A Three-Layer Transformation Strategy toward Functionalized Fused Hydantoins and Diketopiperazines

Abstract

We present mAUCy (modified Asinger–Ugi cyclization), a scalable three-layer strategy enabling rapid synthesis of diverse thiazolo hydantoins and diketopiperazines. Beginning from 3-thiazolines via a modified Asinger reaction, followed by an Ugi–Joullié multicomponent reaction and base-induced annulation, the method delivers complex compounds in less than 3 h. Operable on a multigram scale without chromatography, it allows telescoped one-pot processing, a broad substrate scope, and late-stage modifications. Single-crystal analysis confirmed the scaffold structures.

Through organic synthesis, humanity has addressed numerous challenges, developing life-saving pharmaceuticals, innovative energy solutions, and cutting-edge materials that improve daily life. − Recognizing its importance, both the United Nations, through the Sustainable Development Goals (SDGs), and the European Union, with the European Green Deal, have emphasized the need for organic synthesis to align with principles of sustainability. Today, organic synthesis must be not only efficient and cost-effective but also environmentally responsible, incorporating renewable resources and minimizing waste to ensure a cleaner and more sustainable future. − Multicomponent reaction (MCR) chemistry has been established as a prominent synthetic methodology toward functionalized molecules complying with the aforementioned principles. MCRs are among the most efficient processes for achieving high atom economy and rapidly constructing molecular complexity. − As a result, they have been extensively utilized in the total synthesis of complex natural products as well as in drug discovery and development. ,− The union of MCRs is an elegant strategy for performing higher-order MCRs, enabling access to diverse and complex molecular architectures. − Coined by Ugi, this approach is typically achieved through tandem MCRs. A key aspect of this strategy is the orthogonal reactivity of at least one reactant, allowing it to participate in at least two different MCRs without the need for functional group protection. This concept significantly enhances the synthetic complexity and efficiency, offering new scaffold types for various applications. Although multitude examples of MCRs exist combined with secondary transformations (postmodifications), only a few examples of rationally combined MCRs have been developed (Figure A). ,− We believe that it holds great potential for further exploration in the synthesis of bioactive molecules. Our group, aiming for an efficient and sustainable approach to accessing privileged structures, − has focused on fused 1,5-hydantoins and 2,5-diketopiperazines (DKPs) for two main reasons. First, hydantoins and DKPs are widely represented in approved drugs and clinical trials for treating various conditions and diseases (Figure B). − Second, they have frequently been utilized as structural peptidomimetics, capable of mimicking protein secondary structures such as α-helices and β-turns. , On the other hand, efficient synthetic methodologies for fused 1,5-hydantoins are limited, mostly using proline or urea, whereas both thiazolo-1,5-hydantoins and 2,5-diketopiperazines are synthetically underexplored. ,,,− Thus, the starting point of our strategy (Figure C) was a 3-thiazoline scaffold that can be derived via the modified Asinger reaction (A-4CR, first layer of transformation). − The latter affords the scaffold of thiazoline, reported numerous times in drug discovery campaigns, but importantly creates a suitable electrophilic imine bond that can serve as an orthogonal handler for subsequent MCRs. ,,

1.

(A) Synthetic capabilities of a union of MCRs, accessing a high degree of diversity and complexity. (B) Hydantoin (green ring) and DKP (yellow ring) as privileged scaffolds in approved and marketed drugs. (C) Our proposed work based on a one-pot union of MCRs, combined with a postmodification toward thiazolo-1,5-hydantoins and thiazolo-2,5-diketopiperazines.

