Enantioselective synthesis of 2-substituted 2-phenylethylamines by lithiation - Substitution sequences: Synthetic development and mechanistic pathway

Article abstract of DOI:10.1021/jo0258251

The lithiation and asymmetric substitution of N-(2-phenylethyl)isobutyramide (2) with selected electrophiles, under the influence of (-)-sparteine, provides benzylically substituted products in 58-90% yields with enantiomeric ratios (ers) from 72:28 to 91:9. Syntheses of enantioenriched dihydroisoquinolines (S)-18 and (S)-19 and a tetrahydroisoquinoline (4S)-20 provide examples of synthetic applications. Mechanistic investigations suggest the enantiodetermining step at -78°C is a dynamic thermodynamic resolution.

Full text of DOI:10.1021/jo0258251

En a n tioselective Syn th esis of 2-Su bstitu ted 2-P h en yleth yla m in es
by Lith ia tion -Su bstitu tion Sequ en ces: Syn th etic Develop m en t
a n d Mech a n istic P a th w a y
J ason M. Laumer, Dwight D. Kim, and Peter Beak*
Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
beak@scs.uiuc.edu
Received April 16, 2002
The lithiation and asymmetric substitution of N-(2-phenylethyl)isobutyramide (2) with selected
electrophiles, under the influence of (-)-sparteine, provides benzylically substituted products in
58-90% yields with enantiomeric ratios (ers) from 72:28 to 91:9. Syntheses of enantioenriched
dihydroisoquinolines (S)-18 and (S)-19 and a tetrahydroisoquinoline (4S)-20 provide examples of
synthetic applications. Mechanistic investigations suggest the enantiodetermining step at -78 °C
is a dynamic thermodynamic resolution.
In tr od u ction
aromatic ring regioselectively but at different sites with
each base. In 1993, we reported asymmetric lithiation
substitutions of N-methyl-3-phenylpropionamide with
sec-butyllithium/(-)-sparteine ((sec-BuLi)/1) and subse-
quently of (S)-N-(1-phenylethyl)-3-phenylpropionamide
with sec-BuLi to provide enantiomerically and diastereo-
merically enriched products.4 The â-lithiations in these
reactions may be viewed as a manifestation of the
complex induced proximity effect.2,5
The 2-phenylethylamine framework is a recurrent
pharmacophore which is found in many acyclic and
heterocyclic bioactive compounds. The development of
methodology for the synthesis and modification of 2-
phenylethylamines as well as for dihydro- and tetra-
hydroisoquinoline derivatives is of continuing interest.1
We have previously reported lithiation-substitution
sequences in the presence of (-)-sparteine (1) for asym-
metric replacement of prochiral hydrogens adjacent to
nitrogen and/or in benzylic or allylic positions.2 We now
report application of this methodology to the synthesis
of 2-substituted 2-phenylethylamines with good yields
and enantiomeric ratios. We establish the enantiodeter-
mining step to be a dynamic thermodynamic resolution
in which the less stable diastereoisomeric complex is the
more reactive species.
Benzylic lithiations â to amide activating groups have
been previously reported. In 1991 Simig and Schlosser
reported that reaction of N-pivaloyl-2-phenylethylamine
with excess tert-butyllithium (t-BuLi) followed by reaction
with carbon dioxide provided 2-phenyl-3-(N-pivaloyl-
amino)propionic acid.3 The Swiss workers also found
lithiation to occur at the benzylic position with a methoxy
group on the aromatic ring using t-BuLi. However, if
n-butyllithium (n-BuLi) or a mixture of n-BuLi and
potassium tert-butoxide was used as the base, lithiation
was directed adjacent to the methoxy group of the
Resu lts a n d Discu ssion
Asymmetric lithiation-substitution sequences of N-(2-
phenylethyl)isobutyramide (2) have been investigated as
prototypical for the 2-phenylethylamine framework. The
amide 2 was selected because of structural analogy to
earlier cases for directed asymmetric â-lithiations and
for its amenability for further transformations.
(1) Urban, J . J .; Cronin, C. W.; Roberts, R. R.; Famini, G. R. J . Am.
Chem. Soc. 1997, 119, 12292 and references therein. Shamma, M. The
Isoquinoline Alkaloids, Chemistry and Pharmacology; Academic
Press: New York, 1972.
(2) Weisenberger, G. A.; Faibish, N. C.; Pippel, D. J .; Beak, P. J .
Am. Chem. Soc. 1999, 121, 9522. Beak, P.; Anderson, D. R.; Curtis,
M. D.; Laumer, J . M.; Pippel, D. J .; Weisenburger, G. A. Acc. Chem.
Res. 2000, 33, 715. Beak, P.; Basu, A.; Gallagher, D. J .; Park, Y. S.;
Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552.
(4) (a) Beak, P.; Du, H. J . Am. Chem. Soc. 1993, 115, 2516. Lutz, G.
P.; Du, H.; Gallagher, D. J .; Beak, P. J . Org. Chem. 1996, 61, 4542. (b)
Pippel, D. J .; Curtis, M. D.; Du, H.; Beak, P. J . Org. Chem. 1998, 63,
2.
(3) Simig, G.; Schlosser, M. Tetrahedron Lett. 1991, 32, 1963.
Schlosser, M.; Simig, G. Tetrahedron Lett. 1991, 32, 1965.
(5) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356.
10.1021/jo0258251 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/29/2002
J . Org. Chem. 2002, 67, 6797-6804
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Laumer et al.
TABLE 1. Yield s a n d En a n tiom er ic Ra tios of P r od u cts 4-10
SCHEME 1
Lith ia tion -Su bstitu tion . Treatment of N-(2-phenyl-
ethyl)isobutyramide (2) in 3:1 MTBE/THF with 2.2 equiv
of sec-BuLi/1 at -78 °C for 1 h forms the dilithiated
species 3‚1.6 Reaction of this complex with selected
electrophiles followed by quenching with methanol at
-78 °C yields the substituted products in moderate to
good yields with enantiomeric ratios (ers) of 72:28-91:9,
as shown in Table 1.
The absolute configuration of (2S)-10 and the relation-
ship of the stereochemical course of reaction of 3‚1 with
alkyl halides and with carbonyl electrophiles were ad-
dressed by the conversion of 10 to 6 (Scheme 2). Com-
parison of the CSP-HPLC trace of 6 obtained from
reaction of 3‚1 with benzyl bromide and reaction of 3‚1
with benzaldehyde followed by deoxygenation shows
identity.
Reactions of chlorotrimethylsilane and chlorotributyl-
stannane with 3‚1 provide the benzylic substituted
products (S)-4 and (S)-5 in 90% and 86% yields with ers
of 91:9 and 88:12, respectively. Reactions of benzyl
bromide, allyl bromide and iodoethane afford products
(S)-6, (S)-7, and (S)-8 in slightly lower yields of 68-82%
and with similar enantiomeric ratios of 83:17 to 91:9.
