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Conformation of oxathiaphospholane and dithiaphospholane rings in the solid state
Journal of
MOLECULAR STRUCTURE ELSEVIER
Journal of Molecular Structure 374 (1996) 85-96
Conformation
of oxathiaphospholane and dithiaphospholane rings in the solid state
Jaroslaw BlaszczykaT*, Michal W. Wieczoreka, Andrzej Okruszekb “Technical University of tddi, Institute of Technical Biochemistry, Stefanowskiego 4110, 90-924 tddi, Poland bPolish Academy of Sciences, Centre of Molecular and Macromolecular Studies, Department of Bioorganic Chemistry, Sienkiewicza 112, 90-363 Lbdi, Poland
Received 1 February 1995; accepted in final form 28 April 1995
Abstract
In this paper, the geometry and conformation of oxathiaphospholane and dithiaphospholane rings in the solid state rings in the are described on the basis of our recent work and compared with literature data. For oxathiaphospholane solid state, both envelope and half-chair conformations, differently distorted, are observed. In oxathiaphospholane rings with the envelope conformation, the endocyclic carbon atom next to the ring oxygen atom is in the flap position. For dithiaphospholane compounds, the heterocyclic rings prefer a half-chair conformation or the conformation intermediate between half-chair and envelope forms; the envelope conformation is observed only in one case.
1. Introduction Oligonucleotides and their structural analogues have recently drawn much interest in the development of a new antiviral and anticancer strategy involving inhibition of “unwanted” genes by the so-called antisense approach [l]. The phosphorothioate and phosphorodithioate analogues of oligonucleotides have drawn considerable attention in this strategy by virtue of their WatsonCrick hybridization properties combined with resistance to degradation by cellular nucleases. The successful application of oxathiaphospholane and dithiaphospholane derivatives as reactive precursors of the sulphur-modified oligonucleotides has raised interest in their molecular geometry and, in particular, in the conformation of heterocyclic rings [2-91. * Corresponding author.
In this paper we describe the geometry and conformation of oxathiaphospholane and dithiaphospholane rings in the solid state and we compare the results of our structural studies’ [6-91 with available literature data [lo- 131. The conclusions regarding the solid-state conformation of the oxathiaphospholane and dithiaphospholane ringcontaining compounds, shown in Figs. 1 and 2, may be readily transferred to nucleoside analogues, ’ In our previous paper [7] containing the results of the X-ray analysis of the &naphthoxy-substituted 2-thio- 1,3,2-oxathiaphospholanes (2 and 3) and 2-thio-1,3,2-dithiaphospholane (7), we forgot to give the details of absorption correction. The omitted data are: 2: min. correction factor 0.8055, max. 0.9982, and av. 0.9187, min. transmission 64.89%, max. 99&l%, and av. 84.40%; 3: min. correction factor 0.9173, max. 0.9980, and av. 0.9748, min. transmission 84.14%, max. 99.60%, and av. 95.03%; 7: min. correction factor 0.7694, max. 0.9984, and av. 0.8967, min. transmission 59.20%, max. 99.68%, and av. 80.40%.
0022-2860/96/%15.000 1996 Elsevier Science B.V. All rights reserved SSDZ 0022-2860(95)08929-2
J. Blaszczyk et al./Journal of Molecular Structure 374 (1996) M-96
86
R1= NH-CH(CHa)-a-naphthyl;
1:
H2i4\)(1
RI= 0-(/II-naphthyl);
R2=R3= H
R’= 0-(f3-naphthyl);
R2=R3= CH3 [7l
Ii
: R1= 0-cholesteryl;
R2--cs
R1= phenyl ; R2 =R3 = H; the exocyclic sulphur atom is replaced by the hetero-
of compounds
1-6, containing
not obtained in crystalline form suitable for X-ray analysis. Knowledge of the molecular structure of compounds l-11 should give better insight into the molecular basis of their reactivity and, in particular, into the mechanism of cleavage of the fivemembered heterocyclic ring accompanying their reaction with nucleophiles [2-41.
2. Geometry and conformation of oxathiaphospholane and dithiaphospholane rings Comparison of bond lengths and valence angles in structures containing an oxathiaphospholane and a dithiaphospholane ring system (Figs. 1 and 7: R=
H2c
PS
1
R2=R3= H
system
191
[lOI
an oxathiaphospholane
ring [6-lo].
2) given in Tables 1 and 2, shows that the differences in bond lengths arise mostly from the unsymmetrical structure of oxathiaphospholane with respect to the dithiaphospholane ring. Analysis of bond lengths and valence angles in compounds containing the oxathiaphospholane ring (Table 1) reveals that, in general, corresponding values do not differ significantly. The only appreciable deviation occurs within the S-C bond and ranges between 4a and 160. Taking into account the valence angles, one can see that the endocyclic angles at sulphur and at phosphorus are smaller than other angles in the heterocyclic ring. This probably reflects the extraordinary strain present in that region of the oxathiaphospholane ring, leading to greater susceptibility of
0-(B-naphthyl)
[71
,%L i ! &~~,~~~Z~
‘2
[81
6:
‘0
H2i
R2=R3= H
R1= O- +NH(CaHJ2;
‘C’ /
I81
S 11:
R= 2,6_dimethylphenoxy, sulphur atom is replaced P
cyclic
‘0 Fig. 2. Formulae
of compounds
7-11,
containing
161
171
5:
cyclic Fig. 1. Formulae
R2=R3= H
1
system
a dithiaphospholane
the exocyclic by the hetero1131 ring [8-9,l
l-131.
