Synthesis of novel bicyclic ketals of galacturonic acid as potential glycosidase inhibitors

Article abstract of DOI:10.1055/s-2006-939693

A synthesis of novel bicyclic ketals of galacturonic acid is described. The key cyclisation step was realised under acidic anhydrous conditions in very good yield. X-ray crystal structure analysis determined the correct regio- and stereochemistry. Georg T

Full text of DOI:10.1055/s-2006-939693

LETTER
1067
Synthesis of Novel Bicyclic Ketals of Galacturonic Acid as Potential
Glycosidase Inhibitors
Synthesisof
N
ovelBic
i
yclic
K
c
etalsof
G
a
h
lacturonic
A
a
cid el Rommel,a Alexander Ernst,b,1 Klaus Harms,a Ulrich Koert*a
a
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany
Fax +49(6421)2825677; E-mail: koert@chemie.uni-marburg.de
b
Schering AG, Medicinal Chemistry IV, Müllerstr. 178, 13342 Berlin, Germany
Received 13 February 2006
Abstract: A synthesis of novel bicyclic ketals of galacturonic acid
is described. The key cyclisation step was realised under acidic an-
hydrous conditions in very good yield. X-ray crystal structure anal-
ysis determined the correct regio- and stereochemistry.
O
HO
O
OH
HO
O
OH
Key words: galactose, glycosidase inhibitors, bicyclic acetal/ketal,
lactol Wittig reaction, d-amino acids
O
O
HO
H
HO
O
HO
O
O
HO
O
HO
Glycosidase inhibitors present an important substance
class for drug development.2 Currently they are estab-
lished for the treatment of diabetes3 and influenza.4 Fur-
thermore, their function as antiviral agents is also a basis
for the potential application against hepatitis,5 HIV6 and
cancer.7
The proposed mechanism8–10 for retaining b-glycosidases
is shown in Scheme 1. The cleavage of the b-glycosidic
bond proceeds via conformers (e.g., 1,4B, 4E, 1S3) in which
the scissile C–O bond is antiperiplanar oriented to the
doubly occupied non-bonding orbital of the endocyclic
oxygen to the half-chair conformation of the hypothetical
oxocarbenium intermediate. Most glycosidase inhibitors
mimic the shape of the latter one by an imino or carba
sugar, often in combination with a fused (hetero)bicyclic
structural element, and are only partial transition state
analogues.2d,8,9
O
O
OH
O
OH
O
HO
O
O
HO
HO
O
OH
HO
O
O
HO
H
O
HO
O
O
O
Scheme 1 Cleavage of a glycosidic bond by a retaining b-glycosi-
dase
O
O
OH
ketalisation
HO
HO
O
O
NH3
O
HO
OH
Wittig reaction
Based on structural evidence from complexes of glycosi-
dases with modified substrates, Vasella and co-workers
were the first to synthesize glycosidase inhibitors with
locked boat conformations.11 Here we present a synthetic
route to bridged bicyclic ketals of type 1, which address
the charge of the oxonium ion in combination with a
locked boat (1,4B) conformation (Scheme 2). Glucuronic
acid was chosen as cleavage point in the oligosaccharide
chain. In order to mimic a boat-like conformation of
glucuronic acid, galactose was selected as a synthetic
entry. Our synthetic plan intended a ketalisation of the
acyclic precursor 2 as a key step for the construction of 1.
Compound 2 should be available from D-galactose via a
C1 homologation, e.g. by a Wittig reaction.
