1 Introduction
Pyrrolidines are of great importance five-membered ring heterocycles in natural product synthesis and medicinal chemistry, and this structural motif can be found in many natural products and bioactive molecules. Particularly, pyrrolidines containing spirocyclic scaffolds are known to have a broad spectrum of medicinal properties,[1] including anti-plasmodium,[2] anti-cancer,[3] sepiapterin reductase (SPR) inhibition,[4] HIV-protease inhibitory activity,[5] etc. (Figure 1). In recent decades, numerous studies on the synthesis of these molecules have been conducted, employing catalysis methods such as base, metal, and Brønsted acid catalysis. For example, in 2012, Marinetti et al.[6] reported a phosphine-catalyzed [3＋2] cyclization between allenoates and enones, affording the highly functionalized heterocyclic spiranes with excellent enantioselectivity. In 2019, Li et al.[7] reported a copper-catalyzed [3＋2] cycloaddition of azomethine ylides with activated alkenes, giving the desired compounds in good yields with high enantioselectivity. Despite significant progress made in this field, developing an efficient, catalytic asymmetric method for stereoselectively constructing optically active pyrrolidines containing a thia-spirocyclic scaffold is necessary.
The [3＋2] cycloadditions have emerged as reliable and powerful tools for the synthesis of five-member rings. Among them, since Grigg’s pioneering work using stoichiometric chiral metal complexes,[8] copper-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with various electron-deficient olefins has been widely used to construct optically active pyrrolidines, especially spirocyclic pyrrolidines, a key subset of pyrrolidine-based molecules.[9] Up to now, a wide range of crucial ligands, such as Wang’s TF-Biphamphos,[10] Carretero’s Fe-sul- phos,[11] Zhang’s Sad-Phos,[12] Fukuzawa’s ThioClickFerrophos,[13] and Xu’s Xing-Phos[14] etc., have been developed for the enantioselective bond-forming processes.
Recently, our group[15] developed a type of P-chiral ligands ZD-Phos, which performed well in copper-catalyzed enantioselective 1,3-dipole cycloaddition reactions. Encouraged by these findings, we expect to explore the reactions of conformationally restricted dienones. Their rigid structures prevent the required conformation for the second intermolecular conjugate addition, thereby halting the reaction after the first addition. This interest is driven by the established significance of analogous compounds in medicinal chemistry and enantioselective synthesis.
3,5-Diarylidenetetrahydro-4H-thiopyran-4-one are useful substrates for synthesizing pharmaceuticals and chiral ligands.[16] In 2017, Zhou et al.[17] reported the stereoselectivity of asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides with cyclohexanones, however, giving low enantioselectivities and diastereoselectivities in most cases. Although the limitation had been overcome by using our developing Ag(I)/Gan-Phos complex, when 3,5-diaryl- idenetetrahydro-4H-thiopyran-4-ones were used under the optimized reaction conditions, the low-level enantioselectivities were still obtained.[18] Given the importance of these molecules, developing an efficient catalytic system that tolerates variations in dipole components is highly desirable (Scheme 1).
2 Results and discussion
We initiated our studies using (Z)-3,5-dibenzylidene- tetrahydro-4H-thiopyran-4-one (1a) and glycine methyl ester 2a as model substrates, with AgNTf₂ (5 mol%) and chiral Gan-Phos L1' (6 mol%) as the catalysts and Et₃N (20 mol%) as the base in tetrahydrofuran (THF) at room temperature (Table 1, Entry 1). The reaction proceeded smoothly, yielding the desired product 3a in 95% yield with >20:1 dr and 51% ee. Encouraged by this result, various metal catalysts, bases, and catalyst loadings were screened, finding that AgNTf2 as the catalyst and Et3N as the base at 10 mol% loading provided the best outcome. Notably, solvent screening revealed that CH₃CN was optimal (Table 1, Entries 1~4). Next, a series of chiral Gan-Phos ligands were investigated, suggesting that the AgNTf₂/L1' system gave relatively higher enantioselectivity (Table 1, Entries 5~15). Replacing Et3N with iPr2NEt, the desired product 3a was obtained in >99% yield with 73% ee (Table 1, Entry 16). Reducing the loading of iPr2NEt did not affect the enantioselectivity of 3a (Table 1, Entry 17). Reaction temperature screening indicated that -20 ℃ was optimal (Table 1, Entries 18~20). When glycine tert-butyl ester 2b was used, the reactions proceeded smoothly, affording the desired product 3ab in >99% yield with 97% ee (Table 1, Entry 21).
Table 1 Reaction condition optimizationa |
| Entry | L | Solvent | Yieldb/% | eec/% |
|---|---|---|---|---|
| 1 | L1' | THF | 95 | 51 |
| 2 | L1' | DCM | 74 | 55 |
| 3 | L1' | CH3CN | 92 | 72 |
| 4 | L1' | Toluene | 70 | 44 |
| 5 | L1 | CH3CN | 99 | -39 |
| 6 | L2 | CH3CN | 96 | -29 |
| 7 | L2' | CH3CN | >99 | 60 |
| 8 | L3 | CH3CN | 96 | -7 |
| 9 | L3' | CH3CN | 89 | 50 |
| 10 | L4 | CH3CN | 91 | -27 |
| 11 | L4' | CH3CN | 95 | 61 |
| 12 | L5' | CH3CN | >99 | 33 |
| 13 | L6' | CH3CN | >99 | 61 |
| 14 | S1 | CH3CN | 96 | -6 |
| 15 | S2 | CH3CN | 96 | 30 |
| 16d | L1' | CH3CN | >99 | 73 |
| 17d,e | L1' | CH3CN | 94 | 75 |
| 18d,e,f | L1' | CH3CN | >99 | 71 |
| 19d,e,g | L1' | CH3CN | >99 | 83 |
| 20d,e,h | L1' | CH3CN | >99 | 84 |
| 21d,e,g,i | L1' | CH3CN | >99 | 97 |
a 1a (0.1 mmol), 2a (0.24 mmol), Ag(I) (0.01 mmol), L or L' (0.01 mmol), NEt3 (0.02 mmol), solvent (3 mL) at room temperature. b Isolated yield, all product pairs exhibit >20:1 diastereoselectivity. c Determined by chiral HPLC analysis. d Replace NEt3 with iPr2NEt. e iPr2NEt (0.5 equiv.) was used. f Reaction at 40 ℃. g At -20 ℃ for 2 d. h At -40 ℃ for 4 d. i Replace 2a with 2b, reaction time: 18 h. |
Under optimized conditions, 1,3-dipolar cycloaddition reactions between various 3,5-diarylidenetetrahydro-4H- thiopyran-4-ones 1 and azomethine ylide 2b (Table 2) were performed. Both electron-rich and electron-deficient aryl- substituted 1 reacted smoothly with 2b, yielding the desired products 3 in 74%~99% yields with >20:1 dr and high enantioselectivities (up to 97% ee) (3ab~3pb). Notably, sterically hindered (4-tBu) and electron-deficient (4-CN) aryl-substituted compounds 1 reacted smoothly with 2b, yielding products with high yields and diastereoselectivities, albeit with slightly lower enantioselectivities (3fb and 3gb). Next, the m- and o-position groups of aryl-substi- tuents in 1 were also examined. The reactions proceeded smoothly, yielding the desired products with high yields, good enantioselectivities, and excellent diastereo-selecti- vities in most cases (3ib~3mb). When 2-Cl-4-F substituted 1n was used as reactive substrate, the desired product 3nb was obtained in 74% yield with 86% ee (3nb). Furthermore, substrate 1o derived from naphthyl aldehyde reacted with 2b to produce cycloadduct 3ob in 83% yield, 87% ee, and 20:1 dr (3ob). 2-Thienyl substituted 1p also worked well in this transformation to give the corresponding addition product 3pb in >99% yield with >20:1 dr and 87% ee (3pb). The relative and absolute configuration of the major diastereoisomer of 3nb was determined as endo-(1R,3R, 4R,5S) by single-crystal X-ray crystallographic analysis (CCDC 2417260), which can be applied to all cycloadducts.
