On the scope of diastereoselective allylation of various chiral glyoxylic oxime ethers with allyltributylstannane in the presence of?a Lewis acid and triallylaluminum

Article abstract of DOI:10.1016/j.tet.2007.05.091

The nucleophilic allylation of various chiral auxiliaries derived glyoxylic oxime ethers was studied. The use of allyltributylstannane in the presence of a Lewis acid and triallylaluminum provided the corresponding homoallylic amines in high chemical yiel

Full text of DOI:10.1016/j.tet.2007.05.091

Tetrahedron 63 (2007) 7816–7822
On the scope of diastereoselective allylation of various chiral
glyoxylic oxime ethers with allyltributylstannane in the presence
of a Lewis acid and triallylaluminum
*
Neelesh A. Kulkarni, Ching-Fa Yao and Kwunmin Chen
Department of Chemistry, National Taiwan Normal University, Taipei 116, Taiwan, ROC
Received 20 April 2007; revised 23 May 2007; accepted 24 May 2007
Available online 27 May 2007
Abstract—The nucleophilic allylation of various chiral auxiliaries derived glyoxylic oxime ethers was studied. The use of allyltributylstan-
nane in the presence of a Lewis acid and triallylaluminum provided the corresponding homoallylic amines in high chemical yields (up to 89%)
and excellent stereoselectivities (up to >99%). The stereochemical bias of the allylation is proposed.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
a new route for the preparation of a-amino acids. In this re-
port, the scope and generality of the diastereoselective ally-
lation of various chiral glyoxylic oxime ethers are described.
In addition to the more commonly employed allyltributyl-
stannane in the presence of a Lewis acid, a more reactive tri-
allylaluminum reagent was also studied. High to excellent
material yields and stereoselectivity were obtained for
some of the chiral glyoxylic oxime ethers. The stereochem-
ical course of the reactions is proposed.
The nucleophilic addition of organometals to a carbonyl/
imine group represented one of the most straightforward
methods for the construction of C–C bonds. The allylation
of an a-imino carbonyl group provides the corresponding al-
lylglycine derivatives, which are attractive targets as build-
ing blocks for synthesis of peptides,1 lactams,2 and a
number of biologically active compounds.3 Numerous al-
lylic reagents have been developed over the last several de-
cades for the allylation of carbonyl/imine functionalities.4
These include allyllithium,5 allylsilane,6 allylstannane,7
and other allylmetals.8 The Barbier-type allylation using al-
lyl halides with different metal sources has been reported.9
On the other hand, applications of organoaluminum reagents
in organic synthesis have received less attention, compared
to other organometallic reagents.10
2. Results and discussion
The starting a-glyoxylic oxime ethers bearing various
auxiliaries are readily prepared. Treatment of O-benzyloxy-
amine hydrochloride with glyoxylic acid in H2O affords the
corresponding oxime ether 2 in 90% yield. The a-oxime
ether glyoxylic acid chloride was then prepared (SOCl2) fol-
lowed by the treatment of the chiral auxiliaries (a–h) with
NaH in THF at 0 ꢀC for 2 h. Awide structural variety of chiral
auxiliaries were examined, including camphorsultam,
N-phenyl camphorpyrazolidinone, N-tosyl camphorpyrazo-
lidinone, (S)-(+)-4-phenyl-oxazolidin-2-one, 10,10-diphenyl-2,
10-camphandiol, (ꢁ)-menthol, (ꢁ)-borneol, and (ꢁ)-pina-
nediol. The desired chiral glyoxylic oxime ethers (3a–h)
were obtained in good to high material yields (76–90%).14
With the chiral glyoxylic oxime ethers in hand, we then
turned our attention to the allylation reaction. The camphor-
sultam derived glyoxylic oxime ether 3a was chosen as the
probe substrate. The palladium–indium iodide-mediated
allylation/alkylation reaction of camphorsultam derived
glyoxylic oxime ether in aqueous media has been reported.15
However, these reports were limited to camphorsultam
Considerable progress has been achieved in stereoselective
nucleophilic allylation of imines11 and hydrazones12 in re-
cent years. The allylation of the less reactive imine function-
ality usually requires the presence of a Lewis acid. Very
recently we reported on the diastereoselective allylation of
glyoxylic oxime ethers derived from camphorsultam, N-
phenyl and N-tosyl camphorpyrazolidinone using allyltri-
butylstannane in the presence of Sn(OTf)2.13 The desired
homoallylic amine derivatives were obtained in excellent
diastereoselectivity and high material yields. This offers
Keywords: Allylation; Glyoxylic oxime ether; Chiral auxiliary; Triallyl-
aluminum.
* Corresponding author. Tel.: +886 2 89315831; fax: +886 2 29324249;
e-mail: kchen@ntnu.edu.tw
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.091

N. A. Kulkarni et al. / Tetrahedron 63 (2007) 7816–7822
7817
1. SOCl2
NOBn
NOBn
O
2. XcH, NaH, THF
H2NOBn, H2O
(90%)
Xc
HO
OH
OH
HO
Me
O
O
1
3
2
Me
Me
Me
Me
Me
Xc:
Me
Me
O
Me
Me
Me
N
O
O
Me
O
N
O
N
O
Me
O
OH
Ph
S
O
N
R
OH
Ph
Ph
O
a (87%)
b = Ph (87%)
c = Ts (76%)
d (90%)
e (80%)
f (76%)
g (84%)
h (82%)
derived substrates. Various metal triflates were then
screened. No reaction occurred when 3a was treated with
allyltributylstannane in the presence of various Lewis acids
(Sc(OTf)3, Yb(OTf)3, Eu(OTf)3, Sm(OTf)3, La(OTf)3, and
PdCl2) in CH3CN (Table 1, entries 1–6). Both the stereo-
selectivity and the rate of the reaction were improved when
Zn(OTf)2 was used at ambient temperature (Table 1, entry
7). A slight improvement in diastereoselectivity was ob-
served when the reaction was carried out at 0 ꢀC (Table 1,
entry 8). The diastereoselectivity of the reaction was deter-
mined based on 1H NMR and HPLC analysis. The absolute
stereochemistry of the newly generated stereogenic center
of the major diastereomer was assigned as an S configuration
by single crystal X-ray analysis. No further improvement was
observedwhenvarious solvents (THF, ether, CH2Cl2, and tol-
uene) were used under the same reaction conditions (data not
shown). The reaction proceeded to completion in 6 h when
AgOTf was used and was complete after 30 min when
Sn(OTf)2 was used at ambient temperature (entries 9 and
10). Stereoselectivity was slightly improved when the
reaction was carried out at 0 and ꢁ25 ꢀC and further im-
proved at ꢁ40 ꢀC for a reaction in the presence of Sn(OTf)2
(entries 11–13). This is comparable to the best results ob-
tained for the allylation of the camphorsultam derived gly-
oxylic oxime ether. This also turned out to be the optimum
condition for the diastereoselective allylation.
