Catalytic Approaches to Optically Active 1,5-Benzothiazepines

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Catalytic Approaches to Optically Active 1,5-Benzothiazepines Keisuke Asano, and Seijiro Matsubara ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00908 • Publication Date (Web): 23 May 2018 Downloaded from http://pubs.acs.org on May 23, 2018

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ACS Catalysis

Catalytic Approaches to Optically Active 1,5-Benzothiazepines Keisuke Asano* and Seijiro Matsubara* Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan ABSTRACT: The 1,5-benzothiazepine framework is well-known as a versatile pharmacophore and its derivatives have numerous biological activities. Therefore, various synthetic routes to these important compounds have already been investigated. However, in light of the increase in optically active pharmaceuticals, it is of significance to also develop enantioselective synthetic methods. Among various strategies, methods based on enantioselective catalysis are generally efficient in both academia and industry with respect to different factors such as atom or step-economy, economic reasons, and diversity-oriented synthesis. While various methodologies have already been investigated until the 1990s, soon after the discovery of marketed pharmaceuticals such as diltiazem, a blockbuster drug containing a 1,5-benzothiazepine unit, additional catalytic strategies have also appeared. Thus, the perspective presented herein provides an account on the progress on enantioselective catalysis for the asymmetric synthesis of 1,5benzothiazepine derivatives.

KEYWORDS: 1,5-benzothiazepines, asymmetric catalysis, medicinal chemistry, process chemistry, library synthesis

1. INTRODUCTION 1,5-Benzothiazepines, a well-known class of molecules representative in the field of pharmaceutical science (Figure 1), are expected to exhibit useful biological activities in the central nervous system, as well as other therapeutic actions. Moreover, they belong to the most widely used group of medicines for the treatment of cardiovascular diseases.1,2 Among such privileged heterocyclic scaffolds, chiral structures are frequently contained. For example, diltiazem (Herbesser), a marketed medication for the treatment of hypertension and angina, contains two chiral centers, and only the (2S,3S)-stereoisomer has the desired coronary vasodilating action. Thus, in light of the increase in optically active pharmaceuticals on the market, synthetic approaches to optically active 1,5-benzothiazepine derivatives are crucial not only for the creation of efficient industrial processes but also for the development of novel pharmaceuticals. Most specifically, quantitative asymmetric transformations are desirable to inducing higher efficiency, rather than methods based on optical resolutions. Interestingly, unlike general cases where seeds found in academia are further improved to satisfy industrial needs, the remarkable success of pharmaceutical companies on the chemistry of 1,5-benzothiazepines has stimulated academic chemists to develop additional efficient synthetic methods. In particular, catalytic asymmetric approaches have recently attracted an increasing amount of attention, as those methods are generally efficient with respect to different factors such as atom3 or step4-economy, economic reasons, and diversity-oriented synthesis. While a few reviews on the synthesis of these privileged compounds already exist,2 the perspective presented herein provides the first account on the progress on enantioselective catalysis used for asymmetric synthesis of 1,5-benzothiazepines. It focuses mainly on 2,3dihydro-1,5-benzothiazepin-4-ones, which are the most thoroughly studied 1,5-benzothiazepine derivatives due to their numerous important biological activities. As

chemoenzymatic enantioselective syntheses including kinetic resolution methodologies have already been included in previous reviews,2 this report does not deal with them.

Figure 1. Chiral 1,5-benzothiazepines: the privileged structures in pharmaceuticals.

2. ASYMMETRIC EPOXIDATION Diltiazem (Herbesser) was developed by Tanabe Seiyaku (currently Mitsubishi Tanabe Pharma Corporation) as an effective medication for the treatment of hypertension and angina, and is currently used in over 100 countries. While various synthetic routes have been investigated,1,5 the most efficient industrial process established by Tanabe Seiyaku employs a method that utilizes an optically active glycidic ester, which is accessed via an asymmetric epoxidation, as a key intermediate.6

