Structural revision of the hancock alkaloid (-)-galipeine

Article abstract of DOI:10.1021/acs.joc.7b01720

The 1H and 13C NMR data of synthetic samples of (S)-N1-methyl-2- [2′-(3″-hydroxy-4″-methoxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline, the originally proposed structure of the Hancock alkaloid (-)-galipeine, do not match those of the natural product. Herein, the preparation of the regioisomer (S)-N1-methyl-2-[2′- (3″-methoxy-4″-hydroxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline is reported, the 1H and 13C NMR data of which are in excellent agreement with those of (-)-galipeine. Comparison of specific rotation data enables assignment of the absolute (S)- configuration of the alkaloid, and together, these data engender the structural revision of (-)-galipeine to (S)-N1-methyl-2-[2′-(3″-methoxy-4″-hydroxyphenyl)ethyl]- 1,2,3,4-tetrahydroquinoline.

Full text of DOI:10.1021/acs.joc.7b01720

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Note
Structural Revision of the Hancock Alkaloid (-)-Galipeine
Stephen G. Davies, Ai M. Fletcher, Ian T. T. Houlsby, Paul M. Roberts, and James E. Thomson
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01720 • Publication Date (Web): 15 Aug 2017
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Structural Revision of the Hancock Alkaloid (−)ꢀGalipeine
Stephen G. Davies,* Ai M. Fletcher, Ian T. T. Houlsby, Paul M. Roberts, and James E. Thomson
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Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
Supporting Information Placeholder
1
ABSTRACT: The H and 13C NMR data of synthetic samples of (S)ꢀN(1)ꢀmethylꢀ2ꢀ[2′ꢀ(3″ꢀhydroxyꢀ4″ꢀmethoxyphenyl)ethyl]ꢀ
1,2,3,4ꢀtetrahydroquinoline, the originally proposed structure of the Hancock alkaloid (−)ꢀgalipeine, do not match those of the natuꢀ
ral product. Herein, the preparation of the regioisomer (S)ꢀN(1)ꢀmethylꢀ2ꢀ[2′ꢀ(3″ꢀmethoxyꢀ4″ꢀhydroxyphenyl)ethyl]ꢀ1,2,3,4ꢀ
tetrahydroquinoline is reported, the 1H and 13C NMR data of which are in excellent agreement with those of (−)ꢀgalipeine. Comparꢀ
ison of specific rotation data enables assignment of the absolute (S)ꢀconfiguration of the alkaloid and together, these data engender
the structural revision of (−)ꢀgalipeine to (S)ꢀN(1)ꢀmethylꢀ2ꢀ[2′ꢀ(3″ꢀmethoxyꢀ4″ꢀhydroxyphenyl)ethyl]ꢀ1,2,3,4ꢀtetrahydroquinoline.
1
The isolation of the alkaloid (−)ꢀgalipeine from the angostuꢀ
ra (trunk bark) of Galipea officinalis Hancock was first reportꢀ
ed by JacquemondꢀCollet et al. in 1999.1,2 Following interroꢀ
gation by NMR spectroscopy and mass spectrometry, it was
assigned the gross structure of N(1)ꢀmethylꢀ2ꢀ[2′ꢀ(3″ꢀhydroxyꢀ
4″ꢀmethoxyphenyl)ethyl]ꢀ1,2,3,4ꢀtetrahydroquinoline (its abꢀ
solute configuration was not determined).1 (−)ꢀGalipeine toꢀ
gether with (−)ꢀangustureine, (−)ꢀcuspareine and (−)ꢀ
galipinine (Figure 1) comprise a small family of congeneric
inspection of the H and 13C NMR data reported for (−)ꢀ
galipeine with those of both Zhou et al.11 and Hii et al.13 for
their synthetic samples of (S)ꢀN(1)ꢀmethylꢀ2ꢀ[2′ꢀ(3″ꢀhydroxyꢀ
4″ꢀmethoxyphenyl)ethyl]ꢀ1,2,3,4ꢀtetrahydroquinoline shows
some discrepancies. In this manuscript, we report the preparaꢀ
tion of an independent sample of (S)ꢀN(1)ꢀmethylꢀ2ꢀ[2′ꢀ(3″ꢀ
hydroxyꢀ4″ꢀmethoxyphenyl)ethyl]ꢀ1,2,3,4ꢀtetrahydroquinoline
by a new route involving conjugate addition of lithium (R)ꢀNꢀ
benzylꢀNꢀ(αꢀmethylꢀpꢀmethoxybenzyl)amide
to
4ꢀ(oꢀ
angostura alkaloids based on
a 2ꢀsubstituted 1,2,3,4ꢀ
bromophenyl)ꢀNꢀmethoxyꢀNꢀmethylpentꢀ2ꢀenamide to set the
stereochemistry, and use of a BuchwaldꢀHartwig coupling
reaction to construct the 1,2,3,4ꢀtetrahydroquinoline core. The
1H and 13C NMR data (as well as the specific rotation value) of
our sample of this material are in accord with those of Zhou et
al.11 and Hii et al.13 but these data do not match those for the
natural product (−)ꢀgalipeine, as expected.1 A more detailed
analysis of the available data led us to propose that (−)ꢀ
galipeine is in fact the regioisomeric compound N(1)ꢀmethylꢀ
2ꢀ[2′ꢀ(3″ꢀmethoxyꢀ4″ꢀhydroxyphenyl)ethyl]ꢀ1,2,3,4ꢀ
tetrahydroquinoline core, which are popular targets for laboraꢀ
tory syntheses.3–10 However, galipeine has received scant atꢀ
tention from the synthetic community compared to the reꢀ
mainder of the tetrad: more than ten syntheses of each of the
other alkaloids have been reported, whilst only two studies
concerning galipeine have appeared to date. Zhou et al. were
first to report their synthesis of enantiopure (S)ꢀN(1)ꢀmethylꢀ2ꢀ
[2′ꢀ(3″ꢀhydroxyꢀ4″ꢀmethoxyphenyl)ethyl]ꢀ1,2,3,4ꢀ
tetrahydroquinoline [possessing the gross structure assigned to
1
(−)ꢀgalipeine] in 2004,11 and concluded that the H and 13C
tetrahydroquinoline. We prepared an authentic, enantiopure
sample of this material and its H and 13C NMR data were
1
NMR data of this material were identical to those of the natuꢀ
ral product. Comparison of their specific rotation value of
found to be effectively identical to those of the natural prodꢀ
uct. Comparison of specific rotation data allowed us to assign
the absolute (S)ꢀconfiguration to (−)ꢀgalipeine. Together, these
data thus call for the structural revision of (−)ꢀgalipeine to (S)ꢀ
N(1)ꢀmethylꢀ2ꢀ[2′ꢀ(3″ꢀmethoxyꢀ4″ꢀhydroxyphenyl)ethyl]ꢀ
1,2,3,4ꢀtetrahydroquinoline and the studies contained herein
comprise the unambiguous structural determination of (−)ꢀ
galipeine, its first asymmetric synthesis, and assignment of its
absolute configuration.
20
[α]D −26.1 (c 0.44 in CHCl3)12 with that reported for the
natural product of [α]D −13.6 (temperature, concentration nor
solvent were specified)1 led Zhou et al. to propose the absolute
(S)ꢀconfiguration for the natural product.11 Subsequently, Hii
et al. reported an alternative approach to (S)ꢀN(1)ꢀmethylꢀ2ꢀ
[2′ꢀ(3″ꢀhydroxyꢀ4″ꢀmethoxyphenyl)ethyl]ꢀ1,2,3,4ꢀ
tetrahydroquinoline in 201213 and asserted the congruency of
their synthetic sample with the natural product by comparison
of NMR data and sign of the specific rotation value. In fact,
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configuration. Thus, the absolute configurations that had been
assigned to the precursors 6–8, 11 and 12 were also confirmed
(Figure 2).
1
2
Me
Me
N
N
3
4
5
6
Scheme
1.