Table 2 Substrate scope of 3,5-diarylidenetetrahydro-4H-thiopyran-4-ones |
 |
a 1 (0.1 mmol), 2b (0.24 mmol), Ag(I) (0.005 mmol), ligand (0.06 mmol), iPr2NEt (0.02 mmol), and CH3CN (3.0 mL), -20 ℃, 18 h in a sealed tube. b Isolated yield, all product pairs exhibit >20:1 diastereoselectivity. c The ee values were determined by chiral HPLC analysis. d Diastereoisomers were isolated by column chromatography and total yield of mixtures of the diastereomers. |
We then turned our attention to check the substrate scope of azomethine ylides 2. Aryl imine esters with electron-rich, electron-deficient and electron-neutral substituents were tolerated in this catalytic system, yielding the corresponding adducts 3ac~3al in excellent yields with moderate to high enantioselectivities, and excellent diastereoselectivities (Table 3). Even, the strong electron-deficient substituents (NO2 and CF3) also worked well in the reactions, affording the desired products 3ah~3ai in >99% yields with 85% ee (3ah~3ai). Notably, low enantioselectivity was obtained when 3,4,5-MeO3C6H2 group was used (3aj). Azomethine ylides containing a 2-thiethyl group proceeded smoothly, affording the desired product 3ak in an excellent yield with acceptable enantioselectivity.
Table 3 Substrate scope of azomethine ylides |
 |
a 1 (0.1 mmol), 2b (0.24 mmol), Ag(I) (0.005 mmol), ligand (0.06 mmol), iPr2NEt (0.02 mmol), and CH3CN (3.0 mL), -20 ℃, 18 h in a sealed tube. b Isolated yield, all product pairs exhibit >20:1 diastereoselectivity. c The ee values were determined by chiral HPLC analysis. d Diastereoisomers were isolated by column chromatography and total yield of mixtures of the diastereomers. |
To demonstrate the synthetic utility of this catalytic system, the model reaction was scaled up to the gram level, yielding 3a in 94% yield, 96:4 dr, and 97% ee. In addition, we realized methylation of 3ba by using CH3I as methyl- ating agent and K2CO3 as base in N,N-dimethylformamide (DMF) at room temperature, and the desired product 3bc was obtained in 65% yield, >20:1 dr as well as 90% ee (Scheme 2).
3 Conclusions
In conclusion, an efficient catalytic asymmetric 1,3-di- polar cycloaddition of azomethine ylides with 3,5-diaryli- denetetrahydro-4H-thiopyran-4-ones to construct spirocyclic scaffolds containing a pyrroline motif with adjacent quaternary and tertiary stereogenic centers was developed. The catalytic system was highly effective in this transformation, yielding excellent diastereoselectivities (>20:1 dr) and good to excellent enantioselectivities (70%~97% ee) for various azomethine ylides and 3,5-diarylidenetetra- hydro-4H-thiopyran-4-ones with overall yields of 74%~>99%. The synthetic potential of this methodology has been demonstrated by the gram scale experiment. Further investigations into the application of this method in organic synthesis and studies on its scope and limitations are ongoing.
4 Experimental section
4.1 General experimental
All reactions were performed under nitrogen using solvents dried by standard methods. NMR spectra were obtained using a Bruker AV300 spectrometer. TMS was used as internal standard. HRMS spectra were obtained on an Agilent 1290-6540 UHPLC Q-Tof HR-MS spectrometer. X-ray crystallographic analyses were performed on an Oxford diffraction Gemini E diffractometer. Enantiomer excesses were determined by chiral HPLC analysis on a Chiralcel IA/OD/AD in comparison with the authentic racemates. Chiral HPLC analysis recorded on a Shimadzu labtotal LC-20AT. Silica gel (200~300 mesh) was used for the chromatographic separations. All commercially available reagents were used without further purification.
4.2 General procedure for the Ag-catalyzed 1,3- dipolar cycloaddition reaction
AgNTf2 (0.005 mmol) and L1' (0.006 mmol) were added to a 10 mL Schlenk tube under nitrogen. Then anhydrous CH3CN (1 mL) was added into the tube. After being stirred for 1 h at room temperature, the 3,5-dibenzylidene-tetra- hydrothiopyran-4-one 1 (0.1 mmol), glycine tert-butyl ester 2 (0.24 mmol), and CH3CN (2 mL) were added subsequently. Then at -20 ℃, iPr2NEt (0.05 mmol) was added to the reaction. The reaction mixture was stirred at -20 ℃ until the 3,5-dibenzylidene-tetrahydrothiopyran-4-one was totally consumed. When the reaction was completed as monitored by thin-layer chromatography (TLC), the mixture was filtered through celite and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silicagel (petroleum ether/ethyl acetate, V:V=5:1) to give the products 3.
tert-Butyl (3R,4R)-9-((Z)-benzylidene)-10-oxo-1,4-di-phenyl-7-thia-2-azaspiro[4.5]decane-3-carboxylate (3ab): Yellow oil, >99% yield. [α]26 D＋65 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.26 (s, 9H), 2.87~2.85 (m, 2H), 3.35 (dd, J=14.7, 1.8 Hz, 1H), 3.53 (dd, J=14.7, 1.5 Hz, 1H), 4.20 (d, J=11.2 Hz, 1H), 4.59 (d, J=11.2 Hz, 1H), 4.93 (s, 1H), 6.13 (s, 1H), 6.94~6.92 (m, 2H), 7.25 (d, J=4.3 Hz, 1H), 7.28 (d, J=2.0 Hz, 2H), 7.30 (s, 1H), 7.36~7.32 (m, 7H), 7.48 (d, J=1.5 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.7, 36.6, 56.7, 63.2, 67.3, 73.3, 81.7, 127.1, 127.8, 128.1, 128.2, 128.3, 128.4, 129.0, 129.5, 129.8, 135.0, 135.7, 135.8, 136.5, 140.0, 172.2, 200.8; HRMS (ESI) calcd for C32H34NO3S [M＋H]＋ 512.2254, found 512.2256. The product was analyzed by HPLC to determine the enantiomeric excess: 97% ee (Chiralpak AD-H, hexane/i-propanol, V:V=95:5, flow rate 1.0 mL/min, λ=254 nm); tR=18.232 and 20.484 min.
