Asymmetric synthesis of (+)- and (-)-latifine

Article abstract of DOI:10.1016/S0957-4166(03)00175-7

A concise and novel synthesis of isoquinoline alkaloids (S)-latifine and of its antipode is reported. The key step relies on the stereoselective reduction of an appropriately substituted diarylenamine equipped with a chiral auxiliary followed by Pictet-Sp

Full text of DOI:10.1016/S0957-4166(03)00175-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1309–1316
Asymmetric synthesis of (+)- and (−)-latifine
Axel Couture,* Eric Deniau, Pierre Grandclaudon and Ste´phane Lebrun
Laboratoire de Chimie Organique Physique, UMR 8009, Universite´ des Sciences et Technologies de Lille, Baˆtiment C3(2),
F-59655 Villeneuve d’Ascq Cedex, France
Received 22 January 2003; accepted 20 February 2003
Abstract—A concise and novel synthesis of isoquinoline alkaloids (S)-latifine and of its antipode is reported. The key step relies
on the stereoselective reduction of an appropriately substituted diarylenamine equipped with a chiral auxiliary followed by
Pictet–Spengler cyclization to generate the tetrahydroisoquinoline unit. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
protonation of chiral lactam enolates.8 However appli-
cations of these elegant concepts have been mainly
confined to structurally simple models, particularly
devoid of competing metallation sites and/or phenolic
hydroxy functions on the environmentally different aro-
matic moieties.
1,2,3,4-Tetrahydroisoquinolines of synthetic, plant and
mammalian origin have been extensively studied
because of their manifold pharmacological properties.1
In
particular,
enantiomerically
pure
tetra-
hydroisoquinolines arylated at C(4) are of considerable
interest because compounds possessing this heteroring
unit display biological activities of medicinal interest2 as
witnessed by nomifensine3 1 and dichlofensine4 2 which
exhibit central nervous activity and inhibit serotonin
and dopamine uptake mechanisms. The 4-aryltetra-
hydroisoquinoline unit also represents the basic skele-
ton of the unique 5,6- and 6,7-dioxygenated naturally
occurring alkaloids latifine 3 and cherylline 4 which
have been isolated from Amaryllidaceae plants.5
Although this substitution pattern is found quite often
in nature and in the biological domain, there are only a
few efficient and general stereoselective methods avail-
able to control the stereochemistry at the C(4) position
of the heterocyclic framework. Indeed compounds pos-
sessing the 4-aryltetrahydroisoquinoline unit are usually
synthesized in their racemic form followed by a supple-
mentary step of resolution.6 Recently Levacher tackled
this challenge and developed two complementary
approaches to enantiopure compounds based upon the
deracemization of racemic models via a metallation
reprotonation sequence with the mediation of an enan-
tiodiscriminating ligand.6,7 Alternatively they are also
accessible by chirality transfer upon diastereoselective
In continuation of our investigation into the asymmet-
ric synthesis of alkaloids with a tetrahydroisoquinoline
ring system as the main structural subunit,9 we herein
wish to disclose a novel and concise route to enan-
tiomerically pure (+)- and (−)-latifine 3 which has been
isolated from Crinum latifolium,10 a plant used as rube-
faciant and tonic.11 This exemplary representative was
chosen as a model since synthetic methods for the
elaboration of this structurally challenging alkaloid in
the racemic form are extremely rare.12 Furthermore,
extension to the enantioselective synthesis of the unnat-
* Corresponding author. Tel.: +33-(0)3-2043-4432; fax: +33-(0)3-
2033-6309; e-mail: axel.couture@univ-lille1.fr
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00175-7

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A. Couture et al. / Tetrahedron: Asymmetry 14 (2003) 1309–1316
ural enantiomer was envisaged but the observed specific
rotation of the synthetic material is still open to discus-
sion.12a It is noteworthy that all prior attempts to
deracemizate the protected precursor12e 5 by applying
the asymmetric deprotronation protonation sequence
were unrewarding even when varying the protections of
the hydroxy phenolic groups (e.g. benzyl, isopropyl).
This may tentatively be attributable to the sensitivity of
the diverse functionalities with regard to the long reac-
tion times and the harsh experimental conditions
needed.