(S)ꢀN(1)ꢀMethylꢀ2ꢀ[2′ꢀ(3″ꢀhydroxyꢀ4″ꢀ
methoxyphenyl)ethyl]ꢀ1,2,3,4ꢀtetrahydroquinoline 13
MeO
MeO
O
Swern
oxidation
NaBH4
BF3—OEt2
CO2H
Me
7
(−)ꢀangustureine
(−)ꢀcuspareine
OH
N
8
9
OMe
then 3
rt, 16 h
THF, 0 °C
1 h
Me
Me
10
11
12
13
14
15
16
17
18
19
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N
N
Br
Br
Br
1
2, 92%
4, 78%, >95:5 dr
[(E):(Z) ratio]
O
HO
(R)ꢀ5, THF
78 °C, 2 h
Ph
O
O
Ph3P
Me
−
N
PMP
N
Li
3
Ph
Ph
OMe
MeO
(−)ꢀgalipeine
originally proposed
(−)ꢀgalipinine
(R)ꢀ5
HN
O
PMP
N
O
Me
Me
HCO2H
N
N
Figure 1. Structures of tetrahydroquinoline Hancock alkaloids.
OMe
OMe
Et3SiH
Alerted to discrepancies in the reported data, our initial goal
was the preparation of an independent sample of (S)ꢀN(1)ꢀ
methylꢀ2ꢀ[2′ꢀ(3″ꢀhydroxyꢀ4″ꢀmethoxyphenyl)ethyl]ꢀ1,2,3,4ꢀ
tetrahydroquinoline [the structure originally assigned to (−)ꢀ
galipeine].1 Our synthesis commenced from commercially
available 3ꢀ(oꢀbromophenyl)propanoic acid 1. Reduction of 1
90 °C, 16 h
Br
Br
7, 81%
6, 80%, >95:5 dr
Pd(OAc)2, XPhos, Cs2CO3
PhMe, reflux, 24 h
14
Ph
Ph
using NaBH4 in the presence of BF3·OEt2 gave the correꢀ
10
sponding alcohol 2 in 92% yield. Oneꢀpot Swern oxidaꢀ
tion/Wittig reaction of 2 using Ph3P=CHCON(Me)(OMe) 3 as
the ylide then gave 4 as a single diastereoisomer [>95:5 dr,
(E):(Z) ratio], which was isolated in 78% yield. The geometry
of the olefin within 4 was assigned on the basis of the diagnosꢀ
N
N
THF, −78 °C
90 min
2''
5''
Me
TBSO
3''
4''
1''
6''
N
O
O
6
3
1
3
3
TBSO
MeO
X
1
2
5
4
tic H NMR J coupling constant: JHꢀ2,Hꢀ3 = 15.4 Hz. Conjuꢀ
gate addition of lithium (R)ꢀNꢀbenzylꢀNꢀ(αꢀmethylꢀpꢀ
methoxybenzyl)amide 5 then delivered βꢀamino amide 6 as a
single diastereoisomer (>95:5 dr), which was isolated in 80%
yield. The absolute configuration of the newly formed C(3)ꢀ
stereogenic center of 6 was assigned by reference to the transiꢀ
tion state mnemonic devised by us to predict the stereochemiꢀ
cal outcome of this type of conjugate addition reaction.15 Subꢀ
sequent treatment of 6 with HCO2H in the presence of
Et3SiH16–18 effected chemoselective removal of the Nꢀαꢀ
methylꢀpꢀmethoxybenzyl group to furnish 7 in 81% yield.
Treatment of 7 with 5 mol% Pd(OAc)2 in the presence of
XPhos and Cs2CO3 in PhMe at reflux for 24 h gave tetrahyꢀ
droquinoline 8 quantitatively. OꢀtertꢀButyldimethylsilylꢀ5ꢀ
bromoguaiacol 9 was converted to the corresponding aryllithiꢀ
um regent 10 upon reaction with nꢀBuLi; addition of 8 to the
reaction flask then produced ketone 11 after workꢀup, which
was isolated in 88% yield. Treatment of 11 with LiAlH4 and
then TFA in the presence of Et3SiH gave 12 in 50% yield (i.e.,
in addition to reduction of the ketone functionality, deprotecꢀ
tion of the Oꢀsilyl group had also occurred during this twoꢀ
step sequence). Subjection of 12 to an atmosphere of hydrogen
in the presence of Pd/C and aqueous formaldehyde (formalin)
resulted in hydrogenolytic Nꢀdebenzylation and reductive Nꢀ
methylation, giving 13 in 57% yield (Scheme 1). The identity
of 13 was unambiguously secured by single crystal Xꢀray difꢀ
fraction analysis,19 and the determination of a Flack x parameꢀ
ter20,21 for the crystal structure of −0.1(2), which satisfies the
criterion for reliable configurational assignment of a material
known to be enantiopure, confirmed its absolute (S)ꢀ
OMe
MeO
8, quant
11, 88%
LiAlH4, THF, reflux, 16 h
then TFA, Et3SiH, rt, 16 h
9, X = Br
10, X = Li
Ph
Me
H2, Pd/C
N
N
formalin
MeOH, rt
24 h
HO
HO
MeO
MeO
13, 57%
12, 50%
PMP = pꢀmethoxyphenyl. TBS = tertꢀbutyldimethylsilyl.
Figure 2. Chem3D representation of the Xꢀray crystal structure of
(S)ꢀ13 (selected H atoms are omitted for clarity).
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here (compared to those reported in Ref 1) by analysis of the H
NMR spectrum of the natural product.
The specific rotation of our sample of 13 was [α]D −26.2
20
1
2
3
4
5
6
7
8
(c 1.0 in CHCl3) whilst Zhou et al. measured [α]D −26.1 (c
0.44 in CHCl3)11,12 and Hii et al. obtained [α]D −27.0 (c 0.7
25
Further analysis of the H and 13C NMR data of 13 and the
1
in CHCl3),13 demonstrating truly remarkable parity. The 13C
NMR data of all three samples also display excellent agreeꢀ
ment (ꢀδC ≤ 0.2 ppm),22 as do the 1H NMR data of our sample
of 13 and those of Hii et al. (ꢀδH ≤ 0.05 ppm).22 Our 1H NMR
chemical shift values of 13 are in very good accord with those
reported by Zhou et al. (ꢀδH ≤ 0.04 ppm)22 although the relaꢀ
tive integrations of some of the multiplets below ~2.7 ppm are
not the same. There are, however, clearly issues associated
with the relative integrations of the 1H NMR data presented by
Zhou et al. as twentyꢀfour protons are listed in total11 (the forꢀ
mula of 13 being C19H23NO2). Notwithstanding these differꢀ
ences, it is unequivocal that the three samples of (S)ꢀN(1)ꢀ
methylꢀ2ꢀ[2′ꢀ(3″ꢀhydroxyꢀ4″ꢀmethoxyphenyl)ethyl]ꢀ1,2,3,4ꢀ
tetrahydroquinoline 13 are the same.23
data reported for (−)ꢀgalipeine1 revealed a likely origin of the
structural misassignment. Much of the H and 13C NMR data
1
of the two compounds is effectively identical and is entirely
consistent with them both sharing a 2ꢀsubstituted N(1)ꢀmethylꢀ
1,2,3,4ꢀtetrahydroquinoline moiety, whilst the variances sugꢀ
gest that differentially substituted aryl rings cap the C(2)ꢀside
chain. As the locations of the hydroxy and methoxy substituꢀ
ents within (−)ꢀgalipeine were assigned on the basis of the
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interpretation of its H–13C HMBC NMR spectrum,1 we proꢀ
1
posed that (−)ꢀgalipeine is in fact the regioisomer (S)ꢀN(1)ꢀ
methylꢀ2ꢀ[2′ꢀ(3″ꢀmethoxyꢀ4″ꢀhydroxyphenyl)ethyl]ꢀ1,2,3,4ꢀ
tetrahydroquinoline 18. In order to investigate this hypothesis,
an authentic sample of 18 was prepared. Oꢀtertꢀ
Butyldimethylsilylꢀ4ꢀbromoguaiacol 14 was converted to the
aryllithium regent 15, which reacted with 8 to give ketone 16
in 62% yield. Sequential treatment of 16 with LiAlH4 and then
TFA and Et3SiH gave 17 in 62% yield. Finally, hydrogenolyꢀ
sis of 17 in the presence of formalin gave 18 in 70% yield
(Scheme 2).