The scope and generality of the present method was investi-
gated by performing allylation reactions of various glyoxylic
oxime ethers under the optimum conditions. The efficient al-
lylation of an aldehyde with allyldiethylaluminum has been
reported.16 The use of triallylaluminum for the allylation of
carbonyl/aldimine/ketimine group to give the corresponding
homoallylic alcohols and amines with excellent material
yields was recently reported.17 Stereoselective allylation
by allyl metals such as Mg, Zn, B, Sn have been extensively
studied while the use of economical allylaluminum reagents
have received relatively less attention.18 To the best of our
knowledge, the diastereoselective allylation of the electron
deficient C]N bond by triallylaluminum has not been re-
ported in the literature. In our previous study, no desired
product was isolated when glyoxylic oxime ether 3a was
treated with allyltributylstannane in the absence of Sn(OTf)2
in CH3CN at ꢁ40 ꢀC, while excellent yield and a high dia-
stereoselectivity was achieved in the presence of Sn(OTf)2
(Table 1, entry 13). Treatment of 3a with freshly prepared
triallylaluminum in ether at ꢁ78 ꢀC resulted in no reaction
(Table 2, entry 1). On the other hand, reasonable stereoselec-
tivity was obtained when the reaction was carried out in THF
(Table 2, entry 2). Both the chemical yield and diastereo-
selectivity were further improved when 3a was treated
with triallylaluminum in CH2Cl2 at ꢁ78 ꢀC for 10 min (Ta-
ble 2, entry 4). The operationally simple procedure provided
an attractive alternative for the allylation of the imine bond.
A similar result was obtained by the slow addition of triallyl-
aluminum using a syringe pump under the same reaction
conditions. Dichloromethane was found to be the solvent
of choice for the allylation of 3a when triallylaluminum
was used. The absolute stereochemistry of the newly gener-
ated stereogenic center was assigned as an S configuration,
which is the same as that obtained when allyltributylstan-
nane is used. These results encouraged us to evaluate and
compare the efficiency of the allylation of a C]N bond
using two different allylating methods (method A: allyltri-
butylstannane (2.0 equiv) and Sn(OTf)2 (1.0 equiv) and
method B: triallylaluminum). A direct comparison of the re-
activity and stereochemical course between allyltributyl-
stannane and triallylaluminum is of interest. Various chiral
glyoxylic oxime ethers were then subjected to the above
Table 1. Nucleophilic allylation of camphorsultam derived glyoxylic oxime
ether 3a with allyltributylstannane in the presence of a Lewis acida
Me
Me
Me
Me
O
O
Allyltributylstannane
Lewis acid,
NHOBn
N
O
N
O
S
S
NHOBn
O
O
3a
4a
Entry Lewis acid Solvent T (ꢀC) t (h) Yieldb (%) dec (%)
1
2
3
4
5
6
7
8
Sc(OTf)3
Yb(OTf)3
Eu(OTf)3
Sm(OTf)3
La(OTf)3
PdCl2
Zn(OTf)2
Zn(OTf)2
AgOTf
Sn(OTf)2
Sn(OTf)2
Sn(OTf)2
Sn(OTf)2
Sn(OTf)2
Sn(OTf)2
CH3CN rt
CH3CN rt
CH3CN rt
CH3CN rt
CH3CN rt
CH3CN rt
CH3CN rt
24
24
24
24
24
24
2
7
6
1/2
1
1
0
0
0
0
0
0
88
89
87
92
90
91
90
84
68
87 (S)
92 (S)
93 (S)
56 (S)
74 (S)
78 (S)d
91 (S)d
82 (S)
87 (S)
CH3CN
0
9
CH3CN rt
CH3CN rt
10
11
12
13
14
15
CH3CN
0
CH3CN ꢁ25
CH3CN ꢁ40
1
3
12
EtCN
EtCN
ꢁ60
ꢁ80
a
Unless otherwise specified, all reactions were carried out using 3a
(0.13 mmol), allyltributylstannane (2.0 equiv) and Sn(OTf)2 (1.0 equiv)
under the solvent and temperature indicated.
Isolated yield.
Absolute configuration was assigned by single crystal X-ray analysis.
See Ref. 13.
b
c
d

7818
N. A. Kulkarni et al. / Tetrahedron 63 (2007) 7816–7822
Table 2. Diastereoselective allylation of glyoxylic oxime ethers 3a–h with
12–15). Finally, excellent stereoselectivities were achieved
when the ester linked auxiliaries ((ꢁ)-borneol and (ꢁ)-pina-
nediol) derived glyoxylic oxime ethers were treated with tri-
allylaluminum at ꢁ78 ꢀC (Table 2, entries 16 and 17). The
reaction proceeded to completion at ꢁ78 ꢀC in 10 min
when triallylaluminum was used, compared to an hour
when allyltributylstannane was used. It can thus be con-
cluded from the above results that triallylaluminum is
more reactive than allyltributylstannane in the presence of
Sn(OTf)2.
