HETEROCYCLES

Paper | Special issue | Vol. 88, No. 1, 2014, pp. 475-491
Received, 28th June, 2013, Accepted, 19th July, 2013, Published online, 23rd July, 2013.
DOI: 10.3987/COM-13-S(S)60

■ Enantioselective Synthesis of Spirooxindoles via Direct Catalytic Asymmetric Aldol-Type Reaction of Isothiocyanato Oxindoles

Shota Kato, Motomu Kanai, and Shigeki Matsunaga*

Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Abstract

Direct catalytic asymmetric aldol-type reaction of aldehydes with isothiocyanato oxindoles is described. A dinuclear (S)-Ni2-Schiff base complex (0.1-10 mol %) efficiently catalyzed the addition of isothiocyanato oxindoles to aliphatic aldehydes, giving spirooxindole products in 80-99% ee and 81:19-91:9 dr. A Sr(O-iPr)2/Schiff base complex (10 mol %) was utilized for aryl aldehydes and spirooxindole products were obtained in 33-78% ee and 96:4-98:2 dr.

INTRODUCTION
Spirooxindoles are privileged structural motifs found in many alkaloids and unnatural biologically active compounds.1 Among them, those with a nitrogen atom at the C3’-position of the oxindole core constitute an important class for the design of medicinally important compounds, such as a CRTH2 antagonist with good oral bioavailability,2 a selective inhibitor of Mycobacterium tuberculosis protein tyrosine phosphatase B,3 a potent anti-malaria agent,4 and an inhibitor of the interaction between the tumor suppressor p53 and its negative regulator Hdm2 (Figure 1).5 Inspired by their important biological activities, various synthetic methods for producing chiral spirooxindoles with a nitrogen atom at the C3’-position have actively been investigated.6,7 For rapid access to the spirooxindole core bearing a nitrogen atom at the C3’-position, the use of isothiocyanato oxindoles 1 as donors in the reaction of electrophiles is an attractive strategy.8-12 In 2011, Yuan and coworkers were the first to demonstrate the utility of 1 as donors in the catalytic asymmetric addition to ketones, affording spirooxindoles with vicinal quaternary carbon stereocenters.8 Several groups have performed organocatalytic Michael reaction/cyclization sequences for the construction of spirocyclic oxindole cores.9 We, in collaboration with Shibasaki, also utilized isothiocyanato oxindoles in the reaction of aldimines with Sr(O-iPr)2/Schiff base 2 complexes (Figure 2).10 In this article, we describe the full details of our efforts to further expand the scope of available chiral spirooxindoles via aldol-type addition with aldehydes under metal/Schiff base catalysis.11

RESULTS AND DISCUSSION
Optimization studies using isothiocyanato oxindole 1a and aliphatic aldehyde 3a as model substrates are summarized in Table 1. Because we have previously reported the utility of various group 2 metal/Schiff base 2a complexes as well as dinuclear transition metal/Schiff base 2b complexes for the enantioselective reaction with related oxindoles, isoindolinones, and α,β-unsaturated γ-butyrolactam as donors,13 we screened those metal/Schiff base complexes for the present reaction. Although the Sr(O-iPr)2/Schiff base 2a (and its biphenyldiamine analogue) = 1:1 complex was suitable for the reaction of 1a with aldimine,10 the Sr-2a catalyst resulted in poor enantioselectivity for aldehyde 3a even at low temperature (entry 1, 3% ee). Among other catalysts screened (entries 2-4),13 the Ni2-2b complex14,15 gave promising results and product 4aa was obtained in 88:12 dr and 84% ee (entry 3). After further optimization of the solvent (entries 5-9) and molecular sieves (entries 10-11), the best stereoselectivity was achieved in 1,4-dioxane at ambient temperature in the presence of molecular sieves 3Å, and 4aa was obtained in 91% yield, 89:11 dr, and 91% ee (entry 11).

Although the Ni2-2b complex gave the optimal results for aliphatic aldehyde 3a, the preliminary survey of substrate scope of aldehydes revealed that the Ni2-2b complex was not suitable for aromatic aldehyde 3b (Table 2, entries 1-2), giving product 4ab in poor diastereo- and enantioselectivity. Thus, we re-screened several metal/Schiff base complexes using aromatic aldehyde 3b. As shown in Table 2, entry 3, the Sr-2a catalyst gave better diastereoselectivity at -40 °C in THF, albeit in poor enantioselectivity (98:2 dr, 27% ee). Other group 2 metal, Bu2Mg, also gave ent-4ab in high diastereoselectivity, but enantioselectivity

