Facile transformation of 3,4-disubstituted 2-azetidinones to chiral 5,6-dihydro-2-pyridones

Article abstract of DOI:10.1016/S0040-4039(01)00470-1

Chiral 5,6-disubstituted-5,6-dihydro-2(1H)-pyridones were prepared efficiently from readily accessible 3,4-disubstituted-2-azetidinones having preadjusted substituents and stereochemistry through the reductive ring opening of 2-azetidinones followed by Z-selective installation of acetate moiety and re-cyclization to 2-pyridones.

Full text of DOI:10.1016/S0040-4039(01)00470-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3483–3486
Facile transformation of 3,4-disubstituted 2-azetidinones to chiral
5,6-dihydro-2-pyridones
Hyeon Kyu Lee,* Jong Soo Chun and Chwang Siek Pak*
Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yusung,
Taejon 305-606, South Korea
Received 20 February 2001; revised 15 March 2001; accepted 21 March 2001
Abstract—Chiral 5,6-disubstituted-5,6-dihydro-2(1H)-pyridones were prepared efficiently from readily accessible 3,4-disubstituted-
2-azetidinones having preadjusted substituents and stereochemistry through the reductive ring opening of 2-azetidinones followed
by Z-selective installation of acetate moiety and re-cyclization to 2-pyridones. © 2001 Elsevier Science Ltd. All rights reserved.
A
number of alkaloids containing piperidine,
For the preparation of chiral 5,6-dihydro-2-pyridones
which can be served as valuable intermediates for aza-
sugars and other piperidine alkaloids, we envisaged that
two-carbon addition to 2-azetidinones will provide an
easy access to 5,6-dihydro-2-pyridones and 3,4,5,6-tetra-
hydro-2-pyridones having substitutents and stereo-
chemistry preadjusted at the 2-azetidinone stage. We
report herein our preliminary result on the facile syn-
thesis of 5,6-disubstituted-5,6-dihydro-2(1H)-pyridones
and 3,4,5,6-tetrahydro-2(1H)-pyridones from readily
available 3,4-disubstituted-2-azetidinones through the
reductive ring opening of 2-azetidinones followed by
Z-selective installation of acetate moiety and re-cycliza-
tion to 2-pyridones (Scheme 1).
indolizidine ring system and polyhydroxylated piperidi-
nes (azasugars) are found frequently in nature and
many of these alkaloids display a wide range of inter-
esting biological activity.1,2 As a result of such interests,
these alkaloids have become important synthetic
targets.3
The 2-azetidinone (b-lactam) skeleton is well known as
the key structural element of the most widely employed
class of antibacterial agents, the b-lactam antibiotics.4
As a consequence, diverse methods for practical and
stereoselective ring formation of 2-azetidinone have
been developed.5 With a plethora of methods for the
synthesis of 2-azetidinone available, applications of 2-
azetidinones as efficient chiral synthons for other
classes of molecules have been subjected to many inves-
tigations.6 For example, transformations of 2-azetidi-
nones by external reagents to nonproteogenic amino
acids and peptides6d and ring expansion of 2-azetidi-
nones by internal or external nucleophiles to 2-
pyrrolidinones6c were reported. However, to our
knowledge, there was no report for the preparation of
5,6-dihydro-2-pyridones from 2-azetidinones.
The requisite optically pure 2-azetidinones were easily
prepared from Bose–Manhas b-lactam 17 as described
in Scheme 2. trans-N-PMP-4-Formyl-2-azetidinone 2b
was prepared from the cis-N-PMP-4-formyl-2-azetidi-
none 2a8 by regiospecific C4-epimerization with
dimethylamine as reported.9
Transformation of cis-N-Boc-2-azetidinone 6a to 5,6-
dihydro-2-pyridones 10a was effected via a two-carbon
R1
R2
R1
R2
R1
R2
R1
R2
NHBoc
O
NHBoc
N
O
N
H
H
O
Boc
CO2Me
Scheme 1.
Keywords: azetidinones; pyridones; piperidines.
