Chemoenzymatic Synthesis of a Chiral Ozanimod Key Intermediate

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Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

Chemoenzymatic Synthesis of a Chiral Ozanimod Key Intermediate Starting from Naphthalene as Cheap Petrochemical Feedstock Florian Uthoff,†,§ Jana Löwe,†,§ Christina Harms,† Kai Donsbach,‡ and Harald Gröger*,† †

J. Org. Chem. Downloaded from pubs.acs.org by UNIV OF LOUISIANA AT LAFAYETTE on 04/12/19. For personal use only.

Chair of Industrial Organic Chemistry and Biotechnology, Faculty of Chemistry, Bielefeld University, Universitätsstr. 25, 33615 Bielefeld, Germany ‡ PharmaZell GmbH, Rosenheimer Str. 43, 83064 Raubling, Germany S Supporting Information *

ABSTRACT: Ozanimod represents a recently developed, promising active pharmaceutical ingredient (API) molecule in combating multiple sclerosis. Addressing the goal of a scalable, economically attractive, and technically feasible process for the manufacture of this drug, a novel alternative synthetic approach toward (S)-4-cyano-1-aminoindane as a chiral key intermediate for ozanimod has been developed. The total synthesis of this intermediate is based on the utilization of naphthalene as a readily accessible, economically attractive, and thus favorable petrochemical starting material. At first, naphthalene is transformed into 4-carboxy-indanone within a four-step process by means of an initial Birch reduction, followed by an isomerization of the CC double bond, oxidative CC cleavage, and intramolecular Friedel−Crafts acylation. The transformation of the 4-carboxy-indanone into (S)-4-cyano-1aminoindane then represents the key step for introducing the chirality and the desired absolute S configuration. When evaluating complementary biocatalytic approaches based on the use of a lipase and transaminase, respectively, the combination of a chemical reductive amination of the 4-carboxyindanone followed by a subsequent lipase-catalyzed resolution turned out to be the most efficient route, leading to the desired key intermediate (S)-4-cyano-1-aminoindane in satisfactory yield and with excellent enantiomeric excess of 99%.

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INTRODUCTION The migration of lymphocytes has been associated with sphingosine-1-phosphate receptors (S1P receptors).1 S1P receptors belong to the G-protein-coupled proteins and are classified into a family of five receptors, S1PR1−S1PR5.2 Drug treatments have been developed to suppress the immune response because S1P receptors trigger autoimmune diseases.3 The ligand for the S1P receptors is sphingosine-1-phosphate. One approved drug for multiple sclerosis treatment is fingolimod (FTY720-P), but its adverse effects motivate the search for alternatives. A highly promising active pharmaceutical ingredient (API) molecule is ozanimod (1), which has been developed by Receptos and is structurally quite different from fingolimod. The major advantages of ozanimod (RPC1063) are the decreased tendency toward adverse effects and the lack of a needed phosphorylation to generate the pharmaceutically active species.2 Furthermore, it has improved oral pharmacokinetics as well as receptor selectivity and a shorter half life.3 A phase-2 study with ozanimod in patients with multiple sclerosis demonstrated a dose-dependent reduction in circulating lymphocytes. This, in turn, was associated with a reduction in inflammatory and neurodegenerative brain lesions.3,4 In addition to multiple sclerosis, this substance can also be used for curing ulcerative colitis.3 Although the active ingredient has not yet been approved as a © XXXX American Chemical Society

drug, its pharmaceutical relevance and importance are underlined by the acquisition of the company Receptos by Celgene for $7.2 billion.5 With respect to the concept for its synthesis, ozanimod can be retrosynthetically subdivided and designed starting from three building blocks (Scheme 1). Two of the three building blocks are comparable in terms of their size, thus enabling an advantageous convergent synthesis. Accordingly, the 1,2,4Scheme 1. Retrosynthetic Synthetic Access to Ozanimod 1

Special Issue: Excellence in Industrial Organic Synthesis 2019 Received: December 30, 2018

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DOI: 10.1021/acs.joc.8b03290 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry oxadiazole heterocycle is built up at the final step of the total synthesis by means of an easy-to-conduct condensation reaction. One of the two key building blocks for the synthetic access to ozanimod is the chiral 1-aminoindane species 2, which is required in enantiomerically pure form. In initial work on the synthesis of ozanimod,6 this 4-cyano-substituted amine 2 was prepared from 4-bromoindanone (3) in three steps (Scheme 2). First, the bromine substituent was replaced by a cyano

Scheme 3. Retrosynthetic Enzymatic Opportunities for the Synthesis of Enantiomerically Pure (S)-4-Cyano-1aminoindanes

Scheme 2. Established Route to the Chiral Amine Key Intermediate (S)-2 Developed by Receptos However, in addition to the choice of the enantioselective biocatalytic route, a further key issue in this total synthesis of key intermediate (S)-2 is the retrosynthetic design of an attractive approach toward suitable substrates, such as the prochiral 1-indanone 4. Toward this end, we envisioned a retrosynthetic approach starting from naphthalene (8) as a very cheap petrochemical raw material being available in bulk quantities (Scheme 4). The initial transformation by partial Scheme 4. Retrosynthetic Concept for Synthesizing (S)-4Cyano-1-aminoindane ((S)-2) Starting from Naphthalene (8)

group via a palladium-catalyzed coupling reaction; subsequently, an imine was formed through a condensation with the chiral Ellman’s auxiliary as an amine component, followed by a diastereoselective reduction.6 Although the desired 1-aminoindane (S)-4-cyano-1-aminoindane 2 ((S)-2) is formed with high enantiomeric excess, the need for a high catalytic loading of the palladium catalyst with 5 mol % in combination with cyanide as a reagent and a stoichiometric amount of a chiral auxiliary represent limitations (marked in red in Scheme 2). Furthermore, in part, yields do not exceed a moderate range. It also has to be taken into account that a brominated starting material has to be prepared and that the insertion of bromine via bromination represents a somewhat more costly type of reaction (compared with, e.g., chlorination). Thus despite the straightforward and elegant formation of the 1,2,4-oxadiazole heterocycle when starting from the 1-aminoindane and the nitrile,6 with respect to a technical process, the current synthesis of the 4-cyano-1-aminoindane (S)-2 as an intermediate consists of the utilization of, in part, relatively expensive components (brominated substrate, chiral auxiliary, palladium catalyst) as well as toxic reagents such as a metal cyanide. As potential alternative approaches toward the 1-aminoindane key building block (S)-2, one can conceive various synthetic options based on biocatalysis (Scheme 3).7 Because of the high enantioselectivity of enzymes, we were interested to study such reactions as key steps. Instead of a diastereoselective reduction of the preformed chiral imine (S)-5, the prochiral ketone 4 can be directly reductively aminated in an asymmetric fashion by means of, for example, a transaminase. A further biocatalytic option is the “classic” chemical reductive amination leading to racemic amine rac-2, followed by an enzymatic kinetic resolution by means of a lipasecatalyzed acylation. Although such a kinetic resolution route is limited, by definition, to a maximum yield of 50%, the high efficiency of lipases in such types of resolutions together with the option to subsequently recycle the undesired enantiomer make this route attractive as well. Both routes were evaluated and, in part, optimized in our work.

