Total syntheses of (±)-cherylline and (±)-latifine

Article abstract of DOI:10.1039/a809925a

A new total synthesis of the two phenolic alkaloids (±)-cherylline 1 and (±)-latifine-2 isolated from Crinum species is described. The two key steps in the elaboration of these natural products are an anionic variant of the Fries rearrangement which gives

Full text of DOI:10.1039/a809925a

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Total syntheses of ( )-cherylline and ( )-latifine
Axel Couture,* Eric Deniau, Stéphane Lebrun and Pierre Grandclaudon
Laboratoire de Chimie Organique Physique, Associé au CNRS (UPRESA 8009),
Université des Sciences et Technologies de Lille 1, F-59655 Villeneuve d’Ascq Cedex, France
Received (in Cambridge) 21st December 1998, Accepted 28th January 1999
A new total synthesis of the two phenolic alkaloids ( )-cherylline 1 and ( )-latifine 2 isolated from Crinum species
is described. The two key steps in the elaboration of these natural products are an anionic variant of the Fries
rearrangement which gives access to the congested o-aroylbenzoic acid derivatives 26 and 27, and an intramolecular
Horner reaction involving the corresponding N-phosphorylmethylbenzamide derivatives 8 and 9.
favour coupling of the carbocation ortho to the hydroxy
Introduction
group.14 Cherylline has also been prepared from the trihydroxy
Cherylline 11 and latifine 22 are new representatives of the rare
derivative 5 by adapting a sophisticated route which mimics
the biogenetic pathway operative in the formation of Amaryl-
lidaceae.13a,c It is also accessible by a synthetic route based upon
the Bischler–Napieralski reaction of N-formyl13b and iso-
cyanide15 derivatives of polyalkoxyphenethylamines accom-
panied by several protection and deprotection steps. This
synthetic approach has also been successfully used for the
enantioselective synthesis of (Ϫ)-cherylline which could equally
be obtained by Polonovski reaction of correctly substituted
dibenzazocine N-oxides.16 Paradoxically, latifine has not elicited
the same interest from the scientific community and total syn-
theses of this structurally challenging alkaloid are extremely
rare. An original and elegant method relying upon the Claisen
rearrangement of benzyloxycinnamyl methoxyphenyl ether has
been reported.17 Extension to the enantioselective synthesis of
the unnatural enantiomer was envisaged in the sequel but the
observed specific rotation of the synthetic material is open to
discussion.17
Results and discussion
We describe here a conceptually new synthetic route which gives
equally easily access to the two alkaloids cherylline 1 and lati-
fine 2. Our approach to the synthesis of compounds 1 and 2,
which is depicted in the retrosynthetic Scheme 1, involved two
phases. Of central importance was the construction of the
4-arylisoquinolone template contiguously and differentially
substituted by phenolic methyl- and benzyl-protected hydroxy
groups on the environmentally different aromatic moieties.
Once prepared, sequential reduction of the carbonyl function
phenolic Amaryllidaceae alkaloids which have been recently
isolated from several Crinum species,3,4 namely Crinum lati-
folium, a plant used as rubefacient and tonic,5 and Crinum
powelli. The structure determination of these unique alkaloids
has revealed latifine to be the first isoquinoline alkaloid possess-
ing a 4-phenyl-5,6-dioxygenated substitution pattern and that it
is isomeric with cherylline, which is the only 4-phenyl-6,7-
dioxygenated isoquinoline alkaloid so far known.4,6
Despite the fact that synthetic studies on aryl 1,2,3,4-tetra-
hydroisoquinolines have attracted much attention owing to
their potential biological activities7,8 and notwithstanding the
increasing medicinal interest in the 4-aryl members of this
family,9–12 synthetic methods for the elaboration of these alkal-
oids, scarce as they are, genuinely lack flexibility and universal-
ity. Thus cherylline has been synthesized in different ways, the
most common ones involving the acid-catalyzed cyclization of
suitably substituted norbelladine derivatives 3.13 The methods
employed differ mainly in the nature of the leaving group Y
prone to generate the carbocationic species involved in the
annulation step. The same methodology has been applied to the
synthesis of regioisomeric latifine but it requires the prelimin-
ary incorporation of a bromine atom in the opened model 4 in
order to circumvent the problem of regioselectivity and to
and of the surviving N–C᎐C unit of the annulated compounds
᎐
