Regioselective conversion of the secondary hydroxyl groups of D-glucuronic acid without the requirement of O-protecting groups

Article abstract of DOI:10.1002/chem.200500515

Trifluoromethanesulfonic acid anhydride (triflic acid anhydride) transforms the bicyclic thiazolidinlactam 1a into the crystalline elimination product 2, in which all four secondary hydroxyl groups of la are differently functionalized. Compound 2 can then

Full text of DOI:10.1002/chem.200500515

FULL PAPER
DOI: 10.1002/chem.200500515
Regioselective Conversion of the Secondary Hydroxyl Groups of
d-Glucuronic Acid without the Requirement of O-Protecting Groups
Kµroly goston[a] and Armin Geyer*[b]
Abstract:
Trifluoromethanesulfonic
stereoselectivity. Altogether, the four
secondary hydroxyl groups of d-glucur-
onic acid are selectively transformed
without the need for any O-protecting
groups. Minimizing the number of O-
protecting groups is a prerequisite for
the use of sugar scaffolds in molecular
libraries. The hapalosin analogues 15,
16, 19, and 22 outline the strategy to-
wards O-diversified glucose derivatives.
acid anhydride (triflic acid anhydride)
transforms the bicyclic thiazolidinlac-
tam 1a into the crystalline elimination
product 2, in which all four secondary
hydroxyl groups of 1a are differently
functionalized. Compound 2 can then
add nucleophiles with high chemo- and
Keywords: carbohydrates · glucose ·
hapalosin · synthetic methods · thia-
zolidinlactams
Introduction
regio- and stereoselectivity to the sterically and functionally
overcrowded synthesis intermediates.
The combination of protection and activation in a single
functional group, which can be an epoxide or an active
ester, allows the straightforward modification of sugar sec-
ondary hydroxyl groups. For example, the Cerny epoxide is
an activated d-glucose derivative that adds nucleophiles se-
lectively without the need for O-protecting groups.[1] The re-
gioselective functionalization of equally reactive secondary
hydroxyl groups in as few as possible synthetic steps is a
prerequisite for the synthesis of sugar-based[2] or other
small-molecule libraries.[3] Carbohydrate scaffolds that bear
a different activating group on every carbon atom offer in-
teresting options for molecular diversity-based synthetic
strategies. Carbohydrate-based chiral-pool strategies are
well established in organic chemistry, but only a few synthet-
ic approaches do not require the tedious shuffling of pro-
tecting groups. Here, we describe the transformation of the
chiral-pool bulk material d-glucuronic acid into selectively
O-diversified products, by the generation of orthogonal re-
active sites at the positions of the secondary hydroxyl
groups, followed by the addition of nucleophiles with high
The elimination cascade that converts polyol 1a into elim-
ination product 2 was observed in an effort to regioselec-
tively functionalize all four hydroxy groups of 1a
(Scheme 1), to obtain bicyclic dipeptides[4] with diversified
Scheme 1. Reaction conditions: a) 5 equiv Tf2O, DMAP (cat.), pyridine/
DCM, 08C!RT, 12 h, 80%; b) 2.5 equiv Tf2O, pyridine/DCM, 08C!RT,
1 h, 37%.
side-chains. The transformation of 2 into hapalosin[5] ana-
logues is shown here as a possible application of the aze-
pane scaffold. Hydroxyazepanes[6] and other perfunctional-
ized medium-sized rings[7] are recurring scaffolds in medici-
nal chemistry, and derivatives of 2 have additional functions.
Peptidomimetics that are based on bicyclic medium-sized
thiazolidinlactam rings have applications ranging from
model peptides[8] to drugs.[9]
[a] Dr. K. goston
Fakultät für Chemie und Pharmazie
Universität Regensburg, 93040 Regensburg (Germany)
[b] Prof. Dr. A. Geyer
Fachbereich Chemie der Philipps-Universität Marburg
35032 Marburg (Germany)
Fax : (+49)6421-282-2021
E-mail: geyer@staff.uni-marburg.de
Chem. Eur. J. 2005, 11, 6407 – 6413
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6407

Results and Discussion
cation of all four stereocenters, as shown in Scheme 2. The
selectivity of the first addition is the most critical step, be-
cause in principle, each of the nucleophiles can add to alter-
native ring positions of 2, leading to complex reaction mix-
Although the simultaneous activation of several sugar hy-
droxyl groups as sulfonate esters has been investigated, the
study of possible applications of sugar polysulfonates has re-
mained limited.[10] The treatment of bicyclic thiazolidinlac-
tam 1a (Scheme 1) with excess triflic acid anhydride does
not result in a polysulfonate, but rather a stable, crystalline
elimination product 2 (Figure 1) in a yield of 80%.[11] The
Scheme 2. Reaction conditions: a) BnOH, CHCl3, BF3/Et2O, 50 8C, 20 h,
75%; b) Ac2O, pyridine, RT, 8 h, quant, then H2O/MeOH, K2CO3,
CHCl3, RT, 1 h, quant; c) MeOH, K2CO3, DCM, RT, 5 d, 78%;
d) NH4HCOO, MeOH, DCM, 508C, 3 d, 82%; e) Ac2O, pyridine, RT,
8 h, 95%; f) NaBH4, MeOH, DCM, RT, 10 min, 90%.
tures. Conjugate addition to C-7 renders the O-6-triflate sus-
ceptible to nucleophilic exchange. However, no over-reac-
tions from the several-fold addition of the same nucleophile
are observed under the conditions used here.
Figure 1. Crystal structures of elimination product 2, lactone 3, and Mi-
chael adduct 8.
Benzyl alcohol opens the oxirane ring of 2 under Lewis
acid assistance (4, Scheme 2). Other alcohols show the same
regioselectivity and the enol triflate remains intact under
the reaction conditions. A selective hydrolysis of the acety-
lated enol-triflate 4 generates the a-ketoamide 5. In the
presence of potassium carbonate, an oxa-Michael reaction is
observed for methanol, which attacks C-7. As expected,
methanol adds to the less-hindered side of the double bond
in 2, affording 6. Compound 2 decomposes in the presence
of alkyl amines, but ammonium formate adds as an N-nucle-
ophile cleanly to C-7, thus transforming 2 into 7 in 82%
yield. Surprisingly, this attack proceeds from the more-hin-
dered side of 2, resulting in the opposite stereochemistry of
four secondary hydroxyl groups of 1a (d-gluco-configura-
tion) are transformed into complementary reactive sites in 2
via sulfonate ester intermediates in a single synthetic step.
No comparable activation/elimination sequences are known
for gluco-pyranoses that bear their hydroxyl groups in equa-
torial positions. The axial orientation of the three hydroxyl
groups 7-O, 8-O, and 9-O in 1a is a key requirement for the
observed formation of the oxirane ring and the enol ether.
The sequence of events, however, remains unclear, because
no intermediates are observed during the conversion of 1a
into 2. The first triflation probably occurs in the a position
to the amide carbonyl group; the only equatorial hydroxyl
group is located at this position.[4,8] Subsequent triflation of
O-7 triggers the elimination reaction to form the vinyltri-
flate, and the triflation of O-8 induces the oxirane ring for-
mation by nucleophilic attack of O-9. Other 7,5-membered
thiazolidinlactams, of which only the acid 1b is shown, yield
partially sulfonated reaction products with triflic anhydride
in lower yields. Crystalline lactone 3 (Scheme 1) is shown as
an example in Figure 1.
