The present invention relates to methods for producing both separated enantiomers from a racemic or scalemic substrate and to devices for performing such methods.

Enantiomers are defined as compounds having the same molecular formula and have identical chemical and physical properties except for their ability to rotate plane- polarized light (+/-) by equal amounts but in opposite directions. Enantiomers - also named "optical isomers" - have at least one chiral element (stereogenic centre atom, axial, planar, helical or inherent chirality), for instance a stereogenic carbon, and the structures of the 2 enantiomers are each a mirror image of each other but these images are not superimposable.

Chemical synthesis of such molecules from achiral or racemic precursors without the action of any chiral reagent or catalyst, leads to a mixture in equal amounts of the different kind of enantiomers, or racemic mixture. In biological environments, (+) and (-) enantiomers often exhibit significant differences in their biological activity.

A dramatic example is the drug called "thalidomide" whose one enantiomer was responsible for sedative and pain-relieving effect, whereas the other enantiomer was teratogenic.

It is therefore desirable in such cases to obtain pure form of one single enantiomer, particularly in the pharmaceutical field. In pharmaceutical study, both enantiomers of a chiral drug candidate and racemic mixture are systematically evaluated in biological essays.

In some cases, the amounts of the different kinds of enantiomer in the mixture are not identical. Such mixture is a scalemic mixture.

Although many single-enantiomer drugs are produced by stereoselective synthesis, these techniques are costly and could not be used for relatively low-cost pharmaceuticals.

Separation of enantiomers from racemic mixtures have been disclosed by several techniques. The main methods involve salt crystallisation, column chromatography, and stereoselective synthesis and catalysis. Membrane-based enantioseparation techniques have also been disclosed.

Kinetic resolution involves the transformation of one of the enantiomers of a racemic mixture: the conversion should not be higher than 50% of the mixture. Sato et al (Angew. Chem. Int. Ed 2015) reports cooperative catalysis involving two successive reactions to convert enantioselectively styrene into 1 -phenylethanol ; the catalyst of the first reaction is not compatible with the enzyme of the second reaction, and the first reaction is therefore conducted in a PDMS thimble, allowing the product of this first reaction to diffuse in a second compartment. This system is intended to obtain only one enantiomer.

Schaaf et al (Chem. Commun. 2018, 12978 - 12981 ) also present a concurrent chemo-biocatalytic one-pot reaction, involving two catalysts which are not compatible. The reaction device is separated into 2 compartments by a PDMS membrane, to obtain one optically pure enantiomer in the second compartment.

Vedejs et al (J. Am. Chem. Soc. 1997, 2584 - 2585) is reporting parallel kinetic resolution of a racemic substrate. Two quasi enantiomers reagents are used to perform 2 reactions in the same medium. The products such obtained are not mirror images of each other; subsequent steps have to be performed to separate them, and the method cannot be performed continuously.

WO 2006/087556 is relating to a process for separating enantiomers or isomers through formation and subsequent decomposition of host-guest complex coupled to membrane nanofiltration. One enantiomer has a higher affinity for the host molecule, and could be then separated by adding subsequent solvents in order to recover the enantiomer.

US 5077217 is relating to methods for enzymatic resolution of racemic mixture of esters. One of the enantiomers is selectively derivatized with group enhancing the aqueous solubility, by an enzymatic catalyzed reaction. The so prepared derivative is then separated from the reaction medium by diffusion through a membrane.

There is still a need for separation techniques appropriate for the large-scale resolution of chiral enantiopure molecules, which are cost effective and allowing the recovering of the two optically pure enantiomers. It is also desirable to have methods which could be performed in continuous.

These goals and others may be achieved with a compartmentalized enantioselective multicatalytic reaction.

This is why the present invention relates to a method for obtaining at least a first separated mixture optically enriched in a first enantiomer B' and second separated mixture optically enriched in a second enantiomer B" from a starting racemic or scalemic mixture of enantiomers A' and A" in liquid medium, wherein the polarity of the starting racemic or scalemic mixture is different from the polarity of each of the first and second enantiomers B' and B" present in the separated first and second mixtures and, wherein the separated enantiomers B' and B" present in the separated mixtures are resulting of selective catalytic reactions carried out on the starting racemic or scalemic mixture in at least two separate compartments of a vessel, said two compartments being separated by a membrane allowing the diffusion of the starting racemic or scalemic mixture, said starting racemic or scalemic mixture being present in all the compartments of the vessel, and the membrane being impermeable to the first and second enantiomers B' and B" resulting from the reaction. Preferably, the membrane is a dense membrane.

The starting racemic mixture is containing an equal amount of enantiomers A' and A" of a starting compound (or molecule) A.

The starting scalemic mixture is containing enantiomer A' and A" respectively in different amounts, i.e. the concentration of one enantiomer is greater than 50% of the mixture and the concentration of the other enantiomer is smaller than 50% of the mixture. For instance, the ratio between the 2 compounds in the starting scalemic mixture can be 70/30, in particular 60/40. The invention will in particular be adapted for starting scalemic mixture wherein the ratio of enantiomers A and A” is from 60/40 to 51/49.

In such case, in the scalemic or racemic starting mixture, the ratio between the 2 enantiomers can be from 60/40 to 50/50.

The separated mixtures, resulting from the reaction, contain a mixtures of enantiomers B' and B" of a product (or molecule) B. However, the amount of enantiomer respectively B' and B" in these mixtures is not equal, each of the said first and second separated mixtures is enriched respectively in one of the two opposite enantiomers B' and B".

The starting racemic or scalemic mixture is present in all the compartment of the vessel, since the polarity of the enantiomers A' and A" is allowing their passage throughout the membrane; the polarity of the resulting enantiomers B' and B" is not allowing the passage throughout the membrane: the mixture enriched in a first enantiomer B' will therefore remain separated from the mixture enriched in the second enantiomer B".

The invention also relates to the use of a membrane which is permeable to the enantiomers A' and A" (of a molecule A) present in a starting racemic or scalemic mixture, for isolating on one side of said membrane a mixture optically enriched in a first enantiomer B' and on the other side of the membrane a mixture optically enriched in a second enantiomer B", the first and the second enantiomer B' and B" resulting of a reaction carried out on the starting racemic or scalemic mixture, the polarity of the starting racemic or scalemic mixture A being different from the polarity of the first and the second enantiomers B' and B" resulting from the reaction. The invention is also directed to a method for obtaining, in liquid medium, a first and a second separated enantiomers B' and B" from a racemic or scalemic mixture A, wherein the polarity of the racemic or scalemic mixture A is different from the polarity of each of the first and the second separated enantiomers B' and B", the racemic or scalemic mixture A being placed in a vessel containing a membrane defining at least a first and a second compartments, the membrane being permeable to the racemic or scalemic mixture A, the first and the second separated enantiomers B' and B" being obtained by carrying out the same reaction with opposite enantioselectivity in the first and the second compartments respectively on the racemic or scalemic mixture A, in order to produce the first separated enantiomer in the first compartment and the second enantiomer in the second compartment, the membrane being impermeable to the first and the second separated enantiomers B' and B" of B.

