.30, N 7.88.
an ion-exchange column (DOWEX 50WX4Ϫ50), washed with
(2S,1ЈS,2ЈS)-(؉)-2-Amino-N-(2Ј-hydroxy-1Ј-methyl-2Ј-phenylethyl)- water until the collected fractions were at pH 7 and eluted with a
N-methyl-2-(3,4-methylenedioxyphenyl)acetamide (3b): Amide 3b
20% NH4OH solution. These basic fractions were collected and the
was prepared by the same procedure as employed for 3a, using 2b solvent was removed in vacuo, yielding arylglycine 4a as a white
(0.58 g, 1.0 mmol) as starting material. Yield: 0.28 g, 79%. M.p. solid. Yield: 0.27 g, 86%. M.p. 178Ϫ181 °C. [α]2D0 ϭ ϩ98.6 (c ϭ
161Ϫ163 °C (Et2O). [α]2D0 ϭ ϩ67.2 (c ϭ 1.8, CH2Cl2). Ϫ IR (KBr):
Eur. J. Org. Chem. 2001, 4343Ϫ4352
0.02, H2O). Ϫ IR (KBr): ν ϭ 3450, 1660 cmϪ1. Ϫ 1H NMR
˜
4347

´
E. Anakabe, J. L. Vicario, D. Badıa, L. Carrillo, V. Yoldi
FULL PAPER
(D2OϩCD3OD): δ ϭ 3.72 (s, 3 H), 3.81 (s, 3 H), 4.05 (s, 1 H), for 5a, using 4c (0.19 g, 0.8 mmol) as starting material. Yield:
6.54Ϫ6.77 (m, 3 H). Ϫ 13C NMR (D2OϩCD3OD): δ ϭ 56.0, 57.2, 0.18 g, 90%. M.p. (as HCl salt) 231Ϫ233 °C. [α]2D0 ϭ ϩ113.5 (c ϭ
0.3, CH2Cl2). Ϫ IR (KBr): ν ϭ 3350, 1740 cmϪ1. Ϫ 1H NMR
˜
65.5, 109.1, 110.2, 111.1, 129.3, 132.0, 141.3, 177.0. Ϫ C10H13NO4:
calcd. C 56.86, H 6.20, N 6.63; found C 56.80, H 6.21, N 6.69.
(CDCl3: δ ϭ 2.15 (sa, 2 H), 3.74 (s, 3 H), 3.84 (s, 3 H), 3.89 (s, 6
H), 4.54 (s, 1 H), 6.87 (s, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ 51.6,
55.2, 56.2, 60.7, 110.1, 132.6, 148.1, 148.7, 174.6. Ϫ MS (EI): m/z
(rel. int.): 255 (1) [Mϩ], 151 (100). Ϫ C12H18ClNO5: calcd. C 49.41,
H 6.22, N 4.80; found C 49.46, H 6.20, N 4.82.
(2S)-(؉)-3,4-Methylenedioxyphenylglycine (4b): Arylglycine 4b was
prepared by the same procedure as employed for 4a, using 3b
(0.61 g, 1.8 mmol) as starting material. Yield: 0.31 g, 89%. M.p.
195Ϫ198 °C. [α]2D0 ϭ ϩ95.5 (c ϭ 0.05, H2O). Ϫ IR (KBr): ν˜ ϭ
1
3455, 1662 cmϪ1. Ϫ H NMR (D2OϩCD3OD): δ ϭ 4.01 (s, 1 H),
Methyl
(2S)-(؉)-2-Amino-2-(3,5-dibenzyloxy-4-methoxyphenyl)-
5.84 (s, 2 H), 6.51Ϫ6.64 (m, 3 H). Ϫ 13C NMR (D2OϩCD3OD):
δ ϭ 64.9, 100.9, 109.3, 110.6, 111.2, 129.6, 132.5, 141.7, 177.6. Ϫ
C9H9NO4: calcd. C 55.39, H 4.65, N 7.18; found C 55.31, H 4.61,
N 7.12.
acetate (5d): Amino ester 5d was prepared by the same procedure
as employed for 5a, using 4d (0.23 g, 0.6 mmol) as starting material.
Yield: 0.21 g, 87%. [α]2D0 ϭ ϩ118.4 (c ϭ 0.3, CH2Cl2). Ϫ IR
(CHCl3): ν ϭ 3344, 1736 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 2.10
˜
(2S)-(؉)-3,4,5-Trimethoxyphenylglycine (4c): Arylglycine 4c was
(sa, 2 H), 3.71 (s, 3 H), 3.86 (s, 3 H), 4.51 (s, 1 H), 5.28 (s, 4 H),
prepared by the same procedure as employed for 4a, using 3c 6.57 (s, 2 H), 7.23Ϫ7.48 (m, 10 H). Ϫ 13C NMR (CDCl3): δ ϭ
(0.58 g, 1.6 mmol) as starting material. Yield: 0.35 g, 91%. M.p. 51.4, 57.2, 60.9, 71.6, 107.5, 127.3, 128.0, 128.9, 129.1, 136.1, 139.8,
201Ϫ203 °C. [α]2D0 ϭ ϩ120.8 (c ϭ 0.04, H2O). Ϫ IR (KBr): ν ϭ
152.3, 173.6. Ϫ MS (EI): m/z (rel. int.): 407 (3) [Mϩ], 91 (100). Ϫ
C24H25NO5: calcd. C 70.74, H 6.18, N 3.44; found C 70.81, H 6.15,
N 3.41.
