Construction of functionalized tricyclic dihydropyrazino-quinazolinedione chemotypes via an Ugi/N-acyliminium ion cyclization cascade

Abstract

Dihydropyrazino-quinazolinedione chemotypes are complex and structurally challenging structures of biological interest, being found in the marine alkaloids such as brevianamide M-N and fumiquinazolines A-C. Herein we report the synthesis of this tricyclic system in three synthetic operations by means of an Ugi multi-component reaction (MCR) followed by a tandem N-acyliminium ion cyclization-intramolecular nucleophilic addition reaction sequence. Additional structural diversification for further library enrichment was also accomplished via sequential N-alkylation and N-acylation/sulfonation.

The compelling quest to discover novel small molecules that modulate protein function has enabled access to ever-growing regions of chemical space.¹ Over the past 20 years, isocyanide-based MCRs (IMCRs) have proven to be a convenient and versatile approach toward expeditious molecular diversity generation, allowing the generation of numerous unique, drug-like small molecules for biological evaluation.² In particular, the Ugi IMCR (Scheme 1), which proceeds through reaction of an aldehyde or ketone, amines, isocyanides and carboxylic acids to produce the dipeptide-like adduct 1, has undergone many post-condensation modifications, accessing numerous new scaffolds. To cite a few examples, these post-MCR transformations comprise Ugi/deprotection/cyclization (UDC),³ Ugi/Heck,⁴ Ugi/Pictet-Spengler,⁵ Ugi/RCM,⁶ Ugi/Knoevenagel,⁷ Ugi/cycloaddition,⁸ Ugi/Diels-Alder,⁹ Ugi/Pd-catalyzed arylation,¹⁰ Ugi/Mitsunobu¹¹ and, most recently, elegant Ugi/Aldol methodologies.¹² In this context, Ugi/N-acyliminium ion sequences used to expand our toolbox of heterocyclic chemotypes are relatively underexploited, and only one article has been published that describes the synthesis of Δ⁵-2-oxopiperazines 3 (Scheme 2) using aminoacetaldehyde diethylacetal 2 as the carbonyl surrogate.¹³ However, reports do exist of N-acyliminium ion strategies being employed with other MCRs.¹⁴ Herein, post-condensation modifications of the Ugi adduct driven by N-acyliminium ion cascade reactions are reported to prepare ketopiperazine containing tricyclic chemotypes 7 (Scheme 3) whose unusual core structure is found in the marine alkaloids brevianamide M-N¹⁵ 8 and 9 and fumiquinazolines A-C¹⁶ 10, 11 and 12 possessing insecticidal and antineoplastic activity, respectively (Figure 1).

Scheme 1.

The Ugi MCR.

Scheme 2.

Synthesis of Δ5-2-oxopiperazines 3

Scheme 3.

General Ugi/N-acyliminium ion cyclization sequences.

Figure 1.

Brevianamide M-N (8 and 9) and fumiquinazolines A-C (10–12).

Thus, studies began with evaluation of reagent compatibility for the Ugi MCR (Scheme 4). Specifically, mixing an aldehyde, 2-fluoro-5-nitro-benzoic acid 4, the ammonia surrogate 2,4-dimethoxybenzylamine 5¹⁷ and 1,1-diethoxy-2-isocyanoethane 6¹⁸ rendered Ugi products 13 upon overnight stirring at ambient temperature in moderate to good yields (43–82%, Table 1). It is worth noting that isocyanide 6 can be readily synthesized in two steps and has also been reported to be an extremely valuable building block for the preparation of several families of heterocycles that include imidazoles¹⁹ and thiazoles.²⁰ Subsequent displacement of the fluorine group in 13 by a primary amine was achieved under mild conditions in DCE and afforded 14, which was subjected without purification to an acid-mediated double cyclization generating tricyclic system 7 (Table 1). Mechanistically, this pathway is presumably initiated by the generation of an oxonium ion and concomitant removal of the acid labile 2,4-dimethoxybenzyl moiety 15 (Scheme 4). Closure of the amidic nitrogen onto the oxonium ion thus leads to the formation of hemiaminal 16, which under the acidic reaction conditions affords N-acyliminium ion 18 with the associated loss of a molecule of ethanol. The sequence concludes through nucleophilic attack of the anilinic amine onto the newly formed N-acyliminium ion 18 to give the desired dihydropyrazino-quinazolinedione 7.

