*2.4. With Halogens*

Metal–salen complexes have seen limited use as catalysts for the ARO of *meso*-epoxides with halogen nucleophiles. The few examples that can be found in literature are focused on fluorinations, most likely owing to the growing interest in and importance of fluorine substituted organic compounds [72–74].

Haufe and coworkers published a number of studies using Cr–salen complex **46** and different fluoride sources to achieve the enantioselective fluorination of epoxides. The reaction of cyclohexene oxide with KHF2/18-crown-6 gave (*R*,*<sup>R</sup>*)-2-fluorocyclohexanol in 64% yield and 55% *ee* when stoichiometric amounts of catalyst **46** was used. Attempts to lower the catalyst loading resulted in a drastic drop in enantioselectivity. The reaction also produced some amount of the corresponding chlorohydrin [75]. Changing the fluoride source to silver fluoride led to improved yields and enantioselectivities, and complete suppression of the formation of the chlorinated by-product, although a high catalyst loading of 50–100 mol% was still required (Scheme 18) [76]. Attempts to lower the necessary quantity of catalyst by using different fluoride sources and reaction conditions proved unsuccessful [77].

**Scheme 18.** The asymmetric ring-opening of cyclohexene oxide with AgF catalyzed by Cr–salen complex **46**.

Doyle and Kalow reported the enantioselective ring-opening of cyclic *meso*-epoxides with fluoride catalyzed by Co(II)salen complex **47** and an enantiopure amine cocatalyst. The protocol included in situ generation of HF from benzoyl fluoride and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). For the ARO of variety cyclic *meso*-epoxides, the use of (-)-tetramisole as the chiral base gave good yields and high enantioselectivities of the resulting fluorohydrins (Scheme 19) [78].

**Scheme 19.** The asymmetric ring-opening of *meso*-epoxides with HF catalyzed by Co(II)salen complex **47**.

Extensive mechanistic studies of the above reaction resulted in some unexpected and seemingly incompatible data. Kinetic studies demonstrated an apparent first-order dependence on the catalyst while substituent and nonlinear effects supported a bimetallic rate-determining step. Based on this, the authors proposed that the active fluorinating agen<sup>t</sup> was a cobalt-bifluoride complex which formed a fluorine-bridged dimer as a resting state. The amine cocatalyst was proposed to facilitate the dissociation of the dimer (Scheme 20). Further support for the proposed bimetallic mechanism was obtained by the use of the covalently linked Co(II)salen dimer **48** (Figure 21), which resulted in increased reaction rates, extended substrate scope and high enantioselectivity [79].

**Scheme 20.** A part of the proposed mechanism of the asymmetric fluorination of *meso*-epoxides catalyzed by Co–salen **47** (Scheme 19), proposed by Doyle and Kalow [79], showing the dimeric resting-state and its dissociated form.

**Figure 21.** Dimeric Co(II)salen catalyst **48**.

#### *2.5. With Thiols and Selenols*

Jacobsen and coworkers applied Cr–salen catalyst **46** (Scheme 18) in the ARO of cyclohexene oxide with benzyl mercaptan as the nucleophile (Scheme 21) [80]. The product was obtained in good yield but with only moderate enantioselectivity. The enantioselectivity could be improved by instead employing 1,4-benzenedimethanethiol as the nucleophile, which resulted in a diastereomeric mixture of *C*2-symmetric and *meso* ring-opened products (Scheme 22). The desired *C*2-symmetric product could be isolated with high enantioselectivity and transformed into the free thiol by a dissolving metal reduction in a subsequent step.

**Scheme 21.** The asymmetric ring-opening of cyclohexene oxide with benzyl mercaptan catalyzed by Cr–salen complex **46** (Scheme 18).

**Scheme 22.** The asymmetric ring-opening of *meso*-epoxides with 1,4-benzenedimethanethiol catalyzed by Cr–salen complex **46** (Scheme 18).

Many of the reported methods for the ARO of *meso*-epoxides with thiols and selenols employ Ti–salen catalysts. One such method was published by Hou and coworker, who used a chiral Ti(IV)salen complex, formed in situ from Ti(O*i*Pr)4 and salen ligand **32** (Scheme 9). This catalyst afforded vicinal hydroxy sulfides in good yields and moderate enantioselectivities (Scheme 23) [81]. The choice of sulphur nucleophile could also be extended to dithiophosphorus acids, which was explored by Zhou and Tang [82,83]. Their protocol gave the ring-opened product in high yield and good enantioselectivity. Subsequent reduction afforded the corresponding vicinal hydroxy sulfide (Scheme 24).

**Scheme 23.** The asymmetric ring-opening of *meso*-epoxides with thiols catalyzed by a Ti–salen complex generated in situ from Ti(O*i*Pr)4 and salen ligand **32** (Scheme 9).

**Scheme 24.** The asymmetric ring-opening of cyclohexene oxide with dithiophosphorous acid catalyzed by a Ti–salen complex generated in situ from Ti(O*i*Pr)4 and salen ligand **32** (Scheme 9).

For the enantioselective addition of aryl selenols to *meso*-epoxides, Zhu and coworkers reported the use of heterobimetallic titanium-gallium-salen complex **49** (Scheme 25) [84]. The "open" complexes were prepared by first incorporating gallium (GaMe3) and then adding Ti(OiPr)4. Catalyst **49** was used in the ARO of a number of cyclic and acyclic *meso*-epoxides with aryl selenols as nucleophiles, affording the products in high yields and up to 97% *ee*. The authors proposed a strong synergistic effect between the two Lewis acids, with the hard Lewis acid titanium activating the epoxide and the softer gallium coordinating the arylselenol and directing the nucleophilic attack. The same method could also be extended to the ARO of *meso*-epoxides with thiols, resulting in high yields and moderate to high enantioselectivities (up to 92% *ee*) [85,86].

