Enantioselective synthesis of 4-(dimethylamino)pyridines through a chemical oxidation-enzymatic reduction sequence. Application in asymmetric catalysis

Article abstract of DOI:10.1002/adsc.200600274

Enantiomerically pure 4-(dimethylamino)-3-(1-hydroxyalkyl)pyridines and 4-(dimethylamino)-3-[hydroxy(phenyl)methyl]pyridine have been prepared through efficient chemoenzymatic routes. For this purpose different lipases and oxidoreductases have been tested

Full text of DOI:10.1002/adsc.200600274

FULL PAPERS
DOI: 10.1002/adsc.200600274
Enantioselective Synthesis of 4-(Dimethylamino)pyridines
through a Chemical Oxidation-Enzymatic Reduction Sequence.
Application in Asymmetric Catalysis
Eduardo Busto,a Vicente Gotor-Fernµndez,a and Vicente Gotora,*
a
Departamento de Química Orgµnica e Inorgµnica, Instituto Universitario de Biotecnología de Asturias, Universidad de
Oviedo, 33006 Oviedo (Asturias), Spain
Fax : (+34)-98-510-3448; e-mail: vgs@fq.uniovi.es
Received: June 10, 2006; Accepted: September 18, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Enantiomerically pure 4-(dimethylamino)- tions of the corresponding ketones. Their applica-
3-(1-hydroxyalkyl)pyridines and 4-(dimethylamino)- tions as enantioselective nucleophilic catalysts have
3-[hydroxy(phenyl)methyl]pyridine have been pre- been studied, important catalytic properties were ob-
N
pared through efficient chemoenzymatic routes. For served in the stereoselective construction of quater-
this purpose different lipases and oxidoreductases nary centers.
have been tested in the preparation of optically
active 4-chloro derivatives and bakerꢀs yeast was Keywords: asymmetric catalysis; bioreduction; 4-(di-
found to be an excellent catalyst for the bioreduc- methylamino)pyridine; kinetic resolution; oxidation
Introduction
tion 4. However, their reactivity is limited due to the
proximity of the catalytic active site, and activation of
4-(Dimethylamino)pyridine (DMAP) is the most the DMAP derivative is required in their use as asym-
common nucleophilic catalyst for acyl transfer and metric catalysts.[6] A number of 3-substituted DMAP
similar transformations,[1] and the design of chiral derivatives have been described throughout the last
DMAP derivatives is a challenge that has been re- decade. Spivey and co-workers described the synthesis
ceiving considerable attention in recent years due to and application of atropoisomeric biaryl 4-(dialkyl-
the demonstration of their interesting properties in amino)pyridines, in which the chirality stems from re-
the development of asymmetric synthetic processes.[2] stricted rotation about an aryl-aryl bond.[7] Other
These compounds have been prepared by different groups have introduced an element of chirality from
chemicalstrategies and the introduction of chirailty
adequate precursors through chemically selective
has been possible by different synthetic procedures. modifications of position 3 in the pyridine ring, and
Fu and co-workers developed the concept of “planar encouraging selectivities have been found when they
chirality” for DMAP analogues, obtaining optically have been employed in different asymmetric process-
active p-complexes of heterocyles with transition es.[8]
metals, which are very versatile catalysts in asymmet-
Biocatalysis has made possible the preparation of
ric synthesis,[3] and similar complexes have been re- optically active pyridine derivatives, via the asymmet-
cently synthesized by other authors.[4] Depending on ric reductions of ketones[9], through lipase-catalyzed
the substituted position in the pyridine ring, the prep- hydrolysis of acetates, or through acylation proce-
aration of chiralDMAP compounds has been report-
dures of alcohols or amines.[10] We have recently de-
