Ribose conversion with amino acids into pyrraline platform chemicals - expeditious synthesis of diverse pyrrole-fused alkaloid compounds.

One-pot conversion of sustainable d-ribose with l-amino acid, methyl esters produced pyrrole-2-carbaldehydes 5 in reasonable yields (32-63%) under pressurized conditions of 2.5 atm at 80 °C. The value-added pyrraline compounds 5 as platform chemicals were utilized for quick installation of poly-heterocyclic cores for the development of pyrrole-motif natural and artificial therapeutic agents. A pyrrole-fused piperazin-2-one scaffold 6 was prepared by reductive amination of pyrralines 5 with benzylamine. While further cyclization of pyrralines 5 with ethane-1,2-diamine produced pyrrolo-piperazin-2-ones 7 with an extra imidazolidine ring, the reaction with 2-amino alcohols derived from natural l-amino acids, alanine, valine, and phenylalanine, respectively provided pyrrolo-piperazin-2-ones 8, 9, and 10 with oxazolidine as the third structural core. Cell viability and an anti-inflammatory effect of the synthesized compounds were briefly tested by the MTT method and the Griess assay, among which 8h and 10g exhibited significant anti-inflammatory effects with negligible cell toxicity. This journal is © The Royal Society of Chemistry.

Introduction

Pyrrole is an interesting five-membered heterocyclic compound with the nitrogen lone-pair electrons being delocalized within the ring for aromaticity. It is therefore non-basic contrary to the six-membered ring homologue, pyridine. Alkaloid natural products containing pyrrole as a pharmacophore exhibit various biological activities such as sedative, anti-inflammatory, anti-biotic, anti-cancer, anti-hypertensive, anti-convulsant, anti-malarial, and many more.[1-6] The organic synthesis of pyrrole was reported in the late 19th century,[7-9] among which the Paal–Knorr method utilizing a 1,4-dicarbonyl compound and primary amine was the first (Fig. 1).[10-12] The Hantzsch method by the reaction of α-haloketone and β-ketoester with a primary amine is useful for the preparation of 3-carboxylated pyrroles.[13,14] In 1948, Clauson-Kaas reported furan conversion into 2,5-dimethoxytetrahydrofuran for the efficient preparation of pyrroles.[15] Many others then modified the above original methods for the syntheses of various pyrrole compounds.[16-33]

Fig. 1

The original synthetic methods of pyrrole and structures of some pyrrole derivatives.

Transformation of d-glucose as sustainable biomass into 5-hydroxymethyl-2-furfural (5-HMF) as a value-added platform chemical has been well documented in the literature in recent years.[34-36] Utilization of reducing sugars for the preparation of pyrroles would also be beneficial and providential. In 1912, Maillard reported the reaction between d-glucose and amino acids at high temperature (>140°) to produce hundreds of small chemicals for flavouring in food chemistry,[37] which was later known to include pyrraline 1, the nitrogen analogue of 5-HMF, in a very small quantity.[38] Pyrraline 1 would be a useful platform chemical for the development of pyrrole-motif natural and artificial therapeutic agents by further reactions.[39-43]

The first chemical synthesis of pyrralines 1 by Kato from the reaction of d-glucose and primary amines either at 100 °C in H2O for 1 h or at 70 °C in MeOH for 3 h both with acetic acid just confirmed the formation of pyrralines 1.[44] Monnier reported the synthesis of butyl pyrraline 1 (R = Bu) in only 3.4% yield by the reaction of d-glucose and butylamine in aqueous acetic acid at 100 °C for 2 h.[38] We believed that the low yield of pyrraline 1 was ascribed to the unstable imine intermediates under the aqueous acidic condition. We recently studied the reaction conditions of d-glucose and primary amines, and significantly improved the yield of pyrralines 1 (20–50%) under non-aqueous condition by use of oxalic acid in DMSO at 90 °C for 30 min.[45] Anti-inflammatory and pain-relieving pyrrolo-lactones 2, which could be isolated from Celastrus orbiculatus (R = Bn) and Capparis spinosa (R = Me), were synthesized in 27% and 32% yields, respectively when methyl esters of amino acids, phenylalanine and alanine, were used as primary amines in the above one-pot reaction condition.[45] Nonetheless, it was still necessary to improve the one-pot reaction conditions of sugars and amino acids for reasonable yields of the pyrrole platform chemicals, which might be realized by reducing the formation of tar by-product under a pressurized reaction condition.

Piperazin-2-one is a privileged structural unit in drug discovery because many of the biologically active natural products and the approved drug molecules contain the above scaffold,[46-49] which exhibit opiate,[50] antiviral,[51] anti-cancer,[52] and anti-diabetes activities[53] as well as treatment effects for immunological disorder[54] and non-Hodgkin's lymphoma.[55] Pyrrole-fused piperazin-2-ones (3 and 4 in Fig. 1) would thus be a very promising structural unit for the discovery of new therapeutic agents. In fact, the structure of pyrrolo-piperazinone 3 has been found in numerous antibiotic and cytotoxic alkaloid natural products, such as agelastatins,[56,57] longamide,[58] hanishin,[59] and agesamides.[60]

We envisioned that the structure of pyrrolo-piperazinone 4 would be obtainable from pyrrole-2-carbaldehyde 5, which might be prepared by the one-pot “Maillard-type” reaction between d-ribose and α-amino acids. Amination of the formyl group and subsequent lactam formation with the carboxylic ester in pyrrole-2-carbaldehyde 5 would form the core structure of pyrrolo-piperazinone 4. In this paper, we described one-pot conversion of d-ribose with various α-amino acids under a pressurized condition to obtain reasonable yields of pyrrole-2-carbaldehydes 5 as platform chemicals and their further cyclization reactions to pyrrolo-piperazinone derivatives 6–10 as new potential therapeutic agents. Finally, cell viability and anti-inflammatory effect of the synthesized pyrrolo-piperazinones were briefly tested for RAW264.7 cells by the MTT method and the Griess assay.

Results and discussion

One-pot ribose conversion with amino acid

d-Ribose was first reacted with l-valine methyl ester in DMSO with oxalic acid at 90 °C for 30 min to produce pyrraline 5 (R = i-Pr) in 24% yield, which was the previous optimized condition for d-glucose.[45] Unlike d-glucose case providing pyrrololactones, pyrrole-2-carbaldehyde 5 with intact methyl ester was obtained. Pyrroles as the glycosylation end products were believed to be formed through 3-deoxyglucosone intermediate after N-glycosylation and Amadori reaction.[38,61,62] The reaction of d-ribose was thus speculated to follow N-glycosylation (A) and Amadori reaction (B) in sequence (Scheme 1). Second amino ester was introduced to give the structure C by imine tautomerization and dehydration, which is the adduct of amino esters to the 3-deoxyglucosone homologue from d-ribose. Cyclization of enamine and dehydration produced pyrrole ring D. Finally, hydrolysis of the imine provided pyrraline 5 and regenerated amino ester. d-Ribose reaction with other amino esters from l-phenylalanine and l-methionine also produced the corresponding pyrralines 5 in 37% (R = Bn) and 30% (R = CH2CH2SMe) yields, respectively, but it was imperative to improve the ribose conversion reaction to utilize pyrralines 5 as sustainable platform chemicals for the discovery of potent therapeutic agents.

Scheme 1

Ribose conversion with amino ester through N-glycosylation, Amadori reaction, and cyclization to produce pyrraline 5 as platform chemicals.

The ribose conversion reaction with α-amino methyl esters under the above condition produced pyrralines 5 in 24–37% yields as the only isolable product together with dark-brown tarry materials, which suggested that reducing the amount of tar would improve the yield of pyrralines 5. The ribose conversion was thus studied for the above three amino esters under pressurized conditions (1–4 atm) at 90 °C to reduce the tar formation (Table 1). We found gradual yield improvements of 5 as pressure was increased with the maximum value at 2.5 atm. The yield of 5 was maintained or slowly fell after 3.0 atm.

Optimization of d-ribose conversion (%yield of 5) with l-amino acid, methyl ester at 90 °C under various pressure conditions

AAa	Yield of 5 (%) under each pressure (atm)
	1	1.5	2	2.5	3	3.5	4
Val	24	29	30	38	36	36	33
Phe	37	38	39	48	47	46	46
Met	30	35	36	42	37	37	37

Amino acid: valine (R = i-Pr), phenylalanine (R = Bn), methionine (R = CH2CH2SMe).

Reaction temperature was then screened from 60 °C to 90 °C at the optimal pressure of 2.5 atm (Table 2). The yield of 5 was progressively improved as temperature was raised up to 80 °C and fell slowly down since then. The best yields of pyrralines 5 were obtained at 80 °C (2.5 atm) for all three amino esters, which were approximately 150% of those at the previous optimal condition for glucose (90 °C, 1 atm).[45]

Optimization of d-ribose conversion (% yield of 5) with l-amino acid, methyl ester at 2.5 atm under various temperature conditions

AAa	Yield of 5 (%) at each temperature (°C)
	60	70	75	80	85	90
Val	29	31	38	42	39	38
Phe	35	41	45	54	48	48
Met	32	35	37	46	43	42

Amino acid: valine (R = i-Pr), phenylalanine (R = Bn), methionine (R = CH2CH2SMe).

Generality of the ribose conversion with α-amino methyl esters and improvement of the yields of pyrralines 5 under the pressure condition (2.5 atm, 80 °C) compared to the original one (1 atm, 90 °C) were summarized in Table 3, in which 150–300% yield increases for pyrralines 5 were notified for eleven natural l-α-amino acids. Amino esters reacted with d-ribose as nucleophile and the yields of pyrralines 1 were reflected by the nucleophilicity of each amino ester, which was differentiated by the α-substituent R in this case. It was initially predicted that R would provide steric hinderance to the amino group, thereby lower yield of 1 could be obtained as the size of R was increased. Surprisingly, it was l-glycine (R = H), however, which gave the lowest yield (32%) of pyrraline 1, and the highest yield of 1 (63%) was obtained for l-leucine (R = i-Bu).

Improvement of d-ribose conversion (% yield of 5) with l-amino acid, methyl ester at 2.5 atm and 80 °C compared at 1.0 atm and 90 °C

Amino Acida	Compound 5	Yield of 5 (%)
		1.0 atm, 90 °C	2.5 atm, 80 °C
Gly	5a	10	32
Ala	5b	23	38
Val	5c	24	42
Leu	5d	43	63
Ile	5e	20	40
Phe	5f	37	54
Bn	5g	20	53
Asp	5h	18	47
Glu	5i	16	37
Met	5j	30	46
Trp	5k	34	55

Amino acid (R): glycine (H), alanine (Me), valine (i-Pr), leucine (i-Bu), isoleucine (s-Bu), phenylalanine (CH2Ph), benzylalanine (CH2CH2Ph), aspartic acid (CH2CO2Me), glutamic acid (CH2CH2CO2Me), methionine (CH2CH2SMe), tryptophane (3-indole).

It seemed that the hydrogen bonding between primary amino and ester groups would reduce the nucleophilicity of amino esters. l-Glycine with no α-substituent may participate in the hydrogen bonding, which reduces the nucleophilicity of the amino group. Primary alkyl or aryl substituents R (e.g., Leu, Phe, Bn) would be good enough to maintain the nucleophilicity of amino group by interrupting the hydrogen bonding without providing steric hinderance to the amino group. Pyrralines 5 can now be obtained in 32–60% yield by one-pot conversion from d-ribose with l-amino acid methyl esters and certainly be flatform chemicals for the syntheses of pyrrole-based poly heterocyclic compounds as potential therapeutic agents.

Cyclization of the platform pyrralines 5 to pyrrolo-piperazinones 6–10

We demonstrated three different methods for further cyclization of pyrralines 5, derived from eight different l-amino acids – glycine (a), alanine (b), valine (c), isoleucine (d), phenylalanine (e), benzylalanine (f), aspartic acid (g), and methionine (h) – with five different nitrogen reagents to produce the 2-piperazin-2-one skeleton as the second pharmacophore with the basic pyrrole scaffold (Scheme 2 and Table 4). The 1,5-relationship between the carbonyl carbons of formyl and ester groups in pyrralines 5 allowed δ-lactam formation with primary amines by reductive amination and cyclization. Benzylamine was utilized for the reductive amination with pyrralines 5, which was carefully carried out first by imine formation in MeOH at 25 °C, followed by selective NaBH4 reduction at 0 °C due to the presence of the sensitive α-amino ester group. The resulting secondary amine underwent lactam formation with the ester group in the presence of DBU at the reflux temperature of toluene to produce pyrrolo-piperazin-2-ones 6 in 36–84% yields (Table 4).

Scheme 2

Further cyclization of pyrraline platform chemicals 5 to pyrrolo-piperazin-2-one derivatives 6–10.

Yields (%) of the reactions in Scheme 2

Entry	R	6	7	8	9	10
a	H	36	58	12	4	6
b	Me	66	87	41	27	32
c	i-Pr	73	94	73	61	41
d	s-Bu	86	91	77	50	31
e	PhCH2	41	86	52	71	62
f	PhCH2CH2	64	88	22	51	57
g	MeO2CCH2	84	72	27	10	14
h	MeSCH2CH2	47	87	24	24	22

α,ω-Alkanediamine (e.g., 1,2-ethanediamine) can be utilized in lactam formation with pyrralines 5, where initially formed imine may react with the second amine by cyclization.[40,41] One of the resulting two symmetrical secondary amines participated in further cyclization with the ester group to form pyrrolo-piperazinones 7 with an imidazolidine ring as the third core in 58–94% yields (Table 4). The conversion of pyrralines 5 with norephedrine was reported,[42] where the initially formed imine was reacted with the alcohol group by cyclization to form an oxazolidine unit, which underwent further cyclization with the ester group to produce pyrrolo-piperazinones with the oxazolidine unit. In a similar manner, 2-amino alcohols derived from natural α-amino acids, alanine (Y = Me), valine (i-Pr), and phenylalanine (Bn), can be utilized for the syntheses of oxazolidine-fused pyrrolo-piperazinones 8, 9, and 10, respectively. Even though somewhat lower yields were notified for the pyrralines 5 from Gly (a, R = H), Asp (g, CH2CO2CH3), and Met (h, CH2CH2SCH3), fare yields of poly heterocyclic products 8–10 were obtained for the pyrralines 5 derived from α-amino acids with a simple alkyl substituent (Table 4).

