Synthesis of novel 3-amino(hydroxy)methyl- l - Fuco -azafagomines as leads for selective inhibitors of α- L -fucosidases

Article abstract of DOI:10.1055/s-0029-1219906

The synthesis of 3-substituted l-fuco-azafagomines from d-lyxose is reported. They represent the first example of aza-C-glycosides having a biimino (-NH-NH-) moiety. The key step of the synthesis is the introduction of the hydrazine moiety by reductive hydrazination of a 1-deoxy-ketohexose with tert-butyl carbazate. Their glycosidase inhibitory properties are also reported.

Full text of DOI:10.1055/s-0029-1219906

LETTER
1367
Synthesis of Novel 3-Amino(Hydroxy)methyl-L-fuco-Azafagomines as Leads
for Selective Inhibitors of a-L-Fucosidases
Synthesisof
N
o
l
vel
L
-
f
e
n
o
-C-Glycos
a
a
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Prof. García González 1, 41012 Seville, Spain
Fax +34(954)624960; E-mail: robina@us.es; E-mail: anatere@us.es
b
Instituto de Investigaciones Químicas ‘Isla de la Cartuja’, CSIC-USE, Américo Vespucio 49, 41092 Sevilla, Spain
Received 8 February 2010
On the other hand, Bols and co-workers have described
the preparation of (3S,4R,5S)-3-methylhexahydropy-
ridazine-4,5-diol (2), the so-called ‘fuco-azafagomine’
(Figure 1) that showed interesting inhibitory properties.10
Abstract: The synthesis of 3-substituted L-fuco-azafagomines from
D-lyxose is reported. They represent the first example of aza-C-gly-
cosides having a biimino (–NH–NH–) moiety. The key step of the
synthesis is the introduction of the hydrazine moiety by reductive
hydrazination of a 1-deoxy-ketohexose with tert-butyl carbazate. To the best of our knowledge, 2 is the only reported exam-
Their glycosidase inhibitory properties are also reported.
ple of a L-fuco polyhydroxylated hexahydropyridazine.
Key words: azasugars, glycosidases, fucosidase inhibitors, aza-
fagomines, C-glycosides
We report herein for the first time the synthesis and the
glycosidase inhibitory properties of the C-3 substituted
fuco-azafagomines 3a and 3b. Both compounds can be
used as new leads in the search for selective and potent in-
a-L-Fucosidase is an exoglycosidase involved in the trim-
ming of nonreducing terminal L-fucose units during the
biosynthetic processing of fucose-containing glycoconju-
gates.1 This enzyme, in common with other glycosidases,
has glycosyl transfer activity and, therefore, can be also
used in the synthesis of fucosyl glycans.2 a-L-Fucosidase
is associated with a great variety of physiological and
pathological events. For example, aberrant distribution of
fucose on fucose-containing glycoconjugates is found in
inflammation processes, cancer, and cystic fibrosis.3 In-
hibitors of a-L-fucosidase can provide useful information
about the functions of the enzyme and the basis for the de-
velopment of potential therapeutic agents.4
hibitors of a-L-fucosidases. The hydroxylated L-fuco-
hexahydropyridazine moiety can be used as core structure
to mimic the fucosyl cation generated in the enzymatic
hydrolysis. Besides, the hydroxymethyl or aminomethyl
groups at C-3 can be further functionalized giving a li-
brary of derivatives by a diversity-oriented synthesis.
These compounds could contribute to a better understand-
ing of the inhibition mechanisms of fucosidases in terms
of structural and conformational changes, charge disloca-
tion, and protonation as it has been made with azafago-
mine analogues in glucosidases.11
The retrosynthetic analysis for the preparation of com-
pounds 3a and 3b is indicated in Scheme 1. The key steps
imply cyclization of 2-methyl glycosylhydrazines, which
were obtained by reductive hydrazination of a 1-deoxyke-
tohexose easily prepared from D-lyxose, which contains
the correct configuration at C-4 and C-5 of our target com-
pounds.
