Unprecedented oxidation of a phenylglycinol-derived 2-pyridone: Enantioselective synthesis of polyhydroxypiperidines

Article abstract of DOI:10.1021/ol016418z

Equation presented The phenylglycinol-derived 2-pyridone 1 undergoes m-CPBA oxidation steroselectively leading to the chiral nonracemic unsaturated bicyclic hydroxylactam 2, from which the enantioselective synthesis of (3R,5R)-3,4,5-trihydroxypiperidine (16) and the formal synthesis of the azasugar epiisofagomine are described. The enantioselective synthesis of (S)-N-Boc-3-hydroxypiperidine and (3R,4S)-3,4-dihydroxypiperidine is also reported.

Full text of DOI:10.1021/ol016418z

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3257-3260
Unprecedented Oxidation of a
Phenylglycinol-Derived 2-Pyridone:
Enantioselective Synthesis of
Polyhydroxypiperidines
,†
Mercedes Amat,* Nu´ria Llor,† Marta Huguet,† Elies Molins,‡
Enrique Espinosa,‡ and Joan Bosch†
Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of Barcelona,
08028-Barcelona, Spain, and Institut de Cie`ncia de Materials (CSIC), Campus UAB,
08193-Cerdanyola, Spain
amat@farmacia.far.ub.es
Received July 10, 2001 (Revised Manuscript Received September 7, 2001)
ABSTRACT
The phenylglycinol-derived 2-pyridone 1 undergoes m-CPBA oxidation steroselectively leading to the chiral nonracemic unsaturated bicyclic
hydroxylactam 2, from which the enantioselective synthesis of (3R,5R)-3,4,5-trihydroxypiperidine (16) and the formal synthesis of the azasugar
epiisofagomine are described. The enantioselective synthesis of (S)-N-Boc-3-hydroxypiperidine and (3R,4S)-3,4-dihydroxypiperidine is also
reported.
Both naturally occurring (e.g., deoxynojirimycin, fagomine)
and synthetic (e.g., miglitol, epiisofagomine) polyhydroxy-
lated piperidines, pyrrolidines, and indolizidines1 have been
shown to be specific and potent inhibitors of glycosidases2
and have been demonstrated to have a great potential as drugs
to treat a variety of carbohydrate-mediated diseases such as
diabetes,3 viral infections including HIV,4 and cancer me-
tastasis5 (Figure 1). As a consequence, in recent years there
has been a great deal of interest not only in the synthesis of
the natural products themselves but also in that of chemically
modified analogues. However, most of the methodologies
described for the synthesis of these compounds, which can
be regarded as azasugars (also called iminosugars), start from
carbohydrates and, in general, require a large number of steps
to reach a specific target. Thus, the development of new
methods for the enantioselective synthesis of polyhydroxy-
lated piperidines constitutes an area of current interest.6
† University of Barcelona.
‡ Institut de Cie`ncia de Materials.
(1) (a) Nash, R. J.; Watson, A. A.; Asano, N. In Alkaloids: Chemical
and Biological PerspectiVes; Pelletier, S. W., Ed.; Elsevier: Oxford, 1996;
Vol. 11, pp 345-376. (b) Elbein, A. D.; Molyneux, R. J. In ComprehensiVe
Natural Products; Barton, D., Nakanishi, K., Eds.; Elsevier: New York,
1999; Vol. 3, pp 129-160.
(2) (a) Bols, M. Acc. Chem. Res. 1998, 31, 1. (b) Iminosugars as
Glycosidase Inhibitors. Nojirimicin and Beyond; Stu¨tz, A. E., Ed.; Wiley-
VCH: Weinheim, 1999.
(3) (a) Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N.; Matsui,
K. J. Med. Chem. 1986, 29, 1038. (b) Drugs Future 1986, 11, 1039; 1987,
12, 1157. (c) Robinson, K. M.; Begovic, M. E.; Reinhart, B. L.; Heineke,
E. W.; Ducep, J.-B.; Kastner, P. R.; Marshall, F. N.; Danzin, C. Diabetes
1991, 40, 825.
Figure 1. Natural and synthetic azasugars as glycosidase inhibitors.
