Chemistry of sulfones: Synthesis of a new chiral nucleophilic catalyst

Article abstract of DOI:10.1016/j.tetasy.2005.08.009

A chiral pyrrolidinopyridine was synthesized by using Buchwald methodology. The sulfone was used to add a benzyl group, which positioned a phenyl near the reacting position.

Full text of DOI:10.1016/j.tetasy.2005.08.009

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2980–2985
Chemistry of sulfones: synthesis of a new chiral nucleophilic catalyst
a,
a
a
a
a
David Dıez, * Maria J. Gil, Rosalina F. Moro, Narciso M. Garrido, Isidro S. Marcos,
´
Pilar Basabe,a Francisca Sanz,b Howard B. Broughtonc and Julio G. Uronesa
aDpto. de Quı´mica Orga´nica, Facultad de Ciencias Quimicas, Universidad de Salamanca, 37008 Salamanca, Spain
bServicio de Rayos X, Facultad de Ciencias Quı´micas, Universidad de Salamanca, 37008 Salamanca, Spain
cLilly, S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain
Received 26 July 2005; accepted 1 August 2005
Abstract—A chiral pyrrolidinopyridine was synthesized by using Buchwald methodology. The sulfone was used to add a benzyl
group, which positioned a phenyl near the reacting position.
ꢀ 2005 Elsevier Ltd. All rights reserved.
4
1. Introduction
by Fuet al. and III is FujiÕs chiral PPY derivative,
which has been used in the non-enzymatic kinetic
resolution of racemic alcohols through an Ôinduced fitÕ
process.5 Recently, Vedejs et al. described compound
IV for acyl transfer,6 while Connon et al.7 reported V
for the kinetic resolution of sec-alcohols. Other ana-
logues of PPY have been reported by Spivey et al.8
and Kotsuki et al.,9 and have been used as chiral nucle-
ophilic catalysts. Recently, we described the synthesis of
pyrrolidine 4 (Fig. 2) starting from epoxide 1, through
the vinylsulfone 3.10 We also reported a facile procedure
for the synthesis of compound 3, starting from 2,3-O-
iso-propylidene-D-erythronolactol 2, on a large scale.11
Compounds such as 4-(dimethylamino)pyridine
(DMAP)1 and 4-(pyrrolidino)-pyridine (PPY) are potent
nucleophilic acylation catalysts, which have been well
known for a long period of time.1 In recent years, there
has been an enormous effort to develop compounds that
could be used as catalysts for enantioselective acyl trans-
fer reactions.2 Some of the resulting derivatives are
shown in Figure 1.
I is an axially chiral DMAP variant developed by Spivey
et al.,3 II is the planar chiral DMAP analogue reported
H
Me2N
Ph
NEt2
OH
N
N
Ph
H
Fe
Ph
Ph
Ph
N
N
Ph
II
I
III
N
N
H
N
N
N
N
N
N
O
R
OR
OR
OR
CAr3
OAc
N
IV
V
VI
VII
Figure 1.
*
Corresponding author. Tel.: +34 923 294474; fax: +34 923 294574; e-mail: ddm@usal.es
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.009

D. Dı´ez et al. / Tetrahedron: Asymmetry 16 (2005) 2980–2985
2981
O
SO2Ph
HO
(-) 1
O
O
O
O
SO2Ph
O
O
N
TsO
4
3
Bn
SO2Ph
OH
O
2
Figure 2.
Having access to gram quantities of vinylsulfone 3 and
pyrrolidine 4, we decided to use them in the synthesis
of PPY analogues (Fig. 2).
O
O
H
2´
N
1´´
O
O
2. Results and discussion
a
b
SO2Ph
H
4
SO2Ph
Initially, we decided to use the traditional methodology
of the displacement of a mesylate or tosylate. Thus,
compounds 5 and 6 were synthesized as previously
described by starting from L-(+)-DET.12 Pyrrolidine
formation took place in low yield in both cases, but
permitted us to have enough compound to test com-
pound 7 as a nucleophilic catalyst (Scheme 1).
N
N
H
9
8
Scheme 2. Reagents and conditions: (a) H2, Pd/C, MeOH, 95%; (b) 4-
bromopyridine, Pd2(dba)3, Cs2CO3, BINAP, toluene, 80 ꢁC, 2 days
60%.
