Deprotection of the Methoxymethyl Group on 3-Spiro-2-oxindole under Basic Conditions

Atsuo Nakazaki; Kanako Iwakiri; Tomohiro Hirano; Takahiro Suzuki; Susumu Kobayashi

doi:10.1248/cpb.c13-00068

Abstract

Deprotection of a methoxymethyl (MOM) group on an oxindole nitrogen under basic conditions is demonstrated. The mechanisms of both the deprotection and the formation of N-methyloxindole were revealed by using deuterated NaOMe–MeOH in mechanistic studies.

We previously reported the total synthesis of (−)-flustramine B¹⁾ via a sequential intramolecular Ullmann coupling (IUC) and Claisen rearrangement leading to a spirocyclic oxindole having a quaternary carbon center^2–4) (Chart 1). This approach offers a potentially useful synthetic route to pyrrolidinoindoline alkaloids bearing a prenyl group at the C-3a position.⁵⁾ During the course of studies on the sequential IUC/Claisen rearrangement, deprotection of the methoxymethyl (MOM) group on the nitrogen of oxindole was unexpectedly encountered in the presence of a catalytic amount of CuCl–2-aminopyridine and excess NaOMe–MeOH. Thus, 2-iodoindole 1 was subjected to 0.2 eq of CuCl and 2-aminopyridine and 4 eq of NaOMe–MeOH in triglyme at 100°C, which led to only trace amounts of the expected N-MOM protected spirocyclic oxindole 2, along with the deprotected spirocyclic oxindole 3 in 69% yield (Chart 1). Based on HPLC monitoring of the reaction mixture, N-MOM oxindole 2 was found to be formed first and then consumed under the reaction conditions. Since acidic conditions for the removal of a MOM group are generally used,^6–8) the reaction mechanism of formation of the unprotected oxindole 3 and N-methyloxindole 4 (vide infra) under basic conditions was quite intriguing. Reported herein are the results of mechanistic studies.

Chart 1. Total Synthesis of (−)-Flustramine B via a Sequential IUC/Claisen Rearrangement

In order to clarify the key reagent(s) for the deprotection of the MOM group in 2, the control experiments shown in Table 1 were performed first. Treatment of 2 with 0.2 eq of CuCl and 2-aminopyridine and 4 equiv of NaOMe in triglyme at 100°C led to the deprotected oxindole 3 and N-methyloxindole 4 in 65% and 7% yield, respectively (entry 1). When the loading amount of CuCl and 2-aminopyridine were reduced to 0.1 eq yields increased slightly (entry 2), but the yield of deprotected oxindole 3 dropped to 52% when 2 eq of NaOMe–MeOH were employed (entry 3). Of particular interest is that CuCl and 2-aminopyridine are not required for this deprotection (entry 4).

Table 1. Control Experiments for the Removal of the MOM Group in 2


Entry	Conditions (eq)			Yield (%)
Entry	CuCl	2-(NH₂)py	NaOMe–MeOH	3	4	2
1	0.2	0.2	4	65	7	Trace
2	0.1	0.1	4	79	11	3
3	0.1	0.1	2	52	6	2
4	0	0	4	69	16	8

Focus was next turned to the reaction mechanism for the formation of the N-methyloxindole 4. A series of related reactions was performed using deuterated sodium methoxide/methanol as a base (s Chart 2–4). N-MOM oxindole 2 was subjected to NaOMe–MeOD under the same conditions as entry 4 above, and the corresponding deprotected deuterated product 3a, deuterated N-methyloxindole 4a and deuterated starting material 2a were obtained in 41%, 19%, and 24% yield, respectively (Chart 2). Interestingly, deuterium was incorporated at the C-7 position of all three products, suggesting that C-7 deuteration takes place after a deprotonation process. The related reaction using NaOCD₃–CD₃OD similarly resulted in the formation of oxindole 3a in 54% yield, along with the N-CH₂D oxindole 4b and the N-(CD₃OCH₂) oxindole 2b (Chart 3). These results indicate that the methyl group on 4 is composed of a methylene group from the MOM moiety of 2 and one hydride derived from the NaOCH₃/CH₃OH mixture. To investigate the generality of this C-7 deuteration, the debromooxindole 6 was employed using the same conditions as in Chart 3. The expected deprotection proceeded to form 8 in lower yield (34%), along with 9 (1%), 7a (20%) and unreacted 6 (27%); however, none of the products were deuterated at the C-7 position (Chart 4). It is thus revealed that the C-7 deprotonation process is not necessary for the deprotection of the MOM group. The precise reaction mechanism of the C-7 deuteration of 2 is still unclear at present; however, it might be a simple deprotonation/protonation process due to the electronegative effect of the 6-bromo substituent.

