US2023151022A1PendingUtilityA1
Prins reaction and compounds useful in the synthesis of halichondrin macrolides and analogs thereof
Est. expiryJan 3, 2038(~11.4 yrs left)· nominal 20-yr term from priority
A61K 31/35C07D 307/28C07D 493/22C07D 493/04C07D 307/20C07D 407/14C07D 407/06A61P 35/00C07F 9/6561A61K 31/335
72
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Claims
Abstract
The invention provides methods utilizing Prins reaction in the preparation of compounds that may be useful as intermediates in the synthesis of halichondrin macrolides and analogs thereof. The invention also provides compounds that may be useful as intermediates in the synthesis of a halichondrin macrolides and methods for preparing the same.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of preparing a compound of formula (A), the method comprising producing the compound of formula (A) from a compound of formula (B), a compound of formula (C), and R 5 OH:
wherein R 5 is optionally substituted acyl; wherein the compound of formula (A) is:
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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;
R 1 is —OP 6 , —CH(Y) 2 , or —CH 2 (Y), wherein P 6 is H or a hydroxyl protecting group;
R 4 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl,
wherein
each P 7 is independently H or a hydroxyl protecting group; and
R 8 is —CH 2 CH 2 —COOR C , —CH═CH—COOR C , —CH 2 CH 2 —SO 2 R D , or —CH═CH—SO 2 R D ;
R 6 is H, optionally substituted alkyl, or optionally substituted arylalkyl;
each Y is independently —COOR C or —SO 2 R D ;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and
each R D , when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;
wherein the compound of formula (B) is:
and
wherein the compound of formula (C) is:
R 4 -R 7 , (C)
wherein R 7 is —CHO or
wherein each R 7A is independently an optionally substituted alkyl.
2 . The method of claim 1 , wherein the producing the compound of formula (A) comprises reacting the compound of formula (B), the compound of formula (C), R 5 OH, and a Lewis acid.
3 . The method of claim 2 , wherein the Lewis acid is an oxophilic Lewis acid.
4 . The method of claim 3 , wherein the oxophilic Lewis acid is boron trifluoride or a solvate thereof.
5 . The method of any one of claims 1 to 3 , further comprising producing the compound of formula (B) comprising reacting a compound of formula (D), a compound of formula (E), and a second Lewis acid, wherein the compound of formula (D) is:
and
where the compound of formula (E) is:
where R S is silyl.
6 . The method of claim 5 , wherein the second Lewis acid is an oxophilic second Lewis acid.
7 . The method of claim 6 , wherein the oxophilic second Lewis acid is boron trifluoride or a solvate thereof.
8 . The method of any one of claims 5 to 7 , wherein the Lewis acid and the second Lewis acid are same.
9 . The method of any one of claims 5 to 8 , wherein the preparing the compound of formula (B) and the preparing the compound of formula (A) are performed as a single-pot transformation.
10 . The method of any one of claims 5 to 9 , further comprising epimerizing the product of reacting the compound of formula (D), the compound of formula (E), and the second Lewis acid.
11 . The method of any one of claims 5 to 10 , wherein the preparing the compound of formula (B) and the preparing the compound of formula (A) are performed as a single-pot transformation.
12 . A method of preparing a compound of formula (B), the method comprising producing the compound of formula (B) from a compound of formula (D) and a compound of formula (E);
wherein the compound of formula (B) is:
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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;
R 1 is —OP 6 , —CH(Y) 2 , or —CH 2 (Y), wherein P 6 is H or a hydroxyl protecting group;
R 6 is H, optionally substituted alkyl, or optionally substituted aryl; and
Y is independently —COOR C or —SO 2 R D ;
R C , when present, is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and
R D , when present, is optionally substituted aryl or optionally substituted non-enolizable alkyl;
wherein the compound of formula (D) is:
and
wherein the compound of formula (E) is:
wherein R S is silyl.
13 . The method of claim 12 , wherein the producing the compound of formula (B) comprises reacting the compound of formula (D), the compound of formula (E), and a Lewis acid.
14 . The method of claim 13 , wherein the Lewis acid is an oxophilic Lewis acid.
15 . The method of claim 14 , wherein the oxophilic Lewis acid is boron trifluoride or a solvate thereof.
17 . The method of any one of claims 13 to 15 , further comprising epimerizing the product of reacting the compound of formula (D), the compound of formula (E), and the Lewis acid.
18 . A method of preparing
a halichondrin macrolide or analog thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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 A 1 , A 2 , and A 3 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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
X 1 is —CH 2 — or —O—;
the method comprising:
(A) producing a compound of formula (IA) from a compound of formula (IIC), a compound of formula (III), and R 5 OH, wherein the compound of formula (IA) is:
wherein
R 1 is —OP 6 , —CH(Y) 2 , or —CH 2 (Y), where P 6 is H or a hydroxyl protecting group, and each Y is independently —COOR C or —SO 2 R D ;
R 4 is
wherein
each P 7 is independently H or a hydroxyl protecting group;
R 8 is —CH 2 CH 2 —COOR C , —CH═CH—COOR C , —CH 2 CH 2 —SO 2 R D , or —CH═CH—SO 2 R D ;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and
each R D , when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl; and
R S is optionally substituted acyl;
wherein the compound of formula (IIC) is:
and
wherein the compound of formula (III) is:
R 4 -R 7 , (III)
wherein R 7 is —CHO or
wherein each R 7A is independently an optionally substituted alkyl; and
(B) producing the halichondrin macrolide or analog thereof from the compound of formula (IA).
19 . A method of preparing:
a halichondrin macrolide or analog thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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 A 1 , A 2 , and A 3 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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
X 1 is —CH 2 — or —O—;
the method comprising:
(A) producing a compound of formula (IVB) from a compound of formula (IIA), a compound of formula (IIB), a compound of formula (IIIA), a compound of formula (IVA), and R 5 OH,
wherein the compound of formula (IIA) is:
wherein
R 1 is —OP 6 , —CH(Y) 2 , or —CH 2 (Y), wherein P 6 is H or a hydroxyl protecting group, and each Y is independently-COOR C or —SO 2 R D ;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
each R D , when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;
R E is —CHO or —CH (1+m) (OR F ) (2−m) ,
wherein
m is 1, and R F is a hydroxyl protecting group,
or
m is 0, and
(i) each R F is independently an alkyl or hydroxyl protecting group, or
(ii) both R F combine to form an alkylene;
wherein the compound of formula (IIB) is:
wherein R S is silyl;
wherein the compound of formula (IIIA) is:
R 4A -R 7 , (IIIA)
wherein
R 4A is
wherein R C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl, and each P 7 is independently H or a hydroxyl protecting group;
R 7 is —CHO or
wherein each R 7A is independently an optionally substituted alkyl;
wherein the compound of formula (IVA) is:
wherein
each P 9 is independently a hydroxyl protecting group;
R 9 is —CHO or —COOH;
(a1) R 10 is H or a hydroxyl protecting group, R 11 is alkyl ether, and R 12 is H;
(a2) R 10 is H or a hydroxyl protecting group, and R 11 and R 12 combine to form a double bond;
or
(a3) R 10 and R 11 combine to form a bond, and R 12 is H;
(b1) A 1 and R 14 combine to form oxo, R 13 is H or a hydroxyl protecting group, and R 15 is H;
or
(b2) A 1 is H or —OP″, and:
(i) R 13 is H or a hydroxyl protecting group, and R 14 and R 15 combine to form a double bond;
or
(ii) R 13 and R 14 combine to form a bond, and R 15 is H or —OP″; and
(c1) R 1 is H, and P 8 is H or a hydroxyl protecting group;
or
(c2) R 1 and P 8 combine to form a double bond;
and
each P″, when present, is independently H or a hydroxyl protecting group;
wherein the compound of formula (IVB) is:
wherein
X 1 is —O—, —C(Y) 2 —, —CH(Y)—, or —CH 2 —;
X 4 is oxo, or X 4 , together with the atom to which it is attached, is —(CH(OP 12 ))—, where P 12 is H or a hydroxyl protecting group; and
R G is
wherein
R 5 is an optionally substituted acyl; and
X 2 is H or —CH 2 -X 2A -CH 2 —CH═CH 2 , wherein X 2A is —O—, —C(R H ) 2 —, or —NR I —, wherein each
R H is independently H or —COOR J , R J is an N-protecting group, and R 1 is C 1-6 alkyl; and
(B) producing a compound of formula (IVC) from the compound of formula (IVB), wherein the compound of formula (IVC) is:
wherein
L 1 is
wherein L 2 and L 3 combine to form a bond;
(C) producing a compound of formula (IVD) from the compound of formula (IVC), wherein the compound of formula (IVD) is:
wherein each of A 1 and A 2 is independently H or —OP″;
and
(D) producing the halichondrin macrolide or analog thereof from the compound of formula (IVD).
