Chiral Bronsted acid-catalyzed tandem aza-ene type reaction/cyclization cascade for a one-pot entry to enantioenriched piperidines

Article abstract of DOI:10.1021/ja0739584

A chiral monophosphoric acid-catalyzed tandem aza-ene type reaction/cyclization cascade enabled the rapid construction of enantioenriched piperidine derivatives as key structural elements of numerous natural products. The potential of such cascade transformations is highlighted through their ability to achieve a rapid increase in molecular complexity from simple enecarbamates and a broad range of aldimines while also controlling three stereogenic centers in a highly diastereo- and enantioselective manner. Copyright

Full text of DOI:10.1021/ja0739584

Published on Web 08/04/2007
Chiral Brønsted Acid-Catalyzed Tandem Aza-Ene Type Reaction/Cyclization
Cascade for a One-Pot Entry to Enantioenriched Piperidines
Masahiro Terada,* Kyoko Machioka, and Keiichi Sorimachi
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received June 1, 2007; E-mail: mterada@mail.tains.tohoku.ac.jp
The development of efficient methods to access complex mole-
cules with multiple stereogenic centers continues to be a substantial
challenge in both academic research and industrial applica-
tions. One approach toward this challenge is the use of catalytic
For the first step of the proposed cascade transformation, we
examined the reaction of benzaldehyde-derived N-Boc aldimine (1a)
with N-Cbz enecarbamate (5a) catalyzed by biphenol-derived
phosphoric acid (9). To our delight, the cascade reaction proceeded
smoothly to afford a diastereomeric mixture of the desired piperidine
derivative (8a: R1 ) Ph) quantitatively (eq 1). Although the
diastereoselectivity was moderate, only two diastereomers were
obtained from among the four possible diastereomers that result
from three stereogenic centers.8
1
enantioselective cascade reactions, which have emerged as power-
ful tools to give a rapid increase in molecular complexity from
simple and readily available starting materials, thus producing
enantioenriched compounds in a single operation. It is obvious that
such transformations require less solvents, adsorbents, and energy,
hence minimizing waste management as compared to a series of
individual stepwise reactions. In recent years, considerable efforts
have been devoted to the development of enantioselective organic
transformations using chiral Brønsted acids as green catalysts.2
Cascade reactions catalyzed by chiral Brønsted acids are attractive
because such catalytic processes would allow the production of
enantioenriched compounds by ecologically and economically
3
favorable methods. In this communication, we describe a chiral
4
,5
monophosphoric acid -catalyzed tandem aza-ene type reaction/
cyclization cascade that enables the rapid and highly enantio- and
diastereoselective construction of piperidine derivatives with mul-
tiple stereogenic centers.
Recently, we successfully developed a highly efficient and
6
enantioselective aza-ene type reaction of N-acyl aldimines (1) with
This preliminary result prompted us to develop enantio- and
diastereoselective variants of our cascade transformation. Our
studies were commenced with the screening of chiral phosphoric
acid catalysts (3) bearing various type of aromatic substituents (Ar)
at the 3,3′-position on the binaphthyl backbone. As shown in Table
1, all of the chiral catalysts (3) exhibited excellent performance
both in terms of catalytic efficiency and enantioselectivity. The
cascade reaction of 1a with 5a was completed within 30 min in
the presence of (R)-3 (2 mol %) to afford the two diastereomers of
the piperidine derivatives (trans- and cis-8a), as observed in the
catalysis by 9 (entries 1-4 vs eq 1). Furthermore, excellent
enantioselectivity was observed for the major trans-isomer, ir-