Chart 2

Chart 3

Chart 4

Based on these results, the reaction mechanism shown in Chart 5 is proposed. Deprotection of the MOM group might proceed via nucleophilic substitution of the methoxide intermediate 2′ activated by sodium ion or a methanolic proton⁹⁾ (Chart 5, path a). In path b, in contrast, the carbonyl carbon of 2′ is attacked by methoxide to form a ring-opened intermediate A, at which point a methoxide could eliminate to form the imine intermediate B. The imine moiety can react with a hydride generated from methoxide and formaldehyde formed in-situ, with concomitant lactamization to provide the N-methyloxindole 4. Methoxide could also attack the imine leading to substrate 2 again.

Chart 5. A Proposed Reaction Mechanism

In conclusion, deprotection of a MOM group on the nitrogen of an oxindole under basic conditions was demonstrated. This method could serve as an alternative for MOM-deprotection.

Experimental

All non-aqueous reactions were performed under an atmosphere of dry argon in oven-dried glassware unless otherwise indicated. Solvents were distilled under an atmosphere of argon before use and transferred via an oven-dried syringe or cannula. 1,2-Bis(2-methoxyethoxy)ethane (triglyme) was distilled from LiAlH₄ and dried over MS 4A. Flash column chromatography was performed with silica gel (PSQ-100B, Fuji Silysia Co., Ltd., Japan). Solvents for chromatography are listed as volume–volume ratios. Analytical thin layer chromatography was performed using commercial silica gel plates (E. Merck, Silica Gel 60 F₂₅₄). Infrared spectra were recorded on a Jasco FT-IR410 spectrometer or a PerkinElmer Spectrum 100 FT-IR spectrometer. Absorbance frequencies are recorded in reciprocal centimeters (cm⁻¹). High resolution mass spectra (HR-MS) were obtained from Applied Biosystems mass spectrometer (API QSTAR pulsar i) for electrospray ionization (ESI), or from Hitachi M-80B for electroimpact ionization (EI, 70 eV). HR-MS data are reported as m/z (relative intensity), with accurate mass reported for the molecular ion [M+Na]⁺. Melting points were recorded on Yanaco MP-3S. Specific optical rotations were recorded on a Jasco P-1030 digital polarimeter. ¹H-NMR spectra were acquired at 400 MHz on a JEOL JNM-LD400 spectrometer. Solvent for NMR is used chloroform-d, unless the otherwise noted. Chemical shifts are reported in delta (δ) units in parts per million (ppm) relative to the singlet (7.26 ppm) for chloroform. Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; sept, septet; m, multiplet and br, broad. Coupling constants are recorded in Hertz (Hz). ¹³C-NMR spectra were acquired at 100 MHz on a JEOL JNM-LD400 spectrometer. Chemical shifts are reported in ppm relative to the central line of the triplet at 77.0 ppm for chloroform-d.

N-MOM Oxindole 2

To a solution of NaH (43.8 mg, 1.83 mmol) in tetrahydrofuran (THF) (0.3 mL) and N,N-dimethylformamide (DMF) (0.2 mL) was added oxindole 3¹⁾ (105 mg, 0.359 mmol). The reaction mixture was stirred at 0°C for 15 min. The mixture was added MOMCl (0.06 mL, 0.825 mmol). The reaction mixture was stirred at room temperature (RT) for 24 h. The reaction mixture was cooled to 0°C, quenched with water, and extracted with Et₂O. The combined organic layer was washed with water, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography with hexane–AcOEt (15 : 1 to 3 : 1) to afford N-MOM oxindole 2 (110 mg, 91% yield) as a white solid. mp 103°C; Rf 0.73 (hexane–AcOEt=3 : 1); ¹H-NMR (400 MHz, CDCl₃) δ: 7.21 (d, J=1.8 Hz, 1H), 7.16 (dd, J=7.8, 1.8 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 5.56–5.52 (m, 1H), 5.10 (dd, J=19.7, 10.9 Hz, 2H), 3.31 (s, 3H), 2.64 (ddt, J=17.3, 5.2, 2.5 Hz, 1H), 2.19 (br s, 2H), 2.13–2.05 (m, 1H), 1.95 (dd, J=17.3, 5.2 Hz, 1H), 1.80 (s, 3H), 1.59–1.52 (m, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 181.1, 142.2, 133.7, 132.8, 125.6, 125.2, 121.3, 118.4, 112.8, 71.30, 56.13, 45.95, 32.11, 29.81, 26.47, 23.42; IR (attenuated total reflection (ATR)) ν_max 3067, 2925, 1720, 1603, 1431, 1339, 1076; HR-MS (ESI) Calcd for C₁₆H₁₈NO₂NaBr [M+Na]⁺ 358.0413; Found 358.0404; [α]_D²¹ +109.2 (c=1.00, CHCl₃).