* Corresponding authors.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00470-1

3484
H. K. Lee et al. / Tetrahedron Letters 42 (2001) 3483–3486
O
O
BnO
O
BnO
O
CHO
PMP
CHO
PMP
BnO
R
BnO
O
R
a
b
c
c
N
N
N
N
PMP
O
PMP
R
Boc
R
2a
6a
4a
1
d
BnO
BnO
BnO
O
b
N
N
N
O
PMP
O
Boc
4b
2b
6b
R=CH2OTBDPS, PMP=4-Methoxyphenyl
Scheme 2. (a) TsOH, THF–H2O, heat, 12 h; NaIO4, MeOH–THF–H2O, rt, 12 h (90%); (b) NaBH4, MeOH, 0°C, 2 h; TBDPSCl,
imidazole, DMF, rt, 24 h; (4a: 90%, 4b: 81%); (c) (NH4)2Ce(NO3)6, CH3CN–H2O, 0°C, 30 min; (Boc)2O, cat. DMAP, CH3CN,
4 h (6a: 82%, 6b: 66%); (d) 40% aq. (CH3)2NH, benzene, rt, 48 h, (96%).
addition reaction, as shown in Scheme 3. Thus, 6a was
reduced to 3-N-Boc-amino alcohol 7a almost quantita-
tively by LiAlH4 in THF at 0°C for 20 min. Oxidation
of 3-N-Boc-amino alcohol 7a by IBX (2-iodoxybenzoic
acid)10 in DMSO for 3 h at rt cleanly produced highly
pure 3-N-Boc-amino aldehyde 8a and it was used in the
next step without further purification. Aldehyde 8a was
dissolved in dry MeOH11,12 and treated with methyl
(triphenylphosphoranylidene)acetate at rt to give a 7:1
mixture of Z-a,b-unsaturated ester 9a as the major
product and its E-isomer in 81% overall yield from 7a.
These two isomers were easily separated by flash chro-
matography and identified by chemical shifts and cou-
pling constants of olefinic protons [6.28 ppm (dd,
J=11.8, 8.9 Hz) and 5.99 ppm (dd, J=11.8, 1.0 Hz) for
the Z-isomer of 9a, and 6.96 ppm (dd, J=15.8, 5.1 Hz)
and 6.08 ppm (dd, J=15.8, 1.2 Hz) for the E-isomer of
9a]. Finally, Z-N-Boc amino ester 9a was subjected to
removal of N-Boc protection under mild conditions
(TMSOTf, 2,6-lutidine, CH2Cl2, 0°C, 1 h)13 and in turn
cyclized with catalytic DMAP in toluene to give the
desired 5,6-cis-disubstituted-5,6-dihydro-2(1H)-pyri-
BnO R1
R2
BnO R1 R2
R
BnO
HO
1R2
a
b
O
NHBoc
8a,b
N
NHBoc
O
Boc
H
7a,b
9a,b
6a,b
R
1R2
BnO
OBn
R1
d
c
NHBoc
O
N
H
R2
CO2Me
10a,b
a(cis): R1=H, R2=CH2OTBDPS
b(trans): R1=CH2OTBDPS, R2=H
Scheme 3. (a) LiAlH4, THF, 0°C, 30 min, (7a: 87%, 7b: 95%); (b) IBX, DMSO, rt, 3 h, (8a: 93%, 8b: 95%); (c) Ph3PꢀCHCO2Me,
MeOH, rt, 12 h, (9a: 87%, E:Z=1:7, 9b: 81%, E:Z=1:4); (d) TMSOTf, 2,6-lutidine, CH2Cl2, 0°C, 1 h, then cat. DMAP, toluene,
reflux, 1 h, (10a: 95%, 10b: 89%).