tert-Butyl (3R,4R)-9-((Z)-4-fluorobenzylidene)-4-(4-fluo- rophenyl)-10-oxo-1-phenyl-7-thia-2-azaspiro[4.5]decane- 3-carboxylate (3bb): Yellow oil, >99% yield. [α]29 D＋46 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.28 (s, 9H), 2.89~2.77 (m, 2H), 3.35 (d, J=14.7 Hz, 1H), 3.49 (d, J=14.7 Hz, 1H), 4.15 (d, J=11.3 Hz, 1H), 4.57 (d, J=11.3 Hz, 1H), 4.93 (s, 1H), 6.04 (s, 1H), 6.93~6.88 (m, 2H), 7.01 (dd, J=16.2, 8.2 Hz, 4H), 7.31 (t, J=6.7 Hz, 5H), 7.47 (d, J=5.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.6, 36.5, 55.8, 63.1, 67.1, 73.2, 81.9, 114.9, 115.2, 115.3, 115.6, 127.9, 128.2, 129.0, 130.9 (d, J=3.1 Hz), 131.2, 131.3, 131.3, 131.4, 132.1 (d, J=3.2 Hz), 134.7, 135.5, 140.0, 171.9, 200.7; 19F NMR (565 MHz, CDCl3) δ: -112.20 (d, J=3.4 Hz); HRMS (ESI) calcd for C32H32- F2NO3S [M＋H]＋ 548.2065, found 548.2066. The product was analyzed by HPLC to determine the enantiomeric excess: 85% ee (Chiralpak IA-H, hexane/i-propanol, V:V=95:5, flow rate 1.0 mL/min, λ=254 nm); tR=18.751 and 21.250 min.
tert-Butyl (3R,4R)-9-((Z)-4-chlorobenzylidene)-4-(4-chlorophenyl)-10-oxo-1-phenyl-7-thia-2-azaspiro[4.5]de- cane-3-carboxylate (3cb): Yellow oil, >99% yield. [α]29 D ＋100 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.29 (s, 9H), 2.82 (dt, J=23.8, 8.0 Hz, 2H), 3.33 (dd, J=14.7, 1.6 Hz, 1H), 3.48 (dd, J=14.8, 1.8 Hz, 1H), 4.15 (d, J=11.3 Hz, 1H), 4.56 (d, J=11.3 Hz, 1H), 4.91 (s, 1H), 6.01 (s, 1H), 6.85 (d, J=8.4 Hz, 2H), 7.35~7.26 (m, 9H), 7.46 (dd, J=7.3, 2.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.6, 36.5, 55.8, 62.9, 67.3, 73.2, 82.0, 127.9, 128.2, 128.3, 128.6, 129.0, 130.7, 131.0, 133.1, 133.2, 134.4, 134.5, 134.9, 136.1, 139.8, 171.8, 200.6; HRMS (ESI) calcd for C32H32Cl2NO3S [M＋H]＋ 580.1474, found 580.1473. The product was analyzed by HPLC to determine the enantiomeric excess: 84% ee (Chiralpak AD-H, hexane/i- propanol, V:V=90:10, flow rate 1.0 mL/min, λ=254 nm); tR=14.513 and 16.860 min.
tert-Butyl (3R,4R)-9-((Z)-4-bromobenzylidene)-4-(4-bro- mophenyl)-10-oxo-1-phenyl-7-thia-2-azaspiro[4.5]decane-3-carboxylate (3db): Yellow oil, >99% yield. [α]31 D＋91 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.29 (s, 9H), 2.79 (dd, J=17.8, 7.9 Hz, 2H), 3.32 (dd, J=14.7, 1.4 Hz, 1H), 3.47 (dd, J=14.8, 1.4 Hz, 1H), 4.14 (d, J=11.3 Hz, 1H), 4.55 (d, J=11.3 Hz, 1H), 4.90 (s, 1H), 5.99 (s, 1H), 6.78 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.36~7.30 (m, 3H), 7.44 (t, J=7.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.6, 36.5, 55.8, 62.9, 67.3, 73.3, 82.1, 121.2, 122.8, 127.9, 128.2, 129.0, 131.0, 131.3, 131.3, 131.6, 133.7, 134.5, 135.5, 136.1, 139.8, 171.7, 200.6; HRMS (ESI) calcd for C32H32Br2NO3S [M＋H]＋ 668.0464, found 668.0469. The product was analyzed by HPLC to determine the enantiomeric excess: 87% ee (Chiralpak AD-H, hexane/i-propanol, V:V=95:5, flow rate 1.0 mL/min, λ=254 nm); tR=29.867 and 39.994 min.
tert-Butyl (3R,4R)-9-((Z)-4-methoxybenzylidene)-4-(4-methoxyphenyl)-10-oxo-1-phenyl-7-thia-2-azaspiro[4.5] decane-3-carboxylate (3eb): Yellow oil, 59% yield. [α]32 D＋111 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.29 (s, 9H), 2.83 (s, 2H), 3.40 (d, J=14.5 Hz, 1H), 3.55 (d, J=14.6 Hz, 1H), 3.80 (d, J=2.0 Hz, 6H), 4.15 (d, J=11.1 Hz, 1H), 4.54 (d, J=11.1 Hz, 1H), 4.90 (s, 1H), 6.13 (s, 1H), 6.87 (dt, J=16.8, 8.5 Hz, 6H), 7.32~7.23 (m, 5H), 7.47 (d, J=6.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.7, 36.2, 55.2, 55.3, 56.1, 63.3, 66.9, 73.1, 81.7, 113.5, 113.8, 127.5, 127.7, 128.1, 128.5, 128.9, 130.7, 131.3, 134.0, 136.0, 140.1, 158.6, 159.8, 172.3, 200.8; HRMS (ESI) calcd for C34H38NO5S [M＋H]＋ 572.2465, found 572.2466. The product was analyzed by HPLC to determine the enantiomeric excess: 83% ee (Chiralpak AD-H, hexane/i-propanol, V:V=80:20, flow rate 1.0 mL/min, λ=254 nm); tR=17.105 and 21.641 min.
tert-Butyl (3R,4R)-9-((Z)-4-(tert-butyl)benzylidene)-4- (4-(tert-butyl)phenyl)-10-oxo-1-phenyl-7-thia-2-azaspiro- [4.5]decane-3-carboxylate (3fb): Yellow oil, 95% yield. [α]33 D＋121 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.24 (s, 9H), 1.30 (s, 9H), 1.32 (s, 9H), 2.91 (s, 2H), 3.42 (dd, J=14.7, 1.2 Hz, 1H), 3.57 (d, J=14.7 Hz, 1H), 4.17 (d, J=11.1 Hz, 1H), 4.54 (d, J=11.1 Hz, 1H), 4.95 (s, 1H), 6.14 (s, 1H), 6.90 (d, J=8.3 Hz, 2H), 7.24 (s, 1H), 7.27~7.26 (m, 1H), 7.33 (d, J=8.2 Hz, 7H), 7.50~7.48 (m, 2H); 13C NMR (75 MHz, CDCl3) δ: 27.7, 29.7, 31.2, 31.4, 34.4, 34.7, 36.3, 56.4, 63.6, 67.0, 73.2, 81.5, 124.9, 125.2, 127.7, 128.1, 128.9, 129.4, 129.5, 132.2, 133.4, 135.1, 135.9, 140.2, 149.9, 151.7, 172.3, 200.8; HRMS (ESI) calcd for C40H50NO3S [M＋H]＋ 624.3506, found 624.3504. The product was analyzed by HPLC to determine the enantiomeric excess: 77% ee (Chiralpak AD-H, hexane/i-propanol, V:V=98:2, flow rate 1.0 mL/min, λ=254 nm); tR=19.086 and 26.855 min.
