Stereoselective synthesis of novel cyclic γ-amino acids and triazole derivatives

Article abstract of DOI:10.1002/ejoc.200800480

Four polyhydroxylated γ-azido and three γ-amino acids 1-4 have been synthesized from (-)-quinic acid. The nitrogen functionality in the reported derivatives was introduced through regioselective ring-opening of cyclic sulfates with azide anion. The synthesis of the 4- and 5-epimers of γ-azido acid 1a - derivatives 2 and 3a, respectively - was achieved by regioselective oxidation of dibutylstannylene acetals derived from 1,2-diols, followed by diastereoselective reduction of their corresponding α-hydroxy ketones. The presence of the azide functional group in the reported γ-azido acids was exploited to permit interlinking of bioactive molecular entities. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800480

FULL PAPER
DOI: 10.1002/ejoc.200800480
Stereoselective Synthesis of Novel Cyclic γ-Amino Acids and Triazole
Derivatives
Verónica F. V. Prazeres,[a] Luis Castedo,[a] and Concepción González-Bello*[a]
In memory of Jonathan Spencer
Keywords: Cyclic γ-amino acids / Regioselectivity / Click chemistry / (–)-Quinic acid
Four polyhydroxylated γ-azido and three γ-amino acids 1–
4 have been synthesized from (–)-quinic acid. The nitrogen
functionality in the reported derivatives was introduced
through regioselective ring-opening of cyclic sulfates with
azide anion. The synthesis of the 4- and 5-epimers of γ-azido
acid 1a – derivatives 2 and 3a, respectively – was achieved by
regioselective oxidation of dibutylstannylene acetals derived
from 1,2-diols, followed by diastereoselective reduction of
their corresponding α-hydroxy ketones. The presence of the
azide functional group in the reported γ-azido acids was ex-
ploited to permit interlinking of bioactive molecular entities.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Cyclic amino acids have been shown to play an impor-
tant role in drug design because they can bear pharmaco-
phoric groups with well defined spatial orientations that
can be used to obtain important information about key
structural features of receptor ligand complexes.[1] In ad-
dition, structural entities possessing polyhydroxylated cy-
clohexanoid cores are found in many biologically important
molecules and natural products.[2] The rich functionality
present in polyhydroxylated amino acids also makes them
attractive candidates for use as core scaffolds in combinato-
rial chemistry.
The important applications of cyclic amino acids in
biology and materials science have encouraged us to pursue
the stereoselective synthesis of a variety of highly function-
alized cyclic γ-amino acids derivatives. Here we disclose the
stereoselective synthesis of four γ-azido acids and three γ-
amino acids 1–4 through the use of (–)-quinic acid as a
chiral template (Figure 1). Our strategy involved the incor-
poration of the nitrogen functionalities of cyclitol deriva-
tives 1–4 through regioselective ring-opening of cyclic sul-
fates with azide anion and subsequent azide reduction.
Figure 1. Cyclic γ-azido and γ-amino acids and triazole derivatives.
The high chemoselectivity of azides towards alkynes, to-
gether with the stability of the triazole ring toward chemical
and enzymatic degradation, makes triazoles useful func-
tional groups for linking bioactive molecular entities.[3] In
this context, the improved version of the Huisgen 1,3-di-
polar cycloaddition reaction,[4] the copper(I)-catalyzed
azide/alkyne cycloaddition, or “Sharpless click reaction”,[5]
has proven to be a powerful tool in synthetic chemistry. The
high regioselectivity and efficiency of the click reaction has
been successfully exploited in polymer and material sci-
[a] Laboratorio de Química Orgánica (CSIC) y Departamento de
Química Orgánica, Facultad de Química, Universidad de Santi-
ago de Compostela,
Avenida de las Ciencias s/n, 15782 Santiago de Compostela,
Spain
Fax: +34-981-595012
E-mail: concepcion.gonzalez.bello@usc.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Eur. J. Org. Chem. 2008, 3991–4003
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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V. F. V. Prazeres, L. Castedo, C. González-Bello
FULL PAPER
ences, particularly in the synthesis of dendrimers containing
sugar-binding units (glycodendrimers).[6] In this paper we
explore the utility of the azide function present in the re-
ported γ-azido acids as a possible linking group through
the use of “Sharpless click chemistry”, an approach demon-
strated with the synthesis of triazole derivatives 5 and 6.
Results and Discussion
Synthesis of γ-Azido and γ-Amino Acids 1a and 1b
Our synthetic approach was based on the functionaliza-
tion of the cyclohexene derived from (–)-quinic acid (com-
pound 8, Scheme 1). This strategy involves the incorpora-
tion of the nitrogen functionality by diastereoselective cis-
dihydroxylation of cyclohexene 8, followed by cyclic sulfate
formation and subsequent regioselective ring-opening with
the azide anion. Through the reasoning that the ring-open-
ing reaction should occur mainly at the less hindered side
of the cyclic sulfate 7, a bulky protecting group (TBS) was
chosen for protection of the tertiary hydroxy group of sul-
fate 7.
Scheme 2. Reagents and conditions: (a) Me2C(OMe)2, HC(OMe)3,
acetone, p-TsOH (cat.), ∆; (b) TBSOTf, Py, DCM, 0 °C Ǟ r.t.; (c)
KCN, MeOH, r.t.; (d) Tf2O, Py, DCM, 0 °C; (e) DBU, CHCl3, ∆.
cis-Dihydroxylation of cyclohexene 8 in the presence of
a catalytic amount of osmium tetroxide gave a mixture of
two hydroxylated products, diol 12 and carbolactone 13,
resulting, in both cases, from reaction at the sterically less
congested face of the double bond, the Si face (Scheme 3
and Figure 2). Carbolactone 13 is presumably formed by
lactonization of the axial hydroxy group at C-3 and the
methyl ester. In fact, diol 12 can also be converted into car-
bolactone 13 by treatment with sodium hydride. Carbolac-
Scheme 1. Strategy for the synthesis of derivatives 1–3.
Scheme 3. Reagents and conditions: (a) OsO4 (cat), NMO, dioxane/
H2O, r.t.; (b) NaH, THF, 0 °C.
The synthesis of cyclohexene 8 was carried out in four
steps from (–)-quinic acid, as shown in Scheme 2. Firstly,
quadruple protection of (–)-quinic acid by a p-TsOH acid-
catalyzed reaction with acetone dimethyl acetal, followed
by TBS protection of the resulting tertiary alcohol 9[7] with
TBSOTf and pyridine, afforded silyl ether 10 in excellent
yield. Treatment of lactone 10 with potassium cyanide in
methanol gave alcohol 11, which was finally converted into
alkene 8 by a sequential two-step procedure. Initial acti-
vation of the free alcohol as a trifluoromethanesulfonate
ester with triflic anhydride in the presence of pyridine in
dichloromethane and subsequent elimination with DBU in
chloroform at reflux afforded the desired cyclohexene deriv-
ative 8 in excellent yield.
Figure 2. Minimum-energy conformation of cyclohexene 8 ob-
tained by molecular modelling calculations (Gaussian 03W).[8,9]
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Cyclic γ-Amino Acids and Triazole Derivatives
tone 13 was employed in the synthesis of derivatives 4, as Synthesis of γ-Azido (2–3a) and γ-Amino (3b) Acids
described below.
The strategy for the synthesis of 4- and 5-epimers of 1a –
Diol 12 was efficiently converted into the desired cyclic
derivatives 2 and 3a, respectively – consisted of the regiose-
sulfate 7 by the Sharpless method (Scheme 4).[10] Azidolysis
lective oxidation of C-4 and C-5 of 15, respectively, followed
of 7 with sodium azide in the presence of a catalytic amount
by diastereoselective reduction of the corresponding ketone.
of 15-crown-5 ether in N,N-dimethylformamide at 90 °C re-
Bearing in mind that dibutylstannylene acetals derived from
gioselectively afforded the desired azido alcohol 14 as a sin-
1,2-diols can be regioselectively oxidized to α-hydroxy
gle diastereoisomer. The regioselectivity of the reaction was
ketones by bromine,[11] N-bromosuccinimide[12] or 1,3-di-
confirmed by NOE experiments. Irradiation of 2-H led to
bromo-5,5-dimethylhydantoin,[13] we investigated the utility
enhancement of the signal for 6-Haxial (4.9%), whereas irra-
of this reaction for the synthesis of compounds 2 and 3
diation of 3-H led to enhancement of the signal for 4-H
(Scheme 5). Moreover, considering that Sn-mediated oxi-
(7.6%). The structure of azido alcohol 14 is also consistent
dation of cyclic 1,2-diols usually occurs at the axial hydroxy
with a diaxial coupling constant between 2-H and 3-H (J2,3
group, one would expect that in our case the oxidation
= 10.5 Hz). Azido alcohol 14 was directly converted into
should take place preferentially at C-4, the more hindered
the desired acid 1a by treatment with trifluoroacetic acid
side of diol 15.[14]
(50%) at 70 °C, followed by basic hydrolysis of the methyl
ester and subsequent protonation with an ion-exchange
resin to afford acid 1a in 97% yield.
Scheme 5. Strategy for the synthesis of derivatives 2–3.
Firstly, TBS protection of the free hydroxy group of 14,
followed by selective deprotection of the isopropylidene
acetal 16 by treatment with aqueous acetic acid (80%) at
65 °C, led to diol 15 in excellent yield (Scheme 6). Oxidation
of the dibutylstannylene acetal derived from 15 (obtained
by treatment of diol 15 with dibutyltin oxide in toluene with
azeotropic removal of water) with N-bromosuccinimide in
chloroform at room temperature gave a chromatographi-
cally separable mixture of the two α-hydroxy ketones 17 and
18, the structures of which were confirmed by analysis of
1
their H NMR spectra. The diaxial coupling constant be-
tween 5-H and 6-Haxial (J5,6ax = 11.0 Hz) confirmed the
structure of ketone 18. As expected, ketone 18 was the main
product of the reaction and was obtained in 64% yield.
Scheme 4. Reagents and conditions: (a) (i) SOCl2, Et3N, DCM, r.t.,
(ii) RuCl3·3H2O (cat.), NaIO4, H2O, CCl4, CH3CN, r.t.; (b) (i)
NaN3, 15-crown-5 ether, DMF, 90 °C, (ii) H2SO4 (aq., 70%), THF,
50 °C; (c) (i) TFA (aq., 50%), 70 °C, (ii) LiOH, r.t., (iii) Amberlite
IR-120 (H+), r.t.; (d) Ac2O, Py, 0 °C to r.t.; (e) H2, PtO2 (cat.),
Boc2O, THF, r.t.; (f) (i) LiOH, r.t.; (ii) Amberlite IR-120 (H+), r.t.
The conversion of azide 1a into the desired γ-amino acid
1b was found to be difficult. Catalytic hydrogenolysis of
azide 1a in acidic media (HCl, HOAc, etc.) or in the pres-
ence of di-tert-butyl dicarbonate to avoid decomposition of
the free amine either did not give any reaction or gave only
low yields of the desired product. Azide reduction could
only be achieved by acetylation of 1a, which was carried
Scheme 6. Reagents and conditions: (a) TBSOTf, Py, DCM, 0 °C
Ǟ r.t.; (b) AcOH (aq., 80%), 65 °C; (c) (i) Bu2SnO, PhMe, ∆, (ii)
out by treatment of 1a with acetic anhydride and pyridine,
followed by catalytic hydrogenolysis with platinum oxide as
NBS, CHCl3, r.t.
catalyst and in the presence of di-tert-butyl dicarbonate. Fi-
nally, removal of the acetyl groups by basic hydrolysis and
acidification with an acidic ion-exchange resin afforded ducing agents was then studied (Table 1). Use of a sterically
Boc-γ-amino acid 1b in 56% overall yield. hindered reducing agent, such as Li-selectride, provided ex-
The stereoselective reduction of ketone 18 by several re-
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V. F. V. Prazeres, L. Castedo, C. González-Bello
FULL PAPER
clusive equatorial hydride delivery. Only with use of a small free secondary hydroxy group gave ketone 19 in excellent
hydride, such as sodium borohydride, was a modest prefer- yield. Alternatively, treatment of ketone 18 with TBSOTf/
ence for axial hydride attack obtained.
pyridine or TBDPSCl/imidazole provided ketones 19 and
20, respectively. However, protection of the hydroxy groups
in ketones 19 and 20 as TBS or TBDPS ethers did not show
any significant influence on the diastereoselectivity of the
sodium borohydride reduction, which seems to be unaffec-
ted by the size of the equatorial substituent in the α-posi-
tion (Table 1).
Table 1. Reduction of ketones 18, 19 and 20.
Finally, γ-azido acid 2 was obtained from alcohol 22b in
the same way as compound 1a from 14 (Scheme 8).
Scheme 8. Reagents and conditions: (a) TFA (aq., 50%), 70 °C; (b)
LiOH, r.t.; (c) Amberlite IR-120 (H+), r.t.
Ketone
Reducing agent
15/21, yield (%)
22, yield (%)
The desired compounds 3 were obtained from ketone 17
by the reaction sequence shown in Scheme 9. Reduction of
17 with sodium borohydride in methanol afforded mainly
axial hydride delivery. In this case, the free hydroxy group,
which is in an axial orientation, directs the hydride attack
to give diaxial diol 23 in 83% yield. Equatorial hydride de-
livery was obtained in only 16% yield. Acidic hydrolysis of
diol 23 with aqueous trifluoroacetic acid at 70 °C gave the
corresponding 1,5-carbolactone, and basic hydrolysis fol-
lowed by ion exchange gave azido acid 3a in excellent yield.