was worse than that with Sr(O-iPr)2 (entry 3 vs entry 4). The N-protecting groups (1b-1d; entries 5-7) slightly affected enantioselectivity, and N-PMB-oxindole 1d was the best (entry 7, 35% ee). Because the synthetic procedure reported for 1a was not applicable for N-allyl-oxindole 1b, we modified the synthetic procedure as shown in Scheme 1.16 Reduction of intermediate 5b with Zn in AcOH, instead of a Pd/C-catalyzed hydrogenation process used for other derivatives, proceeded smoothly, and 3-amino-oxindole intermediate was isolated as its hydrochloric acid 6b. Other steps in Scheme 1 were performed by following the reported conditions.8 Schiff base ligands affected the stereoselectivity (entries 8-9), and Schiff base 2d bearing additional MeO-units (Figure 2) gave ent-4db in 78% ee and 98:2 dr (entry 9). Further trials to improve enantioselectiviy by changing reaction temperature, solvent, and/or molecular sieves, however, resulted in less satisfactory selectivity (entries 10-16). Thus, conditions in entry 9 were selected as optimal for aromatic aldehydes.

The substrate scope of the reaction under the optimized conditions is summarized in Table 3.17 The results of aliphatic aldehydes under Ni2-2b catalysis are summarized in entries 1-13. α-Branched aliphatic aldehydes 3a and 3c-3e gave spirooxindole products in 83:17-89:11 dr and 80-92% ee (entries 1-4). Linear aliphatic aldehydes 3f-3h showed slightly higher enantioselectivity than the α-branched aldehydes, and products were obtained in 90:10-91:9 dr and 88-99% ee (entries 5-7). Aldehyde 3i, bearing a silyl ether moiety, also gave product 4ai with high enantioselectivity and yield, albeit with only moderate diastereoselectivity (81:19 dr, entry 8). In addition to 1a, oxindole donors with either a Me- (1e) or Cl-substituent (1f) on the aromatic ring were applicable, and products were obtained in 98% ee and 92% ee, respectively (entries 9-10). Good stereoselectivity was also achieved with oxindole donor 1b, bearing a removable N-allyl protecting group (entry 11, 89% ee). Trials to reduce catalyst loading are summarized in entries 12 and 13. The reaction was promoted by 1 mol % of the Ni2-2b catalyst without loss of selectivity, and product 4af was obtained in 90% yield (TON = 90), 89:11 dr, and 99% ee (entry 12).

Good yield and enantioselectivity were obtained with as little as 0.1 mol % catalyst loading (TON = 850, 98% ee), although diastereoselectivity decreased to some extent (71:29 dr, entry 13). With aromatic and heteroaromatic aldehydes 3b and 3j-3n under the (S)-Sr-Schiff base 2d catalysis (entries 14-19), the reversal of absolute chemistry in products was observed in comparison with (S)-Ni2-2b. Although the precise reason is not clear, the difference in the structure and dihedral angle of binaphthyl ring might be attributed to the enantiofacial preference of the each catalyst.18 Although high diastereoselectivity was observed in all cases with aromatic aldehydes, enantioselectivity was significantly affected by a subtle change in the substituent on the aromatic ring, giving products in 33-78% ee (entries 14-19).

The postulated catalytic cycle of the reaction under dinuclear nickel catalysis is shown in Figure 3. Based on previous studies of dinuclear Ni-catalysis,13,14 we speculate that one of the Ni-O bonds in the outer O2O2 cavity works as a Brønsted base to deprotonate 1, generating Ni-enolate in situ. The other Ni in the inner N2O2 cavity functions as a Lewis acid to control the position of aldehyde 3, similar to conventional metal-salen Lewis acid catalysis. The C-C bond-formation, followed by intramolecular addition to isothiocyanate unit and protonation, affords product 4 and regenerates the Ni2-2b catalyst.

In summary, we developed a direct catalytic asymmetric aldol-type reaction of aldehydes with isothiocyanato oxindoles under metal/Schiff base catalysis. A dinuclear Ni2-Schiff base complex efficiently catalyzed the addition of isothiocyanato oxindoles to aliphatic aldehydes, giving spirooxindole products in 80-99% ee and 81:19-91:9 dr. High TON, up to 850, was observed under dinuclear Ni-catalysis. Because the Ni2-Schiff base complex gave poor selectivity with aromatic aldehydes, a Sr(O-iPr)2/Schiff base complex (10 mol %) was alternatively utilized for aryl aldehydes, giving products in 33-78% ee and 96:4-98:2 dr.

EXPERIMENTAL
General: Infrared (IR) spectra were recorded on a JASCO FT/IR 410 Fourier transform infrared spectrophotometer. NMR spectra were recorded on JEOL ECX500 spectrometers, operating at 500 MHz for 1H NMR and 125.65 MHz for 13C NMR. Chemical shifts in CDCl3 were reported in the scale relative to tetramethylsilane (0 ppm) for 1H NMR. For 13C NMR, chemical shifts were reported in the scale relative to CHCl3 (77.0 ppm) as an internal reference. Column chromatography was performed with silica gel Merck 60 (230-400 mesh ASTM). Optical rotations were measured on a JASCO P-1010 polarimeter. ESI mass spectra were measured on Waters micromass ZQ (for LRMS) and ESI mass spectra for HRMS were measured on a JEOL JMS-T100LC AccuTOF spectrometer. The enantiomeric excess (ee) was determined by HPLC analysis. HPLC was performed on JASCO HPLC systems consisting of the following: pump, PU-2080 plus; detector, UV-2075 plus, measured at 254 nm; column, DAICEL CHIRALPAK IA, IB, ID, AY-H, or AD-H; mobile phase, hexane-iPrOH. Sr(O-iPr)2 was purchased from Kojundo Ltd. (Fax: +81-492-84-1351, sales@kojundo.co.jp), and used as received.

