A facile synthesis of 5,6-dihydro-5-hydroxy-2(1H)-pyridone

Article abstract of DOI:10.1016/j.tetlet.2009.03.026

A short synthesis of 5,6-dihydro-5-hydroxy-2(1H)-pyridone was achieved from l-serine employing Horner-Emmons olefination as the key step.

Full text of DOI:10.1016/j.tetlet.2009.03.026

Tetrahedron Letters 50 (2009) 2440–2442
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Tetrahedron Letters
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A facile synthesis of 5,6-dihydro-5-hydroxy-2(1H)-pyridone
*
Puspesh K. Upadhyay, Rajendra Prasad, Menaka Pandey, Pradeep Kumar
Division of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A short synthesis of 5,6-dihydro-5-hydroxy-2(1H)-pyridone was achieved from L-serine employing Horn-
Received 27 January 2009
Revised 23 February 2009
Accepted 6 March 2009
Available online 11 March 2009
er–Emmons olefination as the key step.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Horner–Emmons olefination
Pyridone
L-serine
Z-selectivity
Alkaloids
HO
The 2(1H)-pyridone ring system and the corresponding dihydro
and tetrahydro derivatives are found abundantly in a wide variety
of naturally occurring alkaloids and novel synthetic biologically ac-
tive molecules.1 Heterocycles incorporating
a 2(1H)-pyridone
O
N
framework constitute an extensively studied class of compounds
owing to their diverse biological activities ranging from anti-HIV,
antibacterial and antifungal to free radical scavengers. Several 3-
amino-2-pyridinone acetamides act as thrombin inhibitors. Some
non-nucleoside-3-aminopyridin-2(1H)-ones have been reported
to exhibit HIV-1-specific reverse transcriptase inhibitory proper-
ties.2 In addition, dihydro and tetrahydro derivatives of 2(1H)-pyri-
done have been applied as scaffold for the construction of
constrained aminoacids,3 quinoline4a and isoquinoline4b deriva-
tives, indolizidine,4c quinolizidine alkaloids and polyhydroxylated
piperidines5,7 with important pharmaceutical activity.
Ph
O
(R)-pipermethystine
OH
OH
HO
HO
OH
O
OH
O
HO
N
H
O
N
H
N
H
1
(3R,4S,5S)-trihydroxy-2-piperidinone
(3R,4R,5S)-3,4,5-trihydroxy-2-piperidinone
5,6-Dihydro-5-hydroxy-2(1H)-pyridone alkaloid 1 has been iso-
lated from the whole plant of Piper sintenense which exhibits cyto-
toxicity against P-388, H-T-29 or A-549 cell lines in vitro.6 It is an
important building block for the synthesis of (R)-pipermethys-
tine1b and several other polyhydroxylated pyridones7 such as
(3R,4R,5S)-3,4,5-trihydroxy-piperidine-2-one and (3R,4S,5S)-3,4,5-
trihydroxy-piperidine-2-one (Fig. 1). Despite its apparent simple
structure, surprisingly there has been no report on the synthesis
of N-unsubstituted pyridone 1 except for a sole publication of its
S-enantiomer which has been synthesized by Herdeis et al. starting
Figure 1. Structures of 2-pyridone-derived alkaloids.
Nevertheless, there are few methods available in the literature
for preparing the chiral nonracemic N-substituted pyridone deriv-
atives starting from either achiral or chiral pool starting materials
and typically requiring a large number of synthetic steps.1
As a part of our research on the asymmetric synthesis of
hydroxylated piperidines,8 we became interested in developing a
route to 2-pyridone derivatives. Herein we wish to report a new
from D
-ribonolactone.6b
approach to 5,6-dihydro-5-hydroxy-2(1H)-pyridone from L-serine
using Horner–Emmons olefination as the key step.
As illustrated in Scheme 1, the synthesis of 1 commenced with
commercially available -serine as a chiral pool starting material.
Thus, -serine 2 was initially transformed into the diol ester 3 by
the reported procedure.9 Selective primary hydroxyl protection of
L
L
* Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629.
