Enantioselective synthesis of C-linked spiroacetal-triazoles as privileged natural product-like scaffolds

Article abstract of DOI:10.1039/c2ob06802h

The enantioselective synthesis of novel C-linked spiroacetal-triazoles 10 is reported. The key step involves reaction of acetylenic spiroacetal 11 with several azides by the Copper-Catalysed Azide-Alkyne Cycloaddition (CuAAC). The biologically privileged spiroacetal scaffold 11 was prepared from silyl-protected Weinreb amide 19 using several reliable Grignard additions and a highly diastereoselective enzymatic kinetic resolution.

Full text of DOI:10.1039/c2ob06802h

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PAPER
Enantioselective synthesis of C-linked spiroacetal-triazoles as privileged
natural product-like scaffolds†‡
Jui Thiang Brian Kueh, Ka Wai Choi and Margaret A. Brimble*
Received 27th October 2011, Accepted 30th November 2011
DOI: 10.1039/c2ob06802h
The enantioselective synthesis of novel C-linked spiroacetal-triazoles 10 is reported. The key step
involves reaction of acetylenic spiroacetal 11 with several azides by the Copper-Catalysed Azide–Alkyne
Cycloaddition (CuAAC). The biologically privileged spiroacetal scaffold 11 was prepared from
silyl-protected Weinreb amide 19 using several reliable Grignard additions and a highly diastereoselective
enzymatic kinetic resolution.
Introduction
Nature continues to be an important source of lead compounds
for the development of new therapeutic agents, with approxi-
mately 63% of clinically used drugs derived directly or indirectly
from natural products.1 The extreme evolutionary selection pro-
cesses experienced in nature over billions of years results in
complex bioactive natural products with diverse structures that
are optimised to interact with various biological systems. The
potency and structural diversity of natural products is actively
exploited by the pharmaceutical industry for the development of
new therapeutic agents.2
Spiroacetals, in particular 6,6-spiroacetals, are common struc-
tural motifs found in many natural products that exhibit a wide
range of biological activities. For example, simple 6,6-spiroace-
tals function as insect pheromones,3 spongistatin 1 exhibits anti-
motitic activity,4 alotaketal A activates the cAMP cell signalling
pathway,5 the avermectins are anthelmintic and insecticidal
agents,6 and both the bistramides and virgatolides have potential
anti-tumour activity.7
Truncated synthetic spiroacetals derived from complex natural
products have also received considerable interest. These trun-
cated spiroacetals retain the basic spiroacetal pharmacophore and
other essential elements required for biological activity, while
reducing structural complexity for simpler and faster synthesis.
Examples of truncated analogues include the bistramide A ana-
logue 1, SPIKET-P 2, and the simple 6,6-spiroacetals 3 and 4
(Fig. 1).8
Fig. 1 Biologically privileged spiroacetal analogues.8
School of Chemical Sciences, The University of Auckland, 23 Symonds
Street, Auckland, New Zealand. E-mail: m.brimble@auckland.ac.nz;
Fax: +64 9 3737422; Tel: +64 9 9238259
1,4-Disubstituted 1,2,3-triazoles have been used as bioisos-
teres of trans-peptide bonds as both moieties have planar geome-
tries and share similar dipole moments. A key difference is that
triazoles are more stable towards enzymatic and chemical
modification than the corresponding parent peptide bonds.9 The
2,3-diethanthioribonucleoside analogues 5a,b10a and the dimeric
nucleoside analogue 610b feature triazole linkers and were found
†Electronic supplementary information (ESI) available: Experimental
details and characterisation data for compounds 11, 17–19, 23–26,
azides 27a–h, and spiroacetal-triazoles 28a–h and 10a–h. 1H and 13C
NMR spectra of all new compounds. See DOI: 10.1039/c2ob06802h
‡This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5993–6002 | 5993

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cleavage over the N-linked spiroacetal-triazole series.14 By com-
bining the biologically privileged 6,6-spiroacetal scaffold with
triazole moieties, novel hybrid molecules can then be probed for
biological activity.
Results and discussion
Initial synthetic strategy
Our initial retrosynthetic strategy for the C-linked spiroacetal-
triazoles 10 is based on the CuAAC of acetylenic spiroacetal 11
with various azides. This late stage diversification is envisaged
to enable facile access to a broad range of novel structures. Acet-
ylenic spiroacetal 11 can be prepared by the Lewis acid mediated
C-glycosidation14 of ethoxy-spiroacetal 12, which in turn can be
prepared from δ-valerolactone 13 using procedures previously
reported by our group (Scheme 2).12a
Fig. 2 Bioisosteric triazole analogues.10
to exhibit activity against HeLa tumour cells and HIV-1 respect-
ively (Fig. 2).
Ley et al.11 recently reported the synthesis of a library of
structurally related spiroacetal hybrids that bear triazole, amino
acid and carbamate moieties. Subsequent biological evaluation
of these hybrid compounds revealed that the spiroacetal-
carbamate hybrids had high in vitro apoptotic activity against
chronic lymphocytic leukemia (CLL) cells.11b
Our research group has a long-standing interest in the syn-
thesis of spiroacetals present in a wide range of biologically
active compounds.12 Recent efforts culminated in the synthesis
of racemic N-linked hydroxymethyl spiroacetal-triazole ana-
logues 912a via the Copper-Catalysed Azide–Alkyne Cyclo-
addition (CuAAC)13 or the Huisgen 1,3-dipolar cycloaddition of
azido-spiroacetal 7 and substituted alkynes 8 (Scheme 1).
Scheme 2 First generation retrosynthesis of C-linked spiroacetal-tria-
zoles 10.
First generation synthesis
To test the favourable prospect of C-glycosidation, racemic
δ-valerolactone 13 was prepared from commercially available
ethyl 2-oxocyclopentanecarboxylate in 57% yield over five steps
using procedures adapted from Taylor et al.15 δ-Valerolactone 13
was then converted to ethoxy-spiroacetal 12 in 26% yield over
four steps employing procedures recently reported by our
research group (Scheme 3).12a With ethoxy-spiroacetal 12 in
hand, attention turned to the installation of the alkyne moiety by
C-glycosidation of the anomeric ethoxy group.14 Disappoint-
ingly, only trace quantities of the desired silyl-protected acetyle-
nic spiroacetal 16 were obtained upon treatment of a mixture of
ethoxy-spiroacetal 12 and silyl-protected ethynyltributylstannane
15 with trimethylsilyl trifluoromethanesulfonate (TMSOTf) in
CH2Cl2 at −78 °C.16 It was possible that the poor leaving group
ability of the ethoxy group hindered installation of the alkyne
moiety. Based on this idea, ethoxy-spiroacetal 12 was treated
with camphorsulfonic acid (CSA) and the resulting lactol was
acetylated12b to afford the more reactive acetoxy-spiroacetal 14.
