Anomeric oxygen to carbon rearrangements of alkynyl tributylstannane derivatives of furanyl (γ)- and pyranyl (δ)-lactols

Article abstract of DOI:10.1039/b316858a

Tetrahydropyran and tetrahydrofuran containing natural products, drugs and agrochemicals often possess carbon-carbon bonds adjacent to the heteroatom. Consequently, new methods for the construction of anomeric carbon-carbon bonds are of considerable importance. We have devised a new strategy to access these systems that requires the treatment of O-glycoside alkynyl tributylstannane derivatives of furanyl and pyranyl lactols with Lewis acid to effect oxygen to carbon rearrangements. This leads to the formation of the corresponding carbon linked alkynol products that can be further manipulated to produce key structural motifs and building blocks for the assembly of complex molecules.

Full text of DOI:10.1039/b316858a

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Anomeric oxygen to carbon rearrangements of alkynyl
tributylstannane derivatives of furanyl (ꢀ)- and pyranyl (ꢁ)-lactols
Marianne F. Buffet, Darren J. Dixon, Steven V. Ley,* Dominic J. Reynolds and R. Ian Storer
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK
CB2 1EW. E-mail: svl1000@cam.ac.uk; Fax: (ϩ44) 1223-336442; Tel: (ϩ44) 1223-336398
Received 24th December 2003, Accepted 23rd February 2004
First published as an Advance Article on the web 18th March 2004
Tetrahydropyran and tetrahydrofuran containing natural products, drugs and agrochemicals often possess carbon–
carbon bonds adjacent to the heteroatom. Consequently, new methods for the construction of anomeric carbon–
carbon bonds are of considerable importance. We have devised a new strategy to access these systems that requires
the treatment of O-glycoside alkynyl tributylstannane derivatives of furanyl and pyranyl lactols with Lewis acid to
effect oxygen to carbon rearrangements. This leads to the formation of the corresponding carbon linked alkynol
products that can be further manipulated to produce key structural motifs and building blocks for the assembly
of complex molecules.
A few examples of this type of rearrangement had previously
Introduction
been reported for vinylic,8 phenolic,9–11 and allylic12,13 ether
systems. However, more general anomeric oxygen to carbon
rearrangements using a wider range of more synthetically
useful nucleophiles had not been explored in detail.
Tetrahydropyran and tetrahydrofuran ring systems bearing
carbon–carbon bonds adjacent to the ring oxygen are
commonplace amongst natural products.1 Such compounds
frequently exhibit important biological properties that invari-
ably arise from this particular arrangement of atoms. Accord-
ingly, these structural motifs have been incorporated into
synthetic drugs and agrochemicals, many of which exhibit
desirable biological activity.2
The requirement for new methods of anomeric carbon–
carbon bond construction is therefore of considerable import-
ance and consequently a number of solutions have evolved
over recent years.3–5 A popular strategy towards C-glyco-
sidation involves the displacement of a group at the 2-position
mediated by a Lewis acid. However, the generation of the
requisite leaving group followed by displacement often
necessitates two separate chemical transformations.6
We have recently developed a new synthetic approach
towards the formation of carbon–carbon bonds adjacent to the
heteroatom in pyran and furan ring systems. This is based on
the rearrangement of anomeric oxygen-linked substrates to
the corresponding carbon-linked products in a single step,
requiring a precursor that contains a carbon centred nucleo-
phile (Nu) covalently linked to the anomeric position through a
leaving group (X) (Scheme 1). It has been shown that, upon
treatment with Lewis acid, these systems undergo expulsion of
the leaving group, to generate a reactive oxonium intermediate
that is trapped in situ by the nucleophilic component to generate
a new carbon–carbon bond.7 As this generic system encapsul-
ates the three reaction components – substrate, leaving group
and nucleophile – it permits one-step C-glycosidation.
Our studies have revealed that a range of anomerically linked
carbon centred nucleophiles, including electron rich alkenes,7,14
silyl enol ethers15 enol ethers16 and alkynylstannanes17 undergo
rearrangement to afford the corresponding carbon-linked
products in good yields. As this method inherently combines
anomeric activation with side chain heteroatom protection, it
offers good compatibility with target-orientated synthesis.18–23
Alkynyl stannanes had previously been used for inter-
molecular displacement of anomeric halides, but to the best of
our knowledge had never been applied to this type of rearrange-
ment.24 Their ease of preparation and handling, combined
with inherent reactivity towards oxonium ion, made alkynyl
stannanes ideal for subjection to Lewis acid mediated
rearrangement.17 Herein we discuss the development of this
class of the reaction and illustrate its utility by incorporation
into the syntheses of a selection of structurally advanced
fragments and biologically active natural products (Scheme 2).
Scheme 2 The alkynylstannane rearrangement.
Results and discussion
Rearrangements of mono-substituted pyran derivatives
Initial investigations focused on the rearrangement of tributyl
stannane acetylene derivatives of pyran rings. A variety of
Lewis acids, concentrations and reaction conditions were tested
using the readily obtained tetrahydropyran derivatised propar-
gylic alcohol 1. Acetylene deprotonation using nBuLi, followed
by addition of tributyltin chloride, gave the desired stannane 2
in high yield. For the rearrangement step, several commonly
employed Lewis acids were tested in an effort to synthesise
alkynol 3 (Table 1). However, most of these resulted in varying
degrees of decomposition, often providing a mix of the identi-
fied by-products 1, 2 and 4, generated by destannylation of the
acetylene or fragmentation of the glycoside linkage (Scheme 3).
Scheme 1 Anomeric rearrangement. X = leaving group, Nu = nucleo-
phile, LA = Lewis acid.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 4 5 – 1 1 5 4
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Table 1 Optimization of the rearrangement
Lewis acid
Eq.
Temp./ЊC
Time/min
Conc./M
Result
TiCl4
TiCl4
SnCl4
EtAlCl2
Me2AlCl
BF3ؒOEt2
BF3ؒOEt2
BF3ؒOEt2
3
4
3
3
3
3
3
3
Ϫ78
Ϫ78
Ϫ78 Ϫ30
Ϫ78 25
Ϫ78 25
Ϫ30
10
10
30
45
45
5
0.46
0.19
0.15
0.15
0.15
0.45
0.23
0.45
1, 2, 4, plus 1 unidentified
1, 4, plus 1 unidentified
1, 4, plus decomposition
1, 4, plus 2 unidentified
Complex mixture
Complex mixture
Complex mixture
3
Ϫ10
Ϫ10
5
5
Scheme 3 Reagents and conditions: [a]. n-BuLi, THF, Ϫ78 ЊC, then
Scheme 5 Reagents and conditions: [a]. DHP, CSA, CH2Cl2, 0 ЊC; [b].
n-BuLi, THF, Ϫ78 ЊC, then Bu3SnCl, THF; [c] BF3ؒOEt2, CH2Cl2,
Ϫ10 ЊC. DHP = 3,4-dihydropyran, CSA = camphorsulfonic acid.
Bu3SnCl, THF; [b] Lewis acid, CH2Cl2.
The best results were obtained using boron trifluoride etherate
which provided predominantly the desired rearranged material.
Temperature, time and concentration of the reaction were
optimized with boron trifluoride etherate as the Lewis Acid.
The optimal reaction conditions required a high concentration
of substrate (0.45 M) in dichloromethane which was treated
with excess boron trifluoride etherate at Ϫ10 ЊC for 5 minutes
before quenching with NaOH solution (Table 1).
The analogous trimethylstannane derivative 5 was tested as
an alternative under the optimized rearrangement conditions.
This proved less stable than the tributyl derivative, decompos-
ing to a mixture of four identified by-products 1, 4, 5, and 6
(Scheme 4). As a result, tributyl stannanes were subsequently
adopted for further investigations.
substrates were considered. On rearrangement, substituted
pyranyl ether substrates could lead to the formation of two
diastereomeric carbon-linked products. Accordingly, reaction
diastereoselectivities and yields were investigated in the
rearrangement of 2,6-distubstituted pyran derivatives. Readily
available nhexyl-substituted δ-lactol 1919 was alkylated
by treatment with propargylic bromide 20 and KHMDS to
provide terminal acetylene 21 in >95% de, favouring the 2,6-cis-
products (Scheme 6). Acetylene 21 was stannylated and
rearranged to yield the desired alkynol product 23 in 66% yield
as a single trans diastereoisomer (>95% de). The high level
of stereoselectivity in the rearrangement can be readily
rationalized by the kinetically favoured axial approach of the
nucleophile to the intermediate oxonium ion (Fig. 1).25
Scheme 4 Reagents and conditions: [a]. n-BuLi, THF, Ϫ78 ЊC, then
Me3SnCl, THF; [b] BF3ؒOEt2, CH2Cl2.
Scheme 6 Reagents and conditions: [a]. KHMDS, THF, Ϫ78 ЊC (81%);
[b]. n-BuLi, THF, Ϫ78 ЊC, then Bu3SnCl, THF; [c] BF3ؒOEt2, CH2Cl2,
Ϫ10 ЊC (66%, 2 steps). KHMDS = potassium hexamethyldisilazide.
The rearrangement was general for a range of tetrahydro-
pyran “protected” alkynol substrates of differing linker chain
lengths (Scheme 5).
Application to the syntheses of spiroketals
The utility of the rearranged tetrahydropyran products was
exploited by application to the formation of unsubstituted and
substituted 6,6 and 6,5 spiroketals26 (Scheme 7).
Rearrangements of di-substituted pyran derivatives
With the optimal rearrangement conditions established on
simple THP ether derivatives, more complex rearrangement
Both propargylic 21 and homo-propargylic 24 ether deriv-
atives of the nhexyl-substituted δ-lactol 19 were synthesized
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 4 5 – 1 1 5 4
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Fig. 1 Diastereoselective rearrangement of disubstituted pyrans.
Scheme 8 Reagents and conditions: [a]. DHP, CSA, 0 ЊC, (87%, 5 : 4
d.r.); [b]. DIBAL-H, Et2O, Ϫ78 ЊC; [c]. PPh3, CBr4, CH2Cl2, (68%,
2 steps, 5 : 4 d.r.); [d]. n-BuLi, THF, Ϫ78 ЊC, then Bu3SnCl, THF;
[e]. BF3ؒOEt2, CH2Cl2, Ϫ10 ЊC, (16%, 3 steps); [f]. Raney nickel, H2,
EtOH, rt, (45%, 3 : 2 d.r.). DHP = 3,4-dihydropyran, DIBAL-H =
diisobutylaluminium hydride.
stannane under the reaction conditions, but nonetheless con-
stituted a promising initial attempt for future optimisation.
