Enantioselective organocatalytic one-pot amination/aza-Michael/aldol condensation reaction sequence: Synthesis of 3-pyrrolines with a quaternary stereocenter

Article abstract of DOI:10.1002/chem.201202024

Primary amine-catalyzed direct conversion of α,α-disubstituted aldehydes into 3-pyrrolines with a quaternary stereocenter is reported. The one-pot enantioselective sequence is based on a α-amination, an aza-Michael addition of hydrazine, an aldol condensation dehydratation and proceeds with good yields and excellent levels of enantioselectivity. Synthetically attractive applications including the formation of aziridinopyrrolidine or epoxypyrrolidine derivatives with good yields and selectivities are also described. Expect the unexpected: Primary amine-catalyzed direct conversion of α,α-disubstituted aldehydes into 3-pyrrolines with a quaternary stereocenter is reported. The sequence involves an α-amination, an aza-Michael addition of hydrazine, an aldol condensation and proceeds with good yields and excellent levels of enantioselectivity (see scheme). Copyright

Full text of DOI:10.1002/chem.201202024

FULL PAPER
DOI: 10.1002/chem.201202024
Enantioselective Organocatalytic One-Pot Amination/aza-Michael/Aldol
Condensation Reaction Sequence: Synthesis of 3-Pyrrolines with a
Quaternary Stereocenter
Alaric Desmarchelier, Vincent Coeffard,* Xavier Moreau,* and Christine Greck[a]
Abstract: Primary amine-catalyzed direct conversion of a,a-disubstituted alde-
hydes into 3-pyrrolines with a quaternary stereocenter is reported. The one-pot
enantioselective sequence is based on a a-amination, an aza-Michael addition of
hydrazine, an aldol condensation dehydratation and proceeds with good yields and
excellent levels of enantioselectivity. Synthetically attractive applications including
the formation of aziridinopyrrolidine or epoxypyrrolidine derivatives with good
yields and selectivities are also described.
Keywords: hydrazine · one-pot re-
action · organocatalysis · pyrrolines ·
synthetic methods
Introduction
3-Pyrrolines, also called 2,5-dihydropyrroles, present an im-
portant class of heterocycles due to their presence in natural
and synthetic biologically active compounds.[1] These build-
ing blocks are also useful intermediates for direct access to
other significant five-membered nitrogen-containing hetero-
cycles, such as pyrrolidines and pyrroles. The synthetic value
of such units has stimulated the development of various syn-
theses.[2] However, one-pot enantioselective methods for the
Figure 1. Biologically active compounds containing 2,2-disubstituted-3-
pyrroline substructures.
construction of polysubstituted 3-pyrrolines are still limit-
ed.[3] To the best of our knowledge, no direct enantioselec-
tive syntheses of 3-pyrrolines with a quaternary stereocenter
have been reported in the literature.[4] However, these build-
ing blocks are not rare in bioactive molecules (Figure 1).
For example, Erythrina alkaloids exhibit a wide range of
pharmacological effects.[5] (+)-Lapidilectine B was found to
reverse multidrug resistance in vincristine resistant KB
cells[6] and KSP inhibitor developed by Merck[7] contain this
entity.
Scheme 1. Organocatalytic strategy for the synthesis of 2,2-disubstituted-
3-pyrrolines.
À
As part of our program to develop organocatalyzed C N
bond formation,[8] we report the first one-pot enantioselec-
tive synthesis of 2,2-disubstituted-3-pyrrolines through a
new organocatalytic one-pot sequence amination/aza-Mi-
chael/aldol condensation from readily available substrates
(Scheme 1).
