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US 2019/0161495 A1Published application
Prins reaction and intermediates useful in the synthesis of halichondrin macrolides and analogs thereof
AssigneeEisai R&D Management Co., Ltd.
InventorsCharles E. CHASE, Hyeong-Wook CHOI, Atsushi ENDO, Francis G. FANG, Dae-Shik KIM
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Abstract
The invention provides methods for the synthesis of a halichondrin macrolides or analogs thereof through a cyclization reaction strategy. The strategy of the present invention involves subjecting an intermediate to Prins reaction conditions to afford a macrolide. The invention also provides compounds useful as intermediates in the synthesis of a halichondrin macrolides or analogs thereof and methods for preparing the same.
Claims63
A method of preparing a macrocyclic intermediate in the synthesis of a halichondrin macrolide or an analog thereof, the method comprising reacting an intermediate of formula (I) with R12OH and a Lewis acid, the reaction producing the macrocyclic intermediate by forming a bond in the structure of the halichondrin macrolide or an analog thereof,
- wherein R12 is optionally substituted acyl;
- wherein the compound of formula (IA) is:
- or a salt or a tautomer thereof,
- wherein
- each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group;
- and A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
- wherein
- L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
- R1 is H, or R1 and P1 combine to form a bond;
- (i) R2 is H, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
- (ii) R2 is —(CH2)nNP3P4, wherein P3 is an N-protecting group, and (a) P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is an N-protecting group, or (b) P2 and P4 combine to form an alkylidene;
- (iii) R2 is —(CH2)nOP5, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group;
- or P2 and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
- or
- (iv) R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
- wherein each P′ is independently H or a hydroxyl protecting group;
- E is H, optionally substituted alkyl, or optionally substituted alkoxy;
- G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
- each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
- n, when present, is 0, 1, or 2;
- k is 0 or 1;
- X1 is —CH(Y)—, —CH2—, or —O—;
- X2 is ═O or X2, together with the carbon atom to which it is attached, is —(C(RX)2)—;
- wherein each RX is independently H, —ORX1, or —SRX1, provided that at least one RX, when present, is —ORX1 or —SRX1;
- wherein each RX1 is independently optionally substituted alkyl, or both RX1 combine to form optionally substituted alkylene, provided that, when X1 is —O—, X2 is ═O;
- Y is SO2RC or COORC, where, when Y is SO2RC, RC is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COORC, RC is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
- R3 and R5 combine to form a bond, and each of R4 and R6 is H;
- or R3 is H or a hydroxyl protecting group, R5 and one of R4 and R6, together with the atoms to which each is attached, combine to form a double bond, and the remaining R4 or R6 is H;
- A1 and R7 combine to form oxo, P7 is H or a hydroxyl protecting group, and R8 is H;
- or
- A1 is H or OP″, and:
- (a) P7 is H or a hydroxyl protecting group, and R7 and R8, together with the atoms to which each is attached, combine to form a double bond;
- or
- (b) P7 and R7 combine to form a bond, and R8 is H or OP″;
- (i) each P6 is independently H or a hydroxyl protecting group, or both P6, together with the atoms to which each is attached, combine to form a ketal or acetal;
- X is ═O or X combines with the carbon atom, to which it is attached, to form —(CH(OP9))—, wherein P9 is H or a hydroxyl protecting group;
- and each R11 is —OP10, or both R11 combine to form oxo, wherein P10 is alkyl or a hydroxyl protecting group;
- (ii) both P6 and X, together with the atoms to which each is attached, combine to form ketal, P7 and R7 combine to form a bond, and R8 is H or OP″;
- and each R11 is —OP10, or both R11 combine to form oxo, wherein P10 is alkyl or a hydroxyl protecting group;
- or
- (iii) both P6 and both R11, together with the atoms to which they are attached, combine to form acetal;
- and X is ═O or X combines with the carbon atom, to which it is attached, to form —(CH(OP9))—, wherein P9 is H or a hydroxyl protecting group;
- R9 is H, OP″, or Y, and R10 is H;
- or R9 and R10, together with the atoms to which each is attached, combine to form a double bond;
- each P″, when present, is independently H or a hydroxyl protecting group;
- and
- P8 is H or silyl;
- and
- wherein the macrocyclic intermediate in the synthesis of a halichondrin macrolide or an analog thereof is a compound of formula (IB):
- or a salt or a tautomer thereof.
