Synthesis of 2,6-cis-disubstituted 4-methylenetetrahydropyrans by oxy-Michael addition

Article abstract of DOI:10.1016/j.tet.2011.03.113

The combination of an 'ene' reaction between a 2-(2-trialkylsilyloxyalkyl) prop-2-enyl(trimethyl)silane and an alk-1-yn-3-one mediated by zinc(II) iodide, and an intramolecular oxy-Michael reaction, provides an efficient synthesis of cis-2,6-disubstituted 4-methylenetetrahydropyrans of interest in the context of a synthesis of bryostatins. The stereoselective formation of (E)-vinylsilanes in the 'ene' reaction is of interest.

Full text of DOI:10.1016/j.tet.2011.03.113

Tetrahedron 67 (2011) 5034e5045
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 2,6-cis-disubstituted 4-methylenetetrahydropyrans by oxy-Michael
addition
*
Duncan Gill, Nicholas H. Taylor, Eric J. Thomas
School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The combination of an ‘ene’ reaction between a 2-(2-trialkylsilyloxyalkyl)prop-2-enyl(trimethyl)silane
and an alk-1-yn-3-one mediated by zinc(II) iodide, and an intramolecular oxy-Michael reaction, provides
an efficient synthesis of cis-2,6-disubstituted 4-methylenetetrahydropyrans of interest in the context of
a synthesis of bryostatins. The stereoselective formation of (E)-vinylsilanes in the ‘ene’ reaction is of
interest.
Received 14 February 2011
Received in revised form 10 March 2011
Accepted 29 March 2011
Available online 16 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
4-Methylenetetrahydropyran
oxy-Michael addition
Ene reactions
Allyl silane
Vinyl silane
1. Introduction
The hemiacetal at C(9) in bryostatins is synthetically equivalent
to the corresponding hydroxyketone, see partial structure 2. When
The bryostatins, as represented by bryostatin 1 (1), are a group
of important natural products of interest because of their anti-
cancer and other biological activities.1 However, the supply of
bryostatins from natural sources is limited and this has led to
a considerable body of work being carried out on their synthesis
including the completion of several total syntheses2 and the syn-
thesis of analogues.3,4 The synthesis of fragments has also been of
interest.1
planning a synthesis of this fragment, the formation of the OeC(11)
bond by an intramolecular oxy-Michael reaction was considered an
attractive option since many alternatives would be available for the
synthesis of the oxy-Michael precursor 3. However, these oxy-
Michael reactions involve skipped dienes conjugated to a ketone
that might be prone to double bond migration and isomerisation.
There was also the question as to the stereoselectivity of the cyc-
lisation reaction. We here report studies into the assembly of
4-methylenetetrahydropyrans corresponding to the C(7)eC(16)
fragment of brysotatins, albeit lacking the methoxycarbonyl moi-
ety, using the oxy-Michael approach.5,6
Me
Me
H
HO
O
Me
O
MeO2C
9
O
11
O
H
H
O
O
Me
Me
Me
Me
H
9
11
9
15
5
OP
5
OP
5
OH
MeO2C
11
O
H
PO
15
O
OH
O
15
OH
H
OH
OP
O
Me
Me
3
2
(P = protecting groups)
O
Me
CO2Me
OH
n
2. Results and discussion
Pr
O
1
In preliminary studies, a Stille reaction was used to synthesize
an oxy-Michael precursor 13, see Scheme 1. 2-(Acetoxymethyl)
prop-2-enylstannane 67 was prepared by stannylation of 2-meth-
ylprop-2-enol 4 followed by acetylation of the resulting 2-hydrox-
ymethylpropenylstannane 5. The boron trifluoride mediated
* Corresponding author. E-mail address: e.j.thomas@manchester.ac.uk
(E.J. Thomas).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.113

D. Gill et al. / Tetrahedron 67 (2011) 5034e5045
5035
reaction of this stannane with benzaldehyde gave the homoallylic
alcohol 77 that was converted into its tert-butyldimethylsilyl ether 8.
This was taken though to the Stille precursor 11 by saponification
and conversion of the resulting alcohol 9 into the stannane 11 via
a Barbier reaction of the corresponding bromide 10. The Stille cou-
pling of the propenylstannane 11 with 4,4-dimethyl-1-iodopent-
1-en-3-one (12)8 was more effective using PdCl2(MeCN)2 as the
catalyst and gave the dienone 13. Desilylation of this dienone with in
situ cyclisation using HF$pyridine gave the 2,6-cis-disubstituted
4-methylenetetrahydropyran 14 in a 79% yield.
2,6-cis- and 2,6-trans-disubstituted 4-methylenetetrahydropyr-
ans 22 and 23 in overall isolated yields of 61% and 11%.
Similar results were obtained using toluene 4-sulfonic acid in
acetonitrile or pyridinium toluene 4-sulfonate in ethanol for the
deprotectionecyclisation (Scheme 2).
ii, iii
O
X
Me3Si
+
OTIPS
Br
OR
15 X = Br
16 X = SiMe3
17
18 R = H
19 R = TBS
i
OTIPS
OAc
OR1
X
v - vii
+
iii, iv
Me3Si
H
Me
OR
OTBS
Me
Me
R2
Me
6
Ph
Me
Me
iv
Ph
8
O
OTBS
4 R1 = R2 = H
9 X = OH
10 X = Br
11 X = SnBu3
7 R = H
8 R = TBS
i
O
5 R1 = H, R2 = SnBu3
6 R1 = Ac, R2 = SnBu3
OTIPS
ii
20
21
+
Me
Me
H
Me
Me
Me
Me
v
Me
viii
ix
Me
Me
6
O
I
H
Me
Me
O
OTBSO
H
Me
Me
H
Me
Me
2
Ph
O
Ph
6
6
O
H
H
+
14
12
13
O
O
O
2
2
Scheme 1. Reagents and conditions: i, nBuLi, TMEDA, Et2O, ꢀ30 ꢁC to rt, 20 h, nBu3SnCl,
OAc
OAc
0
ꢁC to rt, 15 min (59%); ii, Ac2O, Et3N, DMAP, DCM, rt, 10 h (88%); iii, BF3$Et2O, PhCHO,
DCM, ꢀ78 ꢁC, 1.5 h (99%); iv, tBuMe2SiOTf, 2,6-lutidine, DCM, 0 ꢁC then rt, 3 h; v, K2CO3,
H2O, MeOH, rt, 2 h (91% from 7); vi, (a) MsCl, Et3N, DCM, 0 ꢁC to rt, 3 h (b) NaBr, DMF, rt,
18 h (64%); vii, (nBu3Sn)2O, Mg, 1,2-dibromoethane, 35 ꢁC, sonicate, 1 h (73%); viii,
PdCl2(MeCN)2, DMF, 80 ꢁC, 4 h (45%); ix, HF$pyridine, MeCN, rt, 12 h (79%).
23
22
Scheme 2. Reagents and conditions: i, Cl3SiH, Et3N, CuCl, Et2O, 0 ꢁC to rt, 15 h, then
MeMgBr, Et2O, rt, 15 h (70%); ii, 16, Me3SiCl, Mg, THF, reflux, then 17, CuI, THF, rt, 1 h
(95%); iii, BuMe2SiOTf, 2,6-lutidine, DCM, rt, 18 h (90%); iv, 4 A sieves, ZnI2, DCM, rt,
t
ꢀ
24 h (52%); iv, HF, MeCN, rt, 18 h, then Ac2O, py, DCM, rt, 18 h (22, 61%; 23, 11%).
The structure assigned to the methylenetetrahydropyran 14 was
supported by spectroscopic data. In particular, the relative stereo-
chemistry at C(2) and C(6) was assigned on the basis of a significant
NOE enhancement of H(6) on irradiation of H(2) and vice versa. The
axial hydrogens at C(3) and C(5) were also clearly observable as
triplets with coupling constants of 11.5 Hz consistent with diaxial
coupling to the hydrogens at C(2) and C(6).
The formation of this 2,6-cis-disubstituted stereoisomer 14 was
not unexpected since its 2- and 6-substituents are both equatorial
with respect to the six-membered ring, but whether this was due to
kinetic or thermodynamic control was not clear at this stage.
However, this reaction was usefully stereoselective in that the
2,6-trans-isomer was not isolated.
The stereoselective formation of the 4-methylenetetrahy-
dropyran 14 from dienone 13 by deprotection and a subsequent
oxy-Michael reaction shows that this chemistry is compatible with
a skipped diene. However, a more efficient synthesis of oxy-
Michael precursors was required. Using mild Lewis acids, allyl(-
trimethyl)silanes have been shown to undergo ‘ene’ reactions with
propargylic ketones in a reaction, which preserves the trime-
thylsilyl group,9 and this chemistry was investigated for the syn-
thesis of oxy-Michael precursors with additional functionality.
2-Bromo-3-trimethylsilylpropene (16) was prepared from
2,3-dibromopropene 15 by treatment with trichlorosilane in the
presence of triethylamine and copper(I) chloride followed
by the reaction with methylmagnesium bromide.10 Treatment of
the racemic epoxide 17, in the presence of copper(I) iodide, with
the Grignard reagent generated from the bromide 16, gave the
homoallylic alcohol 18, which was protected as its tert-butyldi-
methylsilyl ether 19. The zinc(II) iodide-catalysed ‘ene’ reaction
of this allylsilane with 4,4-dimethylpent-1-yn-3-one (20)
retained the trimethylsilyl group and gave the (E)-vinylsilane 21
as the only isolated product. The one-pot deprotectionecycli-
sation of the dienone 21 was then carried out using hydrogen
fluoride in acetonitrile and, after acetylation, gave the separable
The structure of the (E)-vinylsilane 21 formed during the ‘ene’
reaction was assigned on the basis of 1H NMR NOE studies in that
a significant enhancement of the methylene proton was observed
on irradiation of 8-H2 but not on irradiation of 6-H2 and was con-
sistent with later studies of similar reactions. The retention of the
silyl group has precedent, indeed the reaction conditions chosen
were known to result in retention of the silyl group. However, the
literature examples9 involve cyclohexenylmethylsilanes and the
high stereoselectivity of the ‘ene’ process in an open-chain system
was not expected. Mechanistic aspects of the reaction were not
studied, but a two-step process via the silicon stabilized carbenium
ion 24 may be involved. If this is the case, the observed stereo-
selectivity is consistent with an intramolecular proton transfer to
the enolate carbon via a six-membered chair-like transition struc-
ture, see structure 25 in Fig. 1. A similar transition structure could
be drawn for a concerted process.
OZnI
R
SiMe3
t
Bu
.
H
I
Me3Si
H
-
+
Zn
I
O
+
H
R
24
IZn
Me3Si
Me
O
Me
Me
SiMe3
H
H
t
Bu
.
O
OTBS
H
+
H
R
OTIPS
21
25
Fig. 1. Formation of (E)-vinylsilane 21.

5036
D. Gill et al. / Tetrahedron 67 (2011) 5034e5045
O
The major product from the oxy-Michael reaction of dienone 21
OH
O
Me Me
PO
Me
was identified as the 2,6-cis-diastereoisomer 22 from 1H NMR data.
PO
Me
ii
i
O
In particular, axial-axial coupling was observed between H(2) and
OH OP
H(3)ax and between H(6) and H(5)ax
.
Me
Me
The analogous cyclisation of the 2-(trimethylsilylethoxy)-
methoxy (SEM) protected hydroxyketone 29 was also in-
vestigated, see Scheme 3. Copper(I)-catalysed ring-opening of the
SEM-protected epoxide 26 using the Grignard reagent derived
from the bromopropenylsilane 16 gave the alcohol 27, which was
protected as its tert-butyldimethylsilyl ether 28. The ‘ene’ reaction
of this allylsilane with the alkynyl ketone 20 gave the (E)-vinyl-
silane 29 with excellent stereoselectivity although other Lewis
acids, including zinc(II) chloride and bromide, trimethylsilyl tri-
fluoromethanesulfonate and bis(cyclopentadienyl)titanium(II)
trifluoromethanesulfonate gave complex mixtures of products.
37 P = PMB
38 P = Bn
33 P = PMB
34 P = Bn
35 P = PMB
36 P = Bn
iii or iv
Me Me
Me Me
Me Me
v
vi
OHC
OP
OH OP
O
OP
39 P = PMB
40 P = Bn
41 P = PMB
42 P = Bn
43 P = PMB
44 P = Bn
+
Me3Si
Me Me
Me3Si
H
Me
Me
Me
vii
iii
O
i, ii
Me3Si
OSEM
H
Me3Si
6
8
OTBS
OSEM
OR
O
OP
OTBS
O
OTBS
OSEM
OSEM
OSEM
29
27 R = H
28 R = TBS
26
45 P = PMB
46 P = Bn
(R)-28
iv or v
X
viii or ix
Me
X
Me
Me
Me
Me
H
Me
Me
H
Me
Me
Me
6
O
6
O
X
X
H
H
Me Me
Me Me
+
O
O
O
H
H
OTBS
2
2
6
O
6
O
H
H
+
OSEM
OR
OR
O
OP
O
OP
2
2
31 X = SiMe3, R = SEM
23 X = H, R = Ac
32
30 X = SiMe3, R = SEM
22 X = H, R = Ac
OR
OR
Scheme 3. Reagents and conditions: i, 16, Me3SiCl, Mg, THF, reflux, then 26, CuI, THF,
47 X = H, P = PMB, R = Ac
48 X = SiMe3, P = PMB, R = SEM
49 X = H, P = Bn, R = Ac
50 X = H, P = PMB, R = Ac
51 X = SiMe3, P = PMB, R = SEM
52 X = H, P = Bn, R = Ac
t
ꢀ
rt, 1 h (88%); ii, BuMe2SiOTf, 2,6-lutidine, DCM, rt, 18 h (77%); iii, 4 A sieves, ZnI2, DCM,
rt, 24 h (62%); iv, HF$pyridine, THF, 0 ꢁC to rt, 18 h (30, 38%; 31, 38%); v, HF, MeCN, rt,
18 h, then Ac2O, py, DCM, rt, 18 h (22, 62%; 23, 10%).
Scheme 4. Reagents and conditions: i, DIBAL-H, THF, ꢀ78 to ꢀ35 ꢁC, 5 h (35, 87%; 36,
n
88%); ii, Ph3PMeBr, THF, BuLi, ꢀ78 to 0 ꢁC, 30 min., ꢀ78 ꢁC, add 35 or 36, rt, 15 h (37,
ꢀ
59%; 38, 82%); iii, TPAP, NMO, 4 A sieves, DCM, rt, 3 h (39, 77%); iv, DMSO, (COCl)2,
Desilylation of the dienylketone 29 was studied under various
conditions. With HF$pyridine in tetrahydrofuran, a 50:50 mixture
of the 2,6-cis- and 2,6-trans-disubstituted 4-(trimethylsilyl-
methylene)tetrahydropyrans 30 and 31 was obtained in which the
vinylic trimethylsilyl and the SEM groups had been retained. Tetra-
n-butylammonium fluoride effected desilylation and double bond
migration but no cyclisation to give the open-chain product 32 as
a mixture of (E)- and (Z)-isomers (82%). However, hydrogen fluo-
ride in acetonitrile with in situ acetylation of the products gave the
previously obtained 2,6-cis- and 2,6-trans-disubstituted methyl-
enetetrahydropyrans 22 and 23, ratio 22/23¼85:15, as before.
The geometry of the vinylsilane 29 was assigned by analogy with
geometry of vinylsilane 21 and was consistent with later work. The
less polar 4-(trimethylsilylmethylene)tetrahydropyran was pro-
visionally identified as the 2,6-cis-epimer 30 by analogy with other
series. The (E)-geometry of its exocyclic double bond was confirmed
by NOE studies since the exocyclic methylene proton, 4-CH, was
significantly enhanced on irradiation of one of the hydrogens at C(3)
but was not affected by either of the hydrogens at C(5).
The less stereoselective desilylation and cyclisation of dien-
ylketone 29 induced by HF$pyridine, may reflect kinetic control,
whereas the more stereoselective reactions of both dienylketones
21 and 29 using hydrogen fluoride in acetonitrile may be due to
thermodynamic control under the more acidic conditions. This
point was not investigated further at this stage. Rather it was de-
cided to study the use of slightly more complex alkynylketones,
which would allow for the subsequent development of the C(1)e
C(8) fragment of bryostatins. The synthesis and cyclisations of the
dienylketones 45 and 46 are outlined in Scheme 4.
DCM, ꢀ78 ꢁC, 1 h, Et3N (40, 94%); v, HCCMgBr, THF, ꢀ78 ꢁC, rt, 18 h (41, 50:50, 96%; 42,
54:46, 93%); vi, DesseMartin periodinane, DCM, 0 ꢁC, rt, 3 h (43, 92%; 44, ca. 100%); vii,
ꢀ
4 A sieves, ZnI2, DCM, rt, 24 h (45, 66%; 46, 75%); viii, HF, MeCN, rt, 18 h, then Ac2O, py,
rt, 18 h (47, 46%; 50, <6%; 49, 66%; 52, 6%); ix, HF$pyridine, THF, 0 ꢁC, rt, 18 h (48, 21%;
51, 21%).
Protection of (R)-pantolactone as its 4-methoxybenzyl ether 33
followed by reduction gave the lactol 35 that was converted into
the pentenol 3711 via a Wittig condensation. Oxidation and addition
of ethynylmagnesium bromide to the resulting aldehyde 39 gave
the propargylic alcohol 41 as a 50:50 mixture of separable epimers.
Oxidation gave the ketone 43 and the zinc(II) iodide promoted ‘ene’
reaction of this ketone with the (R)-enantiomer of the allylsilane 28
gave the trienylketone 45 with excellent stereoselectivity.
The one-pot deprotection and cyclisation of ketone 45 using HF
in acetonitrile gave predominantly the 2,6-cis-4-methylenete-
trahydropyrans 47 after acetylation, the 2,6-cis-47/2,6-trans-50
ratio being ca. 85:15, but only in a modest yield (52%) perhaps due
to the lability of the 4-methoxybenzyl group under these condi-
tions. The 2,6-cis-configuration of the major isomer 47 was con-
firmed by 1H NMR, axialeaxial coupling being observed between
H(2) and H(3)ax and between H(6) and H(5)ax
.
With HF$pyridine, deprotection and cyclisation of ketone 45
proceeded with retention of the trimethylsilyl and SEM groups but,
as observed for the cyclisation of dienone 29, a 50:50 mixture of the
epimeric (E)-4-(trimethylsilylmethylene)tetrahydropyrans 48 and
51 was obtained.
At this stage, since the cyclisation of dienone 45 using HF in
acetonitrile had given only a modest yield of the cyclised products

