Synthesis of amino carba sugars and conformationally restricted polyhydroxy γ-amino acids from (-)-quinic acid

Article abstract of DOI:10.1002/ejoc.200400282

Efficient syntheses of two novel positional stereoisomers of valiolamine, a potent glycosidase inhibitor, and two polyhydroxy γ-amino acids are reported. The syntheses involve regio- and stereoselective azidolysis of epoxides by trimethylsilyl azide with

Full text of DOI:10.1002/ejoc.200400282

FULL PAPER
Synthesis of Amino Carba Sugars and Conformationally Restricted
Polyhydroxy γ-Amino Acids from (؊)-Quinic Acid
[a]
[a]
[a]
´
´
Montserrat Carballido, Luis Castedo, and Concepcion Gonzalez-Bello*
´
Dedicated to Professor Jose Luis Soto on the occasion of his retirement
Keywords: Amino carba sugars / Polyhydroxy γ-amino acids / Regioselectivity / Glycosidase inhibitors
Efficient syntheses of two novel positional stereoisomers of
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
valiolamine, a potent glycosidase inhibitor, and two poly- Germany, 2004)
hydroxy γ-amino acids are reported. The syntheses involve
regio- and stereoselective azidolysis of epoxides by tri-
methylsilyl azide with BF3·OEt2 as Lewis acid.
Introduction
We reported recently a practical route to a variety of po-
lyhydroxycyclohexanes that involved stereocontrolled epox-
ide formation and hydrolysis: epoxidation of cyclohexenes
1 and 3 afforded 2 and 4, respectively,[10] as the sole dia-
stereoisomers (Scheme 1), while subsequent hydrolysis gave
mainly ring opening on C-3 and C-7, respectively.[11] We
now extend this strategy to the regio- and diastereoselective
synthesis of the two novel amino carba sugars 5a and 6a,
which are positional stereoisomers of valiolamine, and the
corresponding polyhydroxy γ-amino acids 5b and 6b, that
could be used to develop more selective nanotubes (Fig-
ure 1).
Sugar analogues in which the ring oxygen atom has been
replaced by a methylene group (carba sugars or pseudo-
sugars[1]) have attracted considerable interest as inhibitors
of glycosidase enzymes. Glycosidases are involved in nu-
merous biological processes, and glycosidase inhibitors have
enormous potential for the treatment of many diseases, in-
cluding cancer, diabetes and viral infections. This is because
they alter the glycosylation or catabolism of glycoproteins,
or block the recognition of specific sugars.[2] Carba sugars
also provide rigid systems that can be used to display phar-
macophoric groups in well-defined spatial orientations.[3]
Examples of naturally occurring carba sugars include
carba-α--galactose,[4] valienamine,[5] validamine,[5b,6] and
valiolamine.[1c,5b,7] On the other hand, in recent years con-
siderable effort has been devoted to the synthesis of cyclic
amino acids which can be incorporated into peptides and
peptidomimetics to create conformationally restricted ana-
logues that can be used to obtain important information
about key structural features of receptor ligand com-
plexes.[8] Also, recently, Granja et al. have used (1R,3S)-3-
aminocyclohexanecarboxylic acid to develop new types of
peptide nanotube with hydrophobic cavities.[9] Appropriate
functionalization of this kind of cyclic amino acid should
lead to nanotubes with greater selectivity as molecule con-
tainers, ion channels, receptors, etc.
[a]
´
´
Departamento de Quımica Organica y Unidad Asociada al
´
CSIC, Facultad de Quımica, Universidad de Santiago de
Compostela,
Avenida de las Ciencias s/n, 15782 Santiago de Compostela,
Spain
Fax: (internat.) ϩ 34-981-595012
E-mail: cgb1@lugo.usc.es
Scheme 1. Stereocontrolled epoxide formation
Eur. J. Org. Chem. 2004, 3663Ϫ3668
DOI: 10.1002/ejoc.200400282
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3663

´
M. Carballido, L. Castedo, C. Gonzalez-Bello
FULL PAPER
therefore removed its trans-diol protecting group, so that
treatment of 4 with aqueous trifluoroacetic acid gave the
diol 7 in good yield. Subsequent azidolysis of epoxide 7 by
TMSN3 with BF3·OEt2 as Lewis acid, in refluxing dichloro-
methane, afforded a chromatographically separable mixture
of the azido ester 8 (81%) and the azido carbolactone 9
(11%). X-ray crystallography was used to confirm the struc-
ture of compound 8 (Figure 2),[12] and the diaxial coupling
constant between 2-H and 3-H (J2,3 ϭ 9.1 Hz) supports
that of 9.
Figure 1. Target compounds
Results and Discussion
Synthesis of Compounds 5
Compounds 5 were synthesized via epoxide 4, which was
prepared in 76% yield (87% taking into account the reco-
vered starting material) by treatment of 3 with trifluoroper-
acetic acid that had been freshly prepared from
ureaϪhydrogen peroxide (UHP) adduct and trifluoroacetic
anhydride. This approach (Scheme 2) improves the pre-
viously reported protocol.[11]
Figure 2. X-ray structure of 8
The desired amino carba sugar 5a was obtained from az-
ido ester 8 by the three-step reaction sequence shown in
Scheme 3. Reduction of 8 with lithium borohydride in
methanol afforded a mixture of alcohols because of a cis-
1,2 migration of the silyl group from the tertiary hydroxy
group to the primary hydroxy group. Treatment of this mix-
ture with aqueous trifluoroacetic acid at 40 °C gave azido
alcohol 10 in 81% yield from 8. Finally, reduction of 10 by
catalytic hydrogenolysis in an acid medium (to avoid de-
composition of the free amine) afforded 5a in 91% yield.