reduction furnishing 1,2-dihydronaphthalene (which could be done, for example, through Birch reduction,8 followed by an isomerization) and the subsequent oxidatively cleavage via an ozonolysis-type reaction8 lead to the diacid (7). A Friedel− Crafts acylation9 of this diacid 5 then gives the 1-indanone derivative 6, now bearing a carboxylate (as a nitrile precursor) in the desired four-position. It should be added that the acylation can take place only in the meta-position, thus avoiding side products with an undesirable substituent pattern. The carboxylic acid moiety of the indanone skeleton in 6 can then be interconverted into the desired nitrile group either prior to or after the formation of the chiral amine moiety through the biocatalytic reactions described above (e.g., by the initial formation of 4 and the subsequent transamination or chemical synthesis of rac-2, followed by enzymatic resolution), thus forming the desired chiral key building block (S)-2. In the following, we report our results on such a chemoenzymatic approach for the enantioselective synthesis of the ozanimod key intermediate (S)-2 based on an evaluation of both biocatalysis concepts, namely, lipase-catalyzed resolution and transaminase-catalyzed reductive amination, as key steps to introduce the chiral amine moiety in an asymmetric fashion. In addition, the optimization of the favored route for (S)-2 is described as well as a “back B


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The Journal of Organic Chemistry

acid chloride as the acyl donor led to an increased byproduct formation, alternatives were studied. Sulfuric acid acts as an efficient catalyst and increases the electrophilicity of the free carboxylic acid 7, leading to a successful aromatic substitution when following a literature protocol. 9 However, such conditions described in the literature led to a high byproduct formation and low yield of 10% for the desired indanone-type product 6. We were pleased to find that by substrate concentration dilution to 56 mM and product isolation by continuous liquid−liquid extraction the yield of 6 is increased to (nonoptimized) 42%. Note that the resulting high purity does not require further purification. Subsequently, the acid 6 is converted to the corresponding nitrile 4 via a primary amide 11. Ethyl chloroformate proved to be a favorable activating reagent, whereas attempts using the more reactive thionyl chloride were not successful. The mixed anhydride reacts quantitatively to the primary amide 11 in the presence of aqueous ammonia. Without isolating the mixed anhydride, a yield of 77% for 11 over these two steps is achieved (Scheme 5). The next step consists of converting the amide moiety in 11 into the cyano group, thus leading to the desired prochiral intermediate 4. For this dehydration, various reagents known for this type of transformation were investigated, and the results are shown in Figure 1. The desired product 4 is formed

integration” of the synthesis of suitable 1-indanone intermediates, for example, 4 and 6, starting from naphthalene (8).

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RESULTS AND DISCUSSION To start with the synthesis of suitable substrates for the biotransformations, in particular, 4-aminoindanone (4), the initial step consists of a partial reduction of naphthalene (8) to 1,2-dihydronaphthalene (Scheme 5). Although being aware Scheme 5. Multi-Step Transformation of Naphthalene (8) into 4-Cyano-1-indanone (4) as a Substrate for the Biotransformations

that a direct partial hydrogenation might be an even more straightforward approach for technical purposes, for practical reasons, in our lab synthesis this step was carried out as a twostep interconversion via a Birch reduction, followed by an isomerization. For the Birch reduction, sodium in the presence of tert-butanol was used as a reducing agent. The product spectrum can vary in dependency on the chosen solvent conditions.8 Naphthalene (8) has been converted to 1,4dihydronaphthalene 9 in 86% yield. Isomerization then leads to 1,2-dihydronaphthalene 10, and after workup, this product is isolated in 98% yield (with a ratio of 10:9 of 97:3, thus corresponding to 95% yield referring to pure 10). For an isomerization, both basic and Brønsted-acid-catalyzed conditions are conceivable. Because in the literature,10,11 only a limited number of data on such reaction conditions can be found, we determine the preferred reaction conditions for this reaction within a reaction parameter screening. No rearrangement is observed by acid catalysis, whereas the rearrangement under basic conditions is strongly dependent on the type of base and solvent. Whereas no rearrangement is found when using toluene and tetrahydrofuran (THF), the treatment of 9 with potassium tert-butylate in tert-butanol results in the formation of the desired isomer 10. Under reflux and thus thermodynamic control, the isomer ratio reaches 97:3 in combination with a yield of 90% (Scheme 5). The isolated double bond in 10 is then oxidatively cleaved by means of potassium permanganate following a literature known protocol,9 leading to the desired diacid 7 in 75% yield after filtering off the manganese dioxide (Scheme 5). The product 7 requires no further purification and can be used directly for the subsequent Friedel−Crafts-type acylation. Because the “classic” way with aluminum trichloride and an

Figure 1. Dehydration of primary amides with different reagents.

when using all of the applied reagents, but the yields vary broadly. The best result is obtained when utilizing trifluoroacetic anhydride (17) under mild reaction conditions and with a short reaction time, leading to product 11 in excellent yield. Subsequently, we focus on the formation of the amine moiety with the desired absolute configuration at the stereogenic center according to the biocatalytic concepts described in the Introduction (see also Scheme 3). First, the results of our study on the asymmetric synthesis of amine (S)2 and related derivatives with a modified substitution pattern in the four-position by means of a transaminase as a biocatalyst are presented. Transaminases catalyze the conversion of a carbonyl compound to a primary amine, while an amine donor is transformed into the corresponding ketone, and, in C


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addition, according to this literature,15 the racemic amines rac24−26 were formed, leading to yields between 28 and 37% (Scheme 6). The amines are easily isolated via extraction and need no further purification prior to their use as substrates for the lipase-catalyzed resolution.

particular, in recent years, this methodology turned out to be highly suitable for the asymmetric synthesis of amines from ketone substrates.7,12 The ketone substrates used in this study are the four-substituted indanones 4 and 19 synthesized in the total synthesis as well as 4-bromoindanone (3) and acetophenone (18) for comparison. For our studies, two transaminases are investigated that differ with respect to the needed cosubstrate (Figure 2). The

Scheme 6. Synthesis of the Racemic Amines via a Two-Step Synthesis Consisting of Ketoxime Formation and Reduction

With the various racemic amines in hand, we next focus on the enzymatic resolution utilizing lipases to obtain the required (S)-enantiomer of the amine. For the identification of a suitable lipase racemic 1-aminoindane, rac-24, is chosen as a commercially readily available model substrate being structurally related to the ozanimod precursor amines rac-2, rac-25, and rac-26. In addition, diethylmalonate is used as an acylation reagent in the initial screening experiments, as Gröger et al. recently showed that this acyl donor enables efficient enzymatic resolutions of 1-arylethylamines.16,17 The results, which are described in the Supporting Information (Table S3), reveal lipase B from Candida antarctica (CAL-B) as the most suitable enzyme for the kinetic resolution of 1-aminoindane rac-24. The next step is the optimization of the kinetic resolution catalyzed by CAL-B, and toward this end, various acyl donors and solvents are examined. Racemic 1-aminoindane, rac-24, is again chosen as a model substrate. Toluene, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (2-MTHF), methylcyclohexane (MCH), and n-heptane are investigated as solvents. Toluene is chosen because it is a readily accessible and low-price solvent.18 Lipases are successfully used in apolar solvents; therefore, MCH and n-heptane were selected,19 and also MTBE was reported to be a suitable solvent for enzymatic kinetic resolution.20 2-MTHF represents a recently introduced green solvent, which can be obtained from biorenewable resources.21 Diethyl malonate 28 and ethyl methoxyacetate 2714b are used as acyl donors. Ethyl methoxyacetate 27 is an acyl donor used by BASF in the synthesis of chiral amines.7,13,14 The related isopropyl methoxyacetate 29 was tested in a later experiment under optimal conditions. In the literature, kinetic resolution using isopropyl methoxyacetate 29 is reported to proceed with high E values.14d,22 The goal of this study was to achieve E values of at least 20 because E values in this range appear to be suitable for industrial applications.23 In Figure 3, the results of the kinetic resolution with the different acyl donors (27−29) and solvents at 60 °C are shown. The reaction is performed for 26 h, and the E values are calculated from the ee values of the remaining amine and amide formed in the resolution. When conducting the kinetic resolution in n-heptane with diethyl malonate 28, an E value between 9 and 12 is obtained (Figure 3), whereas the kinetic resolution of 1-aminoindane, rac-24, with CAL-B in n-heptane with ethyl methoxyacetate 27 gives an increased E value of 56−60. The kinetic resolution in MTBE shows similar E values for both acyl donors: For diethyl

