Cross metathesis of allyl alcohols: How to suppress and how to promote double bond isomerization

Article abstract of DOI:10.1039/c3ob40167g

Under standard conditions the cross metathesis of allyl alcohols and methyl acrylate is accompanied by the formation of ketones, resulting from uncontrolled and undesired double bond isomerization. By conducting the CM in the presence of phenol, the catalyst loading and the reaction time required for quantiative conversion can be reduced, and isomerization can be suppressed. On the other hand, consecutive isomerization can be deliberately promoted by evaporating excess methyl acrylate after completing cross metathesis and by adding a base or silane as chemical triggers.

Full text of DOI:10.1039/c3ob40167g

Organic &
Biomolecular Chemistry
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Cross metathesis of allyl alcohols: how to suppress and
how to promote double bond isomerization†
Cite this: Org. Biomol. Chem., 2013, 11,
4194
Bernd Schmidt* and Sylvia Hauke
Under standard conditions the cross metathesis of allyl alcohols and methyl acrylate is accompanied by
the formation of ketones, resulting from uncontrolled and undesired double bond isomerization. By con-
ducting the CM in the presence of phenol, the catalyst loading and the reaction time required for quan-
tiative conversion can be reduced, and isomerization can be suppressed. On the other hand, consecutive
isomerization can be deliberately promoted by evaporating excess methyl acrylate after completing cross
metathesis and by adding a base or silane as chemical triggers.
Received 25th January 2013,
Accepted 30th April 2013
DOI: 10.1039/c3ob40167g
www.rsc.org/obc
Introduction
De novo synthesis is a useful method to obtain rare carbo-
hydrates from non-carbohydrate precursors.1–21 Our contri-
butions to the field have focused on the application of the
assisted tandem RCM–isomerization sequence22–24 to the syn-
thesis of deoxy glycals.25–27 This synthetic method relies on
the in situ conversion of the Ru-carbene into a Ru-hydride by
the addition of a “chemical trigger”28 after completion of the
metathesis step. The Ru-hydride then catalyzes a subsequent
double bond isomerization. We and others have proposed
several additives to trigger the isomerization reaction, such as
a diluted hydrogen atmosphere,29 inorganic hydrides,30 NaOH
and 2-propanol,31 vinyl ethers32,33 or silanes.32 In particular,
with second generation catalysts, uncontrolled isomerization
reactions may occur even in the absence of isomerization indu-
cing additives, because the propagating Ru-NHC-methylidene
species undergoes a bimolecular decomposition into a Ru-
hydride at elevated temperatures.34,35 In these cases isomeriza-
tion is often an undesired side reaction and measures to
prevent double bond migration by trapping the Ru-hydride,
e.g. with benzoquinone, have been devised.36
Scheme 1 Envisaged synthesis of a protected amicetose.
we found that under standard reaction conditions the cross meta-
thesis reaction leading to 1 is accompanied by an isomerization
of the double bond to furnish a 1,4-dicarbonyl compound.
Although the so-called Ru-catalyzed “redox isomerization” of allyl
alcohols is well documented46–50 and has also been reported as a
side reaction of cross metathesis steps involving allyl alco-
hols,51,52 we were surprised by the extent of this problem in our
case. We expected that the tendency of CM products such as 1 to
isomerize to ketones should be comparatively low, because the
C–C-double bond to be isomerized is electron deficient. In
addition, it has been reported that acrylates inhibit olefin isomer-
ization, presumably by trapping Ru-hydride impurities.53,54
In this contribution we report conditions that allow the
complete suppression of redox isomerization of cross meta-
thesis products of allyl alcohols, and conditions which
promote a subsequent double bond isomerization, leading
selectively to 1,4-dicarbonyl compounds from allyl alcohols
and methyl acrylate.
We encountered such an undesired isomerization side reac-
tion when investigating a new synthesis of the highly deoxyge-
nated carbohydrate amicetose, based on the cross metathesis37,38
reaction of allyl alcohols 2 (derived from S-ethyl lactate)26,39
and methyl acrylate (3) (Scheme 1).
In spite of a literature precedent describing the successful
cross metathesis of various allyl alcohols and methyl acrylate,40–45
Results and discussion
Optimization of cross metathesis conditions
Universitaet Potsdam, Institut fuer Chemie, Organische Synthesechemie,
Karl-Liebknecht-Straße 24-25, D-14476 Potsdam-Golm, Germany.
E-mail: bernd.schmidt@uni-potsdam.de
Initially, we investigated the cross metathesis of 4a and methyl
acrylate (3) using ten equivalents of the CM partner and
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob40167g
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concentration to 1.0 M (entry 9), but conducting the reaction
without any solvent (entry 10) led to a significantly lower yield,
which might, however, be attributed to the lower reaction
temperature. In entries 11 and 12 the results for CM reactions
in the presence of phenol at longer reaction times are listed.
From these experiments it can be concluded that phenol is not
an efficient isomerization inhibitor itself, but that the reduced
extent of isomerization can be mainly attributed to the short
reaction time, which was accomplished by phenol accelerated
cross metathesis.
Table 1 Optimization of CM conditions
Cat.
Entry loading
Phenol/
Yield
Yield
c/mol L−1 equiv.
T/°C t/h of 5aa of 6aa,b
Optimization of cross metathesis–isomerization conditions
Next, we set out to find the conditions that would allow the
selective synthesis of the CM–isomerization product 6a. The
results gathered during the optimization of the cross meta-
thesis reaction suggest that the dicarbonyl compound 6a is not
accessible in synthetically useful yields simply by heating the
reaction mixture for a prolonged period of time. These exper-
iments are listed in Table 1 as entries 1 and 12, and are
repeated for comparison in Table 2 as entries 1 and 3. We sus-
pected that excess methyl acrylate inhibits the isomerization to
a certain extent and tested therefore a modification of the CM
protocol which involves removal of the unreacted methyl acry-
late by evaporation after 0.5 h, re-dissolving the mixture in
toluene and heating to induce the isomerization step (Table 2,
entries 2 and 4). If phenol is present in the reaction mixture,
the product distribution is virtually unaffected by this
measure; however, without added phenol the evaporation of
excess methyl acrylate prior to inducing the isomerization
leads to the formation of a substantial amount of 6a (entry 4).
We then tested various additives to promote the Ru-carbene to
Ru-hydride conversion. Surprisingly, ethyl vinyl ether32,58
proved to be ineffective, as only cross metathesis product 5a
was observed. NaOH did promote the isomerization, but syn-
thetically useful yields could only be obtained in the absence
of phenol (entries 7–10), because removal of the phenol turned
out to be laborious. We then tested triethyl silane (entries 11
and 12) and the cheaper alternative polymethylhydrosiloxane
(PMHS)59,60 (entry 13) and found incomplete isomerization if
phenol was present. However, if the CM reaction was con-
ducted without phenol, the isomerized product 6a could be
isolated in a synthetically useful yield of 76% (entry 14).‡
1
2
3
4
5
6
7
8
9
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
2.5 mol% 0.5
2.5 mol% 0.5
2.5 mol% 1.0
2.5 mol% Neat
1.0
0.5
0.5
0.5
1.0
Neat
—
—
—
—
—
—
—
0.5
0.5
0.5
0.5
0.5
110 12
62%
28%
12%
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
110
110
80
110
80
110
110
110
80
2.5 80%
0.5 83%
0.5 73%
0.5 80%
0.5 83%
0.5 75%
0.5 86%
0.5 98%
0.5 83%
2.5 77%
10
11
12
n.d.
17%
20%
5 mol%
2.5 mol% 1.0
0.5
110
110 12
48%
a Yields of isolated and purified products. b n.d. = not determined.
second generation catalyst A55 in refluxing toluene for
12 hours. Under these conditions, 5a and its isomerization
product 6a were obtained in a 2 : 1 ratio (Table 1, entry 1).
Reducing the reaction time to 2.5 hours (entry 2) and then to
0.5 hours (entry 3) led to a significant improvement. Upon low-
ering the temperature to 80 °C (entry 4) the conversion
remained incomplete and the yield of 5a was only 73%. Com-
parison of entries 2, 5 and 6 suggests that a further improve-
ment by the variation of the initial substrate concentration is
not possible. Reducing the catalyst loading to 2.5 mol% (entry
7) results in a lower yield. Based on these results, we thought
that the key to an isomerization-free cross metathesis could be
a combination of reduced reaction temperatures, short reac-
tion times and lower catalyst loadings, because – as mentioned
in the Introduction – the isomerization is caused by a Ru-
hydride resulting from a thermally induced bimolecular
decomposition of the Ru-NHC-methylidene species.34 Consid-
ering the fact that reducing the reaction temperature to 80 °C
resulted in a decrease of the yield by 10% (compare entries 3
and 4) we decided to maintain a reaction temperature of
110 °C and find other means to accelerate the CM reaction
while reducing the catalyst loading at the same time. A very
simple yet effective method to improve olefin metathesis reac-
tions has been devised by Forman et al., who described a bene-
ficial effect of the added phenol.56,57 Presumably, phenol
coordinates to the catalytically active 14-electron species,
leading to a retarded catalyst decomposition. Indeed, the
addition of phenol to the reaction mixture led to a significant
improvement (86% compared to 75%, entries 7 and 8) under
otherwise identical conditions. The yield could be further
Trost and Kulawiec proposed a mechanism for Ru-catalyzed
redox isomerizations which relies on the initial coordination
of the allylic hydroxy group to the Ru centre, followed by
β-hydride elimination to furnish an enone bound to a Ru-
hydride. This complex reacts further in a migratory insertion
to a Ru-enolate, which then undergoes protonation by the
allylic alcohol, liberating the ketone and a Ru-alkoxide.49 In
our case, however, a slightly modified scenario might be possi-
ble, which is depicted in Scheme 2: after the formation of the
Ru-hydride B from the reaction of the metathesis catalyst and
‡When the isolated and purified CM product 5a was treated with 5 mol% of
catalyst A and isomerization inducing additives such as ethyl vinyl ether or
improved to nearly quantitative by raising the initial substrate silanes isomerization product 6a was obtained in similar yields.
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Table 2 Optimization of CM–isomerization conditions
Entry
Cat. loading
Phenol added?
t/h
Excess 3 evaporated?
Additivec (equiv.)
