α,α-Diarylprolinol-derived chiral ionic liquids: Recoverable organocatalysts for the domino reaction between α,β-enals and N-protected hydroxylamines

Article abstract of DOI:10.1016/j.tetasy.2010.10.020

Chiral ionic liquids bearing α,α-diarylprolinol units were synthesized and applied for the first time as organocatalysts for the domino reaction between α,β-enals and N-protected hydroxylamines involving aza-Michael and intramolecular acetalization steps. Corresponding 5-hydroxy-3-arylisoxazolidines with either an (S)- or (R)-configuration at C-3 were obtained in excellent yields (up to 94%) and with moderate to high enantioselectivities (64 to >99% ee). The ionic liquid supported catalyst can be easily recycled and reused for at least four times without a significant loss of chemical yield or enantioselectivity.

Full text of DOI:10.1016/j.tetasy.2010.10.020

Tetrahedron: Asymmetry 21 (2010) 2659–2670
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
a
,
a
-Diarylprolinol-derived chiral ionic liquids: recoverable organocatalysts
for the domino reaction between
a,b-enals and N-protected hydroxylamines
Oleg V. Maltsev a,b, Alexandr S. Kucherenko a, Alexandr L. Chimishkyan b, Sergei G. Zlotin a,
⇑
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991, Russian Federation
b D. I. Mendeleyev University of Chemical Technology of Russia, Moscow 123480, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral ionic liquids bearing
organocatalysts for the domino reaction between
a
,
a
-diarylprolinol units were synthesized and applied for the first time as
Received 15 September 2010
Accepted 21 October 2010
Available online 20 November 2010
a,b-enals and N-protected hydroxylamines involving
aza-Michael and intramolecular acetalization steps. Corresponding 5-hydroxy-3-arylisoxazolidines with
either an (S)- or (R)-configuration at C-3 were obtained in excellent yields (up to 94%) and with moderate
to high enantioselectivities (64 to >99% ee). The ionic liquid supported catalyst can be easily recycled and
reused for at least four times without a significant loss of chemical yield or enantioselectivity.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
asymmetric Michael reactions between a
,b-enals and CH-acids.16a,b
However, to the best of our knowledge, neither chiral ionic liquids
nor other types of immobilized organocatalysts have been success-
fully applied to domino or cascade reactions. Moreover, polysty-
Asymmetric organocatalysis is a rapidly developing area of
modern organic chemistry.1 Some chiral compounds of natural or
synthetic origin such as amino acids,2 alkaloids,3 thiourea4 deriva-
tives, compounds containing pyrrolidines, and imidazolin-4-one
fragments,5 among others6 are known to have organocatalytic
rene-supported O-TMS-a,a-diarylprolinols became inactive after
the first regeneration in the three-component Michael/Michael/
aldol cascade reaction.13b,f
properties. Among them,
a
,
a
-diarylprolinol derivatives (Jørgen-
Herein, we report for the first time that O-TMS-
nols modified with ionic groups can be used as efficient recover-
able catalysts for the asymmetric domino reaction between
a,a-diarylproli-
sen–Hayashi-type catalysts) have gained considerable attention;7
they activate carbonyl compounds via an enamine7e,7f,8 or imini-
um7e,f,9 ion formation and, therefore, catalyze a broad range of
reactions, including the reaction sequences where these intermedi-
ates are involved in cascade, tandem, or domino processes10
affording complex molecular scaffolds in an efficient one-pot route
from readily available starting materials.
a,
b-enals and N-protected hydroxylamines17 via the Michael addi-
tion stage. We have found that the nature of the substituents in
the aromatic rings and the presence of a linker between the chiral
inductor and the cation unit are crucial for the catalyst activity and
selectivity (Fig. 1). The reaction products, 5-hydroxyisoxazolidines,
are valuable intermediates in the organic synthesis,18 in particular
they are used for the preparation of b-amino acids,19,20 which are
precursors of antibiotics21 and b-peptides.22
However, industrial applications11 of the prolinol-type catalysts
as well as of a majority of other modern organocatalysts with
rather complicated structures demand developing their immobi-
lized versions that can be easily separated from products and re-
used.12 Only a few approaches to the immobilization of prolinol-
type catalysts have been described. Recently, immobilized prolinol
derivatives containing polymeric,13 dendritic,14 perfluoroalkyl,15 or
ionic groups16 have been synthesized. The compounds with ionic
groups have some advantages:12d,e their catalytic properties are
readily tunable by varying the cation and/or anion, their synthesis
does not require expensive reagents or special conditions and they
can be easily monitored by NMR spectroscopy during all steps.
2. Results and discussion
2.1. Synthesis of catalysts
Initially, we synthesized chiral ionic liquids 1, 2a–c, and cis-2a
which differed by the nature of substituents R1 and R2 in the
a,a-diarylprolinol fragment and by the configuration of the pyrrol-
idine C-5 atom (Fig. 2).
Compounds 1 and 2a with a (5S)-configuration and catalyst cis-
2a with a (5R)-configuration were prepared according to the earlier
developed methods.16a,b Unknown chiral ionic liquids 2b and 2c
were synthesized by the synthetic scheme to include reactions of
Chiral ionic liquids bearing the O-TMS-a,a-diarylprolinol frag-
ment appeared to be efficient recoverable organocatalysts for the
⇑
Corresponding author. Tel./fax: +7 499 135 53 28.
E-mail address: zlotin@ioc.ac.ru (S.G. Zlotin).
(2S,4R)-methyl 1-benzyl-4-hydroxypyrrolidine-2-carboxylate
3
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.020

2660
O. V. Maltsev et al. / Tetrahedron: Asymmetry 21 (2010) 2659–2670
genation and O-silylation reactions. The overall yields of com-
pounds 2b and 2c with respect to starting ester 3 were 54% and
46%, respectively.
Next, we attempted to apply this strategy to the preparation of
a,a-diarylprolinol derivatives bearing a shorter acetic acid-derived
Linker
An
cat
Ar
Ar
OR
N
H
linker between the imidazolium cation and the prolinol unit. The
esterification of compound 3 with iodoacetic acid in the presence
of DCC/DMAP and a subsequent reaction of ester 7 with 1-methyl-
1H-imidazole afforded iodide 8-I. However our attempts to depro-
tect this imidazolium salt failed. The hydrogenation of iodide 8-I or
hexafluorophosphate 8-PF6, having been prepared from salt 8-I by
an anion exchange reaction, led to prolinol 3, which was isolated
and characterized as bis-TMS-ether 9, rather than to a correspond-
ing debenzylation product (Scheme 2). This result was unexpected,
since respective Cbz-protected proline derivatives had smoothly
undergone Pd-catalyzed deprotection under the conditions stud-
Figure 1. The constitution of the studied ionic liquid-immobilized organocatalysts.
O
R2
R2
R2
N
N
( )4
O
3
4
5
2
PF6
N
H
OR1
R2
1, 2
1 R1 = R2 = H,
ied.23 Apparently, the presence of the
a,a-diarylprolinol fragment
2 R1 = TMS, R2 = H (a), CH3 (b), CF3 (c)
instead of the amino acid unit enhances the ester group reactivity
O
and makes this immobilization strategy unsuitable.
Recently, stable chiral ionic liquids containing directly linked
ionic and proline fragments have been prepared and studied in
N
N
( )4
O
asymmetric aldol, Michael,24a and
a
-aminoxylation24b reactions,
Ph
Ph
OTMS
however, this strategy has never been applied to the immobiliza-
tion of Jørgensen–Hayashi-type catalysts. To introduce a good leav-
ing group at the 3-position of the pyrrolidine ring we studied a
reaction of compound 3 with the Tf2O/pyridine mixture under
the conditions that had been previously used for the preparation
of 4-triflyloxyprolines.25 However, instead of the expected com-
pound 10, two major products were obtained; then assigned to
isomeric pyrrolines 11a and 11b according to HRMS ([M+H]+
m/z = 342.19) and 1H NMR data. The triflate 10 generated in situ
was unstable and readily eliminated as triflic acid under the
reaction conditions (Scheme 3). Similar elimination products were
reported for the reactions of 4-OTf-proline derivatives with some
nucleophiles.25a
In some cases, less active tosylates can also react with imidazole
derivatives to afford the corresponding substitution products.26
Hence, we prepared tosylate 12 via reaction of prolinol 3 with
TsCl/Py.14d However compound 12 did not react with 1-methyl-
1H-imidazole under the conditions proposed for (2S,4R)-dibenzyl
4-OTf-pyrrolidine-1,2-dicarboxylate.24b,27 On the other hand, a
complex mixture of products was formed under more vigorous
conditions (100 °C) (Scheme 4).
PF6
N
H
cis-2a
Figure 2. Prolinol/imidazolium derived chiral ionic liquids.
with the respective Grignard reagents, esterification of the
corresponding 3-hydroxy-a,a-diarylprolinols 4b,c with 5-bromo-
pentanoic acid, and subsequent reactions of esters 5b,c with
1-methyl-1H-imidazole (Scheme 1).
A sequence of further operations depended on the lipophilic
properties of imidazolium salts 6b and 6c. Bromide 6b, which
was poorly soluble in Et2O, was easily separated from an excess
of 1-methylimidazole by washing with Et2O and converted into
the desired catalyst 2b by a sequence of hydrogenation, O-silyla-
tion, and anion metathesis reactions. On the other hand, bromide
6c, which is soluble in Et2O and in 1-methyl-1H-imidazole, was di-
rectly transformed into hydrophobic hexafluorophosphate 6c-PF6
by the anion exchange reaction. The salt 6c-PF6 after washing with
water to remove 1-methyl-1H-imidazole-derived impurities was
converted into chiral ionic liquid 2c by successive catalytic hydro-
O
Br
O
HO
( )4
HO
O
Br
Ar
( )4
Ar
OH
O
ArMgBr
Ar
OH
Ar
OH
N
N
N
THF, −78 oC to r.t.
overnight
DCC, DMAP, CH2Cl2
0 oC to reflux
95-97%
OMe
Bn
3
Bn
Bn
94-97%
4b,c
5b,c
O
O
N
N
N
N
( )4
An
O
( )4
An
O
1) Me3SiCl,
N
N
Et3N, CH2Cl2
H2, Pd/C
Ar
Ar
2b,c
Ar
OH
Ar
OH
N
H
100 oC, 10 min
88%
N
2) KPF6, H2O
(for 1b-Br)
67-95%
MeOH
Bn
95-100%
1b-Br: An = Br
1c: An = PF6
An = Br
KPF6, H2O
55% (2 steps)
6b,c
(for 6c)
1,2, 4-6: b Ar = 3,5-(CH3)2C6H3,
c Ar = 3,5-(CF3)2C6H3
An = PF6
6c-PF6
Scheme 1. The preparation of chiral ionic liquids 2b and 2c.

