Published on Web 01/04/2006
Direct Asymmetric anti-Mannich-Type Reactions Catalyzed by a Designed
Amino Acid
Susumu Mitsumori,† Haile Zhang,† Paul Ha-Yeon Cheong,§ K. N. Houk,*,§ Fujie Tanaka,*,† and
Carlos F. Barbas, III*,†
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and Department of Chemistry and
Biochemistry, UniVersity of California, Los Angeles, California 90095-1569
Received October 13, 2005; E-mail: carlos@scripps.edu; ftanaka@scripps.edu; houk@chem.ucla.edu
Direct catalytic asymmetric Mannich reactions are highly effective carbon-carbon bond-forming reactions that are used for the
preparation of enantiomerically enriched amino acids, amino
alcohols, and their derivatives.1-7 Because of the utility of these
types of synthons, the demand for Mannich reactions that selectively
afford anti- or syn-products with high enantioselectivities is high.
syn-Selective, direct, catalytic, asymmetric Mannich reactions are
now common and have been performed using Zr-,1a Zn-,1b-d or
Cu-derived1e catalysts, Brønsted acids,2 cinchona alkaloids,3 phasetransfer catalysts,4 and proline and related organocatalysts.5,6
Enantioselective anti-Mannich reactions are, however, considerably
rarer.1a-c,7 Even a non-asymmetric anti selective Mannich reaction
would be of interest.8 Thus, the development of effective enantioselective anti-Mannich catalysts is a challenge in contemporary
asymmetric synthesis. Here we present our studies regarding a
solution to this problem and disclose the design, synthesis, and
evaluation of amino acid catalyst 1 as a highly diastereo- and
enantioselective anti-Mannich catalyst for reactions involving
unmodified aldehydes (Scheme 1).
In the reaction of unmodified aldehydes with N-p-methoxyphenyl
(PMP) protected imines catalyzed by the natural amino acid (S)proline, (2S,3S)-syn-amino aldehydes are obtained with high
enantioselectivities6 (Scheme 1). Although reactions involving some
pyrrolidine derivatives afford anti-diastereomers as their major
products, the enantioselectivities obtained with these organocatalysts
are moderate.6 To design catalysts that provide anti-products with
high levels of enantioselectivities, we revisited the key factors that
control the diastereo- and enantioselectivities of (S)-prolinecatalyzed reactions6,9 (Scheme 2 left). Four considerations are
key: (1) (E)-Enamine intermediates predominate. (2) The s-trans
conformation of the (E)-enamine reacts in the C-C bond-forming
transition state. The s-cis conformation results in steric interaction
between the enamine and the substituent at the 2-position of the
pyrrolidine ring. (3) C-C bond formation occurs at the re face of
the enamine intermediate. This facial selection is controlled by
proton-transfer from the carboxylic acid to the imine nitrogen. (4)
The enamine attacks the si face of the (E)-imine. The facial
selectivity of the imine is also controlled by the proton transfer
that increases the electrophilicity of the imine.
The stereoselective formation of the anti-products necessitates
a reversal in the facial selectivity of either the enamine or the imine,
compared to the proline-catalyzed reactions. A pyrrolidine derivative
bearing substituents at 2- and 4-positions (or at 3- and 5-positions)
(Scheme 2, right) was hypothesized to be an anti-Mannich catalyst.
The steric features of a substituent at the 5-position of the
pyrrolidine can be used to fix the conformation of the enamine
†
§
The Scripps Research Institute.
University of California, Los Angeles.
1040
9
J. AM. CHEM. SOC. 2006, 128, 1040-1041
Scheme 1
Scheme 2
(see point 2 above). This substituent can presumably be any
functional group that cannot initiate proton transfer to the imine.
The acid functionality was then placed at the distal 3-position of
the ring, to affect control of enamine and imine face selection in
the transition state (see points 3 and 4). To avoid steric interactions
between the substituent at the 5-position of the new catalyst and
the imine in the transition state, the substituents at 3- and 5-positions
should be in the trans configuration.
On the basis of these considerations, a new catalyst (3R,5R)-5methyl-3-pyrrolidinecarboxylic acid (RR35, 1) was designed. The
major transition state of the Mannich reaction catalyzed by 1 is
presented in Scheme 2 (right). Computational studies of the
1-catalyzed reaction of propionaldehyde and N-PMP-protected
R-imino methyl glyoxylate using HF/6-31G* level of theory10 were
used to test our design prior to synthesis. The catalyst was predicted
to give 95:5 anti:syn diastereoselectivity and ∼98% ee for the
formation of the (2S,3R)-product (Table 1, entry 1).