allyltributylstannane, Sn(OTf)2, and triallylaluminuma
Allylation
NOBn
NHOBn
Method A or
Method B
Xc
Xc
O
O
3a-h
4a-h
Entry Substrate Methodb Solvent T (ꢀC) Yieldc ded (%)
(equiv)
(%)
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3bf
3b
3b
3cf
3c
3d
3d
3e
3e
3f
B (2.0)
B (2.0)
B (2.0)
B (2.0)
A
B (1.2)
B (2.2)
A
B (2.2)
A
B (2.2)
A
B (2.2)
A
B (2.2)
B (2.2)
B (2.2)
Ether
THF
ꢁ78
ꢁ78
0
87
83
89
92
50
81
94
84
90
81
55
82
62
75
82
80
60 (S)
50 (S)
82 (S)e
>99 (S)e
57 (S)
67 (S)
>99 (S)g
>99 (S)
33 (S)
76 (S)
10
We previously proposed that Sn(OTf)2 coordinates to the sul-
fonyl group in camphorsultam (3a) and N-tosyl camphorpyr-
azolidinone (3c) while forming a chelatewith the oxime ether
nitrogen and adjacent carbonyl group in N-phenyl camphor-
pyrazolidinone (3b) derived substrates.13 The Sn atom coor-
dinates strongly with the carbonyl and a-oxime ether groups
in 3b that serves both to activate and restrict the conforma-
tional populations in the transition state.19 The observed dia-
stereoselectivity for the triallylaluminum allylation of 3a–c
can be explained by a similar argument as proposed in Fig-
ure 1. We propose that the Lewis acid nature of the aluminum
reagent coordinates strongly with the sulfonyl oxygen atoms
in 3a and 3c, similar to Sn(OTf)2. On the other hand, the alu-
minum atom coordinates weakly to the a-oxime ether groups
compared with that of Sn(OTf)2 in the case of 3b. The s-cis/s-
trans transition state conformations then reach an equilib-
rium, which accounts for the low diastereoselectivity (67%
de) when 3b was treated with triallylaluminum. The chela-
tion of the aluminum atom to the Lewis bases also accelerates
the release of the allylating group in the reaction. The allyl
group delivered from the si face to the a-imino carbon, lead-
ing to the desired major products with high to excellent ster-
eoselectivities. The mechanistic explanation for the high to
excellent stereoselectivity of the two ester linkage auxiliaries
(3g and 3h) remains unclear at this moment. The coordina-
tion of the aluminum reagent to the hydroxy group and the
structural skeleton of 3g and 3h may be responsible for the
stereoselectivity.
CH3CN ꢁ40
CH2Cl2 ꢁ78
CH3CN ꢁ40
CH2Cl2 ꢁ78
CH2Cl2 ꢁ78
CH3CN ꢁ40
CH2Cl2 ꢁ78
CH3CN ꢁ78
CH2Cl2 ꢁ78
CH3CN ꢁ78
CH2Cl2 ꢁ78
CH3CN ꢁ78
CH2Cl2 ꢁ78
CH2Cl2 ꢁ78
CH2Cl2 ꢁ78
9
10
11
12
13
14
15
16
17
37
<10
3f
3g
3h
10
>99h
90h
a
Unless otherwise specified, all reactions were carried out using 3a–h
(0.13 mmol) under the solvent and temperature indicated.
Method A: allyltributylstannane (2.0 equiv) and Sn(OTf)2 (1.0 equiv)
were used under the reaction conditions for 1 h; Method B: triallylalumi-
num (1.0 M) was used under the reaction conditions for 10 min.
Isolated yield.
b
c
d
e
f
Diastereoselectivity was determined by 400 MHz 1H NMR.
Absolute configuration was assigned by single crystal X-ray analysis.
See Ref. 13.
g
h
Absolute stereochemistry was assigned by analogy.
Absolute configuration was not assigned.
two allylation reaction conditions. Excellent stereoselectiv-
ity was achieved when N-phenyl camphorpyrazolidinone
derived glyoxylic oxime ether was treated with
allyltributylstannane in the presence of Sn(OTf)2 while
only moderate stereoselectivity was found when triallylalu-
minum was used (Table 2, entries 5 and 6). The stereoselec-
tivity was improved when the amount of triallylaluminum
was increased (Table 2, entry 7). Excellent diastereoselectiv-
ity was achieved when the N-tosyl camphorpyrazolidinone
derived glyoxylic oxime ether was treated with either of
the allylating reagents (Table 2, entries 8 and 9). Allylation
of (S)-(+)-4-phenyl-oxazolidin-2-one derived glyoxylic ox-
ime ether with triallylaluminum gave the desired product
with 76% de compared to 33% de when allyltributylstannane
was used (Table 2, entries 10 and 11). Poor diastereoselectiv-
ities were observed when 10,10-diphenyl-2,10-camphandiol
and the (ꢁ)-menthol derived glyoxylic oxime ether was
used under either of the reaction conditions (Table 2, entries
3. Conclusions
In conclusion, the diastereoselective allylation of various
chiral glyoxylic oxime ethers was examined using allyltribu-
tylstannane and triallylaluminum as the allylating reagents.
This is the first example of the diastereoselective allylation
of chiral glyoxylic oxime ether derivatives with triallylalu-
minum. Allylation of a sulfonyl group containing (3a and
3c) and (ꢁ)-borneol and (ꢁ)-pinanediol derived glyoxylic
oxime ethers (3g and 3h) provided the corresponding homo-
allylic amines in high to excellent diastereoselectivities (up
to >99%). The coordination of the aluminum reagent to the
Me
Me
Me
Me
Me
Me
Me
Me
O
O
H
NOBn
NOBn
H
N
O
N
N
N
H
NOBn
S
O
N
S
NOBn
H
R
N
Ph
N
Ph
R
Al
R
O
O
O
O
O
O
Al
R
Al
R
Tol
R
O
3c
3a
3b
Figure 1. Proposed mechanism for triallylaluminum allylation of glyoxylic oxime ethers 3a–c.

N. A. Kulkarni et al. / Tetrahedron 63 (2007) 7816–7822
7819
Lewis base atoms of the substrates may account for the rapid
reaction rate. Further investigations of the use of organoalu-
minum as a reactive reagent are currently in progress.