O. V. Maltsev et al. / Tetrahedron: Asymmetry 21 (2010) 2659–2670
2661
derivatives.24a The synthetic route included a reaction of tosylate
12 with sodium azide,14d cycloaddition of azide 13 having a reverse
configuration of the C-3 atom to 1-heptyne followed by the alkyl-
ation of triazole 14 with methyliodide (Scheme 5). Iodide 15-I did
not undergo the catalytic hydrogenation, apparently, due to cata-
lyst poisoning by the iodide anion.28 We solved this problem by
the transformation of iodide 15-I into hexafluorophosphate
15-PF6, which was easily deprotected with the formation of pyrrol-
idine 16. The subsequent O-silylation of compound 16 in the
presence of TMSOTf/2,6-lutidine16b afforded target compound 17.
Salts 2b, 2c, and 17 as well as known compounds 1, 2a, and
cis-2a melt below 150 °C and can be described as ionic liquids.
O
I
O
HO
O
I
Ph
Ph
OH
Ph
OH
Ph
OH
N
Bn
3
N
DCC, DMAP, CH2Cl2
0 oC to reflux
95%
Bn
7
O
N
N
O
Ph
N
N
An
H2, Pd/C
Ph
OH
N
70 oC, 10 min
97%
MeOH, r.t.
overnight
100%
2.2. Ionic liquid-catalyzed asymmetric domino reaction
Bn
An = I
8-I
KPF6, H2O
84%
First, we compared the catalytic properties of chiral ionic
liquids 1, 2a–c, and 17 in the model reaction between trans-cinna-
maldehyde 18a and N-Cbz-hydroxylamine 19a to afford chiral
5-hydroxyisoxazolidine 20a via a tandem sequence of the aza-
Michael addition and intramolecular acetalization17 (Scheme 6,
R1 = Ph, R2 = Cbz). The experiments were carried out under similar
conditions (toluene, rt) until complete cinnamaldehyde conversion
was achieved (TLC and NMR monitoring). It was found that enanti-
oselectivity was poor when chiral ionic liquid 1 (10 mol %) bearing
the free hydroxyl group had been used as a catalyst (Table 1, entry
1). On the other hand, O-TMS-protected chiral ionic liquid 2a
showed much better results: the ee value of product 20a was sim-
ilar to the enantioselectivity obtained using Jørgensen–Hayashi
catalyst 21, though it was lower than that reported before (Table 1,
entry 2).17 Evidently, the presence of the TMS-group was crucial for
the stereochemical outcome of the reaction.29 Catalysts 2b and 2c
bearing the electron-donating (CH3) or electron-withdrawing (CF3)
groups in the aromatic rings or ‘‘linker-free’’ chiral ionic liquid 17
were inferior to catalyst 2a in terms of enantioselectivity. More-
over, chiral ionic liquids 2c and 17 were considerably less active
under the conditions studied (Table 1, entries 3–5).
Next, we studied the chiral ionic liquid 2a (10 mol %)-catalyzed
reaction of trans-cinnamaldehyde 18a with N-Cbz-hydroxylamine
19a in various solvents with a focus on the catalyst regeneration.
Therefore, after the reaction had been completed and the product
20a had been isolated, fresh portions of the starting compounds
and corresponding solvent were added to the remaining chiral io-
nic liquid 2a and the reaction was repeated. The reaction was
found to proceed in CH3OH, 96%-EtOH, H2O, Et2O, and CHCl3
(Table 2, entries 1–5) in a less selective manner than in toluene
(Table 2, entry 7). The ee value of the product 20a was slightly
higher in MeCN (90–92% ee), however, the catalyst’s activity in this
solvent dropped in the third cycle (Table 2, entry 6), whereas in
toluene the conversion remained extremely high (99%) for three
successive cycles and became just slightly lower (90%) after the
third regeneration of the catalyst (Table 2, entry 7). A temperature
decrease to 4 °C did not influence the ee value (Table 2, entry 8) but
the ee decreased slightly (88% ee) in the experiment where the
catalyst loading was 20 mol % (Table 2, entry 9).
An = PF6
8-PF6
Me3SiO
An
Ph
Me3SiCl, Et3N
N
N
COOMe
3
+
Ph
N
CH2Cl2, r.t.
overnight
62%
OSiMe3
Bn
An = I or PF6
9
Scheme 2. Attempted synthesis of the chiral ionic liquids with the acetic acid-
derived linker.
HO
TfO
Tf2O, Py, CH2Cl2
Ph
Ph
Ph
-10 oC to r.t.
Ph
OH
N
N
OH
Bn
Ph
4a
10
Ph
Ph
+
Ph
OH
Ph
OH
N
N
82%
Bn
Bn
11a
11b
[M + H]+ = 342.19
Scheme 3. Attempted synthesis of prolinol triflate 10.
HO
TsO
TsCl, Py,
Ph
Ph
Ph
OH
Ph
OH
4
oC to r.t.
overnight
N
N
Bn
Bn
12
4a
57%
N
no reaction
-78oC to r.t., 1 h,
see Ref. 24b
Catalyst 2a was then examined in the reactions between substi-
tuted a,b-enals 18a–g and N-protected hydroxylamines 19a,b un-
der the optimal conditions (Scheme 6, Table 3). In all cases, crude
5-hydroxyisoxazolidines 20a–h were obtained as single diastereo-
mers (1H NMR data). However, compounds 20a–h underwent epi-
merization during purification by column chromatography on
silica gel, probably, via a reversible cleavage of the C5–O bond.17
The 1H NMR spectra of the purified products contained two sets
of signals; the original diastereomer signals representing the major
set (dr 9:1–2:1). The epimerization process occurred during
HPLC analysis as well, however, it did not interfere with the
determination of the enantiomeric composition at C-3 because
N
decomposition
100 oC, 5 min
Scheme 4. Synthesis and reactions of tosylate 12.
Therefore, for the preparation of a ‘linker-free’ a,a-diarylprolin-
ol derived chiral ionic liquids we applied an alternative approach
resembling the Liebscher’s synthesis of 1,2,3-triazolium proline

2662
O. V. Maltsev et al. / Tetrahedron: Asymmetry 21 (2010) 2659–2670
n-C5H11
N
N
TsO
N
N3
n-C5H11
Ph
NaN3, DMSO
Ph
Ph
Ph
Ph
Ph
N
N
N
65 oC, 26 h
86%
CuI, DMSO,
H2O, 65 oC, 48 h
86%
OH
OH
OH
Bn
Bn
Bn
14
12
13
CH3
CH3
N
CH3
N
N
n-C5H11
n-C5H11
n-C5H11
N
N
N
PF6
PF6
An
N
N
N
MeI, MeCN,
Ph
Ph
H2, Pd/C
Me3SiOTf
Ph
Ph
Ph
Ph
OSiMe3
N
H
N
N
H
2,6-lutidine,
CH2Cl2, 48 h, r.t.
94%
reflux, 6 h, then
overnight at r.t.
100%
MeOH, r.t.
overnight
83%
OH
OH
Bn
16
17
An = I
15-I
KPF6, MeOH,
H2O, 89%
An = PF6
15-PF6
Scheme 5. Synthesis of ‘linker-free’ a,a-diarylprolinol-derived chiral ionic liquid 17.
the cases of aldehydes 18e [R1 = 4-OMe-3-(OC5Hcyclo)C6H3] and
R2
OH
11
18f (R1 = 4-NO2C6H4), it increased to 88% ee and to more than
N
H
R2
R1
OH
99% ee, respectively (Table 3, entries 5 and 6). In the presence of
O-TMS-a,a-diarylprolinol cis-2a with an (R)-configuration at the
carbon atom next to the nitrogen atom (see Fig. 2), the correspond-
ing 5-hydroxyisoxazolidine 20g was obtained with excellent
enantioselectivity (>99% ee).
Compounds 20f and 20g had an opposite configurations at C-3
(Table 3, entries 6 and 7): their specific rotations were ꢀ21.7 and
+27.1 (c 1.0, CHCl3), respectively. A difference in absolute magni-
tudes of the measured specific rotations between compounds 20f
and 20g could be explained by the different ratios of C-5 centered
epimers (5:1 and 7:1, respectively, according to 1H NMR) formed
during the final products purification by column chromatography
on silica gel.
2a (10 mol %), toluene,
19a,b
N
+
r.t., 24-48 h
then SiO2
O
R1
O
18a-g
R2
Ph
N
O
Ph
OTMS
3
5
N
H
4
R1
OH
21
20a-h
Scheme 6. Domino reaction between
amines 19a,b.
a,b-enals 18a–g and N-protected hydroxyl-
The chiral ionic liquid 2a-catalyzed reaction of
a,b-enal 18a
Table 1
with N-Boc-hydroxylamine 19b also took place under the condi-
tions studied, yet the enantioselectivity was only moderate
(Table 3, entry 8).
The reaction between trans-cinnamaldehyde 18a and N-Cbz hydroxylamine 19a in
the presence of chiral ionic liquids 1, 2a–c and 17a
Entry
Solvent
Catalyst
Time (h)
Conversionb (%)
eec (%)
Compounds 20 are valuable intermediates in the synthesis of
chiral b-amino acids (Scheme 7), which serve as key motifs of nat-
ural compounds19,20 and precursors for the preparation of b-lactam
antibiotics,21 and b-peptides.22 In this context, the availability of
(S)- and (R)-enantiomers of b-amino acids creates novel opportuni-
ties for their application in the synthesis of practically useful chiral
compounds. The partial racemization of the C-5 atom during the
isolation and purification of heterocycles 20 does not influence
the enantiomeric purity of the 20-derived products, in particular
b-amino acids, where this atom acquires an sp2-configuration.17
1
2
3
4
5
Toluene
Toluene
Toluene
Toluene
Toluene
1
48
24
24
96
96
99
29
2a
2b
2c
17
99 (99d, 94e)
90 (90d, 99e)
99
99
92
83
69
74
a
All reactions were carried out using trans-cinnamaldehyde 18a (20 mg,
0.15 mmol), N-Cbz-hydroxylamine 19a (32 mg, 0.19 mmol) in toluene (0.3 mL) in
the presence of the indicated catalyst (10 mol %) at room temperature.
Estimated by 1H NMR.
b
c
Estimated by a chiral HPLC for the isolated products.
Yield and ee values obtained by us in the presence of catalyst 21 (20 mol %)
d
under the conditions of Ref. 17 for 24 h.
e
3. Conclusion
Yield and ee values according to Ref. 17.
It has been found for the first time that chiral ionic liquids
the diastereomers having opposite configurations at C-5 were
indistinguishable under the HPLC conditions.
bearing
a
,
a
-diarylprolinol units were able to act as efficient
recoverable organocatalysts in domino reactions between
a,b-en-
We established that the ee values of compounds 20a–h de-
pended on the structure of a,b-enals 18a–g. The reactions of cinna-
maldehyde derivatives 18b–d containing halogen atoms (F or Cl) or
a methoxy group at the para-position of the aromatic ring afforded
the corresponding 5-hydroxyisoxazolidines 20b–d with moderate
enantioselectivity (64–77% ee) (Table 3, entries 2–4), whereas in
als and N-protected hydroxylamines involving aza-Michael and
intramolecular acetalization steps. Novel chiral ionic liquids of
this type, different in the nature of the substituents on the aro-
matic rings and in the mode of linkage between ionic and cata-
lytic sites, were synthesized and their catalytic properties were
studied. Chiral 5-hydroxyisoxazolidines with an (S)- or (R)-config-

