Stereoselective intramolecular oxazine formation by a π-allylpalladium complex catalyzed by Pd0

Article abstract of DOI:10.1002/ejoc.200600927

An efficient procedure for synthesizing oxazines was developed by the palladium(0)-catalyzed intramolecular cyclization of a benzamide through a π-allylpalladium(II) complex. Unlike other palladium-catalyzed reactions, the temperature was found to be a ke

Full text of DOI:10.1002/ejoc.200600927

FULL PAPER
DOI: 10.1002/ejoc.200600927
Stereoselective Intramolecular Oxazine Formation by a π-Allylpalladium
Complex Catalyzed by Pd0
Jae-Eun Joo,[a] Kee-Young Lee,[a] Van-Thoai Pham,[a] and Won-Hun Ham*[a]
Keywords: Stereoselective synthesis / Chiral oxazine / Catalysis / Amino alcohol / Palladium / Synthetic methods
An efficient procedure for synthesizing oxazines was devel-
was found to be a key factor in determining the stereochem-
oped by the palladium(0)-catalyzed intramolecular cycliza- istry of the oxazine.
tion of a benzamide through a π-allylpalladium(II) complex.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Unlike other palladium-catalyzed reactions, the temperature
Germany, 2007)
Introduction
Results and Discussion
Allylpalladium chemistry has become one of the most
successful areas of organometallic catalysis due to its re-
markable capacity for continuous renewal.[1] Catalytic
transformations involving nucleophilic attack on (η3-allyl)-
palladium intermediates have been widely used in a number
of important chemical processes including allylic substitu-
tion and the transformation of alkenes.[2]
The palladium(0)-catalyzed intramolecular cyclization of
a benzamide through a π-allylpalladium(II) complex is use-
ful for the synthesis of highly functionalized compounds,
particularly when chirality transfer is involved.[3] A previous
paper described a new procedure for the highly stereoselec-
tive formation of an oxazoline ring from an acyclic allylic
amide possessing a benzoyl substituent as an N-protecting
group in the presence of tetrakis(triphenylphosphane)palla-
dium(0) and base (K2CO3). The synthetic utility of these
oxazolines as chiral building blocks has been demonstrated
by their successful application to the synthesis of β-amino-
α-hydroxy and γ-amino-β-hydroxy acids[4] and biologically
active natural products such as preussin,[5] sphingofungin
F,[6] spectaline,[7] myriocin,[8] L-733060,[9] 1-deoxygalac-
tonojirimycin,[10] and 1-deoxygulonojirimycin.[11]
As a model study, we monitored the reactivity of com-
pound 1a and attempted to identify the optimum condi-
tions for this unusual cyclization reaction. The necessary
cyclization precursor 1a was simply prepared from our ox-
azolines.[12]
The conditions for the cyclization of the oxazine precur-
sor 1a were investigated by examining the effects of the
bases, ligands, and solvents as summarized in Table 1.
Unfortunately, most of the conditions did not work at all
when the leaving group was acetate. However, in the case of
chloride, the reaction proceeded sluggishly under the same
conditions [Pd(PPh3)4, K2CO3, and CH3CN] that were used
in the formation of the oxazoline. The use of a much
stronger base such as NaH improved the yield. Therefore,
under the conditions of Pd(PPh3)4, NaH, and nBu4NI in
THF at room temp., the intramolecular cyclization afforded
the oxazine 2a as a 5:1 syn/anti mixture (as determined by
1H NMR) in a moderate yield (59%).
These reaction conditions were then extended to other
substrates used to investigate the influence of the R group
on the reactivity. The substrates were synthesized according
to the procedure shown in Scheme 1.
As part of an ongoing program directed at expanding the
scope of the palladium(0)-catalyzed intramolecular cycliza-
tion of benzamides through a π-allylpalladium(II) complex,
this study examined the formation of oxazines from γ-allyl-
benzamides, which contain an additional carbon atom com-
pared to the substrates used in the formation of oxazolines.
This paper discusses the results of these reactions.
The ozonolysis of olefins 3a–d and their subsequent
Horner–Wadsworth–Emmons reaction afforded the α,β-un-
saturated esters 4a–d with good (E)/(Z) selectivity (Ͼ15:1
1
as determined by H NMR). The reduction of compounds
4a–d by DIBALH at –78 °C produced the corresponding
allylic alcohols 5a–d in high yield. The conversion of these
alcohols to chlorides and the subsequent acid-catalyzed hy-
drolysis of the oxazolines, followed by the addition of so-
dium hydrogencarbonate to increase the pH of the reaction
mixture to 9.0, furnished the syn-amino alcohols 7a–d.[13]
The protection of the resulting alcohols by TBDMSCl af-
forded the cyclization precursors 1a–d in good yield.
[a] College of Pharmacy, SungKyunKwan University,
Suwon 440-746, Korea
The application of the same method to compound 1 with
benzyl, isopropyl, isobutyl and cyclohexylmethyl as the sub-
Fax: +80-31-292-8800
E-mail: whham@skku.edu
1586
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1586–1593

Stereoselective Oxazine Formation Catalyzed by Pd0
Table 1. Oxazine formation catalyzed by Pd0.
FULL PAPER
X
Pd0[a]
Conditions[b]
Yield [%][c]
syn/anti[d]
OAc
OAc
OAc
OAc
Cl
Cl
Cl
Pd2dba3, dppe
Pd2dba3, dppe
Pd(PPh3)4
K2CO3, CH3CN, reflux, 24 h
NaH, THF, room temp., 24 h
K2CO3, CH3CN, reflux, 24 h
NaH, THF, room temp., 24 h
K2CO3, CH3CN, reflux, 12 h
NaH, THF, room temp., 12 h
K2CO3, CH3CN, reflux, 12 h
NaH, THF, room temp., 12 h
NaH, nBu4NI, THF, room temp., 12 h
no reaction
no reaction
no reaction
–
–
–
–
–
Pd(PPh3)4
low
low
low
15
40
59
Pd2dba3, dppe
Pd2dba3, dppe
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
–
3.1:1
4.5:1
5:1
Cl
Cl
[a] Pd0 was used as follows: Pd(PPh3)4 (0.2 equiv.) or Pd2dba3 (0.1 equiv.) in the presence or absence of dppe (0.4 equiv.). [b] Base was
used as follows: NaH (2 equiv.) or K2CO3 (2 equiv.). [c] Yields refer to pure products or product mixtures (syn/anti). [d] Ratio was
1
determined by H NMR spectroscopy.
Table 2. Oxazine formation from various substrates.[a]
Allyl chloride
Temp.
Time [h] Yield [%][b] syn/anti[c]
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
0 °C
room temp.
40 °C
0 °C
room temp.
40 °C
0 °C
room temp.
40 °C
0 °C
room temp.
40 °C
5
80
59
68
73
64
77
88
76
72
89
66
73
8.3:1
5:1
1:15.2
13.4:1
1:9
1:16
9:1
1:1.4
1:7.5
14:1
4.4:1
1:8.5
12
12
5
12
12
5
12
12
5
12
12
[a] Reaction conditions: Pd(PPh3)4 (0.2 equiv.), NaH (2 equiv.),
nBu4NI (1 equiv.), and THF. [b] Yields refer to pure products or
product mixtures. [c] Ratio was determined by 1H NMR spec-
troscopy.
performed at 0 °C, in which a possible inversion of the
selectivity observed under cold reaction conditions was an-
ticipated, the syn products were produced as major isomers.
It is interesting that the palladium-catalyzed reaction is so
Scheme 1.
stituent group afforded the corresponding oxazines 2a–d in dependent on the temperature. To the best of our knowl-
moderate to good yields and diastereoselectivities as sum- edge, there is no example of a palladium-catalyzed reaction
marized in Table 2.
The reaction at room temp. showed a different selectivity the reaction temperature ranging in the range 0–40 °C.
depending on the R groups. However, it should be noted A possible explanation for the stereoselective formation
that shows a drastic stereochemical change that depends on
that when the reaction temperature was increased to 40 °C, of syn-2 or anti-2 is as follows (Scheme 2). The chair-like
a drastic change was observed in the diastereoselectivity, transition states A and B which have the bulky tert-butyldi-
particularly in the case of benzyl and cyclohexylmethyl as methylsilyloxy (TBDMSO) group in an equatorial orienta-
the substituents, where the anti adducts were obtained as tion to minimize the conformational energy, are proposed
the major isomers. In contrast, when the same reaction was to explain the stereochemical outcome of the cyclization.
