A new synthesis of (+)- and (-)-cherylline.

Article abstract of DOI:10.1039/b302168h

A new and concise synthesis of enantiopure antipodes of alkaloid cherylline has been devised. The synthetic strategy relies upon the reduction of a diversely and polyprotected diarylenamine bearing a chiral auxiliary. Separation of diastereopure intermediates, concomitant deprotections and intramolecular reductive amination complete the synthesis of the natural (S)-enantiomer and of the unnatural (R)-configured antipode.

Full text of DOI:10.1039/b302168h

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A new synthesis of (؉)- and (؊)-cherylline
Stéphane Lebrun, Axel Couture,* Eric Deniau and Pierre Grandclaudon
Laboratoire de Chimie Organique Physique, associé à l’ENSCL, UMR 8009,
Université des Sciences et Technologies de Lille 1, F-59655 Villeneuve d’Ascq Cedex, France
Received 24th February 2003, Accepted 31st March 2003
First published as an Advance Article on the web 10th April 2003
A new and concise synthesis of enantiopure antipodes of alkaloid cherylline has been devised. The synthetic strategy
relies upon the reduction of a diversely and polyprotected diarylenamine bearing a chiral auxiliary. Separation of
diastereopure intermediates, concomitant deprotections and intramolecular reductive amination complete the
synthesis of the natural (S)-enantiomer and of the unnatural (R)-configured antipode.
quinonoid intermediates14 or (iv) palladium-catalyzed intra-
Introduction
molecular cyclization of amide-enolates.15 Unfortunately, none
During the past few years much effort has been devoted to the
of these methods could be extended to the synthesis of either
the natural (S)-configured compound or the unnatural
antipode. To the best of our knowledge only one asymmetric
synthesis of (Ϫ)-cherylline relying upon a regiocontrolled
stereoselective synthesis of isoquinoline alkaloids owing to
increasing interest in their synthetic organic chemistry.1 In par-
ticular, many strategies have been designed for the highly stereo-
selective synthesis of 1-substituted tetrahydroisoquinolines2
Polonovski-type reaction on dibenzazocine N-oxides has
that have proved to be valuable intermediates for the elabor-
appeared in print,16 whereas otherwise the two antipodes have
ation of a wide array of enantiopure alkaloids.3 Paradoxically,
been obtained from the racemic parent compound by a
although chiral non racemic 4-substituted derivatives are of
resolution process.17
considerable interest, due to their biological activities and as
naturally occurring alkaloids,4 research towards their stereo-
selective syntheses is not as widely extended as in the case of
their 1-substituted congeners. In particular, very little work has
been done on the asymmetric synthesis of arylated or hetero-
arylated C-4 tetrahydroquinolines5 despite the remarkable bio-
logical properties of this class of compounds as exemplified by
nomifensine6 and dichlofensine,7 which inhibit dopamine and
noradrenaline (re)uptake mechanisms.
Results and discussion
We wish therefore to disclose in this paper a new and concise
synthetic approach that gives indiscriminately access to either
(ϩ) or (Ϫ)-cherylline and that involves for the first time the
formation of the (b) carbon–carbon bond of the heterocyclic
unit in the final step. Our synthetic route hinges upon the form-
ation of the diastereomerically pure diarylethylamines
(1R,1ЈR)- and (1S,1ЈR)-2 obtained in the key step by reduction
of the poly and diversely protected diarylenamine 3 equipped
with a stereocontrolling appendage, i.e. the α-methylbenzyl-
amine group (retrosynthetic Scheme 1). When formulating
this synthetic plan we envisioned that the presence of this
chiral auxiliary could significantly act on the level of
diastereoselection at the tertiary carbon centre of 2 and con-
sequently at the dibenzylic carbon centre embedded in the
skeleton of the target natural product 1. Subsequent deprotec-
tion of (1R,1ЈR)- or (1S,1ЈR)-2 followed by regeneration of the
hydroxy phenolic functions on the environmentally different
aromatic moieties and cyclization indeed should not affect the
stereochemistry of the dibenzylic chiral centre and therefore
should complete the synthesis of the target natural product in
both pure enantiomeric forms.