Scheme 2. Reagents and conditions: (i) UHP, TFAA, Na2HPO4,
CH2Cl2, 0 °C; (ii) TFA (aq. 50%), room temp.; (iii) TMSN3,
BF3·OEt2, CH2Cl2, ∆
Scheme 3. Reagents and conditions: (i) 1) LiBH4, MeOH, THF, 0
°C; 2) TFA (aq. 50%), 40 °C; (ii) H2, Pd/C, MeOH, TFA, room
temp.; (iii) TFA (aq. 50%), 80 °C; (iv) 1) H2, Pd/C, Boc2O, EtOAc,
room temp.; 2) LiOH, room temp.; 3) Amberlite IR-120 (Hϩ),
room temp.
Attempts to azidolyse 4 using combinations of various
azides (NaN3, LiN3, NaN3/LiCl, TMSN3), solvents (DMF,
EtOH, MeOH/H2O, H2O, C6H6, CH2Cl2, ClCH2CH2Cl),
Lewis acids [Ti(OiPr)4, ZnCl2, BF3·OEt2] and reaction tem-
peratures all afforded mainly starting material. We reasoned
that the poor reactivity of epoxide 4 might be due to con-
Transformation of 8 into the amino acid 5b was more
formational impediments to trans-diaxial opening and difficult because treatment of 8 with aqueous trifluoroacetic
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Amino Carba Sugars and Conformationally Restricted Polyhydroxy γ-Amino Acids from (Ϫ)-Quinic Acid
FULL PAPER
acid at 80 °C afforded exclusively the 1,5-carbolactone 11. confirmed by studying its acetylated derivative 14 (obtained
1
In order to proceed to 5b, it was necessary firstly to trans- by treatment of 13 with acetic anhydride). The H NMR
form the azide group in the corresponding Boc derivative spectrum of 14 showed that 2-H and 3-H are axial (J2,3
and then hydrolyse the lactone under basic conditions. 10.4, J3,4 ϭ 10.0 Hz).
ϭ
Catalytic hydrogenolysis in the presence of Boc2O gave the
The desired amino carba sugar 6a was obtained from az-
desired Boc-amino carbolactone, and subsequent reaction ido ester 13 by a similar method to that for compound 5a
with lithium hydroxide, followed by treatment with Am- from 8. Reduction of 13 with lithium borohydride in meth-
berlite IR-120 (Hϩ) ion exchange resin and lyophilization, anol, followed by treatment with aqueous trifluoroacetic
gave the desired amino acid derivative 5b in 74% yield acid at 40 °C, gave an 81% yield of azido alcohol 15, which
from 11.
upon catalytic hydrogenolysis in an acidic medium afforded
the desired amino derivative 6a in 92% yield.
Finally, azido ester 13 was transformed into amino acid
6b in 87% overall yield by treatment with aqueous trifluoro-
acetic acid at 80 °C, which afforded carboxylic acid 16 in
90% yield followed by catalytic hydrogenolysis in an acidic
medium.
Synthesis of Compounds 6
For preparation of compounds 6 we employed the epox-
ide 2[11] (Scheme 4). Since this substrate was practically in-
ert when direct azidolysis was attempted (presumably be-
cause the nucleophile must attack from the more hindered
face), we tried to open the lactone to the corresponding
methyl ester. However, attempts using NaOMe/MeOH,
K2CO3/MeOH, Ti(OMe)4/MeOH and Ti(OiPr)4/MeOH all
afforded very low conversion rates, probably due to relac-
tonization to 2. Finally, reaction with 2-propanol and
Ti(OiPr)4 gave the isopropyl ester 12 in 63% yield, and azi-
dolysis of 12 by treatment with TMSN3 and BF3·OEt2 in
refluxing dichloromethane afforded the azido alcohol 13 in
43% yield (65% taking into account the recovered starting
material). The regiochemistry of the azidolysis reaction was
Conclusion
In conclusion, epoxide azidolysis with TMSN3 and
BF3·OEt2 allows the regio- and stereoselective synthesis of
the novel 3-amino carba sugars 5a and 6a, positional ster-
eoisomers of valiolamine, and the new conformationally re-
stricted polyhydroxy γ-amino acids 5b and 6b, from inex-
pensive commercially available (Ϫ)-quinic acid. Confor-
mation seems to have an important influence on the ef-
ficiency of the ring opening reaction.
Experimental Section
General Remarks: All starting materials and reagents were obtained
from commercial sources and used without further purification.
FT-IR spectra were recorded from films sandwiched between NaCl
plates. [α]D values are given in 10Ϫ1 deg·cm2·gϪ1. 1H NMR spectra
(250, 300, 400, and 500 MHz), 19F NMR spectra (282 MHz), and
13C NMR spectra (63, 75, 100, and 125 MHz) were measured in
deuterated solvents. J values are given in Hz. NMR assignments
were made using a combination of 1 D, COSY, and DEPT-135
experiments. All procedures involving the use of ion exchange re-
sins were carried out at room temperature and using Milli-Q deion-
ized water. Amberlite IR-120 (Hϩ) (cation exchanger) was washed
alternately with water, 10% HCl, water, 10% NaOH, 10% HCl, and
finally water before use.