10.1021/ja056984f CCC: $33.50 © 2006 American Chemical Society
COMMUNICATIONS
Table 1. RR35 (1)-Catalyzed Mannich-Type Reactionsa
Scheme 4
entry
R1
R2
time
(h)
product
yield
(%)
drb
anti:syn
eec
(%)
1d
2
3
4
5f,g
6f,h
7
8i
9
10
Me
Me
i-Pr
n-Bu
n-Bu
n-Bu
n-Pent
CH2CHdCH2
i-Pr
n-Pent
Me
Et
Et
Et
Et
Et
Et
Et
i-Pr
i-Pr
1
3
0.5
1
2
3
3
1
1
2
3
4
4
4
5
6
7
8
70
85
54
71
57
80
72
92
85
95:5
94:6
98:2
97:3
97:3
97:3
97:3
96:4
97:3
96:4
98
>99e
99
99
99
>99
>99
>97
98
>99
a Typical conditions: To a solution of N-PMP-protected R-imino ester
(0.25 mmol, 1 equiv) and aldehyde (0.5 mmol, 2 equiv) in anhydrous DMSO
(2.5 mL), catalyst RR35 (1) (0.0125 mmol, 0.05 equiv, 5 mol % to the
imine) was added and the mixture was stirred at room temperature. b The
diastereomeric ratio (dr) was determined by 1H NMR. c The ee of the
(2S,3R)-anti-product was determined by chiral-phase HPLC analysis.
d Indicates computational predictions using methods described in the text.
e The ee was determined by HPLC analysis of the corresponding oxime
prepared with O-benzylhydroxylamine. f The reaction was performed in a
doubled scale. g Catalyst 1 (2 mol %) was used. h Catalyst 1 (1 mol %)
was used. i The reaction was performed with doubled concentration for each
reactant and catalyst 1.
Scheme 3 a
changes to 82:18 anti:syn dr and 92% ee when transition states
with the unmethylated catalyst are located. This unmethylated
catalyst was also tested in an actual reaction, for the case where
R1 ) i-Pr. This derivative afforded (2R,3S)-anti-3 in 95:5 anti:syn
dr and 93% ee, which is a drop of ∼0.6 kcal/mol from the
1-catalyzed reaction with the same substrate (Table 1, entry 3).
An efficient organocatalyst RR35 (1) for anti-Mannich-type
reactions has been developed.14 This catalyst has been demonstrated
to be useful for the synthesis of amino acid derivatives with
excellent anti-diastereoselective control and high enantioselectivities
under mild conditions. Further studies on the full scope of this
Mannich catalyst, computational studies, and other reactions
catalyzed by it and its derivatives will be reported soon.
Acknowledgment. This study was supported by The Skaggs
Institute for Chemical Biology and the National Institute of General
Medical Sciences, National Institutes of Health (GM36700 to
K.N.H.).
Supporting Information Available: Experimental procedures and
spectral and chromatographic data. This material is availablefree of
charge via the Internet at http://pubs.acs.org.
References
a (a) Known procedures (see Supporting Information); (b) (i) MsCl, Et N,
3
(ii) LiBHEt3, (iii) TBAF, 94% (3 steps); (c) TsCl, pyridine, 58%; (d)
NH4OAc, 99%; (e) NaOH, 93%; (f) (i) MsCl, Et3N, (ii) NaCN, 58% (2
steps); (g) (i) HCl, (ii) Dowex 50WX8, 90% (2 steps).
RR35 (1)11 was synthesized (Scheme 3), and Mannich reactions
involving a variety of unmodified aldehydes were studied (Table
1). In accord with the design principles and in quantitative
agreement with the computational predictions, the reactions catalyzed by 1 afforded anti-amino aldehyde products in excellent
diastereo- and enantioselectivities.12 With 5 mol % catalyst loading,
the reaction rates with catalyst 1 were approximately 2- to 3-fold
faster than the corresponding proline-catalyzed reactions that afford
the syn-products. The high catalytic efficiency of 1 allowed the
reactions to be catalyzed with only 1 or 2 mol % to afford the
desired products in reasonable yields within a few hours (Table 1,
entries 5 and 6).
Imidazole isomerization13 of the anti-3 product obtained from
the 1-catalyzed reaction and of the (2S,3S)-syn-3 product obtained
from the (S)-proline-catalyzed reaction6 confirmed that the major
anti-product generated from the 1-catalyzed reaction had a (2S,3R)
configuration. (Scheme 4).
The relative contributions of the carboxylic acid and methyl
group of 1 in directing the stereochemical outcome of the reaction
were assessed. Computational studies involving the derivative
lacking the 5-methyl group, (S)-3-pyrrolidinecarboxylic acid,
indicate that the methyl group contributes ∼1 kcal/mol toward the
anti-diastereoselectivity. That is, the result in entry 1 of Table 1
(1) (a) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120,
431. (b) Hamada, T,; Manabe, K.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 7768. (c) Matsunaga, S.; Yoshida, T.; Morimoto, H.; Kumagai, N.;
Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8777. (d) Trost, B.; Terrell,
L. R. J. Am. Chem. Soc. 2003, 125, 338. (e) Kobayashi, S.; Matsubara,
R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2003,
125, 2507.
(2) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed.
2004, 43, 1566.
(3) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. J. Am. Chem. Soc. 2005,
127, 11256.
(4) (a) Ooi, T.; Kameda, M.; Fujii, J.; Maruoka, K. Org. Lett. 2004, 6, 2397.
(b) Okada, A.; Shibuguchi, T.; Ohshima, T.; Masu, H.; Yamaguchi, K.;
Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4564.
(5) (a) Notz, W.; Watanabe, S.; Chowdari, N. S.; Zhong, G.; Betancort, J.
M.; Tanaka, F.; Barbas, C. F., III. AdV. Synth. Catal. 2004, 346, 1131.
(b) Wang, W.; Wang, J.; Li, H. Tetrahedron Lett. 2004, 45, 7243. (c)
Zhuang, W.; Saaby, S.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2004,
43, 4476. (d) Westermann, B.; Neuhaus, C. Angew. Chem., Int. Ed. 2005,
44, 4077. (e) Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G. Angew.
