Synthetic Route To Anhydroryanodol, Ryanodol And Structural Analogues

Patent metadata

Field	Value
Publication number	US-2017174648-A1
Application number	US-201615381595-A
Country	US
Kind code	A1
Filing date	Dec 16, 2016
Priority date	Dec 18, 2015
Publication date	Jun 22, 2017
Grant date	—

Abstract

This disclosure is related to methods for producing anhydroryanodol, ryanodol, or analogues thereof and novel compounds prepared thereby.

First claim

What is claimed:

1 . A method for preparing a compound of Formula (I):

comprising subjecting a compound of Formula (II):

to a source of carbon monoxide in the presence of a catalyst, for a time and at a temperature sufficient to produce the compound of Formula (I);
wherein:
each R 1 is a reductively labile oxygen protecting group or an acid labile oxygen protecting group; and
R 2 is C 1-6 alkyl;
R 3 is C 1-6 alkyl; and
R 4 is C 1-6 alkyl.

2 . The method of claim 1 , wherein each R 1 is —CH 2 —O-benzyl.

3 . The method of claim 1 , wherein R 2 is CH 3 .

4 . The method of claim 1 , wherein R 3 and R 4 are CH 3 .

5 . The method of claim 1 , wherein the source of carbon monoxide is gaseous CO, Co 2 (CO) 8 , or Mo(CO) 3 (DMF) 3 .

6 . The method of claim 1 , wherein the catalyst is a rhodium catalyst, preferably [RhCl(CO) 2 ] 2 .

7 . The method of claim 1 , wherein the compound of formula (I) is produced in a diastereomeric ratio of at least about 3:1.

8 . The method of claim 1 , wherein the compound of formula (I) is compound 17:

9 . The method of claim 1 , wherein the compound of formula (II) is compound 16:

10 . The method of claim 1 , further comprising subjecting the compound of formula (I) to an oxidant, in an organic solvent, for a time and at a temperature sufficient to form a compound of formula (III):

11 . The method of claim 10 , wherein the oxidant is selenium dioxide or molecular oxygen.

12 . The method of claim 10 , wherein the organic solvent is anhydrous.

13 . The method of claim 10 , wherein the compound of formula (III) is compound 18:

14 . The method of claim 10 , further comprising treating the compound of formula (III) with a triflating agent to form a compound of formula (IV):

wherein R 5 is Tf (—SO 2 CF 3 ).

15 . The method of claim 14 , wherein the triflating agent is N-(5-chloro-2-pyridyl) bis(trifluoromethanesulfonimide).

16 . The method of claim 14 , wherein the compound of formula (IV) is compound 19:

17 . The method of claim 14 , further comprising treating the compound of formula (IV) with R 6 C(═CH 2 )Sn(C 1-6 alkyl) 3 in the presence of a catalyst to provide a compound of formula (V):

wherein R 6 is C 1-6 alkyl.

18 . The method of claim 17 , wherein R 6 C(═CH 2 )Sn(C 1-6 alkyl) 3 is CH 3 C(═CH 2 )SnBu 3 .

19 . The method of claim 17 , wherein the catalyst is a palladium catalyst.

20 . The method of claim 17 , wherein the catalyst is PdCl 2 (PPh 3 ) 2 .

21 . The method of claim 17 , wherein the compound of formula (V) is compound 20:

22 . The method of claim 17 , further comprising treating the compound of formula (V) with one or more reducing agents, and optionally a catalyst, for a time and at a temperature sufficient to provide a compound of formula (VI):

23 . The method of claim 22 , wherein the reducing agent is a hydride, hydrogen, or a mixture thereof.

24 . The method of claim 22 , wherein the reducing agent is lithium borohydride.

25 . The method of claim 22 , wherein the reducing agent is hydrogen.

26 . The method of claim 22 , wherein the catalyst is a palladium catalyst.

27 . The method of claim 26 , wherein the catalyst is Pd(OH) 2 /C.

28 . The method of claim 22 , wherein the compound of formula (VI) is compound 3:

29 . The method of claim 22 , further comprising:
(i) reacting the compound of formula (VI) with trifluoroperacetic acid; and (ii) reacting the compound of step (i) with lithium metal in liquid ammonia to provide a compound of formula (VII):

30 . The method of claim 29 , wherein the compound of formula (VII) is compound 2:

31 . The method of claim 29 , wherein the compound of formula (VII) is (+)-ryanodol.

32 . A compound which is:

Assignees

• California Inst Of Techn

Inventors

• Reisman Sarah
• Chuang Kangway V
• Xu Chen

Classifications

• C07C49/577

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07C49/753

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07D309/30 Primary

  Oxygen atoms, e.g. delta-lactones · CPC title

• C07C43/23

  containing hydroxy or O-metal groups · CPC title

• C07D309/32

  having two double bonds between ring members or between ring members and non-ring members · CPC title