Enantioselective Mannich Reactions of 3-Fluorooxindoles with Cyclic

Subscriber access provided by UNIV OF LOUISIANA

Article

Enantioselective Mannich Reactions of 3Fluorooxindoles with Cyclic N-Sulfamidate Aldimines Jianbo Zhao, Ya Li, Ling-Yan Chen, and Xinfeng Ren J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00007 • Publication Date (Web): 12 Apr 2019 Downloaded from http://pubs.acs.org on April 12, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Enantioselective Mannich Reactions of 3-Fluorooxindoles with Cyclic N-Sulfamidate Aldimines Jianbo Zhao, Ya Li,* Ling-Yan Chen, Xinfeng Ren Department of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai, 201620 E-mail: [email protected]

Abstract: Both the 3-fluorooxindole and cyclic sulfamidate frameworks are important in medicinal chemistry owing to their associated biological activities. We report an approach to accessing 3-fully substituted 3-fluorooxindoles containing a benzo-fused sulfamidate subunit through highly enantioselective Mannich-type reactions between 3-fluorooxindoles and cyclic benzo-fused N-sulfamidate aldimines. These reactions are promoted by a commercially available cinchona alkaloid catalyst, accommodate a broad substrate scope, and deliver the desired products in a yield of up to 99% with enantiomeric excess up to 94%. A plausible reaction pathway is also presented.

1

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 41

INTRODUCTION The incorporation of one or more fluorine atoms into an organic molecule can result in improved thermal/metabolic stability, bioactivity, and lipophilicity.1 Not surprisingly, organofluorine molecules, especially chiral, nonracemic molecules that contain a fluorinated stereogenic center, have been playing an increasingly important role in furthering advancements in the pharmaceutical and life science industries.2 For example, compound A, a potent and effective maxi-K channel opener known as BMS-204352 (Fig. 1a),3 contains an enantioenriched 3-aryl 3-fluorooxindole structural unit, and compound B, which features a 3-alkyl 3-fluoroxindole fragment, has been reported to be bioactive against various neurological disorders (Fig. 1b).4 In this context, intense research efforts have been devoted to the construction of enantioenriched oxindoles that have a tertiary fluorinated stereogenic center at the 3-position.5 Two main strategies, direct fluorination of 3-alkyl- and 3-aryloxindoles,6 and the use of 3-fluorooxindoles as the building blocks,7,8 have emerged for their asymmetric

syntheses.

Recently,

the

asymmetric

Mannich

reaction

of

3-fluorooxindoles has attracted great interest, and several papers have documented the use of such reactions on the syntheses of 3-fully substituted 3-fluorooxindoles containing a chiral β-amine fragment (Scheme 1).9 As examples, we have reported the diastereoselective

Mannich

reactions

of

3-fluorooxindoles

with

N-(tert-butylsulfinyl)imines (Scheme 1a),9a while Song and co-workers have described an enantioselective Mannich reaction of 3-fluorooxindoles with α-amidosulfones as the bench-stable imine precursors by using Song’s cation-binding 2


Page 3 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


catalyst (Scheme 1b).9c Recently, Du and co-workers reported a highly enantioselective Mannich reaction of fluorooxindoles with isatin-derived ketimines using a chiral squaramide catalyst (Scheme 1c).9d

Figure 1 Bioactive chiral compounds containing a 3-fluorooxindole unit.

Cyclic chiral amines containing sulfamidate functionality in the ring are important synthetic targets because they have a broad spectrum of biological activities 10 and are valuable synthetic reagents and intermediates.11 Thus, to connect these simple structures with 3-fluorooxindoles at the 3-position would not only have potential biological applications but also constitute a useful contribution to synthetic methodologies. For this purpose, asymmetric addition of 3-fluorooxindoles to cyclic N-sulfamidate aldimines represents an attractive and straightforward route to the target molecules. However, in contrast to the significant progress achieved on the asymmetric Mannich reactions of 3-fluorooxindoles with common aldimines and ketimines, the Mannich reaction of 3-fluorooxindoles with cyclic imines has not yet been reported. As a continuation of our own interest in the functionalization of 3-fluorooxindoles,9a,9b we herein disclose a highly enantioselective Mannich reaction between 3-fluorooxindoles and cyclic N-sulfamidate aldimines, which enabled us to synthesize 3-fully substituted 3-fluorooxindoles containing a benzo-fused sulfamidate 3



fragment (Scheme 1d).

Scheme 1 Asymmetric Mannich reactions of 3-fluorooxindoles with non-cyclic and cyclic imines.

RESULTS and DISCUSSION At the outset, benzo-fused six-membered cyclic imine 1a was used as a model substrate and its Mannich reaction with 3-fluorooxindole 2a was first examined through the evaluation of a series of organocatalysts 3 (Fig. 2). With DCM as solvent, no reaction occurred under the effect of the tertiary amine-thiourea catalyst 3a (Table 4


Page 4 of 41

Page 5 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1, entry 1), and the tertiary amine-squaramide catalyst 3b enabled the reaction to proceed to give the desired product in a yield of 45% after a 48 h reaction, but with a low stereocontrol (62:38 dr and −30% ee, entry 2). Bifunctional cinchona alkaloid catalysts, including hydroquinine 3c, quinine 3d, 6′-OH cinchona-alkaloids 3e–3h, and quinidine 3i (entries 3–9), provided an improvement in the yield, with catalysts 3e–3h giving an enhanced ee (entries 5–8). Interestingly, a switch in the enantioselectivity was observed when the quinidine-derived 6′-OH catalysts 3j–3m were used (entries 10–13). Among the catalysts 3j–3m, catalyst 3j, which featured a C9–OBn structural fragment, gave the best yield and stereoselectivity (64% yield, 77:23 dr and 76% ee, entry 10), whereas the catalysts containing bulky (3k and 3l, entries 11 and 12) or small (3m, entry 13) substituents at this position provided no improvement in enantioinduction. C9-OH-Protected quinidine 3n was also tried and 94:6 dr and 84%–94% ee): the 6-chloro substrate gave the best enantioselectivity (4f, 94% ee). The influence of the N-substituent on the reaction was also examined (4i–4q). Compared with their N-methyl analogues, N-ethyl (4i vs 4a) and N-benzyl (4j vs 4d) substitutions both resulted in decreased stereoselectivities (4i, 89:11 dr and 86% ee; 4j, 82:18 dr and 70% ee). Further optimization revealed that lowering the reaction temperature to ‒10 oC gave improved stereoselectivity (4j, 90:10 dr and 84% ee), although a prolonged reaction time was required for high conversion (120 h.). N-Propargyl and N-phenyl 3-fluorooxindoles were also succesully used to afford products 4k and 4l with high efficiency and moderate to very good stereoselectivities (4k, 86 % yield, 74:26 dr, and 90% ee; 4l, 98 % yield, 88:12 dr, and 82% ee). In addition, N-Boc 3-fluorooxindole can react with imine 1a to give the corresponding product 4m in a good yield (68%) and excellent diastereoselectivity (>99:1), but with complete loss of enantioselectivity (0% ee). Finally, N–H oxindoles with 5-methyl, 6-chloro, and 6-bromo substituents were all proved to be effective, affording products 4n–4q as expected in satisfactory yields (82–99%) with high stereoselectivities (85:15 to 96:4 dr and 80%–84% ee). These result indicated that the subtle steric and electronic attributes of the N-substituents have a considerable impact on the stereochemical outcome of the reaction. 9



Table 3 Scope of the Mannich reaction with respect to cyclic imine 1 a,b

a

The yields refer to the isolated yields of stereoisomers. b Both the dr and ee were determined

by HPLC analysis. c The dr was determined by 19 FNMR.

We subsequently examined the substrate scope of the reaction using different imines. As shown in Table 3, imines with substitutions at the 3–5 positions all reacted as anticipated to give the desired products 4r–4x in good to excellent yields (72%– 10


Page 10 of 41

Page 11 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


97%). An electron-donating group, such as methoxy and methyl, at the 3-position gave very high diastereoselectivity and enantioselectivity (4r, 92:8 dr, 92% ee; 4s, 94:6 dr, 92% ee). The 4-substituted substrates also reacted smoothly to afford the expected products (4t and 4u) with a high enantioselectivity (82–84% ee), albeit with a low to moderate diastereoselectivity (4t, 55:45 dr; 4u, 78:22 dr). In addition, 5-fluoro imine underwent the reaction with high efficiency, affording product 4v in a yield of 92% with 98:2 dr and 88% ee. In comparison, 5-methyl substitution resulted in

a

decreased

stereoselectivity

(4w,

83:17

dr

and

70%

ee).