Chem., Int. Ed. 2005, 44, 4079.
(6) Notz, W.; Tanaka, F.; Watanabe S.; Chowdari, N. S.; Turner, J. M.;
Thayumanuvan, R.; Barbas, C. F., III. J. Org. Chem. 2003, 68, 9624 and
references therein.
(7) Yoshida, T.; Morimoto, H.; Kumagai, N.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2005, 44, 3470.
(8) Takahashi, E.; Fujisawa, H.; Mukaiyama, T. Chem. Lett. 2005, 34, 84.
(9) Bahmanyar, S.; Houk, K. N. Org. Lett. 2003, 5, 1249.
(10) HF/6-31G* was used for rapid computation of the stereoselectivity.
(11) For racemic, cis and trans mixtures of this compound, see: Juaristi, E.;
Quintana, D.; Lamatsch, B.; Seebach, D. J. Org. Chem. 1991, 56, 2553.
(12) DMSO provided the best anti selectivity and enantioselectivity of the
solvents tested for the RR35-catalyzed Mannich reaction to afford anti-3.
Reactions in DMF (anti:syn ) 97:3, 97% ee), CH3CN (96:4, 96% ee),
EtOAc (94:6, 96% ee), and dioxane (97:3, 95% ee) were as efficient with
respect to reaction rate as in DMSO.
(13) Ward, D. E.; Sales, M.; Sasmal, P. J. Org. Chem. 2004, 69, 4808.
(14) After submission of this paper, another anti-Mannich catalyst has been
reported. Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem.
Soc. 2005, 127, 16408.
JA056984F
J. AM. CHEM. SOC.
9
VOL. 128, NO. 4, 2006 1041
Supporting Information
Direct Asymmetric anti-Mannich-Type Reactions Catalyzed by a Designed Amino Acid
Susumu Mitsumori,† Haile Zhang,† Paul Ha-Yeon Cheong,§ K. N. Houk,*§ Fujie Tanaka,*† and
Carlos, F. Barbas, III*†
†
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
§
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-
1569
General: Moisture sensitive reactions were carried out under an argon atmosphere. For thin
layer chromatography (TLC), silica gel plates VWR GL60 F254 were used and compounds were
visualized by irradiation with UV light and/or by treatment with a solution of phosphomolybdic
acid (25 g), Ce(SO4)2•H2O (10 g), and conc. H2SO4 (60 mL) in H2O (940 mL) followed by
heating or by treatment with a solution of p-anisaldehyde (23 mL), conc. H2SO4 (35 mL), and
acetic acid (10 mL) in ethanol (900 mL) followed by heating. Flash column chromatography
was performed using Bodman silica gel 32-63, 60Å. 1H NMR and 13C NMR spectra were
recorded on INOVA-400 or Mer-300. Proton chemical shifts are given in δ relative to
tetramethylsilane (δ 0.00 ppm) in CDCl3 or to the residual proton signals of the deuterated
solvent in CD3OD (δ 3.35 ppm). Carbon chemical shifts were internally referenced to the
deuterated solvent signals in CDCl3 (δ 77.00 ppm) or CD3OD (δ 49.00 ppm). High-resolution
mass spectra were recorded on an Agilent ESI-TOF mass spectrometer. Enantiomeric excesses
were determined by chiral-phase HPLC using a Hitachi instrument. Optical rotations were
measured on a Perkin-Elmer 241 polarimeter.
S1
Synthesis of catalyst 1 (Scheme S1).
Scheme S1
S1
HO
HO
TBSO
(1) TBS-Cl, imidazole
(1) SOCl2, MeOH
CO2H (2) Boc2O, Na2CO3
1,4-dioxane, H2O
y. quant.
N
H
(1) MsCl, Et3N
OMs
N
Boc
AcO
9
aq. NaOH,
MeOH
Me
N
Boc 12
N
Boc
HO
TBSO
y.97%
OH
CO2Me (2) LiBH
N
4
Boc
y. 83%
y. 93%
(2) LiBHEt3, THF
(3) TBAF, THF
y. 97%
TsO
NH4OAc,
Toluene
TsCl, pyridine
Me
N
Boc 10
HO
y.58%
Me
N
Boc 11
NC
(1) MsCl, Et3N
(1) conc. HCl
Me (2) NaCN, DMSO
N
Boc 13
y. 58 %
8
Me (2) DOWEX 50W 8
N
Boc
y. 90%
14
y. 99%
HO2C
N
H
Me
1
(2S,4R)-tert-Butyl 4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1carboxylate.S1
TBSO
OH
N
Boc
This compound was synthesized from trans-4-hydroxy-L-proline by the reported procedures.S1
1
H NMR (400 MHz, CDCl3): δ 0.08 (s, 6H), 0.87 (s, 9H), 1.47 (s, 9H), 1.96 (m, 1H), 1.98 (s,
1H), 3.34 (dd, J = 4.0, 14.6Hz, 1H), 3.42 (d, J = 12.0Hz, 1H), 3.55 (m, 1H), 3.71 (m, 1H), 4.11
(m, 1H), 4.27 (m, 1H), 4.91 (dd, J = 0.8 Hz, 12.0 Hz, 1H).
(2S,4R)-tert-Butyl 4-(tert-butyldimethylsilyloxy)-2-((methylsulfonyloxy)methyl)pyrrolidine1-carboxylate (9).
