development of new synthetic methodologies: section a ... · of different chlorinating agents such...
TRANSCRIPT
Chapter 3
Chapter 3 Development of New Synthetic
Methodologies:
Section A: Reaction of Carbohydrates with
Vilsmeier reagent: A tandem selective chloro
O-formylation of sugars
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 123
Reaction of Carbohydrates with Vilsmeier reagent: A tandem selective
chloro O-formylation of sugars:
1. Introduction:
Naturally occurring carbohydrates and their derivatives have been useful during
the last few decades as chiral pool constituents in the enantioselective synthesis of
biologically active natural and non-natural products. The ready availability of a wide
range of carbohydrates in nature and their multi chiral architecture, coupled with their
well-defined stereochemistry, make them attractive starting materials in organic
synthesis. The synthesis of key intermediates by incorporation of suitable functional
groups onto carbohydrates, which can then be further exploited, can be achieved by an
efficient protecting group strategy.1
Development of such protecting group strategy wherein more than one useful
transformation can be carried out under the same reaction conditions without adding
additional reagents and catalysts makes the process more advantageous and
environmentally benign. In this respect, synthesis of the terminal chlorodeoxy sugars via
direct substitution of hydroxyl groups by chlorine is of particular interest as they are in
demand as precursors2,
for the synthesis of deoxy, amino-deoxy and unsaturated sugars
and also as sweetening, anticarcinogenic, and potential male contraceptive agents.
Similarly, O-formylation could be the method of choice for protecting sugar hydroxyl
groups in a complex synthetic sequence because de-esterification can be effected
selectively in the presence of other ester protecting groups e.g. a formate ester can be
cleaved selectively in the presence of acetate and/or benzoate even in neutral alcoholic
conditions.3 Further, if the alcohol group is planned to be oxidized later in a multistep
synthetic scheme, the formylated alcohol can be directly oxidised under Oppenauer
1 Liptak, A.; Borbas, A.; Bajza, I. Protecting Group Manipulation in Carbohydrate Synthesis,
Comprehensive
Glycoscience, Elsevier B. V., 2007, 203. 2 (a)Akhrem, A. A.; Zaitseva, G. V.; Mikhailopulo, I. A. Carbohydrate Research, 1973, 30, 223. (b)
Akhrem, A. A.; Zaitseva, G. V.; Mikhailopulo, I. A. Carbohydrate Research, 1976, 50, 143. (c) Hansessian,
S.; Plessas, N. R. J. Org. Chem., 1969, 34, 2163. (d) Kikugawa, K.; Ichino, M. J. J. Org. Chem., 1972, 37,
284. 3 Reese, C. B.; Stewart, J. C. M. Tetrahedron. Lett., 1968, 9, 4273.
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 124
conditions.4 Moreover formate esters can also serve as intermediates for the preparation
of glycopolymers.5
Presently several methods are available for selective halogenation and O-
formylation using different sets of reaction conditions. Garegg and Samuelsson6
converted 3-hydroxy sugar derivatives to 3-deoxy-3-iodo sugars using
triphenylphosphine, iodine and imidazole in toluene under reflux conditions, whereas
Hanessian and Plessas7 converted 1,2:5,6-di-O-isopropylidene D-glucofuranoside to the
6-bromo-6-deoxy derivative by treatment with N-bromosuccinimide and
triphenylphosphine in N,N-dimethylformamide. Numerous other reagents have been
developed for the O-formylation of sugar hydroxyl groups,
A brief account on the reported methods for halogenations and O-formylation of sugar
derivatives is described below.
2. Reported methods for halogenations and O-formylation of sugar
derivatives:
2.1. Marta approach:8 Conversion of O-silyl protected sugars into their
corresponding O- formates:
Marta et al. reported direct conversion of O-TBDMS and O-TBDPS protected
primary alcohol of mono and disaccharides into their corresponding O-formates in good
to excellent yields under mild reaction conditions (Scheme-1) using V-H complex
without formation of intermediate alcohol. However, this method is limited to primary
hydroxyl group of sugar derivates into their formates.
OAcO
AcO
OMeOAc
OR
R = TBDMS/TBDPS
OAcO
AcO
OMeOAc
OCHO1) POCl3/DMF
2) NaHCO3
Scheme-1
4 Ringold, H. J.; Loken, B.; Rosenkranz, G.; Sondheimer, F. J. Am. Chem. Soc., 1956, 78, 816
5 (a) David, R.; B. F. Martin, B. F.; Jay, T. G.; Carolyn, R. B. J. Am. Chem. Soc., 2008, 130, 5947. (b)
Rawle, I. H.; Guijun, W. Chem. Rev., 2000, 100, 4267. 6 Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. I, 1980, 2866.
7 Hansessian, S.; Plessas, N. R. Chem. Commun., 1967, 1152.
8 Mart, M. A.; Barros, M. T. Tetrahedron, 2004, 60, 9235.
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 125
2.2. Jialong approach:9 Conversion of Glycosyl Bromide and Ethyl thio glycosides in
to O-formates:
Jialong et al. prepared 1-O-formyl glycosides, as intermediates in glycopolymers
synthesis from different glycosyl donors (Scheme-2). The synthesized formyl derivatives
appeared to be air and moisture stable.
OAcO
AcOOAc
OAc
SEt HCOOH, NIS, TfOH
4A0 MS, 0 0C
OAcO
AcOOAc
OAc
Br
HCOOH/AgNO3OAcO
AcOOAc
OAc
OCHO
Scheme-2
2.3. Gyorgy approach:10
Halogen exchange in carbohydrates using new Vilsmeier-
type reagent:
Gyorgy et al. achieved O-formylation and halogenation at primary hydroxy group
of sugars derivatives under different set of reaction conditions. In the presence of
triphenylphosphine and N-bromosuccinimide initially formed alkoxy phosphonium salt of
diisopropylidene galactose intermediate had been converted into their corresponding
bromo and O-formate derivatives depending on different reaction condition (Scheme-3).
O
O
OO
OH
O
O
O
OO
O
O
O
O
OO
O
O
PPh3
Br
NMe2 Br
O
O
OO
Br
O
O
O
OO
OCHO
O
H2O
t1/2 40 min
70 0C
70 0C
t1/2 120 min
NO O
Br
PPh3/DMF
Scheme-3
9 Jialong, Y.; Kristof, L.; Holger, L. J. Org. Chem., 2006, 71, 5457.
10 Gyorgy, H.; Benjamin, P.; Janos, K. Carbohydrate Research, 1990, 206, 65.
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 126
2.4. Ram N. Ram approach:11
Selective formylation of sugar hydroxyl groups:
Ram et al. attempted the selective O-formylation of alcohols in the presence of
chloral. Chloral reacts with alcohol easily to form stable hemiacetals.12
It is also known to
formylate the primary hydroxyl group of methyl manopyranoside when 2 heated in
dichloromethane at reflux in the presence of DCC.13
However the reaction was not found
to be selective on primary sugars hydroxy groups and other hydroxy groups reacted
differently as shown above Scheme-4.
OHO
HO
OHOH
OMe
OO
O
OCONHC6H11OCHO
OMeCl3C
CCl3CHO/DCC
1 2
Scheme-4
2.5. Hanessian approach:4 Migration followed by chlorination:
Hanessian reported the anomalous behavior of Vilsmeier reaction for which they
have chosen 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (3) containing an isolated
secondary hydroxyl group. Compound 3 was allowed to react with Vilsmeier reagent at
room temperature in 1,1,2,2-tetrachloroethane. The major product obtained was its
corresponding 3-O-formate ester (4). Refluxing the same reaction mixture afforded a
syrupy product characterized as 5 (Scheme-5) instead of 3-chlorodeoxy derivative. Here
migration of the 5,6-O-isopropylidene group is noteworthy.14
OO
OHOO
O
OO
OOCl O
(Me2N:CHCl)Cl
OO
OO Oreflux
34 5
OHCO
Scheme-5
11
Ram R. N.; Meher, N. K. Tetrahedron, 2002, 58, 2997. 12
Luknitskii, F. I.; Chem. Rev., 1975, 75, 259-289. 13
Miethchen, R.; Rentsch, D. Synthesis, 1994, 827 14
Baddiley, J.; Buchanan, J. B.; Hardy, F. E. J. Chem. Soc., 1961, 2180.
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 127
2.6. Akhrem approach:2,3
Tandem chloro acetylation of sugars:
Akhrem and his co-workers were first to report the preparation of chloro
acetylated sugar derivatives for which they choose 3-O-acetyl-1,2-O-isopropylidene-α-D-
ghrcofuranose (6) containing primary and secondary hydroxyl groups, compound 6 was
allowed to react with acetyl salicyloyl chloride (7) in anhydrous p-dioxane at room
temperature to gave 3,5-di-O-actyl-6-chloro-1,2-O-isopropylidine-α-D-glucofuranose (8)
in good yields (Scheme-6). Till date this is only one report of tandem chlorination
acetylation of sugar hydroxy compounds.
OO
OAcO
HO
HO
OO
OAcO
Cl
AcOCOCl
OAcO
O
6 87
+
Scheme-6
Some applications that are pertinent to synthetic carbohydrate chemistry include one step
and selective conversion of silyl ethers of sugar derivatives into their corresponding
formates using either PPh3/CBr4 in HCOOEt/H2O15
or Vilsmeier reagent,16
and reaction
of halomethyleniminium salts with various sugar alcohols to afford formate esters and
chlorodeoxy sugars under different sets of experimental conditions.
All these halo and formylating reagents described above have their limitations. As a result
of the harsh experimental conditions such as medium acidity and high temperature and/or
accompanying side reactions such as migration of isopropylidene rings,4,17
none of them
has given halo-deoxy O-formylated sugars exclusively.
15
Hagiwara, H.; Morohashi, K.; Sakai, H.; Suzuki, T.; Ando, M. Tetrahedron, 1998, 54, 5845. 16
Vilsmeier, A.; Haack, A. Chem. Ber., 1927, 60, 119. 17
(a) Hardegger, E.; Zanetti G.; Steiner, K. Helv. Chim. Acta., 1963, 46, 282. (b) Baddiley, J.; Buchanan J.
B.; Hardy, F. F. J. Chem. Soc., 1961, 2180.
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 128
3. Present work:
There are several examples of polymers with sugar residues attached to the
backbone via either their anomeric oxygen2, or 3/6-oxygen
3 without a spacer. The
selective derivation of sugars with unsaturated moieties is one of the easiest routes to
prepare such polymers, which in turn require synthesis of O-formyl esters at the
respective position. O-Formylation of alcohols is one of the most useful and versatile
reactions in protective organic chemistry as formate esters can be removed easily and
selectively. The Vilsmeier–Haack (V–H) reaction (discovered in 1927)16
is recognized as
one of the best methods for the direct formylation of electron-rich aromatic nuclei,
enolizable ketones, enol ethers and other active hydrogen compounds. This reaction
continues to receive wide attention in organic chemistry because of its simplicity and
convenience. However according to our knowledge there is no report till date of one pot
chloro-esterification under Vilsmeier conditions. The present work therefore envisaged to
attempt Vilsmeier reaction foe the preparation chloro esters with replacement of OH
group by chlorine atom or exclusively O-formylation.
4. Result and Discussion:
In the present study Vilsmeier reaction has been utilized as a simple, efficient
method initially for O-formylation and thereafter synthetically more useful tandem
selective chloro O-formyaltion under mild reaction conditions. These chloro O-
formylated sugar derivatives can be utilized further for selective amination and/or
reduction to afford 6-amino-6-deoxy sugar derivatives, which are biologically important
precursors.
We initially took protected sugars having one hydroxy group free to investigate the effect
of different chlorinating agents such as thionyl chloride, oxaloyl chloride and benzoyl
chloride along with DMF at room temperature. Thus from 1,2:5,6-di-O-isopropylidene-α-
D-glucofuranose (9) we got O-formylated sugars as a sole products without migration or
cleavage of sensitive isopropylidene group as we anticipated in good yields with POCl3
(Scheme-7) (Entrys 9-11 Table-1). The presence of singlet at δ 8 in the 1H NMR confirms
the formylation of OH group. No chlorinated product was observed during this reaction.
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 129
DMF/PhCOCl
DMF/POCl3
DMF/SOCl2
DMF/(COCl)2
or
or
0-60 0C 1 h
OOO
O
O
HO
OOO
O
O
OHCO
9 9a
Scheme-7
Further to check the behavior of our reagent system towards anomeric free hydroxy
group; 2,3,4,6-tetra-O-acetylated sugar derivatives were taken into consideration
(Scheme-8). While they turned out to be easily anomerized or hydrolyzed during column
chromatography with both silica gel and aluminum oxide as the column materials but
they can be easily converted into O-vinyl derivatives using Tebbe condensation9 without
further purification. All synthesized O-formates were typically obtained in anomerically
pure form by recrystallization.
V-H reagent
0-60 0C
12-14 12a-14a
O
OAc
AcO
OH
O
OAc
AcO
OCHO
Scheme-8
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 130
Table 1: Reaction of different sugar derivatives with V-H reagent
S. No Substrate Producta Time (h)
b Yield %
c
1 OOO
O
O
HO
9
OOO
O
O
OHCO
9a
1 87
2
OO
O
O
O
HO
10
OOO
O
O
OHCO
10a
1 83
3
O
O
OO
OH
O
11
O
O
OO
OCHO
O
11a
1 82
4
OAcO
AcOOAc
OH
OAc
12
OAcO
AcOOAc
OCHO
OAc
12a
1 82
5
OAcO
AcO
AcO
OH
OAc
13
OAcO
AcO
AcO
OCHO
OAc
13a
1.5 87
6
O
AcO
AcO
OAcOH
OAc
14
O
AcO
AcO
OAcOCHO
OAc
14a
1.5 87
aCharacterised by
1H NMR and
13C NMR:
bTotal reaction time (sugar: V–H complex, 1:10):
cYield of the
formylated product obtained after column chromatography.
