Preparation of Chiral 2-(2-Bromobenzyl)-1,3-dioxolanes and Their Addition to Acylimines

Article abstract of DOI:10.1002/(SICI)1099-0690(199804)1998:4<711::AID-EJOC711>3.0.CO;2-A

A series of enantiomerically pure 2-(2-bromobenzyl)-1,3-dioxolanes 10 has been prepared by transacetalization of the dimethyl acetal 8 or the enol ether 7 with enantiomerically pure C₂ symmetric 1,2-diols. We investigated the ability of the chiral 1,3-dioxolane moiety to control the diastereoselectivity during the addition of the aryllithium intermediates 18 to the acylimines 17. Those reactive aryllithium species were generated by bromine/lithium exchange at the bromo acetals 10. In this series the best diastereoselectivity was obtained by addition of the aryllithium intermediate 18b to the acylimine 17a to yield the diastereomeric addition products 19c/ 20c in a ratio of 72:28. After separation, the main diastereomer 19c was cyclized to afford the dihydroisoquinoline (R)-21, which was then hydrogenated to give the NMDA antagonistic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (R)-2. The chiral auxiliary, the diol 9b, cleaved during the cylization of 19c, could be recovered in 89% yield.

Full text of DOI:10.1002/(SICI)1099-0690(199804)1998:4<711::AID-EJOC711>3.0.CO;2-A

FULL PAPER
Asymmetric Synthesis of 1-Aryl-1,2,3,4-tetrahydroisoquinolines, 2[᭛]
Preparation of Chiral 2-(2-Bromobenzyl)-1,3-dioxolanes and Their Addition to
AcyliminesȠ
Bernhard Wünsch* and Sven Nerdinger
Pharmazeutisches Institut der Universität Freiburg,
Hermann-Herder-Straße 9, D-79104 Freiburg i. Br., Germany
Received October 10, 1997
Keywords: Asymmetric synthesis / (2-Bromophenyl)acetaldehyde acetals, enantiomerically pure / BromineϪlithium
exchange / 1-Phenyl-1,2,3,4-tetrahydroisoquinoline / NMDA antagonists
A series of enantiomerically pure 2-(2-bromobenzyl)-1,3-di-
by addition of the aryllithium intermediate 18b to the acyli-
oxolanes 10 has been prepared by transacetalization of the mine 17a to yield the diastereomeric addition products 19c/
dimethyl acetal 8 or the enol ether 7 with enantiomerically
pure C2 symmetric 1,2-diols. We investigated the ability of
20c in a ratio of 72:28. After separation, the main diastere-
omer 19c was cyclized to afford the dihydroisoquinoline (R)-
the chiral 1,3-dioxolane moiety to control the diastereoselec- 21, which was then hydrogenated to give the NMDA antago-
tivity during the addition of the aryllithium intermediates 18
to the acylimines 17. Those reactive aryllithium species were
generated by bromine/lithium exchange at the bromo acetals
10. In this series the best diastereoselectivity was obtained
nistic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (R)-2. The chi-
ral auxiliary, the diol 9b, cleaved during the cylization of 19c,
could be recovered in 89% yield.
the chirality in position 1,[5][6][7][8][9] we followed another
strategy. In the first step an aryllithium intermediate (3) was
generated by halogen/metal exchange of an appropriate aryl
halide, and this should be added to imine derivatives (4) to
give the addition products 5. The diastereoselectivity during
this addition should be controlled by the chiral acetal moi-
ety of 3. Hydrolysis of the acetal, with recovery of the chiral
auxiliary, and subsequent cyclization should complete
the synthesis of the enantiomerically pure 1-phenyltetra-
hydroisoquinoline (R)-2.
Introduction
1,2,3,4-Tetrahydroisoquinolines of synthetic, plant and
mammalian origin have been intensively studied because of
their manifold pharmacological properties, e.g. fibrinolytic,
antiviral, tranquilizing, muscle relaxant, hypotensive, hallu-
cinogenic, positive inotropic effects.[2] Our interest has been
focused on 1-aryl-1,2,3,4-tetrahydroisoquinolines pos-
sessing antagonistic effects at dopamine D1 and NMDA re-
ceptors (NMDA: N-methyl--aspartate). Thus, tetrahydro-
isoquinolinol (±)-1 binds with high affinity (Ki ϭ 12.5 n)
and selectivity to the D1 receptors,[3] whereas the isoquino-
line (±)-2 interacts with the phencyclidine binding site of
the NMDA receptors.[4] In both cases the enantiomers with
the (S) configuration, (S)-1 and (S)-2, exhibit higher affinity
than their mirror images (R)-1 and (R)-2.[3][5]
Scheme 2
Scheme 1
Preparation of the Enantiomerically Pure
2-(2-Bromobenzyl)-1,3-dioxolanes 10
We therefore planned to devise a novel asymmetric syn-
thesis to obtain enantiomerically pure 1-aryl-1,2,3,4-tetra-
The starting material for the preparation of the dioxol-
hydroisoquinolines. In contrast to the established asymmet- anes 10 is (2-bromophenyl)acetaldehyde dimethyl acetal (8),
ric syntheses of 1-aryltetrahydroisoquinolines, which utilize which has been obtained by a two-step homologization of
complete isoquinoline ring systems for the introduction of 2-bromobenzaldehyde (6) consisting of a Wittig reaction
with (methoxymethyl)triphenylphosphonium chloride and
subsequent addition of methanol to the resulting enol ether
[᭛]
Part 1: Ref.[1]
.
Eur. J. Org. Chem. 1998, 711Ϫ718
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1434Ϫ193X/98/0404Ϫ0711 $ 17.50ϩ.50/0
711

B. Wünsch, S. Nerdinger
FULL PAPER
Scheme 3
7.[10] Transacetalization of the dimethyl acetal 8 with the the enol ether 7 instead of the dimethyl acetal 8 led to a
enantiomerically pure C2 symmetric 1,2-diols 9a, 9b[11] and further improvement in the yield (72%). Although the reac-
9c[12] in the presence of p-toluenesulfonic acid, furnished tion conditions were optimized, only low yields of the di-
the 2-(2-bromobenzyl)-1,3-dioxolanes 10a؊c in 80Ϫ89% ethyl dicarboxylate 10e (22%) and the diisopropyl dicar-
yield. The reaction sequence could be shortened by reacting boxylate 10f (24%) were obtained. Side reactions leading to
the diols 9a؊c with the enol ether 7 to give the dioxolanes the phenylacetaldehyde 11, the indanone 12 and the transes-
10a؊c in comparable yields (79Ϫ90%). Alternatively, the terified products 13a and 13b (mixture of diastereomers)
branched acetal 10c was prepared by derivatization of the are responsible for the low yields.
diester 10d: Reaction of 10d with an excess of methylmag-
In contrast to the diols 9a؊f, the tartaramide 9g and the
nesium iodide provided the diol 10i, which was alkylated
diaminodiol 9h did not react with the dimethyl acetal 8 or
with methyl iodide to give the dimethyl ether 10c. In the
the enol ether 7 to yield the dioxolanes 10g and 10h. There-
case of 10c the derivatization of the diester 10d is not a
fore, the diamide 10g was prepared by aminolysis of the
better method than the direct reaction of the dimethyl ace-
dimethyl dicarboxylate 10d with an excess of dimethyl-
tal 8 or the enol ether 7 with the diol 9c. However, this
amine. However, reduction of the diamide 10g with LiAlH4
sequence may be advantageous in the preparation of steri-
furnished the debrominated diamine 14 instead of the
cally more demanding acetals.
bromo derivative 10h.
