A new approach to 3-substituted tetrahydro-β-carboline derivative via diethyl acetamidomalonate

Article abstract of DOI:10.1007/s00726-010-0792-z

Strategically a new approach for the synthesis tetrahydro-β-carboline unit with the aid of diethyl acetamidomalonate as a glycine equivalent has been described. Springer-Verlag 2010.

Full text of DOI:10.1007/s00726-010-0792-z

Amino Acids (2011) 41:933–936
DOI 10.1007/s00726-010-0792-z
ORIGINAL ARTICLE
A new approach to 3-substituted tetrahydro-b-carboline
derivative via diethyl acetamidomalonate
•
Sambasivarao Kotha Shilpi Misra
•
Shaikh M. Mobin
Received: 30 August 2010 / Accepted: 19 October 2010 / Published online: 9 November 2010
Ó Springer-Verlag 2010
Abstract Strategically a new approach for the synthesis
tetrahydro-b-carboline unit with the aid of diethyl acetami-
domalonate as a glycine equivalent has been described.
for assembling THBC unit. More recently, intense efforts
are directed towards to synthesize THBC skeleton using dif-
ferent approaches (Fujii et al. 2009; Pfeffer et al. 2010;
Shipman et al. 2008). As a part of major project aimed at
developing new methodologies for the synthesis of unusual
a-amino acid (AAA) derivatives (Kotha et al. 2010) we have
utilize diethyl acetamidomalonate (DEAM) as a useful gly-
cine equivalent (Kotha and Singh 2004; Kotha and Halder
2010). In this regard, we envisioned that DEAM is an attrac-
tive option for the synthesis of THBC derivatives (Fig. 2).
Keywords Diethyl acetamidomalonate Á
Indole alkaloids Á Tetrahydro-b-carboline Á
Unusual a-amino acid derivatives
Introduction
Tetrahydro-b-carboline (THBC) unit is an important
structural element present in many biologically active
alkaloids (Bailey and Hollinshead 1988; Soderberg and
Dantale 2003; Szawkało et al. 2007). A number of THBC
derivatives exhibit promising biological activity. To this
end, various b-carboline derivatives are involved in the
treatment of alcoholism (Cook et al. 2010). In addition,
indole alkaloids (Jenkins et al. 2008; Shen et al. 2005;
Moody et al. 1995; Moody and Roffey 2000) (Fig. 1)
displayed interesting physiological properties and also
show diverse medicinal applications. For example, reser-
pine exhibits cardiovascular effect (Chopra et al. 1933;
Petter and Engelmann 1974).
Experimental
General procedure for tetrahydro-b-carboline derivative
To a stirred suspension of potassium carbonate (5 equiv.)
and DEAM (1 equiv.) in dry acetonitrile was added
N-protected indole dibromide 10 after 15 min. The resulting
reaction mixture was stirred at 70°C for 8 h under nitrogen.
At the conclusion of the reaction (TLC monitoring), the
reaction mixture was cooled and filtered on a Celite pad.
The filtrate was evaporated at reduced pressure. The resi-
due was purified by silica gel column chromatography
(30% petroleum ether/ethyl acetate) to give the desired
compound as white solid.
Generally, syntheses of various b-carboline-based indole
alkaloids involve utilization of traditional reactions such as
the Bischler–Napieralski (Ho and Lin 2008; Liu and Xu
1989; Magnus et al. 1999) and the Pictet–Spengler reaction
(Cook and Cox 1995; Mergott et al. 2008; Ma et al. 2007) etc.
Spectroscopic data for compound: (11)
1H NMR (400 MHz, CDCl3): d 1.21 (t, J = 7.17 Hz, 6H),
2.31 (s, 3H), 3.51 (s, 2H), 4.07 (s, 3H), 4.16–4.21 (m, 4H),
5.05 (s, 2H), 7.26–7.33 (m, 2H) 7.46 (d, J = 6.72 Hz, 1H),
8.05(d, J = 7.94 Hz, 1H). 13C NMR (100.5 MHz CDCl3):
d 14.0, 22.9, 27.9, 45.9, 54.1, 62.4, 67.6, 113.8, 115.7,
118.4, 123.6, 125.0, 128.4, 167.5, 173.0. HRMS (Q-ToF):
S. Kotha (&) Á S. Misra Á S. M. Mobin
Department of Chemistry, Indian Institute
of Technology-Bombay, Mumbai 400076, India
e-mail: srk@chem.iitb.ac.in
123