6 and 7 generated the tetrahydroisoquinoline ring system, and
O-deprotection of the aromatic amines thus obtained com-
pleted the synthesis of the target natural products. For the
assembly of the isoquinolones 6 and 7 equipped with a pendant
aromatic unit at the 4-position of the heterocyclic nucleus we
have taken advantage of the remarkable nucleophilicity of the
stabilized α-amino carbanions deriving from the phosphoryl-
ated o-aroylbenzamide derivatives 8 and 9 and their ability to
generate the N–C᎐C moiety inter-18 and intra-molecularly.19
᎐
The synthesis of the phosphorylated benzamide derivatives
started with the elaboration of the diprotected o-aroylbenzoic
acid derivatives 26 and 27, which is presented in Scheme 2. The
key step in the elaboration of these rather congested benzo-
phenone derivatives is an anionic homologous variant of the
Fries rearrangement.20 Initially the benzyl protected bromo-
methoxybenzaldehyde derivatives 11 and 12 were obtained by
J. Chem. Soc., Perkin Trans. 1, 1999, 789–794
789

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appropriate hexahydrotriazine with diphenylphosphine oxide.24
This coupling protocol provided the fully benzyl-protected
4-arylisoquinolone progenitors 8 and 9 in excellent yields.
Exposure of the phosphorylated benzamide derivatives 8 and
9 to potassium bis(trimethylsilyl)amide (KHMDS, 1 equiv.) at
Ϫ78 ЊC in THF induced the formation of the phosphoryl
stabilized α-amino carbanion. Addition of this suitably placed
carbon nucleophile to the vicinal aroyl moiety causes the annu-
lation reaction. Warming the reaction mixture to room tem-
perature ensured completion of the reaction and protic work up
afforded straightforwardly the 4-arylisoquinolones 6 and 7 in
excellent yields, probably due to the high degree of conjugation
of the fused compounds. For the final access to the targeted
natural products 1 and 2, sequential reduction of the carbonyl
and enamine functions was subsequently envisaged. It was
found more judicious to adopt an expeditious protocol that
precludes isolation of the intermediates. To this end, the
4-arylisoquinolones 6 and 7 were first treated with LiAlH4 in
THF which led intermediately to the 4-aryl-1,2-dihydroiso-
quinolines 29 and 30.
The adoption of the benzyl-derived protecting groups for the
latent functionalities in this double reduction process was
rewarded here: mild palladium-catalyzed hydrogenolysis of the
transient dihydroisoquinolines 29 and 30 at ambient temper-
ature in the presence of ammonium formate caused reduction
of the N–C᎐C unit and the concomitant deprotection of the
᎐
hydroxy phenolic groups. This protocol resulted in the gener-
ation of ( )-cherylline 1 and ( )-latifine 2 with very satisfactory
yields (47 and 44% respectively over the last four steps). The
final compounds exhibited characterisation data consistent
1
with the proposed structures and H, 13C NMR spectra that
correlated precisely with that of authentic samples.1,2
Scheme 1
Experimental
General methods
sequential benzyl protection followed by bromination of the
syringaldehyde 10 for 11 and by reversing the sequence for 12.
Reduction of the aldehydes 11 and 12 delivered the benzylic
alcohols 13 and 14 which were subsequently treated with 4-
benzyloxybenzoic acid 15 according to the Mitsonobu protocol
to provide the ester precursors 16 and 17. At this stage it
was anticipated that the aryllithium species 18 and 19 could be
readily obtainable from the corresponding aryl bromide by low
temperature halogen–metal exchange with n-butyllithium, since
this reaction is known to proceed at a significantly greater rate
than the alternative pathway of ester attack.21 We further
assumed that these aryllithium species 18 and 19 would under-
go intramolecular attack of the ester moiety and thus generate
the desired ketone linkage between the two aromatic com-
ponents.20 Indeed, such a rearrangement might be expected to
prove very favourable in the light of the greater thermodynamic
stability of the resultant alkoxide ions 20 and 21. Compounds
16 and 17 were thus subjected to halogen–lithium exchange at
low temperature (Ϫ95 ЊC) with n-butyllithium followed by
warming the reaction mixture to Ϫ50 ЊC. To our delight this
treatment gave the desired rearrangement and protic work up
resulted in the formation of the benzophenone derivatives 22
and 23. Although these could be isolated, they proved some-
what unstable and direct oxidation to aldehydes 24 and 25 with
tetrapropylammonium perruthenate() (TPAP) and 4-methyl-
morpholine N-oxide (NMO)22 was generally more convenient.
