General Approach to Enantiopure 1-Aminopyrrolizidines: Application to the Asymmetric Synthesis of the Loline Alkaloids

The synthesis of a range of loline alkaloids is reported. The C(7) and C(7a) stereogenic centers for the targets were formed by the established conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 5-benzyloxypent-2-enoate, ensuing enolate oxidation to give an α-hydroxy-β-amino ester, and then formal exchange of the resultant amino and hydroxyl functionalities (via the intermediacy of the corresponding aziridinium ion) to give an α-amino-β-hydroxy ester. Subsequent transformation gave a 3-hydroxyprolinal derivative which was converted to the corresponding N-tert-butylsulfinylimine. Mannich-type reaction with the enolate derived from O-Boc protected methyl glycolate then formed the remaining C(1) and C(2) stereogenic centers for the targets. The 2,7-ether bridge was formed by a displacement reaction, completing construction of the loline alkaloid core. Facile manipulations then gave a range of loline alkaloids, including loline itself.

Purification via flash column chromatography (eluent 30-40 °C petrol/Et2O, 1:1) gave 15 as a colourless oil A solution of 16 (4.86 g, 16.9 mmol) in THF (40.0 mL) was added dropwise to a suspension of NaH (60% dispersion in mineral oil, 676 mg, 16.9 mmol) in THF (45.0 mL) at rt, and the resultant mixture was stirred at rt for 15 min. TIPSCl (7.20 mL, 33.8 mmol) was added and the resultant mixture was stirred at rt for 16 h. H2O (100 mL) was added and the reaction mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organics were washed with brine (100 mL), then dried, filtered and concentrated in vacuo.
Step 2. Et3N (4.40 mL, 31.4 mmol) was added to the residue from the previous step (2.01 g) in CH2Cl2 (31.4 mL) at rt, and the resultant mixture was stirred at rt for 15 min. Allyl bromide (1.35 mL, 15.7 mmol) was added and the resultant mixture was stirred at rt for 16 h. H2O (100 mL) was added and the reaction mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organics were washed with brine (100 mL), then dried, filtered and concentrated in vacuo to give 18 as a white residue (2.28 g, 94%); 1 H NMR (CDCl3,  Step 1. DIBAL-H (1.0 M in CH2Cl2, 20.9 mL, 20.9 mmol) was added dropwise to a solution of 18 (1.59 g, 4.14 mmol) from the previous step in CH2Cl2 (26.1 mL) at −78 °C and the resultant mixture was stirred at −78 °C for 15 min. The reaction mixture was allowed to warm to rt and stirred at rt for 2 h. Satd aq NH4Cl (20 mL) and satd aq Rochelle salt (50 mL) were added and the resultant mixture was stirred at rt for 2 h. The reaction mixture was filtered through Celite ® (eluent CH2Cl2) and concentrated in vacuo to give a colourless oil (1.22 g).
Step 2. DMSO (1.49 mL, 20.9 mmol) was added dropwise to a stirred solution of (COCl)2 (0.840 mL, 10.4 mmol) in CH2Cl2 (10.3 mL) and the resultant mixture was stirred at −78 °C for 20 min. A solution of the residue from the previous step (1.22 g) in CH2Cl2 (16.0 mL) was added dropwise and the reaction mixture was stirred at −78 °C for 30 min. Et3N (4.40 mL, 31.3 mmol) was added and the reaction mixture was stirred at −78 °C for 30 min. The reaction mixture was allowed to warm to rt and stirred at rt for 16 h. H2O (100 mL) was added and the resultant mixture was extracted with CH2Cl2 (3 × 150 mL). The combined organics were washed with brine (50 mL), dried, filtered and concentrated in vacuo to give 19 as a yellow residue.
The reaction mixture was allowed to warm to rt and stirred at rt for 2 h. Satd aq NH4Cl (20 mL) and satd aq Rochelle salt (50 mL) were added and the resultant mixture was stirred at rt for 2 h. The reaction mixture was filtered through Celite ® (eluent CH2Cl2) and concentrated in vacuo to give a colourless oil (1.79 g).
Step 2. DMSO (1.80 mL, 25.1 mmol) was added dropwise to a stirred solution of (COCl)2 (1.02 mL, 12.6 mmol) in CH2Cl2 (20.4 mL) and the resultant mixture was stirred at −78 °C for 20 min. A solution of the residue from the previous step (1.79 g) in CH2Cl2 (11.0 mL) was added dropwise and the reaction mixture was stirred at −78 °C for 30 min. Et3N (5.30 mL, 37.7 mmol) was added and the reaction mixture was stirred at −78 °C for 30 min. The reaction mixture was allowed to warm to rt and stirred at rt for 16 h. H2O (100 mL) was added and the resultant mixture was extracted with CH2Cl2 (3 × 150 mL). The combined organics were washed with brine (50 mL), dried, filtered and concentrated in vacuo to give 19 as a yellow oil (1.95 g).