Compound 3a: Rf¼0.58 (4:1 hexanes/EtOAc); [a]3D1 ꢁ79.7
1
(c 1, CHCl3); H NMR (400 MHz, CDCl3) d 8.21 (s, 1H),
7.39–7.32 (m, 5H), 5.31 (s, 2H), 3.97 (dd, 1H, J¼7.6,
5.0 Hz), 3.52 (d, 1H, J¼13.8 Hz), 3.44 (d, 1H,
J¼13.8 Hz), 2.13–2.11 (m, 1H), 2.06 (dd, 1H, J¼13.9,
7.6 Hz), 1.92–1.86 (m, 3H), 1.43–1.30 (m, 2H), 1.15 (s,
3H), 0.96 (s, 3H); 13C NMR (100 MHz, CDCl3) d 160.4,
143.2, 138.1, 130.0, 129.9, 129.8, 78.9, 66.1, 53.9, 50.5,
49.0, 46.3, 39.5, 33.5, 27.2, 21.7, 20.5; LRMS (FAB)
[M+1] m/z (relative intensities) 377.2 (100), 347.3 (2),
307.2 (2), 289 (2), 242.2 (3), 214.3 (2), 214.3 (2), 154.2
(13), 107 (11) (calcd for C19H24N2O4S: 377.15). Crystal
data for 3a at 27 ꢀC: C19H24N2O4S, M 376.46, monoclinic,
4. Experimental
4.1. General methods
All reagents were used as purchased from the commercial
suppliers without further purification. NMR spectra were re-
corded on a Bruker Avance 400 NMR spectrometer
1
(400 MHz for H, and 100 MHz for 13C). Chemical shifts
˚
˚
˚
are reported in d parts per million referenced to an internal
P21, a¼7.8927 (2) A, b¼23.0682 (6) A, c¼10.9889 (4) A,
1
3
V¼1899.78 (10) A , Z¼4, Dx¼1.316 Mg/m3, m¼
˚
TMS standard for H NMR and chloroform-d (d 77.0) for
13C NMR. Optical rotations were measured on a JASCO P-
1010 polarimeter. EI mass spectra were recorded on a Finni-
gan TSQ-700 instrument at an ionizing energy of 70 eVand
HRMS spectra were recorded on JEOL SX-102A. Routine
monitoring of reactions was performed using silica gel,
glass-backed TLC plates (Merck Kieselgel 60 F254) and visu-
alized by UV light (254 nm). Analytical high performance
liquid chromatography was performed on a JASCO PU-
1580 HPLC. Solutions were evaporated to dryness under re-
duced pressure using a rotary evaporator and the residue was
purified by flash column chromatography on silica gel (230–
400 mesh) with the indicated eluents. Air and/or moisture
sensitive reactions were performed under inert atmosphere
conditions.
0.197 mmꢁ1, 5846 reflections, 470 parameters, R¼0.0988,
Rw¼0.1889 for all of the data.
Compound 3b: Rf¼0.52 (4:1 hexanes/EtOAc); [a]3D2 +61.2 (c
1, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.51 (s, 1H), 7.39–
7.33 (m, 7H), 7.30–7.28 (m, 2H), 7.20–7.16 (m, 1H), 5.22 (d,
1H, J¼12.0 Hz), 5.17 (d, 1H, J¼12.0 Hz), 4.21 (dd, 1H,
J¼7.8, 5.0 Hz), 2.27–2.21 (m, 2H), 1.95–1.94 (m, 1H),
1.86–1.84 (m, 1H), 1.41–1.35 (m, 2H), 1.20 (m, 1H), 1.11
(s, 6H); 13C NMR (100 MHz, CDCl3) d 172.0, 158.9,
144.2, 139.6, 138.6, 130.5, 130.0, 129.9, 129.8, 129.7,
127.0, 78.5, 69.9, 60.4, 53.4, 48.2, 40.4, 29.0, 27.3, 21.1,
20.7; HRMS (EI) m/z 417.2044 (calcd for C25H27N3O3:
417.2047). Crystal data for 3b at 20 ꢀC: C25H27N3O3, M
˚
417.5, orthorhombic, P21, 2121, a¼9.1750 (2) A, b¼
3
˚
˚
˚
Crystallographic data for the structures in this paper have
been deposited at the Cambridge Crystallographic Data Cen-
ter and allocated the CCDC deposit numbers.20
10.3510 (2) A, c¼23.4620 (5) A, V¼2228.20 (8) A , Z¼4,
Dx¼1.245 Mg/m3, m¼0.083 mmꢁ1, 5011 reflections, 281
parameters, R¼0.0609, Rw¼0.1125 for all of the data.
4.1.1. Synthesis of glyoxylic oxime 2. To a solution of
O-benzylhydroxylamine hydrochloride (1.0 g, 6.2 mmol)
in H2O (15 mL) was added glyoxylic acid (0.92 g,
12.5 mmol) in one portion. The reaction mixture was stirred
at ambient temperature. After 2 h, CH2Cl2 (20 mL) was
added to the reaction mixture and the aqueous layer was
extracted with CH2Cl2 (2ꢂ15 mL). The combined organic
extracts were dried over anhydrous MgSO4 and after
evaporation of the solvent, a white solid product (1.0 g,
90%) was obtained: 1H NMR (400 MHz, CDCl3) d 10.9 (s,
1H), 7.53 (s, 1H), 7.37–7.33 (m, 5H), 5.30 (s, 2H); 13C
NMR (100 MHz, CDCl3) d 166.3, 140.2, 135.6, 128.6
(ꢂ4), 78.5.
Compound 3c: Rf¼0.3 (2:1 hexanes/EtOAc); [a]3D2 ꢁ124.7
1
(c 1, CHCl3); H NMR (400 MHz, CDCl3) d 8.3–7.85 (m,
3H), 7.38–7.28 (m, 6H), 5.29 (m, 2H), 3.68 (br s, 1H),
2.62 (br s, 1H), 2.46 (s, 3H), 2.03–1.86 (m, 3H), 1.20 (m,
1H), 1.85 (m, 2H), 1.6 (m, 1H), 1.01 (s, 3H), 1.00 (s, 3H);
13C NMR (100 MHz, CDCl3) d 176.3, 162.0, 148.4, 143.8,
138.5, 135.7, 131.6, 130.2, 130.0, 129.9, 129.8, 79.6, 78.6,
71.9, 61.4, 53.8, 48.5, 29.9, 27.4, 22.3, 20.9, 20.7; HRMS
(EI) m/z 495.1826 (calcd for C26H29N3O5S: 495.1828).