Finally, reduction of 3a in the same way as compound 1b
from 1a afforded amino acid 3b in 56% yield.
18
18
19
19
20
L-Selectride
NaBH4
L-Selectride
NaBH4
94
57
100
34
0
43
0
51
42
NaBH4
41
The influence of hydroxy group protection of 18 on the
reaction diastereoselectivity was also investigated, with
TBS- and TBDPS-protected ketones 19 and 20, respectively,
being synthesized. TBS derivative 19 was prepared from
diol 15 or ketone 18 as shown in Scheme 7. Treatment of
diol 15 with TBSOTf at 0 °C regioselectively afforded TBS
ether 21b in 90% yield. The regiochemistry of the protec-
tion was confirmed by NOE experiments. Inversion of the
hydroxy group led to enhancement of the signals for
6-Haxial (2.8%) and for 2-H (1.4%). Swern oxidation of the
Scheme 9. Reagents and conditions: (a) NaBH4, MeOH, r.t.; (b) (i)
TFA (aq., 50%), 70 °C, (ii) LiOH, r.t., (iii) Amberlite IR-120 (H+),
r.t.; (c) Ac2O, Py, 0 °C Ǟ r.t.; (d) H2, PtO2 (cat.), Boc2O, THF, r.t.;
(e) (i) LiOH, r.t., (ii) Amberlite IR-120 (H+), r.t.
Synthesis of Compounds 4
γ-Amino acid 4b was synthesized via γ-azido acid 4a,
which was obtained by nucleophilic ring opening of cyclic
sulfate 24 (Scheme 10). This key step was expected to take
place mainly at C-5, the less congested side of the sulfate
24.
Scheme 7. Reagents and conditions: (a) TBSOTf, Py, DCM, 0 °C
Ǟ r.t.; (b) (i) DMSO, TFAA, DCM, –60 °C, (ii) Et3N, –60 °C Ǟ
r.t.; (c) TBDPSCl, Im, DMF, 0 °C Ǟ r.t.
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Cyclic γ-Amino Acids and Triazole Derivatives
Synthesis of Triazoles 5 and 6
Finally, we explored the reactivities of azides 2 and 4a in
1,3-cycloaddition reactions with alkynes to form triazoles
(Scheme 12). Copper(I)-catalyzed cycloaddition reactions
between alkynes and azides do not usually require protec-
tion of any hydroxy groups that may be present in both
reagents. In our case, however, purification of the corre-
sponding triazoles 5 and 6 proved difficult, so we decided
to carry out the cycloaddition reactions on the acetyl-pro-
tected azides 28 and 29, which would be expected to provide
less polar triazole derivatives. Indeed, treatment of acetyl-
protected azides 28 and 29 with phenyl propargyl ether un-
der standard Sharpless click conditions efficiently afforded
the corresponding triazoles. The reactions were regioselec-
tive in both cases, and only single regioisomers were ob-
tained. Finally, basic removal of the acetyl protecting
groups from the resulting cycloadducts, followed by proton-
ation with an ion-exchange resin, led to triazoles 5 and 6,
respectively, in 33% and 60% overall yields.
Scheme 10.
The key intermediate 24 was prepared in three steps from
carbolactone 13 (Scheme 11). Initial protection of the free
hydroxy group of 13, followed by acid removal of the iso-
propylidene acetal of 25, gave diol 26, which was converted
into cyclic sulfate 24 as described above. Subsequent azi-
dolysis of sulfate 24 with sodium azide in the presence of a
catalytic amount of 15-crown ether in DMF at 90 °C af-
forded azido alcohol 27 as a single regioisomer. The stereo-
chemistry of the azidolysis was confirmed by NOE experi-
ments. Irradiation of 6-Haxial led to enhancement of the sig-
nal for 5-H (7.6%). The regiochemistry of the reaction can
be explained in terms of an axial attack of the azide anion
from the less hindered side of the cyclic sulfate.
Scheme 12. Reagents and conditions: (a) Ac2O, Py, 0 °C Ǟ r.t.; (b)
PhOCH2CϵCH, sodium ascorbate, tBuOH/H2O, CuSO4, r.t.; (c)
(i) LiOH, r.t., (ii) Amberlite IR-120 (H+), r.t.
Conclusions
Regioselective ring-opening of cyclic sulfates 7 and 24,
derived from inexpensive, commercially available (–)-quinic
acid, with azide anion can be used for the efficient synthesis
of azido acids and Boc-γ-amino acids 1–4. The equatorial
substituent at the C-1 position has been successfully used
to control the facial selectivity of the ring-opening reaction,
as well as to direct the regioselective formation of the cyclic
sulfate 7.
Scheme 11. Reagents and conditions: (a) TBSOTf, Py, DCM, 0 °C
Ǟ r.t.; (b) AcOH (aq., 80%), 65 °C; (c) (i) SOCl2, Et3N, DCM, r.t.,
(ii) RuCl3·3H2O (cat.), NaIO4, H2O, CCl4, CH3CN, r.t.; (d) (i)
NaN3, DMF, 90 °C, (ii) H2SO4 (70%), THF, r.t.; (e) (i) TFA (aq.,
50%), 70 °C, (ii) LiOH, r.t., (iii) Amberlite IR-120 (H+), r.t.; (f)
Ac2O, Py, 0 °C Ǟ r.t.; (g) H2, PtO2 (cat.), Boc2O, THF, r.t.; (h) (i)
LiOH, r.t., (ii) Amberlite IR-120 (H+), r.t.
The Sn-mediated oxidation of cyclic-1,2-diol 15 by N-
bromosuccinimide and the stereoselective reduction of the
Acid removal of the TBS protecting groups, basic hydro- corresponding α-hydroxy ketones 17 and 18 have been
lysis of the carbolactone and protonation with an ion-ex- studied and used in the synthesis of compounds 2 and 3 –
change resin led to azido acid 4a. Finally, catalytic hydro- 4- and 5-epimers of 1 –, respectively. The axial free hydroxy
genolysis of the acetyl-protected derivative of 4a in the pres- group of α-hydroxy ketone 17 directs the hydride attack
ence of di-tert-butyl dicarbonate, followed by hydrolysis of from the same side of the hydroxy group. However, no sig-
the acetyl groups, afforded the desired γ-amino acid 4b in nificant influence was observed for the reduction of α-hy-
63% yield.
droxy ketone 18.
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V. F. V. Prazeres, L. Castedo, C. González-Bello
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for 1 h. Dichloromethane and water were added. The organic layer
was separated, and the aqueous layer was extracted with dichloro-
methane (3ϫ). All the combined organic extracts were dried (anh.
Na2SO4) and filtered, and the solvents were evaporated. The ob-
tained residue was purified by flash chromatography, with elution
with a gradient of ethyl acetate/hexane (25:75 to 50:50) to yield
alcohol 11 (358 mg, 82%) as a light yellow, amorphous solid.
Finally, the reactivities of azides 2 and 4a with alkynes
in click chemistry techniques was explored and is demon-
strated with triazoles 5 and 6. The efficiency and high re-
gioselectivity achieved make the azide functions present in
derivatives 2 and 4a an attractive means to link these highly
hydroxylated acid moieties to polymers or bioactive molec-
ular entities.
1
[α]2D0 = –12.8 (c = 1.3, CHCl3). H NMR (250 MHz, CDCl3): δ =
The cis- and trans-γ-cyclohexane amino acid entities re-
ported here, functionalized with many stereochemically di-
4.36 (dd, J = 11.3, 5.6 Hz, 1 H, 4-H), 4.13–4.04 (m, 1 H, 5-H), 3.90
(t, J = 6.2 Hz, 1 H, 3-H), 3.70 (s, 3 H, OCH3), 2.94 (d, J = 3.0 Hz,
verse hydroxy groups, may be used in the stereocontrolled 1 H, OH), 2.23 (dd, J = 14.8, 5.6 Hz, 1 H, 2-Hax), 2.03 (m, 2 H, 2-
Heq + 6-Heq), 1.87 (dd, J = 13.8, 9.8 Hz, 1 H, 6-Hax), 1.47 (s, 3 H,
CH3), 1.32 (s, 3 H, CH3), 0.85 [s, 9 H, C(CH3)3], 0.04 (s, 6 H,
2ϫSiCH3) ppm. 13C NMR (63 MHz, CDCl3): δ = 175.0 (C), 108.7
(C), 79.6 (CH), 75.7 (C), 72.7 (CH), 67.8 (CH), 52.2 (CH3), 39.7
(CH2), 37.2 (CH2), 28.1 (CH3), 25.7 [C(CH3)3], 25.5 (CH3), 18.2
assembly of simple or complex molecules with tailored
properties, as well as in the synthesis of new oligosaccha-
rides, such as validamycin derivatives,[15] and peptidomi-
metics.
[C(CH ) ], –3.3 (SiCH ), –3.4 (SiCH ) ppm. IR (KBr): ν = 3565
˜
3 3
3
3
(O–H) and 1725 (C=O) cm–1. MS (CI): m/z = 361 [M + H]+.
HRMS: calcd. for C17H33O6Si [M + H]+ 361.2046; found 361.2034.
C17H32O6Si (360.52): calcd. C 56.64, H 8.95; found C 56.30, H
9.02.
Experimental Section
General Procedures: All starting materials and reagents were com-
mercially available and used without further purification. FT-IR
spectra were recorded as NaCl plates or KBr discs. [α]D values are
given in 10–1 degcm2 g–1. 1H NMR spectra (250, 300, 400 and
500 MHz) and 13C NMR spectra (63, 75, 100 and 125 MHz) were
measured in deuterated solvents. J values are given in Hertz. NMR
assignments were determined by a combination of 1D, NOE,
COSY, and DEPT-135 experiments. All procedures involving the
use of ion-exchange resins were carried out at room temperature,
with use of Mili-Q deionized water. Amberlite IR-120 (H+) (cation
exchanger) was washed alternately with water, NaOH (10%), water,
HCl (10%), and finally water before use.
Methyl (1S,4S,5R)-1-(tert-Butyldimethylsilyloxy)-4,5-O-isopropyl-
idenecyclohex-2-ene-1-carboxylate (8): Freshly distilled trifluoro-
acetic anhydride (55 µL, 0.32 mmol) was added at 0 °C under argon
to a stirred solution of the alcohol 11 (653 mg, 1.82 mmol) in
dry dichloromethane (18.2 mL) and dry pyridine (0.37 mL,
4.55 mmol). The resulting mixture was stirred at this temperature
for 45 min and then diluted successively with dichloromethane and
water. The organic phase was separated, and the aqueous layer was
extracted with dichloromethane (2ϫ). All combined organic ex-
tracts were washed with CuSO4 (sat.), dried (anh. Na2SO4), filtered
and concentrated under reduced pressure. The obtained yellow oil
was dissolved in dry chloroform (9.1 mL), DBU (0.35 mL,
2.37 mmol) was added, and the mixture was heated at reflux under
argon for 24 h. After the mixture had cooled to room temperature,
water and dichloromethane were added. The organic layer was sep-
arated, and the aqueous phase was extracted with dichloromethane
(2ϫ). All the combined organic extracts were washed twice with
NaHCO3 (sat.), dried (anh. Na2SO4) and filtered, and the solvents
were evaporated. The obtained residue was purified by flash
chromatography, with elution with ethyl acetate/hexane (5:95) to
afford alkene 8 (615 mg, 99%) as a colourless oil. [α]2D0 = +104.4 (c
(1S,3R,4R,5R)-1-(tert-Butyldimethylsilyloxy)-4,5-O-isopropylidene-
cyclohexane-1,3-carbolactone (10): tert-Butyldimethylsilyl trifluoro-
methanesulfonate (6.44 mL, 28.04 mmol) was added under an inert
gas and at 0 °C to a stirred solution of the alcohol 9[7] (4.0 g,
18.69 mmol) in dry dichloromethane (62 mL) and pyridine
(2.64 mL, 32.70 mmol). The resulting solution was stirred at 0 °C
for 30 min and at room temperature for 15 h. The reaction mixture
was diluted with dichloromethane and water. The aqueous layer
was acidified with HCl (10%), and the organic phase was sepa-
rated. The aqueous layer was extracted twice with dichlorometh-
ane. All the combined organic extracts were dried (anh. Na2SO4)
and filtered, and the solvents were evaporated. The obtained resi-
due was purified by flash chromatography, with elution with ethyl
acetate/hexanes (10:90) to yield silyl ether 10 (6.06 g, 99%) as white
needles. [α]2D0 = +1.9 (c = 1.1, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 4.56 (dd, J = 6.0, 2.5 Hz, 1 H, 4-H), 4.40 (td, J = 7.5,
2.9 Hz, 1 H, 5-H), 4.19 (m, 1 H, 3-H), 2.47 (d, J = 11.7 Hz, 1 H,
2-Hax), 2.35 (ddd, J = 14.7, 7.5, 2.2 Hz, 1 H, 6-Hax), 2.23–2.15 (m,
1 H, 2-Heq), 1.99 (dd, J = 14.7, 2.9 Hz, 1 H, 6-Heq), 1.44 (s, 3 H,
CH3), 1.24 (s, 3 H, CH3), 0.82 [s, 9 H, C(CH3)3], 0.10 (s, 3 H,
SiCH3), 0.06 (s, 3 H, SiCH3) ppm. 13C NMR (63 MHz, CDCl3): δ
= 176.9 (C), 109.3 (C), 74.7 (CH), 73.1 (C), 72.0 (CH), 71.4 (CH),
39.1 (CH2), 35.3 (CH2), 26.9 (CH3), 25.4 [C(CH3)3], 24.1 (CH3),
1
= 1.2, CHCl3). H NMR (250 MHz, CDCl3): δ = 5.90 (br. s, 2 H,
2-H, 3-H), 4.56–4.44 (m, 2 H, 4-H, 5-H), 3.68 (s, 3 H, OCH3), 2.43
(dd, J = 12.3, 5.3 Hz, 1 H, 6-Heq), 1.71 (ddd, J = 12.3, 10.7, 3.5 Hz,
1 H, 6-Hax), 1.47 (s, 3 H, CH3), 1.35 (s, 3 H, CH3), 0.86 [s, 9 H,
C(CH3)3], 0.09 (s, 3 H, SiCH3), 0.07 (s, 3 H, SiCH3) ppm. 13C
NMR (63 MHz, CDCl3): δ = 173.0 (C), 135.2 (CH), 125.6 (CH),
109.8 (C), 76.0 (CH), 71.6 (CH), 70.0 (C), 52.2 (OCH3), 38.2 (CH2),
28.0 (CH3), 25.6 [C(CH3)3], 25.6 (CH3), 18.1 [C(CH3)3], –2.9
(SiCH ),–3.3 (SiCH ) ppm. IR (film): ν = 1739 (C=O) cm–1. MS
˜
3
3
(CI): m/z = 343 [M + H]+. HRMS: calcd. for C17H31O5Si [M +
H]+ 343.1941; found 343.1939. A small amount of the triflate inter-
mediate was purified by flash chromatography, with elution with
ethyl acetate/hexane (10:90 to 15:85), and characterized. Data for
triflate intermediate: [α]2D0 = –46.8 (c = 1.9, CHCl3). 19F NMR
(282 MHz, CDCl3): δ = –75.5 (s, 3 F, CF3) ppm. 1H NMR
(250 MHz, CDCl3): δ = 5.26 (ddd, J = 11.8, 7.8, 4.0 Hz, 1 H, 5-
17.8 [C(CH ) ], –3.1 (SiCH ) and –3.2 (SiCH ) ppm. IR (KBr): ν
˜
3 3
3
3
= 1804 (C=O) cm–1. MS (CI): m/z = 329 [M + H]+. HRMS: calcd.