4: mp 103°C; Rf 0.59 (hexane–AcOEt=3 : 1); ¹H-NMR (400 MHz, CDCl₃) δ: 7.12 (dd, J=7.8, 1.7 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 7.00 (d, J=1.7 Hz, 1H), 5.55–5.51 (m, 1H), 3.19 (s, 3H), 2.62 (ddt, J=17.2, 5.2, 2.5 Hz, 1H), 2.18 (br s, 2H), 2.11–2.02 (m, 1H), 1.88 (dd, J=17.2, 5.2 Hz, 1H), 1.79 (s, 3H), 1.53–1.47 (m, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 180.7, 144.2, 133.7, 133.3, 125.1, 124.9, 121.1, 118.6, 111.3, 45.67, 31.93, 29.40, 26.60, 26.35, 23.43; IR (ATR) ν_max 2924, 1711, 1601, 1368, 748, 509; HR-MS (ESI) Calcd for C₁₅H₁₆NO₂NaBr [M+Na]⁺ 328.0307; Found 328.0292; [α]_D²¹ +123.0 (c=1.00, CHCl₃).

Preparation of NaOMe–MeOH Solution

Sliced Na (847 mg) was added to MeOH (9.02 mL) slowly at 0°C. The reaction mixture was warmed to RT and stirred overnight. With the same way, NaOMe–MeOD reagent was preparated from MeOD, NaOCD₃–CD₃OD reagent from CD₃OD. Titration: NaOMe–MeOH reagent (1.0 mL) was added (COOH)₂ (300 mg), and diluted with water. The mixture was titrated with 1.0 m aqueous NaOH.

Deprotection of N-MOM Oxindole 2 Using NaOMe–MeOD (Chart 2)

To a solution of N-MOM oxindole 2 (59.9 mg, 0.178 mmol) in triglyme (3.6 mL) in a two-necked round-bottomed flask was added NaOMe–MeOD solution (3.94 m, 0.18 mL, 0.713 mmol) at RT. The reaction mixture was warmed to 100°C and stirred vigorously for 3.5 h before the reaction was quenched with saturated aqueous NH₄Cl solution and water. The aqueous layer was extracted with hexane–AcOEt (5 : 1), and the combined organic layer was washed with water and brine, dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography with hexane–AcOEt (97 : 3 to 4 : 1) to afford 3a (21.4 mg, 41% yield) and a mixture (26.3 mg) of 4a (19% yield) and 2a (24% yield) as a white solid.

3a: mp 192°C; Rf 0.36 (hexane–AcOEt=3 : 1); ¹H-NMR (400 MHz, CDCl₃) δ: 8.39 (br s, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 5.56–5.53 (m, 1H), 2.62 (ddt, J=17.2, 5.0, 2.4 Hz, 1H), 2.19 (br s, 2H), 2.11–2.03 (m, 1H), 1.96 (dd, J=17.2, 5.0 Hz, 1H), 1.80 (s, 3H), 1.64–1.56 (m, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 182.9, 141.1, 133.7, 128.3, 125.5, 125.1, 121.0, 118.4, 113.0, 46.17, 31.82, 29.46, 26.49, 23.45; IR (ATR) ν_max 2094, 1709, 1599, 1451, 1322, 1228, 805; HR-MS (ESI) Calcd for C₁₄H₁₃²HNONaBr [M+Na]⁺ 315.0213; Found 315.0220; [α]_D²⁰ +126.9 (c=0.73, CHCl₃).