Without further purification, we performed an Ugi–Joullie three-component reaction − (UJ-3CR, second layer of transformation) with a variety of isocyanides and two different acids. In a one-pot fashion, by tweaking the cyclization conditions (third layer of transformation), we obtained both the desired thiazolo-hydantoins and thiazolo-diketopiperazines in less than 3 h (whole procedure). We coin this strategy as modified Asinger–Ugi cyclization (mAUCy), adding to the landscape of Asinger–Ugi combinations , and further expanding its possibilities. Our three-layer mAUCy strategy began with thiazoline derivatives 1a–c, which were obtained via a non-isocyanide-based MCR, the A-4CR using chloroacetaldehyde, and various ketones in aqueous media. , Asymmetrical, symmetrical, and cyclic ketones were utilized, generating either a stereogenic center or a spiro system at position 2 of the corresponding thiazoline. The reaction was completed within 30 min, yielding the desired adducts quantitatively without the need for further purification (Scheme ). Thiazolines 1, featuring an electrophilic imine bond, serve as excellent substrates for the subsequent multicomponent reaction (MCR), specifically the Ugi–Joullié three-component reaction (UJ-3CR). Upon treatment with a variety of isocyanides and trichloroacetic or chloroacetic acid in methanol at room temperature, Ugi adducts 2 and 3 were rapidly obtained in less than 30 min. In most cases, the reaction was completed as soon as the acid was added, accompanied by a color change or formation of the solid. The reaction demonstrated a broad scope, accommodating both aliphatic and aromatic (phenyl and benzyl) isocyanides with diverse substitution patterns, including bulky and linear derivatives. In addition, derivatives bearing synthetically versatile tosylate, ether, and ester functionalities were prepared, providing handles for downstream derivatizations. The choice of the acid was based to facilitate the subsequent cyclization, , yielding the desired fused heterocycles, thereby expanding the scope to cover this entire peptidomimetic family (Scheme ). Thus, without any further purification, the third layer of the whole transformation was completed with a heteroannulation toward the targeted scaffolds. After some optimization (see the Supporting Information), treatment of 2 with Et₃N in MeOH and 3 with NaH in dry THF afforded thiazolo-1,5-hydantoins 4a–m (49–90% total yield, three steps) and thiazolo-2,5-diketopiperazines 5a–i (65–83% total yield, three steps), respectively. The cyclization procedure was instant, especially in the case of the thiazolo-1,5-hydantoins (exothermic reaction), as in 20–30 min, the reactions were completed (Scheme ). Taking our strategy a step further and amplifying its impact, we systematically optimized reagent stoichiometry, base loading, and solvent ratios. By employing a methanolic ammonia solution in combination with Na₂SO₄ as a drying agent, we achieved a fully telescoped, one-pot, six-component transformation, proceeding without any intermediate workup or filtration. This protocol delivers the fused thiazolo-hydantoin and DKP products directly from the starting ketone, chloroacetaldehyde, sulfur, ammonia, isocyanide, and acid in a single operational step, as demonstrated with certain representative examples (Scheme ). The UJ-3CR has often been associated with specific diastereoselectivity outcomes. , This provided additional motivation for employing asymmetric thiazoline 1c. Accordingly, the UJ-3CR of 1c toward 2g–i yielded the corresponding Ugi adducts in a 1:1 dr ratio. This lack of selectivity is likely due to the strong acidity (low pK _a) of trichloroacetic acid in a protic solvent, which leads to full protonation of the imine nitrogen and the formation of a less stabilized iminium ion. This favors an SN1-type transition state, resulting in no stereochemical preference for the approach of the isocyanide to either face of the thiazoline ring. In contrast, the UJ-3CR of 1c to 3i (chloroacetic acid) yielded a dr of 1:0.5. In this case, the weaker acidity of chloroacetic acid leads to a highly stabilized (more neutral) iminium ion, which in combination with a protic solvent results in some differentiation between the two faces of the thiazoline ring (SN2-type transition state). Notably, upon cyclization, the dr ratio of adducts derived from 2 changed to 1:0.6, while that of the adducts from 3 equilibrated to 1:1, possibly due to epimerization.

1. Three-Layer mAUCy Strategy and Synthesized Libraries of Hydantoins 4a–m and DKPs 5a–i Demonstrating a Broad Diversity.

^* Final conversion as calculated by ¹H NMR spectra.

^** The dr ratio refers to the crude mixture before purification.

To assess the scalability of our approach, a critical factor in modern synthetic methodology, we performed a 10 mmol scale-up of both a representative hydantoin (4a) and a diketopiperazine (5a) in 95% and 91% overall yields, respectively, over three steps. All three steps proceeded smoothly and without complications. Remarkably, the final adducts were obtained without the need for column chromatography or even washing steps. The overall process was completed in approximately 3 h, including reaction and workup (Scheme A).

2. (A) Scalability of Our Approach, (B) Employment of a Convertible Isocyanide (including a vial photo of 4j) Yielding Free -NH Hydantoin 6, Exploiting the Full Potential of Our Synthesis, (C) Selective Oxidation of Compounds 4a and 5a toward Sulfoxides 7a and 8a and Sulfones 9a and 10a, Respectively .

^a Compounds 4a and 5a were scaled up to 10 mmol, without the need for column chromatography.

^b Single-crystal structures of enantiomers R _S R-8a and S _S S-8a (CCDC 2479402) and 10a (CCDC 2479403) are shown (thermal ellipsoids at the 50% probability level).