Methyl (1R,3S,4S,6S,7R,8R,9R)-9-(tert-Butyldimethylsilyloxy)-7,8-
epoxy-3,4-dimethoxy-3,4-dimethyl-2,5-dioxabicyclo[4.4.0]decane-9-
carboxylate (4): Freshly distilled trifluoroacetic anhydride (2.14
mL, 15.12 mmol) was added to a suspension of ureaϪhydrogen
peroxide adduct (UHP) (1.22 g, 12.98 mmol) in dry dichlorometh-
ane (10 mL) at 0 °C and under an inert gas. The resultant solution
was stirred at this temperature for 2 h and then was added to a
suspension of anhydrous Na2HPO4 (84 g, 28.08 mmol) in dry di-
chloromethane (10 mL) at 0 °C and under an inert gas. After 30
min, a solution of alkene 3[11] (0.9 g, 2.16 mmol) in dry dichloro-
methane (12 mL) was added dropwise and the resulting solution
was stirred at this temperature for 72 h. Powdered K2CO3 was ad-
ded and after 15 min, the suspension was filtered and washed with
dichloromethane. The filtrate and washings were concentrated to
give a white solid which was purified by flash chromatography elut-
Scheme 4. Reagents and conditions: (i) Ti(OiPr)4, iPrOH, C6H6, ∆;
(ii) TMSN3, BF3·OEt2, DCM, ∆; (iii) Ac2O, Et3N, DMAP, DCM,
room temp.; (iv) 1) LiBH4, MeOH, THF, 0 °C; 2) TFA (aq. 50%),
40 °C; (v) H2, Pd/C, TFA, MeOH, room temp.; (vi) TFA (aq. 50%),
90 °C
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ing with 15% diethyl ether/hexanes, to yield 0.71 g of epoxide 4[11]
(76%) and 0.12 g of starting material (13%).
at 0 °C. The reaction mixture was stirred at room temperature for
45 min and then ethyl acetate (1 mL) and water (2 mL) were added.
The organic layer was separated and the aqueous layer was ex-
tracted with ethyl acetate (4 ϫ 3 mL). The combined organic ex-
tracts were dried (anhydrous Na2SO4), filtered and concentrated
under reduced pressure. The crude reaction mixture was purified
by flash chromatography [eluent: 1. dichloromethane, 2. methanol/
dichloromethane (2%)] to yield 54 mg of a mixture of hydroxysilyl
ethers. A solution of the crude reaction mixture (54 mg) in aqueous
TFA (1.7 mL, 50%) was heated at 40 °C for 1h. The solvent was
evaporated and the residue was purified by flash chromatography
eluting with 10% methanol/ethyl acetate to yield azido alcohol 10
(37 mg, 81%) as a white foam. [α]2D0 ϭ Ϫ4 (c ϭ 1.5 in MeOH). IR
Methyl (1R,2R,3R,4S,5R)-1-(tert-Butyldimethylsilyloxy)-2,3-epoxy-
4,5-dihydroxycyclohexane-1-carboxylate (7): A solution of the epox-
ide 4 (0.5 g, 1.16 mmol) in aqueous TFA (50%, 12 mL) was stirred
at room temperature for 15 min. Powdered K2CO3 was added and
the solvent was evaporated. The crude reaction mixture was puri-
fied by flash chromatography eluting with 80% diethyl ether/hex-
anes to yield 318 mg of the diol 7 (87%) as white needles, and 38
mg of starting material (7%). M.p. 95Ϫ97 °C (hexane). [α]2D0 ϭ Ϫ31
(c ϭ 1.1 in CHCl3). IR (film): ν˜ ϭ 1742 (CϭO), 3478 (OϪH) cmϪ1
.
1H NMR (250 MHz, CDCl3): δ ϭ 0.10 (s, 3 H), 0.14 (s, 3 H), 0.88
(s, 9 H), 1.77 (dd, J ϭ 13.6, 11.5 Hz, 1 H), 1.91 (ddd, J ϭ 1.2, 3.7,
13.6 Hz, 1 H), 2.42 (s, 1 H, OH), 2.89 (s, 1 H, OH), 3.20 (d, J ϭ
3.3 Hz, 1 H), 3.28 (d, J ϭ 3.3 Hz, 1 H), 3.78 (m, 2 H), 3.79 (s, 3
H) ppm. 13C NMR (62.5 MHz, CDCl3): δ ϭ Ϫ3.5 (SiCH3), Ϫ3.4
(SiCH3), 18.4 [C(CH3)3], 25.7 [C(CH3)3], 34.8 (CH2), 52.5 (OCH3),
55.9 (CH), 56.5 (CH), 69.4 (CH), 72.1 (CH), 76.3 (C), 172.1 (C)
ppm. MS (CI): m/z ϭ 319 [MHϩ]. HRMS: calcd. for C14H27O6Si
[MHϩ] 319.1577; found 319.1577.
1
(film): ν˜ ϭ 2120 (NϭN), 3377 (OϪH) cmϪ1. H NMR (500 MHz,
CD3OD): δ ϭ 1.74 (dd, J ϭ 6.2, 14.0 Hz, 1 H), 1.86 (dd, J ϭ 3.4,
14.0 Hz, 1 H), 3.59 (d, J ϭ 11.2 Hz, 1 H), 3.69 (d, J ϭ 11.2 Hz, 1
H), 3.73 (dd, J ϭ 2.7, 7.6 Hz, 1 H), 3.83Ϫ3.83 (m, 2 H), 3.91 (d,
J ϭ 7.6 Hz, 1 H) ppm. 13C NMR (125 MHz, CD3OD): δ ϭ 37.3
(CH2), 65.7 (CH), 67.5 (CH2), 69.3 (CH), 74.0 (CH), 74.5 (CH),
76.0 (C) ppm. MS (CI): m/z ϭ 194 [MHϩ Ϫ N2]. HRMS: calcd.
for C7H16NO5 [MHϩ Ϫ N2] 194.1028; found 194.1025.
Methyl (1R,2R,3S,4R,5R)-3-Azido-1-(tert-butyldimethylsilyloxy)-
2,4,5-trihydroxycyclohexane-1-carboxylate (8) and (1R,2R,3S,
4R,5R)-3-Azido-1-(tert-butyldimethylsilyloxy)-2,4-dihydroxycyclo-
hexane-1,5-carbolactone (9): TMSN3 (0.44 mL, 3.3 mmol) and
BF3·OEt2 (0.57 mL, 4.5 mmol) were added to a stirred solution of
the epoxide 7 (320 mg, 1.01 mmol) in dry dichloromethane (10
mL). The resultant solution was heated under reflux for 1.5 h. The
mixture was diluted with dry dichloromethane and then poured
into saturated K2CO3 at 0 °C. The organic phase was separated
and the aqueous phase was extracted twice with dichloromethane.
