Facile preparation of a highly functionalized tetrahydropyran by catalytic hydrogenation of an oxazoline

Article abstract of DOI:10.1021/jo801037z

(Chemical Equation Presented) 2-Amino-1,5-anhydro-2-deoxy-D-glucitol, a highly functionalized tetrahydropyran, is a versatile building unit in many natural products. A facile route to this type of synthetic building unit from the corresponding 2-aminopyra

Full text of DOI:10.1021/jo801037z

SCHEME 1. Known Synthetic Entries to
2-Acetamido-3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-glucitol
Facile Preparation of a Highly Functionalized
Tetrahydropyran by Catalytic Hydrogenation of
an Oxazoline
Dusan Hesek, Mijoon Lee, Takao Yamaguchi,
Bruce C. Noll, and Shahriar Mobashery*
Department of Chemistry and Biochemistry,
UniVersity of Notre Dame, Notre Dame, Indiana 46556
the chloride 2 and its reduction in the presence of AIBN and
mobashery@nd.edu
tributyltin hydride under reflux.10
ReceiVed May 14, 2008
Tetrahydropyrans such as 1 are valuable synthetically tools.
They can be accessed from the corresponding aminopyra-
noses, yet the structural class is highly functionalized with
defined stereochemistry at various positions, all of which can
in turn be manipulated further by selective reactivity of each
stereogenic center. These tetrahydropyrans are found as
structural modules of many D-glucosamine-related natural
products mimics.1-5
We report herein a new method for the generation of
2-acetamido-1,5-anhydro-2-deoxy-D-glucitol derivative (as an
example, see 8f) using a simple catalytic hydrogenation reaction
to access the structural class. The method might arguably be
the most facile entry into these molecules from the readily
available precursors. Its facility should make the approach
amenable to a host of synthetic applications.
The oxazoline intermediates of the type 7 have widely been
used as glycosyl donors in sugar chemistry.11 They are easily
accessed from N-acetyl-D-glucosamine (5) in two to three steps
(Scheme 2). They direct the formation of the ꢀ-(1,4) glycosidic
linkage, and they do not require additional steps to protect and
to deprotect the amino functionality. We prepared the oxazoline
7 in two steps starting from N-acetyl glucosamine (5) according
to literature precedents.12,13 Catalytic hydrogenation of com-
pound 7 could potentially result in several products, as depicted
in Scheme 2. These potential reactions include reduction of the
benzylidene by itself (8a), reduction of the benzylidene in
conjunction with reduction at C-1 (8b), or reduction of the
benzylidene concurrent with methanolysis at C-1 in the presence
of a metal catalyst (8c). Alternatively, one could envision
methanolysis taking place at C-1 (8d), reduction of the imine
2-Amino-1,5-anhydro-2-deoxy-D-glucitol, a highly function-
alized tetrahydropyran, is a versatile building unit in many
natural products. A facile route to this type of synthetic
building unit from the corresponding 2-aminopyranoses, as
exemplified by an application to D-glucosamine, is outlined.
A simple catalytic hydrogenation at C-1 of an oxazoline
constructed from the corresponding 2-aminopyranose results
in the desired product.
2-Amino-1,5-anhydro-2-deoxy-D-glucitol (1) and its deriva-
tives serve as a mimic of glucosamine-containing natural
products1-5 or as intermediates in syntheses of D-galactitol
derivatives.6 There are literature precedents on the synthesis of
1, which exploit the two main approaches shown in Scheme 1.
7-10
One is the use of Raney nickel desulfurization of 1-thio-
glucopyranose derivatives (3), which in turn have been prepared
from glucopyranosyl chloride (2).7,8 Yields are generally good
by this method, but it requires the use of excess Raney nickel
(5-10 g of metal per 1 g of substrate). The use of the excess
metal catalyst has problems of its own, such as partial removal
of the acetyl groups necessitating reacetylation of the samples.
Removal of the 1-phenyl sulfide moiety was observed also
during deprotection of the benzyl ether and phenylsulfonamide,
using sodium in liquid ammonia, as an undesired side reaction.9
The second approach is a more recent application, starting from
(1) Lim, J.; Grove, B. C.; Roth, A.; Breaker, R. R. Angew. Chem., Int. Ed.
2006, 45, 6689–6693.
(2) Vegaperez, J. M.; Espartero, J. L.; Ruiz, F. J.; Alcudia, F. Carbohydr.
Res. 1992, 232, 235–247.
(3) Hasegawa, A.; Hioki, Y.; Seki, E.; Kiso, M.; Azuma, I. Agric. Biol. Chem.
