Asymmetric 1,4-reductions of and 1,4-additions to enoates and related systems
One aspect of the present invention relates to methods for the transition-metal-catalyzed asymmetric 1,4-addition of a nucleophile, e.g., hydride, to cyclic and acyclic enoates and enones. In certain embodiments of the methods of the present invention, the transition metal catalyst consists essentially of copper and an asymmetric bidentate bisphosphine ligand.
1 . The method represented by the generalized reaction depicted in Scheme 1:
wherein
Z represents an electron withdrawing group selected from the group consisting of formyl, acyl, —CN, —C(O)OR, —C(O)N(R) 2 , nitro, nitroso, —S(O) 2 R, —S(O) 2 N(R) 2 , —C(NR)—R, —C(NOR)—R, and —C(NN(R) 2 )—R;
R represents independently for each occurrence hydrogen, alkyl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or —(CH2) m —R 80 ;
R 1 , R 2 , and R 3 are independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —Si(R) 3 , and —(CH 2 ) m —R 80 ;
the transition metal catalyst consists essentially of a transition metal atom and an asymmetric ligand;
Nu represents hydrogen, alky, heteroalkyl, aryl, heteroaryl, —(CH 2 ) m —R 80 , —Si(R) 3 , —Sn(R) 3 , —CN, or —N(R) 2 ;
W represents a Group 1 cation, Group 2 cation, transition metal cation, silyl, or stannyl;
the base is selected from the set consisting of hydrides, carbonates, fluorides, phosphates, alkoxides, phenoxides, amides, carbanions, and silyl anions;
taken together, any two groups selected from Z, R 1 , R 2 , and R 3 may form a ring comprising a total of 5-7 atoms in the backbone of said ring; said ring may comprise one or two heteroatoms in its backbone; and said ring may bear instances of R;
R 80 represents independently for each occurrence aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl;
m is an integer in the range 0 to 8 inclusive; and
the carbon marked with an asterisk in compound 2 is asymmetric.
2 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a transition metal atom and an asymmetric bidentate ligand.
3 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a transition metal atom and an asymmetric bidentate bisphosphine ligand.
4 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric ligand.
5 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate ligand.
6 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand.
7 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and p-tol-BINAP.
8 . The method of claim 1 , wherein the base is selected from the set consisting of alkoxides, phenoxides, and amides.
9 . The method of claim 1 , wherein the base is an alkoxide.
10 . The method of claim 1 , wherein the base is sodium tert-butoxide.
11 . The method of claim 1 , wherein NuW is a silane; and Nu is hydrogen.
12 . The method of claim 1 , wherein NuW is polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, or dimethylphenylsilane; and Nu is hydrogen.
13 . The method of claim 1 , wherein Nu is alkyl aryl, —CN, —Si(R) 3 , or —Sn(R) 3 .
14 . The method of claim 1 , wherein Nu is alkyl, aryl, or —CN.
15 . The method of claim 1 , wherein Z is selected from the group consisting of formyl, acyl, —CN, —C(O)OR, —C(O)N(R) 2 , nitro, nitroso, —S(O) 2 R, and —S(O) 2 N(R) 2 .
16 . The method of claim 1 , wherein Z is selected from the group consisting of formyl, acyl, —CN, —C(O)OR, and —C(O)N(R) 2 .
17 . The method of claim 1 , wherein Z is selected from the group consisting of acyl, —C(O)OR, and —C(O)N(R) 2 .
18 . The method of claim 1 , wherein Z is selected from the group consisting of acyl and —C(O)OR.
19 . The method of claim 1 , wherein Z is —C(O)OR.
20 . The method of claim 1 , wherein Z is acyl.
21 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is a silane; and Nu is hydrogen.
22 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, or dimethylphenylsilane; and Nu is hydrogen.
23 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is a silane; Nu is hydrogen; and Z is selected from the group consisting of formyl, acyl, —CN, —C(O)OR, and —C(O)N(R) 2 .
24 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is a silane; Nu is hydrogen; and Z is selected from the group consisting of acyl, —C(O)OR, and —C(O)N(R) 2 .
