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US 2005/0148675 A1Published application
Practical, cost-effective synthesis of ubiquinones
AssigneeZymes, LLC
InventorsBruce Lipshutz, Volker Berl, Karin Schein, Frank Wetterich
Life of this patent
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Abstract
The present invention provides a convergent method for the synthesis of ubiquinones and ubiquinone analogues. Also provided are precursors of ubiquinones and their analogues that are useful in the methods of the invention. The invention further provides an improved method for the carboalumination of alkyne substrates.
Claims47
A method of preparing a compound of Formula
- said method comprising:
- contacting a compound that is a member selected from:
- in which
- R1, R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl groups;
- R7 is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, SOR9, SO2R9, C(O)R9, C(O)OR9, P(O)OR9OR10, P(O)N(R9)2(R10)2, and P(O)R9R10
- wherein
- each R9 and R10 is a member independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl;
- and
- Z′ is a leaving group other than halogen,
- with a compound having the structure
- wherein
- each L is independently selected from substituted or unsubstituted alkyl, alkoxy, aryl or aryloxy with 1 to 10 carbon atoms;
- M is aluminum;
- p is 1 or 2
- n is an integer from 0 to 19,
- in the presence of a coupling catalyst effective at catalyzing coupling between the methylene carbon of the quinone of Formula (VII) a or (XXIV) and the vinylic carbon attached to M,
- thus preparing said compound of Formula (III).
14 more elements
A method of preparing a compound having the formula:
- wherein
- R1, R2 and R3 are members independently selected from substituted or unsubstituted C1-C6 alkyl groups;
- and
- n is an integer from 0 to 19, said method comprising:
- (a) performing the transformation:
- wherein
- X′ is OH or a leaving group;
- and
- (b) contacting the product of (a) with:
- wherein
- each L is independently selected from substituted or unsubstituted alkyl, alkoxy, aryl or aryloxy with 1 to 10 carbon atoms;
- M is aluminum;
- n is an integer from 0 to 19;
- p is 1 or 2;
- in the presence of a coupling catalyst effective at catalyzing coupling between the methylene carbon of the quinone of Formula XXVIII and the vinylic carbon attached to M in Formula (IV)
- thus preparing said compound of Formula (III).
13 more elements
A method of preparing a compound having the formula:
- wherein
- R1, R2 and R3 are members independently selected from substituted or unsubstituted C1-C6 alkyl groups;
- and
- n is an integer from 0 to 19, said method comprising:
- (a) performing the transformation:
- wherein
- R1, R2 and R3 are members independently selected from substituted or unsubstituted C1-C6 alkyl groups;
- and
- R7 is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, SOR9, SO2R9, C(O)R9, C(O)OR9, P(O)OR9OR10, P(O)N(R9)2(R10)2, and P(O)R9R10
- wherein each R9 and R10 is a member independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl;
- and
- (b) oxidizing the product of (a) to a compound having the formula:
- (c) contacting the product of (b) with:
- wherein
- each L is independently selected from substituted or unsubstituted alkyl, alkoxy, aryl or aryloxy with 1 to 10 carbon atoms;
- M is aluminum;
- p is 1 or 2;
- n is an integer from 0 to 19
- in the presence of a coupling catalyst effective at catalyzing coupling between the quinone methylene carbon of the compound of Formula (XXIV) and the vinylic carbon attached to M,
- thus preparing said compound of Formula (III).
17 more elements
A method of preparing a compound having the formula:
- wherein
- R1, R2 and R3 are members independently selected from substituted or unsubstituted C1-C6 alkyl groups;
- and
- n is an integer from 0 to 19, said method comprising:
- (a) performing the transformation:
- wherein
- R1, R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl groups;
- R4 is a member selected from hydrogen, substituted or unsubstituted alkyl, and protecting groups;
- and
- X is a leaving group;
- (b) contacting the product of (a) with:
- wherein
- each L is independently selected from substituted or unsubstituted alkyl, alkoxy, aryl or aryloxy with 1 to 10 carbon atoms;
- M is aluminum;
- p is 1 or 2;
- n is an integer from 0 to 19
- in the presence of a coupling catalyst effective at catalyzing coupling between the substituted methylene carbon atom of the compound of Formula (XXXVI) and the vinylic carbon attached to M, forming:
- (c) deprotecting the product of (b), forming:
- (d) oxidizing the product of (c), thus forming said compound of Formula (III).