With these materials in hand, we then employed sodium
chlorite oxidation23 to obtain the carboxylic acids 26 and 27.
Connection of the aminomethyldiphenylphosphine oxide
appendage at the eastern part of the molecule was effected by
reaction of the carboxylic acids 26 and 27 with N-diphenyl-
phosphinoylmethyl-N-methylamine 28 under standard condi-
tions (DCC, DMAP) (Scheme 3). The phosphorylated amine
28 was readily obtained beforehand by treatment of the
Mps were determined on a Reichert-Thermopan apparatus and
are uncorrected. IR spectra were recorded on a Perkin-Elmer
881 spectrometer. 1H (300 MHz) and 13C NMR (75 MHz) spec-
tra 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 stand-
ard. Coupling constants (J) are given in Hz and rounded to the
nearest 0.1 Hz. Mass spectra analyses (MALDI/TOF) were per-
formed on a Finnigan MAT Vision 2000 spectrometer. Elem-
ental analyses were determined by the CNRS microanalysis
centre. TLC was performed with plates coated with Kieselgel G
(Merck). The plates were developed with hexane–ethyl acetate.
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 tech-
niques. Tetrahydrofuran (THF) was distilled from sodium
benzophenone ketyl immediately before use and dichlorometh-
ane (CH2Cl2) was distilled from CaH2. Methanol and ethanol
were distilled from magnesium turnings and acetonitrile from
CaH2 before storage on 4 Å molecular sieves.
Starting materials
Aldehydes 11,25 12,26 benzylic alcohols 13,27 1428 and benzyl
protected benzoic acid 1529 were prepared according to stand-
ard procedures. The phosphorylated amine 2824 was syn-
thesized according to an already reported procedure.
General procedure for the synthesis of esters 16 and 17
A solution of carboxylic acid 15 (2.5 g, 11 mmol), benzylic
790
J. Chem. Soc., Perkin Trans. 1, 1999, 789–794

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Scheme 2 Reagents and conditions: i, BnBr, K2CO3, DMF, reflux, then Br2, AcONa, AcOH (for 11) or Br2, AcOH, reflux, then BnBr, K2CO3, DMF,
reflux (for 12); ii, NaBH4, EtOH, room temp.; iii, 4-BnOC6H4CO2H 15, DEAD, Ph3P, THF, 0 ЊC to room temp., 40 min; iv, BuLi, THF, Ϫ98 to
Ϫ50 ЊC, 30 min; v, NaHCO3, H2O; vi, NMO, TPAP, MeCN, 25 ЊC, 30 min; vii, NaClO2, NaHPO4, 2-methylbut-2-ene, THF, ButOH, H2O, 25 ЊC, 8 h.
alcohol 13 or 14 (3.55 g, 11 mmol) and triphenylphosphine
(3.17 g, 12.1 mmol) in THF (40 mL) was cooled to 0 ЊC and
treated with diethyl azodicarboxylate (DEAD, 1.9 mL, 12.1
mmol). The resultant mixture was then warmed to 25 ЊC and
stirred for 40 min. The reaction mixture was concentrated and
the residue passed through a short column (silica gel, AcOEt–
hexanes 1:5). The eluent was then concentrated and the residue
purified by flash column chromatography using AcOEt–
hexanes (40:60) as eluent to afford the esters 16 and 17 which
were finally purified by recrystallization from MeOH.
(2 H, s, COOCH2Ph), 6.89 (1 H, d, J 8.5, Harom), 7.00 (2 H, d,
J 9.0, Harom), 7.24 (1 H, d, J 8.5, Harom), 7.31–7.60 (10 H, m,
Harom), 8.05 (2 H, d, J 9.0, Harom); δC(CDCl3) C, 120.2 (C–Br),
122.8, 128.6, 136.2, 137.0, 153.8 (C–O), 162.6 (C–O), 166.0
(C᎐O); CH, 111.0, 114.5, 125.8, 127.5, 128.1, 128.2, 128.4,
᎐
128.5, 128.7, 131.8; CH2, 66.2, 70.1, 74.6; CH3, 56.2; m/z (MHϩ)
533, 535.
