Highly efficient organocatalytic kinetic resolution of activated nitroallylic acetates with aldehydes via conjugate addition-elimination

Article abstract of DOI:10.1021/ol200133y

A novel, efficient, and unprecedented organocatalytic kinetic resolution has been developed. For the first time, a variety of nitroallylic acetates 1a-i have been resolved with aldehydes in the presence of 2 (2.5 mol %) via conjugate addition-elimination.

Full text of DOI:10.1021/ol200133y

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1458–1461
Highly Efficient Organocatalytic Kinetic
Resolution of Activated Nitroallylic
Acetates with Aldehydes via Conjugate
Addition-Elimination
Raju Jannapu Reddy and Kwunmin Chen*
Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan 116, ROC
kchen@ntnu.edu.tw
Received January 18, 2011
ABSTRACT
A novel, efficient, and unprecedented organocatalytic kinetic resolution has been developed. For the first time, a variety of nitroallylic acetates
1a-i have been resolved with aldehydes in the presence of 2 (2.5 mol %) via conjugate addition-elimination. The densely functionalized products
3a-o were obtained with excellent enantioselectivities (up to >99% ee), and unreacted substrates 1a-i were recovered with good to excellent
optical purity (up to 98% ee).
Kinetic resolution (KR) is an important and attractive
method for the production of enantiomerically enriched
substances from racemic mixtures.1 The process of kinetic
resolution involves a chiral agent that promotes the selective
reaction of one enantiomer over the other. In the best
scenario, both the product and the less reactive enantiomeric
substrate are obtained with high enantiomeric purity. Many
metal-catalyzed kinetic resolution procedures have been
realized.2 Nonenzymatic KR has been predominately devel-
oped to resolve various alcohols and amines via organic
molecule-mediated O/N-acylation3 and O-silylation.4 One
of the advantages and challenges of the KR process is the
creation of new chiral centers in the more reactive enantio-
mer with high asymmetric induction.5 Although small
(1) For selected reviews in KR reaction, see: (a) Keith, J. M.; Larrow,
J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5. (b) Robinson, D. E. J.
E.; Bull, S. D. Tetrahedron: Asymmetry 2003, 14, 1407. (c) Vedejs, E.; Jure,
M. Angew. Chem., Int. Ed. 2005, 44, 3974. (d) For special issue on kinetic
resolution, see: Kagan, H. B.; Fiaud, J. C. Topics in Stereochemistry; Eliel,
E. L., Fiaud, J. C., Eds.; Wiley: New York, 1988; Vol. 18, p 249.
(2) For selected references on metal-mediated kinetic resolution, see: (a)
Morken, J. P.; Didiuk, M. T.; Visser, M. S.; Hoveyda, A. H. J. Am. Chem.
Soc. 1994, 116, 3123. (b) Ramdeehul, S.; Dierkes, P.; Aguado, R.; Kamer,
P. C. J.; van Leeuwen, P. W. N. M.; Osborn, J. A. Angew. Chem., Int. Ed.
1998, 37, 3118. (c) Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 10296.
(4) For selected catalytic silylation, see: (a) Zhao, Y.; Mitra, A. W.;
Hoveyda, A. H.; Snapper, M. L. Angew. Chem., Int. Ed. 2007, 46, 8471.
(b) Isobe, T.; Fukuda, K.; Araki, Y.; Ishikawa, T. Chem. Commun. 2001,
243.
(5) For metal-mediated KR that involved the creation of new stereo-
genic centers, see: (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.;
Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103,
6237. (b) Gilbertson, S. R.; Lan, P. Org. Lett. 2001, 3, 2237. (c) Naasz,
R.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed.
