Synthesis of novel C2-symmetric chiral bis(oxazoline) ligands and their application in the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2003.11.006

Novel chiral bis(oxazoline) ligands bearing dibenzo[a,c]cycloheptadiene and a dihydroxy group have been synthesized and their application in the catalytic asymmetric addition of diethylzinc to aldehydes investigated. The enantioselectivities for the aroma

Full text of DOI:10.1016/j.tetasy.2003.11.006

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 119–126
Synthesis of novel C2-symmetric chiral bis(oxazoline) ligands
and their application in the enantioselective addition of diethylzinc
to aldehydes
Bin Fu, Da-Ming Du* and Jianbo Wang
Department of Chemical Biology, College of Chemistry and Molecular Engineering, Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education, Peking University, Beijing 100871, PR China
Received 6 September 2003; revised 25 October 2003; accepted 10 November 2003
Abstract—Novel chiral bis(oxazoline) ligands bearing dibenzo[a,c]cycloheptadiene and a dihydroxy group have been synthesized
and their application in the catalytic asymmetric addition of diethylzinc to aldehydes investigated. The enantioselectivities for the
aromatic aldehydesare generally high and up to 96% ee wasobtained.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
the asymmetric addition of diethylzinc to aldehydes and
high enantioselectivities were obtained. Ligands 4 and 5,
explored by Bolm et al.14 and ligand 6 designed by
Pastor and Adolfsson,15 respectively, also showed good
catalytic activity (Scheme 1). In these ligands, the
oxazoline unit and adjacent hydroxy group function
together to control the catalytic process.
The catalytic enantioselective addition of organozinc
reagent to aldehydes is one of the most widely used
methodologiesin asymmetric carbon–carbon bond for-
mation.1 Asymmetric organozinc addition to aldehydes
provides the synthesis of various chiral alcohols, which
are important structural components of natural pro-
ducts and fine chemicals. Over the past decade, many
chiral ligands and catalysts have been designed and
synthesized, and high enantioselectivities have been
achieved.2 Among the diverse chiral ligand structures,
chiral amino alcoholsare predominant. In recent years,
other types of ligands, such as diols TADDOLs,3 and
BINOLs,4 amino thiols,5 iminyl alcohols,6 carbohydrate
derivatives,7 sulfonamides,8 and phosphoramide,9 have
also been explored for catalyzing this type of reaction.
On the other hand, chiral oxazolines, especially chiral
bis(oxazoline), have been widely applied in many cata-
lytic asymmetric reactions as versatile ligands.10
Recently, oxazoline-based ligands were also found to be
effective for the asymmetric addition of diethylzinc to
aldehydes.11 In particular, the ligand combining the
oxazoline ring and hydroxy group or an amino group
have been reported to show excellent catalytic activity in
the asymmetric addition of diethylzinc to aldehydes.12–15
For example, Ikeda et al.13 developed the ligands 1–3 for
Asa continuation of our ongoing project on the devel-
opment of novel chiral bis(oxazoline) ligands,16;17 we
report herein the synthesis and application of novel
C2-symmetric bis(oxazoline) ligands 11a and 11b with
dibenzo[a,c]cycloheptadiene and a hydroxy group as
substituents on the oxazoline ring. These ligands were
expected to furnish a new chiral environment in asym-
metric catalysis reactions by a combination of a hydroxy
group, oxazoline ring, and dibenzo[a,c]cycloheptadiene.
2. Results and discussion
The ligand 11 was synthesized starting from the cyclic
diethyl dicarboxylate 7.18 The cyclic carboxylate was
converted into the dihydroxy diamide 8 by the following
procedure: (1) hydrolysis in methanol solution of
NaOH; (2) acyl chloride formation with thionyl chlor-
ide; and (3) condensation with amino alcohol in the
presence of excess Et3N. The overall yield of three steps
wasup to 72%. Subsequently, the method explored by
Denmark et al.19 wasselected for cyclization. However,
* Corresponding author. Tel.: +86-10-6275-6568; fax: +86-10-6275-
1708; e-mail: dudm@pku.edu.cn
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.11.006

120
B. Fu et al. / Tetrahedron: Asymmetry 15 (2004) 119–126
O
O
R
R
N
N
R
HO
O
R
CPh2OH
CPh2OH
Fe
Fe
R
R
N
N
R
N
CPh2OH
OH
O
N
O
R
CPh2OH
O
3a R = Me 3b R = i-Pr
3c R = t-Bu
2a R = i-Pr
2b R = t-Bu
1a R = i-Pr
1b R = t-Bu
O
O
CPh2OH
O
O
HN
HN
N
Ph
O
Ph
N
N
CPh2OH
Fe
N
Fe
O
R
R
5
4
6a R = i-Pr
6b R = Ph
Scheme 1.
