Direct Asymmetric anti -Mannich-Type Reactions Catalyzed by a DesignedAmino Acid

Susumu Mitsumori,† Haile Zhang,† Paul Ha-Yeon Cheong,§ K. N. Houk,*,§ Fujie Tanaka,*,† andCarlos F. Barbas, III*,†

The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology, The ScrippsResearch 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 effec-tive carbon-carbon bond-forming reactions that are used for thepreparation of enantiomerically enriched amino acids, aminoalcohols, and their derivatives.1-7 Because of the utility of thesetypes of synthons, the demand for Mannich reactions that selectivelyafford anti- or syn-products with high enantioselectivities is high.syn-Selective, direct, catalytic, asymmetric Mannich reactions arenow common and have been performed using Zr-,1a Zn-,1b-d orCu-derived1e catalysts, Brønsted acids,2 cinchona alkaloids,3 phase-transfer catalysts,4 and proline and related organocatalysts.5,6

Enantioselectiveanti-Mannich reactions are, however, considerablyrarer.1a-c,7 Even a non-asymmetricanti selective Mannich reactionwould be of interest.8 Thus, the development of effective enanti-oselectiveanti-Mannich catalysts is a challenge in contemporaryasymmetric synthesis. Here we present our studies regarding asolution to this problem and disclose the design, synthesis, andevaluation of amino acid catalyst1 as a highly diastereo- andenantioselectiveanti-Mannich catalyst for reactions involvingunmodified aldehydes (Scheme 1).

In the reaction of unmodified aldehydes withN-p-methoxyphenyl(PMP) protected imines catalyzed by the natural amino acid (S)-proline, (2S,3S)-syn-amino aldehydes are obtained with highenantioselectivities6 (Scheme 1). Although reactions involving somepyrrolidine derivatives affordanti-diastereomers as their majorproducts, the enantioselectivities obtained with these organocatalystsare moderate.6 To design catalysts that provideanti-products withhigh levels of enantioselectivities, we revisited the key factors thatcontrol the diastereo- and enantioselectivities of (S)-proline-catalyzed reactions6,9 (Scheme 2 left). Four considerations arekey: (1) (E)-Enamine intermediates predominate. (2) The s-transconformation of the (E)-enamine reacts in the C-C bond-formingtransition state. The s-cis conformation results in steric interactionbetween the enamine and the substituent at the 2-position of thepyrrolidine ring. (3) C-C bond formation occurs at there face ofthe enamine intermediate. This facial selection is controlled byproton-transfer from the carboxylic acid to the imine nitrogen. (4)The enamine attacks thesi face of the (E)-imine. The facialselectivity of the imine is also controlled by the proton transferthat increases the electrophilicity of the imine.

The stereoselective formation of theanti-products necessitatesa reversal in the facial selectivity of either the enamine or the imine,compared to the proline-catalyzed reactions. A pyrrolidine derivativebearing substituents at 2- and 4-positions (or at 3- and 5-positions)(Scheme 2, right) was hypothesized to be ananti-Mannich catalyst.The steric features of a substituent at the 5-position of thepyrrolidine can be used to fix the conformation of the enamine

(see point 2 above). This substituent can presumably be anyfunctional group that cannot initiate proton transfer to the imine.The acid functionality was then placed at the distal 3-position ofthe ring, to affect control of enamine and imine face selection inthe transition state (see points 3 and 4). To avoid steric interactionsbetween the substituent at the 5-position of the new catalyst andthe imine in the transition state, the substituents at 3- and 5-positionsshould be in thetrans configuration.

On the basis of these considerations, a new catalyst (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid (RR35,1) was designed. Themajor transition state of the Mannich reaction catalyzed by1 ispresented in Scheme 2 (right). Computational studies of the1-catalyzed reaction of propionaldehyde andN-PMP-protectedR-imino methyl glyoxylate using HF/6-31G* level of theory10 wereused to test our design prior to synthesis. The catalyst was predictedto give 95:5anti:syn diastereoselectivity and∼98% ee for theformation of the (2S,3R)-product (Table 1, entry 1).

† The Scripps Research Institute.§ University of California, Los Angeles.