In order to extend the influence of the chirality in the
molecule, to the catalytically active centre, we decided
to exploit the reactivity of the sulfone and introduce a
benzyl group, using the usual conditions. Due to the
nucleophilicity of the pyridine nitrogen, it was necessary
to use a less than stoichiometric quantity of the electro-
phile (Scheme 3). When 1.2 equiv of the benzyl bromide
was used, compound 10 was obtained in reasonable
yield, whereas when only 0.5 equiv of benzyl bromide
was employed, compound 11 could be isolated in a
40% yield (Scheme 3). Compound 11 can be trans-
formed into 10 in excellent yield, by treatment with
1 equiv of benzyl bromide.
BnO
TsOH2C
BnO
OBn
BnO
OBn
a
CH2OTs
OBn
5
N
N
b
7
MsOH2C
CH2OMs
6
Scheme 1. Reagents and conditions: (a) 4-Aminopyridine, NaH, THF,
reflux, 10%; (b) 4-aminopyridine, NaH, THF, reflux, 20%.
In a previous paper, we described a simple way of obtain-
ing pyrrolidine 4 from vinyl sulfones 3, using benzyl-
amine in refluxing methanol.10,11 In contrast, all
attempts to use this methodology with 4-aminopyridine
and vinylsulfone 3 failed to give any of the desired prod-
uct. Therefore, we decided to use the coupling of a pyr-
rolidine to a pyridine. Sulfone 4 was deprotected under
the usual conditions to give pyrrolidine 8 in 95% yield.
Coupling of this sulfone with 4-chloropyridine in the
presence of caesium carbonate in DMF,13 or under a
number of other conditions,14 also failed to produce
the PPY analogue we sought. Finally, we turned our
attention to the use of coupling with a palladium catalyst
under Buchwald conditions.14 When pyrrolidine 8 was
treated with 4-bromopyridine in the presence of a palla-
dium catalyst, pyrrolidinopyridine 9 was obtained in 60%
yield. Compound 9 was expected to behave as a nucleo-
philic catalyst, although the stereogenic centre is not near
the active one and therefore would not be expected to
produce much asymmetric induction (Scheme 2).
O
O
O
O
H
H
SO2Ph
H
SO2Ph
H
2´
N
N
1´´
b
a
2´´
9
+
c
Br- N
N
Bn
10
11
Scheme 3. Reagents and conditions: (a) (1) n-BuLi, THF, À78 ꢁC, (2)
BnBr 1.2 equiv, THF, 50%; (b) (1) n-BuLi, THF, À78 ꢁC, (2) BnBr
0.5 equiv, THF, 40%; (c) BnBr 1.0 equiv, THF, rt, 90%.
NMR studies indicated that a change in the stereochem-
istry of C-20 had occurred. In order to corroborate this,
compound 10 was crystallized in hexane/CHCl3, 1/9,
meaning that its structure could be established by

2982
D. Dı´ez et al. / Tetrahedron: Asymmetry 16 (2005) 2980–2985
X-ray crystallography.15 An ORTEP view of this com-
pound as observed in the crystal structure is shown in
Figure 3, with 3/2 molecules of CHCl3 omitted for clar-
ity. As can be seen, there is a change in the configuration
at C-20 of the pyrrolidine.
10 and 11. Even allowing for solvent effects and errors in
the forcefield, it seems unlikely that the small calculated
preference in favour of the (S)-stereochemistry would be
converted into a decisive preference for the observed
(R)-product. Therefore, we studied all four possible dia-
stereomers of 11, taking into account the stereogenic
centres C-20 and C-100 and using the same methodology
as before. Compound 11, with (R,R)-stereochemistry at
C-20 and at C-100, was only the second lowest in energy
(418.5 kJ/mol for the lowest-energy conformer found),
with the (S,S)-stereoisomer 8.5 kJ/mol lower in energy
in its lowest-energy conformation. However, it is worth
noting that within a 50 kJ/mol ÔwindowÕ above the low-
est-energy conformation found, 30 conformations of 11
were found compared to only 6 for the (S,S)-stereoiso-
mer, consistent with a far more cluttered environment
for the entire C-20 substituent in the latter compound.
We therefore consider it likely that the stereocontrol in
this reaction is produced principally by a kinetic effect,
in which the more exposed (R)-enantiomer at C-20, once
formed by the ring-opening and ring-closing sequence,
is rapidly quenched from the less hindered face of the
anion to give (R,R)-product 11.
Figure 3. ORTEP view of 10.
The kinetic resolution of 7, 9 and 11 was briefly tested
using 1-phenylethanol, with the results shown in Table 1.