4a: mp 103°C; Rf 0.59 (hexane–AcOEt=3 : 1); ¹H-NMR (400 MHz, CDCl₃) δ: 7.11 (d, J=8.3 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 5.56–5.51 (m, 1H), 3.19 (s, 3H), 2.61 (ddt, J=9.3, 4.9, 2.3 Hz, 1H), 2.18 (br s, 2H), 2.13–2.02 (m, 1H), 1.88 (dd, J=17.1, 4.9 Hz, 1H), 1.80 (s, 3H), 1.59–1.46 (m, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 180.6, 144.1, 133.6, 133.3, 125.0, 124.9, 121.0, 118.6, 111.3, 45.66, 31.92, 29.39, 26.60, 26.35, 23.41; IR (ATR) ν_max 2923, 2853, 1713, 1596, 1465, 1367, 1085; HR-MS (ESI) Calcd for C₁₅H₁₅²HNONaBr [M+Na]⁺ 329.0370; Found 329.0370; [α]_D²¹ +112.0 (c=0.20, CHCl₃).

2a: mp 98°C; Rf 0.63 (hexane–AcOEt=3 : 1); ¹H-NMR (400 MHz, CDCl₃) δ: 7.17 (d, J=8.1 Hz, 1H), 7.05 (d, J=8.1 Hz, 1H), 5.57–5.52 (m, 1H), 5.11 (dd, J=19.5, 10.7 Hz, 2H), 3.31 (s, 3H), 2.65 (ddt, J=17.2, 5.2, 2.5 Hz, 1H), 2.19 (br s, 2H), 2.14–2.06 (m, 1H), 1.95 (dd, J=17.2, 5.2 Hz, 1H), 1.81 (s, 3H), 1.60–1.52 (m, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 181.2, 142.2, 133.8, 132.8, 125.7, 125.3, 121.2, 118.4, 112.8, 71.36, 56.18, 46.01, 32.15, 29.85, 26.51, 23.45; IR (ATR) ν_max 2925, 2853, 1721, 1597, 1464, 1336, 1079; HR-MS (ESI) Calcd for C₁₆H₁₇²HNO₂NaBr [M+Na]⁺ 359.0475; Found 359.0460; [α]_D²¹ +133.1 (c=0.07, CHCl₃).

Deprotection of N-MOM Bromooxindole 2 Using NaOCD₃–CD₃OD (Chart 3)

To a solution of N-MOM oxindole 2 (60.0 mg 0.178 mmol) in triglyme (3.6 mL) in a two-necked round-bottomed flask was added NaOCD₃–CD₃OD solution (3.22 m, 0.22 mL, 0.714 mmol) at RT. The reaction mixture was warmed to 100°C and stirred vigorously for 3.5 h before the reaction was quenched with saturated aqueous NH₄Cl solution and water. The aqueous layer was extracted with hexane–AcOEt (5 : 1), and the combined organic layer was washed with water and brine, dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography with hexane–AcOEt (97 : 3 to 4 : 1) to afford 3a (28.3 mg, 54% yield) and a mixture (17.0 mg) of 4b (18% yield) and 2b (11% yield) as a white solid.

4b: mp 100°C; Rf 0.59 (hexane–AcOEt=3 : 1); ¹H-NMR (400 MHz, CDCl₃) δ: 7.12 (d, J=7.8 Hz, 1H), 7.03 (d, J=7.8 Hz, 1H), 5.55–5.52 (m, 1H), 3.18 (t, J=2.0 Hz, 2H), 2.62 (ddt, J=17.3, 5.3, 2.6 Hz, 1H), 2.17 (br s, 2H), 2.13–2.02 (m, 1H), 1.89 (dd, J=17.3, 5.3 Hz, 1H), 1.80 (s, 3H), 1.54–1.47 (m, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 180.7, 144.2, 133.7, 133.3, 125.1, 124.9, 121.1, 118.6, 111.3, 45.70, 31.96, 29.42, 26.63, 26.49 (t, J=10.8 Hz), 23.45; IR (ATR) ν_max 2923, 1711, 1596, 1466, 1367, 807, 753; HR-MS (ESI) Calcd for C₁₅H₁₄²H₂NONaBr [M+Na]⁺ 330.0433; Found 330.0424; [α]_D²¹ +114.3 (c=0.73, CHCl₃).

