Synthesis of dihydrofurans and dihydropyrans with unsaturated side chains based on ring size-selective ring-closing metathesis

Article abstract of DOI:10.1002/adsc.200600473

Enantiomerically pure 1,5-hexadiene-3,4-diol, derived from D-mannitol in a few steps, may serve as a starting material for enantiopure dihydropyrans and dihydrofurans bearing an unsaturated side chain which is amenable for further synthetic transformations. The synthesis relies on a ring size- selective ring-closing metathesis reaction of a triene. Most likely, a catalyst-directing effect of an allylic hydroxy group is responsible for the selectivity.

Full text of DOI:10.1002/adsc.200600473

FULL PAPERS
DOI: 10.1002/adsc.200600473
Synthesis of Dihydrofurans and Dihydropyrans with Unsaturated
Side Chains Based on Ring Size-Selective Ring-Closing Metathe-
sis
Bernd Schmidta,* and Stefan Navea
a
Universität Potsdam, Institut für Chemie, Organische Chemie II, Karl-Liebknecht-Straße 24-25, 14476 Golm, Germany
Fax : (+49)-331-977-5059; e-mail: bernd.schmidt@uni-potsdam.de
Received: September 15, 2006
th
´
Dedicated to Prof. Philip J. Kocienski on the occasion of his 60 birthday.
Abstract: Enantiomerically pure 1,5-hexadiene-3,4- selective ring-closing metathesis reaction of a triene.
diol, derived from d-mannitol in a few steps, may Most likely, a catalyst-directing effect of an allylic
serve as a starting material for enantiopure dihydro- hydroxy group is responsible for the selectivity.
pyrans and dihydrofurans bearing an unsaturated
side chain which is amenable for further synthetic Keywords: dihydrofurans; dihydropyrans; metathe-
transformations. The synthesis relies on a ring size- sis; oxacycles; ruthenium
Introduction
Particularly important structural elements present in
these compounds are tetrahydrofurans I bearing a
Five- and six-membered oxacycles are ubiquitious side chain with an a-hydroxy group in the 2-position,
structural motifs in a large number of natural and and tetrahydropyrans II with a 2,3-arrangement of an
non-natural biologically active compounds, or serve as alkyl side chain and a hydroxy group. Some examples
key intermediates in their synthesis.[1–5] The Annona- also include an adjacent bis-THF moiety III. Figure 1
ceous acetogenins, for instance, are prominent exam- illustrates this point for the structures of the Annona-
ples. They have attracted considerable interest over ceous acetogenins goniotetracin, pyragonicin and bul-
the past few decades due to their promising biological lacin.[7]
activities, such as antitumor or pesticidal activity.[6,7]
Figure 1. Structures of Annonaceous acetogenins with representative structural motifs.
Adv. Synth. Catal. 2007, 349, 215 – 230
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Bernd Schmidt and Stefan Nave
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reactions of trienes 2,[36] two reports by Crimmins
et al. were published where the regioselective ring
closure of structurally closely related trienes is de-
scribed and efficiently used in the total syntheses of
the Annonaceous acetogenin (ꢀ)-mucocin[37] and the
microbial metabolite (+)-SCH 351448.[38] In this
paper, we provide a full account of our studies dedi-
cated to the selective construction of structural pat-
terns I, II and III via regioselective RCM of tri- and
tetraenes 2.
Results and Discussion
Scheme 1. Common precursor for skeletons I–III.
Synthesis of Metathesis Precursors
It is an interesting feature of the structural motifs The common starting material for all metathesis pre-
I–III that they display a common skeleton of carbon cursors of general structure 2 was R,R-1,5-hexadiene-
and oxygen atoms, which is highlighted in Scheme 1. 3,4-diol (1), which was synthesized from d-mannitol
In continuing previous works in our group dedicated in three steps, following a slightly modified literature
to the exploitation of the olefin metathesis reac- procedure.[20,21] To this end, d-mannitol was first treat-
tion[8–13] for the synthesis of functionalized oxacy- ed with acetyl bromide, followed by acetylation of the
cles,[14–19] we wondered if the common arrangement of remaining hydroxy groups to give 3.[20] Compound 3
carbon and oxygen atoms in I, II and III could be ac- undergoes elimination of bromide and acetate under
cessed by a common precursor, hexadienediol 1, after reducing conditions, as previously described by Burke
its transformation to tri- or tetraenes 2 (Scheme 1). et al.,[21] to give the diacetate 4. Deacetylation of 4
This would be particularly attractive from the synthet- was conducted as a separate step and achieved by
ic point of view, as 1 is easily available in multi-gram methanolysis in the presence of a catalytic amount
quantities from d-mannitol,[20,21] while its enantiomer of aqueous K2CO3, rather than NaOMe. Thus, 1
ent-1 can be synthesized from R,R-dimethyl tar- becomes available from d-mannitol in three steps
trate.[22]
in multi-gram quantities in 35% overall yield
Both 1 and ent-1 have previously been used as (Scheme 2).
building blocks for the synthesis of metathesis precur-
Starting from dienediol 1, a set of metathesis pre-
sors: for instance, Quinn et al. reported the total syn- cursors of the general structure 2 with various steric
thesis of the five-membered ring lactones muricata- and electronic properties was prepared by various
cin[23] and rollicosin[24] from 1, while Michaelis and methods. In most cases, a selective functionalization
Blechert recently published a synthesis of the six- of one OH group is required prior to modification of
membered ring lactone phomopsolide C from ent-1.[22] the second one. Table 1 and Scheme 3 provide an
Burke et al. exploited the C2-symmetry of dienediol 1 overview of the metathesis precursors employed in
in the total synthesis of several natural products, such this study and the methods used for their preparation.
as brevicomin,[25] sialic acids,[26] and densely function-
alized spiroacetals.[27] Finally, Donohoe et al. used a
mixture of racemic 1 and its meso-diastereomer, after
acetalization with methoxyallene and double RCM of
the resulting tetraene, as a precursor for bisfuran.[28]
Obviously, like for many other tri-, tetra- or polyenes,
the use of metathesis precursors derived from 1 in
RCM reactions is associated with either stereo- or re-
gioselectivity issues. This aspect of olefin metathesis
has recently been reviewed by us.[29] Particularly rele-
vant for the subject of this study are reports where
different modes of cyclization result in different ring
sizes,[30] such as the RCM-based synthesis of fused vs.
“dumbbell”-type bicyclic lactams,[31,32] the strong pref-
erence for “dumbbell”-type oxacycles in the RCM of
Scheme 2. Reagents and conditions: i) acetyl bromide, diox-
ane; then Ac2O, pyridine (50%); ii) Zn, glacial acetic acid
tetra-[33,34] or hexaenes.[35] Parallel to our preliminary
account on the control of ring size-selectivity in RCM (85%); iii) MeOH, K2CO3 (aqueous) (86%).
216
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Synthesis of Dihydrofurans and Dihydropyrans with Unsaturated Side Chains
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Table 1. Yields of protected metathesis substrates 6a–j (right
half of table), their corresponding starting materials 1 and
5a–f (left half of table), and the general method of synthesis
(see Scheme 3).
Scheme 3. General reagents and conditions: Method A:
NaH, R’X, THF, 658C; Method B: R’X, imidazole or pyri-
dine, DCM, 258C; Method C: allyl ethyl carbonate,
Pd(PPh3)4, THF, 658C; Method D: “Bu2SnO”, benzene,
A
R’X.
method for the synthesis of 6b,c from 5a,b. Selective
mono-functionalization of 1 cannot be achieved by
Williamson ether synthesis, as double etherification
will inevitably occur under these conditions. There-
fore, method D was used which proceeds via the in-
termediate formation of a stannylene diacetal of 1,
which is subsequently cleaved with an appropriate al-
kylating agent. This method, which had originally
been developed for selective manipulation of OH
groups in carbohydrates,[40] has previously been used
for the preparation of 5c.[23] Scheme 3 summarizes the
four synthetic methods used to convert 1 into the
metathesis precursors 5 and 6 in one or two steps, re-
spectively.
Regioselective Double RCM: Fused vs. Dumbbell-
Type Bicyclic Structures
A considerable number of ruthenium-based metathe-
sis precatalysts has been described in the litera-
ture.[9,10] Figure 2 shows the structures of the first-gen-
eration ruthenium precatalysts A[41] and B[42] and the
second-generation precatalysts C,[43] D and E[44] which
have been used in the course of this study.
Method A is a routine Williamson ether synthesis.
Ring-closing metathesis of tetraene 6a may result in
This can only be used for the double allylation of tet- the formation of four products: apart from the fused
raene 6a and alkylation of alcohols 5c,d where the (9) and dumbbell-type bicyclic product (10) mono-
first OH group has already been converted to a cyclized dihydropyran 7a and dihydrofuran 8a have to
stable, non-migrating group. Method B is the selective be expected (Scheme 4 and Table 2). At the begin-
introduction of one bulky protecting group under ning, RCM of 6a in the presence of 5 mol% A or C–
moderately basic conditions. Functionalization of the E, respectively, was investigated at ambient tempera-
second OH group is unfavorable due to steric hin- ture under otherwise identical conditions.
drance. Compounds 5a[24] and 5b[22] have previously
Surprisingly, a small amount of monocyclized prod-
been obtained via this method. Method C is a Pd-cat- ucts 7a and 8a could be detected with phosphine-free
alyzed O-allylation[39] which has proven useful in catalysts D and E (entries 3 and 4) while A and C
cases where a protecting group migration or rather (normally considered to be less active) lead to the ex-
low reactivity has to be expected. We used this clusive formation of bicyclic products 9 and 10. With
Adv. Synth. Catal. 2007, 349, 215 – 230
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217

Bernd Schmidt and Stefan Nave
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first generation catalyst A the reaction is highly selec-
tive, giving exclusively the bis-dihydrofuran 10
(1H NMR, entry 1), whereas C results in the forma-
tion of fused (9) and dumbbell-type product (10) in a
ratio of 1.0:1.7 (entry 2). Both bicyclic products could
be isolated and were characterized by one- and two-
dimensional NMR spectroscopy. The structural as-
signment is based on the value for the vicinal coupling
3
ꢀ
ꢀ
constant J
A
6.3 Hz for 10, with both values being typical for dihy-
dropyrans and dihydrofurans, respectively.[19] Another
distinctive feature is the chemical shift value of the
ether carbon atoms (9: 67.8 and 65.4 ppm; 10: 88.0
and 75.8 ppm). These values are also in the normal
range for dihydropyrans or dihydrofurans, respective-
ly.[19] Apart from the incomplete conversion observed
for catalysts D and E, the ratio of bicyclic products 9
and 10 is comparable to that observed for C (Table 2,
entries 1–4). Given the high selectivity obtained with
the least reactive catalyst A, one might speculate that
kinetic control is the origin of the perfect ring size-se-
lectivity. Consequently, the ring-closing metathesis of
6a was repeated in refluxing toluene. Under these
conditions all catalysts give full conversion to bicyclic
products 9 and 10 and the amount of six-membered
product 9 increases slightly (Table 2, entries 5–8). If
there is indeed a thermodynamic preference for the
fused six-membered ring product 9, it should be possi-
ble to promote its formation by conducting the reac-
tion under an atmosphere of ethylene. This might fa-
cilitate a ring-opening metathesis of the kinetic prod-
uct and eventually result in a larger quantity of 9. To
check this possibility, all four experiments were re-
peated in toluene at 1108C under an atmosphere of
Figure 2. Ruthenium precatalysts used in this study.
