Synthesis of oxido-bridged analogs of 18-hydroxyprogesterone

ELSEVIER

Synthesis of oxido-bridged analogs of 18-hydroxyprogesterone M.O. Violeta Benedetti Doctorovich, Alberto A. Ghini, and Gerardo Burton Departamento de Qufmica Org6nica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina

18-Hydroxy-6,19-oxidoprogesterone and 18-hydroxy- l l,19-oxidoprogesterone were synthesized from readily available materials. The functionalization of C- 18 was accomplished with phenyliodosodiacetate/iodine, whereas that of C-19 was carried out with the mercuric oxide/iodine system, both under irradiation with visible light. For 18-hydroxy- 11,19-oxidoprogesterone, C- 19 was functionalized before C- 18, whereas the reverse order had to be used for the 6,19-oxido derivative. (Steroids 61:345-348, 1996)

Keywords:oxido-bridged pregnanes; 18-hydroxypregnanes

Introduction The introduction of oxido-bridges involving the angular methyls and selected carbons of the steroid nucleus produces major changes in the overall shape of steroid molecules, l Both 11,18-oxido and 18,20-oxido-bridges are present in the active form of the natural mineralocorticoid aldosterone, conferring overall planarity and eliminating steric interactions on the 13 face of the molecule, in addition to giving rise to a fairly rigid structure. 2 In a similar way, an 11,19-oxido-bridge introduced in the progesterone molecule also renders a highly planar molecule that is a strong mineralocorticoid. 1 Conversely, a 6,19-oxido-bridge bends A 43-ketosteroids at the A/B ring junction, giving rise, in the case of the progesterone derivative, to a compound almost devoid of mineralocorticoid activity.1 Prompted by the latter results, it was of interest to have available for biological testing molecules with oxido-bridges involving both angular methyls. W e now describe the preparation of 18-hydroxyl 1,19-oxidoprogesterone (1) and 18-hydroxy-6,19-oxidoprogesterone (2), both of which exist exclusively as the corresponding 18 ---> 20 hemiketals and thus contain this oxido-bridge of aldosterone, which functionally modifies and fixes the position of the pregnane side chain.

Experimental Melting points (m.p.) were determined on a Fisher Johns apparatus and are uncorrected. ~H and ~3C NMR spectra were measured in Address reprint requests to Professor Gerardo Burton, Departamento de Qufmica Org~inica,Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabell6n 2, Ciudad Universitaria, (1428) Buenos Aires, Argentina. Received November 9, 1995; accepted January 31, 1996. Steroids 61:345-348, 1996 © 1996 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

deuteriochloroform on a Bruker AC-200 at 200.13 and 50.32 MHz, respectively. Chemical shifts are given in ppm downfield from TMS (internal standard); assignments are based on multiplicity determination (DEPT), and 2D NMR spectra were obtained using standard Bruker software. Electron impact mass spectra were collected on a VG Trio-2 and high-resolution mass spectra on a VG ZAB-BEQQ mass spectrometer. Conventional work-up means exhaustive extraction with the solvent indicated, washing with water, drying with anhydrous sodium sulfate, and evaporation of the solvent at reduced pressure at -40-60°C. Reverse-phase flash chromatography was carried out on octadecyl-functionalized silica gel (Aldrich Chemical Co.). The homogeneity of all compounds was confirmed by thin-layer chromatography. 20[3-Formyloxy-3[3-hydroxy-ll,19-oxidopregn-5-ene (3) was prepared as described previously.3 313-Formyloxypregn-5-en-20one (7) was obtained by treatment of pregnenolone with formic acid.4

2 0 ~ - H y d r o x y - l l, 1 9 - o x i d o p r e g n - 4 - e n - 3 - o n e (4) Pyridinium chlorochromate (544 mg), barium carbonate (314 mg), and 4-A molecular sieves (440 mg) in dry dichloromethane (20 mL) were vigorously stirred at room temperature for 20 min, and then compound 3 (157 mg) was added. After a further 60 min, the reaction mixture was diluted with ether and percolated through Florisil with dichloromethane. Evaporation of the solvent rendered 20l~-formyloxy-l l, 19-oxidopregn-5-en-3-one (152 mg) as a white solid, homogeneous by thin-layer chromatography; 1H NMR: 0.80 (s, 3H, H-18), 1.22 (d, J = 6.0 Hz, 3H, H-21), 3.86 (d, J = 9.0 Hz, 1H, H-19a), 4.12 (d, J = 9.0 Hz, 1H, H-19b), 4.24 (br s, 1H, H-11), 4.90 (m, 1H, H-20), 5.60 (br d, J = 4.0 Hz, 1H, H-6), 8.04 (s, 1H, formate). The product obtained above without purification was dissolved in dichloromethane (4.4 mL) and methanol 0 7 mL); water (1.1 mL) and concentrated hydrochloric acid (2.5 mL) were added, and the mixture was vigorously stirred 16 h at 25°C. After dilution with 0039-128X/96/$15.00 PII S0039-128X(96)00034-1

