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J. Org. Chem. 2000, 65, 316-321
Synthesis and Conformational Study of 1,3,2-Oxazaphosphorino[4,3-a]isoquinolines: A New Ring System Tama´s Martinek,† Eniko _ Forro´,† Ga´bor Gu¨nther,† Reijo Sillanpa¨a¨,‡ and Ferenc Fu¨lo¨p*,† Institute of Pharmaceutical Chemistry, Albert Szent-Gyo¨ rgyi Medical University, H-6701 Szeged, POB 121, Hungary, and Department of Chemistry, University of Turku, FIN-20500 Turku, Finland Received June 30, 1999
A set of 1,3,2-oxazaphosphorino[4,3-a]isoquinolines 6a,b-9a,b, a new ring system, was synthesized, and their stereochemical and conformational analyses were performed by 1H, 13C, and 31P NMR methods. X-ray measurements were also carried out to confirm the stereochemical assignments and conformational results obtained by means of NMR. Intermediate coupling constants 3J(P,H) were found for compounds 7 and 9; these do not relate to equilibria between previously reported conformers, but are indicative of new distorted conformational states in solution. The connecting isoquinoline and the steric interaction between the aromatic moiety and the Me-1 substituent can block the oxazaphosphorinane ring. The conformational behavior of compounds 6 and 8 was characterized by the usual chair-twist equilibrium. Introduction Oxazaphosphorinane derivatives have been compounds of interest for the past 20 years. A number of studies have been carried out on their biological activities and conformational behavior. Their antitumor activity is a valuable property,1 and the conformational studies were rationalized by the clinical use of oxazaphosphorinane ring-containing compounds. On the other hand, the extreme sensitivity of the conformational behavior of the oxazaphosphorinane ring to the various substituents makes these compounds an excellent model for studies of the steric and electronic effects of functional groups in different positions. In a series of publications, it was shown that the size of R3 and the steric and electronic properties of the substituents Z exert strong effects on the conformational equilibrium of the oxazaphosphorinane ring2 1. Further, the sterically demanding substituents R1 and R2 (tertbutyl or phenyl) are readily able to force the system to occupy a twist conformation.3 An exhaustive study has been carried out on oxazaphosphorinane derivatives fused with cyclohexane, in which the existence of separate conformations in equilibrium was revealed by low* E-mail:
[email protected]. † Institute of Pharmaceutical Chemistry, Albert Szent-Gyo ¨ rgyi Medical University. ‡ Department of Chemistry, University of Turku. (1) Ludeman, S. M.; Boyd, V. L.; Regan, J. B.; Gallo, K. A.; Zon, G.; Ishii, K. J. Med. Chem. 1986, 29, 716. (2) (a) Bentrude, W. G.; Setzer, W. N.; Khan, M.; Sopchik, A. E.; Ramli, E. J. Org. Chem. 1991, 56, 6127. (b) Bentrude, W. G.; Setzer, W. N.; Sopchik, A. E.; Chandrasekaran, S.; Ashby, M. T. J. Am. Chem. Soc. 1988, 110, 7119. (c) Bentrude, W. G.; Setzer, W. N.; Sopchik, A. E.; Bajwa, G. S.; Burright, D. D.; Hutchinson, J. P. J. Am. Chem. Soc. 1986, 108, 6669. (d) Bentrude, W. G.; Setzer, W. N.; Newton, M. G.; Meehan, E. J., Jr.; Ramli, E.; Khan, M.; Ealick, S. Phosphorus, Sulfur, Silicon 1991, 57, 25. (e) Bentrude, W. G.; Setzer, W. N.; Kergaye, A. A.; Ethridge, V.; Saadein, M. R.; Arif, A. M. Phosphorus, Sulfur, Silicon 1991, 57, 37. (f) Setzer, W. N.; Sopchik, A. E.; Bentrude, W. G. J. Am. Chem. Soc. 1985, 107, 2083. (g) Spassov, S. L.; Lyapova, M. J.; Ivanova, M. E. Phosphorus, Sulfur, Silicon 1988, 37, 199. (3) (a) Bentrude, W. G.; Day, R. O.; Holmes, J. N.; Quin, G. S.; Setzer, W. N.; Sopchik, A. E.; Holmes, R. R. J. Am. Chem. Soc. 1984, 106, 106. (b) Holmes, R. R.; Day, R. O.; Setzer, W. N.; Sopchik, A. E.; Bentrude, W. G. J. Am. Chem. Soc. 1984, 106, 2353.
