Methods and compositions for terpenoid tricycloalkane synthesis

Patent metadata

Field	Value
Publication number	US-10894763-B2
Application number	US-201916567643-A
Country	US
Kind code	B2
Filing date	Sep 11, 2019
Priority date	May 16, 2018
Publication date	Jan 19, 2021
Grant date	Jan 19, 2021

Abstract

In one aspect, the disclosure relates to methods for preparation of intermediates useful for the preparation of terpenoid cores. In a further aspect, the disclosed methods pertain to the preparation of compounds comprising a terpenoid core or scaffold, such as 6/7/5 tricycloalkanes. The disclosed methods utilize abundant starting materials and simple reaction sequences that can be used to tunably and scalably assemble common terpenoid cores. In various aspects, the present disclosure pertains to compounds prepared using the disclosed methods. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

First claim

What is claimed is:

1. A method of synthesizing an allenyne precursor to a terpenoid scaffold, the method comprising:
(a) heating a 1,5-enyne;
wherein the 1,5-enyne has a formula represented by a structure:

wherein E is —CN or —(C═O)OR 10 ;
wherein R 10 is C1-C6 alkyl;

wherein each of R 1a , R 1b , R 1c , and R 1d is independently hydrogen, C1-C6 alkyl, aryl, or —(CH 2 ) m (C═O)OR 11 ; or wherein R 1a and R 1c are covalently bonded and, together with more intermediate carbons, comprise —CH 2 CH 2 —, or —CH═CH—;
wherein m is an integer selected from 0, 1, 2, and 3; and
wherein R 11 is C1-C6 alkyl;

wherein R 2 is hydrogen, C1-C6 alkyl, aryl, or —(CH 2 ) n (C═O)OR 12 ;
wherein n is an integer selected from 0, 1, 2, and 3; and
wherein R 12 is C1-C6 alkyl;

wherein A 1 is —C(R 20 )(R 21 )—, —NR 22 — or —CH 2 —;
wherein R 20 is hydrogen, C1-C6 alkyl, or —(CH 2 ) p (C═O)OR 30 ;

wherein R 30 is C1-C6 alkyl; and wherein p is an integer selected from 0, 1, 2, and 3;
wherein R 21 is hydrogen, C1-C6 alkyl, or —(CH 2 ) q (C═O)OR 31 ;

wherein R 31 is C1-C6 alkyl; and wherein q is an integer selected from 0, 1, 2, and 3; and
wherein R 22 is C1-C6 alkyl, or —(C═O)OR 32 ; and wherein R 32 is C1-C6 alkyl;

thereby synthesizing a γ-allenyl Knoevenagel adduct;
wherein the γ-allenyl Knoevenagel adduct has a formula represented by a structure:

(b) reacting the γ-allenyl Knoevenagel adduct prepared in the previous step with a propargyl electrophile in the presence of a metal hydride; and, wherein the propargyl electrophile has a formula represented by a structure:

wherein R 3 is hydrogen, C1-C6 alkyl, aryl, trimethylsilyl, or —(CH 2 ) r (C═O)OR 15 ;
wherein r is an integer selected from 0, 1, 2, and 3; and
wherein R 15 is C1-C6 alkyl;

thereby synthesizing the allenyne precursor to the terpenoid scaffold; wherein the allenyne precursor to the terpenoid scaffold has a formula represented by a structure:

2. The method of claim 1 , wherein the metal hydride is LiH, NaH, or KH.

3. The method of claim 1 , wherein E is —CN or —(C═O)OCH 3 .

4. The method of claim 1 , wherein E is —CN.

5. The method of claim 1 , wherein each of R 1a , R 1b , R 1c , and R 1d is independently hydrogen, methyl, phenyl, or —CH 2 (C═O)OCH 3 .

6. The method of claim 1 , wherein each of R 1b and R 1d are hydrogen; and wherein R 1a and R 1c are covalently bonded and, together with more intermediate carbons, comprise —CH 2 CH 2 — or —CH═CH—.

