Synthesis of spiroacetal-triazoles as privileged natural product-like scaffolds using click chemistry

Article abstract of DOI:10.1039/b808454h

The elaboration of a 6,6-spiroacetal scaffold to incorporate a triazole unit as a peptide bond surrogate at the anomeric position is described. The novel spiroacetal-triazole hybrid structures were generated via cycloaddition of a spiroacetal azide to a series of alkynes. The spiroacetal framework was constructed via Barbier reaction of bromide 10 with Weinreb amide 11, followed by acid-catalysed deprotection and cyclisation to afford the 6,6-spiroacetal ring system. The resultant ethoxy-spiroacetal 8 was converted to spiroacetal azide 5, which was then elaborated into a series of spiroacetal-triazole derivatives 7.

Full text of DOI:10.1039/b808454h

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Volume 6 | Number 19 | 7 October 2008 | Pages 3441–3628
ISSN 1477-0520
FULL PAPER
Ka Wai Choi and Margaret A. Brimble
Synthesis of spiroacetal-triazoles as
privileged natural product-like scaffolds
using“click chemistry”
1477-0520(2008)6:19;1-E

PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of spiroacetal-triazoles as privileged natural product-like scaffolds
using “click chemistry”†‡
Ka Wai Choi and Margaret A. Brimble*
Received 19th May 2008, Accepted 9th July 2008
First published as an Advance Article on the web 5th August 2008
DOI: 10.1039/b808454h
The elaboration of a 6,6-spiroacetal scaffold to incorporate a triazole unit as a peptide bond surrogate at
the anomeric position is described. The novel spiroacetal-triazole hybrid structures were generated via
cycloaddition of a spiroacetal azide to a series of alkynes. The spiroacetal framework was constructed
via Barbier reaction of bromide 10 with Weinreb amide 11, followed by acid-catalysed deprotection and
cyclisation to afford the 6,6-spiroacetal ring system. The resultant ethoxy-spiroacetal 8 was converted
to spiroacetal azide 5, which was then elaborated into a series of spiroacetal-triazole derivatives 7.
observed biological activity.11,12 The 6,6-spiroacetal unit has also
been used to replace the rigid galactose disaccharide core in a sialyl
Lewis X mimetic 4 (Fig. 1).13
Introduction
Nature has traditionally been the most important source of lead
compounds for the development of new therapeutic agents. Evolu-
tionary selection pressures have resulted in chemical biodiversity
that has been exploited extensively by the pharmaceutical industry.
By modifying a biologically active lead compound, libraries of
structurally similar, but non-natural, synthetic analogues are
then synthesised such that the molecular complexity is kept
to a minimum whilst improvements are made to the desired
pharmacological activity.1
The number of biological targets available for screening has
increased substantially in recent years through a better under-
standing of biological pathways and the successful sequencing of
the human genome.2 Hence, it has become increasingly common
to subject natural products and their synthetic analogues to
broad phenotypic discovery screens to identify any biological
activity that is not found in the original natural product. By
combining biologically active motifs within a natural product-
inspired scaffold system, a library of compounds can be generated
for screening of potential bioactivity.3,4
Fig. 1 Privileged 6,6-spiroacetal structures.11–13
Spiroacetals, in particular 1,7-dioxaspiro[5.5]undecanes, are a
common structural element in many natural products isolated
from a variety of sources that display a wide range of bi-
Several research groups have reported the generation of libraries
based on a 6,6-spiroacetal scaffold. For example, Ley et al.3 and
Porco et al.14 synthesised a series of 6,6-spiroacetal derivatives
ological activities. For example, many simple spiroacetals are
containing three sites for further synthetic elaboration to probe
insect pheromones;5,6 routiennocin is an ionophore antibiotic;7
for biological activity. A structurally diverse 6,6-spiroacetal-based
okadaic acid and tautomycin are protein phosphatase inhibitors;8
library constructed by Waldmann et al.12 resulted in the discovery
of the lead compound 3 as an inhibitor of several important protein
integramycin is a HIV-1 integrase inhibitor;9 the milbemycins
and avermectins are anthelmintic and insecticidal agents5 and the
phosphatases (Fig. 1).
spongistatins are antimitotic agents.10
The 1,4-disubstituted 1,2,3-triazoles (“triazoles”) are used as the
mimics (isosteres) of amide/peptide bonds. Being a rigid linker, a
More importantly, many truncated synthetic spiroacetals de-
rived from more complex spiroacetal containing natural products,
triazole ring system holds the substituents in a similar geometry
such as spiroacetals 1–3, provide the basic pharmacophore for the
and distance to those of an amide as well as providing a com-
parable dipole moment. However, unlike the amide counterpart,
triazoles are stable towards hydrolytic cleavage (especially under
Department of Chemistry, The University of Auckland, 23 Symonds St,
enzymatic conditions), oxidation and reduction.15
Auckland, New Zealand. E-mail: m.brimble@auckland.ac.nz; Fax: +64 9
3737422; Tel: +64 9 3737599
Our research group has a long standing interest in the synthesis
of spiroacetals present in a wide range of biologically significant
compounds.16,17 This synthetic effort has prompted the investiga-
tion of elaborating the 6,6-spiroacetal unit to provide novel diverse
functionality. In particular, we were interested in the chemical
† Dedicated to Professor Andrew B. Holmes on the occasion of his 65th
birthday.
‡ Electronic supplementary information (ESI) available: Experimental
details and characterisation data of triazoles 14a–g and 7a–g. See DOI:
10.1039/b808454h
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attachment of the spiroacetal scaffold to a biologically relevant
1,2,3-triazole unit. Further incorporation of a hydroxymethyl
group on the spiroacetal ring also provides an additional site
for further derivatisation. As a result, the combination of these
important bioactive motifs generates a novel hybrid of function-
ality that can be probed for biological activity. The collection
of spiroacetal-triazoles reported herein provides novel probes to
screen for potential bioactivity in phenotypic assays.
Moreover, these spiroacetal derivatives allow diversification at
the anomeric position, providing spiroacetal-based triazoles in
which the triazole unit acts as an isostere to mimic the biologically
relevant peptide bond. We therefore herein report the synthesis of
a series of spiroacetal-triazoles 7 based on the cycloaddition of
spiroacetal azide 5 to alkynes 6 (Scheme 1).
procedures adapted from the work reported by Taylor et al.18
Lactone 12 was then treated with the aluminium amide
intermediate generated from trimethylaluminium and N,O-
dimethylhydroxylamine in CH2Cl2. Subsequent silylation of the
resultant alcohol 13 afforded Weinreb amide 11 in 85% yield over
two steps. Bromide 10 was readily prepared from tetrahydrofuran
via adaptation of the literature procedure.19
With bromide 10 and Weinreb amide 11 in hand, attention
focused on their union via generation of the Grignard reagent
derived from bromide 10 (Scheme 3). Due to the instability of
the resultant Grignard reagent,20 utilisation of Barbier conditions
was implemented under the reaction conditions that have been
successfully used for related reactions by our research group.17,21
After activation of the magnesium turnings with iodine and 1,2-
dibromoethane, Weinreb amide 11 and bromide 10 were added
Scheme 1 Synthesis of spiroacetal-triazoles 7 based on the cycloaddition
of azide 5 to a range of alkynes 6.
To date, only Ley et al.3 have reported the synthesis of a struc-
turally related spiroacetal-triazole analogue which includes viable
procedures for the synthesis of a series of these triazole derivatives.