The combined organic extracts were dried (anhydrous Na2SO4),
filtered and the solvents evaporated. The residue was purified by
flash chromatography eluting with diethyl ether giving azido ester
8 (293 mg, 81%) as white prisms and azido carbolactone 9 (37 mg,
11%) as white needles.
(1S,2R,3S,4R,5R)-3-Amino-1-hydroxymethyl-1,2,4,5-cyclohexane-
tetrol, Trifluoroacetic Acid Salt (5a): A suspension of the azide 10
(16 mg, 0.07 mmol) and 10% palladium on carbon (2 mg) in meth-
anol (0.75 mL) and TFA (17 µL) was shaken under hydrogen at
room temperature for 1 h. The mixture was filtered through
Fluorosil, which was then washed with methanol. The filtrate and
washings were concentrated under reduced pressure to yield am-
monium salt 5a (22 mg, 91%) as a colourless oil. [α]2D0 ϭ Ϫ5 (c ϭ
1
1.1 in MeOH). IR (film): ν˜ ϭ 3398 (OϪH) cmϪ1. H NMR (250
MHz, CD3OD): δ ϭ 1.83Ϫ1.70 (m, 2 H), 3.43 (m, 2 H), 3.62 (d,
J ϭ 11.5 Hz, 1 H), 3.90Ϫ3.83 (m, 3 H) ppm. 13C NMR (125 MHz,
CD3OD): δ ϭ 36.6 (CH2), 56.3 (C), 56.8 (CH), 67.2 (CH2), 68.5
(CH), 71.0 (CH), 76.6 (CH), 118.1 (C, JC,F ϭ 290 Hz), 163.3 (C,
JC,F ϭ 34 Hz) ppm. MS (CI): m/z ϭ 194 [MHϩ Ϫ TFA]. HRMS:
calcd. for C7H16NO5 [MHϩ Ϫ TFA] 194.1028; found 194.1019.
8: M.p. 126Ϫ128 °C (10% diethyl ether/hexane). [α]2D0 ϭ Ϫ23 (c ϭ
1.4 in CHCl3). IR (film): ν˜ ϭ 1715 (CϭO), 2121 (NϭN), 3358
(OϪH) cmϪ1. 1H NMR (250 MHz, CDCl3): δ ϭ 0.09 (s, 3 H), 0.10
(s, 3 H), 0.88 (s, 9 H), 2.26Ϫ2.10 (m, 2 H), 2.93 (d, J ϭ 5.5 Hz, 1
H), 3.79 (s, 3 H), 4.10Ϫ3.94 (m, 3 H) ppm. 13C NMR (62.5 MHz,
CDCl3): δ ϭ Ϫ3.6 (SiCH3), Ϫ3.2 (SiCH3), 18.3 [C(CH3)3], 25.6
[C(CH3)3], 37.0 (CH2), 52.5 (OCH3), 63.1 (CH), 68.1 (CH), 72.5
(CH), 75.4 (CH), 79.6 (C), 175.0 (C) ppm. MS (CI): m/z ϭ 362
[MHϩ]. HRMS: calcd. for C14H28N3O6Si [MHϩ] 362.1747;
found, 362.1760.
(1R,2R,3S,4R,5R)-3-Azido-1,2,4-trihydroxycyclohexan-1,5-carbo-
lactone (11): A solution of the silyl ether 8 (60 mg, 0.17 mmol) in
aqueous TFA (1.7 mL, 50%) was heated at 80 °C for 5 h. The
solvent was evaporated and the residue was purified by flash chro-
matography eluting with 5% methanol/dichloromethane to afford
hydroxy carbolactone 11 (33 mg, 92%) as a colourless oil. [α]2D0
ϭ
ϩ7 (c ϭ 1.5 in MeOH). IR (film): ν˜ ϭ 1784 (CϭO), 2116 (NϭN),
1
3410 (OϪH) cmϪ1. H NMR (250 MHz, CD3OD): δ ϭ 2.11 (dd,
J ϭ 5.6, 12.0 Hz, 1 H), 2.24 (d, J ϭ 12.0 Hz, 1 H), 3.03 (dd, J ϭ
4.6, 9.6 Hz, 1 H), 3.69 (d, J ϭ 9.6 Hz, 1 H), 4.00 (dd, J ϭ 4.6, 4.5
Hz, 1 H), 4.42 (t, J ϭ 5.3 Hz, 1 H) ppm. 13C NMR (125 MHz,
CD3OD): δ ϭ 36.1 (CH2), 66.0 (CH), 68.5 (CH), 74.8 (CH), 76.2
(C), 77.1 (CH), 176.9 (C) ppm. MS (CI): m/z ϭ 216 [MHϩ].
HRMS: calcd. for C7H10N3O5 [MHϩ] 216.0620; found 216.0616.
9: M.p. 89Ϫ90 °C (hexane). [α]2D0 ϭ Ϫ24 (c ϭ 1.5 in CHCl3). IR
1
(film): ν˜ ϭ 1790 (CϭO), 2110 (NϭN), and 3520 (OϪH) cmϪ1. H
NMR (250 MHz, CDCl3): δ ϭ 0.13 (s, 3 H), 0.22 (s, 3 H), 0.91 (s,
9 H), 2.37 (dd, J ϭ 5.9, 11.9 Hz, 1 H), 2.50 (d, J ϭ 11.9 Hz, 1 H),
2.66 (d, J ϭ 1.9 Hz, 1 H, OH), 2.96 (d, J ϭ 1.3 Hz, 1 H, OH),
3.58 (dd, J ϭ 4.5, 9.1 Hz, 1 H), 3.98 (dd, J ϭ 1.1, 9.1 Hz, 1 H),
4.21 (ddd, J ϭ 1.3, 4.6, 4.5 Hz, 1 H), 4.71 (dd, J ϭ 5.9, 4.6 Hz, 1
H) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ Ϫ3.4 (SiCH3), Ϫ3.3
(SiCH3), 18.1 [C(CH3)3], 25.6 [C(CH3)3], 35.1 (CH2), 64.3 (CH),
66.9 (CH), 74.5 (CH), 75.7 (CH), 76.8 (C), 173.0 (C) ppm. MS
(CI): m/z ϭ 330 [MHϩ]. HRMS: calcd. for C13H24N3O5Si [MHϩ]
330.1485; found, 330.1486.
