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

Article abstract of DOI:10.1039/c4ra01387e

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.

Full text of DOI:10.1039/c4ra01387e

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Unexplored reactivity of 2-oxoaldehydes towards
Pictet–Spengler conditions: concise approach to
b-carboline based marine natural products†
Cite this: RSC Adv., 2014, 4, 26258
ab
Narsaiah Battini,ab Anil K. Padala,ab Nagaraju Mupparapu,ab Ram A. Vishwakarma
Received 17th February 2014
Accepted 28th May 2014
*
ab
*
and Qazi Naveed Ahmed
DOI: 10.1039/c4ra01387e
www.rsc.org/advances
Novel reactions under Pictet–Spengler conditions between trypto- presence of iodine in DMSO. The reaction of 1 (1 equiv.) and 2
phan methyl ester/tryptamine and 2-oxoaldehydes have been devel- (1 equiv.) with I2 (1 equiv.) in DMSO at 90 ꢀC for 1.5 h afford the
oped and successfully utilized for the total synthesis of desired product in low yield (38%, Table 1, entry 15). To improve
Merinacarboline (A and B), Eudistomin Y1, Pityriacitrin B, Pityriacitrin, upon the yields of desired product, a preliminary set of reac-
Fascaplysin and analogues.
tions between tryptophan methyl ester (1 equiv.) and aceto-
phenone (1 equiv.) under different condition were carried out
(Table 1).
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
Table 1 Optimization studies for synthesis of 3a employing 2,4-
dimethoxy acetophenone as building blocka
reported on OA leading to the synthesis of b-carbolines.2–11
A
large number of naturally occurring b-carbolines with acyl
substitution at the C-1 position have shown promising anti-
inammatory,2 anti-malarial,12 anti-cancer,3,13 anti-phospholi-
pase 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
Entry
(Equiv.)
Temp.
RT
Time
Yieldb (%)
b-carbolines has been explored,2,6
a few areas are still
1
2
3
4
5
6
7
8
I2 (0.25)
I2 (0.25)
I2 (0.25)
I2 (0.25)
I2 (0.25)
I2 (0.25)
I2 (0.25)
I2 (0.25)
I2 (0.50)
I2 (0.50)
I2 (0.50)
I2 (0.75)
I2 (0.75)
I2 (0.75)
I2 (1)
24 h
1.5 h
24 h
1.5 h
3 h
1.5 h
2 h
3 h
1.5 h
2 h
3 h
1.5 h
2 h
3 h
1.5 h
2 h
3 h
1.5 h
3 h
24 h
—
5
untouched. As we know in contemporary organic synthesis,
coupled domino reactions, wherein two or more domino
processes occur sequentially in the same reaction, are consid-
ered 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.
60 ꢀ
60 ꢀ
75 ꢀ
75 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
18
10
25
32
40
65
35
42
68
36
60
80
38
45
85
45
85
—
9
10
11
12
13
14
15
16
17
18
19
20
We initiated the present study with a reaction of 2,4-dime-
thoxy acetophenone 1 with tryptophan methyl ester 2 in the
I2 (1)
I2 (1)
I2 (2)
I2 (2)
aAcademy of Scientic and Innovative Research, India
bCSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India. E-mail:
naqazi@iiim.ac.in; ram@iiim.ac.in; Fax: +91-191-2569333; Tel: +91-191-2569000-
292
I2 (0)
a
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra01387e
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.
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The effects of reaction temperature on the yields of 3a at
Under these optimized conditions, the scope of various
different time intervals (I2 taken at 0.25 equiv.) were subse- substituted acetophenones 1 and styrenes 4 were investigated
quently examined. A higher conversion rate was obtained when (Table 3). Both electron-rich and electron-decient acetophe-
the reaction was performed at 90 ꢀC for 3 h (65%, Table 1, entry nones/styrenes could be smoothly transformed into the desired
8). No further increase in yield was obtained when the reaction products. Compared to styrenes, acetophenones gave us better
temperature was >90 ꢀC and time more than 3 h. Next, various results as far as yields are concerned. Furthermore, substituents
concentrations of I2 were screened at 90 ꢀC (entry 6–19). 1 equiv. at different positions of the arene group and their electronic
of iodine was subsequently determined to be the best concen- nature do not affect the efficiency of the reaction. Both electron-
tration for the reaction. Finally as observed, the optimal reac- donating and electron-withdrawing groups attached to the
tion conditions for the reaction turned out to be acetophenone phenyl rings of substrates could afford the corresponding
1a (1 equiv.) with tryptophan methyl ester 2 (1 equiv.), at 90 ꢀC products in moderate to good yields (60–85%). Notably, this
with I2 (1 equiv.) in DMSO (85%, entry 17).