Cell viability (MTT test) and anti-inflammation assays (Griess method)

All the synthesized pyrrolo-piperazinones 6–10 (a–h) were briefly screened for cytotoxicity to RAW264.7 cells (Murine macrophages) at a fixed concentration at 20 μg mL−1. Four compounds 7a, 7c, 8h, and 10g showed 80% or higher cell viability by Formazan formation in MTT {3-(4,5-dimetnythiazol-2-yl)-2,5-diphenyl-thetazolium bromide} assay (see ESI†).[63] The other regents might still be good candidates for antibiotics.

Anti-inflammatory activities to RAW264.7 cells were then tested for the above four samples at five different concentrations (0, 1, 5, 10, 20 μg mL−1 each) in 24 h after triggering by 1 μg mL−1 of LPS (lipopolysaccharides). Nitric oxide concentration, which is correlated with the inflammation level, was determined by the Griess method.[64] The measurements were repeated three times. The mean and standard deviation values of the NO concentration (μg mL−1) for the cell treated by each compound at each concentration are listed in Table 5. Pyrrolo-piperazinones 8h and 10g containing oxazolidine as the third core exhibited significant anti-inflammation activities, in which IC50 values were estimated to be 20 μg mL−1 and 10 μg mL−1, respectively. For comparison, IC50 of NIL {l-N6-(1-iminoethyl)lysine} as a positive control was measured as 10.17 mM, which is converted as 2.64 μg mL−1 (see ESI†).

Nitric oxide concentration (μM) by Griess assay for RAW264.7 cells after treatment of each reagent (μg mL−1) and lipopolysaccharides (LPS, 1 μg mL−1)

Conc. (μg mL−1)
0a	3.21 ± 0.15	3.21 ± 0.15	3.21 ± 0.15	3.21 ± 0.15
0	25.54 ± 2.60	25.54 ± 2.60	25.54 ± 2.60	25.54 ± 2.60
1	26.23 ± 2.60	25.03 ± 2.13	22.23 ± 2.13	17.31 ± 1.31
5	22.31 ± 1.65	24.32 ± 1.31	21.32 ± 1.31	15.32 ± 2.60
10	20.30 ± 2.65	23.51 ± 1.10	16.31 ± 1.10	14.31 ± 2.11
20	20.02 ± 3.64	21.65 ± 2.51	14.32 ± 2.51	11.10 ± 1.31

Without LPS treatment.

Experimental

General experimental

Reactions were performed in a well-dried flask under argon atmosphere unless noted otherwise. A mini-clave steel reactor (100 mL, up to 15 bar) made from büchiglasuster (Switzerland) was used for the pressurized reactions. The pressure was controlled by argon gas (see ESI† for picture demonstration). Solvents used as reaction media were dried over pre-dried molecular sieve (4 Å) by microwave oven. Solvents for extraction and chromatography were reagent grade and used as received. The flash column chromatography was performed by the method of Still (J. Org. Chem., 1978, 43, 2923) with silica gel 60 (70–230 mesh) using a mixture of EtOAc/hexane as gradient eluent. 1H and 13C NMR spectra were respectively recorded on a 400 MHz and 100 MHz NMR spectrometer in deuterated chloroform (CDCl3) with tetramethylsilane (TMS) as an internal reference unless noted otherwise.

Cell viability assay (MTT method)[63]

RAW264.7 cells (Murine macrophages) were cultured using Dulbecco's modified Eagle medium (DMEM) (Welgene, Seoul, Korea) containing 10% fetal bovine serum (FBS), 2 mM glutamine, and 100 unit/mL of antibiotics (Gibco BRL, Rockville, MD). Cells were incubated at 37 °C incubators, which maintained a humidified atmosphere of 5% (v/v) air/CO2. The incubated RAW264.7 cells (5 × 103/well) were seeded to a 96-cell culture plate to conduct a cell viability assay. The RAW264.7 cells prepared for the viability assay went through 18 h of attachment and stabilization. The growth medium was removed and replaced by a fresh medium without FBS. The synthetic compounds were treated to the cells at a concentration of 20 μg mL−1 and the resulting cells were incubated for 24 h. The sample-treated culture medium was removed and 100 μg mL−1 of 3-(4,5-dimetnythiazol-2-yl)-2,5-diphenyl-thetazolium bromide (MTT) was added to each well. In 1 h, purple formazan produced by cellular respiration was dissolved in a 200 μL DMSO solution and the absorbance at 560 nm was measured using a multi-plate reader. The analyses were repeated three times. The results were expressed as means of three independent experiments.

Measurement of nitric oxide concentration (Griess assay)[64]

RAW264.7 cells were transferred into 3 × 105 cells per well in a 96-cell culture plate and incubated for 24 h in a 5% CO2 incubator at 37 °C. Four different concentrations (1, 5, 10, and 20 μg mL−1) of synthetic compounds was treated to the incubated RAW264.7 cells. Simultaneously, 1 μg mL−1 of lipopolysaccharides (LPS) (Sigma-Aldrich, St. Louis, MO) was added and the resulting cells were incubated for 24 h. The same amount of Griess reagent (Sigma-Aldrich) equal to 100 μL of the culture solution was added according to the manufacturer's recommendations, and the absorbance was measured at 540 nm with a multi-plate reader. The NO concentration in the culture medium was determined using a standard curve for each concentration of sodium nitrite.

General procedure for d-ribose conversion with l-amino acids for the synthesis of pyrraline 5

Methyl 2-(2-formyl-1H-pyrrol-1-yl)acetate (5a)

To a stirred solution of glycine (10.0 g, 0.133 mol, 1 equiv.) in MeOH (7 mL) at 0 °C under argon atmosphere was slowly added thionyl chloride (9.73 mL, 0.133 mol, 1 equiv.) through a syringe. The mixture was then heated at 65 °C for 8 h and cooled to room temperature. The mixture was triturated with Et2O to give glycine methyl ester, ammonium chloride salt as white crystalline salt (16.57 g, 0.133 mol).

Under ambient pressure

To a stirred solution of the above glycine methyl ester, ammonium chloride salt (8.35 g, 66.5 mmol, 1 equiv.) in DMSO (20 mL) were added Et3N (18.4 mL, 0.133 mol, 2 equiv.) and d-ribose (10.0 g, 66.6 mmol, 1 equiv.). After complete dissolution, oxalic acid (12.0 g, 0.133 mol, 2 equiv.) was added and the resulting mixture was heated at 90 °C for 30 min. Upon cooling to room temperature, the mixture was filtered through a short pad of SiO2 with EtOAc rinsing. The filtrate was concentrated and purified by SiO2 flash column chromatography to give 5a (1.08 g, 6.45 mmol) in 10% yield as light-yellow liquid.

Under pressure bottle at 2.5 bar

A mixture of glycine methyl ester, ammonium chloride salt (2.00 g, 15.9 mmol) and Et3N (2.18 mL, 15.9 mmol) in dry DMSO (10 mL) was stirred in a mini-clave steel reactor and then d-ribose (4.73 g, 31.8 mmol) and oxalic acid (1.41 g, 15.9 mmol) were added. The mixture was pressurized to 2.5 bar with argon and heated at 80 °C for 0.5 h. The mixture was then cooled to room temperature and depressurized. The resulting viscous mixture was filtered through a short pad of SiO2 rinsing with EtOAc. The filtrate was concentrated and purified by SiO2 flash column chromatography (eluent 7 : 1 EtOAc/hexane) to give 5a (0.85 g, 5.09 mmol) in 32% yield as light-yellow liquid.

Data for 5a

R f = 0.50 (4 : 6 EtOAc/hexane); 1H NMR δ = 3.77 (s, 3H), 5.08 (s, 2H), 6.31 (dd, J = 2.4, 1.6 Hz, 1H), 6.92 (dd, J = 4.0, 2.4 Hz, 1H), 7.00 (dd, J = 4.0, 1.6 Hz, 1H), 9.54 (s, 1H) ppm; 13C NMR δ = 50.0, 52.5, 110.2, 124.6, 124.6, 132.0, 168.7, 179.8 ppm; IR ν = 3111, 2941, 2904, 2840, 1740, 1650, 1528, 1480, 1403, 1359, 1321, 1216, 1081, 1031, 999, 761 cm−1; HRMS (EI) calcd for C8H9NO3 167.0582, found 167.0582.

Methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)propanoate (5b)

The mixture of l-alanine methyl ester, ammonium chloride salt (2.00 g, 14.3 mmol), Et3N (2.0 mL, 14.3 mmol), d-ribose (4.35 g, 28.6 mmol), and oxalic acid (1.27 g, 14.3 mmol) in dry DMSO (10 mL) was pressurized to 2.5 bar by argon and reacted at 80 °C for 30 min to give 5b (985 mg, 5.4 mmol) in 38% yield as light-brown liquid after purification by SiO2 column chromatography.

Data for 5b

R f = 0.53 (4 : 6 EtOAc/hexane); 1H NMR δ =1.73 (d, J = 7.6 Hz, 3H), 3.71 (s, 3H), 5.86 (q, J = 7.6 Hz, 1H), 6.30 (dd, J = 4.0, 2.0 Hz, 1H), 6.98 (dd, J = 4.0, 1.6 Hz, 1H), 7.18 (ddd, J = 2.0, 1.6, 1.2 Hz, 1H), 9.50 (d, J = 1.2 Hz, 1H) ppm; 13C NMR δ = 17.6, 52.2, 55.1, 110.0, 125.1, 128.7, 131.3, 171.2, 179.3 ppm; IR ν = 3116, 2999, 2954, 2851, 2809, 1729, 1608, 1517, 1470, 1406, 1364, 1339, 1313, 1211, 1090, 1066, 1033, 983, 743 cm−1; HRMS (ESI) calcd for C9H11NO3 + Na 204.0631, found 204.0636.

Methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-3-methylbutanoate (5c)

The mixture of l-valine methyl ester, ammonium chloride salt (2.00 g, 11.9 mmol), Et3N (1.7 mL, 11.9 mmol), d-ribose (3.59 g, 23.8 mmol), and oxalic acid (1.07 g, 11.9 mmol) in dry DMSO (10 mL) was pressurized to 2.5 bar by argon and reacted at 80 °C for 30 min to give 5c (1.05 g, 5.0 mmol) in 42% yield as light-brown liquid after purification by SiO2 column chromatography.

Data for 5c

R f = 0.76 (4 : 6 EtOAc/hexane); 1H NMR δ = 0.78 (d, J = 6.4 Hz, 3H), 1.01 (d, J = 6.4 Hz, 3H), 2.40 (m, 1H), 3.75 (s, 3H), 5.99 (d, J = 10.4 Hz, 1H), 6.31 (ddd, J = 4.0, 2.8, 1.2 Hz, 1H), 6.93 (ddd, J = 4.0, 1.6, 1.6 Hz, 1H), 7.39 (ddd, J = 2.8, 1.6, 1.2 Hz, 1H), 9.54 (dd, J = 1.6, 1.2 Hz, 1H) ppm; 13C NMR δ = 18.5, 19.2, 33.0, 52.2, 63.8, 110.7, 125.3, 129.9, 131.9, 171.2, 179.9 ppm; IR ν = 3126, 2952, 2874, 2846, 2813, 1729, 1655, 1523, 1460, 1408, 1373, 1338, 1258, 1201, 1147, 1062, 1033, 1000, 877, 825, 743 cm−1; HRMS (ESI) calcd for C11H15NO3 + Na 232.0944, found 232.0942.

Methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-4-methylpentanoate (5d)

The mixture of l-leucine methyl ester, ammonium chloride salt (2.00 g, 11.0 mmol), Et3N (1.6 mL, 11.0 mmol), d-ribose (3.32 g, 22.0 mmol), and oxalic acid (0.99 g, 11.0 mmol) in dry DMSO (10 mL) was pressurized to 2.5 bar by argon and reacted at 80 °C for 30 min to give 5d (1.55 g, 6.93 mmol) in 63% yield as light-brown liquid after purification by SiO2 column chromatography.

Data for 5d

R f = 0.76 (4 : 6 EtOAc/hexane); 1H NMR δ = 0.90 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H), 1.40 (m, 1H), 1.99 (dd, J = 8.0, 6.8 Hz, 2H), 3.72 (s, 3H), 6.10 (t, J = 8.0 Hz, 1H), 6.32 (dd, J = 4.0, 2.8 Hz, 1H), 6.96 (dd, J = 4.0, 1.6 Hz, 1H), 7.21 (ddd, J = 2.8, 1.6, 1.2 Hz, 1H), 9.52 (d, J = 1.2 Hz, 1H) ppm; 13C NMR δ = 21.3, 22.8, 24.6, 41.3, 52.4, 57.4, 110.4, 125.5, 129.5, 131.6, 171.5, 179.6 ppm; IR ν = 3119, 2963, 2873, 2810, 2773, 2729, 1750, 1657, 1534, 1473, 1411, 1373, 1348, 1273, 1203, 1164, 1132, 1080, 1029, 1001, 911, 878, 832, 778, 753 cm−1; HRMS (EI) calcd for C12H17NO3 223.1208, found 223.1207.

