Complex and structurally diverse compounds

Patent metadata

Field	Value
Publication number	US-10081592-B2
Application number	US-201314387028-A
Country	US
Kind code	B2
Filing date	Mar 25, 2013
Priority date	Mar 23, 2012
Publication date	Sep 25, 2018
Grant date	Sep 25, 2018

Abstract

The invention a novel, general, and facile strategy for the creation of small molecules with high structural and stereochemical complexity. Aspects of the methods include ring system distortion reactions that are systematically applied to rapidly convert readily available natural products to structurally complex compounds with diverse molecular architectures. Through evaluation of chemical properties including fraction of sp 3 carbons, ClogP, and the number of stereogenic centers, these compounds are shown to be significantly more complex and diverse than those in standard screening collections. This approach is demonstrated with natural products (gibberellic acid, adrenosterone, and quinine) from three different structural classes, and methods are described for the application of this strategy to any suitable natural product.

First claim

What is claimed is:

1. A method for preparing a high-throughput screening library comprising:
a) carrying out a ring expansion reaction, a ring fusion reaction, a ring rearrangement reaction, a ring cleavage reaction, or a combination thereof, on a natural product wherein the natural product is adrenosterone, quinine, gibberellic acid or a derivative of gibberellic acid having Formula X-G:

wherein R 1 is H or Me; and R 2 is OH or OMe;
b) carrying out an oxidation reaction, a reduction reaction, an esterification, an amidation, an addition reaction, a substitution reaction, an elimination reaction, an aromatization reaction, or a protection or deprotection reaction; optionally followed by carrying out an additional ring expansion reaction, a ring fusion reaction, a ring rearrangement reaction, or a ring cleavage reaction; and
c) repeating steps a) and b) one to four times on the resulting products using different selections of reactions to provide a series of products for a high-throughput screening library;
wherein the products comprise at least one ring distortion compared to the natural product; the products comprise at least three oxygen atoms, or at least two oxygen atoms and three nitrogen atoms; the products comprise at least two stereogenic centers, and the molecular weights of the products are at least about 300 Daltons and less than about 750 Daltons.

2. The method of claim 1 further comprising a one or more additional ring expansion reactions, ring fusion reactions, ring rearrangement reactions, ring cleavage reactions, oxidation reactions, reduction reactions, esterifications, amidations, addition reactions, substitution reactions, elimination reactions, aromatization reactions, functional group transformations, protection reactions, or deprotection reactions.

3. The method of claim 1 wherein the natural product is gibberellic acid, adrenosterone, or quinine.

4. The method of claim 1 wherein steps a) and b) comprise a ring cleavage reaction and an esterification, and step c) comprises one or more of:
i) a ring cleavage reaction, an esterification, and ring cleavage reaction or a ring fusion reaction;
ii) a ring rearrangement reaction, an amidation, and a ring rearrangement reaction;
iii) a ring cleavage reaction, an esterification, and a ring expansion reaction;
iv) a ring cleavage reaction with concomitant a decarboxylation and aromatization, an esterification, and a ring rearrangement; and
v) a ring cleavage reaction with concomitant a decarboxylation and aromatization, a ring rearrangement, and a ring expansion reaction.

5. The method of claim 1 wherein the products of the high-throughput screening library comprise a compound of formula GAX or GAZ:

wherein
R 1 is alkyl, alkylaryl, or aryl; and
R 2 is H, OH, halo, alkoxy, or OP wherein P is an oxygen protecting group.

6. The method of claim 1 wherein the products of the high-throughput screening library comprise the compound GA-4 or GA-81:

7. The method of claim 1 wherein the products of the high-throughput screening library comprise one or more of:

8. A method for preparing a high-throughput screening library comprising:
a) carrying out a ring expansion reaction, a ring fusion reaction, a ring rearrangement reaction, a ring cleavage reaction, or a combination thereof, on a natural product, wherein the natural product is gibberellic acid or a derivative of gibberellic acid having Formula X-G:

Wherein R 1 is H or Me; and R 2 is OH or OMe;
b) carrying out an oxidation reaction, a reduction reaction, an esterification, an amidation, an addition reaction, a substitution reaction, an elimination reaction, an aromatization reaction, or a protection or deprotection reaction; optionally followed by carrying out an additional ring expansion reaction, a ring fusion reaction, a ring rearrangement reaction, or a ring cleavage reaction; and
c) repeating steps a) and b) one to four times on the resulting products using different selections of reactions to provide a series of products for a high-throughput screening library; wherein the products comprise at least one ring distortion compared to the natural product; the products comprise at least three oxygen atoms, or at least two oxygen atoms and three nitrogen atoms; the products comprise at least two stereogenic centers, the molecular weights of the products are at least about 300 Daltons and less than about 750 Daltons, and the products of the high-throughput screening library comprise a compound of formula GAX or GAZ:

wherein
R 1 is alkyl, alkylaryl, or aryl; and

R 2 is H, OH, halo, alkoxy, or OP wherein P is an oxygen protecting group.

9. The method of claim 8 wherein the products of the high-throughput screening library comprise the compound GA-4 or GA-81:

10. The method of claim 8 wherein the products of the high-throughput screening library comprise one or more of:

11. The method of claim 1 wherein the products of the high-throughput screening library comprise carbon skeletons X1-G to X6-G:

12. The method of claim 11 wherein the products of the high-throughput screening library comprise carbon skeletons X1-G, X2-G, X4-G and X5-G.

Assignees

• Univ Illinois
• Hergenrother Paul J
• Huigens Iii Robert W
• Morrison Karen C
• Hicklin Ii Robert W
• Flood Jr Timothy A

Inventors

• Hergenrother Paul J
• Huigens Iii Robert W
• Morrison Karen C
• Hicklin Ii Robert W
• Flood Jr Timothy A

Classifications

• C07D303/10

  in which the oxirane rings are condensed with a carbocyclic ring system having three or more relevant rings · CPC title

• C07J21/008

  at position 17 · CPC title

• C07J73/005

  by nitrogen as hetero atom · CPC title

• C07D307/93

  condensed with a ring other than six-membered · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title