General procedure for the synthesis of o-aroybenzylic alcohols 22
and 23
A solution of ester 16 or 17 (1.07 g, 2 mmol) in THF (30 mL)
was cooled to Ϫ98 ЊC and treated with BunLi (2.2 mmol, 1.38
mL, 1.6  in hexanes). The resultant mixture was then warmed
to Ϫ50 ЊC and stirred for 30 min. After quenching the reaction
with saturated aqueous NaHCO3 (50 mL), the THF was evap-
orated in vacuo and the residue extracted with AcOEt (2 × 100
mL). The combined organic layers were washed with brine (100
mL) and then dried (Na2SO4), filtered and concentrated. The
residue containing the benzylic alcohols 22 and 23 was used
directly in the next step without further purification.
(5-Benzyloxy-2-bromo-4-methoxyphenyl)methyl 4-benzyloxy-
benzoate 16. White crystals (4.98 g, 85%), mp 96–97 ЊC (Found:
C, 65.2; H, 4.8. C29H25BrO5 requires C, 65.3; H, 4.7%);
νmax(KBr)/cmϪ1 1707 (CO); δH(CDCl3) 3.88 (3 H, s, OCH3), 5.13
(4 H, two s, OCH2Ph), 5.28 (2 H, s, COOCH2Ph), 6.98 (2 H, d,
J 9.0, Harom), 7.02 (1 H, s, Harom), 7.08 (1 H, s, Harom), 7.25–7.44
(10 H, m, Harom), 7.96 (2 H, d, J 9.0, Harom); δC(CDCl3) C, 114.6
(C–Br), 122.6, 128.6, 136.2, 136.5, 147.4 (C–O), 150.2 (C–O),
162.6 (C–O), 165.9 (C᎐O); CH, 114.5, 115.8, 116.0, 127.3,
᎐
127.5, 128.0, 128.2, 128.7, 131.8; CH2, 65.9, 70.1, 71.2; CH3,
56.3; m/z (MHϩ) 533, 535.
General procedure for oxidation of benzylic alcohols 22 and 23 to
benzaldehydes 24 and 25
(3-Benzyloxy-2-bromo-4-methoxyphenyl)methyl 4-benzyloxy-
benzoate 17. White crystals (4.69 g, 80%), mp 105–106 ЊC
(Found: C, 65.3; H, 4.65. C29H25BrO5 requires C, 65.3; H,
4.7%); νmax(KBr)/cmϪ1 1714 (CO); δH(CDCl3) 3.88 (3 H, s,
OCH3), 5.06 (2 H, s, OCH2Ph), 5.11 (2 H, s, OCH2Ph), 5.40
A suspension of the crude benzylic alcohol derivative 22 or 23,
NMO (352 mg, 3 mmol) and activated 3 Å molecular sieves in
acetonitrile (10 mL) was treated with TPAP (35.2 mg, 0.1
mmol) and stirred at 25 ЊC for 30 min. The reaction mixture
J. Chem. Soc., Perkin Trans. 1, 1999, 789–794
791

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General procedure for oxidation of benzaldehydes 24 and 25 to
benzoic acids 26 and 27
A solution of aldehyde 24 or 25 (4.5 g, 10 mmol) in THF (45
mL), ButOH (45 mL) and water (15 mL) was treated with
2-methylbut-2-ene (80 mmol, 40 mL, 2.0  in THF), NaH2PO4
(30 mmol, 30 ml, 1.0  in THF) and 80% NaClO2 (3.39 mg,
30 mmol). The reaction mixture was stirred at 25 ЊC until the
oxidation was complete (8 h) and the organic solvents were then
evaporated in vacuo. The residue was then treated with KHSO4
(100 mL, 0.5  in water) and the resultant aqueous mixture was
extracted with AcOEt (2 × 100 mL). The combined layers were
washed with water (100 ml), saturated Na2SO3 (50 mL) and
brine (100 mL) and then dried (Na2SO4), filtered and concen-
trated. Purification of the residue by recrystallization of the
products from hexane–toluene then afforded the corresponding
o-aroylbenzoic acid derivatives 26 and 27.
