US2023128195A1PendingUtilityA1
Synthesis of halichondrins
Est. expiryJul 6, 2037(~10.9 yrs left)· nominal 20-yr term from priority
Inventors:Yoshito KishiYanran AiNing YeQiaoyi WangKenzo YahataKentaro IsoSanthosh Reddy NainiShuji YamashitaJihoon LeeIsao OhashiTakashi Fukuyama
C07D 493/22C07D 493/04
65
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Claims
Abstract
The present invention provides methods for the synthesis of ketones involving a Ni/Zr-mediated coupling reaction. The Ni/Zr-mediated ketolization reactions can be used in the synthesis of halichondrins (e.g., halichondrin A, B, C; homohalichondrin A, B, C; norhalichondrin A, B, C), and analogs thereof. Therefore, the present invention also provides synthetic methods useful for the synthesis of halichondrins, and analogs thereof. Also provided herein are compounds (i.e., intermediates) useful in the synthesis of halichondrins, and analogs thereof. In particular, the present invention provides methods and compounds useful in the synthesis of compound of Formula (H3-A):
Claims
exact text as granted — not AI-modified1 - 581 . (canceled)
582 . A method of preparing a compound of Formula (H3-2-I):
or a salt thereof, comprising cyclizing a compound of Formula (H3-2-II):
or a salt thereof, wherein:
R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl;
each instance of R 4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 groups are taken together to form:
each instance of R 6 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 groups are taken together to form:
R P4 , R P5 , and R P6 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; or wherein two R P6 are joined with the intervening atoms to form optionally substituted heterocyclyl;
R X is hydrogen or —OR Xa , wherein R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and
R Y is hydrogen or —OR Ya , wherein R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
or wherein R Xa and R Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.
583 . The method of claim 582 further comprising coupling a compound of Formula (L-2-6):
or a salt thereof, with a compound of Formula (R-2-I):
or a salt thereof, to yield a compound of Formula (H3-2-II):
or a salt thereof, wherein:
R S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and
X 1 is halogen or a leaving group.
584 . A method of preparing a compound of Formula (R-2-I):
or a salt thereof, comprising reacting a compound of Formula (R-4-11B):
or a salt thereof, in the presence of a nucleophile, thereby substituting the group —OR P7 with the group —X 1 ; wherein:
X 1 is halogen or a leaving group;
R 3 and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl;
each instance of R 4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 groups are taken together to form:
each instance of R 6 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 groups are taken together to form:
R P5 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
R P7 is optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted phosphoryl, optionally substituted acyl, or an oxygen protecting group;
R X is hydrogen or —OR Xa , wherein R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and
R Y is hydrogen or —OR Ya , wherein R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
or wherein R Xa and R Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.
585 . A method of preparing a compound of Formula (L-2-6):
or a salt thereof, comprising reacting a compound of Formula (L-5-7B):
or a salt thereof, in the presence of a thiolating agent; wherein:
R S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 1 and R 2 are independently hydrogen, halogen, or optionally substituted alkyl; each instance of R P4 and R P6 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; or wherein two R P6 are joined with the intervening atoms to form optionally substituted heterocyclyl; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.
586 . The method of claim 582 , wherein the method is a method of preparing Compound (2):
or a salt thereof, the method comprising cyclizing Compound (C):
or a salt thereof.
587 . The method of claim 583 , wherein the method comprises coupling a compound of Formula (E-L):
or a salt thereof, with a compound of Formula (E-R):
or a salt thereof, to yield a compound of Formula (E-1):
or a salt thereof, wherein:
R S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and
X 1 is halogen or a leaving group.
588 . The method of claim 587 further comprising a step of deprotecting a compound of Formula (E-1), or a salt thereof, to yield a compound of the formula:
or a salt thereof.
589 . The method of claim 584 , wherein the method is a method of preparing a compound of Formula (E-R):
or a salt thereof, the method comprising reacting a compound of Formula (E-R-1):
or a salt thereof, in the presence of a nucleophile, thereby substituting the group —OR P7 with the group —X 1 .
590 . The method of claim 585 , wherein the method is a method of preparing a compound of Formula (E-L):
or a salt thereof, the method comprising a step of reacting a compound of Formula (E-L-1):
or a salt thereof, in the presence of a thiolating agent.
591 . A compound of Formula (H3-N3):
or a salt thereof, wherein:
R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl;
each instance of R 4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 groups are taken together to form:
each instance of R 6 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 groups are taken together to form:
R P6 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
R X is hydrogen or —OR Xa , wherein R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and
R Y is hydrogen or —OR Ya , wherein R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
or wherein R Xa and R Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.
592 . The compound of claim 591 , wherein the compound is Compound (B):
or a salt thereof.
593 . A compound of Formula (H3-L):
or a salt thereof, wherein:
R L is optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted phosphoryl, or optionally substituted acyl;
R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl;
each instance of R 4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 groups are taken together to form:
each instance of R 6 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 groups are taken together to form:
R P6 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
R X is hydrogen or —OR Xa , wherein R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and
R Y is hydrogen or —OR Ya , wherein R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
or wherein R Xa and R Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.
594 . The compound of claim 593 , wherein the compound is Compound (A):
or a salt thereof.
595 . A compound of Formula (H3-2-I):
or a salt thereof, wherein:
R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl;
each instance of R 4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 groups are taken together to form:
each instance of R 6 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 groups are taken together to form:
each instance of R P6 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; or wherein two R P6 are joined with the intervening atoms to form optionally substituted heterocyclyl;
R X is hydrogen or —OR Xa , wherein R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and
R Y is hydrogen or —OR Ya , wherein R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
or wherein R Xa and R Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.
596 . The compound of claim 595 , wherein the compound is Compound (2):
or a salt thereof.
597 . A compound of Formula (H3-2-II):
or a salt thereof, wherein:
R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl;
each instance of R 4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 groups are taken together to form:
each instance of R 6 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 groups are taken together to form:
R P4 , R P5 , and R P6 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; or wherein two R P6 are joined with the intervening atoms to form optionally substituted heterocyclyl;
R X is hydrogen or —OR Xa , wherein R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and
R Y is hydrogen or —OR Ya , wherein R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
or wherein R Xa and R Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.
598 . The compound of claim 597 , wherein the compound is of Formula (E-1):
or a salt thereof, wherein:
599 . A compound of Formula (L-2-6):
or a salt thereof, wherein:
R S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;
R 1 and R 2 are independently hydrogen, halogen, or optionally substituted alkyl; and
R P4 and R P6 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; or wherein two R P6 are joined with the intervening atoms to form optionally substituted heterocyclyl.
600 . The compound of claim 599 , wherein the compound is of Formula (E-L):
or a salt thereof.
601 . A compound of Formula (R-2-I):
or a salt thereof, wherein:
X 1 is halogen or a leaving group;
R 3 and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl;
each instance of R 4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 groups are taken together to form:
each instance of R 6 is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 groups are taken together to form:
R P5 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
R X is hydrogen or —OR Xa , wherein R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and
R Y is hydrogen or —OR Ya , wherein R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group;
or wherein R Xa and R Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.
602 . The compound of claim 601 , wherein the compound is of Formula (E-R):
or a salt thereof.Join the waitlist — get patent alerts
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