Enantioselective formation of tert-alkylamines by desymmetrization of 2-substituted serinols

Article abstract of DOI:10.1002/chem.200701875

Novel enantioselective desymmetrization of 2-substituted 2-amino-1,3-propanediols has been established to generate asymmetric quaternary carbon centers comprising an amino group. Enantioselective as well as chemical conversion proved to be greatly dependent on the protecting group of the amino group in the substrate, desymmetrizing reagent, base, solvent, and naturally, catalyst. The highly effective desymmetrization has been implemented by using N-benzoylated substrates with benzoyl Chloride and triethylamine in the presence of tetraphenylbisoxazoline (24)-CuCl₂ complex in THF at ambient temperature. An extensive survey of catalysts revealed that dimethylmalonate- bridged bisoxazoline-CuCl₂ complexes were superior. Among them, the tetraphenylbisoxazoline (24)-CuCl₂ complex turned out to work most efficiently with a wide array of the substrates. All the examined substrates, with the exception of 2-phenylserinol 36, were desymmetrized in the presence of 24-CuCl₂ complex to give high enantioselectivities ranging from 85 to 95% ee. Complementary use of the diisopropylbisoxazoline (22)-CuCl₂ complex has remedied the mediocre desymmetrization of 36 to give a significantly improved enantioselectivity from 63 to 83% ee.

Full text of DOI:10.1002/chem.200701875

DOI: 10.1002/chem.200701875
Enantioselective Formation of tert-Alkylamines by Desymmetrization of
2-Substituted Serinols
Mi Sook Hong, Tae Woo Kim, Byunghyuck Jung, and Sung Ho Kang*[a]
Dedicated to Professor Yoshito Kishi on the occasion of his 70th birthday
Abstract: Novel enantioselective de-
symmetrization of 2-substituted 2-
amino-1,3-propanediols has been estab-
lished to generate asymmetric quater-
nary carbon centers comprising an
amino group. Enantioselective as well
as chemical conversion proved to be
greatly dependent on the protecting
group of the amino group in the sub-
strate, desymmetrizing reagent, base,
solvent, and naturally, catalyst. The
highly effective desymmetrization has
been implemented by using N-
chloride and triethylamine in the pres-
ence of tetraphenylbisoxazoline (24)–
CuCl2 complex in THF at ambient tem-
perature. An extensive survey of cata-
lysts revealed that dimethylmalonate-
bridged bisoxazoline–CuCl2 complexes
were superior. Among them, the tetra-
phenylbisoxazoline (24)–CuCl2 com-
plex turned out to work most efficient-
ly with a wide array of the substrates.
All the examined substrates, with the
exception of 2-phenylserinol 36, were
desymmetrized in the presence of 24–
CuCl2 complex to give high enantiose-
lectivities ranging from 85 to 95% ee.
Complementary use of the diisopropyl-
bisoxazoline (22)–CuCl2 complex has
remedied the mediocre desymmetriza-
tion of 36 to give a significantly im-
proved enantioselectivity from 63 to
83% ee.
Keywords: alkylamines
·
desym-
metrization · Lewis acids · organic
chemistry · stereoselectivity
benzoylaACHTREUNGted substrates with benzoyl
Introduction
ficult installation of the chiral centers. Most of the stereo-
genic tert-alkylamines have been generated by utilizing the
preexisting asymmetric centers of substrates themselves or
chiral auxiliary-attached substrates.[5] In recent years, their
enantioselective formation has been developed through al-
kylation of alanine and glycine esters,[6] allylic alkylation of
azlactones,[7] and cyanide addition to ketoimines[8] in the
presence of chiral catalysts. Asymmetric desymmetrization
methods have been exploited as powerful synthetic means
to engender enantiomerically enriched stereocenters bonded
to heteroatoms from meso stereoisomers. The structural fea-
Biologically potent small molecules embedded with nitro-
gen-comprising stereogenic quaternary centers (tert-alkyl-
ACHTREUNGamines) are ubiquitous in natural products and pharmaceuti-
cals, such as manzacidins, sphingofungins, lactacystin,[1] sor-
binil,[2] and MK801 (dizociline).[3] In addition, optically pure
tert-alkylamino acids have recently become an active re-
search subject because their geometric constraints exert pro-
nounced effects on the three-dimensional conformations of
their incorporated peptides.[4] It is of great value and a sig-
nificant challenge to synthesize such structurally (as well as
physiologically) intriguing compounds as a result of the dif-
tures of these compounds have been mainly limited to hy-
[9,10,11]
droxyl-containing carbonic groups.
However, desym-
metrization has rarely been documented to synthesize chiral
tert-alkylamine building blocks.[12] Herein, we report a highly
effective enantioselective monobenzoylation of 2-substituted
2-benzamido-1,3-propanediols by catalytic desymmetrization
to install chiral quaternary carbon centers.
[a] M. S. Hong, T. W. Kim, B. Jung, Prof. Dr. S. H. Kang
Center for Molecular Design and Synthesis
Department of Chemistry
School of Molecular Science (BK21)
KAIST, Daejeon 305–701 (Korea)
Fax : (+82)42-869-2810
E-mail: shkang@kaist.ac.kr
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
3290
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3290 – 3296

FULL PAPER
Results and Discussion
tion but with insufficient chemical conversion and with the
formation of considerable amounts of the corresponding di-
benzoates (entries 2and 3). While the monobenzoylation of
the phosphinamide 5, the trifluoroacetamide 6, and the tert-
butyl carbamate 7 resulted in moderate stereoselection, the
reaction with the latter two substrates proceeded with exten-
sive decomposition (entries 4–6). The best desymmetrization
was attained with the benzamide diol 8 (entry 7). As the re-
action was not forwarded at all in the absence of catalyst,
the background reaction certainly had little adverse effect
on the enantioselectivity (entry 8). Lowering the reaction
temperature turned out to be detrimental to the desymmet-
rization (entry 9). Besides benzoyl chloride, some other pro-
tecting reagents (Bz2O, AcCl, Ac2O, and TESCl; TES=tri-
In consideration of their easy accessibility and the potential
synthetic versatility of the desymmetrization products, 2-
substituted serinols were selected as substrates. It was plan-
ned that these substrates would be desymmetrized under
basic benzoylation conditions in the presence of a chiral
Lewis acid catalyst. Choice of the amino protecting group
was considered to be critical because its electronic and
steric environments certainly have a great influence on the
coordination bond strengths and the spatial arrangement in
the complex among the substrate, catalyst, and/or benzoylat-
ing reagent. With initial use of the benzyloxycarbonyl (Cbz)
group as the N-protecting group, the N-Cbz-serinol 2 was
extensively investigated in the search for a prospective
asymmetric catalyst. The model survey suggested bisoxazo-
line–CuCl2 complexes, which were pioneered for kinetic rec-
ognition of 1,2-diols by Matsumura et al,[11e] would be the
most effective catalysts. From this group of complexes, di-
AHCTREUNG
monobenzoylation, our efforts were focused on elaborating
the most effective catalyst by scouting a wide array of chiral
bisoxazoline ligands. Representative results are presented in
Table 2. Perusal of the results reveals that a specific size of
the 4-substituent in the bisoxazoline seems to be advanta-
geous for the enhanced stereoinduction and chemical con-
version. It is reasoned that while a smaller substituent itself
could not impose influential steric congestion to discern the
two hydroxymethyl groups of the substrate, a bulkier sub-
stituent might impede a proximal approach of the substrate
to the catalyst. With the exception of the diisopropylbisox-
[13]
phenylbisoxazoline (1)–CuCl2 was employed with benzoyl
chloride in the monobenzoylation of 2 to examine the de-
pendence of the desymmetrization on solvents and bases.
