Synthesis of D-gluco-, L-ido-, D-galacto-, and L-altro-configured glycaro-1,5-lactams from tartaric acid

Article abstract of DOI:10.1016/j.tetlet.2005.03.188

The D-gluco-, L-ido-, D-galacto-, and L-altro-configured glycaro-1,5-lactams 1-4 were prepared from the known tartaric anhydride 5 via the aldehyde 6. These lactams are known (1) or potential (2-4) inhibitors of β-D-glucuronidases and α-L-iduronidases. Ol

Full text of DOI:10.1016/j.tetlet.2005.03.188

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3619–3622
Synthesis of D-gluco-, L-ido-, D-galacto-, and L-altro-configured
glycaro-1,5-lactams from tartaric acid
Jagadish Pabba and Andrea Vasella*
Laboratorium f u€r Organische Chemie, ETH Ho€nggerberg, Wolfgang-Pauli Strasse 10, CH-8093 Zu€rich, Switzerland
Received 16 March 2005; revised 24 March 2005; accepted 25 March 2005
Available online 11 April 2005
Abstract—The D-gluco-, L-ido-, D-galacto-, and L-altro-configured glycaro-1,5-lactams 1–4 were prepared from the known tartaric
anhydride 5 via the aldehyde 6. These lactams are known (1) or potential (2–4) inhibitors of b-D-glucuronidases and a-L-iduron-
idases. Olefination of 6 to the (E)- and (Z)-alkenes 7 or 8, followed by reagent or substrate controlled dihydroxylation, lactonization,
azidation, reduction, and deprotection led in 10 steps and in overall yields of 11–20% to the title lactams.
Ó 2005 Elsevier Ltd. All rights reserved.
b-D-Glucuronidases (EC 3.2.1.31) and a-L-iduronidases
(EC 3.2.1.76) cleave b-, and a-glycuronic acid residues,
respectively, from the non-reducing end of glycosamino-
glycans, such as chondroitin sulfate and hyaluronic acid.
These glycosidases are essential for the normal restruc-
turing and turnover of extracellular matrix compo-
nents.1 Glycuronidases also play crucial roles in
pathophysiological processes. Deficiency of b-D-glucu-
ronidase and a-L-iduronidase in humans leads to muco-
polysaccharidosis of type VII (Sly syndrome)2 and of
type I (Hurler syndrome),3 respectively, while release of
b-D-glucuronidase from cancer cells2 and breakdown
of the basement membrane are required for metastasis
of adenocarcinoma. Induction of b-D-glucuronidase in
the intestinal flora may also be responsible for the patho-
genesis of colon cancer.4 In addition, b-D-glucuronidase
and other lysosomal enzymes are released into the syno-
vial fluid in inflammatory joint diseases like rheumatoid
arthritis and contribute to their symptoms.5 Strong
and selective inhibitors of b-D-glucuronidase and a-L-
iduronidase are thus of pharmacological interest.
known b-D-glucuronidase inhibitor. Its synthesis by cata-
lytic oxidation of gluconolactam (obtained from nojir-
imycin) requires a rather expensive Pt catalyst loading
(ca. 50 wt %). A synthesis of the methyl ester of benzyl
protected glucarolactam from methylglucopyranoside
in 14 steps and an overall yield of 15% was also
reported.8 The glycarolactams 2–4 are not known.
(R,R)- and (S,S)-Tartaric acid (L- and D-threaric acid)
and their derivatives were used extensively as chiral aux-
iliaries, resolving agents, and building blocks,9 yet, there
are few instances only where tartaric acid derivatives
were used as building blocks for the synthesis of (chain
extended) carbohydrates and analogues;9 examples are
the syntheses of deoxynojirimycin,10 castanospermine,11
polyhydroxy piperidines,12 conduritol,13 and a myoinositol
HO
CO2Na
NH
CO2Na
NH
HO
HO
HO
O
O
O
O
Considering the potential pharmacological use of glycu-
ronidase inhibitors and the use of glycosidase inhibitors
in analyzing the mechanism of action of glycosidases6
we wished to synthesize the four diastereoisomeric
glycarolactams 1–4 (Fig. 1). Glucarolactam 17 is a well
OH
OH
1
2
HO
NH
OH
NH
OH
HO
HO
NaO2C
HO
NaO2C
Keywords: Carbohydrates; Synthesis; Tartaric acid; Lactam;
Glycarolactam.
3
4
*
Corresponding author. Tel.: +41 44 6325130; fax: +41 44 6321136;
e-mail: vasella@org.chem.ethz.ch
Figure 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.188

