A versatile and efficient synthesis of (2S)-2-(hydroxymethyl)-N-Boc-2,3-dihydro-4-pyridone

Article abstract of DOI:10.1016/S0040-4039(03)00888-8

A versatile and efficient method for the preparation of (2S)-2-(hydroxymethyl)-N-Boc-2,3-dihydro-4-pyridone from L-(-)-phenylalanine 2 utilising the aromatic system as a masked β-keto aldehyde was developed. The key step in the sequence is an intramolecular cyclisation of 6 to give 2,3-dihydropyridin-4-ones.

Full text of DOI:10.1016/S0040-4039(03)00888-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4261–4263
A versatile and efficient synthesis of
(2S)-2-(hydroxymethyl)-N-Boc-2,3-dihydro-4-pyridoneꢀ
A. Shashidhar Kumar, B. Haritha and B. Venkateswara Rao*
Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 6 January 2003; revised 21 March 2003; accepted 4 April 2003
Abstract—A versatile and efficient method for the preparation of (2S)-2-(hydroxymethyl)-N-Boc-2,3-dihydro-4-pyridone from
-(−)-phenylalanine 2 utilising the aromatic system as a masked b-keto aldehyde was developed. The key step in the sequence is
an intramolecular cyclisation of 6 to give 2,3-dihydropyridin-4-ones. © 2003 Elsevier Science Ltd. All rights reserved.
L
2,3-Dihydro-4-pyridones and their N-acyl derivatives
are interesting building blocks for a large variety of
nitrogen-containing heterocycle syntheses. The amino-
enone moiety can be used in various reactions leading
to key intermediates and is also particularly useful in
the synthesis of biologically active compounds and
alkaloids.1 Therefore, some general methods for the
synthesis of chiral dihydropyridones have been
reported. Comins and co-workers synthesised dihydro-
4-pyridones with the use of organometallics and 1-acyl
pyridinium salts.2 Dallemagne et al. converted b-aryl-b-
amino acids to dihydropyridones via d-aryl-d-amino-b-
ketoketones and also by condensing the b-aryl-b-amino
acids with b-ketoesters.3 Another method involves the
reaction of aromatic imines with the Danishefsky’s
diene (hetero Diels–Alder reaction) in the presence of a
chiral catalyst to form dihydropyridin-4-ones.4
A
racemic synthesis of dihydropyridones by the condensa-
tion of a Schiff’s base with b-diketones has also been
reported.5 In particular the chiral dihydropyridones of
Type 1 (Scheme 1) have been utilised for the synthesis
of some chiral piperidine skeletal natural products e.g.
(+)-dienomycin C,2e (+)-deoxoprosopinine,2g and 1-
deoxynojirimycin.2d Herein we report a novel and sim-
ple method for the synthesis of 1 starting from
3-aryl-2-aminopropanol 4 (obtained from aryl amino
Scheme 1. Reagents and conditions: (a) AcCl, MeOH, reflux, 3 h, then (Boc)2O, Et3N, THF, 0°C–rt, 8 h, 95%; (b) LiCl, NaBH4,
EtOH, THF, 0°C–rt, 12 h, 82%; (c) Li, (100 equiv.)/liq. NH3, THF, −78°C, EtOH, 1 h; (d) O3, EtoAc, −78°C, 1.5 h, then H2,
Pd(OH)2 rt, 3 h; (e) PPTS/THF, −20°C, 1 h, 43% (overall yield for three steps).
ꢀ IICT Communication Number: 021206.
* Corresponding author. Fax: +91-40-27160512; e-mail: venky@iict.ap.nic.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00888-8