ed extensively in the last decade. 4-Pyrrolidinopyri- scribed the synthesis of a new family of chiral DMAP
dine analogues are the most common derivatives pos- catalysts substituted in the C-2 position of the pyri-
sesing chirality in position 4 of the pyridine struc- dine ring using either Pseudomonas cepacia lipase
ture,[5] but although they are very reactive, the enan- (PSL-C) as biocatalyst,[11] or using different oxidore-
tiopreferences shown in asymmetric processes are ductases, especially bakerꢀs yeast.[12]
generally moderate. Chemical access to 2-substituted
Here we report the development of an efficient
DMAPs is more difficult, but they act with higher se- chemoenzymatic strategy for the synthesis of chiral3-
lectivities than derivatives with substituents in posi- substituted DMAP analogues. Different enzymatic
2626
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Adv. Synth. Catal. 2006, 348, 2626 – 2632

Enantioselective Synthesis of 4-(Dimethylamino)pyridines
FULL PAPERS
procedures have been explored for the introduction yield, for instance, in the case of 3d. However, the re-
of chirality, such as the lipase-catalyzed transesterifi- action with benzaldehyde afforded 4-chloro-3-
cation of alcohols, or the bioreduction of ketones [hydroxy(phenyl)methyl]pyridine (3e) in 90% isolat-
G
mediated by oxidoreductases of different sources. Fi- ed yield with just 1 equivalent of LDA. This is a
nally the application of the chiral DMAP analogues better yield than those obtained with 3a–d due to the
in stereoselective processes is studied.
absence of hydrogen atoms in the a-position to the
carbonylgroup.
Initially enzymatic resolution of (Æ)-3a was at-
tempted by enzymatic transesterification using vinyl
acetate (VA, 4) as acyldonor, under different reac-
Results and Discussion
For the preparation of 4-chloro-3-(1-hydroxyalkyl)- tion conditions and employing Pseudomonas cepacia
pyridines (3a–d) and 4-chloro-3-[hydroxy- lipase (PSL-C) and Candida antarctica lipase B
(phenyl)methyl]pyridine (3e), we followed a modified (CAL-B) as biocatalysts since they were the best en-
ACHTREUNG
procedure of the method described by QuØguiner and zymes in the resolution of 4-chloro-2-(1-hydroxyal-
co-workers for the preparation of 3,4-disubstituted kyl)pyridines (Scheme 2, Table 1).[11]
pyridines (Scheme 1).[13] Commercially available 4-
Scheme 2. Kinetic resolution of (Æ)-3a–e by lipase-catalyzed
Scheme 1. Chemicalsynthesis of ( Æ)-3a–e.
transesterification.
chloropyridine hydrochloride salt (1) was extracted in
basic media to isolate the corresponding pyridine 2,
Both PSL-C and CAL-B achieved an excellent
which was used as starting material. Selective ortho- enantioselectivity in the reaction with racemic 3a
lithiation in dry diethyl ether with 1 equivalent of lith- using 3 equivs. of VA and THF as solvent at 308C
ium diisopropylamide (LDA) and later reaction with (entries 1 and 2). CAL-B showed a higher reaction
the corresponding aldehyde, afforded 3a–d in low rate, although longer reaction times led to a decrease
yields (40–45%). Reactions were then attempted in in the conversion. Reactions at higher temperature or
the presence of 2 equivalents of LDA, enhancing the with 10 equivs. of VA led to a slight increase in the
conversion values and affording higher isolated yields conversion values (data not shown). Next, reactions
(61–68%). Use of more equivalents of LDA did not were carried out in VA as solvent and acyl donor (en-
increase the amount of finalproduct; 64% isoalted
tries 3–5) providing both product and substrate in
Table 1. Enzymatic kinetic resolution of (Æ)-3a–e using vinylacetate and different ilpases.
Entry
3
Enzyme
Solvent
VA [equivs.]
