Diastereoselective addition of chiral (2-lithiophenyl)acetaldehyde acetals to various imines as key step in the asymmetric synthesis of 1- aryltetrahydroisoquinolines, part 4

Article abstract of DOI:10.1002/(SICI)1099-0690(199902)1999:2<503::AID-EJOC503>3.0.CO;2-I

A novel asymmetric synthesis of 1-aryl-1,2,3,4-tetrahydroisoquinolines has been developed. The key step in this synthesis is the diastereoselective addition of homochiral (2-lithiophenyl)acetaldehyde acetals to the sulfonylimine 25 and to the arylimines 28 and 31. The best diastereoselectivity is obtained by addition of the bis(2-methoxypropan-2- yl)-substituted 1,3-dioxolane 6e to benzylidene-p-anisidine (31) with an HPLC-determined diastereomeric ratio 32c/33c = 92.1:7.9. The N-tosyl and the N-(4-methoxyphenyl) groups of the addition products 26d, 27d, 32c, and 33c are cleaved with sodium in liquid ammonia and ammonium cerium(IV) nitrate, respectively, to yield the primary amines 35 and 36. The acid-catalysed cyclization of the sulfonamides 26d and 27d and the carbamates 37 and 38, prepared from 35 and 36, leads to the enantiomerically pure dihydroisoquinolines 40 and 41, respectively. During the cyclization of the sulfonamides 26d, 27d and the carbamates 37, 38 the chiral auxiliary - the diol 39 - is cleaved unchanged and can be recovered in good yields.

Full text of DOI:10.1002/(SICI)1099-0690(199902)1999:2<503::AID-EJOC503>3.0.CO;2-I

FULL PAPER
Diastereoselective Addition of Chiral (2-Lithiophenyl)acetaldehyde
Acetals to Various Imines as Key Step in the Asymmetric
Synthesis of 1-Aryltetrahydroisoquinolines, Part 4[°]
Bernhard Wünsch*[a] and Sven Nerdinger[b]
Keywords: Enantiomerically pure (2-bromophenyl)acetaldehyde acetals / Halogen-metal exchange / Diastereoselective
addition to imines / Asymmetric synthesis / Tetrahydroisoquinolines / NMDA antagonists
A
novel asymmetric synthesis of 1-aryl-1,2,3,4-tetrahy-
sodium in liquid ammonia and ammonium cerium(IV) nitrate,
respectively, to yield the primary amines 35 and 36. The acid-
catalysed cyclization of the sulfonamides 26d and 27d and
the carbamates 37 and 38, prepared from 35 and 36, leads
to the enantiomerically pure dihydroisoquinolines 40 and 41,
respectively. During the cyclization of the sulfonamides 26d,
27d and the carbamates 37, 38 the chiral auxiliary – the diol
39 – is cleaved unchanged and can be recovered in good
yields.
droisoquinolines has been developed. The key step in this
synthesis is the diastereoselective addition of homochiral (2-
lithiophenyl)acetaldehyde acetals to the sulfonylimine 25
and to the arylimines 28 and 31. The best diastereoselectivity
is obtained by addition of the bis(2-methoxypropan-2-yl)-
substituted 1,3-dioxolane 6e to benzylidene-p-anisidine (31)
with an HPLC-determined diastereomeric ratio 32c/33c =
92.1:7.9. The N-tosyl and the N-(4-methoxyphenyl) groups of
the addition products 26d, 27d, 32c, and 33c are cleaved with
Introduction
The structure of a great number of pharmacologically ac-
tive compounds is based on the 1-substituted 1,2,3,4-tetra-
hydroisoquinoline skeleton.[1] Therefore, several methods
for the synthesis of optically active tetrahydroisoquinolines
have been developed during the last twenty years.[2] During
the course of our work on central nervous system (CNS)
receptor ligands we have been engaged in the synthesis of
1-aryl-1,2,3,4-tetrahydroisoquinolines 5 possessing antag-
onistic activity at dopamine D1[3] and NMDA (N-methyl--
aspartate) receptors.[4] For this purpose a novel asymmetric
synthesis for 1-aryl-1,2,3,4-tetrahydroisoquinolines 5 has
been elaborated, in which the addition of chiral phenylacet-
aldehyde acetals 1 to activated imine components 2 is the
key step. The chiral acetal moiety should thereby control
Scheme 1
Preparation of Enantiomerically Pure
the diastereoselectivity.[5] This strategy differs from the (2-Bromophenyl)acetaldehyde Acetals
known 1-aryltetrahydroisoquinoline syntheses in two as-
The preparation of the 1,3-dioxolanes 6a, 6b, 6e, and 6g
pects. Firstly, the stereogenic centre in position 1 of 5 is
established before building up the isoquinoline ring sys-
tem.[6Ϫ10] Secondly, the chiral auxiliary Ϫ usually an enan-
tiomerically pure diol Ϫ is liberated during the cyclization
step without destroying the stereogenic centres and can be
recovered in good yields.[6Ϫ9]
Herein, we report on an extension of our procedure to
more stable imine components instead of the highly reactive
and thus unstable acylimines 2 (RЈ ϭ COtBu, CO2Bn).
Moreover, additional acetalic heterocycles (see Scheme 2),
which should improve the diastereoselectivity during the
nucleophilic addition to the imines, are investigated.
succeeded by transacetalization of the enol ether 10[11] or
the dimethyl acetal 11[11] with the corresponding 1,2-
diols.[5] In analogy, the reaction of 10 and/or 11 with the
1,2-diols 14,[12] 15, 20b or the 1,4-diol 16[12b,13] provided the
1,3-dioxolanes 6c, 6d, 6f, and the 1,3-dioxepane 8, respec-
tively.
The 1,2-diol 15 was prepared by alkylation of the tartaric
acid derivative 13a[12b,14] with 1-bromo-2-methoxyethane
(Ǟ 13b) and subsequent hydrolysis. In contrast to a re-
ported method,[15] the diol 20b could not be obtained by
hydrolysis of its acetonide. Therefore, an alternative four-
step route for the preparation of 20b analogous to
the described synthesis of tetraaryldialkoxybutane-2,3-diols
(TADDOLs)[16] was elaborated. Reaction of the p-meth-
oxybenzaldehyde acetal 18 with excess ethylmagnesium
iodide led to the diol 19a, which was alkylated with methyl
[°]
Part 3: Ref.[20]
[a]
Pharmazeutisches Institut der Universität Freiburg,
Hermann-Herder-Straße 9, D-79104 Freiburg i. Br., Germany
[b]
CarboGen Laboratories AG,
Schachenallee 29, CH-5001 Aarau, Switzerland
Eur. J. Org. Chem. 1999, 503Ϫ517
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0202Ϫ0503 $ 17.50ϩ.50/0
503

B. Wünsch, S. Nerdinger
FULL PAPER
Scheme 4
and subsequent methylation of the resulting diol 6h rep-
resents an attractive alternative.
Transacetalization of the phenylacetaldehyde dimetyl ace-
tal 11 with the (S)-configured butanetriol 21 furnished an
80:20 mixture of the 1,3-dioxane 7a and the 1,3-dioxolane
22. Whereas the 1H-NMR spectrum of 7a displays only sig-
nals for the cis isomer, two sets of signals appear in the 1H-
NMR spectrum of the 1,3-dioxolane 22 (cis-22/trans-22 ϭ
1:1). A comparable regio- and diastereoselectivity is ob-
served during the acetalization of benzaldehyde derivatives
with the butanetriol 21.[17] Since a halogen/metal exchange
reaction was planned as the next step, the hydroxy group
of 7a was protected with sterically different silyl protective
groups (7b؊7d). The butanetriol 23 differing from 21 by an
additional benzyloxy substituent (and the configuration)
was derived from (R,R)-tartaric acid.[14] Transacetalization
of the dimethyl acetal 11 with 23 resulted in a somewhat
lower regioselectivity (7e/24 ϭ 60:40). Again, the six-mem-
bered acetal 7e, whose configuration and conformation was
deduced from a NOESY spectrum, was formed diastereo-
selectively, whereas the five-membered 1,3-dioxolane 24 was
isolated as 1:1 cis/trans-isomeric mixture. With methyl
iodide the hydroxy group of 7e was protected to give the
methoxymethyl derivative 7f.
Scheme 2
Scheme 3
iodide to yield the dimethoxy derivative 19b. After oxidative
cleavage of the acetal moiety with 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) the intermediate p-methoxyben-
zoate 20a was reduced with LiAlH4 to afford the diol 20b.
In the case of the tetraethyl derivative 6f, Grignard reaction
of the diester 6g[5] with an excess of ethylmagnesium iodide Scheme 5
504
Eur. J. Org. Chem. 1999, 503Ϫ517

Key Step in the Asymmetric Synthesis of 1-Aryltetrahydroisoquinolines
FULL PAPER
The 1,3-oxazolidine 9 could not be obtained by transace- Table 1. Addition of lithiated 6Ϫ8 to the tosylimine 25
talization of the enol ether 10 or the dimethyl acetal 11
entry
acetal
product ratio
yield (%)
with the enantiomerically pure 1,2-amino alcohol (1R,2S)-
ephedrine (17). However, reaction of the aldehyde 12[11]
with 17 furnished a diastereomeric mixture of N/O-acetals
from which the diastereomer 9 was isolated by fractional
crystallization (60% yield).
1
6a
6b
6c
6d
6e
6f
6g
7a
7b
7c
7d
7f
8
26a/27a ϭ 45:55
26b/27b ϭ 55:45
no addition
76
66
Ϫ
65
62
32
Ϫ
2
3
4
26c/27c ϭ 52:48
26d/27d ϭ 61:39
26e/27e ϭ 62:38
no addition
5
6
7
8
no addition
Ϫ
Addition of Lithiated Phenylacetaldehyde
Acetals to Various Imines
9
26f/27f ϭ 44:56
26g/27g ϭ 33:67
26h/27h ϭ 32:68
26i/27i ϭ 56:44
no addition
75
71
61
49
Ϫ
10
11
12
13
At Ϫ85°C to Ϫ100°C various imine components were
added to the aryllithium intermediates, which had been gen-
erated by reaction of the aryl bromides 6؊9 with n-butyl-
lithium at Ϫ100°C (bromine/lithium exchange).
In the dioxolane series electronic or steric variations of
the substituents in position 4 and 5 of the dioxolane ring
had only little influence on the diastereoselectivity (ratio
55:45 to 62:38, entries 1Ϫ7). Protection of the hydroxy
group of the 1,3-dioxane 7a with sterically different silyl
protective groups raised the diastereoselectivity from 44:56
(26f/27f) to 32:68 (26h/27h, entries 8Ϫ12). However, even
with the very large triphenylsilyl protective group (7d) the
diastereomeric ratio did not exceed 32:68. Unexpectedly, en-
largement of the 1,3-dioxane ring to the homologous,
seven-membered 1,3-dioxepane ring (8) reduced the reactiv-
ity of the corresponding aryllithium intermediate to such
an extent that an addition to the tosylimine 25 did not take
place (entry 13).
At first, the diastereoselectivity in the addition of the
aryllithium intermediates to the tosylimine 25, which is eas-
ily available by condensation of benzaldehyde or its diethyl
acetal with p-toluenesulfonamide,[18] was investigated. The
activation of the imine moiety by the tosyl group in 25 is
comparable to the imine activation by acyl groups in acyl-
imines. In contrast to the acylimines, the crystalline tosyl-
imine 25 is not sensitive to air and moisture and, therefore,
can be stored for several months without degradation. Ad-
ditionally, a different geometry around the imine moiety is
caused by the tetrahedral sulfur atom of the tosylimine 25.
The configuration of the novel stereogenic centre in the
addition products 26 and 27 was determined by transfor-
mation of the separated sulfonamides 26d and 27d into the
known 1-phenyltetrahydroisoquinolines (R)-43 and (S)-43,
respectively [see part Preparation of (R)- and (S)-1-phenyl-
1,2,3,4-tetrahydroisoquinoline]. In the 1,3-dioxane series
the diastereomeric mixture 26g/27g (de ϭ 34%) was cy-
clized to afford the levorotatory 1,2-dihydroisoquinoline
(S)-40. Comparison of the specific optical rotation
20
([α]D ϭ Ϫ94.7, c ϭ 0.93 in CHCl3, ee ϭ 35%) with the
specific optical rotation of the enantiomerically pure 1,2-
Scheme 6
20
dihydroisoquinoline (S)-40 prepared from 27d ([α]D
ϭ
The results of the addition of various homochiral (2-li- Ϫ269.8, c ϭ 1.04 in CHCl3) reveals that (S) configuration
thiophenyl)acetaldehyde acetals to the tosylimine 25 are has to be assigned to the novel stereogenic centre in the
1
summarized in Table 1. Good chemical yields of the ad- main diastereomer 27g. Correlation of the H-NMR spec-
dition products 26/27 were obtained with the dioxolanes 6a, tra of all addition products 26 and 27 led to the stereochem-
b, d, e (entries 1, 2, 4, 5) and the 1,3-dioxanes 7b؊d (entries ical assignment as depicted in Table 1.
9Ϫ11). Addition products after reaction of 6c, 6g, 7a (dili-
The separation of the diastereomers 26 and 27 by flash
thiated derivative generated with two equivalents of n-butyl- chromatography or even by HPLC proved to be difficult.
lithium), and 8 with the tosylimine 25 even at ϩ25°C could After many attempts an eluent was found for the separation
not be detected. In the 1H-NMR spectra of the crude reac- of the diastereomeric pair 26d and 27d.
tion products only signals for the debrominated phenylacet-
aldehyde acetals (H instead of Br) were identified.
Because of the unsatisfactory diastereoselectivity in the
addition of the chiral (2-lithiophenyl)acetaldehyde acetals
Integration of the separated benzylic methine signals to the tosylimine 25 (Table 1), benzylidenaniline 28 was
(aryl2CHϪNHϪ) in the 1H-NMR spectra of the unpurified considered as alternative imine component. The air- and
addition products provided the diastereomeric ratio of the moisture-stable benzylidenaniline 28 is easily prepared by
addition products 26 and 27 (e.g. 26d: δ ϭ 5.38; 27d: δ ϭ condensation of benzaldehyde with aniline. Compared with
5.80). In the case of 26d/27d a HPLC analysis confirmed acylimines and sulfonylimines the reactivity of the arylimine
1
the H-NMR result (26d/27d ϭ 60.9:39.1).
28 towards nucleophiles is markedly reduced and, more-
Eur. J. Org. Chem. 1999, 503Ϫ517
505

B. Wünsch, S. Nerdinger
FULL PAPER
over, the steric environment of the imine moiety of 28, benzaldehyde with 4-methoxyaniline.[21] In 31 the imine re-
which exists in a stable nonplanar conformation[19], is activity is slightly reduced by the electron-releasing p-meth-
changed.
oxy substituent. This reduced reactivity of 31 is reflected in
the decreased yields of the addition products 32 and 33
(Table 3). However, performing the additions at a reaction
temperature of 0°C for two hours instead of Ϫ85 to
Ϫ100°C increased the yields to 62Ϫ67% without changing
the diastereoselectivity (entries 2/3 and 4/5). Again the 1,3-
dioxolane 6f with the large (3-methoxypentan-3-yl) sub-
stituents did not react with benzylidene-p-anisidine (31) (en-
try 6). In the 1,3-dioxane series the addition with the tert-
butyldimethylsilyl-protected derivative 7c worked well to
furnish the addition products 32d/33d (entry 7), whereas the
reaction with the triphenylsilyl-protected derivative 7d
failed to give any addition products (entry 8).
Scheme 7
Nevertheless, the addition of the homochiral aryllithium
derivatives Ϫ generated from the aryl bromides 6a, b, e, and
7d Ϫ to benzylidenaniline 28 resulted even in better yields
(Table 2) than the corresponding additions to the tosylimine
25 (Table 1). A dramatic enhancement of the diastereoselec-
tivity was observed when the 1,3-dioxolane 6e with the two
large (2-methoxypropan-2-yl) residues was added to benzyl-
idenaniline (29c/30c ϭ 91:9, entry 3). Aiming at a further
enhancement of the diastereoselectivity the homologous
doubly (3-methoxypentan-3-yl)-substituted 1,3-dioxolane 6f
was included in the study. Unfortunately, treatment of 6f
with n-butyllithium and subsequently with 28 did not pro-
vide any addition products even at a reaction temperature
of ϩ25°C. In the 1H-NMR spectrum of the unpurified
product only debrominated 6f (H instead of Br) could be
detected. Obviously, the very large substituents in the di-
oxolane ring of 6f prevent the addition to the arylimine 28
(entry 4) and diminishes the yield in the addition to the
tosylimine 25 (entry 6, Table 1).
Scheme 8
Table 3. Addition of lithiated 6 and 7 to benzylidenanisidine 31
entry
acetal
product ratio
yield (%)
1
2
3
4
5
6
7
8
6a
6b
6b
6e
6e
6f
32a/33a ϭ 48:52
32b/33b ϭ 61:39
32b/33b ϭ 61:39
32c/33c ϭ 91:9
32c/33c ϭ 91:9
no addition
37
37
62
38
67
Ϫ
Table 2. Addition of lithiated 6 and 7 to benzylidenaniline 28
7c
7d
32d/33d ϭ 34:66
no addition
58
Ϫ
entry
acetal
product ratio
yield (%)
1
2
3
4
5
6a
6b
6e
6f
29a/30a ϭ 49:51
29b/30b ϭ 57:43
29c/30c ϭ 91:9
no addition
82
82
75
Ϫ
[a] Addition: 6 h at Ϫ85 to Ϫ100°C. Ϫ [b] Addition: 2 h at Ϫ85 to
Ϫ100°C, then 2 h at 0°C.
7d
29d/30d ϭ 25:75
69
The addition of the aryllithium derivatives to the aryl-
imines 28 and 31 resulted in comparable diastereoselectivit-
The addition of the six-membered 1,3-dioxane 7d to the ies (see Tables 2 and 3). Again, a large diastereoselectivity
arylimine 28 also resulted in a better yield and an increased improvement was observed with the (2-methoxypropan-2-
diastereoselectivity (entry 5, Table 2) in comparison with yl)-substituted 1,3-dioxolane 6e (entries 4, 5). The dia-
the addition to the tosylimine 25 (entry 11, Table 1).
stereomeric ratio 32c/33c ϭ 91:9 (entries 4, 5) determined
1
In summary, the results of the addition to acylimines,[5] by H-NMR spectroscopy was specified by HPLC analysis
benzylimines,[20] to the sulfonylimine 25, and the arylimine to be 92.1:7.9.
28 lead to the conclusion that a N-aryl-substituted imine
Reaction of the oxazolidinyl-substituted aryl bromide 9
component with moderate reactivity (e.g. 28) seems to be with n-butyllithium and, subsequently, with the tosylimine
favorable with regard to high diastereoselectivities (and 25, or the arylimines 28 or 31 resulted in complex product
yields). However, the N-phenyl group of the benzylideneani- mixtures. Flash chromatography of the product mixture
line addition products 29 and 30 cannot be cleaved under from the tosylimine addition led to isolation of the hydroxy-
mild reaction conditions.
substituted isoquinoline 34 in 39% yield (cis/trans ϭ 1:1).
This problem was solved with the imine component Obviously, the oxazolidine ring containing the chiral auxili-
benzylidene-p-anisidine (31), the condensation product of ary ephedrine was hydrolysed during workup with NH4Cl
506
Eur. J. Org. Chem. 1999, 503Ϫ517

