One-Pot Multicomponent Synthesis of Diversely Substituted 2-Aminopyrroles. A Short General Synthesis of Rigidins A, B, C and D

Abstract

Privileged medicinal scaffolds based on the structures of tetra- and penta-substituted 2-aminopyrroles were prepared via one-pot multicomponent reactions of structurally diverse aldehydes and N-(aryl-, hetaryl-, alkyl-sulfonamido)-acetophenones with activated methylene compounds. This methodology was used in a four-step synthesis of alkaloids rigidins A, B, C and D in overall yields 61%, 58%, 60% and 53%, respectively. Of these, rigidins B, C and D were synthesized for the first time.

Polysubstituted pyrroles are an important class of heterocycles that display diverse pharmacological activities.¹ Furthermore, they are useful building blocks in the synthesis of natural products and heterocyclic chemistry. Although a large number of new pyrrole syntheses,² including multicomponent reactions (MCRs),³ have been reported in recent years, relatively few examples are known for the preparation of polysubstituted 2-aminopyrroles.⁴ Aminopyrroles are not readily available through general pyrrole ring-formation methods. At the same time the 2-aminopyrrole fragment is part of many different bioactive compounds and it is recognized as a privileged medicinal structure. Known bioactivities for this class of compounds include anti-inflammatory,⁵ anticancer,⁶ antiviral,⁷ antifungal,⁸ pesticidal,⁹ radioprotective,¹⁰ MEK inhibitory,¹¹ MK2 inhibitory,¹² FAK, KDR and Tie2 inhibitory,¹³ PDE inhibitory,¹⁴ anti-interleukin-6,¹⁵ TNF-α production inhibitory,¹⁶ and afferent pelvic nerve activity inhibitory.¹⁷ Moreover, 2-aminopyrroles are precursors for the synthesis of purine analogs – pyrrolopyrimidines, pyrrolotriazines and pyrrolopyridines.^18–24 These pyrrole containing heterocycles are widely investigated for their multiple bioactivities, which, among many others, are known to include anti-inflammatory,¹⁸ anticancer,¹⁹ antiviral,²⁰ antifungal,²¹ adenosine A₁ receptor inhibitory,²² adenosine kinase²³ and dihydrofolate reductase²⁴ inhibitory. The pyrrolo[2,3-d]pyrimidine ring system is also a common motif in several natural products, such as nucleoside antibiotics tubercidin, toyocamyin, sangivamycin,²⁵ and marine alkaloids rigidins A, B, C, D and E.²⁶

Previously, we described a novel method for the synthesis of multisubstituted pyrrolines using a multicomponent reaction of various N-(aryl-and alkylsulfonamido)-acetophenones with aldehydes and malononitrile (see Table 1 graphic).²⁷ While the reaction is regioselective, it is not stereoselective and gives mixtures of cis and trans 2-pyrrolines, which are not easily separable. Utilizing this methodology as a starting point, we developed a new muticomponent one-pot method for the synthesis of tetra-and penta-diversely substituted 2-aminopyrroles. In addition, we utilized the new method for a short total synthesis of alkaloids rigidins A, B, C and D.

Table 1.

Synthesis of Penta-substituted Pyrroles A

Pyrrole	Ar	R1	R2	E	yield %
A1	Ph	4-O2N-Ph	4-Cl-Ph	CN	81
A2	Ph	2,4,6-i-Pr-Ph	3,4,5-MeO-Ph	CN	91
A3	Ph	4-MeO-Ph	3,4,5-MeO-Ph	CN	89
A4	4-MeO-Ph	4-MeO-Ph	3-Br-4,5-MeO-Ph	CN	78
A5	Ph	Me	3-Br-4-MeO-Ph	CN	37
A6	Ph	4-MeO-Ph	3,5-Br-Ph	CN	56
A7	Ph	4-MeO-Ph		CN	41
A8	Ph	4-MeO-Ph	2,6-Cl-Ph	CN	78
A9	Ph	4-F-Ph	2,6-Cl-Ph	CN	55
A10	Ph	Bu	4-O2N-Ph	CN	71
A11	Ph	4-Me-Ph	Pr	CN	55
A12	Ph	Me		CN	50
A13	Ph		4-MeOOC-Ph	CN	96
A14	Ph	Me	2-Cl-6-F-Ph	CN	88
A15	Ph	Me	2,6-Cl-Ph	CN	65
A16a	Ph	4-MeO-Ph	4-Br-Ph	CONH2	38
A17a	Ph	4-MeO-Ph	3,4,5-MeO-Ph	COOEt	76

^aThe intermediate pyrrolines were obtained in EtOH.

Penta-substituted 2-aminopyrroles A_1–17 were prepared by a multicomponent reaction of N-(aryl-, hetaryl-and alkylsulfonamido)-acetophenones, aldehydes and cyanoacetic acid derivatives in acetonitrile, followed by oxidation with DDQ in one pot (Table 1). This three-component process works well for any tested combination of aliphatic, aromatic (including sterically hindered or heteroaromatic) aldehydes and malononitrile, cyanoacetamide or ethyl cyanoacetate. Because of the lower reactivity of the intermediate Knoevenagel products of cyanoacetamide or ethyl cyanoacetate, the reactions were sluggish in acetonitrile (A₁₆ and A₁₇). In these cases the pyrrolines were obtained in ethanol, the solvent was then evaporated and the crude material redissolved in acetonitrile for the subsequent oxidation with DDQ. When phenylsulfonyl-or 4-methoxybenzoylacetonitriles were used in this reaction, a mixture of pyrrolines was obtained, which did not undergo oxidation to the corresponding pyrroles.

