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US 7,842,814 B2Granted
Total synthesis of salinosporamide A and analogs thereof
AssigneeNereus Pharmaceuticals, Inc.
InventorsTaotao Ling, Venkata Rami Reddy Macherla, Barbara Christine Potts, Rama Rao Manam, Katherine A. McArthur
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Abstract
The present invention relates to certain compounds and to methods for the preparation of certain compounds that can be used in the fields of chemistry and medicine. Specifically, described herein are methods for the preparation of various compounds and intermediates, and the compounds and intermediates themselves. More specifically, described herein are methods for synthesizing Salinosporamide A and its analogs from a compound of formula (V).
Claims27
A method of chemical synthesis comprising the steps of:
- (a) reacting a compound of formula (I):
- with a compound of formula (II):
- to form a compound of formula (III):
- (b) deprotecting the compound of formula (III) to form a compound of formula (IV):
- (c) performing an intramolecular aldol reaction on the compound of formula (IV) to form a compound of formula (V):
- (d) cleaving the carbon-carbon double bond of the compound of formula (V) and cyclizing the cleaved double bond with the tertiary hydroxy group to form a compound of formula (VI):
- (e) protecting the hemiacetal of the compound of formula (VI) to form a compound of formula (VII):
- (f) reducing the COOR2 group of the compound of formula (VII) to an alcohol to form a compound of formula (VIII):
- (g) oxidizing the alcohol of the compound of formula (VIII) to form a compound of formula (IX):
- (h) adding R4 to the compound of formula (IX) by reacting the compound of formula (IX) with an organometallic moiety containing at least one R4 to form a compound of formula (X):
- (i) removing PG1 on the compound of formula (X) and reductively opening the hemiacetal of the compound of formula (X) to form a compound of formula (XXIII):
- (j) protecting the primary hydroxy group of the compound of formula (XXIII) to form a compound of formula (XXIV):
- (k) cleaving the aminal group of the compound of formula (XXIV) to form a compound of formula (XXV):
- (l) protecting the secondary alcohol of the compound of formula (XXV) to form a compound of formula (XXVp):
- (m) converting the primary alcohol group and removing the PG2 protecting group moiety on the secondary alcohol of the compound of formula (XXVp) to form a compound of formula (XXVI):
- (n) removing the PG3 protecting group moiety on the primary alcohol of the compound of formula (XXVI) to form a compound of formula (XXVII):
- (o) protecting the primary alcohol of the compound of formula (XXVII) with the PG3 protecting group moiety to form a compound of formula (XXVI), wherein the PG3 can be same or different from the PG3 in step (m):
- (p) performing a lactonization reaction on the compound of formula (XXVI) to form a compound of formula (XXVIII):
- (q) removing the PG3 protecting group moiety on the compound of formula (XXVIII) to form a compound of formula (XV):
- wherein:
- R1 is hydrogen or substituted or unsubstituted C1-6 alkyl;
- R2 is selected from the group consisting of hydrogen, or substituted or unsubstituted variants of the following:
- C1-6 alkyl aryl, and arylalkyl;
- R3 is selected from the group consisting of substituted or unsubstituted variants of the following:
- C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C3-6 cycloalkenyl, aryl, and arylalkyl;
- R4 can be selected from the group consisting of substituted or unsubstituted variants of the following:
- C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, C3-C12 cycloalkynyl, C3-C12 heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, acyl, acylalkyl, alkyloxycarbonyloxy, carbonylacyl, aminocarbonyl, azido, azidoalkyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, salt of carboxyalkyl, alkylaminoalkyl, salt of an alkylaminoalkyl, dialkylaminoalkyl, salt of a dialkylaminoalkyl, phenyl, alkylthioalkyl, arylthioalkyl, carboxy, cyano, alkanesulfonylalkyl, alkanesulfinylalkyl, alkoxysulfinylalkyl, thiocyanoalkyl, boronic acidalkyl, boronic esteralkyl, guanidinoalkyl, salt of a guanidinoalkyl, sulfoalkyl, salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, salt of a pyridinylalkyl, salt of a heteroarylalkyl and halogenated alkyl including polyhalogenated alkyl;
- R5 is selected from the group consisting of —C(═O)OR6, —C(═O)SR6, —C(═O)NR6R6 and —C(═O)Z;
- each R6 can be independently selected from the group consisting of hydrogen, halogen, or substituted or unsubstituted variants of the following:
- C1-C24 alkyl, acyl, alkylacyl, arylacyl, aryl, arylalkyl, p-nitrophenyl, pentafluorophenyl, pentafluoroethyl, trifluoroethyl, trichloroethyl, and heteroaryl;
- RA and RB are each independently selected from the group consisting of substituted or unsubstituted variants of the following:
- C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, wherein RA and RB can be optionally bound together to form an optionally substituted 5, 6, 7, or 8 membered heterocyclyl;
- Y is oxygen or sulfur;
- Z is a halogen;
- and
- PG1 and PG3 are each a protecting group moiety.
