The tandem ring-closing metathesis-isomerization approach to 6-deoxyglycals

Article abstract of DOI:10.1002/chem.200800567

Protected 3,6-dideoxyglycals have been synthesized de novo as single isomers starting from ethyl lactate by using the tandem RCM-isomerization reaction as the key step. Different relative configurations become accessible by addition of vinyl- or allylmeta

Full text of DOI:10.1002/chem.200800567

FULL PAPER
DOI: 10.1002/chem.200800567
The Tandem Ring-Closing Metathesis–Isomerization Approach to
6-Deoxyglycals
Bernd Schmidt* and Anne Biernat[a]
Abstract: Protected 3,6-dideoxyglycals
have been synthesized de novo as
single isomers starting from ethyl lac-
tate by using the tandem RCM–isomer-
ization reaction as the key step. Differ-
ent relative configurations become ac-
cessible by addition of vinyl- or allyl–
metal compounds to protected lactal-
dehydes under Cram-chelate or
Felkin–Anh control. The concept is ex-
emplified for glycals of l-rhodinose
and l-amicetose, as well as for ring-ex-
panded non-natural analogues thereof.
This novel approach to glycals is also
applicable to the synthesis of disacchar-
ide glycals via a reiterative strategy, as
exemplified for the dimer of l-rhodi-
nose and its non-natural ring expanded
analogue.
Keywords:
heterocycles
carbohydrates
· isomerization
·
·
metathesis · ruthenium
Introduction
ed by co-crystallization of an oligonucleotide with the anti-
tumor agent daunomycin, where the deoxy sugar moiety
binds to the minor groove of the DNA duplex.[7] Although
deoxygenated carbohydrates, such as d- and l-amicetose,
have been accessed by combination of antibiotic gene clus-
ters, and their transfer to the ellaromycin aglycon by an ap-
propriate glycosyltransferase has been demonstrated,[5] the
chemical synthesis still remains an important issue. Deoxy
sugars can either be synthesized from other more common
carbohydrates by deoxygenation, or de novo.[8] For the as-
sembly of oligosaccharide chains and their connection to
aglycons by chemical means glycals have evolved as particu-
larly useful building blocks.[9–12] The term glycal, introduced
in the literature by Fischer and Zach in their original contri-
bution[13] to describe the chemical resemblance of these
compounds to aldehydes, is nowadays used for 1,2-unsatu-
rated sugars. Due to their enol ether structure, they show in-
teresting reactivities that have proven useful in target mole-
cule synthesis, beyond carbohydrate chemistry.[14–16] While
most glycal syntheses rely on reductive elimination of glyco-
sides in one way or the other,[17,18] over the past few years
transition metal mediated or catalyzed cyclization reactions
became more and more important. In particular, the cycliza-
tion of alkynols[19–21] and the ring-closing metathesis[22–24] of
enol ethers[25–29] has attracted considerable attention. The
observation that the well established ruthenium-based meta-
thesis catalysts sometimes catalyze other reactions with
comparable efficiency[30,31] has not only stimulated research
directed at a deeper understanding of the degradation reac-
tions of these complexes,[32,33] but has also led to the devel-
opment of new metathesis–non-metathesis tandem sequen-
Various deoxygenated carbohydrates are found in nature,
and considerable efforts have been made to gain insight into
their biological function[1] and the deoxygenation mecha-
nisms leading to their biosynthesis.[2–5] They are frequently
constituents of oligosaccharide side chains present in numer-
ous antibiotics and anticancer agents (see examples in
Figure 1).[6]
Figure 1. Representative deoxy sugars.
While it was commonly assumed for many years that the
glycosylation pattern in these drugs primarily affects their
pharmacokinetics, more recent investigations show that the
oligosaccharide side chains of glycoconjugates influence mo-
lecular recognition. This has, for instance, been demonstrat-
[a] Prof. Dr. B. Schmidt, Dipl.-Chem. A. Biernat
Universität Potsdam, Institut für Chemie, Organische Chemie II
Karl-Liebknecht-Strasse 24–25, Haus 25, 14476 Golm (Germany)
Fax : (+49)331-977-5059
E-mail: bernd.schmidt@uni-potsdam.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2008, 14, 6135 – 6141
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6135

ces.[34] One example for this type of tandem processes is the
RCM–isomerization sequence, which has been developed by
Snapper et al.[35] and by us.[36–38] In this sequence, a heterocy-
cle is formed by ring-closing metathesis, and—after comple-
tion of the metathesis step—the metathesis catalyst is con-
verted to an isomerization catalyst, which induces a subse-
quent migration of the double bond formed in the metathe-
sis step. It turned out that this method is particularly useful
for the synthesis of cyclic enol ethers, because it helps to
overcome the difficulties associated with the RCM of enol
ethers. These are the sometimes laborious synthesis of ap-
propriate precursors, the necessity to use high dilution con-
ditions and the more active but less conveniently available
molybdenum[39] and second-generation ruthenium cata-
lysts.[40] Herein, we report our results on the synthesis of gly-
cals related to important natural or non-natural deoxy
sugars using the tandem RCM–isomerization method.
Scheme 1. Protected l-rhodinal. i) H2C=CHCH2OCO2Et, [PdACHTREUNG(PPh3)4]
(2.5 mol%), THF, 658C; ii) DIBAL-H, then H2C=CHMgCl, CH2Cl2,
ꢀ908C; iii) TBSCl, imidazole, DMF; iv) NaH, PhCH2Br, THF, 658C;
v) A (5 mol%), toluene, 208C, then add 2-propanol (20 vol%) and
NaOH (30 mol%), 1108C.
Results and Discussion
l-Rhodinal and its ring-expanded analogue: We started with
an approach to the 2,3,6-trideoxy substitution pattern pres-
ent in rhodinose. Ethyl lactate (1) was identified as the start-
ing material of choice,[41] because addition of a vinyl nucleo-
phile to an appropriately O-protected lactaldehyde will
either proceed via Cram-chelate control,[42,43] eventually
leading to the rhodinal series, or via Felkin–Anh con-
trol,[43,44] eventually leading to the amicetal series. With a
view to the synthesis of protected l-rhodinals, ethyl lactate
(1) was first allylated with allyl ethyl carbonate catalyzed by
Pd0.[45] This reaction proceeds without racemization, in con-
trast to a standard Williamson ether synthesis, and gives
magnesium bromide, under otherwise identical conditions.
The resulting alcohol 6 was protected as TBS ether 7, which
gave, under tandem RCM–isomerization conditions, a ring
expanded l-rhodinal analogue 8 (Scheme 2). Evidence for
the assigned relative configuration of 8 comes, in analogy to
3
protected l-rhodinals 5, from the small J
A
2.3 Hz.
enantiomerically pure 2. As previously reported by us,[42]
2
can be converted to 3 by a one-pot reduction of the ester
function, followed by addition of vinyl magnesium chloride.
However, this step proceeds with only moderate diastereo-
selectivity, which might result from insufficient Cram-che-
late control due to competing complexation of the ether sol-
vent. Gratifyingly, exchange of the Et2O solvent by dichloro-
methane[46] gave (S,S)-3 as a single stereoisomer. Alcohol 3
can be protected as a TBS-ether 4a, or as a benzyl ether 4b
under standard conditions. Both undergo the desired
tandem RCM–isomerization cleanly if 2-propanol and solid
NaOH are used as additives to induce the conversion of the
metathesis catalyst to the isomerization catalyst.[37] TBS-pro-
Scheme 2. Protected ring-expanded l-rhodinal analogue. i) DIBAL-H,
then H2C=CHCH2MgBr, CH2Cl2, ꢀ908C; ii) TBSCl, imidazole, DMF;
iii) A (5 mol%), toluene, 208C, then add 2-propanol (20 vol%) and
NaOH (30 mol%), 1108C.
l-Amicetal and its ring-expanded analogue: As mentioned
above, a route to the l-amicetal series starting from ethyl
lactate is also feasible: silylation of 1 gives TBS-protected
ethyl lactate (9). Reduction of 9 with DIBAL-H to the cor-
responding lactaldehyde[48] and subsequent addition of vinyl
magnesium chloride to give 10 have previously been report-
ed.[44] Although we were able to reproduce this two-step
procedure with a slightly better diastereoselectivity ((S,R)-
tected (5a) and benzyl protected (5b) l-rhodinal are identi-
3
fied by their small J
A
cative for a cis-arrangement of methyl group and OTBS or
OBn group (Scheme 1).