In this context, the synthesis of cherylline 1, a unique repre-
sentative of rare phenolic Amaryllidaceae alkaloids, which has
been isolated from several Crinum species8 and assigned the
(S)-configured structure 1, has proved to be exemplary. Several
racemic syntheses of this structurally challenging alkaloid have
indeed appeared in print and can be cursorily classified into
three main categories which differ in the nature of the carbon–
carbon bond formed in the ultimate step (Fig. 1). In most cases
regioselective regeneration of the phenolic hydroxy functions
and/or reduction of intermediately formed 1- or 3-oxo com-
pounds complete the synthesis of the racemic product. Thus
generation of the (a) carbon–carbon bond has been achieved by
cyclization of suitably substituted β-phenethylisocyanates9 and
by Bischler–Napieralski reaction of N-formyl derivatives of
polyalkoxyphenethylamines.10 (d) Carbon–carbon bond form-
ation has been secured by intramolecular Horner reaction
followed by two reduction processes11 but the most popular
methods involve the creation of the (e) carbon–carbon bond
by (i) photoinduced cyclization of ortho-halogenated N-acyl-
benzylamines,12 (ii) acid catalyzed cyclization of suitably substi-
tuted norbelladine derivatives,13 (iii) intramolecular coupling of
Scheme 1
The synthesis started with the assemblage of one of the
major partners involved in the elaboration of 3, i.e. the rather
congested benzophenone derivative 4 (Scheme 2). Initially,
Fig. 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 7 0 1 – 1 7 0 6
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Scheme 2 Reagents and conditions: (i) Br2, AcONa, AcOH, rt, 70 h;
(ii) 1,3-propanediol, p-TsOH, toluene, reflux, 3 h; (iii) t-BuLi, THF,
Ϫ85 ЊC, then 8, Ϫ85 ЊC to rt, 1 h, then H2O; (iv) PDC, CH2Cl2, 3 h.
benzyl protected isovanillin 5 was regioselectively brominated
to furnish the bromobenzaldehyde 6 which was converted
into the acetal 7 in order to save the formyl functionality for
subsequent manipulations. Bromine–lithium exchange was
performed with t-BuLi at low temperature and quenching
with 4-benzyloxybenzaldehyde 8 delivered the unsymmetrically
substituted dibenzylalcohol 9 in an excellent yield (60% over
three steps). Oxidation under classical conditions furnished the
desired diarylketone derivative 4 with a very satisfactory yield
(81%).
For the synthesis of the diarylenamine 3 equipped with
the chiral auxiliary we opted to adopt a synthetic method that
has been mainly used for homologation of carbonyl com-
pounds and for the generation of acyl anion equivalents.18
This method relies upon Horner reaction between the diaryl-
ketone 4 and the anion derived from the phosphorylated
methylamine 12 bearing the stereocontrolling agent (Scheme
3). Beforehand the mandatory chiral amine 12 was prepared
by N-methylation of the secondary phosphorylated amine 11
obtained by treatment of the triazine 1019 with diphenyl-
phosphine oxide.20
With the rather unstable diarylenamine 3 in hand we
anticipated that the bulky stereocontrolling agent, i.e. the
α-methylbenzyl group, could influence the degree of asym-
metric induction upon hydrogenation of the diarylmethyl-
ene unit namely through chirality transfer via the transient
species involved in the chemical process, i.e. enammonium
and immonium ions.21 Rather disappointingly, modest dia-
stereoselectivity of this process was observed even by varying
the nature of the reducing agent and the temperature. Table 1
summarizes results obtained with NaBH4, NaBH3CN and
NaBH(OAc)3 in MeOH–HCl and it can be seen that the best
diastereoselection [major diastereomer (1R,1ЈR)-13] was
obtained with NaBH3CN for reactions carried out at Ϫ35 ЊC
(entry 3) or with NaBH(OAc)3 for reactions carried out at
Ϫ20 ЊC (entry 4). Interestingly, catalytic hydrogenation of the
parent diarylenamine decreased the diastereoselectivity to some
Scheme 3 Reagents and conditions: (i) Ph2P(O)H, toluene, reflux, 2 h;
(ii) CH2᎐᎐O (37%), NaBH3CN, CH3CN, pH 3–4, rt, 2 h; (iii) n-BuLi,
THF, Ϫ15 ЊC; then 4, Ϫ15 ЊC to rt, 2 h, NH4Cl (10%); (iv)
NaBH3CN, sat. MeOH–HCl, Ϫ35 ЊC, 2 h or NaBH(OAc)3, sat.
MeOH–HCl, Ϫ20 ЊC, 2 h; (v) p-TsOH, toluene, H2O, reflux, 4 h; then
HPLC, chiralcel OD, ethanol–heptane (35 : 65); (vi) Pd/C, H2, MeOH,
rt, 24 h; (vii) p-TsOH, MeOH–toluene, reflux, 9 h.
extent as under these conditions the de was notably lowered to
<10% (entry 7).
