US 10,308,661 B2 · Macrocyclization reactions and intermediates and other fragments useful in the synthesis of halichondrin macrolides

Abstract

The invention provides methods for the synthesis of a halichondrin macrolides through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Homer-Wadsworth-Emmons olefination), catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic macrolide. The invention also provides compounds useful as intermediates in the synthesis of a halichondrin macrolides and methods for preparing the same.

Claims26

Dependent claims

A method of preparing a macrocyclic intermediate in the synthesis of a halichondrin macrolide, said method comprising performing a macrocyclization reaction on a non-macrocyclic intermediate, said macrocyclization reaction producing said macrocyclic intermediate by forming C.2-C.3, C.3-C.4, C.12-C.13, C.15-C.16, C.19-C.20, or C.26-C.27 bond in the structure of the halichondrin macrolide.

A method of preparing:

or a salt thereof,
wherein
each of A1 and A2 is independently H or OP″, where each P″ is independently H or a hydroxyl protecting group;
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;
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;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or 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 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, NRA(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;
k is 0 or 1;
n is 0, 1, or 2;
(1) said method comprising:
(A) producing a compound of formula (IB) from a compound of formula (IA), the compound of formula (IA) having the following structure:
or a salt or a tautomer thereof,
wherein
each R is independently optionally substituted alkyl or optionally substituted aryl;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group;
or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
and
P5 is H or a hydroxyl protecting group;
and
the compound of formula (IB) having the following structure:
or a salt or a tautomer thereof;
and
(B) producing the halichondrin macrolide from compound (IB);
(2) said method comprising:
(A) producing a compound of formula (IB) from a compound of formula (IIA), the compound of formula (IIA) having the following structure:
or a salt or a tautomer thereof,
wherein
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group;
or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
and
P5 is H or a hydroxyl protecting group;
and
The compound of formula (IB) haying the following structure:
or a salt or a tautomer thereof;
and
(B) producing the halichondrin macrolide from compound (IB);
(3) said method comprising:
(A) producing a compound of formula (IIIB) from a compound of formula (IIIA), the compound of formula (IIIA) haying the following structure:
or a salt or a tautomer thereof,
wherein
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond:
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group;
or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
and
P5 is H or a hydroxyl protecting group;
and
the compound of formula (IIIB) having the following structure:
or a salt or a tautomer thereof;
and
(B) producing the halichondrin macrolide from the compound of formula (IIIB):
(4) said method comprising:
(A) producing a compound of formula (IVB) from a compound of formula (IVA), the compound of formula (IVA) having the following structure:
or a salt thereof,
wherein
(i) R3 is H or a hydroxyl protecting group, R4 is alkyl ether, and R5 is H;
(ii) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(iii) R3 and R4 combine to form a bond, and R5 is H;
each P4 and P5 is independently H or a hydroxyl protecting group;
R6 is H, and P6 is H or a hydroxyl protecting group;
or R6 and P6 combine to form a double bond;
and
the compound of formula (IVB) haying the following structure:
or a salt thereof;
and
(B) producing the halichondrin macrolide from the compound of formula (IVB);
(5) said method comprising:
(A) producing a compound of formula (VB) from a compound of formula (VA), the compound of formula (VA) haying the following structure:
or a salt or a tautomer thereof,
wherein
(a1) R3 is H or a hydroxyl protecting group, R4 is alkyl ether, and R5 is H;
(a2) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(a3) R3 and R4 combine to form a bond, and R5 is H;
(b1) A1 and R7 combine to form oxo, R6 is H or a hydroxyl protecting group, and R8 is H;
or
(b2) A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R6 is H or a hydroxyl protecting group, and R7 and R8 combine to form a double bond;
or
(ii) R6 and R7 combine to form a bond, and R8 is H or OP″;
(c1) R9 is H, and P4 is H or a hydroxyl protecting group;
or
(c2) R9 and P4 combine to form a double bond;
R10 is H or —CH2X1CH2CH═CH2 , wherein X1 is O, —C(R11)2—, or NP6, and wherein each R11 is independently H or —COOR12, P6 is an N-protecting group, and R12 is alkyl;
each P5 is independently H or a hydroxyl protecting group;
and
wherein said macrocyclic intermediate in the synthesis of a halichondrin macrolide is a compound of formula (VB):
or a salt or a tautomer thereof;
(B) producing a compound of formula (VC) from the compound of formula (VB), the compound of formula (VC) having the following structure:
or a salt thereof,
wherein each of A1 and A2 is independently H or OP″;
(C) producing a compound of formula (IVC) from the compound of formula (VC), the compound of formula (IVC) haying the following structure:
or a salt thereof,
wherein each of A1 and A2 is independently H or OP″;
and
(D) producing the halichondrin macrolide from the compound of formula (IVC);
(6) said method comprising:
(A) producing a compound of formula (VIB) from a compound of formula (VIA), the compound of formula (VIA) haying the following structure:
or a salt or a tautomer thereof,
wherein
Y is iodide, bromide, or trifluoromethanesulfonate;
b designates (R)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide;
or b designates (S)-stereogenic center, and Z is OR6, wherein R6 is a hydroxyl protecting group;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
and each P4 is independently H or a hydroxyl protecting group, and X1 is oxo;
or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
the compound of formula (VIB) having the following structure:
or a salt or a tautomer thereof,
wherein
b designates (R)-stereogenic center, c designates (S)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide;
or
b designates (S)-stereogenic center, c designates (R)-stereogenic center, and Z is OR6,
wherein R6 is a hydroxyl protecting group;
(B) producing the halichondrin macrolide from the compound of formula (VIB);
or
(7) said method comprising:
(A) producing a compound of formula (VIIB) from a compound of formula (VIIA), the compound of formula (VIIA) having the following structure:
or a salt thereof,
wherein
Y is iodide, bromide, or trifluoromethanesulfonate;
(a1) R3 is H or a hydroxyl protecting group, R4 and R5 combine to form a double bond, each P4 is independently H or a hydroxyl protecting group, and X1, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR8))—;
or
(a2) R3 and R4 combine to form a bond, R5 is H, and
each P4 is independently H or a hydroxyl protecting group, and X1, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR8))—;
or
both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
(b1) Z is chloride, bromide, or iodide, and R6 and R7 combine to form a bond;
or
(b2) Z and R7 combine to form a double bond, and R6 is a hydroxyl protecting group;
and
wherein R8 is H or a hydroxyl protecting group
the compound of formula (VIIB) having the following structure:
or a salt thereof,
wherein each of P5 and R6 is H or a hydroxyl protecting group;
(B) producing a compound of formula (VIIC) from the compound of formula (VIIB), the compound of formula (VIIC) having the following structure:
or a salt or a tautomer thereof,
wherein A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
(C) producing a compound of formula (VIID) from the compound of formula (VIIC), the compound of formula (VIID) having the following structure:
or a salt thereof,
wherein each of A1 and A2 is independently H or OP″;
and
(D) producing the halichondrin macrolide from the compound of formula (VIID).