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J. Pabba, A. Vasella / Tetrahedron Letters 46 (2005) 3619–3622
derivative.14 We report a divergent synthesis of the gly-
carolactams 1–4 from the tartaric anhydride 5.15
yielded 85% of a 1:1 (E/Z) mixture of the dehydroamino
acids 10 (Scheme 1).
Methanolysis of the anhydride 515 followed by for-
mation of the mixed anhydride with methyl chloroformate,
ZnBH4 reduction, and oxidation with trichlorocyanuric
acid and TEMPO16 gave the aldehyde 6 (60% from 5).
Wittig–Horner olefination of the aldehyde 6 led to the
(E)-alkene 7 (80%). The Still–Genari version of the Wit-
tig–Horner olefination of 6 provided the (Z)-alkene 8
(75%), while olefination with the phosphonate derived
from Z-protected methyl glycinate17 provided mainly
the (Z)-configured dehydroamino acid 9 (85%; E/Z =
1:13). The analogous olefination of 6 with the phos-
phonate derived from Boc protected methyl glycinate
Aminohydroxylation of 7, hydroboration of 9, and 1,4-
addition of alcoholates to the dehydroamino acids 9 and
10 failed, and starting material was recovered. However,
reagent controlled dihydroxylation of 7 with OsO4 in the
presence of NMOÆH2O and (DHQ)2-PHAL followed by
spontaneous c-lactonization gave selectively the L-idaro-
lactone 11 (75%). Triflation of 11 followed by substitu-
tion with tetramethyl guanidinium azide18 led almost
quantitatively to the D-gluco azido lactone 13.
Pd/CaCO3 (10%) catalyzed hydrogenation of the azide
13 in EtOH followed by spontaneous lactamization
OBn
b)
c)
EtO2C
CO2Me
OBn
7
8
OBn
CO2Me
O
OBn
MeO2C
OBn
BnO
a)
OHC
O
OBn
CO2Me
CO2Me
BnO
OBn
MeO2C
MeO2C
d)
e)
O
5
6
OBn
NHZ
9
OBn
CO2Me
BocHN
OBn
10
Scheme 1. Reagents and conditions: (a) (1) MeOH; (2) ClCO2Me, iPr2NEt, THF, 0 °C, then ZnBH4, MeOH, 0 ! 10 °C; (3) trichlorocyanuric acid,
TEMPO, CH2Cl2, ꢀ78 ! 0 °C; 60%. (b) (EtO)2P(O)CH2CO2Et, NaH, THF, 0 °C; 80%. (c) (F3CCH2O)2P(O)CH2CO2Me, KHMDS, 18-crown-6,
THF, ꢀ78 °C; 75%. (d) (MeO)2P(O)CH(NHZ)CO2Me, 1,1,3,3-tetramethylguanidine, THF, ꢀ78 ! 25 °C; 85% (E/Z 1:13). (e) (MeO)2P(O)CH(NH-
Boc)CO2Me, DBU, THF, ꢀ0 ! 25 °C; 85% (E/Z 1:1).
R1 R2
OBn
CO2Me
CO2R1
O
O
EtO2C
EtO2C
a)
e)
NH
HO
H
R2O
O
OR2
OBn
OBn
BnO
7
11 R1 = OH R2 = H
12 R1 = OTf R2 = H
13 R1 = H R2 = N3
14 R1 = Et
R2 = Bn
c)
d)
f)
15 R1 = Ph2CH R2 = Bn
g)
1 R1 = Na
R2 = H
b)
HO
H
O
BnO
O
H
N
EtO2C
R2
O
NH
OH
e)
g)
RO2C
HO
HO
NaO2C
O
R1
BnO
OBn
OBn
16 R1 = OH R2 = H
17 R1 = OTf R2 = H
18 R1 = H R2 = N3
19 R = Et
4
c)
d)
f)
20 R = Ph2CH
Scheme 2. Reagents and conditions: (a) OsO4, K3[Fe(CN)6], (DHQ)2-PHAL, MeSO2NH2, K2CO3, tBuOH/H2O (1:1), 0 °C; 75%. (b) OsO4,
NMOÆH2O, acetone/H2O (4:1); 87%. (c) Tf2O, 2,6-lutidine, CH2Cl2, ꢀ78 ! 0 °C; 93% of 12, 94% of 17. (d) Tetramethyl guanidinium azide, CH2Cl2,
ꢀ90 ! 0 °C; 98% of 13, 98% of 18. (e) Pd/CaCO3, H2 (1 bar), EtOH, 4 h then N2, 12 h; 65% of 14, 63% of 19. (f) (1) LiOHÆH2O, MeOH/H2O (1:1);
(2) Ph2CN2, acetone; 85% of 15, 84% of 20. (g) Pd/C, H2 (6 bar), MeOH/H2O (1:1) then ion exchange on Dowex 50 W X2 (Na+); 98% of 1, 98% of 4.

