Diastereodivergent pictet-spengler cyclization of bicyclic N-acyliminium ions: Controlling a quaternary stereocenter

Article abstract of DOI:10.1002/ejoc.201403469

The diastereoselectivity of the Pictet-Spengler cyclization of bicyclic N-acyliminium ions that contain a 3-azabicyclo-[n.3.0]alkane core and an electron-rich ?-nucleophilic moiety, such as an indol-2-yl, indol-3-yl, 1-methylpyrrol-2-yl, or 3,5-dimethoxyphenyl group, was examined. The N-acyliminium ions were generated by protonation of the corresponding enamides or hemiaminals, which were derived from imides. Control of the quaternary stereocenter created at the newly formed ring junction was achieved in a diastereodivergent manner by fine-tuning the reaction conditions, which determined whether the reaction proceeded under kinetic or thermodynamic control. Mechanistic studies indicated that a retro-Pictet-Spengler reaction pathway is involved in the equilibration process.

Full text of DOI:10.1002/ejoc.201403469

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FULL PAPER
DOI: 10.1002/ejoc.201403469
Diastereodivergent Pictet–Spengler Cyclization of Bicyclic N-Acyliminium
Ions: Controlling a Quaternary Stereocenter
[
a]
[a]
[b]
Benoît de Carné-Carnavalet, Jean-Philippe Krieger, Benoît Folléas,
[b]
[b]
[a]
[a]
Jean-Louis Brayer, Jean-Pierre Demoute, Christophe Meyer,* and Janine Cossy*
Keywords: Synthetic methods / Polycycles / Cyclization / Diastereoselectivity / Kinetic control / Thermodynamic control
The diastereoselectivity of the Pictet–Spengler cyclization of
bicyclic N-acyliminium ions that contain a 3-azabicyclo-
from imides. Control of the quaternary stereocenter created
at the newly formed ring junction was achieved in a dia-
stereodivergent manner by fine-tuning the reaction condi-
tions, which determined whether the reaction proceeded
[
n.3.0]alkane core and an electron-rich π-nucleophilic
moiety, such as an indol-2-yl, indol-3-yl, 1-methylpyrrol-2-yl,
or 3,5-dimethoxyphenyl group, was examined. The N-acyl- under kinetic or thermodynamic control. Mechanistic studies
iminium ions were generated by protonation of the corre-
sponding enamides or hemiaminals, which were derived
indicated that a retro-Pictet–Spengler reaction pathway is in-
volved in the equilibration process.
Introduction
stereomer C is preferentially formed under kinetic control
and that a thermodynamically controlled epimerization to
The intramolecular reaction between an electron-rich
heteroaromatic or aromatic group and an iminium ion
species, known as the Pictet–Spengler cyclization, is a
[5]
give the more stable trans diastereomer CЈ can occur.
Mechanistic studies have shown this equilibration process
to proceed by ionization of the C-1–N bond under acidic
conditions, which leads to carbocationic intermediate D
and a ring closure, rather than by a retro-Pictet–Spengler
powerful method for the biomimetic synthesis of bioactive
isoquinoline and indole alkaloids.[
1,2]
The control of the
configuration of the new stereocenter that is formed during
[5q]
process (Scheme 1).
the course of a Pictet–Spengler cyclization has been the
focus of numerous investigations.[
1–8]
In the last decade,
these research efforts have culminated in the development
of catalytic enantioselective reactions by using chiral thio-
[
3]
[4]
ureas or Brønsted acids, but the control of the newly
formed asymmetric carbon often relies on diastereoselective
[
1,2]
reactions.
One of the classical versions of the Pictet–
Spengler reaction arguably involves the condensation of N-
substituted tryptophan ester A with an aldehyde in the pres-
ence of an acid catalyst. The subsequent cyclization of the
resulting iminium ion B provides tetrahydro-β-carbolines C
and CЈ with stereocenters at C-1 and C-3.[ The diastereo-
selectivity of this reaction, which depends on the substitu-
ents of the ester group, the nitrogen atom, and the aldehyde
as well as on the experimental conditions, has been widely
1]
[
5]
investigated. It is now well established that cis dia-
Scheme 1. Classical version of the Pictet–Spengler cyclization to
lead to tetrahydro-β-carbolines C and CЈ by starting from trypto-
phan ester A.
[
a] Laboratory of Organic Chemistry, Institute of Chemistry,
Biology and Innovation (CBI), ESPCI ParisTech,
CNRS UMR8231, PSL Research University,
The Pictet–Spengler cyclization, which generally pro-
ceeds under mild conditions, involves π-nucleophiles and
N-acyliminium ions, which are more electrophilic than
1
0 Rue Vauquelin, 75231 Paris Cedex 05, France
E-mail: christophe.meyer@espci.fr
janine.cossy@espci.fr
http://www.lco.espci.fr/
b] Diverchim,
[
2]
[
iminium ions. Substituted N-acyliminium ions E, with
6
Rue du Noyer, ZAC du Moulin, 95700 Roissy-en-France,
stereocenters contained within the structure, can be
France
[
2]
generated from a wide variety of precursors, and in recent
years, elegant organocatalyzed processes have been devel-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403469.
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C. Meyer, J. Cossy et al.
FULL PAPER
oped.[6,7] The configuration of the newly formed stereocen- diastereoselectivity that was observed in the Pictet–Spengler
ter at the ring junction of resulting heterocycle F is then cyclization corresponded to the kinetically controlled ad-
produced by a diastereoselective Pictet–Spengler cyclization dition of the 3,4-dimethoxyphenyl group to the less-
(Scheme 2).
hindered face (opposite to the cyclopropane) of the bicyclic
[
9]
N-acyliminium ion J. It is worth noting that tetracyclic
compound K is configurationally stable even upon pro-
longed heating in the presence of MsOH (Ms = methylsulf-
[
12]
onyl) in toluene at reflux (Scheme 3).
In contrast, we observed that enamide 1, derived from
tryptamine, exhibited a different behavior. Indeed, under
the previously developed conditions (MsOH, CH Cl ,
Scheme 2. Pictet–Spengler cyclization that involves π-nucleophiles
and substituted N-acyliminium ions.
