Asymmetric synthesis of 2-alkyl-substituted tetrahydroquinolines by an enantioselective aza-Michael reaction

Article abstract of DOI:10.1039/c2ob25122a

An optically active tetrahydroquinoline intermediate (5) was prepared in 8 steps from monoprotected ethylene glycol, using a Pd-catalysed aza-Michael reaction to induce chirality. This can be transformed into three Galipea alkaloids (angustureine, galipeine and cuspareine). The proximity of a benzyloxy group is found to exert profound effects in several steps of the synthesis.

Full text of DOI:10.1039/c2ob25122a

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PAPER
Asymmetric synthesis of 2-alkyl-substituted tetrahydroquinolines by an
enantioselective aza-Michael reaction†
Laura L. Taylor,a Frederick W. Goldbergb and King Kuok (Mimi) Hii*a
Received 16th January 2012, Accepted 12th April 2012
DOI: 10.1039/c2ob25122a
An optically active tetrahydroquinoline intermediate (5) was prepared in 8 steps from monoprotected
ethylene glycol, using a Pd-catalysed aza-Michael reaction to induce chirality. This can be transformed
into three Galipea alkaloids (angustureine, galipeine and cuspareine). The proximity of a benzyloxy
group is found to exert profound effects in several steps of the synthesis.
reaction scope was rather limited, prolonged reaction times were
required, and product yields and/or selectivity were modest, even
at high catalyst loadings (≥10 mol%).
Introduction
Angustureine (1), galipeine (2), galipinine (3) and cuspareine (4)
constitute a family of anti-malaria and cytotoxic tetrahydroqui-
noline alkaloids extracted from the bark of a Venezuelan tree
(Galipea officinalis Hancock) (Fig. 1).1–4 Asymmetric synthesis
of these natural products was first achieved by Zhou et al. by cat-
alytic hydrogenation of the corresponding 2-alkyl substituted
quinolines, where up to 97% ee was attained.5,6 The reduction
can also be effected by a non-metal catalyst in 90–91% ee, but
this requires an excess of Hantzsch ester (2.4 eq.) as the hydride
source.7 In comparison, other attempts to access these com-
pounds by catalytic methodologies had been less efficient; these
include Pd-catalysed asymmetric intramolecular alkyne hydro-
amination,8 nucleophilic addition of arylboronic acids to quino-
lines catalysed by chiral thioureas,9 and more recently,
Ir-catalysed allylic substitution by an amine.10 In all cases,
Herein, we will describe the synthesis of these alkaloids from
an optically pure tetrahydroquinoline intermediate (5), derived
from an aza-Michael adduct prepared by the enantioselective
addition of aniline to 7 (Scheme 1).11 In this approach, the
stereogenic centre is installed by a non-hydrogenative step,
allowing the 2-substituent to be defined in the last step of the
synthesis.
Results and discussion
Preparation of Michael acceptors (Scheme 2)
Following published procedures, ethylene glycol was desym-
metrised by using two different O-protecting groups (benzyl and
tert-butyldiphenylsilyl).12,13 Oxidation of 8a–b under Swern
conditions furnished protected β-hydroxy aldehydes 9a and 9b,
respectively. Initial attempts to subject these compounds to the
Horner–Wadsworth–Emmons olefination reaction, using phos-
phonate carbamates 10a–b and DBU, afforded low yields of the
expected products (Table 1, entries 1–3). Attributing this to the
instability of the aldehyde under basic conditions, the reaction
Fig. 1 2-Alkyl tetrahydroquinoline alkaloids isolated from Galipea
officinalis Hancock.
aDepartment of Chemistry, Imperial College London, South Kensington,
London SW7 2AZ, UK. E-mail: mimi.hii@imperial.ac.uk
bAstraZeneca, Mereside, Alderley Park, Cheshire SK10 4TG, UK.
E-mail: frederick.goldberg@astrazeneca.com
†Electronic supplementary information (ESI) available: Copies of 1H
and 13C NMR spectra and chiral HPLC chromatograms for 6b. See
DOI: 10.1039/c2ob25122a
Scheme 1 Retrosynthetic scheme for the synthesis of the Galipea alka-
loids via an aza-Michael reaction.
4424 | Org. Biomol. Chem., 2012, 10, 4424–4432
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Scheme 3 Aza-Michael addition reactions.
Due to their lower solubility, reactions of the TBDPS derivatives
were performed at 50 °C and higher dilutions. Interestingly, the
addition is highly dependent on the O-protecting group
employed on the Michael acceptors: while the addition of aniline
to 7a and 7b was complete within 18 h to give the expected pro-
ducts in moderate ee values (Table 2, entries 1 and 2), reactions
with 7c and 7d were incomplete even after three days (entries 3
and 4). Compounded by their low solubility, and difficulty in the
separation of the enantiomers by chiral HPLC, further work with
the silyl-protected substrates 7c and 7d was consequently
abandoned.
Previously, we have found that the coordination of the
N-nucleophile to the metal centre can have a significant inhibi-
tory effect on the conjugate addition.11b With this in mind, the
addition of aniline was examined at different concentrations of
7a between 1–0.075 M. As expected, an increase in dilution led
to a marked improvement to the enantioselectivity without com-
promising the reaction yield (entries 5–9). Further improvement
was achieved by slow addition of the nucleophile via a program-
mable syringe pump (entries 10 and 11), to afford good enantios-
electivities of 81 and 84% for adducts 6a and 6b, respectively.
Finally, products 6a–b can be rendered enantiomerically pure
by recrystallisation from toluene–cyclohexane, whereby optically
pure material can be recovered from the mother liquor.
Scheme 2 Preparation of Michael acceptors by tandem oxidation and
olefination reactions.
Table 1 Preparation of Michael acceptors 7a–d (Scheme 2, step ii)a
Olefination
Entry Reactant P-reagent Product conditions
Yieldb/%
1
2
3
4
5
6
7
8
9
10
9a
9b
9b
9a
9a
9b
9b
9a
9a
9a
10a
10a
10b
10a
10b
10a
10b
11a
11b
11b
7a
7c
7d
7a
7b
7c
7d
7a
7b
7b
DBU
DBU
DBU
i-PrEt2N, LiCl
i-PrEt2N, LiCl
i-PrEt2N, LiCl
i-PrEt2N, LiCl
—
23
20
21
44
42
32
45
53c
75c
79d,e
—
—
a See Experimental section for reaction conditions. b Isolated yield after
column chromatography. c Mixture of E : Z isomers (ca. 3.5 : 1). d DMP
utilised in the oxidation step. e E-isomer only.
was repeated under Masamune–Roush modified conditions
(Hünig’s base/LiCl),14 but this led only to a marginal improve-
ment (entries 4–7). By using phosphonium ylides 11a and 11b,
the products were attained in acceptable yields as a mixture of
E/Z isomers (ca. 3.5 : 1, entries 8 and 9). Although the selectiv-
ity was somewhat compromised, the isomers can be separated by
column chromatography, and the reaction can be used to furnish
the Michael acceptors on a multigram scale. In a further attempt
to improve the efficiency of this process, a tandem one-pot oxi-
dation–olefination procedure was performed by using DMP
as the oxidant and 11b. In this case, the exclusive formation
of the E-isomer can be achieved in 79% yield over two steps
(entry 10).
