Enantiopure 2,3-dihydro-4-pyridones as synthetic intermediates: Asymmetric synthesis of 1-deoxynojirimycin

Article abstract of DOI:10.1016/S0040-4039(01)01432-0

An asymmetric synthesis of 1-deoxynojirimycin (2) mediated by a chiral auxiliary is reported. The dihydropyridone 4 was converted to diol 11 in three steps by acetoxylation, hydrolysis, and stereoselective reduction. Dihydroxylation of 11 followed by catalytic reduction afforded 2.

Full text of DOI:10.1016/S0040-4039(01)01432-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6839–6841
Enantiopure 2,3-dihydro-4-pyridones as synthetic intermediates:
asymmetric synthesis of 1-deoxynojirimycin
Daniel L. Comins* and Alan B. Fulp
Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8204, USA
Received 20 July 2001; revised 31 July 2001; accepted 3 August 2001
Abstract—An asymmetric synthesis of 1-deoxynojirimycin (2) mediated by a chiral auxiliary is reported. The dihydropyridone 4
was converted to diol 11 in three steps by acetoxylation, hydrolysis, and stereoselective reduction. Dihydroxylation of 11 followed
by catalytic reduction afforded 2. © 2001 Elsevier Science Ltd. All rights reserved.
Considerable synthetic effort has been devoted to the
preparation of azasugars such as nojirimycin (1) and
1-deoxynojirimycin (2). These natural products and
related monosaccharide analogs have shown promise as
potential chemotherapeutic agents for treating diabetes,
cancer, and viral infections.1,2 Derivatives of 1-
deoxynojirimycin have been shown to inhibit the devel-
opment of HIV in vitro.3
(1R,2S)-2-(1-methyl-1-phenylethyl)cyclohexanol ((−)-
TCC),7 gave dihydropyridone 8 in 64% yield (Scheme
2). HPLC analysis of the crude product showed that the
reaction proceeded in 90% de. One-pot removal of the
chiral auxiliary (>95% recovery) and the C-5 TIPS
group provided enantiopure 9 in 74% yield as a white
solid, mp 107–107.5°C. Deprotonation with n-BuLi and
addition of benzyl chloroformate gave a 99% yield of
carbamate 4; [h]2D7 −40.2 (c 1.31, CHCl3). Acetoxyla-
tion of 4 with Pb(OAc)4 in refluxing toluene (22 h)
OH
OH
HO
OH
OH
HO
HO
OH
OH
N
H
N
H
OR
O
OR
OBn
OH
OBn
nojirimycin
1-deoxynojirimycin
2
N
1
N
2
Cbz
Cbz
As part of the program directed at exploring the utility
of N-acyl-2,3-dihydro-4-pyridones as chiral building
blocks, we examined a strategy (Scheme 1) for an
asymmetric synthesis of 1-deoxynojirimycin (2).
6
5
It was anticipated that the target molecule (2) could be
prepared from tetrahydropyridine 6, which would arise
via hydroxydihydropyridone 5. The precursor 4 would
be synthesized in an asymmetric fashion from pyridine
3 using our 1-acylpyridinium salt chemistry.4
O
OMe
TIPS
OBn
The required N-acyldihydropyridone 4 was prepared in
three steps. The addition of (benzyloxy)methylcuprate
75 to a 1-acylpyridinium salt, formed in situ from
N
N
Cbz
4-methoxy-3-(triisopropylsilyl)pyridine6
(3)
and
3
4
* Corresponding author.
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01432-0

