A new general method for the asymmetric synthesis of 4-alkyl-3-aryl- 1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1021/jo982008l

A highly enantioselective method for the synthesis of 4-alkyl substituted 1,2,3,4-tetrahydroisoquinolines is reported. The key step relies on the asymmetric synthesis of α-alkylarylacetic acids by alkylation of their corresponding amides employing (S,S)-(+)-pseudoephedrine as chiral inductor. Subsequent Friedel-Crafts acylation, stereocontrolled reductive amination and Pictet-Spengler cyclization affords the title compounds in excellent yields and enantioselectivities.

Full text of DOI:10.1021/jo982008l

4610
J . Org. Chem. 1999, 64, 4610-4616
A New Gen er a l Meth od for th e Asym m etr ic Syn th esis of
4-Alk yl-3-a r yl-1,2,3,4-tetr a h yd r oisoqu in olin es
J ose L. Vicario, Dolores Bad´ıa,* Esther Dom´ınguez,* and Luisa Carrillo
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad del Pais Vasco, P.O. Box 644,
48080 Bilbao, Spain
Received October 5, 1998
A highly enantioselective method for the synthesis of 4-alkyl substituted 1,2,3,4-tetrahydroiso-
quinolines is reported. The key step relies on the asymmetric synthesis of R-alkylarylacetic acids
by alkylation of their corresponding amides employing (S,S)-(+)-pseudoephedrine as chiral inductor.
Subsequent Friedel-Crafts acylation, stereocontrolled reductive amination and Pictet-Spengler
cyclization affords the title compounds in excellent yields and enantioselectivities.
Sch em e 1
In tr od u ction
During the last few years the stereoselective synthesis
of isoquinoline alkaloids has been a field of increasing
interest in synthetic organic chemistry.1 Many methods
have been already published for highly stereoselective
syntheses of 1-substituted tetrahydroisoquinolines2 that
are very useful intermediates for the preparation of a
wide range of enantiopure alkaloids.3 However, although
chiral nonracemic 3- and/or 4-substituted tetrahydroiso-
quinoline derivatives are of considerable interest due to
their biological activity and as naturally occurring alka-
loids,4 the research toward their stereoselective synthesis
is not as extended as in the case of the 1-substituted
tetrahydroisoquinolines. Some papers have appeared for
the asymmetric synthesis of tetrahydroisoquinoline de-
rivatives when the substituent at C-4 bears an hydroxy
function,5 but only few reports can be found when the
substitution at this position is an alkyl chain,6 and none
can be found in which additionally the substitution at
the 3-position is an aryl moiety, which is found in nature
quite often, e.g. in the protoberberine alkaloids thalic-
trifoline and corydalin methyl ester.
In this context, and in connection with our studies in
the field of the asymmetric synthesis of isoquinoline
alkaloids,5,7 we have developed a suitable and general
enantioselective synthetic method to obtain 4-alkyl-3-
aryl-1,2,3,4-tetrahydroisoquinolines starting from chiral
1,2-diarylethylamine precursors (Scheme 1) that were
prepared from appropriately substituted chiral nonrace-
mic aryl benzyl ketones more commonly referred to as
deoxybenzoins. The developed protocol is interesting from
a synthetic point of view taking into account the pos-
sibility of introducing any kind of alkyl chain at the
4-position of the isoquinoline core and the high degree
of stereoselectivity in which all the chiral centers in the
molecule are generated. This can lead to the synthesis
of a wide range of naturally and unnaturally occurring
isoquinoline derivatives.
* Corresponding author: E-mail qopbaurm@lg.ehu.es.
(1) For a review, see: Rozwadowska, M. D. Heterocycles 1994, 39,
903-931.
(2) For the asymmetric synthesis of 1-substituted tetrahydroiso-
quinolines see, for example: (a) Kano, S.; Yuasa, Y.; Shibuya, S.
Heterocycles 1985, 23, 395-398. (b) Chan, W.; Lee, A. W. M.; J iang,
L. Tetrahedron Lett. 1995, 36, 715-718. (c) Polniaszek, R. P.; Kaufman,
C. R. J . Am. Chem. Soc. 1989, 111, 4859-4863. (d) Noyori, R.;
Hashiguchi, S. Acc. Chem. Res. 1997, 30, 90-102. (e) Kang, J .; Kim,
J . B.; Cho, K. H.; Cho, B. T. Tetrahedron: Asymmetry 1997, 8, 657-
660. (f) Munchoff, M. J .; Meyers, A. I. J . Org. Chem. 1996, 61, 4607-
4610. (g) Suzuki, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 1995,
36, 6709-6712. (h) Ukaji, Y.; Kenmoku, Y.; Inomata, K. Tetrahedron:
Asymmetry 1996, 7, 53-56. (i) Pyne, S. G.; Hajipour, A. R. Tetrahedron
1992, 48, 9385-9390. (j) Murahashi, S.; Sun, J .; Tsuda, T. Tetrahedron
Lett. 1993, 34, 2645-2648.
Resu lts a n d Discu ssion
(3) See, for example: (a) Dyke, S. F.; Kinsman, R. G. Kametami, T.
G.; Fukumato, K.; McDonald, E. Isoquinolines. In Heterocyclic Com-
pounds; Grethe, G., Ed.; Wiley: New York, 1981; Vol. 38, pp 1-275.
(b) Meyers, A. I. Tetrahedron 1992, 48, 2589-2612.
The synthetic pathway designed for the synthesis of
the precursor ketones 4 (Scheme 2) consists of the
asymmetric alkylation of an arylacetic acid via its (S,S)-
pseudoephedrine amide 1.8 Then, a sequence of trans-
(4) (a) Kihara, M.; Kashimoto, M.; Kobayasi, S.; Ishida, Y.; Moritoki,
H.; Taira, Z. J . Med. Chem. 1990, 33, 2283-2286. (b) Mondeshka, D.
M.; Stensland, B.; Angelova, I.; Ivanov, C. B.; Atanasova, R. Acta Chem.
Scand. 1994, 48, 689-698. (c) Aboul-Enein, H. Y.; Islam, M. R.; Bakr,
S. A. J . Liq. Chromatog. 1988, 11, 1485-1493. (d) Rinehart, K. L.;
Holt, T. G.; Frege, N. L.; Stroh, J . G.; Keifer, P. A.; Sun, F.; Li, L. H.;
Martin, D. G. J . Org. Chem. 1990, 55, 4512-4217. (e) Wright, A. E.;
Forleo, P. A.; Gumahandana, G. P.; Gunasekera, S. P.; Koehn, F. E.;
McConnell, O. J . J . Org. Chem. 1990, 55, 4508-4512. (f) Kobayashi,
J .; Kondo, J .; Shigemori, H.; Ishibashi, M.; Sasaki, T.; Mikami, Y. J .
Org. Chem. 1992, 57, 6680-6682. (g) Davidson, B. S. Tetrahedron Lett.
1992, 33, 3721-3724.
(6) (a) Philippe, N.; Levacher, V.; Dupas, G.; Duflos, J .; Que´guiner,
G.; Bourguignon, J . Tetrahedron: Asymmetry 1997, 7, 417-420. (b)
Tietzle, L. F.; Burkhardt, O. Synthesis 1994, 1331-1336. (c) Coote, S.
G.; Davies, S. G.; Mobbs, B. E. J . Chem. Soc., Perkin Trans. 1 1986,
2257-2261.
(7) Carrillo, L.; Bad´ıa, D.; Dom´ınguez, E.; Vicario, J . L.; Tellitu, I.
J . Org. Chem. 1997, 62, 6716-6721.; Carrillo, L.; Bad´ıa, D.; Dom´ıngu-
ez, E.; Ortega, F.; Tellitu, I. Tetrahedron: Asymmetry 1998, 9, 151-
155.
(5) Carrillo, L.; Bad´ıa, D.; Dom´ınguez, E.; Tellitu, I.; Vicario, J . L.
Tetrahedron: Asymmetry 1998, 9, 1809-1816 and references therein.
(8) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J . L. J . Am. Chem.
Soc. 1994, 116, 9361-9362.
10.1021/jo982008l CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/09/1999

Synthesis of Tetrahydroisoquinolines
J . Org. Chem., Vol. 64, No. 13, 1999 4611
Sch em e 2a
Sch em e 3a
a
Reagents and conditions: (i) (1) DPPA, Et3N, benzene, reflux;
(2) t-BuOH, TMSCl, CH2Cl2, rt. (ii) NaIO4, RuCl3xH2O, rt.
a
Reagents and conditions: (i) (1) SOCl2, toluene, reflux; (2) (+)-
F igu r e 1. Proposed mechanism in the asymmetric alkylation
of pseudophedrine-derived amide enolates. X denotes solvent
or (iPr)2NH molecules.
(S,S)-pseudoephedrine, Et3N, THF, -20 °C. (ii) (1) LDA, LiCl,
THF, -78 °C; (2) RI, THF, 0 °C. (iii) 4 M H2SO4/dioxane, reflux.