O. V. Maltsev et al. / Tetrahedron: Asymmetry 21 (2010) 2659–2670
2663
Table 2
The chiral ionic liquid 2a catalyzed reaction of trans-cinnamaldehyde 18a with N-Cbz-hydroxylamine 19a in various solventsa
Entry
Solvent
Temp (°C)
Conversionb (%) (cycle)
eec (%) (cycle)
1
2
3
4
5
6
7
8
9d
MeOH
96%-EtOH
H2O
Et2O
CHCl3
rt
rt
rt
rt
rt
rt
rt
4
88 (1) 73 (2)
98 (1) 88 (2)
77 (1) 77 (2)
87 (1) 87 (2)
87 (1) 86 (2) 87 (3)
70 (1) 69 (2) 70 (3) 69 (4)
86 (1) 86 (2) 85 (3) 86 (4)
92 (1) 90 (2) 91 (3)
90 (1) 90 (2) 90 (3) 90 (4)
90 (1) 90 (2) 90 (3)
97 (1) 91 (2) 75 (3)
99 (1) 99 (2) 93 (3) 50 (4)
99 (1) 98 (2) 96 (3) 86 (4)
98 (1) 95 (2) 77 (3)
99 (1) 99 (2) 99 (3) 93 (4)
99 (1) 98 (2) 95 (3)
99 (1) 99 (2) 99 (3)
MeCN
Toluene
Toluene
Toluene
4
88 (1) 88 (2) 88 (3)
a
Unless specified otherwise, all reactions were carried out using trans-cinnamaldehyde 18a (20 mg, 0.15 mmol), N-Cbz-hydroxylamine 19a (32 mg, 0.19 mmol) in the
indicated solvent (0.3 mL) in the presence of catalyst 2a (10 mg, 10 mol %) for 24 h.
b
Estimated by 1H NMR.
Estimated by a chiral HPLC for the isolated products.
The reaction was carried out in the presence of 20 mol % of catalyst 2a.
c
d
Table 3
Scope and limitations of the domino reaction between
a
,b-enals 18a–g and N-protected hydroxylamines 19a–b in the presence of catalyst 2aa
Entry
Aldehyde, 18
Hydroxylamine, 19
Product, 20
Time (h)
Yieldb (%) (lit.)
eec (%) (lit.)
90 (99d)
Cbz
N
O
O
CbzNHOH
19a
1
24
90 (94d)
OH
O
18a
20a
Cbz
O
N
CbzNHOH
19a
Cl
2
3
4
24
24
48
91
91
79
75
64
77
OH
OH
18b
Cl
20b
Cbz
O
N
O
CbzNHOH
19a
F
18c
F
20c
Cbz
O
O
N
N
O
CbzNHOH
19a
MeO
OH
18d
MeO
20d
Cbz
O
CbzNHOH
19a
O
O
5
48
73
88
OH
MeO
MeO
O2N
O2N
20e
18e
18f
Cbz
O
N
O
CbzNHOH
19a
O2N
O2N
6
24
24
24
94
>99
OH
20f
Cbz
O
N
O
CbzNHOH
19a
7e
87
>99
OH
18f
20g
Boc
O
N
O
BocNHOH
19b
8
78 (80d)
67 (99d)
OH
18a
20h
Unless specified otherwise, all reactions were carried out using the respective trans-cinnamaldehyde 18 (0.35 mmol) and N-protected hydroxylamine 19 (0.44 mmol) in
a
toluene (0.7 mL) in the presence of catalyst 2a (10 mol %, 23 mg) at room temperature.
b
Isolated yield.
Estimated by a chiral HPLC of the isolated products.
Yield and enantioselectivity according to Ref. 17.
The reaction was carried out in the presence of catalyst cis-2a (10 mol %, 23 mg).
c
d
e

2664
O. V. Maltsev et al. / Tetrahedron: Asymmetry 21 (2010) 2659–2670
Cbz
romethane-sulfonate (TMSOTf) was prepared by the method
reported for tert-butyldimethylsilyl trifluoromethanesulfonate
(TBDMSOTf).38
NH2
O
N
O
Ar
OH
Ar
Cbz
OH
OH
5
[lit. 18]
2 steps
3
(S)−β-aminoacids
4
4.2. Synthesis of the catalysts
NH2
O
N
O
Ar
OH
4.2.1. (3R,5S)-1-Benzyl-5-(bis(3,5-dimethylphenyl)-
(hydroxy)methyl)pyrrolidin-3-ol 4b
Ar
(R)−β-aminoacids
(3,5-Dimethylphenyl)magnesium bromide (Me2C6H3MgBr) pre-
pared from Mg (0.46 g, 19.1 mmol), 1-bromo-3,5-dimethylbenzene
(3.37 g, 18.2 mmol), and THF (20 ml) was added to a solution of
Scheme 7. 5-Hydroxyisoxazolidines as intermediates in the synthesis of b-
aminoacids.
methyl (2S,4R)-1-benzyl-4-hydroxypyrrolidine-2-carboxylate
3
(0.54 g, 2.28 mmol) in freshly distilled THF (10 ml) at ꢀ78 °C. Then
the reaction mixture was stirred overnight at room temperature.
Saturated aqueous NH4Cl (10 ml) was added. The organic layer
was separated and the water phase was extracted with Et2O
(3 ꢃ 15 ml). The combined organic extracts were washed with sat-
urated aqueous NH4Cl (2 ꢃ 15 ml) and dried over MgSO4. The sol-
vents were evaporated under reduced pressure. The residue was
purified by column chromatography (l = 17 cm, d = 2 cm) using a
mixture of n-hexane/EtOAc (from 5:1 to 2:1) to afford 0.89 g
(94%) of 4b as a pale yellow oil. Rf 0.18 (n-hexane/EtOAc, 5:1).
uration at the C-3 atom were obtained in the presence of cata-
lysts 2a and cis-2a in excellent yields (up to 94%) and with mod-
erate to high enantioselectivities (up to >99%) retained over four
cycles.
4. Experimental
4.1. General
The reagents were used as purchased from commercial suppli-
ers without further purification if otherwise is not indicated. The
p.a. quality solvents were pre-dried by standard procedures, if
appropriate. DMSO and DMF were distilled over CaH2 and THF
was distilled over LiAlH4 before usage.
The NMR spectra were recorded on a Bruker AM300 NMR spec-
trometer (300 MHz for 1H, 75 MHz for 13C, 282 MHz for 19F,
121 MHz for 31P) at 25 °C. Chemical shifts are given in d ppm refer-
enced to an internal TMS standard for 1H NMR, CDCl3 for 13C NMR,
CFCl3 for 19F NMR, and H3PO4 for 31P NMR. High resolution mass
spectra (HR MS) were measured on a Bruker micrOTOF II instru-
ment using electrospray ionization (ESI).30 The measurements
were carried out in a positive ion mode (interface capillary voltage
ꢀ4500 V); mass range from m/z 50 to m/z 3000 Da; external or
internal calibration was done with Electrospray Calibrant Solution
(Fluka). A syringe injection was used for solutions in acetonitrile or
½
a 2D1
ꢁ
¼ þ58:8 (c 1.0, CHCl3). 1H NMR (CDCl3): d 1.91 (m, 2H, 4-H),
2
3
2.28 (m, 12H, CH3), 2.53 (dd, JH,H = 10.7 Hz, JH,H = 3.3 Hz; 1H,
2
3
2-H), 3.09 (dd, JH,H = 11.7 Hz, JH,H = 4.4 Hz; 1H, 2-H), 3.27 (s, 2H,
CH2Ph), 4.30 (m, 2H, 5-H, OH), 4,81 (s, 1H, 3-H), 6.73 (s, 1H,
Ar-H), 6.80 (s, 1H, Ar-H), 7.04 (m, 2H, Ph-H), 7.23 (m, 5H, Ph-H,
Ar-H), 7.34 (s, 2H, Ar-H) ppm. 13C NMR (CDCl3): d 21.6, 21.7,
38.8, 61.3, 62.2, 70.8, 71.0, 77.1, 123.4, 123.6, 127.0, 128.1, 128.3,
128.7, 137.4, 137.6, 139.9, 145.9, 147.7 ppm. Anal. Calcd for
C28H33NO2 (415.57): C, 80.93; H, 8.00; N, 3.37. Found: C, 80.59;
H, 8.34; N, 3.30.
4.2.2. (3R,5S)-1-Benzyl-5-(bis(3,5-bis(trifluoromethyl)-
phenyl)(hydroxy)methyl)pyrrolidin-3-ol 4c
The title compound was prepared according to the procedure for
4b from a solution of (3,5-bis(trifluoromethyl)phenyl)magnesium
bromide ((CF3)2C6H3MgBr) prepared from Mg (0.36 g, 14.7 mmol),
1-bromo-3,5-bis(trifluoromethyl)benzene (4.1 g, 14.0 mmol), and
THF (16 ml) and a solution of 3 (0.48 g, 2.0 mmol) in freshly distilled
THF (10 ml).
Product 4c was purified by column chromatography (l = 20 cm,
d = 2 cm) using a mixture of n-hexane/EtOAc (6:1) to afford 1.25 g
(97%) of 6c as a pale yellow oil. Rf 0.13 (n-hexane/EtOAc, 6:1).
MeOH (flow rate 3
lL/min). Nitrogen was applied as a dry gas; the
interface temperature was set at 180 °C. Specific optical rotations
ꢂC
½
a tD;
were measured on a Jasco DIP–D360 instrument at 589 nm.
ꢁ
The IR spectrum of 13 (KBr pellets) was recorded on a Specord
M82 instrument. Analytical high performance liquid chromatogra-
phy (HPLC) was performed on a Stayer chromatograph equipped
with an UV detector (k = 254 nm), using a DAICEL ChiralpakÒ
AD–H column and eluent: n-hexane/iPrOH = 70/30, flow rate:
0.7 mL/min. Melting points were measured with a Franz Küstner
Nachf. KG, Dresden HMK (Germany) apparatus and were uncor-
rected. Silica gels (0.060–0.200 nm and 0.035–0.070 (Acros)) were
used for column chromatography with the indicated eluents. The
reactions were monitored by TLC (silufol plates; visualization by
I2, UV, and for carbonyl compounds—by 0.5% 2,4-dinitrophenylhy-
drazine in 2 M HCl) with the indicated eluents. Air and/or moisture
sensitive compounds were kept under inert atmosphere at ꢀ14 °C.
Compounds 1, 2a,16a cis-2a,16b 3,31 19a,32 and 19b33 were pre-
pared according to the literature procedures. (E)-Cinnamaldehyde
18a was obtained from commercial sources and purified by
vacuum distillation before usage. 4-Chloro- 18b, 4-fluoro- 18c,
4-methoxy- 18d, 4-nitro- 18f (E)-cinnamaldehydes were prepared
according to the Battistuzzi’s procedure34 and purified by recrys-
tallization or distillation under reduced pressure. 3-Cyclopentyl-
oxy-4-methoxy-(E)-cinnamaldehyde 18e was prepared according
to Palomo’s procedure.35 Catalyst 21 was prepared according to
Ref. 36. Racemic compounds 20a–h were prepared using a race-
mic catalyst rac-2136 according to Ref. 17. All Grignard reagents
were prepared by a general procedure.37 Trimethylsilyl trifluo-
½
a 2D5
ꢁ
¼ þ7:2 (c 1.0, CHCl3). 1H NMR (CDCl3): d 1.75 (m, 2H, 4-H),
3
2.72 (d, JH,H = 11.7 Hz; 1H, 2-H), 3.20 (m, 2H, 2-H, CH2Ph), 3.52
3
(d, JH,H = 12.8 Hz; 1H, CH2Ph), 4.33 (m, 1H, 3-H), 4.52 (t,
3JH,H = 8.0 Hz; 1H, 5-H), 5,56 (s, 1H, OH), 6.96 (m, 2H, Ph-H), 7.23
(m, 3H, Ph-H), 7.75 (m, 2H, Ar-H), 8.06 (s, 2H, Ar-H), 8.24 (s, 2H,
Ar-H) ppm. 13C NMR (CDCl3): d 38.9, 61.8, 62.7, 70.8, 71.1, 76.2,
121.5, 121.6, 121.7, 125.1 (d, 3JC,F = 3.3 Hz), 125.7 (d, 3JC,F = 3.3 Hz),
126.1 (d, 3JC,F = 3.3 Hz), 127.6, 128.2, 128.7, 132.1 (q,
2JC,F = 33.7 Hz), 132.2 (q, JC,F = 33.2 Hz), 138.5, 147.2, 149.5 ppm.
2
Anal. Calcd for C28H21F12NO2 (631.45): C, 53.26; H, 3.35; N 2.22.
Found: C, 53.05; H, 3.19; N, 2.06.
4.2.3. (3R,5S)-1-Benzyl-5-(bis(3,5-dimethylphenyl)-
(hydroxy)methyl)pyrrolidin-3-yl 5-bromopentanoate 5b
5-Bromopentanoic acid (0.48 g, 2.7 mmol) was added to a solu-
tion of DCC (0.55 g, 2.7 mmol) and DMAP (0.03 g, 0.2 mmol) in
CH2Cl2 (20 ml) at 0 °C and compound 4b (0,89 g, 2.1 mmol) was
added in 10 min. The reaction mixture was stirred at 0 °C for 1 h.
Then DCC (0.27 g, 1.3 mmol) and 5-bromopentanoic acid (0.24 g,
1.3 mmol) were added and the reaction mixture was refluxed for
30 min. The reaction progress was monitored by TLC (n-hexane/
EtOAc, 6:1, Rf prod 0.32). The precipitate was filtered off and washed

