Hydroxy-α-amino acids modified by ionic liquid moieties: recoverable organocatalysts for asymmetric aldol reactions in the presence of water

Article abstract of DOI:10.1016/j.tet.2008.12.045

New chiral ionic liquids bearing proline, serine or threonine moieties were synthesized. Compounds that contain 1-dodecylimidazolium or 4-(5-n-nonyl)-pyridinium cations and NTf₂ or PF₆ anions efficiently catalyze the asymmetric aldol reaction between aldehydes and ketones in the presence of water to generate aldols with high distereo- (up to 98:2) and enantioselectivity (up to >99% ee). 4-Hydroxyproline modified by the 4-(5-n-nonyl)-pyridinium hexafluorophosphate moiety retains its activity and selectivity over at least eight reaction cycles.

Full text of DOI:10.1016/j.tet.2008.12.045

Tetrahedron 65 (2009) 1366–1372
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Hydroxy-a-amino acids modified by ionic liquid moieties: recoverable
organocatalysts for asymmetric aldol reactions in the presence of water
*
Dmitriy E. Siyutkin, Alexander S. Kucherenko, Sergei G. Zlotin
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prospect, 119991 Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
New chiral ionic liquids bearing proline, serine or threonine moieties were synthesized. Compounds that
contain 1-dodecylimidazolium or 4-(5-n-nonyl)-pyridinium cations and NTf2 or PF6 anions efficiently
catalyze the asymmetric aldol reaction between aldehydes and ketones in the presence of water to
generate aldols with high distereo- (up to 98:2) and enantioselectivity (up to >99% ee). 4-Hydroxy-
proline modified by the 4-(5-n-nonyl)-pyridinium hexafluorophosphate moiety retains its activity and
selectivity over at least eight reaction cycles.
Received 17 September 2008
Received in revised form 26 November 2008
Accepted 11 December 2008
Available online 24 December 2008
Keywords:
Direct asymmetric aldol reaction
Water
Ó 2009 Elsevier Ltd. All rights reserved.
Chiral ionic liquid
Recoverable organocalatyst
a
-Amino acid
1. Introduction
establishing the acid–base equilibrium and on the energy and
special architecture of the enamine transition state. The highest
An asymmetric aldol reaction is one of the most common
methods for C–C bond formation in organic molecules. It is
extensively applied in the synthesis of carbohydrates, amino
sugars, steroids, and other valuable chiral organic compounds.1 In
nature, the reaction is catalyzed by aldolase enzymes.2 It was
ascertained that the reaction could be performed at a higher rate
and with higher selectivity under the action of some more ele-
mentary organic molecules, so-called ‘organocatalysts’. These
include proline,3 its derivatives,4 other natural amino acids,5 2-
pyrrolidine derivatives,6 and small peptides.5c,7 Note that some of
the recently synthesized organocatalysts exceed proline and other
amino acids in their activity and selectivity. Unlike aldolases that
catalyze the aldol reaction in aqueous medium, the reactions
catalyzed by synthetic organocatalysts are normally carried out
in an excess of reacting ketone,3b,4a,b,d,f,l,6c,d,7a,c,e organic sol-
vents,3a–d,g,i,n,q,4a,f,h,i,5c,6a,c,d,7a–c,h or ionic liquids.3e,j,4c
conversion and selectivity were achieved in the reactions running
under the action of water-insoluble catalysts that include hydro-
phobic structural moieties such as long-chain hydrocarbon8b,d and
perfluorohydrocarbon8a,h fragments, aryl,4l,o,8g siloxy,8c,e,f poly-
meric,9a–c or dendrimeric9d groups. Of note is that the reactions
occur in heterophase systems related to those characterized by
Sharpless as the ‘on water’ reactions.10a Reagents and a catalyst in
such systems react with each other on the surface or inside of
concentrated organic associates (micelles)10b where hydrophobic
structural moieties protect the chiral transient complex from the
racemizing water impact.10c The important role of the interfacial
region is affirmed by the fact that aldol reactions catalyzed by
water-soluble amino acids run in water slowly and less selectively5d
than where affected by water-insoluble catalysts or performed
under PTC-conditions.3h,10d
Since many catalysts used for reactions in the presence of water
have a rather complex structure, a critical issue here is to develop
efficient methods for their regeneration. A solution to this problem
may be approached through the introduction of polymer or ionic
groups to the catalyst’s framework. They facilitate catalyst separa-
tion from the reagents and products by reducing the solubility in
the reaction system components. However, the synthesis of re-
coverable catalysts having been designed by now, which comprise
either a polymer or dendritic moiety, is quite challenging and de-
mands costly starting compounds.7f,9d The activity of more avail-
able siloxy ethers of hydroxyproline declines as early as in the third
Meanwhile there is a group of organocatalysts that allow an
aldol reaction in the presence of water,8,9 i.e., the most low-cost and
environment-friendly solvent, which makes it attractive for re-
searchers. An asymmetric aldol reaction in the presence of water
has specific features due to the limited solubility of reagents and
catalysts in it as well as due to the water impact on the rate of
* Corresponding author. Tel.: þ7 499 137 13 53; fax: þ7 499 135 53 28.
E-mail address: zlotin@ioc.ac.ru (S.G. Zlotin).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.045

D.E. Siyutkin et al. / Tetrahedron 65 (2009) 1366–1372
1367
O
and fewer nitrogen atoms than imidazole derivatives). Finally, the
use of serine and threonine moieties as chiral inductors in com-
pounds 8 and 9 is related with an ability of hydrophobic derivatives
of these amino acids, as has been recently stated, to efficiently
catalyze the aldol reaction in the presence of water.8e,f It should be
pinpointed that serine and threonine derivatives bearing ionic
liquid moieties had not been earlier studied as organocatalysts for
enantioselective organic reactions.
O
O
NTf2
O
BF4
N
N
N
N
N
N
H
C4H9
COOH
O
C4H9
COOH
1
N
H
BF4
N
H
3
2
O
n-C12H25
N
N
4
COOH
N
4
PF6
H
Compound 5 was synthesized by replacing the anion Brꢀ in
bromide 10, which we had described before,11d for the anion NTfꢀ2
(Scheme 1).
Figure 1. Known organocatalysts bearing ionic liquid moieties.
trans-4-Hydroxyproline derivatives 6 and 7 were prepared
through the interaction of protected amino acid ester 11 containing
the terminal bromoalkyl group11d with pyridine or 4-(5-nonyl)-
pyridine,13 the anion metathesis in alkylation products 12a and b,
and the removal of protective groups from hexafluorophosphates
13a and b (Scheme 2).
