Asymmetric alkaloid synthesis: A one-pot organocatalytic reaction to quinolizidine derivatives

Article abstract of DOI:10.1002/anie.200805130

(Chemical Equation Presented) One pot+two steps = three stereocenters: A short enantioselective synthesis to access the indolo[2,3a]quinolizidine and the benzo[a]quinolizidine skeleton has been developed (see scheme; TMS = trimethylsilyl, R¹ =

Full text of DOI:10.1002/anie.200805130

Angewandte
Chemie
DOI: 10.1002/anie.200805130
Asymmetric Catalysis
Asymmetric Alkaloid Synthesis: A One-Pot Organocatalytic Reaction
to Quinolizidine Derivatives**
Johan Franzꢀn* and Andreas Fisher
The quinolizidine skeleton is found in a large number of
naturally occurring compounds and these alkaloids, together
with non-natural derivatives thereof, have attracted much
interest among both chemists and biologists because they are
challenging synthetic targets and have diverse biological
activity .[1]
Scheme 1. Retrosynthetic analysis of the indolo[2,3a]quinolizidine skel-
eton.
thermodynamically stable trans configuration in the cyclic
structure, and the stereocenter at C12b can be formed
through a diastereoselective cyclization of the N-acyliminium
ion.[9,10] Recently, highly efficient protocols for enantioselec-
Although several asymmetric methods for the construc-
tion of optically active quinolizidine derivatives have been
developed, these strategies are in general target specific,
multistep syntheses relying on starting material from the
chiral pool.[2,3] In contrast to syntheses based on molecules
from the chiral pool, only a few strategies that relay on
asymmetric catalysis have been described.[4,5] The develop-
ment of new stereoselective, efficient, and short routes to this
class of compound would therefore open up new opportu-
nities for natural product synthesis and medicinal chemistry.[6]
To devise such a method a retrosynthetic analysis of
indolo[2,3a]quinolizidine skeleton was carried out, taking in
account the selective formation of the three stereocenters
indicated (C2, C3, and C12b; Scheme 1). It was anticipated
that the stereocenter at C2 could be introduced in the first
step through an enantioselective, organocatalytic conjugate
addition.[7,8] The selective formation of the C2 center would
control the formation of the two remaining stereocenters. The
stereochemically labile stereocenter at C3 should adopt the
tive secondary-amine-catalyzed conjugate addition of malo-
nates, b-ketoesters, and enamides to a,b-unsaturated alde-
hydes[11] and ketones[12] have been developed. However, to
the best of our knowledge, the asymmetric organocatalytic
enol addition of activated amides to a,b-unsaturated alde-
hyde has not been previously reported. Herein we report the
ꢀ
enantioselective organocatalytic C C bond-forming reaction
of activated amides and a,b-unsaturated aldehydes with the
purpose of developing a fast and selective approach to give
optically active indolo[2,3a]quinolizidine and benzo[a]quino-
lizidine derivatives.
The organocatalytic conjugate addition, for cinnamic
aldehyde 1 and the indol substituted amide 2a using the
proline derivative (S)-A as the catalyst, was initially studied in
different solvents (Table 1). After full conversion of amide 2a
(determined by 1H NMR spectroscopy), excess trifluoroacetic
acid (TFA) was added to the reaction mixture and after an
additional 30 minutes, compounds 3a and 4a were isolated as
a diastereomeric mixture. The screening of different solvents
showed that the reaction performed best in CH2Cl2, and gave
full conversion of amide 2a within 2 days at room temper-
ature (Table 1, compare entry 1 to entries 4–7). Although the
conversion varied substantially, the enantioselectivity was
more or less independent of the solvent. However, the
enantioselectivity could be increased from 88% to 94% by
lowering the reaction temperature to 38C (Table 1, entry 2). If
the temperature was further decreased to ꢀ208C, less then
5% conversion was observed after 2 days (Table 1, entry 3).
