Synthesis of novel chiral lipophilic pyridyl-containing β-amino alcohol ligands and enantioselective hydrolysis of α-amino acid esters by chiral metallomicelles

Article abstract of DOI:10.1016/S0957-4166(98)00512-6

Seven novel chiral lipophilic pyridyl-containing β-amino alcohol ligands have been synthesized by coupling of 6-alkoxymethyl-2- chloromethylpyridine 3 with the corresponding chiral β-amino alcohols or L- cysteine. Their metal ion complexes have been inves

Full text of DOI:10.1016/S0957-4166(98)00512-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 243–254
Synthesis of novel chiral lipophilic pyridyl-containing β-amino
alcohol ligands and enantioselective hydrolysis of α-amino acid
esters by chiral metallomicelles
Jingsong You,a Xiaoqi Yu,a Ke Liu,a Lin Tao,b Qingxiang Xiang a and Rugang Xie a,∗
aDepartment of Chemistry, Sichuan University, Chengdu, 610064, People’s Republic of China
bDepartment of Chemistry, Sichuan Educational College, Chengdu, 610041, People’s Republic of China
Received 4 November 1998; accepted 17 December 1998
Abstract
Seven novel chiral lipophilic pyridyl-containing β-amino alcohol ligands have been synthesized by coupling
of 6-alkoxymethyl-2-chloromethylpyridine 3 with the corresponding chiral β-amino alcohols or L-cysteine. Their
metal ion complexes have been investigated as catalysts for the enantioselective hydrolysis of N-protected α-
amino acid esters in aqueous comicellar solution. The results indicate that the hydrophobic interactions between
substrate and metallocatalyst, the rigidity of the ligand, the hydroxyl group of the ligand acting as a nucleophile
for the transacylation process, and the micellar microenvironment are important factors for the activity and
enantioselectivity. Large rate accelerations (up to three orders of magnitude) and moderate enantioselectivities
(up to 7.81 (kR/kS)) employing 4a–Cu2+ have been observed. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Metallomicelles are currently receiving considerable interest as new catalytic systems.1–7 These
supramolecular systems are made up of ligand surfactants (or lipophilic ligands) chelating metal ions.
Of particular interest are the micellar models of hydrolytic metalloenzymes that are able to promote
the cleavage of phosphoric and carboxylic esters or amides. Most of them are focused on the ligands
containing imidazole, pyridine or 1,10-phenanthroline as the basic chelating subunit and as the molecular
junction for the paraffinic chain. Despite such progress, there are only a few examples dealing with
the enantioselective hydrolysis by chiral homo and mixed metallomicelles as models for hydrolytic
metalloenzymes.8 We have recently reported the first example of chiral macrocyclic metallomicelles and
their effect on the enantioselective cleavage of N-dodecanoylamino acid p-nitrophenyl esters.9 In this
paper, we report our work on the synthesis of new chiral lipophilic pyridyl-containing β-amino alcohol
∗
Corresponding author. Fax: +86-28-541-0187; e-mail: schemorg@mail.sc.cninfo.net
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00512-6

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ligands, 4–8, and the enantioselective hydrolysis of α-amino acid esters by their metal ion complexes in
chiral metallomicelles. Ligands 4, 6 and 8 contain the rigid prolinol group, the flexible leucinol group and
the flexible cysteinol group with one stereogenic center, respectively, and ligand 7 contains the ephedrine
group with two stereogenic centers. Ligand 5, the O-methylated analogue of 4a, lacks the hydroxymethyl
group with the aim of defining the role of the hydroxy function in the complexes with ligands 4, 6, 7 and 8.
The water soluble ligand 4b, which does not contain a hydrophobic long chain, has also been investigated
so that the catalytic activity of this compound can be used for comparison.
2. Results and discussion
2.1. Ligands and substrates
Ligands 4–8 were synthesized according to the procedures outlined in Scheme 1 using 2,6-
bis(hydroxymethyl)pyridine 1 as a starting material, which was selectively partially O-alkylated to
6-alkoxymethyl-2-hydroxymethylpyridine 2, in the presence of a slight excess of NaH in dry dioxane in
good yield. It is necessary to point out that the halide should be added dropwise; otherwise bis-alkylation
mainly occurred. Compound 2 was then converted to 6-alkoxymethyl-2-chloromethylpyridine 3 by
addition of SOCl2.
Scheme 1.
Ligands 4a, 4b, 6, 7a and 7b were obtained by coupling of 3 with the desired chiral β-amino alcohols.
In the case of ligand 8, 3a selectively reacted with the mercapto instead of the amino in the presence of
NaOH and NaI, and the adduct was converted to the ester derivative and subsequently reduced to ligand

J. You et al. / Tetrahedron: Asymmetry 10 (1999) 243–254
245
8 with NaBH4.9,10 Ligand 5 was obtained by the reaction of ligand 4a with CH3I. Their structures are
confirmed by elemental analysis, MS and 1H NMR.