E-mail address: pk.tripathi@ncl.res.in (P. Kumar).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.026

P. K. Upadhyay et al. / Tetrahedron Letters 50 (2009) 2440–2442
2441
NH2
OH
OH
OH
a
HO
OH
b
N3
OMe
BocHN
OMe
O
HO
OMe
a
10
4
O
2
O
3
O
O
OTBDPS
OTBDPS
OH
OAc
c
d
BocHN
BocHN
OMe
N3
OMe
N3
OMe
OMe
c
b
12
11
4
O
O
O
5
TBDPSO
OAc
OAc
OTBDPS
O
d
f
e
BocHN
OMe
BocHN
OH
H2N
7
OMe
N
H
O
6
O
13
OAc
O
OAc
HO
BocHN
OMe
BocHN
+
OMe
e
9
8
O
N
E-isomer, 30%
O
Z-isomer, 40%
H
Scheme 1. Reagents and conditions: (a) NaNO2, aq H2SO4, 3 days, 100%; (b) (i) TsCl,
Bu2SnO, Et3N, CH2Cl2, 0 °C, 2 h, 75%; (ii) NaN3, DMF, 80 °C, 70%; (c) Ac2O, Et3N,
DMAP, CH2Cl2, 0 °C-rt, 3 h, 70%; (d) H2, Pd(OH)2/C, Boc2O, MeOH, 5 h, 75%; (e)
DIBAL-H, CH2Cl2, À78 °C, 2 h, 70%; (f) (i) IBX, EtOAc, reflux, 2 h; (ii) Ph3P@CHCO2Me,
MeOH, 0 °C, 24 h, 70%.
1
Scheme 2. Reagents and conditions: (a) H2, Pd(OH)2/C, Boc2O, MeOH, 5 h, 75%; (b)
TBDPS-Cl, imidazole, DMAP, CH2Cl2, 0 °C, 4 h, 80%; (c) (i) DIBAL-H, toluene, À78 °C,
2 h; (ii) (CH3–C6H4O)2–P(O)CH2CO2Me, NaH, À78 °C, THF, 5 h, 72%; (d) TMS-OTf,
2,6-lutidine, CH2Cl2, 0 °C, 5 h, then satd NaHCO3, 24 h, 55%; (e) TBAF, THF, 0 °C-rt,
12 h, 40%.
diol was performed with tosyl chloride in the presence of catalytic
amount of dibutyltin oxide10 followed by the nucleophilic dis-
placement of resulting tosylate with sodium azide to afford com-
pound 4 in 70% yield. The acylation of hydroxyl group (4?5)
followed by azide reduction in the presence of Boc2O under hydro-
genation conditions11 using Pd(OH)2/C furnished the desired ami-
no alcohol 6 in 75% yield. Subsequent reduction using 2 equiv of
DIBAL-H at À78 °C produced alcohol 7 in 70% yield. It may be noted
that we did not observe any cleavage of acetoxy group during DI-
BAL-H reduction. Oxidation of alcohol 7 with IBX followed by
two carbon Wittig olefination in MeOH12 at 0 °C resulted in a mix-
ture of both cis- and trans-isomers in the ratio 4:3. The ratio of de-
sired cis-isomer could not be improved even after performing the
reaction at lower temperature (Scheme 1).
