Diverse asymmetric quinolizidine synthesis: A stereodivergent one-pot approach

Article abstract of DOI:10.1002/adsc.200900686

A diverse stereodivergent organocatalytic one-pot addition/cyclization/ annulation sequence to optically active quinolizidine derivatives from easily available starting materials is presented. The one-pot sequence relies on a pyrrolidine-catalyzed enantioselective conjugate addition of electron-deficient amide a-carbons to α,β-unsaturated aldehydes, spontaneous hemiaminal formation and acid-catalyzed/mediated N-acyliminium ion cyclization to give the quinolizidine framework. Simple tuning of the reaction conditions in the N-acyliminuim ion cyclization step provides a diastereomeric switch, which gives access to both of the two bridgehead epimers through kinetic, thermodynamic or chelation control. The methodology display a broad substrate scope that is demonstrated by the stereoselective formation of indolo-, thieno-, benzofuro-, furo- and different benzoquinolizidine derivatives with high atom efficiency, up to >99% ee and up to >95:5 dr. Due to its efficiency, synthetic diversity and operational simplicity, this protocol has the potential to find important use as a key step in natural product synthesis, biochemistry and pharmaceutical science. The stereochemical outcome of the one-pot sequence was investigated, and the mechanism and origin of stereoselectivity of the different steps is discussed.

Full text of DOI:10.1002/adsc.200900686

FULL PAPERS
DOI: 10.1002/adsc.200900686
Diverse Asymmetric Quinolizidine Synthesis: A Stereodivergent
One-Pot Approach
Wei Zhanga and Johan Franzꢀna,*
a
Department of Chemistry, Organic Chemistry, Royal Institute of Technology (KTH), Teknikringen 30, SE-100 44
Stockholm, Sweden
Fax : (+46)-8-791-2333; phone: (+46)-8-790-8125; e-mail: jfranze@kth.se
Received: October 1, 2009; Published online: February 10, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900686.
Abstract: A diverse stereodivergent organocatalytic that is demonstrated by the stereoselective formation
one-pot addition/cyclization/annulation sequence to of indolo-, thieno-, benzofuro-, furo- and different
optically active quinolizidine derivatives from easily benzoquinolizidine derivatives with high atom effi-
available starting materials is presented. The one-pot ciency, up to >99% ee and up to >95:5 dr. Due to
sequence relies on a pyrrolidine-catalyzed enantiose- its efficiency, synthetic diversity and operational sim-
lective conjugate addition of electron-deficient plicity, this protocol has the potential to find impor-
amide a-carbons to a,b-unsaturated aldehydes, spon- tant use as a key step in natural product synthesis,
taneous hemiaminal formation and acid-catalyzed/ biochemistry and pharmaceutical science. The ste-
mediated N-acyliminium ion cyclization to give the reochemical outcome of the one-pot sequence was
quinolizidine framework. Simple tuning of the reac- investigated, and the mechanism and origin of ste-
tion conditions in the N-acyliminuim ion cyclization reoselectivity of the different steps is discussed.
step provides a diastereomeric switch, which gives
access to both of the two bridgehead epimers Keywords: N-acyliminuim ion cyclization; alkaloids;
through kinetic, thermodynamic or chelation control. one-pot reaction; organocatalysis; quinolizidines;
The methodology display a broad substrate scope stereodivergent synthesis
Introduction
ing materials by combining two or more reaction
steps, where at least one involves an asymmetric pro-
Over the last decades, the state of art in total synthe- cess, to take place in the same reaction vessel. This
sis has developed tremendously and today organic avoids time-consuming and costly processes, including
chemists can synthesize, in principle, any organic mol- the purification of intermediates and steps involving
ecule no matter what its size or complexity.[1] How- the protection and deprotection of functional groups.
ACHTUNGTRENNUNGever, as complexity and size increase, so does the In addition to high efficiency, these processes are also
number of chemical transformations required to as- environmentally friendly since the generation of
semble the desired molecule and each of these trans- chemical waste is reduced. In particular, organocata-
formations usually involves tedious isolation and pu- lytic reactions[4] have been found to be powerful par-
rification processes of synthetic intermediates. This ticipants to include in asymmetric one-pot and
makes the synthesis of complex molecules highly de- domino reactions.[5,6] This can mainly be accounted
manding with respect to resources and time. Further- for by the robustness of the catalysts, insensitivity to-
more, the loss of material in each transformation and wards air and moisture and extensive functional
purification step of a multi-step sequence dramatically group tolerance.
decreases chemical efficiency, making larger scale syn-
In an attempt to meet the challenge of efficient
thesis on an industrial level almost impossible.[2] A so- construction of complex organic molecules, we
lution to these problems is the recently increased in- became interested in the development of novel strat-
terest for the development of asymmetric domino and egies for the asymmetric synthesis of quinolizidine al-
one-pot reactions.[3] In these reactions, complex or- kaloids. Although quinolizidine alkaloids are com-
ganic scaffolds are easily accessed from simple start- monly found in nature and often show high biological
Adv. Synth. Catal. 2010, 352, 499 – 518
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Wei Zhang and Johan Franzꢀn
FULL PAPERS
Figure 1. Representative quinolozidine alkaloids with “thermodynamic” and “kinetic” stereochemistry.
activity,[7] their enantioselective synthesis has been tion of the resulting reaction mixture initiates an in-
rather scarcely investigated and the strategies used tramolecular N-acyliminiumion cyclization[18,19] to give
are mainly target-specific multistep synthesis relying indoloACTHNUTRGNEUNG[2,3-a]quinolizidines (9) and benzo[a]quinolizi-
on starting material from the chiral pool.[8] Although, dines (10). The N-acyliminiumion cyclization was ob-
there are a few examples of target-specific strategies served to be under kinetic control and gave the ther-
relying on asymmetric catalysis as one of the key modynamically less stable epimers 12ba-9 and 11ba-
steps,[9,10] efficient methodology based on asymmetric 10 as the major products.[20]
catalysis with high synthetic diversity of quiniolizidine
These quinolizidine derivatives can be regarded as
stereochemical analogues to hirsutine and adapt the
derivatives have been scarcely reported.[11,12]
One of the key features to account for in the syn- same V-shaped conformation (cf. Figure 1).
thesis of quinolizidine frameworks is the configura- Taking into account the higher thermodynamic sta-
tion of the bridgehead carbon. This stereochemistry bility of the flat b-epimer compared to the V-shaped
has a great impact on the conformation of the alka- a-epimer and the fact that N-acyliminiumion cycliza-
loid that can be exemplified by the epimeric natural tions are under kinetic control, we envisioned that it
products
dihydrocorynantheine
and
hirsutine could be possible to find stereodivergent one-pot reac-
(Figure 1).
tion conditions that could selectively favor formation
Dihydrocorynantheine has a flat structure with all of either the a-epimer (kinetic reaction conditions) or
groups of the piperidine ring in equatorial positions. the b-epimer (thermodynamic reaction conditions)
On the other hand, the epimer hirsutine has the (Scheme 2).
indole moiety in an axial position giving this com-
Such a diastereomeric switch will provide efficient
pound a V-shaped conformation that is very different protocols for the enantio- and diastereoselective syn-
in geometry compared to dihydrocorynantheine.[13] thesis of both the bridgehead epimers of the quinolizi-
Furthermore, the axial indolo group will make hirsu- dine skeleton. Furthermore, we wanted to widen the
tine thermodynamically less stable compared to the scope of the one-pot sequence by using different aro-
all-equatorial epimer, dihydrocorynantheine. This matic and heteroatom aromatic groups on the amide.
means that special considerations have to be taken In this way, a wide variety of optically active quinoli-
into account during the synthesis of the desired epi- zidine derivatives can be easily accessed with high
mer.[8i]
Recently in our group we developed an enantiose-
lective one-pot reaction to the 12ba-indoloACHTNUGTRNE[NUG 2,3-a]qui- ment of a diverse, enantioselective one-pot reaction
control of absolute and relative stereoselectivity.
Here we wish to present our result on the develop-
nolizidine 9 and the 11ba-benzo[a]quinolizidine 10 with a diastereomeric switch that allows for the selec-
skeleton (Scheme 1).[14] The one-pot reaction se- tive formation of both of the two bridgehead epimers
quence is based on a domino organocatalytic conju- of a vast number of quinolizidine derivatives from
gate addition[15,16]/hemiaminal formation.[17] Acidifica- easily available starting materials. During the process
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Adv. Synth. Catal. 2010, 352, 499 – 518

Diverse Asymmetric Quinolizidine Synthesis: A Stereodivergent One-Pot Approach
Scheme 1. Stereoselective one-pot reaction to 12ba-indoloACTHNUTRGENUGN[2,3-a]quinolizidines and 11ba-benzo[a]quinolizidines.
Scheme 2. A stereodivergent enantioselective one-pot cyclization/annulation.
we also disclose new findings and developments con- lectivity in N-acyliminium ion cyclizations and orga-
cerning the factors controlling reactivity and stereose- nocatalytic conjugate additions.
Adv. Synth. Catal. 2010, 352, 499 – 518
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Wei Zhang and Johan Franzꢀn
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Results and Discussion
reoisomers at room temperature (Table 1, entry 4).