Reaction of the ketone electrophile cyclohexanone with
3‚1 affords alcohol (S)-9 in 58% yield with an er of 72:
28. With benzaldehyde as the electrophile, the alcohol
(2S)-10 is obtained in 70% yield with a 79:21 dr and a
78:22 er for the major diastereomer.
The absolute configuration of (S)-8 was determined by
hydrolysis to the primary amine and comparison of the
optical rotation to (S)-13 with a value of [R]D ) +7.3, to
a literature value of [R]D ) +10 as shown in Scheme 1.7
Formation of the N-Boc amide 11, followed by hydrolysis
of the substituted amide affords 12. Deprotection of the
Boc group with trifluoroacetic acid (TFA) provides the
primary amine (S)-13. The absolute configurations for
(S)-4, (S)-5, (S)-6, and (S)-7 in Table 1 are assigned to
be the same by analogy.
The assignment of absolute configuration to (2S)-10
demonstrates that C-C bond formation affords products
with the same sense of configuration at the newly formed
stereogenic center for both alkyl halides and carbonyl
compounds. The assignment of the absolute configuration
to (S)-9 is provisional and made by analogy to the
reaction with benzaldehyde. Our working hypothesis is
that fast reacting electrophiles or electrophiles which do
not have the ability to coordinate to the lithiated species
react with inversion of configuration, and that slow
reacting electrophiles which can coordinate to the lithi-
ated species react with retention of configuration. The
present results can be rationalized if benzaldehyde is
considered to react with 3‚1 rapidly with inversion of
configuration at the anionic center. However, the lower
enantioselectivity for the carbonyl electrophiles may be
attributed to a competitive pathway involving coordina-
tion of the carbonyl oxygen to the lithiated species and
reaction with retention of configuration.
2-P h en yleth yla m in e Der iva tives. The asymmetric
lithiation-substitution of N-(2-(3-methoxyphenyl)ethyl)-
isobutyramide (14) illustrates the versatility of this
methodology for ring substituted 2-phenylethylamine
derivatives.
Treatment of 14 with 2.2 equiv of sec-BuLi/1 in a 3:1
MTBE/THF solvent mixture at -78 °C for 1 h followed
(6) The absolute configuration of 3‚1 is provisional and based on
the assumption of reaction with electrophiles with inversion of con-
figuration as is observed with related systems.2
(7) Pettersson, K. Ark. Kemi 1957, 10, 297.
6798 J . Org. Chem., Vol. 67, No. 19, 2002

Synthesis of 2-Substituted 2-Phenylethylamines
SCHEME 2
SCHEME 3
SCHEME 4
by reaction with benzyl bromide at -78 °C for 1 h
provides the benzylated product (S)-15 in 86% yield with
an er of 89:11. The absolute configuration of (S)-15 is
assigned by analogy to (S)-6.
A variation of the hydrolysis procedure used in the
synthesis of (S)-13 is illustrated by the synthesis of the
easily isolable hydrochloride salt (S)-16 from (S)-15
(Scheme 3). Activation of the amide with BocOBoc, basic
hydrolysis, and removal of the Boc group is carried out
with an aqueous workup after each step. The overall yield
from (S)-15 to (S)-16 is 75%.
The amide (S)-15 and the benzamide (S)-17, which can
be obtained in 97% yield from reaction of (S)-16 with
benzoyl chloride, have been used to prepare isoquinoline
derivatives. Cyclization of (S)-15 with phosphorus penta-
chloride affords (4S)-4-benzyl-6-methoxy-1-isopropyl-3,4-
dihydroisoquinoline ((S)-18) in 92% yield (Scheme 4).
Cyclization of the corresponding benzamide (S)-17 is
achieved using phosphorus pentachloride, providing (4S)-
4-benzyl-6-methoxy-1-phenyl-3,4-dihydroisoquinoline ((S)-
19) in 96% yield.
The dihydroisoquinoline (S)-19 has been reduced with
sodium borohydride to give (4S)-4-benzyl-6-methoxy-1-
phenyl-1,2,3,4-tetrahydroisoquinoline ((4S)-20) in 81%
yield with a 95:5 dr, as shown in Scheme 4. However,
the absolute configuration at C-1 remains unassigned.8
Rea ction P a th w a y. The two limiting pathways for
asymmetric replacement of a prochiral hydrogen in a
lithiation-substitution sequence are: asymmetric depro-
tonation in which one of the prochiral hydrogens is
selectively removed to give a configurationally stable
organolithium anion which reacts stereoselectively with
electrophiles, or asymmetric substitution in which the
enantiomeric ratio is established in a step after the initial
deprotonation.2
To differentiate between these two pathways for the
present case, the racemic lithiated intermediate was
generated through tin-lithium exchange of rac-5 and
allowed to react with an electrophile in the presence of
(8) The absolute configuration of 20 could not be assigned by analogy
to a similar compound reported by J ullian, V.; Quirion, J .-C.; Husson,
H.-P. Eur. J . Org. Chem. 2000, 1319, nor did NOE NMR experiments
provide elucidation of the absolute configuration.
J . Org. Chem, Vol. 67, No. 19, 2002 6799

Laumer et al.
SCHEME 5
Benzyl bromide has also been tested as an electrophile
in the “poor man’s Hoffmann test” with 3‚1. The results
shown in Table 3 for entries 1 through 4 show there is
no difference in the products’ enantiomeric ratios with
excess and limited amounts of the electrophile. This is
consistent with a dynamic thermodynamic resolution in
which the energies of activation for the reactions of each
diastereomer are indistinguishable.
However, another possibility is that there are higher
barriers for reaction of the diastereomeric intermediates
with benzyl bromide than with chlorotrimethylsilane. In
effect this would allow a change in the reaction pathway
from a dynamic thermodynamic resolution with chloro-
trimethylsilane to a dynamic kinetic resolution with
benzyl bromide.2 To evaluate this issue, a competitive
reaction was carried out in which 3‚1 was cooled to -100
°C and allowed to react with a mixture of 2 equiv of
benzyl bromide and 2 equiv of chlorotrimethylsilane. The
products were (S)-6 in 50% yield with a 96:4 er and (S)-4
in 13% yield with an 88:13 er.10 This product ratio
establishes that the activation barrier for the reaction
with benzyl bromide is lower than for the reaction with
chlorotrimethylsilane. The reaction pathway with benzyl
bromide therefore is assigned as a dynamic thermody-
namic resolution with indistinguishable barriers for
reaction of each diastereomeric complex.
(-)-sparteine to determine if the product is enantiomeri-
cally enriched. Racemic N-(2-tributylstannyl-2-phenyl-
ethyl)isobutyramide (5) was synthesized in 76% yield
using chlorotributylstannane as the electrophile after
lithiation of 2 with sec-BuLi/TMEDA. Transmetalation
of rac-5 using 2.2 equiv of sec-BuLi/1 followed by reaction
with chlorotrimethylsilane affords (S)-4 with an er of 89:
11. Unreacted 5 was isolated, analyzed by CSP-HPLC,
and determined to be racemic, ruling out a kinetic
resolution in the initial tin-lithium exchange. The fact
that asymmetric induction arises from a racemic starting
material in the presence of the chiral ligand shows that
the enantiodetermining step is an asymmetric substitu-
tion (Scheme 5).
