US 2008/0287482 A1 · Production of Polyketides and Other Natural Products

Abstract

The present invention relates to production of polyketides and other natural products and to libraries of compounds and individual novel compounds. One important area is the isolation and potential use of novel FKBP-ligand analogues and host cells that produce these compounds. The invention is particularly concerned with methods for the efficient transformation of strains that produce FKBP analogues and recombinant cells in which cloned genes or gene cassettes are expressed to generate novel compounds such as polyketide (especially rapamycin) FKBP-ligand analogues, and to processes for their preparation, and to means employed therein (e.g. nucleic acids, vectors, gene cassettes and genetically modified strains).

Claims45

Dependent claims

1-66. (canceled)

A compound of the formula:

wherein
R1 is selected from the group consisting of A, B, C, D, E, F, G, H, and I where
A is
and B is
where:
Y=bond or CH2;
and
R21, R22, R23, R24, R25 and R26 are independently selected from the group consisting of Cl, F, OH, SH, H, alkyl, CN, Br, R27, OR27, C(O)R27 and HNR27, wherein R27 is a C1-C4 alkyl, wherein R21, and R23, R22 and R24, R23 and R25, R24 and R26, R21, and R25, or R22 and R26 optionally form a substituted or unsubstituted methylene link, an ether link, a thia link or an amino link, and wherein R21 and R22, R23 and R24 or R25 and R26 optionally form a ketone;
wherein no more than 4 of R21, R22, R23, R24, R25 and R26 are Cl;
wherein no more than 2 of R21, R22, R23, R24, R25 and R26 are HNR27;
wherein no more than 2 of R21, R22, R23, R24, R25 and R26 are SH;
and
wherein both R groups from one carbon on the ring are not OH;
C is
where:
Y=bond or CH2;
R31 and R32 are independently selected from the group consisting of F, Cl, OH, SH, H, CN, OR37, C(O)R37, and NHR37, wherein R37 is a C1-C4 alkyl, and wherein R31 and R32 optionally form a ketone, a spirocyclopropyl group or are joined by —OCH2—, —CH2O—, —SCH2— or —CH2S—;
and
R33 and R34 are independently selected from the group consisting of F, Cl, Br, OR37, H, and CN, wherein R37 is a C1-C4 alkyl;
wherein both R groups from one carbon on the ring are not OH;
D is
and E is
where:
R41, R42, R43, R44, R45 and R46 are independently selected from the group consisting of Cl, F, OH, SH, H, alkyl, CN, Br, R47, OR47, C(O)R47 and HNR47, wherein R47 is a C1-C4 alkyl, wherein R41 and R43, R42 and R44, R43 and R45, R44 and R46, R41 and R45, or R42 and R46 optionally form a substituted or unsubstituted methylene link, an ether link, a thia link or an amino link, and wherein R43 and R44 or R45 and R46 optionally form a ketone;
wherein both R groups from one carbon on the ring are not OH;
F is
where:
R51 and R52 are independently selected from the group consisting of F, Cl, OH, SH, H, CN, OR57, C(O)R57, and NHR57, wherein R57 is a C1-C4 alkyl, wherein R51 and R52 optionally form a ketone, a spirocyclopropyl group or are joined by —OCH2—, —CH2O—, —SCH2— or —CH2S—;
and
R53 and R54 are independently selected from the group consisting of F, Cl, Br, OR57, H and CN, wherein R57 is a C1-C4 alkyl;
wherein both R groups from one carbon on the ring are not OH;
G is
where:
Y=bond or CH2;
and
R61, R62, R63, R64 and R65 are independently selected from the group consisting of Cl, F, OH, SH, H, alkyl, CN, Br, R67, OR67, C(O)R67 and HNR67, wherein R67 is a C1-C4 alkyl, wherein R61 and R63 or R62 and R64 optionally form a ketone, wherein R61 and R53 or R62 and R64 optionally form a substituted or unsubstituted methylene link, an ether link, a thia link or an amino link, and wherein R61 and R62 or R63 and R64 optionally form a spirocyclopropyl group or are linked by —OCH2— or —CH2O— or —SCH2— or —CH2S—;
wherein no more than two of R61, R62, R63, R64 and R65 are SH;
and
wherein both R groups from one carbon on the ring are not OH;
H is
where:
R71, R72, R73 and R74 are independently selected from the group consisting of Cl, F, OH, SH, H, alkyl, CN, Br, R77, OR77, C(O)R77, and HNR77, wherein R77 is a C1-C4 alkyl, and wherein R71 and R72 or R73 and R74 optionally form a ketone;
wherein both R groups from one carbon on the ring are not OH;
and
I is
where:
R81 is OH and R82 is selected from the group consisting of H, OH, halo, thiol, and alkyl;
R9=H, OH, OCH3;
R10=H or CH3;
R11=H, H or ═O;
with the provisos that when R1 is A and one or two of R21, R22, R23, R24, R25, and R26 is OH, then the remainder of R21, R22, R25, and R26 cannot all be H;
and with the proviso that when R1 is A and one of R21, R22, R25, and R26 is OCH3 or Me, and one of R23 and R24 is OH, then the remainder of R21, R22, R25, and R26 cannot all be H.