Papers water and neutralization with aqueous sodium bicarbonate, workup with dichloromethane followed by flash chromatography gave 2013-hydroxy-11,19-oxidopregn-4-en-3-one (4) (133 rag), m.p. 203-205°C (from methanol). Found C 76.5, H 9.3%; C2tH3oO 3 requires C 76.33, H 9.15%. ~H NMR: 5 0.96 (s, 3H, H-181, 1.15 (d, J = 6.0 Hz, 3H, H-211, 3.80 (m, IH, H-20), 3.82 (d, J = 9.0 Hz, IH, H-19a), 4.00 (d, J = 9.0 Hz, IH, H-19b), 4.36 (br s, 1H, H-ll), 5.89 (s, IH, H-4). t3C NMR: ~ 14.6 (C-181, 23.5 (C-15), 23.6 (C-21), 25.5 (C-16), 28.2 (C-71, 32.7 (C-6), 33.5 (C-2), 34.4 (C-8), 34.6 (C-l), 42.0 (C-121, 42.8 (C-13), 47.4 (C-10), 51.9 (C-14), 57.4 (C-9), 59.0 (C-17), 69.4 (C-19), 70.0 (C-20), 78.5 (C-11), 127.8 (C-4), 164.0 (C-5), 198.7 (C-3).

18-Hydroxy-11,19-oxidopregn-4-ene-3, 20-dione (1) Phenyliodosodiacetate (104 mg) and iodine (73 mg) were added to a suspension of 4 (92 mg) in recently distilled carbon tetrachloride (18 mL). The reaction mixture was stirred while irradiating with a 300-W tungsten lamp (5000 lumen) for 30 rain at 25°C and then poured over 5% aqueous sodium thiosulfate. Work-up with dichloromethane rendered a mixture of iodobenzene and 20[3-hydroxy18-iodo-ll,19-oxidopregn-4-en-3-one (5) (116 mg). A sample from a parallel preparation purified by reverse-phase flash chromatography had ~H NMR: 8 1.26 (d, J = 6.0 Hz, 3H, H-21), 3.10 ( d , J = 11Hz, 1H, H-18a), 3.30 (d, J = 11 Hz, 1H, H-18b), 3.73 (d, J = 9.0 Hz, 1H, H-19a), 3.80 (m, 1H, H-20), 4.08 (d, J = 9.0 Hz, 1H, H-19b), 4.34 (br s, 1H, H-I1), 5.89 (s, 1H, H-4). 13C NMR: 8 11.3 (C-18), 22.4 (C-21), 23.3 (C-15), 25.5 (C-16), 27.6 (C-7), 32.9 (C-6), 33.3 (C-2), 34.5 (C-8), 34.6 (C-I), 41.3 (C-12), 44.8 (C-13), 46.9 (C-10), 52.6 (C-14), 57.6 (C-9), 60.0 (C-17), 68.1 (C-20), 69.9 (C-19), 77.6 (C-IlL 128.1 (C-4), 165.5 (C-5), 198.3 (C-3). The crude iodoalcohol obtained above without purification was dissolved in acetone (30 mL) under a nitrogen atmosphere; Jones reagent (0.1 mL) was added, and the reaction was stirred at 0°C for 10 min. The excess oxidant was destroyed with 2-propanol, and the reaction mixture was diluted with water and concentrated in vacuo to a third of its volume. Work-up with dichloromethane followed by purification by reverse-phase flash chromatography (CH3CN-HzO) afforded 18-iodo-I 1,19-oxidopregn-4-ene-3,20dione (6) (31 mg). ~H NMR: ~ 2.18 (s, 3H, H-21), 3.18 (br s, 2H, H-18), 3.75 (d, J = 9 Hz, IH, H-19a), 3.97 (d, J = 9 Hz, 1H, H-19b), 4.35 (br s, IH, H-I 1), 5.87 (s, IH, H-4). Iodoketone 6 was dissolved in acetic acid containing 0.2% water (4.9 mL), and silver acetate (183 mg) was added. The suspension was stirred at 25°C for 2.5 h under a nitrogen atmosphere. After filtration, the solution was neutralized with aqueous sodium bicarbonate. Extractive work-up with dichloromethane followed by purification by reverse-phase flash chromatography (CH3CNH20) rendered 18-hydroxy- 11,19-oxidopregn-4-ene-3,20-dione (1) (14 mg, 13.5% from 3); m.p. 140-145°C (from ethyl acetate). IH NMR: 8 1.48 (s, 3H, H-21), 3.75 (d, J = 9.0 Hz, 1H, H-19a or H-18a), 3.76 (d, J = 9 . 0 H z , 1H, H-18a or H-19a), 3.99 (d, J = 9.0 Hz, 1H, H-19b), 4.07 (d, J = 9.0 Hz, 1H, H-18b), 4.40 (br s, IH, H-11), 5.88 (s, 1H, H-4). ]3C NMR: $ 24.6 (C-21), 25.5 (C-15), 27.3 (C-16), 28.5 (C-7), 33.1 (C-6), 33.5 (C-2), 34.7 (C-l), 37.0 (C-8), 40.4 (C-121, 47.3 (C-10), 51.4 (C-14), 54.2 (C-131, 57.0 (C-9), 57.3 (C-17), 69.8 (C-19), 74.3 (C-18), 107.1 (C-20), 128.0 (C-4), 163.5 (C-5), 198.6 (C-3). The mass spectrum showed prominent peaks at m/z 326 (100%, M-H20), 296 (35%, 326H2CO), 268 (12%), 253 (20%). High-resolution mass spectrum for C21H2603 326.1881 (M-H20), calculated 326.1882.

