The Hancock Alkaloids (-)-Cuspareine, (-)-Galipinine, (-)-Galipeine, and (-)-Angustureine: Asymmetric Syntheses and Corrected 1H and 13C NMR Data

Article abstract of DOI:10.1021/acs.jnatprod.8b00672

The asymmetric syntheses of all members of the Hancock alkaloid family based upon a 2-substituted N-methyl-1,2,3,4-tetrahydroquinoline core are delineated. The conjugate addition of enantiopure lithium N-benzyl-N-(α-methyl-p-methoxybenzyl)amide to 5-(o-br

Full text of DOI:10.1021/acs.jnatprod.8b00672

Article
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Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
The Hancock Alkaloids (−)-Cuspareine, (−)-Galipinine, (−)-Galipeine,
and (−)-Angustureine: Asymmetric Syntheses and Corrected 1H and
13C NMR Data
Stephen G. Davies,* Ai M. Fletcher, Ian T. T. Houlsby, Paul M. Roberts, James E. Thomson,
and David Zimmer
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: The asymmetric syntheses of all members of
the Hancock alkaloid family based upon a 2-substituted N-
methyl-1,2,3,4-tetrahydroquinoline core are delineated. The
conjugate addition of enantiopure lithium N-benzyl-N-(α-
methyl-p-methoxybenzyl)amide to 5-(o-bromophenyl)-N-me-
thoxy-N-methylpent-2-enamide is used to generate the
requisite C-2 stereogenic center of the targets, while an
intramolecular Buchwald−Hartwig coupling is used to form
the 1,2,3,4-tetrahydroquinoline ring. Late-stage diversification
completes construction of the C-2 side chains. Thus, (−)-cuspareine, (−)-galipinine, (−)-galipeine, and (−)-angustureine were
prepared in overall yields of 30%, 28%, 15%, and 39%, respectively, in nine steps from commercially available 3-(o-
bromophenyl)propanoic acid in all cases. Unambiguously corrected 1H and 13C NMR data for the originally isolated samples of
(−)-cuspareine, (−)-galipinine, and (−)-angustureine are also reported, representing a valuable reference resource for these
popular synthetic targets.
Galipea officinalis Hancock1 is a shrubby tree that can be found
growing on the mountainsides of Venezuela and on the banks
of the Orinoco River and which is revered in the indigenous
folk medicine for its healing properties. Reports concerned
with the determination of the alkaloid content of the trunk
bark (called angostura) of this plant appeared from the
1880s,2,3 and one of the alkaloids identified in early reports was
given the name cuspareine (without a structure).4,5 It was not
̈
until 1950 that Schlager and Leeb proposed the gross structure
of N-methyl-2-[2′-(3″,4″-dimethoxyphenyl)ethyl]-1,2,3,4-tet-
rahydroquinoline for cuspareine (Figure 1), on the basis of
degradation studies.6 They confirmed their postulate by
preparing a synthetic sample of this material as the racemate,6
although the natural product itself was evidently nonracemic
{[α]2D0 −20.4 (c 6.8 in EtOH)}.6 Cuspareine was then largely
ignored for over 50 years, with the only other syntheses (of the
7
̌
racemate) being reported by Stanek in 1957 and by
Terashima et al. in 1985,8 with limited accompanying
characterization data. However, Jacquemond-Collet et al.
described their re-evaluation of the alkaloid content of
angostura, which culminated in the isolation, identification,
and biological profiling of a range of known and new alkaloids,
in a series of reports that appeared at the end of the 1990s and
in the early 2000s.9−12 Cuspareine was one of the alkaloids
isolated in these studies {[α]D −22.8 (c 0.0135 in CHCl3)},13
and it was fully characterized by NMR spectroscopy (1H, 13C)
for the first time.9,14 Three other alkaloids with an N-methyl-
1,2,3,4-tetrahydroquinoline scaffold bearing a C-2 substituent
Figure 1. Structures of the Hancock alkaloids (naturally occurring
isomers shown).
were also isolated and identified, and these were named
galipinine {[α]D −33.4 (c 0.0055 in CHCl3)},9,13,14 galipeine
{[α]D −13.6},10,15 and angustureine {[α]D −7.16}10,15 (Figure
1). This tetrad has since captivated the interest of the synthetic
Received: August 9, 2018
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
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community:16−26 relatively simple structures coupled with
biological activity have no doubt contributed to their
subsequent and common occurrence as targets to validate
the synthetic utility of newly developed methods to enable the
preparation of tetrahydroquinolines or else to showcase the use
of the same. These synthetic studies have also enabled the
absolute configurations of the alkaloids to be determined, with
the assignments being based upon comparison of specific
rotation values in all cases. Considering the interest that has
been lavished on them since 2000 (16 syntheses of cuspareine,
14 of galipinine, and 27 of angustureine reported to date),16−26
aryl- or alkyllithium reagent to the amide functionality within 4
would then allow the construction of the C-2 side chains, with
functional group manipulation then giving the target alkaloids
5 (Figure 2).
1
it is incredible that discrepancies between the H and 13C
NMR spectroscopic data reported by Jacquemond-Collet et
al.9,10 for the natural products and synthetic samples thereof
did not attract comment for over 15 years. In 2017, however,
Diaz-Mun
̃
oz et al.25 reported their approach to the alkaloids in
racemic form and noted differences between the 13C NMR
data of their synthetic samples of cuspareine and galipinine and
those reported by Jaquemond-Collet et al.9 for the natural
samples isolated from angostura. These observations led Diaz-
Mun
inadvertently transposed some of the 13C NMR data for
cuspareine and galipinine.25 Although Diaz-Mun
oz et al. made
̃
oz et al. to propose that Jaquemond-Collet et al. had
̃
no comment regarding the agreement of NMR spectroscopic
data for galipeine and angustureine, we26 simultaneously
reported the results of our own, independent investigations
Figure 2. Proposed synthesis of the Hancock alkaloids (−)-cuspar-
eine, (−)-galipinine, (−)-galipeine, and (−)-angustureine.
1
into discrepancies that we had noted between the H and 13C
NMR data reported by Jaquemond-Collet et al.10 for
(−)-galipeine and the analogous data for purported synthetic
samples thereof.27,28 In fact, our study revealed that the
originally proposed structure of this alkaloid was, unfortu-
nately, erroneous and culminated in its structural revision; our
study therefore also constitutes the first time (and to date the
only time)29 that a synthetic sample of this alkaloid has been
prepared.26 In this article, we delineate the full development of
our approach to enable access to all of the members of this
alkaloid family, which thus enabled preparation of (−)-cuspar-
eine, (−)-galipinine, and (−)-angustureine, as well as
(−)-galipeine. Furthermore, we report unambiguously cor-
(−)-Cuspareine, (−)-Galipinine, and (−)-Galipeine.
The preparation of the three members of the Hancock alkaloid
family based upon an N-methyl-2-(2′-arylethyl)-1,2,3,4-tetra-
hydroquinoline core, viz. (−)-cuspareine, (−)-galipinine, and
(−)-galipeine, was first pursued. α,β-Unsaturated Weinreb
amide 9 was prepared from commercially available 3-(o-
bromophenyl)propanoic acid 6. Attempted reduction of 6 with
LiAlH4 was accompanied by significant debromination
(∼50%), as has been previously observed,31 and therefore
reduction of 6 was carried out using NaBH4 in the presence of
32
BF3·OEt2 to give the corresponding alcohol 7 in 97% yield.
1
rected H and 13C NMR data for (−)-cuspareine, (−)-galipi-
One-pot Swern oxidation and Wittig olefination of 7 using
Ph3PCHCON(Me)(OMe) 8 (prepared from bromoacetyl
bromide) as the ylide gave 9 as a single diastereoisomer [>95:5
dr, (E):(Z) ratio], which was isolated in 87% yield; the
1
nine, and (−)-angustureine from analysis of the original H
and 13C NMR spectra for these alkaloids, which were kindly
supplied to us by Professor Nicolas Fabre (a member of the
team involved in the seminal studies describing the isolation of
these alkaloids).30
3
diagnostic value J2,3 = 15.4 Hz enabled confident assignment
of the geometry of the newly formed olefin functionality
(Scheme 1).
RESULTS AND DISCUSSION
As the naturally occurring isomers of the three N-methyl-2-
(2′-arylethyl)-1,2,3,4-tetrahydroquinoline alkaloid targets share
an (S)-configuration, and given the presence of the N-methyl
group in the targets, the conjugate addition of lithium (R)-N-
methyl-N-(α-methyl-p-methoxybenzyl)amide (R)-10 to α,β-
unsaturated Weinreb amide 9 was first assessed. However, this
produced a 75:25 mixture of the two diastereoisomeric β-
amino amides 12 and 13 in 93% combined yield. The reaction
diastereoselectivity was determined by integration of both of
the singlet resonances associated with both of the N-methyl
groups of the major diastereoisomer 12 at δH 2.24 and δH 3.14
and those of the minor diastereoisomer 13 at δH 2.09 and δH
■
Syntheses of (−)-cuspareine, (−)-galipinine, (−)-galipeine,
and (−)-angustureine that involved late-stage construction of
the C-2 side chains from a common intermediate alongside the
ability to access either enantiomeric form were envisaged,
given the differences in both structure and absolute
configuration of the four alkaloids. In the forward sense,
conjugate addition of an enantiopure, secondary lithium amide
2 (derived from the corresponding enantiomer of α-methyl-p-
methoxybenzylamine) to an α,β-unsaturated amide 1 [derived
from 3-(o-bromophenyl)propanoic acid] would give the
corresponding enantiopure β-amino amide 3. Mono-N-
deprotection of the N-α-methyl-p-methoxybenzyl substituent
under acidic conditions would leave the aryl bromide
functionality untouched, thus enabling subsequent intra-
molecular Buchwald−Hartwig coupling to give the common
1,2,3,4-tetrahydroquinoline scaffold 4. Addition of the requisite
1
3.17 in the H NMR spectrum of the crude reaction mixture;
the relative configurations of 12 and 13 were not, however,
unambiguously assigned. In contrast, conjugate addition of
lithium (R)-N-benzyl-N-(α-methyl-p-methoxybenzyl)amide
(R)-11 to 9 delivered β-amino amide (3R,αR)-14 as a single
B
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of PPh3 also gave quantitative conversion, and (R)-16 was
isolated in quantitative yield in this case (Scheme 3).