General Procedure for Ni2-Schiff Base-catalyzed Addition to Aliphatic Aldehydes:
A test tube flask charged with MS 3Å (60 mg) was well dried under reduced pressure (around 1.0 kPa) using a heat gun. After cooling to room temperature, argon was re-filled, (S)-Ni2-Schiff base 2b (19.1 mg, 0.030 mmol) and oxindole 1 (0.36 mmol, 1.2 equiv), and anhydrous 1,4-dioxane (1.5 mL) were added to the test tube. To a mixture suspension was added aldehyde 3 (0.30 mmol), and the resulting suspension was stirred at room temperature under Ar atmosphere for 12 h. The reaction was quenched by adding a suspension of silica gel in EtOAc. The mixture was filtered through a filter paper, and sufficiently washed with EtOAc. The diastereomeric ratio of the product was determined at this stage by analysis of crude 1H NMR. After evaporation of the solvent, the crude mixture was purified by flash silica gel column chromatography with CH2Cl2/Et2O (10:1 to 2:1, v:v) to afford product 4.

(3R,5'S)-5'-Cyclohexyl-1-methyl-2'-thioxospiro[indoline-3,4'-oxazolidin]-2-one (4aa): a colorless amorphous; IR (KBr) ν 3254, 2928, 2853, 1719, 1613, 1471, 1190 cm-1; 1H NMR (CDCl3, 500 MHz) δ 0.57–0.84 (m, 3 H), 1.00–1.20 (m, 3 H), 1.35–1.44 (m, 1 H), 1.60–1.77 (m, 3 H), 2.12–2.25 (m, 1 H), 3.24 (s, 3 H), 4.72 (d, J = 10.9 Hz, 1 H), 6.90 (d, J = 8.0 Hz, 1 H), 7.15–7.24 (m, 2 H), 7.38–7.50 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 24.6, 24.7, 25.7, 26.7, 27.0, 29.5, 37.7, 68.5, 92.8, 109.1, 123.8, 124.1, 125.5, 131.2, 142.6, 172.1, 189.3; HRMS (ESI): m/z calculated for C17H20N2NaO2S+ [M+Na]+: 339.1128, found: 339.1124; HPLC (chiral column: CHIRALPAK IA; solvent: hexane/EtOH = 12/1; flow rate: 1.0 mL/min; detection: at 254 nm; at rt): tR = 23.2 min (major) and 36.9 min (minor); [α]D23.4 –105 (c 0.76, CHCl3 for >99% ee sample).

(3R,5'S)-5'-Cyclopentyl-1-methyl-2'-thioxospiro[indoline-3,4'-oxazolidin]-2-one (4ac): a colorless amorphous; IR (neat) ν 3245, 2956, 2868, 1730, 1613, 1471, 1184 cm-1; 1H NMR (CDCl3, 500 MHz) δ 0.53–0.81 (m, 2 H), 1.20–1.33 (m, 1 H), 1.39–1.68 (m, 4 H), 1.88–2.09 (m, 2 H), 3.24 (s, 3 H), 4.79 (d, J = 10.9 Hz, 1 H), 6.90 (d, J = 8.0 Hz, 1 H), 7.09 (s, 1 H), 7.16 (dd, J = 7.4, 7.7 Hz, 1 H), 7.37–7.46 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 25.1, 25.2, 26.1, 27.0, 30.9, 39.9, 68.9, 94.1, 109.0, 123.7, 124.6, 125.7, 131.2, 142.8, 172.6, 190.0; HRMS (ESI): m/z calculated for C16H18N2NaO2S+ [M+Na]+: 325.0981, found: 325.0991; HPLC (chiral column: CHIRALPAK IB; solvent: hexane/EtOH = 7/1; flow rate: 1.0 mL/min; detection: at 254 nm; at rt): tR = 10.2 min (minor) and 13.3 min (major); [α]D23.2 –156 (c 0.57, CHCl3 for >99% ee sample).

