Preparation of cyclic ethers for polyether synthesis by catalytic ring-closing enyne metathesis of alkynyl ethers

Article abstract of DOI:10.1016/S0040-4020(02)00053-4

Alkenyl-substituted six- and seven-membered cyclic enol ethers, which are potential building blocks for the synthesis of marine polyether natural products, can be prepared in high yield (70-97%) from alkynyl ethers by ruthenium-catalysed ring-closing enyn

Full text of DOI:10.1016/S0040-4020(02)00053-4

TETRAHEDRON
Pergamon
Tetrahedron 58 12002) 1973±1982
Preparation of cyclic ethers for polyether synthesis by catalytic
ring-closing enyne metathesis of alkynyl ethers
a,p
a
a
a
a
 Â
J. Stephen Clark, Frederic Elustondo, Graham P. Trevitt, Dean Boyall, Jerod Robertson,
Alexander J. Blake,a Claire Wilsona and Blanda Stammenb
aSchool of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
bDiscovery Chemistry, P®zer Global Research and Development, Sandwich, Kent CT13 9NJ, UK
Received 11 October 2001; accepted 6 November 2001
AbstractÐAlkenyl-substituted six- and seven-membered cyclic enol ethers, which are potential building blocks for the synthesis of marine
polyether natural products, can be prepared in high yield 170±97%) from alkynyl ethers by ruthenium-catalysed ring-closing enyne
metathesis. The carbene-bearing ruthenium complex 9 is generally the most ef®cient catalyst for the reaction. q 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
voltage-sensitive sodium channels in vertebrates at very low
concentrations.1
Polycyclic ethers of marine origin, such as the brevetoxins
and the ciguatoxins, continue to be highly attractive
synthetic targets because of their structural complexity
and the signi®cant biological activities they display.1,2
These marine natural products possess extended arrays of
trans-fused cyclic ethers and their size coupled with the
high proportion of medium-sized rings and the large number
of stereogenic centres they contain makes them formidable
targets. In addition, marine polyethers of the brevetoxin and
the ciguatoxin families are of interest because of their potent
neurotoxicity; most of them interfere with the function of
Two typical marine polyether natural products are
gambierol3 and gambieric acid A,4 both of which are
produced by Gambierdiscus toxicus, a dino¯agellate
organism responsible for ciguatera poisoning in humans.1
Gambierol and the gambieric acids are notable for the
predominance of six- and seven-membered ether rings in
their polyether structures. The gambieric acids are of
particular pharmacological signi®cance because they
display potent anti-fungal activity against a variety of
®lamentous fungi.4,5
Keywords: cyclic ethers; polyether synthesis; metathesis.
Corresponding author. Tel.: 144-115-9513542; fax: 144-115-9513564; e-mail: j.s.clark@nottingham.ac.uk
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020102)00053-4

1974
J. S. Clark et al. / Tetrahedron 58 /2002) 1973±1982
Scheme 1.
In recent years, we6 and other workers7 have reported that
ring-closing metathesis8 is a powerful reaction for the
synthesis of cyclic ethers of the type found in polyether
natural products of marine origin. We have demonstrated
that ring-closing metathesis of acyclic enol ethers and
hydroboration of the resulting cyclic enol ethers can be
used to prepare six- and seven-membered cyclic ethers,6a,e
and that ring-closing metathesis of allylic ethers can be used
to prepare seven-, eight- and nine-membered cyclic ethers
in excellent yield.6b,c In addition, we have demonstrated
that ring-closing metathesis can be employed as the
key reaction for two-directional assembly of polycyclic
ethers.6f
Figure 1. Candidate catalysts for ring-closing enyne metathesis of alkynyl
ethers.
work we had found that substituted enol ethers are less
reactive metathesis partners than alkenes and are usually
poor substrates for the ruthenium catalyst 8.6,12 At the outset
it was not clear whether alkynyl ethers would display an
analogous decrease in reactivity compared to alkynes. It
was also necessary to establish whether terminal alkynyl
ethers would undergo ef®cient ring-closing metathesis
because literature data suggested that ring-closing enyne
metathesis reactions of terminal alkynes were sometimes
problematic.13
As part of our ongoing research programme directed
towards the synthesis of marine polyethers in general and
the gambieric acids in particular, we have investigated
enyne metathesis as a method for cyclic ether construction
to complement our recently developed enol ether and allylic
ether ring-closing metathesis approaches.6 Our strategy for
the preparation of trans-fused polyethers using ring-closing
enyne metathesis is summarised in Scheme 1. We envisaged
preparing the suitably functionalised alkynyl ethers 2 from
the functionalised alcohols 1 and then converting them into
the alkenyl-substituted cyclic enol ethers 3 by catalytic ring-
closing metathesis.6d,8 Elaboration of these products by
The alkynyl ethers required for our study were synthesised
from the alcohols 10a and 10b 1Scheme 2). These alcohols
were prepared from 1R)-2,3-O-isopropylidene glyceralde-
hyde14 by diastereoselective Grignard addition of allylmag-
nesium bromide or 3-butenylmagnesium bromide followed
by acetonide cleavage and p-methoxybenzylidene acetal
formation, as described previously by us 1Scheme 2).6,15
The cyclisation substrates 12a and 12b were prepared
using a modi®cation of Greene's method for the synthesis
of alkynyl ethers from hindered secondary alcohols.16 The
original method involves deprotonation of the alcohol,
reaction of the resulting alkoxide with trichloroethene, and
treatment of the intermediate dichloro enol ethers with
n-butyllithium in a one-pot fashion.16 However, modest
yields were obtained when we employed this procedure to
convert the alcohols 10a and 10b directly into the alkynyl
ethers 12a and 12b. As a consequence, we discovered that it
was best to isolate the intermediate enol ethers 11a and 11b
and generate the alkynyl ethers in a separate reaction. The
enol ethers 11a and 11b were isolated as stable crystalline
solids in high yield, and their subsequent treatment with
n-butyllithium provided the alkynyl ethers 12a and 12b in
excellent yield. In fact, the combined yields over two
steps were comparable to those obtained by Greene and
1
hydroboration or by cycloaddition with O2 followed by
hydrogenation of the resulting cyclic endo-peroxides 4,9
would provide the diols 5. In the case where R3 is a tri-
alkylsilyl group, ring-closing metathesis would deliver a
vinylic silane 13, R3ˆSiR3). Subsequent hydroboration
and oxidative work-up would produce a b-hydroxy silane
15, R3ˆSiR3) which would then undergo immediate
Peterson elimination to deliver the alcohol 6.10 Attachment
of an unsaturated chain to the secondary hydroxyl group of
the alcohol 6 would then allow an additional cyclic ether to
be constructed by ring-closing diene metathesis of the
alkene with the pendant vinylic group.
2. Results and discussion
In initial studies we sought to establish whether alkynyl
ethers would undergo metathesis using a variety of catalysts
17±9, Fig. 1).6d Preliminary work revealed that the Schrock
molybdenum complex 7 is not a suitable metathesis catalyst
in this context, and so we concentrated on using the
ruthenium complexes 8 and 9 as catalysts.11 In previous

J. S. Clark et al. / Tetrahedron 58 /2002) 1973±1982
1975
Scheme 2. Reagents: 1a) 1i) KH, THF, rt, 1ii) Cl2CCHCl, THF, 08C 111a 81%, 11b 89%); 1b) 1i) n-BuLi, Et2O, 2788C 112a 88%, 12b 84%); 1c) 1i) n-BuLi,
Et2O, 278!2108C, 1ii) MeI, DMPU, 2108C!rt 113a 80%, 13b 77%); 1d) 1i) n-BuLi, Et2O, 2788C, 1ii) Me3SiCl, 278!08C 114a 87%, 14b 46%); 1e) 1i)
n-BuLi, THF, 278!2108C, 1ii) 1CH2O)n, 2108C!rt 166%); 1f) Ac2O, DMAP, Et3N, CH2Cl2, rt 183%); 1g) t-BuPh2SiCl, imidazole, CH2Cl2, rt 194%).
co-workers when they used their one-pot procedure to
prepare analogous alkynyl ethers.16
this complex was used as the catalyst, the yields of the six-
membered cyclic ethers 1entries 1±6, Table 1) were usually
,90% and yields of the seven-membered cyclic ethers were
.70%.