the treatment of dihydroxy diamide 8 with mesyl chlo-
ride (2.2 equiv) and Et3N (4.4 equiv) in dichloromethane
led to unexpected product 9. The methanesulfonate is a
good leaving group and with assistance of the adjacent
carboxylate group, the elimination reaction will be
With the ligandsin hand, we proceeded to invetsigate
their efficiency in catalytic asymmetric addition of
diethylzinc to aldehydes. Catalytic asymmetric addition
of diethylzinc to aldehydesisone of mots common
reactionsfor carbon–carbon bond formation. At firts,
we screened the normal reaction conditions for this
typical reaction. Thus, the effect of solvent and reaction
temperature on the catalytic addition of diethylzinc to
benzaldehyde was investigated using 10% mol ligand
11a. The results are summarized in Table 1. With hexane
asthe oslvent, the reaction wascarried at room tem-
perature for 24 h, after work-up and column chroma-
tography, (R)-1-phenyl-1-propanol wasobtained only in
40% yield with 2% ee (Table 1, entry 1). Although it was
reported that hexane isfavorable for high enantio-
selectivity,22a;b it seems not to be the case in our reaction
system. Subsequently, other solvents were tested (Table
1, entries2–4). In a mixed solvent of dichloromethane–
hexane (1:1), the chemical yield islow (38%), but the
enantioselectivity is improved to 65% ee; in THF–hex-
ane (1:1), both chemical yield and ee rise significantly to
68% and 77% ee, respectively. The best solvent system
wasfound to be toluene–hexane (1:1). At room tem-
perature, this solvent system gave 88% chemical yield
and 84% ee (Table 1, entry 4). The reaction at low
temperature was found to give slightly better results
(Table 1, entry 5). However, when the volume ratio of
toluene–hexane waschanged to 5:1, the yield dropped to
32% and the ee value did not change (86% ee) (Table 1,
entry 6). Thisreuslt isdifferent from the previous
observation that dilute toluene solutions give higher
yields and enantioselectivities.23
dominant and thusa more tsable conjugate product
wasformed. We then tried a different dehydration
reagent, diethylaminosulfur trifluoride (DAST),
9
20
according to the work of Williamset al. Thus, treat-
ment of the dihydroxy diamide 8 with a slight excess
(1.1 equiv) of DAST at )78 ꢁC in CH2Cl2, followed by
addition of K2CO3 and warming to room temperature,
afforded the desired bis(oxazoline) biscarboxylate 10 in
high yield (86%). Treatment of compound 10 with
Grignard reagent (11 equiv) in THF ()78 ꢁC to rt) gave
the target bis(oxazoline) ligands 11a,b in good yields(for
11a 75% and 11b 71%) (Scheme 2). For comparison,
ligands 10 and 13, which bear CO2Me and tert-butyl on
the oxazoline ring, respectively, were also synthesized
following the same procedure (Scheme 2). The mono-
oxazoline ligand 17 wasobtained according to the above
similar procedure from mono-acid 14, which can be
obtained by decarbonylation of corresponding diacid
(Scheme 3).18 The structures of these new compounds
were characterized by NMR, MS, IR, and elemental
analysis.
Despite the existence of axial chirality in compound 11,
fast interconversion between (R) and (S) enantiomersof
biphenyl occursat room temperature owing to the low
rotational energy barrier along the 1,10-bond of biphenyl
moiety.21 Consequently, the chirality of 10, 11a,b, 13, 16,
and 17 only derivesfrom the chiral oxazoline.s The
formation of dibenzo[a,c]cycloheptadiene ring from
linking the biphenyl reducesthe difficulty in separating
the diastereoisomers from the double chirality of
biphenyl backbone and oxazoline ring, and makesthe
synthesis procedure convenient.
The chiral ligand 11b wasfound not to be aseffective as
11a. Under the same conditions as entry 5, the ligand
11b gave only 38% yield and 50% ee (Table 1, entry 7).
The electron-rich dimethylhydroxymethyl group in 11a
should increase the Lewis basicity of the alkoxide and

B. Fu et al. / Tetrahedron: Asymmetry 15 (2004) 119–126
121
R
CO2Me
R
OH
O
O
CONHC=CH2
N
N
CONHC=CH2
OH
R
CO2Me
R
9
11a, R = Me
11b, R = Ph
d
f
CO2Me
CH2OH
O
CONHCHCO2Me
CO2Et
CO2Et
N
a, b, c
e
CONHCHCO2Me
N
O
CH2OH
CO2Me
8
7
10
CH2OH
CMe3
O
a, b, c
CONHCHC(Me)3
N
d
CONHCHC(Me)3
CH2OH
N
O
CMe3
12
13
Scheme 2. Reagentsand conditions: (a) NaOH, CH 3OH; (b) SOCl2; (c) aminol alcohol, Et3N, 72%; (d) MsCl, Et3N; (e) DAST, K2CO3, 86%; (f)
RMgBr, THF, )78 ꢁC to rt, 71–75%.
O
CH2OH
a, b
CO2H
N
H
CO2Me
15
14
O
N
O
c
d
Me
Me
OH
N
CO2Me
17
16
Scheme 3. Reagentsand conditions: (a) SOCl 2; (b) aminol alcohol, Et3N, 78%; (c) DAST, K2CO3, 85%; (d) MeMgBr, THF, )78 ꢁC to rt, 76%.
enhancesthe rigidity of the five-membered chelate and
thus results in a better stereochemical control.22e On the
other hand, bis(oxazoline) 10 afforded racemic product
in 81% yield (entry 8), while ligand 13 gave only 28%
yield and 18% ee (Table 1, entry 9). These results dem-
onstrate that the hydroxyl substituent on the oxazoline
ring playsan important role on the catalytic activity.
For comparison, the mono-oxazoline 17 wastetsed
under the same conditions, 70% yield and 61% ee are
obtained (entry 10).
using ligand 11a. The results are collected in Table 2. As
can be seen from Table 2, high yields and enantio-
selectivities were obtained for most aromatic aldehydes
(Table 2, entries1–7). The additionsof diethylzinc to
p-methoxybenzaldehyde and p-chlorobenzaldehyde give
high enantioselectivity to afford the corresponding
alcoholswith 95% ee and 96% ee, repsectively. Gen-
erally, higher enantioselectivities were obtained with
para-substituted aryl aldehydes than their ortho- and
meta-substituted analogues. The electronic nature of the
substituent also seems to affect the enantioselectivity.
A strong electron-withdrawing group such as NO2
decreases the enantioselectivity (Table 2, entry 8).
With the optimized conditions, we then proceeded to
examine the addition of diethylzinc to other aldehydes

122
B. Fu et al. / Tetrahedron: Asymmetry 15 (2004) 119–126
Table 1. Diethylzinc addition to benzaldehyde using ligands 10, 11a,b, 13, and 17
OH
10 mol% L
CHO
Et Zn
+
2
*
solvent
Entry
Liganda
Solvent
Hexane
CH2Cl2–hexane (1:1)b
THF–hexane (1:1)
Temp.
