HETEROCYCLES

Paper | Special issue | Vol. 88, No. 2, 2014, pp. 1337-1353
Received, 31st July, 2013, Accepted, 25th September, 2013, Published online, 27th September, 2013.
DOI: 10.3987/COM-13-S(S)104

■ Highly Efficient Preparation of Both Enantiomers of Versatile Chiral Synthon for 1,2-Diamines via the Fe(III)-Catalyzed Oxidation of 2-Imidazolone

Hirofumi Matsunaga,* Iori Eshita, Shoichi Tsunoda, Naoko Ishimoto, Shin Ando, and Tadao Ishizuka*

Department of Pharmaceutical Sciences, Graduate School of Life Sciences, Kumamoto University, 5-1 Oe-hon-machi, Kumamoto 862-0973, Japan

Abstract

A new method was established for the preparation of both of the enantiomers of trans-4,5-dimethoxy-2-imidazolidinone (DMIm) via the Fe(III)-catalyzed oxidation of 2-imidazolone by H2O2-urea, which allowed the subsequent achievement of optical resolution via the introduction of a MAC moiety and a 2-mesitylenesulfonyl group at the two nitrogen positions of DMIm, which then were easily removed. The two enantiomers are useful as versatile chiral synthons for 1,2-diamines.

INTRODUCTION
1,2-Diamine is a fundamental component of a substantial number of compounds that are of biological and medicinal importance.1,2 Also, in asymmetric reaction systems 1,2-diamine and its derivatives, imidazoline and Schiff base, function as chiral ligands.3
Until now, there have been a number of methodologies for the synthesis of chiral 1,2-diamines such as derivatization from amino acids,4 substitutional induction of nitrogen nucleophiles to haloalkanes,5 conjugate addition of nitrogen nucleophiles to nitroalkenes and aziridines,6 diamination of 1,2-dilos,7 and the coupling reaction of imines,8 and most of these are primarily for the construction of a specific side chain structure and/or a stereocenter. Therefore, the need remains for a versatile method for the chiral syntheses of various types of C2-symmetric and unsymmetric1,2-diamines.
We previously reported that optically active trans-4,5-dimethoxy-2-imidazolidinone (DMIm), the enantiomers of which were both readily available, functioned as a versatile chiral synthon for the construction of various types of symmetric (R1 = R2) and unsymmetric (R1 ≠ R2) 1,2-diamines, including the stepwise and stereoselective conversion of two aminal moieties to other substituents followed by ring-opening (Scheme 1).9 This methodology has an advantage over other methods, in that various types of symmetric and unsymmetric 1,2-diamines and their enantiomers can be easily prepared. The construction of a chemical library in the field of medicinal research would be easier with this methodology.

Both of the optically pure enantiomers of DMIm were provided from a simple 5-membered heterocycle. 1,3-Diacetyl-2-imidazolone underwent the smooth electrophilic addition of bromine to give trans-1,3-diacetyl-4,5-dibromo-2-imidazolidinone and that was methanolyzed to the corresponding (4RS,5RS)-1-acetyl-DMIm followed by N-acylation with (1S,2R)-2-exo-methoxyapocamphanecarbonyl chloride (MAC-Cl), which proved to be a versatile auxiliary of choice for optical resolution,10 and led to the subsequent optical resolution of both diastereomers.9 However, this synthetic methodology includes some drawbacks: i) bromine is harmful and difficult to handle, and it was needed for the first step; and, ii) the direct optical resolution of the diastereomers of 1-MAC-DMIm was impossible, which necessitated a somewhat lengthy and tedious process that included the replacement of one methoxy moiety with a benzyloxy moiety in the presence of a large amount of benzyl alcohol (that was difficult to remove from the reaction mixture), and the subsequent optical resolution of their diastereomers had to be followed by the re-methoxylation of the benzyloxy moiety. Therefore, the need remains for a more practical and facile method for the preparation of both enantiomers (diastereomers) of DMIm.
Meanwhile, we recently attempted to oxidize the olefinic moiety of a 2-imidazolone heterocycle to obtain its epoxide as a DMIm equivalent and unexpectedly found that the FeCl3-catalyzed oxidation of 2-imidazolone using aqueous hydrogen peroxide (30%) as an oxidant yielded hydroxy/alkoxy-functionalized 2-imidazolidinones in place of its epoxide.11 This accidental result prompted us to conceive of this new strategy for DMIm without the use of bromine. Concurrently, during the course of other research, we also discovered that the racemic DMIm were optically resolved by the introduction of a MAC moiety and a specific arylsulfonyl group at the N-position of DMIm. Herein, we describe an efficient method for the preparation of both enantiomers of DMIm using the Fe(III)-catalyzed oxidation of 2-imidazolone followed by the optical resolution of the N-arylsulfonyl derivatives using MAC acid.

RESULTS AND DISCUSSION
1. Exploration of a simple method for the preparation of racemic DMIm using Fe(III)-catalyzed oxidation:

According to our preliminary results,11 we first examined the efficient functionalization of 2-imidazolone to a DMIm precursor using Fe(III)-catalyzed oxidation (Table 1). Using methanol rather than t-butanol as the solvent, the reaction did not proceed well and gave the corresponding 4-methoxy-5-hydroxy-2-imidazolone 2 in a poor yield (entry 1). We speculated that this was the result of the oxidation of methanol, and chose trimethyl orthoacetate as the next candidate for a methoxy donor. However, the hydrolysis of trimethyl orthoacetate with aqueous hydrogen peroxide solution resulted in methanol, which resulted in lower reactivity (entry 2). Compared with previous trials, the use of a hydrogen peroxide-urea complex, instead of aqueous hydrogen peroxide, induced a higher yield of 4-methoxy derivative 2 (entry 3).
A similar moderate yield of 2 (entry 5) was obtained when we tried a pre-synthesized Fe(III)-dipicolinate complex (FeCl(dipic)(H2O)2) in order to simplify the reaction procedure and maintain uniformity of the catalyst: the combination of FeCl(dipic)(H2O)2, 0.1 equivalent of diisopropylamine, and a hydrogen peroxide-urea complex. Intriguingly, the addition of diisopropylammonium chloride in place of diisopropylamine also activated the reaction to give a higher yield of 2 (entry 6). This reaction system was also greatly affected by the amount of trimethyl orthoacetate. The 30% trimethyl orthoacetate solvent system showed the highest reactivity, and produced an 85% yield of 2 (entry 8).
With 5-hydroxy-4-methoxy-2-imidazolidinone 2 thus obtained, the conversion to (4RS,5RS)-DMIm 4 resulted in a 77% yield that was easily accomplished in two steps: i) diacetylation of 2, and ii) the regioselective cleavage of a 1-benzoyl group followed by the substitution of the acetoxy group with a methoxy group (Scheme 2).