The other substrates required for our studies were prepared
from the enol ethers 11a/b or the alkynyl ethers 12a/b. The
cyclisation precursors 13a and 13b were prepared by
deprotonation of the alkynyl ethers 12a and 12b with
n-butyllithium and alkylation of the resulting anions with
methyl iodide. The substrates 14a, 14b and 15 were
obtained by treatment of the enol ethers 11a and 11b with
n-butyllithium and reaction of the resulting acetylide anions
with either trimethylsilylchloride or paraformaldehyde.
Acetylation of the alcohol 15 with acetic anhydride
delivered the acetate 16, and the corresponding silyl ether
17 was prepared by treatment of the same alcohol with
t-butyldiphenylsilyl chloride in the presence of imidazole.
The ruthenium-catalysed ring-closing enyne metathesis
reaction was successful with substrates bearing a wide
variety of alkyne substituents. In general, the ruthenium
complex 9 is a more ef®cient catalyst than the related
complex 8, especially in cases where the alkyne possesses
a bulky substituent or the metathesis reaction delivers a
seven-membered cyclic ether as the product. The only
case in which the complex 8 proved to be superior to the
complex 9 as a metathesis catalyst was the cyclisation
reaction of the alcohol 15. When this reaction was
performed using the ruthenium catalyst 9, only a trace
amount of the product 21 was produced after several days,
and large amounts of the enyne 15 were recovered. In this
case, the ruthenium catalyst 9 appears to complex to the free
hydroxyl group of the substrate or product to such an extent
that the catalyst is effectively deactivated and the catalytic
cycle is not established.
The ring-closing metathesis reactions of the alkynyl ethers
12±17 promoted by the catalysts 817 and 918 were explored
1Table 1). Treatment of each substrate with the complex 8 in
dichloromethane at re¯ux or the complex 9 in toluene at
808C, resulted in ring-closing metathesis to afford the
alkenyl-substituted cyclic enol ethers 18±23 1Table 1). In
general, the highest yields of the required dienes were
obtained from those reactions in which the more reactive
ruthenium complex 9 was employed as the catalyst.18 When
Two other notable ®ndings emerge from the results given in
Table 1. Firstly, terminal alkynyl ethers, such as 12a
and 12b, are good substrates for the ruthenium catalysed
Table 1.
Entry
Substrate
R
n
Product
Yield 1%; 8)
Yield 1%; 9)
1
2
3
4
5
6
7
8
9
12a
13a
14a
15
16
17
12b
13b
14b
H
Me
SiMe3
CH2OH
CH2OAc
CH2OTBDPS
H
Me
SiMe3
1
1
1
1
1
1
2
2
2
18a
19a
20a
21
22
23
18b
19b
20b
65
77
20
84
54
61
33
27
±
90
98
88
8
72
91
70
72
0

1976
J. S. Clark et al. / Tetrahedron 58 /2002) 1973±1982
form. Chemical shifts are quoted in parts per million 1ppm)
and J values are given in Hertz. 1H NMRsignals are
described as singlets 1s), doublets 1d), triplets 1t), quartets
1q), multiplets 1m), or broad 1br) or a combination of these.
Signals in 13C NMRspectra are quoted in parts per million
1ppm) with residual chloroform 1dˆ77.1 ppm) as the
internal standard and peaks are given as singlets 1s),
doublets 1d), triplets 1t) or quartets 1q) indicating the number
of protons attached to each carbon atom. IRspectra were
recorded using
a Perkin±Elmer 1600 series FT-IR
spectrometer with internal calibration using solution cells
unless otherwise stated. Melting points were determined
using a Mel-Temp II melting point apparatus. Elemental
analyses were performed by the microanalysis section of
the School of Chemistry, University of Nottingham. Mass
spectra and accurate mass measurements were recorded
using a Fisons VG Autospec or VG Micromass 70E
instrument. Optical rotations were determined using a
Jasco DIP-370 digital polarimeter. Reactions were
monitored by TLC and were performed on Merck Kieselgel
60 F254 plates and visualized by a combination of UV light
and ethanolic anisaldehyde with heat. Flash column
chromatography was performed using Fluka silica gel 60.
Solvents and reagents were distilled using standard methods
prior to use and air sensitive compounds were handled under
nitrogen or argon. The ruthenium complexes 8 and 9 were
either purchased from Strem Chemicals or prepared accord-
ing to the procedures of Grubbs.17,18a All reactions were
performed in ¯ame-dried glassware under nitrogen or
argon unless otherwise indicated.
Figure 2. The X-ray crystal structures of the ring-closing enyne metathesis
products 18a and 19b.19
ring-closing enyne metathesis reaction, and secondly, ring-
closing enyne metathesis to give the seven-membered cyclic
ethers 18b and 19b is signi®cantly more dif®cult to achieve
than ring closure to give the corresponding six-membered
cyclic ethers 18a and 19a.
The ring-closing metathesis products 18a and 19b were
obtained as crystalline solids and crystals suitable for
X-ray crystallography were obtained by slow recrystallisa-
tion from petroleum ether. The structures of both of the
cyclic ethers 18a and 19b were con®rmed by X-ray analysis
1Fig. 2).19
4.1.1. ,2R,4S,5R)-4-Allyl-5-[,E)-1,2-dichlorovinyloxy]-2-
,4-methoxyphenyl)-1,3-dioxane ,11a). A solution of the
alcohol 10a 11.07 g, 4.28 mmol) in dry THF 110 mL) was
added by cannula to a stirred suspension of KH 1345 mg,
8.60 mmol) in dry THF 120 mL) at room temperature. The
reaction was stirred for 1 h and freshly distilled trichloro-
ethane 1630 mg, 4.79 mmol) in dry THF 15 mL) was then
added dropwise at 08C. The reaction was stirred for 1 h at
room temperature and then quenched with methanol 11 mL).
The solvent was removed and the residue was dissolved in
diethyl ether 1100 mL). The solution was washed with water
12£50 mL) and then dried 1MgSO4). The solvent was
removed in vacuo to give a solid which was puri®ed by
¯ash column chromatography on silica gel 11% Et3N,
diethyl ether±hexane, 1:10) to give the enol ether 11a as a
colourless crystalline solid 11.2 g, 81%): mp 89±918C;
3. Conclusions
Our results demonstrate that ring-closing metathesis
reactions of alkynyl ethers promoted by the ruthenium
complexes 8 and 9 can be used to prepare six- and seven-
membered alkenyl-substituted cyclic enol ethers in high
yield. In addition, we have shown that optimum yields are
usually obtained using the more reactive carbene-
substituted complex 9 as the metathesis catalyst and that
ruthenium metathesis catalysts are tolerant of a wide
range of alkyne substituents.
26
[a]D ˆ214.9 1c 0.895, CHCl3); nmax 1CHCl3) 3110,
2928, 2865, 1616, 1589, 995, 916 cm21
;
1H NMR
We are currently exploring the elaboration of the alkenyl-
substituted cyclic enol ethers obtained by ring-closing
enyne metathesis, and the conversion of these compounds
into polycyclic ethers fragments of the natural products will
be reported in due course.
1400 MHz, CDCl3) d 7.43 12H, d, Jˆ8.8 Hz, Ar), 6.91
12H, d, Jˆ8.8 Hz, Ar), 5.99 11H, dddd, Jˆ6.6, 7.4, 10.1,
17.2 Hz, CHvCH2), 5.60 11H, s, ClCH), 5.50 11H, s,
OCHO), 5.25±5.18 11H, m, CHvCH2), 5.20±5.16 11H,
m, CHvCH2), 4.41 11H, dd, Jˆ5.2, 10.8 Hz, CHHO),
4.27 11H, ddd, Jˆ5.2, 9.3, 10.0 Hz, CHO), 3.95 11H, ddd,
Jˆ3.2, 7.2, 9.3 Hz, CHO), 3.83±3.78 11H, m, CHHO), 3.82
13H, s, OCH3), 2.74±2.69 11H, m, CH2CHvCH2), 2.54±
2.46 11H, m, CH2CHvCH2); 13C NMR1100 MHz, CDCl 3)
d 160.1 1s), 142.1 1s), 133.3 1d), 129.8 1s), 127.4 1d), 118.1
1t), 113.7 1d), 101.0 1d), 99.2 1d), 78.7 1d), 72.8 1d), 68.3 1t),
55.3 1q), 35.8 1t); LRMS 1EI) m/z 344 1M1, 3), 233 132), 137
1100), 136 165), 135 185), 97 151); HRMS 1EI) Calcd for
C16H18O435Cl2 1M1): 344.0582. Found 344.0598. Anal.