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A. Shashidhar Kumar et al. / Tetrahedron Letters 44 (2003) 4261–4263
acids) in three steps, using Birch reduction and
ozonolysis.6
Tetrahedron Lett. 1989, 30, 5053–5056; (k) Comins, D. L.;
Killpack, M. O.; Despagnet, E.; Zeller, E. Heterocycles
2002, 58, 505–519.
Compound 4 is commercially available and can also be
3. (a) Renault, O.; Guillon, J.; Dallemagne, P.; Rault, S.
Tetrahedron Lett. 2000, 41, 681–683; (b) Leflemme, N.;
Dallemagne, P.; Rault, S. Tetrahedron Lett. 2001, 42,
8997–8999.
easily prepared from -(−)-phenylalanine in three steps.
L
L
-(−)-phenylalanine 2 was converted to N-Boc-methyl
ester 3 in the presence of acetyl chloride and methanol
followed by treatment with (Boc)2O. The resultant ester
3 was reduced to alcohol 4 using LiBH4. Birch reduc-
tion of 4 gave the corresponding dihydro derivative 5
which on ozonolysis followed by quenching the resul-
tant ozonide with H2/Pd(OH)2 yielded the b-keto alde-
hyde 6. Compound 6 without isolation was subjected to
acid-catalysed cyclisation to give the dihydro-4-pyridi-
none 1.7
4. (a) Yuan, Y.; Li, X.; Ding, K. Org. Lett. 2002, 4, 3309–
3311; (b) Carruthers, W. Cycloaddition Reactions In
Organic Synthesis; Pergamon: Oxford, 1990; (c) Oppolzer,
W. In Comprehensive Organic Synthesis; Paquette, L. A.,
Ed.; Pergamon: Oxford, 1991; Vol. 5, p. 315; (d) Weinreb,
S. M. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Hetero Dienophile Addition to Dienes,
Pergamon: Oxford, 1991; Vol. 5, p. 401; (e) Waldmann, H.
Synthesis 1994, 535–551; (f) Collin, J.; Jaber, N.; Lannou,
M. I. Tetrahedron Lett. 2001, 42, 7405–7407; (g) Badorrey,
R.; Cativiela, C.; Diaz-de-villegas, M. D.; Galvez, J. A.
Tetrahedron 2002, 58, 341–354; (h) Avenoza, A.; Busto, J.
H.; Cativiela, F. C.; Peregrina, J. M.; Zurbano, M. M. J.
Org. Chem. 2002, 67, 598–601; (i) Badorrey, R.; Cativiela,
C.; Diaz-de-Villegas, M. D.; Galvez, J. A. Tetrahedron
Lett. 1997, 38, 2547–2550.
This method is novel and general in nature to obtain
the skeleton of a 2,3-dihydro-4-piperidinone, by using
an appropriate amino-aryl precursor.
Acknowledgements
5. (a) Sugiyama, N.; Yamamoto, M.; Kashima, C. Bull.
Chem. Soc. Jpn. 1970, 43, 901–904 and references cited
therein; (b) Leflemme, N.; Dallemagne, P.; Rault, S. Syn-
thesis 2002, 1740–1746.
A.S.K. thanks the CSIR, New Delhi for a research
fellowship (S.R.F.). One of the authors (B.H.) thanks
the UGC, New Delhi for financial assistance. We also
thank Dr. J. S. Yadav and Dr. G. V. M. Sharma for
their support and encouragement.
6. For Birch reduction and ozonolysis, see: (a) Rao, B. V.;
Rao, A. S. Synth. Commun. 1995, 25, 1531–1543; (b)
Birch, A. J.; Fitton, P.; Smith, D. C. C.; Steere, D. E.;
Stelfox, A. R. J. Chem. Soc. 1963, 2209–2216; (c) Kirkeno,
C. L.; White, J. D. J. Org. Chem. 1985, 50, 1316–1319; (d)
Bringmann, G. Liebigs Ann. Chem. 1985, 2105–2115; (e)
Evans, D. A.; Gauchet-prunet, J. A.; Carreira, E. M.;
Charette, A. B. J. Org. Chem. 1991, 56, 741–750; (f) Wipf,
P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558–559; (g)
Wipf, P.; Reeves, J. T. Chem. Commun. 2002, 2066–2067.
7. Typical experimental procedure: (2S)-2-(hydroxymethyl)-
N-(tert-butoxycarbonyl)-2,3-dihydro-4-pyridone, 1
References
1. (a) Coutts, R. T.; Scott, J. R. Can. J. Pharm. Sci. 1971, 6,
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R.; Hata, E.; Matsuki, T.; Kawanisi, M. J. Org. Chem.
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cycles 1985, 23, 831–834; (i) Natsume, M.; Utsunomiya, I.;
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2. (a) Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1986,
27, 4549–4552; (b) Comins, D. L.; Killpack, M. O. J. Am.
Chem. Soc. 1992, 114, 10972–10974; (c) Comins, D. L.;
Josef, S. P.; Goehring, R. R. J. Am. Chem. Soc. 1994, 116,
4719–4728; (d) Comins, D. L.; Fulp, A. B. Tetrahedron
Lett. 2001, 42, 6839–6841; (e) Comins, D. L.; Green, G.
M. Tetrahedron Lett. 1999, 40, 217–218; (f) Comins, D. L.;
Zeller, E. Tetrahedron Lett. 1991, 32, 5889–5892; (g)
Comins, D. L.; Sandelier, M. J.; Grillo, T. A. J. Org.
Chem. 2001, 66, 6829–6832; (h) Brown, J. D.; Foley, M.
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To a solution of lithium (5.57 g, 796.7 mmol) in liquid
ammonia (200 mL) at −78°C (cooling was maintained with
acetone/dry ice in a cold finger and cold bath) was added
N-Boc-phenylalaninol 4 (2.0 g, 7.96 mmol) in dry THF (15
mL). The acetone/dry ice bath was replaced by a CCl4/dry
ice bath and stirred for 2 h, after which time the reaction
mixture was cooled to −78°C. The blue solution was
stirred for 1 h and dry EtOH (10 mL) and solid NH4OAc
(5.0 g) was added and the reaction mixture was brought to
rt. After all the ammonia had evaporated the residue was
partitioned between EtOAc/H2O. The aqueous layer was
separated and extracted with EtOAc (2×20 mL) and the
combined organic layers were washed with brine (30 mL),
dried (Na2SO4) and concentrated in vacuo to afford N-
Boc-dihydro derivative 5 (2.54 g) as a colourless oil, which
was taken to the next step without any purification. (The
1
crude H NMR showed a 3:2 ratio of dihydroproduct 5 to
starting material 4, both compounds have the same Rf
value on TLC).
A dilute stream of ozone was passed into a solution of
crude N-Boc-dihydro derivative 5 (2.5 g) in EtOAc (25
mL) at −78°C for 1 h, the reaction mixture turned light
blue.