Scheme 1 Synthesis of N-linked spiroacetal-triazoles by Brimble
et al.12a Reagents and conditions: (a) 8a–d, CuI·P(OEt)3 (cat.), toluene,
reflux, 83–98% or 8e–g, toluene, reflux, 64–84%; (b) then 3HF·NEt3 or
HF·pyridine or TBAF, 69–99%.
As part of our on-going studies to increase chemical diversity
utilizing spiroacetal and triazole moieties, we decided to embark
on the enantioselective synthesis of C-linked hydroxymethyl
spiroacetal-triazoles 10, wherein the anomeric C-linkage is
anticipated to provide increased stability towards hydrolytic
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Preparation of acetylenic spiroacetal 11
The synthesis of acetylenic spiroacetal 11 is outlined in
Scheme 5. Commerically available (R)-(+)-glycidol (21) was
converted to (S)-valerolactone 13 by literature procedures in
40% yield over four steps.17 (S)-Valerolactone 13 was then con-
verted to Weinreb amide 22 employing N,O-dimethylhydro-
xylamine hydrochloride (HCl·HN(CH3)OCH3) followed by
protection using TBDMSCl to give silyl-protected Weinreb
amide 19.12a Reaction of 19 with the Grignard reagent prepared
from 5-bromo-1-pentene18 afforded ketone 23 in 79% yield.
Subsequent protection of ketone 23 via bismuth(III) catalysed
acetalisation with ethylene glycol,19 followed by ozonolysis of
the resultant alkene 1820 afforded aldehyde 24 in 59% yield
over 2 steps. Attempts at the direct asymmetric alkynylation of
aldehyde 24 with trimethylsilylacetylene in the presence of
stoichiometric quantities of NEt3, (+)-N-methylephedrine, and
Zn(OTf)2,21 proved unsuccessful with only starting material
being recovered. Nonetheless, addition of ethynyl magnesium
bromide to aldehyde 24 furnished alkynol 17a : 17b as an in-
separable, 1 : 1 mixture of diastereomers.
Scheme 3 First generation synthesis of acetylenic spiroacetal 16.
Reagents and conditions: (a) CSA, aq. THF, 40 °C, 18 h; (b) Ac2O,
DMAP (cat.), NEt3, CH2Cl2, RT, 4 h, 44% over 2 steps; (c) TMSOTf,
15, CH2Cl2, −78 °C, 3.5 h, trace.
An oxidation/asymmetric reduction sequence was then investi-
gated to obtain the desired (3S,11S) stereochemistry in alkynol
17a from the mixture of alkynols 17a : 17b. Heating alkynols
17a : 17b with 2-iodoxybenzoic acid (IBX) in DMSO at 40 °C
furnished ynone 26 in 96% yield.22 A range of asymmetric redu-
cing agents and reaction conditions were then evaluated as
summarised in Table 1.23 The use of alpine borane,23a CBS cata-
Unfortunately, despite screening various Lewis acids and reac-
tion conditions,16 only trace quantities of protected acetylenic
spiroacetal 16 were obtained upon treatment of acetoxy-spiroace-
tal 14 with TMSOTf and silyl-protected ethynyltributylstannane
15 in CH2Cl2 at −78 °C.
23c
lysts,23b and TarB-NO2 only afforded alkynol 17 in low dia-
stereomeric excess or resulted in decomposition of the starting
material. After much investigation, it was revealed that the
(S)-CBS-Me catalyst and BH3·diethylaniline in THF at 0 °C
gave the best overall result with alkynol 17a : 17b obtained in
88% yield and 67% d.e.23b,24 Treating the diastereo-enriched
mixture of 17a : 17b with CSA furnished acetylenic spiroacetal
as a mixture of isomers that were difficult to separate by flash
chromatography, thus indicating that 67% d.e. was insufficient to
direct spirocyclisation of alkynols 17a : 17b to access exclusively
the desired bis-anomerically stabilised acetylenic spiroacetal 11.
Gratifyingly, Novozyme-435 promoted enzymatic kinetic resolu-
tion converted a mixture of alkynols 17a : 17b to (3S,11S)-
acetate 25 and the unreacted alkynol 17b (Scheme 5).25 Facile
Second generation synthesis
With the first generation synthesis proving unsuccessful, the syn-
thesis was revised such that the alkyne moiety was installed
prior to spirocyclisation (Scheme 4). Acetylenic spiroacetal 11
could be formed via acid-catalysed spirocyclisation of linear
alkynol 17 which is obtained by oxidative cleavage of alkene 18
and addition of ethynylmagnesium bromide to the resulting alde-
hyde. Alkene 18 in turn is obtained by addition of the Grignard
reagent formed from bromide 20 to Weinreb amide 19. Finally,
19 is available from known chiral δ-valerolactone 13.17
Scheme 4 Retrosynthesis of C-linked spiroacetal-triazoles 10.
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Scheme 5 Synthesis of acetylenic spiroacetal 11. Reagents and conditions: (a) HCl·HN(CH3)OCH3, Al(CH3)3, CH2Cl2, 0 °C to RT, 3 h; (b)
TBDMSCl, DMAP, imidazole, CH2,Cl2, 40 °C, 24 h, 78% over two steps; (c) 5-bromo-1-pentene, Mg, I2, Et2O, 0 °C, 3 h, 79%; (d) ethylene glycol,
Bi(OTf)3, (EtO)3CH, RT, 1.25 h; (e) O3, NaHCO3, Sudan III, CH2Cl2, −78 °C, NEt3, 0.5 h, 59% over 2 steps; (f) ethynylmagnesium bromide, THF,
0 °C, 2 h, 73%; (g) lipase acrylic resin (Novozyme 435), vinyl acetate, hexanes, microwave reactor (50 W), 50 °C, 1 h; (h) K2CO3, CH3OH, RT,
20 min, 30% (90–96% d.e.) over 2 steps; (i) CSA, aq. EtOH, RT, 3 h, 75%.
Scheme 6 Asymmetric reduction of ynone 26 to alkynol 17a : 17b. Reagents and conditions: (a) IBX, DMSO, 40 °C, 2.5 h, 96%; (b) See Table 1
for results.