Methyl (2S,3S)-2-(2-formyl-1H-pyrrol-1-yl)-3-methylpentanoate (5e)

The mixture of l-isoleucine methyl ester, ammonium chloride salt (2.00 g, 11.0 mmol), Et3N (1.5 mL, 11.0 mmol), d-ribose (3.31 g, 22.0 mmol), and oxalic acid (0.88 g, 11.0 mmol) in dry DMSO (10 mL) was pressurized to 2.5 bar by argon and reacted at 80 °C for 30 min to give 5e (982 mg, 4.4 mmol) in 40% yield as light-brown liquid after purification by SiO2 column chromatography.

Data for 5e

R f = 0.80 (4 : 6 EtOAc/hexane); 1H NMR δ = 0.83 (t, J = 7.2 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 1.00–1.24 (m, 2H), 2.18 (m, 1H), 3.74 (s, 3H), 6.06 (d, J = 9.6 Hz, 1H), 6.31 (dd, J = 3.2, 2.4 Hz, 1H), 6.93 (dd, J = 3.2, 1.6 Hz, 1H), 7.41 (ddd, J = 2.4, 1.6, 1.2 Hz, 1H), 9.53 (s, 1H) ppm; 13C NMR δ = 10.5, 15.3, 24.7, 38.8, 52.0, 62.6, 110.5, 125.2, 129.7, 131.8, 171.0, 179.6 ppm; IR ν = 3116, 2961, 2862, 2703, 1735, 1655, 1530, 1468, 1410, 1375, 1343, 1250, 1202, 1151, 1070, 1026, 991, 750 cm−1; HRMS (EI) calcd for C12H17NO3 223.1208, found 223.1207; HRMS (ESI) calcd for C12H17NO3 + Na 246.1101, found 246.1105.

Methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-3-phenylpropanoate (5f)

The mixture of l-phenylalanine methyl ester, ammonium chloride salt (2.00 g, 9.3 mmol), Et3N (1.3 mL, 9.3 mmol), d-ribose (2.80 g, 18.6 mmol), and oxalic acid (0.84 g, 9.3 mmol) in dry DMSO (10 mL) was pressurized to 2.5 bar by argon and reacted at 80 °C for 30 min to give 5f (1.29 g, 5.02 mmol) in 54% yield as light-brown liquid after purification by SiO2 column chromatography.

Data for 5f

R f = 0.88 (4 : 6 EtOAc/hexane); 1H NMR δ = 3.27 (dd, J = 14.0, 10.0 Hz, 1H), 3.54 (dd, J = 14.0, 5.6 Hz, 1H), 3.74 (s, 3H), 6.06 (br s or dd, J = 10.0, 5.6 Hz, calcd. 1H), 6.21 (dd, J = 4.0, 2.8 Hz, 1H), 6.91 (dd, J = 4.0, 1.6 Hz, 1H), 6.98–7.03 (m, 3H), 7.15–7.23 (m, 3H), 9.43 (d, J = 0.8 Hz, 1H) ppm; 13C NMR δ = 39.0, 52.6, 61.1, 110.2, 125.6, 126.9, 128.4, 128.9, 130.6, 131.2, 136.0, 170.3, 179.5 ppm; IR ν = 3114, 3067, 3029, 2955, 2845, 2812, 1740, 1654, 1530, 1500, 1472, 1409, 1373, 1343, 1277, 1215, 1079, 1032, 1002, 744, 698 cm−1; HRMS (EI) calcd for C15H15NO3 + Na 280.0944, found 280.0948.

Methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-4-phenylbutanoate (5g)

The mixture of l-homophenylalanine methyl ester, ammonium chloride salt (2.00 g, 8.7 mmol), Et3N (1.2 mL, 8.7 mmol), d-ribose (2.62 g, 17.4 mmol), and oxalic acid (0.79 g, 8.7 mmol) in dry DMSO (10 mL) was pressurized to 2.5 bar by argon and reacted at 80 °C for 30 min to give 5g (1.25 g, 4.6 mmol) in 53% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 5g

R f = 0.71 (4 : 6 EtOAc/hexane); 1H NMR δ = 2.26–2.36 (m, 1H), 2.45–2.60 (m, 3H), 3.70 (s, 3H), 5.89 (br d, J = 8.0 Hz, 1H), 6.34 (dd, J = 4.0, 2.8 Hz, 1H), 6.98 (dd, J = 4.0, 1.6 Hz, 1H), 7.07–7.12 (m, 2H), 7.15–7.20 (m, 2H), 7.22–7.28 (m, 2H), 9.51 (d, J = 1, 2 Hz, 1H) ppm; 13C NMR δ = 31.8, 34.0, 52.5, 58.9, 110.5, 125.5, 126.2, 128.2, 128.4, 129.7, 131.6, 140.0, 170.8, 179.6 ppm; IR ν = 3114, 3067, 3027, 2955, 2847, 2810, 1735, 1644, 1532, 1502, 1472, 1413, 1375, 1340, 1254, 1209, 1179, 1087, 1031, 1008, 734, 686 cm−1; HRMS (FAB) calcd for C16H18NO3 272.1287, found 272.1284.

Dimethyl (S)-2-(2-formyl-1H-pyrrol-1-yl)succinate (5h)

The mixture of l-aspartic acid dimethyl ester, ammonium chloride salt (2.00 g, 10.1 mmol), Et3N (1.4 mL, 10.1 mmol), d-ribose (3.04 g, 20.2 mmol), and oxalic acid (0.92 g, 10.1 mmol) in dry DMSO (10 mL) was pressurized to 2.5 bar by argon and reacted at 80 °C for 30 min to give 5h (1.14 g, 4.76 mmol) in 47% yield as light-brown liquid after purification by SiO2 column chromatography.

Data for 5h

R f = 0.45 (4 : 6 EtOAc/hexane); 1H NMR δ = 3.06 (dd, J = 17.2, 8.4 Hz, 1H), 3.39 (dd, J = 17.2, 4.8 Hz, 1H), 3.66 (s, 3H), 3.74 (s, 3H), 5.42 (d, J = 14.8 Hz, 1H), 5.87 (br s, 1H), 6.29 (dd, J = 4.0, 2.8 Hz, 1H), 7.01 (dd, J = 4.0, 1.6 Hz, 1H), 7.13 (ddd, J = 2.8, 1.6, 1.2 Hz, 1H), 9.48 (d, J = 1.2 Hz, 1H) ppm; 13C NMR δ = 37.1, 52.1, 52.9, 57.5, 110.2, 125.9, 131.0, 131.9, 169.2, 170.7, 179.3 ppm; IR ν = 3116, 3002, 2952, 2848, 2817, 1737, 1652, 1533, 1474, 1433, 1413, 1370, 1339, 1276, 1221, 1166, 1084, 1039, 1008, 755 cm−1; HRMS (EI) calcd for C11H13NO5 239.0794, found 239.0797.

Dimethyl (S)-2-(2-formyl-1H-pyrrol-1-yl)pentanedioate (5i)

The mixture of l-glutamic acid dimethyl ester, ammonium chloride salt (2.00 g, 9.45 mmol), Et3N (1.3 mL, 9.45 mmol), d-ribose (2.84 g, 18.9 mmol), and oxalic acid (0.86 g, 9.45 mmol) in dry DMSO (10 mL) was pressurized to 2.5 bar by argon and reacted at 80 °C for 30 min to give 5i (885 mg, 3.50 mmol) in 37% yield as light-brown liquid after purification by SiO2 column chromatography.

Data for 5i

R f = 0.46 (4 : 6 EtOAc/hexane); 1H NMR δ = 2.19–2.37 (m, 3H), 2.55–2.65 (m, 1H), 3.65 (s, 3H), 3.74 (s, 3H), 5.95 (br s, 1H), 6.33 (dd, J = 4.0, 2.8 Hz, 1H), 6.99 (dd, J = 4.0, 1.6 Hz, 1H), 7.15 (ddd, J = 2.8, 1.6, 1.2 Hz, 1H), 9.51 (d, J = 1.2 Hz, 1H) ppm; 13C NMR δ = 27.8, 30.0, 51.8, 52.7, 58.6, 110.7, 125.6, 130.1, 131.6, 170.4, 172.6, 179.7 ppm; IR ν = 3120, 2996, 2960, 2927, 2857, 2811, 2727, 1744, 1664, 1535, 1478, 1443, 1417, 1368, 1337, 1268, 1211, 1181, 1097, 1036, 1017, 887, 849, 834, 765 cm−1; HRMS (EI) calcd for C12H15NO5 253.0950, found 253.0948.

Methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-4-(methylthio)butanoate (5j)

The mixture of l-methionine methyl ester, ammonium chloride salt (2.00 g, 10.0 mmol), Et3N (1.4 mL, 10.1 mmol), d-ribose (3.01 g, 20.0 mmol), and oxalic acid (0.90 g, 10.0 mmol) in dry DMSO (10 mL) was pressurized to 2.5 bar by argon and reacted at 80 °C for 30 min to give 5j (1.11 g, 4.60 mmol) in 46% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 5j

R f = 0.59 (4 : 6 EtOAc/hexane); 1H NMR δ = 2.07 (s, 3H), 2.21–2.36 (m, 2H), 2.36–2.44 (m, 1H), 2.48–2.58 (m, 1H), 3.74 (s, 3H), 5.91 (br s, 1H), 6.33 (dd, J = 4.0, 2.8 Hz, 1H), 7.00 (dd, J = 4.0, 1.6 Hz, 1H), 7.16 (dd, J = 2.8, 1.6 Hz, 1H) ppm; 13C NMR δ = 16.2, 30.1, 31.4, 52.7, 58.7, 110.5, 110.0, 125.7, 130.5, 131.5, 170.5, 179.5 ppm; IR ν = 3112, 2946, 2918, 2843, 2817, 1741, 1650, 1532, 1472, 1407, 1373, 1342, 1272, 1226, 1208, 1085, 1031, 1003, 750 cm−1; HRMS (EI) calcd for C11H15NO3S 241.0773, found 241.0771.

Methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-3-(1H-indol-3-yl)propanoate (5k)

The mixture of l-tryptophan methyl ester, ammonium chloride salt (2.00 g, 7.85 mmol), Et3N (1.1 mL, 7.85 mmol), d-ribose (2.36 g, 15.7 mmol), and oxalic acid (0.71 g, 7.85 mmol) in dry DMSO (10 mL) was pressurized to 2.5 bar by argon and reacted at 80 °C for 30 min to give 5k (1.28 g, 4.32 mmol) in 55% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 5k

R f = 0.40 (4 : 6 EtOAc/hexane); 1H NMR δ = 3.47 (dd, J = 14.4, 9.2 Hz, 1H), 3.71 (dd, J = 14.4, 5.6 Hz, 1H), 3.73 (s, 3H), 6.09 (br s, 1H), 6.17 (dd, J = 3.6, 2.4 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.93 (dd, J = 3.6, 1.6 Hz, 1H), 7.01 (br s, 1H), 7.11 (ddd, J = 8.4, 6.8, 0.8 Hz, 1H), 7.18 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.99 (br s, 1H), 9.48 (d, J = 1, 2 Hz, 1H) ppm; 13C NMR δ = 28.6, 52.6, 60.5, 110.0, 110.3, 111.1, 118.3, 119.6, 122.1, 122.7, 125.7, 127.0, 130.8, 131.2, 135.9, 170.6, 179.5 ppm; IR ν = 3017, 2872, 1743, 1658, 1457, 1402, 1372, 1345, 1223, 1151, 1092, 1079, 1034, 997, 977, 912, 758, 733 703, 666, 651 cm−1; HRMS (FAB) calcd for C17H17N2O3 297.1239, found 297.1237.

General procedure for reductive amination of pyrralines 5 with benzylamine

2-Benzyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-one (6a)

The mixture of methyl 2-(2-formyl-1H-pyrrol-1-yl)acetate (5a) (120 mg, 0.72 mmol) and benzylamine (116 mg, 1.08 mmol) in MeOH (5 mL) was stirred at room temperature for 12 h, and then NaBH4 (20 mg, 0.53 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 9 h, quenched with 10% NaHCO3 solution, and extracted with EtOAc. The organic layer was washed with brine and H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was treated with DBU (0.53 g, 3.48 mmol) in toluene (10 mL). The mixture was heated at 120 °C for 12 h and cooled to room temperature. The reaction mixture was concentrated under reduced pressure and purified by SiO2 flash column chromatography to give 6a (59 mg, 0.26 mmol) in 36% yield as light-yellow liquid.

Data for 6a

1H-NMR δ = 4.43 (s, 2H), 4.70 (s, 2H), 4.75 (s, 2H), 5.91 (dd, J = 2.4, 1.6 Hz, 1H), 6.21 (dd, J = 3.6, 2.4 Hz, 1H), 6.61 (dd, J = 2.4, 1.6 Hz, 1H), 7.26–7.37 (m, 5H) ppm; 13C-NMR δ = 44.2, 48.4, 50.0, 103.2, 109.6, 118.0, 121.9, 127.9, 128.2, 128.8, 135.8, 164.6 ppm; IR (neat) ν = 3034, 2926, 2848, 1715, 1651, 1543, 1491, 1450, 1424, 1323, 1256, 1204, 1182, 1073, 1025, 950, 902, 816, 742, 697, 608 cm−1; HRMS (ESI) calcd for C14H14N2O + Na 249.0998, found 249.1001.