Scheme 1. Preparation of α,β-Unsaturated Weinreb Amide
9
a
Scheme 3. Preparation of 1,2,3,4-Tetrahydroquinoline
a
Scaffold (R)-16
a
Reagents and conditions: (i) NaBH4, BF3·OEt2, THF, 0 °C, 1 h; (ii)
a
Reagents and conditions: (i) Pd(OAc)2, ligand, Cs2CO3, PhMe,
(COCl)2, DMSO, CH2Cl2, −78 °C, 40 min, then Et3N, −78 °C to rt,
30 min, then 8, rt, 16 h.
reflux, 24 h.
It was envisaged that the aryllithium reagents required for
diversification of the common intermediate (R)-16 to the
alkaloid targets could be prepared in situ upon treatment of the
corresponding aryl bromides with n-BuLi.38,39 Reaction of (R)-
16 with the aryllithium reagent 18 (derived from 4-
bromoveratrole 17) was first investigated for purposes of
optimization (Scheme 4). Initially, 1.0 equiv of n-BuLi was
diastereoisomer (>95:5 dr), which was isolated in 80% yield.
The absolute configuration at the newly formed C-3
stereogenic center of (3R,αR)-14 was assigned by reference
to the transition state mnemonic that we have developed to
predict the stereochemical outcome of this class of conjugate
addition reactions.33 Subsequent treatment of (3R,αR)-14 with
HCO2H in the presence of Et3SiH34−36 effected chemo-
selective removal of the N-α-methyl-p-methoxybenzyl group to
furnish (R)-15 in 81% yield (Scheme 2).
a
Scheme 4. Preparation of Ketone 19
Scheme 2. Preparation of Enantiopure β-Amino Amides 14
a
and 15
a
Reagents and conditions: (i) n-BuLi, THF, −78 °C, 30 min; (ii) 18,
THF, see table.
a
Reagents and conditions: (i) (R)-10, THF, −78 °C, 2 h; (ii) (R)-11,
added to 1.0 equiv of 17 in tetrahydrofuran (THF) at −78 °C,
followed by the addition of Weinreb amide (R)-16. Under
these conditions, however, only 40% conversion to ketone 19
was observed after 90 min, and thus 19 was isolated in only
37% yield. Neither increasing the reaction duration (to 16 h)
nor increasing the reaction temperature (to 0 °C) had a
significant impact upon the conversion to 19 (43% and 33%
conversion, respectively). To ascertain whether reaction of n-
BuLi with n-BuBr (formed in situ as the side product of the
lithium−halogen exchange) was depleting the amount of base,
THF, −78 °C, 2 h; (iii) HCO2H, Et3SiH, 90 °C, 16 h. PMP = p-
methoxyphenyl.
Treatment of (R)-15 with 5 mol % Pd(OAc)2 in the
presence of PPh3 and Cs2CO3 in PhMe at reflux for 24 h37
gave 43% conversion to tetrahydroquinoline (R)-16, which
was isolated in 37% yield. Increasing the catalyst loading to 15
mol % resulted in quantitative conversion, and (R)-16 was
isolated in 79% yield. Alternatively, the use of XPhos in place
C
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and so was responsible for the low levels of conversion
observed, an experiment was performed using 2.0 equiv of n-
BuLi and 1.0 equiv of 17. In this case, 84% conversion of (R)-
16 into a 30:70 mixture of ketone 19 and n-butyl ketone 20
was observed, indicating that the excess n-BuLi had not been
consumed and was able to undergo reaction with Weinreb
amide (R)-16. The identity of 20 was confirmed upon
treatment of (R)-16 with 2.0 equiv of n-BuLi alone, which
(interestingly) gave quantitative conversion to 20 as the
exclusive product, which was isolated in 71% yield (Scheme 5).
Alternatively, when the TFA/Et3SiH reaction was left to run
for 16 h, 25 was formed as the only product and isolated in
77% yield from 19. Subjection of 25 to an atmosphere of
hydrogen in the presence of Pd/C and formalin (37% aqueous
HCHO) resulted in tandem hydrogenolytic N-debenzylation
and reductive N-methylation, giving (−)-cuspareine (26) in
90% yield, corresponding to 27% yield over nine steps from
commercially available 3-(o-bromophenyl)propanoic acid 6
(Scheme 7).
a
Scheme 7. Preparation of (−)-Cuspareine (26)
a
Scheme 5. Preparation of Ketone 20
a
Reagents and conditions: (i) n-BuLi, THF, −78 °C, 1.5 h.
The effect of reaction stoichiometry was next investigated in
order to promote formation of the target aryl ketone 19. It was
found that the use of 7.0 equiv of n-BuLi and 7.0 equiv of 17
delivered quantitative conversion to 19, allowing its isolation in
79% yield (Scheme 4). Using this protocol, ketone 23 was
produced in a similar manner from (R)-16 and the requisite
aryl bromide, viz., 5-bromo-1,3-benzodioxole 21, in 82%
isolated yield (Scheme 6).
a
a
Reagents and conditions: (i) LiAlH4, THF, reflux, 16 h; (ii) TFA,
Scheme 6. Preparation of Ketone 23
Et3SiH, 70 °C, 16 h; (iii) H2, formalin, Pd/C, MeOH, rt, 24 h.
With an end-game established, sequential treatment of
ketone 23 with LiAlH4 and then TFA and Et3SiH gave 28 in
77% yield. Subsequent one-pot hydrogenolytic N-debenzyla-
tion and reductive N-methylation of 28 gave (−)-galipinine
(29) in 81% yield, corresponding to 25% yield over nine steps
from commercially available 3-(o-bromophenyl)propanoic acid
6 (Scheme 8).
We again wish to extend our gratitude to Professor Nicolas
Fabre for supplying us with copies of the NMR spectra
recorded for the samples of the alkaloids isolated from
angostura.30 Unfortunately, when we analyzed these spectra for
(−)-cuspareine and (−)-galipinine, we noted that several
a
1
Reagents and conditions: (i) n-BuLi, THF, −78 °C, 30 min; (ii) 22,
transcriptional errors had occurred between the raw H and
13C NMR data and those reported.9 We therefore first
THF, −78 °C, 1.5 h.
1
validated the H and 13C NMR data for the natural samples
of both (−)-cuspareine (Figure 3) and (−)-galipinine (Figure
Initial attempts at the reduction of ketone 19 to give 25, or
to provide (−)-cuspareine (26) directly, were unsuccessful
under a range of conditions, and therefore a stepwise approach
to the alkaloid target was investigated. Reduction of 19 with
LiAlH4 gave the corresponding alcohol 24 (of undetermined
and unimportant stereoisomeric constitution at the carbinol
stereocenter) and was followed by treatment of 24 with
tetrafluoroacetic acid (TFA) in the presence of Et3SiH for 6 h,
which gave an 80:20 mixture of 25 and the corresponding
styrene derivative. Hydrogenolysis of this mixture in the
presence of formalin resulted in convergence to (−)-cuspar-
eine (26), which was thus isolated in 35% yield from 19.
4); this included correction of the reference frequencies in the
1
1H and 13C NMR spectra for cuspareine and the H NMR
1
spectrum for galipinine (for H NMR, CHCl3, δH = 7.26; for
13C NMR, CDCl3, δC = 77.16).40,41 It was not possible to
determine (and hence correct if necessary) the reference
frequency in the 13C NMR spectrum for galipinine due to the
poor resolution of the copy of the original spectrum. As a result
of this analysis, we are able to confirm unambiguously that a
large amount of the 13C NMR data reported for cuspareine and
galipinine was indeed transposed,9 as Diaz-Mun
̃
oz et al. had
speculated.25 With these data in hand, it was apparent that the
D
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a
Scheme 8. Preparation of (−)-Galipinine (29)
Figure 4. H and 13C NMR data of 29 and natural (−)-galipinine.
Midpoints of all multiplets are quoted. Values of ΔδC are given in
parentheses. NMR data of natural (−)-galipinine are corrected here
(compared to those reported in ref 9) by analysis of the NMR spectra
of the natural product. Reference frequencies employed are CHCl3,
δH = 7.26; CDCl3, δC = 77.16 (refs 40, 41), although it was not
possible to determine the reference frequency of the 13C NMR
spectrum for natural (−)-galipinine. *These (overlapping) resonances
were not resolvable in the spectrum of the natural product but could
be resolved in the spectrum of 29.
1
a
Reagents and conditions: (i) LiAlH4, THF, reflux, 16 h; (ii) TFA,
Et3SiH, 70 °C, 16 h; (iii) H2, formalin, Pd/C, MeOH, rt, 24 h.
natural (−)-cuspareine was reported to have [α]2D0 −20.4 (c 6.8
in EtOH)6 and [α]D −22.8 (c 0.0135 in CHCl3),9 while for 26
we obtained [α]2D5 −17.6 (c 0.2 in EtOH) and [α]2D5 −25.0 (c
0.3 in CHCl3), and natural (−)-galipinine was reported to have
[α]D −33.4 (c 0.0055 in CHCl3),9 while for 29 we obtained
[α]2D5 −23.7 (c 1.0 in CHCl3).
We have previously reported the application of this
methodology to the synthesis of (−)-galipeine and the analysis
of its NMR and specific rotation data; in this case the alkaloid
could be prepared in 15% yield over nine steps from
commercially available 3-(o-bromophenyl)propanoic acid 6.26
(−)-Angustureine. The preparation of the final member of
this natural product family, i.e., (−)-angustureine, was next
pursued. As it has been determined that the naturally occurring
isomer has the (R)-configuration, the enantiomeric tetrahy-
droquinoline (S)-16 was first prepared. Conjugate addition of
lithium (S)-N-benzyl-N-(α-methyl-p-methoxybenzyl)amide
(S)-11 to α,β-unsaturated Weinreb amide 9 gave β-amino
amide (3S,αS)-14 as a single diastereoisomer (>95:5 dr), in
99% yield. Chemoselective removal of the N-α-methyl-p-
methoxybenzyl group from (3S,αS)-14 using HCO2H in the
presence of Et3SiH34−36 gave (S)-15 in 80% yield. Finally,
intramolecular Buchwald−Hartwig coupling provided (S)-16
quantitatively (Scheme 9).