Lipophilic ligands 5, 6 and 7 are barely soluble in neutral water. Their clear solutions, free or as
transition metal ion complexes, can be obtained only in the presence of micelles of inert surfactants such
as Brij35 as a matrix of comicellar aggregates. The kinetic experiments were carried out using mixed
micelles, composed of a metal ion complex and a cosurfactant. Compounds 4a and 8 are soluble in water
and form micellar aggregates: the critical micellar concentrations (cmc) are 2.0×10−4 M and 2.8×10−4
M in MES buffer (0.05 M, pH 6.30), respectively.8c
Scheme 2 shows the substrates investigated: they are all chiral, nonmetallophilic substrates, i.e., the
N-protected p-nitrophenyl esters of R(S)-phenylalanine, R(S)-leucine and R(S)-alanine.
Scheme 2.
2.2. Kinetics
The rate of hydrolysis was followed by observing the release of p-nitrophenol spectrophotometrically
under pseudo-first-order conditions. The pseudo-first-order constants (kR and kS) for the cleavage of
R(S)-C12-Phe-PNP catalyzed by metal ion complexes comicellized with Brij35 are summarized in
Table 1. The enantioselectivity of each system is indicated by the ratio kR/kS. The results show that
large rate enhancements and enantioselectivities are observed only in the presence of both the ligand and
metal ion. The catalytic activity is the result of synergistic cooperation of the ligand and metal ion. More
strikingly, the enantioselectivity of 4a–M2+ shows a distinct dependence on the nature of the transition
metal ion, and has the order of Cu2+>Zn2+>Mn2+>Co2+>Ni2+. For ligands with one stereogenic center
(except ligand 5) they react faster with the enantiomeric substrate of opposite absolute configuration. For
the diastereomeric 7a and 7b an inversion of stereoselectivity is observed.
Normal micelles have a loose and mobile structure that is not very effective at inducing stereoselecti-
vity. However, in the present system good enantioselectivity is obtained. We believe that this is caused
by a highly oriented substrate–metallocatalyst ternary complex. In this ternary complex, the motional
freedom of both the hydroxyl group of the ligand and the substrate is restricted by the template effect of
the metal ion.
Although for both 4a and 6 the OH group is located at the δ-position in the side group of the pyridine
residue, ligand 6 exhibits less activity and stereoselectivity compared to ligand 4a. According to CPK
models, by binding of the metal ion to the nitrogen atom of the rigid (S)-prolinol group of ligand 4, the
structure of the (S)-prolinol group is frozen, and the OH group is in close proximity to metal ion. For
ligand 6, binding the metal ion to the nitrogen atom of the flexible (S)-leucinol group does not induce
complete fixation of the side group, and rotation around the C1–C2 axis of the (S)-leucinol group is
still possible. This indicates that the rigid structure of the ligand is more efficient, as expected from the
reduction in the degrees of freedom of the system. The lower activity and enantioselectivity of 7 and 8
are also probably attributed to the higher structural flexibility of the ephedrine moiety and the cysteinol

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Table 1
Pseudo-first-order constants (kR and kS, s−1) and enantioselectivities (kR/kS) for the cleavage of R(S)-
C12-Phe-PNP by ligands 4–8 and M2+ comicellized with Brij35
group, and the lower nucleophilicity of the more sterically hindered secondary OH in ligand 7. Taking the
analogous ligands 4a and 5 as an exemplary case (compare entries 6 and 11), methylation of the hydroxy
group leads to a dramatic decrease in rate and enantioselectivity, and an inversion of enantioselectivity is
observed. This suggests that the free hydroxy group of a ligand is mandatory in the transacylation process
as a nucleophile, as reported previously.9 From the data in Table 1, we notice that the water-soluble
4b–Cu2+ lacking a long chain is also less reactive and enantioselective in comparison with the lipophilic
4a–Cu2+, indicating that the hydrophobic interactions between substrate and metallocatalyst are favorable
for both high rate acceleration and good enantioselectivity. A lipophilic long chain can introduce an extra
orientation requirement in the supramolecular assembly between the metal ion complex and the lipophilic
substrate coexisting in the micelle by the hydrophobic interactions.
Table 2 shows the kinetic data observed for the cleavage of R(S)-C12-Phe-PNP in the absence
and presence of anionic n-dodecyl sodium sulfate (SDS), cationic n-hexadecyltrimethylammonium
bromide (CTABr), nonionic polyethylene glycol dodecyl ether (Brij35) or chiral n-dodecylquininium
bromide (DQB) as the matrix of comicellar aggregates. In the Brij35 micelle the enantioselectivity
induced by 4a–Cu2+ is higher than in CTABr and SDS. It is clearly seen that the chiral DQB has
no significant effect on the observed rate and enantioselectivity. Its blank reaction in the absence
of metallocatalyst also displays an insignificant enantioselectivity (kR/kS=0.86). These observations
indicate that chiral DQB hardly recognizes the chirality of metallocatalyst and substrate. In summary
the micellar microenvironment is of importance for the activity and the enantioselectivity.