Regeneration of the formyl functionality delivered quanti-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 7 0 1 – 1 7 0 6
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Table 1 Diastereoselectivity of the reduction of the diarylenamine 3
Entry
Reducing agent
Temp/ЊC
Time/h
Yield (%)
Dec (%)
a
1
2
3
4
5
6
7
NaBH4
Ϫ35
0
Ϫ35
Ϫ20
Ϫ35
Ϫ78
20
2
2
2
2
2
4
2
72
80
75
78
<10
10
25
25
18
—
<10
NaBH3CNa
NaBH3CNa
a
NaBH(OAc)3 a
NaBH(OAc)3 a
NaBH(OAc)3
70
No reaction
85
b
H2, PtO2
a The reduction was conducted in a saturated solution of MeOH–HCl. b The hydrogenation was conducted in MeOH under H2 (3 atm).
c The diastereomeric excess (de) was estimated by the integration of the N–CH3 signal [(1R,1ЈR)-13, major isomer: δ 2.26 ppm; (1S,1ЈR)-13: δ 2.23
ppm] in the 1H NMR spectrum of the crude reaction mixture.
tatively the benzaldehyde derivatives 2 and preparative HPLC
separation of this pair of enriched diastereomers furnished the
diastereopure isomers (1R,1ЈR)-2 and (1S,1ЈR)-2. Catalytic
hydrogenation of each of the diastereochemically pure
(1R,1ЈR)-2 and (1S,1ЈR)-2 separately with Pd on C offered a
triple advantage in effecting simultaneously the reduction of
the carboxaldehyde function with concomitant removal of the
chiral appendage and retrieval of the hydroxy phenolic func-
tions. This efficient process gave straightforward access to (R)-
14 and (S)-14, direct candidates for the annulation reaction.
The creation of the hetero-ring unit of the natural product pro-
ceeded uneventfully under acid conditions to afford the target
alkaloids (R)-1 and (S)-1. Chiral HPLC analysis by com-
parison with racemic standard unambiguously indicated that
compound (R)-1 and (S)-1 were obtained with excellent
enantioselectivity thus indicating that the stereogenic centre
in (1R,1ЈR)-13 and (1S,1ЈR)-13 was spared and resisted the
different chemical transformations on the pathway to the
annulation reaction.
In conclusion, we have devised a new and concise method for
the preparation of enantiopure (ϩ) and (Ϫ)-cherylline. We suc-
ceeded in accomplishing the synthesis of the two antipodes of
this alkaloid through reduction of a diarylenamine equipped
with a chiral auxiliary, concomitant and differentiated depro-
tections followed by ultimate cyclization. Additionally this
strategy is undoubtedly adaptable to the preparation of a
range of substituted analogues and could be applied to other
4-(hetero)arylated models.
Starting materials
6
Aldehydes 5,22 23 and 822 were prepared according to standard
procedures.
(1R)-N-Diphenylphosphinoylmethyl-N-phenylethylamine 11
A suspension of paraformaldehyde (1 g, 33.33 mmol) in a solu-
tion of (R)-(ϩ)-α-methylbenzylamine (4 g, 33 mmol) in CH2Cl2
(20 mL) was stirred at room temperature for 3 h. Filtration and
evaporation of the solvent left a colourless oil (12.5 g, 95%)
corresponding to the hexahydrotriazine 10 which was used in
the next step without further purification.
A solution of hexahydrotriazine 10 (10 g, 25 mmol) and di-
phenylphosphine oxide (15.2 g, 75 mmol) was refluxed in tolu-
ene (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 phos-
phorylated amine was finally purified by recrystallization from
hexane–toluene to afford 11 as white crystals (20.2 g, 80%).
Mp 190–191 ЊC (Found: C, 75.4; H, 6.8; N, 4.3. C21H22NOP
requires C, 75.1; H, 6.6; N, 4.2%); [α]2D0 = ϩ21 (c 1.0, CHCl3). IR
νmax (KBr)/cmϪ1 3426 (NH), 1185 (P᎐O); H NMR (CDCl )
1
᎐
3
δ (ppm): 1.30 (3 H, d, J = 6.5), 1.94 (1 H, brs, NH), 3.25 (2 H,
dd, J = 8.0, 3.6, NCH2P), 3.76 (1 H, q, J = 6.5), 7.12–7.31 (5 H,
m, Har), 7.34–7.56 (6 H, m, Har), 7.58–7.75 (4 H, m, Har). 13C
NMR (CDCl3) δ (ppm): 24.5 (CH3), 47.1 (d, JCP = 81, NCH2P),
60.0 (d, J = 14, NCH), 126.7 (CHar), 126.8 (CHar), 127.2 (CHar),
128.5 (d, JCP = 11.5, CHar), 128.6 (d, JCP = 11.5, CHar), 131.0 (d,
JCP = 9.5, CHar), 131.3 (d, JCP = 9, CHar), 131.6 (d, JCP = 98, Car),
131.9 (d, JCP = 3, CHar), 132.2 (d, JCP = 98, Car), 144.4. 31P NMR
(CDCl3) δ (ppm): 30.1.