(S)-2-Benzyl-4-methyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-one (6b)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)propanoate (5b) (120 mg, 0.66 mmol) and benzylamine (106 mg, 0.99 mmol) in MeOH (5 mL) at room temperature for 12 h, followed by NaBH4 (20 mg, 0.53 mmol) reduction at 0 °C for 9 h, and then cyclization by DBU (0.50 g, 3.28 mmol) in toluene (10 mL) at 120 °C for 12 h produced 6b (105 mg, 0.44 mmol) in 66% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 6b

1H-NMR δ = 1.68 (d, J = 7.2 Hz, 3H), 4.36 (A of ABq, J = 15.2 Hz, 1H), 4.42 (B of ABq, J = 15.2 Hz, 1H), 4.72 (s, 2H), 4.74 (q, J = 7.2 Hz, 1H), 5.89 (m, 1H), 6.20 (dd, J = 3.6, 2.8 Hz, 1H), 6.64 (dd, J = 2.8, 2.0 Hz, 1H), 7.24–7.36 (m, 5H) ppm; 13C-NMR δ = 20.2, 43.8, 50.2, 54.7, 103.1, 109.4, 117.0, 121.6, 127.7, 128.0, 128.7, 135.9, 168.1 ppm; IR (neat) ν = 3068, 3030, 2974, 2926, 2848, 1711, 1651, 1543, 1483, 1450, 1319, 1256, 1204, 1144, 1073, 1029, 965, 932, 896, 738, 697, 611 cm−1; HRMS (ESI) calcd for C15H16N2O + Na 263.1155, found 263.1158.

(S)-2-Benzyl-4-isopropyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-one (6c)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-3-methylbutanoate (5c) (120 mg, 0.57 mmol) and benzylamine (87 mg, 0.81 mmol) in MeOH (5 mL) at room temperature for 12 h, followed by NaBH4 (16 mg, 0.43 mmol) reduction at 0 °C for 9 h, and then cyclization by DBU (0.41 g, 2.69 mmol) in toluene (10 mL) at 120 °C for 12 h produced 6c (112 mg, 0.42 mmol) in 73% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 6c

1H-NMR δ = 0.84 (d, J = 7.2 Hz, 3H), 1.06 (d, J = 7.2 Hz, 3H), 2.39 (m, 1H), 4.27 (A of ABq, J = 15.6 Hz, 1H), 4.39 (B of ABq, J = 15.6 Hz, 1H), 4.52 (d, J = 4.4 Hz, 1H), 4.59 (A of ABq, J = 14.8 Hz, 1H), 4.82 (B of ABq, J = 14.8 Hz, 1H), 5.89 (dd, J = 3.6, 1.6 Hz, 1H), 6.16 (dd, J = 3.6, 2.8 Hz, 1H), 6.57 (dd, J = 2.8, 1.6 Hz, 1H), 7.22–7.34 (m, 5H) ppm; 13C-NMR δ = 17.6, 19.9, 34.7, 44.2, 50.2, 65.2, 103.0, 108.6, 119.1, 122.5, 127.7, 128.2, 128.7, 136.0, 167.4 ppm; IR (neat) ν = 3094, 3027, 2967, 2933, 2870, 1655, 1543, 1495, 1469, 1454, 1387, 1353, 1290, 1275, 1216, 1152, 1070, 991, 957, 891, 861, 790, 749, 716, 696, 662, 615 cm−1; HRMS (ESI) calcd for C17H20N2O + Na 291.1468, found 291.1470.

(S)-2-Benzyl-4-((S)-sec-butyl)-1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-one (6d)

The reaction of methyl (2S,3S)-2-(2-formyl-1H-pyrrol-1-yl)-3-methylpentanoate (5e) (0.12 g, 0.54 mmol) and benzylamine (87 mg, 0.81 mmol) in MeOH (5 mL) at room temperature for 12 h, followed by NaBH4 (16 mg, 0.43 mmol) reduction at 0 °C for 9 h, and then cyclization by DBU (0.41 g, 2.69 mmol) in toluene (10 mL) at 120 °C for 12 h produced 6d (131 mg, 0.46 mmol) in 86% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 6d

1H-NMR δ = 0.90 (t, J = 7.2 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 1.05–1.17 (m, 1H), 1.49–1.60 (m, 1H), 2.05–2.16 (m, 1H), 4.30 (A of ABq, J = 15.2 Hz, 1H), 4.43 (B of ABq, J = 15.2 Hz, 1H), 4.62 (d, J = 4.4 Hz, 1H), 4.67 (A of ABq, J = 14.8 Hz, 1H), 4.78 (B of ABq, J = 14.8 Hz, 1H), 5.89 (dd, J = 3.2, 2.0 Hz, 1H), 6.18 (dd, J = 3.2, 2.8 Hz, 1H), 6.59 (dd, J = 2.8, 2.0 Hz, 1H), 7.26–7.36 (m, 5H) ppm; 13C-NMR δ = 11.5, 15.9, 24.9, 41.7, 44.3, 50.3, 64.3, 103.0, 108.9, 118.8, 122.6, 127.8, 128.3, 128.7, 136.1, 167.2 ppm; IR (neat) ν = 3019, 2963, 2926, 2874, 1707, 1651, 1543, 1487, 1454, 1323, 1215, 1141, 1073, 1029, 950, 928, 898, 742, 697, 667, 634, 611 cm−1; HRMS (ESI) calcd for C18H22N2O + Na 305.1624, found 305.1628.

(S)-2,4-Dibenzyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-one (6e)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-3-phenylpropanoate (5f) (120 mg, 0.47 mmol) and benzylamine (76 mg, 0.71 mmol) in MeOH (5 mL) at room temperature for 12 h, followed by NaBH4 (17 mg, 0.45 mmol) reduction at 0 °C for 9 h, and then cyclization by DBU (0.43 g, 2.82 mmol) in toluene (10 mL) at 120 °C for 12 h produced 6e (61 mg, 0.19 mmol) in 41% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 6e

1H-NMR δ = 3.09 (d, J = 15.2 Hz, 3H), 3.26 (d of A of ABq, JAB = 13.6, Jd = 4.4 Hz, 1H), 3.41 (d of B of ABq, JAB = 13.6, Jd = 4.4 Hz, 1H), 3.93 (d, J = 15.2 Hz, 1H), 4.39 (A of ABq, JAB = 14.8 Hz, 1H), 4.65 (B of ABq, JAB = 14.8 Hz, 1H), 5.03 (t, J = 4.4 Hz, 1H), 5.71 (dd, J = 3.6, 1.6 Hz, 1H), 6.22 (dd, J = 3.6, 2.8 Hz, 1H), 6.62 (dd, J = 2.8, 1.6 Hz, 1H), 6.66–6.70 (m, 2H), 7.00–7.06 (m, 2H), 7.13–7.17 (m, 3H), 7.24–7.32 (m, 3H) ppm; 13C-NMR δ = 41.5, 43.6, 50.1, 60.0, 102.4, 109.8, 116.9, 122.8, 127.2, 127.7, 128.1, 128.5, 128.6, 129.6, 134.9, 135.6, 166.6 ppm; IR (neat) ν = 3068, 3027, 2933, 2844, 1647, 1483, 1439, 1394, 1327, 1252, 1204, 1170, 1077, 1029, 965, 898, 861, 742, 693, 663, 630, 611 cm−1; HRMS (ESI) calcd for C21H20N2O + Na 339.1468, found 339.1470.

(S)-2-Benzyl-4-phenethyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-one (6f)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-4-phenylbutanoate (5g) (120 mg, 0.44 mmol) and benzylamine (71 mg, 0.66 mmol) in MeOH (5 mL) at room temperature for 12 h, followed by NaBH4 (13 mg, 0.34 mmol) reduction at 0 °C for 9 h, and then cyclization by DBU (0.34 g, 2.23 mmol) in toluene (10 mL) at 120 °C for 12 h produced 6f in 64% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 6f

1H-NMR δ = 2.25–2.40 (m, 2H), 2.44–2.53 (m, 1H), 2.56–2.65 (m, 1H), 4.31 (A of ABq, JAB = 15.6 Hz, 1H), 4.39 (B of ABq, JAB = 15.6 Hz, 1H), 4.61 (A of ABq, JAB = 14.4 Hz, 1H), 4.74 (B of ABq, JAB = 14.4 Hz, 1H), 4.75 (dd, J = 5.6, 5.2 Hz, 1H), 5.89 (dd, J = 3.6, 1.6 Hz, 1H), 6.21 (dd, J = 3.6, 2.8 Hz, 1H), 6.60 (dd, J = 2.8, 1.6 Hz, 1H), 7.09–7.18 (m, 3H), 7.21–7.33 (m, 7H) ppm; 13C-NMR δ = 30.6, 36.2, 43.9, 50.1, 58.7, 103.1, 109.4, 117.6, 121.9, 126.0, 127.7, 128.0, 128.2, 128.3, 128.6, 135.9, 140.2, 167.2 ppm; IR (neat) ν = 3067, 3027, 2922, 2856, 1652, 1485, 1452, 1328, 1256, 1078, 1026, 746, 698 cm−1; HRMS (ESI) calcd for C22H22N2O + Na 353.1624, found 353.1626.

Methyl (S)-2-(2-benzyl-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (6g)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)succinate (5h) (120 mg, 0.50 mmol) and benzylamine (80 mg, 0.75 mmol) in MeOH (5 mL) at room temperature for 12 h, followed by NaBH4 (15 mg, 0.40 mmol) reduction at 0 °C for 9 h, and then cyclization by DBU (0.38 g, 2.50 mmol) in toluene (10 mL) at 120 °C for 12 h produced 6g (125 mg, 0.42 mmol) in 84% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 6g

1H-NMR δ = 3.14 (d of A of ABq, JAB = 16,8, Jd = 4.8 Hz, 1H), 3.18 (d of B of ABq, JAB = 16,8, Jd = 5.2 Hz, 1H), 3,62 (s, 3H), 4.37 (d of A of ABq, JAB = 15.2, Jd = 0.8 Hz, 1H), 4.68 (B of ABq, JAB = 15.2 Hz, 1H), 4.70 (A of ABq, JAB = 14.8 Hz, 1H), 4.79 (B of ABq, JAB = 14.8 Hz, 1H), 5.05 (dd, J = 5.2, 4,8 Hz, 1H), 5.88 (dd, J = 3.6, 1.6 Hz, 1H), 6.19 (dd, J = 3.6, 2.8 Hz, 1H), 6.63 (dd, J = 2.8, 1.6 Hz, 1H), 7.26–7.37 (m, 5H) ppm; 13C-NMR δ = 38.3, 44.0, 50.4, 52.0, 55.0, 103.3, 109.7, 117.3, 122.2, 127.7, 128.1, 128.7, 135.7, 166.4, 170.2 ppm; IR (neat) ν = 3031, 2923, 2854, 1735, 1654, 1487, 1437, 1370, 1330, 1249, 1201, 1168, 1077, 1018, 987, 896, 744, 699 cm−1; HRMS (ESI) calcd for C17H18N2O3 + Na 321.1210, found 321.1214.

(S)-2-Benzyl-4-(2-(methylthio)ethyl)-1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-one (6h)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-4-(methylthio)butanoate (5j) (120 mg, 0.50 mmol) and benzylamine (80 mg, 0.75 mmol) in MeOH (5 mL) at room temperature for 12 h, followed by NaBH4 (15 mg, 0.40 mmol) reduction at 0 °C for 9 h, and then cyclization by DBU (0.38 g, 2.50 mmol) in toluene (10 mL) at 120 °C for 12 h produced 6h (71 mg, 0.24 mmol) in 47% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 6h

1H-NMR δ = 2.06 (s, 3H), 2.23–2.33 (m, 2H), 2.34–2.49 (m, 2H), 4.33 (A of ABq, J = 15.6 Hz, 1H), 4.41 (B of ABq, J = 15.6 Hz, 1H), 4.67 (A of ABq, J = 14.8 Hz, 1H), 4.73 (B of ABq, J = 14.8 Hz, 1H), 4.87 (t, J = 5.6 Hz, 1H), 5.89 (dd, J = 2.8, 1.6 Hz, 1H), 6.19 (dd, J = 3.6, 2.8 Hz, 1H), 6.63 (dd, J = 2.8, 1.6 Hz, 1H), 7.24–7.36 (m, 5H) ppm; 13C-NMR δ = 15.2, 29.2, 33.6, 44.0, 50.4, 58.0, 103.4, 109.6, 117.9, 122.1, 127.9, 128.2, 128.8, 136.0, 167.3 ppm; IR (neat) ν = 3008, 2915, 2837, 1647, 1483, 1431, 1331, 1286, 1252, 1159, 1073, 1025, 950, 898, 820, 742, 697, 626, 611 cm−1; HRMS (ESI) calcd for C17H20N2OS + Na 323.1189, found 323.1192.

General procedure for cyclization of pyrralines 5 with ethane-1,2-diamine

1,2,3,10b-Tetrahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (7a)

The mixture of methyl 2-(2-formyl-1H-pyrrol-1-yl)acetate (5a) (1.00 g, 5.98 mmol) and ethane-1,2-diamine (360 mg, 5.99 mmol) in MeOH (10 mL) was heated at 70 °C for 1 h and cooled to room temperature. The reaction mixture was concentrated under reduced pressure and purified by SiO2 flash column chromatography to give 7a (615 mg, 3.47 mmol) in 58% yield as white solid.

