Tetralin-based α-amino acid derivatives were assembled through the application of Diels-Alder reaction as a key step. Here, Rongalite has been used to generate the key o-xylylene intermediate

Kotha, Sambasivarao

Krishna, Nimita Gopal

English

Publications of the IAS Fellows

CHEMISTRY – STRUCTURE, SYNTHESIS AND DYNAMICS 
 
CURRENT SCIENCE, VOL. 101, NO. 7, 10 OCTOBER 2011 923
*For correspondence. (e-mail: srk@chem.iitb.ac.in) 
Synthetic approach to linearly annulated 
tetralin-based constrained α-amino acid  
derivatives via Rongalite 
 
Sambasivarao Kotha* and Nimita Gopal Krishna 
Department of Chemistry, Indian Institute of Technology – Bombay, Mumbai 400 076, India 
 
Tetralin-based α-amino acid derivatives were assem-
bled through the application of Diels–Alder reaction 
as a key step. Here, Rongalite has been used to gener-
ate the key o-xylylene intermediate. 
 
Keywords: Diels–Alder reaction, diversity-oriented  
approach, Rongalite, tetralin derivatives, unusual α-amino 
acid derivatives. 
Introduction 
α,α-DISUBSTITUTED amino acids play a critical role in 
stability, conformational and biological activity of pep-
tides1. Incorporation of these α-amino acids (AAAs) into 
biologically active peptides enhances their selectivity and 
efficacy. Unnatural AAAs based on indane 2, 2-amino-
tetralin-2-carboxylic acid (Atc) 3 and 1,2,3,4-tetrahydro-
isoquinoline-3-carboxylic acid (Tic) 4 are considered as 
conformationally restricted AAA analogues of phenyl-
alanine (Phe) 1 (Figure 1) because the amino acid side 
chain has been fixed by the bridging methylene unit(s). 
Moreover, the bicyclic nature of these molecules limits 
the dihedral angle in the N-C(α)-C(β)-C(γ)- and C(α)-
C(β)-C(γ)-C(δ)-segments to a small range2. The interest 
in various derivatives of these AAAs propelled their syn-
thetic routes. In several instances, Atc 3 has been incor-
porated in biologically active peptides to modulate their 
pharmacological properties3. Recently, several deriva-
tives of Atc 3 have been used as immunosuppressants in 
treatment of transplant rejection, multiple sclerosis, 
rheumatoid arthritis, etc.4. 
 A tetralin unit is a core structural element which can 
fix the relative position of functional groups to impart 
greater specificity in biological activity. Daunomycin and 
adriamycin are clinically important tetralin-based anti-
tumour antibiotics5. Compound 6 is an extremely potent 
competitive inhibitor of system L in murine L1210 leu-
kemia cells6. Compound 7 was found to be a far superior 
ligand than 5 and is expected to show improved delivery 
to brain and activity against brain tumours7 (Figure 2). 
 2-Aminotetralin derivatives are novel chemical struc-
tural entities owing to their high antifungal activity with 
low toxicity. For instance, 2-amino-nonyl-6-methoxyl-
tetralin muriate 8 inhibits sterol C-14 reductase in the  
ergosterol biosynthetic pathway8. 
Results and discussion 
Generally, tetralin-based AAA derivatives are assembled 
by Bücherer–Berg or Strecker method starting from keto 
derivatives3. As the keto precursors are not easy to pre-
pare, this methodology has a few limitations. In this  
regard, we have shown that o-xylylene intermediates9 are 
used to prepare tetralin-based AAA derivatives10. By  
selecting suitably functionalized tetralin derivatives, 
these AAA derivatives can be further expanded to small 
‘drug-like’ molecules via Suzuki–Miyaura cross-coupling 
strategy11. Kotha et al. have utilized sultine intermediate 
such as 9 to generate o-xylylene intermediate 10 and sub-
sequently trapped the reactive intermediate in a Diels–
Alder (DA) fashion to design novel ΑΑΑ derivatives  
 
 
 
 
Figure 1. Phenylalanine (Phe) 1 and its constrained analogs. 
 
 
 
 
Figure 2. Biologically important phenylalanine 5- and tetralin-based 
analogs. 
SPECIAL SECTION:  
 
CURRENT SCIENCE, VOL. 101, NO. 7, 10 OCTOBER 2011 924 
 
 
Scheme 1. Diels–Alder approach to Atc derivatives. 
 
 
 
 
Scheme 2. Preparation of sultine intermediates 15 and 18. 
 
 
 
 
Scheme 3. Preparation of indane-based Atc derivative. 
 
 
 
 
Scheme 4. Preparation of tetralin-based Atc derivative. 
 