20 . The method of claim 19 , wherein step (A) comprises:
(E) producing a compound of formula (IA) from the compound of formula (IIA), the compound of formula (IIIA), and R 5 OH, wherein the compound of formula (IA) is:
and
(F) producing the compound of formula (IVB) from the compound of formula (IF) and the compound of formula (IVA).
21 . The method of claim 20 , wherein step (E) comprises reacting the compound of formula (IIA), the compound of formula (IIIA), R 5 OH, and a Lewis acid.
22 . The method of claim 21 , wherein the Lewis acid is an oxophilic Lewis acid.
23 . The method of claim 22 , wherein the oxophilic Lewis acid is boron trifluoride or a solvate thereof.
24 . The method of any one of claims 20 to 23 , wherein step (F) comprises reacting R 4A that is
with a glycol cleaving agent, and a Horner-Wadsworth-Emmons reaction with (R C O) 2 P(O)—CH 2 —COOR C to produce R 4A that is
25 . The method of any one of claims 20 to 24 , wherein step (F) comprises reacting R 4A that is
with a 1,2-reducing agent and further reacting with an allyl halide or allyl pseudohalide.
26 . The method of any one of claims 19 to 25 , wherein R 9 is —CHO, X 1 is —C(Y) 2 —, —CH(Y)—, or —CH 2 —, and step (A) comprises reacting R 9 with R 1 that is —CH(Y) 2 or —CH 2 (Y) treated with a Brønsted base.
27 . The method of any one of claims 19 to 25 , wherein X 1 is —O—, and step (A) comprises esterifying R 1 that is —OP 6 , where P 6 is H, with R 9 that is —COOH.
28 . The method of any one of claims 19 to 27 , wherein step (B) comprises reacting the compound of formula (IVB) with an olefin metathesis catalyst
29 . The method of any one of claims 19 to 28 , wherein P 9 is H, R 16 is H, and step (C) comprises:
oxidizing the compound of formula (IVC) to produce a compound of formula (IVCa):
and reacting the compound of formula (IVCa) with a 1,4-reducing agent to produce the compound of formula (IVD).
30 . The method of any one of claims 19 to 29 , wherein the compound of formula (IVB) is, or is converted to, a compound of formula (IVBa) prior to producing the compound of formula (IVC), wherein the compound of formula (IVBa) is:
31 . The method of any one of claims 19 to 30 , wherein the producing the halichondrin macrolide or analog thereof comprises reacting the compound of formula (IVD) with a hydroxyl protecting group removing agent.
32 . A method of preparing:
a halichondrin macrolide or analog thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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 A 1 , A 2 , and A 3 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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
X 1 is —CH 2 — or —O—;
the method comprising:
(A) producing a compound of formula (VB) from a compound of formula (IIA), a compound of formula (IIB), a compound of formula (IIIB), a compound of formula (VA), and R 5 OH,
wherein R 5 is optionally substituted acyl;
wherein the compound of formula (IIA) is:
wherein
R 1 is —OP 6 , —CH(Y) 2 , or —CH 2 (Y), wherein P 6 is H or a hydroxyl protecting group, and each Y is independently —COOR C or —SO 2 R D ;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
R D , when present, is optionally substituted aryl or optionally substituted non-enolizable alkyl;
R E is —CHO or —CH (1+m) (OR F ) (2−m) ,
wherein
m is 1, and R F is a hydroxyl protecting group,
or
m is 0, and
(i) each R F is independently an alkyl or hydroxyl protecting group, or
(ii) both R F combine to form an alkylene;
wherein the compound of formula (IIB) is:
wherein R S is silyl;
wherein the compound of formula (IIIB) is:
R 4B -R 7 , (IIIB)
wherein
R 4B is but-3-en-1-yl,
wherein each P 7 is independently H or a hydroxyl protecting group; and
R 7 is —CHO or
wherein each R 7A is independently an optionally substituted alkyl;
wherein the compound of formula (VA) is:
wherein
a designates (R)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide; or a designates (S)-stereogenic center, and Z is OR 16 , wherein R 16 is a hydroxyl protecting group;
(a1) R 10 is a hydroxyl protecting group, R 1 is alkyl ether, and R 12 is H;
(a2) R 10 is a hydroxyl protecting group, and R 1 and R 12 combine to form a double bond;
or
(a3) R 10 and R 11 combine to form a bond, and R 12 is H;
(b1) A 1 and R 14 combine to form oxo, R 13 is a hydroxyl protecting group, and R 15 is H;
or
(b2) A 1 is H or —OP″, and:
(i) R 13 is a hydroxyl protecting group, and R 14 and R 15 combine to form a double bond;
or
(ii) R 13 and R 14 combine to form a bond, and R 15 is H or —OP″;
Y 1 is iodide, bromide, or trifluoromethanesulfonate;
R 9 is —CHO or —COOH;
each P 9 is independently a hydroxyl protecting group, and X 3 is oxo; or both P 9 groups and X 3 , together with the atoms to which each is attached, combine to form a ketal; and
each P′ is independently a hydroxyl protecting group; and
wherein the compound of formula (VB) is:
wherein
X 1 is —CH 2 —, —CH(Y)—, —C(Y) 2 —, or —O—, wherein each Y is independently —COOR C or —SO 2 R D ;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
each R D , when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl; and
R K is
(B) producing a compound of formula (VC) from the compound of formula (VB), wherein the compound of formula (VC) is:
wherein
L 1 is
wherein L 2 and L 3 combine to form a bond;
b designates (S)-stereogenic center, if a designates (R)-stereogenic center;
and
b designates (R)-stereogenic center, if a designates (S)-stereogenic center; and
(C) producing the halichondrin macrolide or analog thereof from the compound of formula (VC).
33 . The method of claim 32 , wherein step (A) comprises:
(D) producing a compound of formula (ID) from the compound of formula (IIA), the compound of formula (IIB), the compound of formula (IIIB), and R 5 OH, wherein the compound of formula (ID) is:
and
(E) producing the compound of formula (VB) from the compound of formula (ID) and the compound of formula (VA).
34 . The method of claim 33 , wherein the producing the compound of formula (ID) comprises reacting the compound of formula (IIC), the compound of formula (IIIB), R 5 OH, and a Lewis acid.
35 . The method of claim 34 , wherein the Lewis acid is boron trifluoride or a solvate thereof.
36 . The method of any one of claims 33 to 35 , wherein step (D) comprises a Sakurai reaction between the compound of formula (IIA) and the compound of formula (IIB) to produce a compound of formula (IIC), and a Prins reaction between the compound of formula (IIC), the compound of formula (IIIB), and R 5 OH, wherein the compound of formula (IIC) is:
37 . The method of any one of claims 32 to 36 , wherein X 1 is —CH 2 —, —CH(Y)—, or —C(Y) 2 —, and step (A) comprises reacting R 9 , wherein R 9 is —CHO, with R 1 that is —CH(Y) 2 or —CH 2 (Y) treated with a Brønsted base, to produce —CO—X 1 —.
38 . The method of any one of claims 32 to 36 , wherein X 1 is —O—, and step (A) comprises esterifying R 9 that is —COOH with R 1 that is —OP 6 , where P 6 is H, to produce —CO—X 1 —.
39 . The method of any one of claims 32 to 38 , wherein step (B) comprises reacting the compound of formula (VB) with a Cr(II) salt and a Ni(II) salt.
40 . The method of any one of claims 32 to 39 , wherein step (C) comprises a step of nucleophilic ring-closing of the compound of formula (VC).
41 . The method of any one of claims 32 to 40 , wherein both P 9 groups and X 3 , together with the atoms to which each is attached, combine to form a ketal.
42 . The method of any one of claims 32 to 41 , wherein R 10 and R 11 combine to form a bond, and R 12 is H.
43 . The method of any one of claims 32 to 42 , wherein R 4B is but-3-en-1-yl, and step (A) comprises OP 7 reacting the but-3-en-1-yl group with a dihydroxylating agent to produce R 4B that is
and cleaving the
through a reaction with a glycol cleaving agent.