D. Gill et al. / Tetrahedron 67 (2011) 5034e5045
5037
47 (and 50), the benzyl protected cyclisation precursor 46 was
prepared from benzyl protected (R)-pantolacone, see Scheme 4. In
this case, the configuration of the vinylsilane 46, prepared from the
zinc(II) iodide promoted reaction between the allylsilane (R)-28
and the alkynyl ketone 44 was confirmed by NOE. Cyclisation of
dienone 46 using HF in acetonitrile gave the desilylated 4-meth-
ylenetetrahydropyrans 49 and 52 in a 78% yield, ratio 90:10. The
2,6-cis-configuration assigned to the major isomer 49 was con-
firmed by 1H NMR in that a significant NOE enhancement of H(2)
was observed on irradiation of H(6) and vice versa. Moreover, both
the 2- and 6-substituents were shown to be equatorial in this major
isomer by the observation of trans-diaxial coupling between H(2)
Hydroboration of the 2,6-cis-disubstituted methylenetetrahy-
dropyran 53 took place preferentially on the exocyclic methylene
group to give a mixture of epimeric primary alcohols 55 after oxi-
dation of the intermediate organoborane. Similarly, epoxidation of
the analogous tert-butyldiphenylsilyl ether 56 also took place on
the exocyclic methylene group to give a mixture of the exocyclic
epoxides 58. Although it is likely that these reactions took place
selectively from the equatorial direction on the less hindered face of
the methylenetetrahydropyrans 53 and 56, the configurations
of the major products 55 and 58 were not formally confirmed
although reasonable stereoselectivities were observed.
and H(3)ax and between H(6) and H(5)ax
.
3. Summary and conclusions
To complete a synthesis of the C(1)eC(16) fragment of the
bryostatins, the exocyclic methylene group of the 2,6-disubstituted
4-methylenetetrahydropyrans would need to be converted ster-
eoselectively into the required 4-(methoxycarbonylmethylene)
moiety and the terminal double-bond elaborated into the C(1)e
C(5) fragment. Since it was possible that the primary acetate sub-
stituent would limit the chemistry, which could be used for these
conversions the analogous SEM- and tert-butyldiphenylsilyl-pro-
tected 4-methylenetetrahydropyrans 53/54 and 56/57 were pre-
pared by cyclisation of dienone 46 using HF in acetonitrile followed
by protection of the primary alcohol using either SEM or tert-
butyldiphenylsilyl chloride, see Schemes 5 and 6.
The oxy-Michael reaction of skipped dienones has proved useful
for the synthesis of 4-methylenetetrahydropyrans that may be
useful in the context of a synthesis of bryostatins.5,6 Deprotection
with in situ cyclisation of the hydroxyl protected dienones 13, 21,
29, 45 and 46, under acidic conditions using hydrogen fluoride in
acetonitrile, gave 2,6-cis-disubstituted 4-methylenetetrahydropyr-
ans preferentially. The analogous deprotection and cyclisation re-
actions of dienones 29 and 45 under less acidic conditions using
hydrogen fluoride in pyridine were less stereoselective. It is sug-
gested that the cyclisations in acetonitrile are under thermody-
namic control since the 2,6-cis-disubstituted tetrahydropyrans, in
which the 2- and 6-substituents are both equatorial, are believed to
be the more stable. Also of interest in this work are the stereo-
selective ‘ene’ reactions between 2-substituted allylsilanes and
propargylic ketones, which gave (E)-vinylsilanes with excellent
stereoselectivity even for the acyclic systems.9 Although giving the
wrong stereoisomer in these cases for conversion with retention of
configuration into the 4-(methoxycarbonylmethylene)tetrahy-
dropyran present in bryostatins,2g these reactions may be useful in
the general context of the stereoselective synthesis of skipped di-
enes. Finally, the exocyclic epoxide 58, prepared by regioselective
epoxidation of diene 56, after cleavage to the corresponding ketone,
should provide access to the required 4-(methoxycarbonyl-
methylene)tetrahydropyran on treatment with the appropriate
enantiomerically enriched phosphine oxide.2d Details of the com-
pletion of a synthesis of the C(1)eC(16) fragment of a bryostatin
using this chemistry will be reported elsewhere.12
Me Me
Me Me
H
H
6
O
i
6
O
H
+
H
46
O
OBn
O
OBn
2
2
OSEM
OSEM
53
54
ii
Me Me
H
H
HO
6
O
H
O
OBn
2
OSEM
55
4. Experimental
4.1. General
Scheme 5. Reagents and conditions: i, HF, MeCN, rt, 18 h, then SEMCl, iPr2NEt, DCM, rt,
15 h (53, 48%; 54, 9%); ii, 9-BBN, THF, rt, 18 h, aq NaOH (3 M), H2O2 (30%), rt, 3 h (73%,
70:30 mixture of epimers).
Melting points were recorded on a Gallenkamp apparatus, and
optical rotations measured on an AA-100 polarimeter at 589 nm.
Proton NMR spectra were recorded using Varian Unity Inova 300
and Varian Unity 500 spectrometers. Coupling constants are given
in hertz and chemical shifts relative to Me4Si. IR spectra were
recorded on an ATI Mattson Genesis FTIR spectrometer and were
run as liquid films unless otherwise stated. Low resolution mass
spectra were measured on a Fisons Trio 2000 spectrometer and
high resolution spectra on a Kratos Concept-IS spectrometer.
Chromatography refers to flash chromatography using Merck
silica gel 60H (40e63 nm3, 230e400 mesh). Light petroleum refers
to the fraction boiling at 40e60 ꢁC and ether to diethyl ether. All
solvents and reagents were purified by standard techniques and all
non-aqueous reactions were performed under an atmosphere of
dry argon or nitrogen.
Me Me
Me Me
H
H
i
6
O
6
O
46
H
H
+
O
OBn
O
OBn
2
2
OTBDPS
OTBDPS
57
56
ii
Me Me
H
O
6
H
O
O
OBn
2
OTBDPS
4.2. Experimental procedures
58
Scheme 6. Reagents and conditions: i, HF, MeCN, rt, 18 h, then tBuPh2SiCl, imid., DCM,
rt, 18 h (56, 57%; 57, 10%); ii, m-CPBA, DCM, 0 ꢁC, 5 h (95%, 85:15 mixture of epimers).
4.2.1. 3-Acetoxymethyl-1-phenylbut-3-en-1-ol
6 (5.73 g, 14 mmol) and boron trifluoride diethyletherate (4.4 mL,
(7)7. Stannane

