*3.5. With Halogens*

Haufe and coworker investigated Cr–salen complex **46** (Scheme 18) as catalyst for the enantioselective fluorination of epoxides [75–77]. The studies included a limited number of examples of the KR of terminal epoxides. The reaction required a very high catalyst loading (50 mol%) and the ring-opened products were obtained in moderate yield (28–29%) and moderate to high enantioselectivity (62–90% *ee*).

A more recent example of the enantioselective fluorination of epoxide was reported by Kalow and Doyle [79]. Using dimeric Co(II)salen complex **48** (Figure 21) together with cocatalyst 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and HF (formed in situ from benzoyl fluoride and HFIP), the ring-opened products of a number of terminal epoxides were obtained in high yields and with excellent enantioselectivities (Scheme 50). The dimeric catalyst also showed a significant rate enhancement compared to the monomeric analogue and reactions were completed in 2–4 h.

**Scheme 50.** The kinetic resolution of terminal epoxides with fluoride catalyzed by Co–salen complex **48** (Figure 21).

Kim and coworkers reported the KR of terminal epoxides with HCl catalyzed by dimeric Co(II)salen complexes linked by Lewis acids of group 13 metals (catalysts **54–56**, Scheme 34). Catalyst **55** afforded both ring-opened products and unreacted epoxides in high yields and enantioselectivities (up to 90% *ee* and 89% *ee*, respectively) for terminal alkyl epoxides and glycidyl ethers (Scheme 51). Aryl glycidyl ethers gave significantly lower *ee* values than alkyl glycidyl ethers and terminal alkyl epoxides. It was discovered that the *ee* value of the unreacted epoxide decreased over time, as the formed chlorohydrin was capable of performing the reverse ring-closing reaction in the presence of catalyst **55**. To prevent this, the reaction had to be terminated once a high *ee* value was reached for the unreacted epoxide. Di fferent group 13 metals and anions were evaluated but showed similar reactivities and enantioselectivities [127,128].

**Scheme 51.** The kinetic resolution of terminal epoxides with hydrochloric acid catalyzed by dimeric Co–salen complex **55** (Scheme 34).

### *3.6. With Carbon-Containing Nucleophiles*

Cozzi and Umani-Ronchi [90] used Cr–salen-SbF6 complex **133** (Figure 53) as a catalyst for the KR of 1,2-disubstituted aromatic epoxides with indoles. The ring-opened products were obtained in high yields and with high enantioselectivities (Scheme 52). Notably, this constitutes a rare example of a reported method for the KR of epoxides that is e fficient for both *cis* and *trans* aromatic epoxides. For all substrates, the ring-opened products were obtained with complete regioselectivity (nucleophilic attack at the benzylic carbon of the epoxides). Moreover, by adjusting the amount of indole used, the reaction could be tuned to a fford unreacted epoxides in satisfactory yields and with excellent enantioselectivities (91–99% *ee*).

Recently, Hajra and Roy [171] reported the first enantioselective construction of an all-carbon quaternary center from an epoxide by KR, using Co(III)salen catalysts **73** (Figure 29) and **134** (Figure 54) and spiro-epoxides with *N*-benzylindoles as nucleophiles. The desired 3,3'-bisindole methanols were obtained with complete regioselectivity, that is, with reaction of the nucleophile at the more substituted carbon of the epoxide. The excellent regioselectivity of the reaction was explained by a proposed mechanism where the Lewis acid coordinating to the epoxyindole led to the ring-opening of the epoxide to the more stabilized tertiary carbocation before the nucleophile attacks [172]. Under optimized conditions with Co(III)salen(OTf) catalyst **73**, which included the addition of 1 equivalent of water, the ring-opened products were obtained in good yields and with high enantioselectivities. The unreacted epoxides were recovered in low-to-moderate enantioselectivities. Using Co(III)salen(SbF6) complex **134** as catalyst resulted in a DKR, giving ring-opened products in good yields and with moderate-to-good enantioselectivities, with no unreacted epoxides recovered (Scheme 53). Mechanistic studies indicated that the ring-opening reaction of spiro-epoxides was governed by an equilibration between KR and DKR processes, and that this equilibrium was further controlled by feedback inhibition caused by the formation of a catalyst–product complex. Catalyst **134** with a non-coordinating counterion was less influenced by the feedback inhibition and could therefore be operated by the dynamic kinetic process [171].

**Figure 54.** Co(II)salen complex **134**.

**Scheme 53.** (**a**) The kinetic resolution (KR) of spiro-epoxides with *N*-benzylindoles catalyzed by Co–salen complex **73** (Figure 29). (**b**) The dynamic kinetic resolution (DKR) of spiro-epoxides with *N*-benzylindoles catalyzed by Co–salen complexes **134** (Figure 54). Both processes generate quaternary all-carbon centers with high enantioselectivity.

#### **4. Conclusions and Outlook**

The catalytic asymmetric ring-opening of epoxides is a highly useful method for the preparation of synthetically important, vicinally difunctionalized organic compounds such as amino alcohols, diols, and halohydrins in high yield and with high enantiomeric purity. The use of metal–salen complexes as catalysts for ARO reactions has seen much development since the first reports some 25 years ago. From an enantioselectivity standpoint, the original monosalen catalysts reported by Jacobsen (Cr–salen for ARO with azides, Scheme 4, and Co–salen for ARO with water, Scheme 40) remain competitive to this day, but significant progress has been made in terms of catalyst loading, substrate scope, and recyclability.