˜
3500, 1600 cmϪ1(CϭO). Ϫ 1H NMR (D2OϩCD3OD): δ ϭ 3.74
(s, 3 H), 3.82 (s, 6 H), 4.07 (s, 1 H), 6.71 (s, 2 H). Ϫ 13C NMR
(D2OϩCD3OD: δ ϭ 56.1, 57.1, 65.8, 109.3, 129.5, 132.2, 148.5,
177.1. Ϫ C11H15NO5: calcd. C 54.77, H 6.27, N 5.81; found C
54.72, H 6.23, N 5.80.
(2S)-(؉)-2-Amino-2-(3,4-dimethoxyphenyl)ethanol (6a): TMSCl
(14.37 g, 132.3 mmol) was added to a cooled (0 °C) suspension of
LiBH4 (1.44 g, 66.1 mmol) in dry THF (33 mL). Arylglycine 4a
(7.00 g, 33.1 mmol) was then added and the mixture was stirred at
0 °C for 1 h and at room temp. for 24 h. The mixture was then
cooled to 0 °C, MeOH (50 mL) was added, and the resulting solu-
tion was stirred for an additional 10 min. The volatiles were re-
moved in vacuo and a 20% KOH solution (20 mL) was added to
the resulting oil, after which the mixture was stirred for 1 h. The
mixture was extracted with CH2Cl2 (3 ϫ 50 mL) and the combined
organic extracts were dried over Na2SO4 and filtered, and the sol-
vent was removed in vacuo to afford a yellowish oil, which was
purified by crystallization (hexane/EtOAc 1:1). Yield: 5.21 g, 80%.
(2S)-(؉)-3,5-Dibenzyloxy-4-methoxyphenylglycine (4d): Arylglycine
4d was prepared by the same procedure as employed for 4a, using
3d (0.58 g, 1.1 mmol) as starting material. Yield: 0.35 g, 83%. M.p.
114Ϫ117 °C. [α]2D0 ϭ ϩ93.5 (c ϭ 0.1, H2O). Ϫ IR (KBr): ν ϭ 3437,
˜
1
1680 cmϪ1. Ϫ H NMR (D2OϩCD3OD): δ ϭ 3.87 (s, 3 H), 4.23
(s, 1 H), 5.31 (s, 4 H), 6.63 (s, 2 H), 7.25Ϫ7.41 (m, 10 H). Ϫ 13C
NMR (D2OϩCD3OD): δ ϭ 60.6, 65.3, 71.2, 107.2, 127.1, 127.8,
128.5, 129.1, 136.3, 139.7, 152.6, 175.2. Ϫ C23H23NO5: calcd. C
70.21, H 5.89, N 3.56; found C 70.16, H 5.94, N 3.49.
Methyl (2S)-(؉)-2-Amino-2-(3,4-dimethoxyphenyl)acetate (5a): A
suspension of arylglycine 4a (0.33 g, 1.6 mmol) in MeOH (5 mL)
and HClconc (5 mL) was refluxed until all the arylglycine was dis-
solved. It was then cooled to room temp., 2,2-dimethoxypropane
(4 mL) was added, and the reaction mixture was stirred for 24 h.
Water (20 mL) was added and the mixture was basified with NaOH
and extracted with CH2Cl2 (3 ϫ 20 mL). The combined organic
extracts were dried over Na2SO4 and filtered, and the solvent was
remover in vacuo to afford α-amino ester 5a after flash column
chromatography purification (hexanes/ethyl acetate 1:1). Yield:
0.31 g, 88%. M.p. (as HCl salt) 209Ϫ212 °C. [α]2D0 ϭ ϩ131.2 (c ϭ
[α]2D0 ϭ ϩ12.1 (c ϭ 0.6, 1  HCl). M.p. (hexane/EtOAc 1:1): 92Ϫ94
1
°C. Ϫ IR (KBr): ν ϭ 3500Ϫ3000 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ
˜
2.67 (s, 3 H), 3.50 (dd, J ϭ 10.7, 8.5 Hz, 1 H), 3.66 (dd, J ϭ 10.7,
4.0 Hz, 1 H), 3.81 (s, 3 H), 3.84 (s, 3 H), 3.96 (dd, J ϭ 8.5, 4.0 Hz,
1 H), 6.76Ϫ6.84 (m, 3 H). Ϫ 13C NMR (CDCl3): δ ϭ 55.7, 56.9,
67.8, 109.5, 110.9, 118.4, 134.8, 148.1, 148.8. Ϫ MS (EI): m/z (rel.
int.): 166 (100) [Mϩ Ϫ 31]. Ϫ C10H15NO3: calcd. C 60.9, H 7.67,
N 7.10; found C 61.2, H 7.90, N 7.32.
(2S)-(؊)-2-Amino-2-(3,4-methylendioxyphenyl)ethanol (6b): Aryl-
glycinol 6b was prepared by the same procedure as employed for
6a, using 4b (6.45 g, 33.1 mmol) as starting material. Yield: 4.67 g,
78%. [α]2D0 ϭ Ϫ45.0 (c ϭ 0.1, HCl 1 ). M.p. (hexane/EtOAc 1:1):
0.3, CH2Cl2). Ϫ IR (KBr): ν ϭ 3350, 1750 cmϪ1. Ϫ 1H NMR
˜
(CDCl3): δ ϭ 2.11 (sa, 2 H), 3.70 (s, 3 H), 3.86 (s, 3 H), 3.88 (s, 3
H), 4.56 (s, 1 H), 6.82 Ϫ6.91 (m, 3 H). Ϫ 13C NMR (CDCl3): δ ϭ
51.8, 55.4, 56.0, 60.1, 109.4, 110.6, 118.2, 132.2, 148.3, 148.9, 174.1.
