An observation on the regioselectivity of ring-opening of some substituted cyclohexenyl epoxides

Attempted epoxidation of the cyclohexenyl carboxylic acid 11 using m -chloroperoxybenzoic acid was accompanied by epoxide ring-opening and gave a mixture of lactones 13 , 14 and 15 , ratio 20 : 40 : 40, respectively. In contrast, treatment of the cis -hydroxyepoxide 18 of the methyl ester 12 with aqueous sulfuric acid in acetonitrile gave the lactone 14 with excellent regioselectivity together with the triol 22 . The trans -hydroxyepoxide 19 gave only the lactone 14 under these conditions.


Introduction
The abyssomicins are a small group of antibacterial macrocyclic polyketides isolated from a marine Verrucosispora strain which exhibit biological activity as inhibitors of p-aminobenzoic acid biosynthesis. 1Several approaches to the total synthesis of these compounds have been reported 2 and two total syntheses have already been described. 3We independently 4 envisaged a strategy for the synthesis of abyssomicin C 1 in which the C8-C9 double-bond would be introduced by ring-closing metathesis, and the metathesis precursor 2 prepared by fusing the tetronic acid fragment onto the bicyclic lactone 3.This lactone, in turn, was to be prepared by regioselective ring-opening of epoxides 4.This approach to the tricyclic core of the abyssomicins differs from those already reported 2a,2b,3b where preformed tetronic acids act as the nucleophile for intramolecular epoxide ring-opening.Since our approach is dependent on the ring-opening of epoxides 4 being regioselective, we report preliminary studies on the regioselectivity of ringopening of these epoxides which were carried out in order to evaluate routes to lactones 3.
Having prepared esters 10 and 12, and the acid 11, the stereoselectivity of epoxidation of these compounds and the regioselectivity of epoxide ring-opening was investigated.First, a one-step procedure of epoxidation and ring-opening was attempted on the acid 11.After treatment of the acid 11 with m-chloroperoxybenzoic acid at room temperature in chloroform for 72 h, three products were isolated which were identified, in increasing order of polarity (tlc), as lactone 13 (15%), the required lactone 14 (30%) and the regioisomeric lactone 15 (30%).The structure of the crystalline lactone, which was the second product off the column, was identified as the required lactone 14 by X-ray diffraction, see Figure 1.The most polar lactone was shown to be the regioisomeric lactone 15 by oxidation to the ketone 16 followed by reduction which gave a mixture of the separable lactones 15 and 17.Spin-decoupling experiments on lactone 17 indicated that the CHOH proton was coupled with the CHCH 3 proton so confirming the regiochemistry of lactones 15 and 17 as shown.The configuration of the hydroxyl bearing carbon, C-4, in lactones 15 and 17 was provisionally assigned on the assumption that the hydroxyl group would be introduced trans with respect to the lactone bridge by epoxide opening.However, this assignment is tentative since the products may be the result of thermodynamic control.The structure of lactone 13 was assigned by comparison of the carbonyl stretching frequency in its IR with that of lactone 14, from its 1 H NMR, and from the identification of lactones 14, 15 and 17 as the other three possible regio-and stereo-isomers.
To see whether a regioselective synthesis of the lactone 14 could be achieved, rearrangements of the epoxides obtained from the ester 12 were investigated.Epoxidation of this ester using m-chloroperoxybenzoic acid gave a 25 : 75 mixture of the cis-hydroxyepoxide 18 and its trans-diastereoisomer 19 (82%) whereas epoxidation using tert-butyl hydroperoxide in the presence of vanadyl acetylacetonate gave the cis-isomer 18 (81%) only.The structures of epoxides 18 and 19 were assigned by analogy with the literature, 2b and were consistent with nOe studies since enhancement of an epoxide proton was observed on irradiation of the 5-CH 3 group only for the cis-epoxide 18 and irradiation of H-2 and H-5 enhanced the epoxide protons only for the trans-isomer 19.The benzyl ester 10 was also epoxidised using m-chloroperoxybenzoic acid to give a 33 : 67 mixture of the cis-and trans-hydroxyepoxides 20 and 21, the stereochemistry of these epoxides being assigned by analogy with the literature 2b and by comparison with methyl esters 18 and 19.Acid catalysed rearrangement of the cis-hydroxyepoxide 18 using aqueous sulfuric acid in acetonitrile gave the required bicyclic lactone 14 (61%) together with the trihydroxy-ester 22 (33%).Under these conditions, the trans-epoxide 19 gave only the lactone 14 (88%), and the mixture of benzyl ester epoxides 20 and 21 gave the lactone 14 (70%) and the trihydroxy-ester 23 (30%).The configuration of the triol 23 was assigned on the basis of the diaxial couplings of ca. 10 Hz observed between H-3 and H-4 and between H-4 and H-5, and the axial -equatorial coupling of 3 Hz observed between H-2 and H-3.The structure of the trihydroxy methyl ester 22 was assigned by analogy.