3~-Formyloxy-18-iodopregn-5-en-20-one (9) 313-Formyloxypregn-5-en-20-one (7) (450 rag) was dissolved in methanol (20 mL) containing a trace of methyl orange as indicator,

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and sodium cyanoborohydride (225 mg) was added at 25°C. The solution was kept at pH 3 (orange color) by regular addition of a solution of methanol-IN hydrochloric acid (1:1) during 100 min. The reaction mixture was diluted with water; extractive work-up and purification by flash chromatography rendered the 2013alcohol (410 mg) m.p. 189-191°C (from methanol). ~H NMR: 0.78 (s, 3H, H-18), 1.04 (s, 3H, H-19), 1.14 (d, J = 6 Hz, 3H, H-21), 3.72 (br s, IH, H-20), 4.74 (br s, 1H, H-3), 5.40 (br d, J = 4 Hz, H-6), 8.04 (s, IH, formate). ~3C NMR: 5 12.3 (C-18), 19.2 (C-19), 20.8 (C-II), 23.5 (C-21), 24.5 (C-151, 25.6 (C-161, 27.2 (C-21, 31.6 (C-8), 31.8 (C-7), 36.5 (C-10), 36.8 (C-l), 38.0 (C-41, 39.6 (C-12), 42.3 (C-131, 49.9 (C-9), 56.0 (C-141, 58.2 (C-171, 70.3 (C-20), 73.8 (C-3), 122.6 (C-6), 139.1 (C-5). The latter compound (400 mg) was suspended in recently distilled carbon tetrachloride (80 mL), and phenyliodosodiacetate (410 mg) and iodine (290 mg) were added. The reaction mixture was stirred while irradiating with a 300-W tungsten lamp (5000 lumen) for 3(1 rain at 25°C and was then poured over 5% aqueous sodium thiosulfate. Extractive work-up with ether and percolation through Florisil yielded crude 313-formyloxy-2013-hydroxy-18iodopregn-5-ene (8) (420 mg). An analytical sample had m.p.(dec.) 128-130°C (from ether-dichoromethane). Found C 55.9, H 7.1%; C22H3303I requires C 55.9, H 7.0%. tH NMR: ~ 1.04 (s, 3H, H-19), 1.14 (d,J = 6 Hz, 3H, H-21), 3.15 (d,J = 11Hz, 1H, H-18a), 3.35 (d, J = 11 Hz, 1H, H-18b), 4.00 (br s, IH, H-20), 4.73 (br s, 1H, H-31, 5.40 (br d, J = 4 Hz, H-6), 8.04 (s, IH, formate). ~3C NMR: 5 10.6 (C-18), 19.2 (C-191, 20.3 (C-I 1), 22.3 (C-21), 24.3 (C-15), 25.2 (C-16), 27.6 (C-2), 31.9 (C-7), 32.2 (C-8), 36.4 (C-10), 36.7 (C-l), 37.9 (C-4), 37.9 (C-14), 40.1 (C12), 44.1 (C-13), 49.5 (C-9), 58.4 (C-17), 68.2 (C-201, 73.8 (C-3), 122.8 (C-6), 139.3 (C-51. Oxidation of crude iodoalcohol 8 (420 rag) in acetone (65 mE) with Jones reagent (0.2 mL), as described for 5, followed by percolation through Florisil rendered crude 313-formyloxy-18iodopregn-5-en-20-one (9) (400 mg). An analytical sample had m.p.(dec.) 87-89°C (from methanol). Found C 56.4, H 6.5%; C22H3jO3I requires C 56.2, H 6.6%. JH NMR: 8 1.04 (s, 3H, H-19), 2.30 (s, IH, H-21), 3.23 (s, 2H, H-18), 4.73 (br s, 1H, H-3), 5.40 (br d, J = 4 Hz, H-6), 8.04 (s, lH, formate). 13C NMR: ~ 9.6 (C-18), 19.2 (C-19), 20.8 (C-II), 22.9 (C-16), 24.4 (C-15), 27.6 (C-2), 31.5 (C-7), 32.1 (C-8), 33.7 (C-21), 36.5 (C-10), 36.7 (C-l), 37.9 (C-41, 39.6 (C-12), 46.2 (C-13), 49.5 (C-9), 56.7 (C-14), 62.2 (C-17), 73.5 (C-31, 122.0 (C-6), 139.3 (C-51, 208.6 (C-20).