Furthermore, spirocyclisation would complete a short synthesis
of wasp pheromone natural product 41.
Scheme 7 Reagents and conditions: [a]. Amberlyst® A-15, toluene,
reflux; [b]. n-BuLi, THF, Ϫ78 ЊC, then Bu3SnCl, THF; [c] BF3ؒOEt2,
CH2Cl2, Ϫ10 ЊC; [d]. Raney nickel, H2, EtOH, rt; [e]. I2, HgO,
cyclohexane, reflux.
Rearrangements of di-substituted furan derivatives
Having investigated the rearrangements and diastereoselect-
ivities across unsubstituted and substituted 6-membered pyran
ring systems, the same was attempted for 5-membered furan
rings. The known heptane-substituted γ-lactol 4219 was alkyl-
ated by KHMDS deprotonation and reaction with proparyl
bromide to provide terminal alkyne 43 in 85% yield. The identi-
cal stannylation-rearrangement conditions as established on the
pyranyl ring systems were then applied. This reaction pro-
ceeded in a pleasing 78% yield over the two steps to provide the
desired rearranged alcohol 45. As anticipated, the furan dis-
played diminished diastereoselectivity in the rearrangement
compared to the equivalently substituted pyran ring, providing
the heptane substituted adduct 45 in an unselective 50 : 50 d.r.
(Scheme 9).
by an alternative Fischer glycosidation method employing the
corresponding alcohols at reflux in benzene or toluene with
catalytic Amberlyst® A-15.27,28 The resulting alkynes were
stannylated and rearranged to provide alkynols 23 and 26 in
excellent >95 : 5 d.r. and good yields. Following screening of
various hydrogenation catalysts, reduction of alkynes 23 and 26
was facilitated over Raney nickel to provide the corresponding
alkanes 28 and 29 in high yield.29 In accordance with literature
procedure,30,31 the hydroxy alkanes were cyclised by treatment
with iodine and mercuric oxide to yield the corresponding
6,5-(31) and 6,6-(32) spiroketals as single diastereoisomers.32
Similarly, rearranged homopropargyl monosubstituted
tetrahydropyran 16 was reduced using the Raney nickel
hydrogenation to alcohol 27. Spirocyclisation then accessed the
6,6-spiroketal, olive fly pheromone natural product 30.
With a versatile method in hand for the rearrangement of
unbranched alkyne linkers, rearrangement of an enantiopure
branched chain precursor was investigated. Tetrahydropyranyl
ether derivative 34 of (R)-methyl lactate 33 was synthesized
in a 5 : 4 d.r. (Scheme 8). Reduction proceeded smoothly
by treatment with DIBAL-H to provide the corresponding
aldehyde 35. This was reacted without further purification
under Corey–Fuchs conditions to yield dibromide 36 in 68%
yield over the 2 steps, maintaining the 5 : 4 ratio of two
diastereoisomers.33 Dibromide 36 was treated with nBuLi (2 eq.)
to provide the corresponding lithium acetylide that was
quenched directly with tributyltin chloride to yield stannane
derivative 37. As before, this was used without further purifi-
cation in the rearrangement reaction using borontrifluoride
etherate. Without further optimisation, the rearrangement
provided some alkynol product 38 in 16% yield and 3 : 2 d.r.
The corresponding destannylated terminal alkyne 39 was
isolated as the main reaction by-product, also in 16% yield. This
result highlighted the increased instability of this branched
Scheme 9 Reagents and conditions: [a]. KHMDS, THF, Ϫ78 ЊC (85%);
[b]. n-BuLi, THF, Ϫ78 ЊC, then Bu3SnCl, THF; [c] BF3ؒOEt2, CH2Cl2,
Ϫ10 ЊC (78%, 2 steps). KHMDS = potassium hexamethyldisilazide.
In order to obtain some stereocontrol in the O to C
rearrangements of the furanyl systems, a TBDPS protected
hydroxymethyl substituted γ-lactol system was investigated.
Lactol 47 was readily prepared from (R)-glycidol in three steps
as a 3 : 2 mixture of anomers in 70% overall yield (Scheme 10).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 4 5 – 1 1 5 4
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Scheme 10 Reagents and conditions: [a]. TBDPSCl, NEt3, DMAP,
CH2Cl2, rt, 24 h, (85%); [b]. allylMgBr, CuLi2Cl4, (10 mol%), THF, 15
min, Ϫ30 ЊC, (89%); [c]. O3, NaHCO3, CH2Cl2, 20 min, Ϫ78 ЊC; PPh3,
14 h, Ϫ78 ЊC
rt, 14 h, (93%). TBDPS = tert-butyldiphenylsilyl.
It was envisaged that the bulky OTBDPS substituent would
not only permit a degree of stereocontrol, but the protected
oxygen would provide a latent functionality for subsequent
development and scaffold elaboration of the rearrangement
product (Fig. 2).
Scheme 12 Reagents and conditions: [a]. KHMDS, THF, 30 min,
Ϫ78 ЊC; BnBr, THF, Ϫ78ЊC
rt, 2 h, (78%); [b]. TBAF, THF, 3 h, rt
(95%); [c]. Raney nickel, H2, EtOH, 30 min, rt, (70%); [d]. DMSO,
(COCl)2, CH2Cl2, Ϫ78 ЊC, 30 min; NEt3, Ϫ78 ЊC 0 ЊC, (used crude
in coupling). KHMDS = potassium hexamethyldisilazide, Bn-benzyl,
TBAF = tetra-butylammonium fluoride, DMSO = dimethyl sulfoxide.
Fig. 2 Steric interactions force a trans-delivery of the nucleophile to
the THF oxonium intermediate.
Treatment of the lactol 47 with excess propargylic alcohol 4
and catalytic Amberlyst® A-15 provided propargylic ether 48 in
high yield, as a 3 : 2 anomeric mixture (Scheme 11). Subjection
of this intermediate to the stannylation-rearrangement con-
ditions gave the desired carbon-linked products 50 in a pleasing
5.5 : 1 ratio in favour of the trans-adduct in high overall yield.
This pleasing result confirmed that the increased bulk offered
by the OTBDPS group is able to invoke appreciable levels of
diastereoselectivity in the synthesis of versatile alkynol building
blocks.
Fig. 3 NOE analysis of rearranged intermediate 51.
isolation of unstable aldehyde 54 in a 70% yield over the 2 steps.
This intermediate was subsequently coupled at each termini to
form the central core in the total synthesis of muricatetrocin C.
Application to the total synthesis of CMI-97721,22
Drug molecule CMI-977 56, a potent 5-lipoxygenase inhibitor
that is known to block the generation of leukotriene B4, was
developed for the prophylactic treatment of chronic asthma35
(Fig. 4).
Scheme 11 Reagents and conditions: [a]. prop-2-yn-1-ol, Amberlyst A-
15®, benzene, 15 min, reflux, (91%); [b]. n-BuLi, THF, 30 min, Ϫ78 ЊC;
Fig. 4 CMI-977.
Bu3SnCl, 30 min, Ϫ78 ЊC
(85%, 2 steps, 5.5 : 1 trans : cis).
rt; [c]. BF3ؒOEt2, CH2Cl2, 10 min, Ϫ10 ЊC,
It was initially expected that enantiopure lactol 47 could be
used in the synthesis of CMI-977, using a homo-proparylic
linker. Lactol 47 was heated with homo-propargylic alcohol 7
and catalytic Amberlyst A-15 in benzene to yield tetrahydro-
furanyl ether 57 in 95% yield as a 3 : 2 mixture of anomers on
multi-gram scale (Scheme 13). The stannylation-rearrangement
conditions were successfully applied to provide the carbon
linked adducts 59. Inspection of the crude 1H NMR indicated a
5 : 1 ratio in favour of the desired trans product. The rearranged
alcohol diastereoisomers proved inseparable by chromato-
graphy but the material was carried through the synthesis as a
mixture, anticipating the possibility of separation at a later
stage. Although the N-hydroxy urea portion was installed with-
out difficulty, the subsequent displacement of the hydroxy
methyl by para-fluoro phenol proved troublesome. After unsuc-
cessfully investigating a range of etherification conditions, this
synthetic route was abandoned.36
Application to the total synthesis of muricatetrocin C20,23
Isolated in limited supply in 1996 by McLaughlin and
coworkers, muricatetrocin C had been shown to inhibit the
growth of lung and pancreatic carcinomas.34
It was envisaged that the versatility of orthogonally
functionalized alcohol 50 could be exploited in the total
synthesis of this annonaceous acetogenin 55 (Scheme 12).
Inseparable diastereoisomers 50a and 50b were benzylated
at the primary hydroxyl using KHMDS in the presence of
benzyl bromide to provide benzyl ether 51. At this point the
diastereoisomers became separable by chromatography, per-
mitting isolation of isomer 51a in 78% yield. Analysis by NMR
nOe experiments corroborated the predicted trans-relationship
of the major component 51a (Fig. 3).
Cleavage of the TBDPS ether 51 to primary alcohol 52
proceeded in an excellent 95% yield under treatment with
TBAF. Exhaustive reduction of the alkyne 52 by hydrogenation
over Raney nickel, followed by Swern oxidation, permitted
As an alternative to avoid the late stage etherification, the
rearrangement was examined for a p-fluoro-phenol substituted
lactol 62. This lactol was formed from available (S)-γ-hydroxy-
methyl-γ-butyrolactone 60 (Scheme 14). Conversion to the
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 4 5 – 1 1 5 4
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Fig. 5 X-Ray crystal structure of rearranged intermediate 65.
for 20 hours then gave CMI-977 56 in 59% yield as a white
solid.
Scheme 13 Reagents and conditions: [a]. but-3-yn-1-ol, Amberlyst
A-15®, benzene, 15 min, reflux, (95%); [b]. n-BuLi, THF, 30 min,
Conclusions
Ϫ78 ЊC; Bu3SnCl, 30 min, Ϫ78 ЊC
rt; [c]. BF3ؒOEt2, CH2Cl2, 5 min,
In summary, a new anomeric oxygen to carbon rearrangement
of alkynyl tributylstananes has been developed. The utility
of the procedure has been illustrated by the conversion of
rearrangement products into important spiroketal motifs, and
by strategic incorporation into the total syntheses of drug
molecule CMI-977 and natural product muricatetrocin C. We
believe that this method will continue to provide great utility for
the synthesis of naturally occurring and biologically important
compounds.
Ϫ10 ЊC, (75%, 2 steps, 4.8 : 1). TBDPS = tert-butyldiphenylsilyl.