This inversion of stereochemistry can be explained by
the opening and re-closing of the pyrrolidine ring, but
it was not immediately clear whether the stereochemical
control observed was due to thermodynamic or kinetic
effects, or both. As a result, we built a model of the
two stereoisomers of 9 (using maestro v.7.0.113) and
carried out a conformational exploration using the
mixed torsional search with low mode sampling avail-
able in macromodel v.9.0.016 with the MMFF94s force-
The modest enantiomeric excess obtained for 11 is con-
sistent with the lowest-energy conformation found for it
(Fig. 4), which is representative of the low-energy con-
formations as a whole, with the benzyl group below
the pyridine ring, but still somewhat distant from the
catalytic centre. Nonetheless, we believe that our results
are encouraging and that it will be possible, by appropri-
ate modifications to this structure (such as using larger
aromatic rings than phenyl), to achieve higher enantio-
meric excesses.
field and
a limit of 5000 iterations of TNCG
minimization, with all other parameters set to default
values. Under these conditions, 9 appeared slightly more
stable than its epimer at C-20 (361.1 vs 369.0 kJ/mol). In
view of the availability of the oxygen atoms of the
dioxolane ring on the top face of the molecule, it seems
likely that many of the possible anionic species would
also be expected to show a preference of the stereochem-
istry at C-20 of 9 rather than that found in the products
3. Conclusion
Herein, we have reported the synthesis of a new pyrroli-
dinopyridine chiral catalyst that opens the way for a new
series of nucleophilic catalysts.
Table 1. Kinetic resolution of 1-phenylethanol using different catalysts
OH
OH
R
OAc
S
Ac2O (0.75 equiv)
Et3N (0.75 equiv)
+
catalyst ( 2 mol%)
THF, -78ºC
Catalyst
T/min
Ca (%)
(R)-Al eeb (%)
(S)-Ac eec (%)
s
(+)-7
(+)-7
(+)-9
(+)-9
(+)-11
(+)-11
120
520
120
520
120
520
57.0
62.0
8.6
21.3
28.0
40.0
0.8
1.8
6.9
4.1
1.2
2.5
18.0
22.0
23.0
16.0
18.0
12.0
1.77
2.14
1.63
1.44
1.54
1.37
a Conversion by (HPLC) mass balance.
b By using HPLC using a Chiralcel OD column.
c (R)-Alcohol and (S)-acetate obtained as major enantiomers.

D. Dı´ez et al. / Tetrahedron: Asymmetry 16 (2005) 2980–2985
2983
m, Ar), 4.45 (4H, d, J = 11.4 Hz, 2CH2-Ph), 3.95–4.12
(4H, m, 2CH2-O), 3.62–3.78 (2H, m, 2CH-O), 2.43
(6H, s, CH3-Ph-SO2); 13C NMR (CDCl3, 50.3 MHz):
144.9 (Tos-meta), 137.4 (2C-ipso), 130.2 (Tos-ipso),
130.2 (Tos-ortho), 128.7 (4CH-meta), 128.3 (4CH-
ortho), 127.9 (2CH-para), 75.6 (CH-2 and CH-3), 73.5
(2Ph-CH2O), 68.8 (CH2-1 and CH2-4), 21.9 (2CH3);
EIMS m/z (%) 610 (M++1, 100), 154 (55), 136 (50),
107 (25), 80 (45), HRMS (EI) m/z calcd for
C32H34O8S2 610.7246, found 610.7396 (M++1).
4.1.2.
sulfonyloxy)butane, 6. To
(2S,3S)-2,3-Bis(phenylmethoxy)-1,4-bis(methyl-
solution of 500 mg
a
(1.65 mmol) of (2S,3S)-2,3-bis(phenylmethoxy)-1,4-
butanediol in 8 mL of CH2Cl2 was added 0.91 mL
(6.60 mmol) of Et3N. After this, 4.95 mL (0.38 mmol)
of MsCl was added dropwise at 0 ꢁC. The reaction
mixture was stirred for 1 h and then diluted with H2O
and extracted with CH2Cl2. The combined organic
extracts were washed with H2O and dried over Na2SO4.
Figure 4.
After concentration and chromatography (n-hexane–
20
EtOAc, 8:2) gave 6 (603 mg, 85%). ½aŠ ¼ þ17.9
D
4. Experimental
(c 0.5, CHCl3), IR (film) m (cmÀ1): 2934, 2849, 1453,
1360, 1174, 1054, 808; 1H NMR (CDCl3, 200 MHz)
d (ppm): 7.32 (10H, m, Ar), 4.45 (4H, d, J = 11.2 Hz,
2CH2-Ph), 4.21–4.42 (4H, m, 2CH2-O), 3.78–3.85
(2H, m, 2CH-O), 2.93 (6H, s, 2CH3-SO2); 13C NMR
(CDCl3, 50.3 MHz): 137.3 (2C-ipso), 128.8 (4CH-meta),
128.5 (4CH-ortho), 127.9 (2CH-para), 75.9 (CH-2
and CH-3), 73.6 (2Ph-CH2O), 68.4 (CH2-1 and
CH2-4), 37.6 (2CH3-SO2); EIMS m/z (%) 458 (M++1,
100), 154 (55), 126 (50), 90 (25), 80 (45), HRMS (EI)
m/z calcd for C20H26O8S2 458.1103, found 458.1069
(M++1).