It is also possible to adopt the concept for highly deoxy-
genated ring-expanded septanose glycals. Septanoses have
attracted some attention recently as non-natural analogues
of pyranoses which are expected to display significantly dif-
ferent conformational behavior.[47] To this end, the vinyl
magnesium chloride used in the sequence outlined above
for the protected l-rhodinals was simply replaced by allyl
10/ACHTRE(UNG S,S)-10 8:1) than reported in the literature, it turned out
to be far more convenient to avoid the isolation of the alde-
hyde and perform reduction and Grignard addition in a
one-pot sequence, as described above in the rhodinal series.
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Chem. Eur. J. 2008, 14, 6135 – 6141

Ring-Closing Metathesis
FULL PAPER
The diastereoselectivities of both reactions are practically
identical, but the overall yield is significantly better for the
one-pot method. The secondary alcohol in 10 was subse-
quently protected as MEM-ether 11, which upon desilyla-
tion and O-allylation under standard conditions gave precur-
sor 13. Subjecting 13 to the same tandem RCM–isomeriza-
tion conditions mentioned above gives a MEM-protected l-
amicetal 14 in 70% yield as a single diastereoisomer after
column chromatography. The trans-arrangement of methyl
3
group and -OMEM group leads to a larger J
A
of 7.8 Hz (Scheme 3).
Scheme 4. Protected ring-expanded l-amicetal analogue. i) DIBAL-H,
then H2C=CHCH2MgBr, CH2Cl2, ꢀ908C; ii) MEMCl (2 equiv), NEt2iPr
(3 equiv), CH2Cl2, 0!208C; iii) TBAF (2 equiv), THF, 658C; iv) NaH,
H2C=CHCH2Br, THF, 658C; v) A (5 mol%), toluene, 208C, then add 2-
propanol (20 vol%) and NaOH (30 mol%), 1108C, then separate by
column chromatography.
peated application of glycosylation, deprotection and endo-
cyclization of alkynols.[49] Implementing our glycal synthesis
into a reiterative strategy should in principle be possible. In
this section, we would like to illustrate the concept for a dis-
accharide consisting of l-rhodinose and its ring expanded
septanose homologue. Related disaccharides containing one
heptose and one hexose unit have previously attracted some
attention as potential substrates for glycosyl transferases.[50]
Starting from l-rhodinal benzyl ether (5b) glycosylation
with precursor 6 gave the desired glycoside 20. Different
glycosylation procedures were tested: with triphenyl phos-
phonium bromide[51] the required precursor was obtained,
but only as a mixture of epimers and in extremely poor
yield. Thiemꢁs iodoglycosylation method[9,52] was tested next.
In spite of difficulties that may obviously arise from the
Scheme 3. Protected l-amicetal. i) TBSCl, imidazole, DMF; ii) DIBAL-
H, then H2C=CHMgCl, Et2O, ꢀ908C; iii) MEMCl (2 equiv), NEt2iPr
(3 equiv), CH2Cl2, 0!208C; iv) TBAF (2 equiv), THF, 658C; v) NaH,
H2C=CHCH2Br, THF, 658C; vi) A (5 mol%), toluene, 208C, then add 2-
propanol (20 vol%) and NaOH (30 mol%), 1108C.
The same approach was pursued towards a ring-expanded
l-amicetal analogue. Starting from 9, 15 was obtained via
one-pot reduction and addition of allyl magnesium bromide.
In contrast to allylic alcohol 10, the homoallylic derivative
15 was obtained in lower diastereoselectivity (dr 2:1). Sepa-
ration of the two diastereomers is not possible at this stage
and therefore the following steps were conducted for the
mixture: MEM protection, followed by desilylation and O-
allylation gives the metathesis precursor 18. 18 is cleanly
converted under tandem RCM–isomerization conditions to
a mixture of (S,R)-19 and (S,S)-19 in a 2:1 ratio. These dia-
stereomers are easily separated by column chromatography,
ꢀ
presence of three different C C double bonds, successful ap-
plication of the method to glycoside formation with an allyl-
ic alcohol has been reported in the literature.[53] Unfortu-
nately, in our case the treatment of 5b with NIS in the pres-
ence of alcohol 6 resulted in the formation of a complex
mixture. It was not possible to decide whether the electro-
ꢀ
philic attack of the C C double bond was insufficiently se-
lective, or if the problems were caused by insufficient diaste-
reoselectivity of the glycosylation step. Gratifyingly, the re-
quired precursor 20 could be obtained in good yield as a
separable 5:1 mixture of anomers by using a catalytic
amount of p-TSA. Conversion of 20 to the disaccharide
glycal 21 proceeded smoothly under tandem RCM–isomeri-
zation conditions similar to those applied for 8. This se-
quence is summarized in Scheme 5.
and an assignment of the relative configuration is conven-
3
iently achieved via the J
A
19 (l-rhodinal homologue) and 9.0 Hz for (S,R)-19 (l-amice-
tal homologue). The sequence leading to 19 is outlined in
Scheme 4.
6-Deoxy-disaccharide glycals: Oligosaccharides and glyco-
conjugates containing oligosaccharide side chains may be as-
sembled on solid support. Obviously, it is a prerequisite that
efficient reiterative strategies are available. Such a strategy
is, for instance, the glycal assembly method, where oligosac-
charides result from epoxidation of a glycal, followed by ep-
Conclusion
In summary, we have shown that the tandem RCM–isomeri-
zation approach is a useful synthetic method to access vari-
ous 6-deoxy glycals. We were also able to demonstrate that
novel ring-expanded analogues of highly deoxygenated gly-
cals become available via the sequences described herein.
For a disaccharide containing one septanose and one hexose
oxide cleavage with
a second selectively deprotected
glycal.[12] Another example, where formation of a glycal
structure is one of the repetitive steps, has been devised by
McDonald and Zhu, who obtained oligosaccharides by re-
Chem. Eur. J. 2008, 14, 6135 – 6141
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6137

B. Schmidt and A. Biernat
OCH2CH=), 3.93 (dddd, 1H, J=12.8, 5.5, 1.3, 1.3 Hz, OCH2CH=), 3.89
(dd, 1H, J=7.0, 6.5 Hz, CH(OH)), 3.32 (dq, 1H, J=7.0, 6.3 Hz,
CHCH3), 2.80 (brs, 1H, OH), 1.11 ppm (d, 3H, J=6.3 Hz, CH3);
13C NMR (100 MHz, CDCl3): d=136.8 (1), 134.8 (1), 117.4 (2), 117.0 (2),
78.0 (1), 76.5 (1), 70.0 (2), 15.5 ppm (3); IR (film, KBr plates): n˜ =3372
(bm), 2933 (m), 1455 (m), 1377 cmꢀ1 (m).
AHCTRE(GNU 3S,4S)-4-Allyloxy-3-(tert-butyldimethylsilyloxy)pent-1-ene (4a): TBSCl
(600 mg, 4.0 mmol) and imidazole (306 mg, 4.5 mmol) was added to a so-
lution of 3 (440 mg, 3.1 mmol) in DMF (20 mL). After stirring for 12 h,
the mixture was diluted with water (20 mL) and extracted with pentane.