This methodology was also used for the synthesis of tetra-substituted NH-pyrroles by base-promoted dehydrosulfinylation of the 2-pyrroline mixtures. It was previously reported that DBU was able to promote the elimination toluenesulfinic acid from N-tosyl-3-pyrrolines to give pyrroles.²⁸ In our case, the treatment of mixtures of 2-pyrrolines with DBU in DMF leads to the formation tetra-substituted NH-pyrroles B_1–5 (Table 2). We found that 4-MeO-PhSO₂-and MeSO₂-leaving groups are the best for this reaction, but it is necessary to change the solvent from acetonitrile to DMF. Furthermore, after the experimentation with different solvents, bases and reaction temperatures we found that simply refluxing a solution of the three reactants containing 0.6 equivalents K₂CO₃ in ethanol results in pyrroles B_5–17 (Table 3).²⁹

Table 2.

Synthesis of Tetra-substituted Pyrroles B

Pyrrole	Ar	R1	R2	yield %
B1	Ph	Me	Pr	43
B2	Ph	4-MeO-Ph		80
B3	Ph	4-MeO-Ph	2,6-Cl-Ph	70
B4	Ph	4-MeO-Ph	3,5-Br-Ph	70
B5	Ph	4-O2N-Ph	3,4,5-MeO-Ph	19
B5	Ph	2,4,6-i-Pr-Ph	3,4,5-MeO-Ph	24
B5	Ph	4-Me-Ph	3,4,5-MeO-Ph	45
B5	Ph	4-MeO-Ph	3,4,5-MeO-Ph	59
B5	Ph	Me	3,4,5-MeO-Ph	78

Table 3.

Synthesis of Tetra-substituted Pyrroles B

pyrrole	Ar	R2	E	yield %
B5	Ph	3,4,5-MeO-Ph	CN	80
B6	Ph	2-Cl-6-F-Ph	CN	76
B7	Ph	4-MeO-Ph	CN	55
B8	4-MeO-Ph	3,4,5-MeO-Ph	CN	85
B9	Ph	4-Br-Ph	CN	73
B10	4-MeO-Ph	4-MeO-Ph	4-MeO-Bz	48
B11	Ph	4-O2N-Ph	SO2Ph	28
B12	Ph	4-Br-Ph	SO2Ph	40
B13	Ph	3,4,5-MeO-Ph	SO2Ph	52
B14	Ph	3,4,5-MeO-Ph	COOEt	57
B15	Ph	2,6-Cl-Ph	CONH2	48
B16	Ph	4-MeO-Ph	CONH2	93
B17	4-MeO-Ph	4-MeO-Ph	CONH2	89

The reaction scope encompasses the use of aliphatic, aromatic, and heterocyclic aldehydes as well as diverse activated methylene compounds including cyano, acyl, sulfono, alkoxycarbono and carbamido acetonitriles.

Tetra-substituted 2-aminopyrroles, containing a 3-carbamido-group, are a structural unit of marine alkaloids rigidins (Figure 1). These alkaloids have been isolated from tunicates obtained near Okinawa and New Guinea and have been shown to possess calmodulin antagonistic and cytotoxic activities.²⁶ Several syntheses of rigidins A and E have been reported.³⁰ Using our methodology for the synthesis of tetra-substituted pyrroles, we developed the shortest general approach to obtain these alkaloids. Moreover, rigidins B, C and D were synthesized for the first time (Figure 1). Commercially available aminoacetophenones were converted to N-(methanesulfonamido)-acetophenones 1 and 2 in almost quantitative yields and the latter were used in the three-component reaction to obtain 2-aminopyrroles B₁₈-B₂₁. Carbonylation was achieved with oxalyl chloride in diglyme to give pyrimidinediones C₁-C₄, these were subjected to hydrogenolysis to yield the desired rigidins with overall yields of 61% for A, 58% for B, 60% for C and 53% for D. Our synthesis compares favorably with the published approaches for rigidin A (7–9 steps and 26–40% overall yields).³⁰ The spectral data are consistent with those published for the natural products.²⁶ At the present time, we are preparing a library of rigidin analogues for biological testing.

Figure 1.

Total Synthesis of Rigidins A, B, C and D.

We performed a preliminary biological evaluation of the synthesized tetra-and penta-substituted pyrroles for anticancer and antibacterial activities. The antiproliferative activity was assessed using the cancer cell line, HeLa, as a model for human cervical adenocarcinoma, through the measurements of mitochondrial dehydrogenase activities using MTT method.³¹ In addition, pyrroles A and B were tested against Staphylococcus epidermidis (ATCC 75984), where Minimum Inhibitory Concentrations (MICs) were determined by broth microdilution method.³² We found that selected synthesized pyrroles exhibit activities in these assays (Table 4), supporting the idea that diverse biological activities are likely to be found within the libraries of privileged medicinal structures such as 2-aminopyrroles. More detailed biological evaluation will be published elsewhere later.

Table 4.

Biological Activities of Pyrroles A and B.

	IC50,μM (HeLa)	MIC, μM (S. epi)		IC50, μM (HeLa)	MIC, μM (S. epi)
A2	12.5	>200	B2	37.5	>200
A3	17	>200	B3	>100	30
A6	20	>200	B4	3.1	>200
A7	6.2	>200	B5	75	>200
A8	50	>200	B6	>100	25
A13	75	>200	B8	37.5	>200
A14	25	>200	B10	20	50
A15	>100	25

In summary, a one-pot, multicomponent reaction of structurally diverse aldehydes, N-(aryl-, hetaryl and alkylsulfonamido)-acetophenones, with activated methylene compounds results in the formation of tetra-and penta-substituted 2-aminopyrroles. This methodology was used for a four-step total synthesis of natural products rigidins A, B, C and D. This synthesis is flexible and can be adapted to the preparation of a library of rigidin analogs.