5038
D. Gill et al. / Tetrahedron 67 (2011) 5034e5045
36 mmol) were added to benzaldehyde (1.2 mL, 12 mmol) in
dichloromethane (22 mL) at ꢀ78 ꢁC. After 1.5 h, the reaction
mixture was poured into saturated aqueous ammonium chloride.
The aqueous solution was extracted with ether and the combined
organic extracts were dried (Na2SO4) and concentrated under
reduced pressure. Chromatography of the residue using petrol/
ether (2:1) gave the title compound 7 (2.60 g, 99%) as a colourless
extracted with ethyl acetate (3ꢂ20 mL). The combined organic
extracts were washed with brine (20 mL), dried (MgSO4) and
concentrated under reduced pressure. Flash chromatography using
petrol as eluent gave the title compound 11 (1.17 g, 2.06 mmol, 73%)
as a colourless oil; nmax 669, 776, 835, 944, 1069, 1085, 1255, 1463,
1627 cmꢀ1
; dH (300 MHz, CDCl3) 0.00 and 0.19 (each 3H, s, SiCH3),
0.98e1.38 [24H, m, 3ꢂCH3CH2CH2CH2Sn and SiC(CH3)3], 1.38e1.50
(6H, m, 3ꢂCH3CH2CH2CH2Sn), 1.58e1.68 (6H, m, 3ꢂCH3CH2-
CH2CH2Sn), 1.85 and 2.00 (each 1H, d, J 11, 1-H), 2.31 and 2.49 (each
1H, dd, J 13.5, 5.0, 3-H), 4.60 and 4.72 (each 1H, t, J 9.5, 2-CH), 4.92
(1H, dd, J 8.0, 5.0, 4-H) and 7.35e7.47 (5H, m, ArH); dC (75 MHz,
CDCl3) ꢀ5.03, ꢀ4.76, 9.37, 13.62, 18.14, 19.40, 25.79, 27.29, 28.90,
50.01, 74.79, 107.87, 125.87, 126.75, 127.83, 145.68, 146.32; m/z (EI)
509 (Mþꢀ57, 20%), 507 (15), 451 (10), 449 (7), 291 (90), 289 (80), 41
(100).
oil; nmax 1050, 1235, 1375, 1739, 3447 cmꢀ1
; dH (300 MHz, CDCl3)
2.15 (3H, s, CH3CO), 2.31 (1H, s, OH), 2.54 (2H, m, 2-H2), 4.61 and
4.63 (each 1H, d, J 15.0, 13.0, 3-CH), 4.90 (1H, t, J 6.5, 1-H), 5.13 and
5.23 (each 1H, s, 4-H), 7.41 (5H, m, ArH); dC (75 MHz, CDCl3) 21.0,
38.2, 43.7, 66.7, 72.5, 115.9, 125.6, 127.6, 128.4, 140.5, 143.7; m/z
(EI) 220 (Mþ, 10%), 203 (75), 143 (100), 107 (99), 79 (62), 72 (64),
43 (55); HRMS (CI): MþþNH4, found 238.1437. C13H20NO3 re-
quires 238.1443.
4.2.2. 4-tert-Butyldimethylsilyloxy-2-methylene-4-phenylbut-1-yl(-
tributyl)stannane (11). tert-Butyldimethylsilyl trifluoromethane/
sulfonate (2.52 g, 9.52 mmol) was added to the alcohol 7 (1.40 g,
6.36 mmol) and 2,6-lutidine (1.36 g, 12.7 mmol) in dichloro-
methane (20 mL) at 0 ꢁC and the mixture allowed to warm to
ambient temperature, stirred for 3 h, then poured into saturated
aqueous ammonium chloride (50 mL). The aqueous layer was
separated and extracted with dichloromethane (2ꢂ50 mL). The
combined organic extracts were dried (MgSO4) and concentrated
under reduced pressure to give the acetate 8 as a colourless oil; dH
(300 MHz, CDCl3) 0.00 and 0.17 (each 3H, s, SiCH3), 1.03 [9H, s,
SiC(CH3)3], 2.25, (3H, s, CH3CO), 2.56 (1H, dd, J 13.5, 5, 3-H), 2.63
(1H, dd, J 13.5, 6.3, 3-H0), 4.65 and 4.72 (each 1H, d, J 10, 1-H), 4.95
(1H, m, 4-H), 5.07 and 5.24 (each 1H, m, 2-CH), 4.72 (5H, m, ArH); dC
(75 MHz, CDCl3) ꢀ5.11, ꢀ4.78, 18.09, 20.85, 25.73, 44.75, 67.09,
74.35, 115.46, 125.83, 127.04, 127.96, 140.40, 144.74, 170.57. This
acetate was dissolved in methanol (20 mL) and saturated aqueous
potassium carbonate (2 mL) was added. The mixture was stirred at
ambient temperature for 2 h then concentrated under reduced
pressure. Ethyl acetate (20 mL) was added and the mixture was
washed with saturated aqueous ammonium chloride (20 mL) and
brine (20 mL), then dried (MgSO4) and concentrated under reduced
pressure. Chromatography using petrol/ether (95:5) as eluent gave
the alcohol 9 (1.69 g, 5.78 mmol, 91%) as a colourless oil. Methane
sulfonic anhydride (2.02 g, 11.6 mmol) was added to the alcohol 9
(1.70 g, 5.82 mmol) and triethylamine (2.94 g, 29.1 mmol) in
dichloromethane (20 mL) at 0 ꢁC and the mixture stirred at ambi-
ent temperature for 3 h then poured into saturated aqueous am-
monium chloride (20 mL). The aqueous layer was extracted with
dichloromethane (2ꢂ50 mL) and the combined organic extracts
were washed with brine (50 mL), dried (MgSO4) and concentrated
under reduced pressure to give the corresponding methanesulfo-
nate as a brown oil. This sulfonate was dissolved in N,N-dime-
thylformamide (10 mL) and sodium bromide (2.40 g, 23.3 mmol)
was added. The mixture was stirred at ambient temperature for
18 h then poured into water (50 mL). The mixture was extracted
with ether (3ꢂ50 mL) and the combined organic extracts were
washed with brine (50 mL), dried (MgSO4) and concentrated under
reduced pressure. Chromatography using petrol/ether (99:1) as
eluent gave the bromide 10 (1.32 g, 3.71 mmol, 64%) as a colourless
oil; dH (300 MHz, CDCl3) 0.00 and 0.19 (each 3H, s, SiCH3), 1.04 [9H,
s, SiC(CH3)3], 2.73 (2H, d, J 6.0, 3-H2), 4.10 (2H, s, 2-CH2), 4.99 (1H, t, J
6.0, 4-H), 5.08 and 5.37 (each 1H, s, 1-H), 7.45 (5H, m, ArH); dC
(75 MHz, CDCl3) ꢀ5.06, ꢀ4.75, 18.10, 25.76, 37.54, 44.46, 74.50,
118.27, 125.84, 127.10, 128.00, 142.20, 144.54. Magnesium turnings
(0.155 g, 6.48 mmol) was added to 1,2-dibromoethane (0.583 g,
3.10 mmol), the bromide 10 (1.00 g, 2.82 mmol) and bis(tributyltin)
oxide (1.68 g, 2.82 mmol) in tetrahydrofuran (10 mL) and the
mixture sonicated at 35 ꢁC for 1 h. It was then poured into saturated
aqueous ammonium chloride (20 mL) and the mixture was
4.2.3. (E)-9-tert-Butyldimethylsilyloxy-2,2-dimethyl-7-methylene-9-
phenylnon-4-en-3-one (13). Vinyl iodide 128 (44 mg, 0.177 mmol),
allylstannane 11 (100 mg, 0.177 mmol) and bis(acetonitrile)
dichloropalladium(II) (9 mg, 0.036 mmol) were heated at 80 ꢁC in
degassed N,N-dimethylformamide (5 mL) for 4 h. The mixture was
allowed to cool to ambient temperature, water (10 mL) was added
and the mixture was extracted with ether (3ꢂ10 mL). The com-
bined organic extracts were washed with brine (10 mL), dried
(MgSO4) and concentrated under reduced pressure. Chromatogra-
phy using petrol/ether (99:1) as eluent gave the title compound 13
(31 mg, 0.080 mmol, 45%) as a colourless oil; nmax 700, 777, 836,
1069, 1091, 1256, 1364, 1473, 1623, 1692 cmꢀ1
; dH (300 MHz, CDCl3)
0.00 and 0.19 (each 3H, s, SiCH3), 1.04 [9H, s, SiC(CH3)3], 1.33 [9H, s,
C(CH3)3], 2.48 (1H, dd, J 13.5, 5.0, 8-H), 2.61 (1H, dd, J 13.5, 8.0, 8-H0),
3.04 (2H, d, J 7.0, 6-H2), 4.92 (1H, dd, J 8.0, 5.0, 9-H), 5.00 (2H, s,
7-CH2), 6.64 (1H, d, J 15.0, 4-H), 7.08 (1H, dt, J 15.0, 7.0, 5-H),
7.38e7.48 (5H, m, ArH); dC (75 MHz, CDCl3) ꢀ5.06, ꢀ4.73, 18.11,
25.75, 26.09, 39.58, 42.74, 47.41, 74.68, 114.76, 125.57, 125.84,
127.00, 127.95, 142.94, 144.31, 144.98, 204.02.
4.2.4. (2RS,6SR)-6-(2-Oxo-3,3-dimethylbutyl)-4-methylene-2-phenyl-
tetrahydropyran (14). Hydrogen fluorideepyridine complex (0.1 mL)
was added to the dienone 13 (25 mg, 0.065 mmol) in acetonitrile
(0.5 mL) at ambient temperature and the mixture stirred for 12 h.
Saturated aqueous sodium hydrogen carbonate (10 mL) was added
and the mixture was extracted with ethyl acetate (3ꢂ10 mL). The
combined organic extracts were washed with saturated copper(II)
sulfate solution (10 mL), water (10 mL) and brine (10 mL), then
dried (MgSO4) and concentrated under reduced pressure. Chro-
matography of the residue using petrol/ether (98:2) gave the title
compound 14 (14 mg, 0.051 mmol, 79%) as a colourless oil; dH
(300 MHz, CDCl3) 1.34 [9H, s, C(CH3)3], 2.21 (1H, t, J 11.5, 5-H), 2.42
(1H, t, J 11.5, 3-H), 2.64 (2H, m, 3-H0 and 5-H0), 2.79 and 3.22 (each
1H, dd, J 16.5, 6.5, 10-H), 4.20 (1H, dtd, J 11.5, 6.5, 2.5, 6-H), 4.56 (1H,
dd, J 11.5, 2.5, 2-H), 5.03 (2H, m, 4-CH2), 7.40e7.60 (5H, m, ArH); dC
(75 MHz, CDCl3) 25.99, 40.17, 42.49, 43.12, 44.25, 75.12, 80.12,
109.35, 125.67, 127.30, 128.19, 142.29, 143.77, 213.45; m/z (CI) 290
(Mþþ18, 80%), 273 (Mþþ1, 100), 255 (Mþꢀ17, 50); HRMS (CI): Mþ,
found 272.1774. C18H24O2 requires 272.1776.
4.2.5. 2-(Tri-iso-propylsilyloxymethyl)oxirane (17). Imidazole (9.2 g,
149 mmol) was added to (ꢃ)-glycidol (2 g, 27 mmol) in DCM
(50 mL), followed by tri-iso-propylsilyl chloride (5.8 mL, 27 mmol)
and the solution stirred at rt for 18 h. Saturated aqueous ammo-
nium chloride (20 mL) was added and the organic layer was
washed with DCM (40 mL). The combined organic extracts were
washed with water (40 mL) and brine (40 mL), dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue using ether/petrol (4:96) as eluent gave the title compound
17 (5.28 g, 86%) as a colourless oil; nmax 684, 780, 843, 883, 918, 991,

D. Gill et al. / Tetrahedron 67 (2011) 5034e5045
5039
1103, 1254, 1385, 1164 cmꢀ1
;
dH (300 MHz, CDCl3) 1.11 [21H, m,
zinc(II) iodide (1.87 g, 5.8 mmol) was added. The mixture was stirred
for 24 h, then the orange solution was filtered though Celite and the
filtrate washed with DCM (2ꢂ20 mL) and ethyl acetate (10 mL). After
dilution with DCM (30 mL) and water (50 mL), the mixture was
shaken until the orange colour had faded. The aqueous layer was
washed with DCM (2ꢂ20 mL) and the combined organic extracts
were washed with water (20 mL), brine (20 mL), (MgSO4) and con-
centrated under reduced pressure. Chromatography of the residue
using ether/petrol (1:99) as the eluent gave the title compound 21
(1.15 g, 52%) as a colourless oil; nmax 683, 775, 838, 990, 1087, 1116,
3ꢂSiCH(CH3)2], 2.71 (1H, dd, J 3, 5, 3-H), 2.82 (1H, dd, J 4, 5, 3-H0),
3.16 (1H, m, 2-H), 3.80 (1H, dd, J 4.5, 11.5, 10-H) and 3.96 (1H, dd,
J 3.5,11.5,10-H0); dC (75 MHz, CDCl3) 11.87,17.82, 44.38, 52.50, 63.86;
m/z (CI) 248 (Mþþ18, 100%), 231 (48), 162 (11); HRMS (CI):
MþþNH4, found 248.2053. C12H30NO2Si requires 248.2046.
4.2.6. 1-(Tri-iso-propylsilyloxy)-4-(trimethylsilylmethyl)pent-4-en-
2-ol (18). Trimethylsilyl chloride (170 ml, 1.6 mmol) was added to
a flask containing magnesium (423 mg, 17.4 mmol) and THF
(10 mL). The mixture was heated under reflux for 1 min then cooled
to rt. The remaining solution was removed and the magnesium
washed with THF (5ꢂ10 mL). THF (10 mL) was added to the
flask followed by 2-bromo-3-trimethylsilylpropene 16 (306 mg,
1.6 mmol). The mixture was heated until the reaction was initiated
and then the remaining 2-bromo-3-trimethylsilylpropene 16
(2.75 g, 14.2 mmol) in THF (10 mL) was added at a rate so as to
maintain gentle reflux. On completion of addition, the solution was
heated under reflux for 0.5 h then allowed to cool to rt. Copper(I)
iodide (301 mg, 1.6 mmol) was added to the epoxide 17 (3.52 g,
15.3 mmol) in THF (10 mL) at ꢀ10 ꢁC followed by the solution of 2-
bromo-3-trimethylsilylpropenylmagnesium bromide. The mixture
was stirred at this temperature for 1 h and saturated aqueous
ammonium chloride (15 mL) was added. The organic layer was
washed with ether (3ꢂ10 mL) and the combined organic extracts
were washed with aqueous ammonia (10%, 20 mL), water (20 mL)
and brine (20 mL), then dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue using ether/
petrol (3:97) as the eluent gave the title compound 18 (5.26 g, 95%)
as a colourless oil; nmax 685, 795, 853, 955, 1065, 1117, 1249, 1385,
1250, 1364, 1466, 1621, 1693 cmꢀ1
; dH (300 MHz, CDCl3) 0.00 and
0.01 (each 3H, s, SiCH3), 0.07 [9H, s, Si(CH3)3], 0.83 [9H, s, SiC(CH3)3],
1.02 [21H, m, 3ꢂSiCH(CH3)2], 1.11 (9H, s, 1-H3 and 2ꢂ2-CH3), 2.06
(1H, dd, J 8, 13.5, 8-H), 2.40 (1H, dd, J 4, 13.5, 8-H0), 3.04 (2H, dd, J 1.5,
6.5, 6-H2), 3.42 (1H, dd, J 7, 9.5, 10-H), 3.58 (1H, dd, J 5, 9.5, 10-H0),
3.76 (1H, m, 9-H), 5.45 (1H, s, 7-CH), 6.46 (1H, dt, J 15, 1.5, 4-H), 6.88
(1H, dt, J, 15, 6.5, 5-H); dC (75 MHz, CDCl3) ꢀ4.66, ꢀ4.39, 0.17, 11.87,
17.96, 18.04, 25.85, 26.08, 39.20, 42.82, 44.08, 67.18, 72.77, 125.05,
129.91, 144.90, 151.83, 203.82; m/z (CI) 586 (Mþþ18, 26%), 569
(Mþþ1, 44), 174 (18), 132 (17), 90 (100) and 58 (26); HRMS (CI):
MþþH, found 569.4248. C31H65O3Si3 requires 569.4241.
4.2.9. (2RS,6SR)- and (2RS,6RS)-2-Acetoxymethyl-4-methylene-6-
(3,3-dimethyl-2-oxobutyl)tetrahydropyrans (22) and (23). Aqueous
hydrogen fluoride (58e62%, 100 ml) was added dropwise to the
dienone 21 (40 mg, 0.07 mmol) in acetonitrile (1 mL) in a Teflon
tube and the solution stirred for 18 h. Saturated aqueous sodium
hydrogen carbonate was added until effervescence ceased and the
mixture diluted with DCM (10 mL) and water (10 mL). The aqueous
layer was washed with DCM (2ꢂ10 mL) and the combined organic
extracts were washed water (10 mL) and brine (10 mL), then dried
(MgSO4) and concentrated under reduced pressure. Pyridine
1418, 1464, 1632, 3465 cmꢀ1
; dH (300 MHz, CDCl3) 0.00 [9H, s,
Si(CH3)3], 1.04 [21H, m, 3ꢂSiCH(CH3)2], 1.56 (2H, m, 4-CH2), 2.12
(2H, m, 3-H2), 2.42 (1H, d, J 3, OH), 3.55 (1H, dd, J 7.5, 10, 1-H), 3.65
(1H, dd, J 4.5, 10, 1-H0), 3.79 (1H, m, 2-H), 4.61 and 4.66 (each 1H, m,
5-H); dC (75 MHz, CDCl3) ꢀ1.46, 11.84, 17.89, 26.71, 42.06, 67.01,
69.91, 109.82 and 144.09; m/z (CI) 345 (Mþþ1, 7%), 327 (50), 289
(42), 255 (95), 234 (20), 216 (50), 174 (21), 132 (42) and 90 (100);
HRMS (CI): MþþH, found 345.2641. C18H41O2Si2 requires 345.2645.
(100 ml), DCM (500 ml) and acetic anhydride (300 ml) were added
and the solution was stirred at rt for 18 h. Saturated aqueous am-
monium chloride (10 mL) and DCM (10 mL) were added and the
organic layer was washed with DCM (2ꢂ10 mL). The combined
organic extracts were washed with brine (10 mL), dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
residue using ether/petrol (5:95) as the eluent gave the major di-
astereoisomer of the title compound 22 (11.5 mg, 61%) as a colour-
less oil; nmax 769, 840, 895, 992, 1049, 1108, 1169, 1329, 1333, 1368,
4.2.7. 2-(tert-Butyldimethylsilyloxy)-1-(tri-iso-propylsilyloxy)-4-(tri-
methylsilylmethyl)pent-4-ene (19). 2,6-Lutidine (960 ml, 8.7 mmol)
was added to the pentenol 18 (1.5 g, 4.35 mmol) in DCM (10 mL),
followed by tert-butyldimethylsilyl trifluoromethane sulfonate
(1 mL, 4.35 mmol). The solution was stirred at rt for 18 h then
saturated ammonium chloride (10 mL) was added. The aqueous
layer was washed with DCM (2ꢂ10 mL) and the combined organic
extracts were washed with water (10 mL) and brine (10 mL), then
dried (MgSO4) and concentrated under reduced pressure. Chro-
matography of the residue using petrol as the eluent gave the title
compound 19 (1.79 g, 90%) as a colourless oil; nmax 684, 776, 838,
1475, 1655, 1706, 1741 cmꢀ1
; dH (300 MHz, CDCl3) 1.08 (9H, s, 4"-H3
and 2ꢂ3"-CH3), 1.85 (1H, t, J 11.5, 5-H), 2.00 (1H, br t, J 11.5, 3-H),
2.02 (3H, s, CH3CO), 2.22 (1H, d, J 12.5, 3-H0), 2.28 (1H, d, J 12, 5-H0),
2.47 (1H, dd, J 6.5, 16.5, 1"-H), 2.88 (1H, dd, J 6, 16.5, 1"-H0), 3.59 (1H,
m, 2-H), 3.85 (1H, ddt, J 2.5, 6, 12, 6-H), 4.06 (1H, dd, J 4, 11.5, 10-H),
4.12 (1H, dd, J 6.5, 11.5, 10-H0), 4.81 and 4.83 (each 1H, d, J 2, 4-CH);
dC (75 MHz, CDCl3) 20.78, 25.96, 36.49, 40.03, 42.89, 44.78, 66.64,
74.89, 75.81, 109.87, 142.57, 170.81, 213.38; m/z (CI) 286 (Mþþ18,
68%), 269 (Mþþ1, 100) and 169 (2); HRMS (CI): MþþH, found
269.1748. C15H25O4 requires 269.1753. The minor diastereoisomer
of the title compound 23 (2 mg, 11%) was isolated as a colourless oil;
dH (300 MHz, CDCl3) 1.06 (9H, s, 4"-H3 and 2ꢂ3"-CH3), 1.94 (1H, dd,
J 6, 13, 5-H), 2.02 (4H, m, CH3CO and 3-H), 2.25 (1H, dd, J 4, 13, 3-H0),
2.38 (1H, dd, J 4.5, 13, 5-H0), 2.61 (1H, dd, J 5, 17, 1"-H), 2.70 (1H, dd,
J 7, 17, 1"-H0), 3.88 (1H, dq, J 4.5, 11.5, 2-H), 3.98 and 4.11 (each 1H,
dd, J 7,11.5,10-H), 4.35 (1H, m, 6-H), 4.72 and 4.76 (each 1H, s, 4-CH);
dC (75 MHz, CDCl3) 20.84, 26.11, 36.02, 38.73, 39.74, 44.29, 65.05,
69.29, 70.35, 111.41, 140.52, 170.89 and 212.99.
Alternatively, toluene 4-sulfonic acid (1 mg, 0.01 mmol) was
added to a stirred solution of dienone 21 (40 mg, 0.07 mmol) in
acetonitrile (1 mL) and water (one drop) and the solution was heated
to 50 ꢁC overnight. DCM (10 mL) and water (10 mL) were added and
the aqueous layer was washed with DCM (2ꢂ10 mL). The combined
organic extracts were washed water (10 mL) and brine (10 mL), then
dried (MgSO4) and concentrated under reduced pressure.
878, 992, 1066, 1115, 1251, 1465, 1633 cmꢀ1
; dH (300 MHz, CDCl3)
0.00 [9H, s, Si(CH3)3], 0.03 (6H, s, 2ꢂSiCH3), 0.86 [9H, s, SiC(CH3)3],
1.05 [21H, m, 3ꢂSiCH(CH3)2], 1.53 (2H, d, J 4, 4-CH2), 1.99 (1H, dd,
J 7.5, 13.5, 3-H), 2.30 (1H, dd, J 4.5, 13.5, 3-H0), 3.48 (1H, dd, J 6.5, 9.5,
1-H), 3.60 (1H, dd, J 5, 9.5, 1-H0), 3.78 (1H, m, 2-H), 4.55 and 4.63
(each 1H, m, 5-H); dC (75 MHz, CDCl3) ꢀ4.73, ꢀ4.48, ꢀ1.49, 11.88,
17.95, 25.85, 26.94, 43.42, 67.37, 72.38, 109.93 and 144.12; m/z (CI)
459 (Mþþ1, 0.2%), 403 (30), 327 (88), 216 (36),174 (70),170 (29) and
90 (100); HRMS (CI): MþþH, found 459.3517. C24H55O2Si3 requires
459.3510.
4.2.8. (E)-9-(tert-Butyldimethylsilyloxy)-2,2-dimethyl-10-(tri-iso-
propylsilyloxy)-7-[(E)-trimethylsilylethylidene]dec-4-en-3-one
(21). Activated powdered 4 A molecular sieves (500 mg) were
added to the allylsilane 19 (1.79 g, 3.9 mmol) and ketone 20 (857 mg,
7.8 mmol) in DCM (1 mL). The flask was screened from light and
ꢀ