Experimental
General
All reactions were carried out under an atmosphere of argon,
and those not involving aqueous reagents were carried out in
oven-dried (200 ЊC) glassware, cooled under vacuum. Ether and
tetrahydrofuran were distilled from sodium benzophenone
ketyl; dichloromethane, benzene and toluene were distilled
from calcium hydride; pentane was distilled from sodium; and
triethylamine from potassium hydroxide. All other solvents
and reagents were used as supplied unless otherwise stated.
Ozonolyses were carried out using a Peak Scientific ozone
generator. Flash column chromatography was carried out using
Merck 60 Kieselgel (230–400 mesh) under pressure unless
otherwise stated. Analytical thin layer chromatography (TLC)
was performed on glass plates pre-coated with Merck Kieselgel
60 F254, and visualised by ultra-violet irradiation (254 nm),
or by staining with aqueous acidic ammonium molybdate,
or aqueous acidic potassium permanganate solutions as
appropriate. Melting points were measured on a Reichert hot
stage apparatus, and are uncorrected. Infra-red spectra were
obtained on Perkin Elmer 983G, FTIR 1620, or Spectrum One
FT-IR ATR (Attenuated Total Reflectance) spectrometers,
from a thin film deposited onto the ATR, a sodium chloride
plate, or mixed with potassium bromide as a tablet. Micro-
analyses were performed in the microanalytical laboratories at
the Department of Chemistry, Lensfield Road, Cambridge
using a CE-440 Elemental Analyser. Mass spectra and accurate
mass data were obtained on a Micromass Platform LC-MS,
Kratos MS890MS, Kratos Concept IH, Micromass Q-TOF, or
Bruker BIOAPEX 4.7 T FTICR spectrometer, by electron ion-
isation, chemical ionisation or fast atom/ion bombardment
techniques at the Department of Chemistry, Lensfield Road,
Cambridge. 1H NMR spectra were recorded in CDCl3, at
ambient temperature on Bruker AM-200, Bruker AM-400,
Bruker DPX-400, DRX-400, or Bruker-DRX-600 spectro-
meters, at 200, 400 or 600 MHz, with residual protic solvent
CHCl3 as the internal reference (δH = 7.26 ppm); Chemical
shifts (δ) are given in parts per million (ppm), and coupling
constants (J) are given in Hertz (Hz). The proton spectra are
reported as follows δ/ppm (number of protons, multiplicity,
coupling constant J/Hz, assignment). 13C NMR spectra were
recorded in CDCl3 at ambient temperature on the same spec-
trometers at 50, 100 or 150 MHz, with the central peak of
CHCl3 as the internal reference (δC = 77.0 ppm). DEPT135 and
Scheme 14 Reagents and conditions: [a]. p-fluorophenol PPh3, DIAD,
THF, 0 ЊC
reflux, 3h, (73%); [b]. DIBAL-H, toluene, Ϫ78 ЊC,
(100%); [c]. but-3-yn-1-ol, Amberlyst A-15®, benzene, reflux, 15 min,
(96%); [d]. n-BuLi, Bu3SnCl, Ϫ78 ЊC rt, 30 min; [e]. BF3ؒOEt2,
CH2Cl2, Ϫ10 ЊC, 5 min, (2 steps, 85%, 2 : 1); [f]. PPh3, DIAD,
N,O-diphenoxycarbonyl hydroxylamine, THF, 0 ЊC rt, (91%);
[g]. Ammonia 0.88 sp. gr., rt, 12 h, (59%). DIAD=di-iso-propyl
azodicarboxylate.
p-fluoro phenyl ether 61 proceeded in 73% yield under modified
Mitsunobu conditions, followed by quantitative reduction
using DIBAL-H to furnish the desired lactol 62 as a 3 : 2
mixture of anomers.36 Glycosidation with homo-propargylic
alcohol, followed by rearrangement afforded 65 in good yield.
Inspection of the crude NMR revealed a 2 : 1 trans : cis ratio
across the ring.
As predicted, the trans-selectivity of the reaction was
diminished compared to the analogous OTBDPS substituted
system 47, due to the reduced steric bulk of the aryl ether side
chain. However, it was pleasing to note the improved selectivity
relative to the n-alkyl substituted system 43. Furthermore, the
rearrangement diastereoisomers proved readily separable by
flash column chromatography, affording diastereomerically
pure alkynol 65 in 57% yield. A single crystal X-ray diffraction
of 65 was obtained, providing unambiguous proof of the
assigned trans-stereochemistry (Fig. 5).37
Having formed key rearranged intermediate 65, conversion
to CMI-977 56 was possible following a modification of a
2-step literature procedure (Scheme 14). Mitsunobu reaction
with N,O-diphenoxycarbonyl hydroxylamine converted the
free hydroxyl group of 65 to the protected N-hydroxy urea
derivative 66.36 Direct aminolysis of this material by treatment
with concentrated ammonium hydroxide at room temperature
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 4 5 – 1 1 5 4
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two dimensional (COSY, HMQC, HMBC) NMR spectroscopy
were used where appropriate, to aid in the assignment of signals
in the 1H and 13C NMR spectra; gradient nOe experiments were
also performed in certain cases and their salient results are
detailed in the text. Where a compound has been characterised
as an inseparable mixture of diastereoisomers, the NMR data
for each individual isomer has been reported as far as was
discernible from the spectrum of the mixture. Where coincident
coupling constants have been observed in the NMR spectrum,
the apparent multiplicity of the proton resonance concerned
has been reported.
of THP, 3 × Bu of SnBu3); 13C NMR (50 MHz, CDCl3)
δ = 105.7, 93.3, 89.9, 61.9, 54.9, 30.3, 25.4, 19.1, 28.9, 26.9, 10.9,
13.5; m/z (EI) 331 (36%), 453 (64%); m/z (ESI) 453.1792 [M ϩ
Na]ϩ; C20H38O2SnNa requires 453.1791.
2-(1-Tributylstannyl-4-butynyloxy) tetrahydropyran 13. The
same procedure was used as for compound 2 to give stannane
13 from alkyne 10 as a pale yellow oil (3.2 g, 100%). This was
used in the subsequent reaction without further purification;
1
νmax (film)/cmϪ1 2920–2870, 2153, 1063, 1122; H NMR (200
MHz, CDCl3) δ = 4.61 (1 H, s, OCHO), 3.88–3.70 (2 H, m,
CHHO, OCHH), 3.55–3.43 (2 H, m, CHHO, OCHH),
2-(But-1-yne-4-oxy) tetrahydropyran 1038. A solution of
DHP (5.0 mL, 55.0 mmol) was added dropwise to a solution of
3-butyn-1-ol 7 (3.5 g, 50.0 mmol) and camphorsulfonic acid
(0.1 g, 0.50 mmol) in CH2Cl2 (25 mL) at 0 ЊC. The mixture was
stirred for 30 min at rt, diluted with CH2Cl2 (30 mL) then
extracted with a solution of NaHCO3 (25 mL) followed by
brine (25 mL). The combined organics were dried over MgSO4,
filtered and concentrated under reduced pressure. Purification
by flash column chromatography (petroleum ether : ether 15 : 1)
᎐
2.52–2.45 (2 H, t, J 7.3, CH C᎐CH), 1.78–0.94 (33 H, m,
᎐
2
3 × CH2 of THP and 3 × Bu of SnBu3); 13C NMR (50 MHz,
CDCl3) δ = 107.8, 98.4, 82.7, 66.1, 61.8, 30.4, 26.2, 25.4, 19.2,
28.9, 26.8, 10.8, 13.5.
2-(1-Tributylstannyl-5-pentynyloxy) tetrahydropyran 14. The
same procedure was used as for compound 2 to give stannane
14 from alkyne 11 as a pale yellow oil (5.4 g, 100%). This was
used in the subsequent reaction without further purification;
1
νmax (film)/cmϪ1 2854–2871, 2149, 1062, 1035; H NMR (200
1
yielded alkyne 10 as a colourless oil (4.49 g, 58%); H NMR
MHz, CDCl3) δ = 4.60–4.59 (1 H, m, OCHO), 3.92–3.80 (2 H,
(200 MHz, CDCl3) δ = 4.49 (1 H, dd, J 3.4, 3.1, OCHO), 3.76–
3.61 (2 H, m, CHHOax, OCHHCH2CCH), 3.44–3.33 (2 H, m,
m, CHHO, OCHH), 3.77–3.43 (2 H, m, CHHO, OCHH),
᎐
᎐
᎐
2
2.39–2.29 (2 H, m, CH C᎐C), 1.93–1.69 (4 H, m, OCH CH ,
CHHO , OCHHCH CCH), 2.32–2.30 (2 H, m, CH C᎐CH),
᎐
2
2
2
eq
2
1.70–1.39 (6 H, m, 3 × CH2 of THP); 13C NMR (50 MHz,
CDCl3) δ = 98.0, 80.8, 68.9, 64.9, 61.3, 30.0, 25.0, 19.4, 18.8.
CH2CHO2 of THP), 1.63–0.87 (31 H, 2 × CH2 of THP, 3 × Bu
of SnBu3); 13C NMR (50 MHz, CDCl3) δ = 111.3, 98.7, 77.5,
65.9, 62.0, 30.6, 28.8, 25.5, 19.4, 16.9, 29.3, 26.9, 10.9, 13.6.
2-(Pent-1-yne-5-oxy) tetrahydropyran 1139. The same pro-
cedure was used as for compound 10 to give alkyne 11 as a
colourless oil (3.46 g, 87%), obtained after silica gel flash
column chromatography (petroleum ether : ether 5 : 1);
2-(1-Tributylstannyl-6-hexynyloxy) tetrahydropyran 15. The
same procedure was used as for compound 2 to give stannane
15 from alkyne 12 as a pale yellow oil (5.2 g, 100%). This was
used in the subsequent reaction without further purification;
1
νmax (film)/cmϪ1 3298, 2942–2871, 2118, 1034, 1062; H NMR
1
νmax (film)/cmϪ1 2939, 2148, 1026, 1056; H NMR (200 MHz,
(200 MHz, CDCl3) δ = 4.57 (1 H, t, J 3.1, OCHO), 3.90–3.75
(2 H, m, CHHOax of THP, OCHOCHH), 3.53–3.40 (2 H, m,
CDCl3) δ = 4.58–4.55 (1 H, m, OCHO), 3.90–3.71 (2 H, m,
CHHO, OCHH), 3.53–3.34 (2 H, m, CHHO, OCHH),
᎐
CHHO of THP, OCHOCHH ), 2.33–2.24 (2 H, m, CH C᎐CH),
᎐
2
᎐
᎐
2.30–2.21 (2 H, m, CH C᎐C), 1.77–0.81 (39 H, m, 3 × CH
1.93–1.91 (1H, t, J 2.6, C᎐CH ), 1.86–1.72 (4 H, m, CH -
᎐
2
2
᎐
2
of the chain, 3 × CH2 of THP, 3 × Bu of SnBu3); 13C NMR (200
MHz, CDCl3) δ = 111.5, 104.5, 98.7, 66.9, 62.1, 30.7, 28.8, 25.9,
25.4, 19.5, 16.9, 29.0, 26.9, 10.9, 13.6.