Scheme 4. General reagents and conditions: i) catalyst (5
mol%), (for details with respect to solvent, temperature and
pressure see Table 2).
Table 2. Ring size-selective double RCM of 6a. Conditions and product ratios.
Entry
Solvent
T [8C]
Catalyst (5 mol%)
P [bar]
Conversion [%]
Product Ratio
[9:10:
(7a+8a)][a]
AHCTREUNG
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
20
20
20
20
A
C
D
E
A
C
D
E
A
C
D
E
A
C
D
E
1 (Ar)
1 (Ar)
1 (Ar)
1 (Ar)
1 (Ar)
1 (Ar)
1 (Ar)
1 (Ar)
12 (C2H4)
12 (C2H4)
12 (C2H4)
12 (C2H4)
12 (C2H4), 30 (Ar)
12 (C2H4) 30 (Ar)
12 (C2H4), 30 (Ar)
12 (C2H4), 30 (Ar)
99
99
90
90
99
99
99
99
99
80
85
85
95
99
90
90
only 10[b]
1.0:1.7:0
1.0:1.9:0.6
1.0:1.8:0.4
1.0:11.0:0
1.0:1.4:0
110
110
110
110
110
110
110
110
110
110
110
110
1.0:1.6:0
1.0:1.4:0
9
1.0:8.0:0.2
1.0:1.5:0.4
1.0:0.8:0.2
1.0:1.5:0.3
1.0:5.0:0.3
1.0:1.4:0
10
11
12
13
14
15
16
1.0:1.4:0.2
1.0 : 1.6 : 0.2
[a]
1
Conversion and product ratios were determined by H NMR spectroscopy of the crude reaction mixture.
Isolated yield: 49%.
[b]
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Synthesis of Dihydrofurans and Dihydropyrans with Unsaturated Side Chains
FULL PAPERS
12 bars of ethylene. Not surprisingly, small amounts
of monocyclic products are now observed for all cata-
lysts (Table 2, entries 9–12). Remarkably, we observed
for the first time that the six-membered ring product
9 is formed in a larger quantity than the five-mem-
bered product 10 (Table 2, entry 11) if precatalyst D
is used. Finally, it was investigated whether the prob-
lem of incomplete conversion observed under an at-
mosphere of ethylene could be circumvented by dilut-
ing the ethylene atmosphere with an inert gas, thereby
reducing the number of unproductive metathesis
cycles. Although the overall conversion is slightly
better if the experiments are run under 12 bars of eth-
ylene and 30 bars of argon (Table 2, entries 13–16),
no improvement of the selectivity was observed com-
pared to the previous sets of experiments. Our obser-
vations differ somewhat from those recently published
Scheme 5. Proposed influence of different OR groups on
ring size-selectivity.
by Honda et al. who investigated the double RCM of
a tetraene structurally related to 6a. These authors re-
ported a remarkably strong tendency towards the for-
mation of fused six-membered ring products structur- sufficiently bulky – in a faster formation of dihydro-
ally related to 7a and 9, while a dumbbell-type prod- furan 8 compared to the dihydropyran 7. Alternative-
uct analogous to 10 could not be accessed selectively. ly, a coordinating OR group could serve as a catalyst-
However, only catalysts bearing N-heterocyclic car- directing group, which might result in a preferred ini-
bene ligands were investigated in this study.[32]
tiation at the closest C/C double bond “b” in sub-
The results discussed above are related to previous strates 2. The resulting carbene complex 13 should
reports describing a significant erosion in selectivity then cyclize to dihydropyrans 7 (Scheme 5). Exploit-
of double ring-closing metathesis reactions whenever ing catalyst-directing effects for regio- or stereoselec-
ruthenium carbenes with an NHC ligand are used as tive synthesis is a well-known principle in homogene-
catalysts. This is not limited to ring size-selectivi- ous catalysis, which has been reviewed.[49] For olefin
ty,[31,45] as in our example, but has also been observed metathesis reactions such effects are less common, al-
in diastereoselective double RCM reactions.[46–48] though they have been proposed, e.g., for MOM pro-
However, the level of selectivity towards the forma- tecting groups.[22] Another variable site of the sub-
tion of bis-dihydrofuran 10 with the first-generation strate structure is the terminus of the “a” double
catalyst A is quite remarkable.
bond. Introducing a substituent Rꢁ here will disfavor
initiation at this particular site and hopefully support
a catalyst-directed initiation at “b”. An example for
the efficient discrimination of one double bond in the
initiating step by terminal substitution has been de-
scribed by Honda et al. for a diene-yne metathesis.[50]
Apart from these substrate-specific parameters,
Regioselective Single RCM: 2,3-Disubstituted
Dihydropyrans 7 vs. 2-Substituted Dihydrofurans 8
If R in structure 2 is not an allyl group, as required
for double RCM, different ring size-selectivities have those that have been investigated for the double
to be expected if the steric or electronic properties of RCM need to be considered here as well: the nature
R are changed. In particular, R might be a bulky pro- of the catalyst, the temperature and the pressure
tecting group leading to sterically congested inter- might have an influence on the ratio of dihydropyrans
mediates or transition states during the RCM step. 7 to dihydrofurans 8.
For instance, a high degree of ring size-selectivity
We started this investigation by conducting ring
might be expected if one of the two possible ruthena- closing metathesis reactions of trienes 6b–h and 5d
cyclobutanes 11 (leading to dihydropyrans 7) or 12 (Table 1) in the presence of 5 mol% of a first- or
(leading to dihydrofurans 8) is much more destabi- second-generation ruthenium catalyst. The results are
lized by steric interactions than the other. Thus, it summarized in Table 3. With sterically demanding
might be speculated that for 11 steric interactions be- TBS- or trityl protecting groups, only dihydrofurans
tween the OR group, the vinyl group in 2-position 8b and c, respectively, are formed if the less active
and the ruthenacyclobutane moiety are stronger than precatalyst A is used (entries 1 and 3). Similar to the
for 12, where the OR group can adopt an orientation pattern observed for the double RCM of tetraene 6a,
away from the ruthenacyclobutane ring, thereby mini- a significant erosion of selectivity occurs with the
mizing steric interactions. This should result – if R is NHC-ligated precatalyst C, although it should be
Adv. Synth. Catal. 2007, 349, 215 – 230
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Bernd Schmidt and Stefan Nave
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Table 3. Results obtained for the ring size-selective RCM of trienes 6b–h and 5d (R’=H in all cases).
Entry
Triene
R
Catalyst (5 mol%).
Conversion [%][a]
7:8
Product (yield)[b]
1
2
3
4
5
6
7
8
6b
6b
6c
6c
6d
6d
6d
6d
6d
6e
6e
6f
TBS
TBS
CPh3
CPh3
Bn
Bn
Bn
Bn
Bn
A
C
A
C
A
C
C
A
C
A
C
A
C
A
C
D
A
C
A
A
C
D
A
C
A
C
99
99
90
99
99
99
<1:20
1:2
<1:20
1:3
1:12
1:1
n.d.
1:7
1:1
1:3
1:1
<1:20
1:1
1:10
1:1
1:1
1:11
1:1.3
1:10
1:12
1:1
8b (90%)
7b+8b
8c (68%)
7c+8c
8d (88%)
7d+8d
–
<5[c]
55[d]
99[d]
99
8d
9
7d+8d
7e+8e
7e+8e
8f (89%)
7f+8f
8g (88%)
7g+8g
7g+8g
8g
7g+8g
8g
8g
7g+8g
7g+8g
8h (99%)
7h + 8h
7i+8i
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Me
Me
99[e]
99
CH2OBn
CH2OBn
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
COCCl3
COCCl3
H
6f
99
99
99
6g
6g
6g
6g
6g
6g
6g
6g
6g
6h
6h
5d
5d
99[f]
99 g]
99 g]
99 h]
99[i]
99[i]
99[i]
99
1:1
<1:20
1 : 3
1:1
70
90
H
99[e]
–
[a]
All reactions were conducted in DCM at ambient temperature (208C) with 5 mol% of the appropriate Ru precatalyst.
Conversion and product ratios were determined by H NMR-spectroscopy of the crude reaction mixture.
Yields are given in parentheses for isolated, single isomers.
In CH2Cl2 at 08C.
[b]
[c]
[d]
[e]
[f]
In toluene at 1108C
Complex mixture, refer to discussion.
In CH2Cl2 at ꢀ308C.
[g]
[h]
[i]
In CH2Cl2 at 808C in pressurized vessel.
Addition of CuCl (5 mol%).
Atmosphere of ethene (1 bar).
noted that the five-membered ring systems are still identical conditions for the same substrate 6d. The
preferred (entries 2 and 4). It is in line with the pro- ratio of 7d to 8d is the same as observed at ambient
posal discussed above (Scheme 5) that for a sterically temperature, however, new signals appear in the
less hindered benzyl ether (6d) selectivity drops to 1H NMR spectrum which might be assigned to a
1:12 for precatalyst A (entry 5) and to 1:1 for C cyclic enol ether arising from double bond migra-
(entry 6). With this substrate we planned to investi- tion.[52,53] Interestingly, no isomerization products
gate if variation of the temperature exerts a signifi- were observed for first-generation catalyst A under
cant influence. It turned out that at 08C the second- otherwise identical conditions, which is in accord with
generation catalyst C was virtually inactive, with the previously published observations from our group
rate of conversion being less than 5% (entry 7). In- that first-generation catalyst A requires additives to
creasing the temperature to 1108C (refluxing toluene) be transformed into an active isomerization cata-
did not change the observed pattern significantly: lyst.[15] It is most likely that C decomposes bimolecu-
with precatalyst A (entry 8), the dihydrofuran 8d is larly under the reaction conditions to a ruthenium hy-
still the major product, although formed with lower dride species,[54] which has previously been postulated
selectivity. However, under these conditions only in- as the actual isomerization catalyst.[55,56] The necessity
complete conversion is observed, which might be ex- for a certain degree of steric hindrance in the OH
plained by a comparatively rapid decomposition of protecting group in order to obtain preparatively
the catalyst.[51] Incomplete conversion is not a prob- useful selectivities towards dihydrofurans
lem if second-generation catalyst C is used under strongly underlined when RCM of methyl ether 6e
8 was
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Synthesis of Dihydrofurans and Dihydropyrans with Unsaturated Side Chains
FULL PAPERS
was investigated. In this case, selectivity drops even exerts primarily a steric rather than an electronic in-
with the first-generation catalyst to 1:3 (entry 10). fluence.