25 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is a silane; Nu is hydrogen; and Z is selected from the group consisting of acyl and —C(O)OR.
26 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is a silane; Nu is hydrogen; and Z is —C(O)OR.
27 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is a silane; Nu is hydrogen; and Z is acyl.
28 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, or dimethylphenylsilane; Nu is hydrogen; and Z is selected from the group consisting of formyl, acyl, —CN, —C(O)OR, and —C(O)N(R) 2 .
29 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, or dimethylphenylsilane; Nu is hydrogen; and Z is selected from the group consisting of acyl, —C(O)OR, and —C(O)N(R) 2 .
30 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, or dimethylphenylsilane; Nu is hydrogen; and Z is selected from the group consisting of acyl and —C(O)OR.
31 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, or dimethylphenylsilane; Nu is hydrogen; and Z is —C(O)OR.
32 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, or dimethylphenylsilane; Nu is hydrogen; and Z is acyl.
33 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is a silane; Nu is hydrogen; and the base is selected from the set consisting of alkoxides, phenoxides, and amides.
34 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is a silane; Nu is hydrogen; and the base is an alkoxide.
35 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is a silane; Nu is hydrogen; and the base is sodium tert-butoxide.
36 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, or dimethylphenylsilane; Nu is hydrogen; and the base is selected from the set consisting of alkoxides, phenoxides, and amides.
37 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, or dimethylphenylsilane; Nu is hydrogen; and the base is an alkoxide.
38 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, or dimethylphenylsilane; Nu is hydrogen; and the base is sodium tert-butoxide.
39 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is a silane; Nu is hydrogen; the base is selected from the set consisting of alkoxides, phenoxides, and amides; and Z is selected from the group consisting of formyl, acyl, —CN, —C(O)OR, and —C(O)N(R) 2 .
40 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is a silane; Nu is hydrogen; the base is an alkoxide; and Z is selected from the group consisting of formyl, acyl, —CN, —C(O)OR, and —C(O)N(R) 2 .
41 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is a silane; Nu is hydrogen; the base is sodium tert-butoxide; and Z is selected from the group consisting of formyl, acyl, —CN, —C(O)OR, and —C(O)N(R) 2 .
42 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, or dimethylphenylsilane; Nu is hydrogen; the base is selected from the set consisting of alkoxides, phenoxides, and amides; and Z is selected from the group consisting of formyl, acyl, —CN, —C(O)OR, and —C(O)N(R) 2 .
43 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand; NuW is polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, or dimethylphenylsilane; Nu is hydrogen; the base is an alkoxide; and Z is selected from the group consisting of formyl, acyl, —CN, —C(O)OR, and —C(O)N(R) 2 .
44 . The method of claim 1 , wherein the transition metal catalyst consists essentially of a copper atom and an asymmetric bidentate bisphosphine ligand;. NuW is polymethylhydrosiloxane (PMHS), phenylsilane, diphenylsilane, or dimethylphenylsilane; Nu is hydrogen; the base is sodium tert-butoxide; and Z is selected from the group consisting of formyl, acyl, —CN, —C(O)OR, and —C(O)N(R) 2 .
45 . The method of claim 1 , wherein the solvent is a hydrocarbon.
46 . The method of claim 1 , wherein the solvent is an aromatic hydrocarbon.
47 . The method of claim 1 , wherein the solvent is toluene.
48 . The method of claim 1 , wherein the method is conducted at or below about 50 C.
49 . The method of claim 1 , wherein the method is conducted at or below ambient temperature.
50 . The method of claim 1 , wherein the method is conducted at or below about 0 C.
51 . The method of claim 1 , wherein the method is conducted at or below about −70 C.
52 . The method of any of claim 1 , wherein the product has an enantiomeric excess greater than about 50%.
53 . The method of claim 1 , wherein the product has an enantiomeric excess greater than about 70%.
54 . The method of claim 1 , wherein the product has an enantiomeric excess greater than about 90%.
55 . The method of claim 1 , wherein the product has an enantiomeric excess greater than about 95%.