174 more elements

A method of preparing an intermediate in the synthesis of a halichondrin macrolide, said method comprising performing an allene-Prins reaction by contacting a compound of formula (VIIIA) with a compound of formula (VIIIB) and R4OH,

wherein R4 is an optionally substituted acyl;
wherein the compound of formula (VIIIA) has the following structure:
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;
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;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or 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 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, NRA(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;
k is 0 or 1;
n is 0, 1, or 2;
X is O, or X, together with the carbon atom to which it is attached, forms —(C(OPZ)2)—, wherein each PZ is independently optionally substituted alkyl or optionally substituted aryl, or both PZ combine to form optionally substituted alkylene or optionally substituted arylene;
and
P4 is H or a hydroxyl protecting group;
wherein the compound of formula (VIIIB) has the following structure:
wherein
R3 is —CH2—OP5, —CH═CH2,
wherein P5 is H or a hydroxyl protecting group;
each P6 is independently a hydroxyl protecting group, or both P6 groups, together with the atoms to which each is attached, combine to form a cyclic protected diol;
and R5 is H or —CH2X1CH2CH═CH2, wherein X1 is O, —CH2—, or NP7, wherein P7 is a sulfonyl;
and wherein said intermediate is a compound of formula (VIIIC):
or a salt thereof.