Gratifyingly, when the reaction temperature was in-
creased (refluxing TFA), high selectivity for the ther-
modynamic product was obtained (Table 1, entry 5).
Prolonged reaction times resulted mainly in decompo-
One-Pot Synthesis of Indolo
Derivatives
ACHTUNGERTN[NUNG 2,3-a]quinolizidine
Recently, the asymmetric organocatalytic a-carbon sition of the product; however, the diastereomeric
addition of activated amides to a,b-unsaturated alde- ratio did not change (Table 1, entry 6). Interestingly,
hydes was independently developed by our group[14] tin(IV) chloride also favored the thermodynamic
and Rios et al.[16g] In our study towards the one-pot product although with low selectivity (Table 1,
reaction to quinolizidine derivatives, we found that entry 3).[21]
conjugate addition of indole-substituted amide 2a to
After having established methodology for the ster-
cinnamaldehyde 1a catalyzed by pyrrolidine deriva- eodivergent one-pot procedure, we wanted to investi-
tive (S)-4 preformed best in DCM at 38C to give the gate the effect of the ester moiety on the amide with
hemiaminal intermediate 7. In the second step of the respect to reactivity, enantio- and diastereoselectivity.
one-pot sequence, HCl (20 mol%) was added to the A series of amides (2a–d) with different sterically de-
reaction mixture at low temperature to give the kinet- manding ester groups were tested and it was found
ically favored epimer 12ba-9 (Table 1, entry 2). Al- that reactivity decreased with the steric bulk of the
though N-acyliminium cyclizations are known to ester group. On the other hand, the enantioselectivity
occur under kinetic control[20] we observed that the di- of the conjugate addition step increased substantially
asterioselectivity is highly dependent on both the re- when going from methyl ester 2a to ethyl ester 2b
action temperature and the choice of acid. It was an- (Table 2, entries 1 and 3). Further increases of steric
ticipated that the reaction conditions could be opti- bulk did not improve the enantioselectivity (Table 2,
mized in order to favor the thermodynamically more entries 5 and 7). The diastereoselectivity in the acid-
stable epimer 12bb-9. When the previously estab- catalyzed N-acyliminium ion cyclization was not af-
lished kinetic conditions (HCl, 20 mol%) were used fected when going from the methyl ester 2a to the
at elevated temperature, a decrease in selectivity was ethyl ester 2b and good selectivity was obtained
observed for the epimer 12ba-9. The same trend was under both kinetic and thermodynamic reaction con-
also observed for several acids, increasing tempera- ditions to give 12ba-9ab and 12bb-9ab, respectively,
ture resulted in a decrease in selectivity. The first as the major epimers. (Table 2, entries 1–4). For the
promising result was obtained using excess trifluoro- sterically more demanding i-Pr and t-Bu esters 2c, d
acetic acid (TFA), which gave a 1:1 mixture of diaste- the selectivity decreased (Table 2, entries 5–7). The t-
Table 1. Screening of acids for the selective formation of 12ba-9 and 12bb-9.[a]
Entry
Acid
Equivalents
Temperature T [oC]
Time t [h]
dr[b]
1
2
3
4
5
6
HCl
HCl
SnCl4
TFA
TFA
TFA
0.2
0.2
1.2
0.2
0.1M
0.1M
r.t.
ꢀ78!r.t
r.t.
1
O.N.
12
1
2
18
70:30
85:15
42:58
r.t.
70
70
50:50
18:82
trace (18:82)[c]
[a]
A solution of cinnamaldehyde 1a (1.2 equiv.), amide 2a (1 equiv.) and catalyst 4 (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.
12ba-9 and 12bb-9, determined by H NMR spectroscopy on the crude reaction mixture.
Mainly decomposition of product/intermediate.
[b]
[c]
1
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Diverse Asymmetric Quinolizidine Synthesis: A Stereodivergent One-Pot Approach
Table 2. Effect of ester group on enantioselectivity and diastereoselectivity.[a]
Entry
Amide
R
Time t [days]
Conditions
Product
ee[b]
dr[c]
1
2
3
4
5
6
7
8
2a
2a
2b
2b
2c
2c
2d
2d
Me
Me
Et
1
1
1
1
3
3
3
3
A
B
A
B
A
B
A
B
12ba-9aa
12bb-9aa
12ba-9ab
12bb-9ab
12ba-9ac
12bb-9ac
12ba-9ad
–
88
–
93
–
93
–
92
–
85:15
18:82
82:18
19:81
75:25
22:78
75:25
Et
i-Pr
i-Pr
t-Bu
t-Bu
[d]
–
[a]
A solution of cinnamaldehyde 1a (1.2 equiv.), amide 2 (1 equiv.) and catalyst 4 (20 mol%) in CH2Cl2 (0.9 mM) was stirred
at room temperature. After full conversion of 2, acid was added to the reaction mixture according to conditions A or B.
Conditions A: the reaction mixture was cold down to ꢀ788C and HCl (20 mol%, 1M in Et2O) was added. The mixture
was stirred at ꢀ788C for 3 h and slowly allowed to reach room temperature overnight. Conditions B: to the reaction mix-
ture was added TFA (0.5 mLmmolꢀ1) and the resulting mixture was heated at 708C in an open vessel for 5 min (to
remove DCM) followed by further heating in a closed vessel for additional 1 h at 708C.
[b]
[c]
[d]
Determined by chiral HPLC on the major diastereoisomer.
1
12ba-9 and 12bb-9, determined by H NMR on the crude reaction mixture.
Decomposition.
Bu ester derivative 2d was not stable under the ther- namic reaction conditions. The reactions of cinnamal-
modynamic reaction conditions (reflux, TFA) and re- dehyde 1a and o/p-nitrocinnamaldehydes 1b and 1d
sulted in decomposition of the intermediate/product, with both the methyl and ethyl esters 2a, b were
most likely through cleaving of the t-Bu group and found to give similar results in terms of enantio- and
subsequent decarboxylation (Table 2, entry 8). Based diastereoselectivity and a series of both kinetic (12ba-
on these results, the methyl and ethyl esters 2a, b ap- 9) and thermodynamic (12bb-9) products could be
peared to be the most promising substrates with re- isolated in 93–96% ee with 78:22 to 90:10 dr (Table 3,
spect to reactivity and selectivity.
entries 1–8 and 13, 14). Interestingly, for the pyrroli-
Therefore, we decided to proceed with these two dine 4 catalyzed conjugate addition of amides 2a, b to
amides to investigate the substrate scope of the one- p-methoxycinnamaldehyde 1c, the ester group turned
pot reaction. The reactions of cinnamaldehyde, o/p-ni- out to be of crucial importance for the enantioselec-
trocinnamaldehyde and p-methoxycinnamaldehyde tivity of the reactions and after acidification under ki-
with both amides 2a, b in the presence of catalyst 4 netic and thermodynamic conditions, the methyl ester
were studied. After full conversion of amide 2, acid derivatives 12ba-9ca and 12bb-9ca were isolated in
was added to the reaction mixture under kinetic 88–89% ee, whereas only one enantiomer could be
(HCl, ꢀ788C!r.t.) and thermodynamic reaction con- detected for the corresponding ethyl esters 12ba-9cb
ditions (TFA, reflux). The first observation we made and 12bb-9cb (Table 3, entries 9–12).
was the pronounced difference in reaction rate be-
In contradiction to the cinnamaldehyde derivatives,
tween the different cinnamaldehydes, where electron- 2-furylacrolein 1e reacted much less selectively in the
withdrawing groups tend to increase and electron-do- conjugate addition and gave only 50% enantiomeric
nating substituents tend to decrease the reaction time excess with the methyl ester 2a and 70% with the
for the conjugate addition (Table 3, entries 1–14).
ethyl ester 2b. Disappointingly, the reaction of 2-pen-
In general, the yields are all moderate to good, tenal with amide 2a in the presence of catalyst 4 re-
with a tendency to be somewhat higher for the kinetic sulted in decomposition of 2-pentenal and no hemia-
reaction conditions than under the harsher thermody- minal intermediate could be observed.
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Wei Zhang and Johan Franzꢀn
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Table 3. Stereoselective indoloACHTUNGTRNEUNG
[2,3-a]quinolizidine synthesis.[a]
Entry
R1
R2
Time t [days]/Temperature T [oC] Conditions
Product
Yield [%][b]
ee[c]
dr[d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1a
1a
1a
1a
1b
1b
1b
1b
H
H
H
H
o-NO2
o-NO2
o-NO2
o-NO2
Me
Me
Et
3/3
3/3
4/3
A
B
A
B
A
B
A
B
A
B
A
B
A
A
A
A
B
12ba-9aa
12bb-9aa
12ba-9ab
12bb-9ab
12ba-9ba
12bb-9ba
12ba-9bb
12bb-9bb
12ba-9ca
12bb-9ca
12ba-9cb
12bb-9cb
12ba-9da
12ba-9db
12ba-9ea
12ba-9eb
12bb-9eb
69
64
53
75
53
36
64
43
71
38
51
71
47
52
74
46
41
94
94
95
96
95
94
93
94
89
85:15
18:82
82:18
22:78
90:10
17:83
83:17
14:86
83:17
18:82
91:9
17:83
72:28
75:25
69:31[e]
63:37
45:55
Et
4/3
Me
Me
Et
5/r.t.
5/r.t.