(Scheme 2).14 This operation might then address the
problem of stereocontrol at the stereogenic center adja-
cent to the differentially substituted aromatic units in 6
and consequently of the annulated model 3.
Scheme 2. Transient imminium ion.
The chiral appendage would be incorporated in the
desired enamine 7 under the agency of the Horner
process involving the benzophenone derivative 8 and
the appropriate chiral phosphorylated amine 9. Cleav-
age of the chiral auxiliary followed by Pictet–Spengler
cyclization to generate the piperidine ring system and
ultimate deprotection should complete the synthesis of
the target product 3.
2. Results and discussion
Our strategy, which is depicted in the retrosynthetic
Scheme 1, hinges upon our longstanding experience in
the field of N-substituted enamine chemistry.13
The first facet of the synthesis was the elaboration of
the rather congested benzophenone derivative 8. This
unsymmetrically trisubstituted diarylketone was con-
structed by reacting protected isovanillin 12 with the
aryllithium species obtainable from the corresponding
aryl bromide 11 by low temperature halogen metal
exchange (Scheme 3). This coupling reaction delivered
the dibenzylic alcohol 13 in an excellent yield. Oxida-
tion with pyridinium dichromate generated the desired
ketone linkage between the two aromatic components
thus providing almost quantitatively the desired
diarylketone 8.
The key step of our conceptually new synthetic route
was the diastereoselective hydrogenation of the
appended diarylmethylene unit of the diarylenamine 7
derived from a tertiary amine bearing a removable
stereocontrolling agent, i.e. the a-methylbenzyl group.
We anticipated that the bulky a-methylbenzyl group
might influence the sense and extent of diastereoselec-
tion associated with the formation of the transient
iminium ion 10b involved in the reduction of the enam-
ine moiety and arising from the enammonium ion 10a
Scheme 3. Synthesis of the diarylketone 8.
The synthetic route to the requisite diarylenamine 7
then necessitated the preliminary formation of the chi-
ral phosphorylated amine 9. We found that this amine
Scheme 1. Retrosynthetic scheme.

A. Couture et al. / Tetrahedron: Asymmetry 14 (2003) 1309–1316
1311
could be readily prepared via the three step sequence
depicted in Scheme 4 involving the treatment with
diphenylphosphine oxide of the appropriate hexahydro-
triazine 14 product of the Mannich reaction of (R)-(+)-
a-methylbenzylamine. Eischweiler–Clarke methylation
of the resulting secondary amine 15 delivered the
required phosphorylated amine 9 with an excellent yield
(68% over the three steps).
THF and the so formed carbanion was reacted with the
diarylketone 8 (Scheme 5). Warming to room tempera-
ture resulted in direct completion of the Horner reac-
tion and almost exclusive formation of the prochiral
enamine 7 (95%). Enamine 7 was obtained with a very
high degree of stereoselectivity and the E-configuration
1
of the exclusive stereomer was assigned from the H
NMR spectrum. The formation of the unique E-
configured substrate may be tentatively explained by
the presence of the bulky O-isopropyl group ortho to
the styrylamine moiety. The driving force arising from
the high degree of conjugation of this 1,1-diarylethylene
model accounts for the high yield of the synthesis of
Scheme 4. Synthesis of phosporylated amine derivatives.
Interestingly, at this stage we envisaged the alternative
synthesis of the diarylated enecarbamate 17 assuming
that the N-Boc group could be readily replaced by the
mandatory N-methyl group and that catalytic asym-
metric hydrogenation could be performed with a high
degree of diastereoselectivity. Literature precedent,
although scarce,9a,15 indeed gave support to the feasibil-
ity of such an approach. For this purpose the phospho-
rylated N-Boc protected amine 16 was prepared but,
unfortunately, all attempts to prepare the enecarbamate
17 by Horner reaction between the metalated carba-
mate 16 and the benzophenone derivative 8 were unre-
warding, probably due to the steric congestion of both
partners.
For the subsequent synthesis of the required enamine 7,
the Horner protocol, which has been mainly employed
in related systems for homologation of a variety of
carbonyl compounds16 and for the generation of acyl
anion equivalents,17 was also applied. Deprotonation of
9 was conducted at −15°C using 1.1 equiv. of n-BuLi in
Scheme 5.

