Supporting Information

© Wiley-VCH 2008

69451 Weinheim, Germany

Organocatalytic Asymmetric Synthesis of Versatile γ-Lactams

Thomas B. Poulsen, Gustav Dickmeiss, Jacob Overgaard and Karl Anker Jørgensen* Danish National Research Foundation: Center for Catalysis

Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark e-mail: kaj@chem.au.dk

Supporting Information

Contents

Table S1, Schemes S1-S2 ……………………………………………. page S2

General Methods ……………………………………………………… page S4

Materials …..…..……………………………………………………. page S4

Synthesis of Catalysts and Starting Materials ......................................... page S4

Experimental Procedure for the Vinylic Substitution ………………... page S8

Spectral Data for Products 4 ..................................................................... page S8

Procedures and Data for Cross-coupling Products 5-7 .......................... page S11

Procedures and Data for Products 8-10 ……….................................. page S13

Procedures and Data for Products 11-12 ……………………………… page S15

Spectra ……………………………………………………………… page S17

mailto:kaj@chem.au.dk

Table S1 – Initial Screening

NHBoc

NC CO2Et+

Cl

I

CO2Et

Cat. (5 mol%)33% K2CO3

BocHN

EtO2C CN

EtO2C I

NI

CNCO2Et

Boc

O

1.2 equiv.

-EtOHTol. /CHCl3 (3:1)(0.15M)-20 oC

full conv.

entry Cat ee (%) 1 HCd-1a +45 2 Cn-1a -61 3 Cd-1b -47 4 Cn-1b +45 5 Cd-1c +30 6 Cn-1d -22 7 Cn-1e +39 8 Qd-1e +20 9 Cn-1f +7

10 Cn-1g -23 11 Cd-1h +60 12 HCn-1h -78 13 HCn-1i -72

N

N

ROH

H

H Ar

X

HCd-1a: Ar = anthracene, R = H, X = ClCn-1a: Ar = anthracene, R = H, X = ClCd-1b: Ar = 3,5-(MeO)2-C6H3, R = H, X = BrCn-1b: Ar = 3,5-(MeO)2-C6H3, R = H, X = BrCd-1c: Ar = 3,5-(MeO)2-C6H3, R = Allyl, X = BrCn-1d: Ar = 4-CF3-C6H4, R = H, X = BrCn-1e: Ar = 3,4,5-(MeO)3-C6H2, R = H, X = BrQd-1e: Ar = 3,4,5-(MeO)3-C6H2, R = H, X = BrCn-1f: Ar = 3,4,5-(BnO)3-C6H2, R = H, X = BrCn-1g: Ar = 2-F-C6H4, R = H, X = ClCd-1h: Ar = 10-CN-anthracene, R = H, X = BrHCn-1h: Ar = 10-CN-anthracene, R = H, X = BrHCn-1i: Ar = acridine, R = H, X = Br

S2

Scheme S1 – Further Screening

+HCn-1 (5 mol%)

conditions

Cl

HCn-1h(HCn-1 in manuscript)

NOH

NH

9

CO2RCl

I

CNR = Me (3a)R = Et (3b)

NI

CNCO2Et

Boc

O

71b

Conditions1) 3b, 33% K2CO3, Tol./CHCl3 (7:1), -20 oC: +78% ee2) 3a, 33% K2CO3, Tol./CHCl3 (7:1), -20 oC: +74% ee3) 3a, 33% K2CO3, Toluene, -20 oC: +77% ee4) 3a, 33% K2CO3, o-Xylene, -20 oC: +80% ee5) 3a, 50% K2CO3, Toluene, -35 oC: +86% ee

NHBoc

NC CO2Et

2a

Scheme S2 – Synthesis of ent-4b

NHBoc

NC CO2tBu+

Cl

I

CO2Me

IsoCd-1 (3 mol%)50% K2CO3 N

I

CO2tBuCN

Boc

O

1.2 equiv.full conv.

Tol. /CHCl3 (4:1)(0.15M)-30 oC

isoCd-1

Br

NOH

NH

Me

NC

Catalyst pre-treated with SiO2, 5% MeOH/CH2Cl2 for: 0 min, 78% ee30 min, 94% ee60 min, 87% ee90 min, 79% ee

S3

General Methods. NMR spectra were acquired on a Varian AS 400 spectrometer, running at 400 and

100 MHz for 1H and 13C, respectively. Chemical shifts (δ) are reported in ppm relative to residual solvent

signals (CHCl3, 7.26 ppm for 1H NMR, CDCl3, 77.0 ppm for 13C NMR; CHD2OD, 3.30 ppm for 1H NMR,

CD3OD, 52.0 ppm for 13C NMR; H2O, 4.80 for 1H NMR). 13C NMR spectra were acquired on a broad

band decoupled mode. Mass spectra were recorded on a micromass LCT spectrometer using electrospray

(ES+) ionization techniques. Analytical thin layer chromatography (TLC) was performed using pre-coated

aluminium-backed plates (Merck Kieselgel 60 F254) and visualized by ultraviolet irradiation or KMnO4

dip. Melting points are uncorrected. Optical rotations were measured on a Perkin-Elmer 241 polarimeter.

The enantiomeric excess (ee) of the products was determined by chiral stationary phase HPLC (Daicel

Chiralpak AS/AD or Daicel Chiralcel OD/OJ columns). Racemic samples were prepared using TBAI as

the catalyst. Materials. Analytical grade solvents and commercially available reagents were used as received. For

flash chromatography (FC) silica gel was purchased from Iatron Laboratories Inc. (Iatrobeads 6RS-8060)

or from Fluka (Silica gel 60, 230-400 mesh). The synthesis of the phase-transfer catalysts HCn-1 and

isoCd-1, amino-α-cyanoacetates 2, and the α,β-dihalogenated acrylate esters 3 was performed as outlined

below.

