A new synthetic approach to 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives via enyne metathesis and the Diels-Alder reaction

Article abstract of DOI:10.1039/a910217p

Various substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives are synthesized via enyne metathesis and the Diels-Alder reaction.

Full text of DOI:10.1039/a910217p

A new synthetic approach to 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
(Tic) derivatives via enyne metathesis and the Diels–Alder reaction
Sambasivarao Kotha* and Nampally Sreenivasachary
Department of Chemistry, Indian Institute of Technology-Bombay, Mumbai, 400 076, India.
E-mail: srk@ether.chem.iitb.ernet.in
Received (in Cambridge, UK) 20th December 1999, Accepted 7th February 2000
Various subtituted 1,2,3,4-tetrahydroisoquinoline-3-car-
boxylic acid (Tic) derivatives are synthesized via enyne
metathesis and the Diels–Alder reaction.
Realization of the strategies shown in Fig. 1 require the
preparation of key building blocks 7, 8 and 9. In this regard,
ethyl N-(diphenylmethylene)glycinate 107 was treated with
allyl bromide in the presence of K2CO3 to give allylated product
11 (82%, Scheme 1). Hydrolysis of 11 with 1 M HCl in diethyl
ether gave the amino ester which upon treatment with tosyl
chloride in presence of triethylamine gave 12 in 78% yield [mp
43–44 °C, 13C NMR (CDCl3, 75 MHz) d 170.7, 143.1, 137.4,
131.5, 129.5, 127.4, 119.6, 61.4, 55.2, 37.7, 21.6, 14.0].
Reaction of 12 with propargyl bromide in the presence of
K2CO3 gave 13 in quantitative yield. Under similar reaction
conditions, enyne 14 was prepared in 90% yield.
1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (Tic) is a
phenylalanine analogue in which the dihedral angle c is limited
to a very small range because of its bicyclic nature.1 In
connection with the design of topographically constrained
peptides Tic has been utilized in several instances as a
replacement of phenylalanine or tyrosine.2 Moreover, the
tetrahydroisoquinoline unit is an important structural element in
several important alkaloids and other medicinally useful
products.3 Availability of synthetic methods for the preparation
of various Tic derivatives with varying degrees of steric/
electronic and hydrophobic properties are useful in receptor
mapping and also in designing meaningful QSAR studies.4 In
connection with our building block approach for the preparation
of constrained amino acid derivatives5 we sought a Diels–Alder
strategy to prepare various unknown Tic derivatives 1–3. Most
of the known methods such as Bischler–Napieralski6a Picter–
Spengler6b and among others6c for Tic preparation starts with
the preformed benzene derivatives while our methodology
involves generation of a benzene ring via the cycloaddition
reaction as a key step. Consequently, the present methodology
provides a unique opportunity to efficiently enhance the
molecular complexity of inaccessible Tic derivatives. Here, we
report our preliminary results for the preparation of various Tic
derivatives using enyne metathesis and the Diels–Alder reaction
as key steps.
Retrosynthetic routes for various Tic derivatives via Diels–
Alder strategy as a key step are shown in Fig. 1. Pathways a and
b in Fig. 1 lead to angularly substituted and pathway c to linearly
substituted Tic derivatives. In exploring the synthesis of inner–
outer ring dienes such as 4 and 5 containing a dehy-
dropipicolinic acid moiety, we conceived a relatively less
explored enyne metathesis reaction as a viable option. Con-
ceptually, cycloiosomerization of a suitably functionalised
1,7-enyne building block is expected to deliver the 4,5-di-
methylene pipicolinic acid derivative (e.g. 6).
Scheme 1 Reagents and conditions: i, allyl bromide, K2CO3, MeCN, 82%;
ii, 1 M HCl, diethyl ether, 85%; iii, TsCl, Et3N, CH2Cl2, 78%; iv, K2CO3,
RC·CCH2Br, MeCN.
Towards the preparation of building blocks related to 8,
sequential reaction of ethyl N-(diphenylmethylene)glycinate 10
with propargyl bromide and 3-bromo-1-trimethylsilylprop-
1-yne in the presence of K2CO3 in acetonitrile gave 15 (86%)
and 16 (88%) respectively (Scheme 2). Hydrolysis of 15 with
1 M HCl in diethyl ether gave amino ester 17 (88%) which was
protected as a tosyl derivative using tosyl chloride/triethylamine
in dichloromethane at room temperature to give 19 (mp
1
48–49 °C). The structure of 19 is established by H and 13C
NMR spectral data. During the hydrolysis of compound 16, a
minor amount of desilylated product was obtained which was
separated (11%) after a protection sequence. The required
compound 20 was obtained in 77% yield. Then allylation of
compounds 19 and 20 in the presence of K2CO3 with allyl
bromide gave 21 and 22 in 98 and 90% yields, respectively.
Scheme 2 Reagents and conditions: i, RC·CCH2Br, K2CO3, MeCN; ii, 1 M
HCl, diethyl ether; iii, TsCl, Et3N, CH2Cl2, 78%.
Having accomplished a high yielding synthesis of enyne
building blocks 13 and 21, we then focussed our attention
towards the preparation of inner–outer ring dienes 24 and 25.
Fig. 1
DOI: 10.1039/a910217p
Chem. Commun., 2000, 503–504
This journal is © The Royal Society of Chemistry 2000
503

