A fused GalNAc-thiazole from a singular and unanticipated fragmentation

Article abstract of DOI:10.1016/j.tetlet.2004.09.091

Attempted O-desilylation of an elaborated GalNAc-thiazoline t-butyl ester gave rise instead to a GalNAc-thiazole wherein the two-carbon acetate side chain has been severed by a process heretofore undescribed. The corresponding ether ester rearranged to a

Full text of DOI:10.1016/j.tetlet.2004.09.091

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8507–8510
A fused GalNAc-thiazole from a singular and
unanticipated fragmentation
Spencer Knapp,a,* Benjamin Amorellia and George A. Dossb
aDepartment of Chemistry & Chemical Biology, Rutgers—The State University of New Jersey, 610 Taylor Road,
Piscataway, NJ 08854-8087, USA
bMerck & Co., PO Box 2000, Rahway, NJ 07065-0900, USA
Received 28 July 2004; revised 7 September 2004; accepted 13 September 2004
Available online 29 September 2004
Abstract—Attempted O-desilylation of an elaborated GalNAc-thiazoline t-butyl ester gave rise instead to a GalNAc-thiazole
wherein the two-carbon acetate side chain has been severed by a process heretofore undescribed. The corresponding ether ester rear-
ranged to a C-furanoside by a quite different pathway.
Ó 2004 Elsevier Ltd. All rights reserved.
The GlcNAc-thiazoline 1 is a powerful inhibitor of certain
N-acetylhexosaminidases, including the human enzyme
HEX B, owing to its structural resemblance to the cyclized
and highly reactive oxazolinium intermediate 2.1 1-C-
Elaborated gluco and galacto analogues (3) are therefore
also of interest as potential inhibitors with stronger bind-
ing or greater selectivity or interesting conjugative appli-
cations.2 We have examined, as a means to the synthesis
of the latter compounds, the carbon chain extension of
glyconolactones such as 7, and have prepared the two-car-
bon extended GalNac-thiazoline 8 (Scheme 1). Attempted
O-desilylation of 8 under basic conditions, however, did
not afford the expected thiazoline triol, but rather a trun-
cated and aromatized product, the GalNAc-thiazole 10.
Inasmuch as 10 is a new fused pyranose-heterocycle
hybrid, and the two-carbon fragmentation (formal overall
loss of tert-butylacetate) leading to its formation corre-
sponds to no previously described reaction of which we
are aware, we report this preliminary investigation into
the mechanism of its formation.
The silylated3 D-galactal derivative 4 was converted4 to
the phenyl 2-azido-2-deoxy 1-selenogalactopyranoside,
which in turn was hydrolyzed4 at C-1 to the galactopyr-
anose 5 (Scheme 1). Oxidation3 to the 2-azidogalactono-
lactone was followed by efficient reductive acetylation5
to provide the 2-acetamido-2-deoxy-D-galactolactone
6, and then treatment with Lawessonꢀs reagent gave
the thioacetamido lactone 7. This lactone reacted reluc-
tantly upon heating with tert-butoxycarbonylmethylene-
triphenylphosphorane,5 but at 140°C gave an
equilibrium mixture of the chain extended vinylogous
carbonate 9 and the corresponding S-cyclized thiazoline
ester 8 (55% combined isolated yield, respective ratio
1:2.6). Although 8 and 9 could not be separated, they
could be characterized by NMR analysis on the mixture
and by comparison to closely related compounds.2,6
Attempted removal of the O-silyl protecting groups with
4.1equiv of n-Bu4NFÆH2O caused the fragmentation of
the two-carbon side chain of 8/9, and led to the isolation
of the unusual thiazole triol 10 in high yield. The struc-
ture of 10 follows from spectroscopic analysis, as well as
further characterization of its derived triacetate 11. No
comparable pyranose-fused thiazole has been reported,7
to our knowledge, and no good mechanistic precedent
exists for the apparent loss of the elements of tert-butyl
acetate under such mild conditions.8 Both 8 and 9 were
converted to 10 in this reaction, because the amount of
either precursor in the starting mixture is alone insuffi-
cient to account for the yield of 10.
