Methods of synthesis of ingenol and intermediates thereof
AssigneeLeo Laboratories Limited
InventorsPhillipe S. BARAN, Lars JØRGENSEN, Christian A. KUTTRUFF, Steven J. MCKERRALL, Chien-Hung YEH
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Abstract
The present invention relates generally to methods of synthesis of diterpene heterocylic compounds. More particularly, the present invention relates to efficient methods of synthesis of ingenol (Formula (21), CAS 30220-46-3), from a compound of formula (1). The present invention also provides for various advantageous intermediates along the synthetic route of ingenol. Efficient synthesis of ingenol is important in the design and synthesis of related analogues, such as ingenol-3-angelate.
Claims27
A method of synthesizing ingenol (21) from a compound of formula 5, which comprises:
- contacting the compound of formula 5 with an alkynylating reagent to form a compound of formula 31
- wherein Q is an alkyne protecting group or hydrogen, and
- converting compound 31 to ingenol in one or more steps.
A method of synthesizing ingenol (21), which comprises:
- (a) chlorinating the compound of formula 1 to form a compound of formula 2:
- (b) ozonolysing the compound of formula 2 to form a compound of formula 3:
- (c) reductively alkylating 3 to form a compound of formula 4:
- (d) forming an alcohol of formula 5 from the compound of formula 4:
- (e) forming a compound of formula 31 by acetylide addition to the compound of formula 5:
- (f) deprotecting the compound of formula 31 when Q is not hydrogen, to form a compound of formula 7:
- (g) protecting the compound of formula 7 to form a compound of formula 32:
- (h) protecting the compound of formula 32 to form a compound of formula 33:
- (i) cyclizing the compound of formula 33 to form a compound of formula 34:
- (j) methylating the compound of formula 34 to form a compound of formula 35:
- (k) dihydroxylating the compound of formula 35 to form a compound of formula 36:
- (l) protecting the compound of formula 36 to form a compound of formula 37:
- (m) performing a pinacol rearrangement of the compound of formula 37 to form a compound of formula 38:
- (n) oxidizing the compound of formula 38 to form a compound of formula 39:
- (o) protecting the compound of formula 39 to form a compound of formula 40:
- (p) deprotecting the compound of formula 40 to form a compound of formula 41:
- (q) activating the compound of formula 41 with an hydroxyl activating group to form a compound of formula 42:
- (r) eliminating the activated hydroxyl group of the compound of formula 42 to form a compound of formula 43:
- (s) deprotecting the compound of formula 43 to form a compound of formula 20:
- and
- (t) oxidizing the compound of formula 20 to form the compound of formula 21,
- wherein step (d) comprises incubating a reagent of formula 23 with the compound of formula 4:
- wherein
- P1, P2, and P3 are each individually a hydroxyl protecting group,
- Q is an alkyne protecting group or hydrogen,
- L is an hydroxyl activating group derivative, and
- R is a diol protecting group.
A method of synthesizing compound 34 from compound 7, which comprises:
- protecting compound 7 hydroxyl moieties to yield compound 33
- and cyclizing compound 33 by incubation of compound 33 with a chlorodicarbonylrhodium(I) dimer selected from the group consisting of:
- ([RhCl(CO)2]2), [RhCl(COD)]2, [RhCl(CO)(dppp)]2, and [Rh(dppp)2]Cl, to yield compound 34:
- wherein P1 and P2 are each individually a hydroxyl protecting group.
A method of synthesizing compound 44 from compound 34, which comprises:
- incubating compound 34 with Grignard reagent XMgBr to produce compound 44
- wherein P1 and P2 are each individually a hydroxyl protecting group and X is an alkyl group.
A method of synthesizing compound 36 from compound 35, which comprises:
- incubating compound 35 with catalytic amounts of OsO4 to produce compound 36.
- wherein P1 and P2 are each individually a hydroxyl protecting group.
A method of synthesizing compound 38 from compound 37, which comprises:
- incubating compound 37 with a Lewis acid under reducing conditions, to yield compound 38
- wherein P1 and P2 are each individually a hydroxyl protecting group and R is a diol protecting group.
A compound selected from the group consisting of:
- wherein P1, P2, and P3 are each individually a hydroxyl protecting group,
- Q is an alkyne protecting group,
- L is an hydroxyl activating group, and
- R is a diol protecting group.
A compound selected from the group consisting of:
Dependencies are inferred from the claim text.