X-Ray crystal structure determination for 29 [CCDC 2212756]
Single crystals of 29 were obtained upon crystallisation via the slow diffusion method (CHCl3/heptane, v:v 1:1). Data were collected using an Oxford Diffraction SuperNova diffractometer with graphite monochromated Cu-K radiation using standard procedures at 150 K. The structure was solved by direct methods (SIR92); all non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms were added at idealised positions. The structure was refined using CRYSTALS.

X-ray crystal structure determination for 30·BH3·H2O [CCDC 2212757]
Single crystals of 30·BH3·H2O were obtained upon crystallisation via the slow diffusion method (CHCl3/heptane, v:v 1:1). Data were collected using an Oxford Diffraction SuperNova diffractometer with graphite monochromated Cu-K radiation using standard procedures at 150 K. The structure was solved by direct methods (SIR92); all non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms were added at idealised positions. The structure was refined using CRYSTALS.

X-ray crystal structure determination for 30·0.5H2O [CCDC 2212758]
Single crystals of 30·0.5H2O were obtained upon crystallisation via the slow diffusion method (CHCl3/heptane, v:v 1:1). Data were collected using an Oxford Diffraction SuperNova diffractometer with graphite monochromated Cu-K radiation using standard procedures at 150 K. The structure was solved by direct methods (SIR92); all non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms were added at idealised positions. The structure was refined using CRYSTALS.

X-ray crystal structure determination for 33·2HCl [CCDC 2212759]
Single crystals of 33·2HCl were obtained upon crystallisation via the slow diffusion method (MeOH/heptane, v:v 1:1). Data were collected using an Oxford Diffraction SuperNova diffractometer with graphite monochromated Cu-K radiation using standard procedures at 150 K. The structure was solved by direct methods (SIR92); all non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms were added at idealised positions. The structure was refined using CRYSTALS.

X-ray crystal structure determination for 39 [CCDC 2212760]
Single crystals of 39 were obtained upon crystallisation via the slow diffusion method (CHCl3/heptane, v:v 1:1). Data were collected using an Oxford Diffraction SuperNova diffractometer with graphite monochromated Cu-K radiation using standard procedures at 150 K. The structure was solved by direct methods (SIR92); all non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms were added at idealised positions. The structure was refined using CRYSTALS. S30 Figure S11. X-ray crystal structure of 39 (selected H atoms are omitted for clarity). Ellipsoids shown at 50% probability level. Figure S12. Ortep representation of the asymmetric unit of the X-ray crystal structure of 39 (ellipsoids shown at the 50% probability level).

Notes
Data are reported in CDCl3 (except for loline dihydrochloride, for which data are reported in D2O). Good agreement between data sets was observed in all cases; note, however, that in most instances a systematic error between the data sets was observed, consistent with an error in the referencing of the spectra of the natural products. It was not possible to confirm the reference frequency for the NMR spectra of the natural materials. Reference frequencies employed in this study were: CHCl3, H 7.26; CDCl3, C 77.16. Midpoints of all multiplets have been reported. Values of X are given in parentheses [X = X (synthetic) − X (natural)], for ease of comparison. *Signals associated with the diastereotopic C(6)H2 protons were reported as overlapping in this case; the associated H value therefore refers to the midpoint between the two distinct signals reported for the natural product.