The biological screening of the spiroacetal-triazole unit is currently
under evaluation.
Results and discussion
The retrosynthesis adopted for the key spiroacetal-triazole target
7 hinges on disconnection of the anomeric C–N bond linking
the spiroacetal to the triazole motif. Thus, ethoxy-spiroacetal 8
is converted to azide 5 which is then elaborated to a triazole.
Ethoxy-spiroacetal 8 is formed via acid-catalysed deprotection and
cyclisation of ketone 9 which in turn, is available from the Barbier
coupling of bromide 10 with Weinreb amide 11. Weinreb amide 11
is then easily accessed from lactone 12 (Scheme 2).
Scheme 3 Synthesis of spiroacetal azides 5a and 5b. Reagents and condi-
tions: (a) i. N,O-dimethylhydroxylamine hydrochloride, AlMe3, CH2Cl2,
0
DMAP (cat.), CH2Cl2, rt, 3 d, 85% over 2 steps; (c) i. 11, Mg, I2 (cat.),
1,2-dibromoethane, THF, rt, 1 h; ii. 10, 33 ◦C, 2 h, 80%; (d) CSA, aq.
EtOH, rt, 3 h, 86%; (e) TMSN3, TMSOTf, CH2Cl2, −10 ◦C, 3 h, 5a: 36%,
5b: 15%; (f) TMSN3, TMSOTf, CH2Cl2, −10 ◦C, 3 h, 5a: 43%, 5b: 20%.
◦C, 20 min; ii. 12, CH2Cl2, 0 ◦C→rt, 2 h; (b) TBSCl, imidazole,
Preparation of spiroacetal-azide 5
Lactone 12 was prepared from commercially available ethyl 2-
oxocyclopentanecarboxylate in 87% yield over five steps using
Scheme 2 Retrosynthesis of spiroacetal-triazoles 5.
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sequentially and the reaction was triggered with the addition of
iodine. Initially, the reaction afforded ketone 9 in only 42–65%
yield when the reaction temperature was not carefully controlled.
However, it was later found that a higher yield (78–80%) was
obtained when the reaction was conducted under concentrated
conditions with careful control of the temperature to be less than
33 ◦C in order to minimise degradation of Grignard reagent. The
use of magnesium powder was also attempted, but this reagent
only afforded ketone 9 in 12% yield only (Scheme 3).
With the basic spiroacetal skeleton assembled, the carbonyl
cascade cyclisation of ketone 9 to ethoxy-spiroacetal 8 was next
pursued. Similar deprotection and cyclisation sequences have
been used by Mead and Zemribo22 as well as de Greef and
Zard23 to prepare structurally related spiroacetals. After much
experimentation, simultaneous unmasking of the aldehyde and
the secondary alcohol in ketone 9 followed by cyclisation and
subsequent ethoxylation of the resulting lactol was best carried
out using camphorsulfonic acid (CSA) in aqueous ethanol at room
temperature for 3 hours. Ethoxy-spiroacetal 8 was then carefully
separated from the unreacted ketone 9 by flash chromatography.
The crude residue was recycled by subjecting it to the same
cyclisation conditions (CSA in aqueous ethanol) to give 86%
overall yield of ethoxy-spiroacetal 8 after three iterations of
recycling (Scheme 3).
azides 5a and 5b in 42% and 3% yield respectively, over two steps
from ethoxy-spiroacetal 8 (Scheme 3).
NMR analysis of azide 5a revealed a characteristic anomeric
2-H resonance at dH 4.94 ppm (dd, J2ax,3ax 10.8 Hz and J2ax,3eq
2.5 Hz), which indicated that the azide substituent adopted an
equatorial position. A NOESY correlation between 2-H and 8-
H also confirmed the presence of the bis-anomerically stabilised
spiroacetal ring system (Fig. 2). On the other hand, NMR analysis
of azide 5b revealed a characteristic anomeric 2-H resonance
at dH 4.61 ppm (t, J2,3 6.4 Hz), which indicated that the azide
substituent adopted an axial position. In this case, a NOESY
correlation between 5-H and 8-H confirmed the presence of the
mono-anomerically stabilised spiroacetal ring system (Fig. 2). The
characteristic quaternary spirocarbon C-6 in both equatorial azide
5a and axial azide 5b resonated at dC 93.2 ppm.
Preparation of spiroacetal-triazoles 14
In 2001, Sharpless et al.24 proposed the concept of “click chem-
istry” following nature’s lead and assembled a set of powerful,
highly reliable, and selective reactions for the rapid synthesis
of new compounds through carbon–heteroatom linkages. Since
the introduction of this concept, the 1,3-dipolar cycloaddition
of azides to alkynes is the most extensively studied and applied
“click reaction” used. The popularity of this reaction is due
to the versatility of triazoles as chemically stable peptide bond
surrogates and the introduction of the synthetically useful copper-
catalysed azide–alkyne cycloaddition (CuAAC) by Meldal et al.25
and Sharpless et al.26
With azides 5a and 5b in hand, attention next turned to
their subsequent cycloaddition to a range of alkynes in order to
prepare spiroacetal-triazoles 14 (Scheme 4). The cycloaddition of
the major equatorial azide 5a was carried out using a catalytic
quantity of phosphine-stabilised copper(I) salt27 [CuI·P(OEt)3] in
the presence of excess terminal alkynes 6a–d in toluene under reflux
to afford spiroacetal-triazoles 14a–d in excellent yield (83–98%). It
is known that CuAAC only catalyses the cycloaddition of an azide
to a terminal alkyne to afford a 1,4-disubstituted triazole as the
only regioisomer due to the involvement of the copper acetylide
intermediate. This excellent regioselectivity was clearly observed in
the formation of triazoles 14a–d that were prepared using CuAAC
(Table 1, entry 1–4).
NMR analysis of ethoxy-spiroacetal 8 revealed a characteristic
anomeric 2-H resonance at dH 4.83 ppm (dd, J2ax,3ax 10.0 Hz and
J
2ax,3eq 2.3 Hz), which indicated that the ethoxy substituent adopted
an equatorial position. A characteristic quaternary spirocarbon C-
6 resonated at dC 98.1 ppm and a NOESY correlation between 2-H
and 8-H confirmed the presence of the bis-anomerically stabilised
spiroacetal ring system (Fig. 2).
Fig. 2 Structures of azide 5a and 5b showing the anomerically stabilised
spiroacetal rings and their substituents. NOESY correlations are denoted
by arrows.
Conversion of ethoxy-spiroacetal 8 to azide 5 was next per-
formed using TMSOTf and TMSN3 in CH2Cl2 at −10 ◦C to
yield a diastereomeric mixture of equatorial azide 5a and axial
azide 5b. Carefully controlled separation by flash chromatography
afforded equatorial azide 5a and axial azide 5b in 36% and 15%
yield, respectively. Treating pure axial azide 5b with TMSOTf and
TMSN3 in CH2Cl2 at −10 ◦C led to epimerisation of 5b into a
separable 2.2 : 1 mixture of equatorial azide 5a and axial azide
5b in 63% yield. Thus, combination of this epimerisation process
with the initial displacement reaction afforded equatorial and axial
In contrast, the cycloaddition of the major equatorial azide 5a
to the internal alkyne, dimethyl acetylenedicarboxylate (6e), was
promoted thermally using an excess of alkyne 6e in toluene at
110 ◦C, affording spiroacetal-triazoles 14e in good yield (78%,
Table 1, entry 5).