OH
OH
1
D
-galactose
PGO HO PGO
N3
HO PGO
O
2
Scheme 2 Retrosynthesis of the bridged bicyclic compound 1
was replaced by an allyl ether using allyl alcohol and
BF3·OEt2,13 and the remaining acetate groups were re-
moved by treatment with cat. NaOMe in MeOH.14 Subse-
quently, the 4,6-diol function was selectively protected as
benzylidene acetal15 to yield compound 4. Protection of
the two remaining free alcohol functions with NaH/BnBr
led to the fully protected galactose. Next, the anomeric
protecting group was removed by initial treatment with
t-BuOK in DMSO at 100 °C and subsequent cleavage
of the resultant enol ether using HgCl2/HgO in acetone–
Starting point for the synthesis was b-D-galactose
pentaacetate12 (3, Scheme 3). The anomeric acetate in 3
SYNLETT 2006, No. 7, pp 1067–1070
0
3.
0
5.
2
0
0
6
Advanced online publication: 24.04.2006
DOI: 10.1055/s-2006-939693; Art ID: G05606ST
© Georg Thieme Verlag Stuttgart · New York

1068
M. Rommel et al.
LETTER
water to give the lactol 5.16 Attempts to cleave the enol
ether with Brønsted acids resulted in concurrent partial
deprotection of the benzylidene acetal. A lactol Wittig
reaction17 was performed by adding 5 to [Ph3PMe]+Br–
/n-BuLi at –30 °C18 to yield 90% of the corresponding
alkene.19 Subsequent cleavage of the benzylidene acetal
with CSA in MeOH proceeded quantitatively only upon
addition of 1,3-propanedithiol to trap the emerging ben-
zaldehyde. The primary hydroxy function was protected
selectively using TBDPSCl and TEA/DMAP to give the
silyl ether 6.
c, d
a, b
O
OBn
6
O
O
OBn
TBDPSO
7
TBDPSO
O
O
OBn
e
N3
O
O
BnO
N3
OBn
Ph
OBn
O
TBDPSO
OAc
O
O
AcO
a–c
8
9
O
O
AcO
OAc
HO
O
AcO
HO
O
O
O
O
HO
3
4
O
h
f, g
NH3
N3
O
O
HO
BnO
Ph
TBDPSO
OH OBn
O
OH
OBn
d, e
f–h
O
1
10
O
BnO
OH
OH OBn
Scheme 4 Reagents and conditions: (a) 1,1-dimethoxycyclopen-
tane, CSA, MeCN, r.t., 25 min, 93%; (b) MCPBA, CH2Cl2, 0 °C to
r.t., 60 h, 87%; (c) NaN3, NH4Cl, EtOH, 78 °C, 45 h, 94%; (d)
(COCl)2, DMSO, TEA, CH2Cl2, –60 °C to r.t., 1.5 h, 83%; (e) TFA–
CH2Cl2 1:1 (v/v), MS 4 Å, r.t., 30 min, 89%; (f) TBAF, THF, r.t., 1 h,
93%; (g) PhI(OAc)2, cat. TEMPO, wet CH2Cl2, r.t., 2 h, 83%; (h) H2,
Pd(OH)2/C, EtOAc–MeOH 2:1 (v/v), r.t., 4 h, quant.
BnO
5
6
Scheme 3 Reagents and conditions: (a) CH2CHCH2OH, BF3·OEt2,
CH2Cl2, 0 °C to r.t., 24 h; (b) cat. NaOMe, MeOH, r.t., 18 h; (c)
PhCH(OMe)2, CSA, MeCN, r.t., 1.5 h, 63% over three steps; (d) i.
NaH, ii. BnBr, THF, r.t., 24 h, 93%; (e) i. t-BuOK, DMSO, 100 °C,
20 min; ii. yellow HgO, HgCl2, acetone–water 9:1 (v/v), r.t., 15 h,
83%; (f) [Ph3PMe]+Br–, n-BuLi, THF, –30 °C to r.t., 24 h, 90%; (g)
lents of palladium catalyst was necessary to achieve a
HS(CH2)3SH, CSA, MeOH, r.t., 15 h, 97%; (h) TBDPSCl, TEA, cat. nearly quantitative yield. The crude product was dissolved
DMAP, CH2Cl2, 0 °C to r.t., 3 d, 83%
in MeOH and precipitated on addition of ethyl acetate to
yield the target compound 123 as a white powder. The
structure of the final product 1 was confirmed by X-ray
crystal structure analysis.24 Crystals were grown from
EtOH–H2O 4:1 (Figure 1).