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A. Couture et al. / Tetrahedron: Asymmetry 14 (2003) 1309–1316
Performing all these operations on the (R)-configured
diarylethylamine (R)-18 led to the unnatural antipode 3
with the (R)-configuration. The data obtained for both
enantiomeric forms unequivocally proved that the
configuration of the unnatural enantiomer was (R) with
a specific rotation value matching that of the natural
product, thus putting an end to the controversy.12a
this enamine. Because the enamine partially hydrolyzed
during chromatographic treatment, it was directly sub-
jected to the reduction conditions.
A contentious issue in the formation of the diastereo-
chemically enriched dibenzylamine derivative 6 was to
determine the proper conditions to optimize the yield
and the diastereoselective level of this simple process,
namely by varying the nature of the reducing agent, the
solvent and the temperature. NaBH4, NaBH3CN and
NaBH(OAc)3 were used in this study and results are
presented in Table 1. From Table 1 it can be seen that
satisfactory diastereoselection was obtained with NaB-
H(OAc)3 for reactions carried out in MeOH/HCl at low
temperature (entry 6). The diastereomeric excess (de)
was estimated by the integration of relevant signals in
3. Experimental
3.1. General
Mps were determined on
a Reichert–Thermopan
1
apparatus and are uncorrected. H (300 MHz) and 13C
NMR (75 MHz) spectra were recorded on a Bruker
AM 300 spectrometer and were referenced against
internal tetramethylsilane; 31P NMR (121 MHz) spectra
were referenced against H3PO4 as external standard.
Coupling constants (J) are given in Hz and rounded to
the nearest 0.1 Hz. Elemental analyses were determined
by the CNRS microanalysis center. TLC was per-
formed with plates coated with Kieselgel G (Merck).
The plates were developed with petroleum ether (PE)–
ethyl acetate (EA). The silica gel used for flash column
chromatography was Merck Kieselgel of 0.040–0.063
mm particle size. Dry glassware was obtained by oven-
drying and assembly under Ar. Ar was used as the inert
atmosphere and was passed through a drying tube to
remove moisture. The glassware was equipped with
rubber septa and reagent transfer was performed by
syringe techniques. Tetrahydrofuran (THF) was dis-
tilled from sodium benzophenone ketyl immediately
before use. Methanol was distilled from magnesium
turnings and acetonitrile from CaH2 before storage
1
the H NMR spectrum of the crude reaction mixture.
An interesting observation emerging from this experi-
ment is that the major diastereomer resulting from
hydride reduction is the (1R,2R)-amine prone to give
access to the unnatural compound. For all cases yields
were quite acceptable. Separation of the pair of
diastereomers proved more difficult than we anticipated
and compounds (1R,2S)-6 and (1R,2R)-6 were finally
separated by preparative HPLC.
The adoption of the isopropyl protecting group was
rewarded here: hydrogenolysis of (1R,2S)-6 with Pearl-
man’s catalyst clipped the chiral appendage and deliv-
ered the enantiomerically pure diarylamine (S)-18 while
sparing the isopropyl protection. The diastereomeric
amine (1R,2R)-6 was transformed analogously into the
enantiomeric (R)-configured diarylamine (R)-18. The
cyclomethylenation of (S)-18 by the Pictet–Spengler
heterocyclization reaction proceeded uneventfully to
furnish the initial annulated compound (S)-19. Analysis
by chiral HPLC, under conditions optimized with use
of racemic standard, showed that compound (S)-19 was
obtained as only one detectable enantiomer indicating
that both processes, removal of chiral auxiliary and
cyclization, proceeded without racemization of the pre-
viously formed stereogenic center. Finally the two phe-
nolic hydroxy functions of the target natural product
were easily retrieved by removal of the isopropyl pro-
tecting group of (S)-19 and this simple operation deliv-
ered the natural enantiomer (S)-3 with an excellent
enantioselectivity (>95%) (Scheme 5).
,
over 4 A molecular sieves.
3.2. (1R)-N-Diphenylphosphinoylmethyl-N-1-
phenylethylamine, 15
A suspension of paraformaldehyde (1 g, 33.3 mmol) in
a solution of (R)-(+)-a-methylbenzylamine (4 g, 33.1
mmol) in CH2Cl2 (20 ml) was stirred at rt for 3 h. After
filtration, evaporation of the solvent left a colorless oil
(12.5 g, 95%) corresponding to the hexahydrotriazine
14 which was used in the next step without further
purification.
