Regulation of the flexibility of planar chiral [2.2]paracyclophane ligands and its significant impact on enantioselectivity in asymmetric reactions of diethylzinc with carbonyl compounds

Article abstract of DOI:10.1016/j.tetasy.2004.06.026

A series of planar chiral ligands derived from [2.2]paracyclophane were synthesized and applied as catalysts in enantioselective additions of diethylzinc to aldehydes and α,β-unsaturated ketones. When ligand 10 with a dimethyl hydroxymethyl as the substituent was used, the enantioselectivity of the reaction of diethylzinc with aldehydes was much higher than when using ligand 3c with diphenyl hydroxymethyl as the substituent. The situation was the same with the 1,4-addition of diethylzinc to α,β-unsaturated ketones with 63-83% ee being obtained when the hydroxymethyl substituted ligand 7b was used, while almost no enantioselectivity was afforded if ligand 3c was used. The role of planar chirality is also studied.

Full text of DOI:10.1016/j.tetasy.2004.06.026

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2357–2365
Regulation of the flexibility of planar chiral [2.2]paracyclophane
ligands and its significant impact on enantioselectivity
in asymmetric reactions of diethylzinc with carbonyl compounds
Xun-Wei Wu,a Tang-Zhi Zhang,a Ke Yuana and Xue-Long Houa,b,
*
aState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
bShanghai–Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 10 May 2004; accepted 22 June 2004
Available online 31 July 2004
This paper is dedicated to Professor Chang Tao Qian on the occasion of his 70th birthday
Abstract—A series of planar chiral ligands derived from [2.2]paracyclophane were synthesized and applied as catalysts in enantio-
selective additions of diethylzinc to aldehydes and a,b-unsaturated ketones. When ligand 10 with a dimethyl hydroxymethyl as the
substituent was used, the enantioselectivity of the reaction of diethylzinc with aldehydes was much higher than when using ligand 3c
with diphenyl hydroxymethyl as the substituent. The situation was the same with the 1,4-addition of diethylzinc to a,b-unsaturated
ketones with 63–83% ee being obtained when the hydroxymethyl substituted ligand 7b was used, while almost no enantioselectivity
was afforded if ligand 3c was used. The role of planar chirality is also studied.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
of novel chiral ligands in asymmetric catalysis,5 we pre-
viously synthesized several novel chiral P,N- and N,O-
[2.2]paracyclophane ligands and used them in asymmet-
ric catalysis.2 We found that the location of the sub-
stituents on the ligands strongly affected the enantio-
selectivity of the reactions.2a We also found that N,O-
[2.2]paracyclophane ligands were effective as catalysts
in the enantioselective addition of diethylzinc to
aldehydes.2b Unexpected results have been obtained in
ongoing studies on the structure–reactivity relationships
in chiral ligands,5j which has prompted us to study
further the structure of [2.2]cyclophanes. Herein, we
report the synthesis of new chiral cyclophane ligands
and describe the unforeseen significant effect of the
rigidity and flexibility of cyclophane-based ligands on
the enantioselectivity of the reactions of diethylzinc with
aldehydes and a,b-unsaturated ketones as well as the
role of their planar chirality in these reactions.
Over the past few years, [2.2]paracyclophane derivatives
have attracted growing attention as novel chiral ligands
in asymmetric catalysis, with excellent asymmetric
induction being realized in many types of asymmetric
reactions.1,2 These ligands, which have a framework of
two benzene rings connected at the para-position by
two ethylene chains, are chemically stable3a and undergo
racemization only at relatively high temperature.3b Be-
sides, planar chirality can be introduced when there is
a substituent at any position of the benzene rings.4 How-
ever, only a few structural characteristics of cyclophanes
have been shown to influence the reactivity and enantio-
selectivity in asymmetric catalysis. For example, the
[2.2]paracyclophane framework is usually considered
to be rigid,3c but our understanding of the effect of this
rigidity in asymmetric catalysis is not yet complete. As
part of a program aimed at the synthesis and application
2. Results and discussions
*
We have previously reported the synthesis of ligands
3 and 4 and their application in the enantioselective
Corresponding author. Tel.: +86-21-6416-3300; fax: +86-21-6416-
6128; e-mail: xlhou@mail.sioc.ac.cn
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.06.026

2358
X.-W. Wu et al. / Tetrahedron: Asymmetry 15 (2004) 2357–2365
addition of Et2Zn to aldehydes.6 The synthesis of the
new chiral [2.2]cyclophane ligands in this work is based
on the same strategy that was used to obtain ligands 3
and 4. Diastereoisomeric oxazolinlycyclophanes 1 and
2 are key intermediates for the synthesis of new planar
chiral N,O-[2.2]paracyclophane ligands.2b Bromo-lith-
ium exchange of 1 and 2 at ꢀ78ꢁC, followed by trapping
of the anion with DMF gave compounds 5 and 6.
Reduction of 5 and 6 with NaBH4 in MeOH and THF
afforded the desired ligands 7 and 8 with a hydroxy-
methyl groupas the substituent, which is smaller than
the diphenylhydroxymethyl unit. To study further the
effect of the rigid [2.2]paracyclophane backbone on
asymmetric catalytic reactions, ligands 9, 10, and 11
were also synthesized. These ligands contain a dimethyl-
hydroxymethyl group, which is medium-sized compared
to the diphenylhydroxymethyl and hydroxymethyl
groups (Scheme 1).
matched, those in ligands 8 are not. However, ligands
9 and 10 with a dimethylhydroxymethyl groupnot only
showed higher reactivity but also provided better enan-
tioselectivities (97.9% and 98.4% ee, respectively) than
ligands 3a–c and 7a–c (Table 1, entries 7 and 8 vs entries
3 and 5). The effectiveness of ligand 10 was further dem-
onstrated when other aromatic aldehydes were used,
with 96% ee being achieved regardless of the presence
of electron-withdrawing or -donating groups on the benz-
ene ring (Table 1, entries 10–13). These ee values are far
better than those given by ligands 3, with the ee values
increasing as much as 14% and 15% in some cases (Table
1, entries 12 and 13). These results reflect the influence of
changes in the ligand structure on the enantioselectivity
of the reaction. There have already been many discus-
sions on the effects of the rigidity and flexibility of lig-
ands on enantioselectivity.8–10 Most examples have
shown that the enantioselectivity increases with an in-
crease in the rigidity of the ligands.8a–c In particular,
the introduction of a diphenylhydroxymethyl group into
a chiral ligand usually leads to an increase in enantiose-
lectivity in various reactions; a groupof this type is
known as a ÔmagicÕ group.9 Only a few reports have
noted that the introduction of flexibility has provided
excellent enantioselectivity in the reaction.10 Interest-
ingly, in our case the less sterically demanding dime-
thylhydroxymethyl groupgave better results than the
more sterically demanding diphenylhydroxymethyl
With these new ligands in hand, the addition reaction of
diethylzinc to aldehydes was used to examine the effects
of different substituents on the cyclophane on the reac-
tion,7 with the results shown in Table 1. It can be seen
that ligands 7a–c, with a hydroxymethyl moiety, gave
enantioselectivities that were equal to or greater than
with ligands 3a–c, which have a diphenylhydroxymethyl
moiety (Table 1, entries 1–6). Furthermore, while the
planar chirality and central chirality in ligands 7 are
R1
O
R1
R2
O
R2
N
N
Br
OH
Ph
O
O
N
N
Ph
OH
Ph
R2
R2
Br
R1
R1
Ph
(S,4Sp,13Rp)-3a-c
(S,4Rp,13Sp)-1a-c
(S,4Sp,13Rp)-2a-c
(S,4Rp,13Sp)-4a-c
R1
R2
O
N
a) BuLi/THF
-78oC
b) DMF
93-98%
O
N
1a-c
2a-c
CHO
+
R2
R1
CHO
6a-c
5a-c
R1
R2
O
N
NaBH4
O
+
MeOH/THF(1:1)
92%-97%
CH2OH
N
R2
CH2OH
R1
(S,4Sp,13Rp)-7a-c
(S,4Rp,13Sp)-8a-c
O
R
N
a) BuLi/THF
-78oC
OH
O
1b-c
CH3
N
OH
CH3
b) CH3COCH3
78-82%
2c
Bn
CH3
H3C
(S,4Sp,13Rp)-9, R=tBu
(S,4Sp,13Rp)-10, R=Bn
(S,4Rp,13Sp)-11
a: R1=H, R2=iPr; b: R1=H, R2=tBu; c: R1=H, R2=Bn.