In preferred embodiments of the invention the starting mixture is a racemic mixture.

Advantageously, the reaction carried out in the first compartment is catalyzed by a first catalyst and the reaction carried out in the second compartment is catalysed by a second catalyst with opposite enantioselectivity, the first catalyst being an enantioselective catalyst allowing the production of the first separated enantiomer B' and the second catalyst being an enantioselective catalyst allowing the production of the second separated enantiomer B".

According to the invention, the composition of the liquid medium is similar on the two sides of the membrane, and has a similar polarity, and the same pH. In particular, the racemic or scalemic mixture A could bear functional groups conferring a hydrophilic/hydrophobic balance or a polarity allowing the passage of the molecules through the diffusion membrane. The concentration of the racemic or scalemic mixture A on both sides of the membrane will therefore be equilibrated via the diffusion phenomenon.

The polarity of the separated enantiomers of B will be different from the polarity of the racemic or scalemic mixture A. In order to obtain these separated enantiomers, enantioselective reactions are performed on the racemic or scalemic mixture A; preferably the reactions are performed simultaneously in each of the different compartments of the vessel. These catalytic reactions are activated with chiral catalysts and are leading respectively to the formation of opposite enantiomers in each of said compartments. The chiral catalysts are preferably optically pure.

Preferably, said two chiral catalysts cannot pass through the membrane; in particular, the chiral catalysts have a polarity which is not allowing their diffusion through the membrane separating the different compartments. According to some embodiments, the polarity of said chiral catalysts is similar to the polarity of the separated resulting enantiomers.

According to some other preferred embodiments, the said two chiral catalysts are immobilized on a support, not allowing the diffusion through the membrane.

Said chiral catalysts have opposite enantioselectivity. The chiral catalyst activates the transformation of a functional group on the racemic substrate A present in the mixture, to obtain a different functional group, having a polarity different from the polarity of the starting material. Since each of the catalyst is present in a different compartment, the modification of the functional group will occur preferably on a single enantiomer A' or A" of the racemic or scalemic substrate A. After formation of the derivatized functional group, the said mixture optically enriched in one enantiomer of B remains in the compartment defined by the diffusion membrane and is therefore separated from the mixture optically enriched its opposite enantiomer, which has been formed by the reaction in the other compartment of the vessel.

The starting racemic or scalemic starting mixtures A can continuously diffuse through the membrane, so ensuring an optimal concentration of the substrate and allowing a full conversion of the racemic mixture. The yield of the reaction is therefore improved.

The reaction of transformation of the functional group is rapid on the selected enantiomer. Advantageously, the rate of the reactions conducted in parallel are similar.

The conversion rate can be as high as 88% in each compartment. The concentration of the separated enantiomer resulting from the reaction is therefore high in each compartment.

As mentioned above, the compartments are separated by a membrane having selective permeability, depending on the polarity of the substrate and of the polarity of the reaction products. The racemic or scalemic substrate A can go through the membrane, but the products B of the reaction in each compartment cannot diffuse through the membrane.

Another advantage of the invention is the use of a chiral supplementary molecule as a catalyst, and not as a reagent. This allows to use only small amount of these agents with respect to the enantiomers of interest. This is both cost-effective and advantageous in terms of sustainability.

The membranes for use in the invention may be selected from regenerated cellulose, the esters of cellulose, polyacrylonitrile, polyacrylonitrile copolymers, polyurethane- containing copolymers, polyarylsulfones, polyarylethersulfones, polyarylsulfone blends, polyaryethersulfone blends, polyvinylidene fluoride, polytetrafluoroethylene, polyvinylalcohol, aliphatic polyamides, aromatic polyamides, polyimides, polyetherimides, polyesters, polycarbonates, polyolefins, polybenzimidazole, and polybenzimidazolone. More particularly, the membranes are selected from polydimethylsiloxane membrane and modified polydimethylsiloxane membranes by surface modification or incorporation of nanocomposite (mixed matrix membrane).

The use and method of the invention can in particular comprise the following steps: a) Providing in a first fluid a starting racemic or scalemic mixture to one side of a diffusion membrane selective according to the polarity of the compounds, and providing in a second fluid the same starting racemic or scalemic mixture to the opposite side of said diffusion membrane, the polarity of the enantiomers A' and A" of the starting racemic or scalemic mixture allowing their diffusion through the diffusion membrane, b) Providing in the first fluid containing the starting or scalemic racemic mixture a first catalyst, said first catalyst activating the transformation of the racemic or scalemic mixture into a first mixture enriched in a product B’ which is a first enantiomer, and providing in the second fluid containing the racemic or scalemic mixture a second catalyst, said second catalyst activating the transformation of the racemic or scalemic mixture into a second mixture enriched in a product B” which is a second enantiomer opposite to the enantiomer B’ obtained with the first catalyst, wherein the polarity of the first and second catalysts is not allowing their diffusion through the diffusion membrane, c) Performing simultaneously the reactions with said first and second catalysts in the fluid medium on each side of the diffusion membrane to obtain said first and second mixtures optically enriched in first and second opposite enantiomers B’ and B” on each side of the diffusion membrane, the polarity of said enantiomers B’ and B” not allowing their diffusion through the diffusion membrane, d) Recovering the first separated mixture optically enriched in a first enantiomer from the fluid medium on one side of the diffusion membrane and recovering the second separated mixture optically enriched in the second opposite enantiomer from the fluid medium on the opposite side of the diffusion membrane

During step c, the first catalyst, preferably optically pure, is mainly transforming the starting racemic or scalemic mixture into a first enantiomer B'. However, a small part of the starting racemic or scalemic mixture may be transformed into the second enantiomer B". This second reaction will occur at very low level, therefore, the composition of the mixture in the compartment will comprise principally enantiomer B'.

The same phenomenon may occur with the second catalyst, also preferably optically pure, which is mainly resulting in obtaining the second enantiomer B"; but a small part of the starting racemic or scalemic mixture is transformed into the first enantiomer B'. The optical purity is defined as the ratio of the observed optical rotation of a sample consisting of a mixture of enantiomers to the optical rotation of one pure enantiomer.