Yield (%)c
Ee (%)d
Config.e
1
2
11a
11a
11a
11a
11a
11a
11b
10
rt
40
38
68
88
86
32
38
81
28
70
2
65
77
84
87
86
50
0
R
R
R
R
R
R
R
––
R
R
rt
3
rt
4
Toluene–hexane (1:1)
Toluene–hexane (1:1)
Toluene–hexane (5:1)
Toluene–hexane (1:1)
Toluene–hexane (1:1)
Toluene–hexane (1:1)
Toluene–hexane (1:1)
rt
5
0 ꢁC
0 ꢁC
0 ꢁC
0 ꢁC
0 ꢁC
0 ꢁC
6
7
8
9
10
13
17
18
61
a The reaction wascarried out in the presence of 10% ligand for 24 h.
b Volume ratio of the solvents.
c Isolated yield by column chromatography.
d Determined by HPLC on Chiracel OB [hexane–2-propanol 95:5, 0.5 mL/min, tR 11.1 min (S), tR 12.4 min (R)].
e Determined by comparison with literature data.22a;d
Table 2. Diethylzinc addition to variousaldehydesusing ligand 11aa
complex13b may be involved in the catalytic cycle. It is
necessary to have ligand backbone dibenzo[a,c]cyclo-
heptadiene for achieving high enantioselectivity. The
ligand 3a gave 93% yield and 78% ee in the diethylzinc
addition to benzaldehyde, the corresponding mono-
oxazoline gave 9% yield and 37% ee.13b Our ligand 11a
gave 87% ee in the diethylzinc addition to benzaldehyde
and 96% ee to p-chlorobenzaldehyde. The correspond-
ing mono-oxazoline 17 also can give better enantio-
selectivity in the diethylzinc addition to benzaldehyde
(61% ee).
OH
10 mol % 11a
+
Et2Zn
RCHO
R
*
PhMe-hexane (1:1)
Yield (%)b Ee (%)c
Entry
R
Config.d
1
p-MeOC6H4
m-MeOC6H4
o-MeC6H4
91
88
90
92
90
91
90
84
86
86
82
95
92
84
89
96
94
90
75
74
61
47
R
R
R
R
R
R
R
R
R
R
R
2
3
4
o-FC6H4
p-ClC6H4
m-BrC6H4
5
6
7
1-Naphthyl
p-NO2C6H4
p-Me2NC6H4
trans-PhCH@CH
3-PhCH2CH2
8
9
3. Conclusion
10
11
In conclusion, we have synthesized new C2-symmetric
bis(oxazoline) ligands with dibenzo[a,c]cycloheptadiene
backbone and a hydroxy group as the substituent on the
oxazoline ring. The catalytic activity for the asymmetric
addition of diethylzinc to aldehydeswasinvetsigated.
The high enantioselectivities and yields have been
obtained for bis(oxazoline) dihydroxy ligand 11a. These
results show that the novel dibenzo[a,c]cycloheptadiene
bis(oxazoline) dihydroxy ligands have potential for
asymmetric reaction. Further studies are in progress in
our laboratory in order to expand the application of these
chiral ligands to other catalytic asymmetric reactions.
a The reaction were carried out in toluene–hexane at 0 ꢁC for 24 h.
b Isolated yields after column chromatography.
c Determined by HPLC on Chiracel OD, OB, AD with hexane–2-
propanol aseluant.
d By comparison with the literature data.22a;d–f
However, it was also found that the strong electron-
donating group p-Me2N decreases the enantioselectivity
(Table 2, entry 9), thismay be ascribed to the nitrogen
atom of the amino group, which could compete with the
hydroxyl group to interact with zinc. The basic
dimethylamino group in the substrate and the product
may contribute to some minor catalytic pathways. On
the other hand, it isworthwhile to note that the addition
to trans-cinnamaldehyde and phenylpropionaldehyde
gave good yieldsand moderate enantioselectivities(61%
ee and 47% ee, respectively) (Table 2, entries 10 and 11).
The absolute configurations of the products were
determined as R for reactionsof all aldehydesexamined
in this study by comparison with the literature data.
4. Experimental section
Melting pointswere measured on an XT-4 melting point
apparatusand are uncorrected. 1H NMR spectra were
recorded on a Mercury 200 or 300 MHz spectrometer
with tetramethylsilane as the internal standard. Infrared
spectra were obtained on a Bruker Vector 22 spec-
trometer. Mass spectra were obtained on a VG-ZAB-HS
mass spectrometer. Optical rotations were measured on
The mono-oxazoline 17 isleseffective than the corre-
sponding bis(oxazoline) 11a suggesting a binuclear zinc

B. Fu et al. / Tetrahedron: Asymmetry 15 (2004) 119–126
123
20
D
a Perkin–Elmer 341 LC polarimeter. Elemental analyses
were carried out on an Elementar Vario EL instrument.
The enantiomeric excesses of (R)- and (S)-alcoholswere
determined by HPLC analysis over a chiral column
(Daicel Chiralcel OB, AD or OD; eluted with hexane–
isopropyl alcohol; UV detector, 254 nm). The absolute
configuration of the major enantiomer was assigned
according to the sign of the specific rotation. Solvents
were purified and dried by standard procedures.
viscous oil 10 (0.48 g, 86%). ½aŠ ¼ +74.9 (c 0.69,
CHCl3). IR: 2955, 1741, 1648, 1439, 1357, 1208 cmÀ1; 1H
NMR (200 MHz, CDCl3): d 7.41–7.21 (m, 8H, ArH),
4.81–4.66 (dd, J ¼ 7:2, 2H, 9.8 Hz), 4.63 (m, 2H), 4.45
(dd, J ¼ 8:8 Hz, 10.0 Hz, 2H), 3.75 (s, 6H, CO2Me),
3.40–2.90 (m, 4H, ArCH2); 13C NMR (50 MHz, CDCl3):
d 171.0, 169.1, 140.8, 135.1, 130.0, 127.9, 127.5, 127.2,
70.0, 68.0, 53.3, 52.5, 52.5, 37.6, 37.4; MS (m=z, relative
intensity): 448 (Mþ, 35), 389 (21), 320 (100). HRMS (EI)
calcd for C25H24N2O6: 448.1634. Found: 448.1633.