5040
D. Gill et al. / Tetrahedron 67 (2011) 5034e5045
Alternatively, pyridinium toluene 4-sulfonate (10 mg, 0.02 mmol)
found 336.2386. C15H38NO3Si2 requires 336.2390. The (R)-epoxide
was added to the dienone 21 (40 mg, 0.07 mmol) in ethanol (1 mL)
and the solution was heated to 60 ꢁC overnight. DCM (10 mL) and
water (10 mL) were added and the aqueous layer was washed with
DCM (2ꢂ10 mL). The combined organic extracts were washed water
(10 mL) and brine (10 mL), then dried (MgSO4) and concentrated
under reduced pressure.
Following the procedure outlined for the synthesis of tetrahy-
dropyrans 22 and 23 from dienone 21, treatment of the dienone 29
(80 mg, 0.15 mmol) in acetonitrile (2 mL) with aqueous hydrogen
(R)-26 gave the (R)-enantiomer of alcohol 27; [
a
]
20 ꢀ 0.6 (c 1.0
D
in DCM).
4.2.12. 2-tert-Butyldimethylsilyloxy-1-(trimethylsilylethoxy)me-
thoxy-4-(trimethylsilylmethyl)pent-4-ene (28). 2,6-Lutidine (5.3 mL,
45.6 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate
(5.8 mL, 25.1 mmol) were added to the alcohol 27 (7.2 g,
22.7 mmol) in DCM (50 mL) at 0 ꢁC and the solution stirred at rt for
18 h. Saturated aqueous ammonium chloride (30 mL) was added
and the organic layer was washed with DCM (2ꢂ20 mL). The
combined organic extracts were washed with water (20 mL) and
brine (20 mL), then dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using ether in petrol
(2:98) as the eluent gave the title compound 28 (7.55 g, 77%) as
a colourless oil; nmax 693, 775, 836, 992,1058,1109,1156,1251,1468,
1633; dH (300 MHz, CDCl3) 0.00 [18H, s, 2ꢂSi(CH3)3], 0.04 (6H, s,
2ꢂSiCH3), 0.86 [9H, s, SiC(CH3)3], 0.92 (2H, m, CH2Si), 1.52 (2H, s, 4-
CH2), 2.07 (1H, dd, J 6.5, 14, 3-H), 2.18 (1H, dd, J 6.0, 14, 3-H0), 3.40
(1H, dd, J 6, 10, 1-H), 3.46 (1H, dd, J 4.5, 10, 1-H0), 3.59 (2H, m,
OCH2CH2Si), 3.91 (1H, m, 2-H), 4.56 and 4.62 (each 1H, m, 5-H), 4.65
(2H, m, OCH2O); dC (75 MHz, CDCl3) ꢀ4.76, ꢀ4.56, ꢀ1.49, ꢀ1.45,
18.05, 25.83, 26.99, 43.55, 64.93, 70.57, 71.89, 95.05, 110.09, 128.25,
143.76; m/z (CI) 450 (Mþþ18, 1%), 301 (9), 243 (11) and 90 (100);
HRMS (CI): MþþNH4, found 450.3262. C21H52NO3Si3 requires
450.3255. The (R)-alcohol (R)-27 gave the (R)-enantiomer of the
fluoride (58e62%, 200
ml) and acetylation using pyridine (500
ml),
DCM (500 l) and acetic anhydride (500
m
m
l) gave the tetrahy-
dropyran 22 (24 mg, 62%) as a colourless oil and the tetrahy-
dropyran 23 (4 mg, 61%) also as a colourless oil.
4.2.10. 2-(2-Trimethylsilylethoxymethoxy)methyloxirane (26). Di-iso-
propylethylamine (36 mL, 135 mmol) and 2-trimethylsilylethox-
ymethyl chloride (12 mL, 67.6 mmol) were added to (ꢃ)-glycidol
(5.00 g, 64.1 mmol) at 0 ꢁC in DCM (100 mL) and the solution
stirred at rt for 16 h. Saturated aqueous ammonium chloride
(50 mL) was added and the organic layer was washed with
DCM (50 mL). The combined organic extracts were washed with
water (50 mL) and brine (50 mL), dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue using ethyl
acetate/petrol (11:89) as eluent gave the title compound 26 (9.55 g,
73%) as a colourless oil; nmax 694, 762, 837, 859, 1056, 1109, 1156,
silyl ether 28; [
a]
2D0ꢀ 0.2 (c 1.0 in DCM).
1194, 1249, 1378, 1409 cmꢀ1
; dH (300 MHz, CDCl3) 0.00 [9H, s,
Si(CH3)3], 0.92 (2H, m, SiCH2), 2.61 (1H, dd, J 3, 5, 3-H), 2.79 (1H, dd,
J 4, 5, 3-H0), 3.15 (1H, m, 2-H), 3.50 (1H, dd, J 6, 11.5, 2-CH), 3.62 (2H,
m, OCH2CH2Si), 3.77 (1H, dd, J 3.5, 11.5, 2-CH0), 4.68 (2H, s, OCH2O);
dC (75 MHz, CDCl3) ꢀ1.50, 18.01, 44.44, 50.58, 65.21, 68.16, 94.95;
m/z (CI) 222 (Mþþ18, 38%), 205 (Mþþ1, 4), 164 (10), 131 (22), 90
(100); HRMS (CI): MþþNH4, found 222.1522. C9H24NO3Si requires
222.1525. (S)-(ꢀ)-Glycidol gave the (R)-enantiomer (R)-26 with
4.2.13. (E)-9-(tert-Butyldimethylsilyloxy)-2,2-dimethyl-10-(trime-
thylsilylethoxy)methoxy-7-[(E)-trimethylsilylethylidene]dec-4-en-3-
one (29). Activated powdered 4 A molecular sieves (1 g) were
ꢀ
added to the allylsilane 28 (1.53 g, 3.56 mmol) and the alkynone 20
(200 mg, 1.78 mmol) in DCM (1.5 mL). The flask was screened from
light and zinc(II) iodide (0.58 g, 1.82 mmol) was added. The mixture
was stirred for 24 h, then the resulting orange solution was filtered
though Celite and the filtrate washed with DCM (20 mL) and ethyl
acetate (10 mL). The solution was diluted with DCM (20 mL) and
water (30 mL) and shaken until the orange colour had faded. The
aqueous layer was washed with DCM (2ꢂ20 mL) and the combined
organic extracts were washed with water (20 mL) and brine
(20 mL), then dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using ether/petrol (3:97)
as the eluent gave the title compound 29 (610 mg, 62%) as a col-
ourless oil; nmax 692, 775, 838, 936, 987, 1057, 1110, 1195, 1251, 1366,
[
a]
2D0ꢀ2.3 (c 1.0 in DCM).
4.2.11. 1-(2-Trimethylsilylethoxy)methoxy-4-(trimethylsilylmethyl)
pent-4-en-2-ol (27). Trimethylsilyl chloride (330 l, 2.6 mmol) was
m
added to magnesium (996 mg, 40.1 mmol) and THF (20 mL). The
mixture was heated under reflux for 1 min then cooled to rt. The
remaining solution was removed and the magnesium washed with
THF (5ꢂ20 mL). THF (20 mL) was added followed by 2-bromo-3-
trimethylsilylpropene (0.55 g, 2.85 mmol). The mixture was heated
until the reaction was initiated and the 2-bromo-3-trimethylsilyl-
propene 16 (4.95 g, 25.6 mmol) in THF (10 mL) was added at a rate
so as to maintain gentle reflux. On completion of the addition the
solution was heated under reflux for 0.5 h then allowed to cool to
rt. Copper iodide (494 mg, 2.6 mmol) was added to the epoxide 26
(5.3 g, 26 mmol) in THF (20 mL) at ꢀ10 ꢁC followed by the solution
of 2-bromo-3-trimethylsilylpropylmagnesium bromide. The mix-
ture was stirred at this temperature for 1 h then saturated aqueous
ammonium chloride (30 mL) was added. The organic layer was
washed with ether (3ꢂ30 mL) and the combined organic extracts
were washed aqueous ammonia (10%, 20 mL), water (20 mL) and
brine (20 mL), then dried (MgSO4) and concentrated under re-
duced pressure. Chromatography of the residue using ethyl ace-
tate/petrol (1:10) as the eluent gave the title compound 27 (7.2 g,
88%) as a colourless oil; nmax 694, 840, 857, 1033, 1055, 1114, 1157,
1471, 1619, 1692 cmꢀ1
; dH (300 MHz, CDCl3) 0.00 [9H, s, Si(CH3)3],
0.01 and 0.04 (each 3H, s, SiCH3), 0.08 [9H, s, Si(CH3)3], 0.85 [9H, s,
SiC(CH3)3], 0.91 (2H, m, CH2Si), 1.12 (9H, s, 1-H3 and 2ꢂ2-CH3), 2.12
(1H, dd, J 7, 13, 8-H), 2.31 (1H, dd, J 4,13, 8-H0), 3.04 (2H, dd, J 1.5, 6.5,
6-H2), 3.40 (2H, m, 10-H2), 3.58 (2H, m, CH2CH2Si), 3.89 (1H, m, 9-
H), 4.63 (2H, s, OCH2O), 5.45 (1H, s, 7-CH), 6.48 (1H, d, J 15, 4-H),
6.87 (1H, dt, J 15, 6.5, 5-H); dC (75 MHz, CDCl3) ꢀ4.69, ꢀ4.47, ꢀ1.48,
ꢀ0.15, 18.03, 25.82, 26.05, 39.09, 42.83, 44.27, 64.99, 70.84, 71.97,
95.08, 125.23, 130.06, 144.62, 151.26; m/z (CI) 560 (Mþþ18, 8%), 203
(3), 174 (9), 132 (21) and 90 (100); HRMS (CI): MþþNH4, found
560.3977. C28H62NO4Si3 requires 560.3986.
4.2.14. (2RS,6SR)- and (2RS,6RS)-6-(3,3-Dimethyl-2-oxobutyl)-2-(tri-
methylsilylethoxymethoxy)methyl-4-[(E)-trimethylsilylmethylene]tet-
rahydropyrans (30) and (31). A Teflon tube was charged with the
dienone 29 (200 mg, 0.37 mmol) in dry THF (7 mL) and the solution
1249, 1417, 1632, 3465 cmꢀ1
; dH (300 MHz, CDCl3) 0.00 [18H, s,
cooled to 0 ꢁC. HF$pyridine (250
ml) was added and the mixture
2ꢂSi(CH3)3], 0.93 (2H, m, CH2Si), 1.55 and 1.56 (each 1H, d, J 13.5,
4-CH), 2.12 (2H, m, 3-H2), 2.60 (1H, d, J 3, OH), 3.44 (1H, dd, J 5,
10.5, 1-H), 3.62 (3H, m, 1-H0 and OCH2CH2Si), 3.90 (1H, m, 2-H),
4.66 (4H, m, 5-H2 and OCH2O); dC (75 MHz, CDCl3) ꢀ1.50, ꢀ1.46,
18.02, 26.58, 42.30, 65.32, 68.36, 72.71, 95.38, 110.21, 143.73; m/z
(CI) 336 (Mþþ18, 0.5%), 132 (9) and 90 (100); HRMS (CI): MþþNH4,
stirred for 0.5 h at 0 ꢁC and at rt for 18 h. Ether (20 mL) was added
followed by saturated aqueous sodium hydrogen carbonate until
effervescence ceased. The organic layer was washed with ether
(2ꢂ10 mL) and the combined organic extracts were washed with
water (10 mL) and brine (10 mL), then dried (MgSO4) and