(1S,3R,4S,8R,9S)-1-((10-Cyanoanthracen-9-yl)methyl)-8-ethyl-2-(hydroxy(quinolin-4-yl)methyl)-1-

azoniabicyclo[2.2.2]octane bromide (HCn-1):

To a solution of HCn1 (89.4 mg, 0.30 mmol) in THF/CH2Cl2 (4:1, 3.0 mL)

was added the cyanoanthracenemethyl bromide (193.8 mg, 0.60 mmol).

The mixture was stirred at 55 oC for 4.0 h and then the solvent was

evaporated. The mixture was purified by FC (SiO2, 12x2 cm) eluting with

MeOH/CH2Cl2 0:100 to 5:95. The CH2Cl2-fractions contain unreacted

cyanoanthracenemethyl bromide which could be recovered. The product

was obtained as a yellow solid (162.9 mg, 0.275 mmol) along with trace impurities. The solid was

suspended in EtOAc/CH2Cl2 (1:6, ca. 3 mL) and then MeOH was added until everything dissolved. Into

this solution was diffused n-hexane at room temperature. The solid which precipitated (155.2 mg, 0.26

mmol, 87%) was pure from 1H NMR.

Br

NOH

NH

9

CN

8

3

4

1

1H NMR (CD3OD) δ 9.07 (d, J 8.7 Hz, 1H), 9.03 (d, J 4.6 Hz, 1H), 8.70 (m, 2H), 8.54 (m, 2H), 8.16 (m,

1H), 8.11 (d, J 4.6 Hz, 1H), 7.93 (m, 6H), 7.03 (s, 1H), 6.42 (d, J 14.0 Hz, 1H), 6.10 (d, J 14.0 Hz, 1H),

4.47 (br t, J 8.0 Hz, 1H), 4.24 (m, 2H), 3.01 (br t, J 8.0 Hz, 1H), 2.79 (br q, J 8.0 Hz, 1H), 2.41 (br t, J 1 Blaser, H.-U.; Jalett, H.-P.; Garland, M.; Studer, M.; Thies, H.; Wirth-Tijani, A. J. Catal. 1998, 173, 282.

S4

12.0 Hz, 1H), 1.82 (m, 2H), 1.60 (m, 1H), 1.45 (m, 4H), 1.06 (m, 1H), 0.70 (t, J 7.1 Hz, 3H). 13C NMR

(CD3OD) δ 151.2, 148.9, 147.4, 134.3, 134.1, 133.9, 131.5, 130.5, 130.4 (2C), 129.9 (2C), 129.4, 127.8,

127.5, 127.3 (2C), 126.5 (2C), 124.9, 121.6, 117.5, 112.0, 96.0, 69.5, 68.2, 59.7, 55.4, 55.0, 37.0, 25.7,

25.6, 25.5, 22.9, 11.6. HRMS calc.: C35H34N3O 512.2696; found: 512.2692.

(1S,4S,8S,9R)-1-((10-Cyanoanthracen-9-yl)methyl)-5-ethylidene-2-(hydroxy(quinolin-4-yl)methyl)-

1-azoniabicyclo[2.2.2]octane bromide (isoCD-1):

To a solution of iso-CD 2 (2:1 mixture of double-bond isomers + 8%

dihydrocinchonidine, 89.4 mg, 0.30 mmol) in THF/CH2Cl2 (4:1, 3.0 mL)

was added the cyanoanthracenemethyl bromide (193.8 mg, 0.60 mmol).

The mixture was stirred at 55 oC for 3.5 h and then the solvent was

evaporated. The mixture was purified by FC (SiO2, 12x2 cm) eluting with

MeOH/CH2Cl2 0:100 to 5:95. The CH2Cl2-fractions contain unreacted

cyanoanthracenemethyl bromide which could be recovered (101 mg, 0.31 mmol). The product was

obtained as a yellow solid (162.5 mg, 0.275 mmol) as a mixture of double-bond isomers (3:1) along with

the corresponding dihydrocinchonidine (HCd) phase-transfer catalyst (8%) and trace impurities. The solid

was dissolved in EtOAc/CH2Cl2 (1:6, ca. 3 mL) and into this solution was diffused n-hexane at room

temperature. The solid which precipitated (145.6 mg, 0.25 mmol, 82%) contained isoCD-1 as a mixture

(3:1) of double bond isomers along with 8% of the HCd-derived catalyst.

BrN

OH

NH

9

Me

NC

8

4

1

Both isomers: 1H NMR (CD3OD) δ 9.17 (d, J 9.0 Hz, 0.75H), 9.14 (d, J 9.0 Hz, 0.25H), 9.01 (d, J 4.6 Hz,

0.25H), 9.00 (d, J 4.6 Hz, 0.75H), 8.72 (m, 2H), 8.45 (m, 2H), 8.11 (m, 2H), 7.90 (m, 6H), 7.08 (d, J 2.7

Hz, 0.75H), 7.05 (d, J 2.8 Hz, 0.25H), 6.49 (d, J 14.0 Hz, 0.75H), 6.44 (d, J 14.0 Hz, 0.25H), 6.13 (d, J

14.0 Hz, 1H), 5.20 (m, 1H), 4.99 (d, J 15.2 Hz, 0.75H), 4.77 (m, 1.25H), 4.56 (t, J 9.7 Hz, 0.75H), 4.51 (d,

J 10.5 Hz, 0.25H), 3.47 (d, J 14.6 Hz, 1H), 2.79 (m, 1H), 2.40 (m, 2H), 2.00 (m, 1H), 1.40 (m, 2H), 1.25

(m, 4H). Major isomer: 13C NMR (CD3OD) δ 151.2, 148.8, 147.5, 134.1 (2C), 134.0, 133.8, 131.8, 131.4,

131.1, 130.4, 130.3, 129.9, 129.7, 129.4, 127.7, 127.5 (2C), 127.1, 126.5, 126.4, 125.1, 121.6, 120.2,

117.4, 112.0, 70.8, 67.9, 64.8, 55.9, 54.2, 31.7, 28.9, 26.5, 12.8. HRMS calc.: C35H32N3O 510.2540;

found: 510.2540.