5eL-Bromo-3~-formyloxy-18-iodo-6,19oxidopregnan-20-one (10) To a stirred solution of iodoketone 9 (400 mg) obtained above, in ether (3.2 mL) and tetrahydrofuran (1.3 mL) cooled to 10°C, was added 12% aqueous perchloric acid (0.4 mL) followed by Nbromoacetamide ( 170 mg) in eight portions during a 25-min period at 10-15°C protected from light. The reaction mixture was stirred for 30 min at 25°C, then 1% aqueous sodium thiosulfate was added and the mixture was poured over dichoromethane:methanol (10:1). Extractive work-up gave the 5~-bromo-613-hydroxy derivative (455 mg). This compound was suspended in recently distilled carbon tetrachloride (45 mL), and mercuric oxide (1.16 g) and iodine (1.73 g) were added. The reaction mixture was vigorously stirred while irradiating with a 300-W tungsten lamp (5000 lumen) for 45 min at 25°C and then poured over 5% aqueous sodium thiosulfate. Work-up with dichloromethane rendered 5~-bromo313-formyloxy-18-iodo-6,19-oxidopregnan-20-one (10) (402 mg); an analytical sample had m.p.(dec) 123-125°C (from methanol). Found C 46.5, H 5.6%; Cz2H3oOaBrI requires C 46.7, H 5.4%. IH NMR: 5 2.28 (s, 3H, H-21), 3.18 (d, J = 11 Hz, IH, H-18a), 3.36 (d, J = ] ] Hz, IH, H-18b), 3.72 (d, J = 9 Hz, 1H, H-19a), 3.98

Oxido-bridged analogs of 18-hydroxyprogesterone: Doctorovich et al. (d, J = 9 Hz, IH, H-19b), 4.10 (br d, J = 4 Hz, 1H, H-6), 5.40 (brs, IH, H-3), 8.04 (s, 1H, formate). 13C NMR: ~ 9.8 (C-18), 22.6 (C-I l), 23.2 (C-16), 23.3 (C-7), 23.9 (C-15), 26.8 (C-2), 32.7 (C-I), 33.7 (C-21), 33.9 (C-8), 40.2 (C-12), 41.2 (C-4), 45.9 (C10), 46.7 (C-13), 48.4 (C-9), 55.0 (C-14), 62.3 (C-17), 67.3 (C-19), 69.8 (C-3), 74.1 (C-5), 82.0 (C-6), 208.4 (C-20).

