Synthesis of macrocyclic cancer chemotherapy agents and methods of use
Herein are described a process for forming a quaternary carbon useful in the preparation of macrolactones, an enantioselective synthesis of (+)-peloruside A, and methods for treating a patient in need of relief from cancer or a cancer-related disease. The described processes are useful for preparing compounds containing quaternary carbons, including structural analogs and derivatives of peloruside A.
1. A process for forming a quaternary carbon between a hydroxymethylene or alkoxymethylene carbon and a ketone (or hemiketal or ketal thereof) carbon or a hydroxymethylene reduction product of said ketone, the process comprising the steps of
reacting a first compound containing an α-alkyl-α,β-unsaturated ketone moiety with a source of nucleophilic hydride, wherein the source of nucleophilic hydride is lithium (sec-butyl) 3 borohydride; and adding a second compound containing an aldehyde to form the quaternary carbon.
2. A process of forming a compound wherein the compound contains a quaternary carbon between a hydroxymethylene or alkoxymethylene carbon and a ketone (or hemiketal or ketal thereof) carbon or a hydroxymethylene reduction product of said ketone comprising the steps of
reacting a first compound containing an α-alkyl-α,β-unsaturated ketone moiety with a source of nucleophilic hydride, wherein the source of nucleophilic hydride is lithium (sec-butyl) 3 borohydride; and adding a second compound containing an aldehyde to form the quaternary carbon.
3. The process of claim 2 wherein the compound containing a quaternary carbon is a bryostatin, a peloruside, a mycalamide or an epothilone.
4. The process of claim 2 wherein the compound containing a quaternary is a macrolactone which has the formula
wherein:
R 1 is
where * shows the point of attachment and R 8 and R 12 are independently hydrogen, alkyl, heteroalkyl, arylalkyl, heteroarylalkyl, or an oxygen protecting group;
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, alkyl, hydroxy, and alkoxy; and X 1 is hydrogen, hydroxy, alkoxy or together with the carbon to which it is attached forms a carbonyl or an oxime.
5. The process of claim 4 wherein the macrolactone has the formula
wherein:
R 1 is
where * shows the point of attachment;
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, alkyl, hydroxy, and alkoxy; X 1 is hydrogen, hydroxy, alkyl, alkoxy or together with the carbon to which it is attached forms a carbonyl or an oxime; and
R 8 and R 12 are independently hydrogen, alkyl, heteroalkyl, arylalkyl, heteroarylalkyl, or an oxygen protecting group.
6. The process of claim 5 wherein the macrolactone has the formula
wherein
R 1 is
where * shows the point of attachment;
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, alkyl, hydroxy, and alkoxy; X 1 is hydrogen, hydroxy, alkyl, alkoxy or together with the carbon to which it is attached forms a carbonyl or an oxime; and
R 8 and R 12 are independently hydrogen, alkyl, heteroalkyl, arylalkyl, heteroarylalkyl, or an oxygen protecting group.
7. The process of claim 6 wherein R 3 is methoxy and R 7 is methoxy.
8. The process of claim 6 wherein R 6 is hydrogen.
9. The process of claim 6 wherein R 2 is hydrogen.
10. The process of claim 6 wherein R 2 is hydroxy; R 4 is methoxy; R 5 is hydroxy; R 6 is hydroxy; X 1 is hydroxy; and
R 1 is
where * shows the point of attachment and R 8 and R 12 are independently hydrogen, alkyl, heteroalkyl, arylalkyl, heteroarylalkyl, or an oxygen protecting group.
11. The process of claim 6 wherein R 2 is hydroxy; R 4 is methoxy; R 5 is hydroxy; R 6 is hydrogen, hydroxy, alkyl, or alkoxy; X 1 is hydroxy; and R 1 is 4-(R)-hydroxymethyl-hex-2-(Z)-ene-2-yl.
12. The process of claim 6 wherein R 2 is hydroxy; R 4 is methoxy; R 5 is hydroxy; R 6 is hydroxy; X 1 is hydrogen, or epi-hydroxy, alkoxy, or alkyl, or X 1 and the attached carbon form a carbonyl; and R 1 is 4-(R)-hydroxymethyl-hex-2-(Z)-ene-2-yl.
13. The process of claim 6 wherein R 2 is hydrogen, hydroxy, or alkyl; R 4 is methoxy; R 5 is hydroxy; R 6 is hydroxy; X 1 is hydroxy; and R 1 is 4-(R)-hydroxymethyl-hex-2-(Z)-ene-2-yl.
14. The process of claim 6 wherein R 2 is hydroxy; R 4 is hydrogen, hydroxy, alkoxy, or alkyl; R 5 is hydroxy; R 6 is hydroxy; X′ is hydroxy; and R 1 is 4-(R)-hydroxymethyl-hex-2-(Z)-ene-2-yl.
15. The process of claim 6 wherein R 2 is hydroxy; R 4 is methoxy; R 5 is hydrogen, hydroxy, alkoxy, or alkyl; R 6 is hydroxy; X 1 is hydroxy; and R 1 is 4-(R)-hydroxymethyl-hex-2-(Z)-ene-2-yl.
16. The process of claim 1 wherein alkyl is C 1 -C 4 alkyl.
17. The process of claim 16 wherein alkyl is methyl.
18. The process of claim 1 wherein a moiety of the following formula
comprises the quaternary carbon formed.
19. The process of claim 1 wherein a moiety of the following formula
comprises the quaternary carbon formed.
20. The process of claim 2 wherein alkyl is C 1 -C 4 alkyl.
21. The process of claim 20 wherein alkyl is methyl.
22. The process of claim 2 wherein a moiety of the following formula
comprises the quaternary carbon formed.
23. The process of claim 2 wherein a moiety of the following formula
comprises the quaternary carbon formed.