Design, synthesis, and diversification of 3,5-substituted enone library

DOI: 10.1021/co200070m

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ACS Combinatorial Science p. 351 - 356 (2011)

Update date:2022-08-05

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Authors:

Khalaf, Juhienah

Estrella-Jimenez, Maria E.

Shashack, Matthew J.

Phatak, Sharangdhar S.

Zhang, Shuxing

Gilbertson, Scott R.

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Article abstract of DOI:10.1021/co200070m

This paper describes the synthesis of a 300 member library of 3,5-substituted enones. The synthesis starts with 6 different bromoenones that are accessed from the corresponding 1,3 diones. These bromides are then diversified by Suzuki coupling with a variety of aromatic and vinyl boronic acids. Additionally a small series of triazoles was synthesized by a Sonogashira coupling reaction dipolar cycloaddition sequence. The library was analyzed by principal component analysis to examine its diversity.

Full text of DOI:10.1021/co200070m

LETTER

pubs.acs.org/acscombsci

Design, Synthesis, and Diversification of 3,5-Substituted

Enone Library

Juhienah Khalaf,^†Maria E. Estrella-Jimenez,^†Matthew J. Shashack,^†Sharangdhar S. Phatak,^‡,§

Shuxing Zhang,^‡and Scott R. Gilbertson*^,†

^†Department of Chemistry, University of Houston, Houston, Texas 77204-5003, United States

^‡Integrated Molecular Discovery Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson

Cancer Center, 1515 Holcombe Blvd, Houston Texas 77030, United States

^§School of Biomedical Informatics, The University of Texas Health Science Center, 7000 Fannin Street, Houston,

Texas 77030, United States

S Supporting Information

ABSTRACT: This paper describes the synthesis of a 300

member library of 3,5-substituted enones. The synthesis starts

with 6 diﬀerent bromoenones that are accessed from the

corresponding 1,3 diones. These bromides are then diversiﬁed

by Suzuki coupling with a variety of aromatic and vinyl boronic

acids. Additionally a small series of triazoles was synthesized by

a Sonogashira coupling reaction dipolar cycloaddition se-

quence. The library was analyzed by principal component analysis to examine its diversity.

KEYWORDS: enone, Suzuki, library

he ever-increasing demand for novel medicinally active

compounds has resulted in a continuous search for simple

and eﬃcient methods for the generation of libraries to be

examined in biological systems. With that in mind, and as a

continuation of an eﬀort to develop small molecule inhibitors

of anthrax edema factor,¹a library of cyclohexenones has

been developed. In an earlier paper it was reported that

mono substituted cyclohexenones possess activity against the

adenylyl cyclase inhibitor, anthrax edema factor.¹In an

attempt to improve the activity, a new series of cyclohexe-

nones (1) has been developed possessing substituents at the 3

and 5 positions (Figure 1).

Figure 1

Scheme 1^a

For generation of ensembles of the desired molecules, the

Suzuki reaction was an ideal choice in generating libraries with the

basic structure 1.^2,3Diversity at position R¹was obtained by reaction

of bromoenones (Scheme 1) with commercially available boronic

acids (diversity reagent 4).

Six diﬀerent bromoenones (Figure 2, diversity reagent 3) were

used. These consisted of ﬁve with aromatic substituents at position 5

and one with dimethyl substitution at that location. The necessary

bromoenones were prepared in good to excellent yield from 1,3-

diones in a single step through bromination with triphenylpho-

sphine and bromine (Scheme 1).⁴These types of bromides are

excellent substrates for the Suzuki coupling to a variety of boronic

acids in generally good to excellent yields.^1,2

^a(a) PPh₃, Br₂, Et₃N, C₆H₆; 65À90%; (b) 3 mol % FC 1007, K₂CO₃,

Microwave, 110 °C, 10 min; 65À95%.