47 more elements
A method of preparing
- a halichondrin macrolide or an analog thereof,
- or a salt thereof,
- wherein
- each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group;
- and A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
- wherein
- L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
- R1 is H, or R1 and P1 combine to form a bond;
- (i) R2 is H, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
- (ii) R2 is —(CH2)nNP3P4, wherein P3 is H or an N-protecting group, and (a) P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is an N-protecting group, or (b) P2 and P4 combine to form an alkylidene, or (c) each of P2 and P4 is H;
- (iii) R2 is —(CH2)nOP5, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group;
- or P2 and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
- or
- (iv) R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
- wherein each P′ is independently H or a hydroxyl protecting group;
- each of A1, A2, and A3 is independently H or OP″, wherein each P″ is independently H or a hydroxyl protecting group;
- E is H, optionally substituted alkyl, or optionally substituted alkoxy;
- G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
- each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
- n, when present, is 0, 1, or 2;
- k is 0 or 1;
- and
- X1 is —CH2— or —O—, and X2 is ═O;
- the method comprising:
- (A) producing a compound of formula (IB) from a compound of formula (IA) and R12OH, wherein R12 is optionally substituted acyl, and the compound of formula (IA) is of the following structure:
- or a salt or a tautomer thereof,
- wherein
- each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group;
- and A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
- wherein
- L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
- R1 is H, or R1 and P1 combine to form a bond;
- (i) R2 is H, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
- (ii) R2 is —(CH2)nNP3P4, wherein P3 is an N-protecting group, and (a) P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is an N-protecting group, or (b) P2 and P4 combine to form an alkylidene;
- (iii) R2 is —(CH2)nOP5, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group;
- or P2 and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
- or
- (iv) R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
- wherein each P′ is independently H or a hydroxyl protecting group;
- E is H, optionally substituted alkyl, or optionally substituted alkoxy;
- G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
- each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
- n, when present, is 0, 1, or 2;
- k is 0 or 1;
- X1 is —CH(Y)—, —CH2—, or —O—, and X2 is ═O or X2, together with the carbon atom to which it is attached, is —(C(RX)2)—;
- wherein each RX is independently H, —ORX1, or —SRX1, provided that at least one RX, when present, is —ORX1 or —SRX1;
- wherein each RX1 is independently optionally substituted alkyl, or both RX1 combine to form optionally substituted alkylene, provided that, when X1 is —O—, X2 is ═O;
- and wherein Y is SO2RC or COORC, where, when Y is SO2RC, RC is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COORC, RC is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
- R3 and R5 combine to form a bond, and each of R4 and R6 is H;
- or R3 is H or a hydroxyl protecting group, R5 and one of R4 and R6, together with the atoms to which each is attached, combine to form a double bond, and the remaining R4 or R6 is H;
- A1 and R7 combine to form oxo, P7 is H or a hydroxyl protecting group, and R8 is H;
- or
- A1 is H or OP″, and:
- (i) P7 is H or a hydroxyl protecting group, and R7 and R8, together with the atoms to which each is attached, combine to form a double bond;
- or
- (ii) P7 and R7 combine to form a bond, and R8 is H or OP″;
- (i) each P6 is independently H or a hydroxyl protecting group, or both P6, together with the atoms to which each is attached, combine to form a ketal or acetal;
- X is ═O or X combines with the carbon atom, to which it is attached, to form —(CH(OP9))—, wherein P9 is H or a hydroxyl protecting group;
- and each R11 is —OP10, or both R11 combine to form oxo, wherein P10 is alkyl or a hydroxyl protecting group;
- (ii) both P6 and X, together with the atoms to which each is attached, combine to form ketal, P7 and R7 combine to form a bond, and R8 is H or OP″;
- and each R11 is —OP10, or both R11 combine to form oxo, wherein P10 is alkyl or a hydroxyl protecting group;
- or
- (iii) both P6 and both R11, together with the atoms to which they are attached, combine to form acetal;
- and X is ═O or X combines with the carbon atom, to which it is attached, to form —(CH(OP9))—, wherein P9 is H or a hydroxyl protecting group;
- R9 is H, OP″, SO2RC, or COORC, and R10 is H;
- or R9 and R10, together with the atoms to which each is attached, combine to form a double bond;
- each P″, when present, is independently H or a hydroxyl protecting group;
- and
- P8 is H or silyl;
- and
- the compound of formula (IB) is of the following structure:
- or a salt or a tautomer thereof;
- wherein
- R12 is optionally substituted acyl;
- (B) producing the halichondrin macrolide or the analog thereof from compound (IB).