49 more elements

A compound of the formula:

wherein:
R2=H, alkyl, halo, hydroxyl, or thiol;
R3=H, alkyl, halo, hydroxyl, or thiol;
R4=H, alkyl, halo, hydroxyl, or thiol;
R5=OCH3, CH3 or H;
R6=OCH3, CH3 or H;
R7=CH2CH3 or CH2CH═CH2;
R8=OH;
R9=H, OH, halo, thiol, or alkyl;
Z=keto or CH2;
X=X′=bond;
X=bond and X′=CH2, S, O;
or X=CH2, S, O, or a fused cyclopropyl unit and X′=bond;
with the proviso that A is not 3-cis,4-trans-dihydroxycyclohexane.

11 more elements

A compound according to claim 1 which is selected from the group consisting of:

31-desmethoxy-FK506, 31-desmethoxy-31-cis-hydroxy-32-trans-hydroxy-FK506, 31-desmethoxy-31-cis-hydroxy-32-cis-hydroxy-FK506, 31-desmethoxy-31-trans-hydroxy-32-trans-hydroxy-FK506, 31-O-desmethyl-32-dehydroxy-FK506, 31-O-desmethyl-FK506, 31-desmethoxy-31-methyl-FK506, 31-O-desmethyl-32-dehydroxy-32-methyl-FK506, 31-O-desmethyl-32-dehydroxy-32-fluoro-FK506, 31-desmethoxy-31-fluoro-FK506, 31-O-desmethyl-32-dehydroxy-32-chloro-FK506, 31-desmethoxy-31-chloro-FK506, 31-O-desmethyl-32-dehydroxy-32-tert-butyl-FK506, 29-de(3-methoxy-4-hydroxy-cyclohexyl)-29-(hydroxy-cycloheptyl)-FK506, 29-de(3-methoxy-4-hydroxy-cyclohexyl)-29-(hydroxy-norbornyl)-FK506, 9-deoxo-31-desmethoxy-FK506, 9-deoxo-31-desmethoxy-31-cis-hydroxy-32-trans-hydroxy-FK506, 9-deoxo-31-desmethoxy-31-cis-hydroxy-32-cis-hydroxy-FK506, 9-deoxo-31-desmethoxy-31-trans-hydroxy-32-trans-hydroxy-FK506, 9-deoxo-31-O-desmethyl-32-dehydroxy-FK506, 9-deoxo-31-O-desmethyl-FK506, 9-deoxo-31-desmethoxy-31-methyl-FK506, 9-deoxo-31-O-desmethyl-32-dehydroxy-32-methyl-FK506, 9-deoxo-31-O-desmethyl-32-dehydroxy-32-fluoro-FK506, 9-deoxo-31-desmethoxy-31-fluoro-FK506, 9-deoxo-31-O-desmethyl-32-dehydroxy-32-chloro-FK506, 9-deoxo-31-desmethoxy-31-chloro-FK506, 9-deoxo-31-O-desmethyl-32-dehydroxy-32-tert-butyl-FK506, 9-deoxo-29-de(3-methoxy-4-hydroxy-cyclohexyl)-29-(hydroxy-cycloheptyl)-FK506, 9-deoxo-29-de(3-methoxy-4-hydroxy-cyclohexyl)-29-(hydroxy-norbornyl)-FK506, 30-desmethoxy-prolyl-FK506, 30-desmethoxy-30-cis-hydroxy-31-trans-hydroxy-prolyl-FK506, 30-desmethoxy-30-cis-hydroxy-31-cis-hydroxy-prolyl-FK506, 30-desmethoxy-30-trans-hydroxy-31-trans-hydroxy-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-prolyl-FK506, 30-O-desmethyl-prolyl-FK506, 30-desmethoxy-30-methyl-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-31-methyl-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-31-fluoro-prolyl-FK506, 30-desmethoxy-30-fluoro-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-31-chloro-prolyl-FK506, 