Enantiomerically enriched (enantioenriched) corresponds to a sample of a chiral substance whose enantiomeric ratio is greater than 50:50 but less than 100:0.

By optically pure is intended a compound which is enantiomerically pure (or enantiopure), i.e. a sample all of whose molecules have the same chirality sense.

By optically enriched in one enantiomer is intended a mixture comprising one enantiomer of the molecule in an amount higher than the amount of the opposite enantiomer of the same molecule. This is therefore different from racemic mixtures, wherein in the amounts of the 2 enantiomers are equal.

Starting from a racemic mixture, a mixture of enantiomers optically enriched in one enantiomer B' is comprising at least 51 % of said enantiomer, based on the total amount of enantiomers (B' and B"). For instance, a mixture optically enriched in one enantiomer is comprising at least 55% of said enantiomer, in particular at least 60%, and preferably at least 70% of the enantiomer. In advantageous embodiments, the mixture optically enriched in one enantiomer is comprising an amount equal or greater than 80% of said enantiomer, and possible at least 99,9% of the enantiomer, based on the total amount of enantiomers of the molecule.

A mixture optically enriched in one enantiomer will comprise at least 2% of excess of said enantiomer over the other enantiomer, in particular it comprises at least 10%, at Ieast15% or at least 20 % more of the said enantiomer when compared to the other enantiomer. The enantiomeric excess is preferably greater or equal to 60%, in particular greater or equal to 70%, and could be greater or equal to 90%.

The enantiomeric excess in the enriched mixture is therefore generally comprised between 2% and 100%, in particular between 10% and 100% with respect to the opposite enantiomer.

According to the invention, on one side of the membrane the mixture may therefore comprise between 65% and 100% of the first enantiomer, based on the total amount of enantiomers; on the other side of the membrane, the mixture may comprise between 65% and 100% of the second enantiomer, based on the total amount of enantiomers.

The enantiomeric excess (ee) is a measure of the enantiomeric purity of a chiral compound. It is defined (in percents) by the following formula:

((nB' -nB") x 100 )/ (nB' + nB"), wherein nB' is the number of moles of the major enantiomer, and nB" is the number of moles of the other enantiomer. Said optically enriched mixtures, present in separate compartments, are recovered and the isolation of an optically pure enantiomer can then be performed easily.

When starting from a scalemic mixture, the mixture obtained in each compartment comprises preferably at least 2% more of the respective enantiomer than in the starting scalemic mixture.

The transformation of the enantiomers present in the starting racemic or scalemic mixture may in particular be a hydrolysis, but is not limited to such reaction. Other transformations involve a reaction selected from dihydroxylation, reduction of ketones, esterification or alkylation.

According to an embodiment of the invention, the starting racemic or scalemic mixture A is less polar than the products B of the catalytic reactions. In such embodiments, the membrane is hydrophobic.

The invention relates in particular to use of a membrane and to methods for separating enantiomers as described above, wherein the starting racemic or scalemic mixture is non-polar and the diffusion membrane is a hydrophobic membrane.

The first enantiomer B’ and the second enantiomer B” are in such embodiments, polar products. As well, the catalysts used respectively to activate the conversion of the starting racemic mixture into a polar product are polar too.

Selectivity is possible due to the difference of permeability of the molecules through the hydrophobic membrane

The method and use according to the invention may comprise the following steps: a) Providing in a first fluid a starting racemic or scalemic mixture to one side of a hydrophobic diffusion membrane, and providing in a second fluid the same starting racemic or scalemic mixture to the opposite side of said hydrophobic diffusion membrane, wherein the enantiomers of the racemic or scalemic mixture are not polar such allowing their diffusion through the diffusion membrane, b) Providing in the first fluid containing the starting racemic or scalemic mixture a first catalyst, preferably a first optically pure catalyst, said first catalyst activating the transformation of the racemic or scalemic mixture into a first mixture optically enriched in a product B’ which is an enantiomer, and providing in the second fluid containing the starting racemic or scalemic mixture a second catalyst, preferably a second optically pure catalyst ,said second catalyst activating the transformation of the racemic or scalemic mixture into a second mixture optically enriched in a product B” which is an enantiomer opposite to the enantiomer B’ obtained with the first catalyst, wherein the first and second catalysts are polar and cannot pass through the diffusion membrane, c) Performing simultaneously the reactions with said first and second catalysts in the fluid medium on each side of the diffusion membrane to obtain said first and second mixtures optically enriched in said first and second opposite enantiomers B’ and B” on each side of the diffusion membrane, wherein said enantiomers B’ and B” are polar and cannot pass through the diffusion membrane, d) Recovering the first separated mixture optically enriched in a first enantiomer from the fluid medium on one side of the diffusion membrane and recovering the second separated mixture optically enriched in the second opposite enantiomer from the fluid medium on the opposite side of the diffusion membrane.

The chiral catalyst activates the transformation of a functional group on the racemic substrate present in the mixture, to obtain a different functional group, which is more polar on the resultant enantiomer product; the resultant enantiomer is not allowed to diffuse through the hydrophobic membrane, and remains in the compartments where it was produced.

The chiral catalyst used for the transformation can in particular be a Jacobsen catalyst.

The diffusion membrane may be in particular a hydrophobic polydimethylsiloxane (PDMS) membrane.

PDMS membrane is selectively permeable to apolar molecules and impermeable to polar molecules.

Hydrophobic PDMS membranes are known in the art and will be readily purchased or prepared by the man skilled in the art. They were disclosed for instance by Sato et al (2015).

Membranes adapted for implementing the invention may be prepared from the precursors of membranes commercialized under the trade name Sylgard 184.

Such membranes are notably dense non-porous membranes. They are inter alia, used for ultra-filtration and permeation for the purification of water.

According to another embodiment of the invention, the racemic or scalemic mixture is polar and the diffusion membrane is an hydrophilic membrane.

The first enantiomer B’ and the second enantiomer B” are, in such embodiments, non-polar products, or at least products which are less polar than the starting racemic or scalemic mixture. The catalysts used respectively to activate the conversion of the starting racemic or scalemic mixture into a non-polar product are under a form not allowing their passage through the hydrophilic diffusion membrane. Catalysts may be for instance immobilized on a support, or treated to avoid their passage.