26 more elements

A compound of

(1) formula (IA) or formula (IB),
or a salt or a tautomer thereof,
wherein
each R is independently optionally substituted alkyl or optionally substituted aryl;
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;
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;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H,
optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or 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 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, NRA(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;
k is 0 or 1;
n is 0, 1, or 2;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group;
or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
and
P5 is H or a hydroxyl protecting group;
(2) formula (IIA), formula (IIIA), or formula (IIIB):
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:
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) haying 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;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or 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 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 a is independently ORA SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRA(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;
k is 0 or 1;
n is 0, 1, or 2;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group;
or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
and
P5 is H or a hydroxyl protecting group;
(3) formula (IVA), formula (IVB), or formula (IVC):
or a salt thereof,
wherein
each of A1 and A2 is H or OP″, where P″ is H or a hydroxyl protecting group;
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;
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;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or 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 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, NRA(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;
k is 0 or 1;
n is 0, 1, or 2;
(i) R3 is H or a hydroxyl protecting group, R4 is alkyl ether, and R5 is H;
(ii) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(iii) R3 and R4 combine to form a bond, and R5 is H;
each P4 and P5 is independently H or a hydroxyl protecting group;
and
R6 is H, and P6 is H or a hydroxyl protecting group;
or R6 and P6 combine to form a double bond;
(4) formula (VA), formula (VB), or formula (VC):
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;
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;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or 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;
A2 is H or OP″;
E is 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, NRA(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;
k is 0 or 1;
n is 0, 1, or 2;
(a1) R3 is H or a hydroxyl protecting group, R4 is alkyl ether, and R5 is H;
(a2) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(a3) R3 and R4 combine to form a bond, and R5 is H;
(b1) A1 and R7 combine to form oxo, R6 is H or a hydroxyl protecting group, and Rs is H;
or
(b2) A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R6 is H or a hydroxyl protecting group, and R7 and R8 combine to form a double bond;
or
(ii) R6 and R7 combine to form a bond, and R8 is H or OP″;
(c1) R9 is H, and P4 is H or a hydroxyl protecting group;
or
(c2) R9 and P4 combine to form a double bond;
R10 is H or —CH2X1CH2CH═CH2 wherein X1 is O, —C(R11)2—, or NP6, and wherein each R11 is independently H or —COOR12 P6 is an N-protecting group, and R12 is alkyl;
each P5 is independently H or a hydroxyl protecting group;
(5) formula (VIA):
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;
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;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or 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 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, NRA(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;
k is 0 or 1;
n is 0, 1, or 2;
Y is iodide, bromide, or trifluoromethanesulfonate;
b designates (R)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide;
or b designates (S)-stereogenic center, and Z is OR6, wherein R6 is a hydroxyl protecting group;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group;
or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
(6) formula (VIB):
or a salt or a tautomer thereof,
wherein
b designates (R)-stereogenic center, c designates (S)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide;
or
b designates (S)-stereogenic center, c designates (R)-stereogenic center, and Z is OR6,
wherein R6 is a hydroxyl protecting group;
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;
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;
R2 is H or —(CH2) nOP3 and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or 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 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;
k is 0 or 1;
n is 0, 1, or 2;
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″;
each P4 is independently H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group;
or both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
(7) formula (VIIA) or formula (VIIB):
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;
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;
R2 is H or —(CH2)nOP3 and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or 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 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, NRA(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;
k is 0 or 1;
n is 0, 1, or 2;
(a1) R3 is H or a hydroxyl protecting group, R4 and R5 combine to form a double bond, each P4 is independently H or a hydroxyl protecting group, and X1, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR8))—;
or
(a2) R3 and R4 combine to form a bond, R5 is H, and
each P4 is independently H or a hydroxyl protecting group, and X1, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR8))—;
or
both P4 groups and X1, together with the atoms to which each is attached, combine to form ketal;
(b1) Z is chloride, bromide, or iodide, and R6 and R7 combine to form a bond;
(b2) Z and R7 combine to form a double bond, and R6 is a hydroxyl protecting group;
or
(b3) when Z and R7 are absent, R6 is H or a hydroxyl protecting group;
P5 is H or a hydroxyl protecting group;
wherein R8 is H or a hydroxyl protecting group;
or
(8) formula (VIIC):
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;
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;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or 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 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, NRA(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;
k is 0 or 1;
n is 0, 1, or 2;
each P4 is H or a hydroxyl protecting group, and X1 is oxo or X1, together with the carbon atom to which it is attached, is —(CH(OPY))—, wherein PY is H or a hydroxyl protecting group;
or both P4 groups and X1, together with the atoms to which each is attached, combine to form a ketal;
and
A1 and R4 combine to form oxo, R3 is H or a hydroxyl protecting group, and R5 is H;
or
A1 is H or OP″, where P″ is H or a hydroxyl protecting group, and:
(i) R3 is H or a hydroxyl protecting group, and R4 and R5 combine to form a double bond;
or
(ii) R3 and R4 combine to form a bond, and R5 is H or OP″.

224 more elements

A compound of formula (VIIC):

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;
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;
R2 is H or —(CH2)nOP3, and each of P2 and P3 is independently H, optionally substituted alkyl,
or a hydroxyl protecting group, or P2 and P3, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo;
or 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 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, NRA(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;
k is 0 or 1;
n is 0, 1, or 2;
P4 is H or a hydroxyl protecting group;
and
R3 is —CH2OP5, —CH═CH2,
wherein P5 is H or a hydroxyl protecting group;
each P6 is independently a hydroxyl protecting group, or both P6 groups, together with the atoms to which each is attached, combine to form a cyclic protected diol;
and R5 is H or —CH2X1CH2CH═CH2, wherein X1 is O, —CH2—, or NP7, wherein P7 is a sulfonyl.

19 more elements

Dependencies are inferred from the claim text.

Facts

Application

15/571,921Filed 9 May 2016 · us provisional application

Priority

7 May 2015

Published

US 2018/0118755 A13 May 2018

Granted

4 Jun 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07D 493/22
Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system: in which the condensed system contains four…
C07F 9/6552
Having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms: the oxygen atom being part of a…
C07D
Heterocyclic compounds
C07F
Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen

Macrocyclization reactions and intermediates and other fragments useful in the synthesis of halichondrin macrolides

Life of this patent

Macrocyclization reactions and intermediates and other fragments useful in the synthesis of halichondrin macrolides

Life of this patent

Abstract

Claims26