4.1. General
Unless otherwise stated, all chemicals were purchased in
the highest purity commercially available and used with-
out further purification. Melting points were determined
with a Kofler hot stage melting point apparatus and are
uncorrected. IR spectra were recorded on a BOMEM
1
100 FT IR spectrophotometer. H and 13C NMR spec-
tra were performed in deuterochloroform and refer-
enced to the residual peak of CHCl3 at d 7.26 ppm
and d 77.0 ppm, for 1H and 13C, respectively, in a
Bruker WP-200 SY and a BRUKER DRX 400 MHz.
Chemical shifts are reported in d, parts per million
and coupling constants (J) given in Hertz. MS were
performed in a VG-TS 250 spectrometer at 70 eV
ionizing voltage. Mass spectra are presented as m/z
(% rel. int.). HRMS were recorded in a VG Platform
spectrometer using electronic impact (EI) or fast atom
bombardment (FAB) technique. Optical rotations were
determined in a Perkin–Elmer 241 polarimeter in 1 dm
cells. Diethyl ether, THF and benzene were distilled
from sodium, and pyridine and dichloromethane were
distilled under argon from CaH2.
4.1.3. (30S,40S)-4-[(30,40)-Bis(benzyloxy)pyrrolidin-10-yl]-
pyridine, 7. A solution of 280 mg (2.98 mmol) of 4-
aminopyridine in 18 mL of THF was added dropwise
to a suspension of 238 mg (5.96 mmol) of NaH, which
had been previously washed with n-hexane. The reaction
mixture was stirred for 3 h and 4-aminopyridine was
deprotonated, after which 908 mg (1.49 mmol) of tosyl-
ate 5 was added and the reaction mixture then heated
under reflux for 3 days. The excess hydride was
destroyed by the slow addition of 3 mL of NH4OH
(1 M). The reaction was extracted with CH2Cl2. The
combined organic extracts were washed with H2O, brine
and dried over Na2SO4. After concentration and
4.1.1. (2S,3S)-2,3-Bis(phenylmethoxy)-1,4-bis[[(4-methyl-
phenyl)sulfonyl]oxy]butane, 5. To a stirred solution of
500 mg (1.65 mmol) of (2S,3S)-2,3-bis(phenylmeth-
oxy)-1,4-butanediol in 8 mL of pyridine at À5 ꢁC was
added 943 mg (4.95 mmol) of tosyl chloride in one
portion. After all the chloride had dissolved, the reac-
tion mixture was allowed to stand at 0 ꢁC for 15 h.
The reaction mixture was then diluted with H2O and
extracted with CH2Cl2. The combined organic extracts
were washed with 1 M HCl and saturated NaCl
and then dried over Na2SO4. Concentration followed
chromatography (CH2Cl2–MeOH 9:1), 57 mg of 7
20
(10%) was obtained. ½aŠ ¼ þ8.9 (c 1.2, CHCl3),
D
IR (film) m (cmÀ1): 2913, 1875, 1615, 1561, 1462, 1107;
1H NMR (CDCl3, 200 MHz) d (ppm): 8.19 (2H, d,
J = 6.4 Hz, H-1 py, H-5 py), 7.32 (10H, m, Ar), 6.42
(2H, d, J = 6.4 Hz, H-2 py, H-4 py), 4.58 (4H, s,
2CH2-Ph), 4.21 (2H, d, J = 4.0 Hz, 2CH-O), 3.60 (2H,
dd, J = 11.8 Hz and J = 4.0 Hz, 2CH2-N, HA), 3.44
(2H, d, J = 11.8 Hz, 2CH2-N, HB); 13C NMR (CDCl3,
50.3 MHz): 159.0 (C-py), 142.4 (CH-2 py and CH-4
py), 129.7 (2C-ipso), 128.9 (4CH-meta), 128.5 (4CH-
ortho), 128.1 (2CH-para), 109.1 (CH-1 py and CH-5