Table 1. Diastereoselectivity of the reductiona of the diarylenamine 7
Entry
Reducing agent
Temp. (°C)
Time (h)
Yield (%)
Deb (%)
1
2
3
4
5
6
NaBH4
NaBH4
NaBH3CN
NaBH3CN
NaBH(OAc)3
NaBH(OAc)3
−25
−78
−25
−78
−30
−78
1
2
1
3
1
4
80
62
75
70
78
60
10
30
24
40
35
85
a The reaction was conducted in a saturated solution of MeOH–HCl.
b The diastereomeric excess (de) was estimated by the integration of the N-CH3 signal [(1R,2S)-6: l 2.19 ppm; (1R,2R)-6: l 2.30 ppm] in the 1H
NMR spectrum of the crude reaction mixture

A. Couture et al. / Tetrahedron: Asymmetry 14 (2003) 1309–1316
1313
A solution of hexahydrotriazine 14 (10 g, 25 mmol) and
diphenylphosphine oxide (15.2 g, 75 mmol) was
refluxed in toluene (100 ml) for 2 h under Ar. After
evaporation of the solvent under vacuum, the crude
product was chromatographed on SiO2 column using
acetone/PE (80:20) as eluent and the phosphorylated
amine was finally purified by recrystallization from
hexane–toluene to afford 15 as a pale yellow solid (20.2
g, 80%). Mp 190–191°C; [h]2D0=+21.0 (c 1.0, CHCl3);
[h]2D0=+48.5 (c 1.3, MeOH). 1H NMR (CDCl3) l
(ppm): 1.30 (d, J=6.5, 3H), 1.94 (brs, 1H, NH), 3.25
(dd, J=8.0, 3.6, 2H, NCH2P), 3.76 (q, J=6.5, 1H),
7.12–7.31 (m, 5H, Harom.), 7.34–7.56 (m, 6H, Harom.),
7.58–7.75 (m, 4H, Harom.). 13C NMR (CDCl3) l (ppm):
24.5, 47.1 (d, J=81, NCH2P), 60.0 (d, J=14, NCH),
126.8, 127.2, 128.4, 128.6, 130.9, 131.0, 131.2, 131.3,
131.5, 131.9, 132.2, 132.8. 31P NMR (CDCl3) l (ppm):
30.1. Anal. calcd for C21H22NOP (335) C, 75.12; H,
6.61; N, 4.17. Found C, 74.99; H, 6.54; N, 4.07.
6.77 (d, J=9.0, 2H, Harom.), 7.36 (d, J=9.0, 2H,
Harom.). 13C NMR (CDCl3) l (ppm): 21.9, 70.2, 112.5,
117.7, 132.3, 157.0.
3.5. 2-Isopropoxy-3-methoxybenzaldehyde, 12
To a solution of isovanillin (10 g, 65 mmol) and
isopropyl bromide (8.85 g, 72 mmol) in DMF (100 ml)
was added potassium carbonate (10.9 g, 79 mmol) and
the mixture was refluxed overnight. After cooling,
DMF was removed under reduced pressure and the
residue was dissolved in Et2O (200 ml) and washed with
water (50 ml) and KOH (1N, 3×50 ml). The organic
layer was dried over MgSO4 and evaporation of the
solvents left an oily residue which was purified by
distillation under reduced pressure [bp 146°C (12 torr):
lit.20 142°C (12 torr)] to give 12 as a colorless liquid
(8.68 g, 68%). 1H NMR (CDCl3) l (ppm): 1.22 (d,
J=6.2, 6H, 2CH3), 3.77 (s, 3H, OCH3), 4.54 (sept.,
J=6.2, 1H), 6.96–7.05 (m, 2H, Harom.), 7.31 (dd, J=
7.3, 2.1, 1H, Harom.). 13C NMR (CDCl3) l (ppm): 22.2,
55.9, 76.1, 117.8, 118.7, 123.6, 130.7, 150.5, 153.2, 190.7
(CHO).