The conversion of the diol 6 into the target compound 1 is
summarised in Scheme 4. The choice of the diol protect-
ing group was crucial for the final ketalisation. Initial
attempts with an isopropylidene ketal suffered from prob-
lems in the key bicyclisation step. Thus, the more labile
cyclopentylidene ketal was chosen.20 Subsequent treat-
ment with MCPBA gave the epoxide 7 as a diastereomeric
mixture in 87% yield.
The following epoxide opening was performed with NaN3
and NH4Cl in refluxing ethanol yielding 94% of the
corresponding azidoalcohol. A Swern oxidation led to the
ketone 8, which was the cyclisation precursor. The bi-
cyclisation was accomplished in a mixture of CH2Cl2 and
TFA containing powdered molecular sieve. After chroma-
tography the bicyclic compound 921 was obtained in 89%
yield. The TBDPS ether in 9 was stable under the anhy-
drous reaction conditions, which was crucial for the regio-
selectivity of the cyclisation. It was cleaved by treatment
with TBAF and the resulting primary alcohol (93%) was
oxidised to the corresponding carboxylic acid 10 in a one
step procedure22 with diacetoxyiodobenzene and cat.
TEMPO. Final deprotection of the benzyl ethers and si-
multaneous reduction of the azide was accomplished by
hydrogenation with Pd(OH)2/C. The use of two equiva-
Figure 1 Crystal structure of the target compound 1 with hydrogen
bonds
Synlett 2006, No. 7, 1067–1070 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Bicyclic Ketals of Galacturonic Acid
1069
3787. (d) Böhm, M.; Lorthiois, E.; Meyyappan, M.; Vasella,
A. Helv. Chim. Acta 2003, 86, 3818. (e)Moreno-Vargas, A.
J.; Schütz, C.; Scopelliti, R.; Vogel, P. J. Org. Chem. 2003,
68, 5632. (f) Böhm, M.; Vasella, A. Helv. Chim. Acta 2004,
87, 2566. (g) Blériot, Y.; Vadivel, S. K.; Herrera, A. J.;
Greig, I. R.; Kirby, A. J.; Sinaÿ, P. Tetrahedron 2004, 60,
6813. (h) Kapferer, P.; Vasella, A. Helv. Chim. Acta 2004,
87, 2764. (i) Buser, S.; Vasella, A. Helv. Chim. Acta 2005,
88, 3151.
In summary, we have developed an efficient synthetic
route to the bicyclic ketal 1 of galacturonic acid in 16 steps
with an overall yield of 15% starting from b-D-galactose
pentaacetate. The synthetic route offers variability and
should be suitable for the preparation of a library of poten-
tial b-glycosidase inhibitors.
Acknowledgment
(12) (a) Wolfrom, M. L.; Thompson, A. Methods Carbohyd.
Chem. 1963, 2, 211. (b) Konstantinovic, S.; Dimitrijevic,
B.; Radulovic, V. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 2002, 41, 598.
(13) Liu, M.-Z.; Fan, H.-N.; Guo, Z.-W.; Hui, Y.-Z. Carbohydr.
Res. 1996, 290, 233.
We thank the Schering AG, Berlin and the Fonds der Chemischen
Industrie for the generous financial support of this work. A.E.
thanks E. Ottow and R. Metternich (both Schering AG) for their en-
couragement and A. Vasella (ETH Zürich) for advice.
(14) Ohlsson, J.; Magnusson, G. Carbohydr. Res. 2000, 329, 49.
(15) Wong, C.-H.; Moris-Varas, F.; Hung, S.-C.; Marron, T. G.;
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Tetrahedron 1993, 49, 5291.
