A new synthetic approach to 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives via a [2 + 2 + 2] cycloaddition reaction

Article abstract of DOI:10.1016/S0960-894X(00)00259-6

Tetrahydroisoquinoline-3-carboxylic acid derivatives are prepared via a [2 + 2 + 2] cycloaddition reaction as a key step using Wilkinson's and CpCo(CO)₂ catalysts. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00259-6

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1413±1415
A New Synthetic Approach to 1,2,3,4-Tetrahydroisoquinoline-3-
carboxylic Acid (Tic) Derivatives Via a [2+2+2]
Cycloaddition Reaction
Sambasivarao Kotha* and Nampally Sreenivasachary
Department of Chemistry, Indian Institute of Technology-Bombay, Mumbai 400 076, India
Received 14 February 2000; accepted 12 April 2000
AbstractÐTetrahydroisoquinoline-3-carboxylic acid derivatives are prepared via a [2+2+2] cycloaddition reaction as a key step
using Wilkinson's and CpCo(CO) catalysts. # 2000 Elsevier Science Ltd. All rights reserved.
2
Tetrahydroisoquinoline (THIQ) is a rather celebrated unit
and much e€ort has been spent in the literature because of
its importance as a structural component in many biologi-
ꢀ
1†
1
cally active natural products. In addition, various deriva-
tives of THIQ show promising biological activity. While
designing conformationally restricted peptides, 1,2,3,4-tet-
rahydroisoquinoline-3-carboxylic acid (Tic) has been uti-
lized as a restricted analogue of phenylalanine. Tic
moiety was also used as a synthon for the preparation
of biologically active peptides and enzyme inhibitors.2
Incorporation of Tic in d opioid receptors enhances d
receptor binding anity and selectivity.3
Preparation of the key building block 1 starts with N-
7
(diphenylmethelene)glycine ethyl ester 2. Propargyla-
tion of 2 (Scheme 1) in presence of K CO /acetonitrile
2
3
re¯ux gave 3 (86% yield). Compound 3 was hydrolyzed
with dilute HCl and the resulting amino ester was pro-
ꢀ
1
tected as N-tosyl derivative to give 4 (mp 48±49 C, 78%
yield). The structure of 4 is well established by H NMR
and 13C NMR spectral data (CDCl , 75.0 MHz: d 169.3,
3
4
The traditional methods such as Bischler-Napieralski,
5
143.2, 137.3, 129.5, 127.2, 77.6, 72.2, 61.9, 54.0, 24.0, 21.5,
14.0). Sequential reaction of 4 with propargyl bromide
and 3-bromo-1-(trimethylsilyl)-1-propyne in presence of
K CO in acetonitrile gave 1 (99%) and 5 (98%) isolated
Picter-Spengler among others for Tic preparation can
deliver a limited degree of functionality in the aryl ring
and the substitution pattern is set prior to the cycliza-
tion step. A method that would generate the Tic ring
system via a cycloaddition approach would provide a
unique opportunity for the introduction of various sub-
stituents by judicious choice of the reacting partners. The
currently available approaches to THIQ unit cannot
2
3
yields respectively.
Having prepared the building blocks 1 and 5 we then
examined [2+2+2]-cycloaddition of diyne 1 with var-
ious acetylenic moieties using Wilkinson's catalyst (WC)
6
8
easily be extended to the synthesis of Tic derivatives. In
(Table 1 entry no 1±5). Co-trimerization reaction under
essence, preparation of Tic derivatives impose more
constraints in the design of synthetic strategy. In this
communication we report a general method involving a
[2+2+2]-cycloaddition reaction as a key step for the
construction of various Tic derivatives (eq 1).
WC conditions were performed using excess amount (5
equiv) of monoyne. The reaction of diyne building block
1 with propargyl alcohol smoothly proceeded to give an
inseparable mixture of Tic derivatives (1:1) the regio-
isomers of the hydroxy methyl group on the aromatic ring.
Similarly with phenylacetylene, and propyne-4-ol gave
inseparable mixture of regioisomers. Later on, e€orts
were focused on the co-trimerization reaction of diyne 5.
The reaction of diyne 5 with butyne 1±4 diol and dime-
thyl acetylenedicarboxylate (DMAD) in presence of WC
conditions were unsuccessful.
*
3
Corresponding author. Tel.: +91-22-576-7160; fax: +91-22-572-
480; e-mail: srk@ether.chem.iitb.ernet.in
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00259-6