2. Effective optical resolution of racemic DMIm:
As mentioned above, a lengthy and tedious process was required for the production of both enantiomers of DMIm using MAC acid. The process included the conversion of methoxy to a benzyloxy group in the presence of a large amount of benzyl alcohol. Therefore, the investigation of a more facile method for the optical resolution of DMIm is needed.
During the course of our recent research, we found that the introduction of some arylsulfonyl moieties to the nitrogen position of N-MAC-DMIm changed the separability of diastereomers during silicagel column chromatography. Thus, several types of 1-arylsulfonyl-3-MAC-DMIm were examined and 1-benzenesulfonyl and 1-(2-mesitylenesulfonyl) derivatives could be effectively separated to the diastereomers 6 and 7 (Table 2, entries 5, 6).12

There are two ways to transform these diastereomers into chiral synthons for 1,2-diamines. Desulfonylation and deacylation are the valid routes for mono-N-substituted DMIm, with a methoxy group at the “NH” side that can be converted into another substituent. As a result of our examinations, the selective removal of both groups, arylsulfonyl and MAC, was accomplished. Thus, the diastereomers of 1-(2-mesitylenesulfonyl)-3-MAC-DMIm, 6f and 7f, were treated with LiBH4/MeOH (1:2) and PhCH2SLi, respectively, to yield a pair of deacylated DMIm enantiomers, 8f and 9f, in excellent yields (90 and 98%, respectively; Scheme 3).13 The same trials using 1-benzenesulfonyl derivatives 6e and 7e gave inferior results (72% of 8e and 68% of 9e).

On the other hand, UV-irradiation to 1-(2-mesitylenesulfonyl)-3-MAC-DMIm 7f in the presence of sodium cyanoborohydride and anisole gave the corresponding desulfonylated DMIm 10 in a 90% yield (Scheme 4). The compound 6f also gave similar results under the same conditions.

In conclusion, we established a complementary method for the preparation of both of the enantiomers of DMIm, using the Fe(III)-catalyzed oxidation of 2-imidazolone via a H2O2-urea complex with subsequent optical resolution via the introduction of a MAC moiety and a 2-mesitylenesulfonyl group at the two nitrogen positions of DMIm, which were then selectively removed. Compared with the previous method, this new procedure required neither hazardous bromine, which is difficult to handle, nor the multi-step conversion of the alkoxy moiety, which requires the use of a large amount of benzyl alcohol that is difficult to remove from the reaction mixture. This new method features ease of handling and a simple attach-detach process, and, therefore, is more suitable for the multi-gram scale preparation of both enantiomers of chiral DMIm.

EXPERIMENTAL
Melting points were determined using a Yanaco micro melting point apparatus and were uncorrected. Optical rotations were measured with a JASCO P-1010 polarimeter. 1H NMR spectra were recorded in CDCl3 with tetramethylsilane as the internal standard using JEOL ALPHA 500 (500 MHz), JEOL JNM-GX400 (400 MHz) and JEOL JNM-AL300 (300 MHz) spectrometers. 13C NMR spectra were recorded in CDCl3 with tetramethylsilane as the internal standard using JEOL ALPHA 500 (125 MHz), JEOL JNM-GX400 (100 MHz) and JEOL JNM-AL300 (75 MHz) spectrometers with broad-band proton decoupling. Infrared spectra were measured with a JEOL JIR-6500W and JASCO FT/IR-410 FT-IR spectrometer. MS and HRMS (EI or FAB) were obtained with a JEOL JMS-700 mass spectrometer. Fuji silysia silica gel (PSQ60B) was used for flash chromatography. Fe(III)-dipicolinate complex (FeCl(dipic)(H2O)2) was prepared following a previously reported procedure.14