The experimental data indicated that when using Et3N as
the base, the highest chemical conversion was obtained in
THF; however, the lowest conversion was obtained when
using other ethereal solvents. Hindered amine bases, such as
2,6-lutidine and iPr2NEt, displayed much inferior reactivity.
The best enantioselectivity (though far from ideal) and
chemical conversion were reached with Et3N in THF
(Table 1, entry 1).
Table 2. Desymmetrization of 8 by using 10 mol% of (16–24)–CuCl2
complexes.
Table 1. Desymmetrization of 2–8 by using 10 mol% of 1–CuCl2 com-
plex.
Entry
P
Substrate/product
Yield [%][a]
ee [%]
1
Cbz
2/9
74 (24)
38 (32) [15]
39 (25) [35]
55 (40)
13 (0)
6 (48)
66 (28)
0 (97)
53
58
71
55
57
49
80
-
2PhSO
3
4
5
3/10
4/11
5/12
6/13
7/14
8/15
8/15
8/15
Yield [%][a]
ee [%][b]
2
Entry
Ligand
pNs[b]
Ph2PO
CF3CO
Boc[c]
PhCO
PhCO
PhCO
1
2
3
4
5
6
7
8
1
66 (28)
27 (63)
71 (20)
11 (88)
42(50)
49 (50)
38 (57)
29 (70)
31 (64)
73 (22)
74 (20)
72 (22)
74 (20)
94
80 (R)
20 (R)
84 (R)
44 (R)
30 ( R)
0
16
17
18
19
20
21
22
23
24
1
6
7
8[d]
9[e]
38 (56)
69
2( R)
[a] Percentage of recovered starting material in parentheses; percentage
of dibenzoate in square brackets. [b] pNs=p-nitrobenzenesulfonyl.
[c] Boc=tert-butoxycarbonyl. [d] In the absence of complex. [e] The reac-
tion was carried out at À208C.
78 (S)
15 (S)
84 (S)
84 (R)
87 (R)
90 (S)
92( S)
9
10
11[c]
12[c]
13[c]
14[d]
17
24
24
The intrinsic stereoselection in the desymmetrization of 2
was screened by varying the amino protecting group under
the modulated conditions. As shown in Table 1, the sulfona-
mides 3 and 4 were desymmetrized with high stereoinduc-
[a] Percentage of recovered starting material in parentheses. [b] Major
configuration in parentheses. [c] 20 mol% of complex. [d] 20 mol% of
24–CuCl2 complex, 2.0 equiv of BzCl and 1.5 equiv of Et3N.
Chem. Eur. J. 2008, 14, 3290 – 3296
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3291

S. Ho Kang et al.
A
irrespective of their sizes and electronic properties
(entries 1–9). Vinylic and acetylenic substituents are also ef-
fective, albeit 34 and 35 gave slightly lower ee values, which
were still higher than a 14:1 enantiomeric ratio (entries 10–
12). Among the aryl-substituted substrates 36–38, the de-
symmetrization of only the phenyl-substituted substrate 36
proceeded with significantly lowered enantioselectivity
(entries 13, 15 and 16). In consequence of our endeavor to
restore the stereoselectivity, the ligand was switched from 24
to 22 to give a substantially improved enantioselectivity of
83% ee (entry 14).[16] To establish whether or not the im-
proved enatioselectivity stemmed from a kinetic resolution
or the intrinsic stereoselection, the monobenzoate 50 with
an 83% ee value was treated under desymmetrization condi-
tions (described in entry 14 of Table 3) to give the corre-
sponding dibenzoate in 10% yield along with 85% of recov-
ered 50 with 84% ee. Consequently, the intrinsic stereoselec-
tion seemed to be responsible for the observed enhance-
ment.
A plausible mechanism of the desymmetrization is pro-
posed based on the assumption that the substrate works as a
tridentate ligand to the catalyst to form a pyramidal-shaped
complex, the electrophilic CuII atom of which coordinates
with benzoyl chloride from the open-bottomed face for the
activation of the benzoyl group (Figure 1, pathway A). The
subsequent benzoyl transfer to the equatorial hydroxyl
group renders the observed configuration. On the other
hand, the desymmetrization through the other diastereo-
merically arranged complex is conceived to be in a higher
energy state because it causes steric interactions between
the apical hydroxymethyl group and the phenyl substituent
in the oxazoline ring (pathway B). Furthermore, in the pro-
cess of the benzoyl transfer to the equatorial hydroxyl
group, severe steric congestion, between the pending benzo-
yl chloride and the phenyl substituent in the other oxazoline
ring, is expected to disfavor pathway B.
tivity also produced high chemical yield (entries 1, 3, 8
and 10). The value for the percentage ee with 4-alkyl-substi-
tuted bisoxazolines[14] increased from methyl to ethyl and
isopropyl substituents, but dropped drastically when using a
tert-butyl substituent (entries 2, 3, 8 and 9). In the cases of 4-
aryl-substituted bisoxazolines,[15] remarkable asymmetric in-
duction was achieved when using a phenyl substituent, but
the bulkier naphthyl substituent yielded almost a racemate
(entries 1, 7 and 10). As 1, 17, and 24 pertained to the most
effective ligand group with similar potency, their assessment
was carried out by using increasing amounts of the corre-
sponding catalysts. The maximal ee values were gained with
20 mol% of the catalysts, among which 24–CuCl2 complex
brought about the highest stereoinduction, though the differ-
ences were marginal (entries 11–13). Furthermore, applica-
tion of greater quantities of benzoyl chloride and Et3N
drove the monobenzoylation to completion (entry 14). In
addition, the ligand recovery was practiced by decomplexing
the 24–CuCl2 catalyst with 25 mol% of N,N,N’,N’-tetrame-
thylethylenediamine to recover more than 85% of the bis-
ACHTREUNG
symmetrized by the established procedure as described in
entry 14 of Table 2. Outstanding asymmetric monobenzoyla-
tions were carried out with most of the substrates as illus-
trated in Table 3. A variety of alkyl substituents comprising
silyloxy, benzyloxy, phenyl, and vinyl groups are tolerable,
Table 3. Enantioselective monobenzoylation of 25–38 by using 20 mol%
of 24–CuCl2 complex.
