IP Library › Granted Patent US 8,530,677

Granted Patent B2

US 8,530,677 · App. 12/592,280 · Granted Sep 10, 2013

Substituted 3-hydroxy-delta-lactones from epoxides

Inventors: Geoffrey W. Coates (Lansing, NY); John W. Kramer (Mt. Pleasant, MI)

Assignee: Cornell University

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Quick Facts

Patent No.: US 8,530,677
App. No.: 12/592,280
Granted: Sep 10, 2013
Kind: B2

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Abstract

Catalysts and methods for the carbonylation of epoxides to substituted 3-hydroxy-δ-lactones and β-lactones are disclosed.

Claims (162)

1. A method comprising the steps of:

reacting an epoxide of formula:

wherein:

n is an integer between 0 and 3, inclusive;

R a and R b are each independently hydrogen; halogen; C 1 to C 20 alkyl; C 2 to C 20 alkenyl; C 2 to C 20 alkynyl; up to a C 16 carbocycle; up to a C 16 heterocycle; —C(R 13 ) z H (3-z) ; or a polymer chain; or

R a and R b are taken together with intervening atoms to form one or more optionally substituted rings optionally containing one or more heteroatoms, and either of R a or R b may optionally be further substituted with one or more X groups;

R c , R d , and each R group are hydrogen;

P′ is hydrogen;

each occurrence of X is independently halogen; a phosphorus-containing moiety, —OR 10 ; —OC(O)R 13 ; —OC(O)OR 13 ; —OC(O)NR 11 R 12 ; —CN; —CNO; —C(O)R 13 ; —C(O)OR 13 ; —C(O)NR 11 R 12 ; —C(R 13 )) z H (3-z) ; —NR 11 C(O)R 10 ; —NR 11 C(O)OR 10 ; —NCO; —NR 12 SO 2 R 13 ; —S(O) x R 13 ; —S(O) 2 NR 11 R 12 ; —NO 2 ; —N 3 ; —(CH 2 ) k R 14 ; —(CH 2 ) k —Z—R 14 ; and —(CH 2 ) k —Z—(CH 2 ) m —R 14 ;

R 10 at each occurrence can be independently selected from the group consisting of: hydrogen; —C(R 13 ) z H (3-z) ; C 1 to C 12 alkyl; C 2 to C 12 alkenyl; C 2 to C 12 alkynyl; up to a C 12 carbocycle; up to a C 12 heterocycle; —S(O) 2 R 13 ; —Si(R 15 ) 3 ; and a hydroxyl protecting group;

R 11 and R 12 at each occurrence can be independently selected from the group consisting of: hydrogen; C 1 to C 12 alkyl; C 2 to C 12 alkenyl; C 2 to C 12 alkynyl; and —C(R 13 ) z H (3-z) ;

R 11 and R 12 ; when both present, can optionally be taken together with the atom to which they are attached to form an optionally substituted 3- to 10-membered ring, optionally containing one or more additional heteroatoms;

R 13 at each occurrence can be independently selected from the group consisting of: hydrogen; halogen; C 1 to C 12 alkyl; C 2 to C 12 alkenyl; C 2 to C 12 alkynyl; up to a C 12 carbocycle; or up to a C 12 heterocycle;

R 14 at each occurrence can be independently selected from the group consisting of halogen; —OR 10 ; —OC(O)R 13 ; —OC(O)OR 13 ; —OC(O)NR 11 R 12 ; —CN; —CNO; —C(R 13 ) z H (3-z) ; —C(O)R 13 ; —C(O)OR 13 ; —C(O)NR 11 R 12 ; —NR 11 C(O)R 13 ; —NR 11 C(O)OR 10 ; —NR 11 SO 2 R 13 ; —NCO; —N 3 ; —NO 2 ; —S(O) x R 13 ; —SO 2 NR 11 R 12 ; up to a C 12 heterocycle; and up to a C 12 carbocycle;

R 15 at each occurrence can be independently selected from the group consisting of: C 1 to C 6 alkyl; C 2 to C 6 alkenyl; C 2 to C 6 alkynyl; and up to C 12 substituted or unsubstituted carbocycle;

Z is a divalent linker and can be selected from the group consisting of: —(CH═CH) a —; —(CH≡CH) a —; —C(O)—; —C(═NOR 11 )—; —C(═NNR 11 R 12 )—; —O—; —N(R 11 )—; —N(C(O)R 13 )—; —S(O) x ; a polyether; and a polyamine;

a can be 1, 2, 3, or 4;

k can be an integer from 1 to 8 inclusive;

m can be an integer from 1 to 8 inclusive;

x can be 0, 1, or 2; and

z can be 1, 2, or 3;

with carbon monoxide (CO) in the presence of a catalytically effective amount of a catalyst of the formula:

[Lewis acid] u+ {[QT(CO) v ] s− } t II

wherein:

Q is any ligand or set of ligands and need not be present;

T is a metal selected from group 7, 8, or 9 of the periodic table;

s is an integer from 1 to 4 inclusive;

t is a number such that t multiplied by s equals u;

u is an integer from 1 to 6 inclusive;

v is an integer from 1 to 9 inclusive; and

the Lewis acid is H+ or is of formula [M(L) b ] c+ , wherein

M is a transition metal or group 13 or 14 metal;

L is a ligand and need not be present;

b is an integer from 1 to 6, inclusive; and

c is 1, 2, or 3;

to produce a compound of the formula:

2. The method of claim 1 , wherein the epoxide is of the formula:

wherein p is an integer between 1 and 4, inclusive.

3. The method of claim 1 , wherein the epoxide is of the formula:

wherein p is an integer between 1 and 4, inclusive.

4. The method of claim 1 , wherein the epoxide is of the formula:

5. The method of claim 1 , wherein the epoxide is of the formula:

wherein m is an integer between 0 and 10, inclusive.

6. The method of claim 1 , wherein the epoxide is of the formula:

7. The method of claim 6 , wherein X is a halogen.

8. The method of claim 6 , wherein X is chlorine.

9. The method of claim 1 , wherein the epoxide is of the formula:

10. The method of claim 1 , wherein the epoxide is of the formula:

11. The method of claim 10 , wherein R 10 is a suitable protecting group or hydrogen.

12. The method of claim 11 , wherein R 10 is a silyl protecting group.

13. The method of claim 12 , wherein R 10 is tert-butyldimethylsilyl.

14. The method of claim 1 , wherein the epoxide is of the formula:

15. The method of claim 1 , wherein the epoxide is of the formula:

16. The method of claim 1 , wherein the epoxide is of the formula:

17. The method of claim 1 , wherein the epoxide is of the formula:

18. The method of claim 1 , wherein T is cobalt.

19. The method of claim 1 , wherein Q is absent.

20. The method of claim 1 , wherein v is 4.

21. The method of claim 1 , wherein the Lewis acid is H + .

22. The method of claim 1 , wherein the carbonylation catalyst is HCo(CO) 4 .

23. The method of claim 1 , wherein the Lewis acid is of formula IIIa:

wherein:

R e at each occurrence is independently selected from the group consisting of: hydrogen; C 1 -C 12 alkyl; C 2 -C 12 alkenyl; C 2 -C 12 alkynyl; aryl; heteroaryl; halogen; —OR 10 ; —OC(O)R 13 ; —OC(O)OR 13 ; —OC(O)NR 11 R 12 ; —CN; —CNO; —C(O)R 13 ; —C(R 13 ) z H (3-z) ; —C(O)OR 13 ; —C(O)NR 11 R 12 ; —NR 11 R 12 ; —NR 11 C(O)R 10 ; —NR 11 C(O)OR 13 ; —NR 11 SO 2 R 13 ; —NCO; —N 3 ; —NO 2 ; —S(O) x R 13 ; —SO 2 NR 11 R 12 ; —C(R 13 ) z H (3-z) ; —(CH 2 ) k R 14 ; —(CH 2 ) k —Z—R 16 —; and —(CH 2 ) k —Z—(CH 2 ) m —R 14 , where two or more R e groups may optionally be taken together to form an optionally substituted ring; and

wherein M, L, R 10 , R 11 , R 12 , R 13 , R 14 , R 16 , Z, k, m, x, and z are as defined in claim 1 .

24. The method of claim 23 , wherein M is Al.

25. The method of claim 23 , wherein the Lewis acid is of formula IIIa(ii):

wherein -Ph represents an optionally substituted phenyl group and L is as defined in claim 1 .

26. The method of claim 23 , wherein the carbonylation catalyst is of formula IIa(i):

27. The method of claim 1 , wherein the Lewis acid is of formula IIIb:

wherein:

R 1 and R 1′ are independently selected from the group consisting of: hydrogen; C 1 to C 12 alkyl; C 2 to C 12 alkenyl; C 2 to C 12 alkynyl; —C(R 13 ) z H (3-z) ; —(CH 2 ) k R 14 ; and —(CH 2 ) k —Z—R 14 ;

R 2 , R 2′ , R 3 , and R 3′ are independently selected from the group consisting of: (i) C 1 -C 12 alkyl; (ii) C 2 -C 12 alkenyl; (iii) C 2 -C 12 alkynyl; (iv) up to a C 12 carbocycle; (v) up to a C 12 heterocycle; (vi) —(CH 2 ) k R 14 ; (vii) R 20 ; and (viii) —C(R 13 ) z H (3-z) ,

wherein each of (i) through (v) may optionally be further substituted with one or more R 20 groups; and where R 2 and R 3 , and R 2′ and R 3′ may optionally be taken together with the carbon atoms to which they are attached to form one or more rings which may in turn be substituted with one or more R 20 groups;

