Synthesis and elaboration of trans 2,3-diaryloxiranes

2,3-Diaryloxiranes represent challenging intermediates for both their preparation and synthetic elaboration. Provided their synthesis in enantiopure form, they can be considered as suitable starting material for the synthesis of functionalized 1,2-diarylethanols, which are easily found in chiral auxiliaries, ligands and organocatalysts. The most efficient asymmetric methods for their preparation and synthetic elaboration are herein described. Regio-and stereoselective ring opening reactions, as reduction, nucleophilic opening with halides and oxygen nucleophiles have allowed straightforward access to versatile chiral intermediates such as aniline alcohols, halohydrins and 1,3-dioxolanes, their transformation affords chiral bases and bi-or tridentate ligands to use in asymmetric synthesis.


Introduction
Epoxides are among the most intriguing and challenging moieties in organic synthesis because they are not only significant synthetic endpoints, 1 but also highly useful synthetic intermediates.Due to their strain ring (having a thermodynamic driving force usually greater than 20 kcal/mol), they are considered "spring loaded" for nucleophilic ring opening reactions and among the best candidates for click chemistry. 2Utility and convenience of their use can be enhanced by the modulation of their reactivity with the help of Lewis acids coordinating the oxygen atom.Thus, ring-openings of epoxides have been applied in industrial scale for the synthesis of bulk chemicals, and in the synthesis of natural products and pharmaceuticals.A wide range of nucleophiles are described to react efficiently with epoxides and the regioselectivity of the opening is usually predicted by the different electrophilicity of the two oxiranyl carbons and/or the formation of chelates in presence of other coordinating moieties in the molecule.The high stereoselectivity in the opening reaction is mostly assured by the S N 2 pathway and there is usually low, if any, epimerization at the electrophilic oxiranyl carbon.Such general stereospecificity highly encourages the use of enantiopure epoxides as key intermediates in asymmetric synthesis, since no loss of enantiomeric purity in the subsequent steps is generally reported.One of the major advantages of nucleophilic openings of three member rings is stereoelectronically disfavored competing elimination process. 3he importance of all these procedures lies not only in the synthesized product, but also in the availability of the starting materials.Usually, epoxides are easily prepared by oxidation process of the corresponding alkenes and many enantioselective versions of this reaction have been developed.
2,3-Diaryloxiranes can be considered non conventional epoxides in terms of their synthesis and, above all, their reactivity.The classical metal-catalyzed epoxidation of olefins and, in general, any oxidative procedure is usually slower in the case of stilbene compounds and high HOMO aromatic π-systems (as in polyphenolic stilbenes) are hardly preserved in presence of strong oxidants.Compared to alkyl ones, 2,3-diaryloxiranes usually show lower reactivity towards nucleophiles and they need some activation by Lewis acid.Due to the characteristic chemical behavior of benzyl type carbons in neutral or acidic medium they appear challenging substrates for the little reactivity differences of the two oxiranyl carbons and the possible side reactions such as eliminations or rearrangements.
This report deals with the most efficient methods of preparation and opening reactions of optically active 2,3-diaryloxiranes and their applications in the synthesis of key enantiopure intermediates.

Synthesis of 2,3-diaryloxiranes 1.1 Epoxidation of stilbenic olefins
Since of the Sharpless epoxidation reaction of allylic alcohols many efforts have been done to discover a more general protocol which might be effective for the asymmetric epoxidation of unfunctionalized olefins.Chiral metal complexes were found firstly to effect highly enantioselective oxo-transfer to unfunctionalized olefins, as mimic the stereoselectivity found in biological systems. 4In the last decade chiral dioxiranes have been developed as effective epoxidation catalysts and have expanded the range of the substrate requirement in many cases. 5his paragraph presents an overview of the most efficient methods of epoxidation of stilbene olefins, and shows the scope, advantages and limitation of this approach.