Finally,

1-hydroxy-2-naphthaldehyde-derived imine can also react with 2a to give product 4x in a very good yield (82%), but with low stereoselectivity (55:45 dr and 20%/57% ee). Cyclic ketimines were also tried using the optimal catalytic system (Table 1, entry 25). However, the reaction of 4-methylbenzo[e][1,2,3]oxathiazine 2,2-dioxide 5a or methyl benzo[e][1,2,3]oxathiazine-4-carboxylate 2,2-dioxide 5b with 2a failed to give the corresponding condensation products, with ketimines recovered quantitatively. The synthetic utility of our method was demonstrated by transformation of compound 4 to its N–Me and N-allyl derivatives 6a and 6b (Scheme 2). X-ray crystallography analysis of compound 6a was performed, where the two stereogenic centers were confirmed to have the (R, R)-configuration.12 By analogy, the same configuration was assigned to all products 4 in Table 2 and Table 3. To account for the observed stereoselectivity of the reaction, a transition state model was proposed. As shown in Scheme 3, the two reactants were activated concurrently: the 3-fluorooxindole 2 was deprotonated by the tertiary amine moiety of catalyst 3j, and 11



the C=N functionality was activated by the C9-OH group through hydrogen-bonding. Thus, the enolate of 3-fluorooxindole would attack the Si-face of the cyclic aldimine 1 from its Re-face to obtain the highly enantioselective products (R, R)-4.

Scheme 2 Synthesis of product 6 by methylation or allylation of compound 4.

Scheme 3 Transition state models proposed for the Mannich reaction of 3-fluorooxindoles with cyclic aldimines.

CONCLUSION We have successfully developed a highly enantioselective synthesis of 3-fully substituted 3-fluorooxindoles bearing a benzo-fused sulfamidate fragment, based on a straightforward addition of 3-fluorooxindoles to cyclic N-sulfamidate aldimines. The reaction uses commercially available cinchona alkaloid catalyst, has broad substrate scope with respect to both 3-fluorooxindoles and sulfamidate imines, and is 12


Page 12 of 41

Page 13 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


operationally simple. Finally, a reasonable reaction pathway is proposed. Further explorations of the applications of 3-fluorooxindoles in asymmetric reactions are underway in our laboratory.

EXPERIMENTAL SECTION Unless otherwise mentioned, all commercial reagents and solvents were used directly as purchased. Chloroform was dried with 4Å molecular sieves. Flash chromatography was performed on silica gel (200–300 mesh) with petroleum ether/ethyl acetate as the eluent. Optical rotations were measured with a polarimer with the solvent indicated. Melting points were measured on an electrothermal digital melting point apparatus. 1H, 13C and

19

FNMR spectra were performed on a 400/500

MHz NMR spectrometer. HPLC analysis was carried out using Shimadzu® LC 20A apparatus with a UV/visible detector at 214nm. HRMS (ion trap) were recorded on a high-resolution mass spectrometer in the ESI mode (SHIMADZU LCMS-IT-TOF or Thermo Fisher LTQFTICR-MS). Chemical shifts (δ) are reported in ppm relative to the residual solvent peak, and J values are given in hertz (Hz). Synthesis of Starting Materials: Benzo-fused six-membered cyclic imines 1 were prepared following the literature procedure.13 3-Fluorooxindoles (2a–2i and 2l) were prepared through fluorination of the corresponding oxindoles following the literature procedure.8a 3-Fluorooxindoles (2j, 2k and 2m–2p) were prepared from hydrazonooxindoles following the literature procedure.14 The identity of known compounds 1 (except 1t) and 2 (except 2f, 2h, 2o, and 2p) were confirmed by comparison with the characterization data of the literature.8a,13,14 13



Page 14 of 41

7-methoxybenzo[e][1,2,3]oxathiazine 2,2-dioxide (1t). Compound 1t was prepared following the literature procedure.13 Colorless solid (1.30 g, yield = 89 %); m. p. 123.4–123.6 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 6.92 (dd, J = 8.7, 2.4 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 3.96 (s, 3H).

13

C{1H}

NMR (101 MHz, CDCl3) δ 167.3, 166.8, 156.8, 132.5, 113.5, 109.2, 102.9, 56.4. HRMS (ESI) m/z: [M + H]+ calcd for C8H8O4NS+ 214.0169, found 214.0168. 6-chloro-3-fluoro-1-methylindolin-2-one (2f). Compound 2f was prepared following the literature procedure.8a Pink solid (540.1 mg, yield = 42 %); m. p. 122.9– 123.0 ˚C. 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 7.9, 1.6 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.86 (s, 1H), 5.65 (d, J = 51.0 Hz, 1H), 3.19 (s, 3H). 19F NMR (376 MHz, CDCl3) δ −192.9 (s).

13

C{1H} NMR (101 MHz, CDCl3) δ 170.9 (d, J = 18.1 Hz),

146.0, 137.5, 127.0, 123.1 (d, J = 2.9 Hz), 121.0 (d, J = 16.6 Hz), 109.6 (d, J = 1.3 Hz), 84.7 (d, J = 189.3 Hz), 26.3. HRMS (ESI) m/z: [M + H]+ calcd for C9H8ClFON+ 200.0273, found 200.0272. 3-fluoro-1,6-dimethylindolin-2-one (2h). Compound 2h was prepared following the literature procedure.8a Pink solid (380.0 mg, yield = 35 %); m. p. 99.2–99.8 ˚C. 1H NMR (400 MHz, CDCl3) δ 7.35 (dd, J = 7.5, 1.8 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.68 (s, 1H), 5.64 (d, J = 51.4 Hz, 1H), 3.19 (s, 3H), 2.42 (d, J = 2.3 Hz, 3H).

19

F

NMR (376 MHz, CDCl3) δ −191.7 (s). 13C{1H} NMR (101 MHz, CDCl3) δ 171.4 (d, J = 18.2 Hz), 144.9 (d, J = 5.1 Hz), 142.1 (d, J = 3.6 Hz), 125.8 (d, J = 1.2 Hz), 123.7 (d, J = 3.1 Hz), 119.9 (d, J = 16.6 Hz), 109.6 (d, J = 1.5 Hz), 85.4 (d, J = 187.5 Hz),

14


Page 15 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


26.1, 22.0. MS (ESI) m/z: 180.1 [M + H]+. HRMS (ESI) m/z: [M + H]+ calcd for C10H11FON+ 180.0819, found 180.0815. 6-chloro-3-fluoroindolin-2-one (2o). Compound 2o was prepared following the literature procedure.14 Pink solid (130.8 mg, yield = 14 %); m. p. 154.1–154.9 ˚C. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.48 (dd, J = 7.9, 1.2 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 6.90 (s, 1H), 5.88 (d, J = 50.4 Hz, 1H). 19F NMR (376 MHz, DMSO-d6) δ −192.1 (s). 13C{1H} NMR (101 MHz, DMSO-d6) δ 172.7 (d, J = 17.4 Hz), 145.3 (d, J = 5.7 Hz), 136.0 (d, J = 4.0 Hz), 128.1, 122.7 (d, J = 16.2 Hz), 122.4 (d, J = 3.0 Hz), 110.9, 85.8 (d, J = 183.4 Hz). HRMS (ESI) m/z: [M + H]+ calcd for C8H6ClFON+ 186.0116, found 186.0112. 6-bromo-3-fluoroindolin-2-one (2p). Compound 2p was prepared following the literature procedure.14 Pink solid (211.1 mg, yield = 19 %); m. p. 193.2–194.1 ˚C. 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.03 (s, 1H), 5.86 (d, J = 50.4 Hz, 1H). 19F NMR (376 MHz, DMSO-d6) δ −192.4 (s).

13

C{1H} NMR (101 MHz, DMSO-d6) δ 172.6 (d, J = 17.3 Hz), 145.4 (d, J

= 5.7 Hz), 128.4, 125.3 (d, J = 2.9 Hz), 124.5 (d, J = 4.3 Hz), 123.1 (d, J = 16.1 Hz), 113.7, 85.9 (d, J = 183.5 Hz). HRMS (ESI) m/z: [M + H]+ calcd for C8H6BrFON+ 229.9611, found 229.9610. General Catalysis Procedure for the Synthesis of Product 4.

Under a N2

atmosphere, a 10 mL reaction tube was charged with 3-fluorooxindole 2a (0.24 mmol), cat. 3j (12.0 mg, 0.03 mmol), and dried CHCl3 (2.0 mL). The reaction mixture was cooled to 0 ˚C, followed by the addition of cyclic imine 1 (0.2 mmol). The 15



reaction mixture was stirred at 0 ˚C until the complete conversion of compound 1, which was then purified by flash chromatography to give the desired product. (R)-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-fluoro-1-met hylindolin-2-one (4a). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1). Colorless solid (67.5 mg, yield = 97 %, d. r. = 95:5, ee = 92 %); [α]22D = −105.3 (c = 0.54, CHCl3, 92% ee); m. p. 205.0–205.3 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.3 Hz, 1H), 7.42 (dd, J = 13.9, 6.6 Hz, 2H), 7.21 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 6.88 (t, J = 7.6 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 5.41 (d, J = 12.4 Hz, 1H), 3.19 (s, 3H). 19F NMR (471 MHz, DMSO-d6) δ −149.2 (s) . 13C{1H} NMR (126 MHz, DMSO-d6) δ 170.3 (d, J = 19.9 Hz), 151.7, 145.9 (d, J = 6.0 Hz), 132.6 (d, J = 3.0 Hz), 131.3, 128.9 (d, J = 8.9 Hz), 126.1, 125.8, 123.1, 122.2 (d, J = 18.1 Hz), 119.3, 118.2, 110.1, 93.4 (d, J = 188.5 Hz), 58.1 (d, J = 34.5 Hz), 26.7. MS (ESI) m/z: 346.9 [M − H]−. HRMS (ESI) m/z: [M + H]+ calcd for C16H14O4N2FS+ 349.0653; Found 349.0654. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 19.3 min (major), 15.9 min (minor)). (R)-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-fluoro-5-met hoxy-1-methylindolin-2-one (4b). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1). Colorless solid (71.9 mg, yield = 95 %, d. r. = 86:14, ee = 86 %); [α]22D = +86.7 (c = 0.32, CHCl3, 86% ee); m. p. 199.1–199.2 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.79 (d, J = 16