30-desmethoxy-30-chloro-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-31-tert-butyl-prolyl-FK506, 28-de(3-methoxy-4-hydroxy-cyclohexyl)-28-(hydroxy-cycloheptyl)-FK506, 28-de(3-methoxy-4-hydroxy-cyclohexyl)-28-(hydroxy-norbornyl)-FK506, 8-deoxo-30-desmethoxy-31-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-cis-hydroxy-31-trans-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-cis-hydroxy-31-cis-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-trans-hydroxy-31-trans-hydroxy-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-prolyl-FK506, 8-deoxo-30-O-desmethyl-prolyl-FK506, 8-deoxo-30-desmethoxy-30-methyl-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-31-methyl-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-31-fluoro-prolyl-FK506, 8-deoxo-30-desmethoxy-30-fluoro-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-31-chloro-prolyl-FK506, 8-deoxo-30-desmethoxy-30-chloro-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-31-tert-butyl-prolyl-FK506, 8-deoxo-28-de(3-methoxy-4-hydroxy-cyclohexyl)-28-(hydroxy-cycloheptyl)-prolyl-FK506, 8-deoxo-28-de(3-methoxy-4-hydroxy-cyclohexyl)-28-(hydroxy-norbornyl)-prolyl-FK506, 30-desmethoxy-3-hydroxy-prolyl-FK506, 30-desmethoxy-30-cis-hydroxy-31-trans-hydroxy-3-hydroxy-prolyl-FK506, 30-desmethoxy-30-cis-hydroxy-31-cis-hydroxy-3-hydroxy-prolyl-FK506, 30-desmethoxy-30-trans-hydroxy-31-trans-hydroxy-3-hydroxy-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-3-hydroxy-prolyl-FK506, 30-O-desmethyl-3-hydroxy-prolyl-FK506, 30-desmethoxy-30-methyl-3-hydroxy-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-31-methyl-3-hydroxy-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-31-fluoro-3-hydroxy-prolyl-FK506, 30-desmethoxy-30-fluoro-3-hydroxy-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-31-chloro-3-hydroxy-prolyl-FK506, 30-desmethoxy-30-chloro-3-hydroxy-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-31-tert-butyl-3-hydroxy-prolyl-FK506, 28-de(3-methoxy-4-hydroxy-cyclohexyl)-28-(hydroxy-cycloheptyl)-3-hydroxy-prolyl-FK506, 28-de(3-methoxy-4-hydroxy-cyclohexyl)-28-(hydroxy-norbornyl)-3-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-31-hydroxy-3-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-cis-hydroxy-31-trans-hydroxy-3-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-cis-hydroxy-31-cis-hydroxy-3-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-trans-hydroxy-31-trans-hydroxy-3-hydroxy-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-3-hydroxy-prolyl-FK506, 