(7) Horton, D.; Wolfrom, M. L. J. Org. Chem. 1962, 27, 1794–1800.
(8) Hough, L.; Taha, M. I. J. Chem. Soc. 1956, 2042–2048.
(9) Wang, Z. G.; Warren, J. D.; Dudkin, V. Y.; Zhang, X. F.; Iserloh, U.;
Visser, M.; Eckhardt, M.; Seeberger, P. H.; Danishefsky, S. J. Tetrahedron 2006,
62, 4954–4978.
1986, 50, 1873–1878.
(10) Bamford, M. J.; Pichel, J. C.; Husman, W.; Patel, B.; Storer, R.; Weir,
N. G. J. Chem. Soc., Perkin Trans. 1 1995, 1181–1187.
(11) Banoub, J.; Boullanger, P.; Lafont, D. Chem. ReV. 1992, 92, 1167–
1195.
(12) Srivastava, V. K. Carbohydr. Res. 1982, 103, 286–292.
(13) Yonehara, K.; Hashizume, T.; Mori, K.; Ohe, K.; Uemura, S. J. Org.
Chem. 1999, 64, 9374–9380.
(4) Durette, P. L.; Dorn, C. P.; Shen, T. Y.; Friedman, A. Carbohydr. Res.
1982, 108, 139–147.
(5) Paul, B.; Bernacki, R. J.; Korytnyk, W. Carbohydr. Res. 1980, 80, 99–
115.
(6) Kroger, L.; Scudlo, A.; Thiem, J. AdV. Synth. Catal. 2006, 348, 1217–
1227.
10.1021/jo801037z CCC: $40.75
Published on Web 08/09/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7349–7352 7349

SCHEME 2
SCHEME 3
the pure form after a single recrystallization, was compound
9a. The deuterium in 9a was at the equatorial position according
to the NMR results. As shown by the 1H NMR spectra of Figure
2, the doublet of doublet of equatorial H-1 in compound 8f
disappeared and a triplet signal of axial H-1 in compound 8f
became a doublet on formation of compound 9a. The multiplet
resonance of H-2 in 8f simplified to a triplet in compound 9a.
No trace of compound 9b was observed. We hasten to add that
some 8f was also present (see Figure 2 and the larger spectrum
in the Supporting Information). We attributed this to the
existence of some H2 in the commercial sample of D2 and also
to the possibility that some H2 having been absorbed on the
commercial sample of the palladium, as it was supplied to us.
moiety in the oxazoline ring (8e), or merely reduction at C-1
(8f). As is disclosed in this paper, we can set up the system to
give exclusively the reduction at C-1, leading to the formation
of the desired tetrahydropyran.
The main product of catalytic hydrogenation of oxazoline 7
in the presence of palladium (10% Pd/C, 20 wt % at room
temperature) in a 1:1 mixture of methanol and THF was
compound 8f, which was formed by the reduction of 7 at C-1
in the 1,2-oxazoline ring. The 4,6-O-benzylidene remained
intact. Analyses by NMR and mass spectrometry were entirely
consistent with this assignment of structure, but the structure
was confirmed by X-ray crystallography (Figure 1B).
Compound 8f shows a slightly distorted chair (4C1) pyranose
conformation with O1 out of plane by 0.20 Å. The X-ray
structure of the precursor oxazoline 7 exhibits a distorted half-
chair (4H5) pyranose conformation with O1 out of plane by
0.29 Å.
FIGURE 2. 1H NMR spectra of compounds 8f and 9a in CD3OD.
A pertinent question is whether this reaction proceeds in a
regiospecific manner. If the reaction were run under a deuterium
(D2) atmosphere, the possible outcomes could be compound 9a,
9b, or a mixture of the two.
We set up the deuteration reaction of compound 7 under
identical catalytic hydrogenation conditions, except using D2
and CD3OD (Scheme 3). The product, which was isolated in
We have found one literature precedent for synthesis of a
deuterated derivative at C-1 by transmetalation of 1-pyranosyl-
stannane, obtained from the corresponding 1-chloride analogue
and the subsequent quenching with CD3OD.14 The deuterated
analogues are useful for elucidation of biosynthetic pathways
of molecules of this kind and indeed are difficult to access in
regiospecific manner.
We also have noticed that triacetyl oxazoline (10) was
resistant to the kind of catalytic hydrogenation discussed above.
