Stereoselective Synthesis of Conjugated Polyenes Based on Tethered Olefin Metathesis and Carbonyl Olefination: Application to the Total Synthesis of (+)-Bretonin B

Article abstract of DOI:10.1021/acs.joc.0c00446

The combination of a highly stereoselective tethered olefin metathesis reaction and a Julia-Kocienski olefination is presented as a strategy for the synthesis of conjugated polyenes with at least one Z-configured Ca?C bond. The strategy is exemplified by the synthesis of the marine natural product (+)-bretonin B.

Full text of DOI:10.1021/acs.joc.0c00446

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Note
Stereoselective Synthesis of Conjugated Polyenes Based
on Tethered Olefin Metathesis and Carbonyl Olefination:
Application to the Total Synthesis of (+)-Bretonin B
Kajsa Lood, and Bernd Schmidt
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00446 • Publication Date (Web): 12 Mar 2020
Downloaded from pubs.acs.org on March 12, 2020
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The Journal of Organic Chemistry
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Stereoselective Synthesis of Conjugated Polyenes Based on
Tethered Olefin Metathesis and Carbonyl Olefination: Application to
the Total Synthesis of (+)-Bretonin B
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Kajsa Lood and Bernd Schmidt*
Universität Potsdam, Institut für Chemie, Karl-Liebknecht-Strasse 24-25, D-14476 Potsdam-Golm, Germany
Supporting Information
OTBDPS
OTBDPS
O
SO2
O
Ph
O
Julia-Kocienski
olefination
N
N
N
N
OH
O
O
O
(+)-Bretonin B
OH
tethered RCM
O
O
ABSTRACT: The combination of a highly stereoselective tethered olefin metathesis reaction and a Julia-Kocienski olefination is
presented as a strategy for the synthesis of conjugated polyenes with at least one Z-configured C-C-double bond. The strategy is
exemplified for the synthesis of the marine natural product (+)-bretonin B.
The stereoselective construction of polyenes is
a
diastereoselective synthesis of functionalized conjugated
dienes,12 including -halodienes.13 Olefin cross metathesis
(CM) has also been investigated as a method for the synthesis
of conjugated polyenes, e. g. in the total synthesis of
violaxanthin,14 -carotene6 or dermostatin A.15,16 For the
latter example, a moderate E/Z-selectivity of 4 : 1 was
reported for the cross metathesis step, which might explain
why this otherwise attractive and straightforward method has
so far found only limited application in polyene synthesis.
challenging task in natural product synthesis1,2 as products
and intermediates are often prone to decomposition through
photochemical3,4 or oxidative pathways.5-7 In those cases
where one or more double bonds are Z-configured,
isomerization to the all-E-isomers, which are in general more
stable, arises as an additional problem.8 The most commonly
used methods for the total synthesis of polyene natural
products are Pd-catalyzed coupling and cross coupling
reactions.2 These methods have been successfully applied in
several cases, e. g. very recently for the synthesis of
xanthomonadin analogues,7 in the construction of the Z,Z,E-
configured triene moiety in fostriecin9 and in an iterative
approach to a truncated amphotericin B fragment.10 The
stereoselective synthesis of the required coupling partners, -
iodo- or bromodienes and vinyl metal compounds, can be a
drawback because these often start from unstable haloenals,11
which are subjected to carbonyl olefination reactions to
furnish iodo- or bromodienes. One possibility to circumvent
these difficulties has been devised by Maulide and
coworkers, who developed the stereospecific electrocyclic
ring opening of cyclobutenes into a method for the
Herein, we report an alternative approach to the
stereoselective synthesis of conjugated polyenes for the
example of E,Z,E-configured triene pattern 5. As outlined
above, polyenes with at least one Z-configured double bond
have a strong tendency to isomerize to the all-E-configured
isomers for thermodynamic reasons, which makes the
methodology development more challenging. Over the past
few years we investigated a novel type of tethered olefin
metathesis reaction that makes Z,E-configured dienoates 3
accessible in high yields and diastereoselectivities from
allylic butenoates 1.17,18 In the olefin metathesis field, the
tether approach19,20 is mainly used to address stereoselectivity
and reactivity issues often associated with CM reactions by
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temporarily connecting the reactants through a labile bond.
Page 2 of 10
commercially available enantiopure acetonide 7, which was
reacted with mesylate 827 to furnish benzyl ether 9.
1
2
3
4
5
6
7
8
The metathesis step then becomes a ring closing metathesis
(RCM) reaction. Traceless removal of the tether after the
RCM reaction, e. g. by hydrolysis, furnishes acyclic Z-
alkenes that can not be obtained by standard CM
reactions.21,22 In our tethered RCM variant cleavage of the
tether is accomplished by a base-induced elimination of RCM
products 2 that generates an additional E-configured double
bond conjugated to a Z-double bond. A further difference to
other tethered RCM reactions is that the tether is retained in
the product as a valuable carboxylate group. In our approach
to E,Z,E-configured trienes 5 we envisaged a conversion of
this functional group to aldehydes 4, which could
subsequently undergo an E-selective olefination.