method has successfully overcome the challenges of earlier
Encouraged by our results obtained in the above method, we methods regarding selectivity and yields of the desired
focused our attention on terminal aromatic alkenes as well. A products.5
multicomponent reaction was tried between 3,4-dimethoxy-
Aiming to support our methodology, compound 3a was
styrene 4 and tryptophan methyl ester 2 in the presence of I2 generated by another reported method (Table 4, entry 1).2
ꢀ
(1 equiv.) and IBX (1 equiv.) in DMSO at 60 C (Table 2). The Reaction between tryptophan methyl ester hydrochloride 2 and
reaction gave the desired product in low yield (12%, entry 2). 2,4-dimethoxyphenylglyoxal 5 in methanol under reux condi-
This reaction did not work when tried at RT (entry 1). Further tion gave the expected product (compound 3a) in 35% yield.
studies on optimization were planned at different temperatures Supplementary analytical data of 3a produced by both the
and concentrations of IBX (entry 3–7). The results clearly methods were the same. However along with expected product
revealed that the desired product was obtained in a maximum we isolated a novel compound 6a in 20% yield (entry 1, Table 4).
Compound 6a on 1H-NMR characterization pointed towards an
ꢀ
yield when tried at 1 equiv. of IBX at 90 C (56%, entry 5).
These methods so developed are typical examples of multi- extra peak at d 4.51 (s, 2H, corresponding to –CH2 at 1-postion of
coupled domino reactions. In one pot, OA is generated that b-carboline) when compared with the spectra of 3a. Presence of
undergoes a novel type of reaction under Pictet–Spengler methylene protons was further conrmed by 13C/DEPT-NMR
condition with tryptophan methyl ester catalysed by HI (34.32 ppm) and mass analysis (376 Da). The production of
(generated in in situ, Scheme 1) to afford tetrahydro-b-carboline Compound 6a existence in the reaction can be explained on the
as an intermediate followed by self aromatization to the desired basis of multicoupled one-pot reaction which involves Pictet–
product. This work corresponds to a rst report for the Spengler reaction, self aromatization followed by C]O reduc-
synthesis of b-carbolines using in situ generated glyoxal. The tion to CH2. This reaction between the 2-oxaldehyde and tryp-
reaction is catalysed by HI produced within the reaction. On tophan methyl ester hydrochloride leading to synthesis of 6a
basis of the experimental results and previous works, we through multicoupled domino reaction has clearly revealed the
propose a possible mechanism as follows (Scheme 1).17
different behavior of substrates in different conditions towards
Pictet–Spengler reaction and hence needs to be explored.
To improve upon the yields of 6a a preliminary set of
different reactions between tryptophan methyl ester hydro-
chloride 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 reux condi-
tion 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 2 Optimization studies for the synthesis of 3b employing
3,4-dimethoxy styrene as building blocka
Reaction with different OA generated three different prod-
ucts 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
Oxidant IBX
(equiv.)
Entry
I2 (equiv.)
Temp.
RT
Yieldb (%)
1
2
3
4
5
6
7
1
1
1
1
1
1
1
1
1
1
1
1
1.5
2
—
12
20
45
56
56
56
60 ꢀ
75 ꢀ
80 ꢀ
90 ꢀ
90 ꢀ
90 ꢀ
C
C
C
C
C
C
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.
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Scheme 1 Proposed mechanism.
Table 3 Scope of reaction for acetophenone/styrene with tryptophan Table 4 Synthesis of 6a under different reaction conditionsa
methyl ester
Entry
Solvent
Temp.