The structural effect of substrates on the hydrolysis catalyzed by mixed micelles composed of 4a–Cu2+

J. You et al. / Tetrahedron: Asymmetry 10 (1999) 243–254
247
Table 2
Pseudo-first-order constants (kR and kS, s−1) and enantioselectivities (kR/kS) for the cleavage of R(S)-
C12-Phe-PNP by 4a and Cu2+ comicellized with different cosurfactants
Table 3
Structural effect of substrates on pseudo-first-order constants (kR and kS, s−1) and enantioselectivities
(kR/kS) catalyzed by a mixed micellar system composed of 4a–Cu2+ and Brij35
and Brij35 is depicted in Table 3. The increase in the size of the amino acid side chain of residue R2 from
alanine up to phenylalanine is accompanied by an increase in the selectivity from kR/kS=2.55 up to
7.81. The enhancement of selectivity is almost exclusively due to the increasing rate of the (R)-substrate
whereas the rate of the (S)-substrate is hardly affected. The hydrophobicity of the amino acid side chain
increases from the methyl moiety in the alanyl residue up to the benzyl moiety in the phenylalanyl
residue. Quite likely, the increase in the rate of the (R)-substrate is due to an increased hydrophobically
driven interaction between metallocatalyst and (R)-substrate. Such an interaction is absent with the
(S)-substrate. In the deacylation of R(S)-C2-Ala-PNP, the extent of the enantioselectivity increase is
negligibily small (kR/kS=1.37). As discussed above, this indicates that such ester substrates as R(S)-C2-
Ala-PNP lacking the hydrophobic long chain are likely to be adsorbed onto the water–micelle interface
and are hardly incorporated into the micellar phase, leading to insufficient substrate–metallocatalyst
approximation.
2.3. Stoichiometry of the reactive complexes
In order to determine the stoichiometry of the kinetically reactive complexes, the kinetic version of
Job plots was examined by plotting kR and kS as a function of molar fraction of ligand (γ), keeping the
total concentrations of the ligand and metal ion constant. The results shown in Fig. 1 indicate that in the
case of Cu2+ and ligand 4a the rate maxima are observed at γ=0.5, which correspond to a stoichiometry

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J. You et al. / Tetrahedron: Asymmetry 10 (1999) 243–254
Figure 1. Kinetic Job plots for the cleavage of (R)-Phe-PNP (×) and (S)-Phe-PNP (•) by ligand 4a and Cu2+ in MES buffer, pH
6.30, 25ꢀ0.1°C. [4a]+[Cu2+]=1.0×10−3 M. See Table 1 for other conditions
of ligand:Cu2+=1:1. Ligand 4a forms stable complexes with Cu2+ as indicated by the sharp maxima in
the Job plots.
2.4. pH-Rate profile
As discussed above, from the analysis of Table 1, a free hydroxyl in the ligand structure is of
importance for high rate acceleration and good enantioselectivity in micelles. The pH-rate constant
profiles were determined for reactions of (R)-C12-Phe-PNP with catalyst 4a–Cu2+ and (S)-C12-Phe-PNP
with 8–Cu2+. The pH value was checked before and after any kinetic run and proved to be constant to
within ꢀ0.05 pH unit. The inflections in the pH-rate profiles are diagnostic of an operative pKa value of
ca. 6.7 and 7.0, respectively (Fig. 2). They are taken as the systematic pKa of the hydroxyl bound to Cu2+
under our micellar reaction conditions. A pKa=7.2 for a Cu2+ coordinated primary hydroxyl has been
recently reported by our laboratory.9 It would be very interesting to know the pKa of the Cu2+-bound
secondary alcohol. Regrettably, solutions of the complex 7a–Cu2+ were unstable at pH>7.6. Up to that
pH we did not observe any break in the log k versus pH profile.
Figure 2. Log k versus pH for the hydrolysis of (R)-C12-Phe-PNP by 4a–Cu2+ (•) and (S)-C12-Phe-PNP by 8–Cu2+ (×). See
Table 1 for other conditions

J. You et al. / Tetrahedron: Asymmetry 10 (1999) 243–254
249
2.5. Mechanism
The above kinetic behavior of 4a–M2+-catalyzed hydrolysis of N-protected α-amino acid esters is
outlined in Scheme 3 on the basis of previous reports.3c,4b,8c The possible mechanism is based on an
octahedral geometry of the metal ion complex although for Ni2+, Cu2+, Zn2+, Co2+ and Mn2+ alternative
forms are possible.11 The mechanism involves:
(i) The formation of the metal complex A: M2+ coordinates up to six donors in an octahedral geometry.