Metal catalysed epoxidations
Oxo transfer from metal complexes results in a net two electron reduction at the metal center.Thus, iron, manganese, ruthenium and chromium have proven effective for catalytic epoxidation via oxo-transfer, 6 and these metals are mostly coordinated by tetradentate porphyrin and salen ligands.The lack of stereospecificity in the epoxidation of certain olefins gives evidence for a stepwise oxo-transfer mechanism competing with the direct attack with concerted C-O bond formation.Alkyl-substituted olefins generally undergo stereospecific epoxidation, with cisolefins affording cis-epoxides exclusively.Acyclic olefins conjugated to aryl, vinyl, or alkynyl groups undergo nonstereospecific epoxidation, with cis-olefins affording mixtures of cis and trans epoxides.Non-polar radical intermediates are involved in the case of non-concerted epoxidation with Mn(salen) catalysts. 7Among these complexes, catalyst 1 (Figure 1) has been employed widely on both laboratory and industrial scale for the epoxidation of cis-disubstituted and trisubstituted olefins. 8trans-olefins remain particularly challenging substrates for asymmetric epoxidation with oxo-transfer catalyst.However, catalysts bearing stereogenic centers on the 3-and 3'-positions of the salen ligand, as in 2 and 3 have been examined, with a promising 61% ee in the epoxidation of trans-stilbene (by catalyst 2). 9
A more successful strategy for the enantioselective synthesis of trans-epoxides has been developed with the [Mn(salen)]-catalyzed epoxidation of cis-disubstituted olefins in the presence of alkaloid-derived phase transfer catalysts such as 5 (Scheme 1).In this case the reaction resulted in the formation of the trans epoxide as the major, and in some cases nearly exclusive, product.

Scheme 1
Recently, three novel chiral binuclear Mn(III)-Schiff-base complexes have been synthesized and used in the asymmetric epoxidation of trans-stilbene.The best result was obtained using 6c and NaClO as terminal oxidant (43% yield, 40% ee). 12RKAT USA, Inc.

Figure 2
Even lower ees (3-12%) were obtained if using such dimeric complexes in the presence of pyridine N-oxide or Fujita's porous coordination polymer ({[Cd(4,4'-bpy) 2 (NO 3 ) 2 } ∞ ). 13 Analogous chromium-salen systems appear complementary to their manganese counterpart, since good enantioselectivity was obtained in the epoxidation of the "difficult" transdisubstituted olefins.Chromium oxo complexes as 8, derived from the parent salen complexes 7 (Figure 3) are isolable and have been studied deeply in both stoichiometric and catalytic epoxidations.
These chiral chromium(V) catalysts have shown good enantioselectivity in the epoxidation of trans-disubstituted olefins, as in the case of trans-β-methylstyrene, in which the corresponding epoxide was obtained in 45% yield and in 92% ee, by use of stoichiometric quantity of 7 (X -= NO 3 -, L = Ph 3 PO) and 1.2 equivalents of iodosyl benzene.Under catalytic conditions (10 mol% of 7) in the presence of PhIO, the epoxide was formed in higher yield (71%) but with a slightly lower ee (82%). 14any others metals, ligands and terminal oxidants have been used to broaden the scope of the reaction, but examples of metal catalysed asymmetric epoxidation of stilbene type olefins are only occasionally described in the literature. 15Ruthenium catalysts based on pyridine-2,6bisoxazoline (pybox) ligands, as 9 (Scheme 2), have been used in combination with iodosyl benzene, bisacetoxyiod benzene [PhI(OAc) 2 ], or TBHP for the oxidation of trans stilbene.In the best results, with PhI(OAc) 2 as oxidant, trans-stilbene oxide was obtained in 80% yield and with 63% ee. 16Such catalytic system was also reexamined, finding that asymmetric epoxidations could be performed even with 30% aqueous hydrogen peroxide.

Scheme 3
The yields were from good to excellent in all cases and exploiting the broad coverage of substitution pattern of the ligands, both enantiomers of trans-stilbene oxide could be obtained, with ees ranging from 52% to 71%. 17 More easily tunable N,N,N-pyridinebisimidazoline (pybim) ligands 12 (Figure 4) have also been synthesized and tested as ruthenium complexes, giving excellent yields and moderate to good enantioselectivities in the epoxidation of aromatic olefins (up to 71% ee for trans-stilbene oxide). 18

. Epoxidation by dioxiranes
The oxidation of organic compounds with dioxirane reagents has emerged since late '80 as an important synthetic method.Currently, chiral dioxiranes, derived in situ from the oxidation of suitable chiral ketones by the triple salt oxone (2KHSO 5 •KHSO 4 •K 2 SO 4 ), have emerged as some of the most effective organocatalysts in the asymmetric epoxidation of alkenes. 19Excellent enantioselectivity has been achieved with trisubstituted and trans-alkenes, while moderate to good selectivity has been achieved for other alkenes, thus making this method complementary to the metal catalyzed epoxidation.The discovery that ketones bearing electron-withdrawing groups such as halogen and OAc adjacent to the carbonyl showed higher activity in epoxidation reactions led to design C 2 -symmetric ketones as 13 which effected the catalytic epoxidation of unfunctionalized olefins with high level of enantioselectivity in the case of stilbene derivatives (Scheme 4). 20RKAT USA, Inc.

