Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-31
2003-06-03
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C544S176000, C546S134000, C546S136000, C560S012000, C562S553000, C562S575000, C564S164000
Reexamination Certificate
active
06573387
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the conversion of &agr;,&bgr;-unsaturated amides and esters to &agr;,&bgr;-substituted amino amides, esters, and acids. More particularly, the invention relates to three-step converion processes employing an osmium-catalyzed aminohydroxylation step to produce &agr;,&bgr;-hydroxysulfonamide or hydroxycarbamate amide or ester intermediates, a cyclodehydration step to produce an &agr;,&bgr;-N-sulfonyl- or the &agr;,&bgr;-N-carbamoylaziridine amides or esters and a regioselective nucleophilically induced ring-opening step to give the &agr;,&bgr;-substituted amino- amides or esters.
SUMMARY
One aspect of the invention is directed to a method for converting an &agr;,&bgr;-unsaturated substrate to a blocked or unblocked &agr;,&bgr;-substituted amino product. The &agr;,&bgr;-unsaturated substrate may be an &agr;,&bgr;-unsaturated amide or an &agr;,&bgr;-unsaturated ester. The &agr;,&bgr;-substituted amino product corresponds to the &agr;,&bgr;-unsaturated substrate, i.e., it is an &agr;,&bgr;-substituted amino amide or &agr;,&bgr;-substituted amino ester. The &agr;,&bgr;-substituted amino product may be either blocked or unblocked. The blocked &agr;,&bgr;-substituted amino product includes a blocked amino group. The unblocked &agr;,&bgr;-substituted amino product includes an unblocked amino group.
In the first step of the conversion, the &agr;,&bgr;-unsaturated substrate is oxidized with a nitrogen source for making a racemic mixture of an &agr;,&bgr;-hydroxy-amino intermediate. The &agr;,&bgr;-hydroxy-amino intermediate includes a blocked amino group and corresponds to the substrate, i.e., it is an &agr;,&bgr;-hydroxy-amino amide or an &agr;,&bgr;-hydroxy-amino ester. Preferred nitrogen sources include carbamate and sulfonamide. In a preferred mode, the oxidation is a regioselective osmium-catalyzed aminohydroxylation. Then, the above &agr;,&bgr;-hydroxy-amino intermediate is cyclodehydrated for producing an &agr;,&bgr;-N-blocked-aziridine intermediate having an aziridine ring, the &agr;,&bgr;-N-blocked-aziridine intermediate. The aziridne intermediate corresponds to the starting material, i.e., it is an &agr;,&bgr;-N-blocked-aziridine amide or an &agr;,&bgr;-N-blocked-aziridine ester. Then, the aziridine ring of the &agr;,&bgr;-N-blocked-aziridine intermediate is opened with a nucleophile in a regioselective manner for making the blocked &agr;,&bgr;-substituted amino product. Preferred nucleophiles are hydrocarbons having a nucleophilic moiety selected from a group consisting of thiol, alcohol, nitrile and amine. Finally, the amino group of the blocked &agr;,&bgr;-substituted amino product is optionally unblocked to produce the unblocked &agr;,&bgr;-substituted amino product. The amide or ester group of the blocked or unblocked &agr;,&bgr;-substituted amino product may be hydrolyzed for forming a blocked or unblocked &agr;-substituted &bgr;-amino acid.
Another aspect of the invention is directed to the synthesis of a library comprising a plurality of compounds using the above described method.
Another aspect of the invention is directed to a method for converting an &agr;-&bgr; unsaturated substrate to a racemic mixture of an &agr;-hydroxy-&bgr;-amino regio-isomer product having a blocked amino group. The &agr;-&bgr; unsaturated substrate may be an &agr;-&bgr; unsaturated amide or an &agr;-&bgr; unsaturated ester. The &agr;-hydroxy-&bgr;-amino regio-isomer product is formed by admixing a nitrogen source and a hydroxyl radical with the &agr;-&bgr; unsaturated substrate. The method is of a type which employs a reaction solution which includes osmium as a catalyst, The &agr;-&bgr; unsaturated amide substrate is present and soluble at a stoichiometric concentration within the reaction solution. The osmium is present and soluble within the reaction solution at a catalytic concentration. Preferred nitrogen source include sulfonamide and carbamate.
Another aspect of the invention is directed to a method for converting an &agr;-&bgr; unsaturated substrate to an asymmetric &agr;-hydroxy-&bgr;-amino regio-isomer product having a blocked amino group. The &agr;-&bgr; unsaturated substrate may be an &agr;-&bgr; unsaturated amide or an &agr;-&bgr; unsaturated ester. The asymmetric &agr;hydroxy-&bgr;-amino regio-isomer product is formed by admixing a nitrogen source, a chiral ligand, and a hydroxyl radical with the &agr;-&bgr; unsaturated substrate. The method employs a reaction solution which includes osmium as a catalyst. The &agr;-&bgr; unsaturated substrate is present and soluble at a stoichiometric concentration within the reaction solution. The osmium is present and soluble within the reaction solution at a catalytic concentration. Preferred nitrogen sources include sulfonamide and carbamate. The chiral ligand is selected for enantiomerically directing the addition of the nitrogen source and hydroxyl radical. In a preferred mode, the admixture occurs in a co-solvent mixture containing an organic component and an aqueous component.