TBSO
OMs
N
Boc
9
To a solution of (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine1-carboxylate (6.50 g, 19.6 mmol) and Et3N (5.5 mL, 39.2 mmol) in CH2Cl2 (80 ml) was added
MsCl (2.3 mL, 29.4 mmol) at 4 °C.S1 After stirring for 3 h at the same temperature, the mixture
was poured into water and extracted with AcOEt. The organic layers were combined, washed
(S1) Rosen, T.; Chu, D. T. W.; Lico, I. M.; Fernandes, P. B.; Marsh, K.; Shen, L.; Cepa, V. G.; Pernet, A.
G. J. Med. Chem. 1988, 31, 1598.
S2
with brine, dried over Na2SO4, and concentrated in vacuo to afford 9 (7.80 g, 97%). 1H NMR
(400 MHz, CDCl3): δ 0.07 (s, 6H), 0.87 (s, 9H), 1.58 (s, 9H), 2.04 (m, 1H), 3.00 (s, 3H), 3.36 (d,
J = 1.2Hz, 2H), 3.51 (m, 1H), 4.18 (m, 1H), 4.29 (m, 1H), 4.37 (m, 1H), 4.55 (m, 1H).
(2R,4R)-tert-Butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate (10).
HO
Me
N
Boc
10
To a solution of compound 9 (7.80 g, 24.7 mmol) in THF (20 mL) was slowly added 1 M
LiBHEt3 in THF solution (76.2 mL) at 4 °C and the mixture was allowed to warm to room
temperature. After stirring for 2.5 h, the mixture was quenched with crushed-ice and extracted
with AcOEt.S1 The organic layers were combined, washed with brine, dried over Na2SO4, and
concentrated. The residue was dissolved in THF (100 mL) and 1 M n-Bu4NF solution was added
at 4 °C.S1 After stirring for 16 h, the mixture was poured into water and extracted with AcOEt.
The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was purified by flash chromatography (hexane/AcOEt = 3:1 – 2:1) to afford
10 (3.70 g, 97%). 1H NMR (400 MHz, CDCl3): δ 1.23 (m, 3H), 1.47 (s, 9H), 1.55 (br, 1H), 1.74
(m, 1H), 2.10 (m, 1H), 3.44-3.49 (m, 2H), 4.00 (m, 1H), 4.40 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 21.20, 28.43, 42.44, 51.56, 54.28, 69.43, 79.34, 155.14. HRMS: calcd for C10H19NO3
(MNa+) 224.1257, found 224.1255.
(2R,4R)-tert-Butyl 2-methyl-4-(tosyloxy)pyrrolidine-1-carboxylate (11).
TsO
Me
N
Boc
11
To a solution of compound 10 (1.30 g, 6.46 mmol) in pyridine (10 mL) was added TsCl (2.22 g,
11.6 mmol) at 4 °C and the mixture was allowed to warm to room temperature.S2 After stirring
for 30 h, the mixture was poured into 2 N HCl solution and extracted with AcOEt. The organic
layers were combined, washed with sat. NaHCO3 solution and brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash chromatography (hexane/AcOEt = 10:1
– 6:1) to afford 11 (1.33 g, 58%). 1H NMR (400 MHz, CDCl3): δ 1.21 (d, J = 6.0, 3H), 1.44 (s,
9H), 1.74 (m, 1H), 2.26 (m, 1H), 2.46 (s, 3H), 3.41 (m, 1H), 3.62 (d, J = 13.2 Hz, 1H), 3.96 (m,
1H), 4.97 (m, 1H), 7.35 (d, J = 12.0 Hz, 2H), 7.78 (d, J = 12.0 Hz, 2H).
(S2) (a) Bridges, R. J.; Stanley, M. S.; Anderson, M. W.; Cotman, C. W.; Chamberlin, A. R.. J. Med.
Chem. 1991, 34, 717. (b) Heindl, C.; Hubner, H.; Gmeiner, P. Tetrahedron: Asymmetry 2003, 14, 3141.
S3
(2R,4S)-tert-Butyl 4-acetoxy-2-methylpyrrolidine-1-carboxylate (12).
AcO
Me
N
Boc
12
To a solution compound 11 (1.35 g, 3.80 mmol) in toluene (15 mL) was added NH4OAc (1.49 g,
4.94 mmol).S2 After reflux for 4 h, the mixture was cooled to room temperature, poured into
water, and extracted with AcOEt. The organic layers were combined, washed with brine, dried
over Na2SO4, and concentrated in vacuo. The residue was purified flash column chromatography
(hexane/AcOEt = 10:1) to afford 12 (0.91 g, 99%). 1H NMR (400 MHz, CDCl3): δ 1.30 (d, J =
5.2 Hz, 3H), 1.47 (s, 9H), 1.77 (dd, J = 0.4Hz, 14.0 Hz, 1H), 2.07 (s, 3H), 2.30 (m, 1H), 3.46 (m,
1H), 3.65 (m, 1H), 3.97 (m, 1H), 5.23 (m, 1H).
(2R,4S)-tert-Butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate (13).