2-(4-Benzyloxybenzoyl)-4-methoxy-5-benzyloxybenzoic acid
26. White crystals (3.88 g, 83% before recrystallization), mp
167–168 ЊC (Found: C, 74.45; H, 5.2. C29H24O6 requires C,
74.35; H, 5.15%); νmax(KBr)/cmϪ1 1675 (CO), 1665 (CO);
δH(CDCl3) 3.81 (3 H, s, OCH3), 5.17 (2 H, s, OCH2Ph), 5.23
(2 H, s, OCH2Ph), 6.98 (1 H, s, Harom), 7.09–7.17 (2 H, m,
Harom), 7.28–7.65 (13 H, m, Harom), 11.25 (1 H, s, COOH);
δC(CDCl3) C, 129.5, 133.2, 135.8, 136.5, 136.6, 147.6 (C–O),
151.2 (C–O), 162.0 (C–O), 166.4 (COOH), 194.5 (C᎐O); CH,
᎐
110.5, 113.2, 114.6, 127.8, 127.9, 128.5, 128.6, 129.3, 131.1;
CH2, 69.5, 70.0; CH3, 56.0; m/z (MHϩ) 469.
2-(4-Benzyloxybenzoyl)-4-methoxy-3-benzyloxybenzoic acid
27. White crystals (4.16 g, 89% before recrystallization), mp
174–175 ЊC (Found: C, 74.5; H, 5.1. C29H24O6 requires C, 74.35;
H, 5.15%); νmax(KBr)/cmϪ1 1680 (CO), 1655 (CO); δH(CDCl3)
3.96 (3 H, s, OCH3), 4.77 (2 H, s, OCH2Ph), 5.15 (2 H, s,
OCH2Ph), 7.04–7.15 (4 H, m, Harom), 7.18–7.49 (9 H, m, Harom),
7.62 (2 H, d, J 8.8, Harom), 7.85 (1 H, d, J 8.6, Harom), 11.25 (1 H,
s, COOH); δC(CDCl3) C, 121.2, 130.8, 136.5, 136.7, 136.8, 143.8
Scheme 3 Reagents and conditions: i, DCC, DMAP, CH3NHCH2-
P(O)Ph2 28, CH2Cl2, room temp., 12 h; ii, KHMDS, THF, Ϫ78 ЊC to
room temp., 30 min; iii, LiAlH4, THF, reflux, 2 h; iv, HCO2NH4, Pd/C,
MeOH, reflux, 30 min.
(C–O), 156.2 (C–O), 162.0 (C–O), 165.9 (COOH), 192.8 (C᎐O),
᎐
CH, 112.6, 114.6, 127.5, 127.8, 127.9, 128.0, 128.1, 128.5, 130.6;
was then diluted with AcOEt and filtered through a pad of
silica gel. The filtrate was concentrated and the residue purified
by flash column chromatography using AcOEt–hexanes
(50:50) as eluent to afford the aldehydes 24 and 25.
CH2, 69.5, 74.6; CH3, 56.2; m/z (MHϩ) 469.
General procedure for the synthesis of the phosphorylated
o-aroylbenzamide derivatives 8 and 9
A solution of the benzoic acid derivative 26 or 27 (1 g, 2.14
mmol) in anhydrous CH2Cl2 (50 mL) was added with vigorous
stirring under Ar to a cooled solution (0 ЊC) of the phosphoryl-
ated amine 28 (0.52 g, 2.14 mmol), DCC (0.45 g, 2.14 mmol)
and DMAP (30 mg, 0.214 mmol) in anhydrous CH2Cl2 (20
mL). The mixture was stirred at room temperature for 2 h, then
filtered on Celite and the solvent was evaporated on a rotary
vacuum evaporator. The crude phosphorylated benzamide 8 or
9 was purified by flash column chromatography using acetone–
hexane (65:35) as eluent and finally recrystallized from hexane–
toluene.