Experimental
General methods
(1R)-N-Diphenylphosphinoylmethyl-N-methyl-N-phenylethyl-
Mps were determined on a Reichert-Thermopan apparatus
and are uncorrected. Infrared spectra were recorded on a FT-
IR Bruker Vector 22 spectrometer. 1H (300 MHz) and 13C
NMR (75 MHz) spectra were recorded on a Bruker AM 300
spectrometer and were referenced against internal tetra-
methylsilane; 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 centre.
TLC was performed with plates coated with Kieselgel G
(Merck). The plates were developed with petroleum ether
(PE)–ethyl acetate (EA). Optical rotations are measured in
amine 12
To a solution of the phosphorylated amine 11 (4 g, 12 mmol) in
acetonitrile (40 mL) at 0 ЊC 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 room temperature. The mixture was basified with
saturated sodium carbonate solution, extracted with CH2Cl2
(3 × 30 mL), dried over MgSO4, filtered and the solvent evapor-
ated. The crude product was purified by flash chromatography
on silica gel using acetone–PE (75 : 25) as eluent to yield amine
12 which was finally purified by recrystallization from hexane–
toluene, white crystals (3.54 g, 85%). Mp 113–114 ЊC (lit.24 114–
117 ЊC); [α]2D0 = ϩ10.5 (c 1.6, CHCl3), [α]2D0 = ϩ49.3 (c 1.0,
MeOH) {lit.24 [α]2D2 = ϩ49.9 (c 1.0, MeOH)}. IR νmax (KBr)/cmϪ1
1174 (P᎐O); 1H NMR (CDCl ) δ (ppm): 1.28 (3 H, d, J = 6.8),
10Ϫ1 deg cm2
g
Ϫ1. 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 a rubber septa and reagent
transfer was performed by syringe techniques. Tetrahydro-
furan (THF) was distilled from sodium benzophenone ketyl
immediately before use. Methanol was distilled from mag-
nesium turnings and acetonitrile from CaH2 before storage on
4 Å molecular sieves.
᎐
3
2.44 (3 H, s, NCH3), 3.22 (1 H, dd, J = 15.0, 6.1, NCH2P), 3.31
(1 H, dd, J = 15.0, 6.5, NCH2P), 3.69 (1 H, q, J = 6.8), 7.09–7.25
(5 H, m, Har), 7.34–7.56 (6 H, m, Har), 7.58–7.73 (4 H, m, Har).
13C NMR (CDCl3) δ (ppm): 15.9 (CH3), 40.5 (d, JCP = 2,
NCH3), 54.1 (d, J = 89, NCH2P), 64.7 (d, J = 12, NCH), 127.3
(CHar), 127.6 (CHar), 128.4 (CHar), 128.7 (d, JCP = 11.5, CHar),
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 7 0 1 – 1 7 0 6
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128.8 (d, JCP = 11.5, CHar), 131.4 (d, JCP = 9, CHar), 131.5 (d,
JCP = 8.5, CHar), 132.0 (d, JCP = 3, CHar), 132.3 (d, JCP = 97, Car),
132.4 (d, JCP = 98, Car), 142.9 (Car). 31P NMR (CDCl3) δ (ppm):
29.6.