€
(d) Lussem, B. J.; Gais, H.-J. J. Am. Chem. Soc. 2003, 125, 6066. (e) Fischer,
C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc. 2004, 126,
1628. (f)Notte, G. T.;Sammakia, T.;Steel, P. J.J. Am. Chem. Soc. 2005, 127,
13502. (g) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 14264. (h) Hou,
X. L.; Zheng, B. H. Org. Lett. 2009, 11, 1789.
(3) For selected O-acylation reactions, see: (a) Shiina, I.; Nakata, K.;
Ono, K.; Sugimoto, M.; Sekiguchi, A. Chem.;Eur. J. 2010, 16, 167. (b)
€
~
Muller, C. E.; Wanka, L.; Jewell, K.; Schreiner, P. R. Angew. Chem., Int. Ed.
2001, 40, 927. (d) Ohkuma, T.; Koizumi, M.; Muniz, K.; Hilt, G.;
ꢀ
2008, 47, 6180. (c) Li, X.; Liu, P.; Houk, K. N.; Birman, V. B. J. Am. Chem.
Soc. 2008, 130, 13836. (d) Birman, V. B.; Guo, L. Org. Lett. 2006, 8, 4859. (e)
Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel,
E. M. J. Am. Chem. Soc. 1998, 120, 1629. (f) Kawabata, T.; Nagato, M.;
Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169. For selected N-
acylation reactions, see: (g) Arseniyadis, S.; Valleix, A.; Wagner, A.;
Mioskowski, C. Angew. Chem., Int. Ed. 2004, 43, 3314. (h) Kanta De, C.;
Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2009, 131, 17060.
Kabuto, C.; Noyori, R. J. Am. Chem. Soc. 2002, 124, 6508. (e) Suarez,
A.; Downey, C. W.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 11244. (f)
Gayet, A.; Bertilsson, S.; Andersson, P. G. Org. Lett. 2002, 4, 3777. (g)
Faller, J. W.; Wilt, J. C.; Parr, J. Org. Lett. 2004, 6, 1301. (h) Soeta, T.;
Selim, K.; Kuriyama, M.; Tomioka, K. Tetrahedron 2007, 63, 6573. (i)
Lei, B.-L.; Ding, C.-H.; Yang, X.-F.; Wan, X.-L.; Hou, X.-L. J. Am.
Chem. Soc. 2009, 131, 18250. (j) Sibi, M. P.; Kawashima, K.; Stanley,
L. M. Org. Lett. 2009, 11, 3894.
r
10.1021/ol200133y
Published on Web 02/18/2011
2011 American Chemical Society

Table 1. Optimization of the Organocatalytic Kinetic
Resolutiona
Table 2. Substrate Scope of the Organocatalytic Kinetic
Resolutiona
time
(h)
conv
(%)b
3a,b
% eec,d
(þ)-1a
entry
R
solvent
% eed
1
Pri
Pri
Pri
Pri
Pri
Pri
Pri
Pr
toluene
CH2Cl2
Et2O
3
5
52
30
43
20
48
47
48
65
3a/>99
3a/>95
3a/>99
3a/>96
3a/>99
3a/>99
3a/>99
3b/>95
52
38
26
11
26
20
63
94
time
(h)
conv
(%)b
yield
yield
ee (%)e
2
Entry
1
R1
3 (%)c,d
1 (%)c
3/1
3
5
4
THF
5
1
1a
1a
1a
1b
1b
1c
1c
1d
1e
1f
Pr
Et
Bn
Pr
Et
Pr
Et
Et
Pr
Pr
Pri
Pr
Pri
Pri
10
10
12
12
12
12
12
12
10
15
15
12
20
48
65
68
52
57
58
66
65
55
66
61
53
68
28
40
3b/50
3c/52
3d/38
3e/42
3f/42
3g/50
3h/49
3i/40
3j/51
3k/48
3l/42
3m/54
3n/20
3o/22
1a/26
1a/28
1a/40
1b/32
1b/32
1c/30
1c/34
1d/38
1e/30
1f/36
1g/40
1g/28
1h/56
1i/35
>95/94
>99/97
>90/80
>99/90
>99/91
>99/90
>98/90
>95/91
>99/96
>99/82
>99/84
>99/98
>99/32
>89/39
5
xylenes
hexanes
toluene
toluene
2
2
6
2
3f
4
7e
8e
15
10
5
6
a Unless otherwise noted, all reactions were carried out with 1a (0.2
mmol) and isovaleraldehyde (0.6 mmol) with 2 (5 mol %) in the indicated
solvent (0.4 mL) at 0 °C. b Determined by 1H NMR analysis of the crude
mixture. c The syn-diastereoselectivity (>99:1) was determined by crude
1H NMR analysis. d Determined by chiral HPLC analyses. e 1.5 equiv of
aldehyde and 2.5 mol % of 2 were used.