The organic extracts were dried with MgSO4, filtered and evaporated.
The residue was purified by flash chromatography on silica to yield 4a
(600 mg, 75%). [a]2D6 = ꢀ15.38 (c=1.01 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=5.90 (dddd, 1H, J=17.3, 10.3, 5.5, 5.5 Hz, OCH2CH=), 5.85
(ddd, 1H, J=17.3, 10.5, 5.3 Hz, CHACTHRE(UNG OTBS)CH=), 5.24 (dm, 1H, J=
17.3 Hz, =CH2), 5.24 (dm, 1H, J=17.3 Hz, =CH2), 5.13 (dm, 1H, J=
10.5 Hz, =CH2), 5.13 (dm, 1H, J=10.5 Hz, =CH2), 4.16 (dd, 1H, J=5.5,
5.3 Hz, CHACTHRE(UNG OTBS)), 4.06 (ddm, 1H, J=12.8, 5.5 Hz, OCH2CH=), 4.01
Scheme 5. Disaccharide glycal of l-rhodinose and its ring-expanded ana-
logue. i) p-TSA (8 mol%), CH2Cl2, 08C; ii) A (5 mol%), toluene, 208C,
then add 2-propanol (20 vol%) and NaOH (30 mol%), 1108C.
(ddm, 1H, J=12.8, 5.5 Hz, OCH2CH=), 3.39 (dq, 1H, J=6.3, 5.5 Hz,
CHCH3), 1.03 (d, 3H, J=6.3 Hz, CH3), 0.88 (s, 9H, tBu), 0.04 (s, 3H, Si-
(CH3)2); 13C NMR (100 MHz, CDCl3): d=
ACHRTEU(NG CH3)2), 0.04 ppm (s, 3H, SiACHTREUGN
unit it was demonstrated that this novel glycal synthesis can
in principle be executed in a reiterative manner. Extension
to other glycals and applications of these compounds are
currently under investigation.
137.3 (1), 135.4 (1), 116.5 (2), 115.5 (2), 78.0 (1), 75.2 (1), 70.5 (2), 25.8
(3), 18.2 (0), 14.8 (3), ꢀ4.7 (3), ꢀ4.9 ppm (3); IR (film, KBr plates): n˜ =
2956 (m), 2929 (m), 2856 (m), 1646 (w), 1472 cmꢀ1 (m); LRMS (70 eV,
EI): m/z (%): 279 (30) [M++Na], 213 (100); HRMS (ESI): m/z: calcd for
C14H28O2Si: 279.1751, found 279.1744 [M++H].
AHCTRE(GNU 3S,4S)-4-Allyloxy-3-benzyloxy-pent-1-ene (4b): NaH (60% dispersion in
mineral oil, 120 mg, 3.0 mmol) was added to a solution of 3 (200 mg,
1.4 mmol) in THF (20 mL) and the mixture was heated to reflux for
30 min. Benzyl bromide (0.36 mL, 3.0 mmol) was added, and the mixture
was again heated to reflux for 30 min. Aqueous workup, followed by
flash chromatography on silica, yielded 4b (250 mg, 77%). [a]2D6 = ꢀ0.98
(c=1.55 in CH2Cl2); 1H NMR (500 MHz, CDCl3): d=7.40–7.25 (5H, Ph),
5.93 (dddd, 1H, J=17.0, 10.5, 5.7, 5.3 Hz, OCH2CH=), 5.82 (ddd, 1H, J=
17.2, 10.2, 7.2 Hz, CHACHTRE(UNG OTBS)CH=), 5.36–5.24 (3H, =CH2), 5.16 (dm,
1H, J=10.5 Hz, =CH2), 4.66 (d, 1H, J=12.0 Hz, -OCH2Ph), 4.44 (d, 1H,
J=12.0 Hz, OCH2Ph), 4.15–4.05 (2H, OCH2CH=), 3.81 (dd, 1H, J=7.0,
Experimental Section
All experiments were conducted in dry reaction vessels under an atmos-
phere of dry argon. Solvents were purified by standard procedures.
1H NMR spectra were obtained at 300, 400, 500, or at 600 MHz in CDCl3
with CHCl3 (d=7.26 ppm) as an internal standard or in C6D6 with
C6D5H (d=7.18 ppm) as an internal standard. Coupling constants are
given in Hz. 13C NMR spectra were recorded at 75 MHz, 100 MHz,
125 MHz or at 150 MHz in CDCl3 with CDCl3 (d=77.0 ppm) as an inter-
nal standard or in C6D6 with C6D6 (d=128.0 ppm) as an internal stan-
dard. The number of coupled protons was analyzed by DEPT or APT ex-
periments and is denoted by a number in parentheses following the
chemical shift value. Whenever NMR-peak assignments in the 13C NMR
spectra are given, these are based on H,H- and H,C-correlation spectros-
copy. IR spectra were recorded as films on NaCl or KBr plates. The peak
intensities are defined as strong (s), medium (m) or weak (w). Mass spec-
tra were obtained at 70 eV. Ruthenium catalyst A[54] was used as pur-
chased without further purification. Compounds 2,[55] and 9,[48] were pre-
pared as previously reported in the literature. Compound 10 has previ-
ously been reported,[44] but was prepared by a modified procedure (see
below).
6.0 Hz, CHACHTRE(UNG OBn)), 3.58 (dq, 1H, J=6.2, 6.2 Hz, CHCH3), 1.15 ppm (d,
3H, J=6.3 Hz, CH3); 13C NMR (125 MHz, CDCl3): d=138.6 (0), 135.4
(1), 135.2 (1), 128.2 (1), 127.6 (1), 127.4 (1), 118.6 (2), 116.4 (2), 83.2 (1),
76.6 (1), 70.8 (2), 70.5 (2), 16.1 ppm (3); IR (film, KBr plates): n˜ =3065
(m), 3029 (m), 2978 (m), 2863 (m), 1645 (m), 1454 cmꢀ1 (s); LRMS
(70 eV, EI): m/z (%): 233 (40) [M++H], 131 (100); HRMS (ESI): m/z:
calcd for C15H20O2: 233.1536; found 233.1517; elemental analysis calcd
(%) for C15H20O2: C 77.6, H 8.7; found: C 77.1, H, 8.7.
tert-Butyldimethyl-[(2S)-methyl-3,4-dihydro-2H-pyran-(3S)-yloxy]silane
(5a): Ruthenium catalyst A (82 mg, 4.8 mol%) was added to a solution
of 4a (550 mg, 2.1 mmol) in toluene (10 mL). The solution was stirred at
ambient temperature, until the starting material was fully consumed as
indicated by TLC. 2-Propanol (2 mL) and solid NaOH (60 mg) was
added, and the mixture was heated to reflux for 30 min. After this time,
the intermediate RCM product was completely converted to 5a, as indi-
cated by TLC. The solution was washed with water, and all volatiles were
evaporated. The residue was purified by flash chromatography, followed
by Kugelrohr distillation (1008C, 10 mbar) to give 5a (440 mg, 92%).