Ϫ MS (EI): m/z (rel. int.): 225 (1) [Mϩ], 151 (100). Ϫ C11H16ClNO4:
calcd. C 50.48, H 6.16, N 5.35; found C 54.41, H 6.19, N 5.30.
76Ϫ78 °C. Ϫ IR (KBr): ν ϭ 3500Ϫ3000 cm .
Ϫ1 Ϫ 1H NMR (CDCl3):
˜
δ ϭ 3.31 (s, 3 H), 3.48Ϫ3.69 (m, 2 H), 3.96 (s, 1 H), 5.92 (s, 2 H),
6.76Ϫ6.82 (m, 3 H). Ϫ 13C NMR (CDCl3): δ ϭ 57.0, 67.5, 101.0,
106.9, 108.2, 110.9, 119.8, 135.8, 146.9, 147.8. Ϫ MS (EI): m/z (Int.
Rel.): 164 (100) [Mϩ Ϫ 17]. Ϫ C9H11NO3: calcd. C 59.66, H 6.12,
N 7.73; found C 60.12, H 6.15, N 7.41.
Methyl
(2S)-(؉)-2-Amino-2-(3,4-methylenedioxyphenyl)acetate
(5b): Amino ester 5b was prepared by the same procedure as em-
ployed for 5a, using 4b (0.28 g, 1.4 mmol) as starting material.
Yield: 0.24 g, 79%. M.p. (HCl salt) 221Ϫ223 °C. [α]2D0 ϭ ϩ128.4
(2S)-(؉)-2-Amino-2-phenylethanol (6c): Phenylglycinol 6c was pre-
pared by the same procedure as employed for 6a, using (S)-(ϩ)-
phenylglycine (5.0 g, 33.1 mmol) as starting material. Yield: 3.9 g,
86%. [α]2D0 ϭ ϩ31.5 (c ϭ 0.8, HCl 1 ). M.p. (hexane/EtOAc 1:1):
(c ϭ 0.3, CH2Cl2). Ϫ IR (KBr): ν ϭ 3300, 1770 cmϪ1. Ϫ 1H NMR
˜
(CDCl3): δ ϭ 2.19 (sa, 2 H), 3.69 (s, 3 H), 4.54 (s, 1 H), 5.82 (s, 2
H), 6.81 (d, J ϭ 8.6 Hz, 1 H), 6.88 (m, 2 H). Ϫ 13C NMR (CDCl3):
δ ϭ 51.6, 60.6, 101.8, 109.5, 110.4, 118.7, 132.6, 148.9, 149.2, 174.6.
75Ϫ78 °C. Ϫ IR (KBr): ν ϭ 3400Ϫ2860 cmϪ1. Ϫ 1H NMR
˜
Ϫ
MS (EI): m/z (rel. int.): 209 (1) [Mϩ], 135 (100).
Ϫ
(CDCl3): δ ϭ 2.94 (s, 3 H), 3.55 (dd, J ϭ 10.8, 8.3 Hz, 1 H), 3.72
(dd, J ϭ 10.8, 4.1 Hz, 1 H), 4.03 (dd, J ϭ 8.3, 4.1 Hz, 1 H,
7.25Ϫ7.30 (m, 5 H). Ϫ 13C NMR (CDCl3): δ ϭ 57.3, 68.0, 126.4,
C10H12ClNO4: calcd. C 48.89, H 4.92, N 5.70; found C 48.92, H
4.97, N 5.69.
Methyl (2S)-(؉)-2-Amino-2-(3,4,5-trimethoxyphenyl)acetate (5c): 127.5, 128.6, 143.2. Ϫ C8H11NO: calcd. C 70.04, H 8.08, N 10.21;
Amino ester 5c was prepared by the same procedure as employed
found C 70.65, H 8.15, N 10.45.
Eur. J. Org. Chem. 2001, 4343Ϫ4352
4348

Asymmetric Synthesis of Arylglycines and Their Use as Chiral Templates
FULL PAPER
(2S)-(؊)-2-[(E)-2,3-Dimethoxybenzylideneamino]-2-(3,4-dimeth- moved in vacuo to afford amino alcohol 3a as a white solid. Yield:
0.31 g, 90%. [α]2D0 ϭ ϩ14.7 (c ϭ 0.3, CH2Cl2). Ϫ IR (KBr): ν ϭ
˜
oxyphenyl)ethanol (7a): A suspension of arylglycinol 6a (2.68 g,
13.6 mmol) and 2,3-dimethoxybenzaldehyde (2.50 g, 15.1 mmol) in 3500Ϫ3200 cmϪ1. Ϫ 1H NMR (CDCl3) δ ϭ2.10 (s, 2 H), 3.49Ϫ3.81
˚
benzene (100 mL) containing 4A molecular sieves was refluxed for (m, 5 H), 3.78 (s, 3 H), 3.81 (s, 3 H), 3.85 (s, 3 H), 3.89 (s, 3 H),
4 h. The mixture was allowed to come to room temperature and 6.80Ϫ7.04 (m, 6 H). Ϫ 13C NMR (CDCl3) δ ϭ46.4, 55.6, 55.8,
filtered, and solvent was removed in vacuo, yielding imino alcohol 60.7, 63.4, 66.8, 110.1, 110.9, 111.4, 119.5, 121.9, 123.9, 133.0,
7a as an oil. Yield: 4.23 g, 90%. [α]2D0 ϭ Ϫ6.4 (c ϭ 0.6, EtOH). Ϫ
133.6, 147.2, 148.2, 149.0; 152.6. Ϫ MS (EI): m/z (rel. int.): 316
IR (KBr): ν ϭ 3600Ϫ3300, 1630 cmϪ1. Ϫ 1H NMR (CD3OD) : (19) [Mϩ Ϫ 31], 151 (100). Ϫ C19H25NO5: calcd. C 65.69, H 7.25,
δ ϭ 3.75Ϫ3.90 (m, 2 H), 3.82 (s, 12 H), 4.43 (t, J ϭ 6.3 Hz, 1 H), N 4.03; found C 65.34, H 7.36, N 4.41.