Synthesis of the common intermediate 5
The tetrahydroquinoline 5 has been previously synthesised by an
aza-Diels–Alder reaction as a racemic mixture, and shown to be
a viable intermediate for the synthesis of Galipea alkaloids.15,16
In this work, electrophilic cyclisations of N-aryl amino acids to
4-keto tetrahydroquinoline were attempted initially under
Friedel–Crafts conditions,17 or by using the Brønsted acid
PPA.18 Application of these procedures to 13, however, led to
highly capricious reaction mixtures, from which a small amount
of the lactone 14 can be isolated (Scheme 4), i.e. the O-benzyl
protecting group is unstable under these acidic conditions.
The formation of the heterocycle was ultimately achieved by a
reductive cyclization of 6a to afford 4-amino-2-substituted tetra-
hydroquinoline 15 as the syn isomer (Scheme 5).11a,19 Methyl-
ation of 15 at N-1, followed by deprotection of N-2, furnished
compound 17, which was subjected to transamination using
Rapoport’s reagent20 to the 4-keto derivative 18. Finally,
Pd-catalysed enantioselective aza-Michael reactions
The addition of aniline to the series of Michael acceptors 7a–d
was initially performed in toluene in the presence of (R)-
BINAP-complex 12 as a chiral Lewis acid catalyst (Scheme 3).
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Table 2 Optimisation of the aza-Michael reaction (Scheme 5)a
Entry
Substrate
Product
Dilutionb/M
Time
Conversionc/%
eed/%
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7a
6a
6b
6c
6d
6a
0.3
0.4
0.2
0.2
1
0.6
0.3
0.2
16
16
71
71
16
16
16
16
16
17
18
100
100
93
78
96
98
98
95
97
96
96
69
61
ND
ND
39
58
67
74
76
81
84
9
10
11
0.075
e
7a
7b
6a
6b
e
a General reaction condition: catalyst (R)-12 (0.015 mmol, 5 mol%), 10a–d (0.3 mmol, 1 eq.), aniline (0.3 mmol, 1 eq.), toluene, 50 °C. b With respect
to substrate 10a–d. c Determined by 1H NMR. d Determined by chiral HPLC. e Slow addition of aniline (see Experimental section).
Scheme 4 Attempted electrophilic cyclisation. (i) 1 M aq. KOH; (ii)
either: (a) chlorination followed by AlCl3, or (b) PPA.
complete reduction using LiAlH4, facilitated by AlCl3,21 furn-
ished the key intermediate 19.
Unexpectedly, the O-benzyl protecting group of 5 proved to
be inert to most hydrogenation protocols, including the use of
10% Pd/C and a number of hydrogen sources (H2 and 1,4-cyclo-
hexadiene). Ultimately, nickel sponge proved to be an efficient
catalyst,22,23 affording slow but clean conversion of 19 to the
intermediate 5.24
Scheme 5 Transformation of the Michael adduct to 5: (i) MgCl2,
NaBH4, EtOH–THF, −10 °C, 87%; (ii) HCHO, NaCNBH3, AcOH–
CH3CN, 0 °C, 88%; (iii) TMSI, CH3CN, 78%; (iv) a. 4-formyl-1-
Synthesis of three Galipea alkaloids
methylpyridinium benzenesulfonate, DBU, DCM–DMF, rt; b. oxalic
Finally, the tetrahydroquinoline 5 was transformed into the
acid, 75%; (v) LiAlH4, AlCl3, THF, 87%; (vi) RANEY® Ni, H2, EtOH–
Galipea alkaloids by a sequence of oxidation–Wittig–reduction
THF, reflux, 71%.
reactions (Scheme 6), performed in tandem without isolation or
purification of the intermediates 20 (unstable) or 21 (mixture of
E/Z isomers). Overall yields of 44, 32 and 31% (over three
steps) were obtained for the synthesis of angustureine (1), gali-
peine (2) and cuspareine (4), respectively. The benzylic phos-
phonium salts 22a and 22b required for the Wittig reaction were
prepared from commercially available alcohols (Scheme 7). For
the synthesis of galipeine, the phenolic moiety was masked as a
benzyloxy group in 22b, which was removed in the subsequent
catalytic hydrogenation step.
From our previous work, it was expected that the R-enantio-
mer of the key intermediate 5 will be preferentially formed by
employing (R)-BINAP ligated catalyst 12.11a,b Assuming that the
stereochemistry is preserved in subsequent reactions, this will
produce the opposite and natural enantiomeric forms of alkaloids
1 and 2, respectively. Indeed, this was verified by comparing
their spectroscopic and optical rotatory data with reported values
(Table 3). As noted previously,25 the optical rotation of the enan-
tiomerically pure sample of galipeine 2 is considerably larger
than that reported for the natural isomer.
Scheme 6 Transformation of 5 to Galipea alkaloids.
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100 MHz, respectively. Chemical shifts are reported in δ (ppm),
referenced to TMS. Multiplicity is abbreviated to s (singlet),
d (doublet), t (triplet), q (quartet), and m (multiplet). Melting
points were recorded using an Electrothermal Gallenhamp appar-
atus, and were uncorrected. IR spectra were recorded on a Perkin
Elmer Spectrum 100 series FT-IR spectrometer, fitted with a
beam-condensing ATR accessory. Chiral HPLC was performed
on Gilson and Hewlett Packard HPLC systems, each equipped
with variable wavelength UV detectors, using chiral HPLC
columns (250 × 4.6 mm). Mass spectrometry and elemental ana-
lyses were performed by the relevant technical support units at
Imperial College and London Metropolitan University,
respectively.
Scheme 7 Preparation of phosphonium salts used in the Wittig reac-
tion in Scheme 6: (i) BnBr, K2CO3, acetone, reflux; (ii) PBr3, CH2Cl2;
(iii) PPh3, toluene.
Table 3 Synthesis and optical properties of compounds 1, 2 and 4a
All reactions with air- or moisture-sensitive materials were
carried out under N2 using standard Schlenk techniques. Anhy-
drous solvents were dried by passing through molecular sieves
under N2 in purification towers. Unless otherwise stated, all
chemical reagents and precursors were procured from commer-
cial sources and used without purification. The following com-
pounds were prepared by following literature procedures: 2-
(benzyloxy)ethanol (8a),12 2-(2,2-dimethyl-1,1-diphenylpro-
poxy)ethanol (8b),13 benzyl (10a) and methyl (10b) 2-(diethoxy-
phosphoryl)acetylcarbamates.10
Yieldb/%
Obs. [α]D
Lit. [α]2D0
c
Entry
Product
1
2
3
1
2
4
44
32
31
+7.5
−7.16d
−27.0
—
−13.6d, −26.1e
−33.41
f
a Reaction procedures are described in the Experimental section.
b Isolated yield after column chromatography, over two steps. c Recorded
in CHCl3. d Optical rotation reported of the natural product.2,26 e Optical
rotation reported of 2 obtained by asymmetric synthesis (96% ee).25
f Performed only with rac-5.
Synthesis of phosphonium ylides, 11a–b
PPh3 (38.4 g, 146 mmol) was added to benzyl 2-chloroacetylcar-
bamate (27.8 g, 122 mmol) in THF (300 mL). The reaction was
heated to reflux until complete consumption of starting material
occurred (TLC). The reaction mixture was cooled to room temp-
erature, whereupon the phosphonium salt precipitated, which
was collected by filtration.
Fig. 2 Biologically active tetrahydroquinoline derivatives.