C-7. Acylation of
7 yields the crystalline product 8
(Figure 1).[11] In spite of kinetic studies, the reason for these
opposite selectivities could not be clarified. The amide
proton and the ester carbonyl group form a hydrogen bond
in the crystal structure of 8, suggesting that this carbonyl
group assists the nucleophilic attack of NH3 to C-7 of 2. The
alternative stereochemistries of compounds 6 and 8 at C-7
were confirmed by the results of NMR spectroscopy (see
Table 1). The chemical shifts and the coupling constants
3
3J9H,9aH and J8H,9H indicate that the epoxide remains intact.
Different nucleophiles add selectively to one of the four
electrophilic sites of 2, thus permitting the stepwise modifi-
Differences in J7,8 and J6,7 between both compounds prove
the inverted stereochemistry at C-7. The anti orientation of
6408
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Chem. Eur. J. 2005, 11, 6407 – 6413

Secondary Hydroxyl Groups of d-Glucuronic Acid
FULL PAPER
Table 1. 1H NMR chemical shifts (600 MHz, [D6]DMSO) and 3J-cou-
plings of 6 and 8.
6
8
d [ppm]
JH,H [Hz]
d [ppm]
JH,H[Hz]
6
7
8
9
5.20
3.85
3.35
3.29
5.48
J
J
J
J
6,7 =9.9
7,8 <1
8,9 =3.8
9,9a <1
6.18
5.07
3.60
3.42
5.98
J
J
J
J
6,7 =2.6
7,8 =7.6
8,9 =4.3
9,9a <1
9a
the two groups in compound 6 explains the high value of
3J6H,7H. Strong NOEs between the 9a-H and 6-H in com-
pounds 6 and 8 determine the equatorial orientation of the
O-triflate groups. Sodium borohydride cleanly adds hydride
equivalents from the less-hindered side of the double bond
in 2, leading to the deoxyhexuronic derivative 9[11] shown in
Scheme 2 and Figure 2.
Scheme 3. Reaction conditions: a) NaN3, CHCl3, DMF, 8 h, 78%; b) iso-
valeryl chloride, DMF, pyridine, 20 min, 87%; c) Pd/C, H2, MeOH, 3 h,
then benzoyl chloride, pyridine, 30 min, 80%; d) Ac2O, pyridine, 408C,
48 h, quant; e) AcOH, MeOH, H2O, 24 h, 77%; f) caproyl chloride, pyri-
dine, 8 h, 85%.
C-6 opposes the one observed in the reaction of azide with
the 6-O-triflate of the parent compound 1a, as described in
the literature [8]. Acylation of 10 with isovaleryl chloride af-
forded 11. Subsequently, the azide was reduced and the re-
sulting amine was acylated with benzoyl chloride. Unexpect-
edly, in a one-pot reaction, the benzoyl carbonyl oxygen at-
tacked the epoxide regioselectively, thus forming the oxa-
zine 12 and rendering O-9 accessible for further transforma-
tions. Crystalline 13[11] (Figure 2) was obtained after
acylation of O-9 with Ac2O. The six-membered oxazine ring
was opened under mild acidic conditions (13!14) and the
resulting derivative was acylated with caproyl chloride,
yielding 15. The thiazolidine ring remains intact under the
transformations studied so far. Compound 15 can be ob-
tained from the commercial sugar precursor d-glucorono-
1,3-lactone in only nine steps, and contains all of the phar-
macophoric groups that were identified for the macrolide
hapalosin in sugar molecular libraries: methyl, branched
alkyl, long-chain alkyl, and aromatic side-chains.[12] The
seven-membered ring populates a twist-boat conformation
because it cannot bear four axial groups, and the substitu-
ents in ring positions 6 and 7 assume pseudoequatorial ori-
Figure 2. Crystal structures of triflate 9, oxazine 13, and azide 17.
3
In principle, each of the monoadducts 4, 6, 8, and 9 can
add a second and even a third nucleophile. Only a few of
the many possible combinations have been studied to date,
and only O- and N-nucleophiles are described in this manu-
script. The reaction sequence in Scheme 3 shows that all of
the reactive sites of 2 remain accessible to nucleophiles, in
spite of the increasing steric bulk visible in the crystal struc-
tures of Figure 1. The triflate group of 7 was exchanged
against azide to form compound 10 (Scheme 3). An SN2-
type reaction is expected, although the stereochemistry at
entations. As a consequence, large J coupling constants are
3
3
measured for J6H,7H (10.1 Hz) and J7H,8H (9.1 Hz), whereas
3J8H,9H (2.5 Hz) and J9H,9aH (<2 Hz )
3
remain small. The unexpectedly
stable oxazine derivative is not
only formed with benzoyl chloride:
acylation of 11 with caproyl chlo-
ride (Scheme 3 step c) followed by
benzoyl chloride (step f) leads to
16, in which the side chains in ring
Chem. Eur. J. 2005, 11, 6407 – 6413
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6409

A. Geyer and K. goston
positions 6 and 8 are swapped relative to the situation in
compound 15.
The C-7 defunctionalized thiazolidinlactam 9 can also be
converted into bicyclic peptidomimetics, as shown in
Scheme 4. Clean inversion of the configuration at C-6 is ob-
ing materials d-glucuronic acid and l-cysteine methyl ester
in only two synthetic steps, and has as many orthogonal re-
action centers as other molecular library templates.[3a] Com-
pound 2 offers alternative reaction scenarios, such as the
one exemplified in Scheme 3, and the methyl ester function
of compound 1 remains intact in all transformations. This
allows the syntheses shown here to be transferred to a solid
support to diversify the key intermediate 2 into a four-point
molecular library.
Experimental Section
General remarks: Solvents were purified according to standard proce-
dures. Flash chromatography was performed by using J. T. Baker silica
gel 60 (0.040–0.063 mm) at a pressure of 0.4 bar. Thin layer chromatogra-
phy was performed by using Merck silica gel plastic plates, 60F254; com-
pounds were visualized by treatment with
a
solution of
(NH4)6Mo7O24·4H2O (20 g) and Ce(SO4)2 (0.4 g) in 10% sulfuric acid
(400 mL) and heating at 1508C. All compounds had a white to yellowish
color, unless otherwise indicated. NMR spectra were recorded by using
Bruker Avance 400 or 600 spectrometers. TMS, or the resonance of the
residual solvent ([D6]DMSO: d=2.49 ppm), was used as internal stan-
dard. All 13C assignments are based on inverse CH correlations (HMQC
and HMBC). ROESY spectra were aquired for most of the compounds,
to confirm relative stereochemistries.
Scheme 4. Reaction conditions: a) NaN3, CHCl3, DMF, 0.5 h, 80%;
b) EtOH, CHCl3, BF3/Et2O, 7 d, 85%; c) HS-(CH2)3-SH, MeOH, 5 h,
then benzoyl chloride, pyridine, 2 h, 60%; d) BnOH, CHCl3, BF3/Et2O,
7 d, 85%; e) NaBH4, MeOH, DCM, RT, 30 min, then NaN3, DMF, 2 h,
75%; f) Pd/C, H2, MeOH, 1 h, then isobutyryl chloride, pyridine, 30 min,
68%; g) 1n LiOH, MeOH, then neutralization with HCl and hexylamine,
pyBOP, DMF, 2 h, 60%.