D. Gill et al. / Tetrahedron 67 (2011) 5034e5045
5041
concentrated under reduced pressure. Chromatography of the resi-
due using ether/petrol (6:94) as eluent gave the 2,6-cis-di-
astereoisomer of the title compound 30 (60 mg, 38%) as a colourless
oil; nmax 692, 725, 838, 936, 987, 1057, 1110, 1195, 1251, 1366, 1410,
(1:2) as eluent gave the title compound 36 (13.8 g, 88%) as a colour-
less oil, a 75:25 mixture of diastereoisomers; nmax 699, 739, 909,
1042, 1132, 1204, 1361, 1394, 1463, 3356 cmꢀ1
; dH (300 MHz, CDCl3)
1.11 (0.75H, s, 4-CH3), 1.15 and 1.16 (each 2.25H, s, 4-CH3), 1.17
(0.75H, s, 4-CH3), 3.05 (0.75H, br s, OH), 3.48 (0.25H, d, J 10, 3-H),
3.52 (0.25H, m, OH), 3.57 (0.75H, d, J 3, 3-H), 3.69 (0.75H, d, J 8.5, 5-
H), 3.77 (0.25H, d, J 8, 5-H), 3.86 (0.75H, d, J 8.5, 5-H), 4.04 (0.25H, d,
J 8, 5-H), 4.63 (0.75H, d, J 12, HCHAr), 4.68 and 4.72 (each 0.25H, d, J
12, HCHAr), 4.75 (0.75H, d, J 12, HCHAr), 5.42 (0.75H, t, J 3.5, 2-H),
5.51 (0.25H, dd, J 4.5, 10, 2-H), 7.37 (5H, m, ArH); dC (75 MHz, CDCl3)
19.76, 20.33, 21.49, 24.01, 25.70, 42.02, 72.30, 74.31, 78.59, 78.85,
85.26, 91.39, 97.50, 102.77, 127.37, 127.48, 127.75, 127.88, 128.09,
128.24, 128.44, 128.50; m/z (CI) 240 (Mþþ18, 29%), 223 (Mþþ1, 13),
222 (Mþ, 100), 205 (7), 108 (9); HRMS (CI): Mþ, 222.1261. C13H18O3
requires 222.1256.
1471, 1619 cmꢀ1
; dH (300 MHz, CDCl3) 0.00 and 0.09 [each 9H, s,
Si(CH3)3], 0.92 (2H, m, CH2Si), 1.11 (9H, s, 400-H3 and 2ꢂ300-CH3), 1.80
(1H, br t, J 12, 5-H), 2.13 (2H, m, 3-H2), 2.53 (1H, m, 5-H0), 2.59 (1H,
dd, J 6.5, 17, 100-H), 2.92 (1H, dd, J 5, 17, 100-H0), 3.52 (5H, m, 2-H, 10-H2
and CH2CH2Si), 3.77 (1H, m, 6-H), 4.67 (2H, s, OCH2O), 5.26 (1H, s,
4-CH); dC (75 MHz, CDCl3) ꢀ1.47, 0.14, 18.00, 26.04, 39.48, 41.55,
43.19, 44.14, 64.96, 70.44, 74.68, 77.51, 94.95, 124.04, 152.17, 213.11;
m/z (CI) 446 (Mþþ18, 31%), 211 (23), 179 (12), 90 (100); HRMS (CI):
MþþNH4, found 446.3122. C22H48NO4Si3 requires 446.3122. The 2,6-
trans-diastereoisomer of the title compound 31 (60 mg, 38%) was
isolated as a colourless oil; dH (300 MHz, CDCl3) 0.00 and 0.06 [each
9H, s, Si(CH3)3], 0.92 (2H, m, CH2Si), 1.11 (9H, s, 2ꢂ300-CH3 and 400-H3),
2.16 (2H, m, 3-H and 5-H), 2.32 (1H, dd, J 3.5,13.5, 3-H0), 2.52 (1H, dd,
J 4.5, 13.5, 5-H0), 2.61 (1H, dd, J 5, 17.5, 100-H), 2.87 (1H, dd, J 4.5, 17.5,
100-H0), 3.51 (1H, dd, J 5, 10.5, 10-H), (3H, m, 10-H0 and CH2CH2Si), 3.90
(1H, m, 2-H), 4.32 (1H, br dq, J 4.5, 9, 6-H), 4.67 (2H, s, OCH2O), 5.32
(1H, s, 4-CH); dC (75 MHz, CDCl3) ꢀ1.44, 0.17, 18.04, 26.30, 38.16,
40.58, 40.97, 44.21, 65.06, 68.73, 69.19, 71.95, 95.02, 126.00, 150.04,
213.30.
4.2.17. (3S)-3-(4-Methoxybenzyloxy)-2,2-dimethylpent-4-en-1-ol
(37). nButyllithium (1.61 M in hexanes, 172 mL, 276 mmol) was
added dropwise to methyltriphenylphosphonium bromide (81 g,
227 mmol) in THF (300 mL) at ꢀ78 ꢁC. The solution was allowed to
warm to 0 ꢁC, stirred for 0.5 h then cooled to ꢀ78 ꢁC. The lactol 35
(20 g, 79.3 mmol) in THF (100 mL) was added dropwise and the
mixture was allowed to warm to rt and was stirred overnight.
Aqueous ammonium chloride (100 mL) was added and the mix-
ture diluted with DCM (200 mL) and water (200 mL). The aqueous
layer was washed with DCM (3ꢂ100 mL) and the combined or-
ganic extracts were washed with water (100 mL) and brine
(100 mL), then dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using ethyl acetate/
petrol (25:75) as the eluent gave the title compound 37 (11.8 g,
4.2.15. 9-tert-Butyldimethylsilyloxy-2,2,7-trimethyl-10-[(trimethylsi-
lylethoxy)methoxy]deca-4,6-dien-3-one (32). TBAF (1 M in THF,
55
m
l, 0.055 mmol) was added to the dienone 29 (30 mg,
l) and the solution stirred for 4 h. Water
0.055 mmol) in THF (500
m
(10 mL) and ether (10 mL) were added and the organic layer was
washed with ether (2ꢂ10 mL). The combined organic extracts were
washed with water (10 mL) and brine (10 mL), dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue using ether/petrol (3:97) as eluent gave the title compound
32 (21 mg, 82%) as a colourless oil, a 66:33 mixture of geometrical
isomers; nmax 776, 836, 1062, 1109, 1250, 1365, 1471, 1587, 1626,
59%) as a colourless oil, [
a
]2D0þ41.9 (c 1.0 in DCM); nmax 823, 1037,
1175, 1248, 1301, 1465, 1513, 1613, 3439 cmꢀ1
; dH (300 MHz,
CDCl3) 0.91 (6H, s, 2ꢂ2-CH3), 2.92 (1H, br m, OH), 3.55 and 3.58
(each 1H, dd, J 5, 11, 1-H), 3.63 (1H, d, J 8.5, 3-H), 3.84 (3H, s,
OCH3), 4.26 and 4.58 (each 1H, d, J 11.5, HCHAr), 5.27 and 5.41
(each 1H, m, 5-H), 5.84 (1H, ddd, J 8.5, 10.5, 17.5, 4-H), 6.91 and
7.27 (each 2H, d, J 9.5, ArH); dC (75 MHz, CDCl3) 19.70, 22.56,
38.44, 55.18, 69.93, 71.31, 87.72, 113.76, 119.58, 129.37, 130.05,
134.93, 159.12; m/z (EI) 250 (Mþ, 9%), 194 (41), 137 (16), 122 (22),
121 (100); HRMS (EI): Mþ, found 250.1573. C15H22O3 requires
250.1569.
1679 cmꢀ1
; dH (300 MHz, CDCl3) 0.01 (3H, s, SiCH3), 0.02 [6H, s,
Si(CH3)3], 0.05 (3H, s, SiCH3), 0.08 [3H, s, Si(CH3)3], 0.83 [3H, s,
SiC(CH3)3], 0.85 [6H, s, SiC(CH3)3], 0.91 (2H, m, CH2Si), 1.15 (3H, s, 1-
H3 and 2-CH3), 1.16 (6H, s, 1-H3 and 2-CH3), 1.91 (3H, m, 7-CH3),
2.22e2.62 (2H, m, 8-H2), 3.43 (2H, m, 10-H2), 3.61 (2H, m,
CH2CH2Si), 3.91 (1H, m, 9-H), 4.66 (0.66H, s, OCH2O), 4.67 (1.34H, s,
OCH2O), 6.06 (0.66H, d, J 12, 6-H), 6.11 (0.34H, d, J 12, 6-H), 6.45
(0.33H, d, J 15, 4-H), 6.47 (0.66H, d, J 15, 4-H), 7.58 (0.66H, dd, J 15,
12, 5-H), 7.60 (0.34H, dd, J 15,12, 5-H); dC (75 MHz, CDCl3) ꢀ4.90,
ꢀ4.67, ꢀ1.46, 17.97, 18.07, 25.52, 25.74, 25.77, 26.32, 38.09, 42.86,
45.75, 65.09, 70.06, 70.34, 71.80, 72.01, 95.15,122.40,122.53,126.83,
138.69, 139.23, 146.89, 147.20, 204.98; m/z (CI) 488 (Mþþ18, 8%),
471 (Mþþ1, 4), 443 (31), 413 (24), 353 (24), 130 (24), 130 (21), 90
(100); HRMS (CI): MþþH, found 471.3331. C25H51O4Si2 requires
471.3326.
4. 2.18. (3S)-3-Benzyloxy-2, 2-dimethylpent-4-en-1-ol
(38). nButyllithium (1.63 M, 95 mL, 154 mmol) was added drop-
wise to methyltriphenylphosphonium bromide (47.6 g, 133 mmol)
in THF (200 mL) at ꢀ78 ꢁC. The solution was allowed to warm to
0 ꢁC, stirred for 0.5 h, then cooled to ꢀ78 ꢁC and the lactol 36
(13.7 g, 61.7 mmol) in a THF (50 mL) was added dropwise. The
mixture was allowed to warm to rt overnight then saturated
aqueous ammonium chloride (50 mL) was added dropwise. Ether
(100 mL) and water (100 mL) were added and the aqueous was
layer washed with ether (3ꢂ50 mL). The combined organic extracts
were washed with water (50 mL) and brine (50 mL), dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
residue using ethyl acetate/petrol (1:3) as eluent gave the title
4.2.16. (3R)-3-Benzyloxy-4,4-dimethyltetrahydrofuran-2-ol
(36). DIBAL-H (1 M in THF, 107 mL, 107 mmol) was added dropwise
to the lactone 34 (15.7 g, 71 mmol) in THF (100 mL) at ꢀ78 ꢁC over
1 h and the solution warmed to ꢀ35 ꢁC and stirred for 5 h. The
mixture was cooled to ꢀ78 ꢁC and precooled methanol (10 mL) was
added. The mixture was allowed to warm slowly to 0 ꢁC, then satu-
rated aqueous ammonium chloride (100 mL) was added. Celite (20 g)
was stirred into the mixture and the suspension stirred until a gel
formed exothermically. The gel was broken up and ether (100 mL)
added. The mixture was filtered and the filter cake washed twice
with methanol in ethyl acetate (1%, 3ꢂ50 mL). The organic layer was
separated and the aqueous layer extracted with ether (3ꢂ50 mL). The
combined organic extracts were washed with water (50 mL) and
brine (50 mL), dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using ethyl acetate/petrol
compound 38 (11 g, 82%) as a colourless oil, [
a
]2D0þ17.8 (c 1.0 in
DCM); nmax 698, 737, 826, 930, 1058, 1389, 1422, 1458, 1604, 1640,
1710, 3396 cmꢀ1
; dH (300 MHz, CDCl3) 0.95 and 0.96 (each 3H, s, 2-
CH3), 2.92 (1H, br m, OH), 3.41 (1H, dd, J 4.5, 11, 1-H), 3.58 (1H, dd,
J 6, 11, 1-H0), 3.68 (1H, d, J 8.5, 3-H), 4.35 and 4.66 (each 1H, d, J 12,
HCHAr), 5.30 (1H, ddd, J 0.5, 2, 17, 5-H), 5.43 (1H, ddd, J 0.5, 2, 10.5,
5-H0), 5.86 (1H, ddd, J 8.5, 10.5, 17, 4-H), 7.30e7.45 (5H, m, ArH); dC
(75 MHz, CDCl3) 19.79, 22.48, 39.56, 70.37, 71.13, 88.01, 119.67,
127.61, 127.74, 128.34, 134.88, 138.07; m/z (CI) 238 (Mþþ18, 100%),
221 (Mþþ1, 19), 220 (Mþ, 3); HRMS (CI): MþþH, 220.1465. C14H20O2
requires 220.1463.