Fe(III)-catalyzed oxidation of 1-benzoyl-2-imidazolone (1) by hydrogen peroxide (Table 1):
i) Typical procedure using FeCl3•6H2O/dipicolinic acid/i-Pr2NH and 30% H2O2 aq (entry 2). To a suspension of FeCl3•6H2O (7.2 mg, 0.1 eq) and dipicolinic acid (4.4 mg, 0.1 eq) in CH2Cl2 (1 mL) was added i-Pr2NH (7.5 µL) and the suspension was stirred at 26 °C for 30 min. After the addition of a solution of 1-benzoyl-2-imidazolone (1) (50 mg, 0.2657 mmol)in CH2Cl2 (1.4 mL) to the catalyst mixture with stirring for 10 min at 26 °C, trimethyl orthoacetate (2.4 mL) was added along with an aqueous H2O2 solution (30%) in trimethyl orthoacetate (0.48 mL), which were added to the reaction mixture over 1 h using a syringe pump at 0 °C followed by stirring for 24 h at 0 °C. The reaction mixture was passed through SiO2 pad (EtOAc as eluent) to quench the reaction and the eluent was evaporated in vacuo followed by flash column chromatography on silica gel (hexane/EtOAc; 5/5 to 2/8) to yield a mixture of (4RS,5RS)-trans-1-benzoyl-5-hydroxy-4-methoxy-2-imidazolidinone (2) (18.8 mg, 0.0795 mmol, 30%) and the starting material (1) (27.9 mg, 0.1484 mmol, 56%) as a colorless amorphous solid, the ratio of which was determined by 1H NMR spectrometry.
ii) Typical procedure using FeCl(dipic)(H2O)2/i-Pr2NH•HCl and H2O2 urea (entry 8). A suspension of FeCl(dipic)(H2O)2 (7.8 mg, 0.1 eq) and i-Pr2NH•HCl (3.7 mg, 0.1 eq) in CH2Cl2 (2.3 mL) was stirred at 26 °C for 30 min. After the addition of a solution of 1-benzoyl-2-imidazolone (1) in CH2Cl2 (1.4 mL) to the catalyst mixture with stirring for 10 min at 26 °C, trimethyl orthoacetate (1.59 mL) and H2O2-urea (37.5 mg) were subsequently added at 0 °C and then stirred at 26 °C for 3 h. The reaction mixture was passed through a SiO2 pad (EtOAc as eluent) to quench the reaction and the eluent was evaporated in vacuo followed by flash column chromatography on silica gel (hexane/EtOAc; 5/5 to 2/8) to yield (4RS,5RS)-trans-1-benzoyl-5-hydroxy-4-methoxy-2-imidazolidinone (2) (53.3 mg, 0.2256 mmol, 85%) as colorless crystals; mp 145-148 °C (CH2Cl2); IR (KBr) ν 3410, 3207, 3128, 2935, 2916, 2835, 1741, 1680, 1448, 1427, 1404 cm-1; 1H NMR (300 MHz), CDCl3) d 3.42 (3H, s), 4.29(1H, d, J = 2.6 Hz), 4.68 (1H, d, J = 2.6 Hz), 5.73 (1H, d, J = 1.1 Hz), 6.00 (1H, br s), 7.40-7.45 (2H, m), 7.53-7.58 (1H, m), 7.66-7.69 (2H, m); 13C-NMR (75 MHz, CD3CN) d 53.1, 81.9, 85.7, 126.6, 127.7, 130.6, 133.6, 152.6, 169.0. MS (FAB) m/z 237 (MH+, 52), 105 (PhCO, 100), 77 (Ph, 23); HRMS (FAB) Calcd for C11H13N2O4 (MH+): m/z 237.0875. Found: m/z 237.0875.
(4RS,5RS)-trans-5-Acetoxy-3-acetyl-1-benzoyl-4-methoxy-2-imidazolidinone (3). To a solution of (4RS,5RS)-trans-1-benzoyl-5-hydroxy-4-methoxy-2-imidazolidinone (2) (340 mg, 1.439 mmol) in CH2Cl2 (14 mL) were added i-Pr2NEt (0.63 mL, 3.598 mmol, 2.5 eq) and acetyl chloride (0.26 mL, 3.598 mmol, 2.5 eq) at 0 °C with stirring at room temperature for 4 h. The reaction mixture was passed through a SiO2 pad (EtOAc as eluent) to quench the reaction and the eluent was evaporated in vacuo followed by flash column chromatography on silica gel (hexane/CH2Cl2 (2/8) - CH2Cl2 - EtOAc/CH2Cl2 (2/8)) to yield 3 (440.4 mg, 1.375 mmol, 96%) as a pale yellow oil; IR (KBr) ν 3014, 2943, 2846, 1782, 1753, 1716, 1699, 1373 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.16 (3H, s), 2.50 (3H, s), 3.65 (3H, s), 5.30 (1H, s), 6.54 (1H, s), 7.44 (2H, m), 7.57-7.66 (3H, m); 13C NMR (75 MHz, CDCl3) δ 20.7, 24.3, 58.0, 79.6, 85.7, 128.0, 128.8, 132.7, 132.8, 150.2, 168.6, 169.3, 170.3. MS (FAB) m/z 321 (MH+, 4), 289 (M+-OMe, 3), 261 (M+-OAc, 10), 105 (PhCO, 100), 77 (Ph, 7); HRMS (FAB) Calcd for C15H17N2O6 (MH+): m/z 321.1087. Found: m/z 321.1066.
(4RS,5RS)-trans-1-Acetyl-4,5-dimethoxy-2-imidazolidinone (4). To a solution of (4RS,5RS)-trans-5-acetoxy-3-acetyl-1-benzoyl-4-methoxy-2-imidazolidinone (3) (271 mg, 0.846 mmol) in MeOH (17 mL) was added pyridine (0.067 mL, 0.846 mmol, 1.0 eq) with stirring at 50 °C for 21 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatographed on silica gel (CH2Cl2/EtOAc (9/1 to 7/3)) to obtain 4 (127 mg, 0.677 mmol, 80%) as colorless crystals; mp 100-102 °C (hexane); IR (KBr) ν 3248, 3145, 3014, 2985, 2941, 2846, 2825, 1732, 1707, 1464, 1406 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.52 (3H, s), 3.36 (3H, s), 3.53 (3H, s), 4.57 (1H, d, J = 1.3 Hz), 5.34 (1H, d, J = 1.3 Hz), 6.77 (1H, br s); 13C NMR (75 MHz, CDCl3) δ 24.0, 54.2, 57.3, 85.6, 88.2, 155.4, 170.9. MS (FAB) m/z 189 (MH+, 100), 157 (M+-OMe, 20), 115 (MH+-OMe-OAc, 37); HRMS (FAB) Calcd for C7H13N2O4 (MH+): m/z 189.0875. Found: m/z 189.0868.
