Solid-phase supported chiral lithium amides used in deprotonation reactions

Article abstract of DOI:10.1016/S0957-4166(03)00280-5

The lithium salt of polymer supported phenylethyl amine showed surprisingly high enantioselectivity in the asymmetric deprotonation reaction of cyclohexene oxide. The polymer supported chiral lithium amide base also proved to be more reactive compared to the free chiral lithium amide base. This is a new insight in the development and mechanism of chiral lithium amide bases used in asymmetric reactions.

Full text of DOI:10.1016/S0957-4166(03)00280-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1261–1266
Solid-phase supported chiral lithium amides used in
deprotonation reactions
a,
b
b,
Anna Johansson, * Peter Abrahamsson and Ojvind Davidsson *
8
a
Dept. of Organic Chemistry, G o¨ teborg University, Kemiv a¨ gen 10, SE-412 96 G o¨ teborg, Sweden
b
Medicinal Chemistry, AstraZeneca, SE-431 83 M o¨ lndal, Sweden
Received 22 November 2002; accepted 12 March 2003
Abstract—The lithium salt of polymer supported phenylethyl amine showed surprisingly high enantioselectivity in the asymmetric
deprotonation reaction of cyclohexene oxide. The polymer supported chiral lithium amide base also proved to be more reactive
compared to the free chiral lithium amide base. This is a new insight in the development and mechanism of chiral lithium amide
bases used in asymmetric reactions. © 2003 Published by Elsevier Science Ltd.
1
. Introduction
lel synthesis where normal extraction procedures are
not possible. In solid supported case only a filtration
and wash is necessary which gives higher flexibility if
the asymmetric deprotonation is a part of a multistep
synthesis performed on for instance a Bohadan
miniblock. Furthermore, the possibility of recycling the
chiral amine base could be a large benefit when using
amines that are not commercially available and have
been synthesized. Two earlier reports have shown that
chiral lithium and magnesium amide bases attached to
a solid support can be used in enantioselective deproto-
Over the last few decades methods for using chiral
lithium amides in organic transformations such as
deprotonation reactions of conformationally locked
prochiral cyclic ketones, asymmetric deprotonation
reactions of epoxides to allylic alcohols, aromatic and
1
2
6
benzylic functionalization of tricarbonyl(h -arene)-
3
chromium complexes has been developed. The devel-
opment of new chiral bases to be used as ligands in
deprotonation reactions has been intense. Deprotona-
tion reactions can also be performed by using sub-stoi-
chiometric amounts of chiral bases together with bulk
bases. One disadvantage with several of these chiral
bases is that they are expensive, due to long and
complicated synthetic routes.
6
nation reactions. To the best of our knowledge there
exists only one paper describing the use of solid sup-
4
6a
ported chiral lithium amide bases. Recently, a method
using bulk bases on solid support and a catalytic
amount of chiral lithium amide was developed for
7
deprotonation of epoxides. This encouraged us to start
The stereoselectivity and especially the conversion in
the deprotonation reactions are highly dependent on
the aggregation of the lithium amides. It has been
shown that smaller aggregates react faster than larger
a study on the asymmetric deprotonation of prochiral
epoxides.
5
In this paper we will present the use of solid supported
chiral lithium amides used in asymmetric deprotonation
reaction of cyclohexene oxide 1 to give the allylic
alcohol 2-cyclohexene-1-ol 2 (Scheme 1).
ones.
To avoid complications from formation of several
diverse aggregates, and to promote small aggregates
one approach could be the utilization of solid sup-
ported chiral lithium amide bases. A polymer solid
supported chiral amide base also has the advantage that
it can be utilized in combinatorial chemistry and paral-
*
Corresponding author. Tel.: +46-31-772-3843; fax: +46-31-772-3840;
e-mail: annajo@organic.gu.se
Scheme 1.
0
957-4166/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0957-4166(03)00280-5

1
262
A. Johansson et al. / Tetrahedron: Asymmetry 14 (2003) 1261–1266
Scheme 2.
We have chosen two ligands on the polymer support,
phenylethylamine 3c and 1-phenyl-2-pyrrolidin-1-yl-
propylamine 4c, the latter is a derivate of methyl-(1-
phenyl-2-pyrrolidin-1-yl-propyl)-amine 4b a ligand with
reaction and coordination will be more accessible for
coordinating solvent and substrate.