Among the most powerful a-L-fucosidase inhibitors are L-
fuco hydroxylated piperidines such as L-fuconojirimycin
(FNJ, 1),5 although the intrinsic instability caused by the
lability of the N,O-acetal function prevents its biological
use. The 1-hydroxymethyl-FNJ6 and 1-aminomethyl-
FNJ,7 which have a C–C bond at C-1, are stable C-glyco-
syl analogues8 that have been used to generate potent in-
hibitors of a-L-fucosidases.9
OH
Me
Me
NHBoc
NH
O
OH
PO
PO
D-lyxose
3
H
H
NH
OH
OH
O
O
O
O
Me
N
Me
N
HO
HO
HO
1
2
HO
Ki = 1 nΜ
Ki = 0.81 μΜ
Scheme 1
(α-L-fucosidases)5
(α-L-fucosidases)10
H
N
Thus, starting from D-lyxose, tri-O-protected D-lyxono-
lactone 5 could be easily obtained following a similar pro-
cedure to that described in the literature12 (Scheme 2).
Addition of MeLi13 afforded the protected 1-deoxy-keto-
hexose 6 as a 3:1 mixture of anomers. Reductive hydrazi-
nation of 6 using tert-butyl carbazate, NaBH3CN, and
acetic acid in MeOH at 65 °C afforded the mixture of hy-
drazines 7 in 82% yield. Reaction of 7 with benzyl chlo-
roformate, followed by mesylation and selective Boc
deprotection gave crude monohydrazides that were treat-
NH
Me
3a R = OH
3b R = NH2
R
HO
HO
Figure 1
SYNLETT 2010, No. 9, pp 1367–1370
Advanced online publication: 10.05.2010
DOI: 10.1055/s-0029-1219906; Art ID: D03910ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
0

1368
E. Moreno-Clavijo et al.
LETTER
ed with Et3N in MeOH at reflux to afford cyclic deriva- of 5.0 Hz between H-4 and H-5 indicated that 9 had a chair
tives 8 and 9 as a 2.1:1 mixture of diastereomers. This conformation with the C-3 substituent in equatorial and
sequence could be efficiently carried out without interme- the Me-6 in axial positions. However, although the X-ray
1
diate purification, affording the corresponding hexa- structure of 10 indicated a chair conformation, its H
hydropyridazines in 71% overall yield after NMR spectrum16 showed coupling constant values of 4.5,
chromatographic separation.
5.5 and 5.5 Hz for J3,4, J4,5, and J5,6, respectively. These
values were also observed for compound 8, which indi-
cates that a conformational equilibrium for both deriva-
tives takes place in solution.
1. 2,2-DMP, PTSA
DMF
2. TBDPSCl, Et3N
DMF, DMAP, 0 °C
O
OH
TBDPSO
Reaction of 10 with TBAN3 followed by reduction of the
azido group with H2S afforded protected aminomethyl de-
rivative 11.
D-lyxose
61%
O
O
4
1. ClCOCOCl,
DMSO, CH2Cl2
–78 to –60 °C
2. Et3N, –60 to 25 °C
93%
OH
Me
O
O
O
MeLi
TBDPSO
THF, –78 °C
TBDPSO
91%
O
O
O
O
6
5
NH2NHBoc, NaBH3CN
MeOH, AcOH, 65 °C
82%
Me
OH
NHBoc
N
TBDPSO
H
O
O
7
1. CbzCl, NaOH, EtOH
2. MsCl, CH2Cl2–Py
3. TMSOTf, 2,6-lutidine, CH2Cl2
4. Et3N, MeOH, reflux
5. chromatographic separation
71%
H
H
N
2N
1
TBDPSO
NCbz
TBDPSO
NCbz
Me
3
Figure 2 X-ray crystallographic structure for compound 10
6
4
O
Me
O
5
O
8
O
Hydrogenation of compound 8 afforded hydrazone 12 in
good yield. The formation of this product can be ex-
plained by oxidation of the hydrazine to the corresponding
azo compound, followed by isomerization of the double
bond to the more stable hydrazone.17 Then, deprotection
of compounds 8 and 9 was attempted by treatment with
TBAF, followed by acidic removal of the acetonide af-
fording N-protected alcohols 13 and 14 in good to excel-
lent yields. Final hydrogenation of these compounds
under acidic conditions afforded desired hydroxylated
hexahydropyridazines 3a and 15,18 in quantitative yields
as the corresponding hydrochloride salts. Acidic treat-
ment of 11 and subsequent catalytic hydrogenation fur-
nished compound 3b as hydrochloride salt in excellent
overall yield (Scheme 3). Hydrogenation under acidic
conditions is critical to avoid undesired oxidation.