Typical procedure for the preparation of (4RS,5RS)-1-arylsulfonyl-4,5-dimethoxy-2-imidazolidinones 5a-f. (4RS,5RS)-4,5-dimethoxy-1-toluenesulfonyl-2-imidazolidinone (5a). To a solution of (4RS,5RS)-trans-1-acetyl-4,5-dimethoxy-2-imidazolidinone (4) (200 mg, 1.06 mmol) in CH2Cl2 (11 mL) were added diisopropylethylamine (0.56 mL, 3.18 mmol, 3 eq), p-toluenesulfonyl chloride (0.405 g, 2.12 mmol, 2 eq) and DMAP (0.013 g, 0.106 mmol, 0.1 eq) with stirring at room temperature for 18 h. The reaction mixture was passed through a SiO2 pad (EtOAc as eluent) to quench the reaction, and the eluent was evaporated in vacuo followed by flash chromatography on silica gel (hexane/EtOAc (19/1 to 8/2)) to yield (4RS,5RS)-3-acetyl-4,5-dimethoxy-1-(p-toluenesulfonyl)-2-imidazolidinone (355 mg, 1.04 mmol) as a colorless oil, which was subsequently dissolved in MeOH (10.4 mL) and Cs2CO3 (34 mg, 0.104 mmol, 0.1 eq) with stirring for 10 min at room temperature. Citric acid (20 mg, 0.104 mmol, 0.1 eq) was added to the reaction mixture to quench the reaction and the mixture was concentrated in vacuo followed by flash column chromatography on silica gel (hexane/EtOAc (6/4 to 5/5)) to yield (4RS,5RS)-4,5-dimethoxy-1-(p-toluenesulfonyl)-2-imidazolidinone (309 mg, 1.03 mmol, 97% from 4) as a colorless solid; mp 143.5-144.0 °C; IR (KBr) ν 3356, 3228, 2947, 1763, 1338, 1165, 1107, 933, 667, 601, 544 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.43 (3H, s), 3.31 (3H, s), 3.53 (3H, s), 4.58 (1H, d, J = 1.5 Hz), 5.31(1H, d, J = 1.5 Hz), 5.74 (1H, br s), 7.32 (2H, d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz); 13C NMR (100 MHz, CDCl3) δ 21.7, 54.1, 56.0, 85.9, 91.6, 128.2, 129.5, 135.9, 144.9, 154.1. MS (FAB) m/z 301 (MH+, 39), 269 (M+-OMe, 100), 91 (CH3C6H5+, 22); HRMS (FAB) Calcd for C12H17N2O5S (MH+): m/z 301.0858. Found: m/z 301.0873.
(4RS,5RS)-4,5-Dimethoxy-1-(p-nitrobenzenesulfonyl)-2-imidazolidinone (5b): a colorless solid; mp 138-139 °C; IR (KBr) ν 3251, 3140, 2939, 1743, 1531, 1377, 1184, 949, 856, 744, 621 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.33 (3H, s), 3.54 (3H, s), 4.60 (1H, d, J = 1.3 Hz), 5.28 (1H, d, J = 1.3 Hz), 6.61 (1H, br s), 8.23 (2H, d, J = 9.1 Hz), 8.35 (2H, d, J = 9.1 Hz); 13C NMR (100 MHz, CDCl3) δ 54.5, 56.4, 85.9, 91.8, 124.1, 129.7, 144.2, 150.7, 153.6. MS (FAB) m/z 332 (MH+, 3), 300 (M+-OMe, 4), 154 (100); HRMS (FAB) Calcd for C11H13N3O7SNa (MNa+): m/z 354.0372. Found (MNa+): m/z 354.0382.
(4RS,5RS)-4,5-Dimethoxy-1-(o-nitrobenzenesulfonyl)-2-imidazolidinone (5c): a colorless solid; mp 161-162 °C; IR (KBr) ν 3313, 3124, 2951, 1751, 1543, 1369, 1180, 1088, 602 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.41 (3H, s), 3.61 (3H, s), 4.64 (1H, s), 5.40 (1H, s), 5.95 (1H, br s), 7.67-7.84 (3H, m), 8.42-8.44 (1H, m); 13C NMR (100 MHz, CDCl3) δ 54.7, 56.9, 87.4, 91.6, 124.6, 131.6, 132.1, 134.4, 135.0, 148.1, 153.1. MS (FAB) m/z 332 (MH+, 3), 300 (M+-OMe, 29), 154 (100); HRMS (FAB) Calcd for C11H14N3O7S (MH+): m/z 332.0552. Found: m/z 332.0564.
(4RS,5RS)-1-(p-Chlorobenzenesulfonyl)-4,5-dimethoxy-2-imidazolidinone (5d): a colorless solid; mp 119.5-120.5 °C; IR (KBr) ν 3356, 3105, 2943, 2839, 1755, 1577, 1365, 1176, 1095, 945, 764, 633 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.30 (3H, s), 3.52 (3H, s), 4.58 (1H, s), 5.27 (1H, s), 6.50 (1H, br s), 7.47-7.50 (2H, d, J = 8.6 Hz), 7.96-7.99 (2H, d, J = 8.6 Hz); 13C NMR (125 MHz, CDCl3) δ 54.1, 56.2, 85.9, 91.6, 129.2, 129.8, 137.3, 140.5, 153.5. MS (FAB) m/z 321 (MH+, 43), 323 ((M+2)H+, 18), 289 (M+-OMe, 100), 291 ((M+2)+-OMe, 39); HRMS (FAB) Calcd for C11H14ClN2O5S (MH+): m/z 321.0312. Found: m/z 321.0307.
(4RS,5RS)-1-Benzenesulfonyl-4,5-dimethoxy-2-imidazolidinone (5e): a colorless solid; mp 161-162 °C; IR (KBr) ν 3602, 3305, 2951, 1763, 1724, 1430, 1365, 1173, 1099, 945, 605 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.28 (3H, s), 3.51 (3H, s), 4.58 (1H, d, J = 1.1 Hz), 5.30 (1H, d, J = 1.1 Hz), 6.48 (1H, br s), 7.49-7.54 (2H, m), 7.59-7.65 (1H, m), 8.02-8.06 (2H, m); 13C NMR (125 MHz, CDCl3) δ 54.0, 56.1, 85.9, 91.5, 128.2, 128.8, 133.8, 138.9, 153.7. MS (FAB) m/z 287 (MH+, 43), 255 (M+-OMe, 100), 77 (C6H5+, 21); HRMS (FAB) Calcd for C11H15N2O5S (MH+): m/z 287.0702. Found: m/z 287.0707.
(4RS,5RS)-4,5-Dimethoxy-1-(2-mesitylenesulfonyl)-2-imidazolidinone (5f): a colorless solid; mp 179-182 °C; IR (KBr) ν 3317, 2951, 1755, 1601, 1450, 1400, 1353, 1288, 1168, 1072, 941, 852, 660, 598, 536 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.29 (3H, s), 2.65 (6H, s), 3.28 (3H, s), 3.61 (3H, s), 4.56 (1H, s), 5.33 (1H, s), 6.28 (1H, br s), 6.95 (2H, s); 13C NMR (125 MHz, CDCl3) δ 21.0, 22.6, 54.5, 56.2, 86.8, 91.5, 132.0, 132.3, 141.3, 143.7, 154.1. MS (FAB) m/z 329 (MH+, 28), 297 (M+-OMe, 81), 183 (Me3C6H2SO2, 72), 119 (Me3C6H2, 100); HRMS (FAB) Calcd for C14H21N2O5S (MH+): m/z 329.1171. Found: m/z 329.1176.