To further demonstrate the utility of our synthesis, we carried out selected postmodification reactions on the synthesized adducts. Obtaining the free NH form of thiazolo-1,5-hydantoins is particularly important. − The free NH group not only enables further chemical derivatization but also plays a crucial role in drug development by participating in intricate hydrogen-bonding networks, including trifurcated hydrogen bonds. This feature is exemplified in several approved drugs (Figure ). For that reason, we have employed the convertible isocyanide 2-nitrobenzyl isocyanide, exploiting the synthetic capabilities of our chemistry. Treatment of compound 4j with ^t BuOK in MeOH afforded the desired 6 in 39% yield (Scheme B).

Both scaffolds, 4 and 5, contain an oxidizable sulfur atom. In drug discovery campaigns, oxidation of sulfur to sulfones is a common strategy, as it can introduce additional molecular interactions, impose conformational constraints, particularly valuable in peptidomimetic scaffolds like ours, and improve physicochemical properties. We successfully achieved selective oxidation toward sulfoxides and sulfones by carefully controlling the reaction conditions. Using m-CPBA, oxidation of substrates 4a and 5a to the corresponding sulfoxides was completed within 15 min, affording products 7a and 8a in 90% and 73% yields, respectively, without the need for column chromatography. Extending the reaction time to 1–3 h allowed isolation of sulfones 9a and 10a in 88% and 47% yields, respectively (Scheme C). Notably, the oxidation to sulfoxides proceeded with excellent diastereoselectivity. Single-crystal diffraction and NMR analysis confirmed the exclusive formation of the R _S R and S _S S diastereomers, enantiomeric pairs, in both sulfoxide products 7a and 8a, respectively. We propose that the stereogenic center in the heterocyclic scaffold influences the conformation of the thiazolidine ring, which, in turn, governs the spatial orientation of the methyl substituents. This conformational bias results in one sulfur lone pair being sterically exposed and accessible to oxidation, while the opposite lone pair is shielded by the axial methyl group, directing the selective formation of a single sulfoxide diastereomer. Attempts to further derivatize acetal-substituted hydantoins under acidic conditions were unsuccessful due to preferential thiazolidine ring opening (see the Supporting Information).

To support proposed scaffolds 4 and 5 and to highlight their value as peptidomimetics, we determined the crystal structures of both compounds (Figure ). Τhe hydantoin ring in compound 4a is nearly planar (C9–N1–C8–N2 torsion angle of 7.3°), with the benzyl group oriented perpendicular to the plane of the ring (∼80° (see the Supporting Information)). In contrast, the diketopiperazine ring in compounds 5a and 5e adopts a boat conformation (C10–N2–C11–C8 torsion angle of 38.7°), likely due to the conformational constraints imposed by the fused thiazolidine ring. ,− Understanding the spatial characteristics and conformation of those systems (geometrical features shown in Figure ) is crucial for elucidating their molecular properties and, consequently, for gaining deeper insight into their interactions with biological targets. Notably, they appeared mostly spherical in shape and rigid (see the Supporting Information).

2.

Single-crystal structures of hydantoin 4a (CCDC 2479401) and DKPs 5a (CCDC 2479399) and 5e (CCDC 2479400) were obtained as racemic mixtures (the hydrogen atoms have been omitted in the crystal structures for the sake of clarity with thermal ellipsoids drawn at the 50% probability level). Certain geometrical features are also depicted.

In summary, we have developed mAUCy, a modular and scalable three-layer synthetic strategy integrating a union of MCRs, a modified Asinger reaction, and an Ugi–Joullié reactions, with a base-induced cyclization to access fused thiazolo hydantoins and diketopiperazines. The process is rapid (<3 h), is often free of chromatography, and accommodates a wide range of substrates, enabling structural diversity and straightforward scale-up. We were able to establish a fully telescoped reaction, representing the first reported example of such a high-order multicomponent transformation operating in a single operational sequence. The structures of representative hydantoin and diketopiperazine adducts were confirmed by single-crystal structures, providing insight into their potential binding modes. Furthermore, targeted postmodifications, including stereoselective access to the corresponding sulfoxides and sulfones, demonstrated the strong applicability of this approach in peptidomimetic and medicinal chemistry contexts.

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.5c05391.

• General procedures, optimization table, and characterization data for products (PDF)

The open access publishing of this article is financially supported by HEAL-Link.

The authors declare no competing financial interest.