The metal complex may be represented as A where the two nitrogen atoms and two oxygen atoms
of ligand 4a occupy the strongest position in a planar configuration.
Scheme 3. A possible mechanism of the cleavage of α-amino acid esters by chiral metallomicelles
(ii) The formation of the ternary complex B: this is the key step of the hydrolysis. The oxygen atom
of the CH3(CH2)nOCH2 group of the ligand is not a strong donor. For the formation of the ternary
complex, it should be displaced by the carbonyl group of the substrate.3b,12 Therefore the function
of this group will primarily incorporate the ligand into the micellar phase. The hydroxyl group of
ligand is activated by the metal ion, and its pKa value is reduced to provide the effective nucleophile
at near neutral pH.
(iii) The formation of the transacylation intermediate C: in the above mentioned ternary complex,
a pseudo-intramolecular nucleophilic attack of the activated ligand hydroxyl on the carbonyl
function of the substrate results in the expulsion of p-nitrophenol and the formation of an acylated
intermediate C.
(iv) The cleavage of the intermediate: this intermediate is hydrolyzed to release the amino acid and
regenerate the catalytic species by attack of the free or metal-ion-bound hydroxide ion to the
coordinated ester group, thus defining the catalytic cycle.
3. Experimental
3.1. General methods and materials
Melting points were taken on a micro-melting apparatus and are uncorrected. 1H NMR spec-
tra were recorded at 90 MHz and 299.95 MHz, and chemical shifts in ppm are reported relative

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J. You et al. / Tetrahedron: Asymmetry 10 (1999) 243–254
to internal Me4Si. Mass spectra data were recorded on a Finnigan MAT 4510 spectrometer. Ele-
mental analyses were performed with a Carlo Erba 1106 instrument. Optical rotations were taken
on a WZZ-1 polarimeter. Kinetic runs were conducted on a Shimadzu UV-265FW spectrophotome-
ter equipped with a thermostated cell compartment. Zn(NO3)2·6H2O, Cu(NO3)2·6H2O, Co(NO3)2,
Ni(NO3)2, MnCl2, n-dodecyl sodium sulfate (SDS), n-hexadecyltrimethylammonium bromide (CTABr)
and polyethylene glycol dodecyl ether (Brij35) were purchased from commercial sources and used
without further purification. The buffers were 2-morpholinoethanesulfonic acid (MES) (pH=5.0–6.8),
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) (pH=6.8–7.8) and 4-(2-hydroxyethyl)-1-
piperazinepropanesulfonic acid (EPPS) (pH=7.7–8.5). The following compounds were prepared ac-
cording to literature procedures: 2,6-bis(hydroxymethyl)pyridine,13 the p-nitrophenyl esters of the N-
protected α-amino acids,14 and (S)-amino alcohols.15 Chloroform, tetrahydrofuran and dioxane were
purified according to the standard methods. All other chemicals and reagents were obtained commercially
and used without further purification.
3.2. General procedure for the synthesis of 2
To a solution of 2,6-bis(hydroxymethyl)pyridine 1 (4.5 g, 32.4 mmol) in 50 mL of dry dioxane was
added NaH (1.17 g of 80% dispersion in mineral oil) under a nitrogen atmosphere. After the mixture
was kept for 2 h, the halide (1-bromododecane for 2a or iodomethane for 2b) (32.4 mmol) in 25 mL
of dioxane was added dropwise. The mixture was stirred at room temperature overnight. The slurry was
filtered, the organic solvent was evaporated, and the crude material purified by column chromatography
(SiO2, CHCl3:CH3OH, 100:5) to give a pale yellow oil.
3.2.1. 6-(n-Dodecyloxymethyl)-2-(hydroxymethyl)pyridine 2a
The resulting oil was recrystallized from petroleum (b.p. 30–60°C) to give white needles (yield 81.0%);
m.p. 44–45°C. δH (90 MHz, CDCl3): 0.88 (t, J=6.4 Hz, 3H, CH3), 1.26 (s, 18H, (CH2)9CH3), 1.56 (m,
2H, OCH2CH2(CH2)9), 3.55 (t, J=6.7 Hz, 2H, OCH2(CH2)10CH3), 4.63 (s, 2H, PyCH2OC12H25), 4.74
(s, 2H, PyCH2OH), 7.09 and 7.31 (2d, J=7.6 Hz, 2H, PyH5 and PyH3), 7.71 (t, J=7.6 Hz, 1H, PyH4).
MS (m/z): 308 (M++1, 20).
3.2.2. 6-(Methyloxymethyl)-2-(hydroxymethyl)pyridine 2b
Pale yellow oil (yield 88.5%). δH (90 MHz, CDCl3): 3.50 (s, 3H, CH3), 4.58 (s, 2H, PyCH2OCH3),
4.71 (s, 2H, PyCH2OH), 7.20 and 7.34 (2d, J=7.5 Hz, 2H, PyH5 and PyH3), 7.65 (t, J=7.5 Hz, 1H,
PyH4). MS (m/z): 154 (M++1, 80).