8-deoxo-30-O-desmethyl-3-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-methyl-3-hydroxy-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-31-methyl-3-hydroxy-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-31-fluoro-3-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-fluoro-3-hydroxy-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-31-chloro-3-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-chloro-3-hydroxy-3-hydroxy-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-31-tert-butyl-3-hydroxy-prolyl-FK506, 8-deoxo-28-de(3-methoxy-4-hydroxy-cyclohexyl)-28-(hydroxy-cycloheptyl)-3-hydroxy-prolyl-FK506, 8-deoxo-28-de(3-methoxy-4-hydroxy-cyclohexyl)-28-(hydroxy-norbornyl)-3-hydroxy-prolyl-FK506, 30-desmethoxy-4-hydroxy-prolyl-FK506, 30-desmethoxy-30-cis-hydroxy-31-trans-hydroxy-4-hydroxy-prolyl-FK506, 30-desmethoxy-30-cis-hydroxy-31-cis-hydroxy-4-hydroxy-prolyl-FK506, 30-desmethoxy-30-trans-hydroxy-31-trans-hydroxy-4-hydroxy-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-4-hydroxy-prolyl-FK506, 30-O-desmethyl-4-hydroxy-prolyl-FK506, 30-desmethoxy-30-methyl-4-hydroxy-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-31-methyl-4-hydroxy-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-31-fluoro-4-hydroxy-prolyl-FK506, 30-desmethoxy-30-fluoro-4-hydroxy-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-31-chloro-4-hydroxy-prolyl-FK506, 30-desmethoxy-30-chloro-4-hydroxy-prolyl-FK506, 30-O-desmethyl-31-dehydroxy-31-tert-butyl-4-hydroxy-prolyl-FK506, 28-de(3-methoxy-4-hydroxy-cyclohexyl)-28-(hydroxy-cycloheptyl)-4-hydroxy-prolyl-FK506, 28-de(3-methoxy-4-hydroxy-cyclohexyl)-28-(hydroxy-norbornyl)-4-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-31-hydroxy-4-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-cis-hydroxy-31-trans-hydroxy-4-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-cis-hydroxy-31-cis-hydroxy-4-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-trans-hydroxy-31-trans-hydroxy-4-hydroxy-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-4-hydroxy-prolyl-FK506, 8-deoxo-30-O-desmethyl-4-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-methyl-4-hydroxy-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-31-methyl-4-hydroxy-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-31-fluoro-4-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-fluoro-4-hydroxy-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-31-chloro-4-hydroxy-prolyl-FK506, 