Catalytic asymmetric Mannich-type reactions of fluorinated ketoesters with N-Boc aldimines in the presence of chiral palladium complexes

Article abstract of DOI:10.1016/j.tetlet.2011.02.087

The catalytic enantioselective Mannich reaction promoted by chiral palladium complexes is described. The treatment of α-fluoro-β- ketoesters with N-Boc-aldimines under mild reaction conditions afforded the corresponding β-aminated α-fluoro-β-ketoesters wi

Full text of DOI:10.1016/j.tetlet.2011.02.087

Tetrahedron Letters 52 (2011) 2356–2358
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalytic asymmetric Mannich-type reactions of fluorinated ketoesters with
N-Boc aldimines in the presence of chiral palladium complexes
⇑
Young Ku Kang, Dae Young Kim
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic enantioselective Mannich reaction promoted by chiral palladium complexes is described.
Received 1 February 2011
Accepted 18 February 2011
Available online 24 February 2011
The treatment of
a-fluoro-b-ketoesters with N-Boc-aldimines under mild reaction conditions afforded
the corresponding b-aminated
a
-fluoro-b-ketoesters with excellent enantioselectivities (up to 99% ee).
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Mannich reaction
Asymmetric catalysis
Chiral palladium catalysts
a-Fluoro-b-ketoesters
Aldimines
Fluorine-containing compounds are of importance in organic
synthesis because of their use as medicinals and agrochemicals
and in fundamental studies of biochemical and metabolic pro-
cesses.1 Introduction of fluorine atom into biologically active com-
pounds often leads to improvement of their biological
characteristics due to the unique properties of the fluorine atom.2
Chiral fluorine-containing compounds are interesting and impor-
tant materials with uses in analytical, biological, and medicinal
chemistry and also in the chemistry of polymers and materials.
In particular, Chiral organofluorine compounds containing a fluo-
rine atom bonded directly to a stereogenic center have been uti-
lized in the studies of enzyme mechanisms and as intermediates
in asymmetric syntheses.3
for enantioselective Mannich reactions with preformed enolates10
and enolizable b-dicarbonyl and related compounds.11 Recently,
several groups report the catalytic enantioselective Mannich reac-
tions of a-fluoro-b-ketoesters with N-Boc-aldimines using various
organocatalysts.12
As part of a research program related to the development of
synthetic methods for the enantioselective construction of
stereogenic carbon centers.13 we recently reported chiral palla-
dium complexes 4 (Fig. 1) to be highly selective catalysts for the
enantioselective addition of active methines.14 In this Letter, we
wish to describe the direct enantioselective Mannich reaction of
a
-fluoro-b-ketoesters with simple N-Boc imines catalyzed by chiral
palladium complexes 4 which are air- and moisture-stable.15
Among various strategies, electrophilic fluorination of active
methines and C–C bond formation of fluorocarbon nucleophiles
are two typical approaches for the construction of fluorine-con-
taining molecules, and their asymmetric versions are particularly
attractive. Enantioselective electrophilic fluorination has been
achieved with the aid of electrophilic fluorinating agents using chi-
ral transition-metal catalysts and organocatalysts with excellent
enantioselectivities.4,5 On the other hand, the use of fluorinated ac-
In an attempt to validate the feasibility of the catalytic enantio-
selective Mannich reaction of
a-fluoro-b-ketoesters, we initially
investigated the reaction system with
a
-fluoro-b-ketoester 1a
2+
Pd
P
P
OH2
2X
P
P
*
PAr2
PAr2
=
NCMe
*
tive methine nucleophiles, such as fluoromalonate,6
a-fluoro-b-
ketoesters,7 and fluorobis(phenylsulfonyl)methane8 for a catalytic
asymmetric reaction has become increasingly popular. Enantiose-
lective Mannich reactions are efficient and powerful methods to
prepare chiral b-amino carbonyl derivatives.9 Tremendous efforts
have been made in the development of efficient chiral catalysts
4a: Ar = Ph: (R)-BINAP, X = SbF6
4b: Ar = Ph: (R)-BINAP, X = PF6
4c: Ar = Ph: (R)-BINAP, X = OTf
4d: Ar = Ph: (R)-BINAP, X = BF4
4e: Ar = 4-Me-C6H4: (R)-Tol-BINAP, X = SbF6
4f: Ar = 4-Me-C6H4: (R)-Tol-BINAP, X = BF4
4g: Ar = 3,5-Me2-C6H3: (R)-Xylyl-BINAP, X = SbF6
4h: Ar = 3,5-Me2-C6H3: (R)-Xylyl-BINAP, X = BF4
⇑
Corresponding author. Tel.: +82 41 530 1244; fax: +82 41 530 1247.