We report herein that a surprisingly high enantiomeric
excess and an increase in reactivity in the deprotonation
reaction when using polymer supported phenylethyl
amine as ligand was obtained.
8,13
well known reaction properties.
The ligand 4b
exhibits one additional property to form internal coor-
dination with a lithium cation, an ability that the
polymer supported phenylethyl amine lacks (Scheme 2).
The reason for using a spacer of six carbons is to
increase the distance between the amine proton and the
polymer support to facilitate both the lithiation of the
amine and the deprotonation reaction: The site of
2. Results and discussion
By using equal amounts of the polymer supported
phenylethyl amine 3a and n-BuLi in the deprotonation
Table 1. The results from deprotonation of 1 in THF at
20°C

A. Johansson et al. / Tetrahedron: Asymmetry 14 (2003) 1261–1266
1263
reaction we observed an astonishing high increase of
the stereoselectivity (91% ee instead of 5.3% from the
lithium salt of phenylethyl amine 3c itself) (entries 1
and 5, Table 1).
ing in a reagent exhibiting low selectivity and reactivity.
However, in the polymer supported case we define only
one type of aggregate, the monomer, with only coordi-
nating solvent molecules. This is a reagent with high
accessibility for substrate, which will result in a high
selectivity and reactivity in the asymmetric deprotona-
tion reaction. These observations clearly support a
mechanistic pathway involving a monomeric activated
complex.
Polymer supported phenylethyl amine 3a is built from a
secondary amine while phenylethyl amine 3c itself is a
primary amine. To be able to compare 3a with a
secondary amine, phenylethyl amine was methylated to
3b and used together with n-BuLi in the deprotonation
reaction. An expected increase of the enantiomeric out-
come was observed, but still the results are far from the
results of the polymer supported ligand. Even when
comparing 3a with 3d, a secondary amine with a n-
hexyl chain which in a comparison can correspond to
the spacer in 3a, the increase in the stereoselectivity was
striking.
3. Conclusions
In summary, we have shown that a well studied and
commercial available chiral amine can be used as a
chiral lithium amide base, giving high enantiomeric
excess (91%) of the 2-cyclohexene-1-ol in the deproto-
nation reaction of cyclohexeneoxide, provided that it is
attached to a solid support. However, a chiral amine
designed to be used in solution with internal coordinat-
ing groups resulted, when attached to a solid support,
in a decrease of the enantiomeric excess from 93 to 70%
of the 2-cyclohexene-1-ol. This difference we attribute
to reduction of aggregation diversity and inhibition of
availability to substrate, respectively. Simple commer-
cial solid supported chiral amine bases show a potential
to be used in combinatorial chemistry and parallel
synthesis where extraction procedures of the free base is
not possible.
However, the polymer supported lithium salt of 1-
phenyl-2-pyrrolidin-1-yl-propylamine 4a did not show
the same stereoselectivity (70% ee) in the deprotonation
reaction as the free secondary amide 4b (93% ee). It
seems that the bidentate amide does not reach the high
ee observed for the non-polymer supported one.
Another interesting observation is that the yield doesn’t
seem to be affected using 3a compared to 3b. The
non-polymer supported bidentate ligand, 4b, resulted in
a higher yield compared to the polymer supported 4a.
The explanations for this might be found in the dynam-
ics of these species.
The loading of the polymer supported ligands was
measured by FMOC quantitation to 0.34 mmol/g for
3a and 0.27 mmol/g for 4a. This gives a total reaction
yield of 47 and 40%, respectively of the synthesis of 3a
and 4a, respectively.
