Diphenylprolinol silyl ether as a catalyst in an enantioselective, catalytic, formal aza [3+3] cycloaddition reaction for the formation of enantioenriched piperidines

Article abstract of DOI:10.1002/anie.200800662

(Chemical Presented) Aza-ene reaction: Diphenylprolinol silyl ether was found to be an effective organocatalyst for the formal aza [3+3] cycloaddition reaction of a,b-unsaturated aldehydes and enecarbamates (see scheme). The reaction proceeds through an asymmetric catalytic ene reaction, isomerization, hydrolysis, and cyclization to afford piperidine derivatives in good yields and excellent enantioselectivities.

Full text of DOI:10.1002/anie.200800662

Communications
DOI: 10.1002/anie.200800662
Organocatalysis
Diphenylprolinol Silyl Ether as a Catalyst in an Enantioselective,
Catalytic, Formal Aza [3+3] Cycloaddition Reaction for the Formation
of Enantioenriched Piperidines**
Yujiro Hayashi,* Hiroaki Gotoh, Ryouhei Masui, and Hayato Ishikawa
The piperidine ring system is one of the most common
structural subunits in natural products and biologically
significant compounds.[1] The aza Diels–Alder reaction[2]
and the aza [3+3] cycloaddition reaction[3] are straightforward
synthetic methods for making piperidine ring systems. Several
methods have been developed for formal aza [3+3] cyclo-
addition reactions, such as reactions of 1,3-cyclic sulfonates
with C/N dianions,[4] vinylogous amides with a,b-unsaturated
iminium ions,[5] and aziridines with Pd–trimethylenemethane
complexes.[6] In spite of these formal aza [3+3] cycloaddition
methods, and to the best of our knowledge, an enantioselec-
tive catalytic version has not been reported.
Enecarbamates and enamides have been successfully
utilized as reactive nucleophiles by the group of Kobayashi,[15]
and Terada et al. recently used them in an aza-ene-type
reaction.[16] Having reported the asymmetric ene reaction of
cyclopentadiene,[9] we employed an enamide and an a,b-
unsaturated aldehyde with the expectation that an ene
reaction would occur. Notably, the asymmetric, catalytic
intermolecular ene reaction of a,b-enals as enophiles is rare.[9]
The reaction of cinnamaldehyde and N-(1-phenylvinyl)acet-
amide 9 was selected as a model reaction and we expected
Asymmetric catalytic reactions promoted by organocata-
lysts is a rapidly growing area of research.[7] Our group
developed diarylprolinol silyl ether as an effective catalyst in
the Michael reaction,[8] the ene reaction,[9] the Diels–Alder
reaction,[10] the tandem Michael/Henry reaction,[11] and the
Michael reaction of nitroalkanes.[12] At the time of our first
report, the group of Jørgensen also developed the same type
of catalyst;[13] the diarylprolinol silyl ether catalyst has been
widely used in enantioselective reactions.[14] We have applied
diphenylprolinol silyl ether to the reaction of a,b-unsaturated
aldehydes with enecarbamates and found that a formal aza
[3+3] cycloaddition reaction proceeds in a highly enantiose-
lective manner as reported herein (Figure 1).
that an amine catalyst and cinnamaldehyde would afford an
iminium ion, which would react with enamide 9 to generate 7
by an ene reaction, to afford ketoaldehyde 5[17] after hydration
(Scheme 1). When cinnamaldehyde and enamide 9 were
treated with a catalytic amount of diphenylprolinol trimeth-
ylsilyl ether (1), ketoaldehyde 5 was obtained in 18% yield in
nearly optically pure form along with an unexpected piper-
idine derivative (6) in 47% yield as a mixture of a and
b isomers (44:56). The a and b isomers were separated and
their optical purities were found to be the same (87% ee,
Table 1, entry 1). A pure sample of the a isomer resulted in a
Figure 1. Organocatalysts examined in the present study.