tert-Butyl (3R,4R)-9-((Z)-4-cyanobenzylidene)-4-(4- cyanophenyl)-10-oxo-1-phenyl-7-thia-2-azaspiro[4.5]de-cane-3-carboxylate (3gb): Yellow oil, 79% yield. [α]32 D＋116 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.27 (s, 9H), 2.71 (d, J=13.9 Hz, 1H), 2.89 (dd, J=13.8, 1.8 Hz, 1H), 3.37 (dd, J=35.4, 15.2 Hz, 2H), 4.19 (d, J=11.4 Hz, 1H), 4.63 (d, J=11.4 Hz, 1H), 4.95 (s, 1H), 5.97 (s, 1H), 6.99 (d, J=8.1 Hz, 2H), 7.34 (d, J=3.7 Hz, 3H), 7.49~7.45 (m, 4H), 7.62 (dd, J=14.0, 8.2 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.7, 36.7, 56.1, 62.6, 67.8, 73.4, 82.4, 111.3, 112.0, 128.1, 118.3, 118.6, 128.4, 129.1, 129.8, 130.5, 132.0, 132.1, 133.3, 137.7, 139.3, 139.6, 142.2, 171.2, 200.3; HRMS (ESI) calcd for C34H32N3O3S [M＋ H]＋ 562.2159, found 562.2158. The product was analyzed by HPLC to determine the enantiomeric excess: 79% ee (Chiralpak AD-H, hexane/i-propanol, V:V=70:30, flow rate 1.0 mL/min, λ=254 nm); tR=16.984 and 30.026 min.
tert-Butyl (3R,4R)-10-oxo-1-phenyl-9-((Z)-4-(trifluoro-methyl)benzylidene)-4-(4-(trifluoromethyl)phenyl)-7-thia-2-azaspiro[4.5]decane-3-carboxylate (3hb): Yellow oil, 96% yield. [α]28 D＋93 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.26 (s, 9H), 2.76 (d, J=13.9 Hz, 1H), 2.90 (dd, J=13.9, 2.0 Hz, 1H), 3.33 (d, J=14.9 Hz, 1H), 3.46 (dd, J=14.8, 1.5 Hz, 1H), 4.22 (d, J=11.3 Hz, 1H), 4.65 (d, J=11.3 Hz, 1H), 4.96 (s, 1H), 6.05 (s, 1H), 7.02 (d, J=8.0 Hz, 2H), 7.36~7.34 (m, 3H), 7.48 (d, J=7.9 Hz, 4H), 7.58 (dd, J=10.8, 8.5 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.6, 36.6, 56.0, 62.8, 67.5, 73.3, 82.3, 125.1 (dd, J=7.4, 3.6 Hz), 125.3 (dd, J=7.4, 3.6 Hz), 128.1, 128.4, 129.0, 129.5, 130.1, 133.9, 137.2, 138.3, 139.6, 140.6, 171.4, 200.4; 19F NMR (565 MHz, CDCl3) δ: -62.81; HRMS (ESI) calcd for C34H32F6NO3S [M＋H]＋ 648.2002, found 648.2000. The product was analyzed by HPLC to determine the enantiomeric excess: 90% ee (Chiralpak AD-H, hexane/i-propanol, V:V=95:5, flow rate 1.0 mL/min, λ=254 nm); tR=16.323 and 18.474 min.
tert-Butyl (3R,4R)-9-((Z)-3-fluorobenzylidene)-4-(3-fluorophenyl)-10-oxo-1-phenyl-7-thia-2-azaspiro[4.5]de-cane-3-carboxylate (3ib): Yellow oil, >99% yield. [α]34 D＋112 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.29 (s, 9H), 2.82 (dd, J=16.5, 8.1 Hz, 2H), 3.34 (dd, J=14.7, 1.6 Hz, 1H), 3.50 (dd, J=14.7, 1.9 Hz, 1H), 4.15 (d, J=11.3 Hz, 1H), 4.59 (d, J=11.2 Hz, 1H), 4.92 (s, 1H), 6.01 (s, 1H), 6.61 (d, J=9.8 Hz, 1H), 6.70 (d, J=7.7 Hz, 1H), 7.01~6.94 (m, 2H), 7.13~7.05 (m, 2H), 7.28~7.23 (m, 2H), 7.35 - 7.31(m, 3H), 7.47 (dd, J=7.3, 2.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.7, 36.6, 56.0, 63.0, 67.4, 73.3, 82.0, 114.0, 114.3, 115.2, 115.5, 115.9, 116.2, 116.5, 116.8, 125.1 (d, J=2.9 Hz), 125.4 (d, J=2.9 Hz), 128.0, 128.3, 129.0, 129.6 (d, J=8.3 Hz), 129.9 (d, J=8.4 Hz), 134.2 (d, J=2.0 Hz), 136.6, 139.8, 171.7, 200.6; 19F NMR (565 MHz, CDCl3) δ: -113.27 (d, J=3.8 Hz); HRMS (ESI) calcd for C32H32F2NO3S [M＋H]＋ 548.2065, found 548.2064. The product was analyzed by HPLC to determine the enantiomeric excess: 81% ee (Chiralpak AD-H, hexane/i-propanol, V:V=90:10, flow rate 1.0 mL/min, λ=254 nm); tR=9.760 and 12.510 min.
tert-Butyl (3R,4R)-9-((Z)-3-methylbenzylidene)-10-oxo-1-phenyl-4-(m-tolyl)-7-thia-2-azaspiro[4.5]decane-3-car-boxylate (3jb): Yellow oil, >99% yield. [α]33 D＋111 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.27 (s, 9H), 2.32 (s, 3H), 2.35 (s, 3H), 2.86 (s, 2H), 3.36 (dd, J=14.7, 0.8 Hz, 1H), 3.54 (d, J=14.7 Hz, 1H), 4.19 (d, J=11.1 Hz, 1H), 4.55 (d, J=11.1 Hz, 1H), 4.91 (s, 1H), 6.11 (s, 1H), 6.74 (d, J=5.1 Hz, 2H), 7.09 (t, J=6.9 Hz, 3H), 7.16 (d, J=4.5 Hz, 2H), 7.20~7.18 (m, 1H), 7.33 (d, J=6.6 Hz, 3H), 7.49 (d, J=5.9 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ: 21.4, 21.5, 27.8, 29.7, 36.6, 56.7, 63.3, 67.1, 73.4, 81.6, 126.6, 126.8, 127.8, 127.8, 128.0, 128.2, 129.0, 129.2, 130.2, 130.5, 135.0, 135.6, 135.9, 136.4, 137.6, 137.9, 140.0, 172.2, 200.9; HRMS (ESI) calcd for C34H38NO3S [M＋H]＋ 540.2567, found 540.2563. The product was analyzed by HPLC to determine the enantiomeric excess: 81% ee (Chiralpak AD-H, hexane/i-propanol, V:V=98:2, flow rate 1.0 mL/min, λ=254 nm); tR=24.292 and 30.261 min.