well as acids, esters, amides, aldehydes, nitriles, triﬂuoromethyl

groups, and alkyl groups. Polycyclic aromatic rings such as

naphthalene, phenanthrene, indole, thiophene, benzofuran, and

quinoline were also included. While all possible combinations of

elements 3 and 4 are not represented, three hundred unique

The boronic acids are predominantly aryl with only four vinyl

boronic acids being used in the library (Figure 3). However, the

variety of aromatic boronic acids is extensive; oxygen, nitrogen,

and sulfur heterocycles were used. Substitutents on the benzene

rings were varied from ethers, bromides, chlorides, iodides as

Received: April 13, 2011

Revised:

June 3, 2011

Published: June 07, 2011

2011 American Chemical Society

351

dx.doi.org/10.1021/co200070m ACS Comb. Sci. 2011, 13, 351–356

ACS Combinatorial Science

LETTER

compounds were prepared. The examples that were synthesized

are represented in Table 1.

The library was subjected to principal component analysis

(PCA) to characterize its diversity.⁵Members of the library were

Figure 2. Diversity Reagent 3 {1À6}.

Figure 3. Continued

352

dx.doi.org/10.1021/co200070m |ACS Comb. Sci. 2011, 13, 351–356

ACS Combinatorial Science

LETTER

Figure 3. Diversity Reagent 4 {1À60} and {61À115}.

Scheme 2^a

^a(a) Pd(PPh₃)₂Cl₂, CuI, Et₃N, DMF, 110 °C, μW; (65À86%) (b) NaN₃, DMF, 100 °C; (45À65%).

