Catalytic asymmetric S-oxidation of N-benzoyl-1,5-benzothiazepines

Tetrahedron Letters 58 (2017) 2885–2888

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Catalytic asymmetric S-oxidation of N-benzoyl-1,5-benzothiazepines Kosho Makino, Tetsuya Yoneda, Risa Ogawa, Yuki Kanase, Hidetsugu Tabata, Tetsuta Oshitari, Hideaki Natsugari, Hideyo Takahashi ⇑ Faculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan

a r t i c l e

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Article history: Received 20 April 2017 Revised 3 June 2017 Accepted 9 June 2017 Available online 11 June 2017 Keywords: Asymmetric synthesis Sulfoxidation Ti-catalyst Dynamic kinetic resolution

a b s t r a c t An efficient catalytic asymmetric oxidation reaction of N-benzoyl-1,5-benzothiazepines using a chiral titanium complex formed in situ from Ti(O-iPr)4, (R, R)-diethyl tartrate was developed. This reaction is helpful for the synthesis of the active form of (E, aS, 1S)-sulfoxide of N-benzoyl-1,5-benzothiazepines which should be recognized by vasopressin receptors. Furthermore, a prospective dynamic kinetic resolution utilizing this system was achieved. Ó 2017 Elsevier Ltd. All rights reserved.

Introduction As part of our research on atropisomerism in biologically active molecules,1 new vasopressin (VP) receptor ligands with a 1,5-benzothiazepine nucleus were described to reveal the important stereochemistry around the seven-membered ring for exerting their biological activity.2 In that study,2a N-benzoyl-1,5benzothiazepine S-oxide derivatives (2a–c) were prepared from N-benzoyl-1,5-benzothiazepines (1a–c) with mCPBA (Scheme 1). The N-benzoyl-1,5-benzothiazepines (1, 2), in which the E/Zamide rotamers around the NA(C@O) bond and (aS)/(aR)3-axial isomers based on the ArAN (C@O) axis were considered, exist predominantly in the E-form, and the Z-isomer was negligible in 1H NMR. Thus, they exist only as a mixture of (aS)/(aR)-axial isomers. In order to examine the biological activity as VP receptor ligands, the racemic compounds (2a–c) were separated into the enantiomers using a chiral column to reveal the chiroptical properties. Hence, it was assumed that the active form recognized by the receptor is (E, aS, 1S).2a These results prompted us to develop an efficient catalytic reaction for the synthesis of enantiopure benzothiazepine S-oxide derivatives. Here we report an asymmetric oxidation of N-benzoyl-1,5-benzothiazepines (1a–d) with cumene hydroperoxide (CHP) in the presence of a catalytic amount of a chiral titanium complex. Enantioselective Soxidation by dynamic kinetic resolution of the racemizing Nbenzoyl-1,5-benzothiazepine derivative (2d) was also achieved. ⇑ Corresponding author. E-mail address: [email protected] (H. Takahashi). http://dx.doi.org/10.1016/j.tetlet.2017.06.021 0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.

Scheme 1. Oxidation of N-benzoyl-1,5-benzothiazepine.

Optimization of reaction conditions Since the initial reports by the groups of Kagan4a and Modena,4b the enantioselective synthesis of sulfoxides has received much attention.5 A well-known method for drug synthesis was developed by Unge and colleagues.6 Thus, the S-enantiomer of omeprazole, a potent proton pump inhibitor, was successfully provided.7 In order to synthesize N-benzoyl-1,5-benzothiazepine S-oxide derivatives enantioselectively, we planned to modify Unge’s catalytic system. Using a combination of CHP, Ti(O-iPr)4, and chiral tartrate ligands, we first examined the enantioselective S-oxidation of N-benzoyl-9-methyl-benzothiazepine 1b. Based on the typical procedure,6 the catalyst was prepared in situ by treatment of Ti