for the erythro adduct due to the steric hindrance of the aryl group
and also silyloxy group at
a-position rather than the electronic
effect.13 The Boc group was deprotected under standard conditions
using TMS-OTf and 2,6-lutidine as base15 and subsequently neu-
tralized with saturated sodium bicarbonate solution to produce
the pyridone derivative 13 in 55% yield.6b,16 Finally, TBDPS group
was deprotected with tetrabutyl ammonium fluoride to furnish
25
the desired pyridone 1 as an oily compound in 40% yield, [
a]
+53.4 (c 0.23, MeOH); [lit.6a 26 +55.7 (c 0.2, MeOH)]. The spectral
[a]
data of pyridone 1 were in accord with those described in the
literature.6a
In conclusion, we have achieved a concise synthesis of 5, 6-
The poor yield obtained for cis-isomer could probably be attrib-
uted to the electron-withdrawing effect of acetoxy group. To cir-
cumvent the problem of low yield, we thought of masking the
hydroxyl group preferably with a bulky protecting group. Towards
this end, the azido compound was first reduced to amine in the
presence of Boc2O under hydrogenation conditions using
(Pd(OH)2/C) (4?10) followed by the hydroxyl group protection
with tert-butyldiphenylsilyl chloride in the presence of imidazole
to furnish compound 11 in 80% yield (Scheme 2). The ester group
was reduced with 1.2 equiv of DIBAL-H at À78 °C to the corre-
sponding aldehyde and subsequently subjected to two carbon
Wittig olefination in MeOH at À78 °C. However, we could not ob-
serve much improvement in the ratio of cis-isomer. With an aim
to prepare the required cis-compound, we then employed the
new Horner–Emmons reagent, diarylphosphonoacetate for the
highly selective synthesis of Z-unsaturated ester as reported by
Ando.13 Thus, the aldehyde obtained from 11 was treated with
Horner–Emmons reagent, methyl (ditolylphosphono) acetate to
produce the cis-olefin 1214 as the major isomer (98:2) as confirmed
from the 1H NMR spectroscopy of the crude product. The Z-selec-
tivity of the (diarylphosphono) acetate reagent is a result of kinetic
control and can be interpreted by the predominant formation of
erythro adduct which irreversibly collapses to the Z-olefin. This
could probably be attributed to the enhanced kinetic selectivity
dihydro-5-hydroxy-2(1H)-pyridone from L-serine in overall 5%
yield using Horner–Emmons olefination as the key step. The gener-
ality of method shown has significant potential of its further exten-
sion to the other isomer and also to the construction of variety of
materials derived from 2-pyridone derivatives. Currently studies
are in progress towards this direction.
Acknowledgements
P.K.U. thanks CSIR, New Delhi, for the award of a senior research
fellowship. We are grateful to Dr. Ganesh Pandey, Head, Organic
Division, NCL, for his encouragement. Financial support for funding
of the project (Grant No. SR/S1/OC-40/2003) from Department of
Science & Technology, New Delhi is gratefully acknowledged.
References and notes
1. (a) Paulvanan, K.; Chen, T. J. Org. Chem. 2000, 65, 6160; (b) Arrayas, R. G.;
Alcudia, A.; Liebeskind, L. S. Org. Lett. 2001, 3, 3381.
2. Yadav, L. D. S.; Kapoor, R. Synlett 2008, 2348.
3. (a) Hannesian, S.; Mcnaughton-Smith, G.; Lombart, H. G.; Lubell, W. D.
Tetrahedron 1997, 53, 12789; (b) Creswell, M. W.; Balton, G. L.; Hodges, J. C.;
Meppen, M. Tetrahedron 1998, 54, 3983; (c) Feng, Z.; Lubell, W. D. J. Org. Chem.
2001, 66, 1181; (d) Polyak, F.; Lubell, W. D. J. Org. Chem. 2001, 66, 1171.
4. (a) Fujita, R.; Watanabe, K.; Ikeura, W.; Ohtake, Y. H. Heterocycles 2000, 53,
2607; (b) Casamitjana, N.; Lopez, V.; Jorge, A.; Bosch, J.; Molins, E.; Roig, A.

2442
P. K. Upadhyay et al. / Tetrahedron Letters 50 (2009) 2440–2442
Tetrahedron 2000, 56, 4027; (c) Grundon, M. F. Nat. Prod. Rep. 1989, 6, 523; (d)
Elbein, A. D.; Molyneux, R. J. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, 1981; Vol. 5, pp 1–54.
10. Martinelli, M. J.; Vaidyanathan, R.; Pawlak, J. M.; Nayyar, N. K.; Dhokte, U. P.;
Doecke, C. W.; Zollars, L. M. H.; Moher, E. D.; Khau, V. V.; Komrlj, B. J. Am. Chem.
Soc. 2002, 124, 3578.
5. (a) Fodor, G. B.; Colasanti, B. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 3, pp 1–90; (b) Piro, J.;
Rubiralta, M.; Giralt, E.; Diez, A. Tetrahedron Lett. 1999, 40, 4865.
6. (a) Chen, J.-J.; Duh, C.-Y.; Huang, H.-Y.; Chen, I.-S. Helv. Chim. Acta 2003,
86, 2058; (b) Herdeis, C.; Waibel, D. Arch. Pharm. (Weinheim) 1991, 324,
269.