A series of catalysts was screened and evaluated with respect
to the ee value and the conversion. The analogue, catalyst (S)-
B, was less active and less selective for this reaction and
required prolonged reaction time at an elevated temperature
[*] Dr. J. Franzꢀn
Department of Chemistry, Organic Chemistry
Royal Institute of Technology (KTH)
Teknikringen 30, 10044 Stockholm (Sweden)
Fax: (+46)8-791-2333
E-mail: jfranze@kth.se
Dr. A. Fisher
Department of Chemistry, Inorganic Chemistry
Royal Institute of Technology (KTH; Sweden)
[**] This work was made possible by a grant from the Swedish Research
Council (VR).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805130.
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Table 1: Screening of the reaction conditions for the amide addition to
a,b-unsaturated aldehydes.[a]
Table 2: Screening of acids for the formation of 3a and 4a.[a]
Entry
Acid
Equiv
T [8C]
3a/4a[b]
1
2
3
4
5
6
TFA
HCl
HCl
0.2
0.2
0.2
0.4
0.2
–
RT
RT
50:50
70:30
85:15
70:30
83:17
63:27
ꢀ78!RT
BF3·OEt2/MgSO4
BF3·OEt2/MgSO4
amberlyst 15
RT
ꢀ78!RT
ꢀ20
[a] A solution of cinnamic aldehyde 1a (1.5 equiv), amide 2a (1 equiv)
and catalyst A (20 mol%) in CH2Cl2 (0.9 mm) was stirred at room
temperature for 2 days. After full conversion of 2a, the given acid was
added to the reaction mixture at the given temperature. [b] Determined
by 1H NMR spectroscopy on the crude reaction mixture.
Entry
Cat.
Solvent
T [8C]
Conv. [%][b]
ee [%][d]
lectivity ranged from ranged from 83:17 up to 90:10 (Table 3,
entries 1, 2, 4, and 5) with the exception of the 4-acetoxy-3-
methoxyphenyl substituent (1c) where the selectivity drop-
ped to 74:26 (Table 3, entry 3).[13]
In the further development of this reaction, the 3-indolyl
moiety of 2a was replaced with an electron-rich phenyl group
(3,4-dimethoxyphenyl) 2b. The reaction of 2b together with
a,b-unsaturated aldehydes 1 in the presence of catalyst A and
1
2
3
4
5
6
7
A
A
A
A
A
A
A
B
C
D
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
toluene
Et2O
RT
3
full (57)
full (63)
88
94
–
92
89
–
88
54
–
ꢀ20
RT
RT
RT
RT
39
<5
33
65
–
44
45
0
DMF
8[d]
9
10
CH2Cl2
CH2Cl2
CH2Cl2
RT
RT
0
–
[a] A solution of cinnamic aldehyde 1a (1.5 equiv), amide 2a (1 equiv)
and catalyst (20 mol%) was stirred at the given temperature in the
solvent (0.9 mm). After 2 days, TFA (10 equiv) was added to the reaction
mixture and the products were isolated after 30 minutes. [b] Determined
by 1H NMR spectroscopy on the crude reaction mixture before the
addition of TFA. The value within the parentheses indicate the yield of the
product upon isolation. [c] Determined by HPLC on a chiral stationary
phase. [d] Reaction time of 4 days. DMF=N,N-dimethylformamide,
TMS=trimethylsilyl.
Table 3: One-pot synthesis of indolo[2,3a]quinolizidine.[a]
Entry
R
t
T
Yield ee [%][c]
[days] [8C] [%][b] of 3
d.r.[d]
of 3/4
(Table 1, entry 8). The imidazolidinone C and proline D were
inactive as catalysts for this reaction, and only the starting
materials were isolated (Table 1, entries 9 and 10).
1
2
1a
1b
3
5
3
69
53
94 (96)[e] 85:15
After establishing the best reaction conditions for the
conjugate addition, the acid-catalyzed cyclization of the
acyliminium ion was investigated. When a catalytic amount
of TFA (20 mol%) was added to the reaction mixture after
full conversion of the amide 2a, a non-selective reaction
occurred to give 3a and 4a in a 1:1 ratio (Table 2, entry 1).
However, when catalytic amounts of HCl were used some
selectivity for 3a over 4a was observed, and cooling the
reaction mixture prior to the addition of HCl increased the
selectivity up to 85:15 (Table 2, entries 2 and 3). Similar
selectivity was also observed for boron trifluoride etherate
(Table 2, entries 4 and 5).