5-Benzyloxy-2-(4-benzyloxybenzoyl)-4-methoxybenzaldehyde
24. White crystals (0.72 g, 80% over two steps), mp 134–135 ЊC
(Found: C, 76.9; H, 5.4. C29H24O5 requires C, 77.0; H,
5.35%); νmax(KBr)/cmϪ1 1680 (CO), 1650 (CO); δH(CDCl3)
3.93 (3 H, s, OCH3), 5.15 (2 H, s, OCH2Ph), 5.26 (2 H, s,
OCH2Ph), 7.00 (1 H, s, Harom), 7.04 (2 H, d, J 8.6, Harom),
7.31–7.35 (10 H, m, Harom), 7.62 (1 H, s, Harom), 7.82 (2 H, d,
J 8.6, Harom), 9.87 (1 H, s, CHO); δC(CDCl3) C, 128.0, 128.9,
130.9, 135.9, 137.2, 149.6 (C–O), 153.4 (C–O), 163.3 (C–O),
194.2 (C᎐O); CH, 111.4, 114.8, 127.5, 127.6, 128.3, 128.4,
᎐
128.6, 128.8, 132.6, 189.1 (CH᎐O); CH , 70.3, 71.0; CH ,
᎐
2
3
56.4; m/z (MHϩ) 453.
N-Diphenylphosphinoylmethyl-N-methyl-2-(4-benzyloxy-
benzoyl)-4-methoxy-5-benzyloxybenzamide 8. White crystals
(1.16 g, 78%), mp 75–76 ЊC (Found: C, 74.3; H, 5.4; N, 2.2.
C43H38NO6P requires C, 74.2; H, 5.5; N, 2.0%); νmax(KBr)/cmϪ1
1641 (CO), 1637 (CO), 1166 (PO); δH(CDCl3) 2.98 (3 H, s,
NCH3), 3.80 (3 H, s, OCH3), 4.44 (2 H, d, J 5.1, NCH2P), 4.90
(2 H, s, OCH2Ph), 5.11 (2 H, s, OCH2Ph), 5.98 (1 H, s, Harom),
6.97 (1 H, s, Harom), 6.98 (2 H, d, J 8.8, Harom), 7.26–7.58 (17 H,
m, Harom), 7.73 (2 H, d, J 8.8, Harom), 7.87–7.94 (3 H, m, Harom);
δC(CDCl3) C, 130.0, 130.3, 130.4, 131.1 (Carom–P, d, JCP 94),
135.6, 136.0, 149.1 (C–O), 150.2 (C–O), 162.8 (C–O), 170.5
3-Benzyloxy-2-(4-benzyloxybenzoyl)-4-methoxybenzaldehyde
25. White crystals (0.68 g, 86% over two steps), mp 86–87 ЊC
(Found: C, 77.0; H, 5.4. C29H24O5 requires C, 77.0; H, 5.35%);
νmax(KBr)/cmϪ1 1680 (CO), 1660 (CO); δH(CDCl3) 3.99 (3 H, s,
OCH3), 4.92 (2 H, s, OCH2Ph), 5.09 (2 H, s, OCH2Ph), 6.97 (2
H, d, J 8.9, Harom), 7.13 (1 H, d, J 8.6, Harom), 7.19–7.31 (5 H, m,
Harom), 7.33–7.46 (5 H, m, Harom), 7.76 (1 H, d, J 8.6, Harom),
7.78 (1 H, d, J 8.9, Harom), 9.75 (1 H, s, CHO); δC(CDCl3) C,
128.1, 128.8, 130.7, 135.3, 136.8, 148.5 (C–O), 157.9 (C–O),
163.1 (C–O), 193.7 (C᎐O); CH, 112.1, 114.7, 127.5, 127.9,
᎐
128.2, 128.7, 131.6, 188.9 (CH᎐O); CH , 70.2, 75.9; CH , 56.2;
(NC᎐O), 194.0 (C᎐O); CH, 111.9, 113.9, 114.4, 127.5, 128.3 (d,
JCP 6), 128.6, 128.7, 128.8, 131.2, (d, JCP 10), 132.3 (d, JCP 14);
᎐
᎐ ᎐
2
3
m/z (MHϩ) 453.