(iv) (1) SOCl2, toluene, reflux; (2) 1,2-dimethoxybenzene, AlCl3,
CH2Cl2, -20 °C.
an (S) stereochemistry for the newly created chiral center
in the diastereoselective alkylation of the amide 1.
In a previously proposed mechanism,14 the high dia-
stereocontrol observed in the reported alkylation was
attributed to the exclusive formation of the Z enolate (Ar
cis to the oxygen) followed by the attack of the alkyl
halide to yield a reactive open intermediate which
remains in an opened staggered conformation (Figure 1).
We believe that a more rigid structure for the reaction
intermediate should be required in order to explain the
high degree of stereoselection obtained and therefore
there must be an interaction between the lithium ion on
the enolate oxygen and the lithium alkoxide in the
pseudoephedrine moiety that avoids the rotation around
the C1-C2 axis in the pseudoephedrine moiety. This Li-
X-Li interaction should be achieved through a bridging
species present in the reaction media like the amine
generated from the amide base after the deprotonation
step, the solvent, or a chlorine anion from LiCl. When
the alkylation is performed either in the absence of LiCl
or when it is carried out in toluene as solvent, no
variation is observed in the ee of the final product (ee
>99%) and a very small decrease (ee 94-96%) is observed
when switching to n-BuLi as base and THF as solvent.
However, when both n-BuLi and toluene are employed,
the enantioselectivity of the reaction suffers a significant
lowering (ee 88%). This is indicating that the intermedi-
ate has a pronounced tendency to adopt the proposed
staggered conformation by itself, but both the amine
generated from the base after the deprotonation and the
presence of a coordinating solvent have a significant
contribution in the stereochemical outcome of the reac-
tion, and therefore, it can be proposed that these two
species are acting as a bridge between both metal ions
on the intermediate, thus affording the required high
level of rigidity for the reaction to proceed with such a
high degree of stereoselection. The presence of LiCl in
the reaction media does not exert any influence on the
diastereoselectivity, but in its absence the rate of the
formations (hydrolysis and Friedel-Crafts acylation)
leads to the obtention of the chiral nonracemic ketones
4 with the appropriate substitution at the benzylic carbon
atom.
The key step in the synthesis consists of the asym-
metric alkylation of the (S,S)-pseudoephedrine amide 1
by kinetic deprotonation with LDA/LiCl in THF at -78
°C followed by electrophilic attack of the corresponding
alkyl halide to the formed dianion. The ratio of the
diastereomeric mixture of amides 2a -d was determined
1
by H NMR spectroscopy and in all cases was found to
be >95%. The stereochemistry of the final product was
1,4-syn, which was a posteriori confirmed on the aryl-
acetic acids 3a -d . The absolute configuration of the
newly created chiral center was assigned as (S) by
synthesizing the parent 2-phenylpropionic acid starting
from the corresponding phenylacetic acid derived (+)-
(S,S)-pseudoephedrine amide and comparing the ob-
tained [R]20 value with data for commercially available
D
(+)-(S)-2-phenylpropionic acid..10 However a more rigor-
ous absolute configuration assignment prompted us to
correlate the structure of the arylacetic acids 3a -d with
other compounds of known stereochemistry. Therefore,
the acids 3a -c were subjected to a Curtius rearrange-
ment, which is known to proceed with retention of
configuration at the chiral center,11 to afford N-Boc-2-
alkylbenzylamines.12 The crude carbamates yielded
after exhaustive oxidation of the aryl ring13 the desired
N-Boc R-amino acids (Scheme 3), whose [R]20 values
D
were correlated with data found in the literature for the
same compounds, thus corroborating the assignment of
(9) Sotomayor, N.; Vicente, T.; Dom´ınguez, E.; Lete, E.; Villa, M.-J .
Tetrahedron 1994, 50, 2207-2218.
(10) The obtained 2-phenylpropionic acid showed [R]20 ) +72.3
D
(c ) 1.6 CHCl3), which was compared with the [R]20 value of
D
commercially available (S)-(+)-2-phenylpropionic acid [[R]20 ) +72°
D
(c ) 1.6 CHCl3)].
(11) Fodor, G.; Csepreghy, G. J . Chem. Soc. 1961, 3222-3224.
(12) J acobi, P. A.; Murphree, S.; Rupprecht, F.; Zheng, W. J . Org.
Chem. 1996, 61, 2413-2427.
(13) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936-3938.
(14) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J .; Gleason, J . L. J . Am. Chem. Soc. 1997, 119, 6496-6511.

4612 J . Org. Chem., Vol. 64, No. 13, 1999
Vicario et al.
Ta ble 1. Yield s a n d Ster eoselectivities Obta in ed in th e Asym m etr ic Syn th esis of th e Deoxyben zoin s 4a -d
prod.
R
yield (%)
de (%)a
prod.
yield (%)
prod.
yield (%)
ee (%)b
tR (min)c
tR (min)d
2a
2b
2c
2d
Me
Et
89
84
91
89
>95
>95
>95
>95
3a
3b
3c
3d
98
96
97
98
4a
4b
4c
4d
86
90
86
80
>99
>99
>99
>99
16.6
16.9
12.7
12.9
19.3
18.3
16.6
21.3
iPr
Bn
a
b
Determined by 1H NMR. Determined by chiral HPLC (Chiracel OD, UV detector, hexanes/isopropyl alcohol 93:7 as eluent, flow rate
1.0 mL/min.). c Retention time for the (R)-ketones 4a -d observed in the analysis of the racemate synthesized by other methods.9 Retention
time for the (S)-ketones 4a -d .
d
Sch em e 4a
Ta ble 3. Tem p er a tu r e in th e Im in e F or m a tion Step a n d
Obta in ed En a n tioselectivities for th e Red u ctive
Am in a tion of 4a
T (°C)
Yield (%)a
ee (%)b
reflux
r.t.
0
89
88
88
91
0
57
79
a
Reagents and conditions: (i) (1) BnNH2, Et3N, TiCl4; THF,
-20 °C; (2) NaBH4, THF, -20 °C.
-20
>99
a
b
Global yield including both diastereoisomers. ee of a n ti-5a
Ta ble 2. Yield s, En a n tioselectivities, a n d
Dia ster eom er ic r a tio of P r od u cts Obta in ed in th e
determined by chiral HPLC (Chiracel OD, UV detector, hexanes/
isopropyl alcohol 90:10 as eluent, flow rate 0.80 mL/min.).
Red u ctive Am in a tion of th e Deoxyben zoin s 4a -d
p r od .
R
yield (%)a anti/synb ee (%)c tR (min)d tR (min)e
5a
5b
5c
5d
Me
Et
91
82
84
85
78/22
87/13
94/6
>99
>99
>99
>99
8.9
8.6
7.7
8.5
10.7
11.0
10.3
9.9
iPr
Bn
94/6
a
b
F igu r e 2.
Global yield including both diastereoisomers. Determined by
1H NMR. c ee of the anti isomer determined by chiral HPLC
(Chiracel OD, UV detector, hexanes/isopropyl alcohol 90:10 as
triethylborohydride were not able to react with the
intermediate ketimines. The two obtained diastereoiso-
mers were separated by flash column chromatography
and it could be determined that the major product showed
the relative stereochemistry of the two chiral groups to
be anti16 from the value of the coupling constant J (H-H)
between the two benzylic protons of the 1,2-diarylethyl-
amine moiety. This could be also proved a posteriori by
the stereochemistry of the final tetrahydroisoquinoline
derivatives employing NOE difference experiments. As
the absolute configuration of the remaining chiral center
at C-2 was already known and it remains unchanged, a
(1S,2S) absolute configuration for the anti 1,2-diaryl-
ethylamines 5a -d can also be proposed.
The choice of temperature when forming the interme-
diate imine was found to have a critical effect on the ee
of the final product. At high temperatures, the imine-
enamine tautomerism takes place at a fast enough rate
to allow notable racemization in the molecule, but upon
lowering the temperature to -20 °C, no racemization
occurred and the sought 1,2-diarylethylamines were
obtained with no loss of enantiomeric purity compared
to the starting ketones (Table 3).
d
eluent, flow rate 0.80 mL/min.). Retention time for the (1R,2R)-
amines a n ti-5a -d observed in the analysis of the racemate
synthesized by other methods.9 e Retention time for the (1S,2S)-
amines a n ti-5a -d .
alkylation was dismished, that is, LiCl is acting most
probably by modifiying the aggregation state of the
enolate and thus enhancing its reactivity.15
The chiral inductor was cleanly removed by hydrolysis,
thus providing, after typical acid-base workup, the
R-alkylated arylacetic acids 3a -d in excellent yield. From
the extracts obtained from the aqueous basic layer it was
possible to recover the chiral auxiliary (S,S)-(+)-pseu-
doephedrine in 88% yield after crystallization (hexanes/
ethyl acetate 1:1) and without any racemization as the
measurements of the [R]20 value indicated. Finally, the
D
so obtained R-alkylated arylacetic acids were converted
into the corresponding acid chloride derivative and
subjected to Friedel-Crafts acylation with 1,2-dimethoxy-
benzene (veratrole) using AlCl3 as Lewis acid, yielding
the corresponding deoxybenzoins 4a -d in good yields and
with no loss of enantiomeric purity compared with the
starting amides 2a -d (Table 1).