1
Figure 3. H and 13C NMR data of 26 and natural (−)-cuspareine.
Midpoints of all multiplets are quoted. Values of ΔδC are given in
parentheses. NMR data of natural (−)-cuspareine are corrected here
(compared to those reported in ref 9) by analysis of the NMR spectra
of the natural product. Reference frequencies employed are CHCl3,
δH = 7.26; CDCl3, δC = 77.16 (refs 40, 41). *These (overlapping)
resonances were not resolvable in the spectrum of the natural product
but could be resolved in the spectrum of 26.
spectra of our synthetic samples of 26 and 29 were effectively
superimposable with those for the natural materials: for 26 and
natural (−)-cuspareine, ΔδH ≤ 0.0642,43 and ΔδC = 0.042
In order to facilitate construction of the n-pentyl side chain
required for the natural product, the addition of n-
propyllithium to the Weinreb amide functionality of (S)-16
was evaluated. It was envisaged that n-propyllithium could be
prepared in situ upon lithium−halogen exchange of t-BuLi and
n-propyl bromide. The key to the success of this reaction was
the mode of addition of the two reagents. When 2.0 equiv of n-
(Figure 3), while for 29 and natural (−)-galipinine, ΔδH
≤
0.0441,42 and ΔδC ≤ 0.241 (Figure 4). In addition, the specific
rotation values of our synthetic samples were in good
agreement with those reported for the natural products:
E
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a
Scheme 9. Preparation of 1,2,3,4-Tetrahydroquinoline
Scaffold (S)-16
Scheme 10. Preparation of Ketone 32
a
a
Reagents and conditions: (i) (S)-11, THF, −78 °C, 2 h; (ii)
HCO2H, Et3SiH, 90 °C, 16 h; (iii) Pd(OAc)2, XPhos, Cs2CO3,
PhMe, reflux, 24 h. PMP = p-methoxyphenyl.
a
Reagents and conditions: (i) add n-PrBr to t-BuLi, THF, −78 °C, 30
min; (ii) add t-BuLi to n-PrBr, THF, −78 °C, 30 min; (iii) add 16,
THF, −78 °C, 1.5 h.
propyl bromide were added to a solution of 4.0 equiv of t-BuLi
in THF at −78 °C followed by addition of (S)-16, the result
was formation of 32 exclusively, and thus 32 was isolated in
85% yield. In contrast, when 4.0 equiv of t-BuLi was added to a
solution of 2.0 equiv of n-propyl bromide in THF at −78 °C
(i.e., the inverse addition to the previous experiment), followed
by addition of (S)-16, a 67:33 mixture of ketone 32 and N-
methyl amide 33 was formed, and 32 and 33 were isolated in
52% and 15% yields, respectively. Such demethoxylation of
Weinreb amides upon exposure to strongly basic conditions
has been previously documented.44 Plausibly, addition of 4.0
equiv of t-BuLi to 2.0 equiv of n-propyl bromide allows
deleterious reaction of in situ formed n-propyllithium with t-
BuBr (the other product of the lithium−halogen exchange),
depleting the amount of the former reagent. Complete
consumption of the t-BuLi cannot therefore occur under
these conditions, and at the end of the addition, unreacted t-
BuLi is present in solution; upon introduction of (S)-16,
deprotonation of either the α-proton (forming the enolate) or
the methoxy group by t-BuLi is followed by liberation of
formaldehyde and the anion of N-methyl amide 33 (Scheme
10).
could be isolated in ∼35% yield. When the solvent was
swapped to AcOH,51 a marked improvement in reaction
efficiency was noted; optimization of the reaction then gave 34
in 99% isolated yield. Reduction of 34 using Raney-Ni in a
mixture of EtOH and THF for 1 h effected complete
desulfurization to give predominantly 35, although partial N-
debenzylation was also evident; when the reaction was left to
run for extended time periods, hydrogenation of the aromatic
ring also occurred (in addition to N-debenzylation). Thus, the
crude reaction mixture was subjected to the conditions
successfully employed for one-pot hydrogenolytic N-debenzy-
lation and reductive N-methylation in the synthesis of the
other alkaloids, which in this case gave (−)-angustureine (36)
in 69% yield from 34, corresponding to 39% yield over nine
steps from commercially available 3-(o-bromophenyl)-
propanoic acid 6 (Scheme 11).
We next validated the 1H and 13C NMR data for the natural
sample of (−)-angustureine,30 which were generally in accord
with those reported, with the exception of the resonance for
C(5′)H3;10 in addition to correction of this value, we corrected
the reference frequency for the 13C NMR spectrum (CDCl3,
δC = 77.16)40,41 in our analysis (Figure 5). The 13C NMR
spectroscopic data for 36 were thus found to be in excellent
agreement with data for the natural product (ΔδC ≤ 0.2). It
was not possible to determine (and hence correct if necessary)
Reduction of the carbonyl group of 32 to a methanediyl
group could not be achieved in the same manner as that
employed in the syntheses of other members of the alkaloid
family, as that process was reliant upon formation of a highly
stabilized, benzylic cation.45 Attempted deoxygenation via a
Wolff−Kischner reduction under standard (NH2NH2, KOH)46
or modified (NH2NHTs, ZnCl2, then NaBH3CN)47,48
conditions or under modified Clemmensen-type conditions
(Zn, TMSCl, H2O, THF)49 resulted in low mass return and/or
a complex mixture of products. A Mozingo reaction (reduction
of the corresponding dithiolane by Raney-Ni) was therefore
explored. Initial attempts at formation of dithiolane 34 using
1
the reference frequency in the H NMR spectrum, as no
residual solvent signal was evident; a systematic error of 0.13
ppm ( 0.02 ppm) was noted when the data for 36 were
compared with those for the natural product, which may arise
1
from differences in the referencing of the spectra. The H and
13C NMR data acquired for a synthetic sample of (R)-
angustureine previously prepared in our laboratory,52 however,
matched well with the data for the present sample 36 (ΔδH ≤
0.03 and ΔδC ≤ 0.2). Comparison of specific rotation data for
angustureine is hampered by the fact that the natural product
50
ethane-1,2-dithiol in the presence of BF3·OEt2 in CH2Cl2
were accompanied by formation of inseparable (and thus
unidentifiable) byproducts, and only an impure sample of 34
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a
Scheme 11. Preparation of (−)-Angustureine (36)
Figure 5. 1H and 13C NMR data of 36 and natural (−)-angustureine.
Midpoints of all multiplets are quoted. Values of ΔδC are given in
parentheses. NMR data of natural (−)-angustureine are corrected
here (compared to those reported in ref 10) by analysis of the NMR
spectra of the natural product. Reference frequencies employed were
as follows: CHCl3, δH = 7.26; CDCl3, δC = 77.16 (refs 40, 41)
although it was not possible to determine the reference frequency of
a
Reagents and conditions: (i) HSCH2CH2SH, BF3·OEt2, AcOH, rt,
16 h; (ii) Raney-Ni, EtOH, THF, 80 °C, 1 h; (iii) H2, formalin, Pd/C,
MeOH, rt, 24 h.
was reported to have [α]D −7.1610 (i.e., the solvent,
temperature, and concentration were not reported).53
However, a synthetic sample of (S)-angustureine was
determined to have uniform positive sign of specific rotation
values determined in a range of common solvents ([α]2D3 +7.9
(c 1.00, CHCl3); [α]D26 +4.4 (c 1.00, CH2Cl2); [α2D6] +5.2 (c
1.00, MeOH); [α]2D6 +5.1 (c 1.00, EtOH)),54 and on this basis
the (R)-configuration was assigned to the naturally occurring
enantiomer of angustureine. More than 20 other synthetic
investigations have independently confirmed the positive sign
of specific rotation of (S)-angustureine (for example, Pandey et
al. reported [α]2D5 +7.6 (c 0.4, CHCl3)21 and Ma et al. reported
[α]2D0 +8.0 (c 1.00, CHCl3))55 and the negative sign of specific
rotation of (R)-angustureine (for example, Aponick et al.
reported [α]2D4 −7.7 (c 1.00, CHCl3)19 and Fan et al. reported
[α]2D0 −7.33 (c 1.00, CHCl3)).56 In this study, we obtained
[α]2D5 −10.6 (c 0.2, CHCl3) for 36 {our sample of (R)-
angustureine previously prepared via an independent synthetic
route had [α]2D5 −7.0 (c 1.0, CHCl3)}.52 The sign and
magnitude of the specific rotation value for 36 are, therefore,
entirely as expected (in accord with the wealth of literature
data), although it is intriguing that natural angustureine is not
homochiral with respect to the remainder of the tetrad isolated
from the same plant. Unfortunately we have, to date, been
unable to either obtain or isolate an authentic sample of natural
angustureine to verify the sign of the specific rotation of the
natural product.
In conclusion, asymmetric syntheses of the Hancock
alkaloids (−)-cuspareine, (−)-galipinine, (−)-galipeine, and
(−)-angustureine have been accomplished in nine steps from
commercially available 3-(o-bromophenyl)propanoic acid in all
cases. Late-stage diversification contributes to the efficiency of
this protocol, which delivers the target alkaloids in overall
yields of 30%, 28%, 15%, and 39%, respectively. Key steps in
the synthesis are the use of the conjugate addition of the
requisite enantiomer of lithium N-benzyl-N-(α-methyl-p-
methoxybenzyl)amide to 5-(o-bromophenyl)-N-methoxy-N-
methylpent-2-enamide to set the configuration at the C-2
stereogenic center of the targets, and the use of a Buchwald−
Hartwig coupling reaction to construct the tetrahydroquinoline
1
the H NMR spectrum for natural (−)-angustureine.
core. The inherent flexibility of this approach should ensure
that this method is applicable to the synthesis of a range of
1
analogues. The H and 13C NMR spectroscopic data for the
naturally occurring samples of (−)-cuspareine, (−)-galipinine,
and (−)-angustureine have been unambiguously corrected, and
thus the data contained herein also constitute a reference
resource for these popular synthetic targets.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Melting points are un-
corrected. Specific rotations are reported in 10−1 deg cm2 g−1 and
concentrations in g/100 mL. IR spectra were recorded using an ATR
module. Selected characteristic peaks are reported in cm−1. NMR
spectra were recorded in CDCl3. Reference frequencies employed
were as follows: CHCl3, δH = 7.26; CDCl3, δC = 77.16.40,41 1H−1H
COSY and 1H−13C HSQC analyses were used to establish atom
connectivity. Accurate mass measurements were run on a MicroTOF
instrument internally calibrated with polyalanine. Reactions involving
moisture-sensitive reagents were carried out under a nitrogen
atmosphere using standard vacuum line techniques and glassware
that was flame-dried and allowed to cool under nitrogen before use.
