Analogues and derivatives of cephalotaxine and methods for making and using the compounds

1. A compound having a formula

or a salt, solvate, N-oxide, diastereomer or enantiomer thereof, wherein:

x is from 0 to 4;

each R 1 independently is hydroxyl, halogen, aliphatic, alkoxy, haloalkyl, amino, protected amino, carboxylic ester, or two R 1 s, together with the atoms to which they are attached, form an aryl or heterocyclyl;

each of R 2 , R 3 , R 4 and R 5 independently is H, halogen, aliphatic, hydroxyalkyl, protected hydroxyalkyl, aryl, heteroaryl, hydroxyl, protected hydroxyl, haloalkyl, amino, protected amino, carboxylic ester, or two of R 2 , R 3 , R 4 and R 5 that are attached to the same carbon together form ═O or ═S; and

each of Q 1 and Q 2 independently is aliphatic.

2. The compound of claim 1 , wherein x is 2, 3, or 4.

3. The compound of claim 1 , wherein two R 1 s together with the atoms to which they are attached, form an aryl or 5- or 6-membered heterocyclyl ring.

4. The compound of claim 3 , wherein the 5- or 6-membered heterocyclyl is a pyridinyl, imidazolyl, pyrazolyl, pyrrolyl, oxazolyl, thiazolyl, furanyl, thiophenyl, 1,3-dioxole, 1,4-dioxine, 2,3-dihydro-1,4-dioxine, 1,4-oxazine, or 3,4-dihydro-1,4-oxazine.

5. The compound of claim 1 , wherein the

moiety is

6. The compound of claim 1 , wherein the

moiety is

7. The compound of claim 1 , wherein each of Q 1 and Q 2 independently is alkyl optionally substituted with 1, 2, 3, or 4 substituents from halogen, alkyl, hydroxyalkyl, protected hydroxyalkyl, ═O, ═S, aryl, hydroxyl, protected hydroxyl, haloalkyl, amino, protected amino, or carboxylic ester.

8. The compound of claim 7 , wherein each of Q 1 and Q 2 independently is C 1-2 alkyl optionally substituted with 1, 2, 3, or 4 substituents from halogen, alkyl, hydroxyalkyl, protected hydroxyalkyl, ═O, ═S, aryl, hydroxyl, protected hydroxyl, haloalkyl, amino, protected amino, or carboxylic ester.

9. The compound of claim 8 ,

wherein one or more of the following applies:

i) Q 1 is —CH 2 — or —CH 2 CH 2 —;

ii) Q 2 is —CH 2 — or —CH 2 CH 2 ; or

iii) Q 1 is —CH 2 — or —CH 2 CH 2 — and Q 2 is —CH 2 — or —CH 2 CH 2 .

10. The compound of claim 8 , wherein one or both of the following applies:

Q 1 is substituted with 1, 2, 3, or 4 substituents from methyl, ethyl, ═O, ═S, hydroxyl, phenyl, hydroxyethyl, hydroxypropyl, protected hydroxyalkyl, protected hydroxyl, or protected amino;

Q 2 is substituted with 1, 2, 3, or 4 substituents from Cl, methyl, ethyl, ═O, ═S, hydroxyl, protected hydroxyl, hydroxyethyl, hydroxypropyl, protected hydroxyalkyl, protected hydroxyl, or protected amino.

11. The compound of claim 1 , wherein each of R 2 , R 3 , R 4 and R 5 independently is H, halogen, aliphatic, hydroxyalkyl, protected hydroxyalkyl, aryl, heteroaryl, hydroxyl, protected hydroxyl, or two of R 2 , R 3 , R 4 and R 5 that are attached to the same carbon together form ═O or ═S.

12. The compound of claim 1 , wherein each of R 2 , R 3 , R 4 and R 5 is H.

13. The compound of claim 1 , wherein the

moiety is

wherein PG is a hydroxyl protecting group.

