Synthesis and radical oxidation of steroidal 1-oxo-5 α -alcohols

A new synthetic approach is described for the preparation of steroidal 1-oxo-5 α -alcohols. A key step in the synthesis was the [2,3]sigmatropic rearrangement of allylic 3 α -selenide ensuring the introduction of the desired functional groups at C-1 and C-5. The radical oxidation of 1-oxo-5 α - alcohol was shown to proceed with the formation of 5,10-seco steroid. Its structural assignment was based on NMR and CD spectroscopic studies.


Introduction
A key step in the preparation of 5,10-seco steroids (which are characterized by enhanced backbone flexibility) 1,2 is a rupture of endocyclic bonds.Oxidative β-fragmentation of 5αalcohols by lead tetraacetate in the presence of iodine has been used repeatedly to synthesize such compounds. 3

Scheme 1
The course of the reaction is rather complex (Scheme 1): [4][5][6][7] the intermediate formation of radical species 2 and 3 has been suggested to give ultimately a number of compounds like enones 4, cyclization products 5 and iodides 6. 8 This limits the applicability of the reaction in a directed synthesis of corresponding seco steroids.
A similar reaction was used for the preparation of 13,14-seco steroids based on the radical oxidation of 14α-alcohols.Basically, the obtained results were the same. 9However, there was an exception in the case of derivatives containing a keto group at C-17.Their oxidation proceeded smoothly, resulting in a good yield of iododiketones, which are convenient intermediates for further modifications. 10This approach was successfully used to prepare a number of androstane 13,14-seco steroids. 11,12he main idea of the present investigation, which aimed to develop new synthetic approaches to 5,10-seco steroids, was to examine the influence of a carbonyl group at C-1 (in β-position to hydroxyl group at C-5) on the course of radical oxidation.

Results and Discussion
Synthesis of the required 1-oxo-5α-alcohol posed certain problems.In general, the functionalization at C-1 in steroids remains a difficult challenge, which is associated first and foremost with the preparation of vitamin D metabolites. 13However, the experience accumulated in this field could not be applied in our case because of the necessity of a 5α-hydroxy group.Using a method employed earlier to prepare a germacrane alcohol, allohedycaryol, solved the problem. 14e started (Scheme 2) with the allylic alcohol 7 that has already been described in the literature. 15Its treatment with o-nitrophenyl selenocyanate proceeded by inverting stereochemical configuration 16 at C-3 to give α-derivative 8. Oxidation of this allylic selenide with hydrogen peroxide triggered a [2,3]sigmatropic rearrangement 17 that finally led to compound 9 which has a ∆ 2 -1α-hydroxy functionality.What is remarkable for the rearrangement of such a specific system 14 as that in AB-cycles of selenide 8 is the simultaneous α-epoxidation of ∆ 5 -double bond, probably as a result of the intermediate formation of arylperoxyseleninic acid derivative. 18

