A new organocatalyst for 1,3-dipolar cycloadditions of nitrones to α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tetlet.2006.11.029

The triflate salt resulting from the treatment of diphenyl-S-prolinol with trimethylsilyl triflate, catalyzes the addition of nitrones to α,β-unsaturated aldehydes to provide isoxazolidines in high yields and excellent diastereo- and enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2006.11.029

Tetrahedron Letters 48 (2007) 277–280
A new organocatalyst for 1,3-dipolar cycloadditions
of nitrones to a,b-unsaturated aldehydes
*
San San Chow, Marta Nevalainen, Catherine A. Evans and Charles W. Johannes
Infinity Pharmaceuticals, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA
Received 29 September 2006; revised 2 November 2006; accepted 5 November 2006
Available online 27 November 2006
Abstract—The triflate salt resulting from the treatment of diphenyl-S-prolinol with trimethylsilyl triflate, catalyzes the addition of
nitrones to a,b-unsaturated aldehydes to provide isoxazolidines in high yields and excellent diastereo- and enantioselectivities.
Ó 2006 Elsevier Ltd. All rights reserved.
In the past few years organocatalysis has emerged as a
powerful approach for the preparation of important
optically active building blocks. The LUMO-lowering
activation of a,b-unsaturated aldehydes using the
reversible formation of iminium ions with chiral imid-
azolidinones was reported by MacMillan and co-work-
ers as a valuable platform for the development of
various enantioselective organocatalytic cycloaddi-
1
2
tions. We decided to apply that strategy to the [3+2]
2
b
cycloaddition of a,b-unsaturated aldehydes to nitrones
using catalysts that could be synthesized in one step
from commercially available starting materials. As
Table 1. Catalyst screen for the cycloaddition of N-benzylidenebenzylamine N-oxide and crotonaldehyde
Bn
Bn
2
0 mol%
N O
N O
O
catalyst 1x
Bn
O
N
+
Ph
Me
endo
+
Ph
Me
H
Me
CH
2
Cl
2
:i-PrOH
Ph
o
exo
(
85:15), 4 C
H
O
H
O
a
b
Entry
1
Catalyst
Time (days)
endo:exo
% ee (endo)
1
78:22
37
COOMe
N
H
HOTf
1a
Ph
COOMe
HOTf
2
3
N
H
0.5
2
78:22
—
26
—
1b
OTMS
Ph
N
H
Ph
HOTf 1c
c
4
1c
3
1
3.5
93:7
98:2
96:4
96
93
83
d
5
1c
1c
e
6
(
continued on next page)
Keywords: Enantioselectivity; [3+2] Cycloadditions; Organocatalysis; Nitrones; Isoxazolidines; Diphenyl-prolinol; Asymmetric catalysis.
*
Corresponding author. Tel.: +1 6174531248; fax: +1 6174531001; e-mail: Marta.Nevalainen@ipi.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.029

278
S. S. Chow et al. / Tetrahedron Letters 48 (2007) 277–280
Table 1 (continued)
a
b
Entry
Catalyst
Time (days)
>7
endo:exo
% ee (endo)
H
Ph
Ph
N
H
HOTf
7
8
9
84:16
98:2
91:9
14
1d
O
NMe
Ph
O
0.5
97
42
N
H
1
e
HOTf
NMe
1
N
H
HOTf 1f
a
b
c
1
Determined by H NMR.
Determined by chiral SFC on the corresponding alcohol.
Reaction conducted in toluene at 4 °C.
Reaction conducted in toluene at rt.
2 2
Reaction conducted in CH Cl at rt.
d
e
revealed in Table 1, the reaction of N-benzylideneben-
zylamine N-oxide with (E)-crotonaldehyde was success-
ful with a variety of amine catalysts (entries 1–9,
prepared in one step from commercially available diphe-
nyl-S-prolinol; the synthesis of second generation Mac-
3
3
Millan catalyst 1e requires multiple synthesis steps from
6
1
4–97% ee) in CH Cl –IPA (85:15) at +4 °C. This
phenylalanine methyl ester. All other catalysts screened
2
2
solvent system was unsuitable for catalyst 1c, as presum-
ably its sensitive trimethylsilyl moiety was cleaved under
those conditions. A solvent screen revealed that toluene
was optimal for that catalyst (Table 1, entries 4 and 5).
