Method for improved chemical synthesis of guanidinium alkaloids
AssigneeThe Regents of the University of California
InventorsLarry Overman, Frank Stappenbeck, Andrew McDonald
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Abstract
Improved methods for convergent, total enantioselective synthesis of guanidinium alkaloid compounds including ones having cis- or -trans-1-oxo-and 1-iminohexahydropyrrolo [1,2c]pyrimidine units including, 13,14,15-isocrambescidin 800, crambescidin 800 and ptilomycalin A, for use as therapeutic agents having antifungal and/or antiviral and/or antitumor activity are provided. Methods for preparing novel pentacyclic intermediates for the preparation of the crambescidin/ptilomycalin family of guanidinium alkaloids and congeners are also disclosed.
Claims46
A compound of the formula:
- Wherein,
- R=H, a carboxylic acid protecting group, an ω-alkoxycarboxylic acid or an ω-alkoxycarboxylic acid ester, and
- X=any pharmaceutically acceptable counterion.
A compound of the formula:
- Wherein,
- R=H, a carboxylic acid protecting group, an ω-alkoxycarboxylic acid or an ω-alkoxycarboxylic acid ester, and
- X=any pharmaceutically acceptable counterion.
A compound of the formula:
- Wherein,
- R=H, a carboxylic acid protecting group, an ω-alkoxycarboxylic acid or an ω-alkoxycarboxylic acid ester, and
- X=any pharmaceutically acceptable counterion.
A compound of the formula:
- Wherein,
- R=H, a carboxylic acid protecting group, an ω-alkoxycarboxylic acid or an ω-alkoxycarboxylic acid ester, and
- X=any pharmaceutically acceptable counterion.
A compound of the formula:
- Wherein,
- R=H, a carboxylic acid protecting group, an ω-alkoxycarboxylic acid or an ω-alkoxycarboxylic acid ester, and
- X=any pharmaceutically acceptable counterion.
A compound of the formula:
A compound of the formula:
A compound of the formula:
A compound of the formula:
A compound of the formula:
A method for synthesizing a pentacyclic compound of the formula:
- Wherein,
- R=H, a carboxylic acid protecting group, an ω-alkoxycarboxylic acid or an ω-alkoxycarboxylic acid ester, and
- X=any pharmaceutically acceptable counterion
- which method comprises reacting a compound of the formula:
- wherein G=a carboxylic acid protecting group, an ω-alkoxycarboxylic acid or and ω-alkoxycarboxylic acid ester, and
- Y=alcohol protecting group
- with a compound of the formula:
- wherein X2=O or ketone protecting group
- Z=alkene or carbonyl protecting group
- P=alcohol protecting group and
- Q=amino carbonyl group
- to produce a compound of the formula:
- wherein X2=O or ketone protecting group
- P=alcohol protecting group, and
- R=carboxylic acid protecting group, ω-alkoxycarboxylic acid or ω-alkoxycarboxylic acid ester
- which compound is subsequently converted to the pentacyclic compound by deprotection, incorporation of ammonia, and cyclization.
A method for synthesizing a pentacyclic compound of the formula:
- Wherein,
- R=H, a carboxylic acid protecting group, an ω-alkoxycarboxylic acid or an ω-alkoxycarboxylic acid ester, and
- X=any pharmaceutically acceptable counterion,
- which comprises epimerizing the stereocenter at carbon-14 of the compound of the formula:
A method for synthesizing pentacyclic compounds B and C of the formulae:
- Wherein,
- R=H, a carboxylic acid protecting group, an ω-alkoxycarboxylic acid or an ω-alkoxycarboxylic acid ester, and
- X=any pharmaceutically acceptable counterion,
- which comprises reacting a compound of the formula:
- wherein G=a carboxylic acid protecting group, an ω-alkoxycarboxylic acid or
- an ω-alkoxycarboxylic acid ester, and
- Y=an alcohol protecting group
- with a compound of the formula:
- wherein X2=O or a ketone protecting group
- Z=an alkene or carbonyl protecting group
- P=an alcohol protecting group, and
- Q=an amidinyl group
- To produce a compound of the formula:
- wherein X2=O or a ketone protecting group
- P=an alcohol protecting group and
- R=a carboxylic acid protecting group, an ω-alkoxycarboxylic acid or an ω-alkoxycarboxylic acid ester
- which is subsequently converted to the pentacyclic compound by deprotection and cyclization.
A method for synthesizing a pentacyclic compound of the formula:
- R=H, a carboxylic acid protecting group, an ω-alkoxycarboxylic acid or an ω-alkoxycarboxylic acid ester, and
- X=any pharmaceutically acceptable counterion.
- which comprises epimerizing the stereocenter at carbon-14 and carbon 15 of the compound of the formula:
A compound of the formula:
- wherein R1=any alkyl, aryl or substituted alkyl group
- R2=O−, OH, OG1, a spermidine moiety or a substituted spermidine moiety
- wherein G1=a carboxylic acid protecting group and
- X=any pharmaceutically acceptable counterion.
A compound of the formula:
- wherein R1=any alkyl, aryl or substituted alkyl group
- R2=O−, OH, OG1, a spermidine moiety or a substituted spermidine moiety
- wherein G1=a carboxylic acid protecting group and
- X=any pharmaceutically acceptable counterion.
A compound of the formula:
- wherein R1=any alkyl, aryl or substituted alkyl group
- R2=O−, OH, OG1, a spermidine moiety or a substituted spermidine moiety
- wherein G1=a carboxylic acid protecting group and
- X=any pharmaceutically acceptable counterion.
A compound of the formula:
- wherein R1=any alkyl, aryl or substituted alkyl group
- R2=O−, OH, OG1, a spermidine moiety or a substituted spermidine moiety
- wherein G1=carboxylic acid protecting group, and
- X=any pharmaceutically acceptable countenon.
A compound of the formula:
- wherein R1=any alkyl, aryl or substituted alkyl group
- R2=O−, OH, OG1, a spermidine moiety or a substituted spermidine moiety
- wherein G1=carboxylic acid protecting group and
- X=any pharmaceutically acceptable counterion.
Dependencies are inferred from the claim text.