Solvents were dried according to the procedure outlined by Grubbs
and co-workers.57 Organic layers were dried over Na2SO4 or MgSO4.
Flash column chromatography was performed on Kieselgel 60 silica.
3-(2′-Bromophenyl)propan-1-ol, 7. BF3·Et2O (16.0 mL, 130
mmol) was added dropwise to a stirred solution of 6 (14.9 g, 65.0
mmol) and NaBH4 (4.91 g, 130 mmol) in THF (130 mL) at 0 °C.
The resultant mixture was stirred at 0 °C for 1 h; then MeOH (65
mL) and 1.0 M aqueous HCl (65 mL) were added sequentially. The
resultant mixture was extracted with EtOAc (3 × 150 mL), and the
combined organic extracts were dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30−40 °C
petroleum ether/Et2O/NH4OH, 50:50:1) gave 7 as a colorless oil
(13.6 g, 97%):26,58 1H NMR δH (400 MHz, CDCl3) 1.37 (1H, t, J 5.8,
OH), 1.88−1.95 (2H, m, C(2)H2), 2.86 (2H, t, J 7.8, C(3)H2), 3.72
(1H, app q, J 5.8, C(1)H2), 7.04−7.11 (1H, m, C(4′)H), 7.23−7.28
(2H, m, C(5′)H, C(6′)H), 7.55 (1H, d, J 8.1, C(3′)H).
(E)-5-(2′-Bromophenyl)-N-methoxy-N-methylpent-2-enam-
ide, 9. DMSO (17.2 mL, 60.4 mmol) was added to a stirred solution
G
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Article
of (COCl)2 (10.2 mL, 121 mmol) in CH2Cl2 (330 mL) at −78 °C,
and the resultant solution was stirred at −78 °C for 20 min. A
solution of 7 (13.0 g, 60.4 mmol) in CH2Cl2 (30 mL) was added, and
the resultant solution was stirred at −78 °C for 40 min. Et3N (50.5
mL, 363 mmol) was added, the resultant solution was allowed to
warm to rt over 30 min, then 8 (33.0 g, 90.7 mmol) was added, and
the resultant solution was stirred at rt for 16 h. Saturated aqueous
K2CO3 (300 mL) was added, and the resultant mixture was extracted
with CH2Cl2 (3 × 300 mL). The combined organic extracts were
washed with brine (600 mL), then dried and concentrated in vacuo to
give (E)-9 in 92:8 dr [(E):(Z) ratio]. Purification via flash column
chromatography (eluent 30−40 °C petroleum ether/Et2O/NH4OH,
50:50:1) gave (E)-9 as a pale yellow oil (15.7 g, 87%, >95:5 dr [(E):
(Z) ratio]):26 1H NMR δH (400 MHz, CDCl3) 2.53−2.59 (2H, m,
C(4)H2), 2.91 (2H, t, J 7.5, C(5)H2), 3.23 (3H, s, NMe), 3.65 (3H, s,
OMe), 6.41 (1H, d, J 15.4, C(2)H), 6.98−7.08 (2H, m, C(3)H, C(4′)
H), 7.19−7.25 (2H, m, C(5′)H, C(6′)H), 7.52−7.54 (1H, m, C(3′)
H).
raphy (eluent 30−40 °C petroleum ether/Et2O/NH4OH, 50:50:1)
gave (3R,αR)-14 as a pale yellow oil (273 mg, 80%, >95:5 dr):26 [α]D25
+21.8 (c 1.0 in CHCl3); 1H NMR δH (400 MHz, CDCl3) 1.39 (3H, d,
J 7.0, C(α)Me), 1.57−1.65 (1H, m, C(4)HA), 1.73−1.83 (1H, m,
C(4)HB), 2.00 (1H, app d, J 14.0, C(2)HA), 2.23−2.29 (1H, m, C(2)
HB), 2.71 (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), 3.58−
3.64 (1H, m, C(3)H) overlapping 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), 7.00−7.04 (1H,
m, C(4′)H), 7.17−7.28 (5H, m, C(5′)H, C(6′)H, C(2″)H, C(6″)H,
p-Ph), 7.36 (2H, t, J 7.5, m-Ph), 7.50 (1H, d, J 7.8, C(3′)H), 7.54
(2H, d, J 7.5, o-Ph).
(3S,αS)-3-[N-Benzyl-N-(α-methyl-p-methoxybenzyl)amino]-
5-(2′-bromophenyl)-N-methoxy-N-methylpentanamide,
(3S,αS)-14. BuLi (2.3 M in hexanes, 31.6 mL, 72.8 mmol) was added
dropwise to a stirred solution of (S)-N-benzyl-N-(α-methyl-p-
methoxybenzyl)amine (18.1 g, 75.1 mmol, >98% ee) in THF (150
mL) at −78 °C, and the resultant mixture was stirred at −78 °C for
30 min. A solution of 9 (14.0 g, 46.9 mmol, >95:5 dr [(E):(Z) ratio])
in THF (80 mL) at −78 °C was then added, and the resultant mixture
was stirred at −78 °C for 2 h. Saturated aqueous NH4Cl (200 mL)
was added, and the reaction mixture was allowed to warm to rt, then
concentrated in vacuo. The residue was partitioned between CH2Cl2
(200 mL) and 10% aqueous citric acid (200 mL), and the organic
layer was washed with saturated aqueous NaHCO3 (200 mL) and
brine (200 mL), then dried and concentrated in vacuo to give
(3S,αS)-14 in >95:5 dr. Purification via flash column chromatography
(eluent 30−40 °C petroleum ether/Et2O/NH4OH, 50:50:1) gave
(3S,αS)-14 as a pale yellow oil (24.7 g, 99%, >95:5 dr); [α]2D5 −23.5
(c 1.0 in CHCl3).
(3R,αR)- and (3S,αR)-3-[N-Methyl-N-(α-methyl-p-
methoxybenzyl)amino]-5-(2′-bromophenyl)-N-methoxy-N-
methylpentanamide, 12 and 13. BuLi (2.3 M in hexanes, 3.9 mL,
9.1 mmol) was added dropwise to a stirred solution of (R)-N-methyl-
N-(α-methyl-p-methoxybenzyl)amine (1.55 g, 9.39 mmol, >98% ee)
in THF (20 mL) at −78 °C, and the resultant mixture was stirred at
−78 °C for 30 min. A solution of 9 (1.75 g, 5.87 mmol, >95:5 dr
[(E):(Z) ratio]) in THF (5 mL) at −78 °C was then added, and the
resultant mixture was stirred at −78 °C for 2 h. Saturated aqueous
NH4Cl (5 mL) was added, and the reaction mixture was allowed to
warm to rt, then concentrated in vacuo. The residue was partitioned
between CH2Cl2 (20 mL) and 10% aqueous citric acid (20 mL), and
the organic layer was washed with saturated aqueous NaHCO3 (20
mL) and brine (20 mL), then dried and concentrated in vacuo to give
12 and 13 in 75:25 dr. Purification via flash column chromatography
(eluent 30−40 °C petroleum ether/Et2O/NH4OH, 66:33:1) gave 12
and 13 as a colorless oil (2.53 g, 93%, 75:25 dr): IR νmax 2968, 2934,
2864, 2835, 1658; 1H NMR δH (400 MHz, CDCl3) 1.33 (3H, d, J 6.7,
C(α)Me), 1.46−1.57 (1H, m, C(4)HA), 1.59−1.83 (1H, m, C(4)HB),
2.09 (0.75H, s, C(3)NMe, 13), 2.24 (2.25H, s, C(3)NMe, 12), 2.30−
2.70 (3H, m, C(2)H2, C(5)HA), 2.88−3.00 (1H, m, C(5)HB), 3.15
(2.25H, s, C(1)NMe, 12), 3.18 (0.75H, s, C(1)NMe, 13), 3.31−3.41
(1H, m, C(3)H), 3.55−3.66 (4H, m, C(α)H, NOMe), 3.78 (2.25H, s,
ArOMe, 12), 3.79 (0.75H, s, ArOMe, 13), 6.81−6.85 (2H, m, C(3″)
H, C(5″)H), 6.98−7.04 (1H, m, C(4′)H), 7.14−7.26 (4H, m, C(5′)
H, C(6′)H, C(2″)H, C(6″)H), 7.48−7.51 (1H, m, C(3′)H); 13C
NMR δC (100 MHz, CDCl3) 21.8, 22.1 (C(α)Me), 32.0, 32.2, 32.2,
32.4, 32.6 (C(2), C(4), C(1)NMe, C(3)NMe),59 33.9, 33.9 (C(5)),
55.0, 55.3, 55.4, 55.7, 61.3, 61.6 (C(3), C(α), NOMe, ArOMe), 113.6,
113.7 (C(3″), C(5″)), 124.5 (C(2′)), 127.4, 127.5, 127.5 (C(3′),
C(4′)), 128.4, 128.5 (C(2″), C(6″)), 130.4, 130.6 (C(6′)), 132.7,
132.8 (C(5′)), 138.3, 138.7 (C(1″)), 142.3, 142.3 (C(1′)), 158.4,
158.5 (C(4″)), 173.8, 173.9 (C(1)); m/z (ESI+) 465 ([M(81Br) +
H]+, 100%), 463 ([M(79Br) + H]+, 100%); HRMS (ESI+)
(R)-3-(N-Benzylamino)-5-(2′-bromophenyl)-N-methoxy-N-
methylpentanamide, (R)-15. Et3SiH (25 μL, 0.16 mmol) was
added to a stirred solution of (3R,αR)-14 (87 mg, 1.10 mmol, >95:5
dr) in HCO2H (0.6 mL), and the resultant solution was heated at 90
°C for 16 h. The resultant mixture was allowed to cool to rt and then
concentrated in vacuo. The residue was partitioned between CH2Cl2
(5 mL) and saturated aqueous NaHCO3 (5 mL), and the organic
extract was washed with brine (5 mL), then dried and concentrated in
vacuo. Purification via flash column chromatography (eluent 30−40
°C petroleum ether/Et2O/NH4OH, 50:50:1) gave (R)-15 as a
colorless oil (35 mg, 81%):26 [α]D25 −7.1 (c 1.0 in CHCl3); H NMR
1
δH (400 MHz, CDCl3) 1.76−1.90 (2H, m, C(4)H2), 2.67 (2H, d, J
5.8, C(2)H2), 2.77−2.88 (2H, m, C(5)H2), 3.16−3.22 (1H, m, C(3)
H) overlapping 3.18 (3H, s, NMe), 3.67 (3H, s, OMe), 3.81 (1H, d, J
12.9, NCHAHBPh), 3.86 (1H, d, J 12.9, NCHAHBPh), 7.01−7.08
(1H, m, C(4′)H), 7.21−7.37 (7H, m, C(5′)H, C(6′)H, Ph), 7.52
(1H, d, J 7.8, C(3′)H).
