Lewis acid-catalyzed claisen rearrangement in the preparation of chiral products

{
  "publication_number": "US6359174B1",
  "country": "US",
  "kind": "B1",
  "title": "Lewis acid-catalyzed claisen rearrangement in the preparation of chiral products",
  "abstract": "A novel Claisen rearrangement reaction is provided. An allylic reactant such as an allylic amine, an allylic ether or an allylic thioether is reacted with an acid chloride in the presence of a Lewis acid catalyst composition composed of a Lewis acid and a base selected from the group consisting of tertiary amines and non-nitrogenous bases. The stereochemistry of the reaction product is readily controlled by the positioning and size of substituents on the allylic reactant. The reaction may be carried out on a solid support, i.e., on the surface of a substrate suitable for conducting solid phase chemical reactions.",
  "claims": [
    "1. A method for conducting a Claisen rearrangement reaction, comprising reacting an allylic reactant with an acid chloride in the presence of a Lewis acid catalyst composition comprising a first catalyst component composed of a Lewis acid, and a second catalyst component selected from the group consisting of tertiary amines and non-nitrogenous bases.",
    "2. The method of claim 1, wherein the allylic reactant is selected from the group consisting of allylic amines, allylic ethers and allylic thioethers.",
    "3. The method of claim 2, wherein the allylic reactant is an allylic amine.",
    "4. The method of claim 3, wherein the allylic reactant is an allylic tertiary amine.",
    "5. The method of claim 1, wherein the acid chloride is a 2-substituted acetyl chloride.",
    "6. The method of claim 1, wherein the molar ratio of the allylic reactant to the acid chloride is in the range of approximately 2:1 to 1:2.",
    "7. The method of claim 1, wherein the molar ratio of the allylic reactant to the acid chloride is approximately 1:1.",
    "8. The method of claim 1, wherein the reaction is carried out under inert, nonaqueous conditions.",
    "9. The method of claim 1, wherein the reaction is carried out at a temperature in the range of approximately −110° C. to 200° C.",
    "10. The method of claim 9, wherein the reaction is carried out at a temperature in the range of approximately −78° C. to 100° C.",
    "11. The method of claim 1, wherein one of the allylic reactant, the acid chloride and the catalyst composition is covalently linked, either directly or indirectly, to the surface of a solid support.",
    "12. The method of claim 1, wherein the size and/or positioning of substituents on the allylic reactant results in an enantioselective reaction.",
    "13. The method of claim 1, wherein the second catalyst component is a tertiary amine.",
    "14. The method of claim 1, wherein the second catalyst component is a non-nitrogenous base.",
    "15. The method of claim 14, wherein the non-nitrogenous base is selected from the group consisting of inorganic hydroxides, inorganic oxides, and metal carbonates.",
    "16. A method for synthesizing a compound having the structural formula (III) wherein R 1, R 2, R 3, R 4, R 5 and R 6 are independently selected from the group consisting of hydrido, halo, hydroxyl, sulfhydryl, amino, substituted amino, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, Z is N, O or S, n is zero or 1, with the proviso that when Z is N, n is 1, and when Z is O or S, n is zero, and Q 1 and Q 2 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, or, when Z is N and n is 1, Q 1 and Q 2 are joined together in a ring structure or together with Z form an azide group - N 3, the method comprising: reacting an allylic reactant having the structure of formula (I) with an acid chloride having the structure of formula (II) in the presence of a Lewis acid catalyst composition comprising a first catalyst component composed of a Lewis acid, and a second catalyst component selected from the group consisting of tertiary amines and non-nitrogenous bases.",
    "17. A method for synthesizing a compound having the structural formula (IIIa) wherein R 1, R 2, R 3, R 4, R 5 and R 6 are independently selected from the group consisting of hydrido, halo, hydroxyl, sulfhydryl, amino, substituted amino, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, Z is N, O or S, n is zero or 1, with the proviso that when Z is N, n is 1, and when Z is O or S, n is zero, and Q 1 and Q 2 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, or, when Z is N and n is 1, Q 1 and Q 2 are joined together in a ring structure or together with Z form an azide group - N 3, the method comprising: reacting an allylic reactant having the structure of formula (Ia) with an acid chloride having the structure of formula (II) in the presence of a Lewis acid catalyst composition comprising a first catalyst component composed of a Lewis acid, and a second catalyst component selected from the group consisting of tertiary amines and non-nitrogenous bases.",