HO
HO
HO
HO
HO
HO
HO
O
O
O
R
H
H
HO
HO
H
H
H
S
O
H
S
N
N
N
CH3
CH3
CH3
1
2
3
Keywords: Retro-aldol; Rearrangement; Aromatization.
*
Corresponding author. Tel.: +1 732 445 2627; fax: +1 732 445
5312; e-mail: knapp@rutchem.rutgers.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.091

8508
S. Knapp et al. / Tetrahedron Letters 45 (2004) 8507–8510
1. PhI(OAc)2, PhSeSePh,
OTBDPS
OTBDPS
O
TBSO
n-Bu4NN3
TBSO
TBSO
1. PCC, NaOAc, CH2Cl2
2. Ra-Ni, Ac2O, THF
2. Hg(OCOCF3)2, aq THF
O
OH
TBSO
74% overall
N3
88% overall
5
4
OTBDPS
OTBDPS
TBSO
TBSO
TBSO
TBSO
O
O
Lawesson's reagent
toluene, 80 ˚C, 2 h
O
t-BuOCOCH=PPh3
toluene, 140 ˚C, 16 h
O
HN
S
88%
NHAc
55%, 8/9 = 2.6:1
6
CH3
7
OTBDPS
OTBDPS
O
TBSO
TBSO
TBSO
TBSO
OR
n-Bu4NF·H2O
THF, 23 ˚C, 2 h
O
O
S
N
CO2t-Bu
CH3
CO2t-Bu
S
H
89%
N
HN
S
RO
OR
10: R = H
11: R = Ac
CH3
CH3
8
9
Scheme 1. Attempted synthesis of an elaborated GalNAc-thiazoline.
Given the presence of sufficient amounts of water in the
commercial n-Bu4NFÆH2O reagent, it is possible to sug-
gest (Scheme 2) that Michael addition of water to the
C@C of 9 has occurred under the basic conditions of
the reaction, followed by retro-aldol reaction to give
the lactone 13 (loss of tert-butyl acetate), then cycliza-
tion of the thioacetamido to produce 14, and finally loss
of water and aromatization. The timing of the O-desilyl-
ation steps relative to other proposed processes is un-
known. To help evaluate this mechanism, thioamide
lactone 7 was exposed to the same desilylation condi-
tions (Scheme 2). No thiazole 10 was detected by TLC
or NMR analysis, but instead the rearranged c-lactone
15 was formed as the major product.9 It was further
characterized by acetylation to give the known10 N,O-
diacetyl derivative 16 (Z/E ꢀ 2:1) with matching 1H
NMR spectrum. Ring contraction of the d-lactone to
the c-lactone is well established for galactonolactones,11
so this is not a surprising result, but it does appear to
rule out 7 as an intermediate.
An admittedly speculative mechanism invoking partici-
pation by one of the pyranose hydroxyls is proposed
in Scheme 3. In this formulation, the pyranose ring
OR
O
OR
O
RO
RO
RO
RO
OR
RO
H2O
F–
retro-aldol
O
OH – H2O
9
10
O
S
RO
CH3CSNH
H
S
CO2t-Bu
N
HN
OH
CH3
CH3
12 (R = H or silyl PG)
13
14
control:
7
HO
H
O
O
Ac2O, pyridine
54%
n-Bu4NF·H2O, THF
O
O
AcO
HO
82%
NHAc
HO
NHCSCH3
16
15
Scheme 2. A retro-aldol mechanism for thiazole formation.
O
OH
2
O
OH
O
O
O
1. S-cyclize
2. – H2O
S
N
H3C
HO
F–
retro-aldol
CH3
7
4
6
OH
O
O
12
HO
4
AcO
HO
– t-BuO–
5
O
S
CH3CSNH
OH
HN
19
17
18
CH3
AcO
6
acetyl
migration
HO–
O
S
TLC-monitored deprotection:
10
CH3
N
HO
n-Bu4NF·H2O
5 min only
n-Bu4NF·H2O
2 h
OH
20
10
12
20
Scheme 3. A retro-aldol mechanism with hydroxyl participation.