3.3. (1R)-N-Diphenylphosphinoylmethyl-N-methyl-N-1-
phenylethylamine, 9
To a solution of phosphorylated amine 15 (4 g, 12
mmol) in dry acetonitrile (40 ml) at 0°C was added
formaldehyde (37%, 5.6 ml) with constant stirring. To
this suspension was added sodium cyanoborohydride
(1.2 g, 20 mmol). The pH of the mixture was adjusted
to 3–4 using AcOH and then stirred for 2 h at rt. The
mixture was basified with saturated sodium carbonate
solution, extracted with CH2Cl2 (3×30 ml), dried over
MgSO4, filtered and the solvent evaporated. The
product was purified by flash chromatography on silica
gel using acetone/PE (75:25) as eluent followed by
recrystallization from hexane/toluene to yield 9 as a
white solid (3.54 g, 85%). Mp 113–114°C (lit.18 114–
117°C); [h]2D0=+10.5 (c 1.6, CHCl3); [h]2D0=+49.3 (c 1.0,
3.6. (2-Isopropoxy-3-methoxy)-(4%-isopropoxyphenyl)-
methanol, 13
4-Isopropoxybromobenzene 11 (2 g, 9.3 mmol) was
dissolved in dry THF (50 ml) and cooled to −100°C
under Ar. n-BuLi (1.6 M in hexanes, 10.24 mmol) was
added dropwise. After 15 min, 2-isopropoxy-3-
methoxybenzaldehyde 12 (1.62 g, 8.37 mmol) in THF (2
ml) was added dropwise. After being stirred at −100°C
for 10 min, the reaction mixture was allowed to warm
to rt over 1 h. Saturated aqueous NH4Cl (40 ml) was
added and the organic layer separated. The aqueous
layer was extracted with Et2O (2×40 ml) and the com-
bined organic layers were dried over MgSO4. Evapora-
tion of the solvent furnished an oily product which was
purified by flash column chromatography using AE/PE
(20:80) as eluent to yield 13 as a slightly yellow solid
1
MeOH) {lit.18 [h]D22=+49.9 (c 1.0, MeOH)}. H NMR
(CDCl3) l (ppm): 1.28 (d, J=6.8, 3H), 2.44 (s, 3H,
NCH3), 3.22 (dd, J=15.0, 6.1, 1H, NCH2P), 3.31 (dd,
J=15.0, 6.5, 1H, NCH2P), 3.69 (q, J=6.8, 1H), 7.09–
7.25 (m, 5H, Harom.), 7.34–7.56 (m, 6H, Harom.), 7.58–
7.73 (m, 4H, Harom.). 13C NMR (CDCl3) l (ppm): 24.5,
40.7 (NCH3), 54.8 (d, J=89, NCH2P), 64.9 (d, J=12,
NCH), 127.0, 127.9, 128.1, 128.4, 128.5, 131.0, 131.2,
131.3, 131.5, 131.7, 132.3, 132.8. 31P NMR (CDCl3) l
(ppm): 29.6. Anal. calcd for C22H24NOP (349) C, 75.62;
H, 6.92; N, 4.01. Found C, 75.77; H, 7.11; N, 4.20.
1
(2.34 g, 85%). Mp 64°C. H NMR (CDCl3) l (ppm):
1.17 (d, J=6.2, 3H, CH3), 1.22 (d, J=6.2, 3H, CH3),
1.31 (d, J=6.1, 6H, 2CH3), 3.01 (brd, 1H, OH), 3.82 (s,
3H, OCH3), 4.51 (sept., J=6.1, 1H), 4.69 (sept., J=6.2,
1H), 6.09 (brd, 1H), 6.80–6.86 (m, 4H, Harom.), 6.99 (t,
J=7.9, 1H, Harom.), 7.25–7.30 (m, 2H, Harom.). 13C
NMR (CDCl3) l (ppm): 22.1, 22.4, 22.6, 55.7, 69.9,
71.4, 74.5, 115.6, 116.6, 119.8, 123.3, 127.8, 135.6,
138.2, 143.9, 152.4, 157.0. Anal. calcd for C20H26O4
(330) C, 72.70; H, 7.93. Found C, 72.87; H, 8.07.