requires C, 75.3; H, 5.9%). IR νmax (KBr)/cmϪ1 2850 (OCHO),
1
1646 (C᎐O); H NMR (CDCl ) δ (ppm): 1.31 (1 H, m, Hacetal),
᎐
3
2.02–2.13 (1 H, m, Hacetal), 3.71 (2 H, m, Hacetal), 3.82 (3 H, s,
OCH3), 4.07 (2 H, m, Hacetal), 5.13 (2 H, s, OCH2Ph), 5.20 (2 H,
s, OCH2Ph), 5.59 (1 H, s, OCHO), 6.87 (1 H, s, Har), 7.01 (2 H,
d, J = 8.6, Har), 7.33–7.49 (11 H, m, Har), 7.78 (2 H, d, J = 8.6,
Har). 13C NMR (CDCl3) δ (ppm): 25.6 (CH2), 56.2 (OCH3), 67.3
(OCH2), 70.2 (OCH2Ph), 70.9 (OCH2Ph), 98.7 (OCHO), 111.1
(CHar), 112.2 (CHar), 114.4 (2 CHar), 127.6 (CHar), 127.8
(CHar), 128.1 (CHar), 128.3 (CHar), 128.6 (CHar), 128.7 (CHar),
130.9 (Car), 131.0 (Car), 131.3 (Car), 132.4 (CHar), 136.2 (Car),
136.6 (Car), 148.7 (OCar), 149.8 (OCar), 162.6 (OCar), 195.7
(CO).
2-(5-Benzyloxy-2-bromo-4-methoxyphenyl)-1,3-dioxane 7
To a solution of bromoaldehyde 6 (14.5 g, 45 mmol) in toluene
(100 mL) was added 1,3-propanediol (7.6 g, 100 mL) and
p-TsOH (135 mg). The mixture was refluxed for 3 h and the
water formed removed by azeotropic distillation using a Dean–
Stark apparatus. The solvent was removed and the crude prod-
uct was dissolved in CH2Cl2 (50 mL). The organic layer was
washed successively with a saturated sodium hydrogen carb-
onate solution (40 mL) and brine (30 mL) and finally dried over
MgSO4. Evaporation of the solvent afforded 7 as a white solid
which was recrystallized from hexane–toluene (14.5 g, 85%).
Mp 115–116 ЊC (Found: C, 57.2; H, 5.2. C18H19BrO4 requires C,
Synthesis of the diarylenamine 3
In an atmosphere of dry Ar, a solution of n-BuLi (1.6 M in
hexanes, 1.35 mL, 2.16 mmol) was added dropwise to a solution
of the phosphorylated amine 12 (0.68 g, 1.96 mmol) in THF
(50 mL) at Ϫ15 ЊC with stirring. The orange solution was
stirred for an additional 15 min and a solution of ketone 4
(0.5 g, 0.98 mmol) in THF (5 mL) was then slowly added. After
stirring at Ϫ15 ЊC for 5 min, the reaction mixture was allowed
to come to rt over 30 min and further stirred for 2 h. Aqueous
10% NH4Cl (10 mL) and Et2O (50 mL) were added and the
organic layer separated, rinsed with brine (20 mL), dried
(Na2SO4) and concentrated to dryness. The crude product
was analysed by 1H NMR spectroscopy in order to deter-
mine the stereochemistry of the exclusively formed isomer.
(E)-Diarylenamine 3 obtained almost quantitatively was used
directly in the following reduction step.
1
57.0; H, 5.05%). IR νmax (KBr)/cmϪ1 2854 (OCHO); H NMR
(CDCl3) δ (ppm): 1.43 (1 H, m, Hacetal), 2.31–2.50 (1 H, m,
Hacetal), 3.83 (3 H, s, OCH3), 4.00 (2 H, m, Hacetal), 4.25 (2 H, m,
Hacetal), 5.11 (2 H, s, OCH2Ph), 5.68 (1 H, s, OCHO), 7.00 (1 H,
s, Har), 7.25–7.47 (6 H, m, Har). 13C NMR (CDCl3) δ (ppm):
25.7 (CH2), 56.2 (OCH3), 67.6 (OCH2), 71.1 (OCH2Ph), 100.9
(OCHO), 112.6 (CHar), 113.0 (Car), 115.6 (CHar), 127.8 (CHar),
128.0 (CHar), 128.5 (CHar), 129.8 (Car), 136.6 (Car), 147.9
(OCar), 150.5 (OCar).