Page 16 of 41

Page 17 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


7.8 Hz, 1H), 7.58 (td, J = 11.4, 4.2 Hz, 1H), 7.61–7.55 (m, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.98 (dd, J = 6.2, 4.2 Hz, 1H), 5.94 (s, 1H), 5.41 (d, J = 12.5 Hz, 1H), 3.51 (s, 3H), 3.17 (s, 3H). 19F NMR (471 MHz, DMSO-d6) δ −149.1 (s). 13

C{1H} NMR (126 MHz, DMSO-d6) δ 169.9 (d, J = 20.0 Hz), 155.5, 151.8, 139.2 (d,

J = 6.0 Hz), 131.3, 128.9 (d, J = 8.6 Hz), 126.1, 123.2 (d, J = 17.9 Hz), 119.3, 118.1, 116.5, 113.1, 110.6, 93.5 (d, J = 189.0 Hz), 58.1 (d, J = 34.5 Hz), 55.7, 26.9. MS (ESI) m/z: 376.9 [M − H]−. HRMS (ESI) m/z: calcd for C17H16O5N2FS+ [M + H]+ 379.0758, found 379.0758. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 90/10 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 42.7 min (major), 32.2 min (minor)). (R)-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-fluoro-1,5-di methylindolin-2-one (4c). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1). Colorless solid (68.1 mg, yield = 94 %, d. r. = 80:20, ee = 80 %); [α]22D = +102.1 (c = 0.32, CHCl3, 80% ee); m. p. 213.0– 213.0 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 5 Hz, 1H), 7.42 (td, J = 7.7, 1.0 Hz, 1H), 7.26–7.20 (m, 2H), 6.98 (d, J = 8.0 Hz, 1H), 6.20 (s, 1H), 5.38 (d, J = 12.2 Hz, 1H), 3.16 (s, 3H), 2.05 (s, 3H). NMR (471 MHz, DMSO-d6) δ −149.7 (s).

13

19

F

C{1H} NMR (126 MHz, DMSO-d6) δ

170.1 (d, J = 20.0 Hz), 151.8, 143.5 (d, J = 6.1 Hz), 132.6 (d, J = 3.1 Hz), 131.9 (d, J = 2.9 Hz), 131.2, 128.9 (d, J = 8.6 Hz), 126.6, 126.0, 122.2 (d, J = 17.9 Hz), 119.2, 118.3, 109.8, 93.5 (d, J = 188.8 Hz), 58.1 (d, J = 34.5 Hz), 26.7, 21.0. MS (ESI) m/z: 360.9 [M − H]−. HRMS (ESI) m/z: calcd for C17H16O4N2FS+ [M + H]+ 363.0809, 17



found 363.0809. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 15.3 min (major), 13.2 min (minor)). (R)-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3,5-difluoro-1methylindolin-2-one (4d). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1). Colorless solid (71.1 mg, yield = 97 %, d. r. = 92:8, ee = 86 %); [α]22D = +115.6 (c = 0.52, CHCl3, 86% ee); m. p. 201.1–201.2 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.3 Hz, 1H), 7.30 (t, J = 10.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 8.5, 3.8 Hz, 1H), 6.12 (dd, J = 5.9, 2.1 Hz, 1H), 5.45 (d, J = 13.1 Hz, 1H), 3.20 (s, 3H).

19

F NMR (471 MHz, DMSO-d6) δ −120.3 (s), −150.0 (s).

13

C{1H} NMR (126 MHz, DMSO-d6) δ 170.0 (d, J = 19.9 Hz), 158.4 (dd, J = 238.6,

3.5 Hz), 151.7, 142.2 (dd, J = 6.1, 1.9 Hz), 131.4, 128.8 (d, J = 9.0 Hz), 126.2 (d, J = 1.0 Hz), 123.7 (dd, J = 18.0, 8.5 Hz), 119.4, 118.8 (dd, J = 23.3, 3.1 Hz), 117.7 (d, J = 2.2 Hz), 113.5 (d, J = 25.8 Hz), 111.3 (d, J = 7.2 Hz), 93.3 (dd, J = 189.9, 1.5 Hz), 57.9 (d, J = 34.0 Hz), 26.9. MS (ESI) m/z: 364.9 [M − H]−. HRMS (ESI) m/z: calcd for C16H13O4N2F2S+ [M + H]+ 367.0559, found 367.0560. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 94/6 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 44.8 min (major), 40.3 min (minor)). (R)-5-bromo-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-flu oro-1-methylindolin-2-one (4e). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1). Colorless solid 18


Page 18 of 41

Page 19 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(81.2 mg, yield = 95 %, d. r. = 76:24, ee = 80 %); [α]22D = +92.7 (c = 0.54, CHCl3, 80% ee); m. p. 214.8–215.5 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.63 (dt, J = 8.3, 1.9 Hz, 1H), 7.59 (d, J = 5 Hz, 1H), 7.45 (td, J = 7.7, 1.1 Hz, 1H), 7.25 (dd, J = 8.3, 0.9 Hz, 1H), 7.09 (dd, J = 8.4, 0.9 Hz, 1H), 6.42 (t, J = 2.0 Hz, 1H), 5.44 (d, J = 13.3 Hz, 1H), 3.19 (s, 3H). 19F NMR (471 MHz, DMSO-d6) δ −150.0 (s).

13

C{1H} NMR (126 MHz, DMSO-d6) δ 169.8 (d, J = 19.9 Hz), 151.7,

145.2 (d, J = 5.8 Hz), 135.1, 131.5, 128.8 (d, J = 8.8 Hz), 128.5, 126.2, 124.4 (d, J = 18.2 Hz), 119.3, 117.7, 114.5 (d, J = 3.4 Hz), 112.2, 93.1 (d, J = 190.4 Hz), 57.9 (d, J = 34.1 Hz), 26.9. MS (ESI) m/z: 424.7 [M − H]−. HRMS (ESI) m/z: calcd for C16H13O4N2BrFS+ [M + H]+ 426.9758, found 426.9758. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 14.3 min (major), 15.3 min (minor)). (R)-6-chloro-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-flu oro-1-methylindolin-2-one (4f). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1). Colorless solid (72.0 mg, yield = 94 %, d. r. = 94: 6, ee = 94 %); [α]22D = +38.2 (c = 0.5, CHCl3 = 94% ee); m. p. 225.1–226.2 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.28 (s, 1H), 7.21 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.37 (d, J = 8.0 Hz, 1H), 5.43 (d, J = 12.6 Hz, 1H), 3.21 (s, 3H). 19F NMR (471 MHz, DMSO-d6) δ −149.3 (s). 13C{1H} NMR (126 MHz, DMSO-d6) δ 170.3 (d, J = 20.0 Hz), 151.7 (s), 147.5 (d, J = 6.0 Hz), 137.2 (d, J = 3.8 Hz), 131.4, 128.7 (d, J = 9.0 Hz), 127.0, 126.2, 122.9 (d, J = 3.0 Hz), 121.1 (d, J 19



= 18.5 Hz), 119.4, 117.8 (d, J = 2.3 Hz), 110.8, 93.0 (d, J = 189.5 Hz), 58.0 (d, J = 34.5 Hz), 27.0. MS (ESI) m/z: 380.8 [M − H]−. HRMS (ESI) m/z: calcd for C16H13O4N2ClFS+ [M + H]+ 383.0263, found 383.0262. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 82/18 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 11.6 min (major), 17.5 min (minor)). (R)-6-bromo-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-flu oro-1-methylindolin-2-one (4g). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1). Colorless solid (84.6 mg, yield = 99 %, d. r. = 95:5, ee = 90 %); [α]22D = +35.2 (c = 0.50, CHCl3, 90% ee); m. p. 208.1–208.9 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.3 Hz, 1H), 7.43 (td, J = 11.0, 4.2 Hz, 1H), 7.40 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.30 (dd, J = 8.0, 2.1 Hz, 1H), 5.42 (d, J = 12.6 Hz, 1H), 3.20 (s, 3H).

19

F NMR (471 MHz, DMSO-d6) δ −149.5 (s).

13

C{1H} NMR (126 MHz, DMSO-d6) δ 170.2 (d, J = 19.9 Hz), 151.7, 147.4 (d, J =

6.1 Hz), 131.4, 128.7 (d, J = 9.2 Hz), 127.3, 126.2, 125.8 (d, J = 3.8 Hz), 121.6, 121.4, 119.4, 117.7 (d, J = 2.3 Hz), 113.5, 93.0 (d, J = 189.5 Hz), 57.9 (d, J = 34.6 Hz), 27.0. MS (ESI) m/z: 424.7 [M − H]−. HRMS (ESI) m/z: calcd for C16H13O4N2BrFS+ [M + H]+ 426.9758, found 426.9758. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 94/6 hexane/i-PrOH; flow rate: 0.75 mL/min; λ = 214 nm; 41.6 min (major), 62.5 min (minor)). (R)-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-fluoro-1,6-di methylindolin-2-one (4h). The crude product was purified by flash chromatography 20


Page 20 of 41

Page 21 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


on silica gel (petroleum ether/ethyl acetate = 5:1). Colorless solid (68.9 mg, yield = 95 %, d. r. = 95:5, ee = 84 %); [α]22D = +76.5 (c = 0.50, CHCl3, 84% ee); m. p. 185.7– 186.7 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 6.93 (s, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.27 (dd, J = 7.6, 2.0 Hz, 1H), 5.37 (d, J = 12.0 Hz, 1H), 3.17 (s, 3H), 2.30 (s, 3H).