temperature NMR measurements, because the conformers could be frozen out.4
Fused oxazaphosphorinane ring systems with N-3 in a bridgehead position have also been synthesized with the aim of achieving lower systemic toxicity and greater selectivity, and their conformational properties have been discussed.5 Depending on the substituents on N-3, P, and C-5, the oxazaphosphorinane ring tends to occupy a conformational state other than chair. However, the unusual conformational behavior of these rings has been handled in terms of the chair-alternative chair and the chairtwist equilibrium, and the intermediate coupling constants 3J(H,P) were used as unambiguous indicators of possible dynamic processes.6 In the present work, we report a systematic conformational study on 1,3,2-oxazaphosphorinane derivatives condensed with isoquinoline, and an example will be given where certain intermediate coupling constants 3 J(H,P) need not necessarily be considered indicators of an equilibrium between idealized conformational states. Results and Discussion The 1-methyltetrahydroisoquinoline-1-ethanol derivatives 3 and 5 were synthesized in two independent ways. (4) Viljanen, T.; Ta¨htinen, P.; Pihlaja, K.; Fu¨lo¨p, F. J. Org. Chem. 1998, 63, 618. (5) (a) Schmidt, B. F.; Tang, W. C.; Eisebrand, G.; Lieth, C. W.; Hull, W. E. Magn. Reson. Chem. 1992, 30, 1224. (b) Sosnovsky, G.; Paul, B. D. Z. Naturforsch. 1983, 38b, 1146. (6) (a) Bentrude, W. G. in Phosphorus-31 NMR Spectral Properties in Compound Chracterization and Structural Analysis; Quin, L., Verkade J. G., Eds.; VCH: New York, 1994; Chapter 4. (b) Bentrude, W. G.; Setzer W. N. In Phosphorus-31 NMR Spectroscopy in Stereochemical Analysis; Verkade J. G., Quinn, L. D., Eds.; VCH: Deerfield Beach, FL, 1987; Chapter 11.2.
10.1021/jo991047+ CCC: $19.00 © 2000 American Chemical Society Published on Web 12/29/1999
1,3,2-Oxazaphosphorino[4,3-a]isoquinolines Scheme 1.
J. Org. Chem., Vol. 65, No. 2, 2000 317 Synthesis of the Studied Compoundsa
a (i) CH O/NaOEt, then NaBH and fractional crystallization, 51%; (ii) MeI, then Pt/H , then LiAlH and fractional crystallization, 2 4 2 4 44%; (iii) Cl2OPX/Et3N or pyridine and column chromatography, 40-45%.
Table 1. Selected Chemical Shifts in CDCl3 (δTMS ) 0 ppm, δCHCl3 ) 77.7 ppm, δH3PO4 ) 0 ppm) 6a 6b 7a 7b 8a 8b 9a 9b
H-2eq
H-2ax
H-1
Me-1
H-11b
H-11
H-8
H-7eq
H-7ax
H-6ax
H-6eq
P
C-1
C-2
C-11a
4.19 4.16 3.88 4.10 4.24 4.20 3.88 4.22
4.55 4.78 4.35 4.19 4.38 4.93 4.48 4.29
2.22 2.33 2.28 2.30 2.16 2.44 2.22 2.51
0.91 0.89 1.01 1.23 0.95 1.05 0.99 1.36
4.77 4.85 4.20 4.24 4.71 5.00 4.00 4.40
6.52 6.58 6.59 6.64 6.48 6.62 6.52 6.50
6.63 6.60 6.67 6.71 6.63 6.55 6.68 6.76
2.61 2.59 2.61 2.69 2.65 2.41 2.75 2.46
2.90 2.89 3.09 2.91 2.96 2.73 3.01 2.57
3.01 2.89 2.94 3.15 3.10 2.94 3.20 3.14
3.81 3.60 3.79 3.55 4.09 3.17 3.98 3.53
10.8 16.8 13.3 13.2 19.3 24.5 22.0 19.8
38.1 35.1 36.9 36.7 38.0 35.8 38.8 37.5
73.1 71.9 70.9 70.7 72.7 71.1 72.1 69.8
59.1 59.7 62.0 61.4 58.9 58.2 61.0 60.8
Table 2. Selected Vicinal H, H and P, H Coupling Constants (Hz) 6a 6b 7a 7b 8a 8b 9a 9b a
P, 2eq
P, 2ax
P, 6ax
P, 6eq
P, 11b
1, 2ax
1, 11b
1, 2eq
6eq, 7ax
6eq, 7eq
6ax, 7ax
6ax, 7eq
17.6 23.7 15.1 20.0 21.9 22.9 10.7 16.3
8.8 2.4 10.1 7.3 4.9 3.7 16.1 10.7
11.7 a 8.0 5.4 1.7