Such support may for instance be selected from silica, polystyrene or tentagel® resin. The method and use will typically comprise the following steps: a) Providing in a first fluid a starting racemic or scalemic mixture to one side of a hydrophilic diffusion membrane, and providing in a second fluid the same starting racemic or scalemic mixture to the opposite side of said hydrophilic diffusion membrane, wherein the enantiomers of the racemic or scalemic mixture are polar such allowing their diffusion through the diffusion membrane, b) Providing in the first fluid containing the starting racemic or scalemic mixture a first optically pure catalyst, said first catalyst activating the transformation, in particular by hydrolysis, of the racemic or scalemic mixture into a first mixture optically enriched in a product B’ which is an enantiomer, and providing in the second fluid containing the racemic or scalemic mixture a second optically pure catalyst, said second catalyst activating the transformation, in particular by hydrolysis, of the racemic or scalemic mixture into a second mixture optically enriched in a product B” which is an enantiomer opposite to the enantiomer B’ obtained with the first catalyst, wherein the first and second catalysts cannot pass through the diffusion membrane, c) Performing simultaneously the reactions with said first and second catalysts in the fluid medium on each side of the diffusion membrane to obtain said first and second mixtures optically enriched in said first and second opposite enantiomers B’ and B” on each side of the diffusion membrane, wherein said enantiomers B’ and B” are non-polar and cannot pass through the diffusion membrane, d) Recovering the first separated mixture optically enriched in a first enantiomer from the fluid medium on one side of the diffusion membrane and recovering the second separated mixture optically enriched in the second opposite enantiomer from the fluid medium on the opposite side of the diffusion membrane.

Selectivity is possible due to the difference of permeability of the molecules through the hydrophilic membrane.

Hydrophilic membranes are also known in the art. Such membranes are for instance derivatized or functionalized PDMS membranes, where the PDMS is modified by surface functionalization, in particular via glycan surface functionalization (as disclosed by Esteba-Tejeda et al, Polymer, 2016, 1 - 7).

The method of compartmentalized kinetic resolution according to the invention can be performed with various catalytic reactions, as far as the polarity of the product is different from the polarity of the starting racemic material.

The general scheme of the methods and of the reactions are represented on figure 1. As mentioned above, the racemic substrates are bearing at least a functional group which is modified by the catalytic reaction in a functional group having a different polarity.

In this respect, the reaction on the racemic mixture can be for instance selected from dihydroxylation reactions of alkene and epoxide ring-opening reactions.

The reaction activated by the said chiral catalysts may be the transformation of an epoxide structure present on the racemic mixtures, which is opened to give alcoholic functions. Such reaction can be catalyzed by a complex of cobalt. Each chiral form of the complex will selectively catalyze the reaction of one of the enantiomers.

Other reactions leading to the formation of an enantiomeric product having a polarity greater than the polarity of the racemic substrate include enantioselective dihydroxylation of racemic alkenes. Such reactions are disclosed for instance by VanNieuwenhze and Sharpless (J. Am. Chem. Soc., 1993, 7864 - 7865) and can be implemented in the process and methods according to the invention.

The use of the permeable membranes and the methods of the invention can be realized in continuous process. That is the optically enriched separated enantiomers are recovered from the corresponding compartment defined by the membrane, while the reactions on the racemic mixtures are performed, such leading to renewed amounts of modified optically pure enantiomers. Racemic or scalemic mixtures can be feed at another part of the vessel, in order to have substrate for the catalytic reactions.

According to other embodiments, the use of the permeable membranes and the methods of the invention are realized as batch process.

Typically, the invention will be performed in a compartmentalized reactor. Said reactor employs a membrane reactor/separator system which allows racemic reaction mixture or phase circulating in contact with each side of a membrane.

Reactors useful for the invention are commercialized for instance by SES GmbH- Analytical systems.

The ratio between the volume of the compartments and surface of the membrane will be adapted, according to the polarity of the starting racemic mixtures and of the enantiomers resulting from the enantioselective reaction.

The methods of the invention are particularly useful for obtaining mixtures optically enriched in desired enantiomers in pharmaceutical applications ; possibly, optically pure enantiomers will be separated from the enriched mixtures.

The methods of the invention are also useful for obtaining mixtures optically enriched in desired enantiomers and optically pure enantiomers in the agrochemical or food industry, or in any field requiring high optical purity of the compounds. Examples of enantiomers which have different properties depending on their optical form and could benefit from separation include but are not limited to propoxyphene, of which R form is an analgesic, while its S form is an anticough.

Levodropropizine is effective as an antitussive, but appears to carry a lower risk of daytime somnolence than dropropizine. Propranolol has a beta-blocking action, and the S form is approximately 100 times more active than the R form. Similarly, the ( ?)-isomer of salbutamol, a broncho dilatating drug, has 150 times greater affinity for the beta2- receptor than the (S)-isomer and the (S)-isomer has been associated with toxicity.

Mephenesine and methocarbamol also exhibits different levels of activity, depending in the optical form, and could benefit from the separation method according to the invention.

The invention will be better understood in view of the following examples. In these examples, it will be referred to the following figures

[Fig. 1] schematic representation of the steps of the compartmentalized enantioselective multicatalytic resolution.

[Fig. 2] resolution of an epoxy enantiomer with a chiral catalyst complex of cobalt [Fig. 3] reactor 1 for implementing the catalytic separation

Example of preparation:

1- Preparation of PDMS membrane

1 ) Precuring: The elastomer and curing agent (Sylgard 184) were mixed and then the casting solution was degassed in a desiccator under vacuum for 2 hours.

2) Glass pretreatment: For easy delamination, glass plates were placed in a desiccator with 5 drops of trichloro(1 H,1 H,2H,2H-perfluoro-octyl)-silane (silanizer) under vacuum for 2 hours.

3) PDMS casting and cooking: The casting solution was spread on the pretreated glass plate to fabricate flat PDMS membranes by automatic film applicator (As shown in the Figure and the thickness of membrane can be tuned by the scraper). After that, PDMS membranes were placed in the oven at 65 °C for 1 hour for half-curing. Then cooking the membranes in oven at 110 °C for 3 hours to cross-link.

4) Delaminating: PDMS membranes were removed from the glass by placing in petroleum ether (PE).

5) Washing and drying: The membranes were washed by PE for 10 mins and soaked in dichloromethane twice for 2h to the remove silicone. In the end, all the membranes were dried in the oven at 110 °C for 2 hours. Keep them out of light. 2. Description of reactors

Reactor 1 : The effective area of membrane is 0.95 cm ² and each compartment (C1 was the left and C2 was the right) has a volume of 10 mL. (0.095 cm ² /mL)

Reactor 2: The effective area of membrane is 11.34 cm ² and each compartment has a volume of 50 mL. (0.2268 cm ² /mL)

Reactor 3: This reactor was purchased from PERME GEAR. The effective area of membrane is 1.13 cm ² and each compartment has a volume of 5 mL. (0.226 cm ² /mL).