7
8
9
10
11
12
13f
14g
1g
1g
1h
1i
organic molecule catalysis has been reported,3g,h,6 the crea-
tion of new stereogenic centers via the organocatalytic KR
process has not yet been explored.7 In this communication,
we wish to describe our preliminary results on the unprece-
dented organocatalytic kinetic resolution of a functionalized
racemic nitroallylic acetates (derived from nitroallylic
alcohols8) with aldehydes via conjugate addition-elimina-
tion reactions (SN20 reaction).
a All reactions performed on a 0.2 mmol scale. b Determined by 1H
NMR analyses of crude reaction mixtures. c Isolated yield. d Diastereos-
electivities of products 3a-o by crude 1H NMR analyses (see Supporting
Information). e Determined by chiral HPLC analyses. f 5 mol % of 2 was
used. g With 10 mol % of 2.
isovaleraldehyde as model substrates in the presence of 2
(Table 1). After extensive optimization, catalyst 2 was
shown to be highly active for this process with the desired
product 3a being obtained with excellent enantioselectivity
(>99% ee) (Table 1, entry 1). However, the unreacted
acetate 1a was also obtained with unsatisfactory enantios-
electivity. While various solvents afforded the product with
excellent enantioselectivity, they failed to improve the en-
antioselectivity of the recovered substrate (Table 1, entries
2-6). Further optimization of the reaction conditions was
carried out by varying the catalyst loadings, concentration,
temperature, and additive effects in toluene (see Supporting
Information). The resolution proceeded smoothly with 2
(2.5 mol %) and isovaleraldehyde (1.5 equiv), and the
recovery of acetate 1a was obtained with a reasonably good
enantioselectivity (63% ee) at 48% conversion (Table 2,
entry 7). Surprisingly, the KR process with valeraldehyde
proceeded smoothly with a high level of conversion (Table 1,
entry 8). Gratifyingly, both the product 3b and the unreacted
Diphenylprolinol trimethylsilyl ether (2)9 is now recog-
nized as one of most useful catalysts in asymmetric
organocatalysis.10 Thus, we began our study of the afore-
mentioned kinetic resolution process by using rac-1a and
(6) For other organocatalytic kinetic resolutions, see: (a) Berkessel,
A.; Cleemann, F.; Mukherjee, S. Angew. Chem., Int. Ed. 2005, 44, 7466.
(b) Chen, L.; Luo, S.; Li, J.; Li, X.; Cheng, J.-P. Org. Biomol. Chem.
2010, 8, 2627.
(7) (a) Xie, J.-W.; Fan, L.-P.; Su, H.; Li, X.-S.; Xu, D.-C. Org.
Biomol. Chem. 2010, 8, 2117. (b) Yu, J.; Chen, W.-J.; Gong, L.-Z.
Org. Lett. 2010, 12, 4050. (c) Shimada, K.; Ashburn, B. O.; Basak, A. K.;
Bow, W. F.; Vicic, D. A.; Tius, M. A. Chem. Commun. 2010, 46, 3774.
(8) (a) Deb, I.; Shanbhag, P.; Mobin, S. M.; Namboothiri, I. N. N.