4. Experimental
4.1. General
1H and 13C NMRspectra were recorded at ambient tempera-
ture using Bruker AM 400, AV 400 and DRX 500
instruments, and samples were dissolved in deuterochloro-

J. S. Clark et al. / Tetrahedron 58 /2002) 1973±1982
1977
Calcd for C16H18O4Cl2: C, 55.67; H, 5.26; Cl, 20.54. Found:
C, 55.32; H, 5.14; Cl, 20.33.
CH2CHvCH2), 2.45±2.53 11H, m, CH2CHvCH2), 1.62
11H, s, CuCH); 13C NMR1100 MHz, CDCl ) d 160.2
3
1s), 133.0 1d), 129.6 1s), 127.5 1d), 118.4 1t), 113.8 1d),
101.1 1d), 88.6 1d), 78.1 1d), 67.6 1t), 55.4 1q), 35.9 1t),
27.8 1s); HRMS 1EI) Calcd for C16H18O4 1M1): 274.1205.
Found 274.1212.
4.1.2. ,2R,4S,5R)-4-,But-3-enyl)-5-[,E)-1,2-dichlorovinyl-
oxy]-2-,4-methoxyphenyl)-1,3-dioxane ,11b). A solution
of the alcohol 10b 11.0 g, 3.8 mmol) in dry THF 110 mL)
was added by cannula to a stirred suspension of KH
1345 mg, 8.60 mmol) in dry THF 115 mL) at room tempera-
ture. The reaction was stirred for 1 h and freshly distilled
trichloroethane 1600 mg, 4.57 mmol) in dry THF 12 mL)
was then added dropwise at 08C. The reaction was stirred
for 1 h at room temperature and then quenched with
methanol 11 mL). The solvent was removed and the residue
was dissolved in diethyl ether 1100 mL). The solution was
washed with brine 12£50 mL) then dried 1MgSO4). The
solvent was removed in vacuo to give a solid which was
puri®ed by ¯ash column chromatography on silica gel 11%
Et3N, diethyl ether±hexane, 1:10) give the enol ether 11b as
a colourless crystalline solid 11.21 g, 89%): mp 94±958C;
4.1.4.
,2R,4S,5R)-4-,But-3-enyl)-5-ethynyloxy-2-,4-
methoxyphenyl)-1,3-dioxane ,12b). A solution of the
dichloroenol ether 11b 1370 mg, 1.03 mmol) in dry ether
110 mL) was added dropwise to a solution of n-BuLi
11.25 mL of a 2.5 M solution in hexane, 3.1 mmol) in dry
ether 110 mL) at 2788C over a period of 10 min. The
reaction mixture was stirred at 2788C for 30 min then
warmed to 08C and stirred for a further 50 min. The reaction
was quenched with methanol 11 mL), extracted with diethyl
ether 12£20 mL) and washed with brine 12£20 mL). The
organic extracts were dried 1MgSO4) and the solvent was
removed in vacuo to give a yellow oil which was puri®ed by
¯ash column chromatography on silica gel 11% Et3N,
diethyl ether±hexane, 1:1) to afford the alkynyl ether 12b
1250 mg, 84%) as a colourless solid: mp 30±358C;
25
[a]D ˆ237.3 1c 0.885, CHCl3); nmax 1CHCl3) 3110, 2936,
1
2865, 1665, 1627, 1614, 1589, 1002, 914 cm21; H NMR
1400 MHz, CDCl3) d 7.43 12H, d, Jˆ8.6 Hz, Ar), 6.92 12H,
d, Jˆ8.6 Hz, Ar), 5.87 11H, dddd, Jˆ6.3, 7.0, 10.1, 17.2 Hz,
CHvCH2), 5.60 11H, s, ClCH), 5.49 11H, s, OCHO), 5.08
11H, dddd, Jˆ1.7, 1.7, 1.7, 17.2 Hz, CHvCH2), 5.04±5.00
11H, m, CHvCH2), 4.40 11H, dd, Jˆ5.2, 10.8 Hz, CH2O),
4.22 11H, ddd, Jˆ5.2, 9.2, 10.2 Hz, CHO), 3.87 11H, ddd,
Jˆ2.6, 9.1, 9.2 Hz, CHO), 3.82 13H, s, OCH3), 3.81 11H, dd,
Jˆ10.2, 10.8 Hz, CH2O), 2.42±2.31 11H, m,
CH2CHvCH2), 2.30±2.18 11H, m, CH2CHvCH2), 2.06
11H, dddd, Jˆ2.6, 7.0, 9.5, 14.0 Hz, OCHCH2), 1.76 11H,
dddd, Jˆ5.1, 9.0, 9.1, 14.0 Hz, OCHCH2); 13C NMR
1100 MHz, CDCl3) d 160.2 1s), 142.2 1s), 138.0 1d), 130.0
1s), 127.4 1d), 115.2 1t), 113.7 1d), 101.1 1d), 99.3 1d), 78.5
1d), 73.8 1d), 68.4 1t), 55.4 1q), 30.8 1t), 28.9 1t); HRMS 1EI)
Calcd for C17H20O435Cl2 1M1): 358.0738. Found 358.0739.
Anal. Calcd for C17H20O4Cl2: C, 56.84; H, 5.61; Cl, 19.74.
Found C, 56.90; H, 5.79; Cl, 19.33.
20
[a]D ˆ248.9 1c 0.986, CHCl3); nmax 1CHCl3) 3322,
1
2935, 3865, 2154, 1641, 1615, 1589, 967, 913 cm21; H
NMR1400 MHz, CDCl ) d 7.30 12H, d, Jˆ8.6 Hz, Ar),
3
6.90 12H, d, Jˆ8.6 Hz, Ar), 5.86 11H, dddd, Jˆ6.3, 6.9,
10.2, 17.1 Hz, CHvCH2), 5.45 11H, s, OCHO), 5.09 11H,
dddd, Jˆ1.6, 1.6, 1.6, 17.1 Hz, CHvCH2), 5.03 11H, m,
CHvCH2), 4.56 11H, dd, Jˆ5.2, 10.8 Hz, CH2O), 4.00
11H, ddd, Jˆ5.2, 9.4, 10.2 Hz, CHO), 3.84±3.75 12H, m,
CHO, CH2O), 3.82 13H, s, OCH3), 2.41±2.32 11H, m,
CH2CHvCH2), 2.30±2.17 11H, m, CH2CHvCH2), 2.12±
2.03 1m, 1H, OCHCH2CH2), 1.83±1.72 11H, m,
OCHCH2CH2), 1.61 11H, s, CuCH); 13C NMR
1100 MHz, CDCl3) d 160.2 1s), 137.8 1d), 129.7 1s), 127.4
1d), 115.3 1t), 113.7 1d), 101.1 1d), 88.7 1d), 79.1 1d), 78.0
1d), 67.6 1t), 55.4 1q), 30.9 1t), 28.8 1t), 27.5 1s); HRMS 1EI)
Calcd for C17H20O4 1M1): 288.1362. Found 288.1363. Anal.
Calcd for C17H20O4: C, 70.81; H, 6.99. Found C, 70.39; H,
7.10.
4.1.3.