Scheme 1

Scheme 2

Published on Web 01/04/2006

1040 9 J. AM. CHEM. SOC. 2006 , 128, 1040-1041 10.1021/ja056984f CCC: $33.50 © 2006 American Chemical Society

RR35 (1)11 was synthesized (Scheme 3), and Mannich reactionsinvolving a variety of unmodified aldehydes were studied (Table1). In accord with the design principles and in quantitativeagreement with the computational predictions, the reactions cata-lyzed by 1 afforded anti-amino aldehyde products in excellentdiastereo- and enantioselectivities.12 With 5 mol % catalyst loading,the reaction rates with catalyst1 were approximately 2- to 3-foldfaster than the corresponding proline-catalyzed reactions that affordthe syn-products. The high catalytic efficiency of1 allowed thereactions to be catalyzed with only 1 or 2 mol % to afford thedesired products in reasonable yields within a few hours (Table 1,entries 5 and 6).

Imidazole isomerization13 of the anti-3 product obtained fromthe1-catalyzed reaction and of the (2S,3S)-syn-3 product obtainedfrom the (S)-proline-catalyzed reaction6 confirmed that the majoranti-product generated from the1-catalyzed reaction had a (2S,3R)configuration. (Scheme 4).

The relative contributions of the carboxylic acid and methylgroup of1 in directing the stereochemical outcome of the reactionwere assessed. Computational studies involving the derivativelacking the 5-methyl group, (S)-3-pyrrolidinecarboxylic acid,indicate that the methyl group contributes∼1 kcal/mol toward theanti-diastereoselectivity. That is, the result in entry 1 of Table 1

changes to 82:18anti:syn dr and 92% ee when transition stateswith the unmethylated catalyst are located. This unmethylatedcatalyst was also tested in an actual reaction, for the case whereR1 ) i-Pr. This derivative afforded (2R,3S)-anti-3 in 95:5anti:syndr and 93% ee, which is a drop of∼0.6 kcal/mol from the1-catalyzed reaction with the same substrate (Table 1, entry 3).

An efficient organocatalyst RR35 (1) for anti-Mannich-typereactions has been developed.14 This catalyst has been demonstratedto be useful for the synthesis of amino acid derivatives withexcellentanti-diastereoselective control and high enantioselectivitiesunder mild conditions. Further studies on the full scope of thisMannich catalyst, computational studies, and other reactionscatalyzed by it and its derivatives will be reported soon.

Acknowledgment. This study was supported by The SkaggsInstitute for Chemical Biology and the National Institute of GeneralMedical Sciences, National Institutes of Health (GM36700 toK.N.H.).

Supporting Information Available: Experimental procedures andspectral and chromatographic data. This material is availablefree ofcharge via the Internet at http://pubs.acs.org.

References

(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 andreferences 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 bestanti selectivity and enantioselectivity of thesolvents tested for the RR35-catalyzed Mannich reaction to affordanti-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 withrespect 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, anotheranti-Mannich catalyst has beenreported. Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K.J. Am. Chem.Soc.2005, 127, 16408.

JA056984F

Table 1. RR35 (1)-Catalyzed Mannich-Type Reactionsa

entry R1 R2

time(h) product

yield(%)

drb

anti:syneec

(%)

1d Me Me - - - 95:5 982 Me Et 1 2 70 94:6 >99e

3 i-Pr Et 3 3 85 98:2 994 n-Bu Et 0.5 4 54 97:3 995f,g n-Bu Et 1 4 71 97:3 996f,h n-Bu Et 2 4 57 97:3 >997 n-Pent Et 3 5 80 97:3 >998i CH2CHdCH2 Et 3 6 72 96:4 >979 i-Pr i-Pr 1 7 92 97:3 9810 n-Pent i-Pr 1 8 85 96:4 >99

a Typical conditions: To a solution ofN-PMP-protectedR-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 theimine) was added and the mixture was stirred at room temperature.b Thediastereomeric ratio (dr) was determined by1H 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 oximeprepared withO-benzylhydroxylamine.f The reaction was performed in adoubled scale.g Catalyst1 (2 mol %) was used.h Catalyst1 (1 mol %)was used.i The reaction was performed with doubled concentration for eachreactant and catalyst1.

Scheme 3 a

a (a) Known procedures (see Supporting Information); (b) (i) MsCl, Et3N,(ii) LiBHEt 3, (iii) TBAF, 94% (3 steps); (c) TsCl, pyridine, 58%; (d)NH4OAc, 99%; (e) NaOH, 93%; (f) (i) MsCl, Et3N, (ii) NaCN, 58% (2steps); (g) (i) HCl, (ii) Dowex 50WX8, 90% (2 steps).