Scheme 4
The fructose-derived ketone 15 (Shi's ketone) was discovered to be particularly effective for the epoxidation of trans-olefins (Scheme 5).Trans-stilbene was epoxidized in 95% ee using stoichiometric amount of ketone. 21The method has been rendered catalytic (30% mol) upon the discovery that higher pH led to improved substrate conversion.The discovery of the activating effect of a single fluorine atom adjacent to carbonyl in the dioxirane-mediated epoxidation of olefins has widened the choice of enantiopure ketone potential catalysts, which could be suitable dioxirane precursors.Thus, many structurally different chiral fluoroketones have been prepared and successfully tested to trans olefins.Fluoro tropanone ammonium triflate 16 slowly converted trans-stilbene to the corresponding (S,S)-epoxide in 79% yield and 58% ee, while C 2 biphenyl cyclic fluoro ketone 17 gave (R.R)-epoxide in 46% yield and 94% ee (Figure 5). 23 Figure 5 Armstrong has studied different chiral fluorinated bicyclo[3.2.1]octan-3-ones, as 18 and 19 (Figure 6), which gave high yields and good enantioselectivities. 24 α-fluorotropinone 18 has been also supported on silica materials and its activity appeared comparable to that of homogenous counterpart, 25  trans-stilbene 83% ee (R,R)

Figure 6
Solladié-Cavallo's studies on α-fluorocyclohexanones derived from chiral pool have introduced efficient and easy-to-make enantiopure fluoroketones, which worked well in catalytic amounts and gave among the highest enantioselectivities in the epoxidation of trans-olefins.C8substituted ketones 20-23 (Figure 7) provided enantioselectivity ranging between 82 and 90%, 27 while unsubstituted ketone 24 gave only 60% ee in the case of trans-stilbene epoxidation. 28

Epoxidation of carbonyl compounds
There are two general approaches to the direct asymmetric epoxidation of carbonyl compounds: ylide-mediated epoxidation and α-halo enolate epoxidation (Darzens reaction).While the latter has been successfully used for the synthesis of epoxy esters, the first has shown particularly useful for the preparetion of 2,3-diaryloxiranes (Scheme 6).
or SeR 2 R 3 or R 4 = alkyl, aryl vinyl or amide Scheme 6

Scheme 7
This sulfide was initially benzylated to form a single diastereoisomer of the sulfonium salt 26.The corresponding ylide was formed by the aid of sodium hydride and the epoxidation was carried out at low temperature to afford trans-diaryl epoxides 27 with good stereoselctivity and high enantioselectivity with recovery of the chiral sulfide 25.The use of a phosphazene base (EtP 2 ) resulted in rapid ylide formation and allowed the preparation of aryl-vinyl epoxides 30 and heteroaromatic aryl-epoxides 31 in good chemical yield and high stereo-and enantioselectivity.Such procedure has been used for the synthesis of different substituted trans-2,3-diaryloxiranes (vide infra), proving its high versatility.
The Aggarwal group has used chiral sulfide 28, derived from camphorsulfonyl chloride, in asymmetric epoxidation.Once preformed the salt 29 from either the bromide or the alcohol, the ylide was prepared using different bases in presence of a range of carbonyl compounds.The method proved effective for the synthesis of aryl-aryl, aryl-heteroaryl, aryl-alkyl, and aryl-vinyl epoxides 32 (Scheme 8).

Catalytic ylide-mediated epoxidation
Many efforts have been made to render the ylide-mediated epoxidation catalytic.Aggarwal has developed an efficient catalytic cycle, in which the sulfur ylide is generated through the reaction between chiral sulfide 28 and a metallocarbene.The metallocarbene is generated by the decomposition of a diazo compound 32, which can in turn be generated in situ from the tosylhydrazone salt 31 by warming in the presence of phase transfer catalyst.The tosylhydrazone salt can also be generated in situ from the corresponding aldehyde 30 and tosylhydrazine in presence of base (Scheme 9).

