HETEROCYCLES

Paper | Regular issue | Vol. 81, No. 2, 2010, pp. 293-304
Received, 5th October, 2009, Accepted, 12th November, 2009, Published online, 13th November, 2009.
DOI: 10.3987/COM-09-11850

■ Stereoselective Intramolecular Cyclization of Isopentenyl Benzamide via π-Allylpalladium Complex Catalyzed by Pd(0)

Jae-Eun Joo, Yu Mu, Yiu-Suk Lee, Yong-Shou Tian, Gyu-Jin Lee, and Won-Hun Ham*

Department of Chemistry, Sung Kyun Kwan University, Suwon 440-746, Korea

Abstract

An efficient procedure was developed to synthesize oxazoline as key intermediate in the total synthesis of (+)-lactacystin using palladium(0)-catalyzed intramolecular cyclization of isopentenyl benzamide via a π–allylpalladium complex. A convenient and efficient method was developed for the synthesis of the optically pure α-amino-β-hydroxy acid.

INTRODUCTION
The palladium(0)-catalyzed intramolecular cyclization of a benzamide through a π-allylpalladium(II) complex is useful for the synthesis of highly functionalized compounds, particularly when chirality transfer is involved.
In previous papers, we described a new palladium(0)-catalyzed procedure for the stereoselective formation of an oxazoline ring from a homoallylic amide having a benzoyl substituent as an N-protection group. The most significant point of this method is that it is based on trans-oxazoline ring formation in palladium(0)-catalyzed conditions (Scheme 1).1 We have also been exploring the utility of enantiopure oxazoline as a chiral building block for the stereocontrolled syntheses of natural products.2
To extend the scope of this method, we replaced the vinyl group with isopropenyl group as testing in view of its selectivity in the formation of the corresponding oxazoline.
Based on our previous research, we anticipated that the palladium(0)-catalyzed oxazoline formation of isopentenyl benzamide might proceed with high stereoselectivity.

RESULTS AND DISCUSSION
Our initial efforts in the synthesis of the requisite isopentenyl benzamide commenced with the protected N-benzoyl amino alcohols 1a-e as shown in Scheme 2. Oxidation of the alcohols 1a-e with Dess-Martin periodinane gave the corresponding aldehydes, which were reacted with isopropenylmagnesium bromide in THF at 0 °C to afford secondary 2-isobutenyl alcohols 2a-d as 1.09-1.57:1 mixtures of syn/anti isomers (1H NMR).

Acetylation of the hydroxyl group yielded the corresponding acetates 3a-e. Under the same conditions [Pd(PPh3)4, K2CO3, in CH3CN] used in the formation of oxazolines, the intramolecular cyclization of isobutenylic acetates afforded the designed trans-oxazolines in good yields. (Table 1)

The stereochemistry of the oxazoline obtained above was elucidated by the 1H NMR data. The J values (J4,5=5.9-7.0 Hz) observed in all oxazolines 4a-e clearly indicate that the conpounds possess the assigned trans structures.
It is reasonable to assume that the palladium(0)-catalyzed oxazoline ring formation reaction proceeded via π-allylpalladium complex that arose from the secondary allylic acetates.

The high stereoselectivity of the cyclization of 3a-e may arise due to differences in the steric interactions between the bulky R group and the methyl group of the π-allylpalladium complex in transition states A and B. Consequently, cyclization proceeds through the more favored transition state A as shown in Figure 1.

This change in the diastereoselectivity of oxazoline ring formation is predominantly controlled by steric repulsion between R groups and the methyl group.
There is excellent evidence for the diastereoselectivity ratios reported herein and the ratios from palladium(0)-catalyzed oxazoline ring formation of allyl and homoallyl benzamide.1b
Deprotection of the silyl ether 4e with tetrabutylammonium fluoride gave the corresponding primary alcohol in 90% yield. Oxidation of the primary alcohol with potassium persulfate and ruthenium(III) chloride hydrate in a 1:1 mixture of H2O/CH3CN gave the corresponding carboxylic acid, which was treated with diazomethane in EtOH to afford ester 6. Reduction of ester 6 in MeOH was catalyzed by Pd/C under 70 psi of H2 at ambient temperature. Under these conditions, the trans-oxazoline 7 was produced. The optical rotation of 7 {[α] 25 D = -107.81 (c = 1.0, CHCl3)} was in good agreement with the reported value, which also conclusively proved the stereochemical assignment5a (Scheme 3).

(+)-Lactacystin 8, a potent proteasome inhibitor, was isolated from the fermentation broth of Streptomyces sp. OM-6519 by Omura et al. (-)-Clasto-lactacystin (also known as Omuralide 9) is the cell-permeable and biologically active form of 7.

The combination of these potent biological activities and their novel structures has widely increased the interest of the synthetic community. The first complete synthesis of (+)-lactacystin 8 was reported by Corey and coworkers in 1992,3 and a number of synthetic approaches have been reported in the past several years.4
Many of the published procedures have recently used oxazoline 7 as a key intermediate in the total syntheses of (+)-lactacystin and omuralide.5

CONCLUSION
An efficient procedure for synthesizing oxazoline 7 as a key intermediate for the total synthesis of (+)-lactacystin was developed using the palladium(0)-catalyzed intramolecular cyclization of isopentenyl benzamide via a π–allylpalladium complex. A convenient and efficient method was developed for the synthesis of the optically pure α-amino-β-hydroxy acid.
Indeed, such synthetic strategies have successfully been applied to the syntheses of trans-oxazolines, and these have prompted research into the development of an oxazoline synthesis method that is practical and adaptable for relatively large-scale production.

