An unusual synthesis of 2-pyridone and 3,5-dihydroxypyridine from a carbohydrate

Article abstract of DOI:10.1016/j.tetlet.2013.03.083

An unusual aromatization to perbenzylated 3,5-dihydroxy-6-(hydroxymethyl)- 2-pyridone was demonstrated utilizing sugar lactam, under strong basic conditions, derived from d-Galactose. 2-Pyridone was efficiently converted into a pharmaceutically relevant s

Full text of DOI:10.1016/j.tetlet.2013.03.083

Accepted Manuscript
An unusual synthesis of 2-pyridone and 3,5-dihydroxypyridine from a carbo‐
hydrate
Jaggaiah N. Gorantla, Divya Kovval, Ravi S. Lankalapalli
PII:
S0040-4039(13)00486-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.03.083
TETL 42709
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
19 January 2013
6 March 2013
12 March 2013
Please cite this article as: Gorantla, J.N., Kovval, D., Lankalapalli, R.S., An unusual synthesis of 2-pyridone and
3,5-dihydroxypyridine from a carbohydrate, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.03.083
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An unusual synthesis of 2-pyridone and 3,5-dihydroxypyridine from a
carbohydrate
Jaggaiah N. Gorantla, Divya Kovval, Ravi S. Lankalapalli*
Agroprocessing and Natural Products Division,
National Institute for Interdisciplinary Science
Thiruvananthapuram-695019, Kerala, India
&
Technology (NIIST), CSIR,
* Corresponding author:
Dr. Ravi S. Lankalapalli,
Agroprocessing and Natural Product Division,
NIIST, CSIR, Thiruvananthapuram-695019, Kerala, India.
Phone: 91-471-2515353; Fax: 91-471-2491795,
E-mail: ravishankar@niist.res.in
Abstract
An unusual aromatization to perbenzylated 3,5-dihydroxy-6-(hydroxymethyl)-2-pyridone was
demonstrated utilizing sugar lactam, under strong basic conditions, derived from D-Galactose. 2-
Pyridone was efficiently converted to a pharmaceutically relevant structure 3,5-dihydroxy
pyridine salt to demonstrate its synthetic utility. This result is the first report for 2-pyridone
synthesis from a carbohydrate, and also first of its kind for a novel 3,5-dihydroxypyridine.
Keywords: 2-Pyridone; 3,5-Dihydroxypyridine.

Among the heteroaromatic rings 2-pyridone plays a pivotal role as a privileged scaffold in drug
design due to its inherent amide functionality which serves as a peptidomimetic backbone.
Several derivatives of 2-pyridone are associated with diverse biological activities.1-7 2-Pyridone
is a core structure in the well-known anticancer agent camptothecin (Figure 1) isolated from
Chinese plant Camptotheca acuminate.8 Structural modification of camptothecin resulted in
derivatives irinotecan and topotecan which are used in treating colorectal and ovarian cancer.9 To
date, several synthetic strategies have been developed to construct 2-pyridone scaffold.4, 10-14 An
equally important scaffold is 3-hydroxypyridine which is present in diverse bioactive substances
like pyridoxin (vitamin B6), orellanine,15 fumonisin16 (Figure 1). Few of the recent significant
contributions involving development of novel methods in 3-hydroxypyridine synthesis includes
usage of α,α-dicyanoalkenes in a hetero Diels-Alder reaction with 1-aza-dienes,17 from δ-diazo
oxime ethers using dirhodium complex,18 and from ring-closing olefin metathesis reaction of
nitrogen containing dienes.19
Figure 1. Bioactive natural substances containing 2-pyridone and 3-hydroxypyridine rings.
In our endeavor to synthesize aza-sugars involving D-Galactose, a key intermediate lactam 6
(Scheme 2) was envisaged to undergo E2 eliminations under strong basic conditions.