Key Step in the Asymmetric Synthesis of 1-Aryltetrahydroisoquinolines
FULL PAPER
and/or flash chromatography preventing a diastereomeric with ammonium cerium(IV) nitrate[23] also furnished the
separation.
primary amine 35 (de ϭ 84%). A further purification of 35
(de ϭ 84%) succeeded via the chromatographically sepa-
rable sulfonamides 26d and 27d. The enantiomerically pure
primary amine 35 was acylated with benzyl chloroformate
to yield the carbamate 37. With p-toluenesulfonic acid the
carbamate 37 reacted to form the cyclization product (R)-
41 liberating the chiral auxiliary, the diol 39, which could
be isolated in 75% yield. Treatment of the dihydroisoquino-
line (R)-41 with H2 and Pd/C furnished the (R)-configured
1-phenyltetrahydroisoquinoline (R)-43.[5]
Scheme 9
Dehydration of 34 was performed with methanesulfonyl
chloride and triethylamine to yield the dihydroisoquinoline
(S)-40. The specific optical rotation of (S)-40 ([α]D
20
ϭ
More directly, heating of the diastereomerically pure sul-
fonamide 26d with an excess of HCl and p-toluenesulfonic
acid led to the tosyl-substituted dihydroisoquinoline (R)-40
and the enantiomerically pure diol 39, which was recovered
in 72% yield. Subsequent reduction of (R)-40 with LiAlH4
provided the tetrahydroisoquinoline (R)-42. In the last step
the N-tosyl group of (R)-42 was cleaved with sodium in
liquid ammonia[22] to furnish the (R)-configured 1-phenyl-
1,2,3,4-tetrahydroisoquinoline (R)-43. The diastereomeric
sulfonamide 27d was transformed analogously into the en-
antiomeric (S)-configured 1-phenyl-1,2,3,4-tetrahydroiso-
quinoline (S)-43 via the primary amine 36 and the carb-
amate 38[5] or via the dihydroisoquinoline (S)-40 and the
tetrahydroisoquinoline (S)-42.
Ϫ135.6, c ϭ 1.90 in CHCl3) indicates an enantiomeric ratio
of (R)-40/(S)-40 ϭ 25:75 [see part Preparation of (R)- and
(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline]. On the suppo-
sition that epimerization and racemization do not occur
during workup, FC purification and dehydration, the en-
antiomeric ratio (25:75) reflects the diastereoselectivity
(25:75) of the addition of lithiated 9 to the tosylimine 25.
Starting from this considerable diastereoselectivity further,
more stable, chiral oxazolidine and imidazolidine ring sys-
tems will be investigated for controlling the diastereoselec-
tivity.
Preparation of (R)- and (S)-1-Phenyl-1,2,3,4-
tetrahydroisoquinoline [(R)-43 and (S)-43]
In contrast to previous data,[7a] Wanner and co-workers
unequivocally proved, that the configuration of the dextro-
For the preparation of (R)- and (S)-1-phenyltetrahydro- rotatory isoquinoline enantiomer (ϩ)-43 is (S).[24] This as-
isoquinolines (R)-43 and (S)-43 various reaction pathways signment was confirmed by studies of Marazano and co-
were investigated. The sulfonyl group of the diastereomer- workers.[9] The stereochemical specifications of the dia-
ically pure sulfonamide 26d was cleaved with sodium in stereomeric addition products 26/27, 29/30, 32/33 and the
liquid ammonia[22] to yield the primary amine 35. Oxidative intermediates 35Ϫ38, (R)- and (S)-40, (R)- and (S)-41, and
cleavage of the p-methoxyphenyl group of 32c (de ϭ 84%) (R)- and (S)-42 are based on this assignment.
Scheme 10. Reaction conditions: (a) Na, NH3 liquid, Ϫ78°C, 45 min; (b) TosCl, NEt3, THF, room temp., 8 h; (c) (NH4)2Ce(NO3)6,
CH3OH, H2O, room temp., 3 h; (d) p-TolSO3H, HCl conc., CH3OH, H2O, reflux, 4 d; (e) CbzCl, NEt3, THF, room temp., 8 h; (f)
LiAlH4, THF, reflux, 16 h; (g) p-TolSO3H, CH3OH, reflux, 16 h; (h) H2, Pd/C, CH3OH, 1.7 bar, room temp.,4 h[5b]
Eur. J. Org. Chem. 1999, 503Ϫ517
507

B. Wünsch, S. Nerdinger
FULL PAPER
20
Table 4. Specific optical rotation [α]D of (R)-43 and (S)-43
found
references
(R)-43
(S)-43
[α] ϭ Ϫ10.12 (c ϭ 0.98, CHCl3) [from (R)-41]
[α] ϭ Ϫ10.2 (c ϭ 0.17, CHCl3)[7a]
[α] ϭ ϩ12.3 (c ϭ 1.0, CH2Cl2)[8a,24]
[α] ϭ Ϫ10.20 (c ϭ 0.99, CHCl3) [from (R)-42]
[α] ϭ ϩ12.20 (c ϭ 0.99, CH2Cl2) [from (S)-41]
[α] ϭ ϩ12.20 (c ϭ 0.85, CH2Cl2) [from (S)-42]
cmϪ1 (CϪH), 2927 (CϪH), 1598 (CϭC), 1359 (SO2), 1174 (CϪO).
1H NMR (CDCl3): δ ϭ 2.48 (s, 3 H, aryl-CH3), 2.50 (s, 3 H,
According to the specific optical rotation the enantio-
meric purity of the prepared tetrahydroisoquinolines (R)-43
and (S)-43 is higher than 99% ee (see Table 4).
Ϫ
aryl-CH3), 2.99Ϫ3.10 [m, 2 H, CH2-CH(OR)2], 3.99Ϫ4.09 (m, 6 H,
4-H, 5-H and 2 ϫ CH2OTos), 5.22 (dd, J ϭ 5.1/4.7 Hz, 1 H, 2-H),
7.11Ϫ7.25 (m, 3 H, 4-H, 5-H, 6-H arom.), 7.35 (d, J ϭ 8.1 Hz, 2
H, SO2C6H4CH3), 7.40 (d, J ϭ 8.1 Hz, 2 H, SO2-C6H4CH3), 7.55
(d, J ϭ 8.1 Hz, 1 H, 3-H arom.), 7.78 (d, J ϭ 8.1 Hz, 2 H,
SO2C6H4CH3), 7.82 (d, J ϭ 8.1 Hz, 2 H, SO2C6H4CH3). Ϫ 13C
NMR (CDCl3): δ ϭ 21.0 (q, 2 ϫ aryl-CH3), 40.6 [t, CH2CH(OR)2],
68.2 (t, CH2OTos), 68.4 (t, CH2OTos), 75.2 (d, C-4), 75.4 (d, C-5),
104.2 (d, C-2), 125.0 (s, C-1 arom.), 127.3 (d, C-6 arom.), 128.0 (d,
2 ϫ arom.), 128.6 (d, C-5 arom.), 130.0 (d, 2 ϫ arom.), 132.0 (d,
C-4 arom.), 132.3 (s, 2 ϫ arom.), 132.6 (d, C-3 arom.), 134.9 (s, C-
2 arom.), 145.3 (s, 2 ϫ arom.).
Experimental Section
General: Unless otherwise stated, moisture-sensitive reactions were
conducted under dry nitrogen. Ϫ THF was distilled from sodium
benzophenone ketyl prior to use. Ϫ Flash chromatography (FC)[25]
:
Silica gel 60, 0.040Ϫ0.063 mm (Merck). Ϫ HPLC: Column filled
with silica gel (5 µm particles, LiChrosorb Si 60, Merck); pump
L-6200 (Merck), pressure 40 bar, rate 1 mL/min; L-4250-UV/VIS
detector (Hitachi), λ ϭ 254 nm; eluent petroleum ether/diethyl
ether (60:40). Ϫ Melting points: Melting point apparatus Dr. Tot-
toli (Büchi), uncorrected values. Ϫ Optical rotation: Polarimeter
241 (Perkin Elmer); 1.0-dm tube; concentration c [g/100 mL]; tem-
perature 20°C. Ϫ Elemental analyses: CHN elemental analyser Ra-
pid (Heraeus). Ϫ MS: Mass spectrometer 5989A (Hewlett Pack-
ard); CI ϭ chemical ionization. Ϫ IR: IR spectrophotometer 1600
(4S,5S)-(؉)-2-(2-Bromobenzyl)-4,5-bis[(2-methoxyethoxy)methyl]-
1,3-dioxolane (6d): a) According to General Procedure 1, a mixture
of 11 (3.10 g, 12.7 mmol), 15 (3.17 g, 13.3 mmol) and THF (50
mL) was heated to reflux. The residue was purified by FC: diameter
of the column 3 cm, petroleum ether/ethyl acetate (1:1), Rf ϭ 0.25.
Colourless oil, yield 4.36 g (82%), [α]589 ϭ ϩ1.20 (c ϭ 1.00 in
CHCl3). Ϫ C18H27BrO6 (419.3): calcd. C 51.6, H 6.49; found C
51.6, H 6.45. Ϫ MS (CI): m/z ϭ 421/419 (M ϩ Hϩ). Ϫ IR (film):
ν˜ ϭ 2923 cmϪ1 (CϪH), 1473 (CϭC), 1136 (CϪO). Ϫ 1H NMR
(CDCl3): δ ϭ 3.11Ϫ3.21 [m, 2 H, CH2CH(OR)2], 3.37 (s, 3 H,
CH2OCH3), 3.39 (s, 3 H, CH2OCH3), 3.53Ϫ3.71 (m, 12 H, 2 ϫ
CH2OCH2CH2OCH3)2), 3.97Ϫ4.03 (m, 2 H, 4-H and 5-H), 5.34
(dd, J ϭ 5.1/4.4 Hz, 1 H, 2-H), 7.09 (td, J ϭ 8.1/2.2 Hz, 1 H, 5-H
arom.), 7.25 (td, J ϭ 8.1/2.2 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 b) 10 (3.00 g, 14.1 mmol), 15 (3.42 g, 14.8 mmol) and
THF (50 mL) were heated to reflux according to General Pro-
cedure 1. FC purification (see under a) provided 4.78 g (81%) of 6d.
1
FT-IR and 2000 FT-IR (PerkinϪElmer). Ϫ H NMR (400 MHz),
13C NMR (100 MHz): GSX FT NMR spectrometer (Jeol), tetra-
methylsilane as internal standard, δ in ppm.
General Procedure 1. ؊ Preparation of the (2-Bromophenyl)acet-
aldehyde Acetals 6؊8 by Transacetalization of 10 or 11 with Diols:
A mixture of 10 or 11, p-toluenesulfonic acid (200 mg per 10 mmol
of 10 or 11), the corresponding diol (ca. 1.1 equiv.) and the appro-
priate solvent (THF or toluene) was heated to reflux in a Soxhlet
˚
apparatus filled with molecular sieves (4 A) to remove methanol.
After 3 d, the solution was diluted with CH2Cl2, washed with a
saturated solution of NaHCO3 and then with water, dried
(MgSO4), and concentrated in vacuo. The residue was purified by
FC, recrystallization, or distillation.
(4R,5R)-(؊)-2-(2-Bromobenzyl)-4,5-bis(3-methoxypentan-3-yl)-1,3-
dioxolane (6f): a) According to General Procedure 1 a solution of
11 (4.22 g, 17.2 mmol) and 20b (5.00 g, 19.1 mmol) in THF (85
mL) was heated to reflux. FC purification [diameter of the column
4 cm, petroleum ether/ethyl acetate (90:10), Rf ϭ 0.85] provided a
colourless oil, yield 3.86 g (51%), [α]589 ϭ Ϫ4.10 (c ϭ 1.95 in
CHCl3). Ϫ C22H35BrO4 (443.4): calcd. C 59.6, H 7.96; found C
59.9, H 7.69. Ϫ MS (CI): m/z ϭ 445/443 (M ϩ Hϩ). Ϫ IR (film):
ν˜ ϭ 2968 cmϪ1 (CϪH), 1593 (CϭC), 1141 (CϪO). Ϫ 1H NMR
(CDCl3): δ ϭ 0.89 (m, 12 H, 4 ϫ CH2CH3), 1.45Ϫ1.72 (m, 8 H, 4
ϫ CH2CH3), 3.04 [dd, J ϭ 14.1/5.5 Hz, 1 H, CH2CH(OR)2], 3.15
[dd, J ϭ 13.9/4.3 Hz, 1 H, CH2CH(OR)2], 3.20 (s, 3 H, OCH3),
3.23 (s, 3 H, OCH3), 4.23 (d, J ϭ 3.9 Hz, 1 H, 4-H), 4.26 (d, J ϭ
3.9 Hz, 1 H, 5-H), 5.38 (dd, J ϭ 5.5/4.3 Hz, 1 H, 2-H), 7.05 (td,
J ϭ 7.7/1.7 Hz, 1 H, 5-H arom.), 7.21 (td, J ϭ 7.7/1.3 Hz, 1 H, 4-
H arom.), 7.34 (dd, J ϭ 7.7/1.3 Hz, 1 H, 6-H arom.), 7.50 (dd, J ϭ
General Procedure 2. ؊ Bromine/Lithium Exchange at the Aryl Bro-
mides 6؊9 and Subsequent Reaction of the Aryllithium Intermedi-
ates with the Imines 25, 28, 31: An enantiomerically pure aryl bro-
mide 6؊9 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. Then, a solution of an imine 25, 28, or 31 (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 separated, dried (MgSO4),
concentrated in vacuo, and the residue was purified by FC. Before
1
carrying out the purification procedure, H-NMR spectra were re-
corded to determine the diastereomeric ratio of the crude products.
(4S,5S)-(؊)-2-(2-Bromobenzyl)-4,5-bis(tosyloxymethyl)-1,3-dioxo-
lane (6c): According to General Procedure 1 a solution of 11 (5.07
g, 20.7 mmol) and 14 (10.0 g, 22.8 mmol) in THF (100 mL) was 7.7/1.3 Hz, 1 H, 3-H arom.). Ϫ 13C NMR (CDCl3): δ ϭ 7.77 (q,
heated to reflux. The residue was purified by FC: diameter of the
CH2CH3), 7.78 (q, CH2CH3), 8.04 (q, CH2CH3), 8.09 (q,
column 4 cm, petroleum ether/ethyl acetate (70:30), Rf ϭ 0.36. Pale CH2CH3), 23.9 (t, CH2CH3), 24.8 (t, CH2CH3), 25.7 (t, CH2CH3),
yellow oil, yield 11.1 g (87%), [α]589 ϭ Ϫ10.3 (c ϭ 1.52 in CHCl3).
Ϫ C26H27BrO8S2 (611.5): calcd. C 51.1, H 4.45: found C 50.8, H
26.1 (t, CH2CH3), 41.1 [t, CH2CH(OR)2], 50.03 (q, OCH3), 50.08
(q, OCH3), 78.6 (d, C-4), 80.0 (d, C-5), 80.5 (s, 2 C, CEt2OCH3),
4.74. Ϫ MS (CI): m/z ϭ 613/611 (M ϩ Hϩ). Ϫ IR (film): ν˜ ϭ 3066 103.7 (d, C-2), 125.0 (s, C-1 arom.), 127.3 (d, C-6 arom.), 128.1 (d,
508
Eur. J. Org. Chem. 1999, 503Ϫ517