EXPERIMENTAL
1. General methods
Optical rotations were measured on a JASCO DIP 1020 digital polarimeter. 1H NMR spectra were recorded on a Varian inova FT-NMR at 500 MHz in CDCl3. 13C NMR spectra were recorded at 125 MHz in CDCl3. Chemical shifts are reported as δ values in ppm relative to CHCl3 (7.26) in CDCl3. IR spectra were measured on a Bruker FT-IR spectrometer. Mass spectral data were obtained from the Korea Basic Science Institute (Daegu) on a Jeol JMS 700 high resolution mass spectrometer. Flash chromatography was executed with Merck Kiesegel 60 (230-400 mesh) using mixtures of EtOAc and hexane as eluents. Ethyl acetate and hexane were dried and purified by distillation prior to use. Tetrahydrofuran (THF) and Et2O were distilled over sodium and benzophenone (indicator). Methylene chloride (CH2Cl2) was shaken with concentrated sulfuric acid, dried over potassium carbonate, and distilled. Commercially available compounds were used without further purification.

2. General procedure for 2-Isobutenyl alcohols 2
To a solution of Dess-Martin periodinane (9.65 g, 22.76 mmol, 1.5 equiv) in CH2Cl2 (50 mL) at 25 °C was added a solution of alcohol 1 (15.17 mmol, 1.0 equiv) in CH2Cl2 (75 mL). The reaction mixture was stirred for 2 h at 25 °C, after which time TLC analysis indicated complete reaction. The reaction mixture was diluted with ether (150 mL) and poured into saturated aqueous NaHCO3 (300 mL) containing Na2S2O3 (39.53g, 159.29 mmol, 10.5 equiv). The mixture was stirred to dissolve the solid, and the layers were separated. The ether layer was extracted with saturated aqueous NaHCO3 (150 mL) and with water (150 mL), then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give crude aldehyde. This aldehyde was immediately employed in the next step without further purification. To a stirred solution of crude aldehyde in THF (75 mL) at 0 °C was added a solution of isopropenylmagnesium bromide (1.0 M in THF, 75.85 mL, 75.85 mmol, 5.0 equiv). After being stirred for 1 h, the reaction mixture was washed with saturated aqueous NH4Cl (30 mL×2), brine (30 mL×2), dried with MgSO4 and evaporated in vacuo. Purification by silica gel chromatography (EtOAc / hexane =1/2) gave 2.

2.1. (S)-N-(3-Hydroxy-4-methyl-1-phenylpent-4-en-2-yl)-benzamide, 2a
74% yield, syn/anti = 1.26/1, white solid. IR (neat): 3336, 2966, 1639 cm-1; 1H NMR (500 MHz, CDCl3): δ = 1.69 (s, 1.5H), 1.86 (s, 1.5H), 2.59 (s, 0.5H), 2.73 (s, 0.5H), 2.91 (dd, J = 9.0, 14.0 Hz, 0.5H), 3.00-3.04 (m, 1H), 3.11 (dd, J = 7.0, 13.5 Hz, 0.5H), 4.09 (d, J = 9.0 Hz, 0.5H), 4.32 (d, J = 3.0 Hz, 0.5H), 4.47 (ddd, J = 3.0, 7.5, 16.0 Hz, 0.5H), 4.53 (ddd, J = 4.5, 8.5, 13.5 Hz, 0.5H), 4.91 (dd, J = 1.5, 2.5 Hz, 0.5H), 5.02 (dd, J = 1.5, 2.5 Hz, 0.5H), 5.06 (d, J = 1.0 Hz, 0.5H), 5.12 (d, J = 1.0 Hz, 0.5H), 6.22 (d, J = 8.5 Hz,0.5H), 6.45 ( d, J = 8.5 Hz, 0.5H), 7.18-7.33 (m, 5H), 7.36-7.49 (m, 2H), 7.58-7.68 (m, 2H) 13C NMR (125 MHz, CDCl3): δ 19.30, 19.35, 34.34, 38.43, 53.22, 53.57, 74.78, 111.45, 112.68, 126.75, 126.84, 127.07, 127.14, 128.77, 128.79, 128.87, 129.55, 131.66, 131.73, 1379, 134.89, 138.40, 138.44, 145.08, 145.84, 167.90, 168.00; HRMS(EI, 70eV) calcd for C19H21NO2(M+1) 295.1572; found 295.1577.