(S)-3-(N-Benzylamino)-5-(2′-bromophenyl)-N-methoxy-N-
methylpentanamide, (S)-15. Et3SiH (10.2 mL, 63.9 mmol) was
added to a stirred solution of (3S,αS)-14 (23.0 g, 42.6 mmol, >95:5
dr) in HCO2H (120 mL), and the resultant solution was heated at 90
°C for 16 h. The resultant mixture was allowed to cool to rt and then
concentrated in vacuo. The residue was partitioned between CH2Cl2
(500 mL) and saturated aqueous NaHCO3 (500 mL), and the organic
extract was washed with brine (500 mL), then dried and concentrated
in vacuo. Purification via flash column chromatography (eluent 30−
40 °C petroleum ether/Et2O/NH4OH, 50:50:1) gave (S)-15 as a
colorless oil (13.6 g, 80%): [α]2D5 +7.5 (c 1.0 in CHCl3).
(R)-2-[N(1′)-Benzyl-1′,2′,3′,4′-tetrahydroquinolin-2′-yl]-N-
methoxy-N-methylacetamide, (R)-16. Pd(OAc)2 (26 mg, 0.12
mmol) was added to a stirred solution of (R)-15 (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 mixture was heated at
reflux for 24 h. The resultant mixture was allowed to cool to rt and
then concentrated in vacuo. The residue was partitioned between
CH2Cl2 (100 mL) and H2O (100 mL), and the organic extract was
then dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30−40 °C petroleum ether/Et2O/NH4OH,
50:50:1) gave (R)-16 as a pale yellow solid (751 mg, quant):26 [α]D25
+
C23H3281BrN2O3 ([M(81Br) + H]+) requires 465.1570; found
+
465.1568; C23H3279BrN2O3 ([M(79Br) + H]+) requires 463.1591;
found 463.1588.
(3R,αR)-3-[N-Benzyl-N-(α-methyl-p-methoxybenzyl)amino]-
5-(2′-bromophenyl)-N-methoxy-N-methylpentanamide,
(3R,αR)-14. BuLi (2.3 M in hexanes, 0.45 mL, 1.0 mmol) was added
dropwise to a stirred solution of (R)-N-benzyl-N-(α-methyl-p-
methoxybenzyl)amine (259 mg, 1.07 mmol, >98% ee) in THF (2
mL) at −78 °C, and the resultant mixture was stirred at −78 °C for
30 min. A solution of 9 (200 mg, 0.671 mmol, >95:5 dr [(E):(Z)
ratio]) in THF (1 mL) at −78 °C was then added, and the resultant
mixture was stirred at −78 °C for 2 h. Saturated aqueous NH4Cl (1
mL) was added, and the reaction mixture was allowed to warm to rt
and then concentrated in vacuo. The residue was partitioned between
CH2Cl2 (10 mL) and 10% aqueous citric acid (10 mL), and the
organic layer was washed with saturated aqueous NaHCO3 (10 mL)
and brine (10 mL), then dried and concentrated in vacuo to give
(3R,αR)-14 in >95:5 dr. Purification via flash column chromatog-
H
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−11.0 (c 1.0 in CHCl3); 1H NMR δH (400 MHz, CDCl3) 1.96−2.12
(2H, m, C(3′)H2), 2.71 (2H, d, J 6.5, C(2)H2), 2.78 (1H, dt, J 16.5,
3.7, C(4′)HA), 2.96 (1H, ddd, J 16.5, 12.8, 5.7, C(4′)HB), 3.16 (3H, s,
NMe), 3.57 (3H, s, OMe), 4.03−4.08 (1H, m, C(2′)H), 4.52 (1H, d, J
17.2, NCHAHBPh), 4.58 (1H, d, J 17.2, NCHAHBPh), 6.44 (1H, d, J
7.7, C(8′)H), 6.60 (1H, t, J 7.7, C(6′)H), 6.96 (1H, t, J 7.7, C(7′)H),
7.03 (1H, d, J 7.7, C(5′)H), 7.19−7.31 (5H, m, Ph).
(C(4)), 25.8 (C(3)), 25.9 (C(4′)), 43.8 (C(3′)), 45.7 (C(1′)), 53.9
(C(2)), 54.3 (NCH2Ph), 112.2 (C(8)), 116.2 (C(6)), 121.3 (C(4a)),
126.6 (o,m-Ph), 126.9 (p-Ph), 127.3 (C(7)), 128.7 (o,m-Ph), 129.2
(C(5)), 139.1 (i-Ph), 144.3 (C(8a)), 210.0 (C(2′)); m/z (ESI+) 322
([M + H]+, 100%); HRMS (ESI+) C22H28NO+ ([M + H]+) requires
322.2165; found 322.2157.
(R)-N-Benzyl-2-[2′-oxo-2′-(3″,4″-methylenedioxyphenyl)-
ethyl]-1,2,3,4-tetrahydroquinoline, 23. n-BuLi (2.3 M in
hexanes, 2.4 mL, 5.4 mmol) was added dropwise to a stirred solution
of 21 (1.08 g, 5.39 mmol) in THF (15 mL) at −78 °C, and the
resultant mixture was stirred at −78 °C for 30 min. A solution of (R)-
16 (250 mg, 0.771 mmol) in THF (2 mL) at −78 °C was then added,
and the resultant mixture was stirred at −78 °C for 1.5 h. Saturated
aqueous NH4Cl (3 mL) was added, and the reaction mixture was
allowed to warm to rt and then concentrated in vacuo. The residue
was partitioned between CH2Cl2 (20 mL) and H2O (20 mL), and the
organic extract was dried and concentrated in vacuo. Purification via
flash column chromatography (eluent 30−40 °C petroleum ether/
Et2O/NH4OH, 75:25:1) gave 23 as a yellow oil (244 mg, 82%): [α]D25
−6.4 (c 1.0 in CHCl3); IR νmax 3036, 3027, 2927, 1671; 1H NMR δH
(400 MHz, CDCl3) 1.99 (1H, app ddt, J 13.1, 5.7, 2.8, C(3)HA), 2.10
(1H, app tt, J 13.1, 5.0, C(3)HB), 2.82 (1H, ddd, J 16.8, 5.0, 2.8, C(4)
HA), 2.96 (1H, ddd, J 16.8, 13.1, 5.7, C(4)HB), 3.11 (1H, dd, J 16.0,
8.0, C(1′)HA), 3.16 (1H, dd, J 16.0, 5.3, C(1′)HB), 4.17−4.22 (1H,
m, C(2)H), 4.50 (1H, d, J 17.0, NCHAHBPh), 4.58 (1H, d, J 17.0,
NCHAHBPh), 6.04 (2H, s, OCH2O), 6.49 (1H, d, J 8.1, C(8)H), 6.64
(1H, app td, J 7.3, 0.9, C(6)H), 6.82 (1H, d, J 8.2, C(5″)H), 6.97−
7.02 (1H, m, C(7)H), 7.06 (1H, d, J 7.3, C(5)H), 7.21−7.33 (5H, m,
Ph), 7.40 (1H, d, J 1.7, C(2″)H), 7.47 (1H, dd, J 8.2, 1.7, C(6″)H);
13C NMR δC (100 MHz, CDCl3) 23.6 (C(4)), 25.5 (C(3)), 41.0
(S)-2-[N(1′)-Benzyl-1′,2′,3′,4′-tetrahydroquinolin-2′-yl]-N-
methoxy-N-methylacetamide, (S)-16. Pd(OAc)2 (319 mg, 1.42
mmol) was added to a stirred solution of (S)-15 (11.5 g, 28.4 mmol),
XPhos (2.03 g, 4.26 mmol), and Cs2CO3 (18.5 g, 56.8 mmol) in
PhMe (350 mL), and the resultant mixture was heated at reflux for 24
h. The resultant mixture was allowed to cool to rt and then
concentrated in vacuo. The residue was partitioned between CH2Cl2
(500 mL) and H2O (500 mL), and the organic extract was then dried
and concentrated in vacuo. Purification via flash column chromatog-
raphy (eluent 30−40 °C petroleum ether/Et2O/NH4OH, 50:50:1)
gave (S)-16 as a pale yellow solid (9.87 g, quant): mp 62−64 °C;
[α]2D5 +10.2 (c 1.0 in CHCl3).