S. Knapp et al. / Tetrahedron Letters 45 (2004) 8507–8510
8509
TBSO
TBSO
OTBDPS
O
HO
CO2Et
2
Ph3P=CHCO2Et
toluene, 111 ˚C, 16 h
n-Bu4NF·H2O
as before
H
O
HO
7
6
H
4
CO2Et
65%
61%
H
S
HO
H
N
NHCSCH3
CH3
NOE
NOE
21
22
OH
O
OH
HO
HO
H
HO
6
HO
HO
O
HF, pyridine
THF
7
O
CO2Et
H
HO
CO2Et
O
CO2Et
21
3
H
S
N
47%
NHCSCH3
NHCSCH3
CH3
25
24
23
Scheme 4. The contrasting rearrangement of the ethyl ester.
undergoes a conformational change to bring the C-6
hydroxyl close to the ester carbonyl, whereupon cycliza-
tion to the lactone 17 can occur. n-Bu4NF promoted lac-
tonizations of hydroxy esters have a precedent,12 and
alternative isomeric lactone intermediates might also
be drawn invoking participation of the C-5 or C-8 hydr-
oxyl, respectively. Retro-aldol cleavage would lead to
lactone 18, and then thioamide cyclization and loss of
water can occur to produce 19. The 4-O-acetyl group
of 19 specifically blocks the d-lactone to c-lactone ring
contraction pathway described above (see 15). Hydr-
oxide promoted hydrolysis of the acetate would lead
to the thiazole 10, possibly by acetyl migration13
through the 6-O-acetyl isomer 20.
The subtleties of these polyfunctional substrates, parti-
cularly in regard to the reactivity differences between
tert-butyl and ethyl esters (8 and 21, respectively), can-
not in our view be accounted for by a single simple
explanation. However, the apparent ease of the retro-
Michael thiazoline ring opening reaction of 8 relative
to that of 21 (and perhaps relative to O-desilylation)
might set the stage for the emergence of the distinctive
subsequent pathways that have been proposed in
Scheme 3.14
Acknowledgements
We are grateful to NIH (AI055760) for financial sup-
port. We thank Christian Ventocilla for assisting with
the preparation of starting materials and Etzer Darout
for helpful discussions.
A subsequent deprotection experiment established the
6-O-acetyl thiazole 20 as an intermediate. When the
desilylation reaction was analyzed by TLC after only
5min (Scheme 3), the major product observed was a
higher Rf (with respect to 10) thiazole, 20. Upon further
exposure to the reaction conditions, 20 was slowly
converted to 10. The structure of 20 was secured by its
isolation and spectroscopic characterization (the
ꢁ0.5ppm downfield shift of the H-6ꢀs versus those of
10 indicates the 6-O-acetyl); furthermore, independent
acetylation of 20 gave the previously described thiazole
triacetate 11.
References and notes
1. Mark, B. L.; Mahuran, D. J.; Cherney, M. M.; Zhao, D.;
Knapp, S.; James, M. N. G. J. Mol. Biol. 2003, 327, 1093–
1109.
2. Knapp, S.; Yang, C.; Haimowitz, T. Tetrahedron Lett.
2002, 43, 7101–7104.
3. Koviach, J. L.; Chappell, M. D.; Halcomb, R. L. J. Org.
Chem. 2001, 66, 2318–2326.
4. Czernecki, S.; Ayadi, E. Can. J. Chem. 1995, 73, 343–350.
5. Xie, J.; Molina, A.; Czernecki, S. J. Carbohydr. Chem.
1999, 18, 481–498.
Lactone 7 also undergoes chain extension when treated
with
(carbethoxymethylene)-triphenylphosphorane
(Scheme 4). In this case, no alkene analogous to 9 is pre-
sent in the product; cyclization to thiazoline 21 is com-
plete. Treatment of 21 with n-Bu4NF under the same
conditions as for 8 led to no thiazole 10 whatsoever. In-
stead, the only isolated product proved to be the depro-
tected and rearranged thioamide ester 22. Its structure
and stereochemistry are based on fully assigned 1H
and 13C NMR spectra, and NOESY, HSQC and HMBC
analysis. In particular, NOE cross-peaks were observed
for H-2/H-4 and H-4/H-6. The source of 22 might be
intramolecular conjugate addition of O-6 at C-3 of the
unsaturated ester 23 to give a bicyclic intermediate 24,
followed by cleavage of the O-7 ether bond by b-elimi-
nation. This may be thought of as a process vinylogous
to that which formed 15. Successful desilylation of 21 to
25 without rearrangement was later achieved under
acidic conditions (HF, pyridine).