Key Step in the Asymmetric Synthesis of 1-Aryltetrahydroisoquinolines
FULL PAPER
C-5 arom.), 132.4 (d, C-4 arom.), 132.3 (d, C-3 arom.), 136.4 (s, C-
2 arom.). Ϫ b) A solution of methyl iodide (9.24 g, 65.1 mmol) and
6h (9.00 g, 21.7 mmol) in THF (100 mL) was added to a suspension
of NaH (1.56 g, 65.1 mmol) in THF (200 mL). The reaction mix-
ture was heated to reflux for 18 h. After addition of H2O (200 mL),
the layers were separated, the aqueous layer was extracted with
Et2O (150 mL), the organic layers were dried (MgSO4) and concen-
trated in vacuo. FC purification [diameter of the column 5 cm,
petroleum ether/ethyl acetate (90:10), Rf ϭ 0.85] of the residue fur-
nished 6.98 g (72%) of 6f, [α]589 ϭ Ϫ3.91 (c ϭ 1.98 in CHCl3).
3.46Ϫ3.60 (m, 2 H, CH2OH), 3.68Ϫ3.80 (m, 2 H, 5-H), 4.06Ϫ4.22
(m, 1 H, 4-H), 5.17 (t, J ϭ 4.4 Hz, 0.5 H, 2-H), 5.29 (t, J ϭ 5.1
Hz, 0.5 H, 2-H), 7.08 (td, J ϭ 8.1/1.5 Hz, 1 H, 5-H arom.),
7.20Ϫ7.33 (m, 2 H, 4-H, 6-H arom.), 7.53 (d, J ϭ 8.1 Hz, 1 H, 3-
H arom.). Ϫ Ratio cis-22/trans-22 ϭ 1:1.
(2S,4S)-(؊)-2-(2-Bromobenzyl)-4-(trimethylsilyloxymethyl)-1,3-di-
oxane (7b): Chlorotrimethylsilane (1.08 g, 15.7 mmol) was added
to an ice-cold solution of 7a (3.00 g, 10.5 mmol) and imidazole
(1.07 g, 15.7 mmol) in THF (50 mL). After stirring at room tem-
perature for 3 h, the reaction mixture was filtered, washed with
H2O, dried (MgSO4) and concentrated in vacuo. The residue was
purified by FC: diameter of the column 3 cm, petroleum ether/ethyl
acetate (90:10), Rf ϭ 0.80. Colourless oil, yield 3.25 g (86%),
[α]589 ϭ Ϫ22.8 (c ϭ 1.85 in CHCl3). Ϫ C15H23BrO3Si (359.3): calcd.
C 50.1, H 6.45; found C 50.3, H 6.34. Ϫ MS (70 eV): m/z ϭ 345/
343 (M Ϫ CH3). Ϫ IR (film): ν˜ ϭ 2956 cmϪ1 (CϪH), 1474 (Cϭ
C), 1250 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 0.04 [s, 9 H, Si(CH3)3],
1.39 (dq, J ϭ 12.5/2.9 Hz, 1 H, 5-H eq.), 1.63 (qd, J ϭ 12.5/5.1
Hz, 1 H, 5-H ax.), 2.96Ϫ3.06 [m, 2 H, CH2CH(OR)2], 3.45Ϫ3.69
(m, 4 H, 4-H ax., 6-H ax., CH2OR), 4.05 (dd, J ϭ 12.5/2.9 Hz, 1
H, 6-H eq.), 4.75 (t, J ϭ 5.1 Hz, 1 H, 2-H ax.), 6.96 (td, J ϭ 8.1/
1.5 Hz, 1 H, 5-H arom.), 7.11 (td, J ϭ 8.1/1.5 Hz, 1 H, 4-H arom.),
7.24 (dd, J ϭ 8.1/2.2 Hz, 1 H, 6-H arom.), 7.41 (dd, J ϭ 8.1/1.5
Hz, 1 H, 3-H arom.). Ϫ 13C NMR (CDCl3): δ ϭ 0.00 [q, Si(CH3)3],
28.2 (t, C-5), 42.1 [t, CH2CH(OR)2], 66.1 (t, C-6), 66.8 (t, CH2OR),
77.1 (d, C-4), 100.8 (d, C-2), 125.3 (s, C-1 arom.), 127.5 (d, C-6
arom.), 128.5 (d, C-5 arom.), 132.7 (d, C-4 arom.), 132.9 (d, C-3
arom.), 136.5 (s, C-2 arom.).
(4R,5R)-2-(2-Bromobenzyl)-4,5-bis(3-hydroxypentan-3-yl)-1,3-di-
oxolane (6h): A solution of ethyl iodide (34.8 g, 0.22 mol) in Et2O
(50 mL) was added to magnesium (5.35 g, 0.22 mol) in Et2O (150
mL). The mixture was heated to reflux for 30 min, then it was
cooled to 0°C and a solution of 6g (10.0 g, 27.9 mmol) in THF
(60 mL) was added. After stirring at room temperature for 2 h, a
saturated solution of NH4Cl (300 mL) was added, the aqueous
layer was separated and extracted with Et2O (3 ϫ 150 mL). The
combined organic layers were dried (MgSO4), econcentrated in va-
cuo and the residue was methylated (Ǟ 6f) without further purifi-
cation. Ϫ MS (CI): m/z ϭ 417/415 (M ϩ Hϩ). Ϫ IR (film): ν˜ ϭ
3354 cmϪ1 (OH), 2984 (CϪH), 1465 (CϭC), 1108 (CϪO). Ϫ 1H
NMR (CDCl3): δ ϭ 0.94Ϫ1.02 (m, 12 H, 4 ϫ CH2CH3), 1.53Ϫ1.92
(m, 8 H, 4 ϫ CH2CH3), 1.96Ϫ2.00 (m, 2 H, 2 ϫ OH, H/D ex-
change), 3.05 [dd, J ϭ 14.1/4.3 Hz, 1 H, CH2CH(OR)2], 3.12 [dd,
J ϭ 14.1/4.3 Hz, 1 H, CH2CH(OR)2], 3.80 (d, J ϭ 4.4 Hz, 1 H, 4-
H), 3.89 (d, J ϭ 4.4 Hz, 1 H, 5-H), 5.38 (t, J ϭ 4.3 Hz, 1 H, 2-H),
6.95 (td, J ϭ 8.8/1.7 Hz, 1 H, 5-H arom.), 7.21 (td, J ϭ 8.8/1.7 Hz,
1 H, 4-H arom.), 7.32 (dd, J ϭ 8.1/2.2 Hz, 1 H, 6-H arom.), 7.47
(dd, J ϭ 8.1/1.7 Hz, 1 H, 3-H arom.).
(2S,4S)-(؊)-2-(2-Bromobenzyl)-4-(tert-butyldimethylsilyloxy-
methyl)-1,3-dioxane (7c): As described for 7b, the alcohol 7a (3.00
g, 10.5 mmol) was silylated with tert-butylchlorodimethylsilane
(2.36 g, 15.7 mmol). FC: see 7b, Rf ϭ 0.90. Colourless oil, yield
3.46 g (82%), [α]589 ϭ Ϫ29.6 (c ϭ 4.76 in CHCl3). Ϫ C18H29BrO3Si
(401.4): calcd. C 53.9, H 7.28; found C 53.8, H 7.31. Ϫ MS (70
eV): m/z ϭ 345/343 (M Ϫ tBu.). Ϫ IR (film): ν˜ ϭ 2928 cmϪ1
(CϪH), 1473 (CϭC), 1251 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 0.00
[s, 6 H, OSi(CH3)2], 0.82 [s, 9 H, OSiC(CH3)3], 1.41Ϫ1.45 (m, 1
H, 5-H eq.), 1.58Ϫ1.68 (m, 1 H, 5-H ax.), 2.97Ϫ3.06 [m, 2 H,
CH2CH(OR)2], 3.46Ϫ3.69 (m, 4 H, 4-H ax., 6-H ax., CH2OR),
4.06 (ddd, J ϭ 11.5/3.9/1.3 Hz, 1 H, 6-H eq.), 4.75 (t, J ϭ 5.1 Hz,
1 H, 2-H ax.), 7.01 (td, J ϭ 7.7/1.6 Hz, 1 H, 5-H arom.), 7.15 (td,
J ϭ 7.5/1.3 Hz, 1 H, 4-H arom.), 7.26 (dd, J ϭ 7.7/1.3 Hz, 1 H, 6-
H arom.), 7.46 (dd, J ϭ 7.7/1.3 Hz, 1 H, 3-H arom.).
(؊)-[(2S,4S)-2-(2-Bromobenzyl)-1,3-dioxan-4-yl]methanol (7a) and
2-[(2R,4S)- and (2S,4S)-2-(2-Bromobenzyl)-1,3-dioxolan-4-yl]etha-
nol (22): According to General Procedure 1, a mixture of 11 (3.11
g, 12.7 mmol), (S)-(ϩ)-butane-1,2,4-triol (21, 1.32 g, 12.7 mmol),
˚
molecular sieves 4 A and THF (50 mL) was heated to reflux for 4
d. The residue (7a/22 ϭ 80:20 by 1H-NMR spectroscopy) was puri-
fied by FC [diameter of the column 3.5 cm, petroleum ether/ethyl
acetate (75:25)].
7a: Rf ϭ 0.33; colourless oil, yield 2.88 g (79%); [α]589 ϭ Ϫ4.96
(c ϭ 1.37 in CHCl3). Ϫ C12H15BrO3 (287.3): calcd. C 50.2, H 5.27;
found C 50.1, H 5.38. Ϫ MS (CI): m/z ϭ 289/287 (M ϩ Hϩ). Ϫ
IR (film): ν˜ ϭ 3442 cmϪ1 (OH), 2925 (CϪH), 1473 (CϭC), 1141
1
(CϪO), 1028 (CϪO). Ϫ H NMR (CDCl3): δ ϭ 1.23 (d, J ϭ 12.5
Hz, 1 H, 5-H eq.), 1.69 (qd, J ϭ 12.5/5.1 Hz, 1 H, 5-H ax.), 1.91
(t, J ϭ 5.1 Hz, 1 H, OH H/D exchange), 2.94Ϫ3.04 [m, 2 H,
CH2CH(OR)2], 3.40Ϫ3.55 (m, 2 H, CH2OH), 3.58Ϫ3.70 (m, 2 H,
4-H ax., 6-H ax.), 3.97Ϫ4.04 (m, 1 H, 6-H eq.), 4.73 (t, J ϭ 5.1
Hz, 1 H, 2-H ax.), 6.97 (td, J ϭ 8.1/1.5 Hz, 1 H, 5-H arom.),
7.13Ϫ7.17 (m, 2 H, 4-H, 6-H arom.), 7.42 (d, J ϭ 8.1 Hz, 1 H, 3-
(2S,4S)-(؊)-2-(2-Bromobenzyl)-4-(triphenylsilyloxymethyl)-1,3-di-
oxane (7d): As described for 7b, the alcohol 7a (4.00 g, 13.9 mmol)
was silylated with chlorotriphenylsilane (4.92 g, 16.7 mmol). FC:
diameter of the column 4 cm, petroleum ether/ethyl acetate (85:15),
Rf ϭ 0.70. Colourless oil, yield 7.11 g (94%), [α]589 ϭ Ϫ11.8 (c ϭ
0.71 in CHCl3). Ϫ C30H29BrO3Si (545.5): calcd. C 66.0, H 5.36;
found C 65.9, H 5.56. Ϫ MS (70 eV): m/z ϭ 469/467 (M Ϫ C6H5).
Ϫ IR (film): ν˜ ϭ 3067 cmϪ1 (CϪH), 2924 (CϪH), 1589 (CϭC),
1
H arom.). Ϫ H NOE (CDCl3, pulse delay 8 s, 37.5 dB): irrad. at
δ ϭ 4.73 (2-H ax.), NOE at δ ϭ 2.99 (aryl-CH2), 3.67 (4-H ax., 6-
H
ax.). Ϫ 13C NMR (CDCl3): δ ϭ 26.8 (t, C-5), 41.7 [t,
CH2CH(OR)2], 65.7 (t, CH2OH), 66.2 (t, C-6), 77.1 (d, C-4), 100.5
(d, C-2), 124.9 (s, C-1 arom.), 127.2 (d, C-6 arom.), 128.3 (d, C-5
arom.), 132.2 (d, C-4 arom.), 132.7 (d, C-3 arom.), 135.94 (s, C-
2 arom.).
1
1142 (CϪO). Ϫ H NMR (CDCl3): δ ϭ 1.36Ϫ1.42 (m, 1 H, 5-H
eq.), 1.63 (qd, J ϭ 12.5/5.1 Hz, 1 H, 5-H ax.), 2.96Ϫ3.06 [m, 2 H,
CH2CH(OR)2], 3.66Ϫ3.92 (m, 4 H, 4-H ax., 6-H ax., CH2OR),
4.11 (dd, J ϭ 11.8/3.7 Hz, 1 H, 6-H eq.), 4.79 (t, J ϭ 5.9 Hz, 1 H,
2-H ax.), 7.04Ϫ7.64 (m, 19 H, arom.). Ϫ 13C NMR (CDCl3): δ ϭ
22: Rf ϭ 0.25; colourless oil, yield 0.68 g (19%). Ϫ C12H15BrO3
(287.3): calcd. C 50.2, H 5.27; found C 50.1, H 5.35. Ϫ MS (70 27.8 (t, C-5), 41.6 [t, CH2CH(OR)2], 66.4 (t, C-6), 66.7 (t, CH2OR),
eV): m/z ϭ 287/285 (Mϩ Ϫ H), 257/255 (M Ϫ CH2O). Ϫ IR (film): 76.8 (d, C-4), 100.4 (d, C-2), 124.9 (s, C-1 arom.), 127.5 (d, C-6
ν˜ ϭ 3425 cmϪ1 (OH), 2930 (CϪH), 1474 (CϭC), 1140 (CϪO). Ϫ arom.), 127.8 (d, arom. C), 127.9 (d, C-5 arom.), 130.1 (d, arom.
1H NMR (CDCl3): δ ϭ 1.72Ϫ1.82 (m, 2 H, CH2CH2OH), 2.52 C), 132.3 (d, C-4 arom.), 132.5 (d, C-3 arom.), 134.0 (s, arom. C),
(m, 1 H, OH, H/D exchange), 3.04Ϫ3.16 [m, 2 H, CH2CH(OR)2],
135.3 (d, arom. C), 136.1 (s, C-2 arom.).
Eur. J. Org. Chem. 1999, 503Ϫ517
509

B. Wünsch, S. Nerdinger
FULL PAPER
(؉)-[(2R,4S,5S)-5-Benzyloxy-2-(2-bromobenzyl)-1,3-dioxan-4-yl]-
J ϭ 12.8/1.5 Hz, 1 H, 6-H eq.), 4.56 (d, J ϭ 12.4 Hz, 1 H,
methanol (7e) and (2S)-2-Benzyloxy-2-[(2R,4S)- and (2S,4S)-2-(2- OCH2C6H5), 4.79 (d, J ϭ 12.4 Hz, 1 H, OCH2C6H5), 4.90 (t, J ϭ
bromobenzyl)-1,3-dioxolan-4-yl]ethanol (24): According to General
Procedure 1, a mixture of 11 (3.11 g, 12.7 mmol), (2S,3S)-(ϩ)-3-
benzyloxybutane-1,2,4-triol (23, 2.69 g, 12.7 mmol), molecular
5.1 Hz, 1 H, 2-H ax.), 7.10 (td, J ϭ 8.1/1.5 Hz, 1 H, 5-H arom.),
7.22Ϫ7.41 (m, 7 H, arom.), 7.55 (dd, J ϭ 8.1/1.5 Hz, 1 H, 3-H
arom.). Ϫ 13C NMR (CDCl3): δ ϭ 41.3 [t, CH2CH(OR)2], 59.2 (q,
OCH3), 67.9 (t, CH2OCH3), 69.5 (t, C-6), 71.3 (d, C-5), 71.7 (t,
OCH2C6H5), 77.9 (d, C-4), 100.7 (d, C-2), 124.8 (s, C-1 arom.),
127.1 (d, C-6 arom.), 127.8 (d, C arom.), 128.1 (d, C arom.), 128.2
(d, C-5 arom.), 128.3 (d, C arom.), 132.5 (d, C-4 arom.), 132.5 (d,
C-3 arom.), 135.9 (s, C-2 arom.), 137.9 (s, C arom.).
˚
sieves 4 A and THF (50 mL) was heated to reflux for 4 d. Recrys-
tallization of the residual mixture of 7e and 24 (60:40 by 1H-NMR
spectroscopy) provided 7e, the dioxolane 24 was isolated by sub-
sequent FC of the mother liquor [diameter of the column 4 cm,
petroleum ether/ethyl acetate (75:25), Rf(7e) ϭ 0.28, Rf(24) ϭ 0.25].
7e: Colourless solid (iPr2O), m.p. 131Ϫ133°C; yield 3.00 g (60%),
[α]589 ϭ ϩ144.4 (c ϭ 0.78 in CHCl3). Ϫ C19H21BrO4 (393.3): calcd.
C 58.0, H 5.38; found C 58.0, H 5.39. Ϫ MS (CI): m/z ϭ 394/392
(5S,6S)-(؉)-2-(2-Bromobenzyl)-5,6-dimethoxy-1,3-dioxepane (8): a)
According to General Procedure 1, a solution of 11 (5.00 g, 20.4
mmol) and (2S,3S)-(ϩ)-2,3-dimethoxybutane-1,4-diol (16, 3.40 g,
(M ϩ Hϩ). Ϫ IR (film): ν˜ ϭ 3442 cmϪ1 (OH), 2925 (CϪH), 1473 22.5 mmol) in THF (100 mL) was heated to reflux. Recrystalliza-
(CϭC), 1141 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 1.83 (dd, J ϭ 9.5/
4.4 Hz, H, OH H/D exchange), 3.15Ϫ3.24 [m, H,
tion of the residue provided a colourless solid (iPr2O), m.p.
66Ϫ68°C, yield 4.88 g (90%), [α]589 ϭ ϩ121.2 (c ϭ 1.00 in CHCl3).
Ϫ C14H19BrO4 (331.2): calcd. C 50.8, H 5.78, Br 24.1; found C
50.6, H 5.66, Br 24.0. Ϫ MS (70 eV): m/z ϭ 332/330 (Mϩ). Ϫ IR
(KBr): ν˜ ϭ 3057 cmϪ1 (CϪH), 2973 (CϪH), 1473 (CϭC), 1145
1
2
CH2CH(OR)2], 3.29 (“q”, J ϭ 1.5 Hz, 1 H, 5-H eq.), 3.60 (ddd,
J ϭ 11.3/4.4/2.2 Hz, 1 H, CH2OH), 3.68 (dd, J ϭ 12.5/1.5 Hz, 1
H, 6-H ax.), 3.76Ϫ3.79 (m, 1 H, 4-H ax.), 3.87Ϫ3.92 (m, 1 H,
CH2OH), 4.29 (dd, J ϭ 12.5/1.5 Hz, 1 H, 6-H eq.), 4.46 (d, J ϭ
12.1 Hz,1 H, OCH2C6H5), 4.82 (d, J ϭ 12.4 Hz, 1 H, OCH2C6H5),
4.87 (t, J ϭ 5.1 Hz, 1 H, 2-H ax.), 7.09 (td, J ϭ 8.1/1.5 Hz, 1 H,
1
(CϪO), 1114 (CϪO). Ϫ H NMR (CDCl3): δ ϭ 3.01Ϫ3.99 [m, 2
H, CH2CH(OR)2], 3.25Ϫ3.35 (m, 2 H, 5-H, 6-H), 3.44 (s, 3 H,
OCH3), 3.46 (s, 3 H, OCH3), 3.61Ϫ3.75 (m, 2 H, 4-H eq., 7-H eq.),
5-H arom.), 7.21Ϫ7.39 (m, 7 H, 4-H, 6-H arom., OCH2C6H5), 7.54 3.93Ϫ4.03 (m, 2 H, 4-H ax., 7-H ax.), 4.97 (dd, J ϭ 5.9/5.1 Hz, 1
(dd, J ϭ 8.1/1.5 Hz, 1 H, 3-H arom.). A H/H COSY spectrum led
to this 1H-NMR signal-proton assignment. Ϫ 1H NOESY (CDCl3,
pulse delay 4.5 s, 37.5 dB): irrad. at δ ϭ 4.87 (2-H ax.), NOE (cross
peak) at δ ϭ 3.19 (arylCH2), 3.68 (6-H ax.), 3.78 (4-H ax.). Ϫ 13C
H, 2-H), 7.06 (td, J ϭ 8.1/2.2 Hz, 1 H, 5-H arom.), 7.20Ϫ7.27 (m,
2 H, 4-H, 6-H arom.), 7.52 (dd, J ϭ 8.1/2.2 Hz, 1 H, 3-H arom.).
Ϫ
13C NMR (CDCl3): δ ϭ 39.9 [t, CH2CH(OR)2], 57.4 (q, OCH3),
57.5 (q, OCH3), 61.1 (t, C-4), 63.2 (t, C-7), 81.0 (d, C-5), 81.4 (d,
NMR (CDCl3): δ ϭ 41.4 [t, CH2CH(OR)2], 62.7 (t, CH2OH), 67.5 C-6), 101.7 (d, C-2), 124.9 (s, C-1 arom.), 127.3 (d, C-6 arom.),
(t, C-6), 69.7 (d, C-5), 70.9 (t, OCH2C6H5), 78.8 (d, C-4), 100.8 (d,
C-2), 124.8 (s, C-1 arom.), 127.2 (d, C-6 arom.), 128.1 (d, C arom.),
128.2 (d, C arom.), 128.4 (d, C-5 arom.), 128.6 (d, C arom.), 132.5
(d, C-4 arom.), 132.6 (d, C-3 arom.), 135.8 (s, C-2 arom.), 137.6 (s,
C arom.).
128.2 (d, C-5 arom.), 131.9 (s, C-4 arom.), 132.6 (s, C-3 arom.),
136.3 (s, C-2 arom.). Ϫ b) According to General Procedure 1, a
solution of 10 (5.00 g, 23.5 mmol) and (2S,3S)-(ϩ)-2,3-dimeth-
oxybutane-1,4-diol (16, 3.85 g, 26.0 mmol) in THF (100 mL) was
heated to reflux. Recrystallization furnished a colourless solid
(iPr2O), yield 6.85 g (89%), m.p. 66Ϫ68°C.
24: Pale yellow oil, yield 1.85 g (37%). Ϫ C19H21BrO4 (393.3):
calcd. C 58.0, H 5.38; found C 57.8, H 5.54. Ϫ MS (CI): m/z ϭ
394/392 (M ϩ Hϩ). Ϫ IR (film): ν˜ ϭ 3457 cmϪ1 (OH), 3061
(CϪH), 2932 (CϪH), 1474 (CϭC), 1134 (CϪO). Ϫ 1H NMR
(2S,4S,5R)-(؊)-2-(2-Bromobenzyl)-3,4-dimethyl-5-phenyl-1,3-ox-
azolidine (9): A solution of 12 (5.00 g, 25.2 mmol), (1R,2S)-(Ϫ)-
ephedrine (4.98 g, 30.2 mmol), and p-toluenesulfonic acid (400 mg)
(CDCl3): δ ϭ 2.47 (m, 1 H, OH, H/D exchange), 3.23Ϫ3.34 [m, 2 in toluene (100 mL) was heated to reflux. After 36 h, the solvent
H, CH2CH(OR)2], 3.61Ϫ3.78 (m, 2 H, CH2OH), 3.81Ϫ3.88 (m, 1
H, CHOBn), 3.95Ϫ4.03 (m, 1 H, 4-H), 4.20Ϫ4.29 (m, 1 H, 5-H),
4.36Ϫ4.44 (m, 1 H, 5-H), 4.83Ϫ4.88 (m, 2 H, OCH2C6H5), 5.33 (t,
was evaporated in vacuo and the residue was recrystallized (iPr2O).
Colourless solid (iPr2O), m.p. 65Ϫ67°C, yield 6.25 g (72%),
[α]589 ϭ Ϫ138.8 (c ϭ 1.06 in CHCl3). Ϫ C18H20BrNO (346.3):
J ϭ 4.4 Hz, 0.5 H, 2-H; trans-24), 5.46 (t, J ϭ 5.1 Hz, 0.5 H, 2-H; calcd. C 62.4, H 5.82, N 4.05; found C 62.5, H 5.80, N 4.00. Ϫ MS
cis-24), 7.22Ϫ7.70 (m, 9 H, arom.). Ϫ 1H NOE (CDCl3, pulse delay (CI): m/z ϭ 348/346 (M ϩ Hϩ). Ϫ IR (KBr): ν˜ ϭ 3063 cmϪ1
8 s, 37.5 dB): irrad. at δ ϭ 5.33 (2-H), NOE at δ ϭ 3.23Ϫ3.34
(CϪH), 2967 (CϪH), 1494 (CϭC), 1094 (CϪO). Ϫ 1H NMR
(arylCH2), 4.36Ϫ4.44 (5-H); irrad. at δ ϭ 5.46 (2-H), NOE at δ ϭ (CDCl3): δ ϭ 0.69 (d, J ϭ 6.4 Hz, 3 H, CHCH3), 2.40 (s, 3 H,
3.23Ϫ3.34 (arylCH2), 3.95Ϫ4.03 (4-H), 4.20Ϫ4.29 (5-H). Ratio cis- NCH3) , 2.82 (dq, J ϭ 8.0/6.4 Hz, 1 H, 4-H), 3.02 [dd, J ϭ 13.9/
24/trans-24 ϭ 1:1.
8.3 Hz, 1 H, CH2CH(OR)2], 3.48 [dd, J ϭ 13.9/1.9 Hz, 1 H,
CH2CH(OR)2], 4.14 (dd, J ϭ 8.3/1.9 Hz, 1 H, 2-H), 4.98 (d, J ϭ
8.0 Hz, 1 H, 5-H), 7.08 (td, J ϭ 7.7/1.7 Hz, 1 H, 5-H arom.),
7.20Ϫ7.33 (m, 6 H, arom.), 7.43 (dd, J ϭ 7.7/1.7 Hz, 1 H, 6-H
arom.), 7.54 (dd, J ϭ 8.1/1.7 Hz, 1 H, 3-H arom.). Ϫ 1H NOE
(CDCl3, pulse delay 8 s, 37.5 dB): irrad. at δ ϭ 2.82 (4-H), NOE
at δ ϭ 0.69, 2.40, 4.14 (2-H), 4.98; irrad. at δ ϭ 4.14 (2-H), NOE
at δ ϭ 2.40, 2.82 (4-H), 3.02, 3.48, 4.98 (5-H); irrad. at δ ϭ 4.98
(5-H), NOE at δ ϭ 2.82, 4.14 (2-H). Ϫ 13C NMR (CDCl3): δ ϭ
14.9 (q, CHCH3), 36.7 (q, NCH3), 40.4 [t, CH2CH(OR)2], 64.1 (d,
C-4), 82.1 (d, C-5), 96.5 (d, C-2), 124.7 (s, C-1 arom.), 127.3 (s, C
arom.), 127.5 (d, C-6 arom.), 127.7 (d, C arom.), 127.9 (d, C arom.),
128.2 (d, C-5 arom.), 132.4 (s, C-4 arom.), 132.6 (d, C arom.), 137.1
(s, C-3 arom.), 139.9 (s, C-2 arom.).
(2R,4S,5S)-(؉)-5-Benzyloxy-2-(2-bromobenzyl)-4-(methoxymethyl)-
1,3-dioxane (7f): A solution of 7e (2.00 g, 5.09 mmol) and methyl
iodide (0.35 mL, 5.60 mmol) in THF (10 mL) was added to a sus-
pension of NaH (0.22 g, 5.60 mmol) in THF (100 mL). The reac-
tion mixture was heated to reflux for 16 h, then it was filtered and
concentrated in vacuo. The residue was purified by FC [diameter
of the column 3 cm, petroleum ether/ethyl acetate (80:20), Rf ϭ
0.65]. Colourless solid, m.p. 88Ϫ90°C, yield 1.96 g (95%), [α]589
ϭ
ϩ26.6 (c ϭ 0.64 in CHCl3). Ϫ C20H23BrO4 (407.3): calcd. C 59.0,
H 5.69; found C 58.5, H 6.12. Ϫ MS (70 eV): m/z ϭ 408/406 (Mϩ),
317/315 (M Ϫ Bn). Ϫ IR (KBr): ν˜ ϭ 3062 cmϪ1 (CϪH), 2920
(CϪH), 1473 (CϭC), 1159 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ
3.15Ϫ3.25 [m, 2 H, CH2CH(OR)2], 3.28Ϫ3.33 (m, 1 H, 5-H eq.),
3.34 (s, 3 H, OCH3), 3.58Ϫ3.61 (m, 2 H, CH2OCH3), 3.68 (dd, J ϭ (4S,5S)-(؉)-4,5-Bis[(2-methoxyethoxy)methyl]-2,2-dimethyl-1,3-di-
13.2/1.5 Hz, 1 H, 6-H ax.), 3.89Ϫ3.93 (m, 1 H, 4-H ax.), 4.26 (dd,
oxolane (13b): At room temperature a solution of 1-bromo-2-me-
510
Eur. J. Org. Chem. 1999, 503Ϫ517