3/40
3/40
1/3
Et
1c p-MeO Me
1c p-MeO Me
1c p-MeO
1c p-MeO
1d
1d
1e
1e
1e
1/3
88
Et
Et
Me
Et
Me
Et
3/r.t.
3/r.t.
3/40
5/40
3/r.t.
1/39
1/39
>99
>99
96
96
50
p-NO2
p-NO2
Furyl
Furyl
Furyl
71
70
Et
[a]
For reaction conditions see Table 2 footnote[a]
Total yield of 12ba-9 and 12bb-9.
.
[b]
[c]
[d]
[e]
Determined by chiral HPLC on the major diastereoisomer.
1
Determined by H NMR on the crude reaction mixture.
HCl (20 mol%, 1M in Et2O) was added at room termperature.
One-Pot Synthesis of Benzofuro
Derivatives
[2,3-a]quinolizidine
40 mol% gave full conversion to the kinetic 12ba-
benzofuro[2,3-a]quinolizidine 17aa in good diastereo-
selectivity (Table 4, entry 1). After further screening
In contrast to the numerous reports on the synthesis of acidic conditions we found that formic acid was the
and bioactivity of indolo[2,3-a]quinolizidine deriva- superior acid for the benzofuran moiety and the ki-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
tives, very few examples are reported where the netic product 12ba-17aa could be isolated in excellent
indole NH group has been substituted for oxygen to yield, diastereo- and enantioselectivity (Table 4,
the analogous benzofuroACHTNUTGRNEUNG
[2,3-a]quinolizidines.[22] Fur- entry 5). Best selectivity was obtained from o-nitro-
thermore, the benzofuran moiety has been rarely cinnamaldehyde 1b that gave the kinetic products
used as nucleophile in N-acyliminium ion cycliza- 12ba-17ba, bb as the only observable diastereoiso-
tions.[23] We therefore decided to investigate the com- mers with excellent enantioselectivity. It is also inter-
patibility of the benzofuran moiety in our one-pot esting to point out that the methyl ester amide 11a
cyclization/annulation reaction. Reaction of amide gave higher enantioselectivity than the ethyl ester
11a with cinnamaldehyde 1a at 38C gave full conver- amide 11b for all cinnamaldehydes investigated
sion of amide 11a in 3 days. The benzofuran moiety (Table 4). Unfortunately, employing the thermody-
was expected to be less reactive in the second acylimi- namic reaction conditions (TFA, reflux) used for the
nium cyclization and the kinetic reaction conditions synthesis 12bb-indolo
(HCl 20 mol%, ꢀ788C!r.t) used for the 12ba- was not successful for the benzofuran derivatives and
indolo[2,3-a]quinolizidine derivatives 9 gave no reac- only the kinetic product 12ba-17aa was obtained in
tion. However, increasing the amount of HCl to high dr (Table 4, entry 2). Several different Brøndsted
ACHTUNGTRENN[UNG 2,3-a]quinolizidine derivatives 9
ACHTUNGTRENNUNG
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Diverse Asymmetric Quinolizidine Synthesis: A Stereodivergent One-Pot Approach
[2,3-a]quinolizidine synthesis.[a]
Table 4. Stereoselective benzofuroACTHUNGTRENNNUG
Entry
R1
R2
Time t [days]/Temperature T [oC]
Acid/T [oC]
Product
Yield [%][b]
ee[c]
dr[d]
1
2
3
4
5
6
7
8
9
H
H
H
H
H
Me
Me
Me
Me
Me
Et
Me
Et
Me
Et
3/3
3/3
3/3
3/3
3/3
3/r.t.
3/40
3/40
4/3
HCl/ꢀ78!r.t.
TFA/70
12ba-17aa
12ba-17aa
12ba-17aa
12ba-17aa
12ba-17aa
12ba-17ab
12ba-17ba
12ba-17bb
12ba-17ca
12ba-17cb
–
–
–
–
–
–
86:14
84:16
56:44
–
92:8
91:9
>95:5
>95:5
93:7
SnCl4/r.t.
[e]
BF3·Et2O/ꢀ20
HCO2H/r.t.
HCO2H/r.t.
HCO2H/r.t.
HCO2H/r.t.
HCO2H/r.t.
HCO2H/r.t.
–
–
86
71
55
57
87
70
91
90
97
92
96
86
H
o-NO2
o-NO2
p-MeO
p-MeO
10
3/r.t.
90:10
[a]
A solution of aldehyde 1 (1.2 equiv.), amide 11 (1 equiv.) and catalyst 4 (20 mol%) in CH2Cl2 (0.9 mM) was stirred at
room temperature. After full conversion of 11, formic acid (0.5 mLmmolꢀ1) was added and the resulting mixture was
stirred at room temperature for 2 h.
[b]
[c]
Total yield of 12ba-17 and 12bb-17.
1
Determined by chiral HPLC on the major diastereoisomer.[d] 12ba-17/12bb-17, determined by H NMR on the crude re-
action mixture.
Decomposition of product/intermediate cinnamaldehyde.
[e]
acid and Lewis acids were screened in order to obtain ble for the synthesis of 12ba-benzofuroACHTUNTRGNEUNG[2,3-a]quinoli-
thermodynamic control.[21] The highest selectivity for zidine 17 (formic acid, room temperature), the selec-
the thermodynamic product was obtained with tivity could be increased to 74:26 in favor of the ki-
tin(IV) chloride which gave 12ba-17aa and 12bb-17aa netic product 10ba-18aa (Table 5, entry 5).[21] In order
in 56:44 dr (Table 4, entry 3).
to gain access to the thermodynamic product, an addi-
tional set of acids was screened. Interestingly, reflux-
ing TFA gave the almost the same selectivity as hy-
drochloric acid at low temperature (Table 5, entries 1
and 2). Some success was met with BF3·Et2O and the
thermodynamic product 10bb-18aa was formed in low
One-Pot Synthesis of Thieno
Derivatives
ACHTUNGERTN[NUNG 3,2-a]quinolizidine
After investigating the nitrogen- and oxygen-contain- excess (Table 5, entry 3). When an excess of tin(IV)
ing heterocyclic compounds in the one-pot procedure, chloride (1.2 equiv.) was used a distinct improvement
we turned our attention to the sulfur-containing het- in selectivity towards the thermodynamic product was
erocycles. The thiophene scaffolds are of interest in observed and epimer 10bb-18aa could be isolated in
pharmaceutical chemistry due to the higher stability good yield and enantioselectivity and in a diasterio-
and structural chemical resemblance with the pyrrole meric ratio of 75:25 (Table 5, entry 6).
and furan rings and specifically annulated thiophenes
However, when the amount of tin(IV) chloride was
are becoming more and more interesting as therapeu- reduced to 40 mol% the selectivity dropped to give
tic agents.[24,25] The thiophene substituted amide 12a close to a 1:1 mixture of isomers (Table 5, entry 4).
reacted smoothly with 1a and gave, after full conver- With those optimized condition in hand, the stereodi-
sion of 12a and subsequent treatment with acid under vergent one-pot reaction was successfully employed
kinetic conditions, the corresponding 10ba-thienoACHTUNTRGENNUG[3,2- in the synthesis of a series thienoAHCTUNGTREN[NUGN 3,2-a]quinolizidine
a]quinolizidine 18aa as the major epimer although derivatives 18 having either the 10ba- or the 10bb-
with moderate diastereoselectivity (Table 5, entry 1). configuration in high to excellent enantioselectivity,
However, applying the reaction conditions most suita- good yields and moderate to good diastereoselectivity
Adv. Synth. Catal. 2010, 352, 499 – 518
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Wei Zhang and Johan Franzꢀn
FULL PAPERS
Table 5. Stereoselective thienoACHTUNGTRNEUNG
[3,2-a]quinolizidine synthesis.[a]
Entry
R1
R2
Time t [days]/Temperature T [oC]
Acid/T [oC]
Product
Yield [%][b]
ee[c]
dr[d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Et
3/3
3/3
3/3
HCl/ꢀ78!r.t.
TFA/70
BF3·Et2O/ꢀ78
SnCl4/r.t.[e]
HCO2H/r.t.
SnCl4/r.t.
HCO2H/r.t.
SnCl4/r.t.
HCO2H/r.t.
SnCl4/r.t.
HCO2H/r.t.
SnCl4/r.t.
HCO2H/r.t.
SnCl4/r.t.
HCO2H/r.t.
SnCl4/r.t.
10ba-18aa
10ba-18aa
10ba-18aa
10ba-18aa
10ba-18aa
10bb-18aa
10ba-18ab
10bb-18ab
10ba-18ba
10bb-18ba
10ba-18bb
10bb-18bb
10ba-18ca
10bb-18ca
10ba-18cb
10bb-18cb
–
–
–
–
–
–
–
66:34
61:39
40:60
55:45
74:26
25:75
75:25
33:67
83:17
83:17
80:20
44:56
75:25
24:76
68:32
34:66
3/3
–
3/r.t.
3/r.t.
3/r.t.
3/r.t.
3/39
3/39
3/39
3/39
3/r.t.
3/r.t.
3/r.t.
3/r.t.