Compound 2: Tf2O (81.9 mmol, 13.8 mL) was added dropwise to a solu-
tion of alcohol 1a (4 g, 13.6 mmol) and 4-dimethylaminopyridine
(DMAP) (200 mg) in pyridine (30 mL) and dry DCM (200 mL) at 08C.
The mixture was stirred for 12 h at RT, then diluted with toluene
(500 mL) and washed with water (2”100 mL). The organic phase was
dried (NaSO4), filtered, and concentrated. Column chromatography (pe-
troleum ether/ethyl acetate 1:1) of the residue afforded crystalline elimi-
nation product 2 (4.2 g, 80%). [a]2D0 =ꢀ207.8 (c=1, CHCl3); 1H NMR
served with the azide nucleophile, leading to 17. The SN2-
type reaction is proven by the crystal structures of 9 and 17
shown in Figure 2. Reduction of the azide and subsequent
acylation yielded the benzamide 19. The azide 20 was ob-
tained by two routes: Firstly, by the BF3/Et2O-catalyzed nu-
cleophilic opening of the oxirane 17. Secondly, along an ex-
changed order of Lewis acid-catalyzed oxirane opening (2!
4), double-bond reduction with NaBH4, and triflate-to-azide
exchange, yielding 20. A branched alkyl chain was intro-
duced by reduction and amide bond formation with isobu-
tyryl chloride, yielding 21. The linear alkyl chain was intro-
duced by ester saponification and coupling to hexylamine
with benzotriazol-1-yl-oxytripyrrolidinophosphonium hexa-
fluorophosphate pyBOP (22).
3
(600 MHz, [D6]DMSO): d=7.03 (d, J7,8 =5.71 Hz, 1H; H-7), 5.35 (s, 1H;
H-9a), 5.01 (dd, 3J3,2 =6.78, 4.94 Hz, 1H; H-3), 3.88 (d, 3J8,9 =4.06 Hz,
1H; H-9), 3.66 (s, 3H; OMe), 3.62 (dd, 1H; H-8), 3.42, 3.26 ppm (each
dd, Jgem =11.89 Hz, 2H; H-2, 2a); 13C NMR: d=168.29, 158.08 (C=O),
140.29 (C-6), 128.16 (C-7), 67.73 (C-9), 63.81 (C-3), 58.46 (C-9a), 52.26
(OMe), 46.90 (C-8), 31.35 ppm (C-2); ESI-MS: m/z: 407.0 [M++NH4],
796.1 [2M++NH4]; HRMS: m/z: calcd for C11H11F3NO7S2: 389.9924;
found: 389.9923 [M+].
Compound 3: Tf2O (3 mL) was added dropwise to a solution of acid 1b
(1.5 g 5.37 mmol) in pyridine (50 mL) and dry DCM (25 mL) at 08C. The
mixture was stirred for 1 h at RT, then diluted with toluene (500 mL) and
washed with water (2”100 mL). The organic phase was dried (NaSO4),
filtered, and concentrated. Column chromatography (petroleum ether/
1
ethyl acetate 2:3) afforded lactone 3 (790 mg, 37%). H NMR (600 MHz,
[D6]DMSO): d=6.29 (s, 1H; H-6), 6.28 (d, J7,OH =4.80 Hz, 1H; 7-OH),
6.25 (d, J8,OH =4.30 Hz, 1H; 8-OH), 6.23 (s, 1H; H-9a), 5.31 (d, J2,3
=
5.29 Hz, 1H; H-3), 4.36 (d, J8,9 =3.71 Hz, 1H; H-9), 4.07 (m, 1H; H-8),
4.05 (m, 1H; H-7), 3.33 ppm (m, 2H; H-2); 13C NMR: d=165.52 (CO2),
164.02 (C-5), 84.42 (C-6), 83.95 (C-9), 72.85 (C-7), 69.10 (C-8), 61.15 (C-
Conclusion
3), 52.67 (C-9a), 33.53 ppm (C-2); HMBC: JH9,COO.
Compound 4: BF3/EtO2 (100 mL) was added to a solution of epoxide 2
(1 g, 2.57 mmol) and benzyl alcohol (12.8 mmol, 1.32 mL) in dry CHCl3
(50 mL). The mixture was stirred for 20 h at 508C, then diluted with
DCM (200 mL), washed with saturated NaHCO3 (2”50 mL) and water
(2”50 mL), dried (NaSO4), filtered, and concentrated. Column chroma-
tography (dichloromethane/ethyl acetate 97:3) of the residue afforded
The axial hydroxyl groups of 1 react in elimination reactions
and can be refunctionalized subsequently by the addition of
nucleophiles. The 7,5-bicyclic thiazolidinlactam scaffold can
lock substituents in preferred conformations more efficiently
than is possible with a monocyclic pyranose ring. Thus, some
reaction channels are opened and others are closed, with the
effect that Michael addition, epoxide opening, and triflate
exchange have different susceptibilities towards nucleophilic
attack. Compound 2 can be obtained from the cheap start-
benzyl ether
4 (960 mg, 75%) as a
syrup. 1H NMR (600 MHz,
[D6]DMSO): d=7.38 (m, 5H; Ph), 6.97 (d, 3J7,8 =4.04 Hz, 1H; H-7), 6.09
(d, 3JOH,9 =4.64 Hz, 1H; OH), 5.26 (d, 3J9,9a =3.03 Hz, 1H; H-9a), 4.89
(dd, 3J3,2 =6.86, 9.08 Hz, 1H; H-3), 4.66 (ABq, 2H; CH2Ph), 4.34 (dd,
3J8,9 =7.06 Hz, 1H; H-8), 4.11 (ddd, 1H; H-9), 3.63 (s, 3H; OMe), 3.41,
3.34 ppm (each dd, Jgem =11.10 Hz, 2H; H-2, 2a); 13C NMR: d=168.81,
6410
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Secondary Hydroxyl Groups of d-Glucuronic Acid
FULL PAPER
159.63 (C=O), 138.35, 137.62 (C-6, aromatic quat), 133.78 (C-7), 128.80,
128.50 (Ph), 79.74 (C-9), 79.50 (C-8), 72.19 (CH2Ph), 66.37 (C-9a), 62.68
(C-3), 52.42 (OMe), 32.61 ppm (C-2); ESI-MS: m/z: 498.0 [M++H],
515.0 [M++NH4], 536.0 [M++K].
tate 1:1) of the residue afforded crystalline triflate 9 (450 mg, 90%).
1H NMR (600 MHz, [D6]DMSO): d=5.93 (dd, 3J6,7 =4.12, 12.08 Hz, 1H;
H-6), 5.90 (s, 1H; H-9a), 4.98 (pt, 3J3,2 =5.76 Hz, 1H; H-3), 3.65 (s, 3H;
OMe), 3.42–3.12 (m, 4H; H-8, H-9, H-2, 2a), 2.55, 2.35 (each m, 2H;
H-7, 7a); ESI-MS: m/z: 409.0 [M++NH4], 800.0 [2M++NH4].