3.4. 4-Isopropoxybromobenzene, 11
To a solution of 4-bromophenol (10 g, 58 mmol) and
isopropyl bromide (7.87 g, 64 mmol) in DMF (100 ml)
was added potassium carbonate (9.52 g, 69 mmol) and
the mixture was heated overnight to reflux. After cool-
ing, DMF was removed under reduced pressure and the
residue was dissolved in Et2O (100 ml) and washed with
KOH (1N, 3×50 ml) and brine (50 ml). The organic
layer was dried over MgSO4, evaporated and purified
by distillation under reduced pressure [bp 110°C (12
torr); lit.19 110–112°C (12 torr)] to afford 11 as a
3.7. 2-Isopropoxy-3-methoxy-4%-isopropoxybenzophe-
none, 8
To a solution of alcohol 13 (2 g, 6.1 mmol) in CH2Cl2
(100 ml) was added portionwise pyridinium dichromate
(PDC, 4.6 g, 12.2 mmol). The reaction mixture was
stirred at rt for 10 h. After dilution with Et2O (100 ml),
filtration through a plug of Celite and evaporation of
the solvents, the crude product was purified by flash
column chromatography using AE/PE (20:80) as eluent
to afford 8 as a colorless solid (1.79 g, 90%). Mp 34°C.
1
colorless oil (7.7 g, 52%). H NMR (CDCl3) l (ppm):
1.32 (d, J=7.0, 6H, 2CH3), 4.47 (sept., J=7.0, 1H),

1314
A. Couture et al. / Tetrahedron: Asymmetry 14 (2003) 1309–1316
1H NMR (CDCl3) l (ppm): 1.01 (d, J=6.2, 6H, 2
CH3), 1.33 (d, J=6.1, 6H, 2CH3), 3.86 (s, 3H,
OCH3), 4.21 (sept., J=6.2, 1H), 4.61 (sept., J=6.1,
1H), 6.85 (d, J=8.8, 2H, Harom.), 6.94 (dd, J=7.5,
1.6, 1H, Harom.), 7.00 (dd, J=8.2, 1.6, 1H, Harom.),
7.08–7.11 (m, 1H, Harom.), 7.78 (d, J=8.8, 2H Harom.).
13C NMR (CDCl3) l (ppm): 21.9, 22.1, 55.8, 70.0,
76.7, 113.6, 114.8, 120.8, 123.9, 129.9, 132.5, 135.4,
144.3, 153.0, 162.1, 195.3 (CO). Anal. calcd for
C20H24O4 (328) C, 73.15; H, 7.37. Found C, 73.39; H,
7.55.
62.3, 69.8, 74.2, 109.8, 115.4, 120.8, 122.9, 126.4,
127.8, 127.9, 129.5, 135.4, 138.4, 144.1, 144.4, 152.7,
155.9. Anal. calcd for C30H39NO3 (461) C, 78.05; H,
8.52; N, 3.03. Found C, 78.22; H, 8.37; N, 2.79.
3.9.2. (1R,2R)-N-[2-((2-Isopropoxy-3-methoxy)phenyl)-
4%-isopropoxyphenyl]ethyl-N-methyl-N-1-phenylethyl-
amine, 6. Second product separated by HPLC column
t2=5.84 min. Oil; [h]2D0=−74.8 (c 1.23, CHCl3). 1H
NMR (CDCl3) l (ppm): 1.22 (d, J=6.2, 3H, CH3),
1.28–1.36 (m, 12H, 4 CH3), 2.30 (s, 3H, NCH3), 2.70
(dd, J=12.5, 5.9, 1H), 3.02 (dd, J=12.5, 9.6, 1H),
3.65 (q, J=6.2, 1H), 3.82 (s, 3H, OCH3), 4.53 (sept.,
J=6.1, 1H), 4.62 (sept., J=6.1, 1H), 4.76 (dd, J=9.6,
5.9, 1H), 6.68 (dd, J=7.8, 1.3, 1H, Harom.), 6.75 (dd,
J=8.2, 1.3, 1H, Harom.), 6.81 (d, J=8.6, 2H, Harom.),
6.93 (t, J=7.8, 1H, Harom.), 7.14 (d, J=8.6, 2H,
Harom.), 7.19–7.27 (m, 5H, Harom.). 13C NMR (CDCl3)
l (ppm): 16.7, 22.2, 22.6, 22.9, 37.7, 40.9, 55.6, 59.8,
63.6, 69.8, 74.2, 109.9, 115.5, 120.6, 122.9, 126.5,
127.8, 127.9, 129.7, 135.5, 138.4, 144.2, 144.3, 152.7,
156.0. Anal. calcd for C30H39NO3 (461) C, 78.05; H,
8.52; N, 3.03. Found C, 77.98; H, 8.43; N, 2.97.