Eur. J. Org. Chem. 2007, 1586–1593
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J.-E. Joo, K.-Y. Lee, V.-T. Pham, W.-H. Ham
FULL PAPER
The initial π-allylpalladium complexes A and B were equili- to overcome the higher energy barrier for the formation of
brated by π-σ-π isomerization.[14] Although the axially dis- transition state D than that of transition state C, once this
posed π-allylpalladium complex in transition state A might barrier is overcome, the thermodynamic product anti-2 is
suffer from a non-bonding gauche repulsion with the preferred because it is more stable than syn-2, which is ther-
TBDMSO group, transition state B appears to be further modynamically not favored due to the presumed 1,3-
destabilized by non-bonded steric repulsion between the pseudodiaxial interaction between the vinyl and R groups.
equatorial π-allylpalladium complex and the TBDMSO
At room temp., the presumed 1,3-diaxial interaction in
group. It is reasonable to assume that the formation of tran- transition state C could compete with the non-bonded steric
sition state C followed by the intramolecular cyclization to repulsion in transition state B. This rationale is partly sup-
syn-2 is kinetically preferred due to the non-bonded steric ported by the relatively high anti stereoselectivities (thermo-
repulsion in transition state B. This appears to be the dynamic product formation) at room temp. in the more
reason why the kinetic product syn-2 was obtained at 0 °C. bulky precursors (where R = isopropyl or isobutyl).
On the other hand, the observed stereochemical outcome at
In order to confirm the role of the TBDMSO group in
40 °C can be regarded to be a consequence of the selective stereoselectivity, (E,R)-N-(6-chloro-1-phenylhex-4-en-2-yl)-
formation of transition state D. Although it is more difficult benzamide was prepared from -phenylalanine. The expo-
sure of allyl chloride lacking the bulky TBDMSO group to
the same conditions for oxazine formation resulted in an
approximately 1:1 mixture of the syn- and anti-oxazines in
57% yield. This result verified that the bulky TBDMSO
group plays an important role in determining the stereose-
lectivity during oxazine formation.
Although it is difficult to fully rationalize these results at
this stage, this phenomenon is beneficial from a synthetic
viewpoint because one can take advantage of the unique
amino alcohol moiety present in the oxazines for the syn-
thesis of natural products.
To verify the stereochemical outcome of the newly gener-
ated stereocenter, C-6, the oxazines were transformed into
their acetonides because the coupling constants of 4-H, 5-
H, and 6-H obtained for the oxazines did not provide con-
crete information as to their stereochemistry. This was ac-
complished by hydrolyzing the oxazine ring to the benzo-
ylamino alcohol by a simple treatment with 3 ⁿ HCl, and
the TBDMSO group was then removed with TBAF to give
the diol. The resulting diol was protected as the acetonide
by a reaction with 2,2-dimethoxypropane and TsOH in ace-
tone (Scheme 3).
Initially, the coupling constants of 3-H and 4-H in the
acetonides were determined, but unfortunately, they had
similar values of 8.5 Hz and 7.5 Hz. Therefore, the NOE
spectrum was studied under the assumption that there must
be an NOE difference between the two isomers because in
Scheme 2.
the case of the cis-acetonide, 3-H and 4-H are on the same
Scheme 3.
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Stereoselective Oxazine Formation Catalyzed by Pd0
FULL PAPER
spectra were recorded with a JMS-700 Mstation. Flash chromatog-
raphy was executed with Merck Kiesegel 60 (230–400 mesh) with
mixtures of ethyl acetate and hexane as eluents. Ethyl acetate and
hexane were dried and purified by distillation prior to use. Tetra-
hydrofuran (THF) and diethyl ether (Et2O) were distilled from so-
dium and benzophenone (indicator). Dichloromethane (CH2Cl2)
was shaken with concentrated sulfuric acid, dried with potassium
carbonate, and distilled. Commercially available compounds were
used without further purification.
side. It was expected that both protons would show a sim-
ilar NOE with the neighboring methyl group [CH3(b)] but
not with the methyl group [CH3(a)] on the opposite side.
However, in the trans-acetonide, each proton (3-H and 4-
H) had a single NOE with the methyl group sharing the
same space (Figure 1).
Methyl (E)-3-[(4S,5S)-4-Benzyl-4,5-dihydro-2-phenyloxazol-5-yl]-
acrylate (4a): Oxazoline 3a (6.78 mmol, 1 equiv.) was dissolved in
dry methanol (50 mL) and cooled to –78 °C. Ozonized oxygen was
bubbled into the solution until the reaction was complete. The reac-
tion mixture was quenched with (CH3)2S (1.0 mL) and warmed to
room temp. The solvents were evaporated under reduced pressure.
The crude aldehyde was immediately employed in the next step
without further purification. To a stirred solution of LiCl (0.34 g,
8.14 mmol, 1.2 equiv.) in CH3CN (80 mL), were added trimethyl-
phosphonoacetate (1.18 mL, 8.14 mmol, 1.2 equiv.) and 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (1.01 mL, 6.78 mmol, 1 equiv.), and stir-
ring was continued for 1 h. The crude aldehyde in CH3CN (10 mL)
was added, and the reaction mixture was stirred for 2 h. The reac-
tion mixture was poured into H2O (50 mL) and extracted with
EtOAc (3ϫ50 mL). The combined organic layers were washed with
brine, dried with MgSO4, and concentrated in vacuo. Purification
by silica gel chromatography (ethyl acetate/hexane = 1:6) gave (E)-
α,β-unsaturated ester 4a in 80% yield (2 steps); colorless oil. [α]2D0
= +106.7 (c = 1.0, CHCl ). IR (neat): ν = 3027, 2948, 1725, 1651,
˜
3
Figure 1. Observed NOEs in acetonides 10 and 11.
1322 1274 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.76 (dd, J =
13.5, 9 Hz, 1 H), 3.30 (dd, J = 13.5, 5 Hz, 1 H), 3.68 (s, 3 H), 4.32
(ddd, J = 9, 6.5, 5 Hz, 1 H), 4.89 (ddd, J = 6.5, 5, 1.5 Hz, 1 H),
5.80 (dd, J = 15.5, 1.5 Hz, 1 H), 6.65 (dd, J = 15.5, 5 Hz, 1 H),
7.24–7.34 (m, 5 H), 7.40–7.44 (m, 2 H), 7.48–7.50 (m, 1 H), 7.96–
7.98 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 42.2, 52.4,
74.6, 82.6, 121.3, 127.6, 127.9, 129.05, 129.17, 129.46, 130.1, 132.4,
137.6, 145.8, 163.6, 166.9 ppm. According to the procedure de-
scribed above for the ester 4a, olefins 3b–d were converted into
esters 4b–d.
A similar increase in the NOE value of CH3(b)–3-H and
CH3(b)–4-H of the cis-acetonide was observed, but there
were no NOEs involving CH3(a). Unfortunately, the NOE
experiment for the trans-acetonide was unsuccessful be-
cause the chemical shifts of 3-H and 4-H are almost the
same. However, the NOE for the cis-acetonide was suf-
ficient to verify the stereochemistry of the oxazines.
Methyl (E)-3-[(4S,5S)-4,5-Dihydro-4-isopropyl-2-phenyloxazol-5-yl-
]acrylate (4b): 78% yield (2 steps); colorless oil. [α]2D0 = +115.2 (c
Conclusions
This study developed an efficient procedure for synthe- = 1.0, CHCl ). IR (neat): ν = 2956, 1727, 1655, 1450, 1274,
˜
3
1193 cm–1. H NMR (500 MHz, CDCl3): δ = 0.97 (d, J = 6.5 Hz,
1
sizing oxazines by a palladium(0)-catalyzed intramolecular
cyclization of benzamides through a π-allylpalladium(II)
complex. It should be noted that unlike other palladium-
catalyzed reactions, temperature is the critical factor in de-
termining the stereochemistry of the oxazine. A means of
generating an alcohol moiety stereoselectively in the γ-posi-
tion of the amine is important from a synthetic point of
view. Studies examining the reactivity and stereoselectivity
3 H), 1.05 (d, J = 6.5 Hz, 3 H), 1.95 (m, J = 6.5, 6.5, 6.5 Hz, 1 H),
3.74 (s, 3 H), 3.88 (dd, J = 6.5, 6.5 Hz, 1 H), 4.92 (ddd, J = 6.5, 5,
1.5 Hz, 1 H), 6.08 (dd, J = 15.5, 1.5 Hz, 1 H), 6.94 (dd, J = 15.5,
5 Hz, 1 H), 7.40–7.44 (m, 2 H), 7.48–7.51 (m, 1 H), 7.97–7.99 (m,
2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 18.7, 19.4, 52.5, 79.3,
80.7, 121.3, 128.1, 129.0, 129.1, 132.2, 146.6, 162.8, 167.1 ppm.