E-mail address: dyoung@sch.ac.kr (D.Y. Kim).
Figure 1. Structure of chiral palladium catalysts.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.087

Y. K. Kang, D. Y. Kim / Tetrahedron Letters 52 (2011) 2356–2358
2357
Table 3
and N-Boc aldimine 2a in the presence of 5 mol % of palladium
complexes in toluene at room temperature. We first examined
the impact of the structure of catalysts 4a–h on enantioselectivities
(Table 1, 34–99% ee, entries 1–8).
Variation of a-fluoro-b-ketoesters
O
O
NBoc
F
O
O
Ar
OEt
cat. 4d (5 mol%)
Catalyst 4d gave the desired product 3a with high enantioselec-
tivity (99% ee, entry 4). Based on the exploratory studies, we
decided to select catalyst 4d for further optimization of reaction
conditions. A survey of the reaction media indicated that many
common solvents, such as toluene, DCM, acetone, and THF (entries
4 and 9–11), were well tolerated in this Mannich reaction with
moderate to high enantioselectivities. Among the solvents probed,
the best results (78% yield, 75:25 dr, and 99% ee) were achieved
when the reaction was conducted in toluene (entry 4). We then ex-
plored the possibility of using a wide range of N-Boc protected
+
Ar
OEt
NHBoc
PhMe, rt, 7 h
F
1
2a
3
Entry
1, Ar
Yielda (%)
drb (%)
eec (%)
1
2
3
4
1a, p-Me-Ph
1b, m-Br-Ph
1c, m-Cl-Ph
1d, 2-thienyl
3j, 78
3k, 77
3l, 80
3m, 89
67:35
56:44
59:41
64:36
93
94
99
93
a
Yield of the isolated product.
substituted aromatic and heteroaromatic aldimines
2
with
The diastereomeric ratio was determined by 1H NMR spectroscopic analysis of
b
a-fluoro-b-ketoester 1a under the optimized reaction condition.
the crude product.
c
Enantiopurity of major diastereomer of 3j–3m was determined by HPLC anal-
ysis with Chiralpak IC (for 3j, 3l), IA (for 3k) and AS-H (for 3m) columns.
Table 1
Optimization of the reaction conditions
O
O
NBoc
F
O
O
O
O
Ph
OEt
cat. 4 (5 mol%)
F
NBoc
+
OEt
O
O
Ph
OR
NHBoc
cat. 4d (5 mol%)
solvent, rt
NHBoc
F
+
OR
PhMe, rt, 10 h
F
1a
2a
3a
3n, R = Et, 73%, 87:13 dr, 86% ee
3m, R = Bn, 85%, 72:28 dr, 87% ee
1e, R = Et
1f, R = Bn
2a
Entry
Cat
Solvent
Time (h)
Yielda (%)
drb (%)
eec (%)
Scheme 1.
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4d
4d
4d
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DCM
5
5
5
7
5
5
5
5
5
5
5
72
74
65
78
73
75
62
90
65
45
61
70:30
74:26
42:58
75:25
67:33
66:34
61:39
63:37
66:34
56:44
60:40
67
64
34
99
92
93
41
73
76
56
74
As shown in Table 2, the products 3a–i were formed in high yields
(73–88%), excellent diastereoselectivities (62:38–>99:1), and
excellent enantioselectivities (94–99%).
To examine the generality of the catalytic enantioselective Man-
-fluoro-b-ketoesters 1 by using chiral palladium
complex 4d, we studied the addition of various
ers 1 to N-Boc aldimine 2a. As it can be seen by the results summa-
rized in Table 3, the corresponding products 3j–m were obtained
in high to excellent yields (77–89%), high diastereoselectivities
(59:41–67:35), and excellent enantioselectivities (93–99%).16
Absolute configuration of major diastereomer of 3a was deter-
mined to be (2S,3S) by comparison of the optical rotation and chiral
HPLC data with the published values in literature.12a
nich reaction of
a
a-fluoro-b-ketoest-
9
10
11
Acetone
THF
a
Yield of isolated product.