72 more elements
A compound of formula (IA):
- or a salt or a tautomer thereof,
- wherein
- each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group;
- and A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
- wherein
- L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
- R1 is H, or R1 and P1 combine to form a bond;
- (i) R2 is H, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
- (ii) R2 is —(CH2)nNP3P4, wherein P3 is an N-protecting group, and (a) P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is an N-protecting group, or (b) P2 and P4 combine to form an alkylidene;
- (iii) R2 is —(CH2)nOP5, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group;
- or P2 and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
- or
- (iv) R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
- wherein each P′ is independently H or a hydroxyl protecting group;
- E is H, optionally substituted alkyl, or optionally substituted alkoxy;
- G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
- each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
- n, when present, is 0, 1, or 2;
- k is 0 or 1;
- X1 is —CH(Y)—, —CH2—, or —O—;
- X2 is ═O or X2, together with the carbon atom to which it is attached, is —(C(RX)2)—;
- wherein each RX is independently H, —ORX1, or —SRX1, provided that at least one RX, when present, is —ORX1 or —SRX1;
- wherein each RX1 is independently optionally substituted alkyl, or both RX1 combine to form optionally substituted alkylene, provided that, when X1 is —O—, X2 is ═O;
- Y is SO2RC or COORC, where, when Y is SO2RC, RC is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COORC, RC is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
- R3 and R5 combine to form a bond, and each of R4 and R6 is H;
- or R3 is H or a hydroxyl protecting group, R5 and one of R4 and R6, together with the atoms to which each is attached, combine to form a double bond, and the remaining R4 or R6 is H;
- A1 and R7 combine to form oxo, P7 is H or a hydroxyl protecting group, and R8 is H;
- or
- A1 is H or OP″, and:
- (i) P7 is H or a hydroxyl protecting group, and R7 and R8, together with the atoms to which each is attached, combine to form a double bond;
- or
- (ii) P7 and R7 combine to form a bond, and R8 is H or OP″;
- (i) each P6 is independently H or a hydroxyl protecting group, or both P6, together with the atoms to which each is attached, combine to form a ketal or acetal;
- X is ═O or X combines with the carbon atom, to which it is attached, to form —(CH(OP9))—, wherein P9 is H or a hydroxyl protecting group;
- and each R11 is —OP10, or both R11 combine to form oxo, wherein P10 is alkyl or a hydroxyl protecting group;
- (ii) both P6 and X, together with the atoms to which each is attached, combine to form ketal, P7 and R7 combine to form a bond, and R8 is H or OP″;
- and each R11 is —OP10, or both R11 combine to form oxo, wherein P10 is alkyl or a hydroxyl protecting group;
- or
- (iii) both P6 and both R11, together with the atoms to which they are attached, combine to form acetal;
- and X is ═O or X combines with the carbon atom, to which it is attached, to form —(CH(OP9))—, wherein P9 is H or a hydroxyl protecting group;
- R9 is H, OP″, or Y, and R10 is H;
- or R9 and R10, together with the atoms to which each is attached, combine to form a double bond;
- each P″, when present, is independently H or a hydroxyl protecting group;
- and
- P8 is H or silyl.
42 more elements
A compound of formula (IB):
- or a salt or a tautomer thereof.