Data for 7a

1H-NMR δ = 2.14 (br s, 1H), 3.18–3.30 (m, 1H), 3.48–3.62 (m, 3H), 4.55 (A of ABq, J = 16.8 Hz, 1H), 4.60 (B of ABq, J = 16.8 Hz, 1H), 5.25 (br s, 1H), 6.22–6.26 (m, 2H), 6.66 (dd, J = 2.0, 1.6 Hz, 1H) ppm; 13C-NMR δ = 43.9, 45.0, 49.0, 70.4, 104.2, 109.5, 119.1, 124.8, 162.1 ppm; IR (KBr) ν = 3226, 3115, 3098, 2976, 2960, 2885, 2857, 1636, 1470, 1441, 1305, 1216, 1173, 1159, 1126, 1070, 1004, 968, 951, 932, 906, 856, 770, 756, 729, 681 cm−1; HRMS (ESI) calcd for C9H11N3O + Na 200.0794, found 200.0797.

(6S)-6-Methyl-1,2,3,10b-tetrahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (7b)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)propanoate (5b) (1.00 g, 5.52 mmol) and ethane-1,2-diamine (332 mg, 5.52 mmol) in MeOH (10 mL) at 70 °C for 1 h produced 7b (918 mg, 4.80 mmol) in 87% yield (a 3 : 1 mixture of stereoisomers) as white solid after purification by SiO2 column chromatography.

Data for 7b

1H-NMR (major) δ = 1.61 (d, J = 7.2 Hz, 3H), 2.14 (br s, 1H), 3.20–3.31 (m, 1H), 3.47–3.61 (m, 3H), 4.68 (q, J = 7.2 Hz, 1H), 5.26 (br s, 1H), 6.22–6.28 (m, 2H), 6.68 (dd, J = 2.4, 2.0 Hz, 1H) ppm; 13C-NMR (major) δ = 21.2, 43.8, 44.8, 55.8, 69.7, 103.8, 109.3, 117.9, 124.2, 165.7 ppm; (minor) δ = 14.6, 44.2, 44.8, 53.4, 69.7, 103.9, 108.7, 116.9, 125.9, 164.6 ppm; IR (KBr) ν = 3065, 3030, 2946, 2920, 2872, 2844, 1648, 1543, 1486, 1460, 1431, 1357, 1329, 1252, 1221, 1140, 1073, 1025, 962, 766, 739, 700 cm−1; HRMS (ESI) calcd for C10H13N3O + Na 214.0951, found 214.0954.

(6S)-6-Isopropyl-1,2,3,10b-tetrahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (7c)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-3-methylbutanoate (5c) (1.00 g, 4.78 mmol) and ethane-1,2-diamine (287 mg, 4.78 mmol) in MeOH (10 mL) at 70 °C for 1 h produced 7c (985 mg, 4.49 mmol) in 94% yield as white solid after purification by SiO2 column chromatography.

Data for 7c

1H-NMR δ = 0.93 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H), 2.10 (br s, 1H), 2.22–2.34 (m, 1H), 3.17–3.28 (m, 1H), 3.47–3.60 (m, 3H), 4.39 (d, J = 5.2 Hz, 1H), 5.25 (s, 1H), 6.22 (dd, J = 3.6, 2.0 Hz, 1H), 6.24 (dd, J = 3.6, 1.2 Hz, 1H), 6.64 (dd, J = 2.0, 1.2 Hz, 1H) ppm; 13C-NMR δ = 18.1, 19.6, 34.3, 44.2, 45.0, 66.3, 70.4, 103.8, 108.7, 120.0, 125.6, 165.1 ppm; IR (KBr) ν = 3278, 2971, 2891, 1654, 1567, 1463, 1430, 1395, 1372, 1325, 1303, 1251, 1221, 1178, 1153, 1112, 1075, 950, 922, 903, 855, 750, 717, 667 cm−1; HRMS (ESI) calcd for C12H17N3O + Na 242.1264, found 242.1265.

(6S)-6-((S)-sec-Butyl)-1,2,3,10b-tetrahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (7d)

The reaction of methyl (2S,3S)-2-(2-formyl-1H-pyrrol-1-yl)-3-methylpentanoate (5e) (1.00 g, 4.48 mmol) and ethane-1,2-diamine (270 mg, 4.48 mmol) in MeOH (10 mL) at 70 °C for 1 h produced 7d (951 mg, 4.08 mmol) in 91% yield as white solid after purification by SiO2 column chromatography.

Data for 7d

1H-NMR δ = 0.90 (t, J = 7.2 Hz, 3H), 0.98 (d, J = 7.2 Hz, 3H), 1.05–1.17 (m, 1H), 1.49–1.61 (m, 1H), 1.92–2.04 (m, 1H), 2.25 (br s, 1H), 3.13–3.24 (m, 1H), 3.42–3.56 (m, 3H), 4.42 (d, J = 5.6 Hz, 1H), 5.21 (br s, 1H), 6.17–6.21 (m, 2H), 6.62 (dd, J = 2.0, 2.0 Hz, 1H) ppm; 13C-NMR δ = 11.1, 15.3, 24.7, 40.8, 44.0, 44.7, 65.0, 70.2, 103.5, 108.6, 119.3, 125.4, 164.6 ppm; IR (KBr) ν = 3292, 3103, 2962, 2931, 2880, 2860, 1638, 1464, 1430, 1349, 1323, 1277, 1247, 1221, 1189, 1108, 1078, 1025, 958, 902, 877, 772, 710 cm−1; HRMS (ESI) calcd for C13H19N3O + Na 256.1420, found 256.1421.

(6S)-6-Benzyl-1,2,3,10b-tetrahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (7e)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-3-phenylpropanoate (5f) (1.00 g, 3.89 mmol) and ethane-1,2-diamine (234 mg, 3.89 mmol) in MeOH (10 mL) at 70 °C for 1 h produced 7e (894 mg, 3.34 mmol) in 86% yield as white solid after purification by SiO2 column chromatography.

Data for 7e

1H-NMR δ = 1.94 (br s, 1H), 2.90–2.99 (m, 1H), 3.24 (d of A of ABq, JAB = 13.6, Jd = 4.4 Hz, 1H), 3.30 (d of B of ABq, JAB = 13.6, Jd = 4.8 Hz, 1H), 3.25–3.39 (m, 2H), 3.43–3.52 (m, 1H), 3.79 (s, 1H), 4.90 (dd, J = 4.8, 4.4 Hz, 1H), 6.07 (dd, J = 3.6, 1.2 Hz, 1H), 6.23 (dd, J = 3.6, 2.8 Hz, 1H), 6.59 (dd, J = 2.8, 1.2 Hz, 1H), 6.74–6.79 (m, 2H), 7.12–7.18 (m, 2H), 7.19–7.24 (m, 1H) ppm; 13C-NMR δ = 41.4, 43.6, 44.7, 61.3, 69.6, 103.5, 109.7, 118.2, 125.6, 127.5, 128.2, 129.5, 134.8, 164.0 ppm; IR (KBr) ν = 3276, 3064, 3031, 2951, 2885, 2857, 1644, 1469, 1459, 1436, 1328, 1306, 1217, 1173, 1119, 1076, 942, 914, 773, 728, 696 cm−1; HRMS (ESI) calcd for C16H18N3O [M + 1]+ 268.1444, found 268.1448.

(6S)-6-Phenethyl-1,2,3,10b-tetrahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (7f)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-4-phenylbutanoate (5g) (1.00 g, 3.69 mmol) and ethane-1,2-diamine (222 mg, 3.69 mmol) in MeOH (10 mL) at 70 °C for 1 h produced 7f (914 mg, 3.25 mmol) in 88% yield as white solid after purification by SiO2 column chromatography.

Data for 7f

1H-NMR δ = 2.08 (br s, 1H), 2.14–2.24 (m, 1H), 2.25–2.35 (m, 1H), 2.58–2.67 (m, 1H), 2.68–2.77 (m, 1H), 3.17–3.28 (m, 1H), 3.47–3.60 (m, 3H), 4.63 (dd, J = 6.8, 6.4 Hz, 1H), 5.24 (s, 1H), 6.23–6.27 (m, 2H), 6.66 (dd, J = 2.4, 1.6 Hz, 1H), 7.13–7.21 (m, 3H), 7.24–7.30 (m, 2H) ppm; 13C-NMR δ = 31.3, 36.7, 44.2, 45.0, 60.1, 70.2, 104.2, 109.4, 119.1, 125.1, 126.2, 128.3, 128.5, 140.0, 165.3 ppm; IR (KBr) ν = 3276, 3028, 2950, 2885, 2859, 1652, 1458, 1429, 1334, 1305, 1221, 1158, 1118, 1073, 912, 771, 752, 698 cm−1; HRMS (ESI) calcd for C17H20N3O [M + 1]+ 282.1601, found 282.1604.

Methyl 2-((6S)-5-oxo-1,2,3,5,6,10b-hexahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-6-yl)acetate (7g)

The reaction of dimethyl (S)-2-(2-formyl-1H-pyrrol-1-yl)succinate (5h) (1.00 g, 4.18 mmol) and ethane-1,2-diamine (251 mg, 4.18 mmol) in MeOH (10 mL) at 70 °C for 1 h produced 7g (750 mg, 3.01 mmol) in 72% yield (a 3 : 1 mixture of stereoisomers) as white solid after purification by SiO2 column chromatography.

Data for 7g

1H-NMR (major) δ = 2.31 (br s, 1H), 2.91 (d of A of ABq, JAB = 16.8, Jd = 8.0 Hz, 1H), 3.02 (d of B of ABq, JAB = 16.8, Jd = 4.4 Hz, 1H), 3.17–3.48 (m, 1H), 3.45–3.59 (m, 3H), 3.66 (s, 3H), 4.99 (dd, J = 8.0, 4.4 Hz, 1H), 5.26 (s, 1H), 6.18–6.23 (m, 2H), 6.72 (br s, 1H) ppm; (minor) δ = 2.31 (br s, 1H), 3.17–3.38 (m, 3H), 3.45–3.58 (m, 3H), 3.67 (s, 3H), 4.91 (dd, J = 5.2, 4.8 Hz, 1H), 5.23 (s, 1H), 6.22–6.27 (m, 2H), 6.62 (br s, 1H) ppm; 13C-NMR (major) δ = 38.9, 44.0, 44.8, 52.0, 56.1, 70.0, 104.1, 109.5, 119.1, 124.7, 163.7, 169.9 ppm; (minor) δ = 35.1, 44.3, 44.8, 51.9, 54.5, 70.0, 104.7, 109.3, 116.8, 125.1, 163.7, 170.5 ppm; IR (KBr) ν = 3287, 2999, 2941, 2878, 1734, 1653, 1461, 1438, 1376, 1330, 1307, 1214, 1173, 1118, 1072, 909, 750, 725 cm−1; HRMS (ESI) calcd for C12H16N3O3 [M + 1]+ 250.1186, found 250.1188.

(6S)-6-(2-(Methylthio)ethyl)-1,2,3,10b-tetrahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (7h)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-4-(methylthio)butanoate (5j) (1.00 g, 4.18 mmol) and ethane-1,2-diamine (251 mg, 4.18 mmol) in MeOH (10 mL) at 70 °C for 1 h produced 7h (914 mg, 3.64 mmol) in 87% yield as white solid after purification by SiO2 column chromatography.

Data for 7h

1H-NMR δ = 2.00–2.11 (m, 1H), 2.07 (s, 3H), 2.15–2.25 (m, 1H), 2.38–2.46 (m, 1H), 2.50–2.58 (m, 1H), 3.14–3.24 (m, 1H), 3.42–3.52 (m, 3H), 4.71 (dd, J = 8.0, 5.2 Hz, 1H), 5.20 (s, 1H), 6.17–6.21 (m, 2H), 6.67 (dd, J = 2.8, 1.6 Hz, 1H) ppm; 13C-NMR δ = 14.7, 29.1, 33.6, 43.7, 44.6, 58.5, 69.7, 103.7, 108.9, 118.7, 124.6, 164.6 ppm; IR (KBr) ν = 3272, 3108, 2959, 2922, 2885, 2851, 1643, 1454, 1412, 1335, 1298, 1220, 1159, 1156, 1073, 948, 923, 897, 761, 708 cm−1; HRMS (ESI) calcd for C12H18N3OS [M + 1]+ 252.1165, found 252.1168.

General procedure for cyclization of pyrralines 5 with (S)-2-aminopropan-1-ol

(3S)-3-Methyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (8a)

The mixture of methyl 2-(2-formyl-1H-pyrrol-1-yl)acetate (5a) (1.12 g, 6.70 mmol) and (S)-2-aminopropan-1-ol (0.52 mL, 6.70 mmol) in toluene (5 mL) was stirred at room temperature for 2.5 h and then heated at 110 °C for 6 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by SiO2 flash column chromatography to give 8a (154 mg, 0.80 mmol) in 12% yield as light-yellow liquid.

Data for 8a

1H-NMR δ = 1.41 (d, J = 6.0 Hz, 3H), 3.63 (ddd, J = 6.8, 6.4, 1.2 Hz, 1H), 4.40 (dd, J = 7.2, 6.8 Hz, 1H), 4.44 (ddq, Jd = 7.2, 6.4, Jq = 6.0 Hz, 1H), 4.60 (A of ABq, JAB = 16.8 Hz, 1H), 4.65 (d of B of ABq, JAB = 16.8, Jd = 0.8 Hz, 1H), 5.88 (br s, 1H), 6.29 (dd, J = 4.0, 2.4 Hz, 1H), 6.33 (ddd, J = 4.0, 1.6, 0.8 Hz, 1H), 6.64 (dd, J = 2.4, 1.6 Hz, 1H) ppm; 13C-NMR δ = 18.0, 48.5, 51.0, 72.2, 81.7, 106.2, 110.3, 119.1, 122.2, 162.7 ppm; IR (neat) ν = 2928, 2870, 1712, 1660, 1542, 1463, 1428, 1345, 1310, 1229, 1168, 1075, 1046, 976, 747, 720 cm−1; HRMS (ESI) calcd for C10H12N2O2 + Na, 215.0791, found 215.0791.