py), 79.8 (CH-2 and CH-3), 71.9 (2Ph-CH2O), 51.8
(CH2-1 and CH2-4); EIMS m/z (%) 360 (M++1, 100),
115 (52), 105 (48), 175 (29), 203 (34), 256 (32), 313 (9),
by chromatography (n-hexane–EtOAc, 8:2) gave 5 (908
20
mg, 90%). ½aŠ ¼ þ14.6 (c 0.3, CHCl3), IR (film) m
D
(cmÀ1): 3050, 2930, 1600, 1462, 1375, 1188, 1100, 938,
1
825; H NMR (CDCl3, 200 MHz) d (ppm): 7.27 (10H,

2984
D. Dı´ez et al. / Tetrahedron: Asymmetry 16 (2005) 2980–2985
371 (22). HRMS (EI) m/z calcd for C23H24O2N2
py and H-5 py), 4.85 (1H, m, H-4), 4.78 (1H, t,
J = 6.4 Hz, H-30), 4.45 (1H, dd, J = 6.4 Hz and
J = 8.5 Hz, H-20), 3.90 (1H, dd, J = 9.6 Hz and J =
14.3 Hz, H-10A0 ), 3.57 (1H, dd, J = 6.9 Hz and
J = 11.0 Hz, H-50A), 3.47 (1H, dd, J = 3.7 Hz and J =
11.0 Hz, H-50B), 3.33 (1H, d, J = 14.3 Hz, H-10B0 ), 1.49
(3H, s, acetonide), 1.31 (3H, s, acetonide); 13C NMR
(CDCl3, 50.3 MHz): 151.6 (C-py), 148.6 (CH-2 py and
CH-6 py), 139.5 (C-ipsoSO2Ph), 134.0 (CH-paraSO2Ph),
129.3 (2CH-metaSO2Ph), 128.2 (2CH-orthoSO2Ph),
113.1 (C-acetonide), 108.7 (CH-3 py and CH-5 py),
78.9 (CH-3), 77.6 (CH-4), 55.4 (CH-20), 53.3 (CH2-5),
52.8 (CH-100), 26.6 (CH3-acetonide), 25.0 (CH3-aceto-
nide); EIMS m/z (%) 374 (M++1, 100), 154 (98), 375
(39), 107 (36), 77 (30), 307 (18), HRMS (EI) m/z calcd
for C19H22N2O4S 374.1113, found 374.1128 (M++1).
360.4489, found 360.4838 (M++1).
4.1.4. (30S,40S)-4-[(30,40)-Bis(benzyloxy)pyrrolidin-10-yl]-
pyridine, 7. A solution of 263 mg (2.80 mmol) of 4-
aminopyridine in 17 mL of THF was added dropwise
to a suspension of 224 mg (5.60 mmol) of NaH, which
had previously been washed with n-hexane. The reaction
mixture was stirred for 3 h and 4-aminopyridine was
then deprotonated, after which 603 mg (1.40 mmol) of
mesylate 6 was added and the reaction mixture heated
under reflux for 3 days. The excess hydride was
destroyed by the slow addition of 2 mL of NH4OH
(1 M). The reaction was then extracted with CH2Cl2.
The combined organic extracts were washed with H2O,
brine and dried with Na2SO4. After concentration and
chromatography (CH2Cl2–MeOH 9:1), 101 mg of 7
(20%) was obtained.
4.1.7.
(20R,30S,40R,100R)-4-[20-(100-Benzenesulfonyl-200-
phenylethyl)-30,40-isopropylidenedioxypyrrolidin-1-yl]N-
benzylpyridinium bromide, 10. To a solution of 118 mg
(0.32 mmol) of compound 9 in 3 mL THF at À78 ꢁC was
added 0.24 mL (0.38 mmol) of n-BuLi and the mixture
stirred for 15 min. Afterwards, 31 lL (0.38 mmol) of
BnBr was added and the reaction mixture allowed to
warm to room temperature. Then, 1 mL of saturated
aqueous NH4Cl solution was added. The mixture was
extracted with EtOAc. The organic layer was washed
with H2O and brine and dried over Na2SO4. After
4.1.5. (2S,3S,4R)-2-Benzenesulfonylmethyl-3,4-isopropyl-
mixture of 500 mg
(1.11 mmol) of compound 4 and a catalytic amount of
Pd/C in 5 mL of MeOH was degassed and then hydroge-
nated under 3.5 atm of H2 for 24 h. The reaction was fil-
idenedioxypyrrolidine, 8.
