Chiral Bronsted acid catalyzed enantioselective aza-Diels-Alder reaction of Brassard's diene with imines

Article abstract of DOI:10.1002/anie.200601345

(Chemical Equation Presented) Bronsted, Brassard, Diels, and Alder: Aldimines 1 undergo aza-Diels-Alder reactions with Brassard's diene 2 in the presence of a chiral cyclic phosphate pyridinium salt 4 as a chiral Bronsted acid to give α,β-unsaturated δ-la

Full text of DOI:10.1002/anie.200601345

Communications
Organocatalysis
enantioselective reaction of Brassardꢀs diene with imines has,
to the best of our knowledge, not been reported.[10] The high
reactivity and lability of Brassardꢀs diene is associated with
the paucity of its hetero-Diels–Alder reaction.
DOI: 10.1002/anie.200601345
Chiral Brønsted Acid Catalyzed Enantioselective
Aza-Diels–Alder Reaction of Brassardꢀs Diene
with Imines**
Recently, chiral Brønsted acid catalysis,[11,12] a variant of
metal-free organocatalysis, has become a rapidly growing
area.[13] We have already developed chiral phosphoric acid 2,
Junji Itoh, Kohei Fuchibe, and Takahiko Akiyama*
Piperidine derivatives are precursors of the biologically
important piperidine alkaloids,[1] peptides, and aza sugars,
and are therefore important synthetic targets. Development
of novel efficient methods for the synthesis of piperidine
derivatives in optically pure form is important from the
standpoint of the pharmaceutical sciences as well as synthetic
organic chemistry. The enantioselective aza-Diels–Alder
reaction of electron-rich dienes with aldimines provides an
efficient protocol for the preparation of piperidine derivatives
in scalemic form.[2] Thus, the aza-Diels–Alder reaction of an
imine with 1-alkoxy-3-siloxy-1,3-butadienes and its deriva-
tives (Danishefskyꢀs diene)[3] furnishes functionalized piper-
idinones. A catalytic asymmetric version of the aza-Diels–
Alder reaction was investigated recently, and high enantio-
selectivity was attained.[4] Another potential candidate as an
electron-rich diene is 1,3-dimethoxy-1-(trimethylsiloxy)buta-
diene 1 (Brassardꢀs diene),[5] the reaction of which provides
piperidinone derivatives (Scheme 1).[6] In contrast to Dani-
shefskyꢀs diene, Brassardꢀs diene has been less extensively
studied. Although diastereoselective versions of aza-Diels–
Alder reactions with chiral imines that lead to optically active
piperidinone derivatives have been reported by Waldmann
et al.,[7] Midland and Koops,[8] and Kawecki,[9] the catalytic
derived from (R)-BINOL, as a chiral Brønsted acid cata-
lyst.[14,15] One of the potential problems associated with 2 lies
in its strong acidity,[16] in particular when applied to labile
substrates. We have found that its pyridinium salt 3 also
exhibits efficient catalytic activity as a chiral Brønsted acid
catalyst but is more compatible than 2 with labile substrates
such as Brassardꢀs diene. Herein, we report the chiral
Brønsted acid catalyzed aza-Diels–Alder reaction of aldi-
mines with Brassardꢀs diene 1 to afford piperidinone deriv-
atives in high yields and with excellent enantioselectivities (up
to 99% ee). To our knowledge, this is the first report of an
enantioselective aza-Diels–Alder reaction of Brassardꢀs diene
with aldimines.[17]
Screening of substituents at the 3,3’-positions of phospho-
ric acid 2 revealed that 9-anthryl groups as in 2a[15c] were the
most effective for the aza-Diels–Alder reaction. Thus, aldi-
mine 4a (R = Ph), derived from benzaldehyde and 2-amino-4-
methylphenol, and Brassardꢀs diene 1 were treated with 2a
(3 mol%) in mesitylene at À408C for 24 h. Treatment of the
reaction mixture with PhCO2H (1 equiv) with heating for 12 h
afforded cycloadduct 5a in 72% yield and with 92% ee
(Table 1, entry 1). Note that as little as 3 mol% of the catalyst
suffices for the reaction to proceed efficiently. Interestingly,
use of the equivalent amount (3 mol%) of its pyridinium salt
3 improved the yield significantly with comparable enantio-
selectivity (Table 1, entry 2). A range of aldimines derived
from aromatic and heteroaromatic aldehydes underwent the
aza-Diels–Alder reaction to afford cyclization products with
excellent enantioselectivities (Table 1, entries 3–14). Ali-
phatic aldimines, which were generated in situ, also gave
corresponding cycloadducts with excellent ee values (Table 1,
entries 15, 16). The absolute stereochemistry of 5 (R = p-
BrC6H4; Table 1, entry 3) was unambiguously determined by
X-ray crystallographic analysis,[18] and those of the other
cycloadducts were assigned by analogy.
Scheme 1. The aza-Diels–Alder reaction. TMS=trimethylsilyl.
[*] J. Itoh, Dr. K. Fuchibe, Prof. Dr. T. Akiyama
Department of Chemistry
Faculty of Science
Gakushuin University
Mejiro, Toshima-ku, Tokyo 171-8588 (Japan)
Fax: (+81)3-5992-1029
E-mail: takahiko.akiyama@gakushuin.ac.jp
To demonstrate the utility of the present aza-Diels–Alder
reaction, the experiment was performed on a gram scale.
Thus, when 1.01 g of aldimine 4a was treated with 3
(3 mol%), 1.40 g of the corresponding cyclization product
5a was obtained without any loss in the enantioselectivity or
yield (Scheme 2).
[**] We thank Professor Youichi Ishii and Dr. Yoshiaki Tanabe (Chuo
University, Tokyo, Japan) for the X-ray structural determination. This
work was partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports, Culture,
and Technology, Japan. J.I. is grateful for a JSPS Research Fellowship
for Young Scientists.
The methoxy group in 5a could be transformed into other
functionalities. As an example, acid hydrolysis of the methyl
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
4796
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Angew. Chem. Int. Ed. 2006, 45, 4796 –4798