,2R,4S,5R)-4-Allyl-5-ethynyloxy-2-,4-methoxy-
phenyl)-1,3-dioxane ,12a). A solution of the dichloroenol
ether 11a 1790 mg, 2.29 mmol) in dry ether 110 mL) was
added dropwise to a solution of n-BuLi 13.1 mL of a 2.2 M
solution in hexane, 6.8 mmol) in dry ether 110 mL) at
2788C over a period of 10 min. The reaction mixture was
stirred at 2788C for 30 min then warmed to 08C and stirred
for a further 30 min. The reaction was quenched with water
and extracted with diethyl ether 12£50 mL) and washed
with brine 12£20 mL). The organic extracts were dried
1MgSO4) and the solvent was removed in vacuo to give a
yellow oil which was puri®ed by ¯ash column
chromatography on silica gel 11% Et3N, diethyl ether±
hexane, 1:10) to afford the alkynyl ether 12a 1550 mg,
4.1.5. ,2R,4R,5S)-4-Allyl-2-,4-methoxyphenyl)-5-,prop-1-
ynyloxy)-1,3-dioxane ,13a). A solution of the alkyne 12a
1200 mg, 0.729 mmol) in dry diethyl ether 110 mL) was
added dropwise to a solution of n-BuLi 11.0 mL of a
2.2 M solution in hexane, 2.2 mmol) in dry diethyl ether
11 mL) at 2788C. The mixture was stirred at 2788C for
20 min and then allowed to warm at 2108C and stirred
for a further 10 min. Freshly distilled methyl iodide
1426 mg, 3.00 mmol) in dry DMPU 15 mL) was then
added dropwise and the resulting solution allowed to
warm slowly to room temperature. After 1 h, the reaction
was quenched with water 15 mL) and diluted with diethyl
ether 150 mL). The mixture was washed with brine
12£50 mL) and then dried 1MgSO4). The solvent was
removed in vacuo to afford a yellow oil which was puri®ed
by ¯ash column chromatography on silica gel 11% Et3N,
diethyl ether±hexane, 1:10) to give the alkynyl ether 13a
25
88%) as a colourless oil: [a]D ˆ221.7 1c 1.40, CHCl3);
nmax 1CHCl3) 3322, 2866, 2155, 1615, 968, 912 cm21
;
1H NMR1400 MHz, CDCl ) d 7.40 12H, d, Jˆ8.8 Hz,
3
Ar), 6.90 12H, d, Jˆ8.8 Hz, Ar), 5.96 11H, dddd, Jˆ6.7,
7.2, 10.2, 17.1 Hz, CHvCH2), 5.46 11H, s, OCHO),
5.23 11H, dddd, Jˆ1.6, 1.6, 1.6, 17.2 Hz, CHvCH2),
5.20±5.16 11H, m, CHvCH2), 4.55 11H, dd, Jˆ5.3,
10.8 Hz, CH2O), 4.07 11H, ddd, Jˆ5.3, 9.5, 10.2 Hz,
CHO), 3.88±3.80 11H, m, CHO), 3.82 11H, dd, Jˆ10.2,
10.8 Hz, CH2O), 3.82 13H, s, OCH3), 2.68±2.75 11H, m,
23
1168 mg, 80%) as a colourless oil: [a]D ˆ225.8 1c 1.16,
CHCl3); nmax 1CHCl3) 2937, 2922, 2862, 2839, 2282, 1642,
1616, 1589, 987, 915 cm21; 1H NMR1500 MHz, CDCl 3) d
7.40 12H, d, Jˆ8.7 Hz, Ar), 6.90 12H, d, Jˆ8.7 Hz, Ar), 5.95
11H, dddd, Jˆ6.7, 7.3, 10.2, 17.1 Hz, CHvCH2), 5.44 11H,

1978
J. S. Clark et al. / Tetrahedron 58 /2002) 1973±1982
22
1410 mg, 87%) as a colourless oil: [a]D ˆ216.4 1c 1.05,
s, OCHO), 5.23 11H, dd, Jˆ1.0, 17.1 Hz, CHvCH2), 5.15
11H, dd, Jˆ1.0, 10.2 Hz, CHvCH2), 4.52 11H, dd, Jˆ5.2,
10.8 Hz, CH2O), 3.92 11H, ddd, Jˆ5.3, 9.3, 10.2 Hz, CHO),
3.81±3.74 12H, m, CHO, CH2O), 3.81 13H, s, OCH3), 2.72±
2.67 11H, m, CH2CHvCH2), 2.46 11H, dddd, Jˆ0.9, 7.3,
7.3, 14.7 Hz, CH2CHvCH2), 1.73 13H, d, Jˆ1.0 Hz,
1
CHCl3); nmax 1CHCl3) 2956, 2183, 1615, 967 cm21; H
NMR1400 MHz, CDCl ) d 7.40 12H, d, Jˆ8.8 Hz, Ar),
3
6.91 12H, d, Jˆ8.8 Hz, Ar), 5.96 11H, ddd, Jˆ6.9, 7.1,
10.2, 17.2 Hz, CHvCH2), 5.45 11H, s, OCHO), 5.23 11H,
dddd, Jˆ1.6, 1.6, 1.6, 17.2 Hz, CHvCH2), 5.20±5.15 11H,
m, CHvCH2), 4.54 11H, dd, Jˆ5.3, 10.8 Hz, CH2O), 4.08
11H, ddd, Jˆ5.3, 9.6, 10.0 Hz, CHO), 3.87±3.76 12H, m,
CHO, CH2O), 3.82 13H, s, OCH3), 2.76±2.68 11H, m,
CH2CHvCH2), 2.53±2.44 11H, m, CH2CHvCH2), 0.00
CCH3); 13C NMR167.8 MHz, CDCl ) d 160.0 1s), 133.1
3
1d), 129.7 1s), 127.3 1d), 118.0 1t), 113.5 1d), 100.9 1d),
86.1 1s), 78.3 1d), 77.3 1d), 67.7 1t), 55.2 1q), 35.8 1t), 33.4
1s), 1.4 1q); HRMS 1EI) Calcd for C17H20O4 1M1): 288.1362.
Found 288.1357. Anal. Calcd for C17H20O4: C, 70.81; H,
6.99. Found: C, 71.20; H, 7.41.
19H, s, Si[CH3]3); 13C NMR1100 MHz, CDCl ) d 160.2
3
1s), 133.0 1d), 129.7 1s), 127.5 1d), 118.4 1t), 113.7 1d),
107.2 1s), 101.1 1d), 78.4 1d), 78.2 1d), 67.5 1t), 55.3 1q),
38.0 1s), 35.9 1t), 0.6 1q); HRMS 1FAB) Calcd for
C19H27O4Si 1M11H): 347.1679. Found 347.1706. Anal.
Calcd for C19H26O4Si: C, 65.86; H, 7.56. Found: C, 65.59;
H, 7.62.
4.1.6. ,2R,4S,5R)-4-,But-3-enyl)-2-,4-methoxyphenyl)-5-
,prop-1-ynyloxy)-1,3-dioxane ,13b). A solution of the
alkyne 12b 1160 mg, 0.555 mmol) in dry diethyl ether
11 mL) was added dropwise to a solution of n-BuLi
10.67 mL of a 2.5 M solution in hexane, 1.7 mmol) in dry
diethyl ether 15 mL) at 2788C. The reaction was stirred at
2788C for 30 min and then allowed to warm to 2108C and
stirred for a further 30 min. Freshly distilled methyl iodide
1315 mg, 2.22 mmol) in dry DMPU 12 mL) was added drop-
wise and the resulting solution allowed to warm slowly to
room temperature. After 1 h, the reaction was quenched
with water 15 mL) and diluted with diethyl ether 150 mL).
