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US 5,466,834 AGranted
Preparation of substituted isoserine esters using metal alkoxides and .beta .
AssigneeFlorida State University
InventorRobert A. Holton
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Abstract
A process for preparing N-acyl, N-sulfonyl and N-phosphoryl substituted isoserine esters in which a metal alkoxide is reacted with a .beta.-lactam.
Claims15
A process for the preparation of an isoserine ester having the formula ##STR50## comprising reacting a .beta.-lactam with the metal alkoxide of a secondary or tertiary alcohol, the .beta.-lactam having the formula ##STR51## and the alkoxide having the formula ##STR52## wherein R.sub.1 is --OR.sub.6, --SR.sub.7, or --NR.sub.8 R.sub.9 ;
- R.sub.2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
- R.sub.3 and R.sub.4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R.sub.3 and R.sub.4 are not both acyl;
- R.sub.5 is --COR.sub.10, --COOR.sub.10, --COSR.sub.10, --CONR.sub.8 R.sub.10, --SO.sub.2 R.sub.11, or --POR.sub.12 R.sub.13,
- R.sub.6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or a hydroxy protecting group,
- R.sub.7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group,
- R.sub.8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
- R.sub.9 is an amino protecting group;
- R.sub.10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl,
- R.sub.11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR.sub.10, or --NR.sub.8 R.sub.14,
- R.sub.12 and R.sub.13 are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR.sub.10, or --NR.sub.8 R.sub.14, and
- R.sub.14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
- M is a Group IA, IIA, IIIA, IVA, VA, VIA or transition metal, zinc, or cadmium;
- E.sub.1 and E.sub.2 and the carbon to which they are attached comprise a carbocyclic or heterocyclic skeleton containing about 6 to 20 ring atoms, the hetero atoms being oxygen;
- and
- E.sub.3 is hydrogen or a hydrocarbon.
12 more elements
A process as set forth in claim 1 wherein
- the metal alkoxide has the formula ##STR56## Z is --OCOCH.sub.3 or --OT.sub.2 ;
- T.sub.1 and T.sub.2 are hydroxy protecting groups;
- M is as defined in claim 46;
- Ph is phenyl;
- Ac is acetyl;
- R.sub.1 is --OR.sub.6 ;
- R.sub.2 is hydrogen;
- R.sub.3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
- R.sub.4 is hydrogen;
- R.sub.5 is --COR.sub.10 or --COOR.sub.10 ;
- R.sub.6 is a hydroxy protecting group;
- and
- R.sub.10 is alkyl, alkenyl, aryl or heteroaryl.
10 more elements
A process for the preparation of a taxane comprising:
- reacting an alkoxide having the formula MOCE.sub.1 E.sub.2 E.sub.3 with a .beta.-lactam to form an intermediate and converting the intermediate to the taxane, wherein the .beta.-lactam has the formula:
- ##STR57## M is a Group IA, IIA, ILIA, IVA, VA, VIA or transition metal, zinc or cadmium;
- one of E.sub.1, E.sub.2 and E.sub.3 is hydrogen or a hydrocarbon and the other two of E.sub.1, E.sub.2 and E.sub.3 together with the carbon to which they are attached comprise a taxane nucleus,
- R.sub.1 is --OR.sub.6, --SR.sub.7, or --NR.sub.8 R.sub.9 ;
- R.sub.2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
- R.sub.3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R.sub.3 and R.sub.4 are not both acyl;
- R.sub.5 is --COR.sub.10, --COOR.sub.10, --CONR.sub.8 R.sub.10, --COSR.sub.10, --SO.sub.2 R.sub.11, or --POR.sub.12 R.sub.13 ;
- R.sub.6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group;
- R.sub.7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group;
- R.sub.8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
- R.sub.9 is an amino protecting group;
- R.sub.10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
- R.sub.11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR.sub.10, or --NR.sub.8 R.sub.14 ;
- R.sub.12 and R.sub.13 are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR.sub.10, or --NR.sub.8 R.sub.14 ;
- and
- R.sub.14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl.
13 more elements
A process for the preparation of taxol comprising reacting a metal alkoxide with a .beta.-lactam wherein,
- the metal alkoxide has the formula ##STR58## the .beta.-lactam has the formula:
- ##STR59## Z is --OCOCH.sub.3 or --OT.sub.2, T.sub.1 is a hydroxy protecting group,
- T.sub.2 is a hydroxy protecting group,
- Ph is phenyl,
- Ac is acetyl,
- M is a Group IA, IIA, IIIA, IVA, VA or VIA or transition metal, zinc, or cadmium,
- R.sub.1 is --OR.sub.6,
- R.sub.2 is hydrogen,
- R.sub.3 is phenyl,
- R.sub.4 is hydrogen,
- R.sub.5 is --COR.sub.10,
- R.sub.6 is a hydroxy protecting group, and
- R.sub.10 is phenyl.
10 more elements
Dependencies are inferred from the claim text.