Short communication
Synthesis of 17p-Hydroxy Steroidal Oxalate Dimers from Naturally Occurring Steroids
Lutfun Nahara *, Satyajit D. Sarkerb and Alan B. Turnera
a Japp Laboratory, Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, Scotland, UK
b School of Biomedical Sciences, University of Ulster at Coleraine, Cromore Road, Coleraine BT52 ISA,
Co. Londonderry, Northern Ireland, UK
* Corresponding author: Tutu Villa, 3 Glenkeen Hollow, Coleraine BT51 4EN, N. Ireland, UK. E-mails: l.nahar@ulster.ac.uk; lnahar2003@yahoo.co.uk
Received: 01-08-2006
Abstract
Three new symmetrical steroidal oxalate dimers (2, 4 and 6) were synthesised from naturally occurring 17P-hydroxyste-roids, namely, testosterone (1), 5a-androst-2-en-17P-ol (3) and 3-oxo-5a-androstan-17P-ol (5), using oxalyl chloride in the presence of pyridine.
Keywords: Steroid, oxalyl chloride, esterification, oxalate dimers, NMR.
1. Introduction
Steroid-based dimers are an important group of biologically active organic molecules. They were initially isolated as synthetic by-products1'2 and are also found in nature.3'4 Dimeric steroids exhibit micellar, detergent, and liquid crystal behaviour5 and are pharmaceutical^ important6. They have been utilised as catalysts for certain organic reactions7 and can be used to develop new pharmacologically active steroids.6 As part of our on going studies on the synthesis of steroidal di-mers and monomers,810 we now report here the synthesis of three new steroidal dimers which contain an oxalate ester linkage between the C-17 positions of two molecules.
2. Results and Discussion
Three symmetrical steroidal 17p-oxalate dimers (2, 4 and 6) were synthesised from their respective alcohols using oxalyl chloride in presence of pyridine as a base. Generally, oxalyl chloride with pyridine gives esters of oxalic acid with various types of alcohols.11 Because of the presence of secondary alcohol functionality at C-17, testosterone (1) which is a natural steroid hormone, was an ideal starting material for the synthesis of a ring D-ring
D dimer via oxalic acid spacer. The treatment of 1 with oxalyl chloride in presence of pyridine for 18 h resulted in the synthesis of bis (androst-5-en-3-on)-17p-yl oxalate (2) in a yield of 51% (Scheme 1). The IR absorption bands at 1763 and 1741 cm1 were for the oxalate carbonyls, and that at 1712 cm-1 was for the ketone carbonyl functionality at C-3. In the 1H NMR spectrum, the signal for the oxymethine proton at C-17 and C-17' showed a deshiel-ded triplet at 5 4.68 as opposed to 5 3.66 of the starting material. The 13C chemical shift of C-17 and C-17' oxy-methine carbons (Table 1) was also deshielded further (5 85.1 as opposed to 5 81.6 of 1) as a result of the oxalate ester formation at C-17 and C-17'. The presence of oxalate functionality was confirmed further from a 1H-13C long-range (3J) correlation from the oxymethine protons (5h 4.68) to the oxalate carbonyls (5C 158.1) observed in the HMBC spectrum.
The IR spectra of oxalate dimers 4 and 6 showed two characteristic absorption bands, similar to those observed in case of 2, in the region of 1768-1738 cm-1. The 1H and 13C NMR spectra of these dimers demonstrated signals similar to those of respective starting materials (1, 3 and 5) with the exception that significant downfield shifts of the signals for the protons and carbons adjacent to the oxalate group were observed. The 13C NMR spectra (Table 1) displayed a signal at 5 157.6 or 158.1 characteristics for the oxalate carbonyls.
Scheme 1
a yield of 47% (Scheme 2). In the 1H NMR spectrum of 4, the signal for the oxymethine proton at C-17 and C-17' showed a deshielded triplet at 5 4.67 as opposed to 5 3.71 of the starting material. The 13C chemical shift of C-17 and C-17' oxymethine carbons (Table 1) was also deshielded further (5 85.3 as opposed to 5 81.8 of 3) as a result of the oxalate ester formation at C-17 and C-17'. The presence of oxalate functionality was confirmed further from a :H-13C long-range (3J) correlation from the oxymethine protons (5 4.67) to the oxalate carbonyls (5 157.6) observed in the HMBC spectrum (Figure 1).