BnO
O
OTBDPS
a
BnO
HO
OTBDPS
BnO
OTBDPS
b
c
N
NHCbz
O
NHCbz
Cbz
H
11
12
13
BnO
OTBDPS
d
OBn
OBn
OTBDPS
d
NH
Cbz
O
N
H
OTBDPS
O
N
H
10a
MeO2C
15
14
Scheme 4. (a) NaBH4, MeOH, 0°C, 2 h, (90%); (b) IBX, DMSO, rt, 3 h, (89%); (c) Ph3PꢀCHCO2Me, benzene, reflux, 5 h, (88%,
E:Z=11:1); (d) H2–Pd/C, EtOAc, rt, 12 h (96%).

H. K. Lee et al. / Tetrahedron Letters 42 (2001) 3483–3486
3485
done 10a14 in excellent yield from 9a. 5,6-trans-Disub-
stituted-5,6-dihydro-2(1H)-pyridone 10b was also pre-
pared from 3,4-trans-N-Boc-2-azetidinone 6b through
essentially the same procedure for 6a to 10a.14
VCH: Weinheim, 1998; (b) Sears, P.; Wong, C. H.
Angew. Chem., Int. Ed. 1999, 38, 2300; (c) Jacob, G. S.
Curr. Opin. Struct. Biol. 1995, 5, 605; (d) Hughes, A. B.;
Rudge, A. J. Nat. Prod. Rep. 1994, 11, 135.
3. For some representative examples of previous work, see:
(a) Mehta, G.; Mohal, N. Tetrahedron Lett. 2000, 41,
5741; (b) Sun, H.; Millar, K. M.; Yang, J.; Abboud, K.;
Horenstein, B. A. Tetrahedron Lett. 2000, 41, 2801; (c)
Ma, D.; Sun, H. Org. Lett. 2000, 2, 2503; (d) Yokoyama,
H.; Otaya, K.; Kobayashi, H.; Miyazawa, M.;
Yamaguchi, S.; Hirai, Y. Org. Lett. 2000, 2, 2427; (e)
Davis, F. A.; Chao, B.; Fang, T.; Szewczyk, J. M. Org.
Lett. 2000, 2, 1041; (f) Bailey, P. D.; Millwood, P. A.;
Smith. P. D. J. Chem. Soc., Chem. Commun. 1998, 633;
(g) Yoda, H.; Kawauchi, M.; Takabe, K. Synlett 1998,
137; (h) Goti, A.; Cardona, F.; Brandi, A. Synlett 1996,
761; (i) Toyooka, N.; Yoshida, Y.; Momose, T. Tetra-
hedron Lett. 1995, 36, 3715; (j) Altenbach, H.-J.; Him-
meldirk, K. Tetrahedron: Asymmmetry 1995, 6, 1077; (k)
Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1995, 60, 398; (l) Cook, G. R.; Beholz, L. G.;
Stille, J. R. J. Org. Chem. 1994, 59, 3575; (m) Casiraghi,
G.; Rassu, G.; Spanu, P.; Pinna, L.; Ulgheri, F. J. Org.
Chem. 1993, 58, 3397.
Next we investigated the synthesis of 3,4,5,6-tetra-
hydro-2(1H)-pyridone 15. Although hydrogenation of
5,6-cis-disubstituted-5,6-dihydro-2(1H)-pyridone
10a
under Pd/C catalyst afforded 3,4,5,6-tetrahydro-2(1H)-
pyridone 15, we have found more efficient synthetic
route to 3,4,5,6-tetrahydro-2(1H)-pyridone 15 from N-
Cbz-2-azetidinone 11 as shown in Scheme 4.
Thus, N-Cbz-2-azetidinone 11 was converted to 3-N-
Cbz-amino aldehyde 13 via 3-N-Cbz-amino alcohol 12
and treatment of methyl (triphenylphosphoranyli-
dene)acetate in MeOH or benzene afforded 5-N-Cbz
amino-Z- or E-2,3-unsaturated ester 14. Hydrogena-
tion of unsaturated ester 14 in the presence of Pd/C
catalyst for saturation of olefininc bond and removal of
N-Cbz group produced directly 3,4,5,6-tetrahydro-
2(1H)-pyridone 1514 with concomitant cyclization of
intermediate 5-amino ester in excellent yields. The
efficiency of the steps employed in the present work as
well as easy access of starting chiral 2-azetidinones with
different substitutents would provide a new efficient
method for various chiral 5,6-dihydro-2-pyridones and
3,4,5,6-tetrahydro-2-pyridones. The application of the
present work to the preparation of various piperidine
and indolizidine alkaloids and azasugars are underway
and will be reported in due course.