Conclusions
Since the ester and the epoxide are cis-disposed in the trans-hydroxyepoxide 19, direct participation of the ester in epoxide ring-opening is not possible and so the epoxide ring-opening must involve a regioselective acid catalysed attack of water at C-1 (epoxide numbering), with subsequent lactonisation giving lactone 14.For the cis-hydroxyepoxide 18, the triol 22 must also have been formed by ring-opening of the epoxide initiated by attack of water at C-1.However, the mechanism of formation of the lactone 14 from the cis-hydroxyepoxide 18 is ambiguous since either hydrolysis of the epoxide followed by lactonisation or direct acid-catalysed epoxide ring-opening involving the ester carbonyl oxygen may be involved.Similar processes must be involved in the fomation of the lactones 13, 14 and 15 during the reaction between the acid 11 and m-chloroperoxybenzoic acid with a double-inversion process giving the unexpected hydroxylactone 13 in which the hydroxyl group is cis-disposed with respect to the lactone bridge.However, notwithstanding mechanistic complexities, this work has resulted in a regioand stereo-selective synthesis of lactone 14 which may be useful for a synthesis of the abyssomicins.

Experimental Section
General Procedures.Low resolution mass spectra were recorded on a Micromass Trio 200 spectrometer and high resolution mass spectra on a Kratos Concept IS spectrometer using electron impact ionisation (EI), chemical ionisation using ammonia (CI) or electrospray in the positive mode (ES).For selenium containing compounds, only peaks corresponding to isotope 80 Se are quoted although characteristic isotope patterns were seen.Infrared spectra were recorded on a Genesis FTIR as evaporated films on sodium chloride plates and nuclear magnetic resonance (NMR) spectra using deuterated chloroform as solvent unless otherwise stated.Proton NMR spectra were recorded on Bruker (500 MHz) and Varian Unity 500 (500 MHz) spectrometers.Residual non-deuterated solvent was used as internal standar and coupling constants are in Hz.Flash column chromatography was carried out using silica gel 60H (40 -60 nm, 230 -300 mesh) from Merck.Light Petroleum refers to the fraction that boils between 40 o C and 60 o C and was distilled prior to use.Ether refers to diethyl ether which was used without purification.(1RS,2SR,3SR,6RS)-3-Methyl-9-oxo-8-oxabicyclo[4.3.0]non-4-ene-2-carboselenoicacid Sephenyl ester ( 6) and (1RS,2RS,3SR,6RS)-3-methyl-9-oxo-8-oxabicyclo[4.3.0]non-4-ene-2carboselenoicacid Se-phenyl ester (7).A solution of triethylamine (4.74 mL, 34 mmol) in CH 2 Cl 2 (55 mL) was added to a suspension of the acid 5 7 (6.68 g, 34 mmol), in CH 2 Cl 2 (165 mL) at r.t under N 2 and the mixture stirred at room temperature for 10 min before being concentrated under reduced pressure to give the triethylammonium carboxylate salt as an orange oil.Tributylphosphine (12.63 mL, 51.17 mmol) was separately added dropwise to phenyl selenenyl chloride (10 g, 51.17 mmol) in tetrahydrofuran (250 mL) under N 2 and the resulting yellow solution stirred for 15 min.The triethylammonium carboxylate salt was then added as a suspension in tetrahydrofuran (250 mL).The cloudy mixture was stirred at ambient temperature under N 2 , for 48 h, added to ether (300 mL), and the mixture washed with water (2 x 500 mL) and dried (MgSO 4 ).After concentration under reduced pressure, the orange residue was chromatographed (1:1, ether: light petroleum) to give title compound 7 (2.27 g, 6.76 mmol, 20 %) as an oil (Found: M + +NH

Figure 1 .
Figure 1.The structure of the lactone 14 as established by X-ray diffraction.