᎐
CH C᎐CH, 1 × CH of THP), 1.69–1.49 (4 H, m, 2 × CH of
᎐
2
2
2
THP); 13C NMR (50 MHz, CDCl3) δ = 98.7, 83.9, 68.3, 65.7,
62.1, 30.6, 28.6, 25.4, 19.4, 15.2; m/z (CI) 85 (41%), 102 (100%),
103 (8%), 186 (7%); m/z (CI) found 169.1228 ([M ϩ H]ϩ
C10H17O2 requires 169.1229).
2-(Propyn-1-ol) tetrahydropyran 3. A solution of boron tri-
fluoride etherate (0.43 mL, 3.5 mmol) was added dropwise to a
solution of stannane 2 (0.5 g, 1.1 mmol) in CH2Cl2 (3 mL) at
Ϫ10 ЊC. After stirring for 5 min at this temperature the reaction
was quenched by the addition of sodium hydroxide solution
(2.5 M) and diluted with 4 mL of CH2Cl2. The organic phase
was washed with water (3 mL) then brine (3 mL), dried over
MgSO4, filtered and concentrated. The product was purified by
repeated flash column chromatography on silica gel (petroleum
ether : Et2O, 1 : 2 to 1 : 1 to neat Et2O) to give alkynol 3 as a
colourless oil (0.078 g, 49%);νmax (film)/cmϪ1 3410, 2938–2857,
2-(Hex-1-yne-6-oxy) tetrahydropyran 1240. The same pro-
cedure was used as for compound 10 to give alkyne 12 as a
colourless oil (5.56 g, 90%), obtained after silica gel flash
column chromatography (petroleum ether : ether 5 : 1);
1
νmax (film)/cmϪ1 3298, 2942–2871, 2118, 1034, 1075; H NMR
(200 MHz, CDCl3) δ = 4.56 (1 H, t, J 2.8, OCHO), 3.89–3.69
(2 H, m, CHHOax of THP, OCHOCHH), 3.53–3.34 (2 H, m,
᎐
CHHO of THP, OCHOCHH ), 2.55–2.14 (2 H, m, CH C᎐CH),
᎐
2
᎐
1.94–1.91 (1 H, t, J 1.00, C᎐CH ), 1.89–1.49 (10 H, m, 3 ×
᎐
1
CH2of THP 2 × CH2 of chain); 13C NMR (50 MHz, CDCl3)
δ = 98.7, 84.3, 68.2, 66.8, 62.2, 30.6, 28.7, 25.4, 25.3, 19.5, 18.2.
2190, 1034, 1067; H NMR (200 MHz, CDCl3) δ = 4.65–4.28
(2 H, dd, J 5.0, CH2OH), 4.02–3.44 (1 H, m, CHHOax), 3.52–
3.42 (1 H, m, CHHOeq), 2.22–1.38 (6 H, m, 3 × CH2 of THP);
13C NMR (50 MHz, CDCl3) δ = 84.7, 83.4, 66.9, 66.7, 51.0,
31.9, 25.5, 21.7; m/z (CI) 85 (10%), 158 (100%); m/z (CI) found
141.0915 ([M ϩ H]ϩ C8H13O2 requires 141.0916).
2-(1-Tributylstannyl-3-propynyloxy) tetrahydropyran 2.
A
solution of butyllithium (11.0 mL, 17.6 mmol, 1.6 M in
hexanes) was added dropwise at Ϫ78 ЊC to a solution of alkyne
1 (2.2 mL, 16.0 mmol) in 60 mL of THF. The reaction mixture
was stirred for 30 minutes at Ϫ78 ЊC before slow addition of
tributyltin chloride. The mixture was stirred for 30 min and
allowed to slowly warm from Ϫ78 ЊC to Ϫ30 ЊC. The reaction
mixture was extracted using ether (60 mL) and water (60 mL).
The aqueous phase was washed using ether (2 × 40 mL) and the
combined organic phase dried over MgSO4, filtered and con-
centrated to yield stannane 2 as a pale yellow oil (6.8 g, 100%).
This was used in the subsequent reaction without purification;
2-(Butyn-1-ol) tetrahydropyran 16. The same procedure was
used as for compound 3 to give alkynol 16 from stannane 13
(0.41 M in CH2Cl2) as a colourless oil (0.12 g, 50%, 2 steps from
alkyne 10), obtained after repeated flash column chromato-
graphy on silica (petroleum ether : Et2O, 1 : 2 to 1 : 1 to neat
Et2O); νmax (film)/cmϪ1 3398, 2938–2854, 2141, 1012, 1080,
1035; 1H NMR (400 MHz, CDCl3) δ = 4.23 (1 H, dd, J 8.4, 2.0,
᎐
OCHC᎐C), 4.00–3.94 (1 H, m, CHHO), 3.72 (2 H, q, J 6.2
᎐
νmax (film)/cmϪ1 2954–2860, 2358; 1H NMR (600 MHz, CDCl3)
CH2OH), 3.54–3.44 (1 H, m, CHHO), 2.50 (2 H, td, J 6.2, 1.9,
CH2CH2OH), 1.97 (1 H, t, J 6.0, OH ), 1.89–1.78 (2 H, m,
CH2CHO), 1.68–1.50 (4 H, m, 2 × CH2); 13C NMR (100 MHz)
δ = 82.0, 81.3, 67.3, 66.9, 61.0, 32.4, 25.6, 23.1, 22.0; m/z (CI)
᎐
δ = 4.84 (1 H, t, J 3.4, OCHO), 4.29–4.22 (2 H, m, OCH C᎐C),
᎐
2
3.84–3.80 (1 H, m, CHHOax), 3.51–3.48 (1 H, m, CHHOeq of
THP), 1.84–1.69 (2 H, m, CH2CHO), 1.62–0.86 (31 H, 2 × CH2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 4 5 – 1 1 5 4
1150

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172 ([M ϩ NH4]ϩ, 100%); m/z (EI) found 137.0966 ([M Ϫ OH]ϩ
(1.29 g, 1.07 mL, 3.9 mmol). After stirring for a further 30
C9H13O requires 137.0966).
minutes, ether (100 mL) and distilled water (100 mL) were
added. The aqueous phase was extracted with ether (50 mL).
The combined organic phases were washed with brine (50 mL)
and dried over anhydrous MgSO4. The product material was
filtered and concentrated in vacuo to afford stannane 22, as a
pale yellow crude oil. The stannane 22 was used directly in the
next reaction.
2-(Pentyn-1-ol) tetrahydropyran 17. The same procedure was
used as for compound 3 to give alkynol 17 from stannane
14 (0.47 M in CH2Cl2) as a colourless oil (0.22 g, 62%, 2 steps
from alkyne 11), obtained after repeated flash column
chromatography on silica (petroleum ether : Et2O, 1 : 2 to 1 : 1
to neat Et2O); νmax (film)/cmϪ1 3394, 2998–2857, 2241, 1012,
1079, 1034; 1H NMR (200 MHz, CDCl3) δ = 4.21–4.17 (1H, m,
Boron trifluoride etherate (1.3 mL, 10.1 mmol) was added
dropwise to a stirred solution of stannane 22 in CH2Cl2 (1 mL)
at Ϫ10 ЊC. After 15 minutes stirring, the reaction was quenched
by the addition of a 10 M sodium hydroxide solution (50 mL).
Ether was added (50 mL), then distilled water (100 mL). The
aqueous layer was extracted with ether (50 mL). The combined
organic extracts were washed with brine (50 mL) and dried
over anhydrous MgSO4. The material was filtered and then
concentrated in vacuo to afford a pale yellow oil. Purification
by repeated flash chromatography on silica gel (petroleum
ether : ether, 50 : 1 then 2 : 1) afforded alkynol 23 (0.496 g, 66%),
as a single diastereoisomer and as a colourless oil; νmax(film)/
cmϪ1 3384 2928, 2247, 909, 1029; 1H NMR (400 MHz, CDCl3)
δ = 4.78 (1 H, br s, OCHCC), 4.34 (2 H, dd, J 6.1, 1.7,
CH2OH), 3.83–3.76 (1 H, m, CH3(CH2)CHO), 1.90–1.12 (16 H,
m, 8 × CH2), 0.88 (3 H, t, J 6.8, CH3(CH2)5); 13C NMR (100
MHz) δ = 84.7, 83.4, 71.8, 65.0, 51.2, 36.1, 31.8, 31.3, 30.5, 29.3,
25.3, 22.6, 19.4, 14.0; m/z (EI) found 225.1854 ([M ϩ H]ϩ
C14H25O2 requires 225.1855).
CHO), 3.99–3.90 (1 H, m, CHHO), 3.76 (1 H, t, J 8.3, OH ),
᎐
3.68–3.31 (1 H, m, CHHO), 2.52–2.44 (2 H, dt, C᎐CCH ),
᎐
2
1.86–1.11 (8 H, m, CH2 of the chain, 3 × CH2 of THP); 13C
NMR (50 MHz, CDCl3) δ = 84,8, 79,1, 67.2, 66.6, 61.5, 32.4,
31.2, 25.5, 21.9, 15.2; m/z (CI) found 169.1228 ([M ϩ H]ϩ
C8H13O2 requires 169.1229).
2-(Hexyn-1-ol) tetrahydropyran 18. The same procedure was
used as for compound 3 to give alkynol 18 from stannane 15
(0.60 M in CH2Cl2) as a colourless oil (0.46 g, 60%, 2 steps from
alkyne 12), obtained after repeated flash column chromato-
graphy on silica (petroleum ether : Et2O, 1 : 2 to 1 : 1 to neat
Et2O); νmax (film)/cmϪ1 3405, 2937–2859, 2241, 1012, 1081,
1034; 1H NMR (200 MHz, CDCl3) δ = 4.25–4.19 (1H, m,
CHO), 4.00–3.90 (1H, m, CHHO of THP), 3.64–3.47 (2H, m,
CHHO of THP, CHHOH), 3.45–3.40 (1H, m, CHHOH),
᎐
2.28–2.21 (2H, m, CH C᎐C), 1.81–1.35 (11 H, m, 2 × CH of
᎐
2
2
chain, 3 × CH2 of THP); 13C NMR (50 MHz, CDCl3) δ = 85.2,
79.5, 67.3, 66.6, 62.2, 32.4, 31.7, 25.6, 24.8, 21.9, 18.4; m/z (EI)
found 182.1385 ([M]ϩ C11H18O2 requires 182.1307).