6.84Ϫ7.07 (m, 5 H), 7.56Ϫ7.58 (m, 1 H), 8.76 (s, 1 H). Ϫ 13C NMR
˜
(2S)-(؉)-2-(2,3-Dimethoxybenzyl)amino-2-(3,4-methylenedioxy-
(CD3OD): δ ϭ 56.2, 56.3, 62.0, 67.8, 78.3, 112,1, 115.9, 119.9,
phenyl)ethanol (8b): Amino alcohol 8b was prepared by the same
120.8, 125.2, 130.7, 135.0, 149.6, 150.3, 150.7, 154.1, 159.6. Ϫ MS
procedure as employed for 7a, using imino alcohol 7b (0.33 g,
1.1 mmol) as starting material. Yield: 0.31 g, 90%. [α]2D0 ϭ ϩ5.43
(EI): m/z (rel. int.): 315 (20) [Mϩ Ϫ 30], 151 (100). Ϫ C19H23NO5:
calcd. C 66.07, H 6.71, N 4.05; found C 66.36, H 6.35, N 4.25.
(c ϭ 0.3, CH2Cl2). Ϫ IR (KBr): ν ϭ 3500Ϫ3200 cmϪ1. Ϫ 1H NMR
˜
(2S)-(؉)-(E)-2-(2,3-Dimethoxybenzylideneamino)-2-(3,4-methylene- (CDCl3) δ ϭ 3.41Ϫ3.82 (m, 5 H), 3.81 (s, 3 H), 3.82 (s, 3 H), 5.94
dioxyphenyl)ethanol (7b): Imino alcohol 7b was prepared by the (s, 2 H), 6.78Ϫ7.87 (m, 5 H), 6.96Ϫ699 (m, 1 H). Ϫ 13C NMR
same procedure as employed for 7a, using arylglycinol 6b (2.47 g, (CDCl3) δ ϭ46.3, 55.6, 60.6, 63.5, 66.8, 100.9, 107.4, 108.1, 120.7,
13.6 mmol) and 2,3-dimethoxybenzaldehyde (2.50 g, 15.2 mmol) as 121.8, 123.6, 133.6, 134.6, 146.7, 147.2, 147.7, 152.5. Ϫ MS (EI):
starting materials. Yield: 3.81 g, 85%. [α]2D0 ϭ ϩ10.29 (c ϭ 0.3,
m/z (rel. int.) ϭ 314 (3) [Mϩ Ϫ 17], 151 (100). Ϫ C18H21NO5: calcd.
EtOH). Ϫ IR (KBr): ν ϭ 3600Ϫ3300, 1631 cmϪ1. Ϫ 1H NMR C 65.24, H 6.39, N 4.23; found C 65.54, H 6.15, N 4.20.
(CD3OD): δ ϭ 3.71Ϫ3.79 (m, 2 H), 3.78 (s, 3 H), 3.79 (s, 3 H),
˜
(2S)-(؉)-2-(2,3-Dimethoxybenzyl)amino-2-phenylethanol (8c): Am-
4.34 (t, J ϭ 6.1 Hz, 1 H), 5.84 (s, 2 H), 6.71Ϫ7.04 (m, 5 H),
ino alcohol 8c was prepared by the same procedure as employed
for 7a, using imino alcohol 7c (0.28 g, 1.0 mmol) as starting mat-
7.53Ϫ7.56 (m, 1 H), 8.71 (s, 1 H). Ϫ 13C NMR (CD3OD: δ ϭ
56.3, 62.0, 67.8, 78,2, 102.2, 108.7, 109.1, 115.8, 119.9, 121.5, 125.2,
130.7, 136.2, 148.1, 149.0, 150.7, 154.1, 159.5. Ϫ MS (EI): m/z (rel.
int.): 299 (20) [Mϩ Ϫ 30], 135 (100). Ϫ C18H19NO5: calcd. C 65.64,
H 5.81, N 4.25; found C 65.32, H 6.01, N 4.41.
erial. Yield: 0.30 g, 98%. [α]2D0 ϭ ϩ46.0 (c ϭ 1.8, CH2Cl2). Mp:
Ϫ1
˜
66Ϫ68 °C (Et2O). Ϫ IR (KBr): ν ϭ 3500Ϫ3200, 3450Ϫ3300 cm
.