44 . The method of any one of claims 32 to 42 , wherein R 4B is
and step (A) comprises reacting the
with an oxidizing agent capable of converting an alcohol into a carbonyl group.
45 . The method of any one of claims 32 to 42 , wherein R 4B is
and step (A) comprises cleaving the
through a reaction with a glycol cleaving agent.
46 . A method of preparing:
a halichondrin macrolide or analog thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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 A 1 , A 2 , and A 3 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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
X 1 is —CH 2 — or —O—;
the method comprising:
(A) producing a compound of formula (IF) from a compound of formula (IIA), a compound of formula (IIB), a compound of formula (IIIC), and R 5 OH,
wherein R 5 is optionally substituted acyl;
wherein the compound of formula (IF) is:
wherein
R 1 is —OP 6 , —CH(Y) 2 , or —CH 2 (Y), wherein P 6 is H or a hydroxyl protecting group, and each Y is independently-COOR C or —SO 2 R D ;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
each R D , when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;
R 4C is
wherein R C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl, and each P 7 is independently H or a hydroxyl protecting group; and
R 5 is optionally substituted acyl;
wherein the compound of formula (IIA) is:
wherein
R 1 is —OP 6 , —CH(Y) 2 , or —CH 2 (Y), wherein P 6 is H or a hydroxyl protecting group, and each Y is independently —COOR C or —SO 2 R D ;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
R D , when present, is optionally substituted aryl or optionally substituted non-enolizable alkyl;
R E is —CHO or —CH (1+m) (OR F ) (2−m) ,
wherein
m is 1, and R F is a hydroxyl protecting group,
or
m is 0, and
(i) each R F is independently an alkyl or hydroxyl protecting group, or
(ii) both R F combine to form an alkylene;
wherein the compound of formula (IIB) is:
wherein R S is silyl;
and
wherein the compound of formula (IIIC) is:
R 4C -R 7 , (IIIC)
wherein R 7 is —CHO or
wherein each R 7A is independently an optionally substituted alkyl;
(B) producing a compound of formula (IG) from the compound of formula (IF), wherein the compound of formula (IG) is:
wherein
R E 1 is
and
(C) producing the halichondrin macrolide or analog thereof from the compound of formula (IG) and one or more intermediates.
47 . The method of claim 46 , wherein step (B) comprises reacting R 4C that is
with a glycol cleaving agent to produce an aldehyde, reacting the aldehyde with (R C O) 2 P(O)—CH 2 —COOR C to produce R 4C that is
48 . The method of claim 46 or 47 , wherein step (B) comprises reducing R 4C that is
with a 1,4-reducing agent to produce R 4C that is
49 . The method of claim 46 , wherein step (B) comprises reducing R 4C that is
with an allylic reducing agent to produce R 4C that is
50 . The method of claim 46 , 48 , or 49 , wherein step (B) comprises reducing R 4C that is
with a 1,2-reducing agent to produce a carbonyl group in R E 1.
51 . The method of claim 49 , wherein the reducing R 4C that is
comprises an esterification reaction producing R 4C that is
52 . The method of claim 46 , wherein step (B) comprises reacting R 4C that is
with an oxidizing agent capable of converting an alcohol to a carbonyl group in R E 1.
53 . The method of any one of claims 46 to 52 , wherein the one or more intermediates is a compound of formula (VIA):
wherein
R 10A is —CH 2 —CH═CH 2 , —(CH 2 ) 2 —CH═CH 2 , or —(CH 2 ) 3 —OP 10 ;
each R 10 , R 13 , P 5 and P 10 is independently a hydroxyl protecting group;
A 1 is H or —OP″; and
Y 1 is chloro, bromo, iodo, trifluoromethanesulfonate, or trialkylsilane;
and step (C) comprises:
(D) producing a compound of formula (VIB) from the compound of formula (IG) and the compound of formula (VIA), wherein the compound of formula (VIB) is:
wherein
L 4 is
R 1 is —OP 6 or —CH(Y), wherein P 6 is H or a hydroxyl protecting group, and Y is —COOR C or —CHO;
A 1 and R 14 combine to form oxo, R 13 is H or a hydroxyl protecting group, and R 15 is H;
or
A 1 is H or —OP″, and:
(i) R 13 is H or a hydroxyl protecting group, and R 14 and R 15 combine to form a double bond;
or
(ii) R 13 and R 14 combine to form a bond, and R 15 is H or —OP″;
and
each P 9 is independently a hydroxyl protecting group, and X 3 is oxo or X 3 , together with the carbon atom to which it is attached, is —(CH(OP 11 ))—, wherein P 11 is H or a hydroxyl protecting group; or both P 9 groups and X 3 , together with the atoms to which each is attached, combine to form a ketal.
54 . The method of claim 53 , wherein step (D) comprises reacting the compound of formula (VIA) and the compound of formula (IG) with a Cr(II) salt and a Ni(II) salt.
55 . The method of claim 53 or 54 , wherein R 10A is —CH 2 —CH═CH 2 , and step (C) comprises:
(E) producing a compound of formula (VIC) from the compound of formula (VIB) and R 17 —CH 2 CH═CH 2 , wherein R 17 is —COOH or a metallic or metalloid moiety, and the compound of formula (VIC) is:
wherein
L 5 is
X 1 is —CH 2 — or —O—;
X 4 is oxo, or X 4 , together with the atom to which it is attached, is —(CH(OP 12 ))—, wherein P 12 is H or a hydroxyl protecting group;
(F) producing a compound of formula (VID) from the compound of formula (VIC), wherein the compound of formula (VID) is:
wherein
L 1 , is
wherein L 2 and L 3 combine to form a bond; and
(G) producing the halichondrin macrolide or analog thereof from the compound of formula (VID).
56 . The method of claim 55 , wherein R 1 is —CH 2 (Y), X 1 is —CH 2 —, X 4 is oxo or —(CH(OP 12 ))—, and step (E) comprises reacting the compound of formula (VIB) with R 17 —CH 2 CH═CH 2 , wherein R 17 is a metallic or metalloid moiety.
57 . The method of claim 55 , wherein R 1 is —OP 6 , P 6 is H, X 1 is —O—, X 4 is oxo, and step (E) comprises esterifying the compound of formula (VIB) with R 17 —CH 2 CH═CH 2 , wherein R 17 is —COOH.
58 . The method of any one of claims 55 to 57 , wherein the producing step (F) comprises reacting the compound of formula (VIC) with an olefin metathesis catalyst.
59 . The method of any one of claims 55 to 58 , wherein step (G) comprises reacting the compound of formula (VID) with a hydroxyl protecting group removing agent.
60 . The method of claim 53 or 54 , wherein R 10A is —CH 2 —CH 2 —CH═CH 2 , R 1 is —OP 6 or —CH 2 (Y), wherein P 6 is H or a hydroxyl protecting group, and Y is —COOR C , and step (C) comprises:
(H) producing a compound of formula (VIE) from the compound of formula (VIB) and R 17 —CH═CH 2 , wherein R 17 is —COOH or a metallic or metalloid moiety, wherein the compound of formula (VIE) is:
wherein
L 6 is
X 1 is —CH 2 — or —O—; and
X 4 is oxo, or X 4 , together with the atom to which it is attached, is —(CH(OP 12 ))—, wherein P 12 is H or a hydroxyl protecting group;
(I) producing a compound of formula (VIF) from the compound of formula (VIE), wherein the compound of formula (VIF) is:
wherein
L 1 is
wherein L 2 and L 3 combine to form a bond; and
(J) producing the halichondrin macrolide or analog thereof from the compound of formula (VIF).
61 . The method of claim 60 , wherein step (I) comprises reacting the compound of formula (VIE) with an olefin metathesis catalyst.
62 . The method of claim 60 or 61 , wherein step (J) comprises reacting the compound of formula (VIF) with a hydroxyl protecting group removing agent.
63 . The method of claim 53 or 54 , wherein R 10A is —(CH 2 ) 3 —OP 10 , and step (C) comprises:
(K) producing a compound of formula (VIG) from the compound of formula (VIB) and (R C O) 2 P(O)—CH 2 —R P , wherein each R C is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl, and R P is H or —COOH, and wherein the compound of formula (VIG) is:
wherein
L 7 is
and
X 1 is —CH 2 — or —O—;
(L) producing a compound of formula (VIF) from the compound of formula (VIG), wherein the compound of formula (VIF) is:
wherein
L 1 is
wherein L 2 and L 3 combine to form a bond; and
X 4 is oxo;
and
(M) producing the halichondrin macrolide or analog thereof from the compound of formula (VIF).