2.2. (S)-N-[3-Hydroxy-1-(4-methoxyphenyl)-4-methylpent-4-en-2-yl]-benzamide, 2b
69% yield, syn/anti = 1.17/1, white solid. IR (neat): 3350, 2933, 1639 cm-1; 1H NMR (500 MHz, CDCl3): δ = 1.68 (s, 1.5H). 1.84 (s, 1.5H), 2.85 (dd, J = 9.0, 15.0Hz, 0.5H), 2.94-2.98 (m, 1H), 3.03 (dd, J = 6.5, 14.0 Hz, 1H), 3.76 (s, 1.5H), 3.79 (s, 1.5H), 4.08 (d, J = 10.0Hz, 0.5H), 4.29 (d, J = 4.0 Hz, 0.5H), 4.40 (ddd, J = 3.0, 6.5, 18.0 Hz, 0.5H), 4.49 (ddd, J = 4.0, 8.5, 13.5 Hz, 0.5H), 4.89 (d, J = 1.0 Hz, 0.5H), 5.00 (d, J = 1.0 Hz, 0.5H), 5.05 (d, J = 1.0 Hz, 0.5H), 5.11 (d, J = 1.0 Hz, 0.5H), 6.28 (d, J = 7.5 Hz, 0.5H), 6.51 (d, J = 7.5 Hz, 0.5H), 6.78-6.85 (m, 2H), 7.12-7.24 (m, 2H), 7.35-7.48 (m, 3H), 7.60-7.69 (m, 2H),; 13C NMR (125 MHz, CDCl3): δ 19.31, 19.35, 33.45, 37.52, 53.44, 53.58, 55.44, 55.47, 74.43, 111.40, 112.63, 114.17, 114.26, 127.12, 127.19, 128.74, 128.76, 130.38, 130.50, 130.55, 131.63, 131.69, 134.79, 134.89, 145.11, 145.88, 158.45, 158.52, 167.94, 168.09; HRMS(EI, 70eV) calcd for C20H23NO3(M+1) 325.1678; found 325.1677.

2.3. (S)-N-(4-Hydroxy-2,5-dimethylhex-5-en-3-yl)-benzamide, 2c
70% yield, syn/anti = 1.57/1, colorless needles. IR (neat): 3351, 2961, 1640 cm-1; 1H NMR (500 MHz, CDCl3): δ = 0.98-1.25 (m, 6H), 1.78 (s, 1.5H), 1.81 (s, 1.5H), 2.02-2.09 (m, 0.5H), 2.11-2.18 (m, 0.5H), 2.22 (d ,J = 4.0 Hz, 0.5H), 2.29 (d, J = 3.0 Hz, 0.5H), 3.99 (ddd, J = 3.0, 7.5, 10.0 Hz, 0.5H), 4.23 (dd, J = 4.0, 5.5 Hz, 0.5H), 4.29 (ddd, J = 4.5, 6.0, 10.0 Hz, 0.5H), 4.33 (m, 0.5H), 4.88 (d, J = 1.5 Hz, 0.5H), 4.96 (d, J = 1.5 Hz, 0.5H), 5.01 (d, J = 1.5 Hz, 0.5H), 5.04 (d, J = 1.5, 0.5H), 6.13 (d, J = 9.0 Hz, 0.5H), 6.41 (d, J = 9.0 Hz, 0.5H), 7.40-7.52 (m, 3H), 7.74-7.76 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 17.49, 18.64, 19.45, 19.63, 20.23, 21.37, 28.19, 30.48, 56.02, 56.98, 74.43, 110.99, 113.10, 127.10, 127.17, 128.75, 128.86, 131.52, 131.69, 135.14, 145.92, 146.43, 168.05, 168.26; HRMS(EI, 70eV) calcd for C15H21NO2(M+1) 247.1572; found 247.1570.

2.4. (S)-N-(3-Hydroxy-2,6-dimethylhept-1-en-4-yl)-benzamide, 2d
68% yield, syn/anti =1.20/1, colorless needles. IR (neat): 3338, 2954, 1638 cm-1; 1H NMR (500 MHz, CDCl3): δ = 0.92-1.03 (m, 6H), 1.25-1.32 (m, 0.5H), 1.43-1.50 (m, 0.5H), 1.62-1.74 (m, 1H), 1.80 (s, 3H), 4.10 (d, J = 3.5 Hz, 0.5H), 4.26 (d, 9.5 Hz, 0.5H),4.38 (ddt, J = 3.5, 5.0, 9.5 Hz, 0.5H), 4.43 (ddt, J = 3.0, 6.0, 9.0 Hz, 0.5H), 4.89 (d, J = 1.0 Hz, 0.5H), 4.98 (d, J = 1.0 Hz, 0.5H), 5.00 (d, J = 1.0 Hz, 0.5H), 5.07 (d, J = 1.0 Hz, 0.5H), 6.29 (d, J = 9.0 Hz, 0.5H), 6.37 (d, J = 9.0 Hz, 0.5H), 7.39-7.52 (m, 3H), 7.73-9.68 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 19.25, 19.74, 21.86, 22.56, 23.35, 24.04, 25.07, 25.32, 37.20, 41.90, 50.20, 50.43, 111.61, 127.22, 128.68, 128.75, 131.55, 131.67, 134.81, 134.93, 145.06, 145.85, 167.92, 168.33; HRMS(EI, 70eV) calcd for C16H23NO2(M+1) 261.1729; found 261.1729.

2.5. (S)-N-[1-(tert-Butyldimethylsilyloxy)-3-hydroxy-4-methylpent-4-en-2-yl]-benzamide, 2e
75% yield, syn/anti = 1.09/1, colorless oil. IR (neat): 3327, 2930, 1643 cm-1; 1H NMR (500 MHz, CDCl3): δ = 0.02-0.12 (m, 6H), 0.91 (s, 9H), 1.70 (s, 1.5H), 1.82 (s, 1.5H), 3.72 (s, 0.5H), 3.76 (d, J = 8.0 Hz, 0.5H), 3.87 (dd, J = 4.5, 10.0 Hz, 0.5H), 3.90 (dd, J = 3.5, 10.0 Hz, 0.5H), 4.01-4.04 (m, 1H), 4.24-4.29 (m, 1.5H), 4.51 (m, 0.5H), 4.95 (d, J = 1.5Hz, 0.5H), 5.06 (d, J = 1.5Hz, 0.5H), 5.14 (d, J = 1.5Hz, 0.5H), 5.17 (d, J = 1.5Hz, 0.5H), 6.72 (d, J = 8.0 Hz, 0.5H), 6.95 (d, J = 7.5 Hz, 0.5H), 7.40-7.55 (m, 3H), 7.75-7.81 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 5.31, 5.45, 18.27, 18.33, 19.14, 19.34, 25.98, 26.02, 51.22, 51.98, 63.20, 64.95, 75.25, 111.89, 112.28, 127.13, 128.76, 128.82, 131.71, 131.77, 134.65, 134.70, 144.33, 144.88, 167.33, 167.88; HRMS (EI, 70eV) calcd for C19H31NO3Si(M+1) 349.5416; found 349.5417.