7. (a) Godskesen, M.; Lindt, I.; Madsen, R.; Wenchester, B. Bioorg. Med. Chem.
1996, 4, 1857; (b) Bouchez, V.; Stasik, I.; Beaupere, D.; Uzan, R. Tetrahedron
Lett. 1997, 38, 7733; (c) Noris, P.; Horton, D.; Levine, B. R. Tetrahedron Lett.
1995, 36, 7811; (d) Defoin, A.; Sarazin, H.; Sifferlen, T.; Strehler, C.; Streith,
J. Helv. Chim. Acta 1998, 81, 1417; (e) Hanessian, S. J. Org. Chem. 1964, 34,
675.
11. (a) Sakaitani, M.; Hori, K.; Ohfune, Y. Tetrahedron Lett. 1998, 29, 2983; (b) Saito,
S.; Nakajima, H.; Inaba, M.; Moriwake, T. Tetrahedron Lett. 1989, 30, 837.
12. Methanol has been used occasionally as a solvent in the Wittig reaction of
stabilized ylides to get Z-isomer, see: Valverde, S.; Martin-Lomas, M.
Tetrahedron 1987, 43, 1895. and references cited therein.
13. Ando, K. J. Org. Chem. 1997, 62, 1934.
14. Spectral data of 12: [a]
25 +1.4 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3) d: 1.09 (s,
9H), 1.42 (s, 9H), 3.30–3.47 (m, 2H), 3.55 (s, 3H), 4.81–4.91 (m, 1H), 5.59 (d,
J = 10.4 Hz, 1H), 6.12 (dd, J = 11.8 Hz, J = 8.1 Hz, 1H), 7.34–7.46 (m, 6H), 7.60–
7.71 (m, 4H); 13C NMR (50 MHz, CDCl3) d: 26.8, 28.2, 45.9, 51.7, 71.7, 79.2,
119.3, 127.4, 127.5, 127.6, 127.7, 129.7, 129.8, 129.9, 132.6, 132.8, 133.3, 133.4,
135.6, 135.6, 135.7, 135.8, 149.5, 155.7, 165.7.
8. (a) Pandey, S. K.; Kumar, P. Synlett 2007, 2894; (b) Pandey, S. K.; Kumar, P.
Tetrahedron Lett. 2005, 46, 4091; (c) Cherian, S. K.; Kumar, P. Tetrahedron:
Asymmetry 2007, 18, 982; (d) Kandula, S. V.; Kumar, P. Tetrahedron 2006, 62,
9942; (e) Kumar, P.; Bodas, M. S. J. Org. Chem. 2005, 70, 360; (f) Bodas, M. S.;
Upadhyay, P. K.; Kumar, P. Tetrahedron Lett. 2004, 45, 987.
9. Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.; Ohkawa, N.;
Sakoh, H.; Nishimura, K.; Tani, Y.; Hasegawa, M.; Yamada, K.; Saitoh, K. Chem.
Eur. J. 1999, 5, 121.
15. Lee, H. K.; Chun, J. S.; Pak, C. S. Tetrahedron 2003, 59, 6445.
25
16. Spectral data of 13. [
a
]
À62.4 (c 1.9, CHCl3); IR. m
max/cmÀ1 (CHCl3): 3290,
1628, 1614; 1H NMR (400 MHz CDCl3) d: 1.07 (s, 9H), 3.32 (dd, J = 12.5 Hz,
J = 2.7 Hz, 1H), 3.42 (dd, J = 12.6 Hz, J = 2.2 Hz, 1H), 4.43–4.50 (m, 1H), 5.83 (d,
J = 9.9 Hz, 1H), 6.43 (dd, J = 9.9 Hz, J = 3.2 Hz, 1H), 6.20 (s, 1H, NH), 7.38–7.48
(m, 6H), 7.64–7.67 (m, 4H); 13C NMR (50 MHz, CDCl3) d: 19.0, 19.3, 26.8, 47.0,
124.2, 127.9, 130.1, 133.0, 133.1, 135.7, 144.2, 165.5; Mass (LCMS): [M+ Na]+
374, 358, 306,280, 251, 221, 174.