3.3. General procedure for the synthesis of 3
To 15 mL of SOCl2 was added compound 2 (4.1 mmol) at 0°C. The reaction mixture was stirred for 20
h at room temperature, and then concentrated in vacuo. The residue was dissolved in 100 mL of CHCl3
and washed with a saturated solution of NaHCO3 until the pH was 8.5. The organic phase was separated,
dried over Na2SO4 and concentrated under reduced pressure. The crude was chromatographed on silica
gel (ethyl acetate:methanol, 100:5).
3.3.1. 6-(n-Dodecyloxymethyl)-2-(chloromethyl)pyridine 3a
White solid (yield 89.1%); m.p. 35–36°C. δH (90 MHz, CDCl3): 0.88 (t, J=6.2 Hz, 3H, CH3), 1.26 (s,
18H, (CH2)9CH3), 1.65 (m, 2H, OCH2CH2(CH2)9), 3.56 (t, 2H, J=6.5 Hz, OCH2(CH2)10CH3), 4.61 (s,

J. You et al. / Tetrahedron: Asymmetry 10 (1999) 243–254
251
2H, PyCH2 Cl), 4.65 (s, 2H, PyCH2OC12H25), 7.27 and 7.40 (2d, J=7.6 Hz, 2H, PyH3 and PyH5), 7.73
(t, J=7.6 Hz, 1H, PyH4). MS (m/z): 326 (M+, 30).
3.3.2. 6-(Methyloxymethyl)-2-(chloromethyl)pyridine 3b
Pale yellow oil (yield 95.4%). δH (90 MHz, CDCl3): 3.56 (s, 3H, CH3), 4.63 (s, 2H, PyCH2Cl), 4.70
(s, 2H, PyCH2OCH3), 7.21 and 7.39 (2d, J=7.5 Hz, 2H, PyH3 and PyH5), 7.71 (t, J=7.5 Hz, 1H, PyH4).
MS (m/z): 172 (M+, 70).
3.4. General procedure for the synthesis of ligands 4, 6 and 7
To a stirred mixture of K2CO3 (1.0 g) and the appropriate amino alcohol (3.1 mmol of (S)-prolinol for
4, 3.1 mmol of ephedrine for 7, or 6.2 mmol of (S)-leucinol for ligand 6) in 20 mL of freshly distilled
CHCl3 was added, dropwise, 3.1 mmol of the appropriate 6-alkoxymethy-2-chloromethylpyridine (com-
pound 3a for ligands 4a, 6 and 7, or compound 3b for ligand 4b) dissolved in 15 mL of CHCl3 at reflux
under a nitrogen atmosphere. After the addition was complete, the mixture was kept at this temperature
for 4 h. Water (15 mL) was then added. The organic layer was separated, dried over Na2SO4, evaporated
under reduced pressure, and the raw product purified by column chromatography (SiO2, CHCl3:CH3OH,
100:3).
3.4.1. (S)-N-[6-(n-Dodecyloxymethyl)pyridine-2-yl]methylprolinol 4a
Pale yellow oil (yield 83.6%); [α]25=−10.8 (c=1.0, CHCl3). δH (299.95 MHz, CDCl3): 0.88 (t,
D
J=6.9 Hz, 3H, CH3), 1.26 (s, 18H, (CH2)9CH3), 1.37 (m, 2H, OCH2CH2(CH2)9), 1.65 (m, 4H,
(CH2)2CHCH2OH), 1.92 (m, 1H, CH2a(CH2)2CHCH2OH), 2.51 (m, 1H, CH2b(CH2)2CHCH2OH), 2.87
(m, 1H, CHCH2OH), 3.11 (br s, 1H, OH), 3.43 (dd, J=3.3, 4.2 Hz, 1H, CH2aOH), 3.48 (dd, J=3.3, 4.5
Hz, 1H, CH2bOH), 3.55 (t, J=6.6 Hz, 2H, OCH2(CH2)10), 3.71 (d, J=14.4 Hz, 1H, PyCH2aN), 4.04 (d,
J=14.4 Hz, 1H, PyCH2bN), 4.62 (s, 2H, PyCH2O), 7.20 and 7.34 (2d, J=7.5 Hz, 2H, PyH3 and PyH5),
7.67 (t, J=7.5 Hz, 1H, PyH4). Anal. calcd for C24H42N2O2: C, 73.79, H, 10.84, N, 7.17; found: C, 73.46,
H, 11.02, N, 6.95. MS (m/z): 391 (M++1, 90).