2
2
5
0 °C, 4 h), the Pictet–Spengler cyclization of 1 proceeded
through N-acyliminum ion intermediate 2 to generate a
A few examples of the acid-promoted epimerization of mixture of epimeric nitrogen heterocycles 3 and 3Ј in a
[
9]
the stereocenter of nitrogen heterocycle F, which resulted 40:60 ratio (84% yield). Because of the higher nucleo-
from a Pictet–Spengler cyclization of an indole and an N- philic character of indole compared to the 3,4-dimeth-
acyliminium ion, have been reported.[ Additionally, oxyphenyl group, the Pictet–Spengler cyclization of 1 could
diastereodivergent Pictet–Spengler reactions that control be carried out at room temperature. Under these milder
the resulting tertiary stereocenter and involve electron-rich conditions, the reaction produced tetracyclic compound 3
π-nucleophiles, such as indoles, furans, and 3,5-dimeth- (84% yield) as a single diastereomer (3/3Ј Ͼ 96:4) as a result
oxyphenyl groups, have also been observed to depend on of the kinetically controlled nucleophilic attack of the C-2
the reaction conditions (kinetic vs. thermodynamic con- indole atom on the less-hindered face of N-acyliminium ion
8]
[
7]
trol). Recently, we reported a new access to bicyclic en- 2. In contrast, harsher conditions (MsOH, toluene, 120 °C,
amides I, which contain a 4-methylene-3-azabicyclo[3.1.0]- 1 h) resulted in the highly diastereoselective formation of
hexan-2-one core, by employing a two-step procedure that tetracyclic compound 3Ј (86% yield), which is an epimer of
started from cis-2-iodocyclopropanecarboxamides G, de- 3 at the newly formed quaternary stereocenter at the ring
rived from homoveratrylamine.[ The sequence relied on a junction (3Ј/3, Ͼ96:4).
9]
[13]
In this latter case, the observed
copper-free Sonogashira cross-coupling[ reaction between diastereoselectivity was explained by a thermodynamically
iodocyclopropane G and terminal aryl alkynes, heteroaryl controlled epimerization of the initially formed kinetic
alkynes, or conjugated enynes [PdCl (MeCN) (3 mol-%), product, diastereomer 3. Indeed, this result was confirmed
10]
2
2
X-Phos (2-dicyclohexylphosphino-2Ј,4Ј,6Ј-triisopropylbi- by subjecting nitrogen heterocycle 3 to prolonged heating in
[
11]
phenyl, 9 mol-%), Cs CO (2.5 equiv.), toluene, 100 °C]
the presence of MsOH (CH
Cl , 50 °C, 18 h). Under these
2 2
2
3
to lead to cis-2-alkynylcyclopropanecarboxamide H, which conditions, the thermodynamic product, epimer 3Ј, was ob-
[
9]
was not purified but directly subjected to a 5-exo-dig cycli- tained in nearly quantitative yield (Scheme 4).
zation (Cs CO , MeCN, 100–200 °C, sealed vial). The N- Herein, we report new examples of the diastereo-
2
3
acyliminium ion J, which was generated by protonation of divergent Pictet–Spengler cyclization of bicyclic N-acyl-
enamide I (MsOH, CH Cl , 50 °C, sealed vial), underwent iminum ion L, which leads to epimeric nitrogen heterocycles
2
2
a highly diastereoselective Pictet–Spengler cyclization to M or MЈ with a quaternary stereocenter at the newly
afford tetracyclic nitrogen heterocycle K. As anticipated, the formed ring junction. These processes can occur with high
Scheme 3. Pictet–Spengler cyclization of bicyclic N-acyliminium ion J to lead to nitrogen heterocycle K that contains a quaternary center.
2
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Diastereodivergent Pictet–Spengler Cyclization
Scheme 6. Diastereodivergent Pictet–Spengler cyclization of en-
amide 4.
The Pictet–Spengler cyclization of enamide 6, which
contains a remote 2-thienyl group as the π-nucleophile,
delivered the same tetracyclic compound 7 as a single dia-
stereomer irrespective of the reaction conditions (MsOH,
Scheme 4. Diastereodivergent Pictet–Spengler cyclization of en-
amide 1, which is derived from tryptamine.
[9]
CH Cl , 50 °C or MsOH, toluene 120 °C; Scheme 7). In
2
2
levels of diastereoselectivity for a variety of substrates, and contrast, the structurally related enamide 8, which contains
the configuration of the quaternary stereocenter can be a 1-methylpyrrol-2-yl group, displayed different behavior.
controlled by fine-tuning the reaction conditions, which de- Because the nucleophilic character of 1-methylpyrrole is
[
14]
termine whether the reaction proceeds under kinetic or greater than thiophene,
the Pictet–Spengler cyclization
thermodynamic control. Additionally, we provide evidence occurred at room temperature to afford tetracyclic com-
that a retro-Pictet–Spengler reaction is involved in the pound 9 as a single diastereomer (80% yield). Although
equilibration process of M into MЈ (Scheme 5).
heating this reaction mixture in CH
alter the stereochemical outcome, harsher conditions
MsOH, toluene, 120 °C, 7 h) induced a complete reversal
of diastereoselectivity to give epimer 9Ј selectively (9Ј/9 Ͼ
Cl at reflux did not
2 2
(
[
13]
9
6:4). However, compound 9Ј was only isolated in mod-
erate yield (53%) because of the sensitivity of the pyrrole
ring under acidic conditions, which resulted in partial de-
composition (Scheme 7).
Scheme 5. This work involves the diastereodivergent Pictet–
Spengler cyclization of bicyclic N-acyliminium ion L and the con-
trol a the newly formed quaternary stereocenter at the ring junc-
tion.
Results and Discussion
The possibility of achieving a diastereodivergent Pictet–
Spengler cyclization was first explored by using other 4-
benzylidene-3-azabicyclo[3.1.0]hexan-2-ones that contain
different remote electron-rich π-nucleophilic heteroaromatic
groups. Thus, enamide 4, which is derived from 2-(indol-2-
yl)ethylamine, underwent a highly diastereoselective kinet-
ically controlled cyclization in the presence of MsOH
(
CH Cl , r.t.), which involved the C-3 nucleophilic position
2 2
of the indole to produce compound 5 as a single detectable
diastereomer (84% yield). Under harsher conditions
(MsOH, toluene, 120 °C), a reversal of diastereoselectivity
took place, and epimer 5Ј was selectively obtained (82%
[
13]
yield) with high diastereocontrol (5Ј/5 Ͼ 96:4; Scheme 6).
