Selective Oxidation Reactions of Natural Compounds with Hydrogen Peroxide Mediated by Methyltrioxorhenium

We have investigated the oxidative behaviour of natural compounds such as methyl abietate (1), farnesyl acetate (2), α-ionone (3), β-ionone (4), methyl linolelaidate (5), methyl linolenate (6) and bergamottin (7) with the oxidant system methyltrioxo-rhenium/H2O2/pyridine. The reactions, performed in CH2Cl2/H2O at 25 °C, have shown good regio- and stereoselectivity. The oxidation products were isolated by HPLC or silica gel chromatography and characterized by MS(EI), 1H-, 13C-NMR, APT, gCOSY, HSQC, TOCSY and NOESY measurements. The selectivity seems to be controlled by the nucleophilicity of double bonds and by stereoelectronic and steric effects.


Introduction
Oxyfunctionalization of cheap natural compounds is a useful protocol to obtain molecules widely employed in the fine chemicals-based industries as fragrances, flavors, and therapeutically active substances [1]. The most commonly employed stoichiometric oxidants are organic peroxyacids, particularly m-chloroperbenzoic acid (MCPBA). However, these oxidants are economically unattractive and are not selective for the preparation of acid-sensitive epoxides [2].
The active species involved in the oxygen transfer to the olefinic double bond are probably a monoperoxo complex [MeRe(O) 2 (O 2 )] and a diperoxo complex [MeRe(O)(O 2 ) 2 ], obtained respectively by the addition of one or two H 2 O 2 molecules to MTO [23]. However, depending on the nature of the epoxide, a ring opening catalyzed by the Re(VII) metal center can also occur to give 1,2-diols [3]. Moreover, the epoxide ring opening can be minimized by employing pyridine as a basic ligand. Mechanistic investigations [24], incorporating the positive pyridine effect [16], showed that the added pyridine minimizes also the MTO decomposition to perrhenate (ReO 4 − ) [25][26][27][28][29]. In this report we have investigated the oxidation reactions of some natural compounds by MTO/H 2 O 2 /pyridine, leading to products of practical interest or of interest as synthons in the synthesis of fine chemicals, with the aim of assessing the parameters controlling the process.

(100)
Entries 1-7 referred to the starting natural compounds reported in Figure 1, respectively. a Substrate/H 2 O 2 /MTO/pyridine (1:1.5:0.05:0.12); b A mixture of bisepoxides is also obtained (47%). (1) The oxyfunctionalization of methyl abietate (1), the diterpene which is the main component of rosin acids, is of interest in the research field on separation of rosin acids from pine oleoresin-based on double bond oxidation processes-and in the low cost synthesis of rosin acid derivatives having multiple functional groups. The oxidation of methyl abietate with MTO/H 2 O 2 /pyridine leads to synthons for the stereoselective syntheses of bioactive natural compounds. Ketone 8, derived from the oxidation of ring B, is the main product. Formation of 8 has been already observed by Haslinger et al. [30]. Probably, the first step of the reaction involves the formation of the epoxide obtained by electrophilic oxygen transfer to the double bond of ring B. Subsequent reorganization of the epoxide mediated by the presence of the rhenium derivative (Lewis acid) leads to the formation of the ketone 8 (Scheme 1).

Scheme 1. Suggested formation pathway for the oxidation product 8.
Lewis acid promoted rearrangement of epoxides into carbonyl compounds is an important and well known reaction [31,32] utilised in many cases for the synthesis of biologically active compounds. The remaining oxidation products 9 [33,34] and 10 are secondary oxidation products derived from the further oxidation of 8 (Scheme 2).
The diastereoselective formation of compound 9 by oxidation of 8 is probably due to the presence of the methyl group in position 10 which makes the attack of the upper face of the ring C by the bulky oxidant reagent (rhenium peroxide) sterically hard. The formation of the α-epoxide is supported by the 1 H-NMR signal of H-14 which appears as a singlet rather than a doublet indicating that there is no coupling with H-8 because the two protons form a 90° dihedral angle. Hydration of ketoepoxide 9 leads to the formation of diol 10a, which undergoes a 1,2-elimination assisted by rhenium and pyridine to yield the γ-hydroxyketone 10. Since it is reported [33,34] that when the OH group of the γ-hydroxyketone 10 linked at the C-13 atom is in axial position the 1 H-NMR signal of H-14 occurs at 6.75 ppm, we assume that in our case this OH group is in equatorial position because H-14 signal shifts upfield to 5.26 ppm. (2) Farnesyl epoxides are very useful starting compounds for the biomimetic synthesis of a large variety of natural monocyclic terpenoids [35,36]. Oxidation of farnesyl acetate (2) afforded the two monoepoxides 11 [37] and 12 [35,37] and a mixture of stereoisomeric diepoxides 13 [38] (see Table 1). The formation of the oxidation products, in agreement with the electrophilic oxygen transfer mechanism, is controlled by the nucleophilicity of double bonds. Therefore the reaction occurs in a regioselective manner at the double bonds C10-C11 and C6-C7 since the double bond C2-C3 is less reactive because is located nearby an electron withdrawing functional group.

All-Trans Farnesyl Acetate
The formation of the mixture of stereoisomeric diepoxides 13 was confirmed by the presence in the 1 H-NMR spectrum (see ESI, S18) of six singlets assigned to the three methyl groups linked to carbons C-11 and C-7 of the two three-membered rings, respectively.

