Fluorous Synthesis of Hydantoin-, Piperazinedione-, and Benzodiazepinedione-Fused Tricyclic and Tetracyclic Ring Systems

Abstract

Fluorous proline derivatives generated from one-pot, three-component [3+2] cycloaddition of azomethine ylides are employed for different post-condensation reactions to form hydantoin-, piperazinedione-, and benzodiazepinedione-fused tricyclic and tetracyclic ring systems. The high synthetic efficiency is achieved by conducting fast microwave reactions and easy fluorous-solid phase extractions for reaction mixture purifications. Methods developed for these novel drug-like heterocyclic compounds can be applied to diversity-oriented library synthesis.

Introduction

Fluorous synthesis employs perfluoroalkyl (Rf) chains as “phase tags”¹ to improve the efficiency of reaction mixture purifications.² This technology shares the characteristics of solution-phase synthesis, which has homogenous reaction enviroment,³ easy intermediate analysis,⁴ and good compatibility to other synthetic techniques such as microwave⁵ and multicomponent reactions.⁶ Compared to its counterpart solid-phase synthesis, fluorous synthesis requires less development time and has the capability to explore new reactions on fluorous support directly.⁷ As a “beadless” synthetic technology, fluorous synthesis has been applied to parallel and mixture synthesis⁸ of small molecules, peptides,⁹ and oligosaccharides.¹⁰

We have recently developed several methods for synthesis of heterocyclic systems by using an orchestrated sequence of microwave-assisted fluorous multicomponent reaction (F-MCR) and fluorous-solid phase extraction (F-SPE) to speed up reactions and simplify purifications.^6,11 Reported in this paper are approaches to three novel triaza tricyclic and tetracyclic ring systems 2–4 (Scheme 1). Proline derivatives 1 generated from one-pot, three-component [3+2] cycloaddition¹² of azomethine ylides are further converted to hydantoin-, piperazinedione-, and benzodiazepinedione-fused compounds 2–4, respectively. Each of these three heterocyclic scaffolds has four stereocenters on the central pyrrolidine ring and up to four points of diversity (R¹ to R⁴). Compound 2 has a similar ring skeleton as tricyclic thrombin inhibitors.¹³ The structure of compound 3 is partially related to diketopiperazine-based inhibitors of human hormone-sensitive lipase.^14,15 Compound 4 contains a privileged benzodiazepine moiety which has a wide range of pharmaceutical utilities.¹⁶

Scheme 1.

Fluorous Synthesis of Heterocyclics 2–4

Results and Discussion

Preparations of fluorous amino esters 5 and one-pot, three-component 1,3-dipolar cycloaddition reactions were conducted by following established procedures.^6a,b Thus a mixture of 1.0 equiv of a fluorous aminoester, 1.2 equiv of a benzaldehyde, 1.5 equiv of an N-alkylmaleimide, and 3 equiv of Et3N in DMF was heated under microwave at 130 °C for 20 min to afford proline derivative 1 (Scheme 2).^17,18 Since the fluorous amino ester 5 was used as the limiting agent, only the desired product 1 was expected to be fluorous. The crude product was loaded on a FluoroFlash cartridge. The non-fluorous components such as unreacted aldehyde, N-alkylmaleimide, and Et₃N salt were eluted out with a fluorophobic solvent (80:20 MeOH-H₂O). Fluorous compound 1 was collected by eluting with MeOH, a more fluorophilic solvent. After F-SPE purification, the purity of the product is usually greater than 90% by ¹H NMR analysis (Figure 1). Bicyclic prolins 1 with different R¹–R³ substitution groups were synthesized in 75–90% yields. The stereochemistry of compound 1a was established based on the literature information^17c,17g and confirmed by single-crystal X-ray diffraction (Figure 2, left). No evidence shows the racemization of the amino acid 5 during the cycloaddition.

Scheme 2.

Synthesis of fluorous proline derivatives by one-pot [3+2] cycloaddition of azomethine ylides. a) 5 (1 equiv), aldehyde (1.2 equiv), maleimide (1.5 equiv), Et₃N (3 equiv), DMF, μw (130 °C, 20 min), F-SPE.