Figure 2. Enzymatic transamination with two different cosubstrates.

transaminase from Arthrobacter sp.12 (ArS-TA), which accepts isopropylamine (20) as an amine donor, shows a low activity against the model substrate acetophenone in aqueous buffer solution. In the organic medium, it loses almost all of the activity. In addition, 4-cyano-1-indanone (7) is not converted. In contrast, when using the transaminase from Vibrio f luvialis12a,c,d (VF-TA) for all studied indanones, at least a reasonable activity is observed (Figure 2). For this enzyme, Lalanine ((S)-22) serves as an amine donor, and the coupling to an enzyme cascade using a lactate dehydrogenase (LDH) and a glucose dehydrogenase (GDH) together with glucose as a reducing agent shifts the equilibrium to the product side. Surprisingly, the ee values for the bromo- and cyanosubstituted indanones 3 and 4 are 99% and 58% conversion. A challenge of this synthetic sequence for future work is the “classic chemical” reductive amination process with (nonoptimized) yields being so far in the range between 28 and 35%. As for the technical purpose, the biocatalyst loading is a crucial reaction parameter in terms of the reduction of the costs of the biocatalyst; next, the overall amount of the used lipase CAL-B is decreased (Figure 5), and, in addition, the same enzyme charge is used for several cycles to demonstrate a proof-of-concept for recycling of the enzyme in this process (Figure 6).

Figure 6. Recycling experiment with CAL-B.

is carried out, and the enzyme is used six times. As indicated by the comparable conversions, ee values for the amine (S)-24 and ee values for the amide (R)-30 obtained through all of the reaction cycles, there is no loss of activity of CAL-B after reuse over six reaction cycles. Thus besides showing a high robustness and reproducibility, this biocatalytic resolution process is also efficient in terms of biocatalyst loading and recyclability.

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CONCLUSIONS In summary, a chemoenzymatic synthetic route toward (S)-2 as a chiral key intermediate for API ozanimod is presented. The total synthesis of this intermediate is based on the utilization of naphthalene as a readily accessible starting material, which is transformed into 4-carboxy-indanone within a four-step process by means of an initial Birch reduction, followed by an isomerization of the CC double bond, oxidative CC cleavage, and intramolecular Friedel−Crafts acylation. For the transformation of the 4-carboxy-indanone into (S)-2 as a key step for introducing the chirality and the desired absolute S configuration, complementary biocatalytic approaches based on the use of a lipase and a transaminase, respectively, were evaluated. As a key enantioselective step, lipase-catalyzed resolution turned out to be the most efficient route, leading to the desired key intermediate (S)-2 in satisfactory yield and with excellent enantiomeric excess of 99%. For industrial application, the replacement of the initial Birch reduction of naphthalene by an efficient electrochemical reaction step would be desirable, and the development of such technical transformation represents a task for future process research work.

Figure 5. Reduction of catalyst amount in CAL-B-catalyzed resolution of the model substrate1-aminoindane, rac-24.

As for the reduction of the biocatalyst, the enzyme per substrate ratio is stepwise reduced from originally 40 mg enzyme per mmol of amine substrate (rac-24) to 20, 10, and 5 mg/mmol (Figure 5). It is noteworthy that the reaction also works with decreased CAL-B amount, and after 3 h, nearly the same ee values are found when using 10, 20, and 40 mg of lipase CAL-B per mmol of substrate. However, when further reducing the CAL-B amount to only 5 mg of CAL-B per mmol of substrate, the ee value after 3 h is at only 60%. In this case, however, when increasing the reaction time, the reaction also reaches completion. With this reduced CAL-B amount, the reaction is also conducted with 4-cyano-1-aminoindane, rac-2, and after 5 h, a conversion of 57% and an ee value of 99% for the desired amine (S)-2 are reached. Furthermore, recycling of the biocatalyst CAL-B has been studied (Figure 6). Therefore, the acylation of 1-aminoindane, rac-24, with isopropyl methoxyacetate, 29, in toluene at 60 °C

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EXPERIMENTAL SECTION

Chemistry: General Remarks. NMR spectra are recorded on Bruker Avance 500 and Bruker DRX 500 spectrometers. Chemical shifts (ppm) are given relative to a tetramethylsilane (TMS) standard. The deuterated solvents present the reference for all spectra (chloroform-d: 7.26 ppm; dimethylsulfoxide: 2.50 ppm). Multiplets are assigned as s (singlet), d (doublet), t (triplet), dd (doublet of doublet), and m (multiplet). Gas chromatography analysis is F