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Jacobsen and coworkers reported an enantioselective epoxidation of cinnamate esters using (salen)Mn(III) catalyst 2 (Scheme 1).7 In this reaction, cis-olefin substrates are crucial for achieving high enantioselectivity, and the obtained cisepoxide (3) is smoothly incorporated in the formal asymmetric synthesis of diltiazem (8).1d Other protocols to the synthesis of the analogous glycidic ester (11) include La-(S)-BINOLPh3As=O-catalyzed asymmetric epoxidations (Scheme 2),8 asymmetric Darzens reactions (Scheme 3),9 and other similar strategies.5n

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Scheme 2. La-(S)-BINOL-Ph3As=O-catalyzed Asymmetric Epoxidation

Scheme 1. (Salen)Mn(III)-catalyzed Asymmetric Epoxidation

Scheme 3. Chiral Lithium Amide-mediated Asymmetric Darzens Reaction

Although the above-mentioned methods accomplished high enantioselectivities, in a pursuit of a more practical process, using less expensive catalysts or reagents and avoiding extremely low temperature, Seki and coworkers in Tanabe Seiyaku developed a mild method using the Yang catalyst (15)10 (Scheme 4).11,6c In their studies, they used 1,4-dioxane as a solvent and employed shorter reaction times and ambient temperature due to economic reasons, eventually achieving high yield and satisfactory enantioselectivity. The reaction proceeds via the formation of dioxirane 19, and the enantioselectivity is assumed to be determined by the avoidance of the steric clash between 14 and the H atoms of 15 on the 3,3’-positions (see 20 and 21) and the electrostatic repulsion between the ester moieties of 14 and 15.6c,12 This epoxidation process was additionally improved to fulfill industrial requirements by developing economical and nontoxic methods for the preparation of catalyst 15 and starting material 14 as well as an efficient protocol for isolating product 11.6c


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ACS Catalysis

Scheme 4. Tanabe’s Method via Asymmetric Epoxidation with the Yang Catalyst

Scheme 5. Tin-catalyzed Ring-opening of Oxirane

Scheme 6. Juliá–Colonna Epoxidation with Poly-L-leucine Catalyst

Furthermore, there was another obstacle to applying transepoxide 11 to the synthesis of diltiazem, even though it is easier to prepare than the cis-isomer (similar to 3 in Scheme 1). In order to construct the cis-disubstituted lactam ring of diltiazem, trans-epoxide 11 should undergo a ring-opening reaction with 2-nitrothiophenol (4) while still retaining its stereochemistry. However, this process typically proceeds in an SN2 manner accompanied with stereoinversion. Inoue and coworkers from Tanabe Seiyaku overcame this challenge by developing a tin-catalyzed reaction (Scheme 5).13 The transition state is proposed to involve the coordination of tin derivatives to both 2-nitrothiophenol (4) and the epoxy oxygen of compound 11, allowing for the highly specific cis-opening (see 23). This process affords threo-product 22, which can readily be transformed to diltiazem (8) through synthetic routes analogous to those indicated in Scheme 1.

Inoue et al. from Tanabe Seiyaku14 and Schwartz et al. from Hoffmann-La Roche5d demonstrated that the cis-opening of epoxides also takes place predominantly at higher temperatures even in the absence of any catalyst. However, the mechanism for this reaction is still controversial. The group of Roberts utilized this method in the transformation of 26 to 28 with 2-aminothiophenol (27) after an asymmetric Juliá–Colonna epoxidation of 24 to 25 using an immobilized poly-L-leucine catalyst to synthesize diltiazem (8) (Scheme 6).5j 3. ASYMMETRIC SULFA-MICHAEL ADDITION Along with the significant advances in asymmetric catalysis,15 several catalytic enantioselective reactions tackling the synthesis of 1,5-benzothiazepines have recently appeared in academic research. In 2011, the group of Yuan reported an


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enantioselective 1,6-Michael addition of arylthiols to 3methyl-4-nitro-5-alkenylisoxazoles using the Takemoto catalyst (31) (Scheme 7).16 It is proposed that a double hydrogen bond forms in the transition state between the thiourea moiety of the catalyst (31) and the nitro group of the starting material (29). Simultaneously, the tertiary amino group of 31 also interacts with nucleophilic thiol 30, which leads to a si-face attack, affording 32 with an (S)-configuration (see 33). Moreover, this reaction can be carried out on a gram-scale. Additionally, the formal synthesis of (S)-(+)thiazesim (35), an enantiomer of a representative antidepressant bearing a 2-substituted 1,5-benzothiazepine structure, is achieved through the synthesis of 34.17

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to the reaction mixture provides product 38 as a solid with >99% ee. This catalytic system specifically activates the thioamide functionality of 36 with a soft Lewis acidic copper thiolate (complex 39). Presumably, a favorable six-membered transition state is formed, which then leads to the Michael adduct (40). The compatibility of this catalytic reaction with a free amino group allows for a quick access to an enantioenriched 1,5-benzothiazepine skeleton (41), which can be further transformed to thiazesim (42).