After accomplishing monoformylation successfully, our next goal was to see how
anomeric protected poly hydroxy sugar derivatives behave towards modified Vilsmeier-
Haack complex. So, we took methyl glucoside 15 as a model compound. Treatment of 15
with DMF–POCl3 complex (6 eq.) at 0 0C to rt indeed proceeded to completion in 1 h, but
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 131
afforded a mixture of two products 15a and 15b in almost equal amounts (Scheme-9)18
.
Gratifyingly compound 15a was identified as methyl-2,3,4-tri-O-formyl-6-chloro-6-
deoxy-α-D-glucopyranoside instead of expected performylated derivatives on the basis of
NMR and mass-spectral data. The signals for H-6,6’ and C-6 in the 1HNMR and
13C
NMR spectra of 15a were shifted upfield compared to those of the corresponding nuclei
in the performylated product 15b thereby indicating the introduction of the chlorine
substituent at position 6 (Scheme-9) (Table-3).
OOHCO
OHCO
OMeOHCO
Cl
OOHCO
OHCO
OMeOHCO
OCHO
+
15a 15b
OHO
HO
OMeOH
OH
15
DMF/PhCOCl
DMF/POCl3
DMF/SOCl2
DMF/(COCl)2
or
or
0-60 0C 1 h
Scheme-9
In a bid to obtain 15a as a sole product, modifications in experimental conditions were
effected such as raising the temperature to 60 0C and also allowing more time (6 h) and
this afforded 15a in 85% yield along with only a trace amount of 15b. In a separate
control experiment treatment of 15b with DMF–POCl3 complex (6 eq.) at room
temperature indeed afforded 15a almost exclusively suggesting that the latter could be the
thermodynamically controlled product.
In addition to POCl3 we have also used different chlorinating agents such thionyl chloride
(SOCl2), benzoyl chloride (PhCOCl), and oxaloyl chloride (COCl)2 along with DMF at
room temperature to 60 0C failed to improve the yields as shown in Table-2.
18
Thota, N.; Debaraj. M.; Reddy, M. V.; Syed. K. Y.; Koul. S.; Taneja. S. C. Organic & Biomolecular
Chem., 2009, 7, 1280.
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 132
Table 2: Optimization of reaction conditions for methyl glucoside 15.
Entry Chlorinating agent Ratioa
Temp (0C) Time (h) Yield
b (9a:9b)
1 DMF+POCl3 1:6 0 to rt 0.5 50:50
2 DMF+POCl3 1:6 0 to rt 1 70:30
3 DMF+POCl3 1:10 0 to rt 1 55:45
4 DMF+POCl3 1:6 0 to 60 1 55:45
5 DMF+POCl3 1:10 rt to 60 6 85:trace
6 DMF+SOCl2 1:10 0 to rt 6 45:trace
7 DMF+SOCl2 1:10 rt to 60 6 45:trace
8 DMF+PhCOCl 1:10 rt to 60 6 30:45
9 DMF+(COCl)2 1:10 rt to 60 6 50:50
a Ratio between methyl glucoside and V-H- complex:
b Yield obtained after column chromatography.
Encouraged by this observation, this method was extended to check the reactivity
of various protected sugar derivatives with Vilsmeier reagent for the synthesis of formate
esters and chloroformate esters. Allyl glucoside 16 was subjected to Vilsmeier reagent,
the product 16a was obtained in good yields (83%) and 16b was obtained in traces, after
purification of the crude reside on silica gel column chromatography (Scheme-10). The
products 16a and 16b confirmed by 1H/
13C NMR spectra.
OHO
HO
OHO
OH
OOHCOOHCO
OHCOO
Cl
DMF/POCl3
16
OOHCOOHCO
OHCOO
OCHO
+
16b16a
Scheme-10
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 133
The phenyl-β-D-thio-glucoside 17 also proved to be efficient by reacting with Vilsmeier
reagent to afford the corresponding chloroformylated product 17a was obtained in good
yields (82%) and per formylated product 17b in traces amount (Scheme-11).
DMF/POCl3
17 17a
OHO
HO
OH
S
OH
OOHCO
OHCO
OCHO
S
Cl
OOHCO
OHCO
OCHO
S
OCHO
+
17b
Scheme-11
In addition, several other chloro formylated and performylated derivatives have been
prepared (Table-3 18-22) from different derivatives of sugars using similar reaction
conditions. In all the cases the chloro-formylated products were obtained in good yields
except with galactopyranoside 13 (Scheme-12) (Table -3 entry no 11) where the O-
formylated product 19b was isolated with traces of the chloro-formylated product 19a.
+DMF/POCl3
19 19a
O
HO
HO
OHOMe
OH
O
OHCO
OHCO
OHCOOMe
Cl
O
OHCO
OHCO
OHCOOMe
OCHO
19b
Scheme-12
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 134
5. Mechanism of Vilsmeier-Haack reaction:
The sequence of reactions leading to tandem chlorination and O-formylation is
depicted in Scheme 13. It is well known that during Vilsmeier-Haack reaction DMF
combines with inorganic acid chloride to form active reagent halomethyleniminium salt
which is an equilibrium mixture of the two salts A and B (Vilsmeier-Haack reagent).19
This is useful as formylating, halogenating, and dehydroxylating agents.20
We envisioned
that equilibrium mixture of A to B can effective both O-formylation and chlorination
simultaneously in polyhydroxy sugar derivatives. This sequence of reactions leading to
formylation and chlorination of alcohols is illustrated in Scheme-13.
NMe Me
Cl2P(O)O
ClN
Me Me
Cl
Cl2P(O)ODMF-POCl3
A B
RCHOH
R'
+ Me2N CHO(O)PCl2 Cl R CHOHCH
R'
NMe2
Cl
+ HCl
RHC
R'
O CH NMe2
Cl
RCHOCHO + Me2NH + HCl
R'
H2O
RCHCl +Me2NCHO
R'
A B C
D
+ HOPOCl2
RHC
R'
O CH NHMe2
OH
Scheme-13
19
(a) Bosshard, H. H.; Mory, R.; Schmid, M.; Zollinger, H. Helv. Chim. Acta, 1959, 42, 1653. (b) Bosshard,
H. H.; Zollinger, H.; ibid., 1959, 42, 1859. 20
Fieser, L. F.; Fieser, M. “Reagents for Organic Synthesis,” Wiley, New York, New. York., 1967, 284.
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 135
6. Anomalous behavior of galactose has fallows:
It is noteworthy that the reaction proceeded smoothly without affecting other
protecting groups. In all the cases chlorination took place selectively at the sterically less
crowded primary hydroxy group of the sugar moiety leaving the secondary hydroxy
groups, perhaps due to easy access of the bulky chloride ion. The anomalous behaviour of
the galactose derivative can be rationalized as follows. The C6–O bond needs to be
oriented anti to the C5–H for smooth attack by the chloride ion (Scheme 14). However
this conformation is less favoured in the galactose series (Newman projection-A) than in
the glucose series (Newman projection-B) due to torsional strain involving the axial C4–
OR group and oxoforminium group in the case of the former. Therefore the galactose
substrate furnishes the performate as the major product. With the exception of
galactosides our results clearly show that compounds having primary hydroxyl groups
afforded the chloro-formylated product.
O
H
O
HH
CHNMe2
O
O
H
O
HH
CHNMe2
H
O
R
R
H
A B
Scheme-14
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 136
Table 3: Reaction of different sugar derivatives with V-H reagent:
S. No Substrate Chloro formylated
Producta
Performylated
producta
Time
(h)b
Yield
(a:b)%c
7 O
HOHO
OHOMe
OH
15
OOHCO
OHCO
OHCOOMe
Cl
15a
OOHCO
OHCO
OHCOOMe
OCHO
15b
6 85:10
8 O
HOHO
OHO
OH
16
OOHCOOHCO
OHCOO
Cl
16a
OOHCOOHCO
OHCOO
OCHO
16b
5 83:10
9 O
HOHO
OH
SPh
OH
17
OOHCOOHCO
OCHO
SPh
Cl
17a
OOHCOOHCO
OCHO
SPh
OCHO
17b
4 82:17
10 O
HOHO
HO
OMe
OH
18
OOHCOOHCO
OCHO
OMe
Cl
18a
OOHCOOHCO
OCHO
OMe
OCHO
18b
7 77:15
11 O
HO
HO
OHOMe
OH
19
O
OHCO
OHCO
OHCOOMe
Cl
19a
O
OHCO
OHCO
OHCOOMe
OCHO
19b
5 25:65d
12 O
HOHO
OH
OPMP
OH
20
OOHCOOHCO
OCHO
OPMP
Cl
20a
-
7 85:ND
13
OHO
HO
O
O
HO
21
OClOHCO
O
O
OHCO
21a
-
2
79d
14
OHO
HO
O
O
HO
22
OClOHCO
O
O
OHCO
22a
- 2
81d
a Characterised by
1H NMR and
13C NMR:,
b Total reaction time (sugar:V–H complex, 1:10):
c Yield of the
a and b products obtained after column chromatography. d Performylated product obtained in major amount
(65-81%). ePMP=p-methoxyphenol and SPh=thiophenol.
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 137
7. Conclusion:
In conclusion, the Vilsmeier reaction proved to be a versatile method for the
preparation of various unsubstituted 1-O-formyl as well as tandem one pot selective
chloro-O-formylation of sugars, the 1-O-alkyl glycosides used as the substrates. The
application of the 1-O-formyl glycosides as chiral auxiliaries for the preparation of
glycopolymers and glycoconjugates. And also this method offers operational simplicity
and proceeds with moderate to high yields. This together with the enormous importance
of the downstream products in the synthesis of glycopolymers and glycoconjugates
establishes the utility of the method.
8. Experimental:
8.1. General methods:
All reagents for chemical synthesis were purchased from Sigma–Aldrich and used
as received. And some of the substrates like 12-14,21
16, 1722
, 20, 21, and 2223
were
prepared according to the literature methods. All the solvents used in reactions were
distilled and dried before use. All reactions were monitored by TLC on 0.25 mm silica gel
60 F254 plates coated on aluminum sheet (E. Merck). 1H NMR and
13C NMR spectra
were recorded on Brucker Avance DPX-200 instrument at 200 MHz and 50 MHz,
respectively, using CDCl3 as solvent with TMS as internal standard. Chemical shifts are
expressed in parts per million (δ ppm); and coupling constant values are given in Hertz.
Mass spectra were recorded on ESI-esquire 3000 Bruker Daltonics instrument.
8.2. Typical procedure for chloro-O-formylation:
A stirred, cooled DMF solution of the complex POCI3/DMF (prepared from 1.52
g POCl3, in 5 mL anhydrous DMF, 0 0C) was added dropwise to a cold solution of α-D-
methyl-glucopyranoside 15 (0.2 g, 1.0 mmol in 10 mL DMF) under an inert atmosphere.
The mixture was then agitated at 60 0C and the reaction monitored by TLC. After
completion of the reaction (reaction time given in table-3) the contents were treated with
21
(a) Wolfrom, M. L.; Thompson, A. Methods in Carbohydr. Chem., 1963, 2, 211 (b) Steglich, W.; Hofle,
G. Angew. Chem., Int. Ed. Engl., 1969, 8, 981. 22
Fernandez-Bolanos, J. G.; Al-Masoudi, N. A. L.; Maya, I. Adv. Carbohydr. Chem. Biochem., 2001, 57,
21. 23
(a) Manna, S.; Jacques, Y. P.; Falck, J. R. Tetrahedron Lett., 1986, 27, 2679. (b)Hanessian, S, Ed.;
Marcel, D. Synthesis of Isopropylidene Benzylidene and Related Acetals, New York, 1997, 3.
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 138
saturated NaHCO3 solution (30 mL), then extracted with solvent ether (4 x 30 mL), the
organic solvent was evaporated, and the crude product was purified by column
chromatography over silica gel to afford a syrupy mass methyl 6-chloro-2,3,4-tri-O-
formyl-α-D-glucopyranoside (15a) and methyl-2,3,4,6-tetra-O-formyl-α-D-
glucopyranoside (15b) in 85:10% with overall yields.
9. Spectral data:
9.1. 3-O-Formyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (9a):
1H NMR (200 MHz, CDCl3): δ 1.25, 1.29, 1.35, 1.47 (3H each, s,
4xC-CH3), 4.01-4.07 (3H, m, H-5, H-6a, H-6
b), 4.12 (1H, br s, H-4),
4.53 (1H, d, J = 3.6 Hz, H-2), 5.35 (1H, br s, H-3), 5.89 (1H, d, J =
3.6 Hz, H-1), 8.08 (1H, s, -OCHO). 13
C NMR (50 MHz, CDCl3): δ
24.0, 24.2, 25.2, 25.6, 66.1, 69.0, 71.1, 77.8, 82.0, 103.9, 107.3, 109.9, 158.2. MS (%) M
at m/z 289. Anal. Calcd. For C13H20O7: C, 54.16, H, 6.99. Found: C, 54.86, H, 7.16.
9.2. 3-O-Formyl-1,2:5,6-di-O-isopropylidene-β-D-glucofuranose (10a):
1H NMR (200 MHz, CDCl3): δ 1.25, 1.29, 1.35, 1.47 (3H each, s,
4xC-CH3), 4.04-4.17 (3H, m, H-5, H-6a, H-6
b), 4.19 (1H, br s, H-
4), 4.54 (1H, d, J = 3.6 Hz, H-2), 5.35 (1H, br s, H-3), 5.89 (1H, d,
J = 7.6 Hz, H-1), 8.10 (1H, s, -OCHO). 13
C NMR (50 MHz,
CDCl3): δ 24.1, 24.2, 25.1, 25.6, 66.3, 69.0, 71.1, 77.8, 82.0, 103.9, 107.3, 109.9, 158.2.
MS (%) M at m/z 289. Anal. Calcd. For C13H20O7: C, 54.16, H, 6.99. Found: C, 54.86,
H, 7.16.