Previous studies have shown that the bidentate chiral
lithium amide form, in coordinating solvents, a dimer
in solution in which the lithiums exhibit different
9
degrees of coordination. One of the lithiums is tetra-
coordinated and the other one is tri-coordinated. Coor-
dination of substrate is supposed to take place at the
9
tri-coordinated site. This tri-coordinated lithium lacks
4. Experimental
4.1. General
the coordination from internal coordinating groups
since it is only coordinated by two amide nitrogens and
one solvent molecule. In the solid supported case the
lithium has to have an internal coordination from the
pyrrolidine amine nitrogen and this might have a nega-
tive effect upon reactivity and selectivity. The amide
has to be a monomer in the solid supported case. Thus,
the conclusion to be drawn could be that reactions in
solution demand internal coordinating groups, limits
the number of different aggregates formed, and the
reactivity and the selectivity will be enhanced. In the
solid supported case this internal coordination might be
deleterious for the reaction. Previously we have shown
that chiral lithium amide bases possessing several inter-
nal coordination group result in inactive non selective
and sluggish reagents, due to lack of accessibility of the
Glassware and syringes were dried at 50°C in a vacuum
oven before transfer into a glove box (Mecaplex GB 80
equipped with a gas purification system removing oxy-
gen and moisture) containing a nitrogen atmosphere.
All dry solvents was distilled from sodium/benzophe-
none and stored under N . Chromatographic analyses
2
were carried out on a Varian Star 3400 CX gas chro-
matograph. All GC analyses were run on a chiral
stationary phase column (CP-Chirasil-DEX CB, 25 m,
0.32 mm) from Chrompack. All analyses were per-
formed at 135°C (injector: 225°C; detector: 250°C) with
He as carrier gas. All UV-analysis were performed on a
Varian Cary 100 Bio UV–vis spectrophotometer with a
Varian Cary Win UV Scan application at 301 nm.
NMR spectra were recorded using a Varian Unity 400
MHz spectrometer. IR spectra were recorded using a
Perkin–Elmer 1600 series FTIR.
1
0
substrate for the reagent. Furthermore, chiral lithium
amide bases with internal coordination potential gener-
ated from primary amines are well documented to have
1
1
low selectivity.
The chiral lithium amide bases lacking internal coordi-
nating groups show a very different behavior. In solu-
tion, these bases form several different types of
aggregates such as ladders, dimers, trimers, etc. result-
4.2. HRMS analysis
The samples were weighed, 0.5 mg of each compound,
dissolved and diluted to 1 ml with methanol. From

1
264
A. Johansson et al. / Tetrahedron: Asymmetry 14 (2003) 1261–1266
each solution an aliquot of 5 ml was injected on an
analytical column, Ace C18 3 mm, 150×3.0 mm. Sepa-
rated through a gradient (5–95% acetonitrile in 0.2%
formic acid, flow rate 0.5 ml/min, column oven temper-
ature 50°C) and detected by a diode-array detector
2.20 g, 2.35 ml) in dry THF (37 ml). The solution was
stirred over night. Methyl iodide (18.2 mmol, 2.63 g,
1.16 ml) in dry THF (23 ml) was added dropwise over
2 h. The solution was stirred for 8 h. The reaction was
quenched with ice cold brine (100 ml) and extracted
with diethyl ether (4×25 ml). The combined organic
(
190–350 nm) and a quadrupole time-of-flight mass
spectrometer (QTof micro, Micromass UK) operated in
electrospray ionization positive ion mode (capillary
voltage 3.0 kV, cone voltage 40 V, ion energy 10 eV,
mass range 80–1000 m/z, scan rate 1 s and inter scan
delay 0.1 s). The detector signals were monitored, eval-
uated and reported. To compensate for drifts in the
mass scale a reference solution with a known com-
pound was infused continuously, i.e. a lock mass. In
this case the lock mass was leucine enkephaline (m/z
phases were dried over Na SO . Evaporation in vacuo
2 4
gave a light yellow oil which was distilled (bp 86°C/20
mmHg) at reduced pressure using a vigreux to yield 3b
2
5
(
−
2.14 g, 87%) as a colorless oil (>99% NMR). [h] =
D
1
69 (c 1.25, CHCl ); H NMR (400 MHz, CDCl , 293
3
3
K): l 7.33 (2H, d, JHꢀH=5.6, Ph), l 7.30 (2H, d,
JHꢀH=5.6, Ph), l 7.23 (1H, t, JHꢀH=7.38, Ph), 4.08
ppm (1H, q, JHꢀH=5.22, PhCH
NH), 1.38 ppm (3H, s, CH
NMR (125 MHz, CDCl , 293 K): l 147.73 (Ph), l
6 ), 2.47 ppm (3H, dd,
13
JHꢀH=6.6, CH3
6
6
3CH);
C
5
56.2771 in positive ionization mode). The purity of
3
1
28.38 (Ph), l 128.11 (Ph), 126.82 (Ph), l 126.70 (Ph),
l 125.59 (Ph), l 76.95 (CH), l 43.21 (CH ), l 25.65
H ); IR: 3330, 2977–2771, 1599, 1491, 1448, 1371,
each sample was defined as the relative purity of the
total absorbance chromatogram between 190 and 350
nm. The accurate mass was calculated and compared to
the suggested elemental composition. The error was
reported in mDa. The instrument specification for cal-
culations of accurate mass is 5 ppm.