6. The 1H NMR signal for the thiazoline methyl of 8 at
2.17ppm (br s, long range coupled to H-2) is diagnostic:
Knapp, S.; Myers, D. S. J. Org. Chem. 2002, 67, 2995–
2999. The thioacetamide methyl singlet of 9, observed at
2.47ppm, is also diagnostic, and integration gives their
ratio. Complete spectra are given in Ref. 14.
7. The closest analogous non-aromatized structure is the
corresponding GalNac-thiazoline (Ref. 6). Analogous
benzo-fused glycals have also been synthesized: Pacha-
muthu, K.; Schmidt, R. R. Synlett 2003, 1355–1357.
8. The thermal reversion of glyconolactone-thiazole adducts
back to the glyconolactones has been observed: Dondoni,
A.; Marra, A. Heterocycles 1999, 50, 419–426.
9. The corresponding acetamido lactone has been reported:
Zsoldos-Mady, V.; Pinter, I.; Nesmelyi, A.; Messmer, A.
Carbohydr. Res. 1994, 252, 85–95.
10. Horton, D.; Thomson, J. K.; Varela, O.; Nin, A.; de
Lederkremer, R. M. Carbohydr. Res. 1989, 193, 49–60.

8510
S. Knapp et al. / Tetrahedron Letters 45 (2004) 8507–8510
11. Bierenstiel, M.; Schlaf, M. Eur. J. Org. Chem. 2004, 1474–
1481; Pravdic, N.; Fletcher, H. G., Jr. Carbohydr. Res.
1970, 12, 471–474.
12. Adiyaman, M.; Lawson, J. A.; Hwang, S.-W.; Khanapure,
S. P.; FitzGerald, G. A.; Rokach, J. Tetrahedron Lett.
1996, 37, 4849–4852.
163.4, 159.5, 135.6, 135.5, 133.4 (2Cꢀs), 133.1, 129.9 (2Cꢀs),
129.7 (2Cꢀs), 127.8, 127.7 (2Cꢀs), 127.6, 104.3, 80.9, 80.8,
79.8, 78.1, 75.6, 75.3, 70.9, 69.9, 69.3, 68.4, 62.0, 61.7, 58.0,
48.6, 34.3, 27.8, 26.4, 26.2, 25.9, 22.3, 19.2, 19.1, 18.5, 18.4,
À3.7, À4.1, À4.5, À4.7, À5.0, À5.4; ESI-MS m/z 822
MNa+. Compound 10: 1H NMR (400MHz, CD3OD) 4.79
(d, 1H, 4.8), 4.26 (ddd, 1H, 7.2, 4.4, 1.2), 4.08 (dd, 1H, 4.8,
2.0), 3.96 (dd, 1H, 12.0, 7.2), 3.87 (dd, 1H, 11.6, 4.4), 2.53
(s, 3H); 13C NMR (100MHz, CD3OD) 154.6, 154.2, 132.4,
83.9, 67.1, 66.3, 61.8, 19.1; ESI-MS m/z 240 MNa+.
13. Motawia, M. S.; Olsen, C. E.; Denyer, K.; Smith, A. M.;
Moller, B. L. Carbohydr. Res. 2001, 56, 6511–6516.