Entry
R
Substrate/product Yield [%][a] ee [%][b]
1
2Me
3
4
5
6
7
8
9
10
11
12C
13
14[d]
15[d,e]
16[d,f]
CH2CH2Ph
8/15
94
96
95
95
98
96
9294
94
96
93
95
96
80 (14)
87 (6)
97
92( S)
91
95 (S)
92
90
92( R)
Conclusion
25/39
26/40
27/41
28/42
29/43
30/44
31/45
32/46
33/47
Et
CH2-cHx[c]
iBu
Highly enantioselective formation of tert-alkylamines has
been established by desymmetric benzoylation of 2-substi-
tuted serinols in the presence of the bisoxazoline–CuCl2
complexes. The most effective ligands have been demon-
strated to be tetraphenylbisoxazoline (24) for the serinols
containing 2-alkyl, alkenyl, and alkynyl substituents, and
CH2OTBDPS
A
Bn
90 (S)
92
92( S)
88 (S)
87
63 (S)
83 (S)
85
CH2CH=CH2
CH=CH2
(E)-CH=CHCO2Et 34/48
=CSiMe3
Ph
Ph
AHCTREdUNG iisopropylbisoxazoline (22) for the 2-arylserinols. Construc-
35/49
36/50
36/50
37/51
38/52
tion of nitrogen-attached quaternary carbon centers with
high stereoinduction has rarely been realized and pertains
to one of the most difficult synthetic issues. Our desymmet-
rization approach to generate enantiomerically enriched
amino functional groups provides uniquely remarkable solu-
tion. Furthermore, this functionality is embedded in a varie-
ty of physiologically significant natural products and phar-
maceuticals. With this in mind, the developed protocol is ex-
pected to offer great synthetic utility and versatility in terms
of enantioselectivity and structural diversity in the synthesis
pClPh
pMePh
97
88
[a] Percentage of dibenzoate in parentheses. [b] Major configuration in
parentheses (see the Supporting Information). [c] cHx=cyclohexyl.
[d] 20 mol% of 22–CuCl2 complex, 4.0 equiv of BzCl, and 3.0 equiv of
Et3N. [e] Similar results were obtained when using 20 mol% of 24–CuCl2
complex, 3.0 equiv of PhCOCl, and 2.0 equiv of Et3N. [f] 97% yield and
85% ee were obtained when using 20 mol% of 24–CuCl2 complex,
3.0 equiv of PhCOCl, and 2.0 equiv of Et3N.
3292
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3290 – 3296

Enantioselective Formation of tert-Alkylamines
FULL PAPER
tion (EtOAc/hexane 1:5) afforded the
tosylate (2.014 g, 92% yield). NaH
(60% dispersion in mineral oil,
316 mg, 7.92mmol) was added to the
tosylate (2.742 g, 6.60 mmol) in THF
(20 mL) portionwise at 08C. After stir-
ring the reaction mixture at 08C for
20 min and then at room temperature
for 40 min, it was quenched with H2O
(20 mL) at 08C and worked up with
EtOAc (10 mL, ”3). Column chroma-
tography (EtOAc/hexane 1:3) of the
crude product furnished the N-Boc-
aziridine
(1.567 g,
98%
yield).
BnMgBr (1.0m in THF, 12.3 mL,
12.3 mmol) was then added to CuI
(234 mg, 1.23 mmol) in THF (5 mL) at
À788C and the resulting mixture was
reacted at that temperature for
15 min. The aziridine (1 g, 4.11 mmol)
dissolved in THF (5 mL) was injected
into the prepared Grignard reagent at
À788C and the reaction temperature
was raised from À78 to 08C over a
period of 1h. After quenching the re-
action with saturated aqueous NH4Cl
(10 mL), followed by a workup with
Figure 1. A plausible pathway for the desymmetrization.
EtOAc (5 mL, ”3), the residue was
purified by column chromatography
(EtOAc/hexane 1:10) to give the pro-
tected serinol with a 2-phenylethyl substituent (1.334 g, 97% yield). The
protected serinol (500 mg, 1.49 mmol) was demasked by using concen-
trated HCl (2mL) in MeOH (5 mL) at room temperature for 7 h. After
evaporation of all the volatile materials in vacuo, the residue was dis-
solved in CH2Cl2 (5 mL), and Et3N (0.62mL, 4.45 mmol) and benzoyl
chloride (0.21 mL, 1.82 mmol) were added to the solution at 08C. After
the reaction mixture had been stirred at 08C for 30 min and then at room
temperature for 3 h, it was quenched with saturated aqueous NH4Cl
(5 mL) and worked up with CH2Cl2 (5 mL, ”3). Chromatographic purifi-
cation (EtOAc/hexane 1:2) delivered the serinol 8 (361 mg, 81% yield)
along with the monobenzoate benzamide (84 mg, 14%).
and development of these compounds. In addition, the bene-
ficial features of this methodology for practical applications
include the facile accessibility of the ligands and substrates,
mild reaction conditions, feasible experimental manipula-
tion, and short reaction times.
Experimental Section
N-(1-Hydroxy-2-(hydroxymethyl)-4-phenylbutan-2-yl)benzamide
(8):
1H NMR (300 MHz, CDCl3): d=7.65–7.21 (10H, m), 6.62 (1H, s), 4.04
(2H, d, J=3.8 Hz), 3.76 (2H, d, J=3.8 Hz), 2.78–2.73 (2H, m), 2.16–
2.11 ppm (2H, m); 13C NMR (75 MHz, CDCl3): d=168.5, 141.5, 134.4,
131.7, 128.6, 128.3, 126.9, 126.1, 65.9, 61.5, 34.5, 29.7 ppm; HRMS (EI):
m/z: calcd for C18H21NO3: 299.1521; found: 299.1514.
General information: NMR spectra were obtained on a Bruker DPX300
1
spectrometer (300 MHz for H NMR spectra, 75 MHz for 13C NMR spec-
tra) and measured in CDCl3. Chemical shifts were recorded in ppm rela-
tive to internal standard CDCl3, and coupling constants were reported in
Hz. High-resolution mass spectra were recorded on VG Autospec Ultima
and JMS-700 spectrometers. Enantioselectivities were determined by
HPLC. HPLC measurements were done on a DIONEX model equipped
with P580G pump, UV 525 detector (Thermo Science, Waltham, MA)
measured at 254 nm, and chiral columns DAICEL AD-H, AS-H, OD-H,
and OJ-H. The eluting solvent was a mixture of 2-propanol and hexane.