10.1021/ol016418z CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/20/2001

The potential of chiral nonracemic bicyclic lactams derived
from (R)- or (S)-phenylglycinol as versatile building blocks
for the enantioselective synthesis of piperidine derivatives
has previously been demonstrated with the synthesis of
diversely substituted piperidines. In these syntheses the
oxazolopiperidine ring system is usually generated by
cyclocondensation of a 5-oxoacid derivative with phenylg-
lycinol. A subsequent introduction of substituents on the
carbon atoms of the piperidine ring is achieved by R-ami-
doalkylation, enolate or homoenolate alkylations, manipula-
tion of the amide carbonyl group, or addition to the
corresponding R,â-unsaturated lactams.7 We describe here
the one-pot generation of the highly functionalized chiral
bicyclic hydroxylactam 2 by an alternative procedure involv-
ing an unprecedented diastereoselective oxidation of an (R)-
phenylglycinol-derived 2-pyridone and its subsequent con-
version into an enantiopure trihydroxypiperidine through a
route that establishes a formal synthesis of epiisofagomine.
The starting pyridone 1 was prepared from the pyridine
Zincke salt and (R)-phenylglycinol as previously described.8
Oxidation of 1 with m-CPBA (4 equiv) in methylene chloride
at room temperature for 4 days afforded the unsaturated
hydroxylactam 2 in 35-40% yield as a single stereoisomer
(Scheme 1).9 Modification of the reaction conditions, such
The stereochemical assignment of compounds 2, 4, and 5
was inferred by NMR spectroscopy. Moreover, the config-
uration of 2 was confirmed by X-ray analysis of a crystal of
the acetylated derivative 3.11
Formation of the bicyclic lactam 2 can be rationalized by
considering the initial regioselective epoxidation of the C5-
C6 double bond of the pyridone ring, followed by ring
cleavage of the resulting epoxide A promoted by the lone
electron pair of the nitrogen, to give the acyliminium cation
B, which would undergo the intramolecular attack of the
hydroxy group present in the chiral inductor. The stereo-
chemical outcome of this reaction can be attributed to the
directing influence of the hydroxy group of the phenylgly-
cinol moiety, which is capable of hydrogen bonding with
the oxygen atom of the epoxidant. Thus, for pyridone 1 there
are two conformations, 1a and 1b, in which the hydroxy
group can stabilize the two possible diastereotopic transition
states of the epoxidation step by hydrogen bonding (Scheme
2). The interactions between the phenyl ring and the carbonyl
Scheme 2. Diastereoselective Epoxidation of the Pyridone
Ring
Scheme 1. m-CPBA Oxidation of the
(R)-Phenylglycinol-Derived Pyridone 1
group in conformation 1a favor the reaction taking place
stereoselectively through conformation 1b, on the si-si face,
affording epoxide A. A subsequent epoxide cleavage and
oxazolidine ring formation also takes place stereoselectively
to give lactam 2, with the thermodynamically more stable
trans-3,8a configuration.12 Although the directing effect of
allylic and homoallylic hydrogen bond donating groups in
the peracid epoxidation of alkenes is well documented, there
are relatively few examples in which the directing group is
as the amount of reagent, time, or temperature, did not
improve the yield.10 In some runs, in which the yield of 2
was lower, small amounts of epoxides 4 (∼10%) and 5
(∼5%) were isolated after column chromatography on silica
gel. Although the yield of 2 is only moderate, it should be
noted that in a single step, from an easily accessible starting
material, a lactam functionalized in all carbon positions of
the piperidine ring, with a defined configuration in the two
new stereogenic centers, has been formed.
(7) (a) Amat, M.; Llor, N.; Bosch, J. Tetrahedron Lett. 1994, 35, 2223.
(b) Amat, M.; Llor, N.; Hidalgo, J.; Herna´ndez, A.; Bosch, J. Tetrahedron:
Asymmetry 1996, 7, 977. (c) Amat, M.; Pshenichnyi, G.; Bosch, J.; Molins,
E.; Miravitlles, C. Tetrahedron: Asymmetry 1996, 7, 3091. (d) Amat, M.;
Llor, N.; Bosch, J.; Solans, X. Tetrahedron 1997, 53, 719. (e) Amat, M.;
Hidalgo, J.; Llor, N.; Bosch, J. Tetrahedron: Asymmetry 1998, 9, 2419.
(f) Amat, M.; Bosch, J.; Hidalgo, J.; Canto´, M.; Pe´rez, M.; Llor, N.; Molins,
E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org. Chem. 2000, 65, 3074.
(g) Amat, M.; Pe´rez, M.; Llor, N.; Bosch, J.; Lago, E.; Molins, E. Org.
Lett. 2001, 3, 611. For reviews, see: (h) Meyers, A. I.; Brengel, G. P. Chem.
Commun. 1997, 1. (i) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000,
56, 9843. (j) For the use of related chiral bicyclic phenylglycinol-derived
2-cyanopiperidines, see: Husson, H.-P.; Royer, J. Chem. Soc. ReV. 1999,
28, 383.