The thermally promoted conditions were also used for the
cycloaddition of azide 5a to trimethylsilyl-substituted alkynes 6f
and 6g to afford spiroacetal-triazoles 14f and 14g in good yield (64–
84%). However, prolonged heating in a sealed tube was required
Scheme 4 Cycloadditions of azides 5a to a range of alkynes under copper(I)-catalysed or thermally-promoted conditions.
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Table 1 Summary of reagents and conditions used for the cycloaddition of azide 5a
Products
Entry
1
Alkynes
Reagents and conditions
a
R1
H
R2
Yield (%)
98
14a
(CH2)2OBn
2
a
14b
H
CH2OH
83
3
4
5
6
7
a
a
b
c
14c
14d
14e
14f
14g
H
Ph
96
H
CO2Et
CO2Me
TMS
TMS
84
CO2Me
H
78
64a(+ 36% 5a)
c
CO2Et
84
Reagents and conditions: (a) CuI·P(OEt)3 (10 mol%), toluene, reflux, 1 h; (b) toluene, reflux, 1 h; (c) toluene, sealed tube, reflux, 2 d.a Azide starting
material 5a was recovered from the cycloaddition due to the high volatility of trimethylsilylacetylene 6f despite using a large excess of the alkyne in a
sealed tube.
for these cycloadditions (Table 1, entry 6 and 7). Although the
cycloaddition of azide 5a to terminal trimethylsilylacetylene (6f,
Table 1, entry 6) can be catalysed by CuAAC, the thermally
promoted conditions were adopted in order to demonstrate the
increased reaction times required compared to the use of CuAAC
and to demonstrate the regio-directing effect of the silyl substituent
on the alkyne.
Fig. 3 The characteristic deshielding of 2ꢀ-H resonance in trisubstituted
triazole 14g was due to the through-space electron withdrawing effect and
anisotropic effect exerted by the neighbouring carbonyl group.
The regio-directing effect of the silyl substituent in alkynes
6f and 6g was clearly observed with 4-trimethylsilyl substituted
triazoles 14f and 14g being obtained as the sole regioisomers from
the cycloadditions (Table 1). This regioselectivity resulted from the
steric bulk exerted by the trimethylsilyl substituent and the ability
of silicon to stabilise a developing partial positive charge on the
alkyne b-carbon in the transition state for the reaction. Mono-
substituted triazole 7f and 1,5-disubstituted triazole 7g were then
obtained upon removal of the 4-trimethylsilyl group in 14f and
14g. A 1,5-disubstituted triazole is a stable isostere of a cis-peptide
bond commonly found in turns and loops of peptide secondary
structures.28
the newly formed axial triazole substituent at C-2ꢀ and the
TBDPS-protected hydroxymethyl substituent at C-8ꢀ destabilised
the resulting triazole 15 leading to degradation and a complex
mixture of products (Scheme 5).
For all the cycloadditions performed using equatorial azide
5a, only the corresponding equatorial triazoles 14a–g resulted
from the reaction with no epimerisation at the anomeric or
the spiroacetal centre being observed as confirmed by NMR
studies. The axial anomeric 2ꢀ-H resonance in spiroacetal-triazole
14g showed characteristic deshielding (dH 6.65 ppm) due to the
through-space electron withdrawing effect and anisotropic effect
exerted by the neighbouring carbonyl group at C-5 of the triazole
ring (Fig. 3).
The cycloaddition of axial azide 5b to alkynes 6a and 6c was
also attempted. However, in these cases, only complex mixtures
were obtained. It was postulated that the steric clash between
Scheme 5 Attempted cycloaddition of azides 5b to alkynes 6a or 6c.
Reagents and conditions: (a) 6a or 6c, CuI·P(OEt)3 (cat.), toluene, reflux,
1 h, complex mixture.
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Deprotection of the silyl ether group in spiroacetal-triazoles 7
However, use of catalytic HCl,30 generated in situ from the addition
of acetyl chloride to methanol, failed to give triazole 7g and only
a complex mixture resulted.
Deprotection of the silyl ether group in spiroacetal-triazoles 14a–
g was effected using a variety of reagents (Scheme 6). Firstly,
desilylation of TBDPS ethers 14a and 14c was effected using TBAF
in the presence of molecular sieves to give triazoles 7a and 7c in
74% and 82% yield, respectively. However, the use of TBAF could
not be extended to the desilylation of TBDPS ethers 14e and 14g,
which only resulted in complex mixtures presumably due to the
basicity of the fluoride reagent used (Table 2).
Conclusion
In conclusion, the elaboration of a 6,6-spiroacetal ring system to
incorporate a triazole unit at the anomeric position together with
a synthetic useful hydroxymethyl group has been successfully ac-
complished. Given the importance of a triazole unit as a practical
isostere/surrogate of a peptide bond, the assembly of a spiroacetal
and a triazole unit demonstrated herein generates a novel series
of spiroacetal-containing peptide bond mimics. The knowledge
gleaned in this synthetic study also provides momentum for future
elaboration of 6,6-spiroacetals to incorporate other biologically
active motifs. In addition to the chemical diversity reflected by this
series of spiroacetal hybrids, compounds prepared in this study can
also be used as probes to screen for potential bioactivity in broad
phenotypic assays.
Scheme 6 Desilylations of spiroacetal-triazoles 14a–g.
Secondly, the less basic reagent, HF·pyridine was used to
successfully effect desilylation of TBDPS ethers 14b and 14d in
70–71% yield. The use of HF·pyridine for the deprotection of
TBDPS ethers 14a proceeded in a comparable yield (72–75%)
to that observed using TBAF (74%). However, these reaction
conditions were found to be too harsh for the deprotection of
TBDPS ethers 14e and 14f, only affording triazoles 7e and 7f in
23–26% yield (Table 2).
Finally, the mild reagent, HF·triethylamine,29 was used to
effect desilylation of the sensitive triazoles 14e–g. Using the
deprotection of TBDPS ether 14a as a trial reaction, desilylation
using HF·triethylamine in THF at room temperature afforded
triazole 7a in 99% yield although a long reaction time was
required (2 days). Satisfied with the high yield obtained for this
reaction, the desilylation of the sensitive triazoles 14e and 14f
using HF·triethylamine was next carried out. Pleasingly, triazoles
7e and 7f were afforded in 69% and 86% yield, respectively. The
4-silyl group in 14f was also simultaneously removed to give the
monosubstituted compound 7f (Table 2).
Experimental
General
Experiments requiring anhydrous conditions were performed
under a dry nitrogen or argon atmosphere using oven- or flame-
dried apparatus and standard techniques in handling air- and/or
moisture-sensitive materials unless otherwise stated. Solvents
used (except for Et2O) for reactions, work-up extractions and
chromatographic purifications were distilled, unless otherwise
stated. Commercial reagents were analytical grade or were purified
by standard procedures prior to use.31 Separation of mixtures
was performed by flash chromatography using Kieselgel S 63–
100 lm (Riedel-de-Hahn) silica gel with the indicated eluent.