9.3. 6-O-Formyl-1,2:3,4-di-O-isopropylidene-α-D-galactopyranose (11a):
1H NMR (500 MHz, CDCl3): δ 1.33, 1.34, 1.45, 152 (3H each, s, 4xC-
CH3), 4.08 (1H, br s, H-5), 4.24-4.37 (4H, m, H-2, H-4, H-6a, H-6
b),
4.64 (1H, d, J = 7.8 Hz, H-3), 5.56 (1H, d, J = 4.7 Hz, H-1), 8.09 (1H,
s, -OCHO). 13C NMR (125 MHz, CDCl3): δ 24.3, 24.5, 25.9, 26.0,
60.4, 63.0, 70.4, 70.6, 70.7, 96.3, 108.8, 109.7, 160.9. MS (%) M at
m/z 288. Anal. Calcd. For C13H20O7: C, 54.16, H, 6.97. Found: C, 54.89, H, 7.06.
OO
OO O
OHCO
OO
OO O
OHCO
O
O
OO
OCHO
O
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 139
9.4. Formyl-2,3,4,6-Tetra-O-acetyl-α-D-glucopyranoside (12a):
1H NMR (500 MHz, CDCl3): δ 1.96, 1.97, 1.98, 2.03 (3H each, s,
4xCH3), 4.05 (1H, dd, J = 12.4, 4.6 Hz, H-6a), 4.08-4.12 (1H, m,
H-5), 4.19-4.29 (1H, dd, J = 12.5, 2.5 Hz, H-6b), 5.05 (1H, dd, J =
10.1, 3.7 Hz, H-2), 5.10 (1H, t, J = 10.1 Hz, H-4), 5.46 (1H, t, J =
10.2 Hz, H-3), 6.38 (1H, d, J = 3.7 Hz, H-1), 8.10 (1H, s, -OCHO). 13
C NMR (125 MHz,
CDCl3): δ 20.2, 20.4, 20.7, 20.9, 61.2, 67.5, 69.0, 69.4, 70.0, 88.8, 158.4, 169.2, 170.3.
MS (%) (M + Na)
+ at m/z 399. Anal. Calcd. For C15H20O11: C, 47.88, H, 5.43. Found: C,
48.06, H, 5.49.
9.5. Formyl-2,3,4,6-Tetra-O-acetyl-α-D-galactopyranoside (13a):
1H NMR (500 MHz, CDCl3): δ 1.97, 1.98, 1.99, 2.04 (3H each, s,
4xCH3), 4.00 (1H, m, H-5), 4.07-4.12 (1H, dd, J = 12.4, 4.6 Hz, H-
6a), 4.19-4.29 (1H, dd, J = 12.5, 2.5 Hz, H-6
b), 4.44 (1H, d, J = 3.7
Hz, H-2), 5.24-5.31 (2H, m, H-3, H-4), 5.66 (1H, d, J = 3.7 Hz, H-
1), 8.08 (1H, s, -OCHO). 13
C NMR (125 MHz, CDCl3): δ 20.3, 20.4, 20.6, 20.9, 61.4,
67.5, 69.1, 69.5, 70.2, 88.9, 158.4, 169.6, 170.5. MS (%) (M + Na)
+ at m/z 399. Anal.
Calcd. For C15H20O11: C, 47.88, H, 5.43. Found: C, 48.06, H, 5.49.
9.6. Formyl 2,3,4,6-Tetra-O-acetyl-α-D-manopyranoside (14a):
1H NMR (500 MHz, CDCl3): δ 1.94, 1.96, 1.98, 2.03 (3H each, s,
4xCH3), 4.05 (1H, dd, J = 12.4, 4.6 Hz, H-6a), 4.08-4.12 (1H, m,
H-5), 4.17-4.27 (1H, dd, J = 12.5, 2.5 Hz, H-6b), 5.10 (1H, dd, J =
10.3, 3.9 Hz, H-2), 5.16 (1H, t, J = 10.6 Hz, H-4), 5.49 (1H, t, J =
9.7 Hz, H-3), 6.38 (1H, d, J = 3.9 Hz, H-1), 8.10 (1H, s, -OCHO). 13
C NMR (125 MHz,
CDCl3): δ 20.3, 20.5, 20.7, 20.9, 61.4, 67.7, 69.1, 69.6, 70.4, 88.9, 158.4, 169.6, 170.7.
MS (%) (M + Na)
+ at m/z 399. Anal. Calcd. For C15H20O11: C, 47.88, H, 5.43. Found: C,
48.06, H, 5.49.
9.7. Methyl 6-chloro-2,3,4-tri-O-formyl-α-D-glucopyranoside (15a):
1H NMR (500 MHz, CDCl3): δ 3.47 (3H, s, -OCH3), 3.59 (1H, dd,
J = 12.2, 6.1 Hz, H-6a), 3.69 (1H, dd, J = 12.2, 2.4 Hz, H-6
b), 4.10
(1H, ddd, J = 9.6, 6.1, 2.4 Hz, H-5), 5.03-5.05 (1H, m, H-2), 5.08
OOHCO
OHCO
OHCOOMe
Cl
OAcO
AcO
OCHOAcO
OAc
O
AcO
AcO
OCHOAcO
OAc
OAcO
AcO
OCHO
OAcOAc
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 140
(1H, d, J = 3.4 Hz, H-1), 5.23 (1H, t, J = 9.6 Hz, H-3/H-4), 5.69 (1H, t, J = 9.5 Hz, H-
3/H-4), 8.05 (2H, s, 2x-OCHO), 8.08 (1H, s, -OCHO). 13
C NMR ( 125 MHz, CDCl3): δ
43.6, 56.1, 68.9, 69.2, 69.6, 71.5, 96.7, 159.9, 160.7, 160.9. MS (%) M at m/z 297. Anal.
Calcd. For C10H13ClO8: C, 40.49; H, 4.42; Cl, 11.95. Found: C, 40.52; H, 4.49; Cl, 11.99.
9.8. 2,3,4,6-tetra-O-formyl-α-D-methyl-glucopyranoside (15b):
1H NMR (500 MHz, CDCl3): δ 3.47 (3H, s, -OCH3), 4.12-4.18
(1H, m, H-5), 4.19-4.24 (1H, dd, J = 11.3, 6.3 Hz, H-6a), 4.35-4.38
(1H, dd, J = 11.3, 2.4 Hz, H-6b), 4.44 (1H, d, J = 3.8 Hz, H-2),
5.25-5.38 (2H, m, H-3, H-4), 5.63 (1H, br s, H-1), 8.05 (2H, s, 2x-
OCHO), 8.08 (2H, s, 2x-OCHO). 13
C NMR (125 MHz, CDCl3): δ 55.2, 61.4, 66.5, 68.9,
70.3, 70.9, 101.6, 159.9, 160.7, 160.9. MS (%) M at m/z 307. Anal. Calcd. For
C11H14O10: C 43.14, H 4.61. Found: C, 43.24; H, 4.69.
9.9. Allyl 6-chloro-2,3,4-tri-O-formyl-α-D-glucopyranoside (16a):
1H NMR (500 MHz, CDCl3): δ 3.56 (1H, dd, J =12.2, 6.1 Hz, H-
6a), 3.63 (1H, dd, J = 12.2, 2.5 Hz, H-6
b), 4.04 (1H, dd, J = 12.8,
6.3 Hz, -OCH2), 4.11 (1H, ddd, J = 9.3, 6.3, 2.5 Hz, H-5), 4.22
(1H, dd, J = 12.8, 5.3 Hz, -OCH2), 5.00-5.03 (1H, m, H-2), 5.18-
5.24 (3H, m, =CH2 & H-1), 5.32 (1H, t, J = 9.6 Hz, H-3/H-4), 5.68 (1H, t, J = 10.0 Hz, H-
3/H-4), 5.82-5.90 (1H, m, =CH), 8.02, 8.03, 8.04 (1H each, s, 3x-OCHO). 13
C NMR (125
MHz, CDCl3): δ 43.6, 56.1, 68.9, 69.2, 69.6, 71.5, 96.7, 159.9, 160.7, 160.9. MS (%) M
at m/z 297. Anal. Calcd. For C10H13ClO8: C, 40.49; H, 4.42; Cl, 11.95. Found: C, 40.52;
H, 4.49; Cl, 11.99.
9.10. Allyl-2,3,4,6-tetra-O-formyl-α-D-glucopyranoside (16b):
1H NMR (500 MHz, CDCl3): δ 3.32-3.43 (1H, m, H-5), 3.56 (1H,
dd, J = 12.2, 6.1 Hz, H-6a), 3.63 (1H, dd, J = 12.2, 2.5 Hz, H-6
b),
4.04 (2H, dd, J = 12.8, 6.3 Hz, -OCH2), 5.00-5.03 (1H, m, H-2),
5.18-5.24 (3H, m, =CH2 & H-1), 5.32-5.57 (2H, m, H-3, H-4),
5.82-5.90 (1H, m, =CH), 8.02, 8.03, 8.04, 8.06 (1H each, s, 4x-OCHO). 13
C NMR (125
MHz, CDCl3): δ 43.9, 56.5, 67.8, 69.6, 70.6, 71.3, 96.6, 159.7, 160.9. MS (%) M
at m/z
332. Anal. Calcd. For C13H16O10: C, 46.99; H, 4.85. Found: C, 47.52; H, 4.99.
OOHCOOHCO
OHCOO
Cl
OOHCO
OHCO
OMeOHCO
OCHO
OOHCOOHCO
OHCOO
OCHO
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 141
9.11. Phenyl 6-chloro-2,3,4-tri-O-formyl-β-D-thio-glucopyranoside (17a):
1H NMR (500 MHz, CDCl3): δ 3.55-3.57 (1H, dd, J = 12.3,
6.1 Hz, H-6a), 3.60-3.65 (1H, dd, J = 12.3, 2.4 Hz, H-6
b),
3.74-3.78 (1H, ddd, J = 9.3, 6.1, 2.4 Hz, H-5), 4.71 (1H, d,
J = 10.1 Hz, H-1), 5.02 (1H, t, J = 9.6 Hz, H-2), 5.12 (1H, t, J = 10.7 Hz, H-3/H-4), 5.39
(1H, t, J = 9.3 Hz, H-3/H-4), 7.24-7.28 (3H, m, 3xAr-H), 7.48 (2H, d, J = 5.4 Hz, 2xAr-
H), 7.93, 7.96, 7.99 (1H each, s, 3xOCHO). 13
C NMR (125 MHz, CDCl3): δ 41.8, 67.6,
68.0, 71.4, 84.3, 127.7, 128.0, 129.7, 132.5, 157.8, 157.9, 158.4. MS (%) M+
at m/z 475.
Anal. Calcd. For C15H15ClO7S: C, 48.07; H, 4.03; Cl, 9.46; S, 8.56. Found: C, 48.04; H,
4.09; Cl, 9.53; S, 8.62.
9.12. Phenyl-2,3,4,6-tetra-O-formyl-β-D-thio-glucopyranoside (17b):
1H NMR (500 MHz, CDCl3): δ 3.77-3.83 (1H, m, H-5),
4.25-4.29 (1H, dd, J = 12.3, 5.1 Hz, H-6a), 4.35-4.38 (1H,
dd, J = 12.3, 1.9 Hz, H-6b), 4.76 (1H, d, J = 10.0 Hz, H-1),
5.13 (1H, t, J = 9.6 Hz, H-3/H-4), 5.25 (1H, t, J = 9.8 Hz, H-3/H-4), 5.49 (1H, t, J = 9.4
Hz, H-2), 7.26-7.39 (3H, br s, 3xAr-H), 7.50 (2H, d, J = 6.2 Hz, 2xAr-H), 8.01 (2H, br s,
2x-OCHO), 8.07 (2H, br s, 2x-OCHO). 13
C NMR (125 MHz, CDCl3): δ 60.9, 68.1, 69.8,
73.2, 76.0, 129.6, 129.7, 129.9, 134.0, 159.6, 160.1, 160.4, 160.9. MS (%) M+
at m/z 475.
Anal. Calc. For C16H16ClO9S: C, 50.00; H, 4.20; S, 8.34. Found: C, 51.00; H, 4.29; S,
8.39.
9.13. Methyl 6-chloro-2,3,4-tri-O-formyl-α-D-manopyranoside (18a):
1H NMR (500 MHz, CDCl3): δ 3.46 (3H, s, -OCH3), 3.59 (1H, dd,
J = 12.2, 6.2 Hz, H-6a), 3.69 (1H, dd, J = 12,2, 2.6 Hz, H-6
b), 4.06
(1H, ddd, J = 9.3, 6.2, 2.6 Hz, H-5), 4.79 (1H, d, J = 1.4 Hz, H-1),
5.43-5.57 (3H, m, H-2, H-3, H-4), 7.96, 8.08, 8.12 (1H each, s, 3x-
OCHO). 13
C NMR (125 MHz, CDCl3): δ 43.2, 55.7, 66.7, 68.3, 68.8, 69.7, 98.2, 159.4,
159.5, 160.9. MS (%) M at m/z 296. Anal. Calcd. For C10H13ClO8: C, 40.55; H, 4.42; Cl,
11.95. Found: C, 40.59; H, 4.46; Cl, 12.02.
OOHCOOHCO
OCHO
OMe
Cl
OOHCOOHCO
OCHO
S
Cl
OOHCOOHCO
OCHO
S
OCHO
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 142
9.14. Methyl-2,3,4,6-tetra-O-formyl-α-D-methyl-mano pyranoside (18b):
1H NMR (500 MHz, CDCl3): δ 3.54 (3H, s, -OCH3), 3.79-3.85 (1H,
m, H-5), 4.33-4.38 (1H, dd, J = 12.2, 5.2 Hz, H-6a), 4.51-4.60 (1H,
dd, J = 12.1, 2.5 Hz, H-6b), 4.72 (1H, d, J = 2.5 Hz, H-1), 5.22-5.29
(2H, m, H-2, H-3), 5.45 (1H, d, J = 9.7 Hz, H-4), 7.95, 8.06, 8.10,
8.15, (1H each, s, 4x-OCHO). 13
C NMR (125 MHz, CDCl3): δ 55.4, 61.2, 66.2, 68.1,
70.3, 70.7, 101.3, 115.8, 159.3, 159.5, 159.7, 160.2. MS (%) M at m/z 307. Anal. Calcd.