4.1. 6,6-Bis[N-(10S)-(10-(methoxycarbonyl)hydroxy-
ethyl)amido]-dibenzo[a,c]-1,3-cycloheptadiene 8
4.3. 6,6-Bis[(40S)-40-(isopropanolyl)oxazolin-20-yl]-
dibenzo[a,c]-1,3-cycloheptadiene 11a
To a solution of diethyl dibenzo[a,c]-1,3-cyclohepta-
diene-6,6-dicarboxylate 7 (1.0 g, 2.96 mmol) in CH3OH
(10 mL) wasadded aqueousNaOH oslution (10 mL,
2 N). The mixture wasrefluxed for 8 h, then the meth-
anol wasremoved in vacuo. The residue wascooled to
0 ꢁC and acidified with aqueousHCl (6 N). The acidified
mixture wasextracted with ether (10 mL · 3), the
organic layer wasdried over anhydrousNa 2SO4 and
evaporated. The obtained white solid was directly ref-
luxed with SOCl2 (5 mL) for 2 h, the excess SOCl2 was
removed in vacuo. Anhydrousbenzene (10 mL) was
added to the above crude diacyl dichloride and the
solvent was removed again to dryness (to remove the
trace of SOCl2). The diacyl dichloride in CH2Cl2
To a solution of bis(oxazoline) carboxylate 10 (0.5 g,
1.12 mmol) in THF (20 mL) wasadded a oslution of
MeMgBr in THF (4.5 mL, 3 M) at )78 ꢁC, the mixture
waswarmed to room temperature and stirred for 12 h,
and then wasquenched with saturated NH 4Cl solution.
After most solvent was removed in vacuo, water (20 mL)
wasthen added, and the mixture wasextracted with
CH2Cl2 (15 mL · 3). The organic layer wasdried over
anhydrousNa SO4 and concentrated in vacuo to give a
2
pale yellow oil. Purification by silica gel column chro-
matography (petroleum ether–ethyl acetate 3:2) afforded
20
D
a colorless viscous oil 11a (0.38 g, 75%). ½aŠ ¼ +73.8 (c
0.40, CHCl3). IR: 3448, 2958, 1658, 1448 cmÀ1
;
1H
(20 mL) was added dropwise to a solution of
L
-serine
NMR (CDCl3): d 7.42–7.25 (m, 8H, ArH), 4.38–4.33 (t,
J ¼ 7:8 Hz, 2H), 4.26 (t, J ¼ 9:0 Hz, 2H), 4.04 (dd,
J ¼ 7:6, 9.0 Hz, 2H), 3.22 (s, 2H, CH2), 2.99 (s, 2H,
CH2), 2.75 (s, 2H, OH), 1.28 (s, 6H, CH3), 1.13 (s, 6H,
CH3); 13C NMR (50 MHz, CDCl3): 169.2, 140.7, 135.5,
130.1, 128.1, 127.6, 127.3, 74.5, 71.7, 69.3, 54.0, 37.6,
26.8, 25.2; MS (m=z, relative intensity): 448 (Mþ, 20),
433 (10), 389 (78), 320 (100). HRMS (EI) calcd for
C27H32N2O4: 448.2362. Found: 448.2367.
methyl ester hydrochloride (1.0 g, 6.43 mmol) and Et3N
(8 mL, 57.8 mmol) in CH2Cl2 (20 mL) at 0 ꢁC and
the mixture wasstirred at room temperature for 4 h. The
reaction mixture waswahsed with water (5 mL · 2).
The organic layer wasdried over anhydrousNa 2SO4
and concentrated to give a crude solid. Purification by
silica gel column chromatography (ethyl acetate–petro-
leum ether 1:1) afforded the dihydroxy diamide 8 (1.04 g,
20
D
73%). Mp 82–83.5 ꢁC; ½aŠ ¼ )15.3 (c 0.30, CHCl3). IR:
3374, 2972, 1737, 1656, 1526, 1439 cmÀ1
;
1H NMR
(200 MHz, CDCl3): d 7.40–7.26 (m, 8H, ArH), 6.97 (s,
2H, NH), 4.63 (t, J ¼ 3:4 Hz, 2H, CHCO2Me), 4.06–
3.95 (m, 4H, CH2OH), 3.79 (s, 6H, CO2Me), 3.52–2.80
(m, 4H, ArCH2); 13C NMR (50 MHz, CDCl3): d 171.4,
170.6, 140.3, 135.2, 130.2, 127.9, 127.5, 65.5, 61.9, 55.2,
52.7, 36.7; MS (FAB): 485 (M+Hþ). Anal. Calcd for
C25H28N2O8: C, 61.98; H, 5.82; N, 5.78. Found: C,
62.11; H, 5.92; N, 5.70.