RT
95
95
87
89
90:10
74:26
83:17
83:17
3
4
5
1c
1d
1e
2
1
5
RT
3
62
71
56
RT
With the optimized reaction conditions in hand, a series of
aromatic a,b-unsaturated aldehydes were employed in the
one-pot, two-step reaction (Table 3). Good to excellent
enantioselectivity were obtained for all the annulation
products 3, ranging from 87% to 95% ee. The diastereose-
[a] See the Supporting Information. [b] Total yield of 3 and 4. [c] Deter-
mined by HPLC on a chiral stationary phase. [d] Determined by 1H NMR
spectroscopy on the crude reaction mixture. [e] After single recrystalliza-
tion from iPrOH.
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subsequent addition of acid gave direct access to the
benzo[a]quinolizidine skeleton with good to high enantiose-
lectivity (Table 4). Although yields and enantioselectivities
were compatible with the formation of indolo-
[2,3a]quinolizidine, the diastereoselectivity in the acid-cata-
lyzed step was lower in all cases.[13] The formation of the
benzo[a]quinolizidine required stronger acidic conditions
(40 mol%) than for the indolo[2,3a]quinolizidine. This differ-
ence is believed to result from the poorer nucleophilicity of
the phenyl ring compared to the 3-indolyl moiety.[14]
Table 4: One-pot synthesis of benzo[a]quinolizidine.[a]
Figure 1. X-ray crystal structure of (2R,3S,11bS)-5 f.
Thus, the R configuration at C2 is formed through
efficient shielding of the Re face of the chiral iminium
intermediate 7 by the aryl groups on catalyst A, thus leaving
the Si face open for conjugate addition of amide
2
(Scheme 2). Next, intermediate 8 cyclizes spontaneously
Entry
R
t
T
Yield ee [%][c] d.r.[d]
[days] [8C] [%][b] of 5
of 5/6
1
2
1a
1b
3
5
3
69
53
90
91
62:38
RT
83:17
69:31
3
1c
2
RT
62
90
4
5
1d
1 f
1
5
3
71
56
89
98
76:24
72:28
Scheme 2. Proposed mechanism for the one-pot reaction (Nu=3-
indolyl or 3,4-dimethoxyphenyl).
RT
[a] See the Supporting Information. [b] Total yield of 5 and 6. [c] Deter-
mined by HPLC on a chiral stationary phase. [d] Determined by 1H NMR
spectroscopy on the crude reaction mixture.
under these reaction conditions to give hemiacetal 9, then
epimerization of the stereochemically labile stereocenter at
C3 will establish the more thermodynamically stable 2R,3S-
trans configuration. Treatment of 9 with catalytic amounts of
acid will result in the formation of acyliminium ion 10, which
will undergo an electrophilic aromatic substitution with the
aromatic moiety to give the quinolizidine products. The
diastereoselectivity observed in the acid-catalyzed cyclization
of the acyliminium ion is rationalized as being under kinetic
control, as is exemplified by the formation indolo-
[2,3a]quinolizidine in Scheme 3.[16,17] Formation of 4 would
give the thermodynamically more stable isomer owing to the
equatorial orientation of the indol moiety. However, the
formation of isomer 3 is rationalized as being faster under
kinetic conditions (ꢀ788C) owing to less steric hindrance
from the equatorial a proton in the transition state, as
compared to the axial a proton in the transition state, which
leads to isomer 4.[18]
The annulation reactions of amides 2a,b and a,b-unsatu-
rated aldehydes 1 (Table 3 and 4) tolerate several functional
groups in ortho, meta, and para position on the aromatic ring
of 1. However, the reaction time was highly dependent on the
electronic properties of the functional group. Electron-with-
drawing groups increase the reaction time (Table 3, entries 2
and 5, and Table 4, entries 2 and 5) whereas electron-donating
groups decrease the reaction time (Table 3, entries 3 and 4,
and Table 4, entries 3 and 4). This observation is in accord-
ance with the rate-determining step for the conjugate addition
being the formation of the iminium ion and not the
nucleophilic addition. Electron-donating groups on the
phenyl ring of 1 will facilitate the elimination of water and
therefore stabilize the cationic iminium ion intermediate.