3.4.2. (S)-N-[6-(Methyloxymethyl)pyridine-2-yl]methylprolinol 4b
Pale yellow oil (yield 80.7%); [α]25=−31.2 (c=1.0, CHCl3). δH (299.95 MHz, CDCl3): 1.86 (m, 4H,
D
(CH2)2CHCH2OH), 2.10 (m, 1H, CH2a(CH2)2CHCH2OH), 2.52 (m, 1H, CH2b(CH2)2CHCH2OH), 2.65
(m, 1H, CHCH2OH), 3.03 (br s, 1H, OH), 3.46 (dd, J=3.2, 4.2 Hz, 1H, CH2aOH), 3.51 (dd, J=3.2, 4.5
Hz, 1H, CH2bOH), 3.58 (s, 3H, OCH3), 3.82 (d, J=14.5 Hz, 1H, PyCH2aN), 4.05 (d, J=14.5 Hz, 1H, Py
CH2bN), 4.62 (s, 2H, PyCH2O), 7.20 and 7.33 (2d, J=7.5 Hz, 2H, PyH3 and PyH5), 7.70 (t, J=7.5 Hz,
3H, PyH4). Anal. calcd for C13H20N2O2: C, 66.07, H, 8.53, N, 11.86; found: C, 65.79, H, 8.70, N, 11.57.
MS (m/z): 237 (M++1, 90).
3.4.3. (S)-N-[6-(n-Dodecyloxymethyl)pyridine-2-yl]methylleucinol 6
Pale yellow oil (yield 75.8%); [α]25=+10.0 (c=1.0, CHCl3). δH (299.95 MHz, CDCl3): 0.89 (m, 9H,
D
CH3), 1.26 (m, 18H, CH2(CH2)9), 1.38 (m, 2H, OCH2 CH2(CH2)9), 1.65 (m, 3H, CH2CH(CH3)2), 2.78
(m, 1H, CHCH2OH), 3.01 (br s, 2H, NH, OH), 3.34 (dd, J=3.6, 6.3 Hz, 1H, CH2aOH), 3.37 (dd, J=3.6,
6.3 Hz, 1H, CH2bOH), 3.55 (t, J=6.6 Hz, 2H, OCH2(CH2)9), 3.89 (d, J=15.0 Hz, 1H, PyCH2aN), 3.99 (d,
J=14.7 Hz, 1H, PyCH2bN), 4.61 (s, 2H, PyCH2O), 7.14 and 7.33 (2d, J=7.5 Hz, 2H, PyH3 and PyH5),
7.66 (t, J=7.5 Hz, 1H, PyH4). Anal. calcd for C25H46N2O2: C, 73.84, H, 11.40, N, 6.89; found: C, 73.49,
H, 11.10, N, 6.65. MS (m/z): 407 (M++1, 100).

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J. You et al. / Tetrahedron: Asymmetry 10 (1999) 243–254
3.4.4. (1R,2S)-N-[6-(n-Dodecyloxymethyl)pyridine-2-yl]methylephedrine 7a
The crude was purified by column chromatography (SiO2, CHCl3:CH3OH, 100:1) and then by treat-
ment with charcoal from absolute methanol under a nitrogen atmosphere to give a pale yellow oil (yield
54.0%); [α]25=−15.9 (c=1.9, CHCl3). δH (299.95 MHz, CDCl3): 0.88 (t, J=6.0 Hz, 3H, (CH2)11CH3),
D
1.04 (d, J=7.1 Hz, 3H, CHCH3), 1.19 (m, 18H, (CH2)9CH3), 1.57 (m, 2H, OCH2CH2(CH2)9), 2.30 (s,
3H, NCH3), 2.99 (m, 1H, CHCH3), 3.54 (t, J=6.5 Hz, 2H, OCH2(CH2)10), 3.62 (d, J=14.4 Hz, 1H,
PyCH2aN), 3.79 (d, J=14.4 Hz, 1H, Py CH2bN), 4.09 (br s, 1H, OH), 4.60 (s, 2H, PyCH2O), 4.89 (d,
J=4.1 Hz, 1H, CHOH), 7.05–7.72 (m, 8H, HPh and HPy). Anal. calcd for C29H46N2O2: C, 76.60, H,
10.20, N, 6.16; found: C, 76.05, H, 9.98, N, 5.80. MS (m/z): 456 (M++1, 70).
3.4.5. (1S,2S)-N-[6-(n-Dodecyloxymethyl)pyridine-2-yl]methylephedrine 7b
The crude was purified by column chromatography (SiO2, CHCl3:CH3OH, 100:1) and then by treat-
ment with charcoal from absolute methanol under a nitrogen atmosphere to give a pale yellow oil (yield
61.0%); [α]25=+5.1 (c=1.9, CHCl3). δH (299.95 MHz, CDCl3): 0.87 (t, 3H, J=6.4 Hz, (CH2)11CH3),
D
0.96 (d, J=7.2 Hz, 3H, CHCH3), 1.21 (m, 18H, (CH2)9CH3), 1.59 (m, 2H, OCH2CH2(CH2)9), 2.30 (s,
3H, NCH3), 2.90 (m, 1H, CHCH3), 3.01 (br s, 1H, OH), 3.56 (t, J=6.6 Hz, 2H, OCH2(CH2)10), 3.70 (d,
J=14.0 Hz, 1H, PyCH2aN), 3.89 (d, J=14.0 Hz, 1H, PyCH2bN), 4.31 (d, J=7.2 Hz, 1H, CHOH), 4.60 (s,
2H, PyCH2O), 7.05–7.79 (m, 8H, HPh and HPy). Anal. calcd for C29H46N2O2: C, 76.60, H, 10.20, N,
6.16; found: C, 76.18, H, 10.34, N, 6.06. MS (m/z): 456 (M++1, 50).