3. General procedure for Benzamides 3
Acetic anhydride (1.24 mL, 13.18 mmol, 1.1 equiv.), pyridine (1.07 mL, 13.18 mmol, 1.1 equiv) and DMAP ( 147 mg, 1.20 mmol, 0.1 equiv.) were added to a stirred solution of alcohol 2 (11.98 mmol, 1.0 equiv.) in CH2Cl2 (50 mL) and stirring was continued for 12 h. The reaction mixture was washed with 1 N HCl (50 mL x 2), saturated aqueous NaHCO3 solution (50 mL x 2), and brine (50 mL x 2); dried with MgSO4; and evaporated in vacuo. The resulting substance was purified by silica gel column chromatography (EtOAc/ hexane = 1/2) and gave isobutenylic acetate 3.

3.1. (S)-4-Benzamido-2-methyl-5-phenylpent-1-en-3-yl acetate, 3a
97% yield, syn/anti = 1.33/1, colorless oil. IR (neat): 3300, 2932, 1737, 1644 cm-1; 1H NMR (500 MHz, CDCl3): δ = 1.63 (s, 1.5H), 1.77 (s, 1.5H), 2.10 (s, 3H), 2.83 (dd, J = 8.5, 14.5 Hz, 0.5H), 2.92(ddd, J = 6.5, 13.5, 20.5 Hz, 1H), 3.09 (dd, J = 5.0, 14.5 Hz, 0.5H), 4.72-4.79 (m, 1H), 4.92 (d, J = 1.0 Hz, 0.5H), 4.95 (d, J = 1.0Hz, 0.5H), 5.01 (m, 1H), 5.22 (d, J = 4.0 Hz, 0.5H), 5.35 (d, J = 6.0 Hz, 0.5H), 5.92 (d, J = 9.0 Hz, 0.5H), 6.20 (d, J = 9.0 Hz, 0.5H), 7.18-7.30 (m, 5H), 7.35-7.50 (m, 3H), 7.56-7.58 (m, 1H), 7.66-7.68 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 19.14, 19.35, 21.19, 21.28, 35.78, 38.62, 50.83, 51.44, 113.39, 114.62, 126.91, 126.99, 127.04, 128.79, 128.82, 128.86, 128.87, 129.51, 131.70, 131.72, 134.83, 134.86, 137.31, 137.48, 141.23, 141.32, 167.22, 167.31, 170.06, 170.22; HRMS(EI, 70eV) calcd for C21H23NO3(M+1) 337.1678; found 337.1677.

3.2. (S)-4-Benzamido-5-(4-methoxyphenyl)-2-methylpent-1-en-3-yl acetate, 3b
96% yield, syn/anti = 1.28/1, colorless oil. IR (neat): 3305, 2942, 1737, 1644 cm-1; 1H NMR (500 MHz, CDCl3): δ = 1.76 (s, 1.5H), 1.85 (s, 1.5H), 2.12 (s, 1.5H), 2.13 (s, 1.5H), 3.03 (dd, J = 5.0, 14.5 Hz, 0.5H), 3.76 (s, 1.5H), 3.78 (s, 1.5H), 4.68-4.72 (m, 1H), 4.92 (d, J = 1.0 Hz, 0.5H), 4.94 (d, J = 1.0 Hz, 0.5H) 5.00 (d, J = 1.0 Hz, 0.5H), 5.01 (d, J = 1.0 Hz, 0.5H) 5.21 (d, J = 3.5 Hz, 0.5H), 5.31 (d, J = 6.0 Hz, 0.5H), 5.88 (d ,J = 9.0 Hz, 0.5H), 6.17 (d, J = 9.5 Hz, 0.5H), 6.80-6.84 (m, 2H), 7.09-7.14 (m, 2H), 7.37-7.51 (m, 3H), 7.58-7.59 (m. 1H), 7.67-7.69 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 19.08, 19.37, 21.21, 21.31, 31.13, 34.82, 37.69, 50.81, 51.60, 55.46, 76.67, 78.36, 113.31, 114.25, 114.31, 114.70, 126.99, 127.05, 128.83, 128.86, 129.27, 130.49, 130.52, 131.70, 134.84, 134.89, 141.27, 141.38, 158.63, 158.70, 167.15, 167.28, 170.07, 170.21; HRMS(EI, 70eV) calcd for C22H25NO4(M+1) 367.1784; found 367.1786.