Scheme 9
This process enables the coupling of two different aldehydes to produce trans-epoxides in high enantio-and diastereoselectivity.A range of aldehydes have been used in this process with phenyl tosylhydrazone salt and good selectivity was observed with aromatic and heteroaromatic aldehydes. 33Pyridyl aldehydes proved to be incompatible with this process, presumably due to the presence of a nucleophilic nitrogen atom, which can compete with the sulfide for the metallocarbene to form a pyridinium ylide.Sulfide loadings as low as 5 mol % could be used in many cases.Benzaldehyde was also treated with a range of tosylhydrazone salts and the scope of the process has been extensively mapped out, enabling the optimum disconnection for epoxidation to be chosen.

Elaboration of 2,3-diaryloxiranes
Among the various methods for the preparation of a single enantiomer, asymmetric catalysis represents the most attractive method from the atom-economy point of view.Chiral ligands play a fundamental role in the complex phenomenon of asymmetric catalysis.Among the possible key intermediates for the synthesis of functionalized alcohols, epoxides are considered the most versatile and convenient, due to their well known enantioselective preparation methods and regioselective ring opening and subsequent protections. 34In recent years, our research group has started a study on regio-and stereoselective ring opening reactions on 2,3-diaryloxiranes, with the aim to afford, in a simple and immediate way, functionalized 1,2-diarylethanols, which are found in chiral auxiliaries, ligands and stationary phases for chiral HPLC.Moreover, the contemporary presence of two aromatic rings promotes non covalent π−π interactions, which are more and more studied because they are involved in a wide variety of chemical and biological processes. 35Despite the high chemical versatility of such epoxides, literature data on their use are few, probably due to the difficulty of obtaining efficient regioselective ring openings on epoxide benzylic carbons which have very similar reactivity.Our study allowed to individuate original and efficient synthetic procedures of regio-and stereoselective ring opening reactions on such substrates, obtaining new enantiopure aniline aminoalcohols and benzoxazines, 1,2diarylbromo alcohols and acetonides.