64 . The method of claim 63 , wherein the producing step (K) comprises:
reacting the compound of formula (VIB) with (R C O) 2 P(O)—CH 2 —R P under Claisen reaction conditions, wherein R P is H and R 1 is —CH 2 (Y), or esterifying the compound of formula (VIB) with (R C O) 2 P(O)—CH 2 -R P , wherein R P is —COOH and R 1 is —OP 6 , wherein P 6 is H.
65 . The method of claim 63 or 64 , wherein step (M) comprises reacting the compound of formula (VIF) with a hydroxyl protecting group removing agent.
66 . The method of any one of claims 46 to 52 , wherein step (C) comprises:
(N) producing a compound of formula (VIIB) from the compound of formula (IG) and a compound of formula (VIIA):
wherein
(i) R 10 is a hydroxyl protecting group, R 1 is alkyl ether, and R 12 is H;
(ii) R 10 is a hydroxyl protecting group, and R 1 and R 12 combine to form a double bond;
or
(iii) R 10 and R 11 combine to form a bond, and R 12 is H;
R 9 is —CH 2 —OP″ or —COOP;
R 13 and each P 9 is independently a hydroxyl protecting group;
A 1 is H or —OP″;
each P″ is independently H or a hydroxyl protecting group; and
Y 1 is chloro, bromo, iodo, trifluoromethanesulfonate, or trialkylsilane;
wherein the compound of formula (VIIB) is:
wherein
L 4 is
R 1 is —OP 6 , —CH 2 (Y), or —CH(Y) 2 , wherein P 6 is H or a hydroxyl protecting group, and Y is —COOR C or —CHO;
A 1 and R 14 combine to form oxo, R 13 is H or a hydroxyl protecting group, and R 15 is H;
or
A 1 is H or —OP″, and:
(i) R 13 is H or a hydroxyl protecting group, and R 14 and R 15 combine to form a double bond;
or
(ii) R 13 and R 14 combine to form a bond, and R 15 is H or —OP″;
R 9 is —CHO or —COOP;
and
each P 9 is independently a hydroxyl protecting group, and X 3 is oxo or X 3 , together with the carbon atom to which it is attached, is —(CH(OP 11 ))—, wherein P 1 is H or a hydroxyl protecting group; or both P 9 groups and X 3 , together with the atoms to which each is attached, combine to form a ketal;
(O) producing a compound of formula (VIIC) from the compound of formula (VIIB), wherein the compound of formula (VIIC) is:
wherein
L 1 is
wherein L 2 and L 3 combine to form a bond;
X 1 is —CH 2 —, —CH(Y)—, —C(Y) 2 —, or —O—, wherein each Y is independently —COOR C or —SO 2 R D ;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and
each R D , when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl; and
X 4 is oxo, or X 4 , together with the atom to which it is attached, is —(CH(OP 12 ))—, where P 12 is H or a hydroxyl protecting group;
and
(P) producing the halichondrin macrolide or analog thereof from the compound of formula (VIIC).
67 . The method of claim 66 , wherein step (N) comprises reacting the compound of formula (VIIA) and the compound of formula (IH) with a Cr(II) salt and a Ni(II) salt.
68 . The method of claim 66 or 67 , wherein step (O) comprises an esterification reaction between R 1 that is —OP 6 , wherein P 6 is H, and R 9 that is —COOH.
69 . The method of claim 66 or 67 , wherein step (O) comprises a reaction between R 1 that is —CH(Y) 2 or —CH 2 (Y), and R 9 that is —CHO.
70 . The method of any one of claims 66 to 69 , wherein step (P) comprises reacting the compound of formula (VIIC) with a hydroxyl protecting group removing agent.
71 . A method of preparing:
a halichondrin macrolide or analog thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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 A 1 , A 2 , and A 3 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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
X 1 is —CH 2 — or —O—;
the method comprising:
(A) producing a compound of formula (VIID) from a compound of formula (IIA), a compound of formula (IIB), a compound of formula (IIIC), a compound of formula (VIIA), and R 5 OH,
wherein R 5 is optionally substituted acyl;
wherein the compound of formula (IIA) is:
wherein
R 1 is —OP 6 , —CH(Y) 2 , or —CH 2 (Y), wherein P 6 is H or a hydroxyl protecting group, and each Y is independently-COOR C or —SO 2 R D ;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
each R D , when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;
R E is —CHO or —CH (1+m) (OR F ) (2−m) ,
wherein
m is 1, and R F is a hydroxyl protecting group,
or
m is 0, and
(i) each R F is independently an alkyl or hydroxyl protecting group, or
(ii) both R F combine to form an alkylene;
wherein the compound of formula (IIB) is:
wherein R S is silyl;
wherein the compound of formula (IIIC) is:
R 4C -R 7 , (IIIC)
wherein
R 7 is —CHO or
wherein each R 7A is independently an optionally substituted alkyl;
R 4C is
wherein each P 7 , when present, is independently H or a hydroxyl protecting group;
wherein the compound of formula (VIIA) is:
wherein
(i) R 10 is a hydroxyl protecting group, R 11 is alkyl ether, and R 12 is H;
(ii) R 10 is a hydroxyl protecting group, and R 11 and R 12 combine to form a double bond;
or
(iii) R 10 and R 11 combine to form a bond, and R 12 is H;
R 9 is —CHO or —COOH;
R 13 and each P 9 is independently a hydroxyl protecting group;
A 1 is H or —OP″, wherein P″ is H or a hydroxyl protecting group; and
Y 1 is chloro, bromo, iodo, trifluoromethanesulfonate, or trialkylsilane;
wherein the compound of formula (VIID) is:
wherein
X 1 is —CH 2 —, —CH(Y)—, —C(Y) 2 —, or —O—, wherein each Y is independently —COOR C or —SO 2 R D ;
X 4 is oxo, or X 4 , together with the atom to which it is attached, is —(CH(OP 12 ))—, where P 12 is H or a hydroxyl protecting group;
R L is
wherein
R 18 is —CHO or —CH 2 OP 7 ;
R 5 is optionally substituted acyl;
(B) producing a compound of formula (VIIE) from the compound of formula (VIID), wherein the compound of formula (VIIE) is:
wherein
L 1 is
wherein L 2 and L 3 combine to form a bond;
each P 9 is independently a hydroxyl protecting group, and X 3 is oxo or X 3 , together with the carbon atom to which it is attached, is —(CH(OP 11 ))—, wherein P 1 is H or a hydroxyl protecting group;
and
(C) producing the halichondrin macrolide or analog thereof from the compound of formula (VIIC).
72 . The method of claim 71 , wherein step (A) comprises:
(D) producing a compound of formula (IIC) from the compound of formula (IIA) and the compound of formula (IIB), wherein the compound of formula (IIC) is:
(E) producing a compound of formula (IF) from the compound of formula (IIC), the compound of formula (IIIC), and R 5 OH, wherein the compound of formula (IF) is:
and
(F) producing the compound of formula (VIIB) from the compound of formula (VIIA) and the compound of formula (IF).
73 . The method of claim 72 , wherein the producing the compound of formula (IF) comprises reacting the compound of formula (IIC), the compound of formula (IIIC), R 5 OH, and a Lewis acid.
74 . The method of claim 73 , wherein the Lewis acid is an oxophilic Lewis acid.
75 . The method of claim 74 , wherein the oxophilic Lewis acid is boron trifluoride or a solvate thereof.
76 . The method of any one of claims 71 to 75 , wherein step (F) comprises:
(G) producing a compound of formula (IH) from the compound of formula (IF), wherein the compound of formula (IH) is:
and
(H) producing the compound of formula (VIID) from the compound of formula (IH) and the compound of formula (VIIA).
77 . The method of claim 76 , wherein the producing step (G) comprises reacting the compound of formula (IF) with an allylic reducing agent.
78 . The method of any one of claims 71 to 77 , wherein step (A) comprises reducing R 4C that is
with a 1,2-reducing agent.