Eur. J. Org. Chem. 2009, 4091. (b) Deb, I.; Dadwal, M.; Mobin, S. M.;
Namboothiri, I. N. N. Org. Lett. 2006, 8, 1201. (c) Kuan, H.-H.; Reddy,
R. J.; Chen, K. Tetrahedron 2010, 66, 9875.
(9) For selected references of enamine catalysis using 2, see: (a) Marigo,
M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2005, 44, 794. (b) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem., Int. Ed. 2005, 44, 4212. (c) Enders, D.; Hqttl, M. R. M.; Grondal, C.;
ꢀ ꢀ
Raabe, G. Nature 2006, 441, 861. (d) Garcia-Garcia, P.; Ladepeche, A.;
Halder, R.; List, B. Angew. Chem., Int. Ed. 2008, 47, 4719. (e) Chi, Y.; Guo,
L.; Kopf, N. A.; Gellman, S. H. J. Am. Chem. Soc. 2008, 130, 5608. (f)
Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song,
M.-P.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200. (g)
Belot, S.; Vogt, K. A.; Besnard, C.; Krause, N.; Alexakis, A. Angew. Chem.,
Int. Ed. 2009, 48, 8923. (h) Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Angew. Chem.,
Int. Ed. 2010, 49, 4656. (i) For a review on diaryl prolinol ether, see: Palomo,
C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876 and references cited
therein.
€
(10) For recent reviews, see: (a) Enders, D.; Grondal, C.; Huttl,
M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (b) Dondoni, A.;
Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (c) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47,
6138. (d) MacMillan, D. W. C. Nature 2008, 455, 304. (e) Bertelsen, S.;
Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178. (f) Grondal, C.; Jeanty,
M.; Enders, D. Nat. Chem. 2010, 2, 167.
Org. Lett., Vol. 13, No. 6, 2011
1459

Scheme 1. Reactivity and Resolution Effect of 1a
Scheme 2. Synthesis of both enantiomers of 3c
substrate 1a were obtained with excellent enantioselectivity
at 65% conversion when 1.5 equiv of valeraldehyde was used
in the presence of 2.5 mol % of 2 in toluene at 0 °C.
aliphatic substrate 1i were found to be poor substrates with
isovaleraldehye under the optimal reaction conditions.
The reaction required the use of 5 and 10 mol % of 2,
respectively, for reasonable conversions. However, to our
satisfaction, the desired products 3n and 3o were obtained
with high enantioselectivity (Table 2, entries 13 and 14).
These data demonstrate that the organocatalytic KR
protocol has broad applicability to resolve the multifunc-
tional acetates (1a-i) with high chemical yields and en-
antioselectivities. Notably, the densely functionalized
products (3a-o) were obtained in a nearly optically pure
form with high stereospecificity in most cases examined.
The absolute configuration of product 3a was determined
to be as an (R, S) configuration by single crystal X-ray data
analysis of camphanyl ester derived from 3a.11
The excellent enantioselectivities of 3 and the recovery of
optically active nitroallylic acetate 1 are impressive. In
order to understand this, the reactivity and resolution
process were studied using enantiomerically enriched ni-
troallylic acetate 1a. Interestingly, the acetate 1a (33% ee)
reacted slower with butyraldehyde under similar reaction
conditions (Scheme 1 vs Table 2, entry 2). Additionally,
only10% conversion wasobservedwhenthesame reaction
Encouraged by these results, we next examined the scope
of different nitroallylic acetates (1a-i) with aldehydes to
establish the general utility of our organocatalytic KR
process (Table 2). Various aldehydes reacted comfortably
with nitroallylic acetates 1 to give highly functionalized
products 3a-o with high chemical yields and excellent
enantioselectivities under the optimal reaction conditions.
With 2.5 mol % of catalyst 2, the reactions with linear
aldehydes (valeraldehyde and butyraldehyde) proceeded
in comparable smooth conversions. High chemical yields
and excellent enantioselectivities were obtained for desired
products 3b and 3c as well as the recovery substrate 1a
(Table 2, entries 1 and 2). The use of 3-phenyl propional-
dehyde with 1a in the presence of 5 mol % of 2 afforded a
high level of enantioselectivity (80% ee) of recovered 1a
with minimal sacrifice of the enantioselectivity of 3d
(Table 2, entry 3). The resolution of nitroallylic acetates
(1b-f) with electron-withdrawing and electron-donating
groupson the aromaticringalsoproceededwithhighlevels
of conversion (Table 2, entries 4-10). The 2-naphthyl
substituent 1g was an excellent substrate for this kinetic
resolution, which proceeded remarkably well with isova-
leraldehyde and valeraldehyde (Table 2, entries 11 and 12).