- wherein
- each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group;
- and A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1, the group of formula (1) having the structure:
- wherein
- L is —(CH(OP2))—, —(C(OH)(OP2))—, or —C(O)—;
- R1 is H, or R1 and P1 combine to form a bond;
- (i) R2 is H, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
- (ii) R2 is —(CH2)nNP3P4, wherein P3 is an N-protecting group, and (a) P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is an N-protecting group, or (b) P2 and P4 combine to form an alkylidene;
- (iii) R2 is —(CH2)nOP5, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group;
- or P2 and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
- or
- (iv) R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
- wherein each P′ is independently H or a hydroxyl protecting group;
- E is H, optionally substituted alkyl, or optionally substituted alkoxy;
- G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
- each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
- n, when present, is 0, 1, or 2;
- k is 0 or 1;
- X1 is —CH(Y)—, —CH2—, or —O—;
- X2 is ═O or X2, together with the carbon atom to which it is attached, is —(C(RX)2)—;
- wherein each RX is independently H, —ORX1, or —SRX1, provided that at least one RX, when present, is —ORX1 or —SRX1;
- wherein each RX1 is independently optionally substituted alkyl, or both RX1 combine to form optionally substituted alkylene, provided that, when X1 is —O—, X2 is ═O;
- Y is SO2RC or COORC, where, when Y is SO2RC, RC is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COORC, RC is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
- R3 and R5 combine to form a bond, and each of R4 and R6 is H;
- or R3 is H or a hydroxyl protecting group, R5 and one of R4 and R6, together with the atoms to which each is attached, combine to form a double bond, and the remaining R4 or R6 is H;
- A1 and R7 combine to form oxo, P7 is H or a hydroxyl protecting group, and R8 is H;
- or
- A1 is H or OP″, and:
- (a) P7 is H or a hydroxyl protecting group, and R7 and R8, together with the atoms to which each is attached, combine to form a double bond;
- or
- (b) P7 and R7 combine to form a bond, and R8 is H or OP″;
- (i) each P6 is independently H or a hydroxyl protecting group, or both P6, together with the atoms to which each is attached, combine to form a ketal or acetal;
- X is ═O or X combines with the carbon atom, to which it is attached, to form —(CH(OP9))—, wherein P9 is H or a hydroxyl protecting group;
- or
- (ii) both P6 and X, together with the atoms to which each is attached, combine to form ketal, P7 and R7 combine to form a bond, and R8 is H or OP″;
- R9 is H, OP″, or Y, and R10 is H;
- or R9 and R10, together with the atoms to which each is attached, combine to form a double bond;
- each P″, when present, is independently H or a hydroxyl protecting group;
- and
- R12 is optionally substituted acyl.
38 more elements
A compound of formula (IC)
- or a salt or tautomer thereof,
- wherein
- each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group;
- and A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, and Q1, the group of formula (1) having the structure:
- wherein
- L is —(CH(OP2))— or —C(O)—;
- R1 is H, or R1 and P1 combine to form a bond;
- (i) R2 is H, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
- (ii) R2 is —(CH2)nNP3P4, wherein P3 is an N-protecting group, and (a) P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is an N-protecting group, or (b) P2 and P4 combine to form an alkylidene;
- (iii) R2 is —(CH2)nOP5, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is optionally substituted alkyl or a hydroxyl protecting group;
- or P2 and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
- or
- (iv) R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
- wherein each P′ is independently a hydroxyl protecting group;
- E is H, optionally substituted alkyl, or optionally substituted alkoxy;
- G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
- each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
- n, when present, is 0, 1, or 2;
- k is 0 or 1;
- X1 is —CH(Y)— or —CH2—;
- X2 is ═O or X2, together with the carbon atom to which it is attached, is —(C(RX)2)—;
- wherein each RX is independently H, —ORX1, or —SRX1, provided that at least one RX, when present, is —ORX1 or —SRX1;
- wherein each RX1 is independently optionally substituted alkyl, or both RX1 combine to form optionally substituted alkylene;
- Y is SO2RC or COORC, wherein, when Y is SO2RC, RC is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COORC, RC is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
- R3 and R5 combine to form a bond, and each of R4 and R6 is H;
- or R3 is H or a hydroxyl protecting group, R5 and one of R4 and R6, together with the atoms to which each is attached, combine to form a double bond, and the remaining R4 or R6 is H;
- (i) each P6 is independently a hydroxyl protecting group, or both P6, together with the atoms to which each is attached, combine to form a ketal or acetal;
- each R11 is independently —OP10, or
- both R11 combine to form oxo, wherein P10 is alkyl or a hydroxyl protecting group;
- or
- (ii) both P6 and both R11, together with the atoms to which they are attached, combine to form an acetal;
- R13 is H or —CH2P(O)(ORE)2, wherein each RE, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
- X is ═O or X combines with the carbon atom, to which it is attached, to form —(CH(OP9))—, wherein P9 is H or a hydroxyl protecting group;
- A1 and R7 combine to form oxo, P7 is H or a hydroxyl protecting group, and R8 is H;
- or
- A1 is H or OP″, and:
- (i) P7 is H or a hydroxyl protecting group, and R7 and R8, together with the atoms to which each is attached, combine to form a double bond;
- or
- (ii) P7 and R7 combine to form a bond, and R8 is H or OP″;
- and
- each P″, when present, is independently H or a hydroxyl protecting group.