Methyl (E)-3-[(4S,5S)-4,5-Dihydro-4-isobutyl-2-phenyloxazol-5-yl]-
acrylate (4c): 81% yield (2 steps); colorless oil. [α]2D0 = +67.2 (c =
during the formation of the oxazine when various alkyl
groups are substituted for the TBDMSO group are cur-
rently underway.
1.0, CHCl ). IR (neat): ν = 2955, 1727, 1654, 1450, 1367, 1321,
˜
3
1
1171 cm–1. H NMR (500 MHz, CDCl3): δ = 0.98 (d, J = 6.5 Hz,
3 H), 1.00 (d, J = 6.5 Hz, 3 H), 1.46 (ddd, J = 6.5, 6.5, 6.5 Hz, 1
H), 1.68 (ddd, J = 6.5, 6.5, 6.5 Hz, 1 H), 1.90 (m, 1 H), 3.76 (s, 3
H), 4.09 (ddd, J = 6.5, 6.5, 6.5 Hz, 1 H), 4.78 (ddd, J = 6.5, 5.5,
1.5 Hz, 1 H), 6.10 (dd, J = 15.5, 1.5 Hz, 1 H), 6.98 (dd, J = 15.5,
5.5 Hz, 1 H), 7.40–7.43 (m, 2 H), 7.47–7.49 (m, 1 H), 7.95–7.97 (m,
2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 26.83, 26.85, 27.19,
34.10, 34.20, 35.17, 44.7, 52.5, 71.1, 84.2, 121.6, 128.10, 128.98,
129.09, 132.20, 145.7, 163.0, 167.0 ppm.
Experimental Section
General: Optical rotations were measured with a JASCO DIP 1020
1
digital polarimeter. H and 13C NMR spectra were recorded with
a Varian INOVA FT-NMR spectrometer at 500 and 125 MHz,
respectively, in CDCl3. Chemical shifts are reported as δ values in
ppm relative to CHCl3 (δ = 7.26 ppm) in CDCl3. IR spectra were
measured with a Bruker FT-IR spectrometer. High-resolution mass
Methyl (E)-3-[(4S,5S)-4-(Cyclohexylmethyl)-4,5-dihydro-2-phen-
yloxazol-5-yl]acrylate (4d): 84% yield (2 steps); colorless oil. [α]2D0
Eur. J. Org. Chem. 2007, 1586–1593
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J.-E. Joo, K.-Y. Lee, V.-T. Pham, W.-H. Ham
FULL PAPER
= +44.7 (c = 1.0, CHCl ). IR (neat): ν = 2923, 1727, 1654, 1448,
(4S,5S)-4-Benzyl-5-[(E)-3-chloroprop-1-enyl]-4,5-dihydro-2-phenyl-
oxazole (6a): p-Toluenesulfonyl chloride (6.38 g, 33.45 mmol,
10 equiv.) and 4-(dimethylamino)pyridine (2.04 g, 16.73 mmol,
5 equiv.) were added to a stirred solution of allylic alcohol 5a
(3.35 mmol, 1 equiv.) in dry CH2Cl2 (35 mL) at room temp., and
stirring was continued for 24 h. The reaction mixture was quenched
with H2O (50 mL) and extracted with CH2Cl2 (3ϫ30 mL). The
combined organic layers were washed with brine, dried with
MgSO4, and concentrated in vacuo. Purification by silica gel
chromatography (ethyl acetate/hexane = 1:6) gave allyl chloride 6a
in 86% yield; colorless oil. [α]2D0 = +25.6 (c = 1.0, CHCl3). IR (neat):
˜
3
1372, 1271 cm–1. H NMR (500 MHz, CDCl3): δ = 0.96–0.99 (m,
1
2 H), 1.16–1.28 (m, 3 H), 1.42–1.45 (m, 1 H), 1.50–1.64 (m, 1 H),
1.66–1.73 (m, 4 H), 1.79–1.80 (m, 2 H), 3.76 (s, 3 H), 4.12 (ddd, J
= 7, 7, 7 Hz, 1 H), 4.78 (ddd, J = 7, 5.5, 1.5 Hz, 1 H), 6.09 (dd, J
= 15.5, 1.5 Hz, 1 H), 6.97 (dd, J = 15.5, 5.5 Hz, 1 H), 7.40–7.43
(m, 2 H), 7.47–7.49 (m, 1 H), 7.95–7.97 (m, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 23.40, 23.52, 25.8, 46.0, 52.5, 71.7, 84.1,
121.7, 128.10, 128.97, 129.08, 132.19, 145.7, 162.9, 167.0 ppm.
(E)-3-[(4S,5S)-4-Benzyl-4,5-dihydro-2-phenyloxazol-5-yl]prop-2-en-
1-ol (5a): iBu2AlH (1.0  solution in hexane (13.13 mL,
13.13 mmol, 3 equiv.) was added to a solution of the α,β-unsatu-
rated ester 4a (4.38 mmol, 1 equiv.) in dry THF (25 mL) at –78 °C.
The reaction mixture was stirred at –78 °C for 2 h and diluted with
Et2O (25 mL) and saturated aqueous NH4Cl (5 mL). After being
stirred at room temp. for 2 h, the resulting suspension was filtered
through a Celite pad. The filtrate was concentrated in vacuo to give
the crude product, which upon purification by column chromatog-
raphy on silica gel (ethyl acetate/hexane = 1:2) gave the allylic
ν = 1649, 1494, 1450, 1328, 1061 cm–1 1H NMR (500 MHz,
.
˜
CDCl3): δ = 2.76 (dd, J = 13.5, 8.5 Hz, 1 H), 3.29 (dd, J = 13.5,
5.5 Hz, 1 H), 3.93 (m, 2 H), 4.26 (ddd, J = 8.5, 7, 5.5 Hz, 1 H),
4.77 (dd, J = 7, 6 Hz, 1 H), 5.62 (m, 2 H), 7.22–7.33 (m, 5 H),
7.40–7.51 (m, 3 H), 7.95–7.98 (m, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 42.15, 44.48, 74.51, 83.95, 127.40, 128.22, 128.54,
129.02, 129.10, 129.30, 130.17, 132.24, 133.02, 137.89, 163.70 ppm.
According to the procedure described above for the allylic chloride
6a, alcohols 5b–d were converted into allylic chlorides 6b–d.
alcohol 5a in 93% yield; colorless oil. [α]2D0 = +15.4 (c = 1.0,
1
CHCl ). IR (neat): ν = 3271, 1644, 1495, 1450, 1331 cm–1. H
(4S,5S)-5-[(E)-3-Chloroprop-1-enyl]-4,5-dihydro-4-isopropyl-2-phen-
˜
3
NMR (500 MHz, CDCl3): δ = 2.76 (dd, J = 13.5, 8.5 Hz, 1 H), yloxazole (6b): 84% yield; colorless oil. [α]2D0 = +0.7 (c = 1.0,
3.24 (dd, J = 13.5, 5.5 Hz, 1 H), 4.01 (m, 2 H), 4.23 (ddd, J = 8.5,
7, 5.5 Hz, 1 H), 4.78 (dd, J = 7, 6 Hz, 1 H), 5.57–5.66 (m, 2 H),
7.20–7.31 (m, 5 H), 7.39–7.50 (m, 3 H), 7.94–7.96 (m, 2 H) ppm.
CHCl ). IR (neat): ν = 2958, 1652, 1449, 1327, 1249, 1062 cm–1.
˜
3
1H NMR (500 MHz, CDCl3): δ = 0.96 (d, J = 6.5 Hz, 3 H), 1.01
(d, J = 6.5 Hz, 3 H), 1.92 (m, 1 H), 3.81 (dd, J = 6.5, 6.5 Hz, 1 H),
13C NMR (125 MHz, CDCl3): δ = 42.2, 63.0, 74.3, 84.8, 127.31, 4.08 (m, 2 H), 4.81 (dd, J = 6.5, 6.5 Hz, 1 H), 5.85–5.97 (m, 2 H),
128.23, 129.02, 129.09, 129.20, 129.22, 130.26, 132.23, 132.91, 7.40–7.43 (m, 2 H), 7.47–7.50 (m, 1 H), 7.96–7.98 (m, 2 H) ppm.