Typical procedure for the conjunction of (4RS,5RS)-1-arylsulfonyl-4,5-dimethoxy-2-imidazolidinones 5a-f with MAC-Cl. Optical resolution of 6a and 7a. To a solution of (4RS,5RS)-4,5-dimethoxy-1-toluenesulfonyl-2-imidazolidinone (5a) (251 mg, 0.837 mmol) in THF (4.2 mL) was added NaH (60% in oli, 81 mg, 2.4 eq) at 0 °C with stirring for 15 min at room temperature followed by the addition of MAC-Cl, prepared from MAC acid (200 mg, 1 mmol, 1.2 eq) and thoinyl chloride (0.293 mL, 4 mmol, 4.8 eq) under reflux for 1 h with the subsequent removal of the remaining thoinyl chloride, HCl and SO2 by toluene-azeotrope, and further stirring for 2 h. The reaction was quenched by the addition of satd. NH4Cl aq., and the product was extracted (EtOAc, 40 mL x 3), washed (brine, 30 mL x 3) and dried (anhyd. Na2SO4). After the concentration of the organic layer in vacuo, the residue was purified by flash column chromatography on silica gel (hexane/EtOAc (6/4 to 5/5)) to afford a colorless amorphous solid of a 1:1 mixture of 6a and 7a (386 mg, 0.804 mmol, 96%), the elements of which were scarcely separable on SiO2. Absolute configurations of both products were estimated based on comparisons of the 1H NMR spectroscopies of 6f and 7f.15
(4S,5S)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-toluenesulfonyl)-2-imidazolidinone (7a, higher polarity): IR (neat) ν 3664, 3521, 3020, 2877, 1766, 1697, 1597, 1454, 1373, 1180, 1092, 945, 814, 733, 667 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.05-1.11 (1H, m), 1.11 (3H, s), 1.19 (3H, s), 1.54-1.65 (2H, m), 1.76-1.80 (3H, m), 2.27-2.33 (1H, m), 2.42 (3H, s), 2.78 (3H, s), 3.45 (3H, s), 3.48 (3H, s), 4.11 (1H, dd, J = 3.7, 7.7 Hz), 5.21 (1H, s), 5.30 (1H, s), 7.33 (2H, d, J = 8.4 Hz), 7.95 (2H, d, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 21.1, 21.7, 21.8, 27.0, 28.5, 37.2, 45.4, 50.7, 55.5, 55.7, 56.8, 62.1, 83.0, 87.1, 88.9, 128.8, 129.5, 135.3, 145.2, 148.7, 173.2. MS (FAB) m/z 481 (MH+, 4), 449 (M+-OMe, 14), 181 (MAC moiety, 100); HRMS (FAB) Calcd for C23H32N2O7SNa (MNa+): m/z 503.1828. Found (MNa+): m/z 503.1793.
(4R,5R)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-toluenesulfonyl)-2-imidazolidinone (6a, lower polarity): IR (neat) ν 3687, 2943, 1766, 1697, 1597, 1454, 1373, 1184, 1107, 941, 818, 744, 667 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.04 (3H, s), 1.04-1.08 (1H, m), 1.25 (3H, s), 1.59-1.69 (5H, m), 2.04-2.09 (1H, m), 2.42 (3H, s), 2.92 (3H, s), 3.40 (3H, s), 3.54 (3H, s), 4.37 (1H, dd, J = 3.7, 7.9 Hz), 5.18 (1H, s), 5.41 (1H, s), 7.32 (2H, d, J = 7.9 Hz), 7.92 (2H, d, J = 7.9 Hz) ; 13C NMR (100 MHz, CDCl3) δ 21.3, 21.5, 21.7, 26.65, 26.67, 37.9, 45.4, 50.7, 56.1, 56.3, 56.8, 62.0, 84.4, 86.7,
89.2, 128.7, 129.5, 135.3, 145.2, 148.6, 173.1. MS (FAB) m/z 481 (MH+, 4), 449 (M+-OMe, 8), 181 (MAC moiety, 100); HRMS (FAB) Calcd for C23H32N2O7SNa (MNa+): m/z 503.1828. Found (MNa+): m/z 503.1865.
trans-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-nitrobenzenesulfonyl)-2-imidazolidinone (6b, 7b): From 277 mg (0.837 mmol) of 5b, a colorless amorphous solid of a mixture of 6b and 7b (331 mg, 0.65 mmol, 78%), both of which were slightly separable on SiO2, was obtained. Absolute configurations of both products were estimated based on comparisons of the 1H NMR spectroscopies of 6f and 7f.15
(4S,5S)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-nitrobenzenesulfonyl)-2-imidazolidinone (7b, higher polarity): IR (neat) ν 3656, 3109, 3001, 2881, 1770, 1701, 1608, 1535, 1458, 1377, 1188, 1088, 945, 856, 741, 621, 567 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.10 (3H, s), 1.04-1.14 (1H, m), 1.19 (3H, s), 1.53-1.64 (3H, m), 1.71-1.84 (2H, m), 2.16-2.28 (1H, m), 2.79 (3H, s), 3.47 (3H, s), 3.53 (3H, s), 4.07 (1H, dd, J = 7.7, 3.7 Hz), 5.20 (1H, s), 5.34 (1H, s), 8.27 (2H, d, J = 9.1 Hz), 8.38 (2H, d, J = 9.1 Hz); 13C NMR (100 MHz, CDCl3) δ 21.0, 21.5, 26.8, 28.4, 37.0, 45.2, 50.7, 55.4, 56.0, 57.2, 62.1, 83.0, 87.1, 89.2, 124.0, 130.2, 143.6, 148.4, 150.8, 173.0. MS (FAB; +NaI) m/z 534 (MNa+, 45), 181 (MAC moiety, 100); HRMS (FAB) Calcd for C22H29N3O9SNa (MNa+): m/z 534.1522. Found (MNa+): m/z 534.1537.
(4R,5R)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-nitrobenzenesulfon- yl)-2-imidazolidinone (6b, lower polarity): IR (neat) ν 3599, 3109, 2943, 1770, 1701, 1608, 1535, 1458, 1373, 1188, 1092, 945, 856, 741, 621, 567 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.04 (3H, s), 1.02-1.16 (1H, m), 1.25 (3H, s), 1.55-1.75 (3H, m), 1.78-1.88 (1H, m), 1.95-2.03 (1H, m), 2.99 (3H, s), 3.43 (3H, s), 3.56 (3H, s), 4.34 (1H, dd, J = 7.9, 3.7 Hz), 5.19 (1H, s), 5.46 (1H, s), 8.26 (2H, d, J = 9.2 Hz), 8.38 (2H, d, J = 9.2 Hz); 13C NMR (100 MHz, CDCl3) δ 21.2, 21.4, 26.6, 26.7, 37.7, 45.3, 50.7, 56.0, 56.4, 57.0, 62.0, 84.2, 86.3, 89.3, 124.0, 130.1, 143.7, 148.3, 150.8, 173.0. MS (FAB; +NaI) m/z 534 (MNa+, 100), 181 (MAC moiety, 97); HRMS (FAB) Calcd for C22H29N3O9SNa (MNa+): m/z 534.1522. Found (MNa+): m/z 534.1534.