T [8C]
t [h]
ees [%][a]
eep [%][a]
c [%][b]
E[c]
1
2
3
4
5
6
7
8
9
10
3a
3a
3a
3a
3a
3b
3c
3d
3c
3e
PSL-C
CAL-B
PSL-C
CAL-B
CAL-B
CAL-B
CAL-B
CAL-A
CAL-A
CAL-A
THF
THF
VA
VA
VA
VA
VA
VA
VA
VA
3
3
–
–
–
–
–
–
–
–
30
30
30
30
60
60
60
60
60
60
62
38
63
85
14
38
62
136
24
48
20
45
86
>99
>99 (86)
93 (88)
–
16
12
55
>99
>99
96
>99
>99 (96)
97 (89)
–
>99
76
87
17
31
47
50
50
49
–
14
13
39
>200
>200
137
>200
>200
195
–
>200
8
25
[a]
Calculated by HPLC.
[b]
[c]
[d]
c=eeS/
E=ln
[(1Àc)”(1ÀeeS)]/ln
Isolated yields in brackets.
(eeS+eeP).
E
G
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2627

Eduardo Busto et al.
FULL PAPERS
high isolated yields and enantiomeric excesses in the the ketones using the corresponding alcohols as start-
case of CAL-B. ing materials. Oxidation of alcohol 3a with MnO2 in
With the best reaction conditions in hand, exten- CHCl3 led to ketone 6a in quantitative yield, although
sion of this enzymatic study was done for substrates unfortunately it looked very unstable in the presence
3b–d. CAL-B catalyzed the kinetic resolution of 3b of air. This process was repeated for 3b–e but just
with high enantioselectivity (entry 6). However, it achieved around 50% conversion, with the stability
completely failed with bulkier substrates such as 3c problems persisting in the case of the compounds
and d, which seem not to fit in the active site of with smaller aliphatic substituents. Trying to over-
CAL-B.[14] Candida antarctica lipase A (CAL-A) has come both problems, we designed a two-step proce-
been identified as an idealenzyme in the resoultion
dure of chemicaloxidation and enzymatic enantiose-
of sterically hindered compounds,[15] for which reason lective reduction using the system CrO3 in acetone for
we decided to explore the possibilities of this catalyst the chemicaloxidation. The ketones 6a–e were ob-
in the kinetic resolution of 3b–d. The high enantiose- tained, and were rapidly filtered in celite, stabilized
lectivity in the case of R=Bu (entry 8) was of note, with 2-propanol( i-PrOH) to avoid dryness and used
but this decreased with a smaller substituent (R=Pr, in the subsequent bioreduction step with different oxi-
entry 9). Reaction of this biocatalyst with pyridine 3e doreductases (Scheme 3).
was also attempted resulting in a moderate enantio-
preference (entry 10).
Three different oxidoreductases were used in the
asymmetric reduction of 6a–e, bakerꢀs yeast, alcohol
Traditionally, bioreduction of ketones has appeared dehydrogenase from Thermoanaerobacter species (T-
as an attractive alternative for the production of ADH), and alcohol dehydrogenase from Lactobacil-
enantiomerically pure pyridine alcohols. For instance, lus brevis (LB-ADH). The oxidation step was carried
bakerꢀs yeast has demonstrated its potentialin the
out at room temperature and the enzymatic reduction
asymmetric reduction of 2-alkanoyl-4-chloropyridines was done in an orbitalshaker at 30 8C, the results
and 2-benzoyl-4-chloropyridine.[12] Before developing being shown in Table 2. Bakerꢀs yeast and TS-ADH
this enzymatic study, it was necessary to synthesize showed excellent enantiopreferences in the prepara-
Scheme 3. Preparation of optically active alcohols through a chemical oxidation and enzymatic reduction sequence.
Table 2. Preparation of optically active 3a–e in a chemicaloxidation-enzymatic reduction sequence.