Scheme 7. 1,6-Sulfa-Michael Addition to 3-Methyl-4-nitro-5alkenylisoxazole with the Takemoto Catalyst

Kumagai, Shibasaki, and coworkers reported an asymmetric conjugate addition of thiols to α,β-unsaturated thioamides using a mesitylcopper/chiral bisphosphine catalyst (Scheme 8).18 The reaction can be performed on a gram-scale, and a simple work-up just by filtration after the addition of n-hexane


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ACS Catalysis

Scheme 8. Sulfa-Michael Addition to α,β-Unsaturated Thioamide with Mesitylcopper/(R)-DTBM-segphos Catalyst

introduction of an electron-withdrawing hexafluoroisopropyl group is the key to enhancing the electrophilicity of an α,βunsaturated ester as a Michael acceptor. Moreover, this method is compatible with a free amino group, and the corresponding product (45) from it can be employed in the concise synthesis of thiazesim (42). In addition, a one-pot protocol for the three-step transformation of 43 to 42 is feasible in good overall yield (75%) without erosion of the optical purity. Scheme 9. Organocatalytic Sulfa-Michael Addition to α,βUnsaturated Hexafluoroisopropyl Ester

4. ASYMMETRIC ENOLATE PROTONATION An approach to key intermediates leading to another type of 1,5-benzothiazepines has been presented by the group of Singh. They reported on an enantioselective enolate protonation via a sulfa-Michael addition using a bifunctional organocatalyst (Scheme 10).20 It was found that the use of αsubstituted N-acryloyloxazolidin-2-ones as prochiral templates led to high enantioselectivities. Moreover, it was proposed that substrate 46 and thiol 27 are simultaneously activated by catalyst 47 through multiple hydrogen bonding to undergo a sulfa-Michael addition (see 49). Then, a proton is delivered from the quinuclidine nitrogen of 47 to the Si face of a transient enolate (see 50). Finally, product 48 is converted to a 3-substituted 1,5-benzothiazepine framework (51) without any losses in the enantiomeric excess.

Furthermore, the group of Wang reported an organocatalytic asymmetric sulfa-Michael addition to α,β-unsaturated hexafluoroisopropyl esters (Scheme 9).19 They found that the


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Scheme 10. Enantioselective Protonation of Enolate Formed via Sulfa-Michael Addition to α-Substituted NAcryloyloxazolidin-2-one with Bifunctional Organocatalyst

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Scheme 11. Net Cycloaddition of β-Substituted α,βUnsaturated Carbonic Anhydrides with 2-Aminothiophenols Using Isothiourea Catalyst

5. ASYMMETRIC NET CYCLOADDITION In an effort to create a concise synthetic route to a number of derivatives of the privileged title compounds, in 2015 our group reported the first facile net cycloaddition approach (Scheme 11).21 This [4+3] net cycloaddition affords 1,5benzothiazepines such as 55 in perfect regioselectivity and good-to-excellent enantioselectivity regardless of the steric and electronic characteristics of R1 and R2 in substrates 52 and 53, respectively. The reaction involves α,β-unsaturated acylammonium intermediates generated by a chiral isothiourea catalyst (54). It was found that the sulfa-Michael addition of 2-aminothiophenol 53 to the acylammonium intermediate is reversible (see 56), and that the subsequent intramolecular amidation is the stereo-determining step (see 57 and 58). This process can be referred to as a dynamic kinetic asymmetric transformation (DYKAT).22 In addition, further optimization of the net cycloaddition enables the use of α,β-unsaturated acid chloride 59 as a substrate in the presence of N,N-diisopropylethylamine, resulting in a comparably high enantioselectivity (Scheme 12).23 Moreover, product 61 can be readily transformed to optically active thiazesim (42). Therefore, the synthesis of 42 is attained directly from commercially available materials (59 and 60), which represents a straightforward and highly stereroselective route to this antidepressant.