Table 1 Summary of reagents and conditions for the asymmetric reductions of ynone 26 (Scheme 6)
Entry
Reductanta
Solvent
Reaction conditions
% Yield of 17b (% d.e.)b,c
1
2
3
4
5
6
7
8
(S)-Alpine Borane
D-TarB-NO2, NaBH4
D-TarB-NO2, LiBH4
THF
THF
THF
THF
THF
THF
THF
Toluene/THF
EtNO2
EtNO2
THF
−78 °C to RT, 7.5 h
−78 °C to RT, overnight
0 °C to RT, 2.5 h
RT, 10 min
0 °C, 40 min
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
70 (69)
Decomposition
56 (2)
Decomposition
32 (20)
(S)-CBS-Me, BH3·S(CH3)2
(S)-CBS-Me, BH3·S(CH3)2
(S)-CBS-Me, BH3·S(CH3)2
(S)-CBS-Me, catecholborane
(S)-CBS-o-tolyl, BH3·S(CH3)2
(S)-CBS-Me, catecholborane
(S)-CBS-Me, BH3·S(CH3)2
(S)-CBS-Me, BH3·diethylaniline
−30 °C, 20 min
−78 °C to 0 °C, 6 h, then RT, overnight
−40 °C, 3 h
9
10
11
−78 °C to 0 °C, 6 h, then RT, overnight
−78 °C 1 h, then RT, overnight
0 °C, 2.5 h
88 (67)
a Reactions were performed with 1.0–2.0 equiv. of catalyst and reductant. b Yields of alkynol 17 isolated after flash chromatography. c % d.e. were
obtained by Mosher ester analysis. No attempt was made to establish the absolute stereochemistry of 17.
basic hydrolysis of acetate 25 gave 17a in 90–96% d.e.,24 and
Preparation of spiroacetal-triazoles 26
acidic spirocyclisation with CSA12a furnished the required acety-
With acetylenic spiroacetal 11 in hand, attention turned to the
CuAAC with various azides.12a,26 A mixture of acetylenic
spiroacetal 11, azide and catalytic quantities of the copper(I) salt,
lenic spiroacetal 11 in 75% yield.
The stereochemistry of acetylenic spiroacetal 11 was
confirmed by NMR analysis. A distinct resonance at δH
27
3
3
CuI·P(OEt)3 were heated to reflux in toluene for one hour to
4.53 ppm for the anomeric proton, 8–H (dt, J8,9ax 11.4, J8,9eq
4
afford the triazole analogues 28 as single regioisomers (Table 2).
Moderate to good yields were obtained for the CuAAC of spiroa-
cetal 11 with aliphatic azides 27a–e (entries 1–5). CuAAC
of spiroacetal 11 with aryl azides 27f–h also gave the
2.6, and J8,2′ 2.3 Hz), established that the alkyne substituent
adopted an equatorial position. In addition, an nOe correlation
observed between 2–H and 8–H, confirmed formation of the bis-
anomerically stabilised spiroacetal system.
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Scheme 7 CuAAC of acetylenic spiroacetal 11 to azides 27 followed by desilylation of TBDPS-protected spiroacetal-triazoles 28. See Table 2 for
results.
Table 2 Summary of CuAAC and desilylation of C-Linked Spiroacetal-Triazole Analogues (Scheme 7)
CuAAC yield
28a–h
Desilylation yield
10a–h
Entry CuAAC producta
1
Desilylation product
99
58
55
57
78
85
54
52b
63
38
2
3
4
5
6
81
59
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Table 2 (Contd.)
CuAAC yield
28a–h
Desilylation yield
10a–h
Entry CuAAC producta
7
Desilylation product
65
99
8
75
67
a Azides 27a, b, e–h were prepared by literature procedures.26 Azide 27c was prepared from 11-bromoundec-1-ene by Wacker oxidation and
subsequent azide substitution. Azide 27d was prepared by tosylation and azide displacement of the corresponding silyl protected alcohol using
standard procedures.26a b Alternatively, desilylation of 28c using TBAF, 3 Å mol. sieves, THF, RT, 2 h gave 10c in 14% yield.
corresponding triazole analogues in moderate yields (entries
6–8). Further attempts were made to extend the scope of the
CuAAC of 11 to free acids, alcohols and simple amino acids.
However, the reaction of 11 with 4-azidobutyric acid, 6-azido-
hexanoic acid, 2-azidobenzoic acid and 2-azidophenol using the
CuAAC conditions developed gave only trace quantities of the
desired triazole products (not shown), whereas no reaction was
observed between 11 and N-Fmoc-protected azido alanine with a
catalytic quantity of CuI·P(OEt)3 after one hour of reflux in a
t-BuOH–toluene solvent mixture.28 It was possible that Cu(I)
complexed with the free acid and alcohol groups of the respect-
ive azides, thus preventing the formation of the requisite copper
acetylide, a key intermediate in the proposed CuAAC mechan-
ism.29 In addition, it was postulated that steric hindrance caused
by the close proximity of the azide moiety to the acid or alcohol
groups was preventing 2-azidobenzoic acid and 2-azidophenol
from participating in CuAAC with 11.
Conclusion
In conclusion, an enantioselective synthesis of novel bis-anom-
erically stabilised 6,6-spiroacetal-triazoles bearing a hydroxy-
methyl group has been completed. CuAAC of acetylenic
spiroacetal 11 with various azides allows access to a chemically
diverse set of analogues that can be probed for bioactivity in
broad phenotypic assays. Incorporation of the triazole moiety at
the anomeric position of the spiroacetal ring system via a chemi-
cally stable carbon–carbon bond, along with the inherent bioi-
sosteric property of triazoles as hydrolytically-resistant peptide
bond mimetics, could confer desirable biological properties to
these spiroacetal hybrids. The methodology developed in this
study also provides the platform for future research involving the
incorporation of other bioactive motifs to the 6,6-spiroacetal
scaffold.
Experimental
General
Deprotection of the silyl ether group in spiroacetal-triazoles 26
Experiments requiring anhydrous conditions were performed
under a dry nitrogen or argon atmosphere using apparatus heated
and dried under vacuum and standard techniques in handling air-
and/or moisture-sensitive materials unless otherwise stated. Sol-
vents used for reactions and chromatographic purifications were
distilled, unless otherwise stated. Commercial reagents were
analytical grade or were purified by standard procedures prior to
use.32 Reactions were monitored by thin layer chromatography
(TLC) carried out on 0.2 mm Kieselgel F254 (Merck) silica gel
plates using UV light as a visualising agent and then stained and
developed with heat using either vanillin in ethanolic sulfuric
acid, ammonium heptamolybdate and cerium sulfate in aqueous
sulfuric acid or potassium permanganate and potassium
With several spiroacetal-triazoles prepared, the final step
involved cleavage of the silyl ether group. Desilylation of spiroa-
cetal-triazoles 28a–h with trihydrogen fluoride-triethylamine
complex (3HF·NEt3),12a,30 furnished the C-linked hydroxy-
methyl spiroacetal-triazole analogues 10a–h in satisfactory
yields (38–99%). Although a long reaction time was required to
effect desilylation using 3HF·NEt3 (48 h), the reagent proved
reliable. Furthermore, the lower toxicity of 3HF·NEt3 made it
more desirable to use than the related reagent, HF·pyridine.12a,31
TBAF was briefly investigated as an alternative desilylating
reagent, however, treatment of 28c with TBAF,12a gave desily-
lated triazole 10c after 2 h but in only 14% yield.