87
J. Btaszczyk et al./Journal of Molecular Structure 374 (1996) 85-96 Table 1 Endocyclic
bond lengths
(A) and valence angles (deg) in structures
l-6
containing
an oxathiaphospholane
_
1.598(11) 1.927(4) 2.046(9) 1.613(14) 1.788(18) 1.482(22) 1.511(25) 98.8(6) 85.9(6) 116.6(12) 110.3(12) 104.6(14)
1.924(2) 2.094(2) 1.634(4) 1.859(7) 1.444(8) 1.510(10) 96.9(2) 93.2(2) 114.4(4) 105.7(4) 108.9(S)
1.590(5) 1.890(3) 2.038(4) 1.610(7) 1.850(8) 1.503(17) 1.431(15) 100.0(3) 92.4(3) 111.9(7) 108.1(7) 110.6(10)
a Data for the ring position with a higher occupation factor. b Asymmetric part of the unit cell of 5 contains two independent ’ Exocyclic bond. d No available data.
1.566(6) 1.916(8) 2.052(6) 1.599(13) 1.742(10) 1.482(16) 1.501(12) 95.0(5) 92.9(4) 117.3(9) 114.8(6) 100.4(8)
molecules
the P-S bond to cleavage following nucleophilic attack at the phosphorus atom. The interesting relationship for valence angles in the oxathiaphospholane rings indicates that the endocyclic valence angles at the sulphur atom are always smaller than these at phosphorus. In the structure of 5, the two P=S bonds (in the two independent molecules a and b) are slightly longer than a typical P=S (double) bond and significantly shorter than the respective P-S Table 2 Endocyclic
P-Ob P=Sb PPS
s-c c-c S-P-S P-S-C
s-c-c
bond lengths
(A) and valence angles (deg) in structures
7a [71
8 PI
1.612(11) 1.985(6) 2.046(11) 2.056(11) 1.792(14) 1.790(18) 1.512(19) 102.5(4) 92.1(6) 95.4(7) 110.4(11) 115.8(12)
1.584(5) 1.924(3) 2.083(2) 2.059(3) 1.836(9) 1.806(8) 1.493(12) 99.6(l) 98.1(3) 92.8(3) 111.0(6) 111.2(6)
a Data for the ring position b Exocyclic bond.
6 WI
sb [91
2= [71 P-oc P=S” P-S P-O s-c o-c c-c O-P-S P-S-C P-O-C s-c-c o-c-c
ring system
with a higher occupation
9 Pll
_ 1.91 l(5) 2.051(4) 2.052(5) 1.811(15) 1.833(14) 1.475(19) 100.4(2) 94.1(4) 97.9(5) 111.6(10) 113.7(10) factor.
1.497(7) 1.952(3) 2.081(3) 1.701(8) 1.795(17) 1.424(14) 1.427(18) 98.5(3) 91.3(5) 112.4(7) 111.4(11) 114.4(11)
1.502(7) 1.953(4) 2.122(4) 1.613(6) 1.805(11) 1.420(14) 1.545(15) 96.3(3) 93.2(4) 114.9(6) 105.9(8) 108.7(9)
_ 2.080(2) 1.632(4) 1.773(8) 1.436(7) 1.550(10) :2.8(2) d d d
a and b.
(single) bond. Similarly, the lengths of exocyclic P-O bonds are significantly shorter than those of the typical P-O (single) bond but longer than those of the typical P=O (double) bond. This may be explained in terms of the resonance effect [9]. Further analysis of the data listed in Table 2 reveals a notable relationship between the electronegativity of the exocyclic phosphorus substituent and bond lengths in the dithiaphospholane ring.
containing
a dithiaphospholane 10 [12]
ring system 11 [13]
_ 1.937(2) 2.087(2) 2.087(2) 1.751(11) 1.751(11) 1.460(25) 106.4(l) 99.4(4) 99.4(l) 107.0(8) 107.0(8)
_ 2.162(l) 2.106(l) 1.756(3) 1.824(3) 1.517(5) 94.5(l) 96.4(l) 101.6(2) 110.5(3) 111.6(3)
88 Table 3 Conformation
J. Blaszczyk et aLlJournal of Molecular Structure 374 (1996) 85-96
of oxathiaphospholane 1
rings: torsion
angles (deg) and asymmetry
2
3
parameters 4
5
(67.2%)
(32.8%)
(76.1%)
(23.9%)
(61.6%)
(38.4%)
(Mol. a)
(Mol. b)
Torsion angles (deg) -25.1(4) S-P-O-C P-O-C-C 48.9(6) o-c-c-s -46.6(6) C-C-S-P 26.0(S) C-S-P-O - 1.9(3)
-14.1(13) -16.3(17) 45.8(16) -47.3(11) 32.5(8)
-49.5(20) 17.6(26) 32.6(28) -54.4(23) 48.1(14)
-20.9(8) 43.2(11) -43.3(11) 25.2(7) -2.0(4)
36.8(27) -49.5(32) 35.9(27) -16.0(18) -8.9(11)
-33.8(9) 48.6(10) -40.0(9) 19.7(7) 6.5(6)
5.6(14) 23.1(14) -47.6(10) 49.8(7) -27.0(7)
-8.4(7) 30.4(13) -39.9(14) 27.5(10) -10.1(6)
-25.3(7) 48.8(10) -47.2(10) 26.2(7) -2.6(5)
Asymmetry parameters ACs (P) 56.3(2) ACs (0) 38.2(2) ACs (C) 1.7(2) 36.3(2) ACs (C) 53.5(2) ACs (S) 62.7(2) AC2 (P-O) 24.9(2) AC2 (O-C) 23.1(2) AC2 (C-C) AC2 (C-S) 61.1(2) 76.6(2) AC2 (S-P)
46.8(15) 59.4(15) 48.2(15) 11.5(15) 24.7(15) 74.3(15) 70.6(15) 39.6(15) 9.5(15) 49.8(15)
26.0(20) 61.4(20) 8 1.6(20) 48.9(20) 12.8(20) 65.2(20) 92.9(20) 85.8(20) 48.7(20) 11.2(20)
51.0(10) 35.7(10) 3.0(10) 31.8(10) 48.3(10) 58.0(10) 24.9(10) 18.5(10) 53.9(10) 69.3(10)
50.3(20) 21.1(20) 17.6(20) 43.6(20) 54.3(20) 46.6(20) 5.1(20) 40.1(20) 68.8(20) 7 1.0(20)
52.0(10) 25.9(10) 11.7(10) 41.5(10) 55.4(10) 51.7(10) 10.3(10) 35.1(10) 66.9(10) 73.2(10)
53.7(15) 56.5(15) 42.8(15) 3.2(15) 33.8(15) 77.4(15) 66.1(15) 29.8(15) 19.1(15) 59.0(15)
43.0(9) 38.6(9) 15.1(9) 16.8(9) 36.3(9) 55.6(9) 34.7(9) 2.4(9) 34.6(9) 55.8(9)
56.6(9) 38.9(9) 1.3(9) 35.9(9) 53.9(9) 63.4(9) 25.6(9) 22.7(9) 61.2(9) 77.0(9)
Conformation
Table 4 Conformation