Serine 8 and threonine 9 derivatives bearing the 4-(5-n-nonyl)-
pyridinium moiety were synthesized in a similar manner from the
respective amino acids protected by Cbz and Bn groups 14a and
b (Scheme 3).
Compound 5 is a viscous oil and compounds 6–9 are crystalline
substances with melting points <117 ꢁC, therefore they can be
assigned as ionic liquids.
The synthesized compounds 5–9 were investigated as organo-
catalysts in the aldol reaction between cyclohexane 18a and
p-nitrobenzaldehyde 19a in the presence of water. All reaction runs
were performed in the presence of 15 mol % of the catalyst at room
temperature without an organic solvent and with the use of 3 equiv
of ketone 18a.
Aldol 20a was synthesized under the action of bis(triflyl)imide
salt 5 with the conversion, distereo- and enantioselectivities, which
were comparable with the values having been previously obtained
in the reaction catalyzed by hexafluorophosphate 4 (Table 1, entry
1).11d However, unlike catalyst 4, the activity of catalyst 5 decreased
as early as in the third cycle (Table 1, entries 1–3) due to its washout
to the organic solvent used for the product extraction. The NMR
spectrum of crude aldol contained signals of catalyst 5.
Compound 6, despite the presence of PFꢀ6 , is significantly water-
soluble and does not catalyze the aldol reaction under the exam-
ined conditions (Table 1, entry 4). Whereas compound 7, which has
the hydrophobic 5-n-nonyl group in the pyridine cycle and given
that is actually insoluble in water, displayed high activity and se-
lectivity in the model reaction (Table 1, entry 5). Also, opposite to
catalyst 5, catalyst 7 retained activity and selectivity at least eight
reaction cycles (Table 1, entries 5–12).
reaction cycle8c,e assumingly because of the Si–O bond hydrolysis
and/or good solubility of such catalysts in the organic solvent
employed for the products extraction. Systems with acid or sur-
factant additives were only one-cycle usable.3h,8b,10d
Derivatives of proline 1 and 2 bearing an ionic group11a,b can act
as recoverable catalysts for aldol reactions in organic solvents or
ionic liquids (Fig. 1). Ionic catalyst 3 (Fig. 1) was examined in the
asymmetric aldol reaction in aqueous medium with AcOH as an
additive.11c Whereas the aldol reactions catalyzed by 1 and 2 pro-
ceeded with satisfactory distereo- and enantioselectivity, these
characteristics of the reactions catalyzed by 3 were much lower.
Our attempts to perform the aldol reaction under the action of 1 in
water failed: compound 1, readily soluble in water, does not cata-
lyze the aldol reaction under these conditions.
To improve the activity of catalyst 1 in aqueous medium, we
recently designed catalyst 4 with a structure close to 1 (Fig. 1).
Along with the imidazolium hydrophilic cation, it incorporated
hydrophobic alkyl groups containing 4–12 carbon atoms and the
hydrophobic anion PF6.11d The catalyst demonstrated high activity
and selectivity values in reactions between cycloalkanones and
aromatic aldehydes in aqueous media and remained usable for at
least five cycles without decrease in conversion and selectivity.
2. Results and discussion
To elucidate the role of hydrophobic interactions in organo-
catalytic aldol reactions in the presence of water, herein we syn-
thesized a few new amphiphilic compounds 5–9 differing from
compound 4 by the type of the chiral inductor and the cation or
anion (Fig. 2). We examined their catalytic properties in the ‘on
water’ aldol reaction.
The choice of compound 5 bearing the anion NTfꢀ2 as a research
subject was reasoned by the fact that imidazolium salts with such
an anion usually have lower solubility in water (more hydrophobic)
than their respective salts with the anion PF6.12 The incorporation
of pyridinium or 4-(5-nonyl)-pyridinium cations to catalysts 6–9
was also intended to improve the catalysts’ hydrophobic properties
that influence the activity through increasing the C/N ratio in the
cation structure (pyridine derivatives contain more carbon atoms
Catalysts 8 and 9 also showed rather good results in the aldol
reaction between compounds 18a and 19a in the aqueous medium
(Table 1, entries 13 and 14). However, the conversion, distereo- and
enantioselectivity values were slightly lower than the values
afforded in the reaction catalyzed by 7.
PF6
N
PF6
O
O
O
NTf2
n-C12H25
O
O
O
N
N
N
4
4
4
COOH
COOH
COOH
N
H
N
H
N
H
5
6
7
PF6
PF6
N
O
O
O
O
N
4
4
H2N
COOH
H2N
COOH
9
8
Figure 2. New amphiphilic derivatives of a-amino acids.

1368
D.E. Siyutkin et al. / Tetrahedron 65 (2009) 1366–1372
O
O
O
O
N
N
N
n-C12H25
N
LiNTf2, H2O
85%
n-C12H25
4
4
COOH
COOH
N
H
N
H
NTf2
Br
O
5
10
Scheme 1. Synthesis of IL-containing catalyst 5 with the NTfꢀ2 anion.
O
O
O
Br
R
N
4-RPy
HPF6
4
11
4
COOBn
heating
COOBn
N
N
Br
12:
Cbz
Cbz
78-91%
R = H (a),
81-87%
R = 5-n-nonyl (b)
O
O
O
O
R
N
R
N
H2, Pd/C
HPF6
4
4
COOBn
COOH
MeOH
N
N
H
PF6
PF6
13:
R = H (a),
78-91%
Cbz
6: R = H,
92-96%
R = 5-n-nonyl (b)
7: R = 5-n-nonyl
Scheme 2. Synthesis of trans-4-hydroxy-(S)-proline derivatives 6 and 7 bearing pyridinium moieties.
O
O
HO
HN
R
O
R
O
R
Br(CH2)4COOH
Br
N
4-(5-n-nonyl)-P
HPF6
y
4
4
COOBn
HN
Cbz
COOBn
HN
Cbz
COOBn
heating
DCC, DMAP,
CH2Cl2 , 5°C
82-88%
Br
Cbz
80-85%
14: R = H (a),
15: R = H (a),
16: R = H (a),
83-85%
O
R = Me (b)
R = Me (b)
R = Me (b)
O
O
R
O
R
N
N
H2, Pd/C
MeOH
HPF6
4
4
HN
Cbz
COOBn
H2N
COOH
82-88%
PF6
PF6
94-97%
17: R = H (a),
8: R = H,
9: R = Me
R = Me (b)
Scheme 3. Synthesis of serine (8) and threonine (9) derivatives bearing the 4-(5-n-nonyl)-pyridinium moiety.