R 4 is selected from the group consisting of:

wherein X′ is a divalent linker selected from the group consisting of: —N(R 11 )—; —O—; —S(O) x —; —(CH 2 ) k —; —C(O)—; —C(═NOR 10 )—; —C(R f ) 2 —; a polyether; a C 3 to C 8 substituted or unsubstituted carbocycle; and a C 1 to C 8 substituted or unsubstituted heterocycle;

R e is as defined above;

R f at each occurrence is independently selected from the group consisting of: (a) C 1 -C 12 alkyl; (b) C 2 -C 12 alkenyl, (c) C 2 -C 12 alkynyl; (e) up to a C 12 carbocycle, (f) up to a C 12 heterocycle; (g) R 20 ; and (h) —C(R 13 ) z H (3-z) ; or wherein:

two or more R f groups may be taken together with the carbon atoms to which they are attached to form one or more rings; or

wherein when two R f groups are attached to the same carbon atom, they may be taken together to form a moiety selected from the group consisting of: a 3- to 8-membered spirocyclic ring; a carbonyl (C═O), an oxime (C═NOR 10 ); a hydrazone (C═NNR 11 R 12 ); an imine (C═NR 11 ); and an alkenyl group (C═CR 11 R 12 );

R 20 at each occurrence is independently selected from the group consisting of: hydrogen; halogen; —OR 10 ; —OC(O)R 13 ; —OC(O)OR 13 ; —OC(O)NR 11 R 12 ; —CN; —CNO; —C(O)R 13 ; —C(O)OR 13 ; —C(O)NR 11 R 12 ; —C(R 13 ) z H (3-z) ; —NR 11 R 12 ; —NR 11 C(O)R 10 ; —NR 11 C(O)OR 10 ; —NCO; —NR 12 SO 2 R 13 ; —S(O) x R 13 ; —S(O) 2 NR 11 R 12 ; —NO 2 ; —N 3 ; —(CH 2 ) k R 14 ; —(CH 2 ) k —Z—R 16 ; and —(CH 2 ) k —Z—(CH 2 ) m —R 14 ; and

L, M, R 10 , R 11 , R 12 , R 13 , R 14 , R 16 , Z, k, m, x, and z are as defined in claim 1 .

28. The method of claim 27 , wherein M is Al.

29. The method of claim 27 , wherein the Lewis acid is of formula IIIb(i):

wherein M is Al and L is as defined in claim 1 .

30. The method of claim 27 , wherein the carbonylation catalyst is of formula IIb(ii):

31. The method of claim 1 , wherein the Lewis acid is of formula IIIc:

wherein M and L are as defined in claim 1 .

32. The method of claim 31 , wherein M is Ti.

33. The method of claim 31 , wherein the carbonylation catalyst is of formula IIc(i):

34. The method of claim 1 , wherein carbonylation proceeds with retention of stereochemistry.

35. A method comprising steps of:

reacting an epoxide of formula S-Ia′:

wherein:

is a single bond;

P′ is hydrogen;

Q′ is selected from the group consisting of: hydrogen; halogen; (a) C 1 to C 20 alkyl; (b) C 2 to C 20 alkenyl; (c) C 2 to C 20 alkynyl; (d) up to a C 16 carbocycle; (e) up to a C 16 heterocycle; and (f) —C(R 13 ) z H (3-z) ; or

Q′ is a core of a statin molecule;

with carbon monoxide (CO) in the presence of a catalytically effective amount of a catalyst of the formula:

[Lewis acid] u+ {[QT(CO) v ] s− } t II

wherein:

Q is any ligand or set of ligands and need not be present;

T is a metal selected from group 7, 8, or 9 of the periodic table;

s is an integer from 1 to 4 inclusive;

t is a number such that t multiplied by s equals u;

u is an integer from 1 to 6 inclusive;

v is an integer from 1 to 9 inclusive; and

the Lewis acid is H+ or is of formula [M(L) b ] c+ , wherein

M is a transition metal or group 13 or 14 metal;

L is a ligand and need not be present;

b is an integer from 1 to 6, inclusive; and

c is 1, 2, or 3;

to produce a compound of the formula S-I′:

36. The method of claim 35 , wherein the statin molecule is selected from the group consisting of: atorvastatin, lovastatin, mevastatin, pravastatin, and simvastatin.

37. The method of claim 36 , wherein the statin molecule is atorvastatin.

38. The method of claim 35 , wherein the