With second generation catalyst C, the selectivity is
With the results described so far in mind, it was
again 1:1. In this case at least one additional product quite unexpected that the unprotected parent diene
is formed, which might be a product resulting from 5d did not cyclize with a more or less pronounced se-
self-metathesis of 7e or 8e, or a cross-metathesis of 7e lectivity to a dihydrofuran 7i, but gave 7i and its iso-
and 8e. This assumption is supported by the observa- meric dihydropyran 8i in a 1:1 ratio. Compounds 7i
tion that the new product(s) do not contain any termi- and 8i were also formed with second-generation cata-
nal alkene groups, which is easily seen from the lyst C, but along with other products. Due to the very
13C NMR spectrum (entry 11).
complex NMR spectra of the reaction mixtures it was
Apart from steric effects, coordinative or electronic difficult to analyze its composition. In order to make
effects might have an influence on ring size-selectivity, at least a qualitative structural assignment of the new
as outlined above. Alkoxymethyl ethers have previ- products, the mixture was fractionated by column
ously been proposed as catalyst-directing groups[22] in chromatography. A first fraction contained 7i and 8i
olefin metathesis and we wanted to examine the influ- in a 3:1 ratio. A second fraction contained a single
ence of such a potentially coordinating protecting product 14, which has NMR spectral data similar to
group by investigating the outcome of an RCM reac- those assigned to dihydropyran 8i, with the striking
tion of BOM-protected 6f. The result was very similar difference that 14 contains no terminal =CH2 group.
to those observed for trienes 6b–d and we can, from In the 13C NMR spectrum six signals, and in the
these experiments, discover no piece of evidence for a 1H NMR spectrum eight signals are observed, which
catalyst-directing effect of BOM ethers (entries 12 suggests that 14 is the C2-symmetrical self-metathesis
and 13). Protection of the OH group as a carbonate product of dihydropyran 7i (Scheme 6). Unfortunate-
also results in a metathesis precursor 6g with a func- ly, it was not possible to obtain mass spectrometric
tional group that might also have catalyst-directing ef- evidence that would unambigously prove this structur-
fects. Selectivities observed under standard conditions al assignment. A third fraction of the mixture con-
(DCM, 208C) were very similar to those previously tains additional products which are most likely dimers
observed for the other derivatives (entries 14 and 15). of 8i and cross-metathesis products of 7i and 8i.
Temperature effects were re-examined for this sub-
At this point it was possible to access carbon skele-
strate in both directions: as was found for the at- tons I and III (Scheme 1) selectively, while all at-
tempted RCM of 6d, no conversion was observed tempts to obtain a precursor for dihydropyran skele-
with second-generation precatalyst C at 08C (entry 7). ton II selectively by extensive variation of catalysts
We were therefore surprised to see that, with Grelaꢁs and reaction conditions failed. Although the RCM ex-
catalyst D, 6g is completely converted to its metathe- periments with 5d turned out to be particularly unse-
sis products even at ꢀ308C. This observation is indica- lective in both directions, as described above, the sur-
tive for the extraordinarily high activity of nitro-sub- prisingly high amount of six-membered ring products
stituted catalysts. Somewhat disappointingly, no influ- was quite striking. This observation can be under-
ence on the ring size-selectivity was observed, com- stood by assuming a catalyst-directing effect of the
pared to the reaction at ambient temperature free OH group, which would cause preferred initia-
(entry 16). Conducting the reaction at 808C in a pres- tion of the catalyst at double bond “b” (Scheme 5).
surized vessel (entries 17 and 18) also results in nearly That ruthenium atoms in metathesis catalysts display
the same product ratios for both first- and second- a certain oxophilicity, especially to alcohols, is under-
generation catalysts. In the following set of experi- lined by a number of literature reports, describing,
ments (entries 19–22) it was checked whether activa-
tion of the metathesis catalyst with copper chloride or
addition of an ethylene atmosphere leads to any devi-
ation from the results obtained under standard condi-
tions, but no significant changes could be observed. In
an attempt to modify the electronic nature of one C/
C double bond of the metathesis substrate, a strongly
electron-withdrawing trichloroacetyl group was at-
tached to the hydroxy group and the resulting triene
6h was subjected to metathesis conditions. The results
obtained for first (entry 23) and second (entry 24)
generation catalysts resemble those obtained for the
sterically demanding protecting groups TBS and trityl
(entries 1–4), suggesting that a trichloroacetyl group
Scheme 6. General reagents and conditions: i) catalyst A (5
mol%), CH2Cl2, 208C (7i:8i=1:1); ii) catalyst C (5 mol%),
CH2Cl2, 208C (7i+8i+14+unidentified products).
Adv. Synth. Catal. 2007, 349, 215 – 230
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
221

Bernd Schmidt and Stefan Nave
FULL PAPERS
Table 4. Results obtained for the ring size selective RCM of trienes with a terminal substituent at double bond “a” (R’¼H
in all cases).
Entry
Triene
R
R’
Catalyst (5 mol%)
Conversion [%][a]
7i:8i
Product (yield)[b]
[c]
1
2
3
4
5
6
7
8
5e
5e
5f
5f
5f
5f
5f
5f
5f
5f
6i
6i
6i
6i
6i
6i
6j
6j
H
H
H
H
H
H
H
H
Ph
Ph
A
A
A
A
A
C
B
B
B
B
A
C
A
C
A
C
A
C
25
10
60
65
70
99
85
–
–
–
–
7i
[c,d]
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
>20:1
>20:1[e]
7i (52%)
7i
–
7i
>20:1[d,e]
[f]
–
>20:1
>20:1
>20:1
>20:1
95 g]
75 h]
95 g,h]
10
7i (83%)
9
H
H
7i
7i
–
–
–
–
–
–
–
10
11
12
13
14
15
16
17
18
BOM
BOM
BOM
BOM
BOM
BOM
COCCl3
COCCl3
–
–
–
–
–
–
–
–
25
<5[i]
<5[i]
<5[j]
<5[j]
<5
<5
–
[a]
All reactions were conducted in DCM at ambient temperature (208C) with 5 mol% of the appropriate Ru precatalyst
unless otherwise stated. Conversion and product ratios were determined by H NMR-spectroscopy of the crude reaction
mixture.
[b]
[c]
[d]
[e]
[f]
Yields are given in parentheses for isolated, single isomers.
Unidentified product formed along with unreacted starting material.
10 mol% of catalyst used.
In CH2Cl2 at 408C.
complex mixture of products obtained, refer to discussion.
In CH2Cl2 at 408C.
2.5 mol% of catalyst used.
In toluene at 1108C.
In CH2Cl2 at 1108C in a pressurized vessel.
[g]
[h]
[i]
[j]
e.g., the formation of chelates if hydroxyalkyl side takes place prior to ring closure. Although the latter
chains are attached to ligands,[57,58] alkoxy-substitued scenario has been discussed by Quinn et al. for the
ruthenium carbenes,[59] or the significant rate en- RCM of related acrylates,[24] we believed that it would
hancement of A upon addition of phenols.[60] The in- not play a major role in our case, as ring-closing
teraction of hydroxy groups with metathesis catalysts metathesis of allyl ethers is normally much faster than
can, however, also be a source of trouble, as it is the analogous process for acrylates. Thus, if there is a
known that alcohols induce a degradation of Grubbsꢁ significant catalyst directing effect, this should result
catalysts to ruthenium hydride species,[61–63] that may in a high selectivity towards six-membered ring prod-
catalyze isomerization[64] or degradation[65] of the sub- ucts, if initiation at double bond “a” is reduced.
strate.[52,53] However, in our experiments we could not
As outlined in Scheme 5, this can be achieved by
detect any products resulting from an undesired non- attaching a substituent Rꢁ to the terminus of double
metathesis transformation of the unprotected alcohol bond “a”. To check whether this would result in im-
5d.
proved selectivities towards dihydropyrans 8, we in-
Three reasons might exist for the still comparatively vestigated the selectivity of RCM reactions of trienes
large amount of dihydrofuran 8i in the reaction mix- 5e, 5f, 6i and 6j. The results are summarized in Table
tures: a) the proposed catalyst directing effect is not 4. At the beginning, ring-closing metathesis of cin-
very strong, resulting in a certain amount of initiation namyl ether 5e with first generation catalyst A was in-
at double bond “c”; b) initiation occurs to a large vestigated. Double bonds bearing a terminal phenyl
extent at the least hindered double bond “a” and the substituent have recently been employed in a number
resulting carbene complex cyclizes preferably under of RCM reactions. Although these proceed with the
kinetic control to five-membered ring products; c) ini- liberation of non-volatile styrene, good yields have
tiation occurs with high selectivity at the double bond often been reported.[66] In our case, however, only
“b”, but a rapid intermolecular transfer to “c” or “a” poor conversions of 25% or 10%, respectively, were
222
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 215 – 230

Synthesis of Dihydrofurans and Dihydropyrans with Unsaturated Side Chains
observed (entries 1 and 2). Furthermore, it turned out
FULL PAPERS
1
to be quite difficult to analyze the H-NMR spectra
of the crude reaction mixture, because additional sig-
nals appear that cannot be assigned to 5e, 7i or 8i. It
might be possible that a cross-metathesis product of
7i or 8i with styrene is formed in small amounts. As
the reactivity of the double bond “a” is obviously too
strongly reduced with a terminal phenyl group, we in-
vestigated the RCM of crotyl ether 5f. Under stan-
dard conditions, the desired dihydropyran 7i was the
only product. However, conversion was only 60%
with first generation catalyst A (entry 3) and could be
improved only slightly by heating the mixture to 408C
or by using 10 mol% of catalyst (entries 4 and 5).
Nevertheless, it was possible to obtain pure 7i by
column chromatography in an isolated yield of 52%
from these reactions. Using the more active catalyst C
Scheme 7. Reagents and conditions: i) catalyst A (5 mol%),
CH2Cl2, 208C; add 15 (2.0 equivs. relative to 5f), pyridine,
triethylamine and DMAP; separate by column chromatogra-
phy (43% of 7g and 56% of 6k).
resulted in full conversion of the starting material group in 7g can serve as a leaving group in Pd-cata-
(entry 6), but at the expense of selectivity: a complex lyzed transformations. Such a sequence is a conven-
mixture of products was obtained which contained, ient entry into the stereoselective synthesis of 2,5-cis-
among other products, the homodimeric dihydropyran disubstituted dihydropyrans.[69,70]
14 (similar to table 3, entry 26). We were able to
obtain significantly better conversions and isolated
yields while maintaining the high level of selectivity Conclusions
towards dihydropyran 8i by using the precatalyst B,
where the catalytically active species is stabilized by a Starting from a conveniently available chiral building
hemilabile benzylidene ligand. Under standard condi- block, hexadienediol 1, various tri- and tetraenes have
tions, the conversion is 85% for B, compared to 60% been prepared and subjected to ring-closing metathesis
for A (entry 7). This value increases to more than reactions using different catalysts and conditions. We
95% at 408C (entry 8). It is even possible to reduce have successfully realized our goal to make both dihy-
the amount of catalyst to 2.5 mol%: at ambient tem- drofurans and dihydropyrans accessible from the same
perature, a conversion of 75% and at 408C a conver- precursors via a ring size-selective RCM reaction. In
sion of more than 95% is observed (entries 9 and 10). summary, it can be stated that the effect of tempera-
It is in line with the proposed catalyst-directing effect ture and pressure on the product ratios is negligible.
of the free OH group in 5f that its protection results Significant differences were observed for first- and
in a dramatic decrease of conversion. Under various second-generation catalysts, with the first generation
conditions (entries 11 to 18), neither BOM-protected catalysts being generally more selective. Another sig-
6i nor trichloroacetate 6j could be converted to RCM nificant influence on the selectivity of the reaction is
products in significant amounts. This observation sug- exerted by the OH protecting group. A combination of
gests that the OH group does not only direct the cata- first-generation catalyst and a bulky protecting group
lyst to a certain site of the molecule, but that it also yields five-membered rings with virtually perfect selec-
leads to an overall activation of the molecule to tivity, whereas the free alcohol – in combination with
RCM.