Entry
3
Enzyme
T [8C]
t [h]
c [%][a]
eep [%][b]
Configuration[c]
1
2
3
4
5
6
7
8
3a
3a
3a
3b
3b
3b
3c
3c
3c
3d
3e
3e
3e
bakerꢀs yeast
TS-ADH
LB-ADH
bakerꢀs yeast
TS-ADH
LB-ADH
bakerꢀs yeast
TS-ADH
LB-ADH
bakerꢀs yeast
bakerꢀs yeast
bakerꢀs yeast
bakerꢀs yeast[d]
30
30
30
30
30
30
30
30
30
30
30
45
30
14
45
69
14
88
88
14
90
90
14
115
24
43
100 (79)
100 (89)
100 (91)
100 (76)
43
–
100 (73)
–
>99
>99
98
>99
93
–
98
–
–
S
S
R
S
S
–
S
–
–
S
S
–
S
9
–
10
11
12
13
100 (74)
82
–
>99
>99
–
100 (75)
>99
[a]
1
Conversions calculated by H NMR and isolated yields in brackets.
Calculated by HPLC.
[b]
[c]
[d]
Determined by Mosherꢀs esters.
Use of double amount of enzyme.
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Enantioselective Synthesis of 4-(Dimethylamino)pyridines
FULL PAPERS
tion of (S)-3a in line with Prelogꢀs rule (entries 1 and when complete disappearance of the starting material
2), as did LB-ADH. However, the latter showed a was observed (Table 3). Firstly the reaction was per-
complementary selectivity yielding the (R)-alcohol formed at 258C using 9a as catalyst affording 10 in a
(entry 3). Bakerꢀs yeast reacted with all the com- high isolated yield but low ee (entry 1). To improve
pounds possesing alkyl rests with enantiomerically
pure (S)-3b–d being isolated in high yields (entries 4,
Table 3. Catalytic enantioselective rearrangement of 8 medi-
ated by chiralDMAP anaol gues.
7 and 10). TS-ADH showed a very high enantiopre-
ference in the bioreduction of 6b but this did not go
through to its full extent (entry 5). Meanwhile, no re-
action was observed with other more sterically hin-
dered substrates or using LB-ADH as enzyme (en-
tries 6, 8, 9). Finally bioreduction with Bakerꢀs yeast
of 6e was successfully achieved at 308C using double
the amount of enzyme (entry 13) because the same
amount of biocatalyst was not enough to reach a com-
plete conversion (entry 11) and an increase in the
temperature led to the inactivation of the catalyst
(entry 12).
Determination of the stereochemicalconfiguration
of the chiral center was done on the basis of Kellyꢀs
method,[16] transforming the corresponding alcohols to
their ester derivatives (see ExperimentalSection).
Enantiomerically pure (S)-4-chloro-3-(1-hydroxyal-
Entry Catalyst
R
T [8C] t [h] Yield [%][a] ee [%][b]
1
2
3
4
5
9a
9a
9d
9e
11
Me 25
5
7
8
8
8
91
94
93
92
91
18
20
55
70
41
Me À10
Bu À10
Ph À10
Bu À10
[a]
[b]
Isolated yields after flash chromatography.
Calculated by HPLC.
kyl)pyridines
and
(S)-4-chloro-3-[hydroxy-
ACHTREUNG
responding (S)-4-(dimethylamino)-3-(1-hydroxyalkyl)- À108C, the minimum temperature possible for this
pyridines (7a–d) and (S)-4-(dimethylamino)-3- solvent due to its melting point of À138C. The result
[hydroxy(phenyl)methyl]pyridine (7e) by reaction at was the formation of the finalproduct in 20% ee
A
1008C with an aqueous solution of dimethylamine, (entry 2). Under similar reaction conditions the cata-
the potential nucleophilic catalysts being obtained in lysts with the butyl (9d) and phenylsubstituent ( 9e)
nearly quantitative yields.