All reactions were carried out in oven-dried glassware under a N2 atmos-
phere. All solvents were distilled from the indicated drying reagents just
before use: Et2O and THF (Na, benzophenone), CH2Cl2 (P2O5), and
MeCN, 1,4-dioxane and DMF (CaH2). The normal workup included ex-
traction, drying over Na2SO4, and evaporation of volatile materials in
vacuo. Purification by column chromatography was performed by using
Merck (Darmstadt, Germany) silica gel 60 (230ꢀ400 mesh).
N-(1,3-Dihydroxy-2-methylpropan-2-yl)benzamide
(25):
1H NMR
(300 MHz, CDCl3): d=7.79–7.76 (2H, m), 7.54–7.43 (3H, m), 6.66 (1H,
s), 3.89 (2H, d, J=3.8 Hz), 3.75 (2H, d, J=3.8 Hz), 1.37 ppm (3H, s);
13C NMR (75 MHz, CDCl3): d=168.6, 134.4, 131.7, 128.6, 126.9, 67.5,
59.0, 19.8 ppm; HRMS (EI): m/z: calcd for C11H15NO3: 209.1052; found:
209.1072.
N-(1-Hydroxy-2-(hydroxymethyl)butan-2-yl)benzamide (26): 1H NMR
(300 MHz, CDCl3): d=7.80–7.77 (2H, m), 7.55–7.45 (3H, m), 6.61 (1H,
s), 3.98 (2H, d, J=3.8 Hz), 3.71 (2H, d, J=3.8 Hz), 1.82(2H, q,
J=
2.5 Hz), 0.99 ppm (3H, t, J=2.5 Hz); 13C NMR (75 MHz, CDCl3): d=
168.8, 134.6, 131.7, 128.6, 126.9, 65.4, 61.5, 25.1, 7.7 ppm; HRMS (EI):
m/z: calcd for C12H17NO3: 223.1208; found: 223.1223.
Representative procedure for the preparation of serinol 8: Tris(hydroxy-
methyl)aminomethane was converted to the known N-Boc-protected ace-
tonide alcohol.[17] The structures of the alcohol and the subsequent inter-
mediates are shown in the Supporting Information. Et3N (0.64 mL,
4.59 mmol), pTsCl (pTs=p-toluenesulfonyl; 875 mg, 4.59 mmol), and 4-
(dimethylamino)pyridine (46 mg, 0.38 mmol) were added in sequence at
room temperature to the alcohol (1 g, 3.83 mmol) dissolved in CH2Cl2
(10 mL), and the tosylation was carried out at that temperature for 1h.
After quenching the reaction mixture with saturated aqueous NH4Cl
(10 mL), workup with CH2Cl2 (5 mL, ”3) and chromatographic purifica-
N-(1-Cyclohexyl-3-hydroxy-2-(hydroxymethyl)propan-2-yl)benzamide
(27): 1H NMR (300 MHz, CDCl3): d=7.77–7.74 (m, 2H), 7.55–7.44 (3H,
m), 6.52(1H, s), 4.04 (2H, d, J=3.8 Hz), 3.70 (2H, d, J=3.8 Hz), 1.81–
1.64 (7H, m), 1.57–1.48 (1H, m), 1.30–1.06 ppm (5H, m); 13C NMR
(75 MHz, CDCl3): d=168.3, 134.6, 131.7, 128.7, 126.8, 66.5, 61.8, 41.0,
35.1, 33.0, 26.2, 26.0 ppm; HRMS (EI): m/z: calcd for C17H25NO3:
291.1834; found: 291.1847.
N-(1-Hydroxy-2-(hydroxymethyl)-4-methylpentan-2-yl)benzamide (28):
1H NMR (300 MHz, CDCl3): d=7.83–7.75 (2H, m), 7.55–7.43 (3H, m),
Chem. Eur. J. 2008, 14, 3290 – 3296
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3293

S. Ho Kang et al.
6.56 (1H, s), 4.05 (2H, d, J=3.8 Hz), 3.70 (2H, d, J=3.8 Hz), 1.84–1.82
(1H, m), 1.68 (1H, d, J=2.0 Hz), 1.02 (3H, s), 1.00 ppm (3H, s);
13C NMR (75 MHz, CDCl3): d=168.5, 134.7, 131.7, 128.6, 126.8, 66.5,
61.7, 42.1, 24.6, 23.6 ppm; HRMS (EI): m/z: calcd for C14H21NO3:
251.1521; found: 251.1511.
134.2, 132.0, 129.6, 128.7, 127.1, 126.0, 67.6, 65.7, 20.9 ppm; HRMS (EI):
m/z: calcd for C17H19NO3: 285.1365; found: 285.1352.
General procedure for the enantioselective desymmetrization: Tetra-
AHCTREpUNG henylbisoxazoline (97 mg, 0.2mmol) in THF (8 mL) was added to
CuCl2 (26 mg, 0.2 mmol), which had been dried under vacuum
(0.5 mmHg) at 1208C for 5 h, and the resulting mixture was complexed
at that temperature for 2h. The serinol (1.0 mmol) in THF (16 mL),
Et3N (0.21 mL, 1.5 mmol), and benzoyl chloride (0.23 mL, 2.0 mmol)
were injected to the generated catalyst, and the mixture was desymme-
trized at room temperature for 1h. After quenching the benzoylation
with saturated aqueous NH4Cl (5 mL), workup with EtOAc (5 mL, ”3)
and subsequent chromatographic separation rendered the monobenzoate.
N-(1-(tert-Butyldiphenylsilyloxy)-3-hydroxy-2-(hydroxymethyl)propan-2-
yl)benzamide (29): 1H NMR (300 MHz, CDCl3): d=7.79–7.76 (2H, m),
7.68–7.65 (4H, m,), 7.48–7.39 (9H, m), 7.31 (1H, s), 3.92(2H, d,
J=
3.9 Hz), 3.86 (2H, s), 3.64 (2H, d, J=3.9 Hz), 1.12ppm (9H, s);
13C NMR (75 MHz, CDCl3): d=168.3, 135.5, 134.0, 132.1, 131.9, 130.2,
128.7, 128.0, 126.9, 64.2, 63.3, 61.8, 26.9, 19.2 ppm; HRMS (EI): m/z:
calcd for C27H33NO4Si: 463.2179; found: 463.2163.
2-Benzamido-2-(hydroxymethyl)-4-phenylbutyl benzoate (15): 1H NMR
(300 MHz, CDCl3): d=8.08–8.05 (2H, m), 7.73–7.70 (2H, m), 7.51–7.44
(6H, m), 7.29–7.22 (5H, m), 6.78 (1H, s), 4.82 (1H, d, J=3.8 Hz), 4.61
(1H, d, J=3.8 Hz), 4.58 (1H, s), 3.96–3.95 (2H, m), 2.85–2.71 (2H, m),
2.50–2.44 (1H, m), 2.26–2.21 ppm (1H, m); 13C NMR (75 MHz, CDCl3):
d=168.3, 167.1, 141.4, 134.3, 133.5, 131.8, 129.7, 129.3, 128.6 (two carbon
atoms), 128.3, 127.2, 126.9, 126.1, 66.1, 65.4, 61.3, 34.3, 29.9 ppm; HRMS
(EI): m/z: calcd for C25H25NO4: 403.1783; found: 403.1772.