first generation catalysts – cyclizes selectively to dihy-
Dihydropyran 7i is quite volatile which makes it dropyrans. We propose a catalyst-directing effect of
necessary to take special precautions during chroma- the allylic hydroxy group as a rationale for the selectiv-
tography and work-up. We thought it might be more ity patterns observed in this study. Further investiga-
practical to functionalize the free OH group in situ tions of such effects in olefin metathesis reactions and
and trap the dihydropyran as a less volatile derivative. their exploitation for control of selectivity issues are
To this end, 5f was treated with precatalyst A as de- currently in progress in our laboratory.
scribed above, and – after conversion had ceased –
the reaction mixture containing unreacted 5f and di-
hydropyran 7i was treated with oxybenzotriazole car-
bamate (15).[67,68] The products 7g and 6k were isolat-
ed by column chromatography without taking any
precautions against loss of material by evaporation
(Scheme 7). The sequence might also be practical
Experimental Section
General Remarks
Experiments were conducted in dry reaction vessels under
from the synthetic point of view, as the carbonate an atmosphere of dry argon. Solvents were purified by stan-
Adv. Synth. Catal. 2007, 349, 215 – 230
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
223

Bernd Schmidt and Stefan Nave
FULL PAPERS
dard procedures. 1H NMR spectra were recorded on a
Bruker Avance 300, Bruker Avance DRX 400, Bruker
Avance DRX 500, or Varian Inova 600 in CDCl3 or ben-
zene-d6. Chemical shifts (d) are reported in ppm relative to
TMS with CHCl3 (dH =7.24 ppm, dC =77.0 ppm) or C6D5H
(dH =7.18 ppm, dC =128.0 ppm) as internal standard. Cou-
pling constants (J) are given in Hertz. In 13C NMR spectra
the number of coupled protons was analyzed by APT or
DEPT experiments and is denoted by a number in parenthe-
ses following the dC value. 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 spectra were ob-
tained at 70 eV. The following compounds have previously
been described in the literature: 5a,[24] 5b,[22] 5c.[23]
(eluent: n-hexane:ethyl acetate, 1:1). After full conversion
(approx. 30 min), aqueous HCl (1M, 8 mL) is added in
1 mLportions. The mixture is dried over magnesium sulfate,
and the solvent is carefully removed under reduced pressure
(100 mbar, 408C) until the solution becomes turbid. Diethyl
ether is added and the solution is dried over magnesium sul-
fate again. The solvent is removed under vacuum and the
yellowish crude product is distilled under vacuum (bp 438C,
0.4 mbar) to afford (R,R)-1 as a colorless oil; yield: 6.40 g
1
(86%). H NMR (CDCl3, 400 MHz): d=5.83 (2H, ddd, J=
ꢀ
17.2, 10.6, 5.6 Hz,
=CH2,trans), 5.22 (2H, d, J=10.6 Hz, =CH2,cis), 3.97 (2H, m,
HC=), 5.33 (2H, d, J=17.2 Hz,
OCH), 2.80 [2H, s(br), OH]; 13C NMR (CDCl3, 100 MHz):
d=136.5 (1, HC=), 117.3 (2, =CH2), 75.7 (1, OCH); [a]D :
+41.0 (c 0.98, CH2Cl2).
20
ꢀ
Synthesis of Dienediol 1 from d-Mannitol
Selective Mono-Etherification of Diol 1 via
(2R,3S,4S,5R)-2,3,4,5-Tetraacetoxy-1,6-dibromohexane
(3):[20] d-Mannitol (54.7 g, 0.300 mol) is suspended in dry di-
oxane (600 mL) under an argon atmosphere. Acetyl bro-
mide (88.9 g, 0.723 mol) is added slowly, and stirred for 4 d
at room temperature. A clear, yellowish solution is formed.
After 4 d, the solution is heated to 408C and stirred at that
temperature for another 4 h. The solvent and other volatiles
are removed under vacuum. The viscous residue is dissolved
in anhydrous pyridine (300 mL), and acetic anhydride
(245.0 g, 2.400 mol) is added slowly. The solution is stirred
overnight at room temperature. Pyridine and other volatiles
are removed under vacuum. The greenish residue is crystal-
lized from a small amount of ethanol (approx. 50 mL) to
afford 3 as a white, crystalline solid; yield: 71.2 g (50%); mp
120–1228C. 1H NMR (CDCl3, 500 MHz): d=5.35 (2H, d,
J=8.1 Hz, 3-H, 4-H), 5.04 (2H, m, 2-H, 5-H), 3.48 (2H, dd,
J=11.6, 3.8 Hz, 1-H2,a), 3.30 (2H, dd, J=11.6, 6.0 Hz, 1-
H2,b), 1.98–2.10 (12H, CH3); 13C NMR (CDCl3, 125 MHz): d
=168.7, 168.6 (0, C=O), 68.2, 68.0 (1, O-CH), 29.7 (2,
Br-CH2), 19.8, 19.7 (3, CH3); [a]2D0: +29.6 (c 0.95, CH2Cl2).
Formation of a Stannylene Acetal
A
(5d):
A
Dean–Stark tube, which is filled with MS 4 Š, is charged
with 1 (615 mg, 5.4 mmol) in benzene (65 mL). Di-n-butyltin
oxide (1.48 g, 5.9 mmol) and Bu4NI (497 mg, 1.35 mmol) are
added and heated to reflux until formation of water stops
(approx. 1.5 h). The mixture is cooled below its boiling
point, the Dean–Stark tube is removed, and allyl bromide
(1.0 mL, 11.6 mmol) is added. The mixture is heated to
reflux for 16 h. If the conversion is incomplete after this
time, additional allyl bromide (1.0 mL, 11.6 mmol) is added
and the mixture is again heated to reflux for 6 h. After cool-
ing to ambient temperature, diethyl ether (40 mL) is added
and the mixture is washed carefully with aqueous sodium
thiosulfate solution (10%, 50 mL). The aqueous phase is ex-
tracted three times with diethyl ether (50 mLeach). The
combined organic phases are washed with water (50 mL),
dried over magnesium sulfate, and all volatiles are removed
under vacuum. After column chromatography (silica, penta-
ne:diethyl ether 15:1!7:1), 5d is obtained as a colourless
liquid; yield: 709 mg (85%). 1H NMR (CDCl3, 500 MHz):
A
(50.2 g, 0.105 mol) is dissolved in glacial acetic acid
(525 mL). Sodium acetate (19.0 g, 0.232 mol) and zinc dust
(27.5 g, 0.421 mol) are added. The mixture is heated to
1108C, and stirred until the evolution of gas has ceased and
the solution becomes clear (approx. 1 h). After cooling, the
zinc dust is filtered off and the acetic acid is removed under
vacuum. The viscous, colorless residue is dissolved in water
and extracted three times with diethyl ether (150 mL). The
combined organic layers are washed with saturated aqueous
NaHCO3 solution (caution: vigorous evolution of gas!),
dried over magnesium sulfate, and the solvent is removed
under vacuum. The colorless crude product is distilled under
vacuum (bp 59–618C, 0.8 mbar) to afford 4 as a colorless
liquid; yield: 17.7 g (89.3 mmol, 85%). 1H NMR (CDCl3,
ꢀ
d=5.88 (1H, dddd, J=16.4, 10.3, 5.1, 0.9 Hz, HC=), 5.79
ꢀ
(1H, ddd, J=17.1, 10.5, 5.8 Hz, HC=), 5.64 (1H, ddd, J=
17.3, 10.4, 7.8 Hz, HC=), 5.36–5.14 (6H, =CH2), 4.09 (1H,
ꢀ
dddd, J=12.7, 5.1, 1.5, 1.5 Hz, OCH2,a), 4.01 (1H, dd, J=
6.5, 6.5 Hz, OCH), 3.85 (1H, ddd, J=12.7, 6.2, 1.3, 1.3 Hz,
OCH2,b), 3.58 (1H, dd, J=6.6, 6.5 Hz, OCH), 2.81 [1H,
s(br), OH]; 13C NMR (CDCl3, 125 MHz): d=136.0, 134.6,
ꢀ
134.4 (1, HC=), 119.9, 117.3, 117.0 (2, =CH2), 83.8, 74.6 (1,
OCH), 69.4 (2, OCH2); ; [a]20: ꢀ20.4 (c 1.04, CH2Cl2); IR
(film): n=3462 [m (br)], 3081D(m), 2983 (m), 2864 (s), 1867
(w), 1646 (m), 1423 (s), 1343 (m), 1255 (m), 1121 (s), 1075
(vs), 992 (vs), 926 (vs) cmꢀ1; MS (ESI): m/z=137 (M+ꢀOH,
100%); 105 (20%), 81 (75%); HR-MS (FAB): m/z=
177.0900, calcd. for C9H14O2Na (M+ +Na): 177.0891.
ꢀ
500 MHz): d=5.72 (2H, ddd, J=17.2, 10.7, 6.0 Hz, HC=),
ꢀ
ꢀ
5.37 (2H, d, J=5.1 Hz, OCH ), 5.30 (2H, d, J=17.2 Hz, =
CH2,trans), 5.24 (2H, d, J=10.7 Hz, =CH2,cis), 2.05 (6H, s,
CH3); 13C NMR (CDCl3, 125 MHz): d=169.7 (0, C=O),
ACHTREUNG
1
(1.90 g, 16.2 mmol) and cinnamyl bromide (3.82 g,
132.0 (1, HC=), 119.1 (2, =CH2), 74.3 (1, OCH), 20.9 (3,
CH3).
19.4 mmol); yield: 1.60 g (43%). 1H NMR (CDCl3,
300 MHz): d=7.43–7.24 (5H, CAr-H), 6.63 (1H, d, J=
16.1 Hz, Ph-HtransC=), 6.30 (1H, ddd, J=15.9, 6.5, 5.7 Hz,
ꢀ
(3R,4R)-3,4-Dihydroxy-1,5-hexadiene [(R,R)-1]:[21] Com-
ꢀ
pound
4
(13.0 g, 65.0 mmol) is dissolved in methanol
PhCH=CH-), 5.87 (1H, ddd, J=17.2, 10.5, 5.7 Hz, HC=),
ꢀ
(260 mL), and an aqueous solution of potassium carbonate
(2M, 4 mL) is added. The progress is monitored by TLC
5.75 (1H, ddd, J=18.3, 10.5, 7.7 Hz, HC=), 5.43–5.31 (3H,
=CH2), 5.24 (1H, ddd, J=10.5, 1.7, 1.4 Hz, =CH2,cis), 4.31
224
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Adv. Synth. Catal. 2007, 349, 215 – 230

Synthesis of Dihydrofurans and Dihydropyrans with Unsaturated Side Chains
FULL PAPERS
ꢀ
(1H, ddd, J=12.6, 5.7, 1.6 Hz, OCH2,a), 4.10 (1H, m, OCH),
4.07 (1H, ddd, J=12.6, 6.6, 1.3 Hz, OCH2,b), 3.70 (1H, dd,
J=7.5, 7.5 Hz, HO-CH), 2.89 [1H, s(br), OH]; 13C NMR
(CDCl3, 75 MHz): d=136.6 (0), 136.1, 134.7, 132.6, 128.5,
7.25 (5H, Ph), 5.95–5.75 (3H, CH=), 5.32–5.24 (5H,
=CH2), 5.16 (1H, d, J=10.4 Hz, =CH2), 4.67 (1H, d,
J=12.1 Hz, OCH2,a-Ph), 4.48 (1H, d, J=12.1 Hz, OCH2,b
Ph), 4.12 (1H, dd, J=13.2, 2.8 Hz, OCH2,a CH=), 3.95 (1H,
-
ꢀ
ꢀ
ꢀ
127.7, 126.5, 125.7 (1, CAr-H and HC=), 119.9, 116.9 (2,
dd, J=13.2, 5.8 Hz, OCH2b CH=), 3.87 (2H, dm, J=3.9 Hz,
=CH2), 83.8, 74.6 (1, OCH), 69.2 (2, OCH2); [a]20: ꢀ17.2 (c
1.40, CH2Cl2); IR (film): n=3439 [s (br)], 3026D (m), 2863
(m), 1876 (w), 1702 (m), 1495 (s), 1422 (s), 1049 (s), 991 (s)
CHO); 13C NMR (CDCl3, 125 MHz): d=138.6 (0, ipso-C),
ꢀ
135.2, 135.1, 135.0, 128.2, 127.6, 127.4 (1, CAr-H and HC=),
118.5, 118.2, 116.6 (2, =CH2), 82.3, 82.2 (1, OCH), 70.7, 69.9
(2, OCH2); [a]20: ꢀ7.42 (c 0.51, CH2Cl2); IR (film): n=3346
(w), 3078 (m), D3029 (m), 2982 (m), 2863 (s), 1645 (w), 1454
+
cmꢀ1; MS (EI): m/z=117 (82, PhCHCHCH2 ), 57 (100);
HR-MS (FAB): m/z=253.1213, calcd. for C15H18O2Na
(M+ +Na): 253.1204.