A
tered over Celite and concentrated to afford 313 mg of
20
compound 8 (95%). ½aŠ ¼ À26.0 (c 0.1, CHCl3), IR
D
(film) m (cmÀ1): 3000, 2936, 1447, 1381, 1308, 1148,
1
1086, 650; H NMR (CDCl3, 200 MHz) d (ppm): 7.95–
7.50 (5H, m, Ar), 4.67 (1H, dd, J = 4.0 Hz and
J = 5.3 Hz, H-4), 4.54 (1H, dd, J = 4.2 Hz and
J = 5.3 Hz, H-3), 3.57 (1H, dd, J = 5.0 Hz and J =
14.0 Hz, H-10A), 3.36 (1H, dd, J = 7.0 Hz and J =
14.0 Hz, H-10B), 3.32 (1H, m, H-2), 3.13 (1H, d,
J = 12.7 Hz, H-5A), 2.69 (1H, dd, J = 4.0 Hz and
J = 12.7 Hz, H-5B), 2.20 (1H, s, H-1), 1.41 (3H, s, aceto-
nide), 1.25 (3H, s, acetonide); 13C NMR (CDCl3,
50.3 MHz): 139.7 (C-ipso), 133.7 (CH-para), 129.2
(2CH-meta), 127.2 (2CH-ortho), 111.1 (C-acetonide),
81.0 (CH-3), 80.8 (CH-4), 57.1 (CH-2), 55.9 (CH2-10),
52.6 (CH2-5), 25.7 (CH3-acetonide), 24.0 (CH3-aceto-
nide); EIMS m/z (%) 298 (M++1,100), 154 (55), 136
(50), 107 (25), 80 (45), HRMS (EI) m/z calcd for
C14H19NO4S 298.1068, found 298.1128 (M++1).
concentration and chromatography (CH2Cl2–MeOH
20
9:1), 73 mg of 10 (50%) was obtained. ½aŠ ¼ À22.2
D
(c 0.6, MeOH), IR (film) m (cmÀ1): 2945, 1830, 1555,
1
1531, 1220, 1100, 980; H NMR (CD3OD, 200 MHz) d
(ppm): 8.25 (2H, dd, J = 7.4 Hz and 9.8 Hz, H-2 py,
H-6 py), 7.85 (2H, m, Hortho-SO2Ph), 7.45–7.13 (14H,
m, Ar), 6.72 (1H, dd, J = 7.4 Hz and J = 2.9 Hz, H-5
py), 6.20 (1H, dd, J = 9.8 Hz and J = 2.9 Hz, H-3 py),
5.51 (1H, d, J = 5.8 Hz, H-30), 5.39 (2H, s, N-CH2-Ar),
5.10 (1H, t, J = 5.8 Hz, H-40), 4.45 (1H, d, J = 2.3 Hz,
H-20), 4.10 (1H, m, H-100), 3.90 (1H, dd, J = 11.2 Hz
and J = 5.8 Hz, H-5A), 3.80 (1H, d, J = 11.2 Hz, H-
5B), 3.21 (1H, dd, J = 2.6 Hz and J = 14.2 Hz, H-200 ),
A
2.98 (1H, dd, J = 11.5 Hz and J = 14.2 Hz, H-20B0 ), 1.36
(3H, s, acetonide), 1.30 (3H, s, acetonide); 13C NMR
(CD3OD, 50.3 MHz): 155.3 (C-py), 143.7 (CH-1 py
and CH-5 py), 139.3 (C-ipsoAr1), 136.6 (C-ipsoSO2Ph),
135.7 (C-ipsoAr2), 135.4 (CH-paraSO2Ph), 130.6 (2CH-
metaSO2Ph), 130.5 (2CH-paraAr1 and Ar2), 130.3
(2CH-orthoAr1), 130.0 (2CH-orthoAr2), 129.3 (2CH-
metaAr1), 129.0 (2CH-metaAr2), 128.4 (2CH-orthoSO2Ph),
113.2 (CH-4 py), 111.1 (CH-2 py), 108.7 (C-acetonide),
82.3 (CH-3), 79.3 (CH-40), 66.4 (CH-20), 64.0 (CH-100),
62.0 (N-CH2-Ar2), 57.3 (CH2-50), 33.6 (CH2-200), 26.8
(CH3-acetonide), 24.7 (CH3-acetonide).
4.1.6.
isopropylidenedioxypyrrolidin-10-yl)pyridine, 9. To
(20S,30S,40R)-4-(20-Benzenesulfonylmethyl-30,40-
a
solution of 313 mg (1.05 mmol) of compound 8 in
10.5 mL of toluene were added 408 mg (2.10 mmol) of
4-bromopyridine, 46 mg (0.05 mmol) of Pd2(dba)3,
1.37 g (4.20 mmol) of Cs2CO3 and 131 mg (0.21 mmol)
of BINAP. The reaction mixture was bubbled under an
argon atmosphere for 5 min and then heated at 80 ꢁC
for 2 days. Afterwards, the reaction was diluted with
2 mL of NH4OH (1 M) and extracted with CH2Cl2.