Scheme 1.

X.-W. Wu et al. / Tetrahedron: Asymmetry 15 (2004) 2357–2365
2359
Table 1. Enantioselective addition of diethylzinc to aldehydes with planar chiral N,O-ligands
OH
Ligand (5 mol%)/Et2Zn (220 mol%)
ArCHO
PhCH3/25oC
*
Ar
Entry
Ar
Ligand
Time (h)
Yield (%)a,b
Ee (%)a,c
Config.d
1
Ph
Ph
7a (3a)
8a (4a)
7b (3b)
8b (4b)
7c (3c)
8c (4c)
9
5 (9)
24 (24)
7 (24)
24 (24)
5 (7)
24 (24)
3.5
94 (96)
49 (35)
93 (37)
46 (13)
94 (93)
51 (12)
93
91 (93)
25 (5)
94 (32)
36 (7)
91 (93)
45 (7)
97.9
R (R)
S (S)
R (R)
S (S)
R (R)
S (S)
R
2
3
Ph
Ph
4
5
Ph
Ph
6
7
Ph
Ph
8
10
11
1.5
48
95
<5
98.4
––
R
9
Ph
––
10
11
12
13
p-ClC6H4
p-BrC6H4
p-MeOC6H4
o-MeOC6H4
10 (3c)
10 (3c)
10 (3c)
10 (3c)
2 (8)
2 (9)
3.5 (24)
1 (4)
96 (96)
95 (95)
94 (86)
96 (94)
97.6 (94)
96.8 (93)
96 (82)
96 (81)
R (R)
R (R)
R (R)
R (R)
a The yield, the ee value and the configuration in parenthesis were given using ligand 3 or 4.2b
b Isolated yield based on aldehyde.
c Determined by HPLC (chiracel OD column).
d Configurations were assigned by comparison with the sign of specific rotation of known compounds.
group( Table 1, entries 10–13). It could be deduced that
as the backbone of cyclophane is rigid, and the introduc-
tion of a more sterically demanding diphenylhydroxy-
methyl group into the rigid [2.2]paracyclophane
backbone may have made the ligand even more rigid,
then the dimethylhydroxymethyl groupmay have made
the ligand more flexible, which enabled it to assume a
more favorable conformation in the reaction. Similar
results were obtained in our previously reported planar
chiral N,S and N,Se-[2.2]paracyclophane ligand system
and in N,S-ligands, with oxazoline, and thiophenyl
groups at benzene and benzylic positions, in that benz-
ylic-substituted ligands were more flexible than benzene
ring-substituted ligands and provided far better reactiv-
ity and enantioselectivity.2a
The above results prompted us to extend the application
of these new N,O-[2.2]paracyclophane ligands to the Ni-
catalyzed asymmetric 1,4-addition reaction of diethyl-
zinc reagent to chalcones.11 In the presence of catalyst
prepared in situ from 5mol% of Ni(acac)2 and
10mol% of ligands 3 and 4, the reaction gave the corre-
sponding addition products in good yield, but the enan-
tioselectivity was almost zero (Table 2, entry 1). Ligand
9, which showed excellent enantioselectivity in the addi-
tion of diethylzinc to aldehydes, gave an enantiomeric
excess of only 8% (Table 2, entry 2). This may be the re-
sult of it being difficult for chalcone to move close to the
ligands and thus not be strongly affected by the chiral
environment of the ligands; chalcone is more sterically
demanding than benzaldehyde, so ligands 7 and 8 with
Table 2. Enantioselective 1,4-addition of diethylzinc to a,b-unsaturated ketones with planar chiral N,O-ligands
Ligand/Ni(acac)2 (5 mol%)
Et
O
O
Ar1
Ar2
Et2Zn (200 mol%)/CH3CN
2.5-4h/ -20oC
Ar1
Ar2
91-96% yield
Entry
Ar1
Ar2
Ligand
Ligand (mol%)
Ee (%)a
Config.b
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3–4
9
10
10
10
10
10
20
20
20
20
20
20
0
––
S
2
8
3
Ph
Ph
7a (8a)
7b (8b)
7c (8c)
7b
52 (0)
63 (0)
53 (4)
75
S (ꢀ)
S (ꢀ)
S (R)
S
4
5
Ph
Ph
6
7
p-MeC6H4
p-BrC6H4
p-ClC6H4
Ph
7b
7b
63
71
––
––
8c
9
7b
7b
72
61
––
––
10
11
p-BrC6H4
p-MeOC6H4
Ph
7b
83
––
a Determined by chiral HPLC.
b Configurations were assigned by comparison with the sign of specific rotation of known compounds.
c The solvent is CH3CN/CH2Cl2 (2/1).

2360
X.-W. Wu et al. / Tetrahedron: Asymmetry 15 (2004) 2357–2365
Et2Zn (220 mol%)
Ligand (5 mol%)
an even less sterically demanding hydroxymethyl group
might provide better results. Indeed, a significant in-
crease in enantioselectivity was observed when ligands
7 and 8 were used as catalysts in this reaction (Table
2, entries 3–6). When 20mol% of 7b was used as a lig-
and, even higher enantioselectivity was achieved with
the ee increasing from 63% to 75% (Table 2, entry 4 vs
6). Under the same reaction conditions, several chal-
cones were tested with ligand 7b (entries 7–11) with up
to 83% ee being obtained (Table 2, entry 11). These re-
sults suggest that introduction of the least sterically
demanding hydroxymethyl groupto ligand 7b may have
buffered the intrinsic rigidity in the [2.2]paracyclophane
framework so that the enantioselectivity of the reaction
was improved.