1
414
S. Kotha, N. Sreenivasachary, / Bioorg. Med. Chem. Lett. 10 (2000) 1413±1415
Scheme 1. (i) K
CH CN.
2
CO
3
propargyl bromide, CH
3
CN 86%; (ii) 1N HCl ether, 80%; (iii) Et
3
N, TsCl, CH Cl
2
2
, RT, 78%; (iv) BrCH
2
C ꢁCTMS K
2 3
CO
3
Table 1.
Entry No
Diyne building block
Monoyne
Product
Catalyst
Yield (%)
53
1
2
(PPh
3
)
3
RhCl
(
PPh
CpCo(CO)
3
)
3
RhCl
15
30
2
(
PPh
3
)
3
RhCl
60
65
3
4
(PPh
3
)
)
3
RhCl
(
PPh
3
3
RhCl
30
40
5
6
7
CpCo(CO)
CpCo(CO)
CpCo(CO)
2
2
2
20
19
8
9
CpCo(CO)
2
45
CpCo(CO)
CpCo(CO)
2
42
40
1
0
2
Alternatively co-trimerization of diyne 5 with various
monoynes was explored with other catalyst conditions
partners. While using CpCo(CO)2 conditions the
cycloaddition reaction was performed using syringe
pump technique. On completion of the cycloaddition
reaction (TLC monitoring) co-trimerized products were
isolated by ¯ash chromatography. Various substrates
9
(
e.g., [CpCo(CO) ]). In particular, this catalyst found
2
to be extremely useful when the alkynes containing tri-
methylsilyl groups are present in any of the reacting