trans-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(o-nitrobenzenesulfonyl)-2-imidazolidinone (6c, 7c): From 277 mg (0.837 mmol) of 5c, a colorless amorphous solid of a mixture of 6c and 7c (418 mg, 0.82 mmol, 98%), both of which were slightly separable on SiO2, was obtained. Absolute configurations of both products were estimated based on comparisons of the 1H NMR spectroscopies of 6f and 7f.15
(4S,5S)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(o-nitrobenzenesulfon-yl)-2-imidazolidinone (7c, lower polarity): IR (neat) ν 3575, 3101, 2943, 1766, 1701, 1547, 1454, 1377, 1188, 1092, 945, 737 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.12 (3H, s), 1.05-1.16 (1H, m), 1.24 (3H, s), 1.60-1.87 (5H, m), 2.15-2.24 (1H, m), 3.18 (3H, s), 3.55 (3H, s), 3.57 (3H, s), 4.20 (1H, dd, J = 7.6, 3.8 Hz), 5.28 (1H, s), 5.30 (1H, s), 7.77-7.80 (3H, m), 8.44-8.47 (1H, m); 13C NMR (100 MHz, CDCl3) δ 21.1, 21.7, 27.1, 28.6, 37.3, 45.4, 50.9, 56.2, 56.3, 57.1, 62.1, 83.0, 88.7, 89.0, 124.9, 131.3, 132.1, 134.4, 135.3, 148.3, 148.5, 172.9. MS (FAB; +NaI) m/z 534 (MNa+, 86), 181 (MAC moiety, 100); HRMS (FAB) Calcd for C22H29N3O9SNa (MNa+): m/z 534.1522. Found (MNa+): m/z 534.1530.
(4R,5R)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(o-nitrobenzenesulfon-yl)-2-imidazolidinone (6c, higher polarity): IR (neat) ν 3683, 3105, 2943, 1766, 1701, 1547, 1454, 1377, 1188, 1095, 945, 737 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.07 (3H, s), 1.07-1.12 (1H, m), 1.26 (3H, s), 1.56-1.87 (5H, m), 2.05-2.15 (1H, m), 2.86 (3H, s), 3.48 (3H, s), 3.59 (3H, s), 4.31 (1H, dd, J = 7.7, 3.8 Hz), 5.26 (1H, s), 5.38 (1H, s), 7.76-7.80 (3H, m), 8.49-8.43 (1H, m); 13C NMR (100 MHz, CDCl3) δ 21.2, 21.4, 26.6, 26.9, 37.8, 45.3, 50.7, 55.9, 56.9, 57.0, 62.0, 84.5, 87.9, 89.3, 124.7, 131.2, 131.9, 133.8,
135.0, 148.1, 148.3, 172.7. MS (FAB; +NaI) m/z 534 (MNa+, 100), 181 (MAC moiety, 92); HRMS (FAB) Calcd for C22H29N3O9SNa (MNa+): m/z 534.1522. Found (MNa+): m/z 534.1531.
trans-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-chlorobenzenesulfonyl)-2-imidazolidinone (6d, 7d): From 162 mg (0.505 mmol) of 5d, a mixture of 6d and 7d (218 mg, 0.44 mmol, 87%), both of which were partly separable on SiO2, was obtained. Absolute configurations of both products were estimated based on comparisons of the 1H NMR spectroscopies of 6f and 7f.15
(4S,5S)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-chlorobenzenesulfon-yl)-2-imidazolidinone (7d, higher polarity): colorless crystals; mp 102-103 °C (from hexane-CH2Cl2); [α]D30 -9.5 (c 1.01, CHCl3); IR (KBr) ν 3390, 2966, 1770, 1693, 1581, 1466, 1377, 1188, 1092, 945, 764, 629, 567 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.04-1.13 (1H, m), 1.11 (3H, s), 1.20 (3H, s), 1.55-1.65 (2H, m), 1.71-1.85 (3H, m), 2.20-2.30 (1H, m), 2.79 (3H,s), 3.46 (3H, s), 3.49 (3H, s), 4.09 (1H, dd, J = 7.9, 3.8 Hz), 5.18 (1H, s), 5.32 (1H, s), 7.51 (2H, d, J = 8.7 Hz), 8.01 (2H, d, J = 8.7 Hz); 13C NMR (125 MHz, CDCl3) δ 21.0, 21.6, 26.9, 28.4, 37.2, 45.3, 50.7, 55.4, 55.8, 56.9, 62.1, 83.0, 87.0, 89.0, 129.1, 130.2, 136.7, 140.8, 148.6, 173.1. MS (FAB) m/z 501 (MH+, 4), 469 (M+-OMe, 7), 181 (MAC moiety, 100); HRMS (FAB) Calcd for C22H29ClN2O7SNa (MNa+): m/z 523.1282. Found (MNa+): m/z 523.1291.
(4R,5R)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-chlorobenzenesulfon-yl)-2-imidazolidinone (6d, lower polarity): colorless crystals; mp 118-118.5 °C (from hexane-CH2Cl2); [α]D30 -35.1 (c 1.00, CHCl3); IR (KBr) ν 3429, 2947, 1766, 1701, 1581, 1466, 1377, 1184, 1095, 945, 760, 629, 575 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.04 (3H, s), 1.04-1.11 (1H, m), 1.25 (3H, s), 1.59-1.75 (4H, m), 1.78-1.86 (1H, m), 2.00-2.07 (1H, m), 2.96 (3H, s), 3.41 (3H, s), 3.54 (3H, s), 4.36 (1H, dd, J = 7.7, 3.7 Hz), 5.17 (1H, s), 5.43 (1H, s), 7.51 (2H, d, J = 8.7 Hz), 7.99 (2H, d, J = 8.7 Hz); 13C NMR (125 MHz, CDCl3) δ 21.2, 21.4, 26.61, 26.64, 37.8, 45.3, 50.7, 56.0, 56.3, 56.8, 62.0, 84.3, 86.6, 89.3, 129.1, 130.1, 136.6, 140.8, 148.5, 173.0. MS (FAB) m/z 501 (MH+, 5), 469 (M+-OMe, 6), 181 (MAC moiety, 100); HRMS (FAB) Calcd for C22H29ClN2O7SNa (MNa+): m/z 523.1282. Found (MNa+): m/z 523.1267.
trans-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-benzenesulfonyl-2-imidazolidinone (6e, 7e): From 140 mg (0.489 mmol) of 5e, a mixture of 6e and 7e (218 mg, 0.44 mmol, 87%), both of which were almost separable on SiO2, was obtained. Absolute configurations of both products were estimated based on comparisons of the 1H NMR spectroscopies of 6f and 7f.15
