Experimental for Chapter 3

3,7-Diisopropyl-3,7-diazabicyclo[3.3.1]nonan-9-one 176¹³¹

N N

O

176

i-PrNH2 (12.2 mL, 142.0 mmol) was added dropwise to a stirred solution of
-i-Pr-4-piperidone (21.1 mL, 142.0 mmol), paraformaldehyde (12.78 g, 426.0 mmol) and AcOH (8.46 mL, 148.0 mmol) in MeOH (200 mL) at rt under Ar. The resulting solution was stirred and heated at reflux for 16 h. The solvent was evaporated under reduced pressure.

Then, 50% KOH(aq) solution (500 mL) and Et2O (500 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with Et2O (2 × 500 mL) and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give the crude product. Purification by fractional distillation gave bispidone 176 (21.39 g, 67%) as a colourless oil, bp 128-130 ºC/2.0 mmHg (lit.,^X bp 110-120 ºC/10^-5 mmHg);

1H NMR (400 MHz, CDCl3) δ 3.01 (dd, J = 10.5, 3.0 Hz, 4H, NCHAHB), 2.86 (dd, J = 10.5, 7.0 Hz, 4H, NCHAH_B), 2.85-2.76 (m, 2H, NCH), 2.61-2.54 (m, 2H, COCH), 0.99 (d, J = 6.5 Hz, 12H, Me). Spectroscopic data consistent with those reported in the literature.¹³²

Lab Book reference GB2/113

3,7-Diisopropyl-3,7-diazabicyclo[3.3.1]nonane 7

N N

7

Hydrazine monohydrate (6.22 mL, 127.9 mmol) was added dropwise to a stirred mixture of bispidone 176 (5.17 g, 23.0 mmol) and KOH (15.1 g, 269.0 mmol) in diethylene

for 16 h. After cooling to 60 °C,¹ the mixture was transferred to a separating funnel and H2O (155 mL) was added. Then, Et2O (85 mL) was added and the layers were separated.

The aqueous layer was extracted with Et2O (6 × 85 mL) and the combined organic layers were washed with 20% NaOH(aq) (6 × 100 mL), dried (Na2SO4) and evaporated under reduced pressure to give di-i-Pr bispidine 7 (4.29 g, 88%) as a colourless oil, ¹H NMR (400 MHz, CDCl3) δ 2.68-2.57 (m, 2H, NCH), 2.53 (dd, J = 10.5, 5.5 Hz, 4H, NCH2), 2.46 (br d, J = 10.5 Hz, 4H, NCH2), 1.97-1.92 (m, 2H, NCH2CH), 1.46-1.41 (m, 2H, NCH2CHCH2), 0.97 (d, J = 6.5 Hz, 12H, NCHMe2). Spectroscopic data consistent with those reported in the literature.¹³¹ Di-i-Pr bispidine 7 was purified by Kügelrohr distillation (bp 110-120 °C, 0.4 mmHg) immediately before use.

Lab Book Reference GB2/109

3,7-Diisopropyl-9-methylene-3,7-diazabicyclo[3.3.1]nonane 156

N N

156 CH₂

KHMDS (65.4 mL of a 0.5 M solution in toluene, 32.7 mmol) was added dropwise to a stirred solution of MePh3P⁺Br^– (11.68 g, 32.7 mmol) in THF (240 mL) at 0 °C under Ar.

After stirring at 0 °C for 30 min, a solution of bispidone 176 (7.00 g, 31.2 mmol) in THF (60 mL) was added dropwise. The resulting solution was stirred at 0 °C for 15 min and then stirred and heated at reflux for 16 h. The solvent was evaporated under reduced pressure and 5 M HCl(aq) solution (250 mL) was added to the residue. The aqueous solution washed with CH2Cl2 (2 × 500 mL) and then basified to pH 14 by addition of 5 M NaOH(aq). The aqueous solution was stirred at rt for 1 h and then extracted with Et2O (8 × 200 mL). The combined organic extracts were dried (Na2SO4) and evaporated under reduced pressure to give the crude product as a yellow oil. Purification by Kügelrohr distillation gave alkene 156 (4.48 g, 65%) as a colourless oil, bp 120-130 °C/1.2 mmHg;