4.4. Bis[(40S)-40-(diphenylmethanolyl)oxazolin-20-yl]-
dibenzo[a,c]-1,3-cycloheptadiene 11b
The same procedure as for 11a wasfollowed with
PhMgBr in THF (1 M, 6 mL) and bis(oxazoline) car-
boxylate 8 (0.3 g, 0.67 mmol) astsarting material to
20
afford 11b (0.33 g, 71%). ½aŠ ¼ )7.8 (c 0.45, CHCl3). IR:
D
3452, 2960, 1656, 1642, 1448 cmÀ1; 1H NMR (CDCl3): d
7.42–6.92 (m, 28H, ArH), 5.34 (t, J ¼ 7:2 Hz, 2H), 4.33–
4.23 (m, 2H), 4.10 (t, J ¼ 7:2 Hz, 2H), 3.23 (s, 2H, CH2),
3.06 (d, J ¼ 7:4 Hz, 2H, CH2), 2.75 (s, 2H, OH); 13C
NMR (50 MHz, CDCl3): d 170.3, 144.3, 140.7, 135.6,
130.3, 128.7, 128.3, 127.9, 127.4, 127.2, 127.0, 126.0,
78.9, 71.9, 69.7, 54.1, 37.5; MS (FAB) 697 (M+Hþ).
Anal. Calcd for C47H40N2O4: C, 81.01; H, 5.79; N, 4.02.
Found: C, 81.10; H, 5.82; N, 4.00.
4.2. 6,6-Bis[(40S)-40-(methoxycarbonyl)oxazolin-20-yl]-
dibenzo[a,c]-1,3-cycloheptadiene 10
To a solution of the dihydroxy diamide 8 (0.6 g,
1.24 mmol) in CH2Cl2 (30 mL) wasadded DAST (0.44 g,
2.73 mmol) at )78 ꢁC, after stirring for 1 h, anhydrous
K2CO3 (50 mg) wasadded. The mixture wasallowed to
warm to room temperature and wasstirred for another
1 h. The mixture wasquenched by 20 mL of asturated
NaHCO3 solution. The solution was washed with water
(10 mL · 2). The organic layer wasdried over anhydrous
Na2SO4 and concentrated in vacuo to give a pale yellow
oil. Purification by silica gel column chromatography
(petroleum ether–ethyl acetate 5:1) to afford a colorless
4.5. 6,6-Bis[N-(10S)-(10-(tert-butyl)hydroxyethyl)amido]-
dibenzo[a,c]-1,3-cycloheptadiene 12
From diethyl dibenzo[a,c]-1,3-cycloheptadiene-6,6-
dicarboxylate
(0.75 g, 6.4 mmol), and Et3N (4 mL, 28.9 mmol), the
7
(1.0 g, 2.96 mmol),
L-tert-leucinol

124
B. Fu et al. / Tetrahedron: Asymmetry 15 (2004) 119–126
same procedure as for 8 afforded the dihydroxy diamide
12 (0.98 g, 68%). Mp 142–144 ꢁC; ½aŠ ¼ )13.3 (c 0.23,
;
1264 cmÀ1 1H NMR (CDCl3): d 7.41–7.23 (m, 8H,
130.8, 129.2, 128.2, 127.6, 127.2, 106.7, 52.8, 52.5, 34.1;
MS (m=z, relative intensity): 448 (Mþ, 30), 320 (18), 219
(100), 191 (60). HRMS (EI) calcd for C25H24N2O6:
448.1634. Found: 448.1631.
20
D
CHCl3). IR (KBr): 3406, 2960, 1638, 1534, 1452,
ArH), 6.41 (s, 2H, NH), 3.92–3.81 (m, 4H), 3.52–3.38
(m, 6H), 2.76 (s, 2H, OH), 0.86 (s, 18H); 13C NMR
(50 MHz, CDCl3): 172.7, 140.3, 135.6, 130.5, 127.9,
127.5, 66.2, 62.1, 59.7, 37.4, 33.2, 26.8; MS (FAB): 481
(M+Hþ). Anal. Calcd for C29H40N2O4: C, 72.47; H,
8.39; N, 5.83. Found: C, 72.52; H, 8.30; N, 5.61.
4.8. 6-[N-(10S)-(10-methoxycarbonyl)hydroxyethyl-
amido]-dibenzo[a,c]-1,3-cycloheptadiene 15
Dibenzo[a,c]-1,3-cycloheptadiene-6,6-dicarboxylic acid
0.80g (2.84 mmol) (prepared from dicarboxylate 7 in
Section 4.1) washeated at 160 ꢁC for 1 h and then cooled
to room temperature. The white solid mono-acid 14 was
obtained and directly refluxed with SOCl2 (4 mL) for
2 h, the excess SOCl2 wasremoved in vacuo. Benzene
(10 mL) wasadded and the solvent wasremoved again
to dryness to remove the trace of SOCl2 and afford the
corresponding acyl chloride. The acyl chloride in
CH2Cl2 (20 mL) was added dropwise to a solution of
4.6. 6,6-Bis[(40S)-40-(tert-butyl)oxazolin-20-yl]-dibenzo-
[a,c]-1,3-cycloheptadiene 13
To an ice-cooled solution of the dihydroxy diamide 12
(0.60 g, 1.25 mmol) and Et3N (2 mL, 14 mmol) in
CH2Cl2 (20 mL) wasadded MCsl (0.30 g, 2.6 mmol)
slowly. The mixture was allowed to warm to room
temperature and wastsirred for 1 h. The mixture was
washed with water (5 mL). The organic layer was dried
L
-serine methyl hydrochloride (0.5 g, 3.21 mmol) and
Et3N (4 mL, 28.9 mmol) in CH2Cl2 (20 mL) at 0 ꢁC. The
reaction mixture wastsirred at room temperature for
4 h. Then the mixture waswashed with water (5 mL · 2).