Mass spectra were recorded on a VG-70SE mass spectrometer
at a nominal accelerating voltage of 70 eV for low resolution and
at a nominal resolution of 5000 to 10 000 as appropriate for high
resolution. Ionisation was effected using electron impact (EI+),
fast atom bombardment (FAB+) using 3-nitrobenzyl alcohol as
the matrix or chemical ionisation (CI+) using ammonia as a carrier
gas. Major and significant fragments are quoted in the form x (y),
where x is the mass to charge ratio (m/z) and y is the percentage
abundance relative to the base peak (100%). Infrared spectra were
obtained using a Perkin Elmer Spectrum 1000 Fourier Transform
Use of HF·triethylamine was found to be too harsh to effect the
deprotection of 14g and only a complex mixture was obtained.
Subsequently, excess triethylamine was added to buffer the reac-
tion, and gratifyingly, the desired triazole 7g was afforded in 93%
yield (Table 2). The 4-silyl group in 14g was also simultaneously
removed to give the 1,5-disubstituted compound 7g. The use of
non-fluoride based desilylation reagents was also investigated.
Table 2 Summary of reagents and conditions used for the desilylations of spiroacetal-triazoles 14a–g
Products
Yield (%)
Entry
TBDPS ether
R1
R2
(a) TBAF
(b) HF·py
(c) 3HF·NEt3
1
2
3
4
5
6
7
14a
14b
14c
14d
14e
14f
14g
7a
7b
7c
7d
7e
7f
H
H
H
H
CO2Me
H
CO2Et
(CH2)2OBn
CH2OH
Ph
CO2Et
CO2Me
H
74
—
82
—
72–75
71
—
70
23
26
—
99
—
—
—
69
86
93a
c. mixture
—
c. mixture
7g
H
a
˚
Reagents and conditions: (a) TBAF, 3 A molecular sieves, THF, rt, 4 h; (b) HF·pyridine, THF, rt, 18–24 h; (c) 3HF·NEt3, THF, rt, 2–3 d. Excess NEt3
was added to buffer the reaction mixture. A complex mixture resulted when NEt3 was not used.
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Infrared spectrometer as a thin film between sodium chloride
plates. Absorption peaks are reported as wavenumbers (m, cm−1).
NMR spectra were recorded on either a Bruker DRX300 spec-
trophotometer operating at 300 MHz for 1H nuclei and 75 MHz for
13C nuclei, or on a Bruker DRX400 spectrophotometer operating
at 400 MHz for 1H nuclei and 100 MHz for 13C nuclei, at ambient
and TBSCl (1.87 g, 12.4 mmol). After 24 h, a second portion
of TBSCl (170 mg, 1.13 mmol) was added and the mixture
was concentrated in vacuo to half of its volume. After 2 h,
saturated NaHCO3 solution (25 mL) was added. The aqueous
phase was extracted with Et2O (3 × 25 mL) and the combined
organic extracts were dried over MgSO4 and concentrated in
vacuo. Purification by flash chromatography (twice) using hexane–
EtOAc (19 : 1 to 3 : 2) as eluent yielded the title compound 11
(4.80 g, 82% from valerolactone 12 over 2 steps) as a colourless oil
and valerolactone 12 (0.56 g, 14%). HRMS (FAB): found MH+,
544.3273, C30H50NO4Si2 requires 544.3278. mmax (film)/cm−1: 2930
1
temperature. H NMR chemical shifts are reported in parts per
million (ppm) relative to the tetramethylsilane peak (d 0.00 ppm).
1H NMR values are reported as chemical shift d, relative integral,
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quintet; m,
multiplet), coupling constant (J, Hz) and assignment. Coupling
constants were taken directly from the spectra. 13C NMR chemical
shifts are reported in ppm relative to the chloroform peak (d
77.0 ppm). 13C NMR values are reported as chemical shifts d,
multiplicity and assignment. Assignments were made with the aid
of DEPT, COSY, HSQC, HMBC and NOESY experiments.
=
(C–H), 1667 (C O), 1428, 1254 (C–O), 1112 (C–O), 702. dH
t
(400 MHz; CDCl3): −0.08 (3 H, s, OSiMe2 Bu), 0.00 (3 H, s,
t
t
t
OSiMe2 Bu), 0.83 (9 H, s, OSiMe2 Bu), 1.04 (9 H, s, OSiPh2 Bu),
1.45–1.55 (1 H, m, 4-HA), 1.58–1.77 (3 H, m, 3-H and 4-HB),
2.43 (2 H, m, 2-H), 3.17 (3 H, s, NMe), 3.47 (1 H, dd, JAB 10.0
and J6A,5 6.7, 6-HA), 3.57 (1 H, dd, JAB 10.0 and J6B,5 5.1, 6-HB),
3.66 (3 H, s, OMe), 3.68–3.79 (1 H, m, 5-H), 7.34–7.42 (6 H, m,
Ph), 7.64–7.68 (4 H, m, Ph). dC (100 MHz; CDCl3): −4.83 (CH3,
Synthesis towards spiroacetal azides 5a and 5b
6-(tert-Butyldiphenylsilyloxy)-5-hydroxy-N-methoxy-N-
methylhexanamide (13)
t
t
t
OSiMe2 Bu), −4.48 (CH3, OSiMe2 Bu), 18.0 (C, OSiMe2 Bu), 19.2
t
t
(C, OSiPh2 Bu), 20.3 (CH2, C-3), 25.8 (CH3, OSiMe2 Bu), 26.8
t
(CH3, OSiPh2 Bu), 32.3 (CH3 and CH2, NMe and C-2), 34.1 (CH2,
To
a suspension of N,O-dimethylhydroxylamine (2.20 g,
C-4), 61.1 (CH3, OMe), 67.5 (CH2, C-6), 72.6 (CH, C-5), 127.6
22.5 mmol) in anhydrous CH2Cl2 (80 mL) at 0 ◦C was added
dropwise a solution of AlMe3 (11.3 mL, 2.0 mol L−1 in toluene,
22.5 mmol). The mixture was stirred until the solid dissolved. A
solution of valerolactone 12 (3.97 g, 10.8 mmol) in anhydrous
CH2Cl2 (40 mL) was added and the mixture was warmed to room
temperature. After 3 h, the reaction was carefully poured into an
ice-cold 1 : 1 solution mixture of saturated NH4Cl and Rochelle’s
salt (80 mL). The resulting mixture was stirred vigorously for
30 min with warming to room temperature. The aqueous phase
was extracted with Et2O (3 × 60 mL). The combined organic
extracts were dried over MgSO4 and concentrated in vacuo to
yield the crude title compound 13 as a yellow oil (4.85 g, 100%)
that was used in the hydroxyl protection step without further
purification. Purification by flash chromatography was performed
using hexane–EtOAc (7 : 3 to 3 : 2) as eluent to yield the
title compound 13 as a colourless oil. HRMS (CI): found MH+,
430.2415, C24H36NO4Si requires 430.2414. mmax (film)/cm−1: 3430
(CH, Ph), 129.6 (CH, Ph), 133.6 (C, Ph), 133.6 (C, Ph), 135.6
+
=
(CH, Ph), 174.6 (C, C O). m/z (FAB): 544 (MH , 20%), 528
t
(M − Me, 5), 486 (M − Bu, 72), 412 (M − OTBDMS, 39), 217
(25), 209 (50), 197 (45), 193 (30), 147 (23), 135 (100), 73 (98).
8ꢀ-(tert-Butyldimethylsilyloxy)-9ꢀ-(tert-butyldiphenylsilyloxy)-1ꢀ-
(1,3-dioxolan-2-yl)nonan-4ꢀ-one (9)
To a mixture of Mg turnings§ (1.07 g, 44.0 mmol) in THF
(5.0 mL) at room temperature under an atmosphere of argon were
added I2 (1 crystal) and 1,2-dibromoethane (228 lL, 2.64 mmol).