Yield of 5aa,b
Yield of 6aa,b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2.5 mol%
2.5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
Yes
Yes
No
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
12
12
12
12
12
12
3
3
3
3
12
12
12
12
No
Yes
No
—
—
—
—
EVE (5)
EVE (5)
NaOH (0.5)
NaOH (0.5)
NaOH (1.5)
NaOH (1.5)
TESH (0.5)
TESH (0.5)
PMHS (0.2)d
PMHS (0.2)d
48%
55%
62%
26%
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
23%
n.d.
29%
n.d.
20%
21%
28%
56%
<5%
<5%
29%
65%
70%
70%
45%
67%
39%
76%
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
a Yields of isolated and purified products. b n.d. = not determined. c Abbreviations for additives: EVE = ethyl vinyl ether; TESH = triethylsilane;
PMHS = polymethylhydrosiloxane. d Equivalents of PMHS were calculated based on an effective mass of 60 g mol−1 per hydride.59
Ru-enolate F. Due to the large excess of acrylate, the equili-
brium is shifted to the enolate, thereby removing major
amounts of the isomerization catalyst from the reaction
mixture.
Application of isomerization-free CM and CM–isomerization
conditions to other allyl alcohols
The optimization studies revealed that the best conditions for
a cross metathesis–isomerization sequence of allyl alcohols
appear to be the use of a higher catalyst loading of 5 mol%,
absence of phenol, removal of excess acrylate after the com-
pletion of the CM step, and addition of either 1.5 equiv. of
NaOH or 0.2 equiv. of PMHS to trigger the formation of the
isomerization catalyst. On the other hand, for isomerization-
free cross metathesis, a reduced catalyst loading of 2.5 mol%,
addition of phenol as a rate accelerating agent and short reac-
tion times of 0.5 h at 110 °C appear to be beneficial. Having
established the optimum conditions for isomerization-free
cross metathesis and for the CM–isomerization sequence of
allyl alcohol 4a, we applied these protocols to several other
allyl alcohols 4b–4p (Table 3). In general, the CM products 5
were obtained in high yields of ca. 90%. For the 1,4-dicarbonyl
compounds 6, yields of approximately 70% could be obtained.
Although the yields obtained with NaOH are somewhat lower
for most examples, reaction times for the isomerization step
are significantly shorter (ca. 3 h) compared to those with
PMHS as an additive (ca. 12 h). Notably, isomerization
induced by PMHS as a chemical trigger appears to be signifi-
cantly faster than reduction of the C–C-double bond, which
Scheme 2 Mechanistic rationale for the isomerization step.
the isomerization inducing additive, a conjugate addition to
the cross metathesis product 5 occurs, yielding a Ru-enolate C.
Precedence for the formation of such Ru-enolates61 and their
intermediacy in catalytic cycles62,63 exists. In this particular
case, the enolate may undergo cyclization to D, which reacts in
an inter- or intramolecular proton transfer to furnish Ru-alkox-
ide E. From this intermediate, the Ru-hydride can be regener-
ated via β-hydride elimination and formation of the
isomerized product 6. In this scenario, the inhibitory effect of
excess methyl acrylate53,54 can be explained by a conjugate
addition of the Ru-hydride to methyl acrylate (3), giving the
4196 | Org. Biomol. Chem., 2013, 11, 4194–4206
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Table 3 Scope of isomerization-free CM and CM–isomerization sequence
Entry
1
4
Allyl alcohol
5
CM product
Yielda
98%
6
CM–isomerization product
Yieldb
70%
Yieldc
76%
4a
5a
6a
2
3
4
5
4b
4c
4d
4e
5b
5c
5d
5e
91%
94%
91%
85%
6b
6c
6d
6e
83%
63%
45%
65%
71%
67%
72%
68%
6
7
8
4f
5f
92%
88%
94%
6f
27%
70%
71%
76%
d
4g
4h
5g
5h
6g
6h
—
68%
66%
9
4i
5i
88%
6i
64%
10
11
4j
5j
90%
94%
6j
80%
44%
73%
61%
4k
5k
6k
12
4l
5l
91%
6l
41%
67%

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has also been observed with silanes in the presence of Ru-
carbene complexes.64,65
Synthesis of BOM-protected amicetose
Hydrogenation of 5a using commercial Pd/C as a catalyst
resulted in spontaneous cyclization to the γ-butyrolactone 7.
For these reasons we thought it might be advantageous to
mask the C4–OH group prior to hydrogenation with a protect-
ing group orthogonal to TBS. Initially, the MOM-group was
chosen, and the corresponding MOM-ether 8a could be iso-
lated in 81% yield. Hydrogenation was again accomplished in
quantitative yield using hydrogen and Pd/C. Unfortunately,
this method turned out to be very unreliable, because when
we changed the sample of Pd/C the reaction failed completely.
Reproducibility problems associated with Pd/C have been
known for quite some time66 and the in situ preparation of
such catalysts from Pd(OAc)2 and activated carbon has been
suggested as an alternative.67,68 Considering that the hydro-
genation in question involves a double bond in conjugation
with an ester group, we thought that Lipshutz’ variant60 of
Stryker’s reagent69 should work well. Indeed, the desired ester
9a was reliably and reproducibly obtained in nearly quantitat-
ive yield with [(BDP)CuH] as a catalyst, which was formed in
situ from 1,2-bis(diphenyl-phosphino)benzene (BDP), Cu-(II)-
acetate and polymethylhydro-siloxane (PMHS) as a reducing
agent (Scheme 3).
Unfortunately, it turned out at this point that the MOM-
protecting group was rather impractical, because after desilyla-
tion it became virtually impossible to control the progress of
any reaction steps via TLC. For this reason, we replaced the
MOM-group by the UV-active benzyloxymethyl-(BOM)-protect-
ing group. The analogous compound 8b was obtained in
somewhat better yield than 8a, and the subsequent conjugate
reduction with the modified Stryker’s reagent gave 9b in quan-
titative yield. Desilylation and lactonization led to compound
10, which was finally reduced with DIBAl-H to the desired
BOM-protected amicetose 11 (Scheme 4).
Scheme 3 Towards MOM-protected amicetose.
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0.5 mmol) in dry toluene (1.0 mL) was added Ru-catalyst A
(21.2 mg, 2.5 mol%). The solution was heated to 110 °C for
0.5 h, all volatiles were removed in vacuo and the residue was
purified by column chromatography on silica using hexane–
MTBE mixtures of increasing polarity.
(4R, 5S, E)-Methyl-5-(tert-butyldimethylsilyloxy)-4-hydroxy-
hex-2-enoate (5a). Following the general procedure, 5a was
obtained from 4a (200 mg, 0.92 mmol) as a colourless oil
(249 mg, 98%). [α]D27 = +21.3 (c = 0.61, CH2Cl2); 1H NMR
(300 MHz, CDCl3) δ 6.89 (dd, J = 15.7, 4.7, 1H), 6.10 (dd, J =
15.7, 1.8, 1H), 4.22 (ddd, J = 8.6, 4.0, 1.8, 1H), 3.91 (qd, J = 6.3,
3.9, 1H), 3.73 (s, 3H), 2.57 (d, J = 4.0, 1H), 1.07 (d, J = 6.3, 3H),
0.89 (s, 9H), 0.07 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 167.2 (0), 146.4 (1), 121.7 (1), 75.2 (1), 71.1 (1), 51.9
(3), 26.1 (1), 18.4 (0), 18.2 (1), −4.7 (3), −4.8 (3); IR (neat): ν
3481 (w), 2930 (m), 2857 (m), 1726 (s), 1093 (s), 834 (s), 775 (s);
MS (EI): m/z 275 (23), 257 (100), 213 (34), 143 (11), 111 (90);
HRMS (ESI) calcd for C13H27O4Si [M + H]+: 275.1679, found:
275.1694; Anal. calcd for C13H26O4Si: C, 56.9; H, 9.6; found: C,
56.9; H, 9.7.
Scheme 4 Synthesis of BOM-protected amicetose.
Conclusions
(E)-Methyl-4-hydroxy-4-phenylbut-2-enoate (5b). Following
the general procedure, 5b was obtained from 4b (134 mg,
1.0 mmol) as a colourless liquid (174 mg, 91%). 1H NMR
(300 MHz, CDCl3) δ 7.43–7.22 (5H), 7.02 (d, J = 15.6, 1H), 6.14
(d, J = 15.6, 1H), 5.31 (bs, 1H), 3.70 (s, 3H), 2.62 (bs, 1H); 13C
NMR (75 MHz, CDCl3) δ 167.0 (0), 148.9 (1), 140.8 (0), 128.8
(1), 128.3 (1), 126.5 (1), 119.6 (1), 73.4 (1), 51.6 (3); IR (neat): ν
3430 (w), 2952 (w), 1705 (s), 1657 (m), 1436 (m), 1271 (s), 1167
(s), 981 (s), 698 (s); MS (EI): m/z 192 (10, [M + H]+), 174 (30),
163 (100), 131 (100), 115 (41), 105 (74), 87 (60), 77 (85), 55 (33);
HRMS (EI): calcd for C11H12O3 [M]+: 192.0786, found:
192.0776; Anal. calcd for C11H12O3: C, 68.7; H, 6.3, found: C,
68.2; H, 6.5.
In summary, we have described a protocol for the rapid, iso-
merization-free cross metathesis of allyl alcohols and methyl
acrylate using phenol as an efficient rate-accelerating reagent.
These conditions were applied to an allylic alcohol derived
from S-ethyl lactate, and the resulting cross metathesis
product could be elaborated in a few steps to the 2,3,6-trideoxy
sugar amicetose as a BOM-ether. The isomerization-free CM
conditions were complemented by the development of a proto-
col which allows the synthesis of 1,4-dicarbonyl compounds
from allyl alcohols through an assisted tandem CM–isomeriza-
tion sequence, using a single precatalyst and base or a silane
as a chemical trigger for inducing the conversion of the Ru-
carbene catalyst into a Ru-hydride.
(E)-Methyl-4-(4-bromophenyl)-4-hydroxy-but-2-enoate (5c).
