Diastereoselective synthesis of (±)-epianastrephin, (±)-anastrephin and analogs thereof

Patent metadata

Field	Value
Publication number	US-10011580-B2
Application number	US-201715492340-A
Country	US
Kind code	B2
Filing date	Apr 20, 2017
Priority date	Apr 21, 2016
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

Abstract

A process for the synthesis of trans-fused γ-lactones having Formula (IV) from substituted cyclic ketones having Formula (I). A diastereoselective synthesis of (±)-epianastrephin (1) (wherein: R 1 is ethenyl, R 2 and R 3 is methyl, and n is 1), (±)-anastrephin (2) (wherein: R 2 is ethenyl, R 1 and R 3 is methyl and n is 1), and analogs thereof (wherein: R 1 is H, C 1-5 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, R 2 is H, C 1-5 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, R 1 and R 2 together with the carbon atom they are attached form a C 3-6 cycloalkyl ring, R 3 is C 1-5 alkyl and n is 0-2):

First claim

We claim:

1. A process of making trans-fused γ-lactones of the Formula (IV)

wherein:
R 1 is H, C 1-5 alkyl, C 2-6 alkenyl or C 2-6 alkynyl,
R 2 is H, C 1-5 alkyl, C 2-6 alkenyl or C 2-6 alkynyl,
R 1 and R 2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl ring,
R 3 is C 1-5 alkyl,
n is 0, 1 or 2 to form a 5-, 6- or 7-membered ring, said process comprising:
(a) reacting the cyclic ketone of Formula (I) with an organometallic reagent MCH 2 CO 2 R 4 where M is Li, Na, K, or MgX, where X is Cl, Br or I, where is R 4 is C 1-4 alkyl, in a solvent to form the alcohol of Formula (II)

(b) reacting the alcohol of Formula (II) with an acylating agent, or a chloroformate in the presence of a catalyst or a base in a solvent, or an acyl transfer reagent in the presence of an acid catalyst and organic catalyst in a solvent, to provide a compound of Formula (III) where R 5 is —C(O)C 1-6 alkyl or —C(O)OC 1-6 alkyl

(c) cyclizing the compound of Formula (III) with an organic acid or a Lewis acid in a solvent to form the trans-fused γ-lactone of Formula (IV)

2. The process according to claim 1 , wherein the solvent of step (a) is selected from the group consisting of THF, Et 2 O, MTBE, DME or dioxane.

3. The process according to claim 1 , wherein the organometallic reagent (MCH 2 CO 2 R 4 ) of step (a) is generated from (1) the corresponding neutral acetate precursor with a base selected from the group consisting of LDA or LiHMDS, NaHMDS, KHMDS, sodium hydride, potassium hydride, or from (2) the Grignard reagent generated from the corresponding α-halo ester XCH 2 CO 2 R 4 where X is Cl, Br or I and isopropyl magnesium bromide or magnesium.

4. The process according to claim 1 , wherein the solvent of step (b) is selected from the group consisting of DCM, acetonitrile or nitromethane.

5. The process according to claim 1 , wherein the catalyst of step (b) is selected from the group consisting of indium (III) chloride, LiOTf or NBS.

6. The process according to claim 1 , wherein the organic base of step (b) is selected from the group consisting of Et 3 N or Hunig's base.

7. The process according to claim 1 , wherein the acyl transfer reagent of step (b) is selected from the group consisting of isopropenyl acetate, vinyl acetate or methyl vinyl acetate.

8. The process according to claim 1 , wherein the acid catalyst of step (b) is selected from the group consisting of p-TsOH.H 2 O or methane sulfonic acid.

9. The process according to claim 1 , wherein the acyl transfer organic catalyst of step (b) is an oxime.

10. The process according to claim 1 , wherein the organic acid of step (c) is selected from the group consisting of p-TsOH.H 2 O or MeSO 3 H, and a Lewis acid complex of step (c) is selected from the group consisting of BX 3 .L, GaX 3 .L or AIX 3 where X is F, Cl or Br, and where L is Et 2 O or acetonitrile or dimethyl sulfide.

11. The process according to claim 1 , wherein a solvent of step (c) is selected from the group consisting of acetonitrile or nitromethane.

12. The process according to claim 1 of making diastereoselectively trans-fused γ-lactones of the Formula (IV)

wherein:
R 1 is H, C 1-5 alkyl, C 2-6 alkenyl or C 2-6 alkynyl,
R 2 is H, C 1-5 alkyl, C 2-6 alkenyl or C 2-6 alkynyl,
R 1 and R 2 are not equal,
R 3 is C 1-5 alkyl,
n is 0, 1 or 2 to form a 5-, 6- or 7-membered ring.

13. The process according to claim 1 wherein said trans-fused γ-lactone of Formula (IV)

is (±)-epianastrephin (2),
wherein:
R 1 is ethenyl,
R 2 is methyl,
R 3 is methyl, and
n is 1 to form a 6-membered ring,
said process comprising:
(a) reacting ketone 9 with a base followed by zinc chloride and acetaldehyde in a solvent to form alcohol 10

(b) reacting alcohol 10 with a dehydrating agent in a solvent to form the vinyl ketone 11, or reacting alcohol 10 with a sulfonyl chloride followed by elimination with a base to form the vinyl ketone 11

(c) reacting ketone 11 with an organometallic reagent MCH 2 CO 2 R 4 where M is Li, Na, K or MgX, where X is Cl, Br or I, where R 4 is t-butyl in a solvent to form alcohols 12A and 12B

(d) reacting alcohol 12A with an acylating agent in the presence of an acid catalyst in a solvent to provide the acylated alcohol 13

(e) cyclizing compound 13 with a Lewis acid complex in a solvent to form the trans-fused γ-lactone, (±)-epianastrephin (1)

14. The process according to claim 13 , wherein the dehydrating agent of step (b) is selected from the group consisting of Martin's sulfurane, Burgess's reagent, P 2 O 5 or SOCl 2 .

15. The process according to claim 1 wherein said trans-fused γ-lactone of Formula (IV)

is (±)-anastrephin (2),
wherein:
R 1 is methyl,
R 2 is ethenyl,
R 3 is methyl, and
n is 1 to form a 6-membered ring,
said process comprising:
(a) reacting ketone 9 with a silyl chloride, a base and sodium iodine in a solvent to form the silyl enol ether 14; or reacting ketone 9 with a base and a silyl chloride in a solvent to form the silyl enol ether 14

(b) reacting silyl enol ether 14 with TMSA in the presence of a Lewis acid in a solvent followed by the addition of THF and an acid to form the ketone 15

(c) reacting ketone 15 with an organometallic reagent MCH 2 CO 2 R 4 where M is Li, Na, K or MgX, where X is Cl, Br or I, where R 4 is t-butyl in a solvent to form alcohols 16A and 16B

(d) reacting alcohol 16A with an acylating agent in the presence of an acid catalyst and cyclohexanone oxime in a solvent to provide acylated alcohol 17

(e) cyclizing compound 17 with a Lewis acid or Lewis acid complex in a solvent to form the trans-fused γ-lactone, (±)-anastrephin (2

Assignees

• Us Agriculture

Inventors

• Walse Spencer S
• Kuzmich Daniel

Classifications

• C07C67/327

  by elimination of functional groups containing oxygen only in singly bound form · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• C07C69/734

  Ethers · CPC title

• C07C69/732

  of unsaturated hydroxy carboxylic acids · CPC title

• C07C45/66

  by dehydration · CPC title