The mixture was washed with brine 12£20 mL) and then
dried 1MgSO4). The solvent was removed in vacuo to give
a yellow oil which was puri®ed by ¯ash column chromato-
graphy on silica gel 11% Et3N, diethyl ether±hexane, 1:10)
to afford the alkynyl ether 13b 1130 mg, 77%) as a colour-
4.1.8. ,2R,4S,5R)-4-,But-3-enyl)-2-,4-methoxyphenyl)-5-
[,trimethylsilyl)ethynyloxy]-1,3-dioxane ,14b). n-BuLi
11.4 mL of a 2.4 M solution in hexane, 3.4 mmol) was
added dropwise to a solution of the enol ether 11b
1400 mg, 1.11 mmol) in dry THF 110 mL) cooled to
2788C. The mixture was stirred at 2788C for 30 min,
allowed to warm at 08C and stirred for another 30 min at
this temperature. Freshly distilled chlorotrimethylsilane
1480 mg, 4.42 mmol) was added in one portion and the
reaction was warmed to room temperature and stirred for
2 h. The reaction was quenched with water 15 mL) and the
THF was removed in vacuo. The residual material was
extracted with ether 12£50 mL) and the organic extracts
were washed with brine 12£50 mL) and then dried
1MgSO4). The solvent was removed in vacuo to give a
pale yellow solid which was puri®ed by ¯ash column
chromatography on silica gel 11% Et3N, diethyl ether±
hexane, gradient 1:10!1:1) to afford the alkynyl ether
20
less solid: mp 33±368C; [a]D ˆ240.5 1c 1.13, CHCl3);
nmax 1CHCl3) 3082, 2923, 2861, 2282, 1640, 1616, 1589,
990, 914 cm21; 1H NMR1400 MHz, CDCl 3) d 7.43 12H, d,
Jˆ8.6 Hz, Ar), 6.92 12H, d, Jˆ8.8 Hz, Ar), 5.88 11H, dddd,
Jˆ6.2, 6.9, 10.2, 17.1 Hz, CHvCH2), 5.44 11H, s, OCHO),
5.12 11H, dddd, Jˆ1.6, 1.6, 1.6, 17.1 Hz, CHvCH2), 5.09±
5.01 11H, m, CHvCH2), 4.54 11H, dd, Jˆ5.0, 10.6 Hz,
CH2O), 3.89 11H, Jˆ5.0, 9.5, 10.0 Hz, CHO), 3.84±3.72
12H, m, CH2O, CHO), 3.83 13H, s, OCH3), 2.43±2.32
11H, m, CH2CHvCH2), 2.28±2.17 11H, m, CH2CHvCH2),
2.02±2.11 11H, m, OCHCH2CH2), 1.83±1.72 11H, m,
OCHCH2CH2), 1.75 13H, s, CCH3); 13C NMR1100 MHz,
CDCl3) d 160.1 1s), 137.9 1d), 129.8 1s), 127.4 1d), 115.1 1t),
113.6 1d), 100.9 1d), 86.2 1s), 78.2 1d), 78.1 1d), 67.9 1t), 55.3
1q), 33.4 1s), 30.8 1t), 28.8 1t), 1.6 1q); HRMS 1EI) Calcd for
C18H22O4 1M1): 302.1518. Found 302.1517.
20
14b 1203 mg, 46%) as a colourless oil: [a]D ˆ229.5 1c
0.895, CHCl3); nmax 1CHCl3) 2958, 2966, 1640, 1615,
1
1592, 993, 943, 915 cm21; H NMR1400 MHz, CDCl ) d
3
7.43 12H, d, Jˆ8.7 Hz, Ar), 6.91 12H, d, Jˆ8.7 Hz, Ar), 5.86
11H, dddd, Jˆ6.3, 6.9, 10.2, 17.1 Hz, CHvCH2), 5.49 11H,
s, OCHO), 5.08 11H, dd, Jˆ1.7, 17.1 Hz, CHvCH2), 5.03±
4.98 11H, m, CHvCH2), 4.37 11H, dd, Jˆ5.2, 10.6 Hz,
CH2O), 4.28 11H, ddd, Jˆ5.2, 9.2, 10.0 Hz, CHO), 11H,
ddd, Jˆ2.6, 9.0, 9.2 Hz, CHO), 3.82 13H, s, OCH3), 3.82
11H, dd, Jˆ10.0, 10.6 Hz, CH2O), 2.42±2.31 11H, m,
CH2CHvCH2), 2.30±2.17 11H, m, CH2CHvCH2), 2.10±
2.00 11H, m, OCHCH2CH2), 1.75 11H, m, Jˆ5.1, 9.0, 9.0,
14.1 Hz, OCHCH2CH2), 0.30 19H, s, Si[CH3]3); 13C NMR
1100 MHz, CDCl3) d 160.1 1s), 145.9 1s), 138.1 1d), 130.1
1s), 127.4 1d), 115.1 1t), 113.7 1d), 101.0 1d), 78.7 1d), 73.4
1d), 68.6 1t), 55.4 1q), 30.8 1t), 29.0 1t), 20.9 1q).
4.1.7. ,2R,4S,5R)-4-Allyl-2-,4-methoxyphenyl)-5-[,tri-
methylsilyl)ethynyloxy]-1,3-dioxane
,14a).
n-BuLi
11.7 mL of a 2.5 M solution in hexane, 4.3 mmol) was
added dropwise over a 2 min period to a solution of the
enol ether 11a 1500 mg, 1.45 mmol) in dry diethyl ether
125 mL) at 2788C. The reaction was stirred for 30 min at
2788C and a solution of freshly distilled chlorotrimethyl-
silane 1470 mg, 4.33 mmol) in dry diethyl ether 18 mL) was
added dropwise. The mixture was allowed to warm to 08C
and stirred for 2 h 30 min and then quenched with water
15 mL). The mixture was extracted with diethyl ether
170 mL) and the organic extract washed with brine
12£25 mL) then dried 1MgSO4). The solvent was removed
in vacuo to give a yellow oil which was puri®ed by ¯ash
column chromatography on silica gel 11% Et3N, diethyl
ether±hexane, 1:30) to afford the alkynyl ether 14a
4.1.9.
,2R,4S,5R)-4-Allyl-2-,4-methoxyphenyl)-5-[,3-
hydroxy)prop-1-ynyloxy]-1,3-dioxane ,15). The enol
ether 11a 1700 mg, 2.03 mmol) was dissolved in dry THF
110 mL) and the solution was cooled at 2788C. n-BuLi
12.5 mL of a 2.4 M solution in hexane, 6.0 mmol) was
added dropwise over a 5 min period to the solution and
the mixture was stirred at 2788C for 30 min. The reaction
was warmed to 2108C and stirred for a further 30 min, and
then paraformaldehyde 11 g, predried by azeotropic removal
of water with toluene) in dry THF 15 mL) was added in one

J. S. Clark et al. / Tetrahedron 58 /2002) 1973±1982
1979
portion. The mixture was warmed to room temperature and
then stirred at re¯ux for 2 h. The reaction was quenched
with water 15 mL) and the THF was removed in vacuo.
The residual material was extracted with diethyl ether
12£100 mL) and the organic extracts were washed with
brine 12£50 mL) then dried 1MgSO4). The solvent was
removed in vacuo to give a pale yellow solid which was
puri®ed by ¯ash column chromatography on silica 11%
Et3N, diethyl ether±hexane, gradient 1:5!1:1) to afford
the alcohol 15 1410 mg, 66%) as a colourless solid: mp
was stirred overnight at room temperature. The reaction
mixture was diluted with dichloromethane 110 mL) and
then washed with water 12£5 mL). The aqueous layer was
washed with additional dichloromethane 15 mL) and the
combined organic extracts were dried 1MgSO4). Removal
of the solvent in vacuo afforded the crude product which
was puri®ed by ¯ash column chromatography on silica gel
11% Et3N, hexane then diethyl ether±hexane, 1:20) to give
the protected alcohol 17 187 mg, 94%) as a viscous oil:
26
[a]D ˆ215.4 1c 0.920, CHCl3); nmax 1CHCl3) 2932,
2860, 2272, 1642, 1615, 1589, 982, 916 cm21; H NMR
26
1
85±878C; [a]D ˆ220.1 1c 0.820 in CHCl3); nmax
1CHCl3) 3611, 2937, 2867, 2839, 2271, 1642, 1615, 1589,
980, 916 cm21; 1H NMR1400 MHz, CDCl 3) d 7.40 12H, d,
Jˆ8.7 Hz, Ar), 6.90 12H, d, Jˆ8.7 Hz, Ar), 5.95 11H, dddd,
Jˆ6.9, 7.0, 10.2, 17.2 Hz, CHvCH2), 5.45 11H, s, OCHO),
5.22 11H, dd, Jˆ1.5, 17.2 Hz, CHvCH2), 5.17 11H, d,
Jˆ10.2 Hz, CHvCH2), 4.53 11H, dd, Jˆ5.3, 10.8 Hz,
OCH2), 4.26 12H, s, CH2OH), 4.03 11H, ddd, Jˆ5.3, 9.7,
9.8 Hz, CHO), 3.87±3.74 12H, m, CHO, CH2O), 3.81 13H, s,
OCH3), 2.73±2.64 11H, m, CH2CHvCH2), 2.52±2.43 11H,
m, CH2CHvCH2) 1.81 11H, br, OH); 13C NMR1100 MHz,
CDCl3) d 160.2 1s), 133.0 1d), 129.6 1s), 127.4 1d), 118.3 1t),
113.7 1d), 101.1 1d), 92.4 1s), 78.2 1d), 78.2 1d), 67.6 1t), 55.3
1q), 50.6 1t), 37.7 1s), 35.9 1t); HRMS 1EI) Calcd for
C17H20O5 1M1): 304.1311. Found 304.1300. Anal. Calcd
for C17H20O5: C, 67.09; H, 6.62. Found C, 66.82; H, 6.67.