8-deoxo-30-desmethoxy-30-chloro-3-hydroxy-4-hydroxy-prolyl-FK506, 8-deoxo-30-O-desmethyl-31-dehydroxy-31-tert-butyl-4-hydroxy-prolyl-FK506, 8-deoxo-28-de(3-methoxy-4-hydroxy-cyclohexyl)-28-(hydroxy-cycloheptyl)-4-hydroxy-prolyl-FK506, 8-deoxo-28-de(3-methoxy-4-hydroxy-cyclohexyl)-28-(hydroxy-norbornyl)-4-hydroxy-prolyl-FK506, 31-desmethoxy-trans-3-bicyclo[3.1.0.]FK506, 31-desmethoxy-31-cis-hydroxy-32-trans-hydroxy-trans-3-bicyclo[3.1.0.]FK506, 31-desmethoxy-31-cis-hydroxy-32-cis-hydroxy-trans-3-bicyclo[3.1.0.]FK506, 31-desmethoxy-31-trans-hydroxy-32-trans-hydroxy-trans-3-bicyclo[3.1.0.]FK506, 31-O-desmethyl-32-dehydroxy-trans-3-bicyclo[3.1.0.]FK506, 31-O-desmethyl-trans-3-bicyclo[3.1.0.]FK506, 31-desmethoxy-31-methyl-trans-3-bicyclo[3.1.0.]FK506, 31-O-desmethyl-32-dehydroxy-32-methyl-trans-3-bicyclo[3.1.0.]FK506, 31-O-desmethyl-32-dehydroxy-32-fluoro-trans-3-bicyclo[3.1.0.]FK506, 31-desmethoxy-31-fluoro-trans-3-bicyclo[3.1.0.]FK506, 31-O-desmethyl-32-dehydroxy-32-chloro-trans-3-bicyclo[3.1.0.]FK506, 31-desmethoxy-31-chloro-trans-3-bicyclo[3.1.0.]FK506, 31-O-desmethyl-32-dehydroxy-32-tert-butyl-trans-3-bicyclo[3.1.0.]FK506, 29-de(3-methoxy-4-hydroxy-cyclohexyl)-29-(hydroxy-cycloheptyl)-trans-3-bicyclo[3.1.0.]FK506, 29-de(3-methoxy-4-hydroxy-cyclohexyl)-29-(hydroxy-norbornyl)-trans-3-bicyclo[3.1.0.]FK506, 9-deoxo-31-desmethoxy-trans-3-bicyclo[3.1.0.]FK506, 9-deoxo-31-desmethoxy-31-cis-hydroxy-32-trans-hydroxy-trans-3-bicyclo[3.1.0.]FK506, 9-deoxo-31-desmethoxy-31-cis-hydroxy-32-cis-hydroxy-trans-3-bicyclo[3.1.0.]FK506, 9-deoxo-31-desmethoxy-31-trans-hydroxy-32-trans-hydroxy-trans-3-bicyclo[3.1.0.]FK506, 9-deoxo-31-O-desmethyl-32-dehydroxy-trans-3-bicyclo[3.1.0.]FK506, 9-deoxo-31-O-desmethyl-trans-3-bicyclo[3.1.0.]FK506, 9-deoxo-31-desmethoxy-31-methyl-trans-3-bicyclo[3.1.0.]FK506, 9-deoxo-31-O-desmethyl-32-dehydroxy-32-methyl-trans-3-bicyclo[3.1.0.]FK506, 9-deoxo-31-O-desmethyl-32-dehydroxy-32-fluoro-trans-3-bicyclo[3.1.0.]FK506, 9-deoxo-31-desmethoxy-31-fluoro-trans-3-bicyclo[3.1.0.]FK506, 9-deoxo-31-O-desmethyl-32-dehydroxy-32-chloro-trans-3-bicyclo[3.1.0.]FK506, 9-deoxo-31-desmethoxy-31-chloro-trans-3-bicyclo[3.1.0.]FK506, 9-deoxo-31-O-desmethyl-32-dehydroxy-32-tert-butyl-trans-3-bicyclo[3.1.0.]FK506, 9-deoxo-29-de(3-methoxy-4-hydroxy-cyclohexyl)-29-(hydroxy-cycloheptyl)-trans-3-bicyclo[3.1.0.]FK506, and 9-deoxo-29-de(3-methoxy-4-hydroxy-cyclohexyl)-29-(hydroxy-norbornyl)-trans-3-bicyclo[3.1.0.]FK506.