The mixture was stirred until the yellow colour faded. Weinreb
amide 11 (4.79 g, 8.80 mmol) in THF (31 mL) was added to
the above activated magnesium via cannula followed by addition
of bromide 10 (2.87 mL, 17.6 mmol) dropwise. The reaction was
initiated with the addition of I2 (1 crystal) and the interna◦l reaction
temperature was regulated carefully to be less than 33 C. After
1 h, a second portion of bromide 10 (1.44 mL, 8.80 mmol) was
added dropwise. After 1 h, saturated NaHCO3 solution (30 mL)
was added and the aqueous phase was extracted with Et2O (3 ×
50 mL). The combined organic extracts were dried over MgSO4
and concentrated in vacuo. Purification by flash chromatography
using hexane–EtOAc (19 : 1 to 9 : 1) as eluent yielded the title
compound 9 (4.23 g, 80%) as a pale yellow oil. HRMS (CI): found
MH+, 599.3562, C34H55O5Si2 requires 599.3588. mmax (film)/cm−1:
=
br (O–H), 2931 (C–H), 1651 (C O), 1427, 1112 (C–O), 703. dH
(300 MHz; CDCl3): 1.07 (9 H, s, OSiPh2 Bu), 1.47 (2 H, dt, J4,5
t
7.7 and J4,3 6.5, 4-H), 1.62–1.83 (2 H, m, 3-H), 2.43 (2 H, t, J2,3
7.4, 2-H), 2.64 (1 H, br s, OH), 3.16 (3 H, s, NMe), 3.51 (1 H, dd,
JAB 10.0 and J6A,5 7.4, 6-HA), 3.66 (1 H, dd, JAB 10.0 and J6B,5 3.6,
6-HB), 3.66 (3 H, s, OMe), 3.71–3.77 (1 H, m, 5-H), 7.35–7.47 (6
H, m, Ph), 7.63–7.68 (4 H, m, Ph). dC (75 MHz; CDCl3): 19.2 (C,
t
t
OSiPh2 Bu), 20.5 (CH2, C-3), 26.8 (CH3, OSiPh2 Bu), 31.6 (CH2,
C-2), 32.2 (CH3, NMe), 32.4 (CH2, C-4), 61.1 (CH3, OMe), 68.0
=
2930 (C–H), 1714 (C O), 1428, 1254 (C–O), 1112 (C–O), 836, 703.
(CH2, C-6), 71.6 (CH, C-5), 127.7 (CH, Ph), 129.8 (CH, Ph), 133.2
t
dH (300 MHz; CDCl3): −0.08 (3 H, s, OSiMe2 Bu), −0.01 (3 H, s,
+
=
(C, Ph), 135.5 (CH, Ph), 174.3 (C, C O). m/z (CI): 430 (MH ,
t
t
t
OSiMe2 Bu), 0.83 (9 H, s, OSiMe2 Bu), 1.04 (9 H, s, OSiPh2 Bu),
t
38%), 412 (M − OH, 3), 372 (M − Bu, 22), 353 (26), 352 (M −
1.40–1.46 (1 H, m, 7ꢀ-HA), 1.60–1.78 (7 H, m, 1ꢀ-HA, 1ꢀ-HB, 2ꢀ-HA,
Ph, 100), 322 (52), 291 (31), 264 (17), 199 (29), 78 (24).
2ꢀ-HB, 6ꢀ-HA, 6ꢀ-HB and 7ꢀ-HB), 2.38 (2 H, t, J5 ,6 6.9, 5ꢀ-H), 2.45
ꢀ
ꢀ
(2 H, t, J3 ,2 7.1, 3ꢀ-H), 3.45 (1 H, dd, JAB 10.0 and J9 A,8 6.8,
ꢀ
ꢀ
ꢀ
ꢀ
9ꢀ-HA), 3.57 (1 H, dd, JAB 10.0 and J9 B,8 5.0, 9ꢀ-HB), 3.64–3.74 (1
5-(tert-Butyldimethylsilyloxy)-6-(tert-butyldiphenylsilyloxy)-N-
methoxy-N-methylhexanamide (11)
ꢀ
ꢀ
H, m, 8ꢀ-H), 3.81–3.89 (2 H, m, 4-H), 3.89–3.98 (2 H, m, 5-H),
To a solution of crude alcohol 13 (ca. 4.85 g, 10.8 mmol) in
anhydrous CH2Cl2 (50 mL) at room temperature was added
imidazole (1.69 g, 24.9 mmol), DMAP (276 mg, 2.26 mmol)
§ The Mg turnings were pre-washed with aqueous HCl (0.10 mol L−1) and
water then flame-dried in vacuo.
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−10 ◦C was added freshly prepared TMSOTf solution (1.16 mL,
0.70 mol L−1 in CH2Cl2, 811 lmol) dropwise. After 3 h, ice-cold
saturated NaHCO3 solution (3 mL) was added and the mixture
was warmed to room temperature. Saturated NaHCO3 (10 mL)
and CH2Cl2 (10 mL) were added and the aqueous phase was
extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts
were filtered through a pad of silica and concentrated in vacuo.
Purification by flash chromatography using hexane–Et2O–EtOAc
(99 : 1 : 0, 49 : 1 : 0 to 97 : 0 : 3) as eluent yielded the title equatorial
azido-spiroacetal 5a (106 mg, 36%) and axial azido-spiroacetal 5b
(42.9 mg, 15%) as pale yellow oils. Unreacted ethoxy-spiroacetal
8 (13.6 mg, 5%) was also recovered.
ꢀ
4.85 (1 H, t, J2,1 4.4, 2-H), 7.34–7.44 (6 H, m, Ph), 7.64–7.68 (4
t
H, m, Ph). dC (75 MHz; CDCl3): −4.81 (CH3, OSiMe2 Bu), −4.46
(CH3, OSiMe2 Bu), 18.0 (C, OSiMe2 Bu), 18.2 (CH2, C-2ꢀ), 19.2
t
t
(C, OSiPh2 Bu), 19.5 (CH2, C-6ꢀ), 25.8 (CH3, OSiMe2 Bu), 26.9
t
t
(CH3, OSiPh2 Bu), 33.1 (CH2, C-1ꢀ), 33.9 (CH2, C-7ꢀ), 42.2 (CH2,
t
C-3ꢀ), 43.1 (CH2, C-5ꢀ), 64.8 (2 × CH2, C-4 and C-5), 67.5 (CH2,
C-9ꢀ), 72.6 (CH, C-8ꢀ), 104.3 (CH, C-2), 127.6 (CH, Ph), 129.6
=
(CH, Ph), 133.7 (C, Ph), 135.6 (CH, Ph), 210.5 (C, C O). m/z
(CI): 599 (MH+, 17%), 541 (26), 412 (M − OSiMe2 Bu, 100), 343
t
t
(M − OSiPh2 Bu, 11), 211 (27), 197 (16), 149 (20), 135 (24), 121
(36), 99 (40), 91 (20), 78 (37), 73 (94).