Key Step in the Asymmetric Synthesis of 1-Aryltetrahydroisoquinolines
FULL PAPER
thoxyethane (36.4 g, 0.26 mol) and 13a[12b,14] (20.0 g, 0.12 mol) in
mmol) was added to a solution of 19b (6.00 g, 15.8 mmol) in
THF (150 mL) was added to a suspension of NaH (6.22 g, 0.26 CH2Cl2 (290 mL) and H2O (20 mL). After 1.5 h, a saturated solu-
mol) in THF (200 mL). Then, the reaction mixture was heated to
reflux for 18 h. After filtration, the mixture was distilled in vacuo.
tion of NaHCO3 (330 mL) and CH2Cl2 (800 mL) were added, the
organic layer was separated, dried (MgSO4) and concentrated in
Colourless oil, b.p.0.015 86Ϫ88°C, yield 27.9 g (84%), [α]589 ϭ ϩ4.71 vacuo. FC purification [diameter of the column 6 cm, petroleum
(c ϭ 2.23 in CHCl3). Ϫ C13H26O6 (278.3): calcd. C 56.1, H 9.42; ether/ethyl acetate (85:15), Rf ϭ 0.42] of the residue provided a pale
found C 56.0, H 9.52. Ϫ MS (CI): m/z ϭ 279 (M ϩ Hϩ). Ϫ IR
yellow oil, yield 4.42 g (71%), [α]589 ϭ Ϫ6.08 (c ϭ 2.20 in CHCl3).
(film): ν˜ ϭ 2984 cmϪ1 (CϪH), 1248 (CϪO). Ϫ 1H NMR (CDCl3): Ϫ C22H36O6 (396.5): calcd. C 66.6, H 9.15; found C 66.9, H 8.80.
δ ϭ 1.44 [s, 6 H, (CH3)2C(OR)2], 3.40 (s, 6 H, 2 ϫ OCH3),
3.56Ϫ3.80 (m, 12 H, 6 ϫ OCH2), 4.02Ϫ4.06 (m, 2 H, 4-H, 5-H).
Ϫ MS (70 eV): m/z ϭ 396 (Mϩ). Ϫ IR (film): ν˜ ϭ 3528 cmϪ1 (OH),
1713 (CϭO), 1604 (CϭC), 1169 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ
0.75Ϫ0.87 (m, 12 H, 4 ϫ CH2CH3), 1.45-1.71 (m, 8 H, 4 ϫ
CH2CH3), 3.07 (s, 3 H, OCH3), 3.33 (br. s, 3 H, OCH3 ), 3.79 (s,
3 H, aryl-OCH3) , 4.02Ϫ4.08 (m, 2 H, CHOH, H/D exchange),
5.47 (s, 1 H, CHOCOAr), 6.86 (d, J ϭ 8.8 Hz, 2 H, 3-H, 5-H
arom.), 8.00 (d, J ϭ 8.8 Hz, 2 H, 2-H, 6-H arom.).
(2S,3S)-(؊)-1,4-Bis(2-methoxyethoxy)butane-2,3-diol (15): A mix-
ture of 13b (5.00 g, 18.0 mmol), H2O (1.30 g, 72 mmol), p-tolu-
enesulfonic acid ϫ 1 H2O (400 mg), and methanol (75 mL) was
heated to reflux for 24 h. Then, the reaction mixture was stirred
with K2CO3 (400 g) for 1 h, filtered, the solvent was evaporated in
vacuo and the residue was filtered through silica gel [n-hexane/ethyl
acetate (1:1), Rf ϭ 0.75]. Pale yellow oil, yield 3.53 g (82%), [α]589 ϭ
Ϫ2.32 (c ϭ 6.93 in CHCl3). Ϫ C10H22O6 (238.3): calcd. C 50.4, H
9.31; found C 49.9, H 9.75. Ϫ MS (CI): m/z ϭ 239 (M ϩ Hϩ). Ϫ
IR (film): ν˜ ϭ 3388 cmϪ1 (OH), 2923 (CϪH), 1245 (CϪO), 1098
(CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 3.31 (s, 3 H, OCH3), 3.32 (s, 3 H,
OCH3), 3.39Ϫ3.68 (m, 14 H, 6 ϫ OCH2, 2 ϫ OH, H/D exchange),
4.01Ϫ4.06 (m, 2 H, CHOH).
(4R,5R)-(؉)-3,6-Diethyl-3,6-dimethoxyoctane-4,5-diol (20b): At
0°C, a solution of 20a (1.94 g, 4.89 mmol) in THF (20 mL) was
added to a suspension of LiAlH4 (0.93 g, 24.5 mmol) in Et2O (150
mL) and the reation mixture was heated to reflux for 14 h. Then,
at 0°C H2O (1.0 mL) was added cautiously, subsequently 2 
NaOH (1.0 mL) and H2O (3.0 mL) were added. The mixture was
filtered, dried (MgSO4), concentrated in vacuo, and the residue was
purified by FC [diameter of the column 3 cm, petroleum ether/ethyl
acetate (1:1), Rf ϭ 0.82]. Pale yellow oil, yield 0.69 g (54%), [α]589 ϭ
ϩ0.71 (c ϭ 1.41 in CHCl3). Ϫ C14H30O4 (262.4): calcd. C 64.1, H
11.5; found C 64.5, H 11.8. Ϫ MS (CI): m/z ϭ 263 (M ϩ Hϩ). Ϫ
IR (film): ν˜ ϭ 3420 cmϪ1 (OH), 1108 CϪO). Ϫ 1H NMR (CDCl3):
δ ϭ 0.93Ϫ0.98 (m, 12 H, 4 ϫ CH2CH3), 1.55 (q, J ϭ 7.3 Hz, 2 H,
CH2CH3), 1.71 (q, J ϭ 7.3 Hz, 2 H, CH2CH3), 1.80Ϫ1.91 (m, 4
H, 2 ϫ CH2CH3), 3.44 (s, 6 H, 2 ϫ OCH3) , 3.85 (d, J ϭ 2.1 Hz, 2
H, 2 ϫ CHOH, H/D exchange), 4.16 (d, J ϭ 2.1 Hz, 2 H, CHOH).
(4R,5R)-(؊)-4,5-Bis(3-hydroxypentan-3-yl)-2-(4-methoxyphenyl)-
1,3-dioxolane (19a): To an ice-cold solution of EtMgI in Et2O [pre-
pared from iodoethane (53.0 g, 0.34 mol), magnesium (8.27 g, 0.34
mol) and Et2O (200 mL)], a solution of 18[16] (10.0 g, 33.8 mmol)
in THF (60 mL) was added and the reaction mixture was stirred
at room temperature for 2 h. A saturated solution of NH4Cl (300
mL) was added, the aqueous layer was separated, and extracted
with Et2O (3 ϫ 150 mL). The combined organid layers were dried
(MgSO4), concentrated in vacuo and the residue was purified by
FC [diameter of the column 7 cm, petroleum ether/ethyl acetate
N-[(αR
and
αS)-2-{[(4R,5R)-4,5-Dimethyl-1,3-dioxolan-2-yl]-
methyl}benzhydryl]-4-methylbenzenesulfonamide (26a/27a): Accord-
ing to General Procedure 2, 6a (120 mg, 0.44 mmol) was treated
with 25 (0.13 g, 0.49 mmol). FC purification [diameter of the col-
umn 2 cm, petroleum ether/ethyl acetate (85:15), Rf ϭ 0.36] pro-
vided a colourless oil, yield 0.15 g (76%). Ϫ C26H29NSO4 (451.6):
calcd. C 69.2, H 6.47, N 3.10, S 7.10; found C 69.1, H 6.60; N
3.00; S 6.82. Ϫ MS (70 eV): m/z ϭ 451 (M.ϩ), 296 (M.ϩ Ϫ Tos).
Ϫ IR (film): ν˜ ϭ 3263 cmϪ1 (NH), 3062 (CϪH), 2974 (CϪH), 1599
(85:15), Rf ϭ 0.45]. Colourless oil, yield 9.78 g (82%), [α]589
ϭ
Ϫ4.08 (c ϭ 2.31 in CHCl3). Ϫ C20H32O5 (352.5): calcd. C 68.2, H
9.15; found C 67.9, H 9.40. Ϫ MS (EI): m/z ϭ 351 (Mϩ Ϫ H.). Ϫ
IR (film): ν˜ ϭ 3425 cmϪ1 (OH), 2969 (CϪH), 1615 (CϭC), 1088
(CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 0.92Ϫ1.03 (m, 12 H, 4 ϫ
CH2CH3), 1.53Ϫ1.92 (m, 8 H, CH2CH3), 1.98 (br. s, 1 H, OH, H/
D exchange), 2.18 (br. s, 1 H, OH, H/D exchange), 3.85 (s, 3 H,
aryl-OCH3), 4.30 (d, J ϭ 5.1 Hz, 1 H, 4-H), 4.39 (d, J ϭ 5.1 Hz,
1 H, 5-H), 6.08 (s, 1 H, 2-H), 6.95 (d, J ϭ 8.8 Hz, 2 H, 3-H, 5-H
arom.), 7.47 (d, J ϭ 8.8 Hz, 2 H, 2-H, 6-H arom.).
1
(CϭC), 1160 (CϪO). Ϫ H NMR (CDCl3): δ ϭ 1.21 (d, J ϭ 5.9
Hz, 3 ϫ 0.55 H, CHCH3), 1.26 (d, J ϭ 6.6 Hz, 3 H, CHCH3), 1.32
(d, J ϭ 5.9 Hz, 3 ϫ 0.45 H, CHCH3), 2.37 (s, 3 H, aryl-CH3),
2.57Ϫ2.70 [m, 2 H, CH2CH(OR)2], 3.50 (dq, J ϭ 6.6/2.2 Hz, 1 ϫ
0.55 H, 4-H), 3.62Ϫ3.66 (m, 2 ϫ 0.45 H, 4-H, 5-H), 3.70 (dq, J ϭ
6.6/2.2 Hz, 1 ϫ 0.55 H, 5-H), 5.17Ϫ5.20 (m, 1 H, 2-H), 5.52 (d,
J ϭ 8.1 Hz, 1 ϫ 0.45 H, CHNH-Tos, s after addition of D2O), 5.66
(d, J ϭ 7.3 Hz, 1 ϫ 0.55 H, CHNH-Tos, s after addition of D2O),
6.65 (d, J ϭ 8.1 Hz, 1 ϫ 0.45 H, CHNH-Tos, H/D exchange), 6.73
(d, J ϭ 7.3 Hz, 1 ϫ 0.55 H, CHNH-Tos, H/D exchange), 6.89Ϫ6.97
(m, 1 H, arom.), 7.10Ϫ7.26 (m, 10 H, arom.), 7.56Ϫ7.59 (m, 2 H,
arom.). Ratio 26a/27a ϭ 45:55.
(4R,5R)-(؊)-4,5-Bis(3-methoxypentan-3-yl)-2-(4-methoxyphenyl)-
1,3-dioxolane (19b): A solution of 19a (9.00 g, 25.6 mmol) and
methyl iodide (10.9 g, 76.7 mmol) in THF (100 mL) was added to
a suspension of NaH (1.84 g, 76.7 mmol) in THF (200 mL). The
reaction mixture was heated to reflux for 18 h, then H2O (200 mL)
was added, the organic layer was separated, dried (MgSO4), con-
centrated in vacuo, and the residue was purified by FC [diameter
of the column 5 cm, petroleum ether/ethyl acetate (85:15), Rf ϭ
0.65]. Pale yellow oil, yield 6.99 g (72%), [α]589 ϭ -3.05 (c ϭ 2.13
in CHCl3). Ϫ C22H36O5 (380.5): calcd. C 69.4, H 9.54; found C
69.9, H 9.10. Ϫ MS (70 eV): m/z ϭ 380 (Mϩ). Ϫ IR (film): ν˜ ϭ 2969
cmϪ1 (CϪH), 1613 (CϭC), 1090 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ
0.78Ϫ0.89 (m, 12 H, 4 ϫ CH2CH3), 1.41Ϫ1.74 (m, 8 H, 4 ϫ
CH2CH3), 3.07 (s, 3 H, OCH3), 3.09 (s, 3 H, OCH3), 3.68 (s, 3 H,
aryl-OCH3) , 4.26 (d, J ϭ 4.3 Hz, 1 H, 4-H), 4.32 (d, J ϭ 4.3 Hz,
1 H, 5-H), 5.91 (s, 1 H, 2-H), 6.77 (d, J ϭ 8.6 Hz, 2 H, 3-H, 5-H
arom.), 7.32 (d, J ϭ 8.6 Hz, 2 H, 2-H, 6-H arom.).
N-[(αR and αS)-2-{[(4S,5S)-4,5-Bis(methoxymethyl)-1,3-dioxolan-2-
yl]methyl}benzhydryl]-4-methylbenzenesulfonamide (26b/27b): Ac-
cording to General Procedure 2, 6b (0.50 g, 1.51 mmol) was treated
with 25 (0.41 g, 1.60 mmol). FC [diameter of the column 3 cm,
petroleum ether/ethyl acetate (85:15), Rf ϭ 0.24] afforded a colour-
less oil, yield 0.51 g (66%). Ϫ C28H33NO6S (511.6): calcd. C 65.7,
H 6.50, N 2.74, S 6.27; found C 65.3, H 6.74, N 3.01, S 6.35. Ϫ
MS (70 eV): m/z ϭ 357 (Mϩ Ϫ Tos). Ϫ IR (film): ν˜ ϭ 3260 cmϪ1
(NH), 3062 (CϪH), 2926 (CϪH), 1599 (CϭC), 1160 (CϪO). Ϫ 1H
(؊)-[(4R,5R)-3,6-Diethyl-5-hydroxy-3,6-dimethoxyoctan-4-yl]
4-
Methoxybenzoate (20a): At room temperature, DDQ (5.35 g, 23.6 NMR (CDCl3): δ ϭ 2.37 (s, 3 H, aryl-CH3), 2.69Ϫ2.71 [m, 2 H,
Eur. J. Org. Chem. 1999, 503Ϫ517 511