3.5. (S)-N-[6-(n-Dodecyloxymethyl)pyridine-2-yl]methylprolinol methyl ether 5
To a solution of ligand 4a (0.63 g, 1.61 mmol) in 30 mL of dry THF was added NaH (0.1 g
of 80% dispersion in mineral oil) in an ice bath under a nitrogen atmosphere. After the mixture
had been stirred at this temperature for 1.5 h, CH3I (0.23 g, 1.61 mmol) in 10 mL of THF was
added dropwise. Water (20 mL) was added, and the solvent evaporated. The residue was extracted
with CHCl3 and evaporated under reduced pressure. The raw product was chromatographed on silica
gel (CHCl3:CH3OH, 100:3) to give a pale yellow oil (yield 58.4%); [α]25=−34.8 (c=1.0, CHCl3).
D
δH (299.95 MHz, CDCl3): 0.93 (t, J=6.9 Hz, 3H, CH3), 1.31 (s, 18H, (CH2)9CH3), 1.38 (m, 2H,
OCH2CH2(CH2)9), 1.68 (m, 4H, (CH2)2CHCH2OCH3), 2.01 (m, 1H, CH2a(CH2)2CH CH2OCH3), 2.35
(m, 1H, CH2b(CH2)2CHCH2OCH3), 2.91 (m, 1H, CHCH2OCH3), 3.33 (s, 3H, OCH3), 3.46 (d, J=4.5
Hz, 2H, CHCH2OCH3), 3.56 (t, J=6.6 Hz, 2H, OCH2(CH2)10), 3.76 (d, J=14.5 Hz, 1H, PyCH2aN), 4.10
(d, J=14.5 Hz, 1H, PyCH2bN), 4.61 (s, 2H, PyCH2O), 7.21 and 7.34 (2d, J=7.5 Hz, 2H, PyH3 and PyH5),
7.65 (t, J=7.5 Hz, 1H, PyH4). Anal. calcd for C25H44N2O2: C, 74.21, H, 10.96, N, 6.92; found: C, 74.00,
H, 11.23, N, 6.70. MS (m/z): 405 (M++1, 70).
3.6. (R)-S-[6-(n-Dodecyloxymethyl)pyridine-2-yl]methylcysteinol 8
L-Cysteine hydrochloride (0.48 g, 3.06 mmol) and NaI (0.1 g) were dissolved in a solution of 3.06 mL
of water and 20 mL of ethanol, and NaOH (6.12 mmol) was added slowly with stirring in an ice bath.
After compound 3a (1.0 g, 3.06 mmol) in 10 mL of ethanol was added, the mixture was kept for 4 h at
60°C. The precipitate was filtered off and sequentially washed with water and ethanol, and dried to give
a white solid (yield 71.5%).
The above amino acid (0.9 g, 2.2 mmol) was suspended in 25 mL of methanol and cooled to 0°C in
an ice bath. SOCl2 (0.7 mL) was added dropwise with stirring and the mixture was stirred at the same

J. You et al. / Tetrahedron: Asymmetry 10 (1999) 243–254
253
temperature for 24 h and then at 60°C for another 1 h. The solvent was evaporated under vacuum to give
the ester of amino acid hydrochloride (yield 81.1%).
The above ester (0.9 g, 1.81 mmol) was dissolved in 60 mL of EtOH containing NaBH4 (0.5 g, 13.2
mmol). After it was stirred at room temperature for 1 h, the mixture was refluxed for 5 h. The solvent was
evaporated and the residue was treated with water and extracted with CHCl3 (4×30 mL). The organic
layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by
column chromatography (SiO2, CHCl3:CH3OH, 5:1) to give a white solid (yield 51.0%); m.p. 51–52°C;
[α]25=−10.0 (c=1.0, CHCl3). δH (299.95 MHz, CDCl3): 0.88 (t, J=6.6 Hz, 3H, CH3), 1.26 (s, 18H,
D
CH2(CH2)9), 1.35 (m, 2H, OCH2CH2(CH2)9), 1.64 (m, 2H, SCH2CHNH2), 2.67 (m, 2H, NH2), 3.24
(s, 1H, OH), 3.54 (t, 2H, J=6.6 Hz, OCH2(CH2)9CH3), 3.60 (m, 2H, CH2OH), 3.84 (s, 2H, PyCH2S),
4.60 (s, 2H, PyCH2 O), 7.23 and 7.32 (2d, J=7.8 Hz, 2H, PyH3 and PyH5), 7.65 (t, J=7.8 Hz, 1H, PyH4).