14. Spectra for new compounds. Compound 5 (ꢀ1:1 mixture
of a- and b-anomers): IR (film, cmÀ1) 2112; 1H NMR
(400MHz, CDCl3, d in parts per million, multiplicity,
integration, J in hertz) 7.67–7.61 (m, 4H), 7.46–7.35 (m,
6H), 5.23 (d, 0.5H, 2.8), 4.35 (d, 0.5H, 7.6), 4.06 (br s,
0.5H), 3.98 (dd, 1H, 10.4, 2.0), 3.86 (br t, 1H, 6.4), 3.82–
3.63 (m, 5.5H), 3.49 (dd, 0.5H, 10.0, 7.6), 3.34 (dd, 0.5H,
10.0, 7.6), 3.25 (t, 0.5H, 6.8), 2.85 (br s, 1H), 1.07 (s, 9H),
0.98 (s, 4.5H), 0.97 (s, 4.5H), 0.87 (s, 9H), 0.20 (s, 1.5H),
0.18 (s, 3H), 0.16 (s, 4.5H), 0.06 (s, 1.5H), 0.05 (s, 1.5H);
13C NMR (100MHz, CDCl3) 136.0, 135.6 (two peaks),
135.5, 134.8, 133.7, 133.6, 133.4, 133.1, 130.0, 129.8 (two
peaks), 129.7, 129.6, 129.5, 127.9, 127.7 (two peaks), 96.7,
75.8, 74.5, 71.1, 70.2, 66.1, 62.5, 31.6, 26.9, 26.5, 26.3, 26.2,
26.0, 25.5, 22.6, 19.2, 18.5, À3.6, À3.7, À3.9, À4.1, À4.6,
À4.7, À4.8 (two peaks); ESI-MS m/z 694 MNa+. Com-
pound 6: IR 1744, 1658; 1H NMR 7.65–7.58 (m, 4H), 7.46–
7.35 (m, 6H), 6.26 (d, 6.8, 1H), 4.39–4.35 (m, 2H), 4.33 (br
s, 1H), 3.87–3.79 (m, 3H), 2.02 (s, 3H), 1.07 (s, 9H), 0.94 (s,
9H), 0.82 (s, 9H), 0.16 (s, 3H), 0.11 (s, 3H), 0.08 (s, 3H),
0.07 (s, 3H); 13C NMR 170.9, 168.1, 135.5 (2Cꢀs), 132.9,
132.7, 130.0, 129.9, 127.9, 127.8, 78.7, 71.6, 69.5, 60.8, 56.2,
26.9, 26.1, 25.9, 22.8, 19.1, 18.4, 18.3, À3.8, À4.1, À4.9,
1
Compound 11: H NMR (300MHz, CDCl3)6.15 (d, 1H,
4.5), 5.63 (dd, 1H, 4.5, 2.1), 4.57 (ddd, 1H, 7.5, 4.8, 2.1),
4.41 (dd, 1H, 11.7, 7.5), 4.29 (dd, 1H, 12.0, 4.8), 2.58 (s,
3H), 2.11 (three s, 3H each); 13C NMR (75MHz, CDCl3)
170.3, 170.0, 169.7, 154.3, 153.9, 126.6, 77.2, 64.5, 64.3,
61.3, 21.0, 20.8, 20.7, 19.8; ESI-MS m/z 366 MNa+.
Compound 15: IR 1773; 1H NMR (300MHz, CD3OD)
5.92 (d, 1H, 5.7), 4.61 (d, 1H, 6.0), 4.59 (d, 1H, 1.5), 3.88–
3.82 (m, 2H), 3.59–3.57 (m, 2H), 2.57 (s, 3H); ESI-MS m/z
1
258 MNa+. Compound 20: IR 1732; H NMR (300MHz,
CD3OD/CDCl3) 4.80 (d, 1H, 4.2), 4.57–4.49 (m, 1H), 4.45–
4.42 (m, 1H), 4.40 (dd, 1H, 10.5, 3.3), 4.08 (dd, 1H, 4.5,
10.8), 2.55 (s, 3H), 2.09 (s, 3H); 13C NMR (75MHz,
CD3OD/CDCl3) 171.9, 155.6, 153.3, 131.3, 80.5, 66.5, 65.2,
63.6, 20.9, 18.9; ESI-MS m/z 260 MH+. Compound 21: IR
1740, 1615; 1H NMR (300MHz, CDCl3) 7.66–7.60 (m,
4H), 7.46–7.33 (m, 6H), 4.19 (d, 1H, 8.7), 4.09 and 4.05