B. Wünsch, S. Nerdinger
FULL PAPER
CH2CH(OR)2], 3.34 (s, 3 H, OCH3), 3.36 (s, 3 H, OCH3),
3.46Ϫ3.48 (m, 4 H, 2 ϫ CH2OCH3), 3.98Ϫ4.02 (m, 2 H, 4-H, 5-
H), 5.19Ϫ5.21 (m, 1 H, 2-H), 5.62 (d, J ϭ 8.1 Hz, 1 ϫ 0.55 H,
J ϭ 3.7 Hz, 1 H, 4-H), 4.11 (d, J ϭ 3.7 Hz, 1 H, 5-H), 5.38 (d,
J ϭ 8.1 Hz, 1 H, CHNH-Tos, s after addition of D2O), 5.41 (dd,
J ϭ 8.1/2.9 Hz, 1 H, 2-H), 6.52 (d, J ϭ 8.1 Hz, 1 H, CHNH-Tos,
CHNH-Tos s after addition of D2O), 5.68 (d, J ϭ 8.1 Hz, 1 ϫ 0.45 H/D exchange), 6.88 (dd, J ϭ 8.1/2.2 Hz, 1 H, arom.), 7.10 (d, J ϭ
H, CHNH-Tos, s after addition of D2O), 6.52 (d, J ϭ 8.1 Hz, 1 ϫ 8.1 Hz, 1 H, arom.), 7.17Ϫ7.28 (m, 9 H, arom.), 7.58 (d, J ϭ 8.1
0.55 H, CHNH-Tos, H/D exchange), 6.75 (d, J ϭ 8.1 Hz, 1 ϫ
0.45 H, CHNH-Tos, H/D exchange), 6.78Ϫ6.96 (m, 2 H, arom.),
7.09Ϫ7.27 (m, 9 H, arom.), 7.57Ϫ7.59 (m, 2 H, arom.). Ϫ 13C
NMR (CDCl3): δ ϭ 21.3 (q, aryl-CH3), 36.8 [t, 1 ϫ 0.45 C,
Hz, 2 H, arom.). Ϫ 13C NMR (CDCl3): 21.1 [q, C(CH3)2], 21.2 [q,
C(CH3)2], 21.4 [q, C(CH3)2 and aryl-CH3], 21.8 [q, C(CH3)2], 38.2
[t, CH2CH(OR)2], 49.2 (q, OCH3), 49.3 (q, OCH3), 60.4 (d,
CHNH-Tos), 75.8 [s, C(CH3)2], 77.1 [s, C(CH3)2], 82.0 (d, C-4),
CH2CH(OR)2], 37.2 [t, 1 ϫ 0.55 C, CH2CH(OR)2], 59.0 (q, 1 ϫ 84.5 (d, C-5), 107.1 (d, C-2), 126.1 (d, arom.), 126.2 (d, arom.),
0.45 C, OCH3), 59.2 (q, 1 ϫ 0.55 C, OCH3), 59.2 (d, 1 ϫ 0.55 C,
CHNH-Tos and q, 1 ϫ 0.45 H, OCH3), 59.5 (d, 1 ϫ 0.45 C,
CHNH-Tos), 59.7 (q, 1 ϫ 0.55 C, OCH3), 72.1 (t, 1 ϫ 0.45 C,
CH2OCH3), 72.2 (t, 1 ϫ 0.55 C, CH2OCH3), 72.4 (t, 1 ϫ 0.45 C,
CH2OCH3), 72.6 (t, 1 ϫ 0.55 C, CH2OCH3), 77.1 (d, C-4), 77.5
(d, 1 ϫ 0.55 C, C-5), 77.7 (d, 1 ϫ 0.45 C, C-5), 104.9 (d, 1 ϫ 0.55
C, C-2), 105.1 (d, 1 ϫ 0.45 C, C-2), 126.2 (d, arom.), 126.4 (d,
arom.), 126.5 (d, arom.), 126.8 (d, arom.), 126.9 (d, arom.), 127.0
(d, arom.), 127.2 (d, arom.), 127.5 (d, arom.), 127.6 (d, arom.),
128.1 (d, arom.), 128.2 (d, arom.), 129.1 (d, arom.), 129.5 (d,
arom.), 129.6 (d, arom.), 129.7 (d, arom.), 131.8 (d, arom.), 133.5
(s, arom.), 137.6 (s, arom.), 141.0 (s, arom.), 142.7 (s, arom.). Ϫ
Ratio 26b/27b ϭ 55:45.
126.4 (d, arom.), 126.6 (d, arom.), 126.9 (d, arom.), 127.0 (d,
arom.), 127.3 (d, arom.), 127.4 (d, arom.), 127.9 (d, arom.), 128.0
(d, arom.), 128.2 (d, arom.), 128.4 (d, arom.), 129.1 (d, arom.),
129.2 (s, arom.), 130.6 (s, arom.), 131.6 (s, arom.), 134.7 (s, arom.),
150.5 (s, arom.).
27d: Rf ϭ 0.38; colourless oil, yield 0.18 g (26%), [α]589 ϭ ϩ2.42
(c ϭ 2.97 in CHCl3). Ϫ C32H41NO6S (567.7): calcd. C 67.7, H 7.28,
N 2.47; found C 67.6, H 7.29, N 2.54. Ϫ MS (CI): m/z ϭ 569 (M
ϩ Hϩ). Ϫ IR (film): ν˜ ϭ 3207 cmϪ1 (NH), 3060 (CϪH), 2973
(CϪH), 1597 (CϭC), 1157 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 1.09
[s, 3 H, C(CH3)2], 1.12 [s, 3 H, C(CH3)2], 1.26 [s, 3 H, C(CH3)2],
1.27 [s, 3 H, C(CH3)2], 2.37 (s, 3 H, aryl-CH3), 2.66Ϫ2.77 [m, 2 H,
CH2CH(OR)2], 3.14 (s, 3 H, OCH3), 3.18 (s, 3 H, OCH3), 3.79 (d,
N-[(αR and αS)-2-{[(4S,5S)-4,5-Bis(2-methoxyethoxymethyl)-1,3-di- J ϭ 3.7 Hz, 1 H, 4-H), 4.07 (d, J ϭ 3.7 Hz, 1 H, 5-H), 5.33 (t, J ϭ
oxolan-2-yl]methyl}benzhydryl]-4-methylbenzenesulfonamide (26c/ 3.7 Hz, 1 H, 2-H), 5.80 (d, J ϭ 6.9 Hz, 1 H, CHNH-Tos, s after
27c): According to General Procedure 2, 6d (0.63 g, 1.50 mmol) was addition of D2O), 6.22 (d, J ϭ 6.9 Hz, 1 H, CHNH-Tos, H/D
treated with 25 (0.41 g, 1.60 mmol). FC [diameter of the column 3 exchange), 6.89 (d, J ϭ 7.3 Hz, 1 H, arom.), 7.10 (dd, J ϭ 8.1/2.2
cm, petroleum ether/ethyl acetate (50:50), Rf ϭ 0.26] gave a colour- Hz, 1 H, arom.), 7.11Ϫ7.29 (m, 9 H, arom.), 7.58 (d, J ϭ 8.1 Hz,
less oil, yield 0.59 g (65%). Ϫ C32H41NO8S (599.7): calcd. C 64.1,
2 H, arom.). Ϫ 13C NMR (CDCl3): 21.2 [q, C(CH3)2], 21.3 [q,
H 6.89, N 2.34; found C 64.2, H 7.03, N 2.05. Ϫ MS (70 eV): m/ C(CH3)2], 21.4 [q, C(CH3)2 and aryl CH3], 22.1 [q, C(CH3)2], 36.4
z ϭ 599 (Mϩ), 444 (M Ϫ Tos.), 429 (M Ϫ NHTos). Ϫ IR (film): [t, CH2CH(OR)2], 49.1 (q, OCH3), 49.2 (q, OCH3), 60.5 (d,
ν˜ ϭ 3235 cmϪ1 (NH), 3061 (CϪH), 2926 (CϪH), 1599 (CϭC),
1160 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 2.37 (s, 3 H, aryl-CH3),
CHNH-Tos), 75.7 [s, C(CH3)2], 77.2 [s, C(CH3)2], 81.5 (d, C-4),
83.9 (d, C-5), 104.5 (d, C-2), 126.6 (d, arom.), 127.0 (d, 2 C, arom.),
2.69Ϫ2.71 [m, 2 H, CH2CH(OR)2], 3.33 (s, 3 H, OCH3), 3.36 (s, 3 127.1 (d, arom.), 127.2 (d, arom.), 127.3 (d, arom.), 128.0 (d,
H, OCH3), 3.39Ϫ3.69 (m, 12 H, 6 ϫ OCH2), 3.93Ϫ4.16 (m, 2 H,
4-H, 5-H), 5.19Ϫ5.21 (m, 1 H, 2-H), 5.58 (d, J ϭ 7.3 Hz, 1 ϫ 0.52
arom.), 128.1 (d, arom.), 128.3 (d, arom.), 129.1 (d, arom.), 130.1
(d, arom.), 132.9 (s, arom.), 133.8 (s, arom.), 139.3 (s, arom.), 148.7
H, CHNH-Tos, s after addition of D2O), 5.63 (d, J ϭ 7.3 Hz, 1 ϫ (s, arom.).
0.48 H, CHNH-Tos, s after addition of D2O), 6.50 (d, J ϭ 7.3 Hz,
b) p-Toluenesulfonyl chloride (87.5 mg, 0.46 mmol) was added to
1 ϫ 0.52 H, CHNH-Tos, H/D exchange), 6.71 (d, J ϭ 8.1 Hz, 1
H, arom.), 6.80 (d, J ϭ 7.3 Hz, 1 ϫ 0.48 H, CHNH-Tos, H/D
exchange), 6.90Ϫ6.95 (m, 1 H, arom.), 7.10Ϫ7.27 (m, 9 H, arom.),
7.57Ϫ7.60 (m, 2 H, arom.). Ratio 26c/27c ϭ 52:48.
a cooled solution of 35/36 (92:8 mixture, 0.18 g, 0.44 mmol) in
THF (15 mL) and triethylamine (63 mg, 0.63 mmol). After stirring
for 8 h at room temperature, water, 2  NaOH and Et2O were
added, the organic layer was separated, dried (MgSO4), concen-
trated in vacuo, and the residue was purified by FC as described
under a). Colourless oil (26d), yield 0.20 g (81%).
(؊)-N-[(αR)-2-{[(4R,5R)-4,5-Bis(2-methoxypropan-2-yl)-1,3-dioxo-
lan-2-yl]methyl}benzhydryl]-4-methylbenzenesulfonamide (26d) and
(؉)-N-[(αS)-2-{[(4R,5R)-4,5-Bis(2-methoxypropan-2-yl)-1,3-dioxo-
lan-2-yl]methyl}benzhydryl]-4-methylbenzenesulfonamide (27d): a)
According to General Procedure 2, 6e (465 mg, 1.2 mmol) was
treated with 25 (0.34 g, 1.30 mmol). The HPLC analysis [eluent
N-[(αR and αS)-2-{[(4R,5R)-4,5-Bis(3-methoxpentan-3-yl)-1,3-diox-
olan-2-yl]methyl}benzhydryl]-4-methylbenzenesulfonamide (26e/27e):
According to General Procedure 2, 6f (133 mg, 0.30 mmol) was
treated with 25 (85.5 mg, 0.33 mmol). FC [diameter of the column
2 cm, petroleum ether/ethyl acetate (90:10), Rf ϭ 0.24] provided a
pale yellow oil, yield 59.9 mg (32%). Ϫ C36H49NO6S (623.9): calcd.
C 69.3, H 7.92, N 2.25, S 5.14; found C 69.2, H 7.82, N 2.42, S
5.13. Ϫ MS (70 eV): m/z ϭ 454 (M Ϫ NHTos). Ϫ IR (film): ν˜ ϭ
3269 cmϪ1 (NH), 3062 (CϪH), 2969 (CϪH), 1599 (CϭC), 1160
1
petroleum ether/ethyl acetate (85:15)] and the H-NMR spectrum
of the unpurified product showed a diastereomeric ratio 26d (reten-
tion time 10.4 min)/27d (retention time 12.2 min) of 61:39. The
diastereomeres were separated by FC: diameter of the column 2
cm, petroleum ether/ethyl acetate (85:15).
26d: Rf ϭ 0.40; colourless oil, yield 0.25 g (37%), [α]589 ϭ Ϫ4.32 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 0.85Ϫ1.00 (m, 12 H, 4 ϫ
(c ϭ 3.92 in CHCl3). Ϫ C32H41NO6S (567.7): calcd. C 67.7, H 7.28,
N 2.47; found C 67.8, H 7.40, N 2.25. Ϫ MS (CI): m/z ϭ 568 (M
CH2CH3), 1.26Ϫ1.80 (m, 8 H, 4 ϫ CH2CH3), 2.37 (s, 3 ϫ 0.62
H, aryl-CH3), 2.38 (s, 3 ϫ 0.38 H, aryl-CH3), 2.57Ϫ2.74 [m, 2 H,
ϩ Hϩ). Ϫ IR (film): ν˜ ϭ 3204 cmϪ1 (NH), 3062 (CϪH), 2977 CH2CH(OR)2], 3.10 (s, 3 H, OCH3), 3.22 (s, 3 H, OCH3), 4.17 (d,
(CϪH), 1600 (CϭC), 1160 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 1.08 J ϭ 4.3 Hz, 1 ϫ 0.62 H, 4-H), 4.27 (d, J ϭ 4.3 Hz, 1 ϫ 0.62 H, 5-
[s, 3 H, C(CH3)2], 1.14 [s, 3 H, C(CH3)2], 1.15 [s, 3 H, C(CH3)2],
H), 4.32 (d, J ϭ 3.4 Hz, 1 ϫ 0.38 H, 4-H), 4.38 (d, J ϭ 3.4 Hz, 1
1.19 [s, 3 H, C(CH3)2], 2.38 (s, 3 H, aryl-CH3), 2.51 [dd, J ϭ 14.2/ ϫ 0.38 H, 5-H), 5.27 (t, J ϭ 3.9 Hz, 1 ϫ 0.62 H, 2-H), 5.32 (dd,
8.1 Hz, 1 H, CH2CH(OR)2], 2.65 [dd, J ϭ 14.2/2.9 Hz, 1 H,
CH2CH(OR)2], 3.16 (s, 3 H, OCH3), 3.23 (s, 3 H, OCH3), 4.10 (d,
J ϭ 4.7/3.0 Hz, 1 ϫ 0.38 H, 2-H), 5.49 (d, J ϭ 8.1 Hz, 1 ϫ 0.62
Hz, CHNH-Tos, s after addition of D2O), 5.84 (d, J ϭ 7.3 Hz, 1
512
Eur. J. Org. Chem. 1999, 503Ϫ517