O. V. Maltsev et al. / Tetrahedron: Asymmetry 21 (2010) 2659–2670
2665
with CH2Cl2 (3 ꢃ 15 ml). The organic filtrate was washed with
conc. HCl (1 ml), saturated aqueous NaHCO3 (2 ꢃ 10 ml), water
(15 ml), and dried over MgSO4. The solvent was evaporated in va-
cuo, and the product was isolated by column chromatography
(l = 17 cm, d = 2 cm) using a mixture of n-hexane/EtOAc (from
10:1 to 4:1) to afford 1.19 g (97%) of 5b as colorless oil.
and then cooled to room temperature. The product was dissolved
in a mixture of water (15 ml) and MeOH (5 ml). A solution of
KPF6 (0.34 g, 1.85 mmol) in water (10 ml) was added. MeOH was
removed under reduced pressure. When transparent solution was
formed, aqueous phase was decanted, and the residue was washed
with water (3 ꢃ 5 ml) to remove an excess of 1-methyl-1H-imidaz-
ole. Then the residue was dissolved in CH2Cl2 (30 ml), washed with
0.1 M solution of KPF6 (2 ꢃ 10 ml), and dried over MgSO4. The sol-
vent was evaporated, and the residue was dried under reduced
pressure (2 barr) to afford 0.32 g (55%) 6c-PF6 as a colorless solid.
½
a 2D5
ꢁ
¼ þ20:4 (c 1.0, CHCl3). 1H NMR (CDCl3): d 1.87 (m, 6H, 4-H,
2
CH2CH2CH2CO), 2.31 (m, 14H, CH3, CH2COO), 2.60 (dd, JH,H
=
3
11.7 Hz, JH,H = 3.3 Hz; 1H, 2-H), 3.24 (m, 3H, 2-H, CH2Ph), 3.43
3
3
(t, JH,H = 6.2 Hz; 2H, BrCH2), 4.26 (t, JH,H = 7.7 Hz; 1H, 5-H), 4.70
(s, 1H, OH), 5.05 (m, 1H, 3-H), 6.74 (s, 1H, Ar-H), 6.80 (s, 1H,
Ar-H), 7.00 (m, 2H, Ph-H), 7.22 (m, 5H, Ph-H, Ar-H), 7.34 (s, 2H,
Ar-H) ppm. 13C NMR (CDCl3): d 21.6, 21.7, 23.7, 32.1, 33.1, 33.6,
35.7, 59.5, 61.1, 70.7, 74.0, 76.9, 123.3, 123.6, 127.1, 128.3, 128.4,
128.7, 137.5, 137.6, 139.5, 145.6, 147.4, 172.6 ppm. Anal. Calcd
for C33H40BrNO3 (578.58): C, 68.50; H, 6.97; N, 2.42. Found: C,
68.27; H, 7.12; N, 2.22.
½
a 2D3
ꢁ
¼ ꢀ3:3 (c 1.0, CHCl3). 1H NMR (CDCl3): d 1.64 (m, 2H, 4-H),
1.92 (m, 4H, CH2CH2CH2COO), 2.41 (m, 2H, CH2COO), 2.82 (m,
1H, 2-H), 3.35 (m, 3H, 2-H, CH2Ph), 3.91 (s, 3H, CH3), 4.18 (m, 2H,
NCH2), 4.56 (m, 1H, 5-H), 5.06 (m, 1H, 3-H), 6.94 (br s, 2H, Ph-H),
7.21 (br s, 5H, Ph-H, NCHCHN), 7.73 (s, 2H, Ar-H), 8.09 (s, 2H, Ar-
H), 8.28 (s, 2H, Ar-H), 8.63 (s, 1H, NCHN) ppm. 13C NMR (CDCl3):
d 21.1, 29.1, 33.1, 35.9, 36.3, 49.7, 59.7, 61.2, 70.2, 73.6, 76.6,
3
121.5, 121.6, 122.3, 123.7, 125.1 (d, JC,F = 3.0 Hz), 125.8 (d,
3
4.2.4. (3R,5S)-1-Benzyl-5-(bis(3,5-bis(trifluoromethyl)-phenyl)-
(hydroxy)methyl)pyrrolidin-3-yl 5-bromopentanoate 5c
The title compound was prepared according to the procedure for
5b from 5-bromopentanoic acid (0.66 g, 3.68 mmol), DCC (0.75 g,
3.68 mmol), DMAP (24 mg, 0.20 mmol), 4c (1.24 g, 1.96 mmol),
and CH2Cl2 (16 ml).
3JC,F = 3.0 Hz), 126.2 (d, JC,F = 3.0 Hz), 127.6, 128.3, 128.7, 132.0
2
2
(q, JC,F = 33.6 Hz), 132.2 (q, JC,F = 33.6 Hz), 136.2, 138.2, 147.1,
149.3, 172.8 ppm. 19F NMR (CDCl3): d –72.5 (d, JP–F = 712 Hz)
1
ppm. 31P NMR (CDCl3): d ꢀ144.0 (heptet, 1JP–F = 712 Hz) ppm. Anal.
Calcd for C37H34F18N3O3P (941.63): C, 47.19; H, 3.64; N, 4.46.
Found: C, 47.02; H, 3.81; N, 4.59.
Product 5c was purified by column chromatography (l = 19 cm,
d = 2 cm) using a mixture of n-hexane/EtOAc (6:1) to afford 1.48 g
(95%) of 7c as a pale yellow oil. Rf 0.36 (n-hexane/EtOAc, 6:1).
4.2.7. 1-(5-((3R,5S)-5-(bis(3,5-Dimethylphenyl)-
(hydroxy)methyl)pyrrolidin-3-yloxy)-5-oxopentyl)-3-methyl-
1H-imidazol-3-ium bromide 1b-Br
½
a 2D5
ꢁ
¼ ꢀ3:9 (c 1.0, CHCl3). 1H NMR (CDCl3): d 1.87 (m, 6H, 4-H,
CH2CH2CH2COO), 2.36 (m, 2H, CH2COO), 2.81 (m, 1H, 2-H), 3.38
(m, 5H, 20-H, CH2Ph, BrCH2), 4.45 (m, 1H, 5-H), 5.12 (m, 1H, 3-H),
5.38 (s, 1H, OH), 6.95 (m, 2H, Ph-H), 7.25 (m, 3H, Ph-H), 7.77 (m,
2H, Ar-H), 8.05 (s, 2H, Ar-H), 8.24 (s, 2H, Ar-H) ppm. 13C NMR
(CDCl3): d 23.6, 32.1, 33.1, 33.6, 36.0, 60.0, 61.4, 70.6, 73.4, 76.3,
121.5, 121.7, 121.8, 125.1 (d, 3JC,F = 2.5 Hz), 125.6 (d, 3JC,F = 2.5 Hz),
A mixture of compound 6b (1.11 g, 1.7 mmol), 5% Pd/C (0.16 g),
and MeOH (22 ml) was stirred under a H2 atmosphere overnight at
room temperature. The catalyst was filtered off, the filtrate was
evaporated under reduced pressure, and the product obtained
was dried under a vacuum pump to give 0.96 g (100%) of 1b-Br
as a white hydroscopic solid. ½a D28
ꢁ
¼ ꢀ43:7 (c 1.0, CHCl3). 1H NMR
3
2
126.1 (d, JC,F = 2.5 Hz), 127.9, 128.3, 128.8, 132.3 (q, JC,F
=
(CDCl3): d 1.62 (m, 3H, 4-H, CH2CH2CH2COO), 2.06 (m, 3H, 4-H,
CH2CH2CH2COO), 2.34 (m, 14H, CH2COO, (CH3)2C6H3), 3.22 (d,
2
33.2 Hz), 132.4 (q, JC,F = 33.7 Hz), 138.7, 146.9, 149.0, 172.5 ppm.
Anal. Calcd for C33H28BrF12NO3 (794.47): C, 49.89; H, 3.55; N,
1.76. Found: C, 50.01; H, 3.79; N, 1.67.
2
2JH,H = 12.1 Hz; 1H, 2-H), 3.37 (d, JH,H = 12.1 Hz; 1H, 2-H), 4.02 (s,
3H, CH3), 4.35 (m, 3H, OH, NCH2), 4.66 (m, 1H, 5-H), 5.15 (m, 1H,
3-H), 6.79 (m, 2H, Ar-H), 7.05 (m, 2H, Ar-H), 7.35 (m, 4H, Ar-H,
NCHCHN), 10.28 (s, 1H, NCHN) ppm. 13C NMR (CDCl3): d 21.1,
21.4, 21.5, 29.4, 33.1, 33.2, 36.7, 49.5, 52.6, 63.7, 75.3, 76.9,
122.3, 123.0, 123.5, 123.6, 123.8, 128.2, 128.5, 137.2, 137.4,
137.7, 144.5, 146.9, 172.7 ppm. Anal. Calcd for C30H40BrN3O3
(570.56): C, 63.15; H, 7.07; N, 7.36. Found: C, 63.00; H, 7.30; N,
7.19.
4.2.5. 1-(5-((3R,5S)-1-Benzyl-5-(bis(3,5-dimethyl-
phenyl)(hydroxy)methyl)pyrrolidin-3-yloxy)-5-oxopentyl)-3-
methyl-1H-imidazol-3-ium bromide 6b
A mixture of compound 5b (1.17 g, 2 mmol) and 1-methyl-1H-
imidazole (0.41 g, 5 mmol) was heated at 100 °C for 10 min, cooled
to room temperature and washed with Et2O (5 ꢃ 4 ml) to separate
an excess of 1-methyl-1H-imidazole. The residue was dissolved in
MeOH (1 ml), and Et2O (20 ml) was added to the solution. The
ether layer was separated and the residue was washed with Et2O
(5 ꢃ 4 ml). The obtained product was dried under reduced pressure
(2 barr) to afford 1.17 g (88%) 6b as a colorless hydroscopic solid.
4.2.8. 1-(5-((3R,5S)-5-(bis(3,5-bis(Trifluoromethyl)-
phenyl)(hydroxy)methyl)pyrrolidin-3-yloxy)-5-oxo-pentyl)-3-
methyl-1H-imidazol-3-ium hexafluorophosphate 1c
The title compound was prepared according to the procedure
for 1b-Br from 6c-PF6 (0.30 g, 0.32 mmol), 5% Pd/C (100 mg), and
MeOH (5 ml). Yield 259 mg (95%). White solid. Mp 49–51 °C.
½
a 2D6
ꢁ
¼ þ19:5 (c 2.0, CHCl3). 1H NMR (CDCl3): d 1.64 (m, 2H, 4-H),
2.00 (m, 4H, CH2CH2CH2COO), 2.32 (m, 14H, CH2COO, (CH3)2C6H3),
2.66 (m, 1H, 2-H), 3.21 (m, 3H, 2-H, CH2Ph), 4.04 (s, 3H, CH3), 4.37
(m, 3H, 5-H, NCH2), 5.03 (m, 1H, 3-H), 6.76 (m, 2H, Ar-H), 7.03 (m,
2H, Ar-H), 7.27 (m, 9H, Ar-H, NCHCHN), 10.62 (s, 1H, NCHN) ppm.
13C NMR (CDCl3): d 21.2, 21.5, 21.6, 29.5, 33.2, 35.5, 36.7, 49.6, 59.2,
60.9, 70.4, 73.6, 77.0, 122.2, 123.2, 123.4, 127.0, 128.1, 128.3, 128.6,
137.4, 137.6, 139.1, 145.5, 147.1, 172.5 ppm. Anal. Calcd for
½
a 2D4
ꢁ
¼ ꢀ27:5 (c 1.0, CHCl3). 1H NMR (DMSO-d6): d 1.50 (m, 2H,
4-H), 1.90 (m, 4H, CH2CH2CH2COO), 2.37 (t, 3J = 7.0 Hz; 2H,
CH2COO), 3.13 (m, 2H, 2-H), 3.84 (s, 3H, CH3), 4.14 (m, 4H, OH,
NCH2, 5-H), 5.15 (m, 1H, 3-H), 7.70 (s, 1H, NCHCHN), 7.75 (s, 1H,
NCHCHN), 8.03 (s, 2H, Ar-H), 8.31 (s, 2H, Ar-H), 8.40 (s, 2H, Ar-
H), 9.12 (s, 1H, NCHN) ppm. 13C NMR (CD3OD): d 22.2, 30.3, 34.0,
34.3, 36.4, 50.4, 53.6, 65.0, 76.0, 78.6, 122.8, 122.9, 123.6, 124.9,
C37H46BrN3O3 (660.68): C, 67.26; H, 7.02; N, 6.36. Found: C,
67.02; H, 7.35; N, 6.52.
3
3
126.4, 126.5, 127.5 (d, JC,F = 2.8 Hz), 128.1 (d, JC,F = 2.8 Hz),
133.2 (q, JC,F = 32.6 Hz), 137.8, 148.3, 148.7, 174.4 ppm. 19F NMR
2
4.2.6. 1-(5-((3R,5S)-1-Benzyl-5-(bis(3,5-bis(trifluoromethyl)-
phenyl)(hydroxy)methyl)pyrrolidin-3-yloxy)-5-oxopentyl)-3-
methyl-1H-imidazol-3-ium hexafluorophosphate 6c-PF6
A mixture of compound 5c (0.49 g, 0.62 mmol) and 1-methyl-
1H-imidazole (0.26 g, 3.1 mmol) was heated at 100 °C for 10 min
(CD3OD): d ꢀ71.0 (d, JP–F = 710 Hz), ꢀ61.2, ꢀ61.1 ppm. 31P NMR
1
1
(CD3OD): d ꢀ139.7 (heptet, JP–F = 710 Hz) ppm. Anal. Calcd for
C
30H28F18N3O3P (851.51): C, 42.32; H, 3.31; N, 4.93. Found: C,
42.17; H, 3.50; N, 4.76.