The transacetalization of the dimethyl acetal 8 with the
dimethyl tartrate 9d required refluxing toluene instead of
Transacetalization of the dimethyl acetal 8 with the non-
THF to provide the dimethyl dicarboxylate 10d (50% yield) C2-symmetric diol 9j (the reduction product of (R)-(Ϫ)-
along with the (2-bromophenyl)acetaldehyde 11 and the in- mandelic acid) led to a 65:35 mixture of the diastereomers
danone 12 as side products. Removal of the liberated meth- cis-10j and trans-10j. However, all attempts to separate the
˚
anol with molecular sieves (4 A) in a Soxhlet apparatus diastereomers cis-10j and trans-10j by fractional crystalliza-
shortened the reaction time from seven days to three days tion or flash chromatography failed. Since the 1,3-dioxolane
and, moreover, raised the yield of 10d to 63%. Starting with moiety of 10j should control the diastereoselectivity the dia-
712
Eur. J. Org. Chem. 1998, 711Ϫ718

Asymmetric Synthesis of 1-Aryl-1,2,3,4-tetrahydroisoquinolines, 2
FULL PAPER
stereomeric mixture of cis-10j and trans-10j is not suitable methyldioxolane 10a the corresponding diastereoselectivi-
as starting material for asymmetric syntheses.
ties (entries 1 and 2) are reversed in comparison with entries
3Ϫ6. Table 1 shows comparable diastereoselectivities in the
entries 1/2, in the entries 3/4, and in the entries 5/6. This
leads to the conclusion that the diastereomeric ratio is not
influenced appreciably by the acylimine component. The
substitution pattern of the dioxolane ring, however, can in-
fluence the diastereoselectivity to a greater extent. Thus, en-
largement of the methyl substituent in 18a to a meth-
oxymethyl substituent (18b) improved the diastereomeric
ratio from 62:38 (20a/19a, entry 1) to 72:28 (19c/20c, entry
3). Surprisingly, a further expansion of the dioxolane sub-
stituents [18c, R1 ϭ C(CH3)2OCH3] led to complete loss of
the diastereoselectivity (19e/20e ϭ 51:49, entry 5).
Addition of the Lithiated Dioxolanes 18 to the Acylimines
17
The required acylimines 17 were obtained by an aza-anal-
ogous Peterson olefination of benzaldehyde (15) with lith-
ium bis(trimethylsilyl)amide[13] and subsequent acylation of
the silylimine 16 with acyl chlorides.[14] Thus, 17a with the
easily cleavable benzyloxycarbonyl residue and 17b with the
sterically demanding pivaloyl residue were prepared.
Scheme 4
Table 1. Results of the addition of 18aϪc to 17a, b
The aryllithium intermediates 18aϪg were generated by
treatment of the 2-(2-bromobenzyl)-1,3-dioxolanes 10aϪg
with n-butyllithium at Ϫ100°C. However, only the methyl
and the methoxyalkyl substituted 1,3-dioxolanes 18aϪc re-
acted with the acylimines 17a, b to give the addition prod-
ucts 19/20 in good yields. In contrast, the reaction (5 h,
Ϫ100°C) of the lithiobenzyl-1,3-dioxolanes 18dϪg, bearing
ester or amide substituents, with the acylimine 17b led to
complex mixtures of products. The same result was ob-
tained after a reaction time of 2 h (Ϫ100°C) and after rais-
ing the reaction temperature to Ϫ20°C or ϩ20°C.
As the addition of 18aϪc to the acylimines 17a,b resulted
in good yields of 19/20 we investigated the analogous ad-
dition of the aryllithium intermediates 18aϪc to the silylim-
ine 16, which should give an unprotected primary amine.
But, all attempts to perform the addition to the silylimine
16 failed. Only debrominated derivatives of 10aϪc and ben-
zaldehyde were detected in the product mixture.
The diastereomeric ratios 19/20 were determined by inte-
gration of characteristic signals in the 400 MHz H-NMR
1
spectra of the unpurified addition products 19/20. For ex-
1
ample, the H-NMR spectrum of the crude addition prod-
uct of 18b to 17a (entry 3) shows two doublets at δ ϭ 6.29
(19c) and δ ϭ 6.26 (20c) in the ratio 72:28 for the proton
Ph2CHϪNHCO2Bn. Since the combination of 18b and 17a
led to the best diastereoselectivity in this series (entry 3),
the diastereomeric ratio 19c/20c was confirmed by a HPLC
analysis to be 72.1:27.9.
Scheme 5
The separation of the diastereomers 19 and 20 turned out
to be very problematic. After many attempts, the dia-
stereomers 19c and 20c were successfully separated by flash
chromatography (19c: Rf ϭ 0.18; 20c: Rf ϭ 0.16).
Synthesis of the 1-Phenyltetrahydroisoquinoline (R)-2 and
Determination of the Absolute Configuration
Heating a methanolic solution of the main diastereomer
19c with an excess of p-toluenesulfonic acid afforded the
dihydroisoquinoline (R)-21 and the chiral auxiliary 9b,
which were isolated in 82% and 89% yield, respectively. Fi-
nally, the tetrahydroisoquinoline (R)-2 was obtained by
catalytic hydrogenation of the dihydroisoquinoline (R)-21.
20
The specific optical rotation [α]589 of the isolated 1-
phenyl-1,2,3,4-tetrahydroisoquinoline (R)-2 was determined
to be Ϫ10.12 (c ϭ 0.60 in CHCl3). Yamato and coworkers
The results of the addition of the aryllithium intermedi- assigned the (S)-configuration to the laevorotatory enanti-
24
ates 18aϪc to the acylimines 17a, b are summarized in omer (Ϫ)-2 ([α]589 ϭ Ϫ10.2, c ϭ 0.17 in CHCl3) by com-
Table 1. Because of the opposite configuration of the di- parison of the 1-phenyltetrahydroisoquinoline (Ϫ)-2 with 1-
Eur. J. Org. Chem. 1998, 711Ϫ718
713

B. Wünsch, S. Nerdinger
FULL PAPER
˚
with molecular sieves (4 A) to remove methanol. After three days
the solution was diluted with CH2Cl2, washed with a saturated
solution of NaHCO3 and then with water, dried (MgSO4), and con-
centrated in vacuo. The residue was purified by FC or distillation.
Scheme 6
General Procedure 2 (GP2). Ϫ Bromine/Lithium Exchange at the
Aryl Bromides 10aϪc and Subsequent Reaction with the Acylimines
17a, b: An enantiomerically pure aryl bromide 10 was dissolved in
THF (20 ml) and cooled to Ϫ100°C. A solution of n-butyllithium
(1.6 mol/l in n-hexane, 1.05 equiv.) was added and the reaction
mixture was stirred for 15 min at Ϫ100°C. A solution of an acyl-
imine 17 (1.05 equiv.) in THF (10 ml) was added. The reaction
mixture was stirred for 6 h at Ϫ85 to Ϫ100°C and then a saturated
solution of NH4Cl (20 ml) was added. The organic layer was sepa-
rated, dried (MgSO4), concentrated in vacuo, and the residue was
purified by FC. Before carrying out the purification procedure, 1H-
NMR spectra were recorded to determine the diastereomeric ratio
of the crude products.
(a) p-Toluenesulfonic acid, methanol, 16 h, 65°C, (R)-21: 82%, 9b:
89%. Ϫ (b) H2, 1.7 bar, Pd/C, methanol, 4 h, room temp., 45%.
alkylated tetrahydroisoquinolines.[8a] However, very re-
cently Wanner and coworkers reinvestigated the absolute
configuration of the 1-phenyl-1,2,3,4-tetrahydroisoquinol-
ines (ϩ)-2 and (Ϫ)-2. The X-ray analysis of (ϩ)-2, which
is acylated with an enantiomerically pure carboxylic acid,
unequivocally revealed the dextrorotatory enantiomer (ϩ)-
2 to have the (S) configuration.[15] Thus, the (R) configura-
tion has to be assigned to the dihydroisoquinoline (R)-(ϩ)-
21 and the new stereogenic center of the addition product
19c.[16]
(4R,5R)-(Ϫ)-2-(2-Bromobenzyl)-4,5-dimethyl-1,3-dioxolane
(10a): (a) According to GP1 a solution of 8 (5.00 g, 20.4 mmol)
and 9a (2.02 g, 22.4 mmol) in THF (100 ml) was heated to reflux.
The residue was purified by distillation. Colourless oil, b.p.0.018
ϭ
70Ϫ75°C, yield 4.43 g (80.0%), [α]589 ϭ Ϫ60.0 (c ϭ 1.00 in CHCl3).