1
Ϫ H NMR (CDCl3) δ ϭ 3.40Ϫ3.60 (m, 3 H), 3.73 (s, 3 H), 3.78
(s, 3 H), 3.71Ϫ3.81 (m, 2 H), 6.77Ϫ6.81 (m, 2 H), 6.93Ϫ6.99 (m,
(2S)-(؉)-(E)-2-(2,3-Dimethoxybenzylideneamino)-2-phenylethanol 1 H), 7.29Ϫ7.33 (m, 5 H). Ϫ 13C NMR (CDCl3): δ ϭ45.9, 55.2,
(7c): Imino alcohol 7c was prepared by the same procedure as em-
60.2, 63.6, 66.3, 111.1, 121.5, 123.5, 127.0, 127.2, 128.0, 133.1,
ployed for 7a, using (S)-(ϩ)-phenylglycinol 6c (4.00 g, 29.2 mmol) 140.2, 146.9, 152.2. Ϫ MS (EI): m/z (rel. int.): 256 (21) [Mϩ Ϫ 31],
and 2,3-dimethoxybenzaldehyde (5.00 g, 30.1 mmol) as starting 151 (99), 136 (100). Ϫ C17H21NO3: calcd. C 71.04, H 7.37, N 4.88;
materials. Yield: 7.24 g, 87%. [α]2D0 ϭ ϩ10.5 (c ϭ 1.5, EtOH). M.p. found C 71.45, H 7.15, N 4.50.
˜
(Et2O/pentane 1:2.5): 68Ϫ71 °C. Ϫ IR (KBr): ν ϭ 3500Ϫ3200,
(2S)-(؉)-2-(2-Benzyloxy-3-methoxybenzyl)amino-2-phenylethanol
(8d): Amino alcohol 8d was prepared by the same procedure as
employed for 7a, using imino alcohol 7d (0.46 g, 1.3 mmol) as start-
ing material. Yield: 0.45 g, 98%. [α]2D0 ϭ ϩ54.5 (c ϭ 0.1, CH2Cl2).
1
1631 cmϪ1. Ϫ H NMR (CD3OD): δ ϭ 3.89Ϫ3.99 (m, 2 H), 3.94
(s, 6 H), 4.54 (t, J ϭ 6.4 Hz, 1 H), 7.18 (d, J ϭ 4.9 Hz, 2 H), 7.67
(m, 1 H), 7.30Ϫ7.56 (m, 5 H), 8.85 (s, 1 H). Ϫ 13C NMR (CD3OD):
δ ϭ 56.6, 62.4, 68.1, 79.0, 116.3, 120.3, 125.5, 128.7, 129.8, 131.1,
142.6, 151,2, 154.6, 160.1. Ϫ MS (EI): m/z (Rel. Int): 284 (4) [Mϩ
Ϫ 1], 254 (100). Ϫ C17H19NO3: calcd. C 71.59, H 6.71, N 4.91;
found C 71.56, H 6.57, N 4.82.
1
Mp: 65Ϫ67 °C (Et2O). Ϫ IR (KBr): ν˜ ϭ 3600Ϫ3200 cmϪ1. Ϫ H
NMR (CDCl3): δ ϭ3.1 (s, 1 H), 3.47Ϫ3.81 (m, 5 H), 3.89 (s, 3 H),
4.99 (d, J ϭ 11.1 Hz, 1 H), 5.09 (d, J ϭ 11.1 Hz, 1 H), 7.04Ϫ7.07
(m, 2 H), 7.11Ϫ7.38 (m, 11 H). Ϫ 13C NMR (CDCl3): δ ϭ 46.2,
(2S)-(؉)-(E)-2-(2-Benzyloxy-3-methoxybenzylideneamino)-2- 55.4, 63.7, 66.4, 74.5, 111.2, 121.7, 123.8, 127.1, 127.3, 127.6, 127.9,
phenylethanol (7d): Imino alcohol 7d was prepared by the same 128.1, 128.3, 133.7, 137.3, 140.2, 145.7, 152.3. Ϫ MS (EI): m/z (rel.
procedure as employed for 7a, using (S)-(ϩ)-phenylglycinol 6c int.): 280 (80) [Mϩ Ϫ 83], 178 (100). Ϫ C23H25NO3: calcd. C 76.01,
(0.26 g, 1.9 mmol) and 2-benzyloxy-3-methoxybenzaldehyde H 6.93, N 3.85; found C 76.45, H 7.15, N 3.45.
(0.48 g, 1.9 mmol) as starting materials. Yield: 0.63 g, 90%. [α]2D0
ϭ
(2S)-(؉)-2-(2,3-Dimethoxybenzyl)-N-methylamino-2-(3,4-
dimethoxyphenyl)ethanol (9a): A suspension of amino alcohol 8a
(1.70 g, 4.9 mmol) and 35% aq. HCHO (2.0 mL) in 40 mL of ace-
tonitrile was stirred for 15 minutes. The solution was then cooled
(0 °C) and NaBH3CN (1.55 g, 24.7 mmol) was added in three por-
tions. The mixture was stirred until TLC indicated full conversion
(typically 24 h). Water (25 mL) was added, the mixture was ex-
tracted with CH2Cl2 (3 ϫ 50 mL), and the combined organic frac-
tions were collected, dried over Na2SO4 and filtered. The solvent
was removed in vacuo to afford N-methylamino alcohol 4a as a
ϩ29.1 (c ϭ 0.1, EtOH). Mp: 120Ϫ121 °C. Ϫ IR (KBr): ν˜ ϭ
1
3500Ϫ3100, 1640 cmϪ1. Ϫ H NMR (CD3OD): δ ϭ 3.88 (d, J ϭ
6.5 Hz, 2 H), 3.99 (s, 3 H), 4.38 (t, J ϭ 6.4 Hz, 1 H), 5.07 (d, J ϭ
11.0 Hz, 1 H), 5.16 (d, J ϭ 11.0 Hz, 1 H), 7.11Ϫ7.64 (m, 13 H),
8.69 (s, 1 H). Ϫ 13C NMR (CD3OD): δ ϭ 56.4, 67.3, 76.8, 115.9,
119.9, 125.3, 128.4, 128.5, 129.3, 129.4, 129.9, 131.2, 138.4, 142.2,
149.2, 154.3, 160.3. Ϫ MS (EI): m/z (%) ϭ 300 [Mϩ Ϫ 61] (7), 255
(6), 194 (39), 166 (16), 135 (66), 91 (100). Ϫ C23H23NO3: calcd. C
76.43, H 6.41, N 3.87; found C 76.65, H 6.15, N 3.48.