Advantageously, this strategy allows the construction of
E,Z,E-trienes from both directions which increases the
number of available synthetic routes (Scheme 1).
Scheme 2. Acetonide protected bretonin B precursor.
NaH, DMF
8
BnO(CH2)4OSO2CH3 ( )
O
O
O
O
HO
RO
O
7
9
R = Bn: (75%)
Pd(OH)2/C
H2 (1 bar)
9
10
EtOAc, 20 °C
R = H:
MgBr
(quant.)
10
11
12
13
14
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17
18
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DMP
pyridine
CH2Cl2
O
O
THF, 0 °C
to 20 °C
O
O
O
HO
O
O
12
(74%)
11
(76%)
3-butenoic acid
DCC, DMAP (cat.)
Et2O
Scheme 1. E,Z,E-Configured trienes by tethered RCM.
A
(3.0 mol %), CH2Cl2, 40 ° C, 0.5 h
O
then NaHMDS (1.2 equiv.), 0 °C - 20 °C;
then add Et3OBF4 (1.5 equiv.), 20 °C
stereoselective
carbonyl olefination
O
O
O
O
R1
R2
R1
R2
13
(69%)
O
O
O
O
EtO2C
O
4a
5
4b
MesN
Cl
NMes
Cl
14
(93%)
tethered RCM-
elimination
Ru
1) DIBAl-H, CH2Cl2, 0 °C
2) DMP, CH2Cl2
R1/2
Ph
R2
R1
PCy3
O
O
CO2Et
EtO2C
A
O
O
O
O
3a
2a b
/
3b
15
(73%)
 (13C) 135.6, 134.4, 128.1,
127.5, 126.4, 126.0 ppm
R1/2
KHMDS, THF
- 78 °C
O
OH
O
O
O
O
O
1a b
/
O
O2S
Ph
O
(76%)
N
17
16
N
N
6
N
(+)-Bretonin B ( )
 (13C) 135.6, 134.8, 134.1, 133.1,
131.5, 131.3, 130.6, 130.6, 128.3,
127.4, 126.5, 126.0 ppm
OH
p-toluenesulfonic
acid (10 mol %),
methanol, 20 °C, 3 h
As a showcase example for the application of this strategy
we chose the marine natural product (+)-bretonin B (6) as a
target molecule. Bretonins and isobretonins23 are glyceryl
mono ethers with a dodecatrienyl substituent at one primary
position and a para-hydroxybenzoate at the secondary
position (bretonins) or at the other primary position
(isobretonins). They were isolated from a demosponge found
at the coast of Brittany and structurally characterized.24
Bretonin A and isobretonin A are more abundant and possess
a (4E,6E,8E)-dodecatrienyl substituent, whereas bretonin B
is 6Z-configured. Two syntheses of bretonin B have been
published previously. Both rely on the construction of the C6-
C7-double bond by olefination methods: in the first synthesis
an unselective Wittig-olefination was used that furnished the
(4E,6E,8E)- and (4E,6Z,8E)-isomers in a ca. 1 : 1 ratio.25
More recently, Bach and coworkers used a Peterson
elimination of a stereodefined -silyl alcohol for the
stereoselective construction of the (4E,6Z,8E)-moiety of
bretonin B.26
OH
O
OH
6
4
8
18
18
(ca 50%, inseparable mixture)
(4E,6E,8E)- and (4E,6Z,8E)-
Hydrogenolytic cleavage of the benzyl ether in compound
9 with Pd/C had previously been reported to furnish alcohol
10 selectively,28 but in our hands this reaction was
accompanied by a cleavage of the acetal. The problem was
circumvented by using Pd(OH)2/C as catalyst in the solvent
ethyl acetate. Oxidation of 10 with Dess-Martin
periodinane29 furnished aldehyde 11,28 which was reacted
with vinylmagnesium bromide to allylic alcohol 12.