Angewandte
Chemie
Table 1: Results of the aza-Diels–Alder reaction.[a]
surmised that the present aza-Diels–Alder reaction proceeds
via a nine-membered cyclic transition state, wherein the
phosphoryl oxygen atom forms a hydrogen bond with the
hydrogen atom of the imine OH moiety, with the nucleophile
attacking the Re face of the aldimine preferentially
(Figure 1).[21,22]
Entry
Catalyst
R
Yield [%]
ee [%]
1[b]
2[b]
3
2a
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
C6H5
C6H5
p-BrC6H4
p-ClC6H4
p-FC6H4
p-CH3C6H4
p-CH3OC6H4
o-BrC6H4
o-ClC6H4
o-CH3C6H4
1-naphthyl
2-naphthyl
2-furyl
72
87
86
90
76
90
84
83
86
76
79
91
63
76
69
65
92
94
96
97
98
95
99
98
98
96
98
97
97
98
99
93
4
5[b]
6
7
8[b]
9[b]
10
11
12[b]
13[b,c,d]
14[b,c]
15
=
PhCH CH
cyclohexyl
iPr
16
Figure 1. Chem3D representation of a minimized structure of the
complex derived from 2a and 4a. Most of the hydrogen atoms are
omitted for clarity. Hydrogen bonds are shown. P pink, O red, N blue,
C gray, H turqoise. The arrow indicates Re facial attack.
[a] 3.0 equiv of 1 was employed. [b] 5 equiv of PhCO2H was employed.
[c] 4.0 equiv of 1 was employed. [d] 1 was added in one portion.
In summary, we have developed the aza-Diels–Alder
reaction of Brassardꢀs diene with imines, catalyzed by a chiral
Brønsted acid derived from (R)-BINOL, to give dihydropyr-
idone derivatives with excellent enantioselectivities. The
application of the present chiral Brønsted acid catalysis
system to other asymmetric reactions is underway.
Received: April 5, 2006
Published online: June 23, 2006
Scheme 2. Scaled-up version of the aza-Diels–Alder reaction.
ether and a subsequent addition–elimination reaction of the
Keywords: asymmetric synthesis · aza-Diels–Alder reaction ·
Brønsted acids · enantioselectivity · organocatalysis
.
tosylate with Me2CuLi introduced
(Scheme 3).
a
methyl group
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Communications
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