Another aspect of the invention is directed to a method for converting an &agr;,&bgr;-hydroxy-amino substrate having a blocked amino group to an &agr;,&bgr;-N-blocked-aziridine product. The &agr;,&bgr;-hydroxy-amino substrate may be an &agr;,&bgr;-hydroxy-amino amide or an &agr;,&bgr;-hydroxy-amino ester. The hydroxyl moiety of the &agr;,&bgr;-hydroxy-amino substrate is activated with an activating agent for producing an activated &agr;,&bgr;-hydroxy-amino intermediate having an activated hydroxyl moiety and an amino nitrogen. The activated &agr;,&bgr;-hydroxy-amino intermediate corresponds to the substrate and may be an activated &agr;,&bgr;-hydroxy-amino amide or an activated &agr;,&bgr;-hydroxy-amino ester. Then, the activated hydroxyl moiety of the activated &agr;,&bgr;-hydroxy-amino intermediate is displaced with the amino nitrogen by base promoted ring closure for forming the &agr;,&bgr;-N-blocked-aziridine product.
REFERENCES:
patent: 5859281 (1999-01-01), Sharpless et al.
Sharpless, et al., “Osmium-Catalyzed Vicinal Oxyamination of Olefins by Chloramine-T”,J. Org. Chem. 41:177-179 (1976).
Herranz, et al., “Improvements in the Osmium-Catalyzed Oxyamination of Olefins by Chloramine-T”,J. Org. Chem. 43: 2544-2548 (1978).
Bennani, et al., “Asymmetric Dihydroxylation (AD) of N,N-Dialkyl and N-Methoxy-N-methyl &agr;,&bgr;- and &bgr;,&ggr;-Unsaturated Amides”,Tet. Lett. 34: 2079-2082 (1993).
Evans, et al., “Bis(oxazoline)-Copper Complexes as Chiral Catalysts for the Enantioselective Aziridination of Olefins”,J. Am. Chem. Soc. 115: 5328-5329 (1993).
Tanner, “Chiral Aziridines—Their Synthesis and Use in Stereoselective Transformations”,Angew. Chem. Int. Ed. Engl. 33: 599-619 (1994).
Davis, et al., “Asymmetric Synthesis and Reactions of cis-N-(p-Toluenesulfinyl)aziridine-2-carboxylic Acids”,J. Org. Chem. 59: 3243-3245 (1994).
Li, et al., “Catalytic Asymmetric Aminohydroxylation (AA) of Olefins”,Angew. Chem. Int. Ed. Engl. 35: 451-454 (1996).
Shibasaki, et al., “Catalytic Asymmetric Carbon-Carbon Bond-Forming Reaction Utilizing Rare Earth Metal Complexes”,Pure. Appl. Chem. 68: 523-530 (1996).
Larrow, et al., “Kinetic Resolution of Terminal Epoxides via Highly Regioselective and Enantioselective Ring Opening with TMSN3. An Efficient, Catalytic Route to 1,2-Amino Alcohols”,J. Am. Chem. Soc. 118: 7420-7421 (1996).
Rudolph, et al., “Smaller Substituents on Nitrogen Facilitate the Osmium-Catalyzed Asymmetric Aminohydroxylation”,Angew. Chem. Int. Ed. Engl. 35: 2810-2813 (1996).
Li, et al., “N-Halocarbamate Salts Lead to More Efficient Catalytic Asymmetric Aminohydroxylation”,Angew. Chem. Int. Ed. Engl. 35: 2813-2817 (1996).
Bruncko, et al., “N-Bromoacetamide—A New Nitrogen Source for the Catalytic Asymmetric Aminohydroxylation of Olefins”,Angew. Chem. Int. Ed. Engl. 36: 1483-1486 (1997).
Maligres, et al., “Nosylaziridines: Activated Aziridine Electrophiles”,Tet. Lett. 38: 5253-5256 (1997).
Sun, et al., “tert-Butylsulfonyl (Bus), a New Protecting Group for Amines”,J. Org. Chem. 62: 8604-8608 (1997).
Osborn, et al., “The Asym
Rubin A. Erik
Sharpless K. Barry
Kumar Shailendra
Lewis Donald G.
The Scripps Research Institute
LandOfFree
Synthesis of &agr;,&bgr;-substituted amino amides, esters,... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Synthesis of &agr;,&bgr;-substituted amino amides, esters,..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Synthesis of &agr;,&bgr;-substituted amino amides, esters,... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3109302