Following the general procedure, 5c was obtained from 4c
1
(213 mg, 1.0 mmol) as a colourless liquid (254 mg, 94%). H
NMR (300 MHz, CDCl3) δ 7.46 (ddd, J = 8.4, 2H), 7.18 (ddd, J =
8.5, 2H), 6.95 (dd, J = 15.6, 4.9, 1H), 6.10 (dd, J = 15.6, 1.6, 1H),
5.26 (dm, J = 4.0, 1H), 3.70 (s, 3H), 3.01 (bs, 1H); 13C NMR
(75 MHz, CDCl3) δ 166.8 (0), 148.4 (1), 139.8 (0), 131.8 (1),
128.2 (1), 122.1 (0), 120.1 (1), 72.6 (1), 51.7 (3); IR (neat): ν 3426
(m), 2951 (w), 1703 (s), 1436 (m), 1275 (s), 1167 (s), 1010 (s),
827 (s); MS (EI): m/z 270 (8, [M + H]+), 255 (18), 254 (28), 243
(79), 241 (100), 213 (25), 211 (65), 185 (57), 183 (62), 131 (47),
87 (91), 77 (54), 55 (28); HRMS (ESI): calcd for C11H12O3Br
[M + H]+: 270.9970, found: 270.9994.
Experimental
General remarks
All experiments were conducted in dry reaction vessels in an
atmosphere of dry nitrogen. Solvents were purified by standard
1
procedures. H NMR spectra were obtained at 300 MHz or at
600 MHz in CDCl3 with CHCl3 (δ = 7.24 ppm) as an internal
standard. Coupling constants (J) are given in Hz. 13C NMR
spectra were recorded at 75 MHz or at 150 MHz in CDCl3 with
CDCl3 (δ = 77.0 ppm) as an internal standard. The number of
coupled protons was analyzed by APT-experiments and is
denoted by the number in parentheses following the chemical
shift value. IR spectra were recorded neat on NaCl or KBr
plates. Wavenumbers (ν) are given in cm−1. The peak intensi-
ties are defined as strong (s), medium (m) or weak (w). Mass
spectra were obtained at 70 eV.
(E)-Methyl-4-hydroxy-4-(4-methoxyphenyl)-but-2-enoate (5d).
Following the general procedure, 5d was obtained from 4d
1
(164 mg, 1.0 mmol) as a colourless liquid (203 mg, 91%). H
NMR (300 MHz, CDCl3) δ 7.24 (dm, J = 8.5, 2H), 7.02 (ddd, J =
15.6, 4.7, 0.5, 1H), 6.87 (dm, J = 8.6, 2H), 6.14 (ddd, J = 15.6,
0.8, 0.7, 1H), 5.28 (d, J = 4.6, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 2.37
(bs, 1H); 13C NMR (75 MHz, CDCl3) δ 167.0 (0), 159.6 (0), 149.1
(1), 133.0 (0), 128.0 (1), 119.5 (1), 114.2 (1), 73.0 (1), 55.3 (3),
General procedure for isomerization-free cross metathesis
To a solution of the corresponding allyl alcohol (1.0 mmol), 51.6 (3); IR (neat): ν 3443 (m), 2953 (w), 1716 (s), 1511 (s), 1247
methyl acrylate (0.9 mL, 10.0 mmol) and phenol (47 mg, (s), 1168 (s), 1030 (s), 833 (m); MS (EI): m/z 222 (41, [M]+), 193
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(28), 161 (75), 145 (41), 135 (100), 121 (43), 91 (37), 77 (55), 55 55 (31); HRMS (EI): calcd for C11H11O3F [M]+: 210.0692, found:
(31); HRMS (EI): calcd for C12H14O4 [M]+: 222.0892, found: 210.0685.
222.0874; Anal. calcd for C12H14O4: C, 64.9; H, 6.4, found: C,
64.6; H, 6.5.
(E)-Methyl-4-hydroxy-5-phenylpent-2-enoate (5i). Following
the general procedure, 5i was obtained from 4i (148 mg,
(E)-Methyl 4-hydroxy-4-(3-methoxy-4-(methoxymethoxy)- 1.0 mmol) as a colourless liquid (182 mg, 88%). 1H NMR
phenyl)-but-2-enoate (5e). Following the general procedure, 5e (300 MHz, CDCl3) δ 7.42–7.17 (5H), 7.02 (dm, J = 15.7, 1H),
was obtained from 4e (224 mg, 1.0 mmol) as a colourless 6.06 (d, J = 15.6, 1H), 4.52 (bs, 1H), 3.74 (s, 3H), 3.02–2.72
1
liquid (239 mg, 85%). H NMR (300 MHz, CDCl3) δ 7.09 (d, J = (2H), 2.09 (bs, 1H); 13C NMR (75 MHz, CDCl3) δ 167.0 (0),
8.2, 1H), 7.01 (dd, J = 15.6, 4.8, 1H), 6.88 (d, J = 2.0, 1H), 6.82 149.2 (1), 136.8 (0), 129.4 (1), 128.6 (1), 126.9 (1), 120.1 (1), 71.7
(dd, J = 8.3, 2.0, 1H), 6.13 (dd, J = 15.6, 1.7, 1H), 5.28 (m, 1H), (1), 51.6 (3), 43.2 (2); IR (neat): ν 3435 (m), 2950 (w), 1707 (s),
5.19 (s, 2H), 3.85 (s, 3H), 3.71 (s, 3H), 3.48 (s, 3H), 2.53 (bs, 1437 (m), 1275 (s), 1168 (s), 702 (s); MS (EI): m/z 206 (1, [M]+),
1H); 13C NMR (75 MHz, CDCl3) δ 166.7 (0), 148.8 (1), 135.3 (0), 115 (18), 91 (100), 83 (76); HRMS (EI): calcd for C12H14O3 [M]+:
119.6 (1), 119.0 (1), 116.5 (1), 110.0 (1), 95.4 (2), 73.2 (1), 56.1 206.0943, found: 206.0954; Anal. calcd for C12H14O3: C, 69.9;
(3), 55.9 (3), 51.6 (3); IR (neat): ν 3454 (w), 2952 (w), 1720 (m), H, 6.8, found: C, 69.4; H, 7.1.
1508 (m), 1261 (s), 1152 (s), 979 (s); MS (EI): m/z 282 (87, [M]+),
(E)-Methyl-4-hydroxy-6-phenylhex-2-enoate (5j). Following
265 (27), 233 (30), 220 (29), 45 (100); HRMS (ESI): calcd for the general procedure, 5j was obtained from 4j (162 mg,
C14H19O6 [M + H]+: 283.1182, found: 283.1198; Anal. calcd for 1.0 mmol) as a colourless solid (197 mg, 90%), mp 29–31 °C.
C14H18O6: C, 59.6; H, 6.4; found: C, 59.4; H, 6.6.
1H NMR (300 MHz, CDCl3) δ 7.36–7.16 (5H), 6.97 (dd, J = 15.7,
(E)-Methyl-4-(4-(tert-butyldimethylsilyloxy)phenyl)-4-hydro- 4.9, 1H), 6.07 (dd, J = 15.6, 1.7, 1H), 4.32 (m, 1H), 3.75 (s, 3H),
xybut-2-enoate (5f). Following the general procedure, 5f was 2.85–2.66 (2H), 2.41 (bs, 1H), 1.98–1.81 (2H); 13C NMR
obtained from 4f (264 mg, 1.0 mmol) as a colourless liquid (75 MHz, CDCl3) δ 167.0 (0), 150.3 (1), 141.2 (0), 128.4 (1),
1
(295 mg, 92%). H NMR (300 MHz, CDCl3) δ 7.18 (d, J = 7.4, 128.4 (1), 126.0 (1), 119.9 (1), 70.2 (1), 51.6 (3), 37.9 (2), 31.3
2H), 7.03 (dm, J = 15.6, 1H), 6.81 (d, J = 7.4, 2H), 6.14 (d, J = (2); IR (neat): ν 3436 (m), 2949 (w), 1705 (s), 1275 (s), 1169 (m),
15.6, 1H), 5.28 (bs, 1H), 3.73 (s, 3H), 2.30 (bs, 1H), 0.97 (s, 9H), 700 (s); MS (EI): m/z 221 (18, [M + H]+), 220 (7, [M]+), 202 (18),
0.18 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 167.0 (0), 155.8 (0), 142 (30), 128 (30), 105 (67), 91 (100), 87 (46); HRMS (EI): calcd
149.1 (1), 133.6 (0), 127.9 (1), 120.4 (1), 119.5 (1), 73.1 (1), 51.6 for C13H16O3 [M]+: 220.1099, found: 220.1111; Anal. calcd for
(3), 25.7 (3), 18.2 (0), −4.5 (3); IR (neat): ν 3431 (m), 2932 (w), C13H16O3: C, 70.9; H, 7.3, found: C, 70.4; H, 7.2.
1723 (m), 1508 (s), 1255 (s), 1165 (s), 910 (s), 837 (s), 780 (s);
(E)-Methyl-4-hydroxy-6-methylhept-2-enoate (5k). Following
MS (EI): m/z 322 (38, [M]+), 291 (31), 265 (100), 235 (50), 209 the general procedure, 5k was obtained from 4k (114 mg,
(49), 179 (30), 135 (25), 89 (50), 55 (20); HRMS (EI): calcd for 1.0 mmol) as a colourless liquid (162 mg, 94%). 1H NMR
C17H26O4Si [M]+: 322.1600, found: 322.1628; Anal. calcd for (300 MHz, CDCl3) δ 6.93 (dm, J = 15.7, 1H), 6.02 (d, J = 15.6,
C17H26O4Si: C, 63.3; H, 8.1, found: C, 63.2; H, 8.4.