tert-Butyl (3R,4R)-9-((Z)-3-methoxybenzylidene)-4-(3-methoxyphenyl)-10-oxo-1-phenyl-7-thia-2-azaspiro[4.5]decane-3-carboxylate (3kb): Yellow oil, 80% yield. [α]34 D＋113 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.30 (s, 9H), 2.84 (s, 2H), 3.35 (d, J=14.5 Hz, 1H), 3.54 (d, J=14.8 Hz, 1H), 3.78 (s, 3H), 3.81 (s, 3H), 4.17 (d, J=11.0 Hz, 1H), 4.57 (d, J=11.1 Hz, 1H), 4.89 (s, 1H), 6.08 (s, 1H), 6.43 (s, 1H), 6.53 (d, J=7.6 Hz, 1H), 6.81 (d, J=8.4 Hz, 2H), 6.94~6.89 (m, 2H), 7.23~7.18 (m, 2H), 7.33 (q, J=5.9 Hz, 3H), 7.48 (d, J=6.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.7, 36.6, 55.2, 55.2, 56.6, 63.3, 67.2, 73.4, 81.7, 112.5, 113.9, 114.9, 115.6, 121.7, 122.0, 127.8, 128.2, 129.0, 129.3, 135.6, 135.9, 136.3, 138.1, 139.9, 159.3, 159.4, 172.1, 200.9; HRMS (ESI) calcd for C34H38NO5S [M＋H]＋ 572.2465, found 572.2464. The product was analyzed by HPLC to determine the enantiomeric excess: 83% ee (Chiralpak AD-H, hexane/i-propanol, V:V=90:10, flow rate 1.0 mL/min, λ=254 nm); tR=15.666 and 21.628 min.
tert-Butyl (3R,4R)-9-((Z)-2-fluorobenzylidene)-4-(2-fluorophenyl)-10-oxo-1-phenyl-7-thia-2-azaspiro[4.5]de-cane-3-carboxylate (3lb): Yellow oil, 96% yield. [α]33 D ＋121 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.26 (s, 9H), 2.96 (d, J=13.8 Hz, 1H), 3.12 (t, J=11.8 Hz, 1H), 3.31 (q, J=15.1 Hz, 2H), 4.42 (d, J=10.9 Hz, 1H), 4.58 (d, J=10.9 Hz, 1H), 4.85 (s, 1H), 6.26 (s, 1H), 6.85 (t, J=6.9 Hz, 1H), 7.14~6.97 (m, 5H), 7.31 (dt, J=15.1, 6.3 Hz, 5H), 7.47 (d, J=6.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ: 27.7, 30.2, 36.0 (d, J=4.1 Hz), 54.4, 62.5 (d, J=6.5 Hz), 67.4, 73.8, 81.6, 115.7, 115.8, 116.0, 116.1, 123.8 (d, J=3.5 Hz), 124.2 (d, J=3.4 Hz), 127.9, 128.2, 128.9, 129.0 (d, J=1.7 Hz), 129.1, 129.2, 130.4, 130.5, 130.7 (d, J=3.0 Hz), 132.9 (d, J=5.3 Hz), 137.2, 139.1, 171.9, 200.2; 19F NMR (565 MHz, CDCl3) δ: -111.18; HRMS (ESI) calcd for C32H32F2NO3S [M＋H]＋ 548.2065, found 548.2068. The product was analyzed by HPLC to determine the enantiomeric excess: 83% ee (Chiralpak AD-H, hexane/i- propanol, V:V=90:10, flow rate 1.0 mL/min, λ=254 nm); tR=11.928 and 14.287 min.
tert-Butyl (3R,4R)-9-((Z)-2-methylbenzylidene)-10-oxo-1-phenyl-4-(o-tolyl)-7-thia-2-azaspiro[4.5]decane-3-carbo- xylate (3mb): Yellow oil,>99% yield. [α]30 D＋87 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.35 (s, 9H), 2.01 (s, 3H), 2.43 (s, 3H), 2.86 (d, J=14.2 Hz, 1H), 2.97 (d, J=15.1 Hz, 1H), 3.24 (t, J=10.5 Hz, 2H), 4.13 (d, J=8.7 Hz, 1H), 4.63 (s, 1H), 4.68 (d, J=8.7 Hz, 1H), 6.74 (d, J=7.4 Hz, 1H), 6.90 (s, 1H), 7.10 (ddd, J=8.6, 5.9, 1.5 Hz, 3H), 7.19 (d, J=4.0 Hz, 2H), 7.28~7.23 (m, 3H), 7.31 (s, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.47~7.44 (m, 2H); 13C NMR (75 MHz, CDCl3) δ: 19.9, 20.8, 27.9, 30.1, 36.0, 54.3, 65.7, 67.1, 75.4, 81.4, 125.4, 125.8, 127.0, 128.0, 128.2, 128.5, 128.6, 128.9, 129.0, 130.1, 130.9, 134.2, 134.9, 136.0, 137.0, 137.5, 138.1, 138.1, 172.0, 201.1; HRMS (ESI) calcd for C34H38NO3S [M＋H]＋ 540.2567, found 540.2568. The product was analyzed by HPLC to determine the enantiomeric excess: 91% ee (Chiralpak AD-H, hexane/i-propanol, V:V=98:2, flow rate 1.0 mL/min, λ=254 nm); tR=24.423 and 30.805 min.
tert-Butyl (1R,3R,4S,5S)-9-((Z)-2-chloro-6-fluoroben-zylidene)-4-(2-chloro-6-fluorophenyl)-10-oxo-1-phenyl-7- thia-2-azaspiro[4.5]decane-3-carboxylate (3nb): Yellow oil, 74% yield. [α]29 D＋193 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.39 (s, 9H), 2.81 (d, J=14.6 Hz, 1H), 3.10 (s, 2H), 3.15 (d, J=14.7 Hz, 1H), 3.59 (s, 1H), 4.38 (d, J=8.4 Hz, 1H), 4.46 (s, 1H), 4.77 (d, J=8.6 Hz, 1H), 6.73 (s, 1H), 6.94~6.88 (m, 1H), 7.10 (dd, J=9.3, 3.5 Hz, 1H), 7.15 (d, J=4.7 Hz, 1H), 7.19 (dd, J=8.2, 2.5 Hz, 1H), 7.30 (qd, J=10.8, 7.5 Hz, 7H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 30.1 (d, J=5.9 Hz), 33.6 (d, J=4.1 Hz), 54.9 (d, J=3.8 Hz), 64.2 (d, J=8.9 Hz), 65.8, 74.8 (d, J=4.2 Hz), 81.6, 114.0, 114.3, 125.3 (d, J=3.4 Hz), 127.5, 128.1, 128.3, 128.5, 129.2, 129.4, 130.1, 130.3, 135.0 (d, J=4.7 Hz), 136.1, 138.1, 171.0, 202.2; HRMS (ESI) calcd for C32H30- Cl2F2NO3S [M＋H]＋ 616.1286, found 616.1289. The product was analyzed by HPLC to determine the enantiomeric excess: 86% ee (Chiralpak AD-H, hexane/i-propanol, V:V=80:20, flow rate 1.0 mL/min, λ=254 nm); tR=7.103 and 15.204 min.