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8.03 (d, 3J = 7.6 Hz, 1H), 8.38 (d, 3J = 8.0 Hz, 1H). 13C{1H}-NMR (126 MHz, CDCl3) δ 206.4, 156.8, 138.4, 136.6, 129.8, 128.6, 128.1, 127.6, 36.2, 27.4. MS m/z: 174.8 [M−H]−. The analytical data are in agreement with the literature.27 Derivatization of the 4-Carboxy Substituent of Indanone. 4Carboxy-1-indanone (6, 200 mg, 1.14 mmol, 1.00 equiv) and triethylamine (551 μL, 5.79 mmol, 1.5 equiv) are dissolved in THF (5 mL) and cooled to 0 °C. Ethyl chloroformate (540 μL, 5.67 mmol, 5.00 equiv) is added. The reaction mixture is stirred for 2 h at rt. After quenching with water (3 mL), the mixture is extracted with DCM (3 × 7 mL). The combined organic layers are washed with water (15 mL) and dried with MgSO4. The solvent is removed to give 262.6 mg of a brown oil (85% yield). (Ethyl carbonic) 1-Oxo-2,3-dihydro-1Hindene-4-carboxylic anhydride: 1H NMR (500 MHz, CDCl3) δ: 1.45 (t, 3 J = 7.1 Hz, 3H), 2.77 (m, 2H), 3.55 (m, 2H), 4.45 (q, 3J = 7.2 Hz, 2H), 7.56 (m, 1H), 8.05 (d, 3J = 7.6 Hz, 1H), 8.32 (d, 3J = 8.0 Hz, 1H). 13C{1H}-NMR (126 MHz, CDCl3) δ: 205.8, 158.0, 148.9, 138.8, 137.0, 129.6, 127.9, 125.8, 66.0, 36.0, 27.4, 14.0. MS m/z: 271.1 [M+Na]+, HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C13H12O5Na 271.0582. Found 271.0577. The mixed anhydride (100 mg, 0.40 mmol, 1.00 equiv) is given to an ammonia solution (2.5 mL, 25%, 14.7 equiv) and heated to 60 °C. The reaction mixture is stirred for 24 h at rt. The mixture is extracted with DCM (3 × 5 mL). The combined organic layers are washed with water (15 mL) and dried with MgSO4. The solvent is removed to give 63.77 mg of a brown oil (91% yield, corresponding to a total yield of 77% over two steps from compound 6). 1-Oxo-2,3-dihydro-1H-indene4-carboxamide (11): 1H NMR (500 MHz, CDCl3) δ: 2.76 (m, 2H), 3.49 (m, 2H), 7.49 (m, 1H), 7.89 (dd, 3J = 7.6 Hz, 3J = 1.1 Hz, 1H), 7.93 (dd, 3J = 7.6 Hz, 3J = 1.1 Hz, 1H). 13C{1H}-NMR (126 MHz, CDCl3) δ: 206.4, 168.7, 154.7, 138.5, 132.8, 132.0, 127.7, 126.8, 36.2, 26.3. MS m/z: 173.8 [M−H]−. The primary amide (11, 150 mg, 0.85 mmol, 1.00 equiv) and triethylamine (356 μL, 2.55 mmol, 3.00 equiv) are suspended in toluene (5 mL). Phosphorus pentoxide (48 mg, 0.34 mmol, 0.40 equiv) is added, and the mixture is heated to 80 °C. The reaction mixture is stirred for 5 h. After quenching with water (3 mL), the mixture is extracted with DCM (3 × 7 mL). The combined organic layers are washed with water (15 mL) and dried with MgSO4. The solvent is removed to give 39.0 mg of a brown oil (29% yield). 1-Oxo2,3-dihydro-1H-indene-4-carbonitrile (4): 1H NMR (500 MHz, CDCl3) δ: 2.82 (m, 2H), 3.36 (m, 2H), 7.54 (tt, 3J = 7.6 Hz, 3J = 0.9 Hz, 1H), 7.91 (dd, 3J = 7.5 Hz, 3J = 1.2 Hz, 1H), 7.99 (m, 1H). 13C{1H}-NMR (126 MHz, CDCl3) δ: 204.5, 157.7, 138.2, 137.7, 128.2, 128.1, 116.1, 111.5, 35.8, 25.3. MS m/z: 179.0 [M−H]+. General Procedures. Reductive Amination. 1-Indanone and four-substituted 1-indanone derivatives (1 equiv) and hydroxylamine hydrochloride (1.5 equiv) are dissolved in ethanol and water (1:1 v/ v). Meanwhile, sodium hydroxide (1.75 equiv) dissolved in water is added to the suspension. The mixture is heated to reflux for 90 min. The crude product is filtered over Celite and washed with water. The oxime is dissolved in acetic acid. Under an argon atmosphere, zinc dust (5 equiv) is added, and the suspension is stirred at room temperature for 48 h. The reaction mixture is filtered over Celite and washed with ethyl acetate, and the solvent is removed in vacuo. The oil is dissolved in ethyl acetate and hydrogen chloride (1:1 v/v) and extracted twice with 2 M hydrogen chloride. The pH value of the aqueous phase is adjusted to 10, and afterward extracted three times with ethyl acetate. The organic phase is washed with brine and dried over MgSO4. The solvent is removed in vacuo. The remaining solvent is removed in a Schlenk flask under an argon atmosphere. 2,3-Dihydro-1H-inden-1-amine (rac-24). The product is isolated in a yield of 0.18 g (1.38 mmol, 37%). 1H NMR (500 MHz, CDCl3) δ: 1.70−1.76 (m, 1H), 2.51−2.56 (m, 1H), 2.83−2.87 (m, 1H), 2.95−3.02 (m, 1H), 4.37 (t, 3J = 7.5 Hz, 1H), 7.19−7.25 (m, 2H), 7.33−7.35 (m, 1H). MS m/z 134.5 [M+H]+. 4-Bromo-2,3-dihydro-1H-inden-1-amine (rac-25). The product is isolated in a yield of 0.36 g (1.68 mmol, 28%). 1H NMR (500 MHz, CDCl3) δ: 1.61−1.64 (m, 1H), 2.42−2.50 (m, 1H), 2.69−2.75 (m, 1H), 2.91−2.97 (m, 1H), 4.33 (t, 3J = 7.5 Hz, 1H), 7.00 (t, 3J = 7.6

performed on a GC-2010 Plus instrument from a Shimadzu Phenomenex ZB-SMS capillary column (polydimethylsiloxane with 5% polyphenylmethylsiloxane, 30 m, 0.25 mm i.d., 0.25 μm film thickness) using argon as a carrier gas. All HPLC chromatograms are recorded on a Jasco LC Net II/ADC machine with PU-2080 pumps. Chiral columns (Chiralpak AD-H, OB-H, and OJ-H) for the separation of the enantiomers for analytical purposes are commercially available from Daicel Chemical Industries. All of the reagents were purchased from Sigma-Aldrich, Alfa Aesar, ApplChem, Roth, Oxchem, Merck, TCI, VWR, Fluorochem, Deutero, Acros Organics, Amano Enzyme, Oriental Yeast, and Fisher Scientific and were used without further purification. Reduction of Naphthalene and Rearrangement toward 1,2Dihydronaphthalene. Naphthalene (8, 10.00 g, 78 mmol, 1.00 equiv) is dissolved in Et2O (150 mL). Small pieces of sodium (5.00 g, 217 mmol, 2.78 equiv) are given to the solution. The atmosphere over the sodium is nitrogen flushed. tBuOH (14.5 g, 196 mmol, 2.50 equiv) is dissolved in Et2O (50 mL) and dropped into the sodium suspension. After stirring for 16 h at rt, the reaction mixture is quenched with water and extracted with ethyl acetate (three times). The combined organic layers are dried with Na2SO4 and separated from the solvent in vacuo. Conversion is calculated by the NMR spectrum, determining an amount of 8.73 g of 1,4-dihydronaphthalene (86%). 1,4-Dihydronaphthalene (9): 1H NMR (500 MHz, CDCl3) δ: 3.41 (d, 3J = 1.3 Hz, 2H), 5.94 (t, 3J = 1.5 Hz, 2H), 7.09 (m, 4H). 13C{1H}-NMR (126 MHz, CDCl3) δ: 134.2, 128.4, 125.9, 124.8, 29.8. The analytical data are in agreement with the literature.24 For the rearrangement, 1,4-dihydronaphthalene (9, 7.92 g, 60.1 mmol, 1 equiv) is dissolved in tert-butanol (6 mL). Potassium tertbutylate (2.5 g, 22.3 mmol, 0.4 equiv) is given to the solution, and the mixture is stirred for 12 h at 60 °C under an argon atmosphere. The reaction mixture is admixed with dichloromethane (DCM) (10 mL) and washed three times with water (15 mL). The solvent is removed in vacuo, and the product is recovered as a slightly yellowish liquid. The reaction control is carried out by GC, and the purity of the product is determined by 1H NMR, leading to a yield of 7.43 g of 1,2dihydronaphthalene (97%; ratio of 10:9 of 97:3, thus corresponding to 95% of pure 10). 1,2-Dihydronaphthalene (10): 1H NMR (500 MHz, CDCl3) δ: 2.34 (m, 1H), 2.82 (t, 3J = 8.2 Hz, 1H), 6.05 (m, 1H), 6.48 (m, 1H), 6.85−7.29 (m, 4H). 13C{1H}-NMR (126 MHz, CDCl3) δ: 135.4, 134.2, 128.5, 127.8, 127.5, 126.8, 126.4, 125.9, 27.5, 23.2. The analytical data are in agreement with the literature.25 Oxidative Cleavage of the CC Double Bond in 1,2Dihydronaphthalene. 1,2-Dihydronapthalene (10, 15.00 g, 115 mmol, 1.00 equiv) is dissolved in methylene chloride (50 mL) and then slowly added dropwise to a potassium permanganate solution (2000 mL, 230 mmol, 230 mM, 4.00 equiv). The reaction mixture is stirred for 3 h at 0 °C. After adding sodium hydroxide (32 g, 800 mmol, 6.96 equiv) the solution is filtrated to separate manganese dioxide. The filtrate is extracted by methylene chloride (three times 1000 mL). The aqueous layer is acidified with concentrated hydrochloric acid (70 mL, 840 mmol, 12 M, 7.30 equiv) to pH 12 to give a precipitate. After filtration, the diacid 7 is isolated with a yield of 75% (15.53 g, 80 mmol). 3-(2-Carboxyphenyl)propionic acid (7): 1H NMR (500 MHz, CDCl3) δ: 2.73 (t, 3J = 7.8 Hz, 2H), 3.42 (t, 3J = 7.9 Hz, 2H), 7.35 (m, 2H), 7.52 (m, 1H), 8.06 (d, 3J = 7.7 Hz, 1H). 13C{1H}-NMR (126 MHz, CDCl3) δ: 174.7, 167.6, 142.8, 132.7, 131.7, 131.4, 131.2, 127.2, 36.3, 30.0. MS: m/z = 192.8 [M− H]−, MS m/z: 217.0 [M+Na]+. The analytical data are in agreement with the literature.26 Intramolecular Friedel−Crafts Acylation under the Formation of 4-Carboxylic-Acid-Substituted Indan-1-one. 3-(2Carboxyphenyl)propionic acid (7, 500 mg, 2.57 mmol, 1.00 equiv) is dissolved in sulfuric acid (30 mL). The reaction mixture is stirred for 2 h at 130 °C. The complete reaction mixture is given on ice (20 g). The solution is stored at 8 °C for 65 h to give a precipitate. After filtration, 209.6 mg (42% yield) of the analytically pure but browncolored product 6 (analytically determined by NMR) is isolated. 1Oxo-2,3-dihydro-1H-indene-4-carboxylic acid (6): 1H NMR (500 MHz, CDCl3) δ: 3.16−3.22 (m, 2H), 3.54−3.58 (m, 2H), 7.62 (m, 1H), G


