General Procedures

General Procedure A: Stoichiometric lithiation-trapping of -Boc pyrrolidine 38 s-BuLi (1.3 M solution in hexanes, 1.3 eq.) was added dropwise to a stirred solution of
-Boc pyrrolidine 38 (342 mg, 350 µL, 2.0 mmol) and diamine (1.3 eq.) in Et2O (7 mL) at –78 °C under Ar. The resulting solution was stirred at –78 °C for 1 or 3 h. Then, the electrophile (2.0 eq.) was added and the resulting solution was stirred at –78 °C for 10 min and allowed to warm to rt. Saturated NH4Cl(aq) (10 mL) was added and the two layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the crude product.

General Procedure B: Catalytic two-ligand lithiation-trapping of -Boc pyrrolidine 38

s-BuLi (1.3 M solution in hexanes, 1.0-1.6 eq.) was added dropwise to a stirred solution of chiral diamine (0.2-0.3 eq.) and achiral diamine (1.0-1.3 eq.) in Et2O (6 mL) at –78 °C under Ar. After stirring at –78 °C for 15 min, a solution of
-Boc pyrrolidine 38 (161 mg, 165 µL, 0.94 mmol) in Et2O (1 mL) was added dropwise. The resulting pale yellow solution was stirred at –78 °C for 4 h. Then, benzaldehyde (2.0 eq.) was added and the resulting solution was allowed to warm to rt over 16 h. Saturated NH4Cl(aq) (10 mL) was added and the two layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the crude product.

General Procedure C: Catalytic two-ligand lithiation-7egishi trapping of -Boc pyrrolidine 38

s-BuLi (1.3 M solution in hexanes, 1.0-1.6 eq.) was added dropwise to a stirred solution of chiral diamine (0.25-0.3 eq.) and achiral diamine (1.0-1.3 eq.) in Et2O (6 mL) at –78

°C under Ar. After stirring at –78 °C for 15 min, a solution of
-Boc pyrrolidine 38 (493 mg, 493 µL, 2.88 mmol) in Et2O (1 mL) was added dropwise. The resulting pale yellow solution was stirred at –78 °C for 4 h. Then, ZnCl2 (1.0 M solution in Et2O, 0.6 eq.) was added and the resulting solution was stirred at –78 °C for 30 min. The solution was allowed to warm to rt and stirred for 30 min. Then, the aryl bromide (0.7 eq.) was added.

and the resulting mixture was stirred at rt for 16 h. Then, 35% NH4OH(aq) (0.2 mL) was added and the resulting mixture was stirred at rt for 1 h. The solids were removed by filtration through a pad of Celite^® and washed with Et2O (2 × 10 mL). The filtrate was washed with 1 M HCl(aq) (20 mL) and H2O (2 × 20 mL), dried (MgSO4) and evaporated under reduced pressure to give the crude product.

General Procedure D: Stoichiometric lithiation-arylation of -Boc pyrrolidine 38 s-BuLi (1.3 M solution in hexanes, 1.3 eq.) was added dropwise to a stirred solution of
-Boc pyrrolidine 38 (171 mg, 175 µL, 1.0 mmol) and (–)-sparteine (1.3 eq.) in Et2O (7 mL) at –78 °C under Ar. The resulting solution was stirred at –78 °C for 1 h. Then, ZnCl2

(1.0 M solution in Et2O, 0.6 eq.) was added and the resulting solution was stirred at –78

°C for 30 min. The solution was allowed to warm to rt and stirred for 30 min. Then, the aryl bromide (0.7 eq.) was added. A mixture of t-Bu3PHBF4 (6.25 mol%) and Pd(OAc)2

(5 mol%) was added in one portion and the resulting mixture was stirred at rt for 16 h.

Then, 35% NH4OH(aq) (0.3 mL) was added and the resulting mixture was stirred at rt for 1 h. The solids were removed by filtration through a pad of Celite^®, and washed with Et2O (20 mL). The filtrate was washed with H2O (20 mL) and brine (20 mL), dried (Na2SO4) and evaporated under reduced pressure to give the crude product.

