Synthesis of new pantolactam-based chiral auxiliaries and applications to the asymmetric synthesis of drugs
Research Interests
Our research interest is focused on the development of new chiral auxiliaries having the core of pantolactam (3-hydroxy-4,4-dimethyl-2-pyrrolidinone), to be used in the enantioselective synthesis of pharmaceutically interesting chiral compounds.
Synthesis and application of (R)- and (S)-N-phenylpantolactam and other N-substituted derivatives thereof as new chiral auxiliaries for the enantioselective preparation of pharmaceutically interesting chiral compounds:
Based on the structure of (R)-pantolactone and its succesful
applications as chiral auxiliary in a large variety of asymmetric transformations,
we became interested in the development of new pantolactone derivatives
which could exhibit the same properties than (R)-pantolactone
as chiral auxiliary, but overcoming its limitations due to its hygroscopic
character, hydrosolubility and the high price of the (S)-enantiomer.
Thus, we have efficiently synthesized both enantiomers of 3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone
(N-phenylpantolactam) from the known racemic compound through
two alternative procedures based on enzymatic kinetic resolution or
enantioselective reduction of a ketone precursor. These two new compounds
are easily available, easily crystallizable non-hygroscopic solids more
lipophilic than pantolactone, and easily detectable by chiral HPLC under
UV detection due to the presence of the aniline chromophore. We have
proved the advantages derived from the use of these new chiral auxiliaries
over pantolactone in different asymmetric transformations including
asymmetric Diels Alder reactions, nucleophilic substitution reactions
on alpha-halo esters and deracemization of alpha-disubstituted carboxylic
acids, which have allowed the preparation of a series of biologically
important compounds in enantiopure form, after cleavage of the auxiliary,
such as antiinflammatory alpha-arylpropanoic and alpha-substituted alpha-arylacetic
acids, alpha-aryloxypropanoic acid herbicides, alpha-chloro acids, alpha-amino
acids, and alpha-aryl-gamma-aminobutyric acids. The outstanding properties
of (R)- and (S)-N-phenylpantolactam as chiral auxiliaries,
have promted us to develop a general and simple one-pot procedure to
gain access to a series of differently N-substituted pantolactams
in racemic form, from pantolactone and the corresponding primary amine
in methanol under acid catalysis at 250ºC in a pressure reactor.
We are currently exploring the application of (R)- and (S)-N-phenylpantolactam
as chiral auxiliaries in other asymmetric transformations such as dihydroxylation
or epoxidation reactions, Michael additions or 1,3-dipolar cycloadditions,
through which a wide series of pharmaceutically interesting compounds
could become readily available in enantiopure form.
Recent papers
Camps, P.; Giménez, S.; Font-Bardia, M.; Solans, X. "(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone by Lipase-Catalyzed Resolution of the Racemic Mixture: New Chiral Auxiliaries Related to Pantolactone", Tetrahedron: Asymmetry 1995, 6, 985-990.
Camps, P.; Giménez, S. "(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone, New Chiral Auxiliaries for the Asymmetric Synthesis of alpha-Arylpropanoic Acids", Tetrahedron: Asymmetry 1995, 6, 991-1000.
Camps, P.; Giménez, S. "Deracemization of alpha-Substituted Arylacetic Acids", Tetrahedron: Asymmetry 1996, 7, 1227 1234. PDF
Camps, P.; Pérez, F.; Soldevilla, N. "(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as Chiral Auxiliaries for the Asymmetric Synthesis of alpha-Hydroxy Acids", Tetrahedron: Asymmetry 1997, 8, 1877-1894.PDF
Camps, P.; Pérez, F.; Soldevilla, N. "(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as Chiral Auxiliaries in the Enantioselective Preparation of alpha-Arylpropanoic Acid Herbicides and alpha-Chlorocarboxylic Acids", Tetrahedron: Asymmetry 1998, 9, 2065-2079.PDF
Camps, P.; Pérez, F.; Soldevilla, N. "Enantioselective Synthesis of Both Enantiomers of 3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone", Tetrahedron Letters 1999, 40, 6853-6856.PDF
Camps, P.; Pérez, F.; Soldevilla, N.; Borrego, M.A. "(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as Chiral Auxiliries in the Enantioselective Preparation of alpha-Amino Acids", Tetrahedron: Asymmetry 1999, 10, 493-509. PDF
Camps, P.; Font-Bardia, M.; Giménez, S.; Pérez, F.; Solans, X.; Soldevilla, N. "(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as Chiral Auxiliaries in Diels Alder Reactions", Tetrahedron: Asymmetry 1999, 10, 3123-3138.PDF
Barrios, I.; Camps, P.; Comes-Franchini, M.; Muñoz-Torrero,
D.; Ricci, A.; Sánchez, L. "One-Pot Synthesis of N-Substituted
Pantolactams from Pantolactone", Tetrahedron 2003,
59, 1971-1979.PDF
Camps, P.; Muñoz-Torrero, D.; Sánchez, L. "Stereoselective synthesis of both enantiomers of N-Boc- -aryl- -aminobutyric acids", Tetrahedron: Asymmetry 2004, 15, 311 321.PDF
Camps, P.; Muñoz-Torrero, D. "Synthesis and applications of (R)- and (S)-pantolactone as chiral auxiliaries", Current Organic Chemistry 2004, 8, 1339 1380.
Camps, P.; Muñoz-Torrero, D.; Sánchez, L. "New synthesis
of both enantiomers of baclofen using (R)- and (S)-N-phenylpantolactam
as chiral auxiliaries", Tetrahedron: Asymmetry 2004,
15, 2039 2044. PDF
Current collaborations
Prof. Dr. Alfredo Ricci, Department of Organic Chemistry "A. Mangini", University of Bologna (Italy)
| Prof. Dr. Pelayo Camps
camps@ub.edu |
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