Methods and compositions for terpenoid tricycloalkane synthesis

Patent metadata

Field	Value
Publication number	US-10287239-B1
Application number	US-201815981833-A
Country	US
Kind code	B1
Filing date	May 16, 2018
Priority date	May 16, 2018
Publication date	May 14, 2019
Grant date	May 14, 2019

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:
reacting a γ-allenyl Knoevenagel adduct and a propargyl electrophile in the presence of a metal hydride;
wherein the γ-allenyl Knoevenagel adduct 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;

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

wherein R 5 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 —, —CH 2 CH 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. A compound, wherein the compound 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 30 ;

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;

and 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.

12. The compound of claim 11 , wherein E is —CN or —(C═O)OCH 3 .

13. The compound of claim 11 , wherein E is —CN.

14. The compound of claim 11 , 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 11 , 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 11 , wherein R 2 is hydrogen, methyl, phenyl, or —CH 2 (C═O)OCH 3 .

17. The compound of claim 11 , wherein A 1 is —CH 2 —, —CHCH 3 , —CH(C═O)OCH 2 CH 3 , or
—N(C═O)OC(CH 3 ) 3 .

18. The compound of claim 11 , wherein R 3 is hydrogen, methyl, phenyl, trimethylsilyl, or —CH 2 (C═O)OCH 3 .

19. The compound of claim 11 , wherein the compound has a formula represented by a structure:

20. The compound of claim 11 , wherein the compound has a formula represented by a structure:

Assignees

• Univ Florida

Inventors

• Grenning Alexander James
• Scott Sarah

Classifications

• C07C2603/78

  containing seven-membered rings · CPC title

• C07C255/31

  having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic rings · CPC title

• C07C255/47

  to carbon atoms of rings being part of condensed ring systems · CPC title

• C07C2603/30

  containing seven-membered rings · CPC title

• C07C253/30 Primary

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