2-(3-Hydroxy-n-propyl)-6-n-hexyl tetrahydropyran ether 28.
A 50% Raney nickel slurry in water (1.0 g) was washed with
ethanol (3 × 5 mL) and absolute ethanol (3 × 5 mL), before
resuspension in absolute ethanol (3 mL). An ethanol solution
of alkynol 31 (59 mg, 0.26 mmol) was then added to the nickel
suspended in ethanol. The solvent was degassed under vacuum
and exposed to an atmosphere of hydrogen. The heterogeneous
solution was stirred vigorously for 3 hours at room temperature,
then filtered through a plug of silica gel. The silica gel was
washed with absolute ethanol and the filtrate concentrated
in vacuo to yield a colourless oil. Purification by silica gel flash
column chromatography (petroleum ether : ether 1 : 1) afforded
alcohol 28 (48 mg, 81%) as a colourless oil; νmax(film)/cmϪ1
3387, 2936; 1H NMR (400 MHz, CDCl3) δ = 3.75–3.57 (4 H, m,
CH3(CH2)5CHO, OCH(CH2)3OH, CH2OH), 2.35 (1 H, s, OH ),
1.75–1.15 (20 H, m, 10 × CH2), 0.88 (3 H, t, J 6.3,
CH3(CH2)5);13C NMR (100 MHz) δ = 71.5, 70.6, 63.0, 32.8,
31.8, 30.6, 29.5, 29.3, 25.8, 22.6, 21.2, 18.6, 15.2, 14.1; m/z (EI)
found 228.2081 ([M]ϩ C14H28O2 requires 228.2089).
2-(1-Trimethylstannyl-3-propynyloxy) tetrahydropyran 5. The
same procedure was used as for compound 2 to give stannane
5 from alkyne 1 as a pale yellow oil (3.5 g, 100%). This was
used in the subsequent reaction without further purification;
νmax (film)/cmϪ1 2954–2860, 2358, 1034, 1120; H NMR (200
1
MHz, CDCl3) δ = 4.82–4.79 (1 H, m, OCHO), 4.34–4.12 (2 H,
᎐
m, OCH C᎐C), 3.88–3.68 (1 H, m, CHHO ), 3.54–3.40 (1 H,
᎐
2
ax
m, CHHOeq), 1.86–1.48 (6 H, m, 3 × CH2 of THP), 0.64–0.11
(9 H, m, 3 × CH3 of SnMe3); 13C NMR (50 MHz, CDCl3)
δ = 104.5, 73.9, 96.7, 61.9, 54.9, 30.1, 25.2, 18.9, Ϫ7.9.
2-(Prop-1-yne-3-oxy)-6-n-hexyl tetrahydropyran ether 21.
Propargylic alcohol 4 (0.65 mL, 10.6 mmol), was added to a
suspension of lactol 19 (1.0 g, 5.3 mmol), Amberlyst® A-15
(150 mg) and toluene (20 mL) and refluxed with stirring for
15 minutes. The reaction mixture was filtered and concentrated
in vacuo to afford a yellow oil. Purification by silica gel flash
column chromatography (petroleum ether : ether 20 : 1, then
10 : 1) afforded ether 21, as a colourless oil (1.00 g, 85%) and
mixture of diastereoisomers (trans : cis = 5 : 2). Analysis was
undertaken on this mixture of isomers; νmax(film)/cmϪ1 3310,
7-n-Hexyl-1,6-dioxaspiro[4,5]decane 31. Iodine (21 mg, 0.080
mmol) and mercuric oxide (20 mg, 0.086 mmol) were added to a
solution of 28 (18 mg, 0.078 mmol) in cyclohexane (10 mL) and
refluxed for 17 hours. The residual mercury salts were removed
by filtration through a plug of silica gel before solvent removal
in vacuo to yield a deep yellow oil. Purification via silica gel
chromatography (petroleum ether : ether 2 : 1), then sephadex
LH-20 chromatography (CH2Cl2 : methanol; 1 : 1) afforded
spiroketal 31 (8.2 mg, 46%) as a pale yellow oil; νmax(film)/cmϪ1
1
2931, 2119, 1026, 947; H NMR (400 MHz, CDCl3) δ (major
trans) = 4.99 (1 H, br s, OCHO), 4.22 (1 H, dd, J 15.6, 2.4,
OCHHCCH), 4.18 (2 H, dd, J 15.6, 2.4, OCHHCCH),
3.70–3.60 (1 H, m, CH3(CH2)5CHO), 2.39 (1 H, t, J 2.3, CCH ),
1.87–1.14 (16 H, m, 8 × CH2), 0.88 (3 H, t, J 6.68, CH3(CH2)5;
δ (minor cis) = 4.56 (1 H, dd, J 9.4, 2.0, OCHO), 4.36 (2 H, d,
J 2.3, OCH2CCH), 3.33–3.38 (1 H, m, CH3(CH2)5CHO), 2.39
(1 H, t, J 2.3, CCH ), 1.87–1.14 (16H, m, 8 × CH2), 0.88 (3 H, t,
J 6.68, CH3(CH2)5); 13C NMR (100MHz) δ (major trans) = 96.0,
80.0, 76.3, 69.1, 53.5, 36.2, 31.8, 31.1, 29.4, 25.5, 22.6, 18.0,
14.0; δ (minor cis) = 100.0, 80.0, 76.3, 69.1, 54.6, 36.1, 31.8,
31.0, 29.3, 25.5, 22.1, 18.0, 14.0; m/z (ESI) found 247.1672
([M ϩ Na]ϩ C14H24O2Na requires 247.1674).
1
2935; H NMR (400 MHz, CDCl3) δ = 3.92–3.82 (2 H, m,
OCH2), 3.71–3.66 (1 H, m, CH3(CH2)5CHO), 2.07–1.99, 1.95–
1.72, 1.70–1.55, 1.43–1.11 (20 H, m, 10 × CH2), 0.88 (3 H, t,
J 6.8, CH3(CH2)5); 13C NMR (100 MHz) δ = 105.8, 70.2, 66.6,
37.8, 36.3, 32.9, 31.9, 31.0, 29.3, 25.6, 23.7, 22.6, 20.5, 14.1; m/z
(FAB) found 227.2011 ([M ϩ H]ϩ C14H27O2 requires 227.2011).
2-(But-1-yne-4-oxy)-6-n-hexyl tetrahydropyran ether 24.
Amberlyst® A-15 (150 mg) and 3-butyn-1-ol (0.7 mL, 9.26
mmol) were added to a solution of lactol 19 (861 mg, 4.63
mmol) in toluene (20 mL) and refluxed. The toluene–water
azeotrope was removed over 15 minutes. The reaction mixture
was filtered and concentrated in vacuo to afford a pale yellow
oil. Purification by silica gel flash column chromatography
2-(3-Hydroxypropyn-1-yl)-6-n-hexyl tetrahydropyran ether 23.
A 1.6 M solution in hexanes of n-butyllithium (2.4 mL,
3.8 mmol) was added dropwise to a Ϫ78 ЊC stirred solution of
21 (0.80 g, 3.6 mmol) in THF (20 mL). The mixture was stirred
for 30 minutes at Ϫ78 ЊC before addition of tributyltin chloride
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 4 5 – 1 1 5 4
1151

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(petroleum ether : ether 20 : 1, then 10 : 1) afforded alkyne 24
(958 mg, 87%), as a 7 : 2 mixture of diastereoisomers and as
a colourless oil. All analysis was undertaken on a mixture of
70.5, 63.0, 33.2, 32.7, 31.9, 30.3, 30.2, 29.3, 25.8, 22.6, 22.0,
18.7, 15.2, 14.1; m/z (EI) 242.2 [M]ϩ; m/z (EI) found 242.2251
([M]ϩ C15H30O2 requires 242.2246).
1
isomers; νmax(film)/cmϪ1 3313, 3100–2800, 2122, 1090–960; H
2-n-Hexyl-1,7-dioxaspiro[5,5]undecane 32. Iodine (22 mg,
0.085 mmol) and mercuric oxide (20 mg, 0.09 mmol) were
added to a solution of alcohol 29 (21 mg, 0.09mmol) in cyclo-
hexane (10 mL). The mixture was refluxed for 17 hours then
filtered through a plug of silica gel to remove residual mercury
salts. The solvent was removed in vacuo to yield a yellow–red
oil. Purification via silica gel flash column chromatography
(petroleum ether : ether, 2 : 1), then sephadex column chrom-
atography (CH2Cl2 : methanol, 1 : 1) afforded spiroketal
32 (13.7 mg, 68%), as a pale yellow oil; νmax(film)/cmϪ1
NMR (400 MHz, CDCl3) δ (major trans isomer) = 4.85 (1 H, br
᎐
s, OCHO), 3.85–3.70 (1 H, m, OCHHCH C᎐CH), 3.70–3.60
᎐
2
᎐
(1 H, m, OCHHCH C᎐CH), 3.80–3.70 (1 H, m, CH -
(CH ) HCO), 2.54–2.47 (2 H, m, CH C᎐CH), 1.97 (1 H, t,
J 2.6, C᎐CH ), 1.90–1.11 (16H, m, 8 × CH ), 0.88 (3 H, t, J 6.4,
᎐
2
3
᎐
᎐
2
2
5
᎐
᎐
2
CH3(CH2)5); δ (minor cis isomer), 4.41 (1 H, dd, J 9.4, 2.0,
᎐
OCHO), 4.0–3.93 (1 H, m, OCHHCH C᎐CH), 3.60–3.50 (1 H,
᎐
2
᎐
m, OCHHCH C᎐CH), 3.35–3.32 (1 H, m, CH (CH ) HCO),
᎐
2
3
2 5
᎐
᎐
2.54–2.47 (2 H, m, CH C᎐CH), 1.97 (1 H, t, J 2.6, C᎐CH ),
᎐
᎐
2
1.90–1.11 (16H, m, 8 × CH2), 0.88 (3 H, t, J 6.4, CH3(CH2)5; 13
C
1
2941; H NMR (400 MHz, CDCl3) δ = 3.69–3.55 (3 H, m,
NMR (100 MHz) δ (major trans isomer) = 97.2, 80.8, 69.0, 68.8,
64.7, 36.3, 31.8, 31.2, 29.8, 29.4, 25.5, 22.6, 19.9, 18.2, 14.1;
δ (minor cis isomer) = 97.2, 80.8, 69.0, 68.8, 64.7, 36.3, 31.8,
31.2, 29.8, 29.4, 25.5, 22.6, 19.9, 18.2, 14.1; m/z (EI) found
239.2006 ([M ϩ H]ϩ C15H27O2 requires 239.2011).