3. Preparation of Jacobsen catalyst

M = Co: (R, R)-l;

M = Co(OAc): (R,R)-l-OAc

Both optically pure pre-catalysts 1 (S,S) and (R,R) were used as purchased.

Typically, the Co(ll) complex 1 (0.12 g, 0.2 mmol) was dissolved in toluene (1 mL, 0.2 M), then acetic acid (229 mL, 0.4 mmol, 2 equiv.) was added. The mixture was stirred open to air at room temperature for 1 h, during which the color of the mixture changed from red to dark red. In the end, toluene was removed by vacuum evaporation and 1 xQAc was obtained.

4. Synthesis of diol by parallel hydrolytic kinetic resolution of terminal epoxides

The reaction is represented on figure 2

All the terminal racemic epoxides were purchased or prepared by well-known procedures. CH3CN was used as purchased. Both optically pure catalysts 1 xQAc (S,S) and (R,R) were introduced into C1 and C2 respectively, as shown in the picture.

Example 1 : 1-Phenyl-1 ,2-ethanediol

Chromatogram of pure racemic diol: Chiral HPLC on column Lux-i-Cellulose-5; Mobile phase: Heptane/isopropanol (95/5); Flow rate 1.0 mL/min; Retention time: 21.9 min, 23.5 min. Example 1.1

(Cepoxide = 5.3 M, T = rt, Reactor 1 , thickness = 150 mm)

In compartment Ci, styrene oxide (4.81 g, 40 mmol, 1 equiv.) and (S,S)-catalyst 1- OAc (0.13 g, 0.2 mmol, 0.5 mol %) were introduced with 3 mL of CH3CN while in C2, the same amount of styrene oxide (4.81 g, 40 mmol, 1 equiv.) were introduced but with (R,R)- catalyst 1-OAc (0.13 g, 0.2 mmol, 0.5 mol %) with 3 mL of CH3CN. In each compartment, H2O (864 mL, 48 mmol, 1.2 equiv.) was added dropwise at 0 °C. A balloon with air (P= 1 atm) was placed on the top of both compartments. The reaction mixture was then allowed to warm at room temperature.

The reaction was followed by NMR and chiral HPLC to evaluate the conversion and enantiomeric excess (ee) respectively. Each compartment is purified separately by chromatography on silica gel (ethylacetate/ petroleum ether: 5/5 v/v). The conversion in the double reactor reached 83 % in 120 h. Enantioenriched diol from Ci was obtained with 64 % isolated yield in 87 % ee. From C2, the configurationally opposite diol was obtained with 66 % isolated yield in 87 % ee.

¹ H NMR (400 MHz, Chloroform-d) 5 7.37 (d, J = 4.4 Hz, 4H), 7.35 - 7.28 (m, 1 H), 4.82 (dt, J = 8.0, 3.3 Hz, 1 H), 3.77 (ddd, J = 11 .0, 7.2, 3.6 Hz, 1 H), 3.67 (ddd, J = 11 .2, 8.1 , 4.4 Hz, 1 H), 2.62 (d, J = 3.3 Hz, 1 H), 2.17 (dd, J = 7.3, 4.8 Hz, 1 H).

Chiral HPLC on column Lux-i-Cellulose-5; Mobile phase: Hexane/isopropanol (95/5); Flow rate 1.0 mL/min; Retention time: 19.5 min, 20.1 min. Chromatograms of the diol from Ci and from C2 were shown below (Ci-120 h, C2-120 h).

Example 1.2

(Cepoxide = 5.3 M, T = 40 °C, Reactor 1 , thickness = 150 pm)

In compartment Ci, styrene oxide (4.81 g, 40 mmol, 1 equiv.) and (S,S)-catalyst 1- OAc (0.13 g, 0.2 mmol, 0.5 mol %) were introduced with 3 mL of CH3CN while in C2, the same amount of styrene oxide (4.81 g, 40 mmol, 1 equiv.) were introduced but with (R,R)- catalyst 1-OAc (0.13 g, 0.2 mmol, 0.5 mol %) with 3 mL of CH3CN. In each compartment, H2O (864 pL, 48 mmol, 1.2 equiv.) was added dropwise at 0 °C. The reaction mixture was then allowed to warm at 40 °C. The conversion in the double reactor reached 50 % in 48 h. Each compartment was purified separately by chromatography on silica gel (ethylacetate/petroleum ether: 5/5 v/v). Enantioenriched diol from Ci was obtained with 40 % isolated yield in 82 % ee. From C2, the configurationally opposite diol was obtained with 31 % isolated yield in 85 % ee.

Chiral HPLC on column Lux-i-Cellulose-5; Mobile phase: Hexane/isopropanol (95/5); Flow rate 1.0 mL/min; Retention time: 21.5 min, 23.5 min. Peaks of the chromatograms of the diol from Ci and from C2 are shown on the tables below (Ci-48 h, C ₂ -48 h).

<Peak Table*

Example 1.3:

(Cepoxide = 2.6 M, T = rt, Reactor 1 , thickness = 150 pm)

In compartment Ci, styrene oxide (2.40 g, 20 mmol, 1 equiv.) and (S,S)-catalyst 1- OAc (0.06 g, 0.1 mmol, 0.5 mol %) were introduced with 5.5 mL of CH3CN while in C2, the same amount of styrene oxide (2.40 g, 20 mmol, 1 equiv.) were introduced but with (R,R)-catalyst 1 -OAc (0.06 g, 0.1 mmol, 0.5 mol %) with 5.5 mL of CH3CN. In each compartment, H2O (432 pL, 24 mmol, 1.2 equiv.) was added dropwise at 0 °C. The reaction mixture was then allowed to warm at room temperature. The conversion in the double reactor reached 69 % in 120 h. The ee of diol in Ci and C2 were 87 % and 88 % in 120 h respectively.