were employed. This achieved better ee in the forma-
tion of 10 (entries 3 and 4), and especially in the case
A representative range of chemicalcataylsts were
then selected to evaluate their properties as nucleo- of 9e which allowed the preparation of the desired
philic catalysts. Compounds 7a, 7d and 7e were pro- product in 70% ee. Finally the effect of varying the
tected like O-acetylderivatives ( 9a, 9d and 9e) to acetylprotecting group on oxygen was expolred.
avoid side reactions, and were tested in the enantiose- However, the use of highly hindered derivatives like
lective construction of quaternary centers through the the O-benzyloxycarbonyl derivative 11 led to low
rearrangement of enolcarbonates. This appiclation
enantiopreference (entry 5). These results are in ac-
allows the formation of carbon-carbon bonds in a ste- cordance with the levels of enantioselection obtained
reoselective fashion, which is considered to be one of previously by Vedejs and co-workers,[8b,f] and showed
the most difficult challenges in asymmetric organic certain advantages like the easy preparation of these
synthesis. For simplicity we chose to examine the novel catalysts by simple chemoenzymatic routes, or
Steglich rearrangement of the enol carbonate 8 pre- the recovery of the catalysts in quantitative yields
cursor of the azlactone 10 (Scheme 4).
after flash chromatography once that the reactions
are finished, allowing the re-use of the catalyst as
Reactions were carried out in tert-amylacloholat
different temperatures and all of them were stopped often as necessary.
Scheme 4. Enantioselective rearrangement of 8 catalyzed by DMAP derivatives.
Adv. Synth. Catal. 2006, 348, 2626 – 2632
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Eduardo Busto et al.
FULL PAPERS
Conclusions
chloropyridine (500 mg, 4.40 mmol) in 4 mL of dry Et2O
was added. The reaction mixture was stirred for additional
4 h, and then the corresponding aldehyde (4.40 mmol) was
added and the mixture was stirred and allowed to warm to
room temperature during 15 min. Excess of LDA was de-
stroyed with H2O (25 mL), and the mixture extracted with
Et2O (3”25 mL). The organic phases were combined, dried
over Na2SO4 and the solvent evaporated under reduced
pressure obtaining a crude materialthat was purified by
flash chromatography (20–40% EtOAc/hexane) isolating
the corresponding alcohol 3a–e.
In summary, we have synthesized novelenantiomeri-
cally pure 4-(dimethylamino)-3-substituted-pyridines,
exploring different chemoenzymatic approaches for
the introduction of chirality. In this manner, bioreduc-
tion processes using bakerꢀs yeast have made possible
the preparation of optically active (S)-alcohols, which
have been easily converted into adequate nucleophilic
catalysts in a globally economic sequence. The effi-
ciency of these catalysts in asymmetric synthesis has
been positively tested in the rearrangement of enol
carbonates. The enantioselective formation of quater-
nary stereogenic centers has been observed, and the
possibility of recovering the catalyst at the end of the
process has been demonstrated. Further research ex-
ploring the scope of these catalysts is currently under
investigation.
Enzymatic Kinetic Resolution of 4-Chloro-3-(1-
hydroxyalkyl)pyridines (3a–d) and 4-Chloro-3-
[hydroxy
Transesterification
(phenyl)methyl]pyridine (3e) by Enzymatic
A
suspension under nitrogen atmosphere of 3a–e
(0.94 mmol) and CAL-B (150 mg) in vinyl acetate (9.4 mL),
was shaken at 608C and 250 rpm. Aliquots were regularly
analyzed by HPLC and the reaction was stopped by filtering
the enzyme with CH2Cl2 (3”10 mL). The solvent was evapo-
rated and the crude of reaction purified by flash chromatog-
raphy (20–40% EtOAc/hexane) isolating optically active
(R)-5a–e and (S)-3a–e.
Experimental Section
General Remarks
Candida antarctica lipase type B (CAL-B, Novozyme 435,
7300 PLU/g) was a gift from Novo Nordisk Co. Candida ant-
arctica lipase type A (CAL-A, Chirazyme L-5, c-f, lyophi-
lized, 1000 U/g using tributyrin) was acquired from Roche.