8:9 = 2.1:1
9
1. TBAF, THF
2. TsCl, Py
85%
H
N
H
N
TsO
NCbz
H2N
NCbz
Me
1.TBAN3, THF, 50 °C
2. H2S, Py–H2O
O
Me
O
82%
O
O
11
10
Scheme 2
Compounds 8 and 9 were fully characterized by their
spectroscopic data14 but the configuration of C-6 was dif-
ficult to assign. Fortunately, deprotection of 8 followed by
tosylation afforded crystalline tosyl derivative 10, the
structure of which was unambiguously confirmed by X-
Derivatives 3a, 3b, and 15 have been analyzed for their in-
hibitory activities towards twelve commercially available
glycosidases (Table 1).19 Compound 3a was a selective
and competitive inhibitor of a-L-fucosidase from bovine
kidney (97% at 1 mM concentration, Ki = 4.2 mM) which
ray crystallography (Figure 2).15 The H NMR spectrum
1
of 9 showed a large coupling constant (J = 9.3 Hz) be-
tween H-3 and H-4 and no coupling constant between H-
5 and H-6. These results together with a coupling constant
Synlett 2010, No. 9, 1367–1370 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel 3-Substituted L-fuco-Azafagomines
1369
H2, Pd/C
MeOH
imines20 or through the in situ evaluation of libraries of
amides.7
8
9
H
N
73%
90%
TBDPSO
N
1. TBAF/THF
The use of lead compounds 3a and 3b in the synthesis of
new derivatives, the conformational analysis and the cor-
responding biological studies are currently in progress in
our laboratory and will be reported in due course.
83%
2. HCl–THF (1:1)
O
Me
HO
12
O
H
N
H
N
HO
HO
NCbz
NCbz
Me
HO
Me
Acknowledgment
OH
OH
13
14
11
We thank the Ministerio de Ciencia e Innovación of Spain
(CTQ2008-01565/BQU) and the Junta de Andalucía (FQM-345 and
P07-FQM-03056) for financial support. We also thank CITIUS of
the University of Seville. E.M.C. thanks the Ministerio de Educa-
ción for a FPU fellowship.
1. HCl–THF (1:1)
2. HCl, H2, Pd/C
H2, Pd/C
94%
quant
quant
MeOH, HCl
H
Me
H
N
H
N
NH
NH
OH
3a (HCl)
NH
N
Me
Me
NH2
HO
HO
HO
HO
HO
OH
HO
3b (2HCl)
15(HCl)
References and Notes
Scheme 3
(1) (a) Ma, B.; Simala-Grant, J. L.; Taylor, D. E. Glycobiology
2006, 16, 158R. (b) Vocadlo, D.; Davies, G. J. Curr. Opin.
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31, 523. (d) Benesova, E.; Markova, M.; Lipovova, P.;
Kralova, B. Chem. Listy 2005, 99, 324.
Table 1 Inhibitory Activities of 3-substituted L-fuco-azafago-
minesa–c
Compound
a-L-Fucosidase (%)
(2) (a) Berteau, O.; Bielicki, J.; Kilonda, A.; Delphine Machy,
D.; Anson, D. S.; Kenne, L. Biochemistry 2004, 43, 7881.
(b) Osanjo, G.; Dion, M.; Drone, J.; Solleux, C.; Tran, V.;
Rabiller, C.; Tellier, C. Biochemistry 2007, 46, 1022.
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(b) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9,
3077. (c) Springer, T. A.; Lasky, L. A. Nature (London)
1991, 349, 196. (d) Ayude, D.; Fernández-Rodríguez, J.;
Rodríguez-Berrocal, F. J.; Martínez-Zorzano, V. S.; De
Carlos, A.; Gil, E.; De la Cadena, M. P. Oncology 2000, 59,
310. (e) Michalski, J. C.; Klein, A. Biochim. Biophys. Acta
1999, 1455, 69. (f) Glick, M. C.; Kothari, V. A.; Liu, A.;
Stoykova, L. I.; Scanlin, T. F. Biochimie 2001, 83, 743.
(4) (a) Kajimoto, T.; Node, M. Curr. Top. Med. Chem. 2009, 9,
13. (b) D’Alonzo, D.; Guaragna, A.; Palumbo, G. Curr.
Med. Chem. 2009, 16, 473. (c) Gerber-Lemaire, S.;
Juillerat-Jeanneret, L. Mini-Rev. Med. Chem. 2006, 6, 1043.