3.3. (S)-4-Benzamido-2,5-dimethylhex-1-en-3-yl acetate, 3c
98% yield, syn/anti = 1.57/1, colorless needles. IR (neat): 3316, 2964, 1737, 1650 cm-1; 1H NMR (500 MHz, CDCl3): δ = 093-1.03 (m, 12H), 1.80-1.87 (m, 7H), 2.01-2.05 (m, 1H), 2.09 (s, 6H), 4.32 (ddd, J = 5.0, 6.0, 11.0 Hz, 1H), 4.48 (ddd, J = 4.0,7.0,11.0 Hz, 1H), 4.92 (m, 1H), 4.99 (d, J = 1.0 Hz, 0.5H), 5.02 (d, J = 1.0 Hz, 0.5H), 5.29 (d, J = 8.0 Hz, 1H), 4.45 (d, J = 4.5 Hz, 1H), 5.85 (d, J = 10.5 Hz, 1H), 6.08 (d, J = 10.0Hz, 1H), 7.42-7.46 (m, 4H), 7.49-7.52 (m, 2H), 7.70-7.75 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 16.65, 18.46, 18.55, 19.25, 20.25, 20.82, 21.23, 21.35, 28.48, 30.27, 53.81, 55.33, 76.58, 113.21, 115.70, 127.03, 127.07, 128.87, 128.91, 131.66, 131.72, 135.05, 141.65, 141.90, 167.78, 170.31; HRMS(EI, 70eV) calcd for C17H23NO3(M+1) 289.1678; found 289.1681.

3.4. (S)-4-Benzamido-2,6-dimethylhept-1-en-3-yl acetate, 3d
98% yield, syn/anti = 1.19/1, colorless needles. IR (neat): 3303, 2955, 1738, 1642,cm-1; 1H NMR (500 MHz, CDCl3): δ = 0.93-0.99 (m, 6H),1.32-1.46 (m, 2H), 1.65-1.71 (m, 1H), 1.85 (s, 3H), 2.08 (s, 1.5H), 2.11 (s, 1.5H), 4.56 (4.5, 9.5, 14.5 Hz, 0.5H), 4.63 (ddd, J = 5.0, 5.0, 10.0 Hz, 0.5H), 4.95 (m, 2H), 5.26 (dd, J = 4.5, 8.0 Hz, 1H), 5.97 (d, J = 9.5 Hz, 0.5H), 6.03 (d, J = 9.0 Hz, 0.5H), 7.41-7.44 (m, 2H), 7.47-7.51 (m, 1H), 7.71-7.74 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 19.25, 19.73, 21.20, 21.27, 21.80, 22.38, 23.48, 23.97, 25.05, 25.13, 38.99, 41.95, 48.58, 78.77, 79.56, 113.45, 113.63, 127.07, 127.09, 128.85, 131.66, 131.71, 134.92, 141.30, 141.42, 167.23, 16741, 170.41, 170.47; HRMS(EI, 70eV) calcd for C18H25NO3(M+1) 303.1834; found 303.1832.

3.5. (S)-4-Benzamido-5-(tert-butyldimethylsilyloxy)-2-methylpent-1-en-3-yl acetate, 3e
99% yield, syn/anti = 1.09/1, colorless oil. IR (neat): 3322, 2931, 1745, 1646 cm-1, 1H NMR (500 MHz, CDCl3): δ = 0.02-0.05 (m, 6H), 0.91 (s, 9H), 1.80 (s, 1.5H), 1.84 (s, 1.5H), 2.04 (s, 1.5H), 2.09 (s, 1.5H), 3.65 (dd, J = 5.5, 10.5 Hz, 0.5H), 3.73 (dd, J = 3.5, 7.0Hz, 0.5H), 3.76 (dd, J = 3.5, 6.0 Hz, 0.5H), 3.86 (dd, J = 3.0, 10.0 Hz, 0.5H), 4.49-4.51 (m, 1H), 4.99-5.06 (m, 2H), 5.37 (d, J = 8.5 Hz, 0.5H), 5.61 (d, J = 7.0 Hz, 0.5H), 6.42 (d, J = 8.0 Hz, 0.5H), 6.45 (d, J = 9.0 Hz, 0.5H) 7.41-7.52 (m, 3H), 7.70-7.75 (m, 2H); 13C NMR (125 MHz, CDCl3): δ; 3.36 5.35 18.39 19.02 21.21 25.90 50.86 51.72 61.43 62.02 76.07 114.97 115.87 127 27 128 90 131.93 134.63 141.38 167.02 167.33 169.86 170.63;HRMS(EI, 70eV) calcd for C21H32NO4Si(M+1) 391.5822; found 391.5827.

4. General procedure for Oxazolines 4
To a stirred solution of isobutenylic acetate (0.42 g, 1.06 mmol) and K2CO3 (0.44 g, 3.18 mmol, 3.0 equiv) in MeCN (20 mL) was added Pd(PPh3)4 (6.1 mg, 0.05 mmol, 0.05 equiv) under an argon atmosphere. The solution was refluxed for 24 h, whereupon it was cooled to rt and the catalyst was removed by filtration over a pad of silica. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (EtOAc/hexane = 1/20).

4.1. (4S,5S)-4-Benzyl-2-phenyl-5-(prop-1-en-2-yl)-4,5-dihydrooxazole, 4a
74% yield, colorless oil. [α]25D +11.88 (c 1.0, CHCl3); IR (neat): 2924, 1649 cm-1; 1H NMR (500 MHz, CDCl3): δ = 1.51 (s, 1H), 2.76 (dd, J = 8.5, 13.5 Hz, 1H), 3.21 (dd, J = 5.5, 13.5 Hz, 1H), 4.24 (dt, J = 6.0, 8.0 Hz, 1H), 4.71 (d, J = 6.5 Hz, 1H), 4.73 (m, 2H), 7.20-7.31 (m, 5H), 7.39-7.43 (m, 2H), 7.46-7.49 (m, 1H), 7.97-7.99 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 16.82, 42.40, 73.11, 86.81, 112.12, 126.80 128.03 128.55 128.60 128.71 129.91 131.61 137.85 143.32 163.45 ; HRMS (EI, 70eV) calcd for C19H19NO(M+1) 277.1467; found 277.1465.