Concerning comparison of the H and 13C NMR data of 13
1
with those of (−)ꢀgalipeine, we must first express our gratitude
to Professor Nicolas Fabre who supplied us with copies of the
NMR spectra of (−)ꢀgalipeine for this purpose. Unfortunately,
some transcription errors (mainly concerning determination of
the relative integrations of the multiplets below ~2.7 ppm)
Scheme
2.
(S)ꢀN(1)ꢀMethylꢀ2ꢀ[2′ꢀ(3″ꢀmethoxyꢀ4″ꢀ
1
were noted when the raw H NMR spectrum of (−)ꢀgalipeine
hydroxyphenyl)ethyl]ꢀ1,2,3,4ꢀtetrahydroquinoline 18
was compared to the reported data.1 We therefore first correctꢀ
1
ed the H NMR data of (−)ꢀgalipeine from the original specꢀ
trum (Figure 3). Whilst casual inspection of the H NMR data
1
of 13 and (−)ꢀgalipeine indicates broad agreement, more careꢀ
ful analysis reveals that 13 shows a 1H multiplet at 6.66 ppm
and a 2H multiplet at 6.77 ppm; in (−)ꢀgalipeine the relative
integrations associated with the analogous signals are transꢀ
posed. Perhaps less subtle, the 13C NMR data displays ꢀδC ≥
1.0 ppm22 for four of the carbon atoms. Such large differences
clearly suggest that the structures of 13 and (−)ꢀgalipeine are
not the same, and it followed that the structure of the alkaloid
had been erroneously assigned (Figure 3).
1H NMR (400 MHz, CDCl3)
13C NMR (100 MHz, CDCl3)
13
(
)-galipeine
13
(
)-galipeine
23.6 (0.1)
24.4 (0.1)
32.1 (0.5)
33.2 (0.3)
38.2 (0.2)
56.0 (0.0)
58.5 (0.3)
110.7 (0.2)
110.8 (0.2)
114.3 (0.2)
115.4 (0.1)
120.9 (1.4)
121.8 (0.1)
127.2 (0.1)
128.8 (0.2)
134.0 (1.3)
143.7 (1.0)
145.4 (0.1)
146.5 (1.0)
1.71 (1H, m)
1.92 (3H, m)
2.49 (1H, ddd) 2.50 (1H, m)a
2.66 (2H, m)
2.68 (2H, m)a
2.84 (1H, ddd) 2.82 (1H, m)
1.70 (1H, m)a
1.90 (3H, m)a
23.5
24.3
31.6
32.9
TBS = tertꢀbutyldimethylsilyl.
38.0
2.90 (3H, s)
3.27 (1H, m)
3.87 (3H, s)
5.56 (1H, s)
6.52 (1H, d)
6.59 (1H, td)
2.89 (3H, s)
3.26 (1H, m)
3.85 (3H, s)
5.45 (1H, s)a
6.51 (1H, d)
6.57 (1H, td)
56.0
1
Comparison of the H and 13C NMR data of 18 and (−)ꢀ
58.2
galipeine showed excellent agreement, with the spectra being
effectively superimposable (ꢀδH ≤ 0.04 ppm, ꢀδC ≤ 0.2
ppm).22 These data therefore validate our proposal that 18 and
(−)ꢀgalipeine are the same (Figure 4). We surmise that the
structural misassignment of JacquemondꢀCollet et al. arose
110.5
110.6
114.5
115.3
119.5
121.7
127.1
128.6
135.3
144.7
145.3
145.5
6.66 (1H, dd) 6.65 (2H, m)
6.77 (2H, m)
6.98 (1H, d)
7.08 (1H, td)
6.80 (1H, d)
6.96 (1H, d)
7.06 (1H, t)
3
due to misinterpretation of a JCꢀ4′–Hꢀ2′ HMBC correlation (obꢀ
served for 18) as 2JCꢀ4′–Hꢀ5′ in the data of the natural product,1 as
3
2
well as a JCꢀ3′ꢀHꢀ5′ HMBC correlation (observed for 18) as JCꢀ
in the data of natural product,1 as this has the result of
3′ꢀHꢀ2′
transposing the positions of the hydroxy and methoxy substitꢀ
uents. (−)ꢀGalipeine was reported to have [α]D −13.61 altꢀ
hough the conditions under which this value was measured,
i.e., temperature, concentration and solvent, were not speciꢀ
fied.24 We investigated the effect of concentration and solvent
1
Figure 3. H and 13C NMR data of 13 and (−)ꢀgalipeine. Midꢀ
points of all multiplets are quoted. Values of ꢀδC are given in
a
1
parentheses. These H NMR data of (−)ꢀgalipeine are corrected
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standard vacuum line techniques and glassware that was flameꢀdried
and cooled under nitrogen before use. Solvents were dried according
on the observed value of the specific rotation of 18 and obꢀ
25
tained the following data: [α]D25 −22.0 (c 0.2 in CHCl3); [α]D
1
2
3
4
5
6
7
8
25
25
to the procedure outlined by Grubbs and coꢀworkers.25 Water was
purified by an Elix® UVꢀ10 system. nꢀBuLi was purchased as a 2.5
M solution in hexanes and titrated against diphenylacetic acid before
use. Organic layers were dried over MgSO4 unless otherwise stated.
Thin layer chromatography was performed on aluminium plates coatꢀ
ed with 60 F254 silica. Flash column chromatography was performed
on Kieselgel 60 silica on a glass column.
−22.4 (c 1.0 in CHCl3); [α]D −14.0 (c 1.0 in MeOH); [α]D
−11.9 (c 1.0 in EtOH). Given the uniform negative value obꢀ
served in these common solvents, it seems certain that (−)ꢀ
galipeine possesses the absolute (S)ꢀconfiguration. On the
basis of all of our data, therefore, the structure of (−)ꢀgalipeine
should henceforth be revised to (S)ꢀN(1)ꢀmethylꢀ2ꢀ[2′ꢀ(3″ꢀ
methoxyꢀ4″ꢀhydroxyphenyl)ethyl]ꢀ1,2,3,4ꢀtetrahydroquinoline
18.
Melting points were recorded on a Gallenkamp Hot Stage appaꢀ
ratus and are uncorrected. Optical rotations were recorded on a Perꢀ
kinꢀElmer 241 polarimeter with a waterꢀjacketed 10 cm cell. Specific
rotations are reported in 10−1 deg cm2 g−1 and concentrations in g/100
mL. IR spectra were recorded on a Bruker Tensor 27 FTꢀIR specꢀ
trometer using an ATR module. Selected characteristic peaks are
reported in cm−1. NMR spectra were recorded on Bruker Avance
spectrometers in the deuterated solvent stated. The field was locked
by external referencing to the relevant deuteron resonance. 1H–1H
COSY and 1H–13C HMQC analyses were used to establish atom conꢀ
nectivity. Lowꢀresolution mass spectra were recorded on either a VG
MassLab 20ꢀ250 or a Micromass Platform 1 spectrometer. Accurate
mass measurements were run on either a Bruker MicroTOF internally
calibrated with polyalanine, or a Micromass GCT instrument fitted
with a Scientific Glass Instruments BPX5 column (15 m × 0.25 mm)
using amyl acetate as a lock mass.
3ꢀ(2'ꢀBromophenyl)propanꢀ1ꢀol 2. NaBH4 (225 mg, 6.74 mmol)
was added portionwise to a stirred solution of 1 (771 mg, 3.37 mmol)
in THF (7 mL) at 0 °C, then BF3·Et2O (0.84 mL, 6.7 mmol) was addꢀ
ed dropwise. The resultant mixture was stirred at 0 °C for 1 h, then
MeOH (4 mL) and 1 M aq HCl (4 mL) were added sequentially. The
resultant mixture was extracted with EtOAc (3 × 10 mL) and the
combined organic extracts were dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30–40 °C petꢀ
rol/Et2O/NH4OH, 50:50:1) gave 2 as a colourless oil (664 mg, 92%);26
δH (400 MHz, CDCl3) 1.37 (1H, t, J 5.8, OH), 1.87–1.96 (2H, m,
C(2)H2), 2.85 (2H, t, J 7.8, C(3)H2), 3.72 (2H, app q, J 5.8, C(1)H2),
7.04–7.11 (1H, m, C(4')H), 7.23–7.29 (2H, m, C(5')H, C(6')H), 7.55
(1H, d, J 8.1, C(3')H).