envelope
half-chair
of dithiaphospholane
half-chair
rings: torsion
angles (deg) and asymmetry
I
Torsion angles (deg) S-P-S-C P-S-C-C s-c-c-s C-C-S-P C-S-P-S Asymmetry parameters ACs (P) ACs (S) ACs (C) ACs (C) ACs (S) AC2 (P-S) AC2 (S-C) AC2 (C-C) AC2 (C-S) AC2 (S-P) Conformation
half-chair
envelope
half-chair
envelope
half-chair
envelope
parameters
8
9
10
11
(80.2%)
(19.8%)
-14.4(7) -16.4(13) 47.2(15) -49.0(11) 34.3(7)
-11.1(19) -21.6(30) 56.9(35) -60.3(30) 33.6(16)
-34.3(3) 54.0(6) -51.0(7) 19.0(6) 13.1(3)
-13.9 -15.7 45.0 -48.8 32.8
-18.5 13.7 0.0 -13.7 18.5
-11.2 -18.8 49.4 -52.3 33.0
48.3(15) 61.6(15) 49.8(15) 12.7(15) 25.4(15) 76.9(15) 73.3(15) 41.4(15) 9.2(15) 51.2(15)
60.1(20) 68.0(20) 56.3(20) 8.8(20) 37.5(20) 91.6(20) 82.0(20) 41.8(20) 18.1(20) 65.5(20)
53.8(4) 30.2(4) 11.0(4) 52.6(4) 64.4(4) 57.3(4) 12.5(4) 41.7(4) 77.2(4) 83.3(4)
47.5 58.9 48.9 12.4 24.7 74.7 71.2 40.5 8.7 49.5
0.0 13.5 24.7 24.7 13.5 10.3 26.3 32.6 26.3 10.3
52.6 62.0 49.8 10.2 30.3 80.7 74.0 39.2 12.8 56.3
half-chair
envelope (deform.)
half-chair
half-chair
half-chair
J. Blaszczyk
et aLlJournal of Molecular Structure 374 (1996) 85-96
The most distinct effect could be seen with the length of one of the C-S bonds which, in compound 9, possessing a strongly electronegative chlorine atom, equals 1.833(14) A, but in 10, with an electron-donating phenyl group attached Oto phosphorus, is considerably shorter (1.75 l( 11) A). Similarly, as with compounds containing an oxathiaphospholane ring system, each of the two endocyclic valence angles at the sulphur atoms in dithiaphospholane rings is always smaller than that at phosphorus. Compound 11 does not obey these rules, due to a completely different structure of the exocyclic substituent and its linkage to the phosphorus atom.
2:
Ring
67.2
Torsion angles and asymmetry parameters [14], presented in Table 3, describe in detail the conformation of oxathiaphospholane rings, depicted in Fig. 3. The heterocyclic ring in compound 1 assumes in the solid state an almost ideal envelope conformation with the carbon atom next to endocyclic oxygen in the flap position [6]. The molecular structure of 1 is depicted in Fig. 4. The X-ray analysis of compound 2 revealed that the structure is disordered [7] (Fig. 5a). Fig. Sb shows the two positions of molecule 2 drawn separately for clarity. In the disordered structure of 2, the oxathiaphospholane ring adopts a half-chair
% w
@gZ@ 3:
Ring
76.1
61.6
4:
Ring
5:
Ring A
%
%
Fig. 3. Conformation
w
89
3:
Ring
23.9
%
4:
Ring
38.4
%
5:
Ring
B
of oxathiaphospholane
rings in compounds
Cl
1-5.
J. Blmzczyk et a/./Journal of Molecular Structure 374 (1996) 85-96
90
Fig. 4. Thermal ellipsoidal view of compound 1 with a 50% probability level.
conformation in both positions with a larger and a smaller occupation factor [7]. The X-ray investigation of compound 3 showed that the 4,4_dimethylated analogue of 2 has a different solid-state conformation and its molecule is also disordered (Fig. 6) [7]. In 3, the presence of two methyl groups attached to the endocyclic carbon atom next to endocyclic sulphur, changes the conformation of the oxathiaphospholane ring. The heterocyclic ring in position with the larger occupation factor in the disordered structure of 3 adopts an almost ideal envelope conformation, with the endocyclic carbon atom next to endocyclic oxygen in the flap position, whereas a half-chair conformation is observed for the ring with the smaller occupation factor [7]. X-ray analysis of compound 4 also shows a disordered structure: the endocyclic sulphur and oxygen atoms in the oxathiaphospholane ring
a)
b)
Fig. 5. Disordered structure of 2: (a) general view; (b) two positions of the molecule drawn separately. The bonding of atom positions with a smaIler occupation factor (32.8%) is depicted with open lines.
91
J. Blaszczyk et al./Journal of Molecular Structure 374 (1996) 85-96
Fig. 6. Disordered structure of 3: (a) general view; (b) two positions of the molecule with a smaller occupation factor (23.9%) is depicted with open lines.
and one of the carbon atoms in the terminal cholesteryl side chain are disordered (Fig. 7) [S]. The conformation of the disordered oxathiaphospholane ring was found to be half-chair with the exception of the less occupied position, where a deformed envelope conformation was observed [8]. The X-ray analysis of compound 5 revealed that an asymmetric part of the unit cell of 5 contains two independent pairs (a and b) of the
drawn separately.