Ϫ C12H15BrO2 (271.2): calcd. C 53.2 H 5.58 Br 29.5 found C 53.4
H 5.93 Br 29.4. Ϫ MS; m/z: 272/270 [M.ϩ], 200/198 [M Ϫ
CH3COC2H5]. Ϫ IR (film): ν˜ ϭ 1473 cmϪ1 (CϭC), 1145 (CϪO),
1114 (CϪO), 1076 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 1.22 (d, J ϭ
3.7 Hz, 3 H, CHCH3), 1.27 (d, J ϭ 4.4 Hz, 3 H, CHCH3), 3.09
(dd, J ϭ 13.2/5.1 Hz, 1 H, aryl-CH2), 3.14 (dd, J ϭ 13.2/4.4 Hz, 1
H, aryl-CH2), 3.60 (m, 2 H, 4-H and 5-H), 5.32 (dd, J ϭ 5.1/4.4
Hz, 1 H, 2-H), 7.08 (td, J ϭ 8.1/1.5 Hz, 1 H, 5-H arom.), 7.22 (td,
J ϭ 8.1/1.5 Hz, 1 H, 4-H arom.), 7.34 (dd, J ϭ 8.1/1.5 Hz, 1 H, 6-
H arom.), 7.52 (dd, J ϭ 8.1/1.5 Hz, 1 H, 3-H arom.). Ϫ 13C NMR
(CDCl3): δ ϭ 16.9 (q, CHCH3), 17.0 (q, CHCH3), 41.6 (t, aryl-
CH2), 78.1 (d, C-4), 79.7 (d, C-5), 102.1 (d, C-2), 125.0 (s, C-1
arom.), 127.2 (d, C-6 arom.), 128.2 (d, C-5 arom.), 132.0 (d, C-4
arom.), 132.6 (d, C-3 arom.), 136.0 (s, C-2 arom.). (b) As described
for (a), 7 (5.00 g, 23.5 mmol) was reacted with 9a (2.31 g, 25.7
mmol). Yield 5.70 g (89.5%).
The stereochemical assignment of the compounds in
1
Table 1 is deduced from the H-NMR spectra. The signal
for the proton Ph2CHϪNHCOR3 of the main diastereomer
is always shifted downfield in relation to the analogous sig-
nal of the minor diastereomer. Thus, the addition of 18b, c
led to main diastereomers with (R) configuration (entries
3Ϫ6), whereas (S) configuration is assigned to the main dia-
stereomers obtained in the addition of 18a with the op-
posite configuration in the acetal moiety (entries 1 and 2).
We wish to thank Prof. Dr. Dr. h. c. F. Eiden and Prof. Dr. K.
Th. Wanner for their generous support. Thanks are also due to
the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen
Industrie for financial support, and to Degussa AG for the donation
of chemicals.
(4S,5S)-(ϩ)-2-(2-Bromobenzyl)-4,5-bis(methoxymethyl)-1,3-
dioxolane (10b): (a) According to GP1 a solution of 8 (6.20 g, 25.3
mmol) and 9b[11] (4.00 g, 26.7 mmol) in THF (95 ml) was heated
to reflux. The residue was purified by distillation. Colourless oil,
b.p.0.014 ϭ 113Ϫ117°C, yield 7.40 g (88.3%), [α]589 ϭ ϩ3.20 (c ϭ
1.00 in CHCl3). Ϫ C14H19BrO4 (331.2): calcd. C 50.8 H 5.78 found
C 50.9 H 5.69. Ϫ MS (CI); m/z: 333/331 [M ϩ Hϩ]. Ϫ IR (film):
Experimental Section
General: Unless otherwise stated, moisture sensitive reactions
were conducted under dry nitrogen. Ϫ THF was distilled from so-
dium benzophenone ketyl prior to use. Ϫ Flash chromatography
(FC)[17]: Silica gel 60, 0.040Ϫ0.063 mm (Merck). Ϫ HPLC: Col-
umn filled with silica gel (5 µm particles, LiChrosorb Si 60, Merck);
ν
˜ ϭ 2926 cmϪ1 (CϪH), 1473 (CϭC), 1136 (CϪO), 1106 (CϪO).
1
pump L-6200 (Merck), pressure 40 bar, rate 1 ml/min; L-4250-UV/ Ϫ H NMR (CDCl3): δ ϭ 3.14 (dd, J ϭ 13.9/5.1.4 Hz, 1 H, aryl-
VIS-detector (Hitachi), λ ϭ 254 nm; eluent petroleum ether/diethyl CH2), 3.18 (dd, J ϭ 13.9/4.4 Hz, 1 H, aryl-CH2), 3.38 (s, 3 H,
ether (60:40). Ϫ Melting points: Melting point apparatus Dr. Tot-
toli (Büchi), uncorrected. Ϫ Optical rotation: Polarimeter 241 (Per-
OCH3), 3.40 (s, 3 H, OCH3), 3.49 (m, 4 H, 2 ϫ CH2OCH3), 3.98
(m, 2 H, 4-H and 5-H), 5.35 (dd, J ϭ 5.1/4.4 Hz, 1 H, 2-H), 7.09
kin-Elmer); 1.0 dm tube; concentration c [g/100 ml]; temperature (td, J ϭ 8.1/2.2 Hz, 1 H, 5-H arom.), 7.25 (td, J ϭ 8.1/2.2 Hz, 1
20°C. Ϫ Elemental analyses: CHN elemental analyzer Rapid H, 4-H arom.), 7.36 (dd, J ϭ 8.1/1.5 Hz, 1 H, 6-H arom.), 7.53
(Heraeus). Ϫ MS: Mass spectrometer 5989A (Hewlett Packard);
(dd, J ϭ 8.1/1.5 Hz, 1 H, 3-H arom.). Ϫ 13C NMR (CDCl3): δ ϭ
40.9 (t, aryl-CH2), 59.3 (q, OCH3), 59.4 (q, OCH3), 72.8 (t,
CI ϭ chemical ionization. Ϫ IR: IR spectrophotometer 1600 FT-
1
IR and 2000 FT-IR (Perkin-Elmer). Ϫ H NMR (400 MHz), 13C CH2OCH3), 73.0 (t, CH2OCH3), 77.2 (d, C-4), 77.8 (d, C-5), 103.5
NMR (100 MHz): GSX FT NMR spectrometer (Jeol), tetrameth-
ylsilane as internal standard, δ in ppm.
(d, C-2), 125.1 (s, C-1 arom.), 127.3 (d, C-6 arom.), 128.3 (d, C-5
arom.), 132.1 (d, C-4 arom.), 132.6 (d, C-3 arom.), 135.7 (s, C-2
arom.). (b) As described for (a), 7 (5.00 g, 23.5 mmol) was reacted
with 9b (3.66 g, 24.4 mmol). Yield 6.66 g (85.7%).
General Procedure 1 (GP1). Ϫ Preparation of 1,3-Dioxolanes
10aϪj by Transacetalization of 7 or 8 with Diols 9: A mixture of
7 or 8, p-toluenesulfonic acid (200 mg per 10 mmol 7 or 8), the
(4R,5R)-(ϩ)-2-(2-Bromobenzyl)-4,5-bis(2-methoxypropan-2-
corresponding diol 9 (ca. 1.1 equiv.) and the appropriate solvent yl)-1,3-dioxolane (10c): (a) According to GP1 a solution of 8 (6.10
(THF or toluene) was heated to reflux in a Soxhlet apparatus filled
714
g, 24.9 mmol) and 9c[12] (5.42 g, 26.3 mmol) in THF (100 ml) was
Eur. J. Org. Chem. 1998, 711Ϫ718

Asymmetric Synthesis of 1-Aryl-1,2,3,4-tetrahydroisoquinolines, 2
FULL PAPER
heated to reflux. The residue was purified by FC (diameter of the CHCl3). Ϫ C16H19BrO6 (387.2): calcd. C 49.6 H 4.95 found C 49.4
column 5 cm, petroleum ether/ethyl acetate, 90:10, 50 ml fractions, H 4.91. Ϫ MS; m/z: 388/386 [Mϩ], 315/313 [M.ϩ Ϫ CO2CH2CH3].