[*] Prof. Dr. Y. Hayashi, H. Gotoh, R. Masui, Dr. H. Ishikawa
Department of Industrial Chemistry
Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
Fax: (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
Homepage: http://www.ci.kagu.tus.ac.jp/lab/org-chem1/
[**] This work was partially supported by the Toray Science Foundation
and a Grant-in-Aid for Scientific Research from MEXT.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. The reaction mechanism of 5 and 6.
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Table 1: Optimization of the reaction conditions.[a]
Table 2: Catalytic asymmetric formal aza [3+3] cycloaddition reaction of
enecarbamate and a,b-unsaturated aldehydes.[a]
Entry Catalyst Ene Solvent T [8C] Yield [%][b] Ratio[c]
ee [%][d]
6a 6b
5
6
a:b
5
Entry
1
Product
t [h]
Yield
[%][b]
Ratio[c]
a:b
ee [%][d]
a
b
1
2
3
4
1
1
1
1
2
3
2
9
9
9
9
9
9
(ClCH2)2 40
PhH 40
CH3CN 40
(ClCH2)2 70
(ClCH2)2 70
(ClCH2)2 70
18
29
19
17
18
47
14
10
68
69
44:56 99 87 86
45:55 99 87 87
51:49 99 87 86
45:55 n.d. 85 86
46:54 n.d. 95 97
34
90
83
34:66
29:71
94
91
93
5
6
<5 <5 n.d.
0 90 34:66 n.d. 94 93
n.d. n.d. n.d.
7[e]
10 (ClCH2)2 70
[a] Unless otherwise shown, the reaction was performed by employing
cinnamaldehyde (0.5 mmol), enamide (1.0 mmol) or enecarbamate
(0.75 mmol), and organocatalyst (0.05 mmol) in the indicated solvent
(1.0 mL) at the indicated temperature for 22 h. n.d.=not determined.
2
3
4
38
22
22
90
97
92
1
[b] Yield of isolated product. [c] Determined by H NMR analysis. [d] Deter-
mined by HPLC analysis on a chiral phase after separation of a and b isomers
by TLC. [e] The reaction time was 34 h.
83
88
29:71
31:69
95
91
mixture of a and b isomers (44:56) upon standing at room
temperature for two hours, indicating that there is an
equilibrium between the isomers. Piperidine derivative 6 is
proposed to be derived from acylimine 7, which is generated
by an ene reaction, with subsequent isomerization to enamide
8 and then successive cyclization (Scheme 1); formally,
piperidine 6 was obtained by an enantioselective aza [3+3]
cycloaddition reaction. Optimization of the reaction condi-
tions was investigated in detail because a one-step synthesis of
chiral piperidine rings by a catalytic asymmetric method is
synthetically important (Table 1). First, the solvent was
examined and benzene and CH3CN were found to not be
suitable as they led to a decreased yield of 6 (Table 1, entries 2
and 3). When the reaction was performed at a higher
temperature (708C) in dichloroethane the yield of 6 increased
without compromising the enantioselectivity (Table 1,
entry 4). In the reaction catalyzed by a catalyst with a bulkier
silyl substituent, such as a tert-butyldimethylsilyl (TBS) group
(2), the enantioselectivity increased to 95% ee (Table 1,
entry 5). Bis(trifluoromethyl) substituted arylprolinol silyl
ether[13] 3 was not effective in the present reaction (Table 1,
entry 6); and when enecarbamate 10 was employed instead of
enamide 9 (Table 1, entry 7), piperidine derivative 6 was
formed in excellent yield and high enantioselectivity without
the formation of ketoaldehyde 5. In the reaction of enecar-
bamate 10, hydrolysis of 7 would be retarded and isomer-
ization from 7 to 8 would be facilitated. The formation of 6
depends on a subtle balance of several competing reactions,
such as the ene reaction, isomerization, hydrolysis, and
aminoacetalization.
