Journal of Molecular Structure 554 (2000) 119±125
www.elsevier.nl/locate/molstruc
Synthesis and stereochemistry of 1,3,2-oxazaphosphorino [4,3-a]isoquinolines F. FuÈloÈp a,*, E. Forro a, T. Martinek a, G. GuÈnther a, R. SillanpaÈaÈ b a
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, P.O. Box 121, Hungary b Department of Chemistry, University of Turku, FIN-20014 Turku, Finland Received 27 March 2000; revised 3 May 2000; accepted 3 May 2000
Abstract 1,3,2-Oxazaphosphorino[4,3-a]isoquinolines 8a,b, 9a,b and 10a were synthesized by the reactions of homocalycotomine 7 with appropriate dichlorophosphorus derivatives, such as phenylphosphonic dichloride, bis(2-chloroethyl)phosphonic dichloride or phosphoryl chloride. In spite of the blocking effect of the connecting isoquinoline ring system, the oxazaphosphorinane moiety exists as a chair±twist equilibrium, where the conformer ratios are strongly dependent on the P-4 con®guration and the stereoelectronic properties of the substituents. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Oxazaphosphorinane; Conformational equilibria; Crystal structure
1. Introduction Phosphorus-containing heterocycles such as oxazaphosphorinanes are subjected to extensive investigations in consequence of their pharmacological relations [1] and their unique conformational behaviour. A great number of studies have been carried out on various monocyclic 1,2,3-oxazaphosphorinane derivatives with respect to synthesis, bioactivity and conformational analyses [2±10]. As a result of the basic importance, various 1,3,2-oxazaphosphorinanes have been synthesized. Interest has recently shifted towards fused bicyclic and tricyclic derivatives, which raises new questions concerning the bioactivity and conformational properties of these compounds. * Corresponding author. Tel: 136-62-545-564; fax: 1 36-62545-705. E-mail address:
[email protected] (F. FuÈloÈp).
Bicyclic cyclophosphamide analogues 1 and 2 with nitrogen at bridgehead position 3 have been synthesized for medical purposes, but the conformational analysis was not reported [11]. Bicyclic sulphurcontaining oxazaphosphorinanes 3 and 4 have been synthesized and subjected to conformational investigation [12]. Octahydrobenzoxazaphosphorinane derivatives 5 with moderate activity against lymphocytic leukaemia have been described and their exhaustive conformational analysis has been carried out [13,14]. The spectral parameters of phosphorus such as 31 P± 1H vicinal couplings facilitate accurate analysis of the conformational equilibria for the oxazaphosphorinane ring system. Intermediate coupling constants 3J(P,H) were recently found [15] for the b-methyl-substituted 6; 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
0022-2860/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0022-286 0(00)00662-1
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and the Me substituent at position 1 can block the oxazaphosphorinane ring. The conformational behaviour of the a-methyl-substituted compounds 6 was characterized by the usual chair±twist equilibrium. Following the recent trend and as a continuation of our systematic studies on isoquinoline-fused 1,3heterocycles [16±19], our present aim was to prepare and investigate the stereochemistry of the title compounds, with no substituent at position 1. 2. Experimental The NMR spectra were recorded in CDCl3 solution at 300 K on a Bruker AVANCE DRX 400 spectrometer, with the deuterium signal of the solvent as the lock. During 1H and 13C NMR measurements, TMS was applied as internal standard; for the 31P NMR spectra, 85% H3PO4 was used as an external standard. Samples were dissolved in 0.5 cm 3 solvent and placed in 5 mm Aldrich NMR tubes. Nitrogen bubbling was used to degas samples. 1D spectra were evaluated with the help of PERCH software. For evaluation of the NOESY spectra and integration of the crosspeaks, NMRView [20] was used. The physical and analytical data on the compounds prepared are listed in Table 6. 2.1. X-ray diffraction studies All data were collected on a Rigaku AFC5S diffractometer, with graphite-monochromated MoKa in the v ±2u scan mode radiation