(3R,5'S)-5'-Isopropyl-1-methyl-2'-thioxospiro[indoline-3,4'-oxazolidin]-2-one (4ad): a colorless amorphous; IR (KBr) ν 3231, 2967, 1728, 1615, 1472, 1187 cm-1; 1H NMR (CDCl3, 500 MHz) δ 0.36 (d, J = 6.3 Hz, 3 H), 1.13 (d, J = 6.9 Hz, 3 H), 1.86–1.96 (m, 1 H), 3.24 (s, 3 H), 4.67 (d, J = 10.9 Hz, 1 H ), 6.91 (d, J = 8.0 Hz, 1 H ), 6.98 (s, 1 H), 7.17 (dd, J = 6.9, 7.4 Hz, 1 H), 7.40 (brd, J = 6.9 Hz, 1 H), 7.44 (ddd, J = 1.2, 7.4, 8.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 16.8, 20.3, 27.5, 29.4, 69.1, 94.9, 109.6, 124.3, 124.7, 126.1, 131.8, 143.3, 172.6, 190.0; HRMS (ESI): m/z calculated for C14H16N2NaO2S+ [M+Na]+: 299.0825, found: 299.0834; HPLC (chiral column: CHIRALPAK IA; solvent: hexane/EtOH = 7/1; flow rate: 1.0 mL/min; detection: at 254 nm; at rt): tR = 16.7 min (major) and 22.1 min (minor); [α]D22.9 –167 (c 0.34, CHCl3 for >99% ee sample).

(3R,5'S)-1-Methyl-5'-(pentan-3-yl)-2'-thioxospiro[indoline-3,4'-oxazolidin]-2-one (4ae): a colorless oil; IR (neat) ν 3254, 2966, 2876, 1731, 1614, 1471, 1188 cm-1; 1H NMR (CDCl3, 500 MHz) δ 0.47 (dd, J = 7.4, 7.4 Hz, 3 H), 0.53–0.64 (m, 1 H), 0.64–0.69 (m, 1 H), 0.86 (dd, J = 6.9, 7.2 Hz, 3 H), 1.52–1.75 (m, 3 H), 3.25 (s, 3 H), 4.91 (d, J = 10.9 Hz, 1 H), 6.91 (d, J = 7.5 Hz, 1 H), 7.00 (brs, 1 H), 7.17 (dd, J = 6.9, 7.2 Hz, 1 H), 7.39–7.45 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 9.3, 9.6, 19.2, 20.9, 27.2, 40.0, 68.9, 91.2, 109.4, 124.0, 126.0, 131.5, 143.0, 172.6, 189.6; HRMS (ESI): m/z calculated for C16H20N2NaO2S+ [M+Na]+: 327.1138, found: 327.1150; HPLC (chiral column: CHIRALPAK IB; solvent: hexane/EtOH = 5/1; flow rate: 1.0 mL/min; detection: at 254 nm; at rt): tR = 6.8 min (minor) and 9.1 min (major); [α]D22.8 –77.4 (c 0.50, CHCl3 for >99% ee sample).

(3R,5'S)-1-Methyl-5'-pentyl-2'-thioxospiro[indoline-3,4'-oxazolidin]-2-one (4af): a colorless oil; IR (neat) ν 3245, 2954, 1730, 1614, 1471, 1185 cm-1; 1H NMR (CDCl3, 500 MHz) δ 0.76 (t, J = 6.9 Hz, 3 H), 1.23–1.31 (m, 6 H), 1.31–1.44 (m, 1 H), 1.62–1.76 (m, 1 H), 3.24 (s, 3 H), 4.98 (dd, J = 7.2, 9.2 Hz, 1 H), 6.90 (d, J = 8.1 Hz, 1 H), 7.16 (dd, J = 7.7, 7.7 Hz, 1 H), 7.32 (brs, 1 H), 7.37 (d, J = 7.5 Hz, 1 H), 7.43 (dd, J = 7.7, 8.1 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 13.7, 22.1, 24.7, 27.0, 30.1, 31.0, 69.2, 89.4, 109.2, 123.7, 124.0, 125.8, 131.2, 142.7, 172.7, 189.7; HRMS (ESI): m/z calculated for C16H20N2NaO2S+ [M+Na]+: 327.1138 found: 327.1154; HPLC (chiral column: CHIRALPAK ID; solvent: hexane/EtOH = 7/1; flow rate: 1.0 mL/min; detection: at 254 nm; at rt): tR = 28.1 min (minor) and 29.4 min (major); [α]D22.8 –102 (c 1.29, CHCl3 for >99% ee sample).

(3R,5'S)-1-Methyl-5'-phenethyl-2'-thioxospiro[indoline-3,4'-oxazolidin]-2-one (4ag): a colorless foam; IR (neat) ν 3252, 2933, 1730, 1614, 1471, 1183 cm-1; 1H NMR (CDCl3, 500 MHz) δ 1.39–1.51 (m, 1 H), 1.97–2.07 (m, 1 H), 2.38–2.47 (m, 1 H), 2.70–2.80 (m, 1 H), 3.23 (s, 3 H), 5.04 (dd, J = 4.6, 9.1 Hz, 1 H), 6.90 (d, J = 7.9 Hz, 1 H), 6.95-6.99 (m, 2 H), 7.12–7.23 (m, 4 H), 7.31 (brs, 1 H), 7.36–7.46 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 27.6, 32.1, 32.9, 69.6, 89.1, 109.8, 124.3, 124.3, 126.3, 128.7, 129.0, 131.8, 140.3, 143.3, 173.1, 190.1; HRMS (ESI): m/z calculated for C19H18N2NaO2S+ [M+Na]+: 361.0981, found: 361.0995; HPLC (chiral column: CHIRALPAK AY-H; solvent: hexane/2-propanol = 7/1; flow rate: 1.0 mL/min; detection: at 254 nm; at rt): tR = 46.3 min (major) and 72.1 min (minor); [α]D23.3 –138 (c 0.84, CHCl3 for >99% ee sample).