[a]2D0 = ꢀ33.6 (c=0.72 in CH2Cl2); 1H NMR (400 MHz, [D6]benzene):
d=6.33 (ddd, 1H, J=6.0, 1.8, 1.8 Hz, H1), 4.45 (ddd, 1H, J=6.0, 3.8,
3.8 Hz, H2), 3.96 (qdd, 1H, J=6.5, 3.0, 1.0 Hz, H5), 3.78 (ddd, 1H, J=
6.3, 5.5, 3.0 Hz, H4), 2.02 (dm, 1H, J=16.8 Hz, H3), 1.93 (dddd, 1H, J=
16.8, 6.3, 3.3, 2.0 Hz, H3’), 1.24 (d, 3H, J=6.3 Hz, CH3), 0.95 (s, 9H,
ACHTREUNG(3S,4S)-4-Allyloxy-pent-1-en-3-ol (3): A solution DIBAL-H (1.0m in
CH2Cl2, 14.0 mL, 14.0 mmol) was added at ꢀ908C to a solution of 2
(1.62 g, 10.2 mmol) in CH2Cl2 (60 mL). After stirring at this temperature
for 10 min, TLC (cyclohexane/MTBE 5:1) indicated complete consump-
tion of the starting material. Vinyl magnesium chloride (1.7m solution in
THF, 11.8 mL, 20.0 mmol) was then added via syringe and the mixture
was allowed to warm to ambient temperature. It was then poured onto
water and diethyl ether, and the precipitate was dissolved with a saturat-
ed solution of K/Na tartrate. The organic layer was separated, and the
aqueous layer was extracted twice with diethyl ether. The combined or-
ganic extracts were dried with MgSO4, filtered and evaporated. Caution:
due to the rather high volatility of the product, the minimum pressure
during evaporation should be 300 mbar! The residue was distilled (b.p.
458C/30 mbar) to give 3 (1160 mg, 80%). [a]2D5 = +41.88 (c=0.79 in
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=5.89 (dddd, 1H, J=17.3, 10.5,
5.5, 5.5 Hz, OCH2CH=), 5.79 (ddd, 1H, J=17.3, 10.5, 6.5 Hz,
CH(OH)CH=), 5.34 (dd, 1H, J=17.3, 1.5, 1.5 Hz, =CH2), 5.25 (dm, 1H,
J=17.3 Hz, =CH2), 5.19 (ddd, 1H, J=10.5, 1.5, 1.5 Hz, =CH2), 5.15 (dm,
1H, J=10.5 Hz, =CH2), 4.12 (dddd, 1H, J=12.8, 5.5, 1.3, 1.3 Hz,
tBu), 0.00 (s, 3H, Si
A
(CH3)2); 13C NMR
ACHTREUNG
(100 MHz, [D6]benzene): d=142.6 (1), 96.7 (1), 73.1 (1), 66.9 (1), 28.0
(2), 25.9 (3), 18.2 (0), 14.2 (3), ꢀ4.6 (3), ꢀ4.9 ppm (3); IR (film, KBr
plates): n˜ =2956 (s), 2930 (s), 1651 (s), 1240 (s), 1100 (s), 874 cmꢀ1 (s);
LRMS (70 eV, EI): m/z (%): 171 (49) [M+ꢀtBu], 115 (29), 75 (100); ele-
mental analysis calcd (%) for C12H24O2Si: C 63.1, H, 10.6; found: C 62.6,
H 10.6.
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Chem. Eur. J. 2008, 14, 6135 – 6141

Ring-Closing Metathesis
FULL PAPER
A
was purified by Kugelrohr distillation (1008C, 3 mbar). Yield: 1.30 g
(80%). [a]2D5 =+19.6 (c=0.65 in CH2Cl2); 1H NMR (400 MHz, CDCl3):
d=5.79 (ddd, 1H, J=17.3, 10.5, 6.3 Hz, CH=), 5.26 (ddd, 1H, J=17.3,
1.5, 1.5 Hz, =CH2), 5.17 (ddd, 1H, J=10.5, 1.5, 1.5 Hz, =CH2), 4.00 (m,
=
ꢀ19.6 (c=0.97 in
CH2Cl2); 1H NMR (500 MHz, [D6]benzene): d=7.25 (d, 2H, J=7.2 Hz,
Ph), 7.17 (dd, 2H, J=7.2, 7.2 Hz, Ph), 7.11 (t, 1H, J=7.2 Hz, Ph), 6.33
(d, 1H, J=6.0 Hz, H1), 4.44 (ddd, 1H, J=6.2, 3.5, 3.5 Hz, H2), 4.34 (d,
1H, J=12.2 Hz, OCH2Ph), 4.19 (d, 1H, J=12.2 Hz, OCH2Ph), 4.06 (qd,
1H, J=6.5, 2.9 Hz, H5), 3.44 (m, 1H, H4), 2.05–1.95 (2H, H3), 1.28 ppm
(d, 3H, J=6.5 Hz, CH3); 13C NMR (125 MHz, [D6]benzene): d=142.8
(1), 139.2 (0), 128.5 (1), 127.7 (1), 127.6 (1), 96.7 (1), 72.9 (1), 71.6 (1),
70.8 (2), 24.0 (2), 14.5 ppm (3); IR (film, KBr plates): n˜ =3062 (w), 2979
(w), 2865 (w), 1649 (m), 1453 cmꢀ1 (m); LRMS (70 eV, EI):
m/z (%): 205 (20) [M++H], 281 (100); HRMS (ESI): m/z: calcd for
C13H16O2: 205.1223, found 205.1228; elemental analysis calcd (%) for
C13H16O2: C 76.4, H 7.9; found: C 76.2, H 8.3.
1H, CHOH), 3.82 (qd, 1H, J=6.3, 3.8 Hz, OCH
OH), 1.06 (d, 3H, J=6.3 Hz, CH3), 0.88 (s, 9H, tBu), 0.06 (s, 3H, Si-
(CH3)2), 0.06 ppm (s, 3H, Si
(CH3)2); 13C NMR (100 MHz, CDCl3): d=
ACHTRE(UNG CH3)), 2.30 (brs, 1H,
A
ACHTREUNG
136.5 (1), 116.5 (2), 76.6 (1), 71.3 (1), 25.8 (3), 18.0 (0), 17.6 (3), ꢀ4.5 (3),
ꢀ4.9 ppm (3); IR (film, KBr plates): n˜ =3443 (s), 2957 (s), 1472 (s), 1376
(s), 1255 (s), 1097 (s), 1005 (s), 836 (s), 776 cmꢀ1 (s); LRMS (70 eV, EI):
m/z (%): 159 (58) [M+ꢀtBu], 75 (100); elemental analysis calcd (%) for
C11H24O2Si: C 61.1, H 11.2; found: C 60.8, H 11.4.