(2-(Benzyloxycarbonylamino)-2-oxoethyl)triphenyl-phos-
phonium chloride was collected as a white solid (45.5 g, 76%);
mp 147–149 °C; νmax/cm−1 2870, 1778, 1437, 1109, 687; δH:
12.25 (1H, s, NH), 7.85–7.70 (10H, m, ArH), 7.61–7.55 (5H, m,
ArH), 7.40–7.19 (5H, m, ArH), 5.44 (2H, d, J = 14.0 Hz,
PCH2), 5.11 (2H, s, OCH2Ph); δC: 163.0, 150.6, 135.1, 135.0,
134.0 (d, J = 11 Hz), 130.3 (d, J = 13 Hz), 128.6, 128.4, 128.1,
117.9 (d, J = 89 Hz), 67.0, 33.5 (d, J = 58 Hz); m/z
(HRMS-ESI) 454.1568 ([M − Cl]+ C28H25NO3P requires
454.1572), 326 (6), 224 (15).
Conclusions
Synthesis of Galipea alkaloids 1, 2 and 4 was achieved via a cat-
alytic aza-Michael reaction in 12 steps.27 The proximity of the
O-benzyl group in 7a presented unexpected effects in several
steps of the synthesis. Most crucially, the failure of the electro-
philic cyclisation necessitated a rather circuitous route to the qui-
nolone 18 (steps i–iv, Scheme 5). Nevertheless, the additional
steps provide novel enantiomerically pure tetrahydroquinoline
derivatives (Fig. 2) that are important pharmacophores, for
which there are few synthetic methods.28 For very recent
examples, 4-amino-substituted tetrahydroquinolines I are found
to be non-steroidal selective androgen receptor modulators29 and
bromodomain inhibitors,30,31 while quinolin-4-one derivatives II
have also been reported to have potent binding affinity for 5-
HT6 serotonin receptors.32 Further applications of the catalytic
asymmetric aza-Michael reaction for the synthesis of such highly
functionalised tetrahydroquinolines are currently in progress.
(2-(Methoxycarbonylamino)-2-oxoethyl)triphenyl-phos-
phonium chloride was similarly obtained from methyl 2-chloroa-
cetylcarbamate as a white solid (39 g, 78%); mp 184–186 °C;
νmax/cm−1 3090, 2060, 2890, 3830, 2770, 1780, 1620, 1530,
1440; δH: 12.25 (1H, br. s, NH), 7.83–7.70 (9H, m, Ar-H),
7.55–7.65 (6H, m, Ar-H), 5.45 (2H, d, J = 16.0 Hz, PCH2), 3.62
(3H, s, OCH3); δC: 163.1 (d, J = 4 Hz), 151.2, 135.1, 134.0 (d,
J = 10 Hz), 130.2 (d, J = 13 Hz), 118.0 (d, J = 88 Hz), 52.7,
33.4 (d, J = 58 Hz); m/z (HRMS-ESI) 378.1253 ([M − Cl]+
C22H21NO3P requires 378.1259), 326 (4), 303 (6).
KOtBu (9.92 g, 88.2 mmol) was added slowly in several por-
tions to a suspension of the phosphonium salt (21.6 g,
44.1 mmol) in THF (150 mL) at −5 °C. The solid phosphonium
carbamate salt gradually dissolved during the addition, and the
resultant homogeneous reaction mixture was stirred for 1 h.
CH2Cl2 (300 mL) and H2O (150 mL) were then added.
Experimental
General experimental conditions
1H and 13C NMR spectra were recorded in CDCl3 (unless other-
wise stated) on Bruker AVANCE machines operating at 400 and
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The aqueous layer was extracted with CH2Cl2 (200 mL) and the
combined organic extracts were dried over MgSO4 and concen-
trated under vacuum. The ylide is used directly in the following
reactions without further purification.
δH: 7.79–7.65 (5H, m, Ar-H and NH), 7.52–7.35 (11H, m,
Ar-H), 7.23 (1H, d, J = 15.2 Hz, CHCO), 7.17 (1H, br. d, J =
15.2 Hz, CH2CH), 5.25 (2H, s, OCH2Ar), 4.45–4.40 (2H, m,
OCH2CH), 1.13 (9H, s, CH3); δC: 165.6, 151.4, 148.8, 135.5,
135.1, 133.0, 130.1, 128.7, 128.6, 128.4, 127.8, 119.8, 67.9,
63.3, 26.7, 19.3; m/z (EI) 473.2026 (M+ C28H31NO4Si requires
473.2022) 256 (4), 199 (100).
Preparation of the Michael acceptors by a typical tandem
oxidation–Wittig reaction
Under a N2 atmosphere, DMSO (29.5 mL, 0.415 mol) was
added to a solution of oxalyl chloride (18.1 mL, 0.207 mol) in
CH2Cl2 (600 mL) over 20 min, at −78 °C. The reaction was
stirred for 10 min, followed by the addition of a solution of 8a
(21.0 g, 0.138 mol) in CH2Cl2 (10 mL) over 10 min. After stir-
ring for a further 30 min, NEt3 (91 mL, 0.650 mol) was added
over 20 min. The reaction was allowed to warm to room temp-
erature, diluted with Et2O (600 mL) and filtered through a pad of
MgSO4. The filtrate was concentrated under vacuum to yield the
aldehyde 9a as an unstable yellow oil, to which a solution of the
ylide (0.415 mol, 1 eq.) in CH2Cl2 was immediately added. The
solution was stirred for 16 h, before it was concentrated under
vacuum to give the olefinated product as a mixture of E and Z
isomers, separable by column chromatography.
(E)-Methyl 4-(tert-butyldiphenylsilyloxy)but-2-enoylcarbamate,
7d
White solid purified by recrystallisation from EtOAc–n-hexane
(0.41 g, 45%); mp 134–136 °C; νmax/cm−1 3169, 1746, 1655,
1540, 1230; δH: 7.69 (4H, dd, J = 1.3, 7.7 Hz, Ar-H), 7.62 (1H,
br. s, NH), 7.51–7.36 (6H, m, Ar-H), 7.23 (1H, d, J = 15.2 Hz,
CHCO), 7.16 (1H, dt, J = 2.7, 15.2 Hz, CH2CH), 4.45–4.38
(2H, m, OCH2CH), 3.83 (3H, s, OCH3), 1.12 (9H, s, CH3); δC:
165.8, 152.2, 148.9, 135.5, 132.9, 129.9, 127.8, 119.7, 63.2,
53.1, 26.7, 19.3; m/z (HRMS-ESI) 398.1790 (MH+
C22H28NO4Si requires 398.1788), 256 (10), 199 (100).
Methods for the aza-Michael reaction
Method A (substrate screening): A Radley’s reaction tube was
charged with a stir bar and (R)-12, placed under vacuum for
30 min and then flushed with N2 before toluene was added. The
reaction tube was placed in the heating block and the temperature
was adjusted to 50 °C using a thermostat. The Michael acceptor
(E)-Benzyl 4-(benzyloxy)-but-2-enoylcarbamate, 7a
White solid purified by column chromatography (1.0 g, 61%). Rf
= 0.3 (EtOAc–n-hexane, 3 : 2), E-isomer; mp 98–100 °C; νmax
/
cm−1 3260, 1747, 1650, 1510; δH: 7.76 (1H, br s, NH),
7.44–7.29 (10H, m, Ar-H), 7.15 (1H, dt, J = 3.9, 15.5 Hz,
CH2CH), 7.06 (1H, br d, J = 15.5 Hz, CHCO), 5.22 (2H, s,
CO2CH2), 4.60 (2H, s, OCH2Ar), 4.23 (2H, dd, J = 1.6, 3.9 Hz,
CH2CH); δC: 165.3, 151.4, 146.1, 137.7, 135.0, 128.7, 128.6,
128.5, 128.4, 127.9, 127.8, 121.2, 72.8, 68.8, 67.9; m/z
(HRMS-ESI) 326.1387 (MH+, C19H20NO4 requires 326.1392),
243 (78), 91 (100). Z-isomer Rf = 0.35: mp 72–75 °C; δH: 8.26
(1H, br. s, NH), 7.50–7.26 (10H, m, Ar-H), 6.73 (1H, br. d, J =
11.7 Hz, CHCO), 6.60 (1H, dt, J = 4.5, 11.7 Hz, CH2CH), 5.22
(2H, s, CO2CH2), 4.67 (2H, dd, J = 2.2, 4.5 Hz, CH2CH), 4.57
(2H, s, OCH2Ar); δC: 165.6, 151.6, 150.5, 137.9, 135.0, 128.7,
128.6, 128.5, 128.4, 127.9, 127.8, 119.5, 72.9, 69.3, 67.9.