The diastereoselectivity in the metal hydride reduction
of the CdN double bond becomes controlled by the
configuration of the chiral center R to it, as should be
expected by employing a σ*-π* dominated Felkin-Ahn
model17 (Figure 2) in which the Ar group at the R-position
to the imine double bond acts as the best σ-aceptor and
therefore it should be aligned anti to the face undergoing
Proceeding with the synthesis, the deoxybenzoins
4a -d were submitted to reductive amination (Scheme
4). Thus the ketones 4a -d were converted into N-
benzylketimine intermediates which were reduced in situ
with several reducing agents, yielding the wanted 1,2-
diarylethylamines 5 as N-benzyl derivatives in good yield
and with a variable diastereomeric ratio. Among all the
hydride reagents employed, the most efficient one was
proved to be NaBH4 (Table 2). Bulkier metal hydride
reagents such as sodium triacetoxyborohydride or lithium
(16) The anti/syn nomenclature used makes reference to the relative
positions of both benzylic protons in the 1,2-diarylethylamine skeleton
when the carbon chain is drawn in a way in which both aryl groups
are placed with the less steric repulsions between each other. Masam-
une, S.; Choy, W.; Petersen, J . S.; Sita, L. R. Angew. Chem. 1985, 97,
1-12.
(17) (a) Cherest, M.; Felkin, H. Tetrahedron Lett. 1968, 18, 2205-
2208. (b) Ahn, N. T. Top. Curr. Chem. 1980, 88, 145-162. (c) Lodge,
E. P.; Heathcock, C. H. J . Am. Chem. Soc. 1987, 109, 3353-3361.
(15) For the influence of LiCl on the reactivity of metal enolates,
see: (a) Miller, S. A.; Griffiths, S. L.; Seebach D. Helv. Chim. Acta
1993, 76, 563-571. (b) Bossler, H. G.; Seebach, D. Helv. Chim. Acta
1994, 77, 1124-1129.

Synthesis of Tetrahydroisoquinolines
J . Org. Chem., Vol. 64, No. 13, 1999 4613
by UV light or by spraying with Dragendorff’s reagent.20 Flash
column chromatography21 on silica gel was performed with
Merck Kiesegel 60 (230-400 mesh). Determination of enan-
tiomeric excesses was performed by chiral HPLC analysis of
noncrystallized samples using a Chiracel OD column with a
UV detector and the eluents and flow rates as indicated in
each case. All solvents used in reactions were dried and
purified according to standard procedures.22 n-BuLi was
titrated with diphenylacetic acid periodically prior to use. All
air- or moisture-sensitive reactions were performed under
argon. The glassware was oven dried (140 °C) overnight and
purged with argon.
Sch em e 5a
a
Reagents and conditions: (i) aq HCHO, 1 M HCl, 60 °C, 24 h.
Ta ble 4. Yield s a n d En a n tioselectivities in th e
P ictet-Sp en gler Cycliza tion of th e Am in es a n ti-5a -d
Acyla tion of (+)-(S,S)-P seu d oep h ed r in e. Syn th esis of
(+)-[1′S,2′S]-N-(2′-H yd r oxy-1′-m et h yl-2′-p h en ylet h yl)-2-
(3,4-d im et h oxyp h en yl)-N-m et h yla cet a m id e (1). SOCl2
(13.94 mL, 111.13 mmol) was carefully added over a cooled (0
°C) solution of (3,4-dimethoxyphenyl)acetic acid (15.00 g, 76.45
mmol) in dry toluene (200 mL). The reaction was refluxed for
3h, after which the volatiles were removed in vacuo. The
resulting oil was dissolved in dry THF (150 mL) and was added
dropwise within 45 min over a cooled (-10 °C) solution of (+)-
(S,S)-pseudoephedrine (12.71 g, 76.45 mmol) and triethy-
lamine (12.77 mL, 91.75 mmol) in dry THF (300 mL). The
reaction was stirred for 1 h and quenched with saturated
ammonium chloride (100 mL). The mixture was extracted with
CH2Cl2 (3 × 100 mL), the combined organic fractions were
collected, dried over Na2SO4, and filtered, and the solvent was
removed in vacuo, affording a yellowish oil which was purified
by flash column chromatography (hexanes/ethyl acetate 2:8)
to yield pure 1 as a sticky solid. An analytically pure sample
was obtained by crystallization in toluene. Yield: 87%. Mp:
p r od .
R
yield (%)
ee (%)a
tR (min)b
tR (min)c
6a
6b
6c
6d
Me
Et
83
89
86
84
>99
>99
>99
>99
8.4
8.3
7.9
8.9
10.6
10.2
10.0
11.1
iPr
Bn
a
Determined by chiral HPLC (Chiracel OD, UV detector,
hexanes/isopropyl alcohol 90:10 as eluent, flow rate 0.50 mL/min.).
Retention time for the (3R,4R)-tetrahydroisoquinolines 6a -d
observed in the analysis of the racemate synthesized by other
methods.9 c Retention time for the (3S,4S)-tetrahydroisoquinolines
6a -d .
b
attack by the nucleophile. The steric bulk of the R alkyl
chain in the 2-position of the deoxybenzoins 4a -d will
have a critical effect on the ratio of the diastereomeric
amines 5a -d obtained as the final products of the
reaction and becomes increased when going from small
alkyl groups to bigger ones (Table 2).
110-112 °C (toluene). [R]20 ) +82.0 (c ) 0.2, CH2Cl2). 1H
D
To complete the synthesis, the amines a n ti-5a -d were
subjected to a standard Pictet-Spengler cyclization
procedure18 employing aqueous formaldehyde and 1 M
HCl and stirring for 12 h at 60 °C, yielding the wanted
4-alkyl-3-aryl-1,2,3,4-tetrahydroisoquinolines 6a -d in
excellent yield, with no racemization (Scheme 5). As
shown in Table 4, the optical purity in all cases was
shown to be higher than 99% by HPLC.
In summary, we have developed a short and efficient
access to enantiomerically pure 4-alkyl-3-aryl-1,2,3,4-
tetrahydroisoquinolines starting form arylacetic acids in
good yields and excellent enantioselectivities. Our ap-
proach was based on the asymmetric alkylation of the
(+)-(S,S)-pseudoephedrine-derived amides of the corre-
sponding acids followed by hydrolysis to remove the
chiral appendage, yielding the wanted R-alkylated ary-
lacetic acid which was subjected to Friedel-Crafts acy-
lation and an stereocontrolled reductive amination step
to yield the corresponding amines that, upon Pictet-
Spengler cyclization, afforded the desired heterocycles.
NMR (CDCl3) (3:2 rotamer ratio; *denotes minor rotamer
peaks): 0.63* (d, 3H, J ) 6.6); 0.88 (d, 3H, J ) 6.6); 2.68 (s,
3H); 2.75* (s, 3H); 3.47 (s, 2H); 3.67* (s, 3H); 3.69 (s, 3H); 3.70
(s, 3H); 3.90 (m, 1H); 4.49 (bs, 1H); 4.53 (m, 1H); 6.53-6.74
(m, 3H); 7.21-7.32 (m, 5H). 13C NMR (CDCl3) (2:1 rotamer
ratio; *denotes minor rotamer peaks): 13.7, 14.7*, 26.7, 31.7*,
40.4*, 40.7, 55.3, 55.7*, 56.6*, 58.3, 74.6*, 75.3, 110.8, 111.5*,
111.6, 120.3*, 126.1, 126.3*, 126.8, 127.0*, 127.4, 127.6*,
127.7*, 127.9, 141.6, 141.8, 147.1, 147.2* 148.4*, 148.5, 172.0*,
172.5. IR (KBr): υ 3389, 1619 cm-1. MS (EI) m/z (rel int): 343
(M+, 1), 58 (100). Anal. Calcd for C20H25NO4: C, 69.93; H, 7.34;
N, 4.08. Found: C, 69.98; H, 7.28; N, 4.00.
Typ ica l P r oced u r e for th e Asym m etr ic Alk yla tion of
t h e P seu d oep h ed r in e Am id e (1). Syn t h esis of (+)-
[2S,1′S,2′S]-N-(2′-H yd r oxy-1′-m et h yl-2′-p h en ylet h yl)-2-
(3,4-d im eth oxyp h en yl)-N-m eth ylp r op ion a m id e (2a ). Over
a cooled (-78 °C) suspension of LiCl (738 mg, 17.42 mmol)
and LDA (5.90 mmol) in dry THF (20 mL) was slowly added a
cooled solution (0 °C) of the amide 1 (1.00 g, 2.90 mmol) in
dry THF (10 mL). The mixture was stirred for 1 h at -78 °C
and 15 min at 0 °C, after which a solution of MeI (0.73 mL,
11.61 mmol) in dry THF (5 mL) was added at once. The
reaction was stirred for 2-3 h at 0 °C and quenched with
saturated Na2CO3 (20 mL). The mixture was extracted with
CH2Cl2 (3 × 30 mL), the combined organic fractions were
collected, dried over Na2SO4, and filtered, and the solvent was
removed in vacuo, affording crude 2a which was purified by
flash column chromatography (hexanes/ethyl acetate 2:8).