The organic layer wasdried over anhydrousNa 2SO4
and concentrated to give crude solid. Purification by
silica gel column chromatography (ethyl acetate–petro-
over anhydrousNa SO4 and concentrated to dryness in
2
vacuo to give the crude bismesylate as yellow oil. The
crude bismesylate was dissolved in CH3OH (20 mL) and
wastreated with NaOH oslution (4 mL, 1 N) at room
temperature for 12 h. The methanol wasremoved in
vacuo and 30 mL CH2Cl2 wasadded to it. The solution
waswashed with water (5 mL · 2). The organic layer was
dried over anhydrousNa 2SO4 and concentrated in
vacuo to give pale yellow oil. Purification by silica gel
column chromatography (petroleum ether–ethyl acetate
leum ether 1:1) afforded the hydroxy amide 15 (0.75 g,
20
D
3401, 3323, 3014, 2951, 1737, 1645, 1526, 1434, 1385,
78%). Mp 122–124 ꢁC; ½aŠ ¼ +20.0 (c 0.21, CHCl3). IR:
1
1348, 1238, 1199, 747 cmÀ1; H NMR (CDCl3): 7.41–
7.25 (m, 8H, ArH), 6.51 (d, J ¼ 10:8 Hz, 1H), 4.71–4.66
(m, 1H, CH), 4.05–3.92 (m, 2H, CH2), 3.80 (s, 3H, CH3),
3.24–3.14 (m, 1H, CH), 2.87–2.68 (m, 4H, ArCH2), 2.51
(s, 1H, OH); 13C NMR (CDCl3): 175.0, 171.0, 140.6,
136.6, 129.2, 128.4, 127.7, 127.4, 63.5, 54.6, 52.8, 52.7,
51.6, 34.4, 34.2. MS (m=z, relative intensity): 339 (Mþ,
24), 220 (M)119, 15), 192 (100), 178 (50), 165 (25). Anal.
Calcd for C20H21NO4: C, 70.78; H, 6.24; N, 4.13.
Found: C, 70.58; H, 6.47; N, 3.91.
5:1) afforded a colorless viscous oil 13 (0.46 g, 83%).
20
D
½aŠ ¼ )44.6 (c ¼ 0:18, CHCl3). IR (KBr): 3010, 2965,
1
1654, 1508, 1484 cmÀ1; H NMR (200 MHz, CDCl3): d
7.47–7.23 (m, 8H, ArH), 4.19 (t, J ¼ 9:2 Hz, 2H), 4.08 (t,
J ¼ 7:7 Hz, 2H), 3.87 (dd, J ¼ 7:5, 8.7 Hz, 2H), 3.45–
2.69 (m, 4H, PhCH2), 0.81 (s, 18H, CH3); 13C NMR
(50 MHz, CDCl3): d 166.2, 140.8, 135.9, 131.2, 127.9,
127.2, 126.9, 75.6, 68.9, 53.5, 37.5, 33.9, 25.7; MS (m=z,
relative intensity): 444 (Mþ, 50), 387 (100), 344 (17).
HRMS (EI) calcd for C29H36N2O2: 444.2777. Found:
444.2774.
4.9. 6-[N-(40S)-(40-methoxycarbonyl)oxazolin-20-yl]-
dibenzo[a,c]-1,3-cycloheptadiene 16
4.7. 6,6-Bis[N-(10-(methoxycarbonyl)vinyl)amido]-
dibenzo[a,c]-1,3-cycloheptadiene 9
To a solution of the hydroxy amide 15 (0.42 g,
1.24 mmol) in CH2Cl2 (20 mL) wasadded DAST (0.22 g,
1.37 mmol) at )78 ꢁC, after stirring for 1 h, anhydrous
K2CO3 (25 mg) wasadded. The mixture wasallowed to
warm to room temperature and stirred for 1 h. The
reaction mixture wasquenched by the addition of 20 mL
of saturated NaHCO3 solution. The solution was
washed with water (10 mL · 2). The organic layer was
dried over anhydrousNa 2SO4 and concentrated in
vacuo to give a pale yellow oil. Purification by silica gel
column chromatography (petroleum–ethyl acetate 6:1)
To an ice-cooled solution of the dihydroxy diamide 8
(0.50 g, 1.03 mmol) and Et3N (2 mL, 14.5 mmol) in
CH2Cl2 (20 mL) wasadded MCs l (0.25 g, 2.17 mmol)
slowly. The mixture was allowed to warm to room
temperature and wastsirred for 1 h. The mixture was
washed with water (5 mL · 2). The organic layer was
dried over anhydrousNa 2SO4 and concentrated in
vacuo to give the crude product asyellow oil. Purifica-
tion by silica gel column chromatography (petroleum
ether–ethyl acetate 10:1) afforded a colorless viscous oil
to afford colorless viscous oil 16 (0.34 g, 85%).
20
D
½aŠ ¼ +27.1 (c 0.15, CHCl3). IR: 2950, 2359, 1741,
9 (0.39 g, 85%). IR: 2981, 1750, 1690, 1513, 1316 cmÀ1
;
1651, 1440, 1208, 1176, 752 cmÀ1; H NMR (CDCl3):
1
1H NMR (200 MHz, CDCl3): d 8.59 (s, 2H, CONH),
7.50–7.25 (m, 8H, ArH), 6.63 (d, J ¼ 5:6 Hz, 2H,
@CH2), 5.91 (d, J ¼ 2:0 Hz, 2H, @CH2), 3.87 (s, 6H,
7.42–7.26 (m, 8H, ArH), 4.75–4.69 (m, 1H, CH), 4.57–
4.35 (m, 2H, CH2), 3.78 (s, 3H, CH3), 3.40–3.33 (m, 1H,
CH), 2.96–2.70 (m, 4H, ArCH2); 13C NMR (CDCl3):
172.1, 171.7, 140.75, 140.72, 136.8, 129.2, 128.2, 127.5,
127.4, 127.2, 69.4, 67.9, 52.5, 43.9, 34.0, 33.98. MS (m=z,
CO2Me), 3.48 (s, 2H, ArCH2), 2.85 (s, 2H, ArCH2); 13
C
NMR (50 MHz, CDCl3): d 173.0, 164.4, 140.4, 136.2,

B. Fu et al. / Tetrahedron: Asymmetry 15 (2004) 119–126
125
relative intensity): 321 (Mþ, 82), 306 (5), 262 (15), 191
References and Notes
(56), 178 (60), 143 (100). HRMS (EI) calcd for
C20H19O3N: 321.1365. Found: 321.1355.
1. Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994.
2. (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl.
1991, 30, 49–69; (b) Soai, K.; Niwa, S. Chem. Rev. 1992, 92,
833; (c) Pu, L.; Yu, H. B. Chem. Rev. 2001, 101, 757–824.
3. (a) Schmidt, B.; Seebach, D. Angew Chem., Int. Ed. Engl.
1991, 30, 99–101; (b) Schmidt, B.; Seebach, D. Angew.
Chem., Int. Ed. Engl. 1991, 30, 1321–1323; (c) Weber, B.;
Seebach, D. Tetrahedron 1994, 50, 7473–7478; (d) Ito, Y.
4.10. 6-[N-(40S)-(40-isopropanolyl)oxazolin-20-yl]-
dibenzo[a,c]-1,3-cycloheptadiene 17
To a solution of oxazoline carboxylate 16 (0.34 g,
1.06 mmol) in THF (20 mL) wasadded a oslution of
MeMgBr in THF (1.4 mL, 3 M) at )78 ꢁC, then the
mixture waswarmed to room temperature and tsirred
for 12 h. The reaction mixture wasquenched with ast-
urated NH4Cl solution. After removing most of the
solvent in vacuo, water (20 mL) was then added, and
ꢀ
N.; Ariza, X.; Beck, A. K.; Bohac, A.; Ganter, C.; Gawley,
R. E.; Kuhnle, F. N. M.; Tuleja, J.; Wang, Y. M.;
Seebach, D. Helv. Chim. Acta 1994, 77, 2071–2210; (e)
Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y. M.
Tetrahedron 1994, 50, 4363–4384.
4. (a) Pu, L. Chem. Rev. 1998, 98, 2405–2494; (b) Mori, M.;
Nakai, T. Tetrahedron Lett. 1997, 38, 6233–6236; (c)
Zhang, F. Y.; Yip, C. W.; Cao, R.; Chan, A. S. C.
Tetrahedron: Asymmetry 1997, 8, 585–589; (d) Davis, T. J.;
Balsells, J.; Carroll, P. J.; Walsh, P. J. Org. Lett. 2001, 3,
2161–2164; (e) Huang, W. S.; Hu, Q. S.; Pu, L. J. Org.
Chem. 1999, 64, 7940; (f) Chen, Y.; Yekta, S.; Martyn, L.
J. P.; Zheng, J.; Yudin, A. K. Org. Lett. 2000, 2, 3433–
3436; (g) Shen, X. Q.; Guo, H.; Ding, K. L. Tetrahedron:
Asymmetry 2000, 11, 4321–4327.
5. (a) Hof, R. P.; Poelert, M. A.; Peper, N. C. M. W.;
Kellogg, R. M. Tetrahedron: Asymmetry 1994, 5, 31–34;
(b) Kang, J.; Lee, J. W.; Kim, J. I. J. Chem. Soc., Chem.
Commun. 1994, 2009–2010.
6. (a) Cozzi, P. G.; Papa, A.; Umani-Ronchi, A. Tetrahedron
Lett. 1996, 37, 4613; (b) Mino, T.; Oishi, K.; Yamashita,
M. Synlett 1998, 965–966; (c) Fleischer, R.; Braun, M.
Synlett 1998, 1441–1443.
the mixture wasextracted with CH Cl2 (15mL · 3). The
2
organic layer wasdried over anhydrousNa 2SO4 and
concentrated in vacuo to give a pale yellow oil. Purifi-
cation by silica gel column chromatography (petroleum–
ethyl acetate 3:1) afforded colorless viscous oil 17
20
D
(0.26 g, 76%). ½aŠ ¼ +17.6 (c 0.42, CHCl3). IR: 3410,
1
2967, 2359, 1658, 1481, 1452, 1377, 1174, 752 cmÀ1; H
NMR (CDCl3): 7.42–7.22 (m, 8H, ArH), 4.29–4.10 (m,
2H, CH2N), 4.05–3.99 (m, 1H, CH), 3.35–3.25 (m, 1H,
CH), 2.86–2.70 (m, 4H, ArCH2), 1.85 (s, 1H, OH), 1.24
(s, 3H, CH3), 1.10 (s, 3H, CH3); 13C NMR (CDCl3):
170.49, 140.75, 140.70, 137.11, 136.78, 129.06, 128.18,
127.37, 127.22, 127.10, 74.88, 71.05, 68.56, 43.93, 34.13,
34.02, 26.77, 24.78. MS (m=z, relative intensity): 321
(Mþ, 46), 306 (8), 263 (20), 193 (100), 178 (54). HRMS
(EI) calcd for C21H23O2N: 321.1729. Found: 321.1731.
ꢀ
7. (a) Bauer, T.; Tarasiuk, J.; Pasniczek, K. Tetrahedron:
Asymmetry 2002, 13, 77–82; (b) Cho, B. T.; Chun, Y. S.;
Yang, W. K. Tetrahedron: Asymmetry 2002, 11, 2149–
2157; (c) Cho, B. T.; Kim, N. J. Chem. Soc., Perkin Trans.
1 1996, 2901–2907.
4.11. General procedure for the addition of diethylzinc to
aldehyde
8. (a) Royo, E.; Betancort, J. M.; Davis, T. J.; Caroll, P.;
Walsh, P. J. Organometallics 2000, 19, 4840–4851; (b)
Paquette, L. A.; Zhou, R. J. Org. Chem. 1999, 64, 7929–
7934; (c) Hwang, C. D.; Uang, B. J. Tetrahedron:
Asymmetry 1998, 54, 8275–8319; (d) Knochel, P.; Perea,
J.; Almena, J.; Jones, P. Tetrahedron 1998, 54, 8275–8319;
(e) Guo, C.; Qiu, J.; Zhang, X.; Verduge, D.; Larter, M. L.;
Christie, R.; Kenney, P.; Walsh, P. J. Tetrahedron 1997,
53, 4145–4158.