38 more elements
A compound of formula (IE):
- or a salt or tautomer thereof,
- wherein
- each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group;
- and A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, and Q1, the group of formula (1) having the structure:
- wherein
- L is —(CH(OP2))— or —C(O)—;
- R1 is H, or R1 and P1 combine to form a bond;
- (i) R2 is H, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
- (ii) R2 is —(CH2)nNP3P4, wherein P3 is an N-protecting group, and (a) P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is an N-protecting group, or (b) P2 and P4 combine to form an alkylidene;
- (iii) R2 is —(CH2)nOP5, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is optionally substituted alkyl or a hydroxyl protecting group;
- or P2 and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
- or
- (iv) R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
- wherein each P′ is independently a hydroxyl protecting group;
- E is H, optionally substituted alkyl, or optionally substituted alkoxy;
- G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
- each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
- n, when present, is 0, 1, or 2;
- k is 0 or 1;
- X1 is —CH(Y)— or —CH2—,
- X2 is ═O or X2, together with the carbon atom to which it is attached, is —(C(RX)2)—;
- wherein each RX is independently H, —ORX1, or —SRX1, provided that at least one RX, when present, is —ORX1 or —SRX1;
- wherein each RX1 is independently optionally substituted alkyl, or both RX1 combine to form optionally substituted alkylene;
- Y is SO2RC or COORC, wherein, when Y is SO2RC, RC is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COORC, RC is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
- R3 and R5 combine to form a bond, and each of R4 and R6 is H;
- or R3 is H or a hydroxyl protecting group, R5 and one of R4 and R6, together with the atoms to which each is attached, combine to form a double bond, and the remaining R4 or R6 is H;
- R7 and P7 combine to form a bond, and R8 is H;
- or P7 is a hydroxyl protecting group, and R7 and R8, together with the atoms to which each is attached, combine to form a double bond;
- (i) each P6 is independently a hydroxyl protecting group, or both P6, together with the atoms to which each is attached, combine to form a ketal or acetal;
- each R11 is independently —OP10, or
- both R11 combine to form oxo, wherein P10 is alkyl or a hydroxyl protecting group;
- or
- (ii) both P6 and both R11, together with the atoms to which they are attached, combine to form an acetal;
- X3 is —CH2OPA, —CH═CH2, or —CH(OPA)CH2OPA, wherein each RE is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl, and wherein each PA is independently H or a hydroxyl protecting group, or both PA combine to form a cyclic protected diol.