(m), 1423 (m), 1345 (m), 1069 (vs), 992 (vs), 927 (vs) cmꢀ1
;
A
MS (FAB): m/z=245 (M+ +H, 10%); 243 (5%); 197
(15%); 91 (100%); HR-MS (FAB): m/z=245.1512, calcd.
for C16H21O2 (M+ +H): 245.1542.
lowing the procedure given for 5d, 5f was obtained from 1
(2.28 g, 20 mmol) and crotyl bromide (4.9 mL, 40 mmol) as
a 4:1 mixture of E/Z-isomers; yield: 2.92 g (88%). NMR
data are given for the major isomer: 1H NMR (CDCl3,
(3R,4R)-3-(Methoxy)-4-allyloxyhexa-1,5-diene (6e): Fol-
lowing the procedure given for 6a, 6e was obtained from 5d
(308 mg, 2.0 mmol) and methyl iodide (0.13 mL, 2.0 mmol);
ꢀ
500 MHz): d=5.79 (1H, ddd, J=17.2, 10.6, 1.8 Hz, HC=),
5.72–5.51 (3H, HC=), 5.36–5.16 (4H, =CH2), 4.15–3.91
1
ꢀ
yield: 202 mg (60%); H NMR (CDCl3, 400 MHz): d=5.86
ꢀ
(2H, OCH, OCH2,a), 3.77 (1H, ddt, J=11.5, 6.5, 0.9 Hz,
OCH2,b), 3.56 (1H, dd, J=7.7, 7.7 Hz, OCH), 2.80 [1H, s
(br), OH], 1.70 (3H, dd, J=6.4, 1.1 Hz, CH3); 13C NMR
(1H, ddd, J=17.1, 11.2, 6.1 Hz, CH=), 5.76–5.66 (2H,
ꢀ
CH=), 5.26–5.19 (5H, =CH2), 5.12 (1H, ddd, J=10.3, 1.3,
1.3 Hz, =CH2,cis), 4.07 (1H, ddd, J=12.9, 5.2, 1.4 Hz,
OCH2,a), 3.88 (1H, ddd, J=13.0, 6.1, 1.2 Hz, OCH2,b), 3.77
(1H, m, OCH), 3.60 (1H, m, OCH), 3.29 (1H, s, OCH3);
13C NMR (CDCl3, 100 MHz): d =135.1, 134.9, 134.8 (1,
ꢀ
(CDCl3, 125 MHz): d=136.0, 134.7, 130.0, 127.1 (1, HC=),
119.8, 117.0 (2, =CH2), 83.6, 74.6 (1, OCH), 69.3 (2, OCH2),
17.8 (3, CH3); [a]20: ꢀ24.1 (c 1.47, CH2Cl2); IR (film): n=
3465 [m (br)], 302D2 (m), 2860 (m), 1728 (w), 1644 (w), 1423
(m), 1257 (w), 1047 (s), 992 (s), 927 (s) cmꢀ1; MS (ESI):
m/z=151.3 (M+ꢀOH, 100%); 138.3 (80%); 123.4 (50%);
anal. calcd. for C10H16O2: C 71.4%, H 9.6%; found: C
71.0%, H 9.6%.
ꢀ
CH=), 118.6, 118.5, 116.8 (2, =CH2), 84.8, 82.0 (1, OCH),
69.6 (2, OCH2), 56.9 (3, OCH3); [a]2D0:5: ꢀ9.50 (c 1.37,
CH2Cl2); IR (film): n=3080 (m), 2983 (s), 2933 (s), 2871 (s),
2359 (w), 1864 (w), 1731 (s), 1645 (m), 1423 (s), 1331 (w),
1086 (vs), 927 (vs) cmꢀ1; MS (FAB or ESI): no M+ peak
could be detected.
Alkylation of Sodium Alkoxides (Williamson Ether
Synthesis)
Pd-Catalyzed O-Allylation
A
N
G
of 1 (770 mg, 6.7 mmol) in anhydrous THF (49 mL) is added
NaH (60% dispersion in paraffin, 750 mg, 18.9 mmol), and
the resulting suspension is heated to reflux for 1 h. The mix-
ture is cooled below its boiling point, and allyl bromide
(1.80 mL, 20.2 mmol) is added. The mixture is again heated
to reflux until TLC (silica, n-hexane:MTBE 10:1) indicates
full conversion. After cooling to ambient temperature the
mixture is poured onto saturated NH4Cl solution, extracted
three times with MTBE (20 mLeach), washed with brine
(15 mL) and dried over magnesium sulfate. After evapora-
tion of the solvents under vacuum, the residue is purified by
flash chromatography (silica, n-hexane:MTBE 15:1) to give
6a as a colourless liquid; yield: 1.13 g (5.84 mmol, 87%).
1H NMR (CDCl3, 500 MHz): d=5.88 (2H, ddd, J=16.3,
10.7, 5.6 Hz, HC=), 5.74 (2H, m, HC=), 5.27–5.21 (6H,
=CH2), 5.13 (2H, dd, J=10.4, 1.4 Hz, =CH2,cis), 4.08 (2H,
ddt, J=13.0, 3.7, 1.4 Hz, OCH2a), 3.91 (2H, ddm, J=13.0,
6.0 Hz, OCH2,b), 3.81 (2H, m, OCH); 13C NMR (CDCl3,
125 MHz): d =135.2, 135.0 (1, HC=), 118.2, 116.6 (2,
=CH2), 82.2 (1, OCH), 69.9 (2, OCH2); [a]20: ꢀ3.2 (c 1.49,
CH2Cl2); IR (film): n=3080 (w), 2925 (m), D2859 (m), 1732
(w), 1645 (m), 1424 (m), 1262 (w), 1124 (s), 1080 (vs), 992
(s), 925 (vs) cmꢀ1; MS (FAB): no M+ peak could be detect-
ed.
lowing the procedure given for 6a, 6d was obtained from 5c
(472 mg, 2.3 mmol) and allyl bromide (0.40 mL, 4.6 mmol);
Yield: 545 mg (97%). H NMR (CDCl3, 500 MHz): d=7.38–
Adv. Synth. Catal. 2007, 349, 215 – 230
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
225

Bernd Schmidt and Stefan Nave
FULL PAPERS
A
1644 (w), 1454 (m), 1097 (s), 1040 (vs), 928 (s) cmꢀ1; MS
(FAB): m/z=290 (M+ +H, 7%); 181 (30%); 197 (15%); 91
(100%); 56 (25%); HR-MS (FAB): m/z=289.1815, calcd.
for C18H25O3 (M+ +H): 289.1804; anal. calcd. for C18H24O3:
C 75.0%, H 8.4%; found: C 74.6%, H 8.5%.
(6c): Following the procedure given for 6b, 6c was obtained
from 5b (1.07 g, 3.0 mmol); yield: 980 mg (82%). H NMR
(CDCl3, 500 MHz): d=7.53–7.48 (6H, Ar-H), 7.29–7.19
(9H, Ar-H), 5.86–5.72 (3H, HC=), 5.22–4.99 (6H, =CH2),
4.21 (1H, m, OCH), 3.68 (1H, ddd, J=12.9, 1.5, 1.3 Hz,
OCH2,a), 3.50 (1H, ddd, J=12.9, 1.4, 1.3 Hz, OCH2,b), 2.84
(1H, m, OCH); 13C NMR (CDCl3, 125 MHz): d=144.8
(0, ipso-C), 135.7, 134.8, 129.1, 127.7, 127.0, 127.0 (1, CAr,
A
(6g): Compound 5d (2.29 g, 14.8 mmol) is dissolved in dry
diethyl ether (15 mL) and cooled to 08C. Pyridine (2.42 mL,
29.6 mmol), followed by ethyl chloroformate (1.42 mL,
14.8 mmol) are added slowly. The cooling bath is removed,
and after 1 h, the mixture is heated to reflux until TLC
(silica, pentane:diethyl ether 9:1) indicates complete conver-
sion. Aqueous HCl (1M, 10 mL) is added. The resulting
aqueous layer is extracted three times with diethyl ether
(25 mLeach). The combined organic layers are washed with
brine (25 mL) and dried over magnesium sulfate. After re-
moval of all volatiles under vacuum and column chromatog-
raphy (silica, pentane:diethyl ether 10:1), 6g is obtained as a
pale yellow oil; yield: 2.63 g (79%). 1H NMR (CDCl3,
ꢀ
CH=), 118.0, 116.2, 116.2 (2, =CH2), 87.6 (0, OCq), 80.5,
75.3 (1, OCH), 69.5 (2, OCH2); [a]20: +54.8 (c 0.63,
CH2Cl2); IR (film): n=3059 (m), 2923 (Dm), 2360 (w), 1960
(w), 1734 (w), 1644 (m), 1597 (m), 1491 (s), 1448 (s), 1043
(s), 923 (s) cmꢀ1; anal. calcd. for C28H28O2: C 84.8%, H
7.1%; found: C 84.2%, H 7.0%.
