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US 2017/0320893 A1Published application
Nannocystin process and products
AssigneeThe Research Foundation for The State University of New York
InventorsZhang WANG, Jun HUANG
Life of this patent
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Abstract
Described herein is a process for the total synthesis of macrolactones and macrolactams of formula I including E- and Z-configuration thereof, in particular, nannocystins.
Claims21
A compound of formula I
A process for preparing macrolactones and macrolactams of formula I
- wherein
- A is —O— or —NH—;
- Q is —O—, —NR7—, or —C(R11R12)—;
- R1 is aryl optionally substituted with one or more substituents chosen independently from —(C1-C3)alkyl, halogen, —(C1-C3)haloalkyl, —(C1-C3)alkyl-OH, and —O(C1-C3)alkyl;
- R2 is chosen from hydrogen, (C1-C12)hydrocarbyl and —(C1-C12)hydrocarbyl-OH;
- R3 is phenyl or benzyl optionally substituted with one or more substituents chosen independently from —(C1-C3)alkyl, halogen, —(C1-C3)haloalkyl, —(C1-C3)alkyl-OH, and —O(C1-C3)alkyl;
- R4 is hydrogen or (C1-C7)hydrocarbyl;
- R5 is hydrogen, (C1-C7)hydrocarbyl or the side chain of a natural amino acid;
- R6 is hydrogen or (C1-C7)hydrocarbyl;
- R7 is hydrogen or (C1-C3)alkyl;
- R8 is chosen from hydrogen, —(C1-C3)alkyl, halogen, hydroxyl, —(C1-C3)haloalkyl, —(C1-C3)alkyl-OH, and —O(C1-C3)alkyl;
- R9 is chosen from hydrogen, —(C1-C3)alkyl, halogen, hydroxyl, —(C1-C3)haloalkyl, —(C1-C3)alkyl-OH, —O(C1-C3)alkyl, and —C(O)O(C1-C3)alkyl
- R10 is chosen from hydrogen, (C1-C7)hydrocarbyl and (C1-C7)oxaalkyl;
- said process comprising:
- reacting a compound of formula II
- with a ring-closing metathesis catalyst.
13 more elements
A process for preparing a compound of formula II
- comprising reacting a compound of formula III
- with a compound of formula IV
- under conditions to form an amide bond.
A process for preparing a compound of formula III
- comprising oxidizing a compound of formula V
A process for preparing a compound of formula Va
- comprising epoxidizing a compound of formula VI
A process for preparing a compound of formula VI
- comprising cross coupling of VII
- with tributylvinylstannane in the presence of a palladium catalyst.
A process for preparing a compound of formula VII
- comprising cross metathesis of VIII
- with methacrolein in the presence of a palladium catalyst, followed by reduction.
A process for preparing a compound of formula IV
- comprising coupling an amine X with a protected acid XI
- under conditions to form an amide bond and deprotecting, wherein PG is a protecting group for an amine.
A process for preparing an amine of formula Xa
- comprising esterification of an alcohol of formula XII
- with a protected amino acid of formula XIII,
- followed by deprotection of the amine.
A process for preparing macrolactones and macrolactams of formula I
- wherein
- A is —O— or —NH—;
- Q is —O—, —NR7—, or —C(R11R12)—;
- R1 is aryl optionally substituted with one or more substituents chosen independently from —(C1-C3)alkyl, halogen, —(C1-C3)haloalkyl, —(C1-C3)alkyl-OH, and —O(C1-C3)alkyl;
- R2 is chosen from hydrogen, (C1-C12)hydrocarbyl and —(C1-C12)hydrocarbyl-OH;
- R3 is phenyl or benzyl optionally substituted with one or more substituents chosen independently from —(C1-C3)alkyl, halogen, —(C1-C3)haloalkyl, —(C1-C3)alkyl-OH, and —O(C1-C3)alkyl;
- R4 is hydrogen or (C1-C7)hydrocarbyl;
- R5 is hydrogen, (C1-C7)hydrocarbyl or the side chain of a natural amino acid;
- R6 is hydrogen or (C1-C7)hydrocarbyl;
- R7 is hydrogen or (C1-C3)alkyl;
- R8 is chosen from hydrogen, —(C1-C3)alkyl, halogen, hydroxyl, —(C1-C3)haloalkyl, —(C1-C3)alkyl-OH, and —O(C1-C3)alkyl;
- R9 is chosen from hydrogen, —(C1-C3)alkyl, halogen, hydroxyl, —(C1-C3)haloalkyl, —(C1-C3)alkyl-OH, —O(C1-C3)alkyl, and —C(O)O(C1-C3)alkyl
- R10 is chosen from hydrogen, (C1-C7)hydrocarbyl and (C1-C7)oxaalkyl;
- said process comprising:
- (a) preparing an amine of formula Xa
- by esterification of an alcohol of formula XII
- with a protected amino acid of formula XIII,
- followed by deprotection of the amine;
- (b) preparing a compound of formula IV
- by coupling an amine X with a protected acid XI
- under conditions to form an amide bond and deprotecting, wherein PG is a protecting group for an amine;
- (c) preparing a compound of formula VII
- by cross metathesis of VIII
- with methacrolein in the presence of a palladium catalyst, followed by reduction;
- (d) preparing a compound of formula VI
- by cross coupling of VII
- with tributylvinylstannane in the presence of a palladium catalyst;
- (e) preparing a compound of formula Va
- by epoxidizing a compound of formula VI;
- (f) preparing a compound of formula III
- by oxidizing a compound of formula V;
- (g) preparing a compound of formula II
- by reacting a compound of formula III
- with a compound of formula IV
- under conditions to form an amide bond;
- (h) reacting a compound of formula II
- with a ring-closing metathesis catalyst.
34 more elements
Dependencies are inferred from the claim text.