IR (film) 3069, 2931, 1670 (C=C), 1469, 1386, 1358, 1176, 880 cm^-1; ¹H NMR (400 MHz, CDCl3) δ 4.67 (s, 2H, C=CH2), 2.78-2.68 (m, 2H, NCH), 2.68-2.60 (m, 8H,

NCH2), 2.58-2.40 (m, 2H, NCH2CH), 0.99 (d, J = 6.5 Hz, 12H, Me); ¹³C NMR (100.6 MHz, CDCl3) δ 151.4 (C=CH2), 104.7 (C=CH2), 53.8 (NCH2), 53.4 (NCH), 39.0 (NCH2CH), 18.1 (Me); MS (ESI) m/z 223 [(M + H)⁺, 100], 150 (15), 123 (30); HRMS (ESI) m/z calcd for C14H26N2 (M + H)⁺ 223.2169, found 223.2169 (–0.26 ppm error).

Lab Book Reference GB1/77

3,7-Diisopropyl-9-methyl-3,7-diazabicyclo[3.3.1]nonane 157

N N

157 Me

H

A solution of alkene 156 (4.48 g, 20.1 mmol) and NH4+

HCO2–

(4.16 g, 66.0 mmol) in EtOH (130 mL) was stirred and heated at reflux under Ar. Then, 20% Pd(OH)2/C (1.22 g, 1.4 mmol) was added in one portion. The resulting mixture was stirred and heated at reflux for 2 h. After cooling to rt, the resulting mixture was basified to pH 14 by addition of 5 M NaOH(aq) solution. The aqueous solution was stirred at rt for 1 h. Then, the solids were removed by filtration through a minimum amount of Celite^® and washed with 5 M NaOH(aq) solution (20 mL). The EtOH was evaporated under reduced pressure and the aqueous residue was extracted with Et2O (8 × 200 mL). The combined organic extracts were dried (Na2SO4) and evaporated under reduced pressure to give the crude product as a yellow oil. Purification by Kügelrohr distillation gave methyl bispidine 157 (2.87 g, 65%) as a colourless oil, bp 130-140 °C/0.4 mmHg; IR (film) 2963, 2932, 1381, 1179, 1110 cm^-1; ¹H NMR (400 MHz, CDCl3) δ 2.79-2.60 (m, 8H, NCH2), 2.40-2.34 (m, 2H, NCH), 1.86-1.78 (m, 1H, CHMe), 1.66 (br s, 2H, NCH2CH), 1.05-0.95 (m, 15H, CHMe + CHMe2); ¹³C NMR (100.6 MHz, CDCl3) δ 53.9 (NCH), 53.6 (NCH), 53.5 (NCH2), 47.1 (NCH2), 34.2 (CH), 30.2 (CH), 18.2 (Me), 17.9 (Me), 16.5 (Me); MS (ESI) m/z 225 [(M + H)⁺, 100]; HRMS (ESI) m/z calcd for C14H28N2 (M + H)⁺ 225.2325, found 225.2326 (–0.42 ppm error).

Lab Book Reference GB1/80

3,7-Diisopropyl-3,7-diazabicyclo[3.3.1]nonan-9-ol 158

N N

158 OH

H

A solution of NaBH4 (37 mg, 1.0 mmol) in H2O (1.5 mL) was added dropwise to a stirred solution of bispidone 176 (200 mg, 0.9 mmol) in EtOH (3.0 mL) at rt under air. The resulting solution was stirred at rt for 16 h. The EtOH was evaporated under reduced pressure and the residue was basified to pH 14 by addition of 5 M NaOH(aq) solution. The solution was stirred at rt for 1 h and then extracted with Et2O (8 × 10 mL). The combined organic extracts were dried (Na2SO4) and evaporated under reduced pressure to give bispidol 158 (138 mg, 69%) as a colourless oil, bp 170-180 ºC/5 mmHg; IR (film) 3328 (OH), 2965, 2924, 1469, 1382, 1360, 1221, 1174, 1096, 1069, 1052 cm^-1; ¹H NMR (400 MHz, CDCl3) δ 6.06 (br s, 1H, OH), 3.31 (br s, 1H, CHOH), 2.99 (br t, J = 10.5 Hz, 2H), 2.72-2.62 (m, 2H), 2.62-2.42 (m, 4H), 2.28-2.15 (m, 4H), 0.99 (d, J = 6.5 Hz, 6H, Me), 0.94 (d, J = 6.5 Hz, 6H, Me); ¹³C NMR (100.6 MHz, CDCl3) δ 73.2 (CHOH), 53.3 (NCH), 52.9 (NCH), 52.4 (NCH2), 48.5 (NCH2), 34.6 (NCH2CH), 18.2 (Me), 18.1 (Me);