Ethyl 2-(tert-butoxycarbonylamino)-2-cyanoacetate (2a):

To a suspension of ethyl-2-amino-2-cyanoacetate (p-TsOH salt) (6.02 g, 20.0 mmol)

in toluene (20.7 mL) was added Boc2O (7.64 g, 35.0 mmol) and iPr2EtN (2.59 g,

CN

CO2EtBocHN

2 Blaser, H.-U.; Burkhardt, S.; Kirner, H. J.; Mössner, T.; Studer, M. Synthesis 2003, 1679.

S5

3.42 mL, 20.0 mmol). The mixture was heated to 100 oC (reflux condenser) for 5 h and was then cooled

to room temperature. 20 mL of H2O was added and the mixture was extracted with 300 mL EtOAc. The

organic phase was washed with 200 mL 1:1 H2O/sat. aq. NaHCO3, 200 mL H2O, and 200 mL brine. After

drying (Na2SO4) the mixture was concentrated in vacuo. The product was obtained after FC (SiO2, 17x4

cm) eluting with EtOAc/n-hexane 1:9 to 1:1 as a white solid (4.02 g, 17.6 mmol, 88%). 1H NMR (CDCl3) δ 5.34 (d, J 8.2 Hz, 1H), 5.24 (d, J 8.2 Hz, 1H), 4.34 (q, J 7.2 Hz, 2H), 1.45 (s, 9H),

1.34 (t, J 7.2 Hz, 3H). 13C NMR (CDCl3) δ 163.8, 154.3, 114.6, 82.2, 64.3, 44.8, 28.3 (3C), 14.1. HRMS

calc.: C10H16N2NaO4 251.1008; found: 251.1015.

tert-Butyl-2-(tert-butoxycarbonylamino)-2-cyanoacetate (2b):

To a suspension of tert-butyl-2-amino-2-cyanoacetate (p-TsOH salt) (16.4 g, 50.0

mmol) in toluene (52 mL) was added Boc2O (19.1 g, 87.5 mmol) and iPr2EtN (6.46

g, 8.56 mL, 50.0 mmol). The mixture was heated to 100 oC (reflux condenser) for 5

h and was then cooled to room temperature. 50 mL of H2O was added and the mixture was extracted with

500 mL EtOAc. The organic phase was washed with 250 mL 1:1 H2O/sat. aq. NaHCO3, 250 mL H2O,

and 150 mL brine. After drying (Na2SO4) the mixture was concentrated in vacuo. The product was

obtained after FC (SiO2, 18x4 cm) eluting with EtOAc/n-hexane 1:9 to 1:1 as a white solid (9.20 g, 35.9

mmol, 72%). 1H NMR (CDCl3) δ 5.29 (br s, 1H), 5.12 (d, J 7.2 Hz, 1H), 1.52 (s, 9H), 1.45 (s, 9H). 13C δ

162.4, 154.2, 114.9, 86.2, 81.9, 45.3, 28.3 (3C), 27.9 (3C). HRMS calc.: C12H20N2NaO4 279.1321; found:

279.1331.

CN

CO2tBuBocHN

tert-Butyl-2-cyano-2-((2,2,2-trichloroethoxy)carbonylamino)acetate (2c):

To a solution of tert-butyl-2-amino-2-cyanoacetate (p-TsOH salt) (1.20 g, 3.65

mmol) in sat. aq. NaHCO3 (12 mL) was added Troc-Cl (0.87 g, 4.12 mmol)

dropwise over 15 min with vigorous stirring. The reaction was stirred at room

temperature for 5 h and then H2O and CH2Cl2 was added. The mixture was extracted with CH2Cl2 (2x).

The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated. The mixture

was subjected to FC (SiO2, 13x2.7 cm) eluting with Et2O/CH2Cl2 3:97 to 5:95 which afforded the product

along with trace impurities. The solid was dissolved n-hexane (2 mL) at reflux and 5-6 drops of EtOAc

was added. When the solution was allowed to cool slowly to room temperature (in an oil-bath), the clean

product precipitated as a white solid (905 mg, 2.73 mmol, 75%). 1H NMR δ 5.82 (br s, 1H), 5.15 (d, J 7.7

Hz, 1H), 4.75 (s, 2H), 1.53 (s, 9H). 13C NMR δ 161.6, 153.6, 114.1, 94.8, 87.1, 75.4, 45.7, 27.9 (3C).

HRMS calc.: C10H13Cl3N2NaO4 352.9839; found: 352.9838.

CN

CO2tBuTrocHN

tert-Butyl 2-(benzyloxycarbonylamino)-2-cyanoacetate (2d):

S6

To a solution of tert-butyl-2-amino-2-cyanoacetate (p-TsOH salt) (1.31 g, 4.0 mmol)

in sat. aq. NaHCO3 (13 mL) was added Cbz-Cl (0.77 g, 0.64 mL 4.5 mmol) dropwise

over 10 min with vigorous stirring. The reaction was stirred at room temperature for

5 h 15 min and then H2O and CH2Cl2 was added. The mixture was extracted with CH2Cl2 (3x). The

combined organic extracts were washed with brine, dried over Na2SO4, and evaporated. The product was

obtained after FC (SiO2, 15x2.7 cm) eluting with Et2O/CH2Cl2 0:100 to 3:97 as a white solid (938 mg,

3.23 mmol, 81%). 1H NMR δ 7.35 (m, 5H), 5.55 (br s, 1H), 5.17 (d, J 7.2 Hz, 1H), 5.16 (s, 2H), 1.51 (s,

9H). 13C NMR δ 162.1, 155.1, 135.5, 128.8 (2C), 128.7, 128.5 (2C), 114.6, 86.6, 68.2, 45.6, 27.9 (3C).

HRMS calc.: C15H18N2NaO4 313.1164; found: 313.1164.

CN

CO2tBuCbzHN

(E)-Methyl-3-chloro-2-iodoacrylate (3a)3:

To a flame-dried flask equipped with a magnetic stirring bar and a reflux condenser was

added methyl propiolate (4.00 g, 47.6 mmol), 1,2-dichloroethane (300 mL), and

tetrabutylammonium iodide (52.7 g, 143.0 mmol) under argon. The mixture was heated

to 90 oC for 15 h (full conversion from 1H NMR) and then cooled to room temperature and diluted with

600 mL Et2O. The organic solution was washed with 20% w/w NaHSO3 (100 mL), H2O (200 mL), sat. aq.