Another oxalate dimer, bis (5a-androst-2-en)-17p-yl oxalate (6), connected by ring D-ring D via oxalic acid spacer, was synthesised from another androgen derivative, 5a-androst-2-en-17p-ol (5) in a yield of 54% (Scheme 3).
3. Experimental
The steroid starting materials [testosterone (1), 5a-androst-2-en-17p-ol (3) and 3-oxo-5a-androstan-17p-ol (5)] and oxalyl chloride were purchased from Aldrich and
Similar reaction protocol was adopted to synthesise a ring D-ring D dimer via an oxalic acid spacer. A 5a-te-stosterone derivative, 3-oxo-5a-androstan-17ß-ol (3) was treated with oxalyl chloride in presence of pyridine for 18h to yield bis (5a-androstan-3-on)-17ß-yl oxalate (4) in
Table 1: 13C NMR (CDCl3, 100 MHz) data of dimers 2, 4 and 6
Carbon no.	Chemical shifts (8) in ppm
	2	4	6
1 and 1'	35.7	38.5	39.6
2 and 2'	33.9	38.1	125.6
3 and 3'	199.4	211.7	125.6
4 and 4'	124.0	44.6	30.1
5 and 5'	170.7	46.6	41.3
6 and 6'	32.7	28.7	28.4
7 and 7'	31.4	31.2	31.2
8 and 8'	35.3	35.2	35.2
9 and 9'	53.9	53.6	53.8
10 and 10'	38.6	35.7	34.5
11 and 11'	20.5	20.9	20.2
12 and 12'	36.5	36.7	36.7
13 and 13'	42.3	43.0	42.8
14 and 14'	50.1	50.4	50.5
15 and 15'	23.5	23.5	23.4
16 and 16'	27.3	27.3	27.2
17 and 17'	85.1	85.3	85.3
18 and 18'	12.0	11.4	11.6
19 and 19'	17.4	12.2	11.9
2 x CO	158.1	157.6	158.1
Figure 1: Key 1H-BC spectrum of 4
3C long-range correlations observed in the HM-
used as received. All chemicals and solvents were used without further purification. The reactions were monitored and the purity of the products was assessed by thin-layer chromatography (TLC) performed on silica gel (Merck type 60) and visualised under UV illumination and/or by I2 vapour. Melting points of the products were determined on a Gallen-kamp melting point apparatus. Infrared spectra (wave numbers in cm1) were recorded on an ATI Mattson Genesis FTIR spectrophotometer as KBr pellets. Nuclear magnetic resonance (NMR) spectra were recorded on a Varian Unity INOVA 400 MHz NMR spectrometer. NMR spectra were obtained in CDCl3. Chemical shifts (5) are reported in ppm downfield from TMS, using the residual solvent peak (7.25 ppm for 1H and 77.23 ppm for 13C) as an internal standard and coupling constants (J) in Hz. Mass spectroscopic analyses were performed at the EPSRC Mass Spectrometry Service at Swansea.
Each individual stirred solution of testosterone (1, 600 mg, 2.08 mmol), 3-oxo-5a-androstan-17p-ol (3, 3.82 g, 13.15 mmol) and 5a-androst-2-en-17p-ol (5, 200 mg, 0.73 mmol) in dry pyridine (10, 15 and 6 ml, respectively) was treated dropwise with oxalyl chloride (132 mg, 1.04 mmol; 835 mg, 6.58 mmol; 47 mg, 0.37 mmol, respectively) over 5 min under N2 (strongly exothermic reaction and white fumes evolved). After standing 18h at r.t., each product was treated as follows.