~ C O H I,U

Results and discussion

For the preparation of 18-hydroxy- 11,19-oxidoprogesterone (1), the 11,19-oxidosteroid 3 was used as starting material (Figure 1); this compound may be obtained at -60% from commercially available pregnen-4-ene-3,11,20-trione using the procedure described previously. 3 The key step of the synthetic sequence was the remote functionalization of the angular methyl group at C- 13 by means of a hypoiodite-type reaction. This reaction may be carried out in the presence of a Aa-3-keto moiety using Suarez reagent, phenyliodosodiacetate. 5'6 Semiempirical calculations (AM1, AMPAC 5.0) indicated that the distance between the 20[3-hydroxyl and the 13-CH 3 in compound 4 was adequate for this reaction. 7 Hence the 11,19-oxidosteroid 3 was converted to 4 by oxidation with pyridinium chlorochromate (PCC) followed by acid-catalyzed isomerization of the 5,6-double bond and concomitant deformylation. Reaction of 4 with phenyliodosodiacetate/iodine rendered iodoalcohol 5; this compound slowly decomposed on standing, even at low temperature, and had to be used immediately. Thus, the crude iodoalcohol was oxidized with Jones reagent, yielding iodoketone 6, which was purified by reverse-phase column chromatography (24,5% yield from 4). PCC could be used

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18-Hydroxy-6,19-oxidopre gn-4-ene-3,20-dione (2) Bromoether 10 (402 rag) was dissolved in methanol (50 mL), and potassium bicarbonate (400 mg) was added. The reaction mixture was stirred for 90 min at 25°C under a nitrogen atmosphere, and the solution was neutralized with acetic acid, concentrated, and diluted with water. Extractive work-up with ether gave the 313hydroxy steroid (350 rag), which was dissolved in acetone (90 mL) under a nitrogen atmosphere and oxidized with Jones reagent (0.21 mL) as described for 5. Work-up with ether rendered 5a-bromo18-iodo-6,19-oxidopregnane-3,20-dione (335 rag). The latter compound without purification was dissolved in acetic acid containing 0.2% water (17 mL), and silver acetate (870 rag) was added. The suspension was stirred at 60°C for 5 h under a nitrogen atmosphere and protected from light. After filtration the solution was neutralized with aqueous sodium bicarbonate. Work-up with dichloromethane, followed by percolation through Florisil with hexane-ethyl acetate mixtures of increasing polarity, afforded crude compound 2, which was purified by preparative reverse-phase high-performance liquid chromatography (RP-18, acetonitrilewater 60:40 v/v) to yield 18-hydroxy-6,19-oxidopregn-4-ene-3,20dione (2) (35 rag, 8% from 7); m.p.(dec) 153-155°C (from ethyl acetate). Found C 73.4, H 8.5%; C 2 1 H 2 8 0 4 requires C 73.2, H 8.2%. ~H NMR: ~ 1.50 (s, 3H, H-21), 3.50 (d, J = 9 Hz, IH, H-19a), 3.78 (br s, 2H, H-18), 4.12 (d, J = 9 Hz, 1H, H-19b), 4.72 (br d, J = 4 Hz, 1H, H-6), 5,84 (s, IH, H-4). ]3C NMR: 3 24.5 (C-21), 25.8 (C-l 1), 26.4 (C-7), 26.4 (C-15), 27.1 (C-16), 33.0 (C-6), 33.1 (C-I), 36.4 (C-8), 37.4 (C-12), 41.3 (C-2), 45.7 (C-10), 49.2 (C-9), 53.6 (C-14), 55.1 (C-13), 55.9 (C-17), 73.4 (C-18), 75.3 (C-19), 107.1 (C-20), 114.9 (C-4), 171.4 (C-5), 198.5 (C-3). The mass spectrum showed peaks at m/z 326 (100%, M-H20), 268 (54%), 255 (10%). High-resolution mass spectrum for C2]H260 3 326.1881 (M-H~O); calculated 326.1882.