Exp er im en ta l Section
Melting points were determined in unsealed capillary tubes
and are uncorrected. IR spectra were obtained on KBr pellets
(solids) or CHCl3 solution (oils). NMR spectra were recorded
at 20-25 °C, running at 250 MHz for 1H and 62.8 MHz for
13C in CDCl3 solution, and resonances are reported in ppm
relative to tetramethylsilane, unless otherwise stated. Assign-
ment of individual 13C resonances is supported by DEPT
Yield: 89% (oil). [R]20 ) +90.0 (c ) 0.3, CH2Cl2). 1H NMR
D
(CDCl3) (3:2 rotamer ratio; *denotes minor rotamer peaks):
0.45* (d, 3H, J ) 6.7); 1.03 (d, 3H, J ) 5.9); 1.35 (d, 3H, J )
6.5); 2.64 (s, 3H); 2.85* (s, 3H); 3.68 (q, 1H, J ) 6.5); 3.76* (s,
3H); 3.77* (s, 3H); 3.79 (s, 3H); 3.80 (s, 3H); 4.05 (m, 1H); 4.43
(m, 1H); 4.47 (bs, 1H); 6.70-6.78 (m, 3H); 7.19-7.30 (m, 5H).
13C NMR (CDCl3) (3:2 rotamer ratio; *denotes minor rotamer
peaks): 13.8, 14.4*, 20.6, 27.1, 43.0*, 43.5, 55.6, 57.7, 75.0*,
1
experiments. H-{1H} NOE experiments were carried out in
the difference mode by irradiation of all the lines of a
multiplet.19 Mass spectra were recorded under electron impact
at 70 eV. TLC was carried out with 0.2 mm thick silica gel
plates (Merck Kiesegel GF254). Visualization was accomplished
(20) Stahl, E. Thin Layer Chromatography; 2nd ed.; Springer-
Verlag: Berlin, 1969.
(18) For a recent review on Pictet-Spengler cyclization, see: Cox,
E. D.; Cook, J . M. Chem. Rev. 1995, 95, 1797-1842.
(19) Kinss, M.; Sanders, J . K. M. J . Magn. Reson. 1984, 56, 518-
523.
(21) Still, W. C.; Kann, H.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2929.
(22) Perrin, D. D.; Armarego, W. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: Berlin, 1988.

4614 J . Org. Chem., Vol. 64, No. 13, 1999
Vicario et al.
76.2, 109.8, 109.9*, 111.1, 119.0*, 119.3, 126.2, 126.6*, 127.3,
127.9, 128.1, 128.4*, 133.7, 134.8*, 141.5*, 142.0, 147.3*, 147.5,
3.81 (s, 3H); 3.83 (s, 3H); 6.76-6.86 (m, 3H); 11.0-12.0 (bs,
1H). 13C NMR (CDCl3): 17.8, 44.6, 55.5, 110.5, 110.9, 119.4,
132.0, 148.0, 148.6, 180.6. IR (CHCl3): υ 3123, 1707 cm-1. MS
(EI) m/z (rel int): 211 (M+ + 1, 5), 210 (M+, 37), 165 (100).
Anal. Calcd for C11H14O4: C, 62.83; H, 6.72. Found: C, 62.95;
H, 6.81.
148.9*, 149.0, 174.7*, 175.9. IR (CHCl3): υ 3413, 1619 cm-1
.
MS (EI) m/z (rel int): 357 (M+, 1), 58 (100). Anal. Calcd for
C21H27NO4: C, 70.55; H, 7.62; N, 3.92. Found: C, 70.53; H,
7.60; N, 3.95.
(+)-[2S,1′S,2′S]-N-(2′-Hydr oxy-1′-m eth yl-2′-ph en yleth yl)-
(+)-(S)-2-(3,4-Dim et h oxyp h en yl)b u t a n oic Acid (3b ).
Yield: 96% (oil). [R]20 ) +73.5 (c ) 0.2, CH2Cl2). 1H NMR
2-(3,4-d im et h oxyp h en yl)-N-m et h ylb u t a n a m id e
(2b ).
D
Yield: 84% (white solid). Mp: 58-60 °C (toluene). [R]20 ) +
(CDCl3): 0.90 (t, 3H, J ) 7.3); 1.81 (m, 1H); 2.05 (m, 1H); 3.39
(t, 1H, J ) 7.7); 3.82 (s, 3H); 3.84 (s, 3H); 6.77-6.86 (m, 3H);
10.9-11.2 (bs, 1H). 13C NMR (CDCl3): 11.9, 26.2, 52.8, 55.8,
110.9, 111.0, 120.2, 130.7, 148.2, 148.9, 180.5. IR (CHCl3): υ
3412, 1701 cm-1. MS (EI) m/z (rel int): 224 (M+, 51), 179 (100).
Anal. Calcd for C12H16O4: C, 64.26; H, 7.19. Found: C, 63.93;
H, 7.11.
(+)-(S)-2-(3,4-Dim eth oxyph en yl)-3-m eth ylbu tan oic Acid
(3c). Yield: 97% (oil). [R]20D ) +81.3 (c ) 0.2, CH2Cl2). 1H NMR
(CDCl3): 0.70 (d, 3H, J ) 6.6); 1.06 (d, 3H, J ) 6.4); 2.29 (m,
1H); 3.68 (d, 1H, J ) 10.7); 3.84 (s, 3H); 3.85 (s, 3H); 6.75-
6.89 (m, 3H); 9.5-10.2 (bs, 1H). 13C NMR (CDCl3): 20.0, 21.4,
31.6, 55.6, 59.5, 110.9, 111.2, 120.9, 130.2, 148.3, 148.8, 180.1.
IR (CHCl3): υ 3412, 1590 cm-1. MS (EI) m/z (rel int): 239 (M+
+ 1, 8), 238 (M+, 41), 195 (100). Anal. Calcd for C13H18O4: C,
65.51; H, 7.62. Found: C, 65.41; H, 7.69.
D
1
124.0 (c ) 0.3, CH2Cl2). H NMR (CDCl3) (2:1 rotamer ratio;
*denotes minor rotamer peaks): 0.47* (d, 3H, J ) 6.7); 0.75
(t, 3H, J ) 7.4); 1.03 (d, 3H, J ) 6.7); 1.57 (m, 1H); 1.99 (m,
1H); 2.65 (s, 3H); 2.82* (s, 3H); 3.39 (t, 1H, J ) 7.4); 3.65* (t,
1H, J ) 7.4); 3.75* (s, 3H); 3.77* (s, 3H); 3.79 (s, 3H); 3.82 (s,
3H); 4.01 (m, 1H); 4.47 (bs, 1H); 4.51 (m, 1H); 6.68-6.74 (m,
3H); 7.17-7.31 (m, 5H). 13C NMR (CDCl3) (2:1 rotamer ratio;
*denotes minor rotamer peaks): 11.9*, 13.6, 14.2, 26.9, 27.6*,
27.7, 50.1*, 50.8, 55.3, 57.2, 75.9*, 76.2, 109.9, 110.1*, 110.7,
119.6*, 119.8, 125.9, 126.3*, 126.9*, 127.6, 127.7*, 128.1, 131.7,
132.7*, 141.4*, 141.8, 147.1*, 147.4, 148.6*, 148.9, 173.8*,
175.1. IR (KBr): υ 3380, 1619 cm-1. MS (EI) m/z (rel int): 371
(M+, 1), 58 (100). Anal. Calcd for C22H29NO4: C, 71.12; H, 7.87;
N, 3.77. Found: C, 71.22; H, 7.93; N, 3.70.
(+)-[2S,1′S,2′S]-N-(2′-Hydr oxy-1′-m eth yl-2′-ph en yleth yl)-
2-(3,4-d im eth oxyp h en yl)-N,3-d im eth ylbu ta n a m id e (2c).
(+)-(S)-2-(3,4-Dim et h oxyp h en yl)-3-p h en ylp r op a n oic
Yield: 91% (oil). [R]20 ) +88.2 (c ) 0.2, CH2Cl2). 1H NMR
D
Acid (3d ). Yield: 98% (oil). [R]20 ) +74.3 (c ) 0.2, CH2Cl2).