6
6
3
(C6
3
−
1
1
312, 1143, 1073, 1030, 948, 835, 759, 699 cm ;
+
HRMS: calcd for C H N 135.10408 found [M+H ]
9
13
1
36.1126, error −0.3.
4
.3.3. Synthesis of 3d. Phenylethyl amine (7.27 g, 60
4
4
.3. Synthesis
mmol) was dissolved in chloroform (50 ml) and 1-hex-
anal (120 mmol, 12.01 g) was added. The solution was
allowed to reflux with a heavier-than water trap over
night. The solvent was removed by evaporation in
vacuo and the imine was dissolved in ethanol (50 ml).
.3.1. Synthesis of polymer with a spacer. Transhalo-
genation: To a round-bottom flask Merrifield resin
®
(
0.84 mmol/g, 5 g, 4.2 mmol) was added. To the
polymer acetone (75 ml) and NaI (8.4 mmol, 1.25 g).
The reaction mixture was refluxed for 48 h. The solvent
was filtered off and the polymer was washed with DMF
NaBH (3.4 g, 90 mmol) was added and reaction mix-
4
ture was allowed to stand for 6 h at rt. The solvent was
removed evaporation in vacuo and water (20 ml) was
added. The aqueous phase was extracted three times
with dichloromethane and the collected organic phases
were washed with brine, dried over Na SO . Evapora-
(
3×30 ml).
Homologation: DMF (75 ml) was added to the polymer
and NaH (washed with hexane, 0.5 equiv., 2.1 mmol,
2
4
tion in vacuo gave a yellow oil which was distilled
0
.05 g) and 1,6-hexanediol (1.5 equiv., 0.75 g, 6.3
mmol) was added. The reaction mixture was heated at
0°C for 48 h. The solvent was filtered off and the
−3
(
110°C/7×10
mbar) at reduced pressure using a
vigreux to yield the amine 3d (9.85 g, 80%) as a
6
25
D
colorless oil (>99% NMR) [h] =−58 (c 3.0, CHCl );
3
polymer was washed with DMF (3×30 ml) and
dichloromethane (3×30 ml).
1
H NMR (400 MHz, CDCl , 293 K): l 7.21 (2H, d,
3
JHꢀH=5.0, Ph), l 7.12 (2H, d, JHꢀH=5.3, Ph), l 7.08
1H, t, JHꢀH=7.9, Ph), 4.05 ppm (1H, q, JHꢀH=6.47,
PhCH), 3.65 ppm (2H, t, JHꢀH=6.47, CH2NH), 2.21
ppm (2H, m, CH CH ), 1.31 ppm (3H, dd, JHꢀH=6.69,
(
Transhalogenation:
dichloromethane (75 ml) was added. Triphenylphos-
phine (1.2 equiv., 5 mmol, 1.31 g) imidazole (1.2 equiv.,
In
a
round-bottom
flask,
6
6
6
2
2
CH6 ), 1.18–1.33 ppm (6H, m, CH6 CH ), 0.83 ppm (3H,
3 2 2
13
5
mmol, 0.34 g), and iodine (1.2 equiv., 5 mmol, 1.3 g)
t, CH
6 3CH2); C NMR (125 MHz, CDCl , 293 K): l
3
and then finally the polymer was added and the reac-
1
47.73 (Ph), l 128.40 (Ph), l 128.30 (Ph), 126.70 (Ph),
tion was stirred at rt for 4 days according to published
procedures. The solvent was filtered off and the poly-
mer was washed with dichloromethane (3×30 ml).