Compound 5: Ac2O (1 mL) was added to a solution of alcohol 4 (100 mg,
200 mmol) in pyridine (2 mL). The mixture was maintained for 8 h at RT,
then concentrated. K2CO3 (200 mg) was added to a solution of the crude
intermediate in CHCl3 (10 mL), MeOH (10 mL), and water (0.5 mL).
The mixture was stirred for 1 h, then diluted with ethyl acetate (50 mL)
and washed with water (2”10 mL). The organic phase was dried
(NaSO4), filtered, and concentrated. Column chromatography (petroleum
ether/ethyl acetate 1:1) of the residue afforded ketoamide 5 (80 mg
quant). 1H NMR (600 MHz, [D6]DMSO): d=7.40–7.25 (m, 5H; aromat-
ic), 5.61 (d, J9,9a =2.22 Hz, 1H; H-9a), 5.32 (dd, J8,9 =6.86 Hz, 1H; H-9),
4.97 (pt, J2,3 =6.46 Hz, 1H; H-3), 4.58 (ABq, 2H; -CH2Ph), 4.10 (ddd,
Compound 10: NaN3 (320 mg, 4.92 mmol) was added to a solution of tri-
flate 7 (1.00 g, 2.46 mmol) in DMF (20 mL) and DCM (5 mL), and the
mixture was stirred for 8 h at RT. Then the solvents were removed and
column chromatography (toluene/ethyl acetate/methanol 1:4:1) of the
residue gave azide 10 (574 mg, 78%) as a syrup. 1H NMR (600 MHz,
[D6]DMSO): d=5.85 (s, 1H; H-9a), 4.88 (dd, J2,3 =4.42, 6.30 Hz, 1H; H-
3), 4.30 (d, J6,7 =5.45 Hz, 1H; H-6), 3.63 (s, 3H; OMe), 3.48 (dd, J7,8
<2 Hz, 1H; H-7), 3.38–3.15 (m, 4H; H-8, H-9, H-2), 1.80 ppm (brs, 1H;
NH2); 13C NMR: d=168.77, 164.73 (C=O), 68.15 (C-6), 64.49 (C-3), 59.22
(C-9a), 56.98, 55.04 (C-8, C-9), 52.09 (OMe), 47.07 (C-7), 29.85 ppm (C-
2); ESI-MS: m/z: 299.8 [M++H], 599.2 [2M++H]; elemental analysis
calcd (%) for C10H13N5O4S (299.31): C 40.13, H 4.38, N 23.40; found: C
39.98, H 4.34, N 23.21.
J
J
7,8 =3.03, 10.70 Hz, 1H; H-8), 3.61 (s, 3H; OMe), 3.35, 3.24 (each dd,
gem =11.30 Hz, 2H; H-2), 3.13, 2.96 (each dd, Jgem =14.56 Hz, H-7),
2.03 ppm (s, 3H; OAc); 13C NMR: d=196.48 (C-6), 169.36, 168.68,
161.78 (C=O), 137.96, 128.21, 127.65, 127.56 (aromatic), 74.67 (C-9),
74.42 (C-8), 70.49 (-CH2Ph), 61.98 (C-3), 61.26 (C-9a), 52.29 (OMe),
41.17 (C-7), 31.57 (C-2), 20.54 ppm (Ac); ESI-MS: m/z: 407.2 [M+]; ele-
mental analysis calcd (%) for C19H21NO7S (407.44): C 56.01, H 5.20, N
3.44; found: C 56.21, H 5.20, N 3.41.
Compound 11: Isovaleryl chloride (300 mL) was added to a solution of
amine 10 (500 mg, 1.67 mmol) in DMF (5 mL) and pyridine (1 mL), and
the mixture was kept for 20 min at RT. Then the solvents were removed
and column chromatography (petroleum ether/ethyl acetate1:2) of the
residue gave amide 11 (556 mg, 87%) as a syrup. 1H NMR (600 MHz,
[D6]DMSO): d=7.00 (d, J7,NH =8.68 Hz, 1H; NH), 5.89 (s, 1H; H-9a),
4.90 (dd, J2,3 =5.04, 6.46 Hz, 1H; H-3), 3.48 (ddd, J6,7 =5.86 Hz, J7,8
<2 Hz, 1H; H-7), 4.37 (d, 1H; H-6), 3.70 (s, 3H; OMe), 3.47 (m, 2H; H-
8, H-9), 3.38, 3.15 (each dd, Jgem =11.70 Hz, 2H; H-2), 2.01 (m, 2H;
COCH2-), 1.95 (m, 1H; -CH(CH3)2), 0.89, 0.87 ppm (each d, 6H; -CH-
(CH3)2); 13C NMR: d=171.24, 169.58, 164.34 (C=O), 64.62 (C-3), 64.04
(C-6), 59.18 (C-9a), 56.58, 52.58 (C-8, C-9), 52.46 (OMe), 44.56 (CO-
CH2-), 43.68 (C-7), 29.92 (C-2), 25.45 (CH(CH3)2), 22.28, 22.19 ppm (CH-
(CH3)2); ESI-MS: m/z: 383.9 [M++H], 405.9 [M++Na]; elemental analy-
sis calcd (%) for C15H21N5O5S (383.42): C 46.99, H 5.52, N 18.27; found:
C 46.79, H 5.50, N 18.11.
Compound 6: K2CO3 (100 mg) was added to a solution of enol-triflate 2
(100 mg, 0.26 mmol) in MeOH (1 mL) and DCM (5 mL). The mixture
was stirred for 5 d, then diluted with DCM (50 mL), and washed with
water (3”20 mL). The organic phase was dried (NaSO4), filtered, and
concentrated. Column chromatography (petroleum ether/ethyl acetate
6:4) of the residue afforded methyl ether 6 (82 mg, 78%) as a syrup.
3
1H NMR (600 MHz, CDCl3): d=5.48 (s, 1H; H-9a), 5.20 (d, J6,7
=
9.87 Hz, 1H; H-6), 5.08 (dd, 3J3,2 =5.43, 5.46 Hz, 1H; H-3), 3.85 (d, 1H;
H-7), 3.78 (s, 3H; OMe), 3.63 (s, 3H; OMe), 3.43, 3.25 (each dd, Jgem
=
11.85 Hz, 2H; H-2, 2a), 3.35 (d, 3J8,9 =3.75 Hz, 1H; H-8), 3.29 ppm (d,
1H; H-9); 13C NMR: d=167.95, 160.90 (C=O), 82.17 (C-6), 73.93 (C-7),
64.45 (C-3), 60.13 (OMe), 59.32 (C-9a), 55.31 (C-8), 55.16 (C-9), 52.79
Compound 12
(OMe), 31.23 ppm (C-2); MS (in DCM
+
NH4Ac): m/z: 438.9 [M+
Procedure A: Propanedithiol (100 mL) was added to a solution of azide
11 (100 mg, 0.26 mmol) in MeOH (10 mL) and the mixture was kept for
two days at RT, then benzoyl chloride (150 mL) was added at 08C and
stirred for 30 min. The solvents were removed and column chromatogra-
phy (petroleum ether to petroleum ether/ethyl acetate 4:1) of the residue
gave oxazine 12 (78 mg, 65%) as a syrup.
+NH4].