Lithiation-substitution reactions of 2 also have been
carried out at -100 °C. Two separate sets of experiments
were performed, one using chlorotrimethylsilane as the
electrophile and the second using benzyl bromide as the
electrophile. After lithiation in the presence of 1, the
lithiated intermediates were then allowed to react with
either 1.1 or 0.1 equiv of electrophile.
The results with benzyl bromide are consistent with
the above analysis. However, the results with chlorotri-
methylsilane as the electrophile shown in Table 2 as
entry 6 suggested a more complex situation.
The ers of (S)-4 from lithiation at -78 °C with reaction
at -78 °C and at -100 °C are comparable (entries 1-4,
Table 2). Both of these sets of sequences are consistent
with a dynamic thermodynamic resolution with the less
populated diastereomeric intermediate having a lower
barrier to reaction with chlorotrimethylsilane. When the
entire sequence is carried out at -100 °C using an excess
amount of chlorotrimethylsilane (entry 5), the product
is obtained with an er of 52:48. This result could be taken
to suggest that the initial deprotonation is unselective
and that the diastereomeric lithiated intermediates do
not equilibrate at -100 °C. If the diastereomeric inter-
mediates formed by lithiation at -78 °C are the same as
those obtained on lithiation at -100 °C, addition of a
deficient amount of chlorotrimethylsilane to the -100 °C
lithiation should provide more (R)-4 than is observed in
entry 6.
For reaction pathways of asymmetric substitution,
there are two limiting modes of stereoinduction:
a
dynamic thermodynamic resolution in which the diaster-
eomeric lithiated complexes may equilibrate on the time
scale of metalation, but not on the time scale of reaction
with the electrophile, or a dynamic kinetic resolution in
which the diastereomeric lithiated complexes equilibrate
rapidly relative to the rate of reaction with electrophile.2
The “poor man’s Hoffmann test” using different amounts
of the electrophile may be used to differentiate between
a dynamic thermodynamic resolution and a dynamic
kinetic resolution.2 In the present case reaction of 3‚1
with 1.1 equiv of chlorotrimethylsilane and 0.1 equiv of
chlorotrimethylsilane afforded (S)-4 with the ers shown
in Table 2.
In the case of a dynamic kinetic resolution, the enan-
tiomeric ratio depends solely on ∆∆Gq and would be
independent of the amount of electrophile. However, for
a dynamic thermodynamic resolution if the two diaster-
eomeric lithiated complexes have different energy bar-
riers for reaction with an electrophile, the amount of the
electrophile can affect the degree of enantioenrichment
in the product. Entries 1 and 2 in Table 2 show (S)-4 is
obtained with different enantiomeric ratios with different
amounts of chlorotrimethylsilane, suggesting the mode
of enantioinduction for the present reaction is a dynamic
thermodynamic resolution.9 However, the difference is
close to our conservative experimental error for er
determinations of (3%. Entries 3 and 4 provide further
data in support of this reaction pathway, albeit for
reactions at -100 °C. The decrease in enantiomeric ratio
of (S)-4 with the limited amount of the electrophile shows
that the more stable diastereomeric complex has a higher
energy barrier to reaction with chlorotrimethylsilane.
This result is not consistent with a straightforward
dynamic thermodynamic resolution in which the same
complexes are formed by cooling from -78 °C to -100
°C, and by carrying out the whole sequence at -100 °C.11
The results in entry 5 suggest that unequilibrated
(10) The increased er of (S)-6 is noted and of interest.
(11) For an investigation which shows more than one initial pre-
lithiation complex can be present in a lithiation, see: Pippel, D. J .;
Weisenburger, G. A.; Fabish, N. A.; Beak, P. J . Am. Chem. Soc. 2001,
123, 4919.
(9) To determine whether a halide effect could influence the er of
the product, the reaction was run with 0.1 equiv of chlorotrimethyl-
silane and 1.0 equiv of LiCl. The results were unchanged.
6800 J . Org. Chem., Vol. 67, No. 19, 2002

Synthesis of 2-Substituted 2-Phenylethylamines
TABLE 2. Effect of Lith ia tion a n d Rea ction Tem p er a tu r es on th e En a n tioselectivity of Lith ia tion -Su bstitu tion of 2
Usin g Ch lor otr im eth ylsila n e a s th e Electr op h ile
TABLE 3. Effect of Lith ia tion a n d Rea ction Tem p er a tu r e on th e En a n tioselectivity of Lith ia tion -Su bstitu tion of 2
Usin g Ben zyl Br om id e a s th e Electr op h ile
diastereomeric complexes are present and provide, on
reaction with the electrophile, essentially racemic prod-
ucts. If these complexes were the same species that are
present for entries 3 and 4, reaction with 0.1 equiv of
the chlorotrimethylsilane should provide products en-
riched in the R isomer rather than the almost racemic
products observed.
rationalizes the inconsistency of the “poor man’s Hoff-
mann test” of entry 6 of Table 2. Whether this is an
isolated case or a general phenomenon will require an
investigation of the structures of these complexes and the
relative rates of lithiation, epimerization, and complex-
ation.2,4,11
In summary, asymmetric lithiation-substitution se-
quences of N-(2-phenylethyl)isobutyramide can be achieved
at the benzylic position in the presence of (-)-sparteine
to provide 2-substituted 2-phenylethylamines with good
enantioenrichments in good yields. The reaction profile
is consistent with a dynamic thermodynamic resolution,
albeit with the formation of different species under
different lithiation conditions.
In an effort to clarify the source of this discrepancy,
we have carried out an evaluation of the configurational
stability of the epimeric center by generation of complexes
with known configurations by tin-lithium exchanges.
Tin-lithium exchange of (S)-5 which has an er of 88:12
by sec-BuLi/1 was carried out at -78 °C and -100 °C in
3:1 MTBE/THF prior to cooling to -100 °C. After lithia-
tion at -78 °C and cooling to -100 °C, reaction with
chlorotrimethylsilane at -100 °C provided (S)-4 with a
reduced er of 77:23. When the entire sequence was
carried out at -100 °C, (S)-4 was obtained with an even
more reduced er of 63:37. In the later case recovered (S)-5
had an er of 88:12. These results show that in the tin-
lithium exchange epimerization does occur, and there is
more epimerization at the carbanionic center at lower
temperature. The pathway for the formation of the
organolithium from Sn-Li/1 exchange must be subtly
different from the deprotonative pathway of 2 to form
3‚1. A rational possibility is that the initially formed
organolithium from the tin-lithium exchange is rela-
tively free of the ligand, and there is insufficient thermal
energy to fully form the same complexes as from the
deprotonative pathway. This indication of differences
Exp er im en ta l Section
All lithiation-substitution reactions were performed in
oven-dried or flame-dried glassware under a positive pressure
of nitrogen with freshly distilled solvents. Tetrahydrofuran
(THF) and methyl tert-butyl ether (MTBE) were distilled from
sodium and benzophenone. Dichloromethane was distilled
from CaH2. (-)-Sparteine (1) was obtained from a commercial
source and distilled under reduced pressure over CaH2 and
stored under nitrogen. Commercial sec-BuLi (solution in
cyclohexane) and n-BuLi (solution in hexane) were titrated
prior to use against N-pivaloyl-o-toluidine according to litera-
ture procedure.12 All other commercial reagents were used
without further purification unless otherwise indicated.
