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. Author manuscript; available in PMC: 2007 May 3.
Published in final edited form as: Tetrahedron Lett. 2007 Jan 22;48(4):563–565. doi: 10.1016/j.tetlet.2006.11.127

Fluorous synthesis of sclerotigenin-type benzodiazepine-quinazolinones

Wei Zhang a,*, John P Williams b, Yimin Lu a, Tadamichi Nagashima a, Qainli Chu a
PMCID: PMC1865100  NIHMSID: NIHMS16402  PMID: 17479166

Abstract

A new synthetic protocol for sclerotigenin-type benzodiazepine-quinazolinone library scaffold is introduced. A fluorous benzyl protecting group is used for synthesis of 4-benzodiazepine-2,5-dione intermediate and also as a phase tag for fluorous solid-phase extraction (F-SPE).

Keywords: sclerotigenin; benzodiazepine-quinazolinone; 1,4-benzodiazepine-2,5-dione; fluorous synthesis; solid-phase extraction

Sclerotigenin was isolated from the sclerotia of Penicillium sclerotigenum and has shown promising antiinsectan activity.1 It is the simplest member of the benzodiazepine-quinazolinone natural alkaloid family. Other members in this family such as circumdatins A–G isolated from terrestrial fungus Aspergillus ochraceus2 and benzomalvins A–C isolated from fungus Penicillium sp also possess interesting biological activities.3

graphic file with name nihms16402ig1.jpg

Privileged 1,4-benzodiazepine-2,5-dione ring systems are the key intermediates for synthesis of benzodiazepine-quinazolinone alkaloids.4 As part of our continuous effort on the development of fluorous synthetic protocols, we have employed a series of fluorous protecting groups for library synthesis.5,6 Reported here is a new approach to synthesize benzodiazepinedione scaffold using fluorous benzyl as a protecting group and also as a phase tag for fluorous solid-phase extraction (F-SPE).7 Further derivatization of benzodiazepinediones leads to formation of sclerotigenin ring skeleton.

Taking the advantage that numbers of conventional solution-phase and solid-phase synthetic methods for benzodiazepine have been reported in literature,8 we adopted Ellman’s solid-phase method for fluorous synthesis (Scheme 1).9 Fluorous benzaldehyde 1 prepared by reaction of a hydroxybenzaldehyde with a fluorous alcohol was used as the starting material. Compound 2 was produced by reductive amination of 1 with an amino ester. Compound 2 was reacted with an anthranilic acid in the presence of 1-ethyl-3-3-dimethylaminopropyl)carbodiimide (EDCI) and N-methylpyrrolidine (NMP). The 1,4-benzodiazepine-2,5-dione ring formation was accomplished by base-promoted cyclization of 3. Compounds 2, 3, and 4 generated in this reaction sequence were purified by simple workup or F-SPE with FluoroFlash® cartridges.10 In F-SPE, the first wash with 80:20 MeOH–H2O eluted the non-fluorous components. The desired fluorous compound was eluted with 100% MeOH. A total of nine analogs of compound 4 with substitution variations (R1 and R2) were prepared.11

Scheme 1.

Scheme 1

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Fluorous synthesis of benzodiazepinedione 4

With nine different benzodiazepinediones 4 in hand, we then conducted parallel synthesis to construct the quinazolinone ring skeleton (Scheme 2).1c Compound 4 was acylated with 2-nitrobenzoyl chloride in the presence of t-BuN=P(NMe2)3 as a base to give compound 5 (Table 1). If substituted 2-nitrobenzoyl chloride was employed for acylation, the third diversity point (R3) could be introduced. Compounds 5 were purified by automated RapidTrace F-SPE.12 The nitro group of 5 was reduced with zinc dust in acetic acid under sonication conditions. Resulted amino group simultaneously underwent cyclization to form quinazolinone ring of 6. The parallel sonication reactions of 5 gave the reduction/cyclization products 6 in a broad range of yield (21–73%). Since some reactions had low yields, F-SPE was not sufficient for purification. Reverse-phase chromatography was applied to purify compounds 6. The capability to purify fluorous compounds by non-fluorous technique is a useful option. It could be a difficult task in solid-phase synthesis to separate resin-bound impurities. At the last step, F-benzyl tag of compounds 6 was removed by treated with 90:5:5 TFA-H2O-dimethylsulfide (DMS) under microwave radiation, followed by F-SPE on RapidTrace® workstation to give the final product 7 with the sclerotigenin ring skeleton.13

Scheme 2.

Scheme 2

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Parallel synthesis of nine benzodiazepine-quinazolinones 7

Table 1.

Yields for analogs of compounds 5, 6, and 7

a b c d e f g h i
R1 i-Bu i-Bu i-Bu Me Me Me Bn Bn Bn
R2 H 4-Cl 5-Cl H 5-Cl 4-Me H 4-Cl 4-Me
5a–i 82% 80% 90% 75% 94% 90% 75% 72% 81%
6a–i 44% 50% 67% 21% 51% 62% 70% 65% 73%
7a–i 83% 86% 91% 91% 63% 71% 100% 89% 97%
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In summary, we have developed a new approach for the synthesis of fluorous 1,4-benzodiazepine-2,5-diones. The key intermediates can be readily converted to sclerotigenin ring skeleton. The new method which produces the library scaffold with substitution variation coupled with the simple F-SPE separation is an alternative way for solution-phase parallel synthesis of benzodiazepine-quinazolinone analogs.

Acknowledgments

This work was supported by the National Institutes of General Medical Sciences SBIR grant (2R44GM067326-02A1).

Footnotes

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