19

F NMR (471 MHz, DMSO-d6) δ −147.8 (s).

13

C{1H}

NMR (126 MHz, DMSO-d6) δ 170.5 (d, J = 20.0 Hz), 151.8, 146.0 (d, J = 6.0 Hz), 142.8 (d, J = 3.3 Hz), 131.2, 128.8 (d, J = 9.1 Hz), 126.0, 125.6, 123.5, 119.4, 119.2, 118.3, 110.8, 93.4 (d, J = 188.0 Hz), 58.2 (d, J = 35.0 Hz), 26.7, 21.9. MS (ESI) m/z: 360.9 [M − H]−. HRMS (ESI) m/z: calcd for C17H16O4N2FS+ [M + H]+ 363.0809, found 363.0809. The ee was determined by HPLC analysis using a Chiralpak AD-H column (25 ˚C; 78/22 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 12.1 min (major), 13.9 min (minor)). (R)-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-1-ethyl-3-fluor oindolin-2-one (4i). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1). Colorless solid (71.0 mg, yield = 98 %, d. r. = 89:11, ee = 86 %); [α]22D = −76.3 (c = 0.50, CHCl3, 86% ee); m. p. 181.2–182.9 ˚C. 1

H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.74 (d, J = 7.0 Hz, 1H), 7.56 (t, J =

7.8 Hz, 1H), 7.40 (dd, J = 15.6, 7.8 Hz, 2H), 7.20 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.86 (t, J = 7.5 Hz, 1H), 6.42 (d, J = 7.2 Hz, 1H), 5.41 (d, J = 11.8 Hz, 1H), 3.85–3.74 (m, 2H), 3.74–3.64 (m, 3H). 19F NMR (471 MHz, DMSO-d6) δ −150.4 (s). 13

C{1H} NMR (126 MHz, DMSO-d6) δ 170.0 (d, J = 19.7 Hz), 151.7, 144.8 (d, J = 21



6.1 Hz), 132.6, 131.3, 128.8 (d, J = 8.5 Hz), 126.1, 125.9, 123.0 (d, J = 2.8 Hz), 122.4 (d, J = 18.2 Hz), 119.3, 118.0, 110.1, 93.4 (d, J = 189.0 Hz), 58.3 (d, J = 34.7 Hz), 34.8, 12.6. MS (ESI) m/z: 360.9 [M − H]−. HRMS (ESI) m/z: calcd for C17H16O4N2FS+ [M + H]+ 363.0809, found 363.0809. The ee was determined by HPLC analysis using a Chiralpak IC column (25˚C; 90/10 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 21.9 min (major), 25.6 min (minor)). (R)-1-benzyl-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3,5-d ifluoroindolin-2-one (4j). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 6:1). Colorless solid (75.2 mg, yield = 85 %, d. r. = 82:18, ee = 70 %; the reaction at −10 oC, 72.5 mg, yield = 82 %, dr = 90:10, ee = 84 %); [α]19D = +35.1 (c = 0.54, CHCl3, 70% ee); m. p. 189.6–190.7 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.42 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.40–7.27 (m, 5H), 7.27–7.16 (m, 2H), 6.95 (dd, J = 8.5, 3.6 Hz, 1H), 6.14 (d, J = 7.8 Hz, 1H), 5.56 (d, J = 12.3 Hz, 1H), 5.10 (d, J = 15.9 Hz, 1H), 4.88 (d, J = 15.6 Hz, 1H).. 19F NMR (471 MHz, DMSO-d6) δ −120.0 (s), −148.8 (s).

13

C{1H} NMR (126 MHz, DMSO-d6) δ 170.5 (d, J = 20.0 Hz), 158.4 (dd, J =

238.8, 3.3 Hz), 151.7, 141.2, 135.7, 131.5, 129.1, 128.7 (d, J = 8.9 Hz), 128.0, 127.4, 126.3, 119.5, 118.8 (dd, J = 23.2, 3.3 Hz), 117.4, 113.8, 113.6, 111.8 (d, J = 8.1 Hz), 93.4 (d, J = 191.5 Hz), 58.0 (d, J = 34.0 Hz), 43.5. MS (ESI) m/z: 440.9 [M − H]−. HRMS (ESI) m/z: calcd for C22H17O4N2F2S+ [M + H]+ 443.0872, found 443.0871. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C;

22


Page 22 of 41

Page 23 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


90/10 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 30.6 min (major), 81.3 min (minor)). (R)-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-fluoro-1-(pr op-2-yn-1-yl)indolin-2-one (4k). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 6:1). Colorless solid ( the reaction was carried out at −10 oC, 64.0 mg, yield = 86 %, d. r. = 74:26, ee = 90 %); [α]19D = −21.2 (c = 0.50, CHCl3, 90% ee); m. p. 196.7–197.1 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.43 (q, J = 8.1 Hz, 2H), 7.19 (dd, J = 16.5, 8.0 Hz, 2H), 6.92 (t, J = 7.6 Hz, 1H), 6.46 (d, J = 7.5 Hz, 1H), 5.45 (d, J = 12.1 Hz, 1H), 4.69–4.53 (m, 2H), 3.32 (t, J = 2.3 Hz, 1H).

19

F NMR (471 MHz, DMSO-d6) δ −148.1 (s).

13

C{1H} NMR (126 MHz,

DMSO-d6) δ 169.8 (d, J = 20.1 Hz), 151.7, 144.0 (d, J = 6.0 Hz), 132.5 (d, J = 3.3 Hz), 131.3, 128.8 (d, J = 8.9 Hz), 126.1 (d, J = 11.4 Hz), 123.5 (d, J = 3.0 Hz), 122.4, 122.2, 119.3, 117.8 (d, J = 2.1 Hz), 110.7, 93.4 (d, J = 189.3 Hz), 77.7, 75.3, 58.1 (d, J = 34.5 Hz), 29.6. MS (ESI) m/z: 370.9 [M − H]−. HRMS (ESI) m/z: calcd for C18H14O4N2FS+ [M + H]+ 373.0653, found 373.0653. The ee and d.r. was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 92/8 hexane/i-PrOH; flow rate: 0.75 mL/min; λ = 214 nm; 39.0 min (major), 32.9 min (minor)). (R)-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-fluoro-1-phe nylindolin-2-one (4l). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 6:1). Colorless solid (80.4 mg, yield = 98 %, d. r. = 88:12, ee = 82 %); [α]22D = −32.9 (c = 0.54, CHCl3, 82% ee); m. p. 210.2–211.3 23



Page 24 of 41

˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 6.7 Hz, 3H), 7.36 (t, J = 7.7 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 6.51 (d, J = 7.4 Hz, 1H), 5.52 (d, J = 12.6 Hz, 1H).

19

F NMR (471 MHz, DMSO-d6) δ −150.2 (s).

13

C{1H} NMR (126 MHz,

DMSO-d6) δ 169.9 (d, J = 20.0 Hz), 151.8, 145.7 (d, J = 6.2 Hz), 133.6, 132.6 (d, J = 3.2 Hz), 131.4, 130.3, 129.2, 129.0 (d, J = 7.7 Hz), 126.9, 126.2 (d, J = 4.5 Hz), 123.7 (d, J = 2.9 Hz), 122.1, 122.0, 119.3, 118.1 (d, J = 1.7 Hz), 110.4, 93.6 (d, J = 190.8 Hz), 58.8 (d, J = 35.1 Hz). MS (ESI) m/z: 408.9 [M − H]−. HRMS (ESI) m/z: calcd for C21H16O4N2FS+ [M + H]+ 411.0809, found 411.0809. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 16.3 min (major), 24.9 min (minor)). tert-butyl(R)-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-flu oro-2-oxoindoline-1-carboxylate (4m). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1). Colorless solid (59.1 mg, yield = 68 %, d. r. = 99:1, ee = 0 %). m. p. 192.1–193.6 ˚C. 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.79 (t, J = 7.9 Hz, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.46 (dt, J = 15.4, 7.7 Hz, 2H), 7.22 (d, J = 8.2 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 5.50 (d, J = 12.3 Hz, 1H), 1.60 (s, 9H). DMSO-d6) δ −142.5 (s).