(4S,5S)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-benzenesulfonyl-2-imidazolidinone (7e, higher polarity): colorless crystals; mp 163-164 °C (from hexane-CH2Cl2); [α]D30 -3.8 (c 1.01, CHCl3); IR (KBr) ν 3440, 2943, 1774, 1697, 1454, 1381, 1180, 1107, 945, 764, 725, 606, 571 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.04-1.11 (1H, m), 1.11 (3H, s), 1.19 (3H, s), 1.53-1.62 (2H, m), 1.69-1.84 (3H, m), 2.26-2.33 (1H, m), 2.72 (3H, s), 3.45 (3H, s), 3.48 (3H, s), 4.09 (1H, dd, J = 7.7, 3.7 Hz), 5.22 (1H, s), 5.32 (1H, s), 7.52-7.57 (2H, m), 7.60-7.66 (1H, m), 8.07-8.10 (2H, m); 13C NMR (125 MHz, CDCl3) δ 21.0, 21.6, 26.9, 28.4, 37.1, 45.3, 50.6, 55.4, 55.6, 56.8, 62.0, 83.0, 87.0, 88.8, 128.7, 128.8, 134.0, 138.3, 148.6, 173.1. MS (FAB) m/z 467 (MH+, 8), 435 (M+-OMe, 16), 181 (MAC moiety, 100), 77 (C6H5+, 13); HRMS (FAB) Calcd for C22H30N2O7SNa (MNa+): m/z 489.1671. Found (MNa+): m/z 489.1682.
(4R,5R)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-benzenesulfonyl-2-imidazolidinone (6e, lower polarity): colorless crystals; mp 108-109 °C (from hexane-CH2Cl2); [α]D30 -35.3 (c 1.00, CHCl3); IR (KBr) ν 3444, 2947, 1774, 1701, 1454, 1373, 1180, 1103, 949, 756, 602 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.02-1.09 (1H, m), 1.04 (3H, s) 1.24 (3H, s), 1.57-1.72 (4H, m), 1.76-1.84 (1H, m), 2.02-2.09 (1H, m), 2.89 (3H, s), 3.40 (3H, s), 3.56 (3H, s), 4.35 (1H, dd, J = 7.7, 3.7 Hz), 5.20 (1H, s), 5.42 (1H, s), 7.51-7.56 (2H, m), 7.60-7.66 (1H, m), 8.04-8.07 (2H, m); 13C NMR (125 MHz, CDCl3) δ 21.2, 21.4, 26.6, 37.9, 45.4, 50.6, 56.0, 56.3, 56.7, 62.0, 84.3, 86.8, 89.3, 128.6, 128.8, 134.0, 138.3, 148.5, 173.1. MS (FAB) m/z 467 (MH+, 4), 435 (M+-OMe, 8), 181 (MAC moiety, 100), 77 (C6H5+, 12); HRMS (FAB) Calcd for C22H30N2O7SNa (MNa+): m/z 489.1671. Found (MNa+): m/z 489.1677.
trans-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(2-mesitylenesulfonyl)-2-imidazolidinone (6f, 7f): From 135 mg (0.411 mmol) of 5f, the mixture of 6f and 7f (205 mg, 0.40 mmol, 98%), both of which were almost separable on SiO2, was obtained. The absolute configuration of 7f was assigned based on the fact that the optical rotation and 1H NMR data of desulfonylated compound 10 identified it as the same compound that was previously reported.9
(4S,5S)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(2-mesitylenesulfonyl)-2-imidazolidinone (7f, higher polarity): colorless crystals; mp 152-153 °C (from hexane-CH2Cl2); [α]D30 -27.4 (c 1.00, CHCl3); IR (KBr) ν 3440, 2947, 1763, 1697, 1604, 1458, 1362, 1196, 1176, 1088, 941, 733, 663, 586, 528 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.04-1.12 (1H, m), 1.12 (3H, s), 1.21 (3H, s), 1.58-1.85 (5H, m), 2.12-2.19 (1H, m), 2.31 (3H, s), 2.69 (6H, s), 3.13 (3H, s), 3.48 (3H, s), 3.58 (3H, s), 4.13 (1H, dd, J = 7.7, 3.7 Hz), 5.23 (1H, s), 5.30 (1H, s), 6.98 (2H, s); 13C NMR (100 MHz, CDCl3) δ 21.0, 21.1, 21.8, 22.7, 27.0, 28.7, 37.2, 45.3, 50.7, 55.8, 56.1, 57.1, 61.9, 82.9, 88.1, 88.8, 131.8, 132.0, 141.6, 143.9, 148.9, 173.4. MS (FAB) m/z 509 (MH+, 4), 477 (M+-OMe, 6), 181 (MAC moiety, 100); HRMS (FAB) Calcd for C25H36N2O7SNa (MNa+): m/z 531.2141. Found (MNa+): m/z 531.2176.
(4R,5R)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(2-mesitylenesulfonyl)-2-imidazolidinone (6f, lower polarity): colorless crystals; mp 135-135.5 °C (from hexane-CH2Cl2); [α]D30 -19.4 (c 1.00, CHCl3); IR (KBr) ν 3001, 1763, 1697, 1601, 1458, 1365, 1192, 1173, 1111, 1080, 937, 741, 663, 586, 528 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.03-1.11 (1H, m), 1.08 (3H, s), 1.21 (3H, s), 1.54-1.64 (2H, m), 1.68-1.77 (3H, m), 2.10-2.16 (1H, m), 2.28 (3H, s), 2.67 (3H, s), 2.69 (6H, s), 3.44 (3H, s), 3.61 (3H, s), 4.15 (1H, dd, J = 7.7, 3.7 Hz), 5.21 (1H, s), 5.42 (1H, s), 6.95 (2H, s); 13C NMR (100 MHz, CDCl3) δ 21.0, 21.6, 22.7, 26.7, 27.1, 37.8, 45.3, 50.6, 55.8, 56.4, 57.3, 61.8, 84.1, 87.4, 88.8, 131.6, 131.8, 141.7, 143.8, 148.4, 173.2. MS (FAB) m/z 509 (MH+, 4), 477 (M+-OMe, 5), 181 (MAC moiety, 100); HRMS (FAB) Calcd for C25H36N2O7SNa (MNa+): m/z 531.2141. Found (MNa+): m/z 531.2162.