(entries 1, 2, 7 and 9), promoted the desired [3+2] cyclo-
addition, albeit in lower enantioselectivities. The free
base of 1c has been used in previous organocatalytic
7
studies, but to the best of our knowledge this is the first
4
–6
Catalyst 1e (second generation MacMillan catalyst)
report on the organocatalytic properties of triflate salt
8
performed best (Table 1, entry 8) in terms of rate, diaste-
reo- and enantioselectivity. To our delight the perfor-
mance of catalyst 1c was comparable to that of 1e
1c.
The scope of the organocatalytic 1,3-dipolar cyclo-
(
Table 1, entries 5 and 8), with the advantage that it is
addition between a,b-unsaturated aldehydes and various
Table 2. [3+2] Cycloaddition of a,b-unsaturated aldehydes and nitrones: substract generality
OTMS
N
Ph
Ph
HOTf 1c
Z
Z
H
Z
N O
N O
O
R
O
N
+
+
R
R1
endo
R
R1
H
R1
(x mol%)
exo
Toluene, rt
O
H
O
H
a
b
c
Entry
Z
R
R
1
x (mol %)
Time (h)
% Yield
endo:exo
% ee (endo)
1
2
3
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Bn
Bn
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
H
CO
Me
H
CO
Me
H
20
10
5
10
10
10
10
10
10
10
22
24
33
24
24
24
24
24
24
24
75
86
92
79
80
61
47
66
96
70
98:2
97:3
96:4
93:7
99:1
96:4
93:7
99:1
97:3
92:8
93
95
95
86
96
94
88
93
91
66
d
4
5
6
7
2
Et
Et
d
8
2
9
0
Naph
Naph
d
1
a
b
c
After column chromatography.
Determined by H NMR.
Determined by chiral SFC on the corresponding alcohol.
Reaction conducted at 40 °C.
1
d

S. S. Chow et al. / Tetrahedron Letters 48 (2007) 277–280
Table 3. [3+2] Cycloaddition of cyclopentene carboxaldehyde and various nitrones
279
OTMS
Ph
N
Z
Z
H
Ph
O
N O
N O
O
Z
HOTf 1c
H
H
O
R
N
R
H
+
+ R
H
H
(
20 mol%)
Toluene, rt, 3.5 d
% Yield
endo
exo
O
a
b
c
Entry
Z
R
endo:exo
% ee (endo)
1
2
4
Bn
Me
Bn
Ph
Ph
Naph
66
75
75
80:20
79:21
90:10
46
83
37
a
b
c
After column chromatography.
Determined by H NMR.
Determined by chiral SFC on the corresponding alcohol.
1
9
nitrones catalyzed by 1c was investigated (Table 2). The
amount of catalyst used was 10 mol %, as higher or low-
er catalyst loadings seemed to be detrimental either for
yield or reaction rate (compare entries 1–3). The lower
yield attained with 20 mol % catalyst (Table 2, entry 1)
could be attributed to greater aldehyde polymerization
or nitrone decomposition in the presence of a higher
amount of catalyst, but that experimental result is not
totally understood at this time. The cycloaddition was
quite general with respect to the nitrone structure. Var-
iation in the N-alkyl group (Z = Bn, Me) was possible
without loss in enantioselectivity (i.e., entries 2 and 6,
fused isoxazolidines (Table 3) in an endo fashion. In this
instance, the smaller N-methyl group on the nitrone
afforded a better enantioselectivity (entry 2). This
method is complementary to a previous report using a
1
0
different organocatalyst, which afforded selectively the
exo adducts. Endo adducts from 1-cyclopentene-1-
carboxaldehyde and N-benzylidenephenylamine N-oxide
had been obtained earlier via a Lewis acid catalyzed
1
1
approach.