13

19

F NMR (471 MHz,

C{1H} NMR (101 MHz, DMSO-d6) δ 169.1 (d, J = 19.9

Hz), 151.7, 148.2, 141.7 (d, J = 5.9 Hz), 132.9, 131.5, 128.9 (d, J = 8.5 Hz), 126.2, 126.0, 125.1, 121.4 (d, J = 18.7 Hz), 119.4, 117.4, 115.6, 92.9 (d, J = 190.3 Hz), 85.3, 24


Page 25 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


58.6 (d, J = 35.2 Hz), 28.0. HRMS (ESI) m/z: calcd for C20H20O6N2FS+ [M + H]+ 435.1021, found 435.1025. The ee was determined by HPLC analysis using a Chiralpak AD-H column (30 ˚C; 87/13 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 21.2 min (major), 17.5 min (minor)). (R)-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-fluoroindoli n-2-one (4n). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1). Colorless solid (66.1 mg, yield = 99 %, d. r. = 90:10, ee = 82 %); [α]19D = +16.5 (c = 0.50, CHCl3, 82% ee); m. p. 183.3–184.8 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.11 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.37 (d, J = 7.6 Hz, 1H), 5.34 (d, J = 11.9 Hz, 1H). 19F NMR (471 MHz, DMSO-d6) δ −148.6 (s). 13C{1H} NMR (126 MHz, DMSO-d6) δ 172.0 (d, J = 19.2 Hz), 152.0, 144.5 (d, J = 6.5 Hz), 132.4 (d, J = 3.4 Hz), 131.0, 128.6 (d, J = 9.3 Hz), 126.2, 125.8, 122.9 (d, J = 18.6 Hz), 122.4 (d, J = 3.1 Hz), 119.2, 118.4, 111.1, 93.8 (d, J = 188.1 Hz), 58.3 (d, J = 34.6 Hz). MS (ESI) m/z: 332.9 [M − H]−. HRMS (ESI) m/z: calcd for C15H12O4N2FS+ [M + H]+ 335.0496, found 335.0497. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 87/13 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 13.5 min (major), 17.3 min (minor)). (R)-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-fluoro-5-met hylindolin-2-one (4o). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1). Colorless solid (57.1 mg, yield = 82 %, 25



Page 26 of 41

d. r. = 85:15, ee = 80 %); [α]19D = +102.3 (c = 0.55, CHCl3, 80% ee); m. p. 183.3– 183.6 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.05 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.61–7.53 (m, 1H), 7.41 (td, J = 7.7, 1.1 Hz, 1H), 7.21 (dd, J = 8.3, 1.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 6.18 (s, 1H), 5.32 (d, J = 11.5 Hz, 1H), 2.02 (s, 3H).19F NMR (471 MHz, DMSO-d6) δ −149.1 (s).

13

C{1H}

NMR (126 MHz, DMSO-d6) δ 171.8 (d, J = 19.3 Hz), 151.8, 142.0 (d, J = 6.5 Hz), 132.7 (d, J = 3.1 Hz), 131.1 (d, J = 4.5 Hz), 128.7 (d, J = 8.8 Hz), 126.9, 126.0, 122.8, 122.7, 119.2, 118.4, 110.9, 93.7 (d, J = 188.5 Hz), 58.1 (d, J = 34.6 Hz), 21.0. MS (ESI) m/z: 346.9 [M − H]−. HRMS (ESI) m/z: calcd for C16H14O4N2FS+ [M + H]+ 349.0653, found 349.0653. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 11.3 min (major), 16.9 min (minor)). (R)-6-chloro-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-flu oroindolin-2-one (4p). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1). Colorless solid (70.0 mg, yield = 95 %, d. r. = 92:8, ee = 84 %); [α]19D = +49.7 (c = 0.57, CHCl3, 84% ee); m. p. 190.4–190.8 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.19 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 6.91 (s, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.33 (dd, J = 8.0, 1.6 Hz, 1H), 5.37 (d, J = 12.2 Hz, 1H). 19

F NMR (471 MHz, DMSO-d6) δ −148.6 (s). 13C{1H} NMR (126 MHz, DMSO-d6) δ

171.8 (d, J = 19.3 Hz), 151.7, 146.1 (d, J = 6.5 Hz), 136.8 (d, J = 3.9 Hz), 131.3, 128.6 (d, J = 9.3 Hz), 127.6, 126.2, 122.4 (d, J = 2.9 Hz), 121.7 (d, J = 18.6 Hz), 26


Page 27 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


119.4, 117.8 (d, J = 2.3 Hz), 111.4, 93.2 (d, J = 189.3 Hz), 57.9 (d, J = 34.9 Hz). MS (ESI) m/z: 366.8 [M − H]−. HRMS (ESI) m/z: calcd for C15H11O4N2ClFS+ [M + H]+ 369.0107, found 369.0107. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 10.2 min (major), 19.0 min (minor)). (R)-6-bromo-3-((R)-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-fl uoroindolin-2-one (4q). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 6:1). Colorless solid (78.5 mg, yield = 95 %, d. r. = 92:8, ee = 84 %); [α]19D = +21.0 (c = 0.54, CHCl3, 84 % ee); m. p. 187.8–187.9 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.19 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.61–7.53 (m, 1H), 7.42 (td, J = 7.7, 1.1 Hz, 1H), 7.21 (dd, J = 8.3, 1.0 Hz, 1H), 7.04 (s, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.27 (dd, J = 8.0, 2.0 Hz, 1H), 5.38 (s, 1H). 19F NMR (471 MHz, DMSO-d6) δ −148.91 (s).

13


171.7 (d, J = 19.3 Hz), 151.7, 146.1 (d, J = 6.5 Hz), 131.4, 128.6 (d, J = 9.3 Hz), 127.8, 126.2, 125.5 (d, J = 4.2 Hz), 125.3 (d, J = 2.8 Hz), 122.1 (d, J = 18.6 Hz), 119.4, 117.7 (d, J = 2.4 Hz), 114.2, 93.3 (d, J = 189.3 Hz), 57.9 (d, J = 34.7 Hz). MS (ESI) m/z: 410.8 [M − H]−. HRMS (ESI) m/z: calcd for C15H11O4N2BrFS+ [M + H]+ 412.9601, found 412.9600. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 10.4 min (major), 19.5 min (minor)). (R)-3-fluoro-1-methyl-3-((R)-8-methyl-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxa thiazin-4-yl)indolin-2-one (4r). The crude product was purified by flash 27



chromatography on silica gel (petroleum ether/ethyl acetate = 4:1). Colorless solid (66.7 mg, yield = 92 %, d. r. = 92:8, ee = 92 %); [α]19D = −15.4 (c = 0.54, CHCl3, 92 % ee); m. p. 225.7–226.4 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.41 (d, J = 7.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 6.90 (t, J = 7.4 Hz, 1H), 6.46 (d, J = 7.0 Hz, 1H), 5.36 (d, J = 12.4 Hz, 1H), 3.19 (s, 3H), 2.20 (s, 3H). −149.8 (s).

19

F NMR (471 MHz, DMSO-d6) δ

13


145.8 (d, J = 6.0 Hz), 132.5, 132.3, 127.9, 126.4 (d, J = 8.7 Hz), 125.9, 125.4, 123.1, 122.3 (d, J = 17.9 Hz), 118.3, 110.0, 93.4 (d, J = 189.0 Hz), 58.2 (d, J = 34.2 Hz), 26.7, 15.5. MS (ESI) m/z: 360.9 [M − H]−. HRMS (ESI) m/z: calcd for C17H16O4N2FS+ [M + H]+ 363.0809, found 363.0810. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 14.3 min (major), 12.2 min (minor)). (R)-3-fluoro-3-((R)-8-methoxy-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin4-yl)-1-methylindolin-2-one (4s). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1). Colorless solid (73.4 mg, yield = 97 %, d. r. = 94:6, ee = 92 %); [α]19D = −21.6 (c = 0.58, CHCl3, 92% ee); m. p. 185.8–186.8 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.34 (dd, 2H), 7.28 (dd, 1H), 7.08 (d, J = 7.9 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.48 (d, J = 7.6 Hz, 1H), 5.37 (d, J = 12.3 Hz, 1H), 3.85 (s, 3H), 3.19 (s, 3H). 19F NMR (471 MHz, DMSO-d6) δ −148.8 (s).

13


170.3 (d, J = 20.0 Hz), 148.8, 145.9 (d, J = 6.0 Hz), 141.0, 132.6, 125.8 (d, J = 5.5 28


Page 28 of 41

Page 29 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Hz), 123.1, 122.3, 122.1, 119.5 (d, J = 9.4 Hz), 119.0, 113.8, 110.1, 93.4 (d, J = 188.6 Hz), 58.3 (d, J = 34.4 Hz), 56.5, 26.7. MS (ESI) m/z: 376.9 [M − H]−. HRMS (ESI) m/z: calcd for C17H16O5N2FS+ [M + H]+ 379.0758, found 379.0759. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 80/20 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 26.0 min (major), 16.1 min (minor)). (R)-3-fluoro-3-((R)-7-methoxy-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin4-yl)-1-methylindolin-2-one (4t). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1). Colorless solid (72.6 mg, yield = 96 %, d. r. = 55:45, ee = 84%/52%); [α]19D = +52.4 (c = 0.50, CHCl3, 84 % ee); m. p. 209.1–209.5 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 7.68 (dd, J = 8.7, 1.5 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 7.00 (dd, J = 8.8, 2.6 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 2.5 Hz, 1H), 6.47 (d, J = 7.5 Hz, 1H), 5.32 (d, J = 12.3 Hz, 1H), 3.83 (s, 3H), 3.19 (s, 3H).