1H), 4.34 (bs, 1H), 3.72 (s, 3H), 2.10 (bs, 1H), 1.78 (m, 1H),
(E)-Methyl-4-(4-benzyloxyphenyl)-4-hydroxybut-2-enoate (5g). 1.57–1.28 (2H), 0.92 (d, J = 5.2, 6H); 13C NMR (75 MHz, CDCl3)
Following the general procedure, 5g was obtained from 4g δ 167.1 (0), 151.0 (1), 119.3 (1), 69.3 (1), 51.6 (3), 45.6 (2), 24.4
(240 mg, 1.0 mmol) as a colourless solid (263 mg, 88%), mp (1), 23.0 (3), 22.0 (3); IR (neat): ν 3432 (m), 2956 (m), 1706 (s),
69–70 °C. 1H NMR (300 MHz, CDCl3) δ 7.49–7.30 (5H), 7.26 (d, 1275 (s), 1170 (s), 938 (s); MS (EI): m/z 143 (31), 115 (42), 87
J = 6.8, 2H), 7.05 (dm, J = 15.7, 1H), 6.97 (d, J = 6.9, 2H), 6.16 (100), 55 (38), 41 (25); HRMS (ESI): calcd for C9H17O3 [M + H]+:
(d, J = 15.6, 1H), 5.30 (bs, 1H), 5.07 (s, 2H), 3.74 (s, 3H), 3.72 (s, 173.1178, found: 173.1192; Anal. calcd for C9H16O3: C, 62.8; H,
3H), 2.36 (bs, 1H); 13C NMR (75 MHz, CDCl3) δ 167.0 (0), 159.6 9.4, found: C, 62.8; H, 9.6.
(0), 149.1 (1), 133.0 (0), 128.0 (1), 119.5 (1), 114.2 (1), 73.0 (1),
(E)-Methyl-4-hydroxy-4-((R)-1,4-dioxaspiro[4.5]decan-2-yl)-
55.3 (3), 51.6 (3); IR (neat): ν 3436 (m), 3031 (w), 1707 (s), 1509 but-2-enoate (5l). Following the general procedure, 5l was
(s), 1238 (s), 1168 (s), 1016 (s), 739 (s); MS (EI): m/z 298 (20, obtained from 4l (198 mg, 1.0 mmol) as a colourless liquid
[M]+), 281 (7), 91 (100), 65 (7); HRMS (EI): calcd for C18H18O4 (233 mg, 91%) as an inseparable mixture of diastereomers.
[M]+: 298.1205, found: 298.1206; Anal. calcd for C18H18O4: C, Analytical data were obtained from the mixture. 1H NMR
72.5; H, 6.1, found: C, 72.5; H, 6.2.
(300 MHz, CDCl3) δ 6.90 (dd, J = 15.8, 4.1, 0.5H), 6.85 (dd, J =
(E)-Methyl-4-(2-fluorophenyl)-4-hydroxybut-2-enoate (5h). 15.7, 4.7, 0.5H), 6.16 (dd, J = 15.7, 2.6, 0.5H), 6.14 (dd, J = 15.7,
Following the general procedure, 5h was obtained from 4h 2.6, 0.5H), 4.46 (m, 0.5H), 4.21 (m, 0.5H), 4.17–3.78 (3H), 3.73
1
(152 mg, 1.0 mmol) as a colourless liquid (198 mg, 94%). H (s, 3H), 2.68 (bs, 0.5H), 2.57 (bs, 0.5H), 1.69–1.47 (8H),
NMR (300 MHz, CDCl3) δ 7.40 (t, J = 7.2, 1H), 7.27 (m, 1H), 1.47–1.30 (2H); 13C NMR (75 MHz, CDCl3) δ 166.6 (0), 166.5
7.14 (m, 1H), 7.09–6.95 (2H), 6.15 (d, J = 15.6, 1H), 5.66 (bs, (0), 145.4 (1), 145.2 (1), 122.3 (1), 121.6 (1), 110.6 (0), 110.3 (0),
1H), 3.71 (s, 3H), 3.06 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 77.5 (1), 77.0 (1), 71.8 (1), 70.5 (1), 65.3 (2), 64.3 (2), 51.6 (3),
167.0 (0), 159.7 (d, J = 246.9, 0), 147.8 (1), 129.7 (d, J = 8.3, 1), 36.2 (2), 36.1 (2), 34.6 (2), 34.5 (2), 25.0 (2), 25.0 (2), 23.9 (2),
128.0 (d, J = 13.4, 0), 127.7 (d, J = 3.8, 1), 124.5 (d, J = 3.5, 1), 23.9 (2), 23.6 (2); IR (neat): ν 3457 (m), 2936 (w), 1722 (s),
120.0 (1), 115.5 (d, J = 21.5, 1), 67.0 (d, J = 3.4, 1), 51.7 (3); IR 1274 (s), 1165 (s), 1097 (s), 927 (s); MS (EI): m/z 256 (22, [M]+),
(neat): ν 3436 (m), 2953 (w), 1705 (s), 1274 (s), 1171 (s), 759 (s); 227 (23), 213 (83), 141 (100), 109 (35), 81 (31), 55 (42); HRMS
MS (EI): m/z 210 (3, [M]+), 181 (100), 149 (77), 123 (56), 87 (56), (EI): calcd for C13H20O5 [M]+: 256.1311, found: 256.1313;
4200 | Org. Biomol. Chem., 2013, 11, 4194–4206
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Anal. calcd for C13H20O5: C, 60.9; H, 7.9, found: C, 60.7; (94), 55 (74); HRMS (ESI): calcd for C13H20O6Na [M + Na]+:
H, 7.9.
(E)-Methyl-4-hydroxynon-2-enoate
295.1158, found: 295.1164; Anal. calcd for C13H20O6: C, 57.3;
the H, 7.4, found: C, 57.2; H, 7.4.
(5m). Following
general procedure, 5m was obtained from 4m (128 mg,
1
1.0 mmol) (172 mg, 93%). H NMR (300 MHz, CDCl3) δ 6.93
(dm, J = 15.7, 1H), 6.00 (d, J = 15.7, 1H), 4.27 (bs, 1H), 3.71 (s,
General procedure for tandem cross metathesis–isomerization
3H), 2.22 (bs, 1H), 1.63–1.47 (2H), 1.47–1.18 (6H), 0.92–0.78 To a solution of the corresponding allyl alcohol (1.0 mmol)
(3H); 13C NMR (75 MHz, CDCl3) δ 167.1 (0), 150.7 (1), 119.5 (1), and methyl acrylate (0.9 mL, 10.0 mmol) in dry toluene
71.0 (1), 51.6 (3), 36.5 (2), 31.6 (2), 22.5 (2), 13.9 (3); IR (neat): ν (1.0 mL) was added Ru-catalyst A (42.5 mg, 5 mol%). The solu-
3437 (m), 2930 (m), 1723 (s), 1437 (m), 1274 (s), 1169 (s); MS tion was heated to 110 °C for 0.5 h, cooled to ambient temp-
(EI): m/z 157 (39), 115 (46), 87 (100), 55 (32), 43 (20); HRMS erature, and excess methyl acrylate was removed in vacuo. The
(ESI): calcd for C10H19O3 [M + H]+: 187.1334, found: 187.1327; residue was re-dissolved in toluene (5.0 mL), and either NaOH
Anal. calcd for C10H18O3: C, 64.5; H, 9.7, found: C, 64.4; H, (60 mg, 1.5 mmol) was added and the mixture was heated to
10.1.
(E)-Methyl-4-hydroxyhept-2-enoate
reflux (oil bath temperature 130 °C) for 3 h (method A), or
the PMHS (16 μL, 0.2 mmol) was added and the mixture was
(5n). Following
general procedure, 5n was obtained from 4n (100 mg, heated to reflux (oil bath temperature = 130 °C) for 12 h
1.0 mmol) as a colourless liquid (138 mg, 87%). 1H NMR (method B).
(300 MHz, CDCl3) δ 6.93 (dd, J = 15.7, 4.9, 1H), 6.01 (dd, J =
Work-up procedure for method A: The reaction mixture was
15.7, 1.7, 1H), 4.29 (ddm, J = 6.2, 1.6, 1H), 3.72 (s, 3H), 2.09 hydrolyzed, and the aqueous layer was extracted twice with
(bs, 1H), 1.60–1.48 (2H), 1.48–1.30 (2H), 0.92 (t, J = 7.3, 3H); MTBE. The combined organic layers were washed with brine,
13C NMR (75 MHz, CDCl3) δ 150.6 (0), 119.6 (1), 70.8 (1), 51.5 dried with MgSO4, filtered and all volatiles were removed
(3), 38.7 (2), 18.4 (2), 13.8 (3); IR (neat): ν 3441 (w), 2958 (m), in vacuo. The residue was purified by column chromatography
1724 (s), 1705 (s), 1659 (m), 1436 (m), 1274 (s), 1169 (s), 981 on silica, using hexane–MTBE mixtures of increasing polarity.
(s); MS (EI): m/z 129 (44), 115 (50), 87 (100), 83 (37), 71 (25), 55
Work-up procedure for method B: All volatiles were removed
(35); HRMS (ESI): calcd for C8H15O3 [M + H]+: 159.1021, found: in vacuo and the residue was purified by column chromato-
159.1015 Anal. calcd for C8H14O3: C, 60.7; H, 8.9, found: C, graphy, on silica, using hexane–MTBE mixtures of increasing
60.8; H, 8.9.
(2E, 2′E)-Dimethyl-4,4′-(1,4-phenylene)bis(4-hydroxybut-2-
polarity.