(ABq, 2H, 7.2), 3.99 (br d, 1H, 1.5), 3.80–3.64 (m, 3H), 3.59
(dd, 1H, 8.7, 1.8), 2.88 and 2.77 (ABq, 2H, 15.0), 2.17 (s,
3H), 1.18 (t, 3H, 7.2), 1.05 (s, 9H), 0.93 (s, 9H), 0.84 (s, 9H),
0.17 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.04 (s, 3H); 13C
NMR (50MHz, CDCl3) 169.0, 168.7, 136.1, 133.9, 130.2,
128.1, 104.8, 77.8, 76.4, 75.8, 69.1, 62.7, 60.9, 47.4, 27.3,
26.7, 26.5, 22.9, 19.6, 19.0, 18.9, 14.5, À3.2, À3.5, À4.0,
À4.5; ESI-MS m/z 772 MH+. Compound 22: 1H NMR
(600MHz, CD3CN/D2O spike, assignments by HSQC and
HMBC) 5.86 (dd, 7.4, 1.4, H-4), 4.81 (d, 1.4, H-2), 4.39 (t,
7.4, H-5), 4.35 (dd, 7.1, 3.0, H-6), 4.09–4.03 (m,
CH3CH2O), 3.75 (dt, 3.0, 6.2, H-7), 3.67–3.59 (m, two H-
8), 2.51 (s, CH3CSNH), 1.20 (t, CH3CH2O); 13C NMR
(150MHz, CD3CN/D2O spike) 203.7 (CH3CSNH), 168.3
(C-3), 166.2 (C-1), 88.9 (C-2), 87.7 (C-6), 72.8 (C-5), 70.3
(C-7), 64.6 (C-4), 63.0 (C-8), 59.8 (OCH2CH3), 32.9
(CH3CSNH), 13.8 (OCH2CH3); ESI-MS m/z 306 MH+.
1
À5.0; ESI-MS m/z 708 MNa+. Compound 7: IR 1741; H
NMR 7.65–7.61 (m, 4H), 7.47–7.36 (m, 6H), 4.91 (d, 1H,
8.4), 4.37 (dd, 1H, 8.4, 5.6), 4.33 (br s, 1H), 4.00 (app t, 1H,
7.2), 3.92–3.87 (m, 2H), 3.82 (dd, 1H, 10.4, 5.6), 2.51 (s,
3H), 1.08 (s, 9H), 0.92 (s, 9H), 0.85 (s, 9H), 0.17 (s, 3H),
0.13 (s, 3H), 0.10 (s, 3H), 0.05 (s, 3H); 13C NMR 201.9,
166.7, 135.5 (2Cꢀs), 132.9, 132.7, 130.2, 129.9, 127.9, 127.8,
78.0, 69.3, 60.9, 60.3, 55.6, 33.7, 26.9, 26.1, 25.9, 19.1, 18.4,
18.3, À3.7, À4.0, À4.9, À5.0; ESI-MS m/z 724 MNa+.
Compounds 8/9: 1H NMR (300MHz, 2.6:1 respective
mixture, integration given for 8) 7.65–7.60 (m, 4H), 7.44–
7.34 (m, 6H), 5.58 (br s), 5.45 (dd, 6.4, 4.8), 4.18 (br s), 4.14
(d, 1H, 8.4), 4.01 (br d, 1H, 1.8), 4.03–3.91 (m), 3.86 (dd,
5.1, 2.4), 3.82–3.71 (m, 2H), 3.65 (dd, 1H, 7.8, 3.6), 3.58
(dd, 1H, 8.7, 1.8), 2.80 and 2.68 (ABq, 2H, 15.0), 2.47 (s),
2.17 (s, 3H), 1.36 (s, 9H), 1.09 (s), 1.06 (s, 9H), 0.93 (s, 9H),
0.92 (s), 0.86 (s, 9H), 0.23 (s), 0.18 (s, 3H), 0.11 (s), 0.10 (s,
3H), 0.08 (s, 3H), 0.05 (s, 3H); 13C NMR 200.4, 168.0,
1
Compound 25: H NMR (300MHz, CDCl3) 4.44 (d, 1H,
8.1), 4.20 and 4.15 (ABq, 2H, 6.9), 4.00–3.80 (m, 4H), 3.62
(td, 1H, 8.1, 3.0), 3.17 (d, 1H, 17.1), 3.08 (d, 1H, 17.4), 2.81
(d, 1H, 8.4), 2.23 (s, 3H), 2.23–2.20 (m, 1H), 2.09–2.05 (m,
1H), 1.27 (t, 3H, 7.2); ESI-MS m/z 306 MH+.