The bonding
of atom positions
oxathiaphospholane anions and the dicyclohexylammonium cations (Fig. 8) [9]. The solid-state conformation of the two oxathiaphospholane rings a and b is significantly different: the fivemembered ring a adopts the half-chair conformation, whereas ring b forms an almost ideal envelope. Similarly, as for compounds 1 and 3, in ring b the endocyclic carbon atom next to the endocyclic oxygen occupies the flap position [9]. Unfortunately, the available crystal-structure data
J. Biaszczyk et al/Journal of Molecular Structure 374 (1996) 85-96
92
a)
Fig. 7. Disordered structure of 4: (a) general view; (b) two positions of the molecule drawn separately. The bonding of atom positions with a smaller occupation factor (38.4%) is depicted with open lines.
on studies of compound 6 do not contain any information about the solid-state conformation of its oxathiaphospholane ring (no atomic coordinates were given) [IO, 151. Torsion angles and asymmetry parameters, describing the conformation of dithiaphospholane rings in compounds 7-11 in the solid state, are presented in Table 4. The conformation of these rings is depicted in Fig. 9. The X-ray analysis of the dithiaphospholane
analogue of 2 (compound 7) showed similar disorder in the solid state to that in 2 [7]. The conformation of the dithiaphospholane ring in the disordered structure 7 was found to be a half-chair, except for the less occupied position, where an envelope conformation was observed [7]. The molecular structure of 7 is depicted in Fig. 10. In both dithiaphospholane and oxathiaphospholane derivatives of cholesterol (compounds 8 and
J. Btaszczyk et al./Journal of Molecular Structure 374 (1996) 85-96
Fig. 8. Asymmetric part of the unit cell of 5, consisting of two pairs (a and b) of oxathiaphospholane hexylammonium cations.
PI
h
Cl
51
53
Cl
C2'
C2
-
7: Ring 80.2 %
b
PI'
51'
53’
L’
‘I
7: Ring 19.8 %
8
Fig. 9. Conformation of dithiaphospholane
rings in compounds 7-11.
93
anions and dicyclo-
94
J. Btaszczyk et al./Journal of Molecular Structure 374 (1996) 85-96
a)
Fig. 10. Disordered structure of 7: (a) general view; (b) two positions of the molecule drawn separately. with a smaller occupation factor (19.8%) is depicted with open lines.
4) the solid-state conformation of the cholesteryl moiety is almost identical. Similarly, as in 4, in the solid-state structure of 8 the disorder of the same carbon atom in the terminal cholesteryl side chain is observed (Fig. 11). The dithiaphospholane ring in compound 8 adopts a conformation intermediate between half-chair and envelope form [8]. The same conformation has also been observed for compound 11, described by others [13]. The dithiaphospholane ring in compound 9 adopts the half-chair conformation. The ideal envelope conformation of the dithiaphospholane ring was observed only for the symmetrical molecule 10 [12].
The bonding
of atom positions
In summary, inspection of the torsion angles and asymmetry parameters of oxathiaphospholane and dithiaphospholane rings, given in Tables 3 and 4, allows one to conclude that for compounds l-6 both envelope and half-chair conformations of oxathiaphospholane rings occur in the solid state. The conformations are differently distorted, depending on the substituents of the oxathiaphospholane ring. Of the published structures of compounds containing a dithiaphospholane ring (7- 1l), only in one case (10) was the ring found to adopt an envelope conformation. In the remaining four dithiaphospholane compounds, the ring adopts the more-or-less distorted half-chair conformation.
J. Blaszczyk et al./Journal of Molecular Structure 374 (1996) 8.5-96
95
a)
b)
Fig. 11. Disordered structure of 8: (a) general view; (b) two positions of the molecule drawn separately. The bonding of the disordered carbon atom at the end of the cholesteryl side chain, in the position with a smaller occupation factor (33.0%) is depicted with
References [l] J.H. Milligan, M.D. Matteucci and J.C. Martin, J.Med. Chem., 36 (1993) 1923. [2] W.J. Stec, A. Grajkowski, M. Kozioikiewicz and B. Uznanski, Nucleic Acids Res., 19 (1991) 5883. [3] A. Suska, A. Grajkowski, A. Wilk, B. Uznanski, J. Biaszczyk, M. Wieczorek and W.J. Stec, Pure Appl. Chem., 65 (1993) 707. [4] A. Okruszek, A. Sierzchala, M. Sochacki and W.J. Stec, Tetrahedron Lett., 33 (1992) 7585.
[5] A. Okruszek, A. Sierzchafa and W.J. Stec, Angew. Chem., submitted. [6] B. Uznanski, A. Grajkowski, B. Krzyzanowska, A. Kaimierkowska, W.J. Stec, M.W. Wieczorek and J. Blaszczyk, J. Am. Chem. Sot., 114 (1992) 10197. [7] J. Biaszczyk, M.W. Wieczorek, A. Okruszek, M. Olesiak and B. Karwowski, Heteroatom Chem., 5 (1994) 519. [8] J. Bkaszczyk, M.W. Wieczorek, A. Okruszek, A. Sierzchaia, A. Kobylanska and W.J. Stec, J. Chem. Crystallogr., in press. [9] B. Krzyianowska, W.J. Stec, M.W. Wieczorek and J. Biaszczyk, Heteroatom Chem., 5 (1994) 533.
96
J. Blaszczyk et al./Journal of Molecular Structure 374 (1996) 85-96
[IO] E. Duff, D.R. Russell and S. Trippett, Phosphorus, 4 (1974) 203. [l l] J.D. Lee and G.W. Goodacre, Acta Crystallogr., Sect. B, 27 (1971) 1055. [12] J.D. Lee and G.W. Goodacre, Acta Crystallogr., Sect. B, 27 (1971) 1841. [13] J. Hans, R.O. Day, L. Howe and R.R. Holmes, Inorg. Chem., 30 (1991) 3132.
[14] C. Altona, H.J. Geise and C. Romers, Tetrahedron, 24 (1968) 13. [15] Cambridge Structural Database, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 lEZ, UK, 1993.