A compound of the formula

wherein:
R1 is selected from the group consisting of
R1 is selected from the group consisting of A, B, C, D, E, F,
G, and H where
A is
and B is
where:
Y=bond or CH2;
and
R21, R22, R23, R24, R25 and R26 are independently selected from the group consisting of Cl, F, OH, SH, H, alkyl, CN, Br, R27, OR27, C(O)R27 and HNR27, wherein R27 is a C1-C4 alkyl, wherein R21 and R23, R22 and R24, R23 and R25, R24 and R26, R21 and R25, or R22 and R26 optionally form a substituted or unsubstituted methylene link, an ether link, a thia link or an amino link, and wherein R21 and R22, R23 and R24 or R25 and R26 optionally form a ketone;
wherein no more than 4 of R21, R22, R23, R24, R25 and R26 are Cl;
wherein no more than 2 of R21, R22, R23, R24, R25 and R26 are HNR27;
wherein no more than 2 of R21, R22, R23, R24, R25 and R26 are SH;
and
wherein both R groups from one carbon on the ring are not OH;
C is
where:
Y=bond or CH2;
R31 and R32 are independently selected from the group consisting of F, Cl, OH, SH, H, CN, OR37, C(O)R37, and NHR37, wherein R37 is a C1-C4 alkyl, and wherein R31 and R32 optionally form a ketone, a spirocyclopropyl group or are joined by —OCH2—, —CH2O—, —SCH2— or —CH2S—;
and
R33 and R34 are independently selected from the group consisting of F, Cl, Br, OR37, H, and CN, wherein R37 is a C1-C4 alkyl;
wherein both R groups from one carbon on the ring are not OH;
D is
and E is
where:
R41, R42, R43, R44, R45 and R46 are independently selected from the group consisting of Cl, F, OH, SH, H, alkyl, CN, Br, R47, OR47, C(O)R47 and HNR47, wherein R47 is a C1-C4 alkyl, wherein R41 and R43, R42 and R44, R43 and R45, R44 and R46, R41 and R45, or R42 and R46 optionally form a substituted or unsubstituted methylene link, an ether link, a thia link or an amino link, and wherein R43 and R44 or R45 and R46 optionally form a ketone;
wherein both R groups from one carbon on the ring are not OH;
F is
where:
R51 and R52 are independently selected from the group consisting of F, Cl, OH, SH, H, CN, OR57, C(O)R57, and NHR57, wherein R57 is a C1-C4 alkyl, wherein R51 and R52 optionally form a ketone, a spirocyclopropyl group or are joined by —OCH2—, —CH2O—, —SCH2— or —CH2S—;
and
R53 and R54 are independently selected from the group consisting of F, Cl, Br, OR57, H and CN, wherein R57 is a C1-C4 alkyl;
wherein both R groups from one carbon on the ring are not OH;
G is
where:
Y=bond or CH2;
and
R61, R62, R63, R64 and R65 are independently selected from the group consisting of Cl, F, OH, SH, H, alkyl, CN, Br, R67, OR67, C(O)R67 and HNR67, wherein R67 is a C1-C4 alkyl, wherein R61 and R63 or R62 and R64 optionally form a ketone, wherein R61 and R63 or R62 and R64 optionally form a substituted or unsubstituted methylene link, an ether link, a thia link or an amino link, and wherein R61 and R62 or R63 and R64 optionally form a spirocyclopropyl group or are linked by —OCH2— or —CH2O— or —SCH2— or —CH2S—;
wherein no more than two of R61, R62, R63, R64 and R65 are SH;
and
wherein both R groups from one carbon on the ring are not OH;
and
H is
where:
R71, R72, R73 and R74 are independently selected from the group consisting of Cl, F, OH, SH, H, alkyl, CN, Br, R77, OR77, C(O)R77, and HNR77, wherein R77 is a C1-C4 alkyl, and wherein R71 and R72 or R73 and R74 optionally form a ketone;
wherein both R groups from one carbon on the ring are not OH;
R2=H, alkyl, halo, hydroxyl, or thiol;
R3=H, alkyl, halo, hydroxyl, or thiol;
R4=H, alkyl, halo, hydroxyl, or thiol;
R5=OCH3, CH3 or H;
R6=OCH3, CH3 or H;
R7=CH2CH3 or CH2CH═CH2;
R8=OH;
R9=H, OH, halo, thiol, alkyl;
Z=keto or CH2;
Y=bond or CH2;
X=X′=bond;
X=bond and X′=CH2, S, O;
or X=CH2, S, O, or a fused cyclopropyl unit and X′=bond;
with the proviso that A is not 3-cis,4-trans-dihydroxycyclohexane, cycloheptane or 3-(cis/trans)-methylcyclohexane;
and with the proviso that the compound is not FK506 or FK520.

58 more elements

Dependencies are inferred from the claim text.

Production of Polyketides and Other Natural Products

Life of this patent

Production of Polyketides and Other Natural Products

Life of this patent

Abstract

Claims45