For C11H14O10: C 43.14, H 4.61. Found C 44.01, H 4.67.
9.15. Methyl 6-chloro-2,3,4-tri-O-formyl-α-D-galactopyranoside (19a):
1H NMR (500 MHz, CDCl3): δ 3.48 (3H, s, -OCH3), 3.59 (1H, dd,
J = 12.3, 6.1 Hz, H-6a), 3.68 (1H, dd, J = 12.2, 2.4 Hz, H-6
b), 4.10
(1H, ddd, J = 9.7, 6.1, 2.4 Hz, H-5), 5.04-5.07 (1H, m, H-2), 5.08
(1H, d, J = 3.5 Hz, H-1), 5.23 (1H, t, J = 9.6 Hz, H-3/H-4), 5.69
(1H, t, J = 9.5 Hz, H-3/H-4), 8.06 (2H, s, 2x-OCHO), 8.10 (1H, s, -OCHO). 13
C NMR (
125 MHz, CDCl3): δ 43.7, 56.4, 69.1, 69.4, 69.8, 72.0, 97.0, 160.2, 160.7, 161.0. MS (%)
M at m/z 297. Anal. Calcd. For C10H13ClO8: C, 40.48; H, 4.43; Cl, 11.95. Found: C,
40.54; H, 4.49; Cl, 11.99.
9.16. Methyl-2,3,4,6-tetra-O-formyl-α-D-methyl-galactopyranoside (19b):
1H NMR (500 MHz, CDCl3): δ 3.49 (3H, s, -OCH3), 4.03 (1H, t, J
= 6.3 Hz, H-5), 4.19-4.23 (1H, dd, J = 11.3, 6.5 Hz, H-6a), 4.35-
4.38 (1H, dd, J = 11.3, 6.6 Hz, H-6b), 4.40 (1H, d, J = 3.6 Hz, H-
2), 5.22-5.29 (2H, m, H-3, H-4), 5.62 (1H, br s, H-1), 7.95, 8.06,
8.10, 8.15, (1H each, s, 4x-OCHO). 13
C NMR (125 MHz, CDCl3): δ 55.4, 61.2, 66.2,
68.1, 70.3, 70.7, 101.3, 159.3, 159.5, 159.7, 160.2. MS (%) M at m/z 308. Anal. Calcd.
For C11H14O10: C 43.14, H 4.61. Found: C, 44.86, H, 4.66.
9.17. p-methoxy phenol-6-chloro-2,3,4-tri-O-formyl-β-D-glucopyranoside (20a):
1H NMR (500 MHz, CDCl3): δ 3.53-3.59 (1H, dd, J
= 12.1, 6.1 Hz, H-6a), 3.62-3.66 (1H, dd, J = 12.2,
2.4 Hz, H-6b), 3.73 (3H, s, -OCH3), 3.77-3.84 (1H,
m, H-5), 4.89 (1H, d, J = 9.7 Hz, H-1), 5.03 (1H, t, J = 9.6 Hz, H-2), 5.11 (1H, t, J = 10.7
O
OHCO
OHCO
OHCOOMe
Cl
OOHCOOHCO
OCHO
O
Cl
OMe
OOHCO
OHCO
OMe
OCHOOCHO
O
OHCO
OHCO
OMeOHCO
OCHO
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 143
Hz, H-3/H-4), 5.42 (1H, t, J = 9.3 Hz, H-3/H-4), 6.87 (2H, d, J = 8.3 Hz, 2xAr-H), 6.99
(2H, d, J = 8.4 Hz, 2xAr-H), 7.93, 7.96, 7.99 (1H each, s, 3x-OCHO). 13
C NMR (125
MHz, CDCl3): δ 42.1, 56.3, 67.4, 68.2, 71.8, 83.8, 126.9, 128.1, 129.6, 132.5, 157.4,
157.9, 158.4. MS (%) M+
at m/z 362. Anal. Calcd. For C15H15ClO8: C, 50.22; H, 4.21; Cl,
9.88. Found: C, 50.31; H, 4.29; Cl, 9.93.
9.18. 6-Chloro-3,5-di-O-formyl-1,2-O-isopropylidene-β-D-glucofuranose (21a):
1H NMR (500 MHz, CDCl3): δ 1.34 & 1.53 (3H each, s, 2xCH3),
3.77-3.99 (2H, m, CH2Cl), 4.52 (1H, d, J = 3.6 Hz, H-2), 4.59
(1H, d, J = 2.9 Hz, H-4) 5.35-5.41 (1H, m, H-5), 5.46 (1H, d, J =
5.9 Hz, H-3), 5.93 (1H, d, J = 3.5 Hz, H-1), 8.1 (2H, s, 2x-OCHO). 13
C NMR (125 MHz,
CDCl3): δ 26.6, 27.0, 44.3, 66.6, 68.6, 74.7, 83.6, 105.5, 113.3, 159.6, 159.6. MS (%) M
at m/z 295. Anal. Calcd. For C11H15ClO7: C 44.83, H 5.13, Cl 12.03: found C 44.86, H
5.17, Cl 12.08.
9.19. 6-Chloro-3,5-di-O-formyl-1,2-O-isopropylidene-α-D-glucofuranose (22a):
1H NMR (500 MHz, CDCl3): δ 1.33 & 1.54 (3H each, s, 2xCH3),
3.77-3.99 (2H, m, CH2Cl), 4.53 (1H, d, J = 3.5 Hz, H-2), 4.59
(1H, d, J = 2.7 Hz, H-4) 5.31-5.38 (1H, m, H-5), 5.42 (1H, d, J =
2.7 Hz, H-3), 5.93 (1H, d, J = 3.5 Hz, H-1), 8.0 (2H, s, 2x-
OCHO). 13
C NMR (125 MHz, CDCl3): δ 26.7, 27.1, 44.4, 66.6, 68.6, 74.8, 83.4, 105.4,
113.4, 159.6, 159.6. MS (%) M at m/z 295. Anal. Calcd. For C11H15ClO7: C 44.83, H
5.13, Cl 12.03. Found C 44.86, H 5.17, Cl 12.08.
OClOHCO
O
O
OHCO
OClOHCO
O
O
OHCO
Chapter 3
Chapter 3
Some of selected compounds 1H & 13C
Spectra:
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 144
1H NMR spectram of compound 10a in CDCl3 (500 MHz)
13
C NMR spectram of compound 10a in CDCl3 (500 MHz)
OO
OO O
OHCO
OO
OO O
OHCO
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 145
1H NMR spectram of compound 11a in CDCl3 (500 MHz)
13
C NMR spectram of compound 11a in CDCl3 (500 MHz)
O
O
OO
OCHO
O
O
O
OO
OCHO
O
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 146
1H NMR spectram of compound 15a in CDCl3 (500 MHz)
13C NMR spectram of compound 15a in CDCl3 (200 MHz)
OOHCO
OHCO
OHCOOMe
Cl
OOHCO
OHCO
OHCOOMe
Cl
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 147
1H NMR spectram of compound 16a in CDCl3 (500 MHz)
13C NMR spectram of compound 16a in CDCl3 (500 MHz)
OOHCOOHCO
OHCOO
Cl
OOHCOOHCO
OHCOO
Cl
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 148
1H NMR spectram of compound 17a in CDCl3 (500 MHz)
13
C NMR spectram of compound 17a in CDCl3 (500 MHz)
OOHCOOHCO
OCHO
S
Cl
OOHCOOHCO
OCHO
S
Cl
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 149
1H NMR spectram of compound 17b in CDCl3 (500 MHz)
13
C NMR spectram of compound 17b in CDCl3 (500 MHz)
OOHCOOHCO
OCHO
S
OCHO
OOHCOOHCO
OCHO
S
OCHO
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 150
1H NMR spectram of compound 18b in CDCl3 (500 MHz)
13
C NMR spectram of compound 18a in CDCl3 (200 MHz)
OOHCOOHCO
OCHO
OMe
Cl
OOHCOOHCO
OCHO
OMe
Cl
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 151
1H NMR spectram of compound 19b in CDCl3 (500 MHz)
13
C NMR spectram of compound 19b in CDCl3 (500 MHz)
O
OHCO
OHCO
OMeOHCO
OCHO
O
OHCO
OHCO
OMeOHCO
OCHO
Section A: Reaction of carbohydrates with Vilsmeier regent.………………………….. Chapter 3
Page 152
1H NMR spectram of compound 21b in CDCl3 (200 MHz)
13C NMR spectram of compound 21b in CDCl3 (200 MHz)
OClOHCO
O
O
OHCO
OClOHCO
O
O
OHCO
Chapter 3:
Chapter 3:
Section B: Chemo-enzymatic Approach
for the Synthesis chiral Pyridyl
alcohols:
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 153
Chemo-enzymatic Approach for the Synthesis of chiral Pyridyl alcohols:
1. Introduction:
Over the past decade, a great deal of progress has been made in the area of
enantioselective reactions1 and molecular recognition chemistry,
2 in which chiral ligands
play a critical role in stereoselective reactions and recognition processes. Therefore, the
synthesis of novel chiral ligands has become increasingly valuable for organic chemist. In
particular, the three-dimensional design of ligand molecules is important to achieve high
stereoselective face and site recognition. In this context chiral pyridyl ethanols are
important intermediates in the synthesis of a variety of pharmaceuticals as well as
alkaloids such as akuamidine, heteroyohimidine,3 having therapeutic values and have also
been used as common donor ligands.4 These chiral alcohols are useful as dopants, which
give spiral structures for liquid crystal molecules in liquid crystal compositions. Apart
from this, chiral pyridyl ethanols are useful chiral auxiliaries as they serve as an efficient
catalyst in a number of asymmetric addition reactions.5 The asymmetric reduction of
heteroaryl ketones is a straightforward approach to prepare these classes of compounds.
Although many chiral pyridyl ligands have been reported6 so far, most of these have been
constituted involving a non-chiral unit connected by a carbon-heteroatom bond with a
chiral unit. The chiral part is generally obtained from commercial sources. On the other
hand, those with a chiral center on the pyridine side have rarely been adopted as chiral
ligands.7 The limited use of chiral pyridyl and 2,2'-bipyridyl ligands may be due to the
limited availability of chiral pyridines and 2,2'-bipyridines. The introduction of a chiral
center directly attached to pyridyl or 2,2'-bipyridyl rings poses a difficult problem.
1 Stereoselective synthesis, Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.; Eds.; Georg
Thieme Verlag: Stuttgart, 1996. 2 Comprehensive Supramolecular Chemistry; Lehn, J.-M., Ed. In chief; Elsevier Science Ltd.: New York,
1996. 3 Uskokovic, M. R.; Lewis, R. L.; Partridge, J. J.; Despreaux, C. W. J. Am. Chem. Soc., 1979, 101, 6742.
4 Reedijk, J. In Comprehensive Coordination Chemistry; Wilikinson, Sir G., Ed.; Pergamon Press: London,
1987, Vol. 2; p 73. Constable, E. C. Metals and Ligand Reactivity; VCH: Weinheim, 1995. 5 (a) Quallich, G. J.; Woodall, T. M. Tetrahedron Lett., 1993, 34, 4145. (b) Collomb, P.; Zelewsky, A.
Tetrahedron Asymmetry, 1998, 9, 3911. 6 (a) Brunner, H.; Reiter, B.; Riepl, G. Chem. Ber. 1984, 117, 1330. (b) Nishiyama, H.; Sakaguchi, H.;
Nakamura, T.; Horihata, M.; Kondo, M.; Itoh, K. Organometallics, 1989, 8, 846. (c) Chelucci, G.; Falorni,
M.; Giacomelli, G. Tetrahedron Asymmetry, 1990, 1, 843. (d) Brunner, H.; Brandl, P. Tetrahedron
Asymmetry, 1991, 2, 919. (e) Chelucci, G.; Soccolini, F. Tetrahedron Asymmetry, 1992, 3, 1235. (f)
Kandzia, C.; Steckhan, E.; Knoch, F. Tetrahedron Asymmetry, 1993, 4, 39. (g) Scrimin, P.; Tecilla, P.;
Tonellato, U. J. Org. Chem., 1994, 59, 4194. 7 (a) Botteghi, C.; Caccia, G.; Chelucci, G.; Soccolini, F. J. Org. Chem., 1984, 49, 4290. (b) Chelucci, G.
Tetrahedron Asymmetry, 1995, 6, 811. (c) Bolm, C.; Ewald, M. Tetrahedron Lett., 1990, 31, 5011. (d)
Bolm, C.; Schlingloff, G.; Harms, K. Chem. Ber., 1992, 125, 1191.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 154
2. Brief review on Reported methods:
Presently several methods are available for the synthesis of chiral pyridines. A
brief review on the reported methods for the preparation of chiral pyridine compounds are
described here.
2.1. Junichi Approach:8 Optical resolution of 1-(2-pyridyl) and 1-[6-(2,2'-bipyridyl)]
ethanols by lipase-catalyzed enantioselective acetylation:
Recently Junichi et al.8 developed a method for the resolution of racemic 1-(2-
pyridyl) ethanols, by lipase-catalyzed asymmetric acetylation with vinyl acetate.