Key Step in the Asymmetric Synthesis of 1-Aryltetrahydroisoquinolines
ϫ 0.38 Hz, CHNH-Tos, s after addition of D2O), 5.98Ϫ6.02 (m, 1 CHNH-Tos, H/D exchange), 6.90Ϫ7.68 (m, 28 H, arom.). Ratio
FULL PAPER
ϫ 0.62 Hz, CHNH-Tos, H/D exchange), 6.63 (d, J ϭ 7.3 Hz, 1 ϫ
0.38 Hz, CHNH-Tos, H/D exchange), 6.90Ϫ7.26 (m, 11 H, arom.),
7.57 (d, J ϭ 8.1 Hz, 2 H, arom.). Ratio 26e/27e ϭ 62:38.
26h/27h ϭ 32:68.
N-[(αR and αS)-2-{[(2R,4S,5S)-5-Benzyloxy-4-methoxymethyl-1,3-
dioxan-2-yl]methyl}benzhydryl]-4-methylbenzenesulfonamide (26i/
27i): According to General Procedure 2, 7d (118 mg, 0.30 mmol)
was treated with 25 (85.4 mg, 0.33 mmol). FC [diameter of the
column 2 cm, petroleum ether/ethyl acetate (75:25), Rf ϭ 0.26] pro-
vided a colourless oil, yield 85.9 mg (49%). Ϫ MS (CI): m/z ϭ 589
N-[(αR and αS)-2-{[(2S,4S)-4-(Trimethylsiloxymethyl)-1,3-dioxan-2-
yl]methyl}benzhydryl]-4-methylbenzenesulfonamide (26f/27f): Ac-
cording to General Procedure 2, 7b (108 mg, 0.30 mmol) was
treated with 25 (83 mg, 0.32 mmol). FC [diameter of the column 2
cm, petroleum ether/ethyl acetate (90:10), Rf ϭ 0.26] provided a
colourless oil, yield 122.1 mg (75%). Ϫ C29H37NO5SSi (539.8):
calcd. C 64.5, H 6.91, N 2.59; found C 64.6, H 6.81, N 2.66. Ϫ MS
(70 eV): m/z ϭ 524 (M Ϫ CH3). Ϫ IR (film): ν˜ ϭ 3227 cmϪ1 (NH),
3062 (CϪH), 2957 (CϪH), 1599 (CϭC), 1159 (CϪO). Ϫ 1H NMR
(CDCl3): δ ϭ 0.00 [s, 9 H, OSi(CH3)3], 1.35Ϫ1.49 (m, 1 H, 5-H
eq.), 1.51Ϫ1.67 (m, 1 H, 5-H ax.), 2.26 (s, 3 ϫ 0.56 H, aryl-CH3),
2.28 (s, 3 ϫ 0.44 H, aryl-CH3), 2.49Ϫ2.62 [m, 2 H, CH2CH(OR)2],
3.39Ϫ3.62 (m, 4 H, CH2OSiMe3, 6-H ax., 4-H ax.), 3.99Ϫ4.16 (m,
1 H, 6-H eq.), 4.52Ϫ4.62 (m, 1 H, 2-H ax.), 5.39 (d, J ϭ 7.3 Hz, 1
ϫ 0.56 H, CHNH-Tos, s after addition of D2O), 5.51 (d, J ϭ 6.6
Hz, 1 ϫ 0.44 H, CHNH-Tos, s after addition of D2O), 6.24 (d, J ϭ
6.6 Hz, 1 ϫ 0.44 H, CHNH-Tos, H/D exchange), 6.55 (d, J ϭ 7.3
Hz, 1 ϫ 0.56 H, CHNH-Tos, H/D exchange), 6.78Ϫ6.89 (m, 2 H,
arom.), 6.99Ϫ7.18 (m, 9 H, arom.), 7.41 (d, J ϭ 8.1 Hz, 2 ϫ 0.56
H, arom.), 7.46 (d, J ϭ 8.1 Hz, 2 ϫ 0.44 H, arom.). Ratio 26f/
27f ϭ 44:56.
1
(M ϩ Hϩ). Ϫ H NMR (CDCl3): δ ϭ 2.23 (s, 3 ϫ 0.44 H, aryl-
CH3), 2.26 (s, 3 ϫ 0.56 H, aryl-CH3), 2.57Ϫ2.70 [m, 2 H,
CH2CH(OR)2], 3.19Ϫ3.25 (m,
4 H, 5-H eq., CH2OCH3),
3.41Ϫ3.45 (m, 1 H, 6-H ax.), 3.50Ϫ3.60 (m, 2 H, CH2OCH3),
3.74Ϫ3.82 (m, 1 H, 4-H ax.), 4.25Ϫ4.32 (m, 1 H, 6-H eq.),
4.37Ϫ4.44 (m, 1 H, OCH2C6H5), 4.55Ϫ4.76 (m, 2 H, 2-H ax.,
OCH2C6H5), 5.50 (d, J ϭ 8.1 Hz, 1 ϫ 0.56 H, CHNH-Tos, s after
addition of D2O), 5.52 (d, J ϭ 6.6 Hz, 1 ϫ 0.44 H, CHNH-Tos, s
after addition of D2O), 6.27Ϫ6.30 (m, 1 H, CHNH-Tos, H/D ex-
change), 6.72Ϫ7.32 (m, 16 H, arom.), 7.46 (d, J ϭ 7.7 Hz, 2 ϫ 0.56
H, arom.), 7.55 (d, J ϭ 8.8 Hz, 2 ϫ 0.44 H, arom.). Ratio 26i/
27i ϭ 56:44.
N-[(αR and αS)-2-{[(4R,5R)-4,5-Dimethyl-1,3-dioxolan-2-yl]meth-
yl}benzhydryl]aniline (29a/30a): According to General Procedure 2,
6a (200 mg, 0.74 mmol) was treated with 28 (140 mg, 0.77 mmol).
FC [diameter of the column 2 cm, petroleum ether/ethyl acetate
(85:15), Rf ϭ 0.41] provided a pale yellow oil, yield 230 mg (82%).
Ϫ C25H27NO2 (373.5): calcd. C 80.4, H 7.29, N 3.75; found C 80.2,
H 7.53, N 3.69. Ϫ MS (70 eV): m/z ϭ 373 (Mϩ), 282 (M Ϫ
NHC6H5). Ϫ IR (film): ν˜ ϭ 3375 cmϪ1 (NH), 3031 (CϪH), 2941
N-[(αR and αS)-2-{[(2S,4S)-4-(tert-Butyldimethylsiloxymethyl)-1,3-
dioxan-2-yl]methyl}benzhydryl]-4-methylbenzenesulfonamide (26g/
27g): According to General Procedure 2, 7c (280 mg, 0.70 mmol)
was treated with 25 (200 mg, 0.77 mmol). FC [diameter of the
column 2 cm, petroleum ether/ethyl acetate (90:10), Rf ϭ 0.30] fur-
nished a colourless oil, yield 290 mg (71%). Ϫ C32H43NO5SSi
(581.8): calcd. C 66.1, H 7.45, N 2.41; found C 65.9, H 7.39, N
2.64. Ϫ MS (70 eV): m/z ϭ 524 (M Ϫ tert-Butyl). Ϫ IR (film): ν˜ ϭ
3266 cmϪ1 (NH), 3063 (CϪH), 2928 (CϪH), 1599 (CϭC), 1160
(CϪH), 1602 (CϭC), 1071 (CϪO).
1.09Ϫ1.21 (m, H, CHCH3), 2.84Ϫ2.94 [m, 2
Ϫ
1H NMR (CDCl3):
H,
6
2
ϫ
CH2CH(OR)2], 3.42 (q, J ϭ 6.6 Hz, 1 H, 4-H), 3.52 (q, J ϭ 5.9
Hz, 1 H, 5-H), 4.02Ϫ4.08 (m, 1 H, CHNH-C6H5, H/D exchange),
5.18 (dd, J ϭ 5.9/4.4 Hz, 1 H, 2-H), 5.84 (br. s, 1 ϫ 0.49 H,
CHNHC6H5), 5.86 (br. s, 1 ϫ 0.51 H, CHNHC6H5), 6.48Ϫ6.61 (m,
3 H, arom.), 7.01Ϫ7.27 (m, 11 H, arom.). Ratio 29a/30a ϭ 49:51.
1
(CϪO). Ϫ H NMR (CDCl3): 0.00 [s, 6 H, OSi(CH3)2], 0.83 [s, 9
H, OSiC(CH3)3], 1.45Ϫ1.52 (m, 1 H, 5-H eq.), 1.61Ϫ1.72 (m, 1 H,
5-H ax.), 2.33 (s, 3 ϫ 0.67 H, aryl-CH3), 2.34 (s, 3 ϫ 0.33 H, aryl-
CH3), 2.50Ϫ2.68 [m, 2 H, CH2CH(OR)2], 3.46Ϫ3.70 (m, 4 H,
CH2OSi, 6-H ax., 4-H ax.), 4.12Ϫ4.22 (m, 1 H, 6-H eq.), 4.60 (t,
J ϭ 5.1 Hz, 1 ϫ 0.33 H, 2-H ax.), 4.64 (dd, J ϭ 7.2/3.4 Hz, 1 ϫ
0.67 H, 2-H ax.), 5.47 (d, J ϭ 8.1 Hz, 1 ϫ 0.67 H, CHNH-Tos, s
after addition of D2O), 5.56 (d, J ϭ 6.8 Hz, 1 ϫ 0.33 H, CHNH-
Tos, s after addition of D2O), 6.64 (d, J ϭ 7.7 Hz, 1 ϫ 0.67 H,
CHNH-Tos, H/D exchange), 6.76 (d, J ϭ 6.8 Hz, 1 ϫ 0.33 H,
CHNH-Tos, H/D exchange), 6.86Ϫ7.18 (m, 11 H, arom.),
7.47Ϫ7.52 (m, 2 H, arom.). Ratio 26g/27g ϭ 33:67.
N-[(αR and αS)-2-{[(4S,5S)-4,5-Bis(methoxymethyl)-1,3-dioxolan-2-
yl]methyl}benzhydryl]aniline (29b/30b): According to General Pro-
cedure 2, 6b (245 mg, 0.74 mmol) was treated with 28 (140 mg,
0.77 mmol). FC [diameter of the column 2 cm, petroleum ether/
ethyl acetate (85:15), Rf ϭ 0.35] provided a pale yellow oil, yield
260 mg (82%). Ϫ C27H31NO4 (433.5): calcd. C 74.8, H 7.21, N
3.23; found C 74.7, H 7.44, N 3.14. Ϫ MS (CI): m/z ϭ 434 (M ϩ
Hϩ). Ϫ IR (film): ν˜ ϭ 3374 cmϪ1 (NH), 3055 (CϪH), 2926 (CϪH),
1601 (CϭC), 1136 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 3.00Ϫ3.04
[m, 2 H, CH2CH(OR)2], 3.35 (s, 3 H, OCH3), 3.38 (s, 3 H, OCH3),
3.43Ϫ3.46 (m, 4 H, 2 ϫ CH2OCH3), 3.91Ϫ3.95 (m, 2 H, 4-H, 5-
H), 4.30Ϫ4.33 (m, 1 H, CHNHC6H5, H/D exchange), 5.27 (dd,
J ϭ 4.4/3.7 Hz, 1 ϫ 0.57 H, 2-H), 5.34 (t, J ϭ 5.1 Hz, 1 ϫ 0.43
H, 2-H), 5.89 (s, 1 ϫ 0.57 H, CHNHC6H5), 5.90 (s, 1 ϫ 0.43 H,
CHNHC6H5;), 6.55 (dd, J ϭ 7.3/2.2 Hz, 1 H, arom.), 6.67, (dd,
J ϭ 7.3/2.2 Hz, 1 H, arom.), 7.07Ϫ7.36 (m, 12 H, arom.). Ratio
29b/30b ϭ 57:43.
N-[(αR and αS)-2-{[(2S,4S)-4-(Triphenylsiloxymethyl)-1,3-dioxan-2-
yl]methyl}benzhydryl]-4-methylbenzenesulfonamide (26h/27h): Ac-
cording to General Procedure 2, 7d (163 mg, 0.30 mmol) was
treated with 25 (85.5 mg, 0.33 mmol). FC [diameter of the column
2 cm, petroleum ether/ethyl acetate (90:10), Rf ϭ 0.32] gave a pale
yellow oil, yield 220 mg (61%). Ϫ C44H43NO5SSi (725.9): calcd. C
72.8, H 5.97, N 1.93, S 4.42; found C 72.6, H 6.21, N 1.90, S 4.27.
Ϫ MS (CI): m/z ϭ 649 (M ϩ Hϩ Ϫ C6H5). Ϫ IR (film): ν˜ ϭ 3256 oxolan-2-yl]methyl}-benzhydryl]aniline (29c/30c): According to
cmϪ1 (NH), 3058 (CϪH), 2926 (CϪH), 1597 (CϭC), 1155 (CϪO).
Ϫ 1H NMR (CDCl3): δ ϭ 1.37Ϫ1.44 (m, 1 H, 5-H eq.), 1.67Ϫ1.77
N-[(αR and αS)-2-{[(4R,5R)-4,5-Bis(2-methoxypropan-2-yl)-1,3-di-
General Procedure 2, 6e (232 mg, 0.60 mmol) was treated with 28
(110 mg, 0.62 mmol). FC [diameter of the column 2 cm, petroleum
(m, 1 H, 5-H ax.), 2.26 (s, 3 ϫ 0.32 H, aryl-CH3), 2.32 (s, 3 ϫ 0.68 ether/ethyl acetate (90:10), Rf ϭ 0.62] provided a pale yellow oil,
H, aryl-CH3), 2.58Ϫ2.70 [m, 2 H, CH2CH(OR)2], 3.60Ϫ3.90 (m, 4 yield 220 mg (75%). Ϫ C31H39NO4 (489.7): calcd. C 76.0, H 8.03,
H, CH2OSiPh3, 6-H ax., 4-H ax.), 4.10Ϫ4.21 (m, 1 H, 6-H eq.),
4.60Ϫ4.62 (m, 1 H, 2-H ax.), 5.50 (d, J ϭ 8.1 Hz, 1 ϫ 0.68 H,
CHNH-Tos, s after addition of D2O), 5.56 (d, J ϭ 8.1 Hz, 1 ϫ
0.32 H, CHNH-Tos, s after addition of D2O), 6.64Ϫ6.76 (m, 1 H,
N 2.86; found C 76.2, H 8.15, N 2.59. Ϫ MS (70 eV): m/z ϭ 489
(Mϩ), 397 (M Ϫ NHC6H5). Ϫ IR (film): ν˜ ϭ 3374 cmϪ1 (NH),
3055 (CϪH), 2926 (CϪH), 1601 (CϭC), 1136 (CϪO). Ϫ 1H NMR
(CDCl3): δ ϭ 0.93 [s, 3 ϫ 0.91 H, C(CH3)2], 1.00 [s, 3 ϫ 0.91 H,
Eur. J. Org. Chem. 1999, 503Ϫ517
513