792 J. Chem. Soc., Perkin Trans. 1, 1999, 789–794

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CH2, 47.3 (CH2–P, d, JCP 76), 70.1, 70.9; CH3, 39.3 (NCH3),
56.3 (OCH3); δP(CDCl3) 31.5; m/z (MHϩ) 696.
due was then dissolved in anhydrous MeOH (20 mL) and the
solution was treated with ammonium formate (0.66 g, 10.5
mmol) and Pd/C (10%, 20 mg). The resultant reaction mixture
was refluxed for 30 min. MeOH was removed under vacuum
and the crude product was dissolved in CH2Cl2 (30 mL),
washed with water (10 mL) and dried (Na2SO4). Concentration
under vacuum left an oily residue and final recrystallization
from EtOH afforded the desired natural product 1 (0.185 g,
70% after recrystallization) or 2 (0.173 g, 65% after recrystal-
lization). The analytical and spectral data of synthetic 1 and 2
matched those reported for the natural products.
N-Diphenyphosphinoylmethyl-N-methyl-2-(4-benzyloxy-
benzoyl)-4-methoxy-3-benzyloxybenzamide 9. White crystals
(1.22 g, 82%), mp 83–84 ЊC (Found: C, 74.05; H, 5.45; N, 1.95.
C43H38NO6P requires C, 74.2; H, 5.5; N, 2.0%); νmax(KBr)/cmϪ1
1639 (CO), 1633 (CO), 1170 (PO); δH(CDCl3) 3.15 (3 H, s,
NCH3), 3.87 (3 H, s, OCH3), 4.47 (2 H, br s, NCH2P), 4.84 (2 H,
s, OCH2Ph), 5.08 (2 H, s, OCH2Ph), 6.82 (1 H, d, J 8.5, Harom),
6.92 (2 H, d, J 8.7, Harom), 6.95–7.53 (18 H, m, Harom), 7.71 (2 H,
d, J 8.7, Harom), 7.85–7.89 (3 H, m, Harom); δC(CDCl3) C, 125.3,
130.9 (Carom–P, d, JCP 98), 134.0, 136.3, 136.7, 153.4 (C–O),
Acknowledgements
162.9 (C–O), 169.8 (NC᎐O), 193.9 (C᎐O); CH, 112.5, 114.4,
᎐
᎐
122.7, 127.4, 127.8, 128.1 (d, JCP 13.5), 128.2, 128.3, 128.7 (d,
JCP 9), 129.0, 131.1 (d, JCP 10), 132.1 (d, JCP 13.5); CH2, 47.1
(CH2–P, d, JCP 75), 70.1, 75.4; CH3 39.4 (NCH3), 56.0 (OCH3);
δP(CDCl3) 31.5; m/z (MHϩ) 696.
We are grateful to the ‘Centre National de la Recherche
Scientifique’ and the Ministère de l’Enseignement Supérieur et
de la Recherche for a financial support (grant to S. L.). We
would like also to thank G. Bird (Zeneca Pharma, Reims) for
helpful comments on the manuscript.
General procedure for the synthesis of 4-aryl-1(2H)-isoquinol-
ones 6 and 7
References
A solution of KHMDS (1.5 mL, 0.75 mmol, 0.5  in toluene)
was added dropwise to a stirred solution of parent amide 8 or 9
(0.5 g, 0.72 mmol) in THF (30 mL) at Ϫ78 ЊC under Ar. The
solution was stirred for 30 min at Ϫ78 ЊC after which it was
warmed to room temperature and stirred for an additional 30
min. After this, several drops of dilute HCl (10%), water (10
mL), Et2O (20 mL) and CH2Cl2 (20 mL) were added to the
reaction mixture. The organic layer was separated, rinsed with
brine, dried (MgSO4) and concentrated to dryness. The crude
products were purified by flash column chromatography using
AcOEt–hexanes (60:40) as eluent and finally recrystallized
from hexane–toluene.