2666
O. V. Maltsev et al. / Tetrahedron: Asymmetry 21 (2010) 2659–2670
3
4.2.9. 1-(5-((3R,5S)-5-(bis(3,5-Dimethylphenyl)-
(trimethylsilyloxy)methyl)pyrrolidin-3-yloxy)-5-oxopentyl)-3-
methyl-1H-imidazol-3-ium hexafluorophosphate 2b
(m, 2H, 4-H), 2.70 (d, JH,H = 12.4 Hz; 1H, 2-H), 3.17 (d,
3JH,H = 12.4 Hz; 2H, 2-H), 3.37 (s, 2H, CH2Ph), 3.69 (s, 2H, ICH2),
4.41 (t, JH,H = 8.1 Hz; 1H, 5-H), 4.83 (s, 1H, OH), 5.09 (m, 1H,
3
At first, Me3SiCl (98
cooled solution of 1b-Br (228 mg, 0.4 mmol) and Et3N (169
l
l, 87 mg, 0.8 mmol) was added to an ice-
3-H), 7.03 (m, 2H, Ph-H), 7.21 (m, 9H, Ph-H), 7.62 (d, 3JH,H = 7.1 Hz;
2H, Ph-H), 7.79 (d, 3J = 7.1 Hz; 2H, Ph-H) ppm. 13C NMR (CDCl3): d
ꢀ4.9, 35.4, 59.0, 61.1, 70.9, 76.0, 76.7, 125.4, 125.7, 126.7, 126.8,
127.3, 128.3, 128.5, 128.7, 145.6, 147.4, 168.2 ppm. Anal. Calcd
for C26H26INO3 (527.39): C, 59.21; H, 4.97; N, 2.66. Found: C,
59.00; H, 5.11; N, 2.39.
l
l,
121 mg, 1.2 mmol) in CH2Cl2 (1.2 ml) for 15 min. The reaction mix-
ture was stirred at room temperature for 20 h under Ar. The sol-
vent was evaporated and the residue dissolved in a mixture of
water (2 ml) and Et2O (1 ml). Next, Et2O was evaporated (<50 °C),
and MeOH (0.3 ml) was added to the remaining aqueous suspen-
sion. A solution of KPF6 (368 mg, 2.0 mmol) in water (4 ml) was
gradually added and the mixture was stirred for 10 min. The aque-
ous layer was decanted from the resulting oil, after which the res-
idue was dissolved in CH2Cl2 (40 ml) and the solution was washed
with 0.1 M KPF6 (2 ꢃ 10 ml), dried over MgSO4 and evaporated un-
der reduced pressure. The residue was dried in vacuo (2 barr) to af-
ford 2b (189 mg, 67%) as a reddish hydroscopic solid. Mp 47–49 °C.
4.2.12. 1-(2-((3R,5S)-1-Benzyl-5-(hydroxydiphenyl-
methyl)pyrrolidin-3-yloxy)-2-oxoethyl)-3-methyl-1H-imidazol-
3-ium iodide 8-I
The title compound was prepared according to the procedure
for 6b from 7 (0.51 g, 1.0 mmol) and 1-methyl-1H-imidazole
(0.21 g, 2.5 mmol) at 70 °C. Yield 0.58 g (97%). Pale yellow hydro-
scopic solid. ½a D22
ꢁ
¼ ꢀ5:4 (c 1.0, CHCl3). 1H NMR (CDCl3): d 2.11
3
½
a 2D8
ꢁ
¼ ꢀ19:5 (c 1.0, CHCl3). 1H NMR (CDCl3): d ꢀ0.10 (s, 9H,
(m, 2H, 4-H), 2.82 (d, JH,H = 12.5 Hz; 1H, 2-H), 3.26 (d,
3JH,H = 12.5 Hz; 2H, 2-H), 3.42 (s, 2H, CH2Ph), 3.94 (s, 3H, CH3),
4.66 (m, 1H, 5-H), 5.13 (m, 1H, 3-H), 5.50 (dd, J = 62.0 Hz,
J = 18.0 Hz; 2H, ICH2), 7.17 (m, 12H, Ph-H, NCHCHN), 7.57 (s, 1H,
Si(CH3)3), 1.77 (m, 6H, 4-H, CH2CH2CH2COO), 2.34 (m, 14H,
CH2COO, (CH3)2C6H3), 2.95 (m, 2H, 2-H), 3.90 (s, 3H, CH3), 4.16
3
(m, 2H, NCH2), 4.36 (t, JH,H = 7.0 Hz; 1H, 5-H), 4.98 (m, 1H, 3-H),
7.01 (m, 8H, Ar-H, NCHCHN), 8.65 (s, 1H, NCHN) ppm. 13C NMR
(CDCl3): d 2.3, 21.2, 21.5, 21.6, 29.1, 33.3, 34.7, 36.3, 49.7, 53.0,
64.4, 75.4, 83.0, 122.2, 123.7, 125.4, 126.1, 128.8, 128.9, 136.1,
137.1, 137.2, 144.9, 145.8, 173.0 ppm. 19F NMR (CDCl3): d ꢀ71.9
Ph-H), 7.67 (d, JH,H = 7.9 Hz; 2H, Ph-H), 7.83 (d, 3J = 7.9 Hz; 2H,
3
Ph-H), 9.98 (s, 1H, NCHN) ppm. 13C NMR (CDCl3): d 35.6, 37.0,
50.7, 58.8, 60.7, 70.1, 77.0, 77.4, 123.0, 124.1, 125.7, 125.8, 126.5,
126.7, 127.2, 128.0, 128.2, 128.4, 128.7, 137.5, 138.9, 145.7,
147.3, 165.6 ppm. Anal. Calcd for C30H32IN3O3 (609.50): C, 59.12;
H, 5.29; N, 6.89. Found: C, 59.40; H, 5.25; N, 6.68.
1
1
(d, JP–F = 714 Hz) ppm. 31P NMR (CDCl3): d ꢀ144.0 (heptet, JP–
F = 714 Hz) ppm. Anal. Calcd for C33H48F6N3O3PSi (707.80): C,
56.00; H, 6.84; N, 5.94. Found: C, 55.82; H, 6.99; N, 5.68.
4.2.13. (2S,4R)-1-Benzyl-2-(diphenyl(trimethylsilyloxy)-
methyl)-4-(trimethylsilyloxy)pyrrolidine 9
4.2.10. 1-(5-((3R,5S)-5-(bis(3,5-bis(Trifluoromethyl)phenyl)-
(trimethylsilyloxy)methyl)pyrrolidin-3-yloxy)-5-oxopentyl)-3-
methyl-1H-imidazol-3-ium hexafluorophosphate 2c
A mixture of 8-I (0.57 g, 0.93 mmol), 5% Pd/C (0.23 g), and
MeOH (10 ml) was stirred under H2 for 16 h at room temperature.
The catalyst was filtered off, and the filtrate was concentrated in
vacuo. The residue was dried under reduced pressure (2 barr) to
afford a colorless oil (0.5 g) as a mixture of 1-(2-methoxy-2-oxo-
ethyl)-3-methyl-1H-imidazol-3-ium iodide and (3R,5S)-1-benzyl-
5-(hydroxydiphenylmethyl)pyrrolidin-3-ol 3. 1H NMR of above
At first, Me3SiCl (26
ll, 22 mg, 0.2 mmol) was added to an ice-
cooled (0 °C) solution of 1c (85 mg, 0.1 mmol) and Et3N (40
l
l,
30 mg, 0.3 mmol) in CH2Cl2 (0.4 ml). The reaction mixture was stir-
red at room temperature for 20 h under Ar. The solvent was evap-
orated and the residue was dissolved in a mixture of water (2 ml)
and Et2O (1 ml). Next, Et2O was evaporated (<50 °C). The aqueous
layer was decanted from the separated oil, and the residue was dis-
solved in CH2Cl2 (20 ml), washed with 0.1 M KPF6 (2 ꢃ 10 ml),
dried over MgSO4, and evaporated. The residue was dried in vacuo
(2 barr) to afford 2c (87 mg, 95%) as a reddish hydroscopic solid.
3
mixture (CDCl3): d 2.14 (m, 2H, 3-H of 3), 2.89 (d, JH,H = 11.2 Hz;
3
1H, 3-H of 3), 3.28 (d, JH,H = 11.2 Hz; 2H, 5-H of 3), 3.62 (dd,
J = 62.0 Hz, J = 12.1 Hz; 2H, CH2Ph of 3), 3.83 (s, 3H, COOCH3),
3
4.03 (s, 3H, CH3N), 4.40 (m, 1H, 4-H of 3), 4.73 (t, JH,H = 7.7 Hz,
1H, 2-H of 3), 5.44 (s, 2H, ICH2), 7.20 (m, 12H, Ph-H, NCHCHN),
Mp 43–45 °C. ½a 2D4
ꢁ
¼ ꢀ2:9 (c 2.0, CHCl3). 1H NMR (CDCl3): d
7.54 (s, 1H, Ph-H of 3), 7.61 (d, JH,H = 8.1 Hz; 2H, Ph-H of 3), 7.80
3
3
ꢀ0.07 (s, 9H, Si(CH3)3), 1.77 (m, 6H, 4-H, CH2CH2CH2COO), 2.47
(m, 3H, CH2COO, NH), 3.07 (m, 2H, 2-H), 3.90 (s, 3H, CH3), 4.17
(m, 2H, NCH2), 4.55 (m, 1H, 5-H), 4.94 (m, 1H, 3-H), 7.23 (m, 2H,
NCHCHN), 7.77 (s, 2H, Ar-H), 7.85 (s, 2H, Ar-H), 8.00 (s, 2H, Ar-
H), 8.62 (s, 1H, NCHN) ppm. 13C NMR (CDCl3): d 1.9, 21.2, 29.1,
33.2, 34.8, 36.3, 49.7, 53.3, 63.3, 75.7, 82.2, 121.5, 121.6, 122.3,
123.7, 125.1, 125.2, 128.2 (m), 128.8 (m), 130.5, 131.0, 131.6,
132.1, 136.2, 146.1, 148.1, 172.9 ppm. 19F NMR (CDCl3): d ꢀ72.9
(d, JH,H = 8.1 Hz; 2H, Ph-H of 3), 9.93 (s, 1H, NCHN) ppm. 13C
NMR of above mixture (CDCl3): 37.2, 38.4, 50.6, 53.7, 61.5, 61.9,
70.4, 71.5, 77.2, 123.2, 124.0, 125.5, 125.7, 126.6, 126.8, 127.4,
128.2, 128.3, 128.4, 128.9, 137.6, 138.0, 145.7, 147.0, 166.3 ppm.
The oil was dissolved in CH2Cl2 (3.5 ml) and treated with Me3-
SiCl (0.31 ml, 2.4 mmol) and Et3N (0.45 ml, 3.4 mmol) at 0 °C with
stirring. The reaction mixture was kept at room temperature for
15 h. Then the solvent was evaporated, and the residue was dis-
solved in MeOH (20 ml). A solution of KPF6 (0.84 g, 4.5 mmol) in
water (14 ml) was added. After 5 min the water phase was dec-
anted, and the residue was dissolved in CH2Cl2 (25 ml), washed
with 0.1 M solution of KPF6 (2 ꢃ 5 ml), and dried over MgSO4.
The solvent was removed in vacuo. The residue was dried under re-
duced pressure (2 barr) to afford 0.35 g (62%) of 9 as a colorless oil.
1
(d, JP–F = 712 Hz), ꢀ63.7, ꢀ63.6 ppm. 31P NMR (CDCl3): d ꢀ144.9
1
(heptet, JP-F = 712 Hz) ppm. Anal. Calcd for C33H36F18N3O3PSi
(923.69): C, 42.91; H, 3.93; N, 4.55. Found: C, 42.76; H, 4.08; N,
4.38.
4.2.11. (3R,5S)-1-Benzyl-5-(hydroxydiphenylmethyl)-
pyrrolidin-3-yl 2-iodoacetate 7
The title compound was prepared according to the procedure
for 5b from 2-iodoacetic acid (1.16 g, 6.3 mmol), DCC (1.29 g,
6.3 mmol), DMAP (48 mg, 0.4 mmol), 4a (1.44 g, 4.0 mmol), and
CH2Cl2 (31 ml).
½
a 2D4
ꢁ
¼ ꢀ41:6 (c 1.0, CHCl3). 1H NMR (CDCl3): d ꢀ0.19 (s, 9H,
Si(CH3)3), ꢀ0.11 (s, 9H, Si(CH3)3), 1.92 (m, 2H, 3-H), 2.12 (t,
3JH,H = 8.0 Hz; 1H, 5-H), 2.53 (t, JH,H = 8.0 Hz; 1H, 5-H), 3.04 (m,
3
1H, 4-H), 3.87 (dd, J = 207.1 Hz, J = 12.8 Hz; 2H, CH2Ph), 4.08 (t,
3JH,H = 7.3 Hz; 1H, 2-H), 7.21 (m, 11H, Ph-H), 7.56 (m, 4H, Ph-H)
ppm. 13C NMR and JMOD (CDCl3): d ꢀ0.1 (4-(CH3)3SiO), 2.1
((CH3)3SiO), 38.3 (3-C), 61.4, (CH2Ph), 62.6 (5-C), 70.1 (2-C), 71.1
(4-C), 84.6 (C(Ph)2OTMS), aromatic carbons: 126.6, 127.2, 127.3,
127.4, 128.1, 128.8, 129.8, 129.9, 143.4, 143.9 ppm. HRMS (ESI)
Product 7 was purified by column chromatography (l = 15 cm,
d = 2 cm) using a mixture of n-hexane/EtOAc (from 10:1 to 3:1)
to afford 2.01 g (95%) of 7 as a dark yellow oil. Rf 0.6 (n-hexane/
EtOAc, 2:1). ½a 2D2
ꢁ
¼ þ5:0 (c 1.0, CHCl3). 1H NMR (CDCl3): d 1.98