One area of interest has been the development of multi-metallic catalysts capable of enforcing a bimetallic cooperative pathway. Numerous strategies have been employed, ranging from covalently linking two or more salen complexes together by installing them on dendrimers, polymers or in supramolecular assemblies. Although this approach often requires more laborious synthetic e fforts, many of the resulting catalysts have shown significantly increased reaction rates for the ARO of epoxides compared to monosalen analogues, and also enabled e fficient catalysis at considerably lower catalyst loadings. In addition, the development and application of multi-metallic complexes have provided further insight into the reaction mechanism and highlighted the importance of factors such as the orientation of the complexes relative to each other as well as the length and flexibility of bridging linkers.

As large-scale applications depend largely on the separation of the products and recovery and recycling of the catalyst, the development of heterogeneous catalysts has received much attention. Metal–salen complexes have been immobilized on a number of di fferent solid surfaces and materials, providing access to catalysts with good stability that can be easily recycled without loss of catalytic properties. A further challenge in this area is to design the catalyst so that the cooperative interactions are still possible in order to achieve high reactivity and enantioselectivity. In terms of recyclability, the use of ionic liquids has also received some attention and shows much promise. Looking forward, one interesting area that has so far only been sparingly explored is the development of catalysts bridging homogeneous and heterogeneous catalysis, for example, by using soluble supports or encapsulating metal–salen complexes inside porous materials. The facile synthesis and easy modification of metal–salen complexes has also made them attractive catalysts to use for demonstrating the design and e fficacy of new catalytic concepts and systems in general.

Di fferent catalytic systems based on increasing the local concentration of catalyst or improving the cooperative interactions have allowed for significantly decreased catalyst loadings. This includes the development of polymeric salen complexes and the incorporation of metal–salen complexes in nanoreactors. Very low catalyst loadings (< 0.01 mol%) have mainly been realized for the hydrolytic kinetic resolution (HKR) of epoxides catalyzed by Co–salen complexes, with a few examples for the ARO of *meso*-epoxides with azides catalyzed by Cr–salen. However, for other nucleophiles there is still a lot of room for improvement.

Regarding the substrate scope, many of the reported catalysts have only been investigated for a limited number of substrates, both in terms of nucleophiles and epoxides. With regard to the nucleophile, one desirable development would be a wider application and investigation of di fferent carbon-based nucleophiles in the metal–salen catalyzed ARO of epoxides, in order to produce asymmetric C–C bonds. Another class of nucleophiles that merits further investigation is oxygen-containing nucleophiles other than water, as this could result in the regioselective preparation of monoprotected diols, something which can be di fficult to achieve by other methods.

Another aspect of the substrate scope is the epoxide. For the KR of epoxides, the vast majority of the research has been focused on terminal epoxides. This can be explained by the limited availability of enantiopure terminal epoxides by other methods, making the KR of terminal epoxides highly attractive as the unreacted epoxide can be recovered in high *ee*. As such, the metal–salen-catalyzed HKR have been successfully applied to a broad range of terminal epoxides with a wide variety of substituents, although no examples of the HKR of internal epoxides have been published to date. There are a few examples of the KR of *trans*-epoxides with anilines and indoles, and one example of the KR of *cis*-epoxides with indoles, but other than that there is a distinct lack of protocols for the KR of internal epoxides.

Extending the metal–salen catalyzed ARO of epoxides to include internal epoxides would also make it a good complement to other synthetic protocols. For example, the successful HKR of *trans*-epoxides would yield *anti*-diols, making it complementary to Sharpless dihydroxylation of olefins which works well for *trans*-olefins and gives the corresponding *syn*-diols with high regio-, diastereoand enantioselectivity [64]. In addition, since asymmetric epoxidation methods such as Jacobsen's Mn–salen epoxidation usually work poorly for *trans*-alkenes [24,173], achieving an e fficient KR of *trans*-epoxides would give access to otherwise di fficult to obtain enantiopure *trans*-epoxides.

There is also a lack of examples of the ARO of more substituted epoxides, with only a handful reported examples of the ARO of trisubstituted and 2,2-disubstituted epoxides. Extending the substrate scope to more substituted epoxides would also enable further studies of the regioselectivity of this type of catalysis. So far, most studies report complete regioselectivity with the investigated substrate scope, but further studies are needed to better understand, and by extension tune, this selectivity.

There are also several examples of innovative ways of utilizing metal–salen-catalyzed ARO reactions to solve general challenging synthetic problems. This includes the enantioselective construction of all-carbon quaternary centers from epoxides and the development of sequential asymmetric alkene epoxidation/ring-opening reactions. Both of these reactions are potentially of high importance and we hope to see much further research in this direction. Another aspect that merits further study is the dynamic kinetic resolution, which allows the preparation of enantiopure ring-opened products from racemic starting materials in 100% theoretical yield. There are a few examples of the successful application of this highly attractive strategy, mainly for the HKR of terminal epoxides. However, it is an area where much progress remains to be made.

To conclude, catalytic systems for the asymmetric ring opening of epoxides based on metal–salen complexes have been extensively studied and developed. With excellent catalytic activity and selectivity, this class of catalysts is a valuable tool in the area of asymmetric catalysis. As such, it remains an active field of research and we expect further advances are still forthcoming.

**Author Contributions:** Conceptualization, A.L., Y.L. and K.W.; writing—original draft preparation, A.L. and Y.L.; writing—review and editing, A.L., Y.L. and K.W. All authors have read and agreed to the published version of the manuscript.

**Funding:** K.W. thanks the Swedish Research Council, the LMK foundation, the Swedish Foundation for Strategic Research, and the Knut and Alice Wallenbergs Stiftelse for generous grants. Y.L. thanks the Chinese Scholarship Council for the scholarship.

**Conflicts of Interest:** The authors declare no conflict of interest.