79 . The method of any one of claims 71 to 77 , wherein step (A) comprises reducing R 4C that is
with a 1,4-reducing agent to produce a reduction product, and reducing the reduction product with a 1,2-reducing agent.
80 . The method of any one of claims 71 to 77 , wherein step (A) comprises reducing R 4C that is
with an allylic reducing agent to produce an acid product, and reducing the acid product with a 1,2-reducing agent capable of converting the carboxylic acid to an aldehyde.
81 . The method of any one of claims 71 to 77 , wherein step (A) comprises cleaving R 4C that is
with a glycol cleaving agent to produce an aldehyde, reacting the aldehyde (R C O) 2 P(O)—CH 2 —COOR C to produce an enoate, reacting the enoate with a 1,4-reducing agent to produce R 4C that is
and reacting R 4C that is
with a 1,2-reducing agent capable of converting the carboxylic acid to an aldehyde.
82 . The method of any one of claims 71 to 81 , wherein step (A) comprises an esterification reaction between R 1 that is —OP 6 , where P 6 is H, and R 9 that is —COOH.
83 . The method of any one of claims 71 to 81 , wherein step (A) comprises a reaction between R 1 that is —CH(Y) 2 or —CH 2 (Y), and R 9 that is —CHO.
84 . The method of any one of claims 71 to 78 , wherein step (B) comprises reacting the compound of formulas (VIID) with a Cr(II) salt and a Ni(II) salt.
85 . The method of any one of claims 71 to 84 , wherein step (C) comprises reacting the compound of formula (VIIE) with a hydroxyl protecting group removing agent.
86 . A method of preparing:
a halichondrin macrolide or analog thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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 A 1 , A 2 , and A 3 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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
X 1 is —CH 2 — or —O—;
the method comprising:
(A) producing a compound of formula (VIIIB) from a compound of formula (VIIIA), a compound of formula (IIA), a compound of formula (IIB), and a compound of formula (IIIC), and R 5 OH,
wherein R 5 is optionally substituted acyl;
wherein the compound of formula (IIA) is:
wherein
R 1 is —OP 6 , —CH(Y) 2 , or —CH 2 (Y), wherein P 6 is H or a hydroxyl protecting group, and each Y is independently-COOR C or —SO 2 R D ;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
each R D , when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;
R E is —CHO or —CH (1+m) (OR F ) (2−m) ,
wherein
m is 1, and R F is a hydroxyl protecting group,
or
m is 0
(i) each R F is independently an alkyl or hydroxyl protecting group, or
(ii) both R F combine to form an alkylene;
wherein the compound of formula (IIB) is:
wherein R S is silyl;
wherein the compound of formula (IIIC) is:
R 4C -R 7 , (IIIC)
wherein
R 4C is
wherein
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
each P 7 , when present, is independently H or a hydroxyl protecting group;
R 7 is —CHO or
wherein each R 7A is independently an optionally substituted alkyl;
and
wherein the compound of formula (VIIIA) is:
wherein
(i) R 10 is a hydroxyl protecting group, R 1 is alkyl ether, and R 12 is H;
(ii) R 10 is a hydroxyl protecting group, and R 4 and R 5 combine to form a double bond;
or
(iii) R 10 and R 11 combine to form a bond, and R 12 is H;
R 9 is —CHO or —COOH;
and
each P 9 and R 13 is independently a hydroxyl protecting group;
wherein the compound of formula (VIIIB) is:
wherein
X 1 is —CH 2 —, —CH(Y)—, —C(Y) 2 —, or —O—, wherein each Y is independently —COOR C or —SO 2 R D ;
R M is
wherein
R 5 is optionally substituted acyl; and
X 3 is oxo or X 3 , together with the carbon atom to which it is attached, is —(CH(OP 11 ))—,
wherein P 1 is H or a hydroxyl protecting group; and
X 4 is oxo, or X 4 , together with the atom to which it is attached, is —(CH(OP 12 ))—, where P 12 is H or a hydroxyl protecting group;
(B) producing a compound of formula (VIIIC) from the compound of formula (VIIIB), wherein the compound of formula (VIIIC) is:
wherein
L 1 is
wherein L 2 and L 3 combine to form a bond;
A 1 is H or —OP″, wherein P″ is H or a hydroxyl protecting group; and
(C) producing the halichondrin macrolide or analog thereof from the compound of formula (VIIIC).
87 . The method of claim 86 , wherein step (A) comprises:
(D) producing a compound of formula (IIC) from the compound of formula (IIA) and the compound of formula (IIB), wherein the compound of formula (IIC) is:
(E) producing a compound of formula (IF) from the compound of formula (IIC), the compound of formula (IIIC), and R 5 OH, wherein the compound of formula (IF) is:
(F) producing a compound of formula (IJ) from the compound of formula (IF), wherein the compound of formula (IJ) is:
and
(G) producing the compound of formula (VIIIB) from the compound of formula (VIIIA) and the compound of formula (IJ).
88 . The method of claim 87 , wherein step (D) comprises reacting the compound of formula (IIB), the compound of formula (IIA), and a Lewis acid.
89 . The method of claim 87 or 88 , wherein step (E) comprises reacting the compound of formula (IIC), the compound of formula (IIIC), R 5 OH and a Lewis acid.
90 . The method of claim 88 or 89 , wherein the Lewis acid in step (D) and the Lewis acid in step (E) are different.
91 . The method of any one of claims 88 to 90 , wherein the Lewis acid is an oxophilic Lewis acid.
92 . The method of claim 91 , wherein the oxophilic Lewis acid is boron trifluoride or a solvate thereof.
93 . The method of any one of claims 87 to 92 , wherein step (F) comprises converting
using an allylic reducing agent.
94 . The method of claim any one of claims 86 to 92 , wherein step (A) comprises reacting R 4C that is
with a 1,2-reducing agent to produce a product, and reacting the product with a vinyl nucleophile.
95 . The method of any one of claims 86 to 92 , wherein step (A) comprises reacting R 4C that is
with a 1,4-reducing agent to produce a product, reducing the product with a 1,2-reducing agent to produce a reduced product, and reacting the reduced product with a vinyl nucleophile.
96 . The method of any one of claims 86 to 92 , wherein step (A) comprises reacting R 4C that is
with an allylic reducing agent to produce an acid, reducing the acid with a 1,2-reducing agent to produce a reduced product, and reacting the reduced product with a vinyl nucleophile.
97 . The method of any one of claims 86 to 92 , wherein step (A) comprises cleaving R 4C that is
with a glycol cleaving agent to produce an aldehyde, reacting the aldehyde with (R C O) 2 P(O)—CH 2 —COOR C to produce an enoate, reacting the enoate with a 1,4-reducing agent to produce a product, reducing the product with a 1,2-reducing agent to product a reduced product, and reacting the reduced product with a vinyl nucleophile.
98 . The method of any one of claims 86 to 97 , wherein step (A) comprises an esterification reaction between R 1 that is —OP 6 , where P 6 is H, and R 9 that is —COOH.
99 . The method of any one of claims 86 to 97 , wherein step (A) comprises a reaction between R 1 that is —CH(Y) 2 or —CH 2 (Y), and R 9 , wherein R 9 is —CHO.
100 . The method of any one of claims 86 to 99 , wherein step (B) comprises reacting the compound of formula (VIIIB) with an olefin metathesis catalyst.
101 . The method of any one of claims 86 to 100 , wherein step (C) comprises reacting the compound of formula (VIIIC) with a hydroxyl protecting group removing agent.