O. V. Maltsev et al. / Tetrahedron: Asymmetry 21 (2010) 2659–2670
2667
calcd for C30H42NO2Si2 ([M+H]+): 504.2749, found: 504.2737.
13C NMR (CDCl3): d 14.1, 22.5, 25.8, 29.2, 31.5, 36.7, 56.8, 59.9,
60.3, 70.5, 76.7, 118.7, 125.2, 125.5, 126.8, 127.0, 127.4, 128.4,
128.6, 138.6, 145.9, 147.2, 148.5 ppm. Anal. Calcd for C31H36N4O
(480.64): C, 77.47; H, 7.55; N, 11.66. Found: C, 77.59; H, 7.33; N,
11.88.
þ
Anal. Calcd for C30H41NO2Si2 (503.82): C, 71.52; H, 8.20; N, 2.78.
Found: C, 71.40; H, 8.38; N, 2.59.
4.2.14. (3R,5S)-1-Benzyl-5-(hydroxydiphenylmethyl)-
pyrrolidin-3-yl 4-methylbenzenesulfonate 12
At first, 4-toluenesulfonyl chloride (TsCl) (0.94 g, 4.9 mmol) was
added to an ice-cooled solution of 4a (1.41 g, 3.9 mmol) in pyridine
(8 ml). The reaction mixture was stirred at 0 °C for 1 h and then at
room temperature for 25 h (TLC monitoring, n-hexane/EtOAc 2.5:1,
Rf prod 0.56). The solvent was evaporated in vacuo. The residue was
dissolved in CH2Cl2 (50 ml), washed with 1 M HCl (2 ꢃ 12 ml),
water (2 ꢃ 15 ml), and dried over MgSO4. The solvent was removed
under reduced pressure. The product was purified by column chro-
matography (l = 12 cm, d = 2 cm, eluent: a mixture n-hexane/EtOAc
(from 4:1 to 2:1) and then pure CHCl3). Yield 1.15 g (57%). White
4.2.17. 3-((3S,5S)-1-Benzyl-5-(hydroxydiphenylmethyl)-
pyrrolidin-3-yl)-1-methyl-5-pentyl-1H-1,2,3-triazol-3-ium
iodide 15-I
A
solution of 14 (0.39 mg, 0.81 mmol) and MeI (1.61 g,
11.34 mmol) in MeCN (15 ml) was refluxed for 6 h and then stirred
overnight at room temperature. The solvent and an excess of MeI
were evaporated. The residue was dried under reduced pressure
(2 barr) to afford 0.5 g (100%) of 15-I as a yellow solid. Mp
<50 °C. ½a 2D5
ꢁ
¼ þ44:1 (c 1.0, CHCl3). 1H NMR (CDCl3): d 0.94 (m,
3H, (CH2)4CH3), 1.40 (m, 4H, (CH2)2(CH2)2CH3), 1.74 (m, 2H,
CH2CH2(CH2)2CH3), 2.24 (m, 1H, 4-H), 2.84 (m, 3H, 4-H,
CH2(CH2)3CH3), 3.15 (m, 2H, 2-H, CH2Ph), 3.34 (m, 2H, 2-H, CH2Ph),
4.17 (s, 3H, CH3), 4.32 (t, 3JH,H = 13.6 Hz; 1H, 5-H), 4.55 (br, 1H, OH),
solid. Mp 137 °C (decomp.). ½a D24
ꢁ
¼ þ15:6 (c 1.0, CHCl3). 1H NMR
(CDCl3): d 1.84 (m, 1H, 4-H), 2.01 (m, 1H, 4-H), 2.44 (s, 3H, CH3),
3
3
2.81 (d, JH,H = 12.5 Hz, 1H, 2-H), 3.02 (d, JH,H = 11.5 Hz, 1H, 2-H),
3.31 (s, 2H, CH2Ph), 4.37 (m, 1H, 5-H), 4.70 (br, 1H, OH), 4.79 (m,
1H, 3-H), 6.93 (m, 2H, Ar-H), 7.26 (m, 11H, Ar-H), 7.51 (d,
3JH,H = 7.7 Hz; 2H, Ar-H), 7.76 (m, 4H, Ar-H) ppm. 13C NMR (CDCl3):
d 21.7, 36.1, 59.2, 61.2, 70.5, 76.7, 81.7, 125.3, 125.6, 126.6, 126.9,
127.2, 127.8, 128.2, 128.4, 128.5, 128.6, 130.0, 134.1, 139.1, 145.0,
145.4, 147.2 ppm. Anal. Calcd for C31H31NO4S (513.65): C, 72.49; H,
6.08; N, 2.73. Found: C 72.40, H 6.18, N 2.62.
3
5.80 (m, 1H, 3-H), 7.18 (m, 11H, Ph-H), 7.52 (d, JH,H = 7.5 Hz; 2H,
3
Ph-H), 7.71 (d, JH,H = 7.5 Hz; 2H, Ph-H), 8.85 (s, 1H, CCHN) ppm.
13C NMR (CDCl3): d 13.9, 22.2, 23.7, 26.7, 30.9, 36.4, 38.7, 58.4,
59.6, 61.9, 69.7, 77.2, 125.2, 125.5, 126.8, 127.0, 127.4, 128.1,
128.4, 128.5, 138.3, 144.3, 145.5, 146.5 ppm. Anal. Calcd for
C32H39IN4O (622.58): C, 61.73; H, 6.31; N, 9.00. Found: C, 61.49;
H, 6.60; N, 8.88.
4.2.15. ((2S,4S)-4-Azido-1-benzylpyrrolidin-2-yl)-
diphenylmethanol 13
4.2.18. 3-((3S,5S)-1-Benzyl-5-(hydroxydiphenylmethyl)-
pyrrolidin-3-yl)-1-methyl-5-pentyl-1H-1,2,3-triazol-3-ium
hexafluorophosphate 15-PF6
A mixture of 12 (0.56 g, 1.1 mmol), NaN3 (0.21 g, 3.3 mmol), and
dry DMSO (4 ml) was stirred under Ar at 65 °C for 26 h. The mix-
ture was diluted with EtOAc (80 ml), washed with water
(3 ꢃ 15 ml), and dried over MgSO4. The solvent was removed under
reduced pressure to afford a white solid. A mixture of n-hexane/
EtOAc (6:1) was added and the solid was filtered off, washed with
the same mixture, and dried to afford 0.36 g (86%) of 13 as a white
A solution of KPF6 (368 mg, 2.0 mmol) in water (4 ml) was
added to a solution of 15-I (500 g, 0.8 mmol) in a mixture of MeOH
(12 ml) and water (2 ml). Next, MeOH was evaporated. The residue
was extracted with CH2Cl2 (20 ml), washed with 0.1 M KPF6
(2 ꢃ 5 ml), and dried over MgSO4. The solvent was evaporated.
The residue was dried under reduced pressure (2 barr) to afford
solid. Rf 0.73 (n-hexane/EtOAc, 2:1). Mp 198ꢀ200 °C. ½a D22
ꢁ
¼ þ96:1
460 mg (89%) of 15-PF6 as a pale yellow solid. Mp 70ꢀ72 °C. ½a D24
ꢁ
(c 1.0, CHCl3). IR (KBr, cmꢀ1):
m
2108 (N3), 3324 (OH). 1H NMR
¼ þ39:4 (c 1.0, CHCl3). 1H NMR (CDCl3): d 0.93 (m, 3H, (CH2)4CH3),
1.38 (m, 4H, (CH2)2(CH2)2CH3), 1.69 (m, 2H, CH2CH2(CH2)2CH3),
2.20 (m, 1H, 4-H), 2.76 (m, 3H, 4-H, CH2(CH2)3CH3), 3.10 (m, 2H,
2-H, CH2Ph), 3.37 (m, 2H, 2-H, CH2Ph), 4.08 (s, 3H, CH3), 4.31 (m,
2H, 5-H, OH), 5.14 (m, 1H, 3-H), 7.03 (m, 2H, Ph-H), 7.21 (m, 9H,
(CDCl3): d 1.88 (m, 1H, 3-H), 2.30 (m, 1H, 3-H), 2.56 (m, 1H, 5-H),
2.92 (m, 3H, 5-H, CH2Ph), 3.26 (d, J = 13.2 Hz, 1H, CH2Ph), 3.89
(m, 1H, 4-H), 4.06 (m, 1H, 2-H), 4.77 (br, 1H, OH), 7.19 (m, 11H,
3
3
Ph-H), 7.60 (d, JH,H = 7.6 Hz; 2H, Ph-H), 7.74 (d, JH,H = 7.6 Hz;
2H, Ph-H) ppm. 13C NMR (CDCl3): d 35.6, 58.4, 59.9, 60.1, 70.0,
77.0, 125.5, 125.7, 126.6, 126.8, 127.3, 128.4, 128.5, 138.9, 146.5,
147.4 ppm. Anal. Calcd for C24H24N4O (384.47): C, 74.97; H, 6.29;
N, 14.57. Found: C, 75.15; H, 6.11; N, 14.66.
3
3
Ph-H), 7.51 (d, JH,H = 7.7 Hz; 2H, Ph-H), 7.70 (d, JH,H = 7.7 Hz;
2H, Ph-H), 7.98 (s, 1H, CCHN) ppm. 13C NMR (CDCl3): d 13.9,
22.2, 23.2, 26.5, 30.9, 36.1, 37.5, 58.3, 59.7, 61.5, 69.8, 77.2,
125.2, 125.5, 126.8, 127.0, 127.1, 127.6, 128.6, 128.7, 138.2,
1
144.8, 145.5, 146.5 ppm. 19F NMR (CDCl3): d ꢀ74.3 (d, JP–F
=
1
4.2.16. ((2S,4S)-1-Benzyl-4-(4-pentyl-1H-1,2,3-triazol-1-
yl)pyrrolidin-2-yl)diphenylmethanol 14
712 Hz) ppm. 31P NMR (CDCl3): d ꢀ144.6 (heptet, JP–F = 712 Hz)
ppm. Anal. Calcd for C32H39F6N4OP (640.64): C, 59.99; H, 6.14; N,
8.75. Found: C, 59.76; H, 6.53; N, 8.31.
Hept-1-yne (113 mg, 1.18 mmol) and CuI (27 mg, 0.14 mmol)
were added to a suspension of 13 (361 mg, 0.94 mmol) in a mix-
ture of distilled DMSO (3.4 ml) and water (0.4 ml). The reaction
mixture was stirred in a Schlenk flask at 65 °C for 48 h. When
the reaction was complete (TLC monitoring, n-hexane/EtOAc, 2:1,
Rf prod 0.46), the product was dissolved in CHCl3 (100 ml), washed
successively with water (2 ꢃ 20 ml), and brine (1 ꢃ 15 ml), and
dried over MgSO4. Then the solvent was removed under reduced
pressure. The product was purified by column chromatography
(l = 10 cm, d = 2 cm, eluent: n-hexane/EtOAc (from 2:1 to 1:2)) to
afford 387 mg (86%) of 14 as a white solid. Mp 166–168 °C.
4.2.19. 3-((3S,5S)-5-(Hydroxydiphenylmethyl)-pyrroli-din-3-yl)-
1-methyl-5-pentyl-1H-1,2,3-triazol-3-ium hexafluorophosphate
16
The title compound was prepared according to the procedure
for 1b-Br from 15-PF6 (0.46 g, 0.72 mmol), 5% Pd/C (0.17 g), and
MeOH (12 ml). Yield 328 mg (83%). White solid. Mp 86ꢀ88 °C.
½
a 3D0
ꢁ
¼ ꢀ6:9 (c 1.0, CHCl3). 1H NMR (DMSO-d6): d 0.90 (m, 3H,
(CH2)4CH3), 1.37 (m, 4H, (CH2)2(CH2)2CH3), 1.67 (m, 2H, CH2CH2
(CH2)2CH3), 1.84 (m, 1H, 4-H), 2.59 (m, 1H, 4-H), 2.82 (t,
3JH,H = 7.7 Hz; 2H, CH2(CH2)3CH3), 3.74 (m, 1H, 2-H), 3.89 (m, 1H,
2-H), 4.21 (m, 4H, 5-H, CH3), 5.20 (br, 1H, OH), 5.55 (m, 1H, 3-H),
½
a 2D1
ꢁ
¼ þ8:0 (c 1.0, CHCl3). 1H NMR (CDCl3): d 0.90 (m, 3H, CH3),
1.32 (m, 4H, CH2CH2CH3), 1.61 (m, 2H, CH2CH2CH2CH3), 2.14 (m,
1H, 3-H), 2.62 (m, 3H, 3-H, CH2(CH2)3CH3), 3.05 (m, 2H, CH2Ph),
3.21 (m, 1H, 5-H), 3.45 (m, 1H, 5-H), 4.25 (m, 1H, 2-H), 4.79 (br,
1H, OH), 5.00 (m, 1H, 4-H), 7.19 (m, 12H, Ph-H), 7.60 (d,
3
7.29 (m, 6H, Ph-H), 7.52 (d, JH,H = 7.5 Hz; 2H, Ph-H), 7.64 (d,
3JH,H = 7.5 Hz; 2H, Ph-H), 8.97 (s, 1H, CCHN) ppm. 13C NMR
(DMSO-d6): d 13.7, 21.7, 22.3, 25.8, 30.3, 32.1, 37.4, 48.4, 60.1,
64.5, 76.6, 125.3, 125.7, 125.8, 127.2, 127.5, 128.2, 128.4, 128.5,
3JH,H = 7.2 Hz; 2H, Ph-H), 7.78 (d, JH,H = 7.2 Hz; 2H, Ph-H) ppm.
3