19

F NMR (471 MHz,

DMSO-d6) δ −149.0 (s). 13C{1H} NMR (126 MHz, DMSO-d6) δ 170.2, 161.1, 152.6, 145.8 (d, J = 6.1 Hz), 132.5, 129.4 (d, J = 9.3 Hz), 125.8, 123.1 (d, J = 3.0 Hz), 122.3 (d, J = 18.0 Hz), 112.7, 110.0, 109.5, 104.2, 93.5 (d, J = 187.2 Hz), 57.7 (d, J = 34.6 Hz), 56.2, 26.7. MS (ESI) m/z: 376.9 [M − H]−. HRMS (ESI) m/z: calcd for C17H16O5N2FS+ [M + H]+ 379.0758, found 379.0759. The ee and d.r. was determined by HPLC analysisusing a Chiralpak AD-H column (20 ˚C; 88/12 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 29.3 min (major), 25.2 min (minor); the other diastereomer, 41.9 min (major), 33.5 min (minor)). 29



(R)-3-((R)-7-bromo-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-flu oro-1-methylindolin-2-one (4u). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1). Colorless solid (61.5 mg, yield = 72 %, d. r. = 78:22, ee = 82 %); [α]19D = −32.1 (c = 0.50, CHCl3, 82 % ee); m. p. 213.9–214.9 ˚C. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.4, 2.0 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 5.41 (d, J = 12.7 Hz, 1H), 3.19 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ −149.6 (s). 13

C{1H} NMR (101 MHz, DMSO-d6) δ 170.1 (d, J = 19.9 Hz), 152.2, 145.8 (d, J =

6.2 Hz), 132.7, 130.6, 130.5 (d, J = 0.7 Hz), 129.1, 125.9, 123.2 (d, J = 11.4 Hz), 122.2, 122.0 (d, J = 18.2 Hz), 117.6, 110.2, 93.3 (d, J = 188.8 Hz), 57.8 (d, J = 35.6 Hz), 26.8. MS (ESI) m/z: 424.8 [M − H]−. HRMS (ESI) m/z: calcd for C16H13O4N2BrFS+ [M + H]+ 426.9758, found 426.9758. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 85/15 hexane/i-PrOH; flow rate: 0.75 mL/min; λ = 214 nm; 20.7 min (major), 18.7 min (minor)). (R)-3-fluoro-3-((R)-6-fluoro-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4yl)-1-methylindolin-2-one (4v).

The crude product was purified by flash

chromatography on silica gel (petroleum ether/ethyl acetate = 4:1). Colorless solid (67.4 mg, yield = 92 %, d. r. = 98:2, ee = 88 %); [α]19D = −31.0 (c = 0.57, CHCl3, 88% ee); m. p. 213.2–214.1 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.23 (s, 1H), 7.58 (d, J = 6.5 Hz, 1H), 7.49–7.40 (m, 2H), 7.31 (dd, J = 9.1, 4.8 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 7.5 Hz, 1H), 5.43 (d, J = 12.7 Hz, 1H), 3.19 30


Page 30 of 41

Page 31 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(s, 3H). 19F NMR (471 MHz, DMSO-d6) δ −115.7 (s), −150.6 (s). 13C{1H} NMR (126 MHz, DMSO-d6) δ 170.1 (d, J = 19.9 Hz), 158.9 (d, J = 242.7 Hz), 147.9, 145.8 (d, J = 6.0 Hz), 132.7 (d, J = 2.9 Hz), 125.9, 123.3 (d, J = 2.4 Hz), 122.1 (d, J = 18.1 Hz), 121.2 (d, J = 8.6 Hz), 120.1 (d, J = 7.5 Hz), 118.2 (d, J = 23.7 Hz), 115.6 (dd, J = 25.8, 9.0 Hz), 110.1, 93.3 (d, J = 189.5 Hz), 57.9 (d, J = 34.1 Hz), 26.8. MS (ESI) m/z: 364.9 [M − H]−. HRMS (ESI) m/z: calcd for C16H13O4N2F2S+ [M + H]+ 367.0559, found 367.0559. The ee was determined by HPLC analysis using a Chiralpak AD-H column (20 ˚C; 82/18 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 14.7 min (major), 10.0 min (minor)). (R)-3-fluoro-1-methyl-3-((R)-6-methyl-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxa thiazin-4-yl)indolin-2-one (4w). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 5:1). Colorless solid (69.8 mg, yield = 97 %, d. r. = 83:17, ee = 70 %); [α]19D = +84.2 (c = 0.54, CHCl3, 70% ee); m. p. 216.2–216.7 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.57 (s, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.09 (t, J = 7.1 Hz, 2H), 6.89 (t, J = 7.4 Hz, 1H), 6.45 (d, J = 7.0 Hz, 1H), 5.34 (d, J = 12.1 Hz, 1H), 3.19 (s, 3H), 2.39 (s, 3H).

19

F NMR (471 MHz, DMSO-d6) δ −149.2 (s).

13

C{1H} NMR (126 MHz,

DMSO-d6) δ 170.3 (d, J = 20.1 Hz), 149.7, 145.9 (d, J = 5.9 Hz), 135.4, 132.5 (d, J = 3.2 Hz), 131.6, 128.8 (d, J = 8.6 Hz), 125.8, 123.1, 122.3 (d, J = 18.4 Hz), 119.0, 117.8, 110.0, 93.4 (d, J = 188.1 Hz), 58.1 (d, J = 34.6 Hz), 26.7, 20.9. MS (ESI) m/z: 360.9 [M − H]−. HRMS (ESI) m/z: calcd for C17H16O4N2FS+ [M + H]+ 363.0809, found 363.0810. The ee was determined by HPLC analysis using a Chiralpak AD-H 31



column (20 ˚C; 82/18 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 17.7 min (major), 12.4 min (minor)). (R)-3-((R)-2,2-dioxido-3,4-dihydronaphtho[2,1-e][1,2,3]oxathiazin-4-yl)-3-fluoro -1-methylindolin-2-one (4x). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 6:1). Colorless solid (65.3 mg, yield = 82 %, d. r. = 55:45, ee = 20%/57%). [α]19D = −72.2 (c = 0.51, CHCl3, enantiomerically pure); m. p. 202.1–203.1 ˚C (enantiomerically pure). 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.10 (d, J = 7.7 Hz, 1H), 8.01 (dd, J = 16.1, 8.3 Hz, 2H), 7.87 (d, J = 7.8 Hz, 1H), 7.82–7.64 (m, 2H), 7.37 (t, J = 7.7 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 6.38 (d, J = 7.2 Hz, 1H), 5.59 (d, J = 12.3 Hz, 1H), 3.21 (s, 3H). 19F NMR (376 MHz, CDCl3) δ −143.4 (s). 13C{1H} NMR (101 MHz, DMSO-d6) δ 170.3 (d, J = 20.0 Hz), 147.1, 145.9 (d, J = 6.1 Hz), 134.1, 132.5 (d, J = 3.3 Hz), 128.4 (d, J = 12.5 Hz), 128.1, 125.7, 125.3, 124.7 (d, J = 9.8 Hz), 124.1, 123.1 (d, J = 2.9 Hz), 122.4, 122.2, 120.7, 113.7, 110.1, 93.8 (d, J = 188.4 Hz), 58.5 (d, J = 34.5 Hz), 26.8. HRMS (ESI) m/z: calcd for C20H16O4N2FS+ [M + H]+ 399.0809, found 399.0812.The ee was determined by HPLC analysis using a Chiralpak AD-H column (30 ˚C; 85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm; 32.3 min (major), 23.0 min (minor); the other diastereomer, 44.0 min (major), 38.5 min (minor)). Procedure for the synthesis of product 6. To a solution of 4a (0.2 mmol, 69.0 mg) in MeCN (3 mL) at 20 oC was added MeI or allyl bromide (0.4 mmol) and K2CO3 (82.9 mg, 0.6 mmol). The resulting mixture was stirred overnight. The reaction mixture was then diluted with EtOAc (30 mL) and washed with brine (20 32


Page 32 of 41

Page 33 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


mL). The organic layer was dried (MgSO4), filtered through a short pad of silica gel, and concentrated in vacuo. Purification of the residue by column chromatography gave product 5. (R)-3-fluoro-1-methyl-3-((R)-3-methyl-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxa thiazin-4-yl)indolin-2-one (6a). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1). Colorless solid (47.1 mg, yield = 65 %); [α]19D = −90.2 (c = 0.54, CHCl3, enantiomerically pure); m. p. 220.2–221.5 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 7.72 (d, J = 7.8 Hz, 1H), 7.61– 7.56 (m, 1H), 7.47 (td, J = 7.6, 1.1 Hz, 1H), 7.41–7.35 (m, 1H), 7.27 (dd, J = 8.2, 1.0 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H), 6.34 (d, J = 7.7 Hz, 1H), 5.69 (d, J = 14.6 Hz, 1H), 3.19 (s, 3H), 2.98 (s, 3H). 19F NMR (471 MHz, DMSO-d6) δ −146.1 (s).