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Org. Chem. 2002, 67, 4559.
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Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515.
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1999, 38, 750; Angew. Chem. 1999, 111, 794. (b) Zechel,
D. L.; Boraston, A. B.; Gloster, T.; Boraston, C. M.;
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G. J. J. Am. Chem. Soc. 2003, 125, 14313.
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D. L.; Withers, S. G. Acc. Chem. Res. 2000, 33, 11.
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Biol. 2002, 6, 619. (d) Davies, G. J.; Ducros, V. M.-A.;
Varrot, A.; Zechel, D. L. Biochem. Soc. Trans. 2003, 31,
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Commun. 2000, 1829. (b) Fuentes, J.; Gasch, C.; Olano, D.;
Pradera, M. A.; Repetto, G.; Sayago, F. J. Tetrahedron:
Asymmetry 2002, 13, 1743. (c) Böhm, M.; Lorthiois, E.;
Meyyappan, M.; Vasella, A. Helv. Chim. Acta 2003, 86,
(19) Preparation of (2R,3S,4R,5S)-4,5-Di-O-benzyl-1,3-O-
benzylidenehept-6-ene-1,2,3,4,5-pentaol.
A suspension of 4.79 g (13.4 mmol, 4.0 equiv) methyltri-
phenylphosphonium bromide (purchased and stored in
vacuo over P2O5) in 70 mL dry THF was cooled to –30 °C
and 7.9 mL of a solution of n-BuLi in hexane (1.6 M, 12.7
mmol, 3.8 equiv) were added dropwise with a syringe. The
reaction mixture turned to a clear yellow solution within 20
min. At the same temperature a solution of 1.50 g (3.35
mmol, 1.0 equiv) lactol 5 in 30 mL dry THF was added
dropwise with a syringe. The syringe was washed with
2 × 2 mL THF. The reaction mixture was stirred for 24 h
while the temperature gradually came to r.t. The resulting
orange suspension was quenched with 100 mL H2O and the
layers were seperated. The aqueous layer was neutralised
with 100 mL sat. NH4Cl and extracted with 3 × 80 mL
MTBE. The combined organic layers were washed with
2 × 50 mL sat. NH4Cl, 50 mL H2O and 50 mL brine, dried
over MgSO4 and the solvents were evaporated. The
remaining sticky yellow oil was purified by flash column
chromatography (100 g silica, 3:1 → 2:1 pentane–MTBE)
giving 1.35 g (90%) of the corresponding alkene. The
colourless oil solidified on standing at r.t. Rf = 0.19
(n-hexane–MTBE, 3:1); mp 76 °C; [a]D20 +51.8 (c 3.29,
CHCl3). IR (KBr): 578 (w), 598 (w), 698 (vs), 749 (s), 811
(w), 844 (w), 886 (w), 926 (m), 951 (w), 1028 (s), 1089 (vs),
1216 (s), 1308 (m), 1340 (m), 1396 (s), 1454 (s), 1496 (m),
2866 (m), 3031 (m), 3064 (m), 3472 (br m). 1H NMR (400
MHz, CDCl3): d = 2.86 (d, 1 H, J = 10.7 Hz, OH), 3.76 (dd,
1 H, J = 2.4, 8.7 Hz, 4-H), 3.84 (br d, 1 H, J = 10.1 Hz, 2-H),
4.05 (dd, 1 H, J = 1.1, 11.8 Hz, 5-H), 4.08 (dd, 1 H, J = 2.2,
6.8 Hz, 1-Ha), 4.19 (dd, 1 H, J = 1.0, 8.7 Hz, 3-H), 4.24 (dd,
1 H, J = 2.0, 11.9 Hz, 1-Hb), 4.34 (d, 1 H, J = 12.1 Hz,
PhCH2), 4.69 (d, 1 H, J = 12.1 Hz, PhCH2), 4.70 (d, 1 H,
J = 10.9 Hz, PhCH2), 4.78 (d, 1 H, J = 10.9 Hz, PhCH2),
5.27–5.38 (m, 2 H, 7-H2), 5.40 (s, 1 H, PhCH), 5.96 (ddd, 1
H, J = 7.5, 10.2, 17.5 Hz, 6-H), 7.12–7.40 (m, 15 H, Harom).