Compound 7: Ammonium formiate (1 g) was added to a solution of enol-
triflate 2 (1 g, 2.57 mmol) in MeOH (20 mL) and DCM (2 mL). The mix-
ture was kept for 3 d at 508C, then the solvents were removed and the
residue was redissolved in ethyl acetate (500 mL), then washed with
water (3”100 mL). The organic phase was dried (NaSO4), filtered, and
concentrated. Column chromatography (petroleum ether/ethyl acetate
1:4) of the residue afforded amine 7 (855 mg, 82%) as a syrup. 1H NMR
Procedure B: The mixture of Pd/C (100 mg) and azide 11 (500 mg,
1.30 mmol) in MeOH (15 mL) was stirred under H2 for 3 h. Then the
mixture was filtered through celite, washed with MeOH, and concentrat-
ed. The residue was dissolved in pyridine (5 mL), then benzoyl chloride
(200 mL) was added and stirred for 30 min. Then the mixture was concen-
trated. Column chromatography (petroleum ether to petroleum ether/
ethyl acetate 4:1) of the residue gave oxazine 12 (480 mg, 80%) as a
3
(600 MHz, [D6]DMSO): d=5.95 (d, J6,7 =2.75 Hz, 1H; H-6), 5.92 (s, 1H;
H-9a), 4.93 (dd, 3J3,2 =6.60, 6.24 Hz, 1H; H-3), 3.68 (dd, 3J7,8 =7.16 Hz,
1H; H-7), 3.66 (s, 3H; OMe), 3.48 (dd, 3J8,9 =4.22 Hz, 1H; H-8), 3.36 (d,
1H; H-9), 3.34, 3.19 (each dd, Jgem =11.55 Hz, 2H; H-2, 2a), 1.75 ppm (d,
2H; NH2); 13C NMR: d=168.49, 162.92 (C=O), 85.36 (C-6), 63.91 (C-3),
59.51 (C-9), 58.03 (C-9a), 55.01 (C-8), 52.29 (OMe), 48.94 (C-7),
30.50 ppm (C-2); ESI-MS: m/z: 406.8 [M++H], 423.9 [M++NH4].
1
syrup. H NMR (600 MHz, [D6]DMSO): d=7.92–7.41 (m, 5H; aromatic),
7.52 (d, J7,NH =9.50 Hz, 1H; NH), 6.56 (d, J9,OH =5.23 Hz, 1H; 9-OH),
5.10 (s, 1H; H-9a), 4.67 (dd, J2,3 =9.30, 6.95 Hz, 1H; H-3), 4.65 (ddd,
J
7,8 =4.35 Hz, J =
8,9 =5.23 Hz, 4J6,8 <2 Hz, 1H; H-8), 4.62 (ddd, J6,7
Compound 8: Ac2O (1 mL) was added to a solution of amine 7 (100 mg,
0.24 mmol) in pyridine (2 mL) and kept for 8 h at RT, then the mixture
was concentrated. Column chromatography (petroleum ether/ethyl ace-
tate 6:4) of the residue afforded acetamide 8 (105 mg, 95%) as crystals.
6.42 Hz, 1H; H-7), 4.31 (dd, 1H; H-6), 4.08 (dd, 1H; H-9), 3.70 (s, 3H;
OMe), 3.28, 3.24 (each dd, Jgem =11.37 Hz, 2H; H-2), 2.10–2.00 (m, 3H;
COCH2-, -CH(CH3)2), 0.91, 0.88 ppm (each d, 6H; -CH(CH3)2);
3
1H NMR (600 MHz, [D6]DMSO): d=7.07 (d, JNH,7 =10.22 Hz, 1H; NH),
13
ꢀ
C NMR: d=171.32, 169.97, 165.87 (C=O), 155.31 (O C=N), 131.68,
3
6.16 (d, 3J6,7 =2.61 Hz, 1H; H-6), 5.97 (s, 1H; H-9a), 5.06 (ddd, J7,8
=
131.51, 128.24, 127.63 (aromatic), 72.79 (C-8), 72.45 (C-9), 65.63 (C-3),
61.09 (C-9a), 60.95 (C-6), 52.25 (OMe), 44.65 (COCH2-), 41.91 (C-7),
30.68 (C-2), 25.29 (CH(CH3)2), 22.43, 22.16 ppm (CH(CH3)2); ESI-MS:
m/z: 462.1 [M++H], 479.1 [M++NH4], 923 [2M++H]; elemental analysis
calcd (%) for C22H27N3O6S (461.53): C 57.25, H 5.90, N 9.10; found: C
57.29, H 5.88, N 9.04.
7.16 Hz, 1H; H-7), 4.94 (dd, 3J3,2 =6.89, 7.30 Hz, 1H; H-3), 3.76 (s, 3H;
OMe), 3.60 (dd, 3J8,9 =4.28 Hz, 1H; H-8), 3.44 (d, 1H; H-9), 3.42, 3.18
(each dd,
Jgem =11.89 Hz, 2H; H-2, 2a), 1.91 ppm (s, 3H; NHAc);
13C NMR: d=169.60, 168.66, 163.02 (C=O), 83.46 (C-6), 64.24 (C-3),
59.67 (C-9a), 57.99 (C-9), 2”52.92 (C-8, OMe), 44.92 (C-7), 30.51 (C-2),
22.59 ppm (NHAc); ESI-MS: m/z: 449.0 [M++H], 466.0 [M++NH4].
Compound 13: Ac2O (2 mL) was added to a solution of alcohol 12
(100 mg, 0.22 mmol) in pyridine (5 mL) and the mixture was maintained
at 408C for 48 h. Then the mixture was concentrated and column chro-
matography (petroleum ether/ethyl acetate 3:2) of the residue gave ester
13 (102 mg, quant) crystals. 1H NMR (600 MHz, [D6]DMSO): d=7.85–
7.38 (m, 5H; aromatic), 7.34 (d, J7,NH =10.03 Hz, 1H; NH), 5.34 (s, 1H;
Compound 9: NaBH4 (1.42 mmol, 54 mg) was added to a solution of
enol-triflate 2 (500 mg, 1.29 mmol) in MeOH (15 mL) and stirred for
10 min. Then the mixture was diluted with DCM (100 mL) and washed
with water (2”20 mL). The organic phase was dried (Na2SO4), filtered,
and concentrated. Column chromatography (petroleum ether/ethyl ace-
Chem. Eur. J. 2005, 11, 6407 – 6413
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6411

A. Geyer and K. goston
H-9a), 5.22 (dd, J8,9 =4.12 Hz, 1H; H-9), 4.92 (dd, J2,3 =6.96, 7.95 Hz, 1H;
rated. Column chromatography (petroleum ether/ethyl acetate 1:1) of the
4
H-3), 4.82 (ddd, J6,7 =6.64 Hz, J7,8 =5.22 Hz, 1H; H-7), 4.72 (ddd, J6,8
=
residue afforded crystalline azide 17 (47 mg, 80%). 1H NMR (600 MHz,
3
1.95 Hz, 1H; H-8), 4.38 (dd, 1H; H-6), 3.78 (s, 3H; OMe), 3.25, 3.15
[D6]DMSO): d=5.82 (s, 1H; H-9a), 4.82 (dd, J3,2 =3.67, 6.42 Hz, 1H; H-
(each dd, Jgem =11.37 Hz, 2H; H-2), 2.10–2.00 (m, 3H; COCH2-, -CH-
3), 4.40 (dd, 3J6,7 =2.38, 5.14 Hz, 1H; H-6), 3.56 (s, 3H; OMe), 3.26, 3.11
(each dd, Jgem =11.73 Hz, 2H; H-2, H-2a), 3.22–3.20 (m, 2H; H-8, H-9),
2.42, 2.18 ppm (each m, Jgem =14.12 Hz, 2H; H-7, 7a); 13C NMR: d=
168.72, 165.77 (C=O), 64.48 (C-3), 62.23 (C-6), 58.98 (C-9a), 54.52 (C-9),
51.96 (OMe), 51.10 (C-8), 30.07 (C-2), 26.24 ppm (C-7); ESI-MS: m/z:
285.0 [M++H], 302.0 [M++NH4]. C10H12N4O4S (284.29): calcd C 42.25,
H 4.25, N 19.71; found: C 42.04, H 4.23, N 19.60.