138.1, 164.0 ppm. According to the procedure described above for
13C NMR (125 MHz, CDCl3): δ = 18.81, 19.41, 33.3, 44.6, 79.1,
the alcohol 5a, esters 4b–d were converted into alcohols 5b–d.
82.0, 128.34, 128.55, 129.00, 129.02, 132.04, 134.10, 162.94 ppm.
(E)-3-[(4S,5S)-4,5-Dihydro-4-isopropyl-2-phenyloxazol-5-yl]prop-2- (4S,5S)-5-[(E)-3-Chloroprop-1-enyl]-4,5-dihydro-4-isobutyl-2-phen-
en-1-ol (5b): 99% yield; colorless oil. [α]2D0 = –23.4 (c = 1.0, CHCl3).
yloxazole (6c): 87% yield; colorless oil. [α]2D0 = –20.9 (c = 1.0,
1
1
IR (neat): ν = 3273, 1646, 1450, 1343 cm–1. H NMR (500 MHz,
CHCl ). IR (neat): ν = 2955, 1650, 1450, 1325, 1060 cm–1. H
˜
˜
3
CDCl3): δ = 0.96 (d, J = 6.5 Hz, 3 H), 1.02 (d, J = 6.5 Hz, 3 H),
1.90 (m, 1 H), 3.80 (dd, J = 6.5, 6.5 Hz, 1 H), 4.20 (dd, J = 5,
1.5 Hz, 2 H), 4.82 (ddd, J = 6.5, 6.5, 0.5 Hz, 1 H), 5.82 (dddd, J =
NMR (500 MHz, CDCl3): δ = 0.96–1.00 (m, 6 H), 1.42 (m, 1 H),
1.66 (m, 1 H), 1.89 (m, 1 H), 4.01 (dd, J = 14.5, 7.0 Hz, 1 H), 4.08
(m, 2 H), 4.66 (dd, J = 7.0, 7.0 Hz, 1 H), 5.93 (m, 2 H), 7.38–7.40
15, 6.5, 1.5, 1.5 Hz, 1 H), 5.96 (dddd, J = 15, 5, 5, 0.5 Hz, 1 H), (m, 2 H), 7.46–7.49 (m, 1 H), 7.94–7.96 (m, 2 H) ppm. 13C NMR
7.39–7.42 (m, 2 H), 7.46–7.49 (m, 1 H), 7.95–7.98 (m, 2 H) ppm.
(125 MHz, CDCl3): δ = 22.9, 23.2, 25.3, 44.1, 45.4, 71.2, 85.0,
13C NMR (125 MHz, CDCl3) δ 18.83, 19.39, 33.3, 63.3, 79.1, 82.6, 128.0, 128.5, 128.6, 128.7, 131.6, 132.8, 162.6 ppm.
128.46, 128.98, 129.00, 130.61, 131.98, 132.43, 163.1 ppm.
(4S,5S)-5-[(E)-3-Chloroprop-1-enyl]-4-(cyclohexylmethyl)-4,5-di-
(E)-3-[(4S,5S)-4,5-Dihydro-4-isobutyl-2-phenyloxazol-5-yl]prop-2-
en-1-ol (5c): 92% yield; colorless oil. [α]2D0 = –40.9 (c = 1.0, CHCl3).
hydro-2-phenyloxazole (6d): 91% yield; colorless oil. [α]2D0 = –43.3
(c = 1.0, CHCl ). IR (neat): ν = 2921, 1650, 1448, 1329, 1061 cm–1.
˜
3
IR (neat): ν = 3272, 2955, 1645, 1450, 1330 cm–1
.
1H NMR
1H NMR (500 MHz, CDCl3): δ = 0.95–0.99 (m, 2 H), 1.16–1.31
(m, 3 H), 1.40–1.44 (m, 1 H), 1.54–1.58 (m, 1 H), 1.65–1.73 (m, 4
H), 1.77–1.82 (m, 2 H), 4.03–4.10 (m, 3 H), 4.66 (dd, J = 6.5,
6.5 Hz, 1 H), 5.89 (dd, J = 15.5, 6.5 Hz, 1 H), 5.96 (dddd, J = 15.5,
6.5, 6.5, 0.5 Hz, 1 H), 7.26–7.42 (m, 2 H), 7.46–7.48 (m, 1 H), 7.94–
˜
(500 MHz, CDCl3): δ = 0.98 (m, 6 H), 1.41 (ddd, J = 7, 7, 7 Hz, 1
H), 1.64 (ddd, J = 7, 7, 7 Hz, 1 H), 1.89 (m, 1 H), 4.00 (ddd, J =
7, 7, 7 Hz, 1 H), 4.20 (dd, J = 5, 1.5 Hz, 2 H), 4.67 (ddd, J = 7, 7,
0.5 Hz, 1 H), 5.85 (dddd, J = 15, 7, 1.5, 1.5 Hz, 1 H), 5.96 (dddd,
J = 15, 5, 5, 0.5 Hz, 1 H), 7.40 (m, 2 H), 7.46 (m, 1 H), 7.95 (m, 2 7.96 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 26.83, 26.89,
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 23.47, 23.58, 25.68,
27.23, 34.01, 34.32, 35.07, 44.48, 44.52, 71.02, 85.51, 128.46,
45.89, 63.13, 71.45, 86.17, 128.47, 128.96, 129.02, 129.48, 132.02, 128.95, 129.01, 129.14, 131.99, 133.28, 163.03 ppm.
133.27, 163.29 ppm.
N-[(E,2S,3S)-6-Chloro-3-hydroxy-1-phenylhex-4-en-2-yl]benzamide
(E)-3-[(4S,5S)-4-(Cyclohexylmethyl)-4,5-dihydro-2-phenyloxazol-5- (7a): 1 N HCl (14 mL, 14 mmol, 5 equiv.) was added to a stirred
yl]prop-2-en-1-ol (5d): 99% yield; colorless oil. [α]2D0 = –43.9 (c =
solution of allylic chloride 6a (2.81 mmol, 1 equiv.) in THF (28 mL)
and MeOH (28 mL) at room temp., and the reaction mixture was
stirred for 12 h. Saturated aqueous NaHCO3 (70 mL) was added,
1
1.0, CHCl ). IR (neat): ν = 3274, 2921, 1644, 1448, 1333 cm–1. H
˜
3
NMR (500 MHz, CDCl3): δ = 0.94–0.97 (m, 2 H), 1.15–1.29 (m, 3
H), 1.38–1.42 (m, 1 H), 1.51–1.60 (m, 1 H), 1.61–1.72 (m, 4 H), and stirring was continued for 3 h. The reaction mixture was ex-
1.75–1.79 (m, 2 H), 4.02 (ddd, J = 7, 7, 7 Hz, 1 H), 4.18 (dd, J = tracted with EtOAc (4ϫ50 mL), and the combined organic layers
5, 1.5 Hz, 2 H), 4.66 (ddd, J = 7, 7, 0.5 Hz, 1 H), 5.81 (dddd, J =
15, 7, 1.5, 1.5 Hz, 1 H), 5.94 (dddd, J = 15, 5, 5, 0.5 Hz, 1 H),
7.38–7.41 (m, 2 H), 7.44–7.48 (m, 1 H), 7.93–7.95 (m, 2 H) ppm.
were washed with brine (50 mL), dried with MgSO4, and concen-
trated in vacuo. Purification by silica gel chromatography (ethyl
acetate/hexane = 1:1) gave alcohol 7a in 91% yield; white solid.
13C NMR (125 MHz, CDCl3): δ = 26.86, 26.89, 27.23, 44.5, 63.0, [α]2D0 = –61.2 (c = 1.0, CHCl ). IR (neat): ν = 3329, 1633, 1527,
˜
3
1
70.7, 86.2, 128.39, 128.97, 129.02, 129.25, 132.05, 133.35,
163.4 ppm.