Bis (androst-4-en-3-on)-17P-yl oxalate (2): The
resulting yellow solution was evaporated at reduced pressure. The crude solid was purified by recrystallisation from a mixture (2 : 1) of CHCl3 and EtOAc. The title compound 2 (335 mg, 51%) was found as an off-white powder, mp: 256-257 °C. IR (CHCl3; vmax, cm-1): 2943 (C-H), 2858 (C-H), 1763 (oxalate C=O), 1741 (oxalate C=O), 1675 (ketonic C=O), 1613 (C=C), 1433, 1318, 1190 (C-O), 912 and 755. 1H NMR (400 MHz, CDCl3): 5 0.86 (s, 6H, 18-Me and 18'-Me), 1.15 (s, 6H, 19-Me and 19'-Me), 4.68 (t, J = 7.9 Hz, 2H, 17-CH-O and 17'-CH-O), 5.69 (m, 2H, 4-CH and 4'-CH); 13C NMR (Table 1). FABMS: m/z. 631 [M + H]+. HRFABMS: Found: 631.39986; calc. 631.39984 for C40H55O6.
Bis (5a-androstan-3-on)-17p-yl oxalate (4): Water (2 ml) was cautiously added, and the slurry was diluted with more H2O (20 ml). The colourless precipitate was collected, washed with H2O and dried over H2O pump. The crude solid was purified by recrystallisation from a mixture (2:1) of CHCl3 and EtOAc. The title compound 4 (1.98 g, 47%) was obtained as a white amorphous, mp: 283-284 °C (decomp.). IR (CHCl3; vmax, cm-1): 2929 (C-H), 2854 (C-H), 1762 (oxalate C=O), 1740 (oxalate C=O), 1712 (ketonic C=O), 1446, 1314, 1182 (C-O), 996 and 755. 1H NMR (400 MHz, CDCl3): 5 0.83 (s, 6H, 18-Me and 18'-Me), 0.97 (s, 6H, 19-Me and 19'-Me), 4.67 (t, J = 7.5 Hz, 2H, 17-CH-O and 17'-CH-O), 13C NMR (Table 1). FABMS: m/z. 635 [M + H]+. HRFABMS: Found: 635.4313; calc. 635.4311 for C40H59O6.
Bis (5a-androst-2-en)-17p-yl oxalate (6): The resulting solution was rotary evaporated at reduced pressure. The solid was dissolved in DCM and washed with H2O to remove pyridine. The crude was purified by re-crystallisation from a mixture (2:1) of CHCl3 and EtOA-c. The title compound 6 (121 mg, 54%) was found as a white powder, mp: 182-183 °C. IR (CHCl3; vmax cm1): 2963 (C-H), 2848 (C-H), 1768 (oxalate C=O), 1738 (oxalate C=O), 1655 (C=C), 1445, 1379, 1314, 1180 (C-O), 908 and 736. 1H NMR (400 MHz, CDCl3): 5 0.74 (s, 6H, 18-Me and 18'-Me), 0.84 (s, 6H, 19-Me and 19'-Me), 5.56 (br m, 4H, 2-CH, 2'-CH, 3-CH and 3'-CH), 4.69 (t, J = 7.9 Hz, 2H, 17-CH-O and 17'-CH-O); 13C NMR (Table 1). FABMS: m/z 603 [M + H]+, 625 [M + Na]+. HRFABMS: Found: 603.44131; calc. 603.44130
for C40H59O4.
4. Conclusions
Three new 17p-steroidal oxalate dimers (2, 4 and 6) were synthesised from readily available steroid, testosterone (1), 5a-androst-2-en-17p-ol (3) and 3-oxo-5a-an-drostan-17p-ol (5). All three dimers were identified by comprehensive spectroscopic data analyses.
5. Acknowledgements
The authors thank the funding body for the development trust fund for a PhD studentship (LN) and EPSRC National Mass Spectrometry Service Centre (Department of Chemistry, University of Wales Swansea, Swansea, UK) for MS analysis.
6. References
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Povzetek
V prispevku je opisana priprava treh novih simetričnih steroidnih dimerov (2, 4 in 6) iz naravnih 17P-hidroksisteroidov, t.j. testosterona (1), 5a-androst-2-en-17P-ola (3) in 3-okso-5a-androstan-17P-ola (5), z uporabo oksalil klorida in piri-dina.