Reductive ring opening
The reductive ring-opening of epoxides to the corresponding alcohols has become a powerful tool in organic synthesis, due to the rapid development of efficient and practical methods for their preparation, both in racemic and in enantiopure form.Metal hydrides 36 or dissolving metals are frequently employed for this purpose, although the large quantity of metal sludge are often produced. 37The need of a practical version of this reaction with low environmental impact has generated interest in heterogeneous catalytic systems.In particular, various catalysts based on Ni, Pd and Pt has been developed in order to increase the chemo-and regioselectivity of such reactions, even with enantiopure epoxides. 38Different hydrogen sources, such as HCOONH 4 , 39 and catalysts, such as Pd/C ethylendiamine complexes, 40 have been used to improve selectivity and to prevent further hydrogenolysis of the alcoholic C-O bond.Nevertheless, the solvolysis with methanol remains a problem, particularly with benzylic epoxides.Recently, Pd nanoparticles, microencapsulated in polyurea, have been described to be very efficient in the reductive ring-opening of different benzyl and alkyl epoxides. 41Moreover, a magnetically separable palladium catalyst has been synthesized and described to be active and selective for hydrogenolysis of different epoxides. 42Titanocene(III) chloride has been claimed to be one of the best reagent reported carrying out the reductive epoxide opening. 43The β-titanoxy radicals have been reduced efficiently by different hydrogen atom donors and the regioselectivity towards the less-substituted alcohol has been reported to be high. 44hiral pyridyl alcohols have numerous applications, as ligands in asymmetric metal catalysis, 45 as resolving agents 46 or as starting materials for the preparation of more advanced chiral ligands. 47As one of the first applications of the asymmetric synthesis of diaromatic epoxides, with high stereo-and enantioselectivity, Solladié-Cavallo described the reductive ring opening of 2-pyridyl epoxide 33a and 2-furyl epoxide 34 (Scheme 10).Asymmetric synthesis of the epoxides was successfully performed by using the pure benzylsulfonium salt derived from Eliel's oxathiane, the corresponding commercial 2-pyridyl-and 2-furylaldehyde and the phosphazene base EtP 2 . 31RKAT USA, Inc.Although catalytic hydrogenation over Pd/C is one of the most simple and clean reduction procedure, in terms of reagents and subsequent work up, it is only occasionally described to be efficient on epoxides. 48Moreover, no systematic study on 2,3-diaryloxiranes are known so far.Thus, the epoxides of type 33 were reacted with H 2 at 1 atm in presence of catalytic amount of Pd/C 10% in the appropriate solvent.The most significant results are collected in Table 1. 49All reactions were performed using Pd,C(10%)/substrate = 20mg/mmol.The conversions were all higher than 99% and were determined by 1  All reactions were completely regioselective, producing only one of the two possible regioisomers, with chemical yields from good to excellent.Such regioselectivity appeared puzzling, being irrespective to the substituent electronic properties.
In fact, from all the oxiranes with either a strong electron-withdrawing group (33a, 33b, 33d and 33e) or an electron-releasing group (33c) on one phenyl ring, the regioisomer of type 35 was isolated as the major product in the reaction mixture.Even with the weak electron-releasing pfluoro substituent, the same behavior was confirmed (entry 8).These results were quite surprising, if we consider the classical mechanism of hydrogenolysis, with benzyl type radicals as key intermediates.In fact none of the results seemed to suggest the formation of a regular Stype benzyl radical, 50 which should be the substituted one in all cases affording the opposite regioisomer.
The next step of our study was to test reductive ring opening of diaryl epoxides by hydrides, in order to induce a change of regioselectivity.Among various hydrides which are efficient in the reductive opening of epoxides, LiAlH 4 is the most common, 51 and the milder borohydrides often require the presence of a Lewis acid, which activates the epoxide toward nucleophilic attack.Indeed, NaBH 4 /ZrCl 4, 52 or Zn(BH 4 ) 2 /SiO 2 53 systems are described to be efficient and, recently, NaCNBH 3 in presence of ZnI 2 was found to produce regioselective ring opening of benzylic epoxides. 54NaBH 4 /Pd system proved to be highly dependent upon reaction conditions, ranging between a simple source of hydrogen (like in the catalytic hydrogenation) and a more "hydridic" reagent in selective nitro group reactions. 55This suggested to test it with diarylepoxides, looking for a complementary method with respect to catalytic hydrogenation.Thus, the epoxides 33 were treated with NaBH 4 /Pd and the most significant results are collected in Table 2.All the reactions were performed at r.t., with NaBH 4 /substrate = 7.5/1.0,Pd/C(10%)/substrate = 10 mg/mmol.The conversions were all higher than 99% and were determined by 1 H NMR of the crude product.b Isolated yield.c No isolable product was obtained from the rest of the crude.
The regioselectivity was highly affected by substituents electronic properties, combined with the unique characteristic of the reagent.Indeed, ortho and para substituted substrates gave the same regioisomer, in similar chemical yield.In substrates with the strong electron withdrawing group CF 3 (entry 4 and 5), only the regioisomer 35 were detected in the reaction mixture, the attack of the hydrogen being exclusively on the β-carbon with respect to the substituted phenyl ring.These results account for an electron deficient acyclic intermediate, which was already postulated for opening reaction with LiBr/Amb.15 system (vide infra). 56On the other hand, this mechanism can hardly explain the results for epoxides 33a-33c, in which the regioselectivity observed is opposite to that expected for an acyclic intermediate.In the case of pyridyl epoxides 33a and 33b (bearing electron withdrawing groups), only the alcohols of type 36 (α-opening) were isolated (entries 1 and 2); on the other hand, in presence of OCH 3 substituent on one phenyl ring, only regioisomer 35 (β-opening) was obtained (entry 3).These results indicate more likely the activated epoxide as reactive species, in which the electrophilicity of the two oxiranyl carbons rules the reactivity.
Beyond mechanistic considerations, the method appears of synthetic value for the direct access to substituted alcohols of type 35a and 36a (Figure 8), which can be envisaged as ligands in asymmetric synthesis.
ARKAT USA, Inc.The application of the described methodologies led to the preparation of new anilinecontaining aminoalcohols in enantiopure form, as intermediates for the synthesis of chiral ligands and bases.

Scheme 12
Elaboration of amino alcohols allowed the selective alkylation of either amino or hydroxyl group, and all the possible alkylated derivatives were obtained, alternatively (scheme 13).
N,N-dimethylated anilino alcohols were directly obtained in good yield by LiH/CH 3 I system (route A).These compounds were tested as chiral ligands in the asymmetric alkylation of benzaldehyde with Et 2 Zn, and only the product from regioisomer of type 40 gave some induction (40% ee of the corresponding 1-phenylpropanol).Using anhydrous Mg(ClO 4 ) 2 /(Boc) 2 O system 58 on N-Boc protected anilino alcohols, the corresponding O-tert-butyl derivatives were obtained,