1487, 1295 cm–1. H NMR (500 MHz, CDCl3): δ = 3.06 (m, 2 H),
4.01 (m, 2 H), 4.30 (m, 2 H), 5.83 (dd, J = 15.5, 5.5 Hz, 1 H), 5.89
1590
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Stereoselective Oxazine Formation Catalyzed by Pd0
FULL PAPER
(dddd, J = 15.5, 6.5, 6.5, 1 Hz, 1 H), 6.45 (d, J = 8 Hz, 1 H), 7.24–
7.33 (m, 5 H), 7.39–7.43 (m, 2 H), 7.48–7.51 (m, 1 H), 7.66–7.68
1254 cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.08 (dd, J = 5.5,
5.5 Hz, 3 H), 0.12 (dd, J = 3, 3 Hz, 3 H), 0.95 (m, 9 H), 0.99 (d, J
(m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 38.34, 44.89, = 6.5 Hz, 3 H), 1.05 (d, J = 6.5 Hz, 3 H), 1.87 (m, 1 H), 3.79 (ddd,
56.27, 72.06, 127.47, 127.63, 128.52, 129.32, 129.43, 129.99, 132.36,
135.05, 135.40, 138.53, 168.77 ppm. According to the procedure
described above for the alcohol 7a, allylic chlorides 6b–d were con-
verted into alcohols 7b–d.
J = 9.5, 9.5, 1.5 Hz, 1 H), 3.96 (m, 2 H), 4.78 (dd, J = 5, 1.5 Hz,
1 H), 5.77 (m, 2 H), 6.47 (d, J = 9.5 Hz, 1 H), 7.43–7.47 (m, 2 H),
7.49–7.51 (m, 1 H), 7.74–7.76 (m, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = –4.16, –2.91, 18.84, 20.39, 20.59, 26.66, 30.93, 45.07,
60.04, 72.24, 127.43, 127.97, 129.37, 132.10, 135.55, 136.10,
167.82 ppm. HRMS (FAB): calcd. for C21H35ClNO2Si [M + H]+
396.2126; found 396.2149.
N-[(E,3S,4S)-7-Chloro-4-hydroxy-2-methylhept-5-en-3-yl]benzamide
(7b): 97% yield; white solid. [α]2D0 = –36.5 (c = 1.0, CHCl3). IR
(neat): ν = 3341, 1622, 1542, 1413, 1149 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 1.02 (d, J = 6.5 Hz, 3 H), 1.08 (d, J = 6.5 Hz, 3 H),
2.07 (m, 1 H), 3.82 (ddd, J = 9.5, 9.5, 3 Hz, 1 H), 4.01 (m, 2 H),
4.50 (m, 1 H), 5.85 (dd, J = 15, 5 Hz, 1 H), 5.92 (m, 1 H), 6.41 (d,
J = 9.5 Hz, 1 H), 7.43–7.46 (m, 2 H), 7.50–7.53 (m, 1 H), 7.76–
N-[(E,4S,5S)-5-(tert-Butyldimethylsilyloxy)-8-chloro-2-methyloct-6-
en-4-yl]benzamide (1c): 91% yield; white solid. [α]2D0 = –40.8 (c =
1.0, CHCl ). IR (neat): ν = 2954, 2857, 1637, 1520, 1487,
˜
3
1254 cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.08 (s, 3 H), 0.12 (s,
7.78 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 19.95, 20.69, 3 H), 0.90–0.98 (m, 15 H), 1.46 (m, 2 H), 1.65 (m, 1 H), 3.99 (m,
30.46, 44.95, 59.97, 71.91, 127.61, 128.21, 129.34, 132.27, 135.28, 2 H), 4.23 (dd, J = 3.5, 2.5 Hz, 1 H), 5.79 (m, 2 H), 6.23 (d, J =
135.87, 168.90 ppm.
9.5 Hz, 1 H), 7.42–7.45 (m, 2 H), 7.48–7.50 (m, 1 H), 7.73–7.75 (m,
2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = –4.20, –3.40, 18.87,
23.02, 23.96, 25.62, 26.39, 26.55, 26.63, 41.91, 45.08, 52.58, 74.15,
127.44, 128.08, 129.32, 132.10, 135.45, 135.55, 167.59 ppm. HRMS
(FAB): calcd. for C22H37ClNO2Si [M + H]+ 410.2282; found
410.2283.
N-[(E,4S,5S)-8-Chloro-5-hydroxy-2-methyloct-6-en-4-yl]benzamide
(7c): 97% yield; white solid. [α]2D0 = –43.3 (c = 1.0, CHCl3). IR
(neat): ν = 3329, 2955, 1635, 1535, 1289 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 0.96 (m, J = 6.5 Hz, 6 H), 1.49 (m, 1 H), 1.60–1.73
(m, 2 H), 3.12 (s, 1 H), 4.02 (m, 2 H), 4.22–4.27 (m, 2 H), 5.83–
5.93 (m, 2 H), 6.38 (d, J = 9 Hz, 1 H), 7.39–7.43 (m, 2 H), 7.47–7.51 N-[(E,2S,3S)-3-(tert-Butyldimethylsilyloxy)-6-chloro-1-cyclohexyl-
(m, 1 H), 7.73–7.77 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ hex-4-en-2-yl]benzamide (1d): 96% yield; white solid. [α]2D0 = –52.3
= 22.84, 24.00, 25.73, 41.46, 45.03, 52.83, 74.30, 127.66, 128.49,
129.29, 132.30, 135.11, 135.40, 168.79 ppm.
(c = 1.0, CHCl ). IR (neat): ν = 2925, 2853, 1636, 1532, 1487,
˜
3
1252 cm–1. H NMR (500 MHz, CDCl3): δ = 0.08–0.12 (m, 6 H),
1
0.87–1.01 (m, 11 H), 1.15–1.23 (m, 4 H), 1.42–1.50 (m, 2 H), 1.62–
1.70 (m, 4 H), 1.874 (m, 1 H), 3.99 (m, 2 H), 4.25–4.27 (m, 2 H),
5.79 (m, 2 H), 6.19 (d, J = 9 Hz, 1 H), 7.43–7.46 (m, 2 H), 7.49–7.50
(m, 1 H), 7.73–7.75 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= –4.19, –3.41, 18.87, 26.36, 26.55, 26.63, 26.88, 26.98, 27.22, 33.66,
34.61, 35.03, 40.27, 45.10, 51.88, 74.07, 127.44, 128.05, 129.32,
132.07, 135.54, 135.57, 167.52 ppm. HRMS (FAB): calcd. for
C25H41ClNO2Si [M + H]+ 450.2595; found 450.2586.
N-[(E,2S,3S)-6-Chloro-1-cyclohexyl-3-hydroxyhex-4-en-2-yl]-
benzamide (7d): 85% yield; white solid. [α]2D0 = –49.0 (c = 1.0,
CHCl ). IR (neat): ν = 3326, 2921, 1632, 1536, 1488, 1447 cm–1.
˜
3
1H NMR (500 MHz, CDCl3): δ = 0.88–0.91 (m, 1 H), 0.92–0.01
(m, 1 H), 1.13–1.23 (m, 3 H), 1.34–1.37 (m, 2 H), 1.54–1.70 (m, 5
H), 1.86–1.88 (m, 1 H), 3.03 (d, J = 4.5 Hz, 1 H), 3.99–4.08 (m, 2
H), 4.24–4.27 (m, 2 H), 5.83–5.91 (m, 2 H), 6.34 (d, J = 5.5 Hz, 1
H), 7.40–7.44 (m, 2 H), 7.48–7.51 (m, 1 H), 7.73–7.77 (m, 2 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 26.82, 26.97, 27.17, 33.49,
34.60, 35.12, 39.94, 45.03, 52.19, 74.35, 127.66, 127.74, 128.50,
129.30, 129.39, 132.29, 135.16, 135.41, 168.74 ppm.
General Procedure for the Preparation of (4S,5R,6R)-1,3-Oxazines
(at 0 °C): NaH (60% in mineral oil, 32 mg, 0.79 mmol, 2 equiv.)
and nBu4NI (146 mg, 0.40 mmol, 1 equiv.) were added to a stirred
solution of silyl ether 1 (0.40 mmol, 1 equiv.) in dry THF (15 mL)
at 0 °C. After 5 min, Pd(PPh3)4 (92 mg, 0.08 mmol, 0.2 equiv.) was
added, and stirring was continued at the same temperature for 5 h.
The reaction mixture was filtered through a pad of silica and then
concentrated under reduced pressure to give the crude product. Pu-
rification of this material by silica gel chromatography (ethyl ace-
tate/hexane = 1:30) gave mixture 2.