4.2. (4S,5S)-4-(4-Methoxybenzyl)-2-phenyl-5-(prop-1-en-2-yl)-4,5-dihydrooxazole, 4b
74% yield, colorless oil. [α]25D +57.16 (c 1.0, CHCl3); IR (neat): 2924, 1649 cm-1; 1H NMR (500 MHz, CDCl3): δ = 1.53 (s, 1H), 2.76 (dd, J = 8.5, 13.5 Hz, 1H), 3.21 (dd, J = 5.5, 13.5 Hz, 1H), 3.79 (s, 1H), 4.20 (dt, J = 5.5, 8.5 Hz, 1H), 4.71 (d, J = 6.0 Hz, 1H), 4.75 (t, J = 1.0 Hz, 1H), 4.76 (t, J = 1.0 Hz, 1H), 6.83-6.86 (m, 2H), 7.17-7.20 (m, 2H), 7.40-7.51 (m, 3H), 7.97-7.99 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 16.88, 41.41, 55.50, 73.22, 76.69, 86.73, 112.08, 114.10, 127.00, 128.02, 128.53, 128.59, 129.85, 130.85, 131.59, 143.36, 158.56, 163.37 ; HRMS (EI, 70eV) calcd for C20H21NO2(M+1) 307.1572; found 307.1574.

4.3. (4S,5S)-4-Isopropyl-2-phenyl-5-(prop-1-en-2-yl)-4,5-dihydrooxazole, 4c
74% yield, colorless oil. [α]25D -46.32 (c 1.0, CHCl3); IR (neat): 2959, 1652 cm-1; 1H NMR (500 MHz, CDCl3): δ = 0.97-1.03 (m, 6H), 1.73 (s, 3H), 1.91 (dt, J = 6.0, 10.0 Hz, 1H), 3.83 (dd, J = 5.5, 6.0 Hz, 1H), 4.75 (d, J = 6.0Hz, 1H), 4.88 (dd, J = 1,5, 3.0 Hz, 1H), 5.02 (t, J = 1.5 Hz,1H), 7.39-7.42 (m, 2H), 7.45-7.49 (m, 1H), 7.98-8.00 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 16.82, 18.45, 18.90, 33.15, 85.31, 112.55, 128.11, 128.53, 128.54, 131.44, 144.28, 162.81; HRMS (EI, 70eV) calcd for C15H19NO(M+1) 229.1467; found 229.1468.

4.4. (4S,5S)-4-Isobutyl-2-phenyl-5-(prop-1-en-2-yl)-4,5-dihydrooxazole, 4d
74% yield, colorless oil. [α]25D -53.20 (c 1.0, CHCl3); IR (neat): 2950, 1650 cm-1; 1H NMR (500 MHz, CDCl3): δ = 0.96-1.00 (m, 6H), 1.41 (ddd, J = 7.0, 7.0, 10.5 Hz, 1H), 1.65 (ddd, J = 7.0, 7.0, 10.5 Hz, 1H), 1.75 (s, 1H), 1.89-1.97 (m, 1H), 4.03 (dd, J = 7.0, 14.0 Hz, 1H), 4.61 (d, J = 7.0 Hz, 1H), 4.91 (t, d = 1.5 Hz, 1H), 5.03 (d, J = 1.0 Hz, 1H), 7.38-7.42 (m, 2H), 7.45-7.48 (m, 1H), 7.96-7.98 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 16.90, 23.02, 23.10, 25.17, 46.32, 69.78, 88.92, 112.80, 128.22, 128.48, 128.53, 131.42, 143.62, 162.81; HRMS (EI, 70eV) calcd for C16H21NO(M+1) 243.1623; found 243.1626.

4.5. (4S,5S)-4-((tert-Butyldimethylsilyloxy)methyl)-2-phenyl-5-(prop-1-en-2-yl)-4,5-dihydrooxazole, 4e
75% yield, colorless oil. [α]25D +2.4 (c 1.2, CHCl3); IR (neat): 2930, 1649 cm-1, 1H NMR (500 MHz, CDCl3): δ = 0.03 (s, 3H), 0.07 (s, 3H), 0.85 (s, 9H), 1.74 (s, 3H), 3.66 (J = 10.2Hz, 6.7Hz, 1H), 3.89 (dd, J = 10.2Hz, 3.8Hz), 1H),4.05 (dt, J = 6.4Hz, 3.8Hz, 1H), 4.88 ( t, J = 1.4Hz, 1H), 4.97 (d, J = 5.9Hz, 1H), 5.04 (t, J = 0.7Hz, 1H), 7.51-7.38(m, 3H), 8.01-7.95 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 5.10, 5.09, 17.22, 18.45, 26.04, 65.24, 73.39, 85.21, 111.86, 128.02, 128.52, 131.55, 143.75, 164.27; HRMS (EI, 70eV) calcd for C19H29NO2Si(M+1) 331.5289; found 331.5267.