Nucleophilic ring opening by metal halides
Vicinal halo alcohols have attracted the interest of organic chemists for their usefulness as versatile building blocks. 61They are also substrates for a particular class of enzymes, halohydrin dehalogenases, 62 that are of interest both to organic synthesis 63 (e.g., chiral resolution of racemic compounds 64 ) and bioremediation of the environment (e.g., removal of pollutants from soil, ground-water or waste-water 62,65 ).Although various synthetic procedures have been reported, most of them have some limitations, in terms of either harsh reaction conditions or low regioselectivity in the opening of unsymmetrical epoxides. 66In more recent years, new and milder procedures have been proposed, with the use of silyl halides in the presence of different promoters, 67 elemental halogen with various catalysts, 68 borane halogenides 69 and metal halides with Lewis 70 or Brønsted 71 acid systems.The use of ionic liquids has broadened the application of such procedures. 72Among all these methods, very few are suitable for regioselective openings of nonsymmetrical 2,3-disubstituted oxiranes and, in such cases, regio-and stereoselective openings are usually performed on substrates bearing chelating atoms or groups. 73,3-Diaryloxiranes appeared very challenging for ring opening, due to their low reactivity without acid promoters and the possible competitive rearrangements in such conditions. 74n search of efficient conditions for the success of nucleophilic opening of the oxirane ring, different metal halide systems were attempted to the opening of trans-stilbene oxide 41.In particular, the attention was turned to the use of a metal bromide/Amberlyst 15 system 75 and to the MgBr 2 reagent, already successfully employed in the opening of epoxy-and aziridinoalcohols and derivatives. 76The results in Table 3 show a general high chemical yield in the obtaining of the corresponding bromohydrines, with different levels of diastereoselectivity, depending on reagents and reaction conditions. 77Only in the case of MgBr 2 , the reaction can be performed in absence of the acidic resin Amberlyst 15, and the expected anti diastereoisomer 42 was obtained in good yield.On the other hand, using alternatively, MgBr 2 , NaBr or KBr with Amberlyst 15, high syn/anti ratio was always observed and the syn bromohydrin 43 was obtained in good yield.Subsequent studies on nonsymmetrical substituted 2,3-diaryloxiranes showed the efficiency of these procedures in terms of both regio-and stereoselectivity of the ring opening (Table 4).The behaviour of trans 2-pyridyl-and 2-fluorophenyl epoxides 33a and 48 in presence of either MgBr 2 or NaBr/Amberlyst 15 system was studied.In the case of 33a only the regioisomer 49 was obtained in all reaction conditions (with either MgBr 2 or NaBr/Amb.15), in diastereoisomeric ratios ranging from 4/1 to >98/2 in favour of the anti stereoisomer 49I.2fluorophenyl epoxide 48 and MgBr 2 provided only the two anti isomers 50I and 51I (of the four possible isomers) in the ratio ~ 4:1 in favor of regioisomer 50I.On the other hand, NaBr/Amb.15 gave, in quantitative yield, a mixture of all four isomers, with the syn bromohydrin 50II as the major compound. 78The difference found in regioselectivity of the reactions with MgBr 2 has been explained by the assistance of neighbouring group, which is weaker in the case of fluorine (epoxide 48) although the bite angle 80 is more favourable in the case of epoxide 48 (six-membered ring) than in epoxide 33a (five-membered ring) in presence of small cations such as magnesium (Figure 9).The complexing ability of nitrogen is strong enough to overcome the effect of the bite angle and direct the approach of the reagent, resulting in a complete regioselectivity in the case of epoxide 33a.The lower diastereoselectivity obtained with NaBr/Amb.15 protocol (with unexpected 50II as the major product in the case of epoxide 48), suggested a different mechanism for the epoxide ring opening, through the formation of an acyclic intermediate.
All these results prompted us to study, more deeply, both the influence of reaction conditions on the stereoselectivity in the opening of the model (E)-stilbene oxide and on the regioselectivity in the opening of nonsymmetrical substituted 2,3-diaryloxiranes. 81Thus, a systematic study has been conducted, analyzing the influence of different parameters (substrate/bromide ratio, substrate/Amberlyst 15 ratio, temperature, reagents concentration) on the stereoselectivity in the opening of (E)-stilbene oxide 41 with the LiBr/Amberlyst 15 system (Table 5).Among the different parameters, the reaction temperature seems dramatically effect the stereoselectivity of the ring opening.At room temperature, the bromohydrins were obtained in high yield, with a syn/anti ratio ranging between 75/25 and 88/12 (entries 1-3).With lower reaction temperature, the amount of anti-bromohydrin 42 increased, until becoming the major reaction product below -25°C.Basing on these results, the formation of an acyclic cationic-type intermediate, which competes with a classical S N 2 opening has been postulated.The syn bromohydrin 43 resulted more favorable at room temperature.By lowering the temperature the formation of the acyclic intermediate becomes less probable and an S N 2 opening with inversion of configuration becomes competitive with the decreasing of the syn/anti ratio.
The study of the behaviour of nonsymmetrical para-substituted 2,3-diaryloxiranes with LiBr/Amberlyst 15 system also allowed to rationalize of the substituent effects on the regioselectivity of the ring opening. 81Different p-substituted (E)-2,3-diaryloxiranes were prepared in good yield by the reaction of benzyliden sulfurylide with the appropriate aldehyde and then allowed to react with LiBr/Amberlyst 15 at room temperature (Table 6).The results showed a dramatic effect of substituents electronic properties on the regioselectivity.In the oxiranes with one phenyl ring bearing a strong EWG (NO 2 , CF 3 : entries 1 and 2), only the regioisomer 53 was detected in the reaction mixture, with the exclusive attack of the nucleophile is on the β-carbon with respect to the substituted phenyl ring.In the presence of a strong ERG (OCH 3 ) on the phenyl ring, the regioisomer 54 (α-opening) was the only observed reaction product.In the case of trans-β-methyl stirene epoxide (entry 5), the reaction was completely regioselective toward 54, via an attack of the bromide on the most electrophilic benzyl carbon.
The hypothesis of the formation of an acyclic cationic-type intermediate as the key step of the reaction was confirmed by theoretical calculation, run on the protonated epoxides 55 and 56 (Figure 10), which were considered as model structures for the reactive intermediate.In fact these structures invariably converge to acyclic cationic structures, if submitted to semiempirical calculation at the PM3 level.Once carried out a conformational search on the two couples of opened structures by this level of calculation, each conformer was then submitted to ab initio calculation at the DFT/B3LYP/6-31G * level.Comparing the predicted free energies of the two opened p-NO 2 cationic structures 52a(H + )A and 52a(H + )B, which would give products 53 and 54 respectively, a difference in stability of 4.1 kcal/mol in favor of structure 52a(H + )A was calculated, which accounts for the complete regioselectivity of the reaction (Figure 11).The same comparison between the free energies of p-OCH 3 cationic structures 33c(H + )A and 33c(H + )B (Figure 12) provided a difference in stability of 7.6 kcal/mol in favor of 33c(H + )B, in accordance with the opposite regioselectivity observed for epoxide 33c.52a(H + )A more stable 52a(H + )B less stable Useful intermediates of new polydentate ligands were prepared starting from enantiopure ortho substituted 2,3-diaryloxiranes 38 and 33h (Scheme 15).Both the starting epoxides were prepared in good yield using the Solladiè-Cavallo epoxidation methodology. 81Both epoxides afforded the corresponding syn-bromohydrins 57 and 58, respectively, in excellent to quantitative yield, via a regio-and stereoselective opening with retention of configuration at the reactive carbon.Substitution of bromine with azide and final reduction gave the tridentate amino alcohols with no loss of optical purity.