(1S,2R,3S,4R,5R)-3-(tert-Butoxycarbonylamino)-1,2,4,5-tetra-
hydroxycyclohexane-1-carboxylic Acid (5b): A suspension of the az-
ide 11 (30 mg, 0.14 mmol), Boc2O (39 mg, 0.18 mmol), and 10%
palladium on carbon (3 mg) in ethyl acetate (1.5 mL) was shaken
under hydrogen at room temperature for 24 h. The mixture was
filtered through Fluorosil, which was then washed with methanol.
The filtrate and washings were concentrated under reduced press-
ure. A solution of the crude reaction products (30 mg) in THF (1
mL) was treated at 0 °C with aqueous lithium hydroxide (0.3 mL,
0.5 ) and stirred at room temperature for 25 min. THF was re-
moved under reduced pressure, and the remaining aqueous solution
was diluted with water and treated with Amberlite IR-120 until
(1S,2R,3S,4R,5R)-3-Azido-1-hydroxymethyl-1,2,4,5-cyclohexane-
tetrol (10): Lithium borohydride (5 mg, 0.22 mmol) was added to
a stirred solution of the ester 8 (73 mg, 0.20 mmol) in a dry solution
of methanol in tetrahydrofuran (2 mL, 1:20 v/v) under argon and
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Amino Carba Sugars and Conformationally Restricted Polyhydroxy γ-Amino Acids from (Ϫ)-Quinic Acid
FULL PAPER
pH ϭ 6 was reached. The resin was filtered and washed with water.
The filtrate was washed with diethyl ether (ϫ 2) and then lyophil-
Isopropyl (1R,2S,3R,4R,5R)-2,4,5-Triacetoxy-3-azido-1-(tert-butyl-
dimethylsilyloxy)cyclohexane-1-carboxylate (14): Triethylamine
ized to afford amino acid 5b (32 mg, 74%) as an amorphous white (115 µL, 0.81 mmol), acetic anhydride (70 µL, 0.73 mmol) and
solid. M.p. 201Ϫ203 °C. [α]2D0 ϭ Ϫ2 (c ϭ 0.8 in MeOH). IR (film):
DMAP (3 mg, 3 µmol) were added to a stirred solution of the triol
1
ν˜ ϭ 1655 (CϭO), 1691 (CϭO), 3398 (OϪH and NϪH) cmϪ1. H 13 (60 mg, 0.16 mmol) in dry dichloromethane (0.8 mL) under an
NMR (250 MHz, D2O): δ ϭ 1.26 (s, 9 H), 1.66 (m, 2 H), 3.55 (d,
J ϭ 8.2 Hz, 1 H), 3.67 (dd, J ϭ 5.3, 10.4 Hz, 1 H), 3.71 (m, 1 H),
inert gas at 0 °C. The resulting solution was stirred at room tem-
perature for 12 h. Dichloromethane and then water were added.
3.98 (dd, J ϭ 3.0, 7.9 Hz, 1 H) ppm. 13C NMR (125 MHz, D2O): The organic layer was separated and the aqueous phase was ex-
δ ϭ 28.0 [C(CH3)3], 29.9 [C(CH3)3], 35.4 (CH2), 68.4 (C), 72.4
tracted twice with dichloromethane. The combined organic extracts
(CH), 73.4 (CH), 77.9 (CH), 81.4 (C), 157.9 (C), 179.8 (C) ppm. were dried (anhydrous Na2SO4), filtered and the solvents evapo-
MS (CI): m/z ϭ 208 [MHϩ Ϫ Boc]. HRMS: calcd. for C7H14O6N rated. The residue was purified by flash chromatography eluting
[MHϩ Ϫ Boc] 208.0821; found 208.0816.