This might be due to different conformations of the oxazolines
in compounds 7 and 10. Compound 7 in the solid state shows
a distorted half-chair conformation (4H5), the same as in solution
per analysis by the Karplus equation of the NMR data.15
Structural information of triacetyl derivative 10 in the solid state
is not available, since this compound is an oil. Studies have
been done on conformations of compound 10 in solution based
on vicinal coupling constants by NMR and the calculated
dihedral angles by the Karplus equation.15-17 These analyses
suggest that this compound exists is a distorted skew (OS2)
conformation.16,17 X-ray crystal structures of similar or related
compounds are known in the literature.16,18 For example,
phenyloxazoline triacetate (11) is known to exist between a skew
(14) Hoffmann, M.; Kessler, H. Tetrahedron Lett. 1994, 35, 6067–6070.
(15) Coxon, B. Carbohydr. Res. 1970, 13, 321–330.
(16) Focesfoces, C.; Cano, F. H.; Bernabe, M.; Penades, S.; Martinlomas,
M. Carbohydr. Res. 1984, 135, 1–11.
(17) Nashed, M. A.; Slife, C. W.; Kiso, M.; Anderson, L. Carbohydr. Res.
1980, 82, 237–252.
FIGURE 1. ORTEP diagrams of compounds 7 (A) and 8f (B) are
shown at 50% probability level. Hydrogen atoms are omitted for
clarity.
7350 J. Org. Chem. Vol. 73, No. 18, 2008

SCHEME 4
16
(OS2) and diplanar (DO,4
)
conformations and thiazoline tri-
acetate (12) exits in a skew (OS2) conformation.18
The mixture was stirred under an atmosphere of hydrogen at room
temperature overnight. The mixture was diluted with an additional
portion of methanol (10 mL) and filtered through a layer of Celite,
and the Celite pad was washed well with additional methanol. The
solvent was removed in vacuo. The resulting crude product was
1
crystallized from MeOH-CH2Cl2 (0.13 g, 86%): H NMR (600
MHz, methanol-d4) δ 1.91 (s, 3H), 2.02 (s, 3H), 3.39 (t, J ) 11.3
Hz, H-1ax, 1H), 3.45 (td, J ) 9.8, 5.0 Hz, H-5, 1H), 3.71 (t, J )
9.5 Hz, H-4, 1H), 3.75 (t, J ) 10.3 Hz, H-6a, 1H), 3.91 (dd, J )
11.4, 5.6 Hz, H-1eq, 1H), 4.19 (m, J ) 10.7, 5.6 Hz, H-2, 1H),
4.26 (dd, J ) 10.3, 5.0 Hz, H-6b, 1H), 5.15 (t, J ) 9.8 Hz, H-3,
1H), 5.57 (s, CHPh, 1H), 7.33 (m, 3H), 7.41 (m, 2H); 13C NMR
(151 MHz, methanol-d4) δ 20.9, 22.8, 51.3 (C-2), 69.6 (C-1), 69.8
(C-6), 73.0 (C-5), 74.5 (C-3), 80.8 (C-4), 102.9 (CHPh), 127.5,
129.2, 130.1, 139.0, 172.5, 173.6; HRMS (FAB) calcd for
C17H22NO6 (M + H+) 336.1447, found 336.1444.
Assuming that compound 10 exists in the skew conformation,
significant differences would then be present between conforma-
tions of 10 and 7. The acetyl group at C-3 is equatorial in
compound 7, which does not block the trajectory of the
interaction of the compound at the C-1 with the catalyst surface.
On the other hand, the acetyl group at C-3 in compound 10 is
more axially disposed, which would block interactions with the
surface of the palladium catalyst. This might be the reason why
triacetylated oxazoline 10 cannot be hydrogenated to form the
corresponding glucitol.
A pertinent question becomes if there exists any generality
to the observations above regarding the application of hydro-
genation to oxazoline ring opening. Compound 13 was prepared
from 7 in two steps. When compound 13 was subjected to
catalytic hydrogenation in THF, the double bond in the
cinnamoyl group was reduced first within 30 min to yield
compound 14. The desired glucitol 15 was obtained cleanly by
prolonging the hydrogenation reaction to 24 h (Scheme 4).
As a final note, the strategy reported above should be
generally applicable to any oxazoline compounds derived from
2-aminopyranoses, such as galactosamine and mannosamine,
as depicted below.