Enantioselective formation of the endo-(4S)-isoxazol-
idine adduct was observed in all cases involving catalyst
(S)-1c (determined by comparison of their optical rota-
9
5% and 94% ee). Changes in the structure of the di-
2
b
polarophile were also well tolerated; acrolein (Table 2,
entries 4, 7 and 10) and ethyl oxobutenoate (Table 2,
entries 5 and 8) provided isoxazolidines in high diaste-
reo- and enantioselectivities. In the case of acrolein, best
results were attained at 40 °C instead of rt. Indeed the
endo:exo ratio was better at a higher temperature (Table
tion with values reported in the literature). Formation
of the (E)-iminium isomer (Fig. 1) was found to be pref-
erential (PM3-optimized structure). The position of one
of the phenyl groups and the silyl substituent on the
catalyst scaffold effectively shield the Re-face of the
dipolarophile, thus promoting cycloaddition from its
open Si-face.
2
+
, entry 4, 93:7 at 40 °C vs 75:25 at rt and 69:31 at
4 °C), while the ee remained essentially the same. Even
1
-cyclopentene-1-carboxaldehyde reacted to provide
In summary, a new chiral pyrrolidine derivative synthe-
sized in one step from commercially available reagents
has been found to be an excellent organocatalyst for
[
3+2] cycloadditions. This catalyst is now available to
the scientific community to further investigate its scope
and utility in asymmetric reactions.
TMSO
Ph
Ph
N+
Acknowledgements
We thank Dr. Michael A. Foley for his insight and fruit-
ful comments. S. Chow is indebted to the Economic and
Development Board (EDB) of Singapore for a Training
and Attachment Program stipend.
PM3
Si-face attack
H
References and notes
+
N
Bn
1
. For recent reviews on organocatalysis, see: (a) Dalko, P.
-
I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175;
O
(
b) Berkessel, A.; Gr o¨ ger, H. Asymmetric Organocatalysis;
Figure 1. Postulated Si-face attack of the nitrone on the E-iminium
formed from acrolein and catalyst 1c.
VCH Weinheim: Germany, 2004; (c) Seayed, J.; List, B.
Org. Biomol. Chem. 2005, 3, 719–724; (d) List, B. Chem.

280
S. S. Chow et al. / Tetrahedron Letters 48 (2007) 277–280
Commun. 2006, 819–824; (e) Marigo, M.; Jørgensen, K. A.
Chem. Commun. 2006, 2001–2011.
. (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2000, 122, 4243–4244; (b) Jen, W. S.;
Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc.
WO 2003002491 A2 20030109. Only the 2S,5S configura-
tion of second generation MacMillan catalyst (as a free
base) is currently available from Aldrich.
2
3
7. (a) Enders, D.; H u¨ ttl, M. R. M.; Grondal, C.; Raabe, G.
Nature 2006, 441, 861–863; (b) Ibrahem, I.; Zhao, G.;
Sunden, H.; Cordova, A. Tetrahedron Lett. 2006, 47,
4659–4663; (c) Sunden, H.; Ibrahem, I.; Cordova, A.
Tetrahedron Lett. 2006, 47, 99–103; (d) Ibrahem, I.;
Cordova, A. Chem. Commun. 2006, 16, 1760–1762; (e)
Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.;
Masui, R.; Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028–
16029; (f) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M.
Angew. Chem., Int. Ed. 2005, 44, 4212–4215; (g) Marigo,
M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794–797.
8. Two reports have recently appeared in which they use
respectively acetic acid (a) and benzoic acid (b) as
additives along with the free base of 1c (a) Wang, W.;
Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128,
10354–10355; (b) Chi, Y.; Gellman, S. H. J. Am. Chem.
