The Addition of Allyltrimethylsilane to Cyclic N-Acyliminium Ions Derived from ( S )-( + )-Mandelic Acid and Cyclohexyl-Based Chiral Auxiliaries

A adição de aliltrimetilsilano, promovida por TiCl 4, a íons N-aciliminios cíclicos de 5e 6membros derivados do ácido ( S)-(+)-mandélico, ( 1R,2S)-trans-2-fenil-1-cicloexanol e ( 1R,2S,5R)8-fenilmentol ocorreu com baixas a moderadas razões diastereoisoméricas (1:1-6:1) e forneceu as respectivas amidas e carbamatos em bons rendimentos. A melhor diastereosseleção facial foi observada com o uso de ( 1R,2S,5R)-8-fenilmentol como auxiliar quiral. As amidas e carbamatos 2-substituídos foram convertidos nos alcalóides ( S)e (R)-propil pirrolidina e coniina com eficiente recuperação dos auxiliares quirais.


Introduction
The introduction of cyclohexyl-based chiral auxiliaries by Corey 1 in 1975 and mandelic acid by Trost 2 in 1980 stirred the interest for the development of new methodologies for asymmetric carbon-carbon bond formation.Despite that, few asymmetric routes are now available for the regioselective introduction of alkyl groups in the α-nitrogen position of N-acyliminium ions 3 employing recoverable chiral auxiliaries 4 .
The TiCl 4 -promoted reaction of allyltrimethylsilane with chiral cyclic N-acyliminium ions derived from 2-methoxy amides 4a,b and 2-methoxy carbamates 6a,b, except in the reaction with 2-methoxy carbamate 5b, resulted from the approach of the nucleophile to the Si face of the Nacyliminium ions.The better facial discrimination (6:1 d.r) observed with (1R,2S,5R)-8-phenylmenthol as the chiral auxiliary was rationalized from the kinetically preferred attack of the nucleophile to the s-cis conformation of N-acyliminium ions (Figure 1) 9 , which might be enforced by π-stacking 10 interactions involving the low-lying LUMO of the carbamoyl group and HOMO of the phenyl substituent.Comins and coworkers 3a,b (Figure 2) revealed this behavior in the addition of Grignard reagents to chiral Nacylpyridinium salts containing cyclohexyl-based chiral auxiliaries such as (1R,2S,5R)-8-phenylmenthol and the excellent stereocontrol observed was again assigned to π-stacking interactions between the iminium moiety and the phenyl substituent of the chiral auxiliary.ions, followed by in situ addition of allyltrimethylsilane to yield the corresponding 2-allyl pyrrolidines and piperidines.We have shown that the carbon-carbon bond formation in the addition of allyltrimethylsilane to chiral N-acyliminium ions occurred with low diastereoselection (1:1-2:1 d.r) employing (S)-(+)-mandelic acid and (1R,2S)-trans-2phenyl-1-cyclohexanol as chiral auxiliaries.However, moderate diastereoselection (6:1 d.r) was observed with (1R,2S,5R)-8-phenylmenthol as the chiral auxiliary.The results describe an attractive route to pyrrolidine and piperidine derivatives, particularly to pure (S)-2-propyl pyrrolidine (13a) which is present as a structural motif in many naturally occurring and biologically important compounds.The method also allows for an efficient recovery of the chiral auxiliary.

Conclusion
Overall, this paper describes an efficient procedure for generating chiral cyclic 5-and 6-membered N-acyliminium follower, model 176, and Hewlett Packard 6255A (Dual DC Power Supply, 0-40V, 0-1.5A).The 1 H-and 13 C-NMR spectra were recorded on a Bruker AC-300/P (7.05T), Varian Gemini (7.05T) and Varian Inova (11.7T) spectrometers.Chemical shifts (δ) are recorded in ppm with the solvent resonance as the internal standard and coupling constants (J) recorded in Hz.Signals for rotational and/or configurational isomers are denoted inside brackets.The infrared spectra were recorded as films in KBr cells on a Perkin-Elmer 1600 (FTIR) spectrometer (film and NaCl) and Nicolet Impact 410 (FTIR).Elemental analyses and high resolution mass spectroscopy (HRMS) were performed on a 2400 CHN-Perkin Elmer instrument and Autoespec-Micromass-EBE, respectively.Optical rotations were measure on a polarimeter Polamat A Carl Zeiss Jena using a quartz cell and a mercury or sodium lamp.The melting points were measured on an Electrothermal 9100 apparatus.The gas chromatography analyses (FID detector) were performed using a HP-5890-II equipment.Gas chromatography-mass spectrometry (GC/MS) analyses were performed on a Hewlett Packard 5890/Hewlett Packard 5970 MSD.
General procedure for the preparation of 2-propyl pyrrolidine (13a) and coniine (13b) from carbamates 8/ 11a,b and 9/12a,b: A solution of 2-allyl carbamates 8/11a,b or 9/12a,b (0.91 mmol) in ethanol (2 cm 3 ) containing 10% Pd-C was stirred overnight at room temperature under hydrogen atmosphere (H 2 , 1 atm).The catalyst was removed by filtration through Celite ® , and the filter pad was washed with diethyl ether (3 x 10 cm 3 ).The combined filtrates were concentrated under reduced pressure.Method A: To a solution of 2-propyl carbamates derived from 8/ 11a,b in methanol (2 cm 3 ) was added a 4.7 mol.dm -3 solution of NaOMe in methanol (2 cm 3 ) and the reaction mixture was stirred 30 h (n=1) or 36 h (n=2) in a sealed ampoule at 110 o C.After filtration through silica gel with methanol (20 cm 3 ) the combined filtrates were acidified (pH 1.0) with methanolic 10% HCl.Methanol was removed in vacuo and the residue was purified by column chromatography on silica gel.Method B: To a solution of 2-propyl carbamates derived from 9/12a,b in THF (2.0 cm 3 ) was added, at 0 o C, a 1.0 mol.dm -3 solution of MeLi in THF/cumene (2.0 mmol).The reaction mixture was stirred 36 h (n=1) or 48 h (n=2) at room temperature.The reaction was quenched by the addition of water (3 cm 3 ) and extracted with diethyl ether (3 x 5 cm 3 ).The combined filtrates were acidified (pH 1.0) with methanolic 10% HCl and the solvent was removed in vacuo.The residue was purified by column chromatography on silica gel.

3 Figure 1 .
Figure 1.Addition of allyltrimethylsilane to the s-cis conformation of N-Acyliminium ion derived from 6a.

Figure 2 .
Figure 2. Addition of trimethylsilylmagnesium chloride to the s-cis conformation of N-acylpyridinium ion.