Unexplored reactivity of 2-oxoaldehydes towards Pictet–Spengler conditions: concise approach to β-carboline based marine natural products

Abstract

Novel reactions under Pictet–Spengler conditions between tryptophan methyl ester/tryptamine and 2-oxoaldehydes have been developed and successfully utilized for the total synthesis of Merinacarboline (A and B), Eudistomin Y1, Pityriacitrin B, Pityriacitrin, Fascaplysin and analogues.

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2-Oxoaldehydes (OA) are among a few precursors that have been used extensively to synthesize a large variety of heterocyclic compounds.¹ Pictet–Spengler is one of the various reactions reported on OA leading to the synthesis of β-carbolines.^2–11 A large number of naturally occurring β-carbolines with acyl substitution at the C-1 position have shown promising anti-inflammatory,² anti-malarial,¹² anti-cancer,^3,13 anti-phospholipase A2,¹⁴ anti-microbial,¹⁵ and anti-bacterial activities.¹⁶ In view of these biochemical observations, convenient synthetic methods for the synthesis of such constructs are desirable. Even though the Pictet–Spengler reaction of tryptamine/tryptophan/tryptophan methyl ester with OA for generation of 1-substituted β-carbolines has been explored,^2,6 a few areas are still untouched. As we know in contemporary organic synthesis, coupled domino reactions, wherein two or more domino processes occur sequentially in the same reaction, are considered to be most effective for the synthesis of complex organic compounds using simple and readily available building blocks.^17,18 In this context, we developed a few unexplored reactions between tryptophan methyl ester/tryptamine and 2-oxoaldehydes with a focus on establishing a multicoupled domino strategy for the synthesis of various marine based natural products and their analogues.

We initiated the present study with a reaction of 2,4-dimethoxy acetophenone 1 with tryptophan methyl ester 2 in the presence of iodine in DMSO. The reaction of 1 (1 equiv.) and 2 (1 equiv.) with I₂ (1 equiv.) in DMSO at 90 °C for 1.5 h afford the desired product in low yield (38%, Table 1, entry 15). To improve upon the yields of desired product, a preliminary set of reactions between tryptophan methyl ester (1 equiv.) and acetophenone (1 equiv.) under different condition were carried out (Table 1).

Table 1 Optimization studies for synthesis of 3a employing 2,4-dimethoxy acetophenone as building block^a

Entry	(Equiv.)	Temp.	Time	Yield^b (%)
a Reaction condition: 1a (1 equiv.), and I2 (1 equiv.) was heated for 1 h in DMSO and then added 2a (1 equiv.).b Isolated yield.
1	I2 (0.25)	RT	24 h	—
2	I2 (0.25)	60 °C	1.5 h	5
3	I2 (0.25)	60 °C	24 h	18
4	I2 (0.25)	75 °C	1.5 h	10
5	I2 (0.25)	75 °C	3 h	25
6	I2 (0.25)	90 °C	1.5 h	32
7	I2 (0.25)	90 °C	2 h	40
8	I2 (0.25)	90 °C	3 h	65
9	I2 (0.50)	90 °C	1.5 h	35
10	I2 (0.50)	90 °C	2 h	42
11	I2 (0.50)	90 °C	3 h	68
12	I2 (0.75)	90 °C	1.5 h	36
13	I2 (0.75)	90 °C	2 h	60
14	I2 (0.75)	90 °C	3 h	80
15	I2 (1)	90 °C	1.5 h	38
16	I2 (1)	90 °C	2 h	45
17	I2 (1)	90 °C	3 h	85
18	I2 (2)	90 °C	1.5 h	45
19	I2 (2)	90 °C	3 h	85
20	I2 (0)	90 °C	24 h	—

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The effects of reaction temperature on the yields of 3a at different time intervals (I₂ taken at 0.25 equiv.) were subsequently examined. A higher conversion rate was obtained when the reaction was performed at 90 °C for 3 h (65%, Table 1, entry 8). No further increase in yield was obtained when the reaction temperature was >90 °C and time more than 3 h. Next, various concentrations of I₂ were screened at 90 °C (entry 6–19). 1 equiv. of iodine was subsequently determined to be the best concentration for the reaction. Finally as observed, the optimal reaction conditions for the reaction turned out to be acetophenone 1a (1 equiv.) with tryptophan methyl ester 2 (1 equiv.), at 90 °C with I₂ (1 equiv.) in DMSO (85%, entry 17).

Encouraged by our results obtained in the above method, we focused our attention on terminal aromatic alkenes as well. A multicomponent reaction was tried between 3,4-dimethoxystyrene 4 and tryptophan methyl ester 2 in the presence of I₂ (1 equiv.) and IBX (1 equiv.) in DMSO at 60 °C (Table 2). The reaction gave the desired product in low yield (12%, entry 2). This reaction did not work when tried at RT (entry 1). Further studies on optimization were planned at different temperatures and concentrations of IBX (entry 3–7). The results clearly revealed that the desired product was obtained in a maximum yield when tried at 1 equiv. of IBX at 90 °C (56%, entry 5).