(2S)-(؉)-2-(2,3-Dimethoxybenzylamino-2-(3,4-dimethoxyphenyl)- colourless oil after flash column chromatography (hexane/ethyl
ethanol (8a): NaBH4 (0.07 g, 2.0 mmol) was added in three portions acetate 7:3). Yield: 1.43 g, 80%. [α]2D0 ϭ ϩ7.40 (c ϭ 0.2, CH2Cl2).
to a cooled (0 °C) solution of imino alcohol 2a (0.28 g, 1.0 mmol) Ϫ IR (KBr): ν˜ ϭ 3600Ϫ3300 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 2.12
in MeOH (25 mL). The mixture was stirred at room temperature (s, 3 H), 3.38 (d, J ϭ 12.7 Hz, 1 H), 3.65Ϫ3.77 (m, 3 H), 3.84 (s, 3
for 3 h and water (15 mL) was added. The mixture was extracted H), 3.86 (s, 3 H), 3.89 (s, 3 H), 3.90 (s, 3 H), 4.05 (t, J ϭ 9.9 Hz, 1
with CH2Cl2 (3 ϫ 25 mL) and the combined organic extracts were H), 6.80Ϫ6.89 (m, 5 H), 6.99Ϫ7.05 (m, 1 H). Ϫ 13C NMR (CDCl3):
collected, dried over Na2SO4 and filtered, and the solvent was re- δ ϭ 37.7, 52.0, 55.7, 55.8, 55.9, 60.7, 61.0, 68.4, 110.6, 111.4, 112.2,
Eur. J. Org. Chem. 2001, 4343Ϫ4352
4349

´
E. Anakabe, J. L. Vicario, D. Badıa, L. Carrillo, V. Yoldi
FULL PAPER
121.1, 122.6, 123.7, 128.2, 132.4, 147.6, 148.5, 152.7. Ϫ MS (EI): NaOH solution (15 mL). The mixture was extracted with CH2Cl2
m/z (rel. int.): 330 (28) [Mϩ Ϫ 31], 151 (100). Ϫ C20H27NO5: calcd. (3 ϫ 25 mL) and the combined organic fractions were collected,
C 66.46, H 7.53, N 3.87; found C 66.81, H 7.15, N 3.41.
dried over Na2SO4 and filtered, and the solvent was removed in
vacuo, yielding isoquinoline 11a after flash column chromato-
graphy (hexane/EtOAc ϭ 2:8). Yield: 0.46 g, 80%. [α]2D0 ϭ ϩ130.1
(2S)-(؊)-2-(2,3-Dimethoxybenzyl)-N-methylamino-2-(3,4-methyl-
enedioxyphenyl)ethanol (9b): N-methylamino alcohol 9b was pre-
pared by the same procedure as employed for 9a, using amino alco-
hol 8c (1.62 g, 4.9 mmol) as starting material. Yield: 1.35 g, 80%.
[α]2D0 ϭ Ϫ19.67 (c ϭ 0.3, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3600Ϫ3300
cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 2.09 (s, 3 H), 3.30 (d, J ϭ 12.7 Hz,
1 H), 3.61Ϫ3.80 (m, 3 H), 3.85 (s, 3 H), 3.86 (s, 3 H), 4.00 (t, J ϭ
10.1 Hz, 1 H,), 5.96 (s, 2 H), 6.69Ϫ6.79 (m, 5 H), 6.97Ϫ7.04 (m, 1
H). Ϫ 13C NMR (CDCl3): δ ϭ 37.6, 51.9, 55.6, 60.6, 61.0, 68.5,
100.9, 107.9, 109.0, 111.4, 122.3, 122.6, 123.6, 129.4, 132.4, 146.9,
147.4, 147.5, 152.6. Ϫ MS (EI): m/z (rel. int.): 327 (1) [Mϩ Ϫ 18],
151 (100). Ϫ C19H23NO5: calcd. C 66.07, H 6.71, N 4.06; found C
66.20, H 6.55, N 4.41.
(c ϭ 0.5, CH2Cl2). Ϫ IR (KBr): ν ϭ 3550Ϫ3250 cmϪ1. Ϫ 1H NMR
˜
(CDCl3): δ ϭ 2.30 (s, 3 H), 3.46 (d, J ϭ 16.6 Hz, 1 H), 3.51 (d,
J ϭ 2.8 Hz, 1 H), 3.85 (s, 6 H), 3.87 (s, 3 H), 3.88 (s, 3 H), 4.17 (d,
J ϭ 16.6 Hz, 1 H), 4.57 (d, 1 H), 6.79Ϫ7.00 (m, 4 H), 7.12 (d, J ϭ
8.3 Hz, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 43.7, 53.6, 55.7, 55.8,
60.1, 70.3, 70.4, 110.7, 111.1, 112.5, 121.8, 124.4, 128.5, 130.1,
130.2, 144.4, 148.5, 148.6, 151.7. Ϫ MS (EI): m/z (rel. int.): 357 (6)
[Mϩ Ϫ 2], 180 (100), 165 (12). Ϫ C20H25NO5: calcd. C 66.83, H
7.01, N 3.90; found C 66.76, H 6.86, N 3.51.