HO
Me
N
Boc
13
To a solution of compound 12 (0.910 g, 3.74 mmol) in MeOH (5 mL) and THF (1 mL) was
added 2 N NaOH solution (5.6 mL, 11.2 mmol) at room temperature.S2b,S3 After stirring for 30
min, the mixture was poured into water and extracted with AcOEt. The organic layers were
combined, washed with brine, dried over Na2SO4, and concentrated in vacuo to afford 13 (0.703
g, 93%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 1.36 (d, J = 6.4 Hz, 3H), 1.47 (s,
9H), 1.59 (d, J = 3.2Hz, 1H), 1.67 (d, J = 13.6 Hz, 1H), 2.26 (m, 1H), 3.35 (dd, J = 2.0 Hz, 12.0
Hz, 1H), 3.63 (m, 1H), 3.91(m, 1H), 4.41(m, 1H). 13C NMR (100 MHz, CDCl3): δ 21.77, 28.51,
41.53, 52.49, 54.75, 77.21, 79.22, 154.52. HRMS: calcd for C10H19NO3 (MNa+) 224.1257, found
224.1262.
(2R,4R)-tert-Butyl 4-cyano-2-methylpyrrolidine-1-carboxylate (14).
NC
Me
N
Boc
14
To a solution of compound 13 (0.70 g, 3.48 mmol) and Et3N (0.97 mL, 6.96 mmol) in CH2Cl2
(10 mL) was added MsCl (0.40 mL, 5.22 mmol) at 4 °C.S2 After stirring for 3 h at the same
(S3) Zhao, X.; Hoesl, C. E.; Hoefner, G. C.; Wanner, K. T. Eur. J. Med. Chem. 2005, 40, 231.
S4
temperature, the mixture was poured into water and extracted with AcOEt. The organic layers
were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo to give the
mesylated compound (0.97 g, 100%). Without further purification, this residue was dissolved in
DMSO (10 mL) and NaCN (0.256 g, 5.22 mmol) was added.S2 This mixture was stirred at 80 °C
for 20 h. The mixture was treated with sat. NaHCO3 and extracted with AcOEt. The organic
layers were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by flash column chromatography (hexane/AcOEt = 6:1) to give 14 (0.422 g,
58%). 1 H NMR (400MHz, CDCl3): δ 1.20 (d, J = 8.4 Hz, 3H), 1.47 (s, 9H), 1.97 (m, 1H), 2.36
(m, 1H), 3.13 (m, 1H), 3.64-3.72 (m, 2H), 4.06 (br, 1H). 13C NMR (100MHz, CDCl3): δ 20.18,
26.11, 28.32, 36.73, 48.98, 52.00, 80.02, 119.88, 153.59. HRMS: calcd for C11H18N2O2 (MNa+)
233.1260, found 233.1257.
(3R,5R)-5-Methyl-3-pyrrolidinecarboxylic acid (1).
HO2C
N
H
Me
1
A solution of compound 14 (0.42 g, 2.00 mmol) in conc. HCl (4.2 mL) was refluxed for 2 h. The
mixture was concentrated in vacuo. The resulting colorless solid was dissolved in water and the
solution was loaded to Dowex 50WX8-100 ion-exchange resin (H+ form, activated with 0.01 M
HCl). The resin was washed with water then eluted with 1 M ammonium hydroxide. The eluted
fractions were lyophilized to afford 1 (0.232 g, 90%) as a colorless solid. 1H NMR (400 MHz,
CD3OD): δ 1.41 (d, J = 8.4 Hz, 3H), 1.90 (m, 1H), 2.43 (m, 1H), 3.11 (m, 1H), 3.44 (dd, J = 8.0
Hz, 11.6Hz, 1H), 3.56 (dd, J = 5.6 Hz, 11.6 Hz, 1H), 3.78 (m, 1H). 13C NMR (100 MHz,
CD3OD): δ 17.5, 37.6, 45.9, 49.3, 56.8, 179.7. HRMS: calcd for C6H11NO2 (MH+) 130.0863,
found 130.0868. [α]25D +10.3 (c 0.58, MeOH).
Another route from 10 to 13 (Scheme S2).
Scheme S2
S2
HO
O
4-Nitrobenzoic acid,DEAD,
PPh3, CH2Cl2
O
Me
N
Boc 10
HO
NO2
aq.NaOH, MeOH
Me
N
Boc
15
y.73% for 2 steps
Me
N
Boc
13
To a solution of compound 10 (0.70 g, 3.48 mmol) and PPh3 (1.37 g, 5.22 mmol) in CH2Cl2 (7
mL) was added DEAD (0.91 mL, 5.22 mmol) at 4°C.S3 The resulting mixture was stirred for 10
min and then 4-nitrobenzoic acid (1.62 g, 5.22 mmol) was added. This mixture was allowed to
S5
warm up to room temperature and stirred for 16 h. The reaction mixture was quenched with 2 N
NaOH solution and extracted with AcOEt. The organic layers were combined, washed with
brine, dried over Na2SO4, and concentrated. The residue was purified by flash column
chromatography to give 15 (0.885 g, 73 %) as a pale yellow solid. Compound 15: 1H NMR (400
MHz, CDCl3): δ 1.38 (d, J = 0.4 Hz, 3H), 1.48 (s, 9H), 1.96 (d, J = 14.4 Hz, 1H), 2.47 (m, 1H),
3.64-3.83 (m, 2H), 4.11 (m, 1H), 5.55 (m, 1H), 8.21 (d, J = 8.0 Hz, 2H), 8.31 (d, J = 8.0 Hz, 2H).