N-(5-(Benzyloxy)-1-hydroxy-2-(hydroxymethyl)pentan-2-yl)benzamide
(30): 1H NMR (300 MHz, CDCl3): d=7.73–7.71 (2H, m), 7.47–7.23 (8H,
m), 7.09 (1H, s), 4.46 (2H, s), 3.87 (2H, d, J=2.9 Hz), 3.59 (2H, d, J=
2.9 Hz), 3.47 (2H, t, J=1.4 Hz), 1.86–1.83 (2H, m), 1.71–1.64 ppm (2H,
m); 13C NMR (75 MHz, CDCl3): d=168.8, 137.8, 134.5, 131.6, 128.7,
128.5, 128.4, 128.0, 127.0, 73.2, 70.3, 65.4, 61.4, 29.5, 23.3 ppm; HRMS
(EI): m/z: calcd for C20H25NO4: 343.1784; found: 343.1793.
N-(2-Benzyl-1,3-dihydroxypropan-2-yl)benzamide
(31):
1H NMR
(300 MHz, CDCl3): d=7.69–7.66 (2H, m), 7.53–7.30 (8H, m), 6.62 (1H,
s), 3.92(2H, d, J=3.9 Hz), 3.68 (2H, d, J=3.9 Hz), 3.09 ppm (2H, s);
13C NMR (75 MHz, CDCl3): d=168.7, 135.9, 134.4, 131.8, 130.4, 128.7,
128.6, 127.3, 126.9, 64.9, 61.6, 37.6 ppm; HRMS (EI): m/z: calcd for
C13H17NO3: 235.1365; found: 235.1351.
2-Benzamido-3-hydroxy-2-methylpropyl
benzoate
(39):
1H NMR
(300 MHz, CDCl3): d=8.08–8.06 (2H, m), 7.80–7.77 (2H, m), 7.62–7.43
(6H, m), 6.81 (1H, s), 4.66 (1H, dd, J=3.8, 7.6 Hz), 3.85 (1H, dd, J=4.0,
9.3 Hz), 1.56 ppm (3H, s); 13C NMR (75 MHz, CDCl3): d=168.3, 167.1,
134.4, 133.4, 131.6, 129.6, 128.5 (two carbon atoms), 127.7, 127.0, 67.0,
66.8, 58.6, 19.5 ppm; HRMS (EI): m/z: calcd for C18H19NO4: 313.1314;
found: 313.1331.
N-(1-Hydroxy-2-(hydroxymethyl)pent-4-en-2-yl)benzamide
(32):
1H NMR (300 MHz, CDCl3): d=7.77–7.74 (2H, m), 7.55–7.43 (3H, m),
6.72 (1H, s), 5.87–6.11 (1H, m), 5.31–5.26 (2H, m), 3.96 (2H, d, J=
3.9 Hz), 3.69 (2H, d, J=3.9 Hz), 2.53 ppm (2H, d, J=2.5 Hz); 13C NMR
(75 MHz, CDCl3): d=168.5, 134.3, 132.7, 131.8, 128.7, 126.9, 120.2, 65.5,
60.7, 37.5 ppm; HRMS (EI): m/z: calcd for C13H17NO3: 235.1208; found:
235.1227.
1
2-Benzamido-2-(hydroxymethyl)butyl benzoate (40): H NMR (300 MHz,
CDCl3): d=8.07–8.04 (2H, m), 7.80–7.77 (2H, m), 7.62–7.45 (6H, m),
6.71 (1H, s), 4.76 (1H, d, J=3.8 Hz), 4.56 (1H, d, J=3.8 Hz), 3.91–3.89
(2H, m), 2.14–2.12 (1H, m), 1.98–1.96 (1H, m), 1.04 ppm (3H, t, J=
2.5 Hz); 13C NMR (75 MHz, CDCl3): d=168.4, 167.0, 134.5, 133.4, 131.7,
129.7, 128.6, 128.5, 126.9, 126.6, 66.0, 65.2, 61.4, 25.3, 7.8 ppm; HRMS
(EI): m/z: calcd for C19H21NO4: 327.1470; found: 327.1463.
N-(1-Hydroxy-2-(hydroxymethyl)but-3-en-2-yl)benzamide (33): 1H NMR
(300 MHz, CDCl3): d=7.85–7.82(2H, m), 7.57–7.46 (3H, m), 6.93 (1H,
s), 6.04–5.94 (1H, m), 5.40 (1H, d, J=3.5 Hz), 5.30 (1H, d, J=5.7 Hz),
3.88–3.76 ppm (4H, m); 13C NMR (75 MHz, CDCl3): d=168.4, 136.2,
134.2, 131.9, 128.7, 127.0, 116.5, 66.0, 64.2 ppm; HRMS (EI): m/z: calcd
for C12H15NO3: 221.1052; found: 221.1037.
2-Benzamido-3-cyclohexyl-2-(hydroxymethyl)propyl
benzoate
(41):
1H NMR (300 MHz, CDCl3): d=8.07–8.04 (2H, m), 7.77–7.75 (2H, m),
7.61–7.44 (6H, m), 6.71 (1H, s), 4.78 (1H, d, J=3.8 Hz), 4.55 (1H, d, J=
3.8 Hz), 3.93–3.92 (2H, m), 1.91 (2H, t, J=1.9 Hz), 1.72–1.65 (5H, m),
1.27–1.07 ppm (6H, m); 13C NMR (75 MHz, CDCl3): d=168.4, 166.9,
134.4, 133.4, 132.2, 131.8, 129.7, 128.6, 128.5, 126.9, 65.5, 64.3, 60.5, 37.1,
31.5, 25.2, 22.6, 14.0 ppm; HRMS (EI): m/z: calcd for C24H29NO4:
395.2097; found: 395.2079.
(E)-Ethyl 4-benzamido-5-hydroxy-4-(hydroxymethyl)pent-2-enoate (34):
1H NMR (300 MHz, CDCl3): d=7.85–7.82(2H, m), 7.58–7.47 (3H, m),
7.11 (1H, s), 7.02(1H, d, J=5.3 Hz), 5.99 (1H, d, J=5.3 Hz), 4.20 (2H,
t, J=2.3 Hz), 3.88–3.75 (4H, m), 1.29 ppm (3H, t, J=2.3 Hz); 13C NMR
(75 MHz, CDCl3): d=168.2, 165.9, 145.8, 133.7, 132.1, 128.7, 127.1, 122.7,
65.5, 63.6, 60.8, 14.1 ppm; HRMS (EI): m/z: calcd for C15H19NO5:
293.1263; found: 293.1281.