(8) Gnecco, D.; Marazano, C.; Enr´ıquez, R. G.; Tera´n, J. L.; Sa´nchez
S., M. R.; Galindo, A. Tetrahedron: Asymmetry 1998, 9, 2027.
(9) All yields are from material purified by column chromatography.
Satisfactory spectral (IR, 1H and 13C NMR), analytical, and/or HRMS data
were obtained for all new compounds.
(10) Attempts to promote the oxidation of pyridone 1 using trifluorop-
eracetic acid, OsO4 and NMO, DMD or UHP led only to the recovery of
the starting material. Similarly, the O-silyl protected (TBDMS) lactam
derived from 1 was recovered unchanged after exposure to m-CPBA.
(4) (a) Fleet, G. W. J.; Karpas, A.; Dwek, R. A.; Fellows, L. E.; Tyms,
A. S.; Petursson, S.; Namgoong, S. K.; Ramsden, N. G.; Smith, P. W.;
Son, J.-C.; Wilson, F.; Witty, D. R.; Jacob, G. S.; Rademacher, T. W. FEBS
Lett. 1988, 237, 128. (b) Taylor, D. L.; Sunkara, P.; Liu, P. S.; Kang, M.
S.; Bowlin, T. L.; Tyms, A. S. AIDS 1991, 5, 693.
(5) (a) Nishimura, Y. In Studies in Natural Products Chemistry; Atta-
ur-Rahman, Ed.; Elsevier Science B. V.: Amsterdam, 1995; Vol. 16, pp
75-121. (b) Gross, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin.
Cancer Res. 1995, 1, 935.
(6) For reviews on the stereoselective synthesis of piperidines, see: (a)
Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun. 1998, 633.
(b) Laschat, S.; Dickner, T. Synthesis 2000, 1781.
3258
Org. Lett., Vol. 3, No. 21, 2001

located further away from the double bond.13 It is also worth
mentioning that, to our knowledge, this is the first example
of oxidation of a 2-pyridone with m-CPBA.14
The minor compound 4 would be generated by epoxidation
of the double bond of 2 with the excess of m-CPBA, whereas
it is reasonable to asume that epoxide 5 is formed from 4 by
intramolecular ring opening of the oxirane ring, probably
during column chromatography, promoted by the hydroxy
group in anti. In fact, treatment of the unsaturated lactam 2
with m-CPBA led to the epoxide 4 in 28% yield.
In accordance with the above mechanism involving
hydrogen bonding by the phenylglycinol hydroxy group,
m-CPBA oxidation of dihydropyridone 615 took place with
the same π-facial diastereoselectivity to give (51% yield)
the saturated hydroxylactam 7 as a 4:1 mixture of epimers,
7a and 7b, in which the major one (7a) possessed the same
stereochemistry as 2 (Scheme 3). The mixture of isomers
parison of its spectroscopic data with those of a sample
obtained by catalytic hydrogenation of the unsaturated lactam
2. In contrast, treatment of dihydropyridone 6 with bromine
afforded (50% yield) a mixture of bromo lactams 9a and
9b, the latter being the major product (15:85). The reversal
of the diastereoselectivity can be accounted for in terms of
an intramolecular hydrogen bonding between the hydroxy
and carbonyl groups. To avoid steric interactions with the
phenyl substituent, the bromonium intermediate is now
formed by the opposite diastereotopic re-re face.16 Hydroxy-
lactam 7a was converted into the N-Boc protected (S)-3-
hydroxypiperidine 11 by simultaneous reduction of the
lactam carbonyl and C-O bond with borane-THF complex
followed by catalytic hydrogenation of the resulting piperi-
dine 10 in the presence of di-tert-butyl dicarbonate.17
The synthetic potential of the unsaturated hydroxylactam
2 is illustrated by its conversion into the enantiopure
trihydroxypiperidine 16. Thus, the reaction of 2 with catalytic
OsO4 and NMO stereoselectively afforded the trihydroxylated
lactam 12 as a sigle isomer in 78% yield (Scheme 4). The
Scheme 3a
Scheme 4. Synthesis of Enantiopure Trihydroxypiperidine 16.
Formal Synthesis of Epiisofagominea
a Reagents and conditions: (a) m-CPBA (4 equiv), CH2Cl2, 25
°C, 2 h (7, 51%). (b) Br2, NaOMe, MeOH, 25 °C, 3 h (9, 50%).