65
72
79
79
69
20
43
45
83
79
81
84
92
92
95
95
89
Et
o-NO2
o-NO2
o-NO2
o-NO2
p-MeO
p-MeO
p-MeO
p-MeO
Me
Me
Et
[f]
–
93
94
89
89
>99
>99
Et
Me
Me
Et
Et
[a]
A solution of aldehyde 1 (1.2 equiv.), amide 12 (1 equiv.) and catalyst 4 (20 mol%) in CH2Cl2 (0.9 mM) was stirred at
room temperature. After full conversion of 12, formic acid (0.5 mLmmolꢀ1) or SnCl4 (1.2 equiv., 1M in DCM) was added
and the resulting mixture was stirred at room temperature for 5 and 1 h, respectively.
Total yield of 10ba-18 and 10bb-18.
[b]
[c]
[d]
[e]
Determined by chiral HPLC on the major diastereoisomer.
10ba-18/10bb-18, determined by 1H NMR on the crude reaction mixture.
0.4 equivalent of SnCl4.[f] Decomposition of reaction intermediate/product.
(Table 5, entries 5–16). One exception was the o-nitro One-Pot Synthesis of FuroACTHNUTRGNE[UNG 3,2-a]quinolizidine
compound 12a, b that reacted sluggish in the presence Derivatives
tin(IV) chloride. The methyl ester derivative 12a
mainly gave decomposition of the intermediate hemi- Furan derivatives have been rarely used in N-acylimi-
acetal and/or the product and no selectivity for the nium ion cyclizations;[26] most likely as a result of the
thermodynamic product was observed (Table 5, instability of the furan group under acidic conditions
entry 10). In the corresponding reaction with ethyl as well as the difficulties associated with the synthesis
ester 12b, the adduct 10bb-18bb could be isolated in of the cyclization precursors. On the other hand, the
low yield as a 1:1 mixture of diastereoisomers furan moiety is a masked dicarbonyl moiety and a val-
(Table 5, entry 12). For the combination of ethyl ester uable handle for further transformations. The reaction
12b and p-methoxycinnamaldehyde 1c, only one of furan amide 13a with cinnamaldehydes 1a and 1c
enantiomer could be observed, unfortunately, in mod- went smoothly and full conversion was observed
erate diastereoselectivity under both kinetic and ther- within 1–3 days at 38C. For o-nitrocinnamaldehyde a
modynamic reaction conditions (Table 5, entries 15 longer reaction time at elevated temperature was re-
and 16). However, for the corresponding reactions quired to obtain full conversion. The instability of the
with the methyl ester 12a and p-methoxycinnamalde- furan moiety under acidic conditions turned out to be
hyde 1c, higher diastereoselectivity and lower enan- a serious problem and for most of the screened acids
tioselectivity were observed (Table 5, entries 13 and the major observation was decomposition of the con-
14).
jugate addition adduct and/or the product (Table 6,
entries 1–4).[21] Eventually, it was found that addition
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Adv. Synth. Catal. 2010, 352, 499 – 518

Diverse Asymmetric Quinolizidine Synthesis: A Stereodivergent One-Pot Approach
[3,2-a]quinolizidine synthesis.[a]
Table 6. Stereoselective furoACHTNUGTRENNUNG
Entry
R1
R2 Time t [days]/Temperature T [oC]
Acid/T [oC]
Product
Yield [%][b] ee[c]
dr[d]
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
Me
Me
Me
Me
Me
Et
3/3
3/3
3/3
3/3
3/3
4/3
3/39
3/39
6/3
6/3
HCl/ꢀ78!r.t. 10ba-19aa
–
–
–
–
–
–
trace (50:50)[e]
SnCl4/r.t. 10ba-19aa
trace (50:50)[e]
[e]
BF3·Et2O/ꢀ78 10ba-19aa
–
–
[e]
HCO2H/r.t.
TFA/ꢀ78
TFA/ꢀ78
TFA/ꢀ78
TFA/ꢀ78
TFA/ꢀ78
TFA/ꢀ78
10ba-19aa
10ba-19aa
10ba-19ab
10ba-19ba
10ba-19bb
10ba-19ca
10ba-19cb
–
–
62
56
21
19
65
46
92
98
98
96
90
92
78:22
80:20
83:17
78:22
87:13
85:15
o-NO2 Me
o-NO2 Et
p-MeO Me
p-MeO Et
10
[a]
A solution of aldehyde 1 (1.2 equiv.), amide 13 (1 equiv.) and catalyst 4 (20 mol%) in CH2Cl2 (0.9 mM) was stirred at
room temperature. After full conversion of 13, the reaction mixture was cooled to ꢀ788C followed by addition of TFA
(5 equiv., 1M in DCM). The mixture was stirred for at ꢀ788C for 3 h.
[b]
[c]
[d]
[e]
Total yield of 10ba-19 and 10bb-19.
Determined by chiral HPLC on the major diastereoisomer.
1
Determined by H NMR on the crude reaction mixture.
Mainly decomposition of product/intermediate.
of TFA diluted in DCM at ꢀ788C followed by careful
As for the benzofuran derivatives, the furan deriva-
quenching of the acid at ambient temperature gave tives failed to give the thermodynamic product and
the kinetically favored product 10ba-19aa in high se- attempts to use thermodynamic reaction conditions
lectivity (Table 6, entry 5). Considering the sensitivity only resulted in decomposition.
of the furo group, the obtained yields are good for
In order to complete the heterocylic five-mebered
the phenyl derivative 10ba-19aa, ab and p-methoxy- ring series, the N-methylpyrrole amide 24 was reacted
cinnamaldehyde 19ca, cb (Table 6, entries 5 and 6, 9 with cinnamaldehyde in the presence of catalyst 4. Al-
and 10). For the nitro compound 19ba, bb the yields though the amide 24 was consumed fast, only traces
dropped to 21 and 19%, respectively. This is most of product could be detected after addition of HCl
likely the result of the low reactivity of the amide 13 (Scheme 3). Unfortunately, it is believed that the pyr-
and o-nitrocinnamaldehyde 1b in the conjugate addi- role moiety is more reactive as nucleophile than the
tion step and this favors the competing Knoevenagel amide a-carbon in the conjugate addition under these
condensation to give the corresponding dienes 23, reaction conditions.[27]
which was observed as the major product in these re-
actions (Figure 2).
One-Pot Synthesis of Benzo[a]quinolizidine
Derivatives
In order to further expand the scope of this reaction
to the benzo[a]quinolizidine derivatives, we decided
to investigate non-heteroatom aromatics as nucleo-
philes.[18] Since electron-rich aromatics are relatively
strong nucleophiles we started our investigation with
the 3,5-dimethoxyphenyl amide 14a.[8a,d] This com-
pound reacted smoothly with cinnamaldehyde 1a in
Figure 2.
the presence of catalyst 4 to give full conversion of
Adv. Synth. Catal. 2010, 352, 499 – 518
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507

Wei Zhang and Johan Franzꢀn
FULL PAPERS
90:10 dr (Table 7, entry 3). By further following the
reaction conditions developed for 12bb-indoloACHTUNGTRENNUNG[2,3-
a]quinolizidines 9 in the synthesis of thermodynamic
favored 11bb-benzo[a]quinolizidine derivatives, we
changed the reaction conditions of the second step to
refluxing TFA (Table 7, entry 4). Interestingly, if the
reaction was quenched after 1 h reflux, full conversion
to the product was observed, however, the dr was
only 63:37 in favor of 11bb-20aa (Table 7, entry 1).
Further reflux (18 h) resulted in mainly decomposi-
tion of the product and no further increase in dr
could be observed (vide infra). It was also observed
that, in the reaction of the 3,5-dimethoxy derivative
Scheme 3. Attempted one-pot reaction with N-methylpyrrol-
ACHTUNGTRENNUNGamide 24 and cinnamaldehyde.
the amide 14a in 3 days at 38C. By using the kinetic with tin(IV) chloride, the kinetic product 11ba-20aa
reaction conditions developed for the 12ba-indolo- was obtained as the major isomer (Table 7, entry 2).
ACHTUNGTRENNUNG[2,3-a]quinolizidine derivatives 9 (20 mol% HCl, The reaction with the corresponding ethyl ester 14b
ꢀ788C!r.t.) no reaction occurred. However, when turned out to be slower and required 3 days reaction
the acid loading was increased to 40 mol% under the time at room temperature to obtain full conversion of
same reaction conditions the kinetic product 11ba- the amide. Subsequent acid treatment under kinetic
20aa could be isolated in high yield, good ee and and thermodynamic conditions gave 11ba-20ab and
Table 7. Stereoselective 9,11-dimethoxybenzo[a]quinolizidine synthesis.[a]
Entry
R1
R2
Time t [days]/Temperature T [oC]
Acid/T [oC]
Product
Yield [%][b]
ee[c] dr[d]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
o-NO2
o-NO2
o-NO2
o-NO2
p-MeO
p-MeO
p-MeO
p-MeO
Me 3/3
Me 3/3
Me 3/3
Me 3/3
TFA/70
SnCl4/r.t.
11bb-20aa
11ba-20aa
–
–
–
–
37:63
66:34
90:10
28:72
91:9
HCl/ꢀ78!r.t. 11ba-20aa
TFA/70 11bb-20aa
HCl/ꢀ78!r.t. 11ba-20ab
TFA/70 11bb-20ab
HCl/ꢀ78!r.t. 11ba-20ba
TFA/70 11bb-20ba
77
73
78
83
69
93
93
95
95
92
–
93
–
89
87
94
94
Et
Et
3/r.t.