(d) Robina, I.; Moreno-Vargas, A. J.; Carmona, A. T.;
Vogel, P. Curr. Drug Metabol. 2004, 5, 329.
3a
3b
15
97 (Ki = 4.2 mM)
44
17
a For measurement conditions, see ref. 19.
b The mode of inhibition for given Ki is competitive.
c Percentage of inhibition at 1 mM, Ki in mM, when measured. Optimal
pH, 37 °C.
is a comparable value to that reported for fuco-azafagom-
ine 2,10 showing that the C-3 substituent is not detrimental
for the inhibition. It is worth noting that compound 3a did
not inhibit any of the other enzymes assayed: a-galactosi-
dases from coffee beans, b-galactosidases from Escheri-
chia coli and Aspergillus orizae, a-glucosidases from
yeast and from rice, amyloglucosidase from Aspergillus
niger, b-glucosidases from almonds, a-mannosidases
from Jack beans, b-mannosidases from snail, b-xylosidas-
es from Aspergillus niger, and b-N-acetylglucosaminidas-
es from Jack beans. Compounds 3b and 15 are much
weaker inhibitors of a-L-fucosidases from bovine kidney
(44% for 3b and 17% for 15, at 1 mM concentration) and
did not inhibit the other enzymes. Compound 15, epimer
of 3a at C-6, showed a weak inhibition towards a-L-fu-
cosidases indicating the importance of the S configuration
at Me-6 to bind the enzyme.
(5) Dubernet, M.; Defoin, A.; Tarnus, C. Bioorg. Med. Chem.
Lett. 2006, 61, 1172.
(6) (a) Fleet, G. W. J.; Namgoong, S. K.; Barker, C.; Baines, S.;
Jacob, G. S.; Winchester, B. Tetrahedron Lett. 1989, 30,
4439. (b) Andrews, D. M.; Bird, M. I.; Cunningham, M. M.;
Ward, P. Bioorg. Med. Chem. Lett. 1993, 3, 2533.
(c) Beacham, A. R.; Smelt, K. H.; Biggadike, K.; Britten,
C. J.; Hackett, L.; Winchester, B. G.; Nash, R. J.; Griffiths,
R. C.; Fleet, G. W. J. Tetrahedron Lett. 1998, 39, 151.
(7) Wu, C.-Y. i.; Chang, C.-F.; Chen, J. S.-Y.; Wong, C.-H.;
Lin, C.-H. Angew. Chem. Int. Ed. 2003, 42, 4661.
(8) (a) Davis, B. G. Tetrahedron: Asymmetry 2009, 20, 645.
(b) Iminosugars: From Synthesis to Therapeutic
In summary, the synthesis of new C-3-substituted fuco-
configurated hydroxylated hexahydropyridazines from D-
lyxose is reported. They can be considered as the first ex-
amples of aza-C-glycosides having a biimino (–NH–NH–)
moiety and constitute interesting lead compounds for the
search of new a-L-fucosidase inhibitors. In spite of that
compound 3b is a weak inhibitor of a-L-fucosidases, its
triamino functionality makes it a promising candidate for
the discovery of fucosidase inhibitors by combinatorial
procedures through the approach of dynamic libraries of
Applications; Compain, P.; Martin, O. R., Eds.; Wiley-VCH:
Weinheim, 2007. (c) Robina, I.; Vogel, P. Synthesis 2005,
675.
(9) (a) Ho, C.-W.; Lin, Y.-N.; Chang, C.-F.; Li, S.-T.; Wu,
Y.-T.; Wu, C.-Y.; Chang, C.-F.; Liu, S.-W.; Li, Y.-K.; Lin,
C.-H. Biochemistry 2006, 45, 5695. (b) Chang, C.-F.; Ho,
C.-W.; Wu, C.-Y.; Chao, T.-A.; Wong, C.-H.; Lin, C.-H.
Chem. Biol. 2004, 11, 1301.
(10) Jensen, H. H.; Jensen, A.; Hazzel, R. G.; Bols, M. J. Chem.
Soc., Perkin Trans. 1 2002, 1190.