Scheme 4.

Synthesis of dihydropyrazino-quinazolinedione 7.

Table 1.

Tricyclic analogs 7a–f.

Entry	Ugi product	R1	Yield (%)	7	R2	Yield (%)*
1	13a	propyl	67	7a	isobutyl	67
2	13b	phenyl	78	7b	isobutyl	79
3	13c	3-(methylthio)ethyl	43	7c	isobutyl	41
4	13d	cyclopropyl	82	7d	2-methoxyethyl	41

^*two-step yield for fluoride displacement and acid treatment

Scaffold 7 is likely to exist as an anti-diastereomer in which the two hydrogens of the two chiral centers, ‘a’ and ‘b’, are predicted to be in a pseudo-trans relationship (Figure 2). Molecular dynamics studies reveal that both enantiomers of 7a exist in a lower energy state than the corresponding pair of enantiomers (20 and 22) of the alternate diastereomer, thus suggesting preferential formation of 7a.²¹ Observed stereoselectivity may be explained by the steric hindrance between the propyl group and the approaching anilinic nitrogen of intermediate 19 (R-enantiomer) at the si-face that negates formation of 20 (R,R), affording 7a (R,S) as the strongly preferred product (Figure 2). In analogous fashion, si-attack on the intermediate 21 (S-enantiomer) affording 7a (S,R) (Figure 2) is suggested to be favored [Note that comparison of the relative energies of two diastereomers is only justified when assuming reversibility of reactions going through either 19 or 21, with product 7 preferred over 20 under thermodynamic control]. This configuration is in accordance with a report by Patek et al. describing the assembly of 1-acyl-3-oxopiperazines via a multi-step solid-phase synthesis.²² Unequivocal structural confirmation of 7a was also provided by X-ray crystallography (Figure 3).

Figure 2.

Stereoselectivity and calculated energy for each diastereomer.

Figure 3.

Definitive structural confirmation by X-ray crystallography of 11a.

With 7a in hand as the ‘model study’ molecule, a small collection of compounds was prepared to demonstrate the generality of the reaction sequence utilizing different aldehydes and primary amines (Table 1). Concurrently, further functionalization of 7 was also enabled via N-alkylation on the amidic nitrogen and by N-acylation and/or sulfonation upon reduction of the nitro group, leading to the addition of two further diversity points (Scheme 5). Tables 2 and 3 summarize selected alkyl bromides and acyl/sulfonyl chlorides employed to attain 23 and 24, respectively, in high overall yields.

Scheme 5.

Synthesis of dihydropyrazino-quinazolinedione 7.

Table 2.

Functionalized tricyclic chemotype 23.

Entry	7	R3	23	Yield (%)
1	7a	3-methoxybenzyl	23a	94
2	7a	4-fluorophenethyl	23b	87
3	7a	cyclobutylmethyl	23c	87
4	7b	3-methoxybenzyl	23d	71
5	7b	4-fluorophenethyl	23e	46

Table 3.

Functionalized tricyclic chemotype 24.

Entry	23	R4	24	Yield (%)*
1	23a	CO-Ph	24a	85
2	23b	SO2Me	24b	83
3	23b	CO-Ph	24c	75
4	23c	SO2Me	24d	80
5	23c	CO-Ph	24e	89

^*two-step yield for hydrogenation and N-acylation

In summary, a concise three-step synthesis of a collection of tricyclic dihydropyrazino-quinazolinediones 7 has been successfully established with only one diastereomer formed utilizing an Ugi/N-acyliminium ion cyclization-intramolecular nucleophilic addition reaction cascade. Moreover, this scaffold can be readily diversified via sequential N-alkylation and N-acylation and/or sulfonation, adding two further variety points by means of commercially available alkyl bromides and acyl and/or sulfonyl chlorides. Due to the uniqueness of the chemotypes produced, their favorable drug-like properties, and the potential for structural diversification, this procedure represents a practical and enticing approach for the enrichment of small molecules libraries in a high-throughput and operationally friendly manner.