102 . A method of preparing:
a halichondrin macrolide or analog thereof,
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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 A 1 , A 2 , and A 3 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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
X 1 is —CH 2 — or —O—;
the method comprising:
(A) producing a compound of formula (IXB) from a compound of formula (IXA), a compound of formula (IIB), a compound of formula (IIA), a compound of formula (IIIE), and R 5 OH,
wherein R 5 is optionally substituted acyl;
wherein the compound of formula (IXA) is:
wherein
R 9 is —CHO or —COOP″;
(a1) R 10 is a hydroxyl protecting group, R 1 is alkyl ether, and R 12 is H;
(a2) R 10 is a hydroxyl protecting group, and R 1 and R 12 combine to form a double bond;
or
(a3) R 10 and R 11 combine to form a bond, and R 12 is H;
A 1 and R 14 combine to form oxo, R 13 is H or a hydroxyl protecting group, and R 15 is H;
or
A 1 is H or —OP″, and:
(i) R 13 is H or a hydroxyl protecting group, and R 14 and R 15 combine to form a double bond;
or
(ii) R 13 and R 14 combine to form a bond, and R 15 is H or —OP″;
R O is —CHO, —CH 2 OP″, —CH═CH 2 , —CH(OP″)CH 2 OP″, —C(O)—CH 2 P(O)(OR C ) 2 , or halogen;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and
each P″ is independently H or a hydroxyl protecting group; and
each P 9 is independently a hydroxyl protecting group;
wherein the compound of formula (IIA) is:
wherein
R 1 is —OP 6 , —CH(Y) 2 , or —CH 2 (Y), wherein P 6 is H or a hydroxyl protecting group, and each Y is independently-COOR C or —SO 2 R D ;
each R D , when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;
R E is —CHO or —CH (1+m) (OR F ) (2−m) ,
wherein
m is 1, and R F is a hydroxyl protecting group,
or
m is 0, and
(i) each R F is independently an alkyl or hydroxyl protecting group, or
(ii) both R F combine to form an alkylene;
wherein the compound of formula (IIIE) is:
R 4E -R 7 , (IIIE)
wherein
R 4E is
wherein
each P 7 is independently H or a hydroxyl protecting group; and
R 8 is —CH 2 CH 2 —COOR C , —CH═CH—COOR C , —CH 2 CH 2 —SO 2 R D , or —CH═CH—SO 2 R D ; and
R 7 is —CHO or
wherein each R 7A is independently an optionally substituted alkyl;
wherein the compound of formula (IIB) is:
wherein R S is silyl;
and
wherein the compound of formula (IXB) is:
wherein
X 1 is —CH 2 —, —CH(Y)—, —C(Y) 2 —, or —O—;
L 1 is
wherein L 2 and L 3 combine to form a bond;
R 5 is optionally substituted acyl;
A 1 and R 14 combine to form oxo, R 13 is H or a hydroxyl protecting group, and R 15 is H;
or
A 1 is H or —OP″, and:
(i) R 13 is H or a hydroxyl protecting group, and R 14 and R 15 , together with the atoms to which each is attached, combine to form a double bond;
or
(ii) R 13 and R 14 combine to form a bond, and R 15 is H or —OP″;
each P 9 is independently H or a hydroxyl protecting group, and X 3 is oxo, or X 3 , together with the atom to which it is attached, combines to form —(CH(OP 11 ))—, wherein P 1 is H or a hydroxyl protecting group;
or
both P 9 and X 3 , together with the atoms to which each is attached, combine to form a ketal;
and
R 19A is H, —OP″, or Y, and R 19B is H; or R 19A and R 19B , together with the atoms to which each is attached, combine to form a double bond; and
(B) producing the halichondrin macrolide or analog thereof from the compound of formula (IXB).
103 . The method of claim 102 , wherein step (A) comprises reacting R E that is —CHO with the compound of formula (IIB) and a first Lewis acid to produce a group of the structure
104 . The method of claim 103 , wherein step (A) comprises reacting the group of the structure
with R 7 , R 5 OH, and a second Lewis acid to produce a group of the structure
105 . The method of claim 104 , wherein the first Lewis acid and/or second Lewis acid is an oxophilic Lewis acid.
106 . The method of claim 104 or 105 , wherein the first Lewis acid is same as the second Lewis acid.
107 . The method of any one of claims 102 to 106 , wherein step (A) comprises converting R 4E that is
to a group of the structure
and reacting this group with R O that is —C(O)—CH 2 P(O)(OR C ) 2 under Horner-Wadsworth-Emmons reaction conditions.
108 . The method of any one of claims 102 to 106 , wherein step (A) comprises reacting R 4E that is
with R O that is —CHO under Claisen reaction conditions, wherein R 8 is —CH 2 CH 2 —COOR C or —CH 2 CH 2 —SO 2 R D .
109 . The method of any one of claims 102 to 106 , wherein step (A) comprises converting R 4E that is
to a group of the structure
and reacting this group with R O that is a halogen under Nozaki-Hiyama-Kishi reaction conditions, wherein R 8 , when present, is —CH 2 CH 2 —COOR C or —CH═CH—COOR C , and R 14 and R 15 combine to form a double bond.
110 . The method of any one of claims 102 to 109 , wherein step (A) comprises reacting R 1 that is —OP 6 and R 9 under esterification reaction conditions to produce a group of the structure —X 1 —C(O)—, wherein P 6 is H, R 9 is —COOH, and X 1 is —O—.
111 . The method of any one of claims 102 to 110 , wherein step (A) comprises reacting R 1 that is —CH(Y) 2 or —CH 2 (Y) with R 9 under Claisen reaction conditions to produce a group of the structure —X 1 —C(O)—, wherein R 9 is —CHO, and X 1 is —C(Y) 2 — or —CH(Y)—, respectively.
112 . The method of any one of claims 102 to 111 , wherein step (B) comprises reacting the compound of formula (IXB) with a hydroxyl protecting group removing agent.
113 . The method of any one of claims 1 to 112 , wherein D′ is OP 1 , wherein P 1 is alkyl.
114 . The method of any one of claims 1 to 113 , wherein D is H.
115 . The method of any one of claims 1 to 114 , wherein A is of the following structure:
116 . The method of any one of claims 1 to 115 , wherein k is 0.
117 . The method of any one of claims 1 to 116 , wherein R 3 is —(CH 2 ) n NP 3 P 4 or —(CH 2 ) n OP 5 , wherein n is 0.
118 . The method of any one of claims 1 to 112 , wherein D′ is H.
119 . The method of any one of claims 1 to 112 and 118 , wherein A and D combine to form the following structure:
wherein, the bond to oxygen atom originates at the carbon atom, to which D is attached in formula (IA), and
wherein R 3 is —(CH 2 ) n NP 3 P 4 or —(CH 2 ) n OP 5 , wherein n is 2.
120 . The method of any one of claims 1 to 112 , 118 , and 119 , wherein k is 1, and E is optionally substituted alkyl.
121 . The method of any one of claims 1 to 120 , wherein G is O.
122 . A method of preparing:
wherein R 7 is —CHO or
and
each R 7A is independently alkyl or a hydroxyl protecting group; or
both R 7A combine to form an optionally substituted alkylene;
the method comprising:
(A) producing a compound of formula (Z2) from a compound of formula (Z1) and
wherein each R O is independently optionally substituted alkyl, wherein the compound of formula (Z1) is:
wherein
each R 20A is independently a hydroxyl protecting group, or both R 20A , together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene-dioxo;
each R 20B is independently a hydroxyl protecting group, or both R 20B , together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene-dioxo;
P 12A is H;
P 12B is H or a hydroxyl protecting group;
and the compound of formula (Z2) is:
(B) producing a compound of formula (Z3) from the compound of formula (Z2) and
wherein each R 21 is independently optionally substituted alkyl, wherein the compound of formula (Z3) is:
(C) producing a compound of formula (Z4) from the compound of formula (Z3), wherein the compound of formula (Z4) is:
wherein X 5 is a halogen;
(D) producing a compound of formula (Z5) from the compound of formula (Z4), wherein the compound of formula (Z5) is:
wherein
R 20A is H or a hydroxyl protecting group; and
each R 20B is independently H or a hydroxyl protecting group, or both R 20B , together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene-dioxo;
(E) producing a compound of formula (Z6) from the compound of formula (Z5) and R 7A OH
(F) producing a compound of formula (Z7) from the compound of formula (Z6) and
wherein each R 22 is independently optionally substituted alkyl, and the compound of formula (Z7) is:
and
(G) producing the compound of formula (Z) from the compound of formula (Z7).
123 . The method of claim 122 , wherein step (E) comprises reacting the compound of formula (Z5) with R 7A OH and a Brønsted acid.
124 . The method of claim 122 or 123 , wherein step (F) comprises reacting the compound of formula (Z6) with a glycol cleaving agent to produce an aldehyde product, and reacting the aldehyde product with
under Horner-Wadsworth-Emmons reaction conditions.
125 . The method of any one of claims 122 to 124 , wherein step (G) comprises reacting the compound of formula (Z6) with a 1,4-reducing agent.