2668
O. V. Maltsev et al. / Tetrahedron: Asymmetry 21 (2010) 2659–2670
1
143.7, 144.2 ppm. 19F NMR (DMSO-d6): d ꢀ74.0 (d, JP–F = 711 Hz)
158.8, 159.3 ppm. HPLC analysis: tR = 16.6 min (major), 18.7 min
(minor). Anal. Calcd for C17H16ClNO4 (333.77): C, 61.18; H, 4.83;
N, 4.20. Found: C, 61.00; H, 5.02; N, 4.03.
ppm. 31P NMR (DMSO-d6): d ꢀ144.0 (heptet, JP–F = 711 Hz) ppm.
1
Anal. Calcd for C25H33F6N4OP (550.52): C, 54.54; H, 6.04; N,
10.18. Found: C, 54.35; H, 6.37; N, 10.01.
4.3.3. (3S)-Benzyl 3-(4-fluorophenyl)-5-hydroxy-isoxazolidine-
2-carboxylate 20c
4.2.20. 3-((3S,5S)-5-(Diphenyl(trimethylsilyloxy)-
methyl)pyrrolidin-3-yl)-1-methyl-5-pentyl-1H-1,2,3-triazol-3-
ium hexafluorophosphate 17
Yield 91%, 68% ee (major). Mixture of diastereomers, dr = 2.5:1.
Colorless oil. Eluent for column chromatography: n-hexane/EtOAc
(3:1). ½a 2D8
ꢁ
¼ þ0:3 (c 1.0, CHCl3). 1H NMR (CDCl3): d 2.26 (m, 1H, 4-
At first, TMSOTf (109 lL, 133 mg, 0.6 mmol) was added in one
3
H major), 2.50 (m, 1H, 4-H minor), 2.77 (dd, JH,H = 12.5 Hz,
3JH,H = 8.2 Hz; 1H, 4-H major), 3.12 (m, 1H, 4-H minor), 5.18 (m,
portion to an ice-cooled solution of 16 (110 mg, 0.2 mmol) and
2,6-lutidine (107 mg, 1.0 mmol) in dry CH2Cl2 (0.5 ml). The reac-
tion mixture was stirred at room temperature for 48 h. The solvent
was evaporated under reduced pressure. A mixture of water (1 ml)
and Et2O (1 ml) was added to the residue, then Et2O was evapo-
rated, and the water phase was decanted. The residue was washed
with water (2 ꢃ 2 ml) and dissolved in CH2Cl2 (20 ml). The organic
phase was washed with 0.1 M KPF6 (2 ꢃ 3 ml) and dried over
MgSO4. The solvent evaporation afforded 117 mg (94%) of 17 as a
3
2H, CH2Ph mixture of major and minor), 5.35 (t, JH,H = 8.2 Hz;
1H, 3-H major), 5.51 (m, 1H, 3-H minor), 5.78 (m, 1H, 5-H major),
6.16 (m, 1H, 5-H minor), 7.01 (m, 2H, Ar-H mixture of major and
minor), 7.31 (m, 7H, Ar-H mixture of major and minor) ppm. 13C
NMR (CDCl3): d 39.9 (minor), 45.3 (major), 60.9 (major), 62.3
(minor), 68.4 (major), 68.6 (minor), 88.7 (minor), 98.7 (major),
115.6 (m, Ar-H mixture of major and minor), 127.6, 127.8,
127.9, 128.2, 128.3, 128.4, 128.5, 128.6, 135.4, 135.6, 137.2,
156.4, 158.8, 159.3, 159.4, 160.6, 163.9 ppm. HPLC analysis: tR =
15.8 min (major), 17.7 min (minor). Anal. Calcd for C17H16FNO4
(317.31): C, 64.35; H, 5.08; N, 4.41. Found: C, 64.07; H, 5.29; N,
4.09.
yellow oil. ½a 2D8
ꢁ
¼ ꢀ23:6 (c 1.0, CHCl3).1H NMR (CDCl3): d ꢀ0.09
(s, 9H, (CH3)3Si), 0.89 (m, 3H, (CH2)4CH3), 1.34 (m, 4H, (CH2)2(CH2)2
CH3), 1.61 (m, 2H, CH2CH2(CH2)2CH3), 2.38 (m, 1H, 4-H), 2.61 (m,
3H, 4-H, CH2(CH2)3CH3), 3.01 (m, 1H, 2-H), 3.24 (m, 1H, 2-H),
3.85 (m, 1H, 5-H), 3.97 (s, 3H, CH3), 4.84 (br, 1H, OH), 5.56 (m,
1H, 3-H), 7.37 (m, 10H, Ph-H), 7.79 (s, 1H, CCHN) ppm. 13C NMR
(CDCl3): d 1.8, 13.9, 22.2, 23.2, 26.3, 31.0, 31.1, 37.3, 62.2, 65.9,
76.7, 82.0, 126.1, 127.1, 127.8, 128.3, 128.4, 128.8, 128.9, 129.0,
129.5, 129.8, 130.3, 142.1, 144.9 ppm. 19F NMR (CDCl3): d ꢀ73.8
4.3.4. (3S)-Benzyl 3-(4-methoxyphenyl)-5-hydroxy-
isoxazolidine-2-carboxylate 20d
Yield 79%, 77% ee (major). Mixture of diastereomers, dr = 2:1.
Pale yellow oil. Eluent for column chromatography: n-hexane/
1
1
(d, JP–F = 712 Hz) ppm. 31P NMR (CDCl3): d ꢀ144.5 (heptet, JP–F
=
EtOAc (from 3:1 to 2:1). ½a D28
ꢁ
¼ ꢀ4:6 (c 1.0, CHCl3). 1H NMR
712 Hz) ppm. Anal. Calcd for C28H41F6N4OPSi (622.70): C, 54.01;
H, 6.64; N, 9.00. Found: C, 53.78; H, 6.89; N, 9.34.
(CDCl3): d 2.30 (m, 1H, 4-H major), 2.53 (m, 1H, 4-H minor), 2.74
3
3
(dd, JH,H = 12.8 Hz, JH,H = 8.2 Hz; 1H, 4-H major), 3.09 (m, 1H, 4-
H minor), 3.79 (m, 3H, CH3 mixture of major and minor), 5.18
(m, 2H, CH2Ph mixture of major and minor), 5.33 (t, 3JH,H = 8.2 Hz;
1H, 3-H major), 5.49 (m, 1H, 3-H minor), 5.78 (m, 1H, 5-H major),
6.18 (m, 1H, 5-H minor), 6.86 (m, 2H, Ar-H mixture of major and
minor), 7.30 (m, 7H, Ar-H mixture of major and minor) ppm. 13C
NMR (CDCl3): d 39.7 (minor), 45.3 (major), 55.4 (OCH3 mixture of
major and minor), 61.0 (major), 62.6 (minor), 68.2 (major), 68.5
(minor), 88.8 (minor), 98.8 (major), 114.1, 127.2, 127.5, 127.8,
128.2, 128.3, 128.5, 128.6, 133.5, 135.5, 135.7, 156.3, 158.9,
159.1, 159.4 ppm. HPLC analysis: tR = 21.7 min (major), 23.2 min
(minor). Anal. Calcd for C18H19NO5 (329.35): C, 65.64; H, 5.81; N,
4.25. Found: C, 65.44; H, 5.99; N, 4.02.
4.3. General procedure for the domino reaction
A mixture of a,b-unsaturated aldehyde 18 (0.35 mmol, 1 equiv),
N-protected hydroxylamine 19 (0.44 mmol, 1.25 equiv), catalyst 2a
or cis-2a (23 mg, 0.035 mmol, 10 mol %), and toluene (0.7 ml) was
stirred at room temperature for indicated time (Table 3). The sol-
vent was removed under reduced pressure, and the product was
extracted with Et2O (2 ꢃ 1 ml). The combined extracts were evap-
orated to afford crude compounds 20. For analytical purposes com-
pounds 20 were purified by column chromatography with the
indicated solvent. If appropriate, the catalyst was reused.
4.3.5. (3S)-Benzyl 3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-
hydroxyisoxazolidine-2-carboxylate 20e
4.3.1. (3S)-Benzyl 5-hydroxy-3-phenylisoxazolidine-2-
carboxylate 20a
Yield 73%, 88% ee (major). Mixture of diastereomers, dr = 2:1.
Pale yellow oil. Eluent for column chromatography: n-hexane/
Yield 90%, 90% ee. Mixture of diastereomers, dr = 9:1. Colorless
oil. Eluent for column chromatography: n-hexane/EtOAc (3:1). All
analytical data were in agreement with the literature.17 HPLC anal-
ysis: tR = 13.8 min (major), 15.5 min (minor).
EtOAc (from 3:1 to 2:1). ½a D28
ꢁ
¼ ꢀ5:6 (c 1.0, CHCl3). 1H NMR
(CDCl3): d 1.72 (m, 8H, CH2-cyclopentyl mixture of major and min-
or), 2.30 (m, 1H, 4-H major), 2.54 (m, 1H, 4-H minor), 2.74 (dd,
3
3JH,H = 12.8 Hz, JH,H = 8.4 Hz; 1H, 4-H major), 3.09 (m, 1H, 4-H
4.3.2. (3S)-Benzyl 3-(4-chlorophenyl)-5-hydroxy-isoxazolidine-
2-carboxylate 20b
minor), 3.83 (m, 3H, CH3O mixture of major and minor), 4.72 (m,
1H, CH-cyclopentyl mixture of major and minor), 5.19 (m, 2H,
CH2Ph mixture of major and minor), 5.30 (m, 1H, 3-H major),
5.46 (m, 1H, 3-H minor), 5.78 (m, 1H, 5-H major), 6.18 (m, 1H,
5-H minor), 6.85 (m, 2H, Ar-H mixture of major and minor), 7.31
(m, 6H, Ph-H mixture of major and minor) ppm. 13C NMR (CDCl3):
d 24.1, 32.8, 39.7 (minor), 45.3 (major), 56.2, 61.2 (major), 62.8
(minor), 68.2 (major), 68.5 (minor), 80.5, 88.8 (minor), 98.7 (ma-
jor), 112.2, 122.9, 113.1, 118.1, 118.3, 127.8, 128.1, 128.2, 128.3,
128.5, 128.6, 133.8, 133.9, 135.5, 135.6, 135.7, 148.0, 149.5,
156.3, 158.9, 159.5 ppm. HPLC analysis: tR = 16.5 min (major),
17.6 min (minor). Anal. Calcd for C23H27NO6 (413.46): C, 66.81;
H, 6.58; N, 3.39. Found: C, 66.67; H, 6.87; N, 3.12.
Yield 91%, 75% ee (major). Mixture of diastereomers, dr = 6:1.
Colorless oil. Eluent for column chromatography: n-hexane/EtOAc
(3:1). ½a 2D8
ꢁ
¼ ꢀ20:7 (c 1.0, CHCl3). 1H NMR (CDCl3): d 2.25 (m, 1H,
3
4-H major), 2.49 (m, 1H, 4-H minor), 2.78 (dd, JH,H = 12.5 Hz,
3JH,H = 8.2 Hz; 1H, 4-H major), 3.13 (m, 1H, 4-H minor), 5.18 (m,
3
2H, CH2Ph mixture of major and minor), 5.35 (t, JH,H = 8.2 Hz;
1H, 3-H major), 5.50 (m, 1H, 3-H minor), 5.82 (m, 1H, 5-H major),
6.15 (m, 1H, 5-H minor), 7.30 (m, 9H, Ar-H mixture of major and
minor) ppm. 13C NMR (CDCl3): d 39.8 (minor), 45.3 (major), 60.9
(major), 62.4 (minor), 68.4 (major), 68.6 (minor), 88.7 (minor),
98.8 (major), 127.4, 127.6, 127.9, 128.1, 128.2, 128.3, 128.5,
128.6, 128.7, 128.8, 128.9, 133.4, 135.4, 135.6, 140.0, 156.3,