NaHCO3 (100 mL), brine (100 mL), and dried over Na2SO4. Upon concentration of the mixture, a solid

precipitated which was washed several times with Et2O. The Et2O-fractions were carefully concentrated

(compound is volatile) and filtered through a short pad of SiO2 with Et2O/n-hexane 1:1. This mixture was

concentrated and the product was obtained after FC (SiO2, 16x4 cm) eluting with Et2O/n-hexane 0:100 to

7:93 as a yellow oil (5.88 g, 23.9 mmol, 50%). 1H NMR δ 7.02 (s, 1H), 3.84 (s, 3H). 13C NMR δ 163.2,

129.9, 84.6, 53.6.

CO2Me

I

Cl

(E)-Methyl-2,3-dichloroacrylate (3c)4:

To a flame-dried flask containing a magnetic stirring bar was added tetraethyl ammonium

chloride (8.0 g, 48.3 mmol) and CH2Cl2 (160 mL) under argon. Chlorine gas was bubbled

into the solution until saturated (ca. 15 min) at which time yellow/green gas is observed

over the yellow solution. Dry N2 was bubbled through the solution to remove excess

chlorine and then the solvent was evaporated, which afforded tetraethylammonium trichloride as sticky

yellow solid. This solid was redissolved in CH2Cl2 (80 mL) under argon and to this solution was added

methyl propiolate (2.02 g, 24.0 mmol). The solution was stirred at room temperature for 17.5 h at which

time 1H NMR indicated ca. 80% conversion. H2O was added and the phases separated. The aq. phase was

CO2Me

Cl

Cl

3 Lemay, A. B.; Vulic, K. S.; Ogilvie, W. W. J. Org. Chem. 2006, 71, 3615. 4 Schlama, T.; Gabriel, K.; Gouverneur, V.; Mioskowski, C. Angew. Chem. Int. Ed. 1997, 36, 2342.

S7

extracted with CH2Cl2 (1x) and the combined organic extracts were dried over Na2SO4 and concentrated.

The product was obtained after FC (SiO2, 10x4 cm) eluting with Et2O/n-hexane 5:95 as a colourless oil

(2.60 g, 16.8 mmol, 70%) after careful rotary evaporation (compound is volatile). 1H NMR δ 6.85 (s, 1H),

3.85 (s, 3H). 13C NMR δ 161.3, 126.6, 124.4, 53.4.

General Procedure for the Vinylic Substitution:

To a flask equipped with a magnetic stirring bar was added the α-amino-α-cyanoacetate 2 (1 mmol), the

phase-transfer catalyst (3 mol%, 0.03 mmol) HCn-1 or isoCD-1, toluene (6.7 mL) or toluene/CHCl3 (4:1,

6.7 mL), and finally the electrophile 3 (1.1 mmol). The mixture was cooled to -30 oC and the reaction was

started by addition of a pre-cooled (-30 oC) solution of 50% aq. K2CO3 (3.3 mL). The reaction was stirred

vigorously until judged to be complete by TLC-analysis (Et2O/CH2Cl2 3:97) and was then allowed to

warm to room temperature. The mixture was diluted with 10 mL H2O and 15 mL Et2O and the phases

were separated. The aq. phase was extracted with Et2O (2x10 mL), and the combined organics were

washed successively with H2O (10 mL), and brine (10 mL). After drying with Na2SO4 the mixture was

concentrated. The resulting residue was filtered rapidly (using a water aspirator) through a short pad of

SiO2 (3 x 2 cm) with ca. 100 mL Et2O/CH2Cl2 (5:95), which upon concentration afforded the crude

mixture as a viscous yellow oil. Evaporation with pentane afforded a solid material which was

recrystallised from EtOAc/n-hexane as follows: to the solid was added 6-7 mL EtOAc/n-hexane (1:9) and

the suspension was heated to reflux (95 oC). To the mixture was added EtOAc until the solid just

dissolves at reflux. Crystal formation was initiated by cooling to room temperature and the mixture was

placed at 5 oC (refrigerator) overnight. Removal of the mother liquid and washing with cold (-10 oC)

EtOAc/n-hexane (1:9) afforded the product 4 as colourless crystals. The washings and the mother liquor

were combined, seeded with one crystal and placed at -20 oC to afford a second batch of crystalline

material.

(R)-1-tert-Butyl 2-ethyl 2-cyano-4-iodo-5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate (4a):

Prepared according to the general procedure (reaction time 17.5 h) as colourless

crystals (mp = 126-128 oC). Crude ee = 79%. Isolated yield after recrystallisation

73% (>99% ee). 1H NMR (CDCl3) δ 7.40 (s, 1H), 4.36 (m, 2H), 1.56 (s, 9H), 1.36 (t,

J 7.1 Hz, 3H). 13C NMR (CDCl3) δ 162.5, 160.9, 146.3, 143.5, 111.4, 99.1, 86.7, 66.2,

65.2, 27.8. (3C), 13.9. HRMS calc.: C13H15IN2NaO5 428.9923; found: 428.9922. The ee was determined

by HPLC using a Chiralpak AD column [hexane/iPrOH (98:2)]; flow rate 1.0 mL/min; τmajor = 26.3 min,

τminor = 28.3 min (79% ee). [α]Drt -79.4o (c = 0.56, CH2Cl2, >99% ee).

N

O

Boc

CNCO2Et

I

S8

X-Ray Structure of 4a (most hydrogens are omitted for clarity).

(S)-1-tert-Butyl-2-ethyl 2-cyano-4-iodo-5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate (ent-4a):

Prepared according to the general procedure (reaction time 39 h) as colourless

crystals (mp = 126-128 oC). Crude ee = 78%. Isolated yield after recrystallisation

68% (>99% ee). Spectral data were identical to those reported for 4a above. The ee

was determined by HPLC using a Chiralpak AD column [hexane/iPrOH (98:2)]; flow

rate 1.0 mL/min; τmajor = 28.3 min, τminor = 26.3 min (78% ee). [α]Drt +80.8o (c = 0.60, CH2Cl2, >99% ee).