5042
D. Gill et al. / Tetrahedron 67 (2011) 5034e5045
20
4.2.19. (3S)-3-(4-Methoxybenzyloxy)-2,2-dimethylpent-4-enal
(39). 4-Methylmorpholine N-oxide (5.58 g, 47.7 mmol), 4 A mo-
(2.73 g, 48%) was isolated as a colourless oil; [
a
]
þ39.8; dH
D
ꢀ
(300 MHz, CDCl3) 0.97 and 1.08 (each 3H, s, 4-CH3), 2.49 (1H, d, J 2,
1-H), 3.85 (3H, s, OCH3), 4.02 (1H, d, J 8, 3-H), 4.12 (1H, d, J 8, 5-H),
4.22 (1H, d, J 8, OH), 4.34 and 4.55 (each 1H, d, J 11.5, HCHAr), 5.35
(1H, d, J 16, 7-H), 5.44 (1H, dd, J 2, 10.5, 7-H0), 5.83 (1H, ddd, J 8, 10.5,
16, 6-H), 6.91 and 7.30 (each 2H, d, J 7, ArH); dC (75 MHz, CDCl3)
19.16, 22.04, 41.12, 55.20, 70.31, 70.90, 73.55, 83.55, 86.12, 113.79,
120.01, 129.69, 129.75, 134.30, 159.25.
lecular sieves (500 mg) and tetrapropylammonium perruthenate
(558 mg, 1.6 mmol) were added to the alcohol 37 (7.95 g,
31.8 mmol) in DCM (70 mL) and the solution stirred for 3 h. The
reaction mixture was then filtered and the filter cake washed with
DCM (3ꢂ20 mL). The filtrate was diluted with water (30 mL) and
the aqueous layer was washed with DCM (2ꢂ20 mL). The combined
organic extracts were washed with water (30 mL) and brine
(30 mL), dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using ethyl acetate/petrol (17:83) as
eluent gave the title compound 39 (6.12 g, 77%) as a colourless oil,
4.2.22. (3RS,5S)-5-Benyloxy-4,4-dimethylhept-6-en-1-yn-3-ol
(42). Ethynylmagnesium bromide in THF (0.5 M, 74 mL, 37.1 mmol)
was added dropwise to the aldehyde 40 (5.42 g, 24.9 mmol) in THF
(50 mL) at ꢀ78 ꢁC. The mixture was warmed to rt and stirred for
18 h, then saturated aqueous ammonium chloride (50 mL) was
added. The aqueous layer was extracted with ether (3ꢂ50 mL) and
the combined organic extracts washed with water (50 mL) and
brine (50 mL), then dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using ethyl acetate/petrol
(1:2) as eluent gave the title compound 42 (5.65 g, 93%) as a col-
ourless oil, a 54:46 mixture of diastereoisomers; nmax 699, 743, 934,
[
a
]2D0þ4.8 (c 1.0 in DCM); nmax 822, 934, 1035, 1069, 1175, 1248, 1301,
1464, 1513, 1612, 1728 cmꢀ1
; dH (300 MHz, CDCl3) 1.00 and 1.12
(each 3H, s, 2-CH3), 3.82 (4H, m, 3-H and OCH3), 4.27 and 5.33 (each
1H, d, J 11.5, HCHAr), 5.35 (1H, m, 5-H), 5.45 (1H, dd, J 2.5, 10, 5-H0),
5.78 (1H, ddd, J 7.5, 10,18.5, 4-H), 6.90 and 7.23 (each 2H, d, J 7, ArH),
9.54 (1H, s, 1-H); dC (75 MHz, CDCl3) 16.50, 19.44, 49.55, 55.18,
69.76, 83.48, 113.64, 120.51, 129.27, 130.06, 133.66, 159.04, 205.61;
m/z (CI) 266 (Mþþ18, 27%), 138 (25), 121 (100); HRMS (CI):
MþþNH4, found 266.1757. C15H24NO3 requires 266.1756.
1056, 1210, 1388, 1417, 1461, 1640, 1709, 3299, 3435 cmꢀ1
; dH
(300 MHz, CDCl3) 0.97, 0.99, 1.10 and 1.13 (each 1.5H, s, 4-CH3), 2.46
and 2.48 (each 0.5H, d, J 2, 1-H), 3.33 (0.5H, d, J 4, OH), 3.81 (0.5H, d,
J 8.5, 5-H), 3.93 (0.5H, d, J 8.5, OH), 4.14 (0.5H, d, J 8, 5-H), 4.25 (0.5H,
dd, J 2, 8.5, 3-H), 4.36 and 4.41 (each 0.5H, d, J 11.5, HCHAr), 4.44
(0.5H, dd, J 2, 4, 3-H), 4.62 and 4.64 (each 0.5H, d, J 11.5, HCHAr),
5.25e5.50 (2H, m, 7-H2), 5.86 (1H, m, 6-H), 7.29 (5H, m, ArH); dC
(75 MHz, CDCl3) 16.57, 19.14, 20.91, 21.89, 41.20, 41.80, 70.02, 70.41,
70.65, 70.74, 73.60, 73.69, 83.00, 83.51, 86.33, 87.42, 120.10, 120.15,
127.58, 127.75, 128.06, 128.32, 128.39, 134.22, 134.71, 137.62, 137.90;
m/z (CI) 262 (Mþþ18, 100%), 245 (Mþþ1, 47); HRMS (CI): MþþNH4,
found 262.1802. C16H24NO2 requires 262.1806.
4.2.20. (3S)-3-Benzyloxy-2,2-dimethylpent-4-enal (40). DMSO (6.3 mL,
88.9 mmol) in DCM (20 mL) was added dropwise to a solution of
oxalyl chloride (3.81 mL, 44.4 mmol) in DCM (50 mL) at ꢀ78 ꢁC
over 10 min. The solution was stirred for 10 min then the alcohol 38
(8.9 g, 40.4 mmol) in DCM (30 mL) was added. After 1 h, triethyl-
amine (28.2 mL, 202 mmol) was added and the solution stirred at
ꢀ78 ꢁC for 10 min then warmed to rt. Saturated aqueous ammo-
nium chloride, water (150 mL) and DCM (50 mL) were added and
the aqueous layer was washed with DCM (2ꢂ50 mL). The combined
organic extracts were washed with water (50 mL) and brine
(50 mL), dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using ethyl acetate/petrol (14:86) as
eluent gave the title compound 40 (8.36 g, 94%) as a colourless oil,
4.2.23. (5S)-5-(4-Methoxybenzyloxy)-4,4-dimethylhept-6-en-1-yn-
3-one (43). DesseMartin periodinane (7.9 g, 18.9 mmol) was added
slowly to the mixture of epimeric alcohols 41 (5.17 g, 18.9 mmol) in
DCM (50 mL) at 0 ꢁC and the solution stirred for 3 h at rt. Aqueous
sodium hydroxide (3 M, 10 mL) was added and the mixture stirred
for 10 min. The organic layer was washed with aqueous sodium
hydroxide (3 M, 10 mL), water (30 mL) and brine (30 mL), then
dried (MgSO4) and concentrated under reduced pressure. Chro-
matography of the residue using ethyl acetate/petrol (11:89) as
eluent gave the title compound 43 (4.73 g, 92%) as a colourless oil,
[
a
]2D0þ3.5 (c 1.0 in DCM); nmax 699, 741, 800, 934, 1071, 1270, 1390,
1457, 1706 cmꢀ1
; dH (300 MHz, CDCl3) 1.22 and 1.26 (each 3H, s, 2-
CH3), 4.00 (1H, d, J 8, 3-H), 4.41 and 4.67 (each 1H, d, J 12, HCHAr),
5.37 (1H, dd, J 1, 17, 5-H), 5.45 (1H, dd, J 1.5, 10.5, 5-H0), 5.82 (1H,
ddd, J 8,10.5, 17, 4-H), 7.35 (5H, m, ArH), 9.6 (1H, s, 1-H); dC (75 MHz,
CDCl3) 19.64, 22.39, 46.56, 70.61, 85.00, 120.82, 127.47, 127.77,
128.20, 133.62, 137.91, 181.28; HRMS (CI): MþþNH4, found
236.1640. C14H22NO2 requires 236.1650.
[a
]
2D0ꢀ5.3 (c 1.0 in DCM); nmax 823, 936, 1064, 1175, 1248, 1464, 1513,
4.2.21. (3RS,5S)-5-(4-Methoxybenzyloxy)-4,4-dimethylhept-6-en-1-
yn-3-ol (41). Ethynylmagnesium bromide (0.5 M in THF, 62 mL,
31 mmol) was added dropwise to the aldehyde 39 (5.14 g,
20.7 mmol) in THF (30 mL) at ꢀ78 ꢁC and the mixture stirred for
18 h at rt. Saturated aqueous ammonium chloride (50 mL) was
added and the aqueous layer extracted with ether (3ꢂ100 mL). The
combined organic fractions were washed with water (100 mL) and
brine (100 mL), dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using ethyl acetate/petrol
(12:88) as the eluent gave one diastereoisomer of the title com-
1615, 1679, 2089 cmꢀ1
; dH (300 MHz, CDCl3) 1.14 and 1.23 (each 3H,
s, 4-CH3), 3.19 (1H, s, 1-H), 3.82 (3H, s, OCH3), 4.22 (1H, d, J 8, 5-H),
4.32 and 4.54 (each 1H, d, J 11.5, HCHAr), 5.39 (1H, d, J 17.5, 7-H),
5.46 (1H, dd, J 1.5, 10.5, 7-H0), 5.78 (1H, ddd, J 8, 10.5, 17.5, 6-H), 6.88
and 7.27 (each 2H, d, J 7, ArH); dC (75 MHz, CDCl3) 17.21, 21.45, 52.17,
55.19, 70.20, 79.31, 84.01, 113.49, 120.65, 129.28, 130.91, 133.80,
158.96, 191.42; m/z (CI) 290 (Mþþ18, 1%), 273 (Mþþ1, 0.3), 153 (12),
121 (100); HRMS (CI): Mþ, found 272.1413. C17H20O3 requires
272.1412.
pound 41a (2.73 g, 48%) as a colourless oil, [
a
]
2D0þ8.3 (c 1.0 in DCM);
4.2.24. (5S)-5-Benzyloxy-4,4-dimethylhept-6-en-1-yn-3-one
(44). DesseMartin periodinane (10.8 g, 23.2 mmol) was added
slowly to the alcohol 42 (5.65 g, 23.2 mmol) in DCM (50 mL) at 0 ꢁC.
The solution was allowed to warm to rt and was stirred for 3 h.
Aqueous sodium hydroxide (3 M, 20 mL) was added and the mix-
ture stirred for 10 min. The organic layer was then washed with
aqueous sodium hydroxide (3 M, 20 mL), water (20 mL) and brine
(20 mL), then dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using ethyl acetate/petrol
(1:9) as eluent gave the title compound 44 (5.6 g, 100%) as a col-
nmax 824, 934, 1053, 1175, 1249, 1302, 1386, 1418, 1465, 1514, 1586,
1612, 3463 cmꢀ1
; dH (300 MHz, CDCl3) 0.95 and 1.12 (each 3H, s,
4-CH3), 2.46 (1H, d J 2, 1-H), 3.53 (1H, d, J 3.5, OH), 3.78 (1H, d, J 8.5,
5-H), 3.85 (3H, s, OCH3), 4.29 (1H, d, J 11.5, HCHAr), 4.43 (1H, m,
3-H), 5.58 (1H, d, J 11.5, HCHAr), 5.32 (1H, dd, J 1.5, 18, 7-H), 5.44
(1H, dd, J 1.5, 10.5, 7-H0), 5.86 (1H, ddd, J 8.5, 10.5, 18, 6-H), 6.92 and
7.29 (each 2H, d, J 7, ArH); dC (75 MHz, CDCl3) 16.33, 21.21, 41.64,
55.19, 70.02, 73.62, 83.00, 87.30, 113.77, 120.11, 129.45, 129.85,
134.72, 159.15; m/z (CI) 292 (Mþþ18, 4%), 275 (Mþþ1, 10%), 121
(100); HRMS (CI): MþþH, found 275.1651. C17H23O3 requires
275.1647. The other diastereoisomer of the title compound 41b
ourless oil, [
a]
2D0ꢀ12.6 (c 1.0 in DCM); nmax 694, 739, 935, 1061, 1212,
1240, 1317, 1386, 1460, 1678, 2089 cmꢀ1
; dH (300 MHz, CDCl3) 1.15