O. V. Maltsev et al. / Tetrahedron: Asymmetry 21 (2010) 2659–2670
2669
4.3.6. (3S)-Benzyl 3-(4-nitrophenyl)-5-hydroxy-isoxazolidine-2-
References
carboxylate (ꢀ)-20f
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4097.
Yield 94%, 99.5% ee (major). Mixture of diastereomers, dr = 5:1.
White solid. Eluent for column chromatography: n-hexane/EtOAc
(from 3:1 to 1:1). Mp 104 °C (decomp.). ½a D28
¼ ꢀ21:7 (c 1.0, CHCl3).
ꢁ
1H NMR (CDCl3): d 2.25 (m, 1H, 4-H major), 2.50 (m, 1H, 4-H min-
or), 2.86 (dd, 3JH,H = 12.5 Hz, 3JH,H = 8.4 Hz; 1H, 4-H major), 3.22 (m,
1H, 4-H minor), 5.19 (m, 2H, CH2Ph mixture of major and minor),
3
5.47 (t, JH,H = 8.4 Hz; 1H, 3-H major), 5.62 (m, 1H, 3-H minor),
5.83 (m, 1H, 5-H major), 6.16 (m, 1H, 5-H minor), 7.31 (m, 5H,
Ph-H mixture of major and minor), 7.50 (m, 2H, Ar-H mixture of
major and minor), 8.19 (m, 2H, Ar-H mixture of major and minor)
ppm. 13C NMR (CDCl3): d 39.9 (minor), 45.1 (major), 61.0 (major),
62.4 (minor), 68.7 (major), 68.8 (minor), 88.7 (minor), 98.8 (major),
123.8, 124.1, 126.9, 127.0, 127.3, 127.9, 128.1, 128.3, 128.5, 128.6,
135.3, 147.4, 148.7, 156.4, 159.3 ppm. HPLC analysis: tR = 31.8 min
(major), 35.9 min (minor). Anal. Calcd for C17H16N2O6 (344.32): C,
59.30; H, 4.68; N, 8.14. Found: C, 59.16; H, 4.90; N, 7.96.
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4.3.7. (3R)-Benzyl 3-(4-nitrophenyl)-5-hydroxy-isoxazolidine-2-
carboxylate (+)-20g
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11. Gröger, H. Ernst Schering Found Symp Proc 2008, 2007, 141.
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The title compound was prepared according to the general
method using catalyst cis-2a. Yield 87%, >99% ee (major). Mixture
of diastereomers, dr = 7:1. White solid. Eluent for column chroma-
tography: n-hexane/EtOAc (from 3:1 to 1:1). Mp 104 °C (decomp.).
½
a 2D8
ꢁ
¼ þ27:1 (c 1.0, CHCl3). 1H NMR (CDCl3): d 2.25 (m, 1H, 4-H
3
major), 2.49 (m, 1H, 4-H minor), 2.86 (dd, JH,H = 12.8 Hz,
3JH,H = 8.4 Hz; 1H, 4-H major), 3.22 (m, 1H, 4-H minor), 5.19 (m,
3
2H, CH2Ph mixture of major and minor), 5.47 (t, JH,H = 8.4 Hz;
ˇ
M. P.; Afonso, C. A. M. Chem. Rev. 2009, 109, 418; (d) Toma, Š.; Meciarová, M.;
1H, 3-H major), 5.61 (m, 1H, 3-H minor), 5.83 (m, 1H, 5-H major),
6.15 (m, 1H, 5-H minor), 7.31 (m, 5H, Ph-H mixture of major and
minor), 7.50 (m, 2H, Ar-H mixture of major and minor), 8.19 (m,
2H, Ar-H mixture of major and minor) ppm. 13C NMR (CDCl3): d
39.9 (minor), 45.1 (major), 61.0 (major), 62.4 (minor), 68.7 (major),
68.8 (minor), 88.7 (minor), 98.8 (major), 123.8, 124.1, 126.9, 127.0,
127.3, 127.9, 128.1, 128.3, 128.5, 128.6, 135.3, 147.4, 148.7, 156.4,
159.3 ppm. HPLC analysis: tR = 36.05 min (major), n.d. (minor).
Anal. Calcd for C17H16N2O6 (344.32): C, 59.30; H, 4.68; N, 8.14.
Found: C, 59.10; H, 4.95; N, 7.90.
Šebesta, R. Eur. J. Org. Chem. 2009, 321; (e) Šebesta, R.; Kmentová, I.; Toma, Š.
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4.3.8. (3S)-Benzyl 5-hydroxy-3-phenylisoxazolidine-2-
carboxylate 20h
Yield 78%, 67% ee (major). Mixture of diastereomers, dr = 9:1.
Colorless oil. All analytical data were in agreement with the litera-
ture.17 HPLC analysis: tR = 8.3 min (major), 10.1 min (minor).
4.4. Catalyst recycling
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A mixture of (E)-cinnamaldehyde 18a (20 mg, 0.15 mmol),
N-Cbz-hydroxylamine 19a (32 mg, 0.19 mmol), and catalyst 2a
(10 mol %, 10 mg) in the indicated solvent (Tables 1 and 2)
(0.3 ml) was stirred for an indicated time (Tables 1 and 2). The
solvent was evaporated in vacuo, after which product 20a was
extracted with Et2O (2 ꢃ 1 ml). The combined organic extracts
were evaporated to afford product 20a. The remaining catalyst
was dried under reduced pressure (2 barr) and reused in the same
reaction without further purification.
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Acknowledgments
High resolution mass spectra were recorded in the Department
of Structural Studies of N.D. Zelinsky Institute of Organic Chemis-
try, Russian Academy of Sciences. This work was supported by
the Ministry of Education and Science of the Russian Federation
(contract N 02.740.11.0630) and by the Russian Foundation of Ba-
sic Research (grants Nos. 09-03-00384 and 09-03-12164).

2670
O. V. Maltsev et al. / Tetrahedron: Asymmetry 21 (2010) 2659–2670
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