Soc. 2006, 128, 6804–6805.
9. General procedure for [3+2] cycloadditions: To a vial
containing the nitrone (1.0 mmol) in toluene (8.0 mL) was
added the catalyst (0.1 equiv) followed by crotonaldehyde
(4.0 equiv). The resulting mixture was stirred at rt (or
otherwise indicated, Table 2) for 24 h, filtered through a
plug of silica gel with the aid of EtOAc and the filtrate
concentrated under vacuum. The residue was purified by
flash chromatography (EtOAc/hexane as eluant) to render
the cycloadducts as oils. A portion of crude cycloadducts
2000, 122, 9874–9875.
. Catalysts 1a, 1b and 1d–f were synthesized from the
corresponding commercially available Boc-protected
amines (free amine in the case of 1e) upon treatment with
3% solution of triflic acid in dichloromethane. Catalyst 1c
was obtained as follows: To a suspension of diphenyl-S-
prolinol (1.0 g, 3.95 mmol) (purchased from 3B Medical
Systems; both enantiomers available at $9/g) in DCM
(
10.0 mL) at 0 °C under argon atmosphere was added
triethylamine (825 lL, 1.5 equiv, 5.92 mmol). TMSOTf
857 lL, 1.2 equiv, 4.74 mmol) followed dropwise, the
(
resulting mixture was stirred at 0 °C for 1.5 h and was
concentrated under reduced pressure. The residual oil was
dried under vacuum overnight, and the resulting solid was
recrystallized from diethylether to provide 1c as white
20
needles (80% yield). Mp = 146.5–148.5 °C; ½aꢀ ꢁ8.7
D
1
(
c 1.0, toluene). H NMR (400 MHz, CDCl ), d 8.44 (br
3
s, 1H), 7.40–7.30 (m, 10H), 6.50 (br s, 1H), 4.81 (br s, 1H),
3
1
.25 (br s, 1H), 2.69 (br s, 1H), 2.40–2.25 (m, 1H), 2.10–
13
.90 (m, 2H), 1.60–1.48 (m, 1H), ꢁ0.08 (s, 9H). C NMR
), d 141.7, 140.8, 128.9, 128.9, 128.6,
28.6, 128.5, 128.5, 128.2, 128.2, 128.1, 128.1, 81.7, 67.3,
7.0, 27.0, 24.1, 1.6. Anal. (C21 NO SSi): C, 53.00;
(
100 MHz, CDCl
3
1
4
H
28
F
3
4
H, 6.02; N, 2.96; F, 11.66; S, 6.65; Si, 4.18.
4
5
. A full account of the scope of catalyst 1e has not been
reported (Wiener, J. J. M. Ph.D. Thesis, California
Institute of Technology, 2004).
. MacMillan, D. W. C.; Ahrendt, K. A. Chemical synthesis
using nonmetallic organic catalyst compositions. PCT Int.
Appl., 2001, 81pp. CODEN: PIXXD2 WO 2001053241
A1 20010726 CAN 135:122022 AN 2001:545646.
. MacMillan, D. W. C. Enantioselective transformations of
a,b-unsaturated aldehydes by a wide variety of reactions
using imidazolidinone enantiomers as chiral organic
catalysts. PCT Int. Appl., 2003, 67pp. CODEN: PIXXD2
was reduced to the corresponding alcohol with NaBH
4
(3.0 equiv) in EtOH for ee determination via chiral
supercritical fluid chromatography (SFC) using Daicel
Chiralcel OD-H or Chiralpak AD-H columns (IPA/
hexane, 1.0 mL/min flow rate).
10. Karlsson, S.; H o¨ gberg, H.-E. Eur. J. Org. Chem. 2003,
2782–2791.
11. Kezuka, S.; Ohtsuki, N.; Mita, T.; Kogami, Y.; Ashizawa,
T.; Ikeno, T.; Yamada, T. Bull. Chem. Soc. Jpn. 2003, 76,
2197–2207.
6