Anal. calcd for C22H40N2O2S: C, 66.62, H, 10.17, N, 7.06; found: C, 66.34, H, 10.32, N, 6.89. MS (m/z):
397 (M+, 100).
3.7. Kinetic studies
Solutions of the ligands, metal ions and cosurfactants were prepared in the appropriate buffer (0.05
M). The reaction temperature was maintained at 25ꢀ1°C. Kinetics were typically started by injecting
an acetonitrile solution (0.01 M) of substrate ester, into a 1 cm cuvette containing 2.5 mL of buffered
micellar solution and the desired concentration of metal ion and ligand. Pseudo-first-order rate constants
(kR and kS) for the hydrolysis of substrate ester were determined by monitoring the release of p-
nitrophenol at 320 nm (pH 5.0–6.3) or 400 nm (pH 6.3–8.5) for at least five half-lives, and obtained
by linear plots of ln(A −At) versus time. The rate constants for each reaction were determined three
∞
times from three separate runs with an uncertainty of less than 5%.
Acknowledgements
This project was supported by the National Natural Science Foundation of China (No. 29502008 and
29632004).
References
1. Bhattacharya, S.; Snehalatha, K.; George, S. J. Org. Chem. 1998, 63, 27.
2. (a) Scrimin, P.; Tecilla, P.; Tonellato, U. J. Org. Chem. 1991, 56, 161. (b) Scrimin, P.; Tecilla, P.; Tonellato, U. J. Org.
Chem. 1994, 59, 18. (c) Bunton, C. A.; Scrimin, P.; Tecilla, P. J. Chem. Soc., Perkin Trans. 2 1996, 419.
3. (a) Tagaki, W.; Ogino, K.; Tanaka, O.; Machiya, K.; Kashihara, N.; Yoshida, T. Bull. Chem. Soc. Jpn. 1991, 64, 74. (b)
Ogino, K.; Kashihara, N.; Ueda, T.; Isaka, T.; Yoshida, T.; Tagaki, W. Bull. Chem. Soc. Jpn. 1992, 65, 373. (c) Ogino, K.;
Inoue, K.; Tagaki, W. Tetrahedron Lett. 1992, 33, 4191. (d) Ogino, K.; Yamamoto, H.; Yoshida, T.; Tagaki, W. J. Chem.
Soc., Chem. Commun. 1995, 691.
4. (a) Weijnen, J. G. J.; Koudijs, A.; Schellenes, G. A.; Engbersen, J. F. J. J. Chem. Soc., Perkin Trans. 2 1992, 829. (b)
Weijnen, J. G. J.; Engbersen, J. F. J. Recl. Trav. Chim. Pays Bas 1993, 351.
5. Van Esch, J. H.; Damen, M.; Feiters, M. C.; Nolte, R. J. M. Recl. Trav. Chim. Pays Bas 1994, 186.
6. Kimura, E.; Hashimoto, H.; Koike, T. J. Am. Chem. Soc. 1996, 118, 10963.
7. Broxton, T. J.; Cox, R. A. Can. J. Chem. 1993, 71, 670.
8. (a) Cleij, M. C.; Mancin, F.; Scrimin, P.; Tecilla, P.; Tonellato, U. Tetrahedron 1997, 53, 357. (b) Cleij, M. C.; Scrimin, P.;
Tecilla, P.; Tonellato, U. Langmuir 1996, 12, 2956. (c) Scrimin, P.; Tecilla, P.; Tonellato, U. J. Org. Chem. 1994, 59, 4194.
9. You, J.; Yu, X.; Li, X.; Yan, Q.; Xie, R. Tetrahedron: Asymmetry 1998, 9, 1197.

254
J. You et al. / Tetrahedron: Asymmetry 10 (1999) 243–254
10. Li, X.; Qin, J.; Zhang, X.; Xie, R. Synth. Commun. 1997, 27, 3079.
11. Cotton, F. A.; Wilkinson, G. Advanced Inorganic Chemistry, 3rd Edn; Wiley: New York, 1972.
12. Holyer, R. H.; Hubbard, C. D.; Kettle, S. F. A.; Wilkins, R. G. Inorg. Chem. 1965, 4, 929.
13. Newcomb, M.; Timko, J. M.; Walba, D. M.; Cram, D. J. J. Am. Chem. Soc. 1977, 99, 6392.
14. (a) Ingles, D. W.; Knowles, J. R. Biochem. J. 1967, 104, 369. (b) Bodanszky, M.; Vigneaud, V. D. J. Am. Chem. Soc. 1959,
81, 5688.
15. McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org. Chem. 1993, 58, 3568.