Scheme 4

C O M M U N I C A T I O N S

J. AM. CHEM. SOC. 9 VOL. 128, NO. 4, 2006 1041

S1

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.

S2

Synthesis of catalyst 1 (Scheme S1).

NH

CO2H

HO

NBoc

CO2Me

HO(1) SOCl2, MeOH

(2) Boc2O, Na2CO3 1,4-dioxane, H2O

(1) TBS-Cl, imidazole

(2) LiBH4 NBoc

TBSO

OH

NBoc

Me

HO

(1) MsCl, Et3N (2) LiBHEt3, THF

(3) TBAF, THF

NBoc

Me

HO

(1) MsCl, Et3N

(2) NaCN, DMSONBoc

Me

NC(1) conc. HCl

y. quant. y. 83%

y. 97%NBoc

Me

TsO

NBoc

Me

AcO

TsCl, pyridine

y.58%

NH4OAc,Toluene

y. 99%

y. 58 % y. 90%NH

Me

HO2Caq. NaOH, MeOH

y. 93%(2) DOWEX 50W 8

11413

10

12

11

8

NBoc

TBSO

OMs

9y.97%

S1

(2S,4R)-tert-Butyl 4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1-

carboxylate.S1

NBoc

TBSO

OH

This compound was synthesized from trans-4-hydroxy-L-proline by the reported procedures.S1

1H 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)pyrrolidine-

1-carboxylate (9).

NBoc

TBSO

OMs

9

To a solution of (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-

1-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.

Scheme S1

S3

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).

NBoc

Me

HO

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).

NBoc

Me

TsO

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.

S4

(2R,4S)-tert-Butyl 4-acetoxy-2-methylpyrrolidine-1-carboxylate (12).

NBoc

Me

AcO

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).

NBoc

Me

HO

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).

NBoc

Me

NC

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.

S5

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%). 1H 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).

NH

Me

HO2C

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).

NBoc

Me

HO

NBoc

Me

HO4-Nitrobenzoic acid,DEAD, PPh3, CH2Cl2 aq.NaOH, MeOH

y.73% for 2 steps13

10

NBoc

Me

O

ONO2

15

S2

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

Scheme S2

S6

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 αααα-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-PMP-

protected 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).

H CO2Et

O HN

OMe

1H 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).

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13C 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.

Ethyl (E)-3-benzyloxyiminomethyl-2-(p-methoxyphenylamino)butanoate (16).

H CO2Et

NPMP

H

O

Me+

NH

COOH

Me

DMSO(5 mol%) H CO2Et

N

Me

HNPMPOPh

16

PhCH2ONH2•HCl

DMSO/pyridine

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. 1H 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).

H CO2Et

O HN

OMe

1H 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).

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Ethyl (2S,3R)-3-formyl-2-(p-methoxyphenylamino)octanoate (4).

H CO2Et

O

n-Bu

HN

OMe

1H 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, OCH3), 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 C17H26NO4 (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).

Ethyl (2S,3R)-3-formyl-2-(p-methoxyphenylamino)heptanoate (5).

H CO2Et

O

n-Pent

HN

OMe

1H 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).13C 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).

Ethyl (2S,3R)-3-formyl-2-(p-methoxyphenylamino)hex-5-enoate (6).

H CO2Et

O HN

OMe

1H 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, OCH3), 4.08 (brd, J = 10.0 Hz, 1H,

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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).

H

O HN

OMe

O

O

1H 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): δ203.2, 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,

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).

H

O

n-Pent

HN

OMe

O

O

1H 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).

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-0.05

0

0.05

0.1

0.15

0.2

0.25

20 25 30 35 40 45 50 55 60 65 70

Retention time (min)

-0.02

0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

0.16

20 25 30 35 40 45 50 55 60 65 70

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).

H CO2Et

O NHPMP

(2S,3S)-syn-3H CO2Et

O NHPMP

(2R,3S)-anti-3

H CO2Et

O NHPMP

(2R,3R)-syn-3

H CO2Et

O NHPMP

(2S,3R)-anti-3

H CO2Et

O NHPMP

(2S,3S)-syn-3

H CO2Et

O NHPMP

(2R,3S)-anti-3

H CO2Et

O NHPMP

(2R,3R)-syn-3

H CO2Et

O NHPMP

(2S,3R)-anti-3

Time (min)

Time (min)

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S13

S14

S15

S16

S17

S18

S19

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S22

S23

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