Scheme 7. Pictet–Spengler cyclization of enamides 6 and 8.
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FULL PAPER
We previously observed that in the Pictet–Spengler cycli- leads to the accumulation of the thermodynamic product
zation of N-acyliminium ion J, derived from homoveratryl- 11Ј. The second mechanism (Scheme 9, Mechanism B) in-
amine, the 3,4-dimethoxyphenyl group acts as the π-nucleo- volves the initial cleavage of the benzylic carbon–nitrogen
phile to provide nitrogen heterocycle K with a high level bond, which is assisted by protonation of the amide moiety,
of diastereoselectivity. No equilibration took place under to generate benzylic carbocation intermediate 14. A subse-
harsher conditions (Scheme 3). In contrast, a diastereodiv- quent transannular ring closure explains the formation of
ergent cyclization was achieved for enamide 10, which con- the thermodynamic product, epimer 11Ј. It is worth
tains a 3,5-dimethoxyphenyl substituent. This latter aro- pointing out that the location of the two methoxy groups
matic group is much more reactive than the 3,4-dimeth- on the aromatic ring of 11 could significantly contribute to
oxyphenyl group, and the Pictet–Spengler cyclization was the stabilization of either arenium intermediate 12 or benz-
achieved under standard conditions at room temperature to ylic cation 14, which are the key intermediates in the two
provide tetracyclic nitrogen heterocycle 11 (87% yield) as a different mechanisms (Scheme 9). This could explain why
single detectable diastereomer. Heating this reaction at the equilibration reaction does not take place in the case
50 °C did not alter the stereochemical outcome, and the of tetracyclic nitrogen heterocycles K, which arise from the
kinetic product, epimer 11, was still selectively obtained Pictet–Spengler cyclization with a 3,4-dimethoxyphenyl
(88% yield; 11/11Ј Ͼ 96:4). However, harsher conditions group as the π-nucleophile.
(MsOH, toluene, 120 °C) led to the thermodynamic prod-
uct, epimer 11Ј (89% yield), with complete diastereocontrol
[
13]
(Scheme 8).
Scheme 8. Diastereodivergent Pictet–Spengler cyclization of en-
amide 10.
The different behaviors of the substrates, which depend
on the nature of the π-nucleophile (the 2-thienyl and 3,4-
dimethoxyphenyl groups vs. the indol-2-yl, indol-3-yl, 1-
methylpyrrol-2-yl, and 3,5-dimethoxyphenyl groups), have
already been noted by Franzén et al.[ in their organo-
catalyzed asymmetric sequence toward substituted quinol-
Scheme 9. Possible mechanisms for the equilibration reaction of 11
to give 11Ј.
7]
To shed light on the mechanism for the equilibration, we
izidines. Their work features a diastereoselective Pictet– first envisaged trapping one of the possible cationic inter-
Spengler cyclization, which controls the formation of a ter- mediate species, either N-acyliminium species 13 or benzylic
tiary stereocenter in the final step. In contrast to the classi- cation 14, with an external nucleophile. However, when
cal Pictet–Spengler cyclization of iminium ions that are gen- compound 11 was heated in the presence of MsOH and a
[
5]
erated from tryptophan esters and aldehydes (Scheme 1),
large excess amount of triethylsilane, epimer 11Ј, the
little information is available on the observed equilibration thermodynamic product, was isolated in nearly quantitative
mechanism in the case of reactions that involve N-acylimi- yield (Scheme 10). Products that would have resulted from
[
15]
nium ion intermediates and various π-nucleophiles.
As the intermolecular reaction of either 13 or 14 with trieth-
illustrated in the case of compound 11, two mechanisms ylsilane were not detected, presumably because of the much
can be proposed to explain the observed equilibration reac- faster cyclization process (intramolecular reaction) taking
tion that provides the thermodynamic product, epimer 11Ј. place by either one of the two possible mechanisms.[
16]
The first mechanism (Scheme 9, Mechanism A) involves a
To distinguish between both mechanisms (Scheme 9,
retro-Pictet–Spengler reaction, which is initiated by the pro- Mechanisms A and B), which involve the cleavage of a dif-
tonation of the aromatic ring to generate arenium interme- ferent bond, the less-hindered phenolic ether of epimer 11
diate 12. The subsequent fragmentation (by C–C bond scis- was selectively demethylated (BBr , CH Cl , 0 °C to r.t.).
3
2
2
sion) produces N-acyliminium ion 13, and the nucleophilic The resulting phenol was then alkylated by treatment with
attack on the more sterically hindered face of 13 eventually ethyl iodide [Cs CO , dimethyl sulfoxide (DMSO), r.t.] to
2
3
4
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Diastereodivergent Pictet–Spengler Cyclization
cursors to the corresponding N-acyliminium ions under
[
2]
acidic conditions. The behavior of the bicyclic iminium
ions that contained a bicyclo[3.2.0]heptane core and were
generated from hemiaminals 18–20 was first investigated
(Table 1).
Scheme 10. Equilibration of 11 into 11Ј in the presence of triethyl-
silane.
Table 1. Diastereodivergent Pictet–Spengler cyclizations of N-acyl-
iminium ions that contain a bicyclo[3.2.0]heptane core.
obtain ethyl ether 15 (75% yield over two steps from 11).
The same sequence was applied to epimer 11Ј, which pro-
vided epimeric tetracyclic compound 15Ј (74%, over two
steps from 11Ј). Interestingly, the treatment of 15 with
MsOH in toluene (120 °C, 2.5 h) effectively gave rise to
epimer 15Ј, the thermodynamic product. However, this
latter product was accompanied by a regioisomeric com-
pound, the structure of which was assigned to 16Ј (15Ј/16Ј
=
50:50, 90% yield). The formation of compound 16Ј from
tetracyclic nitrogen heterocycle 15 implies the scission of a
[
17]
carbon-carbon bond and not the carbon-nitrogen bond.