2-Benzamido-2-(hydroxymethyl)-4-methylpentyl benzoate (42): 1H NMR
(300 MHz, CDCl3): d=8.07–8.04 (2H, m), 7.79–7.76 (2H, m), 7.62–7.44
(6H, m), 6.73 (1H, s), 4.80 (1H, d, J=3.8 Hz), 4.55 (1H, d, J=3.8 Hz),
3.98–3.88 (2H, m), 1.98–1.87 (3H, m), 1.06–1.00 ppm (6H, m); 13C NMR
(75 MHz, CDCl3): d=168.3, 167.2, 134.5, 133.5, 131.7, 129.7, 129.4, 128.7,
128.5, 126.9, 66.7, 65.8, 61.6, 40.9, 24.7, 23.7 ppm; HRMS (EI): m/z: calcd
for C21H25NO4: 355.1784; found: 355.1773.
N-(1-Hydroxy-2-(hydroxymethyl)-4-(trimethylsilyl)but-3-yn-2-yl)benza-
mide (35): 1H NMR (300 MHz, CDCl3): d=7.82–7.79 (2H, m), 7.56–7.48
(3H, m), 6.75 (1H, s), 4.08–4.04 (2H, m), 3.98–3.91 (2H, m), 3.65–3.68
(2H, m), 0.21 ppm (9H, s); 13C NMR (75 MHz, CDCl3): d=167.9, 134.0,
132.0, 128.7, 127.1, 102.1, 91.3, 66.6, 59.8, 1.01 ppm; HRMS (EI): m/z:
calcd for C15H21NO3Si: 343.1291; found: 343.1277.
2-Benzamido-3-(tert-butyldiphenylsilyloxy)-2-(hydroxymethyl)propylben-
zoate (43): 1H NMR (300 MHz, CDCl3): d=7.96–7.93 (2H, m), 7.79–7.76
(2H, m), 7.65–7.25 (16H, m), 7.14 (1H, s), 4.85 (1H, d, J=3.6 Hz), 4.54
(1H, d, J=3.6 Hz), 4.06 (1H, d, J=3.3 Hz), 3.95–3.94 (2H, m), 3.76 (1H,
d, J=3.3 Hz), 1.10 ppm (9H, s); 13C NMR (75 MHz, CDCl3): d=168.3,
166.3, 135.5, 134.2, 133.2, 132.3, 131.9, 130.0, 129.7, 129.6, 128.7, 128.4,
127.9, 126.9, 63.7, 63.2, 62.7, 61.9, 26.8, 19.2 ppm; HRMS (EI): m/z: calcd
for C34H37NO4Si: 567.2441; found: 567.2457.
N-(1,3-Dihydroxy-2-phenylpropan-2-yl)benzamide
(36):
1H NMR
(300 MHz, CDCl3): d=8.09–8.05 (2H, m), 7.54–7.33 (8H, m), 4.88 (1H,
d, J=2.7 Hz), 4.55 (1H, d, J=2.7 Hz), 3.96 (1H, d, J=3.8 Hz), 3.78 ppm
(1H, d, J=3.8 Hz); 13C NMR (75 MHz, CDCl3): d=168.4, 139.1, 134.1,
132.0, 128.9, 128.8, 127.8, 127.1, 126.1, 67.6, 65.9 ppm; HRMS (EI): m/z:
calcd for C16H17NO3: 291.1291; found: 291.1298.
N-(2-(4-Chlorophenyl)-1,3-dihydroxypropan-2-yl)benzamide
(37):
1H NMR (300 MHz, CDCl3): d=7.89–7.86 (2H, m), 7.60–7.48 (3H, m),
2-Benzamido-5-(benzyloxy)-2-(hydroxymethyl)pentyl
benzoate
(44):
1H NMR (300 MHz, CDCl3): d=7.98–7.95 (2H, m), 7.70–7.67 (2H, m),
7.52–7.19 (11H, m), 6.98 (1H, s), 4.70 (1H, d, J=3.8 Hz), 4.53 (1H, d,
J=3.8 Hz), 4.42 (2H, s), 3.88–3.83 (2H, m), 3.44 (2H, t, J=4.0 Hz), 2.09–
2.04 (1H, m), 1.91–1.84 (1H, m), 1.75–1.67 ppm (2H, m); 13C NMR
(75 MHz, CDCl3): d=168.7, 166.8, 138.0, 134.4, 133.3, 131.7, 129.7, 129.6,
128.6 (two carbon atoms), 128.5, 128.4, 127.7, 127.0, 73.0, 70.1, 65.9, 65.7,
60.9, 29.9, 23.5 ppm; HRMS (EI): m/z: calcd for C27H29NO5: 447.2046;
found: 447.2058.
7.39–7.32(4H, m), 4.11 (2H, d,
J=3.9 Hz), 4.99 (2H, d, J=3.9 Hz),
3.67 ppm (2H, s); 13C NMR (75 MHz, CDCl3): d=168.5, 137.5, 133.7,
133.5, 132.1,128.8, 128.7, 127.6, 127.0, 67.3, 65.1 ppm; HRMS (EI): m/z:
calcd for C16H16ClNO3: 305.0819; found: 305.0808.
N-(1,3-Dihydroxy-2-p-tolylpropan-2-yl)benzamide
(38):
1H NMR
(300 MHz, CDCl3): d=7.89–7.86 (2H, m), 7.58–7.47 (3H, m), 7.31–7.20
(5H, m), 4.18–4.12 (2H, m), 4.03–3.96 (2H, m), 3.77–3.72 (2H, m),
2.35 ppm (3H, s); 13C NMR (75 MHz, CDCl3): d=168.4, 137.5, 136.0,
3294
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3290 – 3296

Enantioselective Formation of tert-Alkylamines
FULL PAPER
2-Benzamido-2-benzyl-3-hydroxypropyl
benzoate
(45):
1H NMR
Acknowledgements
(300 MHz, CDCl3): d=8.06–8.03 (2H, m), 7.72–7.29 (13H, m), 6.59 (1H,
s), 4.67 (1H, d, J=3.8 Hz), 4.47 (1H, d, J=3.8 Hz), 3.99–3.97 (1H, m),
3.90–3.88 (1H, m), 3.47 (1H, d, J=4.5 Hz), 3.23 ppm (1H, d, J=4.5 Hz);
13C NMR (75 MHz, CDCl3): d=168.5, 166.9, 135.5, 134.4, 133.5, 131.8,
130.5, 129.7, 129.3, 128.7, 128.6 (two carbon atoms), 127.1, 126.9, 65.5,
65.3, 61.4, 37.5 ppm; HRMS (EI): m/z: calcd for C24H23NO4: 389.1627;
found: 389.1606.