5. (4R,5S)-Methyl 2-phenyl-5-(prop-1-en-2-yl)-4,5-dihydrooxazole-4-carboxylate, 6
To a solution of oxazoline 4e (1.0 g, 3.0 mmol) in THF (15 mL) was added a solution of tetrabutylammonium fluoride (1 M in THF, 0.96 mL, 3.3 mmol, 1.1 equiv). After being stirred for 4 h, AcOEt (20 mL) and saturated aqueous NH4Cl solution (5 mL) was added and the mixture was diluted with water (20 mL). The aqueous layer was extracted with AcOEt (20 mL × 2). The combined organic layers were dried with MgSO4 and concentrated. The residue was chromatographed on silica gel (EtOAc/hexane =1/2) gave primary alcohol (0.59 g, 90%) as a white solid. [α]25D -51.76 (c 1.0, CHCl3); IR (neat): 3199, 2919, 1645 cm-'; 1H NMR (500 MHz, CDCl3): δ 1.74 (S, 3H), 3.66 (dd, J = 4.0, 12.5 Hz, 1H), 4.05 (m, 2H), 4.94 (t, J = 1.5 Hz, 1H), 4.99 (d, J = 8.0 Hz, 1H), 5.08 (ddd, J = 1.0, 1.0, 1.5 Hz, 1H), 7.34 (m, 2H), 7.45 (m, 1H), 7.85 (m, 2H) ; 13C NMR (125 MHz, CDCl3): δ 16.94, 64.07, 73.09, 84.66, 113.09, 127.31, 128.52, 131.77, 143.01, 165.17; HRMS(EI, 70eV) calcd for C13H15NO2Si(M+1) 217.1103; found 217.1100.
A solution of potassium persulfate (1.1 g, 4.06 mmol, 2.17 equiv.) was dissolved in 1N KOH solution (83 mL), this solution was added to a solution of primary alcohol (0.42 g, 1.92 mmol) in biphasic water/acetonitrile (1/1) (40 mL). RuCl3 hydrate (88 mg, 0.42 mmol, 0.2 equiv.) was then added to the solution under magnetic stirring. The resulting mixture was stirred at room temperature for 24 h. At the end of the reaction, the mixture was extracted with Et2O (5×50 mL). The combined extracts were dried with anhydrous Na2SO4, and the solvent was removed by evaporation under reduced pressure to give the crude product. To the stirred solution of the above the crude product in Et2O (15 mL), an ethereal solution of diazomethane was added dropwise until the reaction mixture turned yellow. The mixture was stirred for 1 h at room temperature. Evaporation of solvents yielded crude compound. The residue was chromatographed on silica gel (EtOAc/hexane = 1/6) gave the compound 6 (0.37 g , 78%) as a colorless oil; [α]25D -63.18 (c 1.0, CHCl3); IR (neat): 2923, 1743, 1644, 1444 cm-1; 1H-NMR (500 MHz, CDCl3) δ 1.77 (s, 3H), 3.84(s, 3H), 4.63-4.64 (d, 7.0 Hz, 1H), 4.68 (dd, J = 1.0 Hz, 1H), 4.68 (dd, J = 1.0 Hz, 1H), 5.30-5.32 (d, J = 7.5 Hz, 1H), 7.41 (m, 2H), 7.51 (m, 1H), 8.03(m, 2H); 13C NMR (125 MHz, CDCl3): δ 17.04, 53.04, 73.48, 85.13, 113.78, 127.15, 128.64, 128.87, 132.18, 141.95, 165.87, 171.75; HRMS(EI, 70eV) calcd for C14H15NO3(M+1) 245.1052; found 245.1050.

6. (4R,5S)-Methyl 5-isopropyl-2-phenyl-4,5-dihydrooxazole-4-carboxylate, 7
To a solution of 6 (100 mg, 4.08 mmol) in MeOH (2 mL) was added 20 mg of 10% Pd/C, and the reaction mixture was vigorously shaken under an atmosphere of hydrogen for 8 h at room temperature. The reaction mixture was filtered through Celite pad, concentrated in vacuo, and purified by column chromatography over silica gel (EtOAc/hexane =1/6) gave 7 (86 mg, 98%) as a colorless oil; [α]25D -107.81 (c 1.0, CHCl3); IR (neat): 2959, 1743, 1645, 1450, 1343 cm-1; 1H-NMR (500 MHz, CDCl3) δ 1.00 (d, J = 7.0 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H), 1.96 (m, 1H), 3.81 (s, 3H), 4.57 (d, 7.0 Hz, 1H), 4.68 (dd, J = 6.5, 7.0 Hz, 1H), 7.41 (m, 2H), 7.50 (m, 1H), 8.00 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 17.52, 17.64, 32.67, 52.91, 71.56, 87.44, 127.45, 128.57, 128.79, 132.01, 165.60, 172.31; HRMS(EI, 70eV) calcd for C14H17NO3(M+1) 247.1208; found 247.1212.

ACKNOWLEDGEMENTS
This work was financially supported by Seoul R & BD Program (10541) and Yonsung Fine Chemicals Co., Ltd.