(CH3)2), 2.09 (s, 3H; OAc), 0.91, 0.88 ppm (each d, 6H; -CH(CH3)2);
13
ꢀ
C NMR: d=171.47, 170.91, 168.7, 165.93 (C=O), 155.35 (O C=N),
131.62, 131.39, 128.18, 127.84 (aromatic), 71.64 (C-9), 69.95 (C-8), 65.27
(C-3), 60.71 (C-6), 59.75 (C-9a), 52.75 (OMe), 44.58 (COCH2-), 40.96 (C-
7), 30.25 (C-2), 25.46 (CH(CH3)2), 22.44, 22.09 (CH(CH3)2), 20.43 ppm
(OAc); ESI-MS: m/z: 503.2 [M+]; elemental analysis calcd (%) for
C24H29N3O7S (503.57): C 57.24, H 5.80, N 8.34; found: C 57.02, H 5.76, N
8.30.
Compound 18: BF3/EtO2 (50 mL) was added to a solution of azide 17
(100 mg, 0.35 mmol) and absolute EtOH (1.0 mL) in dry CHCl3 (10 mL).
The mixture was stirred for 1 week at RT, then diluted with DCM
(200 mL), washed with saturated NaHCO3 (2”50 mL) and water (2”
50 mL), dried (NaSO4), filtered, and concentrated. Column chromatogra-
phy (petroleum ether/ethyl acetate 3:2) of the residue afforded ethyl
Compound 14: AcOH (300 mL) was added to a solution of oxazine 13
(100 mg, 0.20 mmol) in MeOH (2 mL) and water (5 mL), and the mixture
kept at room temperature for 24 h. Then the mixture was concentrated
and subjected to column chromatography (petroleum ether/ethyl acetate
1:3) to give benzamide 14 (80 mg, 77%) as a syrup. 1H NMR (600 MHz,
[D6]DMSO): d=8.53, 8.03 (each brs, 2H; 2NH), 7.75–7.48 (m, 5H; aro-
matic), 6.28 (d, J9,9a =2.47 Hz, 1H; H-9a), 5.43 (brs, 1H; OH), 5.00 (dd,
ether 18 (98 mg, 85%) as a syrup. 1H NMR (600 MHz, [D6]DMSO): d=
3
5.53 (s, 1H; H-9a), 5.20 (d, 3J9,OH =4.52 Hz, 1H; 9-OH), 4.75 (dd, J3,2
=
5.70, 6.89 Hz, 1H; H-3), 4.58 (dd, 3J6,7 =4.52, 8.08 Hz, 1H; H-6), 3.56 (m,
4H; H-9, OMe), 3.58–3.45 (m, 3H; H-8, -OCH2CH3), 3.31, 3.23 (each dd,
J
8,9 =6.59 Hz, 1H; H-9), 4.73 (pt, J2,3 =5.53 Hz, 1H; H-3), 4.52–4.38 (m,
J
gem =11.47 Hz, 2H; H-2, H-2a), 2.11, 2.00 (each m, Jgem =15.03 Hz, 2H;
2H; H-6, H-7), 3.82 (ddd, J7,8 =7.55 Hz, 1H; H-8), 3.68 (s, 3H; OMe),
3.30, 3.13 (each dd, Jgem =11.25 Hz, 2H; H-2), 2.07 (s, 3H; OAc), 2.00–
1.90 (m, 3H; COCH2-, -CH(CH3)2), 0.85 ppm (2”d, 6H; -CH(CH3)2);
13C NMR: d=171.66, 169.32, 169.26, 167.43, 166.2 (C=O), 134.69, 130.98,
128.02, 127.20 (aromatic), 78.04 (C-9), 69.77 (C-8), 65.60 (C-3), 59.72 (C-
9a), 57.53 (C-6), 52.10 (OMe), 44.20 (COCH2-), 31.19 (C-2), 25.42 (CH-
(CH3)2), 22.16 (2CH(CH3)2), 20.71 ppm (OAc); ESI-MS: m/z: 522.3 [M+
+H], 544.3 [M++Na], 1043.5 [2M++H].
H-7, 7a), 1.12 ppm (t, 3J=6.89 Hz, 3H; -CH3); 13C NMR: d=170.4,
166.84 (C=O), 77.91 (C-8), 73.04 (C-9), 64.53 (-OCH2CH3), 63.79 (C-3),
61.42 (C-9a), 61.27 (C-6), 52.37 (OMe), 30.97 (C-2), 28.11 (C-7),
15.25 ppm (CH3). C12H18N4O5S (330.36): calcd C 43.63, H 5.49, N 16.96;
found: C 43.44, H 5.45; N 17.04.
Compound 19: Propanedithiol (10 mL) was added to a solution of azide
18 (50 mg, 0.15 mmol) in MeOH (5 mL) and the mixture was kept for 5 h
at RT, then benzoyl chloride (100 mL) was added at 08C and stirred for
2 h. The solvents were removed and column chromatography (petroleum
ether/ethyl acetate 1:2) of the residue gave benzamide 19 (38 mg, 60%)
as a syrup. 1H NMR (600 MHz, [D6]DMSO): d=8.91 (brs, 1H; 6-NH),
7.80, 7.55, 7.48 (each m, 5H; aromatic), 5.80 (s, 1H; H-9a), 5.28 (d,
3J9,OH =4.60 Hz, 1H; 9-OH), 4.67 (pt, 3J3,2 =6.58 Hz, 1H; H-3), 4.52 (m,
1H; H-6), 3.72 (pt, 3J8,9 =4.60 Hz, 1H; H-9), 3.66 (s, 3H; OMe), 3.60–
3.52 (m, 3H; H-8, -OCH2CH3), 3.33, 3.22 (each dd, Jgem =11.18 Hz, 2H;
H-2, H-2a), 2.17, 2.02 (each m, Jgem =14.69 Hz, 2H; H-7, 7a), 1.12 ppm (t,
3J=6.80 Hz, 3H; -CH3); 13C NMR: d=170.60, 168.85, 165.57 (C=O),
133.70, 131.37, 128.36, 127.04 (aromatic), 79.21 (C-8), 73.99 (C-9), 64.54
(-OCH2CH3), 64.28 (C-3), 61.72 (C-9a), 52.89 (C-6), 52.24 (OMe), 30.88
(C-2), 26.43 (C-7), 15.41 ppm (-CH3); ESI-MS: m/z: 409.0 [M++H],
431.0 [M++Na], 447.0 [M++K], 839.5 [2M++Na]. C19H24N2O6S (408.47):
calcd C 55.87, H 5.92, N 6.86; found: C 56.01, H 5.94, N 6.69.
