2,2′-isopropylidenebis[(4R)-(1-adamantyl)-2-oxazoline] (Adam-Box). A new enantiopure C2-symmetrical ligand: Enantioselective cyclopropanations, Diels-Alder reactions, and allylic oxidations

Article abstract of DOI:10.1016/S0957-4166(02)00404-4

The title bisoxazoline (Box) featuring two adamantane skeletons (Adam-Box) is a ligand of (R,R)-configuration, which combined with copper sources makes excellent catalysts for enantioselective cyclopropanations, Diels-Alder reactions, and allylic oxidations.

Full text of DOI:10.1016/S0957-4166(02)00404-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1551–1554
2,2%-Isopropylidenebis[(4R)-(1-adamantyl)-2-oxazoline]
(Adam-Box). A new enantiopure C2-symmetrical ligand:
enantioselective cyclopropanations, Diels–Alder reactions, and
allylic oxidations
Jaume Clariana, Josep Comelles, Marcial Moreno-Man˜as* and Adelina Vallribera
Department of Chemistry, Universitat Auto`noma de Barcelona, Cerdanyola, 08193 Barcelona, Spain
Received 2 July 2002; accepted 16 July 2002
Abstract—The title bisoxazoline (Box) featuring two adamantane skeletons (Adam-Box) is a ligand of (R,R)-configuration, which
combined with copper sources makes excellent catalysts for enantioselective cyclopropanations, Diels–Alder reactions, and allylic
oxidations. © 2002 Published by Elsevier Science Ltd.
1. Introduction
We present herein some preliminary results on highly
enantioselective cyclopropanations,4 Diels–Alder reac-
tions,5,6 and allylic oxidations7 using (R,R)-Adam-Box,
5, as an ancilliary coordinating agent (Scheme 1).
(R,R)-Adam-Box, bearing bulky adamantyl groups,
allows access to highly pure enantiomers with the oppo-
site configuration compared to the ones normally
obtained in literature. The required (R)-2-(1-
adamantyl)-2-aminoethanol, 2, was prepared by enzy-
matic resolution.8 Reaction of 2 with dimethylmalonyl
Metal complexes of C2-symmetric enantiopure ligands
have gained a reputation as efficient chiral inductors. In
particular, bisoxazolines (Box) have found broad use
due to their versatility and easy preparation.1 Particular
attention has been drawn to Box ligands of general
formula 1 derived from malonic acid (Fig. 1). The
preparation of compounds 1 rely upon enantiomerically
pure amino alcohols, which in general derive from the
related amino acids.2 The easily accessible bis(oxazoli-
nes) have (S,S)-configuration at the stereogenic centers.
OH
X
X
H
N
H
N
Me
O
Me
O
R
NH2
(ClCO)2CMe2
The nitrogen atoms of 1 are excellent coordinating
centres for many metals and the resulting complexes are
useful in enantioselective reactions,3 such as cyclo-
propanations,1c Diels–Alder reactions,1c,e allylic oxida-
tions,1c,f,g and other processes.1c
Et3N, CH2Cl2
83%
Cl2SO,
toluene,
reflux
2
3, X = OH
4, X = Cl
R
R
94%
O
O
Me
N
Me
N
N
O
O
K2CO3, H2O
CH3CN, CH2Cl2
S
S
R'
R'
1
N
R
R
90%
Adam-Box
Figure 1. General formula of the Box ligands.
5
* Corresponding author. http://einstein.uab.es/mmorenom; e-mail:
marcial.moreno@uab.es
Scheme 1. Preparation of (R,R)-Adam-Box, 5.
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00404-4