3/r.t.
24:76
Me 5/39
Me 5/39
>95:5[e]
[f]
–
9
Et
Et
5/39
5/39
HCl/ꢀ78!r.t. 11ba-20bb 77
>95:5[e]
[f]
10
11
12
13
14
TFA/70
11bb-20bb
–
Me 3/3
Me 3/3
HCl/ꢀ78!r.t. 11ba-20ca
TFA/70 11bb-20ca
HCl/ꢀ78!r.t. 11ba-20cb
TFA/70 11bb-20cb
71
77
64
61
84:16
23:27
92:8
Et
Et
3/r.t.
3/r.t
24:76
[a]
A solution of cinnamic aldehyde 1a (1.2 equiv.), amide 14a–d (1 equiv.) and catalyst 4 (20 mol%) in CH2Cl2 (0.9 mM) was
stirred at room temperature. After full conversion of 2, HCl (0.4 equiv., 1M in Et2O) or TFA (0.5 mLmmolꢀ1) was added
to the reaction mixture according to conditions A or B as described in Table 2, footnote[a]
Total yield of 11ba-20 and 11bb-20.
.
[b]
[c]
[d]
[e]
[f]
Determined by chiral HPLC on the major diastereoisomer.
1
Determined by H NMR on the crude reaction mixture.
1
Only one diastereoisomer could be observed by H NMR.
Mainly decomposition of product/intermediate.
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Diverse Asymmetric Quinolizidine Synthesis: A Stereodivergent One-Pot Approach
11bb-20ab, respectively, in good yields and stereose-
We then turned to the regioisomeric 3,4-dimethoxy-
lectivity (Table 7, entries 5 and 6). The reactions of o- phenyl compound. The catechol group is of special in-
nitrocinnamaldehyde 1b with amides 14a, b required terest, since it is an often-occurring subunit in biologi-
5 days in refluxing DCM to go to full conversion. cally active compounds, for example, emetine, the
Subsequent treatment of the reaction mixtures with closely related psychotrine and alangine (Figure 1).
acid under kinetic conditions gave the products 11ba- The 3,4-dimethoxyphenyl amide 3a and cinnamalde-
20ba, bb as single observable diastereoisomers in hyde 1a in the presence of catalyst 4 gave full conver-
good yields and high ee (Table 7 entries 7 and 9). Un- sion to the intermediate hemiaminal in 3 days at 38C.
fortunately, when the harsher thermodynamic reac- To the reaction mixture was then added 40 mol%
tion condition was used only decomposition was ob- HCl and the kinetically favored product 11ba-10aa
served (Table 7, entries 8 and 10). For the one-pot re- could be isolated in 90% ee and moderate dr (Table 8,
action of p-methoxycinnamaldehyde 1c with the entry 3).
methyl and ethyl esters 14a, b under kinetic and ther-
Despite several attempts, the diasteroselectivity
modynamic conditions gave 11ba-20ca, cb and 11bb- could not be improved for the kinetic product 11ba-
20ca, cb, respectively, in good diastereoselectivity. As 10aa.[21] For the diastereoselective synthesis of the
been previously observed for the methoxy derivatives thermodynamic epimer 11bb-10aa, we first investigat-
(vide supra), the methyl ester derivative 11ba-20ca ed the N-acyliminium ion cyclization in refluxing
was isolated in moderate enantioselectivity whereas TFA, which gave moderate diastereoselectivity for
the selectivity increased substantially for the corre- the kinetic product 11ba-10aa. However, extensive
sponding ethyl ester derivative 11ba-20cb (Table 7, screening of acid conditions revealed that using the
entries 11–14).
thermodynamic conditions developed for the 10bb-
Table 8. Stereoselective 9,10-dimethoxybenzo[a]quinolizidine synthesis.[a]
Entry
R1
R2
Time t [days]/Temperature T [oC]
Acid/T [oC]
Product
Yield [%][b]
ee[c]
dr[d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H
H
H
H
H
Me
Me
Me
Me
Et
3/3
3/3
3/3
TFA/70/0.1M
SnCl4[e]/r.t.
HCl/ꢀ78!r.t.
SnCl4/r.t.
11ba-10aa
11bb-10aa
11ba-10aa
11bb-10aa
11ba-10ab
11bb-10ab
11ba-10ba
11bb-10ba
11ba-10bb
11bb-10bb
11ba-10ca
11bb-10ca
11ba-10cb
11bb-10cb
–
–
–
–
62:38
26:74
62:38
26:74
67:33
23:77
83:17
50:50
73:27
25:75
76:24
24:76
67:33
25:75
69
72
41
66
53
52
42
39
71
75
63
72
90
90
95
94
91
91
94
95
89
89
94
95
3/3
1/r.t.
1/r.t.
5/39
5/39
5/39
5/39
1/3
1/3
3/r.t.
3/r.t.
HCl/ꢀ78!r.t.
H
Et
SnCl4/r.t.
o-NO2
o-NO2
o-NO2
o-NO2
p-MeO
p-MeO
p-MeO
p-MeO
Me
Me
Et
HCl/ꢀ78!r.t.
SnCl4/r.t.
HCl/ꢀ78!r.t.
Et
SnCl4/r.t.
Me
Me
Et
HCl/ꢀ78!r.t.
SnCl4/r.t.
HCl/ꢀ78!r.t.
Et
SnCl4/r.t.
[a]
A solution of aldehyde 1 (1.2 equiv.), amide 3 (1 equiv.) and catalyst 4 (20 mol%) in CH2Cl2 (0.9 mM) was stirred at
room temperature. After full conversion of 3, HCl (40 mol%, 1M in Et2O) or SnCl4 (40 mol%, 1M in DCM) was added
at the indicated temperature and stirred overnight and for 1 h, respectively.
Total yield of 10ba-10 and 10bb-10.
[b]
[c]
[d]
[e]
Determined by chiral HPLC on the major diastereoisomer.
10ba-10/10bb-10, determined by 1H NMR on the crude reaction mixture.
1.2 equivalents of SnCl4.
Adv. Synth. Catal. 2010, 352, 499 – 518
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Wei Zhang and Johan Franzꢀn
FULL PAPERS
thienoACHTUNGTRENNUNG[3,2-a]quinolizidine derivatives 18 [tin(IV) chlo- intermediate slowly cyclized to give the benzo[a]qui-
ride, 1.2 equiv.] gave the thermodynamically favored nolizidine derivative. Surprisingly, examination of the
product 11bb-10aa in 74:26 dr (Table 8, entry 2). For stereochemistry revealed that the major product was
the 3,4-dimethoxyphenyl amide 3a, it was found that the thermodynamically favored 11bb-21aa and not the
the tin(IV) chloride could be reduced to a catalytic expected kinetic 11ba-21aa. The thermodynamic reac-
amount (40 mol%) without affecting the diastereose- tion conditions (TFA, reflux) smoothly gave the ben-
lectivity of the reaction (Table 8, entry 4). The corre- zo[a]quinolizidine derivative with a diastereoselectiv-
sponding reactions of the ethyl ester 3b and cinnamal- ity 73:27 in favor of 11bb-21aa (Table 9, entry 5).
dehyde 1a gave similar yields and diastereoselectivity After further optimization it was found that the selec-
but
a pronounced increase in enantioselectivity tivity of the cyclization could be increased up to 83:17
(Table 8, entries 5 and 6). The same trend of in- in favor of 11bb-21aa by reducing the reaction tem-
creased enantioselectivity was also observed for the perature to 38C (Table 9, entry 6). The thermodynam-
corresponding reactions with o-nitrocinnamaldehyde ically favored phenyl derivative 11bb-21ab and p-me-
1b and p-methoxycinnamaldehyde 1c (Table 8, en- thoxyphenyl derivative 11bb-21ca, cb were also ob-
tries 7–14). The diastereoselectivity in the reaction tained in high diastereoselectivity and moderate to
with tin(IV) chloride turned out to be independent of good enantioselectivity through the corresponding re-
which cinnamaldehyde was used and gave the ther- actions (Table 9, entries 6 and 7, 10 and 11). The o-ni-
modynamic product 11bb-10 with approximately trophenyl derivative 11bb-21ba, bb gave good enan-
75:25 diastereomeric ratio (Table 8) with the excep- tioselectivity but lower diasteroselectivity. For all
tion of the methyl ester 3a in combination with o-ni- acids used, the thermodynamic product 11bb-21 was
trocinnamaldehyde 1b that gave 11ba-10ba and 11bb- formed in good to high diastereoselectivity and all at-
10bb in a 1:1 mixture (Table 8, entry 8).
tempts to find reaction conditions favoring the kinetic
The 3,5- and 3,4-dimethoxyphenyl groups are both product failed.[21] Furthermore, the 1-naphthyl amide
relatively strong nucleophiles in aromatic substitution 16 also worked smoothly in the one-pot reaction to
reactions so we wanted to evaluate if the less activat- give the thermodynamically favored tetracyclic com-
ed phenyl group could be used in the N-acyliminiu- pound 13bb-22 in 57% yield, 92% ee and 87:13 dr
mion cyclization. The initial conjugate addition step (Scheme 5).
of phenyl amide 15a and cinnamaldehyde 1a in the
presence of catalyst 4 went as expected with full con-
version of amide 15a in 3 days at 38C. The following Mechanism/Origin of Selectivity
acid promoted N-acyliminiumion cyclization turned
out to be less feasible for the non-activate phenyl The stereochemistry of the three new stereocenters
group compared to the more activated 3,4- and 3,5-di- formed through this one-pot sequence is determined
methoxyphenyl groups and employing the previously during three reaction steps. First; in the conjugate ad-
optimized reaction conditions for kinetic control (vide dition, the nucleophile is directed to the sterically less
supra) did not give any cyclization product.[21] For ex- hindered Si-face by shielding of the Re-face of the
ample, using HCl, formic acid or SnCl4 only resulted iminium intermediate 5 by the bulky aryl groups on
in elimination of water to give the enamide derivative catalyst 4 (Scheme 6).[28] Spontaneous epimerization
25 (Scheme 4, Table 9, entries 1 and 2). The same of the stereochemically labile stereocenter at C-3 to
result was also observed after 2 h reaction time when the thermodynamically more stabile trans conforma-
excess TFA was used. However, after a prolonged re- tion of hemiaminal 7 will establish the second stereo-
action time (24 h) it was observed that the enamide center. Finally, addition of acid to the reaction mix-
Scheme 4.