(12) Suffert, J . J . Org. Chem. 1989, 54, 509.
J . Org. Chem, Vol. 67, No. 19, 2002 6801

Laumer et al.
The purity of compounds reported herein is either estab-
lished by CHN combustion analysis or high-resolution mass
spectrometry (HRMS) supported by a 13C NMR spectrum. In
cases where microanalytical data was not available, the purity
of compounds is estimated to be >95% based on 1H and 13C
NMR spectroscopic data.
40.80 (CH2), 124.10 (Ar-H), 126.28 (Ar-H), 128.56 (Ar-H),
143.33 (Ar), 176.79 (CdO). Anal. Calcd %C: 60.01, %H: 9.02,
%N: 2.92. Found %C: 60.08, %H: 9.37, %N: 3.09. The enan-
tiomeric ratio of (S)-5 was determined to be 88:12 by CSP-
HPLC on a Whelk-O column with 1.5% IPA/hexane mobile
phase; retention times for the minor and major enantiomers
were 21.9 and 24.1 min, respectively.
Product enantiomeric purity was determined by comparison
of chiral stationary phase (CSP) HPLC traces of both racemic
and enantioenriched compounds. Analytical CSP-HPLC was
carried out using a Rainin HPLX pump system on either
Whelk-O (Regis Chemical Co., 25 cm × 4.6 mm i.d.) or
Chiralpak-AD (Chiral Technologies Inc. 25 cm × 4.6 mm i.d.)
(S)-N-(2,3-Dip h en ylp r op yl)isobu tyr a m id e (6). The gen-
eral lithiation procedure was followed using benzyl bromide
as the electrophile to provide crude (S)-6. The crude product
was flushed through a plug of silica with EtOAc and purified
using HPLC (50% EtOAc/hexane) to give (S)-6 (115 mg, 82%)
as a viscous oil. 1H NMR (CDCl3, 400 MHz): δ 0.98 (d, J )
6.8 Hz, 3H, CHCH3), 1.00 (d, J ) 6.8 Hz, 3H, CHCH3), 2.14
(sept, J ) 7.0 Hz, 1H, CH(CH3)2), 2.93 (m, 1H, PhCH2), 3.12
(m, 1H, PhCHCH2N), 3.33 (ddd, J ) 13.4, 9.2, 5.1 Hz, 1H,
PhCHCHHN), 3.71 (ddd, J ) 13.2, 6.5, 5.7 Hz, 1H, PhCH-
CHHN), 5.26 (bs, 1H, NH), 7.05-7.31 (m, 10H, Ar-H). 13C
NMR (CDCl3, 100 MHz): δ 19.28 (CH3), 19.40 (CH3), 35.37
(CH), 40.65 (CH2), 43.99 (CH2), 47.29 (CH), 125.95 (Ar-H),
126.70 (Ar-H), 127.72 (Ar-H), 128.11 (Ar-H), 128.46 (Ar-
H), 128.87 (Ar-H), 139.39 (Ar), 141.97 (Ar), 176.71 (CdO).
Anal. Calcd %C: 81.10, %H: 8.24, %N: 4.98. Found %C:
80.99, %H: 8.18, %N: 5.08. The enantiomeric ratio of (S)-6
was determined to be 83:17 by CSP-HPLC on a Whelk-O
column with 10% IPA/hexane mobile phase; retention times
for the minor and major enantiomers were 16.3 and 18.7 min,
respectively.
chiral columns. The obtained ers are given
a degree of
uncertainty of (1%. Mixtures of 2-propanol and hexane were
used as the mobile phase.
Optical rotations were obtained on a J ASCO Model DIP-
370 Digital Polarimeter (J ASCO Inc., Easton, MD, 21601) in
a cylindrical glass cell (3.5 mm i.d. × 50 mm) with quartz
windows.
Gen er a l Lith ia tion -Su bstitu tion P r oced u r e for 2. To
a flame-dried flask, purged with N2 and charged with 2 (0.095
g, 0.50 mmol), were added MTBE (4.5 mL or 6 mL) and THF
(1.5 mL or 2 mL), maintaining the concentration of 2 between
0.06 and 0.08 M, followed by (-)-sparteine (1) (0.25 mL, 1.09
mmol). The solution was cooled to -78 °C in a dry ice-acetone
bath, and sec-BuLi (0.80 mL, 1.36 M in cyclohexane, 1.09
mmol) was added dropwise. The dark yellow reaction mixture
was stirred at -78 °C for 1 h before the electrophile (1.1-1.2
equiv) was added. The reaction was quenched with 2 mL of
CH3OH after stirring at -78 °C for an additional 1 h. Stirring
was continued as the solution was allowed to warm to room
temperature. The solution was poured into 5% H3PO4 (10 mL),
and 10 mL of ether was added. The layers were separated,
and the aqueous layer was extracted with ether (3 × 10 mL).
The combined ether layers were dried over MgSO4, and the
solvent was removed in vacuo to afford the crude product.
Racemic compounds were prepared using a similar procedure
with TMEDA as the ligand.
(S)-N-(2-Tr im eth ylsilyl-2-p h en yleth yl)isobu tyr a m id e
(4). The general lithiation procedure was followed using 1.1
equiv of chlorotrimethylsilane (70.0 µL, 0.55 mmol) as the
electrophile to provide crude (S)-4. The crude product was
purified using flash chromatography (40% EtOAc/hexane) to
give (S)-4 (131 mg, 90%) as a white solid, mp 72-73 °C. 1H
NMR (CDCl3, 400 MHz): δ -0.02 (s, 9H, Si(CH3)3), 0.97 (d, J
) 7.8 Hz, 3H, CHCH3), 0.99 (d, J ) 7.0 Hz, 3H, CHCH3), 2.13
(sept, J ) 6.9 Hz, 1H, CH(CH3)2), 2.34 (dd, J ) 12.6, 4.2 Hz,
1H, PhCHCH2N), 3.57 (td, J ) 13.4, 4.0 Hz, 1H, PhCHCHHN),
3.85 (ddd, J ) 14.0, 6.3, 4.3 Hz, 1H, PhCHCHHN), 5.25 (bs,
1H, NH), 7.02-7.29 (m, 5H, Ar-H). 13C NMR (CDCl3, 100
MHz): δ -3.09 (CH3), 19.28 (CH3), 19.36 (CH3), 35.34 (CH),
37.34 (CH), 39.15 (CH2), 125.04 (Ar-H), 127.56 (Ar-H), 128.33
(Ar-H), 140.49 (Ar), 176.85 (CdO). Anal. Calcd %C: 68.39,
%H: 9.56, %N: 5.32. Found %C: 68.35, %H: 9.38, %N: 5.52.