Rf ϭ 0.72). Pale yellow oil, yield 7.77 g (80.6%), [α]589 ϭ ϩ4.24
Ϫ IR (film): ν˜ ϭ 1755 cmϪ1 (CϭO), 1221 (CϪO), 1140 (CϪO). Ϫ
(c ϭ 1.00 in CHCl3). Ϫ C18H27BrO4 (387.3): calcd. C 55.8 H 7.03 1H NMR (CDCl3): δ ϭ 1.25 (t, J ϭ 7.3 Hz, 3 H, OCH2CH3), 1.31
found C 56.0 H 6.88. Ϫ MS; m/z: 373/371 [M .ϩ Ϫ CH3], 217 [M.ϩ
(t, J ϭ 7.3 Hz, 3 H, OCH2CH3), 3.16Ϫ3.28 (m, 2 H, aryl-CH2),
Ϫ BrC6H4CH2]. Ϫ IR (film): ν˜ ϭ 2855 cmϪ1 (OCH3), 1471 (Cϭ 4.25 (“q”, J ϭ 7.3 Hz, 4 H, 2 ϫ OCH2CH3), 4.68 (d, J ϭ 3.7 Hz,
1
C), 1135 (CϪO), 1032 (CϪO). Ϫ H NMR (CDCl3): δ ϭ 1.11 [s, 1 H, 4-H), 4.81 (d, J ϭ 3.7 Hz, 1 H, 5-H), 5.53 (dd, J ϭ 5.9/4.4
3 H, C(CH3)2OCH3], 1.12 [s, 3 H, C(CH3)2OCH3], 1.21 [s, 3 H, Hz, 1 H, 2-H), 7.09 (td, J ϭ 8.1/1.5 Hz, 1 H, 5-H arom.), 7.25 (td,
C(CH3)2OCH3], 1.22 [s, 3 H, C(CH3)2OCH3], 3.05 (dd, J ϭ 13.9/ J ϭ 8.1/1.5 Hz, 1 H, 4-H arom.), 7.42 (dd, J ϭ 7.3/2.2 Hz, 1 H, 6-
5.9 Hz, 1 H, aryl-CH2), 3.20 (m, 7 H, aryl-CH2 and 2 ϫ OCH3), H arom.), 7.53 (d, J ϭ 8.1 Hz, 1 H, 2-H arom.). 13a (Rf ϭ 0.29):
3.90 (d, J ϭ 3.7 Hz, 1 H, 4-H), 4.04 (d, J ϭ 2.9 Hz, 1 H, 5-H),
5.48 (t, J ϭ 5.9 Hz, 1 H, 2-H), 7.07 (td, J ϭ 8.1/1.5 Hz, 1 H, 5-H
arom.), 7.25 (td, J ϭ 8.1/1.5 Hz, 1 H, 4-H arom.), 7.36 (dd, J ϭ
8.1/1.5 Hz, 1 H, 6-H arom.), 7.53 (dd, J ϭ 8.1/1.5 Hz, 1 H, 3-H
arom.). Ϫ 13C NMR (CDCl3): δ ϭ 21.0 [q, C(CH3)2OCH3], 21.3
[q, C(CH3)2OCH3], 22.1 [q, C(CH3)2OCH3], 22.2 [q,
C(CH3)2OCH3], 41.2 (t, aryl-CH2), 49.2 (q, OCH3), 49.5 (q,
OCH3), 75.8 [s, C(CH3)2OCH3], 77.2 [s, C(CH3)2OCH3], 82.0 (d,
C-4), 84.0 (d, C-5), 104.6 (d, C-2), 125.1 (s, C-1 arom.), 127.2 (d,
C-6 arom.), 128.1 (d, C-5 arom.), 131.9 (d, C-4 arom.), 132.6 (d,
C-3 arom.), 136.4 (s, C-2 arom.). (b) As described for (a), 7 (5.00
g, 23.5 mmol) was reacted with 9c (5.70 g, 24.7 mmol). Yield 7.15
g (78.7%). (c) A solution of methyl iodide (4.76 g, 33.5 mmol) and
unpurified 10i (4.00 g, 11.1 mmol) in THF (60 ml) was added at
room temperature to a suspension of NaH (95%, 0.85 g, 33.3
mmol) in THF (100 ml). The reaction mixture was heated under
reflux for 18 h. Water (200 ml) was added, the organic layer was
separated, dried (MgSO4), concentrated in vacuo, and the residue
was purified by FC [see method (a) above]. Pale yellow oil, yield
3.66 g (84.9%), [α]589 ϭ ϩ4.22 (c ϭ 1.00 in CHCl3).
Pale yellow oil (not pure), yield 0.42 g.
(ϩ)-Diisopropyl (2R,3R)-2-(2-Bromobenzyl)-1,3-dioxolane-4,5-
dicarboxylate (10f) and 4-Isopropyl 5-Methyl 2-(2-bromobenzyl)-
1,3-dioxolane-4,5-dicarboxylate (13b): According to GP1 a solution
of 8 (3.00 g, 12.2 mmol) and 9f (3.44 g, 14.7 mmol) in toluene (60
ml) was heated to reflux. The residue was purified by FC (diameter
of the column 3 cm, petroleum ether/ethyl acetate 85:15, 25 ml
fractions). 10f (Rf ϭ 0.35): Colourless oil, yield 1.12 g (22.0%);
[α]589 ϭ ϩ1.20 (c ϭ 1.00 in CHCl3). Ϫ C18H23BrO6 (415.2): calcd.
C 52.1 H 5.58 found C 51.9 H 5.40. Ϫ MS; m/z: 416/414 [M.ϩ]. Ϫ
IR (film): ν˜ ϭ 1740 cmϪ1 (CϭO), 1264 (CϪO), 1140 (CϪO), 1104
1
(CϪO). Ϫ H NMR (CDCl3): δ ϭ 1.25 [d, J ϭ 5.9 Hz, 6 H, 2 ϫ
OCH(CH3)2], 1.29 [d, J ϭ 5.9 Hz, 6 H, 2 ϫ OCH(CH3)2], 3.24 (dd,
J ϭ 13.9/5.9 Hz, 1 H, arylϪCH2 ), 3.33 (dd, J ϭ 13.9/4.4 Hz, 1 H,
arylϪCH2), 4.68 (d, J ϭ 3.7 Hz, 1 H, 4-H), 4.80 (d, J ϭ 3.7 Hz, 1
H, 5-H), 5.12 [“sept”, J ϭ 5.9 Hz, 2 H, 2 ϫ OCH(CH3)2], 5.59 (dd,
J ϭ 5.9/4.4 Hz, 1 H, 2-H), 7.09 (td, J ϭ 8.1/1.5 Hz, 1 H, 5-H
arom.), 7.26 (td, J ϭ 7.3/1.5 Hz, 1 H, 4-H arom.), 7.42 (dd, J ϭ
8.1/1.5 Hz, 1 H, 6-H arom.), 7.53 (d, J ϭ 8.1 Hz, 1 H, 3-H arom.).
13b (Rf ϭ 0.30): Colourless oil, yield 1.05 g (22.1%). Ϫ C16H19BrO6
(387.2): calcd. C 49.6 H 4.95 found C 49.4 H 4.77. Ϫ MS (CI);
m/z: 389/387 [M ϩ Hϩ]. Ϫ IR (film): ν˜ ϭ 1740 cmϪ1 (CϭO), 1264
(CϪO), 1140 (CϪO), 1104 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 1.28
[d, J ϭ 5.9 Hz, 6 ϫ 0.5 H, OCH(CH3)2], 1.33 [d, J ϭ 5.9 Hz, 6 ϫ
0.5 H, OCH(CH3)2], 3.23Ϫ3.35 (m, 2 H, arylϪCH2), 3.80 (s, 3 ϫ
0.5 H, CO2CH3), 3.83 (s, 3 ϫ 0.5 H, CO2CH3), 4.67Ϫ4.70 (m, 1
H, 4-H or 5-H), 4.79Ϫ4.83 (m, 1 H, 5-H or 4-H), 5.07Ϫ5.17 [m, 1
H, OCH(CH3)2], 5.59 (dd, J ϭ 5.9/4.4 Hz, 1 H, 2-H), 7.09 (td, J ϭ
8.1/1.5 Hz, 1 H, 5-H arom.), 7.26 (td, J ϭ 7.3/1.5 Hz, 1 H, 4-H
arom.), 7.42 (dd, J ϭ 8.1/1.5 Hz, 1 H, 6-H arom.), 7.53 (d, J ϭ 8.1
Hz, 1 H, 3-H arom.). Ratio of diastereomers 1:1.
(Ϫ)-Dimethyl (4R,5R)-2-(2-Bromobenzyl)-1,3-dioxolane-4,5-di-
carboxylate (10d): (a) According to GP1 a solution of 8 (5.00 g,
20.4 mmol) and 9d (4.00 g, 22.5 mmol) in toluene (100 ml) was
heated to reflux. The residue was purified by FC (diameter of the
column 4 cm, petroleum ether/ethyl acetate, 85:15, 25 ml fractions).