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Adv. Synth. Catal. 2010, 352, 499 – 518

Diverse Asymmetric Quinolizidine Synthesis: A Stereodivergent One-Pot Approach
Table 9. Stereoselective benzo[a]quinolizidine synthesis.[a]
Entry
R1
R2 Time t [days]/Temperature T [oC] Acid/T [oC]
Product
Yield [%][b] ee[c]
dr[d]
[e]
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Et
3/3
3/3
3/3
3/3
3/3
3/3
3/3
7/r.t.
5/40
1/3
HCl/r.t.
SnCl4/r.t.
H2SO4/r.t.
TFA/r.t.
TFA/70
TFA/3
TFA/3
TFA/3
TFA/3
TFA/3
11bb-21aa
11bb-21aa
11bb-21aa
11bb-21aa
11bb-21aa
11bb-21aa
11bb-21ab
11bb-21ba
11bb-21bb
11bb-21ca
11bb-21cb
–
–
–
–
–
78
83
67
78
78
73
–
–
–
–
–
89
92
93
92
82
91
–
–
[e]
trace (39:61)[f]
23:77
27:73
17:83
17:83
37:63
31:69
17:83
17:83
o-NO2 Me
o-NO2 Et
p-MeO Me
p-MeO Et
10
11
1/3
TFA/3
[a]
A solution of aldehyde 1 (1.2 equiv.), amide 15 (1 equiv.) and catalyst 4 (20 mol%) in CH2Cl2 (0.9 mM) was stirred at
room temperature. After full conversion of 15, TFA (0.5 mLmmolꢀ1) was added at ꢀ788C and the mixture was stirred at
ambient temperature for 3 days.
[b]
[c]
[d]
[e]
[f]
Total yield of 11ba-21 and 11bb-21.
Determined by chiral HPLC on the major diastereoisomer.
11ba-21/11bb-21, determined by 1H NMR on the crude reaction mixture.
Only 25 was observed.
Mainly decomposition of product/intermediate.
ture leads to elimination of water and formation of tive, where electron-withdrawing groups increase and
the N-acyliminium ion 8. Subsequent aromatic substi- electron-donating groups decrease the reaction time.
tution gives the a- or b-epimer depending on the re- Interestingly, this is in contradiction with what can be
action conditions.
expected, since electron-deficient cinnamaldehydes
From the data obtained it is observed that the rate should be the better electrophiles and therefore react
of the conjugate addition is mainly determined by the faster.These results rather imply that the rate-deter-
electronic properties of the cinnamaldehyde deriva- mining step is not the conjugate addition but the for-
mation of the iminium ion, which should be facilitated
by electron-donating groups. In an attempt to speed
up the iminium ion formation, p-nitrobenzoic acid
(20 mol%) was added to the reaction of indolyl amide
2a, cinnamaldehyde 1a and catalyst 4; however, under
these reaction conditions, formation of the corre-
sponding Knoevenagel product 23 was favored (see
Figure 2). The pyrrolidine 4 catalyzed conjugate addi-
tion turned out to be highly enantioselective for the
reactions of cinnamaldehyde 1a and o-nitrocinnamal-
dehyde 1b with the methyl and the ethyl ester amides
2a, b and both the kinetic and thermodynamic prod-
ucts could be isolated in 90–98% ee. In general, the
ethyl esters gave somewhat higher enantioselectivity
than the methyl esters in the corresponding conjugate
additions, with the exception of the benzofuran amide
11, where the methyl ester 11a in all cases gave better
Scheme 5. One-pot reaction of 1-naphthyl amide 16 and cin-
namaldehyde 1a.
Adv. Synth. Catal. 2010, 352, 499 – 518
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511

Wei Zhang and Johan Franzꢀn
FULL PAPERS
Scheme 6. Proposed mechanism for the one-pot reaction.
enantioselectivity than the corresponding reactions transition state leading to the a-epimer, as compared
with ethyl ester 11b. When comparing the reactions of to the higher steric interactions between the aromatic
p-methoxycinnamaldehyde 1c with the methyl and moiety and the axial a-proton in the transition state
ethyl esters 2–3 and 11-16, a distinct increase in enan- leading to the b-epimer. This is in agreement with the
tioselectivity was observed, for example, the indolo- observed increase in diastereoselectivity when going
ACHTUNGTRENNUNG
AHCTUNGTREG[NNNU 2,3-a]quinolizi-
The final, bridgehead, stereocenter is formed dine 9 and 11bb-9,11-dimethoxy-benzo[a]quinolizi-
through an N-acyliminium ion cyclization. The N- dine 20 under thermodynamic reaction conditions
acylACHTUNGTRENNUNGiminium ion 8 is formed by acid-catalyzed elimi- (TFA, reflux) it was found that the diastereomeric
nation of water from the hemiaminal 7 and these spe- ratio varied with reaction temperature and reaction
cies are strong electrophiles that readily react in elec- time (see Table 1, entries 10 and 11 and Table 7, en-
trophilic aromatic substitutions. Addition of the aro- tries 1 and 4). These results are in accordance with
matic moiety to the Si-face of the iminium ion 8 the initial formation of the kinetically favored a-
would give the thermodynamically more stable b- epimer and subsequent epimerization to the thermo-
epimer owing to the all-equatorial orientation of the dynamically more stable b-epimer. This was also sup-
substituents on the piperidine ring. However, under ported by the epimerization of the kinetic products
the kinetic reactions conditions used in this study 12ba-indoloACTHUNRTGNE[GNU 2,3-a]quinolizidine 9aa and 11ba-9,11-di-
(vide supra), the a-epimer is obtained as the major methoxybenzo[a]quinolizidine 20aa in refluxing TFA
product, which is in agreement with addition of the which gave the thermodynamic compounds 12bb-9
aromatic moiety from the Re-face of the iminium ion and 11bb-20, respectively (Scheme 7).
(Figure 3). This due to the less steric hindrance from
There are two plausible mechanisms to explain the
the equatorial a-proton of the iminium ion in the epimerization: Through the reversed reaction, that is,
protonation on the fused aromatic ring and subse-
quent ring opening/ring closing involving the inter-
mediate N-acyliminium ion (Scheme 8). Or, by initial
protonation of the amide and breaking of the carbon-
nitrogen bond forming an intermediate ten-membered
ring that will undergo intramolecular cyclization to
the thermodynamic more stable product.[29]
In contrast to the indole and 3,5-dimethoxyphenyl
amides 2a and 14a, the one-pot reaction of thiophene
and 3,4-dimethoxy amides 12a and 3a using refluxing
TFA for the N-acyliminium ion cyclization favored
the kinetic product 10ba-thienoACHTUNTRGNEUNG[3,2-a]quinolizidine
18aa and 11ba-9,10-dimethoxybenzo[a]quinolizidine
10aa in 61:39 dr and 62:38 dr, respectively, and not
the thermodynamic product (Table 5, entry 2 and
Table 8, entry 1). Furthermore, for the kinetic product
Figure 3. Kinetic vs. thermodynamic product formation in
the N-acyliminium ion cyclization (E=CO2R2).
512
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Adv. Synth. Catal. 2010, 352, 499 – 518

Diverse Asymmetric Quinolizidine Synthesis: A Stereodivergent One-Pot Approach
Scheme 9. Tin(IV) chloride-promoted epimerization of 9,10-
dimethoxybenzo[a]quinolizidine.
entry 2). This indicate that the tin(IV) promoted reac-
tions do not proceed through initial formation of the
kinetic product 11ba-10 followed by epimerization to
the thermodynamically favored product 11bb-10.
Thus, this reaction is rationalized to be under chela-
tion control. It is proposed that the ester moiety inter-
changes from an equatorial position to an axial posi-
tion by epimerization of the stereochemically labile
stereocenter on C-3, thereby allowing for tin(IV) to
coordinate between the ester oxygen and the two
Scheme 7. Trifluoroacetic acid-promoted epimerization of
indolo[2,3-a]quinolizidine and 9,11-dimethoxybenzo[a]qui-
nolizidine.