Ring opening by oxygen nucleophiles
Ring opening reaction of epoxides by oxygen nucleophiles represents a traditional method for the preparation of 1,2-diol derivatives. 82Hydrolysis of epoxides is usually catalyzed by acids and bases.Among the acid catalysts perchloric acid is preferred, since side reaction are minimized.Dimethyl sulfoxide appears a superior solvent for the alkaline hydrolysis of epoxides.In general, the reaction remains difficult, mainly because alcohols, and particularly phenols, behave as poor nucleophilic reagents in substitution process.Strong acidic or basic conditions or metal-catalyzed reactions usually occur in anti-stereoselective fashion 83 and catalytic asymmetric versions have also been developed. 84Vinyl and aryl epoxides are only moderately reactive under classical displacement conditions and they need the presence of transition metal catalysts. 85A mild rhodium-catalyzed reaction of vinyl epoxides with alcohols has been described occurring with excellent anti -stereo-and 1,2-regioselectivity. 86 Complementarily, a simple method for the synnucleophilic displacement of aryl and vinyl epoxides with substituted phenols, using aryl borates as activating nucleophiles, has been recently reported. 87Electronegatively-substituted iron porphyrin complex has been shown to efficiently catalyze the ring-opening reaction of various epoxides by methanol and water under mild and neutral conditions to give stereospecifically the corresponding mono-ethers 1,2-diols and with moderate regioselectivity. 88Substrate-dependent stereoselective ring opening of enantiopure epoxides has been described with the use of nitric oxide (and traces of O 2 ).Thus, (R,R) trans stilbene oxide has been transformed in high yield in the corresponding syn hydroxy nitrate. 89he 2,2-dimethyl-1,3-dioxolane (acetonide) group is a widely used protecting group for vicinal diols.The direct conversion of epoxides to the corresponding acetonides has been described with the use of different Lewis acid catalysts.Various degree of success in terms of yield and selectivity has been shown by anhydrous SnCl 2 , 90 tin(IV) tetraphenylporphyrin perchlorate, 91 bismuth(III) salts, 92 titanium complexes, 93 [(C 5 Me 5 )-Ir(NaMe 3 )], 94 RuCl 3 , 95 CH 3 ReO 3 , 96 Cu(OTf) 2 , 97 Er(OTf) 3 , 98 BF 3 •Et 2 O, 99 LiBF 4 , 100 and heteropolyacids. 101he transformation of epoxides into the corresponding acetonides by these reagents usually occurs through a S N 2 mechanism, with inversion of configuration at the oxiranyl carbon approached by acetone.Thus, trans-symmetrical 2,3-substituted oxiranes lead invariably to meso-acetonides, loosing any possible chiral information of the substrate.