l 126.67 (Ph), l 125.59 (Ph), l 77.25 (C
6
H), l 51.27
1
2
(
C
C
6
H ), l 46.6 (C
2
6
H ), l 32.5 (C
6
H ), l 32.2 (C
6
H ), l 27.4
3
2
2
6
2
(
6
H ), l 23.1 (C
6
H ), l 14.0 (C
H ); IR: 3370, 3020–
2
3
2
9
2
858, 1729, 1599, 1485, 1448, 1366, 1241, 1106, 1019,
−1
Amination: The polymer was washed with THF (3×30
ml) before THF (75 ml) was added. The chiral amine (4
equiv., 16.8 mmol) was added and the reaction was
allowed to reflux for 48 h. To the reaction mixture was
10, 856, 758, 699 cm ; HRMS: calcd for C H N
1
4
23
+
05.1830 found [M+H ] 206.1909, error 1.1.
4
.3.4. Synthesis of 4c. The synthesis was prepared as in
added Bu SnH (4.2 mmol, 1.22 g, 1.11 ml) and the
published procedures of (1R,2S)-N-methyl-1-phenyl-2-
pyrrolidinyl-propaneamine but instead of using methyl-
amine (30 ml, 240 mmol, 33% in ethanol), ammonia
(240 mmol, 25% in water, 18 ml) and no additional
3
mixture was then allowed to reflux for 48 h. The final
product was washed with THF, DMF, dichloro-
methane and DEE and was stored under N2.
13
water was added. The product was distilled (bp
4.3.2. Synthesis of 3b. To a round-bottom flask were
140°C/15 mmHg) at reduced pressure using a vigreux to
2
5
added NaH (0.782 g, 19.5 mmol, prewashed with dry
hexane) and dry THF (45 ml). To the round-bottom
flask was added (R)-phenylethyl amine (18.2 mmol,
yield 4c (60%) as a colorless oil (>99% NMR). [h] =
D
1
−30 (c 2.0, CHCl ); H NMR (400 MHz, CDCl , 293
3
3
K): l 7.30 (2H, d, JHꢀH=5.7, Ph), l 7.20 (2H, d,

A. Johansson et al. / Tetrahedron: Asymmetry 14 (2003) 1261–1266
1265
JHꢀH=5.7, Ph), l 7.12 (1H, t, JHꢀH=7.0, Ph), l 4.10
ppm (1H, d, JHꢀH=5.4, PhCHN), 2.50–2.57 ppm (4H,
m, NCH ), l 2.28 ppm (1H, m, CHN), 1.90 ppm (2H,
), 1.75–1.83 ppm (4H, m, CH2), 0.80 ppm (3H,
H3); C NMR (125 MHz, CDCl , 293
4.6. Typical deprotonation reaction of 1 with lithium
amides
6
6
6
2
br s, NH
6
6
These experiments were performed according to earlier
2
13
9
d, JHꢀH=6.0 C
K): l 148.82 (Ph), l 132.51 (Ph), l 132.27 (Ph), 130.30
Ph), l 130.12 (Ph), l 125.54 (Ph), l 77.62 (CHCH ), l
6
published procedures.
3
(
7
(
6
3
2.25 (C
6
HPh), l 51.39 (C
6
H ), l 51.37 (C
6
H ); l 45.12
2
2
Acknowledgements
C
6
H ), l 45.0 (C
2
6
H ) l 25.73 (C
2
6
H ); IR: 3380, 2969,
659, 1620, 1464, 1381, 1322, 1215, 1142, 1103, 1020,
3
1
9
−1
12, 732 cm ; HRMS: calcd for C H N 218.1783
1
4
22
2
Financial support from the natural Swedish science
research council is gratefully acknowledged. The
authors also thank Mr. Daniel Pettersen for fruitful
discussions.
+
found [M+H ] 219.1861, error 0.2.
4
.3.5. Synthesis of 4b. The amine was prepared as
13
previously described.
4
.4. FMOC quantitation
References
1
4
The quantitation was following published procedures.