(R)-N-Benzyl-2-[2′-oxo-2′-(3″,4″-dimethoxyphenyl)ethyl]-
1,2,3,4-tetrahydroquinoline, 19. n-BuLi (2.3 M in hexanes, 0.47
mL, 1.1 mmol) was added dropwise to a stirred solution of 17 (234
mg, 1.08 mmol) in THF (1 mL) at −78 °C, and the resultant mixture
was stirred at −78 °C for 30 min. A solution of (R)-16 (50 mg, 0.15
mmol) in THF (0.5 mL) at −78 °C was then added, and the resultant
mixture was stirred at −78 °C for 1.5 h. Saturated aqueous NH4Cl
(0.5 mL) was added, and the reaction mixture was allowed to warm to
rt and then concentrated in vacuo. The residue was partitioned
between CH2Cl2 (5 mL) and H2O (5 mL), and the organic extract
was dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30−40 °C petroleum ether/Et2O/NH4OH,
80:24:1) gave 19 as an orange oil (49 mg, 79%): [α]2D5 −12.7 (c 1.0 in
(C(1′)), 54.2 (NCH2Ph), 54.9 (C(2)), 102.0 (OCH2O), 107.9, 108.0
(C(2″), C(5″)), 112.1 (C(8)), 116.2 (C(6)), 121.3 (C(4a)), 124.7
(C(6″)), 126.6 (o-Ph), 126.9 (p-Ph), 127.4 (C(7)), 128.7 (m-Ph),
129.3 (C(5)), 132.2 (C(1″)), 139.0 (i-Ph), 144.2 (C(8a)), 148.4
(C(3″)), 152.0 (C(4″)), 197.2 (C(2′)); m/z (ESI+) 386 ([M + H]+,
1
CHCl3); IR νmax 3028, 2962, 2933, 2900, 2838, 1669; H NMR δH
(400 MHz, CDCl3) 1.95−1.99 (1H, m, C(3)HA), 2.09 (1H, app tt, J
13.0, 4.8, C(3)HB), 2.76−2.80 (1H, m, C(4)HA), 2.96 (1H, ddd, J
16.6, 13.0, 5.7, C(4)HB), 3.13 (1H, dd, J 15.9, 8.2, C(1′)HA), 3.20
(1H, dd, J 15.9, 5.1, C(1′)HB), 3.88 (3H, s, OMe), 3.93 (3H, s, OMe),
4.16−4.22 (1H, m, C(2)H), 4.47 (1H, d, J 17.0, NCHAHBPh), 4.54
(1H, d, J 17.0, NCHAHBPh), 6.45 (1H, d, J 7.8, C(8)H), 6.62 (1H,
app td, J 7.8, 0.9, C(6)H), 6.83 (1H, d, J 8.3, C(5″)H), 6.97 (1H, t, J
7.8, C(7)H), 7.04 (1H, d, J 7.8, C(5)H), 7.19−7.32 (5H, m, Ph),
7.45−7.49 (2H, m, C(2″)H, C(6″)H); 13C NMR δC (100 MHz,
CDCl3) 23.6 (C(4)), 25.6 (C(3)), 40.8 (C(1′)), 54.3 (NCH2Ph),
55.1 (C(2)), 56.1 (OMe), 56.2 (OMe), 110.1, 110.1 (C(2″), C(5″)),
112.1 (C(8)), 116.2 (C(6)), 121.3 (C(4a)), 123.0 (C(6″)), 126.5 (o-
Ph), 126.9 (p-Ph), 127.4 (C(7)), 128.7 (m-Ph), 129.3 (C(5)), 130.5
(C(1″)), 139.0 (i-Ph), 144.2 (C(8a)), 149.2 (C(3″)), 153.5 (C(4″)),
197.8 (C(2′)); m/z (ESI+) 402 ([M + H]+, 100%); HRMS (ESI+)
+
100%); HRMS (ESI+) C25H24NO3 ([M + H]+) requires 386.1751;
found 386.1752.
(S)-N-Benzyl-2-[2′-(3″,4″-dimethoxyphenyl)ethyl]-1,2,3,4-
tetrahydroquinoline, 25. Step 1: LiAlH4 (2.4 M in THF, 0.42 mL,
1.0 mmol) was added dropwise to a stirred solution of 19 (200 mg,
0.498 mmol) in THF (3.5 mL) at 0 °C. The resultant mixture was
heated at reflux for 16 h, then allowed to cool to rt. A 2 M aqueous
NaOH (0.5 mL) solution was then added, and the resultant mixture
was heated at reflux for 3 h. The reaction mixture was then allowed to
cool to rt, filtered through Celite (eluent EtOAc), and then
concentrated in vacuo to give 24.
Step 2: Et3SiH (0.80 mL, 4.89 mmol) was added to a stirred
solution of the residue of 24 from the previous step in TFA (2.5 mL),
and the resultant solution was stirred at 70 °C for 16 h. The resultant
mixture was concentrated in vacuo, and the residue was then
partitioned between CH2Cl2 (10 mL) and saturated aqueous
NaHCO3 (10 mL). The organic extract was dried and concentrated
in vacuo. Purification via flash column chromatography (eluent 30−
40 °C petroleum ether/Et2O/NH4OH, 75:25:1) gave 25 as a yellow
oil (148 mg, 77%): [α]D25 +1.8 (c 1.0 in CHCl3); IR νmax 3024, 3000,
2934, 2835, 1601, 1515, 1498; 1H NMR δH (400 MHz, CDCl3)
1.80−1.97 (2H, m, C(1′)H2), 1.97−2.09 (2H, m, C(3)H2), 2.50 (1H,
ddd, J 14.0, 9.8, 6.6, C(2′)HA), 2.66 (1H, ddd, J 14.0, 10.0, 5.6, C(2′)
HB), 2.76 (1H, app dt, J 16.2, 3.9, C(4)HA), 2.94 (1H, ddd, J 16.2,
12.0, 5.9, C(4)HB), 3.39−3.44 (1H, m, C(2)H), 3.84 (3H, s, OMe),
3.85 (3H, s, OMe), 4.43 (1H, d, J 17.0, NCHAHBPh), 4.57 (1H, d, J
17.0, NCHAHBPh), 6.43 (1H, d, J 7.6, C(8)H), 6.59 (1H, app t, J 7.6,
C(6)H), 6.65 (1H, d, J 2.0, C(2″)H), 6.68 (1H, dd, J 8.1, 2.0, C(6″)
H), 6.77 (1H, d, J 8.1, C(5″)H), 6.96 (1H, app t, J 7.6, C(7)H), 7.03
(1H, d, J 7.6, C(5)H), 7.20−7.32 (5H, m, Ph); 13C NMR δC (100
MHz, CDCl3) 23.8 (C(4)), 24.4 (C(3)), 32.0 (C(2′)), 33.9 (C(1′)),
54.3 (NCH2Ph), 56.0 (OMe), 56.1 (OMe), 57.5 (C(2)), 111.3
(C(5″)), 111.6 (C(2″)), 111.9 (C(8)), 115.7 (C(6)), 120.2 (C(6″)),
121.7 (C(4a)), 126.6 (o,m-Ph), 126.8 (p-Ph), 127.2 (C(7)), 128.7
(o,m-Ph), 129.1 (C(5)), 134.6 (C(1″)), 139.4 (i-Ph), 144.6 (C(8a)),
+
C26H28NO3 ([M + H]+) requires 402.2064; found 402.2061.
(R)-N-Benzyl-2-(2′-oxohexanyl)-1,2,3,4-tetrahydroquino-
line, 20. A solution of (R)-16 (133 mg, 1.5 mmol) in THF (1.5 mL)
at −78 °C was added to a stirred solution of n-BuLi (2.3 M in
hexanes, 0.36 mL, 0.82 mmol) in THF (2.5 mL), and the resultant
solution was stirred at −78 °C for 16 h. Saturated aqueous NH4Cl (2
mL) was added, and the reaction mixture was allowed to warm to rt
and then concentrated in vacuo. The residue was partitioned between
Et2O (5 mL) and H2O (5 mL), and the organic extract was dried and
concentrated in vacuo. Purification via flash column chromatography
(eluent 30−40 °C petroleum ether/Et2O, 5:1) gave 20 as a yellow oil
(93 mg, 71%): [α]2D5 −0.8 (c 1.0, CHCl3); IR νmax 3063, 3028, 2956,
2931, 2870, 1709, 1602, 1496, 744; 1H NMR δH (400 MHz, CDCl3)
0.90−0.94 (3H, m, C(6′)H3), 1.26−1.36 (2H, m, C(5′)H2), 1.48−
1.59 (2H, m, C(4′)H2), 1.88−1.93 (1H, m, C(3)HA), 2.04−2.11 (1H,
m, C(3)HB), 2.36 (2H, app t, J, 7.9, C(3′)H2), 2.66 (1H, dd, J 16.5,
8.0, C(1′)HA), 2.75 (1H, dd, J 16.5, 4.9, C(1′)HB), 2.78−2.94 (2H,
m, C(4)H2), 4.04−4.08 (1H, m, C(2)H), 4.48 (1H, d, J 16.9,
NCHAHBPh), 4.56 (1H, d, J 16.9, NCHAHBPh), 6.48 (1H, d, J 8.3,
C(8)H), 6.64 (1H, app td, J 7.3, 1.2, C(6)H), 6.99 (1H, app t, J 7.7,
C(7)H), 7.05 (1H, d, J 7.3, C(5)H), 7.23−7.34 (5H, m, Ph); 13C
NMR δC (100 MHz, CDCl3) 14.0 (C(6′)), 22.4 (C(5′)), 23.7
I
DOI: 10.1021/acs.jnatprod.8b00672
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Journal of Natural Products
Article
147.3, 149.0 (C(3″), C(4″)); m/z (ESI+) 388 ([M + H]+, 100%);
mg, 81%): [α]2D5 −23.7 (c 1.0 in CHCl3); IR νmax 2934, 2891, 1602,
+
1
HRMS (ESI+) C26H30NO2 ([M + H]+) requires 388.2271; found
1500, 1489; H NMR δH (400 MHz, CDCl3) 1.65−1.75 (1H, m,
388.2276.