N

O

Boc

CO2EtCN

I

(R)-di-tert-Butyl 2-cyano-4-iodo-5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate (4b):

Prepared according to the general procedure (reaction time 17 h) as colourless

crystals (mp = 115 oC - decomposition). Crude ee = 89%. Isolated yield after

recrystallisation 71% (>99% ee). 1H NMR (CDCl3) δ 7.39 (s, 1H), 1.57 (s, 9H), 1.52

(s, 9H).13C NMR (CDCl3) δ 162.6, 159.2, 146.3, 143.8, 111.7, 98.6, 87.6, 86.3, 66.8,

27.7 (3C), 27.5 (3C). HRMS calc.: C15H19IN2NaO5 457.0236; found: 457.0254. The ee was determined

by HPLC using a Chiralpak AD column [hexane/iPrOH (97:3)]; flow rate 1.0 mL/min; τmajor = 12.6 min,

τminor = 14.6 min (89% ee). [α]Drt -93.8o (c = 0.57, CH2Cl2, >99% ee).

N

O

Boc

CNCO2tBu

I

X-Ray Structure of 4b (most hydrogens are omitted for clarity).

(S)-di-tert-Butyl-2-cyano-4-iodo-5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate (ent-4b):

S9

Prepared according to the general procedure (reaction time 45 h) as colourless

crystals (mp = 115 oC - decomposition). Crude ee = 73%. Isolated yield after

recrystallisation 62% (>99% ee). Spectral data were identical to those reported fo 4b

above. The ee was determined by HPLC using a Chiralpak AD column

[hexane/iPrOH (97:3)]; flow rate 1.0 mL/min; τmajor = 14.6 min, τminor = 12.6 min (73% ee). [α]Drt +95.4o

(c = 0.58, CH2Cl2, >99% ee).

N

O

Boc

CO2tBuCN

I

(R)-2-tert-Butyl-1-(2,2,2-trichloroethyl)-2-cyano-4-iodo-5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate

(4c):

Prepared according to the general procedure (reaction time 21.5 h) as colourless

crystals (mp = 152 oC, decomposition). Crude ee = 91%. Isolated yield after

recrystallisation 63% (>99% ee). 1H NMR (CDCl3) δ 7.49 (s, 1H), 5.05 (d, J 11.8 Hz,

1H), 4.91 (d, J 11.8 Hz, 1H), 1.55 (s, 9H). 13C NMR (CDCl3) δ 161.9, 158.5, 147.4,

144.9, 111.0, 97.6, 93.4, 88.6, 76.0, 66.4, 27.7 (3C). HRMS calc.: C13H12Cl3IN2NaO5 530.8754; found:

530.8767. The ee was determined by HPLC using a Chiralpak AD column [hexane/iPrOH (97:3)]; flow

rate 1.0 mL/min; τmajor = 29.3 min, τminor = 32.1 min (91% ee). [α]Drt -69.7o (c = 0.60, CH2Cl2, >99% ee).

N

O

Troc

CNCO2tBu

I

S10

(R)-1-Benzyl-2-tert-butyl-2-cyano-4-iodo-5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate (4d):

N

O

Cbz

CNCO2tBu

I

Prepared according to the general procedure (reaction time 17.0 h) as colourless

crystals (mp = 127 oC, decomposition). Crude ee = 80%. Isolated yield after

recrystallization 64% (>99% ee). 1H NMR (CDCl3) δ 7.43 (dd, J 7.8, 1.4 Hz, 2H),

7.41 (s, 1H), 7.35 (m, 3H), 5.37 (s, 2H), 1.39 (s, 9H). 13C NMR (CDCl3) δ 162.5,

159.1, 148.6, 144.7, 134.2, 129.0, 128.9 (2C), 128.6 (2C), 111.7, 98.4, 88.3, 70.0, 66.9, 27.7s (3C).

HRMS calc.: C18H17IN NaO2 5 491.0080; found: 491.0032. The ee was determined by HPLC using a

Chiralpak AD column [hexane/iPrOH (90:10)]; flow rate 1.0 mL/min; τ = 17.6 min, τmajor minor = 22.2 min

(80% ee). [α]Drt o -94.7 (c = 0.59, CH Cl , >99% ee). 2 2 (R)-di-tert-Butyl-4-chloro-2-cyano-5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate (4e):

Prepared according to the general procedure (reaction time 18.5 h) but isolated using

vacuum chromatography (water aspirator, SiO2, 5.5x2 cm, CH2Cl2/n-hexane 40:60 to

100:0 then Et2O/CH2Cl2 1:99 to 5:95) as a viscous colourless oil. Isolated yield 90%

(85% ee). 1H NMR (CDCl3) δ 6.98 (s, 1H), 1.59 (s, 9H), 1.54 (s, 9H). 13C NMR

(CDCl

N

O

Boc

CNCO2tBu

Cl

3) δ 160.2, 159.6, 146.5, 134.1, 132.7, 112.0, 87.8, 86.7, 62.7, 27.8 (3C), 27.6 (3C). HRMS calc.:

C15H19ClN NaO2 5 365.0880; found: 365.0855. The ee was determined by HPLC using a Chiralpak AD

column [hexane/iPrOH (97:3)]; flow rate 1.0 mL/min; τmajor = 9.6 min, τminor = 12.0 min (85% ee). [α]Drt -

100.9o (c = 0.47, CH Cl , 85% ee). 2 2

(S)-di-tert-Butyl-2-cyano-4-(4-methoxyphenyl)-5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate (5):

To a flame dried Schlenk tube equipped with a magnetic stirring bar and

under Ar-atmosphere was added γ-lactam ent-4b (86.8 mg, 0.20 mmol), 4-

methoxyphenylboronic acid (91.2 mg, 0.60 mmol) and Pd(PPhN

O

Boc

CO2tBuCN

MeO

)3 4 (23.1 mg,

0.02 mmol), after which the tube was successively evacuated and filled with

, degassed) and finally 2M aq. Na

COAr twice. Toluene (0.60 mL 2 3 (0.2 mL, degassed) was added, and

the mixture was vigorously stirred at 60 oC for 1 h. When the reaction was estimated to be complete by