General Procedure E: Lithiation-vinylation of -Boc pyrrolidine 38

s-BuLi (1.3 M solution in hexanes, 1.0 eq.) was added dropwise to a stirred solution of
-Boc pyrrolidine 38 (219 mg, 225 µL, 1.28 mmol, 1.0 eq.) and (–)-sparteine (1.3 eq.) in Et2O or TBME (7 mL) at –78 °C under Ar. The resulting solution was stirred at –78 °C for 1 h. Then, ZnCl2 (1.0 M solution in Et2O, 0.6 eq.) was added and the resulting solution was stirred at –78 °C for 30 min. The solution was allowed to warm to rt and stirred at rt for 30 min. Then, a solution of vinyl bromide 227 (0.7 eq.) in Et2O or TBME (1 mL) was added. A mixture of Pd(OAc)2 (5 mol%) or Pd2dba3 (2.5 mol%) and t-Bu3PHBF4 (6.25 mol%) was added in one portion and the resulting solution was stirred at rt for 16 h. Then, 35% NH4OH(aq) (0.5 mL) was added and the resulting mixture was stirred at rt for 1 h. The solids were removed by filtration through a pad of Celite^®, and washed with Et2O (20 mL). The filtrate was washed with 10% NH4Cl(aq), dried (MgSO4) and evaporated under reduced pressure to give the crude product.

General Procedure F: TFA-mediated Boc deprotection

TFA (5-20 eq.) was added dropwise to a stirred solution of
-Boc amine (750 mg, 3.02 mmol) in CH2Cl2 (40 mL) at rt under Ar. The resulting solution was stirred at rt for 4-16 h. The resulting solution was evaporated under reduced pressure. 5 M NaOH(aq) (20 mL) and Et2O (45 mL) were added. The layers were separated and the aqueous layer was extracted with Et2O (7 × 45 mL). The combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give the crude product.

General Procedure G: Eschweiler-Clarke methylation

A solution of unprotected pyrrolidine (169 mg, 1.14 mmol), paraformaldehyde (5 eq.) and formic acid (5 eq.) in H2O (15 mL) under air was stirred and heated at reflux for 16 h. Then, the solvent was evaporated under reduced pressure. 5 M NaOH(aq) (10 mL) and Et2O (25 mL) were added. The two layers were separated and the aqueous layer was extracted with Et2O (8 × 25 mL). The combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give the crude product.

General Procedure H: Lithiation-benzaldehyde trapping of -Boc pyrrolidine 38 s-BuLi (1.0 mL of a 1.3 M solution in hexanes, 1.3 mmol, 1.3 eq.) was added dropwise to a stirred solution of
-Boc pyrrolidine 38 (171 mg, 175 µL, 1.0 mmol, 1.0 eq.) in Et2O, THF or 2-methyl THF (7 mL) at –78 °C, –40 °C, –30 °C, –20 °C, – 10 °C or 0 °C under Ar. The resulting solution was stirred at the specified temperature for 1 min, 2 min, 5 min, 10 min, 30 min or 60 min. Then, benzaldehyde (212 mg, 203 µL, 2.0 mmol, 2.0 eq.) was added and the resulting solution was stirred at the specified temperature for 10 min and allowed to warm to rt. Saturated NH4Cl(aq) (10 mL) was added and the two layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the crude product.