characterized with 185 2D descriptors derived from Molecular

Operating Environment (MOE version 2010.10).⁶PCA was

performed on the matrix to reduce the dimensionality of

chemical space. The three-dimensional plot of the top three

353

dx.doi.org/10.1021/co200070m |ACS Comb. Sci. 2011, 13, 351–356

ACS Combinatorial Science

LETTER

Table 1. Library Members^a

5 {1,1}

5 {1,27}

5 {1,28}

5 {1,29}

5 {1,30}

5 {1,31}

5 {1,32}

5 {1,33}

5 {1,34}

5 {1,36}

5 {1,37}

5 {1,38}

5 {1,39}

5 {1,48}

5 {1,50}

5 {1,60}

5 {1,61}

5 {1,62}

5 {1,64}

5 {1,66}

5 {1,69}

5 {1,74}

5 {1,75}

5 {1,76}

5 {1,77}

5 {1,79}

5 {1,81}

5 {1,87}

5 {1,111}

5 {1,114}

5 {2,1}

5 {2,39}

5 {2,40}

5 {2,41}

5 {2,42}

5 {2,43}

5 {2,44}

5 {2,45}

5 {2,46}

5 {2,48}

5 {2,50}

5 {2,51}

5 {2,58}

5 {2,59}

5 {2,60}

5 {2,61}

5 {2,62}

5 {2,63}

5 {2,64}

5 {2,65}

5 {2,66}

5 {2,67}

5 {2,69}

5 {2,70}

5 {2,71}

5 {2,72}

5 {2,73}

5 {2,74}

5 {2,75}

5 {2,76}

5 {2,77}

5 {2,78}

5 {2,79}

5 {2,80}

5 {2,81}

5 {2,83}

5 {2,84}

5 {2,85}

5 {2,86}

5 {2,87}

5 {2,89}

5 {2,90}

5 {2,92}

5 {2,94}

5 {2,95}

5 {2,96}

5 {2,97}

5 {2,98}

5 {2,100}

5 {2,101}

5 {2,102}

5 {2,104}

5 {2,105}

5 {2,107}

5 {2,108}

5 {2,109}

5 {2,110}

5 {2,112}

5 {2,113}

5 {2,114}

5 {3,1}

5 {3,18}

5 {3,19}

5 {3,20}

5 {3,21}

5 {3,22}

5 {3,23}

5 {3,25}

5 {3,27}

5 {3,28}

5 {3,29}

5 {3,31}

5 {3,32}

5 {3,36}

5 {3,37}

5 {3,38}

5 {3,42}

5 {3,45}

5 {3,49}

5 {3,52}

5 {4,1}

5 {4,9}

5 {4,47}

5 {4,48}

5 {4,49}

5 {4,51}

5 {4,55}

5 {4,58}

5 {4,59}

5 {4,61}

5 {4,62}

5 {4,63}

5 {4,65}

5 {4,66}

5 {4,67}

5 {4,69}

5 {4,70}

5 {4,71}

5 {4,72}

5 {4,73}

5 {4,75}

5 {4,76}

5 {4,77}

5 {4,78}

5 {4,79}

5 {4,81}

5 {4,84}

5 {4,93}

5 {4,94}

5 {4,111}

5 {4,112}

5 {4,113}

5 {5,1}

5 {5,25}

5 {5,26}

5 {5,27}

5 {5,28}

5 {5,29}

5 {5,31}

5 {5,32}

5 {5,34}

5 {5,36}

5 {5,37}

5 {5,38}

5 {5,39}

5 {5,41}

5 {5,42}

5 {5,43}

5 {5,44}

5 {5,45}

5 {5,46}

5 {5,49}

5 {6,2}

5 {6,10}

5 {6,11}

5 {6,13}

5 {6,14}

5 {6,17}

5 {6,19}

5 {6,20}

5 {6,23}

5 {6,27}

5 {6,29}

5 {6,31}

5 {6,32}

5 {6,34}

5 {6,36}

5 {6,37}

5 {6,38}

5 {6,39}

5 {6,41}

5 {6,43}

5 {6,45}

5 {6,46}

5 {6,49}

5 {6,55}

5 {6,56}

5 {6,57}

5 {1,2}

5 {4,11}

5 {4,12}

5 {4,13}

5 {4,14}

5 {4,17}

5 {4,19}

5 {4,20}

5 {4,22}

5 {4,23}

5 {4,24}

5 {4,25}

5 {4,26}

5 {4,27}

5 {4,29}

5 {4,34}

5 {4,36}

5 {4,37}

5 {4,38}

5 {4,39}

5 {4,41}

5 {4,42}

5 {4,43}

5 {4,45}

5 {4,46}

5 {1,3}

5 {1,4}

5 {1,5}

5 {1,6}

5 {2,2}

5 {1,7}

5 {2,3}

5 {5,2}

5 {1,8}

5 {2,5}

5 {5,3}

5 {1,9}

5 {2,6}

5 {5,4}

5 {1,10}

5 {1,11}

5 {1,12}

5 {1,13}

5 {1,14}

5 {1,15}

5 {1,16}

5 {1,17}

5 {1,18}

5 {1,19}

5 {1,20}

5 {1,22}

5 {1,23}

5 {1,24}

5 {1,25}

5 {1,26}

5 {2,7}

5 {5,5}

5 {2,8}

5 {3,2}

5 {5,6}

5 {2,10}

5 {2,12}

5 {2,14}

5 {2,15}

5 {2,18}

5 {2,20}

5 {2,24}

5 {2,25}

5 {2,29}

5 {2,32}

5 {2,34}

5 {2,36}

5 {2,37}

5 {2,38}

5 {3,3}

5 {5,7}

5 {3,4}

5 {5,8}

5 {3,5}

5 {5,9}

5 {3,6}

5 {5,10}

5 {5,12}

5 {5,14}

5 {5,15}

5 {5,17}

5 {5,18}

5 {5,19}

5 {5,20}

5 {5,21}

5 {5,22}

5 {5,23}

5 {3,7}

5 {3,8}

5 {3,9}

5 {3,10}

5 {3,11}

5 {3,12}

5 {3,13}

5 {3,14}

5 {3,15}

5 {3,17}

5 {4,2}

5 {6,3}

5 {4,3}

5 {6,4}

5 {4,4}

5 {6,7}

5 {4,5}

5 {6,8}

5 {4,6}

5 {6,9}

^aAll compounds in Table 1 were produced in greater than 20 mg quantities. The Suzuki used to produce these libraries proceeded in yields from 95% to

35% with 78% being the average yield.