for C16H29O5Si [M + H]+ 329.1784; found 329.1796. C16H28O5Si
(328.48): calcd. C 58.50, H 8.59; found C 58.55, H 8.91.
Methyl
(1R,3R,4S,5R)-1-(tert-Butyldimethylsilyloxy)-3-hydroxy- H), 4.48 (td, J = 5.5, 2.3 Hz, 1 H, 3-H), 4.09 (dd, J = 7.8, 5.5 Hz,
4,5-O-isopropylidenecyclohexane-1-carboxylate (11): Potassium cya-
nide (95 mg, 1.46 mmol) was added under argon to a stirred solu-
tion of the carbolactone 10 (400 mg, 1.22 mmol) in dry methanol
(12.2 mL). The resulting solution was stirred at room temperature
1 H, 4-H), 3.75 (s, 3 H, OCH3), 2.45–2.34 (m, 2 H, 6-Heq, 2-Heq),
2.22 (dd, J = 16.0, 5.5 Hz, 1 H, 6-Hax), 2.00 (t, J = 12.6 Hz, 1 H,
2-Hax), 1.52 (s, 3 H, CH3), 1.36 (s, 3 H, CH3), 0.90 [s, 9 H,
C(CH3)3], 0.09 (s, 3 H, SiCH3), 0.06 (s, 3 H, SiCH3) ppm. 13C
3996
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3991–4003

Cyclic γ-Amino Acids and Triazole Derivatives
NMR (63 MHz, CDCl3): δ = 172.8 (C), 118.4 (JCF = 317 Hz, C),
Sulfate 7: Thionyl chloride (575 µL, 7.91 mmol) was added at 0 °C
109.8 (C), 87.6 (CH), 76.4 (CH), 76.3 (C), 73.6 (CH), 52.4 (OCH3), under argon to a stirred solution of diol 12 (850 mg, 2.26 mmol)
39.2 (CH2), 35.1 (CH2), 27.8 (CH3), 25.6 [C(CH3)3], 25.6 (CH3), and dry triethylamine (1.26 mL, 9.04 mmol) in dry dichlorometh-
18.3 [C(CH ) ], –3.3 (SiCH ), –4.0 (SiCH ) ppm. IR (film): ν = ane (45 mL). The ice bath was removed, and the resulting solution
˜
3 3
3
3
1743 (C=O) cm–1. MS (CI): m/z = 493 [M + H]+. HRMS: calcd.
was stirred at room temperature for 3 h. The reaction mixture was
cooled to 0 °C and diluted with dichloromethane and water. The
organic phase was separated, and the aqueous layer was extracted
with dichloromethane (3 ϫ). All the combined organic extracts
were dried (anh. Na2SO4) and filtered, and the solvents were evapo-
rated. The obtained residue was dissolved in a CCl4/CH3CN mix-
ture (1:1, 45 mL) and cooled to 0 °C. Aqueous NaIO4 (22.6 mL,
0.4 ) and RuCl3·3H2O (48 mg, 0.23 mmol) were then added. The
resulting reaction mixture was stirred at this temperature for 2 h
and then diluted with diethyl ether and water. The organic phase
was separated and successively washed with water, NaHCO3 (sat.)
and NaCl (sat.). The organic extract was dried (anh. Na2SO4) and
filtered, and the solvents were evaporated. The obtained residue
was purified by flash chromatography, with elution with ethyl ace-
tate/hexanes (10:90) to yield sulfate 7 (907 mg, 92%) as a white
amorphous solid. [α]2D0 = –31.2 (c = 1.0, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 5.05 (br. s, 2 H, 2-H, 3-H), 4.58 (br. s, 2
H, 4-H, 5-H), 3.81 (s, 3 H, OCH3), 2.50 (brd, J = 15.0 Hz, 1 H, 6-
Hax), 2.10 (br. d, J = 15.0 Hz, 1 H, 6-Heq), 1.48 (s, 3 H, CH3), 1.34
(s, 3 H, CH3), 0.87 [s, 9 H, C(CH3)3], 0.12 (s, 3 H, SiCH3), 0.09 (s,
3 H, SiCH3) ppm. 13C NMR (63 MHz, CDCl3): δ = 169.9 (C),
110.0 (C), 85.3 (CH), 84.6 (CH), 75.8 (C), 74.6 (CH), 71.5 (CH),
52.8 (OCH3), 33.4 (CH2), 27.5 (CH3), 25.6 [C(CH3)3], 24.7 (CH3),
for C18H32O8SiSF3 [M + H]+ 493.1539; found 493.1558.
Methyl (1S,2S,3R,4S,5R)-1-(tert-Butyldimethylsilyloxy)-2,3-dihy-
droxy-4,5-O-isopropylidenecyclohex-2-ene-1-carboxylate (12) and
(1S,2S,3S,4R,5R)-1-(tert-Butyldimethylsilyloxy)-2-hydroxy-4,5-O-
isopropylidenecyclohexane-1,3-carbolactone (13): A freshly made
aqueous solution of osmium tetroxide (0.12 , 3.8 mL, 0.46 mmol)
was added at room temperature to a stirred solution of the alkene
8 (1.05 g, 3.07 mmol) and NMO (431 mg, 3.68 mmol) in dioxane/
water (1:1, 36 mL). After the system had been stirred for about
20 h, ethyl acetate and then Na2S2O3 (10%, 10 mL) were added.
The resulting reaction mixture was stirred for 20 min. The organic
layer was separated, and the aqueous layer was extracted with ethyl
acetate (2 ϫ). All combined organic layers were dried (anh.
Na2SO4), filtered and concentrated under reduced pressure. The
obtained residue was purified by flash chromatography, with elu-
tion with ethyl acetate/hexane (30:70 then 50:50) to yield diol 12
(430 mg, 37%) as white needles and hydroxy lactone 13 (506 mg,
48%) as a light yellow amorphous solid.
12: [α]2D0 = –21.5 (c = 1.1, CHCl3). 1H NMR (500 MHz, CDCl3): δ
= 4.43 (td, J = 5.5, 3.5 Hz, 1 H, 5-H), 4.14 (dd, J = 7.0, 5.5 Hz, 1
H, 4-H), 4.10–4.06 (m, 2 H, 2-H, 3-H), 3.75 (s, 3 H, OCH3), 2.88
(d, J = 3.0 Hz, 1 H, OH), 2.58 (d, J = 5.0 Hz, 1 H, OH), 2.44 (dd,
J = 15.5, 5.5 Hz, 1 H, 6-Hax), 2.19 (dd, J = 15.5, 3.5 Hz, 1 H, 6-
Heq), 1.48 (s, 3 H, CH3), 1.34 (s, 3 H, CH3), 0.88 [s, 9 H, C(CH3)3],
0.08 (s, 3 H, SiCH3), 0.04 (s, 3 H, SiCH3) ppm. 13C NMR (63 MHz,
CDCl3): δ = 173.2 (C), 108.7 (C), 77.9 (C), 77.9 (CH), 75.4 (CH),
72.9 (CH), 70.4 (CH), 52.2 (OCH3), 31.8 (CH2), 28.4 (CH3), 25.8
18.2 [C(CH ) ], –3.0 (SiCH ), –3.9 (SiCH ) ppm. IR (KBr): ν =
˜
3 3
3
3
1740 (C=O) cm–1. MS (CI): m/z = 439 [M + H]+. HRMS: calcd.
for C17H31O9SiS [M + H]+ 439.1458; found 439.1464. C17H30O9SSi
(438.57): calcd. C 46.56, H 6.89; found C 46.58, H 6.87.
Methyl (1S,2S,3S,4S,5R)-3-Azido-1-(tert-butyldimethylsilyloxy)-2-
hydroxy-4,5-O-isopropylidenecyclohexane-1-carboxylate (14): A
(CH3), 25.6 [C(CH3)3], 18.2 [C(CH3)3], –3.3 (SiCH3),–4.0 (SiCH3) solution of sulfate 7 (804 mg, 1.84 mmol) in dry DMF (46 mL)
ppm. IR (KBr): ν = 3385 (O–H), 1754 and 1735 (C=O) cm–1. MS was treated with sodium azide (471 mg, 7.36 mmol) and 15-crown-
˜
(CI): m/z = 377 [M + H]+. HRMS: calcd. for C17H33O7Si [M +
H]+ 377.1996; found 377.1996. C17H32O7Si·1/4H2O (394.56): calcd.
C 53.59, H 8.60; found C 53.67, H 8.98.
5 ether (35 µL, 0.18 mmol), and the resulting mixture was heated
at 90 °C for 2.5 h. After the mixture had cooled to room tempera-
ture, the solvent was removed under reduced pressure. The ob-
tained residue was dissolved in THF (92 mL) and aqueous H2SO4
(136 µL, 70%) and then heated at 50 °C for 1 h. After the mixture
had cooled to room temperature, powdered NaHCO3 (1.68 g) was
added, and the resulting mixture was stirred for 20 min. The sus-
pension was filtered through a plug of Celite, and the residue was
washed with ethyl acetate. The filtrate and washings were concen-
trated under reduced pressure. The obtained residue was purified
by flash chromatography, with elution with ethyl acetate/hexanes
(20:80), to yield azide 14 (542 mg, 73%) as a white amorphous
solid. [α]2D0 = +8.0 (c = 1.1, CHCl3). 1H NMR (250 MHz, CDCl3):
δ = 4.54–4.46 (m, 1 H, 5-H), 4.40 (dd, J = 4.0, 4.7 Hz, 1 H, 4-H),
4.04 (d, J = 10.5 Hz, 1 H, 2-H), 3.84 (dd, J = 4.0, 10.5 Hz, 1 H, 3-
H), 3.76 (s, 3 H, OCH3), 2.76 (br. s, 1 H, OH), 2.29 (dd, J = 13.5,
6.8 Hz, 1 H, 6-Hax), 1.79 (dd, J = 9.5, 13.5 Hz, 1 H, 6-Heq), 1.51
(s, 3 H, CH3), 1.36 (s, 3 H, CH3), 0.89 [s, 9 H, C(CH3)3], 0.13 (s, 3
H, SiCH3), 0.09 (s, 3 H, SiCH3) ppm. 13C NMR (63 MHz, CDCl3):
δ = 172.8 (C), 109.6 (C), 80.0 (C), 76.1 (CH), 75.3 (CH), 72.6 (CH),
59.7 (CH), 52.3 (OCH3), 38.8 (CH2), 28.4 (CH3), 26.2 (CH3), 25.7
[C(CH3)3], 18.2 [C(CH3)3], –2.8 (SiCH3),–3.3 (SiCH3) ppm. IR
1
13: [α]2D0 = +14.9 (c = 1.2, CHCl3). H NMR (250 MHz, CDCl3):
δ = 4.52 (s, 1 H, 2-H), 4.46 (dd, J = 7.0, 2.0 Hz, 1 H, 5-H), 4.40
(m, 2 H, 4-H, 3-H), 2.82 (br. s, 1 H, OH), 2.51 (dd, J = 15.5, 7.0 Hz,
1 H, 6-Hax), 2.25 (dd, J = 15.5, 2.0 Hz, 1 H, 6-Heq), 1.51 (s, 3 H,
CH3), 1.31 (s, 3 H, CH3), 0.90 [s, 9 H, C(CH3)3], 0.14 (s, 6 H,
2ϫSiCH3) ppm. 13C NMR (63 MHz, CDCl3): δ = 177.2 (C), 109.4
(C), 81.0 (CH), 74.2 (CH), 74.0 (C), 72.4 (CH), 70.9 (CH), 36.0
(CH2), 26.8 (CH3), 25.6 [C(CH3)3], 23.9 (CH3), 18.1 [C(CH3)3], –4.8
(2ϫCH ) ppm. IR (KBr): ν = 3525 (O–H), 1800 (C=O) cm–1. MS
˜
3
(CI): m/z = 345 [M + H]+. HRMS: calcd. for C16H29O6Si [M +
H]+ 345.1733; found 345.1725. C16H28O6Si (344.48): calcd. C 55.79,
H 8.19; found C 55.55, H 8.48.