934
S. Kotha et al.
Fig. 1 Various alkaloids
containing tetrahydro-b-
carboline as a core unit
H
CO2H
N
H
H
O
N
H
N
H
H
OCH3
OCH3
N
H
H
O
H3CO2C
H
OCH3
OCH3
H3CO2C
OH
5β-Yohimbine alkaloid 2
Reserpine
1
H
CO2CH3
H
CO2H
O
N
H
N
H
H
N
OH
H
N
H
H
N
H3CO2C
H
H3C
Methyl Adirubine 3
(+)-7-carboxyevodiamine 4
Fig. 2 Synthetic approach
THBC derivative by Bischler–
Napieralski and Pictet–Spengler
reaction
R
R
R
N
Pictet–Spengler
Bischler–Napieralski
O
NH
NH2
reaction
R1
reaction
R1
N
R2
N
R2
N
R2
6
7
5
Tetrahydro-β-carboline derivative
CO2Et
CO2Et
m/z calcd for C21H24N2O7 (M?H) calcd 417.1662 obs
417.1655. M.P. 174–178°C.
Br
Br
N
Ac
N
R
N
R
Spectroscopic data for compound: (12)
1H NMR (400 MHz, CDCl3): d 1.23 (t, J = 7.17 Hz, 6H),
2.22 (s, 3H), 3.57 (s, 2H), 4.21–4.25 (m, 4H), 4.97 (s, 2H),
6.75 (d, J = 8.2 Hz, 1H), 7.05 (t, J = 7.33 Hz, 1H), 7.21
(t, J = 7.63 Hz, 3H), 7.47–7.55 (m, 2H), 7.66–7.55 (m,
2H). 13C NMR (100.5 MHz CDCl3): d 13.8, 22.6, 27.8,
45.4, 62.3, 67.5, 114.3, 114.9, 118.4, 123.3, 124.0, 128.5,
128.9, 129.0, 130.6, 132.8, 134.7, 136.4, 167.4, 168.8,
172.9. HRMS (Q-ToF): m/z calcd for C26H26N2O6 (M?H)
calcd 463.1869 obs 463.1859. M.P. 134–138°C
Fig. 3 Retrosynthetic analysis towards the THBC derivative
0.13 mm3) mounted on a Oxford Diffraction XCALIBUR-S
CCD system equipped with graphite-monochromated Mo
˚
Ka radiation (0.71073 A). The data were collected by the
x–2h scan mode, and absorption correction was applied by
using Multi-Scan. The structure was solved by direct
methods (SHELXS-97) and refined by full-matrix least
squares against F2 using SHELXL-97 software.
Crystal structure determination for 11
Result and discussion
Suitable X-ray quality crystals of 11 could be grown from
acetonitrile/n-hexane solvent mixture at RT, and X-ray
diffraction studies were undertaken. The details of the
crystal data have been deposited with the Cambridge
Crystallographic Data Center as Supplementary Publica-
tion No. CCDC-776486. X-ray crystallographic data were
collected from single-crystal samples of 11 (0.23 9 0.18 9
In view of our experience to design unusual AAA deriva-
tives via building block approach (Kotha 2003) we con-
ceived DEAM as a useful starting material for construction
of THBC unit which was not reported previously. In other
words, THBC derivatives can be assembled from indole
derivatives instead of tryptophan derivatives (Fig. 3).
123