9
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1
Figure 4. H and 13C NMR data of 18 and (−)ꢀgalipeine. Midꢀ
(E)ꢀ5ꢀ(2'ꢀBromophenyl)ꢀNꢀmethoxyꢀNꢀmethylpentꢀ2ꢀenamide
4. DMSO (0.53 mL, 7.4 mmol) was added dropwise to a stirred soluꢀ
tion of (COCl)2 (0.32 mL, 3.7 mmol) in CH2Cl2 (10 mL) at –78 °C
and the resultant solution was stirred at −78 °C for 20 min. A solution
of 2 (400 mg, 1.86 mmol) in CH2Cl2 (1 mL) was then added and the
resultant solution was stirred at −78 °C for 40 min. Et3N (1.7 mL, 11
mmol) was then added, the resultant solution was allowed to warm to
rt and 3 (1.01 g, 2.79 mmol) was added portionwise. The resultant
solution was stirred at rt for 16 h. Satd aq K2CO3 (20 mL) was added
and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The
combined organics were washed with brine (60 mL), then dried and
concentrated in vacuo. Purification via flash column chromatography
(eluent 30–40 °C petrol/Et2O/NH4OH, 50:50:1) gave 4 as a pale yelꢀ
low oil (435 mg, 78%, >95:5 dr [(E):(Z) ratio]); νmax 2935, 1663,
1632; δH (400 MHz, CDCl3) 2.61 (2H, app q, J 7.5, C(4)H2), 2.95
(2H, t, J 7.5, C(5)H2), 3.28 (3H, s, NMe), 3.70 (3H, s, OMe), 6.54
(1H, d, J 15.4, C(2)H), 7.02–7.14 (2H, m, C(3)H, C(4')H), 7.23–7.32
(2H, m, C(5')H, C(6')H), 7.58 (1H, d, J 7.9, C(3')H); δC (100 MHz,
CDCl3) 32.3 (C(4)), 32.5 (NMe), 34.9 (C(5)), 61.6 (OMe), 119.5
(C(2)), 124.3 (C(2')), 127.5 (C(5')), 127.8 (C(4')), 130.4 (C(6')), 132.8
(C(3')), 140.2 (C(1')), 146.0 (C(3)), 166.7 (C(1)); m/z (ESI+) 300
([M(81Br)+H]+, 100%), 298 ([M(79Br)+H]+, 100%); HRMS (ESI+)
points of all multiplets are quoted. Values of ꢀδC are given in
a
1
parentheses. These H NMR data of (−)ꢀgalipeine are corrected
1
here (compared to those reported in Ref 1) by analysis of the H
NMR spectrum of the natural product.
In conclusion, we have prepared authentic samples of the
regioisomers
(S)ꢀN(1)ꢀmethylꢀ2ꢀ[2′ꢀ(3″ꢀhydroxyꢀ4″ꢀ
methoxyphenyl)ethyl]ꢀ1,2,3,4ꢀtetrahydroquinoline and (S)ꢀ
N(1)ꢀmethylꢀ2ꢀ[2′ꢀ(3″ꢀmethoxyꢀ4″ꢀhydroxyphenyl)ethyl]ꢀ
1
1,2,3,4ꢀtetrahydroquinoline. Comparison of their H and 13C
NMR data with those reported for (−)ꢀgalipeine clearly shows
that the data of (S)ꢀN(1)ꢀmethylꢀ2ꢀ[2′ꢀ(3″ꢀmethoxyꢀ4″ꢀ
hydroxyphenyl)ethyl]ꢀ1,2,3,4ꢀtetrahydroquinoline match those
of the natural product, i.e., the structure of (−)ꢀgalipeine was
misassigned
as
N(1)ꢀmethylꢀ2ꢀ[2′ꢀ(3″ꢀhydroxyꢀ4″ꢀ
methoxyphenyl)ethyl]ꢀ1,2,3,4ꢀtetrahydroquinoline in the origꢀ
inal isolation study, and this error has been perpetuated in two
subsequent synthetic investigations. Comparison of specific
rotation data allowed us to assign the absolute (S)ꢀ
configuration for the natural product. The structure of (−)ꢀ
galipeine is thus herein revised to that of (S)ꢀN(1)ꢀmethylꢀ2ꢀ
[2′ꢀ(3″ꢀmethoxyꢀ4″ꢀhydroxyphenyl)ethyl]ꢀ1,2,3,4ꢀ
tetrahydroquinoline. This study constitutes the unambiguous
structural determination of (−)ꢀgalipeine, its first total asymꢀ
metric synthesis, and assignment of its absolute (S)ꢀ
configuration.
+
C13H1781BrNO2 ([M(81Br)+H]+) requires 300.0417; found 300.0414;
C13H1779BrNO2+ ([M(79Br)+H]+) requires 298.0437; found 298.0435.
(R,R)ꢀ3ꢀ[NꢀBenzylꢀNꢀ(αꢀmethylꢀpꢀmethoxybenzyl)amino]ꢀ5ꢀ(2'ꢀ
bromophenyl)ꢀNꢀmethoxyꢀNꢀmethylpentanamide 6. nꢀBuLi (2.3 M
in hexanes, 0.45 mL, 1.0 mmol) was added dropwise to a stirred soluꢀ
tion of (R)ꢀNꢀbenzylꢀNꢀ(αꢀmethylꢀpꢀmethoxybenzyl)amide (259 mg,
1.07 mmol, >98% ee) in THF (2 mL) at –78 °C and the resultant soluꢀ
tion was stirred at −78 °C for 30 min. A solution of 4 (200 mg, 0.671
mmol, >95:5 dr [(E):(Z) ratio]) in THF (1 mL) at −78 °C was then
added and the resultant solution was stirred at –78 °C for 2 h. Satd aq
NH4Cl (1 mL) was then added and the resultant mixture was allowed
EXPERIMENTAL SECTION
General Experimental Details. Reactions involving moistureꢀ
sensitive reagents were carried out under a nitrogen atmosphere using
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The Journal of Organic Chemistry
to warm to rt, then concentrated in vacuo. The residue was partitioned
172.5 (C(1)); m/z (ESI+) 325 ([M+H]+, 100%); HRMS (ESI+)
C20H25N2O2+ ([M+H]+) requires 325.1911; found 325.1909.