11 and 12 (Rf ϭ 0.45): Colourless oil, yield 1.40 g, ratio 11/12 ca.
1:1. 10d (Rf ϭ 0.20): Pale yellow oil, yield 4.64 g (63.3%), [α]589
ϭ
Ϫ44.8 (c ϭ 1.00 in CHCl3). Ϫ C14H15BrO6 (359.2): calcd. C 46.8
H 4.21 Br 22.2 found C 46.9 H 4.01 Br 22.3. Ϫ MS (CI); m/z: 361/
359 [M ϩ Hϩ]. Ϫ IR (film): ν˜ ϭ 1710 cmϪ1 (CϭO), 1223 (CϪO),
1140 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 3.20Ϫ3.24 (m, 2 H, ar-
ylϪCH2), 3.73 (s, 3 H, CO2CH3), 3.76 (s, 3 H, CO2CH3), 4.67 (d,
J ϭ 3.7 Hz, 1 H, 5-H), 4.80 (d, J ϭ 3.7 Hz, 1 H, 4-H), 5.51 (t, J ϭ
5.1 Hz, 1 H, 2-H), 7.11 (t, J ϭ 8.1 Hz, 1 H, 5-H arom.), 7.26 (t,
J ϭ 8.1 Hz, 1 H, 4-H arom.), 7.42 (d, J ϭ 8.1 Hz, 1 H, 6-H arom.),
(4R,5R)-(ϩ)-2-(2-Bromobenzyl)-N,N,NЈ,NЈ-tetramethyl-1,3-
dioxolane-4,5-dicarboxamide (10g): A mixture of 10d (5.00 g, 13.9
mmol), dimethylamine (100.0 ml, 33% in ethanol) and ethanol (30
ml) was stirred for 48 h at room temperature. The solvent was evap-
orated in vacuo and the residue was purified by FC (diameter of
the column 4 cm, petroleum ether/ethyl acetate 50:50, 20 ml frac-
1
7.55 (d, J ϭ 8.1 Hz, 1 H, 3-H arom.). Ϫ H NOE (CDCl3, pulse
delay ϭ 8 s, 37.5 dB): Irrad. at δ ϭ 4.67 (5-H), NOE at δ ϭ 3.73,
3.76, 4.80, and 5.51; irrad. at δ ϭ 4.80 (4-H), NOE at δ ϭ 3.73,
3.76, and 4.67; irrad.at δ ϭ 5.51 (2-H), NOE at δ ϭ 3.20, 3.24,
and 4.67. Ϫ 13C NMR (CDCl3): δ ϭ 40.6 (t, arylϪCH2), 52.8 (q,
CO2CH3), 52.9 (q, CO2CH3), 76.7 (d, C-4), 76.9 (d, C-5), 106.4 (d,
C-2), 124.9 (s, C-1 arom.), 127.5 (d, C-6 arom.), 128.6 (d, C-5
arom.), 132.2 (d, C-4 arom.), 132.7 (d, C-3 arom.), 134.9 (s, C-2
arom.), 169.7 (s, CO2CH3), 169.9 (s, CO2CH3). (b) As described
for (a), 7 (4.36 g, 20.5 mmol) was reacted with 9d (4.00 g, 22.5
mmol). Yield 6.08 g (82.7%).
tions, Rf ϭ 0.36). Pale yellow oil, yield 4.93 g (92.0%), [α]589
ϭ
ϩ3.60 (c ϭ 1.11 in CHCl3). Ϫ C16H21BrN2O4 (385.3): calcd. C 49.9
H 5.49 N 7.23 Br 20.7 found C 49.6 H 5.67 N 7.05 Br 20.8. Ϫ MS
(CI); m/z: 387/385 [M ϩ Hϩ]. Ϫ IR (film): ν˜ ϭ 1720 cmϪ1 (CϭO),
1
1223 (CϪO), 1140 (CϪO). Ϫ H NMR (CDCl3): δ ϭ 2.95 [s, 3 H,
CON(CH3)2], 2.97 [s, 3 H, CON(CH3)2], 3.13 [s, 3 H, CON(CH3)2],
3.15 [s, 3 H, CON(CH3)2], 3.20 (d, J ϭ 5.1 Hz, 2 H, aryl-CH2),
5.19 (d, J ϭ 5.9 Hz, 1 H, 5-H), 5.30 (d, J ϭ 5.9 Hz, 1 H, 4-H),
5.46 (t, J ϭ 5.1 Hz, 1 H, 2-H), 7.09 (t, J ϭ 8.1 Hz, 1 H, 5-H arom.),
7.24 (t, J ϭ 8.1 Hz, 1 H, 4-H arom.), 7.32 (d, J ϭ 8.1 Hz, 1 H, 6-
H arom.), 7.53 (d, J ϭ 8.1 Hz, 1 H, 3-H arom.).
(ϩ)-Diethyl (4R,5R)-2-(2-Bromobenzyl)-1,3-dioxolane-4,5-di-
carboxylate (10e): According to GP1 a solution of 8 (3.00 g, 12.2
mmol) and 9e (2.61 g, 12.7 mmol) in toluene (60 ml) was heated
to reflux. The residue was purified by FC (diameter of the column
(4R,5R)-2-(2-Bromobenzyl)-Ͱ,Ͱ,ͰЈ,ͰЈ-tetramethyl-1,3-dioxo-
3 cm, petroleum ether/ethyl acetate, 85:15, 15 ml fractions). 11 and lane-4,5-dimethanol (10i): A solution of methyl iodide (15.6 g, 0.11
12 (Rf ϭ 0.45): Colourless oil, ratio 11/12 ca. 1:1. 10e (Rf ϭ 0.32):
Pale yellow oil, yield 1.08 g (22.8%); [α]589 ϭ ϩ2.40 (c ϭ 1.00 in
mol) in diethyl ether (50 ml) was slowly added to a suspension
of Mg (2.66 g, 0.11 mol) in diethyl ether (150 ml) (generation of
Eur. J. Org. Chem. 1998, 711Ϫ718
715

B. Wünsch, S. Nerdinger
FULL PAPER
methylmagnesium iodide). After complete addition of the methyl oil, yield 135 mg (71.0%). Ϫ C27H29NO4 (431.5): calcd. C 75.2 H
iodide solution the reaction mixture was refluxed for 30 min. The 6.77 N 3.25 found C 75.0 H 7.02 N 3.13. Ϫ MS (CI); m/z: 432 [M
mixture was cooled to 0°C and a solution of 10d (5.00 g, 13.9 ϩ Hϩ]. Ϫ IR (film): ν˜ ϭ 3321 cmϪ1 (NH), 1720 (CϭO), 1261
1
mmol) in THF (60 ml) was added and the reaction mixture was
(CϪO), 1232 (CϪO). Ϫ H NMR (CDCl3): δ ϭ 1.01 (d, J ϭ 5.9
stirred for 2 h at room temperature. A saturated solution of NH4Cl Hz, 3 ϫ 0.38 H, CHCH3), 1.06 (d, J ϭ 5.9 Hz, 3 ϫ 0.38 H;
(300 ml) was added, the organic layer was separated, the aqueous
layer was extracted with diethyl ether (3 ϫ 150 ml), the combined
CHCH3), 1.08 (d, J ϭ 5.9 Hz, 3 ϫ 0.62 H, CHCH3), 1.10 (d, J ϭ
5.9 Hz, 3 ϫ 0.62 H, CHCH3), 2.72Ϫ2.84 (m, 2 H, aryl-CH2),
organic layers were dried (MgSO4), and the solvent was evaporated 3.33Ϫ3.49 (m, 2 H, 4-H and 5-H), 5.04 (d, J ϭ 11.7 Hz, 1 H,
in vacuo. Without further purification the residual diol 10i was
employed for methylation to give 10c. 10i: Colourless oil, yield 4.90
g (98.0%). Ϫ C16H23BrO4 (359.3). Ϫ MS (CI); m/z: 361/359 [M ϩ
PhCH2O), 5.08 (d, J ϭ 11.7 Hz, 1 H, PhCH2O), 5.15 (t, J ϭ 3.7
Hz, 1 H, 2-H), 6.16 (d, J ϭ 8.1 Hz, 0.62 H, aryl-CH-NH, s after
H/D exchange), 6.21 (d, J ϭ 8.1 Hz, 0.38 H, aryl-CH-NH, s after
Hϩ]. Ϫ IR (film): ν˜ ϭ 3384 cmϪ1 (OH), 2975 (CH), 1138 (CϪO), H/D exchange), 6.29 (d, J ϭ 7.3 Hz, 0.38 H, aryl-CH-NH, H/D
1031 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 1.11 [s, 3 H, C(CH3)2OH], exchange), 6.38 (d, J ϭ 7.3 Hz, 0.62 H, aryl-CH-NH, H/D ex-
1.12 [s, 3 H, C(CH3)2OH], 1.17 [s, 3 H, C(CH3)2OH], 1.18 [s, 3 H, change), 7.01Ϫ7.33 (m, 14 H, arom.). Ϫ The H-NMR spectra be-
1
C(CH3)2OH], 2.29 (m, 2 H, 2 ϫ OH, H/D exchange), 3.02 (dd, J ϭ fore and after purification by FC reveal a diastereomeric ratio of
14.1/4.3 Hz, 1 H, aryl-CH2), 3.16 (dd, J ϭ 14.1/4.3 Hz, 1 H, aryl-
CH2), 3.70 (d, J ϭ 5.1 Hz, 1 H, 4-H), 3.82 (d, J ϭ 5.1 Hz, 1 H, 5-
H), 5.36 (t, J ϭ 4.3 Hz, 1 H, 2-H), 7.03 (td, J ϭ 7.7/1.3 Hz, 1 H,
5-H arom.), 7.18 (td, J ϭ 7.71/1.3 Hz, 1 H, 4-H arom.), 7.27 (dd,
J ϭ 7.7/1.3 Hz, 1 H, 6-H arom.), 7.48 (d, J ϭ 7.7 Hz, 1 H, 3-
H arom.).