Table 1
Thus, treatment of 13 with Grubb’s catalyst8 in refluxing
toluene gave 24 in 65% isolated yield after column chromatog-
raphy. Under similar reaction conditions diene 25 was prepared
(70%) from enyne 21 (Table 1). Attempts to convert enynes 14
and 22 to the corresponding dienes by enyne metathesis
conditions were not rewarding.
Table 2
Next we turned our attention towards the preparation of
silylated dienes 28 and 30. Towards this goal, enyne 14 was
treated with dicobalt octacarbonyl in diethyl ether to give
compound 26 in 83% yield.9 Similarly, enyne 27 was prepared
in 84% yield (Scheme 3).
Scheme 3 Reagents and conditions: Co2(CO)8, diethyl ether, room temp.
Refluxing of enyne 26 in toluene followed by oxidative
decomposition with N-methylmorpholine N-oxide yielded the
4,5-dimethylene pipicolinic acid derivative 28 in 53% yield
along with a minor amount of Pauson–Khand product 29 (11%).
The other diene 30 was obtained under similar reaction
conditions in 78% yield along with the enone 31 (7%). It is
worth mentioning that compound 31 is a useful precursor for
tecomanine alkaloid.10
Having the dienes 24, 25, 28 and 30 in hand, we then
examined their Diels–Alder chemistry with the readily available
dienophiles (Table 2). The reaction of dienes 24 and 25 with
different dienophiles and subsequent oxidation of Diels–Alder
adducts with DDQ11 gave angularly substituted Tic derivatives
(32–35). Similarily, the Diels–Alder reaction of dienes 28 (or
30) with dimethyl acetylenedicarboxylate (DMAD) and oxida-
tion with DDQ gave desilylated product 36.
In conclusion, for the first time we have demonstrated an
exceptionally simple and versatile method for the synthesis of
several Tic derivatives using enyne metathesis and the Diels–
Alder reaction as key steps.
We gratefully acknowledge the DST for financial support and
RSIC Mumbai, Professor A. Srikrishna for recording the
spectral data. NS thanks CSIR, New Delhi for the award of
research fellowship.
4 E. C. Griffiths, in A Text Book of Drug Design and Development, ed.
Krogsgaard-Larsen and P. Bundgaard, Harwood Academic Publishers,
Tokyo, 1992, pp. 487–528.
5 S. Kotha, N. Sreenivasachary and E. Brahmachary, Tetrahedron Lett.,
1998, 39, 2805.
6 (a) W. Whaley and T. R. Govindachari, Org. React., 1951, VI, 74–150;
(b) W. J. Gensler, Org. React., 1951, VI, 151–206; (c) E. A. Mash, L. J.
Williams and S. S. Pfeiffer, Tetrahedron Lett., 1997, 38, 6977; C. Wang
and H. I. Mosberg, Tetrahedron Lett., 1995, 36, 3623; D. Seebach, E.
Dziadulewicz, L. Behrendt, S. Cantoreggi and R. Fitzi, Liebigs. Ann.
Chem., 1989, 1215.
7 M. J. O’Donnell and R. L. Polt, J. Org. Chem., 1982, 47, 2663.
8 M. Mori, in Alkene Metathesis in Organic Synthesis, ed. A. Fürstner,
Springer, Berlin, 1998, pp. 133–154; R. H. Grubbs and S. Chang,
Tetrahedron, 1998, 54, 4413.
Notes and references
1 S. E. Gibson (nee Thomas), N. Guillo and M. J. Tozer, Tetrahedron,
1999, 55, 585.
2 H. J. Mosberg, A. L. Lomize, C. Wang, H. Kroona, D. L. Heyl, K.
Sobczyk-Kojiro, W. Ma, C. Mousigian and F. Porreca, J. Med. Chem.,
1994, 37, 4371; H. Nakagawa, N. Nihonmatsu, S. Ohta and M. Hirobe,
Biochem. Biophys. Res. Commun., 1996, 225, 1027; W. M. Kazmierski,
Z. Urbanczyk-Lipkowska and V. J. Hruby, J. Org. Chem., 1994, 59,
1789; T. Tancredi, S. Salvadori, P. Amodeo, D. Picone, L. H. Lazarus,
L. D. Bryant, R. Guerrini, R. Marzola and P. A. Temussi, Eur. J.
Biochem., 1994, 224, 241; B. C. Wilkes and P. W. Schiller,
Biopolymers, 1995, 37, 391; V. J. Hruby, Biopolymers, 1993, 33,
1073.
9 M. E. Krafft, A. M. Wilson, O. A. Dasse, L. V. R. Bonaga, Y. Y.
Cheung, Z. Fu, B. Shao and I. L. Scott, Tetrahedron Lett., 1998, 39,
5911; D. Seyferth, M. O. Nestle and A. T. Wehman, J. Am. Chem. Soc.,
1975, 97, 7415; D. Seyferth and A. T. Wehman, J. Am. Chem. Soc.,
1970, 92, 5522.
10 T. Imanishi, N. Yagi and M. Hanaoka, Tetrahedron Lett., 1981, 22, 667.
11 P. P. Fu and R. G. Harvey, Chem. Rev, 1978, 78, 317.
3 K. W. Bentley, The Isoquinoline Alkaloids, Harwood Academic,
Singapore, 1998.
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