D. Gill et al. / Tetrahedron 67 (2011) 5034e5045
5043
and 1.25 (each 3H, s, 4-CH3), 3.18 (1H, s, 1-H), 4.25 (1H, d, J 8, 5-H),
4.39 and 4.61 (each 1H, d, J 12, HCHAr), 5.40 (1H, d, J 17, 7-H), 5.46
(1H, d, J 10.5, 7-H0), 5.79 (1H, ddd, J 8, 10.5, 17, 6-H), 7.34 (5H, m,
ArH); dC (75 MHz, CDCl3) 17.25, 21.43, 52.17, 70.54, 79.36, 79.75,
84.37, 120.73, 127.32, 127.66, 128.09, 133.70, 138.08, 191.33; m/z (CI)
260 (Mþþ18, 100%), 243 (Mþþ1, 5); HRMS (CI): MþþNH4, found
260.1645. C16H22NO2 requires 260.1650.
CH), 5.72 (1H, ddd, J 8, 10.5, 17.5, 2-H), 6.51 (1H, d, J 15, 6-H), 6.85
(1H, dt, J 15, 7, 7-H), 7.20e7.35 (5H, m, ArH); dC (75 MHz, CDCl3)
ꢀ4.68, ꢀ4.66, ꢀ1.46, 0.18, 18.04, 19.45, 21.38, 25.83, 39.21, 44.18,
50.34, 64.99, 70.45, 70.94, 72.01, 85.07, 95.09, 119.77, 126.52, 127.24,
127.48, 128.08, 129.86, 134.44, 138.34, 144.08, 151.42, 202.33; m/z
(CI) 692 (Mþþ18, 1%), 675 (Mþþ1, 1), 90 (100); HRMS (CI): MþþH,
found 675.4290. C37H67O5Si3 requires 675.4296.
4.2.25. (3S,11R,6E)-11-tert-Butyldimethylsilyloxy-4,4-dimethyl-
3-(4-methoxybenzyloxy)-12-(2-trimethylsilylethoxy)methoxy-9-
[(E)-trimethylsilylmethylidene]dodeca-1,6-dien-5-one
4.2.27. (2R,6S)- and (2R,6R)-2-Acetoxymethyl-6-[(4S)-3,3-dimethyl-
4-(4-methoxybenzyloxy)-2-oxohex-5-enyl]-4-methylenetetrahy-
dropyrans (47) and (50). Aqueous hydrogen fluoride (58e62%,
ꢀ
(45). Activated powdered 4 A molecular sieves (500 mg) were
300 ml) was added to the trienone 45 (100 mg, 1.42 mmol) in ace-
added to alkynone 43 (1 g, 3.7 mmol) and allylsilane (R)-28 (2.84 g,
6.6 mmol) in DCM (4 mL). The flask was protected from light and
zinc(II) iodide (1.6 g, 4.9 mmol) was added. The mixture was stirred
for 24 h, filtered and the filtrate washed with DCM (20 mL) and
ethyl acetate (5 mL). DCM (20 mL) and water (20 mL) were added
and the mixture was shaken until the orange colour had faded. The
aqueous layer was washed with DCM (2ꢂ20 mL) and the combined
organic extracts were washed with water (20 mL) and brine
(20 mL), then dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using ether/petrol (3:97)
as eluent gave the title compound 45 (1.71 g, 66%) as a colourless oil,
tonitrile (1 mL) in Teflon tube. The solution was stirred for 18 h, then
ether (10 mL) was added followed by the dropwise addition of
a saturated aqueous sodium hydrogen carbonate until effervescence
ceased. The aqueous layer was washed with ethyl acetate (4ꢂ10 mL)
and the combined organic fractions were washed with water
(10 mL) and brine (10 mL), then dried (MgSO4) and concentrated
under reduced pressure. The mixture was filtered though a short
pad of silica using ethyl acetate/petrol (30:70) as eluent. The residue
was taken up in acetic anhydride (500 ml) and pyridine (500 ml) was
added. The solution was stirred for 18 h then saturated aqueous
ammonium chloride (10 mL) was added. The aqueous layer was
washed with DCM (2ꢂ10 mL) and the combined organic extracts
were washed with water (10 mL) and brine (10 mL), dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
residue using ethyl acetate/petrol (6:94) as eluent gave the (6S)-
[
a]
2D0þ1.8 (c 1.0 in DCM); nmax 774, 836, 1039, 1249, 1466, 1513, 1615,
1688 cmꢀ1
; dH (500 MHz, CDCl3) 0.02 [9H, s, Si(CH3)3], 0.03 and
0.05 (each 3H, s, SiCH3), 0.09 [9H, s, Si(CH3)3], 0.87 [9H, s,
SiC(CH3)3], 0.93 (2H, m, CH2Si), 1.05 and 1.15 (each 3H, s, 4-CH3),
2.12 (1H, dd, J 8, 13, 10-H), 2.31 (1H, dd, J 4.5, 13, 10-H0), 3.03 (2H, m,
8-H2), 3.38 and 3.42 (each 1H, dd, J 5, 10, 12-H), 3.60 (2H, m,
CH2CH2Si), 3.80 (3H, s, OCH3), 3.91 (1H, m, 11-H), 3.92 (1H, d, J 8.5,
3-H), 4.20 and 4.49 (each 1H, d, J 11.5, HCHAr), 4.64 (2H, s, OCH2O),
5.26 (1H, d, J 18, 1-H), 5.34 (1H, dd, J 1.5, 10.5, 1-H0), 5.45 (1H, s,
9-CH), 5.70 (1H, ddd, J 8, 10.5, 18, 2-H), 6.50 (1H, d, J 15, 6-H),
6.84 (3H, m, 7-H and ArH), 7.17 (2H, m, ArH); dC (75 MHz,
CDCl3) ꢀ4.68, ꢀ4.47, ꢀ1.47, 0.18, 18.02, 19.47, 21.33, 25.83, 39.18,
44.18, 50.31, 55.12, 64.98, 70.10, 70.90, 72.01, 84.68, 95.08, 113.48,
119.64, 126.56, 129.07, 129.86, 130.40, 134.53, 143.98, 151.42, 158.87,
202.39; m/z (CI) 722 (Mþþ18, 33%), 705 (Mþþ1, 28), 137 (100), 121
(78); HRMS (CI): MþþNH4, found 722.4675. C38H72NO6Si3 requires
722.4667.
20
epimer of the title compound 47 (28 mg, 46%) as a colourless oil, [
þ5.9 (c 1.0 in DCM); nmax 824, 936,1038,1174,1246,1368,1465,1513,
1611, 1706, 1740 cmꢀ1
dH (300 MHz, CDCl3) 0.89 and 1.05 (each 3H,
a]
D
;
s, 300-CH3),1.69 (1H, br t, J 12, 5-H),1.86 (1H, br t, J 12, 3-H),1.95 (3H, s,
CH3CO), 2.06 (1H, d, J 12, 3-H0), 2.18 (1H, d, J 12, 5-H0), 2.44 (1H, dd, J 7,
17, 100-H), 2.79 (1H, dd, J 6.5,17,100-H0), 3.44 (1H, m, 2-H), 3.68 (4H, m,
6-H and OCH3), 3.82 (1H, d, J 8, 400-H), 3.95 (2H, m 2-CH2), 4.06 and
4.35 (each 1H, d, J 11.5, HCHAr), 4.61 (2H, m, 4-CH2), 5.15 (1H, dd, J 2,
17.5, 600-H), 5.25 (1H, dd, J 2, 10.5, 600-H0), 5.60 (1H, ddd, J 8,10.5, 17.5,
500-H), 6.73 and 7.10 (each 2H, d, J 7, ArH); dC (75 MHz, CDCl3) 18.80,
20.83, 21.80, 36.60, 40.13, 45.02, 51.26, 55.20, 66.78, 70.17, 74.76,
75.92, 85.53, 109.73, 113.59, 120.05, 129.17, 130.45, 134.37, 142.79,
159.00, 170.86, 212.38; m/z (CI) 448 (Mþ18, 25%), 241 (4), 138 (26),
121 (100); HRMS (CI): MþþNH4, found 448.2704. C25H38NO6 re-
quires 448.2699. An impure sample tentatively identified as con-
taining the (6R)-epimer of the title compound 50 (4 mg, 6%) was
isolated as a colourless oil.
4.2.26. (3S,11R,6E)-3-Benzyloxy-11-tert-butyldimethylsilyloxy-4,4-
dimethyl-12-(2-trimethylsilylethoxy)methoxy-9-[(E)-trimethylsi-
ꢀ
lylmethylidene]dodeca-1,6-dien-5-one (46). Activated powdered 4 A
molecular sieves (1 g) were added to the alkynone 44 (2.53 g,
10.45 mmol) and allylsilane (R)-28 (8.98 g, 20.79 mmol) in DCM
(10 mL). The flask was protected from light and zinc(II) iodide (5 g,
15.67 mmol) was added. The mixture was stirred for 24 h, filtered,
and the filtrate washed with DCM (20 mL) and ethyl acetate (5 mL).
DCM (20 mL) and water (20 mL) were added and the mixture
shaken until the orange colour had faded. The aqueous layer was
washed with DCM (2ꢂ20 mL) and the combined organic extracts
were washed with water (20 mL) and brine (20 mL), then dried
(MgSO4) and concentrated under reduced pressure. Chromatogra-
phy of the residue using ether/petrol (2:98) then ethyl acetate/
petrol (6:94) as eluent gave the title compound 46 (5.26 g, 75%) as
4.2.28. (2R,6S)- and (2R,6R)-6-[(4S)-3,3-Dimethyl-4-(4-methoxybe-
nzyloxy)-2-oxohex-5-enyl]-2-(2-trimethylsilylethoxymethoxy)
methyl-4-[(E)-trimethylsilylmethylene]tetrahydropyrans (48) and
(51). HF$pyridine (125 ml) was added dropwise to the trienone 45
(100 mg, 1.42 mmol) in dry THF (4 mL) at 0 ꢁC in a Teflon tube. The
mixture was stirred for 0.5 h, allowed to warm to rt, and stirred for
18 h. Ether (10 mL) was added followed by saturated aqueous so-
dium hydrogen carbonate until effervescence ceased. The organic
layer was washed with ether (2ꢂ10 mL) and the combined organic
extracts were washed with water (10 mL) and brine (10 mL), then
dried (MgSO4) and concentrated under reduced pressure. Chro-
matography of the residue using ether/petrol (2:98) as eluent gave
the (6S)-epimer of the title compound 48 (19 mg, 21%) as a colour-
a colourless oil, [
a]
20ꢀ 1.3 (c 1.0 in DCM); nmax 695, 775, 837, 932,
D
989, 1059, 1107, 1250, 1466, 1615, 1690 cmꢀ1
;
dH (500 MHz, CDCl3)
0.02 [9H, s, Si(CH3)3], 0.03 and 0.06 (each 3H, s, SiCH3), 0.10 [9H, s,
Si(CH3)3], 0.87 [9H, s, SiC(CH3)3], 0.94 (2H, m, CH2Si), 1.08 and 1.18
(each 3H, s, 4-CH3), 2.13 (1H, dd, J 8, 13.5, 10-H), 2.30 (1H, ddd, J 1,
4.5, 13.5, 10-H0), 3.01 (1H, ddd, J 1.5, 7, 12.5, 8-H), 3.05 (1H, ddd, J 1.5,
7,12.5, 8-H0), 3.38 (1H, dd, J 5,10,12-H), 3.42 (1H, dd, J 5.5,10,12-H0),
3.60 (2H, m, CH2CH2Si), 3.90 (1H, br dq, J 5, 8, 11-H), 3.95 (1H, d, J 8,
3-H), 4.29 and 4.56 (each 1H, d, J 12, HCHAr), 4.64 (2H, s, OCH2O),
5.28 (1H, d, J 17.5, 1-H), 5.35 (1H, dd, J 1.5, 10.5, 1-H0), 5.45 (1H, s, 9-
less oil, [
a
]
20þ5.9 (c 1.0 in DCM); nmax 838, 935, 1037, 1058, 1108,
D
1249, 1466, 1514, 1616, 1706 cmꢀ1
;
dH (300 MHz, CDCl3) 0.01 and
0.11 [each 9H, s, Si(CH3)3], 0.92 (2H, m, CH2Si), 1.08 and 1.17 (each
3H, s, 300-CH3), 1.74 (1H, br t, J 13, 5-H), 2.12 (2H, m, 3-H2), 2.58 (1H,
d, J 13, 5-H0), 2.67 (1H, dd, J 8, 17.5, 100-H), 2.94 (1H, dd, J 4.5, 17.5, 100-
H0), 3.45e3.65 (5H, m, 10-H2, 2-H and CH2CH2Si), 3.74 (1H, m, 6-H),
3.76 (3H, s, OCH3), 3.95 (1H, d, J 8, 400-H), 4.18 and 4.44 (each 1H, d,
J 11.5, HCHAr), 4.67 (2H, s, OCH2O), 5.25 (1H, d, J 17, 600-H), 5.26 (1H,

5044
D. Gill et al. / Tetrahedron 67 (2011) 5034e5045
s, 4-CH), 5.34 (1H, d, J 10.5, 600-H0), 5.69 (1H, ddd, J 8, 10.5, 17, 500-H),
6.82 and 7.16 (each 2H, d, J 7, ArH). The (6R)-epimer of the title
18 h. Ether (50 mL) was added followed by aqueous saturated
sodium hydrogen carbonate until effervescence ceased. The aque-
ous layer was washed with ethyl acetate (4ꢂ20 mL) and the com-
bined organic fractions were washed with water (30 mL) and brine
(30 mL), then dried (MgSO4) and concentrated under reduced
pressure. The residue was filtered though a short pad of silica using
ethyl acetate/petrol (30:70) as the eluent. The residue was then
20
compound 51 (19 mg, 21%) was isolated as a colourless oil, [
þ17.5 (c 1.0 in DCM); nmax 838, 933, 1038, 1058, 1106, 1249, 1379,
1466, 1513, 1615, 1706 cmꢀ1
dH (300 MHz, CDCl3) 0.01 and 0.08
a]
D
;
[9H, s, Si(CH3)3], 0.94 (2H, m, CH2Si), 1.02 and 1.14 (each 3H, s, 300-
CH3), 2.08 (1H, dd, J 6.5, 13, 5-H), 2.19 (1H, dd, J 6, 13.5, 3-H), 2.35
(1H, dd, J 4.5, 13, 3-H0), 2.55 (1H, m, 100-H and 5-H0), 2.90 (1H, dd, J 5,
17.5, 100-H0), 3.58 (4H, m, 10-H2 and CH2CH2Si), 3.80 (3H, s, OCH3),
3.90 (2H, m, 400-H and 2-H), 4.10 (1H, d, J 11.5, HCHAr), 4.28 (1H, m,
6-H), 4.46 (1H, d, J 11.5, HCHAr), 4.67 (2H, s, OCH2O), 5.26 (1H, d,
J 17, 600-H), 5.32 (1H, s, 4-CH), 5.35 (1H, dd, J 1.5, 11, 600-H0), 5.69 (1H,
ddd, J 8, 11, 17, 500-H), 6.84 and 7.17 (each 2H, d, J 7, ArH).
taken up in DCM (2 mL) and SEM-chloride (345
ml, 1.39 mmol) and
di-iso-propylethylamine (490 l, 1.84 mmol) was added. The solu-
m
tion was stirred overnight then saturated aqueous ammonium
chloride (10 mL) was added. The aqueous layer was washed with
DCM (2ꢂ10 mL) and the combined organic extracts were washed
with water (10 mL) and brine (10 mL), then dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue using ethyl acetate/petrol (6:94) as eluent gave the (6S)-
epimer of the title compound 53 (355 mg, 48%) as a colourless oil,
4.2.29. (2R,6S)- and (2R,6R)-2-Acetoxymethyl-6-[(4S)-4-benzyloxy-
3,3-dimethyl-2-oxohex-5-enyl]-4-methylenetetrahydropyrans (49)
and (52). Aqueous hydrogen fluoride (58e62%, 200
m
l) was added
[a
]
20ꢀ1.1 (c 1.0 in DCM); nmax 697, 738, 836, 858, 934, 1059, 1105,
D
to the trienone 46 (100 mg, 0.14 mmol) in acetonitrile (1 mL) in
a Teflon tube, and the solution stirred for 18 h. Ether (10 mL) was
added followed by the dropwise addition of saturated aqueous
sodium hydrogen carbonate until effervescence ceased. The aque-
ous layer was washed with ethyl acetate (4ꢂ10 mL) and the com-
bined organic fractions were washed with water (10 mL) and brine
(10 mL), then dried (MgSO4) and concentrated under reduced
pressure. The residue was filtered though a short pad of silica using
ethyl acetate/petrol (30:70) as eluent. The residue was then taken
1249, 1379, 1465, 1654, 1706 cmꢀ1
;
dH (300 MHz, CDCl3) 0.01 [9H, s,
Si(CH3)3], 0.92 (2H, m, CH2Si), 0.99 and 1.16 (each 3H, s, 300-CH3),
1.77 (1H, br t, J 12, 5-H), 2.01 (1H, br t, J 11.5, 3-H), 2.17 (1H, br d, J 12,
3-H0), 2.30 (1H, br d, J 13, 5-H0), 2.63 (1H, dd, J 7.5, 17.5, 100-H), 2.91
(1H, dd, J 5, 17.5, 100-H0), 3.49 (3H, m, 2-CH2 and 2-H), 3.59 (2H, m,
CH2CH2Si), 3.78 (1H, m, 6-H), 3.95 (1H, d, J 8, 400-H), 4.23 and 4.51
(each 1H, d, J 11.5, HCHAr), 4.66 (2H, s, OCH2O), 4.75 (2H, m, 4-CH2),
5.26 (1H, d, J 17, 600-H), 5.39 (1H, dd, J 1.5, 10.5, 600-H0), 5.70 (1H, ddd,
J 8, 10.5, 17, 500-H), 7.26 (5H, m, ArH); dC (75 MHz, CDCl3) ꢀ1.48,
18.01, 18.74, 21.77, 36.93, 40.19, 45.20, 51.22, 64.98, 70.44, 74.63,
76.51, 85.72, 94.96, 109.25, 120.14, 127.29, 127.47, 128.11, 134.20,
138.33, 143.39, 212.33; m/z (CI) 506 (Mþþ18, 100%); HRMS (CI):
MþþNH4, found 506.3300. C28H48NO5Si requires 506.3301. The
(6R)-epimer of the title compound 54 (63 mg, 9%) was isolated as
up in acetic anhydride (500 ml) and pyridine (100 ml) was added.
The solution was stirred for 18 h then saturated aqueous ammo-
nium chloride (10 mL) was added. The aqueous layer was washed
with DCM (2ꢂ10 mL) and the combined organic extracts were
washed with water (10 mL) and brine (10 mL), then dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
residue using ether/petrol (6:94) as eluent gave the (6S)-epimer of
a colourless oil, [
a
]
2D0ꢀ6.15 (c 1.0 in DCM); dH (300 MHz, CDCl3) 0.00
[9H, s, Si(CH3)3], 0.91 (2H, m, CH2Si), 1.02 and 1.12 (each 3H, s, 300-
CH3), 1.95 (1H, br dd, J 5.5, 13, 5-H), 2.09 (1H, br dd, J 7.5, 13.5,
3-H), 2.26 (1H, br dd, J 4,13.5, 3-H0), 2.40 (1H, br dd, J 4.5, 13.5, 5-H0),
2.67 (1H, dd, J 8, 17.5, 100-H), 2.77 (1H, dd, J 5, 17.5, 100-H0), 3.56 (4H,
m, 2-CH2 and CH2CH2Si), 3.83 (1H, m, 2-H), 3.92 (1H, d, J 8, 400-H),
4.23 (1H, d, J 12, HCHAr), 4.34 (1H, m, 6-H), 4.52 (1H, d, J 12, HCHAr),
4.64 (2H, s, OCH2O), 4.73 (2H, m, 4-CH2), 5.27 (1H, dd, J 1.5, 17.5,
600-H), 5.35 (1H, dd, J 1.5, 10.5, 600-H0), 5.69 (1H, ddd, J 8, 10.5, 17.5,
500-H), 7.26 (5H, m, ArH); dC (75 MHz, CDCl3) ꢀ1.48, 18.01, 18.91,
21.91, 36.36, 38.81, 41.64, 51.44, 65.03, 68.78, 69.10, 70.31, 71.51,
85.21, 95.00, 110.89, 120.19, 127.32, 127.50, 128.13, 134.27, 138.20,
141.18, 211.66.
the title compound 49 (39 mg, 66%) as a colourless oil, [
a
]
20ꢀ6.2 (c
D
1.0 in DCM); nmax 699, 737, 896, 934, 1047, 1237, 1370, 1461, 1654,
1707, 1742 cmꢀ1 dH (300 MHz, CDCl3) 1.00 and 1.17 (each 3H, s, 300-
;
CH3),1.79 (1H, br t, J 12.5, 5-H),1.95 (1H, br t, J 12.5, 3-H), 2.04 (3H, s,
CH3CO), 2.16 (1H, br dt, J 13, 2, 3-H0), 2.29 (1H, br dt, J 13, 2, 5-H0),
2.56 (1H, dd, J 7, 17, 100-H), 2.90 (1H, dd, J 5.5, 17, 100-H0), 3.53 (1H,
dddd, J 3.5, 6, 11.5, 13, 2-H), 3.77 (1H, m, 6-H), 3.94 (1H, d, J 8, 400-H),
4.03 (2H, m, 2-CH2), 4.24 and 4.52 (each 1H, d, J 12, HCHAr), 4.75
(2H, m, 4-CH2), 5.32 (1H, d, J 17, 600-H), 5.35 (1H, dd, J 1.5, 10.5, 600-
H0), 5.71 (1H, ddd, J 8, 10.5, 17, 500-H), 7.26 (5H, m, ArH); dC (75 MHz,
CDCl3) 18.74, 20.80, 21.78, 36.54, 40.06, 44.97, 51.25, 66.73, 70.46,
74.10, 75.88, 85.81, 109.72, 120.15, 127.31, 127.49, 128.12, 134.20,
138.32, 142.71, 170.82, 212.30; m/z (CI) 418 (Mþþ18, 100%), 401
(Mþþ1, 30); HRMS (CI): MþþNH4, found 418.2592. C14H36NO5 re-
quires 418.2593. The (6R)-epimer of the title compound 52 (4 mg,
4.2.31. (2R,4RS,6S)-6-[(4S)-4-Benzyloxy-3,3-dimethyl-2-oxohex-5-
enyl]-4-(hydroxymethyl)-2-[(2-trimethylsilylethoxymethoxy)-
methyl]tetrahydropyran (55). 9-BBN (0.5 M in THF, 1.8 mL,
0.88 mmol) was added to an ice cooled solution of the methyl-
enetetrahydropyran 53 (288 mg, 0.59 mmol) in THF. The solution
was stirred at rt for 18 h then ice cooled water (1 mL), aqueous
6%) was isolated as a colourless oil, [
a
]
20ꢀ41 (c 1.0 in DCM); dH
D
(300 MHz, CDCl3) 1.04 and 1.14 (each 3H, s, 300-CH3),1.96 (1H, dd, J 6,
13, 5-H), 2.06 (4H, m, CH3CO and 3-H), 2.27 (1H, dd, J 4, 13, 3-H0),
2.40 (1H, dd, J 4,13, 5-H0), 2.58 (1H, dd, J 7, 17, 100-H), 2.78 (1H, dd, J 5,
17, 100-H0), 3.92 (2H, m, 400-H and 2-H), 4.02 (1H, dd, J 4, 11.5, 2-CH),
4.16 (1H, dd, J 7, 11.5, 2-CH0), 4.26 (1H, d, J 11.5, HCHAr), 4.37 (1H, m,
6-H), 4.54 (1H, d, J 11.5, HCHAr), 4.71 and 4.78 (each 1H, m, 4-CH),
5.29 (1H, ddd, J 1, 2, 17, 600-H), 5.38 (1H, dd, J 1, 10, 600-H0), 5.71 (1H,
ddd, J 8, 10, 17, 500-H), 7.28 (5H, m, ArH); dC (75 MHz, CDCl3) 18.82,
20.88, 21.96, 29.66, 35.98, 38.77, 41.52, 51.44, 65.01, 69.07, 70.27,
85.21, 111.36, 120.35, 127.40, 127.57, 128.19, 134.22, 138.18, 140.54,
170.94, 211.50.
sodium hydroxide (3 M, 800
ml) and aqueous hydrogen peroxide
(30%, 500 l) were added. The mixture was allowed to warm to rt
m
and was stirred for 3 h. Water (5 mL) and ether (5 mL) were added
and the aqueous layer was washed with ether (3ꢂ5 mL). The
combined organic extracts were washed with water (10 mL) and
brine (10 mL), dried (MgSO4), and concentrated under reduced
pressure. Chromatography of the residue using ethyl acetate/petrol
(30:70) as eluent gave the title compound 55 (218 mg, 73%) as
a colourless oil, a 75:25 mixture of epimers; nmax 698, 741, 837, 859,
933, 1057, 1106, 1249, 1381, 1466, 1705, 3475 cmꢀ1
; dH (300 MHz,
4.2.30. (2R,6S)- and (2R,6R)-6-[(4S)-4-Benzyloxy-3,3-dimethyl-2-
oxohex-5-enyl]-4-methylene-2-[(2-trimethylsilylethoxymethoxy)
methyl]tetrahydropyrans (53) and (54). Aqueous hydrogen fluoride
(58e62%, 1.5 mL) was added to the trienone 46 (1 g, 1.5 mmol) in
acetonitrile (7.5 mL) in a Teflon tube and the solution stirred for
CDCl3) 0.01 [9H, s, Si(CH3)3], 0.91 (2H, m, CH2Si), 0.98 and 1.15 (each
3H, s, 300-CH3), 1.20e1.90 (5H, m, 3-H2, 4-H and 5-H2), 2.05 (0.3H, s,
OH), 2.57 (0.3H, dd, J 8, 17.5, 100-H), 2.63 (0.7H, dd, J 8, 17.5, 100-H),
2.86 (0.3H, dd, J 5, 17.5, 100-H0), 2.87 (0.7H, dd, J 5, 17.5, 100-H0), 3.39
(0.7H, d, J 5, 2-CH), 3.53 (4.3H, m, 4-CH2, 2-CH and CH2CH2Si), 3.77