(3S,6S)-3,6-Dimethyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (8b)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)propanoate (5b) (1.12 g, 6.19 mmol) and (S)-2-aminopropan-1-ol (0.49 mL, 6.19 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 8b (523 mg, 2.53 mmol) in 41% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 8b

1H-NMR δ = 1.39 (d, J = 6.8 Hz, 3H), 1.63 (d, J = 6.8 Hz, 3H), 3.59–3.67 (m, 1H), 4.34–4.44 (m, 2H), 4.67 (q, J = 6.8 Hz, 1H), 5.79 (br s, 1H), 6.26–6.31 (m, 2H), 6.60 (dd, J = 2.4, 2.0 Hz, 1H) ppm; 13C-NMR δ = 16.3, 17.9, 51.4, 53.5, 72.1, 81.5, 106.3, 110.0, 117.7, 122.9, 165.7 ppm; IR (neat) ν = 3129, 2989, 2931, 2872, 1714, 1655, 1539, 1460, 1422, 1367, 1302, 1206, 1176, 1142, 1018, 978, 920, 820, 746, 719 cm−1; HRMS (ESI) calcd for C11H14N2O2 + Na, 229.0947, found 229.0952.

(3S,6S)-6-Isopropyl-3-methyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (8c)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-3-methylbutanoate (5c) (1.12 g, 5.36 mmol) and (S)-2-aminopropan-1-ol (0.42 mL, 5.36 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 8c (917 mg, 3.91 mmol) in 73% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 8c

1H-NMR δ = 0.92 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 6.0 Hz, 3H), 2.27 (m, 1H), 3.60–3.68 (m, 1H), 4.33–4.43 (m, 3H), 5.80 (s, 1H), 6.26 (dd, J = 4.0, 2.8 Hz, 1H), 6.30 (ddd, J = 4.0, 1.6, 0.8 Hz, 1H), 6.62 (dd, J = 2.8, 1.6 Hz, 1H) ppm; 13C-NMR δ = 17.8, 18.0, 19.3, 34.9, 51.1, 65.8, 72.3, 82.1, 105.2, 109.4, 119.7, 123.8, 165.0 ppm; IR (neat) ν = 3116, 2963, 2920, 2857, 1714, 1666, 1564, 1449, 1417, 1381, 1370, 1301, 1229, 1197, 1100, 1057, 973, 867, 814, 766, 703 cm−1; HRMS (ESI) calcd for C13H18N2O2 + Na 257.1260, found 257.1262.

(3S,6S)-6-((S)-sec-Butyl)-3-methyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (8d)

The reaction of methyl (2S,3S)-2-(2-formyl-1H-pyrrol-1-yl)-3-methylpentanoate (5e) (1.12 g, 5.02 mmol) and (S)-2-aminopropan-1-ol (0.39 mL, 5.02 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 8d (959 mg, 3.86 mmol) in 77% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 8d

1H-NMR δ = 0.90 (d, J = 6.8 Hz, 3H), 0.93 (t, J = 7.6 Hz, 3H), 1.08–1.20 (m, 1H), 1.38 (d, J = 6.8 Hz, 3H), 1.54–1.65 (m, 1H), 1.91–2.02 (m, 1H), 3.57–3.65 (m, 1H), 4.31–4.40 (m, 2H), 4.51 (d, J = 4.8 Hz, 1H), 5.79 (br s, 1H), 6.24 (dd, J = 3.6, 2.8 Hz, 1H), 6.27 (ddd, J = 3.6, 1.6, 0.8 Hz, 1H), 6.61 (dd, J = 2.8, 1.6 Hz, 1H) ppm; 13C-NMR δ = 11.4, 15.0, 17.6, 25.0, 41.7, 50.9, 64.3, 72.0, 81.9, 104.9, 109.4, 119.0, 123.6, 164.5 ppm; IR (neat) ν = 3099, 2958, 2925, 2867, 1709, 1666, 1563, 1539, 1460, 1430, 1386, 1295, 1216, 1195, 1068, 1055, 978, 871, 817, 766, 708 cm−1; HRMS (ESI) calcd for C14H20N2O2 + Na 271.1417, found 271.1419.

(3S,6S)-6-Benzyl-3-methyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (8e)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-3-phenylpropanoate (5f) (1.12 g, 4.36 mmol) and (S)-2-aminopropan-1-ol (0.34 mL, 4.36 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 8e (639 mg, 2.26 mmol) in 52% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 8e

1H-NMR δ = 1.21 (d, J = 6.0 Hz, 3H), 3.23 (dd, J = 13.6, 4.4 Hz, 1H), 3.30–3.37 (m, 2H), 4.18–4.30 (m, 2H), 4.35 (s, 1H), 4.93 (t, J = 4.4 Hz, 1H), 6.10 (ddd, J = 3.6, 1.6, 0.8 Hz, 1H), 6.31 (dd, J = 3.6, 2.8 Hz, 1H), 6.66–6.72 (m, 3H), 7.11–7.16 (m, 2H), 7.20–7.25 (m, 1H) ppm; 13C-NMR δ = 17.2, 41.8, 50.6, 60.4, 72.1, 80.8, 104.7, 110.5, 117.6, 124.0, 127.5, 128.0, 129.8, 134.3, 163.8 ppm; IR (neat) ν = 3027, 2962, 2923, 2861, 1704, 1659, 1561, 1456, 1437, 1404, 1361, 1311, 1234, 1165, 1077, 1041, 972, 822, 744, 695 cm−1; HRMS (ESI) calcd for C17H18N2O2 + Na 305.1260, found 305.1264.

(3S,6S)-3-Methyl-6-phenethyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (8f)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-4-phenylbutanoate (5g) (1.12 g, 4.13 mmol) and (S)-2-aminopropan-1-ol (0.32 mL, 4.13 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 8f (269 mg, 0.91 mmol) in 22% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 8f

1H-NMR δ = 1.37 (d, J = 6.4 Hz, 3H), 2.24–2.33 (m, 2H), 2.47–2.55 (m, 1H), 2.60–2.68 (m, 1H), 3.59–3.66 (m, 1H), 4.35–4.44 (m, 2H), 4.68 (t, J = 6.0 Hz, 1H), 5.78 (s, 1H), 6.30 (dd, J = 3.6, 2.8 Hz, 1H), 6.32 (ddd, J = 3.6, 1.6, 0.8 Hz, 1H), 6.66 (dd, J = 2.8, 1.6 Hz, 1H), 7.12–7.16 (m, 2H), 7.16–7.22 (m, 1H), 7.24–7.30 (m, 2H) ppm; 13C-NMR δ = 17.8, 30.9, 37.4, 51.1, 59.5, 72.3, 81.7, 105.7, 110.2, 118.7, 122.9, 126.3, 128.3, 128.5, 140.0, 165.6 ppm; IR (neat) ν = 3016, 2966, 2930, 2857, 1714, 1666, 1561, 1449, 1434, 1406, 1359, 1302, 1227, 1168, 1076, 1058, 977, 826, 766, 725, 693 cm−1; HRMS (ESI) calcd for C18H20N2O2 + Na, 319.1417, found 319.1419.

Methyl 2-((3S,6S)-3-methyl-5-oxo-2,3,5,6-tetrahydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-6-yl)acetate (8g)

The reaction of dimethyl (S)-2-(2-formyl-1H-pyrrol-1-yl)succinate (5h) (1.12 g, 4.68 mmol) and (S)-2-aminopropan-1-ol (0.36 mL, 4.68 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 8g (334 mg, 1.26 mmol) in 27% yield (a 1.05 : 1 mixture of stereoisomers) as light-yellow liquid after purification by SiO2 column chromatography.

Data for 8g

1H-NMR (major) δ = 1.42 (d, J = 6.4 Hz, 3H), 2.97 (dd, J = 16.4, 6.8 Hz, 1H), 3.06 (dd, J = 16.4, 4.4 Hz, 1H), 3.60–3.70 (m, 1H), 3.65 (s, 3H), 4.35–4.46 (m, 2H), 4.99 (dd, J = 6.7, 4.4 Hz, 1H), 5.82 (br s, 1H), 6.26 (dd, J = 3.6, 1.6 Hz, 1H), 6.30 (dd, J = 3.6, 2.4 Hz, 1H), 6.70 (dd, J = 2.4, 1.6 Hz, 1H) ppm; (minor) δ = 1.40 (d, J = 6.4 Hz, 3H), 3.21 (dd, J = 17.2, 5.6 Hz, 1H), 3.36 (dd, J = 17.2, 5.6 Hz, 1H), 3.60–3.70 (m, 1H), 3.71 (s, 3H), 4.35–4.48 (m, 2H), 5.00 (t, J = 5.6 Hz, 1H), 5.79 (br s, 1H), 6.27–6.36 (m, 2H), 6.64 (m, 1H) ppm; 13C-NMR (major) δ = 17.9, 39.5, 51.2, 52.2, 54.5, 72.4, 81.5, 106.8, 110.4, 118.8, 122.9, 164.1, 169.9 ppm; (minor) δ = 17.6, 36.2, 51.7, 52.1, 55.8, 72.0, 81.3, 105.8, 110.5, 117.5, 122.7, 164.7, 170.6 ppm; IR (neat) ν = 2957, 2926, 2856, 1737, 1671, 1563, 1461, 1442, 1379, 1336, 1310, 1272, 1220, 1203, 1172, 1077, 1055, 976, 914, 776, 733, 673 cm−1; HRMS (ESI) calcd for C13H16N2O4 + Na 287.1002, found 287.1002.

(3S,6S)-3-Methyl-6-(2-(methylthio)ethyl)-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (8h)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-4-(methylthio)butanoate (5j) (1.12 g, 4.68 mmol) and (S)-2-aminopropan-1-ol (0.36 mL, 4.68 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 8h (299 mg, 1.12 mmol) in 24% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 8h

1H-NMR δ = 1.40 (d, J = 6.0 Hz, 3H), 2.09 (s, 3H), 2.12–2.22 (m, 1H), 2.22–2.31 (m, 1H), 2.33–2.41 (m, 1H), 2.47–2.55 (m, 1H), 3.61–3.69 (m, 1H), 4.34–4.44 (m, 2H), 4.78 (dd, J = 6.8, 5.6 Hz, 1H), 5.80 (s, 1H), 6.28 (dd, J = 4.0, 2.8 Hz, 1H), 6.31 (ddd, J = 4.0, 1.6, 0.8 Hz, 1H), 6.68 (dd, J = 2.8, 1.6 Hz, 1H) ppm; 13C-NMR δ = 15.2, 17.7, 29.2, 34.9, 51.1, 58.6, 72.3, 81.7, 105.8, 110.2, 118.8, 122.9, 165.4 ppm; IR (neat) ν = 2967, 2910, 2862, 1645, 1556, 1465, 1412, 1398, 1354, 1307, 1228, 1168, 1041, 975, 830, 766, 719 cm−1; HRMS (ESI) calcd for C13H18N2O2S + Na, 289.0981, found 289.0985.

General procedure for cyclization of pyrralines 5 with (S)-2-amino-3-methylbutan-1-ol (l-valinol)

(3S)-3-Isopropyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (9a)

The mixture of methyl 2-(2-formyl-1H-pyrrol-1-yl)acetate (5a) (1.12 g, 6.70 mmol) and l-valinol (0.69 g, 6.70 mmol) in toluene (5 mL) was stirred at room temperature for 2.5 h and then heated at 110 °C for 6 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by SiO2 flash column chromatography to give 9a (59 mg, 0.27 mmol) in 4% yield as light-yellow liquid.

Data for 9a

1H-NMR δ = 0.98 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.4 Hz, 3H), 2.14 (m, 1H), 3.83 (dd, J = 8.8, 6.8 Hz, 1H), 4.21 (dd, J = 8.8, 8.0 Hz, 1H), 4.29 (ddd, J = 8.0, 7.2, 6.8 Hz, 1H), 4.63 (A of ABq, JAB = 17.2 Hz, 1H), 4.72 (B of ABq, JAB = 17.2 Hz, 1H), 5.74 (s, 1H), 6.30 (dd, J = 3.6, 2.4 Hz, 1H), 6.33 (ddd, J = 3.6, 1.6, 0.8 Hz, 1H), 6.65 (dd, J = 2.4, 1.6 Hz, 1H) ppm; 13C-NMR δ = 17.5, 19.2, 30.8, 48.4, 60.2, 67.7, 82.5, 106.5, 110.4, 119.1, 121.9, 163.9 ppm; IR (neat) ν = 2952, 2929, 2872, 1666, 1561, 1460, 1429, 1367, 1322, 1268, 1227, 1189, 1081, 1048, 973, 870, 825, 761, 713 cm−1; HRMS (ESI) calcd for C12H16N2O2 + Na, 243.1104, found 243.1107.