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The Journal of Organic Chemistry Hz, 1H), 7.17 (d, 3J = 7.4 Hz, 1H), 7.27 (d, 3J = 7.9 Hz, 1H). 13 C{1H}-NMR (126 MHz, CDCl3) δ: 144.2, 143.1,131.9, 129.0, 123.5, 120.4, 56.8, 31.8, 31.6. MS (ESI) m/z: 211.9 [M+H]+, 213.9 [M+H]+. The analytical data are in agreement with the literature.28 1-Amino-2,3-dihydro-1H-indene-4-carbonitrile (rac-2). The product is isolated in a yield of 28 mg (0.18 mmol, 35%). 1H NMR (500 MHz, CDCl3) δ: 2.11−2.17 (m, 1H), 2.60−2.69 (m, 1H), 3.05−3.10 (m, 1H), 3.28−3.33 (m, 1H), 4.65 (t, 3J = 7.5 Hz, 1H), 7.37 (t, 3J = 7.6 Hz, 1H), 7.56 (d, 3J = 7.4 Hz, 1H), 7.70 (d, 3J = 7.9 Hz, 1H). 13C{1H}-NMR (126 MHz, CDCl3) δ: 148.2, 141.7, 132.6, 129.6, 126.1, 117.3, 109.5, 55.8, 31.3, 30.0. MS (ESI) m/z: 159.0 [M +H]+. The analytical data are in agreement with the literature.6 Methyl 1-Amino-2,3-dihydro-1H-indene-4-carboxylate (rac-26). The product is isolated in a yield of 0.30 g (1.57 mmol, 30%). 1H NMR (500 MHz, CDCl3) δ: 1.69−1.76 (m, 1H), 2.55−2.61 (m, 1H), 3.10−3.17 (m, 1H), 3.37 (s, 3H), 3.45−3.53 (m, 1H), 4.39 (t, 3J = 7.5 Hz, 1H), 7.32 (t, 3J = 7.6 Hz, 1H), 7.54 (d, 3J = 7.4 Hz, 1H), 7.91 (d, 3 J = 7.9 Hz, 1H). Biology. General Remarks. All transaminase plasmids are purchased from Thermo Scientific as codon-optimized genes and overexpressed in E. coli BL21(DE3). Transaminases are used as a lyophilized crude extract. The CAL-B (Candida antarctica lipase B) is purchased from Sigma-Aldrich. Activity Assay for Transaminases. The activity of the transaminase is measured by a photometer assay. The U mg−1 of the ωtransaminase is assayed employing enantiomerically pure 1-phenylethylamine (S)-3 as the substrate (2.5 mM) for VF-TA, sodium pyruvate (2.5 mM) as an acceptor, and pyridoxal phosphate (PLP, 0.1 mM) in phosphate buffer (0.1 M, pH 8.0). A typical sample is prepared using 1 mg of lyophilized crude enzyme in phosphate buffer (1 mL, pH 8, 100 mM). The substrate/buffer solution (980 μL) is heated to 30 °C. The cuvette is filled to 1 mL with enzyme solution. The activity is measured by means of the photometer by UV detection (245 nm) in time-course mode. General Procedures. Transamination with Vibrio f luvialis Transaminase (VF-TA). L-Alanine (275 mM) and glucose (160 mM) are dissolved in a phosphate buffer (0.1 M, pH 8.0). To the solution are given the lyophilizates of transaminase (575 U/mmol substrate) and GDH (1230 U/mmol substrate). LDH (575 U/mmol substrate), organic solvent (MeOH 25% v/v of buffer), solution of PLP (12.5% v/v of buffer, 10 mM, pH 8.0), and acetophenone (50 mM) are added to the suspension. The reaction mixture is stirred for 24 h at 30 °C. After the complete reaction time, the mixture is incubated by hydrochloric acid (50% v/v, 1 M) for 19 h at 30 °C. The pH is changed to 14 with sodium hydroxide solution (10 M) before the suspension is extracted by methylene chloride (three times). The combined organic layers are dried with Na2SO4 and separated from the solvent in vacuum. Conversion is calculated by the NMR spectrum, and enantiomeric excess is determined after derivatization to the corresponding amide by chiral HPLC. The results are shown in Table S1. Transamination with Arthrobacter sp. Transaminase in DMSO. First, isopropylamine (75 μL, 0.90 mmol, 2.1 eq) is dissolved in DMSO (3.0 mL). The solution is added to phosphate buffer (540 μL, 0.1 M, pH 8.0). To the solution is given the lyophilizate of the transaminase of Arthrobacter sp. (76 mg), and PLP solution (4.3 mL, 10 mM, pH 8.0) and acetophenone (50 μL, 0.43 mmol, 1.00 eq) are added to the suspension. The reaction mixture is stirred for 24 h at 45 °C. After the corresponding reaction time, the mixture is extracted by methylene chloride (3 × 10 mL). The combined organic layers are dried with Na2SO4 and separated from the solvent in vacuum. Conversion is calculated according to NMR spectrum, and enantiomeric excess is determined after derivatization to the corresponding amide by chiral HPLC. The results are shown in Table S2. General Procedures. Derivatization for Calculation of Enantiomeric Excess (Transaminase). DMAP (0.8 equiv) is dissolved in acetic anhydride (20.0 equiv). The amine (1.0 equiv) is dissolved in EtOAc and given to the DMAP solution. After the mixture is stirred at room temperature, the reaction is quenched with