AHCTRE(GNU 1S,2R)-tert-Butyl-[2-(2-methoxy-ethoxymethoxy)-1-methyl-but-3-eny-
loxy]-dimethylsilane (11): To a solution of 10 (1.30 g, 6.0 mmol) in dry
CH2Cl2 was added Et2NiPr (3.80 mL, 23.0 mmol) and MEM-chloride
(1.71 mL, 15.0 mmol) at 08C. The mixture was allowed to warm to ambi-
ent temperature, and stirring was continued for 12 h. The solution was di-
luted with MTBE and washed with aqueous Na2CO3 solution. The organ-
ic layer was separated, dried with MgSO4, filtered and evaporated. The
residue was purified by flash chromatography on silica to give 11 (1.64 g,
90%). [a]2D6 =ꢀ25.8 (c=1.01 in CH2Cl2); 1H NMR (400 MHz,
[D6]benzene): d=5.81 (ddd, 1H, J=17.6, 10.3, 7.8 Hz, CH=), 5.19 (dm,
1H, J=17.6 Hz, =CH2), 5.15 (dm, 1H, J=10.3 Hz, =CH2), 4.81 (d, 1H,
J=6.5 Hz, OCHHO), 4.66 (d, 1H, J=6.5 Hz, OCHHO), 3.99 (dd, 1H,
(2S)-Allyloxy-hex-5-en-(3S)-ol (6): Obtained from 2 (780 mg, 5.0 mmol)
and allyl magnesium bromide (1.25m solution in ether, 12.5 mL,
10 mmol) following the procedure given above for 3. Compound 6 was
purified by column chromatography on silica gel (560 mg, 72%). [a]D25
=
+35.8 (c=0.92 in CH2Cl2); 1H NMR (400 MHz, CDCl3): d=5.94–5.90
(2H, CH=), 5.24 (dm, 1H, J=17.1 Hz, =CH2), 5.15 (dm, 1H, J=10.3 Hz,
=CH2), 5.09 (dm, 1H, J=17.3 Hz, =CH2), 5.06 (dm, 1H, J=10.3 Hz, =
CH2), 4.10 (dd, 1H, J=12.6, 5.3 Hz, OCH2CH=), 3.90 (dd, 1H, J=12.6,
5.8 Hz, OCH2CH=), 3.47 (1H, m, CH(OH)), 3.33 (dq, 1H, J=6.0,
6.0 Hz, CHACHTREUNG(CH3)), 2.53 (brs, 1H, OH), 2.32 (dm, 1H, J=14.5 Hz, CH2),
J=7.8, 4.5 Hz, CHOMEM), 3.91 (qd, 1H, J=6.3, 4.5 Hz, OCHACHTREUNG(CH3)),
2.16 (ddd, 1H, J=14.5, 7.5, 7.5 Hz, CH2), 1.12 ppm (d, 3H, J=6.5 Hz,
CH3); 13C NMR (100 MHz, CDCl3): d=134.9 (1), 134.7 (1), 117.1 (2),
116.9 (2), 77.4 (1), 74.1 (1), 69.9 (2), 37.4 (2), 15.4 ppm (3); IR (film, KBr
plates): n˜ =3454 (bw), 3077 (m), 2977 (m), 2867 (m), 1641 cmꢀ1 (m);
LRMS (70 eV, FAB): m/z (%): 157 (5) [M+ꢀH], 197 (100); HRMS
(FAB): m/z: calcd for C9H16O2: 157.1223 [M++H], found 157.1232; ele-
mental analysis calcd (%) for C9H16O2: C 69.2, H 10.3; found: C 69.1, H
11.3.
3.78 (dt, 1H, J=10.8, 5.0 Hz, OCHHCH2O), 3.55 (dt, 1H, J=10.8,
5.0 Hz, OCHHCH2O), 3.38 (2H, t, J=5.0 Hz, OCH2CH2O), 3.14 (s, 3H,
OCH3), 1.20 (d, 3H, J=6.3 Hz, CH3), 1.01 (s, 9H, tBu), 0.14 (s, 3H, Si-
(CH3)2); 13C NMR (100 MHz, [D6]benzene):
ACHRTEU(NG CH3)2), 0.10 ppm (s, 3H, SiACHTREUGN
d=135.8 (1), 118.9 (2), 92.9 (2), 81.6 (1), 72.2 (2), 71.2 (1), 67.4 (2), 58.6
(3), 26.1 (3), 20.2 (3), 18.4 (0), ꢀ4.4 (3), ꢀ4.5 ppm (3); IR (film, KBr
plates): n˜ =2929 (m), 2885 (m), 2857 (m), 1472 (w), 1361 (w), 1252 cmꢀ1
(m); LRMS (70 eV, EI): m/z (%): 327 (10) [M++Na], 199 (100); HRMS
(ESI): m/z: calcd for C15H32O4Si: 327.1962 [M++Na], found 327.1973; el-
emental analysis calcd for C15H32O4Si: C 59.2, H 10.6; found: C 59.2, H
11.0.
ACHTREUNG[(1S,2S)-Allyloxyethyl)-but-3-enyloxy]-tert-butyl-dimethylsilane (7): Ob-
tained from 6 (300 mg, 1.9 mmol) following the procedure given above
for 4a. 7 was purified by column chromatography on silica. Yield: 437 mg
(85%). [a]2D5 =ꢀ5.02 (c=0.88 in CH2Cl2); 1H NMR (400 MHz, CDCl3):
d=5.87 (dddd, 1H, J=17.1, 10.3, 5.8, 5.5 Hz, OCH2CH=), 5.83 (dddd,
1H, J=17.3, 10.0, 7.3, 7.0 Hz, CH2CH=), 5.24 (dm, 1H, J=17.1 Hz, =
CH2), 5.13 (dm, 1H, J=10.3 Hz, =CH2), 5.03 (dm, 1H, J=17.1 Hz, =
CH2), 5.00 (dm, 1H, J=10.0 Hz, =CH2), 4.02 (dd, 1H, J=12.8, 5.5 Hz,
OCH2CH=), 3.95 (dd, 1H, J=12.6, 5.8 Hz, OCH2CH=), 3.68 (m, 1H,
AHCTRE(GNU 2S,3R)-3-(2-Methoxyethoxymethoxy)-pent-4-en-2-ol (12): To a solution
of 11 (1.16 g, 3.8 mmol) in dry THF (30 mL) was added TBAF (2.37 g,
7.5 mmol) and the solution was heated to reflux. After 30 min, the reac-
tion mixture was cooled to ambient temperature, diluted with ethyl ace-
tate (30 mL), and washed with brine. The organic extracts were dried
with MgSO4, filtered and evaporated. The residue was purified by flash
chromatography on silica using cyclohexane/ethyl acetate 2:1 to give 12
(0.72 g, quant.). [a]2D6 =ꢀ65.2 (c=1.01 in CH2Cl2); 1H NMR (400 MHz,
[D6]benzene): d=5.71 (ddd, 1H, J=17.3, 10.5, 7.5 Hz, CH=), 5.14 (dm,
1H, J=17.3 Hz, =CH2), 5.08 (dm, 1H, J=10.5 Hz, =CH2), 4.69 (d, 1H,
J=7.0 Hz, OCHHO), 4.57 (d, 1H, J=7.0 Hz, OCHHO), 4.02 (dd, 1H,
J=7.3, 3.3 Hz, CHOMEM), 3.87 (m, 1H, CHOH), 3.70 (ddd, 1H, J=
10.9, 6.3, 3.5 Hz, OCHHCH2)OCH3), 3.42 (ddd, 1H, J=10.9, 6.3, 3.5 Hz,
CH
14.1 Hz, CH2), 2.08 (ddd, 1H, J=14.1, 7.5, 7.3 Hz, CH2), 1.08 (d, 3H, J=
6.3 Hz, CH3), 0.86 (s, 9H, tBu), 0.02 (s, 3H, Si(CH3)2), 0.02 ppm (s, 3H,
Si
(CH3)2); 13C NMR (100 MHz, CDCl3): d=136.1 (1), 135.5 (1), 116.5
ACHTREUNG(OTBS)), 3.39 (qd, 1H, J=6.3, 5.3 Hz, CHCAHTRE(UNG CH3)), 2.32 (dm, 1H, J=
AHCTREUNG
ACHTREUNG
(2), 116.4 (2), 77.3 (1), 73.9 (1), 70.2 (2), 36.5 (2), 25.9 (3), 18.1 (0), 14.1
(3), ꢀ4.4 (3), ꢀ4.5 ppm (3); IR (film, KBr plates): n˜ =3078 (w), 2929 (m),
2856 (m), 1642 (w), 1472 cmꢀ1 (m); LRMS (70 eV, FAB): m/z (%): 271
(30) [M+ꢀH], 213 (100); HRMS (FAB): m/z: calcd for C15H30O2Si:
271.2088 [M ++H], found 271.2104.