Compound 12 was converted to butenoate 13 by Steglich
esterification.30 This butenoate was subjected to the tethered
RCM-ring opening conditions in a one-flask reaction by
subsequently treating it with second generation Grubbs’
catalyst A31 and the base NaHMDS to induce deprotonation
and eliminative ring opening of the intermediate RCM
product. The resulting Na-2,4-dienoate was trapped by
addition of Meerwein’s salt32 (Et3OBF4) to give ester 14 in
Our first approach to bretonin B along the lines of the
concept shown in scheme 1 required diol 18 as an advanced
intermediate (Scheme 2). The synthesis started from
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very high diastereoselectivity (no other diastereomer was
This prompted us to investigate the construction of the
(4E,6Z,8E)-triene from the opposite terminus via formation
of the C4-C5-double bond rather than the C8-C9-double bond
by a Julia-Kocienski-olefination. This route should allow us
to avoid the deprotection of the acetonide at a late stage, when
the acid-sensitive (4E,6Z,8E)-triene is already in place, and
still use the acetonide 7 as a conveniently available
enantiopure building block (Scheme 3). Sulfone 23 required
for this approach had previously been synthesized by Bach
and co-workers.26 We chose a modified and somewhat
shorter route to 23 that starts from compound 10, an
intermediate in our first approach to the bretonin skeleton
(see scheme 2). Coupling with 1-phenyl-1H-tetrazole-5-thiol
under Mitsunobu conditions40 furnished 19, which was
oxidized to sulfone 20 with m-CPBA. This oxidant had
previously been used for tetrazole sulfides41 and was, in a
comparative investigation, found to give the cleanest and
most selective conversion to the desired sulfones.42 Although
unplanned, the concomitant acetal cleavage led to a
significant shortening of the synthesis, because with diol 20
in hand the synthesis of Julia-Kocienski-reagent 23 was
completed in just two steps by selective protection of the
primary alcohol with a sterically demanding TBDPS group
and introduction of a TBDPS-protected para-hydroxy
benzoate via Mitsunobu inversion of the secondary alcohol
21 with acid 2226 as a nucleophile. As coupling partner for
the envisaged Julia-Kocienski-olefination (2Z,4E)-octa-2,4-
dienal (28) was required. This compound was synthesized
from allylic alcohol 2543 in analogy to the synthesis of dienal
15 (see scheme 2) via Steglich esterification, tethered RCM-
electrophilic trapping sequence and reduction with DIBAl-
H/oxidation with Dess-Martin periodinane. Deprotonation of
sulfone 23 with KHMDS and coupling with aldehyde 28
furnished protected bretonin B 24 as the single (4E,6Z,8E)-
diastereomer. Full NMR-spectroscopic structure elucidation
and signal assignment at 500 MHz revealed the 13C-NMR
chemical shift pattern for E,Z,E-configured conjugated
trienes.
detected by 1H-NMR spectroscopy) and high yield. To
prepare for the envisaged carbonyl olefination step ester 14
was reduced to the alcohol, which is known to be very
sensitive to decomposition and isomerization,18 and was
therefore not purified but immediately oxidized to aldehyde
15. As the stereoselectivity of the following step is crucial,
1
2
3
4
5
6
7
we chose
a
highly E-selective Julia-Kocienski-
olefination.33,34 It should be noted that the number of
examples where this reaction has been used to construct fully
conjugated trienes through olefination of dienals is rather
limited, and we are only aware of reactions involving E,E-
configured dienals.35-37 Known sulfone 1638 was metallated
with KHMDS and then treated with aldehyde 15 (which
should best be freshly synthesized to avoid any
decomposition) to give acetonide protected triene 17 in good
yield as a single diastereoisomer. Assignment of the
(4E,6Z,8E)-configuration is not straightforward based on
routine 1H-NMR-measurements due to overlapping signals in
the olefinic region. However, a reliable configurational
assignment is possible by comparison of the 13C-NMR data
for 17 listed in scheme 2 with those previously reported for
all-E configured 4,6,8-dodecatriene-1-ol ((13C) = 134.6,
133.3, 131.3, 131.1, 130.6, 130.6)23,25 and (4E,6Z,8E)-
dodecatriene-1-ol ((13C) = 135.8, 134.3, 128.3, 127.4, 126.6,
126.0).25,39 With compound 17 in hand, completion of the
synthesis of (+)-bretonin B (6) required deprotection of the
acetonide and selective introduction of the para-
hydroxybenzoate at the secondary position via Mitsunobu
inversion. Unfortunately, we were unable to find conditions
for the acetal cleavage that proceed without substantial
isomerization to the all-E-configured triene. For instance,
treatment with a catalytic amount of p-TSA in methanol at
ambient temperature furnished an inseparable mixture of
(4E,6E,8E)-18 and (4E,6Z,8E)-18 in ca. 50% yield. Reducing
the reaction time, lowering the amount of catalyst or
replacing p-TSA by the milder acid pyridinium p-tosylate
(PPTS) still resulted in considerable amounts of isomerized
products and incomplete conversion.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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Scheme 3. Successful route to (+)-bretonin B based on tethered RCM and Julia-Kocienski-olefination.
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Page 4 of 10
SH
N
m-CPBA
(70 wt-%, 3.0 equiv.)