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ACS Catalysis

Scheme 12. Net Cycloaddition of α,β-Unsaturated Acid Chloride

Scheme 13. (a) Net Cycloaddition of α,β-Unsaturated Pyrazolamide with 2-Aminothiophenol Using N,N’Dioxide/Yb(OTf)3 Catalyst and (b) Its Sequential One-pot Process

In 2017, Liu, Feng, and coworkers reported a net cycloaddition of α,β-unsaturated pyrazoleamides with 2aminothiophenols using a chiral N,N’-dioxide/Yb(OTf)3 complex catalyst (Scheme 13a).24 In this sequential sulfa-Michael addition/cyclization procedure, N-protection of 2aminothiophenol (27) is not necessary. Moreover, this is the first direct synthesis of optically active N–H-free 1,5benzothiazepine derivatives. Catalyst 63/Yb(OTf)3 leads to a rapid intermolecular sulfa-Michael addition affording intermediate 64, in which the enantioselectivity is determined. In addition, the subsequent cyclization process is found to be the rate-determining step. Due to these characteristics, an alternative one-pot sequential process enabling the use of lower chiral catalyst loadings has also proven to be efficient (Scheme 13b). Eventually, the optically active product (41) is readily transformed to thiazesim (42).


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In the same year, the group of Lattanzi independently reported an analogous one-pot enantioselective cyclization affording N-unprotected 1,5-benzothiazepines (Scheme 14).25 This process consists of an organocatalytic enantioselective sulfa-Michael addition of 2-aminothiophenol (27) to α,βunsaturated pyrazolamide 65 followed by a silica gel-mediated lactamization. Hydroquinine-derived squaramide catalyst 66 efficiently furnishes 41 at low catalyst loadings and under mild conditions. This methodology is incorporated in the concise synthesis of thiazesim (42). The optimal process is followed by filtration, and the crude product is directly alkylated to give 42 in 68% overall yield with a comparably high enantioselectivity.

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In addition, Fochi, Bernardi, and coworkers reported a similar protocol of a sulfa-Michael addition using a bifunctional organocatalyst for the asymmetric synthesis of 2,3,4,5-tetrahydro-1,5-benzothiazepines (Scheme 15).26 This two-step protocol is based on the catalytic asymmetric sulfaMichael addition of 2-aminothiophenol (27) to (E)-chalcone (68), followed by an intramolecular reductive amination, finally affording the optically active product (70) as a single trans-diastereomer. This method is the first to present an enantioselective access to 2,3,4,5-tetrahydro-1,5benzothiazepines. Scheme 15. Organocatalytic Asymmetric Sulfa-Michael Addition/Intramolecular Reductive Amination

Scheme 14. One-pot Enantioselective Cyclization via Organocatalytic Sulfa-Michael Addition/Silica Gel-mediated Lactamization Sequence

Moreover, Lu, Du, and coworkers also developed a facile net [4+3] annulation affording N−H-free 1,5-benzothiazepine derivatives using an N-heterocyclic carbene (NHC) catalyst (Scheme 16).27 The annulation takes place between α,βunsaturated acylazolium 74 and 2-aminothiophenol (27). Employing the (Z)-form of α-bromoenal 72 as a substrate in this reaction is crucial for efficient yields and enantioselectivities.