OCHHCH2)OCH3),
OCH2CHH)OCH3),
3.31
3.25
(ddd,
(ddd,
1H,
1H,
J=10.5,
J=10.5,
6.3,
6.3,
3.3 Hz,
3.3 Hz,
OCH2CHH)OCH3), 3.10 (s, 3H, OCH3), 2.77 (brd, 1H, J=3.5 Hz, OH),
1.20 ppm (d, 3H, J=6.3 Hz, CH3); 13C NMR (100 MHz, [D6]benzene):
d=135.1 (1), 118.7 (2), 93.6 (2), 82.7 (1), 72.1 (2), 69.4 (1), 67.6 (2), 58.6
(3), 17.9 ppm (3); IR (film, KBr plates): n˜ =3438 (bm), 2976 (m), 2885
(m), 1643 (m), 1452 cmꢀ1 (m); LRMS (70 eV, EI): m/z (%): 191 (100)
[M++H]; HRMS (ESI): m/z: calcd for C9H18O4: 191.1278 [M++H],
found 191.1292; elemental analysis calcd (%) for C9H18O4: C 56.8, H, 9.5;
found: C 56.4, H 9.7.
tert-Butyldimethyl-(2S-methyl-2,3,4,5-tetrahydro-oxepin-(3S)-yloxy)silane
(8): Obtained from 7 (340 mg, 1.3 mmol) following the procedure given
above for 5a. Compound 8 was purified by column chromatography on
silica. Yield: 268 mg (85%). [a]2D5 =ꢀ53.9 (c=2.72 in CH2Cl2); 1H NMR
(400 MHz, [D6]benzene): d=6.37 (d, 1H, J=6.4 Hz, H1), 4.59 (ddd, 1H,
J=6.4, 6.4, 4.0 Hz, H2), 4.00 (qd, 1H, J=6.5, 2.3 Hz, H6), 3.53 (ddd, 1H,
J=8.3, 5.8, 2.3 Hz, H5), 2.01 (m, 1H, H3/4), 1.94–1.87 (2H, H3/H4), 1.74
(m, 1H, H4/H5), 1.25 (d, 3H, J=6.3 Hz, CH3), 0.99 (s, 9H, tBu), 0.02 (s,
(CH3)2); 13C NMR (100 MHz,
3H, SiACHTREUNG(CH3)2), 0.01 ppm (s, 3H, SiACHTREUGN
AHCTRE(GNU 3R,4S)-4-Allyloxy-3-(2-methoxyethoxymethoxy)-pent-1-ene (13): Ob-
[D6]benzene): d=148.6 (1), 107.9 (1), 80.8 (1), 75.2 (1), 35.0 (2), 26.0 (3),
21.8 (2), 18.3 (0), 17.8 (3), ꢀ4.2 (3), ꢀ4.8 ppm (3); IR (film, KBr plates):
n˜ =3042 (w), 2929 (m), 2856 (m), 1647 (m), 1472 (m) cmꢀ1; LRMS
(70 eV, EI): m/z (%): 243 (100) [M++H]; HRMS (ESI): m/z: calcd for
C13H26O2Si: 243.1775 [M++H], found 243.1775.
tained from 12 (300 mg, 1.6 mmol) following the procedure given above
for 4b, except using allyl rather than benzyl bromide. Compound 13 was
purified by flash chromatography on silica. Yield: 300 g (83%). [a]D26
=
ꢀ60.1 (c=1.07 in CH2Cl2); 1H NMR (400 MHz, [D6]benzene): d=5.89
(dddd, 1H, J=17.1, 10.3, 5.0, 5.0 Hz, CH=), 5.79 (ddd, 1H, J=17.3, 10.5,
7.0 Hz, CH=), 5.30 (d, 1H, J=17.1 Hz, =CH2), 5.22 (d, 1H, J=17.3 Hz, =
CH2), 5.12 (d, 1H, J=10.5 Hz, =CH2), 5.05 (d, 1H, J=10.3 Hz, =CH2),
4.80 (d, 1H, J=6.8 Hz, OCHHO), 4.71 (d, 1H, J=6.8 Hz, OCHHO),
ACHTREUNG(3R,4S)-4-(tert-Butyldimethylsilanyloxy)-pent-1-en-3-ol (10): Obtained
from 9 (1.75 g, 7.5 mmol) following the procedure given above for 3,
except using ether rather than CH2Cl2 for the DIBAL-H reduction. 10
Chem. Eur. J. 2008, 14, 6135 – 6141
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6139

B. Schmidt and A. Biernat
4.21 (dd, 1H, J=7.0, 3.5 Hz, CHOMEM), 3.99 (dd, 1H, J=13.3, 5.0 Hz,
OCHHCH=), 3.93 (dd, 1H, J=13.3, 5.0 Hz, OCHHCH=), 3.82 (ddd, 1H,
J=10.8, 5.0, 5.0 Hz, OCHHCH2)OCH3), 3.57 (ddd, 1H, J=10.8, 5.0,
5.0 Hz, OCHHCH2)OCH3), 3.48 (qd, 1H, J=6.3, 3.8 Hz, CHCH3), 3.39
(t, 2H, J=5.0 Hz, OCH2CH2)OCH3), 3.14 (s, 3H, OCH3), 1.20 ppm (3H,
d, J=6.3 Hz, CH3); 13C NMR (100 MHz, [D6]benzene): d=136.1 (1),
135.9 (1), 118.2 (2), 115.5 (2), 93.2 (2), 79.6 (1), 77.5 (1), 72.2 (2), 70.3 (2),
67.3 (2), 58.6 (3), 15.9 ppm (3); IR (film, KBr plates): n˜ =2880 (m), 1646
(w), 1454 (w), 1374 (w), 1105 cmꢀ1 (s); LRMS (70 eV, EI): m/z (%): 231
(10) [M++H], 186 (100); HRMS (ESI): m/z: calcd for C12H22O4:
231.1591, found 231.1603 [M++H]; elemental analysis calcd for
C12H22O4: C 62.6, H 9.6; found: C 62.1, H 10.1.
67.5 (2), 58.9 (3), 35.3 (2), 17.1 ppm (3); 13C NMR (75 MHz, CDCl3) for
minor isomer: d=134.1 (1), 118.0 (2), 95.8 (2), 83.7 (1), 71.7 (2), 68.9 (1),
67.6 (2), 59.0 (1), 35.6 (2), 17.1 ppm (3).
5-Allyloxy-4-(2-methoxyethoxymethoxy)-hex-1-ene (18): Obtained from
crude 17 (ca 1.0 g, ca 4.7 mmol) following the procedure given above for
13. Compound 18 (approximately 1.1 g, quantitative yield) was used with-
out further purification in the next step. NMR spectra were obtained
from crude reaction mixtures after aqueous workup, extraction, and re-
moval of all volatiles. 1H NMR (500 MHz, CDCl3): d = 6.15–5.78 (2H,
CH=), 5.30–5.00 (4H, =CH2), 4.86–4.70 (2H, OCH2O), 3.97–3.55 (6H),
3.45–3.33 (2H), 3.13 (s, 3H, OCH3), 2.58–2.43 (1H, CH2), 2.32–2.22 (1H,
CH2), 1.16 (d, 3H, J=6.3 Hz, CH3 (major isomer), 1.11 (d, 3H, J=
6.3 Hz, CH3 (minor isomer); 13C NMR (125 MHz, CDCl3) for major
isomer: d=136.0 (1), 135.8 (1), 116.7 (2), 115.5 (2), 95.3 (2), 78.9 (1), 76.8
(1), 72.2 (2), 69.9 (2), 67.5 (2), 58.7 (3), 36.2 (2), 15.2 ppm (3); 13C NMR
(125 MHz, CDCl3) for minor isomer: d=136.1 (1), 135.8 (1), 116.6 (2),
115.6 (2), 95.8 (2), 79.5 (1), 76.2 (1), 70.2 (2), 67.5 (2), 58.7 (3), 34.9 (2),
14.8 ppm (3).