N-[(E,2S,3S)-3-(tert-Butyldimethylsilyloxy)-6-chloro-1-phenylhex-4-
en-2-yl]benzamide (1a): Imidazole (0.92 g, 13.46 mmol, 6 equiv.)
and tert-butylchlorodimethylsilane (2.03 g, 13.46 mmol, 6 equiv.)
were added to a stirred solution of alcohol 7a (2.24 mmol, 1 equiv.)
in DMF (25 mL) at room temp., and stirring was continued for
2 h. The reaction mixture was quenched with H2O (100 mL) and
extracted with EtOAc (5ϫ20 mL). The combined organic layers
were washed with brine, dried with MgSO4, and concentrated in
vacuo. Purification by silica gel chromatography (ethyl acetate/hex-
ane = 1:8) gave silyl ether 1a in 93% yield; white solid. [α]2D0 = –80.9
(4S,5R,6R)-4-Benzyl-5-(tert-butyldimethylsilyloxy)-5,6-dihydro-2-
phenyl-6-vinyl-4H-1,3-oxazine (syn-2a): 80% yield, syn/anti = 8.3:1;
purification by flash column chromatography (ethyl acetate/hexane
(c = 1.0, CHCl ). IR (neat): ν = 3303, 2953, 2856, 1637, 1532 cm–1.
= 1:50) gave pure product as a colorless oil. [α]2D0 = –108.2 (c = 1.0,
˜
3
1
1H NMR (500 MHz, CDCl3): δ = 0.08 (s, 3 H), 0.15 (s, 3 H), 1.00
CHCl ). IR (neat): ν = 2929, 2856, 1659, 1255, 1116 cm–1. H
˜
3
(s, 9 H), 2.93 (m, 2 H), 3.97 (m, 2 H), 4.33 (dd, J = 5.5, 1.5 Hz, 1 NMR (500 MHz, CDCl3): δ = 0.08–0.12 (m, 6 H), 0.87 (m, 9 H),
H), 4.40 (ddd, J = 11.5, 7.5, 2 Hz, 1 H), 5.76 (m, 2 H), 6.47 (d, J 2.89 (m, 2 H), 3.81 (m, 1 H), 4.09 (dd, J = 2.5, 1.5 Hz, 1 H), 4.68
= 8.5 Hz, 1 H), 7.20–7.31 (m, 5 H), 7.41–7.51 (m, 3 H), 7.68–7.70 (ddd, J = 6, 1.5, 1.5 Hz, 1 H), 5.34 (ddd, J = 10.5, 1.5, 1.5 Hz, 1
(m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = –4.05, –3.02, H), 5.46 (ddd, J = 17, 1.5, 1.5 Hz, 1 H), 6.01 (ddd, J = 17, 10.5,
18.91, 26.70, 38.47, 44.92, 56.06, 72.62, 127.27, 127.43, 128.44,
129.28, 129.35, 129.85, 132.16, 135.37, 138.69, 167.55 ppm. HRMS
(FAB): calcd. for C25H35ClNO2Si [M + H]+ 444.2126; found
444.2117. According to the procedure described above for the al-
lylic chloride 1a, alcohols 7b–d were converted into allylic chlorides
1b–d.
6 Hz, 1 H), 7.22–7.25 (m, 1 H), 7.32–7.41 (m, 7 H), 7.95–7.97 (m,
2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = –2.92, –2.63, 19.04,
26.70, 40.36, 60.42, 68.93, 79.62, 118.27, 126.67, 127.98, 128.65,
128.81, 130.26, 130.80, 134.53, 135.83, 141.10, 154.20 ppm. HRMS
(FAB): calcd. for C25H34NO2Si [M + H]+ 408.2359; found
408.2315.
N-[(E,3S,4S)-4-(tert-Butyldimethylsilyloxy)-7-chloro-2-methylhept-
5-en-3-yl]benzamide (1b): 94% yield; white solid. [α]2D0 = –39.1 (c =
(4S,5R,6R)-5-(tert-Butyldimethylsilyloxy)-5,6-dihydro-4-isopropyl-
2-phenyl-6-vinyl-4H-1,3-oxazine (syn-2b): 73 % yield, syn/anti =
1.0, CHCl ). IR (neat): ν = 2955, 2929, 1654, 1513, 1485, 13.4:1; purification by flash column chromatography (ethyl acetate/
˜
3
Eur. J. Org. Chem. 2007, 1586–1593
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1591

J.-E. Joo, K.-Y. Lee, V.-T. Pham, W.-H. Ham
FULL PAPER
hexane = 1:50) gave pure product as a colorless oil. [α]2D0 = –37.6
1.5 Hz, 1 H), 5.35 (ddd, J = 17.5, 1.5, 1.5 Hz, 1 H), 5.85 (ddd, J =
17.5, 10.5, 5.5 Hz, 1 H), 7.22–7.42 (m, 8 H), 7.96–7.97 (m, 2 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = –3.65, –3.59, 18.85, 26.51,
39.08, 56.41, 68.20, 78.64, 118.25, 126.76, 127.97, 128.68, 128.88,
130.27, 131.00, 134.41, 135.30, 140.45, 153.60 ppm. HRMS (EI):
calcd. for C25H33NO2Si [M]+ 407.2281; found 407.2278.
(c = 1.0, CHCl ). IR (neat): ν = 2955, 2858, 1662, 1468, 1254,
˜
3
1108 cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.06 (dd, J = 2.5,
2.5 Hz, 6 H), 0.79 (m, 9 H), 1.01 (d, J = 6.5 Hz, 3 H), 1.25 (d, J =
6.5 Hz, 3 H), 1.83 (ddd, J = 10, 6.5, 6.5 Hz, 1 H), 3.00 (dd, J = 10,
2.5 Hz, 1 H), 4.16 (dd, J = 2.5, 1.5 Hz, 1 H), 4.63 (ddd, J = 6.5,
1.5, 1.5 Hz, 1 H), 5.34 (ddd, J = 10.5, 1.5, 1.5 Hz, 1 H), 5.47 (ddd,
J = 17.5, 1.5, 1.5 Hz, 1 H), 6.01 (ddd, J = 17.5, 10.5, 6.5 Hz, 1 H),
7.33–7.40 (m, 3 H), 7.96–7.98 (m, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = –2.87, –2.74, 19.18, 20.77, 21.04, 26.77, 29.75, 65.64,
67.01, 80.50, 118.40, 127.94, 128.53, 130.63, 134.83, 136.25,
154.10 ppm. HRMS (FAB): calcd. for C21H34NO2Si [M + H]+
360.2359; found 360.2356.
(4S,5R,6S)-5-(tert-Butyldimethylsilyloxy)-5,6-dihydro-4-isopropyl-2-
phenyl-6-vinyl-4H-1,3-oxazine (anti-2b): 77% yield, syn/anti = 1:16;
purification by flash column chromatography (ethyl acetate/hexane
= 1:50) gave pure product as a colorless oil. [α]2D0 = –47.7 (c = 1.0,
CHCl ). IR (neat): ν = 2954, 2858, 1662, 1468, 1356, 1255, 1168,
˜
3
1102 cm–1. H NMR (500 MHz, CDCl3): δ = 0.12 (m, 6 H), 0.86
1
(m, 9 H), 0.99 (d, J = 6.5 Hz, 3 H), 1.22 (d, J = 6.5 Hz, 3 H), 1.91
(4S,5R,6R)-5-(tert-Butyldimethylsilyloxy)-5,6-dihydro-4-isobutyl-2- (m, J = 9, 6.5, 6.5, 6.5 Hz, 1 H), 2.87 (dd, J = 9, 2.5 Hz, 1 H), 4.01
phenyl-6-vinyl-4H-1,3-oxazine (syn-2c): 88% yield, syn/anti = 9.0:1;
purification by flash column chromatography (ethyl acetate/hexane
= 1:50) gave pure product as a colorless oil. [α]2D0 = –37.9 (c = 1.0,
(dd, J = 2.5, 2.5 Hz, 1 H), 4.78 (dddd, J = 4.5, 2.5, 2, 1 Hz, 1 H),
5.26 (ddd, J = 10.5, 1, 1 Hz, 1 H), 5.30 (ddd, J = 17.5, 2, 1 Hz, 1
H), 5.83 (ddd, J = 17.5, 10.5, 4.5 Hz, 1 H), 7.35–7.41 (m, 3 H),
7.99–8.01 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = –3.76,
–3.59, 18.79, 20.45, 20.57, 26.39, 29.94, 59.20, 66.83, 80.01, 117.58,
127.89, 128.62, 130.72, 134.92, 135.36, 152.59 ppm. HRMS (EI):
calcd. for C21H33NO2Si [M]+ 359.2281; found 359.2280.