Synlett 2010, No. 9, 1367–1370 © Thieme Stuttgart · New York

1370
E. Moreno-Clavijo et al.
LETTER
P212121 (no. 19), a = 5.9856 (3) Å, b = 16.5688 (8) Å,
(11) (a) Hansen, S. U.; Bols, M. J. Chem. Soc., Perkin Trans. 2
2000, 665. (b) Bülow, A.; Plesner, I. W.; Bols, M. J. Am.
Chem. Soc. 2000, 122, 8567. (c) Lohse, A.; Hardlei, T.;
Jensen, A.; Plesner, I. W.; Bols, M. Biochem. J. 2000, 349,
211. (d) Jensen, H. H.; Lyngbye, L.; Jensen, A.; Bols, M.
Chem. Eur. J. 2002, 8, 1218. (e) Sivertsen, A. C.; Gasior,
M.; Bjerring, M.; Hansen, S. U.; López López, O.; Nielsen,
N. C.; Bols, M. Eur. J. Org. Chem. 2007, 1735. (f) G loster,
T. M.; Meloncelli, P.; Stick, R. V.; Zechel, D.; Vasella, A.;
Davies, G. J. J. Am. Chem. Soc. 2007, 129, 2345.
(12) Jiang, S.; Rycroft, A. D.; Singh, G.; Wang, X.-Z.; Wu, Y.-L.
Tetrahedron Lett. 1998, 39, 3809; compound 5 was reported
but not characterized
c = 24.4976 (11) Å, V = 2429.5 (2) Å3, Z = 4, rcalcd = 1.341
g cm–3, l (Mo Ka1) = 0.71073 Å, F(000) = 1040, m = 0.180
mm–1, T = 173 (2) K, 34818 reflections measured, 4999
unique (Rint = 0. 0847) which were used in all calculations.
The final R1 = 0.0430 [I > 2s(I)], wR2 = 0.1047 (all data).
Flack parameter = –0.02 (8). Full crystallographic data for
this structure have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
CCDC 764937. These data can obtained free of charge on
application to CCDC, 12, Union Road, Cambridge CB2
1EZ, UK; fax: +44 (1223)336033; or e-mail:
deposit@ccdc.cam.ac.uk.
Characterization Data for 5
(16) Analytical Data for 10
[a]D22 –34.9 (c 0.74, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d = 7.71–7.65 (m, 4 H, Harom), 7.47–7.37 (m, 6 H, Harom),
4.82–4.78 (m, 2 H, H-2, H-3), 4.58 (td, 1 H, J4,5a = J4,5b = 6.4
Hz, J4,3 = 2.6 Hz, H-4), 4.08–3.93 (m, 2 H, H-5a, H-5b), 1.36
[s, 6 H, C(CH3)2], 1.07 [s, 9 H, C(CH3)3] ppm. 13C NMR
(75.4 MHz, CDCl3): d = 173.9 (C=O), 135.8, 133.2, 133.0,
130.0, 128.0, 127.9 (C arom.), 114.2 [C(CH3)2], 79.5 (C-4),
76.2, 75.9 (C-2, C-3), 61.7 (C-5), 26.9 [C(CH3)3], 26.1
[C(CH3)2], 19.4 [C(CH3)3] ppm. MS (CI): m/z (%) = 427 (5)
[M + H]+. HRMS (CI): m/z calcd for C24H31O5Si [M + H]+:
427.1941; found 427.1927.
Mp 130–132 °C (EtOAc–PE). [a]D23 –6.4 (c 0.45, CH2Cl2).
1H NMR (500 MHz, DMSO-d6): d = 7.76 (d, 2 H, 3JH,H = 8.0
Hz, H-Ts), 7.46 (d, 2 H, H-Ts), 7.37–7.30 (m, 5 H, Harom),
5.17 (br s, 1 H, NH), 5.04 (d, 1 H, 2JH,H = 12.7 Hz, CH2 of
Cbz), 5.01 (d, 1 H, CH2 of Cbz), 4.16 (t, 1 H, J5,4 = J5,6 = 5.5
Hz, H-5), 4.04–3.97 (m, 3 H, H-6, H-1′a, H-1′b), 3.83 (dd, 1
H, J4,3 = 4.5 Hz, H-4), 3.10 (m, 1 H, H-3), 2.41 (s, 3 H, CH3
of Ts), 1.28 (d, 3 H, J6,Me-6 = 7.0 Hz, Me-6), 1.31, 1.23 [2 s,
3 H each, C(CH3)2] ppm. 13C NMR (125.7 MHz, DMSO-d6,
353 K): d = 156.1 (C=O of Cbz), 145.1, 136.7, 132.0, 130.2,
128.3, 127.8, 127.6, 127.5 (Carom), 108.1 [C(CH3)2], 72.2 (C-
5), 70.0, 69.9 (C-4, C-1′), 66.3 (CH2 of Cbz), 56.1 (C-3),
50.1 (C-6), 26.6, 25.6 [C(CH3)2], 21.1 (Me of Ts), 15.7 (Me-
6) ppm. MS–FAB: m/z (%) = 513 (100) [M + Na]+, 491 (10)
[M + H]+. HRMS–FAB: m/z calcd for C24H30N2O7SNa [M +
Na]+: 513.1671; found: 513.1678. Anal. Calcd for
C24H30N2O7S: C, 58.76; H, 6.16; N, 5.71; S, 6.54. Found: C,
58.75; H, 6.11; N, 5.82; S, 6.50.