Results and Discussion
We have recently reported an enantioselective a-amination
of a,a-disubstituted aldehydes.[8c] In connection with this
work, we became interested in the implementation of this
transformation into an organocatalytic sequence to synthe-
size nitrogen heterocycles. We reasoned that tert-butoxycar-
bonyl-protected hydrazine 1 (R1 =R2 =tBu) could react with
acrolein under an aza-Michael/aldol condensation by using
the same catalytic conditions as those previously described
for the a-amination, that is, 9-amino-(9-deoxy)-epi-quinine 2
(10 mol%) and TFA (30 mol%) in CHCl3 (0.5m).[9] Under
these reaction conditions, the unexpected formation of a
small amount of 3-pyrroline 3a was detected, whereas cyclic
[a] A. Desmarchelier, Dr. V. Coeffard, Dr. X. Moreau, Prof. C. Greck
Institut Lavoisier de Versailles,UMR CNRS 8180
Universitꢀ de Versailles Saint-Quentin-en-Yvelines
45, Avenue des Etats-unis, 78035 Versailles Cedex (France)
Fax : (+33)1-39-25-44-52
E-mail: vincent.coeffard@chimie.uvsq.fr
xavier.moreau@chimie.uvsq.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202024.
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Table 1. Optimization of the aza-Michael/aldol condensation sequence.
Entry R1
R2
TFA [mol%] Conversion [%][a] Yield [%][b]
1
2
3
4
5
6
tBu tBu
Bn Bn
iPr iPr
tBu tBu
tBu tBu
tBu tBu
tBu tBu
30
30
30
50
75
<5
no reaction
no reaction
30
65
100
100
100
<5
20[c]
37[d]
81
11
60
100
100
7[e]
8
tBu CH2CCl3 100
[a] Estimated by 1H NMR analysis of the crude product. [b] Yield of the
isolated product. [c] Starting material (50%) was recovered. [d] Starting
material (10%) was recovered. [e] Reaction was carried out without cata-
lyst.
hydrazine 5 was not observed (Table 1, entry 1). Considering
the usefulness of structure 3a and the lack of direct enantio-
selective access to these products, we decided to further in-
vestigate the organocatalyzed sequence. The essential depro-
tection of hydrazine 1 was confirmed by using stable carba-
mate-protecting groups under acidic conditions (Table 1, en-
tries 2 and 3).
Scheme 2. Scope of the one-pot enantioselective synthesis of 3-pyrrolines
(yield of the isolated product after purification by chromatography; the
ee value was determined by HPLC). a) Monoprotected aldehyde was iso-
lated (35%; see the Supporting Information for details); b) determined
by 1H NMR analysis of the crude product; c) absolute configuration has
not been determined.
When isopropyloxycarbonyl- or benzyloxycarbonyl- pro-
tected hydrazines were engaged in the sequence, no reaction
occurred, and the starting material was recovered. To pro-
mote the Boc cleavage, which seems to be required for the
aza-Michael step, the amount of TFA was gradually in-
creased (Table 1, entries 4–6). When the reaction was run in
more acidic conditions (50 or 75 mol% TFA), the expected
3-pyrroline 3a was obtained in better yields (20 and 37%,
respectively). The best conditions were found when
100 mol% TFA was used, giving 3a in 81% yield. To con-
firm the iminium activation of the acrolein by primary
amine 2, the reaction was run without a catalyst (Table 1,
entry 7). In this case, extensive decomposition was observed,
and 3a was isolated in 11% yield. Finally, an orthogonally
protected hydrazino aldehyde containing a Boc and a 2,2,2-
trichloroethoxycarbonyl (Troc) group was synthesized to
confirm the formation of the five-membered heterocycle in-
stead of the six-membered one. When this compound was
engaged in the sequence, 3-pyrroline 4 was obtained in 60%
yield (Table 1, entry 8).[10]
(DtBAD, 1 equiv) catalyzed by 2 (10 mol%) and TFA
(30 mol%). The reaction mixture was stirred at room tem-
perature until completion (typically, 2 h) at which point ac-
rolein 7 (R3 =H; 1.2 equiv) and TFA (70 mol%) were
added.[11] In this case, 3-pyrroline 3a was obtained in good
yield (83%) and excellent enantioselectivity (94%). The