between CH2Cl2 (10 mL) and 10% aq citric acid (10 mL), and the
organic layer was washed sequentially with satd aq NaHCO3 (10 mL)
and brine (10 mL), then dried and concentrated in vacuo to give 6 in
>95:5 dr. Purification via flash column chromatography (eluent 30–40
°C petrol/Et2O/NH4OH, 50:50:1) gave 6 as a pale yellow oil (273 mg,
80%, >95:5 dr); [α]D25 +21.8 (c 1.0 in CHCl3); νmax 2998, 2981, 2969,
2932, 2905, 2886, 2868, 1659; δH (400 MHz, CDCl3) 1.39 (3H, d, J
7.0, C(α)Me), 1.55–1.66 (1H, m, C(4)HA), 1.73–1.84 (1H, m,
C(4)HB), 2.00 (1H, d, J 14.0, C(2)HA), 2.21–2.31 (1H, m, C(2)HB),
2.70 (1H, ddd, J 13.8, 11.8, 5.0, C(5)HA), 3.07 (3H, s, NMe), 3.19
(1H, ddd, J 13.8, 11.6, 4.9, C(5)HB), 3.43 (3H, s, NOMe), 3.59–3.66
(1H, m, C(3)H), 3.60 (1H, d, J 14.8, NCHAHBPh), 3.79 (3H, s,
ArOMe), 3.87 (1H, q, J 7.0, C(α)H), 3.93 (1H, d, J 14.8, NCHAHBPh),
6.85 (2H, d, J 8.6, C(3'')H, C(5'')H), 6.99–7.05 (1H, m, C(4')H), 7.16–
7.28 (5H, m, C(5')H, C(6')H, C(2'')H, C(6'')H, Ph), 7.36 (2H, t, J 7.5,
Ph), 7.50 (1H, d, J 7.8, C(3')H), 7.54 (2H, d, J 7.5, Ph); δC (100 MHz,
CDCl3) 20.0 (C(α)Me), 32.1 (NMe), 33.8 (C(2)), 33.9 (C(4)), 34.2
(C(5)), 50.2 (NCH2Ph), 52.9 (C(3)), 55.2 (NOMe), 56.6 (C(α)), 60.8
(ArOMe), 113.4 (C(3''), C(5'')), 124.4 (C(2')), 126.6 (pꢀPh), 127.2
(C(4')), 127.4 (C(5')), 128.3, 128.3 (o,mꢀPh), 129.0 (C(2''), C(6'')),
130.2 (C(6')), 132.6 (C(3')), 135.1 (C(1'')), 141.5 (iꢀPh), 142.1 (C(1')),
158.5 (C(4'')), 173.4 (C(1)); m/z (ESI+) 541 ([M(81Br)+H]+, 100%),
1
2
3
4
5
6
7
8
(R)ꢀN(1)ꢀBenzylꢀ2ꢀ[2'ꢀOxoꢀ2'ꢀ(3''ꢀtertꢀbutyldimethylsilyloxyꢀ4''ꢀ
methoxyphenyl)ethyl]ꢀ1,2,3,4ꢀtetrahydroquinoline 11. Step 1.
Preparation of O-tert-butyldimethylsilyl-5-bromoguaiacol 9. tertꢀ
Butyldimethylsilyl chloride (1.50 g, 10.0 mmol) was added to a
stirred solution of 5ꢀbromoguaiacol (2.00 g, 9.85 mmol) and imidazꢀ
ole (1.36 g, 20.0 mmol) in DMF (5 mL) at rt and the resultant solution
was stirred at rt for 16 h. H2O (15 mL) was then added and the resultꢀ
ant mixture was extracted with hexane (5 × 15 mL). The combined
organics were dried and concentrated in vacuo to give 9 as a colourꢀ
less oil (2.92 g, 93%);27 δH (400 MHz, CDCl3) 0.15 (6H, s, SiMe2),
0.99 (9H, s, SiCMe3), 3.78 (3H, s, OMe), 6.71 (1H, d, J 8.6, C(3)H),
6.98 (1H, d, J 2.4, C(6)H), 7.02 (1H, dd, J 8.6, 2.4, C(4)H).
Step 2. nꢀBuLi (2.3 M in hexanes, 1.9 mL, 4.3 mmol) was added
dropwise to a stirred solution of 9 (1.37 g, 4.32 mmol) in THF (15
mL) at –78 °C and the resultant solution was stirred at –78 °C for 30
min. A solution of 8 (200 mg, 0.616 mmol) in THF (2 mL) at –78 °C
was then added and the resultant solution was stirred at −78 °C for 90
min. Satd aq NH4Cl (3 mL) was then added and the resultant mixture
was allowed to warm to rt and concentrated in vacuo. The residue was
partitioned between CH2Cl2 (20 mL) and H2O (20 mL), and the orꢀ
ganic layer was dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30–40 °C petrol/Et2O/NH4OH,
85:17:1) gave 11 as a yellow oil (273 mg, 88%); [α]D25 –7.7 (c 1.0 in
CHCl3); νmax 2953, 2930, 2857, 1671; δH (400 MHz, CDCl3) 0.15
(6H, s, SiMe2), 0.99 (9H, s, SiCMe3), 1.97 (1H, ddt, J 13.1, 5.7, 2.9,
C(3)HA), 2.09 (1H, tt, J 13.1, 4.8, C(3)HB), 2.74–2.81 (1H, m,
C(4)HA), 2.96 (1H, ddd, J 16.7, 13.1, 5.7, C(4)HB), 3.15 (2H, d, J 6.7,
C(1')H2), 3.86 (3H, s, OMe), 4.15–4.21 (1H, m, C(2)H), 4.49 (1H, d, J
17.2, NCHAHBPh), 4.56 (1H, d, J 17.2, NCHAHBPh), 6.45 (1H, app d,
J 8.2, C(8)H), 6.62 (1H, td, J 7.3, 0.9, C(6)H), 6.83 (1H, d, J 8.5,
C(5'')H), 6.95–7.00 (1H, m, C(7)H), 7.04 (1H, d, J 7.3, C(5)H), 7.18–
7.31 (5H, m, Ph), 7.43 (1H, d, J 2.2, C(2'')H), 7.49 (1H, dd, J 8.5, 2.2,
C(6'')H); δC (100 MHz, CDCl3) –4.6 (SiMe2), 18.4 (SiCMe3), 23.6
(C(4)), 25.4 (C(3)), 25.7 (SiCMe3), 40.8 (C(1')), 54.0 (NCH2Ph), 54.9
(C(2)), 55.5 (OMe), 110.8 (C(5'')), 111.8 (C(8)), 116.0 (C(6)), 120.3
(C(2'')), 121.2 (C(4a)), 123.3 (C(6'')), 126.4 (o,mꢀPh), 126.8 (pꢀPh),
127.2 (C(7)), 128.6 (o,mꢀPh), 129.1 (C(5)), 130.5 (C(1'')), 138.9 (iꢀ
Ph), 144.1 (C(8a)), 145.0 (C(3'')), 155.5 (C(4'')), 197.6 (C(2')); m/z
(ESI+) 502 ([M+H]+, 100%); HRMS (ESI+) C31H40NO3Si+ ([M+H]+)
requires 502.2772; found 502.2768.
9
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20
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+
539 ([M(79Br)+H]+, 100%); HRMS (ESI+) C29H3681BrN2O3+
([M(81Br)+H]+) requires 541.1883; found 541.1882; C29H3679BrN2O3
([M(79Br)+H]+) requires 539.1904; found 539.1902.
(R)ꢀ3ꢀ(NꢀBenzylamino)ꢀ5ꢀ(2'ꢀbromophenyl)ꢀNꢀmethoxyꢀNꢀ
methylpentanamide 7. Et3SiH (25 ꢁL, 0.16 mmol) was added to a
stirred solution of 6 (87 mg, 1.10 mmol, >95:5 dr) in HCO2H (0.6
mL) at rt and the resultant solution was heated at 90 °C for 16 h, then
allowed to cool to rt and concentrated in vacuo. The residue was partiꢀ
tioned between CH2Cl2 (5 mL) and satd aq NaHCO3 (5 mL) and the
organic layer was washed with brine (5 mL), then dried and concenꢀ
trated in vacuo. Purification via flash column chromatography (eluent
30–40 °C petrol/Et2O/NH4OH, 50:50:1) gave 7 as a colourless oil (35
mg, 81%); [α]D25 –7.1 (c 1.0 in CHCl3); νmax 3324, 3085, 3027, 2965,
2935, 2861, 1658; δH (400 MHz, CDCl3) 1.79–1.89 (2H, m, C(4)H2),
2.67 (2H, app d, J 5.8, C(2)H2), 2.80–2.86 (2H, m, C(5)H2), 3.16–3.23
(1H, m, C(3)H), 3.18 (3H, s, NMe), 3.67 (3H, s, OMe), 3.81 (1H, d, J
12.9, NCHAHBPh), 3.85 (1H, d, J 12.9, NCHAHBPh), 7.01–7.08 (1H,
m, C(4')H), 7.20–7.39 (7H, m, C(5')H, C(6')H, Ph), 7.52 (1H, d, J 7.8,
C(3')H); δC (100 MHz, CDCl3) 32.0 (C(3)), 32.4 (C(5)), 34.3 (C(4)),
36.4 (C(2)), 51.0 (NCH2Ph), 53.8 (NMe), 61.2 (OMe), 124.4 (C(2')),
126.8, 127.5, 127.5 (C(4'), C(5'), pꢀPh), 128.2, 128.3 (o,mꢀPh), 130.3
(C(6')), 132.7 (C(3')), 140.6 (iꢀPh), 141.6 (C(1')), 173.3 (C(1)); m/z
(ESI+) 407 ([M(81Br)+H]+, 100%), 405 ([M(79Br)+H]+, 100%); HRMS
(S)ꢀN(1)ꢀBenzylꢀ2ꢀ[2'ꢀ(3''ꢀhydroxyꢀ4''ꢀmethoxyphenyl)ethyl]ꢀ
1,2,3,4ꢀtetrahydroquinoline 12. Step 1. LiAlH4 (2.0 M in THF, 0.46
mL, 0.91 mmol) was added dropwise to a stirred solution of 11 (229
mg, 0.456 mmol) in THF (3.2 mL) at 0 °C. The resultant solution was
heated at reflux for 16 h and then allowed to cool to rt. 2 M aq NaOH
(0.5 mL) was then added and the resultant mixture was heated at reꢀ
flux for 3 h. The resultant mixture was allowed to cool to rt and then
concentrated in vacuo. The residue was dissolved in Et2O and filtered
through a short plug of silica (eluent Et2O), and the filtrate was conꢀ
centrated in vacuo.