(3S,6S)-3-Isopropyl-6-methyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (9b)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)propanoate (5b) (1.12 g, 6.19 mmol) and l-valinol (0.64 g, 6.19 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 9b (392 mg, 1.67 mmol) in 27% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 9b

1H-NMR δ = 0.97 (d, J = 7.2 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H), 1.79 (d, J = 7.2 Hz, 3H), 2.11 (m, 1H), 3.83 (dd, J = 8.8, 6.8 Hz, 1H), 4.17 (dd, J = 8.8, 7.6 Hz, 1H), 4.26 (ddd, J = 8.0, 7.6, 6.8 Hz, 1H), 4.68 (q, J = 7.2 Hz, 1H), 5.74 (s, 1H), 6.30 (dd, J = 3.6, 2.8 Hz, 1H), 6.33 (ddd, J = 3.6, 1.6, 0.8 Hz, 1H), 6.76 (dd, J = 2.8, 1.6 Hz, 1H) ppm; 13C-NMR δ = 17.2, 17.7, 19.3, 30.8, 53.4, 60.7, 67.6, 82.2, 106.6, 110.1, 117.9, 122.4, 167.1 ppm; IR (neat) ν = 2958, 2942, 2872, 1703, 1661, 1562, 1544, 1460, 1422, 1365, 1301, 1216, 1111, 1085, 1058, 984, 950, 857, 825, 751, 708 cm−1; HRMS (ESI) calcd for C13H18N2O2 + Na, 257.1260, found 257.1263.

(3S,6S)-3,6-Diisopropyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (9c)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-3-methylbutanoate (5c) (1.12 g, 5.36 mmol) and l-valinol (0.55 g, 5.36 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 9c (858 mg, 3.27 mmol) in 61% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 9c

1H-NMR δ = 0.95 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 7.2 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 2.17–2.33 (m, 2H), 3.86 (dd, J = 8.8, 6.8 Hz, 1H), 4.17 (dd, J = 8.8, 7.6 Hz, 1H), 4.28 (ddd, J = 7.6, 7.2, 6.8 Hz, 1H), 4.46 (d, J = 5.2 Hz, 1H), 5.77 (s, 1H), 6.26 (dd, J = 3.6, 2.8 Hz, 1H), 6.28 (ddd, J = 3.6, 1.6, 0.8 Hz, 1H), 6.63 (dd, J = 2.8, 1.6 Hz, 1H) ppm; 13C-NMR δ = 17.5, 18.2, 19.2, 19.2, 30.3, 35.0, 60.1, 65.9, 67.2, 83.0, 105.2, 109.5, 119.4, 123.8, 165.9 ppm; IR (neat) ν = 3100, 2958, 2857, 1702, 1661, 1561, 1455, 1429, 1396, 1375, 1306, 1227, 1189, 1105, 1058, 967, 867, 825, 765, 708 cm−1; HRMS (ESI) calcd for C15H22N2O2 + Na, 285.1573, found 285.1575.

(3S,6S)-6-((S)-sec-Butyl)-3-isopropyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (9d)

The reaction of methyl (2S,3S)-2-(2-formyl-1H-pyrrol-1-yl)-3-methylpentanoate (5e) (1.12 g, 5.02 mmol) and l-valinol (0.52 g, 5.02 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 9d (694 mg, 2.51 mmol) in 50% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 9d

1H-NMR δ = 0.90 (d, J = 7.2 Hz, 3H), 0.95 (t, J = 7.6 Hz, 3H), 0.98 (d, J = 6.0 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 1.08–2.22 (m, 1H), 1.57–1.68 (m, 1H), 1.93–2.03 (m, 1H), 2.14–2.26 (m, 1H), 3.85 (dd, J = 8.8, 6.8 Hz, 1H), 4.17 (dd, J = 8.8, 7.6 Hz, 1H), 4.28 (ddd, J = 7.6, 7.2, 6.8 Hz, 1H), 4.56 (d, J = 5.2 Hz, 1H), 5.77 (s, 1H), 6.26–6.28 (m, 2H), 6.63 (dd, J = 2.8, 1.6 Hz, 1H) ppm; 13C-NMR δ = 11.6, 15.2, 17.6, 19.2, 25.4, 30.4, 42.0, 60.2, 64.6, 67.3, 83.0, 105.2, 109.7, 119.0, 123.8, 165.6 ppm; IR (neat) ν = 2958, 2939, 2878, 1709, 1655, 1568, 1544, 1460, 1431, 1381, 1295, 1232, 1200, 1077, 1058, 967, 879, 833, 766, 713 cm−1; HRMS (ESI) calcd for C16H24N2O2 + Na, 299.1730, found 299.1734.

(3S,6S)-6-Benzyl-3-isopropyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (9e)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-3-phenylpropanoate (5f) (1.12 g, 4.36 mmol) and l-valinol (0.45 g, 4.36 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 9e (961 mg, 3.10 mmol) in 71% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 9e

1H-NMR δ = 0.76 (d, J = 7.2 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H), 2.09 (m, 1H), 3.29 (d of A of ABq, JAB = 13.6, Jd = 4.8 Hz, 1H), 3.34 (d of B of ABq, JAB = 13.6, Jd = 4.4 Hz, 1H), 3.68 (dd, J = 8.8, 6.8 Hz, 1H), 4.04 (dd, J = 8.8, 7.6 Hz, 1H), 4.17 (ddd, J = 7.6, 7.2, 6.8 Hz, 1H), 4.86 (s, 1H), 4.96 (t, J = 4.8 Hz, 1H), 6.16 (ddd, J = 3.6, 1.6, 0.8 Hz, 1H), 6.31 (dd, J = 3.6, 2.8 Hz, 1H), 6.64 (dd, J = 2.8, 1.6 Hz, 1H), 6.66–6.70 (m, 2H), 7.12–7.23 (m, 3H) ppm; 13C-NMR δ = 17.1, 19.0, 30.0, 41.6, 60.2, 60.6, 66.6, 82.2, 105.1, 110.4, 117.7, 123.6, 127.2, 128.2, 129.4, 134.5, 165.3 ppm; IR (neat) ν = 3032, 2962, 2926, 2872, 1708, 1661, 1556, 1455, 1430, 1403, 1350, 1306, 1297, 1237, 1175, 1113, 1079, 1041, 967, 853, 816, 729, 693 cm−1; HRMS (ESI) calcd for C19H22N2O2 + Na, 333.1573, found 333.1575.

(3S,6S)-3-Isopropyl-6-phenethyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (9f)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-4-phenylbutanoate (5g) (1.12 g, 4.13 mmol) and l-valinol (0.43 g, 4.13 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 9f (683 mg, 2.11 mmol) in 51% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 9f

1H-NMR δ = 0.99 (d, J = 7.2 Hz, 3H), 1.02 (d, J = 7.2 Hz, 3H), 2.19 (m, 1H), 2.25–2.32 (m, 2H), 2.41–2.50 (m, 1H), 2.63–2.72 (m, 1H), 3.86 (dd, J = 8.8, 6.8 Hz, 1H), 4.20 (dd, J = 8.8, 7.6 Hz, 1H), 4.30 (ddd, J = 7.6, 7.2, 6.8 Hz, 1H), 4.71 (t, J = 5.6 Hz, 1H), 5.79 (s, 1H), 6.29–6.33 (m, 2H), 6.63 (dd, J = 2.4, 1.6 Hz, 1H), 7.11–7.15 (m, 2H), 7.16–7.22 (m, 1H), 7.24–7.30 (m, 2H) ppm; 13C-NMR δ = 17.5, 19.2, 30.6, 31.0, 38.0, 59.6, 60.1, 67.6, 82.6, 105.9, 110.3, 118.6, 122.8, 126.3, 128.3, 128.5, 140.1, 166.6 ppm; IR (neat) ν = 3015, 2963, 2925, 2878, 1709, 1666, 1549, 1455, 1422, 1403, 1343, 1302, 1232, 1158, 1058, 983, 876, 828, 713, 698 cm−1; HRMS (ESI) calcd for C20H24N2O2 + Na, 347.1730, found 347.1732.

Methyl 2-((3S,6S)-3-isopropyl-5-oxo-2,3,5,6-tetrahydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-6-yl)acetate (9g)

The reaction of dimethyl (S)-2-(2-formyl-1H-pyrrol-1-yl)succinate (5h) (1.12 g, 4.68 mmol) and l-valinol (0.48 g, 4.69 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 9g (137 mg, 0.47 mmol) in 10% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 9g

1H-NMR δ = 0.99 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 7.2 Hz, 3H), 2.26 (m, 1H), 3.00 (d of A of ABq, JAB = 16.4, Jd = 6.8 Hz, 1H), 3.08 (d of B of ABq, JAB = 16.4, Jd = 4.4 Hz, 1H), 3.65 (s, 3H), 3.89 (dd, J = 8.0, 6.0 Hz, 1H), 4.21 (dd, J = 8.0, 7.6 Hz, 1H), 4.26 (ddd, J = 7.6, 6.8, 6.0 Hz, 1H), 5.01 (dd, J = 6.4, 4.4 Hz, 1H), 5.79 (s, 1H), 6.27 (dd, J = 4.0, 2.8 Hz, 1H), 6.29 (ddd, J = 4.0, 1.6, 0.8 Hz, 1H), 6.70 (dd, J = 2.8, 1.6 Hz, 1H) ppm; 13C-NMR δ = 17.2, 19.0, 30.4, 39.7, 52.1, 55.9, 60.3, 67.5, 82.5, 106.0, 110.5, 118.6, 122.8, 165.0, 169.8 ppm; IR (neat) ν = 2958, 2931, 2862, 1740, 1655, 1570, 1449, 1439, 1399, 1371, 1317, 1237, 1191, 1168, 1063, 978, 862, 822, 772, 713 cm−1; HRMS (ESI) calcd for C15H20N2O4 + Na, 315.1315, found 315.1316.

(3S,6S)-3-isopropyl-6-(2-(methylthio)ethyl)-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (9h)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-4-(methylthio)butanoate (5j) (1.12 g, 4.68 mmol) and l-valinol (0.48 g, 4.65 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 9h (331 mg, 1.12 mmol) in 24% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 9h

1H-NMR δ = 0.96 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 2.06 (s, 3H), 2.13–2.36 (m, 4H), 2.46–2.55 (m, 1H), 3.84 (dd, J = 8.8, 6.8 Hz, 1H), 4.17 (dd, J = 8.8, 7.6 Hz, 1H), 4.25 (ddd, J = 7.6, 7.2, 6.8 Hz, 1H), 4.78 (dd, J = 6.4, 5.6 Hz, 1H), 5.74 (s, 1H), 6.26 (dd, J = 4.0, 2.8 Hz, 1H), 6.28 (ddd, J = 4.0, 1.6, 0.8 Hz, 1H), 6.67 (dd, J = 2.8, 1.6 Hz, 1H) ppm; 13C-NMR δ = 15.3, 17.5, 19.2, 29.2, 30.5, 35.3, 58.7, 60.1, 67.5, 82.6, 106.0, 110.3, 118.7, 122.8, 166.4 ppm; IR (neat) ν = 2958, 2910, 2872, 1703, 1661, 1550, 1544, 1449, 1422, 1406, 1345, 1307, 1237, 1163, 1114, 1053, 978, 870, 831, 777, 715 cm−1; HRMS (ESI) calcd for C15H22N2O2S + Na, 317.1294, found 317.1296.

General procedure for cyclization of pyrralines 5 with (S)-2-amino-2-phenylethan-1-ol (l-phenylalaninol)

(3S)-3-Benzyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (10a)

The mixture of methyl 2-(2-formyl-1H-pyrrol-1-yl)acetate (5a) (1.12 g, 6.70 mmol) and l-phenylalaninol (1.01 g, 6.70 mmol) in toluene (5 mL) was stirred at room temperature for 2.5 h and then heated at 110 °C for 6 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by SiO2 flash column chromatography to give 10a (108 mg, 0.40 mmol) in 6% yield as light-yellow liquid.

Data for 10a

1H-NMR δ = 2.98 (dd, J = 13.6, 8.8 Hz, 3H), 3.29 (dd, J = 13.6, 4.0 Hz, 1H), 3.85 (dd, J = 9.2, 8.0 Hz, 1H), 4.21 (dd, J = 9.2, 7.6 Hz, 1H), 4.60–4.68 (m, 1H), 4.64 (A of ABq, JAB = 17.2 Hz, 1H), 4.69 (B of ABq, JAB = 17.2 Hz, 1H), 5.54 (s, 1H), 6.26–6.30 (m, 2H), 6.65 (dd, J = 2.4, 1.6 Hz, 1H), 7.22–7.28 (m, 3H), 7.29–7.36 (m, 2H) ppm; 13C-NMR δ = 37.7, 48.6, 55.7, 69.6, 82.5, 106.1, 110.3, 119.1, 122.3, 126.9, 128.7, 129.5, 136.2, 163.0 ppm; IR (neat) ν = 3026, 2925, 2877, 1719, 1666, 1547, 1498, 1465, 1429, 1347, 1317, 1269, 1216, 1079, 1047, 973, 750, 693 cm−1; HRMS (ESI) calcd for C16H16N2O2 + Na, 291.1104, found 291.1107.

(3S,6S)-3-Benzyl-6-methyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (10b)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)propanoate (5b) (1.12 g, 6.19 mmol) and l-phenylalaninol (0.94 g, 6.19 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 10b (559 mg, 1.98 mmol) in 32% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 10b

1H-NMR δ = 1.65 (d, J = 7.2 Hz, 3H), 3.08 (dd, J = 13.6, 8.0 Hz, 3H), 3.18 (dd, J = 13.6, 4.0 Hz, 1H), 3.88 (dd, J = 8.8, 8.0 Hz, 1H), 4.24 (dd, J = 8.8, 8.0 Hz, 1H), 4.62 (dddd, J = 8.0, 8.0, 8.0, 4.0 Hz, 1H), 4.71 (q, J = 7.2 Hz, 1H), 5.41 (s, 1H), 6.22 (ddd, J = 4.0, 1.6, 0.8 Hz, 1H), 6.26 (dd, J = 4.0, 2.8 Hz, 1H), 6.65 (dd, J = 2.8, 1.6 Hz, 1H), 7.20–7.28 (m, 3H), 7.29–7.34 (m, 2H) ppm; 13C-NMR δ = 22.4, 37.2, 55.3, 55.7, 69.4, 82.3, 105.6, 110.3, 118.1, 122.1, 127.0, 128.6, 129.8, 136.1, 166.7 ppm; IR (neat) ν = 3027, 2973, 2920, 2857, 1714, 1655, 1566, 1449, 1422, 1402, 1370, 1307, 1221, 1153, 1114, 1074, 1031, 973, 819, 751, 698 cm−1; HRMS (ESI) calcd for C17H18N2O2 + Na, 305.1260, found 305.1264.