tert-Butyl (3R,4R,Z)-4-(naphthalen-1-yl)-9-(naphthalen-1-ylmethylene)-10-oxo-1-phenyl-7-thia-2-azaspiro[4.5]- decane-3-carboxylate (3ob): Yellow oil, 83% yield. [α]33 D＋65 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.10 (s, 9H), 2.88 (d, J=14.1 Hz, 1H), 3.03 (d, J=14.1 Hz, 1H), 3.16 (s, 2H), 4.32 (d, J=9.8 Hz, 1H), 4.85 (s, 1H), 5.46 (d, J=9.9 Hz, 1H), 6.92 (d, J=7.1 Hz, 1H), 7.21 (d, J=9.3 Hz, 2H), 7.65~7.37 (m, 12H), 7.82 (ddd, J=22.8, 14.3, 8.0 Hz, 4H), 8.46 (d, J=8.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ: 27.6, 30.1, 37.5, 53.0, 66.1, 66.6, 76.1, 81.5, 124.6, 124.8, 124.9, 125.1, 125.7, 126.2, 126.2, 126.5, 126.6, 128.0, 128.3, 128.4, 128.7, 128.9, 129.4, 131.4, 132.3, 133.1, 133.3, 134.1, 135.2, 136.4, 139.0, 171.7, 200.6; HRMS (ESI) calcd for C40H38NO3S [M＋H]＋: 612.2567, found 612.2563. The product was analyzed by HPLC to determine the enantiomeric excess: 87% ee (Chiralpak AD-H, hexane/i-propanol, V:V=95:5, flow rate 1.0 mL/min, λ=254 nm); tR=20.752 and 27.335 min.
tert-Butyl (3R,4R,Z)-10-oxo-1-phenyl-4-(thiophen-2-yl)-9-(thiophen-2-ylmethylene)-7-thia-2-azaspiro[4.5]decane- 3-carboxylate (3pb): Yellow oil, >99% yield. [α]28 D＋50 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.38 (s, 9H), 2.84 (dd, J=14.1, 1.6 Hz, 1H), 2.95 (d, J=14.1 Hz, 1H), 3.53 (dd, J=15.4, 1.1 Hz, 1H), 3.75 (d, J=15.4 Hz, 1H), 4.12 (d, J=10.5 Hz, 1H), 4.81 (d, J=10.6 Hz, 1H), 4.93 (s, 1H), 6.58 (s, 1H), 7.06~6.97 (m, 4H), 7.25 (ddd, J=11.9, 7.0, 1.7 Hz, 4H), 7.44~7.41 (m, 3H); 13C NMR (75 MHz, CDCl3) δ: 27.9, 29.6, 35.0, 52.0, 65.0, 66.4, 72.1, 82.0, 124.6, 126.6, 126.8, 127.6, 127.9, 128.1, 128.3, 129.3, 129.6, 131.6, 132.6, 137.9, 139.2, 139.7, 171.9, 199.4; HRMS (ESI) calcd for C28H30NO3S3 [M＋H]＋ 524.1382, found 524.1383. The product was analyzed by HPLC to determine the enantiomeric excess: 87% ee (Chiralpak AD-H, hexane/i-propanol, V:V=80:20, flow rate 1.0 mL/min, λ=254 nm); tR=12.223 and 13.961 min.
tert-Butyl (1R,3R,4R,5S)-9-((Z)-benzylidene)-1-(4-fluo-rophenyl)-10-oxo-4-phenyl-7-thia-2-azaspiro[4.5]decane- 3-carboxylate (3ac): Yellow oil, 92% yield. [α]27 D＋56 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.25 (s, 9H), 2.85 (s, 2H), 3.38 (dd, J=14.7, 1.5 Hz, 1H), 3.55 (d, J=14.8 Hz, 1H), 4.20 (d, J=11.3 Hz, 1H), 4.59 (d, J=11.3 Hz, 1H), 4.94 (s, 1H), 6.23 (s, 1H), 6.97~6.95 (m, 2H), 7.02 (t, J=8.6 Hz, 2H), 7.32 (d, J=4.3 Hz, 8H), 7.48 (dd, J=8.5, 5.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.6, 36.6, 56.4, 62.9, 67.0, 72.5, 81.8, 114.8, 115.1, 127.2, 128.2, 128.4, 128.6, 129.4, 129.7, 130.7, 130.8, 134.8, 135.5, 136.0, 136.0, 136.2, 172.1, 200.5; 19F NMR (565 MHz, CDCl3) δ: -102.31~-102.61 (m); HRMS (ESI) calcd for C32H33FNO3S [M＋H]＋ 530.2160, found 530.2161. The product was analyzed by HPLC to determine the enantiomeric excess: 88% ee (Chiralpak AD-H, hexane/i-propanol, V:V=90:10, flow rate 1.0 mL/min, λ=254 nm); tR=9.054 and 13.313 min.
tert-Butyl (1R,3R,4R,5S)-9-((Z)-benzylidene)-1-(4-chlo-rophenyl)-10-oxo-4-phenyl-7-thia-2-azaspiro[4.5]decane- 3-carboxylate (3ad): Yellow oi, >99% yield. [α]32 D＋128 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.25 (s, 9H), 2.84 (s, 2H), 3.39 (dd, J=14.7, 1.6 Hz, 1H), 3.56 (d, J=14.8 Hz, 1H), 4.19 (d, J=11.3 Hz, 1H), 4.59 (d, J=11.3 Hz, 1H), 4.91 (s, 1H), 6.21 (s, 1H), 6.97 (d, J=6.5 Hz, 2H), 7.37~7.29 (m, 10H), 7.45 (d, J=8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.7, 36.7, 56.3, 62.9, 67.1, 72.6, 81.8, 127.2, 128.2, 128.2, 128.4, 128.7, 129.5, 129.7, 130.56, 133.5, 134.7, 135.4, 136.1, 136.2, 138.7, 172.0, 200.4; HRMS (ESI) calcd for C32H33ClNO3S [M＋H]＋ 546.1864, found 546.1865. The product was analyzed by HPLC to determine the enantiomeric excess: 87% ee (Chiralpak AD-H, hexane/i-propanol, V:V=90:10, flow rate 1.0 mL/min, λ=254 nm); tR=9.519 and 12.453 min.