Compound 3d: Rf¼0.4 (4:1 hexanes/EtOAc); 1H NMR
(400 MHz, CDCl3) d 8.05 (s, 1H), 7.37–7.28 (m, 10H),
5.43 (dd, 2H, J¼8.7, 4.0 Hz), 5.26 (s, 1H,), 4.67 (t, 1H,
J¼8.8 Hz), 4.27 (dd, 1H, J¼9.0, 4.0 Hz); 13C NMR
(100 MHz, CDCl3) d 159.3, 153.5, 141.5, 137.9, 135.9,
129.1, 128.8, 128.5, 128.46, 128.36, 128.30, 126.1, 78.1,
70.5, 57.4; HRMS (EI) m/z 324.1114 (calcd for
C18H16N2O4: 324.1105).
4.1.2. Typical procedure for the synthesis of glyoxylic
oxime ether 3a–h. Under a N2 atmosphere, a mixture of gly-
oxylic oxime ether 2 (1.0 g, 5.58 mmol) and thionyl chloride
(3.0 mL, 41.96 mmol) was refluxed at 75 ꢀC for 2 h and con-
centrated on a rotary evaporator to remove the excess SOCl2.
The resulting residue was dissolved in THF (5 mL) and
added to a mixture of camphorsultam (0.6 g, 2.78 mmol)
and NaH (0.1 g, 4.16 mmol) in THF (5 mL) at 0 ꢀC. The re-
action mixture was then stirred at 0 ꢀC for 2 h. The reaction
mixture was quenched with H2O (20 mL) and extracted with
EtOAc (3ꢂ20 mL). The combined organic extracts were
dried over anhydrous MgSO4 and concentrated in vacuo.
The crude products were further purified by flash column
chromatography eluted with hexanes/EtOAc (4:1) to give
the product as a white solid (0.91 g, 87%).
Compound 3e: Rf¼0.8 (10:1 hexanes/EtOAc); 1H NMR
(400 MHz, CDCl3) d 7.67–7.63 (m, 4H), 7.47–7.33 (m,
5H), 7.24–7.21 (m, 2H), 7.14–7.11 (m, 4H), 7.08–7.5 (m,
1H), 5.28 (m, 2H), 5.22 (m, 1H), 4.13 (s, 1H), 2.34–2.27
(m, 1H), 2.00–1.89 (m, 2H), 1.85–1.80 (m, 1H), 1.67–1.64
(m, 1H), 1.55–1.49 (m, 4H), 1.18 (m, 1H), 0.65 (s, 3H);
13C NMR (100 MHz, CDCl3) d 159.5, 148.8, 143.6, 140.1,
136.0, 129.1, 128.7, 125.5, 127.7, 126.7, 126.4, 126.2,
126.1, 82.2, 81.0, 78.3, 59.2, 51.3, 47.8, 38.2, 30.9, 27.0,
24.4, 22.6; HRMS (EI) m/z 483.2418 (calcd for

7820
N. A. Kulkarni et al. / Tetrahedron 63 (2007) 7816–7822
C31H33NO4:483.2404). Crystal data for 3e at 20 ꢀC:
C31H33NO4,
483.58, orthorhombic, P212121, a¼
products were subject to flash column chromatography
eluted with hexanes/EtOAc (3:1) to give 4a as a white solid
(45 mg, 89% yield, ratio of diastereomers 82% de).
M
˚
˚
˚
10.6150 (10) A, b¼11.0210 (2) A, c¼44.3470 (7) A, V¼
3
3
ꢁ1
˚
5188.06 (13) A , Z¼8, Dx¼1.238 Mg/m , m¼0.081 mm
,
2064 reflections, 281 parameters, R¼0.0681, Rw¼0.1479
Compound 4a: Rf¼0.60 (4:1 hexanes/EtOAc); [a]3D0 ꢁ46.7
1
for all of the data.
(c 1, CHCl3); H NMR (400 MHz, CDCl3) d 7.37–7.25
(m, 5H), 5.77–5.68 (m, 1H), 5.07 (d, 1H, J¼16.9 Hz), 5.03
(d, 1H, J¼9.8 Hz), 4.73 (d, 1H, J¼11.7 Hz), 4.66 (d,
1H, J¼11.7 Hz), 4.46 (t, 1H, J¼6.4 Hz), 3.96 (t, 1H,
J¼6.4 Hz), 3.51 (d, 1H, J¼13.8 Hz), 3.46 (d, 1H,
J¼13.8 Hz), 2.41–2.30 (m, 2H), 2.06 (d, 2H, J¼6.8 Hz),
1.94–1.85 (m, 4H), 1.44–1.32 (m, 2H), 1.13 (s, 3H), 0.96
(s, 3H); 13C NMR (100 MHz, CDCl3) d 173.2, 137.9,
132.9, 128.8, 128.4, 127.8, 118.6, 76.1, 65.3, 62.6, 53.2,
48.8, 47.9, 44.8, 38.5, 35.0, 33.0, 26.6, 21.0, 20.1; HRMS
(EI) m/z 418.1929 (calcd for C22H30N2O4S 418.1926). Crys-
tal data for 4a at 27 ꢀC: C22H30N2O4S, M 418.5, orthorhom-
1
Compound 3f: Rf¼0.83 (10:1 hexanes/EtOAc); H NMR
(400 MHz, CDCl3) d 7.51 (s, 1H), 7.36–7.28 (m, 5H), 5.26
(s, 2H), 4.88–4.81 (m, 1H), 2.05–2.02 (m, 1H), 1.90–1.84
(m, 1H), 1.70–1.67 (m, 2H), 1.52–1.43 (m, 2H), 1.10–1.02
(m, 2H), 0.91–0.82 (m, 7H), 0.77 (d, 3H, J¼7.0 Hz); 13C
NMR (100 MHz, CDCl3) d 161.25, 141.2, 135.9, 128.4,
128.3, 128.2, 77.2, 75.5, 60.9, 52.2, 46.7, 40.5, 33.0, 31.2,
26.1, 23.4, 21.8, 20.5, 16.2; HRMS (EI) m/z 317.1983 (calcd
for C19H27NO3: 317.1985).