CH2Cl2, 0 °C - 20 °C
N
1
2
3
4
5
6
7
8
OH
OH
O
O
N
O
S
Ph
N
O
N
O
O
O
HO
O
S
N
O
N
DIAD, PPh3
THF, 0 °C - 20 °C
N
N
10
19
20
(90%)
(80%)
N
N
Ph
Ph
N
O
TBDPS-Cl
(1.8 equiv.)
imidazole, DMF
0 °C - 20 °C
OTBDPS
(2.0 equiv.)
OTBDPS
O
OTBDPS
HO
O
S
O
22
O
N
O
O
O
S
O
OH
DIAD, PPh3, THF
0 °C - 20 °C
N
N
N
23
N
9
(72%)
21
(78%)
N
Ph
N
Ph
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(13C) = 135.6, 134.6, 127.8,
127.8, 126.3, 126.1 ppm
OTBDPS
OTBDPS
3'
OH
O
1'
8
HF•pyridine (70 wt-%)
pyridine, THF
KHMDS (2.0 equiv.)
THF, - 78 °C
O
O
O
12
4
1
O
O
1''
6
2''
4''
24
6
(+)-Bretonin B ( , 75%)
(52%)
3''
OH
A
(2.5 mol %), CH2Cl2
OTBDPS
1) DIBAl-H
CH2Cl2, 0 °C
2) DMP, CH2 Cl2
40 ° C, 0.5 h; then
NaHMDS (1.2 equiv.)
3-butenoic
acid, DCC
O
OH
CO2Et
O
O
0 °C - 20 °C;
then add Et3OBF4
(1.5 equiv.), 20 °C
DMAP (cat.)
Et2O
28
27
26
25
(98%)
(80%)
(94%)
The synthesis of (+)-bretonin B was completed by
deprotection of both TBDPS-ethers in 24 with HF•pyridine.
All analytical data obtained by us for (+)-bretonin B,
including the specific rotation, match those previously
reported by Bach and coworkers.26 We found, in agreement
with the report from the Bach group, that (+)-bretonin B (6)
in CDCl3 with CDCl3 (δ = 77.16) as an internal standard. The
following instruments were used for NMR-measurements:
Bruker ARX-300 (1H: 300 MHz; 13C: 75 MHz), Bruker
DRX-500 (1H: 500 MHz; 13C: 125 MHz), Bruker DRX-600
(1H: 600 MHz; 13C: 151 MHz). Whenever signal assignments
are given they are based on a combination of 2D-NMR
undergoes
isomerization
to
the
all-E-configured
experiments
(H,H-COSY,
HMBC,
HSQC).
IR
diastereomer (i. e. bretonin A) to a significant extent within a
few hours. Interestingly, the TBDPS-protected bretonin B
(24), which was not an intermediate in Bach’s total synthesis,
was found to be configurationally stable at ambient
temperature over a period of at least several days.
measurements were carried out as ATR-FTIR spectra using a
Perkin-Elmer UART TWO instrument. Wavenumbers (v) are
given in cm1 and the peak intensities are denoted as: strong
(s), medium (m), weak (w). High-resolution mass spectra
were obtained by ESI-TOF or EI-TOF on Micromass
Manchester Waters Inc. instruments. Specific rotations were
measured using Jasco DIP-1000 and P-2000 polarimeters in
a 10 cm cuvette at 589 nm. Concentrations are given in
g•100mL1. Compound 7 was purchased and used without
further purification. 4-(Benzyloxy)butan-1-ol,45 4-((tert-
butyldiphenylsilyl)oxy)benzoic acid (22)26 and hex-1-en-3-ol
(25)43 were synthesized following the cited literature
procedures.
In summary, we have demonstrated that the combination
of a tethered RCM reaction (with cleavage of the tether by
base-induced eliminative ring opening) and a Julia-Kocienski
olefination provides an efficient and versatile synthesis of
E,Z,E-trienes, as exemplified in two approaches to the natural
product (+)-bretonin B. This triene pattern is synthetically
particularly challenging due to a strong tendency towards
isomerization. Our synthesis provides a short and highly
diastereoselective access to partially Z-configured tri- and
perspectively polyenes that relies on mild conditions. Thus,
it can be expected that this strategy will become a valuable
method in target molecule synthesis in the future.
4-(Benzyloxy)butyl methanesulfonate (8).46 To
a
solution of 4-(benzyloxy)butan-1-ol (6.11 g, 34.7 mmol) in
THF (150 mL) at 0 °C were added Et3N (5.27 g, 6.99 mL,
52.1 mmol) and methanesulfonyl chloride (MsCl) (4.38 g,
2.95 mL, 38.2 mmol). The reaction mixture was stirred at 0
°C for 5 h. A satd. aq. solution of NH4Cl (40 mL) was added.