Compound 15: Caproyl chloride (50 mL) was added to a solution of alco-
hol 14 (50 mg, 96 mmol) in pyridine (2 mL) and the mixture was stirred
for 8 h. Then the mixture was diluted with ethyl acetate, washed three
times with water, the organic phase was dried, filtered, and concentrated.
Column chromatography (petroleum ether/ethyl acetate 1:1) of the resi-
due afforded ester 15 (49 mg, 85%) as a syrup. 1H NMR (600 MHz,
CDCl3): d=7.75–7.38 (m, 5H; aromatic), 7.07 (d, J7,NH =9.33 Hz, 1H; 7-
NH), 6.59 (d, J6,NH =4.94 Hz, 1H; 6-NH), 5.65 (s, 1H; H-9a), 5.47 (d,
J
8,9 =2.47 Hz, 1H; H-9), 5.36 (dd, J7,8 =9.06 Hz, 1H; H-8), 4.99 (dd, J2,3 =
2.31, 7.17 Hz, 1H; H-3), 4.94 (ddd, J6,7 =10.08 Hz, 1H; H-7), 4.86 (dd,
1H; H-6), 3.67 (s, 3H; OMe), 3.37, 3.19 (each dd, Jgem =12.35 Hz, 2H; H-
2), 2.23 (s, 3H; OAc), 2.25, 2.04, 1,49, 1.2, 1.13 (each m, 11H; aliphatic),
0.80, 0.68 (each d, 6H; -CH(CH3)2), 0.72 ppm (t, 3H; -CH2CH3);
13C NMR: d=174.80, 174.54, 169.19, 169.03, 167.25, 167.13 (C=O),
133.01, 132.01, 128.62, 127.13 (aromatic), 73.94 (C-8), 69.33 (C-9), 64.72
(C-3), 62.62 (C-9a), 53.46 (C-6), 52.71 (OMe), 50.90 (C-7), 45.43,
Compound 20
(COCH2-),
34.06
(-COCH2CH2-),
31.50,
29.71,
22.28
Procedure A: BF3/EtO2 (50 mL) was added to a solution of epoxide 17
(100 mg, 0.35 mmol) and absolute BnOH (1.0 mL) in dry CHCl3 (10 mL).
The mixture was stirred for 1 week at RT, then diluted with DCM
(200 mL), washed with saturated NaHCO3 (2”50 mL) and water (2”
50 mL), dried (NaSO4), filtered, and concentrated. Column chromatogra-
phy (petroleum ether/ethyl acetate 3:2) of the residue afforded benzyl-
ether 20 (110 mg, 85%) as a syrup.
(-COCH2CH2CH2CH2-), 31.05 (C-2), 24.43 (-CH(CH3)2), 22.50, 22.14,
20.73, 13.67 ppm (4”CH3); ESI-MS: m/z: 620.3 [M++H], 642.3 [M+
+Na]. C30H41N3O9S (619.73): calcd C 58.14, H 6.67, N 6.78; found: C
58.31, H 6.64, N, 6.58.
Analytical data of compound 16: 1H NMR (600 MHz, [D6]DMSO): d=
8.70 (d, J6,NH =7.23 Hz, 1H; 6-NH), 7.75–7.40 (m, 5H; aromatic), 7.71
(brs, 1H; 7-NH), 6.37 (d, J9a,9 <2 Hz, 1H; H-9a), 5.37 (dd, J8,9 =6.80 Hz,
1H; H-9), 5.22 (dd, J7,8 =10.3 Hz, 1H; H-8), 4.73 (pt, J2,3 =7.02 Hz, 1H;
H-3), 4.62 (m, 1H; H-7), 4.11 (m, 1H; H-6), 3.70 (s, 3H; OMe), 3.30,
3.11 (each dd, Jgem =11.18 Hz, 2H; H-2), 2.10–1.85 (m, 3H; COCH2CH-,
-CH(CH3)2), 2.05 (s, 3H; OAc), 1.45, 1.20 (each m, 6H;
-CH2CH2CH2CH3), 0.88 ppm (m, 9H; 3”CH3); 13C NMR: d=172.68,
171.47, 169.28, 169.22, 167.06, 164.83 (C=O), 133.48, 129.20, 128.59,
128.15 (aromatic), 76.04 (C-9), 72.38 (C-8), 63.78 (C-3), 59.91 (C-9a),
57.79 (C-6), 52.25 (OMe), 44.59 (COCH2CH-), 34.67 (-COCH2CH2-),
30.70 (C-2), 30.59 (COCH2CH2-), 24.52 (-CH(CH3)2), 25.00. 21.67
(-COCH2CH2CH2CH2-), 22.09, 21.82, 21.82 (CH3), 20.41 ppm (Ac); ESI-
MS: m/z: 620.3 [M++H], 642.3 [M++Na]; C30H41N3O9S (619.73): calcd C
58.14, H 6.67, N 6.78; found: C 58.41, H 6.65, N 6.89.
Procedure B: NaBH4 (38 mg, 1.0 mmol) was added to a solution of enol-
triflate 4 (400 mg, 0.80 mmol) in DCM (1 mL) and MeOH (10 mL), and
stirred for 30 min. Then the mixture was diluted with DCM (50 mL) and
washed with water (3”10 mL), dried, filtered, and concentrated. The res-
idue was dissolved in DMF (10 mL), NaN3 (104 mg, 1.6 mmol) was added
and the mixture was stirred for 2 h, then diluted with toluene (50 mL),
and washed with water (3”10 mL), dried, filtered, and concentrated.
Column chromatography (petroleum ether/ethyl acetate 1:1) of the resi-
1
due afforded azide 20 (235 mg, 75% over two steps) as a syrup. H NMR
(600 MHz, [D6]DMSO): d=7.40–7.20 (m, 5H; aromatic), 5.27 (s, 1H; H-
9a), 5.27 (d, J9,OH =5.06 Hz, 1H; OH), 4.76 (dd, J2,3 =5.61, 7.09 Hz, 1H;
H-3), 4.60 (ABq,
Jgem =12.05 Hz, 2H; -CH2Ph), 4.59 (dd, J6,7 =4.64,
8.26 Hz, 1H; H-6), 3.75 (dd, J8,9 =4.32, 1H; H-9), 3.68 (s, 3H; OMe),
3.60 (ddd, J7,8 =3.58, 7.71, 1H; H-8), 3.32, 3.24 (each dd, Jgem =11.56 Hz,
2H; H-2), 2.18, 2.08 ppm (each ddd, Jgem =15.11 Hz, 2H, H-7); 13C NMR:
d=170.45, 166.86 (C=O), 138.37, 128.17, 127.97, 127.45, 127.45, 127.39
(aromatic), 77.73 (C-8), 72.97 (C-9), 70.73 (-CH2Ph), 63.83 (C-3), 61.47
Compound 17: NaN3 (26 mg, 0.4 mmol) was added to a solution of tri-
flate 9 (80 mg, 0.2 mmol) in DCM (5 mL) and DMF (5 mL). The mixture
was stirred for 30 min, then diluted with toluene (50 mL) and washed
with water (3”10 mL). The organic phase was dried, filtered, and evapo-
6412
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6407 – 6413

Secondary Hydroxyl Groups of d-Glucuronic Acid
FULL PAPER
(C-9a), 61.29 (C-6), 52.36 (OMe), 30.97 (C-2), 28.18 ppm (C-7); ESI-MS:
m/z: 393.0 [M++H], 410.1 [M++NH4], 415.0 [M++Na]. C17H20N4O5S
(392.43): calcd C 52.03, H 5.14, N 14.28; found: C 51.91, H 5.14, N 14.09.
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Compound 21: The mixture of azide 20 (200 mg, 0.51 mmol) and Pd/C
(50 mg) in MeOH (5 mL) was stirred under H2 for 1 h. Then the mixture
was filtered through celite and concentrated. The residue was dissolved
in DMF (5 mL) and pyridine (2 mL), and isobutyryl chloride (100 mL)
was added and stirred for 30 min. Then the mixture was diluted with tolu-
ene (50 mL), and washed with water (3”10 mL), dried, filtered, and con-
centrated. Column chromatography (petroleum ether/ethyl acetate/meth-
anol 3:2:1) of the residue afforded amide 21 (151 mg, 68%) as a syrup.
1H NMR (600 MHz, [D6]DMSO): d=8.16 (d, J6,NH =6.14 Hz, 1H; NH),
7.40–7.20 (m, 5H; aromatic), 5.77 (s, 1H; H-9a), 5.30 (d, J9,OH =4.86 Hz,
1H; OH), 4.68 (dd,
J2,3 =6.91, 7.17 Hz, 1H; H-3), 4.58 (ABq, 2H;
-CH2Ph), 4.36 (m, 1H; H-6), 3.75 (dd, J8,9 =5.39 Hz, 1H; H-9), 3.62 (s,
3H; OMe), 3.60 (m, 1H; H-8), 3.24, 3.22 (each dd, Jgem =11.52 Hz, 2H;
H-2), 2.29 (m, 1H; -CH(CH3)2), 2.08, 1.96 (each ddd, Jgem =14.59 Hz, 2H,
H-7), 0.94, 0.91 ppm (each d, 6H; 2”CH3); 13C NMR: d=177.76, 175.52,
170.62 (C=O), 138.43, 128.16, 128.09, 127.82, 127.58, 127.50 (aromatic),
79.04 (C-8), 70.81 (C-9), 64.17 (-CH2Ph), 61.86 (C-3), 61.86 (C-9a), 52.23,
52.09 (C-6, OMe), 33.75 (-CH(CH3)2), 30.98 (C-2), 29.56 (C-7), 19.31,
19.17 ppm (2”CH3); ESI-MS: m/z: 436 (in DCM + NH4Ac), 437.1 [M+
+H], 454.1 [M++NH4]. C21H28N2O6S (436.52): calcd C 57.78, H 6.47, N
6.42; found: C 57.49, H 6.44, N 6.40.
Compound 22: 1n LiOH solution (344 mL) was added to a solution of
methyl ester 21 (75 mg, 0.17 mmol) in MeOH (1 mL): when TLC showed
the disappearance of the starting compound, 1n HCl (344 mL) was added
to neutralize the solution, and the mixture was concentrated. The residue
was dissolved in DMF (2 mL), pyBOP (88 mg, 0.17 mmol) was added,
and the pH was adjusted to 7–8 by adding N,N-diisopropylethylamine
(DIPEA). Then the solution of hexylamine (20 mL, 0.17 mmol) in DMF
(200 mL) was added to the mixture and stirred for 2 h. The solvent was
removed and column chromatography (dichloromethane/acetone 3:2) of
the residue afforded hexylamide 22 (51 mg, 60%) as a syrup. 1H NMR
(600 MHz, [D6]DMSO): d=8.29 (t, JCH ,NH =4.95 Hz, 1H; NH-hexyl),
2
7.92 (d, J6,NH =6.86 Hz, 1H; 6-NH), 7.40–7.20 (m, 5H; aromatic), 6.72 (d,
J
9,OH =5.49 Hz, 1H; OH), 5.72 (s, 1H; H-9a), 4.63 (dd, J2,3 =3.29, 7.41 Hz,
1H; H-3), 4.52 (ABq, 2H; -CH2Ph), 4.42 (m, J6,7 =2.47, 7.41 Hz, 1H; H-
6), 3.85 (dd, J8,9 =3.84 Hz, 1H; H-9), 3.71 (m, J7,8 =3.48, 5.00 Hz, 1H; H-8),
3.26, 3.05 (each dd, Jgem =11.80 Hz, 2H; H-2), 3.05 (m, 1H; -NH2CH2-),
2.28 (m, 1H; -CH(CH3)2), 2.20, 1.95 (each ddd, Jgem =15.13 Hz, 2H, H-7),
1.20 (m, 8H; -(CH2)4CH3), 0.88 ppm (m, 9H; 3”CH3); 13C NMR: d=
175.22, 170.80, 168.62 (C=O), 138.00, 128.19, 127.56, 127.48 (aromatic),
78.91 (C-8), 71.05 (C-9), 70.71 (-CH2Ph), 65.36 (C-3), 60.38 (C-9a), 52.73
(C-6), 38.07 (-NH2CH2-), 33.89 (-CH(CH3)2), 31.89 (C-2), 29.53 (C-7),
30.84, 28.67, 25.80, 21.99 (-(CH2)4CH3), 19.30, 19.10, 19.07 ppm (-CH3);
ESI-MS: m/z: 506.3 [M++H], 523.3 [M++NH4], 528.3 [M++Na], 1011.6
[2M++H], 1033.7 [2M++Na]. C26H39N3O5S (505.67): calcd C 61.76, H
7.77, N 8.31; found: C 61.73, H 7.69, N 8.05.
[8] A. Geyer, F. Moser, Eur. J. Org. Chem. 2000, 1113–1120; P. Trem-
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2004, 69, 2727–2730.
[11] CCDC 250242 (2), 270029 (3), 250244 (8), 250243 (9), 250241 (13),
and 270028 (17) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[12] a) D. Q. Dinh, C. D. Smith, X. Du, R. W. Armstrong, J. Med. Chem.
1998, 41, 981–987; b) J. A. Olsen, K. J. Jensen, J. Nielsen, J. Comb.
Chem. 2000, 2, 143–150; c) S. Sasmal, A. Geyer, M. E. Maier, J.
Org. Chem. 2002, 67, 6260–6263; d) S. Borman, Chem. Eng. News
2003, 81, 45–56.
Acknowledgements
The authors thank Dr. M. Zabel (Fachbereich Chemie, Universität Re-
gensburg) for crystal structure analysis of compounds 2, 3, 8, 9, 13, and
17. This work was supported by the Deutsche Forschungsgemeinschaft,
the Fonds der Chemischen Industrie, and the Innovatec program of the
DAAD.
Received: May 9, 2005
Published online: August 11, 2005
Chem. Eur. J. 2005, 11, 6407 – 6413
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6413