(1S,2S,3S,4R,5R)-1-(tert-Butyldimethylsilyloxy)-2-hydroxy-4,5-O-
isopropylidenecyclohexane-1,3-carbolactone (13) by Lactonisation of
12: Sodium hydride (1.6 mg, 65 µmol, ca. 60% in mineral oil) was
added at 0 °C under argon to a stirred solution of the diol 12
(48 mg, 0.13 mmol) in dry THF (0.5 mL). The resulting suspension
was stirred for 15 min. Diethyl ether and then water were added.
The organic layer was separated, and the aqueous layer was ex-
tracted with diethyl ether (3ϫ5 mL). All combined organic layers
were dried (anh. Na2SO4) and concentrated under reduced pres-
sure. The crude residue was purified by flash chromatography, with
elution with diethyl ether/hexane (50:50), to afford carbolactone 13
(28.5 mg, 64%).
(film): ν = 3504 (O–H), 2106 (NϵN), 1729 (C=O) cm–1. MS (ESI):
˜
m/z = 424 [M + Na]+. HRMS: calcd. for C17H31O6SiN3Na [M +
Na]+ 424.1884; found 424.1874.
(1S,2S,3R,4S,5R)-3-Azido-1,2,4,5-tetrahydroxycyclohexane-1-
carboxylic Acid (1a): A solution of acetal 14 (60 mg, 0.15 mmol) in
aqueous TFA (1.5 mL, 50%) was heated at 70 °C for 3 h. The reac-
Eur. J. Org. Chem. 2008, 3991–4003
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3997

V. F. V. Prazeres, L. Castedo, C. González-Bello
FULL PAPER
tion mixture was cooled to room temperature, and the solvent was
removed under reduced pressure. A solution of the crude product
in water was washed with ethyl acetate (3ϫ) and lyophilised. The
obtained residue was dissolved in water (1.4 mL), treated with
aqueous lithium hydroxide (0.8 mL, 0.5 ) and stirred at room tem-
perature for 4 h. The aqueous solution was treated with Amberlite
IR-120 until pH = 6 was reached. The resin was filtered and washed
with water. The filtrate and the washings were lyophilised to afford
cooled to 0 °C under argon and was then treated with TBSOTf
(344 µL, 1.5 mmol). The resulting mixture was stirred at this tem-
perature for 12 h and then diluted successively with dichlorometh-
ane and water. The aqueous layer was acidified with HCl (10%),
and the organic phase was separated. The aqueous layer was ex-
tracted twice with dichloromethane. All combined organic extracts
were dried (anh. Na2SO4), filtered and concentrated under reduced
pressure. The obtained residue was purified by flash chromatog-
raphy, with elution with ethyl acetate/hexane (10:90), to afford
ether 16 (515 mg, 99%) as a light yellow oil. [α]2D0 = –21.6 (c = 1.0,
azido acid 1a (34 mg, 97%) as a beige, amorphous solid. [α]2D0
=
1
–4.5 (c = 1.3, H2O). H NMR (250 MHz, D2O): δ = 4.15 (m, 2 H,
4-H, 5-H), 3.99 (dd, J = 10.8, 2.5 Hz, 1 H, 3-H), 3.85 (d, J =
1
CHCl3). H NMR (250 MHz, CDCl3): δ = 4.48 (m, 2 H, 4-H, 5-
10.8 Hz, 1 H, 2-H), 2.04 (m, 1 H, 6-Heq), 1.91 (m, 1 H, 6-Hax) ppm. H), 3.90 (d, J = 10.0 Hz, 1 H, 2-H), 3.81 (dd, J = 10.0, 3.3 Hz, 1
13C NMR (100 MHz, D2O): δ = 178.5 (C), 79.7 (C), 76.9 (CH), H, 3-H), 3.73 (s, 3 H, OCH3), 2.27 (m, 1 H, 6-Hax), 1.93 (m, 1 H,
74.1 (CH), 69.0 (CH), 66.2 (CH), 38.8 (CH ) ppm. IR (KBr): ν = 6-Heq), 1.51 (s, 3 H, CH3), 1.35 (s, 3 H, CH3), 0.88 [s, 9 H,
˜
2
3453 (O–H), 3391 (O–H), 3351 (O–H), 3297 (O–H), 2115 (NϵN), C(CH3)3], 0.86 [s, 9 H, C(CH3)3], 0.19 (s, 3 H, SiCH3), 0.18 (s, 3
1743 (C=O) cm–1. MS (ESI) m/z = 256 [M + Na]+. HRMS: calcd.
for C7H11O6N3Na [M + Na]+ 256.0540; found 256.0540. A small
amount of the 1a methyl ester intermediate was characterized.
White foam. [α]2D0 = –8.6 (c = 1.7, MeOH). 1H NMR (400 MHz,
H, SiCH3), 0.12 (s, 3 H, SiCH3), 0.05 (s, 3 H, SiCH3) ppm. 13C
NMR (63 MHz, CDCl3): δ = 173.6 (C), 109.3 (C), 81.4 (C), 76.3
(CH), 75.4 (CH), 72.3 (CH), 63.2 (CH), 51.7 (OCH3), 38.6 (CH2),
27.8 (CH3), 26.2 (CH3), 25.8 [C(CH3)3], 25.6 [C(CH3)3], 18.6
D2O): δ = 4.18 (m, 2 H, 4-H, 5-H), 4.02 (dd, J = 10.8, 2.8 Hz, 1 [C(CH3)3], 17.9 [C(CH3)3], –2.4 (SiCH3), –3.1 (SiCH3), –4.0
H, 3-H), 3.91 (d, J = 10.8 Hz, 1 H, 2-H), 3.84 (s, 3 H, OCH3), 2.09 (SiCH ), –4.7 (SiCH ) ppm. IR (film): ν = 2104 (NϵN), 1761 and
˜
3
3
(dd, J = 13.2, 4.8 Hz, 1 H, 6-Heq), 1.98 (dd, J = 13.2, 12.0 Hz, 1
H, 6-Hax) ppm. 13C NMR (100 MHz, D2O): δ = 177.0 (C), 80.2
(C), 77.1 (CH), 74.0 (CH), 68.9 (CH), 66.2 (CH), 55.9 (CH3), 38.7
1731 (C=O) cm–1. MS (ESI): m/z = 538 [M + Na]+. HRMS: calcd.
for C23H45O6Si2N3Na [M + Na]+ 538.2739; found 538.2734.
Methyl (1S,2S,3R,4S,5R)-3-Azido-1,2-bis(tert-butyldimethyl-
silyloxy)-4,5-dihydroxycyclohexane-1-carboxylate (15): A solution
of isopropylidene acetal 16 (160 mg, 0.31 mmol) in aqueous acetic
acid (5.2 mL, 80%) was heated at 65 °C for 3 h. The reaction mix-
ture was cooled to room temperature, and the solvent was removed
under reduced pressure. The obtained residue was purified by flash
chromatography, with elution with ethyl acetate/hexane (30:70), to
afford diol 15 (147 mg, 99%) as a light yellow oil. [α]2D0 = +0.8 (c
(CH ) ppm. IR (KBr): ν = 3410 (O–H), 2112 (NϵN), 1732 (C=O)
˜
2
cm–1. MS (ESI): m/z = 270 [M + Na]+. HRMS: calcd. for
C8H13O6N3Na [M + Na]+ 270.0697; found 270.0706.
(1S,2S,3R,4S,5R)-3-(tert-Butoxycarbonylamino)-1,2,4,5-tetra-
hydroxycyclohexane-1-carboxylic Acid (1b): A solution of acid 1a
(13.6 mg, 0.058 mmol) in dry pyridine (0.2 mL) was treated under
argon and at 0 °C with acetic anhydride (0.2 mL). The ice bath was
removed, and the resulting mixture was stirred at room temperature
for 36 h. The solvents were removed under reduced pressure
through successive addition of toluene and acetonitrile and subse-
quent concentration. A suspension of the obtained residue, di-tert-
butyl dicarbonate (16.4 mg, 0.075 mmol) and platinium(IV) oxide
(5 mg) in dry THF (0.7 mL) was shaken under hydrogen at room
temperature for 19 h. The mixture was filtered through a plug of
Celite, and the residue was washed with methanol. The filtrate and
washings were diluted with ethyl acetate and water. The organic
layer was separated, washed with water (2ϫ), dried (anh. Na2SO4)
and concentrated under reduced pressure. A solution of the crude
reaction mixture in THF (0.4 mL) was treated with aqueous lith-
ium hydroxide (0.7 mL, 0.5 ) and stirred at room temperature for
30 min. THF was removed under reduced pressure, and the aque-
ous solution was then diluted with water and washed with ethyl
acetate (3ϫ). The aqueous extract was treated with Amberlite IR-
120 until pH = 6 was reached. The resin was filtered and washed
with water. The filtrate and the washings were lyophilised to afford
Boc-amino acid 1b (10 mg, 56%) as an amorphous, beige solid.
1
= 1.6, CHCl3). H NMR (250 MHz, CDCl3): δ = 4.11 (m, 2 H, 4-
H, 5-H), 3.93 (d, J = 8.3 Hz, 1 H, 2-H), 3.75 (dd, J = 8.3, 3.3 Hz,
1 H, 3-H), 3.71 (s, 3 H, OCH3), 3.04 (d, J = 4.0 Hz, 1 H, OH),
2.77 (d, J = 7.3 Hz, 1 H, OH), 2.07 (m, 2 H, 6-H), 0.88 [s, 9 H,
C(CH3)3], 0.82 [s, 9 H, C(CH3)3], 0.18 (s, 3 H, SiCH3), 0.14 (s, 3
H, SiCH3), 0.08 (s, 3 H, SiCH3), 0.06 (s, 3 H, SiCH3) ppm. 13C
NMR (63 MHz, CDCl3): δ = 172.8 (C), 80.2 (C), 75.5 (CH), 70.5
(CH), 67.3 (CH), 65.8 (CH), 51.8 (OCH3), 37.4 (CH2), 26.1
[C(CH3)3], 25.7 [C(CH3)3], 18.5 [C(CH3)3], 17.9 [C(CH3)3], –2.8
(SiCH3), –3.0 (SiCH3), –4.3 (SiCH3), –4.7 (SiCH3) ppm. IR (film):
ν = 3417 (O–H), 2105 (NϵN), 1731 (C=O) cm–1. MS (ESI): m/z =
˜
498 [M + Na]+. HRMS: calcd. for C20H41O6Si2N3Na [M + Na]+
498.2426; found 498.2421.
Methyl (1S,2S,3R,4S)-3-Azido-1,2-bis(tert-butyldimethylsilyloxy)-4-
hydroxy-5-oxocyclohexane-1-carboxylate (17) and Methyl
(1S,2S,3S,5R)-3-Azido-1,2-bis(tert-butyldimethylsilyloxy)-5-
hydroxy-4-oxocyclohexane-1-carboxylate (18) by Sn-Mediated Oxi-
dation of Diol 15: A solution of diol 15 (100 mg, 0.21 mmol) and
Bu2SnO (52 mg, 0.21 mmol) in dry toluene (10 mL) was heated un-
der reflux with azeotropic removal of water in a Dean–Stark appa-
ratus. After 24 h, the solution was cooled to room temperature,
and the solvent was removed under reduced pressure. The obtained
residue was dissolved, under an inert gas, in dry chloroform
(2.3 mL) and then treated with NBS (41 mg, 0.23 mmol). The re-
sulting mixture was stirred at room temperature for 1.5 h and then
concentrated under reduced pressure. The obtained residue was
purified by flash chromatography, with elution with ethyl acetate/
hexane [(1) 5:95; (2) 10:90] to afford ketones 17 (22 mg, 22%) and
18 (64 mg, 64%).
1
[α]2D0 = –10.6 (c = 1.0, H2O). H NMR (400 MHz, D2O): δ = 4.21
(m, 2 H, 4-H, 5-H), 4.01 (m, 1 H, 3-H), 3.64 (d, J = 11.2 Hz, 1 H,
2-H), 1.99 (m, 1 H, 6-Heq), 1.87 (t, J = 12.4 Hz, 1 H, 6-Hax), 1.47
{s, 9 H, [C(CH3)3]} ppm. 13C NMR (100 MHz, D2O): δ = 180.8
(C), 160.9 (C), 84.1 (C), 79.6 [C(CH3)3], 76.6 (CH), 74.7 (CH), 69.9
(CH), 56.8 (CH), 39.4 (CH2) and 30.7 [C(CH3)3] ppm. IR (KBr):
ν = 3400 (O–H), 1684 (C=O), 1616 (C=O) cm–1. MS (ESI): m/z =
˜
330 [M + Na]+. HRMS: calcd. for C12H21O8NNa [M + Na]+
330.1159; found 330.1158.