31 more elements
A compound of formula (IJ):
- where
- each of D and D′ is independently H, optionally substituted alkyl, or OP1, provided that only one of D and D′ is OP1, wherein P1 is H, alkyl, or a hydroxyl protecting group;
- and A is a group of formula (1) or a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, and Q1, the group of formula (1) having the structure:
- where
- L is —(CH(OP2))— or —C(O)—;
- R1 is H, or R1 and P1 combine to form a bond;
- (i) R2 is H, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
- (ii) R2 is —(CH2)nNP3P4, wherein P3 is an N-protecting group, and (a) P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is an N-protecting group, or (b) P2 and P4 combine to form an alkylidene;
- (iii) R2 is —(CH2)nOP5, wherein P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is optionally substituted alkyl or a hydroxyl protecting group;
- or P2 and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
- or
- (iv) R2 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:
- wherein each P′ is independently a hydroxyl protecting group;
- E is H, optionally substituted alkyl, or optionally substituted alkoxy;
- G is O, S, CH2, or NRN, wherein RN is H, an N-protecting group, or optionally substituted alkyl;
- each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, O(CO)RA, (CO)NRBRA, or O(CO)NRBRA, wherein each of RA and RB is independently alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;
- n, when present, is 0, 1, or 2;
- k is 0 or 1;
- X1 is —CH(Y)—, —CH2—, or —O—;
- X2 is ═O or X2, together with the carbon atom to which it is attached, is —(C(RX)2)—;
- wherein each RX is independently H, —ORX1, or —SRX1, provided that at least one RX, when present, is —ORX1 or —SRX1;
- wherein each RX1 is independently optionally substituted alkyl, or both RX1 combine to form optionally substituted alkylene, provided that, when X1 is —O—, X2 is ═O;
- Y is SO2RC or COORC, where, when Y is SO2RC, RC is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COORC, RC is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
- R3 and R5 combine to form a bond, and each of R4 and R6 is H;
- or R3 is H or a hydroxyl protecting group, R5 and one of R4 and R6, together with the atoms to which each is attached, combine to form a double bond, and the remaining R4 or R6 is H;
- (i) each P6 is independently a hydroxyl protecting group, or both P6, together with the atoms to which each is attached, combine to form a ketal or acetal;
- each R11 is independently —OP10, or
- both R11 combine to form oxo, wherein P10 is alkyl or a hydroxyl protecting group;
- or
- (ii) both P6 and both R11, together with the atoms to which they are attached, combine to form an acetal;
- each P7 is independently a hydroxyl protecting group;
- and
- X2 is a halogen or pseudohalogen.
30 more elements
A compound of formula (IN):
- or a salt or tautomer thereof,
- wherein
- R3 and R5 combine to form a bond, and each of R4 and R6 is H;
- or R3 is H or a hydroxyl protecting group, R5 and one of R4 and R6, together with the atoms to which each is attached, combine to form a double bond, and the remaining R4 or R6 is H;
- A1 and R7 combine to form oxo, P7 is H or a hydroxyl protecting group, and R8 is H;
- or
- A1 is H or OP″, and:
- (i) P7 is H or a hydroxyl protecting group, and R7 and R8, together with the atoms to which each is attached, combine to form a double bond;
- or
- (ii) P7 and R7 combine to form a bond, and R8 is H or OP″;
- each P″, when present, is independently H or a hydroxyl protecting group;
- each P6 is independently H or a hydroxyl protecting group, or both P6, together with the atoms to which each is attached, combine to form a ketal or acetal, and X is ═O or X combines with the carbon atom, to which it is attached, to form —(CH(OP9))—, wherein P9 is H or a hydroxyl protecting group;
- or both P6 and X, together with the atoms to which each is attached, combine to form ketal;
- where, when both P6 and X, together with the atoms to which each is attached, combine to form ketal, P7 and R7 combine to form a bond, and R8 is H or OP″;
- R9 is H, SO2RC, or COORC, and R10 is H, where, when R9 is SO2RC, RC is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when R9 is COORC, RC is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
- or R9 and R10, together with the atoms to which each is attached, combine to form a double bond;
- R15 is H or —OP1, wherein P11 is H, a hydroxyl protecting group, or optionally substituted alkyl;
- X4 is ═O or, together with the carbon atom to which it is attached, is —CH2—, provided that when R15 is H, X4 is ═O;
- and
- P8 is H or silyl.
17 more elements
A compound of formula (ID):
- wherein
- P8 is H or a hydroxyl protecting group;
- and
- R9 is SO2RC or COORC, when R9 is SO2RC, RC is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when R9 is COORC, RC is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl.
1 more element
A compound of formula (IDa):
- wherein
- R9 is SO2RC or COORC, when R9 is SO2RC, RC is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when R9 is COORC, RC is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl.
A compound of formula (IDb):
- wherein
- R9′ and R10 are both H, or R9′ and R10 combine to form a double bond;
- R14 is hydroxyl, a halogen, or a pseudohalogen;
- and
- R9 is SO2RC or COORC, when R9 is SO2RC, RC is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when R9 is COORC, RC is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl.
2 more elements
A compound of formula (IDc):
- wherein
- R16 is H, a hydroxyl protecting group, or an optionally substituted alkyl.