+
(ESI+) C20H2681BrN2O2 ([M(81Br)+H]+) requires 407.1152; found
+
407.1148; C20H2679BrN2O2 ([M(79Br)+H]+) requires 405.1172; found
405.1169.
(R)ꢀ2ꢀ[N(1')ꢀBenzylꢀ1',2',3',4'ꢀtetrahydroquinolinꢀ2'ꢀyl]ꢀNꢀ
methoxyꢀNꢀmethylacetamide 8. Pd(OAc)2 (26 mg, 0.12 mmol) was
added to a stirred suspension of 7 (943 mg, 2.33 mmol), XPhos (163
mg, 0.349 mmol) and Cs2CO3 (1.51 g, 4.65 mmol) in PhMe (30 mL)
and the resultant solution was heated at reflux for 24 h, then allowed
to cool to rt and concentrated in vacuo. The residue was partitioned
between CH2Cl2 (100 mL) and H2O (100 mL) and the organic layer
was dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 °C petrol/Et2O/NH4OH, 50:50:1) gave
Step 2. Et3SiH (0.73 mL, 4.6 mmol) was added to a stirred solution
of the residue from the previous step in TFA (2.2 mL) at rt and the
resultant solution was stirred at rt for 16 h, then concentrated in vac-
uo. The residue was partitioned between CH2Cl2 (10 mL) and satd aq
NaHCO3 (10 mL), and the organic layer was dried and concentrated
in vacuo. Purification via flash column chromatography (eluent 30–40
°C petrol/Et2O/NH4OH, 75:25:1) gave 12 as a pale yellow oil (85 mg,
25
8 as a pale yellow solid (751 mg, quant); mp 58–60 °C; [α]D –11.0
25
50%); [α]D +0.5 (c 1.0 in CHCl3); νmax 3513, 3027, 2980, 2971,
(c 1.0 in CHCl3); νmax 3027, 2968, 2935, 2865, 1658; δH (400 MHz,
CDCl3) 1.97–2.13 (2H, m, C(3')H2), 2.71 (2H, app d, J 6.5, C(2)H2),
2.78 (1H, dt, J 16.5, 3.7, C(4')HA), 2.97 (1H, ddd, J 16.5, 12.8, 5.7,
C(4')HB), 3.16 (3H, s, NMe), 3.58 (3H, s, OMe), 4.04–4.10 (1H, m,
C(2')H), 4.53 (1H, d, J 17.2, NCHAHBPh), 4.59 (1H, d, J 17.2,
NCHAHBPh), 6.45 (1H, d, J 7.7, C(8')H), 6.60 (1H, t, J 7.7, C(6')H),
6.97 (1H, t, J 7.7, C(7')H), 7.04 (1H, d, J 7.7, C(5')H), 7.19–7.33 (5H,
m, Ph); δC (100 MHz, CDCl3) 23.6 (C(4')), 25.3 (C(3')), 32.0 (NMe),
34.9 (C(2)), 53.9 (NCH2Ph), 54.8 (C(2')), 61.3 (OMe), 111.7 (C(8')),
115.9 (C(6')), 121.2 (C(4'a)), 126.4 (oꢀPh), 126.7 (pꢀPh), 127.1
(C(7')), 128.5 (mꢀPh), 129.1 (C(5')), 139.0 (iꢀPh), 144.0 (C(8'a)),
2933, 2860, 1600, 1510, 1498; δH (400 MHz, CDCl3) 1.77–2.09 (4H,
m, C(3)H2, C(1')H2), 2.45 (1H, ddd, J 14.0, 9.6, 6.8, C(2')HA), 2.61
(1H, ddd, J 14.0, 9.6, 5.4, C(2')HB), 2.75 (1H, dt, J 16.5, 3.9, C(4)HA),
2.93 (1H, ddd, J 16.5, 12.3, 5.9, C(4)HB), 3.35–3.42 (1H, m, C(2)H),
3.85 (3H, s, OMe), 4.40 (1H, d, J 17.0, NCHAHBPh), 4.56 (1H, d, J
17.0, NCHAHBPh), 5.54 (1H, s, OH), 6.41 (1H, d, J 8.0, C(8)H),
6.55–6.62 (2H, m, C(6)H, C(6'')H), 6.72–6.75 (2H, m, C(2'')H,
C(5'')H), 6.94 (1H, t, J 8.0, C(7)H), 7.01 (1H, d, J 7.3, C(5)H), 7.19–
7.31 (5H, m, Ph); δC (100 MHz, CDCl3) 23.6 (C(4)), 24.2 (C(3)), 31.6
(C(2')), 33.5 (C(1')), 54.0 (NCH2Ph), 56.0 (OMe), 57.2 (C(2)), 110.6
(C(5'')), 111.7 (C(8)), 114.4 (C(2'')), 115.5 (C(6)), 119.5 (C(6'')),
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The Journal of Organic Chemistry
Page 6 of 7
121.6 (C(4a)), 126.5 (o,mꢀPh), 126.6 (pꢀPh), 127.0 (C(7)), 128.5
mL, 0.95 mmol) was added dropwise to a stirred solution of 16 (238
(o,mꢀPh), 128.9 (C(5)), 135.1 (C(1'')), 139.2 (iꢀPh), 144.5 (C(4'')),
144.7 (C(8a)), 145.5 (C(3'')); m/z (ESI+) 374 ([M+H]+, 100%); HRMS
(ESI+) C25H28NO2+ ([M+H]+) requires 374.2115; found 374.2115.
(S)ꢀN(1)ꢀMethylꢀ2ꢀ[2'ꢀ(3''ꢀhydroxyꢀ4''ꢀmethoxyphenyl)ethyl]ꢀ
1,2,3,4ꢀtetrahydroquinoline 13. Pd/C (27 mg, 40% w/w of substrate
12) was added to a stirred solution of 12 (68 mg, 0.18 mmol) and
formalin (37% aq HCHO, 0.13 mL, 1.8 mmol) in degassed MeOH (3
mL) at rt. The resultant suspension was stirred under H2 (1 atm) at rt
for 24 h. The resultant suspension was filtered through a short plug of
Celite® (eluent MeOH) and the filtrate was concentrated in vacuo.
Purification via flash column chromatography (eluent 30–40 °C petꢀ
rol/Et2O/NH4OH, 66:33:1) gave 13 as a pale orange solid (31 mg,
mg, 0.474 mmol) in THF (3.3 mL) at 0 °C. The resultant solution was
heated at reflux for 16 h and then allowed to cool to rt. 2 M aq NaOH
(0.5 mL) was then added and the resultant mixture was heated at reꢀ
flux for 3 h. The resultant mixture was allowed to cool to rt, filtered
through Celite® (eluent EtOAc), and the filtrate was concentrated in
vacuo.