D. Gill et al. / Tetrahedron 67 (2011) 5034e5045
5045
(1.7H, m, 6-H and 400-H), 3.95 (1.3H, m, 2-H and 400-H), 4.22 (0.7H, d,
J 12, HCHAr), 4.23 (0.3H, d, J 12, HCHAr), 4.51 (0.7H, d, J 12, HCHAr),
4.52 (0.3H, d, J 12, HCHAr), 4.64 (0.6H, s, OCH2O), 4.66 (1.4H, s,
OCH2O), 5.27 (1H, m, 600-H), 5.39 (1H, m, 600-H0), 5.70 (1H, m, 500-H),
7.26 (5H, m, ArH); dC (75 MHz, CDCl3) ꢀ1.46, 18.01, 18.67, 18.71,
21.75, 21.85, 28.38, 30.85, 31.91, 33.44, 34.04, 37.52, 45.40, 45.56,
51.17, 51.23, 63.21, 64.95, 67.63, 69.13, 70.43, 70.79, 71.10, 72.06,
73.25, 76.09, 85.73, 85.89, 94.95, 120.11, 127.24, 127.28, 127.35,
127.45, 128.09, 134.15, 138.33, 138.42, 212.75, 213.02; m/z (CI)
524 (Mþþ18, 100%); HRMS (CI): MþþNH4, found 524.3406.
C28H50NO6Si requires 534.3407.
to the methylenetetrahydropyran 56 (457 mg, 0.77 mmol) in DCM
(3 mL) at 0 ꢁC and the mixture stirred for 5 h. Aqueous sodium
thiosulfate (10%, 2 mL), water (5 mL) and DCM (5 mL) were added
and the aqueous layer was washed with DCM (3ꢂ5 mL). The com-
bined organic extracts were washed with saturated aqueous sodium
hydrogen carbonate (10 mL), water (10 mL) and brine (10 mL), then
dried (MgSO4) and concentrated under reduced pressure. Chroma-
tography of the residue using ethyl acetate/petrol (6:94) as eluent
gave the title compound 58 (448 mg, 95%) as a colourless oil, an 85:15
mixture of diastereoisomers; nmax 703, 740, 823, 933, 1111, 1366, 1387,
1426, 1467, 1707, 2360 cmꢀ1
; dH (300 MHz, CDCl3) major isomer 0.97
(3H, s, 3000-CH3), 1.05 [9H, s, SiC(CH3)3], 1.16 (3H, s, 3000-CH3), 1.21 (2H,
m, 3-H and 5-H), 1.66 (1H, m, 5-H0), 1.82 (1H, m, 3-H0), 2.51 (1H, dd,
J 16, 8, 1000-H), 2.58 and 2.66 (each 1H, d, J 5,100-H), 2.82 (1H, dd, J 16, 7,
1000-H0), 3.54 and 3.69 (each 1H, m, 2-CH), 3.83 (1H, m, 2-H), 3.92 (1H,
m, 4000-H), 4.13 (1H, m, 6-H), 4.21 and 4.49 (each 1H, d, J 11.5, HCHAr),
5.25 (1H, d, J 17, 6000-H), 5.33 (1H, m, 6000-H0), 5.69 (1H, m, 5000-H), 7.21
(5H, m, ArH), 7.36 (6H, m, ArH), 7.63 (4H, m, ArH); distinctive peaks
for the minor isomer 1.14 (3H, s, 3000-CH3), 1.35 (1H, t, J 16, 5-H), 1.82
(1H, t, J 16, 3-H), 2.68 (1H, d, J 5, 100-H); dC (75 MHz, CDCl3) major
isomer 18.75, 19.21, 21.84, 26.74, 35.02, 38.34, 44.91, 51.15, 52.83,
56.18, 66.71, 70.49, 71.46, 75.58, 85.83, 120.07, 127.28, 127.47, 127.49,
127.52, 128.11, 129.50, 135.53, 135.59, 138.33, 211.86; m/z (CI) 630
(Mþþ18, 100%); HRMS (CI): MþþNH4, found 630.3615. C38H52NO5Si
requires 630.3614.
4.2.32. (2R,6S)- and (2R,6R)-6-[(4S)-4-Benzyloxy-3,3-dimethyl-2-
oxohex-5-enyl]-2-(tert-butyldiphenylsilyloxy)methyl-4-methylenete-
trahydropyrans (56) and (57). Aqueous hydrogen fluoride (58e62%,
3 mL) was added to the trienone 46 (2 g, 3.1 mmol) in acetonitrile
(15 mL) in a Teflon tube and the solution was stirred for 18 h. Ether
(100 mL) was added followed by saturated aqueous sodium hy-
drogen carbonate, which was added dropwise until effervescence
ceased. The aqueous layer was washed with ethyl acetate
(4ꢂ30 mL) and the combined organic fractions were washed with
water (40 mL) and brine (50 mL), dried (MgSO4) and concentrated
under reduced pressure. The residue was filtered though a short
pad of silica using ethyl acetate/petrol (30:70) as eluent and the
residue was taken up in ice cooled DCM (3 mL). Imidazole (190 mg,
2.8 mmol) and tert-butyldiphenylsilyl chloride (544 ml, 2.1 mmol)
were added and the solution stirred for 18 h. Saturated aqueous
ammonium chloride (5 mL) was added and the organic layer was
washed with DCM (5 mL). The combined organic extracts were
washed with water (5 mL) and brine (5 mL), dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue using ethyl acetate/petrol (3:97) as eluent gave the (6S)-
Acknowledgements
We thank the EPSRC for support (to D.G, and N.H.T.).
References and notes
20
epimer of the title compound 56 (1.07 g, 57%) as a colourless oil, [
þ2.3 (c 1.0 in DCM); nmax 703, 740, 822, 891, 934, 1111, 1362, 1386,
1426, 1467, 1652, 1706 cmꢀ1 dH (300 MHz, CDCl3) 0.93 (3H, s, 300-
a]
D
1. (a) Hale, K. J.; Hummersone, M. G.; Manaviazar, S.; Frigerio, M. Nat. Prod. Rep.
2002, 19, 413; (b) Sharp, J. H.; Winson, M. K.; Porter, J. S. Nat. Prod. Rep. 2007, 24,
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;
CH3), 0.97 [9H, s, SiC(CH3)3], 1.10 (3H, s, 300-CH3), 1.70 (1H, br t, J 12.5,
5-H), 1.88 (1H, br t, J 12.5, 3-H), 2.22 (2H, m, 5-H0 and 3-H0), 2.49
(1H, dd, J 7, 17.5, 100-H), 2.75 (1H, dd, J 5.5,17.5, 100-H0), 3.54 (2H, m, 2-
H and 2-CH), 3.66 (2H, m, 2-CH0 and 6-H), 3.88 (1H, d, J 8, 400-H), 4.17
and 4.44 (each 1H, d, J 11.5, HCHAr), 4.66 (2H, s, 4-CH2), 5.22 (1H, d,
J 17, 600-H), 5.28 (1H, d, J 10.5, 600-H0), 5.64 (1H, ddd, J 8, 10.5, 17, 500-
H), 7.18 (6H, m, ArH), 7.30 (5H, m, ArH), 7.59 (4H, m, ArH); dC
(75 MHz, CDCl3) 18.74, 19.22, 21.80, 26.76, 37.17, 40.45, 45.08, 51.23,
66.96, 70.48, 74.35, 78.56, 85.72, 109.04, 120.11, 127.30, 127.50,
128.12, 129.49, 133.62, 134.22, 135.54, 135.60, 138.29, 143.81,
212.32; m/z (CI) 614 (Mþþ18, 100%); HRMS (CI): MþþNH4, found
614.3667. C38H52NO4Si requires 614.3665. The (6R)-epimer of the
2. (a) Masamune, S. Pure Appl. Chem. 1988, 60, 1587; (b) Kageyama, M.; Tamura, T.;
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20
4. (a) Wender, P. A.; Baryza, J. L.; Bennett, C. E.; Bi, F. C.; Brenner, S. E.; Clarke, M.
ˇ
title compound 57 (176 mg, 10%) was isolated as a colourless oil,[a]
D
O.; Horan, J. C.; Kan, C.; Lacote, E.; Lippa, B.; Nell, P. G.; Turner, T. M. J. Am. Chem.
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ꢀ19.2 (c 1.0 in DCM); dH (300 MHz, CDCl3) 1.06 (3H, s, 300-CH3), 1.10
[9H, s, SiC(CH3)3], 1.18 (3H, s, 300-CH3), 1.98 (1H, br dd, J 5.5, 13.5, 5-
H), 2.20 (1H, br dd, J 6.5, 13, 3-H), 2.38 (2H, m, 3-H0 and 5-H0), 2.64
(1H, dd, J 8,17.5,100-H), 2.78 (1H, dd, J 5,17.5,100-H0), 3.75 (3H, m, 2-H
and 2-CH2), 3.97 (1H, d, J 8, 400-H), 4.30 (2H, m, 6-H and HCHAr),
4.58 (1H, J 12, HCHAr), 4.73 and 4.79 (each 1H, s, 4-CH), 5.33 (1H, d,
J 17, 600-H), 5.41 (1H, dd, J 1.5, 10.5, 600-H0), 5.75 (1H, ddd, J 8, 10.5, 17,
500-H), 7.30 (5H, m, ArH), 7.43 (6H, m, ArH), 7.71 (4H, m, ArH); dC
(75 MHz, CDCl3) 18.82, 19.20, 21.84, 26.79, 36.26, 39.04, 41.78,
51.44, 65.00, 69.24, 70.31, 73.12, 85.15, 110.75, 120.19, 127.35, 127.56,
128.14, 129.54, 133.51, 134.27, 135.52, 135.55, 138.16, 141.41, 211.73.
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1986, 27, 4763.
ꢁ
9. (a) Audran, G.; Monti, H.; Leandri, G.; Monti, J.-P. Tetrahedron Lett. 1993, 34,
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ꢁ
ꢁ
hedron 1996, 52, 6685.
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4.2.33. (2R,6S)-6-[(4S)-4-Benzyloxy-3,3-dimethyl-2-oxohex-5-enyl]-
2-(tert-butyldiphenylsilyloxy)methyl-4-methyl-4,100-epoxytetrahy-
dropyran (58). m-CPBA (207 mg, 0.84 mmol) was added portionwise