The combined organic extracts were washed with H2O
and saturated NaCl and then dried over Na2SO4. Col-
4.1.8.
(20R,30S,40R,100R)-4-[20-(100-Benzenesulfonyl-200-
phenylethyl)-30,40-isopropylidenedioxypyrrolidin-1-yl]pyr-
idine, 11. To a solution of 118 mg (0.32 mmol) of
compound 9 in 3 mL of THF at À78 ꢁC was added
0.24 mL (0.38 mmol) of n-BuLi and the mixture stirred
for 15 min. Afterwards, 13 lL (0.16 mmol) of BnBr
was added and the reaction mixture allowed to warm
to room temperature. Then, 1 mL of saturated aqueous
NH4Cl solution was added. The mixture was extracted
umn chromatography (CH2Cl2–MeOH–NH3 98:1:1)
20
afforded 236 mg (60%) of compound 9. ½aŠ ¼ À13.6 (c
D
0.8, CHCl3), IR (film) m (cmÀ1): 3405, 1595, 1531, 1388,
1302, 1154, 1085; 1H NMR (CDCl3, 200 MHz) d
(ppm): 8.26 (2H, br s, H-2 py and H-6 py), 7.98 (2H,
m, Hortho-SO2Ph), 7.70 (2H, m, Hpara-SO2Ph), 7.60
(2H, m, Hmeta-SO2Ph), 6.52 (2H, d, J = 5.6 Hz, H-3

D. Dı´ez et al. / Tetrahedron: Asymmetry 16 (2005) 2980–2985
2985
with EtOAc. The organic layer was washed with H2O
References
and brine, and dried with Na2SO4. After concentration
1. Ho¨fle, G.; Steglich, W.; Vorbruggen, H. Angew. Chem.,
¨
and chromatography (CH2Cl2–MeOH 95:5), 59 mg of
20
Int. Ed. Engl. 1978, 17, 569.
2. Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40,
3726.
11 (40%) was obtained. ½aŠ ¼ À28.3 (c 0.9, CHCl3),
D
IR (film) m (cmÀ1): 2975, 1850, 1695, 1541, 1320, 1100,
1
980; H NMR (CDCl3, 200 MHz) d (ppm): 8.04 (2H,
3. (a) Spivey, A. C.; Fekner, T.; Spey, S. E.; Adams, H.
J. Org. Chem. 1999, 64, 9430; (b) Spivey, A. C.; Fekner,
T.; Adams, H. Tetrahedron Lett. 1998, 39, 8919.
4. For a review in this chiral catalyst see: Fu, G. Acc. Chem.
Res. 2000, 33, 412, and references cited therein.
5. (a) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J.
Am. Chem. Soc. 1997, 119, 3169; (b) Kawabata, T.;
Yamamoto, K.; Momose, Y.; Yoshida, H.; Nagaoka, Y.;
Fuji, K. Chem. Commun. 2001, 2700.
6. Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc.
2003, 125, 13368.
7. Dalaigh, C. O.; Hynes, S. J.; Maher, D. J.; Connon, S. J.
Org. Biol. Chem. 2005, 3, 981.
br s, H-2 py, H-6 py), 7.76 (2H, m, Hortho-SO2Ph),
7.70 (2H, m, Hpara-SO2Ph), 7.58 (2H, m, Hmeta-
SO2Ph), 5.83 (2H, br s, H-3 py, H-5 py), 5.66 (1H, d,
J = 6.1 Hz, H-30), 5.17 (1H, t, J = 6.1 Hz, H-40), 4.31
(1H, d, J = 1.9 Hz, H-20), 4.04 (1H, dd,0 J = 11.4 Hz
and J = 5.80 Hz, H-5A0 ), 3.53 (2H, m, H-5B and H-100),
3.15 (1H, dd, J = 2.5 Hz and J = 14.2 Hz, H-20A0 ),
2.93 (1H, dd, J = 11.5 Hz and J = 14.2 Hz, H-20B0 ), 1.43
(3H, s, acetonide), 1.40 (3H, s, acetonide); 13C NMR
(CDCl3, 50.3 MHz): 143.8 (CH-2 py and CH-6 py),
138.2 (C-py), 135.3 (C-ipsoSO2Ph), 134.4 (CH-para-
SO2Ph), 129.7 (2CH-metaSO2Ph), 129.3 (2CH-ortho),
129.1 (2CH-meta), 128.0 (2CH-para), 127.9 (2CH-ortho-
SO2Ph), 112.5 (C-acetonide), 108.6 (CH-3 py), 107.5
(CH-5 py), 80.2 (CH-30), 78.6 (CH-40), 64.5 (CH-20),
63.6 (CH-100), 55.8 (CH2-50), 33.6 (CH2-200), 26.9 (CH3-
acetonide), 24.9 (CH3-acetonide); EIMS m/z (%) 465
(M++1, 100), 154 (100), 136 (75), 91 (55), 307 (14),
413 (5), HRMS (EI) m/z calcd for C26H28N2O4S
464.1770, found 464.1803 (M++1).