The diastereomeric ratio was determined by 1H NMR spectroscopic analysis of
the crude product.
Enantiomeric excess of major diastereomer was determined by HPLC analysis
using Chiralpak AD-H column.
b
c
We examined the direct enantioselective Mannich-type reac-
tion of
a-fluoro acetoacetate derivatives 1e–f with N-Boc p-tolu-
Table 2
aldimine (2a) using chiral palladium catalyst 4d in toluene at
room temperature. In the presence of 5 mol % of catalyst 4d, the
reaction proceeded to afford the b-aminated product 3n–m after
10 h with 86–87% ee (Scheme 1).
Variation of N-Boc aldimines
O
O
O
O
F
NBoc
cat. 4d (5 mol%)
+
Ph
OEt
Ph
OEt
Ar
PhMe, rt, 7 h
In conclusion, we have developed a highly efficient catalytic
F
Ar
NHBoc
enantioselective Mannich reaction of
a-fluoro-b-ketoesters using
1a
3
2
chiral palladium complexes 4 which are air- and moisture-stable.
The desired b-aminated products were obtained in good to high
yields, and high enantioselectivities (up to 99% ee) were observed
for all the substrates examined in this work. We believe that this
method provides a practical entry for the preparation of chiral b-
Entry
2, Ar
Yielda (%)
drb (%)
eec (%)
1
2
3
4
5
6
7
8
9
2a, p-MeC6H4
2b, p-FC6H4
2c, p-ClC6H4
2d, Ph
2e, o-FC6H4
2f, o-ClC6H4
2g, 2-naphthyl
2h, thienyl
2i, furyl
3a, 78
3b, 82
3c, 82
3d, 88
3e, 73
3f, 77
3g, 83
3h, 85
3i, 82
75:25
87:13
62:38
77:23
>99:1
67:33
74:26
72:28
69:31
99
94
98
94
95
97
94
95
96
aminated
a-fluoro-b-ketoester derivatives. Further details and
application of this Mannich-type reaction will be presented in
due course.
References and notes
a
Yield of isolated product.
The diastereomeric ratio was determined by 1H NMR spectroscopic analysis of
1. (a) Hudlicky, M.; Pavlath, A. E. Chemistry of Organic Fluorine Compounds II;
American Chemical Society: Washington, DC, 1995; (b) Kirk, K. L. J. J. Fluorine
Chem. 2006, 127, 1013; (c) Isanobor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127,
303; (d) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881; (e) Kirk, K. L.
Org. Process Res. Dev. 2008, 12, 305.
b
the crude product.
c
Enantiopurity of major diastereomer of 3 was determined by HPLC analysis
with Chiralpak AD-H (for 3a), AS-H (for 3g) and IA (for 3b–3f, 3h–3i) columns.

2358
Y. K. Kang, D. Y. Kim / Tetrahedron Letters 52 (2011) 2356–2358
2. (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320; (b) Hiyama, T.; Kanie, K.; Kusumoto, T.; Morizawa, Y.; Shimizu, M.
Organofluorine Compounds: Chemistry and Applications; Springer-Verlag: Berlin,
2000.
3. (a)Enantiocontrolled Synthesis of Fluoro-organic Compounds; Soloshonok, V. A.,
Ed.; John Wiley & Sons: Chichester, 1999; (b) Bravo, P.; Resnati, G. Tetrahedron:
Asymmetry 1990, 1, 661; (c)Asymmetric Fluoroorganic Chemistry: Synthesis,
Application, and Future Directions; Ramachandran, P. V., Ed.ACS Symposium
Series 746; American Chemical Society: Washington, DC, 2000.
4. For reviews, see: (a) Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. Rev. 2004, 104, 1;
(b) Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147; (c) Ma, J.-A.; Cahard, D.
Chem. Rev. 2008, 108, PR1; (d) France, S.; Weatherwax, A.; Lectka, T. Eur. J. Org.
Chem. 2005, 475; (e) Oestreich, M. Angew. Chem., Int. Ed. 2005, 44, 2324; (f)
Pihko, P. M. Angew. Chem., Int. Ed. 2006, 45, 544; (g) Prakash, G. K. S.; Beier, P.
Angew. Chem., Int. Ed. 2006, 45, 2172; (h) Bobbio, C.; Gouverneur, V. Org. Biomol.