tert-Butyl (1R,3R,4R,5S)-9-((Z)-benzylidene)-1-(4-bro-mophenyl)-10-oxo-4-phenyl-7-thia-2-azaspiro[4.5]decane- 3-carboxylate (3ae): Yellow oil, >99% yield. [α]33 D＋117 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.25 (s, 9H), 2.83 (s, 2H), 3.39 (dd, J=14.7, 1.1 Hz, 1H), 3.56 (d, J=14.8 Hz, 1H), 4.19 (d, J=11.3 Hz, 1H), 4.59 (d, J=11.3 Hz, 1H), 4.89 (s, 1H), 6.20 (s, 1H), 6.97 (d, J=6.8 Hz, 2H), 7.34~7.24 (m, 8H), 7.37 (s, 1H), 7.40 (s, 1H), 7.46 (d, J=8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.7, 36.7, 56.3, 62.9, 67.0, 72.7, 81.8, 121.8, 127.2, 128.2, 128.4, 128.7, 129.6, 129.7, 130.8, 131.2, 134.7, 135.4, 136.1, 136.3, 139.3, 172.0, 200.4; HRMS (ESI) calcd for C32H33- BrNO3S [M＋H]＋ 590.1359, found 590.1361. The product was analyzed by HPLC to determine the enantiomeric excess: 86% ee (Chiralpak AD-H, hexane/i-propanol, V:V=90:10, flow rate 1.0 mL/min, λ=254 nm); tR=9.973 and 15.224 min.
tert-Butyl (1R,3R,4S,5S)-9-((Z)-benzylidene)-10-oxo-4-phenyl-1-(m-tolyl)-7-thia-2-azaspiro[4.5]decane-3-carbo-xylate (3af): Yellow oil, 95% yield. [α]27 D＋56 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.26 (s, 9H), 2.33 (s, 3H), 2.85 (d, J=5.2 Hz, 2H), 3.35 (d, J=14.6 Hz, 1H), 3.54 (d, J=14.7 Hz, 1H), 4.19 (d, J=11.2 Hz, 1H), 4.57 (d, J=11.2 Hz, 1H), 4.87 (s, 1H), 6.14 (s, 1H), 6.93 (d, J=6.5 Hz, 2H), 7.11 (d, J=7.2 Hz, 1H), 7.34~7.23 (m, 11H); 13C NMR (75 MHz, CDCl3) δ: 21.5, 27.8, 29.7, 36.6, 56.8, 63.2, 67.3, 73.4, 81.7, 126.0, 127.1, 128.1, 128.2, 128.3, 128.4, 128.6, 129.5, 129.7, 129.8, 135.0, 135.6, 135.8, 136.6, 137.7, 139.8, 172.1, 200.9; HRMS (ESI) calcd for C33H36- NO3S [M＋H]＋ 526.2410, found 526.2413. The product was analyzed by HPLC to determine the enantiomeric excess: 79% ee (Chiralpak IA-H, hexane/i-propanol, V:V=95:5, flow rate 1.0 mL/min, λ=254 nm); tR=13.863 and 16.656 min.
tert-Butyl (1R,3R,4R,5S)-9-((Z)-benzylidene)-1-(3-chlo-rophenyl)-10-oxo-4-phenyl-7-thia-2-azaspiro[4.5]decane- 3-carboxylate (3ag): Yellow oil, >99% yield. [α]30 D＋89 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.26 (s, 9H), 2.88 (s, 2H), 3.37 (dd, J=14.7, 0.9 Hz, 1H), 3.59 (d, J=14.7 Hz, 1H), 4.23 (d, J=11.2 Hz, 1H), 4.58 (d, J=11.3 Hz, 1H), 4.93 (s, 1H), 6.32 (s, 1H), 7.02 (d, J=6.6 Hz, 2H), 7.31 (t, J=6.0 Hz, 10H), 7.46 (d, J=4.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.9, 36.4, 55.9, 63.0, 67.2, 72.3, 81.8, 126.9, 127.2, 127.9, 128.2, 128.4, 128.6, 129.2, 129.6, 129.6, 129.8, 133.8, 134.7, 135.6, 136.1, 136.5, 142.7, 172.2, 200.1; HRMS (ESI) calcd for C32H33ClNO3S [M＋H]＋ 546.1864, found 546.1867. The product was analyzed by HPLC to determine the enantiomeric excess: 75% ee (Chiralpak AD-H, hexane/i-propanol, V:V=98:2, flow rate 1.0 mL/min, λ=254 nm); tR=18.867 and 21.380 min.
tert-Butyl (1R,3R,4R,5S)-9-((Z)-benzylidene)-1-(3-nitro phenyl)-10-oxo-4-phenyl-7-thia-2-azaspiro[4.5]decane- 3-carboxylate (3ah): Yellow oil, >99% yield. [α]29 D＋53 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.28 (s, 9H), 2.93 (s, 2H), 3.40 (dd, J=14.8, 1.6 Hz, 1H), 3.62 (d, J=14.9 Hz, 1H), 4.30 (d, J=11.4 Hz, 1H), 4.62 (d, J=11.4 Hz, 1H), 5.12 (s, 1H), 6.33 (s, 1H), 6.96~6.93 (m, 2H), 7.35 - 7.30 (m, 8H), 7.55 (t, J=8.0 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H), 8.16 (dd, J=8.1, 1.3 Hz, 1H), 8.37 (s, 1H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.8, 36.3, 55.2, 62.7, 67.1, 71.5, 81.9, 122.6, 124.0, 127.4, 128.3, 128.5, 128.9, 129.1, 129.4, 129.8, 130.2, 134.4, 134.8, 135.3, 137.0, 143.4, 147.7, 172.1, 199.4; HRMS (ESI) calcd for C32H33N2O5S [M＋H]＋ 557.2105, found 557.2106. The product was analyzed by HPLC to determine the enantiomeric excess: 85% ee (Chiralpak OD-H, hexane/i-propanol, V:V=95:5, flow rate 1.0 mL/min, λ=254 nm); tR=29.688 and 32.280 min.
tert-Butyl (1R,3R,4R,5S)-9-((Z)-benzylidene)-10-oxo-4-phenyl-1-(3-(trifluoromethyl)phenyl)-7-thia-2-azaspiro-[4.5]decane-3-carboxylate (3ai): Yellow oil, >99% yield. [α]34 D＋119 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.27 (s, 9H), 2.89 (s, 2H), 3.38 (dd, J=14.8, 1.3 Hz, 1H), 3.57 (d, J=14.8 Hz, 1H), 4.25 (d, J=11.2 Hz, 1H), 4.63 (d, J=11.3 Hz, 1H), 5.00 (s, 1H), 6.31 (s, 1H), 6.95~6.93 (m, 2H), 7.31 (t, J=6.1 Hz, 8H), 7.49 (t, J=7.6 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.80~7.73 (m, 2H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.8, 36.6, 56.0, 62.9, 67.0, 72.6, 81.8, 124.5 (dd, J=7.1, 3.5 Hz), 125.8 (dd, J=7.6, 3.7 Hz), 127.3, 128.2, 128.4, 128.7, 128.7, 129.5, 129.7, 132.2 (d, J=0.9 Hz), 134.6, 135.2, 136.1, 136.7, 141.7, 172.0, 199.8; 19F NMR (565 MHz, CDCl3) δ: -63.26 (q, J=9.6, 8.5 Hz); HRMS (ESI) calcd for C33H33F3NO3S [M＋H]＋ 580.2128, found 580.2130. The product was analyzed by HPLC to determine the enantiomeric excess: 84% ee (Chiralpak AD-H, hexane/i-propanol, V:V=95:5, flow rate 1.0 mL/min, λ=254 nm); tR=16.302 and 17.259 min.