MS (ESI) m/z 227 [(M + H)⁺, 100]; HRMS (ESI) m/z calcd for C13H26N2O (M + H)⁺ 227.2118, found 227.2124 (–2.85 ppm error).

Lab Book Reference GB1/48

3,7-Dipropyl-3,7-diazabicyclo[3.3.1]nonan-9-one 180

N N

180 O

n-PrNH2 (5.83 mL, 70.81 mmol) was added dropwise to a stirred solution of
-n-Pr-4-piperidone (10.7 mL, 10 g, 70.81 mmol), paraformaldehyde (6.38 g, 212.4 mmol) and AcOH (4.22 mL, 73.8 mmol) in MeOH (100 mL) at rt under Ar. The resulting solution was stirred and heated at reflux for 16 h. The solvent was evaporated under reduced

residue and the layers were separated. The aqueous layer was extracted with Et2O (2 × 250 mL) and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give the crude product. Purification by fractional distillation gave di-n-Pr bispidone 180 (7.01 g, 44%) as a yellow oil, bp 95-100 °C/0.2 mmHg; IR (film) 2958, 1739 (C=O), 1469, 1359, 1208, 1137, 1087, 1036, 735 cm^-1; ¹H NMR (400 MHz, CDCl3) δ 2.99 (dd, J = 11.0, 2.0 Hz, 4H, NCHAHB), 2.79 (dd, J = 11.0, 6.5 Hz, 4H, NCHAHB), 2.56 (br s, 2H, COCH), 2.31 (t, J = 7.5 Hz, 4H, NCH2CH2), 1.50-1.40 (m, 4H, NCH2CH2), 0.89 (t, J = 7.5 Hz, 6H, Me); ¹³C NMR (100.6 MHz, CDCl3) δ 215.1 (C=O), 58.5 (NCH2), 58.4 (NCH2), 46.6 (NCH2CH), 20.3 (CH₂Me), 11.8 (Me); MS (ESI) m/z 257 [(M + MeOH + H)⁺, 100], 225 [(M + H)⁺, 1]; HRMS (ESI) m/z calcd for C14H24N2O (M + H)⁺ 225.1961, found 225.1770 (minor peak); m/z calcd for C14H24N2O (M + MeOH + H)⁺ 257.2224, found 257.2220 (+1.3 ppm error).

Lab Book Reference GB2/148

3,7-Dipropyl-3,7-diazabicyclo[3.3.1]nonane 159

N N

159

Hydrazine monohydrate (4.72 mL, 86.5 mmol) was added dropwise to a stirred mixture of di-n-Pr bispidone 180 (3.5 g, 15.6 mmol) and KOH (9.11 g, 182.0 mmol) in diethylene glycol (90 mL) at rt under Ar. The resulting mixture was stirred and heated at 180 °C for 16 h. After cooling to 60 °C,² the mixture was transferred to a separating funnel and H2O (80 mL) was added. Then, Et2O (60 mL) was added and the layers separated. The aqueous layer was extracted with Et2O (6 × 60 mL) and the combined organic layers were washed with 20% NaOH(aq) (6 × 90 mL), dried (Na2SO4) and evaporated under reduced pressure to give di-n-Pr bispidine 159 (2.77 g, 84%) as a colourless oil, bp 100-110 °C/2.0 mmHg; IR (film) 2955, 2932, 1462, 1375, 1290, 1272, 1148, 100-1106, 1068, 1001 cm^-1; ¹H NMR (400 MHz, CDCl3) δ 2.69 (br d, J = 10.5 Hz, 4H, NCHAHB), 2.28 (dd, J = 10.5, 4.5 Hz, 4H, NCHAH_B), 2.19 (t, J = 7.5 Hz, 4H, NCH2CH2), 1.91 (br s, 2H, NCH2CH), 1.52-1.41 (m, 6H, NCH2CH2 + CH2CHCH2), 0.87 (t, J = 7.5 Hz, 6H, Me);