7. The method of claim 1 , wherein R 2 is hydrogen, methyl, phenyl, or —CH 2 (C═O)OCH 3 .

8. The method of claim 1 , wherein A 1 is —CH 2 —, —CHCH 3 , —CH(C═O)OCH 2 CH 3 , or —N(C═O)OC(CH 3 ) 3 .

9. The method of claim 1 , wherein R 3 is hydrogen, methyl, phenyl, trimethylsilyl, or —CH 2 (C═O)OCH 3 .

10. The method of claim 1 , wherein the allenyne precursor to the terpenoid scaffold has a formula represented by a structure:

11. The method of claim 1 , further comprising the step of preparation of the 1,5-enyne, the step comprising reacting a Knoevenagel adduct with a propargyl derivative;
wherein the Knoevenagel adduct has a formula represented by a structure:

and, wherein the propargyl derivative has a formula represented by a structure:

thereby synthesizing the 1,5-enyne; wherein the 1,5-enyne has a formula represented by a structure:

12. A compound, wherein the compound has a formula represented by a structure:

wherein E is —(C═O)OR 10 ;
wherein R 10 is C1-C6 alkyl;

wherein each of R 1a , R 1b , R 1c , and R 1d is independently hydrogen, C1-C6 alkyl, aryl, or —(CH 2 ) m (C═O)OR 11 ; or wherein R 1a and R 1c are covalently bonded and, together with more intermediate carbons, comprise —CH 2 CH 2 —, or —CH═CH—;
wherein m is an integer selected from 0, 1, 2, and 3; and
wherein R 11 is C1-C6 alkyl;

wherein R 2 is hydrogen, C1-C6 alkyl, aryl, or —(CH 2 ) n (C═O)OR 12 ;
wherein n is an integer selected from 0, 1, 2, and 3; and
wherein R 12 is C1-C6 alkyl;

wherein A 1 is —C(R 20 )(R 21 )—, —NR 22 — or —CH 2 —;
wherein R 20 is hydrogen, C1-C6 alkyl, or —(CH 2 ) p (C═O)OR 30 ;

wherein R 30 is C1-C6 alkyl; and wherein p is an integer selected from 0, 1, 2, and 3;
wherein R 21 is hydrogen, C1-C6 alkyl, or —(CH 2 ) q (C═O)OR 31 ;

wherein R 31 is C1-C6 alkyl; and wherein q is an integer selected from 0, 1, 2, and 3; and
wherein R 22 is C1-C6 alkyl, or —(C═O)OR 32 ; and wherein R 32 is C1-C6 alkyl.

13. The compound of claim 12 , wherein E is —(C═O)OCH 3 .

14. The compound of claim 12 , wherein each of R 1a , R 1b , R 1c , and R 1d is independently hydrogen, methyl, phenyl, or —CH 2 (C═O)OCH 3 .

15. The compound of claim 12 , wherein each of R 1b and R 1d are hydrogen; and wherein R 1a and R 1c are covalently bonded and, together with more intermediate carbons, comprise —CH 2 CH 2 — or —CH═CH—.

16. The compound of claim 12 , wherein R 2 is hydrogen, methyl, phenyl, or —CH 2 (C═O)OCH 3 .

17. The compound of claim 12 , wherein A 1 is —CH 2 —, —CHCH 3 , —CH(C═O)OCH 2 CH 3 , or —N(C═O)OC(CH 3 ) 3 .

18. A compound, wherein the compound has a formula represented by a structure:

wherein E is —CN or —(C═O)OR 10 ;
wherein R 1 is C1-C6 alkyl;

wherein each of R 1a , R 1b , R 1c , and R 1d is independently hydrogen, C1-C6 alkyl, aryl, or —(CH 2 ) m (C═O)OR 11 ; or wherein R 1a and R 1c are covalently bonded and, together with more intermediate carbons, comprise —CH 2 CH 2 —, or —CH═CH—;
wherein m is an integer selected from 0, 1, 2, and 3; and
wherein R is C1-C6 alkyl;

wherein R 2 is C1-C6 alkyl, aryl, or —(CH 2 ) n (C═O)OR 12 ;
wherein n is an integer selected from 0, 1, 2, and 3; and
wherein R 12 is C1-C6 alkyl;

wherein A 1 is —C(R 20 )(R 21 )—, —NR 22 — or —CH 2 —;
wherein R 20 is hydrogen, C1-C6 alkyl, or —(CH 2 ) p (C═O)OR 30 ;

wherein R 30 is C1-C6 alkyl; and wherein p is an integer selected from 0, 1, 2, and 3;
wherein R 21 is hydrogen, C1-C6 alkyl, or —(CH 2 ) q (C═O)OR 31 ;

wherein R 31 is C1-C6 alkyl; and wherein q is an integer selected from 0, 1, 2, and 3; and
wherein R 22 is C1-C6 alkyl, or —(C═O)OR 32 ; and wherein R 32 is C1-C6 alkyl.

19. A compound, wherein the compound has a formula represented by a structu

Assignees

• Univ Florida

Inventors

• Grenning Alexander James
• Scott Sarah

Classifications

• C07D211/72

  with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms · CPC title

• C07C253/30 Primary

  by reactions not involving the formation of cyano groups · CPC title

• C07D211/70 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07C2603/78

  containing seven-membered rings · CPC title

• C07D227/04

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms · CPC title