1
and aniline were added, and the reaction was monitored by H
NMR spectroscopy. Upon completion, the reaction mixture was
evaporated to dryness and the residue was purified by column
chromatography.
Method B (slow addition): A round-bottomed flask was
charged with (R)-12 (0.35 g, 0.329 mmol) and the Michael
acceptor (6.58 mmol). Dry toluene (20 mL) was added and the
mixture was heated to 50 °C to afford a clear solution. To this, a
solution of aniline (0.6 mL, 6.58 mmol) in toluene (15 mL) was
added slowly using a syringe pump, over 20 h. The reaction
mixture was stirred at 50 °C for an additional 18 h, cooled to
room temperature and concentrated under vacuum. The residue
was purified by column chromatography.
(E)-Methyl 4-(benzyloxy)-but-2-enoylcarbamate, 7b
(R)-(+)-Benzyl 4-(benzyloxy)-3-(phenylamino)-butanoylcarbamate,
6a
White solid purified by column chromatography (12.2 g, 74%).
Rf = 0.28 (EtOAc–n-hexane, 3 : 2); mp 83–85 °C; νmax/cm−1
3250, 1770, 1650, 1200; δH: 8.66 (1H, s, NH), 7.39–7.25 (5H,
m, Ar-H), 7.14 (1H, dt, J = 4.2, 15.4 Hz, CH2CH), 7.01 (1H, br
d, J = 15.4 Hz, CHCO), 4.57 (2H, s, OCH2Ar), 4.21 (2H, dd,
J = 1.8, 4.2 Hz, CH2CH), 3.77 (3H, s, OCH3); δC: 165.8, 152.2,
145.9, 137.7, 128.5, 127.8, 127.7, 121.5, 72.8, 68.8, 53.1; m/z
(HRMS-ESI) 250.1078 (MH+, C13H16NO4 requires 250.1079)
158 (38), 143 (78), 91 (100).
Obtained as a light brown oil after column chromatography, Rf =
0.38 (Et2O–n-pentane, 1 : 1); [α]2D5 +3.5° (c = 1.3, CH2Cl2, 85%
ee); Daicel Chiralpak AD-H, 1 : 9 IPA–n-hexane, 1.0 mL min−1
,
tR = 28.7 (major), 33.9 (minor) min; νmax/cm−1 3380, 3280,
1750, 1660, 1210; δH: 7.90 (1H, br. s, NHCO), 7.45–7.29 (10H,
m, Ar-H), 7.19 (2H, dd, J = 7.3, 7.8 Hz, Ar-H), 6.76 (1H, t, J =
7.3 Hz, Ar-H), 6.66 (2H, d, J = 7.8 Hz, Ar-H), 5.19 (2H, s,
CO2CH2), 4.54 (2H, s, OCH2Ar), 4.16 (2H, br. s, ArNH and
CH), 3.71–3.57 (2H, m, OCH2CH), 3.18–3.00 (2H, m, CH2CO);
δC: 172.3, 151.3, 146.5, 137.9, 134.9, 129.4, 128.7, 128.4,
128.4, 127.8, 127.7, 118.3, 114.1, 73.3, 70.9, 67.9, 50.0, 37.9;
m/z (HRMS-EI) 418.1898 (M+, C25H26N2O4 requires 418.1893)
310 (35), 297 (100), 189 (89), 146 (92), 104 (82), 77 (75); Anal.
(E)-Benzyl 4-(tert-butyldiphenylsilyloxy)-but-2-enoylcarbamate,
7c
White solid purified by recrystallisation from EtOAc–n-hexane
(0.5 g, 32%); mp 93–95 °C; νmax/cm−1 3261, 1750, 1655, 1216;
4428 | Org. Biomol. Chem., 2012, 10, 4424–4432
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Calcd for C25H26N2O4: C, 71.75; H, 6.26; N, 6.69%. Found: C,
71.71; H, 6.16; N, 6.79%.
J = 4.9, 10.2 Hz, OCH2), 3.82–3.75 (5H, m, OCH3 and OCH2),
3.18 (1H, dd, J = 6.6, 16.2 Hz, OCH2), 3.11 (1H, dd, J = 5.6,
16.2 Hz, CH2CO), 1.12 (9H, s, CH3); δC: 172.7, 152.1, 146.6,
135.6, 135.5, 133.1, 133.0, 129.9, 129.8, 129.4, 127.8, 127.7,
118.3, 114.1, 64.5, 53.0, 51.6, 37.8, 26.9, 19.3; m/z 490.2292
(M+, C28H34N2O4Si requires 490.2288), 433 (25), 340 (27), 316
(92), 221 (90), 146 (100).
(R)-(+)-Methyl 4-(benzyloxy)-3-(phenylamino)butanoyl-carbamate,
6b
Purified by column chromatography, Rf = 0.33 (Et2O–n-pentane,
2 : 1); [α]2D5 +4.2° (c = 1.2, CHCl3, 97% ee); Daicel Chiralpak
AD-H, 2 : 98 IPA–n-hexane, 1.0 mL min−1, tR = 22.3 (major),
25.5 (minor) min; νmax/cm−1 3260, 3180, 1755, 1600; δH: 7.92
(1H, br s, NHCO), 7.41–7.30 (5H, m, Ar-H), 7.19 (2H, dd,
J = 7.4, 7.8 Hz, Ar-H), 6.76 (1H, t, J = 7.4 Hz, Ar-H), 6.67 (2H,
d, J = 7.8 Hz, Ar-H), 4.54 (2H, s, OCH2Ar), 4.09–4.23 (2H, br.
m, ArNH and CH), 3.77 (3H, s, OCH3), 3.59–3.68 (2H, m,
OCH2), 2.99–3.15 (2H, m, CH2CO); δC: 172.4, 152.0, 145.6,
137.9, 129.4, 128.4, 127.8, 127.7, 118.3, 114.1, 73.3, 70.9, 53.0,
50.1, 37.9; m/z (HRMS-EI) 342.1581 (M+, C19H22N2O4
requires 342.1580), 310 (15), 221 (69), 189 (48), 146 (100),
104 (41), 91 (60).
A sample of optically active 6b (4.12 g, 84% ee) was sus-
pended in EtOAc (6 mL) and heated to reflux. Hexane was then
added dropwise until the solution started to turn cloudy
(∼18 mL). The mixture was cooled to room temperature, where-
upon white needle-like crystals were formed, which were col-
lected by filtration (2.04 g, 70% ee). The filtrate was evaporated
to give optically enriched material (2.04 g, >99% ee). This
process was repeated with the less optically pure product.
Overall, the optically pure product was obtained can be recov-
ered in 77% yield and >99% ee, as a yellow oil.