14. The compound of claim 13 , wherein PG is methoxymethyl (MOM), tert-butyl, iso-propyl, tert-butyldimethylsilyl (TBS or TBDMS), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), or triisopropylsilyl (TIPS).

15. The compound of claim 1 , wherein the

moiety is

wherein PG is a hydroxyl protecting group.

16. The compound of claim 15 , wherein PG is methoxymethyl (MOM), tert-butyl, iso-propyl, tert-butyldimethylsilyl (TBS or TBDMS), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), or triisopropylsilyl (TIPS).

17. The compound of claim 1 , wherein the compound is

18. A method for making a compound of Formula I, comprising:

i) treating a protected hydroxyl ketone of formula A-1 with a haloacetate ester of formula A-2 to form a compound of formula A-3

ii) treating the compound of formula A-3 with a protected amino compound of formula A-4 to form a compound of formula A-5

iii) converting the OPG moiety of A-5 to a leaving group in a compound of formula A-6

and

iv) cyclizing A-6 to form the compound of Formula I,

or a salt, solvate, N-oxide, diastereomer or enantiomer thereof, wherein:

each PG independently is a protecting group;

LG is a leaving group;

each X 1 independently is a halogen;

x is from 0 to 4;

R A is alkyl;

if present, each R 1 independently is hydroxyl, halogen, aliphatic, alkoxy, haloalkyl, amino, protected amino, carboxylic ester, or two R 1 s, together with the atoms to which they are attached, form an aryl or heterocyclyl;

each of R 2 , R 3 , R 4 and R 5 independently is H, halogen, aliphatic, hydroxyalkyl, protected hydroxyalkyl, aryl, heteroaryl, hydroxyl, protected hydroxyl, haloalkyl, amino, protected amino, carboxylic ester, or two of R 2 , R 3 , R 4 and R 5 that are attached to the same carbon together form ═O or =S; and

each of Q 1 and Q 2 independently is aliphatic.

19. The method of claim 18 , wherein one or more of the following applies:

i) each PG independently is trifluoroacetate or a silyl protecting group;

ii) LG is mesylate;

iii) X 1 is Cl;

iv) R A is C 1-2 alkyl.

20. A method for making a compound of Formula (II), comprising:

treating a compound of Formula I

or a salt, solvate, N-oxide, diastereomer or enantiomer thereof, with an oxidizing agent to form a racemic compound of Formula II

or a salt, solvate, or N-oxide thereof, wherein:

x is from 0 to 4;

if present, each R 1 independently is hydroxyl, halogen, aliphatic, alkoxy, haloalkyl, amino, protected amino, carboxylic ester, or two R 1 s, together with the atoms to which they are attached, form an aryl or heterocyclyl;

each of R 2 , R 3 , R 4 and R 5 independently is H, halogen, aliphatic, hydroxyalkyl, protected hydroxyalkyl, aryl, heteroaryl, hydroxyl, protected hydroxyl, haloalkyl, amino, protected amino, carboxylic ester, or two of R 2 , R 3 , R 4 and R 5 that are attached to the same carbon together form ═O or =S; and

each of Q 1 and Q 2 independently is aliphatic.

21. The method of claim 20 , wherein the oxidizing agent is DDQ.

22. The method of claim 20 , further comprising:

treating the racemic compound of Formula II with Ru(p-cymene)-(S,S)-TsDPEN, trimethylamine, and formic acid to form a compound of Formula A-7 and a (+)-compound of Formula II

23. The method of claim 22 , further comprising treating the (+)-compound of Formula II with 2,2-dimethoxypropane and p-toluene sulfonic acid to form a second portion of racemic compound according to Formula II

24. The method of claim 22 , wherein the compound of formula I is

and the compound of formula A-7 is

25. The method of claim 18 , wherein R 2 , R 3 , R 4 , and R 5 are all H.

26. The method of claim 18 , wherein:

R 2 , R 3 , R 4 , and R 5 are all H;

Q 1 is —CH 2 CH 2 —;

Q 2 is —CH—;

the

moiety is

and

the compound of Formula I is