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carbonate in aqueous sodium hydroxide. Separation of mixtures
was performed by flash chromatography using 0.063–0.1 mm
silica gel with the indicated eluent. Melting points were deter-
mined on a Kofler hot stage apparatus and are uncorrected.
Optical rotations were measured using a Perkin–Elmer 341
polarimeter at a wavelength of 598 nm and are reported in
10−1 °C cm2 g−1. Infrared spectra were obtained using a Perkin
Elmer Spectrum 100 Fourier Transform Infrared spectrometer on
a film ATR sampling accessory. Absorption peaks are reported as
wavenumbers (ν, cm−1). NMR spectra were recorded on either a
Bruker DRX 300 spectrophotometer operating at 300 MHz for
1H nuclei and 75 MHz for 13C nuclei, or a Bruker DRX400 or a
Bruker UltraShield Plus 400 spectrophotometer operating at
(C–H), 1715 (CvO), 1641 (CvC), 1428, 1253, 1111, 824, 774,
t
701; δH (400 MHz, CDCl3) −0.08 (3H, s, OSi(CH3)2 Bu), 0.00
t
t
(3H, s, OSi(CH3)2 Bu), 0.84 (9H, s, OSi(CH3)2 Bu), 1.04 (9H, s,
t
OSiPh2 Bu), 1.40–1.46 (2H, m, 8–HA and 9–HA), 1.55–1.72
(4H, m, 4–H, 8–HB and 9–HB), 2.03–2.08 (2H, m, 3–H),
2
2.37–2.42 (4H, m, 5–H and 7–H), 3.45 (1H, dd, JAB 10.1 and
2
3
3J11A,10 6.9, 11–HA), 3.57 (1H, dd, JAB 10.1 and J11B,10 5.0,
11–HB), 3.66–3.72 (1H, m, 10–H), 4.92–5.04 (2H, m, 1–H),
5.72–5.83 (1H, m, 2–H), 7.36–7.45 (6H, m, Ph), 7.65–7.68 (4H,
t
m, Ph); δC (100 MHz, CDCl3) −4.8 (CH3, OSi(CH3)2 Bu), −4.5
t
t
(CH3, OSi(CH3)2 Bu), 18.0 (C, OSi(CH3)2 Bu), 19.2 (C,
t
OSiPh2 Bu), 19.6 (CH2, C–8), 22.8 (CH2, C–4), 25.8 (CH3,
t
t
OSi(CH3)2 Bu), 26.9 (CH3, OSiPh2 Bu), 33.1 (CH2, C–3), 33.9
(CH2, C–9), 41.8 (CH2, C–5), 43.2 (CH2, C–7), 67.5 (CH2, C–
11), 72.5 (CH, C–10), 115.2 (CH, C–1), 127.6 (CH, Ph), 129.6
(CH, Ph), 133.6 (C, Ph), 133.6 (C, Ph) 135.6 (CH, Ph), 138.0
(CH, C–2) 210.9 (C, C–6); MS m/z (ESI+) 575 ([M + Na]+,
100%), 553 (M + H+, 12), 475 (4), 421 (15); HRMS (ESI+): [M
+ H]+, found 553.3535. C33H53O3Si2+ requires 553.3528.
1
400 MHz for H nuclei and 100 MHz for 13C nuclei at ambient
1
temperature. H NMR chemical shifts are reported in parts per
million (ppm) relative to the chloroform peak (δ 7.26). 1H NMR
values are reported as chemical shifts δ, relative integral, multi-
plicity (s, singlet; d, doublet; t, triplet; dd, doublet of doublets;
dt, doublet of triplets; td, triplet of doublets; m, multiplet), coup-
ling 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 (δ 77.0). 13C
NMR values are reported as chemical shifts δ and assignment.
Assignments were made with the aid of DEPT, COSY, HSQC,
HMBC and NOESY experiments. Mass spectra were recorded
on a VG-70SE mass spectrometer at a nominal accelerating
voltage of 70 eV or on a Bruker micrOTOF-Q II mass spectro-
photometer by electrospray ionisation in positive mode. 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%). High-resolution mass spectra
(HRMS) were obtained with a nominal resolution of 5000 to
10 000.
(10S)-10-(tert-Butyldimethylsilyloxy)-11-(tert-
butyldiphenylsilyloxy)-6-(1,3-dioxolan-2-yl)undec-1-ene (18)
A mixture of ketone 23 (932 mg, 1.69 mmol) and ethylene
glycol (190 μL, 3.41 mmol) were azeotrophically dried with
toluene (3 × 1 mL). Triethyl orthoformate (820 μL, 4.93 mmol)
and Bi(OTf)3 (39 mg, 0.059 mmol) were then added at RT.
After stirring at RT for 1.75 h, the mixture turned homogeneous.