(13) Jones, N. A.; Jenkinson, S. F.; Soengas, R.; Fanefjord, M.;
Wormald, M. R.; Dwek, R. A.; Kiran, G. P.; Devendar, R.;
Takata, G.; Morimoto, K.; Izumoric, K.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2007, 18, 774.
(14) Analytical Data for 8
[a]D25 –18.2 (c 1.19, CH2Cl2). 1H NMR (500 MHz, DMSO-
d6): d = 7.61–7.58 (m, 4 H, Harom), 7.48–7.38 (m, 6 H, Harom),
7.28–7.26 (m, 5 H, Harom), 5.18 (br d, 1 H, JNH,3 = 3.2 Hz,
NH), 5.05 (d, 1 H, 2JH,H = 12.7 Hz, CH2 of Cbz), 5.02 (d, 1
H, CH2 of Cbz), 4.08 (dd, 1 H, J5,4 = 5.5 Hz, J5,6 = 4.8 Hz,
H-5), 3.97 (qd, 1 H, J6,Me-6 = 7.2 Hz, H-6), 3.96 (t, 1 H,
J4,3 = 5.5 Hz, H-4), 3.65 (d, 2 H, J1¢,3 = 6.7 Hz, H-1¢), 3.05
(m, 1 H, H-3), 1.34 (d, 3 H, Me-6), 1.33, 1.24 [2 s, 3 H each,
C(CH3)2], 0.99 [s, 9 H, C(CH3)3] ppm. 13C NMR (125.7
MHz, DMSO-d6): d = 156.0 (C=O of Cbz), 136.7, 135.0,
132.7, 129.9, 128.2, 127.9, 127.8, 127.6, 127.3 (Carom), 108.0
[C(CH3)2], 72.6 (C-5), 70.8 (C-4), 66.2 (CH2 of Cbz), 63.7
(C-1¢), 58.7 (C-3), 50.9 (C-6), 26.8, 25.7 [C(CH3)2], 26.5
[C(CH3)3], 18.7 [C(CH3)3], 15.9 (Me-6) ppm. MS–FAB:
m/z (%) = 597 (40) [M + Na]+, 575 (8) [M + H]+. HRMS–
FAB: m/z calcd for C33H42N2O5NaSi [M + Na]+: 597.2761;
found: 597.2780.
(17) This process of oxidation–isomerization has been previously
studied for hydrazines and some examples are reported, see:
Stone, K. J.; Greenberg, M. M.; Blackstock, S. C.; Berson,
J. A. J. Am. Chem. Soc. 1989, 111, 3659; see also ref. 11a.
(18) Analytical Data for 3a
[a]D22 –44.6 (c 0.6, MeOH). 1H NMR (500 MHz, CD3OD):
d = 3.85–3.82 (m, 2 H, H-5, H-1′a), 3.74 (dd, 1 H,
2J1¢b,1¢a = 11.6 Hz, J1¢b,3 = 5.5 Hz, H-1′b), 3.63 (dd, 1 H,
J4,3 = 10.3 Hz, J4,5 = 2.8 Hz, H-4), 3.35 (qd, 1 H, J6,Me-6 = 6.8
Hz, J6,5 = 1.2 Hz, H-6), 3.24 (ddd, 1 H, J3,1¢a = 2.9 Hz, H-3),
1.28 (d, 3 H, Me-6) ppm. 13C NMR (125.7 MHz, CD3OD):
d = 69.6 (C-5), 68.1 (C-4), 60.1 (C-1′), 58.0 (C-6), 57.5 (C-
3), 14.0 (Me-6) ppm. MS (CI): m/z (%) = 163 (40) [M + H]+.