A new approach to 3-substituted tetrahydro-b-carboline derivative
935
Fig. 4 Synthesis of THBC
derivatives
H2N
CH3OCOCl,
n-BuLi, THF
NH
CAN
CH3OH
60%
O
or PhCOCl,
NaH, THF
HCl
N
H
8
N
R
R = CO2Me
9a = 52%
NBS, CCl4
R = COPh
9b = 60%
CO2Et
Br
Br
Ac
CO2Et
DEAM, K2CO3
CH3CN
N
N
CO2Et
N
Ac
N
R
N
R
R
CO2Et
10a = 62%
10b = 54%
11
13
12
14
11 = 55%
13 = 58%
structure of 11 and structure refinement parameters are
included in Fig. 5. The mechanism for the formation of
single regioisomer is not clear at this point. However, we
plan to explore this aspect in a detail manner.
Since THBC unit is a core structural element for
assembling various alkaloids, our methodology opens up
a new retrosynthetic path to various b-carboline-based
natural products and drugs.
Acknowledgments We are grateful to DST and CSIR for the
financial support and SAIF Mumbai for providing the spectral data.
S. M. thank CSIR (New Delhi) for the award of research fellowship.
S. K. thank DST for the award of J. C. Bose fellowship.
Fig. 5 ORTEP diagram of compound 11
References
To begin with, 2,3-dimethyl indole 8 was prepared via
Fischer indole cyclization using phenylhydrazine hydro-
chloride with methyl ethyl ketone in presence of ceric
ammonium nitrate (CAN) (Fig. 4). Later 2,3-dimethyl
indole 8 was converted to the corresponding N-protected
2,3-dimethyl indole derivatives using benzoyl chloride or
methyl chloroformate (Verma et al. 2009). The required
dibromo indole derivative 10 was prepared by follow-
ing literature procedure (Srinivasan and Saroja 1984)
starting with the N-protected 2,3-dimethyl indole 9 using
N-bromosuccinimide (NBS) under free radical conditions.
Next, the dibromide 10 (1 equiv.) in dry acetonitrile was
treated with DEAM (1 equiv.) and powdered potassium
carbonate (6 equiv.) to generate single coupling compound.
The gross structure of the coupling product was based on
Bailey PD, Hollinshead SP (1988) Application of a modified Pictet–
Spengler reaction to the synthesis of optically active tetrahydro-
b-carbolines, key intermediates in the preparation of many
indole alkaloids. J Chem Soc Perkin Trans 1:739–745
Chopra RN, Gupta JC, Mukherjee B (1933) The pharmacological
action of an alkaloid obtained from Rauvolfia serpentina. Indian
J Med Res 21:261–271
Cook JM, Cox ED (1995) The Pictet–Spengler condensation: a new
direction for an old reaction. Chem Rev 95:1797–1842 (and
references cited therein)
Cook JM, Yin W, Kabir MS, Wang Z, Rallapalli SK, Ma J (2010)
Enantiospecific total synthesis of the important biogenetic
intermediates along the ajmaline pathway, (?)-polyneuridine
and (?)-polyneuridine aldehyde, as well as 16-epivellosimine
and macusine A. J Org Chem 75:3339–3349
Fujii N, Ohno H, Oishi S, Ohta Y (2009) Facile synthesis of 1,2,3,4-
tetrahydro-b-carbolines by one-pot domino three-component
indole formation and nucleophilic cyclization. Org Lett
11:1979–1982
1
the spectral data, such as H and 13C NMR and HRMS. In
this regard one can think of two possible regioisomer 11 or
12. The unambiguous structural assignment for the DEAM
coupling product 11 has been achieved with the aid of
single crystal X-ray diffraction technique. The molecular
Ho TL, Lin QX (2008) Stereoselective synthesis of ( )-tacamonine.
Tetrahedron 64:10401–10405
Jenkins PR, Wilson J, Emmerson D, Garcia MD, Smith MR, Gray SJ,
Britton RG, Mahale S, Chaudhuri B (2008) Design, synthesis
123