(S)-Methyl-5-(tert-butyldimethylsilyloxy)-4-oxohexanoate (6a).
enoate) (5o). Following the general procedure, 5o was Following the general procedure, 6a was obtained from 4a
obtained from 4o (190 mg, 1.0 mmol) as a colourless solid (200 mg, 0.92 mmol) via method A (178 mg, 70%) or via
(254 mg, 83%), mp 98–99 °C, as a mixture of diastereomers. method B (193 mg, 76%) as a colourless liquid. [α]2D6 = −8.2 (c
1
The general procedure was modified by using increased = 0.63, CH2Cl2); H NMR (300 MHz, CDCl3) δ 4.18 (q, J = 6.8,
amounts of catalyst A (85 mg, 10 mol%) and methyl acrylate 1H), 3.66 (s, 3H), 2.97 (ddd, J = 19.1, 6.8, 6.6, 1H), 2.83 (ddd, J
(1.80 mL, 20.0 mmol). Analytical data were obtained from the = 19.1, 6.8, 5.9, 1H), 2.57 (ddd, J = 6.8, 5.9, 2.5, 1H), 2.56 (ddd,
mixture. 1H NMR (300 MHz, CDCl3) δ 7.30–7.22 (4H), 6.94 J = 6.7, 6.6, 3.1, 1H), 1.29 (d, J = 6.8, 3H), 0.91 (s, 9H), 0.08 (s,
(ddm, J = 15.6, 4.8, 2H), 6.14–6.01 (ddm, J = 15.6, 1.6, 2H), 5.28 3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 212.8 (0), 173.6
(bs, 2H), 3.65 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 166.9 (0), (0), 75.2 (1), 52.1 (3), 32.4 (2), 27.7 (2), 26.1 (3), 21.2 (3), 18.4
149.0 (1), 141.1 (0), 126.8 (1), 119.5 (1), 72.7 (1), 51.4 (3); IR (0), −4.3 (3), −4.7 (3); IR (neat): ν 2930 (m), 2857 (m), 1741 (s),
(neat): ν 3424 (m), 2953 (w), 1702 (s), 1437 (m), 1274 (s), 1168 1721 (s), 1116 (s), 832 (s), 776 (s); MS (EI) m/z 275 (19), 259
(s), 983 (m); MS (EI): m/z 277 (91), 245 (100), 219 (49), 159 (30), (21), 243 (100), 213 (9), 185 (11), 143 (82), 111 (29); HRMS (ESI)
131 (52), 115 (58), 87 (77), 55 (36); HRMS (ESI): calcd for calcd for C13H27O4Si (M + H+): 275.1679, found: 275.1653;
C16H19O6 [M + H]+: 307.1182, found: 307.1178; Anal. calcd for Anal. calcd for C13H26O4Si: C, 56.9; H, 9.6; found: C, 57.1;
C16H18O6: C, 62.7; H, 5.9; found: C, 62.7; H, 5.8.
(2E, 9E)-Dimethyl-4,8-dihydroxyundeca-2,9-dienedioate (5p).
H: 9.6.
Methyl 4-oxo-4-phenylbutanoate (6b). Following the general
Following the general procedure, 5p was obtained from 4p procedure, 6b was obtained from 4b (134 mg, 1.0 mmol) via
(156 mg, 1.0 mmol) as a colourless solid (176 mg, 82%), mp method A (160 mg, 83%) or via method B (136 mg, 71%) as a
1
82–84 °C, as a mixture of diastereomers. The general pro- colourless liquid. H NMR (300 MHz, CDCl3) δ 7.98 (ddd, J =
cedure was modified by using increased amounts of catalyst A 7.1, 1.5, 1.0, 2H), 7.56 (tt, J = 7.3, 1.3, 1H), 7.45 (ddd, J = 7.6,
(85 mg, 10 mol%) and methyl acrylate (1.80 mL, 20.0 mmol). 7.3, 1.3, 2H), 3.70 (s, 3H), 3.32 (t, J = 6.6, 2H), 2.76 (t, J = 6.6,
Analytical data were obtained from the mixture. 1H NMR 2H); 13C NMR (75 MHz, CDCl3) δ 197.9 (0), 173.2 (0), 136.6 (0),
(300 MHz, CDCl3) δ 6.92 (dm, J = 15.6, 2H), 6.02 (d, J = 15.6, 133.1 (1), 128.6 (1), 128.0 (1), 51.7 (3), 33.4 (2), 28.0 (2); IR
2H), 4.30 (2H), 3.72 (s, 6H), 2.81 (bs, 2H), 1.75–1.40 (6H); 13C (neat): ν 2952 (w), 1734 (s), 1684 (s), 1218 (s), 1162 (s), 751 (s),
NMR (75 MHz, CDCl3) δ 167.1 (0), 150.4 (1), 119.7 (1), 70.7 (1), 690 (s); MS (EI): m/z 192 (10, [M + H]+), 185 (30), 159 (52), 105
70.6 (1), 51.7 (3), 36.0 (2), 36.0 (2), 20.9 (2), 20.9 (2); IR (neat): ν (100), 77 (40), 73 (55), 45 (80); HRMS (EI): calcd for C11H12O3
3427 (m), 2950 (w), 1706 (s), 1276 (s), 1171 (s), 982 (s); MS (EI): [M]+: 192.0786, found: 192.0783; Anal. calcd for C11H12O3: C,
m/z 255 (16), 223 (54), 191 (54), 162 (43), 140 (100), 111 (76), 83 68.7; H, 6.3, found: C, 68.4; H, 6.8.
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Methyl-4-(4-bromophenyl)-4-oxobutanoate (6c). Following C17H26O4Si [M]+: 322.1600, found: 322.1600; Anal. calcd for
the general procedure, 6c was obtained from 4c (213 mg, C17H26O4Si: C, 63.3; H, 8.1, found: C, 63.3; H, 8.0.
1.0 mmol) via method A (170 mg, 63%) or via method B
Methyl-4-(4-benzyloxyphenyl)-4-oxobutanoate (6g). Follow-
(182 mg, 67%) as a colourless solid, mp 45–47 °C. 1H NMR ing the general procedure, 6g was obtained from 4g (240 mg,
(300 MHz, CDCl3) δ 7.84 (ddd, J = 8.7, 2H), 7.61 (ddd, J = 8.7, 1.0 mmol) via method B (212 mg, 71%) as a colourless solid,
2H), 3.70 (s, 3H), 3.27 (t, J = 6.5, 2H), 2.76 (t, J = 6.6, 2H); 13C mp 70–71 °C. H NMR (300 MHz, CDCl3) δ 7.96 (dm, J = 8.9,
1
NMR (75 MHz, CDCl3) δ 197.0 (0), 173.2 (0), 135.3 (0), 131.9 2H), 7.46–7.30 (5H), 7.01 (dm, J = 8.9, 2H), 5.13 (s, 2H), 3.70 (s,
(1), 129.5 (1), 128.4 (0), 51.8 (3), 33.3 (2), 27.9 (2); IR (neat): ν 3H), 3.27 (t, J = 6.7, 2H), 2.75 (t, J = 6.7, 2H); 13C NMR
2952 (w), 1734 (s), 1686 (s), 1585 (s), 1218 (s), 1167 (s), 1070 (s), (75 MHz, CDCl3) δ 196.4 (0), 173.4 (0), 162.7 (0), 136.2 (0),
816 (s); MS (EI): m/z 272 (13), 270 (15, [M]+), 241 (12), 239 (15), 130.3 (1), 129.9 (0), 128.6 (1), 128.2 (1), 127.4 (1), 114.6 (1), 70.1
185 (90), 183 (100), 157 (20), 155 (22), 76 (17), 75 (15); HRMS (2), 51.7 (3), 33.0 (2), 28.1 (2); IR (neat): ν 3021 (w), 1734 (m),
(EI): calcd for C11H11O3Br [M]+: 269.9892, found: 269.9884; 1676 (m), 1599 (m), 1218 (s), 1165 (s), 746 (s); MS (EI): m/z 299
Anal. calcd for C11H11O3Br: C, 48.7; H, 4.1, found: C, 48.5; H, (13, [M + H]+), 298 (18, [M]+), 267 (6), 211 (5), 115 (15), 91
4.1.
(100); HRMS (EI): calcd for C18H18O4 [M]+: 298.1205, found:
Methyl-4-(4-methoxyphenyl)-4-oxobutanoate (6d). Following 298.1205; Anal. calcd for C18H18O4: C, 72.5; H, 6.1, found: C,
the general procedure, 6d was obtained from 4d (164 mg, 72.0; H, 6.2.
1.0 mmol) via method A (99 mg, 45%) or via method B
Methyl-4-(2-fluorophenyl)-4-oxobutanoate
(6h). Following
(160 mg, 72%) as a colourless solid, mp 43–45 °C. 1H NMR the general procedure, 6h was obtained from 4h (152 mg,
(300 MHz, CDCl3) δ 7.92 (ddd, J = 8.9, 2H), 6.90 (ddd, J = 8.9, 1.0 mmol) via method A (143 mg, 68%) or via method B
2H), 3.82 (s, 3H), 3.66 (s, 3H), 3.23 (t, J = 6.7, 2H), 2.71 (t, J = (159 mg, 76%) as a colourless liquid. 1H NMR (300 MHz,
6.7, 2H); 13C NMR (75 MHz, CDCl3) δ 196.4 (0), 173.3 (0), 163.5 CDCl3) δ 7.87 (td, J = 7.7, 1.9, 1H), 7.50 (m, 1H), 7.21 (ddd, J =
(0), 131.9 (1), 130.1 (1), 129.6 (0), 113.6 (1), 55.3 (3), 51.6 (3), 8.4, 7.9, 1.1, 1H), 7.12 (ddd, J = 11.3, 8.3, 0.9, 1H), 3.69 (s, 3H),
32.8 (2), 28.0 (2); IR (neat): ν 2984 (m), 1738 (s), 1678 (s), 1602 3.30 (td, J = 6.6, 3.3, 2H), 2.73 (t, J = 6.5, 2H); 13C NMR
(s), 1257 (s), 1167 (s), 1030 (s), 833 (m); MS (EI): m/z 223 (5, (75 MHz, CDCl3) δ 196.2 (d, J = 4.1, 0), 173.2 (0), 162.1 (d, J =
[M + H]+), 222 (17, [M]+), 191 (15), 177 (7), 136 (10), 135 (100), 254.8, 0), 134.7 (d, J = 8.8, 1), 130.6 (d, J = 2.5, 1), 125.1 (d, J =
107 (8), 92 (8), 77 (10); HRMS (EI): calcd for C12H14O4 3.2, 0), 124.4 (d, J = 3.4, 1), 116.6 (d, J = 23.8, 1), 51.7 (3), 38.2
[M]+: 222.0892, found: 222.0894; Anal. calcd for C12H14O4: C, (d, J = 8.4, 2), 28.0 (d, J = 2.3, 2); IR (neat): ν 2953 (w), 1734 (s),
64.9; H, 6.4, found: C, 65.0; H, 6.5.