126 . A method of preparing:
wherein
R 7 is —CHO or
and
each R 7A is independently alkyl or a hydroxyl protecting group; or
both R 7A combine to form an optionally substituted alkylene;
R 8 is —CH 2 CH 2 —COOR C , —CH═CH—COOR C , —CH 2 CH 2 —SO 2 R D , or —CH═CH—SO 2 R D ;
R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and
R D , when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;
the method comprising:
(A) producing a compound of formula (Z2) from a compound of formula (Z1) and
wherein each R O is independently optionally substituted alkyl, wherein the compound of formula (Z1) is:
wherein
each R 20A is independently a hydroxyl protecting group, or both R 20A , together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene-dioxo;
each R 20B is independently a hydroxyl protecting group, or both R 20B , together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene-dioxo;
P 12A is H;
P 12B is H or a hydroxyl protecting group;
and the compound of formula (Z2) is:
(B) producing a compound of formula (Z3) from the compound of formula (Z2) and
wherein each R 21 is independently optionally substituted alkyl, wherein the compound of formula (Z3) is:
(C) producing a compound of formula (Z4) from the compound of formula (Z3), wherein the compound of formula (Z4) is:
wherein X 5 is a halogen;
(D) producing a compound of formula (Z5) from the compound of formula (Z4), wherein the compound of formula (Z5) is:
wherein
R 20A is H or a hydroxyl protecting group; and
each R 20B is independently H or a hydroxyl protecting group, or both R 20B , together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene-dioxo;
(E) producing a compound of formula (Z5A) from the compound of formula (Z5) and R 7A OH, wherein the compound of formula (Z5A) is:
wherein
R 20A is H or a hydroxyl protecting group; and
each R 20B is independently H or a hydroxyl protecting group, or both R 20B , together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene-dioxo;
(F) producing a compound of formula (Z5B) from the compound of formula (Z5A), wherein the compound of formula (Z5B) is:
wherein R 23 is H or —OR 20A ;
and
(G) producing the compound of formula (Z8) from the compound of formula (Z5B) and
in which each R 22 is independently optionally substituted alkyl.
127 . The method of claim 126 , wherein step (E) comprises reacting the compound of formula (Z5) with R 7A OH and a Brønsted acid.
128 . The method of claim 126 or 127 , wherein step (F) comprises reacting the compound of formula (Z5A), in which both R 20B are H, with a glycol cleaving agent.
129 . The method of any one of claims 126 to 128 , wherein step (E) or step (F) further comprises reacting —OR 20A , wherein R 20A is optionally substituted acyl with an allylic reducing agent.
130 . The method of any one of claims 126 to 129 , wherein step (G) comprises reacting the compound of formula (Z5B) with
under Horner-Wadsworth-Emmons reaction conditions to produce the compound of formula (Z8), in which R 8 is —CH═CH—COOR C or —CH═CH—SO 2 R D , respectively.
131 . The method of claim 130 , wherein step (G) further comprises reacting the compound of formula (Z8), in which R 8 is —CH═CH—COOR C or —CH═CH—SO 2 R D , with a 1,4-reducing agent to produce the compound of formula (Z8), in which R 8 is —CH 2 CH 2 —COOR C or —CH 2 CH 2 —SO 2 R D , respectively.
132 . The method of any one of claims 122 to 131 , wherein the producing the compound of formula (Z2) comprises reacting the compound of formula (Z1) with
under Horner-Wadsworth-Emmons reaction conditions.
133 . The method of any one of claims 122 to 132 , wherein step (B) comprises reacting the compound of formula (Z2) with a 1,2-reducing agent to produce a reduction product, and reacting the reduction product with
under Horner-Wadsworth-Emmons reaction conditions.
134 . The method of any one of claims 122 to 133 , wherein step (C) comprises substituting free hydroxyl group in the compound of formula (Z3) with a halogen.
135 . The method of any one of claims 122 to 134 , wherein step (D) comprises subjecting the compound of formula (Z4) to reductive metal conditions.
136 . A compound of formula (II):
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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;
R 1 is —OP 6 , —CH(Y) 2 , or —CH 2 (Y), wherein P 6 is H or a hydroxyl protecting group;
R B is H, optionally substituted alkyl, or optionally substituted aryl; and
Y is independently —COOR C or —SO 2 R D ;
R C , when present, is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and
R D , when present, is optionally substituted aryl or optionally substituted non-enolizable alkyl.
137 . A compound of formula (VIIAa):
where
R 7 is —CH 2 OP A , —CHO, or
where each R 7A is independently an optionally substituted alkyl;
R 9 is —CH 2 —OP″, —CHO, or —COOP″;
(i) R 10 is a hydroxyl protecting group, R 11 is alkyl ether, and R 12 is H;
(ii) R 10 is a hydroxyl protecting group, and R 11 and R 12 combine to form a double bond;
or
(iii) R 10 and R 11 combine to form a bond, and R 12 is H;
A 1 and R 14 combine to form oxo, R 13 is H or a hydroxyl protecting group, and R 15 is H;
or
A 1 is H or —OP″, and:
(i) R 13 is H or a hydroxyl protecting group, and R 14 and R 15 combine to form a double bond;
or
(ii) R 13 and R 14 combine to form a bond, and R 15 is H or —OP″;
each P″ is independently H or a hydroxyl protecting group; and
each P 9 is independently a hydroxyl protecting group, and X 3 is oxo or X 3 , together with the carbon atom to which it is attached, is —(CH(OP 11 ))—, where P 11 is H or a hydroxyl protecting group; or both P 9 groups and X 3 , together with the atoms to which each is attached, combine to form a ketal.
138 . A compound of formula (VIAa):
where
R 7 is —CHO or
wherein each R 7A is independently an optionally substituted alkyl;
R 10A is —CH 2 —CH═CH 2 , —(CH 2 ) 2 —CH═CH 2 , or —(CH 2 ) 3 —OP 10 ;
each of R 10 and P 10 is independently a hydroxyl protecting group;
A 1 and R 14 combine to form oxo, R 13 is H or a hydroxyl protecting group, and R 15 is H;
or
A 1 is H or —OP″, and:
(i) R 13 is H or a hydroxyl protecting group, and R 14 and R 15 combine to form a double bond;
or
(ii) R 13 and R 14 combine to form a bond, and R 15 is H or —OP″;
and
each P 9 is independently a hydroxyl protecting group, and X 3 is oxo or X 3 , together with the carbon atom to which it is attached, is —(CH(OP 11 ))—, wherein P 1 is H or a hydroxyl protecting group; or both P 9 groups and X 3 , together with the atoms to which each is attached, combine to form ketal.
139 . A compound of formula (IID) or (IIF):
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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;
X 1 is —CH 2 — or —O—;
X 4 is oxo, or X 4 , together with the atom to which it is attached, is —(CH(OP 12 ))—, where P 12 is H or a hydroxyl protecting group; and
R E is —CHO or —CH (1+m) (OR F ) (2−m) , wherein
m is 1, and R F is a hydroxyl protecting group,
or
m is 0, and
(i) each R F is independently an alkyl or hydroxyl protecting group, or
(ii) both R F combine to form an alkylene.
140 . A compound of formula (IIE) or (IIG):
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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;
X 1 is —CH 2 — or —O—; and
X 4 is oxo, or X 4 , together with the atom to which it is attached, is —(CH(OP 12 ))—, where P 12 is H or a hydroxyl protecting group.
141 . A compound of formula (IIH):
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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;
each R C is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
X 1 is —CH 2 — or —O—;
X 4 is oxo, or X 4 , together with the atom to which it is attached, is —(CH(OP 12 ))—, where P 12 is H or a hydroxyl protecting group; and
R E is —CHO or —CH (1+m) (OR F ) (2−m) , wherein
m is 1, and R F is a hydroxyl protecting group,
or
m is 0, and
(i) each R F is independently an alkyl or hydroxyl protecting group, or
(ii) both R F combine to form an alkylene.
142 . A compound of formula (IIi):
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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;
each R C is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and
X 1 is —CH 2 — or —O—.
143 . A compound of formula (VIIID):
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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;
X 1 is —CH 2 —, —CH(Y)—, —C(Y) 2 —, or —O—, wherein each Y is independently —COOR C or —SO 2 R D ;
X 4 is oxo, or X 4 , together with the atom to which it is attached, is —(CH(OP 12 ))—, wherein P 12 is H or a hydroxyl protecting group;
each P 9 and R 13 is independently a hydroxyl protecting group;
(i) R 10 is a hydroxyl protecting group, R 1 is alkyl ether, and R 12 is H;
(ii) R 10 is a hydroxyl protecting group, and R 4 and R 5 combine to form a double bond; or
(iii) R 10 and R 11 combine to form a bond, and R 12 is H;
R M1 is
wherein
R 5 is optionally substituted acyl;
P 13 is H or a hydroxyl protecting group; and
R 4C is
wherein R C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and P 7 , when present, is independently H or a hydroxyl protecting group.