OH
*
ArCHO
Ph
PhCh3, 25 o
C
ð1Þ
Ligand 15a: 95% yield, 93% ee (S)
Ligand 15b: 90% yield, 92% ee (S)
3. Conclusion
In summary, a series of ligands were synthesized and
used in the addition reactions of the diethyl zinc reagent
to aldehydes and chalcones. The importance of regulat-
ing the flexibility as well as the planar chirality of a rigid
[2.2]paracyclophane ligand system in the reactivity and
enantioselectivity of the reaction has been demon-
strated. This information should be useful for the design
and synthesis of new cyclophane ligands. Further inves-
tigations into the synthesis of chiral cyclophanes and
their use in asymmetric catalysis are currently in
progress.
If we consider the above results along with those ob-
tained previously in the N,S/Se-ligand system,2a we
can see that an increase in the flexibility of the rigid
[2.2]paracyclophane framework leads to a remarkable
increase in enantioselectivity. This regulation of the flex-
ibility of [2.2]paracyclophane ligands is very crucial for
obtaining excellent results.
4. Experimental
Furthermore, the results shown in Tables 1 and 2 also
suggest the importance of matching the planar chirality
and central chirality of the ligands.2b,5e,12 To clarify
further the effect of planar chirality, the N,O-ligands
15a and 15b, which possess only planar chirality,
were synthesized using the methods depicted in
Scheme 2.
4.1. General methods
All reactions were performed under an argon atmos-
phere using oven-dried glassware. Solvents were treated
prior to use according to standard methods. H NMR
1
spectra were recorded in CDCl3 and CD3SOCD3.
Chemical shifts are given in parts per million relative
to tetramethylsilane as an internal standard. IR spectra
were measured in cmꢀ1. The commercially available rea-
gents were used as received without further purification.
Compound 1, 2, 3, and 4 were prepared using our previ-
ously reported procedures.2b The a,b-unsaturated ke-
tones were synthesized according to the similar
procedure of chalcone.13
First, ligands 15a and 15b were applied to the addition
of Et2Zn to benzaldehyde, and the product obtained in
93% and 92% ee, respectively (Eq. 1). These results con-
trast sharply with those using ligand 11, which has pla-
nar chirality with the same configuration (Table 1, entry
9). These results unambiguously demonstrate that the
planar chirality in cyclophane systems plays an impor-
tant role in asymmetric catalysis. Based on the results
of other studies1f,m–p and in our catalytic systems includ-
ing N,S/Se2a- and N,O-ligands,2b the planar chirality in
[2.2]paracyclophane ligands appears to play a greater
role in asymmetric catalysis than that in planar chiral
ferrocene ligands.5a,e,12
4.1.1. (S,4Rp,13Sp)-4-Formyl-13-(4-iso-propyl-oxazolin-
2-yl)[2.2]paracyclophane 5a. n-BuLi (0.75mL, 1.6M in
hexane, 1.2mmol) was added dropwise to a solution of
(S,4Rp,13Sp)-1a (398mg, 1mmol) in THF (10mL) at
ꢀ78ꢁC. The resulting mixture was stirred for 2h at this
H
N
a) (COCl)2
a) CH3I/DMSO/rt.
O
OH
COOH
R
R
b)
b) KOH/H2O/Reflux
R
R
O
N
78%
Br
OH
H2N
Br
Br
(4Sp,13Rp)-12
13a, 96%
13b, 92%
(4Sp,13Rp)-13a, R=H
(4Sp,13Rp)-13b, R=C H
(S,4Sp,13Rp)-2a
3
a) BuLi/THF
O
-78oC
O
PPh3/CCl4
OH
N
Et3N/CH3CN
14a, 96%
14b, 93%
N
b) CH3COCH3
15a, 83%
15b, 85%
R
CH3
R
Br
R
R
CH3
(4Rp,13Sp)-15a, R=H
(4Rp,13Sp)-15b, R=C H
(4Sp,13Rp)-14a, R=H
(4Sp,13Rp)-14b, R=C H
3
3
Scheme 2.

X.-W. Wu et al. / Tetrahedron: Asymmetry 15 (2004) 2357–2365
2361
temperature. The mixture was treated with DMF
(0.39mL, 5mmol) and stirred for another 1h at room
temperature. The reaction was quenched with saturated
aqueous NH4Cl solution (10mL). The organic layer was
extracted twice with dichloromethane (15mL). The com-
bined organic layer was dried over Na2SO4 and concen-
trated in vacuum to give the crude product, which was
purified by column chromatography (ethyl acetate/
J=9.1Hz, 1H), 3.96–4.06 (m, 2H), 4.22–4.3 (m, 2H),
6.48–6.65 (m, 4H), 6.84 (d, J=1.7Hz, 1H), 7.01 (d,
J=2.0Hz, 1H), 9.86 (s, 1H); 13C NMR (CDCl3,
75MHz) 18.5, 19.4, 30.8, 32.9, 34.6, 34.7, 35.0, 69.3,
73.4, 128.6, 133.2, 133.4, 134.2, 135.7, 135.8, 136.1,
138.0, 139.3, 139.9, 140.8, 143.9, 162.1, 190.0; MS (EI)
m/z (rel) 347 (M+); IR (KBr) 2960, 1679, 1639, 1630,
1589cmꢀ1; Anal. Calcd for C23H25NO2: C, 79.51; H,
7.25; N, 4.03. Found: C, 79.28; H, 7.42; N, 3.87.
petroleum ether=1/7) to give (S,4Rp,13Sp)-5a (330mg,
20
D
95%) as a white solid: mp130–132 ꢁC; ½aŠ ¼ ꢀ62:3 (c
1
0.45, CHCl3); H NMR (CDCl3, 300MHz) d 0.87 (d,
J=6.7Hz, 3H), 1.08 (d, J=6.7Hz, 3H), 1.83–1.88 (m,
1H), 2.90–3.09 (m, 6H), 3.86–4.04 (m, 3H), 4.17–4.32
(m, 2H), 6.52–6.56 (m, 3H), 6.64 (dd, J=7.8, 1.9Hz,
1H), 6.93 (s, 1H), 7.00 (d, J=1.9Hz, 1H), 9.81 (s, 1H);
13C NMR (CDCl3, 75MHz) 18.8, 19.9, 31.5, 33.1,
34.6, 34.7, 34.9, 70.1, 73.2, 128.8, 133.4, 134.4, 135.2,
135.8, 135.9, 136.5, 137.9, 139.2, 140.1, 140.5, 143.3,
162.8, 191.1; MS (EI) m/z (rel) 347 (M+); IR (KBr):
2931, 1680, 1633, 1590, 1467cmꢀ1; Anal. Calcd for
C23H25NO2: C, 79.51; H, 7.25; N, 4.03. Found: C,
79.77; H, 7.49; N, 3.90.