    "18. A method for synthesizing a compound having the structural formula (IIIb) wherein R 1, R 2, R 3, R 4, R 5 and R 6 are independently selected from the group consisting of hydrido, halo, hydroxyl, sulfhydryl, amino, substituted amino, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, Z is N, O or S, n is zero or 1, with the proviso that when Z is N, n is 1, and when Z is O or S, n is zero, and Q 1 and Q 2 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, or, when Z is N and n is 1, Q 1 and Q 2 are joined together in a ring structure or together with Z form an azide - N 3, the method comprising: reacting an allylic reactant having the structure of formula (Ib) with an acid chloride having the structure of formula (II) in the presence of a Lewis acid catalyst composition comprising a first catalyst component composed of a Lewis acid, and a second catalyst component composed of a tertiary amine.",
    "19. A method for synthesizing a compound having the structural formula (IIIc) wherein R 1, R 2, R 3, R 4, R 5 and R 6 are independently selected from the group consisting of hydrido, halo, hydroxyl, sulfhydryl, amino, substituted amino, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, Z is N, O or S, n is zero or 1, with the proviso that when Z is N, n is 1, and when Z is O or S, n is zero, and with the further proviso that R 4 is a sterically bulky substituent relative to R 5, and Q 1 and Q 2 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, or, when Z is N and n is 1, Q 1 and Q 2 are joined together in a ring structure or together with Z form an azide - N 3, the method comprising: reacting an allylic reactant having the structure of formula (Ic) with an acid chloride having the structure of formula (II) in the presence of a Lewis acid catalyst composition comprising a first catalyst component composed of a Lewis acid, and a second catalyst component selected from the group consisting of tertiary amines and non-nitrogenous bases.",
    "20. A method for synthesizing a compound having the structural formula (IIId) wherein R 1, R 2, R 3, R 4, R 5 and R 6 are independently selected from the group consisting of hydrido, halo, hydroxyl, sulfhydryl, amino, substituted amino, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, Z is N, O or S, n is zero or 1, with the proviso that when Z is N, n is 1, and when Z is S, n is zero, and with the further proviso that R 5 is a sterically bulky substituent relative to R 4, and Q 1 and Q 2 are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, or, when Z is N and n is 1, Q 1 and Q 2 are joined together in a ring structure or together with Z form an azide - N 3, the method comprising: reacting an allylic reactant having the structure of formula (Ic) with an acid chloride having the structure of formula (II) in the presence of a Lewis acid catalyst composition comprising a first catalyst component composed of a Lewis acid, and a second catalyst component selected from the group consisting of tertiary amines and non-nitrogenous bases.",
    "21. The method of any one of claims 16, 17, 18, 19 and 20, wherein the first catalyst component has the structural formula (V) M(X) a (Y) b (V) wherein M is a metal, X is a halide, a halide-containing group, lower alkoxy, fluorinated lower alkoxy, sulfate, acetate, trifluoroacetate or triflate, Y is hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, or an oxygen-containing or nitrogen-containing organic ligand, a is an integer of 1 or more, and the sum of a and b is in the range of 2 to n max, where n max is the number of atoms that can bind to M through single covalent or coordination bonds.",
    "22. The method of claim 21, wherein M is selected from the group consisting of Groups 2 through 13 of the Periodic Table of the Elements and lanthanides.",
    "23. The method of claim 22, wherein M is selected from the group consisting of Ti, Mg, Al, Sc, Y, Ni, Cu, Zn and Yb.",
    "24. The method of claim 23, wherein M is selected from the group consisting of Ti, Mg and Al.",
    "25. The method of claim 21, wherein a is at least 2.",
    "26. The method of claim 25, wherein X is a halide or triflate.",
    "27. The method of claim 26, wherein Y is a nitrogen-containing ligand.",
    "28. The method of claim 27, wherein Y has the structure of formula (VIa) or (VIb) wherein L is a hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene, substituted heteroatom-containing hydrocarbylene or heteroatom linkage, and R 7, R 8, R 9 and R 10 are independently selected from the group consisting of hydrido, halo, hydroxyl, sulfhydryl, amino, substituted amino, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, or wherein R 7 and R 8 and/or R 9 and R 10 may be linked to form a hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene, or substituted heteroatom-containing hydrocarbylene bridge.",