The aqueous layer was extracted with Et2O (3 times 40 mL)
and the combined organic layers were washed with brine (30
mL), dried with MgSO4, filtered and evaporated under
reduced pressure. The crude product 8 (8.90 g, 34.7 mmol,
quant.) was used in the next step without further purification:
colourless liquid; 1H NMR (300 MHz, CDCl3) δ 7.39 – 7.24
(m, 5H), 4.50 (s, 2H), 4.26 (t, J = 6.3 Hz, 2H), 3.51 (t, J = 6.0
Hz, 2H), 2.97 (s, 3H), 1.94 – 1.80 (m, 2H), 1.78 – 1.67 (m,
2H); 13C{1H} NMR (75 MHz, CDCl3) δ 138.4, 128.5, 127.8,
127.8, 73.1, 70.1, 69.5. Analytical data match those
previously reported in the literature.46
EXPERIMENTAL SECTION
All experiments involving air- and moisture sensitive
chemicals were conducted using standard Schlenk technique
under an atmosphere of dry nitrogen. Dichloromethane
(DCM), diethyl ether, methanol and toluene were purified
with a solvent purification system. All other chemicals were
either purchased or prepared according to cited literature.
Dry column vacuum chromatography44 or standard flash
column chromatography were performed on silica gel 60. 1H
NMR spectra were obtained in CDCl3 with CHCl3 (δ = 7.26)
as an internal standard. Multiplicities are denoted as s
(singlet), d (doublet), t (triplet), q (quartet), p (pentet), sext.
(sextet) and m (multiplet). Coupling constants are given in
Hz. 13C NMR spectra were recorded with proton decoupling
(S)-4-((4-(Benzyloxy)butoxy)methyl)-2,2-dimethyl-1,3-
dioxolane (9).28 To a solution of 7 (3.78 g, 3.53 mL, 28.6
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mmol) in DMF (325 mL) at 0 oC was added NaH (1.26 g, 60
[α]D +3.3 (c 1.0, CHCl3). Analytical data match those
22
previously reported in the literature.28
1
2
3
4
5
6
7
8
wt-% dispersion in mineral oil, 31.3 mmol) in small portions.
After stirring at this temperature for 1.5 h a solution of
mesylate 8 (8.52 g, 29.5 mmol) in DMF (55 mL) was added
dropwise and the reaction mixture was warmed to ambient
temperature and stirred for 16 h. The reaction was quenched
by addition of a satd. aq. solution of NH4Cl (250 mL) and the
mixture was extracted with Et2O (5 times 30 mL). The
combined organic layers were washed with brine, dried with
MgSO4, filtered and evaporated under reduced pressure. The
crude product was purified by dry column vacuum
chromatography (SiO2; eluent: hexanes / ethyl acetate
mixtures of increasing polarity) to give compound 9 (6.29 g,
3-(R,S)-6-(((S)-2,2-Dimethyl-1,3-dioxolan-4-
yl)methoxy)hex-1-en-3-ol (12). A solution of 11 (959 mg,
4.74 mmol) in THF (25 mL) was cooled to 0 °C.
Vinylmagnesium bromide (5.69 mL, 1 M in THF, 5.69
mmol) was added dropwise and the reaction was stirred at
ambient temperature for 18 h. The reaction was quenched
with satd. aq. solution of NH4Cl (25 mL) and the aqueous
layer was separated and extracted with Et2O (3 times 25 mL).