one-pot procedure was then extended to a variety of a,a-
disubstituted aldehydes 6. Different 2-phenyl substituted al-
dehydes could be engaged in this transformation giving 3-
pyrrolines 3b and 3c in good yields and high levels of enan-
tioselectivity. The influence of the aryl unit was next exam-
ined by using various 2-arylpropionaldehydes. Electron-
withdrawing or electron-donating groups were well tolerated
along with the substitution at ortho-, meta-, or para- position
of the aryl moiety. 3-pyrrolines 3d–i were isolated in good
yields and stereoselectivities up to 98%. A lower yield was
observed when R2 =o-MeC6H4 (3e, 42% yield) was used. In
this case, the reaction was very slow and 35% of monopro-
tected aldehyde was also isolated.[12]
With the optimized conditions of the aza-Michael/aldol
condensation sequence in hand, the feasibility of a one-pot
formation of 3-pyrrolines including the enantioselective a-
amination to form the nitrogen-containing quaternary
center was then examined (Scheme 2). First, this organoca-
talytic sequence was attempted with 2-phenylpropanal. The
one-pot procedure consists of the reaction of 2-phenylpropa-
nal 6a (1.2 equiv) with di-tert-butylazodicarboxylate
a,a-Dialkyl aldehyde (2-methylpentanal 6j) was also
tested in the cascade reaction, and the corresponding 3-pyr-
roline 3j was obtained in 69% yield and 30% enantiomeric
excess. More sterically hindered 2-cyclohexylpropionalde-
hyde 6k gave better result in term of enantioselectivity and
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Synthesis of 3-Pyrrolines with a Quaternary Stereocenter
FULL PAPER
pyrroline 3k was synthesized in 75% yield and 50% ee. Fi-
nally, the use of crotonaldehyde 7 (R3 =Me) instead of acro-
lein with 2-phenylpropionaldehyde afforded 2,2,5-trisubsti-
tuted-3-pyrrolines 3l and 3m as a separable mixture of dia-
stereoisomers (diastereomeric ratio (d.r.) 2:1).
eoisomer. This observation prompted us to investigate the
parent epoxidation reaction. Moreover, epoxypyrrolidines
are important intermediates in organic synthesis.[14] Enal 3a
was engaged in an epoxidation reaction under basic condi-
tions (H2O2, NaOH) to afford the polysubstituted pyrroli-
dines 9 and 10 as a separable mixture of diastereoisomers
(d.r. 3:1).
As illustrated in Scheme 3, synthetically attractive appli-
cations can arise from products 3. Cleavage of the hydrazine
Based on the above discussed results, the reaction path-
way described in Scheme 4 is proposed to explain the selec-
Scheme 4. Proposed pathway to 3-pyrrolines 3a supported by ESI analy-
ses.
tive formation of 3. Aldehyde 6 undergoes a-amination with
DtBAD catalyzed by primary amine 2. Under acidic condi-
tions, the selective Boc cleavage of A could be explained by
the formation of cyclic compound B, which might be subject
to decarboxylation and leads to monoprotected aldehyde C.
An organocatalyzed aza-Michael/aldol condensation se-
quence and a final dehydration allow the formation of 3-pyr-
roline 3. Starting from 2-phenylpropionaldehyde 6a, ESI-
MS analyses were carried out to characterize the intermedi-
ates and to support the proposed mechanism. To a solution
of 9-amino-(9-deoxy)-epi-quinine 2 (10 mol%) in CHCl3,
a,a-disubstituted aldehyde 6a, di-tert-butyl azodicarboxy-
late, and TFA (30 mol%) were added successively at room
temperature. The reaction mixture was stirred until the com-
pletion of the reaction. A first analytical sample was taken
and injected. Intermediate A ([A+Na+], m/z 387.1898) was
detected. Acrolein 7 and TFA (70 mol%) were then added,
and the resulting mixture was stirred for 15 min at room
temperature. A second analytical sample was taken and in-
jected. Intermediate B ([B+Na+], m/z 331.1270) and C
([C+Na+], m/z 287.1374) were detected. A third analytical
Scheme 3. Synthetic transformations of 3-pyrroline 3a.