4-(Benzyloxy)-3-(phenylamino)butanoic acid, 13
To a solution of the carbamate 6a or 6b (2.9 mmol) in MeOH
(30 mL) was added 1 M aq. KOH (29 mL, 29 mmol). The resul-
tant solution was stirred at room temperature for 1 hour, before it
was evaporated. H2O (30 mL) was added to the residue and the
aqueous layer was washed with Et2O (2 × 30 mL), before it was
acidified to pH 4 by the addition of 1 M aq. HCl. The acidic
solution was extracted with EtOAc (3 × 50 mL). The combined
organic extracts were washed with brine, dried over MgSO4 and
evaporated to give the acid as a yellow oil (0.58 g, 70%);
νmax/cm−1 3400, 3050, 2920, 2850, 1710, 1600, 1500; δH:
7.45–7.29 (5H, m, Ar-H), 7.22 (2H, dd, J = 7.4, 8.0 Hz, Ar-H),
6.81 (1H, t, J = 7.4 Hz, Ar-H), 6.71 (2H, d, J = 8.0 Hz, Ar-H),
4.55 (2H, s, OCH2Ar), 4.00 (1H, m, NHCH), 3.62 (2H, close
AB, OCH2), 2.74 (2H, dd, J = 2.6, 6.5 Hz, CH2CO), OH and
NH signals were broadened due to fast exchange; δC: 176.1,
146.0, 137.8, 129.5, 128.5, 127.9, 127.7, 119.1, 114.9, 73.4,
70.4, 50.9, 36.0; m/z (HRMS-ESI) 286.1432 (MH+, C17H20NO3
requires 286.1443), 268 (10), 198 (8).
4-(Methyl(phenyl)amino)dihydrofuran-2(3H)-one, 14
Benzyl 4-(tert-butyldiphenylsilyloxy)-3-( phenylamino)-
butanoylcarbamate, 6c
Yellow oil; νmax/cm−1 2933, 1773, 1597; δH: 7.39 (1H, m, ArH),
7.34–7.26 (2H, m, ArH), 6.91 (2H, m, ArH), 4.69 (1H, m, CH),
4.54 (1H, dd, J = 7.0, 10.0 Hz, OCH2), 4.38 (1H, dd, J = 4.0,
10.0 Hz, OCH2), 2.84–2.76 (4H, m, NCH3 and CH2CO), 2.63
(1H, dd, J = 4.5, 18.0 Hz, CH2CO); δC: 175.7, 149.6, 129.3,
119.9, 116.3, 71.1, 56.2, 33.4, 39.1; m/z (EI) 191 (M+, 95%),
132 (100); (HRMS-EI) 191.0943 (M+, C11H13NO2 requires
191.0946).
Purified as a yellow oil after column chromatography, Rf = 0.30
(Et2O–n-pentane, 3 : 2); separation of enantiomers by chiral
HPLC was not possible, νmax/cm−1 2960, 2940, 2870, 1780,
1700, 1610, 1500; δH: 7.85 (1H, br. s, CONH), 7.69–7.57 (4H,
m, Ar-H), 7.49–7.31 (11H, m, Ar-H), 7.14 (1H, dd, J = 7.3, 7.8,
Ar-H), 6.74 (1H, t, J = 7.3 Hz, Ar-H), 6.54 (2H, d, J = 7.8,
Ar-H), 5.20 (2H, s, OCH2Ar), 4.17 (1H, br. s, ArNH), 4.06–3.98
(1H, br. m, CH), 3.82 (1H, dd, J = 4.8, 10.2 Hz, OSiCH2), 3.77
(1H, dd, J = 3.1, 10.2 Hz, SiOCH2), 3.17 (1H, dd, J = 6.4, 16.2
Hz, CHCH2CO), 3.08 (1H, dd, J = 5.6, 16.2, CHCH2CO),
1.09 (9H, CH3); δC: 135.6, 135.6, 135.0, 133.1, 133.0, 129.9,
129.8, 129.4, 128.7, 128.5, 127.9, 127.8, 118.2, 114.1, 67.8,
64.5, 51.5, 37.8, 26.9, 19.3; m/z (HRMS-ESI) 567.2668 (MH+,
C34H38N2O4Si requires 567.2679), 537 (8), 496 (10).
(2R,4R)-(−)-(2-Benzyloxymethyl-1,2,3,4-tetrahydroquinolin-4-
yl)-carbamic acid methyl ester, 15
To a stirred solution of 6a (6.5 g, 19 mmol) dissolved in
ethanol–THF (1 : 1, 65 mL) was added NaBH4 (0.5 g, 13 mmol)
at −10 °C. A solution of MgCl2·6H2O (4.0 g, 20 mmol) in H2O
(10 mL) was slowly added, maintaining the temperature
below 0 °C. When the addition was complete, the reaction was
allowed to continue at 0 °C for 30 min, before it was quenched
by addition of CH2Cl2 (80 mL), 1 M aq. HCl (80 mL) and
citric acid (9 g, 47 mmol). The biphasic layer was stirred at
room temperature for 4 h. The organic layer was separated,
before the addition of H2O (100 mL), followed by another
portion of citric acid (5.5 g, 28 mmol). After stirring at room
temperature for 45 min, the organic layer was separated, dried
over MgSO4 and concentrated under vacuum. The volatiles
remaining in the residue was displaced by co-distillation with
hexane under reduced pressure, to give the 2,4-disubstituted
Methyl 4-(tert-butyldiphenylsilyloxy)-3-( phenylamino)-
butanoylcarbamate, 6d
Obtained as a yellow oil after column chromatography. Rf = 0.34
(EtOAc–n-hexane, 2 : 3); separation of enantiomers by chiral
HPLC was not possible; νmax/cm−1 2960, 2940, 2870, 1770,
1700, 1610, 1500, 1210, 1110; δH: 8.11 (1H, br. s, NHCO),
7.71–7.60 (4H, m, Ar-H), 7.52–7.33 (6H, m, Ar-H), 7.17 (2H,
dd, J = 7.3, 7.8 Hz, Ar-H1), 6.76 (1H, t, J = 7.3 Hz, Ar-H), 6.59
(2H, d, J = 7.8 Hz, Ar-H), 4.17 (1H, br. s, ArNH), 3.85 (1H, dd,
This journal is © The Royal Society of Chemistry 2012
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tetrahydroquinoline as an off-white solid (5.4 g, 87%); mp
90–92 °C; [α]D25 −13.5° (c = 0.7, CHCl3); νmax/cm−1 3370,
3330, 2950, 2940, 2860, 1710, 1520, 1470, 1240, 1090; δH:
7.47–7.29 (5H, m, Ar-H), 7.19 (1H, dd, J = 1.6, 7.7 Hz, Ar-H),
7.05 (1H, dt, J = 1.6, 7.7 Hz, Ar-H), 6.70 (1H, dt, J = 1.2, 7.7
Hz, Ar-H), 6.54 (1H, dd, J = 1.2, 7.7 Hz, Ar-H), 5.12–5.00 (2H,
m, H-4 and NHCO), 4.59 (2H, s, OCH2Ar), 4.41 (1H, br. s,
ArNH), 3.78–3.69 (4H, m, OCH3 and H-2), 3.57 (1H, dd, J =
3.3, 9.1, CHCH2O), 3.40 (1H, t, J = 9.1, CHCH2O), 2.29–2.09
(1H, m, H-3), 1.55–1.35 (1H, m, H-3′); δC: 157.2, 144.5, 137.9,
128.6, 128.4, 127.9, 127.8, 126.9, 121.8, 117.8, 114.7, 74.0,
73.3, 52.2, 50.4, 47.6, 32.7; m/z (HRMS-EI) 326.1620 (M+,
C19H22N2O3 requires 326.1630), 205 (7), 143 (8), 130 (100), 91
(20); Anal. Calcd for C19H22N2O3: C, 69.92; H, 6.79; N, 8.58%.