2-[5-Benzyloxy-2-(4-benzyloxyphenylhydroxymethyl)-4-
methoxy]-1,3-dioxane 9
A solution of t-BuLi (1.7 M in hexanes, 2.3 mL, 3.96 mmol)
was added dropwise over a period of 10 min to a stirred solu-
tion of acetal 7 (1 g, 2.64 mmol) in anhydrous THF (25 mL) at
Ϫ85 ЊC under Ar. The solution was stirred for 15 min at this
temperature after which a solution of 4-benzyloxybenzaldehyde
8 (0.56 g, 2.12 mmol) in THF (5 mL) was added. The solution
was stirred for 5 min at Ϫ85 ЊC and was allowed to warm to rt
within 1 h. After this, water (10 mL), AcOEt (30 mL) were
subsequently added. The organic layer was separated, rinsed
with brine, dried (MgSO4) and concentrated to dryness. Purifi-
cation by flash column chromatography on silica gel using AE–
PE (50 : 50) as eluent afforded alcohol 9, oil (1.08 g, 80%)
(Found: C, 74.8; H, 6.6. C32H32O6 requires C, 75.0; H, 6.3%). IR
νmax (KBr)/cmϪ1 3474 (OH), 2853 (OCHO); 1H NMR (CDCl3)
δ (ppm): 1.40 (1 H, m, Hacetal), 2.16–2.25 (1 H, m, Hacetal), 3.42
(1 H, d, J = 3.9, OH), 3.73 (3 H, s, OCH3), 3.81–3.93 (2 H, m,
Hacetal), 4.22 (2 H, m, Hacetal), 5.03 (2 H, s, OCH2Ph), 5.08 (2 H,
s, OCH2Ph), 5.49 (1 H, s, OCHO), 6.16 (1 H, d, J = 3.9,
ArCHAr), 6.74 (1 H, s, Har), 6.92 (2 H, d, J = 8.7, Har), 7.31–
7.47 (13 H, m, Har). 13C NMR (CDCl3) δ (ppm): 25.5 (CH2),
56.0 (OCH3), 67.4 (OCH2), 70.0 (ArCHAr), 71.1 (OCH2Ph),
71.7 (OCH2Ph), 100.3 (OCHO), 112.2 (CHar), 112.5 (CHar),
114.6 (CHar), 127.5 (CHar), 127.6 (CHar), 127.7 (Car), 127.9
(CHar), 127.95 (CHar), 128.5 (CHar), 128.6 (CHar), 135.4 (Car),
135.6 (Car), 137.1 (Car), 147.4 (OCar), 149.7 (OCar), 157.8
(OCar).
General procedure for reduction of diarylenamine 3 to amines
(1R,1ЈR)-2 and (1S,1ЈR)-2
To a solution of diarylenamine 3 (0.63 g, 0.98 mmol) in a satur-
ated solution of MeOH–HCl (20 mL) at Ϫ35 ЊC was added
sodium cyanoborohydride (5 equiv., 308 mg, 4.9 mmol). The
mixture was stirred at Ϫ35 ЊC for 2 h. Water (20 mL) and satur-
ated sodium hydrogen carbonate solution (20 mL) were succes-
sively added and the aqueous layer was extracted with CHCl3
(3 × 20 mL). The combined organic layers were dried over
Na2SO4. Evaporation of the solvent furnished an oily product
corresponding to a mixture of two diastereomers (1R,1ЈR)-13
and (1S,1ЈR)-13 (yield 75%, de 25%, Table 1, entry 3) which
were purified by flash column chromatography using AE–PE
(50 : 50) as eluent.
The mixture of (1R,1ЈR)-13 and (1S,1ЈR)-13 (1 g, 1.5 mmol)
was dissolved in toluene (100 mL) and p-TsOH (10 mg) and
water (3 mL) were added. The reaction mixture was refluxed for
4 h. After evaporation of the solvent, the crude product was
purified by flash column chromatography using AE–PE
(50 : 50) as eluent to yield (1R,1ЈR)-2 and (1S,1ЈR)-2 as a col-
ourless oil. The mixture of diastereomers was finally separated
by chiral HPLC using a preparative Chiralcel OD column
(internal diameter: 50 mm; column length: 350 mm) with
ethanol–heptane (HPLC grade, 35 : 65) as eluent. In a
representative run 200 mg of material was separated and this
protocol was repeated 5 times.
4,4Ј-Dibenzyloxy-6-(1,3-dioxanyl)-3-methoxybenzophenone 4
To a solution of alcohol 9 (1.27 g, 2.5 mmol) in CH2Cl2 (25 mL)
was added pyridinium dichromate (PDC, 1.41 g, 3.75 mmol)
and the reaction mixture was stirred under Ar for 3 h.