4. For some reviews on b-lactam antibiotics, see: (a) Chem-
istry and Biology of i-Lactam Antibiotics; Morin, R. B.;
Gorman, M., Eds.; Academic Press: New York, 1982;
Vol. 1–3; (b) Recent Advances in the Chemistry of i-Lac-
tam Antibiotics; Brown, A. G., Roberts, S. M., Eds.; The
Royal Society of Chemistry: Burling House, London,
1984; (c) The Chemistry of i-Lactams; Page, M. I., Ed.;
Chapman and Hall: London, 1992.
In summary, we have developed an efficient method for
the synthesis of chiral 5,6-dihydro-2(1H)-pyridones and
3,4,5,6-tetrahydro-2(1H)-pyridones which can be served
as valuable chiral intermediates for different piperidine
and indolizidine alkaloids and azasugars from easily
accessible 2-azetidinones having preadjusted sub-
stituents and stereochemistry through the reductive ring
opening of 2-azetidinones followed by Z-selective
installation of acetate moiety and re-cyclization to 2-
pyridones.
5. (a) Georg, G. I.; Rabikumar, V. T. In The Organic
Chemistry of i-Lactams; Georg, G. I., Ed.; VCH: New
York, 1992; p. 295; (b) Hart, D. J.; Ha, D. C. Chem. Rev.
1989, 89, 1447.
6. (a) Ojima, I. In The Organic Chemistry of i-Lactams;
Georg, G. I., Ed.; VCH: New York, 1992; p. 197; (b)
Palomo, C.; Aizpurua, J. M.; Ganboa, I. In Enantioselec-
tive Synthesis of i-Amino Acids; Juaristi, E., Ed.; Wiley-
VCH: New York, 1997; p. 279; (c) Ha, D.-C.; Kang, S.;
Chung, C.-M.; Lim, H.-K. Tetrahedron Lett. 1998, 39,
7541; (d) Ojima, I. Acc. Chem. Res. 1995, 28, 383; (e)
Palomo, C.; Cossio, F. P.; Cuevas, C.; Odriozola, J. M.;
Ontoria, J. M. Tetrahedron Lett. 1992, 33, 4827; (f)
Manhas, M. S.; Wagle, D. R.; Chiang, J.; Bose, A. K.
Heterocycles 1988, 27, 1755.
7. Wagle, D. R.; Garai, C.; Chiang, J.; Monteleone, M. G.;
Kurys, B. E.; Strohmeyer, T. W.; Hegde, V. R.; Manhas,
M. S.; Bose, A. K. J. Org. Chem. 1988, 53, 4227.
8. Alcaide, B.; Martin-Cantalejo, Y.; Perez-Castells, J.;
Sierra, M. A. J. Org. Chem. 1996, 61, 9156.
9. Alcaide, B.; Aly, M. F.; Rodriguez-Vicente, A. Tetra-
hedron Lett. 1998, 39, 5865.
10. Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano,
G. J. Org. Chem. 1995, 60, 7272.
11. Sanchez-Sancho, F.; Valverde, S.; Herradon, B. Tetra-
hedron: Asymmetry 1996, 7, 3209.
12. Recently, the highly Z-selective Honer–Wadsworth–
Emmons reaction of aldehyde was also reported: Ando,
K. J. Org. Chem. 1998, 63, 8411.
Acknowledgements
We would like to thank the Ministry of Science and
Technology of Korea for financial support.