Thus, compound 16Ј must arise from a retro-Pictet–Speng-
ler reaction that proceeds through N-acyliminium interme-
diate 17 (Scheme 11). This result unambiguously demon-
strates that a retro-Pictet–Spengler pathway (Scheme 9,
Mechanism A) is operating in the equilibration of 11 into
11Ј, although the possibility of an alternative mechanistic
scenario that involves the cleavage of the benzylic C–N
bond (Scheme 9, Mechanism B) cannot be completely ex-
cluded.
[
a] Hemiaminals 18–20 were obtained as single diastereomers, but
their relative configurations were not assigned. [b] Condition A:
MsOH (1.1 equiv.), CH Cl , r.t.; Condition B: MsOH (1.1 equiv.),
toluene, 120 °C. [c] Isolated yields of analytically pure products.
2
2
[d] Yields for the two steps from the imide precursor.
The presence of the four-membered ring did not alter the
diastereodivergent cyclization or the high diastereoselectivi-
ties. Upon treatment with MsOH, hemiaminal 18, which is
derived from tryptamine, led to either pentacyclic com-
pound 21 (98% yield) or to epimer 21Ј (96% yield) with
high diastereoselectivities (dr Ͼ96:4), depending on the re-
action conditions (Table 1, Entries 1 and 2). The same be-
Scheme 11. Occurrence of a retro-Pictet–Spengler pathway in the
equilibration of 11 into 11Ј.
The next goal was to investigate the effect of the size of havior was observed for hemiaminal 19, which contains a
the ring fused to the pyrrolidinone structure on the stereo- 3,5-dimethoxyphenyl group and produced the epimeric
chemical outcome of the Pictet–Spengler cyclization and see tetracyclic compounds 22 (90% yield) or 22Ј (92% yield;
if a diastereodivergent reaction could also be observed. A Table 1, Entries 3 and 4). Interestingly, hemiaminal 20,
more conventional route, which relied on the nucleophilic which contains a phenyl substituent instead of a benzyl
addition of Grignard reagents to bicyclic imides,[
18,19]
was group, also participated in the diastereodivergent Pictet–
followed to prepare bicyclic hemiaminals, which were pre- Spengler cyclization to produce epimeric tetracyclic com-
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C. Meyer, J. Cossy et al.
FULL PAPER
pounds 23 (87% yield) and 23Ј (77% yield; Table 1, En-
tries 5 and 6).
It is interesting to note that the isomerization of the
kinetic products 22 and 23 into 22Ј and 23Ј, respectively,
proceeded at comparable rates.[ Thus, the presence of the
phenyl group at the quaternary center of 23 did not acceler-
ate the equilibration process, thereby suggesting that the
formation of a carbocation at the position adjacent to this
phenyl group may not be involved as the rate-determining
step.
20]
The behavior of hemiaminal 24 with an allyl substituent
deserves specific comments. In the presence of MsOH
Scheme 13. Brønsted and Lewis acid promoted Pictet–Spengler
cyclization of hemiaminal 24.
(
CH Cl , 50 °C), a 75:25 mixture of the epimers 25 and 25Ј
2 2
was formed, from which the kinetic product, diastereomer
2
5, could be separated and isolated in 30% yield. Both Table 2. Pictet–Spengler cyclization of the N-acyliminium ion that
stereoisomers 25 and 25Ј were substituted by an (E)-prop-
is generated from hemiaminal 27.
1-en-1-yl substituent at the quaternary stereocenter, as a re-
sult of isomerization of the terminal olefin of the allyl
group. Under more forcing conditions, decomposition took
place to a significant extent, and the thermodynamic prod-
uct, diastereomer 25Ј, was isolated in a very low yield (10%
yield; Scheme 12).
Entry Temp. [°C] Solvent
Time [h] 28/28Ј[a] Yield [%][b]
1
2
3
4
20
CH
CH
toluene
toluene
2
Cl
Cl
2
2
1
6
6
50:50
53:47
10:90
10:90
93
98
94
90
–40
120
120
2
30
[
a] Determined by 1H NMR spectroscopic analysis of the crude
product. [b] Isolated yield of the mixture of diastereomers 28 and
8Ј.
2
tion provided an equimolar mixture of pentacyclic com-
pounds 28 and 28Ј, which are epimeric at the quaternary
stereocenter (93% yield; Table 2, Entry 1). Decreasing the
reaction temperature to –40 °C did not improve the kinet-
ically controlled diastereoselectivity of the Pictet–Spengler
reaction (28/28Ј = 53:47; Table 2, Entry 2). This low dia-
Scheme 12. Brønsted acid promoted Pictet–Spengler cyclization of
hemiaminal 24.
In the case of hemiaminal 24, lowering the temperature stereoselectivity is probably because of the greater confor-
(
MsOH, CH Cl , –40 °C, 6 h) avoided isomerization of the mational flexibility of the six-membered ring in comparison
2
2
terminal olefin, and compound 26 with its quaternary to a three- or four-membered ring, which results in the in-
stereocenter substituted by an allyl group was isolated in effective discrimination between the two diastereofaces of
74% yield with no trace amounts of the regioisomeric com- the corresponding N-acyliminium ion. When the reaction
pound 25. An alternative option relied on the use a Lewis was carried out in toluene at 120 °C for 6 h, a much im-
acid promoter. When the cyclization of 24 was carried out proved level of diastereoselectivity was attained in favor of
in the presence of BF ·OEt (CH Cl , 0 °C, 4 h), compound the thermodynamically produced epimer 28Ј (94% yield;
3
2
2
2
26 was again isolated in a similar yield of 77%. Interest- 28/28Ј = 10:90; Table 2, Entry 3). This ratio, which was
ingly, access to the epimer of 26 could be achieved by per- reached under thermodynamic control, did not change
forming the reaction in the presence of BF ·OEt in 1,2- when the reaction time was extended (Table 2, Entry 4).
3
2
dichloroethane at 90 °C. Compound 26Ј, in which the qua-
Finally, the reactivity of hemiaminal 29 with the pyrrol-
ternary stereocenter is substituted by an allyl group, was idinone ring fused to a norbornene unit, was studied.[
isolated under these conditions in an excellent 90% yield This sterically hindered and conformationally locked bi-
without any concurrent formation of isomerized product cyclic ring system underwent a highly diastereoselective
18,19]
25Ј (Scheme 13).