13C NMR (100 MHz, CDCl3): d = 63.4 (C-6), 70.6 (PhCH2),
72.8 (C-7), 75.6 (PhCH2), 77.8 (C-5), 78.3 (C-3), 79.9 (C-4),
101.2 (PhCH), 118.6 (C-1), 126.0 (2 C), 127.7, 127.9, 128.2
(2 C), 128.3 (2 C), 2 × 128.4 (4 C), 128.6 (2 C), 129.0
Synlett 2006, No. 7, 1067–1070 © Thieme Stuttgart · New York

1070
M. Rommel et al.
LETTER
(22) (a) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.;
Piancatelli, G. J. Org. Chem. 1997, 62, 6974. (b) Vescovi,
A.; Knoll, A.; Koert, U. Org. Biomol. Chem. 2003, 1, 2983.
(23) Preparation of (1R,3S,4R,5R,6R)-1-Aminomethyl-5,6-
dihydroxy-2,7-dioxabicyclo[2.2.1]heptane-3-carboxylic
Acid (1).
(CHarom), 136.1 (C-2), 137.9, 138.3, 138.5 (Cq arom). HRMS
(ESI): m/z calcd for C28H30NaO5 [M + Na+]: 469.1985;
found: 469.1978.
(20) van Heeswijk, W. A. R.; Goedhart, J. B.; Vliegenthart, J. F.
G. Carbohydr. Res. 1977, 58, 337.
(21) Preparation of (1S,3R,4S,5S,6R)-1-Azidomethyl-3-(tert-
butyldiphenylsilyloxymethyl)-5,6-dibenzyloxy-2,7-
dioxabicyclo[2.2.1]heptane (9).
The amount of 120 mg (0.292 mmol, 1.0 equiv) of the azide
10 was dissolved under argon in 25 mL EtOAc–MeOH 2:1
(v/v, HPLC grade). Then, 819 mg (0.584 mmol, 2.0 equiv)
Pd(OH)2/C (wet, 20% Pd on dry basis, Degussa type E101
NE/W) were added, and the flask was evacuated five times
with subsequent hydrogen insertion. Complete conversion
was achieved within 90 min. The reaction mixture was
filtered through a short column of Celite® and it was washed
with 5 × 5 mL MeOH. Evaporation to dryness gave 60 mg
(quant.) of the title compound 1 as white foam in pure form.
In order to get a powder for better handling, the foam was
dissolved in 1 mL MeOH and precipitated by slow addition
of 4 mL EtOAc. The suspension was centrifuged and the
supernatant was decanted. The resulting white solid was
washed with 4 mL Et2O and dried in vacuo. Rf = 0.26
Powdered molecular sieves (2.30 g, 4 Å) were dried by
heating in vacuo. Subsequently, 45 mL dry CH2Cl2 and
2.30 g (3.19 mmol) of ketone 8 were added. After the
starting material had dissolved, 45 mL TFA were added in
one portion at r.t. resulting in a yellow reaction mixture. TLC
indicated complete conversion of the starting material within
25 min. The suspension was cooled to 0 °C, 20 mL dry
toluene were added and the solvents were evaporated at the
same temperature. The remaining solid was coevaporated
twice with 10 mL dry toluene to remove traces of TFA. The
pale pink crude product was purified by flash column
chromatography (200 g silica, 7:1 pentane–MTBE) to yield
1.80 g (89%) of the bicyclic ketal 9 as colourless oil.