    "29. The method of claim 28, wherein Y has the structure of formula (VIIa) or (VIIb) wherein R 11 is as defined for R 7, R 8 and R 9, and z is an integer in the range of zero to 5 inclusive.",
    "30. The method of claim 29, wherein Y has the structure of formula (VIIa).",
    "31. The method of claim 30, wherein Y has the structure of formula (VIII) wherein R 12, R 13, R 14 and R 15 are defined as for R 11.",
    "32. The method of any one of claims 16, 17, 18, 19 and 20, wherein the second catalyst component is a tertiary amine.",
    "33. The method of claim 32, wherein the tertiary amine has the structure NR 16 R 17 R 18 wherein R 16, R 17 and R 18 are independently hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl or substituted heteroatom-containing hydrocarbyl, or wherein two of R 16, R 17 and R 18 are linked to form a hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene or substituted heteroatom-containing hydrocarbylene bridge.",
    "34. The method of claim 33, wherein the tertiary amine is a trialkylamine.",
    "35. The method of 34, wherein the tertiary amine is a tri(lower alkyl)amine.",
    "36. The method of claim 32, wherein the tertiary amine is comprised of a nitrogen-containing heterocycle in which at least one nitrogen heteroatom is in the form - N═.",
    "37. The method of any one of claims 16, 17, 18, 19 and 20, wherein the second catalyst component is a non-nitrogenous base.",
    "38. The method of claim 37, wherein the non-nitrogenous base is selected from the group consisting of inorganic hydroxides, inorganic oxides, and metal carbonates.",
    "39. The method of claim 38, wherein the non-nitrogenous base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.",
    "40. The method of any one of claims 16, 17, 18, 19 and 20, wherein the molar ratio of the allylic reactant to the acid chloride is in the range of approximately 2:1 to 1:2.",
    "41. The method of any one of claims 16, 17, 18, 19 and 20, wherein the reaction is carried out under inert, nonaqueous conditions.",
    "42. The method of any one of claims 16, 17, 18, 19 and 20, wherein the reaction is carried out at a temperature in the range of approximately −110° C. to 200° C.",
    "43. The method of claim 42, wherein the reaction is carried out at a temperature in the range of approximately −78° C. to 100° C.",
    "44. The method of any one of claims 16, 17, 18, 19 and 20, wherein one of the allylic reactant, the acid chloride and the catalyst composition is covalently linked, either directly or indirectly, to the surface of a solid support."
  ],
  "description_excerpt": "The present invention relates generally to synthetic organic chemistry. More particularly, the invention relates to the Claisen rearrangement reaction and to a novel method of performing such reactions so as to give rise to chiral products. The invention finds utility in the fields of organic synthesis and stereospecific catalysis.\n\nSince its discovery in 1912, the Claisen rearrangement has become one of the most powerfull tools for carbon-carbon bond formation in chemical synthesis. See, e.g., Claisen (1912) Chem. Ber. 45:3157; Enders et al. (1996) Tetrahedron: Asymmetry 7:1847; Blechert et al. (1989) Synthesis 71; Kallmerten et al. (1989) Stud. Nat. Prod. Chem. 3:323; Moody et al. (1987) Adv. Heterocycl. Chem. 42:203; and Ziegler et al. (1988) Chem. Rev. 88:1423. The Claisen reaction is a [3,3]-sigmatropic rearrangement, which involves the conversion of an allylic compound, generally an allylic vinyl ether, to an α,β-disubstituted, α,γ-unsaturated carbonyl compound. The reaction may be illustrated as follows:\n\nAllylic aryl ethers also undergo a Claisen rearrangement to give ortho-allylphenols:\n\nActivation of Claisen reactions has traditionally been accomplished under thermal control, typically at temperatures of 200° C. or more. Activation has also been achieved through the incorporation of cationic or anionic charge in the bond reorganization event (see Takai et al. (1981) Tetrahedron Lett. 22:3985; Takai et al. (1984) Bull. Chem. Soc. 51:446; Stevenson et al. (1982) Tetrahedron Lett. 23:3143; and Takai et al. (1984) Tetrahedron 40:4013; Arnold et al. (1949) J. Am. Chem. Soc. 21:1150; Ireland et al. (1973) J. Am. Chem.",
  "cpc": [
    "C07D 295/185",
    "C07B 2200/07",
    "C07D 263/32",
    "C07D 295/182"
  ],
  "ipc": [
    "C07D 263/32",
    "C07D 295/182",
    "C07D 295/185"
  ],
  "assignees": [
    "University of California San Diego UCSD"
  ],
  "inventors": [
    "David W. C. MacMillan",
    "Vy Dong",
    "Tehshik Yoon"
  ],
  "filing_date": "2000-09-26",
  "publication_date": "2002-03-19",
  "grant_date": "2002-03-19",
  "priority_date": "2000-09-26",
  "application_number": "US-67086300-A",
  "family_id": "24692203",
  "cited_by_count": 3
}