Compound 15 (0.885 g, 2.51 mmol) was dissolved in MeOH (5 mL) and THF (5 mL) and 2 N
NaOH solution was added at room temperature. After stirring for 30min, the mixture was poured
into water and extracted with AcOEt. The organic layers were combined, washed with brine,
dried over Na2SO4, and concentrated in vacuo to give compound 13 (0.52 g, 100%) as a colorless
solid.
General procedure for the Mannich-type reaction between N-PMP protected α-imino ethyl
glyoxylate and aldehyde donors (Table 1). N-PMP-protected α-imino ethyl glyoxylate (0.25
mmol, 1 equiv) was dissolved in anhydrous DMSO (2.5 mL) and aldehyde (0.5 mmol, 2 equiv)
was added, followed by catalyst 1 (0.0125 mmol, 0.05 equiv). After stirring for 0.5-3 h at room
temperature, the mixture was worked up by addition of aqueous saturated ammonium chloride
solution and extracted with AcOEt (three or four times). The combined organic layers were
washed with brine, dried with MgSO4, filtered, concentrated in vacuo, and purified by flash
column chromatography (10-15% AcOEt/hexane) to afford the corresponding Mannich addition
product. When the catalyst loading was 1 or 2 mol%, the reaction was performed using N-PMPprotected α-imino ethyl glyoxylate (0.5 mmol, 1 equiv), aldehyde (1.0 mmol, 2 equiv), and
catalyst 1 (0.005 or 0.01 mmol, 0.01 or 0.02 equiv) in DMSO (5 mL). The reactions were
performed in a closed system (a vial with a cap). An inert atmosphere of nitrogen or argon was
not necessary for the reactions.
Ethyl (2S,3R)-3-formyl-2-(p-methoxyphenylamino)butanoate (2).
OMe
O
H
HN
CO2Et
H NMR (400 MHz, CDCl3): δ 1.17 (d, J = 7.2 Hz, 3H, CHCH3), 1.23 (t, J = 7.2 Hz, 3H,
OCH2CH3), 2.85-2.92 (m, 1H, CHCHO), 3.74 (s, 3H, OCH3), 4.09 (brd, J = 8.4 Hz, 1H,
NHPMP), 4.14-4.23 (m, 2H, OCH2CH3), 4.34-4.37 (brdd, J = 6.0 Hz, 8.8 Hz, 1H, CHNHPMP),
6.66 (d, J = 9.0 Hz, 2H, ArH), 6.78 (d, J = 9.0 Hz, 2H, ArH), 9.73 (d, J = 1.2 Hz, 1H, CHCHO).
1
S6
C NMR (100 MHz, CDCl3): δ 201.9, 171.8, 153.2, 140.1, 115.6, 114.9, 61.6, 58.6, 55.7, 48.5,
14.2, 9.9. HRMS: calcd for C14H20NO4 (MH+) 266.1387, found 266.1382.
13
Ethyl (E)-3-benzyloxyiminomethyl-2-(p-methoxyphenylamino)butanoate (16).
COOH
O
PMP
H
+
Me
H
Me
N
CO2Et
Ph
N
H
(5 mol%)
DMSO
PhCH2ONH2•HCl
DMSO/pyridine
O
N
HN
PMP
CO2Et
H
Me
16
A mixture of N-PMP-protected α-imino ethyl glyoxylate (0.5 mmol, 1 equiv), an aldehyde donor
(1.0 mmol, 2 equiv), and catalyst 1 (0.025 mmol, 0.05 equiv) in DMSO (5 mL) was stirred for 1h
at room temperature. To the mixture, O-benzylhydroxylamine hydrochloride (1.3 mmol) and
pyridine (0.5 mL) were added. The mixture was stirred for an additional 4 h at room
temperature, filtered through Celite, and concentrated in vacuo. The residue was purified by
flash column chromatography to afford oxime 16. 1 H NMR (400 MHz, CDCl3): δ 1.18 (d, J =
6.6 Hz, 3H, CHCH3), 1.21 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.86-2.95 (m, 1H, CH3CHCH=N), 3.74
(s, 3H, OCH3), 3.91-3.98 (m, 2H, NHCHCO2Et), 4.14 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.07 (s,
2H, CH2Ph), 6.55 (d, J = 9.0 Hz, 2H, ArH), 6.75 (d, J = 9.0 Hz, 2H, ArH), 7.31-7.44 (m, 6H,
ArH and CH=N). 13C NMR (100 MHz, CDCl3): δ 172.5, 152.8, 151.8, 140.8, 137.6, 128.4,
128.2, 127.8, 115.2, 114.8, 75.7, 61.3, 61.2, 55.7, 37.5, 14.7, 14.2. HRMS: calcd for C21H27N2O4
(MH+) 371.1965, found 371.1966. HPLC (Daicel Chairalcel AD, hexane/i-PrOH = 99:1, flow
rate 1.0 mL/min, λ = 254 nm): tR (anti major enantiomer) = 66.6 min, tR (anti minor enatiomer) =
57.8 min.
Ethyl (2S,3R)-3-formyl-2-(p-methoxyphenylamino)-4-methylpentanoate (3).