D
1H NMR (CDCl3): 3.09 (dd, 1H, J ) 7.2, 13.7); 3.45 (dd, 1H, J
(CDCl3) (4:1 rotamer ratio; *denotes minor rotamer peaks):
0.41* (d, 3H, J ) 6.7); 0.53 (d, 3H, J ) 6.8); 0.84 (d, 3H, J )
6.3); 0.95 (d, 3H, J ) 6.9); 2.21 (m, 1H); 2.64 (s, 3H); 2.72* (s,
3H); 2.96 (d, 1H, J ) 10.0); 3.30* (d, 1H, J ) 10); 3.69* (s,
3H); 3.71 (s, 3H); 3.73 (s, 3H); 4.28 (m, 1H); 4.40 (m, 1H); 4.55
(bs, 1H); 6.60-6.74 (m, 3H); 7.09-7.27 (m, 5H). 13C NMR
(CDCl3) (4:1 rotamer ratio; *denotes minor rotamer peaks):
13.4, 14.2*, 14.8, 21.5, 21.6*, 27.0, 31.4*, 31.5, 55.1*, 55.2, 55.8,
56.5*, 57.1, 74.7*, 75.3, 110.3*, 110.4, 120.3*, 120.7, 125.8,
126.3*, 126.8, 127.4*, 127.5, 128.0, 130.5, 131.6*, 141.7, 141.8*,
147.1*, 147.4, 148.4*, 148.6, 173.5*, 174.8. IR (CHCl3): υ 3460,
1610 cm-1. MS (EI) m/z (rel int): 385 (M+,1), 58 (100). Anal.
Calcd for C23H31NO4: C, 71.65; H, 8.11; N, 3.63. Found: C,
71.58; H, 8.23; N, 3.73.
) 7.2, 13.6); 3.81 (t, 1H, J ) 7.2); 3.88 (s, 3H); 3.90 (s, 3H);
6.75-7.07 (m, 3H); 7.17-7.40 (m, 5H); 10.0-11.0 (bs, 1H). 13
C
NMR (CDCl3): 39.1, 52.7, 55.6, 110.8, 110.9, 120.1, 126.2,
128.1, 128.7, 130.3, 130.6, 148.2, 148.6, 178.7. IR (CHCl3): υ
2942, 1731 cm-1. MS (EI) m/z (rel int): 287 (M+ + 1, 4), 286
(M+, 18), 195 (100). Anal. Calcd for C17H18O4: C, 71.31; H, 6.34.
Found: C, 71.22; H, 6.39.
Absolu te Con figu r a tion Deter m in a tion of th e 2-Alk yl-
Su bstitu ted Ar yla cetic Acid s 3a -d . Syn th esis of N-Boc-
a la n in e. Over a stirred solution of the starting arylacetic acid
(50 mg, 0.24 mmol) in dried benzene was dropwise added
diphenylphosphoryl azide (DPPA) (52 µL, 0.24 mmol) and
triethylamine (33 µL, 0.24 mmol) at rt. The reaction was
refluxed for 3 h, and the volatiles were removed in vacuo. The
resulting oil was dissolved in CH2Cl2 (5 mL), t-BuOH (69 µL,
0.72 mmol) and TMSCl (91 µL, 0.72 mmol), and the resulting
mixture was stirred for 18 h at rt. The reaction was then
quenched with saturated NaHCO3 (15 mL) and extracted with
ether (3 × 10 mL), the combined organic fractions were
collected, dried over Na2SO4, filtered, and the solvent was
removed in vacuo. The resulting oil was dissolved in dry CCl4
(4 mL), acetonitrile (4 mL), and water (6 mL), to the resulting
biphasic solution were added sodium periodate (1.03 g, 4.80
mmol) and RuCl3‚xH2O (21 mg, 0.1 mmol), and the mixture
was stirred for 24 h at rt. The mixture was quenched with a
4 M NaOH solution (10 mL), the organic layer was discarded,
and the aqueous layer was washed with CH2Cl2 (3 × 10 mL),
after which it was carefully driven to pH ) 2-3 and extracted
with Et2O (3 × 10 mL). The combined ethereal fractions were
collected, dried over Na2SO4, and filtered, and the solvent was
removed in vacuo, after which crystallization in hexane yielded
(+)-[2S,1′S,2′S]-N-(2′-Hydr oxy-1′-m eth yl-2′-ph en yleth yl)-
2-(3,4-d im et h oxyp h en yl)-N-m et h yl-3-p h en ylp r op ion a -
m id e (2d ). Yield: 89% (yellowish solid). Mp: 164-166 °C
(hexanes/ethyl acetate 1:1). [R]20 ) + 168.0 (c ) 0.3, CH2-
D
Cl2). 1H NMR (CDCl3) (3:1 rotamer ratio; *denotes minor
rotamer peaks): 0.53* (d, 3H, J ) 6.7); 1.06 (d, 3H, J ) 6.7);
2.60 (s, 3H); 2.87* (s, 3H); 2.92 (m, 1H); 3.42 (m, 1H); 3.52 (t,
1H, J ) 8.5); 3.74* (s, 3H); 3.79 (s, 3H); 3.85 (s, 3H); 4.11 (m,
1H); 4.43 (bs, 1H); 4.53 (d, 1H, J ) 6.8); 6.59-6.78 (m, 3H);
7.02-7.39 (m, 10H). 13C NMR (CDCl3) (3:1 rotamer ratio;
*denotes minor rotamer peaks): 13.9, 14.4*, 27.4, 41.1, 50.8*,
51.6, 55.6*, 55.7, 57.6, 75.2*, 76.3, 110.5, 110.7*, 110.8*, 111.0,
120.0*, 120.1, 125.7*, 126.0, 126.2*, 126.6, 127.3*, 127.9,
128.0*, 128.1, 128.5, 129.1, 131.3, 131.9*, 139.8, 139.9*, 141.3*,
142.0, 147.6*, 147.8, 148.7*, 148.9, 173.7*, 174.8. IR (KBr): υ
3470, 1625 cm-1. MS (EI) m/z (rel int): 433 (M+,1), 415 (M+
18, 6), 58 (100). Anal. Calcd for C27H31NO4: C, 74.79; H, 7.21;
N, 3.23. Found: C, 74.59; H, 7.33; N, 3.30.
-
pure (S)-(-)-N-(tert-butoxycarbonyl)alanine. (Yield: 59%. [R]20
Gen er a l P r oced u r e for th e Hyd r olysis of th e P seu -
d oep h ed r in e Am id es. Syn th esis of (S)-(+)-2-(3,4-Dim eth -
oxyp h en yl)p r op a n oic Acid (3a ). A solution of the amide
(725 mg, 2.02 mmol) in dioxane (17 mL) was slowly added over
a cooled (0 °C) 4 M H2SO4 solution (17 mL). When the addition
was complete, the mixture was refluxed for 2 h. The reaction
was quenched with water, carefully basified to pH ) 12, and
washed with EtOAc (3 × 20 mL). The aqueous layer was
carefully driven to pH ) 3 and extracted with CH2Cl2 (3 × 20
mL). After drying (Na2SO4), filtration, and removal of the
solvent from the basic organic extracts, it was possible to
recover, after crystallization (hexanes/EtOAc), pure (+)-(S,S)-
pseudoephedrine in 83% yield. The collected organic acidic
fractions were dried over Na2SO4 and filtered, and the solvent
was removed in vacuo, yielding the arylacetic acid as a
D
) -24.9 (c ) 2.0, AcOH) (lit.23 [R]20 -25.5, c ) 2.0, AcOH).
D
The other N-Boc R-amino acids were synthesized in an
analogous way: (S)-(-)-2-[N-(tert-butoxycarbonyl)amino]bu-
tyric acid [Yield: 64%. [R]20 ) -6.3 (c ) 2.2, CH2Cl2) (lit.24
D
[R]20 -9.6, c ) 2.2, CH2Cl2)], and (S)-(-)-N-(tert-butoxycar-
D
bonyl)valine [Yield: 48%. [R]20 ) -5.9 (c ) 1.0, AcOH) (lit.22
D
[R]20 -7.5, c ) 1.0, AcOH)].
D
Typ ica l F r ied el-Cr a fts Acyla tion P r oced u r e: Syn -
t h esis of (+)-(S)-1,2-Bis(3,4-d im et h oxyp h en yl)-1-p r o-
p a n on e (4a ). Over a cooled (0 °C) solution of the starting acid
(235 mg, 1.11 mmol) in dry toluene (15 mL) was slowly added
(23) Keller, O.; Keller, W. E.; van Look, G.; Wersin, G. Org. Synth.
1985, 63, 160-170.