Of note is that all the investigated catalysts (except for 6) were
in the organic layer and in water. Obviously, the catalysts (5, 7–9)
that incorporate the lipophilic alkyl group, along with the hydro-
philic ionic moiety, in these conditions are located on the water/
organic solvent interface where the catalytic conversion occurs.
Higher efficiency of the catalysis in organic solvent/water het-
erophase systems compared to homogeneous systems may also be
associated with special features of hydrophobic molecule solvation
in water. Water has a much higher cohesion energy than organic
solvents (waterd550.2 kcal cmꢀ3, organic solventsd60–380 kcal
cmꢀ3). Given that, water-insoluble hydrophobic organic molecules
experience water cohesion pressure equal to about 23 kbar in con-
ventional units. This accelerates organic reactions characterized by
negative activation volumes, to which the aldol reaction belongs.14
Catalyst 7 retained high activity and selectivity during multiple
model reaction runs in the aqueous medium and was employed in
aldol reactions with the participation of various aldehydes and
ketones (Table 2). It appeared that benzaldehyde 19b and
its derivatives 19a,c–f bearing electron-withdrawing or electron-
donating groups in the aromatic ring entered the reactions with
cyclohexanone 18a catalyzed by 7. The highest conversion, dis-
tereo- and enantioselectivity values were attained in the reactions
with benzaldehyde 19b and aromatic aldehydes with electron-ac-
ceptor substituents 19a,c,d. Less active in the examined reactions
were m-phenoxybenzaldehyde 19e and p-methoxybenzaldehyde
19f. However, in the instance of m-phenoxybenzaldehyde 19e, the
long reaction run (90 h) resulted in product 20e with the high
conversion, distereo- and enantioselectivities. These characteristics
efficient in heterophase systems consisting of three phases re-
strictedly soluble in each other: the eutectic solution of reagents,
water phase, and ionic phase of the catalyst is poorly soluble both
Table 1
Catalytic activities and selectivities of new IL-containing catalysts
O
O
OH
O
catalyst, 15% mol
H2O, rt
+
NO2
NO2
20a
18a, 3 eq.
19a
Entry
Catalyst
Time, h
Conv., %
dr, anti/syn
ee of anti, %
1
2
3
4
5
6
7
8
5
15
15
15
15
15
15
15
15
15
15
15
15
20
20
>99
>99
58
d
98:2
98:2
97:3
d
98
5 (cycle 2)
5 (cycle 3)
6
>99
>99
d
7
97
97:3
97:3
97:3
96:4
97:3
97:3
97:3
97:3
87:13
90:10
99
7 (cycle 2)
7 (cycle 3)
7 (cycle 4)
7 (cycle 5)
7 (cycle 6)
7 (cycle 7)
7 (cycle 8)
8
98
95
98
98
96
94
96
84
89
>99
>99
99
99
99
99
99
91
97
9
10
11
12
13
14
9
Conversion and dr were determined by NMR on crude products, ee was determined
by HPLC (Chiralcel OJ-H) on crude products.

D.E. Siyutkin et al. / Tetrahedron 65 (2009) 1366–1372
1369
Table 2
The aldol reaction between cyclohexanone and aromatic aldehydes catalyzed by 7
4. Experimental
O
O
O
OH
4.1. Synthesis
7, 15% mol
+
R
R
4.1.1. Compound 5
H2O, rt
LiNTf2 solution (65 mg, 0.23 mmol) in water (5 mL) was gradu-
ally added to a stirred solution of bromide 10 (0.12 g, 0.23 mmol) in
water (5 mL). The aqueous phase was decanted, and the resulting
precipitate was washed with water (2ꢂ5 mL) and dried in vacuo
(0.5 Torr) for 2 h to afford trifluoromethanesulfonimidate 5 (0.14 g,
85%) as colorless viscous oil.
18a, 3 eq.
19a-f
20a-f
Entry
R in 19 and 20
Time, h
Conv.,%
dr, anti/syn
ee of anti, %
1
2
3
4
5
6
(a) p-NO2
(b) H
(c) p-CN
(d) p-CO2CH3
(e) m-OC6H5
(f) p-OCH3
15
40
15
15
90
110
97
75
86
>95
87
97:3
95:5
97:3
97:3
96:4
90:10
99
97
99
98
>99
93
4.1.2. Compounds 15a and 15b
38
A mixture of corresponding Cbz,Bn-protected amino acid:
Conversion and dr were determined by NMR on crude products, ee was determined
by HPLC (Chiralcel OJ-H) on crude products.
L
-serine (2.00 g, 6.08 mmol) 14a or L-treonine (2.08 g, 6.06 mmol)
14b, 5-bromovaleric acid (1.10 g, 6.08 mmol), DCC (1.25 g,
6.08 mmol), and DMAP (40 mg, 0.33 mmol) in CH2Cl2 (30 mL) was
stirred at 5 ꢁC for 3 h. The resulting precipitate was filtered off and
washed with CH2Cl2 (3ꢂ5 mL). The combined organic extracts were
evaporated, and the residue was purified by column chromato-
graphy on silica gel (Acros, 0.035–0.070 mm, 60Å, eluent: n-hex-
ane/EtOAc¼4:1) to afford 15a (2.48 g, 83%) or 15b (2.61 g, 85%) as
colorless oil.
Table 3
The aldol reaction between cycloalkanones/isobutyraldehyde and p-nitro-
benzaldehyde catalyzed by 7
O
OH
O
R
O
R
20a,g-i
R
R
NO2
19a
18a-d, 3 eq.
4.1.3. Compounds 12a, 12b, 16a, and 16b
OH
7, 15% mol,
O
H2O, rt
A mixture of corresponding compound 11 (1.55 g, 3.00 mmol,
for 12a; 1.25 g, 2.41 mmol, for 12b)/15a (1.25 g, 2.54 mmol)/15b
(1.25 g, 2.47 mmol) and corresponding pyridine (0.26 g, 3.30 mmol,
for 12a)/4-(5-n-nonyl)-pyridine (0.52 g, 2.53 mmol, for 12b; 0.55 g,
2.67 mmol, for 16a; 0.53 g, 2.59 mmol, for 16b) was heated at 90 ꢁC
for 15 min, cooled to ambient temperature, and washed with Et2O
(6ꢂ15 mL). The residue was dissolved in MeOH (3 mL), and Et2O
(20 mL) was added to a stirred solution. The separated oil was dried
in vacuo (0.5 Torr) for 3 h to afford 12a (1.56 g, 87%)/12b (1.42 g,
81%)/16a (1.51 g, 85%)/16b (1.41 g, 80%) as corresponding aggre-
gative states (see Characterization).
NO2
18e, 3 eq.