Pseudomonas cepacia lipase (PSL-C, 783 U/g) was obtained
from Amano PharmaceuticalCo. Recombinant in E. coli al-
coholdehydrogenases from Thermoanaerobacter species (T-
ADH, 378 U/mL) and Lactobacillus brevis (LB-ADH, 1300
U/mL) were obtained from Jülich Fine Chemicals. Bakerꢀs
yeast (yeast from Saccharomyces cerevisae, type II) was pur-
chased from Sigma. All other reagents were purchased from
different commercialsources and used without further pu-
rification. Solvents were distilled over an adequate desiccant
under nitrogen. Flash chromatographies were performed
using silica gel 60 (230–240 mesh). Detailed characterization
of compounds and instrumentaltechniques used are de-
scribed in the Supporting Information.
Chemical Oxidation-Enzymatic Reduction Sequence
of 4-Chloro-3-(1-hydroxyalkyl)pyridines (3a–d) and 4-
Chloro-3-[hydroxy(phenyl)methyl]pyridine (3e)
G
A solution of 3a–e (0.32 mmol) in dry acetone (1 mL) was
cooled to 08C and CrO3 (96 mg, 0.96 mmol) was added care-
fully in small portions. The resulting solution was stirred at
room temperature untilcompelte consumption of the start-
ing material(3 h), after this time the reaction was quenched
with 2-propanol(160 mL), and the mixture was stirred
during 15 min. A saturated solution of NaHCO3 (5 mL) was
finally added to precipitate the chromium salts that were fil-
tered over celite and washed with CH2Cl2 (6”15 mL). The
solvent was evaporated under reduced pressure avoiding
totaldryness to afford the corresponding ketone 6a–e.
a)Processes with bakerꢀs yeast: additional2-propanol
(500 mL), a glucose solution in H2O (21 mL of 15 mgmLÀ1
concentration) and bakerꢀs yeast (2.45 g for 6a–d or 4.90 g
for 6e) were added, and the resulting solution was shaken
during 14 h at 308C and 250 rpm untilno ketone was detect-
ed by TLC analysis. The reaction was centrifuged and the
supernatant extracted with CH2Cl2 (3”50 mL), the organic
phases were combined, dried over Na2SO4 and the solvent
evaporated under reduced pressure obtaining a crude that
was purified by flash chromatography (40% EtOAc/hexane)
isolating optically active (S)-3a–e (Table 2).
4-Chloropyridine (2)
A
solution of 4-chloropyridine hydrochloride (5 g,
33.3 mmol) in H2O (25 mL) was basified to pH 12 with 4N
NaOH solution (3 mL) and extracted with Et2O (3”50 mL).
The organic phases were combined, dried over Na2SO4 and
the solvent evaporated under reduced pressure at low tem-
perature to afford 2; yield: 3.55 g (94%).
b)Processes with TS-ADH or LB-ADH: additional2-
propanol(500 mL), TRIS/HClbuffer soultion of pH 7
(2.56 mL), NADP (0.56 mg, 6.4”10À4 mmol) and T-ADH
(16 U, 44 mL) or LB-ADH (16 U, 12 mL) were added and
the resulting mixture was shaken at 308C for the required
time. The reaction mixture was extracted with CH2Cl2 (3”
15 mL), the organic phases were combined and the solvent
distilled under reduced pressure, obtaining a crude material
that was purified by flash chromatography (40% EtOAc/
hexane) isolating optically active 3a–e (Table 2).
General Procedure for the Synthesis of 4-Chloro-3-(1-
hydroxyalkyl)pyridines (3a–d) and 4-Chloro-3-
[hydroxy(phenyl)methyl]pyridine (3e)
A
To a solution of diisopropylamine (1.28 mL, 8.80 mmol for
3a–d or 0.64 mL, 4.40 mmolfor 3e) in dry Et2O (20 mL) at
À608C was added a 1.6M BuLi solution in hexane (5.5 mL,
8.80 mmolfor 3a–d or 2.75 mL, 4.40 mmolfor 3e). The mix-
ture was allowed to warm to 08C and stirred during 1 h.