The enantiomeric ratio of (S)-4 was determined to be 91:9 by
CSP-HPLC on a Whelk-O column with 5% IPA/hexane mobile
phase; retention times for the minor and major enantiomers
were 14.1 and 16.2 min, respectively.
(S)-N-(2-P h en yl-4-p en ten yl)isobu tyr a m id e (7). The gen-
eral lithiation procedure was followed using allyl bromide as
the electrophile to provide crude (S)-7. The crude product was
purified using flash chromatography (50% EtOAc/hexane) to
1
give (S)-7 (78 mg, 68%) as a viscous oil. H NMR (CDCl3, 400
MHz): δ 1.02 (d, J ) 6.8 Hz, 3H, CHCH3), 1.04 (d, J ) 6.8 Hz,
3H, CHCH3), 2.19 (sept, J ) 6.8 Hz, 1H, CH(CH3)2), 2.40 (m,
2H, CH2CHdCH2), 2.88 (quint, J ) 7.4 Hz, 1H, PhCHCH2N),
3.20 (ddd, J ) 13.4, 9.0, 4.6 Hz, 1H, PhCHCHHN), 3.74 (ddd,
J ) 13.6, 7.1, 5.9 Hz, 1H, PhCHCHHN), 4.97 (m, 2H, CH2-
CHdCH2), 5.32 (bs, 1H, NH), 5.68 (m, 1H, CH2CHdCH2),
7.16-7.34 (m, 5H, Ar-H). 13C NMR (CDCl3, 100 MHz): δ 19.42
(CH3), 19.56 (CH3), 35.54 (CH), 38.24 (CH2), 44.15 (CH2), 45.37
(CH), 116.58 (CH2), 126.78 (Ar-H), 127.75 (Ar-H), 128.61
(Ar-H), 135.83 (CH), 142.16 (Ar), 176.75 (CdO). HRMS (EI)
C
15H21NO: Calcd 231.1623 Found 231.1623 The enantiomeric
ratio of (S)-7 was determined to be 91:9 by CSP-HPLC on a
Chiralpak-AD column with 5% IPA/hexane mobile phase;
retention times for the major and minor enantiomers were 11.3
and 18.3 min, respectively.
(S)-N-(2-P h en ylbu tyl)isobu tyr a m id e (8). The general
lithiation procedure was followed using ethyl iodide as the
electrophile to provide crude (S)-8. The crude product was
purified using prep-HPLC (45% EtOAc/hexane) to give (S)-8
1
(61 mg, 73%) as a viscous oil. H NMR (CDCl3, 400 MHz): δ
0.80 (t, J ) 7.3 Hz, 3H, CH2CH3), 1.00 (d, J ) 7.3 Hz, 3H,
CHCH3), 1.02 (d, J ) 7.1 Hz, 3H, CHCH3), 1.58 (m, 1H,
CHHCH3), 1.70 (m, 1H, CHHCH3), 2.18 (sept, J ) 6.8 Hz, 1H,
CH(CH3)2), 2.67 (tt, J ) 9.4, 5.0 Hz, 1H, PhCHCH2N), 3.16
(ddd, J ) 13.3, 9.4, 4.6 Hz, 1H, PhCHCHHN), 3.71 (ddd, J )
13.4, 7.1, 5.9 Hz, 1H, PhCHCHHN), 5.32 (bs, 1H, NH), 7.13-
7.32 (m, 5H, Ar-H). 13C NMR (CDCl3, 100 MHz): δ 11.80
(CH3), 19.39 (CH3), 19.54 (CH3), 26.62 (CH2), 35.49 (CH), 44.44
(CH2), 47.50 (CH), 126.60 (Ar-H), 127.78 (Ar-H), 128.53 (Ar-
H), 142.57 (Ar), 176.71 (CdO). HRMS (EI) C14H21NO: Calcd
219.1623 Found 219.1623 The enantiomeric ratio of (S)-8 was
determined to be 88:12 by CSP-HPLC on a Whelk-O column
with 2.5% IPA/hexane mobile phase; retention times for the
minor and major enantiomers were 40.8 and 43.5 min,
respectively.
(S)-N-(2-Tr ibu tylsta n n yl-2-p h en yleth yl)isobu tyr a m id e
(5). The general lithiation procedure was followed using Bu3-
SnCl as the electrophile to provide crude (S)-5. The crude
product was purified using flash chromatography (25% EtOAc/
hexane) to give (S)-5 (200 mg, 86%) as a clear oil. 1H NMR
(CDCl3, 400 MHz): δ 0.80 (m, 6H, Sn(CH2CH2CH2CH3)3), 0.84
(t, J ) 7.2 Hz, 9H, Sn(CH2CH2CH2CH3)3), 0.99 (d, J ) 6.9 Hz,
3H, CHCH3), 1.01 (d, J ) 6.8 Hz, 3H, CHCH3), 1.23 (sext, J )
7.3 Hz, 6H, Sn(CH2CH2CH2CH3)3), 1.37 (m, 6H, Sn(CH2CH2-
CH2CH3)3), 2.16 (sept, J ) 6.9 Hz, 1H, CH(CH3)2), 2.77 (dd,
J
) 12.6, 5.0 Hz, 1H, PhCHCH2N), 3.75-3.90 (m, 2H,
(S)-N-(2-(1′-Cycloh exa n ol)-2-p h en ylet h yl)-isob u t yr a -
m id e (9). The general lithiation procedure was followed using
cyclohexanone as the electrophile to provide crude (S)-9. The
crude product was purified using flash chromatography (3%
PhCHCH2N), 5.35 (bs, 1H, NH), 7.01-7.24 (m, 5H, Ar-H). 13
C
NMR (CDCl3, 100 MHz): δ 8.92 (CH2), 13.56 (CH), 19.46 (CH3),
19.50 (CH3), 27.32 (CH2), 28.88 (CH2) 33.64 (CH3), 35.50 (CH),
6802 J . Org. Chem., Vol. 67, No. 19, 2002

Synthesis of 2-Substituted 2-Phenylethylamines
MeOH/ CH2Cl2) to give (S)-9 (84 mg, 58%) as a white solid,
mp 143-145 °C. H NMR (CDCl3, 400 MHz): δ 0.96 (d, J )
purified using flash chromatography (40% EtOAc/hexane) to
give (S)-15 (134 mg, 86%) as a colorless oil. H NMR (CDCl3,
1
1
6.8 Hz, 3H, CHCH3), 0.98 (d, J ) 6.9 Hz, 3H, CHCH3), 1.64
(bs, 1H, OH), 1.10-1.80 (m, 10H, (CH2)5), 2.14 (sept, J ) 6.8
Hz, 1H, CH(CH3)2), 2.87 (dd, J ) 10.0, 5.1 Hz, 1H, PhCHCH2N),
3.48 (ddd, J ) 14.2, 9.8, 4.4 Hz, 1H, PhCHCHHN), 4.00 (ddd,
J ) 13.1, 6.5, 5.3 Hz, 1H, PhCHCHHN), 5.42 (bs, 1H, NH),
7.25-7.33 (m, 5H, Ar-H). 13C NMR (CDCl3, 100 MHz): δ 19.28
(CH3), 19.54 (CH3), 21.71 (CH2), 21.87 (CH2), 25.52 (CH2), 35.52
(CH), 36.00 (CH2), 36.04 (CH2), 37.34 (CH), 39.13 (CH2), 72.89
(CH), 127.01 (Ar-H), 128.37 (Ar-H), 129.67 (Ar-H), 139.48
(Ar). Anal. Calcd %C: 74.70, %H: 9.26, %N: 4.84. Found
%C: 74.58, %H: 9.51, %N: 4.99. The enantiomeric ratio of
(S)-9 was determined to be 72:28 by CSP-HPLC on a Chiral-
pak-AD column with 10% IPA/hexane mobile phase; retention
times for the minor and major enantiomers were 11.1 and 12.8
min, respectively.