4.1.5. (S,4Sp,13Rp)-4-Formyl-13-(4-tert-butyl-oxazolin-
2-yl)[2.2]paracyclophane 6b. Compound (S,4Sp,13Rp)-
2b was allowed to react according to the procedure for
5a to afford 6b (98%) as a white solid: mp162–164 ꢁC;
20
½aŠ ¼ þ186:0 (c 0.33, CHCl3); 1H NMR (CDCl3,
D
300MHz) d 0.96 (s, 9H), 2.90–2.99 (m, 1H), 3.05–3.16
(m, 5H), 3.96–4.02 (m, 1H), 4.07–4.16 (m, 2H), 4.22–
4.28 (m, 1H), 4.34–4.42 (m, 1H), 6.56 (d, J=8.0Hz,
1H), 6.64 (d, J=7.8Hz, 1H), 6.69–6.73 (m, 2H), 6.86
(s, 1H), 7.13 (s, 1H), 9.98 (s, 1H); 13C NMR (CDCl3,
75MHz) 26.0, 30.1, 33.6, 34.6, 34.7, 35.3, 67.3, 76.8,
128.4, 131.7, 133.3, 133.9, 135.7, 135.8, 135.9, 138.2,
139.3, 139.8, 140.8, 144.2, 161.7, 189.2; MS (EI) m/z
(rel) 361 (M+); IR (KBr): 2946, 1688, 1675, 1639,
1591, 1479cmꢀ1; Anal. Calcd for C24H27NO2: C,
79.74; H, 7.53; N, 3.87. Found: C, 79.77; H, 7.67; N,
3.67.
4.1.2. (S,4Rp,13Sp)-4-Formyl-13-(4-tert-butyl-oxazolin-
2-yl)[2.2]paracyclophane 5b. Compound (S,4Rp,13Sp)-
1b was allowed to react according to the procedure for
5a to afford 5b (98%) as a white solid: mp134–136 ꢁC;
20
½aŠ ¼ ꢀ34:6 (c 0.36, CHCl3); 1H NMR (CDCl3,
D
300MHz) d 1.01 (s, 9H), 3.01–3.18 (m, 6H), 3.96–4.17
(m, 4H), 4.31–4.34 (m, 1H), 6.61–6.64 (m, 3H), 6.73
(dd, J=8.1, 1.9Hz, 1H), 7.01 (s, 1H), 7.06 (s, 1H),
9.83 (s, 1H); 13C NMR (CDCl3, 75MHz) 26.2, 31.9,
33.9, 34.6, 34.7, 68.3, 76.0, 129.1, 133.2, 134.4, 135.6,
135.8, 136.0, 136.5, 137.5, 139.1, 140.0, 143.0, 163.3,
191.5; MS (EI) m/z (rel) 361 (M+); IR (KBr): 2959,
4.1.6. (S,4Sp,13Rp)-4-Formyl-13-(4-benzyl-oxazolin-2-
yl)[2.2]paracyclophane 6c. Compound (S,4Sp,13Rp)-
2c was allowed to react according to the procedure for
5a to afford 6c (93%) as a white solid: mp90–92 ꢁC;
20
½aŠ ¼ þ41:7 (c 0.36, CHCl3); 1H NMR (CDCl3,
D
300MHz) d 2.78 (dd, J=13.7, 9.2Hz, 1H), 2.97–3.20
(m, 6H), 3.30 (dd, J=13.4, 5.0Hz, 1H), 3.99 (t,
J=8.4Hz, 1H), 4.07–4.21 (m, 1H), 4.24–4.32 (m, 2H),
4.55–4.66 (m, 1H), 6.58–6.73 (m, 4H), 6.97 (s, 1H),
7.07 (s, 1H), 7.21–7.35 (m, 5H), 9.89 (s, 1H); 13C
NMR (CDCl3, 75MHz) 31.4, 34.6, 34.7, 34.8, 41.5,
68.3, 71.1, 126.4, 128.4, 128.5, 129.1, 133.4, 134.4,
134.6, 135.7, 135.8, 136.2, 137.9, 138.4, 139.3, 140.0,
140.8, 143.6, 163.2, 190.7; MS (EI) m/z (rel) 395 (M+);
IR (KBr) 2949, 1676, 1629, 1589, 1496cmꢀ1; Anal. Cal-
cd for C27H25NO2: C, 82.00; H, 6.37; N, 3.54. Found: C,
81.78; H, 6.27; N, 3.45.
1678, 1640, 1589, 1475cmꢀ1
;
Anal. Calcd for
C24H27NO2: C, 79.74; H, 7.53; N, 3.87. Found: C,
79.70; H, 7.78; N, 3.69.
4.1.3. (S,4Rp,13Sp)-4-Formyl-13-(4-benzyl-oxazolin-2-
yl)[2.2]paracyclophane 5c. Compound (S,4Rp,13Sp)-
1c was allowed to react according to the procedure for
5a to afford 5c (96%) as a white solid: mp105–106 ꢁC;
20
½aŠ ¼ ꢀ19:0 (c 0.30, CHCl3); 1H NMR (CDCl3,
D
300MHz) d 2.88 (dd, J=13.7, 9.2Hz, 1H), 2.96–3.18
(m, 6H), 3.33 (dd, J=13.7, 5.3Hz, 1H), 4.05–4.61 (m,
5H), 6.60–6.70 (m, 3H), 6.72 (dd, J=7.6, 1.8Hz, 1H),
7.06 (s, 1H), 7.10 (s, 1H), 7.24–7.34 (m, 5H), 9.89 (s,
1H); 13C NMR (CDCl3, 75MHz) 31.7, 34.6, 34.7,
34.8, 41.1, 68.1, 71.2, 126.3, 128.5, 128.6, 129.2, 133.4,
134.6, 135.6, 135.8, 135.9, 136.4, 137.8, 138.4, 139.3,
140.1, 140.7, 143.3, 163.3, 191.3; MS (EI) m/z (rel) 395
(M+); IR (KBr) 2933, 1682, 1642cmꢀ1; Anal. Calcd
for C27H25NO2: C, 82.00; H, 6.37; N, 3.54. Found: C,
81.82; H, 6.33; N, 3.43.
4.1.7.