Methyl (1S,2S,3R,4S,5R)-3-Azido-1,2-bis(tert-butyldimethyl-
silyloxy)-4,5-O-isopropylidenecyclohexane-1-carboxylate (16): A
stirred solution of the alcohol 14 (402 mg, 1.00 mmol) and dry pyr-
idine (0.14 mL, 1.75 mmol) in dry dichloromethane (3.3 mL) was
17: Light orange oil. [α]2D0 = –1.8 (c = 2.3, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 4.64 (t, J = 4.5 Hz, 1 H, 3-H), 4.31 (m, 2
3998
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3991–4003

Cyclic γ-Amino Acids and Triazole Derivatives
H, 4-H, 2-H), 3.74 (s, 3 H, OCH3), 3.52 (d, J = 5.0 Hz, 1 H, OH),
been stirred for 20 min, a solution of the alcohol 21b (113 mg,
3.29 (dd, J = 14.5, 1.0 Hz, 1 H, 6-Heq), 2.76 (dd, J = 14.5, 1.3 Hz, 0.19 mmol) in dry dichloromethane (0.4 mL) was added by can-
1 H, 6-Hax), 0.87 [s, 9 H, C(CH3)3], 0.85 [s, 9 H, C(CH3)3], 0.21 (s,
3 H, SiCH3), 0.09 (s, 3 H, SiCH3), 0.03 (s, 6 H, 2ϫSiCH3) ppm.
13C NMR (63 MHz, CDCl3): δ = 205.7 (C), 170.7 (C), 83.6 (C),
nula. Dry triethylamine (0.11 mL, 0.78 mmol) was added after
1.5 h, and the reaction mixture was allowed to warm slowly to
room temperature. After 8 h, the reaction mixture was diluted suc-
73.0 (CH), 73.0 (CH), 67.4 (CH), 52.4 (CH3), 44.3 (CH2), 25.5 cessively with dichloromethane and water. The aqueous layer was
[C(CH3)3], 25.4 [C(CH3)3], 18.2 [C(CH3)3], 17.7 [C(CH3)3], –3.5 acidified with HCl (10%), and the organic phase was separated.
(SiCH ), –4.2 (2ϫSiCH ),–5.5 (SiCH ) ppm. IR (film): ν = 3481
The aqueous layer was extracted three times with dichloromethane.
˜
3
3
3
(O–H), 2112 (NϵN), 1745 (C=O) cm–1. MS (ESI): m/z = 496 [M All combined organic extracts were dried (anh. Na2SO4), filtered
+ Na]+. HRMS: calcd. for C20H39O6Si2N3Na [M + Na]+ 496.2270; and concentrated under reduced pressure. The obtained residue
found 496.2262.
was purified by flash chromatography, with elution with ethyl ace-
tate/hexane (5:95), to afford ketone 19 (109 mg, 98%) as a colour-
less oil. [α]2D0 = –28.4 (c = 1.4, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 4.79 (dd, J = 11.0, 7.8 Hz, 1 H, 5-H), 4.19 (d, J =
8.0 Hz, 1 H, 3-H), 3.78 (s, 3 H, OCH3), 3.69 (d, J = 8.0 Hz, 1 H,
2-H), 2.57 (dd, J = 14.0, 7.8 Hz, 1 H, 6-Heq), 1.87 (dd, J = 14.0,
11.0 Hz, 1 H, 6-Hax), 0.88 [s, 9 H, C(CH3)3], 0.85 [s, 18 H,
2ϫC(CH3)3], 0.15 (s, 3 H, SiCH3), 0.12 (s, 3 H, SiCH3), 0.11 (s, 3
H, SiCH3), 0.07 (s, 6 H, 2ϫSiCH3), 0.03 (s, 3 H, CH3) ppm. 13C
NMR (63 MHz, CDCl3): δ = 201.7 (C), 172.8 (C), 80.7 (CH), 79.2
(C), 71.1 (CH), 69.1 (CH), 52.0 (CH3), 41.6 (CH2), 26.0
[C(CH3)3], 25.7 [2ϫC(CH3)3], 18.4 [C(CH3)3], 18.3 [C(CH3)3], 17.9
[C(CH3)3], –2.9 (2ϫSiCH3), –4.6 (3ϫSiCH3), –5.4 (SiCH3) ppm.
18: Light yellow oil. [α]2D0 = –36.0 (c = 2.0, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 4.75 (dd, J = 11.0, 8.0 Hz, 1 H, 5-H), 4.41
(d, J = 8.0 Hz, 1 H, 2-H), 3.80 (s, 3 H, OCH3), 3.74 (d, J = 8.0 Hz,
1 H, 3-H), 3.37 (br. s, 1 H, OH), 2.77 (dd, J = 14.0, 8.0 Hz, 1 H,
6-Heq), 1.73 (dd, J = 11.0, 14.0 Hz, 1 H, 6-Hax), 0.86 [s, 9 H,
C(CH3)3], 0.85 [s, 9 H, C(CH3)3], 0.17 (s, 3 H, SiCH3), 0.14 (s, 3
H, SiCH3), 0.09 (s, 3 H, SiCH3), 0.08 (s, 3 H, SiCH3) ppm. 13C
NMR (63 MHz, CDCl3): δ = 204.4 (C), 172.5 (C), 81.3 (CH), 79.2
(C), 69.7 (CH), 69.1 (CH), 52.2 (OCH3), 40.5 (CH2), 26.0
[C(CH3)3], 25.7 [C(CH3)3], 18.4 [C(CH3)3], 17.9 [C(CH3)3], –2.9
(2ϫSiCH ), –4.6 (2 ϫSiCH ) ppm. IR (film): ν = 3454 (O–H),
˜
3
3
2111 (NϵN), 1760 (C=O), 1732 (C=O) cm–1. MS (ESI): m/z =
496 [M + Na]+. HRMS: calcd. for C20H39O6Si2N3Na [M + Na]+
496.2270; found 496.2261.
IR (film): ν = 2109 (NϵN), 1747 (C=O), 1732 (C=O) cm–1. MS
˜
(ESI): m/z = 610 [M + Na]+. HRMS: calcd. for C26H53O6Si3N3Na
[M + Na]+ 610.3134; found 610.3137.
Methyl (1S,2S,3R,4S,5R)-3-Azido-1,2,5-tris(tert-butyldimethyl-
silyloxy)-4-hydroxycyclohexane-1-carboxylate (21b): A stirred solu-
tion of the diol 15 (134 mg, 0.28 mmol) and dry pyridine (30 µL,
0.36 mmol) in dry dichloromethane (0.9 mL) was cooled to
0 °C under argon and was then treated with TBSOTf (64 µL,
0.28 mmol). The resulting mixture was stirred at this temperature
for 1 h, and dry pyridine (10 µL, 0.12 mmol) and TBSOTf (20 µL,
0.09 mmol) were then added. The resulting mixture was stirred at
room temperature for 2 h and then diluted successively with dichlo-
romethane and water. The aqueous layer was acidified with HCl
(10%), and the organic phase was separated. The aqueous layer
was extracted with dichloromethane (2ϫ). All combined organic
extracts were dried (anh. Na2SO4), filtered and concentrated under
reduced pressure. The obtained residue was purified by flash
chromatography, with elution with ethyl acetate/hexane (5:95), to
Methyl (1S,2S,3S,5R)-3-Azido-1,2,5-tris(tert-butyldimethyl-
silyloxy)-4-oxocyclohexane-1-carboxylate (19) by Preparation from
18: A stirred solution of the α-hydroxy ketone 18 (167 mg,
0.35 mmol) and dry pyridine (50 µL, 0.61 mmol) in dry dichloro-
methane (1.5 mL) was cooled to 0 °C under argon and was then
treated with TBSOTf (122 µL, 0.53 mmol). The resulting mixture
was stirred at this temperature for 20 min and 4 h at room tempera-
ture. The resulting mixture was diluted successively with dichloro-
methane and water. The aqueous layer was acidified with HCl
(10%), and the organic phase was separated. The aqueous layer
was extracted with dichloromethane (2ϫ). All combined organic
extracts were dried (anh. Na2SO4), filtered and concentrated under
reduced pressure. The obtained residue was purified by flash
chromatography, with elution with ethyl acetate/hexane (5:95), to
afford silyl ether 19 (197 mg, 96%).
afford silyl ether 21b (149 mg, 90%) as a light yellow oil. [α]2D0
=
Methyl (1S,2S,3S,5R)-3-Azido-1,2-bis(tert-butyldimethylsilyloxy)-5-
(tert-butyldiphenylsilyloxy)-4-oxocyclohexane-1-carboxylate (20): A
stirred solution of the alcohol 18 (34 mg, 0.07 mmol) and imidazole
(15 mg, 0.22 mmol) in dry N,N-dimethylformamide (0.5 mL) was
cooled to 0 °C under argon and was then treated with tert-butyl-
chlorodiphenylsilane (22 µL, 0.09 mmol). The resulting mixture
was stirred at room temperature for 48 h and was then diluted suc-
cessively with diethyl ether and water. The aqueous layer was acidi-
fied with HCl (10%), and the organic phase was separated. The
aqueous layer was extracted with diethyl ether (2ϫ). All combined
organic extracts were dried (anh. Na2SO4), filtered and concen-
trated under reduced pressure. The obtained residue was purified
by flash chromatography, with elution with ethyl acetate/hexane
[(1) 1:99; (2) 2:98] to afford silyl ether 20 (43 mg, 85%) as a light
yellow oil. [α]2D0 = +5.1 (c = 1.3, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 7.67 (m, 4 H, 4ϫArH), 7.47–7.33 (m, 6 H, 6ϫArH),
–24.4 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.31
(ddd, J = 11.2, 5.2, 2.8 Hz, 1 H, 5-H), 4.10 (t, J = 2.8 Hz, 1 H, 4-
H), 3.90 (d, J = 10.0 Hz, 1 H, 2-H), 3.72 (s, 3 H, OCH3), 3.58 (dd,
J = 10.0, 2.8 Hz, 1 H, 3-H), 2.44 (br. s, 1 H, OH), 2.03 (dd, J =
11.2, 13.2 Hz, 1 H, 6-Hax), 1.91 (dd, J = 5.2, 13.2 Hz, 1 H, 6-Heq),
0.89 [s, 9 H, C(CH3)3], 0.88 [s, 9 H, C(CH3)3], 0.86 [s, 9 H,
C(CH3)3], 0.19 (s, 3 H, CH3), 0.17 (s, 3 H, CH3), 0.11 (s, 3 H,
SiCH3), 0.08 (s, 3 H, SiCH3), 0.06 (s, 3 H, SiCH3), 0.06 (s, 3 H,
SiCH3) ppm. 13C NMR (63 MHz, CDCl3): δ = 173.7 (C), 80.8 (C),
76.0 (CH), 72.5 (CH), 67.7 (CH), 64.7 (CH), 51.5 (OCH3), 39.1
(CH2), 26.2 [C(CH3)3], 25.8 [C(CH3)3], 25.7 [2ϫC(CH3)3], 18.5
[C(CH3)3], 18.0 [2 ϫ C(CH3)3], –2.5 (CH3), –2.8 (CH3), –4.0
(SiCH ),–4.8 (3ϫSiCH ) ppm. IR (film): ν = 3466 (O–H), 2102
˜
3
3
(NϵN), 1732 (C=O) cm–1. MS (ESI): m/z = 590 [M + H]+. HRMS:
calcd. for C26H56O6Si3N3 [M + H]+ 590.3471; found 590.3470.
Methyl (1S,2S,3S,5R)-3-Azido-1,2,5-tris(tert-butyldimethyl- 4.65 (ddd, J = 11.8, 7.3, 1.0 Hz, 1 H, 5-H), 4.05 (dd, J = 8.5, 1.0 Hz,
silyloxy)-4-oxocyclohexane-1-carboxylate (19) by Swern Oxidation
of 21b: A flame-dried round-bottomed flask was charged with dry
DMSO (27 µL, 0.38 mmol) and dry dichloromethane (1.5 mL).
The resulting solution was cooled to –60 °C, and then freshly dis-
tilled TFAA (48 µL, 0.34 mmol) was added. After the mixture had
1 H, 3-H), 3.62 (d, J = 8.5 Hz, 1 H, 2-H), 3.54 (s, 3 H, OCH3),
2.29 (dd, J = 13.5, 7.3 Hz, 1 H, 6-Heq), 1.86 (dd, J = 13.5, 11.8 Hz,
1 H, 6-Hax), 1.10 [s, 9 H, C(CH3)3], 0.84 [s, 9 H, C(CH3)3], 0.78 [s,
9 H, C(CH3)3], 0.12 (s, 3 H, SiCH3), 0.08 (s, 3 H, SiCH3), 0.02 (s,
3 H, SiCH3), –0.10 (s, 3 H, SiCH3) ppm. 13C NMR (63 MHz,
Eur. J. Org. Chem. 2008, 3991–4003
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3999

V. F. V. Prazeres, L. Castedo, C. González-Bello
FULL PAPER
CDCl3): δ = 201.0 (C), 172.1 (C), 135.8 (2ϫCH), 135.7 (2ϫCH),
133.2 (C), 132.6 (C), 130.0 (2 ϫ CH), 127.8 (2 ϫ CH), 127.7
[C(CH3)3], 25.7 [C(CH3)3], 19.1 [C(CH3)3], 18.5 [C(CH3)3], 18.0
[C(CH3)3], –2.5 (SiCH3), –2.8 (SiCH3), –4.0 (SiCH3), –4.8 (SiCH3)
(2ϫCH), 80.8 (CH), 79.2 (C), 71.4 (CH), 69.3 (CH), 51.9 (OCH3), ppm. IR (film): ν = 3510 (O–H), 2104 (NϵN), 1759 (C=O) cm–1.