water and extracted with methylene chloride. The crude product is purified by one acidic extraction at pH 1 and one basic (pH 13) extraction (three times for each of them). General Procedures. Derivatization for Calculation of Enantiomeric Excess (Lipase). The amine sample was acetylated with acetyl chloride (1.1 equiv) and triethylamine (1.5 equiv) in methylene chloride for 1 h. The suspension is washed with hydrogen chloride (1:1 v/v). The solvent is removed in vacuo. Enantiomeric excess of the amide is determined via HPLC. N-(2,3-Dihydro-1H-inden-1-yl)acetamide (36). The product is isolated in a yield of 65 mg (0.38 mmol, 51%). 1H NMR (500 MHz, CDCl3) δ: 1.80−1.86 (m, 1H), 2.03 (s, 3H), 2.64−2.69 (m, 1H), 2.86−2.95 (m, 1H), 2.89−2.94 (m, 1H), 5.48 (q, 3J = 7.7 Hz, 1H), 7.20−7.25 (m, 3H), 7.28−7.30 (m, 1H). 13C{1H}-NMR (126 MHz, CDCl3) δ: 177.9, 143.6, 142.7, 128.3, 126.9, 125.0, 124.1, 55.3, 33.8, 30.4, 22.8. MS (EI) m/z: 175.1 [M+H]+. Ethyl-3-((2,3-dihydro-1H-inden-1-yl)amino)-3-oxopropanoate (31). The product is isolated in a yield of 76 mg (0.32 mmol, 86%). 1 H NMR (500 MHz, CDCl3) δ: 1.28 (t, 3J = 7.1 Hz, 3H), 1.85−1.90 (m, 1H), 2.62−2.66 (m, 1H), 2.88−2.94 (m, 1H), 3.00−3.05 (m, 1H), 3.37 (d, 4J = 2.2 Hz, 2H), 4.19 (q, 3J = 7.1 Hz, 2H), 5.51 (q, 3J = 7.7 Hz, 1H), 7.19−7.26 (m, 3H), 7.28−7.32 (m, 1H). N-(2,3-Dihydro-1H-inden-1-yl)-2-methoxyacetamide (30). The product is isolated in a yield 102 mg (0.50 mmol, 67%). 1H NMR (500 MHz, CDCl3) δ: 1.85−1.90 (m, 1H), 2.63−2.70 (m, 1H), 2.90−2.96 (m, 1H), 3.02−3.07 (m, 1H), 3.41 (s, 3H), 3.97 (d, 4J = 1.1 Hz, 2H), 5.55 (q, 3J = 7.9 Hz, 1H), 7.21−7.25 (m, 4H). 13C{1H}NMR (126 MHz, CDCl3): 169.5, 143.5, 143.6, 128.1, 126.9, 124.9, 124.2, 72.1, 59.3, 54.2, 34.2, 30.4. MS (EI) m/z: 205.1 [M+H]+ N-(4-Bromo-2,3-dihydro-1H-inden-1-yl)acetamide (37). The product is isolated in a yield of 65 mg (0.38 mmol, 51%). 1H NMR (500 MHz, CDCl3) δ: 1.80−1.86 (m, 1H), 2.09 (s, 3H) 2.60− 2.66 (m, 1H), 2.85−2.91 (m, 1H), 3.04−3.10 (m, 1H), 5.55 (q, 3J = 7.7 Hz, 1H), 7.09 (t, 3J = 7.6 Hz, 1H), 7.22 (d, 3J = 7.4 Hz, 1H), 7.22 (d, 3J = 7.39 Hz, 1H). 13C{1H}-NMR (126 MHz, CDCl3): 170.0, 145.3, 143.8, 131.3, 128.8, 123.1, 120.4, 55.7, 33.1, 31.7, 23.5. MS (EI) m/z: 253.0 [M+H]+. Ethyl 3-((4-Bromo-2,3-dihydro-1H-inden-1-yl)amino)-3-oxopropanoate (33). The product is isolated in a yield of 76 mg (0.32 mmol, 86%). 1H NMR (500 MHz, CDCl3) δ: 1.27 (t, 3J = 7.2 Hz, 3H),. 1.85−1.93 (m, 1H), 2.61−2.66 (m, 1H), 2.86−2.92 (m, 1H), 3.06−3.12 (m, 1H), 3.36 (d, 4J = 1.3 Hz, 2H), 4.18 (q, 3J = 7.1 Hz, 2H), 5.56 (q, 3J = 7.7 Hz, 1H), 7.08 (t, 3J = 7.6 Hz, 1H), 7.22 (d, 3J = 7.4 Hz, 1H), 7.39 (d, 3J = 7.39 Hz, 1H). 13C-{1H}-NMR (126 MHz, CDCl3) δ: 169.7, 169.7, 145.0, 143.8, 131.3, 128.8, 123.1, 120.4, 61.8, 55.7, 41.2, 33.1, 31.7, 14.2. MS (EI) m/z: 325.0 [M+H]+. N-(4-Bromo-2,3-dihydro-1H-inden-1-yl)-2-methoxyacetamide (32). The product is isolated in a yield of 11 mg (0.04 mmol, 50%). 1 H NMR (500 MHz, CDCl3) δ: 1.79−1.85 (m, 1H), 2.56−2.62 (m, 1H), 2.82−2.89 (m, 1H), 3.98−3.05 (m, 1H), 3.34 (s, 3H), 3.90 (d, 4 J = 1.1 Hz, 2H), 5.54 (q, 3J = 7.9 Hz, 1H), 7.03 (t, 3J = 7.6 Hz, 1H), 7.15 (d, 3J = 7.4 Hz, 1H), 7.34 (d, 3J = 7.9 Hz, 1H). 13C{1H}-NMR (126 MHz, CDCl3) δ: 169.5, 145.0, 143.8, 131.3, 128.8, 123.1, 120.4, 72.1, 59.3, 59.3, 33.0, 31.8. MS (EI) m/z: 283.0 [M+H]+. N-(4-Cyano-2,3-dihydro-1H-inden-1-yl)acetamide (37). The product is isolated in a yield of 10 mg (0.05 mmol, 60%). 1H NMR (500 MHz, CDCl3) δ: 1.87−1.92 (m, 1H), 2.14 (s, 3H) 2.63− 2.69 (m, 1H), 2.87−2.93 (m, 1H), 3.08−3.15 (m, 1H), 5.55 (q, 3J = 7.7 Hz, 1H), 7.30 (dd, 3J = 7.8 Hz, 1H), 7.52 (t, 3J = 7.8 Hz, 2H). 13 C{1H}-NMR (126 MHz, CDCl3) δ: 169.6, 147.4, 144.9, 131.7, 128.8, 127.9, 117.6, 109.3, 53.8, 33.4, 30.0, 23.5. MS (EI) m/z: 253.0 [M+H]+, 255.0 [M+H]+. Ethyl 3-((4-Cyano-2,3-dihydro-1H-inden-1-yl)amino)-3-oxopropanoate (34). The product is isolated in a yield of 15 mg (0.06 mmol, 69%). 1H NMR (500 MHz, CDCl3) δ: 1.28 (t, 3J = 7.2 Hz, 3H) 1.93−2.00 (m, 1H), 2.68−2.73 (m, 1H), 3.03−3.07 (m, 1H), 3.21−3.26 (m, 1H), 3.41 (d, 4J = 2.2 Hz, 2H), 4.19 (q, 3J = 7.1 Hz, 2H), 5.56 (q, 3J = 7.7 Hz, 1H), 7.30 (dd, 3J = 7.7 Hz, 1H) 7.52 (dt, 3J = 7.7 Hz, 2H). 13C{1H}-NMR (126 MHz, CDCl3) δ: 172.9, 169.8, H