1
. (a) Simpkins, N. S. Chem. Commun. 1986, 88; (b) Cain,
C. M.; Cousins, R. P. C.; Coumbarides, G.; Simpkins, N.
S. Tetrahedron 1990, 46, 523; (c) Koga, K. Pure Appl.
Chem. 1994, 66, 1487; (d) Shirai, R.; Tanaka, M.; Koga,
K. J. Am. Chem. Soc. 1986, 108, 543; (e) Shirai, R.; Sato,
D.; Aoki, K.; Tanaka, M.; Kawasaki, H.; Koga, K.
Tetrahedron 1997, 53, 5963; (f) Yamashita, T.; Sato, D.;
Kiyoto, T.; Kumar, A.; Koga, K. Tetrahedron Lett. 1996,
37, 8195; (g) Yamashita, T.; Sato, D.; Kiyoto, T.; Kumar,
A.; Koga, K. Tetrahedron 1997, 53, 16987.
2. (a) O’Brien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439;
(b) Hodgson, D. M.; Witherington, J.; Moloney, B. A.
Tetrahedron: Asymmetry 1994, 5, 337; (c) Hodgson, D.
M.; Witherington, J.; Moloney, B. A. Tetrahedron: Asym-
metry 1994, 4, 1649; (d) Hodgson, D. M.; Gibbs, A. R.;
Lee, G. P. Tetrahedron 1996, 52, 14361; (e) O’Brien, P.;
Poumellec, P. Tetrahedron Lett. 1996, 37, 8057; (f) Bigi,
A.; Mordini, A.; Thurner, A.; Faigl, F.; Poli, G.; Toke,
L. Tetrahedron: Asymmetry 1998, 9, 2293; (g) Whitesell,
J. K.; Felman, S. W. J. Org. Chem. 1980, 45, 755; (h)
Bhuniya, D.; DattaGupta, A.; Singh, V. K. J. Org. Chem.
Protection: To an ice cold slurry of the polystyrene
amino resin (0.5 g) and Na CO (10%, 10 ml), was
2
3
added a solution of FMOC–Cl (1 g, 3.9 mmol) in
dioxane (10 ml). The slurry was allowed to react for 2
h at rt. To the slurry water (200 ml) was added. The
water phase was washed with DEE (2×50 ml) and then
the water phase was acidified to pH 3 with conc. HCl.
The acidic phase was filtered of and the resin was
washed with water and ethyl acetate and allowed to dry
under reduced pressure. The protection of the amine
was repeated twice.
Deprotection: The FMOC amino resin (5 mg) was
weighed into a 10 ml volumetric flask. To the flask were
added piperidine (0.4 ml) and dichloromethane (0.4 ml).
The mixture was allowed to cleave for 30 min. Then
MeOH (1.6 ml) and dichloromethane (7.6 ml) were
added to bring the total volume up to 10 ml. The
spectrophotometer was zeroed with a blank solution
containing piperidine (0.4 ml), MeOH (1.6 ml) and
dichloromethane to make a total volume of 10 ml. The
absorbance was measured at 301 nm and the loading
level was given by following equation.
1
996, 61, 6108; (i) Hodgson, D. M.; Gibbs, A. R. Tetra-
hedron Lett. 1997, 38, 8907; (j) Tierny, J. P.; Alexakis, A.;
Mangeney, P. Tetrahedron: Asymmetry 1997, 8, 1019; (k)
S o¨ dergren, M. J.; Andersson, P. G. J. Am. Chem. Soc.
Loading (mmol/g)=A301×10 ml/7800×wt
(1)
1
998, 120, 10760; (l) S o¨ dergren, M. J.; Bertilsson, S. K.;
Where A301 is the absorbance at 301 nm, 7800 is the
extinction coefficient of the piperidine–fluorenone
adducts, and wt is the weight of resin used in mg.
Andersson, P. G. J. Am. Chem. Soc. 2000, 122, 6610; (m)
Milne, D.; Murphy, P. J. Chem. Commun. 1994, 675; (n)
Asami, M. J. Synth. Org. Chem. (Jpn) 1996, 54, 188; (o)
Asami, M.; Inoue, S. Tetrahedron 1995, 51, 11725; (p)
Asami, M.; Suga, T.; Honda, K.; Inoue, S. Tetrahedron
Lett. 1997, 38, 6425; (q) Cox, J. P.; Simpkins, S. M.