S. Kotha, N. Sreenivasachary, / Bioorg. Med. Chem. Lett. 10 (2000) 1413±1415
1415
that have undergone [2+2+2] cycloaddition reaction to
generate Tic derivatives are shown in Table 1. Some of
the Tic derivatives prepared here deserves a special com-
ment. Trimethylsilyl substituted Tic derivatives (11, 13,
2. Grunewald, G. L.; Caldwell, T. M.; Li, Q.; Criscione, K. R.
Bioorg. Med. Chem. 1999, 7, 869. Kazmierski, W. M.;
Urbanczyk-Lipkowska, Z.; Hruby, V. J. J. Org. Chem. 1994,
5
9, 1789. Prochazka, Z.; Ancans, J. E.; Slaninova, J.;
Machova, A.; Barth, T.; Lebl, M. Collect. Czech. Chem.
Commun. 1990, 55, 1099. Ortwine, D. F.; Malaone, T. C.;
Bigge, C. F.; Drummond, J. T.; Humblet, C.; Johnson, G.;
Pinter. G. W. J. Med. Chem. 1992, 35, 1345.
1
4 and 15) can be used as a building blocks to introduce
10
various electrophiles ipso to the TMS group. Dihy-
droxy compound 6 is a potential precursor for the gen-
eration of Tic-based o-xylylene derivative.11
3
. Moseberg, H. I.; Lomize, A. L.; Wang, C.; Kroona, H.;
Heyl, D. L.; Sobczyk-Kojiro, K.; Ma, W.; Mousigian, C.;
Porreca, F. J. Med. Chem. 1994, 37, 4371; Gibson (nee Tho-
mas), S. E.; Guillo, N.; Tozer, M. J. Tetrahedron 1999, 55, 585.
4. Whaley, W.; Govindachari, T. R. Org. React. 1951, VI, 74;
W. J. Gensler, Org. React. 1951, VI, 191.
In conclusion, we have developed a general strategy for
the synthesis of multifunctional Tic derivatives using tran-
sition metal catalyzed [2+2+2] cycloaddition reaction as
a key step. Given the dearth of Tic derivatives, this
methodology may ®nd useful applications in bioorganic
and medicinal chemistry.
5
. Mash, E. A.; Williams, L. J.; Pfei€er, S. S. Tetrahedron
Lett. 1997, 38, 6977. Verschueren, K.; Toth, G.; Tourwe, D.;
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C.; Mosberg, H. I. Tetrahedron Lett. 1995, 36, 3623.
6
. Beifuss, U.; Kunz, O.; Ledderhose, S.; Taraschewski, M.
General procedure for a [2+2+2] cycloaddition reaction
using CpCo(CO) conditions
T.; Tonko, C. Synlett 1996, 34. Shinohara, T, Takeda, A.;
Toda, J.; Ueda, Y.; Kohno, M.; Sano, T. Chem. Pharm. Bull.
2
1998, 46, 918. Padwa, A.; Brodney, M. A.; Liu, B.; Satake, K.;
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To a re¯uxing solution of diyne building block (0.1
mmol) containing CpCo(CO) (0.3 mL) was added a
solution of monoyne containing CpCo(CO) in toluene/
2
octane under nitrogen atmosphere over a period of 6±10
h (syringe pump). The reaction ¯ask was connected to
vacuum distillation set up and all the volatiles were dis-
tilled o€ to give the crude product. The dark oily resi-
due was chromatographed on a silica gel column by
eluting with pet ether and ethyl acetate mixture to give
cotrimerized product.
2
1
2
8
982 3491. O'Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982,
663.
. Grigg, R.; Scott, R.; Stevenson, P. J. Chem. Soc. Perkin.
Trans. 1 1988, 1357. Muller, E. Synthesis 1974, 761; Colin, P.
D. J. Chem. Soc. Perkin Trans. 1 1998, 3873.
9
. Vollhardt, K. P. C. Pure Appl. Chem. 1993, 65, 153. Toda,
F.; Garratt, P. Chem. Rev. 1992, 92, 1685. Witulski, B.; Sten-
gel, T. Angew. Chem., Int. Ed. Engl. 1999, 38, 2426. Sato, Y.;
Nishimata, T.; Mori, M. Heterocycles 1997, 44, 443. Sato, Y.;
Ohashi, K.; Mori, M. Tetrahedron Lett. 1999, 40, 5231.
1
1
1
0. Bennetau, B.; Dunogues, J. Synlett 1993, 171.
1. Martin, N.; Seoane, C.; Hanack, M. Org. Prep. Pro. Int.
991, 23, 237. 13C NMR data for selected compounds: (1) d
Acknowledgements
We thank DST for the ®nancial support and RSIC Mum-
bai, Prof. A. Srikrishna for recording the spectral data. N.
S. thanks CSIR, New Delhi for the award of fellowship.
13.8, 20.7, 21.4, 34.3, 58.0, 61.7, 71.5, 73.0, 78.3, 78.9, 127.7,
129.3, 136.7, 143.7, 169.0. (5) d 0.03, 14.3, 21.1, 21.9, 35.8,
58.7, 62.1, 71.7, 79.7, 99.3, 100.2, 128.3, 129.7, 137.6, 143.9,
169.4. (6) d 13.7, 21.5, 31.5, 44.0, 53.5, 61.3, 63.5, 127.2, 127.3,
129.5, 129.9, 130.3, 130.6, 135.9, 137.9, 143.6, 170.1. (7) d 13.8,
References and Notes
21.5, 31.7, 44.1, 53.8, 61.3, 126.5, 127.4, 127.8, 128.1, 129.5,
1
29.7, 130.8, 139.1, 140.8, 143.5, 170.2. (11) d 1.9, 14.0, 21.5,
1
. Kametani, T. In The Total Synthesis of Natural Products,
ApSimon, J., Ed.; John Wiley: New York, 1977; Vol. 3, pp 1±
72; Bently, K. W The Isoquinoline Alkaloids, Harwood Aca-
demic: Singapore, 1998.
31.9, 44.2, 53.7, 61.1, 127.4, 129.4, 130.1, 130.9, 133.0, 135.7,
136.5, 143.2, 144.1, 170.1. (12) d 14.0, 21.6, 31.9, 44.1, 52.5,
53.0, 61.2, 127.1, 127.5, 129.5, 130.5, 130.6, 134.3, 134.9, 136.2,
143.4, 167.0, 169.2, 169.4.
2