A. Shashidhar Kumar et al. / Tetrahedron Letters 44 (2003) 4261–4263
4263
The reaction mixture was brought to rt then flushed with
oxygen. To the solution was added Pd(OH)2 (0.018 g)
which was then stirred under a hydrogen atmosphere for
3 h. The reaction mixture was filtered through Celite and
concentrated to give N-Boc-b-ketoaldehyde 6 which was
immediately used in the next step.
To a solution of N-Boc-b-ketoaldehyde 6 in THF (20 mL)
at −20°C, PPTS (0.025 g) was added and the resulting
mixture stirred under nitrogen for 1 h. The reaction mix-
ture was poured onto an ice-cold solution of NaHCO3
and extracted with EtOAc (2×50 mL). The combined
organic extracts were washed with water (50 mL), brine
(20 mL), dried (Na2SO4), concentrated and purified by
column chromatography to afford 1 (0.54 g) as a syrup
and N-Boc-phenylalaninol 4 (0.59 g) was also recovered.
Based on recovery the overall yield for the three steps was
43%.
Spectral data for compound 1: [h]2D5=−26.96 (c 1.8,
CHCl3); IR (KBr, cm−1): 3477, 3256, 2915, 1730, 1599.4,
1
1469, 1342, 1289, 1216, 1146, 1071, 985, 858, 764, 630; H
NMR (200 MHz, CDCl3): l 1.56 (s, 9H), 2.57 (d, 1H,
J=21.3 Hz), 2.85 (dd, 1H, J=7.6, 21.3 Hz), 3.62–3.90 (m,
2H), 4.62–4.78 (m, 1H), 5.25 (d, 1H, J=7.6 Hz), 7.78 (d,
1H, J=7.6 Hz).; 13C NMR (75 MHz, CDCl3): l 27.98,
36.77, 53.79, 61.26, 83.83, 105.92, 142.65, 151.64, 192.95;
MS (m/z): 227 (M+), 171, 154, 127, 96, 86, 57, 41.