B. Wünsch, S. Nerdinger
FULL PAPER
C(CH3)2], 1.02 [s, 3 ϫ 0.09 H, C(CH3)2], 1.03 [s, 3 ϫ 0.09 H,
C(CH3)2], 1.07 [s, 6 ϫ 0.09 H, C(CH3)2], 1.09 [s, 6 ϫ 0.91 H,
C(CH3)2], 2.84 [dd, J ϭ 14.7/4.4 Hz, 1 ϫ 0.91 H, CH2CH(OR)2],
2.88Ϫ2.90 [m, 2 ϫ 0.09 H, CH2CH(OR)2], 2.95 84 [dd, J ϭ 14.7/
5.1 Hz, 1 ϫ 0.91 H, CH2CH(OR)2], 3.06 (s, 3 ϫ 0.91 H, OCH3),
3.08 (s, 3 ϫ 0.09 H, OCH3), 3.09 (s, 3 ϫ 0.09 H, OCH3), 3.10 (s, 3
ϫ 0.91 H, OCH3), 3.75 (d, J ϭ 2.9 Hz, 1 ϫ 0.91 H, 4-H), 3.77 (d,
J ϭ 2.9 Hz, 1 ϫ 0.09 H, 4-H), 3.97 (d, J ϭ 2.9 Hz, 1 ϫ 0.09 H, 5-
H), 3.99 (d, J ϭ 2.9 Hz, 1 ϫ 0.91 H, 5-H), 4.11 (m, 1 ϫ 0.91 H,
CHNH-C6H5, H/D exchange), 4.16 (m, 1 ϫ 0.09 H, CHNH-C6H5,
H/D exchange), 5.28 (t, J ϭ 4.4 Hz, 1 ϫ 0.09 H, 2-H), 5.37 (dd,
N-[(αR and αS)-2-{[(4S,5S)-4,5-Bis(methoxymethyl)-1,3-dioxolan-2-
yl]methyl}benzhydryl]-4-methoxyaniline (32b/33b): According to
General Procedure 2, 6b (0.20 g, 0.60 mmol) was treated with 31
(0.13 g, 0.62 mmol). The reaction mixture was stirred for 2 h at
Ϫ100°C and for 2 h at 0°C. Pruification by FC [diameter of the
column 2 cm, petroleum ether/ethyl acetate (75:25), Rf ϭ 0.37] fur-
nished a pale yellow oil, yield 0.17 g (62%). Ϫ C28H33NO5 (463.6):
calcd. C 72.5, H 7.18, N 3.02; found C 72.7, H 7.56, N 2.47. Ϫ MS
(70 eV): m/z ϭ 463 (Mϩ), 341 (M Ϫ NHC6H4OCH3). Ϫ IR (film):
ν˜ ϭ 3378 cmϪ1 (NH), 3059 (CϪH), 2928 (CϪH), 1601 (CϭC),
1132 (CϪO).
Ϫ 2 H,
1H NMR (CDCl3): 2.97Ϫ2.99 [m,
J ϭ 5.1/4.4 Hz, 1 ϫ 0.91 H, 2-H), 5.87 (m, 1 H, CHNH-C6H5, s CH2CH(OR)2], 3.23Ϫ3.42 (m, 10 H, 2 ϫ CH2OCH3), 3.63 (s, 3 H,
after addition of D2O), 6.46 (d, J ϭ 8.1 Hz, 2 H, arom.), 6.56 (t,
J ϭ 7.3 Hz, 1 H, arom.), 6.97Ϫ7.25 (m, 11 H, arom.). Ratio 29c/
30c ϭ 91:9. Ϫ 13C NMR (CDCl3): δ ϭ 19.1 [q, 1 ϫ 0.91 C,
C(CH3)2], 21.0 [q, 1 ϫ 0.91 C, C(CH3)2], 21.2 [q, 1 ϫ 0.09 C,
C(CH3)2], 21.3 [q, 1 ϫ 0.91 C, C(CH3)2], 22.1 [q, 1 ϫ 0.91 C,
C(CH3)2], 22.1 [q, 1 ϫ 0.09 C, C(CH3)2], 22.5 [q, 1 ϫ 0.09 C,
C(CH3)2], 25.6 [q, 1 ϫ 0.09 C, C(CH3)2], 37.5 [t, 1 ϫ 0.09 C,
CH2CH(OR)2], 37.9 [t, 1 ϫ 0.91 C, CH2CH(OR)2], 49.2 (q, OCH3),
49.4 (q, OCH3), 58.6 (d, 1 ϫ 0.91 C, CHNHC6H5), 59.0 (d, 1 ϫ
0.09 C, CHNHC6H5), 75.8 [s, C(CH3)2], 76.7 [s, C(CH3)2], 81.7 (d,
1 ϫ 0.91 C, C-4), 84.0 (d, 2 ϫ 0.09 C, C-4, C-5), 84.1 (d, 1 ϫ 0.91
C, C-5), 105.9 (d, 1 ϫ 0.09 C, C-2), 106.3 (d, 1 ϫ 0.91 C, C-2),
113.2 (d, 2 ϫ 0.09 C, arom.), 113.4 (d, 2 ϫ 0.91 C, arom.), 117.2
(d, C-3 arom.), 126.9 (d, arom.), 127.1 (d, C-4 arom.), 127.2 (d, C-
5 arom.), 127.8 (d, C-6 arom.), 128.0 (d, 2 C arom.), 128.5 (d, 2 C
arom.), 129.0 (d, 2 C arom.), 131.3 (d, 1 ϫ 0.91 C, arom.), 131.6
(d, 1 ϫ 0.09 C, arom.), 134.9 (s, C-1 arom.), 141.2 (s, C-2 arom.),
142.6 (s, arom.), 147.2 (s, arom.).
aryl-OCH3), 3.80Ϫ3.92 (m, 2 H, 4-H, 5-H), 3.94Ϫ4.00 (m, 1 H,
CHNH-aryl, H/D exchange), 5.18 (dd, J ϭ 4.7/2.1 Hz, 1 ϫ 0.39
H, 2-H), 5.20 (dd, J ϭ 4.3/2.6 Hz, 1 ϫ 0.61 H, 2-H), 5.73 (m, 1 ϫ
0.39 H, CHNH-aryl, s after addition of D2O), 5.74 (m, 1 ϫ 0.61
H, CHNH-aryl, s after addition of D2O), 6.43 (d, J ϭ 8.9 Hz, 2
H, arom.), 6.63 (d, J ϭ 8.9 Hz, 2 H, arom.), 7.08Ϫ7.28 (m, 9 H,
arom.). Ratio 32b/33b ϭ 61:39.
N-[(αR and αS)-2-{[(4R,5R)-4,5-Bis(2-methoxypropan-2-yl)-1,3-di-
oxolan-2-yl]methyl}benzhydryl]-4-methoxyaniline (32c/33c): Accord-
ing to General Procedure 2, 6e (0.23 g, 0.60 mmol) was treated with
31 (0.13 g, 0.62 mmol). The reaction mixture was stirred for 2 h at
Ϫ100°C and for 2 h at 0°C. The HPLC analysis [eluent n-heptane/
ethyl acetate (90:10)] of the unpurified product showed a dia-
stereomeric ratio 32c (retention time 17.7 min)/33c (retention time
17.2 min) of 92.1:7.9. Purification by FC [diameter of the column
2 cm, petroleum ether/ethyl acetate (90:10), Rf ϭ 0.59] furnished a
pale yellow oil, yield 0.21 g (67%). Ϫ C32H41NO5 (519.7): calcd. C
74.0, H 7.95, N 2.70; found C 74.0, H 7.97, N 2.60. Ϫ MS (70 eV):
m/z ϭ 520 (Mϩ), 398 (M Ϫ NHC6H4OCH3). Ϫ IR (film): ν˜ ϭ
3379 cmϪ1 (NH), 3061 (CϪH), 2921 (CϪH), 1602 (CϭC), 1135
N-[(αR and αS)-2-{[(2S,4S)-4-(Triphenylsiloxymethyl)-1,3-dioxan-2-
yl]methyl}benzhydryl]aniline (29d/30d): According to General Pro-
cedure 2, 7d (164 mg, 0.30 mmol) was treated with 28 (60 mg, 0.33
mmol). FC [diameter of the column 2 cm, petroleum ether/ethyl
acetate (90:10), Rf ϭ 0.52] afforded a pale yellow oil, yield 140 mg
(70%). Ϫ C43H41NO3Si (647.9): calcd. C 79.7, H 6.38, N 2.16;
found C 79.6, H 6.76, N 1.92. Ϫ MS (CI): m/z ϭ 648 (M ϩ Hϩ).
Ϫ IR (film): ν˜ ϭ 3418 cmϪ1 (NH), 3068 (CϪH), 2926 (CϪH), 1601
1
(CϪO). Ϫ H NMR (CDCl3): δ ϭ 0.92 [s, 3 ϫ 0.09 H, C(CH3)2],
0.93 [s, 3 ϫ 0.91 H, C(CH3)2], 1.00 [s, 3 ϫ 0.91 H, C(CH3)2], 1.07
[s, 3 ϫ 0.09 H, C(CH3)2], 1.08 [s, 6 ϫ 0.09 H, C(CH3)2], 1.09 [s, 3
ϫ 0.91 H, C(CH3)2], 1.10 [s, 3 ϫ 0.91 H, C(CH3)2], 2.84 [dd, J ϭ
14.7/4.4 Hz, 1 ϫ 0.91 H, CH2CH(OR)2], 2.88Ϫ2.90 [m, 2 ϫ 0.09
H, CH2CH(OR)2], 2.95 [dd, J ϭ 14.7/5.1 Hz, 1 ϫ 0.91 H,
CH2CH(OR)2], 3.07 (s, 3 ϫ 0.91 H, OCH3), 3.08 (s, 3 ϫ 0.09 H,
OCH3), 3.09 (s, 3 ϫ 0.09 H, OCH3), 3.11 (s, 3 ϫ 0.91 H, OCH3),
3.62 (s, 3 ϫ 0.91 H, aryl-OCH3), 3.62 (s, 3 ϫ 0.09 H, aryl-OCH3),
3.75 (d, J ϭ 2.9 Hz, 1 ϫ 0.91 H, 4-H), 3.77 (d, J ϭ 2.9 Hz, 1 ϫ
0.09 H, 4-H), 3.88 (br. s, 1 H, CHNH-aryl, H/D exchange), 3.97
(d, J ϭ 2.9 Hz, 1 ϫ 0.09 H, 5-H), 3.99 (d, J ϭ 2.9 Hz, 1 ϫ 0.91
H, 5-H), 5.27 (t, J ϭ 4.4 Hz, 1 ϫ 0.09 H, 2-H), 5.36 (dd, J ϭ 5.1/4.4
Hz, 1 ϫ 0.91 H, 2-H), 5.79 (m, 1 H, CHNH-aryl, s after addition of
D2O), 6.41 (d, J ϭ 8.8 Hz, 2 H, arom.), 6.60 (d, J ϭ 8.8 Hz, 2 H,
1
(CϭC), 1117 (CϪO). Ϫ H NMR (CDCl3): δ ϭ 1.41Ϫ1.52 (m, 1
H, 5-H eq.), 1.56Ϫ1.66 (m, 1 H, 5-H ax.), 2.82Ϫ3.00 [m, 2 H,
CH2CH(OR)2], 3.50Ϫ3.71 (m,
3 H, CH2OSiPh3, 6-H ax.),
3.84Ϫ3.88 (m, 1 H, 4-H ax.), 4.01Ϫ4.09 (m, 1 H, 6-H eq.),
4.23Ϫ4.29 (m, 1 H, CHNHC6H5, H/D exchange), 4.52Ϫ4.58 (m, 1
H, 2-H ax.), 5.81 (s, 1 ϫ 0.25 H, CHNHC6H5), 5.87 (s, 1 ϫ 0.75
H, CHNHC6H5), 6.47Ϫ6.65 (m, 3 H, arom.), 7.00Ϫ44 (m, 20 H,
arom.), 7.58Ϫ7.64 (m, 6 H, arom.). Ratio 29d/30d ϭ 25:75.
N-[(αR and αS)-2-{[(4R,5R)-4,5-Dimethyl-1,3-dioxolan-2-yl]meth-
yl}benzhydryl]-4-methoxyaniline (32a/33a): According to General arom.), 7.05Ϫ7.24 (m, 9 H, arom.). Ratio 32c/33c ϭ 91:9. Ϫ 13C
Procedure 2, 6a (0.19 g, 0.70 mmol) was treated with 31 (0.19 g,
0.74 mmol). FC [diameter of the column 2 cm, petroleum ether/
ethyl acetate (85:15), Rf ϭ 0.35] provided a pale yellow oil, yield
NMR (CDCl3): δ ϭ 19.1 [q, 1 ϫ 0.09 C, C(CH3)2], 21.1 [q, 1 ϫ
0.91 C, C(CH3)2], 21.4 [q, 1 ϫ 0.91 C, C(CH3)2], 21.8 [q, 1 C,
C(CH3)2], 22.1 [q, 1 C, C(CH3)2], 22.2 [q, 1 ϫ 0.09 C, C(CH3)2],
0.11 g (37%). Ϫ C26H29NO3 (403.5): calcd. C 77.4, H 7.24, N 3.47; 37.5 [t, 1 ϫ 0.09 C, CH2CH(OR)2], 37.9 [t, 1 ϫ 0.91 C,
found C 77.2, H 7.48, N 3.36. Ϫ MS (70 eV): m/z ϭ 403 (Mϩ), 281 CH2CH(OR)2], 49.3 (q, 2 ϫ 0.09 C, OCH3], 49.4 (q, 2 ϫ 0.91 C,
(Mϩ Ϫ NHC6H4OCH3). Ϫ IR (film): ν˜ ϭ 3380 cmϪ1 (NH), 3062 OCH3), 55.8 (q, 1 C, OCH3), 59.3 (d, 1 C, CHNH-aryl), 75.8 [s, 1
(CϪH), 2941 (CϪH), 1600 (CϭC), 1073 (CϪO). Ϫ 1H NMR
(CDCl3): 1.04Ϫ1.17 (m, 6 H, 2 ϫ CHCH3), 2.81Ϫ2.92 [m, 2 H,
CH2CH(OR)2], 3.65 (s, 3 H, aryl-OCH3), 3.72 (q, J ϭ 6.6 Hz, 1 H,
C, C(CH3)2], 77.2 [s, 1 C, C(CH3)2], 81.8 (d, C-4), 84.0 (d, 1 ϫ 0.09
C, C-5), 84.1 (d, 1 ϫ 0.91 C, C-5), 105.9 (d, 1 ϫ 0.09 C, C-2), 106.3
(d, 1 ϫ 0.91 C, C-2), 114.3 (d, 2 ϫ 0.09 C, arom.), 114.4 (d, 2 ϫ
4-H), 3.82 (q, J ϭ 5.9 Hz, 1 H, 5-H), 4.00Ϫ4.06 (m, 1 H, CHNH- 0.91 C, arom.), 114.7 (d, 1 C, arom.), 114.8 (d, 1 C, arom.), 125.1
aryl, H/D exchange), 5.07 (dd, J ϭ 5.9/4.4 Hz, 1 H, 2-H), 5.72 (s,
1 ϫ 0.48 H, CHNH-aryl), 5.74 (s, 1 ϫ 0.52 H, CHNH-aryl),
6.42Ϫ6.59 (m, 3 H, arom.), 7.01Ϫ7.20 (m, 10 H, arom.). Ratio 32a/
33a ϭ 48:52.
(d, 1 ϫ 0.09 C, C-4 arom.), 126.8 (d, 1 ϫ 0.91 C, C-4 arom.), 127.1
(d, C-5 arom.), 127.1 (d, C-6 arom.), 127.7 (d, 2 ϫ 0.09 C, arom.),
128.0 (d, 2 ϫ 0.91 C, arom.), 128.5 (d, 1 C, arom.), 131.2 (d, 1 ϫ
0.91 C, arom.), 131.5 (d, 1 ϫ 0.09 C, arom.), 134.9 (s, C-1 arom.),
514
Eur. J. Org. Chem. 1999, 503Ϫ517

Key Step in the Asymmetric Synthesis of 1-Aryltetrahydroisoquinolines
FULL PAPER
141.4 (s, C-2 arom.), 141.7 (s, arom.), 142.8 (s, arom.), 151.9 (s,
arom.).
0.13 g, 0.25 mmol) in methanol/H2O (9:1, 20 mL). The reaction
mixture was stirred for 3 h at room temperature, then H2O, 1 
HCl and Et2O were added and the organic layer was separated. 2
 NaOH and CH2Cl2 were added to the aqueous layer, the CH2Cl2
layer was separated, dried (MgSO4) and concentrated in vacuo.
Colourless oil, yield 55.0 mg (53%). Ratio 35/36 ϭ 92:8 (1H NMR).
N-[(αR and αS)-2-{[(2S,4S)-4-(tert-Butyldimethylsiloxymethy)-1,3-
dioxan-2-yl]methyl}benzhydryl]-4-methoxyaniline (32d/33d): Ac-
cording to General Procedure 2, 7c (0.24 g, 0.60 mmol) was treated
with 31 (0.13 g, 0.62 mmol). The reaction mixture was stirred for
2 h at Ϫ100°C and for 2 h at 0°C. FC [diameter of the column 2
cm, petroleum ether/ethyl acetate (90:10), Rf ϭ 0.62] provided a
pale yellow oil, yield 0.18 g (58%). Ϫ C32H43NO4Si (533.8): calcd.
C 72.0, H 8.12, N 2.62; found C 71.8, H 8.27, N 2.72. Ϫ MS (70
(S)-(؉)-2-{[(4R,5R)-4,5-Bis(2-methoxypropan-2-yl)-1,3-dioxolan-2-
yl]methyl}benzhydrylamine (36): As described for 35, the tosyl
group of 27d (150 mg, 0.26 mmol) was cleaved with sodium in
liquid ammonia. Colourless oil, yield 56.7 mg (52%), [α]589
ϭ
ϭ Ϫ C(CH3)3], 411 (M Ϫ
533 (Mϩ), 476 [M
ϩ15.1 (c ϭ 0.70 in CHCl3). Ϫ C25H35NO4 (413.6): calcd. C 72.6,
H 8.53, N 3.39; found C 72.6, H 8.44, N 3.46. Ϫ MS (70 eV):
m/z ϭ 397 (M Ϫ NH2). Ϫ IR (film): ν˜ ϭ 3382 cmϪ1 (NH2), 3061
(CϪH), 2974 (CϪH), 1601 (CϭC), 1140 (CϪO) cmϪ1. Ϫ 1H NMR
(CDCl3): δ ϭ 0.97 [s, 3 H, C(CH3)2], 1.03 [s, 3 H, C(CH3)2], 1.09
[s, 3 H, C(CH3)2], 1.10 [s, 3 H, C(CH3)2], 2.09Ϫ2.21 (m, 2 H, NH2,
H/D exchange), 2.96Ϫ3.01 [m, 2 H, CH2CH(OR)2], 3.17 (s, 3 H,
OCH3), 3.20 (s, 3 H, OCH3), 3.84 (d, J ϭ 3.4 Hz, 1 H, 4-H), 4.04
(d, J ϭ 3.4 Hz, 1 H, 5-H), 5.41 (dd, J ϭ 5.6/4.3 Hz, 1 H, 2-H),
5.59 (s, 1 H, CHNH2), 7.16Ϫ7.37 (m, 9 H, arom.).
eV): m/z
NHC6H4OCH3). Ϫ IR (film): ν˜ ϭ 3378 cmϪ1 (NH), 3061 (CϪH),
2954 (CϪH), 1513 (CϭC), 1141 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ
0.00 [s, 6 H, OSi(CH3)2], 0.85 [s, 9 H, OSiC(CH3)3], 1.41Ϫ1.50 (m,
1 H, 5-H eq.), 1.56Ϫ1.67 (m, 1 H, 5-H ax.), 2.84Ϫ3.03 [m, 2 H,
CH2CH(OR)2], 3.44Ϫ3.68 (m, 7 H, CH2OSiR3, aryl-OCH3, 6-H
ax., 4-H ax.), 4.02Ϫ4.07 (m, 2 H, 6-H eq., CHNHC6H4OCH3, H/
D exchange), 4.54Ϫ4.58 (m, 1 H, 2-H ax.), 5.73 (br. s, 1 ϫ 0.34 H,
CHNH-C6H4OCH3), 5.76 (br. s, 1 ϫ 0.66 H, CHNH-C6H4OCH3),
6.46 (d, J ϭ 9.0 Hz, 2 H, arom.), 6.67 (d, J ϭ 9.0 Hz, 2 H, arom.),
7.13Ϫ7.30 (m, 9 H, arom.). Ratio 32 d/33d ϭ 34:66.
(؊)-Benzyl N-[(αR)-2-{[(4R,5R)-4,5-bis(2-methoxypropan-2-yl)-1,3-
dioxolan-2-yl]methyl}-benzhydryl]carbamat (37): Benzyl chloro-
formate (79.0 mg, 0.46 mmol) was added to an ice-cold solution of
35 (0.13 g, 0.31 mmol) and NEt3 (63 mg, 0.63 mmol) in THF (15
mL). After stirring for 8 h at room temperature, H2O, 2  NaOH
and Et2O 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
(1S,3R)- and (1S,3S)-2-(4-Methylphenylsulfonyl)-1-phenyl-1,2,3,4-
tetrahydroisoquinolin-3-ol (34): According to General Procedure 2,
9 (0.21 g, 0.60 mmol) was treated with 25 (0.17 g, 0.66 mmol).
After purification by FC [diameter of the column 2 cm, petroleum
ether/ethyl acetate (90:10), Rf ϭ 0.30] 34 was obtained as pale yel-
low oil, yield 88.7 mg (39%). Ϫ C22H21NO3S (379.5): calcd. C 69.6,
H 5.58, N 3.70, S 8.45; found C 69.9, H 5.62, N 3.43, S 8.06. Ϫ
MS (70 eV): m/z ϭ 362 (M Ϫ OH). Ϫ IR (film): ν˜ ϭ 3546 cmϪ1
(OH), 3062 (CϪH), 2960 (CϪH), 1599 (CϭC), 1187 (CϪO). Ϫ 1H
NMR (CDCl3): δ ϭ 2.21 (s, 3 ϫ 0.84 H, CH3), 2.26 (s, 3 ϫ 0.16
H, CH3.), 2.28Ϫ2.37 (m, 1 ϫ 0.16 H, 4-H), 2.55 (dd, J ϭ 15.0/9.4
Hz, 1 ϫ 0.84 H, 4-H), 2.86 (dd, J ϭ 15.0/5.7 Hz, 1 ϫ 0.84 H, 4-
H), 2.95 (dd, J ϭ 15.4/2.6 Hz, 1 ϫ 0.16 H, 4-H), 3.35Ϫ3.40 (m, 1
ϫ 0.16 H, OH, H/D exchange), 3.64Ϫ3.68 (m, 1 ϫ 0.84 H, OH,
H/D exchange), 5.27Ϫ5.30 (m, 1 H, 3-H), 5.92 (s, 1 ϫ 0.84 H, 1-
H), 5.96 (s, 1 ϫ 0.16 H, 1-H), 6.93Ϫ7.43 (m, 13 H, arom.). Ϫ 13C
NMR (CDCl3): δ ϭ 21.0 (q, 1 ϫ 0.16 C, CH3), 21.4 (q, 1 ϫ 0.84
C, CH3), 34.8 (t, 1 ϫ 0.84 C, C-4), 36.3 (t, 1 ϫ 0.16 C, C-4), 60.2
(d, 1 ϫ 0.16 C, C-1), 61.4 (d, 1 ϫ 0.84 C, C-1), 77.7 (d, 1 ϫ 0.16
C, C-3), 80.0 (d, 1 ϫ 0.84 C, C-3), 126.5 (d, arom.), 126.9 (d,
arom.), 127.0 (d, arom.), 127.1 (d, arom.), 127.4 (d, arom.), 127.9
(d, arom.), 128.3 (d, arom.), 128.5 (d, arom.), 129.2 (d, arom.),
129.5 (d, arom.), 129.5 (d, arom.), 132.5 (s, arom.), 135.7 (s, arom.),
136.6 (s, arom.), 139.9 (s, arom.), 143.6 (s, arom.).
(85:15), Rf ϭ 0.22]. Ϫ Pale yellow oil, yield 0.14 g (81%), [α]546
ϭ
Ϫ14.1 (c ϭ 1.15 in CHCl3). 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 (70 eV):
m/z ϭ 397 (M Ϫ NHCO2Bn). Ϫ IR (film): ν˜ ϭ 3299 cmϪ1 (NH),
3062 (CϪH), 2972 (CϪH), 1714 (CϭO), 1454 (N-H), 1136 (CϪO).
Ϫ
1H NMR (CDCl3): δ ϭ 0.96 [s, 3 H, C(CH3)2], 1.02 [s, 3 H,
C(CH3)2], 1.09 [s, 3 H, C(CH3)2], 1.15 [s, 3 H, C(CH3)2], 2.90Ϫ3.26
[m, 8 H, CH2CH(OR)2, 2 ϫ OCH3], 4.01 (d, J ϭ 2.9 Hz, 1 H, 4-
H), 4.03 (d, J ϭ 2.9 Hz, 1 H, 5-H), 5.11Ϫ5.13 (m, 2 H,
OCH2C6H5), 5.39 (t, J ϭ 4.4 Hz, 1 H, 2-H), 6.07 (d, J ϭ 8.1 Hz,
1 H, NH, H/D exchange), 6.29 (d, J ϭ 8.1 Hz, 1 H, CHNHCO2Bn,
s after addition of D2O), 7.11Ϫ7.36 (m, 14 H, arom.).
(؉)-Benzyl N-[(αS)-2-{[(4R,5R)-4,5-Bis(2-methoxypropan-2-yl)-1,3-
dioxolan-2-yl]methyl}benzhydryl]carbamat (38): As described for 37
the diastereomeric amine 36 was acylated with benzyl chloro-
formate. Colourless oil, yield 0.147 g (85%), [α]546 ϭ ϩ20.9 (c ϭ
0.80 in CHCl3). Ϫ C33H41NO6 (547.7): calcd. C 72.4, H 7.55, N
2.56; found C 72.5, H 7.68, N 2.38. Ϫ MS (70 eV): m/z ϭ 397 (M
Ϫ NHCO2Bn). Ϫ IR (film): ν˜ ϭ 3299 cmϪ1 (NH), 3062 (CϪH),
(R)-(؊)-2-{[(4R,5R)-4,5-Bis(2-methoxypropan-2-yl)-1,3-dioxolan-2-
yl]methyl}benzhydrylamine (35): a) At Ϫ78°C, a solution of 26d
(150 mg, 0.26 mmol) in THF (4 mL) was added to Na (100 mg) in
liquid ammonia. After 45 min at Ϫ78°C, H2O (5 mL) and CH2Cl2
(20 mL) were added, the organic layer was separated, dried
(MgSO4) and concentrated in vacuo. Colourless oil, yield 73.1 mg
(68%), [α]589 ϭ Ϫ43.5 (c ϭ 2.11 in CHCl3). Ϫ C25H35NO4 (413.6):
calcd. C 72.6, H 8.53, N 3.39; found C 73.0, H 8.60, N 2.95. Ϫ MS
(70 eV): m/z ϭ 397 (M Ϫ NH2). Ϫ IR (film): ν˜ ϭ 3382 cmϪ1 (NH2),
3052 (CϪH), 2974 (CϪH), 1601 (CϭC), 1140 (CϪO). Ϫ 1H NMR
1
2972 (CϪH), 1714 (CϭO), 1454 (N-H), 1136 (CϪO). Ϫ H NMR
(CDCl3): δ ϭ 0.92 [s, 3 H, C(CH3)2], 1.02 [s, 3 H, C(CH3)2], 1.13
[s, 3 H, C(CH3)2], 1.15 [s, 3 H, C(CH3)2], 2.90Ϫ3.26 (m, 8 H,
CH2CH(OR)2, 2 ϫ OCH3), 3.75Ϫ3.81 (m, 2 H, 4-H, 5-H),
5.11Ϫ5.13 (m, 2 H, OCH2C6H5), 5.30 (t, J ϭ 4.4 Hz, 1 H, 2-H),
6.09 (d, J ϭ 8.1 Hz, 1 H, NH, H/D exchange), 6.14 (d, J ϭ 8.1
Hz, 1 H, CHNHCO2Bn, s after addition of D2O), 7.11Ϫ7.36 (m,14
H, arom.).
(CDCl3): δ ϭ 1.14 [s, 3 H, C(CH3)2], 1.22 [s, 6 H, C(CH3)2], 1.26 (R)-(؉)-2-(4-Methylphenylsulfonyl)-1-phenyl-1,2-dihydroisoquino-
[s, 3 H, C(CH3)2], 2.09Ϫ2.21 (m, 2 H, NH2, H/D exchange), line [(R)-40]: A solution of 26d (102 mg, 0.18 mmol), p-toluenesul-
3.07Ϫ3.14 [m, 2 H, CH2CH(OR)2], 3.20 (s, 3 H, OCH3), 3.26 (s, 3 fonic acid (0.19 g, 1.08 mmol) and conc. HCl (1 mL) in methanol/
H, OCH3), 3.89 (d, J ϭ 3.4 Hz, 1 H, 4-H), 4.09 (d, J ϭ 3.4 Hz, 1
H, 5-H), 5.33 (dd, J ϭ 5.6/4.3 Hz, 1 H, 2-H), 5.68 (s, 1 H, CHNH2),
H2O (3:1, 20 mL) was heated to reflux for 4 d. Then, a saturated
solution of NaHCO3 (30 mL) and CH2Cl2 (25 mL) were added,
7.20Ϫ7.42 (m, 9 H, arom.). Ϫ b) Ammonium cerium(IV) nitrate the organic layer was separated, dried (MgSO4) and concentrated
(0.35 g, 0.75 mmol) was added to a solution of 32c/33c (92.1:7.9,
Eur. J. Org. Chem. 1999, 503Ϫ517
in vacuo. The residue was separated by FC {diameter of the column
515