J. Pabba, A. Vasella / Tetrahedron Letters 46 (2005) 3619–3622
3621
Scheme 3. Reagents and conditions: (a) OsO4, NMOÆH2O, acetone/H2O (4:1); 78% of 21 and 22 (1:1). (b) Tf2O, 2,6-lutidine, CH2Cl2, ꢀ78 ! 0 °C;
65% of 23 and 24 (1:2), 23% of 21. (c) Tetramethyl guanidinium azide, CH2Cl2, ꢀ90 ! 0 °C; 98% of 24 and 25 (1:2). (d) Pd/CaCO3, H2 (1 bar), THF,
4 h then N2, 12 h; 60% of 27 and 28 (1:2). (e) (1) LiOHÆH2O, MeOH/H2O (1:1); (2) Ph2CN2, acetone; 85% of 29, 83% of 30. (f) Pd/C, H2 (6 bar),
MeOH/H2O (1:1) then ion exchange on Dowex 50 W X2 (Na+); 98% of 3, 98% of 2.
provided the protected D-glucarolactam 14 (65%).
Saponification of 14 led under all conditions tested to
a mixture of C(5) epimeric lactams, which was treated
with Ph2CN2. Chromatography and crystallization gave
the D-gluco and L-ido configured benzyhydryl esters 15
(85%) and 29 (12%), respectively (Scheme 2).
salts 1–4 by passage through a column of Dowex 50 W
X2 (Na+).
In conclusion, we have developed a synthesis of glycaro-
1,5-lactams in 10 steps from the tartaric anhydride 5 in
overall yields of 11–20%. Inhibition by 1–4 of b-D-glucu-
ronidases and a-L-iduronidases and experimental details
will be published elsewhere.
Substrate controlled dihydroxylation of 7 with OsO4
and NMOÆH2O followed by lactonization gave the
D-galactarolactone 16 besides some 11 (98:2, 87%). Tri-
flation of 16 followed by azidation, reduction, saponifica-
tion, and treatment with Ph2CN2 (Scheme 2) resulted in
the L-altro and the D-galacto configured glycarolactams
20 (49%) and 30 (7%).
References and notes
1. Paigen, K. Prog. Nucl. Acid Res. Mol. Biol. 1989, 37, 155.
2. (a) Sly, W. S.; Quinton, B. A.; McAliste, Wh.; Rimoin, D.
L. J. Pediatrics 1973, 82, 249; (b) Hall, C. W.; Cantz, M.;
Neufeld, E. F. Arch. Biochem. Biophys. 1973, 155, 32.
3. (a) Neufeld, E. F.; Muenzer, J. The Mucopolysacchar-
idoses. In The Metabolic Basis of Inherited Disease;
Scriver, C. R., Beaudet, A. L., Sly, W. S., Eds., 7th ed.;
McGraw-Hill: New York, 1995; p 2465; (b) Brooks, D. A.;
Harper, G. S.; Gibson, G. J.; Ashton, L. J.; Taylor, J. A.;
McCourt, P. A. G.; Freeman, C.; Clements, P. R.;
Hoffmann, J. W.; Hopwood, J. J. Biochem. Med. Metab.
Biol. 1992, 47, 211.
4. (a) Kinoshita, N.; Gelboin, H. V. Science 1978, 199, 307;
(b) Kim, D. H.; Kang, H. J.; Park, S. H.; Kobashi, K.
Biol. Pharm. Bull. 1994, 17, 423.
5. (a) Caygill, J. C.; Pitkeathy, D. A. Ann. Rheum. Dis. 1966,
25, 137; (b) Weissman, G.; Zurier, R. B.; Spieler, P. J.;
Goldstein, I. M. J. Exp. Med. 1971, 134, S149.
6. For some recent references, see: (a) Heightman, T. D.;
Vasella, A. T. Angew. Chem., Int. Ed. 1999, 38, 750; (b)
Vasella, A.; Davies, G. J.; Bo¨hm, M. Curr. Opin. Chem.
Biol. 2002, 6, 619; (c) Bo¨hm, M.; Lorthiois, E.; Meyyap-
pan, M.; Vasella, A. Helv. Chim. Acta 2003, 86, 3818; (d)
Gloster, T. M.; Williams, S. J.; Roberts, S.; Tarling, C. A.;
Wicki, J.; Withers, S. G.; Davies, G. J. Chem. Commun.
2004, 1794; (e) Bo¨hm, M.; Vasella, A. Helv. Chim. Acta
2004, 87, 2566; (f) Vincent, F.; Gloster, T. M.; Macdonald,
J.; Morland, C.; Stick, R. V.; Dias, F. M. V.; Prates, J. A.
M.; Fontes, C.; Gilbert, H. J.; Davies, G. J. Chembiochem
2004, 5, 1596; (g) Gloster, T. M.; Macdonald, J. M.;
The D-galacto and L-ido glycarolactams 2 and 3 were
synthesized from the (Z)-alkene 8 following the same
strategy as described above. However, not too surpris-
ingly,19 substrate control of the dihydroxylation of the
(Z)-alkene was not selective, and treatment of 8 with
OsO4 and NMOÆH2O afforded a 1:1 mixture (78%) of
the D-gluco and L-altro lactones 21 and 22. This mixture
was subjected to the same sequence of reactions as de-
scribed above for the transformation of 16, to afford,
after chromatography, the L-ido and the D-galacto gly-
carolactams 27 (13%) and 28 (25%). Saponification of
the lactams 27 and 28 was again unavoidably accompa-
nied by partial epimerization at C(5). Treatment of the
resulting two pairs of isomeric acids with Ph2CN2
followed by chromatography and crystallization of
the resulting benzyhydryl esters provided the protected
L-ido and D-galacto glycarolactams 29 (85%) and 30
(83%) besides minor amounts of their epimers 15 and
20 (Scheme 3).
Each one of the diastereoisomeric lactams 15, 30, 29,
and 20 was deprotected by hydrogenolysis (aq MeOH,
6 bar) in the presence of Pd/C (10%). The resulting acids
were converted to the configurationally stable sodium