CHCl ). IR (neat): ν = 2954, 2859, 2659, 1467, 1255, 1113 cm–1.
˜
3
1H NMR (500 MHz, CDCl3): δ = 0.06 (s, 3 H), 0.07 (s, 3 H), 0.83
(s, 9 H), 0.97 (d, J = 7 Hz, 3 H), 1.00 (d, J = 7 Hz, 3 H), 1.36 (m,
1 H), 1.57 (m, 3 H), 2.08 (m, 1 H), 3.61 (m, 1 H), 3.92 (dd, J =
2.5, 1.5 Hz, 1 H), 4.68 (ddd, J = 6, 1.5, 1.5 Hz, 1 H), 5.31 (ddd, J
= 10.5, 1.5, 1.5 Hz, 1 H), 5.44 (ddd, J = 17.5, 1.5, 1.5 Hz, 1 H),
5.99 (ddd, J = 17.5, 10.5, 6 Hz, 1 H), 7.33–7.39 (m, 3 H), 7.95–7.97
(m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = –2.97, –2.76,
19.00, 23.03, 24.12, 25.04, 26.71, 42.96, 56.52, 68.76, 79.98, 118.19,
127.95, 128.58, 130.69, 134.75, 136.09, 154.17 ppm. HRMS (EI):
calcd. for C22H35NO2Si [M]+ 373.2437; found 373.2421.
(4S,5R,6S)-5-(tert-Butyldimethylsilyloxy)-5,6-dihydro-4-isobutyl-2-
phenyl-6-vinyl-4H-1,3-oxazine (anti-2c): 72% yield, syn/anti = 1:7.5;
purification by flash column chromatography (ethyl acetate/hexane
= 1:50) gave pure product as a colorless oil. [α]2D0 = –77.3 (c = 1.0,
CHCl ). IR (neat): ν = 2954, 2860, 1659, 1492, 1362, 1256,
˜
3
1111 cm–1. H NMR (500 MHz, CDCl3): δ = 0.09 (m, 6 H), 0.88
1
(m, 9 H), 0.87 (d, J = 6.5 Hz, 3 H), 0.99 (d, J = 6.5 Hz, 3 H), 1.43
(m, 1 H), 1.61 (m, 1 H), 1.98 (m, 1 H), 3.59 (m, 1 H), 3.78 (dd, J
= 5.5, 4.5 Hz, 1 H), 4.65 (dddd, J = 5.5, 5.5, 1.5, 1.5 Hz, 1 H), 5.31
(ddd, J = 10.5, 1.5, 1.5 Hz, 1 H), 5.40 (ddd, J = 17.5, 1.5, 1.5 Hz,
1 H), 5.91 (ddd, J = 17.5, 10.5, 5.5 Hz, 1 H), 7.34–7.43 (m, 3 H),
7.96 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = –3.84, –3.73,
(4S,5R,6R)-5-(tert-Butyldimethylsilyloxy)-4-(cyclohexylmethyl)-5,6-
dihydro-2-phenyl-6-vinyl-4H-1,3-oxazine (syn-2d): 89 % yield,
syn/anti = 14.0:1; purification by flash column chromatography
(ethyl acetate/hexane = 1:50) gave pure product as a colorless oil.
[α]2D0 = –44.5 (c = 1.0, CHCl ). IR (neat): ν = 2925, 1659, 1447,
˜
3
1254, 1155 cm–1. H NMR (500 MHz, CDCl3): δ = 0.06 (s, 6 H), 18.76, 23.29, 24.18, 25.32, 26.43, 41.77, 52.98, 68.72, 78.37, 118.18,
1
0.82 (s, 9 H), 0.88–1.05 (m, 3 H), 1.20–1.40 (m, 5 H), 1.53–1.56 (m,
1 H), 1.69–1.90 (m, 4 H), 3.65 (m, 1 H), 3.91 (dd, J = 2.5, 1.5 Hz,
1 H), 4.67 (ddd, J = 6.5, 1.5, 1.5 Hz, 1 H), 5.31 (ddd, J = 10.5, 1.5,
1.5 Hz, 1 H), 5.44 (ddd, J = 17.5, 1.5, 1.5 Hz, 1 H), 5.99 (ddd, J =
17.5, 10.5, 6.5 Hz, 1 H), 7.33–7.39 (m, 3 H), 7.94–7.96 (m, 2 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = –2.99, –2.72, 19.00, 26.71,
27.02, 27.16, 27.51, 33.82, 34.46, 34.82, 41.54, 55.70, 68.82, 79.97,
118.17, 127.96, 128.58, 130.69, 134.75, 136.09, 154.22 ppm. HRMS
(EI): calcd. for C25H39NO2Si [M]+ 413.2750; found 413.2762.
127.93, 128.67, 130.87, 134.55, 135.72, 153.16 ppm. HRMS (EI):
calcd. for C22H35NO2Si [M]+ 373.2437; found 373.2440.
(4S,5R,6S)-5-(tert-Butyldimethylsilyloxy)-4-(cyclohexylmethyl)-5,6-
dihydro-2-phenyl-6-vinyl-4H-1,3-oxazine (anti-2d): 73 % yield,
syn/anti = 1:8.5; purification by flash column chromatography
(ethyl acetate/hexane = 1:50) gave pure product as a colorless oil.
[α]2D0 = –84.6 (c = 1.0, CHCl ). IR (neat): ν = 2926, 2853, 1658,
˜
3
1448, 1256, 1116 cm–1. H NMR (500 MHz, CDCl3): δ = 0.08 (s,
1
6 H), 0.88 (s, 9 H), 0.88–1.05 (m, 3 H), 1.20–1.40 (m, 5 H), 1.53–
1.56 (m, 1 H), 1.69–1.90 (m, 4 H), 3.61 (m, 1 H), 3.77 (dd, J = 5.5,
4 Hz, 1 H), 4.65 (dd, J = 5.5, 5 Hz, 1 H), 5.30 (ddd, J = 10.5, 1.5,
General Procedure for the Preparation of (4S,5R,6S)-1,3-Oxazines
(at 40 °C): NaH (60% in mineral oil, 10 mg, 0.248 mmol, 2 equiv.)
and nBu4NI (46 mg, 0.124 mmol, 1 equiv.) were added to a stirred 1.5 Hz, 1 H), 5.39 (ddd, J = 17.5, 1.5, 1.5 Hz, 1 H), 5.89 (ddd, J =
solution of silyl ether 1 (0.124 mmol, 1 equiv.) in dry THF (5 mL)
at room temp. After 5 min, Pd(PPh3)4 (29 mg, 0.025 mmol,
0.2 equiv.) was added, and stirring was continued at 40 °C for 12 h.
The reaction mixture was filtered through a pad of silica and then
concentrated under reduced pressure to give the crude product. Pu-
rification of this material by silica gel chromatography (ethyl ace-
tate/hexane = 1:30) gave mixture 2.
17.5, 10.5, 5 Hz, 1 H), 7.35–7.41 (m, 3 H), 7.94–7.97 (m, 2 H) ppm.
13C NMR (125 MHz, CDCl3): δ = –3.83, –3.68, 18.76, 26.44, 26.71,
27.16, 27.44, 34.06, 34.46, 34.88, 40.3652.30, 68.73, 78.33, 118.16,
127.93, 128.66, 130.86, 134.57, 135.71, 153.17 ppm. HRMS (EI):
calcd. for C25H39NO2Si [M]+ 413.2750; found 413.2747.
N-{(S)-1-[(4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]-2-methyl-
propyl}benzamide (10): 3 N HCl (0.49 mL, 1.47 mmol, 15 equiv.)
was added to a stirred solution of oxazine syn-2b (35 mg,
0.097 mmol, 1 equiv.) in THF (1 mL) and MeOH (1 mL) at room
temp. The reaction mixture was stirred for 12 h, saturated aqueous
NaHCO3 (5 mL) was added, and stirring was continued for 3 h.
The reaction mixture was extracted with EtOAc (4ϫ15 mL), and
the combined organic layers were washed with brine (20 mL), dried
(4S,5R,6S)-4-Benzyl-5-(tert-butyldimethylsilyloxy)-5,6-dihydro-2-
phenyl-6-vinyl-4H-1,3-oxazine (anti-2a): 68% yield, syn/anti = 1:15;
purification by flash column chromatography (ethyl acetate/hexane
= 1:50) gave pure product as a colorless oil. [α]2D0 = –116.3 (c = 1.0,
CHCl ). IR (neat): ν = 2928, 2856, 1658, 1493, 1257, 1116 cm–1.