NR Br
NR CHO
NRR'
OH
R'MgBr
Et2O
1) BuLi, -78 0C
Hexane: Et2O: THF (1:2:1), DMA
2) NaBH4/MeOH, rt
Lipase
Vinyl acetate, iso-Pr2O
Molecular sieves 4A0
NRR'
OAc
NRR'
OH
2a-k (racemic)
R (2a-k) S (2a-k)
1a R = H, R' = Me: 1b R = Br, R' = Me: 1c R = TBDMSOCH2, R' = Me: 1d
R = TrOCH2, R' = Me: 1e R = Ph, R' = Me: 1f R = 2-Ph, R' = Me1f:
1g R = , R' = Me: 1h R = , R' = Me:
1i R = H, R' = Et: 1j R = H, R' = Vinyl: 1k R = H, R' = allyl
NBr NTBDMSO
1a-h
1i-k
+
Scheme-1
The reactions were carried out in diisopropyl ether at either room temperature or
60 0C using Candida Antarctica lipase (CAL) to give (R)-acetate and unreacted (S)-
alcohol with excellent enantiomeric purities in good yields.
Junichi and his co-workers have further shown that for substrates bearing a sp3-type
carbon at the 6-position on the pyridine ring, for example methyl substitution, and for
those bearing 1-hydroxypropyl and allyl groups at the 2-position on the pyridine ring the
8 (a) Junichi, U.; Takao, H.; Shinichiro, H.; Kenji, N.; Osamu, Y. J. Org. Chem., 1998, 63, 2481. (b)
Junichi, U.; Nishiwaki, K.; Hata, S.; Nakamura, K. Tetrahedron Lett., 1994, 35, 616.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 155
reaction rate was relatively slow at room temperature in such cases, running the reaction
at higher temperature at 60 0C, resulted in the acceleration 3- to 7-fold without losing the
high enantiospecificity (Scheme-1).
2.2. Yves approach:9 First one-pot chemo-, regio and enantioselective
functionalisation of pyridine compounds:
Yves et al. have developed a novel method for the preparation of optically active
pyridine compounds. They aimed to develop a new and useful super base formed by
association of BuLi with chiral vicinal aminoalkoxides.10
NX
1) BuLi-R*OLi (3 eq)
Hexane, -78 0C
NXR'
OH
2) R1CHO in THF
-78 0C
R*OLi = LiOMe
NMe2
LiO
NMe2
Me
OLi
NMe2
OLi
N
(3) X = Cl, R' = (4) X = Cl, R' = (5) X = Cl, R' =
OMe Cl
Scheme-2
The obtained BuLi–R*OLi reagent should allow direct and regioselective metallation of
the pyridinic ring while controlling unprecedented asymmetric addition of the formed
pyridyl lithium to aldehydes. But the developed method affords products bearing
moderate enantiomeric excess (Scheme-2).
9 Yves, F.; Philippe, G.; Alain, L. R. Tetrahedron Asymmetry, 2001, 12, 2631.
10 Pu, L.; Yu, H.-B. Chem. Rev., 2001, 101, 757.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 156
2.3. Soni approach:11
Biocatalytic reduction of hetero aryl methyl ketones:
Soni and co-workers have accomplished the enantioselective reduction of various
heteroaryl methyl ketones, such as 2-, 3-, and 4-acetyl pyridines, 2-acetyl thiophene, 2-
acetyl furan, and 2-acetyl pyrrole, with the resting cells of a novel yeast strain Candida
viswanathii. Excellent results were obtained with acetyl pyridines. Moderate conversion
took place with 2-acetyl thiophene, but no significant reduction was observed with 2-
acetyl furan and 2-acetyl pyrrole. In the case of acetyl pyridines, the bioreduction was
found to be sensitive toward the nature of substitution on the pyridine nucleus and the
conversion followed the order 4-acetyl pyridine > 3-acetyl pyridine > 2-acetyl pyridine.
Reduction of 3-acetyl pyridine with a high conversion (>98%) and excellent
enantioselectivity (ee >99%) provided the biocatalytic preparation of (S)-(3-pyridyl)
ethanol. Finally, preparative scale reduction of 3-acetyl pyridine has been carried out with
excellent yield (>85%) and almost absolute enantioselectivity (ee >99.9%).
R CH3
O
R CH3
OHCandida viswanathii
0.2 M, pH 7.0 buffer
(6) R = 2-pyridyl (7) R = 3-pyridyl (8) R = 4-pyridyl(9) R = 2-thienyl (10) R = 2-furyl (11) R = 2-pyrrolyl
S-(2a) R = 2-pyridyl S-(12) R = 3-pyridyl S-(13) R = 4-pyridylS-(14) R = 2-thienyl S-(15) R = 2-furyl S-(16) R = 2-pyrrolyl
Scheme-3
The reduction of 2-acetyl pyridine 6 took place with 81–85% conversion. Although 2-
acetyl thiophene 9 was reduced to some extent (9–12% conversion), negligible reduction
of 2-acetyl furan 10, and 2-acetyl pyrrole 11 was observed.
To obtain the best biocatalyst, about 50 oxidoreductase producing soil isolates were tried
for the reduction of ketones (6, 9-11) (Scheme-3). Three yeast species Candida
viswanathii, Candida parapsilopsis, and Candida melibiosa were found to possess
appreciable reductive properties (Table 1).
11
(a) Soni, P.; Kaur, G.; Chakraborti, S. K.; Banerjee, U. C. Tetrahedron Asymmetry, 2005, 16, 2425. (b)
Soni, P.; Kamble, A. L.; Banerjee U. C. Indian Patent Appl, No. 440/DEL/2005. (c) Kamble, A. L.; Soni,
P.; Banerjee, U. C. J. Mol. Catal. B: Enzym., 2005, 35, 1.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 157
Table 1: Screening results of heteroaryl methyl ketone reduction:
Microorganisms 2-acetyl
pyridine 6
2-acetyl
thiophene 9
2-acetylfuran
10
2-acetyl pyrrole
11
C. viswanathii 85.39 12.08 3.07 2.13
C. parapsilopsis 81.05 8.95 - -
C. melibiosa 83.38 10.98 - - Reaction conditions: Resting cells (166 g/L) in phosphate buffer (pH 7.0, 0.2 M) and ketone concn. in
reaction (2 g/L); reaction for 12 h at 30 0C (200 rpm).
2.4. Stepanenko approach:12
Synthesis of pyridyl and related heterocyclic alcohols
using spiroborate esters in the borane-mediated asymmetric reduction:
Stepanenko et al. have shown the effectiveness of several spiroborate ester
catalysts in the asymmetric borane reduction of 2-, 3-, and 4-acetylpyridines (6-8) under
different reaction conditions. Highly enantiomerically enriched 1-(2-, 3-, and 4-pyridyl)
ethanols (2a, 12 and 13) and 1-(heterocyclic)ethanols have been obtained using 1–10%
catalytic loads of the spiroborate derived from diphenylprolinol and ethylene glycol
(Scheme-4).
Cat. (0.1-10%)
BH3-DMS
Cat:
BO O
ONH
R CH3
O
R CH3
OH
(R)- 2a, 12, 13
BO O
ONH
(6) R = 2-pyridyl (7) R = 3-pyridyl (8) R = 4-pyridyl
Scheme-4
2.5. Szatzker approach:13
Chemo enzymatic preparation of all the stereoisomers of
2-(1 hydroxyethyl)-pyridines and their acetates:
Recently Szatzker et al. have screened various lipases for the enantio selective
acetylation of racemic 1-[6-(1-hydroxyethyl)-pyridin-2-yl]ethanone racemic and the
12
Stepanenko, V.; De Jesús, M.; Correa, W.; Guzmán, I.; Vázquez, C.; Ortiz, L.; Ortiz-Marciales, M.
Tetrahedron Asymmetry, 2007, 18, 2738. 13
Szatzker, G.; Moczar, I.; Kolonits, P.; Novak, L.; Huszthy, H.; Poppe, L. Tetrahedron asymmetry, 2004,
15, 2483.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 158
reaction of 18 has furnished alcohol (S)-18 and acetate (R)-19 using most selective
Novozym 435 lipase in vinyl acetate. Furthermore, hydrolysis of acetyl derivatives of
racemic 18 also afforded optically active acetylated product (S)-19 and hydrolyzed
product (R)-18 (Scheme-5).
NH
O
0.25 eq/NaBH4
N
OH
N
OAc
N
OH
Ac2O, Et3N
Novozyme 435
lipase
Vinyl acetate
N
OAc
+
N
OH
N
OAc
+
rac-19
17 rac-18
(R)-18 (S)-19
(S)-18 (R)-19O
H
O
H
O
H
O
H
O
H
O
H
O
H
Scheme-5
2.6. Orrenius approach:14
Preparation of 1-(2-, 3-, and 4-pyridinyl) ethanols of high
enantiomeric purity by lipase catalysed transesterification:
Orrenius et al. reported high enantioselectivity of 1-pyridylethanols in catalyzing
transesterification reaction in non-aqueous media using lipase of the candida Antarctica
yeast.
NOH N
OLipaseS C7H15
O
+ C7H15
O N
OHSH+ +
Racemic 2a, 12, 13 (R = H)Racemic 20 (R = Br)
R R
(S)21-24
25
R
(R)-2a, 12, 13 (R = H)(R)-20 (R = Br)
Scheme-6
This methodology has been exploited by the another to resolve racemates of 1-(2-, 3-, and
4-pyridyl) ethanols (2a, 12 and 13) and 1-(6-bromopyridine-2-yl) ethanol (20). The lipase
esterified the (R)-alcohols (2a, 12 and 13) of the 1-(pyridyl) ethanols in ≥99%
enantiomeric excess in less than three hours with 30-40 isolated yields. Remaining (S)-
14
Orrenius, C.; Mattson, A.; Norin, T. Tetrahedron Asymmetry, 1994, 5, 1363.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 159
enantiomers (21-24) were isolated in similar yields and in 97-98% ee (Scheme-6) (Table-
2).
Table 2: enantiomeric purities and yields of resolved secondary alcohol and their acyl
derivatives: Substrate Convn. (%)
Products
Remaining alcohol Reacted alcohol (Acyl
derivatives)
ee Rot. Conf. Yield ee Rot. Conf. Yield
2a 49 (50) 97 (-) S 45 >99 (+) R 39
12 50 (50) 98 (-) S 44 99 (+) R 35
13 49 (50) 97 (-) S 38 >99 (+) R 33
20 49 (40) 98 (-) S 46 >99 (+) R 31
2.7. Nakamura Approach:15
Asymmetric synthesis of both enantiomers of secondary
alcohols by reduction with a single Microbe:
Recently Nakamura et al. have prepared both enantiomers of secondary alcohols
by reduction of the corresponding ketones with a single microbe. Thus, reduction of
aromatic ketones (6-8) with Geotrichum candidum IFO 5767 afforded the corresponding
(S)-alcohols (2a, 12 and 13) in an excellent ee when amberlite™ XAD-7, a hydrophobic
polymer, was added to the reaction system and the same microbe afforded (R)-alcohols
(2a, 12 and 13) also in an excellent ee when the reaction was conducted under aerobic
conditions (Scheme-7).
(R)-2a-, 12, 13(S)- 2a, 12, 13
92->99%ee96->99%yield
85->99%ee61->99%yield
XAD-7aerobic conditionsN
G. candidum IFO5767a
6-8
G. candidum IFO5767a
OH
N
OH
N
O
Scheme-7
15
Nakamura, K.; Takenaka, K.; Fujiib, M.; Idb, Y. Tetrahedron. Lett., 2002, 43, 3629.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 160
2.8. Carsten Bolm approach:16
Optically active bipyridines in asymmetric catalysis:
Bolm et al. have reported the enantioselective synthesis of homochiral C2-
symmetric bipyridines 31and 32, the X-ray structure analysis of a complex of (R,R)-32
and cobalt (II) chloride, and the first investigations of the use of these optically active
bipyridines as enantioselective catalysis. For the synthesis of the enantiomerically pure
bipyridine (-)-(R,R)-31 they have used the optically active alcohol (R)-27, which is
accessible in a two-step reaction from 2,6-dibromopyridine (26) (Scheme-8).
NBr Br NBr
OH
BuLi, tBuCHO, THF
NBr
O
N
OH
NBr
OH
NBr
OCH3
BuLi,tBuCOOCH3, THF
PCC/CH2Cl2
1) (-)-B-chlorodiisopinocam phenyl borane2) iminodiethanol/ether
NaH, CH3I/THF
Bu3SnH, AIBN/Toluene
NiCl2 . 6H2O, Zn, PPh3, DMF
NiCl2. 6H2O, Zn, PPh3, DMF
26 rac-27
28 (R)-29
(R)-27
(R)-30
31 (-)-(R,R) (R = H) 32 (+)- (R,R) (R = CH3)
N N
OR RO
Scheme-8
16
Bolm, C.; Zehnder, M.; Bur, D. Angew. Chem., 1990, 29, 205.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 161
2.9. Garrett Approach:17
Enantio-complementary preparation of (S)- and (R)-1-
Pyridyl alkanols via ketone reduction and alkane hydroxylation using whole cells of
Pseudomonas putida UV4:
In 2002 Garrett et al. reported the combination of oxidative and reductive
biotransformations that provides a method for the preparation of both enantiomers of
chiral 1-pyridyl alkanols using one biocatalyst (Scheme-9).
N
RPseudomonas putida UV4
N
R
OH
+minor productsincluding
N
R
O
N
R
N
R OH
N
R
OH
NO N
R
OH
N
OO
ADHN
OHOH
33-35 (R)-2a, 12, 13 6-8
35(R)-13
36
6-8
(S)-2a, 12, 13
17 (S,S)-37
alcohol dehydrogenases (ADH)
toluene dioxygenase (TDO)
Scheme-9
For that they have used a previously unreported alcohol dehydrogenase enzyme in
the mutant soil bacterium Pseudomonas putida UV4 catalyses, the reduction of 2-, 3- and
4-acylpyridines (6-8) afforded the corresponding (S)-1-pyridyl alkanols with moderate to
high ee, whilst under the same conditions 2,6-diacetylpyridine (17) is readily converted to
the corresponding enantiopure C2-symmetric (S,S)-diol (37) in one step. In contrast the
17
Garrett, M. D.; Scott, R.; Sheldrake, G. N.; Tetrahedron Asymmetry, 2002, 13, 2201.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 162
toluene dioxygenase enzyme in the same organism catalyses the hydroxylation of 2-, 3-
and 4-alkylpyridines (33-35) to (R)-1-(2-pyridyl) and (R)-1-(3-pyridyl) alkanols. This
process failed to produce (R)-1-(3-pyridyl) alkanols but produced the ring-hydroxylated
product 36 (Scheme-9).