Scheme 16
The study on trans-stilbene oxide has shown, as previously noted in the reaction with lithium bromide, a strong effect of temperature on the reaction stereoselectivity, with the highest trans/cis ratio of 3/2 obtained at room temperature.Upon lowering the temperature, the formation of the cis isomer, by a classical S N 2 ring opening with inversion of configuration, increases, and cis isomer becomes the major reaction product below -10°C.
The procedure has been successfully extended to optically pure and non symmetrically substituted epoxides, such as 33h, 38

Scheme 18
Pasteur, Strasbourg (France).His research interest is focused on new methods of stereoselective functionalization for the synthesis of enantiopure compounds with high molecular recognition capacity, chemo-, regio-and diastereoselective ring opening reactions of epoxides, asymmetric synthesis of pharmaceuticals, chemo-and stereoselective oxidation methods with chiral and achiral dioxiranes.

10
Scheme 10 H NMR of the crude product.b A = CH 3 OH; B = EtOAc, 1% AcOH c Isolated yield.d No isolable product was obtained from the rest of the crude.e Epoxide 33g was prepared by oxidation of commercial trans β-methyl-styrene with m-CPBA.

Table 2 .
Reduction of epoxides by NaBH4/Pd system 60re subsequently reduced by LiAlH 459to afford the N-monomethyl-O-alkylated derivatives, precursors of new strong chiral bases (route B).Selective monomethylated anilino alcohols were obtained by introduction of Boc group on nitrogen followed by reduction with LiAlH 4 (route C).Finally, the synthetically challenging O-alkylated anilino alcohols were obtained from the N-Boc derivatives by the use of wet60Mg(ClO 4 ) 2 /(Boc) 2 O system, which effected tert-butylation of hydroxyl group together with hydrolysis of Boc group (route D).
ARKAT USA, Inc.which D Scheme 13

Table 3 .
Opening of trans stilbene oxide with metal halides 1 Calculated by1H NMR analysis of the crude mixture.bIsolated.Using the results of this investigation, a new stereodivergent synthesis of optically pure anti and syn 2-amino-1,2-diphenylethanols was achieved (scheme 14).After a straightforward ARKAT USA, Inc.

Table 4
a Determined by 1 H NMR spectroscopy of the crude productof the reaction.b 3M solution in Et 2 O, freshly prepared from Mg and 1,2-dibromoethane in diethyl ether 79 c Isolated yield.d Commercial.

Table 5 .
LiBr/Amb 15 promoted ring opening of trans-stilbene oxide in different reaction conditions b Isolated.

Table 6 .
LiBr/Amb 15 promoted ring opening of nonsymmetrical 2,3-substituted oxiranes, at room temperature (except entry 4) Determined by GC/MS analysis of the crude together with GC/MS and 1 H NMR analysis of the alkaline ring closure of the bromohydrins mixture.
c d The bromohydrins were characterized as acetates.
and 41, which has afforded the corresponding enantiopure trans acetonides 61-63 in good yield (Scheme 17).Elaboration of acetonide 61 has allowed the preparation of the aminodiol 65, which can be used as tridentate ligand in asymmetric synthesis (Scheme 18).