(3R,5'S)-1-Methyl-5'-((E)-non-3-en-1-yl)-2'-thioxospiro[indoline-3,4'-oxazolidin]-2-one (4ah): a colorless amorphous; IR (KBr) ν 3250, 2925, 2854, 1732, 1614, 1471, 1186 cm-1; 1H NMR (CDCl3, 500 MHz) δ 0.85 (t, J = 7.2 Hz, 3 H), 1.07–1.31 (m, 7 H), 1.73–1.93 (m, 4 H), 1.97–2.07 (m, 1 H), 3.24 (s, 3 H), 4.97–5.03 (m, 1 H), 5.09–5.20 (m, 1 H), 5.26–5.35 (m, 1 H), 6.91 (d, J = 7.5 Hz, 1 H), 7.17 (dd, J = 6.9, 7.6 Hz, 1 H), 7.28 (brs, 1 H), 7.37 (d, J = 6.9 Hz, 1 H), 7.43 (dd, J = 7.5, 7.6 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 14.0, 22.4, 27.0, 28.1, 28.9, 30.4, 31.3, 32.3, 69.1, 88.7, 109.2, 123.7, 123.9, 125.8, 126.9, 131.2, 132.7, 142.8, 172,6, 189.7; HRMS (ESI): m/z calculated for C20H26N2NaO2S+ [M+Na]+: 381.1607, found: 381.1615; HPLC (chiral column: CHIRALPAK ID; solvent: hexane/EtOH = 7/1; flow rate: 1.0 mL/min; detection: at 254 nm; at rt): tR = 14.6 min (minor) and 15.3 min (major); [α]D23.0 –107 (c 0.88, CHCl3 for >99% ee sample).

(3R,5'S)-5'-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1-methyl-2'-thioxospiro[indoline-3,4'-oxazolidin]- 2-one (4ai): a colorless oil; IR (neat) ν 3247, 2954, 2856, 1732, 1614, 1472, 1185 cm-1; 1H NMR (CDCl3, 500 MHz) δ –0.08 (s, 6 H), 0.77 (s, 9 H), 1.24–1.36 (m, 2 H), 1.55–1.66 (m, 1 H), 1.70–1.78 (m, 1 H), 3.23 (s, 3 H), 3.41–3.54 (m, 2 H), 5.04 (dd, J = 4.6, 7.2 Hz, 1 H), 6.90 (d, J = 8.0 Hz, 1 H), 7.11 (brs, 1 H), 7.16 (dd, J = 7.7, 7.7 Hz, 1 H), 7.37 (d, J = 7.7 Hz, 1 H), 7.42 (dd, J = 7.7, 8.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 18.4, 26.0, 27.2, 27.2, 28.3, 61.9, 69.5, 89.6, 109.4, 123.9, 124.2, 126.0, 131.5, 143.0, 172.9, 190.0; HRMS (ESI): m/z calculated for C20H30N2NaO3SSi+ [M+Na]+: 429.1639, found: 429.1640; HPLC (chiral column: CHIRALPAK IA; solvent: hexane/EtOH = 7/1; flow rate: 1.0 mL/min; detection: at 254 nm; at rt): tR = 13.5 min (major) and 20.5 min (minor); [α]D23.1 –171 (c 0.60, CHCl3 for >99% ee sample).

(3R,5'S)-1,5-Dimethyl-5'-pentyl-2'-thioxospiro[indoline-3,4'-oxazolidin]-2-one (4ef): a colorless oil; IR (neat) ν 2927, 1717, 1622, 1498, 1362 cm-1; 1H NMR (CDCl3, 500 MHz) δ 0.78 (t, J = 7.2 Hz, 3 H), 1.01–1.28 (m, 6 H), 1.32–1.46 (m, 1 H), 1.65–1.78 (m, 1 H), 2.35 (s, 3 H), 3.21 (s, 3 H), 4.95–5.05 (m, 1 H), 6.78 (d, J = 8.1 Hz, 1 H), 6.99 (brs, 1 H), 7.16–7.23 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 14.2, 21.5, 22.7, 25.2, 27.5, 30.5, 31.5, 69.8, 90.0, 109.4, 124.5, 126.9, 132.0, 134.1, 140.8, 172.9, 190.3 HRMS (ESI): m/z calculated for C17H22N2NaO2S+ [M+Na]+: 341.1300, found: 341.1314; HPLC (chiral column: CHIRALPAK IB; solvent: hexane/EtOH = 7/1; flow rate: 1.0 mL/min; detection: at 254 nm; at rt): tR = 14.2 min (minor) and 21.2 min (major); [α]D22.8 –224 (c 0.35, CHCl3 for >99% ee sample).