19a/20a ϭ 38:62.
N-{(ͰR) and (ͰS)-2-[(4R,5R)-4,5-Dimethyl-1,3-dioxolan-2-yl-
methyl]-Ͱ-phenylbenzyl}-2,2-dimethylpropionamide (19b and 20b):
According to GP2, 10a (120 mg, 0.44 mmol) was reacted with 17b
(92.6 mg, 0.49 mmol). FC: Diameter of the column 2 cm, petro-
leum ether/ethyl acetate (80:20), 10 ml fractions, Rf ϭ 0.28. Colour-
less oil, yield 128 mg (76.0%). Ϫ C24H31NO3 (381.5): calcd. C 75.6
H 8.19 N 3.67 found C 75.6 H 8.01 N 3.80. Ϫ MS; m/z: 381 [Mϩ],
324 [Mϩ Ϫ C(CH3)3]. Ϫ IR (film): ν˜ ϭ 3298 cmϪ1 (NH), 1633 (Cϭ
cis-(2S,4R)- and trans-(2R,4R)-2-(2-Bromobenzyl)-4-phenyl-
1,3-dioxolane (cis-10j and trans-10j): (a) According to GP1 a solu-
tion of 8 (2.00 g, 8.16 mmol) and 9j (1.24 g, 8.98 mmol) in THF
(50 ml) was heated to reflux. The residue was purified by FC (diam-
eter of the column 4 cm, petroleum ether/ethyl acetate 90:10, 20
ml fractions, Rf ϭ 0.70). Pale yellow oil, yield 2.46 g (94.6%). Ϫ
C16H15BrO2 (319.2): calcd. C 60.2 H 4.74 found C 60.1 H 4.65. Ϫ
MS; m/z: 320/318 [M.ϩ], 200/198 [M.ϩ Ϫ C6H5ϪCOϪCH3]. Ϫ IR
(film): ν˜ ϭ 1132 cmϪ1 (CϪO), 1028 (CϪO) cmϪ1. Ϫ 1H NMR
(CDCl3): δ ϭ 3.15Ϫ3.35 (m, 2 H, aryl-CH2), 3.67Ϫ3.74 (m, 1 H,
5-H), 4.20 (dd, J ϭ 14.7/7.3 Hz, 0.65 H, 5-H), 4.40 (dd, J ϭ 14.1/
8.1 Hz, 0.35 H, 5-H), 5.02 (dd, J ϭ 7.3/6.6 Hz, 0.65 H, 4-H), 5.07
(dd, J ϭ 8.1/6.6 Hz, 0.35 H, 4-H), 5.35 (t, J ϭ 5.1 Hz, 0.65 H, 2-
H), 5.56 (t, J ϭ 5.1 Hz, 0.35 H, 2-H), 7.06Ϫ7.58 (m, 9 H, arom.).
Ϫ 1H NOE (CDCl3, pulse delay ϭ 8 s, 37.5 dB): Irrad. at δ ϭ 5.35
ppm (2-H, cis-10j), NOE at δ ϭ 3.15Ϫ3.35, 4.20, and 5.02 ppm;
irrad. at δ ϭ 5.56 ppm (2-H, trans-10j), NOE at δ ϭ 3.15Ϫ3.35 and
3.67Ϫ3.74 ppm. The 1H-NMR spectrum of the unpurified product
reveals the signals for cis-10j and trans-10j in the ratio 65:35. (b)
As described for (a), 7 (1.50 g, 7.04 mmol) was reacted with 9j (1.07
g, 7.74 mmol). Yield 2.11 g (93.7%).
1
O), 115 (CϪO). Ϫ H NMR (CDCl3): δ ϭ 1.14 (d, J ϭ 5.9 Hz, 3
ϫ 0.64 H, CHCH3), 1.17 (d, J ϭ 6.6 Hz, 3 ϫ 0.36 H, CHCH3),
1.20 (d, J ϭ 5.9 Hz, 3 ϫ 0.36 H, CHCH3), 1.22 (d, J ϭ 5.9 Hz, 3
ϫ 0.64 H, CHCH3), 1.24 [s, 9 H, C(CH3)3], 2.87Ϫ3.06 (m, 2 H,
aryl-CH2), 3.48Ϫ3.59 (m, 2 H, 4-H and 5-H), 5.22 (dd, J ϭ 5.9/3.7
Hz, 0.64 H, 2-H), 5.25 (dd, J ϭ 5.9/3.7 Hz, 0.36 H, 2-H), 6.27 (d,
J ϭ 7.3 Hz, 0.36 H, arylϪCHϪNH, s after H/D-exchange), 6.32
(d, J ϭ 8.1 Hz, 0.64 H, arylϪCHϪNH, s after H/D-exchange),
6.53 (d, J ϭ 8.1 Hz, 0.64 H, arylϪCHϪNH, H/D-exchange), 6.59
(d, J ϭ 7.3 Hz, 0.36 H, arylϪCHϪNH, H/D-exchange), 7.08Ϫ7.34
(m, 9 H, arom.). The 1H-NMR spectra before and after purification
by FC reveal a diastereomeric ratio of 19b/20b ϭ 36:64.
(ϩ)-Benzyl N-{(ͰR)-2-[(4S,5S)-4,5-Bis(methoxymethyl)-1,3-
dioxolan-2-ylmethyl]-Ͱ-phenyl-benzyl}carbamate (19c) and (ϩ)-
Benzyl N-{(αS)-2-[(4S,5S)-4,5-Bis(methoxymethyl)-1,3-dioxolan-
2-ylmethyl]-α-phenylbenzyl}carbamate (20c): According to GP2,
10b (300 mg, 0.91 mmol) was reacted with 17a (230 mg, 0.96
mmol). The HPLC analysis (eluent petroleum ether/diethyl ether,
60:40) of the crude product (320 mg, 71.9%); showed a dia-
stereomeric ratio 19c (retention time 11.4 min):20c (retention time
(4S,5S)-2-Benzyl-4,5-bis(dimethylaminomethyl)-1,3-dioxolane
(14): A solution of 10g (5.00 g, 13.0 mmol) in THF (50 ml) was
slowly added to a suspension of LiAlH4 (1.23 g, 32.3 mmol) in
THF (100 ml) and the reaction mixture was heated under reflux
for 18 h. The excess LiAlH4 was cautiously (cooling to 0°C) hy-
drolyzed with water (2.5 ml), 2  NaOH (5 ml) and water (5 ml).