Scheme 2
Thus, the overall result of the above process was the functional group at C-1 and providing the necessary prerequisites for proper functionalization at C-5.The stereochemistry of ∆ 2 -bond epoxidation in 9 was synchronously controlled by both adjacent α-hydroxyl group at C-1 and attack of the reagent from the less hindered α-side of the steroidal molecule.Hydride reduction of the diepoxide 10 gave a mixture of products, none of which could be separated at this stage.The problem was solved by acetylation of the mixture which allowed separation and characterization of the acetylated products.Diacetate 11 could be isolated as individual compound to be well suited for our purposes.
Its oxidation with CrO 3 in pyridine smoothly gave the expected 1-oxo-5α-alcohol 12 (Scheme 3).The general procedure for the radical oxidation of 12 was similar to that described in earlier papers. 10,19The reaction was carried out in refluxing benzene using a 1.5 mol excess of lead tetraacetate with the presence of iodine as a catalyst and calcium carbonate as a base.Although it resulted in the formation of a complex mixture of products, compound 13 could be isolated in a reasonable 56% yield.It is noteworthy that the outcome of the reaction is strongly dependent on reaction conditions.Radical oxidation of similar 1-oxo-3β-acetoxy steroids with lead tetraacetate under thermal or hypoiodite conditions or with mercuric oxide/iodine (HgO/I 2 ) reagent was shown 20 to give 1,5dioxo-5,10-secocholest-10( 19)-ene as a main product.
Although iodide 13 produced good crystals suitable for X-ray analysis, because of its photolability this method proved unsuitable for structure elucidation.Fortunately, the problem could be solved by a combination of NMR and CD spectroscopy.Full assignment of signals both in 1 H and 13 C spectra in 5,10-seco steroid 13 was based on the analysis of 2D NMR data.Some signals were partially superimposed in CDCl 3 , and similar spectra were obtained for 13 also in C 6 D 6 (Table 1).Assignment of C-1 and C-5 carbonyl groups relied on analysis of HMBC spectrum, showing coupling of C-1 and H-19, H-2, and H-9, on one hand, and C-5 and H-4 and H-6, on the other hand.Perhaps the most important argument in favor of (10R) stereochemistry for 13 was the nuclear Overhauser effect of C-19 methyl group and proton at C-8.There was also a cross-peak in the NOESY spectrum between signals of C-19 methyl group and 11β-proton.NMR spectrum in C 6 D 6 proved to be especially useful for analyzing the nuclear Overhauser effect, because in CDCl 3 signal of H-8 was partially superimposed on signals of other protons (H-11 and H-12).In C 6 D 6 this proton could be observed as separate signal.Results of CD spectroscopy were in line with the proposed structure.CD spectrum of 13 showed a strong negative Cotton effect due to the n-π * transition at 313 nm.A crucial input in the observed effect probably belongs to the iodine atom located at α-position to C-1 carbonyl group.The octant rule 21 for a model of 13 with a α-orientation of iodine that provides a close relationship between C-19 methyl group and H-8 hydrogen atom shows that the iodine atom occupies the upper right rear octant for which the negative Cotton effect is predicted.
It should be noted that some intermediate compounds in the synthesis of iodide 13 contain a combination of structural elements characteristic of natural steroids.Withanolides and physalins have to be mentioned first. 22For instance, salpichrolide B isolated from from plant Salpichroa origanifolia has the same cycles A and B as epoxide 9. 23 In conclusion, the present study shows definite involvement of 1-keto group in the process of radical oxidation of 5α-hydroxy steroids.The formed compounds are stable enough and can be used as intermediate products to prepare 5,10-seco steroids using approaches described previously. 11perimental Section General Procedures.Melting points were taken on a Boetius micro-melting point apparatus and are uncorrected.IR spectra were recorded on a UR-20 spectrophotometer in KBr tablets.CD spectra were taken on a JASCO J-20 spectropolarimeter. 1 H and 13 C NMR spectra were obtained using a Bruker AVANCE 500 (Bruker Biospin) spectrometer in CDCl 3 (if not stated otherwise) operating at 500 MHz for 1 H and 125 MHz for 13 C.Chemical shifts were determined relative to the residual solvent peaks (CHCl 3 , δ = 7.26 for hydrogen atoms, δ = 77 for carbon atoms).Full assignment of 1 H and 13 C chemical shifts of 5,10-seco steroid 13 (Table 1) was achieved with the aid of COSY, HSQC, HMBC, J-resolved, TOCSY, NOESY experiments using the standard Bruker pulse programs.The exact mass measurements were carried out on a Micromass MasSpec mass spectrometer operating in the 70 eV-EI mode.A direct insertion probe was used to introduce samples for accurate mass measurement by peak matching.All chemicals were of analytical grade.Reactions were monitored by TLC using aluminium or plastic sheets, silica gel 60 F 254 precoated (Merck Art.5715).Column chromatography was carried out on silica gel 60 (Merck Art.7734).

Table 1 .
13 (500 MHz) and13C NMR (125 MHz) data for 13 (δ, J in Hz) * when multiplicities are not specified, the values of the 1 Н chemical shifts are obtained from the HSQC spectrum.** assignments may be reversed.