(24) Cushman, M.; J urayj, J .; Moyer, J .-D. J . Org. Chem. 1990, 55,
3186-3194.
yellowish oil. Yield: 98%. [R]20 ) +64.7 (c ) 0.2, CH2Cl2). 1H
D
NMR (CDCl3): 1.47 (d, 3H, J ) 7.1); 3.65 (q, 1H, J ) 7.1);

Synthesis of Tetrahydroisoquinolines
J . Org. Chem., Vol. 64, No. 13, 1999 4615
SOCl2 (0.17 mL, 2.53 mmol). The mixture was stirred for 15
min at 0 °C and refluxed for 4 h. The volatiles were removed
in vacuo, and the resulting red oil was dissolved in dry CH2-
Cl2 (10 mL) and was dropwise added within 40 min over a
stirred suspension of AlCl3 (358 mg, 2.46 mmol) and 1,2-
dimethoxybenzene (0.16 mL, 1.21 mmol) in dry CH2Cl2 (20 mL)
at -20 °C. The reaction was stirred at this temperature for 2
h and quenched with 4 M HCl (10 mL). The mixture was
extracted with CH2Cl2 (3 × 20 mL), the combined organic
fractions were collected, dried over Na2SO4, and filtered, and
the solvent was removed in vacuo, yielding the pure ketone 4
after flash column chromatography purification (hexanes/ethyl
acetate 1:1). An analytically pure sample was obtained by
crystallization in MeOH. Yield: 86%. Mp: 62-64 °C (MeOH).
140 °C (MeOH). [R]20 ) -38.6 (c ) 0.1, CH2Cl2). 1H NMR
D
(CDCl3): 0.92 (d, 3H, J ) 7.0); 1.72 (bs, 1H); 2.79 (m, 1H);
3.27 (d, 1H, J ) 13.7); 3.46 (d, 1H, J ) 9.6); 3.56 (d, 1H, J )
13.6); 3.82 (s, 3H); 3.89 (s, 3H); 3.91 (s, 3H); 3.92 (s, 3H); 6.67
(d, 1H, J ) 1.6); 6.77 (dd, 1H, J ) 1.8, 8.6); 6.82 (s, 1H); 6.86
(s, 1H); 6.92-6.97 (m, 2H); 7.17-7.26 (m, 5H). 13C NMR
(CDCl3): 19.1, 46.8, 50.8, 55.7, 55.8, 55.9, 67.2, 110.0, 110.4,
111.1, 119.7, 121.1, 121.2, 126.6, 128.0, 128.8, 134.8, 137.1,
140.2, 147.6, 148.0, 148.9, 149.0. IR (KBr): υ 3350 cm-1. MS
(EI) m/z (rel int): 421 (M+, 1), 256 (100). Anal. Calcd for C26H31
-
NO4: C, 74.07; H, 7.42; N, 3.32. Found: C, 74.15; H, 7.46; N,
3.41.
(+)-(1R,2S)-N-Ben zyl-1,2-b is(3,4-d im et h oxyp h en yl)-
p r op yla m in e (syn -5a ). Yield: 19% (oil). [R]20 ) +4.9 (c )
D
[R]20 ) +60.9 (c ) 0.2, CH2Cl2). 1H NMR (CDCl3): 1.44 (d,
0.1, CH2Cl2). 1H NMR (CDCl3): 1.27 (d, 3H, J ) 7.1); 1.67 (bs,
1H); 2.98 (m, 1H); 3.45 (d, 1H, J ) 13.5); 3.66 (d, 1H, J ) 13.5);
3.70 (d, 1H, J ) 5.9); 3.73 (s, 3H); 3.77 (s, 3H); 3.84 (s, 3H);
3.86 (s, 3H); 6.48 (d, 1H, J ) 1.6); 6.61 (dd, 1H, J ) 1.8, 8.6);
6.63-6.83 (m, 4H); 7.14-7.28 (m, 5H). 13C NMR (CDCl3): 16.5,
45.7, 51.4, 55.7, 55.8, 55.9, 67.5, 110.4, 110.6, 111.0, 111.7,
120.0, 120.4, 126.7, 127.9, 128.2, 134.2, 136.2, 140.6, 147.3,
147.7, 148.2, 148.4. IR (CHCl3): υ 3350 cm-1. MS (EI) m/z (rel
int): 421 (M+, 1), 256 (100). Anal. Calcd for C26H31NO4: C,
74.07; H, 7.42; N, 3.32. Found: C, 74.19; H, 7.41; N, 3.47.
(-)-(1S,2S)-N -Be n zyl-1,2-b is(3,4-d im e t h oxyp h e n yl)-
bu tyla m in e (a n ti-5b). Yield: 70% (white solid). Mp: 110-
D
3H, J ) 6.9); 3.76 (s, 3H); 3.78 (s, 3H); 3.82 (s, 3H); 3.83 (s,
3H); 4.53 (q, 1H, J ) 6.8); 6.70-6.79 (m, 4H); 7.47 (d, 1H, J )
2.0); 7.53 (dd, 1H, J ) 2.0, 8.0). 13C NMR (CDCl3): 19.6, 46.9,
55.8, 55.9, 60.0, 109.9, 110.5, 111.0, 111.5, 119.9, 123.3, 129.6,
134.5, 147.9, 148.9, 149.3, 153.0, 199.0. IR (KBr): υ 1670 cm-1
.
MS (EI) m/z (rel int): 330 (M+, 4), 165 (100). Anal. Calcd for
C
19H22O5: C, 69.07; H, 6.71. Found: C, 69.18; H, 6.63.
(+)-(S)-1,2-Bis(3,4-d im eth oxyp h en yl)-1-bu ta n on e (4b).
Yield: 90% (white solid). Mp: 76-78 °C (MeOH). [R]20
)
D
+79.3 (c ) 0.3, CH2Cl2). 1H NMR (CDCl3): 0.88 (t, 3H, J )
7.3); 1.82 (m, 1H); 2.12 (m, 1H); 3.80 (s, 3H); 3.83 (s, 3H); 3.87
(s, 6H); 4.33 (t, 1H, J ) 7.5); 6.74-6.84 (m, 4H); 7.53 (d, 1H,
J ) 1.9); 7.61 (dd, 1H, J ) 1.9, 8.4). 13C NMR (CDCl3): 12.2,
21.7, 54.4, 55.7, 55.8, 55.9, 109.8, 110.7, 110.8, 111.2, 120.5,
123.1, 130.1, 132.6, 147.9, 148.8, 149.1, 152.9, 198.7. IR
(KBr): υ 1663 cm-1. MS (EI) m/z (rel int): 344 (M+, 4), 165
(100). Anal. Calcd for C20H24O5: C, 69.75; H, 7.02. Found: C,
69.80; H, 7.10.
113 °C (MeOH). [R]20 ) -40.2 (c ) 0.3, CH2Cl2). 1H NMR
D
(CDCl3): 0.52 (t, 3H, J ) 7.3); 1.28 (m, 2H); 1.80 (bs, 1H); 2.52
(dt, 1H, J ) 4.7, 9.8); 3.24 (d, 1H, J ) 13.9); 3.49 (d, 1H, J )
9.8); 3.56 (d, 1H, J ) 13.9); 3.75 (s, 3H); 3.83 (s, 3H); 3.84 (s,
3H); 3.85 (s, 3H); 6.61 (d, 1H, J ) 1.8); 6.77 (dd, 1H, J ) 1.8,
8.2); 6.81-6.96 (m, 4H); 7.18-7.26 (m, 5H). 13C NMR
(CDCl3): 12.0, 26.0, 50.6, 54.7, 55.7, 55.8, 55.9, 66.4, 110.5,
111.1, 111.6, 119.9, 121.2, 121.3, 126.6, 128.0, 128.1, 134.7,
(+)-(S)-1,2-Bis(3,4-d im et h oxyp h en yl)-3-m et h yl-1-b u -
ta n on e (4c). Yield: 86% (white solid). [R]20D ) +75.0 (c ) 0.1,
134.8, 140.0, 147.7, 148.1, 149.0, 149.1. IR (KBr): υ 3352 cm-1
MS (EI) m/z (rel int): 435 (M+, 1), 256 (100). Anal. Calcd for
27H33NO4: C, 74.42; H, 7.64; N, 3.22. Found: C, 74.55; H,
.
1
CH2Cl2). H NMR (CDCl3): 0.75 (d, 3H, J ) 6.7); 0.98 (d, 3H,
J ) 6.4); 2.51 (m, 1H); 3.82 (s, 3H); 3.86 (s, 3H); 3.91 (s, 6H);
4.09 (d, 1H, J ) 10.2); 6.74-6.96 (m, 4H); 7.54 (d, 1H, J )
1.0); 7.67 (dd, 1H, J ) 1.0, 8.6). 13C NMR (CDCl3): 20.5, 21.9,
31.8, 56.1, 56.3, 60.2, 109.8, 110.6, 110.9, 121.2, 123.0, 124.2,
130.6, 131.5, 147.9, 148.9, 149.0, 153.0, 199.2. IR (CHCl3): υ
1667 cm-1. MS (EI) m/z (rel int): 358 (M+, 4), 165 (100). Anal.
Calcd for C20H24O5: C, 69.75; H, 7.02. Found: C, 69.62; H,
6.98.
C
7.61; N, 3.30.