(3S,6S)-3-Benzyl-6-isopropyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (10c)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-3-methylbutanoate (5c) (1.12 g, 5.36 mmol) and l-phenylalaninol (0.81 g, 5.36 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 10c (682 mg, 2.20 mmol) in 41% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 10c

1H-NMR δ = 0.89 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.4 Hz, 3H), 2.25 (m, 1H), 2.92 (dd, J = 13.2, 9.2 Hz, 1H), 3.34 (dd, J = 13.2, 4.0 Hz, 1H), 3.85 (dd, J = 8.8, 7.2 Hz, 1H), 4.17 (dd, J = 8.8, 7.6 Hz, 1H), 4.44 (d, J = 4.8 Hz, 1H), 4.60 (dddd, J = 9.2, 7.6, 7.2, 4.0 Hz, 1H), 5.64 (s, 1H), 6.24 (dd, J = 3.6, 2.4 Hz, 1H), 6.26 (ddd, J = 3.6, 1.6, 0.8 Hz, 1H), 6.62 (dd, J = 2.4, 1.6 Hz, 1H), 7.22–7.28 (m, 3H), 7.29–7.34 (m, 2H) ppm; 13C-NMR δ = 18.1, 19.3, 34.8, 37.7, 56.0, 65.9, 69.8, 82.7, 105.2, 109.4, 119.6, 123.8, 126.9, 128.6, 129.5, 136.4, 165.4 ppm; IR (neat) ν = 3032, 2958, 2925, 2878, 1666, 1560, 1465, 1425, 1399, 1361, 1302, 1227, 1194, 1158, 1063, 1058, 1030, 967, 861, 756, 703 cm−1; HRMS (ESI) calcd for C19H22N2O2 + Na, 333.1573, found 333.1576.

(3S,6S)-3-Benzyl-6-((S)-sec-butyl)-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (10d)

The reaction of methyl (2S,3S)-2-(2-formyl-1H-pyrrol-1-yl)-3-methylpentanoate (5e) (1.12 g, 5.02 mmol) and l-phenylalaninol (0.76 g, 5.02 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 10d (505 mg, 1.56 mmol) in 31% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 10d

1H-NMR δ = 0.91 (d, J = 6.8 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H), 1.00–1.14 (m, 1H), 1.50–1.62 (m, 1H), 1.92–2.04 (m, 1H), 2.93 (dd, J = 13.2, 8.8 Hz, 1H), 3.33 (dd, J = 13.2, 4.4 Hz, 1H), 3.85 (dd, J = 8.8, 7.6 Hz, 1H), 4.17 (dd, J = 8.8, 7.6 Hz, 1H), 4.55 (d, J = 5.2 Hz, 1H), 4.60 (dddd, J = 8.8, 7.6, 7.6, 4.4 Hz, 1H), 5.64 (s, 1H), 6.23–6.26 (m, 2H), 6.62 (dd, J = 2.8, 1.6 Hz, 1H), 7.22–7.28 (m, 3H), 7.29–7.35 (m, 2H) ppm; 13C-NMR δ = 11.6, 15.4, 25.1, 37.8, 41.8, 56.1, 64.7, 69.8, 82.7, 105.1, 109.6, 119.2, 123.8, 126.9, 128.6, 129.5, 136.4, 165.2 ppm; IR (neat) ν = 3020, 2958, 2920, 2872, 1705, 1655, 1561, 1455, 1431, 1398, 1366, 1290, 1227, 1189, 1151, 1068, 1052, 1026, 978, 862, 735, 703 cm−1; HRMS (ESI) calcd for C20H24N2O2 + Na, 347.1730, found 347.1732.

(3S,6S)-3,6-Dibenzyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (10e)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-3-phenylpropanoate (5f) (1.12 g, 4.36 mmol) and l-phenylalaninol (0.66 g, 4.36 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 10e (969 mg, 2.70 mmol) in 62% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 10e

1H-NMR δ = 2.41 (dd, J = 13.2, 10.4 Hz, 1H), 3.28 (d of A of ABq, JAB = 13.6, Jd = 4.8 Hz, 1H), 3.32 (d of B of ABq, JAB = 13.6, Jd = 4.8 Hz, 1H), 3.44 (dd, J = 13.2, 4.4 Hz, 1H), 3.56 (dd, J = 9.2, 7.6 Hz, 1H), 3.99 (dd, J = 9.2, 7.6 Hz, 1H), 4.45 (dddd, J = 10.4, 7.6, 7.6, 4.4 Hz, 1H), 4.52 (s, 1H), 4.95 (t, J = 4.8 Hz, 1H), 6.12 (ddd, J = 4.0, 1.6, 0.8 Hz, 1H), 6.28 (dd, J = 4.0, 2.8 Hz, 1H), 6.63 (dd, J = 2.8, 1.6 Hz, 1H), 6.71–6.76 (m, 2H), 7.15–7.32 (m, 8H) ppm; 13C-NMR δ = 37.6, 41.8, 55.7, 60.6, 70.1, 81.4, 104.9, 110.4, 117.9, 123.7, 126.8, 127.5, 128.2, 128.7, 129.1, 129.7, 134.5, 136.5, 164.2 ppm; IR (neat) ν = 3016, 2915, 2862, 1655, 1544, 1460, 1438, 1405, 1361, 1316, 1206, 1158, 1079, 1049, 1029, 975, 851, 740, 698 cm−1; HRMS (ESI) calcd for C23H22N2O2 + Na, 381.1573, found 381.1577.

(3S,6S)-3-Benzyl-6-phenethyl-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (10f)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-4-phenylbutanoate (5g) (1.12 g, 4.13 mmol) and l-phenylalaninol (0.63 g, 4.13 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 10f (877 mg, 2.35 mmol) in 57% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 10f

1H-NMR δ = 2.19–2.36 (m, 2H), 2.47–2.58 (m, 1H), 2.63–2.73 (m, 1H), 2.99 (dd, J = 13.6, 8.4 Hz, 1H), 3.21 (dd, J = 13.6, 4.0 Hz, 1H), 3.86 (dd, J = 8.8, 7.6 Hz, 1H), 4.21 (dd, J = 8.8, 7.6 Hz, 1H), 4.62 (dddd, J = 8.4, 7.6, 7.6, 4.0 Hz, 1H), 4.69 (t, J = 6.0 Hz, 1H), 5.51 (s, 1H), 6.26 (ddd, J = 3.6, 1.6, 0.8 Hz, 1H), 6.28 (dd, J = 3.6, 2.8 Hz, 1H), 6.65 (dd, J = 2.8, 1.6 Hz, 1H), 7.14–7.19 (m, 2H), 7.19–7.33 (m, 8H) ppm; 13C-NMR δ = 31.0, 37.5, 37.5, 55.6, 59.5, 69.6, 82.4, 105.7, 110.2, 118.7, 122.9, 126.3, 127.0, 128.3, 128.6, 128.6, 129.6, 136.2, 140.0, 165.9 ppm; IR (neat) ν = 3025, 2964, 2920, 2862, 1709, 1666, 1544, 1443, 1431, 1338, 1325, 1211, 1074, 1026, 973, 772, 687 cm−1; HRMS (ESI) calcd for C24H24N2O2 + Na, 395.1730, found 395.1733.

Methyl 2-((3S,6S)-3-benzyl-5-oxo-2,3,5,6-tetrahydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-6-yl)acetate (10g)

The reaction of dimethyl (S)-2-(2-formyl-1H-pyrrol-1-yl)succinate (5h) (1.12 g, 4.68 mmol) and l-phenylalaninol (0.71 g, 4.69 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 10g (223 mg, 0.66 mmol) in 14% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 10g

1H-NMR δ = 2.91 (dd, J = 16.4, 7.6 Hz, 1H), 3.02 (dd, J = 13.6, 8.8 Hz, 1H), 3.07 (dd, J = 16.4, 4.0 Hz, 1H), 3.29 (dd, J = 13.6, 4.0 Hz, 1H), 3.69 (s, 3H), 3.89 (dd, J = 9.2, 7.6 Hz, 1H), 4.22 (dd, J = 9.2, 7.6 Hz, 1H), 4.59 (dddd, J = 8.8, 7.6, 7.6, 4.0 Hz, 1H), 5.05 (dd, J = 7.6, 4.0 Hz, 1H), 5.54 (s, 1H), 6.22–6.27 (m, 2H), 6.70 (dd, J = 2.4, 1.6 Hz, 1H), 7.22–7.36 (m, 5H) ppm; 13C-NMR δ = 37.2, 39.7, 52.2, 55.8, 55.9, 69.7, 82.3, 105.8, 110.4, 118.9, 122.8, 127.0, 128.7, 129.6, 136.2, 164.4, 169.9 ppm; IR (neat) ν = 3032, 2947, 2927, 2867, 1735, 1666, 1555, 1455, 1438, 1442, 1400, 1365, 1317, 1221, 1168, 1084, 1026, 1029, 973, 898, 858, 830, 766, 703 cm−1; HRMS (ESI) calcd for C19H20N2O4 + Na, 363.1315, found 363.1319.

(3S,6S)-3-Benzyl-6-(2-(methylthio)ethyl)-2,3-dihydro-10bH-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-one (10h)

The reaction of methyl (S)-2-(2-formyl-1H-pyrrol-1-yl)-4-(methylthio)butanoate (5j) (1.12 g, 4.68 mmol) and l-phenylalaninol (0.70 g, 4.65 mmol) in toluene (5 mL) at room temperature for 2.5 h and then at 110 °C for 6 h produced 10h (353 mg, 1.03 mmol) in 22% yield as light-yellow liquid after purification by SiO2 column chromatography.

Data for 10h

1H-NMR δ = 2.07–2.17 (m, 1H), 2.11 (s, 3H), 2.20–2.31 (m, 1H), 2.32–2.40 (m, 1H), 2.48–2.57 (m, 1H), 3.04 (dd, J = 13.6, 8.4 Hz, 1H), 3.22 (dd, J = 13.6, 4.0 Hz, 1H), 3.88 (dd, J = 9.2, 7.6 Hz, 1H), 4.21 (dd, J = 9.2, 7.6 Hz, 1H), 4.61 (dddd, J = 8.4, 7.6, 7.6, 4.0 Hz, 1H), 4.79 (dd, J = 7.2, 5.6 Hz, 1H), 5.49 (s, 1H), 6.23–6.27 (m, 2H), 6.67 (dd, J = 2.4, 2.0 Hz, 1H), 7.20–7.35 (m, 5H) ppm; 13C-NMR δ = 15.2, 29.3, 35.0, 37.3, 55.6, 58.6, 69.5, 82.4, 105.7, 110.1, 118.9, 122.9, 127.0, 128.6, 129.6, 136.2, 165.7 ppm; IR (neat) ν = 3015, 2915, 2846, 1709, 1655, 1570, 1539, 1478, 1455, 1426, 1347, 1323, 1302, 1211, 1200, 1147, 1075, 1032, 977, 854, 818, 739, 701 cm−1; HRMS (ESI) calcd for C19H22N2O2S + Na, 365.1294, found 365.1296.

Conclusions

We demonstrated a practically efficient transformation method of d-ribose as sustainable reducing sugar with various α-amino acids into pyrralines 5 as platform chemicals. Up to 300% yield increasement of pyrralines 5 (32–63% yield) were realized by one-pot pressurized conversion of d-ribose with various α-amino esters at 2.5 atm and 80 °C. The pyrrole-based platform chemicals 5 containing formyl and ester groups as linchpin units were further cyclized to form the piperazin-2-one scaffold as the second pharmacophore. Reductive amination of the formyl group with benzylamine, followed by intramolecular amination with the ester group provided pyrrolo-piperazinones 6 in reasonable yields. 1,2-Ethanediamine reacted with the formyl group of pyrralines 5 by double amination, and the resulting secondary amine underwent subsequent amination with the ester group to produce pyrrolo-piperazinones 7 with an imidazolidine ring as the third structural unit in high yields. Likewise, 2-amino alcohols derived from natural α-amino acids, alanine, valine, and phenylalanine, respectively reacted with the formyl group of pyrralines 5 to give intermediate oxazolidines, which underwent further cyclization with the ester group to produce triply fused heterocycles 8–10 of pyrrole, piperazin-2-one, and oxazolidine in acceptable yields. Pyrrolo-piperazinones 8h and 10g with an oxazolidine motif exhibited significant anti-inflammation activities with high cell viability. The practical synthetic method of platform chemicals 5 from sustainable biomass would open a paved road to the discovery of new therapeutic agents and value-added functional materials.

Author contributions

S. Cho: synthesis (lead); L. Gu: synthesis (equal); I. J. In: synthesis (supporting); B. Wu: investigation (equal), synthesis (supporting); T. Lee: bioassays (lead); H. Kim: bioassay (equal), funding acquisition (equal); S. Koo: project administration (lead), funding acquisition (lead), investigation (lead), formal analysis (lead), data curation (lead), writing manuscript (lead).

Conflicts of interest

There are no conflicts to declare.