Found: C, 70.14; H, 6.91; N, 8.68%.
to dryness. The amine was obtained as a brown oil (0.65 g,
78%); νmax/cm−1 2920, 1600, 1500, 1450, 1370, 1070; δH:
7.38–7.24 (6H, m, Ar-H), 7.20 (1H, t, J = 7.6 Hz, Ar-H), 6.74
(1H, t, J = 7.6 Hz, Ar-H), 6.63 (1H, d, J = 7.6 Hz, Ar-H), 4.58
(1H, d, J = 11.9 Hz, OCH2Ph), 4.51 (1H, d, J = 11.9 Hz,
OCH2Ph), 4.14 (1H, apparent triplet, J = 5.5 Hz, H-4), 3.77 (1H,
dd, J = 4.6, 9.7 Hz, OCH2), 3.70 (1H, dd, J = 5.3, 9.7, OCH2),
3.59 (1H, m, H-2), 3.38 (2H, br. s, NH2), 2.98 (3H, s, NCH3),
2.33 (1H, dt, J = 5.5, 13.7 Hz, H-3), 2.08 (1H, dt, J = 5.7, 13.7
Hz, H-3′); δC: 145.3, 137.9, 128.5, 128.4, 127.7, 127.6, 127.9,
125.4, 116.4, 111.6, 73.3, 72.2, 57.2, 46.6, 37.7, 34.5; m/z
(HRMS-EI) 282.1731 (M+, C18H22N2O requires 282.1732), 265
(5), 161 (55), 144 (100), 91 (32).
(R)-(−)-2-(Benzyloxymethyl)-1-methyl-2,3-dihydroquinolin-4-
(1H)-one, 18
(2R,4R)-(+)-Methyl 2-(benzyloxymethyl)-1-methyl-1,2,3,4-
tetrahydroquinolin-4-ylcarbamate, 16
4-Formyl-1-methylpyridinium
benzenesulfonate
(3.7
g,
13 mmol) was added to a solution of the 17 (2.5 g, 8.8 mmol) in
CH2Cl2–DMF (1 : 1, 50 mL). After stirring for 1 h, DBU
(3.9 mL, 26 mmol) was added and the resulting dark purple sol-
ution was stirred for a further hour at room temperature. The
reaction was quenched by the addition of sat. oxalic acid
(50 mL) and stirred for a further 16 h. The biphasic mixture was
evaporated to dryness and the residue purified by column chrom-
atography to afford the tetrahydroquinolone as a yellow oil
(1.85 g, 75%); Rf = 0.40 (EtOAc–n-hexane, 1 : 1.5); [α]2D5 −88°
(c = 1.0, CHCl3); νmax/cm−1 2870, 1670, 1600, 1490, 1450,
1350, 1210; δH: 7.88 (1H, dd, J = 1.7, 7.8 Hz, Ar-H), 7.42 (1H,
m, Ar-H), 7.3 (5H, m, Ar-H), 6.68 (1H, m, Ar-H), 6.65 (1H, d,
J = 8.5 Hz, Ar-H), 4.46 (2H, s, OCH2Ph), 3.83 (1H, m, H-2),
3.71 (1H, dd, J = 6.6, 9.5 Hz, OCH2), 3.53 (1H, dd, J = 5.9, 9.5
Hz, OCH2), 3.11 (3H, s, NCH3), 3.00 (1H, dd, J = 6.6, 16.6 Hz,
H-3), 2.73 (1H, dd, J = 2.4, 16.6 Hz, H-3′); δC: 192.9, 150.2,
137.8, 135.8, 128.4, 127.7, 127.6, 127.4, 119.0, 116.2, 112.78,
73.4, 68.9, 60.59, 38.9, 38.8; m/z (HRMS-EI) 281.1416 (M+,
C18H19NO2 requires 281.1416), 174 (12), 160 (100), 91 (20);
Anal. Calcd for C18H19NO2: C, 76.84%: H, 6.81%: N, 4.98%.
Found: C, 76.94%: H, 6.66%: N, 4.85%.
A mixture of tetrahydroquinoline 15 (6.2 g, 19 mmol) and for-
maldehyde (37% w/w solution H2O, 14.2 mL, 0.19 mol) in
MeCN (150 mL) was stirred and cooled to 5 °C. NaCNBH3
(3.6 g, 57 mmol) was added portion-wise to the solution, fol-
lowed by glacial acetic acid (3.8 mL, 66 mmol), maintaining the
temperature below 10 °C during the additions. After stirring at
5 °C for a further 30 min, a further portion of glacial acetic acid
was added (3.8 mL, 66 mmol). Stirring was continued at 5 °C
for another 30 min before Et2O (400 mL) was added. The
organic layer was separated and washed with 1 M aq. KOH (3 ×
100 mL), dried over MgSO4, filtered and evaporated in vacuo.
The residue was purified by column chromatography to afford
the product as an off-white solid (5.7 g, 88%). Rf = 0.35
(EtOAc–n-hexane, 1 : 1.5); mp 90–92 °C; [α]2D5 +10° (c = 1.1,
CHCl3); νmax/cm−1 3320, 3030, 2920, 1710, 1700, 1520, 1490,
1240, 1210; δH: 7.44–7.25 (6H, m, Ar-H), 7.21 (1H, m, Ar-H),
6.72 (1H, t, J = 7.3 Hz, Ar-H), 6.65 (1H, d, J = 8.2 Hz, Ar-H),
5.63 (1H, br. d, J = 7.7 Hz, NH), 4.99–4.85 (1H, m, H-4), 4.53
(2H, s, OCH2Bn), 3.85–3.54 (6H, m, CHCH2O, H-2 and
OCH3), 2.99 (3H, s, NCH3), 2.40–2.28 (1H, m, H-3), 2.28–2.16
(1H, m, H-3′); δC: 156.7, 145.9, 137.8, 128.9, 128.4, 127.8,
127.7, 127.6, 122.3, 116.4, 111.5, 73.4, 71.3, 56.8, 51.9, 45.9,
37.8, 32.1; m/z (HRMS-EI) 340.1789 (M+, C20H24N2O3 requires
340.1787), 219 (19), 187 (6), 144 (100), 91 (15); Anal. Calcd
for C20H24N2O3: C, 70.56; H, 7.11; N, 8.23%. Found: C, 70.74;
H, 6.96; N, 8.16%.
(R)-(−)-2-(Benzyloxymethyl)-1-methyl-1,2,3,4-tetrahydroquinoline,
19
A solution of LiAlH4 (30 mg, 0.75 mmol) in THF (0.75 mL)
was added slowly to a vigorously stirred suspension of AlCl3
(60 mg, 0.43 mmol) in Et2O (1 mL). After 20 min, a solution of
the tetrahydroquinolone 18 (60 mg, 0.21 mmol) in THF (1 mL)
was added a rate that is sufficient to maintain a gentle reflux.