**Scheme 25.** The asymmetric ring-opening of *meso*-epoxide with aryl selenols and thiols catalyzed by Ti-Ga-salen complex **49**.

Another protocol for the asymmetric synthesis of vicinal hydroxy selenides was reported by Tiecco and Marini, who used Cr–salen complexes to catalyze the ARO of *meso*-epoxides with (phenylseleno)silanes as nucleophiles [87]. Complexes with different counter ions, reactions in different solvents and with different additives were evaluated. The best results were obtained with 5 mol% of complex **50** with BF4− as counterion in TBME in the presence of one equivalent of *<sup>N</sup>*,*N*,*N*',*N*'-tetramethylethylenediamine (TMEDA) at −10 ◦C, which gave the products in good to excellent yields and enantioselectivities (Scheme 26). The method gave better results for *meso*-stilbene oxide and its derivatives than for cyclic *meso*-epoxides.

**Scheme 26.** The asymmetric ring-opening of *meso*-stilbene oxide with (*tert*-butyldimethyl(phenylselanyl)silane as nucleophile catalyzed by Cr–salen complex **50**.

## *2.6. With Carbon-Containing Nucleophiles*

The formation of carbon-carbon bonds in one of the most fundamental and important reactions in organic synthesis. Carbon-carbon bonds form the backbone of essentially all organic molecules, and the asymmetric C-C bond formation is of key importance in the synthesis of optically active and highly functionalized molecules, such as biologically active compounds [88,89]. As such, the catalytic ARO of *meso*-epoxides with carbon-based nucleophiles represents a potentially attractive strategy for achieving this task. However, the use of metal–salen complexes as catalysts for these kinds of reactions has been limited. One example comes from Cozzi and Umani-Ronchi, who used enantiopure Cr–salen catalyst **1** (Scheme 4) for the ARO of *meso*-stilbene oxide with indoles as carbon nucleophiles, giving ring-opened products in excellent yields and enantioselectivities (Scheme 27) [90].

**Scheme 27.** The asymmetric ring-opening of *meso*-stilbene oxide with indoles catalyzed by Cr–salen complex **1** (Scheme 4).

Pietrusiewicz and coworkers reported the use of Al(III)salen catalyst **51** in the ARO of 3,4-epoxy-1-phenylphospholane-1-oxide with TMSCN (Scheme 28) and TMSN3 as nucleophiles [22]. The products are potential intermediates in the synthesis of phosphasugar derivatives. It was found that the enantioselectivity was greatly influenced by the choice of solvent. For the azide addition, the highest yield was obtained in THF (90%) and best enantioselectivity in dichloromethane (28% *ee*). The use of an ionic liquid as the reaction medium gave high yields but did not increase the enantioselectivity. For the cyanide addition, the ARO of 3,4-epoxy-1-phenylphospholane-1-oxide performed with 10 mol% catalyst in TBME afforded the corresponding cyanohydrin in 56% yield and 72% *ee* (Scheme 28).

**Scheme 28.** The asymmetric ring-opening of 3,4-epoxy-1-phenylphospholane-1-oxide with TMSCN catalyzed by Al-salen complex **51**.

Another example is the Y-salen complexes explored by RajanBabu and coworkers [23]. A number of salen complexes with different diamine backbones were employed as catalysts in the ARO of cyclohexene oxide with TMSCN. The best result in terms of enantioselectivity was obtained using binaphthyldiamine (BINAP(NH2)2) derived salen complex **52**, which gave the ring-opened product in 77% *ee* (Scheme 29). The catalyst loading could be reduced from 2 mol% to 0.1 mol% without significant loss of reactivity or enantioselectivity and the reaction could also be run under solvent-free conditions.

**Scheme 29.** The asymmetric ring-opening of cyclohexene oxide with TMSCN catalyzed by Y-salen complex **52**.

#### **3. Kinetic Resolution of Epoxides**

Some epoxides, typically terminal ones, are difficult to prepare directly with high enantiomeric purity. Since the racemic mixtures are usually readily available at low cost, using an efficient KR becomes an attractive alternative for obtaining enantiomerically pure epoxides. Ideally, this strategy results in both the enantiopure ring-opened product, as well as the enantiomeric enrichment of the unreacted epoxide [91]. The selectivity can often be tuned towards the ring-opened product or the enantioenriched unreacted epoxide by the amount of nucleophile used.

Most of the examples presented herein concern the KR of terminal epoxides, although there are a few examples of the use of 1,2-disubstituted epoxides (mainly with *trans* stereochemistry) and even trisubstituted epoxides. In general, the reactions proceed with almost exclusive regioselectivity for the nucleophilic attack at the least substituted epoxide carbon.

For most of the reported examples of the KR of epoxides, the focus is on the ring-opened product. The most obvious exception is in the HKR, where the use of water as an inexpensive, environmentally friendly and highly available nucleophile makes it an attractive strategy for the enantioenrichment of the unreacted epoxide. As such, many of the references presented herein only report the yields and *ee* values of the product for which the method was optimized. There are also several ways of calculating the yield of the reaction. Although the theoretical maximum yield of the enantiopure ring-opened product is 50% (given that the starting material is used as a racemic mixture), many of the references calculate the yield based on the amount of nucleophile used, which varies a lot between different papers. To facilitate the comparison of different protocols, we have recalculated all yields based on the epoxide, giving a 50% maximum yield for each product. In some references, the results are reported as conversion instead of yield. In those cases, the products are often not isolated, and the conversion is calculated based on the consumption of each of the two enantiomeric starting materials determined by chiral GC separation.