Pictet–Spengler cyclization under kinetic control (MsOH,
The behavior of bicyclic N-acyliminium ions that contain CH Cl , r.t.) to deliver compound 30 in an excellent 94%
2
2
a six-membered ring fused to the pyrrolidinone unit was yield. Different conditions were then screened to achieve
then investigated (Table 2). the diastereodivergent Pictet–Spengler cyclization of 29.
When bicyclic hemiaminal 27 was treated with MsOH in The best results were obtained by prolonged heating in 1,2-
CH Cl at room temperature, the Pictet–Spengler cycliza- dichloroethane at 70 °C. Under these conditions, epimer 30Ј
2
2
6
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Diastereodivergent Pictet–Spengler Cyclization
was produced with high diastereoselectivity (30/30Ј Ͼ 96:4) diastereoselectivity have been obtained for bicyclic N-acyl-
in 82% isolated yield (Scheme 14).
iminium species that have a pyrrolidinone moiety fused to
a three-membered ring, a four-membered ring, or a nor-
bornene ring system by simply fine-tuning the reaction con-
ditions to proceed under kinetic or thermodynamic control.
Mechanistic studies indicated that a retro-Pictet–Spengler
reaction pathway is operating in the equilibration process
to give the thermodynamic product.
Experimental Section
General Methods: Infrared (IR) spectra were recorded on a Bruker
TENSOR 27 (IR-FT) with attenuated total reflectance (ATR). The
NMR spectroscopic data were recorded with a Bruker AVANCE
1
4
00. The H NMR spectra were recorded at 400 MHz, and the data
are reported in the order of chemical shift in ppm from tetramethyl-
silane, multiplicity, and integration. The C NMR spectra were
recorded at 100 MHz, and the data are reported in the order of
Scheme 14. Pictet–Spengler cyclization of the N-acyliminium ion
that is generated from hemiaminal 29.
1
3
Interestingly, byproduct 31 was also detected in the latter chemical shift in ppm from tetramethylsilane with the deuterated
solvent signal used for calibration [for CDCl
3
, δ = 77.0 ppm, for
reaction (Ͻ10%). Compound 31 formally originated from
an intramolecular ene reaction[ between one allylic C–H
21]
[D ]DMSO, δ = 39.5 ppm, for [D ]acetone, δ (C=O) = 206.2 ppm],
6
6
multiplicity with respect to the number of protons (deduced from
DEPT experiments, s = quaternary C, d = CH, t = CH , q = CH ).
Mass spectrometry was performed by electron impact (EI) ioniza-
tion. The mass spectra were recorded with a Shimadzu GC–MS-
QP2010S gas chromatography–mass spectrometer. High resolution
mass spectra were obtained by electrospray ionization (ESI) with
bond (ene component) of the indole moiety and the C=C
bond of the norbornene (the enophile).[22] Upon prolonged
2
3
heating in toluene (120 °C, 22 h), compound 31 was formed
at the expense of 30Ј, but it was isolated in a low 32% yield
because of partial decomposition. A control experiment re-
vealed that compound 30Ј was unaffected by heating in tol- an orbitrap mass analyzer. Purification by flash chromatography
uene at 120 °C, but the addition of MsOH effectively led to was performed on silica gel (230–400 mesh).
3
1 (40% yield). Thus, formation of compound 31 can be
explained by the reversible protonation of the norbornene
double bond, thereby triggering the nucleophilic attack of acid (14 μL, 0.22 mmol, 1.1 equiv.) was added to a solution of en-
2S*,3S*,5R*)-2-Benzyl-7,11-diazapentacyclo[8.7.0.02,7.03,5.012,17]-
heptadeca-1(10),12(17),13,15-tetraen-6-one (5): Methanesulfonic
(
the indole followed by the loss of a proton (Scheme 15).
2 2
amide 4 (65.0 mg, 0.198 mmol) in CH Cl (1.5 mL) in an oven-
dried resealable vial. The vial was sealed (Teflon cap), and the reac-
tion mixture was stirred at r.t. for 1 h. The vial was then opened,
and a saturated aqueous solution of NaHCO
sulting mixture was extracted with CH Cl . The organic extract
was dried with MgSO , filtered, and concentrated under reduced
3
was added. The re-
2
2
4
1
pressure. Analysis of the residue by H NMR spectroscopy indi-
cated the formation of 5 as a single detectable diastereomer (dr
Ͼ96:4). Purification by flash chromatography on silica gel (petro-
leum ether/EtOAc, from 40:60 to 30:70) gave compound 5
(
54.9 mg, 84% yield) as a yellow solid; m.p. 262 °C (decomposi-
tion). IR (ATR): ν˜ = 3246, 1677, 1618, 1456, 1445, 1396, 1104, 979,
–
1 1
8
=
7
74, 836, 751, 697, 655, 602 cm . H NMR (400 MHz, CDCl
8.12 (br. s, 1 H, NH), 7.27 (d, J = 8.1 Hz, 1 H), 7.21 (m, 1 H),
.14 (br. t, J = 7.6 Hz, 2 H), 7.07 (t, J = 7.5 Hz, 1 H), 7.01 (d, J =
3
): δ
Scheme 15. Formation of compound 31 by a formal intramolecular
ene reaction.
7.8 Hz, 2 H), 6.86 (t, J = 7.9 Hz, 1 H), 6.66 (d, J = 8.0 Hz, 1 H),
4.18 (dd, J = 13.4, 6.8 Hz, 1 H), 3.39 (d, J = 13.0 Hz, 1 H, AB
syst), 3.21 (d, J = 13.1 Hz, 1 H, AB syst), 3.06 (ddd, J = 16.1, 11.4,
6
6
.8 Hz, 1 H), 2.91 (ddd, J = 13.2, 11.6, 5.0 Hz, 1 H), 2.54 (td, J =
.8, 5.0 Hz, 1 H), 2.46 (dd, J = 16.0, 5.0 Hz, 1 H), 1.83 (ddd, J =
13
Conclusions
8.4, 6.4, 3.2 Hz, 1 H), 1.20 (m, 1 H), 1.07 (m, 1 H) ppm. C NMR
100 MHz, CDCl ): δ = 177.8 (s), 136.8 (s), 135.4 (s), 132.2 (s),
30.7 (d, 2 C), 128.1 (d, 2 C), 126.7 (d), 124.8 (s), 121.2 (d), 119.4
(
1
3
We have demonstrated that substituted bicyclic N-acyl-
iminium ions that contain a pyrrolidinone core, in which
the nitrogen atom is connected to an appropriately located
(
d), 119.0 (d), 113.5 (s), 110.8 (d), 64.2 (s), 44.9 (t), 34.6 (t), 24.3
(
d), 22.1 (t), 20.8 (d), 12.3 (t) ppm. MS (EI, 70 eV): m/z (%) = 238
remote π-nucleophile such as an indol-2-yl, indol-3-yl, 1- (17), 237 (100), 235 (4), 207 (4), 180 (5), 168 (4), 167 (6), 144 (9),
methyl-pyrrol-2-yl, or 3,5-dimethoxyphenyl group, can un- 143 (4), 115 (4), 91 (18), 65 (9). HRMS (ESI): calcd. for
22 20 2
C H N
ONa [M + Na]+ 351.14678; found 351.14706.