8. Spivey, A. C.; Maddaford, A.; Fekner, T.; Redgrave, A.
J.; Frampton, C. S. J. Chem. Soc., Perkin Trans. 1 2000,
3460, and references cited therein.
9. Kotsuki, H.; Sakai, H.; Shinohara, T. Synlett 2000, 116.
´
10. Dıez, D.; Beneitez, M. T.; Marcos, I. S.; Garrido, N. M.;
Basabe, P.; Urones, J. G. Tetrahedron: Asymmetry 2002,
13, 639.
´
´
11. Dıez, D.; Templo-Beneitez, M.; Marcos, I. S.; Garrido, N.
M.; Basabe, P.; Urones, J. G. Synlett 2003, 729.
12. Cunningham, A. F.; Kunding, E. P. J. Org. Chem. 1988,
¨
53, 1823.
4.1.9. A representative procedure for catalytic kinetic
resolution of 1-phenylethanol, usingcatalyst (+)-9 as
example. To a solution of catalyst (+)-9 (7.0 mg,
0.02 mmol) and 1-phenylethanol (0.12 mL, 1.0 mmol)
in THF (1 mL) was added Et3N (0.1 mL, 0.75 mmol)
and the reaction cooled to À78 ꢁC. Ac2O (0.71 mL,
0.75 mmol) was then added with vigorous stirring. After
120 min, approx 0.5 mL of the reaction mixture was
removed via syringe and added to MeOH (1 mL). After
10 min, the solvent was removed in vacuo and the crude
material passed through a short plug of silica to remove
the catalyst. After 520 min, MeOH (2 mL) was added to
the reaction mixture and warmed to room temperature.
After 15 min, the solvent was removed in vacuo and the
crude material passed through silica. The ees of both the
alcohol and the acetate were determined for both ali-
quots by analytical chiral HPLC (Chiralcel OD column,
0.46 · 25 cm, 18 ꢁC, hexanes–isopropanol, 85:15,
0.45 mL minÀ1): Rt [(R)-acetate] 10.3 min; Rt [(S)-ace-
tate] 10.7 min; Rt [(R)-alcohol] 12.5 min; Rt [(S)-alcohol]
13.7 min.
13. Priem, G.; Anson, M. S.; Macdonald, S. J. F.; Pelotier, B.;
Campbell, I. B. Tetrahedron Lett. 2002, 43, 6001.
14. (a) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158; (b) Yang, B.
H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125,
and references cited therein.
15. A single crystal of compound 10 was subjected to X-ray
diffraction studies on a Seifert 3003 SC four-circle diffrac-
tometer (CuKa radiation, graphite monochromator) at
293(2) K. Crystal data for 10: C33H37N2O4S, 3/2CHCl3,
BrÀ, M = 816.67, triclinic, space group P1 (no 1), a =
˚
˚
˚
9.794(2) A,
b = 10.351(2) A,
c = 11.030(2) A,
a =
3
˚
83.63(3)ꢁ, b = 74.32(3)ꢁ, c = 67.49(3)ꢁ, V = 994.5(3) A ,
Z = 1, Dc = 1.364 Mg/m3, m = (Cu-Ka) = 4.981 mmÀ1
,
F(000) = 418. 2954 reflections were collected, of which
2404 were considered to be observed with I > 2r(I). The
structure was determined by direct methods using the
SHELXTLTM suite of programs. Many problems involve
the crystal structure refinement of this compound, all of
which are derived from the small size and bad quality of
the crystals. The poorness of the spectra forced the
refinement as rigid body of most part of the molecules.
Hydrogen atoms were placed in calculated positions. Full-
matrix least squares refinement based on F2 with aniso-
tropic thermal parameters for the non-hydrogen atoms led
to agreement factors R1 = 0.1060 and wR2 = 0.2639.
Crystallographic data (excluding structure factors) for
the structure reported in this paper have been deposited at
the Cambridge Crystallographic Data Centre as supple-
mentary material no. CCDC-271242.
Acknowledgements
The authors thank the CICYT and Junta de Castilla y
´
Leon for a doctoral fellowship to M. J. Gil.