References
1. For piperidine and indolizidine alkaloids, see: (a) Elbein,
A. D.; Molyneux, R. In Alkaloids; Chemical and Biologi-
cal Perspectives; Pelletier, S. W., Ed.; John Wiley and
Sons: New York, 1987; Vol. 5; (b) Michael, J. P. Nat.
Prod. Rep. 1999, 16, 675; (c) O’Hagen, D. Nat. Prod.
Rep. 1997, 14, 637; (d) Michael, J. P. Nat. Prod. Rep.
1997, 14, 619.
2. For polyhydroxylated piperidines (azasugars), see: (a)
Stutz, A. E. Iminosugars as Glycosidase Inhibiyors; Wiley-
13. Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.

3486
H. K. Lee et al. / Tetrahedron Letters 42 (2001) 3483–3486
14. Compound 10a: [h]D22=+109.2° (c=1.31, CHCl3); IR
(NaCl): w 3220, 1684, 1618, 1112 cm−1 1H NMR (300
Hz), 3.76 (m, 2H), 3.72 (d, 1H, J=4.5 Hz), 1.05 (s, 9H);
13C NMR (125 MHz, CDCl3): l 164.47, 145.72, 140.09,
137.07, 135.52, 132.62, 130.14, 128.50, 127.88, 127.78,
127.71, 124.94, 71.16, 70.79, 56.09, 26.82, 19.14; HRMS
calcd for C29H33NO3Si 472.2307 (MH+), found 472.2314.
Compound 15: [h]2D2 +7.9° (c, 0.503, CHCl3); IR (NaCl):
w 3205, 1668, 1471, 1439, 1113 cm−1; 1H NMR (300 MHz,
CDCl3): l 7.66–7.60 (m, 5H), 7.50–7.06 (m, 10H), 6.02 (s,
1H), 4.53 (d, 1H, J=12 Hz), 4.30 (d, 1H, J=11.8 Hz),
3.73–3.66 (m, 3H), 3.62–3.56 (m, 1H), 2.51 (dd, 1H,
J=6.3, 11.6 Hz), 2.39 (dd, 1H, J=2.8, 6.3 Hz), 1.82–1.72
(m, 2H), 1.05 (s, 9H); 13C NMR (125 MHz, CDCl3): l
171.17, 137.66, 135.51, 135.47, 132.92, 132.73, 129.88,
128.36, 128.02, 127.84, 127.80, 127.71, 127.37, 70.33,
69.71, 64.50, 58.04, 57.92, 26.79, 23.42, 19.13; HRMS
calcd for C29H35NO3Si 474.2464 (MH+), found 474.2474.
;
MHz, CDCl3): l 7.65 (m, 5H), 7.26 (m, 10H), 6.61 (dd,
1H, J=4.4 Hz), 6.06 (d, 1H, J=9.8 Hz), 6.03 (br s, 1H),
4.50 (d, 1H, J=11.7 Hz), 4.40 (d, 1H, J=11.7 Hz), 4.07
(t, 1H), 3.95 (t, 1H), 3.85 (dd, 1H, J=4.4, 10.2 Hz), 3.75
(m, 1H), 1.08 (s, 9H); 13C NMR (125 MHz, CDCl3): l
164.54, 138.73, 137.28, 135.41, 132.77, 129.83, 128.33,
127.78, 127.53, 127.06, 70.84, 68.06, 62.50, 60.26, 55.81,
26.71, 19.05, 14.09; HRMS calcd for C29H33NO3Si
472.2307 (MH+), found 472.2331. Compound 10b: [h]2D2=
+34.68° (c=1.13, CHCl3); IR (NaCl): w 3213, 1686, 1620,
1
1112 cm−1; H NMR (300 MHz, CDCl3): l 7.60 (m, 5H),
7.26 (m, 10H), 6.57 (dd, 1H, J=2.8, 10.2 Hz), 5.95 (dd,
1H, J=1.6, 9.9 Hz), 5.74 (br s, 1H), 4.58 (d, 1H, J=11.8
Hz), 4.43 (d, 1H, J=11.6 Hz), 4.09 (t, 1H, J=2.8, 4.5
.
.