References

1. For the synthesis of oxazoline: a) K. Y. Lee, Y. H. Kim, M. S. Park, and W. H. Ham, Tetrahedron Lett., 1998, 39, 8129; CrossRef b) K. Y. Lee, Y. H. Kim, M. S. Park, C. Y. Oh, and W. H. Ham, J. Org. Chem., 1999, 64, 9450; CrossRef c) J. E. Joo, K. Y. Lee, V. T. Pham, Y. S. Tian, and W. H. Ham, Org. Lett., 2007, 9, 3627. CrossRef
2. a) K. Y. Lee, Y. H. Kim, C. Y. Oh, and W. H. Ham, Org. Lett., 2000, 2, 4041; CrossRef b) K. Y. Lee, C. Y. Oh, and W. H. Ham, Org. Lett., 2002, 4, 4403; CrossRef c) K. Y. Lee, C. Y. Oh, Y. H. Kim, J. E. Joo, and W. H. Ham, Tetrahedron. Lett., 2002, 43, 9361; CrossRef d) Y. S. Lee, Y. H. Shin, Y. H. Kim, K. Y. Lee, C. Y. Oh, S. J. Pyun, H. J. Park, J. H. Jeong, and W. H. Ham, Tetrahedron: Asymmetry, 2003, 14, 87; CrossRef e) S. J. Pyun, K. Y. Lee, C. Y. Oh, and W. H. Ham, Heterocycles, 2004, 62, 333; CrossRef f) S. J. Pyun, K. Y. Lee, C. Y. Oh, J. E. Joo, S. H. Cheon, and W. H. Ham, Tetrahedron, 2005, 61, 1413; CrossRef g) Y. S. Tian, J. E. Joo, V. T. Pham, K. Y. Lee, and W. H. Ham, Arch. Pharm. Res., 2007, 30, 167; CrossRef h) V. T. Pham, J. E. Joo, Y. S. Tian, Y. S. Chung, K. Y. Lee, C. Y. Oh, and W. H. Ham, Tetrahedron: Asymmetry, 2008, 19, 318; CrossRef i) Y. S. Tian, J. E. Joo, B. S. Kong, V. T. Pham, K. Y. Lee, and W. H. Ham, J. Org. Chem., 2009, 74, 3962. CrossRef
3. For a review of lactacystin syntheses, see: a) M. Shibasaki, M. Kanai, and N. Fukuda, Chem. Asian J., 2007, 2, 20; CrossRef b) Y. Ohfune and T. Shinada, Eur. J. Org. Chem., 2005, 5127; CrossRef c) S. H. Kang, S. Y. Kang, H. S. Lee, and A. J. Buglass, Chem. Rev., 2005, 105, 4537; CrossRef d) C. E. Masse, A. J. Morgan, J. Adams, and J. S. Panek, Eur. J. Org. Chem., 2000, 2513; CrossRef e) E. J. Corey and W. Z. Li, Chem. Pharm. Bull., 1999, 47, 1.
4. For more recent syntheses, see: a) C. B. Gilley, M. J. Buller, and Y. Kobayashi, Org. Lett., 2007, 9, 3631; CrossRef b) J. C. Legeay and N. Langlois, J. Org. Chem., 2007, 72, 10108; CrossRef c) M. Groll, E. P. Balskus, and E. N. Jacobsen, J. Am. Chem. Soc., 2008, 45, 14981; CrossRef d) C. B. Gilley and Y. Kobayashi, J. Org. Chem., 2008, 73, 4198; CrossRef e) C. J. Hayes, A. E. Sherlock, M. P. Green, C. Wilson, A. J. Blake, M. D. Selby, and J. C. Prodger, J. Org. Chem., 2008, 73, 2041; CrossRef f) G. Ma, H. Nguyen, and D. Romo, Org. Lett., 2007, 9, 2143; CrossRef g) T. J. Donohoe, J. Y. K. Chiu, and R. E. Thomas, Org. Lett., 2007, 9, 421; CrossRef h) J. Zhou, M. Gong, P. S. Mariano, and U. C. Yoon, Bull. Korean Chem. Soc., 2008, 29, 89; i) I. Villanueva Margalef, L. Rupnicki, and H. W. Lam, Tetrahedron, 2008, 64, 7896; CrossRef j) G. Pattenden and G. Rescourio, Org. Biomol. Chem., 2008, 6, 3428; CrossRef k) C. H. Yoon, D. L. Flanigan, K. S. Yoo, and K. W. Jung, Eur. J. Org. Chem., 2007, 37. CrossRef
5. a) Q. Li, S. B. Yang, Z. Zhang, L. Li, and P. F. Xu, J. Org. Chem., 2009, 74, 1627; CrossRef b) P. Saravanan, and E. J. Corey, J. Org. Chem., 2003, 68, 2760; CrossRef c) T. Sunazuka, T. Nagamitsu, K. Matsuzaki, H. Tanaka, S. Omura, and A. B. Smith, III, J. Am. Chem. Soc., 1993, 115, 5302; CrossRef d) T. Nagamitsu, T. Sunazuka, H. Tanaka, S. Omura, P. A. Sprengeler, and A. B. Smith, III, J. Am. Chem. Soc., 1996, 118, 3584; CrossRef e) F. Soucy, L. Grenier, M. L. Behnke, A. T. Destree, T. A. McCormack, J. Adams, and L. Plamondon, J. Am. Chem. Soc., 1999, 121, 9967; CrossRef f) S. Iwama, W.-G. Gao, T. Shinada, and Y. Ohfune, Synlett, 2000, 1631; CrossRef g) J. S. Panek and C. E. Masse, Angew. Chem. Int. Ed., 1999, 38, 1093; CrossRef h) J. S. Panek and C. E. Masse, J. Org. Chem., 1998, 63, 2382; CrossRef i) E. J. Corey and S. Choi, Tetrahedron Lett., 1993, 34, 6969; CrossRef j) G. R. Cook and P. S. Shanker, J. Org. Chem., 2001, 66, 6818. CrossRef