Chem. 2006, 4, 2065; (i) Shibata, N.; Ishimaru, T.; Nakamura, S.; Toru, T. J.
Fluorine Chem. 2007, 128, 469; (j) Brunet, V. A.; O’Hagan, D. Angew. Chem., Int.
Ed. 2008, 47, 1179; (k) Smits, R.; Cadicamo, C. D.; Burger, K.; Koksch, B. Chem.
Soc. Rev. 2008, 37, 1727; (l) Kang, Y. K.; Kim, D. Y. Curr. Org. Chem. 2010, 14, 917.
5. For recent selected examples of catalytic asymmetric fluorinations of active
methines, see: (a) Hintermann, L.; Togni, A. Angew. Chem., Int. Ed. 2000, 39,
4359; (b) Kim, D. Y.; Park, E. J. Org. Lett. 2002, 4, 545; (c) Hamashima, Y.; Yagi,
K.; Takano, H.; Tamás, L.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 14530; (d)
Ma, J.-A.; Cahard, D. Tetrahedron: Asymmetry 2004, 15, 1007; (e) Shibata, N.;
Ishimaru, T.; Nagai, T.; Kohno, J.; Toru, T. Synlett 2004, 1703; (f) Bernardi, L.;
Jørgensen, K. A. Chem. Commun. 2005, 1324; (g) Kim, S. M.; Kim, H. R.; Kim, D. Y.
Org. Lett. 2005, 7, 2309; (h) Kim, H. R.; Kim, D. Y. Tetrahedron Lett. 2005, 46,
3115; (i) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru,
T.; Shiro, M. Angew. Chem., Int. Ed. 2008, 47, 4157; (j) Lee, N. R.; Kim, S. M.; Kim,
D. Bull. Korean Chem. Soc. 2009, 30, 829; (k) Kang, S. H.; Kim, D. Y. Adv. Synth.
Catal. 2010, 352, 2783.
10. Selected examples of Mannich-type reactions of enolates, see: (a) Sikert, M.;
Schneider, C. Angew. Chem., Int. Ed. 2008, 47, 3631; (b) Itoh, J.; Fuchibe, K.;
Akiyama, T. Synthesis 2008, 1319; (c) Kobayashi, S.; Yazaki, R.; Seki, K.; Ueno,
M. Tetrahedron 2007, 63, 8425; (d) Saruhashi, K.; Kobayashi, S. J. Am. Chem. Soc.
2006, 128, 11232; (e) Kobayashi, S.; Ueno, M.; Saito, S.; Mizuki, Y.; Ishitani, H.;
Yamashita, Y. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5476; (f) Akiyama, T.; Itoh,
J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566; (g) Wenzel, A.
G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.
11. (a) Hamashima, Y.; Sasamoto, N.; Umebayashi, N.; Sodeoka, M. Chem. Asian J.
2008, 3, 1443; (b) Chen, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2008, 130, 2170; (c) Kobayashi, S.; Gustafsson, T.; Shimizu, Y.;
Kiyohara, H.; Matsubara, R. Org. Lett. 2006, 8, 4923; (d) Hamashima, Y.;
Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem.,
Int. Ed. 2005, 44, 1525; (e) Kang, Y. K.; Kim, D. Y. J. Org. Chem. 2009, 74, 5734; (f)
Lee, J. H.; Kim, D. Y. Adv. Synth. Catal. 2009, 351, 1779; (g) Kim, E. J.; Kang, Y. K.;
Kim, D. Y. Bull. Korean Chem. Soc. 2009, 30, 1437; (h) Lee, J. H.; Kim, D. Y.
Synthesis 2010, 1860.
12. (a) Han, X.; Kwiatkowski, J.; Xue, F.; Huang, K.-W.; Lu, Y. Angew. Chem., Int. Ed.
2009, 48, 7604; (b) Jiang, Z.; Pan, Y.; Zhao, Y.; Ma, T.; Lee, R.; Yang, Y.; Huang,
K.-W.; Wong, M. W.; Tan, C.-H. Angew. Chem., Int. Ed. 2009, 48, 3627; (c) Pan, Y.;
Zhao, Y.; Ma, T.; Yang, Y.; Liu, H.; Jiang, Z.; Tan, C.-H. Chem. Eur. J. 2010, 16, 779;
(d) Yoon, S. J.; Kang, Y. K.; Kim, D. Y. Synlett 2011, 420.