3.8. General procedure for synthesis of (1R)-N-[(2-(2-
isopropoxy-3-methoxy)phenyl)-4%-isopropoxyphenyl]vinyl-
N-methyl-N-1-phenylethylamine, 7
n-BuLi (1.6 M in hexanes, 2.1 ml, 3.3 mmol) was
added dropwise to a solution of 9 (1.06 g, 3.04
mmol) in THF (50 ml) at −15°C for 20 min. A solu-
tion of the ketone 8 (0.5 g, 1.52 mmol) in THF (5
ml) was then added. After being stirred at −15°C for
10 min, the reaction mixture was allowed to come to
rt over 1 h. Water (30 ml) was added and the organic
layer separated. The aqueous layer was extracted with
Et2O (2×50 ml) and the combined organic layers were
dried over Na2SO4. After evaporation of the solvents,
a yellow oily product 7 (0.66 g, 95%) was obtained
and was directly used without further purification.
3.10. (2S)-N-[(2-(2-Isopropoxy-3-methoxy)phenyl)-4%-
isopropoxyphenyl]ethyl-N-methylamine, 18
To a solution of diastereopure amine (1R,2S)-6 (300
mg, 0.65 mmol) in MeOH (15 ml) was added
Pd(OH)2 on C (100 mg). Hydrogen was introduced
and the reaction mixture was magnetically stirred at
rt during 12 h. The solution was then filtered through
Celite and after evaporation of the solvents, the
residue was purified by flash column chromatography
with CHCl3/MeOH (94:6) as eluent and by recrystal-
lization from hexane–toluene to yield (S)-18 as a col-
orless solid (221 mg, 95%). Mp 121–123°C;
[h]2D0=+55.4 (c 1.01, CHCl3). 1H NMR (CDCl3) l
(ppm): 1.18 (d, J=6.1, 3H, CH3), 1.27 (d, J=6.0,
6H, 2 CH3), 1.31 (d, J=6.1, 3H, CH3), 2.45 (brs, 3H,
NCH3), 3.33–3.40 (m, 2H), 3.78 (s, 3H, OCH3), 4.47
(sept., J=6.0, 1H), 4.66 (sept., J=6.1, 1H), 4.93–4.99
(m, 1H), 6.67 (d, J=7.6, 1H, Harom.), 6.77–6.82 (m,
3H, Harom.), 6.96 (t, J=7.9, 1H, Harom.), 7.21 (d, J=
8.5, 2H, Harom.). 13C NMR (CDCl3) l (ppm): 22.0,
22.3, 22.8, 33.2, 40.0, 52.5, 55.6, 69.8, 74.7, 111.5,
116.2, 119.8, 123.8, 129.5, 130.7, 134.3, 144.0, 152.9,
157.1. Anal. calcd for C22H31NO3 (357) C, 73.92; H,
8.74; N, 3.92. Found C, 74.16; H, 8.57; N, 4.03.
3.9. Typical procedure for the reduction of the enamine
7
To a solution of enamine 7 (0.56 g, 1.22 mmol) in a
saturated solution of MeOH–HCl (30 ml) at −78°C
was added sodium triacetoxyborohydride (1.3 g, 5
equiv., 6.1 mmol). The mixture was stirred at −78°C
for
4 h. Water (20 ml) and saturated sodium
hydrogenocarbonate solution (30 ml) were successively
added and the aqueous layer was extracted with
CHCl3 (3×30 ml). The combined organic layers were
dried over Na2SO4. Evaporation of the solvent fur-
nished an oily product which was purified by flash
column chromatography using AE/PE (40:60) as elu-
ent (yield 60%; de 85%; Table 1, entry 6). The mix-
ture of diastereomers was separated by chiral HPLC
using a Chiralcel OD column. The eluent was hexane/
isopropanol (HPLC grade 80:20) at 1 ml per min
flow rate and monitored at a wavelength of 254 nm.