When the reaction was judged to be complete (TLC), the
mixture was cooled to 0 °C, whereupon H2O (5 mL) and Et2O
(3 mL) were added. The Et2O layer was decanted and the
aqueous layer was washed several times with Et2O until the
washings were colourless. The combined organic extracts were
dried over MgSO4, filtered, concentrated and purified by column
chromatography, to give the tetrahydroquinoline as a colourless
oil (50 mg, 87%). Rf = 0.45 (EtOAc–n-hexane, 1 : 1), [α]D25
−4.5° (c = 1.4, CH2Cl2); νmax/cm−1 2920, 2850, 1720, 1600,
1500, 1380, 1250; δH: 7.43–7.30 (5H, m, Ar-H), 7.13 (1H, t,
2-(Benzyloxymethyl)-1-methyl-1,2,3,4-tetrahydroquinolin-4-
amine, 17
To a solution of the tetrahydroquinoline 16 (1.00 g, 3.00 mmol)
in MeCN (20 mL) was added TMSI (1.70 mL, 11.7 mmol). The
resultant solution was stirred at room temperature for 18 h. The
reaction was quenched by the addition of MeOH (10 mL), and
evaporated. Et2O (20 mL) and 1 M aq. HCl (20 mL) were added
to the residue and the aqueous layer was separated. The pH of
the solution was adjusted to 12 by the addition of 1 M aq. KOH.
It was then extracted with CH2Cl2 (3 × 40 mL). The combined
organic layers were dried over MgSO4, filtered, and evaporated
4430 | Org. Biomol. Chem., 2012, 10, 4424–4432
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J = 7.6 Hz, Ar-H), 7.00 (1H, d, J = 7.6 Hz, Ar-H), 6.64 (1H, t,
J = 7.6 Hz, Ar-H), 6.58 (1H, d, J = 7.6, Ar-H), 4.60 (1H, d, J =
12.0 Hz, OCH2Ph), 4.52 (1H, d, J = 12.0 Hz, OCH2Ph),
3.65–3.56 (2H, m, CH2O and H-2), 3.53–3.45 (1H, m, CH2O),
3.03 (3H, s, NCH3), 2.82–2.65 (2H, m, H-4), 2.20–2.11 (1H, m,
H-3), 1.97–1.85 (1H, m, H-3′); δC: 145.1, 138.4, 128.6, 128.4,
127.7, 127.6, 127.2, 121.7, 115.5, 110.3, 73.4, 70.5, 58.2, 38.3,
23.7, 22.9; m/z (HRMS-EI) 267.1620 (M+, C18H21NO requires
267.1623), 146 (100), 131 (8), 91 (8); Anal. Calcd for
C18H21NO: C, 80.86; H, 7.92; N, 5.24%. Found: C, 80.66; H,
8.02; N, 5.26%.
maintaining the temperature below 0 °C. After 20 min the reac-
tion was allowed to warm to room temperature and stirring was
continued for an additional 2 h. The reaction was quenched by
the dropwise addition of sat. aq. NaHCO3 (30 mL) and the
aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The com-
bined organic extracts were dried over MgSO4, filtered and evap-
orated to dryness. The resultant bromide was then dissolved in
toluene (30 mL) and triphenylphosphine (1.0 eq.) was added.
The resultant slurry was heated to reflux for 18 h. After cooling
to room temperature, the precipitated solid was collected by fil-
tration and recrystallised from EtOH.
(R)-(−)-(1-Methyl-1,2,3,4-tetrahydroquinolin-2-yl)-methanol, 5
(Benzo-1,3-dioxol-5-ylmethyl) triphenylphosphonium bromide
22a34
Ni sponge (4 g) was added to a solution of the tetrahydroquino-
line 19 (0.8 g, 3.0 mmol) in a mixture of EtOH and THF
(7 : 8 mL). The reaction was heated to reflux under a H2 atmos-
phere. On completion of the reaction (TLC), the mixture was
filtered through celite to remove the catalyst, and the filtrate was
evaporated to dryness. The residue was purified by column
chromatography, giving the alcohol as a colourless oil (0.37 g,
71%). Rf = 0.4 (EtOAc–hexane, 1 : 1): [α]2D5 −16.7° (c = 0.9,
CHCl3); νmax/cm−1 3370, 2940, 2890, 1600, 1510, 1310, 1220,
1040; δH: 7.14 (1H, t, J = 7.6 Hz, Ar-H), 7.01 (1H, d, J = 7.6
Hz, Ar-H), 6.71–6.62 (2H, m, Ar-H), 3.77–3.67 (2H, m,
CH2OH), 3.44–3.37 (1H, m, H-2), 3.04 (3H, s, NCH3),
2.91–2.64 (2H, m, H-4), 2.14–2.05 (1H, m, H-3), 1.97–1.85
(1H, m, H-3′), 1.65 (1H, br. s, OH); δC: 145.5, 128.7, 127.3,
122.5, 116.2, 111.3, 63.3, 60.1, 38.6, 24.3, 23.0; m/z
(HRMS-EI) 177.1154 (M+, C11H15NO requires 177.1154); Anal.
Calcd for C11H15NO: C, 74.54; H, 8.53; N, 7.90%. Found: C,
74.65; H, 8.46; N, 7.80%.
White solid (5.90 g, 95%); mp 221–223 °C (lit. 227–229 °C);35
δH: 7.83–7.60 (15H, m, Ar-H), 6.65–6.60 (1H, m, Ar-H),
6.58–6.51 (2H, m, Ar-H), 5.88 (2H, s, OCH2), 5.31 (2H, d, J =
13.9 Hz, CH2P); δC: 147.7, 135.0, 134.4 (d, J = 10 Hz), 130.1
(d, J = 12 Hz), 125.5 (d, J = 7 Hz), 120.1 (d, J = 9 Hz), 117.8,
111.4, 108.6, 101.3, 30.5 (d, J = 47 Hz); m/z (HRMS-ESI)
397.1353 ([M − Br]+, C26H22O2P requires 397.1357).
(3-(Benzyloxy)-4-methoxybenzyl)triphenylphosphonium
bromide, 22b
White solid (4.30 g, 92%); mp 223–225 °C; δH: 7.84–7.57
(15H, m, Ar-H), 7.28–7.23 (5H, m, Ar-H), 6.85 (1H, s, Ar-H),
6.69 (1H, d, J = 8.3 Hz, Ar-H), 6.63 (1H, d, J = 8.3 Hz, Ar-H),
5.31 (2H, d, J = 13.7 Hz, CH2P), 4.77 (2H, s, OCH2Ph), 3.81
(3H, s, OCH3); δC: 149.6, 148.1, 136.7, 134.9, 134.5 (d, J = 10
Hz), 130.1 (d, J = 12 Hz), 128.4, 127.8, 127.6, 124.5 (d, J = 6
Hz), 118.9 (d, J = 9 Hz), 118.4, 116.7 (d, J = 5 Hz), 111.7, 70.7,
55.9, 30.3 (d, J = 48 Hz); m/z (HRMS-ESI) 489.1968 ([M −
Br]+, C33H30O2P requires 489.1983).
Protection of 3-hydroxy-4-methoxy-benzyl alcohol (Scheme 7,
step i)
To a mixture of the alcohol (0.50 g, 3.20 mmol) and K2CO3
(0.67 g, 4.80 mmol) in acetone (30 mL) was added benzyl
bromide (0.39 mL, 3.20 mmol). The resultant mixture was
heated to reflux under N2 for 4 h. The reaction was then cooled
to room temperature and stirred overnight. EtOAc (50 mL) and
H2O (50 mL) were added and the aqueous layer was extracted
with EtOAc. The combined organic extracts were dried over
MgSO4, filtered and evaporated to dryness to give the product as
a white solid (0.56 g, 71%); mp 68–70 °C (lit.33 65–66 °C);
νmax/cm−1 3360, 2940, 2880, 2840, 1590, 1520, 1420, 1260,
1140; δH: 7.47 (2H, d, J = 7.3 Hz, Ar-H), 7.39 (2H, t, J = 7.3
Hz, Ar-H), 7.36–7.28 (1H, m, Ar-H), 6.95 (1H, s, Ar-H),
6.92–6.84 (2H, m, Ar-H), 5.14 (2H, s, OCH2Ar), 4.54 (2H, s,
HOCH2), 3.88 (3H, s, OCH3); δC: 149.2, 148.3, 137.1, 133.7,
128.6, 127.9, 127.4, 120.0, 113.1, 111.7, 70.9, 65.0, 56.1; m/z
(HRMS-EI) 244.1094 (M+, C15H16O3 requires 244.1099), 136
(5), 91 (100), 65 (10).