ACHTUNGTRENNUNG
11ba-9,10-dimethoxybenzo[a]quinolizidine 10aa, no oxygen atoms on the 3,4-dimethoxyphenyl or to sulfur
epimerization was observed in refluxing TFA. How- on the thiophene moiety. This will direct the aromatic
ACHTUNGTRENNUNGever, a slow epimerization of 11ba-10 was observed addition to the sterically more hindered Si-face of the
with tin(IV) chloride (1.1 equiv.) at room temperature N-acyliminium ion giving the b-epimer. This is also
giving 11bb-10 in 59:41 dr after 18 h (Scheme 9). consistent with the non or low chelation control ob-
Comparing these results with the one-pot reaction served for the reactions with the 3,5-dimethoxyphen-
starting from 3,4-dimethoxyphenyl amide 3a and cin- yl, furan and benzofuran moieties. These aromatic
namaldehyde 1a with 40 mol% tin(IV) chloride, full compounds have weaker coordinating abilities com-
conversion was obtained to the thermodynamic prod- pared to the 3,4-dimethoxyphenyl and the thiophene
uct 11bb-10 in 74:26 dr after only 1 h (Table 8, moieties and will react through kinetic control.
Scheme 8. Proposed mechanism for the epimerization indoloACTHUNRTGNE[GNU 2,3-a]quinolizidine in refluxing TFA.
Adv. Synth. Catal. 2010, 352, 499 – 518
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asc.wiley-vch.de
513

Wei Zhang and Johan Franzꢀn
FULL PAPERS
Figure 4. Chelation control vs. non-chelation (kinetic) control in the tin(IV) chloride-mediated N-acyliminium ion cyclization
of 3,4-dimethoxyphenyl species (E=CO2R2).
The phenyl amides 15a, b were found to be weak would be diminished and these aromatics will react as
nucleophiles in the N-acyliminium ion cyclization and outlined in Figure 3, Figure 4 and Figure 5.
acid addition mainly resulted in elimination of water
The diastereoselectivity in the N-acyliminium ion
from the intermediate hemiaminal 7 to the corre- cyclization is sensitive to the reaction conditions used
sponding enamide 25 (Scheme 4). Surprisingly, a pro- and each amide required separate optimization in
longed reaction time resulted in slow conversion of order to obtain the best selectivity. In general, the
the enamide 25 to the thermodynamic product 11bb- nitro compounds usually gave high diasteroselectivity
benzo[a]quinolizidine 21. This is in contradiction to under kinetic reaction conditions. However, the nitro
the preference for the kinetic product formation that group was found to be unstable under the harsher
was observed for the other aromatic nucleophiles thermodynamic reaction conditions [TFA, reflux or
used in this study (vide supra). The reason for this be- tin(IV) chloride] resulting in poor yields and often
havior is not established, although it is suggested that also in low diastereoselectivity.
the addition of the phenyl group to the N-acylimini-
um ion occurs through an “endo” approach due to
cation-p interactions of the electron-rich p-system of Conclusions
the phenyl group with the electron-deficient p-system
of the N-acyliminium ion.[30] Through this “endo-tran- In summary, we have reported a fast and general one-
sition state” addition to the Re-face of the iminium pot protocol for construction of a wide number of
ion would encounter higher steric repulsion from the quinolizidine derivates. This methodology relies on an
C-2 carbon then from the axial a-proton of the imini- enantioselective organocatalytic conjugate addition
um ion and favor the Si-face addition (Figure 4). Due followed by hemiaminal formation and a diastereodi-
to the higher steric demands of the 3,4-dimethoxy and vergent N-acyliminium ion annulation. The key ad-
3,5-dimethoxy groups and the lower aromatic charac- vantages are the readily available starting materials,
ter of the heteroatom aromatics, cation-p interactions inexpensive and commercially available catalyst,
broad substrate scope and easy operational protocol
and direct access to structures that usually require
multi-step processes with high stereoselectivity and
yields. Beside this, for several substrates, the one-pot
sequence also benefits from a diastereomeric switch
that allows for the selective formation of either the a-
epimer or the b-epimer by tuning of the reaction con-
ditions of the N-acyliminium ion cyclization. The con-
trol of diastereoselectivity is obtained by taking ad-
vantage of kinetic, thermodynamic and chelation con-
trolled reaction conditions. It is also interesting to
point out the high atom economy[32] for this one-pot
sequence, since the only waste product formed is
water. For example; the major enantiomers of 12ba-
benzofuro
ACHTUNGTREN[NUNG 2,3-a]quinolizidine 17ca and 11ba-9,11-di-
Figure 5. Selectivity control through cationic p-interactions
(E=CO2R2).
methoxybenzo[a]quinolizidine 20bb were obtained
514
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Diverse Asymmetric Quinolizidine Synthesis: A Stereodivergent One-Pot Approach
added and the resulting mixture was heated to 708C in an
with 72% and 71% atom economy, respectively, from
the corresponding amide and cinnamaldehyde deriva-
tive. The present study emphasizes the power of com-
bining several reactions in a one-pot sequence for the
efficient construction of complex organic scaffolds
and further development of this one-pot reaction into
applications for the synthesis of natural products is
under investigation and will be reported in due
course.
open vessel for 5 min (to remove DCM) and in a sealed
vessel for one additional hour at 708C. Saturated NaHCO3
(3 mL) and DCM (3 mL) were added and the water phase
was extracted with DCM (2ꢂ3 mL). The combined organic
phases were dried (Na2SO4), filtered and concentrated
under reduced pressure to give the crude product. The title
compound was isolated as a single diastereoisomer after FC
(pentane:EtOAc). Compound 12ba-9ab and 12bb-9ab was
isolated in 75% total yield, dr. 22:78 and 96% ee. Com-
pound 12bb-9ab: 1H NMR (500 MHz, CDCl3): d=8.06
(broad s, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.32–7.30 (m, 3H),
7.26–7.24 (m, 1H), 7.21–7.17 (m, 3H), 7.13 (t, J=7.5 Hz,
1H), 5.16 (dd, J=12.0, 4.0 Hz, 1H), 4.97 (dd, J=11.5,
4.0 Hz, 1H), 4.05–4.00 (m, 2H), 3.57 (d, J=5.0 Hz, 2H),
2.86 (td, J=11.5, 4.5 Hz, 1H), 2.81–2.78 (m, 1H), 2.61 (ddd,
J=13.0, 4.0, 2.0 Hz, 1H), 2.10–2.02 (m, 1H), 1.03 (t, J=
7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=169.9, 165.2,
140.9, 136.4, 132.4, 129.0, 127.6, 126.9, 126.7, 122.4, 120.0,
118.5, 111.1, 109.6, 61.3, 57.1, 53.9, 40.9, 40.4, 35.6, 21.0,
14.0; MS (APCI): m/z (%)=389 (100) [M+H]+. The enan-
tiomers were separated by HPLC on a Chiralcel OD-RH
column (150ꢂ4.6 mm) with H2O/acetonitrile as the eluent
[70:30 to 20:80 (60 min gradient); 20:80 (isocratic 15 min);
flow rate: 0.25 mLminꢀ1]: Rt (min)=59.5 (minor enantio-
mer); 63.1 (major enantiomer).
Experimental Section
Typical Procedure for the One pot Synthesis of 12ba-
Indolo
ACHTUNGTRENNUNG[2,3-a]quinolizidine Derivatives 9, Conditions
A (Kinetic): Preparation of (2R,3S,12bS)-Ethyl 4-
Oxo-2-phenyl-1,2,3,4,6,7,12,12b-octahydroindoloACHTUNTRGNEUNG[2,3-
a]quinolizine-3-carboxylate 12ba-9ab
A solution of aldehyde 1a (0.42 mmol), catalyst 4 (18 mg,
0.05 mmol) and amide 2b (77 mg, 0.28 mmol) in DCM
(0.3 mL) was stirred for 4 days at 38C. After full conversion
1
of amide 2a (determined by H NMR), the reaction mixture
was cooled to ꢀ788C followed by addition of HCl (50 mL,
0.05 mmol, 1M in diethyl ether). The mixture was stirred for
at ꢀ788C for 3 h and slowly allowed to reach room tempera-
ture. Saturated NaHCO3 (3 mL) and DCM (3 mL) were
added and the water phase was extracted with DCM (2ꢂ
3 mL). The combined organic phases were dried (Na2SO4),
filtered and concentrated under reduced pressure to give
the crude product. The title compound was isolated as a
single diastereoisomer after FC (pentane:EtOAc). Com-
pound 12ba-9ab and 12bb-9ab was isolated in 53% total
Typical Procedure for the One-Pot Synthesis of 11ba-
9,10-Dimethoxybenzo[a]quinolizidine Derivatives 10,
Kinetic Conditions: Preparation of (2R,3S,11bS)-
Ethyl 9,10-Dimethoxy-4-oxo-2-phenyl-2,3,4,6,7,11b-
hexahydro-1H-pyrido
ylate 11ba-10ab
ACHTUNGTRNE[NUNG 2,1-a]isoquinoline-3-carbox-
1
yield, dr 82:18 and 95% ee. Compound 12ba-9ab: H NMR
A solution of aldehyde 1a (0.42 mmol), catalyst 4 (18 mg,
0.05 mmol) and amide 3b (80 mg, 0.28 mmol) in DCM
(0.3 mL) was stirred for 24 h at room temperature. After full
(500 MHz, CDCl3): d=7.73 (broad s, 1H), 7.52 (d, J=
8.0 Hz, 1H), 7.36–7.32 (m, 3H), 7.28 (t, J=7.0 Hz, 1H), 7.21
(d, J=7.0 Hz, 2H), 7.22–7.18 (m, 1H), 7.15 (t, J=8.0 Hz,
1H), 5.12 (dd, J=12.0, 4.5 Hz, 1H), 4.81 (t, J=6.0 Hz, 1H),
4.12–4.02 (m, 2H), 3.76 (d, J=7.5 Hz, 1H), 3.50 (td, J=8.0,
4.5 Hz, 1H), 3.03 (tdd, J=13.5, 5.0, 2.5 Hz, 1H), 2.95 (td,
J=12.0, 3.5 Hz, 1H), 2.77 (dt, J=15.0, 2.0 Hz, 1H), 2.52–
2.43 (m, 2H), 1.09 (t, J=7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=169.5, 165.8, 140.9, 136.1, 132.2, 129.0, 127.5,
127.0, 122.3, 120.0, 118.4, 111.1, 61.4, 55.0, 52.3, 42.0, 38.8,
33.3, 21.0, 14.0; MS (APCI): m/z (%)=389 (100) [M+H]+.