dergo a diastereodivergent Pictet–Spengler cyclization to af-
ford polycyclic nitrogen heterocycles with control of the (2R*,3S*,5R*)-2-Benzyl-7,11-diazapentacyclo[8.7.0.02,7.03,5.012,17]-
quaternary stereocenter at the ring junction. High levels of heptadeca-1(10),12(17),13,15-tetraen-6-one (5Ј): Methanesulfonic
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O43469
/KAP1
Date: 07-01-15 18:17:12
Pages: 11
C. Meyer, J. Cossy et al.
FULL PAPER
acid (14 μL, 0.22 mmol, 1.1 equiv.) was added to a solution of en-
amide 4 (65.0 mg, 0.198 mmol) in toluene (1.5 mL) in an oven-
dried resealable vial. The vial was sealed (Teflon cap) and immersed
in a preheated oil bath at 120 °C. After 3 h, the vial was opened,
3 H), 3.80 (s, 3 H), 3.33 (d, J = 13.7 Hz, 1 H, AB syst), 3.25 (d, J
= 13.7 Hz, 1 H, AB syst), 2.99 (m, 1 H), 2.71 (ddd, J = 16.3, 12.1,
6.9 Hz, 1 H), 2.59 (ddd, apparent dd, J = 16.3, 3.9 Hz, 1 H), 2.37
(ddd, J = 7.7, 5.8, 4.3 Hz, 1 H), 1.40 (ddd, J = 8.3, 5.8, 3.3 Hz, 1
H), 0.71 (ddd, apparent td, J = 8.0, 4.7 Hz, 1 H), 0.06 (ddd, appar-
and a saturated aqueous solution of NaHCO
sulting mixture was extracted with CH Cl . The organic extract
was dried with MgSO , filtered, and concentrated under reduced
3
was added. The re-
1
3
2
2
3
ent td, J = 4.3, 3.7 Hz, 1 H) ppm. C NMR (100 MHz, CDCl ):
4
δ = 173.9 (s), 159.2 (s), 157.2 (s), 136.7 (s), 136.1 (s), 130.3 (d, 2
C), 127.9 (d, 2 C), 126.5 (d), 121.1 (s), 104.5 (d), 97.7 (d), 63.9 (s),
55.5 (q), 55.2 (q), 43.1 (t), 33.7 (t), 29.5 (t), 22.3 (d), 20.5 (d), 9.9
(t) ppm. MS (EI, 70 eV): m/z (%) = 259 (22), 258 (100), 243 (7),
200 (10), 115 (5), 92 (6), 91 (42), 89 (5), 77 (4), 65 (24), 63 (4), 55
1
pressure. Analysis of the residue by H NMR spectroscopy indi-
cated the formation of 5Ј as a single detectable diastereomer (dr
Ͼ96:4). Purification by flash chromatography on silica gel (petro-
leum ether/EtOAc, from 40:60 to 30:70) gave compound 5Ј
(53.6 mg, 82% yield) as a yellow solid; m.p. 202 °C. IR (ATR): ν˜
(4). HRMS (ESI): calcd. for C22
found 372.15737.
H23NO
3
Na [M + Na]+ 372.15701;
=
3253, 1659, 1453, 1419, 1327, 1265, 1216, 1017, 938, 875, 815,
–1 1
7
34, 701, 640 cm . H NMR (400 MHz, CDCl
H), 7.63 (br. d, J = 7.6 Hz, 1 H), 7.35 (m, 1 H), 7.22–7.14 (m, 5
H), 7.08–7.05 (m, 2 H), 4.29 (dd, J = 13.1, 5.9 Hz, 1 H), 3.43 (d, J [8.5.0.0 .0
13.8 Hz, 1 H, AB syst), 3.29 (d, J = 13.8 Hz, 1 H, AB syst), 2.89 phenylmagnesium chloride (1 m in Et
3
): δ = 8.48 (br. s, 1
(1R*,12R*,15S*)-3,5-Dimethoxy-1-phenyl-10-azatetracyclo-
2
,7 12,15
]pentadeca-2(7),3,5-trien-11-one (23): A solution of
O, 0.28 mL, 0.28 mmol,
=
2
(
m, 1 H), 2.70 (ddd, J = 16.0, 11.4, 6.5 Hz, 1 H), 2.54 (ddd, appar-
2 equiv.) was added to a solution of (1R*,5S*)-3-[2-(3,5-dimeth-
oxyphenyl)ethyl]-3-azabicyclo[3.2.0]heptane-2,4-dione[ (40.0 mg,
0.138 mmol) in tetrahydrofuran (THF, 2 mL) at –78 °C. The reac-
tion mixture was warmed to room temp., stirred for 0.5 h, and then
hydrolyzed by the addition of a saturated aqueous solution of
23]
ent dd, J = 16.0, 4.3 Hz, 1 H), 2.27 (ddd, J = 7.4, 5.9, 4.2 Hz, 1
H), 1.68 (ddd, J = 8.4, 5.9, 3.2 Hz, 1 H), 0.76 (ddd, J = 8.4, 7.5,
5
(
.0 Hz, 1 H), 0.10 (ddd, J = 4.9, 4.3, 3.4 Hz, 1 H) ppm. 1 C NMR
3
100 MHz, CDCl
3
): δ = 174.4 (s), 136.2 (s), 136.1 (s), 132.0 (s),
1
30.2 (d, 2 C), 128.1 (d, 2 C), 126.7 (d), 124.4 (s), 121.6 (d), 119.7
NH
the aqueous phase was extracted with Et
t), 22.3 (d), 21.3 (d), 10.5 (t) ppm. MS (EI, 70 eV): m/z (%) = 238 was dried with MgSO , filtered, and concentrated under reduced
4
Cl. After the addition of Et
2
O, the layers were separated, and
(
(
(
d), 118.5 (d), 112.9 (s), 111.2 (d), 63.6 (s), 45.9 (t), 34.3 (t), 22.8
2
O. The organic extract
4
17), 237 (100), 207 (4), 167 (4), 144 (8), 115 (4), 91 (16), 65 (8). pressure. Crude hemiaminal 20 was dissolved in CH
2
Cl
2
(1 mL),
+
HRMS (ESI): calcd. for C22
found 351.14715.