MOLECULAR STRUCTURE ELSEVIER
Journal of Molecular Structure 374 (1996) 85-96
Conformation
of oxathiaphospholane and dithiaphospholane rings in the solid state
Jaroslaw BlaszczykaT*, Michal W. Wieczoreka, Andrzej Okruszekb “Technical University of tddi, Institute of Technical Biochemistry, Stefanowskiego 4110, 90-924 tddi, Poland bPolish Academy of Sciences, Centre of Molecular and Macromolecular Studies, Department of Bioorganic Chemistry, Sienkiewicza 112, 90-363 Lbdi, Poland
Received 1 February 1995; accepted in final form 28 April 1995
Abstract
In this paper, the geometry and conformation of oxathiaphospholane and dithiaphospholane rings in the solid state rings in the are described on the basis of our recent work and compared with literature data. For oxathiaphospholane solid state, both envelope and half-chair conformations, differently distorted, are observed. In oxathiaphospholane rings with the envelope conformation, the endocyclic carbon atom next to the ring oxygen atom is in the flap position. For dithiaphospholane compounds, the heterocyclic rings prefer a half-chair conformation or the conformation intermediate between half-chair and envelope forms; the envelope conformation is observed only in one case.
1. Introduction Oligonucleotides and their structural analogues have recently drawn much interest in the development of a new antiviral and anticancer strategy involving inhibition of “unwanted” genes by the so-called antisense approach [l]. The phosphorothioate and phosphorodithioate analogues of oligonucleotides have drawn considerable attention in this strategy by virtue of their WatsonCrick hybridization properties combined with resistance to degradation by cellular nucleases. The successful application of oxathiaphospholane and dithiaphospholane derivatives as reactive precursors of the sulphur-modified oligonucleotides has raised interest in their molecular geometry and, in particular, in the conformation of heterocyclic rings [2-91. * Corresponding author.
In this paper we describe the geometry and conformation of oxathiaphospholane and dithiaphospholane rings in the solid state and we compare the results of our structural studies’ [6-91 with available literature data [lo- 131. The conclusions regarding the solid-state conformation of the oxathiaphospholane and dithiaphospholane ringcontaining compounds, shown in Figs. 1 and 2, may be readily transferred to nucleoside analogues, ’ In our previous paper [7] containing the results of the X-ray analysis of the &naphthoxy-substituted 2-thio- 1,3,2-oxathiaphospholanes (2 and 3) and 2-thio-1,3,2-dithiaphospholane (7), we forgot to give the details of absorption correction. The omitted data are: 2: min. correction factor 0.8055, max. 0.9982, and av. 0.9187, min. transmission 64.89%, max. 99&l%, and av. 84.40%; 3: min. correction factor 0.9173, max. 0.9980, and av. 0.9748, min. transmission 84.14%, max. 99.60%, and av. 95.03%; 7: min. correction factor 0.7694, max. 0.9984, and av. 0.8967, min. transmission 59.20%, max. 99.68%, and av. 80.40%.
0022-2860/96/%15.000 1996 Elsevier Science B.V. All rights reserved SSDZ 0022-2860(95)08929-2
J. Blaszczyk et al./Journal of Molecular Structure 374 (1996) M-96
86
R1= NH-CH(CHa)-a-naphthyl;
1:
H2i4\)(1
RI= 0-(/II-naphthyl);
R2=R3= H
R’= 0-(f3-naphthyl);
R2=R3= CH3 [7l
Ii
: R1= 0-cholesteryl;
R2--cs
R1= phenyl ; R2 =R3 = H; the exocyclic sulphur atom is replaced by the hetero-
of compounds
1-6, containing
not obtained in crystalline form suitable for X-ray analysis. Knowledge of the molecular structure of compounds l-11 should give better insight into the molecular basis of their reactivity and, in particular, into the mechanism of cleavage of the fivemembered heterocyclic ring accompanying their reaction with nucleophiles [2-41.
2. Geometry and conformation of oxathiaphospholane and dithiaphospholane rings Comparison of bond lengths and valence angles in structures containing an oxathiaphospholane and a dithiaphospholane ring system (Figs. 1 and 7: R=
H2c
PS
1
R2=R3= H
system
191
[lOI
an oxathiaphospholane
ring [6-lo].
2) given in Tables 1 and 2, shows that the differences in bond lengths arise mostly from the unsymmetrical structure of oxathiaphospholane with respect to the dithiaphospholane ring. Analysis of bond lengths and valence angles in compounds containing the oxathiaphospholane ring (Table 1) reveals that, in general, corresponding values do not differ significantly. The only appreciable deviation occurs within the S-C bond and ranges between 4a and 160. Taking into account the valence angles, one can see that the endocyclic angles at sulphur and at phosphorus are smaller than other angles in the heterocyclic ring. This probably reflects the extraordinary strain present in that region of the oxathiaphospholane ring, leading to greater susceptibility of
0-(B-naphthyl)
[71
,%L i ! &~~,~~~Z~
‘2
[81
6:
‘0
H2i
R2=R3= H
R1= O- +NH(CaHJ2;
‘C’ /
I81
S 11:
R= 2,6_dimethylphenoxy, sulphur atom is replaced P
cyclic
‘0 Fig. 2. Formulae
of compounds
7-11,
containing
161
171
5:
cyclic Fig. 1. Formulae
R2=R3= H
1
system
a dithiaphospholane
the exocyclic by the hetero1131 ring [8-9,l
l-131.
87
J. Btaszczyk et al./Journal of Molecular Structure 374 (1996) 85-96 Table 1 Endocyclic
bond lengths
(A) and valence angles (deg) in structures
l-6
containing
an oxathiaphospholane
_
1.598(11) 1.927(4) 2.046(9) 1.613(14) 1.788(18) 1.482(22) 1.511(25) 98.8(6) 85.9(6) 116.6(12) 110.3(12) 104.6(14)
1.924(2) 2.094(2) 1.634(4) 1.859(7) 1.444(8) 1.510(10) 96.9(2) 93.2(2) 114.4(4) 105.7(4) 108.9(S)
1.590(5) 1.890(3) 2.038(4) 1.610(7) 1.850(8) 1.503(17) 1.431(15) 100.0(3) 92.4(3) 111.9(7) 108.1(7) 110.6(10)
a Data for the ring position with a higher occupation factor. b Asymmetric part of the unit cell of 5 contains two independent ’ Exocyclic bond. d No available data.