Protection as BOM Ether, Carbonate or
Trichloroacetate
ꢀ
ꢀ
500 MHz): d =5.89–5.77 (2H, CH=), 5.68 (1H, m, CH=),
5.36–5.21 (5H, =CH2), 5.15–5.11 (2H, =CH2 and EtO-
CO2CH), 4.18 (2H, q, J=7.1, OCO2CH2), 4.05 (1H, dd, J=
13.0, 5.0 Hz, OCH2,a), 3.88 (1H, dd, J=13.0, 5.9 Hz,
OCH2,b), 3.86 (1H, dd, J=6.7, 6.7 Hz, OCH), 1.28 (3H, t,
J=7.1, CH3); 13C NMR (CDCl3, 125 MHz): d=154.5 (0,
(3R,4R)-3-(Benzyloxymethoxy)-4-allyloxyhexa-1,5-diene
(6f): At 08C, 5d (771 mg, 5.0 mmol) is dissolved in dichloro-
methane, then ethyldiisopropylamine (3.30 mL, 20.0 mmol)
and benzyloxymethyl chloride (BOM chloride, 2.50 mL,
18.0 mmol) are added. The mixture is allowed to warm to
ambient temperature and stirred for 16 h. It is diluted with
MTBE (60 mL), washed twice with saturated aqeous
Na2CO3 solution, dried over magnesium sulfate and all vola-
tiles are removed under vacuum. After flash chromatogra-
ꢀ
OCO2); 134.6, 133.9, 132.4 (1, HC=), 119.7, 118.8, 116.8 (2,
=CH2), 80.8, 79.2 (1, OCH), 69.7, 64.0 (2, OCH2), 14.2 (3,
CH3); [a]20: +16.6 (c 1.20, CH2Cl2); IR (film): n=3082 (w),
2985 (m),D2858 (m), 1748 (vs), 1647 (m), 1424 (m), 1372 (s),
1256 (vs), 1082 (s), 995 (s), 930 (s), 876 (m) cmꢀ1; MS
(FAB): m/z=227 (M+ +H, 50%); 137 (100%); 97 (90%);
42 (65%); HR-MS (FAB): m/z=227.1299, calcd. for
C12H19O4 (M+ +H): 227.1284
phy (silica, cyclohexane:MTBE, 40:1!20:1), 6f is obtained
as a colorless liquid; yield: 945 mg (69%); H NMR (CDCl3,
500 MHz): d =7.35–7.26 (5H, Ar-H), 5.90 (1H, ddd, J=
16.5, 10.6, 5.3 Hz, HC=), 5.85–5.76 (2H, HC=), 5.32–5.24
(5H, =CH2), 5.14 (1H, dd, J=10.4, 1.3 Hz, =CH2,cis), 4.79
(2H, s, OCH2O), 4.73 (1H, d, J=11.6 Hz, OCH2,a-Ph), 4.54
(1H, d, J=11.6, OCH2,b-Ph), 4.20 (1H, dd, J=6.3, 6.3 Hz,
OCH), 4.11 (1H, dd, J=13.0, 5.0 Hz, OCH2,aCH=), 3.91
(1H, dd, J=13.0, 6.0 Hz, OCH2,bCH=), 3.82 (1H, dd, J=6.4,
6.4 Hz, OCH); 13C NMR (CDCl3, 125 MHz): d=137.9 (0,
ipso-C), 135.3, 134.9, 134.7, 128.4, 128.1, 127.6 (1, CAr-H,
A
(6h): Compound 5d (771 mg, 5.0 mmol) is dissolved in dry
dichloromethane (5 mL) and cooled to 08C. Triethylamine
(1.4 mL, 10.0 mmol), DMAP (24 mg, 0.2 mmol), and tri-
chloroacetyl chloride (0.61 mL, 6.0 mmol) are added. The
mixture is stirred at 08C for 30 min, then it is warmed to
208C and stirred for another 30 min. It is diluted with
MTBE (5 mL) and hydrolyzed with saturated aqueous
Na2CO3 solution (10 mL). The aqueous layer is extracted
with MTBE (15 mL), and the combined organic layers are
washed with saturated aqueous NH4Cl (10 mL) and brine
(10 mL), and dried over magnesium sulfate. After evapora-
tion of all volatiles and column chromatography (silica, pen-
tane:diethyl ether, 40:1!20:1), 6h is obtained as a yellowish
liquid; yield: 250 mg (1.15 mmol, 23%), along with recov-
ered starting material 5d (364 mg, 2.35 mmol, 47%).
ꢀ
HC=), 118.6, 118.6, 116.7 (2, =CH2), 92.2 (2, OCH2O),
82.3, 79.1 (1, OCH), 69.8, 69.4 (2, OCH2); [a]2D0: ꢀ61.0
(c 0.87, CH2Cl2); IR (film): n=3079 (m), 2886 (s), 2248 (w),
1868 (w), 1645 (m), 1455 (s), 1424 (s), 1382 (m), 1038 (vs),
928 (vs) cmꢀ1; MS (FAB): m/z=276 (M+ +H, 6%); 167
(50%); 137 (35%); 91 (100%); HR-MS (FAB): m/z=
275.1618, calcd. for C17H23O3 (M+ +H): 275.1647; anal.
calcd. for C17H22O3: C 74.4%, H 8.1%; found: C 74.1%, H
8.1%.
(3R,4R)-3-(Benzyloxymethoxy)-4-crotyloxyhexa-1,5-diene
(6i): Following the procedure given for 6f, 6i was obtained
from 5f (841 mg, 5.0 mmol); yield: 1.03 g (71%). H NMR
(CDCl3, 500 MHz): d=7.34–7.26 (5H, Ar-H), 5.84–5.76
(2H, HC=), 5.70–5.53 (2H, HC=), 5.31–5.24 (4H, =CH2),
4.78 (2H, s, OCH2Ph), 4.72 (1H, d, J=11.7 Hz, OCH2,a),
4.53 (1H, d, J=11.7 Hz, OCH2,b), 4.18 (1H, dd, J=6.8,
6.8 Hz, OCH), 4.02 (1H, dd, J=11.8, 5.8 Hz, OCH2,a2), 3.86–
3.78 (2H, OCH, OCH2,b2), 1.67 (3H, dd, J=6.4, 1.1 Hz,
CH3); 13C NMR (CDCl3, 125 MHz): d=137.9 (0, ipso-C),
1H NMR (CDCl3, 500 MHz): d=5.88–5.80 (2H, HC=),
ꢀ
ꢀ
5.67 (1H, ddd, J=16.4, 11.1, 7.4 Hz, HC=), 5.44 (1H, d,
J=17.3 Hz, =CH2,trans), 5.40–5.31 (4H, =CH2, CO2CH), 5.24
(1H, dd, J=17.3, 1.6 Hz, =CH2,trans), 5.15 (1H, dd, J=10.4,
1.4 Hz, =CH2,cis), 4.09 (1H, ddt, J=12.9, 5.1, 1.5 Hz,
OCH2,a), 3.94 (1H, dd, J=7.1, 7.1 Hz, OCH), 3.89 (1H, ddt,
J=12.9, 6.0, 1.3 Hz, OCH2,b); 13C NMR (CDCl3, 125 MHz):
ꢀ
d=160.9 (0, CO2), 134.3, 133.2, 130.8 (1, HC=), 120.5,
120.1, 117.1 (2, =CH2), 90.1 (0, CCl3), 80.6, 80.5 (1, OCH),
69.9 (2, OCH2); [a]2D0: +7.8 (c 1.02, CH2Cl2); IR (film): n=
3083 (w), 2986 (w), 2864 (m), 1770 (vs), 1647 (m), 1424 (m),
1243 (vs), 1084 (s), 987 (s), 934 (s), 826 (s), 680 (s) cmꢀ1; MS
(FAB): m/z=299 (M+, 8%); 98 (40%); 80 (35%); 42
135.6, 134.8, 129.0, 128.3, 128.0, 127.7, 127.6 (1, CAr, HC=),
118.5, 118.3 (2, =CH2), 92.2 (2, OCH2O), 82.0, 79.1 (1,
OCH), 69.7, 69.4 (2, OCH2), 17.7 (3, CH3); [a]20: ꢀ45.1 (c
0.95, CH2Cl2). IR (film): n=3066 (w), 3029 (m)D, 2885 (m),
226
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 215 – 230

Synthesis of Dihydrofurans and Dihydropyrans with Unsaturated Side Chains
FULL PAPERS
(30%); anal. calcd. for C11H13O3Cl3: C 44.1%, H 4.4%;
found: C 44.4%, H 4.5%.
(w), 712 (m) cmꢀ1; MS: no M+ peak detectable with EI,
FAB or ESI methods.
A
(6j): Following the procedure given for 6h, 6j was obtained
from 5f (841 mg, 5.0 mmol); yield: 0.42 g (27%). H NMR
Ring Size -Selective Single RCM
1
Selectivity studies: These were performed using the same
methods and instrumentation as described above for the
double ring closing metathesis reactions. Results are sum-
marized in Table 3 for allyl ethers 5d and 6b–h and in Table
4 for crotyl ethers 5f and 6i,j and cinnamyl ether 5e.
Preparative scale: In those cases where the selectivity
study on 0.1 mmol scale revealed a preparatively useful se-
lectivity towards five- or six-membered ring products (ꢁ
10:1), the reaction was repeated on a ꢁ1 mmol scale follow-
ing the procedure given above for the synthesis of 10.
(CDCl3, 500 MHz): d=5.85 (1H, ddd, J=17.2, 10.7, 6.4 Hz,
ꢀ
ꢀ
ꢀ
HC=), 5.74–5.65 (2H, HC=), 5.54 (1H, m, HC=), 5.45
(1H, d, J=17.2 Hz, =CH2,trans), 5.40–5.32 (4H, =CH2,
CO2CH), 4.03 (dd, J=12.0, 3.7 Hz, OCH2,a), 3.95 (1H, dd,
J=7.0, 7.0 Hz, OCH), 3.85 (1H, dd, J=11.9, 6.6 Hz,
OCH2,b), 1.69 (3H, d, J=6.4 Hz, CH3); 13C NMR (CDCl3,
125 MHz): d =160.9 (0, CO2), 133.4, 130.9, 129.6, 127.1 (1,
ꢀ
HC=), 120.1, 120.0 (2, =CH2), 90.1 (0, CCl3), 80.7, 80.2 (1,
OCH), 69.8 (2, OCH2), 17.7 (3, CH3); [a]2D0: +17.7 (c 0.96,
CH2Cl2); IR (film): n=3085 (w), 3021 (w), 2919 (m), 2860
(m), 1769 (vs), 1647 (w), 1426 (m), 1242 (vs), 1095 (m), 983
(m), 935 (m), 839 (s), 826 (s) cmꢀ1; MS (FAB): m/z=313
(M+ +H, <5%); 281 (15%); 207 (20%); 147 (50%); 74
(100%); anal. calcd. for C12H15O3Cl3: C 46.0%, H 4.8%;
found: C 46.0%, H 4.9%.
RCM Products of 5d–f
RCM of hydroxy derivative 5d: RCM of 5d catalyzed by A
according to the procedure given above for selectivity stud-
ies resulted in the formation of dihydropyran 7i and dihy-
drofuran 8i as an inseparable 1:1 mixture. Selected NMR
spectroscopic data were obtained from the mixture.
Ring Size-Selective Double RCM
1
(R)-2-[(R)-1-Hydroxyallyl]-2,5-dihydrofuran (8i): H NMR
ꢀ
ꢀ
Selectivity studies: Double RCM reactions were conducted
with 6a (19.4 mg, 0.1 mmol) and the appropriate precatalyst
A–E (5 mol%) and solvent (2.0 mL, refer to Table 2 for
specific conditions) in standardized sealable tubes in four
parallel runs. If required, the reaction mixtures were heated
in a stainless steel heating block. For reactions at higher
pressures, the open reaction vessels were kept in a Parr au-
toclave, the appropriate pressure was applied and the whole
autoclave was heated with an external heating mantle. The
solvent was subsequently evaporated, and the residue was
(CDCl3, 400 MHz): d=6.00 (1H, dm, J=6.2 Hz, HC=CH ),
ꢀ
5.86 (1H, ddd, J=17.2, 10.5, 5.9 Hz, HC=CH2), 5.75 (1H,
ꢀ
ꢀ
d, J=6.2 Hz, HC=CH ), 4.70 (1H, m, OCH), 4.72–4.61
(2H, OCH2), 4.01 (1H, m, OCHCH=); 13C NMR (CDCl3,
ꢀ
125 MHz): d=135.0, 130.1, 126.6 (1, HC=), 117.0 (2, =
CH2), 89.2 (1, OCH), 75.5 (2, OCH2), 75.3 (1, OCH).