α-Ionone (3) and β-Ionone (4)
α-Ionone (3) undergoes the oxidation reaction in a very good selective manner to yield mainly the monoepoxide 14 [39] (racemic cis-4,5-epoxy-4,5-dihydro-α-ionone) and small amounts of monoepoxide 15 [39] (racemic trans-4,5-epoxy-4,5-dihydro-α-ionone) (cis/trans ratio ~6), shown in Figure 2.  The reaction is regioselective because the double bond C7-C8 is not involved in the reaction due to its lower nucleophilicity due to the presence of the carbonyl group. Similar results have already been observed using m-chloroperbenzoic acid as oxidant (cis/trans ratio = 5) [39]. The high face selectivity (Table 1) is probably controlled by the larger crowding in the transition state leading to the trans epoxide which increases the activation energy and makes unfavourable the formation of the corresponding isomer. In fact, as Scheme 3 shows, during the oxygen transfer, the C-5 (as well as the C-4) undergoes a rehybridation from sp 2 to sp 3 and the methyl group linked to C-5, which in the transition state forming the trans epoxide is going to occupy an opposite position with respect to that of the incoming oxidant, assumes an axial direction parallel to that of one of the methyl groups linked to C-1, developing therefore repulsive interactions (1,3-diaxial interactions). On the other hand, the oxidation of β-ionone (4) is highly regioselective because the double bond C5-C6 is quite more nucleophilic than the C7-C8 double bond (which bears an electron withdrawing carbonyl functionality in the α-position) and therefore the epoxide 16 [40] is obtained as the solae product (see Table 1). (5) Oxidation of methyl linolelaidate (5) afforded the two monoepoxides 17 (9-undecenoic acid, 11-(3-pentyloxiranyl) methyl ester) and 18 [41,42] (oxiraneoctanoic acid, 3-(2-octenyl)-methyl ester), and, as main product, a mixture of two diastereoisomer diepoxides 19 [41,42] (methyl 9,10-12,13diepoxyoctadecenoate) obtained by a further oxidation of both 17 and 18 epoxides. (6) Oxidation of methyl linolenate leads to the nearly equal formation of three monoepoxides: 9-undecenoic acid,11-[3-(2-pentenyl)oxiranyl]-methyl ester 20 [43,44], 9,12-tetradecadienoic acid,14-(3-ethyloxiranyl)-methyl ester (9Z,12Z) 21 [43,44], and oxiraneoctanoic acid, 3-(2,5-octadienyl)methyl ester [2S[2α,3α(2Z,5Z)]] 22 [43,44] according to the similar nucleophilicity of the corresponding double bonds. (7) The bergamottin is a member of the furanocoumarin family and is most commonly found in grapefruit juice. Along with the chemically related compound 17,18-dihydroxybergamottin (24, Figure 3), it is believed to be responsible for the inhibitory effects of grapefruit juice on cytochrome P450 enzyme activity interfering therefore on the metabolism of a variety of pharmaceutical drugs [45,46]. Hence the need to provide easy and very selective synthetic routes for 24. Since the configuration of the C-17 of 24, isolated from both grapefruit juice and its peel oil [47], is R, we have developed a synthetic strategy to obtain 24 (yield 5%) by the highly regioselective oxidation of the C17-C18 double bond of bergamottin (7) with MTO/H 2 O 2 /pyridine to yield the racemic epoxide 23 and subsequent hydrolytic kinetic resolution (HKR) catalyzed by chiral (S,S)(salen)Co(III) complex [48][49][50]. The oxidation of bergamottin (7) is regioselective because, of the two double bonds, C17-C18 and C12-C13, present in the molecule, only the first one is involved in the oxidative process, probably because the C12-C13 double bond is nearby an electronegative oxygen atom and, being located in a position sterically hindered by the coumarin ring, undergoes unfavourable steric effects which contribute to make it scarcely reactive.

Representative Procedures for the HKR of Terminal Epoxides
The (S,S)salen Co(II) (see ESI, S2) (4.6 × 10 −4 mmol in 20 µL of THF) was treated with racemic 17,18-epoxy bergamottin (9.9 × 10 −2 mmol) in 200 µL of THF and 2.1 × 10 −3 mmol of AcOH. To this solution, cooled to 0 °C, 5.5 × 10 −2 mmol of H 2 O were added. The solution was allowed to warm to room temperature and stirred for 28 h. The reaction mixture was dried over molecular sieves (3 Å) and the solvent was evaporated under reduced pressure. PLC separation with n-hexane/EtOAc 1:1 afforded a pure sample of 17(R)-18 DHB (yield 5%) identified on the basis of its 1 H-NMR data [47]. The presence of a doublet at δ = 3.31 ppm is attributed to the H-17 of the (R)-enantiomer, while the same proton for the (S)-enantiomer is at 3.22 ppm.

Conclusions
We have oxidized some natural compounds, containing conjugate double bonds with the versatile oxidant system MTO/H 2 O 2 /pyridine. Some reactions have shown very good regio-and stereoselectivity. Stereoelectronic and steric effects and nucleophilicity of double bonds control the selectivity. Under the experimental conditions adopted in this work, the oxidation of methyl abietate leads to the oxidation of the double bond of the ring B with formation of the ketone 8, while the remaining oxidation products 9 and 10 are secondary oxidation products derived from the further oxidation of 8. α-and β-ionones are very selectively converted into the corresponding epoxides, whereas oxidation of methyl linolelaidate and methyl linolenate yields mixtures of mono-and diepoxides. Furthermore, we have developed a synthetic strategy leading to the 17(R),18-dihydroxybergamottin by HKR of the racemic epoxide obtained by a very regioselective epoxidation of bergamottin with MTO/H 2 O 2 /pyridine. Some of the oxidation products obtained are relevant as synthons in the biomimetic synthesis of cyclic terpenoids (farnesyl derivatives), in perfumery and fragrance industry (α-and β-ionone epoxides) or in medical implications (17(R),18-dihydroxybergamottin).