˜
41.3 (CH2), 26.8 [C(CH3)3], 26.0 [C(CH3)3], 25.6 [C(CH3)3], 19.2
[C(CH3)3], 18.4 [C(CH3)3], 17.9 [C(CH3)3], –2.9 (SiCH3), –3.0
MS (CI) m/z = 714 [M + H]+. HRMS: calcd. for C36H60O6N3Si3
[M + H]+ 714.3790; found 714.3797.
(SiCH ), –4.6 (SiCH ), –4.7 (SiCH ) ppm. IR (film): ν = 2112
˜
3
3
3
22c: [α]2D0 = +13.2 (c = 1.1, CHCl3). H NMR (400 MHz, CDCl3):
1
(NϵN), 1747 (C=O), 1726 (C=O) cm–1. MS (ESI): m/z = 734 [M
+ Na]+. HRMS: calcd. for C36H57O6Si3N3Na [M + Na]+ 734.3447;
found 734.3443.
δ = 7.64 (m, 4 H, 4ϫArH), 7.46–7.35 (m, 6 H, 6ϫArH), 4.01
(ddd, J = 11.6, 8.8, 4.8 Hz, 1 H, 4-H), 3.56 (m, 1 H, 5-H), 3.53
(dd, J = 9.2, 10.0 Hz, 1 H, 3-H), 3.42 (s, 3 H, OCH3), 3.29 (d, J =
9.2 Hz, 1 H, 2-H), 2.64 (d, J = 1.6 Hz, 1 H, OH), 1.87 (dd, J =
13.6, 4.8 Hz, 1 H, 6-Heq), 1.53 (dd, J = 13.6, 11.6 Hz, 1 H, 6-Hax),
1.07 [s, 9 H, C(CH3)3], 0.81 [s, 9 H, C(CH3)3], 0.79 [s, 9 H,
C(CH3)3], 0.10 (s, 3 H, SiCH3), 0.09 (s, 3 H, SiCH3), 0.03 (s, 3 H,
SiCH3), –0.33 (s, 3 H, SiCH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 172.2 (C), 135.7 (2ϫCH), 135.7 (2ϫCH), 133.5 (C), 133.0 (C),
130.0 (CH), 129.9 (CH), 127.9 (2ϫCH), 127.7 (2ϫCH), 80.5 (C),
79.3 (CH), 77.4 (CH), 71.1 (CH), 67.9 (CH), 51.6 (OCH3), 41.2
(CH2), 26.9 [C(CH3)3], 26.3 [C(CH3)3], 25.8 [C(CH3)3], 19.2
[C(CH3)3], 18.5 [C(CH3)3], 18.0 [C(CH3)3], –2.6 (SiCH3), –3.0
Reduction of Ketones 18–20 with NaBH4. General Procedure: So-
dium borohydride (1 mmol) was added under argon to a stirred
solution of the ketone (1 mmol) in dry methanol (0.1 ). The re-
sulting reaction mixture was stirred at room temperature for 1–2 h
and was then diluted with ethyl acetate and water. The resulting
mixture was treated with aqueous H2SO4 (5%) until pH = 5 was
reached, and the organic layer was separated. The aqueous phase
was extracted with ethyl acetate (3ϫ). All the combined organic
extracts were dried (anh. Na2SO4), filtered and concentrated under
reduced pressure. The resulting residue was purified by flash
chromatography.
(SiCH ), –4.2 (SiCH ), –4.6 (SiCH ) ppm. IR (KBr): ν = 3496 (O–
˜
3
3
3
H), 2108 (NϵN), 1734 (C=O) cm–1. MS (CI): m/z (%) = 714 [M +
H]+. HRMS: calcd. for C36H60O6N3Si3 [M + H]+ 714.3790; found
714.3783.
22a: Colourless oil. [α]2D0 = +15.5 (c = 1.3, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 4.10 (m, 1 H, 5-H), 3.76 (s, 3 H, OCH3),
3.64 (t, J = 9.5 Hz, 1 H, 4-H), 3.40 (d, J = 9.5 Hz, 1 H, 2-H), 3.32
(t, J = 9.5 Hz, 1 H, 3-H), 2.89 (br. s, 1 H, OH), 2.58 (br. s, 1 H,
OH), 2.29 (dd, J = 4.8, 13.5 Hz, 1 H, 6-Heq), 1.57 (dd, J = 12.0,
13.5 Hz, 1 H, 6-Hax), 0.87 [s, 9 H, C(CH3)3], 0.86 [s, 9 H,
C(CH3)3], 0.21 (s, 3 H, SiCH3), 0.15 (s, 3 H, SiCH3), 0.10 (s, 3 H,
SiCH3), 0.08 (s, 3 H, SiCH3) ppm. 13C NMR (63 MHz, CDCl3): δ
= 173.0 (C), 80.7 (C), 79.6 (CH), 76.9 (CH), 68.6 (CH), 68.5 (CH),
51.8 (OCH3), 40.5 (CH2), 26.3 [C(CH3)3], 25.8 [C(CH3)3], 18.5
[C(CH3)3], 18.0 [C(CH3)3], –2.5 (SiCH3), –2.7 (SiCH3), –4.0
(1S,2S,3R,4R,5R)-3-Azido-1,3,4,6-tetrahydroxycyclohexane-1-
carboxylic Acid (2): A solution of protected ester 22b (65 mg,
0.11 mmol) in aqueous TFA (1.0 mL, 50%) was heated at 70 °C for
3 h. The reaction mixture was cooled to room temperature, and the
solvent was removed under reduced pressure. A solution of the
crude product in water was washed with diethyl ether (3ϫ) and
lyophilised. The obtained residue was dissolved in water (1.0 mL),
treated with aqueous lithium hydroxide (0.6 mL, 0.5 ) and stirred
at room temperature for 11 h. The aqueous solution was treated
with Amberlite IR-120 until pH = 6 was reached. The resin was
filtered and washed with water. The filtrate and the washings were
lyophilised to afford azido acid 2 (25.5 mg, 99%) as a beige solid.
(SiCH ), –4.6 (SiCH ) ppm. IR (film): ν = 3375 (O–H), 2110
˜
3
3
(NϵN), 1757 and 1732 (C=O) cm–1. MS (CI): m/z = 461 [M + H –
CH3]+. HRMS: calcd. for C19H39O6N3Si2 [M+ H – CH3]+
461.2377; found 461.2371.
1
[α]2D0 = +13.0 (c = 1.2, H2O). H NMR (400 MHz, D2O): δ = 4.00
22b: Beige solid. [α]2D0 = –7.4 (c = 1.1, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 4.08 (m, 1 H, 5-H), 3.75 (s, 3 H, OCH3), 3.61 (t, J =
10.0 Hz, 1 H, 3-H), 3.36 (m, 2 H, 4-H, 2-H), 2.52 (br. s, 1 H, OH),
2.14 (dd, J = 4.8, 13.5 Hz, 1 H, 6-Heq), 1.54 (dd, J = 11.8, 13.5 Hz,
1 H, 6-Hax), 0.88 [s, 9 H, C(CH3)3], 0.87 [s, 9 H, C(CH3)3], 0.85 [s,
9 H, C(CH3)3], 0.19 (s, 3 H, SiCH3), 0.13 (s, 3 H, SiCH3), 0.09 (s,
3 H, SiCH3), 0.08 (s, 3 H, SiCH3), 0.06 (s, 6 H, 2ϫSiCH3) ppm.
13C NMR (63 MHz, CDCl3): δ = 173.1 (C), 80.7 (C), 79.4 (CH),
77.2 (CH), 70.1 (CH), 67.5 (CH), 51.7 (OCH3), 41.8 (CH2), 26.2
[C(CH3)3], 25.8 [C(CH3)3], 25.7 [2ϫC(CH3)3], 18.5 [C(CH3)3], 18.0
[C(CH3)3], 18.0 [C(CH3)3], –2.5 (SiCH3), –2.8 (SiCH3), –4.2
(m, 1 H, 5-H), 3.90 (t, J = 10.0 Hz, 1 H, 4-H), 3.57 (d, J = 10.0 Hz,
1 H, 2-H), 3.36 (t, J = 9.6 Hz, 1 H, 3-H), 2.28 (dd, J = 4.8, 13.6 Hz,
1 H, 6-Heq), 1.63 (dd, J = 14.0, 13.6 Hz, 1 H, 6-Hax) ppm. 13C
NMR (100 MHz, D2O): δ = 178.3 (C), 79.7 (CH), 78.7 (CH, 1 C),
71.3 (CH), 69.9 (CH), 41.5 (CH ) ppm. IR (KBr): ν = 3398 (O–
˜
2
H), 2119 (NϵN), 1730 (C=O) cm–1. MS (ESI): m/z = 256 [M +
Na]+. HRMS: calcd. for C7H11O6N3Na [M + Na]+ 256.0540; found
256.0540.
Methyl (1S,2S,3R,4S,5S)-3-Azido-1,2-bis(tert-butyldimethyl-
silyloxy)-4,5-dihydroxycyclohexane-1-carboxylate (23): A stirred
solution of ketone 17 (59 mg, 0.12 mmol) in dry methanol (0.6 mL)
was treated at room temperature under an inert gas with sodium
borohydride (5 mg, 0.12 mmol). The resulting mixture was stirred
for 3 h, acidified with H2SO4 (5%) and then diluted with water and
ethyl acetate. The organic phase was separated, and the aqueous
layer was extracted twice with ethyl acetate. All combined organic
extracts were dried (anh. Na2SO4), filtered and concentrated under
reduced pressure. The obtained residue was purified by flash
chromatography, with elution with ethyl acetate/hexane (10:90), to
(SiCH ), –4.5 (2ϫSiCH ), –4.6 (SiCH ) ppm. IR (KBr): ν = 3481
˜
3
3
3
(O–H), 2110 (NϵN), 1738 (C=O) cm–1. MS (CI): m/z = 590 [M +
H]+. HRMS: calcd. for C26H56O6N3Si3 [M + H]+ 590.3477; found
590.3462.
21c: Colourless oil. [α]2D0 = –1.83 (c = 1.2, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 7.61 (m, 4 H, 4ϫArH), 7.41 (m, 6 H,
6ϫArH), 4.18 (m, 2 H, 4-H, 5-H), 3.84 (d, J = 10.0 Hz, 1 H, 2-
H), 3.45 (dd, J = 2.5 and 10.0 Hz, 1 H, 3-H), 3.43 (s, 3 H, OCH3),
2.54 (br. s, 1 H, OH), 2.05 (dd, J = 11.5 and 13.0 Hz, 1 H, 6-Hax),
1.63 (dd, J = 13.0 and 4.5 Hz, 1 H, 6-Heq), 1.07 [s, 9 H, C(CH3)3], afford diol 23 (47 mg, 83%) as a yellow oil that solidified in the
0.85 [s, 9 H, C(CH3)3], 0.79 [s, 9 H, C(CH3)3], 0.13 (s, 3 H, SiCH3),
refridgerator, together with some diol 15 (9 mg, 16%). [α]2D0 = +16.2
0.10 (s, 3 H, SiCH3), 0.06 (s, 3 H, SiCH3), –0.23 (s, 3 H, SiCH3) (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 4.18 (d, J =
ppm. 13C NMR (63 MHz, CDCl3): δ = 172.7 (C), 135.6 (2ϫCH),
135.6 (2ϫCH), 133.2 (C), 132.9 (C), 130.1 (CH), 130.0 (CH), 127.9
(2ϫCH), 127.8 (2 ϫ CH), 80.7 (C), 76.0 (CH), 72.6 (CH), 68.6
3.5 Hz, 1 H, 2-H), 3.98 (t, J = 4.0 Hz, 1 H, 3-H), 3.91 (m, 1 H, 5-
H), 3.77 (m, 1 H, 4-H), 3.71 (s, 3 H, OCH3), 2.17 (m, 2 H, 6-H),
0.91 [s, 9 H, C(CH3)3], 0.84 [s, 9 H, C(CH3)3], 0.14 (s, 3 H, SiCH3),
(CH), 64.7 (CH), 51.4 (OCH3), 38.2 (CH2), 26.9 [C(CH3)3], 26.3 0.08 (s, 3 H, SiCH3), 0.07 (s, 3 H, SiCH3), 0.04 (s, 3 H, SiCH3)
4000
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Eur. J. Org. Chem. 2008, 3991–4003

Cyclic γ-Amino Acids and Triazole Derivatives
ppm. 13C NMR (100 MHz, CDCl3): δ = 172.3 (C), 80.1 (C), 73.4 1.5 Hz, 1 H, 6-Heq), 1.50 (s, 3 H, CH3), 1.28 (s, 3 H, CH3), 0.87 [s,
(CH), 72.4 (CH), 67.5 (CH), 64.9 (CH), 52.1 (CH3), 36.3 (CH2), 18 H, 2ϫC(CH3)3], 0.23 (s, 3 H, SiCH3), 0.15 (s, 3 H, SiCH3), 0.11
25.5 [2ϫC(CH3)3], 18.3 [C(CH3)3], 17.7 [C(CH3)3], –3.6 (SiCH3),
(s, 3 H, SiCH3), 0.09 (s, 3 H, SiCH3) ppm. 13C NMR (63 MHz,
CDCl3): δ = 176.5 (C), 109.2 (C), 81.8 (CH), 76.6 (C), 73.8 (CH),
72.9 (CH), 71.2 (CH), 39.5 (CH2), 26.8 (CH3), 26.0 [C(CH3)3], 25.6
[C(CH3)3], 24.0 (CH3), 18.3 [C(CH3)3], 18.0 [C(CH3)3], –2.5
(SiCH3), –3.2 (SiCH3), –4.6 (SiCH3), –5.1 (SiCH3) ppm. IR (KBr):
–4.2 (SiCH ), –4.4 (SiCH ), –5.2 (SiCH ) ppm. IR (film): ν = 3398
˜
3
3
3
(O–H), 2115 (NϵN), 1741 (C=O) cm–1. MS (CI): m/z = 476 [M +
H]+. HRMS: calcd. for C20H42O6Si2N3 [M + H]+ 476.2612; found
476.2594.