After this time the solution was cooled to À608C and 4-
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Enantioselective Synthesis of 4-(Dimethylamino)pyridines
FULL PAPERS
methyl-5-oxo-2-(4-methoxyphenyl)-4,5-dihydrooxazole-4-
carboxylic acid benzyl ester 10,[17] and recovering the initial
DMAP catalyst by additional elution of solvents (20%
MeOH/EtOAc).
General Procedure for the Synthesis of (S)-4-(Di-
methylamino)-3-(1-hydroxyalkyl)pyridines (7a–d) and
(S)-4-(Dimethylamino)-3-[hydroxy(phenyl)methyl]-
A
pyridine (7e)
A solution of (S)-4-chloro-3-(1-hydroxyalkyl)pyridines (3a–
d) or (S)-4-chloro-3-[hydroxy(phenyl)methyl]pyridine (3e)
General Procedure for the Synthesis of Mosherꢀs
Esters (see Supporting Information for H NMR
Spectra)
AHCTREUNG
1
(1.27 mmol) and a 40% aqueous solution of Me2NH (3 mL,
24 mmol) was stirred in a sealed tube at 1008C untilcom-
plete consumption of the starting material (46 h). Solvent
was evaporated by distillation at reduced pressure and the
resulting crude material purified by flash chromatography
(40% MeOH/EtOAc) yielding (S)-7a–e in nearly quantita-
tive yields.
In a typical procedure the alcohol 4-chloro-3-(1-hydroxyal-
kyl)pyridines (3a–d) or 4-chloro-3-[hydroxy(phenyl)-
T
methyl]pyridine (3e) (0.10 mmol) was dissolved in 1 mL of
dry CH2Cl2, then DMAP (0.20 mmol) and (S)-(+)-a-me-
thoxy-a-trifluoromethylphenyl
acetic
acid
chloride
(0.13 mmol) were successively added. The solution was stir-
red for 14 h at room temperature untilcompelte consump-
tion of the starting material. The solvent was evaporated
under reduced pressure and the crude materialpurified by
flash chromatography (10% EtOAc/hexane) affording the
corresponding Mosherꢀs ester.
To determine the absolute stereochemistry of alcohol 3a,
the Mosherꢀs ester of compound (+)-3a obtained from the
bioreduction of the corresponding ketone 6a with Lactoba-
cillus brevis alcohol dehydrogenase was prepared. In the
1H NMR spectra there are two significant signals: the me-
thoxy group is shield for the pyridine ring so its signal ap-
pears at low fields (3.54 ppm) meanwhile the H2 of the pyri-
dine ring is not shielded for the phenyl group so it appears
at high field (8.63 ppm), with this reasoning the configura-
tion of the alcohol is (R)-3a.
General Procedure for the Synthesis of (S)-1-[4-
(Dimethylamino)-3-pyridinyl]ethyl Acetate (9a), (S)-
1-[4-(Dimethylamino)-3-pyridinyl]pentyl Acetate (9d)
and (S)-1-[4-(Dimethylamino)-3-pyridinyl](phenyl)-
methyl Acetate (9e)
To a solution of the corresponding (S)-4-(dimethylamino)-3-
(1-hydroxyalkyl)pyridine (7a or 7d) or (S)-4-(dimethyla-
mino)-3-[hydroxy(phenyl)methyl]pyridine (7e) (0.18 mmol)
T
in dry CH2Cl2 (4.2 mL) under nitrogen atmosphere were
successively added NEt3 (78 mL, 0.54 mmol) and Ac2O
(32 mL, 0.36 mmol). The mixture was stirred during 2 h after
which time the solvent was evaporated under reduce pres-
sure obtaining a crude that was purified by flash chromatog-
raphy (20% MeOH/EtOAc) isolating the corresponding
acetates 9a–e.