16 more elements
A method of carboaluminating an alkyne substrate, forming a species with an alkyl moiety bound to aluminium, said method comprising:
- (a) contacting said alkyne substrate with (L)p+1M and x molar equivalents of water or R20OH, or, when each L is methyl, with x molar equivalents of water, R20OH or methylaluminoxane relative to said alkyne substrate
- wherein
- 0<x<1;
- each L is independently selected from substituted or unsubstituted alkyl, alkoxy, aryl or aryloxy with 1 to 10 carbon atoms;
- M is aluminium;
- p is 1 or 2 and,
- R20 is branched or unbranched alkyl with 1 to 15 carbon atoms, optionally substituted with 1 to 5 hydroxy substituents,
- thus carboaluminating said alkyne substrate
5 more elements
A method of separating components of a mixture, said components comprising a substituted-methylene quinone and a quinone having the formulae:
- respectively
- in which
- R1, R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl groups;
- X is a leaving group;
- said method comprising:
- (a) contacting the mixture with a reactive species that selectively binds through a heteroatom to the methylene carbon of said substituted-methylene quinone, displacing said leaving group, producing a charged substituted-methylene quinone;
- and
- (b) separating said charged substituted-methylene quinone from said quinone, thereby separating said mixture.
5 more elements
A method of separating a substituted methylene quinone and a halo-quinone having the formulae:
- respectively
- in which
- R1, R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl groups;
- Z is a halogen;
- said method comprising:
- (a) contacting said mixture with a reducing agent that selectively reduces the halo-quinone to a halo-hydroquinone;
- (b) contacting the product of step (a) with a base, forming an anion of said halo-hydroquinone;
- and
- (c) separating said anion from said substituted methylene quinone, thereby separating said mixture.
6 more elements
A method of separating a mixture of a substituted-methylene quinone and a quinone having the formulae:
- respectively
- in which
- R1, R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl groups;
- X is a leaving group;
- said method comprising:
- (a) contacting the mixture with a reactive species that selectively binds through a heteroatom to the methylene carbon of said substituted-methylene quinone, displacing said leaving group;
- (b) separating the product of (a) from said quinone, thereby separating said mixture.
4 more elements
A compound having a structure that is a member selected from:
- in which
- R1, R2 and R3 are independently selected from substituted or unsubstituted C1-C6 alkyl groups;
- R4 is a member selected from H, substituted or unsubstituted alkyl, a metal ion and a protecting group;
- R7 is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, SOR9, SO2R9, C(O)R9, C(O)OR9, P(O)OR9OR10, P(O)N(R9)2(R10)2, and P(O)R9R10 wherein
- each R9 and R10 is a member independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl;
- and
- Y is OR11, SR11, NR11R12, or a leaving group;
- R11 and R12 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl;
- and
- R7a, together with the oxygen to which it attached, is a leaving group.
7 more elements
A compound having the formula:
- wherein
- R1, R2 and R3 are members independently selected from substituted or unsubstituted C1-C6 alkyl groups;
- R4is a member selected from hydrogen, substituted or unsubstituted alkyl, and protecting groups;
- R5 is a member selected from branched, unsaturated alkyl, CH(O), CH2Y wherein
- Y is OR7, SR7, NR7R8 or a leaving group
- wherein
- R7 and R8 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl;
- and
- R6is a member selected from OH and OCH(O).
6 more elements
A mixture comprising:
- wherein
- R1, R2 and R3 are members independently selected from substituted or unsubstituted C1-C6 alkyl groups;
- and
- n is an integer from 0 to 19.
1 more element
Dependencies are inferred from the claim text.