Chiral HPLC on column Chiralpak ID; Mobile phase: Heptane/isopropanol (90/10); Flow rate 1.0 mL/min; Retention time: 10.1 min, 11.4 min. Peaks of the chromatograms of the diol from Ci and from C2 are shown on the tables below (Ci-120 h, C2-120 h). ¹

Example 1.4: (Cepoxide = 1 M, T = rt, Reactor 1 , thickness = 150 pm)

In compartment Ci, styrene oxide (1.20 g, 10 mmol, 1 equiv.) and (S,S)-catalyst 1- OAc (0.03 g, 0.05 mmol, 0.5 mol %) were introduced with 9 mL of CH3CN while in C2, the same amount of styrene oxide (1.20 g, 10 mmol, 1 equiv.) were introduced but with (R,R)-catalyst 1 -OAc (0.03 g, 0.05 mmol, 0.5 mol %) with 9 mL of CH3CN. In each compartment, H2O (216 pL, 12 mmol, 1 .2 equiv.) was added dropwise at 0 °C. A balloon with air (P= 1 atm) was placed on the top of both compartments. The reaction mixture was then allowed to warm at room temperature. The conversion in the double reactor reached 52 % in 168 h. Each compartment was purified separately by chromatography on silica gel (ethylacetate/petroleum ether: 5/5 v/v). Enantioenriched diol from Ci was obtained with 37 % isolated yield in 80 % ee. From C2, the configurationally opposite diol was obtained with 32 % isolated yield in 83 % ee.

Chiral HPLC on column Lux-i-Cellulose-5; Mobile phase: Hexane/isopropanol (95/5); Flow rate 1.0 mL/min; Retention time: 21.5 min, 23.0 min. Peaks of the chromatograms of the diol from Ci and from C2 are shown below (Ci-168 h, C2-I 68 h). min ePeak Table*

Example 1.5: (Cepoxide = 5.3 M, T = rt, Reactor 2, thickness = 150 pm)

In compartment Ci, styrene oxide (28.86 g, 240 mmol, 1 equiv.) and (S,S)-catalyst 1 -OAc (0.78 g, 1 .2 mmol, 0.5 mol %) were introduced with 18 mL of CH3CN while in C2, the same amount of styrene oxide (28.86 g, 240 mmol, 1 equiv.) were introduced but with (R,R)-catalyst 1-OAc (0.78 g, 1.2 mmol, 0.5 mol %) with 18 mL of CH3CN. In each compartment, H2O (5.2 mL, 288 mmol, 1.2 equiv.) was added dropwise at 0 °C. The reaction mixture was then allowed to warm at room temperature. The conversion in the double reactor reached 32 % in 48 h. Each compartment was purified separately by chromatography on silica gel (ethylacetate/petroleum ether: 5/5 v/v). Enantioenriched diol from Ci was obtained with 25 % isolated yield in 86 % ee. From C2, the configurationally opposite diol was obtained with 21 % isolated yield in 86 % ee.

Chiral HPLC on column Lux-i-Cellulose-5; Mobile phase: Hexane/isopropanol (95/5); Flow rate 1.0 mL/min; Retention time: 22.5 min, 24.2 min. peaks of the chromatograms of the diol from Ci and from C2 are shown on the tables below (Ci-48 h, C ₂ -48 h).

<Peak Table*

<Peak Table*

Example 1.6: (Cepoxide = 5.3 M, T = rt, Reactor 1 , thickness = 100 pm)

In compartment Ci, styrene oxide (4.81 g, 40 mmol, 1 equiv.) and (S,S)-catalyst 1- OAc (0.13 g, 0.2 mmol, 0.5 mol %) were introduced with 3 mL of CH3CN while in C2, the same amount of styrene oxide (4.81 g, 40 mmol, 1 equiv.) were introduced but with (R,R)- catalyst 1-OAc (0.13 g, 0.2 mmol, 0.5 mol %) with 3 mL of CH3CN. In each compartment, H2O (864 pL, 48 mmol, 1.2 equiv.) was added dropwise at 0 °C. The reaction mixture was then allowed to warm at room temperature. The conversion in the double reactor reached 81 % in 144 h. The ee of diol in Ci and C2 were 83 % and 87 % in 144 h respectively.

Chiral HPLC on column Lux-i-Cellulose-5; Mobile phase: Hexane/isopropanol (95/5); Flow rate 1.0 mL/min; Retention time: 21.5 min, 23.5 min. Peaks of the chromatograms of the diol from Ci and from C2 were shown on the tables below (Ci-144 h, C2-144 h).

<Peak Table* <Peak T«ble>

Example 1.7: (Cepoxide = 5.3 M, T = rt, Reactor 3, thickness = 150 pm

In compartment Ci, styrene oxide (2.4 g, 20 mmol, 1 equiv.) and (S,S)-catalyst 1- OAc (0.06 g, 0.1 mmol, 0.5 mol %) were introduced with 1.5 mL of CH3CN while in C2, the same amount of styrene oxide (2.4 g, 20 mmol, 1 equiv.) were introduced but with (R,R)-catalyst 1 -OAc (0.06 g, 0.1 mmol, 0.5 mol %) with 1.5 mL of CH3CN. In each compartment, H2O (432 pL, 24 mmol, 1 .2 equiv.) was added dropwise at 0 °C. A balloon with air (P= 1 atm) was placed on the top of both compartments. The reaction mixture was then allowed to warm at room temperature. The conversion in the double reactor reached 88 % in 120 h. Each compartment was purified separately by chromatography on silica gel (ethylacetate/petroleum ether: 5/5 v/v). Enantioenriched diol from Ci was obtained with 60 % isolated yield in 86 % ee. From C2, the configurationally opposite diol was obtained with 65 % isolated yield in 84 % ee.

Chiral HPLC on column Lux-i-Cellulose-5; Mobile phase: Hexane/isopropanol (95/5); Flow rate 1.0 mL/min; Retention time: 19.8 min, 21.0 min. peaks of the chromatograms of the diol from Ci and from C2 are shown on the tables below (Ci-120 h, C2-120 h).

Proceasing Results of Signal: DAD (210)

No. of Peaks in Result List : 2

Processing Results of Signal: DAD (210)

No . of Peaks in Result list: 2

Example 2 : 3-phenylpropane-1 ,2-diol

(Cepoxide = 5.3 M, T = rt, Reactor 1 , thickness = 150 pm) In compartment Ci, (2,3-epoxypropyl)benzene (5.37 g, 40 mmol, 1 equiv.) and (S,S)-catalyst 1-OAc (0.13 g, 0.2 mmol, 0.5 mol %) were introduced with 2.3 mL of CH3CN while in C ₂ , the same amount of (2,3-epoxypropyl)benzene (5.37 g, 40 mmol, 1 equiv.) were introduced but with (R,R)-catalyst 1 -OAc (0.13 g, 0.2 mmol, 0.5 mol %) with 2.3 mL of CH3CN. In each compartment, H ₂ O (864 pL, 48 mmol, 1 .2 equiv.) was added dropwise at 0 °C.