l 0:71069 A at room temperature. The lattice parameters were calculated by least-squares re®nements of 25 re¯ections. The weak re¯ections I , 10a
I were rescanned up to two times. For 8b, 3165 re¯ections were collected
2umax 508: The data were corrected for Lorentz and polarization effects. Crystal data for 8b: C19H22NO4P; Mr 359:35; orthorhombic, space group Pbca (No 60); lattice parametersÐa 13:201
2; b 25:1468
18; c 3 ; Dc 10:846
2 A; Z 8; V 3600:6
10 A 3 21 1:326 g=cm ; m
MoKa 0:176 mm ; F
000 1520; T 294 K; a pale-yellow plate, crystal dimensions 0.22 £ 0.32 £ 0.38 mm 3. The structures were solved by direct methods (SIR92) [21] and re®ned by full-matrix least squares techniques (SHELX-97) [22] to an R1 value of 0.0443
wR2 0:976 for 8b. These ®nal R values are based on the re¯ections with I . 2s
I: The heavy atoms were re®ned anisotropically. The hydrogen atoms on the aliphatic ring carbons were re®ned with ®xed isotropic temperature factors (1.2Ueq of the carrying atom) and the remaining hydrogen atoms were included in the calculated positions with ®xed isotropic temperature factors (1.2 or 1.5 times Ueq of the carrying atom). Calculations were performed with teXsan for Windows [23] crystallographic software. The ®gures were drawn with ORTEP-3 for Windows [24]. 2.2. Synthesis of 9,10-dimethoxy-4-phenyl-4-oxo1,6,7,11b-tetrahydro-1,3,2-oxazaphosphorino[4,3-a]isoquinoline (8a and 8b) To a solution of homocalycotomine (7) (2.52 g, 10.66 mmol) and anhydrous pyridine (1.68 g, 21.32 mmol) in anhydrous toluene (400 ml) at 6± 108C under a nitrogen atmosphere was added dropwise a solution of phenylphosphonic dichloride (2.29 g, 11.72 mmol) in anhydrous toluene (100 ml) over a period of 1 h. When the addition was complete, anhydrous pyridine (1.68 g, 21.32 mmol) in anhydrous toluene (60 ml) was added and the mixture was left to stand overnight at room temperature. The reaction mixture was washed in turn with water (3 £ 100 ml), hydrochloric acid (3 M, 2 £ 100 ml) and sodium hydroxide (3 M, 2 £ 100 ml), then dried (Na2SO4), and the solvent was removed to afford a pale-yellow oil (1.79 g). 31P NMR of the crude product showed the presence of two diastereomers in nearly 1:1 ratio. The crude product was column chromatographed on neutral aluminium oxide, with ethyl acetate as eluent. From the fast-eluting isomer 8a (0.48 g), and from the slow-eluting isomer 8b (0.52 g) was isolated in pure form. 2.3. Synthesis of 4-[bis(2-chloroethyl)amino]-9,10dimethoxy-4-oxo-1,6,7,11b-tetrahydro-1,3,2oxazaphosphorino[4,3-a]isoquinoline (9a and 9b) Homocalycotomine (7) (2.51 g, 10.6 mmol) was allowed to react at room temperature with bis(2-chloroethyl)aminophosphoryl dichloride (2.74 g, 10.6 mmol) and triethylamine (2.15 g, 21.2 mmol) in dry ethyl acetate under a nitrogen atmosphere. The reaction mixture was stirred for 48 h and then ®ltered
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121
Scheme 1.
the ®ltrate was concentrated resulting in pale-yellow crystal (0.4 g). 31P NMR of the crude product showed the presence of only a single diastereomer 10a. The crude product was recrystallized from methanol.
to remove triethylamine hydrochloride. The clear solution was subjected to rotary evaporation. 31P NMR of the crude product showed the presence of two diastereomers in nearly 1:1 ratio. The product (3.1 g) was column chromatographed on neutral silica gel, with ethyl acetate as eluent. From the fast-eluting isomer 9a (0.8 g), and from the slow-eluting isomer 9b (0.7 g) was isolated in pure form.