OCH2, CH3(CH2)5CHO), 1.91–1.77 and 1.60–1.05 (22 H, m, 11
× CH2), 0.89 (3 H, t, J 6.7, CH3(CH2)5); 13C NMR (100 MHz)
δ = 95.4, 69.1, 60.3, 36.5, 36.0, 35.5, 31.9, 31.3, 29.5, 25.8, 25.5,
22.6, 18.9, 18.6, 14.1; m/z (FAB) 241.8 [M ϩ H]ϩ; m/z (FAB)
found 241.2159 [M ϩ H]ϩ C15H29O2 requires 241.2168).
2-(4-Hydroxy-butyn-1-yl)-6-n-hexyl tetrahydropyran ether 26.
A solution of nbutyllithium (1.6 M hexanes, 1.5 mL, 2.5 mmol)
was added dropwise to a Ϫ78 ЊC stirred solution of 24 (0.56 g,
2.3 mmol) in THF (20 mL). The mixture was stirred for
30 minutes at Ϫ78 ЊC before addition of tributyltin chloride
(0.838 g, 0.7 mL, 2.6 mmol). After stirring for a further
30 minutes, ether (100 mL) and distilled water (100 mL) were
added. The aqueous phase was extracted with ether (50 mL)
and the combined organic phases washed with brine (50 mL)
and dried over anhydrous MgSO4. The product material was
filtered and concentrated in vacuo to afford stannane 25 as
a pale yellow crude oil. This oil was used without further
purification or characterisation in the next reaction.
Boron trifluoride etherate (1.1 mL, 1.21 g, 8.5 mmol) was
added dropwise to a stirred solution of stannane 25 in CH2Cl2
(1 mL) at Ϫ10 ЊC. After 15 minutes stirring, the reaction was
quenched by the addition of a 10 M sodium hydroxide solution
(50 mL). Ether (50 mL) and distilled water (100 mL) were
added. The aqueous layer was extracted with ether (50 mL) and
the combined organic extracts were washed with brine, dried
over anhydrous MgSO4, filtered and then concentrated in vacuo
to afford a pale yellow oil. Purification by repeated flash
chromatography on silica gel (petroleum ether : ether, 50 : 1,
2 : 1) afforded alkynol 26 (326 mg, 59%) as a pale yellow oil;
νmax(film)/cmϪ1 3410br, 2932, 2230, 1041; 1H NMR (400 MHz,
CDCl3) δ = 4.72 (1 H, br s, OCHCC), 3.80–3.78 (1 H, m,
CH3(CH2)5CHO), 3.72 (2 H, q, J 6.2, CH2OH), 2.51 (2 H, td,
J 6.3, 2.0, CCCH2CH2OH), 1.95–1.94, 1.88–1.71, 1.67–1.08,
0.89–0.81 (19 H, m, 8 × CH2, 1 × CH3);13C NMR (100 MHz)
δ = 82.9, 81.0, 71.5, 65.1, 61.2, 36.1, 31.8, 31.4, 30.7, 29.3, 25.3,
23.2, 22.6, 19.4, 14.0; m/z (FAB) found 239.2004 ([M ϩ H]ϩ
C15H2702 requires 239.2011).
2-(4-Hydroxy-n-butyl) tetrahydropyran ether 27. A 50%
Raney nickel suspension in water (1.8 g) was washed with
ethanol (3 × 5 mL) and absolute ethanol (3 × 5 mL), before
resuspension in absolute ethanol (6 mL). A solution of alkynol
16 (170 mg, 1.11 mmol) was added to this suspension of
catalyst. The solvent was degassed under vacuum then exposed
to an atmosphere of hydrogen. The heterogeneous solution was
stirred for 4 hours at room temperature then filtered through
a plug of silica gel. The silica gel was washed through with
absolute ethanol and the filtrate concentrated in vacuo to yield
a colourless oil. Purification by silica gel chromatography
(petroleum ether : ether 1 : 1) afforded alcohol 27 as a colourless
oil (148 mg, 86%); νmax(film)/cmϪ1 3377, 2934, 1091, 1048;
1H NMR (400 MHz, CDCl3) δ = 3.99–3.94 (1 H, m,
CHHOCH), 3.65 (2 H, t, J 6.4, CH2OH), 3.40 (1 H, td, J 11.4,
2.6, CHHOCH), 3.26–3.21 (1 H, m, CHHOCH), 1.82 (1 H, br
s, OH ), 1.60–1.35 and 1.31–1.19 (12 H, m, 6 × CH2); 13C NMR
(100 MHz) δ = 77.8, 68.5, 62.9, 36.2, 32.7, 32.0, 26.2, 23.6, 21.7;
m/z (EI) 159.20 [M ϩ H]ϩ, 141.14 [M Ϫ OH]ϩ; m/z (EI) found
141.1291 ([M Ϫ OH]ϩ C9H17O requires 141.1279).
1,7-Dioxaspiro[5,5]undecane (from Dacus oleae) 30.41 Iodine
(35 mg, 0.14 mmol) and mercuric oxide (32 mg, 0.15 mmol)
were added to a solution of 27 (21 mg, 0.14 mmol) in
cyclohexane (5 mL). The mixture was refluxed for 16 hours. The
residual mercury salts were removed by filtration through
a plug of silica gel and the solvent removed in vacuo to yield a
yellow–red oil. Purification by silica gel chromatography
(petroleum ether : ether 2 : 1), then sephadex LH-20 chromato-
graphy afforded spiroketal 30 (<50% – volatile) as a pale yellow
oil; 1H NMR (400 MHz, CDCl3) δ = 3.70–3.58 (4 H, m, OCH2),
1.85–1.74, (4 H, m, CH2CO2), 1.61–1.32 (8 H, m, 4 × CH2);
13C NMR (100 MHz) δ = 95.0, 60.3, 35.7, 25.3, 18.5; All data
identical to that described in the literature.
2-(4-Hydroxy-n-butyl)-6-n-hexyl tetrahydropyran ether 29. A
50% Raney nickel suspension in water (1.0 g) was washed with
ethanol (3 × 5 mL) and absolute ethanol (3 × 5 mL), before
resuspension in absolute ethanol (6 mL). A solution of alkynol
26 (106 mg, 0.44 mmol) was added to the suspension of the
catalyst. The solvent was degassed under vacuum and the
reaction exposed to an atmosphere of hydrogen. The hetero-
geneous solution was stirred vigorously for 4 hours at room
temperature then filtered through a plug of silica gel. The silica
gel was washed with absolute ethanol and the filtrate con-
centrated in vacuo. Purification by silica gel flash column
chromatography (petroleum ether : ether 1 : 1) afforded alcohol
29 as a colourless oil (98 mg, 91%); νmax(film)/cmϪ1 3377, 2932,
2-(Ethyl-2-(R)-methyl-2-oxy methanoate) tetrahydropyran
ether 34. Dihydropyran (4.82 g, 57.2 mmol) and (R)-methyl
lactate 33 (4.97 g, 47.7 mmol) were dissolved in CH2Cl2 (30 mL)
at 0 ЊC. A catalytic amount of camphor sulfonic acid (50 mg)
was added to the mixture which was stirred under an atmos-
phere of argon at 0 ЊC for 1 h 30 min. A colour change from
colourless to deep pink was observed. The reaction was
quenched using triethylamine (0.3 mL) which effected a colour
change from pink to pale green. The solvent was removed
in vacuo to yield a yellow oil. Purification by silica gel flash
column chromatography afforded tetrahydropyranyl ether 34
(7.79 g, 87%) as a colourless oil and a 5 : 4 mixture of dia-
stereoisomers; νmax(film)/cmϪ1 3100–2750, 1754, 1036; 1H NMR
(400MHz, CDCl3) δ (major) = 4.72–4.67 (1 H, m, OCHO), 4.43
(1 H, q, J 7.0, OCHCO2Me), 3.94–3.81 (1 H, m, CHHOCH),
1
1041; H NMR (400 MHz, CDCl3) δ = 3.68–3.63 (2 H, m,
CH3(CH2)5CHO, OCH(CH2)4OH), 3.60–3.55 (2 H, m,
CH2OH), 1.73–1.51, 1.50–1.18, 0.98–0.93, (22 H, m, 11 × CH2),
0.88 (3 H, t, J 6.7, CH3(CH2)5); 13C NMR (100 MHz) δ = 71.0,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 4 5 – 1 1 5 4
1152

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3.73 (3 H, s, OCH3), 3.53–3.43 (1 H, m, CHHOCH), 1.90–1.51
(6H, m, 3 × CH2 of THP), 1.45 (3 H, d, J 7.0, CH3CH);
δ (minor) = 4.72–4.67 (1 H, m, OCHO), 4.21 (1 H, q, J 7.0,
OCHCO2Me), 3.94–3.81 (1 H, m, CHHOCH), 3.74 (3 H, s,
OCH3), 3.53–3.43 (1 H, m, CHHOCH), 1.90–1.51 (6 H, m,
3 × CH2 of THP), 1.39 (3 H, d, J 7.0, CH3CH); 13C NMR (100
MHz, CDCl3) δ (major) = 173.9, 97.6, 69.9, 62.5, 51.9, 30.4, 25.3,
19.2, 18.8; δ (minor) = 173.7, 98.3, 72.4, 62.5, 51.9, 30.4, 25.3,
19.2, 18.0; m/z (CI) 189.31 [M ϩ H]ϩ, 211.16 [M ϩ Na]ϩ; m/z
(EI) found 189.1130 ([M ϩ H]ϩ C9H17O4 requires 189.1127).