(S,4Sp,13Rp)-4-(4-iso-Propyl-oxazolin-2-yl)-13-
hydroxylmethyl[2.2]paracyclophane 7a. NaBH4 (177.6
mg, 4.67mmol) was added to a solution of (S,4Rp,
13Sp)-5a (541mg, 1.56mmol) in methanol (10mL) and
THF (10mL). The resulting mixture was stirred for
0.5h at room temperature. After removal of the reaction
solvent in vacuum, dichloromethane (15mL) and water
(10mL) were added. The organic layer was extracted
twice with dichloromethane (15mL). The combined or-
ganic layer was dried over Na2SO4 and concentrated
in vacuum to give the crude product, which was purified
by column chromatography (ethyl acetate/petroleum
4.1.4. (S,4Sp,13Rp)-4-Formyl-13-(4-iso-propyl-oxazolin-
2-yl)[2.2]paracyclophane 6a. Compound (S,4Sp,13Rp)-
2a was allowed to react according to the procedure for
ether=1/4) to give (S,4Sp,13Rp)-7a (530mg, 97%) as a
20
5a to afford 6a (93%) as a white solid: mp114–116 ꢁC;
white solid: mp107–109 ꢁC; ½aŠ ¼ ꢀ32:5 (c 0.325,
D
20
½aŠ ¼ þ59:6 (c 0.545, CHCl3); 1H NMR (CDCl3,
CHCl3); 1H NMR (CDCl3, 300MHz) d 0.94 (d,
J=6.7Hz, 3H), 1.03 (d, J=6.7Hz, 3H), 1.80–1.87 (m,
1H), 2.81–2.90 (m, 1H), 3.01–3.31 (m, 6H), 3.61–3.71
D
300MHz) d 0.84 (d, J=6.7Hz, 3H), 1.00 (d, J=6.7Hz,
3H), 1.70–1.77 (m, 1H), 2.87–3.06 (m, 6H), 3.84 (t,

2362
X.-W. Wu et al. / Tetrahedron: Asymmetry 15 (2004) 2357–2365
(m, 1H), 4.07–4.15 (m, 2H), 4.29–4.50 (m, 3H), 4.85 (br,
1H), 6.45–6.52 (m, 3H), 6.60 (dd, J=7.7, 1.8Hz, 1H),
6.77 (s, 1H), 7.00 (d, J=1.7Hz, 1H); 13C NMR (CDCl3,
75MHz) 18.5, 18.9, 32.7, 32.8, 33.2, 35.0, 35.1, 61.6,
70.9, 71.6, 126.6, 128.9, 131.0, 133.4, 134.7, 134.8,
135.8, 136.3, 139.8, 139.9, 140.0, 142.4, 166.7; MS (EI)
m/z (rel) 349 (M+); IR (KBr) 3290, 2955, 1627,
1594, 1419cmꢀ1; Anal. Calcd for C23H27NO2: C,
79.05; H, 7.79; N, 4.01. Found: C, 79.16; H, 8.01; N,
3.83.
4.1.11. (S,4Rp,13Sp)-4-(4-tert-Butyl-oxazolin-2-yl)-13-
hydroxylmethyl[2.2]paracyclophane 8b. Compound (S,
4Sp,13Rp)-6b was allowed to react according to the pro-
cedure for 7a to afford 8b (94%) as a white solid: mp
20
1
121–123ꢁC; ½aŠ ¼ ꢀ103:9 (c 0.425, CHCl3); H NMR
D
(CDCl3, 300MHz) d 1.07 (s, 9H), 2.83–3.06 (m, 3H),
3.11–3.20 (m, 3H), 3.33–3.42 (m, 1H), 3.60–3.70 (m,
1H), 4.03–4.17 (m, 2H), 4.33–4.39 (m, 2H), 4.51 (d,
J=16.3Hz, 1H), 6.49–6.60 (m, 4H), 6.72 (s, 1H), 6,93
(s, 1H); 13C NMR (CDCl3, 75MHz) 26.1, 32.3, 32.5,
33.3, 34.6, 34.7, 61.3, 68.2, 76.8, 126.0, 129.5, 130.8,
132.4, 134.3, 134.9, 135.5, 135.8, 139.1, 139.4, 139.6,
141.9, 165.6; MS (EI) m/z (rel) 363 (M+); IR (KBr)
3263, 2930, 1634, 1592, 1478cmꢀ1; Anal. Calcd for
C24H29NO2: C, 79.30; H, 8.04; N, 3.85. Found: C,
79.01; H, 8.19; N, 3.58.
4.1.8.
(S,4Sp,13Rp)-4-(4-tert-Butyl-oxazolin-2-yl)-13-
hydroxylmethyl[2.2]paracyclophane 7b. Compound (S,
4Rp,13Sp)-5b was allowed to react according to the pro-
cedure for 7a to afford 7b (94%) as a white solid: mp
20
133–134ꢁC; ½aŠ ¼ þ99:2 (c 0.37, CHCl3); 1H NMR
D
(CDCl3, 300MHz) d 0.96 (s, 9H), 2.80–2.90 (m, 1H),
3.01–3.31 (m, 6H), 3.56–3.65 (m, 1H), 4.10 (dd,
J=10.1, 7.7Hz, 1H), 4.21–4.35 (m, 2H), 4.41–4.49 (m,
2H), 5.30 (br, 1H), 6.46–6.57 (m, 3H), 6.62 (dd,
J=7.4, 1.2Hz, 1H), 6.79 (s, 1H), 7.01 (s, 1H); 13C
NMR (CDCl3, 75MHz) 26.0, 32.7, 32.8, 34.5, 35.0,
35.1, 61.5, 69.4, 75.1, 126.6, 128.9, 131.0, 133.4, 134.7,
134.8, 135.8, 136.3, 139.8, 139.9, 140.0, 142.6, 166.8;
MS (EI) m/z (rel) 363 (M+); IR (KBr) 3286, 2949,
4.1.12. (S,4Rp,13Sp)-4-(4-Benzyl-oxazolin-2-yl)-13-hydr-
oxylmethyl[2.2]paracyclophane 8c. Compound (S,
4Sp,13Rp)-6c was allowed to react according to the pro-
cedure for 7a to afford 8c (95%) as a white solid: mp
20
D
1
120–121ꢁC; ½aŠ ¼ ꢀ79:2 (c 0.365, CHCl3); H NMR
(CDCl3, 300MHz) d 2.75–2.94 (m, 2H), 3.00–3.19 (m,
5H), 3.31–3.39 (m, 1H), 3.51 (dd, J=13.8, 4.7Hz, 1H),
3.72–3.82 (m, 1H), 4.11 (t, J=8.8Hz, 1H), 4.27–4.62
(m, 4H), 6.50–6.56 (m, 3H), 6.61 (dd, J=7.7, 1.9Hz,
1H), 6.72 (s, 1H), 7.00 (d, J=1.8Hz, 1H), 7.27–7.38
(m, 5H); 13C NMR (CDCl3, 75MHz) 32.7, 32.8, 35.1,
35.2, 41.6, 61.9, 66.9, 72.0, 126.4, 126.9, 128.9, 129.2,
129.6, 131.2, 133.5, 134.8, 135.1, 135.9, 136.4, 137.7,
139.8, 140.0, 140.2, 142.3, 166.9; MS (EI) m/z (rel) 397
1627, 1593, 1482, 1477cmꢀ1
;
Anal. Calcd for
C24H29NO2: C, 79.30; H, 8.04; N, 3.85. Found: C,
79.45; H, 7.94; N, 3.78.