The reaction mixture was filtered, the organic solvent was evapo-
rated in vacuo, and the residue was purified by FC (diameter of
the column 3.5 cm, petroleum ether/ethyl acetate 50:50, 20 ml frac-
tions, Rf ϭ 0.25). Pale yellow oil, yield 3.43 g (95.0%). Ϫ MS (CI);
m/z: 279 [M ϩ Hϩ]. Ϫ IR (film): ν˜ ϭ 1135 cmϪ1 (CϪO), 1031
1
13.9 min) of 72.1:27.9; according to the H NMR: 19c/20c 72:28.
The separation of the diastereomers 19c and 20c was achieved by
FC: Diameter of the column 2 cm, petroleum ether/diethyl ether
60:40, 10 ml fractions). 19c (Rf ϭ 0.18): Colourless oil, yield 100
mg (22.5%), [α]589 ϭ ϩ1.80 (c ϭ 0.83 in CHCl3). Ϫ C29H33NO6
(491.6): calcd. C 70.9 H 6.77 N 2.85 found C 70.5 H 6.99 N 3.01.
Ϫ MS (CI); m/z: 492 [M ϩ Hϩ]. Ϫ IR (film): ν˜ ϭ 3324 cmϪ1 (NH),
1716 (CϭO), 1135 (CϪO), 1105 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ
2.92Ϫ2.95 (m, 2 H, aryl-CH2), 3.24Ϫ3.44 (m, 10 H, 2 ϫ
CH2ϪOCH3), 3.91Ϫ3.94 (m, 2 H, 4-H and 5-H), 5.07Ϫ5.23 (m, 3
H, 2-H and PhCH2O), 6.20 (d, J ϭ 7.3 Hz, 1 H, aryl-CH-NH, H/
D-exchange), 6.29 (d, J ϭ 7.3 Hz, 1 H, arylϪCHϪNH, s after H/
D-exchange), 7.05Ϫ7.35 (m, 14 H, arom.). 20c (Rf ϭ 0.16): Colour-
less oil, yield 60 mg (13.5%), [α]589 ϭ ϩ11.1 (c ϭ 0.71 in CHCl3).
Ϫ C29H33NO6 (491.6): calcd. C 70.9 H 6.77 N 2.85 found C 70.6
H 6.45 N 2.54. Ϫ MS (CI); m/z: 492 [M ϩ Hϩ]. Ϫ IR (film): ν˜ ϭ
3324 cmϪ1 (NH), 1135 (CϪO), 1105 (CϪO). Ϫ 1H NMR (CDCl3):
δ ϭ 2.96Ϫ2.98 (m, 2 H, aryl-CH2), 3.24Ϫ3.44 (m, 10 H, 2 ϫ
1
(CϪO). Ϫ H NMR (CDCl3): δ ϭ 2.78 [s, 6 H, N(CH3)2], 2.80 [s,
6 H, N(CH3)2], 2.86 (mc, 2 H, aryl-CH2), 3.49 (m, 2 H, 4-H and
5-H), 4.24 (mc, 4 H, 2 ϫ CH2NMe2), 5.76 (t, J ϭ 4.4 Hz, 1 H, 2-
H), 6.72Ϫ6.84 (m, 5 H, arom.).
Benzyl N-{(ͰR) and (ͰS)-2-[(4R,5R)-4,5-Dimethyl-1,3-diox-
olan-2-ylmethyl]-Ͱ-phenylbenzyl}carbamate (19a and 20a): Accord-
ing to GP2, 10a (120 mg, 0.44 mmol) was reacted with 17a (117
mg, 0.49 mmol). FC: Diameter of the column 2 cm, petroleum
ether/ethyl acetate (80:20), 10 ml fractions, Rf ϭ 0.23. Colourless CH2ϪOCH3), 3.89Ϫ3.92 (m, 2 H, 4-H and 5-H), 5.08Ϫ5.21 (m, 3
716 Eur. J. Org. Chem. 1998, 711Ϫ718

Asymmetric Synthesis of 1-Aryl-1,2,3,4-tetrahydroisoquinolines, 2
FULL PAPER
H, 2-H and PhCH2O), 6.26 (d, J ϭ 7.3 Hz, 1 H, arylϪCHϪNH,
H, 5-H), 5.34 (t, J ϭ 5.1 Hz, 0.55 H, 2-H), 5.48 (dd, J ϭ 5.1/3.7
s after H/D exchange), 6.55 (d, J ϭ 7.3 Hz, 1 H, arylϪCHϪNH, Hz, 0.45 H, 2-H), 6.17 (d, J ϭ 7.3 Hz, 0.45 H, arylϪCHϪNH, H/
H/D exchange), 7.04Ϫ7.40 (m, 14 H, arom.). In addition to the
D exchange), 6.30 (d, J ϭ 7.3 Hz, 0.55 H, arylϪCHϪNH, H/D
pure diastereomers, 160 mg (36%) of a diastereomeric mixture exchange), 6.57 (d, J ϭ 7.3 Hz, 0.55 H, arylϪCHϪNH, s after H/
was isolated.
D exchange), 6.64 (d, J ϭ 7.3 Hz, 0.45 H, arylϪCHϪNH, s after
H/D exchange), 7.05Ϫ7.38 (m, 9 H, arom.). The H-NMR spectra
1
N-{(ͰR) and (ͰS)-2-[(4S,5S)-4,5-Bis(methoxymethyl)-1,3-di-
oxolan-2-ylmethyl]-Ͱ-phenylbenzyl}-2,2-dimethylpropionamide (19d
and 20d): According to GP2, 10b (200 mg, 0.60 mmol) was reacted
with 17b (123 mg, 0.65 mmol). FC: Diameter of the column 3 cm,
petroleum ether/ethyl acetate (85:15), 13 ml fractions, Rf ϭ 0.28.
Colourless oil, yield 210 mg (78.8%). Ϫ C26H35NO5 (441.6): calcd.
C 70.7 H 7.99 N 3.17 found C 70.3 H 8.54 N 3.18. Ϫ MS; m/z:
426 [Mϩ Ϫ CH3]. Ϫ IR (film): ν˜ ϭ 3319 cmϪ1 (NH), 1650 (CϭO),
1131 (CϪO). Ϫ H NMR (CDCl3): δ ϭ 1.16 [s, 9 H, C(CH3)3],
2.91Ϫ2.93 (m, 2 H, arylϪCH2), 3.23Ϫ3.40 (m, 10 H, 2 ϫ
CH2ϪOCH3), 3.84Ϫ3.87 (m, 2 H, 4-H and 5-H), 5.15 (dd, J ϭ 5.1/
3.7 Hz, 0.68 H, 2-H), 5.19 (dd, J ϭ 5.9/3.7 Hz, 0.32 H, 2-H), 6.14
(d, J ϭ 7.3 Hz, 0.32 H, arylϪCHϪNH, s after H/D exchange),
6.27 (d, J ϭ 7.3 Hz, 0.68 H, arylϪCHϪNH, s after H/D exchange),
6.42 (d, J ϭ 7.3 Hz, 0.68 H, arylϪCHϪNH, H/D exchange), 6.48
(d, J ϭ 7.3 Hz, 0.32 H, arylϪCHϪNH, H/D exchange), 6.93Ϫ7.26
(m, 9 H, arom.). The 1H-NMR spectra before and after purification
by FC reveal a diastereomeric ratio of 19d/20d ϭ 68:32.
before and after purification by FC reveal a diastereomeric ratio of
19f/20f ϭ 55:45.