20j
Entry R, R in 18
Aldol 20 Time, h Conv., % dr, anti/syn ee of anti, %
1
2
3
4
5
(a) –(CH2)3–
(b) –(CH2)2–
(c) –CH2OCH2– (h)
(d) –CH2SCH2– (i)
(a)
(g)
15
15
20
20
96
97
>95
66
78
40
97:3
80:20
97:3
98:2
d
99
92
97
99
99
(e) d
(j)
Conversion and dr were determined by NMR on crude products, ee was determined
by HPLC (Chiralcel OJ-H, OD-H) on crude products.
4.1.4. Compounds 13a, 13b, 17a, and 17b
Solution of corresponding bromide 12a (1.40 g, 2.34 mmol)/12b
(1.20 g, 1.66 mmol)/16a (1.20g, 1.72 mmol)/16b (1.20 g, 1.69 mmol)
in water (15 mL) was adjusted to pHw2–3 with 60% HPF6 (0.8 mL/
0.5 mL/0.5 mL/0.5 mL) at 40–50 ꢁC. The aqueous layer was dec-
anted, and the precipitate washed with water to neutral pH. The
residue was dried in vacuo (0.5 Torr) for 3 h to afford 13a (1.21 g,
78%)/13b (1.19 g, 91%)/17a (1.15 g, 88%)/17b (1.07 g, 82%) as corre-
sponding aggregative states (see Characterization).
of product 20f of the reaction between cyclohexanone 18a and
p-methoxybenzaldehyde 19f were somewhat lower.
Along with cyclohexanone (18a), other cyclic ketones, viz.
cyclopentanone (18b), tetrahydropyran-4-one (18c), and tet-
rahydrothiopyran-4-one (18d), entered the reaction with
p-nitrobenzaldehyde (19a) catalyzed by 7 (Table 3). Also, the
reactions with the participation of six-membered heterocycles
18c,d proceeded with high distereo- and enantioselectivities,
and in the case of cyclopentanone (18b) dr and ee values of
aldol 20g were somewhat lower. Taking isobutyraldehyde
(18e) as an example, we showed the possibility to introduce
aldehyde donors to the aldol reaction catalyzed by 7. The
produced aldol 20j had high enantiomeric purity although
a prolonged reaction period was required to achieve a moder-
ate conversion.
4.1.5. Compounds 6–9
A mixture of corresponding compound 13a (1.10 g, 1.66 mmol)/
13b (1.00 g, 1.27 mmol)/17a (1.00 g, 1.31 mmol)/17b (0.9 g,
1.16 mmol) and Pd/C (5%) (0.30 g) in dry CH3OH (30 mL) was stirred
under H2 (760 Torr) at ambient temperature for 3 h. The resulting
precipitate was filtered off and washed with 10 mL CH3OH. The
combined organic phases were evaporated, and the residue was
dried in vacuo (0.5 Torr) for 3 h to afford 6 (0.67 g, 92%)/7 (0.69 g,
96%)/8 (0.66 g, 94%)/9 (0.62 g, 97%) as corresponding aggregative
states (see Characterization).
3. Conclusion
New chiral ionic liquids bearing 4-hydroxyproline, serine or
threonine moieties, and imidazolium or pyridinium cations capable
to catalyze the asymmetric aldol reaction between aldehydes and
ketones in the presence of water were synthesized. It was estab-
lished that the hydrophobic alkyl groups available in organo-
catalysts improved the reaction efficiency under the examined
conditions. The catalyst with the anion PFꢀ6 can be readily regen-
erated and utilized multiply without a decline in the conversion, dr,
and ee values.
4.1.6. A typical procedure for the aldol reaction
A mixture of the appropriate organocatalyst (0.02 mmol), ke-
tone/aldehyde 18 (0.40 mmol), aldehyde 19 (0.13 mmol), and dis-
tilled water (0.3 mL) was stirred at room temperature for the
period given in Tables 1–3. Aldol 20 and the remained starting
compounds were extracted with Et2O (2ꢂ5 mL), the combined
extracts were filtrated through a silica gel pad (1 g) and evapo-
rated in vacuo (15 Torr). Conversion and dr values of aldols 20

1370
D.E. Siyutkin et al. / Tetrahedron 65 (2009) 1366–1372
were measured by 1H NMR of the crude reaction mixture, ee
values of anti-isomers of 20 were determined by HPLC, chiral
phase: Chiralcel OD-H, OJ-H.
4.2.5. 1-(5-(((3R,5S)-1,5-Bis((benzyloxy)carbonyl)pyrrolidin-3-
yl)oxy)-5-oxopentyl)-4-(1-butylpentyl)pyridinium bromide 12b
24
Light yellow oil. [
a
]
ꢀ17.2 (c 1, CH3OH); 1H NMR (300 MHz,
D
CDCl3)
d
: 9.42 (2H, d, J¼6.1 Hz, CHCHNCHCH), 7.73 (2H, d, J¼6.1 Hz,
CHCHNCHCH), 7.20–7.38 (10H, m, 2C6H5), 5.21–5.28 (1H, m, CHO),
4.98–5.22 (6H, m, 2CH2Ph, NCH2CH2), 4.45–4.56 (1H, m, CHCO2),
3.60–3.78 (2H, m, CHCH2N), 2.72–2.83 (1H, m, (C2H5)2CH), 2.42 (2H,
t, J¼6.9 Hz, CH2CO2), 2.12–2.45 (2H, m, CHCH2CH), 2.02–2.16 (2H,
m, NCH2CH2), 1.65–1.81 (2H, m, CH2CH2CO2), 1.51–1.64 (4H, m,
(CH2CH2)2CH), 1.00–1.33 (8H, m, 2CH2CH2CH3), 0.84 (6H, t,
4.2. Characterization
4.2.1. (4R)-4-((5-(1-Dodecyl-1H-imidazol-3-ium-3-yl)pentanoyl)-
oxy)-
Colorless viscous oil. [
(300 MHz, DMSO-d6)
L-proline trifluoromethanesulfonimide 5
27
a
]
D
ꢀ10.2 (c 1, CH3OH); 1H NMR
d: 9.20 (1H, s, NCHN), 7.80 (2H, s, NCHCHN),
J¼6.9 Hz, 2CH3) ppm; 13C NMR (75 MHz, CDCl3)
d: 172.1, 171.8,
5.16–5.23 (1H, m, CHO), 4.11–4.21 (4H, m, 2CH2CH2N), 3.78 (1H, t,
J¼8.9 Hz, CH2CHN), 3.05–3.48 (2H, m, CHCH2N), 2.31–2.39 (2H, m,
CH2CH2CO2), 2.02–2.21 (2H, m, CH2CHN), 1.72–1.87 (4H, m,
2CH2CH2N), 1.40–1.54 (2H, m, CH2CH2CO2), 1.22 (18H, s, CH3(CH2)9),
167.0, 154.0, 144.4, 135.9, 135.0, 128.4, 128.2, 128.1, 127.9, 127.8,
127.5, 127.0, 71.7, 67.1, 66.8, 60.0, 57.5, 52.4, 46.3, 36.2, 35.1, 33.0,
30.9, 29.3, 22.3, 20.9, 13.6 ppm. Anal. Calcd for C39H51BrN2O6: C,
64.72; H, 7.10; N, 3.87; Br, 11.04. Found: C, 65.01; H, 7.04; N, 3.93; Br,
10.91.