1
2
3
4
5
6
7
8
Step 2. Et3SiH (0.76 mL, 4.7 mmol) was added to a stirred solution
of the residue from the previous step in TFA (2.3 mL) at rt and the
resultant solution was stirred at rt for 16 h, then concentrated in vac-
uo. The residue was partitioned between CH2Cl2 (10 mL) and satd aq
NaHCO3 (10 mL), and the organic extract was dried and concentrated
in vacuo. Purification via flash column chromatography (eluent 30–40
°C petrol/Et2O/NH4OH, 50:50:1) gave 17 as a pale yellow oil (109
mg, 62%); [α]D25 +0.4 (c 1.0 in CHCl3); νmax 3502, 3026, 2934, 1605,
1530; δH (400 MHz, CDCl3) 1.78–2.08 (4H, m, C(3)H2, C(1')H2), 2.47
(1H, ddd, J 13.9, 9.9, 6.6, C(2')HA), 2.64 (1H, ddd, J 13.9, 10.6, 5.1,
C(2')HB), 2.76 (1H, dt, J 16.5, 3.9, C(4)HA), 2.94 (1H, ddd, J 16.5,
11.9, 6.2, C(4)HB), 3.38–3.44 (1H, m, C(2)H), 3.84 (3H, s, OMe),
4.42 (1H, d, J 17.1, NCHAHBPh), 4.57 (1H, d, J 17.1, NCHAHBPh),
5.45 (1H, s, OH), 6.43 (1H, app d, J 8.2, C(8)H), 6.58 (1H, td, J 7.3,
1.1, C(6)H), 6.61 (1H, d, J 1.9, C(2'')H), 6.63 (1H, dd, J 8.0, 1.9,
C(6'')H), 6.81 (1H, d, J 8.0, C(5'')H), 6.93–6.98 (1H, m, C(7)H), 7.02
(1H, d, J 7.3, C(5)H), 7.19–7.32 (5H, m, Ph); δC (100 MHz, CDCl3)
23.6 (C(4)), 24.2 (C(3)), 31.9 (C(2')), 33.9 (C(1')), 54.1 (NCH2Ph),
55.9 (OMe), 57.3 (C(2)), 110.7 (C(2'')), 111.7 (C(8)), 114.2 (C(5'')),
115.6 (C(6)), 120.7 (C(6'')), 121.6 (C(4a)), 126.4 (o,mꢀPh), 126.7 (pꢀ
Ph), 127.1 (C(7)), 128.5 (o,mꢀPh), 128.9 (C(5)), 133.7 (C(1'')), 139.2
(iꢀPh), 143.6 (C(4'')), 144.5 (C(8a)), 146.3 (C(3'')); m/z (ESI+) 374
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
25
57%);11,13 mp 134–138 °C; [α]D –26.2 (c 1.0 in CHCl3); νmax 3501,
2980, 2934, 1601, 1510, 1501; δH (400 MHz, CDCl3) 1.66–1.76 (1H,
m, C(1')HA), 1.84–1.99 (3H, m, C(3)H2, C(1')HB), 2.49 (1H, ddd, J
13.9, 9.9, 6.6, C(2')HA), 2.59–2.72 (2H, m, C(4)HA, C(2')HB), 2.84
(1H, ddd, J 17.6, 11.7, 5.2, C(4)HB), 2.90 (3H, s, NMe), 3.24–3.30
(1H, m, C(2)H), 3.87 (3H, s, OMe), 5.56 (1H, s, OH), 6.52 (1H, app
d, J 8.1, C(8)H), 6.59 (1H, td, J 7.3, 1.0, C(6)H), 6.66 (1H, dd, J 8.2,
2.1, C(6'')H), 6.75–6.79 (2H, m, C(2'')H, C(5'')H), 6.98 (1H, app d, J
7.3, C(5)H), 7.08 (1H, td, J 7.3, 1.2, C(7)H); δC (100 MHz, CDCl3)
23.5 (C(4)), 24.3 (C(3)), 31.6 (C(2')), 32.9 (C(1')), 38.0 (NMe), 56.0
(OMe), 58.2 (C(2)), 110.5 (C(8)), 110.6 (C(5'')), 114.5 (C(2'')), 115.3
(C(6)), 119.5 (C(6'')), 121.7 (C(4a)), 127.1 (C(7)), 128.6 (C(5)), 135.3
(C(1'')), 144.7 (C(4'')), 145.3 (C(8a)), 145.5 (C(3'')); m/z (ESI+) 298
+
([M+H]+, 100%); HRMS (ESI+) C19H24NO2 ([M+H]+) requires
298.1802; found 298.1800.
(R)ꢀN(1)ꢀBenzylꢀ2ꢀ[2'ꢀoxoꢀ2'ꢀ(3''ꢀmethoxyꢀ4''ꢀtertꢀ
+
butyldimethylsilyloxyphenyl)ethyl]ꢀ1,2,3,4ꢀtetrahydroquinoline
16. Step 1. Preparation of O-tert-butyldimethylsilyl-4-bromoguaiacol
14. tertꢀButyldimethylsilyl chloride (1.50 g, 10.0 mmol) was added to
a stirred solution of 4ꢀbromoguaiacol (2.00 g, 9.85 mmol) and imidꢀ
azole (1.36 g, 20.0 mmol) in DMF (5 mL) at rt and the resultant soluꢀ
tion was stirred at rt for 16 h. H2O (15 mL) was then added and the
resultant mixture was extracted with hexane (5 × 15 mL). The comꢀ
bined organics were dried and concentrated in vacuo to give 14 as a
colourless oil (2.98 g, 95%);28 δH (400 MHz, CDCl3) 0.14 (6H, s,
SiMe2), 0.98 (9H, s, SiCMe3), 3.79 (3H, s, OMe), 6.71 (1H, d, J 8.3,
C(6)H), 6.93 (1H, dd, J 8.3, 2.4, C(5)H), 6.95 (1H, d, J 2.4, C(3)H).
Step 2. nꢀBuLi (2.3 M in hexanes, 2.4 mL, 5.4 mmol) was added
dropwise to a stirred solution of 14 (1.71 g, 5.39 mmol) in THF (19
mL) at –78 °C and the resultant solution was stirred at –78 °C for 30
min. A solution of 8 (250 mg, 0.771 mmol) in THF (2 mL) at –78 °C
was then added and the resultant solution was stirred at −78 °C for 90
min. Satd aq NH4Cl (4 mL) was then added and the resultant mixture
was allowed to warm to rt and concentrated in vacuo. The residue was
partitioned between CH2Cl2 (20 mL) and H2O (20 mL), and the orꢀ
ganic layer was dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30–40 °C petrol/Et2O/NH4OH,
90:9:1) gave 16 as a yellow oil (239 mg, 62%); [α]D25 −11.6 (c 1.0 in
CHCl3); νmax 2953, 2930, 2857, 1672; δH (400 MHz, CDCl3) 0.17
(6H, s, SiMe2), 0.99 (9H, s, SiCMe3), 1.98 (1H, ddt, J 13.3, 5.7, 2.8,
C(3)HA), 2.10 (1H, tt, J 13.3, 4.9, C(3)HB), 2.74–2.82 (1H, m,
C(4)HA), 2.97 (1H, ddd, J 17.1, 13.3, 5.7, C(4)HB), 3.13 (1H, dd, J
16.1, 8.3, C(1')HA), 3.21 (1H, dd, J 16.1, 5.1, C(1')HB), 3.81 (3H, s,
OMe), 4.16–4.22 (1H, m, C(2)H), 4.48 (1H, d, J 17.1, NCHAHBPh),
4.55 (1H, d, J 17.1, NCHAHBPh), 6.45 (1H, d, J 8.3, C(8)H), 6.62
(1H, td, J 7.3, 0.9, C(6)H), 6.83 (1H, d, J 8.3, C(5'')H), 6.95–7.00
(1H, m, C(7)H), 7.04 (1H, d, J 7.3, C(5)H), 7.18–7.31 (5H, m, Ph),
7.38 (1H, dd, J 8.3, 2.0, C(6'')H), 7.44 (1H, d, J 2.0, C(2'')H); δC (100
MHz, CDCl3) –4.6 (SiMe2), 18.5 (SiCMe3), 23.5 (C(4)), 25.5 (C(3)),
25.6 (SiCMe3), 40.8 (C(1')), 54.1 (NCH2Ph), 54.9 (C(2)), 55.4 (OMe),
111.0 (C(2'')), 111.9 (C(8)), 116.0 (C(6)), 120.3 (C(5'')), 121.1
(C(4a)), 122.6 (C(6'')), 126.4 (o,mꢀPh), 126.8 (pꢀPh), 127.2 (C(7)),
128.6 (o,mꢀPh), 129.2 (C(5)), 131.3 (C(1'')), 138.9 (iꢀPh), 144.1
(C(8a)), 150.2, 151.1 (C(3''), C(4'')), 197.9 (C(2')); m/z (ESI+) 502
([M+H]+, 100%); HRMS (ESI+) C31H40NO3Si+ ([M+H]+) requires
502.2772; found 502.2768.