3622
J. Pabba, A. Vasella / Tetrahedron Letters 46 (2005) 3619–3622
Tarling, C. A.; Stick, R. V.; Withers, S. G.; Davies, G. J.
12. Pandey, G.; Kapur, M.; Khan, M. I.; Gaikwad, S. M. Org.
Biomol. Chem. 2003, 1, 3321.
13. Lee, W. W.; Chang, S. Tetrahedron: Asymmetry 1999, 10,
4473.
J. Biol. Chem. 2004, 279, 49236; (h) Terinek, M.; Vasella,
A. Helv. Chim. Acta 2004, 87, 3035; (i) Mohal, N.; Vasella,
A. Helv. Chim. Acta 2005, 88, 100.
7. Niwa, T.; Niida, T.; Tsuruoka, T.; Inouye, S.; Koeda, T.;
Naito, Y. J. Biochem. (Tokyo) 1972, 72, 207.
8. Guntha, S.; Mereyala, H. B. Tetrahedron Lett. 1994, 35,
4869.
14. Conrad, R. M.; Grogan, M. J.; Bertozzi, C. R. Org. Lett.
2002, 4, 1359.
15. Ohwada, J.; Inouye, Y.; Kimura, M.; Kakisawa, H. Bull.
Chem. Soc. Jpn. 1990, 63, 287.
9. (a) Gawronski, J.; Gawronska, K. Tartaric and Malic Acids
in Synthesis: A Source Book of Building Blocks, Ligands,
Auxiliaries, and Resolving Agents; John Wiley & Sons, 1998;
(b) Ghosh, A. K.; Koltun, E. S.; Bilcer, G. Synthesis 2001,
1281.
10. Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1987,
52, 3337.
11. Ina, H.; Kibayashi, C. J. Org. Chem. 1993, 58, 52.
16. De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett.
2001, 3, 3041.
17. Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht,
A.; Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992, 487.
18. Wagner, R.; Tilley, J. W.; Lovey, K. Synthesis 1990, 785.
19. (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984,
40, 2247; (b) Brimacombe, J. S.; Hanna, R.; Bennett, F.
Carbohydr. Res. 1985, 135, C17.