(-)-(1R,2S)-N-Ben zyl-1,2-b is(3,4-d im et h oxyp h en yl)-
bu tyla m in e (syn -5b). Yield: 9% (oil). [R]20 ) -4.3 (c ) 0.1,
D
CH2Cl2). 1H NMR (CDCl3): 0.76 (t, 3H, J ) 7.2); 1.57 (m, 1H);
1.71 (bs, 1H); 1.89 (m, 1H); 2.75 (m, 1H); 3.48 (d, 1H, J ) 13.4);
3.65 (d, 1H, J ) 13.4); 3.71 (s, 3H); 3.74 (s, 3H); 3.76 (d, 1H,
J ) 5.2); 3.83 (s, 3H); 3.85 (s, 3H); 6.39 (d, 1H, J ) 1.8); 6.53
(s, 1H); 6.58 (dd, 1H, J ) 1.8, 8.2); 6.68-6.74 (m, 3H); 7.19-
7.31 (m, 5H). 13C NMR (CDCl3): 12.3, 24.2, 51.4, 54.0, 55.6,
55.7, 55.8, 66.8, 110.2, 110.4, 111.2, 112.3, 120.6, 121.2, 126.7,
128.0, 128.2, 133.9, 134.1, 140.7, 147.3, 147.6, 148.1, 148.2.
IR (CHCl3): υ 3350 cm-1. MS (EI) m/z (rel int): 435 (M+, 1),
256 (100). Anal. Calcd for C27H33NO4: C, 74.42; H, 7.64; N,
3.22. Found: C, 74.51; H, 7.68; N, 3.32.
(+)-(S)-1,2-Bis(3,4-d im et h oxyp h en yl)-3-p h en yl-1-p r o-
p a n on e (4d ). Yield: 80% (white solid). [R]20 ) + 103.5 (c )
D
1
0.5, CH2Cl2). H NMR (CDCl3): 3.01 (dd, 1H, J ) 7.2, 13.5);
3.45 (dd, 1H, J ) 7.2, 12.8); 3.71 (s, 3H); 3.72 (s, 3H); 3.74 (s,
3H); 3.76 (s, 3H); 4.68 (t, 1H, J ) 7.1); 6.74-6.78 (m, 4H);
7.00-7.09 (m, 5H); 7.47 (d, 1H, J ) 1.1); 7.57 (dd, 1H, J )
1.1, 8.7). 13C NMR (CDCl3): 39.8, 54.5, 55.3, 55.4, 55.6, 55.7,
109.4, 110.4, 110.5, 110.8, 120.1, 122.9, 125.7, 127.8, 128.8,
129.3, 131.7, 139.5, 147.6, 148.4, 148.7, 152.6, 197.4. IR
(CHCl3): υ 1666 cm-1. MS (EI) m/z (rel int): 406 (M+, 5), 165
(100). Anal. Calcd for C25H26O5: C, 73.87; H, 6.45. Found: C,
73.62; H, 6.12.
(-)-(1S,2S)-N-b en zyl-1,2-b is(3,4-d im et h oxyp h en yl)-3-
m eth ylbu tyla m in e (a n ti-5c). Yield: 77% (oil). [R]20D ) -64.3
(c ) 0.1, CH2Cl2). 1H NMR (CDCl3): 0.42 (d, 3H, J ) 7.1); 1.02
(d, 3H, J ) 7.1); 1.68 (m, 1H); 1.80 (bs, 1H); 2.48 (dd, 1H, J )
4.6, 9.7); 3.22 (d, 1H, J ) 13.9); 3.56 (d, 1H, J ) 9.8); 3.66 (d,
1H, J ) 13.9); 3.78 (s, 3H); 3.82 (s, 3H); 3.89 (s, 3H); 3.92 (s,
3H); 6.63 (d, 1H, J ) 1.7); 6.75 (dd, 1H, J ) 1.7, 8.4); 6.79-
6.91 (m, 4H); 7.12-7.29 (m, 5H). 13C NMR (CDCl3): 12.0, 14.5,
26.5, 52.1, 56.2, 55.6, 55.9, 56.1, 65.4, 110.4, 110.9, 111.7, 119.2,
120.2, 121.4, 126.9, 128.5, 128.9, 134.7, 134.9, 140.6, 146.9,
147.8, 149.2, 149.3. IR (CHCl3): υ 3354 cm-1. MS (EI) m/z (rel
int): 449 (M+, 1), 434 (M+ - 15, 3), 256 (100). Anal. Calcd for
Typ ica l Red u ctive Am in a tion P r oced u r e. Syn th esis of
th e 1,2-Dia r yleth yla m in es (a n ti-5) a n d (syn -5). To a
stirred solution of the deoxybenzoin 4a (1.65 g. 5.00 mmol),
Et3N (2.08 mL, 15.00 mmol), and benzylamine (0.60 mL, 5.50
mmol) in THF (30 mL) at -78 °C was slowly added a 1 M
CH2Cl2 solution of TiCl4 (5.00 mL, 5.00 mmol). The mixture
was stirred for 5 min at -78 °C and for 1 h at -20 °C, after
which a MeOH (20 mL) solution of NaBH4 (851 mg, 22.5 mmol)
was dropwise added within 30 min. The reaction was stirred
for 2 h at -20 °C and quenched with saturated Na2CO3 (20
mL). The mixture was extracted with CH2Cl2 (3 × 15 mL),
the combined organic fractions were collected, dried over Na2-
SO4, and filtered, and the solvent was removed in vacuo,
yielding the separated pure amines syn -5 and a n ti-5 after
flash column chromatography purification (hexanes/ethyl ac-
etate 1:1). An analytically pure sample of the a n ti-5 amines
was obtained by crystallization in MeOH.
C
28H35NO4: C, 74.80; H, 7.85; N, 3.12. Found: C, 74.83; H,
7.78; N, 3.16.
(-)-(1R,2S)-N-Ben zyl-1,2-bis(3,4-d im eth oxyp h en yl)-3-
m eth ylbu tyla m in e (syn -5c). Yield: 5% (oil). [R]20 ) -6.7
D
(c ) 0.1, CH2Cl2). 1H NMR (CDCl3): 0.63 (d, 3H, J ) 7.1); 1.32
(d, 3H, J ) 7.1); 1.73 (bs, 1H); 1.88 (m, 1H); 2.15 (m, 1H); 2.85
(m, 1H,); 3.58 (d, 1H, J ) 13.2); 3.65 (d, 1H, J ) 13.3); 3.70 (s,
3H); 3.73 (s, 3H); 3.79 (d, 1H, J ) 5.2); 3.84 (s, 3H); 3.86 (s,
3H); 6.35 (d, 1H, J ) 1.8); 6.49 (s, 1H); 6.60 (dd, 1H, J ) 1.8,
8.2); 6.68-6.77 (m, 3H); 7.22-7.44 (m, 5H). 13C NMR
(CDCl3): 12.3, 16.5, 24.6, 52.4, 55.3, 55.7, 55.8, 55.9, 65.3,
110.4, 110.5, 111.9, 112.6, 121.9, 121.6, 127.2, 128.0, 128.5,
(-)-(1S,2S)-N -Be n zyl-1,2-b is(3,4-d im e t h oxyp h e n yl)-
p r op yla m in e (a n ti-5a ). Yield: 69% (white solid). Mp: 138-

4616 J . Org. Chem., Vol. 64, No. 13, 1999
Vicario et al.
134.3, 134.8, 140.3, 147.6, 147.9, 148.5, 148.9. IR (CHCl3): υ
3353 cm-1. MS (EI) m/z (rel int): 449 (M+, 1), 434 (M+ - 15,
2), 256 (100). Anal. Calcd for C28H35NO4: C, 74.80; H, 7.85;
N, 3.12. Found: C, 74.81; H, 7.82; N, 3.19.
2), 178 (100). Anal. Calcd for C27H31NO4: C, 74.80; H, 7.21;
N, 3.23. Found: C, 74.87; H, 7.09; N, 3.30.
(+)-(3S ,4S )-N -Be n zyl-3-(3,4-d im e t h oxyp h e n yl)-6,7-
d im eth oxy-4-eth yl-1,2,3,4-tetr a h yd r oisoqu in olin e (6b).
(-)-(1S,2S)-N-b en zyl-1,2-b is(3,4-d im et h oxyp h en yl)-3-
Yield: 89% (white solid). Mp: 112-114 °C (MeOH). [R]20
)
D
p h en ylp r op yla m in e (a n ti-5d ). Yield: 79% (oil). [R]20
)
+66.8 (c ) 0.1, CH2Cl2). 1H NMR (CDCl3): 0.92 (t, 3H, J )
7.4); 1.68 (m, 1H); 1.97 (m, 1H); 2.85 (m, 1H); 3.17 (d, 1H, J )
13.2); 3.25 (d, 1H, J ) 14.9); 3.36 (d, 1H, J ) 14.9); 3.62 (d,
1H, J ) 13.2); 3.71 (s, 3H); 3.73 (d, J ) 4.5); 3.81 (s, 3H); 3.85
(s, 3H); 3.87 (s, 3H); 6.50 (s, 1H); 6.61-6.82 (m, 4H); 7.24-
7.40 (m, 5H). 13C NMR (CDCl3): 11.4, 26.8, 46.1, 51.7, 55.5,
55.6, 55.7, 55.9, 59.4, 64.2, 108.7, 110.4, 111.1, 111.4, 120.9,
126.8, 128.1, 128.6, 127.0, 130.3, 132.7, 139.3, 147.0, 147.5,
147.9, 148.5. MS (EI) m/z (rel int): 447 (M+, 5), 192 (100). Anal.