6840
D. L. Comins, A. B. Fulp / Tetrahedron Letters 42 (2001) 6839–6841
O
O
1) R*OCOCl
TIPS
1) NaOMe
2) H3O+
1) n-BuLi
3
OBn
OBn
N
N
H
2) BnOCH2(2-Th)Cu(CN)Li2
2) BnOCOCl
CO2R*
7
3) H3O+
R* = ( )-TCC
8
9
O
O
Pb(OAc)4
OAc
OBn
1) aq. HCl/EtOH → (5)
OBn
N
Cbz
N
Cbz
toluene, reflux
2) Me4NBH(OAc)3
acetone/AcOH
4
10
OH
OH
HO
HO
OH
OH
OsO4
Pd(OH)2 / H2
OBn
OBn
N
Cbz
N
Cbz
10% HCl
NMO
12
11
OH
OH
HO
OH
OH
HO
OH
OH
N
H
N
H
13
2
Scheme 2.
amenable to the asymmetric synthesis of various nojir-
imycin analogs and other azasugars.
afforded the desired dihydropyridone 10 in 78%
yield. The trans stereochemistry was obtained by ace-
tate delivery from the axial direction via a chair-like
transition state.8 The acetate group of 10 was
hydrolyzed with aqueous 10% HCl in ethanol to
provide alcohol 5 (75%; [h]2D2+50.1 (c 0.67, CHCl3)).
Reduction of 5 with tetramethylammonium triacetoxy-
borohydride afforded diol 11 (83%) with complete
stereoselectivity.9
Acknowledgements
We express appreciation to the National Institutes of
Health (Grant GM 34442) for partial support of this
work. NMR and mass spectra were obtained at NCSU
instrumentation laboratories, which were established by
grants from the North Carolina Biotechnology Center
and the National Science Foundation (Grants CHE-
9121380, CHE-9509532, CHE-0078253).
The next step in our plan called for a stereoselective
hydroxylation of 11 at C-5. Several attempts using
various hydroboration conditions proved nonselective
and/or low yielding.10 Dihydroxylation of 11 was stud-
ied next with the hope that the C-4 hydroxyl group
would direct the oxidation to the opposite face of the
olefin (the Kishi rule).11 Treatment of 11 with osmium
tetroxide and 4-methylmorpholine N-oxide afforded the
tetrahydroxypiperidines 12, which proved unstable to
silica gel chromatography. When the crude mixture was
hydrogenated with Pd(OH)2 and 10% HCl, a 2.7:1 ratio
of 2:13 resulted (13C NMR analysis of the crude
product). Neutralization and chromatographic purifica-
tion (silica gel, 75% MeOH/CH2Cl2;1% TEA) provided
1-deoxynojirimycin (2) in 55% yield and 1-deoxyman-
nojirimycin (13) in 21% yield. The spectral properties of
our (−)-2 and 13 are in agreement with reported data.12
References
1. (a) Stu¨tz, A. E. Iminosugars As Glycosidase Inhibitors:
Nojirimycin and Beyond; Wiley-VCH: Weinheim, 1999;
(b) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int.
Ed. Engl. 1999, 38, 750–770; (c) Zechel, D. L.; Withers, S.
G. Acc. Chem. Res. 2000, 33, 11–18.
2. For recent and leading references, see: (a) Haukaas, M.
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manian, T.; Lin, C.-C.; Lin, C.-C. Tetrahedron Lett. 2001,
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3. (a) Gruters, R. A.; Neefjes, J. J.; Tersmette, M.; de
Goede, R. E. Y.; Tulp, A.; Huisman, H. G.; Miedema,
F.; Ploegh, H. L. Nature 1987, 330, 74–77; (b) Asano, N.;
Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron
Asymmetry 2000, 11, 1645–1680 and references cited
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In summary, 1-deoxynojirimycin was prepared enan-
tioselectively in eight steps from readily available pyri-
dine 3 in 13% overall yield. This strategy should be