Figure 1.

¹H NMR (in CDCl₃) analysis of compound 1a, before (top) and after (bottom) F-SPE.

Figure 2.

Single-crystal X-ray structures of compounds 1a and 2a

With the key intermediates 1 in hands, we then performed post-condensation reactions to generate different heterocyclic ring systems. The reaction of 1 with 5 equiv of a phenylisocyanate or a phenylthioisocyanate in the presence of catalytic amount of N,N-4-dimethylaminopyridine (DMAP) in toluene gave urea or thiourea 6. After F-SPE purification, compound 6 was mixed with K₂CO₃ and heated under microwave at 100 °C for 5 min. Fluorous tag cleavage and hydantoin ring formation produced tricyclic compound 2 (Scheme 3). Four analogs of 2 were produced in 75–85% yields. After F-SPE followed by HPLC purifications, the products had greater than 95% purities. The stererochemistry of compound 2a was confirmed by single-crystal X-ray diffraction (Figure 2, right).

Scheme 3.

Synthesis of hydantoin-fused tricyclic compounds 2a–d. a) R⁴-PhNCX (5.0 equiv), DMAP (0.5 equiv), toluene, μw (130 °C, 10 min), F-SPE. b) K₂CO₃ (2 equiv), DMF, μw (100 °C, 5 min), F-SPE, HPLC.

In the synthesis of piperazinedione-fused tricyclic compounds 3a and 3b (Scheme 4), direct N-acylations of 1a with α-aminoacids or α-aminoacid chlorides were attempted, but reactions gave products in very low yields (10–25%). Acylation of 1a with chloroacetyl chloride followed by chlorine displacement with BuNH₂ or 3,5-dimethylaniline gave compounds 8a and 8b in 92% and 90% yields, respectively. The detag/cyclization reactions were promoted by 1,8-diazabicyclo[4.3.0]non-5-ene (DBU) under microwave irradiation at 180 °C for 15 min to give product 3a in 45% yield. However, under the same conditions, only a very small amount of 3b (<5%) was detected from the reaction mixture by LCMS.

Scheme 4.

Synthesis of piperazinedione-fused tricyclic compounds 3a–d. a) ClCH₂COCl (1.5 equiv), Et₃N (2.5 equiv), CH₂Cl₂, 25 °C, 30 min, F-SPE. b) R⁴NH₂ (2.5 equiv), MeOH, μw (120°C, 10 min), F-SPE. c) DBU (2 equiv), MeOH-DMF, μw (180 °C, 15 min), F-SPE, HPLC.

Synthesis of benzodiazepine-fused tricyclic compounds 4a–c were accomplished by a three-step reaction sequence (Scheme 5). N-acylation of 1 with 2-nitrobenzoyl chloride gave acylation product 9. We have found that the N-acylation reaction was sensitive to the R¹ substitution; only small R¹ groups such as H and Me gave products in good yields. Compounds 9 were then reacted with zinc dust in acetic acid under sonication to reduce the nitro group and form 10. The cyclative tag cleavage of compounds 10 with DBU produced tricyclic compound 4a–c in 45–58% yields.

Scheme 5.

Synthesis of benzodiazepinedione-fused tetracyclic compounds 3a–d.a) 2-nitrobenzoylchloride (3 equiv), Et₃N (2 equiv), DMF, 80 °C, 2 h, F-SPE. b) Zn dust (10 equiv), AcOH, sonication, 25 °C, 2 h, F-SPE, 65–71%. c) DBU (2 equiv), dioxane, μw (130 °C, 5 min), F-SPE, HPLC.

Conclusion

In summary, we have developed synthetic routes to three triaza tricyclic and tetracyclic rings systems using the common intermediates generated by [3+2] cycloaddition of azomethine ylides. Microwave-assisted fluorous synthesis speeds up reactions and simplifies product purifications. These heterocyclic compounds with ring skeleton, stereochemistry, and substitution variations are good candidates for diversity-oriented synthesis.