tert-Butyl (1R,3R,4R,5S)-9-((Z)-benzylidene)-10-oxo-4-phenyl-1-(3,4,5-trimethoxyphenyl)-7-thia-2-azaspiro[4.5] decane-3-carboxylate (3aj): Yellow oil, 91% yield. [α]32 D＋101 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.24 (s, 9H), 2.86 (s, 2H), 3.38 (d, J=14.6 Hz, 1H), 3.58 (d, J=14.7 Hz, 1H), 3.83 (s, 9H), 4.20 (d, J=11.1 Hz, 1H), 4.59 (d, J=11.2 Hz, 1H), 4.88 (s, 1H), 6.37 (s, 1H), 6.75 (d, J=6.6 Hz, 2H), 7.01 (d, J=7.0 Hz, 2H), 7.27 (d, J=5.0 Hz, 3H), 7.32 (d, J=4.0 Hz, 5H); 13C NMR (75 MHz, CDCl3) δ: 27.7, 29.8, 36.6, 56.2, 60.8, 63.0, 67.1, 73.4, 81.6, 105.9, 127.2, 128.1, 128.4, 128.6, 129.5, 129.8, 134.7, 135.5, 135.8, 135.9, 136.3, 137.3, 152.8, 172.3, 200.1; HRMS (ESI) calcd for C35H40NO6S [M＋H]＋ 602.2571, found 602.2575. The product was analyzed by HPLC to determine the enantiomeric excess: 77% ee (Chiralpak AD-H, hexane/i-propanol, V:V=90:10, flow rate 1.0 mL/min, λ=254 nm); tR=14.825 and 20.612 min.
tert-Butyl (1S,3R,4R,5S)-9-((Z)-benzylidene)-10-oxo-4-phenyl-1-(thiophen-2-yl)-7-thia-2-azaspiro[4.5]decane-3-carboxylate (3ak): Yellow oil, 99% yield. [α]31 D＋47 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.28 (s, 9H), 2.84 (dd, J=23.1, 7.8 Hz, 2H), 3.44 (d, J=13.7 Hz, 1H), 3.62 (d, J=14.7 Hz, 1H), 4.17 (d, J=10.7 Hz, 1H), 4.58 (d, J=10.6 Hz, 1H), 5.17 (s, 1H), 6.57 (s, 1H), 7.00 (dd, J=4.7, 3.9 Hz, 1H), 7.07 (d, J=6.5 Hz, 2H), 7.11 (d, J=3.1 Hz, 1H), 7.33~7.24 (m, 9H); 13C NMR (75 MHz, CDCl3) δ: 27.8, 29.6, 35.6, 56.1, 63.3, 66.4, 68.1, 81.7, 125.1, 126.5, 126.7, 127.2, 128.2, 128.4, 128.5, 129.6, 129.8, 135.0, 135.2, 136.2, 136.6, 143.4, 171.7, 200.3; HRMS (ESI) calcd for C30H32NO3S2 [M＋H]＋ 518.1818, found 518.1821. The product was analyzed by HPLC to determine the enantiomeric excess: 70% ee (Chiralpak AD-H, hexane/i-propanol, V:V=95:5, flow rate 1.0 mL/min, λ=254 nm); tR=20.897 and 23.626 min.
tert-Butyl (1R,3R,4R,5S)-1-(4-fluorophenyl)-9-((Z)-2-methylbenzylidene)-10-oxo-4-(o-tolyl)-7-thia-2-azaspiro-[4.5]decane-3-carboxylate (3al): Yellow oil, >99% yield. [α]31 D＋98 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 1.33 (s, 9H), 2.03 (s, 3H), 2.41 (s, 3H), 2.93~2.90 (m, 2H), 3.26 (t, J=6.6 Hz, 2H), 4.11 (d, J=9.0 Hz, 1H), 4.65 (s, 1H), 4.69 (d, J=9.1 Hz, 1H), 6.79 (d, J=7.4 Hz, 1H), 6.93 (s, 1H), 7.00 (t, J=8.6 Hz, 2H), 7.19~7.08 (m, 6H), 7.36 (d, J=7.5 Hz, 1H), 7.48~7.44 (m, 2H); 13C NMR (75 MHz, CDCl3) δ: 19.8, 20.8, 27.8, 30.1, 36.5, 54.1, 65.4, 66.7, 74.8, 81.5, 114.9, 115.2, 125.5, 125.7, 127.1, 128.6, 128.7, 129.1, 130.2, 130.7, 130.8, 130.9, 134.0, 134.4 (d, J=3.0 Hz), 134.7, 136.3, 136.5, 137.6, 138.0, 172.0, 200.8; 19F NMR (565 MHz, CDCl3) δ: -102.46; HRMS (ESI) calcd for C34H37FNO3S [M＋H]＋ 558.2473, found 558.2477. The product was analyzed by HPLC to determine the enantiomeric excess: 90% ee (Chiralpak AD-H, hexane/i-propanol, V:V=80:20, flow rate 1.0 mL/min, λ=254 nm); tR=5.500 and 8.443 min.
4.3 Derivatization experimental procedure
Place 3ba (0.15 mmol, 1.0 equiv.) was added into a 25 mL round-bottom flask and dissolved in DMF (4 mL). Subsequently, methyl iodide (CH3I, 0.18 mmol, 1.2 equiv.) and potassium carbonate (K2CO3, 0.15 mmol, 1.0 equiv.) were added to the mixture. The reaction mixture was stirred at room temperature for 6 h (monitored by TLC). Upon completion, the reaction was quenched by adding saturated ammonium chloride solution (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL×3), and the organic layers was combined, dried over anhydrous magnesium sulfate (MgSO4), and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by preparative TLC with a solvent system of petroleum ether/ethyl acetate (V:V=10:1) to afford the desired product.
tert-Butyl (1R,3R,4R,5S)-9-((Z)-benzylidene)-2-methyl-10-oxo-1,4-diphenyl-7-thia-2-azaspiro[4.5]decane-3-car-boxylate (3bc): Yellow oil, 65% yield. 1H NMR (600 MHz, CDCl3) δ: 7.61 (d, J=7.0 Hz, 2H), 7.32~7.21 (m, 11H), 6.90 (d, J=7.5 Hz, 2H), 6.08 (s, 1H), 4.97 (d, J=11.5 Hz, 1H), 4.11 (s, 1H), 3.70 (dd, J=11.6, 2.1 Hz, 1H), 3.50 (d, J=14.7 Hz, 1H), 3.33 (d, J=14.7 Hz, 1H), 2.73 (s, 2H), 2.30 (d, J=2.1 Hz, 3H), 1.28 (d, J=2.1 Hz, 9H); 13C NMR (151 MHz, CDCl3) δ: 200.0, 171.3, 136.0, 135.9, 135.5, 135.1, 130.5, 129.8, 129.6, 128.6, 128.1, 127.4, 127.1, 81.1, 80.3, 69.4, 64.1, 52.7, 39.3, 38.3, 29.8, 27.9. The product was analyzed by HPLC to determine the enantiomeric excess: 90% ee (Chiralpak AD-H, hexane/i-propanol, V:V=95:5, flow rate 1.0 mL/min, λ=254 nm); tR=7.265 and 8.543 min.
Supporting Information 1H NMR, 13C NMR, and HPLC spectra for compounds 3 and X-ray crystal structure of compound 3nb. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.
(Zhao, C.)