2.10. Busto Approach18
: Kinetic resolution of 4-chloro-2-(1-hydroxyalkyl)-pyridines
using Pseudomonas cepacia lipase:
Busto et al. reported a detailed protocol for the lipase-mediated kinetic resolution
of various 4-chloro-2-(1-hydroxyalkyl) pyridines (38–41) (Scheme-10), as those
compounds are useful intermediates for the production of chemical catalysts derived from
DMAP. Those catalysts can be used in a wide range of asymmetric processes. In addition,
kinetic resolution permits researchers to obtain derivatives of the opposite
stereochemistry, which allows the possibility of stereoselective complementary processes.
The authors have done an exhaustive study to optimize the reaction conditions for the
stereoselective enzymatic transesterification of racemic alcohols (38-41), finding
Pseudomonas cepacia lipase (PSL) as the optimal biocatalyst; the results obtained using
these enzymes are summarized in Table 3.
NR
OH
PSLO
O
+ +
38 = R = Me39 = R = Et40 = R = Pr41 = R = Bu
Cl
THF 30 0C
250 r.p.m
NR
O
Cl
O
CH3
NR
OH
Cl
(R) 42 = R = Me(R) 43 = R = Et(R) 44 = R = Pr(R) 45 = R = Bu
(S) 38 = R = Me(S) 39 = R = Et(S) 40 = R = Pr(S) 41 = R = Bu
Scheme-10
18
Busto, E.; Gotor-Fernandez, V.; Gotor, V. Nature protocols, 2006, 4, 2061.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 163
Table 3: Results of kinetic resolution of alcohols 38–41.
Substrate Time (h) eePa
Yield eeSa
Yield Conversionb Enantioselectivity
c
38 14.5 >99 85% >99 88% 50% >200
39 14.5 99 82% >99 88% 50% >200
40 38 >99 97% >99 89% 50% >200
41 60 >99 88% >99 89% 50% >200
Alcohols were resolved at 30 0C and 250 r.p.m. with vinyl acetate (2) as the acyl donor, P. cepacia lipase as
the biocatalyst and tetrahydrofuran as the solvent. aEnantiomeric excess of the (R)-ester product (eeP) and
the (S)-alcohol remaining substrate (eeS), calculated by HPLC analysis. bConversion ¼ eeS / (eeS + eep).
cEnantioselectivity= ln [(1 – c) x (1 + eeP)] / ln [(1 – c) x (1 – eeP)].
3. Objective of the present work:
Chiral ligands are widely used for asymmetric reactions in organic synthesis. Till
date, a large number of chiral ligands have been prepared (fig-2),19
and their usefulness
for asymmetric reactions also been investigated. Since there is a high demand for new and
efficient chiral ligands for application in asymmetric synthesis, the search for new chiral
ligands and catalysts is continuously increasing. A considerable number of ligands having
phosphine and nitrogen functional moieties have been reported in the past few years.20
In
connection with this, phosphine ligands bearing a pyridine ring are of particular interest to
us. We may said that chiral pyridyl alcohols are of particular interest to us all these can be
an important components of chiral phosphine ligands which have been in use for their
excellent application in chiral asymmetric synthesis.
In addition, Pyridyl alcohols are excellent candidates as chiral substructures of several
ligands for asymmetric synthesis and kinetic resolution. Chiral pyridyl alcohols have
proven to be versatile ligands in a variety of catalytic applications and in many cases
including high stereoselectivity.21
For example chiral pyridines catalyze the
enantioselective addition of diethyl zinc to aldehydes,19f
the nickel catalyzed conjugate
19
(a) Collomb, P.; Von Zelewsky, A. Tetrahedron Asymmetry, 1995, 6, 2903. (b) Macedo, E.; Moberg, C.
Tetrahedron Asymmetry, 1995, 6, 549. (c) Vedejs, E.; Chen, X. J. Am. Chem. Soc., 1996, 118, 1809.(d)
Uenishi, J.; Hamada, M. Tetrahedron Asymmetry, 2001, 12, 2999. (e) Nordstrom, K.; Macedo, E.; Moberg,
C. J. Org. Chem., 1997, 62, 1604. (f) Bolm, C.; Schlingloff, G; Harms, K. Chem, Ber., 1992, 125, 1191. 20
(a) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev., 2000, 100, 2159 and references
cited therein. (b) Mino, T.; Tanaka, Y.; Sakamoto, M.; Fujita, T. Heterocycles, 2000, 53, 1485. (c) Suzuki,
Y.; Abe, I; Hiroi, K. Heterocycles, 1999, 50, 89. (d) Zhu, G.; Terry, M.; Zhang, X. Tetrahedron Lett., 1996,
37, 4475. (e) Dai, X.; Virgil, S. Tetrahedron Lett., 1999, 40, 1245. 21
Noyori, G. Gazz, Chim, Ital., 1992, 122, 89.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 164
addition to enones,22
and asymmetric epoxidation.23
These compounds also serve as
useful starting materials for the preparation of pyridineoxazoline alcohols,24
which
catalyzes other type of processes. Therefore it would be very important to synthesis and
biocatalytic resolution of these pyridyl alcohols and their acyl derivative are the prime
objective of the present work.
NPhN N
OHHO
42
OH
43
N
OH
O
N
44
N
OH
N
45
N
N
X
Y
N
N
Ph2P
N
N
Ph2P
N
N
Ph2P
46 x = H, Y = PPh2
47 x = Ph, Y = PPh2
48 x = 3,5-dimethylphenyl, Y = PPh2
49 x = 2,6-dimethylphenyl, Y = PPh2
50 x = H, Y = OCH3
51 52 53
Fig-2
4. Result and Discussion:
Pyridyl alcohols which serve as chiral auxiliaries in organic synthesis particularly
asymmetric synthesis can be prepared via Grignard reaction or reduction of
corresponding aldehydes. There are a number of reports describing the preparation of
these chiral intermediates by chemical or chemoenzymatic methods all these methods
described above have their limitations.
As a part of the present study, we envisaged the preparation of chiral Pyridyl alcohols and
their acyl derivatives as these compounds can easily be converted to their corresponding
chiral pyridine-phosphine ligands (Fig-2). In this direction pyridyl alcohols (2a, 2i, 2k,
12, 12a, 13, 13a & 56) were prepared by two different methods: (A) 2-, 3- and 4-formyl
22
Bolm, C. Tetrahedron Asymmetry, 1991, 2, 701. 23
Hawkins, J. M.; Sharpless, K, B. Tetrahedron Lett., 1987, 28, 2825. 24
Macedo, E.; Moberg.; C.; Tetrahedron Asymmetry, 1995, 6, 549.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 165
pyridines (1i, 54, 55) were first converted into corresponding alcohols using Grignard
reagent prepared from appropriate alkyl halides and magnesium. (B) By the NaBH4
reduction of 2-, 3- and 4-acetyl pyridines (6-8) (Scheme-11).
Et2O
RMgX
1i R = CH3 (2a)R = C2H5 (2i)R = C2H5 (2k)R = CH2Ph (56)
54 R = CH3 (12)R = C2H5 (12a)
Et2O
C2H5MgI
Et2O
C2H5MgI
55 R = CH3 (13)R = C2H5 (13a )
6
NaBH4/MeOH
NaBH4/MeOH
7
NaBH4/MeOH
8
Method A Method B
H
O
N H3C
O
NR
HO
N
R
HO
NH
O
N H3C
O
N
R
HO
N
H
O
N
H3C
O
N
Scheme-11
Alcohols thus obtained were converted to their acyl derivatives (57-69) (Scheme-12) the
racemic acyl derivatives were directly subjected to kinetic resolution using native as well
as commercial hydrolases for the preparation of corresponding optically enriched alcohols
and their esters.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 166
2a R = CH3
2i R = C2H5
2k R = C3H5
56 R = CH2Ph
12 R = CH3
12a R = C2H5
13 R = CH3
13a R = C2H5
Pyridine
57 R = R1 CH3
58 R = C2H5, R1 = CH3
59 R = R1 C2H5
60 R = C3H5, R1 = CH3
61 R = CH2Ph, R1 = CH3
Pyridine
62 R = CH3, R1 = CH3
63 R = CH3, R1 = C2H5
64 R = CH3, R1 = C3H7
65 R = C2H5, R1 = CH3
(R1CO)2O
(R1CO)2O
Pyridine
(R1CO)2O
66 R = R1 = CH3 67 R = C2H5, R1 = CH3
68 R = CH3, R1 = C2H5
69 R = CH3, R1 = C3H7
R
HO
N
R
HO
N
R
HO
N
R
R1
O
ON
R
R1
O
ON
R
R1
O
O
N
Scheme-12
After the preparation of racemic acyl derivatives (57-69), our initial experiments were
designed to find the suitable lipase for the enantioselective hydrolysis of esters. For this
purpose several native as well as commercial enzymes were screened to effect hydrolysis
of the ester group in 57-69 (Scheme-13). The results of primary screening experiments
are summarized in Table-4.
Lipase+
57a-67a 2a, 2i, 2k, 56, 12, 12a, 13, 13a
N
O
R
R1
ON
O
R
R1
O
57-67
N
OH
RpH 7
Scheme-13
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 167
Table 4: Screening of enzymes for the hydrolysis of 1-(2-, 3- and 4-Pyridyl) alcohol
esters:
Enzyme Substrate
57 58 59 60 61 62 63 64 65 66 67 68 69
CAL + + + + Nd + + + Nd + + + +
CCL + + + + + + + Nd + Nd + + Nd
CRL + + + + + + + + + Nd + + Nd
PLAP + + + + + + + Nd + Nd + Nd Nd
Y-15 + + + + Nd + + Nd + Nd + + Nd
ABL + + + + + + + + + + + + +
BB-1 - - - - - - - - - - - - -
RSP-1 - - - - - - - - - - - - -
RSP-2 - - - - - - - - - - - - -
RSP-3 - - - - - - - - - - - - -
RSP-4 - - - - - - - - - - - - -
RSP-5 - - - - - - - - - - - - -
RSP-6 - - - - - - - - - - - - -
RSP-7 - - - - - - - - - - - - -
RSP-8 - - - - - - - - - - - - -
(+) = hydrolysis; (-) = no reaction; Nd = not determined.
As evident from the above data, out of fourteen enzymes only six lipases i.e. Candida
Antarctica lipase (CAL), Candida cylindracea lipase (CCL), Candida rugosa lipase
(CRL), Pig liver acetone (PLA), Y-15 and ABL were able to hydrolyze the substrate
(shown in positive sign).
The literature study revealed that enzymes such as CAL, CCL, CRL and PLA have been
successfully used in the resolution of pyridyl alcohols using trans-esterification method
and only a few publications have appeared showing hydrolysis of acetates at high
temperatures and high reaction timings. Also after the results of initial screening,
preparation of optically enriched 1-(2, 3- and 4-Pyridyl) acyl derivatives and their
alcohols was achieved (Scheme-14) of the corresponding racemic 1-(2-, 3- and 4-Pyridyl)
alkanoats 57-69 using our native enzymes.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 168
R (57a-67a)S (2a, 2i, 2k, 56, 12, 12a, 13, 13a)
lipase (ABL) +
lipase (Y-15)
pH 7
N
O
R
R1
O
57-67
pH 7
N
R
O
O
R1
N
R
OH
S (57a-67a) R (2a, 2i, 2k, 56, 12, 12a, 13, 13a)
+N
R
O
O
R1N
R
OH
Scheme-14
Table 5: ABL catalyzed kinetic resolution of 1-(2-, 3- and 4-Pyridyl) alkanoates 57-69 in
aqueous buffer phase.
Entry Conv. Time (h) Alcohol Ester E
ee% 25
D
Conf. ee% 25
D
Conf.
57 46 3 98 +16.8 R 93 -41.2 S 39
58 53 3 77 +40.6 R 94 -60.0 S 67
59 26 4 94 +42.3 R 66 -39.0 S 176
60 26 4 92 +36.5 R 78 -33.4 S 58
61 22 10 15 +3.5 R 29 -11.3 S 95
62 49 3 97 +26.8 R 71 -40.3 S 278
63 48 3 92 +22.3 R 87 -41.3 S 171
64 39 4 74 +23.6 R 77 -40.6 S 84
65 26 4 34 +44.0 R 64 -33.6 S 184
66 37 3 77 +33.4 R 56 -24.9 S 95
67 37 3 77 +33.4 R 56 -24.9 S 95
68 33 4 66 +23.6 R 85 -23.7 S 32
69 26 6 59 +31.4 R 48 -23.1 S 44
The optical rotations were measured with c 1 CHCl3.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 169
Table 6: Y-15 catalyzed kinetic resolution of 1-(2-, 3- and 4-Pyridyl) alkanoates 57-69 in
aqueous buffer phase.
Entry Conv.
Time (h) Alcohol Ester E
ee% 25
D
Conf. ee% 25
D
Conf.
57 33 5 66 -22.2 S 73 +32.6 R 165
58 23 5 71 -26.0 S 94 +40.4 R 244
59 21 5 36 -37.0 S 61 +42.3 R 56
60 23 5 77 -33.0 S 71 +39.3 R 225
61 20 12 13 -11.3 S 33 +3.9 R 67
62 49 5 91 -36.5 S 90 +24.6 R 278
63 49 5 86 -40.3 S 94 +20.4 R 24
64 39 5 56 -40.8 S 17 +23.1 R 84
65 33 5 77 -40.0 S 54 +24.5 R 88
66 30 5 77 -24.0 S 56 +33.8 R 32
67 33 5 77 -24.0 S 56 +37.4 R 86
68 21 5 66 -33.0 S 85 +31.8 R 225
69 18 8 64 -33.1 S 38 +31.4 R 48
The optical rotations were measured with c 1 CHCl3.