Yield 3ab (%)
Yield 6ab (%)
1
2
3
4
5
6
7
8
Methanol
DMSO
Toluene
2-Methoxyethanol
Acetone
1,4-Dioxane
DMF
1,2-Dichloroethane
Acetonitrile
Acetonitrile
Water
80 ꢀ
C
35
40
20
25
22
18
15
Trace
Trace
10
20
10
50
50
60
60
65
85
95
40
—
120 ꢀ
100 ꢀ
100 ꢀ
C
C
C
C
C
60 ꢀ
100 ꢀ
100 ꢀC
100 ꢀ
C
C
9
10
11
85 ꢀ
RT
100 ꢀ
C
—
a
Reaction condition: 2a (1.96 mmol), and 5a (1.96 mmol) in 20 mL
b
acetonitrile was stirred at 85 ꢀC for 3 h. Isolated yield.
Table 5 Scope of the reaction of glyoxals with tryptophan methyl
ester hydrochloride
Entry
R1
6
3
7
a
Building blocks corresponding to styrene series.
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
2,4-Di-OMe-C6H3
3,4-OCH2O-C6H3
3,4-Di-OMe-C6H3
3,5-Di-OMe,4-OH-C6H2
3-OMe,4-O-(Benzyl)-C6H3
3-OMe,4-OH-C6H3
3,4,5-Tri-OMe-C6H2
2-OMe-C6H4
2,4-Di-CH3-C6H3
4-OMe-C6H4
3-OMe-C6H4
3-Cl-C6H4
2-CF3-C6H4
95
90
89
88
86
85
84
55
Trace
5
6
—
—
—
—
—
—
—
—
—
5
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-b-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
Trace
4
10
20
44
80
10
15
35
70
70
40
Trace
Trace
—
Trace
—
60
55
42
—
—
2-Cl-C6H4
–C6H5
Trace
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Scheme 2 Proposed mechanism.
intermediate (2c) may either undergoes aerobic oxidation fol- compound 3w which on further reaction with respective amine
lowed by 1,3-H-shi of N–H proton resulting in compound 7 or (4-hydroxy phenylethyamine/4-methoxy phenylethyamine)
may undergo dehydration under H+ condition to promote under neat condition at 85 ꢀC resulted in the synthesis of
formation of 6 (Scheme 2).
Marinacarbolines A & B respectively in ꢁ70% yield. However
In contrast to reaction of tryptophan methyl ester with pure compound 3i, generated by reaction of tryptophan methyl ester
OA our former methods (employing acetophenone as building 2 with 3-acetylindole as per method discussed, on saponica-
blocks) are highly selective (despite the nature of substituted tion produced Pityriacitrin B 10 (90% yield).
glyoxal produced) and generates different b-carboline deriva-
Further examination of the structures of Pityriacitrin and
tives in good yields in short duration of time. This prompted us Eudistomin Y1, inspired us to try a reaction between tryptamine
to investigate the application of our former method towards and acetophenone under optimised condition in order to
total synthesis of few marine based indole alkaloids (Mer- develop a one step total synthetic approach. Earlier few groups
inacarboline A & B, Pityriacitrin B & Pityriacitrin, Eudistomin Y1 tried to achieve the synthesis of Pityriacitrin and Eudistomin Y1
and Fascaplysin).
from different complex intermediates.6,10,15 All these reported
Satoshi and co-workers recently reported the synthesis of approaches are achieved through multistep reactions. Reaction
Marinacarbolines A & B in multiple steps (Scheme 3).19 between tryptamine with 3-acetylindole under optimized
Compared to his work, our approach is an efficient, economical, conditions furnished Pityriacitrin in moderate yield
two step process where in no protecting groups are used for its (11, Scheme 4, 42% yield). However reaction of tryptamine with
isolation and synthesis is completed in comparatively less time 4-hydroxy acetophenone as per our method afford Eudistomins
(Scheme 3). Reaction of tryptophan methyl ester 2 (1 equiv.) Y1 14 in 40% yields.
with acetone (2 equiv.) under optimised conditions afford
Scheme 3 Total synthesis of Merinacarboline (A & B), and Pityriacitrin B.
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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 activi-
ties,20,21 was being synthesized in good yields following our
approach (Scheme 4). Reaction of tryptamine with 2-chloro-
acetophenone 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.
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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, Pity-
riacitrin B, Fascaplysin and analogues. Further application of
the methodology toward the total synthesis of additional bio-
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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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