13C NMR (100.6 MHz, CDCl3) δ 61.0 (NCH2), 57.9 (NCH2), 29.9 (bridge CH2), 29.2 (NCH2CH), 20.1 (NCH2CH2), 11.9 (Me); MS (ESI) m/z 211 [(M + H)⁺, 100], 199 (12);

HRMS (ESI) m/z calcd for C13H26N2 (M + H)⁺ 211.2169, found 211.2162 (+2.97 ppm error).

Lab Book Reference GB2/150

2-(Hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1R,2R)-182 and (1S,2R)-182

N Boc

H Ph

N Boc

H Ph

OH OH

(1R,2R)-182 (1S,2R)-182

Using general procedure A, s-BuLi (2.0 mL of a 1.3 M solution in hexanes, 2.6 mmol),

-Boc pyrrolidine 38 (342 mg, 350 µL, 2.0 mmol) and (–)-sparteine 3 (609 mg, 595 µL, 2.6 mmol) for 1 h and then benzaldehyde (424 mg, 406 µL, 4.0 mmol) gave the crude product which contained a 75:25 mixture of (1R,2R)-182 and (1S,2R)-182 by ¹H NMR spectroscopy. Purification by flash column chromatography on silica with 98:2 CH2Cl2 -acetone as eluent gave (1R,2R)-182 (343 mg, 62%, 97:3 er by CSP-HPLC) as a colourless oil, [α]D –3.1 (c 1.0 in CHCl3) (lit.,¹³⁰ [α]D –1.9 (c 1.0 in CHCl3) for (1R,2R)-182 of 97:3 er); RF (98:2 CH2Cl2-acetone) 0.4; ¹H NMR (400 MHz, CDCl3) δ 7.39-7.25 (m, 5H, Ph), 5.93 (br s, 1H, OH), 4.53 (br d, J = 8.0 Hz, 1H, CHO), 4.10 (td, J = 8.0, 3.5 Hz, 1H, NCH), 3.51-3.42 (m, 1H, NCH2), 3.41-3.33 (m, 1H, NCH2), 1.79-1.15 (m, 2H, CH2), 1.14-1.45 (m, 2H, CH2), 1.53 (s, 9H, CMe3); CSP-HPLC: Chiralcel OD (98:2 hexane-i-PrOH, 0.5 mLmin^-1) (1R,2R)-182 24.12 min, (1S,2S)-182 28.85 min and (1S,2R)-182 (100 mg, 18%, 97:3 er by CSP-HPLC) as a colourless oil, [α]D +75.4 (c 1.00 in CHCl3) (lit.,¹³⁰ [α]D +95.3 (c 1.00 in CHCl3) for (1S,2R)-182 of 97:3 er); RF (98:2 CH2Cl2-acetone) 0.3; ¹H NMR (400 MHz, CDCl3) (75:25 mixture of rotamers) δ 7.41-7.23 (m, 5H, Ph), 5.52 (br s, 0.75H, OH), 5.15 (br s, 0.25H, OH), 4.87 (br s, 0.75H, CHO), 4.31 (br s, 0.75H, NCH), 4.00 (br s, 0.25H, CHO), 3.56 (br s, 0.25H, NCH), 3.30 (br s, 1H, NCH2), 2.82 (br s, 0.75H, NCH2), 2.51 (br s, 0.25H, NCH2), 2.01-1.86 (m, 1H, CH2), 1.85-1.72 (m, 1H, CH2), 1.68 (s, 2.25H, CMe3), 1.66-1.46 (m, 1H, CH2), 1.52 (s, 6.75H, CMe3), 1.21-1.13 (m, 1H, CH2); CSP-HPLC: Chiralcel OD (98:2 hexane-i-PrOH,