4.1.9. (S,4Sp,13Rp)-4-(4-Benzyl-oxazolin-2-yl)-13-hydr-
oxylmethyl[2.2]paracyclophane 7c. Compound (S,
4Rp,13Sp)-5c was allowed to react according to the pro-
cedure for 7a to afford 7c (95%) as a white solid: mp
(M+); IR (KBr): 3260, 2927, 1633, 1595, 1455cmꢀ1
;
Anal. Calcd for C27H27NO2: C, 81.58; H, 6.85; N,
3.52. Found: C, 81.45; H, 6.99; N, 3.44.
20
D
1
116–118ꢁC; ½aŠ ¼ þ116:9 (c 0.395, CHCl3); H NMR
(CDCl3, 300MHz) d 2.73–2.90 (m, 2H), 3.05–3.29 (m,
6H), 3.66–3.75 (m, 2H), 4.18 (dd, J=8.6, 6.9Hz, 1H),
4.31–4.43 (m, 3H), 4.58–4.77 (m, 1H), 6.46–6.55 (m,
3H), 6.62 (dd, J=7.7, 1.8Hz, 1H), 6.74 (s, 1H), 7.05
(d, J=1.8Hz, 1H), 7.21–7.35 (m, 5H); 13C NMR
(CDCl3, 75MHz) 32.8, 32.9, 35.0, 35.1, 41.6, 62.0,
68.2, 72.7, 126.3, 126.9, 129.0, 129.2, 129.5, 131.2,
133.2, 134.8, 135.3, 136.0, 136.5, 138.3, 139.8, 140.0,
140.2, 142.3, 166.8; MS (EI) m/z (rel) 397 (M+); IR
(KBr) 3271, 2920, 1637, 1456cmꢀ1; Anal. Calcd for
C27H27NO2: C, 81.58; H, 6.85; N, 3.52. Found: C,
81.37; H, 6.96; N, 3.39.
4.1.13. (S,4Sp,13Rp)-4-(4-tert-Butyl-oxazolin-2-yl)-13-(a,
a-dimethylhydroxymethyl)[2.2]paracyclophane 9. Com-
pound (S,4Rp,13Sp)-1b was allowed to react according
to the procedure for 5a and quenched with acetone to
afford 9 (82%) as a white solid: mp125–126 ꢁC;
20
½aŠ ¼ þ75:5 (c 0.435, CHCl3); 1H NMR (CDCl3,
D
300MHz) d 0.96 (s, 9H), 1.36 (s, 3H), 1.41 (s, 3H),
2.87–2.97 (m, 1H), 3.01–3.16 (m, 5H), 3.45–3.54 (m,
1H), 3.90–3.98 (m, 1H), 4.05–4.16 (m, 2H), 4.31–4,36
(m, 1H), 5.41 (br, 1H), 6.47–6.53 (m, 2H), 6.64–6.74
(m, 3H), 6.81 (s, 1H); 13C NMR (CDCl3, 75MHz)
25.8, 31.8 31.9, 34.0, 34.5 34.7, 34.8, 36.0, 68.9, 71.7,
75.4, 127.0, 128.2, 131.3, 131.9, 134.8, 135.6, 136.8,
137.0, 138.9, 139.3, 140.0, 145.7, 167.7; MS (EI) m/z
(rel) 391 (M+); IR (KBr) 3251, 2953, 1645, 1628, 1589,
4.1.10. (S,4Rp,13Sp)-4-(4-iso-Propyl-oxazolin-2-yl)-13-
hydroxylmethyl[2.2]paracyclophane 8a. Compound (S,
4Sp,13Rp)-6a was allowed to react according to the pro-
cedure for 7a to afford 8a (96%) as a white solid: mp
1478cmꢀ1
; HRMS: Anal. Calcd for C26H33NO2:
391.2512. Found: 391.2521.
20
D
110ꢁC; ½aŠ ¼ ꢀ123:9 (c 0.355, CHCl3); 1H NMR
(CDCl3, 300MHz) d 1.00 (d, J=6.7Hz, 3H), 1.21 (d,
J=6.5Hz, 3H), 1.92–1.99 (m, 1H), 2.82–2.92 (m, 1H),
2.98–3.23 (m, 6H), 3.27–3.38 (m, 1H), 3.64–4.12 (m,
2H), 4.36–4.52 (m, 3H), 6.50–6.62 (m, 4H), 6.74 (s,
1H), 7.02(s, 1H); 13C NMR (CDCl3, 75MHz) 19.0,
20.4, 32.7, 32.8, 33.1, 35.0, 35.1, 61.8, 71.1, 73.5, 126.4,
129.5, 131.1, 133.2, 134.7, 135.2, 135.9, 136.3, 139.6,
140.0, 140.1, 142.3, 166.4; MS (EI) m/z (rel) 349 (M+);
4.1.14. (S,4Sp,13Rp)-4-(4-Benzyl-oxazolin-2-yl)-13-(a,a-
dimethylhydroxymethyl)[2.2]paracyclophane 10. Com-
pound (S,4Rp,13Sp)-1c was allowed to react according
to the procedure for 5a to afford 10 (81%) as a white
solid (except for being quenched with acetone): mp
20
D
108–110ꢁC; ½aŠ ¼ þ52:5 (c 0.36, CHCl3); 1H NMR
(CDCl3, 300MHz) d 1.26 (s, 3H), 1.52 (s, 3H), 2.72–
2.83 (m, 1H), 2.86–3.23 (m, 6H), 3.40 (dd, J=13.8,
4.2Hz, 1H), 3.88–4.00 (m, 1H), 4.04–4.32 (m, 3H),
4.55–4.67 (m, 1H), 5.37 (br, 1H), 6.48 (s, 1H), 6.53 (s,
IR (KBr): 3459, 3197, 2953, 1635, 1590, 1471cmꢀ1
;
Anal. Calcd for C23H27NO2: C, 79.05; H, 7.79; N,
4.01. Found: C, 78.86; H, 7.81; N, 3.75.

X.-W. Wu et al. / Tetrahedron: Asymmetry 15 (2004) 2357–2365
2363
2H), 6.66 (d, J=7.8Hz, 1H), 6.73 (dd, J=8.0, 1.9Hz,
1H), 6.94 (s, 1H), 7.23–7.36 (m, 5H); 13C NMR (CDCl3,
75MHz) 31.0, 32.9, 33.7, 34.7, 35.0, 36.4, 41.6, 67.8,
71.5, 72.0, 125.9, 126.5, 127.8, 128.6, 129.0, 131.0,
131.8, 136.0, 136.2, 137.0, 137.7, 137.8, 138.8, 139.2,
141.0, 145.2, 166.2; MS (EI) m/z (rel) 425 (M+); IR
(KBr) 3248, 2920, 1645, 1587, 1457cmꢀ1; Anal. Calcd
for C29H31NO2: C, 81.85; H, 7.34; N, 3.29. Found: C,
81.85; H, 7.61; N, 3.17.
5H), 7.13 (d, J=1.7Hz, 1H); MS (EI) m/z (rel) 403
(M++2), 401 (M+); IR (KBr) 3420, 3321, 2920, 1640,
1592, 1454cmꢀ1; Anal. Calcd for C21H24BrO2: C,
62.69; H, 6.01; N, 3.48. Found: C, 62.64; H, 5.78; N,
3.34.