1400 MHz, CDCl3) d 7.78±7.75 14H, m, Ph), 7.50±7.40
18H, m, Ar, Ph), 6.93 12H, d, Jˆ8.8 Hz, Ar), 5.95 11H,
dddd, Jˆ6.9, 7.0, 10.2, 17.2 Hz, CHvCH2), 5.43 11H, s,
OCHO), 5.22 11H, dddd, Jˆ1.7, 1.7, 1.7, 17.2 Hz), 5.17
11H, br d, Jˆ10.2 Hz, CHvCH2), 4.42 11H, dd, Jˆ5.2,
10.7 Hz, CH2O), 4.40 12H, s, CH2OAc), 3.92 11H, ddd,
Jˆ5.2, 9.5, 10.2 Hz, CHO), 3.83 13H, s, OCH3), 3.79 11H,
ddd, Jˆ3.3, 7.2, 9.5 Hz, CHO), 3.72 11H, dd, Jˆ10.2,
10.7 Hz, CH2O), 2.72±2.64 11H, m, CH2CHvCH2),
2.48±2.39 11H, m, CH2CHvCH2), 1.02 19H, s, C[CH3]3);
13C NMR1100 MHz, CDCl ) d 160.2 1s), 135.7 1d), 133.5
3
1s), 133.0 1d), 129.8 1d), 129.7 1s), 127.7 1d), 127.5 1d),
118.3 1t), 113.7 1d), 101.0 1d), 91.9 1s), 78.2 1d), 77.9 1d),
67.6 1t), 55.3 1q), 52.4 1t), 37.8 1s), 35.9 1t), 26.8 1q), 19.2 1s);
HRMS 1EI) Calcd for C33H38O4Si 1M1): 542.2489. Found
542.2486. Anal. Calcd for C33H38O4Si: C, 73.03; H, 7.06.
Found C, 73.01; H, 7.10.
4.1.10.
,2R,4S,5R)-4-Allyl-5-[,3-acetoxy)prop-1-ynyl-
oxy]-2-,4-methoxyphenyl)-1,3-dioxane ,16). The alcohol
15 155 mg, 0.18 mmol) was dissolved in dichloromethane
11 mL) and triethylamine 120 mg, 0.20 mmol), DMAP
124 mg, 0.20 mmol) and acetic anhydride 140 mg,
0.39 mmol) were added at room temperature. The reaction
was stirred at room temperature overnight. The solvent was
removed and the residual material was puri®ed by ¯ash
column chromatography on silica gel 11% Et3N, diethyl
ether±hexane, 1:5) to give the acetate 16 152 mg, 83%
4.1.12. ,2R,4aR,8aS)-2-,4-Methoxyphenyl)-6-vinyl-4,4a,
8,8a-tetrahydropyrano[3,2-d]-1,3-dioxine ,18a). The
ruthenium catalyst 9 115.2 mg, 17.9 mmol) was dissolved
in dry toluene 130 mL) and ethene was bubbled through
the solution for 10 min. The alkyne 12a 190 mg,
0.33 mmol) was dissolved in dry toluene 13 mL) and
added to the solution of catalyst at room temperature
under an atmosphere of ethene. The solution was then
heated at 808C for 25 min. The solvent was removed in
vacuo and the crude product was puri®ed by ¯ash column
chromatography on silica 11% Et3N, diethyl ether±hexane,
1:10) to give the diene 18a 181 mg, 90%) as white solid
which was recrystallised from petroleum ether to afford
crystals suitable for X-ray analysis: mp 150±1518C;
22
yield) as a white solid: mp 95±978C; [a]D ˆ222.6 1c
0.980, CHCl3); nmax 1CHCl3) 2938, 2866, 2839, 2279,
1738, 1642, 1616, 1589, 981, 915 cm21
;
1H NMR
1400 MHz, CDCl3) d 7.38 12H, d, Jˆ8.7 Hz, Ar), 6.90
12H, d, Jˆ8.7 Hz, Ar), 5.95 11H, dddd, Jˆ6.8, 7.2, 10.2,
17.2 Hz, CHvCH2), 5.45 11H, s, OCHO), 5.21 11H, dddd,
Jˆ1.7, 1.7, 1.7, 17.2 Hz, CHvCH2), 5.16 11H, m,
CHvCH2), 4.69 12H, s, CH2OAc), 4.52 11H, dd, Jˆ5.3,
10.8 Hz, CH2O), 4.04 11H, ddd, Jˆ5.3, 9.7, 9.8 Hz,
CHO), 3.86±3.81 11H, m, CHO), 3.81 13H, s, OCH3),
3.79 11H, dd, Jˆ10.2, 10.8 Hz, CH2O), 2.72±2.64 11H, m,
CH2CHvCH2), 2.51±2.42 11H, m, CH2CHvCH2), 2.10
25
[a]D ˆ1106 1c 0.770, CHCl3); nmax 1CHCl3) 2935, 2911,
1
2865, 2840, 1654, 1616, 1601, 984, 947, 916 cm21; H
NMR1400 MHz, CDCl ) d 7.45 12H, d, Jˆ8.7 Hz, Ar),
3
6.91 12H, d, Jˆ8.7 Hz, Ar), 6.08 11H, dd, Jˆ10.9,
17.2 Hz, CHvCH2), 5.60 11H, s, OCHO), 5.46 11H, d,
Jˆ17.2 Hz, CHvCH2), 5.07 11H, d, Jˆ10.9 Hz,
CHvCH2), 4.84 11H, dd, Jˆ2.6, 5.8 Hz, CH2CHvC),
4.50±4.45 11H, m, CH2O), 3.97±3.76 13H, m, CHO,
CHO, CH2O), 3.82 13H, s, OCH3), 2.49 11H, ddd, Jˆ5.8,
5.8, 17.1 Hz, CH2CHvC), 2.40±2.32 11H, m, CH2CHvC);
13H, s, O2CCH3); 13C NMR1100 MHz, CDCl ) d 170.5
3
1s), 160.2 1s), 132.9 1d), 129.6 1s), 127.5 1d), 118.3 1t),
113.7 1d), 101.1 1d), 92.8 1s), 78.4 1d), 78.2 1d), 67.5 1t),
55.3 1q), 52.4 1t), 35.9 1t), 34.0 1s), 20.9 1q); HRMS 1EI)
Calcd for C19H22O6 1M1): 346.1416. Found 346.1408. Anal.
Calcd for C19H22O6: C, 65.88; H, 6.40. Found C, 66.01; H,
6.39.
13C NMR1100 MHz, CDCl ) d 160.2 1s), 150.6 1s), 131.4
3
1d), 130.0 1s), 127.6 1d), 113.8 1d), 113.2 1t), 101.7 1d), 100.5
1d), 74.9 1d), 69.9 1d), 69.1 1t), 55.4 1q), 27.5 1t); HRMS 1EI)
Calcd for C16H18O4 1M1): 274.1205. Found 274.1203. Anal.
Calcd for C16H18O4: C, 70.06; H, 6.61. Found C, 69.83; H,
6.40.
4.1.11. ,2R,4S,5R)-4-Allyl-5-[3-,tert-butyldiphenylsilyl-
oxy)prop-1-ynyloxy]-2-,4-methoxyphenyl)-1,3-dioxane
,17). The alcohol 15 152 mg, 0.17 mmol) was dissolved in
dry dichloromethane 12 mL). Imidazole 123 mg,
0.34 mmol) and t-butylchlorodiphenylsilane 151 mg,
0.19 mmol) were added to the solution and the mixture
4.1.13. ,2R,4aR,8aS)-6-Isopropenyl-2-,4-methoxyphenyl)-
4,4a,8,8a-tetrahydropyrano[3,2-d]-1,3-dioxine ,19a). The
ruthenium catalyst 9 19.6 mg, 11.3 mmol) was dissolved in

1980
J. S. Clark et al. / Tetrahedron 58 /2002) 1973±1982
dry toluene 110 mL) and ethene was bubbled through the
solution for 10 min. The alkyne 13a 166 mg, 0.23 mmol)
was dissolved in dry toluene 112 mL) and added to the solu-
tion of catalyst at room temperature under an atmosphere of
ethene. The solution was then heated at 808C for 10 min.