Tandem oxidation–Wittig–reduction reactions of 5 (Scheme 6)
At −78 °C, a solution of DMSO (40 μL, 0.56 mmol) in CH2Cl2
(0.5 mL) was added to a solution of oxalyl chloride (28 μL,
0.31 mmol) in CH2Cl2 (1 mL). After stirring for 1 h, a solution
of 5 (50 mg, 0.28 mmol) in CH2Cl2 (0.5 mL) was added drop-
wise, carefully maintaining the temperature below −60 °C. The
reaction was stirred for a further 1 h, before the addition of NEt3
(0.19 mL, 1.4 mmol). The reaction mixture was allowed to warm
to room temperature, whereupon it was quenched by the addition
of sat. aq. NH4Cl (2 mL). The organic layer was separated and
washed with additional portions of sat. aq. NH4Cl (3 × 2 mL),
dried (MgSO4), filtered and evaporated to dryness. The aldehyde
was used immediately in the next step without further
purification.
To
a solution of the requisite phosphonium salt 22
(0.62 mmol, 2.2 eq.) in THF (2 mL), a solution of t-BuOK
(63 mg, 0.56 mmol) in THF (0.5 mL) was added at 0 °C. After
stirring for 30 min, a solution of the aldehyde in THF (0.5 mL)
was added, and the reaction was stirred for 16 h. The solvent
was then removed and the residue was purified by flash column
chromatography (EtOAc–n-hexane, 1 : 9), to give the olefinated
Preparation of phosphonium salts 22 from benzyl alcohols
(Scheme 7, steps ii and iii)
To the corresponding alcohol (2.00 g, 1.0 eq.) in CH2Cl2
(30 mL) at −5 °C was added PBr3 (2.0 eq.) dropwise,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4424–4432 | 4431

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product as a mixture of the E- and Z-isomers. This was dissolved
in a mixture of EtOH and THF (0.5 : 0.5 mL), and subjected to
hydrogenation for 16 h, under H2 (1 atm) over 10% Pd/C
(0.2 g). The Pd/C was removed by filtration through celite, and
the solution evaporated to dryness.
Notes and references
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6 The iodine additive can be replaced by a stoichiometric amount of chloro-
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Purified by column chromatography as a colourless oil (27 mg,
44%). Rf = 0.40 (EtOAc–n-hexane, 1 : 100); [α]2D5 +7.5° (c = 0.4,
CHCl3), lit. −7.16 (c = 1.0, CHCl3, natural product);2,26
νmax/cm−1 2930, 2860, 950, 750; δH: 7.11 (1H, t, J = 7.6 Hz,
Ar-H), 6.99 (1H, d, J = 7.6 Hz, Ar-H), 6.60 (1H, t, J = 7.6 Hz,
Ar-H), 6.55 (1H, d, J = 7.6 Hz, Ar-H), 3.31–3.19 (1H, m, H-2),
2.95 (3H, s, NCH3), 2.91–2.74 (1H, m, H-4), 2.75–2.63 (1H, m,
H-4′), 1.97–1.86 (2H, m, H-3), 1.62 (1H, m, CH2), 1.46–1.26
(10H, m, CH2, and CH3); δC: 145.4, 128.6, 127.1, 121.9, 115.2,
110.4, 59.0, 38.0, 32.1, 31.2, 29.7, 25.8, 24.4, 23.6, 22.7; m/z
(HRMS-ESI) 217.1828 (M+, C15H23N requires 217.1830), 146
(100), 83 (60).
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21 Without the Lewis acid the reaction yielded a mixture of products, includ-
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(−)-Galipeine, 2
Obtained as a colourless gum (27 mg, 32%) after column
chromatography, Rf = 0.28 (Et2O–pentane, 3 : 7); [α]2D5 −27° (c =
0.7, CHCl3), lit. −26.1 (c = 0.44, CHCl3, 96%);25 νmax/cm−1
3500, 2940, 2850, 1600, 1500, 1280; δH: 7.12 (1H, t, J = 8.0
Hz, Ar-H), 7.02 (1H, d, J = 7.2 Hz, Ar-H), 6.88–6.76 (2H, m,
Ar-H), 6.70 (1H, dd, J = 2.0, 8.2, Ar-H), 6.63 (1H, t, J = 7.2 Hz,
Ar-H), 6.57 (1H, d, J = 8.0 Hz, Ar-H), 5.61 (1H, br. s, OH),
3.91 (3H, s, OCH3), 3.39–3.23 (1H, m, H-2), 2.94 (3H, s,
NCH3), 2.92–2.82 (1H, m, H-4), 2.79–2.60 (2H, m, H-4 and
CH2), 2.60–2.46 (1H, m, CH2), 2.04–1.86 (3H, m, CH2 and
H-3), 1.84–1.67 (1H, m, CH2); δC: 145.5, 145.4, 144.8, 135.4,
128.8, 127.1, 121.8, 119.6, 115.4, 114.5, 110.7, 110.6, 58.2,
56.0, 38.0, 32.9, 31.6, 24.4, 23.6. m/z (HRMS-ESI) 298.1796
(MH+, C19H24NO2 requires 298.1807), 194 (2).
( )-Galipinine, 4
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Purified by column chromatography as a colourless gum (26 mg,
31%). Rf = 0.31 (Et2O–hexane 1 : 20); νmax/cm−1 2940, 2880,
1610, 1500, 1490, 1450, 1240; δH: 7.12 (1H, t, J = 7.9 Hz, Ar-
H), 7.01 (1H, d, J = 7.2 Hz, Ar-H), 6.78–6.62 (4H, m, Ar-H),
6.56 (1H, d, J = 7.9, Ar-H), 5.95 (2H, s, OCH2), 3.36–3.26 (1H,
m, H-2), 2.95 (3H, s, NCH3) 2.93–2.85 (1H, m, CH2),
2.78–2.60 (2H, m, H-4 and CH2), 2.61–2.46 (1H, m, H-4′),
2.03–1.84 (3H, m, H-3 and CH2), 1.80–1.67 (1H, m, H-3′); δC:
147.6, 145.6, 145.4, 135.9, 128.7, 127.1, 121.7, 120.9, 115.4,
110.6, 108.7, 108.2, 100.8, 58.2, 38.1, 33.2, 32.0, 24.4, 23.6.
m/z (HRMS-ESI) 296.1647 (MH+, C19H22NO2 requires
296.1651).
Acknowledgements
We thank the EPSRC and AstraZeneca for studentship support
(Doctoral Training Grant: GR/T18783/01). We are also grateful
to Johnson Matthey for the loan of Pd salts, and the gift of
nickel sponge.
35 D. C. Harrowven, M. I. T. Nunn, N. J. Blumire and D. R. Fenwick, Tetra-
hedron, 2001, 57, 4447.
4432 | Org. Biomol. Chem., 2012, 10, 4424–4432
This journal is © The Royal Society of Chemistry 2012