ν = 1801 (C=O) cm–1. MS (CI): m/z = 459 [M + H]+. HRMS: calcd.
˜
(1S,2S,3R,4S,5S)-3-Azido-1,2,4,5-tetrahydroxycyclohexane-1-
carboxylic Acid (3a): A solution of ester 23 (78 mg, 0.16 mmol) in
aqueous TFA (1.6 mL, 50%) was heated at 70 °C for 4 h. The reac-
tion mixture was cooled to room temperature, and the solvent was
removed under reduced pressure. A solution of the crude product
in water was washed with diethyl ether (3ϫ) and lyophilised. The
obtained residue was dissolved in water (1.5 mL), treated with
aqueous lithium hydroxide (0.8 mL, 0.5 ) and stirred at room tem-
perature for 16 h. The aqueous solution was treated with Amberlite
IR-120 until pH = 6 was reached. The resin was filtered and washed
with water. The filtrate and the washings were lyophilised to afford
azido acid 3a (37 mg, 99%) as a beige solid. [α]2D0 = +7.6 (c = 1.8,
for C22H43O6Si2 [M + H]+ 459.2598; found 459.2600. C22H42O6Si2
(458.74): calcd. C 57.60, H 9.23; found C 57.62, H 9.44.
(1S,3R,4R,5S,6S)-1,6-Bis(tert-butyldimethylsilyloxy)-3,4-dihydroxy-
cyclohexane-1,5-carbolactone (26): A solution of isopropylidene
acetal 25 (262 mg, 0.57 mmol) in aqueous acetic acid (9.5 mL,
80%) was heated at 65 °C for 3 h. After the mixture had cooled to
room temperature, water (2 mL) was added, and the resulting mix-
ture was heated at 65 °C for another 24 h. The mixture was cooled
to room temperature, and the solvents were evaporated. The ob-
tained residue was purified by flash chromatography, with elution
with ethyl acetate/hexane [(1) 30:70; (2) 50:50] to afford diol 26
(96 mg, 40 %), together with a monodesilylated derivative of 26
(59 mg, 34%), both as light yellow solids.
1
H2O). H NMR (400 MHz, D2O): δ = 4.03 (m, 4 H, 2-H, 3-H, 4-
H, 5-H), 2.11 (m, 2 H, 6-H) ppm. 13C NMR (100 MHz, D2O): δ =
179.5 (C), 80.2 (C), 75.6 (CH), 74.7 (CH), 70.4 (CH), 66.6 (CH),
26: [α]2D0 = +15.9 (c = 1.0, CHCl3). H NMR (250 MHz, CDCl3):
1
38.3 (CH ) ppm. IR (KBr): ν = 3400 (O–H), 2119 (NϵN), 1716
˜
2
δ = 4.49 (d, J = 5.3 Hz, 1 H, 3-H), 4.33 (s, 1 H, 2-H), 4.21 (m, 1
H, 4-H), 3.93 (m, 1 H, 5-H), 2.89 (d, J = 2.5 Hz, 1 H, OH), 2.43
(d, J = 6.3 Hz, 1 H, OH), 2.20 (dd, J = 12.0, 6.5 Hz, 1 H, 6-Heq),
1.89 (t, J = 12.0 Hz, 1 H, 6-Hax), 0.89 [s, 9 H, C(CH3)3], 0.88 [s, 9
H, C(CH3)3], 0.25 (s, 3 H, SiCH3), 0.17 (s, 3 H, SiCH3), 0.12 (s, 3
H, SiCH3), 0.10 (s, 3 H, SiCH3) ppm. 13C NMR (63 MHz, CDCl3):
δ = 175.7 (C), 82.4 (CH), 76.8 (C), 75.7 (CH), 67.8 (CH), 65.6
(C=O) cm–1. MS (ESI): m/z = 256 [M + Na]+. HRMS: calcd. for
C7H11O6N3Na [M + Na]+ 256.0540; found 256.0535.
(1S,2S,3R,4S,5S)-3-(tert-Butoxycarbonylamino)-1,2,4,5-tetra-
hydroxycyclohexane-1-carboxylic Acid (3b): The experimental pro-
cedure used was as for 1b. Firstly, the acetyl derivative of 3a was
prepared from acid 3a (35 mg, 0.15 mmol) with pyridine (0.4 mL)
and acetic anhydride (0.4 mL). 1H NMR (250 MHz, CD3OD): δ = (CH), 38.8 (CH2 ), 25.9 [C(CH3 )3 ], 25.7 [C(CH3 )3 ], 18.3
5.31 (m, 1 H, 2-H), 5.14 (m, 2 H, 4-H, 5-H), 4.28 (m, 1 H, 3-H), [C(CH3)3], 18.0 [C(CH3)3], –2.5 (SiCH3), –3.0 (SiCH3), –4.5
2.60 (dd, J = 12.8, 3.5 Hz, 1 H, 6eq-H), 2.28 (m, 1 H, 6ax-H), 2.03
(s, 3 H, CH3), 2.01 (s, 6 H, 2ϫCH3), 1.96 (s, 3 H, CH3) ppm. For
the reduction step, di-tert-butyl dicarbonate (44 mg, 0.20 mmol),
platinium(IV) oxide (15 mg) and THF (1.7 mL) were used, whereas
(SiCH ), –5.0 (SiCH ) ppm. IR (KBr): ν = 3501 (O–H), 3453 (O–
˜
3 3
H), 1791 and 1766 (C=O) cm–1. MS (CI): m/z = 419 [M + H]+.
HRMS: calcd. for C19H39O6Si2 [M + H]+ 419.2285; found
419.2281. C19H38O6Si2 (418.67): calcd. C 54.51, H 9.15; found C
for the hydrolysis step, LiOH (1.76 mL) and THF (1.1 mL) were 54.28, H 9.10.
used. Yield: 26 mg, 56%. Amorphous beige solid. [α]2D0 = +2.1 (c =
Sulfate 24: Thionyl chloride (24 µL, 0.33 mmol) was added at 0 °C
1.0, H2O). 1H NMR (250 MHz, D2O): δ = 4.14 (m, 1 H, 2-H),
3.88–3.75 (m, 3 H, 3-H, 4-H, 5-H), 2.07 (m, 2 H, 6-H), 1.41 [s, 9
H, (CH3)3] ppm. 13C NMR (63 MHz, D2O): δ = 177.8 (C), 158.4
(C), 81.9 (C), 77.9 [C(CH3)3], 73.2 (CH), 72.0 (CH), 68.0 (CH),
under argon to a stirred solution of diol 26 (39 mg, 0.09 mmol)
and dry triethylamine (52 µL, 0.37 mmol) in dry dichloromethane
(1.9 mL). The ice bath was removed, and the resulting solution was
stirred at room temperature. After 24 h, the reaction mixture was
cooled to 0 °C, and more thionyl chloride (24 µL, 0.33 mmol) and
dry triethylamine (52 µL, 0.37 mmol) were added. The resulting
mixture was stirred at room temperature for 1 h and was then di-
luted with dichloromethane and water. The organic phase was sep-
54.6 (CH), 35.8 (CH ), 28.3 [C(CH ) ] ppm. IR (KBr): ν = 3400
˜
2
3 3
(O–H), 1693 (C=O), 1614 (C=O) cm–1. MS (ESI): m/z = 330 [M +
Na]+. HRMS: calcd. for C12H21O8NNa [M + Na]+ 330.1159; found
330.1150.
(1S,2S,3S,4R,5R)-1,2-Bis(tert-butyldimethylsilyloxy)-4,5-O-iso- arated, and the aqueous layer was extracted with dichloromethane
propylidenecyclohexane-1,3-carbolactone (25): Dry pyridine
(0.41 mL, 5.07 mmol) and then tert-butyldimethylsilyloxy trifluoro-
sulfonate (1.0 mL, 4.35 mmol) were added at 0 °C under argon to
a stirred solution of the alcohol 13 (500 mg, 1.45 mmol) in dry
dichloromethane (4.8 mL). The resulting mixture was stirred at this
temperature for 30 min and at room temperature for 4 d. The reac-
(3ϫ). All the combined organic extracts were dried (anh. Na2SO4)
and filtered, and the solvents were evaporated. The obtained resi-
due was dissolved in a CCl4/CH3CN mixture (1:1, 1.8 mL) and
cooled to 0 °C. Aqueous NaIO4 (0.9 mL, 0.4 ) and RuCl3·3H2O
(2 mg, 9.3 µmol) were then added. The resulting reaction mixture
was stirred at this temperature for 2 h and was then diluted with
tion mixture was diluted successively with dichloromethane and diethyl ether and water. The organic phase was separated and suc-
water. The aqueous layer was acidified with HCl (10%), and the
organic phase was separated. The aqueous layer was extracted with
dichloromethane (2ϫ). All combined organic extracts were dried
(anh. Na2SO4), filtered and concentrated under reduced pressure.
The obtained residue was purified by flash chromatography, with
elution with ethyl acetate/hexane (10:90), to afford silyl ether 25
cessively washed with water, NaHCO3 (sat.) and NaCl (sat.). The
organic extract was dried (anh. Na2SO4) and filtered, and the sol-
vents were evaporated. The obtained residue was purified by flash
chromatography, with elution with ethyl acetate/hexanes (20:80), to
yield sulfate 24 (44 mg, 99%) as a white amorphous solid. [α]2D0
=
+16.2 (c = 1.0, CHCl3). 1H NMR (250 MHz, CDCl3): δ = 5.15 (m,
2 H, 4-H, 5-H), 4.66 (dd, J = 2.6, 0.9 Hz, 1 H, 3-H), 4.43 (s, 1 H,
1
(662 mg, 99%) as a white solid. [α]2D0 = +10.5 (c = 1.4, CHCl3). H
NMR (250 MHz, CDCl3): δ = 4.44–4.31 (m, 4 H, 2-H, 3-H, 4-H, 2-H), 2.73 (m, 1 H, 6-H), 2.42 (m, 1 H, 6-H), 0.90 [s, 9 H,
5-H), 2.50 (dd, J = 15.3, 7.0 Hz, 1 H, 6-Hax), 2.14 (dd, J = 15.3, C(CH3)3], 0.89 [s, 9 H, C(CH3)3], 0.27 (s, 3 H, SiCH3), 0.18 (s, 3
Eur. J. Org. Chem. 2008, 3991–4003
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4001

V. F. V. Prazeres, L. Castedo, C. González-Bello
FULL PAPER
H, SiCH3), 0.16 (s, 3 H, SiCH3), 0.14 (s, 3 H, SiCH3) ppm. 13C
0.18 mmol), platinium(IV) oxide (14 mg) and THF (1.6 mL) for the
reduction step and LiOH (2.1 mL) and THF (1.3 mL) for the hy-
NMR (63 MHz, CDCl3): δ = 173.8 (C), 78.8 (CH), 77.1 (2ϫCH),
75.2 (C), 73.3 (CH), 37.9 (CH2), 25.9 [C(CH3)3], 25.6 [C(CH3)3], drolysis step. Yield: 27 mg, 63%. Amorphous beige solid. [α]2D0
=
1
18.3 [C(CH3)3], 18.0 [C(CH3)3], –2.5 (SiCH3), –3.1 (SiCH3), –4.5
+13.2 (c = 1.4, H2O). H NMR (400 MHz, D2O): δ = 3.85 (m, 2
H, 2-H, 4-H), 3.70–3.61 (m, 2 H, 3-H, 5-H), 2.10–2.03 (m, 1 H, 6-
Hax) 1.84 (dd, J = 12.4 and 3.2 Hz, 1 H, 6-Heq) and 1.46 [s, 9 H,
C(CH3)3] ppm. 13C NMR (100 MHz, D2O): δ = 182.9 (C), 160.9
(C), 84.0 (C), 78.5 [C(CH3)3], 76.5 (CH), 75.4 (CH), 75.0 (CH),
(SiCH ), –5.1 (SiCH ) ppm. IR (KBr): ν = 1811 (C=O) cm–1. MS
˜
3
3
(CI): m/z = 481 [M + H]+. HRMS: calcd. for C19H37O8SSi2 [M +
H]+ 481.1748; found 481.1735. C19H36O8SSi2 (480.72): calcd. C
47.47, H 7.55; found C 47.56, H 7.73.