([M+H]+, 100%); HRMS (ESI+) C25H28NO2 ([M+H]+) requires
374.2115; found 374.2118.
(S)ꢀN(1)ꢀMethylꢀ2ꢀ[2'ꢀ(3''ꢀmethoxyꢀ4''ꢀhydroxyphenyl)ethyl]ꢀ
1,2,3,4ꢀtetrahydroquinoline [(–)ꢀGalipeine] 18. Pd/C (42 mg, 40%
w/w of substrate 17) was added to a stirred solution of 17 (106 mg,
0.284 mmol) and formalin (37% aq HCHO, 0.21 mL, 2.84 mmol) in
degassed MeOH (5 mL) at rt. The resultant suspension was stirred
under H2 (1 atm) at rt for 24 h. The resultant suspension was filtered
through a short plug of Celite® (eluent MeOH) and the filtrate was
concentrated in vacuo. Purification via flash column chromatography
(eluent 30–40 °C petrol/Et2O/NH4OH, 66:33:1) gave 18 as a colourꢀ
less oil (59 mg, 70%);1 [α]D25 −22.0 (c 0.2 in CHCl3); [α]D25 −22.3 (c
25
25
1.0 in CHCl3); [α]D −14.0 (c 1.0 in MeOH); [α]D −11.9 (c 1.0 in
EtOH); νmax (ATR) 3510, 2935, 2860, 2844, 1602, 1514, 1500; δH
(400 MHz, CDCl3) 1.68–1.78 (1H, m, C(1')HA), 1.86–2.00 (3H, m,
C(3)H2, C(1')HB), 2.52 (1H, ddd, J 13.9, 10.2, 6.4, C(2')HA), 2.62–
2.73 (2H, m, C(4)HA, C(2')HB), 2.86 (1H, ddd, J 17.5, 11.6, 6.1,
C(4)HB), 2.92 (3H, s, NMe), 3.26–3.33 (1H, m, C(2)H), 3.88 (3H, s,
OMe), 5.47 (1H, s, OH), 6.54 (1H, app d, J 8.1, C(8)H), 6.60 (1H, td,
J 7.3, 0.9, C(6)H), 6.67–6.71 (2H, m, C(2'')H, C(6'')H), 6.84 (1H, d, J
8.5, C(5'')H), 6.99 (1H, d, J 7.3, C(5)H), 7.07–7.12 (1H, m, C(7)H);
δC (100 MHz, CDCl3) 23.5 (C(4)), 24.3 (C(3)), 32.0 (C(2')), 33.1
(C(1')), 38.1 (NMe), 55.9 (OMe), 58.3 (C(2)), 110.5 (C(8)), 110.7
(C(2'')), 114.2 (C(5'')), 115.3 (C(6)), 120.7 (C(6'')), 121.6 (C(4a)),
127.1 (C(7)), 128.6 (C(5)), 133.9 (C(1'')), 143.6 (C(4'')), 145.2
(C(8a)), 146.3 (C(3'')); m/z (ESI+) 298 ([M+H]+, 100%); HRMS
(ESI+) C19H24NO2+ ([M+H]+) requires 298.1802; found 298.1801.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: xxxxx.
Copies of 1H and 13C NMR spectra (PDF)
Xꢀray data for structure CCDC 1557564 (CIF)
AUTHOR INFORMATION
Corresponding Author
(S)ꢀN(1)ꢀBenzylꢀ2ꢀ[2'ꢀ(3''ꢀmethoxyꢀ4''ꢀhydroxyphenyl)ethyl]ꢀ
1,2,3,4ꢀtetrahydroquinoline 17. Step 1. LiAlH4 (2.4 M in THF, 0.47
*Eꢀmail: steve.davies@chem.ox.ac.uk.
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Page 7 of 7
The Journal of Organic Chemistry
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
We are indebted to Professor Nicolas Fabre for supplying copies
of the NMR spectra of (−)ꢀgalipeine.
7
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9
REFERENCES
(1) JacquemondꢀCollet, I.; Hannedouche, S.; Fabre, N.; Fourasté,
I.; Moulis, C. Phytochemistry 1999, 51, 1167.
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(2) A subsequent study reported the isolation of galipeine as the
racemate; see: JacquemondꢀCollet, I.; BenoitꢀVical, F.; Mustofa;
Valentin, A.; Stanislas, E.; Mallié, M.; Fouraste, I. Planta Med. 2002,
68, 68.
(3) For a review, see: Muñoz, G. D.; Dudley, G. B. Org. Prep.
Proc. Int. 2015, 47, 179. For more recent syntheses of these members
of this alkaloid family, see Refs 4–10.
(4) Chen, F.; Surkus, A.ꢀE.; He, L.; Pohl, M.ꢀM.; Radnik, J.; Topf,
C.; Junge, K.; Beller, M. J. Am. Chem. Soc. 2015, 137, 11718.
(5) Chacko, S.; Ramapanicker, R. J. Heterocyclic Chem. 2015, 52,
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(6) Pappoppula, M.; Cardoso, F. S. P.; Garrett, B. O.; Aponick, A.
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(10) Crisenza, G. E. M.; Dauncey, E. M.; Bower, J. F. Org. Bio-
mol. Chem. 2016, 14, 5820.
(11) Yang, P.ꢀY.; Zhou, Y.ꢀG. Tetrahedron: Asymmetry 2004, 15,
1145.
(12) The temperature at which the specific rotation value was recꢀ
orded is given as either 15 °C or 20 °C within the manuscript.
(13) Taylor, L. L.; Goldberg, F. W.; Hii, K. K. Org. Biomol. Chem.
2012, 10, 4424.
(14) WillandꢀCharnley, R.; Puffer, B. W.; Dussault, P. H. J. Am.
Chem. Soc. 2014, 136, 5821.
(15) Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron:
Asymmetry 1994, 5, 1999.
(16) Zhong, H. M.; Cohen, J. H.; AbdelꢀMagid, A. F.; Kenney, B.
D.; Maryanoff, C. A.; Shah, R. D.; Villani, F. J., Jr.; Zhang, F.;
Zhang, X. Tetrahedron Lett. 1999, 40, 7721.
(17) Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.; Rusꢀ
sell, A. J.; Taylor, R. J.; Thomson, A. D.; Thomson, J. E. Org. Lett.
2012, 14, 1672.
(18) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E.;
Zimmer, D. Org. Lett. 2017, 19, 1638.
(19) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as supꢀ
plementary publication number CCDC 1557564.
(20) Flack, H. D. Acta Cryst. A 1983, 39, 876.
(21) Flack, H. D.; Bernardinelli, G. J. Appl. Cryst. 2000, 33, 1143.
(22) ꢀδX = |δX (data set A) − δX (data set B)|, where X = H or C, for
the two relevant data sets A and B. Herein, data set A is taken as our
values for either 13 or 18, as relevant.
(23) The full data comparison is contained within the Supporting
Information.
(24) Professor Fabre was “almost sure that the solvent was chloro-
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Tzschucke, C. C. J. Am. Chem. Soc. 2003, 125, 3509.
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Asymmetry 1996, 7, 1101.
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