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J. Clariana et al. / Tetrahedron: Asymmetry 13 (2002) 1551–1554
dichloride afforded diamide 3 (83%), which reacts with
purified thionyl chloride to afford dichlorodiamide 4 in
94% yield. The best conditions, giving high yields in the
cyclization step (90%), were achieved with K2CO3 in the
appropriate mixture of solvents as indicated.
for cyclopropane 9 (70% chemical yield) in the presence
of the catalytic system CuOTf-(R,R)-t-Bu-Box.4c
Next, we studied the cyclopropanation of styrene,
which delivered, in two different runs, mixtures 10/11 in
a 75:25 ratio and 56% chemical yield. The trans-(S,S)-
compound 10 had ee of 90 and 94% ([h]D=+298 (c
0.25, CH2Cl2). Evans reported 98% ee for the same
(S,S)-isomer ([h]D=+296, CHCl3) when using (R,R)-t-
Bu-Box,4c and 98% ee for the (R,R)-isomer ([h]D=−279
in chloroform for 96% ee) when using (S,S)-t-Bu-
Box.4d Although our ee values are slightly lower than
those achieved by Evans group, other authors reported
80%10 and 94% ee11 for (R,R)-10 when using (S,S)-t-
Bu-Box.
The results obtained in different enantioselective reac-
tions are shown in Scheme 2. Original protocols were
followed for all reactions in order to compare the new
(R,R)-Adam-Box with the very efficient (S,S)-t-Bu-
Box.
The cyclopropanation of 1,1-diphenylethene afforded
ethyl (S)-2,2-diphenylcyclopropanecarboxylate, 9, in
97.5, 97.5, and >98% enantiomeric excesses (ee) in three
independent reactions as determined by HPLC. The
product from one of the reactions was isolated in 75%
yield. The method used to prepare the catalyst was as
described by Mosset et al.9 Addition of molecular sieves
was essential for successful cyclopropanations. Sapon-
ification gave the corresponding acid which presented
[h]D=+163 (c 1.16, CH2Cl2) to confirm the (S)-configu-
ration.4c An ee value superior to 99% has been reported
The Diels–Alder reaction of N-acryloyloxazolidin-2-
one, 12, with cyclopentadiene was tested with (R,R)-
Adam-Box, 5, as well as with (S,S)-t-Bu-Box with
identical results. Thus, two reactions with 5 as chiral
auxiliary afforded a mixture of isomers in 66% chemical
yield with an endo/exo ratio of 92:8 (the exo-isomer is
not represented in Scheme 2). The endo-isomer 14 (with
(R,R,R)-configuration) had 98.3% ee in both determi-
nations. Two experiments using (S,S)-t-Bu-Box gave
the (S,S,S)-isomer (ent-14) in 97.8% ee and an endo/
exo ratio of 92:8. A ratio of 96:4 with >98% ee for
ent-14 has been reported.12 Our 14 showed [h]D=+146
(c 0.53, CH2Cl2) in agreement with literature values:
+172 in chloroform for 14,13 and −160 in chloroform
for ent-14.6b
Ph
CuOTf.1/2C6H6
(1%) / 5 (2%)
S
Ph
Ph
Ph
7
COOEt
9
+
CHCl3, MS
0ºC to room t
N2CHCOOEt
97.5, 97.5, and >98% ee
6
Finally, allylic oxidation of cyclopentene afforded 17
((R)-configuration) in 64, 76, and 82% ee in three
independent experiments. Pfaltz7a and Andrus7b
reported 74 and 84% ee at rt and at −20°C in CH3CN/
chloroform (3:1 v/v),7a and 70% ee at −20°C in acetoni-
trile.7b Both groups worked with (S,S)-t-Bu-Box to
afford ent-17 with (S)-configuration. Our benzoate 17
presented [h]D=+93 (c 0.30, CH2Cl2) (lit.14 [h]D=
−98.9, chloroform, for ent-17).
Ph
S
S
CuOTf.1/2C6H6
(1%) / 5 (2%)
COOEt
Ph
H
10
8
90 and 94% ee
+
CHCl3, MS
0ºC to room t
N2CHCOOEt
6
Ph
COOEt
11
O
O
2. Conclusions
R
Cu(SbF6)2
O
R
O
N
(10%), 5 (15%)
12
+
In conclusion, we have prepared (R,R)-Adam-Box, 5,
bearing the bulky adamantyl group, which is not com-
mon in chiral ligands.15 We have explored its enantiose-
lective induction properties in three model reactions
with excellent results. Under otherwise identical condi-
tions it behaves in the same way as (S,S)-t-Bu-Box but
affords enantiomeric final products.
R
N
O
O
H2CCl2
, -84ºC
14
98.3 and 98.3% ee
13
OCOPh
CuOTf.1/2C6H6
(5%) / 5 (7-8%)
3. Experimental
R
15
+
3.1. Preparation of N,N%-bis[(1R)-(1-adamantyl)-2-
CH3CN, -20ºC
hydroxyethyl]-2,2-dimethyl-1,3-propanodiamide, 3
17
PhC(O)-OOtBu
64, 76,
and 82% ee
Triethylamine (1 mL, 7.4 mmol) and dimethylmalonyl
dichloride (0.239 g, 1.41 mmol)16 in dichloromethane (4
mL) were sequentially added to a stirred, ice-cooled
solution of 2 (0.524 g, 2.69 mmol)8 in dichloromethane
16
Scheme 2. Enantioselective reactions.