2-Acetamido-3-O-acetyl-1,5-anhydro-4,6-O-benzylidene-2-
deoxy-1-ꢀ-2H-D-glucitol (9a). Compound 9a was prepared accord-
ing to the procedure described above for compound 8f, except D2
and CD3OD were used. The resulting crude product was crystallized
from acetonitrile to give the titled compound as a needle: 1H NMR
(600 MHz, methanol-d4) δ 1.91 (s, 3H), 2.03 (s, 3H), 3.38 (d, J )
11.2 Hz, H-1ax, 1H), 3.45 (td, J ) 9.8, 5.1 Hz, H-5, 1H), 3.72 (t,
J ) 9.4 Hz, H-4, 1H), 3.76 (t, J ) 10.3 Hz, H-6a, 1H), 4.19 (t, J
) 10.7 Hz, H-2, 1H), 4.26 (dd, J ) 10.6, 5.0 Hz, H-6b, 1H), 5.15
(t, J ) 9.8 Hz, H-3, 1H), 5.58 (s, CHPh, 1H), 7.29-7.48 (m, 5H);
13C NMR (151 MHz, methanol-d4) δ 20.9, 22.8, 51.3 (C-2), 69.3
(m, C-1), 69.8 (C-6), 73.0 (C-5), 74.5 (C-3), 80.8 (C-4), 102.9
(CHPh), 127.5, 129.2, 130.1, 139.0, 172.5, 173.6; HRMS (FAB)
calcd for C17H21DNO6 (M + H+) 337.1510, found 337.1493.
2-Methyl-4,5-(3-O-(trans-3-phenylacryloyl)-4,6-O-
benzylidene-1,2-dideoxy-r-D-glucopyrano)[2,1-d]-2-oxazoline
(13). A solution of compound 7 (0.63 g, 1.9 mmol) and NaOMe
(0.05 g) in anhydrous MeOH (15 mL) was stirred at room
temperature until the starting material was consumed (1 h). The
reaction was quenched by the addition of an excess amount of
Amberlite IR-120 (H+). After the mixture was stirred for an
additional 20 min, the resin was filtered and the resulting solution
was concentrated to dryness. The residue was dissolved in CH2Cl2
and was treated with cinnamoyl chloride (0.33 g, 2.0 mmol) in the
presence of pyridine (0.24 mL, 3.0 mmol) at room temperature
overnight. Water was added to the reaction mixture, and the layers
were separated. The organic layer was washed with water and
concentrated to dryness. The residue was chromatographed on silica
Experimental Section
The synthesis of acetyl 2-acetamido-3-O-acetyl-4,6-O-benzylidene-
R,ꢀ-D-glucopyranoside (6) and its conversion to compound 7 (2-
methyl-4,5-(3-O-acetyl-4,6-O-benzylidene-1,2-dideoxy-R-D-glu-
copyrano)[2,1-d]-2-oxazoline) were performed according to literature
procedures.12,13 NMR signal assignments for compounds 8f, 14,
and 15 were performed on the basis of H-H COSY, H-C
HETCOR, and DEPT experiments.
2-Acetamido-3-O-acetyl-1,5-anhydro-4,6-O-benzylidene-2-
deoxy-D-glucitol (8f). Compound 7 (0.15 g, 0.45 mmol) was
dissolved in a 1:1 mixture of methanol and THF (15 mL), and 10%
Pd/C (30 mg) was added to the mixture cautiously to avoid ignition.
1
gel to give the title compound as a white solid (0.6 g, 75%): H
NMR (600 MHz, CDCl3) δ 2.10 (d, J ) 1.8 Hz, 3H), 3.68-3.78
(m, 2H), 3.94 (t, J ) 8.7 Hz, 1H), 4.16-4.20 (m, 1H), 4.42 (dd, J
) 9.7, 4.1 Hz, 1H), 5.32 (dd, J ) 7.8, 3.4 Hz, 1H), 5.57 (s, 1H),
6.03 (d, J ) 7.6 Hz, 1H), 6.49 (d, J ) 15.8 Hz, 1H), 7.33-7.54
(m, 10H), 7.76 (d, J ) 16.1 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 14.1, 62.7, 67.8, 68.6, 76.6, 77.9, 101.3, 101.5, 117.4, 126.0,
128.0, 128.1, 128.8, 129.0, 130.3, 134.1, 136.7, 145.7, 165.5, 165.7;
HRMS (FAB), calcd for C24H24NO6 (M + H+), 422.1604, found
422.1601.
2-Acetamido-1,5-anhydro-4,6-O-benzylidene-3-O-(3-phenyl-
propionyl)-2-deoxy-D-glucitol (15). Compound 15 was prepared
(18) Knapp, S.; Abdo, M.; Ajayi, K.; Huhn, R. A.; Emge, T. J.; Kim, E. J.;
Hanover, J. A. Org. Lett. 2007, 9, 2321–2324.