3. Results and discussion 3.1. Synthesis
2.4. 4-Chloro-9,10-dimethoxy-4-oxo-1,6,7,11btetrahydro-1,3,2-oxazaphosphorino[4,3-a]isoquinoline (10a)
Homocalycotomine 7 was prepared from 6,7dimethoxy-3,4-dihydroisoquinoline by reaction with monoethyl malonate, followed by lithium aluminium hydride reduction, according to literature procedures [25]. When 7 was reacted with the appropriate phenylphosphonic dichloride or bis(2-chloroethyl)phosphoramidic dichloride in the presence of pyridine, the P-4 epimeric structures 8a,b and 9a,b were formed in nearly 1:1 ratio. When phosphoryl chloride was
To a solution of homocalycotomine (7) (1.1 g, 4.6 mmol) and triethylamine (0.64 g, 4.6 mmol) in dry toluene (15 ml) was added dropwise with stirring a solution of phosphoryl chloride (0.78 g, 5 mmol) in toluene (5 ml) under a nitrogen atmosphere. Stirring was continued for 4 h, the triethylamine hydrochloride that precipitated out was ®ltered off, and
Table 1 Selected chemical shifts in CDCl3 (ppm)
dTMS 0; dCHCl3 77; dH3 PO4 0 ppm
8a 8b 9a 9b 10a
1ax
1eq
2ax
2eq
6ax
6eq
7ax
7eq
11b
P
2.24 2.17 2.24 1.98 2.29
2.1 2.49 2.19 2.25 2.14
4.45 4.74 4.36 4.60 4.52
4.26 4.37 4.30 4.32 4.48
3.79 3.38 3.64 3.65 3.96
3.3 3.03 3.11 2.92 2.7
2.73 2.41 2.63 2.61 2.63
2.99 2.66 3.01 2.91 3.04
4.51 4.78 4.6 4.64 4.45
20.1 21.8 11.9 15.8 11.5
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122
Fig. 1. Idealized theoretical conformations of ring C.
applied under the same conditions, the reaction proved to be diastereoselective, resulting in the single diastereomer 10 (Scheme 1). The diastereomeric pairs 8a,b and 9a,b were separated by column chromatography on aluminium oxide, with ethyl acetate as eluent. 3.2. NMR parameters and con®gurations and conformational analysis The assignment of the 1H and 13C NMR signals was straightforward via the standard 2D methods, such as 1 H COSY45, NOESY, HMQC and J-resolved spectra. During measurements of the chemical shifts and coupling constants 3J(H,H), especially for the second-order patterns, the iterative method implemented in the program PERCH [26] was used. The synthesis resulted in P-4 epimer pairs a and b for 8 and 9 and a single diastereomer for 10. The relative con®guration of the P and the orientation of the PyO bond can be determined by means of NMR, Table 2 Selected vicinal P,H and H,H coupling constants (Hz)
from: (i) the 31P chemical shifts; (ii) the 1H chemical shifts due to the 1,3-diaxial interactions; (iii) the 13C chemical shift changes arising from the shielding effect of oxygen; (iv) the NOE effects between the P substituent and other ring protons, and (v) measurement of the coupling constants 1J(P,N) [27]. There is a systematic difference between the 31P chemical shifts in series a and b. The 31P signals for a are up®eld from those for b. Further, the axial H-2 and the H-11b resonances are shifted down®eld for b as compared to a. These observations suggest that the PyO bond is equatorial in compounds a and axial in b (Table 1). The NOE interactions of the P substituents with H-11b and H-2ax for compounds a con®rm the assigned con®guration of the P. For fused heterocyclic systems with N in the bridgehead position, one of the most important questions is the ring anellation. The relative ease of the N inversion can cause equilibrium between cis and trans Table 3 Conformer populations (due to the method used, the error involved is about ^5%)