Anhydrous Et2O (50 mL) was added, the mixture was filtered
on Celite and the filtrate washed with saturated aqueous
sodium hydrogen carbonate solution (20 mL). The organic
layer was dried (Na2SO4) and the residue obtained after
removal of the solvent was purified by flash column chromato-
graphy using AE–PE (40 : 60) as eluent to afford ketone 4
which was recrystallized from hexane–toluene, white crystals
(1.02 g, 81%). Mp 106–107 ЊC (Found: C, 75.3; H, 5.7. C32H30O6
(1R,1ЈR)-5-Benzyloxy-2-{1-(4-benzyloxyphenyl)-2-[methyl-
(1Ј-phenylethyl)amino]ethyl}-4-methoxybenzaldehyde 2
First product separated by HPLC, t1 = 8.32 min. Oil (Found: C,
79.9; H, 6.8; N, 2.7. C39H39NO4 requires C, 80.0; H, 6.7; N
2.4%); [α]2D2 = ϩ53.1 (c 1.05, CHCl3). IR νmax (KBr)/cmϪ1 2862
1
(CHO), 1670 (C᎐O); H NMR (CDCl ) δ (ppm): 1.42 (3 H, d,
᎐
3
J = 6.6, CH3), 2.24 (3 H, s, NCH3), 2.80 (1 H, dd, J = 12.6, 5.5),
3.32 (1 H, dd, J = 12.6, 9.7), 3.56 (1 H, q, J = 6.6), 3.70 (3 H, s,
OCH3), 5.06 (2 H, s, OCH2Ph), 5.11–5.19 (3 H, m, OCH2Ph ϩ
CH), 6.52 (1 H, s, Har), 6.89 (2 H, d, J = 8.7, Har), 7.23–7.47
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 7 0 1 – 1 7 0 6
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(18 H, m, Har), 10.22 (1 H, s, CHO). 13C NMR (CDCl3)
δ (ppm): 17.7 (CH3), 38.7 (NCH3), 40.7 (ArCHAr), 55.8
(OCH3), 60.0 (NCH2), 64.0 (NCH), 70.0 (OCH2Ph), 70.9
(OCH2Ph), 111.4 (CHar), 113.4 (CHar), 114.8 (CHar), 126.7
(CHar), 127.3 (Car), 127.5 (CHar), 127.6 (CHar), 127.7 (CHar),
127.9 (CHar), 128.0 (CHar), 128.5 (CHar), 128.6 (CHar), 129.3
(CHar), 135.3 (Car), 136.6 (Car), 137.0 (Car), 142.1 (Car), 143.7
(Car), 146.6 (OCar), 154.1 (OCar), 157.3 (OCar), 190.0 (CHO).
removed under reduced pressure. The crude product was finally
purified by recrystallization from EtOH.
(4R)-4-(4-Hydroxyphenyl)-6-methoxy-2-methyl-1,2,3,4-tetra-
hydroisoquinolin-7-ol 1
White crystals (80 mg, 85%). Mp 213–214 ЊC (Found: C, 71.4;
H, 6.9; N, 5.0. C17H 19NO3 requires C, 71.6; H, 6.7; N 4.9%);
[α]2D2 = ϩ70.2 (c 0.2, MeOH). IR νmax (KBr)/cmϪ1 3331 (OH); 1H
NMR (CD3OD) δ (ppm): 2.40 (3 H, s, NCH3), 2.40 (1 H, m),
3.04 (1 H, m), 3.42 (1 H, d, J = 14.0), 3.58 (3 H, s, OCH3), 3.68
(1 H, d, J = 14.0), 4.12 (1 H, m, ArCHAr), 6.32 (1 H, s, Har),
6.56 (1 H, s, Har), 6.74 (2 H, m, Har), 7.01 (2 H, m, Har). 13C
NMR (CD3OD) δ (ppm): 45.5 (NCH3), 45.6 (ArCHAr), 56.3
(OCH3), 58.4 (NCH2), 63.0 (NCH2), 113.0 (CHar), 113.5 (CHar),
116.3 (CHar), 127.5 (Car), 129.4 (Car), 131.0 (CHar), 135.8 (Car),
146.3 (OCar), 148.2 (OCar), 157.3 (OCar).