Calcd for C28H33NO4: C, 75.14; H, 7.43; N, 3.13. Found: C,
75.08; H, 7.40; N, 3.19.
D
-157.1 (c ) 0.2, CH2Cl2). 1H NMR (CDCl3): 1.84 (bs, 1H); 2.05
(dd, 1H, J ) 1.1, 11.1); 2.69 (dd, 1H, J ) 3.2, 11.1); 2.75 (dt,
1H, J ) 3.1, 10.3); 3.29 (d, 1H, J ) 13.6); 3.55 (d, 1H, J )
13.6); 3.59 (d, 1H, J ) 10.3); 3.83 (s, 3H); 3.89 (s, 3H); 3.91 (s,
3H); 3.93 (s, 3H); 6.59 (d, 1H, J ) 1.4); 6.74 (dd, 1H, J ) 1.4,
8.1); 6.78-6.95 (m, 4H); 7.22-7.32 (m, 10H). 13C NMR
(CDCl3): 39.9, 50.6, 55.1, 55.7, 55.8, 55.9, 65.3, 110.3, 110.4,
110.6, 110.8, 120.7, 121.2, 125.3, 126.6, 127.6, 127.9, 128.2,
128.6, 133.6, 134.6, 140.1, 140.3, 147.4, 148.0, 148.4, 149.0.
IR (CHCl3): υ 3348 cm-1. MS (EI) m/z (rel int): 497 (M+, 1),
91 (100). Anal. Calcd for C32H35NO4: C, 77.24; H, 7.09; N, 2.81.
Found: C, 77.22; H, 7.11; N, 2.90.
(+)-(3S ,4S )-N -Be n zyl-3-(3,4-d im e t h oxyp h e n yl)-6,7-
d im eth oxy-4-(2-m eth yleth yl)-1,2,3,4-tetr a h yd r oisoqu in o-
lin e (6c). Yield: 86% (white solid). Mp: 120-122 °C (MeOH).
(-)-(1R,2S)-N-Ben zyl-1,2-bis(3,4-d im eth oxyp h en yl)-3-
p h en ylp r op yla m in e (syn -5d ). Yield: 4% (oil). [R]20D ) -20.3
(c ) 0.1, CH2Cl2). 1H NMR (CDCl3): 1.75 (bs, 1H); 2.33 (m,
1H); 2.45 (m, 1H); 2.93 (m, 1H); 3.43 (d, 1H, J ) 13.4); 3.63
(d, 1H, J ) 13.4); 3.74 (s, 3H); 3.77 (s, 3H); 3.84 (d, 1H, J )
5.8); 3.95 (s, 3H); 4.01 (s, 3H); 6.31 (d, 1H, J ) 1.8); 6.51 (dd,
1H, J ) 1.8, 8.1); 6.79-6.88 (m, 4H); 7.12-7.29 (m, 10H). 13C
NMR (CDCl3): 34.3, 51.2, 55.3, 55.7, 55.8, 56.3, 56.5, 63.8,
110.1, 110.4, 110.6, 110.9, 120.3, 121.6, 125.1, 127.2, 127.9,
128.1, 128.2, 128.7, 133.1, 134.5, 140.1, 140.6, 147.2, 148.5,
148.9, 149.3. IR (CHCl3): υ 3348 cm-1. MS (EI) m/z (rel int):
497 (M+, 1), 91 (100). Anal. Calcd for C32H35NO4: C, 77.24; H,
7.09; N, 2.81. Found: C, 77.29; H, 7.01; N, 2.89.
[R]20 ) +77.5 (c ) 0.1, CH2Cl2). 1H NMR (CDCl3): 0.92 (d,
D
3H, J ) 7.6); 1.06 (d, 3H, J ) 7.6); 1.96 (m, 1H); 2.87 (m, 1H);
3.12 (d, 1H, J ) 13.1); 3.31 (d, 1H, J ) 14.7); 3.42 (d, 1H, J )
14.6); 3.65 (d, 1H, J ) 13.2); 3.72 (s, 3H); 3.75 (d, J ) 5.1);
3.83 (s, 3H); 3.85 (s, 3H); 3.87 (s, 3H); 6.54 (s, 1H); 6.63-6.85
(m, 4H); 7.22-7.40 (m, 5H). 13C NMR (CDCl3): 11.4, 12.1, 26.9,
45.8, 52.1, 55.5, 55.6, 55.7, 60.1, 66.3, 108.6, 110.5, 111.0, 111.6,
121.2, 126.8, 128.3, 128.7, 127.2, 130.5, 132.6, 139.2, 147.1,
147.8, 148.3, 148.6. MS (EI) m/z (rel int): 461 (M+, 6), 192
(100). Anal. Calcd for C29H35NO4: C, 75.46; H, 7.64; N, 3.03.
Found: C, 75.48; H, 7.60; N, 3.11.
(+)-(3S ,4S )-N -Be n zyl-3-(3,4-d im e t h oxyp h e n yl)-6,7-
d im eth oxy-4-ben zyl-1,2,3,4-tetr a h yd r oisoqu in olin e (6d ).
Yield: 84% (white solid). Mp: (as HCl salt) 130-136 °C
P ictet-Sp en gler Cycliza tion . Syn th esis of (+)-(3S,4S)-
N-Ben zyl-3-(3,4-dim eth oxyph en yl)-6,7-dim eth oxy-4-m eth -
yl-1,2,3,4-tetr a h yd r oisoqu in olin e (6a ). A solution of the
amine a n ti-5a (100 mg, 0.24 mmol) and formaldehyde (0.12
mL, 1.42 mmol) in 1 M HCl (10 mL) was stirred for 16 h at 60
°C. Saturated Na2CO3 (10 mL) was added and the mixture was
extracted with CH2Cl2 (3 × 15 mL). The combined organic
fractions were collected, dried over Na2SO4, and filtered, and
the solvent was removed in vacuo, yielding the pure hetero-
cycle 6a after flash column chromatography purification
(hexanes/ethyl acetate 1:1). An analytically pure sample was
obtained by crystallization in MeOH. Yield: 83%. Mp: 145-
(MeOH). [R]20 ) +85.7 (c ) 0.1, CH2Cl2). 1H NMR (CDCl3):
D
3.02-3.36 (m, 5H); 3.36 (d, 1H, J ) 14.5); 3.54 (d, 1H, J )
14.5); 3.63 (s, 3H); 3.65 (s, 3H); 3.71 (d, J ) 2.8); 3.82 (s, 3H);
3.84 (s, 3H); 6.33 (s, 1H); 6.51-6.77 (m, 4H); 7.23-7.68 (m,
10H). 13C NMR (CDCl3): 40.0, 46.4, 50.5, 55.4, 55.5, 56.7, 59.3,
63.9, 108.4, 110.3, 111.6, 111.7, 121.0, 125.8, 126.9, 128.1,
128.6, 128.8, 129.5, 130.0, 131.2, 136.5, 139.3, 140.8, 147.0,
147.1, 147.9, 148.2. MS (EI) m/z (rel int): 509 (M+, 6), 91 (100).
Anal. Calcd for C33H35NO4: C, 77.77; H, 6.92; N, 2.75. Found:
C, 77.72; H, 6.98; N, 2.77.
148 °C (MeOH). [R]20 ) + 18.3 (c ) 0.2, CH2Cl2). 1H NMR
D
Ack n ow led gm en t. The authors gratefully acknowl-
edge PETRONOR, S.A. (Muskiz, Bizkaia) for the gener-
ous gift of solvents. Financial support from the Basque
Government (a fellowship to J .L.V.) and from the
University of the Basque Country (Project UPV179.310-
EA167/95) is gratefully acknowledged.
(CDCl3): 1.30 (d, 3H, J ) 6.9); 3.10 (m, 1H); 3.17 (d, 1H, J )
13.3); 3.30 (d, 1H, J ) 6.6); 3.45 (d, 1H, J ) 14.9); 3.36 (d, 1H,
J ) 14.9); 3.72 (d, 1H, J ) 13.3); 3.80 (s, 3H); 3.82 (s, 3H);
3.87 (s, 3H); 3.88 (s, 3H); 6.47 (s, 1H); 6.75 (s, 1H); 6.82-6.90
(m, 3H); 7.23-7.38 (m, 5H). 13C NMR (CDCl3): 20.9, 39.8, 53.6,
55.7, 55.8, 55.9, 59.6, 70.9, 108.8, 110.3, 110.5, 111.0, 121.2,
126.8, 128.1, 128.6, 126.3, 131.3, 133.9, 139.4, 147.1, 147.7,
148.1, 148.9. MS (EI) m/z (rel int): 433 (M+, 4), 418 (M+ - 15,
J O982008L