The combined organic layers were dried with MgSO4,
filtered and evaporated under reduced pressure. The crude
product was purified by dry column vacuum chromatography
(SiO2; eluent: hexanes / ethyl acetate mixtures of increasing
polarity) to give allylic alcohol 12 (807 mg, 3.50 mmol,
74%): pale yellow liquid; 1H NMR (300 MHz, CDCl3) δ 5.84
(ddd, J = 17.3, 10.4, 6.0 Hz, 1H), 5.20 (dt, J = 17.2, 1.5 Hz,
1H), 5.07 (dt, J = 10.4, 1.4 Hz, 1H), 4.24 (p, J = 6.0 Hz, 1H),
4.16 – 4.06 (m, 1H), 4.03 (dd, J = 8.3, 6.4 Hz, 1H), 3.70 (dd,
J = 8.3, 6.3 Hz, 1H), 3.56 – 3.38 (m, 4H), 2.30 (s (br.), 1H),
1.76 – 1.50 (m, 4H), 1.39 (s, 3H), 1.33 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 141.2, 114.6, 109.5, 74.8, 72.8, 72.0,
71.8, 66.9, 34.1, 26.9, 25.7, 25.5; IR (ATR) v 3448 (s, br.),
2935 (w), 2866 (w), 1371 (m), 1212 (s), 1052 (s); HRMS
(ESI) m/z: [M+H]+ calcd for C12H23O4 231.1596; found
231.1605; [α]D22 +7.8 (c 1.0, CHCl3).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
21.4 mmol, 75%): pale yellow liquid; H NMR (300 MHz,
CDCl3) δ 7.40 – 7.24 (m, 5H), 4.50 (s, 2H), 4.25 (p, J = 6.0
Hz, 1H), 4.04 (dd, J = 8.2, 6.4 Hz, 1H), 3.72 (dd, J = 8.2, 6.4
Hz, 1H), 3.57 – 3.42 (m, 5H), 3.41 (dd, J = 9.9, 5.6 Hz, 1H),
1.74 – 1.60 (m, 4H), 1.42 (s, 3H), 1.36 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 138.8, 128.5, 127.7, 127.6, 109.5, 74.9,
73.0, 72.0, 71.6, 70.3, 67.1, 26.9, 26.6, 26.5, 25.6; IR (ATR)
v 2961 (m), 1736 (s), 1249 (m), 1170 (s), 918 (s); HRMS (EI)
m/z: [M+] calcd for C17H26O4 294.1831; found 294.1839;
23
[α]D +9.4 (c 1.0, CHCl3). Analytical data match those
previously reported in the literature.28
(S)-4-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)butan-
1-ol (10).28 Benzyl ether 9 (5.00 g, 17.0 mmol) was dissolved
in EtOAc (85 mL) and Pd(OH)2/C (20 wt-%, 2.04 g) was
added. The system was flushed with H2 and the reaction
mixture was then exposed to H2 (1 bar) at ambient
temperature for 2 h. The heterogeneous mixture was filtered
through celite and washed with EtOAc. The product 10 (3.48
g, 17.0 mmol, quant.) was used in the next step without
6-(((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)hex-1-
en-3-yl but-3-enoate (13). Allyl alcohol 12 (639 mg, 2.77
mmol), DMAP (51.3 mg, 0.42 mmol) and 3-butenoic acid
(286 mg, 0.28 mL, 3.32 mmol) were dissolved in Et2O (28
mL). The solution was cooled to 0 °C and DCC (684 mg, 3.32
mmol) was added. The reaction mixture was warmed to 20
°C and stirred at this temperature for 36 h. It was then cooled
to 0 °C again, filtered and washed with Et2O. The filtrate was
washed with aq. HCl (1 M) and satd. aq. solution of NaHCO3.
The organic phase was dried with MgSO4, filtered and
evaporated under reduced pressure. The crude product was
purified by dry column vacuum chromatography (SiO2;
eluent: hexanes / MTBE mixtures of increasing polarity) to
give ester 13 (570 mg, 1.91 mmol, 69%): colourless liquid;
1H NMR (300 MHz, CDCl3) δ 5.91 (ddt, J = 16.8, 10.0, 7.0
Hz, 1H), 5.76 (ddd, J = 17.0, 10.5, 6.3 Hz, 1H), 5.30 – 5.10
(m, 5H), 4.24 (p, J = 6.0 Hz, 1H), 4.04 (dd, J = 8.2, 6.4 Hz,
1H), 3.71 (dd, J = 8.2, 6.4 Hz, 1H), 3.54 – 3.35 (m, 4H), 3.09
(dt, J = 7.0, 1.5 Hz, 2H), 1.73 – 1.52 (m, 4H), 1.41 (s, 3H),
1.35 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 170.8, 136.4,
130.4, 118.6, 117.0, 109.5, 74.9, 74.8, 72.0, 71.3, 67.0, 39.5,
30.9, 26.9, 25.6, 25.3; IR (ATR) v 2986 (w), 1735 (s), 1370
(w), 1170 (s); HRMS (ESI) m/z: [M+H]+ calcd for C16H27O5
299.1858; found 299.1869; [α]D22 +6.5 (c 1.0, CHCl3).
1
further purification: colourless liquid; H NMR (300 MHz,
CDCl3) δ 4.24 (p, J = 5.9 Hz, 1H), 4.03 (dd, J = 8.2, 6.5 Hz,
1H), 3.70 (dd, J = 8.2, 6.4 Hz, 1H), 3.67 – 3.57 (m, 2H), 3.57
– 3.38 (m, 4H), 2.37 (s, 1H), 1.72 – 1.58 (m, 4H), 1.40 (s,
3H), 1.34 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 109.6,
74.8, 72.0, 71.8, 66.9, 62.7, 30.0, 26.9, 26.5, 25.5; IR (ATR)
v 3420 (s, broad), 2936 (m), 2868 (m), 1455 (w), 1371 (m),
1052 (s); HRMS (ESI) m/z: [M+H]+ calcd for C10H21O4
22
205.1440; found 205.1430; [α]D +8.6 (c 1.0, CHCl3).