OMe
O
H
HN
CO2Et
H NMR (300 MHz, CDCl3): δ 1.07 (d, J = 6.9 Hz, 3H, CHCH3), 1.12 (d, J = 6.9 Hz, 3H,
CHCH3), 1.21 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.02-2.18 (m, 1H, CH(CH3)2), 2.57-2.63 (m, 1H,
CHCHO), 3.74 (s, 3H, OCH3), 4.00 (brs, 1H, NHPMP), 4.15 (q, J = 6.9 Hz, 2H, OCH2CH3), 4.35
(d, J = 7.8 Hz, 1H, CHNHPMP), 6.66 (d, J = 9.0 Hz, 2H, ArH), 6.77 (d, J = 9.0 Hz, 2H, ArH),
9.75 (d, 1H, J = 3.3 Hz, CHCHO). 13C NMR (100 MHz, CDCl3): δ 203.2, 172.8, 153.2, 140.4,
115.9, 114.8, 61.3, 59.6, 57.2, 55.6, 27.5, 21.2, 19.2, 14.1. HRMS: calcd for C16H24NO4 (MH+)
294.1700, found 294.1701. HPLC (Daicel Chairalcel AS-H, hexane/i-PrOH = 99:1, flow rate
1.0 mL/min, λ = 254 nm): tR (anti major enantiomer, (2S,3R)-3) = 24.0 min, tR (anti minor
enatiomer, (2R,3S)-3) = 49.3 min. [α]25D –35.4 (c 1.8, CHCl3).
1
S7
Ethyl (2S,3R)-3-formyl-2-(p-methoxyphenylamino)octanoate (4).
OMe
O
HN
H
CO2Et
n-Bu
H NMR (300 MHz, CDCl3): δ 0.89 (m, 3H, CH2CH2CH3), 1.23 (t, J = 7.2 Hz, 3H, OCH2CH3),
1.25-1.80 (m, 6H), 2.75 (m, 1H, CHCHO), 3.74 (s, 3H, OCH 3), 4.03 (brs, 1H, NHPMP), 4.18
(dq, J = 0.9 Hz, 7.2 Hz, 2H, OCH2CH3), 4.26 (brd, J = 6.3 Hz, 1H, CHNHPMP), 6.65 (d, J = 9.0
Hz, 2H, ArH), 6.78 (d, J = 9.0 Hz, 2H, ArH), 9.65 (d, J = 2.4 Hz, 1H, CHCHO). 13C NMR (75
MHz, CDCl3): δ 202.3, 172.2, 153.2, 140.3, 115.7, 114.8, 61.5, 58.1, 55.7, 53.9, 29.4, 25.4, 22.6,
14.2, 13.8. HRMS: calcd for C17H26NO 4 (MH +) 308.1856, found 308.1852. HPLC (Daicel
Chairalcel AS-H, hexane/i-PrOH = 99:1, flow rate 1.0 mL/min, λ = 254 nm): tR (anti major
enantiomer, (2S,3R)-4) = 24.4 min, tR (anti minor enatiomer, (2R,3S)-4) = 28.5 min. [α]25D –11.0
(c 1.4, CHCl3).
1
Ethyl (2S,3R)-3-formyl-2-(p-methoxyphenylamino)heptanoate (5).
OMe
O
HN
H
CO2Et
n-Pent
H NMR (400 MHz, CDCl3): δ 0.87 (t, J = 6.8 Hz, 3H, CH2CH3), 1.23 (t, J = 7.2 Hz, 3H,
OCH2CH3), 1.24-1.78 (m, 8H), 2.72-2.78 (m, 1H, CHCHO), 3.74 (s, 3H, OCH3), 4.03 (brd, J =
6.4 Hz, 1H, NHPMP), 4.18 (dq, J = 1.6 Hz, 7.2 Hz, 2H, OCH2CH3), 4.26 (m, 1H, CHNHPMP),
6.65 (d, J = 9.2 Hz, 2H, ArH), 6.78 (d, J = 9.2 Hz, 2H, ArH), 9.65 (d, J = 2.4 Hz, 1H, CHCHO).
13
C NMR (100 MHz, CDCl3): δ 202.3, 172.2, 153.1, 140.3, 115.7, 114.8, 61.5, 58.1, 55.6, 53.9,
31.6, 27.0, 25.6, 22.3, 14.1, 13.9. HRMS: calcd for C18H27NO4 (MH + ) 322.2013, found
322.2007. HPLC (Daicel Chiralpak AS, hexane/i-PrOH = 99:1, flow rate 1.0 mL/min, λ = 254
nm): tR (anti major enantiomer, (2S,3R)-5) = 21.5 min, tR (anti minor enatiomer, (2R,3S)-5) =
24.9 min. [α]25D –11.9 (c 1.3, CHCl3).
1
Ethyl (2S,3R)-3-formyl-2-(p-methoxyphenylamino)hex-5-enoate (6).
OMe
O
H
HN
CO2Et
H NMR (400 MHz, CDCl3): δ 1 . 23 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.37-2.59 (m, 2H,
CH2CH=CH2), 2.94-2.99 (m, 1H, CHCHO), 3.74 (s, 3H, OCH 3), 4.08 (brd, J = 10.0 Hz, 1H,
1
S8
NHPMP), 4.18 (dq, J = 0.8 Hz, 7.2 Hz, 2H, OCH2CH3), 4.28 (m, 1H, CHNHPMP), 5.12-5.17
(m, 2H, CH=CH2), 5.77-5.88 (m, 1H, CH=CH2), 6.65 (d, J = 9.2 Hz, 2H, ArH), 6.77 (d, J = 9.2
Hz, 2H, Ar-H), 9.69 (d, J = 1.6 Hz, 1H, CHCHO). 13C NMR (100 MHz, CDCl3): δ 201.9, 172.2,
153.1, 140.5, 134.3, 118.2, 115.8, 114.8, 61.6, 57.7, 55.6, 53.1, 30.0, 14.1. HRMS: calcd for
C16H22NO4 (MH+) 292.1543, found 292.1537. HPLC (Daicel Chairalcel AS-H, hexane/i-PrOH
= 99:1, flow rate 1.0 mL/min, λ = 254 nm): tR (anti major enantiomer, (2S,3R)-6) = 30.2 min, tR
(anti minor enatiomer, (2R,3S)-6) = 38.5 min. [α]25D +21.5 (c 1.0, CHCl3).