General Procedure I: Attempted lithiation-trapping of -Boc pyrrolidine 38 with n-BuLi or LDA

n-BuLi (520 µL of a 2.5 M solution in hexanes, 1.3 mmol, 1.3 eq.) or LDA (1.0 mL of a 1.3 M solution in THF/n-heptane/ethyl benzene, 1.3 mmol, 1.3 eq.) was added dropwise to a stirred solution of
-Boc pyrrolidine 38 (171 mg, 175 µL, 1.0 mmol,

solution was stirred at the specified temperature for 30 min, 60 min or 180 min. Then, benzaldehyde (212 mg, 203 µL, 2.0 mmol, 2.0 eq.) or benzyl bromide (342 mg, 238 µL, 2.0 mmol, 2.0 eq.) was added and the resulting solution was stirred at the specified temperature for 10 min and allowed to warm to rt. Saturated NH4Cl(aq) (10 mL) was added and the two layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the crude product.

General Procedure J: Attempted lithiation-trapping of -Boc piperidine 44 and

-Boc homopiperidine 56

s-BuLi (1.0 mL of a 1.3 M solution in hexanes, 1.3 mmol, 1.3 eq.) was added dropwise to a stirred solution of
-Boc piperidine 44 (185 mg, 192 µL, 1.0 mmol, 1.0 eq.) or
-Boc homopiperidine 56 (199 mg, 1.0 mmol, 1.0 eq.) in THF (7 mL) at –78

°C, –40 °C or –30 °C under Ar. The resulting solution was stirred at the specified temperature for 5 min, 30 min, 60 min, 180 min or 360 min. Then, DMF (146 mg, 155 µL, 2.0 mmol, 2.0 eq.) or methyl chloroformate (189 mg, 155 µL, 2.0 mmol, 2.0 eq.) was added and the resulting solution was stirred at the specified temperature for 10 min and allowed to warm to rt. Saturated NH4Cl(aq) (10 mL) was added and the two layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the crude product.

General Procedure K: Optimised lithiation-trapping of -Boc heterocycles using s-BuLi in THF

s-BuLi (1.0 mL of a 1.3 M solution in hexanes, 1.3 mmol, 1.3 eq.) was added dropwise to a stirred solution of
-Boc heterocycle (1.0 mmol) in THF (7 mL) at –30

°C under Ar. The resulting solution was stirred at –30 °C for 5 min. Then, the electrophile (2.0 mmol) was added and the resulting solution was stirred at –30 °C for 10 min and then allowed to warm to rt over 15 min. Saturated NH4Cl(aq) (10 mL) was added and the two layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the crude product.

General Procedure L: Racemic arylation of -Boc pyrrolidine 38

s-BuLi (10 mL of a 1.3 M solution in hexanes, 13.0 mmol, 1.3 eq.) was added dropwise to a stirred solution of
-Boc pyrrolidine 38 (1.71 g, 1.75 mL, 10.0 mmol) in THF (70 mL) at –30 °C under Ar. The resulting solution was stirred at –30 °C for 5 min. Then, ZnCl2 (6.0 mL of a 1.0 M solution in Et2O, 6.0 mmol, 0.6 eq.) was added and the resulting solution was stirred at –30 °C for 30 min. The solution was allowed to warm to rt and stirred for 30 min.

Aryl bromide (0.7 mmol) was added to a stirred 7.0 mL aliquot of arylzinc reagent at rt. A mixture of Pd(OAc)2 (11 mg, 0.05 mmol, 5 mol%) and t-Bu3PHBF4 (11 mg, 0.0625 mmol, 6.25 mol%) were added in one portion and the resulting solution was stirred at rt for 16 h. Then, 35% NH4OH(aq) was added and the solution was stirred at rt for 1 h. The solids were removed by filtration through a pad of Celite^®, and washed with Et2O (20 mL). The filtrate was washed with a 1 M HCl(aq) (20 mL) and saturated brine (20 mL), dried (MgSO4) and evaporated under reduced pressure to give the crude product.

General Procedure M: Lithiation-trapping of imidazolidine 64

s-BuLi (1.0 mL of a 1.3 M solution in hexanes, 1.3 mmol, 1.3 eq.) was added dropwise to a stirred solution of
-Boc-
ʹ-i-Pr imidazolidine 64 (214 mg, 1.0 mmol) in THF (7 mL) at –30 °C under Ar. The resulting solution was stirred at –30 °C for 5 or 10 min. Then, the electrophile (2.0 mmol) was added and the resulting solution was stirred at –30 °C for 10 min and then allowed to warm to rt over 15 min. Saturated NaHCO3(aq) (10 mL) was added and the two layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL) and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give the crude product.