1 A. Brossi, G. Grethe, S. Tertel, S. C. Wildman and D. T. Bailey,
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3 C. Fuganti, in The Alkaloids, ed. R. H. F. Manske, Academic Press,
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4 M. Shamma and J. L. Moniot, Isoquinoline Alkaloids Research
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4-(4-Benzyloxyphenyl)-6-methoxy-7-benzyloxy-1(2H)-iso-
quinolone 6. White crystals (0.29 g, 85%), mp 168–169 ЊC
(Found: C, 77.8; H, 5.65; N, 3.0. C31H27NO4 requires C, 78.0; H,
5.7; N, 2.9%); νmax(KBr)/cmϪ1 1645 (CO); δH(CDCl3) 3.60 (3 H,
s, NCH3), 3.80 (3 H, s, OCH3), 5.12 (2 H, s, OCH2Ph), 5.27
(2 H, s, OCH2Ph), 6.90 (2 H, s, Harom), 7.07 (2 H, d, J 8.5, Harom),
7.27–7.51 (12 H, m, Harom), 7.96 (1 H, s, Harom); δC(CDCl3)
C, 118.6, 119.8, 129.2, 132.2, 136.5, 136.8, 148.2 (C–O), 153.5
8 Annual Reports in Medicinal Chemistry, ed. H.-J. Hess, Academic
Press, New York, 1978, vol. 13, p. 6; 1978, vol. 14, p. 1; 1981, vol. 16,
p. 89 and references cited therein.
9 J. D. Kohli and L. I. Goldberg, J. Pharm. Pharmacol., 1980, 32, 225.
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1978, 30, 495.
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(C–O), 158.4 (C–O), 161.4 (NC᎐O); CH, 105.3, 109.8, 115.0,
᎐
127.5, 127.6, 128.0, 128.1, 128.5, 128.6, 130.1 (CH᎐), 130.9;
᎐
CH2, 70.1, 70.8; CH3, 37.0 (NCH3), 55.9 (OCH3); m/z (MHϩ)
478.
4-(4-Benzyloxyphenyl)-6-methoxy-5-benzyloxy-1(2H)-iso-
quinolone 7. White crystals (0.28 g, 82%), mp 204–205 ЊC
(Found: C, 78.05; H, 5.6; N, 3.2. C31H27NO4 requires C, 78.0; H,
5.7; N, 2.9%); νmax(KBr)/cmϪ1 1644 (CO); δH(CDCl3) 3.58 (3 H,
s, NCH3), 3.92 (3 H, s, OCH3), 4.30 (2 H, s, OCH2Ph), 4.98
(2 H, s, OCH2Ph), 7.18–7.47 (11 H, m, Harom), 8.38 (1 H, d,
J 8.9, Harom); δC(CDCl3) C, 116.5, 120.7, 131.4, 132.0, 136.9,
137.2, 142.3 (C–O), 156.0 (C–O), 158.0 (C–O), 161.8 (NC᎐O);
CH, 112.1, 113.7, 125.6, 127.5, 127.6, 127.8, 128.0, 128.3, 128.6,
17 S. Takano, M. Akiyama, K. Ogasawara, J. Chem. Soc., Perkin
Trans. 1, 1985, 2447.
᎐
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1993, 34, 1479; (b) B. H. Bakker, D. S. Tjin A-Lim and A. van der
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63, 3128.
130.9, 133.8 (CH᎐); CH , 70.1, 75.4; CH , 36.6 (NCH ), 56.0
᎐
2
3
3
(OCH3); m/z (MHϩ) 478.
General procedure for the synthesis of the targeted ( )-cherylline
1 and ( )-latifine 2
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2091.
A solution of isoquinolone 6 or 7 (500 mg, 1.05 mmol) in
anhydrous THF (20 mL) was treated with LiAlH4 (250 mg, 5.25
mmol) added portionwise at 0 ЊC under Ar over a period of 30
min. The resultant mixture was stirred at 0 ЊC for an additional
30 min then warmed to room temperature and gently refluxed
for 2 h. The excess of hydride was destroyed by careful addition
of EtOH, the reaction mixture was filtered on Celite and the
solvents were subsequently removed under vacuum. The resi-
J. Chem. Soc., Perkin Trans. 1, 1999, 789–794
793

View Article Online
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Tetrahedron Lett., 1996, 37, 7749.
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Perkin Trans. 1, 1987, 931.
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849.
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T. Sugahara, T. Takahashi, Y. Aizawa and M. Toriyama, J. Chem.
Soc., Perkin Trans. 1, 1972, 1435.
29 A. K. Mohammad-Ali, T. H. Chan, A. W. Thomas, B. Jewett and
G. M. Strunz, Can. J. Chem., 1994, 72, 2137.
27 M. R. Paléo, C. Lamas, L. Castedo and D. Dominguez, J. Org.
Chem., 1992, 57, 2029.
Paper 8/09925A
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J. Chem. Soc., Perkin Trans. 1, 1999, 789–794