1.566(6) 1.916(8) 2.052(6) 1.599(13) 1.742(10) 1.482(16) 1.501(12) 95.0(5) 92.9(4) 117.3(9) 114.8(6) 100.4(8)
molecules
the P-S bond to cleavage following nucleophilic attack at the phosphorus atom. The interesting relationship for valence angles in the oxathiaphospholane rings indicates that the endocyclic valence angles at the sulphur atom are always smaller than these at phosphorus. In the structure of 5, the two P=S bonds (in the two independent molecules a and b) are slightly longer than a typical P=S (double) bond and significantly shorter than the respective P-S Table 2 Endocyclic
P-Ob P=Sb PPS
s-c c-c S-P-S P-S-C
s-c-c
bond lengths
(A) and valence angles (deg) in structures
7a [71
8 PI
1.612(11) 1.985(6) 2.046(11) 2.056(11) 1.792(14) 1.790(18) 1.512(19) 102.5(4) 92.1(6) 95.4(7) 110.4(11) 115.8(12)
1.584(5) 1.924(3) 2.083(2) 2.059(3) 1.836(9) 1.806(8) 1.493(12) 99.6(l) 98.1(3) 92.8(3) 111.0(6) 111.2(6)
a Data for the ring position b Exocyclic bond.
6 WI
sb [91
2= [71 P-oc P=S” P-S P-O s-c o-c c-c O-P-S P-S-C P-O-C s-c-c o-c-c
ring system
with a higher occupation
9 Pll
_ 1.91 l(5) 2.051(4) 2.052(5) 1.811(15) 1.833(14) 1.475(19) 100.4(2) 94.1(4) 97.9(5) 111.6(10) 113.7(10) factor.
1.497(7) 1.952(3) 2.081(3) 1.701(8) 1.795(17) 1.424(14) 1.427(18) 98.5(3) 91.3(5) 112.4(7) 111.4(11) 114.4(11)
1.502(7) 1.953(4) 2.122(4) 1.613(6) 1.805(11) 1.420(14) 1.545(15) 96.3(3) 93.2(4) 114.9(6) 105.9(8) 108.7(9)
_ 2.080(2) 1.632(4) 1.773(8) 1.436(7) 1.550(10) :2.8(2) d d d
a and b.
(single) bond. Similarly, the lengths of exocyclic P-O bonds are significantly shorter than those of the typical P-O (single) bond but longer than those of the typical P=O (double) bond. This may be explained in terms of the resonance effect [9]. Further analysis of the data listed in Table 2 reveals a notable relationship between the electronegativity of the exocyclic phosphorus substituent and bond lengths in the dithiaphospholane ring.
containing
a dithiaphospholane 10 [12]
ring system 11 [13]
_ 1.937(2) 2.087(2) 2.087(2) 1.751(11) 1.751(11) 1.460(25) 106.4(l) 99.4(4) 99.4(l) 107.0(8) 107.0(8)
_ 2.162(l) 2.106(l) 1.756(3) 1.824(3) 1.517(5) 94.5(l) 96.4(l) 101.6(2) 110.5(3) 111.6(3)
88 Table 3 Conformation
J. Blaszczyk et aLlJournal of Molecular Structure 374 (1996) 85-96
of oxathiaphospholane 1
rings: torsion
angles (deg) and asymmetry
2
3
parameters 4
5
(67.2%)
(32.8%)
(76.1%)
(23.9%)
(61.6%)
(38.4%)
(Mol. a)
(Mol. b)
Torsion angles (deg) -25.1(4) S-P-O-C P-O-C-C 48.9(6) o-c-c-s -46.6(6) C-C-S-P 26.0(S) C-S-P-O - 1.9(3)
-14.1(13) -16.3(17) 45.8(16) -47.3(11) 32.5(8)
-49.5(20) 17.6(26) 32.6(28) -54.4(23) 48.1(14)
-20.9(8) 43.2(11) -43.3(11) 25.2(7) -2.0(4)
36.8(27) -49.5(32) 35.9(27) -16.0(18) -8.9(11)
-33.8(9) 48.6(10) -40.0(9) 19.7(7) 6.5(6)
5.6(14) 23.1(14) -47.6(10) 49.8(7) -27.0(7)
-8.4(7) 30.4(13) -39.9(14) 27.5(10) -10.1(6)
-25.3(7) 48.8(10) -47.2(10) 26.2(7) -2.6(5)
Asymmetry parameters ACs (P) 56.3(2) ACs (0) 38.2(2) ACs (C) 1.7(2) 36.3(2) ACs (C) 53.5(2) ACs (S) 62.7(2) AC2 (P-O) 24.9(2) AC2 (O-C) 23.1(2) AC2 (C-C) AC2 (C-S) 61.1(2) 76.6(2) AC2 (S-P)
46.8(15) 59.4(15) 48.2(15) 11.5(15) 24.7(15) 74.3(15) 70.6(15) 39.6(15) 9.5(15) 49.8(15)
26.0(20) 61.4(20) 8 1.6(20) 48.9(20) 12.8(20) 65.2(20) 92.9(20) 85.8(20) 48.7(20) 11.2(20)
51.0(10) 35.7(10) 3.0(10) 31.8(10) 48.3(10) 58.0(10) 24.9(10) 18.5(10) 53.9(10) 69.3(10)
50.3(20) 21.1(20) 17.6(20) 43.6(20) 54.3(20) 46.6(20) 5.1(20) 40.1(20) 68.8(20) 7 1.0(20)
52.0(10) 25.9(10) 11.7(10) 41.5(10) 55.4(10) 51.7(10) 10.3(10) 35.1(10) 66.9(10) 73.2(10)
53.7(15) 56.5(15) 42.8(15) 3.2(15) 33.8(15) 77.4(15) 66.1(15) 29.8(15) 19.1(15) 59.0(15)
43.0(9) 38.6(9) 15.1(9) 16.8(9) 36.3(9) 55.6(9) 34.7(9) 2.4(9) 34.6(9) 55.8(9)
56.6(9) 38.9(9) 1.3(9) 35.9(9) 53.9(9) 63.4(9) 25.6(9) 22.7(9) 61.2(9) 77.0(9)
Conformation
Table 4 Conformation
envelope
half-chair
of dithiaphospholane
half-chair
rings: torsion
angles (deg) and asymmetry
I
Torsion angles (deg) S-P-S-C P-S-C-C s-c-c-s C-C-S-P C-S-P-S Asymmetry parameters ACs (P) ACs (S) ACs (C) ACs (C) ACs (S) AC2 (P-S) AC2 (S-C) AC2 (C-C) AC2 (C-S) AC2 (S-P) Conformation
half-chair
envelope
half-chair
envelope
half-chair
envelope