(3R,5'S)-6-Chloro-1-methyl-5'-pentyl-2'-thioxospiro[indoline-3,4'-oxazolidin]-2-one (4ff): a colorless oil; IR (neat) ν 3254, 2955, 2860, 1733, 1611, 1495, 1185 cm-1; 1H NMR (CDCl3, 500 MHz) δ 0.79 (t, J = 6.9 Hz, 3 H), 1.03–1.26 (m, 6 H), 1.35–1.44 (m, 1 H), 1.60–1.74 (m, 1 H), 3.22 (s, 3 H), 4.97 (dd, J = 5.2, 7.2 Hz, 1 H), 6.91 (d, 1.8 Hz, 1 H), 7.16 (dd, J = 1.8, 8.0 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 13.9, 22.4, 25.0, 27.4, 30.4, 31.3, 69.1, 89.6, 110.3, 122.5, 123.9, 127.0, 137.5, 144.2, 173.0, 189.8; HRMS (ESI): m/z calculated for C16H19ClN2NaO2S+ [M+Na]+: 361.0748, found: 361.0754; HPLC (chiral column: CHIRALPAK IB; solvent: hexane/EtOH = 7/1; flow rate: 1.0 mL/min; detection: at 254 nm; at rt): tR = 17.4 min (minor) and 30.3 min (major); [α]D22.9 –208 (c 0.50, CHCl3 for >99% ee sample).

(3R,5'S)-1-Allyl-5'-pentyl-2'-thioxospiro[indoline-3,4'-oxazolidin]-2-one (4bf): a colorless oil; IR (neat) ν 3252, 2954, 2860, 1730, 1613, 1469, 1180 cm-1; 1H NMR (CDCl3, 500 MHz) δ 0.77 (t, J = 6.9 Hz, 3 H), 1.25–1.30 (m, 6 H), 1.43–1.51 (m, 1 H), 1.67–1.78 (m, 1 H), 4.18–4.48 (m, 2 H), 4.96–5.07 (m, 1 H), 5.18–5.31 (m, 2 H), 5.72–5.86 (m, 1 H), 6.85–6.94 (m, 1 H), 7.02–7.20 (m, 2 H), 7.33–7.43 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 13.9, 22.3, 24.8, 30.3, 31.3,43.3, 69.4, 89.7, 110.3, 118.9, 123.9, 124.2, 126.1, 130.5, 131.4, 142.4, 172.5, 190.0; HRMS (ESI): m/z calculated for C18H22N2NaO2S+ [M+Na]+: 353.1294, found: 353.1311; HPLC (chiral column: CHIRALPAK IB; solvent: hexane/EtOH = 7/1; flow rate: 1.0 mL/min; detection: at 254 nm; at rt): tR = 11.9 min (minor) and 15.6 min (major); [α]D23.8 –184 (c 0.42, CHCl3 for >99% ee sample).

General Procedure for Sr-Schiff Base-catalyzed Addition to Aromatic Aldehydes:
A test tube flask charged with MS 5Å (40 mg) was well dried under reduced pressure (around 1.0 kPa) using a heat gun. After cooling to room temperature, argon was re-filled, (S)-Schiff base 2d (0.030 mmol) and Sr(O-iPr) 2 (4.12 mg, 0.020 mmol) in 0.60 mL THF was added. After stirring for 1 h at room temperature, aldehyde 3 (0.20 mmol) and THF (0.30 mL) was added to the test tube. The mixture was cooled to −40 ºC, and 3-isothiocyanato oxindole 1 (0.22 mmol, 1.1 equiv) in THF (0.30 mL) was added slowly. The resulting mixture was stirred at −40 ºC under Ar atmosphere for 12 h. The reaction was quenched by adding a suspension of silica gel in EtOAc. The mixture was filtered through a filter paper, and sufficiently washed with EtOAc. The diastereomeric ratio of the product was determined at this stage by analysis of crude 1H NMR. After evaporation of the solvent, the crude mixture was purified by flash silica gel column chromatography with EtOAc/hexane (10:1 to 2:1, v:v) to afford product 4.