For the detailed investigation, stereoselective hydrolysis was carried out in aqueous 0.1
M-phosphate buffer at pH 7.0 in the temperature range 25-35 0C. It was found that the
reaction time was reduced as well as enantioselectivity was quite high in almost all the
cases (ee 94%). In order to improve the rate of hydrolysis as well as enantioselective
manipulation of the reaction medium was another practical option. Biphasic system using
an organic solvent proved to be advantageous. Both non polar as well as polar solvents 5-
10% v/v were used in the resolution studies and finally acetonitrile was found to be the
co-solvent of choice in terms of conversion rates as well as enantioselectivity as shown in
Table 7 and 8 for the substrate 62. Addition of acetonitrile as co-solvent with (10% v/v)
in buffer reduced the reaction time and also increased the ee. Therefore acetonitrile was
selected as co-solvent for detailed kinetic resolution studies of the other substrates. The
enantiomeric excess of alcohols and their acyl derivatives were determined by chiral
HPLC analysis. The racemic and the resolved byproducts were analyzed using HPLC
with chiral columns like ODH, OJH.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 170
Table 7: Effect of co-solvent on ABL catalyzed hydrolysis of (±) 62.
Co-solvent Convn. T (h) ees eep
Acetonitrile 50 3 >99.99 >99.99
Dimethyl formamide 48 4 94 99
Dimethyl sulphoxide 43 3 99 99
Acetone 39 4 94 81
Hexane 61 3 91 86
Toluene 76 3 78 85
Enantiomeric excess of the (R)-ester remaining substrate (ees) and the (S)-alcohol product (eep),
Table 8: Effect of co-solvent on Y-15 catalyzed hydrolysis of (±) 62.
Co-solvent Convn. T (h) ees eep
Acetonitrile 49 3 >99.99 >99.99
Dimethyl formamide 46 3 99 >99
Dimethyl sulphoxide 44 3 88 86
Acetone 44 4 74 97
Hexane 33 3 68 77
Toluene 36 3 46 64
Enantiomeric excess of the (S)-ester remaining substrate (ees) and the (R)-alcohol product (eep),
In general kinetic resolution studies of compounds 57-69 using acetonitrile as the co-
solvent displayed comparatively faster conversion rates as well as improved
enantioselectivity. The results of the experiments are presented in Table -9.
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 171
Table 9: ABL catalyzed kinetic resolution of 57-69 with acetonitrile as co-solvent.
Sub. Con
v.
Time
(h)
Alcohol Ester E
ee% 26
D Yield Conf. ee% 26
D Yield Conf.
57 47 1.45 >99.99 +17.3 47% R >99.99 -44.2 46% S 225
58 36 1.45 94 +40.8 41% R 99 -66.0 43% S 92
59 49 1.45 94 +42.3 42% R >99 -38.2 43% S 176
60 50 1.45 98 +42.3 42% R 94 -24.6 47 S 177
61 21 6 93 +6.8 12% R 78 -14.6 74% S 92
62 50 0.30 >99.99 +25.8 49% R >99.99 -40.8 48% S 278
63 49 0.30 >99.99 +22.3 48% R >99.99 -41.3 49% S 171
64 49 1 >99 +23.8 31% R >99.99 -40.6 58% S 56
65 49 2 >99 +44.8 47% R >99 -34.0 46% S 184
66 47 1 >99.99 +30.4 43% R >99.99 -24.9 45% S 244
67 33 2 >99 +34.2 43% R >99 -25.6 47% S 95
68 47 1 >99 +23.0 49% R >99.99 -23.7 49% S 500
69 39 1.45 99 +31.4 49% R 94 -23.1 49% S 44
8. ABL catalyzed Transesterification of 1-(2, 3- and 4-Pyridyl) alcohols
(2a, 12 and 13):
In order to further reduce the reaction time as well as to harvest high yield of the
products we used transesterification approach in a bid to obtained enantiomerically pure
1-(2-, 3- and 4-Pyridyl) acyl derivatives from their corresponding alcohols. In this
experiment transesterification of substrates was attempted again with a panel of
biocatalysts encompassing both commercial as well as lyophilized cells preparation of
enzyme from the institute’s repository. The lipase ABL was able to exhibit best results in
less time and with good enantioselectivity as shown in Table 10. Pyridyl ethanols (2a, 12
and 13) were chosen as substrates for the primary examination of lipases. An enzymatic
acetylation was carried out in diisopropyl ether with vinyl acetate in the presence of lipase
(ABL) at room temperature (Scheme-15). Other lipases like CAL (Candida Antarctica
lipase) and Y-15 were also used. Both of these lipases gave (+)-acetates 57a, 62a and 66a
with an (R)-configuration and the recovery of (S)-alcohols respectively with excellent
enantiomeric excess. Among these the lipases used, ABL gave the best enantioselectivity
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 172
and chemical yields for both the acetate and alcohols, while other lipases were less
effective interims of time of the reaction and enantiomeric excess of the byproduct results
are summarized in Table 10.
lipase+
R (57a, 62a, 66a) S (2a, 12, 13)
N
OH
RVinyl acetate
2a, 12, 13
N
R
O
O
R1N
R
OH
Scheme-15
Table 10: ABL catalyzed transesterification of (2a, 12 and 13).
Sub. Convn. Time
(h)
Alcohol ((2a, 12 and 13) Ester (57a, 62a, 66a) E
ee% 26
D Yield Conf. ee% 26
D Yield Conf.
2a 50 1.45 99.99 +18.3 49% S 99.99 -46.2 46% R 225
12 44 1.45 99.99 +42.0 50% S 99.99 -66.6 43% R 92
13 49 1.45 99.99 +42.3 47% S 99.99 -38.2 43% R 176
5. Conclusion:
The synthesis of important enantiopure pyridyl alcohols has been achieved in high
chemical yield by a rapid and practical procedure for small and potentially large-scale
industrial use. Resolution of a wide range of pyridyl ethanols and their derivatives
catalyzed by ABL and Y-15 was achieved with good yields and in excellent optical
purity. This method offers several advantages: 1) A simple and very convenient recipe, 2)
A clean reaction even at a large scale, 3) Excellent enantioselectivity and a high chemical
yield, 4) Both (R)- and (S)-isomers are available in single reaction. The obtained optically
pure pyridyl ethanols and their derivatives may be important building blocks for the
construction of chiral ligand molecules, which should be useful in asymmetric reactions
and molecular recognition chemistry. Among the several commercial as well as native
lipases tested for the hydrolysis of 1-(2-, 3- and 4-Pyridyl)alcohol esters and their
derivatives and trans-esterification of corresponding 1-(2-, 3- and 4-Pyridyl)alcohols,
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 173
ABL was found to exhibit excellent lipase giving good selectivity with less time as well
as good yields. Further exploiting the potential of this microorganism for the synthesis of
other optically active alcohols is also in progress.
6. Experimental:
6.1. Typical procedure for the Preparation of Pyridyl Alcohols:
(Method A):
In a typical procedure to an etheral solution (186 mL) of 2-
pyridinecarboxaldehyde (1i) (2 g, 18.7 mmol) was added ethyl magnesium bromide in
diethyl ether or THF (24.27 mmol) at 0 0C. The mixture was stirred for 2 h, quenched
with ice-water (5 mL), and extracted with EtOAc. The extract was washed with water and
brine and dried over Na2SO4. The solvent was removed, and the residue was purified by
column chromatography over silica gel with hexane: ethyl acetate (50:50) as an eluent to
give oily liquid corresponding alcohols 2i in 95% yield. Compounds 2k, 56, 12a, 13a
were prepared using the same method.
Method B:
To a solution of 2-acetylpyridine 6 (4 g, 25 mmol) in anhydrous ethanol (120 mL)
NaBH4 (0.87 g, 3.7 mmol) was added portion wise at rt and the resulting mixture stirred
overnight. After concentration the contents under reduced pressure on a rotavapour, the
residue was dissolved in ethyl acetate (50 mL) and washed with water (10 mL), 5% HCl
solution (10 mL), saturated NaHCO3 solution (10 mL) and brine (10 mL) and dried over
sodium sulfate. From this solution, ethyl acetate was distilled off by rotary evaporator and
the residue purified by column chromatography over silica gel hexane: acetone (50:50) to
give racemic 2a (1.67 g, 41%) as a colourless oil. Compounds 12, 13 were prepared using
the same method.
6.2. Typical procedure for the alkylation of Pyridyl Alcohols:
In a typical procedure a solution of 2a (1.0 g, 8.13 mmol), acetic anhydride (0.830
g, 8.13 mmol) and pyridine (2 ml) in dichloromethane (10 ml) was kept over night at
room temp. After the completion of the reaction, the contents were poured into ice-cold
water and extracted with dichloromethane (3x50 ml). The organic layer was washed with
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 174
water, dried with sodium sulfate, and concentrated to furnish the crude product which on
purification by column chromatography over silica gel with hexane: ethyl acetate (70:30)
as eluent to give 57. Compounds 58-69 were prepared using same method.
6.3. General procedure of lipase catalyzed kinetic resolution of 43:
In a typical procedure a mixture 57 (100 mg), acetonitrile (0.5 mL) crude enzyme ABL
(100 mg) in phosphate buffer (pH 7.0) was stirred at rt. The course of the reaction was
monitored by chiral HPLC. After the certain degree of conversion the reaction was
terminated, extracted with ethyl acetate (2x20 mL), washed with water, dried over sodium
sulfate and concentrated in vacuo to gave crude product which on column
chromatography on silica gel with ethyl acetate: hexane (30;70) as eluent furnished
corresponding alcohol 2a and recovered compound 57. Using the same procedure all
derivatives (58-69) was resolved.
7. Spectral data:
7.1. 1-(2-pyridyl) ethanol (2a):
1H NMR (200 MHz, CDCl3): δ 1.50 (3H, d, J = 6.5 Hz, CH3), 4.91 (1H, q,
J = 6.6 Hz, CHOH), 7.28 (1H, dd, J = 7.6, 4.3 Hz), 7.34 (1H, d, J = 7.7
Hz), 7.76 (1H, dd, J = 7.6, 1.7 Hz), 8.60 (1H, d, J = 4.8 Hz). 13
C NMR ( 50 MHz, CDCl3):
δ 24.1, 74.1, 120.0, 123.1, 136.4, 148.4, 162.3. MS (%) M at m/z 124. Anal. Calcd. For
C7H9NO: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.52; H, 7.59; N, 11.49.
7.2. 1-(2-pyridyl) propanol (2i):
1H NMR (200 MHz, CDCl3): δ 0.94 (3H, t, J = 7.3 Hz, CH2CH3), 1.64-
1.96 (2H, m, CH2CH3), 4.70 (1H, dd, J = 7.4, 4.7 Hz, CHOH), 7.18 (1H,
dd, J = 7.7, 4.4 Hz), 7.24 (1H, d, J = 7.7 Hz), 7.69 (1H, dd, J = 7.7, 1.7
Hz), 8.55 (1H, d, J = 4.8 Hz). 13
C NMR ( 50 MHz, CDCl3): δ 9.3, 31.1, 73.9, 120.3,
122.1, 136.5, 148.0, 162.2. MS (%) M at m/z 138. Anal. Calcd. For C8H11NO: C, 70.04;
H, 8.08; N, 10.21. Found: C, 70.52; H, 8.49; N, 10.39.
OH
N
HO
N
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 175
7.3. 1-(2-pyridyl)-3-butene-1-ol (2k):
1H NMR (200 MHz, CDCl3): δ 2.49 & 2.63 (1H each, m,
CHCH2CH=), 4.26 (1H, br s, CHCH2CH), 4.81 (1H, dd, J = 7.1, 4.9
Hz, CHOH), 5.08-5.13 (2H, m, CH=CH2), 7.19 (1H, dd, J = 7.7, 4.7
Hz), 7.31 (1H, d, J = 7.7 Hz), 7.68 (1H, td, J = 7.7, 1.7 Hz), 8.52 (1H, d, J = 4.7 Hz). 13
C
NMR (50 MHz, CDCl3): δ 42.8, 72.3, 117.9, 120.4, 122.3, 134.1, 136.6, 148.2, 161.5. MS
(%) M++Na
at m/z 173. Anal. Calcd. For C9H11NO: C, 72.36; H, 7.43; N, 7.43. Found: C,
72.92; H, 7.92; N, 7.87.
7.4. 2-phenyl-1-(pyridine-2-yl) ethanol (56):
1H NMR (200 MHz, CDCl3): δ 2.92 (2H, m, CHCH2), 4.96 (1H,
dd, J = 7.2, 4.7 Hz, CHOH), 7.10-7.27 (7H, m, 5xAr-H & 2pyridyl
protans), 7.63 (1H, dd, J = 7.7, 1.9 Hz), 8.52 (1H, d, J = 4.7 Hz).
13C NMR (50 MHz, CDCl3): δ 44.5, 46.2, 71.3, 120.7, 120.8, 126.5, 129.5, 129.6, 136.5,
137.8, 148.4, 161.3. MS (%) M at m/z 200. Anal. Calcd. For C13H13NO: C, 78.36; H,
6.58; N, 7.03. Found: C, 78.52; H, 6.79; N, 7.39.
7.5. 1-(3-pyridyl) ethanol (12):
1H NMR (200 MHz, CDCl3): δ 1.50 (3H, d, J = 6.49, CH3), 4.92 (1H, q,
1H, CHOH), 5.28 (1H, s, OH), 7.23 (1H, dd, J = 7.8, 4.6 Hz), 7.74 (1H, d,
J = 7.8 Hz), 8.32 (1H, d, J = 4.7 Hz), 8.41 (1H, d, J = 4.9 Hz). 13
C NMR (50 MHz,
CDCl3): δ 25.0, 68.3, 123.8, 133.4, 142.3, 148.0, 148.8. MS (%) M at m/z 124. Anal.