TLC (Et O/CH Cl 1:99), the mixture was diluted with H2 2 2 2O, and the aq. phase was extracted twice with

Et2O. The combined organic phase was washed successively with H O and brine, then dried (Na SO2 2 4),

filtered and concentrated. Purification by FC (SiO 17x2.7 cm) eluting with Et O/CH Cl2, 2 2 2 0:100 to 1:99

afforded the product 5 as a white, foamy solid (59.2 mg, 0.142 mmol, 71%). 1H NMR (CDCl3) δ 7.83 (d,

J 9.0 Hz, 2H), 6.98 (s, 1H), 6.95 (d, J 9.0 Hz, 2H), 3.84 (s, 3H), 1.60 (s, 9H), 1.53 (s, 9H). 13C NMR

(CDCl3) δ 165.4, 161.6, 161.1, 147.4, 138.5, 129.7 (2C), 129.3 (2C), 121.0, 114.4, 113.4, 87.0, 85.9, 63.2,

55.5, 28.1 (3C), 27.8 (3C). HRMS calc.: C22H26N NaO 437.1689; found: 437.1672. The ee was 2 6

S11

determined by HPLC using a Chiralpak AD column [hexane/iPrOH (90:10)]; flow rate 1.0 mL/min; τmajor

= 35.9 min, τminor = 14.2 min (>99% ee). [α]Drt o 91.7 (c = 0.55, CH Cl2 2, >99% ee).

(S)-di-tert-Butyl-2-cyano-4-(oct-1-ynyl)-5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate (6):

ng bar and

tube was purged with A fo

)-di-tert-Butyl-2-cyano-4-methyl-5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate (7):

r and under Ar-

the reaction was e

To a flame dried Schlenk tube equipped with a magnetic stirrinHex Ounder Ar-atmosphere was added Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol), CuI

(5.7 mg, 0.03 mmol), freshly distilled CH2Cl2 (2.2 mL), DIPEA (137 μL,

0.80 mmol) and γ-lactam ent-4b (86.8 mg, 0.20 mmol) in this order. The

r 10 minutes. 1-octyne (88 μL, 0.60 mmol) was then added and after a short

while the reaction mixture turned black. After 40 min the reaction was estimated to be complete by TLC

(Et

r

2O/CH2Cl2 3:97). The mixture was diluted with H2O, and the aq. phase was extracted twice with

EtOAc. The combined organic extracts were washed twice with H2O and once with brine, dried (Na2SO4),

filtered and concentrated. Purification by FC (SiO2, 18x2.0 cm) eluting with Et2O/n-hexane 0:100 to 40:60

afforded the product 6 as a dark oil (69.0 mg, 0.165 mmol, 83%). 1H NMR (CDCl3) δ 6.90 (s, 1H), 2.44 (t,

J 7.1 Hz, 2H), 1.62-1.55 (m, 2H), 1.57 (s, 9H), 1.52 (s, 9H), 1.46-1.37 (m, 2H), 1.35-1.25 (m, 4H), 0.89 (t,

J 6.9 Hz, 3H). 13C NMR (CDCl3) δ 163.2, 160.3, 147.0, 137.4, 126.7, 112.7, 103.9, 87.3, 86.0, 69.4, 63.6,

31.3, 28.6, 28.0, 27.9 (3C), 27.7 (3C), 22.5, 19.8, 14.1. HRMS calc.: C23H32N2NaO5 439.2209; found:

439.2228. The ee was determined by HPLC using a Chiralpak OD column [hexane/iPrOH (95:5)]; flow

rate 1.0 mL/min; τmajor = 7.1 min, τminor = 7.9 min (>99% ee). [α]Drt +87.4o (c = 0.53, CH2Cl2, 99% ee).

(S

To a flame dried Schlenk tube equipped with a magnetic stirring ba

atmosphere was added γ-lactam ent-4b (86.8 mg, 0.20 mmol) and Pd(PPh3)2Cl2 (7.0

mg, 0.01 mmol). The solids were dissolved in dry DMF (0.6 mL) and dry THF (0.6

mL) and finally 2M ZnMe2 in toluene (130 μL, 0.26 mmol) was added. After 105 min.

stimated to be complete by TLC (Et 2O/CH2Cl2 3:97), the reaction was quenched by

careful addition of sat. aq. NH4Cl. The mixture was further diluted with H2O, and the aq. phase was

extracted twice with Et2O. The combined organic extracts were washed successively with H2O and brine,

then dried (NaSO4), filtered and concentrated. Purification by FC (SiO2, 16x2.0 cm) eluting with

Et2O/CH2Cl2 0:100 to 3:97 afforded the product 7 as a white solid (55.3 mg, 0.172 mmol, 86%). 1H NMR

(CDCl3) δ 6.69 (d, J 1.7 Hz, 1H), 1.98 (d, J 1.6 Hz, 3H), 1.58 (s, 9H), 1.52 (s, 9H). 13C NMR (CDCl3) δ

166.9, 160.9, 147.1, 139.3, 133.7, 113.2, 86.9, 85.7, 63.6, 27.9 (3C), 27.7 (3C), 11.2. HRMS calc.:

C16H22N2NaO5 345.1426; found: 345.1438 The ee was determined by HPLC using a Chiralpak AD

N Boc

CO2tBuCN

O

NMe

Boc

CO2tBuCN

S12

column [hexane/iPrOH (97:3)]; flow rate 1.0 mL/min; τmajor = 18.2 min, τminor = 17.3 min (>99% ee).