4.1.19. (4Sp,13Rp)-4-Bromo-13-(oxazolin-2-yl)[2.2]para-
cyclophane 14a. Amide 13a was allowed to react
15
according to a literature procedure
to afford com-
pound 14a (96%) as a white solid: mp229–231 ꢁC;
20
4.1.15. (S,4Rp,13Sp)-4-(4-Benzyl-oxazolin-2-yl)-13-(a,a-
dimethylhydroxymethyl)[2.2]paracyclophane 11. Com-
pound (S,4Sp,13Rp)-2c was allowed to react according
to the procedure for 5a to afford 11 (78%) as a white so-
½aŠ ¼ þ31:3 (c 0.49, CHCl3); 1H NMR (CDCl3,
D
300MHz) d 2.94–3.10 (m, 6H), 3.51–3,61 (m, 1H),
4.03–4.10 (m, 2H), 4.34–4.55 (m, 3H), 6.52–6.66 (m,
5H), 7.25 (d, J=1.5Hz, 1H); 13C NMR (CDCl3,
75MHz) 33.4, 34.4, 34.8, 35.1, 55.0, 66.4, 126.1, 126.5,
131.6, 133.0, 134.8, 135.0, 135.8, 135.9, 138.6, 139.0,
140.6, 141.1, 164.5; MS (EI) m/z (rel) 357(M++2),
355(M+); IR (KBr) 2929, 1635, 1587, 1478cmꢀ1; Anal.
Calcd for C19H18BrNO: C, 64.06; H, 5.09; N, 3.93.
Found: C, 63.98; H, 5.07; N, 3.73.
lid (except for being quenched with acetone): mp 147ꢁC;
20
½aŠ ¼ þ16:2 (c 0.31, CHCl3); 1H NMR (CDCl3,
D
300MHz) d 1.16 (s, 3H), 1.50 (s, 3H), 2.71–3.24 (m,
7H), 3.33 (dd, J=13.8, 5.2Hz, 1H), 3.88–4.00 (m, 1H),
4.04 (t, J=7.5Hz, 1H), 4.14–4.39 (m, 2H), 4.60–4.70
(m, 1H), 5.80 (br, 1H), 6.33 (s, 1H), 6.48–6.54 (m,
2H), 6.65 (d, J=7.8Hz, 1H), 6.72 (dd, J=7.8, 1.8Hz,
1H), 6.89 (d, J=1.5Hz, 1H), 7.19–7.38 (m, 5H); 13C
NMR (CDCl3, 75MHz) 29.9, 33.2, 33.8, 34.7, 35.0,
36.7, 41.6, 67.8, 70.9, 72.2, 125.6, 126.5, 127.8, 128.5,
129.2, 130.8, 132.0, 135.0, 136.4, 137.3, 137.5, 137.7,
138.8, 139.3, 141.5, 145.7, 165.7; MS (EI) m/z (rel) 425
(M+); IR (KBr) 3158, 2934, 1654, 1454cmꢀ1; Anal. Cal-
cd for C29H31NO2: C, 81.85; H, 7.34; N, 3.29. Found: C,
81.55; H, 7.47; N, 3.04.
4.1.20. (4Sp,13Rp)-4-Bromo-13-(4,4-dimethyl-oxazolin-
2-yl)[2.2]paracyclophane 14b. Amide 13b was allowed
16
to react according to a literature procedure to afford
14b (93%) as
a
white solid: mp155–156 ꢁC;
20
D
½aŠ ¼ þ41:1 (c 0.55, CHCl3); 1H NMR (CDCl3,
300MHz) d 1.37 (s, 3H), 1.43 (s, 3H), 2.95–3.10 (m,
6H), 3.49–3.57 (m, 1H), 4.12 (dd, J=18.6, 7.9Hz, 2H),
4.41–4.51 (m, 1H), 6.53–6.57 (m, 3H), 6.60 (dd, J=7.8,
1.8Hz, 1H), 6.64 (s, 1H), 7.23(d, J=1.2Hz, 1H); 13C
NMR (CDCl3, 75MHz) 28.0, 28.3, 32.7, 34.5, 34.8,
35.7, 67.5, 78.2, 126.9, 127.0, 131.3, 132.4, 134.7,
135.0, 135.9, 136.0, 138.5, 139.0, 140.4, 141.2, 162.0;
MS (EI) m/z (rel) 385 (M++2), 383 (M+); IR (KBr):
4.1.16. (4Sp,13Rp)-4-Bromo-13-carboxy[2.2]paracyclo-
phane 12. According to a literature procedure,13 enan-
tiomerically pure compound 12 (78%) was obtained as a
20
white solid: mp228–230 ꢁC; ½aŠ ¼ þ46 (c 0.105,
D
1
DMSO); H NMR (DMSO-d6, 600MHz) d 2.94–3.05
(m, 5H), 3.07–3.13 (m, 1H), 3.32–3.40 (m, 1H), 4.29–
4.34 (m, 1H), 6.60–6.62 (m, 2H), 6.65 (dd, J=7.8,
1.8Hz, 1H), 6.68 (d, J=7.8Hz, 1H), 6.75 (dd, J=7.8,
1.8Hz, 1H), 7.26 (d, J=1.2Hz, 1H), 12.36 (br, 1H);
MS (EI) m/z (rel) 332 (M++2), 330 (M+); IR (KBr):
2934, 1673, 1587cmꢀ1; Anal. Calcd for C17H15BrO2:
C, 61.65; H, 4.56. Found: C, 61.55; H, 4.49.
2972, 2931, 1640, 1588cmꢀ1
;
Anal. Calcd for
C21H22BrNO2: C, 65.63; H, 5.77; N, 3.64. Found: C,
65.80; H, 5.95; N, 3.42.
4.1.21.
(4Rp,13Sp)-4-(Oxazolin-2-yl)-13-(a,a-dimeth-
ylhydroxymethyl)[2.2]paracyclophane 15a. Compound
(4Sp,13Rp)-14a was allowed to react according to the
procedure for 5a to afford 15a (83%) as a white solid (ex-
cept for being quenched with acetone): mp 167–168ꢁC;
20
4.1.17. (4Sp,13Rp)-4-Bromo-N-(1-hydroxy-2-ethyl)[2.2]
paracyclophane-13-carboxamide 13a. Using a literature
procedure,14 amide 13a (96%) was achieved as a white
½aŠ ¼ ꢀ59:0 (c 0.395, CHCl3); 1H NMR (CDCl3,
D
300MHz) d 1.21 (s, 3H), 1.49 (s, 3H), 2.86–2.98 (m,
2H), 3.03–3.24 (m, 4H), 4.00–4.16 (m, 3H), 4.22–4.45
(m, 3H), 6.42 (s, 1H), 6.52 (s, 2H), 6.67 (d, J=7.8Hz,
1H), 6.74 (dd, J=7.2, 1.8Hz, 1H), 6.93 (d, J=1.5Hz,
1H); 13C NMR (CDCl3, 75MHz) 30.5, 33.6, 33.7,
35.1, 35.3, 36.7, 54.7, 67.1, 72.3, 126.2, 128.1, 131.2,
132.2, 135.3, 136.4, 137.4, 137.9, 139.0, 139.6, 141.4,
146.0, 166.8; MS (EI) m/z (rel) 335 (M+); IR (KBr)
3166, 2932, 1648cmꢀ1; Anal. Calcd for C22H25NO2: C,
78.77; H, 7.51; N, 4.18. Found: C, 78.42; H, 7.77; N,
3.87.