Table 2 Optimization studies for the synthesis of 3b employing 3,4-dimethoxy styrene as building block^a

Entry	I2 (equiv.)	Oxidant IBX (equiv.)	Temp.	Yield^b (%)
a Reaction condition: 4b (1 equiv.), and I2 (1 equiv.), IBX (1 equiv.) were heated for 1 h in DMSO and then added 2a (1 equiv.).b Isolated yield.
1	1	1	RT	—
2	1	1	60 °C	12
3	1	1	75 °C	20
4	1	1	80 °C	45
5	1	1	90 °C	56
6	1	1.5	90 °C	56
7	1	2	90 °C	56

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These methods so developed are typical examples of multicoupled domino reactions. In one pot, OA is generated that undergoes a novel type of reaction under Pictet–Spengler condition with tryptophan methyl ester catalysed by HI (generated in in situ, Scheme 1) to afford tetrahydro-β-carboline as an intermediate followed by self aromatization to the desired product. This work corresponds to a first report for the synthesis of β-carbolines using in situ generated glyoxal. The reaction is catalysed by HI produced within the reaction. On basis of the experimental results and previous works, we propose a possible mechanism as follows (Scheme 1).¹⁷

Scheme 1 Proposed mechanism.

Under these optimized conditions, the scope of various substituted acetophenones 1 and styrenes 4 were investigated (Table 3). Both electron-rich and electron-deficient acetophenones/styrenes could be smoothly transformed into the desired products. Compared to styrenes, acetophenones gave us better results as far as yields are concerned. Furthermore, substituents at different positions of the arene group and their electronic nature do not affect the efficiency of the reaction. Both electron-donating and electron-withdrawing groups attached to the phenyl rings of substrates could afford the corresponding products in moderate to good yields (60–85%). Notably, this method has successfully overcome the challenges of earlier methods regarding selectivity and yields of the desired products.⁵

Table 3 Scope of reaction for acetophenone/styrene with tryptophan methyl ester

a Building blocks corresponding to styrene series.

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Aiming to support our methodology, compound 3a was generated by another reported method (Table 4, entry 1).² Reaction between tryptophan methyl ester hydrochloride 2 and 2,4-dimethoxyphenylglyoxal 5 in methanol under reflux condition gave the expected product (compound 3a) in 35% yield. Supplementary analytical data of 3a produced by both the methods were the same. However along with expected product we isolated a novel compound 6a in 20% yield (entry 1, Table 4). Compound 6a on ¹H-NMR characterization pointed towards an extra peak at δ 4.51 (s, 2H, corresponding to –CH₂ at 1-postion of β-carboline) when compared with the spectra of 3a. Presence of methylene protons was further confirmed by ¹³C/DEPT-NMR (34.32 ppm) and mass analysis (376 Da). The production of Compound 6a existence in the reaction can be explained on the basis of multicoupled one-pot reaction which involves Pictet–Spengler reaction, self aromatization followed by C=O reduction to CH₂. This reaction between the 2-oxaldehyde and tryptophan methyl ester hydrochloride leading to synthesis of 6a through multicoupled domino reaction has clearly revealed the different behavior of substrates in different conditions towards Pictet–Spengler reaction and hence needs to be explored.

Table 4 Synthesis of 6a under different reaction conditions^a

Entry	Solvent	Temp.	Yield 3a^b (%)	Yield 6a^b (%)
a Reaction condition: 2a (1.96 mmol), and 5a (1.96 mmol) in 20 mL acetonitrile was stirred at 85 °C for 3 h.b Isolated yield.
1	Methanol	80 °C	35	20
2	DMSO	120 °C	40	10
3	Toluene	100 °C	20	50
4	2-Methoxyethanol	100 °C	25	50
5	Acetone	60 °C	22	60
6	1,4-Dioxane	100 °C	18	60
7	DMF	100 °C	15	65
8	1,2-Dichloroethane	100 °C	Trace	85
9	Acetonitrile	85 °C	Trace	95
10	Acetonitrile	RT	10	40
11	Water	100 °C	—	—

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To improve upon the yields of 6a a preliminary set of different reactions between tryptophan methyl ester hydrochloride 2 and 2,4-dimethoxyphenylglyoxal 5a under different temperature condition in different solvents were carried out (Table 4, entry 2–11). Among different solvents tested, compound 6a was produced in good yield under reflux condition when tried in acetonitrile (95% yield, Table 4, entry 9). The scope of the acetonitrile promoted novel reaction was further expanded to a range of substituted glyoxals (Table 5).