C(1′)HA), 1.84−1.99 (3H, m, C(3)H2, C(1′)HB), 2.50 (1H, ddd, J
13.9, 9.9, 6.6, C(2′)HA), 2.60−2.72 (2H, m, C(4)HA, C(2′)HB),
2.79−2.88 (1H, m, C(4)HB), 2.91 (3H, s, NMe), 3.24−3.30 (1H, m,
C(2)H), 5.92 (2H, s, OCH2O), 6.52 (1H, d, J 8.2, C(8)H), 6.59 (1H,
app td, J 7.4, 1.0, C(6)H), 6.63 (1H, dd, J 7.9, 1.6, C(6″)H), 6.69
(1H, d, J 1.6, C(2″)H), 6.73 (1H, d, J 7.9, C(5″)H), 6.98 (1H, d, J
7.4, C(5)H), 7.08 (1H, app t, J 8.1, C(7)H); 13C NMR δC (100 MHz,
CDCl3) 23.7 (C(4)), 24.5 (C(3)), 32.2 (C(2′)), 33.3 (C(1′)), 38.2
(NMe), 58.4 (C(2)), 100.9 (OCH2O), 108.3 (C(5″)), 108.9 (C(2″)),
110.8 (C(8)), 115.6 (C(6)), 121.1 (C(6″)), 121.9 (C(4a)), 127.3
(C(7)), 128.8 (C(5)), 136.0 (C(1″)), 145.5 (C(8a)), 145.8, 147.8
(C(3″), C(4″)); m/z (ESI+) 296 ([M + H]+, 100%); HRMS (ESI+)
(S)-N-Methyl-2-[2′-(3″,4″-dimethoxyphenyl)ethyl]-1,2,3,4-
tetrahydroquinoline [(−)-cuspareine], 26. Pd/C (26 mg, 40% w/
w of 25) was added to a stirred solution of 25 (64 mg, 0.17 mmol)
and formalin (37% aqueous HCHO, 1.2 mL, 1.7 mmol) in degassed
MeOH (3 mL). The resultant mixture was stirred under H2 (1 atm)
at rt for 24 h. The reaction mixture was filtered through a short plug
of Celite (eluent MeOH), then concentrated in vacuo. Purification via
flash column chromatography (eluent 30−40 °C petroleum ether/
Et2O/NH4OH, 75:25:1) gave 26 as a colorless oil (46 mg, 90%):
[α]2D5 −25.0 (c 0.3 in CHCl3); IR νmax 2981, 2971, 2934, 1602, 1514,
1500; 1H NMR δH (400 MHz, CDCl3) 1.74 (1H, dddd, J 13.9, 10.1,
8.9, 5.4, C(1′)HA), 1.88−2.01 (3H, m, C(3)H2, C(1′)HB), 2.54 (1H,
ddd, J 13.9, 10.2, 6.4, C(2′)HA), 2.65−2.73 (2H, m, C(4)HA, C(2′)
HB), 2.82−2.90 (1H, m, C(4)HB), 2.92 (3H, s, NMe), 3.27−3.32
(1H, m, C(2)H), 3.86 (3H, s, OMe), 3.88 (3H, s, OMe), 6.54 (1H, d,
J 8.2, C(8)H), 6.60 (1H, app td, J 7.3, 1.0, C(6)H), 6.71−6.75 (2H,
m, C(2″)H, C(6″)H), 6.80 (1H, d, J 8.0, C(5″)H), 6.99 (1H, d, J 7.3,
C(5)H), 7.07−7.11 (1H, m, C(7)H); 13C NMR δC (100 MHz,
CDCl3) 23.7 (C(4)), 24.5 (C(3)), 32.1 (C(2′)), 33.2 (C(1′)), 38.3
(NMe), 56.0 (OMe), 56.1 (OMe), 58.6 (C(2)), 110.7 (C(8)), 111.4
(C(5″)), 111.7 (C(2″)), 115.5 (C(6)), 120.2 (C(6″)), 121.9 (C(4a)),
127.3 (C(7)), 128.8 (C(5)), 134.8 (C(1″)), 145.4 (C(8a)), 147.3,
149.0 (C(3″), C(4″)); m/z (ESI+) 312 ([M + H]+, 100%); HRMS
(ESI+) C20H26NO2+ ([M + H]+) requires 312.1958; found 312.1958.
(S)-N-Benzyl-2-[2′-(3″,4″-methylenedioxyphenyl)ethyl]-
1,2,3,4-tetrahydroquinoline, 28. Step 1: LiAlH4 (2.4 M in THF,
0.27 mL, 0.53 mmol) was added dropwise to a stirred solution of 23
(103 mg, 0.267 mmol) in THF (2.0 mL) at 0 °C. The resultant
mixture was heated at reflux for 16 h, then allowed to cool to rt. A 2.0
M aqueous NaOH (0.3 mL) solution was then added, and the
resultant mixture was heated at reflux for 3 h. The reaction mixture
was then allowed to cool to rt, filtered through Celite (eluent EtOAc),
and then concentrated in vacuo to give 27.
+
C19H22NO2 ([M + H]+) requires 296.1645; found 296.1644.
(S)-N-Benzyl-2-(2′-oxopentyl)-1,2,3,4-tetrahydroquinoline,
32. Method A. Addition of t-BuLi to n-Propyl Bromide 30. t-BuLi
(1.7 M in pentane, 4.1 mL, 7.0 mmol) was added dropwise to a stirred
solution of n-propyl bromide 30 (0.32 mL, 3.48 mmol) in THF (12
mL) at −78 °C, and the resultant mixture was stirred at −78 °C for
30 min. A solution of (S)-16 (565 mg, 1.74 mmol) in THF (6 mL) at
−78 °C was then added, and the resultant mixture was stirred at −78
°C for 1.5 h. Saturated aqueous NH4Cl (10 mL) was added, and the
reaction mixture was allowed to warm to rt and then concentrated in
vacuo. The residue was partitioned between Et2O (20 mL) and H2O
(20 mL), and the organic extract was dried and concentrated in vacuo
to give a 67:33 mixture of 32 and 33, respectively. Purification via
flash column chromatography (eluent 30−40 °C petroleum ether/
Et2O, 5:1) gave 32 as a colorless oil (276 mg, 52%): [α]2D5 +0.8 (c 1.0,
CHCl3); IR νmax 3063, 3028, 2960, 2932, 2873, 1708, 1602, 1574,
1496, 1452, 1343, 744l; 1H NMR δH (400 MHz, CDCl3) 0.92 (3H, t,
J 7.5, C(5′)H3), 1.54−1.67 (2H, m, C(4′)H2), 1.88−1.93 (1H, m,
C(3)HA), 2.04−2.13 (1H, m, C(3)HB), 2.35 (2H, t, J, 7.2, C(3′)H2),
2.63−2.76 (2H, m, C(1′)H2), 2.77−2.95 (2H, m, C(4)H2), 4.06−
4.08 (1H, m, C(2)H), 4.49 (1H, d, J 17.1, NCHAHBPh), 4.56 (1H, d,
J 17.1, NCHAHBPh), 6.47 (1H, d, J 8.1, C(8)H), 6.64 (1H, app t, J
7.3, C(6)H), 6.69 (1H, app t, J 7.7, C(7)H), 7.05 (1H, d, J 7.3, C(5)
H), 7.23−7.35 (5H, m, Ph); 13C NMR δC (100 MHz, CDCl3) 13.8
(C(5′)), 17.2 (C(4′)), 23.7 (C(4)), 25.7 (C(3)), 45.7 (C(1′)), 46.0
(C(3′)), 53.9 (C(2)), 54.2 (NCH2Ph), 112.1 (C(8)), 116.2 (C(6)),
121.2 (C(4a)), 126.5, 126.9 (o,m,p-Ph), 127.3 (C(7)), 128.7 (C(5)),
129.2 (o,m-Ph), 139.0 (i-Ph), 144.2 (C(8a)), 210.0 (C(2′)); m/z
(ESI+) 308 ([M + H]+, 100%); HRMS (ESI+) C21H26NO+ ([M +
H]+) requires 308.2009; found 308.2009. Further elution (eluent
Et2O/CH2Cl2, 10:1) gave 33 as a colorless oil (77 mg, 15%): [α]D25
+12.2 (c 1.0, CHCl3); IR νmax 3402, 3293, 3064, 3028, 2934, 2863,
1640, 1602, 1572, 1496, 1451, 745; 1H NMR δH (400 MHz, CDCl3)
1.90−1.97 (1H, m, C(3′)HA), 2.01−2.10 (2H, m, C(3′)HB), 2.26
(1H, dd, J 14.0, 7.3, C(2)HA), 2.47 (1H, dd, J 14.0, 6.4, C(2)HB),
2.74 (3H, d, J 4.5, NMe), 2.75−2.92 (2H, m, C(4′)H2), 3.99−4.04
(1H, m, C(2′)H), 4.50 (1H, d, J 17.0, NCHAHBPh), 4.55 (1H, d, J
17.0, NCHAHBPh), 5.81 (1H, br d, J 4.5, NH), 6.47 (1H, d, J 8.1,
C(8′)H), 6.62 (1H, app td, J 7.3, 1.0, C(6′)H), 6.96−6.99 (1H, m,
C(7′)H), 7.02 (1H, d, J 7.3, C(5′)H), 7.21−7.32 (5H, m, Ph); 13C
NMR δC (100 MHz, CDCl3) 23.7 (C(4′)), 25.5 (C(3′)), 26.4
(NMe), 40.0 (C(2)), 54.4 (NCH2Ph), 55.4 (C(2′)), 112.5 (C(8′)),
116.3 (C(6′)), 121.5 (C(4′a)), 126.5 (o-Ph), 126.8 (p-Ph), 127.3
(C(7′)), 128.6 (m-Ph), 129.2 (C(5′)), 138.9 (i-Ph), 144.0 (C(8′a)),
171.8 (C(1)); m/z (ESI+) 295 ([M + H]+, 100%); HRMS (ESI+)
C19H23N2O+ ([M + H]+) requires 295.1805; found 295.1799.
Step 2: Et3SiH (0.43 mL, 2.7 mmol) was added to a stirred solution
of the residue of 27 from the previous step in TFA (1.3 mL), and the
resultant solution was stirred at 70 °C for 16 h. The resultant mixture
was concentrated in vacuo, and the residue was then partitioned
between CH2Cl2 (10 mL) and saturated aqueous NaHCO3 (10 mL).