Tetrahedron: Asymmetry 1991, 2, 1; (r) Asami, M. Chem.
Lett. 1984, 829–832; (s) Pettersen, D.; Amedjkouh, M.;
Nilsson, L.; Sten, O.; Ahlberg, P. J. Chem. Soc., Perkin 2
2002, 1307.
4
.5. Typical example of deprotonation reaction of 1
with lithiated polystyrene amine resin
The polystyrene amine resin (1 g) was weighed into a
Schlenk-filter and dry THF (3 ml) was added. To the
filter n-BuLi (2.4 M, 3 ml) was added and allowed to
lithiate the amine. The solution was filtered off and the
resin was washed with dry THF (5×5 ml) to remove
unreacted n-BuLi. To the Schlenk-filter dry THF (3 ml)
and freshly distilled cyclohexene oxide (1) (10 ml, 0.1
mmol) was added. The conversion of 1 to 2 and the
enantiomeric outcome of the deprotonation reaction
were measured by chiral GC. (t (1)=4.10 min, t ((S)-
3. (a) Price, D. A.; Simpkins, N. S.; McLeod, A. M.; Watt,
A. P. J. Org. Chem. 1994, 59, 1961; (b) Ewin, R. A.;
Simpkins, N. S. Synlett 1996, 317; (c) Gibson, S. E.;
Potter, P. C. V.; Smith, M. H. Chem. Commun. 1996,
2757; (d) Gibson, S. E.; Ham, P.; Jefferson, G. R.; Smith,
M. H. J. Chem. Soc., Perkin Trans. 1 1997, 2161; (e)
Cowton, E. L. M.; Gibson, S. E.; Schneider, M. J.;
Smith, M. H. Chem. Commun. 1996, 839.
R
R
2
)=7.81 min, t ((R)-2)=8.15 min.
R

1
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A. Johansson et al. / Tetrahedron: Asymmetry 14 (2003) 1261–1266
4
. (a) Pettersen, D.; Amedjkouh, M.; Ahlberg, P. Tetra-
hedron 2002, 58, 4669; (b) Bertilsson, S. K.; S o¨ dergren,
M. J.; Andersson, P. G. J. Org. Chem. 2002, 67,
567.
4377.
10. See Ref. 2h; deSousa, S. E.; O’Brien, P.; Pilgram, C. D.
Tetrahedron 2002, 58, 4643–4654.
11. Johansson, A.; Pettersson, A.; Davidsson,
Organomet. Chem. 2000, 608, 153–163.
12. Lange, G. L.; Gottardo, C. Synth. Commun. 1990, 20,
1473–1479.
13. Pettersen, D.; Amedjkouh, M.; Nilsson Lill, S. O.;
Dahl e´ n, K.; Ahlberg, P. J. Chem. Soc., Perkin Trans. 2
2001, 1654–1661.
1
O
8
.
J.
5
6
. Schlosser, M. In Organometallics in Synthesis; Schlosser,
M., Ed. Organoalkali Reagents; John Wiley & Sons:
Chichester, 1994; p. 17.
. (a) Majewski, M.; Ulaczyk, A.; Wang, F. Tetrahedron
Lett 1999, 40, 8755–8758; (b) Henderson, K. W.; Kerr,
W. J.; Moir, J. H. Chem. Commun. 2001, 1722.
7
8
. Seki, A.; Asami, M. Tetrahedron 2002, 58, 4655.
. Colman, B.; deSousa, S. E.; O%Brien, P.; Towers, D. T.;
Watson, W. Tetrahedron: Asymmetry 1999, 10, 4175.
. Amedjkouh, M.; Pettersen, D.; Nilsson Lill, S. O.;
Davidsson, O.; Ahlberg, P. Chem. Eur. J. 2001, 7, 4368–
14. For FMOC-protection, see: Carpino, L. A.; Han, G. Y.
J. Org. Chem. 1972, 37, 3404–3409. For FMOC-deprotec-
tion and quantitation, see: Bunin, B. Combinatorial
Index; Cloth. Academic Press: London, 1997; pp. 219–
220.
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