HRMS (CI): m/z calcd for C6H15N2O3 [M + H]+: 163.1083;
found: 163.1083.
Analytical Data for 9
Analytical Data for 15
[a]D26 –64.5 (c 0.82, CH2Cl2). 1H NMR (500 MHz, DMSO-
d6): d = 7.63–7.61 (m, 4 H, Harom), 7.49–7.30 (m, 11 H,
Harom), 5.18 (br s, 2 H, CH2 of Cbz), 5.09 (br s, 1 H, NH),
4.56 (q, 1 H, J6,Me-6 = 7.2 Hz, H-6), 3.99 (d, 1 H, J5,4 = 5.0
Hz, H-5), 3.80 (dd, 1 H, J4,3 = 9.4 Hz, H-4), 3.77 (dd, 1 H,
2J1¢a,1¢b = 10.7 Hz, J1¢a,3 = 3.0 Hz, H-1¢a), 3.59 (dd, 1 H,
J1¢b,3 = 9.0 Hz, H-1¢b), 2.89 (m, 1 H, H-3), 1.28 (d, 3 H,
Me-6), 1.20 [s, 6 H, C(CH3)2], 0.98 [s, 9 H, C(CH3)3] ppm.
13C NMR (125.7 MHz, DMSO-d6): d = 155.2 (C=O of Cbz),
136.9, 135.0, 132.6, 129.9, 128.2, 127.9, 127.8, 127.7, 127.1
(Carom), 108.0 [C(CH3)2], 75.0 (C-5), 70.0 (C-4), 66.3 (CH2
of Cbz), 63.3 (C-1¢), 59.9 (C-3), 49.1 (C-6), 27.8, 26.3
[C(CH3)2], 26.5 [C(CH3)3], 18.7 [C(CH3)3], 16.1 (Me-6)
ppm. MS–FAB: m/z (%) = 597 (50) [M + Na]+, 575 (10)
[M + H]+. HRMS–FAB: m/z calcd for C33H42N2O5NaSi [M
+ Na]+: 597.2761; found: 597.2802.
[a]D22 –12.3 (c 0.85, MeOH). 1H NMR (500 MHz, CD3OD):
d = 3.85 (dd, 1 H, 2J1¢a,1¢b = 11.5 Hz, J1¢a,3 = 3.7 Hz, H-1¢a),
3.81 (dd, 1 H, J4,3 = 7.4 Hz, J4,5 = 2.9 Hz, H-4), 3.77 (dd, 1
H, J1¢b,3 = 6.9 Hz, H-1¢b), 3.71 (m, 1 H, H-5), 3.51 (qd, 1 H,
J6,Me-6 = 6.9 Hz, J6,5 = 5.4 Hz, H-6), 3.36 (td, 1 H, H-3), 1.34
(d, 3 H, Me-6) ppm. 13C NMR (125.7 MHz, CD3OD): d =
70.1 (C-5), 65.4 (C-4), 60.5 (C-3), 60.2 (C-1¢), 56.6 (C-6),
13.2 (Me-6) ppm. MS (CI): m/z (%) = 163 (65) [M + H]+.
HRMS (CI): m/z calcd for C6H15N2O3 [M + H]+: 163.1083;
found: 163.1087.
(19) For the conditions used in the biological tests, see: (a) Saul,
R.; Chambers, J. P.; Molyneux, R. J.; Elbein, A. D. Arch.
Biochem. Biophys. 1983, 221, 593. (b) Brandi, A.; Cicchi,
S.; Cordero, F. M.; Frignoli, R.; Goti, A.; Picasso, S.; Vogel,
P. J. Org. Chem. 1995, 60, 6806.
(20) Gerber-Lemaire, S.; Popowycz, F.; Rodriguez-Garcia, E.;
Carmona Asenjo, A. T.; Robina, I.; Vogel, P.
(15) Crystal Data for 10
C24H30N2O7S, Mr = 490.56, orthorhombic, space group
ChemBioChem 2002, 3, 466.
Synlett 2010, No. 9, 1367–1370 © Thieme Stuttgart · New York

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