13. (a) Kim, D. Y.; Huh, S. C.; Kim, S. M. Tetrahedron Lett. 2001, 42, 6299; (b) Kim, D.
Y.; Huh, S. C. Tetrahedron 2001, 57, 8933; (c) Park, E. J.; Kim, M. H.; Kim, D. Y. J.
Org. Chem. 2004, 69, 6897; (d) Mang, J. Y.; Kim, D. Y. Bull. Korean Chem. Soc.
2008, 29, 2091; (e) Kang, Y. K.; Kim, D. Y. Bull. Korean Chem. Soc. 2008, 29, 2093;
(f) Kim, S. M.; Lee, J. H.; Kim, D. Y. Synlett 2008, 2659; (g) Jung, S. H.; Kim, D. Y.
Tetrahedron Lett. 2008, 49, 5527; (h) Kim, D. Y. Bull. Korean Chem. Soc. 2008, 29,
2036; (i) Mang, J. Y.; Kwon, D. G.; Kim, D. Y. Bull. Korean Chem. Soc. 2009, 30,
249; (j) Kwon, B. K.; Kim, D. Y. Bull. Korean Chem. Soc. 2009, 30, 1441; (k) Kang,
Y. K.; Kim, S. M.; Kim, D. Y. J. Am. Chem. Soc. 2010, 132, 11847.
6. For asymmetric Michael-type reactions of
a
-fluoromalonates, see: (a) Kim, D.
14. (a) Kang, Y. K.; Kim, D. Y. Tetrahedron Lett. 2006, 47, 4565; (b) Kang, Y. K.; Cho,
M. J.; Kim, S. M.; Kim, D. Y. Synlett 2007, 1135; (c) Cho, M. J.; Kang, Y. K.; Lee, N.
R.; Kim, D. Y. Bull. Korean Chem. Soc. 2007, 28, 2191; (d) Kim, S. M.; Kang, Y. K.;
Cho, M. J.; Mang, J. Y.; Kim, D. Y. Bull. Korean Chem. Soc. 2007, 28, 2435; (e) Lee,
J. H.; Bang, H. T.; Kim, D. Y. Synlett 2008, 1821; (f) Kang, S. H.; Kang, Y. K.; Kim,
D. Y. Tetrahedron 2009, 65, 5676.
15. (a) Li, K.; Horton, P. N.; Hursthouse, M. B.; Hii, K. K. J. Organomet. Chem. 2003,
665, 250; For a aquapalladium complex, see (b) Shimada, T.; Bajracharya, G. B.;
Yamamoto, Y. Eur. J. Org. Chem. 2005, 59. and references cited therein; (c)
Vicente, J.; Arcas, A. Coord. Chem. Rev. 2005, 249, 1135.
Y.; Kim, S. M.; Koh, K. O.; Mang, J. Y. Bull. Korean Chem. Soc. 2003, 24, 1425; (b)
Nichols, P. J.; DeMattei, J. A.; Barnett, B. R.; LeFur, N. A.; Chuang, T.-H.; Piscopio,
A. D.; Koch, K. Org. Lett. 2006, 8, 1495; (c) Kwon, B. K.; Kim, S. M.; Kim, D. Y. J.
Fluorine Chem. 2009, 130, 759; (d) Companyo, X.; Hejnova, M.; Kamlar, M.;
Vesely, J.; Moyano, A.; Rios, R. Tetrahedron Lett. 2009, 50, 5051; (e) Kang, S. H.;
Kim, D. Y. Bull. Korean Chem. Soc. 2009, 30, 1439.
7. For asymmetric Michael-type reactions of
a-fluoro-b-ketoesters, see: (a)
Nakamura, M.; Hajra, A.; Endo, K.; Nakamura, E. Angew. Chem., Int. Ed. 2005, 44,
7248; (b) He, R.; Wang, X.; Hashimoto, T.; Maruoka, K. Angew. Chem., Int. Ed. 2008,
47, 9466; (c) Mang, J. Y.; Kwon, D. G.; Kim, D. Y. J. Fluorine Chem. 2009, 130, 259;
(d) Han, X.; Luo, J.; Liu, C.; Lu, Y. Chem. Commun. 2009, 2044; (e) Li, H.; Zhang, S.;
Yu, C.; Song, X.; Wang, W. Chem. Commun. 2009, 2136; (f) Oh, Y.; Kim, S. M.; Kim,
D. Y. Tetrahedron Lett. 2009, 50, 4674; (g) Ishimaru, T.; Ogawa, S.; Tokunaga, E.;
Nakamura, S.; Shibata, N. J. Fluorine Chem. 2009, 130, 1049; (h) Cui, H.-F.; Yang, Y.-
Q.; Chai, Z.; Li, P.; Zheng, C.-W.; Zhu, S.-Z. J. Org. Chem. 2010, 75, 117.