with 50% diethyl ether/hexanes to yield the triacetoxy azide 14 (78
mg, 94%) as a colourless oil. [α]2D0 ϭ Ϫ21 (c ϭ 3.8 in CHCl3). IR
1
(film): ν˜ ϭ 1753 (CϭO), 2105 (NϭN) cmϪ1. H NMR (400 MHz,
Isopropyl (1R,2S,3S,4S,5R)-1-(tert-Butyldimethylsilyloxy)-2,3-ep-
oxy-4,5-dihydroxycyclohexane-1-carboxylate (12): Titanium() iso-
propoxide (3.13 mL, 10.60 mmol) and 2-propanol (0.74 mL, 9.72
mmol) were added to a stirred solution of the lactone 2[11] (2.53 g,
8.84 mmol) in dry benzene (88 mL) under argon. The resulting
mixture was heated at 75 °C for 5 h. After cooling to room tem-
perature, diethyl ether and 5% H2SO4 were added. The resulting
suspension was stirred until two clear phases were obtained. The
organic layer was separated and the aqueous phase was extracted
with diethyl ether (ϫ 3). The combined organic extracts were dried
(anhydrous Na2SO4), filtered and concentrated under reduced
pressure. The crude reaction mixture was purified by flash chroma-
tography eluting with diethyl ether to yield the ester 12 as white
needles (1.93 g, 63%). M.p. 108Ϫ109 °C (diethyl ether). [α]2D0 ϭ ϩ1
(c ϭ 1.0 in CHCl3). IR (nujol): ν˜ ϭ 1728, 1742 (CϭO), 3460 (OϪH)
CDCl3): δ ϭ 0.18 (s, 3 H), 0.19 (s, 3 H), 0.96 (s, 9 H), 1.20 (d, J ϭ
6.5 Hz, 3 H), 1.22 (d, J ϭ 6.5 Hz, 3 H), 1.91 (dd, J ϭ 11.6, 13.5
Hz, 1 H), 1.98 (s, 3 H), 2.08 (s, 3 H), 2.09 (s, 3 H), 2.21 (dd, J 5
and 13.5 Hz, 1 H), 3.82 (dd, J ϭ 10.4, 10.0 Hz, 1 H), 4.91 (m, 1
H), 5.08 (t, J ϭ 10.0 Hz, 1 H), 5.2 (ddd, J ϭ 5, ϭ 10.0, 11.6 Hz,
1 H), 5.24 (d, J ϭ 10.4 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ Ϫ3.2 (SiCH3), Ϫ2.8 (SiCH3), 19.0 [C(CH3)3], 20.6
(CH3), 20.7 (CH3), 21.3 (CH3), 21.5 (CH3), 26.2 [C(CH3)3], 37.1
(CH2), 62.5 (CH), 69.1 (CH), 70.4 (CH), 72.7 (CH), 73.8 (CH),
77.7 (C), 168.8 (C), 169.7 (C), 169.6 (C), 169.8 (C) ppm. MS (CI):
m/z ϭ 516 [MHϩ]. HRMS: calcd. for C22H38N3O9Si [MHϩ]
516.2373; found 516.2400.
(1S,2S,3R,4R,5R)-3-Azido-1-hydroxymethyl-1,2,4,5-cyclohexane-
tetrol (15): Lithium borohydride (3 mg, 0.12 mmol) was added to
a stirred solution of the ester 13 (44 mg, 0.11 mmol) in a dry solu-
tion of methanol in tetrahydrofuran (1.1 mL, 1:20 v/v) under argon
and at 0 °C. The reaction mixture was stirred at room temperature
for 45 min and then ethyl acetate (1 mL) and water (2 mL) were
added. The organic layer was separated and the aqueous phase was
extracted with ethyl acetate (4 ϫ 3 mL). The combined organic
extracts were dried (anhydrous Na2SO4), filtered and concentrated
under reduced pressure. The crude reaction mixture was purified
by flash chromatography eluting with diethyl ether giving 31 mg of
a mixture of hydroxysilyl ethers. A solution of the crude reaction
products (31 mg) in aqueous TFA (1 mL, 50%) was heated at 40
°C for 2 h. The solvent was evaporated and the residue was purified
by flash chromatography eluting with 5% methanol/dichlorometh-
ane to yield azido alcohol 15 (20 mg, 81%) as a colourless oil.
[α]2D0 ϭ Ϫ13 (c ϭ 0.8 in MeOH). IR (film): ν˜ ϭ 2118 (NϭN), 3363
1
cmϪ1. H NMR (250 MHz, CDCl3): δ ϭ 0.14 (s, 3 H), 0.15 (s, 3
H), 0.90 (s, 9 H), 1.28 (d, J ϭ 6.3 Hz, 3 H), 1.29 (d, J ϭ 6.3 Hz, 3
H), 1.92 (m, 2 H), 2.24 (d, J ϭ 3.3 Hz, 1 H), 2.37 (d, J ϭ 7.4 Hz,
1 H), 2.51 (br. s, 2 H, OH), 3.50 (dd, J ϭ 3.9, 2.2 Hz, 1 H), 3.54
(d, J ϭ 3.9 Hz, 1 H), 3.91Ϫ3.75 (m, 2 H), 5.07 (sept, J ϭ 6.3 Hz,
1 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ ϭ Ϫ3.2 (SiMe), Ϫ3.2
(SiMe), 18.5 [C(CH3)3], 21.6 (CH3), 21.6 (CH3), 25.8 [C(CH3)3],
41.2 (CH2), 57.5 (CH), 58.0 (CH), 67.4 (CH), 69.5 (CH), 72.9 (CH),
75.1 (C), 172.6 (C) ppm. MS (CI): m/z ϭ 347 [MHϩ]. HRMS:
calcd. for C16H31O6Si [MHϩ] 347.1890; found 347.1896.
Isopropyl (1R,2S,3R,4R,5R)-3-Azido-1-(tert-butyldimethylsilyloxy)-
2,4,5-trihydroxycyclohexane-1-carboxylate (13): TMSN3 (0.31 mL,
2.31 mmol) and BF3·OEt2 (0.33 mL, 2.6 mmol) were added to a
stirred solution of the epoxide 12 (200 mg, 0.58 mmol) in dry di-
chloromethane (2 mL). The resulting solution was heated under
reflux for 2.6 h. The mixture was diluted with dry dichloromethane
and then poured into saturated K2CO3 at 0 °C. The organic layer
was separated and the aqueous phase was extracted twice with di-
chloromethane. The combined organic extracts were dried (anhy-
drous Na2SO4), filtered and the solvents evaporated. The residue
was purified by flash chromatography eluting with 50% diethyl
ether/hexanes to yield 96 mg of azido ester 13 (43%) as a colourless
oil, and 67 mg of starting material (34%). [α]2D0 ϭ Ϫ2 (c ϭ 2.2 in
1
(OϪH) cmϪ1. H NMR (250 MHz, CD3OD): δ ϭ 1.41 (dd, J ϭ
11.8, 13.8 Hz, 1 H), 1.82 (dd, J ϭ 4.9, 13.8 Hz, 1 H), 1.95 (s, 1 H),
2.09 (s, 1 H), 3.03 (t, J ϭ 9.2 Hz, 1 H), 3.26 (d, J ϭ 10.8 Hz, 1 H),
3.40 (dd, J ϭ 9.8, 9.2 Hz, 1 H), 3.50 (d, J ϭ 10.8 Hz, 1 H), 3.70
(ddd, J ϭ 4.9, 9.2, 11.8 Hz, 1 H) ppm. 13C NMR (125 MHz,
CD3OD): δ ϭ 38.4 (CH2), 67.1 (CH2), 69.6 (CH), 70.2 (CH), 73.5
(CH), 74.7 (C), 77.9 (CH) ppm. MS (CI): m/z ϭ 220 [MHϩ].