13


145.5 (d, J = 6.2 Hz), 132.3 (d, J = 3.0 Hz), 131.4, 129.6 (d, J = 6.7 Hz), 126.7, 125.3, 123.1 (d, J = 2.7 Hz), 122.9 (d, J = 18.4 Hz), 119.2, 118.2, 109.9, 93.9 (d, J = 188.0 Hz), 66.4 (d, J = 36.6 Hz), 41.0, 26.7. MS (ESI) m/z: 360.9 [M − H]−. HRMS (ESI) m/z: calcd for C17H16O4N2FS+ [M + H]+ 363.0809, found 363.0810 (R)-3-((R)-3-allyl-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-fluor o-1-(prop-2-yn-1-yl)indolin-2-one (6b). The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1). Colorless solid (74.2 mg, yield = 90 %). [α]19D = −124.0 (c = 0.50, CHCl3, enantiomerically pure). m. p. 111.5–111.8 ˚C. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.06 (t, J = 9.1 Hz, 2H), 6.85 (t, J = 7.6 Hz, 1H), 33



6.40 (d, J = 7.5 Hz, 1H), 6.01–5.75 (m, 1H), 5.45 (dd, J = 15.7, 7.1 Hz, 2H), 5.27 (d, J = 10.0 Hz, 1H), 4.67–4.46 (m, 2H), 4.25 (dd, J = 15.3, 5.1 Hz, 1H), 3.90 (dd, J = 15.3, 8.9 Hz, 1H), 2.32 (t, J = 2.5 Hz, 1H).

19

F NMR (376 MHz, CDCl3) δ −143.4 (s).

13

C{1H} NMR (101 MHz, CDCl3) δ 170.2 (d, J = 19.8 Hz), 151.1, 143.4 (d, J = 6.3

Hz), 131.6 (d, J = 3.5 Hz), 130.6, 129.9, 128.1 (d, J = 8.7 Hz), 125.7 (d, J = 9.7 Hz), 123.2 (d, J = 3.2 Hz), 123.1, 122.9, 122.4, 119.2, 117.5 (d, J = 2.1 Hz), 109.7, 94.0 (d, J = 190.3 Hz), 75.8, 72.9, 63.4 (d, J = 37.1 Hz), 57.4, 29.5. HRMS (ESI) m/z: calcd for C21H18O4N2FS+ [M + H]+ 413.0966, found 413.0967.

Supporting Information Available. Copies of 1H, 19F, and 13C NMR spectra of all new compounds. X-ray crystal structure of compound 6a (CIF). This material is available free of charge via the Internet at http://pubs.acs.org. AKNOWLEDGEMENTS

Support of our work by the Natural Science Foundation of Shanghai (16ZR1413800) and Shanghai University of Engineering Science (2012td09, nhrc-2015-09).

REFERENCES

(1) For selected reviews, see: (a) Liang, T.; Neumann, C. N.; Ritter, T. Introduction of Fluorine and Fluorine-Containing Functional Groups. Angew. Chem. Int. Ed. 2013, 52, 8214–8264. (b) Champagne, P. A.; Desroches, J.; Hamel, J.-D.; Vandamme, M.; Paquin, J.-F. Monofluorination of Organic Compounds: 10 Years of Innovation. Chem. 34


Page 34 of 41

Page 35 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Rev. 2015, 115, 9073–9174. (c) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Asymmetric Construction of Stereogenic Carbon Centers Featuring a Trifluoromethyl Group fromProchiral Trifluoromethylated Substrates. Chem. Rev. 2011, 111, 455–529. (2) For selected examples, see: (a) Wolstenhulme, J. R.; Gouverneur, V. Asymmetric Fluorocyclizations of Alkenes. Acc. Chem. Res. 2014, 47, 3560–3570. (b) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Advances in Catalytic Enantioselective Fluorination, Mono-, Di-, and Trifluoromethylation, and Trifluoromethylthiolation Reactions. Chem. Rev. 2015, 115, 826–870. (c) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas. Chem. Rev. 2016, 116, 422–518. (d) Bégué, J. P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine. Wiley-Interscience. 2008. (3) Gribkoff, V. K.; Starrett Jr, J. E.; Dworetzky, S. I.; Hewawasam, P.; Boissard, C. G.; Cook, D. A.; Frantz, S. W.; Heman, K.; Hibbard, J. R.; Huston, K.; Johnson, G.; Krishnan, B. S.; Kinney, G. G.; Lombardo, L. A.; Meanwell, N. A.; Molinoff, P. B.; Myers, R. A.; Moon, S. L.; Ortiz, A.; Pajor, L.; Pieschl, R. L.; Post-Munson, D. J.; Signor, L. J.; Srinivas, N.; Taber, M. T.; Thalody, G.; Trojnacki, J. T.; Wiener, H.; Yeleswaram, K.; Yeola, S. W. Targeting Acute Ischemic Stroke with a Calcium-Sensitive Opener of Maxi-K Potassium Channels. Nat. Med. 2001, 7, 471– 477. (4) Spear, K. L.; Campbell, U. Heterocyclic Compounds and Methods of Use Thereof. 35



Patent WO2014106238 A1, Jul 3, 2014. (5) For selected examples on the asymmetric synthesis of nonfluorinated 3,3-disubstituted oxindoles, see: (a) Cao, Z.-Y.; Zhou, F.; Zhou, J. Development of Synthetic Methodologies via Catalytic Enantioselective Synthesis of 3,3-Disubstituted Oxindoles. Acc. Chem. Res. 2018, 51, 1443–1454. (b) Dalpozzo, R. Recent Catalytic Asymmetric Syntheses of 3,3-Disubstituted Indolin-2-ones and 2,2-Disubstituted Indolin-3-ones. Adv. Synth. Catal. 2017, 359, 1772–1810. (c) Zhou, F.; Liu, Y.-L.; Zhou, J. Catalytic Asymmetric Synthesis of Oxindoles Bearing a Tetrasubstituted Stereocenter at the C-3 Position. Adv. Synth. Catal. 2010, 352, 1381–1407. (d) Cheng, D.-J.; Ishihara, Y.; Tan, B.; Barbas III, C. F. Organocatalytic Asymmetric Assembly Reactions: Synthesis of Spirooxindoles via Organocascade Strategies. ACS Catal. 2014, 4, 743–762. (e) Zheng, H.; Liu, X.; Xu, C.; Xia, Y.; Lin, L.; Feng, X. Regioand Enantioselective Aza-Diels-Alder Reactions of 3-Vinylindoles: A Concise Synthesis of the Antimalarial Spiroindolone NITD609. Angew. Chem. Int. Ed. 2015, 54, 10958–10962. (f) Jiang, F.; Zhao, D.; Yang, X.; Yuan, F.-R.; Mei, G.-J.; Shi, F. Catalyst-Controlled Chemoselective and Enantioselective Reactions of Tryptophols with Isatin-Derived Imines. ACS. Catal. 2017, 7, 6984–6989. (6) (a) Li, J.; Cai, Y.; Chen, W.; Liu, X.; Lin, L.; Feng, X. Highly Enantioselective Fluorination of Unprotected 3-Substituted Oxindoles: One-step Synthesis of BMS 204352 (MaxiPost). J. Org. Chem. 2012, 77, 9148-9155. (b) Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. Enantioselective Fluorination Mediated by Cinchona Alkaloid Derivatives/Selectfluor Combinations: Reaction Scope and Structural Information 36


Page 36 of 41

Page 37 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


for N-Fluorocinchona Alkaloids. J. Am. Chem. Soc. 2001, 123, 7001–7009. (c) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M. Catalytic Enantioselective Fluorination of Oxindoles. J. Am. Chem. Soc. 2005, 127, 10164– 10165. (d) Shibata, N.; Ishimaru, T.; Suzuki, E.; Kirk, K. L.; Enantioselective Fluorination Mediated by N-Fluoroammonium Salts of Cinchona Alkaloids: First Enantioselective Synthesis of BMS-204352 (MaxiPost). J. Org. Chem. 2003, 68, 2494–2497. (e) Zhang, R.; Wang, D.; Xu, Q.; Jiang, J.; Shi, M. Axially Chiral C2-Symmetric N-Heterocyclic Carbene (NHC) Palladium Complex-Catalyzed Asymmetric Fluorination and Amination of Oxindoles. Chin. J. Chem. 2016, 30, 1295–1304. (f) Zoute, L.; Audouard, C.; Plaquevent, J.-C.; Cahard, D. Enantioselective Synthesis of BMS-204352 (MaxiPost™) Using N-Fluoroammonium Salts of Cinchona Alkaloids (F-CA-BF4). Org. Bio. Chem. 2003, 1, 1833–1834. (g) Gu, X.; Zhang, Y.; Xu, Z.-J.; Che, C.-M. Iron(III)-Salan Complexes Catalysed Highly Enantioselective Fluorination and Hydroxylation of β-keto Esters and N-Boc Oxindoles. Chem. Commun. 2014, 50, 7870–7873. (h) Wang, F.; Li, J.; Hu, Q.; Yang, X.; Wu, X.-Y.; He, H. Enantioselective Fluorination of 2-Oxindoles by Structure-Micro-Tuned N-Fluorobenzenesulfonamides. Eur. J. Org. Chem. 2014, 2014, 3607–3616. (i) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Cinchona Alkaloid Catalyzed Enantioselective Fluorination of Allyl Silanes, Silyl Enol Ethers, and Oxindoles. Angew. Chem. Int. Ed. 2008, 47, 4157–4161. (7) For selected examples on the use of the detrifluoroacetylative in situ generation of 37



Page 38 of 41

3-fluorooxindole enolate, see: (a) Xie, C.; Zhang, L.; Sha, W.; Soloshonok, V. A.; Han, J.;

Pan,

Y.

