HETEROCYCLES

Communication | Special issue | Vol. 80, No. 2, 2010, pp. 847-854
Received, 3rd August, 2009, Accepted, 4th September, 2009, Published online, 11th September, 2009.
DOI: 10.3987/COM-09-S(S)103

■ Diversity-Oriented Approach to 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid (Tic) Derivatives Using Diethyl Acetamidomalonate as a Glycine Equivalent: Further Expansion by Suzuki–Miyaura Cross-Coupling Reaction

Sambasivarao Kotha,* Shilpi Misra, Nimita Gopal Krishna, Nagaraju Devunuri, Henning Hopf, and Abhilash Keecherikunnel

Department of Chemistry, Indian Institute of Technology, Powai, Mumbai 400 076, India

Abstract

Synthesis of diverse 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives and its higher analogues are reported using diethyl acetamidomalonate as a glycine equivalent. In addition, various substituted Tic derivatives are assembled by application of Suzuki−Miyaura cross-coupling reaction as a key step.

Constrained α-amino acid (AAA) derivatives play a critical role in the design of biologically active peptides and peptidomimetics.1 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (Tic) is considered as a constrained analogue of phenylalanine (Phe), where its dihedral angle is limited to a small range (χ = +60o, -60o).2 In addition, Tic has also been employed as a useful building block for the synthesis of various biologically active alkaloid derivatives.3 Peptides containing Tic are also used as δ-opioid receptor antagonists.4 Interestingly, the Tic residue adopts different conformations depending on whether it is incorporated at the N-terminus or at a central location of the peptide chain. Recent studies indicate that by incorporation of Tic residues, the resulting peptide can adopt both helical and β-bonded structures. Generally, Tic derivatives are assembled by Pictet−Spengler or Bischler−Napieralski reactions as a key step.5 In order to expand the synthetic routes to Tic derivatives, development of other approaches is desirable.6 In connection with the studies related to the bioactive conformation of peptide ligands, various Tic derivatives were assembled (Figure 1).7 In continuation of our efforts to design various Tic derivatives by a building block approach,11 we conceived a general strategy to several Tic derivatives involving diethyl acetamidomalonate (DEAM) as a glycine equivalent. Although DEAM is used for the construction of various unusual amino acid derivatives, its utility towards the preparation of Tic derivatives however is less explored.12

Here we describe the synthesis of various Tic derivatives, by treating α,α-dibromo-o-xylenes, with DEAM in presence of a mild base such as K2CO3 (Scheme 1). By choosing an appropriate dibromo derivative one can prepare Tic and its higher analogues (Eq. 1 – Eq. 3).

The required dibromo derivatives can be obtained from the corresponding dimethyl aromatic compounds with the aid of benzylic bromination using N-bromosuccinimide (NBS)13 under free radical condition or by bromination of the corresponding diols with PBr3 (Scheme 2).14 The required diols were assembled by a [2+2+2]cycloaddition reaction and reduction as key steps.15 Alternatively, a bromomethylation16 strategy can also be adopted for this purpose.

Reaction of α,α-dibromo-o-xylene derivatives (Table 1) with DEAM in presence of K2CO3 gave various Tic derivatives in moderate yields. In a typical experimental procedure, a solution of dibromide (1 equivalent) in dry acetonitrile was treated with DEAM (1.1 equivalent), powdered potassium carbonate (6 equivalents) and tetrabutylammonium hydrogen sulfate (0.2 equivalent) as a phase-transfer catalyst. At the conclusion of the reaction (TLC monitoring), the reaction mixture was passed through a small pad of celite. The filtrate was concentrated and extracted with ethyl acetate (3 × 25 mL). The crude product obtained was purified by silica-gel column chromatography. Elution of the column with ethyl acetate-petroleum ether mixture furnished the required Tic derivative.
This methodology was also extended for the synthesis of higher analogues of Tic. Towards the preparation of Sic derivative 26, the required dibromide was prepared from the corresponding anhydride.17 Later, treatment of the dibromide 25 with DEAM in the presence of K2CO3 gave Sic derivative 26. Along similar lines, Hic derivative 28 was assembled starting with the commercially available 2,2′-bis(bromomethyl)-1,1′-biphenyl 27 (Table 2).