Compound 3g: Rf¼0.8 (10:1 hexanes/EtOAc); 1H NMR
(400 MHz, CDCl3) d 7.56 (s, 1H), 7.40–7.32 (m, 5H), 5.29
(s, 2H), 5.38 (m, 1H), 2.43–2.37 (m, 1H), 2.00–1.94 (m,
1H), 1.85–1.80 (m, 1H), 1.70 (t, 1H, J¼9.0 Hz), 1.29–1.22
(m, 2H), 1.05 (dd, 1H, J¼13.9, 3.5 Hz), 0.92 (s, 3H), 0.89
(s, 3H), 0.86 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 161.9, 141.1, 135.9, 128.5, 128.3, 128.2, 81.0, 76.7,
48.8, 47.7, 44.7, 36.4, 27.8, 26.8, 19.5, 18.7,13.3; HRMS
(EI) m/z 315.1848 (calcd for C19H25NO3: 315.1829).
bic, P21, a¼7.6150 (5) A, b¼16.0100 (6) A, c¼17.8800
˚
˚
3
(7) A, V¼2179.86 (19) A , Z¼4, Dc¼1.275 Mg/m3,
˚
˚
m¼0.179 mmꢁ1
,
3808 reflections, 263 parameters,
R¼0.1220, Rw¼0.1976 for all of the data.
Compound 4b: Rf¼0.53 (4:1 hexanes/EtOAc); [a]3D1 ꢁ24.2
1
(c 1, CHCl3); H NMR (400 MHz, CDCl3) d 7.33–7.29
(m, 5H), 7.28–7.26 (m, 5H), 7.18–7.14 (m, 1H), 5.75 (m,
1H), 5.13–5.09 (m, 2H), 4.71 (d, 1H, J¼11.3 Hz), 4.66 (d,
1H, J¼11.3 Hz), 4.07 (dd, 1H, J¼7.9, 5.0 Hz), 3.79 (t, 1H,
J¼6.5 Hz), 2.75–2.71 (m, 1H), 2.30–2.21 (m, 3H), 2.04–
1.94 (m, 2H), 1.90 (t, 1H, J¼3.9 Hz), 1.43–1.30 (m, 2H),
1.05 (s, 3H), 1.0 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 171.8, 170.5, 138.5, 137.5, 133.3, 128.9, 128.5, 128.4,
128.2, 126.0, 122.1, 118.7, 76.4, 66.0, 61.8, 59.2, 53.8,
46.7, 39.5, 33.8, 28.5, 27.0, 20.3, 20.2; HRMS (EI) m/z
459.2507 (calcd for C28H33N3O3: 459.2516). Crystal data
for 4b at 20 ꢀC: C28H33N3O3, M 459.57, monoclinic, P21,
1
Compound 3h: Rf¼0.75 (10:1 hexanes/EtOAc); H NMR
(400 MHz, CDCl3) d 7.59 (s, 1H), 7.38–7.33 (m, 5H), 5.28
(s, 2H), 5.27–5.23 (m, 1H), 2.57–2.53, (m, 2H), 2.6 (m,
1H), 2.02 (t, 1H, J¼5.7 Hz), 1.78–1.73 (m, 1H), 1.52 (d,
2H, J¼10.6 Hz), 1.34 (s, 3H), 1.3 (s, 3H), 1.00 (s, 3H);
13C NMR (100 MHz, CDCl3) d 161.2, 140.8, 135.9, 128.6,
128.5, 128.4, 117.1, 73.9, 73.2, 54.1, 40.2, 38.7, 34.4,
29.7, 28.0, 27.8, 24.2; HRMS (EI) m/z 331.1809 (calcd for
C19H25N2O4: 331.1778).
˚
˚
˚
a¼10.4820 (11) A, b¼10.8420 (11) A, c¼11.3590 (16)ꢁA1,
3
3
˚
V¼1290.5 (3) A , Z¼2, Dc¼1.183 Mg/m , m¼0.077 mm
,
4.1.3. Typical procedure for the allylation of glyoxylic ox-
ime ethers 3a–h using allyltributylstannane in the pres-
ence of Sn(OTf)2 (method A) and triallylaluminum
(method B). Method A. To a solution of 3a (50 mg, 0.13
mmol) in CH3CN (5 mL) Sn(OTf)2 (55.5 mg, 0.13 mmol)
was added. The reactionmixturewas stirred for10 minat am-
bient temperature. The solution was cooled to ꢁ40 ꢀC and al-
lyltributylstannane (81 mL, 0.26 mmol) was added and the
stirring continuedfor1 h. The reactionmixturewas quenched
with H2O (15 mL) and extracted with CH2Cl2 (3ꢂ20 mL).
The organic layers were separated and dried over anhydrous
MgSO4 and concentrated. The resulting crude products were
subject to flash column chromatography purification eluted
with hexanes/EtOAc (3:1) to afford 4a as a white solid
(50 mg, 90% yield, ratio of diastereomers 91% de).
3671 reflections, 308 parameters, R¼0.2229, Rw¼0.2971 for
all the data.
Compound 4c: Rf¼0.3 (2:1 hexanes/EtOAc); [a]3D0 ꢁ46.9 (c
1
1, CHCl3); H NMR (400 MHz, CDCl3) d 8.04 (m, 2H),
7.36–7.28 (m, 7H), 5.91 (br s, 1H), 5.18–5.10 (m, 2H),
4.70 (s, 2H), 4.14 (br s, 1H), 3.80 (br s, 1H), 2.86–2.83 (m,
2H), 2.48 (dd, 1H, J¼15.0, 7.1 Hz), 2.43 (s, 3H), 2.29 (br
s, 1H), 2.09 (br s, 1H), 1.90–1.89 (m, 2H), 1.79 (dd, 1H,
J¼13.3, 8.2 Hz), 1.26–1.25 (m, 2H), 0.97 (s, 3H), 0.89 (s,
3H); 13C NMR (100 MHz, CDCl3) d 173.5, 171.7, 145.5,
137.8, 137.4, 135.6, 134.0, 129.7, 129.2, 129.0, 128.4,
128.0, 118.1, 76.4, 70.0, 60.9, 52.2, 47.9, 38.00, 35.2,
29.8, 29.5, 26.9, 21.9, 20.4, 19.8; HRMS (EI) [M+1] m/z
538.2371 (calcd for C28H36N3O5S: 538.2370).