(2S*,6S*,8S*)-8-(tert-Butyldiphenylsilyloxymethyl)-2-ethoxy-1,7-
dioxaspiro[5.5]undecane (8)
Epimerisation of axial azido-spiroacetal 5b
To a solution of axial azido-spiroacetal 5b (50 mg, 107 lmol)
and TMSN3 (71 lL, 535 lmol) in anhydrous CH2Cl2 (2.0 mL) at
To a solution of ketone 9 (750 mg, 1.25 mmol) in a 99 : 1 mixture
of EtOH–H2O (15 mL) at room temperature was added (+)-10-
camphorsulfonic acid monohydrate (628 mg, 2.51 mmol) in small
portions. After 3 h, solid NaHCO3 (220 mg, 2.63 mmol) was added
and the mixture was concentrated in vacuo. The resulting thick
yellow oil was dissolved in saturated NaHCO3 solution (10 mL)
and Et2O (10 mL) and the aqueous phase was extracted with
Et2O (3 × 10 mL). The combined organic extracts were dried
over MgSO4 and concentrated in vacuo. Purification by flash
chromatography using hexane–EtOAc (99 : 1, 97 : 3 to 9 : 1)
as eluent yielded the title compound 8 (356 mg, 61%) as a pale
yellow oil and a mixture of starting materials (264 mg). The
recovered starting materials were subjected to the above reaction
cycle several times to yield the title compound 8 (503 mg, 86%
overall yield after 3 cycles) after purification. HRMS (FAB): found
MH+, 467.2618, C28H39O4Si requires 467.2618. mmax (film)/cm−1:
2934 (C–H), 1428, 1221, 1187, 1112 (C–O), 1083 (C–O), 973, 955,
◦
−10 C was added freshly prepared TMSOTf solution (0.2 mL,
0.70 mol L−1 in CH2Cl2, 139 lmol) dropwise. After 3 h, ice-
cold saturated NaHCO3 solution (1.5 mL) was added and the
mixture was warmed to room temperature. Saturated NaHCO3
(2 mL) and CH2Cl2 (2 mL) were added and the aqueous phase was
extracted with CH2Cl2 (3 × 4 mL). The combined organic extracts
were filtered through a pad of silica and concentrated in vacuo.
Purification by flash chromatography using hexane–Et2O–EtOAc
(99 : 1 : 0, 49 : 1 : 0 to 97 : 0 : 3) as eluent yielded the title equatorial
azido-spiroacetal 6a (21.5 mg, 43%) and axial azido-spiroacetal 5b
(10.1 mg, 20%) as pale yellow oils.
Equatorial azido-spiroacetal 5a. HRMS (FAB): found [M −
N3]+, 423.2351, C26H35O3Si requires 423.2356. mmax (film)/cm−1:
2929 (C–H), 2104 (N3), 1428, 1248 (C–O), 1112 (C–O), 702. dH
t
(400 MHz; CDCl3): 1.05 (9 H, s, OSiPh2 Bu), 1.16–1.26 (1 H, m,
t
702. dH (300 MHz; CDCl3): 1.05 (9 H, s, OSiPh2 Bu), 1.17–1.22
9-HA), 1.37–1.48 (3 H, m, 3-HA, 5-HA and 11-HA), 1.58–1.66 (4
H, m, 4-HA, 5-HB or 11-HB, 9-HB, and 10-HA), 1.71–1.77 (2 H, m,
3-HB and 5-HB or 11-HB), 1.90–2.02 (2 H, m, 4-HB and 10-HB),
3.58 (1 H, dd, JAB 10.5 and J8-CH2,8 4.2, 8-CHAHBO), 3.66 (1 H,
dd, JAB 10.5 and J8-CH2,8 6.6, 8-CHAHBO), 3.81–3.87 (2 H, m, 8-H),
4.94 (1 H, dd, J2ax,3ax 10.8 and J2ax,3eq 2.5, 2-Hax), 7.35–7.44 (6 H,
m, Ph), 7.68–7.74 (4 H, m, Ph). dC (75 MHz; CDCl3): 17.8 (CH2,
(1 H, m, 9-HA), 1.26 (3 H, t, JCH3,CH2 7.1, OCH2CH3), 1.33–1.50
(3 H, m, 3-HA, 5-HA and 11-HA), 1.56–1.66 (4 H, m, 4-HA, 5-HB
or 11-HB, 9-HB and 10-HA), 1.71–1.81 (2 H, m, 3-HB and 5-HB
or 11-HB), 1.87–2.06 (2 H, m, 4-HB and 10-HB), 3.53 (1 H, dq,
JAB 9.4 and JCH2,CH3 7.1, OCHAHBCH3), 3.59 (1 H, dd, JAB 10.4
and J8-CH2,8 4.2, 8-CHAHBO), 3.68 (1 H, dd, JAB 10.4 and J8-CH2,8
6.5, 8-CHAHBO), 3.86–3.95 (1 H, m, 8-H), 4.00 (1 H, dq, JAB 9.4
and JCH2,CH3 7.1, OCHAHBCH3), 4.83 (1 H, dd, J2ax,3ax 10.0 and
t
C-4 or C-10), 18.3 (CH2, C-4 or C-10), 19.2 (C, OSiPh2 Bu), 26.7
t
(CH2, C-9), 26.7 (CH3, OSiPh2 Bu), 30.2 (CH2, C-3), 34.4 (CH2,
J
2ax,3eq 2.3, 2-Hax), 7.33–7.46 (6 H, m, Ph), 7.69–7.76 (4 H, m, Ph).
C-5 or C-11), 34.8 (CH2, C-5 or C-11), 67.2 (CH2, 8-CH2O), 71.0
(CH, C-8), 83.2 (CH, C-2), 98.4 (C, C-6), 127.6 (CH, Ph), 127.6
(CH, Ph), 129.6 (CH, Ph), 129.6 (CH, Ph), 133.7 (C, Ph), 135.6
(CH, Ph). m/z (FAB): 423 ([M − N3]+, 13%), 199 (57), 197 (39),
139 (18), 137 (35), 135 (100), 105 (16), 91(17), 75(17).
dC (75 MHz; CDCl3): 15.3 (CH3, OCH2CH3), 17.8 (CH2, C-4 or
t
C-10), 18.5 (CH2, C-4 or C-10), 19.2 (C, OSiPh2 Bu), 26.7 (CH3,
t
OSiPh2 Bu), 27.0 (CH2, C-9), 30.9 (CH2, C-3), 34.8 (CH2, C-5
or C-11), 35.2 (CH2, C-5 or C-11), 64.3 (CH2, OCH2CH3), 67.5
(CH2, 8-CH2O), 70.9 (CH, C-8), 96.6 (CH, C-2), 98.1 (C, C-6),
127.6 (CH, Ph), 127.6 (CH, Ph), 129.5 (CH, Ph), 129.6 (CH, Ph),
133.8 (C, Ph), 133.8 (C, Ph), 135.6 (CH, Ph), 135.7 (CH, Ph). m/z
Axial azido-spiroacetal 5b. HRMS (FAB): found MH+,
466.2513, C26H36N3O3Si requires 466.2526. mmax (film)/cm−1: 2956
(C–H), 2858, 2105 (N3), 1428, 1250 (C–O), 1113 (C–O), 1072, 847,
t
(FAB): 467 (MH+, 3%), 423 (M − OEt, 27), 411 (M − Bu, 10),
t
391 (M − Ph, 11), 365 (25), 207 (33), 199 (65), 197 (47), 167 (22),
702. dH (300 MHz; CDCl3): 1.06 (9 H, s, OSiPh2 Bu), 1.19–1.32 (1
149 (37), 137 (35), 135 (98), 85 (100), 75 (22).