Removal of the MAC moiety from 6f. (4R,5R)-4,5-dimethoxy-1-(2-mesitylenesulfonyl)-2-imidazolidinone (8f). To a solution of 6f (170 mg, 0.334 mmol) in THF (3.4 mL) under an argon atmosphere were subsequently added LiBH4 (1.0 M in THF; 0.67 mL, 1.336 mmol, 4 eq) and MeOH (0.11 mL, 2.67 mmol, 8 eq; dissolved in THF (1 mL)) at 0 °C with stirring for 6 h at 0 °C. The reaction was quenched by the addition of satd. NH4Cl aq., and the product was extracted (EtOAc, 40 mL x 3), washed (brine, 30 mL x 3) and dried (anhyd. Na2SO4). After concentration of the organic layer in vacuo, the residue was purified by flash column chromatography on silica gel (hexane/EtOAc (8/2 to 5/5)) to afford 6f (5 mg, 3%) and 8f (99 mg, 0.301 mmol, 90%) as a colorless solid along with an oily amount (50 mg, 80%) of 2-exo-methoxy-l-apocamphanemethanol. 8f: a colorless crystals; mp 158.5-159 °C (from hexane/CH2Cl2); [α]D29 -67.9 (c 0.72, CHCl3); IR (KBr) ν 3320, 2950, 2839, 1755, 1605, 1450, 1354, 1288, 1169, 1074, 941, 852, 775, 660, 590, 525 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.29 (3H, s), 2.65 (6H, s), 3.28 (3H, s), 3.61 (3H, s), 4.56 (1H, s), 5.33 (1H, s), 6.26 (1H, br s), 6.95 (2H, s); 13C NMR (125 MHz, CDCl3) δ 21.0, 22.6, 54.5, 56.2, 86.8, 91.5, 132.0, 141.3, 143.7, 154.1. MS (FAB) m/z 329 (MH+, 48), 297 (M+-OMe, 88), 183 (Me3C6H2SO2, 62), 119 (Me3C6H2, 72); HRMS (FAB) Calcd for C14H20N2O5SNa (MNa+): m/z 351.0991. Found: m/z 351.0992.
Removal of the MAC moiety from 7f. (4S,5S)-4,5-dimethoxy-1-(2-mesitylenesulfonyl)-2-imidazolidinone (9f). To a solution of PhCH2SH (42 µL, 0.358 mmol, 2 eq) in THF (1.8 mL) was added n-BuLi (2.66 M in n-hexane; 0.10 mL, 0.268 mmol, 1.5 eq) at 0 °C under an argon atmosphere with stirring for 10 min to form PhCH2SLi, to which was added 7f (91 mg, 0.18 mmol) in THF (1.8 mL) at 0 °C with stirring for 1 h at 0 °C. The reaction was quenched by the addition of satd. NH4Cl aq. and the product was extracted (EtOAc, 20 mL x 3), washed (brine, 10 mL x 3) and dried (anhyd. Na2SO4). After concentration of the organic layer in vacuo, the residue was purified by flash column chromatography on silica gel (hexane/EtOAc (19/1 to 5/5)) to afford, in addition to the oily thiobenzyl ester of MAC acid (54 mg, 98%), 9f (58 mg, 0.178 mmol, 98%) as colorless crystals; mp 159-160 ℃ (from hexane/CH2Cl2); [α]D30 68.8 (c 0.90, CHCl3); IR (KBr) ν 3316, 2950, 1755, 1600, 1340, 1282, 1160, 1085, 941, 852, 775, 597, 536 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.28 (3H, s), 2.64 (6H, s), 3.21 (3H, s), 3.60 (3H, s), 4.56 (1H, s), 5.31 (1H, s), 6.83 (1H, br s), 6.93 (2H, s); 13C NMR (125 MHz, CDCl3) δ 21.0, 22.6, 54.5, 56.2, 86.8, 91.5, 132.0, 141.3, 143.7, 154.1. MS (FAB) m/z 329 (MH+, 41), 297 (M+-OMe, 92), 183 (Me3C6H2SO2, 74), 119 (Me3C6H2, 98); HRMS (FAB) Calcd for C14H20N2O5SNa (MNa+): m/z 351.0991. Found: m/z 351.0997.
Removal of the mesitylenesulfonyl moiety from 7f. (4S,5S)-4,5-dimethoxy-1-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-2-imidazolidinone (10). A mixture of 7f (87 mg, 0.17 mmol), NaBH3CN (107 mg, 1.7 mmol, 10 eq) and anisole (56 µL, 0.51 mmol, 3 eq) in EtOAc (17 mL) and t-BuOH (1 mL) was placed into a 30 mL quartz flask under an argon atmosphere and was irradiated with a 100 W high-pressure Hg lamp (Ushio Inc.) at 0 °C for 30 min under vigorous stirring. The reaction mixture was passed through SiO2 pad (EtOAc as eluent), and the eluent was evaporated in vacuo followed by flash chromatography on silica gel (hexane/EtOAc (8/2 to 6/4)) to yield 10 (50 mg, 0.154 mmol, 90 %) as colorless crystals; mp 84.5-85.0 ℃ (from hexane); [α]D28 -64.8 (c 1.00, CHCl3); IR (KBr) ν 3460, 3178, 3012, 2831, 1755, 1685, 1454, 1396, 1323, 1238, 1095, 945, 818, 729 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.09-1.17 (1H, m), 1.13 (3H, s), 1.29 (3H, s), 1.61-1.67 (2H, m), 1.75-1.92 (3H, m), 2.39-2.47 (1H, m), 3.15 (3H, s), 3.32 (3H, s), 3.49 (3H, s), 4.40 (1H, dd, J = 3.8, 7.7 Hz), 4.59 (1H, d, J = 1.7 Hz), 5.45 (1H, d, J = 1.7 Hz), 6.08 (1H, br s); 13C NMR (100 MHz, CDCl3) δ 21.3, 21.6, 26.8, 28.2, 37.4, 45.5, 50.4, 53.1, 55.9, 56.7, 61.9, 83.6, 85.2, 89.4, 154.3, 173.4. Anal. Calcd for C16H26N2O5: C, 58.88; H, 8.03; N, 8.58. Found: C, 58.65; H, 8.27; N, 8.50.

ACKNOWLEDGEMENTS
This research was financially supported in part by JSPS KAKENHI (NO. 23590011 to H.M.) and by the Hoansha Foundation (to T.I.).

References

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11. Unpublished data. Following Beller’s procedure,16 the treatment of N-benzoyl-2-imidazolone with aqueous hydrogen peroxide solution (30%) in the presence of catalytic amount of FeCl3•6H2O, dipicolinic acid and diisopropylamine in t-BuOH/CH2Cl2 (1:1) mixture as solvent yielded 4-tert-butoxy-5-hydroxy- and 4,5-dihydroxy-2-imidazolidinone (11, 12) (Sheme 5).
12. Absolute configulation of 7f was assigned from the fact that the optical rotation and 1H NMR data of desulfonylated compound 10 was identical as the same compound which was previously reported9.
13. Selective removal of MAC group of 6f using PhCH2SLi had also tried and only 13% yield of 8f was obtained, accompanying 59% recovered yield of the starting material 6f.
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