HRMS: calcd. for C7H14N3O5 [MHϩ] 220.0934; found 220.0933.
CHCl3). IR (film): ν˜ ϭ 1748 (CϭO), 2115 (NϭN), 3419 (OϪH)
(1S,2S,3R,4R,5R)-3-Amino-1-hydroxymethyl-1,2,4,5-cyclohexane-
1
cmϪ1. H NMR (250 MHz, CDCl3): δ ϭ 0.14 (s, 3 H), 0.20 (s, 3 tetrol, Trifluoroacetic Acid Salt (6a): A suspension of the azide 15
H), 0.91 (s, 9 H), 1.25 (d, J ϭ 6.3 Hz, 6 H), 1.74 (dd, J ϭ 13.7,
(24 mg, 0.11 mmol) and 10% palladium on carbon (3 mg) in meth-
11.6 Hz, 1 H), 2.14 (dd, J ϭ 4.8, 13.7 Hz, 1 H), 2.59 (d, J ϭ 8.5 anol (1.1 mL) and TFA (25 µL) was shaken under hydrogen at
Hz, 1 H), 3.24 (dd, J ϭ 9.3, 9.5 Hz, 1 H), 3.41 (t, J ϭ 9.9 Hz, 1
room temperature for 1 h. The mixture was filtered through
H), 3.85 (m, 3 H), 5.03 (m, 1 H) ppm. 13C NMR (125 MHz, Fluorosil, which was then washed with methanol. The filtrate and
CDCl3): δ ϭ Ϫ3.2 (SiCH3), Ϫ2.6 (SiCH3), 19.0 [C(CH3)3], 21.6 (2 washings were concentrated under reduced pressure to yield the
ϫ CH3), 26.3 [C(CH3)3], 38.4 (CH2), 67.0 (CH), 68.7 (CH), 70.1 ammonium salt 6a (31 mg, 92%) as a colourless oil. [α]2D0 ϭ Ϫ9
(CH), 75.7 (CH), 75.9 (CH), 79.2 (C), 171.5 (C) ppm. MS (CI): (c ϭ 1.5 in MeOH). IR (film): ν˜ ϭ 1681 (CϭO), 3386 (OϪH) cmϪ1
.
m/z ϭ 390 [MHϩ]. HRMS: calcd. for C16H32N3O6Si [MHϩ]
1H NMR (250 MHz, CD3OD): δ ϭ 1.45 (dd, J ϭ 12.2, 14.0 Hz, 1
H), 1.96 (dd, J ϭ 4.8, 14.0 Hz, 1 H), 3.19 (dd, J ϭ 10.6, 10.5 Hz,
390.2060; found 390.2056.
Eur. J. Org. Chem. 2004, 3663Ϫ3668
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3667

´
M. Carballido, L. Castedo, C. Gonzalez-Bello
FULL PAPER
[2] [2a]
J. L. Treadway, P. Mendays, D. J. Hoover, Expert Opin. In-
1 H), 3.35 (dd, J ϭ 9.3, 10.5 Hz, 1 H), 3.40 (d, J ϭ 11.5 Hz, 1 H),
3.48 (d, J ϭ 11.5 Hz, 1 H), 3.61 (d, J ϭ 10.6 Hz, 1 H), 3.71 (ddd,
J ϭ 4.8, 9.3, 12.2 Hz, 1 H) ppm. 13C NMR (125 MHz, D2O): δ ϭ
39.2 (CH2), 58.7 (CH), 68.0 (CH2), 71.8 (CH), 72.5 (CH), 76.3
(CH), 76.6 (C), 119.4 (C, JC,F ϭ 290 Hz), 166.2 (C, JC,F ϭ 36
Hz) ppm. MS (CI): m/z ϭ 194 [MHϩ Ϫ TFA]. HRMS: calcd. for
C7H16NO5 [MHϩ Ϫ TFA] 194.1028; found 194.1019.
vest. Drugs 2001, 10, 439Ϫ454. [2b] J. E. Groopman, Rev. Infect.
Dis. 1990, 12, 908Ϫ911. [2c] N. Zitzmann, A. S. Mehta, S. Car-
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Ther. 2002, 1, 585Ϫ593.
L. Zalah, M. Huleihel, E. Manor,
(1R,2S,3R,4R,5R)-3-Azido-1,2,4,5-tetrahydroxycyclohexane-1-
carboxylic Acid (16): A solution of the ester 13 (50 mg, 0.13 mmol)
in aqueous TFA (1.2 mL, 50%) was heated at 90 °C for 12 h. The
solvent was evaporated and the residue was redissolved in water.
The aqueous solution was washed twice with ethyl acetate and ly-
ophilized to afford hydroxyacid 16 (27 mg, 90%) as an amorphous
white solid. M.p. 175Ϫ177 °C. [α]2D0 ϭ Ϫ1 (c ϭ 1.0 in MeOH). IR
´
A. Konson, H. Ford, V. E. Marquez, D. G. Johns, R. Agbarai,
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[4]
[5]
[4b]
S.
Ogawa, in Carbohydrate Mimics: Concepts and Methods (Ed.:
Y. Chapteur), Wiley-VCH, Weinheim, 1998.
(film): ν˜ ϭ 1608 (CϭO), 2119 (NϭN), 3389 (OϪH) cmϪ1 1H
.