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ACS Catalysis

Scheme 16. NHC-catalyzed Net [4+3] Annulation of α,βUnsaturated Acylazolium with 2-Aminothiophenol

Scheme 17. Net Cycloaddition of α-Substituted α,βUnsaturated Mixed Anhydride with 2-Aminothiophenol Using Isothiourea Catalyst

Scheme 18. Net Cycloaddition of α,β-Disubstituted α,βUnsaturated Mixed Anhydride with 2-Aminothiophenol Using Isothiourea Catalyst The net cycloaddition methods described in this section so far have only been applied to the synthesis of 2-substituted 1,5-benzothiazepines. Meanwhile, according to our protocol (Scheme 11), the generally high enantioselectivity is imparted by the DYKAT mechanism based on the reversibility of the nucleophilic attack by sulfur-centered nucleophiles to α,βunsaturated acylammonium intermediates. The characteristics of this strategy make it useful for the synthesis of 1,5benzothiazepines bearing various substitution patterns: from 2substituted to 3-substituted (Scheme 17) and 2,3-disubstituted (Scheme 18) derivatives.23 Scheme 17 presents a reversible sulfa-Michael addition/protonation, the enantioselectivity of which is presumably determined by the intramolecular cyclization step in a DYKAT manner (see also Scheme 11) rather than the manner of enantioselective enolate protonation shown in Scheme 10. Moreover, Scheme 18 presents the synthesis of an optically active trans-disubstituted cycloadduct (80) as a single diastereomer. Experimental results suggest that the relative stereochemistry is controlled kinetically by virtue of the catalyst rather than thermodynamically. All in all, our net cycloaddition methods (Schemes 11, 17, and 18) are potentially useful in the construction of a library of optically active 1,5-benzothiazepines, supporting assay evaluation. 6. ASYMMETRIC HYDROGENATION In 2016, Glorius and coworkers revealed another strategy for the straightforward access to 2,3-dihydro-1,5benzothiazepinones via the asymmetric hydrogenation of vinylthioether moieties in 1,5-benzothiazepinones (Scheme 19).28 In this transformation, a ruthenium(II)/chiral NHC complex is used to catalyze the hydrogenation of 1,5benzothiazepinones, which are readily synthesized from 2aminothiophenols and β-substituted propiolic acids. As a result from the reaction, optically active 2,3-dihydro-1,5-


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benzothiazepinones are synthesized. The remarkable functional group compatibility of this method allows for the use of 1,5-benzothiazepinone 81, which contains a tertiary amine moiety, as a substrate, directly affording thiazesim (42). Moreover, although only the examples of the synthesis of 2substituted 1,5-benzothiazepine derivatives have been reported, this methodology might be in principle applicable to other substitution patterns. Most specifically, a direct catalytic method to 2,3-cis-disubstituted derivatives, which complements the method supplying 2,3-trans-disubstituted ones in Scheme 18 but is currently missing, could be developed.

advancements in the pharmaceutical studies on those compounds by enabling their rapid and efficient synthesis.

Scheme 19. Hydrogenation of Vinylthioethers in 1,5Benzothiazepinones with Ruthenium(II)/NHC Catalyst

Notes

AUTHOR INFORMATION Corresponding Author [email protected]; [email protected]

ORCID Keisuke Asano: 0000-0002-9272-2937 Seijiro Matsubara: 0000-0001-8484-4574

The authors declare no competing financial interests.

ACKNOWLEDGMENT This work was supported financially by the Japanese Ministry of Education, Culture, Sports, Science and Technology (15H05845, 16K13994, 17K19120, 18K14214, and 18H04258). K.A. also acknowledges Research Institute for Production Development, the Tokyo Biochemical Research Foundation, the Uehara Memorial Foundation, the Kyoto University Foundation, and the Institute for Synthetic Organic Chemistry.

REFERENCES

7. CONCLUSION AND OUTLOOK The recent progress on asymmetric catalysis facilitates the synthetic routes to optically active 1,5-benzothiazepine derivatives. It is expected that the use of a range of alternative catalysts would give rise to the efficient synthetic access to additional patterns of 1,5-benzothiazepines or other pharmaceutically relevant heterocycles such as benzodiazepines and benzoxazepines. In addition, the methods mentioned herein may contribute to the search for unexploited drugs in the field of medicinal chemistry. However, it remains a challenge to incorporate these in the industrial processes. In order to do this, it would be necessary to improve the latest seeds found in academia to satisfy the industrial needs while still considering factors such as mild conditions, toxicity of catalysts or reagents, and environmental and economic sustainability. We hope that the perspective presented herein allows the readers to notice the potential of the current enantioselective catalysis for the synthesis of privileged heterocyclic compounds, and to promote further

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Catalytic Approaches to Optically Active 1,5-Benzothiazepines

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