1686 (s), 1609 (s), 1452 (s), 1212 (s), 1166 (s), 1152 (s), 762 (s);
Methyl-4-(3-methoxy-4-(methoxymethoxy)-phenyl)-4-oxobu- MS (EI): m/z 210 (8, [M]+), 179 (8), 135 (30), 123 (100), 95 (15),
tanoate (6e). Following the general procedure, 6e was obtained 75 (11); HRMS (EI): calcd for C11H11O3F [M]+: 210.0692, found:
from 4e (224 mg, 1.0 mmol) via method A (183 mg, 65%) or 210.0700.
via method B (193 mg, 68%) as a colourless solid, mp
74–75 °C. H NMR (600 MHz, CDCl3) δ 7.56 (dd, J = 8.4, 2.0, procedure, 6i was obtained from 4i (148 mg, 1.0 mmol) via
1H), 7.53 (d, J = 2.0, 1H), 7.16 (d, J = 8.4, 1H), 5.28 (s, 2H), method A (136 mg, 66%) or via method B (132 mg, 64%) as a
Methyl-4-oxo-5-phenylpentanoate (6i). Following the general
1
1
3.91 (s, 3H), 3.68 (s, 3H), 3.49 (s, 3H), 3.27 (t, J = 6.6, 2H), colourless liquid. H NMR (300 MHz, CDCl3) δ 7.37–7.17 (5H),
2.73 (t, J = 6.6, 2H); 13C NMR (150 MHz, CDCl3) δ 196.7, 3.74 (s, 2H), 3.65 (s, 3H), 2.76 (t, J = 6.6, 2H), 2.56 (t, J = 6.6,
173.4, 150.8, 149.4, 130.8, 122.3, 114.3, 110.5, 94.9, 56.4, 2H); 13C NMR (75 MHz, CDCl3) δ 206.2 (0), 173.0 (0), 134.0 (0),
55.9, 51.8, 32.9, 28.1; IR (neat): ν 2953 (w), 1735 (m), 1676 (m), 129.4 (1), 128.7 (1), 127.0 (1), 51.6 (3), 50.0 (2), 36.4 (2), 27.8
1511 (m), 1417 (m), 1262 (s), 1155 (s), 1138 (s), 1080 (s), (2); IR (neat): ν 2952 (w), 1716 (s), 1357 (m), 1200 (s), 1174 (s),
980 (s); MS (EI): m/z 283 (32, [M + H]+), 282 (57, [M]+), 251 (45), 700 (s); MS (EI): m/z 206 (15, [M]+), 175 (20), 115 (100), 91 (63),
181 (38), 165 (30), 151 (10), 137 (18), 115 (23), 45 (100); 55 (26); HRMS (EI): calcd for C12H14O3 [M]+: 206.0943, found:
HRMS (EI): calcd for C14H18O6 [M]+: 282.1103, found: 206.0930; Anal. calcd for C12H14O3: C, 69.9; H, 6.8, found: C,
282.1103; Anal. calcd for C14H18O6: C, 59.6; H, 6.4, found: 69.4; H, 7.0.
C, 59.5; H, 6.7.
Methyl-4-oxo-6-phenylhexanoate (6j). Following the general
Methyl-4-(4-(tert-butyldimethylsilyloxy)phenyl)-4-oxo- procedure, 6j was obtained from 4j (162 mg, 1.0 mmol) via
butanoate (6f). Following the general procedure, 6f was method A (175 mg, 80%) or via method B (160 mg, 73%) as a
1
obtained from 4f (264 mg, 1.0 mmol) via method A (84 mg, colourless liquid. H NMR (300 MHz, CDCl3) δ 7.35–7.15 (5H),
27%) or via method B (225 mg, 70%) as a colourless liquid. 1H 3.67 (s, 3H), 2.92 (td, J = 6.9, 2.4, 2H), 2.79 (td, J = 7.1, 2.3, 2H),
NMR (300 MHz, CDCl3) δ 7.90 (ddd, J = 8.7, 2H), 6.87 (ddd, J = 2.71 (t, J = 6.6, 2H), 2.59 (t, J = 6.6, 2H); 13C NMR (75 MHz,
8.7, 2H), 3.69 (s, 3H), 3.26 (t, J = 6.7, 2H), 2.74 (t, J = 6.7, 2H), CDCl3) δ 207.8 (0), 173.1 (0), 140.9 (0), 128.4 (1), 128.2 (1),
0.97 (s, 9H), 0.22 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 196.6 (0), 126.1 (1), 51.7 (3), 44.2 (2), 37.2 (2), 29.6 (2), 27.6 (2); IR (neat):
173.4 (0), 160.4 (0), 130.2 (1), 119.9 (1), 51.7 (3), 33.0 (2), 28.1 ν 2951 (w), 1735 (s), 1713 (s), 1362 (m), 1204 (s), 1174 (s), 699
(2), 25.5 (3), 18.2 (0), −4.4 (3); IR (neat): ν 2932 (w), 1739 (s), (s); MS (EI): m/z 221 (18, [M + H]+), 220 (55, [M]+), 188 (60), 105
1680 (s), 1597 (s), 1255 (s), 1161 (s), 906 (s), 832 (s), 781 (s); MS (75), 91 (100), 55 (18); HRMS (EI): calcd for C13H16O3 [M]+:
(EI): m/z 322 (38, [M]+), 291 (31), 265 (100), 235 (50), 209 (49), 220.1099, found: 220.1100; Anal. calcd for C13H16O3: C, 70.9;
179 (30), 135 (25), 89 (50), 55 (20); HRMS (EI): calcd for H, 7.3, found: C, 70.6; H, 7.6.
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Methyl-6-methyl-4-oxoheptanoate
(6k). Following
the The general procedure was modified by using increased
general procedure, 6k was obtained from 4k (114 mg, amounts of catalyst A (85 mg, 10 mol%) and methyl acrylate
1.0 mmol) via method A (76 mg, 44%) or via method B (1.80 mL, 20.0 mmol). 1H NMR (300 MHz, CDCl3) δ 8.06
(105 mg, 61%) as a colourless liquid. 1H NMR (300 MHz, (s, 4H), 3.71 (s, 6H), 3.33 (t, J = 6.5, 4H), 2.78 (t, J = 6.5, 4H);
CDCl3) δ 3.62 (s, 3H), 2.66 (t, J = 6.5, 2H), 2.53 (t, J = 6.5, 2H), 13C NMR (75 MHz, CDCl3) δ 197.5 (0), 173.1 (0), 139.8 (0),
2.28 (d, J = 6.8, 2H), 2.12 (tq, J = 6.6, 1.2, 1H), 0.88 (d, J = 1.2, 128.3 (1), 51.9 (3), 33.8 (2), 27.9 (2); IR (neat): ν 2952 (w),
3H), 0.86 (d, J = 1.2, 3H); 13C NMR (75 MHz, CDCl3) δ 208.5 (0), 1722 (s), 1682 (s), 1213 (s), 1162 (s), 754 (s); MS (EI): m/z
173.1 (0), 51.6 (3), 51.6 (2), 37.5 (2), 27.6 (2), 24.6 (1), 22.4 (3); 306 (7, [M]+), 275 (20), 219 (100), 159 (17), 104 (15), 55 (6);
IR (neat): ν 2956 (m), 1738 (s), 1712 (s), 1363 (s), 1206 (s), 1167 HRMS (EI): calcd for C16H18O6 [M]+: 306.1103, found:
(s); MS (EI): m/z 134 (24), 115 (26), 98 (38), 85 (42), 71 (43), 57 306.1098; Anal. calcd for C16H18O6: C, 62.7; H, 5.9, found:
(100), 43 (63); HRMS (ESI): calcd for C9H17O3 [M + H]+: C, 62.7; H, 5.9.
173.1178, found: 173.1194; Anal. calcd for C9H16O3: C, 62.8; H,
9.4, found: C, 62.6; H, 9.6.
Dimethyl-4,8-dioxoundecandioate
general procedure, 6p was obtained from 4p (156 mg,
(6p). Following
the
(R)-Methyl-4-oxo-4-(1,4-dioxaspiro[4.5]decan-2-yl)-butanoate 1.0 mmol) via method B (116 mg, 43%) as a colourless liquid.
(6l). Following the general procedure, 6l was obtained from 4l The general procedure was modified by using increased
(198 mg, 1.0 mmol) via method A (105 mg, 41%) or via amounts of catalyst A (85 mg, 10 mol%) and methyl acrylate
method B (171 mg, 67%) as a colourless liquid. [α]2D4 = +13.9 (c (1.80 mL, 20.0 mmol). 1H NMR (300 MHz, CDCl3) δ 3.65 (s,
1
0.37, CH2Cl2); H NMR (300 MHz, CDCl3) δ 4.45 (dd, J = 7.7, 6H), 2.68 (t, J = 6.8, 4H), 2.56 (t, J = 6.6, 4H), 2.48 (t, J = 7.1,
5.7, 1H), 4.18 (dd, J = 8.7, 7.7, 1H), 4.01 (dd, J = 8.7, 5.7, 1H), 4H), 1.86 (quint, J = 7.0, 2H); 13C NMR (75 MHz, CDCl3) δ
3.66 (s, 3H), 3.04–2.81 (2H), 2.64–2.55 (2H), 1.76–1.50 (8H), 208.3 (0), 173.1 (0), 51.7 (3), 41.4 (2), 37.0 (2), 27.7 (2), 17.1 (2);
1.50–1.34 (2H); 13C NMR (75 MHz, CDCl3) δ 209.3 (0), 173.0 IR (neat): ν 2953 (w), 1733 (s), 1712 (s), 1362 (m), 1198 (s), 1171
(0), 111.7 (0), 79.9 (1), 66.1 (2), 51.7 (3), 35.6 (2), 34.5 (2), 33.4 (s); MS (EI): m/z 273 (10, [M + H]+), 255 (41), 223 (41), 167 (42),
(2), 27.1 (2), 25.0 (2), 23.9 (2), 23.7 (2); IR (neat): ν 2931 (w), 153 (72), 125 (54), 115 (100), 97 (46), 55 (67); HRMS (ESI): calcd
1253 (m), 1090 (m), 832 (s), 775 (s); MS (EI): m/z 256 (15, [M]+), for C13H20O6Na [M + Na]+: 295.1158, found: 295.1153; Anal.
213 (55), 141 (100), 115 (15), 83 (17), 55 (32); HRMS (EI): calcd calcd for C13H20O6: C, 57.3; H, 7.4, found: C, 56.8; H, 7.7.
for C13H20O5 [M]+: 256.1311, found: 256.1309; Anal. calcd for
Synthesis of protected L-amicetose
C13H20O5: C, 60.9; H, 7.9, found: C, 60.9; H, 8.0.