RCM of 5d catalyzed by C according to the procedure
given above for selectivity studies resulted in the formation
of a more complex mixture, containing – apart from 7i and
8i – a third product which could be isolated in very small
amounts by column chromatography and was identified as
self-metathesis product E-bis-[(2R,3R)-3,6-dihydro-3-hy-
1
analyzed by H NMR spectroscopy. Product ratios were de-
termined by comparison of the integrals for the AB system
of the OCHH protons.
droxy-2H-pyran-2-yl]-ethene
500 MHz): d=6.04 (2H, dm, J=10.1 Hz, HC=CH ); 5.95
(14):
1H NMR
(CDCl3,
ꢀ
ꢀ
A
G
(9):
ꢀ
ꢀ
ꢀ
The title compound was obtained in pure form by careful
chromatographic removal of bis-dihydrofuran 10 in suffi-
cient amounts to allow complete NMR spectroscopic char-
[2H, s (br), HC=), 5.93 (2H, dm, J=10.1 Hz, CH=CH ),
4.28 (2H, dm, J=17.0 Hz, OCH2), 4.18 (2H, dm, J=
17.0 Hz, OCH2), 4.10 [2H, s (br), OCH], 3.86 (2H, m,
OCH), 2.33 [2H, s(br), OH]; 13C NMR (CDCl3, 125 MHz):
1
acterization. H NMR (CDCl3, 500 MHz): d=6.08 (2H, dd,
ꢀ
J=10.2, 3.4 Hz, 5-H), 5.95 (2H, m, 4-H), 4.27 (2H, ddd, J=
16.8, 3.8, 1.6 Hz, 6-H2,a), 4.14 (2H, dd, J=16.8, 1.1 Hz, 6-
H2,b), 3.73 (2H, m, 2-H); 13C NMR (CDCl3, 125 MHz): d=
131.9 (1, C-5), 123.7 (1, C-4), 67.8 (1, C-2), 65.4 (2, C-6);
[a]2D0: +202.7 (c 0.44, CHCl3); IR (film): n=3040 (w), 2945
(m), 2854 (m), 2813 (s), 2703 (w), 1682 (w), 1440 (m), 1382
(s), 1342 (s), 1302 (s), 1177 (s), 1084 (s), 856 (s) cmꢀ1; MS:
no M+ peak detectable with EI, FAB or ESI methods.
d=130.1, 129.3, 126.5 (1, HC=), 77.4 (1, OCH), 66.0 (2,
OCH2), 64.1 (1, OCH).
RCM of cinnamyl ether 5e: RCM of 5e catalyzed by A
according to the procedure given above for selectivity stud-
ies resulted in a conversion of less than 10% at ambient
temperature. At 408C or in the presence of catalyst C con-
version was approximately 40%. In all cases very complex
product mixtures resulted which were difficult to analyze.
(R)-2,5-Dihydro-2-[(R)-2,5-dihydrofuran-2-yl]furan (10);
preparative scale: Compound 6a (388 mg, 2.0 mmol) is dis-
solved in anhydrous dichloromethane (40 mL), and catalyst
A (5 mol%, 82 mg) is added. After stirring for 16 h at 208C,
the solvent is removed under reduced pressure and the resi-
due is purified by flash chromatography (silica, cyclohex-
RCM of crotyl ether 5f; (2R,3R)-3,6-dihydro-2-vinyl-2H-
A
pyran-3-ol (7i): Compound 5f (1.79 g, 10.6 mmol) was dis-
solved in dichloromethane (200 mL). Catalyst A (437 mg, 5
mol%) was added and the reaction mixture was stirred
overnight. The solvent was evaporated under vacuum, and
the dark brown residue purified by column chromatography,
followed by Kugelrohr distillation (oven temperature 508C
at 0.23 mbar), to give 7i as a colorless oil; yield: 697 mg
(52%). Conversion (as judged from the NMR spectrum of
1
ane:MTBE, 2:1) to give 10; yield: 189 mg (49%). H NMR
(CDCl3, 500 MHz): d=6.00 (2H, dd, J=6.3, 1.5 Hz, 3-H),
5.74 (2H, m, 4-H), 4.82 (2H, m, 2-H), 4.69–4.60 (4H, 5-H2);
13C NMR (CDCl3, 125 MHz): d=128.6, 126.1 (1, -HC=),
88.0 (1, C-2), 75.8 (2, C-5); [a]D20 =+217.0 (c 0.44, CHCl3);
IR (film): n =3081 (w), 2850 (s), 2359 (w), 1726 (m), 1456
(w), 1382 (w), 1348 (w), 1262 (w), 1074 (s), 1019 (m), 812
1
the crude mixture) is 65%. H NMR (CDCl3, 400 MHz): d=
ꢀ
ꢀ
6.05 (1H, dddd, J=10.2, 5.4, 2.4, 2.2 Hz, HC=CH ), 5.97
ꢀ
(ddd, 1H, J=17.4, 10.8, 5.4 Hz, CH=CH2), 5.94 (1H, ddd,
ꢀ
J=10.2, 3.5, 1.5 Hz, CH=CH<C->), 5.39 (1H, ddd, J=
Adv. Synth. Catal. 2007, 349, 215 – 230
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
227

Bernd Schmidt and Stefan Nave
FULL PAPERS
17.4, 1.6, 1.6 Hz, =CH2,trans), 5.30 (1H, ddd, J=10.8, 1.5,
1.5 Hz, =CH2,cis), 4.28 (1H, ddd, J=17.1, 3.4, 1.8 Hz, OCH2),
4.19 (1H, ddd, J=17.1, 3.8, 1.6 Hz, OCH2), 4.02 (1H, m,
OCH), 3.84 [1H, m, OCH(OH)], 1.84 [1H, s (br), OH];
RCM Products of 6b–h
(R)-2-[(R)-1-(tert-Butyldimethylsilyloxy)allyl]-2,5-dihydro-
furan (8b): Obtained from 6b (274 mg, 1.0 mmol) using cata-
lyst A (41 mg, 5 mol%) as a colorless liquid; yield: 222 mg
13C NMR (CDCl3, 100 MHz): d=135.0, 130.2, 126.6 (1,
ꢀ
1
(90%). H NMR (CDCl3, 500 MHz): d=5.92 (1H, dd, J=
CH=), 117.2 (2, =CH2), 78.4 (1, OCH), 66.0 (2, OCH2), 64.5
[1, OCH(OH)]; [a]2D0: ꢀ200.1 (c 0.93, CH2Cl2); IR (film): n=
3435 [m (br)], 2926 (s), 2853 (m), 2245 (w), 1648 (w), 1446
(m), 1091 (s), 929 (m), 734 (s) cmꢀ1; MS (FAB): m/z=127.1
([M+H]+, 20%); 109.3 ([MꢀOH]+, 50%); anal. calcd. for
C7H10O2: C 66.7%, H 8.0%; found: C 66.2%, H 8.1%.
Improved conversion (95%, as judged by NMR) is ob-
served when 5f (168 mg, 1.0 mmol) is treated with catalyst B
(30 mg, 5 mol%) at 408C. Following the procedure de-
scribed above for the RCM of 5f with A, 7i was obtained as
the only product; yield: 105 mg (83%).
RCM of crotyl ether 5f with in situ derivatization; Ethyl
(2R,3R)-3,6-dihydro-2-vinyl-2H-pyran-3-yl carbonate (7g):
Following the procedure given above for the synthesis of 7i,
5f (336 mg, 2.0 mmol) was treated with catalyst A (82 mg, 5
mol%). After 4 h, the mixture was filtered through a short
pad of silica using diethyl ether as eluent. All volatiles were
evaporated. The crude product was dissolved in pyridine
(8 mL), and triethylamine (0.83 mL, 6.9 mmol), oxybenzo-
triazole carbamate (15) (829 mg, 4.0 mmol) and DMAP
(24 mg, 10 mol%) were added. The mixture was stirred at
208C for 14 h, then water (10 mL) was added, and the re-
sulting aqueous layer was extracted three times with ethyl
acetate (10 mLeach). The combined organic layers were
dried over magnesium sulfate, all volatiles were removed
under vacuum and the residue was chromatographed on
silica (pentane:diethyl ether, 2:1) to give 7g (yield: 170 mg,
43%) and 6k (yield: 270 mg, 56%) as colorless liquids.
Analytical data for 7g: 1H NMR (CDCl3, 500 MHz): d
ꢀ
6.2, 1.4 Hz, HC=), 5.79 (1H, ddd, J=17.2, 10.5, 5.6 Hz,
ꢀ
ꢀ
HC=CH2), 5.77 (1H, d, J=5.4 Hz, HC=), 5.24 (1H, d,
J=17.2 Hz, =CH2,trans), 5.11 (1H, d, J=10.5 Hz, =CH2,cis),
4.75 (1H, m, OCH), 4.59–4.57 (2H, OCH2), 4.15 (1H, dd,
J=5.2, 5.2 Hz, OCHCH=), 0.88 [9H, s, C
-Si(CH3)2,a], 0.02 [3H, -Si
125 MHz): d=137.5, 127.9, 126.7 (1, HC=), 115.7 (2,
=CH2), 89.5, 75.6 (1, OCH), 75.7 (2, OCH2), 25.8 [3,
A
A
ACHTREUNG
ꢀ
(CH3)2]; [a]2D0:
ꢀ
C
(CH3)3], 18.2 (0, SiCq), ꢀ4.7, ꢀ4.9 [3, -Si
+79.1 (c 0.66, CH2Cl2); IR (film): n=2956 (s), 2930 (s),
2857 (s), 1763 (m), 1472 (m), 1254 (s), 1138 (m), 1081 (vs),
1034 (m) cmꢀ1; HR-MS (FAB): m/z=263.1441, calcd. for
C13H24O2NaSi (M+ +Na): 263.1443.
(R)-2-[(R)-1-(Triphenylmethoxy)allyl]-2,5-dihydrofuran
(8c): Obtained from 6c (397 mg, 1.0 mmol) using catalyst A
(41 mg, 5 mol%) as a colorless liquid; yield: 251 mg (68%).
1H NMR (CDCl3, 500 MHz): d=7.52–7.48 (6H, Ar), 7.29–
7.19 (9H, Ar), 5.92–5.86 (2H, OCH), 5.57 (1H, ddd, J=
ꢀ
17.5, 10.6, 7.0 Hz, HC=CH2), 4.86 (1H, dd, J=17.5, 0.6 Hz,
=CH2,trans), 4.80 (1H, d, J=10.6 Hz, =CH2,cis), 4.52–4.42 (2H,
OCH2), 4.34 (1H, m, OCH), 4.11 (1H, dd, J=5.9, 5.9 Hz,
OCHCH=); 13C NMR (CDCl3, 125 MHz): d =144.8 (0, ipso-
C), 135.8, 129.1, 128.6, 127.8, 127.6, 127.5, 127.0, 126.9 (1,
ꢀ
CAr, HC=), 115.9 (2, =CH2), 87.6 (1, OCH), 87.3 (0, OCq),
76.8 (1, OCH), 75.8 (2, OCH2); [a]2D0: +100.1 (c 0.75,
CH2Cl2); IR (film): n=3058 (m), 2917 (m), 2849 (m), 1620
(w), 1490 (m), 1448 (s), 1078 (s), 1049 (s), 917 (m) cmꢀ1
;
HR-MS (FAB): m/z=391.1684, calcd. for C26H24O2Na
(M+ +Na): 391.1674.