[α]Drt +126.7o (c = 0.42, CH Cl , >99% ee). 2 2

(S)-1-tert-Butyl-2-ethyl-2-cyano-5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate (8):

To a solution of ent-4a (81.2 mg, 0.20 mmol) in MeOH (10 mL) was added 10% Pd/C

(10 mg), NaOAc (100 mg), and quinoline (2 drops). The mixture was stirred under 1 atm.

of H2 (balloon) for 2 h (full conversion from TLC: Et2O/CH2Cl2 5:95) and was filtered

through a pad of celite. The product was obtained after FC (SiO2, 14x1.5 cm) eluting with

Et

N

O

Boc

CO2EtCN

2O/CH2Cl (0:100 to 1:99) as a viscous colourless oil (43.4 mg, 0.155 mmol, 77%). 1H NMR (CDCl2 3) δ

7.09 (d, J 5.9 Hz, 1H), 6.44 (d, J 5.9 Hz, 1H), 4.37 (m, 2H), 1.57 (s, 9H), 1.36 (t, J 7.1 Hz, 3H). 13C NMR

(CDCl3) δ 165.4, 161.7, 146.6, 140.4, 130.4, 112.1, 86.0, 64.9, 64.7, 27.7 (3C), 13.9. HRMS calc.:

C13H16N2NaO5 303.0957; found: 303.0944. [α]Drt o +109.1 (c = 0.62, CH Cl , >99% ee). 2 2

(3aR,6R,6aS)-5-tert-Butyl-6-ethyl-2-benzyl-6-cyano-4-oxotetrahydro-2H-pyrrolo[3,4-d]isoxazole-

5,6(3H)-dicarboxylaten (9):

N-benzylhydroxylamine (144.1, 1.17 mmol) was dissolved in abs. EtOH (3 mL) at

room temperature. To the solution was added portion-wise over 1 h a solution of

formaldehyde (37% aq., 102 mg, 1.25 mmol) in abs. EtOH (3 mL). The mixture

was stirred at room temperature for 3.5 h after the addition. At this time toluene

was added and the mixture concentrated in vacuo (NB: it is important not too evaporate to dryness, as this

seems to initiate decomposition of the nitrone). The crude toluene-solution was distributed between

CH

N

O

Boc

CO2EtCN

NO

Bn

H

H

Cl2 2 (ca. 12 mL) and brine (ca. 6 mL). The layers were separated and the aq. layer was extracted (1x)

with CH Cl . The combined organic fractions were dried with Na SO2 2 2 4, filtered and concentrated in vacuo.

During evaporation toluene is continuously added to finally yield a solution of the nitrone in ca. 3.9 mL

toluene. This solution was added to a solution of 8 (324 mg, 0.78 mmol) in c-hexane (3.9 mL) at room

temperature. The mixture was stirred at room temperature for 16 h at which time the conversion is ca.

80% as determined by 1 oH NMR. The temperature was increased to 40 C and after a total time of 40 h the

mixture was cooled and plugged through a pad of SiO with Et O/CH Cl2 2 2 2 3:7. After evaporation, the

crude mixture was subjected to vacuum chromatography on SiO2 eluting with Et2O/CH Cl2 2 0:100 to

10:90 which afforded the cycloadduct 9 as a mixture (4:1) of diastereomers (275 mg, 0.66 mmol, 85%).

The major diastereomer was obtained after FC (SiO , 17x2.2 cm) eluting with Et2 2O/n-hexane 50:50 to

60:40 to 65:35 as a white solid (171.6 mg, 0.413 mmol, 53%). 1 oH NMR (CDCl , 60 3 C) δ 7.34-7.25 (m,

5H), 5.05 (d, J 7.7 Hz, 1H), 4.00 (m, 2H), 3.95 (d, J 13.6 Hz, 1H), 3.86 (d, J 13.1 Hz, 1H), 3.70-3.64 (m,

2H), 2.86 (m, 1H), 1.55 (s, 9H), 1.16 (t, J 7.3 Hz, 3H). 13C NMR (CDCl , 60 oC) δ 170.5, 161.0, 147.0, 3

S13

135.6, 129.3 (2C), 128.3 (2C), 127.7, 115.8, 86.0, 77.8, 63.6, 62.1, 58.3, 51.6, 27.8 (3C), 13.9. Even after

extended acquisition times it was not possible to obtain a chemical shift from the quaternary stereocenter.

The signal is broad due to restricted molecular motion. HRMS calc.: C21H25N NaO3 6 438.1641; found:

438.1634.

(3aS,6R,6aR)-5-tert-Butyl-6-ethyl-2-benzyl-6-cyano-4-oxotetrahydro-2H-pyrrolo[3,4-d]isoxazole-

5,6(3H)-dicarboxylate (9-minor diastereomer): 1H NMR (CDCl , 60 o3 C) δ 7.42-7.26 (m, 5H), 4.56 (d, J 7.7 Hz, 1H), 4.34 (m, 2H),

4.25 (br d, J 12.0 Hz, 1H), 3.92 (br d, J 12.0 Hz, 1H), 3.53 (m, 2H), 2.71 (m, 1H),

1.52 (s, 9H), 1.35 (t, J 7.1 Hz, 3H). 13C NMR (CDCl3) δ 171.4, 165.4, 146.7, 134.6,

129.4 (2C), 128.4 (2C), 127.9, 112.2, 86.5, 75.8, 64.4, 61.3, 58.2, 51.4, 27.7 (3C),

14.0. Even after extended acquisition times it was not possible to obtain a chemical

shift from the quaternary stereocenter. The signal is broad due to restricted molecular motion. HRMS

calc.: C

N

O

Boc

CO2EtCN

NO

Bn

H

H

21H25N NaO 438.1641; found: 438.1647. 3 6

(3aR,6R,6aS)-Ethyl-2-benzyl-6-cyano-4-oxohexahydro-2H-pyrrolo[3,4-d]isoxazole-6-carboxylate

(10):