500 MHz): δ 1.04 (d, J ) 6.8 Hz, 3H, CHCH3), 1.06 (d, J )
6.6 Hz, 3H, CHCH3), 2.19 (sept, J ) 6.9 Hz, 1H, CH(CH3)2),
2.95 (m, 2H, PhCH2), 3.13 (m, 1H, ArCHCH2N), 3.35 (ddd, J
) 13.4, 9.3, 4.9 Hz, 1H, ArCHCHHN), 3.75 (ddd, J ) 13.4,
6.7, 5.7 Hz, 1H, ArCHCHHN), 3.80 (s, 3H, OCH3), 5.33 (bs,
1H, NH), 6.71-6.82 (m, 3H, Ar-H), 7.10-7.30 (m, 6H, Ar-
H). 13C NMR (CDCl3, 125 MHz): δ 19.66 (CH3), 19.81 (CH3),
35.79 (CH), 40.97 (CH2), 44.23 (CH2), 47.66 (CH), 55.39 (CH3),
112.31 (Ar-H), 113.91 (Ar-H), 120.40 (Ar-H), 126.39 (Ar-
H), 128.54 (Ar-H), 129.28 (Ar-H), 129.87 (Ar-H), 139.75 (Ar),
144.09 (Ar), 160.03 (Ar), 177.04 (CdO). HRMS (EI) C20H25
-
NO2: Calcd 311.1885 Found 311.1878 The enantiomeric ratio
of (S)-15 was determined to be 89:11 by CSP-HPLC on a
Whelk-O column with 8% IPA/hexane mobile phase; retention
times for the minor and major enantiomers were 31.6 and 35.3
min, respectively.
(2S)-N-(3-H yd r oxy-2,3-d ip h en ylet h yl)isob u t yr a m id e
(10). The general lithiation procedure was followed using
benzaldehyde as the electrophile to provide crude (2S)-10. The
crude product was purified using prep-HPLC (70% EtOAc/
hexane) to give two diastereomers of (2S)-10 in a dr of 79:21
(82 mg, 70%) as viscous oils. 1H NMR major diastereomer
(CDCl3, 400 MHz): δ 1.06 (d, J ) 6.9 Hz, 3H, CHCH3), 1.08
(d, J ) 6.9 Hz, 3H, CHCH3), 2.28 (sept, J ) 6.9 Hz, 1H, CH-
(CH3)2), 3.10 (dt, J ) 8.6, 5.6 Hz, 1H, PhCHCH2N), 3.51 (dt, J
) 13.9, 5.2 Hz, 1H, PhCHCHHN), 3.72 (bs, 1H, OH), 3.92 (dt,
J ) 14.1, 6.5 Hz, 1H, PhCHCHHN), 4.81 (d, J ) 8.6 Hz, 1H,
PhCHOH), 6.01 (bs, 1H, NH), 7.02-7.20 (m, 10H, Ar-H). 13C
NMR major diastereomer (CDCl3, 100 MHz): δ 19.34 (CH3),
19.53 (CH3), 35.47 (CH), 41.62 (CH2), 53.29 (CH), 75.96 (CH),
126.53 (Ar-H), 126.76 (Ar-H), 127.21 (Ar-H), 127.94 (Ar-
H), 128.35 (Ar-H), 128.44 (Ar-H), 140.09 (Ar), 142.46 (Ar),
177.94 (CdO). Anal. Calcd %C: 76.74, %H: 7.80, %N: 4.71.
Found major diastereomer %C: 76.55, %H: 7.58, %N: 4.66.
The enantiomeric ratio of the major diastereomer of (2S)-10
was determined to be 78:22 by CSP-HPLC on a Whelk-O
column with 15% IPA/hexane mobile phase; retention times
for the major and minor enantiomers were 10.6 and 13.5 min,
respectively.
(S)-N-(2-(m-Meth oxyph en yl)-3-ph en ylp r opyla m in e Hy-
d r och lor id e Sa lt (16). To a flask containing (S)-15 (6.10 g,
19.59 mmol) dissolved in THF (150 mL) at -78 °C was added
n-BuLi (1.5 M, 15.0 mL, 22.50 mmol). After the solution was
allowed to stir for 2 h, Boc anhydride (5.0 mL, 21.74 mmol)
was added. The solution was allowed to slowly warm to room
temperature, and stirring was continued for 12 h. The solution
was poured into water (150 mL), the layers were separated,
and the aqueous layer was extracted with ether (3 × 100 mL).
The ethereal layers were combined, dried (MgSO4), and
filtered. The solvent was removed in vacuo to provide crude
the crude Boc-amide. The crude Boc-amide was dissolved in
dioxane (150 mL). To the solution was added aqueous KOH
(16.48 g, 294 mmol in 100 mL of H2O). The reaction mixture
was stirred at reflux for 18 h. The solution was poured into
H2O (200 mL) and then extracted with ether (3 × 100 mL).
The ethereal layers were combined, dried (MgSO4), and
filtered. The solvent was removed in vacuo to provide the crude
Boc-amine. To the crude Boc-amine dissolved in EtOAc (200
mL) was added EtOH (11.0 mL, 190 mmol). The solution was
cooled to 0 °C, and acetyl chloride (13.5 mL, 190 mmol) was
added dropwise. The solution was allowed to slowly warm to
room temperature, and stirring was continued for 19 h. The
solution was concentrated in vacuo to approximately one-half
the original volume. EtOAc (50 mL) was added to the hetero-
geneous mixture followed by cooling to -25 °C. The mixture
was stirred at -25 °C for 10 min, and the solid was isolated
by filtration (washing with cold EtOAc) to provide pure (S)-
1H NMR minor diastereomer (CDCl3, 400 MHz): δ 1.04 (d,
J ) 7.1 Hz, 3H, CHCH3), 1.05 (d, J ) 7.1 Hz, 3H, CHCH3),
2.32 (sept, J ) 6.9 Hz, 1H, CH(CH3)2), 3.07 (td, J ) 7.8, 5.9
Hz, 1H, PhCHCH2N), 3.33 (ddd, J ) 13.8, 7.4, 5.6 Hz, 1H,
PhCHCHHN), 3.76 (ddd, J ) 13.9, 8.2, 6.8 Hz, 1H, PhCH-
CHHN), 4.89 (d, J ) 5.7 Hz, 1H, PhCHOH), 5.72 (bs, 1H, NH),
7.13-7.32 (m, 10H, Ar-H).