of 2-methyl-2-phenyl-3-pyrroline 3a was envisaged. Reduc-
tion of the aldehyde, Bn-protection of the resulting alcohol
À
and N N bond cleavage with SmI2 after hydrazine activa-
tion gave 3-pyrroline 7. Highly functionalized pyrrolidine
derivatives were synthesized. Product 3a was applied in an
organocatalyzed aziridination reaction developed previously
in our group.[13] When catalyst I was used for the transfor-
mation, a diastereoisomeric mixture of nitrogen-containing
bicyclic compound 8 and 8’ was obtained in 95% yield and
moderate selectivity (d.r. 2:1). To uncover a possible match/
mismatch effect between the chiral substrate and the cata-
lyst, catalyst II was also tested. Indeed, a matched relation-
ship between catalyst II and chiral pyrroline 3a was ob-
served and the aziridinopyrrolidine 8 was obtained in 92%
yield as a single diastereoisomer. It is also worth noting that
the quaternary stereocenter of 3a plays a pivotal role in the
stereochemical relay, because the use of pyrrolidine III as a
catalyst led to compound 8 in 95% as a single diaster-
Chem. Eur. J. 2012, 00, 0 – 0
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Conclusion
We have disclosed an efficient and highly enantioselective
access to 2,2-disubstituted-3-pyrrolines through a new orga-
nocatalytic one-pot sequence amination/aza-Michael/aldol
condensation from readily available substrates. These build-
ing blocks present in natural products or synthetic biologi-
cally active compounds can also be readily converted to dif-
ferent polysubstituted compounds, which should be useful in
organic synthesis and medicinal chemistry. Current work
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Experimental Section
General procedure for the formation of 3-pyrrolines 3a–m: To a solution
of 9-amino-(9-deoxy)-epi-quinine 2 (0.05 mmol, 16 mg) in CHCl3 (1 mL)
were added successively at RT a,a-disubstituted aldehyde 6 (0.6 mmol),
di-tert-butyl azodicarboxylate (0.5 mmol, 115 mg), and TFA (0.15 mmol,
12 mL). The reaction mixture was stirred until the completion of the reac-
tion (typically 2 h, monitored by TLC). a,b-Unsaturated aldehyde
(0.6 mmol) and TFA (0.35 mmol, 27 mL) were then added and the result-
ing mixture was stirred for 16 h at RT. The reaction was quenched with a
saturated solution of NaHCO3. The organic materials were extracted
with CH2Cl2, dried over anhydrous MgSO4, and concentrated in vacuo
after filtration. The residue was purified by flash chromatography (pen-
tane/Et2O) to give the desired product 3.
Acknowledgements
The authors thank the Ministꢂre de la recherche for financial support
(grant for A.D.), F. Bourdreux and E. Galmiche-Loire for NMR and
ESI-MS analyses.
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Received: June 7, 2012
Published online: && &&, 0000
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Synthesis of 3-Pyrrolines with a Quaternary Stereocenter
FULL PAPER
Organocatalysis
A. Desmarchelier, V. Coeffard,*
X. Moreau,* C. Greck ....... &&&& — &&&&
Enantioselective Organocatalytic One-
Pot Amination/aza-Michael/Aldol
Condensation Reaction Sequence:
Synthesis of 3-Pyrrolines with a
Quaternary Stereocenter
Expect the unexpected: Primary
a-amination, an aza-Michael addition
amine-catalyzed direct conversion of
a,a-disubstituted aldehydes into 3-pyr-
rolines with a quaternary stereocenter
is reported. The sequence involves an
of hydrazine, an aldol condensation
and proceeds with good yields and
excellent levels of enantioselectivity
(see scheme).
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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