(R)-(ϩ)-Benzyl 1-Phenyl-1,2-dihydroisoquinoline-2-carboxylate
[(R)-21)]: A solution of 19c (88 mg, 0.18 mmol) and p-toluenesul-
fonic acid monohydrate (78.8 mg, 0.41 mmol) in methanol (20 ml)
was heated under reflux for 16 h. A saturated solution of NaHCO3
(20 ml) and CH2Cl2 (20 ml) were added, the organic layer was
separated, dried (MgSO4), concentrated in vacuo, and the residue
was purified by FC (diameter of the column 2 cm, petroleum ether/
ethyl acetate, 85:15, Rf ϭ 0.78). After complete elution of (R)-21
the chiral auxiliary 9b was eluted with petroleum ether/ethyl acetate
50:50. (R)-21: Pale yellow oil, yield 51.4 mg (82.3%), [α]589 ϭ ϩ83.0
(c ϭ 1.04 in CHCl3). Ϫ C23H19NO2 (341.4): calcd. C 80.9 H 5.61
N 4.10 found C 80.7 H 5.81 N 4.08. Ϫ MS (CI); m/z: 342 [M ϩ
Hϩ]. Ϫ IR (film): ν˜ ϭ 1710 cmϪ1 (CϭO), 1635 (CϭCϪN), 1232
1
(CϪO), 1120 (CϪO). Ϫ H NMR (CDCl3): δ ϭ 5.20Ϫ5.24 (m, 2
H, PhCH2O), 5.85 (d, J ϭ 7.3 Hz, 0.68 H, 4-H), 5.92 (d, J ϭ 7.3
Hz, 0.32 H, 4-H), 6.32 (s, 0.32 H, 1-H), 6.52 (s, 0.68 H, 1-H), 6.89
(d, J ϭ 7.3 Hz, 0.32 H, 3-H), 7.07Ϫ7.34 (m, 14 H, arom. and 1 ϫ
0.68 H, 3-H). Ratio of R2NϪCϭO rotamers 68:32. Ϫ 13C NMR
(CDCl3): δ ϭ 58.1 (d, C-1, main rotamer), 59.1 (d, C-1, minor
rotamer), 68.1 (t, PhCH2O), 108.7 (d, C-4, minor rotamer), 108.9
(d, C-4, main rotamer), 124.7 (d, C-3, main rotamer), 125.0 (d, C
arom.), 125.2 (d, C-3, minor rotamer), 125.7 (d, C arom.), 126.5
(d, C arom.), 127.1 (d, C arom.), 127.2 (d, C arom.), 127.3 (d, C
arom.), 127.4 (d, C arom.), 127.7 (d, C arom.), 127.9 (d, C arom.),
128.1 (d, C arom.), 128.3 (d, C arom.), 128.4 (d, C arom.), 128.6
(d, C arom.), 128.7 (d, C arom.), 130.0 (s, C arom., minor rotamer),
130.2 (s, C arom., main rotamer), 131.6 (s, C arom., main rotamer),
131.9 (s, C arom., minor rotamer), 135.7 (s, C arom., minor rot-
amer), 135.8 (s, C arom., main rotamer), 141.8 (s, C arom., main
rotamer), 142.5 (s, C arom., minor rotamer), 153.1 (s, NCO2Bn,
main rotamer), 153.6 (s, NCO2Bn, minor rotamer). 9b: Colourless
oil, yield 23.7 mg (89.2%).
Benzyl N-{(ͰR) and (ͰS)-2-[(4R,5R)-4,5-Bis(2-methoxypro-
pan-2-yl)-1,3-dioxolan-2-ylmethyl]-Ͱ-phenylbenzyl}carbamate (19e
and 20e): According to GP2, 10c (116 mg, 0.30 mmol) was reacted
with 17a (76.5 mg, 0.32 mmol). FC: Diameter of the column 2 cm,
petroleum ether/ethyl acetate (90:10), 10 ml fractions, Rf ϭ 0.25.
Colourless oil, yield 90 mg (54.8). Ϫ C33H41NO6 (547.7): calcd. C
72.4 H 7.55 N 2.56 found C 72.4 H 7.77 N 2.30. Ϫ MS; m/z: 397
[Mϩ Ϫ NHCO2Bn]. Ϫ IR (film): ν˜ ϭ 3299 cmϪ1 (NH), 1714 (Cϭ
1
O, 1136 (CϪO), 1098 (CϪO). Ϫ H NMR (CDCl3): δ ϭ 0.92 [s, 3
ϫ 0.49 H, C(CH3)2OCH3], 0.96 [s, 3 ϫ 0.51 H, C(CH3)2OCH3],
1.02 [s, 3 H, C(CH3)2OCH3], 1.09 [s, 3 ϫ 0.51 H, C(CH3)2OCH3],
1.13 [s, 3 ϫ 0.49 H, C(CH3)2OCH3], 1.15 [s, 3 H, C(CH3)2OCH3],
2.90Ϫ3.26 (m, 8 H, arylϪCH2 and 2 ϫ OCH3), 3.75Ϫ3.81 (m, 1
H, 4-H), 4.00Ϫ4.04 (m, 1 H, 5-H), 5.10Ϫ5.14 (m, 2 H, PhCH2O),
5.30 (t, J ϭ 4.4 Hz, 0.49 H, 2-H), 5.39 (t, J ϭ 4.4 Hz, 0.51 H, 2-
H), 6.07 (d, J ϭ 8.1 Hz, 0.51 H, arylϪCHϪNH, H/D exchange),
6.09 (d, J ϭ 8.1 Hz, 0.49 H, arylϪCHϪNH, H/D exchange), 6.14
(d, J ϭ 8.1 Hz, 0.49 H, arylϪCHϪNH, s after H/D exchange),
6.29 (d, J ϭ 8.1 Hz, 0.51 H, arylϪCHϪNH, s after H/D exchange),
7.11Ϫ7.36 (m, 14 H, arom.). The 1H-NMR spectra before and after
purification by FC reveal a diastereomeric ratio of 19e/20e ϭ 51:49.
(R)-(Ϫ)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline [(R)-2]: Pd/C
catalyst (10%, 10 mg) was added to a solution of (R)-21 (40 mg,
0.12 mmol) in methanol (20 ml). The reaction mixture was stirred
for 4 h under a hydrogen amosphere (1.7 bar H2) at room tempera-
ture. The mixture was filtered (celite), the filtrate was concentrated
in vacuo and the residue was purified by FC (diameter of the col-
umn 2 cm, CH2Cl2/methanol 90:10, 10 ml fractions, Rf ϭ 0.25).
Colourless oil, yield 10.9 mg (44.6%), [α]589 ϭ Ϫ10.12 (c ϭ 0.60 in
CHCl3) [ref.[8a][15]: [α]589 ϭ Ϫ10.2 (c ϭ 0.17 in CHCl3]. For spectro-
N-{(ͰR) and (ͰS)-2-[(4R,5R)-4,5-Bis(2-methoxypropan-2-yl)-
1,3-dioxolan-2-ylmethyl]-Ͱ-phenylbenzyl}-2,2-dimethylpropion-
amide (19f and 20f): According to GP2, 10c (116 mg, 0.30 mmol)
was reacted with 17b (60 mg, 0.32 mmol). FC: Diameter of the
column 2 cm, petroleum ether/ethyl acetate (90:10), 10 ml fractions,
Rf ϭ 0.25. Colourless oil, yield 100 mg (67.0%). Ϫ C30H43NO5
(497.7): calcd. C 72.4 H 8.10 N 2.81 found C 72.0 H 8.36 N 2.92.
Ϫ MS (CI); m/z: 498 [M ϩ Hϩ]. Ϫ IR (film): ν˜ ϭ 3299 cmϪ1 (NH),
1714 (CϭO), 1136 (CϪO), 1098 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ
1.06 [s, 3 ϫ 0.45 H, C(CH3)2OCH3], 1.13 [s, 3 ϫ 0.55 H,
C(CH3)2OCH3], 1.16 [s, 3 H, C(CH3)2OCH3], 1.22 [s, 3 ϫ 0.45 H,
C(CH3)2OCH3], 1.25 [s, 3 ϫ 0.55 H, C(CH3)2OCH3], 1.27 [s, 3 ϫ
0.45 H, C(CH3)2OCH3], 1.28 [s, 3 ϫ 0.55 H, C(CH3)2OCH3], 1.30
[s, 9 ϫ 0.45 H, C(CH3)3], 1.31 [s, 9 ϫ 0.55 H, C(CH3)3], 2.91Ϫ3.11
(m, 2 H, arylϪCH2), 3.19 (s, 3 ϫ 0.55 H, OCH3), 3.22 (s, 3 ϫ 0.55
H, OCH3), 3.24 (s, 3 ϫ 0.45 H, OCH3), 3.29 (s, 3 ϫ 0.45 H, OCH3),
3.88 (d, J ϭ 2.9 Hz, 0.45 H, 4-H), 3.92 (d, J ϭ 3.7 Hz, 0.45 H, 5-
H), 4.10 (d, J ϭ 2.2 Hz, 0.55 H, 4-H), 4.11 (d, J ϭ 1.5 Hz, 0.55
scopic data see ref.[8a]
.
Ƞ
Dedicated to Prof. Dr. H.-D. Stachel on the occasion of his
70th birthday.
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