Stereoselective intramolecular cyclization of isopentenyl benzamide via π-allylpalladium complex catalyzed by Pd(0)

Article abstract of DOI:10.3987/COM-09-11850

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 ef

Full text of DOI:10.3987/COM-09-11850

HETEROCYCLES, Vol. 81, No. 2, 2010
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HETEROCYCLES, Vol. 81, No. 2, 2010, pp. 293 - 304. © The Japan Institute of Heterocyclic Chemistry
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,a,b Yu Mu,a Yiu-Suk Lee,a Yong-Shou Tian,a Gyu-Jin Lee,a and
Won-Hun Hama*
aSchool of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of
Korea
bYonsung Fine Chemicals Co., Ltd., 129-9 Suchon-ri, Jangan-myeon,
Hwaseong-si, 445-944, Republic of Korea
whham@skku.edu
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 –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.

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HETEROCYCLES, Vol. 81, No. 2, 2010
R
OAc
Pd(PPh3)4
N
R
O
K2CO3, MeCN
reflux
NHBz
Ph
87-100% de
68-83% yield
R = phenyl, benzyl, isobutyl, cyclohexylmethyl
Scheme 1. Palladium(0)-catalyzed oxazoline formation
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).
OH
1) Dess-Martin
R
R
periodinane, CH2Cl2
OH
NHBz
NHBz
THF, 0 oC
MgBr
2)
1a R=benzyl
2a R=benzyl (74%)
1b R=4-methoxylbenzyl
1c R=isopropyl
1d R=isobutyl
2b R=4-methoxylbenzyl (69%)
2c R=isopropyl (70%)
2d R=isobutyl (68%)
1e R=
tert
-butyldimethylsilyloxymethyl
2e R=
tert
-butyldimethylsilyloxymethyl (75%)
OAc
Ac2O, Py.
R
DMAP(cat.), CH2Cl2
NHBz
3a R=benzyl (97%)
4-methoxylbenzyl (96%)
3b R=
3c R=isopropyl (98%)
3d R=isobutyl (98%)
3e R=
tert
-butyldimethylsilyloxymethyl (99%)
Scheme 2
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)

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295
Table 1. Palladium(0)-Catalyzed Oxazoline Formation Reaction of
Isobutenylic Acetates 3a-e
R
R
OAc
Pd(PPh3)4
R
N
O
N
O
K2CO3, MeCN
reflux
NHBz
3a-e
Ph
4a-e
Ph
5a-e
Substrate
Time(h)
Yield(%)a
Ratio(4:5)b
3a
3b
3c
3d
3e
24
24
24
24
24
69
71
70
72
75
17:1
16:1
16:1
13:1
>20:1
Reaction conditions: Pd(PPh3)4 (5 mol%), K2CO3 (2 equiv), MeCN, reflux.
aYields refer to isolated and chromatographically pure products. b Ratios were
determined by 1H NMR.
1
The stereochemistry of the oxazoline obtained above was elucidated by the H 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.
L
L
H3C
R
Pd
L
Pd
R
L
N
CH3
O
N
O
Ph
Ph
A
B
Figure 1
This change in the diastereoselectivity of oxazoline ring formation is predominantly controlled by steric
repulsion between R groups and the methyl group.

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HETEROCYCLES, Vol. 81, No. 2, 2010
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]D25 = -107.81 (c = 1.0, CHCl3)} was in good agreement with the
reported value, which also conclusively proved the stereochemical assignment5a (Scheme 3).
O
O
Pd/C, H2
1) TBAF, THF 90%
MeO
TBSO
MeO
MeOH 98%
2) K2S2O8, RuCl3
H2O:acetone=1:1
3) CH2N2, EtOH 78%
N
O
N
O
N
O
Ph
Ph
4e
Ph
6
7
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.
O
O
HO2C
S
Me
Me
Me
NH
O
NHAc
NH
O
Me
HO
HO
OH
O
(+)-lactacystin 8
9
omuralide
Figure 2. (+)-Lactacystin and Omuralide.
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

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297
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 –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
1
Optical rotations were measured on a JASCO DIP 1020 digital polarimeter. H 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  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

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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 =
13
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) C
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
1
70% yield, syn/anti = 1.57/1, colorless needles. IR (neat): 3351, 2961, 1640 cm-1; H 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

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1
68% yield, syn/anti =1.20/1, colorless needles. IR (neat): 3338, 2954, 1638 cm-1; H 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
13
(m, 2H); C 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
1
75% yield, syn/anti = 1.09/1, colorless oil. IR (neat): 3327, 2930, 1643 cm-1; H 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
1
97% yield, syn/anti = 1.33/1, colorless oil. IR (neat): 3300, 2932, 1737, 1644 cm-1; H 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,

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HETEROCYCLES, Vol. 81, No. 2, 2010
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
1
96% yield, syn/anti = 1.28/1, colorless oil. IR (neat): 3305, 2942, 1737, 1644 cm-1; H 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,
13
3H), 7.58-7.59 (m. 1H), 7.67-7.69 (m, 1H); C 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
1
98% yield, syn/anti = 1.57/1, colorless needles. IR (neat): 3316, 2964, 1737, 1650 cm-1; H 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
1
98% yield, syn/anti = 1.19/1, colorless needles. IR (neat): 3303, 2955, 1738, 1642,cm-1; H 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
1
99% yield, syn/anti = 1.09/1, colorless oil. IR (neat): 3322, 2931, 1745, 1646 cm-1, H 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),

HETEROCYCLES, Vol. 81, No. 2, 2010
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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,
13
2H); C 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]2D5 +11.88 (c 1.0, CHCl3); IR (neat): 2924, 1649 cm-1; H NMR (500 MHz,
1
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,
13
1H), 7.97-7.99 (m, 2H); C 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]2D5 +57.16 (c 1.0, CHCl3); IR (neat): 2924, 1649 cm-1; H NMR (500 MHz,
1
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]2D5 -46.32 (c 1.0, CHCl3); IR (neat): 2959, 1652 cm-1; H NMR (500 MHz,
1
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)

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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]2D5 -53.20 (c 1.0, CHCl3); IR (neat): 2950, 1650 cm-1; H 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
1
13
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); C 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]2D5 +2.4 (c 1.2, CHCl3); IR (neat): 2930, 1649 cm-1, H NMR (500 MHz,
1
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]2D5 -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),
13
7.34 (m, 2H), 7.45 (m, 1H), 7.85 (m, 2H) ; C 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

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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]2D5 -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]D25
-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
13
(dd, J = 6.5, 7.0 Hz, 1H), 7.41 (m, 2H), 7.50 (m, 1H), 8.00 (m, 2H); C 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.
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