(R)-2-[(R)-1-(Benzyloxy)allyl]-2,5-dihydrofuran (8d): Ob-
tained from 6d (242 mg, 1.0 mmol) using catalyst A (41 mg,
5 mol%) as a colorless liquid; yield: 190 mg (88%).
1H NMR (CDCl3, 500 MHz): d=7.38–7.26 (5H), 5.97 (1H,
d, J=6.2 Hz), 5.84–5.75 (2H), 5.36–5.30 (2H), 4.93 (1H, m),
4.67 (1H, d, J=12.2 Hz), 4.65–4.61 (2H), 4.47 (1H, d, J=
12.2 Hz), 3.85 (1H, dd, J=6.7, 6.1 Hz); 13C NMR (CDCl3,
125 MHz): d=138.5 (0, ipso-C), 135.0, 128.2, 128.1, 127.5,
ꢀ
ꢀ
=6.09 (1H, dm, J=10.2 Hz, HC=CH ), 6.00 (1H, dm, J=
ꢀ
ꢀ
ꢀ
10.2 Hz, HC=CH ), 5.90 (1H, ddd, J=17.3, 10.7, 5.5 Hz,
HC=CH2), 5.40 (1H, d, J=17.3 Hz, =CH2,trans), 5.25 (1H, d,
J=10.7 Hz, =CH2,cis), 4.94 [1H, m, CHO(OCO2Et)], 4.34
AHCTREUNG
(1H, d, J=17.1 Hz, OCH2), 4.22–4.13 (4H, OCH2,
OCH2CH3, OCH), 1.26 (3H, t, J=7.1 Hz, CH3); 13C NMR
(CDCl3, 125 MHz): d=155.0 (0, CO2Et), 133.6, 132.8, 122.0
ꢀ
127.3, 126.5 (1, CAr, CH=), 119.2 (2, =CH2), 88.0, 82.3 (1,
ꢀ
(1, HC=), 117.6 (2, =CH2), 76.4, 69.3 (1, OCH), 65.4, 64.0
(2, OCH2), 14.2 (3, -CH3); [a]2D0: ꢀ183.6 (c 0.86, CH2Cl2); IR
(film): n=2984 (w), 2937 (w), 2824 (w), 1741 (s), 1372 (m),
1257 (s), 1095 (s), 1011 (s), 819 (m) cmꢀ1; MS (FAB): no M+
peak observed; anal. calcd. for C10H14O4: C 60.6%, H 7.1%;
found: C 60.7%, H 7.5%.
OCH), 75.6, 70.4 (2, OCH2); IR (film): n=3064 (w), 3030
(w), 2863 (m), 1774 (m), 1454 (m), 1071 (s), 932 (m), 808
(w) cmꢀ1; [a]D20: +29.2 (c 1.12, CH2Cl2); MS (FAB): m/z=
217.0 ([M+H]+, 8%); 215.0 ([MꢀH]+, 5%); 91.6 (100%);
HR-MS (FAB): m/z=217.1235, calcd. for C14H17O2 (M+ +
H+): 217.1229.
RCM of methoxy derivative 6e: RCM of 6e catalyzed by
A according to the procedure given above for selectivity
studies resulted in the formation of dihydropyran 7e and di-
hydrofuran 8e as an inseparable 1 : 3 mixture. NMR-spec-
troscopic data were obtained from the mixture.
1
Analytical data for 6k: H NMR (CDCl3, 500 MHz): d=
ꢀ
5.81 (1H, ddd, J=17.2, 10.6, 6.5 Hz, HC=), 5.70–5.62 (2H,
ꢀ
ꢀ
HC=), 5.51 (1H, m, HC=), 5.35–5.23 (4H, =CH2), 5.12
[1H, dd, J=6.4 Hz, OCH(OCO2Et)], 4.17 (2H, q, J=
A
7.1 Hz, OCH2CH3), 4.00 (1H, dd, J=11.9, 5.7 Hz, OCH2),
3.87–3.79 (2H, OCH2, OCH), 1.67 (3H, d, J=6.4 Hz, =CH-
CH3), 1.28 (3H, t, J=7.1 Hz, OCH2CH3); 13C NMR (CDCl3,
125 MHz): d=154.5 (0, CO2Et), 134.1, 132.5, 129.3, 127.4 (1,
(2R, 3R)-3-Methoxy-2-vinyl-3,6-dihydro-2H-pyran (7e):
1H NMR (CDCl3, 400 MHz): d=6.07–5.98 (2H, HC=
ꢀ
ꢀ
ꢀ
CH ), 5.67 [1H, m, HC=CH2 (not resolved due to signal
overlap)], 5.38 (1H, dm, J=17.3 Hz, =CH2,trans), 5.26 (1H,
dm, J=10.3 Hz, =CH2,cis), 4.31 (1H, d, J=16.3 Hz, OCH2),
4.15 (1H, d, J=16.3 Hz, OCH2), 4.04 [1H, m, OCH
CH2)], 3.62 [1H, m, OCH(OCH3)], 3.38 (3H, s, OCH3);
13C NMR (CDCl3, 100 MHz): d=135.0, 130.8, 123.6 (1,
ꢀ
HC=), 119.4, 118.8 (2, =CH2), 80.5, 79.3 (1, OCH), 69.6,
64.0 (2, OCH2), 17.7, 14.2 (3, -CH3); [a]2D0: +21.3 (c 0.55,
CH2Cl2); IR (film): n=2934 (w), 2859 (w), 1748 (s), 1371
(m), 1256 (s), 1092 (m), 995 (m), 790 (w) cmꢀ1; anal. calcd.
for C13H20O4: C 65.0%, H 8.4%; found: C 64.7%, H 8.2%.
A
AHCTREUNG
ꢀ
228
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 215 – 230

Synthesis of Dihydrofurans and Dihydropyrans with Unsaturated Side Chains
FULL PAPERS
CH=), 116.8 (2, =CH2), 78.0, 72.5 (1, OCH), 65.4 (2, OCH2),
56.5 (3, OCH3).
(m), 827 (s), 680 (s) cmꢀ1; MS: no M+ peak detectable with
EI, FAB or ESI methods.
(R)-2-[(R)-1-Methoxyallyl)-2,5-dihydrofuran
(8e):
1H NMR (CDCl3, 400 MHz): d =5.95 (1H, dm, J=6.2 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
HC=CH ), 5.74 (1H, dm, J=6.2 Hz, HC=CH ), 5.68
Acknowledgements
ꢀ
[1H, m, HC=CH2 (not resolved due to signal overlap)],
5.29 (1H, d, J=10.3 Hz, =CH2,cis), 5.28 (1H, d, J=17.1 Hz,
=CH2,trans), 4.81 (1H, m, OCH), 4.67–4.58 (2H, OCH2), 3.57
Generous financial support by the Deutsche Forschungsge-
meinschaft is gratefully acknowledged. Parts of this work
have been conducted in the department of chemistry of the
university of Dortmund,and financial support by this institu-
tion is also gratefully acknowledged. We thank Stefan Ricken
and Julian Krimmel for assistance in experiments at high
pressures,and Christa Nettelbeck and Nina Meszµros for
technical assistance.
[1H, dd, J=6.9, 6.9 Hz, OCH(OCH3)], 3.31 (3H, s, OCH3);
A
13C NMR (CDCl3, 100 MHz): d=134.7, 128.2, 126.4 (1,
ꢀ
CH=), 119.5 (2, =CH2), 87.9, 85.3 (1, OCH), 75.6 (2,
OCH2), 56.7 (3, OCH3).
(R)-2-[(R)-1-(Benzyloxymethoxy)allyl]-2,5-dihydrofuran
(8f): Obtained from 6f (274 mg, 1.0 mmol) using catalyst A
(41 mg, 5 mol%) as a colorless liquid; yield: 220 mg (89%).
1H NMR (CDCl3, 400 MHz): d=7.35–7.25 (5H, Ar-H), 5.98
ꢀ
ꢀ
(1H, dd, J=6.2, 1.7 Hz, HC=), 5.78 (1H, m, HC=), 5.75
ꢀ
(1H, ddd, J=17.7, 10.4, 9.5 Hz, HC=CH2), 5.32 (1H, d, J=
References
17.7 Hz, =CH2,trans), 5.28 (1H, d, J=11.2 Hz,=CH2,cis), 4.88
(1H, m, OCH), 4.81 (1H, d, J=6.9 Hz, OCH2Ph), 4.78 (1H,
d, J=6.9 Hz, OCH2Ph), 4.72 (1H, d, J=11.7 Hz,
OCH2OCH2Ph), 4.68–4.59 (2H, OCH2), 4.54 (1H, d, J=
11.7 Hz, OCH2OCH2Ph), 4.14 (1H, dd, J=6.6, 6.6 Hz, O-
CH-CH=); 13C NMR (CDCl3, 100 MHz): d=137.9 (0, ipso-
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HC=CH2), 5.73 (1H, dm, J=6.3 Hz, HC=CH ), 5.37
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=CH2,cis), 5.06 [1H, dd, J=6.6, 5.6 Hz, OCH(CH=CH2)],
E
4.89 (1H, m, OCH), 4.68–4.57 (2H, OCH2), 4.16 (2H, q, J=
7.1 Hz, OCH2CH3); 1.27 (3H, t, J=7.1 Hz, CH3); 13C NMR
(CDCl3, 100 MHz): d =154.5 [0, C(=O)], 132.4, 129.4, 125.3
ꢀ
(1, HC=), 119.3 (2, =CH2), 86.8, 79.7 (1, OCHCH=), 75.7,
64.0 (2, OCH2), 14.2 (3, -CH3); [a]2D0: +56.9 (c 2.12, CH2Cl2);
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(w), 1373 (m), 1259 (s), 1083 (m), 1009 (m), 928 (w), 882 (w)
cmꢀ1; MS (FAB): m/z=199 (M+ +H, 45%), 197 (40%), 154
(30%), 109 (100%); HR-MS (FAB): m/z=197.0797, calcd.
for C10H13O4 (M+ꢀH): 197.0841.
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(8h): Obtained from 6h (300 mg, 1.0 mmol) using catalyst A
(41 mg, 5 mol%) as a colorless liquid; yield: 270 mg (99%).
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ꢀ
ꢀ
ꢀ
HC=CH ), 5.91 (1H, ddd, J=17.2, 10.6, 6.6 Hz, HC=
ꢀ
ꢀ
CH2), 5.73 (1H, dm, J=6.2 Hz, HC=CH ), 5.47 (1H, d,
J=17.3 Hz, =CH2,trans), 5.38 (1H, d, J=10.6 Hz, =CH2,cis),
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Adv. Synth. Catal. 2007, 349, 215 – 230
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
229

Bernd Schmidt and Stefan Nave
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