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The Journal of Organic Chemistry 147.4, 144.8, 131.7, 128.9, 127.9, 117.6, 59.3, 53.9, 42.7, 33.3, 30.3, 14.2. MS (EI) m/z: 325.0 [M+H]+, 327.0 325.0 [M+H]+. N-(4-Cyano-2,3-dihydro-1H-inden-1-yl)-2-methoxyacetamide (9). The product is isolated in a yield of 12 mg (0.05 mmol, 64%). 1H NMR (500 MHz, CDCl3) δ: 1.92−2.00 (m, 1H), 2.67−2.71 (m, 1H), 3.07−3.12 (m, 1H), 3.21−3.25 (m, 1H), 3.40 (s, 3H), 3.96 (d, 4J = 2.5 Hz, 2H), 5.58 (q, 3J = 8.1 Hz, 1H), 7.30 (dd, 3J = 7.67 Hz, 1H), 7.51 (dd, 3J = 7.4 Hz, 2H). 13C{1H}-NMR (126 MHz, CDCl3) δ: 169.6, 147.3, 144.7, 131.6, 128.8, 127.7, 117.4, 109.2, 71.8, 59.2, 53.7, 33.2, 29.9. MS (ESI) m/z: 253.1 [M+Na]+, 483.1 [2M+Na]+. IR (neat)/cm−1: 3216, 2920, 2850, 2222, 1654, 1541, 1447, 795. Anal. Calcd for C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.83; H, 6.21; N, 11.73. Methyl-1-acetamido-2,3-dihydro-1H-indene-4-carboxylate (39). The product is isolated in a yield of 7 mg (0.03 mmol, 40%). 1H NMR (500 MHz, CDCl3) δ: 1.80−1.85 (m, 1H), 2.04 (s, 3H) 2.61− 2.66 (m, 1H), 3.12−3.18 (m, 1H), 3.33 (s, 3H), 3.35−3.40 (m, 1H), 5.50 (q, 3J = 7.9 Hz, 1H), 7.29 (t, 3J = 7.6 Hz, 1H), 7.48 (d, 3J = 7.5 Hz, 2H), 7.48 (d, 3J = 7.8 Hz, 1H). 13C{1H}-NMR (126 MHz, CDCl3) δ: 170.0, 167.3, 145.8, 145.1, 130.1, 128.6, 127.1, 126.9, 54.4, 52.0, 33.7, 23.6. MS (EI) m/z: 233.1 [M+H]+. Methyl 1-(2-Methoxyacetamido)-2,3-dihydro-1H-indene-4-carboxylate (35). The product is isolated in a yield of 5 mg (0.03 mmol, 52%). 1H NMR (500 MHz, CDCl3) δ: 1.85−1.90 (m, 1H), 2.62−2.68 (m, 1H), 3.11−3.16 (m, 1H), 3.40 (s, 3H), 3.43−3.49 (m, 1H), 3.47 (d, 3J = 5.3 Hz, 2H), 5.55 (q,3J = 8.1 Hz, 1H), 7.30 (t, 3J = 7.7 Hz, 1H), 7.47 (d, 3J = 7.5 Hz, 1H), 7.92 (d, 3J = 7.7 Hz, 1H). 13 C{1H}-NMR (126 MHz, CDCl3) δ: 171.8, 169.6, 145.8, 144.8, 130.6, 130.1, 128.7, 127.2, 72.0, 53.6, 52.0, 33.6, 31.4. MS (EI) m/z: 263.1 [M+H]+. General Procedure. Resolution of 1-Aminoindane Catalyzed by Lipases. 1-Aminoindane (rac-24, 1.0 equiv) and the acyl donor (1.1 equiv) are dissolved in organic solvent. Lipase is added and heated to 60 °C. At fixed times, samples are taken. The samples are acetylated with acetyl chloride (1.1 equiv) and triethylamine (1.5 equiv) in methylene chloride for 1 h. The suspension is washed with hydrogen chloride (1:1 v/v). The solvent is removed in vacuo. Enantiomeric excess and conversion are determined via HPLC. Solvent, Acyl Donor, Temperature Screening of CAL-B-Catalyzed Reactions. For the determination of optimal solvent, 1-aminoindane (rac-24, 30 mg, 0.22 mmol) and diethyl malonate (28, 40 mg, 0.25 mmol) or ethyl methoxyacetate, (27, 29 mg, 0.29 mmol) are dissolved in the solvent (384 μL), and CAL-B (9 mg) is added. The reactions are carried out in screw cap glasses of 5 mL. The following solvents are tested: toluene, MTBE, 2-MTHF, MCH, and n-heptane. The reaction with isopropyl methoxyacetate (29, 25 mg, 0.19 mmol) is carried in 2-MTHF (384 μL). Samples are taken after 6, 26, and 48 h. The enzyme is filtered and washed with DCM. These samples are acetylated with acetyl chloride (1.1 equiv) and triethylamine (1.5 equiv) in methylene chloride for 1 h. The suspension is washed with hydrogen chloride (1:1 v/v). The solvent is removed in vacuo. Enantiomeric excess and conversion are determined via HPLC. The conversion is carried out using 1H NMR spectroscopy and HPLC. The enantiomeric excess is determined via chiral HPLC. The results are shown in Table S4. CAL-B-Catalyzed Reaction with 1 M Substrate Loading. For the determination of CAL-B-catalyzed reaction with 1 M substrate loading, 1-aminoindane (rac-24, 665 mg, 5.03 mmol), ethyl methoxyacetate (28, 770 mg, 7.09 mmol), and CAL-B (0.20 g) are dissolved in 2-MTHF (5 mL). The reaction is stirred at 60 °C. Samples are taken after 6 and 26 h. The enzyme is filtered off and washed with DCM. This sample is acetylated with acetyl chloride (1.1 equiv) and triethylamine (1.5 equiv) in methylene chloride for 1 h. The suspension is washed with hydrogen chloride (1:1 v/v). The solvent is removed in vacuo. Enantiomeric excess and conversion are determined via HPLC. The conversion is determined via 1H NMR spectroscopy and HPLC. The enantiomeric excess is determined via chiral HPLC. The results are shown in Table S5. CAL-B-Catalyzed Reaction with 1-Aminoindane Derivatives. For the CAL-B-catalyzed reactions, 1-aminoindane derivatives (1.0 equiv)