˜
3
1H NMR (500 MHz, CDCl3): δ = 0.10 (m, 6 H), 0.91 (m, 9 H),
2.90 (dd, J = 13.5, 8.5 Hz, 1 H), 3.06 (dd, J = 13.5, 6 Hz, 1 H), with MgSO4, and concentrated in vacuo. Purification by silica gel
3.75 (ddd, J = 8.5, 6, 3.5 Hz, 1 H), 3.82 (dd, J = 5, 3.5 Hz, 1 H),
4.68 (dddd, J = 5.5, 5.5, 1.5, 1.5 Hz, 1 H), 5.27 (ddd, J = 10.5, 1.5,
chromatography (ethyl acetate/hexane = 1:2) gave alcohol 8. Tetra-
butylammonium fluoride (1  solution in THF, 0.040 mL,
1592
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Eur. J. Org. Chem. 2007, 1586–1593

Stereoselective Oxazine Formation Catalyzed by Pd0
FULL PAPER
0.038 mmol, 1.1 equiv.) was added to a stirred solution of 8
(0.034 mmol, 1 equiv.) in dry THF (1.5 mL) at room temp. After [1] For reviews see: a) B. M. Trost, Comprehensive Organic Synthe-
sis, Pergamon, Oxford, 1991, vol. 4, chapter 3.3; b) J. Tsuji,
Palladium Reagents and Catalysts, Innovations in Organic Syn-
thesis, Wiley and Sons, Chichester, U. K., 1995; c) L. Hegedus,
M. Schlosser, Organometallics in Synthesis, 2nd ed., Wiley,
England, 2002, p. 1123–1217; d) A. Meijere, E. Negishi, Hand-
book of Organopalladium Chemistry for Organic Synthesis,
Wiley, New York, 2002.
1 h, the reaction mixture was diluted with EtOAc (10 mL), washed
with saturated aqueous NH4Cl (2ϫ50 mL), dried with MgSO4,
and concentrated in vacuo to give the crude diol. 2,2-Dimeth-
oxypropane (0.033 mL, 0.272 mmol, 8 equiv.) and p-toluenesul-
fonic acid (0.65 mg, 0.0034 mmol, 0.1 equiv.) were added to a
stirred solution of diol in dry acetone (0.5 mL) at room temp. After
1 h, the reaction mixture was concentrated in vacuo, diluted with
H2O (10 mL), extracted with Et2O (3ϫ10 mL), and the combined
organic layers were dried with MgSO4 and concentrated in vacuo.
Purification of this material by silica gel chromatography (ethyl
acetate/hexane = 1:2) gave acetonide 10 in 70% yield (3 steps); col-
[2] For recent reviews, see: a) G. Consiglio, R. M. Waymouth,
Chem. Rev. 1989, 89, 257; b) C. G. Frost, J. J. Howarth, M. J.
Williams, Tetrahedron: Asymmetry 1992, 3, 1089; c) O. Reiser,
Angew. Chem. Int. Ed. Engl. Angew. Chem. Int. Ed. 1993, 32,
547; d) B. M. Trost, D. L. VanVranken, Chem. Rev. 1996, 96,
395; e) G. Poli, G. Giambastiani, A. Heuman, Tetrahedron
2000, 56, 5959; f) B. M. Trost, M. L. Crawley, Chem. Rev. 2003,
103, 2921.
1
orless oil. H NMR (500 MHz, CDCl3): δ = 1.00 (d, J = 7 Hz, 3
H), 1.02 (d, J = 7 Hz, 3 H), 1.42 (s, 3 H), 1.44 (s, 3 H), 1.94 (m, 1
H), 3.92 (dd, J = 8.5, 1 Hz, 1 H), 4.02 (ddd, J = 9.5, 7, 1 Hz, 1 H),
4.07 (dddd, J = 8.5, 6, 1, 1 Hz, 1 H), 5.30 (ddd, J = 9, 1, 1 Hz, 1
H), 5.48 (ddd, J = 17, 1, 1 Hz, 1 H), 5.83 (ddd, J = 17, 9, 6 Hz, 1
H), 6.52 (d, J = 9.5 Hz, 1 H), 7.44–7.48 (m, 2 H), 7.51–7.52 (m, 1
H), 7.80–7.82 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
19.99, 20.26, 27.75, 27.87, 32.71, 52.54, 80.46, 80.83, 109.85,
120.58, 127.48, 129.41, 132.28, 134.99, 135.12, 167.68 ppm.
[3] J. G. Hansel, S. O’Hogan, S. Lensky, A. R. Ritter, M. J. Miller,
Tetrahedron Lett. 1995, 36, 2913.
[4] a) K. Y. Lee, Y. H. Kim, M. S. Park, W. H. Ham, Tetrahedron
Lett. 1998, 39, 8129; b) K. Y. Lee, Y. H. Kim, M. S. Park, C. Y.
Oh, W. H. Ham, J. Org. Chem. 1999, 64, 9450.
[5] K. Y. Lee, Y. H. Kim, C. Y. Oh, W. H. Ham, Org. Lett. 2000,
2, 4041.
[6] K. Y. Lee, C. Y. Oh, W. H. Ham, Org. Lett. 2002, 4, 4403.
N-{(S)-1-[(4R,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]-2-methyl- [7] Y. S. Lee, Y. H. Shin, Y. H. Kim, K. Y. Lee, C. Y. Oh, S. J.
Pyun, H. J. Park, J. H. Jeong, W. H. Ham, Tetrahedron: Asym-
metry 2003, 14, 87.
[8] K. Y. Lee, C. Y. Oh, Y. H. Kim, J. E. Joo, W. H. Ham, Tetrahe-
dron Lett. 2002, 43, 9361.
[9] Y. J. Yoon, J. E. Joo, K. Y. Lee, Y. H. Kim, C. Y. Oh, W. H.
Ham, Tetrahedron Lett. 2005, 46, 739–741.
[10] S. J. Pyun, K. Y. Lee, C. Y. Oh, W. H. Ham, Heterocycles 2004,
62, 333–341.
[11] S. J. Pyun, K. Y. Lee, C. Y. Oh, J. E. Joo, S. H. Cheon, W. H.
Ham, Tetrahedron 2005, 61, 1413–1416.
propyl}benzamide (11): According to the procedure described above
for 10, oxazine anti-2b gave acetonide 11 in 20% yield; colorless
oil. H NMR (500 MHz, CDCl3): δ = 1.00 (m, 6 H), 1.42 (s, 3 H),
1
1.59 (s, 3 H), 1.96 (m, 1 H), 3.97 (ddd, J = 9, 6.5, 1 Hz, 1 H), 4.45
(dd, J = 7.5, 1 Hz, 1 H), 4.68 (dddd, J = 7.5, 7.5, 1.5, 1.5 Hz, 1 H),
5.19 (ddd, J = 10.5, 1.5, 1.5 Hz, 1 H), 5.30 (ddd, J = 17.5, 1.5,
1.5 Hz, 1 H), 5.79 (ddd, J = 17.5, 10.5, 7.5 Hz, 1 H), 6.56 (d, J =
9 Hz, 1 H), 7.42–7.51 (m, 3 H), 7.75–7.77 (m, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 19.58, 20.15, 25.08, 27.89, 33.29, 53.56,
77.96, 80.08, 108.93, 119.57, 127.45, 129.32, 131.97, 134.18, 135.97,
167.26 ppm.
[12] For the preparation of 1, see Scheme 1 and Experimental Sec-
tion.
[13] In our previous report,[4b] no racemization during this process
was detected.
[14] a) M. Ogasawara, K. I. Takizawa, T. Hayashi, Organometallics
2002, 21, 4853; b) R. J. van Haaren, G. P. F. van Strijdonck, H.
Oevering, J. N. H. Reek, P. C. J. Kamer, P. W. N. M.
van Leeuwen, Eur. J. Inorg. Chem. 2001, 3, 837.
Received: October 24, 2006
Acknowledgments
This study was supported by a grant of the Korea Health 21
R&D Project, Ministry of Health and Welfare, Republic of Korea
(01-PJ1-PG1-01CH13-0002).
Published Online: February 9, 2007
Eur. J. Org. Chem. 2007, 1586–1593
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1593