H, m, 9-HA), 1.32–1.44 (1 H, m, 3-HA), 1.53–1.63 (3 H, m, 3-HB,
10-HA and 10-HB), 1.65–1.81 (7 H, m, 4-HA, 4-HB, 5-HA, 5-HB,
9-HB, 11-HA and 11-HB), 3.54 (1 H, dd, JAB 10.5 and J8-CH2,8 4.8,
8-CHAHBO), 3.62 (1 H, dd, JAB 10.5 and J8-CH2,8 5.3, 8-CHAHBO),
3.85–3.94 (2 H, m, 8-H), 4.61 (1 H, t, J2,3 6.4, 2-Heq), 7.35–7.44 (6
H, m, Ph), 7.66–7.74 (4 H, m, Ph). dC (75 MHz; CDCl3): 18.7 (CH2,
C-4), 19.1 (CH2, C-10), 19.3 (C, OSiPhtBu), 26.8 (CH2, C-9), 26.8
(CH3, OSiPhtBu), 32.0 (CH2, C-3), 34.1 (CH2, C-5), 39.8 (CH2,
(2S*,6S*,8S*)-2-Azido-8-(tert-butyldiphenylsilyloxymethyl)-1,7-
dioxaspiro[5.5]undecane (5a) and (2S*,6R*,8S*)-2-azido-8-(tert-
butyldiphenylsilyloxymethyl)-1,7-dioxaspiro[5.5]undecane (5b)
To a solution of ethoxy-spiroacetal 8 (293 mg, 624 lmol) and
TMSN3 (414 lL, 3.12 mmol) in anhydrous CH2Cl2 (9.7 mL) at
3524 | Org. Biomol. Chem., 2008, 6, 3518–3526
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C-11), 67.0 (CH2, 8-CH2O), 73.3 (CH, C-8), 77.8 (CH, C-2), 93.2
(C, C-6), 127.6 (CH, Ph), 129.6 (CH, Ph), 133.6 (C, Ph), 133.7 (C,
Ph), 135.6 (CH, Ph). m/z (FAB): 466 (MH+, 1%), 423 (M − N3,
Method C: Desilylation using 3HF·NEt3. A solution of
TBDPS-protected triazole 14 and 3HF·NEt3 (2.0–3.0 lL per
micromole of triazole) in anhydrous THF (300 lL–1.0 mL) was
stirred at room temperature under an atmosphere of argon. If
the desilylation was not complete within 18 h (TLC), a second
portion of 3HF·NEt3 (2.0–2.5 lL per micromole of triazole) was
added and the mixture was stirred at room temperature for another
18 h. Saturated NaHCO3 solution (4 mL) was added dropwise.
The aqueous phase was extracted with Et2O (4 × 4 mL) and the
combined organic extracts were concentrated in vacuo. Purification
by flash chromatography using the appropriate eluent yielded
hydroxymethyl spiroacetal-triazole 7.
t
2), 239 (SiPh2 Bu, 7), 214 (32), 207 (13), 199 (38), 197 (37), 183
(13), 137 (24), 135 (100), 121 (14), 105 (14).
General procedures for 1,3-dipolar cycloaddition of azide 5a to
alkynes 6
Method A: For terminal alkynes with catalysis by CuI·P(OEt)3.
To a solution of azide 5a and alkyne 6 (50.0–100 lL) in
anhydrous toluene (250–500 lL) under an atmosphere of argon
was added CuI·P(OEt)3 (0.10–0.12 equiv.). The resulting mixture
was heated to reflux for 1 h. After cooling to room temperature,
the mixture was purified directly by flash chromatography using
hexane–EtOAc as eluent to give the spiroacetal containing a 1,4-
disubstituted triazole substituent.
Method D: Desilylation using 3HF·NEt3 and buffered with NEt3.
A solution of TBDPS-protected triazole 14, 3HF·NEt3 (2.0 lL
per micromole of triazole) and NEt3 (2.5 lL per micromole of
triazole) in anhydrous THF (700 lL) was stirred at 40 ◦C for 48 h
under an atmosphere of argon. A second portion of 3HF·NEt3
(1.0 lL micromole of triazole) and NEt3 (1.3 lL per micr◦omole
of triazole) were added and the mixture was stirred at 40 C for
18 h. Saturated NaHCO3 solution (2 mL) was added dropwise.
The aqueous phase was extracted with EtOAc (3 × 3 mL) and the
combined organic extracts were concentrated in vacuo. Purification
by flash chromatography using hexane–EtOAc as eluent yielded
hydroxymethyl spiroacetal-triazole 7.
Method B: For symmetrical internal alkynes. A solution of
azide 5a and alkyne 6 (100 lL) in anhydrous toluene (500 lL) was
heated to reflux for 1 h. The reaction mixture was purified directly
by flash chromatography using hexane–EtOAc as eluent to give the
spiroacetal containing a 1,4,5-trisubstituted triazole substituent.
Method C: For trimethylsilylacetylenes. A solution of azide
5a and trimethylsilylacetylene 6 (50.0–100 lL) in anhydrous
toluene (500 lL) was heated at 110 ◦C in a sealed vessel. If the
cycloaddition was not complete in 18 h (TLC), a second portion of
trimethylsilylacetylene 6 (50.0–100 lL) was added and the mixture
was heated at 110 ◦C overnight. The reaction mixture was purified
directly by flash chromatography using hexane–EtOAc as eluent
to give the spiroacetal containing a 1,4,5-trisubstituted triazole
substituent.
Acknowledgements
The authors thank the New Zealand Tertiary Education Com-
mission for the award of a Bright Future Top Achiever Doctoral
Scholarship and the University of Auckland for the award of a
Doctoral Scholarship to KWC.
References
General procedures for deprotection of silyl protected
spiroacetal-triazoles 14
1 I. Paterson and E. A. Anderson, Science, 2005, 310, 451–453.
2 J. C. Venter, et al., Science, 2001, 291, 1304–1351.
3 G. Zinzalla, L.-G. Milroy and S. V. Ley, Org. Biomol. Chem., 2006, 4,
1977–2002.
4 R. I. Anegundi, V. G. Puranik and S. Hotha, Org. Biomol. Chem., 2008,
6, 779–786.
Method A: Desilylation using TBAF. To a solution of TBDPS-
protected triazole 14 in anhydrous THF (1.0 mL) under an
atmosphere of argon at room temperature was added activated
molecular sieves (0.20 g) and TBAF solution (1.0 mol L−1 in THF,
2.0–10 equiv.). After 1–3 h, saturated NH4Cl solution (1 mL) was
added. The aqueous phase was extracted with Et2O (3 × 2 mL)
and the combined organic extracts were concentrated in vacuo.
Purification by flash chromatography using the appropriate eluent
yielded hydroxymethyl spiroacetal-triazole 7.
5 F. Perron and K. F. Albizati, Chem. Rev., 1989, 89, 1617–1661.
6 W. Francke and W. Kitching, Curr. Org. Chem., 2001, 5, 233–251.
7 U.S. Pat., US 4547523, 1985; W. P. Cullen, et al., J. Ind. Microbiol.,
1988, 2, 349–357; N. R. Kotecha, S. V. Ley and S. Mantegani, Synlett,
1992, 395–399.