solution (50 mL). Ether (100 mL), then distilled water (100 mL)
were added. The aqueous layer was extracted with ether
(2 × 100 mL) and the combined organic extracts were washed
with brine (100 mL) and dried over anhydrous MgSO4. The
product material was filtered before concentration in vacuo
to afford a pale yellow oil. Purification by repeated flash
chromatography on silica gel (petroleum ether : ether, 50 : 1,
10 : 1, 5 : 1, 1 : 1, ether) afforded alkynol 38 (326 mg, 16%) as a
pale yellow oil and alkyne byproduct 39 (16%) as a yellow oil;
alkynol 38 νmax(film)/cmϪ1 3398., 3050–2750, 1034, 1082;
1H NMR (400 MHz, CDCl3) δ (major) = 4.63–4.53 (1 H, m,
C(Me)HOH), 4.29–4.27 (1 H, d, J 7.9, CHHOax of THP), 4.00–
3.94 (1 H, m, CHO), 3.54–3.46 (1 H, m, CHHOeq of THP), 1.94
(1 H, dd, J 5.0, 2.1, OH ), 1.84–1.81, 1.71–1.48 (6 H, m, 3 × CH2
of THP), 1.45 (3 H, d, J 6.8, CH3CH); δ (minor) = 4.63–4.53
(1 H, m, C(Me)HOH), 4.29–4.27 (1 H, d, J 7.9, CHHOax of
THP), 4.00–3.94 (1 H, m, CHO), 3.54–3.46 (1 H, m, CHHOeq
of THP), 1.94 (1 H, dd, J 5.0, 2.1, OH ), 1.84–1.81, 1.71–1.48
(6 H, m, 3 × CH2 of THP), 1.45 (3 H, d, J 6.8, CH3CH); 13C
NMR (100 MHz) δ (major) = 87.1, 83.0, 67.0, 66.7, 58.3, 32.1,
25.6, 21.8, 24.3; δ (minor) = 87.1, 83.0, 67.0, 66.7, 58.3, 32.1,
25.6, 21.8, 24.3; m/z (EI) found 177.0880 ([M ϩ Na]ϩ
C9H14O2Na requires 177.0892); Side product 39 νmax(film)/cmϪ1
3291, 3000–2800, 1036; 1H NMR (400 MHz, CDCl3)
δ (major) = 4.93 (1 H, d, J 8.2, OCHO), 4.55 (1 H, qd, J 6.8, 2.0,
2-(Prop-1-dibromo-1-ene-3-(R)-methyl-3-oxy)
tetrahydro-
pyran ether 36. Diisobutylaluminium hydride (19.9 mL, 19.9
mmol) was added dropwise to a stirred solution of ester 34
(3.00 g, 16.0 mmol) in ether (45 mL) at Ϫ78 ЊC under argon.
The reaction was stirred for 10 minutes before addition of
methanol (0.8 mL) and water (2.0 mL). Rochel salts (150 mL)
were added and the mixture was allowed to stir for 1 hour. The
aqueous layer was extracted using ether (3 × 50 mL) and the
combined organic extract was dried over anhydrous MgSO4
before solvent removal in vacuo to yield aldehyde 3542 as a
colourless oil. This material was used in the next reaction
without further analysis or purification.
Triphenylphosphine (16.7 g, 63.8 mmol) was added portion-
wise over 5 minutes to a stirred solution of carbon tetrabromide
(10.6 g, 31.9 mmol) in CH2Cl2 (60 mL) at 0ЊC. After 20 minutes,
a solution of crude aldehyde, 35, in CH2Cl2 was added
dropwise. The mixture was allowed to stir under argon at 0 ЊC
for a further 30 minutes, before being poured into petroleum
ether (1 L). A yellow precipitate formed which was removed
via filtration through a pad of silica gel. The filtrate was concen-
trated in vacuo to effect the formation of a white precipitate
(Ph3PO) that was removed via a second filtration through a pad
of silica gel. The solvent was removed in vacuo to yield a colour-
less oil which was purified by silica gel flash column chromato-
graphy (petroleum ether : ether 10 : 1 then 5 : 1 then 2 : 1)
afforded dibromide 36 (3.39 g, 68 %, 2 steps from ester 34) as a
colourless oil of diastereomeric ratio [5 : 4]; νmax(film)/cmϪ1
3000–2800, 1617, 1035, 1076; 1H NMR (400 MHz, CDCl3)
δ (major) 6.34 (1 H, d, J 8.2, CHCBr2), 4.60–4.54 (2 H, m,
CH3CH, OCHO), 3.91–3.83 (1 H, m, CHHOax of THP),
3.56–3.50 (1 H, m, CHHOeq of THP), 1.85–1.78, 1.74–1.68,
1.58–1.50 (6 H, m, 3 × CH2 of THP), 1.30 (3 H, d, J 6.5,
CH3CH); δ (minor) = 6.53 (1 H, d, J 8.2, CHCBr2), 4.71–4.69
(1 H, m, OCHO), 4.46–4.38 (1 H, m, CH3CH ), 3.91–3.83 (1 H,
m, CH2O of THP axial), 3.56–3.50 (1 H, m, CH2O of THP
equatorial), 1.85–1.78, 1.74–1.68, 1.58–1.50 (6 H, m, 3 × CH2
of THP), 1.25 (3 H, d, J 6.5, CH3CH); 13C NMR (100 MHz)
δ (major) = 140.4, 96.5, 90.9, 71.6, 62.9, 30.7, 25.4, 20.1, 19.5;
δ (minor) = 141.1, 97.4, 89.2, 73.5, 62.6, 30.7, 25.4, 19.8, 19.1;
m/z (ESI) found 334.9267 ([M ϩ Na]ϩ C9H14O2Br2Na requires
334.9258).
CH3CH ), 3.85–3.79 (1 H, m, CHHOax of THP), 3.55–3.45
᎐
(1 H, m, CHHOeq of THP), 2.37 (1 H, d, J 2.1, C᎐CH ), 1.87–
᎐
1.70, 1.65–1.51 (6 H, m, 3 × CH2 of THP), 1.47 (3 H, d, J 6.7,
CH3CH); δ (minor) = 4.77 (1 H, d, J 8.2, OCHO), 4.46 (1 H, qd,
J 6.8, 2.0, CH3CH ), 4.01–3.96 (1 H, m, CHHOax of THP),
3.55–3.45 (1 H, m, CHHOeq of THP), 2.42 (1 H, d, J 2.1,
᎐
C᎐CH ), 1.87–1.70, 1.65–1.51 (6 H, m, 3 × CH of THP), 1.44
᎐
2
(3 H, d, J 6.7, CH3CH); 13C NMR (100 MHz) δ (major) = 95.9,
83.7, 72.4, 62.5, 60.6, 30.5, 25.4, 19.5, 21.8; δ (minor) = 97.1,
84.7, 71.9, 62.2, 60.6, 30.5, 25.4, 19.1, 21.8.
2-(3-Hydroxy-3-(R)-methyl-propyl) tetrahydropyran ether 40.
A 50% Raney nickel suspension in water (1.8 g) was washed
with ethanol (3 × 5 mL) and absolute ethanol (3 × 5 mL),
before resuspension in absolute ethanol (6 mL). A solution of
alkynol 38 (106 mg, 0.44 mmol) was added to this suspension of
catalyst. The solvent was degassed under vacuum then exposed
to an atmosphere of hydrogen. The heterogeneous solution was
stirred vigorously for 4 hours at room temperature, then the
reaction mixture was filtered through a short plug of silica gel.
The silica gel was washed with absolute ethanol and the filtrate
concentrated in vacuo to yield a colourless oil. Purification by
silica gel chromatography (petroleum ether : ether 1 : 1) afforded
alcohol 40 (21.0 mg, 45%) as a colourless oil; νmax(film)/cmϪ1
3396, 3050–2750, 1087, 1048; 1H NMR (400 MHz, CDCl3)
δ (major) = 4.0–3.96 (1 H, m, OCH(CH2)2CHOH), 3.82–3.75
(1 H, m, CH(Me)OH), 3.46–3.38 (1 H, m, CHHOax of THP),
3.28–3.25 (1 H, m, CHHOeq of THP), 1.82 (1 H, d, J 10.4, OH ),
1.66–1.20 (10 H, m, 5 × CH2), 1.17 (3 H, d, J 6.2, CH3);
δ (minor) = 4.0–3.96 (1 H, m, OCH(CH2)2CHOH), 3.82–3.75
(1 H, m, CH(Me)OH), 3.46–3.38 (1 H, m, CHHOax of THP),
3.28–3.25 (1 H, m, CHHOeq of THP), 1.82 (1 H, d, J 10.4, OH ),
1.66–1.20 (10 H, m, 5 × CH2), 1.17 (3 H, d, J 6.2, CH3); 13C
NMR (100 MHz) δ (major) = 79.0, 68.5, 67.6, 35.4, 32.6, 31.8,
26.0, 23.5, 23.5; δ (minor) = 79.0, 68.5, 68.2, 36.3, 32.7, 32.1,
26.0, 23.5, 23.5; m/z (CI) 159.08 [M ϩ H]ϩ; m/z (EI) found
181.1200 ([M ϩ Na]ϩ C9H18NaO2 requires 181.1204).
2-(3-Hydroxy-3-(R)-methyl-propyn-1-yl)
tetrahydropyran
ether 38. A solution of n-butyllithium (1.6 M in hexanes,
10.5 mL, 16.7 mmol) was added dropwise at Ϫ78 ЊC to a stirred
solution of dibromide 36 (2.5 g, 7.96 mmol) in THF (60 mL).
The mixture was stirred for 30 minutes at Ϫ78 ЊC before
addition of tributyltin chloride (2.85 g, 2.4 mL, 8.8 mmol).
After stirring for a further 30 minutes, ether (200 mL), then
distilled water (200 mL) were added. The aqueous phase was
extracted with ether (2 × 100 mL) and brine (100 mL). The
combined organic phases were dried over anhydrous MgSO4,
filtered and concentrated in vacuo to afford stannane 37
as a pale yellow crude oil. This oil was used without futher
purification or characterisation in the next reaction.
2-(Prop-1-yne-3-oxy)-6-n-hexyl tetrahydropyran ether 43.
KHMDS (0.5 M in toluene, 3.2 mL, 1.6 mmol) was added
dropwise to a solution of lactol 4219 (0.27 g, 1.45 mmol) in
THF (3.2 mL) at Ϫ78 ЊC. The solution was stirred at Ϫ78 ЊC
for 30 min, then propargyl bromide (0.52 g, 4.4 mmol) was
added dropwise via syringe. The reaction was then allowed to
warm to rt and stirred for a further 2 h. The reaction mixture
A solution of boron trifluoride etherate (3.0 mL, 3.4 g, 23.9
mmol) was added dropwise to a stirred solution of stannane
37 in CH2Cl2 (1 mL), at Ϫ10 ЊC. After 15 minutes the reaction
was quenched by the addition of a 10 M sodium hydroxide
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 4 5 – 1 1 5 4
1153

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7 M. F. Buffet, D. J. Dixon, G. L. Edwards, S. V. Ley and E. W. Tate,
J. Chem. Soc., Perkin Trans. 1, 2000, 1815.
8 R. Menicagli, C. Malanga, M. Dellinnocenti and L. Lardicci,
J. Org. Chem., 1987, 52, 5700.
9 (a) G. Casiraghi, M. Cornia, G. Rassu, L. Zetta, G. G. Fava and
M. F. Belicchi, Tetrahedron Lett., 1988, 29, 3323; (b) T. Matsumoto,
M. Katsuki and K. Susuki, Tetrahedron Lett., 1988, 29, 6935.
10 G. Casiraghi, M. Cornia, G. Rassu, L. Zetta, G. G. Fava and
M. F. Belicchi, Carbohydr. Res., 1989, 191, 243.
11 N. G. Ramesh and K. K. Balasubramanian, Tetrahedron Lett., 1992,
33, 3061.