20
1
solid: mp170–172 ꢁC; ½aŠ ¼ ꢀ22:7 (c 0.5, CHCl3); H
D
NMR (CDCl3, 300MHz) d 2.51 (br, 1H), 2.83–3.17
(m, 6H), 3.52–3.67 (m, 3H), 3.86 (t, J=4.9Hz, 2H),
3.99–4.09 (m, 1H), 6.53–6.63 (m, 5H), 7.08 (s, 1H);
MS (EI) m/z (rel) 375 (M++2), 373 (M+); IR (KBr)
3308, 2952, 2857, 1616, 1586, 1463cmꢀ1; Anal. Calcd
for C19H20BrNO2: C, 60.97; H, 5.39; N, 3.74. Found:
C, 60.67; H, 5.53; N, 3.47.
4.1.18. (4Sp,13Rp)-4-Bromo-N-(1-hydroxy-2-methyl-2-
propyl)[2.2]paracyclophane-13-carboxamide 13b. Using
4.1.22. (4Rp,13Sp)-4-(4,4-Dimethyl-oxazolin-2-yl)-13-(a,a-
a literature procedure,14 amide 13b (92%) was achieved
dimethylhydroxymethyl)[2.2]paracyclophane 15b.
Com-
20
D
as a white solid: mp200–200.5 ꢁC; ½aŠ ¼ þ32:4 (c
pound (4Sp,13Rp)-14b was allowed to react according to
the p rocedure for5a to afford 15b (85%) as a white solid
1
0.51, CHCl3); H NMR (CDCl3, 300MHz) d 1.37 (s,
3H), 1.48 (s, 3H), 2.83–3.20 (m, 6H), 3.55–3.62 (m,
1H), 3.71 (d, J=5.8Hz, 2H), 3.94–3.98 (m, 1H), 5.25–
5.29 (t, J=6.1Hz, 1H), 5.79 (br, 1H), 6.53–6.65 (m,
(except for being quenched with acetone): mp 99–100ꢁC;
20
½aŠ ¼ ꢀ41:4 (c 0.39, CHCl3); 1H NMR (CDCl3,
D
300MHz) d 1.19 (s, 3H), 1.42 (s, 3H), 1.48 (s, 3H), 1.53

2364
X.-W. Wu et al. / Tetrahedron: Asymmetry 15 (2004) 2357–2365
X. L. Chin. J. Org. Chem. 2003, 23, 906 (in Chinese); (c)
Gleiter, G.; Hopf, H. Modern Cyclophane Chemistry;
Wiley-VCH: Weinheim, 2004; (d) Rozenberg, V.; Sergeeva,
E.; Hopf, H. Cyclophanes as Templates in Stereoselective
Synthesis, Some examples of chiral cyclophanes as ligands
n asymmetric catalysis: (e) Pye, P. J.; Rossen, K.; Reamer,
R. A.; Tsou, N. N.; Volante, R. P.; Reider, P. J. J. Am.
Chem. Soc. 1997, 119, 6207; (f) Pye, P. J.; Rossen, K.;
Reamer, R. A.; Volante, R. P.; Reider, P. J. Tetrahedron
Lett. 1998, 39, 4441; (g) Belokon, Y.; Moscalenko, M.;
Ionnikov, N.; Yashkina, L.; Antonov, D.; Vorontsov, E.;
Rozenberg, V. Tetrahedron: Asymmetry 1997, 19, 3245; (h)
Vettte, A. H.; Berkessel, A. Tetrahedron Lett. 1998, 39,
1741; (i) Wo¨rsdo¨rfer, U.; Vo¨gtle, F.; Glorius, F.; Pfaltz, A.
J. Prakt. Chem. 1999, 341, 445; (j) Wo¨rsdo¨rfer, U.; Vo¨gtle,
F.; Niegtle, M.; Waletzke, M.; Grimme, S.; Glorius, F.;
(s, 3H), 2.84–2.98 (m, 2H), 3.00–3.24 (m, 4H), 3.95–4.06
(m, 3H), 4.28 (t, J=7.8Hz, 1H), 5.89 (br, 1H), 6.37 (s,
1H), 6.51–6.57 (m, 2H), 6.64 (d, J=8.1Hz, 1H), 6.72
(dd, J=8.1, 1.8Hz, 1H), 6.87 (s, 1H); MS (EI) m/z (rel)
363 (M+); IR (KBr): 3362, 2958, 1627cmꢀ1; Anal. Calcd
for C24H29NO2: C, 79.30; H, 8.04; N, 3.85. Found: C,
79.20; H, 8.07; N, 3.57.
4.2. General procedure for the catalytic asymmetric
addition of diethylzinc to various aldehydes
To a solution of the chiral N,O-[2.2]paracyclophane lig-
and (0.025mmol) in toluene (2.0mL) was added Et2Zn
(1.0mL, 1.1mmol, 1.1M in toluene) at room tempera-
ture. After 1.0h, the aldehyde (0.5mmol) was added at
the same temperature. After being stirred for an appro-
priate time, the reaction was quenched with 1M HCl.
The mixture was then extracted with dichloromethane
(2·10mL). The organic layer was washed with brine,
dried, and evaporated under reduced pressure to give
an oily residue. Purification of the residue by column
chromatography gave rise to the optically active alco-
hol. The enantiomeric excess was determined by HPLC
analysis using a Chiracel OD column. Configurations
were assigned by comparison of the sign of the specific
rotation of known compounds.
Pfaltz, A. Synthesis 1999, 4, 597; (k) Bolm, C.; Kuhn, T.
¨
Synlett 2000, 6, 899; (l) Rozenberg, V. I.; Antonov, D. Y.;
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Ikonnikov, N. S.; Belokon, Y. N. Tetrahedron: Asymmetry
2000, 11, 2683; (m) Burk, M. J.; Hems, W.; Herzberg, D.;
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4.3. General procedure for catalytic asymmetric addition
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A solution of Ni(acac)2 (3.2mg, 0.0125mmol) and the
chiral N,O-[2.2]paracyclophane ligand (0.05mmol) in
CH3CN (2mL) was stirred at 35ꢁC for 1h. The a,b-
unsaturated ketone (0.25mmol) was then added and
the resultant solution stirred for another 30min. After
cooling to ꢀ20ꢁC, ZnEt2 (0.5mL, 1M in hexane,
0.5mmol) was added and the resulting mixture stirred
at ꢀ20ꢁC for an appropriate time. The reaction was
quenched with 1M HCl. The mixture was extracted with
dichloromethane (2·10mL). The organic layer was
washed with brine, dried and evaporated under reduced
pressure to give an oily residue. Purification of the resi-
due by column chromatography gave rise to the desired
product. The enantiomeric excess was determined by
HPLC analysis using a Chiracel AD column. Configura-
tions were assigned by comparison of the sign of the spe-
cific rotation of known compounds.
4. Eliel, E. L.; Wilen, S. H. Stereochemistry Organic Chem-
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Acknowledgements
This research was financially supported by the National
Natural Science Foundation of China, the Major Basic
Research
Development
Program
(Grant
No
G2000077506), National Outstanding Youth Fund, Chi-
nese Academy of Sciences and Shanghai Committee of
Science and Technology.
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