5
6
7
48
96
48
73
80
89
19:81
27:73
14:86
97
99
90
97
99
90
8
29
23
89
85
26:74
19:81
90
90
88
90
9[e]
[a] Unless otherwise noted, the reaction was performed by employing
a,b-unsaturated aldehyde (0.5 mmol), enecarbamate (0.75 mmol), and
organocatalyst 2 (0.05 mmol) in dichloroethane (1.0 mL) at 708C.
[b] Yield of the isolated product. [c] Determined by 1H NMR analysis.
[d] Determined by HPLC analysis on a chiral phase after separation of a
and b isomers by TLC. [e] The reaction was performed at room
temperature.
The scope of the reaction was investigated once the
optimal reaction conditions were determined (Table 2).
Phenyl- and naphthyl-substituted acrolein (Table 2, entries 1
and 2), as well as acrolein derivatives with aryl groups
possessing electron-withdrawing (Table 2, entries 3, 4) and
electron-donating (Table 2, entry 5) substituents are suitable
substrates that afford the piperidine derivatives in good yield
with excellent enantioselectivity. In the reaction of acrolein
substituted with a heteroaromatic group such as furyl, a
nearly optically pure product was obtained (Table 2, entry 6).
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Alkyl-substituted acrolein did not afford a good result. With
tion, an isomerization from an imine into an enecarbamate,
hydrolysis, and hemiacetal formation in one pot to afford
synthetically important piperidine derivatives with excellent
enantioselectivities from simple starting materials. Notably,
the intermolecular asymmetric, catalytic ene reaction of a,b-
unsaturated aldehydes as the enophile is rare, and the present
reaction is one of the few successful examples of such a
reaction.
Typical procedure (Table 2, entry 1): A dichloroethane
solution (0.66 mL) of enecarbamate 10 (164.5 mg, 0.75 mmol)
was added to a dichloroethane solution (0.33 mL) of catalyst 2
(18.3 mg, 0.05 mmol) and trans-cinnamaldehyde (62.5 mL,
0.5 mmol) at room temperature. After stirring the reaction
mixture at 708C for 34 h, the resulting mixture was quenched
with 1n HCl at 08C and the organic materials were extracted
three times with ethyl acetate. The combined organic extracts
were washed with saturated aqueous NaHCO3, dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(AcOEt/hexane = 1:30) to afford 6a as a mixture of a and
b isomers (158.1 mg, 0.45 mmol, 90%) as a yellow solid. The
ratio of a and b isomers was determined by 1H NMR
spectroscopy. A small portion of the mixture was purified
by TLC to afford a and b isomers, the enantioselectivities of
which were determined by HPLC analysis by using a chiral
column.
regard to the ene component, enecarbamates substituted with
aryl groups having electron-deficient (Table 2, entry 7) and
electron-donating (Table 2, entry 8) substituents, as well as
heteroaromatic groups (e.g. furyl; Table 2, entry 9) can be
successfully employed.
Piperidine derivative 6a was converted into 11 by treat-
ment with 2m HCl, and subsequent oxidation without
compromising the enantioselectivity [Eq. (1)]; the absolute
configuration was determined by comparison of the optical
rotation with that reported in the litera-
ture.[18] This absolute configuration is rea-
sonable considering that the ene compo-
nent approaches opposite to the face with
the bulky diphenyl(tert-butyldimethylsi-
loxy)methyl group (Figure 2)
Compound 6a possesses alkene and
hemiaminal moieties, which makes it an
important synthetic intermediate because
there are several additional transforma-
tions that are possible. For instance, a
Figure 2. The
transition state
of the reaction.
Received: February 11, 2008
Revised: February 27, 2008
Published online: April 10, 2008
Keywords: asymmetric catalysis · cycloaddition · ene reaction ·
.
piperidines · synthetic methods
Wittig reaction and subsequent intramolecular Michael
reaction stereoselectively provided 12 in good yield. Hydro-
genation of 12 also proceeded in a highly stereoselective
manner to afford 2,4,6-trisubstituted piperidine 13 as a single
isomer without affecting the enantioselectivity [Eq. (2)]. The
relative configuration of 13 was determined by using coupling
constants and NOESY spectra.[19]
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