ACHTREUNG(2S,3R)-3-(2-Methoxyethoxymethoxy)-2-methyl-3,4-dihydro-2H-pyran
(14): Obtained from 13 (200 mg, 1.2 mmol) following the procedure given
above for 5a. 13 was purified by column chromatography on silica. Yield:
170 mg (70%). [a]2D0 =ꢀ89.5 (c=1.20 in CH2Cl2); 1H NMR (400 MHz,
[D6]benzene): d=6.32 (d, 1H, J=6.0 Hz, H1), 4.65 (d, 1H, J=6.8 Hz,
OCHHO), 4.57 (d, 1H, J=6.8 Hz, OCHHO), 4.48 (ddd, 1H, J=6.0, 5.0,
2.5 Hz, H2), 3.87 (dq, 1H, J=7.8, 6.3 Hz, H6), 3.60–3.52 (3H, OMEM +
H4), 3.34–3.29 (2H, OMEM), 3.12 (s, 3H, OCH3), 2.25 (ddd, 1H, J=
16.6, 5.0, 5.0 Hz, H3), 1.98 (dddd, 1H, J=16.6, 8.0, 2.5, 2.5 Hz, H3’),
1.33 ppm (d, 3H, J=6.3 Hz, CH3); 13C NMR (100 MHz, [D6]benzene):
d=143.4 (1, C1), 97.6 (1, C2), 94.2 (2, OCH2O), 74.0 (1, C5), 74.0 (1,
C4), 72.1 (2, CH2OCH3), 67.4 (2, CH2CH2OCH3), 58.6 (OCH3), 27.2 (2,
C3), 17.9 (3, C6); IR (film, KBr plates): n˜ =3063 (s), 2936 (s), 1656 (s),
1241 (s), 1048 cmꢀ1 (s); LRMS (70 eV, EI): m/z (%): 127 (3) [M+
ꢀOCH2CH2OCH3], 96 (86), 81 (76), 59 (100); elemental analysis calcd
(%) for C10H18O4: C 59.4, H 9.0; found: C 59.4, H 9.3.
3-(2-Methoxyethoxymethoxy)-2-methyl-2,3,4,5-tetrahydrooxepine [(S,R)-
19] and 3-(2-methoxyethoxymethoxy)-2-methyl-2,3,4,5-tetrahydrooxepine
[(S,S)-19]: Obtained from 18 (0.91 g, 3.7 mmol) following the procedure
given above for 14. The two diastereoisomers were separated by column
chromatography on silica using hexane/MTBE mixtures of increasing po-
larity as eluent. The major isomer (S,R)-19 (0.33 g, 41%) was eluted first,
followed by a fraction containing the minor isomer (S,S)-19 (0.19 g,
23%). Analytically pure samples of both diastereoisomers were obtained
by subsequent Kugelrohr distillation (1208C at 0.02 mbar). (S,R)-19:
[a]2D0 =ꢀ105.8 (c=3.18 in CH2Cl2); 1H NMR (400 MHz, [D6]benzene):
d=6.39 (dd, 1H, J=6.5, 1.8 Hz, H1), 4.63 (d, 1H, J=6.8 Hz, -OCHHO-),
4.62 (m, 1H, H2), 4.52 (d, 1H, J=6.8 Hz, -OCHHO-), 4.12 (dq, 1H, J=
9.0, 6.3 Hz, H6), 3.68 (ddd, 1H, J=9.0, 3.5, 3.5 Hz, H5), 3.63–3.51 (2H,
OMEM), 3.36–3.27 (2H, OMEM), 3.12 (s, 3H, OCH3), 2.48 (ddddd, 1H,
J=17.1, 12.8, 2.3, 2.3, 2.3 Hz, H3), 2.10 (dddd, 1H, J=14.5, 12.8, 4.0,
2.0 Hz, H4), 1.84 (dd, 1H, J=14.5, 6.3 Hz, H4’), 1.70 (ddd, 1H, J=17.1,
6.5, 6.3 Hz, H3), 1.38 (d, 3H, J=6.3 Hz, H7); 13C NMR (100 MHz,
[D6]benzene): d=148.6 (1, C1), 109.3 (1, C2), 94.4 (2, OCH2O), 81.2 (1,
C5), 80.8 (1, C6), 72.1 (2, CH2OCH3), 67.6 (2, CH2CH2OCH3), 58.1
(OCH3), 30.8 (2, C4), 20.9 (2, C3), 19.8 (3, C7); IR (film, KBr plates): n˜ =
3042 (s), 2929 (s), 1649 (s), 1264 (s), 1102 (s), 1039 cmꢀ1 (s); LRMS
(70 eV, EI): m/z (%): 216 (1) [M+], 140 (17), 89 (26), 59 (100); elemental
analysis calcd for C13H24O4: C 61.1, H 9.3; found: C 61.4, H 9.4.
Product (S,S)-19: [a]D20 =ꢀ44.0 (c=1.70 in CH2Cl2); 1H NMR (400 MHz,
[D6]benzene): d=6.36 (dd, 1H, J=6.8 Hz, H1), 4.69 (d, 1H, J=7.0 Hz,
OCHHO), 4.57 (m, 1H, H2), 4.56 (d, 1H, J=7.0 Hz, OCHHO), 4.06 (qd,
1H, J=6.5, 2.5 Hz, H6), 3.64–3.55 (2H, OMEM), 3.52 (ddd, 1H, J=8.0,
5.3, 2.5 Hz, H5), 3.33 (“t”, 2H, J=4.8 Hz, OMEM), 3.12 (s, 3H, OCH3),
2.04 (dddd, 1H, J=15.3, 7.8, 7.8, 7.0 Hz, H4), 1.91–1.82 (3H, H4’, H3’,
H3), 1.30 (d, 3H, J=6.3 Hz, H7); 13C NMR (100 MHz, [D6]benzene): d=
148.5 (1, C1), 108.0 (1, C2), 94.7 (2, OCH2O), 80.2 (1, C5), 79.4 (1, C6),
72.2 (2, CH2OCH3), 67.4 (2, CH2CH2OCH3), 58.6 (OCH3), 31.6 (2, C4),
21.8 (2, C3), 17.5 (3, C7); IR (film, KBr plates): n˜ =3040 (s), 2933 (s),
1648 (s), 1269 (s), 1044 cmꢀ1 (s); LRMS (70 eV, EI): m/z (%): 216 (1)
[M+], 140 (15), 89 (25), 59 (100); elemental analysis calcd (%) for
C13H24O4: C 61.1, H 9.3; found: C 61.2, H 9.5.
2-(tert-Butyldimethylsilanyloxy)-hex-5-en-3-ol (15): Obtained from
9
(2.10 g, 9.0 mmol) and allyl magnesium bromide (0.8m solution in ether,
23.0 mL, 18.0 mmol) following the procedure given above for 10. Com-
pound 15 was purified by column chromatography on silica. Yield: 1.55 g
(75%) of an inseparable 2:1 mixture of diastereoisomers. 1H NMR
(400 MHz, CDCl3): d=5.90–5.75 (1H, CH=), 5.16–5.05 (2H, =CH2), 3.76
(1H, m, CHO (major isomer)), 3.68 (1H, m, CHO (minor isomer)), 3.54
(m, 1H, CHO (major isomer)), 3.36 (m, 1H, CHO (minor isomer)),
2.30–2.10 (2H, CH2), 1.14 (d, 3H, J=6.2 Hz, CH3 (minor isomer)), 1.09
(d, 3H, J=6.2 Hz, CH3 (major isomer)), 0.89 (s, 9H, tBu (minor
isomer)), 0.87 (s, 9H, tBu (major isomer)), 0.09–0.02 ppm (s, 6H, SiMe2);
13C NMR (100 MHz, CDCl3) for major isomer: d=135.1, 117.3, 74.5,
70.9, 36.7, 25.8, 18.0, 17.3, ꢀ4.4, ꢀ4.9 ppm; 13C NMR (100 MHz, CDCl3)
for minor isomer: d=135.2, 116.9, 75.2, 70.9, 38.1, 25.8, 20.1, 18.0, ꢀ4.4,
ꢀ4.9 ppm.
