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Syntheses of a variety of lamellarin compounds and analogues

Imported: 23 Feb '17 | Published: 22 Oct '02

Martin Gerhardt Banwell, Bernard Luke Flynn

USPTO - Utility Patents

Abstract

The present invention relates to methods for preparing a variety of Lamellarin compounds and analogues via a synthetic intermediate, which methods involved the step of performing an intramolecular cyclization of a compound of Formula (I) to produce compounds of Formula(II), wherein the variables are given in the specification.

Claims

1. A method for the preparation of a compound of Formula (II)

comprising the step of performing an intramolecular cyclization of a compound of Formula

wherein:

2. A method according to claim 1 wherein W and X together with the nitrogen and carbon atoms to which they are attached, form a saturated or unsaturated nitrogen containing heterocyclic group which may be optionally substituted or optionally fused to a saturated or unsaturated carbocyclic group, aryl group or heterocyclic group.

3. A method according to claim 2 wherein W and X, together with the nitrogen and carbon atoms to which they are attached, form a group selected from an optionally substituted quinolinyl group, optionally substituted isoquinolinyl group, optionally substituted dihydroquinolinyl group, optionally substituted dihydroisoquinolinyl group, optionally substituted pyridyl group or dihydro or tetrahydro congeners thereof, or optionally substituted phenanthridine.

4. A method according to claim 3 wherein W and X together with the nitrogen and carbon atoms to which they are attached, form an optionally substituted isoquinolinyl or optionally substituted dihydroisoquinolinyl group of general Formula (i):

wherein R

1-R

4 and R

14 are selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano, and represents an optional double bond.

5. A method according to claim 4 wherein R

1-R

4 are independent selected from the group consisting of hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester; optionally substituted amino; carboxamido; or sulfate; and R

14 is hydrogen or hydroxy.

6. A method for the preparation of a compound of Formula (IIa):

comprsing the step of performing two intramolecular cyclizations on a compound of Formula (Ia):

wherein:

7. A method according to claim 6 wherein m is 1 or 2, preferably 2.

8. A method according to claim 1 wherein R

A1R

A2C—CR

A3R

A4 forms an aryl group or an aromatic heterocyclic group, said group selected from: an optionally substituted benzene or naphthalene ring or an optionally substituted pyridine, optionally substituted furan, optionally substituted pyrrole or optionally substituted thiophene and benzene-fused analogues thereof.

9. A method according to claim 8 wherein R

A1R

A2C—CR

A3R

A4 forms an optionally substituted benzene group.

10. A method according to claim 9 wherein the substituents are selected from: hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester; optionally substituted amino; carboxamido; or sulfate.

11. A method according to claim 1 wherein Y is an optionally substituted phenyl group of Formula (ii):

wherein R

9-R

13 are selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano.

12. A method according to claim 11 wherein R

9-R

13 are independently selected from hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester; optionally substituted amino; carboxamido; or sulfate.

13. A method according to claim 10 wherein R

9-R

13 are independently selected from hydrogen, hydroxy, methoxy, ethoxy, iso-propoxy, methyl, ethyl, n-propyl, isopropyl, acetoxy or sulphate.

14. A method of preparing a fused polycyclic pyrrole-containing compound of Formula (IIb):

comprising the step of performing two intramolecular cyclizations on a compound of Formula (Ib):

wherein V is halogen or hydrogen and R

1-R

14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano; and optionally dehydrogenating the cyclized product to form a compound of Formula (Ib) wherein the optional double bond is present.

15. A method according to claim 14 wherein R

1-R

14 are independently selected from: hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester; optionally substituted amino; carboxamido; or sulfate, preferably R

1-R

13 are independently selected from hydrogen; hydroxy; optionally substituted alkyl, such as methyl, ethyl or propyl; optionally substituted alkyloxy such as methoxy, ethoxy, n-propoxy, iso-propoxy; acyloxy such as acetoxy; or sulfate and R

14 is preferably hydrogen or hydroxy and V is bromine, iodine or hydrogen.

16. A method according to claim 1 wherein U, as defined in Z, is selected from one of CH

2, NH or oxygen, preferably oxygen, and n+o=0, 1, 2, 3 or 4, preferably 0.

17. A method according to claim 1 wherein each V is independently hydrogen, bromine or iodine.

18. A method according to claim 1 wherein V is hydrogen, and the cyclization occurs under oxidative conditions.

19. A method according to claim 1 wherein V is a halogen atom, preferably bromine or iodine, and the cyclization occurs via the the generation of a radical of Formula (I).

20. A method according to claim 1 wherein V is a halogen atom, preferably bromine or iodine, and the cyclization occurs via a Pd[0]-catalyzed process.

21. A method according to claim 6 wherein both V are halogen, preferably bromine or iodine, and the two cyclizations are performed in one pot.

22. A method according to claim 21 wherein the one pot double cyclization is Pd[0]-catalyzed.

23. A compound of Formula (I)

wherein:

24. A compound of Formula (Ia):

wherein:

25. A compound according to claim 23 or 24 wherein R

A1R

A2C—CR

A3R

A4 forms an optionally substituted benzene group.

26. A compound of Formula (Ib):

wherein

27. A compound according to claim 26 wherein R

1-R

14 are independently selected from: hydrogen; hydroxy; optionally substituted alkyl; optionally substituted alkyloxy; acyloxy; carboxy; carboxy ester; optionally substituted amino; carboxamido; or sulfate, preferably R

1-R

13 are independently selected from hydrogen; hydroxy; optionally substituted alkyl, such as methyl, ethyl or propyl; optionally substituted alkyloxy such as methoxy, ethoxy, n-propoxy, iso-propoxy; acyloxy such as acetoxy; or sulfate and R

14 is preferably hydrogen or hydroxy; and V is bromine, iodine or hydrogen.

28. A method of preparing fused polycyclic pyrrole-containing compounds comprising the step of performing two intramolecular cyclizations on a compound of Formula (Ib):

wherein V is halogen or hydrogen and R

1-R

14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally protected hydroxy, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryl, optionally substituted heterocyclyl, carboxy, carboxy ester, carboxamido, acyl, acyloxy, mercapto, optionally substituted alkylthio, halogen, nitro, sulfate, phosphate and cyano.