Detrifluoroacetylative

in

Situ

Generation

of

Free

3-Fluoroindolin-2-one-Derived Tertiary Enolates: Design, Synthesis, and Assessment of Reactivity Toward Asymmetric Mannich Reactions. Org. Lett. 2016, 18, 3270– 3273. (b) Zhang, W.; Sha, W.; Zhu, Y.; Han, J.; Soloshonok, V. A.; Pan, Y. Asymmetric Synthesis of Quaternary β-Perfluorophenyl-β-Amino-Indolin-2-ones. Eur. J. Org. Chem. 2017, 2017, 1540–1546. (c) Xie, C.; Sha, W.; Zhu, Y.; Han, J.; Soloshonok,

V.

A.;

Pan,

Y.

Asymmetric

Synthesis

of

C-F

Quaternary

α-Fluoro-β-Amino-Indolin-2-ones via Mannich Addition Reactions; Facets of Reactivity, Structural Generality and Stereochemical Outcome. RSC. Adv. 2017, 7, 5679–5683. (d) Zhang, L.; Zhang, W.; Mei, H.; Han, J.; Soloshonok, V. A.; Pan, Y.; Catalytic Asymmetric Aldol Addition Reactions of 3-Fluoro-Indolinone Derived Enolates. Org. Bio. Chem. 2017, 15, 311–315. (e) Zhu, Y.; Mei, H.; Han, J.; Soloshonok, V. A.; Zhou, J.; Pan, Y. Chemoselective SN2′ Allylations of Detrifluoroacetylatively In Situ

Generated

3-Fluoroindolin-2-one-Derived

Tertiary

Enolates

with

Morita-Baylis-Hillman Carbonates. J. Org. Chem. 2017, 82, 13663–13670. (f) Zhu, Y.; Mao, Y.; Mei, H.; Pan, Y.; Han, J.; Soloshonok, V. A.; Hayashi, T. Palladium-Catalyzed Asymmetric Allylic Alkylations of Colby Pro-Enolates with MBH Carbonates: Enantioselective Access to Quaternary C-F Oxindoles. Chem. Eur. J. 2018, 24, 8994–8998. (8) For selected examples on the straightforward use of 3-fluorooxindoles, see: (a) Jin, Y.; Chen, M.; Ge, S.; Hartwig, J. F. Palladium-Catalyzed, Enantioselective 38


Page 39 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


α-Arylation of α-Aluorooxindoles. Org. Lett. 2017, 19, 1390–1393. (b) Balaraman, K.; Wolf, C. Catalytic Enantioselective and Diastereoselective Allylic Alkylation with Fluoroenolates: Efficient Access to C3-Fluorinated and All-Carbon Quaternary Oxindoles. Angew. Chem. Int. Ed. 2017, 56, 1390–1395. (c) Ding, R.; Wolf, C. Organocatalytic Asymmetric Synthesis of α-Oxetanyl and α-Azetidinyl Tertiary Alkyl Fluorides and Chlorides. Org. Lett. 2018, 20, 892–895. (d) Wang, T.; Hoon, D.-L.; Lu, Y. Enantioselective Synthesis of 3-Fluoro-3-Allyl-Oxindoles via Phosphine-Catalyzed Asymmetric γ-Addition of 3-Fluoro-Oxindoles to 2,3-Butadienoates. Chem. Commun. 2015, 51, 10186–10189. (e) Dou, X.; Lu, Y. Enantioselective Conjugate Addition of 3-Fluoro-Oxindoles to Vinyl Sulfone: an Organocatalytic Access to Chiral 3-Fluoro-3-Substituted Oxindoles. Org. Bio. Chem. 2013, 11, 5217–5221. (f) Balaraman, K.; Ding, R.; Wolf, C. Stereoselective Synthesis of 3,3’-Bisindolines by Organocatalytic Michael Additions of Fluorooxindole Enolates to Isatylidene Malononitriles in Aqueous Solution. Adv. Synth. Catal. 2017, 359, 4165–4169. (g) Moskowitz, M.; Balaraman, K.; Wolf, C. Organocatalytic Stereoselective Synthesis of Fluorinated 3,3′-linked bisoxindoles. J. Org. Chem. 2018, 83, 1661–1666. (9) (a) Chen, X.-Y.; Li, Y.; Zhao, J.-B.; Zheng, B.-Q.; Lu, Q.; Ren, X. Stereoselective Mannich Reaction of N-(tert-Butylsulfinyl) Imines with 3-Fluorooxindoles and Fluoroacetamides. Adv. Synth. Catal. 2017, 359, 3057–3062. (b) Zheng, B.-Q.; Chen, L.-Y.; Zhao, J.-B.; Ji, J.; Qiu, Z.-B.; Ren, X.; Li, Y. Organocatalytic Asymmetric Syntheses of 3-Fluorooxindoles Containing Vicinal Fluoroamine Motifs. Org. Biomol. Chem. 2018, 16, 8989–8993. (c) Paladhi, S.; Park, S. Y.; Yang, J.-W.; Song, C.-E. 39



Page 40 of 41

Asymmetric Synthesis of α-Fluoro-β-Amino-Oxindoles with Tetrasubstituted C-F Stereogenic Centers via Cooperative Cation-Binding Catalysis, Org. Lett. 2017, 19, 5336–5339. (d) Li, B.-Y.; Du, D.-M. Chiral Squaramide-Catalyzed Asymmetric Mannich Reactions for Synthesis of Fluorinated 3,3′-Bisoxindoles. Adv. Synth. Catal. 2018, 360, 3164–3170. (10) For selected examples, see: (a) Ishikawa, T.; Iwami, M. Antifungal Composition Comprising Sulfonyl Compounds. Patent Appl. WO 2018155706 A1, 2018. (b) El-Sawy, E. R.; Ebaid, M. S.; Abo-Salem, H. M.; El-Hallouty, S.; Kassem, E. M.; Mandour, A. H. Synthesis and Biological Activity of Novel Series of 4-Methoxy, and 4,9-Dimethoxy-5-Substituted

Furo[2,3-g]-1,2,3-Benzoxathiazine-7,7-Dioxide

Derivatives. J. Adv. Res. 2014, 5, 337–346. (c) Alig, B.; Mueller, K.-H.; Franken, E.-M.; Goergens, U.; Voerste, A. Preparation of 4-Amino-1,2,3-Benzoxathiazines as Agrochemical Pesticides. WO 2010072310 A1, 2010. (d) Hanson, S. R.; Whalen L. J.; Wong, C.-H. Synthesis and Evaluation of General Mechanism-Based Inhibitors of Sulfatases Based on (Difluoro)Methyl Phenyl Sulfate and Cyclic Phenyl Sulfamate Motifs. Bioorg. Med. Chem. 2006, 14, 8386–8395. (11) (a) Brodsky, B. H.; Bois, J. D. Oxaziridine-Mediated Catalytic Hydroxylation of Unactivated 3 °C-H Bonds Using Hydrogen Peroxide. J. Am. Chem. Soc. 2005, 127, 15391–15393. (b) Achary, R.; Jung, I.-A.; Lee, H.-K. Tandem Rh-Catalyzed Oxidative C-H Olefination and Cyclization Benzo-1,3-Sulfamidates:

Stereoselective

of

Synthesis

Enantiomerically Enriched of

trans-1,3-Disubstituted

Isoindolines, J. Org. Chem. 2018, 83, 3864–3878. (c) Jia, C.-M.; Zhang, H.-X.; Nie, J.; 40


Page 41 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Ma, J.-A. Catalytic Asymmetric Decarboxylative Mannich Reaction of Malonic Acid Half Esters with Cyclic Aldimines: Access to Chiral β ‑ Amino Esters and Chroman-4-Amines. J. Org. Chem. 2016, 81, 8561–8569. (d) Vila, C.; Tortosa, A.; Blay,

G.; Muñoz, M. C.; Pedro, J. R. Organocatalytic enantioselective

functionalization of indoles in the carbocyclic ring with cyclic imines. New. J. Chem. 2019, 43, 130–134. (12) CCDC 1886673 (6a) contains the supplementary crystallographic data for this paper. (13) For the synthesis of compound 1, see: Spielmann, K.; van der Lee, A.; de Figueiredo, R. M.; Campagne, J.-M. Diastereoselective Palladium-Catalyzed (3 + 2)-Cycloadditions from Cyclic Imines and Vinyl Aziridines. Org. Lett. 2018, 20, 1444–1447. (14) For the synthesis of 3-fluorooxindoles, see: Yang, Q.; Dai, G.-L.; Yang, Y.-M.; Luo, Z.; Tang, Z.-Y. Solvent Effects: Syntheses of 3,3-Difluorooxindoles and 3-Fluorooxindoles from Hydrazonoindolin-2-one by Selectfluor. J. Org. Chem. 2018, 83, 6762–6768.

41


Enantioselective Mannich Reactions of 3-Fluorooxindoles with Cyclic

Recommend Documents