[5a] S. Horii, T. Iwasa, E. Mizuta, Y. Kameda, J. Antibiot. 1971,
NMR (400 MHz, D2O): δ ϭ 1.65 (dd, J ϭ 11.9, 13.7 Hz, 1 H),
1.88 (dd, J ϭ 4.9, 13.7 Hz, 1 H), 3.23 (dd, J ϭ 9.4, 10.0 Hz, 1 H),
3.36 (t, J ϭ 10.0 Hz, 1 H), 3.63 (ddd, J ϭ 4.9, 9.4, 11.9 Hz, 1 H),
3.68 (d, J ϭ 10.1 Hz, 1 H) ppm. 13C NMR (100 MHz, D2O): δ ϭ
40.8 (CH2), 70.2 (CH), 72.0 (CH), 76.9 (CH), 78.7 (CH), 80.0 (C),
181.2 (C) ppm. MS (CI): m/z ϭ 234 [MHϩ]. HRMS: calcd. for
C7H12N3O6 [MHϩ] 234.0726; found 234.0724.
24, 59Ϫ63. [5b] X. Chen, Y. Fan, Y. Zheng, Y. Shen, Chem. Rev.
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T. K. M. Shing, T. Y. Li, S. H.-L.
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Y. Kameda, S. Horii, J. Chem. Soc., Chem. Commun. 1972,
746Ϫ747. [6b] Y. Kameda, N. Asano, M. Yoshikawa, M. Takeu-
(1R,2S,3R,4R,5R)-3-Amino-1,2,4,5-tetrahydroxycyclohexane-1-
carboxylic Acid, Trifluoroacetic Acid Salt (6b): A suspension of the
azide 16 (27 mg, 0.12 mmol) and 10% palladium on carbon (3 mg)
in methanol (1.2 mL) and TFA (35 µL) was shaken under hydrogen
at room temperature for 1 h. The mixture was filtered through
Fluorosil, which was then washed with methanol and water. The
filtrate and washings were concentrated under reduced pressure
and then lyophilized to yield amino acid 6b as a colourless oil (36
mg, 97%). [α]2D0 ϭ Ϫ11 (c ϭ 1.9 in MeOH). IR (film): ν˜ ϭ 1633
chi, T. Yamaguchi, K. Matsui, S. Horii, H. Fukase, J. Antibiot.
[6c]
1984, 37, 1301Ϫ1307.
T. K. M. Shing, V. W. F. Tai, J. Org.
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Chem. 1995, 60, 5332Ϫ5334.
K. Tatsuta, H. Mukai, M.
Takahashi, J. Antibiot. 2000, 53, 430Ϫ435.
[7a] S. Horii, H. Fukase, Y. Kameda, Carbohydr. Res. 1985, 140,
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[7b]
185Ϫ200.
S. Horii, H. Fukase, T. Matsuo, Y. Kameda, N.
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Asano, K. Matsui, J. Med. Chem. 1986, 29, 1038Ϫ1046.
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K. M. Shing, L. H. Wang, J. Org. Chem. 1996, 61, 8468Ϫ8479.
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Y. Ooki, M. Mori, M. Itoh, T. Korenaga, Org. Biomol. Chem.
(CϭO), 1680 (CϭO), 3389 (OϪH) cmϪ1 1H NMR (400 MHz,
.
[7e]
2004, 2, 884Ϫ889.
T. K. M. Shing, L. H. Wan, Angew.
D2O): δ ϭ 1.73 (dd, J ϭ 11.8, 13.9 Hz, 1 H), 2.03 (dd, J ϭ 4.9,
13.9 Hz, 1 H), 3.15 (t, J ϭ 10.6 Hz, 1 H), 3.19 (s, 1 H), 3.41 (t,
J ϭ 9.2 Hz, 1 H), 3.67 (ddd, J ϭ 4.9, 9.1, 11.8 Hz, 1 H), 3.97 (d,
J ϭ 10.6 Hz, 1 H) ppm. 13C NMR (100 MHz, D2O): δ ϭ 40.2
(CH2), 58.4 (CH), 71.6 (CH), 74.1 (CH), 76.1 (CH), 79.4 (C), 119.3
(C, JC,F ϭ 290 Hz), 166.0 (C, JC,F ϭ 35 Hz), 178.8 (C) ppm. 19F
NMR (282 MHz, CD3OD): δ ϭ Ϫ73.7 (s, 3 F) ppm. MS (CI):
Chem. Int. Ed. Engl. 1995, 34, 1643Ϫ1645.
M. Aschi, G. Lucente, F. Mazza, A. Mollica, E. Morera, M.
Nalli, M. Paglialunga Paradisi, Org. Biomol. Chem. 2003, 1,
1980Ϫ1988.
[8]
[9]
´
M. Amorın, L. Castedo, Juan R. Granja, J. Am. Chem. Soc.
2003, 125, 2844Ϫ2845.
[10]
CCDC-235508 contains the supplementary crystallographic
data of the corresponding derivative of 4 without TBS protect-
ing group for this paper. These data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from
the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: (internat.) ϩ 44-1223-336-033;
E-mail: deposit@ccdc.cam.ac.uk].
m/z ϭ 208 [MHϩ Ϫ TFA]. HRMS: calcd. for C7H14NO6 [MHϩ
TFA] 208.0821; found 208.0825.
Ϫ
Acknowledgments
Financial support from the Xunta de Galicia under project
PGIDIT02RAG20901PR is gratefully acknowledged. M. C. also
thanks the Xunta de Galicia for a scholarship.
[11]
[12]
´
C. Gonzalez, M. Carballido, L. Castedo, J. Org. Chem. 2003,
68, 2248Ϫ2255.
CCDC-235546 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: (internat.) ϩ 44-1223-336-033;
E-mail: deposit@ccdc.cam.ac.uk].
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Received April 26, 2004
3668
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3663Ϫ3668