(3S,5'R)-1-(4-Methoxybenzyl)-5'-phenyl-2'-thioxospiro[indoline-3,4'-oxazolidin]-2-one (ent-4db): a colorless solid; IR (KBr) ν 3349, 1726, 1611, 1511, 1467, 1172 cm-1; 1H NMR (CDCl3, 500 MHz) δ 3.78 (s, 3 H), 4.72 (d, J = 14.9 Hz, 1 H), 4.98 (d, J = 14.9 Hz, 1 H), 6.15 (s, 1 H), 6.68 (brd, J = 7.5 Hz, 1 H), 6.76–6.92 (m, 4 H), 6.96–7.03 (m, 2 H), 7.06–7.18 (m, 4 H), 7.19–7.25 (m, 2 H), 7.56 (brs, 1 H); 13C NMR (CDCl3, 125 MHz) δ 44.0, 55.2, 70.6, 90.0, 109.6, 114.2, 123.1, 123.6, 125.2, 126.1, 126.8, 128.3, 128.9, 129.0, 130.7, 132.1, 141.7, 159.3, 173.0, 189.9; HRMS (ESI): m/z calculated for C24H20N2NaO3S+ [M+Na]+: 439.1087, found: 439.1086; HPLC (chiral column: CHIRALPAK AD-H; solvent: hexane/2-propanol = 4/1; flow rate: 1.0 mL/min; detection: at 254 nm; rt): tR = 18.4 min (minor) and 24.3 min (major); [α]D28.5 +66.6 (c 0.73, CHCl3 for >99% ee sample).

(3S,5'R)-1-(4-Methoxybenzyl)-2'-thioxo-5'-(m-tolyl)spiro[indoline-3,4'-oxazolidin]-2-one (ent-4dj): a colorless solid; IR (KBr) ν 3350, 1728, 1613, 1513, 1468, 1249, 1173 cm-1; 1H NMR (CDCl3, 500 MHz) δ 2.14 (s, 3 H), 3.78 (s, 3 H), 4.68 (d, J = 15.5 Hz, 1 H), 5.03 (d, J = 15.5 Hz, 1 H), 6.13 (s, 1 H), 6.67 (d, J = 7.6 Hz, 1 H), 6.77–6.87 (m, 5 H), 6.89–6.96 (m, 2 H), 6.97–7.01 (m, 1 H), 7.09 (ddd, J = 1.2, 7.6, 7.6 Hz, 1 H), 7.19–7.24 (m, 2 H), 7.47 (brs, 1 H); 13C NMR (CDCl3, 125 MHz) δ 21.7, 44.6, 55.8, 71.1, 90.6, 110.2, 114.8, 122.9, 123.6, 124.3, 126.3, 126.6, 127.4, 128.7, 129.4, 130.2, 131.2, 132.6, 138.7, 142.3, 159.8, 173.5, 190.5; HRMS (ESI): m/z calculated for C25H22N2NaO3S+ [M+Na]+: 453.1243, found: 453.1232; HPLC (chiral column: CHIRALPAK AD-H; solvent: hexane/2-propanol = 4/1; flow rate: 1.0 mL/min; detection: at 254 nm; rt): tR = 15.2 min (minor) and 16.8 min (major); [α]D24.4 +0.10 (c 0.64, CHCl3 for 68% ee sample).

(3S,5'R)-1-(4-Methoxybenzyl)-2'-thioxo-5'-(p-tolyl)spiro[indoline-3,4'-oxazolidin]-2-one (ent-4dk): a colorless solid; IR (KBr) ν 3434, 1725, 1612, 1514, 1468, 1175 cm-1; 1H NMR (CDCl3, 500 MHz) δ 2.02 (s, 3 H), 3.78 (s, 3 H), 4.72 (d, J = 15.5 Hz, 1 H), 4.97 (d, J = 15.5 Hz, 1 H), 6.09 (s, 1 H), 6.66 (d, J = 7.8 Hz, 1 H), 6.78–6.86 (m, 3 H), 6.88–6.95 (m, 5 H), 7.09 (ddd, J = 1.1, 7.8, 7.8 Hz, 1 H), 7.17–7.23 (m, 2 H), 7.71 (brs, 1 H); 13C NMR (CDCl3, 125 MHz) δ 21.3, 44.2, 55.5, 70.8, 90.4, 109.9, 114.4, 123.4, 123.9, 123.9, 125.5, 126.4, 127.0, 129.1, 129.2, 129.2, 130.9, 139.1, 142.0, 159.5, 173.2, 190.2; HRMS (ESI): m/z calculated for C25H22N2NaO3S+ [M+Na]+: 453.1243, found: 453.1234; HPLC (chiral column: CHIRALPAK AD-H; solvent: hexane/2-propanol = 4/1; flow rate: 1.0 mL/min; detection: at 254 nm; rt): tR = 16.8 min (minor) and 20.1 min (major); [α]D23.3 –43.5 (c 1.2, CHCl3 for 45% ee sample).