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6R,,O Figure 1 Reagents: i, PCC, BaC03, molecular sieves (4 A), CI2CH2;ii, HCl(aq),CIzCH2, MeOH; iii, phenyliodosodiacetate,12, CI4C, hv; iv, CrO3, H2SO4(8N), acetone; v, AgOAc, HOAc(aq). for this oxidation, although it required prepurification of 5 by reverse-phase flash chromatography. The reaction was more simple and faster with Jones reagent and had an identical overall yield. Cyclization of 6 with silver acetate/acetic acid as described previously 6 rendered compound 1, which was purified by reverse-phase flash chromatography. The overall yield of 1 was 13.5%. Attempts to functionalize C-18 using the Suarez reaction on several 20[3-hydroxypregnanes containing the 6,19oxido-bridge were unsuccessful, although the distance between the 20-hydroxyl and the angular methyl, as predicted by AM1 calculations, was still within the required limits (see above). In view of these results, the reverse order was tried for the remote functionalizations in the preparation of 18-hydroxy-6,19-oxidoprogesterone (2), i.e., C-18 was functionalized first and C-19 in the second place (Figure 2). The starting material was pregnenolone formate (7), which

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Figure 2 Reagents: i, NaCNBH 3, MeOH, 1N HCI; ii, phenyliodosodiacetate,iodine,CI4C,/'m;iii, CrO3, H2SOa(8N),acetone; iv, NBA, ether-THF, HClO4(aq); v, HgO, 12, CI4C, hv; vi, KHCO3,

MeOH; vii, AgOAc,HOAc(aq).

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Papers was reduced with sodium cyanoborohydride in methanol to the 20[3-alcohol and treated with phenyliodosodiacetate and iodine as described above to yield iodoalcohol 8. The latter compound, without purification, was oxidized with Jones reagent to iodoketone 9, which was stable enough to withstand the reaction sequence for functionalization of C-19. Thus, compound 9 was converted to the 6,19-oxido-bridged analog (10) by bromohydrin formation (n-bromoacetamideperchloric acid) followed by treatment with HgO/iodine. 8 The resulting bromoether was deformylated by treatment with base and oxidized to the 3-ketone with Jones reagent. The use of a formate ester at position 3 allowed the deprotection to be carried out under very mild conditions (KHCO3/MeOH); stronger basic conditions like those needed to hydrolize a 3-acetate rendered the 17,18cyclopregnane,9 Treatment of 10 with silver acetate in moist acetic acid, as above, produced elimination of the bromine at position 5 and the simultaneous cyclization of the iodoketone to the (18 ---) 20)-hemiketal, rendering 18-hydroxy6,19-oxidoprogesterone (2) in 8% overall yield.

References 1.

2.

3.

4. 5.

6. 7.

Acknowledgments

8.

We thank Universidad de Buenos Aires and CONICET (Argentina) for financial support of this work. Technical assistance by Norberto A. Garcia Espinosa is gratefully acknowledged.

9.

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Burton G, Galigniana M, de Lavallaz S, Brachet-Cota AL, Sproviero EM, Ghini AA, Lantos CP, Damasco MC (1995). Sodium retaining activity of some natural and synthetic 21-deoxysteroids. Mol Pharmacol 47:535-543. Yamakawa M, Ezumi K, Shiro M, Nakai H, Kamata S, Matsui T, Haga N (1986). Relationships of the molecular structure of aldosterone derivatives with their binding affinity for mineralocorticoid receptor. Mol Pharmacol 30:585-589. Veleiro AS, Nevado MV, Monteserfn MC, Burton G (1995). Syntheses of 21-hydroxy-I 1,19-oxidopregn-4-ene-3,20-dione and 21hydroxy-6,19-oxidopregn-4-ene-3,20-dione. Steroids" 60:268-271. Edwards RWH (1963). The paper chromatography of steroids esters. J Chromatogr 12:212-218. de Armas P, Concepci6n JI, Francisco CG, Hermlndez R, Salazar JA, Suarez E (1989). Intramolecular hydrogen abstraction. Hypervalent organoiodine compounds, convenient reagents for alkoxyl radical generation. J Chem Soc (Perkin 1) 405-411. Benedetti MOV, Burton G (1992). Improved preparation of 18hydroxyprogesterone. Org Prep Proc lnt 24:701-704. Burke SD, Silks LA, Strickland SMS (1988). Remote functionalization and molecular modelling. Observations relevant to the Barton and hypoiodite reactions. Tetrahedron Len 29:2761-2764. Brachet-Cota AL, Burton G (1990). An improved preparation of 11,19-oxidopregn-4-ene-3,20-dione and 6,19-oxidopregn-4-ene3,11.20-trione. Z Naturforsch [B] 45b:711-715. Ferrara A, Benedetti MOV, Ghini AA, Burton G (1993). 17(13 --~ 18)-abeo-Pregnanes. Synthesis of progesterone analogues. J Chem Res (S) 276-277.