New C-substituted (1 S ,4 S )-2,5-diazabicyclo[2.2.1]heptane derivatives. Preparation utilizing the directed metalation strategy. Application in enantioselective catalysis

New C-substituted derivatives of (1 S ,4 S )-2-methyl-2,5-diazabicyclo[2.2.1]heptane were synthesized utilizing the directed metalation strategy. The absolute configuration of the 3-substituted derivative rests on the comparison of the NMR spectra with a product of proven configurational assignment by X-ray crystallographic analysis .


Introduction
Various N-substituted derivatives of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane are known in the literature. 1 C-Substituted derivatives are rather scarce and include methyl derivatives, 2 lactams (3-oxo-substituted), 3 and a 7-hydroxy-7-phenyl-substituted species. 4Compounds containing the (1S,4S)-2,5-diazabicyclo[2.2.1]heptane moiety have proven to be useful building blocks in organic synthesis, and particularly, in medicinal chemistry.1d,le,1h,1i,1j,1l Contrary to the conformationally flexible piperazine, the 2,5-diazabicyclo[2.2.1]heptane scaffold is rigid and chiral.The parent compound is synthesized from the naturally occurring amino acid trans-4hydroxy-L-proline.5 Beak and Hoppe pioneered the directed lithiation of N-protected amines, 6 a procedure, which allows asymmetric induction in this step when the generally applicable secbutyllithium/(−)-sparteine system is employed for deprotonation. 7,8n a recent communication we published the synthesis of novel C-substituted derivatives of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane (1) (Scheme 1).This has been achieved by lithiation of the Boc-protected derivative 2 followed by the reaction with suitable electrophiles. 9After deprotection the resulting -functionalized amines have been tested as ligands catalyzing the asymmetric addition of diethylzinc to benzaldehyde. 10ut dramatically decreased the conversion rate and yield (as evidenced from TLC monitoring of the reactions).For most electrophiles, substitution at position 1 of 2 affording 3 is favored over substitution at position 3 furnishing 4 and/or 5. Most 3-substituents R2 have been found to adopt the axial orientation as in products 4 (vide infra).As an exception, the group R2 = 1,1-bis[(3trifluoromethyl)phenyl]-1-hydroxymethyl has been introduced both as axial and equatorial substituent in 4b and 5b, respectively (Table 1).The lithiated species derived from 2 seem to exist in an equilibrium of 1-and 3-deprotonated species before the reaction with the electrophilic reactant furnished either of the three C-substituted products 3, 4, and/or 5.
The coupling patterns of three versus two methylene groups permitted the distinction between 1-and 3-substituted products 3 and 4 and/or 5, respectively.X-Ray diffraction determined the stereochemistry of compound 4b 9 and established the equatorial orientation of the 3-substituent.Conventional NMR techniques were not applicable because the coupling constants required for the configurational assignment were within the linewidths of the NMR signals.Comparison of the 1 H NMR spectrum of 4b with those of other 3-substituted products allowed the unequivocal configurational assignment of these compounds 5a-f.The electrophiles with polycyclic armatic groups (c, e) resulted in predominant substitution at the bridgehead (Table 1), in contrast to the electrophiles with monocycloc aromatic groups (a, d) resulting in low regioselectivity.Surprisingly, with 3,3'-bis(trifluormethyl)benzophenone as electrophile the resulting substituent assumes the equatorial position at C-3.
In the case of 9H-thioxanth-9-one as electrophile two different products were obtained depending on the amount of sec-BuLi utilized for deprotonation.With 1.2 equivalents of sec-BuLi the expected 1-substituted product 3g (Table 1) was isolated in only 4% yield.Using 1.5 equivalents of sec-BuLi resulted in the formation of the spiro compound 6 (24% yield).This is explained by the intramolecular nucleophilic attack of the O-lithiated intermediate (i.e. the lithium salt of 3g) on the carbamate functionality, a mechanism not uncommon in the literature. 12he structure 6 was further proven by the formation of 7 upon LiAlH 4 (LAH) reduction (Scheme 2).TFA 20 Generally, cleavage of the Boc-group in 3, 4, and 5 was achieved either by treatment with trifluoro acetic acid (TFA), aqueous sodium hydroxide or LAH (Table 2).In some cases the yields were disappointingly low.Boc-cleavage of 3d (featuring a thioether functionality) could not be achieved with sodium hydroxide.Utilization of TFA resulted in partial cleavage of the thioether group and decreased the yield of 8d to almost zero.A viable solution was the utilization of LAH although the yield of 8d remained very low.

Application of (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane derivatives in asymmetric catalysis
Three selected compounds 8a-c were also tested as chiral auxiliaries in the asymmetric reduction of propiophenone by a chiral borolidine species formed in situ prior to addition of the ketone.Borolidine reduced propiophenone to 1-phenyl-1-propanol (Scheme 4), and the resulting enantiomers were analyzed by chiral HPLC.Only with 8a very modest enantiomeric excess was achieved.(Table 3).