8 K. Tachibana, P. J. Scheuer, Y. Tsukitani, H. Kikuchi, D. Van Engen,
J. Clardy, Y. Gopichand and F. J. Schmitz, J. Am. Chem. Soc., 1981,
103, 2469–2471; R. E. Honkanen and T. Golden, Curr. Med. Chem.,
2002, 9, 2055–2075; A. B. Dounay and C. J. Forsyth, Curr. Med. Chem.,
2002, 9, 1939–1980; X. C. Cheng, et al., J. Antibiot., 1987, 40, 907–909;
M. Ubukata, X.-C. Cheng, M. Isobe and K. Isono, J. Chem. Soc.,
Perkin Trans. 1, 1993, 617–624; H. Oikawa, Curr. Med. Chem., 2002, 9,
2033–2054.
Method B: Desilylation using HF·pyridine. To a solution of
TBDPS-protected triazole 14 in anhydrous THF (1.0–2.0 mL) in a
plastic vial under an atmosphere of argon was added HF·pyridine
(1.5–3.4 lL per micromole of triazole) and the mixture was stirred
at room temperature. If the desilylation was not complete within
18 h (TLC), a second portion of HF·pyridine (1.3–2.0 lL per
micromole of triazole) was added and the mixture was stirred at
room temperature for another 18 h. Saturated NaHCO3 solution
(4 mL) was added dropwise. The aqueous phase was extracted
with Et2O (4 × 4 mL) and the combined organic extracts
were concentrated in vacuo. Purification by flash chromatography
using the appropriate eluent yielded hydroxymethyl spiroacetal-
triazole 7.
9 S. B. Singh, D. L. Zink, B. Heimbach, O. Genilloud, A. Teran, K. C.
Silverman, R. B. Lingham, P. Felock and D. J. Hazuda, Org. Lett.,
2002, 4, 1123–1126.
10 G. R. Pettit, Z. A. Cichacz, F. Gao, C. L. Herald, M. R. Boyd, J. M.
Schmidt and J. N. A. Hooper, J. Org. Chem., 1993, 58, 1302–1304;
J. S. Guo, K. J. Duffy, K. L. Stevens, P. I. Dalko, R. M. Roth, M. M.
Hayward and Y. Kishi, Angew. Chem., Int. Ed., 1998, 37, 187–192;
M. M. Hayward, R. M. Roth, K. J. Duffy, P. I. Dalko, K. L. Stevens,
J. S. Guo and Y. Kishi, Angew. Chem., Int. Ed., 1998, 37, 192–196.
11 F. M. Uckun, Curr. Pharm. Des., 2001, 7, 1627–1639; F. M. Uckun,
C. Mao, A. O. Vassilev, H. Huang and S.-T. Jan, Bioorg. Med. Chem.
Lett., 2000, 10, 541–545; H. Huang, C. Mao, S.-T. Jan and F. M.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3518–3526 | 3525
©

Uckun, Tetrahedron Lett., 2000, 41, 1699–1702; S. Mitsuhashi, H.
Shima, T. Kawamura, K. Kikuchi, M. Oikawa, A. Ichihara and H.
Oikawa, Bioorg. Med. Chem. Lett., 1999, 9, 2007–2012.
3230–3238; M. Segi, M. Takahashi, T. Nakajima, S. Suga and N.
Sonoda, Synth. Commun., 1989, 19, 2431–2439; D. Wenkert, S. B.
Ferguson, B. Porter, A. Qvarnstrom and A. T. McPhail, J. Org. Chem.,
1985, 50, 4114–4119.
12 O. Barun, K. Kumar, S. Sommer, A. Langerak, T. U. Mayer, O. Mu¨ller
and H. Waldmann, Eur. J. Org. Chem., 2005, 4773–4788.
13 A. A. Birkbeck, S. V. Ley and J. C. Prodger, Bioorg. Med. Chem. Lett.,
1995, 5, 2637–2642.
14 B. A. Kulkarni, G. P. Roth, E. Lobkovsky and J. A. Porco, Jr., J. Comb.
Chem., 2002, 4, 56–72.
15 H. C. Kolb and K. B. Sharpless, Drug Discovery Today, 2003, 8, 1128–
1137; V. D. Bock, H. Hiemstra and J. H. van Maarseveen, Eur. J. Org.
Chem., 2006, 51–68; W. S. Horne, M. K. Yadav, C. D. Stout and M. R.
Ghadiri, J. Am. Chem. Soc., 2004, 126, 15366–15367.
20 C. P. Forbes, G. L. Wenteler and A. Wiechers, J. Chem. Soc., Perkin
Trans. 1, 1977, 2353–2355.
21 M. A. Brimble and D. P. Furkert, Org. Biomol. Chem., 2004, 2, 3573–
3583.
22 K. T. Mead and R. Zemribo, Synlett, 1996, 1063–1064.
23 M. de Greef and S. Z. Zard, Org. Lett., 2007, 9, 1773–
1776.
24 H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int. Ed.,
2001, 40, 2004–2021.
16 J. E. Robinson and M. A. Brimble, Chem. Commun., 2005, 1560–1562;
R. Halim, M. A. Brimble and J. Merten, Org. Biomol. Chem., 2006, 4,
1387–1399; M. A. Brimble, C. L. Flowers, M. Trzoss and K. Y. Tsang,
Tetrahedron, 2006, 62, 5883–5896; M. A. Brimble and C. J. Bryant,
Chem. Commun., 2006, 4506–4508; M. A. Brimble and C. V. Burgess,
Synthesis, 2007, 754–760; M. A. Brimble and C. J. Bryant, Org. Biomol.
Chem., 2007, 5, 2858–2866; J. E. Robinson and M. A. Brimble, Org.
Biomol. Chem., 2007, 5, 2572–2582; K. Y. Tsang and M. A. Brimble,
Tetrahedron, 2007, 63, 6015–6034.
17 K. Meilert and M. A. Brimble, Org. Lett., 2005, 7, 3497–3500; K.
Meilert and M. A. Brimble, Org. Biomol. Chem., 2006, 4, 2184–2192.
18 R. J. K. Taylor, K. Wiggins and D. H. Robinson, Synthesis, 1990, 589–
590.
25 C. W. Tornøe, C. Christensen and M. Meldal, J. Org. Chem., 2002, 67,
3057–3064.
26 V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless, Angew.
Chem., Int. Ed., 2002, 41, 2596–2599.
27 J. M. Casas-Solvas, A. Vargas-Berenguel, L. F. Capitan-Vallvey and F.
Santoyo-Gonzalez, Org. Lett., 2004, 6, 3687–3690.
28 S. J. Coats, J. S. Link, D. Gauthier and D. J. Hlasta, Org. Lett., 2005, 7,
1469–1472.
29 M. C. Pirrung, S. W. Shuey, D. C. Lever and L. Fallon, Bioorg. Med.
Chem. Lett., 1994, 4, 1345–1346; D. K. Ress, S. N. Baytas, Q. Wang,
E. M. Munoz, K. Tokuzoki, H. Tomiyama and R. J. Linhardt, J. Org.
Chem., 2005, 70, 8197–8200.
30 A. T. Khan and E. Mondal, Synlett, 2003, 694–698.
31 W. L. F. Armarego and D. D. Perrin, Purification of Laboratory
Chemicals, Pergamon, Oxford, UK, 4th edn, 1997.
19 P. C. Wa¨lchli and C. H. Eugster, Helv. Chim. Acta, 1978, 61, 885–898;
E. Vedejs, M. J. Arnost and J. P. Hagen, J. Org. Chem., 1979, 44,
3526 | Org. Biomol. Chem., 2008, 6, 3518–3526
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