P,H-2ax P,H-2eq P,H-11b H-11b,H-1ax H-6ax,H-7ax 8a 19.2 8b 2.9 9a 9.3 9b 2.0 10a 11.6
5.1 21.5 13.1 23.4 12.9
3.0 2.5 4.5 1.9 3.0
10.5 11.4 9.2 10.8 10.9
8.8 11.3 9.7 10.3 9.9
8a 8b 9a 9b 10a
[C]%
[A]%
82 8 41 1 47
18 92 59 99 53
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Table 4 Ê ) and angles (8) (esd values are given in Selected bond distances (A parentheses) for 8b P(4)±O(4) P(4)±O(3) P(4)±N(5) P(4)±C(12) O(1)±C(9) O(1)±C(18) O(2)±C(10) O(2)±C(19) O(3)±C(2) N(5)±C(6) N(5)±C(11b) O(4)±P(4)±O(3) O(4)±P(4)±N(5) O(3)±P(4)±N(5) O(4)±P(4)±C(12) O(3)±P(4)±C(12) N(5)±P(4)±C(12) C(9)±O(1)±C(18) C(10)±O(2)±C(19) C(2)±O(3)±P(4) C(6)±N(5)±C(11b) C(6)±N(5)±P(4) C(11b)±N(5)±P(4) O(3)±C(2)±C(1) N(5)±C(6)±C(7) C(8)±C(9)±O(1) O(1)±C(9)±C(10) O(2)±C(10)±C(11) O(2)±C(10)±C(9) N(5)±C(11b)±C(11a) N(5)±C(11b)±C(1)
1.471(2) 1.583(2) 1.640(2) 1.792(3) 1.380(3) 1.415(4) 1.369(3) 1.426(3) 1.453(3) 1.471(3) 1.481(3) 114.54(12) 116.79(13) 104.09(11) 110.73(13) 103.23(12) 106.25(12) 117.2(3) 117.2(2) 120.4(2) 114.0(2) 117.1(2) 126.4(2) 109.5(2) 108.5(3) 126.0(3) 114.5(3) 124.8(2) 116.2(2) 110.5(2) 109.6(2)
Table 5 Selected torsion angles (8) (esd values are given in parentheses) for 8b C(11b)±C(1)±C(2)±O(3) C(1)±C(2)±O(3)±P(4) C(2)±O(3)±P(4)±N(5) O(3)±P(4)±N(5)±C(11b) P(4)±N(5)±C(11b)±C(1) N(5)±C(11b)±C(1)±C(2) C(11b)±N(5)±C(6)±C(7) N(5)±C(6)±C(7)±C(7A) C(6)±C(7)±C(7a)±C(11a) C(7)±C(7a)±C(11b)±C(11b) C(7a)±C(11a)±C(11b)±N(5) C(11a)±C(11b)±N(5)±C(6)
65.7(3) 257.8(3) 33.4(2) 221.8(3) 32.9(3) 252.2(3) 67.9(3) 254.1(3) 21.0(4) 3.5(4) 5.8(4) 241.5(3)
Fig. 2. ORTEP perspective view of 8b showing the labelling system. Thermal ellipsoids are drawn at a probability level of 30%.
ring anellated conformers. It is well known [2±8] that the nitrogen in oxazaphosphorinanes is planar due to the P±N p-bonding. Accordingly, we avoid emphasizing the cis or trans nature of the ring anellation, but use the idealized conformational states described in the literature as the starting-point (Fig. 1). The conformations of the P-containing ring of the title compounds can be deduced mainly from the coupling constants 3J(H,P). The small values of 3 J(H11b,P) indicate that the relevant dihedral angles are close to orthogonal, which rules out B and D. The large vicinal coupling constants between H-2eq and P-4 and the small values of 3J(H2ax,P) point to a predominance of conformer A for 8b and 9b. Intermediate 3J(H2,P) values were observed for 8a, 9a and 10a, which are indicative of conformational equilibrium between conformers A and C (Table 2). The conformation of the isoquinoline moiety does not vary with the con®guration and substituent of the P. NOE interaction was detected between H-11b and H-6ax for each compound. This ®nding, together with the clear diaxial patterns of the coupling constants between H-6 and H-7, reveals a ¯attened twist conformation where C-6 is out of plane.