To determine the absolute stereochemistries of alcohols
3b–d, the Mosherꢀs ester of compounds (À)-3b–d obtained
from the bioreduction of the corresponding ketone 6b–d
Synthesis of Catalyst (S)-4-(Dimethylamino)-3-[1-
(benzyloxycarbonyloxy)pentyl]pyridine (11)
1
with bakerꢀs yeast were prepared. In the H NMR spectra
there are two significant signals: the methoxy groups are not
shielded for the pyridine ring so their signals appear at high
field (3.6 ppm) meanwhile the H2 of the pyridine rings are
shielded for the phenyl group so they appear at low field
(8.3 ppm), with this reasoning the configuration of the alco-
hols is (S)-3b–d.
Catalyst (S)-4-(dimethylamino)-3-(1-hydroxypentyl)pyridine
[(À)-7d] (52 mg, 0.25 mmol) was dissolved in 2 mL of dry
CH2Cl2 under a nitrogen atmosphere, and the resulting solu-
tion was cooled to 08C. Pyridine (22 mL, 0.28 mmol) and
benzylcholroformate (40
mL, 0.28 mmol) were carefully
To determine the absolute stereochemistry of alcohol 3e,
the Mosherꢀs ester of compound (+)-3e obtained from the
bioreduction of of the corresponding ketone 6e with bakerꢀs
added and the mixture was stirred during 6 h at 08C. The re-
action was stopped evaporating the solvent under reduce
pressure obtaining 79 mg of (S)-11 as a colorless oil (92%
isolated yield).
1
yeast was prepared. In the H NMR spectra there is one sig-
nificant signal: the H2 of the pyridine ring is shielded for the
phenyl group so it appears at low field (8.54 ppm), with this
reasoning the configuration of the alcohol is (S)-3e.
Enantioselective Rearrangement of 5-Benzyloxy-
carbonyloxy-4-methyl-2-(4-methoxyphenyl)-oxazole
(8)with Catalysts ( S)-1-[4-(Dimethylamino)-3-
pyridinyl]ethyl Acetate (9a), (S)-1-[4-(Dimethyl-
amino)-3-pyridinyl]pentyl Acetate (9d), (S)-[4-
(Dimethylamino)-3-pyridinyl](phenyl)methyl Acetate
A
(9e)or ( S)-4-(Dimethylamino)-3-(1-benzyloxy-
carbonyloxy-pentyl)pyridine (11)
Acknowledgements
5-Benzyloxycarbonyloxy-4-methyl-2-(4-methoxyphenyl)-oxa-
zole (8, 68 mg, 0.20 mmol) was dissolved in tert-amylaclohol
(3 mL) and the solution was cooled to À108C. The corre-
sponding catalyst (S)-9a, 9d, 9e or 11 (0.20 mmol) was
added in 1 mL of tert-amyl alcohol, and the mixture was stir-
red during 7 h. The solvent was evaporated under reduced
pressure and the crude materialpurified by fal sh chromatog-
raphy (10% EtOAc/hexane) isolating optically active 4-
We thank Novo Nordisk Co. for the generous gift of the
CAL-B (Novozyme 435) and Jülich Fine Chemicals for alco-
hol dehydrogenases from Thermoanaerobacter species (T-
ADH) and Lactobacillus brevis (LB-ADH). Financial sup-
port of this work by the European Project EU-04-LSHB-
2003–503017 is gratefully acknowledged. V.G.-F. thanks
MEC for a personal grant (Juan de la Cierva Program). E.B.
thanks MEC for a pre-doctoral fellowship.
Adv. Synth. Catal. 2006, 348, 2626 – 2632
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
2631

Eduardo Busto et al.
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2632
www.asc.wiley-vch.de
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2626 – 2632