2b: mp 89°C; Rf 0.63 (hexane–AcOEt=3 : 1); ¹H-NMR (400 MHz, CDCl₃) δ: 7.16 (d, J=7.8 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 5.56–5.53 (m, 1H), 5.11 (dd, J=19.4, 10.9 Hz, 2H), 2.64 (ddt, J=17.3, 5.2, 2.5 Hz, 1H), 2.19 (br s, 2H), 2.14–2.05 (m, 1H), 1.95 (dd, J=17.3, 5.2 Hz, 1H), 1.80 (s, 3H), 1.59–1.54 (m, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 181.2, 142.2, 133.8, 132.8, 125.7, 125.3, 121.2, 118.4, 112.8, 71.30, 46.01, 32.15, 29.85, 26.51, 23.45 (one peak missing); IR (ATR) ν_max 2924, 1721, 1598, 1464, 1356, 1337, 1112; HR-MS (ESI) Calcd for C₁₆H₁₄²H₄NO₂NaBr [M+Na]⁺ 362.0664; Found 362.0680; [α]_D²¹ +87.17 (c=0.25, CHCl₃).

N-MOM Debromooxindole 6

To a solution of N-MOM oxindole 2 (80.8 mg, 0.240 mmol) in Et₂O (8.0 mL) was added t-BuLi (0.3 mL, 1.76 m in n-pentane 0.528 mmol) at −78°C. The reaction mixture was stirred at −78°C for 30 min before the reaction was quenched with saturated aqueous NH₄Cl solution. The aqueous layer was extracted with CHCl₃, and the combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography with hexane–AcOEt (97 : 3 to 4 : 1) to afford 6 (24.6 mg, 40% yield) as a white solid. mp 57–58°C; Rf 0.64 (hexane–AcOEt=3 : 1);¹H-NMR (400 MHz, CDCl₃) δ: 7.27 (td, J=7.8, 1.2 Hz, 1H), 7.21 (d, J=7.5 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 7.04 (td, J=7.5, 1.2 Hz, 1H), 5.58–5.54 (m, 1H), 5.15 (dd, J=19.3, 10.7 Hz, 2H), 3.32 (s, 3H), 2.66 (ddt, J=17.3, 5.3, 2.6 Hz, 1H), 2.22 (br s, 2H), 2.15–2.07 (m, 1H), 1.99 (dd, J=17.3, 5.3 Hz, 1H), 1.82 (s, 3H), 1.59 (ddt, J=12.9, 5.5, 2.3 Hz, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 181.6, 140.9, 134.0, 133.7, 127.7, 124.0, 122.8, 118.6, 109.3, 71.27, 56.10, 46.12, 32.29, 29.96, 26.60, 23.48; IR (ATR) ν_max 2925, 1720, 1612, 1485, 1467, 1351, 1089; HR-MS (ESI) Calcd for C₁₆H₁₉NO₂Na [M+Na]⁺ 280.1308; Found 280.1297; [α]_D²⁰ +206.2 (c=0.06, CHCl₃).

Deprotection of N-MOM Debromooxindole 6 (Chart 4)

To a solution of N-MOM debromooxindole 6 (23.9 mg 0.0929 mmol) in triglyme (1.9 mL) in a two-necked round-bottomed flask was added NaOCD₃–CD₃OD reagent (3.22 m, 0.22 mL, 0.714 mmol) at RT. The reaction mixture was warmed to 100°C and stirred vigorously for 3.5 h before the reaction was quenched with saturated aqueous NH₄Cl solution and water. The aqueous layer was extracted with hexane–AcOEt (5 : 1), and the combined organic layer was washed with water and brine, dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography with hexane–AcOEt (97 : 3 to 4 : 1) to afford 8 (6.7 mg, 34% yield) and a mixture (11.8 mg) of 9 (1% yield) and 7a (20% yield) and recovered starting material 6 (6.6 mg, 27%) as a white solid.