It is interesting to note that this strategy could also be extended to cyclophane derivative 29. Accordingly, when tetrabromide 2918 was reacted with DEAM under the above condition to give di-Tic derivative 30 along with mono-Tic derivative 31 in 40% and 35% yields, respectively. The regiochemistry of compound 30 has been established by single crystal X-ray diffraction analysis.19 In view of various recent applications of [2.2] paracyclophane chemistry these results may found useful application in bioorganic chemistry.20

Having prepared various Tic derivatives and its higher analogues, diiodo Tic derivative 10 was chosen as a suitable precursor to realize the Suzuki−Miyaura (SM) cross-coupling step. We found that the corresponding tetrabromo derivative is not a friendly precursor. To this end, we prepared various SM cross-coupling products by reaction of 10 with various boronic acids under Pd catalyst conditions. Several derivatives prepared by SM coupling reaction are included in Table 3.
In a typical reaction procedure, the diiodo Tic derivative 10 was reacted with an appropriate boronic acid, THF/toluene/H2O (1:1:1) in presence of Na2CO3, at 70 oC for 15-20 min followed by addition of [Pd2(dba)3] (1.5 mol%) and Buchwald ligand21 (5 mol%) (condition A). At the end of the reaction (TLC monitoring), the reaction mixture was concentrated and the crude product obtained was purified by silica-gel column chromatography. Elution of the column with an ethyl acetate-petroleum ether mixture gave the cross-coupling product. In some cases, the SM cross-coupling reaction was also carried out in the absence of a ligand by using [Pd2(dba)3] (1.5 mol%), dioxane:H2O = 3:1) in the presence of LiCO3 under microwave irradiation (condition B). All new compounds were characterized on the basis of high resolution 1H NMR and mass spectral data.
In conclusion, we have shown that DEAM is a useful glycine equivalent to prepare diverse Tic derivatives under mild reaction conditions. Further, we have shown that SM cross-coupling reaction is useful to generate various functionalized Tic derivatives. Since a large number (>900) of boronic acids are commercially available, the present strategy can be easily extended to generate a library of Tic derivatives by applying SM cross-coupling reaction. Since the development of new synthetic methods for the preparation of unusual AAA derivatives is important for designing peptide-based drugs, our methodology may be of interest to medicinal and bioorganic chemists.

ACKNOWLEDGMENTS
We thank CSIR, New Delhi for financial support and SAIF, Bombay for recording spectral data. S. Misra thanks CSIR, New Delhi for the award of research fellowship. N. G. Krishna thanks Department of Chemistry, IIT-Mumbai for awarding the research fellowship. Abhilash Keecherikunnel thanks the Alexander von Humboldt foundation for a postdoctoral fellowship.