144 . A compound of formula (IVAb):
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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;
X 1 is —CH 2 —, —CH(Y)—, —C(Y) 2 —, or —O—, wherein each Y is independently —COOR C or —SO 2 R D ;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
each R D , when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;
X 4 is oxo, or X 4 , together with the atom to which it is attached, is —(CH(OP 12 ))—, where P 12 is H or a hydroxyl protecting group;
each P 9 is independently a hydroxyl protecting group;
(a1) R 10 is H or a hydroxyl protecting group, R 1 is alkyl ether, and R 12 is H;
(a2) R 10 is H or a hydroxyl protecting group, and R 1 and R 12 combine to form a double bond;
or
(a3) R 10 and R 11 combine to form a bond, and R 12 is H;
(b1) A 1 and R 14 combine to form oxo, R 13 is H or a hydroxyl protecting group, and R 15 is H;
or
(b2) A 1 is H or —OP″, and:
(i) R 13 is H or a hydroxyl protecting group, and R 14 and R 15 combine to form a double bond;
or
(ii) R 13 and R 14 combine to form a bond, and R 15 is H or —OP″; and
(c1) R 16 is H, and P 8 is H or a hydroxyl protecting group;
or
(c2) R 16 and P 8 combine to form a double bond;
and
each P″, when present, is independently H or a hydroxyl protecting group.
145 . A compound of formula (VAb):
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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;
a designates (R)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide; or a designates (S)-stereogenic center, and Z is OR 16 , where R 16 is a hydroxyl protecting group;
X 1 is —CH 2 —, —CH(Y)—, —C(Y) 2 —, or —O—, where each Y is independently —COOR C or —SO 2 R D ;
each P 9 is independently a hydroxyl protecting group, and X 3 is oxo; or both P 9 groups and X 3 , together with the atoms to which each is attached, combine to form ketal;
Y 1 is iodide, bromide, or trifluoromethanesulfonate;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and
each R D , when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;
(a1) R 10 is a hydroxyl protecting group, R 11 is alkyl ether, and R 12 is H;
(a2) R 10 is a hydroxyl protecting group, and R 11 and R 12 combine to form a double bond;
or
(a3) R 10 and R 11 combine to form a bond, and R 12 is H;
(b1) A 1 and R 14 combine to form oxo, R 13 is a hydroxyl protecting group, and R 15 is H;
or
(b2) A 1 is H or —OP″, and:
(i) R 13 is a hydroxyl protecting group, and R 14 and R 15 combine to form a double bond;
or
(ii) R 13 and R 14 combine to form a bond, and R 15 is H or —OP″;
and
each P″ is independently a hydroxyl protecting group.
146 . A compound of formula (IXD):
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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;
X 1 is —CH 2 —, —CH(Y)—, —C(Y) 2 —, or —O—, each Y is independently —COOR C or —SO 2 R D ;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
each R D , when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;
X 4 is oxo, or X 4 , together with the atom to which it is attached, is —(CH(OP 12 ))—, where P 12 is H or a hydroxyl protecting group;
R 7 is —CHO, —CH 2 OP A or
wherein each R 7A is independently an optionally substituted alkyl;
(i) R 10 is a hydroxyl protecting group, R 11 is alkyl ether, and R 12 is H;
(ii) R 10 is a hydroxyl protecting group, and R 11 and R 12 combine to form a double bond; or
(iii) R 10 and R 11 combine to form a bond, and R 12 is H;
A 1 and R 14 combine to form oxo, R 13 is H or a hydroxyl protecting group, and R 15 is H;
or
A 1 is H or —OP″, and
(i) R 13 is H or a hydroxyl protecting group, and R 14 and R 15 , together with the atoms to which each is attached, combine to form a double bond;
or
(ii) R 13 and R 14 combine to form a bond, and R 15 is H or —OP″; each P 9 is independently H or a hydroxyl protecting group,
each P 9 is independently a hydroxyl protecting group, and X 3 is oxo, or X 3 , together with the atom to which it is attached, combines to form —(CH(OP 11 ))—, where P 11 is H or a hydroxyl protecting group; or both P 9 and X 3 , together with the atoms to which each is attached, combine to form a ketal; and
R 19A is H, —OP″, or Y, and R 19B is H; or R 19A and R 19B , together with the atoms to which each is attached, combine to form a double bond.
147 . A compound of formula (IXF):
wherein
each of D and D′ is independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, a hydroxyl protecting group, and A is a C 1-6 saturated or C 2-6 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 Q 1 , or A is a group of formula (1):
wherein
L is —(CH(OP 2 ))—, —(C(OH)(OP 2 ))—, or —C(O)—;
R 2 is H and P 1 is absent, H, alkyl, or a hydroxyl protecting group, or R 2 and P 1 combine to form a bond;
(i) R 3 is H, and P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;
(ii) R 3 is —(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N-protecting group, (b) P 2 and P 4 combine to form an alkylidene, or (c) each of P 2 and P 4 is H;
(iii) R 3 is —(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 , 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) R 3 and P 2 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, CH 2 , or NR N , wherein R N is H, an N-protecting group, or optionally substituted alkyl;
each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A , or O(CO)NR B R A , wherein each of R A and R B 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;
X 1 is —CH 2 —, —CH(Y)—, —C(Y) 2 —, or —O—, wherein each Y is independently —COOR C or —SO 2 R D ;
X 4 is oxo, or X 4 , together with the atom to which it is attached, is —(CH(OP 12 ))—, where P 12 is H or a hydroxyl protecting group;
each R C , when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;
each R D , when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;
R O is —CHO, —CH 2 OP″, —CH═CH 2 , —CH(OP″)CH 2 OP″, —C(O)—CH 2 P(O)(OR C ) 2 , or halogen;
(i) R 10 is a hydroxyl protecting group, R 11 is alkyl ether, and R 12 is H;
(ii) R 10 is a hydroxyl protecting group, and R 11 and R 12 combine to form a double bond; or
(iii) R 10 and R 11 combine to form a bond, and R 12 is H;
A 1 and R 14 combine to form oxo, R 13 is H or a hydroxyl protecting group, and R 15 is H;
or
A 1 is H or —OP″, and
(i) R 13 is H or a hydroxyl protecting group, and R 14 and R 15 , together with the atoms to which each is attached, combine to form a double bond;
or
(ii) R 13 and R 14 combine to form a bond, and R 15 is H or —OP″; each P 9 is independently H or a hydroxyl protecting group;
and
each of P″, P 9 , and P 13 is independently H or a hydroxyl protecting group.
148 . A compound of formula (IXG):
wherein
R 7 is —CHO, —CH 2 OP A , or
wherein each R 7A is independently an optionally substituted alkyl;
(i) R 10 is a hydroxyl protecting group, R 11 is alkyl ether, and R 12 is H;
(ii) R 10 is a hydroxyl protecting group, and R 1 and R 12 combine to form a double bond; or
(iii) R 10 and R 11 combine to form a bond, and R 12 is H;
A 1 and R 14 combine to form oxo, R 13 is H or a hydroxyl protecting group, and R 15 is H;
or
A 1 is H or —OP″, and
(i) R 13 is H or a hydroxyl protecting group, and R 14 and R 15 , together with the atoms to which each is attached, combine to form a double bond;
or
(ii) R 13 and R 14 combine to form a bond, and R 15 is H or —OP″; each P 9 is independently H or a hydroxyl protecting group,
each P 9 is independently a hydroxyl protecting group, and X 3 is oxo, or X 3 , together with the atom to which it is attached, combines to form —(CH(OP 11 ))—, where P 1 is H or a hydroxyl protecting group; or both P 9 and X 3 , together with the atoms to which each is attached, combine to form a ketal; and
R 19A is H, —OP″, or Y, and R 19B is H; or R 19A and R 19B , together with the atoms to which each is attached, combine to form a double bond.
149 . A compound of formula (Z), (Z1), (Z2), (Z3), (Z4), (Z5), (Z5A), (Z5B), or (Z6).Join the waitlist — get patent alerts
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