The absolute configuration of the annulation products was
established to be 2R,3S,11bS by single-crystal X-ray analysis
of compound 5 f (Figure 1).[15]
In summary, a short enantioselective one-pot, two-step
synthesis to the indolo[2,3a]quinolizidine and the benzo[a]-
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Scheme 3. Kinetic versus thermodynamic product formation in the cyclization of
the acyliminium ion.
quinolizidine skeleton has been developed. The sequence,
that involves an organocatalytic conjugate addition and
subsequent acid-catalyzed cyclization of the acyliminium
ion, gives direct access to the quinolizidine skeleton. The
reaction sequence involves the formation of three new
stereocenters with high to excellent enantioselectivity and
moderate diastereoselectivity. Further investigation of the full
scope and limitations of this one-pot reaction are under
investigation and will be reported in due course.
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2004, 43, 5138; d) A. Berkessel, H. Grꢄger, Asymmetric Organo-
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[8] For recent reviews on organocatalytic conjugate addition, see:
a) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701; b) A. Erkkilꢅ, I.
Majander, P. M. Pihko, Chem. Rev. 2007, 107, 5416.
Experimental Section
General Procedure for the one-pot synthesis of indolo-
[2,3a]quinolizidine derivatives 3:
A solution of aldehyde 1
(0.42 mmol), catalyst A (18 mg, 0.05 mmol) and amide 2a (80 mg,
0.28 mmol) in CH2Cl2 (0.3 mL) was stirred (see Tables for details).
After full conversion of amide 2a (determined by 1H NMR spectros-
copy), the reaction mixture was cooled to ꢀ788C and then HCl
(50 mL, 0.05 mmol, 1m in diethyl ether) was added. The mixture was
stirred at ꢀ788C for 3 hours and slowly allowed to reach room
temperature, and subsequently saturated aqueous NaHCO3 (3 mL)
and CH2Cl2 (3 mL) were added and the aqueous phase was extracted
with CH2Cl2 (2 ꢀ 3 mL). The combined organic extracts were dried
(Na2SO4), filtered, and concentrated under reduced pressure to give
the crude product. The title compound was isolated as a single
diastereoisomer after flash column chromatography (pentane/Et2O).
[9] For reviews, see: a) B. E. Maryanoff, H. Zhang, J. H. Cohen, I. J.
Turchi, C. A. Maryanoff, Chem. Rev. 2004, 104, 1431; b) J. Royer,
M. Bonin, L. Micouin, Chem. Rev. 2004, 104, 2311.
[10] For recent examples of asymmetric cyclizations of the acylimi-
nium ion, see: a) I. T. Raheem, P. S. Thiara, E. A. Peterson, E. N.
Jacobsen, J. Am. Chem. Soc. 2007, 129, 13404; b) M. S. Taylor,
E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 10558.
[11] a) S. Brandau, A. Landa, J. Franzꢃn, M. Marigo, K. A. Jørgen-
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1101; c) M. Marigo, S. Bertelsen, A. Landa, K. A. Jørgensen, J.
Am. Chem. Soc. 2006, 128, 5475; d) A. Carlone, M. Marigo, C.
North, A. Landa, K. A. Jørgensen, Chem. Commun. 2006, 4928;
e) L. Zu, H. Xie, H. Li, J. Wang, X. Yu, W. Wang, Chem. Eur. J.
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[12] a) K. R. Knudsen, C. E. T. Mitchell, S. V. Ley, Chem. Commun.
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Received: October 20, 2008
Published online: December 18, 2008
Keywords: acyliminium ion · alkaloids · asymmetric catalysis ·
.
cyclization · organocatalysis
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790
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[13] The diastereomeric mixtures 3/4 and 5/6 could be separated by
flash column chromatography (see the Supporting Information).
[14] When HCl (20 mol% in Et2O) was used, only the corresponding
hemiacetal 9 was isolated.
[15] CCDC 705562 (5 f) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
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[18] The relative configuration of 3 and 4 was established by analysis
3
1
of the J couplings of the H NMR spectra, see the Supporting
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