Rf = 0.36 (n-hexane–MTBE, 3:1); [a]D20 –1.1 (c 4.89,
CHCl3). IR (film): 607 (m), 700 (s), 739 (m), 823 (m), 998
(w), 1113 (s), 1283 (w), 1361 (w), 1428 (m), 1472 (w), 2104
(s), 2857 (m), 2930 (m), 3069 (w). 1H NMR (500 MHz,
CDCl3): d = 1.06 [s, 9 H, C(CH3)3], 3.40 (d, 1 H, J = 13.7
Hz, CHaHbN3), 3.55 (d, 1 H, J = 13.7 Hz, CHaHbN3), 3.57 (d,
1 H, J = 9.4 Hz, CHaHbOR), 3.61–3.66 (m, 2 H, CHaHbOR,
6-H), 3.80 (dd, 1 H, J = 9.2, 4.6 Hz, 3-H), 3.82 (t, 1 H,
J = 1.5 Hz, 5-H), 4.45 (d, 1 H, J = 11.9 Hz, PhCH2), 4.53 (d,
1 H, J = 11.7 Hz, PhCH2), 4.55 (d, 1 H, J = 12.4 Hz, PhCH2),
4.58 (d, 1 H, J = 12.4 Hz, PhCH2), 4.74 (d, 1 H, J = 1.6 Hz,
4-H), 7.28–7.45 (m, 16 H, Harom), 7.59–7.65 (m, 4 H, Harom).
13C NMR (125 MHz, CDCl3): d = 19.4 [C(CH3)3], 27.0
[C(CH3)3], 48.7 (CH2N3), 63.1 (CH2OR), 71.4, 73.1
(PhCH2), 77.2 (C-3), 81.1 (C-4), 83.6 (C-6), 87.4 (C-5),
106.9 (C-1), 127.9 (2C), 2 × 128.0 (4 C), 128.2, 128.3 (3 C),
2 × 128.7 (4 C), 130.0 (2 C, CHarom), 133.3, 133.4 (Cq arom),
135.6 (4 C, CHarom), 137.4, 137.5 (Cq arom). HRMS (ESI):
m/z calcd for C37H41N3NaO5Si [M + Na+]: 658.2708; found:
658.2701.
20
(n-BuOH–H2O–HOAc 2:1:1); mp 140 °C (dec.); [a]D
+45.1 (c 0.35, H2O). IR (KBr): 696 (w), 824 (w), 958 (m),
1035 (w), 1072 (m), 1170 (w), 1307 (w), 1429 (m), 1510
(w), 1602 (s), 2925 (m), 3401 (br vs). 1H NMR (500 MHz,
DMSO): d = 3.19 (d, 1 H, J = 13.9 Hz, CHaHbNH2), 3.24 (d,
1 H, J = 13.7 Hz, CHaHbNH2), 3.60 (s, 1 H, 5-H), 3.71 (d,
1 H, J = 1.6 Hz, 6-H), 3.96 (s, 1 H, 3-H), 4.42 (s, 1 H, 4-H).
13C NMR (100 MHz, DMSO): d = 36.6 (CH2NH2), 73.9
(C-3), 77.0 (C-6), 82.3 (C-5), 86.5 (C-4), 106.5 (C-1), 171.3
(COOH). HRMS (ESI): m/z calcd for C7H12NO6 [M + H+]:
206.0659; found: 206.0660.
(24) The crystal data of 1 has been deposited in the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC 295618. Crystal Data: C7H11NO6, M = 205.17,
monoclinic, P21, a = 4.9367 (6) Å, b = 13.0534 (19) Å,
c = 7.0289 (8) Å, a = 90°, b = 91.297 (13)°, g = 90°,
V = 452.83 (10) Å3, Z = 2, Dcalcd = 1.505 g/cm3, 4497
collected reflections, 1760 independent (Rint = 0.0347),
R1 = 0.0274, wR2 = 0.0703 (all data).
Synlett 2006, No. 7, 1067–1070 © Thieme Stuttgart · New York