H
20
N
2
ONa [M + Na] 351.14678;
and MsOH (9.8 μL, 0.14 mmol, 1.1 equiv.) was added. The reaction
mixture was stirred at room temp. for 5 h. Workup and purification
by flash chromatography on silica gel (petroleum ether/EtOAc,
(
2S*,3S*,5R*)-2-Benzyl-12,14-dimethoxy-7-azatetracyclo-
50:50) afforded 23 (42.0 mg, 87% yield; dr Ͼ96:4) as a white solid;
8.4.0.02 .0 ]tetradeca-1(10),11,13-trien-6-one (11): The cycliza-
tion of enamide 10 (91.7 mg, 0.262 mmol) was carrried out in the
presence of MsOH (19 μL, 0.29 mmol, 1.1 equiv.) in CH Cl
2.0 mL) at either r.t. for 0.5 h or 50 °C for 4 h. Purification by
,7
3,5
[
m.p. 157 °C. IR (ATR): ν˜ = 1671, 1604, 1583, 1454, 1423, 1337,
–
1 1
1
212, 1195, 1145, 1106, 1055, 911, 884, 831, 728, 701, 644 cm . H
NMR (400 MHz, CDCl ): δ = 7.32–7.21 (m, 5 H), 6.45 (d, J =
.4 Hz, 1 H), 6.25 (d, J = 2.4 Hz, 1 H), 4.21–4.14 (m, 1 H), 3.95
ddd, apparent td, J = 8.6, 5.7 Hz, 1 H), 3.86 (s, 3 H), 3.78 (s, 3
H), 3.09–3.03 (m, 1 H), 3.02–2.93 (m, 2 H), 2.54–2.46 (m, 1 H),
2
2
3
(
2
(
flash chromatography on silica gel (petroleum ether/EtOAc, 50:50)
afforded 11 (79.9 mg, 87% yield; dr Ͼ96:4) as a pale yellow solid;
m.p. 49 °C. IR (ATR): ν˜ = 1687, 1603, 1583, 1454, 1380, 1338,
2
1
1
.38–2.28 (m, 1 H), 2.20–2.12 (m, 1 H), 2.05–1.95 (m, 1 H), 1.89–
–
1 1
1271, 1210, 1192, 1145, 1107, 1092, 1056, 827, 763, 700 cm . H
1
3
.81 (m, 1 H) ppm. C NMR (100 MHz, CDCl
3
): δ = 177.8 (s),
NMR (400 MHz, CDCl ): δ = 7.18–7.14 (m, 3 H), 6.98–6.90 (m, 2
3
59.5 (s), 157.3 (s), 140.8 (s), 137.3 (s), 128.0 (d, 2 C), 127.8 (d, 2
H), 6.39 (d, J = 2.4 Hz, 1 H), 6.20 (d, J = 2.4 Hz, 1 H), 3.93 (appar-
ent dd, J = 13.4, 6.8 Hz, 1 H), 3.84 (s, 3 H), 3.79 (s, 3 H), 3.56 (d,
J = 14.0 Hz, 1 H, AB syst), 3.21 (d, J = 14.0 Hz, 1 H, AB syst),
C), 127.1 (d), 122.4 (s), 105.7 (d), 97.7 (d), 70.8 (s), 55.3 (q, 2 C),
0.8 (d), 40.3 (d), 35.9 (t), 28.3 (t), 22.1 (t), 21.9 (t) ppm. HRMS
ESI): calcd. for C22
Na [M + Na]+ 372.15701; found
4
(
H23NO
3
3
4
.01 (ddd, J = 16.5, 12.4, 7.0 Hz, 1 H), 2.85 (ddd, J = 8.0, 6.2,
.4 Hz, 1 H), 2.70 (ddd, J = 13.2, 12.7, 4.6 Hz, 1 H), 2.34 (apparent
372.15709.
dd, J = 16.5, 4.4 Hz, 1 H), 1.71 (ddd, J = 8.9, 6.2, 3.1 Hz, 1 H),
.87 (ddd, apparent td, J = 8.2, 4.8 Hz, 1 H), 0.55 (ddd, apparent
(
1S*,12R*,15S*)-3,5-Dimethoxy-1-phenyl-10-azatetracyclo-
0
2,7 12,15
[8.5.0.0 .0
]pentadeca-2(7),3,5-trien-11-one (23Ј): This com-
13
td, J = 4.6, 3.2 Hz, 1 H) ppm. C NMR (100 MHz, CDCl
1
1
3
): δ =
77.7 (s), 159.4 (s), 157.3 (s), 137.9 (s), 137.5 (s), 130.4 (d, 2 C),
27.9 (d, 2 C), 126.3 (d), 120.5 (s), 105.2 (d), 97.4 (d), 64.4 (s), 55.2
pound was prepared by using (1R*,5S*)-3-[2-(3,5-dimeth-
oxyphenyl)ethyl]-3-azabicyclo[3.2.0]heptane-2,4-dione
0
2
temp.). Crude hemiaminal intermediate 20 underwent cyclization
in the presence of MsOH (9.8 μL, 0.15 mmol, 1.1 equiv.) in toluene
[23]
(40.0 mg,
O, 0.28 mL, 0.28 mmol,
equiv.) in THF (2.0 mL; –78 °C to room temp., 0.5 h at room
.138 mmol) and PhMgCl (1 m in Et
2
(
(
q), 55.1 (q), 43.0 (t), 34.7 (t), 28.1 (t), 23.4 (d), 19.5 (d), 11.7
t) ppm. MS (EI, 70 eV): m/z (%) = 259 (17), 258 (100), 243 (6),
2
00 (9), 115 (4), 91 (15), 89 (2), 77 (3), 65 (9), 55 (2). HRMS (ESI):
+
3
calcd. for C22H23NO Na [M + Na] 372.15701; found 372.15736.