0.86 (3H, t, J¼6.1 Hz, CH3) ppm; 13C NMR (75 MHz, DMSO-d6)
d:
171.8, 169.8, 135.3, 122.4, 122.3, 73.2, 59.3, 49.9, 48.9, 48.5, 35.0,
32.5, 31.3, 29.3, 29.0, 28.9, 28.8, 28.7, 28.6, 28.4, 25.5, 22.0, 20.7,
13.9 ppm; IR (KBr, cmꢀ1): 3440, 3176, 2928, 2856, 1736, 1628, 1460,
1388, 1312, 1264, 1172, 844, 752. Anal. Calcd for C27H44F6N4O8S2: C,
44.38; H, 6.07; N, 7.67; S, 8.78; F, 15.60. Found: C, 44.27; H, 6.01; N,
7.66; S, 8,80; F, 15.51.
4.2.6. 11-(5-(((3R,5S)-1,5-Bis((benzyloxy)carbonyl)pyrrolidin-3-
yl)oxy)-5-oxopentyl)-4-(1-butylpentyl)pyridinium
hexafluorophosphate 13b
Colorless oil. [
d
a
]
ꢀ16.0 (c 1, CH3OH); 1H NMR (300 MHz, DMSO-
25
D
d6)
: 8.92 (2H, d, J¼6.1 Hz, CHCHNCHCH), 8.02 (2H, d, J¼6.1 Hz,
CHCHNCHCH), 7.22–7.39 (10H, m, 2C6H5), 5.18–5.24 (1H, m, CHO),
4.98–5.17 (4H, m, 2CH2Ph), 4.51 (2H, t, J¼7.4 Hz, NCH2CH2), 4.37–4.45
(1H, m, CHCO2), 3.51–3.72 (2H, m, CHCH2N), 2.82–2.93 (1H,
m, (C2H5)2CH), 2.38 (2H, t, J¼7.4 Hz, CH2CO2), 2.12–2.29 (2H, m,
CHCH2CH), 1.84–1.96 (2H, m, CH2CH2N), 1.45–1.74 (6H, m,
CH2CH2CO2, (CH2CH2)2CH), 0.93–1.27 (8H, m, 2CH2CH2CH3), 0.69(6H,
4.2.2. 1-(5-(((3R,5S)-1,5-Bis((benzyloxy)carbonyl)pyrrolidin-3-yl)-
oxy)-5-oxopentyl)pyridinium bromide 12a
27
Colorless oil. [
a
]
ꢀ17.9 (c 1, CH3OH); 1H NMR (300 MHz, CDCl3)
D
d:
9.48–9.57 (2H, m, CHCHNCHCH), 8.39–8.50 (1H, m,
(CH)2CH(CH)2), 8.00–8.10 (2H, m, CHCHNCHCH), 7.20–7.42 (10H, m,
2C6H5), 4.91–5.28 (7H, m, CHO, 2CH2Ph, CH2CH2N), 4.41–4.55 (1H,
m, CHCO2), 3.60–3.83 (2H, m, CHCH2N), 2.41 (2H, t, J¼6.8 Hz,
CH2CO2), 2.02–2.50 (2H, m, CHCH2CH), 2.02–2.14 (2H, CH2CH2N),
t, J¼7.0 Hz, 2CH3) ppm; 13C NMR (75 MHz, DMSO-d6)
d: 172.1, 171.8,
166.2, 153.7, 144.1, 136.3, 135.5, 128.4, 128.2, 127.9, 127.7, 127.5, 127.4,
126.9, 72.1, 66.5, 66.2, 59.6, 57.2, 52.2, 45.1, 35.8, 34.7, 32.6, 29.8, 28.9,
22.0, 20.7,13.7 ppm. Anal. Calcd for C39H51F6N2O6P: C, 59.38; H, 6.52;
N, 3.55; F, 14.45. Found: C, 59.62; H, 6.41; N, 3.60; F, 14.38.
1.62–1.79 (2H, m, CH2CH2CO2) ppm; 13C NMR (75 MHz, CDCl3)
d:
172.1, 169.8, 153.5, 144.6, 144.3, 136.9, 136.1, 128.4, 128.2, 128.1,
127.9, 127.8, 127.5, 127.4, 72.9, 65.8, 65.4, 59.9, 56.9, 52.1, 35.3, 32.2,
28.8, 20.4 ppm. Anal. Calcd for C30H33BrN2O6: C, 60.31; H, 5.57; N,
4.69; Br, 13.37. Found: C, 60.57; H, 5.52; N, 4.78; Br, 13.23.
4.2.7. (4R)-4-((5-(4-(1-Butylpentyl)pyridinium-1-yl)-
pentanoyl)oxy)-
White solid, mp 97–98 ꢁC. [
(300 MHz, DMSO-d6)
L-proline hexafluorophosphate 7
27
a
]
D
ꢀ12.7 (c 1, CH3OH); 1H NMR
4.2.3. 1-(5-(((3R,5S)-1,5-Bis((benzyloxy)carbonyl)pyrrolidin-3-yl)-
d
: 8.88 (2H, d, J¼6.1 Hz, CHCHNCHCH), 7.99
oxy)-5-oxopentyl)pyridinium hexafluorophosphate 13a
(2H, d, J¼6.1 Hz, CHCHNCHCH), 5.19–5.24 (1H, m, CHO), 4.5 (2H, t,
J¼7.4 Hz, NCH2CH2), 3.81–3.89 (1H, m, CHCO2), 3.12–3.53 (2H, m,
CHCH2N), 2.81–2.92 (1H, m, (C2H5)2CH), 2.37 (2H, t, J¼7.4 Hz,
CH2CO2), 2.02–2.30 (2H, m, CHCH2CH),1.85–1.97 (2H, m, CH2CH2N),
1.45–1.76 (6H, m, CH2CH2CO2, (CH2CH2)2CH), 0.88–1.28 (8H, m,
2CH2CH2CH3), 0.78 (6H, t, J¼7.0 Hz, 2CH3) ppm; 13C NMR (75 MHz,
28
Colorless oil. [
DMSO-d6)
a]
ꢀ19.6 (c 1, CH3OH); 1H NMR (300 MHz,
D
d
: 9.02–9.11 (2H, m, CHCHNCHCH), 8.56–8.67 (1H, m,
(CH)2CH(CH)2), 8.11–8.21 (2H, m, CHCHNCHCH), 7.22–7.41 (10H, m,
2C6H5), 5.19–5.27 (1H, m, CHO), 5.03–5.17 (4H, m, 2CH2Ph), 4.57–
4.65 (2H, m, CH2CH2N), 4.21–4.45 (1H, m, CHCO2), 3.41–3.59 (2H,
m, CHCH2N), 2.33–2.41 (2H, m, CH2CO2), 2.05–2.30 (2H, m,
CHCH2CH), 1.87–2.00 (2H, m, CH2CH2N), 1.45–1.60 (2H, m,
DMSO-d6) d: 172.0, 169.8, 166.1, 144.2, 126.9, 73.2, 59.3, 59.1, 49.8,
44.9, 35.0, 34.6, 32.7, 29.9, 28.8, 21.9, 20.6, 13.7 ppm; IR (KBr, cmꢀ1):
3416, 2936, 2872, 1736, 1640, 1520, 1460, 1384, 1168, 1064, 976, 840.