Saturated NaHCO3 (20 mL) and a few drops of aqueous NaOH
(1 M) were added at RT and the aqueous phase extracted with
EtOAc (3 × 20 mL). The organic extracts were washed with satu-
rated NaCl (20 mL) and the aqueous washing extracted with
EtOAc (20 mL). The combined organic extracts were dried over
Na2SO4 and concentrated in vacuo to afford an opaque yellow
oil. Purification by flash chromatography (0%, 5% EtOAc/n-
hexane) gave the title compound 18 as a pale yellow oil
(10S)-10-(tert-Butyldimethylsilyloxy)-11-(tert-
butyldiphenylsilyloxy)undec-1-en-6-one (23)
(871 mg, 86%). [α]D23 −15.5 (c 1.08 in CHCl3); IR (film) νmax
/
Magnesium turnings (467 mg, 19.21 mmol) were stirred vigor-
ously under an argon atmosphere overnight. To this was added
dry Et2O (2 mL) and a single crystal of I2. The mixture was
heated gently and stirred until the orange colour faded. 5-Bromo-
1-pentene (1.1 mL, 9.30 mmol) was added dropwise with gentle
heating whereupon the reaction was initiated. The reaction
mixture turned bright opaque yellow with evolution of gas that
changed to a white cloudy suspension. Upon cessation of
gaseous evolution (0.5 h), the Grignard reagent was cooled to
0 °C and a solution of Weinreb amide 19 (2.09 g, 3.84 mmol) in
dry Et2O (4 mL, then 2 × 2 mL) were added by cannula. The
resulting dark grey suspension was stirred at 0 °C for 3 h. Satu-
rated NH4Cl (6 mL) was carefully added at 0 °C and the mixture
allowed to warm to RT with vigourous stirring. The organic layer
was separated and the aqueous phase extracted with EtOAc (4 ×
30 mL). The combined organic extracts were washed with satu-
rated NaCl (50 mL), and the aqueous washing extracted with
EtOAc (30 mL). The organic extracts were dried over MgSO4
and concentrated in vacuo to give a yellow oil. Purification by
flash chromatography (0%, 5% EtOAc/n-hexane) gave the title
compound 23 as a pale yellow oil (1.67 g, 79%). [α]2D0 −12.0
(c 1.02 in CHCl3); IR (film) νmax/cm−1 2929 (C–H), 2857
cm−1 2930 (C–H), 2857 (C–H), 1641 (CvC), 1428 (vC–H),
1253, 1112 (C–O–C), 824, 774, 702; δH (400 MHz, CDCl3)
t
t
−0.06 (3H, s, OSi(CH3)2 Bu), 0.01 (3H, s, OSi(CH3)2 Bu), 0.84
t
t
(9H, s, OSi(CH3)2 Bu), 1.05 (9H, s, OSiPh2 Bu), 1.20–1.52 (6H,
m, 4–HA, 5–HA, H–7A, 8–H, and 9–HA) 1.55–1.70 (4H, m, 4–
HB, 5–HB, H–7B, and 9–HB), 2.03–2.08 (2H, m, 3–H), 3.46
2
3
2
(1H, dd, JAB 10.0 and J11A,10 6.7, 11–HA), 3.58 (1H, dd, JAB
3
10.0 and J11B,10 5.0, 11–HB), 3.67–3.71 (1H, m, 10–H), 3.92
(4H, s, 1′–H and 2′–H), 4.93–5.03 (2H, m, 1–H), 5.75–5.85 (1H,
m, 2–H), 7.35–7.44 (6H, m, Ph), 7.66–7.69 (4H, m, Ph); δC
t
(100 MHz, CDCl3) −4.8 (CH3, OSi(CH3)2 Bu), −4.4 (CH3,
t
t
t
OSi(CH3)2 Bu), 18.1 (C, OSi(CH3)2 Bu), 19.2 (C, OSiPh2 Bu),
t
19.5 (CH2, C–8), 23.1 (CH2, C–4), 25.9 (CH3, OSi(CH3)2 Bu),
26.9 (CH3, OSiPh2 Bu), 33.9 (CH2, C–3), 34.7 (CH2, C–9), 36.7
t
(CH2, C–5), 37.5 (CH2, C–7), 64.9 (2 × CH2, C–1′ and C–2′),
67.8 (CH2, C–11), 72.9 (CH, C–10), 111.7 (C, C–6), 114.6
(CH2, C–1) 127.6 (CH, Ph), 129.6 (CH, Ph), 133.7 (C, Ph),
133.7 (C, Ph), 135.6 (CH, Ph), 138.7 (CH, C–2); MS m/z (ESI+,
MS2+ (597)) 597 ([M + H]+ 17%), 519 ([M – Ph]+, 23), 465
([M – OTBDMS]+, 69), 403 (36), 383 (100), 329 (57), 279 (21);
HRMS (ESI+): [M + H]+, found 597.3791. C35H57O4Si2
requires 597.3790.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5993–6002 | 5999

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(9S)-9-(tert-Butyldimethylsilyloxy)-10-(tert-
(11S)-11-(tert-Butyldimethylsilyloxy)-12-(tert-
butyldiphenylsilyloxy)-5-(1,3-dioxolan-2-yl)decanal (24)
butyldiphenylsilyloxy)-7-(1,3-dioxolan-2-yl)dodec-1-yn-3-
one (26)
To a solution of acetal 18 (738 mg, 1.24 mmol) in anhydrous
CH2Cl2 (46 mL) was added a few drops of Sudan III indicator
(0.1% in CH2Cl2). The bright red solution was cooled to −78 °C
and O3 was bubbled through the solution for 1 h (O3 generator
settings, flow rate: 50 L h−1, discharge: 100 V, O2 pressure:
15 psi) until complete discolouration was observed. While main-
taining the reaction mixture at −78 °C, the reaction vessel was
flushed with nitrogen for 0.5 h whereupon the reaction mixture
turned pale orange. Triethylamine (860 μL, 1.65 mmol) was
slowly added at −78 °C, stirred for 5 min, then warmed to RT.
The organic phase was dried over Na2SO4, passed through a
glass sinter and the filtrate concentrated in vacuo to obtain a pale
red oil. Purification by flash chromatography (0%, 20% EtOAc/
n-hexane) afforded the title compound 24 as a yellow oil
IBX (87.3 mg, 0.312 mmol) was dissolved in DMSO (600 μL)
and stirred at RT for 15 min. A solution of alkynol 17a : 17b
(83 mg, 0.133 mmol) in dry DMSO (3 × 900 μL) was added and
the reaction mixture heated to 40 °C. After 2.5 h, the reaction