D. L. Comins, A. B. Fulp / Tetrahedron Letters 42 (2001) 6839–6841
6841
4. (a) Comins, D. L.; Joseph, S. P. In Advances in Nitrogen
Heterocycles; Moody, C. J., Ed.; JAI Press: Greenwich,
CT, 1996; Vol. 2, pp. 251–294; (b) Comins, D. L.; Joseph,
S. P. In Comprehensive Heterocyclic Chemistry, 2nd ed.;
McKillop, A., Ed.; Pergamon Press: Oxford, 1996; Vol. 5,
pp. 37–89; (c) Comins, D. L.; Kuethe, J. T.; Hong, H.;
Lakner, F. J. J. Am. Chem. Soc. 1999, 121, 2651 and
references cited therein.
5. The cuprate was prepared from benzyl chloromethyl
ether via the corresponding tributylstannane. Lithium–tin
exchange with n-BuLi followed by addition of lithium
2-trienylcyanocuprate gave 5.
12. The structure assigned to each new compound is in
accord with its IR and 1H and 13C NMR spectra and
elemental analysis or high-resolution mass spectra.
Selected characterization data: Compound 10: colorless
oil; [h]2D6=+82.9 (c 1.37, CHCl3); IR (neat) 3032, 2867,
1733, 1678, 1605, 1386, 1318, 1266, 1210, 1117, 1030
1
cm−1; H NMR (300 MHz, CDCl3) l 7.90 (d, 1H, J=8.4
Hz), 7.5–7.1 (m, 10H), 5.38 (d, 1H, J=8.4 Hz), 5.25 (s,
3H), 4.78 (t, 1H, J=5.1 Hz), 4.46 (s, 2H), 3.7–3.6 (m,
2H), 2.08 (s, 3H); 13C NMR (75 MHz, CDCl3) l 186.7,
169.6, 152.7, 143.0, 137.4, 134.8, 129.1, 128.9, 128.6,
128.0, 127.9, 127.8, 127.6, 105.6, 73.5, 70.1, 69.5, 67.5,
57.6, 21.1. Anal. calcd for C23H23NO6: C, 67.47; H, 5.66;
N, 3.42. Found: C, 67.51; H, 5.71; N, 3.46.
6. Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am.
Chem. Soc. 1994, 116, 4719.
7. Comins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58,
4656.
Compound 11: colorless oil; [h]2D2=−91.6 (c 1.62, CHCl3);
IR (neat) 3416, 3031, 2871, 1708, 1652, 1397, 1341, 1027
1
8. (a) Comins, D. L.; Stolze, D. A.; Thakker, P.; McArdle,
C. L. Tetrahedron Lett. 1998, 39, 5693; (b) Comins, D.
L.; Huang, S.; McArdle, C. L.; Ingalls, C. L. Org. Lett.
2001, 3, 469.
9. For a related reduction of an a-hydroxyketone with
triacetoxyborohydride, see: Goldstein, S. W.; Overman,
L. E.; Rabinowitz, M. H. J. Org. Chem. 1992, 57, 1179.
10. Hydroboration of N-alkyldihydropyridone derivatives
has been used to prepare 1,6-dideoxy-6,6-difluoroaza-
sugar analogs, see: Kitazume, T.; Murata, K.; Okabe, A.;
Takahashi, Y.; Yamazaki, T. Tetrahedron: Asymmetry
1994, 5, 1029.
cm−1; H NMR (300 MHz, CDCl3) l 7.5–6.9 (m, 11H),
5.3–4.9, (m, 3H), 4.6–4.2 (m, 3H), 4.2–3.6 (m, 4H), 2.1
(bs, 1H); 13C NMR (75 MHz, CDCl3) l 137.0, 135.8,
128.8, 128.7, 128.6, 128.32, 128.26, 127.9, 126.9, 126.8,
126.7, 126.4, 105.1, 73.8, 71.4, 69.2, 68.5, 68.3, 64.6, 56.1,
41.6. Anal. calcd for C21H23NO5; C, 68.28; H, 6.28; N,
3.79. Found: C, 68.32; H, 6.23; N, 3.77.
Compound 2·HCl: white solid, mp 204–205°C; [h]2D7=
+39.8 (c 0.465, H2O); IR (Nujol) 3380, 3175, 1664 cm−1
;
1H NMR (300 MHz, CDCl3) l 3.82 (dd, 1H, J=2.5, 11.5
Hz), 3.62 (dd, 1H, J=6.2, 11.6 Hz), 3.52–3.44 (m, 1H),
3.35–3.18 (m, 2H), 3.11 (dd, 1H, J=4.9, 12.3 Hz), 2.56–
2.40 (m, 2H); 13C NMR (75 MHz, CDCl3) l 79.4, 71.0,
70.1, 63.2, 60.9, 49.1.
11. Cha, J. K.; Christ, W.; Kishi, Y. Tetrahedron 1984, 40,
2247.