General Procedure 7: Diamine free lithiation-methyl chloroformate trapping of phenyl pyrrolidine rac-77

s-BuLi (1.3 M solution in hexanes, 1.3 eq.) or n-BuLi (2.5 M solution in hexanes, 1.3 eq.) was added dropwise to a stirred solution of
-Boc-2-phenylpyrrolidine rac-77 (100 mg, 0.4 mmol) in THF (4 mL) at –78 °C, 0 °C or rt under Ar. The resulting solution was stirred at the specified temperature for 5 min, 10 min, 30 min, 60 min or 180 min. Then, methyl chloroformate (2.0 eq.) was added dropwise and the resulting solution was stirred

mL) was added and the two layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the crude product.

General Procedure O: TMEDA-mediated lithiation-methyl chloroformate trapping of phenyl pyrrolidine rac-77

n-BuLi (2.5 M solution in hexanes, 1.3 eq.) was added dropwise to a stirred solution of

-Boc-2-phenylpyrrolidine rac-77 (100 mg, 0.4 mmol) and TMEDA (1.3 eq.) in THF (4 mL) or Et2O (4 mL) at –78 °C under Ar. The resulting solution was stirred at –78 °C for 60 min or 180 min. Then, methyl chloroformate (2.0 eq.) was added dropwise and the resulting solution was stirred at –78 °C for 10 min and allowed to warm to rt. Saturated NH4Cl(aq) (6 mL) was added and the two layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the crude product.

General Procedure P: Lithiation-trapping of phenyl pyrrolidine rac-77

n-BuLi (2.5 M solution in hexanes, 1.3 eq.) was added dropwise to a stirred solution of

-Boc-2-phenylpyrrolidine rac-77 (110 mg, 0.44 mmol) in THF (4 mL) at 0 °C under Ar.

The resulting solution was stirred at 0 °C for 5 min. Then, the electrophile (2.0 eq.) was added dropwise and the resulting solution was stirred at 0 °C for 10 min and allowed to warm to rt. Saturated NH4Cl(aq) (6 mL) as added and the two layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the crude product.

General Procedure Q: Lithiation-methyl chloroformate trapping of phenyl pyrrolidine (R)-77

n-BuLi (2.5 M solution in hexanes, 1.3 eq.) was added dropwise to a stirred solution of

-Boc-2-phenylpyrrolidine (R)-77 (70 mg, 0.28 mmol, 97:3 er) in THF (4 mL) at –78 °C, –50 °C, –40 °C, –30 °C or 0 °C under Ar. The resulting solution was stirred at the specified temperature for 5 min, 10 min or 60 min. Then, the electrophile (2.0 eq.) was added dropwise and the resulting solution was stirred at the specified temperature for 10 min and allowed to warm to rt. Saturated NH4Cl(aq) (6 mL) was added and the two layers were separated. The aqueous layer was extracted with Et O (3 × 10 mL) and the

combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the crude product.

General Procedure R: Lithiation-trapping of phenyl pyrrolidine (R)-77

n-BuLi (2.5 M solution in hexanes, 1.3 eq.) was added dropwise to a stirred solution of

-Boc-2-phenylpyrrolidine (R)-77 (46 mg, 0.18 mmol, 97:3 er) in THF (4 mL) at –50 °C under Ar. The resulting solution was stirred at –50 °C for 5 min. Then, the electrophile (2.0 eq.) was added dropwise and the resulting solution was stirred at –50 °C for 10 min and allowed to warm to rt. Saturated NH4Cl(aq) (6 mL) was added and the two layers were separated. The aqueous layer was extracted with Et2O (3 × 10 mL) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the crude product.