F. FuÈloÈp et al. / Journal of Molecular Structure 554 (2000) 119±125
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Table 6 Physical and analytical data on compounds 8±10 Compound
8a 8b 9a 9b 10a
Mp (8C)
81±87 172±174 156 oil 157±159
Solvent
EtOAc EtOAc MeOH MeOH
Found (%)
Formula (Mw)
C
H
N
63.46 63.32 47.90 47.88 48.89
6.36 6.28 6.03 6.11 5.57
4.03 3.98 6.57 6.45 4.63
The conformer populations were estimated by applying the well-known formula [10] (Eq. (1)). The references 3 J
H; P 2 Hz for axial protons and 24 Hz for equatorial protons were chosen. N A
%
obs C JH2ax;P 2 JH2ax;P £ 100 A C J2ax;P 2 JH2ax;P
1
obs where N A, the population of conformer A; JH2ax;P 3 C 3 JH2ax;P J
H2ax; P for observed J
H2ax; P; A 3 J
H2ax; P for conformer conformer C and JH2ax;P A. The conformational equilibrium is clearly shifted towards conformer A for diastereomers b where the phenyl and N-bischloroethyl groups are in the equatorial position. For diastereomers a, the 1,3 repulsive interactions are relieved by depopulation of the chair conformer A (Table 3). The extent of population of the twist conformational state C varies with the P substituents as concerns their steric and stereoelectronic properties. In spite of the greater steric demand of the N-bischloroethyl group, conformer A remains more stable structure for 9a, while conformer C is 82% populated for 8a. The interaction between the P±N antibonding orbital and the lone pair of the oxygen has been reported to play an important role in stabilization of the chair conformation [2]. Our ®ndings support the view that the n p ±s interaction must be taken into account in the explanation of the conformer ratio for the model compounds.
3.3. X-ray structure of 8b In the solid state, the asymmetric unit of 8b is formed of an A conformer. Selected bond parameters are presented in Table 4, and the relevant torsion angles in Table 5. A perspective view of molecule 8b is shown in Fig. 2. The X-ray results clearly
C19H22NO4P (359.36) C19H22NO4P (359.36) C17H25Cl2N2O4P (423.28) C17H25Cl2N2O4P (423.28) C13H17ClNO4P (317.71)
Requires (%) C
H
N
63.50 63.50 48.24 48.24 49.15
6.17 6.17 5.95 5.95 5.39
3.90 3.90 6.62 6.62 4.41
support the stereochemical assignments made on the basis of the NMR ®ndings, and provide experimental evidence for the planar arrangement of the bridgehead N. The sum of the bond angles around N-5 in 8b is 357.58. The distance of N-5 from the P(4)±C(11b)± Ê . It can be seen from the Ortep C(6) plane is 0.141(3) A drawing that the methoxy groups are almost coplanar with the benzene ring; C-6 is above, while N-5 is in the opposite position relative to the best plane of the isoquinoline moiety. The oxazaphosphorinane ring has a ¯attened (around N5), chair conformation, oriented trans to the isoquinoline ring. The P(4)±N(5)±C(11b)±C(1) and O(3)±P(4)±N(5)±C(11b) torsion angles are 32.9(3) and 21.8(3)8, respectively. These values indicate the slight ¯attening of the oxazaphosphorinane ring, but, in comparison with the 1-methylsubstituted-1,3,2-oxazaphosphorino[4,3-a]isoquinolines (5.4 and 10.48) [15], unusual distortion is not encountered.
Acknowledgements This work was partly supported by OTKA (TO20454) and MKM-FKFP (0535/1999) grants.
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