B. Wünsch, S. Nerdinger
FULL PAPER
2 cm, petroleum ether/ethyl acetate (85:15), Rf ϭ 0.60 [(R)-40]}.
The chiral diol 39 was isolated by elution of the column with petro-
leum ether/ethyl acetate (50:50), yield 26.4 mg (71%).
for (R)-42. Colourless oil, yield 53.4 mg (86%), [α]589 ϭ Ϫ88.9 (c ϭ
1.88 in CHCl3).
(R)-(؊)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline [(R)-43]:[7a,24]
A
(R)-40: Colourless solid (ethyl acetate/n-hexane), m.p. 80Ϫ82°C,
yield 31.0 mg (48%), [α]589 ϭ ϩ270.1 (c ϭ 1.04 in CHCl3). Ϫ
C22H19NO2S (361.5): calcd. C 73.1, H 5.30, N 3.88; found C 72.9,
H 5.77, N 3.61. Ϫ MS (CI): m/z ϭ 362 (M ϩ H). Ϫ IR (film): ν˜ ϭ
3061 cmϪ1 (CH), 2927 (CϪH), 1663 (CϭC), 1597 (CϭC), 1135
(CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 2.22 (s, 3 H, aryl-CH3), 5.97 (d,
J ϭ 7.3 Hz, 1 H, 4-H), 6.21 (s, 1 H, 1-H), 6.63 (d, J ϭ 7.3 Hz, 1
H, 3-H), 6.93Ϫ7.17 (m, 13 H, arom.). Ϫ 13C NMR (CDCl3): δ ϭ
21.4 (q, aryl-CH3), 59.9 (d, C-1), 113.9 (d, C-4), 125.4 (d, C-3),
125.8 (d, arom.), 127.3 (d, arom.), 127.6 (d, arom.), 127.7 (d,
arom.), 128.3 (d, arom.), 128.4 (d, arom.), 128.6 (d, arom.), 128.9
(d, arom.), 130.0 (d, arom.), 127.9 (d, arom.), 140.7 (s, arom.), 143.5
(s, arom.).
solution of (R)-42 (50 mg, 0.14 mmol) in THF (4 mL) was added
to Na (70 mg) in liquid ammonia at Ϫ78°C. After stirring for 45
min at Ϫ78°C, H2O (10 mL) and CH2Cl2 (20 mL) were added, the
CH2Cl2 layer was separated, dried (MgSO4) and concentrated in
vacuo. FC purification [diameter of the column 2 cm, CH2Cl2/
methanol (90:10), Rf ϭ 0.25] of the residue afforded a colourless
oil, yield 19.7 mg (68%), [α]589 ϭ Ϫ10.2 (c ϭ 0.99 in CHCl3).
(S)-(؉)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline [(S)-43]:[8a,24] As de-
scribed for (R)-43, (S)-42 was treated with Na in liquid ammonia.
Colourless oil, yield 21.7 mg (75%), [α]589 ϭ ϩ12.2 (c ϭ 0.85 in
CH2Cl2).
(S)-(؊)-2-(4-Methylphenylsulfonyl)-1-phenyl-1,2-dihydroisoquinoline
[(S)-40]: a) As described for (R)-40, the sulfonamide 27d was cy-
clized to afford (S)-40. Pale yellow oil, yield 28.7 mg (44%), [α]589 ϭ
Ϫ269.8 (c ϭ 1.04 in CHCl3). Ϫ C22H19NO2S (361.5): calcd. C 73.1,
H 5.30 N, 3.88; found C 72.8, H 5.64, N 3.52. In analogy, 39 (26.0
mg, 71%) was isolated by FC with the eluent petroleum ether/ethyl
acetate (50:50). Ϫ b) Methanesulfonyl chloride (66.3 mg, 0.58
mmol) was added to an ice-cold solution of 34 (0.11 g, 0.29 mmol)
and NEt3 (87.9 mg, 0.87 mmol) in CH2Cl2 (20 mL). The reaction
mixture was stirred for 4 h at room temperature. Then, the CH2Cl2
layer was washed with 1  HCl (20 mL), 2  NaOH (20 mL) and
H2O (20 mL), dried (MgSO4) and concentrated in vacuo. Purifi-
cation by FC provided a colourless oil, yield 0.10 g (97%), [α]589 ϭ
Ϫ135.6 (c ϭ 1.90 in CHCl3, ee ϭ 50%).
Acknowledgments
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 do-
nation of chemicals.
[1]
P. S. Charifson, S. Charifson, Drugs. Fut. 1989, 14, 1179Ϫ1185.
[2]
M. D. Rozwadowska, Heterocycles 1994, 39, 903Ϫ931.
[3]
D. L. Minor, S. D. Wyrick, P. S. Charifson, V. J. Wats, D. E.
Nichols, R. B. Mailman, J. Med. Chem. 1994, 37, 4317Ϫ4328.
[4] [4a]
N. M. Gray, B. K. Cheng, S. J. Mick, C. M. Lair, R. C.
[4b]
Contreras, J. Med. Chem. 1989, 32, 1242Ϫ1248. Ϫ
J. P.
Hodgkins, H. J. Sheriffs, D. A. Cottrell, K. Shirakawa, J. S.
Kelly, A. Kuno, M. Ohkubo, S. P. Butcher, H. J. Olverman, Eur.
J. Pharmacol. 1993, 240, 219Ϫ227.
(R)-(؉)-Benzyl
1-Phenyl-1,2-dihydroisoquinoline-2-carboxylate
[(R)-41]: A solution of 37 (100 mg, 0.18 mmol) and p-toluenesul-
fonic acid ϫ H2O (78.8 mg, 0.41 mmol) in methanol (20 mL) was
heated to reflux for 16 h. The reaction mixture was hydrolysed with
a saturated solution of NaHCO3 (20 mL), extracted with CH2Cl2
(2 ϫ 20 mL), the organic layer was dried (MgSO4) and concen-
trated in vacuo. FC purification [diameter of the column 2 cm,
petroleum ether/ethyl acetate (85:15), Rf ϭ 0.78]. Subsequent elu-
tion of the column with petroleum ether/ethyl acetate (50:50) pro-
vided the homochiral diol 39 in a yield of 28.2 mg (75%). (R)-41:
Pale yellow oil, yield 51.4 mg (82%), [α]589 ϭ ϩ83.0 (c ϭ 1.04
in CHCl3).
[5] [5a]
B. Wünsch, S. Nerdinger, Tetrahedron Lett. 1995, 36,
8003Ϫ8006. Ϫ [5b] B. Wünsch, S. Nerdinger, Eur. J. Org. Chem.
1998, 711Ϫ718.
[6]
[7]
R. P. Polniaszek, L. W. Dilard, Tetrahedron Lett. 1990, 31,
797Ϫ800.
[7a] M. Yamato, K. Hashigaki, N. Oais, S. Ishikawa, Tetrahedron
1990, 46, 5909Ϫ5920. Ϫ [7b] K. Hashigaki, K. Kan, N. Oais, Y.
Takeuchi, M. Yamato, Chem. Pharm. Bull. 1991, 39,
1126Ϫ1131.
[8]
[9]
[8a] K. Th. Wanner, H. Beer, G. Höfner, M. Ludwig, Eur. J. Org.
Chem. 1998, 2019Ϫ2029. Ϫ [8b] K. Th. Wanner, Eur. J. Pharm.
Sci. 1994, 2, 62Ϫ64.
D. Barbier, Ch. Marazano, C. Riche, B. C. Das, P. Potier, J.
Org. Chem. 1998, 63, 1767Ϫ1772.
(S)-(؊)-Benzyl 1-Phenyl-1,2-dihydroisoquinoline-2-carboxylate [(S)-
41]: The cyclization of 38 was performed as described for the prep-
[10] [10a]
K. Yamada, M. Takeda, T. Iwakuma, Tetrahedron Lett.
[10b]
1981, 22, 3869Ϫ3872. Ϫ
K. Yamada, M. Takeda, T. Iwa-
aration of (R)-41. Pale yellow oil, yield 54.5 mg (87%), [α]589
Ϫ82.7 (c ϭ 1.04 in CHCl3).
ϭ
kuma, J. Chem. Soc., Perkin Trans. 1 1983, 265Ϫ270.
B. Wünsch, Arch. Pharm. ( Weinheim, Ger.) 1990, 323,
493Ϫ499.
[11]
[12] [12a] T. P. Dang, W. Dumont, H. B. Kagan, J. C. Poulin, J. Am
(R)-(؉)-2-(4-Methylphenylsulfonyl)-1-phenyl-1,2,3,4-tetahydroiso-
quinoline [(R)-42]: (R)-40 (60.0 mg, 0.17 mmol), LiAlH4 (1.0  in
THF, 0.34 mL) and THF (20 mL) was heated to reflux for 16 h.
Then, H2O (0.5 mL) was added cautiously, the mixture was filtered,
dried (MgSO4) and concentrated in vacuo. The residue was purified
by FC [diameter of the column 2 cm, petroleum ether/ethyl acetate
[12b]
Chem. Soc. 1973, 95, 8295Ϫ8299. Ϫ
D. Seebach, B. Bas-
tani, G. Crass, H. Daum, N. P. DuPreez, V. Ehring, H.-O. Kali-
nowski, W. Langer, C. Nüssler, H. A. Oei, M. Schmidt, Helv.
Chim. Acta, 1977, 60, 301Ϫ325. Ϫ [12c] V. Schurig, B. Koeppen-
hoefer, W. Buerkle, J. Org. Chem. 1980, 45, 538Ϫ541.
A. C. Cope, A. S. Mehta, J. Am. Chem. Soc. 1964, 86,
5626Ϫ5630.
D. Seebach, E. Hungerbühler in Modern Synthetic Methods
(Ed.: R. Scheffold), vol. 2, Sauerländer-Verlag Frankfurt,
Aarau, 1980, chapter 2.
[13]
[14]
(80:20), Rf ϭ 0.23]. Colourless oil, yield 55.4 mg (90%), [α]589
ϭ
ϩ89.3 (c ϭ 1.96 in CHCl3). Ϫ C22H21NO2S (363.5): calcd. C 72.7,
H 5.82, N 3.85; found C 72.5, H 5.73, N 3.75. Ϫ MS (CI): m/z ϭ
364 (M ϩ Hϩ). Ϫ IR (film): ν˜ ϭ 3058 cmϪ1 (CϪH), 2952 (CϪH),
1586 (CϭC), 1135 (CϪO). Ϫ 1H NMR (CDCl3): δ ϭ 2.11 (s, 3 H,
aryl-CH3), 2.74Ϫ2.79 (m, 1 H, 4-H), 2.96Ϫ3.01 (m, 1 H, 4-H),
3.03Ϫ3.06 (m, 1 H, 3-H), 3.19Ϫ3.24 (m, 1 H, 3-H), 5.04 (s, 1 H,
1-H), 6.95Ϫ7.27 (m, 13 H, arom.).
[15] [15a]
T. Hino, T. Kawata, T. Kakikuwa, M. Nakagawa, Tetra-
hedron: Asymmetry 1992, 3, 227Ϫ230. Ϫ [15b] H. Chikashita, K.
Itoh, T. Yuasa, Chem. Lett. 1992, 1457Ϫ1460.
[16]
K. Nakayama, D. Rainier, Tetrahedron 1990, 46, 4165Ϫ4170.
[17] [17a] D. Seebach, E. Hungerbühler, D. Wasmuth, Angew. Chem.
1979, 12, 1025Ϫ1026; Angew. Chem. Int. Ed. Engl. 1979, 18,
[17b]
958. Ϫ
J. Pawlak, K. Nakanishi, J. Org. Chem. 1987, 52,
2896Ϫ2901. Ϫ [17c] B. Herradon, Tetrahedron: Asymmetry 1991,
(S)-(؊)-2-(4-Methylphenylsulfonyl)-1-phenyl-1,2,3,4-tetahydro-
isoquinoline [(S)-42]: (S)-40 was reduced with LiAlH4 as described
[17d]
2, 191Ϫ194. Ϫ
M. Isobe, Y. Ishikawa, D. Bai, T. Goto,
516
Eur. J. Org. Chem. 1999, 503Ϫ517

Key Step in the Asymmetric Synthesis of 1-Aryltetrahydroisoquinolines
FULL PAPER
[17e]
[22]
Tetrahedron Lett. 1985, 26, 5203Ϫ5206. Ϫ
M. Thiam, A.
T. W. Greene, P. G. M. Wuts, Protective groups in organic syn-
thesis, 2nd ed., John Wiley and Sons, New York, Chichester,
Singapore, 1991, p. 379.
Slassi, F. Chastrette, R. Amouroux, Synth. Commun. 1992, 22,
[17f]
83Ϫ95. Ϫ
hedron: Asymmetry 1995, 6, 1527Ϫ1430.
B. Wünsch, H. Diekmann, G. Höfner, Tetra-
[23]
[24]
[25]
D. R. Kronenthal, C. Y. Han, H. K. Taylor, J. Org. Chem. 1982,
47, 2765Ϫ2768.
[18] [18a]
R. Albrecht, G. Kresze, B. Mlakar, Chem. Ber. 1964, 97,
[18b]
483Ϫ489. Ϫ
F. A. Davies, J. Lamendola, U. Nadir, E. W.
Kluger, T. C. Sedergran, T. W. Panunto, R. Billmers, R. Jenkins,
I. J. Turchi, W. H. Watson, J. S. Chen, M. Kimura, J. Am. Chem.
Soc. 1980, 102, 2000Ϫ2005.
M. Ludwig, H. Beer, H. Lotter, K. Th. Wanner, Tetrahedron:
Asymmetry 1997, 8, 2693Ϫ2695.
W. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43,
2923Ϫ2925.
[19]
V. I. Minkin, Y. A. Zhdanov, E. A. Medyantzeva, Y. A. Ostrou-
mov, Tetrahedron 1967, 23, 3651Ϫ3666.
Received July 30, 1998
[O98358]
[20]
[21]
B. Wünsch, S. Nerdinger, Chem. Lett. 1998, 799Ϫ800.
I. Inoue, M. Shindo, K. Koga, T. Tomioka, Tetrahedron 1994,
50, 4429Ϫ4438.
Eur. J. Org. Chem. 1999, 503Ϫ517
517