Analytical data match those previously reported in the
literature.28
(S)-4-((2,2-Dimethyl-1,3-dioxolan-4-
yl)methoxy)butanal (11).28 To a solution of 10 (1.33 g, 6.53
mmol) and pyridine (3.99 mL, 49.0 mmol) in CH2Cl2 (65 mL)
o
at 0 C was added Dess-Martin periodinane (4.16 g, 9.80
mmol) in portions. The reaction mixture was stirred at 20 oC
for 2 h. The reaction was quenched by addition of satd. aq.
solutions of NaHCO3/Na2S2O3 (1 : 1). The aqueous layer was
extracted with CH2Cl2 (3 times 30 mL), dried with MgSO4,
filtered and evaporated under reduced pressure. The crude
product was purified by dry column vacuum chromatography
(SiO2; eluent: hexanes / MTBE mixtures of increasing
polarity) to give aldehyde 11 (1.01 g, 4.99 mmol, 76%): pale
yellow liquid; 1H NMR (300 MHz, CDCl3) δ 9.72 (t, J = 1.6
Hz, 1H), 4.17 (p, J = 5.9 Hz, 1H), 3.99 (dd, J = 8.3, 6,4 Hz,
1H), 3.65 (dd, J = 8.3, 6.4 Hz, 1H), 3.53 – 3.41 (m, 3H), 3.37
(dd, J = 10.0, 5.4 Hz, 1H), 2.47 (td, J = 7.1, 1.6 Hz, 2H), 1.87
(p, J = 6.7 Hz, 2H), 1.36 (s, 3H), 1.30 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 202.1, 109.4, 74.7, 71.9, 70.5, 66.8, 40.8,
26.8, 25.4, 22.5; IR (ATR) v 2934 (m), 2869 (m), 1723 (s),
1370 (m), 1118 (s), 1078 (s), 843 (m); HRMS (ESI) m/z:
[M+Na]+ calcd for C10H18O4Na 225.1103; found 225.1098;
Ethyl
(2Z,4E)-8-(((S)-2,2-dimethyl-1,3-dioxolan-4-
yl)methoxy)octa-2,4-dienoate (14). To a solution of 13 (287
mg, 0.96 mmol) in degassed dry CH2Cl2 (10 mL) at 40 °C
was added second generation Grubbs’ catalyst A (24.4 mg,
3.0 mol%). The reaction mixture was stirred at 40 °C until
the starting material was fully consumed, as indicated by
TLC (2 h). The solution was cooled to 0 °C and NaHMDS (1
M solution in THF, 1.15 mL, 1.15 mmol) was added. The
reaction was warmed to 20 °C and stirred for 3 h. After this
time, Meerwein’s salt [Et3O]BF4 (273 mg, 1.44 mmol) was
added and the reaction mixture was stirred for 3 h. The
solution was then filtered through celite and washed with
CH2Cl2. The solvent was evaporated under reduced pressure
and the crude product was purified by dry column vacuum
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chromatography (SiO2; eluent: hexanes / ethyl acetate
7.4 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 154.6, 133.9,
1
2
3
4
5
6
7
8
mixtures of increasing polarity) to give the ethyl dienoate 14
(267 mg, 0.89 mmol, 93%): pale yellow liquid; 1H NMR (300
MHz, CDCl3) δ 7.37 (ddm, J = 15.2, 11.3 Hz, 1H), 6.52 (t, J
= 11.3 Hz, 1H), 6.04 (dt, J = 15.3, 7.0 Hz, 1H), 5.56 (d, J =
11.3 Hz, 1H), 4.25 (p, J = 6.1 Hz, 1H), 4.17 (q, J = 7.1 Hz,
2H), 4.04 (dd, J = 8.2, 6.4 Hz, 1H), 3.71 (dd, J = 8.2, 6.4 Hz,
1H), 3.56 – 3.35 (m, 4H), 2.26 (q, J = 7.3 Hz, 2H), 1.72 (p, J
= 6.7 Hz, 2H), 1.41 (s, 3H), 1.35 (s, 3H), 1.28 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 166.6, 145.2, 144.6,
127.4, 116.0, 109.5, 74.9, 72.0, 71.1, 67.0, 60.0, 29.7, 28.8,
26.9, 25.6, 14.4; IR (ATR) v 2935 (w), 1712 (s), 1637 (m),
1601 (m), 1370 (m), 1175 (s), 1031 (m); HRMS (ESI) m/z:
130.2, 129.9, 124.0, 33.2, 31.2, 21.9, 13.6; IR (ATR) v 2959
(m), 1597 (m), 1499 (s), 1385 (s), 759 (s); HRMS (EI) m/z:
[M]+ calcd for C11H14N4S 234.0939; found 234.0930.