J. Clariana et al. / Tetrahedron: Asymmetry 13 (2002) 1551–1554
1553
(12 mL). The mixture was stirred at rt for 2 h. Addi-
tional dichloromethane (15 mL) was added to dissolve
all solids. The solution was partitioned with 1 M HCl,
then with saturated aqueous sodium hydrogen carbon-
ate and finally with saturated aqueous sodium chloride.
The organic layer was dried and evaporated to afford 3
(83%) as a white solid, mp 210–212°C (ethyl acetate);
IR (KBr) 3366, 2899, 2847, 1656, 1645, 1551, 1519,
Analysis of 10 and 11: HPLC, Chiracel Daicel-OD
column, eluent hexane–isopropanol (99:1), flow rate 0.5
mL/min, trans 10, tr 11.48 min (R,R) isomer, tr 15.88
min (S,S) isomer. Under these conditions cis isomer 11
could not be resolved.
Analysis of 14: HPLC, Chiracel Daicel-OD column,
eluent hexane–isopropanol (95:5), flow rate 0.8 mL/
min, tr 39.0 min ((S,S,S)-isomer), tr 42.0 ((R,R,R)-iso-
mer). Under these conditions exo isomer could not be
resolved.
1
1463, 1170, 1065 cm−1; H NMR (250 MHz, CDCl3) l
1.53–1.73 (complex absorption, 30H, 24 from adaman-
tane+2×CH3), 1.97 (apparent s, 6H from adamantane),
3.48 (dd, J=9.0 and 11.2 Hz, 2H, H
2H, CHN), 3.87 (dd, J=11.2 and 3.3 Hz, 2H,
HCHOH), 6.42 (d, J=9.7 Hz, 2H, NH
); 13C NMR
6 -CHOH), 3.71 (m,
6
Analysis of 17: HPLC, Chiracel Daicel-OD column,
eluent hexane–isopropanol (99.9:0.1), flow rate 0.5 mL/
min, tr ((S)-isomer): 17.6 min, tr ((R)-isomer): 20.5 min.
6
6
(62.5 MHz, CDCl3) l 23.8, 28.2, 35.5, 36.9, 39.1, 50.4,
60.0, 61.5, 174.0; [h]D=−36 (c 0.55, dichloromethane).
3.2. Preparation of N,N%-bis[(1R)-(1-adamantyl)-2-
chloroethyl]-2,2-dimethyl-1,3-propanodiamide, 4
Acknowledgements
Purified thionyl chloride (2.1 mL)17 was added to a
stirred solution of 3 (0.574 g, 1.18 mmol) in anhydrous
toluene (22 mL). The solution was heated under reflux
for 24 h, and volatile products were evaporated. The
solid residue was digested with pentane to afford 4
(94%) as a white solid, mp 149–151°C (toluene), IR
(KBr) 3333, 2904, 2849, 1645, 1522, 1446, 1255 cm−1;
1H NMR (250 MHz, CDCl3) l 1.69–1.75 (complex
absorption, 30H, 24H from adamantane+2×CH3), 1.99
(apparent s, 6H from adamantane), 3.55 (dd, J=9.2
Financial support from DGYCYT and DGES (MEC
of Spain) (Project PB98-0092) and CIRIT (Generalitat
de
Catalunya,
projects
2000SGR-0062
and
2001SGR0181) is gratefully acknowledged. We are
indebted to Professor Vicente Gotor (University of
Oviedo) for sharing his technology to resolve racemic 2
with us.
References
and 11.3 Hz, 2H, H
Hz, 2H, HCHCl), 4.00 (m, 2H, CH
Hz, 2H, NH
); 13C NMR (62.5 MHz, CDCl3) l 24.6,
6
-CHCl), 3.85 (dd, J=11.3 and 3.5
6
6
N), 6.73 (d, J=10.2
1. For reviews partially or totally dedicated to bisoxazoli-
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6
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3.3. Preparation of 2,2%-isopropylidenebis[(4R)-(1-
adamantyl)-2-oxazoline] (Adam-Box, 5)
To dichlorodiamide 7 (0.580 g, 1.11 mmol) in a mixture
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was added potassium carbonate (9.70 g, 70.3 mmol) in
water (30 mL). The mixture was heated under reflux
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1
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from adamantane), 3.70 (dd, J=7.1 and 9.6 Hz, 2H,
CH6 N), 4.17 (m, 4H, CH6
2O); 13C NMR (62.5 MHz,
CDCl3) l 24.5, 28.2, 35.6, 37.2, 38.3, 67.5, 75.4, 168.0;
[h]D=+116.4 (c 0.55, dichloromethane); HRMS calcd
for C29H42N2O2 450.324629, found 450.326159.
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eluent hexane–isopropanol (99.5:0.5), flow rate 0.5 mL/
min, tr (R)-isomer): 23.18 min, tr ((S)-isomer): 26.19
min.

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17. Purified by destillation from quinoline and linseed oil
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