 
(Scheme 1). The building-block approach involving  
o-xylylene intermediate 10 delivered a wide range of 
tetralin-based AAA derivatives10. 
 To further extend this methodology, we now report 
linearly annulated tetralin-based AAA derivatives. The 
required bromo precursors were initially prepared by 
[2 + 2 + 2] cycloaddition as a key step12. Alternatively, 
the bromo precursors 14 and 17 were also assembled by a 
bromomethylation sequence13. Towards this end, we 
planned to use indane 15 and tetralin 18 based sultines as 
masked diene equivalents. In this regard, we prepared 
bis-bromomethylated indane 14 and bis-bromomethylated 
tetralin 17 by bromomethylation of commercially avail-
able indane 13 and tetralin 16, respectively. Later, the 
bisbromomethylated compounds were treated with com-
mercially available sodium hydroxymethanesulfinate 
(Rongalite) in presence of tetrabutylammoniumbromide 
(TBAB) and N,N′-dimethyl formamide (DMF) at 0°C to 
room temperature (RT) to generate the corresponding 
sultines 15 and 18 in 62% and 48% yield respectively 
(Scheme 2). 
 When the DA reaction of indane-based sultine 15 was 
carried out with methyl-2-acetamido acrylate 11 in tolu-
ene reflux, the corresponding amino acid derivative 19 
was obtained (Scheme 3). 
 After considerable amount of experimentation, we 
found that the sultine 18 reacted with methyl-2-acetamido 
acrylate 11 under toluene reflux conditions to generate 
the desired DA adduct 20. It was necessary to simultane-
ously bubble the reaction mixture with nitrogen to remove 
the SO2 as soon as it was generated, for the success of 
this reaction (Scheme 4). 
 The structures of the final AAA derivatives 19 and 20 
were confirmed by 1H nuclear magnetic resonance 
(NMR) and 13C NMR spectral data. Further, high-
resolution mass spectrometry (HRMS) data supported 
their formation. 
Experimental details 
Melting points were recorded on Labhosp or Veego melt-
ing point apparatus. Infrared (IR) spectra were recorded 
on Nicolet Impact-400 FTIR spectrometer in KBr/ 
CHCl3. 1H NMR (300 and 400 MHz), 13C NMR (75 and 
100.6 MHz) spectral data were determined at RT on a 
Varian VXR 300 or AX 400 mercury plus in CDCl3 solu-
tion. Coupling constants (J values) are given in Hertz 
(Hz). The high-resolution mass measurements were car-
ried out using Micromass Q-T of spectrometer. Analyti-
cal thin layer chromatography (TLC) was performed on 
CHEMISTRY – STRUCTURE, SYNTHESIS AND DYNAMICS 
 
CURRENT SCIENCE, VOL. 101, NO. 7, 10 OCTOBER 2011 925
(10 × 5 cm) glass plates coated with Acme’s silica gel G 
or GF 254 (containing 13% calcium sulphate as a binder). 
Silica gel was coated on glass plates using ‘Sandwich 
Technique’. Column chromatography was performed  
using Acme’s silica gel (100–200 mesh) using double 
spray bellows for application of pressure and the column 
was eluted with ethyl acetate–petroleum ether mixture. 
General procedure for DA reaction of various 
sultine derivatives with methyl 2-acetamidoacrylate 
to generate tetralin-based AAA derivatives 
A solution of sultine (1 equiv) and methyl 2-acetamido-
acrylate 11 (1.5 equiv) in toluene was refluxed until the 
starting materials had disappeared. At the conclusion of 
the reaction (TLC monitoring), the solvent was removed 
at reduced pressure and the crude product was purified by 
silica gel column chromatography. Elution of the column 
with ethyl acetate–petroleum ether mixture released the 
required tetralin-based AAA derivative. 
Synthesis of methyl 6-acetamido-2,3,5,6,7,8-
hexahydro-1H-cyclopenta[b]naphthalene-6-
carboxylate (19) 
To a solution of indane-based sultine 15 (42 mg, 0.2 mmol) 
in toluene (10 mL) was added methyl-2-acetamido acry-
late 11 (43.4 mg, 0.3 mmol) under nitrogen. Nitrogen gas 
was also bubbled through the reaction mixture to remove 
the sulphur dioxide generated during the reaction. The  
reaction mixture was refluxed for 30 h. Then, the solvent 
was removed under reduced pressure and the crude mate-
rial was purified by silica gel column chromatography. 
Elution of the column with 20% ethyl acetate–petroleum 
ether resulted in rearranged sulphone 21 as a white solid 
(12 mg, 28%). 
 