To a solution of ligand 11a (18 mg, 0.04 mmol) in tolu-
ene (1 mL) at room temperature wasadded dropwise a
solution of diethylzinc in hexane (1 mL, 15%,
0.88 mmol). The mixture wastsirred at room tempera-
ture for 15 min. Aldehyde (0.42 mmol) wasadded in one
portion at 0 ꢁC and the reaction mixture wasstirred for
24 h at room temperature or at 0 ꢁC. The reaction was
then quenched by aqueousHCl oslution (2 N, 10 mL)
9. Shi, M.; Sui, W. S. Tetrahedron: Asymmetry 1999, 10,
3319–3325.
and the mixture wasextracted with Et O (20 mL · 2).
2
The combined organic extractswere washed with brine
10. For reviews: (a) Ghosh, A. K.; Mathivanan, P.; Cappiello,
J. Tetrahedron: Asymmetry 1998, 9, 1–45; (b) Johnson,
J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
11. (a) Chan, T. H.; Zheng, G. Z. Can. J. Chem. 1997, 75, 629–
633; (b) Zhu, H. J.; Zhao, B. T.; Dai, W. M.; Zhou, J.; Hao,
X. J. Tetrahedron: Asymmetry 1998, 9, 2879–2888; (c)
Shintani, R.; Fu, G. C. Org. Lett. 2002, 4, 3699–3702.
12. (a) Allen, J. V.; Frost, C. G.; Williams, J. M. J.
Tetrahedron: Asymmetry 1993, 4, 649–650; (b) Deng, W.
P.; Hou, X. L.; Dai, L. X. Tetrahedron: Asymmetry 1999,
10, 4689–4693.
(15 mL · 2), dried over anhydrousMgSO , and concen-
4
trated in vacuo. The crude product waspurified by flash
column chromatography over silica gel with petroleum–
ethyl acetate (8:1 to 5:1) to give the pure alcohol. The
enantiomeric excess was determined by HPLC over a
chiral column (Daicel Chiralcel OD, OB or AD).
13. (a) Zhang, W. B.; Yoshinaga, H.; Imai, Y.; Kida, T.;
Nakatsuji, Y.; Ikeda, I. Synlett 2000;(10), 1512–1514; (b)
Imai, Y.; Matsuo, S.; Zhang, W. B.; Nakatsuji, Y.; Ikeda,
I. Synlett 2000;(2), 239–241.
Acknowledgements
14. (a) Bolm, C.; Muniz-fernandez, K.; Seger, A.; Raabe, G.;
Gunther, J. J. Org. Chem. 1998, 63, 7860–7867; (b) Bolm,
C.; Muniz-fernandez, K.; Hildebrand, J. P. Org. Lett.
1998, 1, 491–493.
We are grateful to the National Natural Science Foun-
dation of China (grant nos. 20172001 and 20372001)
and Peking University for financial support.

126
B. Fu et al. / Tetrahedron: Asymmetry 15 (2004) 119–126
15. Pastor, I. M.; Adolfsson, H. Tetrahedron Lett. 2002, 43,
1743–1746.
21. (a) Mazaleyrat, J. P.; Gaucher, A.; Savrda, J.; Wakselman,
M. Tetrahedron: Asymmetry 1997, 8, 619–631; (b)
Gaucher, A.; Bintein, F.; Wakselman, M.; Mazaleyrat,
J. P. Tetrahedron Lett. 1998, 39, 575–578.
16. (a) Du, D. M.; Wang, Z. Y.; Xu, D. C.; Hua, W. T.
Synthesis 2002, 2347–2352; (b) Wang, Z. Y.; Du, D. M.;
Wu, D.; Hua, W. T. Synth. Commun. 2003, 33, 1275–1283;
(c) Xu, D. C.; Du, D. M.; Ji, N.; Wang, Z. Y.; Hua, W. T.
Synth. Commun. 2003, 33, 2563–2574.
17. (a) Du, D. M.; Fu, B.; Hua, W. T. Tetrahedron 2003, 59,
1933–1938; (b) Fu, B.; Du, D. M. Chin. J. Chem. 2003, 21,
597–599.
18. (a) Kenner, J. J. Chem. Soc. 1913, 613–627; (b) Dvorken,
L. V.; Smyth, R. B.; Mislow, K. J. Am. Chem. Soc. 1958,
80, 486–492.
19. Denmark, S. E.; Nakajima, N.; Nicaise, O. J. C.; Faucher,
A. M.; Edwards, J. P. J. Org. Chem. 1995, 60, 4884–4892.
20. Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D.
R. Org. Lett. 2000, 2, 1165–1168.
22. (a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am.
Chem. Soc. 1986, 108, 6071–6072; (b) Jin, M. J.; Ahn, S. J.;
Lee, K. S. Tetrahedron Lett. 1996, 37, 8767–8770; (c)
Watanabe, M. Tetrahedron Lett. 1995, 36, 8991–8994; (d)
Sola, L.; Reddy, K. S.; Vidal-Ferran, A.; Moyano, A.;
Pericas, M. A.; Riera, A.; Alvarez-Larena, A.; Piniella, J.
F. J. Org. Chem. 1998, 63, 7078–7082; (e) Dai, W. M.; Zhu,
H. J.; Hao, X. J. Tetrahedron: Asymmetry 2000, 11, 2315–
2337; (f) Cardellicchio, C.; Ciccarella, G.; Naso, F.; Perna,
F.; Tortorella, P. Tetrahedron 1999, 55, 14685–14692.
23. (a) Itsumo, S.; Frechet, J. M. J. J. Org. Chem. 1987, 52,
4140; (b) Ko, D. H.; Kim, K. H.; Ha, D. C. Org. Lett.
2002, 4, 3759–3762.