disubstituted enecarbamates (2: G * H) catalyzed by chiral
monophosphoric acid derivatives (3),4d in which the corresponding
products (4) were obtained in ketimine form. Inspired by the forma-
tion of imines, we envisioned a sequential process using mono-
substituted enecarbamates (5: G ) H)4g,6e instead of the disubsti-
tuted versions (2). The acid-catalyzed reaction of initial aldimines
(
(
1) with 5 would generate aza-ene type products of N-acyl aldimines
6) as reactive intermediates and hence 6 would undergo further
aza-ene type reactions leading to the subsequent generation of
aldimines (7). If intramolecular cyclization of 7 could be enacted
to terminate the tandem aza-ene type reaction sequence, our
synthetic methodology would allow rapid access to piperidine
derivatives (8) as key structural elements of numerous natural
products (Scheme 1).7
1
Table 1. Cascade Reaction of 1a (R ) Ph) with 5a Catalyzed by
(
R)-3 Leading to Piperidine Derivatives (8a) (eq 1)a
entry
catalyst (3) (Ar)
yield (%)
trans:cis
ee (%)b,c
ee (%)b,d
Scheme 1. One-Pot Entry to Piperidine Derivatives via Tandem
Aza-ene Type Reaction/Cyclization Cascade
e
1
2
3
4
3a (9-anthryl)
92
92
80:20
86:14
86:14
89:11
87:13
91:9
99
95
96
97
99
99
99
>99
12
19
31
8
8
14
14
40
e
3b (C6H5-)
3c (3,5-Ph2-C6H3-)
>99
>99
>99
>99
97
e
3d (4-Ph-C6H4-)
f
5
3d
3d
3d
3d
g
6
7
h
92:8
95:5
i
8
>99
a
Unless otherwise noted, all reactions were carried out with 0.10 mmol
of 1a, 0.21 mmol of 5a, and 0.002 mmol of (R)-3 (2 mol %) in 1.0 mL of
b
CDCl3 at room temperature for 30 min. Enantiomeric excess was
c
determined by chiral HPLC analysis. % ee of trans-8a (absolute stereo-
d
chemistry: 2R,4R,6S). % ee of cis-8a (absolute stereochemistry: 2R,4S,6S).
e
f
g
(
2S,4R,6R)-8a as the major product. In toluene for 1 h. In (CH2Cl)2
h
i
for 1 h. In CH2Cl2 for 1 h. In CH2Cl2 at 0 °C for 1 h.
10336
9
J. AM. CHEM. SOC. 2007, 129, 10336-10337
10.1021/ja0739584 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of Substrates in Cascade Reaction of 1 with 5a
Catalyzed by (R)-3d (eq 1)
to provide a rapid increase in molecular complexity. Further
investigations of this cascade transformation are currently underway
in our laboratory to elucidate the origin of the stereoselectivity and
to construct more complex heterocyclic systems.
a
entry
1 (R1)
yield (%)
trans:cis
ee (%)b,c
ee (%)b,d
1
2
1b: p-Br-C6H4-
1c: p-Me-C6H4-
1d: 2-furyl
>99
>99
76
70
84
94:6
95:5
88:12
95:5
88:12
94:6
99
98
99
97
98
97
23
4
e
Acknowledgment. This work was supported by JSPS for a
Grant-in-Aid for Scientific Research (B) (Grant No. 17350042) and
The Tokuyama Science Foundation. We also acknowledge the JSPS
Research Fellowship for Young Scientists (K.S.) from the Japan
Society for the Promotion of Sciences.
3
14
36
e
4
5
1e: Ph-CHdCH-
e
f
1f: MeO2C-
ND
e
6
1g: c-C6H11-
68
48
a
Unless otherwise noted, all reactions were carried out with 0.10 mmol
of 1, 0.21 mmol of 5a, and 0.002 mmol of (R)-3d (2 mol %) in 1.0 mL of
Supporting Information Available: Representative experimental
procedure, spectroscopic data for cascade reaction products (8),
determination of relative stereochemistry of 8, and absolute stereo-
chemistry of 8a. This material is available free of charge via the Internet
at http://pubs.acs.org.
b
CH2Cl2 at 0 °C for 5 h. Enantiomeric excess was determined by chiral
c
d
e
HPLC analysis. % ee of trans-8. % ee of cis-8. Reaction was carried
f
out using 0.005 mmol of (R)-3d (5 mol %). Not determined % ee.
respective of the Ar substituent of the chiral catalysts (3) (entries
1-4). Interestingly, the simple phenyl-substituted catalyst (3b) also
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stereogenic centers, the cascade transformations can be widely
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