mixture was allowed to cool to RT and saturated Na2S2O3
(3 mL) and EtOAc (3 mL) were added. The aqueous phase was
extracted with EtOAc (4 × 15 mL) and the organic extracts
washed with saturated NaCl (50 mL). The aqueous washing was
back extracted with EtOAc (50 mL) and the combined organic
extracts dried over Na2SO4 and the EtOAc removed in vacuo to
give an orange solution. Purification by flash chromatography
(0%, 17% EtOAc/n-hexane) afforded the title compound 26 as a
pale yellow oil. (80 mg, 96%). [α]2D2 −11.8 (c 1.07 in CHCl3);
IR (film) νmax/cm−1 3309 (≡C–H), 2929 (C–H), 2858 (C–H),
2091 (CuC), 1734 (CvO), 1683, 1472, 1187, 1106 (C–O–C),
(518 mg, 69%). [α]D22 −13.5 (c 1.04 in CHCl3); IR (film) νmax
/
cm−1 2929 (C–H), 2857 (C–H), 1726 (CvO), 1428 (C–H),
1389, 1111 (C–O–C), 701; δH (300 MHz, CDCl3) −0.06 (3H, s,
t
835, 701;δH (400 MHz, CDCl3) −0.07 (3H, s, OSi(CH3)2 Bu),
t
t
t
t
OSi(CH3)2 Bu), 0.01 (3H, s, OSi(CH3)2 Bu), 0.84 (9H, s, OSi(-
CH3)2 Bu), 1.05 (9H, s, OSiPh2 Bu), 1.32–1.55 (3H, m, 7–H,
and 8–HA), 1.58–1.75 (7H, m, 3–H, 4–H, 6–H, and 8–HB), 2.44
0.00 (3H, s, OSi(CH3)2 Bu), 0.84 (9H, s, OSi(CH3)2 Bu), 1.04
t
t
t
(9H, s, OSiPh2 Bu), 1.29–1.52 (4H, m, 8–H, 9–HA and 10–HA),
1.54–1.69 (4H, m, 6–H, 9–HB, and 10–HB), 1.72–1.80 (2H, m,
2
3
(2H, td, J2,1 1.7 and J2,3 7.2, 2–H), 3.46 (1H, dd, JAB 10.0 and
5–H), 2.60 (2H, t, J4,5 7.3, 4–H), 3.18 (1H, s, 1–H), 3.46 (1H,
3J10A,9 6.7, 10–HA), 3.58 (1H, dd, 2JAB 10.0 and 3J10B,9 5.0, 10–
HB), 3.66–3.71 (1H, m, 9–H), 3.92 (4H, s, 1′–H and 2′–H),
7.34–7.45 (6H, m, Ph), 7.65–7.70 (4H, m, Ph), 9.76 (1H, t, J1,2
dd, JAB 10.0 and J12A,11 6.7, 12–HA), 3.57 (1H, dd, JAB 10.0
and 3J12B,11 5.0, 12–HB), 3.66–3.72 (1H, m, 11–H), 3.92 (4H, s,
1′–H and 2′–H), 7.35–7.44 (6H, m, Ph), 7.65–7.69 (4H, m, Ph);
2
3
2
t
t
1.7, 1–H); δC (75 MHz, CDCl3) −4.8 (CH3, OSi(CH3)2 Bu),
δC (100 MHz, CDCl3) −4.8 (CH3, OSi(CH3)2 Bu), −4.4 (CH3,
OSi(CH3)2 Bu), 18.1 (C, OSi(CH3)2 Bu), 18.1 (CH2, C–5), 19.2
(C, OSiPh2 Bu), 19.4 (CH2, C–9), 25.9 (CH3, OSi(CH3)2 Bu),
26.9 (CH3, OSiPh2 Bu), 34.7 (CH2, C–8), 36.1 (CH2, C–10),
t
t
t
−4.4 (CH3, OSi(CH3)2 Bu), 16.5 (CH2, C–3), 18.1 (C, OSi(-
t
t
t
t
CH3)2 Bu), 19.2 (C, OSiPh2 Bu), 19.5 (CH2, C–7), 25.8 (CH3,
t
t
t
OSi(CH3)2 Bu), 26.9 (CH3, OSiPh2 Bu), 34.7 (CH2, C–8), 36.4
(CH2, C–4), 37.5 (CH2, C–6), 43.9 (CH2, C–2), 65.0 (2 × CH2,
C–1′ and C–2′), 67.8 (CH2, C–10), 72.8 (CH, C–9), 111.3 (C,
C–5), 127.6 (CH, Ph), 129.6 (CH, Ph), 129.6 (CH, Ph), 133.7
(C, Ph), 133.7 (C, Ph), 135.6 (CH, Ph), 135.6 (CH, Ph), 202.3
(CH, C–1); MS m/z (ESI+) 669 (19%), 653 (100), 637 (26), 621
([M + Na]+, 68), 599 ([M + H]+, 4), (7); HRMS (ESI+): [M +
H]+, found 599.3583. C34H55O5Si2+ requires 599.3583.
37.5 (CH2, C–6), 45.4 (CH2, C–4), 65.0 (2 × CH2, C–1′ and C–
2′), 67.8 (CH2, C–12), 72.8 (CH, C–11), 78.3 (CH, C–1), 81.4
(C, C–2) 111.3 (C, C–7), 127.6 (CH, Ph), 129.6 (CH, Ph), 133.7
(C, Ph), 133.7 (C, Ph), 135.6 (CH, Ph), 187.1 (C, C–3); MS m/z
(ESI+) 661 ([M + K]+, 6%), 645 ([M + Na]+, 24), 640 ([M +
H2O]+, 100), 623 ([M + H]+, 14), 605 (30), 545 (15), 527 (7),
491 (16); HRMS (ESI+): [M
+
H]+, found 623.3571.
C36H55O5Si2+ requires 623.3583.
(3S,11S)- and (3R,11S)-11-(tert-Butyldimethylsilyloxy)-12-(tert-
butyldiphenylsilyloxy)-7-(1,3-dioxolan-2-yl)-dodec-1-yn-3-ol
(17a : 17b)
(3S,11S)-11-(tert-Butyldimethylsilyloxy)-12-(tert-
butyldiphenylsilyloxy)-7-(1,3-dioxolan-2-yl)dodec-1-yn-3-yl
acetate (25)
To a solution of aldehyde 24 (1.27 g, 2.12 mmol) in anhydrous
THF (20 mL) at 0 °C under an argon atmosphere was added a
solution of ethynylmagnesium bromide (0.5 M in THF, 34 mL,
17 mmol). After stirring at 0 °C for 3 h, saturated NH4Cl
(10 mL) and distilled H2O (5 mL) were added and the mixture
stirred vigourously. The phases were separated and the aqueous
phase extracted with EtOAc (3 × 20 mL). The organic extracts
were washed with saturated NaCl (50 mL) and the aqueous
washing extracted with EtOAc (40 mL). The combined organic
extracts were then dried over Na2SO4 and the solvent removed in
vacuo. The resulting dark brown oil was purified by flash chrom-
atography (0%, 20% to 33% EtOAc/n-hexane) to afford an inse-
parable diastereomeric mixture of the title compound 17a : 17b
as a thick golden oil (963 mg, 73%). The characterisation data of
compound 17 is provided in the procedure describing the
hydrolysis of acetate 25 to alkynol 17a.
To a solution of alkynol 17a : 17b (1.12 g, 1.79 mmol) in dis-
tilled hexanes (48 mL) in a 80 mL microwave reaction tube, was
added vinyl acetate (300 μL, 3.25 mmol) and Novozyme 435
lipase acrylic resin (252 mg, derived from Candida antarctica,
141 mg mmol−1). The mixture was heated in a microwave
reactor (CEM Discover, 50 W) to a maximum of 50 °C for 1 h.