12 J. Herscovici, S. Delatre and K. Antonakis, J. Org. Chem., 1987, 52,
5691.
13 K. Mikami and H. Kishino, Tetrahedron Lett., 1996, 37, 3705.
14 M. F. Buffet, D. J. Dixon, G. L. Edwards, S. V. Ley and E. Tate,
Synlett, 1997, 1055.
15 D. J. Dixon, S. V. Ley and E. W. Tate, Synlett, 1998, 1093.
16 (a) D. J. Dixon, S. V. Ley and E. W. Tate, J. Chem. Soc., Perkin Trans.
1, 1999, 2665; (b) Y. Zhang, N. T. Reynolds, K. Manju and T. Rovis,
J. Am. Chem. Soc., 2002, 124, 9720.
17 M. F. Buffet, D. J. Dixon, S. V. Ley and E. W. Tate, Synlett, 1998, 1091.
18 D. J. Dixon, S. V. Ley and E. W. Tate, J. Chem. Soc., Perkin Trans. 1,
1998, 3125.
was diluted with ether (50 mL), then quenched by the addition
of water (5 mL). The organic phase was separated, washed with
aqueous hydrochloric acid solution (3 M, 2 × 15 mL) and
saturated sodium chloride solution (20 mL), dried (MgSO4)
and the volatiles removed in vacuo to yield a yellow oil that was
purified by silica gel chromatography (petroleum ether : ethyl
acetate 50 : 1) to give alkyne 43 (0.28 g, 85%); νmax(film)/cmϪ1
1
3312, 2925, 2856, 1460, 1091, 1034, 950; H NMR (400 MHz,
CDCl3) δ (isomer a) = 5.28 (1 H, d, J 8.7, OCHO), 4.22 (1 H, d,
J 2.2, OCHHCCH), 4.18 (1 H, d, J 2.2, OCHHCCH), 4.02
(1 H, m, C7H15CHO), 2.38 (1 H, t, J 2.2, CCH ), 2.12–1.83
(3 H, m, CH2C(O)O, C7H15C(O)CHH), 1.75–1.52 (1 H, m,
C7H15CH(O)CHH ), 1.52–1.20 (12 H, m, 5 × CH2), 0.88 (3 H, t,
J 6.5, CH3); δ (isomer b) = 5.21 (1 H, d, J 8.9, OCHO), 4.22
(1 H, d, J 2.2, OCHHCCH), 4.18 (1 H, d, J 2.2, OCHHCCH),
4.02 (1 H, m, C7H15CHO), 2.38 (1 H, t, J 2.2, CCH ), 2.12–1.83
(3 H, m, CH2C(O)O, C7H15C(O)CHH), 1.75–1.52 (1 H, m,
C7H15CH(O)CHH ), 1.52–1.20 (12 H, m, 5 × CH2), 0.88 (3 H, t,
J 6.5, CH3); 13C NMR (100 MHz) δ (mix of isomers) = 102.4,
102.0, 81.3, 80.0, 78.4, 73.6, 53.8, 53.4, 37.5, 35.4, 32.1, 31.8,
29.6, 29.2, 29.1, 26.1, 22.63, 22.62, 14.05, 14.04; m/z (ESI)
found 247.1674 ([M ϩ Na]ϩ C12H24O2Na requires 247.1674).
19 D. J. Dixon, S. V. Ley and E. W. Tate, J. Chem. Soc., Perkin Trans. 1,
2000, 2385.
20 D. J. Dixon, S. V. Ley and D. J. Reynolds, Angew. Chem., Int. Ed.,
2000, 39, 3622.
2-(3-Hydroxy-propyn-1-yl)-6-n-hexyl tetrahydropyran ether
45. The same procedure was used as for compound 2 to give
stannane 44 from alkyne 43 as a pale yellow oil. This was used
in the subsequent reaction without further purification. The
same procedure was used as for compound 3 to give alkynol
45 from stannane 44 as a colourless oil (0.34 g, 78%, 2 steps
from alkyne 43), obtained after repeated flash column chrom-
atography on silica gel (petroleum ether : ether 10 : 1, then 5 : 1,
then 2 : 1); νmax(film)/cmϪ1 3384, 2926, 2857, 2342, 1458, 1331,
1019; 1H NMR (400 MHz, CDCl3) δ (isomer a) = 4.53 (1 H, dd,
J 7.0 5.9, OCHCC), 4.29 (2 H, s, CH2OH), 3.84–3.80 (1 H, m,
C7H15CHO), 2.23–2.08 (1 H, m, CHHCHOCC), 2.01–1.94
(2 H, m, CHHCHOCC, C7H15CHOCHH), 1.81 (1 H, s, OH ),
1.70–1.51 (1 H, m, C7H15CHOCHH ), 1.50–1.40 (1 H, m,
CH3(CH2)5CHH), 1.38–1.29 (1 H, m, CH3(CH2)5CHH ), 1.28
(10 H, m, 5 × CH2), 0.87 (3 H, t, J 6.5, CH3); (isomer b) = 4.68
(1 H, dd, J 6.8 6.2, OCHCC), 4.29 (2 H, s, CH2OH), 4.07–4.03
(1 H, m, C7H15CHO), 2.23–2.08 (2 H, m, CHHCHOCC,
C7H15CHOCHH), 2.01–1.94 (1 H, m, CHHCHOCC), 1.81
(1 H, s, OH ), 1.70–1.51 (1 H, m, C7H15CHOCHH ), 1.50–1.40
(1 H, m, CH3(CH2)5CHH), 1.38–1.29 (1 H, m, CH3(CH2)5-
21 D. J. Dixon, S. V. Ley, D. J. Reynolds and M. S. Chorghade, Synth.
Commun., 2000, 30, 1955.
22 D. J. Dixon, S. V. Ley, D. J. Reynolds and M. S. Chorghade,
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem., 2001, 40,
1043 and references therein.
23 D. J. Dixon, S. V. Ley and D. J. Reynolds, Chem. Eur. J., 2002, 8,
1621 and references therein.
24 D. G. Zhai, W. X. Zhai and R. M. Williams, J. Am. Chem. Soc.,
1988, 110, 2501.
25 P. Deslongchamps, Pure Appl. Chem., 1993, 65, 1161.
26 F. Perron and K. F. Albizati, Chem. Rev., 1989, 89, 1617.
27 E. Fischer, Chem. Ber., 1893, 26, 2400.
28 A. F. Bockov and G. E. Zaikov, Chemistry of the O-Glycoside Bond,
Pergamon Press, Oxford, 1979, 11.
29 R. S. Mann and T. R. Lien, J. Catal., 1969, 15, 1.
30 M. L. Mihailovic, S. Gojokovic and S. Konstantinovic, Tetrahedron,
1973, 29, 3675.
31 I. T. Kay and E. G. Williams, Tetrahedron Lett., 1983, 24, 5915.
32 NMR analysis confirmed that the spiroketals were present as single
diastereoisomers, although unambiguous assignment of the
stereochemistry could not be achieved by NOE studies due to
coincidental signals for important protons. The predicted most
thermodynamically stable diastereoisomer is shown in each case.
33 E. J. Corey and P. L. Fuchs, Tetrahedron Lett., 1972, 3769.
34 G. Shi, Z. M. Gu, K. He, K. V. Wood, L. Zeng, Q. Ye, J. M.
MacDougal and J. L. McLaughlin, Bioorg. Med. Chem., 1996, 4,
1281.
CHH ), 1.28 (10 H, m, 5 × CH2), 0.87 (3 H, t, J 6.5, CH3); 13
C
NMR (100 MHz) δ (mix of isomers) = 86.1, 86.0, 82.7, 82.6,
80.5, 79.3, 67.8, 67.6, 51.2, 51.1, 35.9, 35.5, 33.4, 33.2, 31.8,
31.7, 31.2, 31.1, 29.6, 29.6, 29.2, 29.2, 26.2, 26.1, 22.6, 14.0;
m/z (ESI) found 247.1666 [M ϩ Na]ϩ C12H24O2Na requires
247.1674).
35 X. Cai, M. S. Chorghade, A. Fura, G. S. Grewal, K. A. Jauregui,
H. A. Lounsbury, R. T. Scannell, C. G. Yeh, M. A. Young, S. X. Yu,
L. Guo, R. M. Moriarty, R. Penmasta, M. S. Rao, R. K. Singhal,
Z. Z. Song, J. P. Staszewski, S. M. Tuladhar and S. M. Yang, Org.
Process Res. Dev., 1999, 3, 73.
36 O. Mitsunobu, Synthesis, 1981, 1.
Acknowledgements
37 We are grateful to Dr Neil Feeder and Dr John Davies of the
Department of Chemistry, Cambridge, UK for the determination of
the single crystal X-ray structure. Single crystals of 65 were
recystallised from ethyl acetate, mounted in inert oil and transferred
to the cold gas stream of the diffractometer. Crystal data.
C15H17F1O3, M = 264.29, orthorhombic, a = 6.8956(2), b = 8.0263(2),
c = 25.0635(7) Å, U = 1387.17(7) Å3, T = 250(2) K, space group
P212121, Z = 4, µ(Mo–Ka) = 0.096 mmϪ1, 3124 reflections measured.
The final wR(F2) was 0.1868 (all data). The Flack parameter was
Ϫ0.7(17). CCDC reference number 229787. See http://www.rsc.org/
suppdata/ob/b3/b316858a/ for crystallographic data in.cif or other
electronic format.
38 Q. H. Huang, J. A. Hunter and R. C. Larock, J. Org. Chem., 2002,
67, 3437.
39 Y. Kita, R. Okunaka, T. Honda, M. Shindo, M. Taniguchi,
M. Kondo and M. Sasho, J. Org. Chem., 1991, 56, 119.
40 M. E. Fox, A. B. Holmes, I. T. Forbes and M. Thompson, J. Chem.
Soc., Perkin Trans. 1, 1994, 3379.
The authors would like to thank the EPSRC (to D.J.D. and
D.J.R.), the University of Cambridge (to R.I.S.), the Novartis
Research Fellowship (to S.V.L.), the BP Research Endowment
(to S.V.L.) and Pfizer Global Research and Development,
Groton, USA for generous financial support for this work.
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1154