(3S,4S)-(؊)-7,8-Dimethoxy-2-methyl-3-(3,4-methylenedi-
oxyphenyl)-1,2,3,4-tetrahydroisoquinolin-4ol (11b): Isoquinoline 11b
was prepared by the same procedure as employed for 11a, using
N-methylamino alcohol 9b (0.55 g, 1.6 mmol) as starting material.
Yield: 0.44 g, 80%. [α]2D0 ϭ Ϫ122.5 (c ϭ 0.4, CH2Cl2). Ϫ IR (KBr):
(2S)-(؉)-2-(2,3-Dimethoxybenzyl)]-N-methylamino-2-phenylethanol
(9c): N-Methylamino alcohol 9c was prepared by the same proce-
dure as employed for 9a, using amino alcohol 8c (1.40 g, 4.9 mmol)
as starting material. Yield: 1.14 g, 76%. [α]2D0 ϭ ϩ29.3 (c ϭ 0.3,
CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3600Ϫ3300 cmϪ1. Ϫ 1H NMR (CDCl3):
δ ϭ2.11 (s, 3 H), 3.51 (d, J ϭ 12.7 Hz, 1 H), 3.70Ϫ3.77 (m, 3 H),
3.83 (s, 3 H), 3.85 (s, 3 H), 4.11 (t, J ϭ 10.1 Hz, 1 H), 6.83Ϫ6.87
(m, 2 H), 7.00 (m, 1 H), 7.26Ϫ7.39 (m, 5 H). Ϫ 13C NMR (CDCl3):
δ ϭ37.4, 51.7, 55.2, 60.2, 60.6, 68.6, 111.1, 122.3, 123.3, 127.3,
127.8, 128.6, 132.1, 135.5, 147.3, 152.3. Ϫ MS (EI): m/z (%) ϭ 270
(86) [Mϩ Ϫ 31], 151 (100). Ϫ C18H23NO3: calcd. C 71.72, H 7.70,
N 4.65; found C 71.54, H 7.90, N 4.30.
ν ϭ 3550Ϫ3250 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ2.29 (s, 3 H), 3.45
˜
(d, J ϭ 16.6 Hz, 1 H), 3.50 (d, J ϭ 2.8 Hz, 1 H), 3.85 (s, 3 H), 3.88
(s, 3 H), 4.13 (d, J ϭ 16.3 Hz, 1 H), 4.53 (d, 1 H), 5.95 (s, 2 H),
6.78Ϫ6.93 (m, 4 H), 7.10 (d, J ϭ 8.3 Hz, 1 H). Ϫ 13C NMR
(CDCl3): δ ϭ 43.5, 53.5, 55.8, 60.1, 70.2, 70.4, 101.0, 107.9, 110.0,
111.1, 122.9, 124.3, 128.4, 130.2, 131.6, 144.4, 147.0, 147.5, 151.7.
Ϫ MS (EI): m/z (rel. int.): 341 (3) [Mϩ Ϫ 2], 164 (100). Ϫ
C19H21NO5: calcd. C 66.46, H 6.16, N 4.08; found C 66.81, H 6.15,
N 4.41.
(3S,4S)-(؉)-7,8-Dimethoxy-2-methyl-3-phenyl-1,2,3,4-tetrahydro-
isoquinolin-4-ol (11c): Isoquinoline 11b was prepared by the same
procedure as employed for 11a, using N-methylamino alcohol 9b
(2S)-(؉)-2-(2-Benzyloxy-3-methoxybenzyl)-N-methyl]amino-2-
phenylethanol (9d): N-Methylamino alcohol 9d was prepared by the
same procedure as employed for 9a, using amino alcohol 8d (0.31 g,
0.80 mmol) as starting material. Yield: 0.23 g, 73%. [α]2D0 ϭ ϩ18.3
(0.48 g, 1.6 mmol) as starting material. Yield: 0.37 g, 78%. [α]2D0
ϭ
ϩ134.2 (c ϭ 0.4, CH2Cl2). M.p. 149Ϫ152 °C (Et2O). Ϫ IR (KBr):
ν˜ ϭ 3550Ϫ3250 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 2.20 (s, 3 H),
3.29 (s, 1 H), 3.39 (d, J ϭ 16.6 Hz, 1 H), 3.48 (d, J ϭ 2.4 Hz, 1 H),
3.85 (s, 3 H), 3.87 (s, 3 H), 4.11 (d, J ϭ 16.6 Hz, 1 H), 4.48 (m, 1
H), 6.85 (d, J ϭ 8.3 Hz, 1 H), 7.07 (d, J ϭ 8.3 Hz, 1 H), 7.30 (m,
5 H). Ϫ 13C NMR (CDCl3): δ ϭ 43.6, 53.7, 56.7, 60.0, 70.1, 70.9,
111.0, 124.,5, 127.5, 128.0, 129.6, 128.5, 130.2, 137.9, 144.3, 151.5.