The reaction mixture was filtered through a glass sinter, washed
with EtOAc (20 mL) and concentrated in vacuo to obtain a pale
yellow oil. Purification by flash chromatography (0%, 14% to
25% EtOAc/n-hexane) gave the title compound 25 as a pale
yellow oil (214 mg, 18%) and alkynols 17a : 17b as a yellow oil
(799 mg, 72%). The alkynol fractions were concentrated and
resubjected to the enzymatic kinetic resolution as described
above to afford a second portion of the title compound 25 as a
pale yellow oil (155 mg, 13%) and alkynols 17a : 17b (617 mg,
6000 | Org. Biomol. Chem., 2012, 10, 5993–6002
This journal is © The Royal Society of Chemistry 2012

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55%). [α]2D0 −28.4 (c 1.07 in CHCl3); IR (film) νmax/cm−1 3293
(≡C–H), 2956 (C–H), 2859 (C–H), 1744 (CvO), 1473, 1429,
1372 (≡C–H), 1233 (C–C(vO)–O), 1112 (C–O–C), 703; δH
8-Ethynyl-2-(tert-butyldiphenylsilyloxymethyl)-1,7-dioxaspiro
[5.5]undecane (11)
t
To a stirred solution of alkynol 17a (337 mg, 0.539 mmol) in
EtOH : H2O (99 : 1 mixture, 5.8 mL) was added (+)-CSA
(272 mg, 1.17 mmol) in three equal portions at RT. After stirring
for 3 h, solid NaHCO3 (104 mg, 0.33 mmol) was added directly
and the solvent was removed in vacuo to afford a yellow oil. The
yellow oil was dissolved in saturated NaHCO3 (10 mL) and the
aqueous phase extracted with EtOAc (3 × 20 mL). The com-
bined organic extracts were dried over MgSO4 and concentrated
in vacuo to afford an orange oil. Purification by flash chromato-
graphy (0%, 9% EtOAc/n-hexane) gave the title compound 11 as
a yellow oil (181 mg, 75%). [α]2D1 −9.3 (c 1.05 in CHCl3); IR
(film) νmax/cm−1 3292 (≡C–H), 2932 (C–H), 2858 (C–H), 1473
(CH2), 1428 (C–H), 1219, 1112 (C–O–C), 1072 (C–O–C), 980;
(400 MHz, CDCl3) −0.07 (3H, s, OSi(CH3)2 Bu), 0.00 (3H, s,
t
t
OSi(CH3)2 Bu), 0.84 (9H, s, OSi(CH3)2 Bu), 1.04 (9H, s,
t
OSiPh2 Bu), 1.30–1.69 (10H, m, 5–H, 6–H, 8–H, 9–H and 10–
H), 1.75–1.80 (2H, m, 4–H), 2.08 (3H, s, COCH3), 2.44 (1H, d,
2
3
4J1,3 2.0, 1–H), 3.46 (1H, dd, JAB 10.0 and J12A,11 6.5, 12–
2
3
HA), 3.57 (1H, dd, JAB 10.0 and J12B,11 5.0, 12–HB),
3.66–3.70 (1H, m, 11–H), 3.90–3.94 (4H, m, 1′–H and 2′–H),
5.34 (1H, td, J3,4 6.5 and J3,1 2.0, 3–H), 7.35–7.44 (6H, m,
Ph), 7.65–7.68 (4H, m, Ph); δC (100 MHz, CDCl3) –4.8 (CH3,
OSi(CH3)2 Bu), –4.4 (CH3, OSi(CH3)2 Bu), 18.1 (C, OSi(-
CH3)2 Bu), 19.2 (C, OSiPh2 Bu), 19.3 (CH2, C–5), 19.5 (CH2,
3
4
t
t
t
t
t
C–9), 21.0 (CH3, COCH3), 25.8 (CH3, OSi(CH3)2 Bu), 26.8
(CH3, OSiPh2 Bu), 34.7 (2 × CH2, C–4 and C–10), 36.7 (CH2,
t
t
δH (300 MHz, CDCl3) 1.06 (9H, s, OSiPh2 Bu), 1.14–1.28
C–6), 37.5 (CH2, C–8), 63.7 (CH2, C–3), 65.0 (2 × CH2, C–1′
and C–2′), 67.8 (CH2, C–12), 72.8 (CH, C–11), 73.6 (CH, C–1),
81.1 (C, C–2) 111.4 (C, C–7), 127.6 (CH, Ph), 129.6 (CH, Ph),
133.6 (C, Ph), 133.7 (C, Ph), 135.6 (CH, Ph), 169.9
(C, COCH3); MS m/z (ESI+) 705 ([M + K]+, 7%), 689 ([M +
Na]+, 100), 684 ([M + H2O]+, 26), 667 ([M + H]+, 6), 645 (25),
589 (13), 535 (7); HRMS (ESI+): [M + H]+, found 667.3846.
C38H59O6Si2+ requires 667.3845.
(1H, m, 3–HA), 1.34–1.64 (6H, m, 3–HB, 4–H, 5–HA, 9–HA,
and 10–HA), 1.66–1.81 (3H, m, 9–HB and 11–H), 1.88–2.03
4
(2H, m, 5–HB and 10–HB), 2.43 (1H, d, J2′,8 2.3, 2′–H), 3.58
(1H, dd, 3JAB 10.3 and 3J2-CH2,2 4.4, 2–CHAHBO), 3.68 (1H, dd,
3
3JAB 10.3 and J2-CH2,2 6.5, 2–CHAHBO), 3.77–3.87 (1H, m,
3
3
4
2–H), 4.53 (1H, dt, J8,9ax 11.4, J8,9eq 2.6, and J8,2′ 2.3, 8–H),
7.35–7.45 (6H, m, Ph), 7.68–7.76 (4H, m, Ph); δC (75 MHz,
CDCl3) 18.35, 18.4 (2 × CH2, C–4 and C–10), 19.2 (C, OSiPh2-
tBu), 26.75 (CH
t
3, OSiPh2 Bu), 26.8 (CH2, C–3), 31.8 (CH2, C–9),
Hydrolysis of (3S,11S)-11-(tert-butyldimethylsilyloxy)-12-(tert-
butyldiphenylsilyloxy)-7-(1,3-dioxolan-2-yl)dodec-1-yn-3-yl
acetate (25) to (3S,11S)-11-(tert-butyldimethylsilyloxy)-12-(tert-
butyldiphenylsilyloxy)-7-(1,3-dioxolan-2-yl)dodec-1-yn-3-ol (17a)
34.7, 35.0 (2 × CH2, C–5 and C–11), 59.8 (CH, C–8), 67.3
(CH2, 2–CH2O), 70.6 (CH, C–2), 71.7 (CH, C–2′), 84.1 (C, C–
1′), 96.6 (C, C–6), 127.6 (CH, Ph), 127.6 (CH, Ph) 129.5 (CH,
Ph), 129.6 (CH, Ph), 133.8 (C, Ph), 135.7 (C, Ph); MS m/z
(ESI+) 487 ([M + K]+, 100%), 471 ([M + Na]+, 11), 429 (22),
371 ([M – Ph]+, 12); HRMS (ESI+): [M + K]+, found 487.2084.