Isopropyl (2S,3R)-3-formyl-2-(p-methoxyphenylamino)-4-methylpentanoate (7).
OMe
O
HN
O
H
O
H NMR (400 MHz, CDCl3): δ 1.07 (d, J = 6.8 Hz, 3H, CCHCH3), 1.12 (d, J = 6.8 Hz, 3H,
CCHCH3), 1.16 (d, J = 6.4 Hz, 3H, OCHCH3), 1.19 (d, J = 6.4 Hz, 3H, OCHCH3), 2.04-2.14 (m,
1H, CCH(CH3)2), 2.54-2.58 (m, 1H, CHCHO), 3.73 (s, 3H, OCH3), 3.90 (brs, 1H, NHPMP), 4.32
(d, J = 8.0 Hz, 1H, CHNHPMP), 4.96 (m, 1H, OCH(CH3)2), 6.66 (d, J = 8.8 Hz, 2H, ArH), 6.76
(d, J = 8.8 Hz, 2H, ArH), 9.73 (d, J = 3.6 Hz, 1H,CHCHO). 13C NMR (100 MHz, CDCl3): δ
203.2, 172.2, 153.2, 140.4, 115.9, 114.7, 69.1, 59.6, 57.4, 55.6, 27.5, 21.7, 21.6, 21.2, 19.1.
HRMS: calcd for C17H25NO4 (MH+) 308.1856, found 308.1859. HPLC (Daicel Chiralpak AS-H,
1
hexane/i-PrOH = 99:1, flow rate 1.0 mL/min, λ = 254 nm), tR (anti major enantiomer, (2S,3R)-7)
= 19.1 min, tR (anti minor enatiomer, (2R,3S)-7) = 50.7 min. [α]25D –34.7 (c 2.3, CHCl3).
Isopropyl (2S,3R)-3-formyl-2-(p-methoxyphenylamino)heptanoate (8).
OMe
O
HN
O
H
n-Pent O
H NMR (400 MHz, CDCl3): δ 0.87 (t, J = 6.9Hz, 3H, CH3), 1.18 (d, J = 6.4 Hz, 3H, OCHCH3),
1.21 (d, J = 6.4 Hz, 3H, OCHCH3), 1.25-1.76 (m, 8H), 2.69-2.74 (m, 1H, CHCHO), 3.74 (s, 3H,
OCH3), 4.02 (d, J = 10.0 Hz, 1H, NHPMP), 4.24 (dd, 1H, J = 6.8 Hz, 10.0 Hz, 1H, CHNHPMP),
4.98-5.08 (m, 1H, OCHCH3), 6.65 (d, J = 8.8 Hz, 2H, ArH), 6.77 (d, J = 8.8 Hz, 2H, ArH), 9.65
(d, J = 2.6 Hz, 1H,CHCHO). 13C NMR (100 MHz, CDCl3): δ 202.2, 171.6, 153.1, 140.3, 115.7,
114.8, 69.4, 58.2, 55.6, 53.9, 31.7, 27.0, 25.6, 22.3, 21.7, 21.7, 13.9. HRMS: calcd for
C19H29NO4 (MH+) 336.2169, found 336.2174. HPLC (Daicel Chiralpak OJ-H, hexane/i-PrOH =
99:1, flow rate 1.0 mL/min, λ = 254 nm); tR (anti major enantiomer, (2S,3R)-8) = 29.9 min, tR
(anti minor enatiomer, (2R,3S)-8) = 27.7 min. [α]25D –20.3 (c 1.5, CHCl3).
1
S9
0.16
0.14
O
NHPMP
H
0.12
CO2Et
(2S,3R)-anti-3
0.1
0.08
O
0.06
NHPMP
H
O
CO2Et
NHPMP
H
O
CO2Et
NHPMP
H
0.04
(2S,3S)-syn-3
CO2Et
(2R,3S)-anti-3
(2R,3R)-syn-3
0.02
0
-0.02 20
25
30
35
40
45
50
55
60
65
70
Time
(min)
Retention time
(min)
0.25
O
H
0.2
NHPMP
CO2Et
(2S,3R)-anti-3
O
0.15
H
0.1
NHPMP
CO2Et
O
H
(2S,3S)-syn-3
NHPMP
O
CO2Et
NHPMP
H
CO2Et
(2R,3S)-anti-3
(2R,3R)-syn-3
0.05
0
20
-0.05
25
30
35
40
45
50
55
60
65
70
Time (min)
Retention time (min)
Figure S1. HPLC charts of the Mannich product 3 generated by the 1-catalyzed reaction
(upper chart) and of a mixture of the diastereomers and enantiomers of 3 (lower chart).
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S11
S12
S13
S14
S15
S16
S17
S18
S19
S20
S21
S22
S23
S24
S25
S26