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(O-iPr)4 (0.25 equiv.) with the corresponding tartrate ligands (0.5 equiv.) at 50 °C for 1 h in the presence of 1b. Subsequently, Hünig’s base (1.3 equiv.) and CHP (1.3 equiv.) were added at 0 °C, and the reaction was allowed to proceed for 4 h. Under these conditions, overoxidation of the sulfoxide products to sulfones could be avoided. As shown in Table 1, various tartrate ligands were employed. Among them, (R, R)-diethyl tartrate {(R, R)-DET} surprisingly achieved a high level of enantioselectivity (entry 1). Although the solvents suited for this reaction were toluene and CH3CN, toluene was thought to be the best (entries 1, 5–7). Next, the effect of the chiral titanium catalyst amount on the reaction was examined (Table 2, entries 1–4). Fortunately, we were able to obtain good yields and enantioselectivity by decreasing the

quantities of the catalyst. 97% ee of S-oxide 2b in 94% yield was obtained even when 0.1 equivalent of the catalyst was used (entry 4). Furthermore, we investigated the basic mechanistic features of this catalytic system in brief. As Kagan and co-workers pointed out that the application of two equivalents of tartrate ligand relative to the titanium catalyst was essential,4 changing the ratio of Ti(O-iPr)4 to (R, R)-DET from 2:1 to 1:1 was examined to achieve a dramatic decrease in the enantioselectivity (entry 5). This result suggests that the well-established binuclear structure of the Sharpless reagent4 should be prepared in this system. It was also found that the preparation of the chiral titanium catalyst in the absence of 1b had very little effect on the reaction (entry 6). Considering that the addition of water to the titanium tartrate catalytic system

Table 1 Asymmetric sulfoxidation of 1b.

Entry

Tartrate ligand

Solvent

Yield (%)

% eea (config)a

1 2 3 4 5 6 7

(R, (R, (R, (R, (R, (R, (R,

Toluene Toluene Toluene Toluene DCE THF CH3CN

95 90 83 67 82 78 94

99 96 55 21 89 61 93

R)-DET R)-DIPTb R)-DBTc R)-TMTAd R)-DET R)-DET R)-DET

(S) (S) (S) (S) (S) (S) (S)

a The absolute configuration at 1S determined based on the data reported in the previous paper,2a and the ee value was determined by HPLC analysis with chiral stationary phase.8 b Diisopropyl L-tartrate. c Dibenzyl L-tartrate. d N, N, N0 , N0 -Tetramethyl-L-tartardiamide.

Table 2 Screening of reaction conditions.

a b c d

Entry

Ti(O-iPr)4 (equiv.)

(R, R)-DET (equiv.)

Yield (%)

% eea

1 2 3 4 5 6b 7c 8d

1 0.5 0.25 0.1 0.1 0.1 0.1 0.1

2 1 0.5 0.2 0.1 0.2 0.2 0.2

97 96 95 94 82 94 67 66

99 98 99 97 30 97 93 97

The ee value was determined by HPLC analysis with chiral stationary phase.8 Catalyst was prepared in the absence of 1b. MS 4Å was added to the reaction system. Using less anhydrous solvent in the air.

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K. Makino et al. / Tetrahedron Letters 58 (2017) 2885–2888 Table 3 Asymmetric sulfoxidation of 1a, c and d.

Entry 1 2 3 4 5

2a 2c 2d 2d 2d

R1

R2

Time (h)

Temp (°C)

Yield (%)

% eea (config)a

H H Me Me Me

H Me Me Me Me

24 24 36 48 1

0 0 0 r.t. 50

83 90 56b 85 90

69 0 77 77 78

(S) (aS, S) (aS, S) (aS, S)

a The absolute configuration at 1S of 2a was determined based on the data reported in the previous paper,2a and the ee value was determined by HPLC analysis with chiral stationary phase.8 b 37%, 82%ee of (aR)-1d was recovered.

is very important to achieve high levels of enantioselection in this type of sulfoxidation reaction,4–7 the addition of MS 4Å or the use of less anhydrous toluene was examined to give decreased yields (entries 7, 8). These results mean that the aggressive removal or addition of water decreases the yields of the reaction. Therefore, we concluded that special care in controlling the water content of the commercially available solvent is not necessary for this system.