1
16 (5.085 g, 77%), mp 141-143 °C. H NMR (DMSO-d6, 400
MHz): δ 2.82 (dd, J ) 13.7, 9.0, Hz, 1H, ArCHCHHN), 3.01
(d, J ) 7.3 Hz, 2H, PhCH2), 3.12 (dd, J ) 13.7, 6.3 Hz, 1H,
ArCHCHHN), 3.27 (quint, J ) 7.0 Hz, 1H, ArCHCH2N), 3.70
(s, 3H, OCH3), 6.75-6.82 (m, 3H, Ar-H), 7.07-7.21 (m, 6H,
Ar-H), 8.19 (bs, 3H, NH3+). 13C NMR (DMSO-d6, 100 MHz):
δ 40.59 (CH2), 43.93 (CH2), 45.68 (CH), 55.63 (CH3), 113.06
(Ar-H), 114.42 (Ar-H), 120.95 (Ar-H), 126.69 (Ar-H), 128.80
(Ar-H), 129.63 (Ar-H), 130.20 (Ar-H), 139.93 (Ar), 142.79
(Ar), 159.97 (Ar), 172.73 (CdO). Anal. Calcd %C: 69.18, %H:
7.26, %N: 5.04. Found %C: 69.25, %H: 7.28, %N: 5.17.
N-(2-(m -Meth oxyp h en yleth yl)isobu tyr a m id e (14). To a
solution of CH2Cl2 (400 mL) and triethylamine (50 mL) was
added m-methoxyphenethylamine (25 g, 165 mmol) followed
by dropwise addition of isobutyryl chloride (18.5 mL, 177
mmol) in CH2Cl2 (170 mL). The reaction mixture was allowed
to stir at room temperature for 24 h. The solution was poured
into 2 M HCl (∼500 mL), the layers were separated, and the
CH2Cl2 layer was washed with 5% NaHCO3 (∼200 mL) and
dried over MgSO4. The solvent was removed in vacuo to
provide an off-white solid. The crude product was recrystallized
from hexane/ethyl acetate to provide pure 14 (31.3 g, 86%),
(S)-N-(2-(m -Met h oxyp h en yl)-3-p h en ylp r op yl)b en za -
m id e (17). To a solution of CH2Cl2 (40 mL) and triethylamine
(3.0 mL) was added (S)-16 (1.211 g, 4.36 mmol). The solution
was cooled to 0 °C followed by dropwise addition of benzoyl
chloride (0.60 mL, 5.17 mmol) in CH2Cl2 (5 mL). The reaction
mixture was allowed to stir at room temperature for 24 h. The
solution was poured into 2 M HCl (∼50 mL), the layers were
separated, and the CH2Cl2 layer was washed with 5% NaHCO3
(∼20 mL) and dried over MgSO4. The solvent was removed in
vacuo to provide crude (S)-17. The crude product was purified
using flash chromatography (30% EtOAc/hexane) to give (S)-
17 (1.469 g, 97%) as a colorless oil. 1H NMR (CDCl3, 500
MHz): δ 3.01 (m, 2H, PhCH2), 3.24 (m, 1H, ArCHCH2N), 3.55
(ddd, J ) 13.5, 8.9, 4.9 Hz, 1H, ArCHCHHN), 3.77 (s, 3H,
OCH3), 3.93 (dt, J ) 13.5, 6.3 Hz, 1H, ArCHCHHN), 6.07 (bs,
1
mp 57-58 °C. H NMR (CDCl3, 400 MHz): δ 1.08 (d, J ) 6.8
Hz, 6H, CH(CH3)2), 2.28 (sept, J ) 6.8 Hz, 1H, CH(CH3)2), 2.76
(t, J ) 7.1 Hz, 2H, PhCH2CH2N), 3.45 (q, J ) 6.5 Hz, 2H,
PhCH2CH2N), 3.74 (s, 3H, OCH3), 5.93 (bs, 1H, NH), 6.70-
6.75 (m, 3H, Ar-H), 7.18 (t, J ) 7.8 Hz, 1H, Ar-H). 13C NMR
(CDCl3, 100 MHz): δ 19.43 (CH3), 35.32 (CH), 35.57 (CH2),
40.25 (CH2), 54.92 (CH3), 111.62 (Ar-H), 114.24 (Ar-H),
120.91 (Ar-H), 129.36 (Ar-H), 140.46 (Ar), 159.59 (Ar), 176.91
(CdO). Anal. Calcd %C: 70.56, %H: 8.65, %N: 6.33. Found
%C: 70.61, %H: 8.67, %N: 6.47.
(S)-N-(2-m -Meth oxyp h en yl-3-p h en ylp r op yl)isobu tyr a -
m id e (15). The general lithiation procedure of 2 was utilized
for the lithiation-substitution of 14 using benzyl bromide as
the electrophile to provide crude (S)-15. The crude product was
J . Org. Chem, Vol. 67, No. 19, 2002 6803

Laumer et al.
1H, NH), 6.75-6.83 (m, 3H, Ar-H), 7.12-7.57 (m, 11H, Ar-
H). 13C NMR (CDCl3, 125 MHz): δ 40.65 (CH2), 44.65 (CH2),
47.32 (CH), 55.06 (CH3), 112.15 (Ar-H), 113.51 (Ar-H), 120.02
(Ar-H), 126.11 (Ar-H), 128.28 (Ar-H), 128.37 (Ar-H), 128.96
(Ar-H), 129.67 (Ar-H), 131.24 (Ar-H), 134.48 (Ar), 139.41
(Ar), 143.71 (Ar), 159.77 (Ar), 167.28 (CdO). HRMS (EI)
1H, PhCH2CH), 3.46 (dd, J ) 15.7, 5.4 Hz, 1H, CHCHHN),
3.75 (s, 3H, OCH3), 3.95 (dd, J ) 15.7, 3.4 Hz, 1H, CHCHHN),
6.73 (d, J ) 2.8 Hz, 1H, Ar-H), 6.81 (dd, J ) 8.6, 2.6 Hz, 1H,
Ar-H), 7.16-7.29 (m, 6H, Ar-H), 7.43-7.46 (m, 3H, Ar-H),
7.60-7.62 (m, 2H, Ar-H). 13C NMR (acetone-d6, 125 MHz): δ
39.59 (CH2), 39.59 (CH), 51.87 (CH2), 55.94 (CH3), 112.95 (Ar-
H), 113.87 (Ar-H), 122.45 (Ar), 127.21 (Ar-H), 129.09 (Ar-
H), 129.36 (Ar-H), 129.41 (Ar-H), 129.94 (Ar-H), 130.12
(Ar-H), 130.43 (Ar-H), 130.54 (Ar-H), 140.79 (Ar), 141.13
(Ar), 145.61 (Ar), 162.38 (Ar), 162.38 (Ar), 166.88 (CdN).