33 more elements
A method of forming a compound of formula (X) from a compound of formula (V) comprising the steps of:
- cleaving the carbon-carbon double bond of the compound of formula (V) and cyclizing the cleaved double bond with the tertiary hydroxy group;
- transforming —COOR2 to an aldehyde, wherein R2 is selected from the group consisting of hydrogen, or substituted or unsubstituted variants of the following:
- C1-6 alkyl, aryl, and arylalkyl;
- and
- adding R4 to the aldehyde using an organometallic moiety containing at least one R4, wherein R4 is selected from the group consisting of substituted or unsubstituted variants of the following:
- C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, C3-C12 cycloalkynyl, C3-C12 heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, acyl, acylalkyl, alkyloxycarbonyloxy, carbonylacyl, aminocarbonyl, azido, azidoalkyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, salt of carboxyalkyl, alkylaminoalkyl, salt of an alkylaminoalkyl, dialkylaminoalkyl, salt of a dialkylaminoalkyl, phenyl, alkylthioalkyl, arylthioalkyl, carboxy, cyano, alkanesulfonylalkyl, alkanesulfinylalkyl, alkoxysulfinylalkyl, thiocyanoalkyl, boronic acidalkyl, boronic esteralkyl, guanidinoalkyl, salt of a guanidinoalkyl, sulfoalkyl, salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, salt of a pyridinylalkyl, salt of a heteroarylalkyl and halogenated alkyl including polyhalogenated alkyl.
3 more elements
A method of forming a compound of formula (XVII) from a compound of formula (V) comprising the steps of:
- cleaving the carbon-carbon double bond of the compound of formula (V) and cyclizing the cleaved double bond with the tertiary hydroxy group;
- and
- adding R4 after cyclization with the tertiary hydroxy group using an organometallic moiety containing at least one R4, wherein R4 is selected from the group consisting of substituted or unsubstituted variants of the following:
- C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, C3-C12 cycloalkynyl, C3-C12 heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, acyl, acylalkyl, alkyloxycarbonyloxy, carbonylacyl, aminocarbonyl, azido, azidoalkyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, salt of carboxyalkyl, alkylaminoalkyl, salt of an alkylaminoalkyl, dialkylaminoalkyl, salt of a dialkylaminoalkyl, phenyl, alkylthioalkyl, arylthioalkyl, carboxy, cyano, alkanesulfonylalkyl, alkanesulfinylalkyl, alkoxysulfinylalkyl, thiocyanoalkyl, boronic acidalkyl, boronic esteralkyl, guanidinoalkyl, salt of a guanidinoalkyl, sulfoalkyl, salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, salt of a phosphorylalkyl, (alkylphosphory)alkyl, pyridinylalkyl, salt of a pyridinylalkyl, salt of a heteroarylalkyl and halogenated alkyl including polyhalogenated alkyl.
1 more element
A method for preparing a compound of formula (V) comprising performing an intramolecular aldol reaction on the compound of formula (IV) to form a compound of formula (V):
- wherein:
- R1 is hydrogen or substituted or unsubstituted C1-6 alkyl;
- R2 is selected from the group consisting of hydrogen, or substituted or unsubstituted variants of the following:
- C1-6 alkyl, aryl, and arylalkyl;
- and
- R3 is selected from the group consisting of substituted or unsubstituted variants of the following:
- C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C3-6 cycloalkenyl, aryl, and arylalkyl.
4 more elements
A method of preparing a compound of formula (VI) comprising cleaving the double bond of the compound of formula (V) and cyclizing the cleaved double bond with the tertiary hydroxy group to form a compound of formula (VI):
- wherein:
- R1 is hydrogen or substituted or unsubstituted C1-6 alkyl;
- R2 is selected from the group consisting of hydrogen, or substituted or unsubstituted variants of the following:
- C1-6 alkyl, aryl, and arylalkyl;
- and
- R3 is selected from the group consisting of substituted or unsubstituted variants of the following:
- C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C3-6 cycloalkenyl, aryl, and arylalkyl.
4 more elements
A compound of formula (V):
- wherein:
- R1 is hydrogen or substituted or unsubstituted C1-6 alkyl;
- R2 is selected from the group consisting of hydrogen, or substituted or unsubstituted variants of the following:
- C1-6 alkyl, aryl, and arylalkyl;
- and
- R3 is selected from the group consisting of substituted or unsubstituted variants of the following:
- C1-6 alkyl, a C3-6 cycloalkyl, a C2-6 alkenyl, C3-6 cycloalkenyl, aryl, and arylalkyl.
4 more elements
Dependencies are inferred from the claim text.