parameters
8
9
10
11
(80.2%)
(19.8%)
-14.4(7) -16.4(13) 47.2(15) -49.0(11) 34.3(7)
-11.1(19) -21.6(30) 56.9(35) -60.3(30) 33.6(16)
-34.3(3) 54.0(6) -51.0(7) 19.0(6) 13.1(3)
-13.9 -15.7 45.0 -48.8 32.8
-18.5 13.7 0.0 -13.7 18.5
-11.2 -18.8 49.4 -52.3 33.0
48.3(15) 61.6(15) 49.8(15) 12.7(15) 25.4(15) 76.9(15) 73.3(15) 41.4(15) 9.2(15) 51.2(15)
60.1(20) 68.0(20) 56.3(20) 8.8(20) 37.5(20) 91.6(20) 82.0(20) 41.8(20) 18.1(20) 65.5(20)
53.8(4) 30.2(4) 11.0(4) 52.6(4) 64.4(4) 57.3(4) 12.5(4) 41.7(4) 77.2(4) 83.3(4)
47.5 58.9 48.9 12.4 24.7 74.7 71.2 40.5 8.7 49.5
0.0 13.5 24.7 24.7 13.5 10.3 26.3 32.6 26.3 10.3
52.6 62.0 49.8 10.2 30.3 80.7 74.0 39.2 12.8 56.3
half-chair
envelope (deform.)
half-chair
half-chair
half-chair
J. Blaszczyk
et aLlJournal of Molecular Structure 374 (1996) 85-96
The most distinct effect could be seen with the length of one of the C-S bonds which, in compound 9, possessing a strongly electronegative chlorine atom, equals 1.833(14) A, but in 10, with an electron-donating phenyl group attached Oto phosphorus, is considerably shorter (1.75 l( 11) A). Similarly, as with compounds containing an oxathiaphospholane ring system, each of the two endocyclic valence angles at the sulphur atoms in dithiaphospholane rings is always smaller than that at phosphorus. Compound 11 does not obey these rules, due to a completely different structure of the exocyclic substituent and its linkage to the phosphorus atom.
2:
Ring
67.2
Torsion angles and asymmetry parameters [14], presented in Table 3, describe in detail the conformation of oxathiaphospholane rings, depicted in Fig. 3. The heterocyclic ring in compound 1 assumes in the solid state an almost ideal envelope conformation with the carbon atom next to endocyclic oxygen in the flap position [6]. The molecular structure of 1 is depicted in Fig. 4. The X-ray analysis of compound 2 revealed that the structure is disordered [7] (Fig. 5a). Fig. Sb shows the two positions of molecule 2 drawn separately for clarity. In the disordered structure of 2, the oxathiaphospholane ring adopts a half-chair
% w
@gZ@ 3:
Ring
76.1
61.6
4:
Ring
5:
Ring A
%
%
Fig. 3. Conformation
w
89
3:
Ring
23.9
%
4:
Ring
38.4
%
5:
Ring
B
of oxathiaphospholane
rings in compounds
Cl
1-5.
J. Blmzczyk et a/./Journal of Molecular Structure 374 (1996) 85-96
90
Fig. 4. Thermal ellipsoidal view of compound 1 with a 50% probability level.
conformation in both positions with a larger and a smaller occupation factor [7]. The X-ray investigation of compound 3 showed that the 4,4_dimethylated analogue of 2 has a different solid-state conformation and its molecule is also disordered (Fig. 6) [7]. In 3, the presence of two methyl groups attached to the endocyclic carbon atom next to endocyclic sulphur, changes the conformation of the oxathiaphospholane ring. The heterocyclic ring in position with the larger occupation factor in the disordered structure of 3 adopts an almost ideal envelope conformation, with the endocyclic carbon atom next to endocyclic oxygen in the flap position, whereas a half-chair conformation is observed for the ring with the smaller occupation factor [7]. X-ray analysis of compound 4 also shows a disordered structure: the endocyclic sulphur and oxygen atoms in the oxathiaphospholane ring
a)
b)
Fig. 5. Disordered structure of 2: (a) general view; (b) two positions of the molecule drawn separately. The bonding of atom positions with a smaIler occupation factor (32.8%) is depicted with open lines.
91
J. Blaszczyk et al./Journal of Molecular Structure 374 (1996) 85-96
Fig. 6. Disordered structure of 3: (a) general view; (b) two positions of the molecule with a smaller occupation factor (23.9%) is depicted with open lines.
and one of the carbon atoms in the terminal cholesteryl side chain are disordered (Fig. 7) [S]. The conformation of the disordered oxathiaphospholane ring was found to be half-chair with the exception of the less occupied position, where a deformed envelope conformation was observed [8]. The X-ray analysis of compound 5 revealed that an asymmetric part of the unit cell of 5 contains two independent pairs (a and b) of the
drawn separately.