The reaction mixture was then allowed to warm at room temperature. The conversion in the double reactor reached 75 % in 168 h. Each compartment was purified separately by chromatography on silica gel (ethylacetate/petroleum ether: 5/5 v/v). Enantioenriched diol from Ci was obtained with 52 % isolated yield in 73 % ee. From C ₂ , the configurationally opposite diol was obtained with 64 % isolated yield in 67 % ee.

¹ H NMR (400 MHz, Chloroform-d) 5 7.32 (m, 2H), 7.28 - 7.20 (m, 3H), 4.01 - 3.90 (m, 1 H), 3.70 (ddd, J = 11 .1 , 6.4, 3.2 Hz, 1 H), 3.53 (ddd, J = 11 .1 , 6.9, 5.1 Hz, 1 H), 2.86 - 2.71 (m, 2H), 2.08 (d, J = 3.8 Hz, 1 H), 1.96 (dd, J = 6.5, 5.3 Hz, 1 H).

Chiral HPLC on column Lux-i-Cellulose-5; Mobile phase: Hexane/isopropanol

(90/10); Flow rate 1.0 mL/min; Retention time: 11.2 min, 12.2 min. Peaks of the chromatograms of the diol from Ci and from C ₂ are shown on the tables below (Ci-168 h, C ₂ -168 h).

Chromatogram of pure racemic diol: Chiral HPLC on column Lux-i-Cellulose-5; Mobile phase: Hexane/isopropanol (90/10); Flow rate 1.0 mL/min; Retention time: 10.1 min, 10.5 min.

Peaks are shown on the table below

Example 3: 3-(o-tolyloxy)propane-1,2-diol

C = 1 M, T = rt, Reactor 1 , thickness = 150 pm In compartment Ci, glycidyl 2-methylphenyl ether (1.64 g, 10 mmol, 1 equiv.) and (S,S)-catalyst 1 -OAc (0.03 g, 0.05 mmol, 0.5 mol %) were introduced with 8.5 mL of CH3CN while in C2, the same amount of glycidyl 2-methylphenyl ether (1.64 g, 10 mmol, 1 equiv.) were introduced but with (R,R)-catalyst 1 -OAc (0.03 g, 0.05 mmol, 0.5 mol %) with 8.5 mL of CH3CN. In each compartment, H2O (216 pL, 12 mmol, 1.2 equiv.) was added dropwise at 0 °C. A balloon with air (P= 1 atm) was placed on the top of both compartments.

The reaction mixture was then allowed to warm at room temperature. The conversion in the double reactor reached 60 % in 120 h. Each compartment was purified separately by chromatography on silica gel (ethylacetate/petroleum ether: 5/5 v/v). Enantioenriched diol from Ci was obtained with 41 % isolated yield in 89 % ee. From C2, the configurationally opposite diol was also obtained with 41 % isolated yield in 89 % ee.

¹ H NMR (400 MHz, Chloroform-d) 5 7.20 - 7.12 (m, 2H), 6.90 (td, J = 7.4, 1.1 Hz, 1 H), 6.86 - 6.80 (m, 1 H), 4.19 - 4.10 (m, 1 H), 4.10 - 4.03 (m, 2H), 3.87 (ddd, J = 11.5, 6.6, 3.8 Hz, 1 H), 3.79 (dt, J = 11 .3, 5.5 Hz, 1 H), 2.57 (d, J = 5.0 Hz, 1 H), 2.24 (s, 3H), 2.03 (dd, J = 6.6, 5.6 Hz, 1 H). (JH2-35-C1-diol)

Chiral HPLC on column Chiralpak OD3; Mobile phase: Heptane/Ethanol (90/10); Flow rate 1.0 mL/min; Retention time: 10.9 min, 12.8 min. Peaks of the chromatograms of the diol from Ci and from C2 are shown on the tables below (Ci-120 h, C2-120 h).

Chromatogram of pure racemic diol: Chiral HPLC on column Chiralpak OD3; Mobile phase: Heptane/Ethanol (90/10); Flow rate 1.0 mL/min; Retention time: 10.9 min, 12.8 min. Example 4: 3-(allyloxy)propane-1 ,2-diol

Chromatogram of pure racemic diol: Chiral HPLC on column Lux-i-Cellulose-4; Mobile phase: Hexane/isopropanol (95/5); Flow rate 1.0 mL/min; Retention time: 10.2 min, 10.7 min.

RT Peak Height Integral Peak Area FWHM Integral Region

Peak [min] [mAU] [ % ] [mAU*s ] [min] [min] Annotation

1 10 .24 196. 63 49.79 2978. 1 0.1889 9. 91 - 10.47

2 10 . 69 188 .03 50.21 3003. 0 0. 1979 10.47 - 11.23

Example 4.1 :

(Cepoxide = 5.3 M, T = rt, Reactor 3, thickness = 150 pm)

In compartment Ci, allyl glycidyl ether (2.42 g, 21 .2 mmol, 1 equiv.) OH and (S,S)-catalyst 1 -OAc (0.06 g, 0.1 mmol, 0.5 mol %) were introduced with 1.5 mL of CH3CN while in C2, the same amount of allyl glycidyl ether (2.42 g, 21.2 mmol, 1 equiv.) were introduced but with (R,R)-catalyst 1 -OAc (0.06 g, 0.1 mmol, 0.5 mol %) with 1 .5 mL of CH3CN. In each compartment, H2O (457 pL, 25.4 mmol, 1 .2 equiv.) was added dropwise at 0 °C. A balloon with air (P= 1 atm) was placed on the top of both compartments. The reaction mixture was then allowed to warm at room temperature. Each compartment is purified separately by chromatography on silica gel (ethylacetate/ petroleum ether: 5/5 v/v). The conversion in the double reactor reached 93 % in 72 h. Enantioenriched diol from Ci was obtained with 73 % isolated yield in 71 % ee. From C2, the configurationally opposite diol was obtained with 71 % isolated yield in 69 % ee.

¹ H NMR (400 MHz, Chloroform-d) 5 5.99 - 5.85 (m, 1 H), 5.34 - 5.18 (m, 2H), 4.04 (d, J = 5.7, 1 .5 Hz, 2H), 3.95 - 3.83 (m, 1 H), 3.78 - 3.69 (m, 1 H), 3.65 (dtd, J = 11 .1 , 5.1 , 3.4 Hz, 1 H), 3.60 - 3.46 (m, 2H), 3.05 - 2.75 (m, 1 H), 2.65 - 2.29 (m, 1 H).