tert-Butyl-[2-(2-methoxyethoxymethoxy)-1-methyl-pent-4-enyloxy]-dime-
thylsilane (16): Obtained from 15 (1.18 g, 5.1 mmol) following the proce-
dure given above for 11. Compound 16 was purified by flash chromatog-
raphy on silica. Yield: 1.54 g (95%) of an inseparable 2:1 mixture of dia-
stereomers. 1H NMR (500 MHz, CDCl3): d=5.88–5.78 (m, 1H, CH=),
5.10–4.98 (2H, =CH2), 4.82–4.68 (2H, OCH2O), 3.90–3.60 (3H), 3.55–
3.44 (3H), 3.35 (s, 3H, OCH3), 2.45–2.08 (2H, CH2), 1.10 (d, 3H, J=
6.2 Hz, CH3 (major isomer), 1.07 (d, 3H, J=6.2 Hz, CH3 (minor isomer),
0.85 (9H, s, tBu), 0.02 ppm (s, 6H, SiMe2); 13C NMR (125 MHz, CDCl3)
for major isomer d=136.8 (1), 118.2 (2), 96.7 (2), 82.6 (1), 73.2 (2), 71.4
(1), 68.5 (1), 60.5 (1), 37.1 (2), 27.3 (3), 20.3 (3), ꢀ3.0 (3), ꢀ3.3 ppm (3);
13C NMR (125 MHz, CDCl3) for minor isomer: d=137.4 (1), 118.0 (2),
97.3 (2), 83.0 (1), 73.2 (2), 70.9 (1), 68.4 (1), 60.5 (1), 35.6 (2), 27.3 (3),
19.7 (3), ꢀ3.0 (3), ꢀ3.3 ppm (3).
AHCTRE(UGN 2S,3S,6S)-6-[(1S,2S)-Allyloxyethyl)-but-3-enyloxy]-3-benzyloxy-2-meth-
yltetrahydropyran (20): To a solution of 5b (100 mg, 0.52 mmol) and 6
(162 mg, 1.04 mmol) in dry benzene (20 mL) with MS 4 Š was added p-
TSA (8 mg, 8 mol%). After stirring for 12 h the solvent was evaporated
and the residue was dissolved in ethyl acetate. The organic layer was
washed with an aqueous solution of sodium bicarbonate and brine, suc-
cessively, dried with MgSO4, filtered and evaporated. The residue was pu-
rified by flash chromatography on silica using cyclohexane/ethyl acetate
3-(2-Methoxyethoxymethoxy)-hex-5-en-2-ol (17): Obtained from 16
(1.50 g, 4.7 mmol) following the procedure given above for 12. After
workup, crude 17 (approximately 1.0 g, corresponding to a quantitative
yield) was directly used in the next step without further purification. For
analytical data the product was purified by flash chromatography on
silica, yielding an inseparable 2:1 mixture of diastereomers.1H NMR
(300 MHz, CDCl3): d=5.92–5.71 (1H, CH=), 5.19–5.00 (2H, =CH2), 4.81
(d, 1H, J=7.8 Hz, OCH2O), 4.76 (d, 1H, J=7.8 Hz, OCH2O), 3.85–3.50
(6H), 3.37 (s, 3H, OCH3), 2.45–2.08 (m, 3H), 1.15 (d, J=6.4 Hz, 3H,
CH3), 1.13 ppm (d, J=6.5 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) for
major isomer: d=134.9 (1), 117.0 (2), 95.9 (2), 83.7 (1), 71.6 (2), 68.6 (1),
1
1:1 to give 20 (110 mg, 60%). [a]2D3 =ꢀ23.5 (c=0.62 in CH2Cl2); H NMR
(300 MHz, CDCl3): d=7.41–7.27 (5H, Ph), 5.96–5.80 (2H, CH=), 5.25
(dddd, 1H, J=17.2, 1.7, 1.7, 1.7 Hz, =CH2), 5.19–4.95 (4H, =CH2,
OCHO), 4.68 (d, 1H, J=12.3 Hz, CH2Ph), 4.43 (d, 1H, J=12.3 Hz,
CH2Ph), 4.12–3.91 (3H, OCH2CH=), 3.72 (m, 1H, OCHCH3), 3.51 (m,
1H, m, OCHCH3), 3.27 (m, 1H, CHO), 2.41 (dm, 1H, J=14.4 Hz,
6140
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6135 – 6141

Ring-Closing Metathesis
FULL PAPER
CHHCH=), 2.20 (ddd, 1H, J=14.4, 7.7, 7.7 Hz, CHHCH=), 2.00 (ddd,
1H, J=13.0, 5.3, 3.6 Hz, CH2CH2), 1.95–1.85 (2H, CH2CH2), 1.51 (dm,
J=13.0 Hz, CH2CH2), 1.15 (d, 3H, J=6.6 Hz, CH3), 1.11 ppm (d, 3H, J=
6.4 Hz, CH3); 13C NMR (75 MHz, CDCl3): d=138.8 (0), 135.8 (1), 135.4
(1), 128.2 (1), 127.8 (1), 127.5 (1), 116.5 (2), 116.3(2), 96.9 (1), 78.1 (1),
75.4 (1), 73.6 (1), 70.8 (2), 70.4 (2), 66.6 (1), 35.2 (2), 24.3 (2), 21.4(2),
17.2 (3), 15.1 ppm (3); IR (film, KBr plates): n˜ =2932 (m), 2348 (m),
1641 (m), 1496 (m), 1435 (m), 1360 cmꢀ1 (m); elemental analysis calcd
(%) for C22H32O4: C 73.3, H 8.9; found: C 72.8, H 8.5.
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ACHTREUNG(2S,3S)-3-((2S,5S,6S)-5-Benzyloxy-6-methyltetrahydropyran-2-yloxy)-2-
methyl-2,3,4,5-tetrahydrooxepine (21): Obtained from 20 (100 mg,
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by column chromatography on silica. Yield: 70 mg (75%). [a]2D3 =ꢀ81.1
(c=1.07 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=7.40–7.26 (5H, Ph),
6.29 (dd, 1H, J=6.3, 1.5 Hz, H1), 4.85 (brs, 1H, OCHO), 4.70 (m, 1H,
H2), 4.69 (d, 1H, J=12.3 Hz, CH2Ph), 4.44 (d, 1H, J=12.3 Hz, CH2Ph),
4.23 (qd, 1H, J=6.6, 2.4 Hz, H6), 4.03 (qd, 1H, J=6.6, 1.3 Hz, CHCH3,
rhodinose), 3.76 (m, 1H, H5), 3.28 (brs, 1H, CHOCH2Ph), 2.24–1.76
(8H, H3, H4, CH2CH2 (rhodinose)), 1.25 (d, 3H, J=6.6 Hz, H7),
1.17 ppm (d, 3H, J=6.6 Hz, CH3 (rhodinose)); 13C NMR (75 MHz,
CDCl3): d=148.2 (1), 138.7 (0), 128.2 (1), 127.8 (1), 127.7 (1), 127.5 (1),
108.3 (1), 99.5 (1), 80.9 (1), 80.4 (1), 73.6 (1), 70.8 (2), 66.8 (1), 33.1 (2),
23.9 (2), 21.9(2), 21.4 (2), 17.3 (3), 17.3 ppm (3); IR (film, KBr plates):
n˜ =3035 (w), 2931 (m), 1647 (m), 1496 (m), 1446 cmꢀ1 (m); elemental
analysis calcd (%) for C20H28O4: C 72.3, H 8.5; found: C 72.2, H 8.0.
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Received: March 27, 2008
Published online: May 28, 2008
Chem. Eur. J. 2008, 14, 6135 – 6141
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6141