(1S,1ЈR)-5-Benzyloxy-2-{1-(4-benzyloxyphenyl)-2-[methyl-
(1Ј-phenylethyl)amino]ethyl}-4-methoxybenzaldehyde 2
Second product separated by HPLC, t2 = 16.35 min. Oil
(Found: C, 80.2; H, 6.8; N, 2.6. C39H39NO4 requires C, 80.0; H,
6.7; N 2.4%); [α]2D2 = Ϫ25.4 (c 1.18, CHCl3). IR νmax (KBr)/cmϪ1
1
2857 (CHO), 1675 (C᎐O); H NMR (CDCl ) δ (ppm): 1.43
᎐
3
(3 H, d, J = 6.7, CH3), 2.24 (3 H, s, NCH3), 2.90–2.99 (2 H, m),
3.64 (1 H, q, J = 6.7), 3.77 (3 H, s, OCH3), 5.04 (2 H, s,
OCH2Ph), 5.10–5.17 (3 H, m, OCH2Ph ϩ CH), 6.65 (1 H, d,
Har), 6.92 (2 H, d, J = 8.7, Har), 7.08–7.52 (18 H, m, Har), 10.24
(1 H, s, CHO). 13C NMR (CDCl3) δ (ppm): 16.1 (CH3), 38.7
(NCH3), 41.1 (ArCHAr), 55.9 (OCH3), 59.4 (NCH2), 63.4
(NCH), 70.0 (OCH2Ph), 70.9 (OCH2Ph), 111.5 (CHar), 113.8
(CHar), 114.8 (CHar), 126.5 (CHar), 127.3 (Car), 127.4 (CHar),
127.5 (CHar), 127.6 (CHar), 127.8 (CHar), 128.1 (CHar), 128.6
(CHar), 128.7 (CHar), 128.8 (CHar), 129.4 (CHar), 135.4 (CHar),
136.6 (CHar), 137.0 (CHar), 141.8 (CHar), 143.5 (CHar), 146.7
(OCar), 154.1 (OCar), 157.1 (OCar), 190.0 (CHO).
(4S )-4-(4-Hydroxyphenyl)-6-methoxy-2-methyl-1,2,3,4-tetra-
hydroisoquinolin-7-ol 1
White crystals (127 mg, 90%). Mp 214–215 ЊC (lit.,16 217–
218 ЊC; lit.,25 210–213 ЊC); [α]2D2 = Ϫ70.3 (c 0.2, MeOH) {lit.,16
[α]2D1 = Ϫ70 (c 0.1, MeOH); lit.,25 [α]2D0 = Ϫ70.6 (c 0.24, MeOH)}.
Acknowledgements
This research was supported by the Centre National de la
Recherche Scientifique (CNRS). Also we wish to acknow-
ledge helpful discussions and advice from Dr T. G. C. Bird
(Astra-Zeneca).
General procedure for the synthesis of amino alcohols (R)-14 and
(S )-14
To a solution of diastereopure amine (1R,1ЈR)-2 (300 mg, 0.51
mmol) or (1S,1ЈR)-2 (400 mg, 0.68 mmol) in MeOH (10 mL)
was added activated Pd/C (10%, 5 mg). Hydrogen was intro-
duced and the reaction mixture was stirred for 24 h at room
temperature, filtered through Celite and the solvent removed
under reduced pressure. The crude product was purified by
recrystallization from methanol.
References
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(4R)-5-Hydroxymethyl-4-[1-(4-hydroxyphenyl)-2-methylamino-
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White crystals (130 mg, 84%). Mp 165–166 ЊC (Found: C, 67.3;
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1
NH); H NMR (DMSO) δ (ppm): 2.24 (3 H, s, NCH3), 2.38
(1 H, dd, J = 11.2, 7.3), 2.75 (1 H, dd, J = 11.2, 5.3), 3.39 (2 H,
m, CH2OH), 3.51 (3 H, s, OCH3), 3.92–3.96 (1 H, m, ArCHAr),
6.24 (1 H, s, Har), 6.48 (1 H, s, Har), 6.65 (2 H, d, J = 8.5, Har),
6.95 (2 H, d, J = 8.5, Har). 13C NMR (DMSO) δ (ppm): 43.7
(NCH3), 45.6 (ArCHAr), 55.5 (OCH3), 57.3 (OCH2), 61.6
(NCH2), 112.5 (CHar), 112.6 (CHar), 114.8 (CHar), 127.5 (Car),
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(4S )-5-Hydroxymethyl-4-[1-(4-hydroxyphenyl)-2-methylamino-
ethyl]-2-methoxyphenol 14
White crystals (166 mg, 80%). Mp 164–165 ЊC (Found: C, 67.4;
H, 7.1; N, 4.5. C17H21NO4 requires C, 67.3; H, 7.0; N 4.6%);
[α]2D0 = Ϫ43.1 (c 0.22, MeOH).
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and (S )-cherylline 1
To a solution of amino alcohol (4R)-14 (100 mg, 0.33 mmol) or
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was refluxed over a period of 9 h and the water formed removed
by azeotropic distillation using a Dean–Stark apparatus. The
end of the reaction was controlled by TLC and the solvent was
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