The solvent was removed in vacuo and the crude product
was puri®ed by ¯ash column chromatography on silica 11%
Et3N, diethyl ether±hexane, 1:10) to give the diene 19a
165 mg, 98%) as white solid which was recrystallised
from petroleum ether to afford crystals suitable for X-ray
the solution of the catalyst at room temperature under an
atmosphere of ethene. The solution was then heated at re¯ux
for 2 h. The solvent was removed in vacuo and the crude
product was puri®ed by ¯ash column chromatography on
silica 11% Et3N, diethyl ether±hexane, 1:1) to give the diene
21 149 mg, 84%) as white solid: mp 185±1868C;
20
[a]D ˆ185.5 1c 0.490, CHCl3); nmax 1CHCl3) 3609,
1
2934, 2866, 1649, 1615, 1589, 948, 914 cm21; H NMR
1400 MHz, CDCl3) d 7.45 12H, d, Jˆ8.7 Hz, Ar), 6.90
12H, d, Jˆ8.7 Hz, Ar), 5.60 11H, s, OCHO), 5.52 11H, s,
CvCH2), 5.24 11H, s, CvCH2), 5.08 11H, dd, Jˆ2.6,
5.7 Hz, CH2CHvC), 4.46 11H, ddd, Jˆ5.8, 10.7, 11.2 Hz,
CHO), 4.28 12H, br s, CH2OH), 3.97±3.78 13H, m, CHO,
CH2O), 3.82 13H, s, OCH3), 2.51 11H, ddd, Jˆ5.7, 5.9,
17.2 Hz, CH2CHvC), 2.38 11H, ddd, Jˆ2.6, 9.7, 17.2 Hz,
CH2CHvC), 1.54 11H, br s, OH); 13C NMR1100 MHz,
CDCl3) d 160.2 1s), 149.5 1s), 140.9 1s), 130.0 1s), 127.6
1d), 113.8 1d), 112.9 1t), 101.7 1d), 97.2 1d), 74.7 1d), 70.0
1d), 69.0 1t), 63.4 1t), 55.4 1q), 27.3 1t); HRMS 1EI) Calcd for
C17H20O5 1M1): 304.1311. Found 304.1318. Anal. Calcd for
C17H20O5: C, 67.09; H, 6.62. Found: C, 66.85; H, 6.68.
22
analysis: mp 160±1628C; [a]D ˆ188 1c 0.61, CHCl3);
nmax 1CHCl3) 2934, 2864, 2839, 1646, 1615, 1589, 998,
1
948, 905 cm21; H NMR1400 MHz, CDCl ) d 7.45 12H,
3
d, Jˆ8.8 Hz, Ar), 6.92 12H, d, Jˆ8.8 Hz, Ar), 5.60 11H, s,
OCHO), 5.37 11H, br d, Jˆ0.7 Hz, CvCH2), 4.99 11H, dd,
Jˆ2.7, 5.6 Hz, CH2CHvC), 4.95 11H, br, CvCH2), 4.47
11H, dd, Jˆ4.3, 10.0 Hz, CH2O), 3.96±3.77 13H, m, CHO,
CHO, CH2O), 3.83 13H, s, OCH3), 2.54±2.46 11H, m,
CH2CHvC), 2.37 11H, Jˆ2.7, 9.8, 17.1 Hz, CH2CHvC),
1.88 13H, s, CH2vCCH3); 13C NMR1100 MHz, CDCl ) d
3
160.6 1s), 152.1 1s), 137.2 1s), 130.4 1s), 127.9 1d), 114.1 1d),
112.5 1t), 102.0 1d), 97.2 1d), 75.2 1d), 70.2 1d), 69.5 1t), 55.7
1q), 27.8 1t), 19.8 1q); HRMS 1EI) Calcd for C17H20O4 1M1):
288.1362. Found 288.1369. Anal. Calcd for C17H20O4: C,
70.81; H, 6.99. Found C, 70.27; H, 6.93.
4.1.16.
,2R,4aR,8aS)-6-,1-Acetoxymethyl)vinyl-2-,4-
methoxyphenyl)-4,4a,8,8a-tetrahydropyrano[3,2-d]-1,3-
dioxine ,22). The ruthenium catalyst 9 16.2 mg, 7.3 mmol)
was dissolved in dry toluene 110 mL) ethene gas was
bubbled through the solution for 10 min. The alkyne 16
150 mg, 0.14 mmol) was dissolved in dry toluene 15 mL)
and to the solution of catalyst at room temperature under
an atmosphere of ethene. The solution was then heated at
808C for 2 h. The solvent was removed in vacuo and the
crude product was puri®ed by ¯ash column chromatography
on silica gel 11% Et3N, diethyl ether±hexane, 1:5) to give
the diene 22 136 mg, 72%) as a white solid: mp 130±1328C;
4.1.14.
,2R,4aR,8aS)-2-,4-Methoxyphenyl)-6-,1-tri-
methylsilyl)vinyl-4,4a,8,8a-tetrahydropyrano[3,2-d]-1,3-
dioxine ,20a). The ruthenium catalyst 9 152 mg, 61 mmol)
was dissolved in dry toluene 160 mL) and ethene was
bubbled through the solution for 10 min. The alkyne 14a
1400 mg, 1.15 mmol) was dissolved in dry toluene 160 mL)
and added to the solution of catalyst at room temperature
under an atmosphere of ethene. The solution was then
heated at 808C for 3 h. The solvent was removed in vacuo
and the crude product was puri®ed by ¯ash column chro-
matography on silica 11% Et3N, diethyl ether±hexane, 1:10)
to give the diene 20a 1350 mg, 88%) as a white solid which
was recrystallised from petroleum ether: mp 125±1278C;
20
[a]D ˆ176.0 1c 0.640, CHCl3); nmax 1CHCl3) 2932, 2865,
1733, 1649, 1615, 1590, 997, 947 cm21
;
1H NMR
1400 MHz, CDCl3) d 7.45 12H, d, Jˆ8.7 Hz, Ar), 6.91
12H, d, Jˆ8.7 Hz, Ar), 5.61 11H, s, CvCH2), 5.60 11H, s,
OCHO), 5.26 11H, s, CvCH2), 5.00 11H, dd, Jˆ2.6, 5.7 Hz,
CH2CHvC), 4.72 12H, s, CH2OAc), 4.46 11H, ddd, Jˆ5.8,
10.8, 10.8 Hz, CHO), 3.97±3.78 13H, m, CHO, CH2O), 3.82
13H, s, OCH3), 2.50 11H, ddd, Jˆ5.7, 5.9, 17.2 Hz,
CH2CHvC), 2.38 11H, ddd, Jˆ2.6, 9.7, 17.2 Hz,
CH2CHvC), 2.11 13H, m, O2CCH3); 13C NMR
1100 MHz, CDCl3) d 170.7 1s), 160.2 1s), 149.2 1s), 136.2
1s), 130.0 1s), 127.6 1d), 115.4 1t), 113.8 1d), 101.7 1d), 97.6
1d), 74.6 1d), 70.0 1d), 69.0 1t), 64.1 1t), 55.4 1q), 27.3 1t),
21.1 1q); HRMS 1EI) Calcd for C19H22O6 1M1): 346.1416.