Methyl-4-oxononanoate (6m). Following the general pro-
(R)-5-((S)-1-(tert-Butyldimethylsilyloxy)ethyl)-dihydro-furan-
cedure, 6m was obtained from 4m (128 mg, 1.0 mmol) via 2(3H)-one (7). To a solution of 5a (300 mg, 1.1 mmol) in dry
method A (79 mg, 42%) or via method B (122 mg, 65%) as a and degassed methanol (20 mL) was added Pd/C (30 mg, 10 wt%).
colourless liquid. 1H NMR (300 MHz, CDCl3) δ 3.63 (s, 3H), The suspension was stirred for 12 h in an atmosphere of
2.68 (t, J = 6.3, 2H), 2.54 (t, J = 6.3, 2H), 2.40 (t, J = 7.5, 2H), hydrogen (1 bar). The mixture was filtered through a pad of
1.62–1.47 (2H), 1.35–1.15 (4H), 0.85 (t, J = 6.9, 3H); 13C NMR Celite®, and the pad was washed three times with MTBE.
(75 MHz, CDCl3) δ 208.9 (0), 173.2 (0), 51.6 (3), 42.6 (2), 31.3 Evaporation of the solvents furnished 7 (235 mg, 88%) as a col-
(2), 27.6 (2), 23.4 (2), 22.3 (2), 13.8 (3); IR (neat): ν 2930 (m), ourless liquid. [α]2D6 = +13.3 (c 0.55, CH2Cl2); 1H NMR
1738 (s), 1715 (s), 1361 (m), 1198 (m), 1166 (m); MS (EI): m/z (300 MHz, CDCl3) δ 4.33 (ddd, J = 8.1, 5.5, 3.2, 1H), 4.06 (qd, J
155 (23), 130 (39), 115 (42), 98 (95), 71 (70), 57 (89), 43 (100); = 6.4, 3.2, 1H), 2.55 (ddd, J = 17.7, 10.2, 7.0, 1H), 2.44 (ddd, J =
HRMS (ESI): calcd for C10H19O3 [M + H]+: 187.1334, found: 17.7, 10.0, 6.6, 1H), 2.27 (dddd, J = 12.6, 10.1, 6.7, 5.6, 1H),
187.1334; Anal. calcd for C10H18O3: C, 64.5; H, 9.7, found: C, 2.22 (m, 1H), 1.13 (d, J = 6.5, 3H), 0.87 (s, 9H), 0.07 (s, 3H),
64.2; H, 9.8.
0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.4 (0), 83.5 (1),
Methyl-4-oxoheptanoate (6n). Following the general pro- 68.8 (1), 28.5 (2), 25.8 (3), 23.6 (0), 20.9 (2), 19.5 (3), −4.8 (3),
cedure, 6n was obtained from 4n (100 mg, 1.0 mmol) via −4.9 (3); IR (neat): ν 2930 (m), 2857 (m), 1776 (s), 1082 (m),
method A (89 mg, 56%) or via method B (110 mg, 70%) as a 834 (s), 776 (s); MS (EI): m/z 245 (35, [M + H]+), 242 (69), 227
colourless liquid. 1H NMR (300 MHz, CDCl3) δ 3.63 (s, 3H), (37), 185 (17), 113 (100); HRMS (ESI): calcd for C12H25O3Si [M
2.68 (t, J = 6.3, 2H), 2.54 (t, J = 6.3, 2H), 2.40 (t, J = 7.4, 2H), + H]+: 245.1573, found: 245.1593; Anal. calcd for C12H24O3Si:
1.58 (tq, J = 7.4, 7.4, 2H), 0.88 (t, J = 7.4, 3H); 13C NMR C, 59.0; H, 9.9, found: C, 58.9; H, 10.2.
(75 MHz, CDCl3) δ 208.8 (0), 173.2 (0), 51.6 (3), 44.6 (2), 36.9
(4R, 5S, E)-Methyl-5-(tert-butyldimethylsilyloxy)-4-(methoxy-
(2), 27.6 (2), 17.2 (2), 13.6 (3); IR (neat): ν 2960 (w), 1737 (s), methoxy)-hex-2-enoate (8a). To a solution of 5a (300 mg,
1713 (s), 1362 (m), 1205 (s), 1165 (s); MS (EI): m/z 148 (23), 134 1.1 mmol) in dry dichloromethane (20 mL) were added iPr2EtN
(33), 115 (55), 98 (48), 71 (88), 57 (77), 43 (100); HRMS (ESI): (0.8 mL, 4.4 mmol) and MOM-bromide (0.3 mL, 3.2 mmol,
calcd for C8H15O3 [M + H]+: 159.1021, found: 159.1029; Anal. 90%). The solution was heated to reflux for 12 h, cooled to
calcd for C8H14O3: C, 60.7; H, 8.9, found: C, 60.5; H, 9.2.
ambient temperature and hydrolyzed. The aqueous layer was
Dimethyl-4,4′-(1,4-phenylen)bis(4-oxobutanoate) (6o). Fol- separated and extracted twice with MTBE. The combined
lowing the general procedure, 6o was obtained from 4o organic layers were dried with MgSO4, filtered and all volatiles
(190 mg, 1.0 mmol) via method A (167 mg, 55%) or via were removed in vacuo. After purification by column chromato-
method B (114 mg, 37%) as a colourless solid, mp 116–117 °C. graphy on silica, using hexane–MTBE mixtures as the eluent,
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8a was obtained as a colourless liquid (280 mg, 81%). [α]D22 in vacuo. After purification by column chromatography on
−38.0 (c 0.50, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 6.86 (dd, J silica, using hexane–MTBE as an eluent, 8b was obtained as a
= 15.8, 6.3, 1H), 6.01 (dd, J = 15.9, 1.3, 1H), 4.63 (s, 2H), 4.04 colourless liquid (1.72 g, 93%). [α]D24 = −39.4 (c 0.73, CH2Cl2);
(ddd, J = 6.3, 5.0, 1.3, 1H), 3.83 (qd, J = 6.2, 5.1, 1H), 3.74 (s, 1H NMR (300 MHz, CDCl3) δ 7.38–7.27 (5H), 6.90 (dd, J = 15.8,
3H), 3.37 (s, 3H), 1.17 (d, J = 6.2, 3H), 0.87 (s, 9H), 0.05 (s, 3H), 6.5, 1H), 6.04 (dd, J = 15.8, 1.3, 1H), 4.79 (d, J = 6.9, 1H), 4.75
0.03 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.8 (0), 146.3 (1), (d, J = 6.9, 1H), 4.67 (d, J = 11.8, 1H), 4.58 (d, J = 11.8, 1H), 4.12
123.3 (1), 95.5 (2), 80.3 (1), 71.1 (1), 56.1 (3), 51.8 (3), 26.1 (3), (ddd, J = 6.3, 5.0, 1.2, 1H), 3.85 (qd, J = 6.2, 5.1, 1H), 3.75 (s,
18.4 (0), −4.3 (3), −4.5 (3); IR (neat): ν 2953 (w), 2932 (w), 1728 3H), 1.19 (d, J = 6.2, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H);
(s), 1102 (s), 1032 (s), 832 (s), 775 (s); MS (EI): m/z 159 (34), 89 13C NMR (75 MHz, CDCl3) δ 166.4 (0), 145.9 (1), 137.6 (0),
(29), 73 (74), 45 (100); HRMS (ESI): calcd for C15H31O5Si [M + 128.4 (1), 127.8 (1), 127.7 (1), 123.0 (1), 93.0 (2), 80.0 (1), 70.6
H]+: 319.1941, found: 319.1938; Anal. calcd for C15H30O5Si: C, (1), 69.7 (2), 51.5 (3), 25.7 (3), 19.9 (3), 18.0 (0), −4.6 (3), −4.8
56.6; H, 9.5, found: C, 56.3; H, 9.6.
(3); IR (neat): ν 2930 (w), 1724 (m), 1034 (m), 753 (s); MS (EI):
(4R, 5S)-Methyl-5-(tert-butyldimethylsilyloxy)-4-(methoxy- m/z 307 (8), 257 (19), 159 (48), 91 (100), 73 (31); HRMS (ESI):
methoxy)-hex-2-anoate (9a)
Hydrogenation catalyzed by Pd/C. To
calcd for C21H34O5SiNa [M + Na]+: 417.2073, found: 417.2083;
Anal. calcd for C21H34O5Si: C, 63.9; H, 8.7, found: C, 63.8;
H, 8.9.
(4R, 5S)-Methyl-4-(benzyloxymethoxy)-5-(tert-butyldimethyl-
silyloxy)-hex-2-anoate (9b). Following the procedure stated
above for 9a, the title compound 9b was obtained from 8b
(395 mg, 1.0 mmol) as a colourless liquid (375 mg, 95%). [α]2D4
= +36.9 (c 0.52, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ
a solution of 8a
(150 mg, 0.47 mmol) in dry and degassed methanol (10 mL)
was added Pd/C (15 mg, 10 wt%). The suspension was stirred
for 12 h in an atmosphere of hydrogen (1 bar). The mixture
was filtered through a pad of Celite®, and the pad was washed
three times with MTBE. Evaporation of the solvents gave 9a
(151 mg, quantitative) as a colourless liquid.