Surprisingly, treatment of lactam 6 with potassium hydroxide under reflux conditions resulted in
a stable aromatized structure 2-pyridone 7. Thus, in the present work we have developed a new
method for an expedient synthesis of polyhydroxylated 2-pyridone, 7, from a carbohydrate as the
starting material and utilizing it we have also synthesized a novel 3,5-dihydroxypyridine.
D-Galactose was initially treated with allyl alcohol in presence of an acidic resin and the
resulting 1-O-allyl galactose 1 was perbenzylated using benzyl bromide to afford protected D-
galactose 2 (Scheme 1). Deprotection of allyl group using t-BuOK afforded lactol 3 which was
converted to lactone 4 under Dess-Martin periodinane conditions.
t
2
2
Scheme 1. Synthesis of lactone 4 from D-galactose.
Lactone 4 was conveniently converted to lactam 6 (Scheme 2) using conditions described by
Overkleeft et al.20 Treatment of lactone 4 with 7 N NH3 in MeOH afforded the ring-opening
product 5 which was oxidized without purification under Dess-Martin conditions to afford the
ketone which instantaneously cyclizes to an epimeric mixture of lactam 6. Lactam epimers 6
were then treated under reflux in presence of potassium hydroxide to afford 2-pyridone 7.

3
2
2
2
2
2
Scheme 2. Synthesis of benzyl protected 2-pyridone 7
The mechanistic rationale behind 2-pyridone formation involves E2, E1cb eliminations
(Scheme 3). Initial E2 elimination reaction affords dihydro-2-pyridone which undergoes facile
E1cb elimination due to the presence of C3 α-acidic proton and also owing to attainment of ring
stability driven by aromatization providing 2-pyridone 7.
-
-
Scheme 3. Possible mechanism for formation of 7 by E2, E1cb eliminations

A clear distinction can be observed in the 1H-NMR spectra by comparison of lactam epimers 6
with complex signal pattern to reduced complexity in 2-pyridone 7 (see Supplementary Data).
The appearance of benzylic protons as distinct singlets in 7 is indicative of the flat structure of
the molecule.
To demonstrate the synthetic utility of 2-pyridone 7, it was converted to a pyridine derivative
conveniently resulting in 2-alkoxy-3,5-dihydroxy pyridine salt 9 (Scheme 4). Treatment of 7
with butyl bromide in presence of cesium carbonate afforded 2-O-alkylated product 8a as
verified from 13C NMR which indicates disappearance of carbonyl peak at δ157 ppm in
compound 7. This result is in contrast to the thermodynamically more stable N-substituted
pyridone product.21 Attempts to remove benzyl protective groups under Pd/H2 in ethanol resulted
in a complex mixture with no trace of the expected pyridine derivative. Surprisingly, when the
same reaction was conducted by addition of a drop conc. HCl it resulted in cleavage of benzyl
protections along with a loss of the primary hydroxyl group to afford 3,5-dihydroxypyridine salt
9a.22 This is the first report towards synthesis of 3,5-dihydroxypyridine providing access to a
second hydroxyl group to the well known privileged structural motif 3-hydroxypyridine. To
demonstrate the substrate scope of this transformation different alkyl halides were converted to
pyridine derivatives 8b-g in moderate to good yields. Subsequently, they were converted to 3,5-
dihydroxypyridine salts 9b-g in a quantitative yield.
Scheme 4. Synthesis of 3,5-dihydroxypyridine salts 9a-g

In summary, we have developed a new route demonstrating synthesis of pyridine derivatives
(9a-g) from a carbohydrate. This is also the first report typifying synthesis of 3,5-
dihydroxypyridine and attempts pertaining to diversification along its core to produce synthetic
libraries of biological interest is underway in our laboratory.
Acknowledgements
Financial support from Department of Science & Technology (DST), India, grant SR/FT/CS-
45/2010 is gratefully acknowledged. We thank Mr. Manoj M. Kushwaha of Thermo Fisher
Scientific India Pvt. Ltd., Mumbai for providing HR-ESI-MS analysis.
Supplementary Data
Supplementary data associated with this article can be found, in the online version, at
http://www.journals.elsevier.com/tetrahedron-letters/.
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