Calcd. For C7H9NO: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.52; H, 7.49; N, 11.39.
7.6. 1-(3-pyridyl) propanol (12a):
1H NMR (200 MHz, CDCl3): δ 0.93 (3H, t, J = 7.4 Hz, CH2CH3), 1.61-
1.94 (2H, m, CH2CH3), 4.70 (1H, dd, J = 7.3, 4.8 Hz, CHOH), 5.28 (1H,
s, 1H, OH), 7.23 (1H, dd, J = 7.8, 4.6 Hz), 7.74 (1H, d, J = 7.8 Hz), 8.32
(1H, d, J = 4.7 Hz), 8.41 (1H, d, J = 1.9 Hz). 13
C NMR (50 MHz, CDCl3): δ 25.0, 68.3,
123.8, 133.4, 142.3, 148.0, 148.8. MS (%) M at m/z 138. Anal. Calcd. For C8H11NO: C,
68.27; H, 7.37; N, 11.37. Found: C, 68.52; H, 7.49; N, 11.39.
OH
N
OH
N
HO
N
OH
N
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 176
7.7. 1-(4-pyridyl) ethanol (13):
1H NMR (200 MHz, CDCl3): δ 1.50 (3H, d, J = 6.5, CH3), 4.94 (1H, q,
CHOH), 7.32 (2H, d, J = 5.7 Hz), 8.48 (2H, d, J = 5.7 Hz). 13
C NMR (50
MHz, CDCl3): δ 22.8, 73.7, 123.8, 123.9, 149.3, 149.8, 152.7. MS (%) M at m/z 124.
Anal. Calcd. For C7H9NO: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.52; H, 7.49; N,
11.39.
7.8. 1-(4-pyridyl) propanol (13a):
1H NMR (200 MHz, CDCl3): δ 0.91 (3H, t, J = 7.1 Hz, CH2CH3), 1.59-
1.91 (2H, m, CH2CH3), 4.70 (1H, dd, J = 7.4, 4.7 Hz, CHOH), 7.34 (2H,
d, J = 5.8 Hz), 8.48 (2H, d, J = 5.8 Hz). 13
C NMR (50 MHz, CDCl3): δ
22.8, 73.7, 123.8, 123.9, 149.3, 149.8, 152.7. MS (%) M at m/z 138. Anal. Calcd. For
C8H11NO: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.52; H, 7.49; N, 11.39.
7.9. 1-(2-pyridyl) ethanol acetate (57):
1H NMR (200 MHz, CDCl3): δ 1.56 (3H, d, J = 6.5 Hz, CH3), 2.03
(3H, s, COCH3), 5.41 (1H, q, CHCH3), 7.27 (1H, dd, J = 7.4, 4.4 Hz),
7.36 (1H, d, J = 7.7 Hz), 7.66 (1H, dd, J = 7.4, 1.7 Hz), 8.63 (1H, d, J
= 4.9 Hz). 13
C NMR ( 50 MHz, CDCl3): δ 21.3, 23.1, 73.4, 120.3, 123.3, 136.4, 148.4,
162.3. MS (%) M at m/z 166. Anal. Calcd. For C9H11NO2: C, 65.44; H, 6.71; N, 8.48.
Found: C, 65.66; H, 7.01; N, 8.93.
7.10. 1-(2-pyridyl) propanol acetate (58):
1H NMR (200 MHz, CDCl3): δ 0.91 (3H, t, J = 7.4 Hz, CH2CH3), 1.98
(2H, m, CH2CH3), 2.13 (3H, s, 3H, COCH3), 5.72 (1H, t, J = 6.6 Hz,
CHCH2), 7.23 (2H, m), 7.67 (1H, dd, J = 7.7, 1.7 Hz), 8.59 (1H, d, J =
4.6 Hz). 13
C NMR ( 50 MHz, CDCl3): δ 9.5, 20.9, 27.7, 77.6, 120.9, 122.4, 136.6, 149.2,
159.3, 170.2. MS (%) M at m/z 180. Anal. Calcd. For C10H13NO2: C, 67.02; H, 7.31; N,
7.82. Found: C, 67.52; H, 7.89; N, 7.99.
OH
N
OH
N
O
ON
O
ON
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 177
7.11. 1-(2-pyridyl) propanol propionate (59):
1H NMR (200 MHz, CDCl3): δ 0.96 (3H, t, J = 7.7 Hz, CHCH2CH3),
1.14 (3H, t, J = 7.7 Hz, COCH2CH3), 1.90 (2H, m, CHCH2CH3), 2.28
(2H, q, J = 4.4 Hz, COCH2CH3), 5.82 (1H, t, J = 6.6 Hz, CHCH2), 7.26
(2H, m), 7.69 (1H, dd, J = 7.8, 1.8 Hz), 8.60 (1H, d, J = 4.6 Hz). 13
C NMR ( 50 MHz,
CDCl3): δ 7.9, 9.5, 27.9, 28.7, 77.1, 122.9, 123.4, 136.6, 149.0, 159.9, 171.2. MS (%) M
at m/z 194. Anal. Calcd. For C11H15NO2: C, 68.39; H, 7.82; N, 7.25. Found: C, 68.52; H,
7.96; N, 7.59.
7.12. 1-(2-pyridyl)-3-butene-1-ol acetate (60):
1H NMR (200 MHz, CDCl3): δ 2.08 (3H, s, COCH3), 2.51 & 2.66 (1H
each, m, CHCH2CH=), 4.29 (1H, br s, CHCH2CH=), 4.81 (1H, dd, J =
7.1, 4.9 Hz, CHCH2CH=), 5.08-5.13 (2H, m, CH=CH2), 7.19 (1H, dd, J
= 7.7, 4.7 Hz), 7.31 (1H, d, J = 7.7 Hz), 7.68 (1H, td, J = 7.7, 1.7 Hz), 8.52 (1H, d, J = 4.7
Hz). 13
C NMR (50 MHz, CDCl3): δ 21.0, 39.0, 75.6, 118.1, 121.1, 122.7, 133.0, 136.5,
149.3, 158.7, 170.2. MS (%) M at m/z 193. Anal. Calcd. For C11H13NO2: C, 69.09; H,
6.85; N, 7.32. Found: C, 70.42; H, 6.91; N, 7.87.
7.13. 2-phenyl-1-(pyridine-2-yl) ethanol acetate (61):
1H NMR (200 MHz, CDCl3): δ 2.07 (3H, s, COCH3), 2.92 (2H, m,
CHCH2), 6.04 (1H, dd, J = 6.7, 5.7 Hz, CHCH2), 7.11-7.25 (7H, m, 5xAr-
H & 2pyridyl protans), 7.63 (1H, dd, J = 7.7, 1.9 Hz), 8.63 (1H, d, J = 4.7
Hz). 13
C NMR (50 MHz, CDCl3): δ 20.0, 40.3, 120.9, 122.2, 125.8, 127.4,
128.7, 136.0, 136.2, 136.3, 148.2, 157.7, 169.5, 176.0. MS (%) M +Na at
m/z 265. Anal. Calcd. For C15H15NO2: C, 74.67; H, 6.27; N, 5.81. Found: C, 74.82; H,
6.79; N, 5.99.
7.14. 1-(3-pyridyl) ethanol acetate (62):
1H NMR (200 MHz, CDCl3): δ 1.56 (3H, d, J = 6.6 Hz, CHCH3), 2.08
(3H, s, COCH3), 5.90 (1H, q, J = 6.6 Hz, CHCH3), 7.28 (1H, dd, J =
7.9, 7.8 Hz), 7.67 (1H, d, J = 7.8 Hz), 8.54 (1H, d, J = 4.6 Hz), 8.62
O
ON
N
O
O
O
O
N
O
ON
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 178
(1H, d, J = 1.7 Hz). 13
C NMR (50 MHz, CDCl3): δ 21.4, 25.3, 67.5, 124.8, 132.4, 141.7,
148.0, 148.8, 165.5. MS (%) M at m/z 166. Anal. Calcd. For C9H11NO2: C, 65.44; H,
6.71; N, 8.48. Found: C, 65.62; H, 6.89; N, 8.79.
7.15. 1-(3-pyridyl) ethanol propionate (63):
1H NMR (200 MHz, CDCl3): δ 1.09 (3H, t, J = 7.4 Hz, CH2CH3), 1.53
(3H, d, J = 6.4 Hz, CHCH3), 2.11 (3H, q, J = 4.4 Hz, CH2CH3), 5.81
(1H, m, CHCH3), 7.25 (1H, dd, J = 7.6, 7.1 Hz), 7.64 (1H, d, J = 7.6
Hz), 8.54 (1H, d, J = 4.5 Hz), 8.66 (1H, d, J = 1.91 Hz). 13
C NMR (50 MHz, CDCl3): δ
9.4, 21.4, 27.3, 67.3, 124.7, 132.3, 140.7, 147.3, 147.8, 166.5. MS (%) M at m/z 180.
Anal. Calcd. For C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C, 67.62; H, 7.66; N,
8.11.
7.16. 1-(3-pyridyl) ethanol butyrate (64):
1H NMR (200 MHz, CDCl3): δ 0.93 (3H, t, J = 7.4 Hz, CH2CH3),
1.60 (5H, m, CH2CH2CH3 & CHCH3), 2.31 (2H, t, J = 5.7 Hz,
COCH2), 5.89 (1H, q, J = 6.7 Hz, CHCH3), 7.27 (1H, dd, J = 7.4,
7.3 Hz), 7.66 (1H, d, J = 7.6 Hz), 8.52 (1H, d, J = 4.5 Hz), 8.66 (1H, d, J = 2.0 Hz). 13
C
NMR (50 MHz, CDCl3): δ 9.4, 18.7, 27.3, 77.3, 123.4, 133.1, 140.1, 147.0, 147.8, 166.5.
MS (%) M at m/z 194. Anal. Calcd. For C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found:
C, 68.62; H, 7.56; N, 7.61.
7.17. 1-(3-pyridyl) propanol acetate (65):
1H NMR (200 MHz, CDCl3): δ 0.97 (3H, t, J = 7.1 Hz, CH2CH3),
2.03-2.14 (5H, m, CH2CH3 & COCH3), 5.45 (1H, m, CHCH2), 7.28
(1H, dd, J = 7.7, 7.4 Hz), 7.67 (1H, d, J = 7.8 Hz), 8.54 (1H, d, J = 4.6
Hz), 8.62 (1H, d, J = 1.7 Hz). 13
C NMR (50 MHz, CDCl3): δ 8.1, 21.3, 28.6, 79.3, 123.7,
135.3, 138.4, 148.1, 148.4, 166.5. MS (%) M at m/z 180. Anal. Calcd. For C10H13NO2:
C, 67.02; H, 7.31; N, 7.82. Found: C, 67.62; H, 7.99; N, 8.11.
O
O
N
O
ON
N
O
O
Section B: Chemo-enzymatic Approach for the Synthesis of.…………………………………. Chapter 3
Page 179
7.18. 1-(4-pyridyl) ethanol acetate (66):
1H NMR (200 MHz, CDCl3): δ 1.53 (3H, d, J = 6.5, CHCH3), 2.09
(3H, s, COCH3), 5.74 (1H, m, CHCH3), 7.34 (2H, d, J = 5.7 Hz), 8.60
(2H, d, J = 5.7 Hz). 13
C NMR (50 MHz, CDCl3): δ 22.8, 24.6, 73.9,
123.6, 123.9, 149.7, 149.9, 154.7. MS (%) M at m/z 166. Anal. Calcd. For C9H11NO2: C,
65.44; H, 6.71; N, 8.48. Found: C, 65.82; H, 6.99; N, 8.79.
7.19. 1-(4-pyridyl) propanol acetate (67):
1H NMR (200 MHz, CDCl3): δ 0.99 (3H, t, J = 7.1 Hz, CH2CH3),
2.03-2.14 (5H, m, CH2CH3 & COCH3), 5.74 (1H, m, CHCH2), 7.34
(2H, d, J = 5.7 Hz), 8.60 (2H, d, J = 5.7 Hz). 13
C NMR (50 MHz,
CDCl3): δ 22.8, 24.6, 73.9, 123.6, 123.9, 149.7, 149.9, 154.7. MS (%) M at m/z 180.
Anal. Calcd. For C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C, 67.71; H, 7.55; N,
7.94.
7.20. 1-(4-pyridyl) ethanol propionate (68):
1H NMR (200 MHz, CDCl3): δ 1.11 (3H, t, J = 5.4 Hz, CH2CH3),
1.71 (3H, d, J = 6.5 Hz, CHCH3), 2.25 (2H, q, J = 4.7 Hz, CH2CH3),
5.71 (1H, m, CHCH3), 7.31 (2H, d, J = 5.7 Hz), 8.65 (2H, d, J = 5.7
Hz). 13
C NMR (50 MHz, CDCl3): δ 9.9, 19.1, 28.3, 74.4, 123.4, 149.1, 152.3, 171.1. MS
(%) M at m/z 180. Anal. Calcd. For C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C,
67.81; H, 7.67; N, 7.97.
7.21. 1-(4-pyridyl) ethanol butyrate (69):
1H NMR (200 MHz, CDCl3): δ 0.96 (3H, t, J = 7.6 Hz,
CH2CH3), 1.45-1.61 (5H, m, CH2CH2CH3 & CHCH3), 2.33 (2H,
t, J = 5.7 Hz, COCH2), 5.89 (1H, q, J = 6.7 Hz, CHCH3), 7.34
(2H, d, J = 5.7 Hz), 8.60 (2H, d, J = 5.7 Hz). 13
C NMR (50 MHz, CDCl3): δ 13.5, 18.3,
19.3, 34.1, 123.3, 148.4, 149.4, 167.7. MS (%) M at m/z 194. Anal. Calcd. For
C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.82; H, 7.91; N, 7.71.
O
O
N
O
O
N
O
O
N
O
O
N
�
�
�
�
�
�
