Addition of trialkylaluminum reagents to glyconolactones. Synthesis of 1-C-methyl GlcNAc oxazoline and thiazoline

Article abstract of DOI:10.1016/S0040-4039(02)01506-X

Addition of carbon nucleophiles to 2-acetamido-2-deoxygluconolactones fails for many reagents, but trialkylaluminums add alkyl smoothly. The product of methyl addition to 2-acetamido-2-deoxy-D-gluconolactone has been converted to 1-C-methyl GlcNAc thiazoline, a potential N-acetylhexosaminidase inhibitor, and to an O-protected 1-C-Me GlcNAc oxazoline, a potential 1-C-Me GlcNAc donor.

Full text of DOI:10.1016/S0040-4039(02)01506-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7101–7104
Addition of trialkylaluminum reagents to glyconolactones.
Synthesis of 1-C-methyl GlcNAc oxazoline and thiazoline
Spencer Knapp,* Chunhua Yang and Thomas Haimowitz
Department of Chemistry & Chemical Biology, Rutgers–The State University of New Jersey, 610 Taylor Road, Piscataway,
NJ 08854-8087, USA
Received 17 June 2002; accepted 11 July 2002
Abstract—Addition of carbon nucleophiles to 2-acetamido-2-deoxygluconolactones fails for many reagents, but trialkylaluminums
add alkyl smoothly. The product of methyl addition to 2-acetamido-2-deoxy-D-gluconolactone has been converted to 1-C-methyl
GlcNAc thiazoline, a potential N-acetylhexosaminidase inhibitor, and to an O-protected 1-C-Me GlcNAc oxazoline, a potential
1-C-Me GlcNAc donor. © 2002 Elsevier Science Ltd. All rights reserved.
GlcNAc and GalNAc thiazolines 1 and 2 are powerful
inhibitors of certain N-acetylhexosaminidases because
they mimic the presumed oxazolinium intermediate 3,
but are not themselves cleaved by the enzyme.1,2 We
sought to modify 1 and 2 by incorporating substruc-
tures, including 1-C-alkyl substituents (‘R’ in box in 4),
that might occupy the aglycon hole and thus increase
inhibition by bisubstrate (linkage-bridging) binding.3
Addition of carbon nucleophiles to 2-acetamido-2-
deoxyglyconolactones 5 and 6, or their 2-azido-2-deoxy
equivalents 7 and 8, represents a possible entry to this
class of higher sugars.4
monoadduct from reactions of 5 or 6 with Wittig
reagents, Tebbe reagent, DMT,10 organolithium
reagents, or Grignard reagents. The competing side
reactions include NH deprotonation, lactone ring open-
ing, and elimination of the C-3 benzyloxy substituent.
The mildly Lewis acidic trialkylaluminum reagents,
however, proved to be well suited for this purpose
(Scheme 1).
The combination of lactone
5 (3.1 mmol), and
trimethylaluminum (6.8 mmol) in 6:1 CH2Cl2/toluene
solution showed no reaction at −40°C according to
TLC analysis, but upon warming to 0°C, the lactone
was consumed over a 4 h period. The reaction was
quenched with saturated aq. NH4Cl, and extracted with
ethyl acetate, which was washed sequentially with 0.5 N
HCl, water, and brine. Chromatography on silica with
Despite numerous reports of nucleophilic carbon addi-
tion to sugar lactones,5,6 and a few examples of the
addition of carbon nucleophiles to 5/6,7 7/8,8 and
related lactones,9 we were unable to isolate a clean
OH
OH
O H
OH
O H
OH
HO
HO
HO
HO
HO
HO
O H
R
S
O
HO
HO
H
H
H
H
S
S
O
N
N
HN
N
CH3
CH3
CH3
CH3
2
1
3
4
OBn
O
OBn
O
OBn
OBn
BnO
BnO
BnO
BnO
O
O
BnO
BnO
BnO
BnO
O
O
O
O
AcHN
AcHN
N3
N3
6
5
7
8
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01506-X

7102
S. Knapp et al. / Tetrahedron Letters 43 (2002) 7101–7104
not occur until the reaction was warmed to 20°C,
OBn
O
OBn
O
AlMe3, CH2Cl2
-40 to 0 °C
whereupon slow (12 h) conversion to monoadduct 12
(63% isolated) took place. In the galacto series, addition
to 7 also took place over 12 h, but the reaction could
not be stopped at the monoadduct. Instead, conversion
to the bis-adduct 13 occurred (66%), with no evidence
for the monoadduct even in the presence of limiting
AlMe3.
BnO
BnO
BnO
CH3
5
O
HN
OH
O
AcHN
CH3
9 (92%)
10 (trace)
OBn
OBn
OBn
BnO
BnO
BnO
OH
O
O
As ordinary esters are inert to these conditions,12 the
reaction of some other lactones with trialkylaluminum
reagents was investigated (Scheme 2). Tetra-O-
benzylgluconolactone13 14 gave the known6 monoad-
duct 15 with AlMe3, and, under more forcing
conditions with AlEt3, the ethyl adduct 16. Al(i-Bu)3,
however, reacted very slowly, even at 45°C, suggesting
a steric limit to this reaction. The simpler lactones
dihydrocoumarin 18 and 3-isochromanone 20 gave only
the bis-adducts 19 and 21, respectively.
CH3
CH3
BnO
BnO
CH3
N3 OH
CH3
OH
CH3
11 (85% from 6)
BnO
HN
N3 OH
O
12 (63% from 7)
13 (66% from 8)
Scheme 1. Reaction of AlMe3 with 2-acetamido/azido-2-
deoxy-glyconolactones.
7:7:1 hexanes/ethyl acetate/methanol as the eluant
afforded the carbinol 9 as a colorless syrup (92%). The
a-anomeric stereochemistry is assigned based on the
anomeric effect and literature precedent.5–9 A trace of
the elimination product 10 was also detected by TLC
The reactivity of the carbonyl group of the starting
material or its AlMe3 Lewis acid–base complex deter-
mines whether addition occurs, and the stability of the
initial alkoxyaluminum tetrahedral adduct determines
whether a second addition occurs. In the family of
2-substituted gluconolactones 5, 12, and 14, the relative
reactivity follows the order: 2-NHAc>2-N3>2-OBn.
Based strictly on inductive effects14 (|I) of the 2-sub-
stituent, the expected order of reactivity would be 2-
N3>2-NHAc:2-OBn. The enhanced reactivity of 5 can
be ascribed to prior complexation of AlMe3 with the
acetamido group. Likewise, the stability of the initial
adduct must be adequate in the cases of 22 (proposed
from 5/6), 23 (from 7), and 24 (from 14), but not for
the initial adduct from 8, which instead adds a second
and H NMR.11 Under the same conditions, the galac-
1
tonolactone 6 gave the monoadduct 11 (85%). The
reactions stop cleanly at the monoaddition stage, as
neither TLC nor H NMR provided any evidence for
double-addition products derived from 5 or 6. With
only 1 equiv. of AlMe3 at 0°C, no addition to 5
occurred in 4 h, and upon warming to 20°C, 10 formed
as the major product.
1
The azidolactones 7 and 8, however, showed a diver-
gent pattern of reactivity. Addition of AlMe3 to 7 did
OBn
OBn
AlR3, CH2Cl2
O
O
BnO
R
BnO
BnO
BnO
O
BnO
OH
BnO
15: R = CH3, 20 °C, 3 h (89%)
14
16: R = CH2CH3, 45 °C, 3 h (69%)
17: R = CH2CH(CH3)2, 45 °C, 3 h (trace)
OH
CH3
CH3
AlMe3, CH2Cl2
20 °C, 12 h
O
O
O
OH
18
19 (89%)
AlMe3, CH2Cl2
20 °C, 12 h
OH
CH3
CH3
O
OH
20
21 (78%)
Scheme 2. Reaction of AlR3 with other lactones.
OBn
BnO
OBn
O
OBn
Bn
AlMe2
O
O
O
CH3
O
BnO
BnO
BnO
BnO
BnO
BnO
R
R
O
O
BnO
AlMe2
O
N
O
HN
O
Bn
O
N
N3
N
CH3
AlMe2
AlMe2
H3C
23
24
22
25

S. Knapp et al. / Tetrahedron Letters 43 (2002) 7101–7104
7103
OBn
attempted
deprotection
1. Lawesson's reagent
THF, 3 h
O
CH3
S
BnO
BnO
9
X
H
2. Eu(OTf)3, NMP
N
80 °C, 4 h
CH3
26 (33%)
OH
OAc
O
1. TESOTf, lutidine
2. H2, Pd(OH)2/C
1. Lawesson's reag.
2. PPTS, THF, 6 h
O
CH3
S
HO
HO
AcO
AcO
CH3
H
HN
OH
3. NaOMe, MeOH
N
3. Ac2O, pyridine
4. TBAF, AcOH
O
CH3
CH3
27 (63%)
28 (20%)
Scheme 3. Synthesis of 1-C-methyl GlcNAc thiazoline.
OBn
O
methyl to a ring opened ketone complex that may
resemble 25. Intramolecularly stabilized initial alkoxy-
aluminum tetrahedral adducts are not possible for 18
and 20, and this may account for the exclusive double
addition observed in these two examples.
BF3·OEt2, CH3CN
CH3
O
BnO
BnO
9
H
N
CH3
29 (48%)
Methyl adduct 9 was converted to the 1-C-methyl
thiazoline target 28 as shown in Scheme 3. Treatment
with Lawesson’s reagent1 gave a crude thioamide
(76%), which was cyclized to thiazoline 26 (43%) by
treatment with the mild Lewis acid Eu(OTf)3 in N-
methylpyrrolidone solution. Other solvents (benzene,
toluene, THF) and protic acids (PPTS) gave similar or
poorer yields, and prior conversion of the tertiary
anomeric hydroxyl to an acetate or mesylate derivative
did not help. Very likely the anomeric leaving group
must be in an equatorial position15 (i.e. b) for cycliza-
tion to occur with S-participation, and thus a prior
inversion at C-1 may be required.
Scheme 4. Synthesis of a 1-C-methyl GlcNAc oxazoline.
1
product, which again showed the five-bond H NMR
coupling that is characteristic of these heterocycles.17
An attempt at O-deprotection of 29 by hydrogenolysis
led only to decomposed material, as commented upon
by others.18 GlcNAc oxazolines are useful as glycosyl
donors,19,20 and 29 is the first example of a 1-C-substi-
tuted representative.
Additional studies will be required to expand the scope
of the organoaluminum/glyconolactone reaction, and
determine the biological activity of 1-C-substituted Glc-
NAc thiazolines related to 28 and the glycosyl donor
properties of 1-C-substituted GlcNAc oxazolines
related to 29.21
A variety of hydrogenolysis catalysts and conditions
were tried for the removal of the O-benzyls of 26, but
without success. The sulfur atom evidently poisons the
catalysts, and at temperatures much above 23°C the
thiazoline ring is destroyed. Trimethylsilyl iodide16
caused decomposition, and sodium/ammonia reduced
the thiazoline competitively. The O-benzyl groups were
therefore replaced by O-acetyl by employing the four
step sequence shown in Scheme 3, beginning with O-
silylation of the anomeric hydroxyl. The resulting tetra-
acetate 27 reacted smoothly with Lawesson’s reagent to
provide the crude thioamide, and cyclization was
achieved in low yield with pyridinium p-toluenesul-
fonate. Methanolysis of the acetates gave the 1-C-
methyl GlcNAc thiazoline 28, which showed the
diagnostic five-bond H-2/methyl coupling (J=1 Hz) in
Acknowledgements
We are grateful to Merck & Co. and Vela Pharmaceuti-
cals Inc. for financial support.
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at 20°C (Scheme 4). Silica chromatography gave the

7104
S. Knapp et al. / Tetrahedron Letters 43 (2002) 7101–7104
Takeuchi, T. Nat. Prod. Lett. 2001, 371–375; (e) Ramana,
138.8, 138.4, 138.2, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2,
128.1, 127.9, 127.7, 98.5, 77.9, 74.6, 73.8, 72.9, 71.8, 70.5,
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IR 2104; H NMR (300 MHz) 7.16–7.40 (m, 15 H), 4.88
(s, 2 H), 4.80 (d, 10.8), 4.60 (d, 12.0), 4.54 (d, 11.0), 4.52
(d, 12.0), 3.96–4.01 (m), 3.95 (dd, 9.9, 9.0), 3.61–3.73 (m,
3 H), 3.22 (d, 9.9), 1.23 (s, 3 H); 13C NMR (50 MHz) 138.4,
138.3, 138.2, 128.3, 127.8, 127.6, 97.4, 81.2, 79.0, 76.0, 75.4,
73.9, 72.2, 69.2, 68.6, 27.6; ES-MS 490 MH+. Compound
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1
13: IR 3438, 2106; H NMR (300 MHz) 7.22–7.36 (m, 15
H), 4.81 (d, 11.4), 4.73 (d, 11.4), 4.72 (d, 11.3), 4.59 (d,
11.4), 4.55 (d, 11.7), 4.49 (d, 11.7), 4.13 (dd, 6.3, 2.4),
3.98–4.07 (m, 1 H), 3.91 (dd, 6.3, 1.8), 3.60 (dd, 9.6, 6.3),
3.50 (dd, 9.6, 6.3), 3.27 (d, 2.4), 2.61 (d, 6.9), 2.45 (s), 1.29
(s, 6 H); 13C NMR (75 MHz) 137.9, 137.8, 137.7, 128.7,
128.7, 128.7, 128.4, 128.3, 128.2, 128.1, 128.1, 127.8, 78.9,
78.8, 75.0, 74.4, 73.8, 73.7, 71.5, 69.7, 68.7, 28.8, 27.5;
ES-MS 506 MH+. Compound 15: IR 3431; 1H NMR (400
MHz) 7.27–7.36 (m, 18 H), 7.17–7.19 (m, 2 H), 4.83–4.96
(m, 4 H), 4.72 (d, 11.1), 4.64 (d, 12.3), 4.58 (d, 10.9), 4.55
(d, 12.3), 4.05 (obscd m), 3.98 (t, 9.3), 3.74–3.78 (m),
3.68–3.75 (m, 2 H), 3.39 (d, 9.3), 2.58 (br s), 1.43 (s, 3 H);
13C NMR (100 MHz) 138.6, 138.2, 138.2, 137.8, 128.3,
128.3, 128.2, 128.2, 127.8, 127.8, 127.7, 127.7, 127.6, 127.5,
97.3, 83.6, 83.1, 78.4, 75.6, 75.5, 74.8, 73.3, 71.5, 68.7, 26.5;
FAB-MS 561 MLi+. Compound 16: IR 3449; 1H NMR
(400 MHz) 7.17–7.43 (m, 20 H), 4.52–4.82 (m, 3 H),
4.50–4.72 (m, 5 H), 3.91–4.12 (m, 2 H), 3.78 (dd, 11.1, 3.9),
3.72–3.84 (m, 2 H), 3.45 (d, 9.0), 2.52 (br s), 1.73 (dq, 3.3,
7.2, 2 H), 0.91 (t, 7.2, 3 H); 13C NMR (75 MHz) 138.8,
138.5, 138.1, 137.6, 128.6, 128.6, 128.6, 128.5, 127.3, 127.0,
127.9, 127.8, 127.8, 127.7, 98.7, 84.1, 81.5, 78.7, 75.9, 75.7,
75.2, 73.6, 71.9, 69.1, 31.8, 7.28; FAB-MS 575 MLi+.
Compound 21: IR 3270, 2973, 1496, 1451, 1141, 1011, 784;
1H NMR (300 MHz) 7.13–7.32 (m, 4 H), 4.84 (br s, 1 H),
4.53 (s, 2 H), 3.58 (br s, 1 H), 2.85 (s, 2 H), 1.27 (s, 6 H);
13C NMR (75 MHz) 140.2, 136.7, 132.4, 130.7, 127.8,
127.0, 70.8, 63.3, 45.6, 30.4; CI-MS 181 MH+. Compound
26: IR 1650; 1H NMR (300 MHz) 7.16–7.39 (m, 15 H), 4.74
(d, 11.7), 4.50–4.65 (m, 4 H), 4.33 (d, 11.7), 4.26 (app quint,
2.1), 4.06 (dd, J=3.0, 4.4), 3.59–3.63 (m, 4 H), 2.21 (d,
J=1.8, 3 H), 1.93 (s, 3 H); 13C NMR (75 MHz) 167.5,
138.4, 138.2, 138.1, 128.6, 128.5, 128.5, 128.2, 128.1, 128.0,
127.9, 127.8, 127.7 103.8, 81.6, 79.6, 76.1, 73.5, 73.4, 72.7,
72.5, 70.0, 30.5, 21.9; FAB-MS 510 MLi+. Compound 27:
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1
IR 3346, 1746, 1657; H NMR (200 MHz) 5.84 (d, 9.9),
20. For oxazoline as enzyme substrate, see: Kobayashi, S.;
Kiyosada, T.; Shoda, S. Tetrahedron Lett. 1997, 38, 2111–
2112.
5.25 (t, 10.0), 5.10 (t, 9.4), 4.01–4.27 (m, 4 H), 3.53 (br s),
2.08, 2.01, 2.00, 1.97, 1.44 (5 s, 3 H each); 13C NMR (50
MHz) 171.7, 171.4, 170.8, 169.9, 98.2, 72.6, 68.9, 68.8, 62.8,
55.8, 26.5, 23.6, 21.3, 21.2, 21.1; ES-MS 362 MH+. Com-
21. Spectra for new compounds. Compound 9: IR (film, cm−1
)
3313, 1655; 1H NMR (400 MHz, CDCl3, l, mult., integr.,
J in Hz) 7.18–7.37 (m, 15 H), 5.66 (d, 9.9), 4.84 (d, 11.4),
4.82 (d, 10.8), 4.67 (d, 11.5), 4.60 (d, 12.3), 4.55 (d, 9.9),
4.54 (d, 12.4), 4.07 (t, 10.1), 3.98–4.01 (m, 1 H), 3.77 (t,
10.2), 3.63–3.69 (m, 4 H), 1.87 (s, 3 H), 1.41 (s, 3 H); 13C
NMR (100 MHz, CDCl3) 170.3, 138.5, 138.1, 138.0, 128.3,
128.3, 128.3, 128.0, 127.9, 127.7, 127.7, 127.6, 127.5, 97.6,
80.9, 78.8, 74.8, 74.7, 73.3, 71.5, 69.1, 56.3, 26.4, 23.3;
FAB-MS m/z 512 MLi+. Compound 11: IR 3300, 1651; 1H
NMR (200 MHz) 7.28–7.33 (m, 15 H), 5.47 (d, 9.8), 4.94
(d, 11.6), 4.74–4.55 (m, 3 H), 4.38–4.49 (m, 3 H), 4.07 (t,
6.5), 3.99 (br s), 3.72 (dd, 10.8, 2.6), 3.56 (d, 6.4, 2 H), 3.18
(br s), 1.95 (s, 3 H), 1.42 (s, 3 H); 13C NMR (75 MHz) 170.8,
1
pound 28: H NMR (500 MHz, CD3OD) 3.80–3.84 (m, 2
H), 3.68 (dd, 12, 6.0), 3.53–3.58 (m, 2 H), 3.38 (dd, 10, 7.0),
2.2 (d, 1.0, 3 H), 1.76 (s, 3 H); 13C NMR (125 MHz,
CD3OD) 172.3, 105.1, 83.1, 77.8, 77.2, 70.4, 62.9, 31.1,
22.0; ES-MS 234 MH+. Compound 29: IR 1669; 1H NMR
(400 MHz, CDCl3) 7.10–7.31 (m, 15 H), 4.60 (d, 12.4), 4.50
(d, 12.4), 4.49 (obscd AB q, 12, 2 H), 4.45 (d, 11.6), 4.20
(d, 12.0), 3.92 (br s, 2 H), 3.43–3.55 (m, 4 H), 1.97 (d, 1.2,
3 H), 1.65 (s, 3 H); 13C NMR (75 MHz, CDCl3) CꢀN not
obsd, 138.4, 138.1, 137.9, 128.6, 128.5, 128.3, 128.1, 128.0,
128.0, 127.9, 127.0, 108.7, 77.1, 75.1, 73.5, 72.0, 71.7, 71.5,
70.1, 69.3, 26.8, 14.8; ES-MS 488 MH+.