Table 5 Scope of the reaction of glyoxals with tryptophan methyl ester hydrochloride

Entry	R1	6	3	7
A	2,4-Di-OMe-C6H3	95	Trace	—
B	3,4-OCH2O-C6H3	90	5	—
C	3,4-Di-OMe-C6H3	89	6	—
D	3,5-Di-OMe,4-OH-C6H2	88	5	—
E	3-OMe,4-O-(Benzyl)-C6H3	86	Trace	—
F	3-OMe,4-OH-C6H3	85	4	—
G	3,4,5-Tri-OMe-C6H2	84	10	—
H	2-OMe-C6H4	55	20	—
I	2,4-Di-CH3-C6H3	40	44	—
J	4-OMe-C6H4	Trace	80
K	3-OMe-C6H4	Trace	10	60
L	3-Cl-C6H4	—	15	55
M	2-CF3-C6H4	Trace	35	42
N	2-Cl-C6H4	—	70	—
O	–C6H5	Trace	70	—

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Reaction with different OA generated three different products depending on the nature of the OA used (compounds 6, 3 and 7). Electronically-rich OA (di/tri-substituted electronic rich groups) resulted in synthesis of 6. Traces of 3 were also observed in these cases. All mono substituted electronic rich groups (like OMe, Me etc. at ortho/meta/para) could not produce 6. ortho-Methoxy substituted OA produced compound 6 in 55% yield along with 3 in 20% yield (entry H). para-Methoxy substituted OA produced traces of 6 but produced 3 as a major product (80%, entry J). The meta substituted one produced 7 as the major product along with traces of 3 (entry K). Other mono substituted OA produced 7 as a major product along with minor amount of 3 (entry K, L, M). These results demonstrate that reactions of electron-rich OA gave higher yields of the desired product (84–95%, entry A–G), whereas other substrates (entry J–O) generated the product in trace amount.

The isolation of compound 6, 3 and 7 can be rationalized by the mechanism proposed in Scheme 2. Under acidic condition, the glyoxal undergoes the Pictet–Spengler reaction generating a tetrahydro-β-carboline intermediate 2a, which may either undergo aerobic oxidation to produce 3 or may takes H⁺ to generate a cationic intermediate 2b that can lose a proton to generate an exocyclic double bond at 1-position 2c. This intermediate (2c) may either undergoes aerobic oxidation followed by 1,3-H-shift of N–H proton resulting in compound 7 or may undergo dehydration under H⁺ condition to promote formation of 6 (Scheme 2).

Scheme 2 Proposed mechanism.

In contrast to reaction of tryptophan methyl ester with pure OA our former methods (employing acetophenone as building blocks) are highly selective (despite the nature of substituted glyoxal produced) and generates different β-carboline derivatives in good yields in short duration of time. This prompted us to investigate the application of our former method towards total synthesis of few marine based indole alkaloids (Merinacarboline A & B, Pityriacitrin B & Pityriacitrin, Eudistomin Y1 and Fascaplysin).

Satoshi and co-workers recently reported the synthesis of Marinacarbolines A & B in multiple steps (Scheme 3).¹⁹ Compared to his work, our approach is an efficient, economical, two step process where in no protecting groups are used for its isolation and synthesis is completed in comparatively less time (Scheme 3). Reaction of tryptophan methyl ester 2 (1 equiv.) with acetone (2 equiv.) under optimised conditions afford compound 3w which on further reaction with respective amine (4-hydroxy phenylethyamine/4-methoxy phenylethyamine) under neat condition at 85 °C resulted in the synthesis of Marinacarbolines A & B respectively in ∼70% yield. However compound 3i, generated by reaction of tryptophan methyl ester 2 with 3-acetylindole as per method discussed, on saponification produced Pityriacitrin B 10 (90% yield).

Scheme 3 Total synthesis of Merinacarboline (A & B), and Pityriacitrin B.

Further examination of the structures of Pityriacitrin and Eudistomin Y1, inspired us to try a reaction between tryptamine and acetophenone under optimised condition in order to develop a one step total synthetic approach. Earlier few groups tried to achieve the synthesis of Pityriacitrin and Eudistomin Y1 from different complex intermediates.^6,10,15 All these reported approaches are achieved through multistep reactions. Reaction between tryptamine with 3-acetylindole under optimized conditions furnished Pityriacitrin in moderate yield (11, Scheme 4, 42% yield). However reaction of tryptamine with 4-hydroxy acetophenone as per our method afford Eudistomins Y1 14 in 40% yields.

Scheme 4 Total synthesis of Pityriacitrin, Fascaplysin and Eudistomin Y1.

Fascaplysin, another well known natural product isolated from a marine sponge with a diverse range of biological activities,^20,21 was being synthesized in good yields following our approach (Scheme 4). Reaction of tryptamine with 2-chloroacetophenone under optimised conditions produced compound 13 (75%) which on further heating at 220 °C furnish Fascaplysin 15 in 82% yield. Total synthesis of this important construct was earlier achieved successfully by eight different synthetic routes.^21–28 Most of the methods described involve harsh conditions and are achieved through multistep processes.

Conclusions

In conclusion, unexplored multicoupled domino reactions between tryptophan methyl ester/tryptamine and oxoaldehydes were developed and successfully applied for the total synthesis of Merinacarboline (A & B), Eudistomin Y1, Pityriacitrin, Pityriacitrin B, Fascaplysin and analogues. Further application of the methodology toward the total synthesis of additional biologically active alkaloid natural products is in progress.

Acknowledgements

The authors NB, AP & NM gratefully acknowledge UGC & CSIR for the award of Senior Research Fellowship. This work was generously supported by network project through grant no. BSC0108. We also thank, analytical department of our institute to their support in obtaining spectral information (NMR, MS and IR). IIIM Publication number IIIM/1586/2013.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra01387e

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