Anal. Calcd for C24H39F6N2O4P: C, 51.06; H, 6.96; N, 4.96; F, 20.19.
Found: C, 51.21; H, 6.88; N, 4.99; F, 20.07.
CH2CH2CO2) ppm; 13C NMR (75 MHz, DMSO-d6)
d: 172.1, 169.8,
153.8, 145.4, 144.6, 136.4, 135.6, 128.5, 128.2, 127.9, 127.8, 127.6,
127.5, 127.2, 72.4, 66.4, 65.9, 60.3, 57.2, 52.2, 35.8, 32.5, 29.9,
20.6 ppm. Anal. Calcd for C30H33F6N2O6P: C, 54.38; H, 5.02; N, 4.23;
F, 17.20. Found: C, 54.52; H, 4.94; N, 4.30; F, 17.06.
4.2.8. Benzyl N-((benzyloxy)carbonyl)-O-(5-bromopentanoyl)-
L
-serinate 15a
27
4.2.4. (4R)-4-((5-Pyridinium-1-ylpentanoyl)oxy)-
L
-proline
Colorless oil. [
a]
ꢀ15.8 (c 1, CH3OH); 1H NMR (300 MHz, CDCl3)
D
hexafluorophosphate 6
d
: 7.29–7.42 (10H, m, 2C6H5), 5.07 (1H, d, J¼7.7 Hz, NH), 5.11–5.21
29
White solid, mp 113–114 ꢁC. [
a
]
ꢀ12.9 (c 1, CH3OH); 1H NMR
(4H, m, 2CH2Ph), 4.65–4.72 (1H, m, CHNH), 4.31–4.55 (2H, m,
CH2CH), 3.38 (2H, t, J¼6.5 Hz, CH2Br), 2.18–2.25 (2H, m, CH2CO2),
1.77–1.89 (2H, m, CH2CH2Br), 1.64–1.75 (2H, m, CH2CH2CO2) ppm;
D
(300 MHz, DMSO-d6)
d
: 9.09 (2H, d, J¼6.1 Hz, CHCHNCHCH), 8.62
(1H, t, J¼7.8 Hz, (CH)2CH(CH)2), 8.18 (2H, t, J¼6.9 Hz, CHCHNCHCH),
5.18–5.26 (1H, m, CHO), 4.61 (2H, t, J¼6.9 Hz, CH2CH2N), 3.80–3.89
(1H, m, CHCO2), 3.08–3.50 (2H, m, CHCH2N), 2.32–2.41 (2H, m,
CH2CO2), 2.05–2.25 (2H, m, CHCH2CH), 1.88–2.00 (2H, m,
CH2CH2N), 1.45–1.58 (2H, m, CH2CH2CO2) ppm; 13C NMR (75 MHz,
13C NMR (75 MHz, CDCl3)
d: 172.4, 169.2, 155.7, 136.0, 135.0, 128.6,
128.5, 128.5, 128.4, 128.2, 128.1, 67.6, 67.2, 64.0, 53.4, 32.9, 32.7, 31.7,
23.1 ppm. Anal. Calcd for C23H26BrNO6: C, 56.11; H, 5.32; N, 2.84; Br,
16.23. Found: C, 56.38; H, 5.30; N, 2.81; Br, 16.10.
DMSO-d6) d: 172.1, 170.3, 145.6, 144.8, 128.2, 73.2, 60.4, 59.3, 50.0,
35.1, 32.6, 30.0, 20.6 ppm; IR (KBr, cmꢀ1): 3416, 2960, 1736, 1636,
1488, 1456, 1396, 1320, 1172, 1064, 840, 776. Anal. Calcd for
C15H21F6N2O4P: C, 41.10; H, 4.83; N, 6.39; F, 26.01. Found: C, 41.22;
H, 4.77; N, 6.43; F, 25.83.
4.2.9. Benzyl N-((benzyloxy)carbonyl)-O-(5-(4-(1-butylpentyl)-
pyridinium-1-yl)pentanoyl)-L-serinate bromide 16a
24
Light yellow oil. [
CDCl3)
a
]
D
ꢀ9.9 (c 1, CH3OH); 1H NMR (300 MHz,
d
: 9.41 (2H, d, J¼6.1 Hz, CHCHNCHCH), 7.69 (2H, d, J¼6.1 Hz,

D.E. Siyutkin et al. / Tetrahedron 65 (2009) 1366–1372
1371
CHCHNCHCH), 7.25–7.40 (10H, m, 2C6H5), 5.87 (1H, d, J¼7.6 Hz,
NH), 5.08–5.22 (4H, m, 2CH2Ph), 4.82–5.02 (2H, m, CH2N), 4.61–
4.70 (1H, m, CHNH), 4.36–4.50 (2H, m, CH2CHNH), 2.70–2.81 (1H,
m, CH2CHCH2), 2.30–2.39 (2H, m, CH2CO2), 1.99–2.11 (2H, m,
CH2CH2N), 1.61–1.80 (4H, m, CH2CHCH2), 1.47–1.60 (2H, m,
CH2CH2CO2), 0.96–1.35 (8H, m, 2CH2CH2CH3), 0.84 (6H, t, J¼7.1 Hz,
m, 2CH2CH2CH3), 0.84 (6H, t, J¼7.2 Hz, 2CH2CH3) ppm; 13C NMR
(75 MHz, CDCl3) d: 171.4, 169.6, 166.9, 156.3, 144.4, 135.9, 134.8,
128.4, 128.3, 128.2, 128.1, 128.0, 127.8, 127.0, 70.1, 67.3, 67.0, 59.9,
57.4, 46.2, 35.1, 32.7, 30.6, 29.2, 22.3, 20.8, 16.7, 13.6 ppm. Anal.
Calcd for C38H51BrN2O6: C, 64.13; H, 7.22; N, 3.94; Br, 11.23. Found:
C, 64.43; H, 7.14; N, 4.01; Br, 11.10.
2CH3) ppm; 13C NMR (75 MHz, CDCl3)
d: 172.2, 169.0, 166.7, 155.7,
144.3, 135.9, 134.7, 129.4, 129.2, 128.3, 127.9, 127.8, 127.6, 126.9, 67.2,
66.6, 63.5, 59.8, 53.2, 46.1, 35.0, 32.4, 30.6, 29.1, 22.2, 20.6, 13.5 ppm.
Anal. Calcd for C37H49BrN2O6: C, 63.69; H, 7.08; N, 4.02; Br, 11.45.
Found: C, 63.98; H, 7.02; N, 4.08; Br, 11.35.
4.2.14. Benzyl N-((benzyloxy)carbonyl)-O-(5-(4-(1-butylpentyl)-
pyridinium-1-yl)pentanoyl)-L-threoninate hexafluorophosphate 17b
24
Colorless oil. [
d
a
]
D
þ0.3 (c 1, CH3OH); 1H NMR (300 MHz, DMSO-
d6)
: 8.92 (2H, d, J¼6.1 Hz, CHCHNCHCH), 8.03 (2H, d, J¼6.1 Hz,
CHCHNCHCH), 7.88 (1H, d, J¼8.6 Hz, NH), 7.25–7.40 (10H, m,
2C6H5), 5.16–5.27 (1H, m, CHCH3), 5.09 (4H, s, 2CH2Ph), 4.40–4.52
(3H, m, CH2N, CHNH), 2.81–2.93 (1H, m, CH2CHCH2), 2.13–2.28 (2H,
m, CH2CO2), 1.77–1.89 (2H, m, CH2CH2N), 1.54–1.77 (4H, m,
CH2CHCH2), 1.38–1.50 (2H, m, CH2CH2CO2), 1.27 (3H, d, J¼6.5 Hz,
CH3CH), 0.90–1.30 (8H, m, 2CH2CH2CH3), 0.79 (6H, t, J¼7.2 Hz,
4.2.10. Benzyl N-((benzyloxy)carbonyl)-O-(5-(4-(1-butylpentyl)-
pyridinium-1-yl)pentanoyl)-L-serinate hexafluorophosphate 17a
25
Colorless oil. [
d
a
]
D
ꢀ8.9 (c 1, CH3OH); 1H NMR (300 MHz, DMSO-
d6)
: 8.92 (2H, d, J¼6.1 Hz, CHCHNCHCH), 8.03 (2H, d, J¼6.1 Hz,
CHCHNCHCH), 7.95 (1H, d, J¼8.1 Hz, NH), 7.25–7.41 (10H, m, 2C6H5),
5.03–5.18 (4H, m, 2CH2Ph), 4.45–4.55 (3H, m, CH2N, CHNH), 4.16–
4.41 (2H, m, CH2CHNH), 2.82–2.95 (1H, m, CH2CHCH2), 2.26–2.36
(2H, m, CH2CO2), 1.81–1.94 (2H, m, CH2CH2N), 1.56–1.78 (4H, m,
CH2CHCH2), 1.41–1.55 (2H, m, CH2CH2CO2), 0.91–1.30 (8H, m,
2CH2CH2CH3), 0.80 (6H, t, J¼7.2 Hz, 2CH3) ppm; 13C NMR (75 MHz,
2CH2CH3) ppm; 13C NMR (75 MHz, DMSO-d6)
d: 171.7, 169.7, 166.4,
156.8, 144.2, 136.9, 135.7, 128.5, 128.3, 128.2, 128.1, 128.0, 127.9,
127.0, 69.5, 66.5, 66.0, 59.7, 57.6, 45.2, 34.8, 32.7, 29.9, 29.0, 22.1,
20.8, 16.6, 13.8 ppm. Anal. Calcd for C38H51F6N2O6P: C, 58.76; H,
6.62; N, 3.61; F, 14.67. Found: C, 58.97; H, 6.50; N, 3.67; F, 14.53.
DMSO-d6) d: 172.2, 169.5, 166.2, 156.1, 144.1, 136.8, 135.7, 129.4,
128.9, 128.4, 128.1, 127.8, 127.3, 126.9, 66.4, 65.8, 62.9, 59.6, 53.1,
45.1, 34.7, 32.4, 29.9, 28.9, 22.0, 20.7, 13.7 ppm. Anal. Calcd for
C37H49F6N2O6P: C, 58.26; H, 6.48; N, 3.67; F, 14.94. Found: C, 58.41;
H, 6.38; N, 3.72; F, 14.82.
4.2.15. O-(5-(4-(1-Butylpentyl)pyridinium-1-yl)pentanoyl)-
L
-threonine hexafluorophosphate 9
26
White solid, mp 116–117 ꢁC. [
(300 MHz, DMSO-d6)
a
]
þ6.5 (c 1, CH3OH); 1H NMR
D
d
: 9.07 (2H, d, J¼6.1 Hz, CHCHNCHCH), 8.04
(2H, d, J¼6.1 Hz, CHCHNCHCH), 5.21–5.35 (1H, m, CHCH3), 4.51–
4.59 (2H, m, CH2N), 3.40–3.48 (1H, m, CHNH2), 2.82–2.96 (1H, m,
CH2CHCH2), 2.25–2.32 (2H, m, CH2CO2), 1.85–2.01 (2H, m,
CH2CH2N), 1.47–1.78 (6H, m, CH2CHCH2, CH2CH2CO2), 1.28 (3H, d,
J¼6.5 Hz, CH3CH), 0.91–1.32 (8H, m, 2CH2CH2CH3), 0.81 (6H, t,
4.2.11. O-(5-(4-(1-Butylpentyl)pyridinium-1-yl)pentanoyl)-L-serine
hexafluorophosphate 8
25
White solid, mp 114–115 ꢁC. [
a]
þ4.6 (c 1, CH3OH); 1H NMR
D
(300 MHz, DMSO-d6)
d
: 9.08 (2H, d, J¼6.1 Hz, CHCHNCHCH), 8.04
(2H, d, J¼6.1 Hz, CHCHNCHCH), 4.44–4.61 (2H, m, CH2N), 4.21–4.37
(2H, m, OCH2), 3.51–3.57 (1H, m, CHNH2), 2.83–2.95 (1H, m,
CH2CHCH2), 2.32–2.46 (2H, m, CH2CO2), 1.85–1.98 (2H, m,
CH2CH2N), 1.48–1.78 (6H, m, CH2CHCH2, CH2CH2CO2), 0.92–1.31
(8H, m, 2CH2CH2CH3), 0.81 (6H, t, J¼7.2 Hz, 2CH3) ppm; 13C NMR
J¼7.2 Hz, 2CH2CH3) ppm; 13C NMR (75 MHz, DMSO-d6)
d: 174.5,
171.9, 166.4, 144.3, 127.1, 70.1, 59.7, 57.6, 45.2, 34.8, 33.0, 30.1, 29.1,
22.1, 21.0, 16.9, 13.9 ppm; IR (KBr, cmꢀ1): 3400, 2936, 2872, 1740,
1640, 1520, 1456, 1396, 1340, 1176, 1032, 840. Anal. Calcd for
C23H39F6N2O4P: C, 50.00; H, 7.11; N, 5.07; F, 20.63. Found: C, 50.16;
H, 7.02; N, 5.13; F, 20.51.
(75 MHz, DMSO-d6) d: 174.3, 172.4, 166.2, 144.3, 127.0, 63.7, 59.7,
53.1, 45.2, 34.8, 32.7, 30.1, 29.0, 22.1, 20.8, 13.8 ppm; IR (KBr, cmꢀ1):
3400, 2936,1740,1640,1520,1456,1412,1172,1024, 836. Anal. Calcd
for C22H37F6N2O4P: C, 49.07; H, 6.93; N, 5.20; F, 21.17. Found: C,
49.28; H, 6.86; N, 5.24; F, 21.02.
Acknowledgements
The work was partially supported by the Russian Foundation of
Basic Research (Grants 06-03-32603 and 09-03-00384) and the
Russian Academy of Sciences.
4.2.12. Benzyl N-((benzyloxy)carbonyl)-O-(5-bromopentanoyl)-L-
threoninate 15b
27
Colorless oil. [
a
]
ꢀ6.1 (c 1, CH3OH); 1H NMR (300 MHz, CDCl3)
D
References and notes
d: 7.31–7.42 (10H, m, 2C6H5), 5.41–5.50 (1H, m, CHCH3), 5.46 (1H, d,
J¼8.7 Hz, NH), 5.14 (4H, s, 2CH2Ph), 4.54 (1H, dd, J1¼9.7 Hz,
J2¼2.3 Hz, CHNH), 3.38 (2H, t, J¼6.5 Hz, CH2Br), 2.09–2.19 (2H, m,
CH2CO2), 1.75–1.86 (2H, m, CH2CH2Br), 1.60–1.71 (2H, m,
CH2CH2CO2), 1.29 (3H, d, J¼6.5 Hz, CH3) ppm; 13C NMR (75 MHz,
1. (a) Guillena, J.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249–
2293; (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107,
5471–5569.
2. Hoffmann, T.; Zhong, G.; List, B.; Shabat, D.; Anderson, J.; Gramatikova, S.;
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Cordova, A.; Notz, W.; Barbas, C. F., III. J. Org. Chem. 2002, 67, 301–303; (e)
Kotrusz, P.; Kmentova, I.; Gotov, B.; Toma, S.; Solcaniova, E. Chem. Commun. 2002,
2510–2511; (f) List, B. Tetrahedron 2002, 58, 5573–5590; (g) Northrup, A. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798–6799; (h) Peng, Y.-Y.; Ding,
Q.-P.; Li, Z.; Wang, P. G.; Cheng, J.-P. Tetrahedron Lett. 2003, 44, 3871–3875; (i)
Chandrasekhar, S.; Narsihmulu, C.; Ramakrishna Reddy, N.; Shameem Sultana, S.
Chem. Commun. 2004, 2450–2451; (j) Cordova, A. Tetrahedron Lett. 2004, 45,
3949–3952; (k) Chandrasekhar, S.; Narsihmulu, C.; Ramakrishna Reddy, N.;
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Cordova, A. Tetrahedron Lett. 2005, 46, 3363–3367; (m) Chandrasekhar, S.;
Ramakrishna Reddy, N.; Shameem Sultana, S.; Narsihmulu, C.; Venkatram
Reddy, K. Tetrahedron 2006, 62, 338–345; (n) Bernard, A. M.; Frongia, A.; Guillot,
R.; Piras, P. P.; Secci, F.; Spiga, M. Org. Lett. 2007, 9, 541–544; (o) Hayashi, Y.;
Aratake, S.; Itoh, T.; Okano, T.; Sumiya, T.; Shoji, M. Chem. Commun. 2007, 957–
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CDCl3) d: 171.5, 169.8, 156.3, 136.0, 135.0, 128.4, 128.3, 128.1, 128.0,
127.9, 127.7, 70.3, 67.8, 66.5, 57.7, 32.9, 32.7, 31.8, 23.2, 16.8 ppm.
Anal. Calcd for C24H28BrNO6: C, 56.92; H, 5.57; N, 2.77; Br, 15.78.
Found: C, 57.16; H, 5.53; N, 2.73; Br, 15.66.
4.2.13. Benzyl N-((benzyloxy)carbonyl)-O-(5-(4-(1-butylpentyl)-
pyridinium-1-yl)pentanoyl)-L-threoninate bromide 16b
24
Colorless oil. [
a]
þ0.9 (c 1, CH3OH); 1H NMR (300 MHz, CDCl3)
D
d
: 9.41 (2H, d, J¼6.1 Hz, CHCHNCHCH), 7.69 (2H, d, J¼6.1 Hz,
CHCHNCHCH), 7.29–7.41 (10H, m, 2C6H5), 5.59 (1H, d, J¼9.5 Hz,
NH), 5.38–5.48 (1H, m, CHCH3), 5.12 (4H, d, J¼10.1 Hz, 2CH2Ph),
4.86–5.04 (2H, m, CH2N), 4.52 (1H, dd, J¼9.1 Hz, J¼2.3 Hz, CHNH),
2.71–2.82 (1H, m, CH2CHCH2), 2.22–2.32 (2H, m, CH2CO2), 1.94–
2.08 (2H, m, CH2CH2N), 1.62–1.82 (4H, m, CH2CHCH2), 1.48–1.62
(2H, m, CH2CH2CO2), 1.29 (3H, d, J¼6.5 Hz, CH3CH), 0.96–1.35 (8H,

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