2-Benzamido-2-(hydroxymethyl)pent-4-enyl benzoate (46): 1H NMR
(300 MHz, CDCl3): d=8.08–8.05 (2H, m), 7.78–7.75 (2H, m), 7.62–7.45
(6H, m), 6.77 (1H, s), 5.96–5.94 (1H, m), 5.29–5.24 (2H, m), 4.77 (1H, d,
J=3.8 Hz), 4.56 (1H, d, J=3.8 Hz), 3.94–3.90 (2H, m), 2.91–2.84 (1H,
m), 2.63–2.56 ppm (1H, m); 13C NMR (75 MHz, CDCl3): d=168.4, 166.9,
134.4, 133.4, 132.2, 131.8, 129.7, 129.4, 128.6, 128.5, 126.9, 120.2, 65.7,
65.6, 60.6, 37.1 ppm; HRMS (EI): m/z: calcd for C20H21NO4: 339.1471;
found: 339.1459.
2-Benzamido-2-(hydroxymethyl)but-3-enyl benzoate (47): 1H NMR
(300 MHz, CDCl3): d=8.06–8.04 (2H, m), 7.84–7.81 (2H, m), 7.62–7.45
(6H, m), 7.01 (1H, s), 6.16–6.07 (1H, m), 5.43–5.37 (2H, m), 4.79 (1H, d,
J=3.8 Hz), 4.65 (1H, d, J=3.8 Hz), 3.96–3.92ppm (2H, m); 13C NMR
(75 MHz, CDCl3): d=168.0, 167.1, 135.5, 134.1, 133.6, 131.9, 129.7, 129.3,
128.7, 128.6, 127.0, 116.9, 66.3, 66.1, 63.3 ppm; HRMS (EI): m/z: calcd
for C19H19NO4: 325.1314; found: 325.1293.
This work was supported by the Korea Science and Engineering Founda-
tion (KOSEF) grant funded by the Korean government (MOST) (R01–
2007–000–10051—0).
[1] S. H. Kang, S. Y. Kang, H.-S. Lee, A. J. Buglass, Chem. Rev. 2005,
105, 4537–4558.
[2] R. Sarges, H. R. Howard, P. R. Kelbaugh, J. Org. Chem. 1982, 47,
4081–4085.
[3] a) K. Funabashi, H. Ratni, M. Kanai, M. Shibasaki, J. Am. Chem.
Soc. 2001, 123, 10784–10785; b) W. J. Thompson, P. S. Anderson,
S. F. Britcher, T. A. Lyle, J. E. Thies, C. A. Magill, S. L. Varga, J. E.
Schwering, P. A. Lyle, M. M. Christy, R. G. Ball, J. S. Amato, R. D.
Larsen, E. H. F. Wong, J. A. Kemp, M. D. Tricklebank, L. Singh, R.
Oles, T. Priestly, G. R. Marshall, A. R. Knight, D. N. Middlemiss,
G. N. Woodruff, L. L. Iversen, J. Med. Chem. 1990, 33, 789–808.
[4] a) D. F. Hook, F. Gessier, C. Noti, P. Kast, D. Seebach, ChemBio-
Chem 2004, 5, 691–706; b) D. J. Hill, M. J. Mio, R. B. Prince, T. S.
Hughes, J. S. Moor, Chem. Rev. 2001, 101, 3893–4011; c) R. P.
Cheng, S. H. Gellman, W. F. DeGardo, Chem. Rev. 2001, 101, 3219–
3232.
[5] a) A. A. Fuller, B. Chen, A. R. Minter, A. K. Mapp, J. Am. Chem.
Soc. 2005, 127, 5376–5383; b) H.-J. Gais, R. Loo, D. Roder, P. Das,
G. Raabe, Eur. J. Org. Chem. 2003, 1500–1526; c) M. Liu, M. P. Sibi,
Tetrahedron 2002, 58, 7991–8035; d) S. Abele, D. Seebach, Eur. J.
Org. Chem. 2000, 1–15.
[6] a) T. Ooi, M. Takeuchi, M. Kameda, K. Maruoka, J. Am. Chem.
Soc. 2000, 122, 5228–5229; b) B. Lygo, J. Crosby, J. A. Peterson, Tet-
rahedron Lett. 1999, 40, 8671–8674; c) Y. N. Belokon, M. North,
V. D. Kublitski, N. S. Ikonnikov, P. E. Krasik, V. I. Maleev, Tetrahe-
dron Lett. 1999, 40, 6105–6108.
(E)-2-Benzamido-5-ethoxy-2-(hydroxymethyl)-5-oxopent-3-enyl benzoate
(48): 1H NMR (300 MHz, CDCl3): d=8.03–8.01 (2H, m), 7.80–7.78 (2H,
m), 7.58–7.42(6H, m), 7.12(1H, d, J=5.3 Hz), 7.05 (1H, s), 6.08 (1H, d,
J=5.3 Hz), 4.76–4.69 (2H, m), 4.18 (2H, q, J=1.7 Hz). 3.96 (1H, d, J=
3.0 Hz), 3.88 (1H, d, J=3.0 Hz), 1.25 ppm (t, 3H, J=1.7 Hz); 13C NMR
(75 MHz, CDCl3): d=167.7, 167.3, 165.7, 144.3, 133.7 (two carbon
atoms), 132.1, 129.8, 129.0, 128.7, 128.6, 127.1, 123.0, 65.5, 65.1, 62.3, 60.7,
14.1 ppm; HRMS (EI): m/z: calcd for C22H23NO6: 397.1525; found:
397.1509.
(E)-2-Benzamido-5-ethoxy-2-(hydroxymethyl)-5-oxopent-3-enyl benzoate
(49): 1H NMR (300 MHz, CDCl3): d=8.11–8.08 (2H, m), 7.82–7.79 (2H,
m), 7.61–7.44 (6H, m), 6.84 (1H, s), 4.84 (2H, s), 4.10–4.07 (2H, m),
0.17 ppm (9H, s); 13C NMR (75 MHz, CDCl3): d=167.5, 166.7, 134.0,
133.4, 131.9, 129.8, 129.5, 128.6, 128.4, 127.1, 101.3, 91.5, 66.3, 65.2, 58.3,
0.2ppm; HRMS (EI): m/z: calcd for C22H25NO4Si: 395.1553; found:
395.1542.
[7] B. M. Trost, Chem. Pharm. Bull. 2002, 50, 1–14.
[8] a) S. Masumoto, H. Usuda, M. Suzuki, M. Kanai, M. Shibasaki, J.
Am. Chem. Soc. 2003, 125, 5634–5635; b) K. Funabashi, H. Ratni,
M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2001, 123, 10784–10785;
c) P. Vachal, E. N. Jacobson, Org. Lett. 2000, 2, 867–870.