Experimental Section
General Procedures.All employed reagents were commercial compounds.(S,trans)-4hydroxyproline was purchased from SIGMA.Dry THF, diethyl ether, and toluene were freshly distilled from sodium/benzophenone ketyl radical.sec-BuLi was purchased from Fluka Corp. and was titrated before use against 2-butanol (in dry toluene, indicated by phenanthroline hydrochloride).Thin-layer chromatography (TLC) was performed using Merck silica gel (60 F-254) plates (0.25 mm).For the monitoring of compounds not detectable under UV light a ninhydrin spray reagent was used.Column chromatography was performed using J. T. Baker silica gel 60 (40-63 m).Melting points (mp) were determined using a Kofler hot stage microscope.Proton ( 1 H) and carbon ( 13 C) magnetic resonance spectra (NMR) were recorded on a Bruker 200 FS (200 MHz for 1 H, 50 MHz for 13 C) Fourier transform spectrometer, and chemical shifts were expressed in parts per million () relative to tetramethylsilane using solvent signals as an internal reference: DMSO-d 6 , 2.50 ( 1 H) and 39.5 ( 13 C) or CHCl 3 , 7.24 ( 1 H) and 77.0 ( 13 C); multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet).Reaction temperatures were measured using a digital thermometer inside the reaction vessel.Enantiomeric excess (ee) was determined by chiral HPLC using a Chiralcel OD-H column (4.6 mm x 250 mm, Daicel Chem.Ind. Ltd), detection at 254 nm, pump and detector from Waters.Optical rotations were determined with a Perkin-Elmer polarimeter.

Lithiation of 2 followed by reaction with an electrophile. General procedure A
To a solution of TMEDA (778 mg, 7.10 mmol, 1.5 equiv.) in dry THF (15 mL) was added 1.3 M sec-BuLi in hexanes (5.4 mL, 7.10 mmol; 1.5 equiv.) at -78 °C.The mixture was stirred for 30 min.A solution of 2 (1.0 g, 4.70 mmol) in dry THF (10 mL) was added drop-wise.The solution was stirred for at -78 °C for 2 h.The appropriate electrophile (14.1 mmol; 3 equiv.)dissolved in dry THF (20 mL) was added through a syringe, and the mixture was warmed up to room temperature in the course of 2 h.The reaction was quenched with a saturated aqueous ammonium chloride solution (40 mL) and stirred for 30 min.The layers were separated, and the aqueous layer was extracted with diethyl ether (3 x 50 mL).The organic layers were collected, dried (sodium sulfate) and evaporated to dryness.The residue was purified by flash chromatography, and the product(s) thus obtained were recrystallized.

Lithiation of 2 followed by reaction with an electrophile. General procedure B
To a solution of TMEDA (778 mg, 7.10 mmol; 1.5 equiv.) in dry diethyl ether (15 mL) was added 1.3 M sec-BuLi in hexanes (5.4 mL, 7.10 mmol; 1.5 equiv.) at -78 °C, and the mixture was stirred for 30 min.A solution of 2 (1.0 g, 4.70 mmol) in dry diethyl ether (10 mL) was added drop-wise.After the solution was stirred at -78 °C for 2 h, the temperature was allowed to rise to -40 °C and was kept for 30 min.The mixture was cooled again to -78 °C, and the appropriate electrophile (14.10 mmol, 3 equiv.)dissolved in dry diethyl ether (20 mL) was added.The mixture was warmed up to room temperature in the course of 2 h.The reaction was quenched with saturated aqueous ammonium chloride solution (40 mL) and stirred for 30 min.The layers were separated, and the aqueous layer was extracted with diethyl ether (3 x 50 mL).The organic layers were combined, dried (sodium sulfate) and evaporated.The residue was purified by flash chromatography and the product(s) thus obtained were recrystallized.

Boc-Deprotection of 3, 4, 5 with trifluoroacetic acid. General procedure A
A solution of the respective starting material 3, 4, 5 (10% w/v, 1 equiv.) in dry dichloromethane was cooled to 5 °C and treated drop-wise with 100 equiv.trifluoroacetic acid.The temperature was allowed to rise to room temperature, and the mixture was stirred for 6 h.The solvent and excess of trifluoroacetic acid was removed, and the residue was suspended in a 100-fold amount of 2 N aqueous potassium hydroxide.The resulting solid product was filtered off, washed with water until neutral and dried at 50°C/0.5 mbar.

Boc-deprotection of 3, 4, 5 with sodium hydroxide. General procedure B
A solution of the respective starting material 3, 4, 5 (10% w/v, 1 equiv.) in ethanol was refluxed with freshly powdered sodium hydroxide (6 equiv.)for 14 h.The solvent was removed and the residue was suspended in water (100-fold amount).The solid product was filtered off, washed with water to neutral pH, and dried at 50 °C/0.5mbar.

Asymmetric reduction of propiophenone. General procedure
A solution (in some cases a suspension) of the ligands 8a, 8b, or 8c (0.10 mmol) in dry THF (1 mL) was treated with trimethyl borate (14 L, 0.12 mmol) and was stirred for 1 h.To this mixture was added borane·dimethylsulfide (neat; 0.1 mL, 1.00 mmol), and the mixture was stirred for further 10 min.With a syringe propiophenone (133 L, 1.00 mmol) was added over a period of 30 min, and the mixture was stirred until completion (as monitored by TLC)of the reaction (usually 30 min after addition of propiophenone).After 2 N hydrochloric acid (5 mL) was added, the layers were separated, and the aqueous layer was extracted with diethyl ether (3 x 5 mL).The organic combined organic layers were dried (sodium sulfate) and evaporated to dryness.The resulting colorless oil was separated by chiral HPLC.tr (R)-1-phenylpropanol: 14 min; tr (S)-1-phenylpropanol: 16 min; cf.Table 3.

Table 1 .
Yields of 3, 4, 5 obtained from the reaction of 2 with electrophiles

Scheme 2 Table 2 .
Yields of the deprotection reactions