(3S,5'R)-1-(4-Methoxybenzyl)-5'-(4-methoxyphenyl)-2'-thioxospiro[indoline-3,4'-oxazolidin]-2-one (ent-4dl): a colorless solid; IR (KBr) ν 3353, 1730, 1612, 1513, 1467, 1251, 1172 cm-1; 1H NMR (CDCl3, 500 MHz) δ 3.69 (s, 3 H), 3.77 (s, 3 H), 4.69 (d, J = 15.5 Hz, 1 H), 4.96 (d, J = 15.5 Hz, 1 H), 6.05 (s, 1 H), 6.57–6.65 (m, 3 H), 6.67 (d, J = 7.9 Hz, 1 H), 6.78–6.86 (m, 3 H), 6.88–6.96 (m, 3 H), 7.10 (dd, J = 7.9, 7.9 Hz, 1 H), 7.14–7.21 (m, 2 H), 7.75 (brs, 1 H); 13C NMR (CDCl3, 125 MHz) δ 44.1, 55.3, 55.4, 70.9, 90.4, 109.9, 113.9, 114.4, 123.4, 123.9, 123.9, 124.2, 126.3, 127.0, 127.2, 129.1, 130.1, 141.9, 160.1, 173.2, 190.3; HRMS (ESI): m/z calculated for C25H22N2NaO4S+ [M+Na]+: 469.1192, found: 469.1206; HPLC (chiral column: CHIRALPAK AD-H; solvent: hexane/2-propanol = 4/1; flow rate: 1.0 mL/min; detection: at 254 nm; rt): tR = 24.5 min (minor) and 29.9 min (major); [α]D25.3 +0.74 (c 1.2, CHCl3 for 34% ee sample).

(3S,5'R)-5'-(4-Fluorophenyl)-1-(4-methoxybenzyl)-2'-thioxospiro[indoline-3,4'-oxazolidin]-2-one (ent-4dm): a colorless solid; IR (KBr) ν 3347, 1726, 1612, 1513, 1468, 1249, 1173 cm-1; 1H NMR (CDCl3, 500 MHz) δ 3.79 (s, 3 H), 4.71 (d, J = 14.9 Hz, 1 H), 4.96 (d, J = 14.9 Hz, 1 H), 6.13 (s, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 6.78–6.88 (m, 5 H), 6.89–7.01 (m, 3 H), 7.14 (ddd, J = 1.2, 8.0, 8.0 Hz, 1 H), 7.18–7.25 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 44.9, 55.7, 71.1, 89.9, 110.2, 114.7, 115.9 (d, 2JC-F = 22.8 Hz), 123.8, 124.0, 126.5, 127.3, 127.7 (d, 3JC-F = 8.4 Hz), 128.4 (d, 4JC-F = 3.6 Hz), 129.5, 131.4, 142.2, 159.9, 162.3 (d, 1JC-F = 248 Hz), 173.2, 190.2; HRMS (ESI): m/z calculated for C24H19N2NaO3FS+ [M+Na]+: 457.0993, found: 457. 0982; HPLC (chiral column: CHIRALPAK AD-H; solvent: hexane/2-propanol = 4/1; flow rate: 1.0 mL/min; detection: at 254 nm; rt): tR = 17.8 min (minor) and 20.1 min (major); [α]D27.8 +99.3 (c 0.29, CHCl3 for 60% ee sample).

(3S,5'S)-5'-(Furan-2-yl)-1-(4-methoxybenzyl)-2'-thioxospiro[indoline-3,4'-oxazolidin]-2-one (ent-4dn): a colorless solid; IR (KBr) ν 3244, 1703, 1612, 1514, 1469, 1176 cm-1; 1H NMR (CDCl3, 500 MHz) δ 3.77 (s, 3 H), 4.75 (d, J = 15.5 Hz, 1 H), 4.94 (d, J = 15.5 Hz, 1 H), 6.11 (s, 1 H), 6.22 (dd, J = 1.7, 3.4 Hz, 1 H), 6.34 (d, J = 1.7 Hz, 1 H), 6.70 (brd, J = 7.9 Hz, 1 H), 6.80–6.86 (m, 2 H), 6.94 (dd, J = 7.9, 7.9 Hz, 1 H), 7.11–7.23 (m, 5 H), 7.36 (brs, 1 H); 13C NMR (CDCl3, 125 MHz) δ 44.1, 55.5, 69.6, 84.1, 110.1, 110.7, 111.1, 114.4, 123.3, 123.6, ,126.2 126.8, 128.8, 131.3, 142.4, 143.9, 145.3, 159.5, 172.9, 189.6; HRMS (ESI): m/z calculated for C22H18N2NaO4S+ [M+Na]+: 429.0879, found: 429.0869; HPLC (chiral column: CHIRALPAK AD-H; solvent: hexane/2-propanol = 4/1; flow rate: 1.0 mL/min; detection: at 254 nm; rt): tR = 22.8 min (major) and 26.9 min (minor); [α]D26.5 −15.8 (c 0.86, CHCl3 for 33% ee sample).

ACKNOWLEDGEMENTS
This work was supported in part by ACT-C from JST, Grant-in-aid for Young Scientist (A) from JSPS, the Naito Foundation, and Takeda Science Foundation. We thank Prof. Dr. M. Shibasaki at Institute of Microbial Chemistry for his fruitful discussion and supports on this work.

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