The enantiomers were separated by HPLC on a Chiralcel
OJ-RH column (150ꢂ4.6 mm) with H2O/acetonitrile as the
eluent [70:30 to 20:80 (40 min gradient); 20:80 (isocratic
20 min); flow rate: 0.3 mLminꢀ1]: Rt (min)=37.3 (minor
enantiomer); 38.0 (major enantiomer).
1
conversion of amide 3b (determined by H NMR), the reac-
tion mixture was cooled to ꢀ788C followed by addition of
HCl (100 mL, 0.10 mmol, 1M in diethyl ether). The mixture
was stirred at ꢀ788C for 3 h and slowly allowed to reach
room temperature. Saturated NaHCO3 (3 mL) and DCM
(3 mL) were added and the water phase was extracted with
DCM (2ꢂ3 mL). The combined organic phases were dried
(Na2SO4), filtered and concentrated under reduced pressure
to give the crude product. The title compound was isolated
as a single diastereoisomer after FC (pentane:EtOAc).
Compound 11ba-10ab and 11bb-10ab was isolated in 41%
total yield, dr. 67:33 and 95% ee. Compound 11ba-10ab:
1H NMR (500 MHz, CDCl3): d=7.37 (t, J=7.5 Hz, 2H),
7.30–7.25 (m, 3H), 6.66 (s, 1H), 6.59 (s, 1H), 4.86 (ddd, J=
12.5, 4.5, 1.5 Hz, 1H), 4.61 (t, J=6.0 Hz, 1H), 4.16–4.06 (m,
2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.79 (d, J=8.0 Hz, 1H), 3.52
(dt, J=6.5, 6.0 Hz, 1H), 3.05 (ddd, J=14.0, 14.0, 5.0 Hz,
1H), 2.93 (dt, J=12.0, 3.0 Hz, 1H), 2.68 (broad d, J=
15.5 Hz, 1H), 2.48 (t, J=6.5 Hz, 2H), 1.13 (t, J=7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3): d=169.9, 165.8, 148.1,
147.8, 141.7, 129.0, 128.1, 127.9, 127.3, 126.9, 112.0, 107.7,
61.3, 56.2, 56.0, 54.4, 54.1, 41.1, 38.8, 35.1, 28.4, 14.0; MS
(APCI): m/z (%)=410 (100) [M+H]+. The enantiomers
were separated by HPLC on a Chiralcel OJ-RH column
(150ꢂ4.6 mm) with H2O/acetonitrile as the eluent [70:30 to
Typical Procedure for the One-Pot Synthesis of 12bb-
IndoloACHTUNGTRENNUNG[2,3-a]quinolizidine Derivatives 9, Conditions
B (Thermodynamic): Preparation of (2R,3S,12bR)-
Ethyl 4-Oxo-2-phenyl-1,2,3,4,6,7,12,12b-octahydro-
indoloACHTUNGTRENNUNG[2,3-a]quinolizine-3-carboxylate 12bb-9ab
A solution of aldehyde 1a (0.42 mmol), catalyst 4 (18 mg,
0.05 mmol) and amide 2b (77 mg, 0.28 mmol) in DCM
(0.3 mL) was stirred for 4 days at 38C. After full conversion
1
of amide 2b (determined by H NMR), TFA (0.2 mL) was
Adv. Synth. Catal. 2010, 352, 499 – 518
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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515

Wei Zhang and Johan Franzꢀn
FULL PAPERS
20:80 (60 min gradient); 20:80 (isocratic 40 min); flow rate:
0.3 mLminꢀ1]: Rt (min)=35.3 (major enantiomer); 36.4
(minor enantiomer).
Tino, K. Ueda, J. Uenishi, J. B. White, M. Yonaga, J.
Am. Chem. Soc. 1989, 111, 7530; d) E. M. Suh, Y.
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[3] For reviews see: a) L.-F. Tietze, G. Brasche, K. M. Ger-
icke, Domino reactions in organic synthesis, Wiley-
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Santos, Coord. Chem. Rev. 2004, 248, 2365.
Typical Procedure for the One-Pot Synthesis of 11bb-
9,10-Dimethoxybenzo[a]quinolizidine Derivatives 10,
Thermodynamic Conditions: Preparation of
(2R,3S,11bR)-Ethyl 2,3,4,6,7,11b-hexahydro-9,10-
dimethoxy-4-oxo-2-phenyl-1H-pyridoACHTUNGTRNE[NUNG 2,1-a]iso-
quinoline-3-carboxylate 11bb-10ab
[4] For recent reviews on general organocatalysis see:
a) M. Ueda, T. Kano, K. Maruoka, Org. Biomol. Chem.
2009, 7, 2005; b) A. Dondoni, A. Massi, Angew. Chem.
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[5] For recent reviews on organocatalytic domino reac-
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R. Ramon, Current Organic Chemistry 2009, 13, 1432;
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[6] For pioneering examples of asymmetric organocatalytic
domino reactions see: a) D. Enders, M. R. M. Hꢃttl, C.
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Marigo, T. Schulte, J. Franzen, K. A. Jorgensen, J. Am.
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C. H. Larsen, D. W. C. MacMillan, J. Am. Chem. Soc.
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A solution of aldehyde 1a (0.42 mmol), catalyst 4 (18 mg,
0.05 mmol) and amide 3b (80 mg, 0.28 mmol) in DCM
(0.3 mL) was stirred for the given time at the given tempera-
ture (see Table 8). After full conversion of amide 3b (deter-
mined by 1H NMR), SnCl4 (100 mL, 0.10 mmol, 1M in
DCM) was added and the resulting mixture was stirred at
ambient temperature for 1 h. Saturated NaHCO3 (3 mL)
and DCM (3 mL) were added and the water phase was ex-
tracted with DCM (2ꢂ3 mL). The combined organic phases
were dried (Na2SO4), filtered and concentrated under re-
duced pressure to give the crude product. The title com-
pound was isolated as a single diastereoisomer after FC
(pentane:EtOAc). Compound 11ba-10ab and 11bb-10ab
was isolated in 66% total yield, dr. 23:77 and 94% ee. Com-
1
pound 11bb-10ab: H NMR (500 MHz, CDCl3): d=7.34 (t,
J=7.5 Hz, 2H), 7.27 (t, J=7.5 Hz, 1H), 7.25 (s, 1H), 7.24 (s,
1H), 6.64 (s, 1H), 6.61 (s, 1H), 4.94–4.91 (m, 1H), 4.86 (dd,
J=11.0, 4.0 Hz, 1H), 4.12–4.02 (m, 2H), 3.87 (s, 3H), 3.81
(s, 3H), 3.57 (broad d, J=5.0 Hz, 1H), 2.93 (td, J=11.5,
4.0 Hz, 1H), 2.88 (td, J=12.0, 2.0 Hz, 1H), 2.71–2.66 (m,
1H), 2.02–1.85 (m, 1H), 1.06 (t, J=7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=170.3, 165.6, 148.5, 148.4, 141.8,
129.3, 128.6, 127.9, 127.4, 127.3, 112.0, 108.4, 61.5, 57.2, 56.7,
56.5, 56.4, 41.7, 40.3, 38.1, 28.8, 14.4; MS (APCI): m/z (%)=
410 (100) [M+H]+. The enantiomers were separated by
HPLC on a Chiralcel OJ-RH column (150ꢂ4.6 mm) with
H2O/acetonitrile as the eluent [70:30 to 20:80 (60 min gradi-
ent); 20:80 (isocratic 40 min); flow rate: 0.3 mLminꢀ1]: Rt
(min)=46.1 (major enantiomer); 47.1 (minor enantiomer).
Acknowledgements
This work was made possible by financial support from The
Swedish Research Council and The Royal Swedish Academy
of Science. W.Z. thanks The Carl Trygger Foundation for Sci-
entific Research for a grant. We also thank Dr. Zoltan Szabo
for performing NOESY experiments.
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