C28H36KO3Si+ requires 487.2065.
To a solution of acetate 25 (369 mg, 0.553 mmol) in CH3OH
(11 mL) at RT was added solid K2CO3 (160 mg, 1.16 mmol).
After stirring for 20 min the mixture was filtered and washed
with EtOAc (20 mL). The filtrate was concentrated in vacuo to
afford a thick yellow oil. Purification by flash chromatography
(0%, 20% to 25% EtOAc/n-hexane) gave (3S,11S)-alkynol 17a
as a colourless oil (337 mg, 97%, 90–96% d.e.).24 [α]D21 −14.0
(c 1.03 in CHCl3); IR (film) νmax/cm−1 3411 (br, O–H), 3309
(≡C–H), 2929 (C–H), 2857 (C–H), 1472, 1428 (C–H), 1253,
1111 (C–O–C), 824, 775, 701; δH (400 MHz, CDCl3) –0.06
General Procedure for the Copper-Catalysed Azide–Alkyne
Cycloaddition (CuAAC) of Acetylenic Spiroacetal 11 to
Azides 27
To a mixture of acetylenic spiroacetal 11 (1.0 equiv.) and azide
27 (1.1–1.4 equiv.) in anhydrous toluene (0.050–0.086 M) under
an argon atmosphere was added a catalytic quantity (a single
crystal) of CuI·P(OEt)3 and the reaction mixture heated to reflux
for 1.0–1.5 h. Upon reaction completion by TLC analysis, the
product was purified directly by flash chromatography (14% to
25% EtOAc/n-hexane) to yield the desired spiroacetal-triazole
analogue 28 (Table 2).
t
t
(3H, s, OSi(CH3)2 Bu), 0.00 (3H, s, OSi(CH3)2 Bu), 0.84 (9H, s,
t
t
OSi(CH3)2 Bu), 1.05 (9H, s, OSiPh2 Bu), 1.33–1.49 (3H, m,
5–HA, 9–HA and 10–HA), 1.51–1.87 (9H, m, 4–H, 5–HB, 6–H,
4
8–H, 9–HB and 10–HB), 2.45 (1H, d, J1,3 2.0, 1–H), 3.46 (1H,
2
3
2
dd, JAB 10.0 and J12A,11 6.6, 12–HA), 3.58 (1H, dd, JAB 10.0
3
and J12B,11 5.0, 12–HB), 3.66–3.73 (1H, m, 11–H), 3.90–3.95
(4H, m, 1′–H and 2′–H), 4.33–4.39 (1H, m, 3–H), 7.35–7.45
(6H, m, Ph), 7.66–7.68 (4H, m, Ph); δC (100 MHz, CDCl3) −4.8
General Procedure for Deprotection of Silyl Protected
Spiroacetal-Triazole Analogues 28
t
t
(CH3, OSi(CH3)2 Bu), −4.4 (CH3, OSi(CH3)2 Bu), 18.1 (C,
t
t
OSi(CH3)2 Bu), 19.2 (C, OSiPh2 Bu), 19.4 (CH2, C–5), 19.5
t
t
(CH2, C–9), 25.8 (CH3, OSi(CH3)2 Bu), 26.8 (CH3, OSiPh2 Bu),
34.7 (CH2, C–10), 36.7 (CH2, C–6), 37.5 (CH2, C–8), 37.8
(CH2, C–4) 62.2 (CH, C–3), 65.0 (2 × CH2, C–1′ and C–2′),
67.8 (CH2, C–12), 72.8 (CH, C–11), 72.9 (CH, C–1), 84.9 (C,
C–2) 111.6 (C, C–7), 127.6 (CH, Ph), 129.6 (CH, Ph), 129.6
(CH, Ph), 133.7 (C, Ph), 133.7 (C, Ph), 135.6 (CH, Ph); MS m/z
(ESI+) 647 ([M + Na]+, 48%), 563 (100), 431 (4), 307 (10);
To a solution of silyl-protected spiroacetal-triazole 28 (1.0
equiv.) in anhydrous THF (0.042–0.078 M) under an argon
atmosphere was added 3HF·NEt3 (2.4–2.8 μL per μmol of spir-
oacetal-triazole) and the mixture stirred at RT for 24 h. A second
portion of 3HF·NEt3 (2.1–2.8 μL per μmol of spiroacetal-tria-
zole) was added and the mixture was stirred at RT for an
additional 24 h. Saturated NaHCO3 was added dropwise (2 mL)
and the aqueous phase extracted with EtOAc (4 × 5–10 mL).
The combined organic extracts were dried over Na2SO4 and
+
HRMS (ESI+): [M + Na]+, found 647.3574. C36H56NaO5Si2
requires 647.3558.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5993–6002 | 6001

View Online
S.-H. Yang and M. A. Brimble, Angew. Chem. Int. Ed., 2011, 50, 8350–
8353; (k) M. A. Brimble, O. C. Finch, A. M. Heapy, J. D. Fraser,
D. P. Furkert and P. D. O’Connor, Tetrahedron, 2011, 67, 995–1001.
13 (a) V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless,
Angew. Chem., Int. Ed., 2002, 41, 2596–2599; (b) C. W. Tornoe,
C. Christensen and M. Meldal, J. Org. Chem., 2002, 67, 3057–3064.
14 (a) A. Dondoni, G. Mariotti and A. Marra, J. Org. Chem., 2002, 67,
4475–4486; (b) T. Nishikawa, Y. Koide, S. Kajii, K. Wada, M. Ishikawa
and M. Isobe, Org. Biomol. Chem., 2005, 3, 687–700.
15 R. J. K. Taylor, K. Wiggins and D. H. Robinson, Synthesis, 1990, 589–
590.
16 Attempts using various Lewis acids (TIPSOTf, BF3.OEt2, Sc(OTf)3, and
InCl3) in CH2Cl2 or CH3CN at temperatures from −78 °C to RT were
conducted but only decomposition of starting materials was observed in
all cases.
concentrated in vacuo. Purification by flash chromatography
(17% n-hexane/EtOAc to 100% EtOAc) afforded the desired
hydroxymethyl spiroacetal-triazole analogue 10 (Table 2).
Acknowledgements
The authors would like to thank Darcy Atkinson and
Dr Jonathan Sperry for their generous gift of the precursors
required to prepare azides 27b and 27d and Dr Daniel Furkert
for his assistance in the preparation of this manuscript. The Uni-
versity of Auckland is also acknowledged for the award of a
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