Found 346.1417. Anal. Calcd for C19H22O6: C, 65.88; H,
6.40. Found C, 65.90; H, 6.47.
25
[a]D ˆ188.2 1c 0.635, CHCl3); nmax 1CHCl3) 2957,
1
2932, 2864, 1615, 1589, 1463, 994, 946 cm21; H NMR
1400 MHz, CDCl3) d 7.46 12H, d, Jˆ8.7 Hz, Ar), 6.92
12H, d, Jˆ8.7 Hz, Ar), 6.06 11H, d, Jˆ3.0 Hz, CvCH2),
5.60 11H, s, OCHO), 5.40 11H, d, Jˆ3.0 Hz, CvCH2),
4.89 11H, dd, Jˆ2.6, 5.7 Hz, CH2CHvC), 4.44 11H, ddd,
Jˆ5.8, 10.8, 11.2 Hz, CHO), 3.96±3.78 13H, m, CHO,
CH2O), 3.83 13H, s, OCH3), 2.48 11H, ddd, Jˆ5.7, 5.9,
16.9 Hz, CH2CHvC), 2.36 11H, ddd, Jˆ2.6, 9.7, 16.9 Hz,
CH2CHvC), 0.19 19H, s, Si[CH3]3); 13C NMR1100 MHz,
CDCl3) d 160.2 1s), 154.1 1s), 145.4 1s), 130.1 1s), 127.6 1d),
125.2 1t), 113.8 1d), 101.7 1d), 97.1 1d), 74.9 1d), 69.9 1d),
69.1 1t), 55.3 1q), 27.6 1t), 20.6 1q); HRMS 1FAB) Calcd for
C19H27O4Si 1M11H): 347.1679. Found 347.1659. Anal.
Calcd for C19H26O4Si: C, 65.86; H, 7.56. Found: C, 65.76;
H, 7.65.
4.1.17. ,2R,4aR,8aS)-6-[1-,tert-Butyldiphenylsilyloxy)-
methyl]vinyl-2-,4-methoxyphenyl)-4,4a,8,8a-tetrahydro-
pyrano[3,2-d]-1,3-dioxine ,23). The ruthenium catalyst 9
13.6 mg, 4.2 mmol) was dissolved in dry toluene 15 mL) and
ethene was bubbled through the solution for 10 min. The
alkyne 17 150 mg, 0.092 mmol) was dissolved in dry
toluene 14 mL) and added to the solution of catalyst at
room temperature under an atmosphere of ethene. The
solution was then heated at 808C for 2 h. The solvent was
removed in vacuo and the crude product was puri®ed by
¯ash column chromatography on silica gel 11% Et3N,
diethyl ether±hexane, 1:30) to give the diene 23 145.3 mg,
4.1.15.
,2R,4aR,8aS)-6-,1-Hydroxymethyl)vinyl-2-,4-
methoxyphenyl)-4,4a,8,8a-tetrahydropyrano[3,2-d]-1,3-
dioxine ,21). The ruthenium catalyst 8 115.7 mg, 19 mmol)
was dissolved in dry dichloromethane 110 mL) and ethene
was bubbled through the solution until the colour changed
from purple to orange. The alkyne 15 158 mg, 0.20 mmol)
was dissolved in dry dichloromethane 110 mL) and added to

J. S. Clark et al. / Tetrahedron 58 /2002) 1973±1982
1981
23
91%) as a viscous oil: [a]D ˆ160.0 1c 0.350, CHCl3); nmax
1400 MHz, CDCl3) d 7.43 12H, d, Jˆ8.7 Hz, Ar), 6.91
12H, d, Jˆ8.7 Hz, Ar), 5.54 11H, s, OCHO), 5.50 11H, dd,
Jˆ4.9, 9.5 Hz, CH2CHvC), 5.36 11H, d, Jˆ0.7 Hz,
CvCH2), 4.92 11H, d, Jˆ0.7 Hz, CvCH2), 4.41 11H, dd,
Jˆ5.3, 10.8 Hz, CH2O), 3.86±3.77 12H, m, CHO, CH2O),
3.82 13H, s, OCH3), 3.39 11H, ddd, Jˆ5.3, 9.1, 10.1 Hz,
CHO), 2.36±2.20 12H, m, CH2CHv), 2.13±2.06 11H, m,
CH2CH2CHv), 1.87 13H, s, CH2vCCH3), 1.59±1.47 11H,
1CHCl3) 2932, 2859, 1614, 1589, 998, 914 cm21; 1H NMR
1400 MHz, CDCl3) d 7.70 14H, m, Ph), 7.48±7.38 18H, m,
Ar, Ph), 6.90 12H, d, Jˆ8.8 Hz, Ar), 5.59 11H, s, OCHO),
5.54 11H, s, CvCH2), 5.44 11H, s, CvCH2), 4.80 11H, dd,
Jˆ2.6, 5.5 Hz, CH2CHvC), 4.46 11H, dd, Jˆ4.3, 9.8 Hz,
CH2O), 4.31 12H, br s, CH2OSi), 3.99±3.76 13H, m, CHO,
CHO, CH2O), 2.41 11H, ddd, Jˆ5.7, 5.9, 17.2 Hz,
CH2CHvC), 2.30 11H, ddd, Jˆ2.6, 9.7, 17.2 Hz,
CH2CHvC), 1.09 19H, s, C[CH3]3); 13C NMR1100 MHz,
CDCl3) d 160.2 1s), 149.4 1s), 140.1 1s), 135.6 1d), 133.5 1s),
130.0 1s), 129.8 1d), 127.8 1d), 127.6 1d), 113.8 1d), 111.2 1t),
101.7 1d), 96.3 1d), 74.8 1d), 69.9 1d), 69.1 1t), 63.1 1t), 55.4
1q), 27.2 1t), 26.9 1q), 19.4 1s); HRMS 1EI) Calcd for
C33H38O5Si 1M1): 542.2489. Found 542.2496. Anal. Calcd
for C33H38O5Si: C, 73.03; H, 7.06. Found C, 73.15; H, 7.12.
m, CH2CH2CHv); 13C NMR1100 MHz, CDCl ) d 160.1
3
1s), 158.3 1s), 138.2 1s), 130.3 1s), 127.5 1d), 113.7 1d), 112.5
1d), 112.0 1t), 101.1 1d), 82.9 1d), 75.4 1d), 69.1 1t), 55.3 1q),
31.4 1t), 21.3 1t), 19.5 1q); HRMS 1CI, CH4) Calcd for
C18H22O4 1M1): 302.1518. Found 302.1520. Anal. Calcd
for C18H22O4: C, 71.50; H, 7.33. Found C, 71.77; H, 7.34.
Acknowledgements
4.1.18. ,5aS,7R,9aR)-7-,4-Methoxyphenyl)-2-vinyl-4,5,
5a,9a-tetrahydrodioxolo[6,5-f]oxepine
,18b).
The
We thank The University of Nottingham for ®nancial
support and the Engineering and Physical Sciences
Research Council for the award 1grant no. GR/M30654)
of a postdoctoral fellowship 1to J. R.) and a CASE Student-
ship 1to D. B.). We also thank the Engineering and Physical
Sciences Research Council for the award of a SMART1000
diffractometer 1grant no. GR/M54728).
ruthenium catalyst 9 13 mg, 4 mmol) was dissolved in dry
toluene 15 mL) and ethene was bubbled through the solution
for 10 min. The alkyne 12b 120 mg, 69 mmol) was dissolved
in dry toluene 13 mL) and added to the solution of catalyst at
room temperature under an atmosphere of ethene. The solu-
tion was then heated at 808C for 2 h. The solvent was
removed in vacuo and the crude product was puri®ed by
¯ash column chromatography on silica 11% Et3N, diethyl
ether±hexane, 1:10) to give the diene 18b 114 mg, 70%) as
white solid which was recrystallised from petroleum ether:
References
25
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2928, 2858, 1644, 1615, 1590, 998, 972, 906 cm21; H
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ruthenium catalyst 9 115 mg, 18 mmol) was dissolved in
dry toluene 115 mL) and ethene was bubbled through the
solution for 10 min. The alkyne 13b 1106 mg, 0.351 mmol)
was dissolved in dry toluene 120 mL) and added to the
solution of catalyst at room temperature under an
atmosphere of ethene. The solution was then heated at
808C for 4 h. The solvent was removed in vacuo and the
crude product was puri®ed by ¯ash column chromatography
on silica gel 11% Et3N, diethyl ether±hexane, 1:10) to give
the diene 19b 176 mg, 72%) as a white solid which was
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Â
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[a]D ˆ137.7 1c 0.920, CHCl3); nmax 1CHCl3) 2929,
2863, 1644, 1615, 998, 972, 902 cm21
;
1H NMR

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