9 (166.2 mg, 0.40 mmol) was dissolved in CH Cl2 2 (4 mL) at room temperature. To

this solution was added anh. Mg(ClO4)2 (20 mol%, 0.080 mmol, 17.7 mg) and the

mixture was warmed to 35 oC. After 1 h 15 min the reaction was judged to be

complete from TLC-analysis (EtOAc/n-hexane 1:1). The mixture was diluted with

EtOAc and washed with H

NH

O

CO2EtCN

NO

Bn

H

H

O (2x) and brine. The organic extracts were dried with Na SO2 2 4, filtered and

evaporated in vacuo to yield the deprotected lactam 10 as a white amorphous solid (126.1 mg, 0.40 mmol,

quantitative). 1 oH NMR (CDCl , 60 3 C) δ 7.32-7.23 (m, 5H), 6.60 (br s, 1H), 5.14 (d, J 7.0 Hz, 1H), 4.13-

3.94 (m, 2H), 4.00 (d, J 13.5 Hz, 1H), 3.82 (d, J 13.5 Hz, 1H) 3.65 (br d, J 9.4 Hz, 1H), 3.57 (t, J 6.7 Hz,

1H), 2.84 (m, 1H), 1.14 (t, J 7.1 Hz, 3H). 13 oC NMR (CDCl , 60 3 C) δ 174.6, 162.3, 136.0, 129.0 (2C),

128.3 (2C), 127.6, 116.3, 81.7, 63.9, 62.7, 61.9, 58.0, 49.9, 13.7. HRMS calc.: C16H17N NaO3 4 338.1117;

found: 338.1108.

S14

X-Ray Structure of 10 (most hydrogens are omitted for clarity).

(2S,4R)-tert-Butyl-2-((tert-butoxycarbonylamino)methyl)-4-methyl-5-oxopyrrolidine-2-carboxylate

(11):

In an autoclave vial with a magnetic stirring bar γ-lactam 7 (96.7 mg, 0.30 mmol)

was dissolved in a 5:3 solution of EtOH/THF (6 mL). Then Boc2O (196 mg, 0.90

mmol), NEt3 (0.42 mL, 3.0 mmol) and 10% Pd/C (193mg) was added in this order.

The solution was placed under 10 bar H2 for 16 h, after which the reaction mixture

was filtered through a short column (SiO

NH

O

CO2tBu

Me

NHBoc

, 10x1.0 cm) eluting with 50:50 Et O/CH Cl2 2 2 2 (75 mL). After

evaporation the crude product was refluxed in dry CH oCl at 55 C with anh. Mg(ClO )2 2 4 2 (13.4 mg, 0.06

mmol). After 22 h the reaction was estimated to be complete by TLC (n-hexane/EtOAc 60:40). The

reaction was then diluted with EtOAc (15 mL), and the organic phase was washed sequentially with H2O

(8 mL) and brine (8 mL), dried (Na SO ) and concentrated. Purification by FC (SiO2 4 2, 17x1.7 cm) eluting

with n-hexane/EtOAc 60:40 to 30:70 afforded the product 11 as a white, foamy solid (80.4 mg, 0.24

mmol, 82%). 1H NMR (CDCl3) δ 6.15 (br s, 1H), 4.84 (br s, 1H), 3.43 (d, J 6.7 Hz, 2H), 2.55 (m, 1H),

2.37 (dd, J 9.1, 13.4 Hz, 1H), 1.94 (dd, J 8.0, 13.5 Hz, 1H), 1.48 (s, 9H), 1.43 (s, 9H), 1.19 (d, J 7.2 Hz,

3H). 13C NMR (CDCl3) δ 179.9, 171.9, 156.2, 83.0, 79.9, 64.9, 47.5, 36.8, 35.9, 28.5 (3C), 28.0 (3C),

16.6. HRMS calc.: C16H28N NaO 351.1896; found: 351.1892. 2 5

S15

X-Ray Structure of 11 (most hydrogens are omitted for clarity).

((2S,4R)-2-carboxy-4-methyl-5-oxopyrrolidin-2-yl)methanaminium trifluoroacetate (12):

In a flame-dried vial with a magnetic stirring bar, 11 (39.8 mg, 0.12 mmol)

was dissolved in dry CH2Cl2 (1.8 mL). TFA (1.8 mL) was added and the

solution was stirred for 3.5 h, after which the reaction was jugded to be

complete by TLC (NH3(aq.)/MeOH/CHCl3 5:30:65). The solution was

diluted with 10 mL n-pentane and extracted with H

NH

O

CO2H

Me

NH3O2CCF3

2O (3x15 mL). The aq. extracts were concentrated and

toluene (3x10 mL) was added during the evaporation to remove TFA as an azeotrope. Purification by FC

(SiO 12x1.6 cm) eluting with NH2, 3(aq.)/MeOH/CHCl3 5:20:75 to 5:40:55 afforded the product 12 as a

sticky solid (29.7 mg, 0.104 mmol, 86%). 1H NMR (D2O) δ 3.31 (d, J 13.2 Hz, 1H), 3.23 (d, J 13.2 Hz, 1H), 2.68 (m, 1H), 2.44 (dd, J 13.7, 9.1 Hz,

1H), 1.95 (dd, J 13.7, 8.7 Hz, 1H), 1.12 (d, J 7.2 Hz, 3H). 13C NMR (D2O, MeCN as internal reference) δ

183.6, 178.0, 163.1 (q, J = 36 Hz), 116.8 (q, J = 290 Hz), 63.1, 45.1, 37.6, 35.8, 15.8. HRMS calc.:

C H7 12N NaO 195.0746; found: 195.0713. 2 3

S16

Spectra

3.44

8.65

2.05

1.00

S17

9.00

8.30

1.24

S18

15.6

9

0.72

0.82

1.00

S19

9.40

2.00

5.40

S20

9.00

10.1

9

0.62

S21

21.8

79.

11

3.00

2.93

1.94

S22

3.68

5.89

3.30

10.7

119

.86

2.00

0.66

S23

8.47

8.33

3.44

1.00

S24

3.64

11.1

3

2.00

0.85

0.83

S25

3.00

10.1

9

1.01

2.11

1.15

3.26

0.93

5.10

S26

3.29

1.07

2.24

1.23

3.36

1.00

0.99

5.48

S27

3.00

16.8

0

0.95

0.93

0.94

1.81

0.80

0.74

S28

3.05

1.00

1.02

0.94

1.00

1.07

S29