936
S. Kotha et al.
and biological evaluation of new tryptamine and tetrahydro-b-
carboline-based selective inhibitors of CDK4. Bioorg Med Chem
16:7728–7739
Moody CJ, Jackson PM, Harrison CA, Williams MJ (1995) Cyclo-
penta [b] indoles. Part 2. Model studies towards the tremorgenic
mycotoxins. J Chem Soc Perkin Trans 1:1131–1136
Kotha S (2003) The building block approach to unusual a-amino acid
derivatives and peptides. Acc Chem Res 36:342–351
Kotha S, Halder S (2010) Ethyl isocyanoacetate as useful glycine
equivalent. Synlett, 337–354
Kotha S, Singh K (2004) N-Alkylation of diethyl acetamidomalonate:
synthesis of constrained amino acid derivatives by ring-closing
metathesis reaction. Tetrahedron Lett 45:9607–9610
Kotha S, Misra S, Krishna NG, Devunuri N, Hopf H, Keecherikunne
A (2010) Diversity oriented approach to 1,2,3,4-tetrahydroiso-
quinoline-3-carboxylic acid (Tic) derivatives using diethyl
acetamidomalonate as a glycine equivalent. Further explansion
by Suzuki–Miyaura cross-coupling reaction. Heterocycles
49:847–852
Liu Z, Xu F (1989) Total synthesis of Na-methyl-D18-isokoumidine, a
possible precursor of the koumine type indole alkaloids.
Tetrahedron Lett 30:3457–3460
Ma J, Yin W, Zhou H, Cook JM (2007) Total synthesis of the opioid
agonistic indole alkaloid mitragynine and the first total syntheses
of 9-methoxygeissoschizol and 9-methoxy-Nb-methylgeisso-
schizol. Org Lett 9:3491–3494
Magnus P, Gazzard L, Hobson L, Payne AH, Lynch V (1999) Studies
on the synthesis of the indole alkaloids pauciflorine A and B.
Tetrahedron Lett 40:5135–5138
Mergott DJ, Zuend SJ, Jacobsen EN (2008) Catalytic asymmetric
total synthesis of (?)-yohimbine. Org Lett 10:745–748
Moody CJ, Roffey JRA (2000) Synthesis of N-protected nortopsentins
B and D. ARKIVOC 3:393–401
Petter A, Engelmann K (1974) Antiarrhythmic action of ajmaline on
the heart. Arzneim Forsch 24:876–880
Pfeffer FM, Stewart SG, Priebbenow DL, Henderson LC (2010)
Domino Heck–Aza-Michael reactions: efficient access to 1-
substituted tetrahydro-b-carbolines. J Org Chem 75:1787–1790
Shen Ya-C, Chen CY, Hsieh PW, Duh CY, Lin YM, Ko CL (2005)
The preparation and evaluation of 1-substituted 1,2,3,4-tetrahy-
dro- and 3,4-dihydro-b-carboline derivatives as potential antitu-
mor agents. Chem Pharm Bull 53:32–36
Shipman M, Hayes JF, Tarver GJ, Shiers JJ, Mumford PM (2008)
Synthesis of 1,1-disubstituted tetrahydro-b-carbolines from 2-
methyleneaziridines. Tetrahedron Lett 24:3489–3491
Soderberg BCG, Dantale SW (2003) A novel palladium-catalyzed
synthesis of b-carbolines: application in total synthesis of
naturally occurring alkaloids. Tetrahedron 59:5507–5514
Srinivasan PC, Saroja B (1984) A simple route to indole-2,3-
quinodimethane-A facile synthesis of carbazoles. Tetrahedron
Lett 25:5429–5430
Szawkało J, Czarnocki SJ, Zawadzka A, Wojtasiewicz K, Leniewski
A, Maurin JK, Czarnocki Z, Drabowicz J (2007) Enantioselec-
tive synthesis of some tetrahydroisoquinoline and tetrahydro-b-
carboline alkaloids. Tetrahedron Asymmetry 18:406–413
Verma PP, Sherigara BS, Mahadevan KM, Hulikal VK (2009)
Efficient and straightforward synthesis of tetrahydrocarbazoles
and 2,3-dimethylindoles catalyzed by CAN. Synth Commun
39:158–165
123