53.2 (CH), 37.5 (CH ) and 30.7 [C(CH ) ] ppm. IR (KBr): ν =
˜
2
3 3
(1S,3S,4R,5S,6S)-3-Azido-1,6-bis(tert-butyldimethylsilyloxy)-4-
hydroxycyclohexane-1,5-carbolactone (27): A solution of sulfate 24
(335 mg, 0.70 mmol) in dry DMF (17.5 mL) was treated with so-
dium azide (182 mg, 2.80 mmol) and 15-crown ether (14 µL,
70 µmol), and the resulting mixture was heated at 90 °C for 4 h.
After the mixture had cooled to room temperature, the solvent was
removed under reduced pressure. The obtained residue was dis-
solved in THF (35 mL) and aqueous H2SO4 (50 µL, 70%) and was
then heated at 50 °C for 1 h. After the mixture had cooled to room
temperature, powdered NaHCO3 (642 mg) was added, and the re-
sulting mixture was stirred for 20 min. The suspension was filtered
through a plug of Celite, and the residue was washed with ethyl
acetate. The filtrate and washings were concentrated under reduced
pressure. The obtained residue was purified by flash chromatog-
raphy, with elution with ethyl acetate/hexanes (20:80), to yield azide
27 (269 mg, 87%) as a beige solid. [α]2D0 = +31.8 (c = 1.1, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 4.47 (d, J = 4.0 Hz, 1 H, 3-H),
4.30 (s, 1 H, 2-H), 4.27 (br. s, 1 H, 4-H), 3.95 (d, J = 5.0 Hz, 1 H,
5-H), 3.20 (br. s, 1 H, OH), 2.34 (dd, J = 14.5, 5.5 Hz, 1 H, 6-Hax),
2.14 (d, J = 14.5 Hz, 1 H, CH), 0.89 [s, 18 H, 2ϫC(CH3)3], 0.29
(s, 3 H, SiCH3), 0.19 (s, 3 H, SiCH3), 0.12 (s, 3 H, SiCH3), 0.10 (s,
3 H, SiCH3) ppm. 13C NMR (63 MHz, CDCl3): δ = 176.1 (C), 82.9
(CH), 77.2 (C), 76.1 (CH), 68.6 (CH), 60.5 (CH), 37.7 (CH2), 25.9
[C(CH3)3], 25.6 [C(CH3)3], 18.3 [C(CH3)3], 18.0 [C(CH3)3], –2.5
(SiCH3), –3.0 (SiCH3), –4.5 (SiCH3),–5.0 (SiCH3) ppm. IR (KBr):
3390 (O–H), 1687 (C=O), 1614 (C=O) cm–1. MS (ESI): m/z = 330
[M + Na]+. HRMS: calcd. for C12H21O8NNa [M + Na]+ 330.1159;
found 330.1155.
(1S,2S,3S,4R,5S)-1,2,4,5-Tetrahydroxy-3-(4-phenoxymethyl-1H-
1,2,3-triazol-1-yl)cyclohexane-1-carboxylic Acid (5): A solution of
acid 2 (25 mg, 0.11 mmol) in dry pyridine (0.4 mL) was treated
under argon at 0 °C with acetic anhydride (0.4 mL). The ice bath
was removed, and the resulting mixture was stirred at room tem-
perature for 17 h. The solvents were removed under reduced pres-
sure by successive addition of toluene and acetonitrile and subse-
quent concentration. Drying under vacuum afforded the acetyl-
protected azide 28 (41 mg, 93 %) as a colourless oil. 1H NMR
(250 MHz, CD3OD): δ = 5.53 (m, 1 H, 5-H), 5.23 (d, J = 10.8 Hz,
1 H, 2-H), 5.07 (t, J = 10.8 Hz, 1 H, 4-H), 4.00 (m, 1 H, 3-H), 3.07
(dd, J = 13.0, 5.3 Hz, 1 H, 6-Heq) and 2.06–1.74 (m, 13 H, 4ϫCH3,
6-Hax) ppm. Freshly prepared aqueous sodium ascorbate solution
(8 µL, 1.0 ), followed by aqueous copper(II) sulfate solution
(3.3 µL, 0.32 ), were added to a solution of the previously ob-
tained azide 28 (31 mg, 0.077 mmol) and phenyl propargyl ether
(10 µL, 0.077 mmol) in a tBuOH/water mixture (1:1, 0.4 mL). The
resulting heterogeneous mixture was stirred vigorously for 36 h and
was then diluted with water and ethyl acetate. The organic layer
was separated, and the aqueous phase was extracted twice with
ethyl acetate. All the combined organic extracts were dried (anh.
Na2SO4) and filtered, and the solvents were evaporated. The ob-
tained residue was dissolved in THF (0.8 mL) and was then treated
with aqueous lithium hydroxide (1.2 mL, 0.5 ) and stirred at room
temperature for 30 min. THF was removed under reduced pressure,
and the aqueous solution was then diluted with water and ethyl
acetate. The aqueous layer was separated and washed with ethyl
acetate (3ϫ). The aqueous extract was treated with Amberlite IR-
120 until pH = 6 was reached. The resin was filtered and washed
with water. The filtrate and the washings were lyophilised and puri-
fied by HPLC, performed on a semipreparative Merck LiChro-
CART RP-18 column (10 µm, 250ϫ 10 mm) with a gradient 0–
50% B (35 min) at a flow rate of 5 mLmin–1. The eluents for this
column were: (A) water with 0.1% TFA and (B) acetonitrile with
0.1% TFA. tR = 20 min. Yield: 9.8 mg (35%). Amorphous white
ν = 3396 (O–H), 2122 and 2090 (NϵN), 1760 (C=O) cm–1. MS
˜
(CI): m/z = 444 [M + H]+. HRMS: calcd. for C19H38O5N3Si2 [M
+ H]+ 444.2350; found 444.2350. C19H37N3O5Si2 (443.69): calcd. C
51.43, H 8.41, N 9.47; found C 51.63, H 8.72, N 9.23.
(1S,3S,4R,5S,6S)-3-Azido-1,4,5,6-tetrahydroxycyclohexane-1-
carboxylic Acid (4a): A solution of lactone 27 (256 mg, 0.58 mmol)
in aqueous TFA (5.8 mL, 50%) was heated at 70 °C for 2 h. The
reaction mixture was cooled to room temperature, and the solvent
was removed under reduced pressure. The crude product was dis-
solved in water and washed with diethyl ether (3ϫ). The aqueous
extract was then lyophilised. The obtained residue was dissolved in
water (5.3 mL) and was then treated with aqueous lithium hydrox-
ide (2.9 mL, 0.5 ) and stirred at room temperature for 8 h. The
aqueous solution was diluted with water and treated with Am-
berlite IR-120 until pH = 6 was reached. The resin was filtered and
washed with water. The filtrate was lyophilised to afford azido acid
1
solid. H NMR (250 MHz, D2O): δ = 8.15 (s, 1 H, 5Ј-H), 7.36 (m,
2 H, 2ϫArH), 7.05 (m, 3 H, 3ϫArH), 5.26 (s, 2 H, CH2OPh),
4.94 (dd, J = 10.3, 11.0 Hz, 1 H, 3-H), 4.15 (d, J = 11.0 Hz, 1 H,
2-H), 4.09 (m, 1 H, 5-H), 3.96 (dd, J = 10.3, 9.3 Hz, 1 H, 4-H),
2.36 (dd, J = 13.5, 4.5 Hz, 1 H, 6-Heq), 1.81 (dd, J = 11.8, 13.5 Hz,
1 H, 6-Hax) ppm. 13C NMR (63 MHz, D2O): δ = 175.8 (C), 157.9
(C), 143.9 (C), 130.5 (2 ϫ CH), 126.4 (CH), 122.7 (CH), 116.0
(2ϫCH), 77.0 (C), 76.4 (CH), 75.5 (CH), 69.2 (CH), 67.4 (CH),
1
4a (130 mg, 96%) as a beige solid. [α]2D0 = –4.5 (c = 1.3, H2O). H
NMR (300 MHz, D2O): δ = 4.00 (d, J = 3.0 Hz, 1 H, 2-H), 3.84
(dd, J = 9.6, 3.0 Hz, 1 H, 3-H), 3.71–3.57 (m, 2 H, 4-H, 5-H) and
2.10 (m, 2 H, 6-H) ppm. 13C NMR (75 MHz, D2O): δ = 177.4 (C),
76.4 (C), 73.7 (CH), 73.4 (CH), 71.7 (CH), 61.1 (CH) and 32.6
(CH ) ppm. IR (KBr): ν = 3419 (O–H), 2115 (NϵN) and 1719
˜
2
61.8 (OCH ), 39.2 (CH ) ppm. IR (KBr): ν = 3398 (O–H), 1726
˜
2
2
(C=O) cm–1. MS (ESI): m/z = 256 [M + Na]+. HRMS: calcd. for
(C=O) cm–1. MS (ESI): m/z = 366 [M + H]+. HRMS: calcd. for
C16H20O7N3 [M + H]+ 366.1296; found 366.1307. C16H19N3O7·
3/4H2O (378.85): calcd. C 50.73, H 5.45, N 11.09; found C 50.89,
H 5.32, N 11.18.
C7H11O6N3Na [M + Na]+ 256.0540; found 256.0528.
(1S,2S,3S,4R,5S)-5-(tert-Butoxycarbonylamino)-1,2,3,4-tetra-
hydroxycyclohexane-1-carboxylic Acid (4b): The experimental pro-
cedure used was as for 1b, with use of acid 4a (33 mg, 0.14 mmol),
pyridine (0.4 mL) and acetic anhydride (0.4 mL) for the prepara-
tion of acetyl derivative of 4a, di-tert-butyl dicarbonate (39 mg,
(1S,2S,3S,4R,5S)-1,2,3,4-Tetrahydroxy-5-[4-(phenoxymethyl)-1H-
1,2,3-triazol-1-yl]cyclohexane-1-carboxylic Acid (6): The experimen-
tal procedure used was as for 5. Firstly, acetyl-protected azide 29
4002
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3991–4003

Cyclic γ-Amino Acids and Triazole Derivatives
Fokin, K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41, 2596–
2599.
(43 mg, 0.18 mmol) was prepared as 28 with pyridine (0.4 mL), and
acetic anhydride (0.4 mL). Yield of 29: 72 mg (99%) of a colourless
oil. 1H NMR (250 MHz, CD3OD): δ = 5.38 (br. s, 1 H, 2-H), 5.13–
5.02 (m, 2 H, 3-H, 4-H), 3.66 (m, 1 H, 5-H), 2.57 (dd, J = 14.8,
4.5 Hz, 1 H, 6-Heq), 2.09 (dd, J = 14.8, 13.5 Hz, 1 H, 6-Hax), 2.00
(s, 3 H, CH3), 1.93 (s, 6 H, 2ϫCH3), 1.78 (s, 3 H, CH3) ppm.
Secondly, triazole 6 was prepared in the same way as triazole 5,
with azide 29 (18 mg, 0.046 mmol), phenyl propargyl ether (6 µL,
0.046 mmol), tBuOH/water (0.2 mL), aqueous sodium ascorbate
(5 µL, 1.0 ) and aqueous copper(II) sulfate (2 µL, 0.32 ). For the
hydrolysis step, LiOH (0.72 mL) and THF (0.45 mL) were used.
Yield of 6: 10 mg (60 %). Amorphous beige solid. 1H NMR
(250 MHz, D2O): δ = 8.15 (s, 1 H, 5Ј-H), 7.34 (m, 2 H, 2ϫArH),
7.04 (m, 3 H, 3ϫArH), 5.23 (s, 2 H, CH2OPh), 4.80–4.64 (m, 1 H,
5-H), 4.07 (m, 2 H, 2-H, 4-H), 3.94 (dd, J = 9.8, 3.0 Hz, 1 H, 3-
H), 2.73 (t, J = 14.0 Hz, 1 H, 6-Hax), 2.20 (ddd, J = 14.0, 4.3,
1.3 Hz, 1 H, 6-Heq) ppm. 13C NMR (63 MHz, D2O): δ = 176.1
(C), 157.9 (C), 130.5 (1 C, 2ϫCH), 125.3 (CH), 122.7 (CH), 116.0
(2ϫCH), 76.3 (C), 73.3 (CH), 72.5 (CH), 71.9 (CH), 61.8 (CH2),
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Geometry optimizations and energy calculations were per-
formed with the Gaussian 03W[9] program with the semiempir-
ical AM1 method.
61.3 (CH), 33.4 (CH ) ppm. IR (KBr): ν = 3410 (O–H), 1732
˜
2
(C=O) cm–1. MS (CI): m/z = 366 [M + H]+. HRMS: calcd. for
C16H20O7N3 [M + H]+ 366.1301; found 366.1301.
[8]
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Supporting Information (see footnote on the first page of this arti-
1
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Acknowledgments
This work was supported by the Xunta de Galicia (under projects
PGIDT07PXIB209080PR and GRC2006/132) and by the Minis-
terio de Educación y Cultura (SAF2007-63533). V. F. V. P. thanks
the Portuguese Fundação para a Ciência e a Tecnologia for an
FCT scholarship.
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Published Online: July 11, 2008
Eur. J. Org. Chem. 2008, 3991–4003
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4003