J. Org. Chem. Vol. 73, No. 18, 2008 7351

according to the procedure described above for compound 8f, except
THF was used as solvent. The resulting crude product was purified
by short column chromatography on silica gel to give the titled
compound (74%). Compound 14 was obtained quantitatively after
30 min of the reaction. Compound 14: 1H NMR (500 MHz, CDCl3)
δ 2.07 (d, J ) 1.0 Hz, 3H), 2.71 (t, J ) 7.7 Hz, 2H), 2.99 (t, J )
7.7 Hz, 2H), 3.62-3.72 (m, 2H, H-5 and H-6a), 3.76 (t, J ) 8.7
Hz, 1H, H-4), 3.96 (dt, J ) 6.0, 1.6 Hz, 1H, H-2), 4.38 (dd, J )
9.1, 3.7 Hz, 1H, H-6b), 5.20 (dd, J ) 7.8, 3.4 Hz, 1H, H-3), 5.51
(s, 1H, CHPh), 5.92 (d, J ) 7.6 Hz, 1H, H-1), 7.15-7.50 (m, 10H);
13C NMR (126 MHz, CDCl3) δ 14.4, 31.0 (t), 35.9 (t), 62.9 (C-5),
67.7 (C-2), 68.9 (C-6), 74.2 (C-3), 78.1 (C-4), 101.6 (C-1), 101.7
(CHPh), 126.3, 126.4, 128.4, 128.4, 128.6, 128.7, 129.3, 137.0,
140.4, 165.8, 171.9; HRMS (FAB) calcd for C24H26NO6 (M + H+)
recrystallization described above, and the resultant colorless crystal
was used for single-crystal X-ray diffraction analysis.
Crystals were examined under Infineum V8512 oil, placed on a
MiTeGen mount, and then transferred to the 100 K N2 stream of a
Bruker SMART Apex CCD diffractometer. Unit cell parameters
were determined from reflections with I > 10σ(I) harvested from
three orthogonal sets of 30 0.5° ω scans. Data collection strategy
was calculated using COSMO, included in the Apex2 suite of
programs19 to maximize coverage of reciprocal space in a minimum
amount of time. Average 4-fold redundancy of measurements was
sought. Data were corrected for Lorentz and polarization effects,
as well as for absorption.
Structure solution and refinement utilized the programs of the
SHELXTL software package.20 Full details of the X-ray structure
determinations are in the CIF files included as Supporting Informa-
tion.
1
424.1760, found 424.1750. Compound 15: H NMR (500 MHz,
CDCl3) δ 1.83 (s, 3H), 2.66-2.76 (m, 2H), 2.93 (t, J ) 7.5 Hz,
2H), 3.17 (t, J ) 10.7 Hz, 1H, H-1eq), 3.40-3.47 (m, 1H, H-5),
3.71 (t, J ) 9.6 Hz, 1H, H-4), 3.73 (t, J ) 10.4 Hz, 1H, H-6a),
4.11-4.24 (m, 2H, H-1ax and H-2), 4.32 (dd, J ) 10.5, 4.9 Hz,
1H, H-6b), 5.10 (t, J ) 9.8 Hz, 1H, H-3), 5.53 (s, 1H, CHPh),
5.91 (d, J ) 7.2 Hz, 1H, NH), 7.14-7.23 (m, 5H), 7.33-7.39 (m,
2H), 7.41-7.46 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 23.3,
30.9 (t), 35.7 (t), 51.3 (C-2), 68.9 (C-6), 69.0 (C-1), 71.9 (C-5),
73.3 (C-3), 79.0 (C-4), 101.7 (CHPh), 126.3, 126.5, 128.3, 128.5,
128.7, 129.3, 137.2, 140.1, 170.6, 174.5; HRMS (FAB) calcd for
C24H28NO6 (M + H+) 426.1917, found 426.1891.
Crystals Growth and Analysis. Compound 8f (50 mg) in MeOH
and CH2Cl2 (1 mL) was heated to produce a clear, colorless solution.
Crystals of suitable size for single-crystal X-ray diffraction analysis
were obtained by recrystallization from MeOH at room temperature
overnight. Compound 7 was subjected to same conditions of
Acknowledgment. This work was supported by the National
Institutes of Health.
Supporting Information Available: Compound character-
ization data, including copies of 1D NMR spectra (1H, 13C
NMR, and DEPT) and 2D NMR spectra (H-H COSY and H-C
HETCOR) of compounds 8f, 9a, 13, 14, and 15, and X-ray data
of compounds 7 and 8f (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JO801037Z
(19) COSMO; Bruker-AXS: Madison, WI, 2008, Vol. 58.
(20) Sheldrick, G. M. Acta Crystallogr. A 2008, 64, 112–122.
7352 J. Org. Chem. Vol. 73, No. 18, 2008