8: mp 140–144°C; Rf 0.31 (hexane–AcOEt=3 : 1); ¹H-NMR (400 MHz, CDCl₃) δ: 7.84 (br s, 1H), 7.21 (dd, J=7.8, 1.2 Hz, 1H), 7.18 (d, J=7.1 Hz, 1H), 6.98 (dd, J=7.6, 1.0 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 5.56–5.55 (m, 1H), 2.67–2.61 (m, 1H), 2.30–2.16 (m, 2H), 2.08 (ddd, J=12.9, 11.2, 6.1 Hz, 1H), 2.02–1.97 (m, 1H), 1.81 (s, 3H), 1.65–1.58 (m, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 182.8, 139.7, 135.0, 133.7, 127.6, 124.3, 122.3, 118.7, 109.4, 46.3, 32.0, 29.6, 26.6, 23.5; IR (KBr, cm⁻¹) 3436, 3182, 3078, 2922, 1702, 1618, 1468, 746; HR-MS (ESI) Calcd for C₁₄H₁₅NONa [M+Na]⁺ 236.1045, Found 236.1043; [α]_D²⁴ +186.0 (c=0.13, CHCl₃).

9: Rf 0.56 (hexane–AcOEt=3 : 1); ¹H-NMR (400 MHz, CDCl₃) δ: 7.28 (td, J=7.8, 1.1 Hz, 1H), 7.19 (dd, J=7.5, 0.7 Hz, 1H), 7.01 (td, J=7.5, 1.1 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 5.56–5.54 (m, 1H), 3.23 (s, 3H), 2.64 (ddt, J=17.4, 5.7, 2.4 Hz, 1H), 2.21 (br s, 2H), 2.15–2.05 (m, 1H), 1.92 (dd, J=17.4, 5.7 Hz, 1H), 1.81 (s, 3H), 1.58–1.51 (m, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 180.9, 142.8, 134.6, 133.7, 127.6, 123.8, 122.3, 118.8, 107.8, 45.88, 32.11, 29.69, 26.76, 26.29, 23.49; HR-MS (ESI) Calcd for C₁₅H₁₇NONa [M+Na]⁺ 250.1202, Found 250.1199.

7a: Rf 0.64 (hexane–AcOEt=3 : 1); ¹H-NMR (400 MHz, CDCl₃) δ: 7.27 (td, J=7.7, 1.0 Hz, 1H), 7.21 (d, J=7.3 Hz, 1H), 7.06 (d, J=7.7 Hz, 1H), 7.04 (td, J=7.3, 1.0 Hz, 1H), 5.58–5.54 (m, 1H), 5.15 (dd, J=19.3, 10.7 Hz, 2H), 2.66 (ddt, J=17.3, 5.2, 2.6 Hz, 1H), 2.22 (br s, 2H), 2.15–2.07 (m, 1H), 1.99 (dd, J=17.3, 5.2 Hz, 1H), 1.82 (s, 3H), 1.62–1.57 (m, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 180.9, 142.8, 133.73, 133.65, 127.7, 124.0, 122.8, 118.6, 109.3, 46.13, 32.30, 29.97, 26.62, 23.49 (two peaks missing); HR-MS (ESI) Calcd for C₁₆H₁₆²H₃NO₂Na [M+Na]⁺ 283.1496, Found 283.1483.

Acknowledgment

This work was supported by a Grant-in-Aid for Young Scientists (B) (KAKENHI 19790026) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, NOVARTIS Foundation (Japan) for the Promotion of Science, and Chugai Pharmaceutical Co., Ltd. (A.N.).

References

1) Hirano T., Iwakiri K., Miyamoto H., Nakazaki A., Kobayashi S., Heterocycles, 79, 805–820 (2009), and references therein.
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4) Nakazaki A., Kobayashi S., J. Synth. Org. Chem. Jpn., 66, 124–138 (2008).
5) For the synthesis of racemic debromoflustramine B via sequential intramolecular Ullmann coupling and Claisen rearrangement, see: Miyamoto H., Okawa Y., Nakazaki A., Kobayashi S., Tetrahedron Lett., 48, 1805–1808 (2007).
6) Wuts P. G. M., Greene T. W., “Green’s protective groups in organic synthesis,” 4th ed., John Wiley & Sons, New Jersey, 2007.
7) Kocieński P. J., “Protective groups,” 3rd ed., Thieme, Stuttgart, 2005.
8) For removal of MOM group on an oxindole under acidic conditions (trimethylsilyl iodide, then Et₃N), see: Fukuyama T., Liu G., J. Am. Chem. Soc., 118, 7426–7427 (1996).
9) A related deprotection of the MOM group through thermolysis in a protic solvent (120–160°C, ethylene glycol) has been reported, see: Miyake H., Tsumura T., Sasaki M., Tetrahedron Lett., 45, 7213–7215 (2004).

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