(c) Ac2O, pyr, DMAP, CH2Cl2, 25 °C, 3 h, 70%. (d) BH3‚THF,
-78 °C (30 min) to 25 °C (3 h), 66%. (e) H2, Pd(OH)2, Boc2O,
AcOEt, 65%.
a Reagents and conditions: (a) OsO4, NMO, aq MeCN, 25 °C,
24 h, 78%. (b) Me2C(OMe)2, p-TsOH, CH2Cl2, 25 °C, 24 h, 85%.
(c) BH3‚THF, -78 °C (30 min) to 25 °C (3 h), 87%. (d) H2, Pd/C,
MeOH, 65%. (e) MeOH, HCl, 95%.
7a and 7b could not be separated by conventional methods,
but it was acetylated to give a mixture of 8a and 8b, from
which the major isomer 8a could be isolated. The stereo-
chemistry of 7a was unambiguously established by com-
same exo-facial diastereoselectivity was also observed in the
dihydroxylation of the unsaturated lactam 18, lacking the
hydroxy substituent, which was easily accessible from the
known lactam 177f by treatment of the corresponding enolate
(11) The experiment was done on a Enraf-Nonius CAD4 diffractometer
using graphite monochromated Mo KR radiation. The structure was solved
by direct methods (SHELXS-86) after applying Lorentz, polarization, and
absorption (empirical PSI scan method) corrections. Full matrix least squares
refinement (SHELXL-93) using anisotropic thermal parameters for non-H
atoms and riding thermal parameters for H atoms (positioned at calculated
positions) converged to a R factor of 0.0396 (for 3) and 0.0733 (for 20)
(calculated for the reflections with I > 2σ(Ι). 3 crystal data: C15H15NO4,
orthorhombic, space group P212121, a ) 5.8363(6), b ) 14.926(2), c )
15.495(3) Å; V ) 1349.8(3) Å3, µ (Mo KR) ) 0.098 mm-1, Dc ) 1.345
g/cm3. Approximate dimensions: 0.11 × 0.15 × 0.55 mm3. Data collection
was up to a resolution of 2θ ) 56.9° producing 1970 reflections. Maximum
and minimum heights at the final difference Fourier synthesis were 0.168
and -0.158 e Å-3. 20 crystal data: C14H13NO5, orthorhombic, space group
P212121, a ) 6.155(1), b ) 12.016(1), c ) 17.465(2) Å; V ) 1291.7(3)
Å3, µ (Mo KR) ) 0.109 mm-1, Dc ) 1.415 g/cm3. Approximate
dimensions: 0.23 × 0.35 × 0.58 mm3. Data collection was up to a resolution
of 2θ ) 60.8° producing 2254 reflections. Maximum and minimum heights
(12) It has been demonstrated that related cis-3,8a bicyclic lactams
equilibrate to the trans isomers; see ref 6f.
(13) (a) Schwesinger, R.; Willaredt, J.; Bauer, T. In StereoselectiVe
Synthesis (Houben-Weyl); Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol. 8, pp 4599-4697. (b)
Adam, W.; Schambony, S. B. Org. Lett. 2001, 3, 79 and references therein.
(14) (a) For the Elbs peroxydisulfate oxidation of 2-pyridone to 5-hy-
droxy-2-pyridone, see: Behrman, E. J.; Pitt, B. M. J. Am. Chem. Soc. 1958,
80, 3717. (b) For the dioxygenase-catalyzed cis-dihydroxylation of N-meth-
yl-2-pyridone, see: Modyanova, L.; Azerard, R. Tetrahedron Lett. 2000,
41, 3865.
(15) Rodr´ıguez, R.; Estiarte, M. A.; Diez, A.; Rubiralta, M.; Colell, A.;
Garc´ıa-Ruiz, C.; Ferna´ndez-Checa, J. C. Tetrahedron 1996, 52, 7727.
at the final difference Fourier synthesis were 0.585 and -0.450 e Å-3
.