8. For asymmetric reactions using fluorobis(phenysulfonyl)methane derivatives,
see: (a) Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T.
Angew. Chem., Int. Ed. 2006, 45, 4973; (b) Mizuta, S.; Shibata, N.; Goto, Y.;
Furukawa, T.; Nakamura, S.; Toru, T. J. Am. Chem. Soc. 2007, 129, 6394; (c)
Furukawa, T.; Shibata, N.; Mizuta, S.; Nakamura, S.; Toru, T.; Shiro, M. Angew.
Chem., Int. Ed. 2008, 47, 8051; (d) Moon, H. W.; Cho, M. J.; Kim, D. Y. Tetrahedron
Lett. 2009, 50, 4896; (e) Furukawa, T.; Goto, Y.; Kawazoe, J.; Tokunaga, E.;
Nakamura, S.; Yang, Y.; Du, H.; Kakehi, A.; Shiro, M.; Shibata, N. Angew. Chem.,
Int. Ed. 2010, 49, 1642.
16. Typical procedure for Mannich Reaction of ethyl 2-fluoro-3-oxo-3-
phenylpropanoate 1a with N-Boc p-tolualdimine 2a: To a stirred solution of
ethyl 2-fluoro-3-oxo-3-phenylpropanoate (1a, 0.3 mmol, 63.0 mg) and catalyst
4d (0.015 mmol, 14.4 mg) in toluene (3 mL) was added N-Boc p-tolualdimine
(2a, 0.45 mmol, 98.6 mg). Reaction mixture was stirred for 7 h at room
temperature, concentrated, and purified by flash column chromatography
(EtOAc/hexane: 1/7) to afford the Mannich adduct 3a (100.4 mg, 78%). (2S, 3S)-
Ethyl 2-benzoyl-3-(tert-butoxycarbonylamino)-2-fluoro-3-p-tolylpropanoate (3a).
Major diastereomer: ½a D31
ꢀ
= 28.7 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) d
1.28 (t, J = 6.9 Hz, 3H), 1.39 (s, 9H), 2.26 (s, 3H), 4.18–4.39 (m, 2H), 5.44 (d,
J = 10.4 Hz, 1H), 5.96 (dd, 2J = 28.9 Hz, 1J = 10.4 Hz, 1H), 7.04–7.08 (m, 2H),
7.26–7.29 (m, 2H), 7.34–7.39 (m, 2H), 7.49–7.54 (m, 1H), 7.81–7.84 (m, 2H);
13C NMR (50 MHz, CDCl3) d 13.77, 20.96, 28.11, 57.11 (d, J = 18.35 Hz), 63.01,
79.96, 102.21 (d, J = 203.75 Hz), 128.35, 128.56, 128.96, 129.33, 129.46, 133.54,
133.66, 137.71, 154.29, 165.49 (d, J = 26.9 Hz), 190.76 (d, J = 25.6 Hz); ESI-
HRMS: m/z calcd for C24H29FNO5 [M+H]+: 430.2030; found 430.2034; HPLC
(80:20, n-hexane: i-PrOH, 254 nm, 1.0 mL/min) Chiralpak AD-H column,
tR = 10.4 min (minor), tR = 14.9 min (major), 99% ee.
9. For selected recent reviews, see: (a) Cordova, A. Acc. Chem. Res. 2004, 37, 102;
(b) Marques, M. M. B. Angew. Chem., Int. Ed. 2006, 45, 348; (c) Ting, A.; Schaus, S.
E. Eur. J. Org. Chem. 2007, 5797; (d) Verkade, J. M. M.; van Hemert, L. J. C.;
Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. Rev. 2008, 37, 29; (e) Hatano,
M.; Ishihara, K. Synthesis 2010, 3785.