References

1. M. Zheng, X. Zhang, M. Zhao, H. W. Chang, W. Wang, Y. Wang, and S. Peng, Bioorg. Med. Chem., 2008, 16, 9574. CrossRef
2. I. Torrini, G. P. Zecchini, M. P. Paradisi, G. Lucente, G. Mastropietro, E. Gavuzzo, F. Mazza, and G. Pochetti, Tetrahedron, 1998, 54, 165. CrossRef
3. S. E. Gibson, N. Guillo, S. B. Kalindjian, and M. J. Tozer, Bioorg. Med. Chem. Lett., 1997, 7, 1289; CrossRef S. E. Gibson, N. Guillo, J. O. Jones, I. M. Buck, S. B. Kalindjian, S. Roberts, and M. J. Tozer, Eur. J. Med. Chem., 2002, 37, 379; CrossRef J. Yang, W. Y. Hua, F. X. Wang, Z. Y. Wang, and X. Wang, Bioorg. Med. Chem., 2004, 12, 6547; CrossRef B. H. Hirth, S. Qiao, L. M. Cuff, B. M. Cochran, M. J. Pregel, J. S. Gregory, S. F. Sneddon, and J. L. Kane, Bioorg. Med. Chem. Lett., 2005, 15, 2087; CrossRef H. Zhang, D. E. Zembower, and Z. Chen, Bioorg. Med. Chem. Lett., 1997, 7, 2687. CrossRef
4. S. Ballet, D. Feytens, R. D. Wachter, M. D. Vlaeminck, E. D. Marczak, S. Salvadori, C. D. Graaf, D. Rognan, L. Negri, R. Lattanzi, L. H. Lazarus, D. Tourwé, and G. Balboni, Bioorg. Med. Chem Lett., 2009, 19, 433. CrossRef
5. A. Pictet and T. Spengler, Ber., 1911, 44, 2030; W. M. Whaley and T. R. Govindachari, Org. React., 1951, 6, 74.
6. S. Kotha and N. Sreenivasachary, J. Indian Inst. Sci., 2001, 81, 277 and references cited therein; P. H. Dixneuf, G. T. Shchetnikov, S. N. Osipov, and C. Bruneau, Synlett, 2008, 578; CrossRef T. Ooi, M. Takeuchi, and K. Maruoka, Synthesis, 2001, 1716; CrossRef C. Wang and H. I. Mosberg, Tetrahedron Lett., 1995, 36, 3623; CrossRef S. Azukizawa, M. Kasai, K. Takahashi, T. Miike, K. Kunishiro, Kanda, C. Mukai, and H. Shirahase, Chem. Pharm. Bull., 2008, 56, 335; CrossRef K. V. Rompaey, I. V. D. Eynde, N. De Kimpe, and D. Tourwé, Tetrahedron, 2003, 59, 4421. CrossRef
7. S. E. Gibson, N. Guillo, R. J. Middleton, A. Thulliez, and M. J. Tozer, J. Chem. Soc., Perkin Trans. 1, 1997, 447. CrossRef
8. S. Kotha and N. Sreenivasachary, Chem. Commun., 2000, 503; CrossRef S. Kotha and N. Sreenivasachary, Eur. J. Org. Chem., 2001, 3375; CrossRef S. Kotha and P. Khedkar, Synthesis, 2008, 2925; CrossRef S. Kotha, M. Meshram, and A. Tiwari, Chem. Soc. Rev., 2009, 38, 2065; CrossRef S. Kotha, K. Lahiri, D. Kashinath, and R. B. Sunoj, Eur. J. Org. Chem., 2004, 4003; CrossRef S. Kotha and K. Lahiri, Eur. J. Org. Chem., 2007, 1221. CrossRef
9. S. Kotha and N. Sreenivasachary, Bioorg. Med. Chem. Lett., 2000, 10, 1413; CrossRef S. Kotha, E. Brahmachary, and K. Lahiri, Eur. J. Org. Chem., 2005, 4741. CrossRef
10. S. Kotha and S. Banerjee, Synthesis, 2007, 1015. CrossRef
11. S. Kotha, Acc. Chem. Res., 2003, 36, 342. CrossRef
12. B. O. T. Kammermeier, U. Lerch, and C. Sommer, Synthesis, 1992, 1157. CrossRef
13. R. P. Kreher and T. Hildebrand, Chem. Ber., 1988, 121, 81. CrossRef
14. R. H. Mitchell and F. Sondheimer, Tetrahedron, 1968, 24, 1397; CrossRef J. Kenner and E. G. Turner, J. Chem. Soc., 1911, 99, 2101; CrossRef B. Saroja and P. C. Srinivasan, Tetrahedron Lett., 1984, 25, 5429; CrossRef For substrate 15 and 17 see reference V. P. Ruggli, Helv. Chim. Acta, 1946, 2995.
15. S. Kotha and P. Khedkar, J. Org. Chem., 2009, 74, 5667. CrossRef
16. V. P. Kreher and N. Kohl, Chemiker-Zeitung, 1986, 110, 299.
17. V. Boekelheide and G. K. Vick, J. Am. Chem. Soc., 1956, 78, 653. CrossRef
18. H. Hopf, I. Böhm, and J. Kleinschroth, Org. Synth., 1990, 7, 485.
19. S. Kotha, S. Misra, H. Hopf, and S. M. Mobin, unpublished results.
20. S. Kotha and S. Halder, Arkivoc (iii), 2005, 56; S. Kotha, S. Halder, L. Damodharan, and V. Pattabh, Bioorg Med. Chem. Lett., 2002, 12, 1113; CrossRef S. Kotha and K. Mandal, Adv. Synth. Catal., 2005, 1215; CrossRef S. Kotha and K. Mandal, Eur. J. Org. Chem., 2006, 5387; CrossRef A. Petler, R. A. C. N. Crump, and H. Kidwell, Tetrahedron Lett., 1996, 37, 1273; CrossRef A. de Meijere and B. König, Synlett, 1997, 1221. CrossRef
21. X. Huang, K. W. Anderson, D. Zin, L. Jiang, A. Klapars, and S. L. Buchwald, J. Am. Chem. Soc., 2003, 125, 6653. CrossRef