(
1.0 mL) at 120 °C for 44 h. Purification by flash chromatography
(
[
2R*,3S*,5R*)-2-Benzyl-12,14-dimethoxy-7-azatetracyclo- (petroleum ether/EtOAc, 50:50) gave 23Ј (37.0 mg, 77% yield; dr
8.4.0.02 .0 ]tetradeca-1(10),11,13-trien-6-one (11Ј): The cycliza-
,7
3,5
Ͼ96:4) as a waxy white solid; m.p. 144 °C. IR (ATR): ν˜ = 1673,
tion of enamide 10 (90.2 mg, 0.258 mmol) was carried out in the
presence of MsOH (18 μL, 0.28 mmol, 1.1 equiv.) in toluene
1603, 1590, 1447, 1426, 1413, 1271, 1195, 1148, 1111, 1051, 933,
840, 817, 755, 698, 633 cm . H NMR (400 MHz, CDCl ): δ =
3
–
1 1
(
1.9 mL) at 120 °C for 6 h. Purification by flash chromatography
7.24–7.19 (m, 3 H), 6.99–6.97 (m, 2 H), 6.36–6.34 (m, 2 H), 4.17–
4.12 (m, 1 H), 3.82 (s, 3 H), 3.72 (dd, J = 14.5, 7.4 Hz, 1 H), 3.60
(s, 3 H), 3.42–3.37 (m, 1 H), 3.03 (m, 1 H), 2.77–2.70 (m, 2 H),
on silica gel (petroleum ether/EtOAc, 50:50) afforded 11Ј (80.6 mg,
8
1
8
7
9% yield; dr Ͼ96:4) as a white solid; m.p. 142 °C. IR (ATR): ν˜ =
1
3
678, 1603, 1591, 1455, 1413, 1273, 1208, 1152, 1106, 1054, 939,
2.38 (m, 1 H), 2.02–1.93 (m, 2 H), 1.71–1.61 (m, 1 H) ppm.
): δ = 174.9 (s), 159.5 (s), 157.6 (s), 145.1
.25–7.19 (m, 3 H), 7.10 (m, 2 H), 6.44 (d, J = 2.4 Hz, 1 H), 6.23 (s), 137.4 (s), 128.0 (d, 2 C), 127.1 (d), 126.0 (d, 2 C), 117.5 (s),
104.7 (d), 97.0 (d), 68.7 (s), 55.2 (q, 2 C), 44.2 (d), 42.8 (d), 34.0
C
–1 1
3 3
25, 761, 752, 703, 648 cm . H NMR (400 MHz, CDCl ): δ = NMR (100 MHz, CDCl
(
d, J = 2.4 Hz, 1 H), 4.17 (ddd, J = 13.3, 6.5, 1.1 Hz, 1 H), 3.94 (s,
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43469
/KAP1
Date: 07-01-15 18:17:12
Pages: 11
Diastereodivergent Pictet–Spengler Cyclization
t), 29.0 (t), 23.5 (t), 22.5 (t) ppm. HRMS (ESI): calcd. for
(
Czerwinski, J. M. Cook, Tetrahedron Lett. 1991, 32, 175–178;
e) K. M. Czerwinski, L. Deng, J. M. Cook, Tetrahedron Lett.
992, 33, 4721–4724; f) P. D. Bailey, S. P. Hollinshead, N. R.
+
22 3
C H23NO Na [M + Na] 372.15701; found 372.15712.
1
Supporting Information (see footnote on the first page of this arti-
cle): All experimental procedures including those involved in the
preparation of the substrates, detailed characterization data, and
NMR spectra of all new compounds.
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Smith, J. M. Vernon, Tetrahedron Lett. 1994, 35, 3587–3588; i)
E. D. Cox, L. K. Hamaker, J. Li, P. Yu, K. M. Czerwinski, L.
Deng, D. W. Bennett, J. M. Cook, W. H. Watson, M. Krawiec,
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A. Tolvanen, Heterocycles 1998, 48, 1275–1290; k) L. Alberch,
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Acknowledgments
One of the authors (B. de C.-C.) thanks Diverchim for a CIFRE
grant.
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2
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volve the 3,4-dimethoxyphenyl group as a π-nucleophile are
Eur. J. Org. Chem. 0000, 0–0
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C. Meyer, J. Cossy et al.
FULL PAPER
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13] The relative configurations of the epimeric quaternary ste-
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[
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ductive cleavage [Zn, trifluoroacetic acid (TFA)]. A mechanism
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[
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3
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17] The formation of 16Ј was also observed when the thermo-
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of 15Ј/16Ј was observed.
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[
Received: November 12, 2014
1998, 54, 12361–12378.
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43469
/KAP1
Date: 07-01-15 18:17:12
Pages: 11
Diastereodivergent Pictet–Spengler Cyclization
Diastereoselective Cyclizations
B. de Carné-Carnavalet, J.-P. Krieger,
B. Folléas, J.-L. Brayer, J.-P. Demoute,
C. Meyer,* J. Cossy* ...................... 1–11
Diastereodivergent Pictet–Spengler Cycliz-
ation of Bicyclic N-Acyliminium Ions:
Controlling a Quaternary Stereocenter
The diastereoselectivity of the Pictet–
Spengler cyclization of bicyclic N-acylimin-
ium ions that have a 3-azabicyclo[n.3.0]-
alkane core and an electron-rich π-nucleo-
philic moiety (indol-2-yl, indol-3-yl, 1-
methylpyrrol-2-yl, or 3,5-dimethoxyphenyl
group) was examined. Control of the new
quaternary stereocenter was achieved in a
diastereodivergent manner by fine-tuning
the reaction conditions.
Keywords: Synthetic methods / Polycycles /
Cyclization / Diastereoselectivity / Kinetic
control / Thermodynamic control
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