ChemInform Abstract: A New Strategy for the Preparation of 11-Oxygenated Steroids Synthesis of (.+-.)-Adrenosterone (original) (raw)
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Tetrahedron, 1985
A novel D + BCD + ABCD route to 1 1-keto steroids fs reported fnvolvfng a high yield stereoselective intramolecular Dlels-Alder reaction of furan-dfene 12 in water as a key-step. The dfenophilfc side chain 1s readily introduced starting from B via a sequence involving alkylatfon wlth ethyl (E)-3-ethoxy-4-lado-2-butenoate, reduction and acid hydrolysis. The reduced adduct 14 1s further converted into (~~-adrenosterone (61 vfa 24, the dfenedfolate equivalent of whfch is a known intermediate in corticosterofd synthesls. Sterolds, and in particular cortlcosterofds, are challenging targets for total synthesis, not only due to their biological importance, but also because they constitute a rich area for the development of novel strategles in synthesis 1.2. In a prevlous report we have described a novel approach to the BCD-rfng system of 1 I-keto sterofds based on the intramolecular Dfels-Alder reaction of furan-enone 1 (scheme 113. The followfng conclusions could be drawn from this exploratory study. Among the investlgated dfenophflfc side chatns the unsubstltuted enone 1 Is, at the same time, a suitable substrate for cycloaddftlon and of further potential Interest for corticosterofd synthesis. Depending on the reaction conditions either adduct 2 (kinetic control) or 3 (thermodynamic control) is formed predomlnantly, allbelt In low yfeid (-40-50 %I. After the hydrogenatlon of the double bond in 2, the opening of the oxygen bridge Is readfly effected with base yfeldlng enone 4; however, the more forceful condftlons required for the opening of the product obtained by hydrogenation of adduct 3 cause eplmerfzatfon at C-14 leading to the a-fused enone 5 @Senior Research Associate of the National Fund for Scfentfffc Research (BelgIumI 4667 L. A. VAN ROYEN et al. In view of the above results an efficient synthesis of 1 I-keto steroids along the proposed Die&-Alder strategy still requires : (1) the development of a short and direct route to enone 1; (2) the finding of approprlate conditions upon which the Diels-Alder reaction would proceed stereoselectively and in high yield to 2; (3) the stereoselectlve appendage of the A-ring with an angular methyl group at C-10. In the present paper we report a solution to these problems which eventually led to a 16-step synthesis of (+I-adrenosterone (6)4es. m (scheme 2). Our previous synthesis of 1 required six steps from the trimethylsilyl enol ether 8. which 1s readily available from cyclopentenonezin 69 W yield via reduction with lithium In liquid ammonia followed by trapping with trimethylsilyl chloride3. Not unexpectedly, the direct introduction of the 2-oxo-3-butenyl side chain by alkylation of the enolate anion derived lrom B (methyllithium) failed; various experirhents with I-iodo-3-buten-2-o& in tetrahydroluran involving variations in temperature, the presence 01 hexamethylphosphoramide and the mode of addition only led to complex reaction mixtures. In view of the kinetic preference of D-alkoxy allylic alcohols (as in J_lJ to yield the corresponding enone in acid', we decided to use a 3-alkoxy-4-halo-2-butenoate ester as the electrophile* for the introduction of the enone side chain in masked form. Thus, alkylatlon of the enolate anion derived from B tmethylllthlum~ with ethyl (f)-3-ethoxy-4-iodo-2butenoate @)a in tetrahydrofuran-hexamethylphosphoramide gave the deslred m-ketone UT in 68 W yleld next to I3 W of 2,5-dialkylated product (undefined stereochemistry at C-5). The m-stereochemistry of JQ is lnlerred from the shielded angular methyl resonance (c.& with fury1 group) in the 1H NMR spectrum (6 0.75); no &-product was isolated in this experiment lo. We should note here that the double bond configuratlon in _lQ and l_L which
First synthesis of a steroid containing an unstable 19-nor-androsta-1,5-dien-3-one system
Tetrahedron, 2006
Mechanisms involved in the maintenance of human pregnancy and initiation of labour are poorly defined. A novel steroid hormone named estradienolone (ED), and having an unusual 19-nor-androsta-1,5-dien-3-one system, was previously reported. However, ED is scarcely available from urine, placenta and blood of pregnant women. For this reason, we have synthesized ED in order to verify its proposed structure. Although a 1,5-dien-3-one system had already been described for a C19-steroid (androstane) nucleus (no possible aromatization), the synthesis of the 19-nor-analogue is a major challenge because this system is very sensitive to aromatization. We now describe the successful construction and characterization of this unstable system. Starting from nortestosterone, the synthesis of 17b-hydroxy-19-nor-androsta-1,5-dien-3-one (1) is based on a protection of the 5,6-double bond, the introduction of the second 1,2-double bond, the careful recovery of the exo double bond and a final regioselective oxidation or reduction. q
ChemInform, 2001
In order to find new ways of introducing oxygenated functions in the 15-, 9-and 11-position on steroid rings and at the same time test the reactivity of a conjugated diene steroid toward methyltrioxorhenium (MTO)-catalyzed oxidation with the urea-hydrogen peroxide adduct (UHP), the reactions of 5α-cholesta-8,14-dien-3β-yl acetate 1 with the MTO-UHP system are performed in aprotic solvents. These oxidations are performed both at 0 ЊC and 25 ЊC in CHCl 3 or diethyl ether as solvent and in the presence of pyridine ligand. From the reaction of diene 1 in CHCl 3 we isolate two new sterols, 9β-hydroxy-15-oxo-5α-cholest-8(14)-en-3β-yl acetate 3 and 9α,11α,15α-trihydroxy-5α-cholest-8(14)-en-3β-yl acetate 7, while oxidation in Et 2 O in the presence of pyridine ligand allows us to isolate the new epoxysteroid 9α,11α-epoxy-15α-hydroxy-5α-cholest-8(14)-en-3β-yl acetate 13. The structure of all new steroids is secured on the basis of chemical evidence and interpretation of spectral data, which include H-H COSY, HMBC and NOESY experiments. These results represent a new and mild method for the functionalization of C and D rings from an 8,14-diene steroid, to give 15-oxygenated sterols, a class of compounds remarkable for their inhibitory action on sterol synthesis in animal cell culture systems.