A compound of formula (IDd):
- wherein
- X6 is —C(R17)═CH2 or —C(O)-Me, wherein R17 is a pseudohalogen or halogen;
- and
- R16 is H, a hydroxyl protecting group, or an optionally substituted alkyl.
1 more element
A compound of formula (IF):
- wherein
- X3 is —CHO, —CH2OPA, —CH═CH2, or —CH(OPA)CH2OPA;
- R3 and R5 combine to form a bond, and each of R4 and R6 is H;
- or R3 is H or a hydroxyl protecting group, R5 and one of R4 and R6, together with the atoms to which each is attached, combine to form a double bond, and the remaining R4 or R6 is H;
- R7 and P7 combine to form a bond, and R8 is H;
- or P7 is a hydroxyl protecting group, and R7 and R8, together with the atoms to which each is attached, combine to form a double bond;
- and
- each P6 is independently a hydroxyl protecting group, or both P6, together with the atoms to which each is attached, combine to form a ketal or acetal.
5 more elements
A compound of formula (IH):
- or a salt thereof,
- where
- X3 is —CHO, —CH2OPA, —CH═CH2, or —CH(OPA)CH2OPA;
- X4 is ═O or X4, together with the carbon atom to which it is attached, combine to form —CH2—;
- R3 and R5 combine to form a bond, and each of R4 and R6 is H;
- or R3 is H or a hydroxyl protecting group, R5 and one of R4 and R6, together with the atoms to which each is attached, combine to form a double bond, and the remaining R4 or R6 is H;
- R7 and P7 combine to form a bond, and R8 is H;
- or P7 is a hydroxyl protecting group, and R7 and R8, together with the atoms to which each is attached, combine to form a double bond;
- each P6 is independently a hydroxyl protecting group, or both P6, together with the atoms to which each is attached, combine to form a ketal or acetal;
- each PA is independently H or a hydroxyl protecting group, or both PA combine to form a cyclic protected diol;
- and
- PB is H, a hydroxyl protecting group, or optionally substituted alkyl.
9 more elements
A compound of formula (IHa):
- wherein
- a identifies the carbon-oxygen bond as or ,
- X3 is —CHO, —CH2OPA, —CH═CH2, or —CH(OPA)CH2OPA;
- X5 is —CH═CH2 or —CH(R4)—CH(R5)—CH(R6)—C(X4)OPB;
- X4 is ═O or X4, together with the carbon atom to which it is attached, combine to form —CH2—;
- R3 and R5 combine to form a bond, and each of R4 and R6 is H;
- or R3 is H or a hydroxyl protecting group, R5 and one of R4 and R6, together with the atoms to which each is attached, combine to form a double bond, and the remaining R4 or R6 is H;
- P6 is a hydroxyl protecting group, or both P6;
- each PA is independently H or a hydroxyl protecting group, or both PA combine to form a cyclic protected diol;
- and
- PB is H, a hydroxyl protecting group, or optionally substituted alkyl.
8 more elements
A compound of formula (IHb):
- wherein
- X5 is —CH═CH2 or —CH(R4)—CH(R5)—CH(R6)—C(X4)OPB;
- X4 is ═O or X4, together with the carbon atom to which it is attached, combine to form —CH2—;
- R3 and R5 combine to form a bond, and each of R4 and R6 is H;
- or R3 is H or a hydroxyl protecting group, R5 and one of R4 and R6, together with the atoms to which each is attached, combine to form a double bond, and the remaining R4 or R6 is H;
- and
- each of P6 and P7 is independently a hydroxyl protecting group, or one P6 and P7, together with the atoms to which each is attached, combine to form a ketal, and the remaining P6 is a hydroxyl protecting group;
- or both P6, together with the atoms to which each is attached, combine to form a ketal, and P7 is a hydroxyl protecting group.
5 more elements
A compound selected from the group consisting of:
- 1, 2, 3, 5, 7, 7a, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 21, 23, 24, 25, 27, 28, 29, 31, 32, 33, 34, 35, 36, 36b, 36c, 37, 38, 39, 40, 41, 43, 44, 44a, 45, 47, 47a, 47b, 47c, 48, 49, 50, 50a, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 66, 67, 68, 69, 70, 71, 72, 73, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87.
Dependencies are inferred from the claim text.