The bonding
of atom positions
oxathiaphospholane anions and the dicyclohexylammonium cations (Fig. 8) [9]. The solid-state conformation of the two oxathiaphospholane rings a and b is significantly different: the fivemembered ring a adopts the half-chair conformation, whereas ring b forms an almost ideal envelope. Similarly, as for compounds 1 and 3, in ring b the endocyclic carbon atom next to the endocyclic oxygen occupies the flap position [9]. Unfortunately, the available crystal-structure data
J. Biaszczyk et al/Journal of Molecular Structure 374 (1996) 85-96
92
a)
Fig. 7. Disordered structure of 4: (a) general view; (b) two positions of the molecule drawn separately. The bonding of atom positions with a smaller occupation factor (38.4%) is depicted with open lines.
on studies of compound 6 do not contain any information about the solid-state conformation of its oxathiaphospholane ring (no atomic coordinates were given) [IO, 151. Torsion angles and asymmetry parameters, describing the conformation of dithiaphospholane rings in compounds 7-11 in the solid state, are presented in Table 4. The conformation of these rings is depicted in Fig. 9. The X-ray analysis of the dithiaphospholane
analogue of 2 (compound 7) showed similar disorder in the solid state to that in 2 [7]. The conformation of the dithiaphospholane ring in the disordered structure 7 was found to be a half-chair, except for the less occupied position, where an envelope conformation was observed [7]. The molecular structure of 7 is depicted in Fig. 10. In both dithiaphospholane and oxathiaphospholane derivatives of cholesterol (compounds 8 and
J. Btaszczyk et al./Journal of Molecular Structure 374 (1996) 85-96
Fig. 8. Asymmetric part of the unit cell of 5, consisting of two pairs (a and b) of oxathiaphospholane hexylammonium cations.
PI
h
Cl
51
53
Cl
C2'
C2
-
7: Ring 80.2 %
b
PI'
51'
53’
L’
‘I
7: Ring 19.8 %
8
Fig. 9. Conformation of dithiaphospholane
rings in compounds 7-11.
93
anions and dicyclo-
94
J. Btaszczyk et al./Journal of Molecular Structure 374 (1996) 85-96
a)
Fig. 10. Disordered structure of 7: (a) general view; (b) two positions of the molecule drawn separately. with a smaller occupation factor (19.8%) is depicted with open lines.
4) the solid-state conformation of the cholesteryl moiety is almost identical. Similarly, as in 4, in the solid-state structure of 8 the disorder of the same carbon atom in the terminal cholesteryl side chain is observed (Fig. 11). The dithiaphospholane ring in compound 8 adopts a conformation intermediate between half-chair and envelope form [8]. The same conformation has also been observed for compound 11, described by others [13]. The dithiaphospholane ring in compound 9 adopts the half-chair conformation. The ideal envelope conformation of the dithiaphospholane ring was observed only for the symmetrical molecule 10 [12].
The bonding
of atom positions
In summary, inspection of the torsion angles and asymmetry parameters of oxathiaphospholane and dithiaphospholane rings, given in Tables 3 and 4, allows one to conclude that for compounds l-6 both envelope and half-chair conformations of oxathiaphospholane rings occur in the solid state. The conformations are differently distorted, depending on the substituents of the oxathiaphospholane ring. Of the published structures of compounds containing a dithiaphospholane ring (7- 1l), only in one case (10) was the ring found to adopt an envelope conformation. In the remaining four dithiaphospholane compounds, the ring adopts the more-or-less distorted half-chair conformation.
J. Blaszczyk et al./Journal of Molecular Structure 374 (1996) 8.5-96
95
a)
b)
Fig. 11. Disordered structure of 8: (a) general view; (b) two positions of the molecule drawn separately. The bonding of the disordered carbon atom at the end of the cholesteryl side chain, in the position with a smaller occupation factor (33.0%) is depicted with
References [l] J.H. Milligan, M.D. Matteucci and J.C. Martin, J.Med. Chem., 36 (1993) 1923. [2] W.J. Stec, A. Grajkowski, M. Kozioikiewicz and B. Uznanski, Nucleic Acids Res., 19 (1991) 5883. [3] A. Suska, A. Grajkowski, A. Wilk, B. Uznanski, J. Biaszczyk, M. Wieczorek and W.J. Stec, Pure Appl. Chem., 65 (1993) 707. [4] A. Okruszek, A. Sierzchala, M. Sochacki and W.J. Stec, Tetrahedron Lett., 33 (1992) 7585.
[5] A. Okruszek, A. Sierzchafa and W.J. Stec, Angew. Chem., submitted. [6] B. Uznanski, A. Grajkowski, B. Krzyzanowska, A. Kaimierkowska, W.J. Stec, M.W. Wieczorek and J. Blaszczyk, J. Am. Chem. Sot., 114 (1992) 10197. [7] J. Biaszczyk, M.W. Wieczorek, A. Okruszek, M. Olesiak and B. Karwowski, Heteroatom Chem., 5 (1994) 519. [8] J. Bkaszczyk, M.W. Wieczorek, A. Okruszek, A. Sierzchaia, A. Kobylanska and W.J. Stec, J. Chem. Crystallogr., in press. [9] B. Krzyianowska, W.J. Stec, M.W. Wieczorek and J. Biaszczyk, Heteroatom Chem., 5 (1994) 533.
96
J. Blaszczyk et al./Journal of Molecular Structure 374 (1996) 85-96
[IO] E. Duff, D.R. Russell and S. Trippett, Phosphorus, 4 (1974) 203. [l l] J.D. Lee and G.W. Goodacre, Acta Crystallogr., Sect. B, 27 (1971) 1055. [12] J.D. Lee and G.W. Goodacre, Acta Crystallogr., Sect. B, 27 (1971) 1841. [13] J. Hans, R.O. Day, L. Howe and R.R. Holmes, Inorg. Chem., 30 (1991) 3132.
[14] C. Altona, H.J. Geise and C. Romers, Tetrahedron, 24 (1968) 13. [15] Cambridge Structural Database, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 lEZ, UK, 1993.