HRMS (EI) C23H21NO (M-1 scanned): Calcd 326.1545 Found
326.1537.
C
23H23NO2: Calcd 345.1729 Found 345.1721.
(S)-4-Ben zyl-6-m eth oxy-1-isopr opyl-3,4-dih ydr oisoqu in -
olin e (18). In a round-bottom flask was dissolved (S)-15 (134
mg, 0.43 mmol) in CH3CN (8 mL). The solution was cooled to
0 °C, and phosphorus pentachloride (716 mg, 3.44 mmol) was
added in three portions, allowing the solution to warm to room
temperature between each addition. After the reaction mixture
was stirred at room temperature for 14 h and cooled to 0 °C,
NaOH was added (10 mL, 6 M). The reaction mixture was
extracted with CH2Cl2 (3 × 10 mL), the combined CH2Cl2
layers were dried over Na2SO4, and the solvent removed in
vacuo to afford crude (S)-18. The crude product was purified
using flash chromatography (60:35:5 hexane/EtOAc/Et3N) to
give (S)-18 (116 mg, 92%) as a yellow oil. 1H NMR (CDCl3,
400 MHz): δ 1.21 (d, J ) 6.8 Hz, 3H, CHCH3), 1.28 (d, J )
6.6 Hz, 3H, CHCH3), 2.65-2.82 (m, 3H, ArCH, PhCH2), 3.29
(sept, J ) 6.7 Hz, 1H, CH(CH3)2), 3.42 (ddd, J ) 15.5, 5.2, 1.4
Hz, 1H, ArCHCHHN), 3.71 (s, 3H, OCH3), 3.89 (dd, J ) 15.6,
3.2 Hz, 1H, PhCHCHHN), 6.41 (d, J ) 2.7 Hz, 1H, Ar-H),
6.80 (dd, J ) 8.5, 2.7 Hz, 1H, Ar-H), 7.07 (m, 2H, Ar-H),
(4S)-4-Ben zyl-6-m eth oxy-1-ph en yl-1,2,3,4-tetr ah ydr oiso-
qu in olin e (20). In a round-bottom flask was dissolved (S)-19
(0.1251 g, 0.38 mmol) in MeOH (2.0 mL). The solution was
cooled to 0 °C, and NaBH4 (41.6 m g, 1.10 mmol) was added.
The reaction mixture was stirred at 0 °C for 18 h. The reaction
mixture was concentrated in vacuo followed by addition of H2O
(∼10 mL). The aqueous solution was extracted with CHCl3
(3 × 10 mL). The combined CHCl3 layers were dried over Na2-
SO4, and the solvent was removed in vacuo to afford crude
(4S)-20. The crude product was purified using prep-HPLC
(50% EtOAc/hexane) to give a diastereomixture of (4S)-20
1
1
(101.9 mg, 81%, 95:5 dr by H NMR) as a yellow oil. H NMR
major diastereomer (CDCl3, 400 MHz): δ 1.84 (bs, 1H, NH),
3.03 (m, 1H, PhCH2CH), 3.13 (d, J ) 2.9 Hz, 2H, PhCH2), 3.17
(dd, J ) 13.4, 5.4 Hz, 1H, CHCHHN), 3.30 (dd, J ) 13.4, 9.8
Hz, 1H, CHCHHN), 3.76 (s, 3H, OCH3), 5.06 (s, 1H, PhCHN),
6.69 (m, 3H, Ar-H), 7.28-7.40 (m, 11H, Ar-H). 13C NMR
major diastereomer (CDCl3, 100 MHz): δ 40.75 (CH), 42.66
(CH2), 45.90 (CH2), 55.05 (CH3), 62.46 (CH), 112.40 (Ar-H),
113.42 (Ar-H), 125.99 (Ar-H), 127.35 (Ar-H), 128.30 (Ar-
H), 128.36 (Ar-H), 128.90 (Ar-H), 128.95 (Ar-H), 129.46
(Ar-H), 130.88 (Ar), 140.30 (Ar), 140.69 (Ar), 145.17 (Ar),
157.54 (Ar). HRMS (EI) C23H23NO (M-1 scanned): Calcd
328.1701 Found 328.1698.
7.17-7.28 (m, 3H, Ar-H), 7.50 (d, J ) 8.5 Hz, 1H, Ar-H). 13
C
NMR: δ 20.17 (CH3), 21.43 (CH3), 31.51 (CH), 38.73 (CH2),
38.78 (CH), 50.08 (CH2), 55.11 (CH3), 112.28 (Ar-H), 112.54
(Ar-H), 121.34 (Ar), 126.01 (Ar-H), 126.52 (Ar-H), 128.17
(Ar-H), 128.93 (Ar-H), 129.23 (Ar-H), 139.69 (Ar), 143.54
(Ar), 160.49 (Ar), 170.80 (CdN). HRMS (EI) C20H23NO: Calcd
293.1780 Found 293.1780.
(S)-4-Ben zyl-6-m eth oxy-1-p h en yl-3,4-d ih yd r oisoqu in o-
lin e (19). In a round-bottom flask was dissolved (S)-17 (1.423
g, 4.12 mmol) in CH3CN (70 mL). The solution was cooled to
0 °C, and phosphorus pentachloride (6.835 g, 32.8 mmol) was
added in three portions, allowing the solution to warm to room
temperature between each addition. After the reaction mixture
was stirred at room temperature for 14 h and cooled to 0 °C,
NaOH was added (70 mL, 6 M). The reaction mixture was
stirred at 0 °C for 1 h followed by extraction with CH2Cl2 (3 ×
10 mL). The combined CH2Cl2 layers were dried over Na2SO4,
and the solvent was removed in vacuo to afford crude (S)-19.
The crude product was purified using flash chromatography
(solvent gradient, 10% EtOAc/hexane increased to 35% EtOAc/
Ack n ow led gm en t. We are grateful to the National
Science Foundation (CHE 98-19422) and the National
Institutes of Health (GM-18874) for support of this
work.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis of starting materials, absolute
configuration determination, and mechanistic studies. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
hexane) to give (S)-19 (1.291 g, 96%) as a yellow oil. H NMR
(acetone-d6, 500 MHz): δ 2.74 (dd, J ) 13.3, 9.0 Hz, 1H,
PhCHH), 2.89 (dd, J ) 13.2, 6.8 Hz, 1H, PhCHH), 2.98 (m,
J O0258251
6804 J . Org. Chem., Vol. 67, No. 19, 2002