are dissolved in the appropriate solvent with acyl donor (1.1 equiv). The reactions are carried out in screw cap glasses with a volume of 5 mL. CAL-B (40 mg/mmol amine) is added to the reaction solution. After 26 h, a sample is taken, which then is acetylated with acetyl chloride (1.1 equiv) and triethylamine (1.5 equiv) in methylene chloride for 1 h. The suspension is washed with hydrogen chloride (1:1 v/v). The solvent is removed in vacuo. Enantiomeric excess and conversion are determined via HPLC. The results are shown in Table S6. CAL-B-Catalyzed Reaction with 4-Cyano-1-aminoindane. 4Cyano-1-indanone (4, 401 mg, 2.551 mmol) and hydroxylamine hydrochloride (0.27 g, 3.84 mmol) are dissolved in 10 mL of ethanol and water (1:1 v/v). Meanwhile, sodium hydroxide (0.17 g, 4.51 mmol) dissolved in 1 mL water is added to the suspension. The mixture is heated to reflux for 90 min. The crude product is filtered over Celite and washed with water. The oxime is dissolved in 10 mL of acetic acid under an argon atmosphere, zinc dust (0.83, 12.77 mmol) is added, and the suspension is stirred at room temperature for 86 h. The reaction mixture is filtered over Celite and washed with ethyl acetate, and the solvent is removed in vacuo. The oil is dissolved in 10 mL of ethyl acetate and hydrogen chloride (1:1 v/v) and extracted with 2 M hydrogen chloride (2 × 10 mL). The pH value of the aqueous phase is adjusted to 10 and afterward extracted with ethyl acetate (3 × 10 mL). The organic phase is washed with brine and dried over MgSO4. The solvent is removed in vacuo. The remaining solvent is removed in a Schlenk flask under an argon atmosphere, furnishing racemic 4-cyano-1-aminoindane (rac-2, 150 mg, 0.948 mmol) in 37% yield. Next, racemic 4-cyano-1-aminoindane (rac-2, 150 mg, 0.948 mmol), ethyl methoxyacetate (29, 0.11 g, 0.99 mmol), and CAL-B (60 mg) are dissolved in 2-MTHF (5 mL) and stirred at 60 °C for 20 h. The sample is acetylated with acetyl chloride (1.1 equiv) and triethylamine (1.5 equiv) in methylene chloride for 1 h. The suspension is washed with hydrogen chloride (1:1 v/v) and sodium hydrogen carbonate. The solvent is removed in vacuo. Enantiomeric excess and conversion are determined via HPLC. The desired product (S)-4-cyano-1-aminoindane ((S)-2, 75 mg, 0.474 mmol) is isolated in a yield of 50% (corresponding to an overall yield of 19% for the two steps when starting from 4) and with an ee of 99%, corresponding to an E value of 24. Recycling Experiments with CAL-B. 1-Aminoindane (rac-24, 67 mg, 0.50 mmol), isopropyl methoxyacetate (29, 73 mg, 0.55 mmol), and CAL-B (20 mg) are dissolved in 5 mL of toluene and stirred at 60 °C. After 7 h, a 200 μL sample is taken. The sample is acylated with acetyl chloride (9 mg, 0.11 mmol) and triethylamine (15 mg, 0.15 mmol). The reaction is repeated for several days. The sample is acetylated with acetyl chloride (1.1 equiv) and triethylamine (1.5 equiv) in methylene chloride for 1 h. The suspension is washed with hydrogen chloride (1:1 v/v) and sodium hydrogen carbonate. The solvent is removed in vacuo. Enantiomeric excess and conversion are determined via HPLC. The results are shown in Table S7.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b03290.

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Experimental procedures related to the conducted biotransformations as well as NMR, GC, and HPLC data (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Harald Gröger: 0000-0001-8582-2107 Author Contributions §

F.U. and J.L. contributed equally.

I


Article

The Journal of Organic Chemistry Funding

Squire, C.; Straatman, H.; Wells, A. S. Efficient Synthesis of (S)-1-(5Fluoropyrimidin-2-yl)ethylamine Using an ω-Transaminase Biocatalyst in a Two-Phase System. Org. Process Res. Dev. 2013, 17, 1117− 1122. (d) Nobili, A.; Steffen-Munsberg, F.; Kohls, H.; Trentin, I.; Schulzke, C.; Höhne, M.; Bornscheuer, U. T. Engineering the Active Site of the Amine Transaminase from Vibrio fluvialis for the Asymmetric Synthesis of Aryl−Alkyl Amines and Amino Alcohols. ChemCatChem 2015, 7, 757−760. (e) Pavlidis, I. V.; Weiß, M. S.; Genz, M.; Spurr, P.; Hanlon, S. P.; Wirz, B.; Iding, H.; Bornscheuer, U. T. Identification of (S)-selective transaminases for the asymmetric synthesis of bulky chiral amines. Nat. Chem. 2016, 8, 1076−1082. (f) Cuetos, A.; Garcia-Ramos, M.; Fischereder, E.; Diaz-Rodriguez, A.; Grogan, G.; Gotor, V.; Kroutil, W.; Lavandera, I. Catalytic Promiscuity of Transaminases: Preparation of Enantioenriched BetaFluoroamines by Formal Tandem Hydrodefluorination/Deamination. Angew. Chem., Int. Ed. 2016, 55, 3144−3147. (13) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Keßeler, M.; Stürmer, R.; Zelinski, T. Industrial Methods for the Production of Optically Active Intermediates. Angew. Chem., Int. Ed. 2004, 43, 788− 824. (14) (a) Balkenhohl, F.; Hauer, B.; Landner, W.; Pressler, U. Racematspaltung primärer und sekundärer Amine durch Enzymkatalysierte Acylierung. Patent DE19934332738, 1994. (b) Ditrich, K. Verfahren zur Racemisierung optisch aktiver Amine. Patent DE19606124 A1, 1996. (c) Balkenhohl, F.; Ditrich, K.; Hauer, B.; Ladner, W. Optisch aktive Amine durch Lipase-katalysierte Methoxyacetylierung. J. Prakt. Chem./Chem.-Ztg. 1997, 339, 381− 384. (d) Ditrich, K. Optically Active Amines by Enzyme-Catalyzed Kinetic Resolution. Synthesis 2008, 2008, 2283−2287. (15) Gillen, K. J.; Gillespie, J.; Jamieson, C.; Maclean, J. K. F.; Moir, E. M.; Rankovic, Z. Indane Derivatives. PCT Patent Applic.WO2010115952, 2010. (16) Uthoff, F.; Reimer, A.; Liese, A.; Gröger, H. Enantioselective synthesis of chiral amines through enzymatic resolution under solvent-free conditions with malonate as reagent for acylation. Sustain. Chem. Pharm. 2017, 5, 42−45. (17) Simon, S.; Oßwald, S.; Roos, J.; Gröger, H. Efficient Enzymatic Amine Resolution at High Substrate Input Using Diethyl Malonate as an Acyl Donor of Low Hazard Potential. Z. Naturforsch., B: J. Chem. Sci. 2012, 67b, 1123−1126. (18) Passos, H.; Freire, M. G.; Coutinho, J. A. P. Ionic liquid solutions as extractive solvents for value-added compounds from biomass. Green Chem. 2014, 16, 4786−4815. (19) Anderson, E. M.; Larsson, K. M.; Kirk, O. One Biocatalyst− Many Applications: The Use of Candida Antarctica B-Lipase in Organic Synthesis. Biocatal. Biotransform. 1998, 16, 181−204. (20) Poulhès, F.; Vanthuyne, N.; Bertrand, M. P.; Gastaldi, S.; Gil, G. Chemoenzymatic Dynamic Kinetic Resolution of Primary Amines Catalyzed by CAL-B at 38−40 °C. J. Org. Chem. 2011, 76, 7281− 7286. (21) Aycock, D. F. Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions. Org. Process Res. Dev. 2007, 11, 156−159. (22) Thalén, L. K.; Bäckvall, J. E. Development of dynamic kinetic resolution on large scale for (±)-1-phenylethylamine. Beilstein J. Org. Chem. 2010, 6, 823−829. (23) Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis: Regio- and Stereoselective Biotransformations, 2nd ed.; Wiley and Sons: Weinheim, Germany, 2006. (24) Yoo, B. I.; Kim, Y. J.; You, Y.; Yang, J. W.; Kim, S. W. Birch Reduction of Aromatic Compounds by Inorganic Electride [Ca2N]+· in an Alcoholic Solvent: An Analogue of Solvated Electrons. J. Org. Chem. 2018, 83, 13847−13853. (25) Cheng, W.-M.; Shang, R.; Fu, Y. Irradiation-induced palladiumcatalyzed decarboxylative desaturation enabled by a dual ligand system. Nat. Commun. 2018, 9, 5215−5224. (26) Genrich, F.; Harms, G.; Schaumann, E.; Gjikaj, M.; Adiwidjaja, G. Functionalized esters as bis-electrophiles in a silicon-induced

This research was financially supported by the company PharmaZell GmbH, Raubling, Germany. Notes

The authors declare no competing financial interest.

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Chemoenzymatic Synthesis of a Chiral Ozanimod Key Intermediate

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