Method B. A solution of 3a (50 mg, 0.13 mmol) in CH2Cl2
(5 mL) was cooled to ꢁ78 ꢀC and triallylaluminum (1.0 M,
0.26 mL, 0.26 mmol) was added dropwise over a period of
20 min. After 10 min, the reaction mixture was quenched
with H2O (5 mL) and aq HCl (1.0 mL, 2 N) was then added
at ꢁ78 ꢀC. The mixture was stirred for an additional 10 min
and warmed to 0 ꢀC. The mixture was further diluted with
H2O (10 mL) and extracted with CH2Cl2 (3ꢂ20 mL). The
organic layers were separated and dried over anhydrous
MgSO4 and concentrated in vacuo. The resulting crude
Compound 4d: An inseparable mixture of diastereomers was
obtained. Selected peaks of the major diastereomer: 1H
NMR (400 MHz, CDCl3) d 8.05 (s, 1H), 7.38–7.27 (m,
10H), 5.60 (m, 1H), 5.48 (dd, 1H, J¼8.7, 3.6 Hz), 4.95–
4.89 (m, 2H), 4.32 (dd, 1H, J¼8.9, 3.6 Hz), 2.35–2.30 (m,
1H), 5.23–5.19 (m, 1H); HRMS (EI) m/z 366.1576 (calcd
for C21H22N2O4: 366.1572).
Compound 4e: An inseparable mixture of diastereomers
was obtained. Selected peaks of the major diastereomer:

N. A. Kulkarni et al. / Tetrahedron 63 (2007) 7816–7822
7821
1H NMR (400 MHz, CDCl3) d 7.74–7.71 (m, 4H), 7.58–7.55
(m, 4H), 7.35 (m, 2H), 7.25–7.16 (m, 3H), 7.12–7.05
(m, 2H), 5.45–5.29 (m, 2H), 5.01–4.93 (m, 2H), 4.71 (m,
1H), 4.19 (s, 1H), 3.39 (t, 1H, J¼6.1 Hz), 2.35–2.28 (m, 1H),
2.06–1.91 (m, 4H), 1.85–1.82 (m, 1H), 1.69–1.56 (m, 1H),
1.55–1.48 (m, 4H), 1.38 (m, 1H), 0.62 (s, 3H); minor diaste-
reomer: 1H NMR (400 MHz, CDCl3) d 7.74–7.71 (m,
4H), 7.58–7.55 (m, 4H), 7.35 (m, 2H), 7.25–7.16 (m, 3H),
7.12–7.05 (m, 2H), 5.45–5.29 (m, 2H), 5.01–4.93 (m, 2H),
4.71 (m, 1H), 4.05 (s, 1H), 3.26 (t, 1H, J¼6.4 Hz), 2.35–
2.28 (m, 1H), 2.06–1.91 (m, 4H), 1.85–1.82 (m, 1H),
1.69–1.56 (m, 1H), 1.55–1.48 (m, 4H), 1.38 (m, 1H), 0.62
(s,3H); HRMS (EI) [M+1] m/z 526.2973 (calcd for
C34H40NO4: 526.2952).
Lee, F. Y. F.; Long, B. H.; Vite, G. D. J. Am. Chem. Soc. 2000,
122, 8890; (b) Besada, P.; Mamedova, L.; Thomas, C. J.;
Costanzi, S.; Jacobson, K. A. Org. Biomol. Chem. 2005, 3,
2016; (c) Jain, R. P.; Williams, R. M. J. Org. Chem. 2002,
67, 6361; (d) Fabio, R. D.; Alvaro, G.; Bertani, B.; Donati,
D.; Giacobbe, S.; Marchioro, C.; Palma, C.; Lynn, S. M.
J. Org. Chem. 2002, 67, 7319.
4. Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
5. Seyferth, D.; Murphy, G. J.; Mauze, B. J. Am. Chem. Soc. 1977,
99, 5317.
6. Davis, A. P.; Jaspars, M. Angew. Chem., Int. Ed. Engl. 1992,
31, 470.
7. Yamamoto, Y.; Yatagai, H.; Ishihara, Y.; Maeda, N.;
Maruyama, K. Tetrahedron 1984, 40, 2239.
8. (a) Hiyama, T.; Sawahata, M.; Obayashi, M. Chem. Lett. 1983,
1237; (b) Petrier, C.; Luche, J.-L. J. Org. Chem. 1985, 50,
910; (c) Nokami, J.; Otera, J.; Sudo, T.; Okawara, R.
Organometallics 1983, 2, 191; (d) Butsugan, Y.; Ito, H.;
Torii, S. Tetrahedron Lett. 1984, 25, 6017; (e) Imamoto, T.;
Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.;
Hatanaka, Y.; Yokayama, M. J. Org. Chem. 1984, 49, 3904.
9. Blomberg, C.; Hartog, F. A. Synthesis 1977, 18.
10. (a) Saito, S. Main Group Metals in Organic Synthesis;
Yamamoto, Y., Oshima, K., Eds.; Wiley-VCH: Weinheim,
2004; Vol. 1, pp 189–300; (b) Mole, T.; Jeffrey, E. A.
Organoaluminum Compounds; Elsevier: Amsterdam, 1972;
For recent developments, see: (c) Liang, B.; Novak, T.; Tan,
Z.; Negishi, E.-i. J. Am. Chem. Soc. 2006, 128, 2770; (d)
Novak, T.; Tan, Z.; Liang, B.; Negishi, E.-i. J. Am. Chem.
Soc. 2005, 127, 2838.
11. (a) Puentes, C. O.; Kouznetsov, V. J. Heterocycl. Chem. 2002,
39, 595; (b) Denmark, S. E.; Almstead, N. G. Modern Carbonyl
Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000;
Chapter 10 and references therein; (c) Chen, Y.; Yekta, S.;
Yudin, A. K. Chem. Rev. 2003, 103, 3155; (d) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069; For more examples,
see: (e) Shimizu, M.; Kimura, M.; Watanabe, T.; Tamaru, Y.
Org. Lett. 2005, 7, 637; (f) Solin, N.; Wallner, O. A.; Szabo,
K. J. Org. Lett. 2005, 7, 689; (g) Fernandes, R. A.;
Yamamoto, Y. J. Org. Chem. 2004, 69, 735; (h) Fernandes,
R. A.; Stimac, A.; Yamamoto, Y. J. Am. Chem. Soc. 2003,
125, 14133.
12. (a) Cook, G. R.; Maity, B. C.; Kargbo, R. Org. Lett. 2004, 6,
1741; (b) Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am.