Chiral HPLC on column Lux-i-Cellulose-4; Mobile phase: Hexane/isopropanol (95/5);

Flow rate 1.0 mL/min; Retention time: 10.2 min, 10.7 min. Chromatograms of the diol from Ci and from C2 were shown below (Ci-72 h, C?-72 h). Example 4.2 : (C _epO xide = neat, T = rt, Reactor 3, thickness = 150 pm)

_0H In compartment Ci, allyl glycidyl ether (3.88 g, 34 mmol, 1 equiv.) and (S,S)-catalyst 1 -OAc (0.10 g, 0.17 mmol, 0.5 mol %) were introduced without any solvent while in C2, the same amount of allyl glycidyl ether (3.88 g, 34 mmol, 1 equiv.) were introduced but with (R,R)-catalyst 1 -OAc (0.10 g, 0.17 mmol, 0.5 mol %) without solvent. In each compartment, H2O (734 pL, 40.8 mmol, 1.2 equiv.) was added dropwise at 0 °C. A balloon with air (P= 1 atm) was placed on the top of both compartments. The reaction mixture was then allowed to warm at room temperature. Each compartment is purified separately by chromatography on silica gel (ethylacetate/ petroleum ether: 5/5 v/v). The conversion in the double reactor reached 84 % in 72 h. Enantioenriched diol from Ci was obtained with 77 % isolated yield in 58 % ee. From C2, the configurationally opposite diol was obtained with 81 % isolated yield in 51 % ee.

¹ H NMR (300 MHz, Chloroform-d) 5 5.89 (ddt, J = 17.2, 10.4, 5.7 Hz, 1 H), 5.34 - 5.14 (m, 2H), 4.01 (d, J = 5.7 Hz, 1 H), 3.87 (m, 1 H), 3.71 (m, 1 H), 3.61 (dd, J = 12.6, 5.9 Hz, 1 H), 3.57 - 3.38 (m, 2H), 2.96 (s, 1 H), 2.57 (s, 1 H).

Chiral HPLC on column Lux-i-Cellulose-4; Mobile phase: Hexane/isopropanol (95/5); Flow rate 1.0 mL/min; Retention time: 10.2 min, 10.7 min. Chromatograms of the diol from Ci and from C2 were shown below (Ci-72 h, C2-72 h).

Example 5: 5-Hexene1,2-diol

Chromatogram of pure racemic diol: Chiral HPLC on column Lux-i-Cellulose-4; Mobile phase: Hexane/isopropanol (95/5); Flow rate 1.0 mL/min; Retention time: 6.3 min, 6.8 min.

2 6.76 274 .88 49. 93 2675.2 0. 1207 6.55 - 7.15 Example 5.1 : (C _epO xide = 5.3 M, T = rt, Reactor 3, thickness = 150 pm)

In compartment Ci, 1 ,2-epoxy-1 -hexene (2.08 g, 21.2 mmol, 1 equiv.) and (S,S)-catalyst 1-OAc (0.06 g, 0.1 mmol, 0.5 mol %) were introduced with 1 .6 mL of CH3CN while in C2, the same amount of 1 ,2- epoxy-1 -hexene (2.08 g, 21.2 mmol, 1 equiv.) were introduced but with (R,R)-catalyst 1- OAc (0.06 g, 0.1 mmol, 0.5 mol %) with 1.6 mL of CH3CN. In each compartment, H2O (457 pL, 25.4 mmol, 1.2 equiv.) was added dropwise at 0 °C. A balloon with air (P= 1 atm) was placed on the top of both compartments. The reaction mixture was then allowed to warm at room temperature. Each compartment is purified separately by chromatography on silica gel (ethylacetate/ petroleum ether: 5/5 v/v). The conversion in the double reactor reached 80 % in 72 h. Enantioenriched diol from Ci was obtained with 56 % isolated yield in 81 % ee. From C2, the configurationally opposite diol was obtained with 57 % isolated yield in 77 % ee.

¹ H NMR (400 MHz, Chloroform-d) 5 5.84 - 5.65 (m, 1 H), 5.05 - 4.84 (m, 2H), 3.86 (d, J = 21 .1 Hz,2H), 3.62 (m, 1 H), 3.54 (dd, J = 11 .4, 2.9 Hz, 1 H), 3.34 (dd, J = 11 .4, 7.7 Hz, 1 H), 2.27 - 1 .98 (m, 2H), 1.54 - 1 .32 (m, 2H).

Chiral HPLC on column Lux-i-Cellulose-4; Mobile phase: Hexane/isopropanol (95/5); Flow rate 1.0 mL/min; Retention time: 6.3 min, 6.8 min. Chromatograms of the diol from Ci and from C2 were shown below (Ci-72 h, C?-72 h).

Example 5.2: (C _epO xide = neat, T = rt, Reactor 3, thickness = 150 pm)

In compartment Ci, 1 ,2-epoxy-1 -hexene (3.34 g, 34 mmol, 1 equiv.) and (S,S)-catalyst 1-OAc (0.10 g, 0.17 mmol, 0.5 mol %) were

30 introduced without any solvent while in C2, the same amount of 1 ,2- epoxy-1 -hexene (3.34 g, 34 mmol, 1 equiv.) were introduced but with (R,R)-catalyst 1- OAc (0.10 g, 0.17 mmol, 0.5 mol %) without solvent. In each compartment, H2O (734 pL, 40.8 mmol, 1.2 equiv.) was added dropwise at 0 °C. A balloon with air (P= 1 atm) was placed on the top of both compartments. The reaction mixture was then allowed to warm at room temperature. Each compartment is purified separately by chromatography on silica gel (ethylacetate/petroleum ether: 5/5 v/v). The conversion in the double reactor reached 75 % in 72 h. Enantioenriched diol from Ci was obtained with 65 % isolated yield in 78 % ee. From C2, the configurationally opposite diol was obtained with 73 % isolated yield in82 % ee.

¹ H NMR (400 MHz, Chloroform-d) 5 5.85 (m, 1 H), 5.16 - 4.93 (m, 2H), 3.75 (m, 1 H), 3.68 (dd, J = 11 .1 , 3.1 Hz, 1 H), 3.47 (dd, J = 11 .1 , 7.6 Hz, 1 H), 2.37 (d, J = 45.3 Hz, 2H), 2.21 (m, 2H), 1.65 - 1.48 (m, 2H).

Chiral HPLC on column Lux-i-Cellulose-4; Mobile phase: Hexane/isopropanol (95/5); Flow rate 1.0 mL/min; Retention time: 6.3 min, 6.8 min. Chromatograms of the diol from Ci and from C2 were shown below (Ci-72 h, C?-72 h).