Org. Lett., Vol. 3, No. 21, 2001
3259

with methyl phenylsulfinate, followed by thermal elimination
of the sulfoxide (Scheme 5). This stereoselectivity was not
Given that the protected intermediate 15 had previously
been converted into epiisofagomine, an extremely potent
inhibitor for â-galactosidase (Ki, 4.1 nM),20 the above route
represents a formal synthesis of this azasugar. 1,5-Dideoxy-
1,5-imino-D-pentitols are known to have a moderate binding
affinity for a broad range of glycosidases. In particular, 1,5-
iminopentitol 16 selectively inhibits the R-L-fucosidase from
human placenta.19b
Scheme 5. Synthesis of Enantiopure
cis-3,4-Dihydroxypiperidinea
On the other hand, the stereochemical identity of diol 19
was confirmed by X-ray crystallography11 of a crystal of the
corresponding carbonate 20. Following a reaction sequence
similar to that described above, diol 19 was converted via
the acetonide derivative 21 to (3R,4S)-3,4-dihydroxypiperi-
dine (24; 2-deoxy-1,5-iminopentitol),21 which has been
shown to be an inhibitor of â-glucosidase (Ki, 6 µM).2
The diastereoselective oxidation of chiral amino alcohol-
derived 2-pyridones opens new possibilities for the straight-
forward preparation of highly functionalized bicyclic lactams,
which are valuable chiral synthons for the synthesis of
enantiopure piperidine derivatives and, in particular, aza-
sugars.
a Reagents and conditions: (a) KH, PhSO2Me, THF, reflux, 90
min, then Na2CO3, toluene, reflux, 7 h, 90%. (b) OsO4, NMO, aq
MeCN, 25 °C, 24 h, 87%. (c) (Cl3CO)2CO, pyr, CH2Cl2, 25 °C,
90 min, (20: 72%). (d) Me2C(OMe)2, p-TsOH, CH2Cl2, 25 °C, 3
h, (21, 93%). (e) BH3‚THF, -78 °C (30 min) to 25 °C (2 h), 70%.
(f) H2, Pd/C, MeOH, 56%. (g) MeOH, HCl, 93%.
Acknowledgment. Financial support from the “La Marato´
de TV3” foundation, the DGICYT, Spain (project BQU2000-
0651), and the CUR, Generalitat de Catalunya (grant
1999SGR-00079) is gratefully acknowledged. Thanks are
also due to the Ministry of Education, Culture and Sport for
a fellowship to M.H. We thank DSM Deretil (Almer´ıa,
Spain) for the generous gift of (R)-phenylglycine.
unexpected because it had already been observed both in
the conjugate addition of lower order cyanocuprates to related
unsaturated bicyclic lactams7f,g and in the dihydroxylation
(OsO4-NMO) of 8a-substituted derivatives.18
After formation of acetonide 13, BH3‚THF reduction gave
piperidine 14, which was debenzylated to 15 and then
converted by methanolysis to 3,4,5-trihydroxypiperidine 16
(1,5-dideoxy-1,5-imino-D-arabitol).19 The fact that 16 was
optically active confirmed the exo-facial configuration of the
two new stereocenters generated in the dihydroxylation step.
1
Supporting Information Available: Copies of H and
13C NMR spectra of compounds 2, 4, 7a, 11, 12, 16, 19,
and 24 and complete X-ray crystallographic data for 3 and
20. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL016418Z
(18) Meyers, A. I.; Andres, C. J.; Resek, J. E.; Woodall, C. C.;
McLaughlin, M. A.; Lee, P. H.; Price, D. A. Tetrahedron 1999, 55, 8931.
(19) For previous syntheses, see: (a) Bernotas, R. C.; Papandreou, G.;
Urbach, J.; Ganem, B. Tetrahedron Lett. 1990, 31, 3393. (b) Legler, G.;
Stu¨tz, A. E.; Immich, H. Carbohydr. Res. 1995, 272, 17. (c) Godskesen,
M.; Lundt, I.; Madsen, R.; Winchester, B. Bioorg. Med. Chem. 1996, 4,
1857.
(16) A similar stereoselectivity was observed in the NIS-promoted
iodination of a phenylglycinol-derived 1,4-dihydropyridine: Lavilla, R.;
Coll, O.; Nicolas, M.; Sufi, B. A.; Torrents, J.; Bosch, J. Eur. J. Org. Chem.
1999, 2997.
(17) For previous enantioselective syntheses of 3-hydroxypiperidine,
see: (a) Huh, N.; Thompson, C. M. Tetrahedron 1995, 51, 5935. (b)
Monterde, M. I.; Nazabadioko, S.; Rebolledo, F.; Brieva, R.; Gotor, V.
Tetrahedron: Asymmetry 1999, 10, 3449 and references therein.
(20) Ichikawa, Y.; Igarashi, Y.; Ichikawa, M.; Suhara, Y. J. Am. Chem.
Soc. 1998, 120, 3007.
(21) For a previous synthesis, see: Chen, L.; Dumas, P.; Wong, C.-H.
J. Am. Chem. Soc. 1992, 114, 741.
3260
Org. Lett., Vol. 3, No. 21, 2001