Dynamic kinetic resolution Having identified the optimized conditions, we next investigated the asymmetric S-oxidation of N-benzoyl 1,5-benzothiazepines 1a, c and d (Table 3). The oxidation of the C6-substituted 1c2awith (R, R)-DET at 0 °C for 1 day gave the racemic sulfoxide 2c in 90% yield (Table 3, entry 2). The sulfoxidation of the unsubstituted 1a under similar conditions gave the S-enantiomer of the sulfoxide (S)-2a in 83% yield with 69% ee (entry 1). These results clarify that the methyl group at C9 is crucial for the asymmetric induction. For the newly prepared compound 1d and its S-oxide 2d, in which both C6 and C9 were replaced by methyl groups, precise conformational analysis was examined. In the 1H NMR spectrum, all the methylene protons of 1d9 appeared as six sharp separated peaks, suggesting that the rotation around the ArAN(C@O) axis is restricted to form stable atropisomers, and hence 1d could be sep-

Fig. 1. X-ray crystal structure of the optically active 2d.

arated into the (aS)- and (aR)-axial isomer using chiral HPLC. The enantiomers of 1d had a DGà310 value of 103 kJ/mol (see the Supplementary Material).10 The asymmetric S-oxidation of racemic 1d using (R, R)-DET under the best reaction conditions proceeded relatively slowly (0 °C for 36 h). Thus, 2d was obtained in 56% yield with 77% ee, and 1d was recovered in 37% yield (entry 3). The configuration of the recovered 1d was determined to be aR with 82% ee. For the absolute stereochemistry of 2d, X-ray structural analysis11 revealed that the major stereoisomer of 2d was (E, aS, S), and thus the syn-form in the crystal structure was confirmed (Fig. 1)12 Based on the 1H NMR spectrum, 2d exists almost as a single isomer in solution. The chiroptical properties [optical rotation ([a]D) and circular dichroism (CD)] of the enantiomers of 2d were also compared with

Fig. 2. DKR of 1d using the chiral titanium catalyst.

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those of similar compounds 2a and 2b2a to determine the syn-form in solution. These results suggest the viability of dynamic kinetic resolution (DKR). Considering the rather high DGà310 value of 103 kJ/mol of 1d, S-oxidation of 1d at higher temperature (50 °C) was examined. Although the ee values of 2d could not be increased, the yield was significantly increased (90% yield, 78% ee; entry 5). This result should be attributed to the oxidative DKR process. By using (R, R)-DET at 0 °C, the matched enantiomer of aS-1d was preferentially oxidized to give (aS, S)-2d so that the unmatched enantiomer of aR-1d remained unreacted. In contrast, at 50 °C, the racemization process occurred so quickly that the unreacted aR-1d kept changing to aS1d at equilibrium as the diastereoselective oxidation of aS-1d proceeded. As a result, the S-oxide (aS, S)-2d was obtained in 90% yield (Fig. 2). We considered two points as the main reason why the DKR was achieved in this reaction. The first is that the specific stereochemical environment provided by the Ti-(R, R)-DET catalyst was maintained even at 50 °C. Secondly, the steric hindrance caused by the C9 methyl group (allylic strain) confined the S-oxide so as to adopt the sterically less hindered pseudo-axial orientation forming the thermodynamically stable syn isomer, (aS, S)-2d.2 With expectation of an increase in% ee, we further examined some other chiral tartrate ligands in this DKR to obtain unsatisfactory results. In summary, the first catalytic asymmetric synthesis of the Nbenzoyl-1,5-benzothiazepine S-oxide derivatives was developed using the Ti-(R, R)-DET catalyst. Although the basic mechanistic features of the selectivity of the asymmetric oxidation of prochiral sulfide 1 with a thiazepine backbone remain unclear, the active form of (E, aS, 1S) recognized by the VP receptors was efficiently produced by this system. Furthermore, the DKR observed here offers rich possibilities for the enantioselective synthesis of bioactive compounds with atropisomeric properties. Acknowledgments This work was supported in part by a Grant-in-Aid for Scientific Research (C) (15K08030) from the Japan Society for the Promotion of Science. HT thanks the MEXT-Supported Program for the Strategic Research Foundation at Private Universities (2013–2017) for financial support.