3.9.1. (1R,2S)-N-[2-((2-Isopropoxy-3-methoxy)phenyl)-
4%-isopropoxyphenyl]ethyl-N-methyl-N-1-phenylethyl-
amine, 6. First product t1=4.74 min. Oil; [h]2D0=+77.6
3.11. (2R)-N-[(2-(2-Isopropoxy-3-methoxy)phenyl)-4%-
isopropoxyphenyl]ethyl-N-methylamine, 18
1
(c 1.02, CHCl3). H NMR (CDCl3) l (ppm): 1.18 (d,
J=6.2, 3H, CH3), 1.30–1.33 (m, 12H, 4 CH3), 2.19 (s,
3H, NCH3), 2.77–2.92 (m, 2H), 3.72 (q, J=6.2, 1H),
3.81 (s, 3H, OCH3), 4.48 (sept., J=6.2, 1H), 4.57
(sept., J=6.2, 1H), 4.75 (t, J=7.6, 1H), 6.67 (dd,
J=7.8, 1.2, 1H, Harom.), 6.71–6.79 (m, 3H, Harom.),
6.92 (t, J=7.8, 1H, Harom.), 7.08 (d, J=8.6, 2H,
Harom.), 7.15–7.25 (m, 5H, Harom.). 13C NMR (CDCl3)
l (ppm): 15.4, 22.1, 22.6, 22.9, 38.1, 40.6, 55.5, 58.8,
Prepared as previously in Section 3.10 starting from
(1R,2R)-6 (400 mg, 0.87 mmol). (R)-18 was obtained
as a colorless solid (300 mg, 97%). Mp 122–123°C.
[h]2D0=−55.3 (c 0.94, CHCl3). Anal. calcd for
C22H31NO3 (357) C, 73.92; H, 8.74; N, 3.92. Found
C, 74.07; H, 8.88; N, 3.78. The spectroscopic data
were similar to those for (S)-18.

A. Couture et al. / Tetrahedron: Asymmetry 14 (2003) 1309–1316
1315
3.12. (4S)-4-Isopropoxyphenyl-5-isopropoxy-6-methoxy-
2-methyl-1,2,3,4-tetrahydroisoquinoline, 19
Acknowledgements
A solution of amine (S)-18 (300 mg, 0.84 mmol) and
formaldehyde (37%, 2.17 ml) in EtOH (15 ml) was
acidified with 0.7 ml of concentrated aqueous HCl. The
mixture was refluxed for 6 h. The solvent and excess
reagent were removed by rotary evaporation and the
residue was dissolved in CHCl3 (20 ml) and treated
successively with a solution of aqueous ammoniac 10%
(20 ml), water (20 ml) and brine (20 ml). The dried
solution (Na2SO4) was subjected to rotary evaporation
and the residual solid was purified by flash column
chromatography with CHCl3/MeOH (93:7) as eluent to
afford (S)-19 as a pale yellow oil (232 mg, 75%).
[h]2D0=−3.4 (c 0.76, CHCl3). 1H NMR (CDCl3) l (ppm):
0.81 (d, J=6.1, 3H, CH3), 1.09 (d, J=6.1, 3H, CH3),
1.29 (d, J=6.0, 6H, 2CH3), 2.32 (s, 3H, NCH3), 2.60–
2.71 (m, 2H), 3.35 (d, J=14.3, 1H), 3.75 (s, 3H, OCH3),
3.80 (d, J=14.3, 1H), 4.49 (sept., J=6.0, 1H), 4.60
(sept., J=6.1, 1H), 6.74 (d, J=8.6, 1H, Harom.), 6.78 (s,
4H, Harom.), 7.05 (d, J=8.6, 1H, Harom.). 13C NMR
(CDCl3) l (ppm): 21.9, 22.2, 22.5, 41.1, 46.3, 55.6, 58.1,
61.7, 69.7, 73.1, 111.0, 115.2, 120.3, 128.9, 129.4, 131.2,
138.6, 144.4, 150.8, 155.8. Anal. calcd for C23H31NO3
(369) C, 74.76; H, 8.46; N, 3.79. Found C, 74.66; H,
8.79; N, 3.98.
This research was supported by the Centre National de
la Recherche Scientifique (CNRS). Also we wish to
acknowledge helpful discussions and advice from Dr. T.
G. C. Bird (Astra-Zeneca).
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