Figure 4. Principal Component Analysis.

354

dx.doi.org/10.1021/co200070m |ACS Comb. Sci. 2011, 13, 351–356

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LETTER

Table 2. Alkynes and Triazoles

principal components illustrates that within each set of com-

pounds there are members of the library that diﬀer considerably

from the aggregate. The labeled circles (Figure 4) represent

examples that fall the farthest from the center of the plot. The

LogP for the library ranged between 1.16 to 6.58 with a mean

value of 4.20. The library’s molecular weigh averaged 335 ranging

from 164 to 462 while the polar surface area ranged from 17 to

103 with a mean value of 35.3. Histograms of this data are

presented in the Supporting Information.

In an extension of this chemistry, a smaller series of triazoles

was synthesized by a Sonogashira coupling to provide an alkyne

that was then reacted with sodium azide. The coupling reaction

(Scheme 2) was catalyzed by PdCl₂(PPh₃)₂and CuI and con-

ducted under microwave conditions (250W at 110 °C for 10 min) in

DMF.⁷In all cases the samples were puriﬁed by column chroma-

tography to remove remaining palladium catalyst and copper iodide.

The corresponding alkynes were reacted with sodium azide in DMF

and heated at 100 °C for 1 h.^8,9The reaction was concentrated and

puriﬁed by column chromatography to give 1,2,3-triazoles analogues

(Table 2). In this case the library size was limited by the use of only

two bromoenones and the availability of diﬀerent alkynes for the

ﬁrst coupling step with 14 alkynes synthesized and corresponding

14 triazoles obtained.

A 300-member library was synthesized by combining six

diﬀerent bromoenones with boronic acids via the Suzuki cou-

pling. The library consisted of enones where the diversity

at position 3 was installed by Suzuki reaction and the diversity

at position 5 originated from the six diﬀerent bromoenones

used as starting material. Principal component analysis (PCA)

indicates that while the molecules are clustered, speciﬁc members

are signiﬁcantly diﬀerent from the group. Additionally fourteen

triazoles were synthesized through a Sonogashira coupling

followed by dipolar cycloaddition of azide. All these compounds

have been submitted to the NIH Molecular Library Small

Molecule Repository (MLSMR) to be distributed to the NIH

screening centers.

355

dx.doi.org/10.1021/co200070m |ACS Comb. Sci. 2011, 13, 351–356

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LETTER

’ ASSOCIATED CONTENT

Supporting Information. General procedures for library

synthesis and ¹H NMR data for the compounds. This material is

available free of charge via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION

Corresponding Author

*E-mail: srgilbe2@central.uh.edu.

Funding Sources

This work was supported by NIGMS GM079558 and

GM089173, the Robert A. Welch Foundation, and the M. D.

Anderson Foundation. S.S.P. was also supported by UTHealth

Innovation for Cancer Prevention Research Predoctoral Fellow-

ship, The University of Texas School of Public HealthÀCancer

Prevention and Research Institute of Texas Grant RP101503.

’ ACKNOWLEDGMENT

We would like to thank University of Kansas Chemical

Methodologies and Library Development Center of Excellence,

in particular Frank Schoenen and Benjamin Neuenswander, for

providing analytical and puriﬁcation support, and David Hill for

chemoinformatics support.

’ REFERENCES

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(4) Piers, E.; Nagakura, I. Reaction of beta-Diketones with Triphenyl-

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(5) Tan, D. S. Diversity-oriented synthesis: exploring the intersections

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(6) Chemical Computing Group, M., Quebec, Canada.

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Article Doi

Design, synthesis, and diversification of 3,5-substituted enone library

DOI: 10.1021/co200070m

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Authors:

Article abstract of DOI:10.1021/co200070m

Full text of DOI:10.1021/co200070m

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