Ϫ MS (EI): m/z (rel. int.): 299 (1) [Mϩ], 120 (100). Ϫ C18H21NO3:
calcd. C 72.20, H 7.07, N 4.68; found C 72.40, H 7.15, N 4.41.
(c ϭ 0.2, CH2Cl2). Ϫ IR (KBr): ν ϭ 3700Ϫ3100 cmϪ1. Ϫ 1H NMR
˜
(CDCl3): δ ϭ 2.09 (s, 1 H), 3.29 (d, J ϭ 13.1 Hz, 1 H), 3.52 (d,
J ϭ 13.1 Hz, 1 H), 3.65 (dd, J ϭ 10.1, 4.8 Hz, 1 H), 3.82 (dd, J ϭ
10.1, 4.8 Hz, 1 H), 3.94 (s, 3 H), 4.01 (t, J ϭ 10.1 Hz, 1 H), 5.02
(d, J ϭ 11.1 Hz, 1 H), 5.09 (d, J ϭ 11.1 Hz, 1 H), 6.89Ϫ6.97 (m,
2 H), 7.09 (t, J ϭ 7.9 Hz, 1 H), 7.35Ϫ7.41 (m, 8 H). Ϫ 13C NMR
(CDCl3): δ ϭ 37.1, 51.8, 55.5, 60.4, 68.3, 74.7, 111.1, 122.0, 123.7,
127.5, 127.8, 127.9, 128.1, 128.5, 128.9, 132.8, 135.2, 137.2, 145.9,
152.5. Ϫ MS (EI): m/z (rel. int.): 273 (31) [Mϩ Ϫ 104], 136 (100).
Ϫ C24H27NO3: calcd. C 76.39, H 7.21, N 3.71; found C 76.45, H
7.55, N 3.35.
(3S,4S)-(؉)-8-Benzyloxy-7-methoxy-2-methyl-3-phenyl-1,2,3,4-
tetrahydroisoquinolin-4-ol (11d): Isoquinoline 11d was prepared by
the same procedure as employed for 11a, using N-methylamino al-
cohol 9d (0.11 g, 0.3 mmol) as starting material. Yield: 0.09 g, 83%.
[α]2D0 ϭ ϩ73.9 (c ϭ 0.2, CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 3600Ϫ3100
cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 2.22 (s, 3 H), 3.35 (d, J ϭ 16.6 Hz,
1 H), 3.53 (d, J ϭ 2.7 Hz, 1 H), 3.91 (s, 3 H), 4.09 (d, J ϭ 16.6 Hz,
1 H), 4.55 (d, J ϭ 2.7 Hz, 1 H), 5.02 (d, J ϭ 11.0 Hz, 1 H), 5.09
(d, J ϭ 11.0 Hz, 1 H), 6.91 (d, J ϭ 8.3 Hz, 1 H), 7.14 (d, J ϭ
8.3 Hz, 1 H), 7.34Ϫ7.49 (m, 10 H). Ϫ 13C NMR (CDCl3): δ ϭ
43.5, 53.8, 55.7, 70.0, 70.9, 74.0, 111.0, 124.6, 127.4, 127.8, 128.3,
129.7, 128.6, 130.2, 137.8, 143.2, 151.5. Ϫ MS (EI): m/z (rel. int.):
285 (4) [Mϩ Ϫ 90], 91 (100). Ϫ C24H25NO3: calcd. C 76.77, H 6.71,
N 3.73; found C 76.55, H 6.55, N 3.35.
(3S,4S)-(؉)-7,8-Dimethoxy-3-(3,4-dimethoxyphenyl)-2-methyl-
1,2,3,4-tetrahydroisoquinolin-4-ol (11a):
A solution of DMSO
(0.25 mL, 3.5 mmol) in CH2Cl2 (3 mL) was added dropwise to a
cooled (Ϫ60 °C) solution of oxalyl chloride (0.15 mL, 1.7 mmol)
in CH2Cl2 (3 mL), and the mixture was stirred for 15 min. A solu-
tion of N-methylamino alcohol 9a (0.57 g, 1.6 mmol) in 15 mL of
CH2Cl2 was added dropwise and the reaction mixture was stirred
for an additional 30 min. Diisopropylethylamine (1.40 mL,
8.0 mmol) was added dropwise and, after stirring for 15 min, the
solution was allowed to reach room temp. The reaction was
quenched with water (10 mL), the mixture was extracted with
CH2Cl2 (3 ϫ 25 mL), and the combined organic fractions were
collected, dried over Na2SO4 and filtered. The solvent was removed
in vacuo to afford the corresponding aldehyde 10. The crude alde-
hyde was dissolved in acetone (8 mL), the solution was cooled to
0 °C, and HClconc (2 mL) was added. The mixture was allowed to
Acknowledgments
Financial support from the Basque Government (a fellowship to
J. L. V. and E. A. and Project GV00170.30Ϫ7307/19) is gratefully
come to room temp., stirred for 2 h and quenched with a 1  acknowledged.
4350
Eur. J. Org. Chem. 2001, 4343Ϫ4352

Asymmetric Synthesis of Arylglycines and Their Use as Chiral Templates
FULL PAPER
[14e]
Acc. Chem. Res. 1995, 28, 299Ϫ305. Ϫ
M. S. Iyer, K. M.
Gigstad, N. D. Namdev, M. Lipton, J. Am. Chem. Soc. 1996,
[1]
For a review:M. D. Rozwadowska, Heterocycles 1994, 39,
903Ϫ931.
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