[9] a) B. Jung, M. S. Hong, S. H. Kang, Angew. Chem. 2007, 119, 2670–
2672; Angew. Chem. Int. Ed. 2007, 46, 2616–2618; b) B. Jung, S. H.
Kang, Proc. Natl. Acad. Sci. USA 2007, 104, 1471–1475; c) M. C.
Willis, J. Chem. Soc. Perkin Trans. 1, 1999, 1765–1784.
[10] For enzymatic desymmetrization see: a) E. Garcia-Urdiales, I. Al-
fonso, V. Gotor, Chem. Rev. 2005, 105, 313–354; b) K. Drauz, H.
Waldmann in Enzymatic Catalysis in Organic Synthesis: A Compre-
hensive Handbook, Wiley-VCH, Weinhein, 2002.
2-Benzamido-3-hydroxy-2-phenylpropyl
benzoate
(50):
1H NMR
(300 MHz, CDCl3): d=8.13–8.11 (2H, m), 8.00–7.97 (2H, m), 7.66–7.39
(12H, m), 5.15 (2H, d, J=3.9 Hz), 5.01 (2H, d, J=3.9 Hz), 4.74–4.69
(1H, m), 4.47–4.40 (1H, m), 4.28–4.22 ppm (1H, m); 13C NMR (75 MHz,
CDCl3): d=168.1, 167.2, 138.5, 134.0, 133.6, 132.0, 129.7, 129.2, 128.8,
128.7, 128.5, 127.9, 127.1, 126,1, 67.9, 67.5, 65.1 ppm; HRMS (EI): m/z:
calcd for C20H21NO4: 339.1471; found: 339.1487.
[11] For desymmetrization by small-molecule catalysts in preparation of
tertiary stereogenic centers see: a) S. Mizuta, T. Tsuzuki, T. Fujimo-
to, I. Yamamoto, Org. Lett. 2005, 7, 3633–3635; b) C. A. Lewis,
B. R. Sculimbrene, Y. Xu, S. J. Miller, Org. Lett. 2005, 7, 3021–3023;
c) E. Vedejs, O. Daugulis, D. Tuttle, J. Org. Chem. 2004, 69, 1389–
1392; d) B. M. Trost, T. Mino, J. Am. Chem. Soc. 2003, 125, 2410–
2411; e) Y. Matsumura, T. Maki, S. Murakami, O. Onomura, J. Am.
Chem. Soc. 2003, 125, 2052–2053; f) S. Mizuta, M. Sadamori, T. Fu-
jimoto, I. Yamamoto, Angew. Chem. 2003, 115, 3505–3507; Angew.
Chem. Int. Ed. 2003, 42, 3383–3385; g) J. C. Ruble, J. Tweddell,
G. C. Fu, J. Org. Chem. 1998, 63, 2794–2795; h) T. Oriyama, K.
Imai, I. Sano, T. Hosoya, Tetrahedron Lett. 1998, 39, 3529–3532;
i) T. Kawabata, M. Nagato, K. Takasu, K. Fuji, J. Am. Chem. Soc.
1997, 119, 3169–3170; j) J. Ichikawa, M. Asami, T. Mukaiyama,
Chem. Lett. 1984, 949–952.
2-Benzamido-2-(4-chlorophenyl)-3-hydroxypropyl
benzoate
(51):
1H NMR (300 MHz, CDCl3): d=8.03–8.00 (2H, m), 7.88–7.85 (2H, m),
7.62–7.37 (11H, m), 4.96 (1H, d, J=3.9 Hz), 4.85 (1H, d, J=3.9 Hz), 4.25
(1H, d, J=4.0 Hz), 4.13 ppm (1H, d, J=4.0 Hz); 13C NMR (75 MHz,
CDCl3): d=168.0, 167.3, 137.0, 133.8, 133.7 (two carbon atoms), 132.1,
129.7, 129.0, 128.9, 128.7, 128.6, 127.7, 127.1, 67.8, 67.0, 64.5 ppm; HRMS
(EI): m/z: calcd for C23H20ClNO4: 409.1081; found: 409.1089.
2-Benzamido-3-hydroxy-2-p-tolylpropyl
benzoate
(52):
1H NMR
(300 MHz, CDCl3): d=8.02–8.00 (2H, m), 7.88–7.85 (2H, m), 7.60–7.21
(11H, m), 5.03 (1H, d, J=3.9 Hz), 4.87 (1H, d, J=3.9 Hz), 4.30 (1H, d,
J=4.0 Hz), 4.12(1H, d,
J=4.0 Hz), 2.36 ppm (3H, s); 13C NMR
(75 MHz, CDCl3): d=168.1, 167.2, 137.7, 135.5, 134.1, 133.5, 131.9, 129.7,
129.6, 128.7, 128.5, 128.4, 127.1, 126.0, 67.8, 67.5, 64.9, 20.9 ppm; HRMS
(EI): m/z: calcd for C24H23NO4: 389.1627; found: 389.1613.
[12] a) Y. Demizu, K. Matsumoto, O, Onomura, Y. Matsumura, Tetra-
hedron Lett. 2007, 48, 7605–7609; b) T. Honjo, M. Nakao, S. Sano,
M. Shiro, K. Yamaguchi, Y. Sei, Y. Nagao, Org. Lett. 2007, 9, 509–
512.
[13] D. A. Evans, C. S. Burgey, M. S. Kozlowski, S. W. Tregay, J. Am.
Chem. Soc. 1999, 121, 686–699.
[14] a) I. Abrunhosa, L. Delain-Bioton, A.-C. Gaumont, M. Gulea, S.
Masson, Tetrahedron 2004, 60, 9263–9272; b) H. Aꢁt-Haddou, O.
Chem. Eur. J. 2008, 14, 3290 – 3296
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3295

S. Ho Kang et al.
Hoarau, D. Cramailere, F. Pezet, J.-C. Daran, G. G. Balavoine,
Chem. Eur. J. 2004, 10, 699–707; c) M. P. Sibi, L. Venkatraman, M.
Liu, C. P. Jasperse, J. Am. Chem. Soc. 2001, 123, 8444–8445; d) M.
Schinnerl, M. Seitz, A. Kaiser, O. Reiser, Org. Lett. 2001, 3, 4259–
4262; e) D. A. Evans, K. A. Woerpel, M. M. Hinman, M. M. Faul, J.
Am. Chem. Soc. 1991, 113, 726–728.
[16] The excess benzoyl chloride was recovered in 90% yield as benzoic
acid.
[17] S. Hatakeyama, J. Org. Chem. 2004, 69, 7765–7768.
[15] a) S. Crosignani, G. Desimoni, G. Faita, P. Righetti, Tetrahedron
1998, 54, 15721–15736; b) G. Desimoni, G. Faita, M. Mella, Tetrahe-
dron 1996, 52, 13649–13654.
Received: November 28, 2007
Published online: February 18, 2008
3296
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3290 – 3296