The organic extract was dried and concentrated in vacuo. Purification
via flash column chromatography (eluent 30−40 °C petroleum ether/
Et2O/NH4OH, 100:5:1) gave 28 as a colorless oil (76 mg, 77%):
[α]2D5 +4.0 (c 1.0 in CHCl3); IR νmax 3027, 2936, 1601, 1500, 1490;
1H NMR δH (400 MHz, CDCl3) 1.77−1.97 (2H, m, C(1′)H2), 1.97−
2.07 (2H, m, C(3)H2), 2.47 (1H, ddd, J 14.0, 9.7, 6.8, C(2′)HA), 2.62
(1H, ddd, J 14.0, 9.7, 5.4, C(2′)HB), 2.76 (1H, dt, J 16.4, 4.0, C(4)
HA), 2.93 (1H, ddd, J 16.4, 11.5, 6.5, C(4)HB), 3.36−3.41 (1H, m,
C(2)H), 4.41 (1H, d, J 17.0, NCHAHBPh), 4.57 (1H, d, J 17.0,
NCHAHBPh), 5.91 (2H, s, OCH2O), 6.43 (1H, d, J 8.0, C(8)H),
6.57−6.60 (2H, m, C(6)H, C(6″)H), 6.62 (1H, d, J 1.6, C(2″)H),
6.70 (1H, d, J 7.8, C(5″)H), 6.95 (1H, app t, J 8.0, C(7)H), 7.02 (1H,
d, J 7.3, C(5)H), 7.20−7.32 (5H, m, Ph); 13C NMR δC (100 MHz,
CDCl3) 23.7 (C(4)), 24.4 (C(3)), 32.1 (C(2′)), 33.9 (C(1′)), 54.3
(NCH2Ph), 57.3 (C(2)), 100.9 (OCH2O), 108.3 (C(5″)), 108.8
(C(2″)), 112.0 (C(8)), 115.8 (C(6)), 121.1 (C(6″)), 121.8 (C(4a)),
126.7 (o,m-Ph), 126.9 (p-Ph), 127.2 (C(7)), 128.7 (o,m-Ph), 129.1
(C(5)), 135.8 (i-Ph), 139.4 (C(1″)), 144.7 (C(8a)), 145.8, 147.7
(C(3″), C(4″)); m/z (ESI+) 372 ([M + H]+, 100%); HRMS (ESI+)
+
C25H26NO2 ([M + H]+) requires 372.1958; found 372.1961.
Method B. Addition of n-Propyl Bromide 30 to t-BuLi. n-Propyl
bromide 30 (0.56 mL, 6.17 mmol) was added dropwise to a stirred
solution of t-BuLi (1.7 M in pentane, 7.3 mL, 12.4 mmol) in THF (20
mL) at −78 °C, and the resultant mixture was stirred at −78 °C for
30 min. A solution of (S)-16 (1.00 g, 3.08 mmol) in THF (30 mL) at
−78 °C was then added, and the resultant mixture was stirred at −78
°C for 1.5 h. Saturated aqueous NH4Cl (30 mL) was added, and the
reaction mixture was allowed to warm to rt and then concentrated in
vacuo. The residue was partitioned between CH2Cl2 (50 mL) and
H2O (50 mL), and the organic extract was dried and concentrated in
(S)-N-Methyl-2-[2′-(3″,4″-methylenedioxyphenyl)ethyl]-
1,2,3,4-tetrahydroquinoline [(−)-galipinine], 29. Pd/C (30 mg,
40% w/w of 28) was added to a stirred solution of 28 (73 mg, 0.19
mmol) and formalin (37% aqueous HCHO, 0.15 mL, 2.0 mmol) in
degassed MeOH (4 mL). The resultant mixture was stirred under H2
(1 atm) at rt for 24 h. The reaction mixture was filtered through a
short plug of Celite (eluent MeOH), then concentrated in vacuo.
Purification via flash column chromatography (eluent 30−40 °C
petroleum ether/Et2O/NH4OH, 90:9:1) gave 29 as a colorless oil (47
J
DOI: 10.1021/acs.jnatprod.8b00672
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Journal of Natural Products
Article
vacuo. Purification via flash column chromatography (eluent 30−40
°C petroleum ether/Et2O, 5:1) gave 32 as a colorless oil (809 mg,
85%).
ORCID
Stephen G. Davies: 0000-0003-3181-8748
Notes
The authors declare no competing financial interest.
(S)-N-Benzyl-2-(2′-oxopentyl)-1,2,3,4-tetrahydroquinoline,
1,2-Ethylenedithioacetal 34. A solution of 32 (200 mg, 0.651
mmol) in AcOH (1.4 mL) was stirred at rt for 30 min. BF3·OEt2
(0.40 mL, 3.25 mmol) and ethane-1,2-dithiol (0.16 mL, 2.0 mmol)
were then added sequentially, and the resultant solution was stirred at
rt for 16 h. The reaction mixture was diluted with 2 M aqueous KOH
(10 mL), then extracted with CHCl3 (3 × 10 mL), and the combined
organic extracts were concentrated in vacuo. Purification via flash
column chromatography (eluent 30−40 °C petroleum ether/EtOAc,
30:1) gave 34 as a colorless oil (248 mg, 99%): [α]2D5 +32.4 (c 1.0,
CHCl3); IR νmax 3061, 3026, 2956, 2926, 2870, 1602, 1500, 1451,
REFERENCES
■
(1) The currently preferred scientific name of this tree is Angostura
trifoliata. The authors would like to thank Dr. Ben Jones, Arboretum
Curator, University of Oxford, Harcourt Arboretum, for this
information.
̈
̈
(2) Korner, W. G.; Bohringer, C. Ann. Chim. 1883, 201;
Alternatively, see: Ber. Dtsch. Chem. Ges. 1883, 16, 2305.
1
̈
̈
(3) Korner, W. G.; Bohringer, C. Gazz. Chim. Ital. 1883, 13, 363;
Alternatively, see: J. Chem. Soc., Abstr. 1884, 46, 341−342.
743; H NMR δH (400 MHz, CDCl3) 0.93 (3H, t, J 7.3, C(5′)H3),
1.53 (2H, app dq, J 15.2, 7.5, C(4′)H2), 1.84−1.96 (2H, m, C(3)H2),
2.02−2.14 (2H, m, C(1′)HA, C(3′)HA), 2.23−2.34 (2H, m, C(1′)HB,
C(3′)HB), 2.76−2.78 (1H, m, C(4′)HA), 2.97−3.06 (1H, m, C(4′)
HB), 3.17−3.33 (4H, m, SCH2CH2S), 3.68−3.69 (1H, m, C(2′)H),
4.61 (1H, d, J 17.4, NCHAHBPh), 4.65 (1H, d, J 17.4, NCHAHBPh),
6.46 (1H, d, J 8.1, C(8)H), 6.59 (1H, app t, J 7.2, C(6)H), 6.96 (1H,
app t, J 7.7, C(7)H), 7.03 (1H, d, J 7.3, C(5)H), 7.22−7.34 (5H, m,
Ph); 13C NMR δC (100 MHz, CDCl3) 14.3 (C(5′)), 20.2 (C(4′)),
23.6 (C(4)), 26.5 (C(3)), 39.6, 40.0 (SCH2CH2S), 44.7 (C(1′)), 47.9
(C(3′)), 53.2 (NCH2Ph), 55.7 (C(2)), 70.4 (C(2′)), 111.7 (C(8)),
115.7 (C(6)), 121.5 (C(4a)), 126.7, 126.8 (o,m,p-Ph), 127.2 (C(7)),
128.6 (C(5)), 129.1 (o,m-Ph), 139.4 (i-Ph), 144.5 (C(8a)); m/z
̈
̈
̈
(4) Troger, J.; Muller, O. Arch. Pharm. 1910, 248, 1−22.
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(ESI+) 384 ([M + H]+, 100%); HRMS (ESI+) C23H30NS2 ([M +
̀
H]+) requires 384.1814; found 384.1811.
́
(R)-N-Methyl-2-pentyl-1,2,3,4-tetrahydroquinoline [(−)-an-
gustureine], 36. Step 1: A solution of 34 (28 mg, 0.073 mmol) in
EtOH/THF (v:v, 1:1, 2 mL) was added to a stirred suspension of
Raney-Ni (∼0.5 g)60 in EtOH/THF (v/v, 1:1, 2 mL), and the
resultant suspension was heated at 80 °C for 1 h. The resultant
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312−319.
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determined was not specified.
(14) Houghton et al. later published the results of their independent
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although the latter was named by them as allocuspareine [this name
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(16) Mun
179−206.
Step 2: Pd/C (9 mg, ∼40% w/w of 35) was added to a stirred
solution of the residue of 35 from the previous step and formalin
(37% aqueous HCHO, 0.05 mL, 0.73 mmol) in degassed MeOH (2
mL). The resultant mixture was stirred under H2 (1 atm) at rt for 24
h. The reaction mixture was filtered through a short plug of Celite
(eluent MeOH), then concentrated in vacuo. Purification via flash
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200:1) gave 36 as a colorless oil (11 mg, 69%): [α]2D5 −10.6 (c 0.2,
1
CHCl3); IR νmax 2954, 2928, 2870, 2857, 1602, 1500, 743; H NMR
̃
oz, G. D.; Dudley, G. B. Org. Prep. Proced. Int. 2015, 47,
δH (400 MHz, CDCl3) 0.89 (3H, t, J 6.6, C(5′)H3), 1.24−1.44 (7H,
m, C(1′)HA, C(2′)H2, C(3′)H2, C(4′)H2), 1.55−1.63 (1H, m, C(1′)
HB), 1.82−1.93 (2H, m, C(3)H2), 2.65 (1H, app dt, J 16.1, 4.2, C(4)
HA), 2.76−2.84 (1H, m, C(4)HB), 2.92 (3H, s, NMe), 3.23 (1H, app
dq, J 8.6, 4.2, C(2)H), 6.52 (1H, d, J 7.9, C(8)H), 6.58 (1H, app td, J
7.4, 1.0, C(6)H), 6.97 (1H, d, J 7.4, C(5)H), 7.07 (1H, app t, J 7.4,
C(7)H); 13C NMR δC (100 MHz, CDCl3) 14.2 (C(5′)), 22.8
(C(4′)), 23.7 (C(4)), 24.6 (C(3)), 25.9 (C(3′)), 31.3 (C(1′)), 32.2
(C(2′)), 38.1 (NMe), 59.1 (C(2)), 110.5 (C(8)), 115.3 (C(6)), 122.0
(C(4a)), 127.2 (C(7)), 128.8 (C(5)), 145.5 (C(8a)); m/z (ESI+) 218
([M + H]+, 100%); HRMS (ESI+) C15H24N+ ([M + H]+) requires
218.1903; found 218.1903.
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ASSOCIATED CONTENT
* Supporting Information
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Chem. 2016, 14, 5820−5825.
■
S
(24) He, Z.; Liu, H.; Qian, Q.; Lu, L.; Guo, W.; Zhang, L.; Han, B.
Sci. China: Chem. 2017, 60, 927−933.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.8b00672.
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1
Copies of H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: steve.davies@chem.ox.ac.uk.
■
(28) Taylor, L. L.; Goldberg, F. W.; Hii, K. K. Org. Biomol. Chem.
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DOI: 10.1021/acs.jnatprod.8b00672
J. Nat. Prod. XXXX, XXX, XXX−XXX

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