Reduction with modified Stryker’s reagent. Cu(OAc)2·H2O 7.39–7.27 (5H), 4.88 (d, J = 6.8, 1H), 4.80 (d, J = 6.8, 1H), 4.70
(10 mg, 5 mol%) and BDP (4.5 mg, 10 mol%) were dissolved in (d, J = 11.9, 1H), 4.59 (d, J = 11.9, 1H), 3.85 (qd, J = 6.3, 3.7,
dry and degassed toluene (2.0 mL) and tert-butanol (1.5 mL). 1H), 3.65 (s, 3H), 3.54 (dt, J = 3.9, 3.9, 1H), 2.59–2.34 (2H),
The mixture was stirred for 10 min at ambient temperature, 1.95–1.75 (2H), 1.15 (d, J = 6.3, 3H), 0.89 (s, 9H), 0.06 (s, 6H);
and PMHS (134 μL, 2.0 mmol) was added. Stirring was contin- 13C NMR (75 MHz, CDCl3) δ 174.1 (0), 137.9 (0), 128.4 (1),
ued for 0.5 h, after which time the colour changed from blue 127.7 (1), 127.6 (1), 94.4 (2), 80.9 (1), 70.2 (1), 69.8 (2), 51.4 (3),
to green. A solution of 8a (318 mg, 1.0 mmol) in toluene 30.2 (2), 25.8 (3), 25.7 (2), 19.1 (3), 18.0 (0), −4.5 (3), −4.9 (3);
(1.0 mL) was added and the solution was stirred at ambient IR (neat): ν 2954 (w), 2858 (w), 1740 (s), 1255 (s), 1104 (s), 1037
temperature for 12 h. The reaction mixture was diluted with (s), 834 (s); MS (EI): m/z 309 (12), 201 (22), 159 (27), 91 (100),
MTBE, and washed with a saturated aqueous NaHCO3 solu- 73 (20); HRMS (ESI): calcd for C21H37O5Si [M + H]+: 397.2410,
tion, followed by aqueous HCl (1 M). The aqueous layer was found: 397.2415; Anal. calcd for C21H36O5Si: C, 63.6; H, 9.2,
extracted twice with MTBE, and the combined organic layers found: C, 63.1; H, 9.3.
were dried with MgSO4. Purification by column chromato-
(5R, 6S)-5-(Benzyloxymethoxy)-6-methyl-tetrahydropyran-2-
graphy on silica, using hexane–MTBE as an eluent, furnished one (10). To a solution of 9b (250 mg, 0.63 mmol) in THF
9a (266 mg, 96%) as a colourless liquid. [α]D22 = +22.1 (c 0.66, (10 mL) was added TBAF (248 mg, 0.95 mmol). The reaction
CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 4.75 (d, J = 6.7, 1H), 4.62 mixture was stirred at ambient temperature for 12 h. Then
(d, J = 6.7, 1H), 3.80 (qd, J = 6.3, 3.7, 1H), 3.66 (s, 3H), 3.44 (dt, aqueous NaOH (5%, 10 mL) was added and the solution was
J = 3.9, 3.9, 1H), 3.38 (s, 3H), 2.55–2.32 (2H), 1.90–1.67 (2H), stirred for 2 h at 40 °C. After neutralization with aqueous HCl
1.12 (d, J = 6.3, 3H), 0.87 (s, 9H), 0.04 (s, 6H); 13C NMR (1 M, 10 mL) the aqueous layer was extracted several times
(75 MHz, CDCl3) δ 174.1 (0), 96.5 (2), 80.9 (1), 70.4 (1), 56.1 (3), with ethyl acetate and the organic layer was dried with MgSO4.
55.8 (3), 51.8 (3), 30.3 (2), 25.9 (2), 25.8 (3), 19.1 (3), 18.0 (0), Purification by column chromatography on silica, using
−4.5 (3), −4.9 (3); IR (neat): ν 2953 (w), 2932 (w), 1740 (s), 1253 hexane–ethyl acetate as an eluent, furnished 10 (107 mg, 68%)
1
(s), 1100 (s), 1032 (s), 832 (s); MS (EI): m/z 289 (7), 233 (40), 201 as a colourless liquid. [α]D24 = −64.1 (c 0.49, CH2Cl2); H NMR
(100), 187 (19), 159 (84), 113 (27), 89 (32), 73 (53), 45 (41); (300 MHz, CDCl3) δ 7.39–7.27 (5H), 4.85 (d, J = 7.2, 1H), 4.81
HRMS (ESI): calcd for C15H33O5Si [M + H]+: 321.2097, found: (d, J = 7.2, 1H), 4.64 (d, J = 11.9, 1H), 4.60 (d, J = 11.9, 1H), 4.45
321.2124; Anal. calcd for C15H32O5Si: C, 56.2; H, 10.1, found: (qd, J = 6.3, 6.2, 1H), 3.72 (ddm, J = 5.6, 4.4, 1H), 2.70 (ddd, J =
C, 56.1; H, 9.9.
17.6, 9.5, 7.2, 1H), 2.48 (ddd, J = 17.6, 6.4, 5.3, 1H), 2.10 (dddd,
(4R, 5S, E)-Methyl-4-(benzyloxymethoxy)-5-(tert-butyldi- J = 13.9, 10.7, 6.5, 4.3, 1H), 2.01–1.87 (1H), 1.38 (d, J = 6.5, 3H);
methylsilyloxy)-hex-2-enoate (8b). To a solution of 5a (1.30 g, 13C NMR (75 MHz, CDCl3) δ 170.5 (0), 137.3 (0), 128.4 (1),
4.70 mmol) in dry dichloromethane (20 mL) were added 127.8 (1), 127.7 (1), 93.2 (2), 78.3 (1), 72.9 (1), 70.0 (2), 26.4 (2),
iPr2EtN (1.3 mL, 7.05 mmol) and BOM-chloride (0.8 mL, 23.2 (2), 19.3 (3); IR (neat): ν 2941 (w), 1731 (s), 1030 (s), 741
6.10 mmol), and the solution was heated to reflux for 12 h. (m); MS (EI): m/z 114 (18), 107 (15), 91 (100), 85 (65), 65 (14),
The reaction mixture was hydrolyzed and the aqueous layer 43 (20); HRMS (ESI): calcd for C14H18O4Na [M + Na]+:
was extracted twice with MTBE. The combined organic layers 273.1103, found: 273.1100; Anal. calcd for C14H18O4: C, 67.2;
were dried with MgSO4, filtered and all volatiles were removed H, 7.3, found: C, 67.1; H, 7.2.
4204 | Org. Biomol. Chem., 2013, 11, 4194–4206
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(5R, 6S)-5-(Benzyloxymethoxy)-6-methyl-tetrahydro-2H- 11 M. Niggemann, A. Jelonek, N. Biber, M. Wuchrer and
pyran-2-ol (11). To a solution of 10 (66 mg, 0.26 mmol) in dry B. Plietker, J. Org. Chem., 2008, 73, 7028–7036.
CH2Cl2 (1.3 mL) was added DIBAL-H (0.77 mL, 1.02 M solution 12 J. A. Bodkin, G. B. Bacskay and M. D. McLeod, Org. Biomol.
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was stirred for 0.25 h and then quenched at this temperature 13 P. A. Wade, S. G. D’Ambrosio, J. A. Rao, S. Shah-Patel,
by the addition of MeOH (1.3 mL). A saturated aqueous solu-
tion of Na+/K+-tartrate (2 mL) was added at ambient tempera-
D. T. Cole, J. K. Murray and P. J. Carroll, J. Org. Chem.,
1997, 62, 3671–3677.
ture and the mixture was repeatedly extracted with MTBE. The 14 F. E. McDonald and H. Y. H. Zhu, J. Am. Chem. Soc., 1998,
combined organic layers were dried with MgSO4 and concen- 120, 4246–4247.
trated under reduced pressure to furnish 11 (57 mg, 86%, a 15 F. E. McDonald, K. S. Reddy and Y. Díaz, J. Am. Chem. Soc.,
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liquid. [α]2D2 = −59.0 (c 0.53, CH2Cl2); 1H NMR (300 MHz, 16 A. Kirschning, U. Hary and M. Ries, Tetrahedron, 1995, 51,
CDCl3) δ 7.40–7.27 (5H), 4.21 (dm, J = 2.6, 0.5H), 4.89 (d, J = 2297–2304.
7.1, 0.5H), 4.85 (d, J = 7.0, 0.5H), 4.82–4.76 (0.5H), 4.77 (d, J = 17 A. Kirschning, M. Jesberger and K.-U. Schöning, Synthesis,
3.3, 0.5H), 4.74 (d, J = 3.2, 0.5H), 4.63 (s, 1H), 4.62 (s, 1H), 3.98 2001, 507–540.
(qd, J = 6.3, 2.9, 0.5H), 3.48 (qd, J = 6.1, 2.9, 0.5H), 3.38–3.23 18 M. W. Peczuh and N. L. Snyder, Tetrahedron Lett., 2003, 44,
(1H), 2.25–2.16 (0.5H), 2.03–1.64 (2.5H), 1.60–1.45 (1H), 1.32 4057–4061.
(d, J = 6.1, 1.5H), 1.26 (d, J = 6.2, 1.5H); 13C NMR (75 MHz, 19 S. Castro, M. Duff, N. L. Snyder, M. Morton, C. V. Kumar
CDCl3) δ 137.7 (0), 137.6 (0), 128.4 (1), 128.4 (1), 127.8 (1), and M. W. Peczuh, Org. Biomol. Chem., 2005, 3, 3869–3872.
127.8 (1), 127.7 (1), 127.7 (1), 95.7 (1), 93.3 (2), 93.0 (2), 90.7 20 S. Castro and M. W. Peczuh, J. Org. Chem., 2005, 70,
(1), 77.2 (1), 76.5 (1), 74.7 (1), 69.6 (2), 69.5 (2), 67.9 (1), 31.8 3312–3315.
(2), 29.3 (2), 28.1 (2), 23.9 (2), 18.3 (3), 18.2 (3); IR (neat): ν 21 J. Saha and M. W. Peczuh, Chem.–Eur. J., 2011, 17,
3405 (m), 2936 (m), 1453 (w), 1032 (s), 989 (s); MS (EI): m/z 235 7357–7365.
(7), 190 (5), 129 (12), 91 (100), 87 (41), 69 (13); HRMS (ESI): 22 B. Schmidt, Eur. J. Org. Chem., 2004, 1865–1880.
calcd for C14H20O4Na [M + Na]+: 275.1259, found: 275.1269.
23 B. Schmidt, Pure Appl. Chem., 2006, 78, 469–476.
24 B. Schmidt, J. Mol. Catal. A: Chem., 2006, 254, 53–57.
25 B. Schmidt and A. Biernat, Org. Lett., 2008, 10, 105–108.
26 B. Schmidt and A. Biernat, Chem.–Eur. J., 2008, 14,
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27 B. Schmidt and A. Biernat, Eur. J. Org. Chem., 2008,
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28 D. E. Fogg and E. N. dos Santos, Coord. Chem. Rev., 2004,
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Acknowledgements
This work was generously supported by the Deutsche For-
schungsgemeinschaft (DFG grant Schm 1095/6-2). We thank
Evonik Oxeno for generous donation of solvents.
29 A. E. Sutton, B. A. Seigal, D. F. Finnegan and M. L.
Snapper, J. Am. Chem. Soc., 2002, 124, 13390–13391.
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