On the other hand, the heteroaromatic acetate 1h and
(11) Detailed X-ray crystallographic data are available from the
CCDC, 12 Union Road, Cambridge CB2, 1EZ, UK (www.ccdc.cam.
ac. uk/data_request/cif) for camphanyl derived ester of 3a (CCDC No.
785442; see Supporting information).
1460
Org. Lett., Vol. 13, No. 6, 2011

was carried out with 96% ee of the recovery acetate 1a.
This clearly demonstrates that the more reactive enantio-
mer of the acetate 1a was swept away. Thus, the present
recovered enantiomer (1a at 96% ee) was not configur-
ationally favored in allowing product formation.
In conclusion, we have successfully developed a novel
and practical organocatalytic KR procedure for the synth-
esis of highly functionalized nitroalkenes. To the best of our
knowledge, nitroallylic acetates have been resolved for the
first time by the use of the popular and prominent diphenyl-
prolinol ether 2. The KR method proceeds with the genera-
tion of new stereogenic centers via an unusual SN20 mecha-
nism. Several other features are worth noting: (a) the
KR process proceeds smoothly with low catalyst loading
(2.5 mol %); (b) the kinetic resolution process affords
excellent enantioselectivities of 3a-o, with the unreactive
substrate 1a-ibeing recovered with good to excellent optical
purity; and (c) the reaction proceeds in a highly stereospecific
fashion, where both enantiomerically enriched products are
obtained when either enantiomeric catalyst is used. The
scope of this novel resolution process and its mechanistic
aspects are currently under investigation.
The capability to produce both enantiomers with high
degrees of optical purity is important in organic synthesis.
We assumed that the in situ formation of a nucleophilic
enamine intermediate was occurring which preferentially
reacted with one enantiomer of a racemate witha high level
of stereospecificity. For practical significance, we studied
the kinetic resolution of racemic 1a and butyraldehyde
catalyzed by enantiomeric catalysts 2 and ent-2 under the
optimal reaction conditions, respectively. From Scheme 2,
the kinetic resolution procedure enabled the synthesis of
both enantiomers of product (-)-(R, S)-3c (>99% ee) and
(þ)-(S, R)-3c (>98% ee) with the recovery of nitroallylic
acetates (þ)- and (-)-1a (70% ee) at ∼50% conversion,
respectively. The recovered nitroallylic acetate (þ)-1a
(obtained from the reaction with 2) was further treated
with butyraldehyde in the presence of catalyst ent-2. The
enantiomeric (þ)-(S, R)-3c was obtained with excellent
enantioselectivity and near complete conversion in 12 h.
This indicates that the recovered acetate (þ)-1a was con-
figurationally favorable for reacting with the ent-2-derived
enamine. Similarly, the recovered acetate (-)-1a (70% ee,
obtained from ent-2 catalyst) was complimented with
catalyst 2 to allow a near complete conversion. Overall,
these studies have revealed matched and mismatched sets
of acetate 1a with organocatalysts 2 and ent-2. This was
also evident from the differing rates of reaction for the
enantiomeric nitroallylic acetates.
Acknowledgment. We thank the National Science Coun-
cil (NSC 99-2113-M-003-002-MY3 and NSC 99-2119-M-
003-001-MY2) of the Republic of China and National
Taiwan Normal University (99T3030-5 and 99-D) for finan-
cial support of this work. Our gratitude extends to the
Academic Paper Editing Clinic at NTNU and to the Na-
tional Center for High-Performance Computing for provid-
ing us with computer time and facilities.
Supporting Information Available. Experimental pro-
cedures, characterization data for new compounds, and
X-ray crystallographic data (CIF) of camphanyl ester
derived from 3a. This material is available free of charge
via the Internet at http://pubs.acs.org
Org. Lett., Vol. 13, No. 6, 2011
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