 
 
 Rf = 0.55 (silica gel, 30% EtOAc–petroleum ether). 
Mp: 206–209°C. IR (KBr) νmax/cm–1: 2948, 1621, 1469. 
1H NMR (300 MHz, CDCl3): δ 2.09 (quintet, J = 7.3 Hz, 
2H), 2.91 (t, J = 7.3 Hz, 4H), 4.32 (s, 4H), 7.15 (s, 2H). 
13C NMR (75.43 MHz, CDCl3): δ 25.50, 32.79, 57.05, 
121.99, 128.72, 145.41. 
 Further elution of the column with 50% ethyl acetate–
petroleum ether resulted in the desired product 19 as a 
white solid (25 mg, 42%). 
 
 
 Rf = 0.2 (silica gel, 30% EtOAc–petroleum ether). Mp: 
168–172°C. IR (KBr) νmax/cm–1: 3289, 2949, 1744, 1659, 
1435, 1390, 1214, 1129, 1092. 1H NMR (400 MHz, 
CDCl3): δ 1.93 (s, 3H), 2.02–2.08 (m, 2H), 2.09–2.15  
(m, 1H), 2.57–2.71 (m, 1H), 2.86 (t, 4H, J = 6.9 Hz), 
2.75–2.81 (m, 2H), 2.93 (d, J = 16.8 Hz, 1H), 3.21 (d, 
J = 16.8 Hz, 1H), 3.77 (s, 3H), 5.68 (s, 1H), 6.95 (s, 1H), 
7.01 (s, 1H). 13C NMR (100.56 MHz, CDCl3): δ 22.9, 
23.4, 24.7, 27.8, 29.1, 37.7, 52.7, 58.1, 128.9, 129.4, 
129.9, 132.1, 135.3, 135.8, 170.8, 174.5. HRMS (Q–Tof): 
m/z calculated for C17H22NO3 (M + H) 288.1600, found 
288.1605. 
Synthesis of methyl 2-acetamido-1,2,3,4,5,6,7,8-
octahydroanthracene-2-carboxylate (20) 
To a solution of tetralin-based sultine 18 (20 mg, 0.1 mmol) 
in toluene (5 mL) was added methyl-2-acetamido acrylate 
11 (19 mg, 0.14 mmol) under nitrogen. Nitrogen gas was 
also bubbled through the reaction mixture to remove the 
sulphur dioxide generated during the reaction. The reaction 
mixture was refluxed for a period of 42 h. The solvent 
was removed under reduced pressure and the crude mate-
rial was purified by silica gel column chromatography. 
Elution of the column with 40% ethyl acetate–petroleum 
ether produced the desired compound 20 (12 mg, 45%). 
 
 
 
 Rf = 0.22 (silica gel, 30% EtOAc–petroleum ether). 
Mp: 177–180°C. IR (KBr) νmax/cm–1: 3310, 2927, 1726, 
1682, 1266.4, 1019.8, 741 cm–1; 1H NMR (400 MHz, 
CDCl3): δ 1.78–1.88 (m, 4H), 1.93 (s, 3H), 2.05–2.12  
(m, 1H), 2.56–2.61 (m, 1H), 2.78 (dd, J = 5.6 Hz, 4H), 
2.80–2.82 (m, 2H), 2.89 (d, J = 16.6 Hz, 1H), 3.17 (d, 
J = 16.6 Hz, 1H), 3.76 (s, 3H), 5.69 (s, 1H), 6.79 (s, 1H), 
6.85 (s, 1H). 13C NMR (100.6 MHz, CDCl3): δ 23.3, 23.4, 
24.8, 27.8, 29.1, 29.2, 37.9, 52.8, 58.1, 128.9, 129.5, 
130.1, 132.2, 135.4, 135.8, 170.3, 174.3. HRMS (Q–Tof): 
m/z calculated for C18H24NO3 (M + H) 302.1748, found 
302.1760. 
Conclusion 
We have designed a simple route for the synthesis of 
various linearly annulated tetralin-based AAA derivatives 
based on DA reaction. This building block approach 
seems to be an attractive strategy for designing various 
tetralin-based AAA derivatives. 
 
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ACKNOWLEDGEMENTS. We thank DST, New Delhi for financial 
support and SAIF, IIT-Bombay for recording the spectral data. S.K. 
thanks the DST for the award of a J. C. Bose Fellowship. 
 
 
 
 
 


Synthetic approach to linearly annulated tetralin-based constrained α-amino acid derivatives via Rongalite

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Synthetic approach to linearly annulated tetralin-based constrained α-amino acid derivatives via Rongalite

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