Chem. Soc. 2003, 125, 9596; (c) Kobayashi, S.; Ogawa, C.;
Konishi, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 6610;
(d) Hamada, T.; Manabe, K.; Kobayashi, S. Angew. Chem.,
Int. Ed. 2003, 42, 3927.
Compound 4f: An inseparable mixture of diastereomers was
obtained. Selected peaks of the major diastereomer: 1H
NMR (400 MHz, CDCl3) d 7.51 (s, 1H), 7.34–7.29 (m,
5H), 5.73 (m, 1H), 5.14–5.07 (m, 2H), 4.73 (s, 2H), 3.71–
3.67 (m, 1H), 2.36–2.34 (m, 2H), 2.95–1.91(m, 2H), 1.71–
1.68 (m, 2H), 1.51–1.39 (m, 2H), 1.08–1.97 (m, 2H),
0.90–0.86 (m, 7H), 0.72 (d, 3H, J¼7 Hz); HRMS (EI) m/z
359.2444 (calcd for C22H33NO4: 359.2455).
Compound 4g: Rf¼0.8 (10:1 hexanes/EtOAc); 1H NMR
(400 MHz, CDCl3) d 7.33–7.25 (m, 5H), 5.91 (br s, 1H),
5.78–5.70 (m, 1H), 5.12–5.06 (m, 1H), 5.0–4.95 (m, 1H),
4.71 (s, 3H), 3.71 (t, 1H, J¼6.9 Hz), 2.35 (t, 3H,
J¼6.9 Hz), 1.97–2.00 (m, 1H), 1.76–1.73 (m, 1H), 1.68
(dd, 1H, J¼7.8, 3.5 Hz), 1.34–1.21 (m, 2H), 1.05–0.96 (m,
1H), 0.90 (s, 3H), 0.87 (s, 3H), 0.83 (d, 3H, J¼7.5 Hz);
13C NMR (100 MHz, CDCl3) d 173.3, 137.7, 133.1, 128.3,
127.7, 118.0, 80.6, 76.1, 63.4, 63.2, 48.8, 47.8, 44.8, 36.6,
33.9, 36.6, 33.9, 27.9, 27.1, 19.6, 18.8, 13.4; HRMS (EI)
m/z 357.2309 (calcd for C26H31NO3: 357.2298).
Compound 4h: An inseparable mixture of diastereomers
were obtained. Selected peaks of the major diastereomer:
1H NMR (400 MHz, CDCl3) d 7.39–7.29 (m, 5H), 5.82–
5.74 (m, 1H), 5.32–5.28 (m, 1H), 5.16–5.09 (m, 2H), 4.73
(m, 2H), 3.70 (t, 1H, J¼7.0 Hz), 2.48–2.38 (m, 2H), 2.26–
2.23 (m, 1H), 2.02–1.95 (m, 2H), 1.68–1.66 (m, 2H), 1.55
(m, 1H), 1.30 (s, 3H), 1.27 (s, 3H), 1.00 (s, 3H); HRMS
(EI) [M+1] m/z 374.2326 (calcd for C22H32NO4: 374.2326).
Acknowledgements
13. Kulkarni, N. A.; Chen, K. Tetrahedron Lett. 2006, 47, 611.
14. Kulkarni, N. A. Ph.D. Thesis, Department of Chemistry,
National Taiwan Normal University, Taipei, Taiwan, 2006.
15. For pioneering work of diastereoselective allylation of cam-
phorsultam derived glyoxime ether, see: (a) Hanessian, S.;
Lu, P.-P.; Sanceau, J.-Y.; Chemla, P.; Gohda, K.; Fonne-
Pfister, R.; Prade, L.; Cowan-Jacob, S. W. Angew. Chem., Int.
Ed. 1999, 38, 3160; (b) Hanessian, S.; Bernstein, N.; Yang,
R.-Y.; Maguire, R. Bioorg. Med. Chem. Lett. 1999, 9, 1437;
(c) Hanessian, S.; Yang, R.-Y. Tetrahedron Lett. 1996, 37,
5273; For recent examples, see: (d) Miyabe, H.; Yamaoka,
Y.; Naito, T.; Takemoto, Y. J. Org. Chem. 2004, 69, 1415; (e)
Miyabe, H.; Yamaoka, Y.; Naito, T.; Takemoto, Y. J. Org.
Chem. 2003, 68, 6745; (f) Miyabe, H.; Nishimura, A.; Ueda,
M.; Naito, T. Chem. Commun. 2002, 1454.
We wish to thank the National Science Council of the
Republic of China (NSC 95-2113-M-003-003) and the
National Taiwan Normal University (ORD 94-G) for finan-
cial support for this work. The X-ray crystal data, which
were collected and processed by National Taiwan Normal
University, are gratefully acknowledged.
References and notes
1. Ryan, S. J.; Zhang, Y.; Kennan, A. J. Org. Lett. 2005, 7, 4765.
2. Ramachandran, P. V.; Burghardt, T. E.; Bland-Barry, L. J. Org.
Chem. 2005, 70, 7911.
3. (a) Borzilleri, R. M.; Zheng, X.; Schmidt, R. J.; Johnson, J. A.;
Kim, S.-H.; DiMarco, J. D.; Fairchild, C. R.; Gougoutas, J. Z.;

7822
N. A. Kulkarni et al. / Tetrahedron 63 (2007) 7816–7822
16. (a) Minowa, N.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1987, 60,
3697; (b) Mukaiyama, T.; Minowa, N.; Oriyama, T.; Narasaka,
K. Chem. Lett. 1986, 97.
17. Shen, K.-H.; Yao, C.-H. J. Org. Chem. 2006, 71, 3980.
18. (a) You, J.-S.; Hsieh, S.-H.; Gau, H.-M. Chem. Commun. 2001,
1546; (b) Rainier, J. D.; Cox, J. M. Org. Lett. 2000, 2, 2707;
(c) Yamamoto, Y.; Komatsu, T.; Maruyama, K. J. Chem. Soc.,
Chem. Commun. 1985, 11, 814.
19. Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2000, 122,
8329.
20. 3a (CCDC 642120), 3b (CCDC 642117), 3e (CCDC 642121),
4a (CCDC 642119), 4b (CCDC 642118).