A. Supplementary material General experimental procedure, 1H, 13C, and 2D NMR spectra and physicochemical properties for new compounds, X-ray crystal data (CIF) for compound (aS, S)-2d, stereochemical stability and CD spectrum of 1d. These materials can be found in the on line version. Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.06. 021. References 1. (a) Tabata H, Nakagomi J, Morizono D, Oshitari T, Takahashi H, Natsugari H. Angew Chem Int Ed. 2011;50:3075–3079. For a review article; (b) Tabata H, Yoneda T, Takahashi H, Natsugari H. Yuki Gosei Kagaku Kyokaishi. 2016;74:60–72. 2. (a) Yoneda T, Tabata H, Tasaka T, Oshitari T, Takahashi H, Natsugari H. J Med Chem. 2015;58:3268–3273; (b) Tabata H, Yoneda T, Oshitari T, Takahashi H, Natsugari H. J Org Chem. 2013;78:6264–6270; (c) Tabata H, Wada N, Takada Y, et al. Chem Eur J. 2012;18:1572–1576. 3. The terms aS and aR are those of the nomenclature based in the chiral axis, which correspond to P and M based on the helix nomenclature, respectively. 4. (a) Pitchen P, Duñach E, Deshmukh MN, Kagan H. J Am Chem Soc. 1984;106:3273–8188; (b) Furia FD, Modena G, Seraglia R. Synthesis. 1984;325–326. 5. (a) Capozzi MAM, Centrone C, Fracchiolla G, Naso F, Cardellicchio C. Eur J Org Chem. 2011;4327–4334; (b) Thakur VV, Sudalai A. Tetrahedron Asymmetry. 2003;14:407–410. 6. Cotton H, Elebring T, Larsson M, Li L, Sörensen H, Unge SV. Tetrahedron Asymmetry. 2000;11:3819–3825. 7. (a) Che G, Xiang J, Tian T, et al. Tetrahedron Asymmetry. 2012;23:457–460; (b) Jiang B, Zhao X-L, Dong J-J, Wang W-J. Eur J Org Chem. 2009;987–991. 8. The separation conditions are as follows: 2a: CHIRALPAK IA (4.6 mmɸ  250 mm); eluent, hexane/ethanol (4:1); flow rate, 1 mL/min; temperature, 23 °C; detection, 254 nm. 2b: CHIRALPAK IA (4.6 mmɸ  250 mm); eluent, hexane/ ethanol (4:1); flow rate, 1 mL/min; temperature, 23 °C; detection, 254 nm. 2d: CHIRALPAK OJ-H (4.6 mmɸ  250 mm); eluent, hexane/ethanol (3:2); flow rate, 0.5 mL/min; temperature, 23 °C; detection, 254 nm. 1d: CHIRALPAK IA (4.6 mmɸ  250 mm); eluent, hexane/2-propanol (9:1); flow rate, 1.0 mL/min; temperature, 23 °C; detection, 254 nm. 9. For the synthesis of compound 1d, see the Supplementary Material. 10. For determination of DGà value, see: Petit M, Lapierre AJB, Curran DPJ. Am Chem Soc. 2005;127:14994–14995. 11. X-ray data (CCDC No. 1541401) can be obtained free of charge from the Cambridge Crystallographic Data Center. 12. The description ‘‘anti/syn” is used for the relative arrangement of the C1 substituent and the N-benzoyl group, i.e., anti and syn denote the arrangement on the opposite and the same side, respectively.