Analytical data match those previously reported in the
literature.38 5-(Butylsulfonyl)-1-phenyl-1H-tetrazole (16):38
5-(Butylthio)-1-phenyl-1H-tetrazole (500 mg, 2.14 mmol)
was dissolved in CH2Cl2 and the solution was cooled to 0 °C.
m-CPBA (70 wt-% aq. dispersion, 1.48 g, 6.42 mmol) was
added and the reaction mixture was stirred at ambient
temperature for 12 h. The reaction was quenched by addition
of satd. aq. solution of Na2S2O3 (80 mL) and the aqueous
phase was extracted with CH2Cl2 (3 times 60 mL). The
combined organic layers were washed with satd. aq. solution
of NaHCO3, dried with MgSO4, filtered and evaporated under
reduced pressure. The crude product was purified by column
chromatography (SiO2; eluent: hexanes / MTBE mixtures of
increasing polarity) to give sulfone 16 (476 mg, 1.79 mmol,
84%): colourless liquid; 1H NMR (300 MHz, CDCl3) δ 7.72
– 7.54 (m, 5H), 3.77 – 3.68 (m, 2H), 1.93 (p, J = 7.7 Hz, 2H),
1.53 (sext., J = 7.8 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ 153.7, 133.2, 131.6, 129.8, 125.2,
55.9, 24.0, 21.6, 13.5; IR (ATR) v 2963 (w), 1595 (w), 1497
(m), 1335 (s), 1149 (s), 762 (s); HRMS (ESI) m/z: [M+H]+
calcd for C11H15N4O2S 267.0916; found 267.0903. Analytical
data match those previously reported in the literature.38
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
24
[M+H]+ calcd for C16H27O5 299.1858; found 299.1869; [α]D
+10.3 (c 1.0, CHCl3).
(2Z,4E)-8-(((S)-2,2-Dimethyl-1,3-dioxolan-4-
yl)methoxy)octa-2,4-dienal (15). A solution of ester 14 (188
mg, 0.62 mmol) in CH2Cl2 (6 mL) was cooled to 0 °C.
DIBAl-H (0.92 mL, 1 M solution in hexane, 0.92 mmol) was
added slowly, the reaction was warmed to 20 °C and stirred
for 10 min.. Brine (5 mL) was added, followed by HCl (aq.,
1 M, minimum amount required to dissolve the precipitate).
The aqueous layer was separated and extracted with CH2Cl2
(3 times 10 mL). The combined organic layers were washed
with satd. aq. solution of NaHCO3 and brine, dried with
MgSO4, filtered and evaporated under reduced pressure. The
crude product was immediately redissolved in CH2Cl2 (6 mL)
and the solution was cooled to 0 °C. Dess-Martin-
periodinane29 (533 mg, 1.24 mmol) was added and the
reaction was stirred at 20°C for 2 h. It was quenched with
satd. aq. aolutions of NaHCO3 and Na2S2O3 (1 : 1 (v/v)). The
aqueous layer was separated and extracted with CH2Cl2 (3
times 10 mL), dried with MgSO4, filtered and evaporated
under reduced pressure. The crude product was purified by
dry column vacuum chromatography (SiO2; eluent: hexanes
/ ethyl acetate mixtures of increasing polarity) to give dieneal
15 (114 mg, 0.45 mmol, 73%): yellow liquid; 1H NMR (300
MHz, CDCl3) δ 10.14 (d, J = 7.9 Hz, 1H), 7.04 (ddm, J =
14.6, 11.8 Hz, 1H), 6.89 (dd, J = 11.3, 11.3 Hz, 1H), 6.16 (dt,
J = 14.6, 7.1 Hz, 1H), 5.78 (ddm, J = 10.8, 7.9 Hz, 1H), 4.25
(p, J = 6.0 Hz, 1H), 4.04 (dd, J = 8.2, 6.4 Hz, 1H), 3.71 (dd,
J = 8.3, 6.4 Hz, 1H), 3.55 – 3.35 (m, 4H), 2.31 (q, J = 7.5 Hz,
2H), 1.74 (p, J = 6.8 Hz, 2H), 1.41 (s, 3H), 1.35 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 190.5, 147.9, 146.2,
126.1, 124.8, 109.6, 74.9, 72.1, 70.9, 66.9, 29.8, 28.7, 26.9,
25.5; IR (ATR) v 2932 (w), 1666 (s), 1635 (s), 1370 (m),
1115 (s); HRMS (ESI) m/z: [M+H]+ calcd for C14H23O4
255.1596; found 255.1586; [α]D24 +8.5 (c 1.0, CHCl3).
(S)-4-((((4E,6Z,8E)-Dodeca-4,6,8-trien-1-
yl)oxy)methyl)-2,2-dimethyl-1,3-dioxolane (17). To
a
solution of sulfone 16 (240 mg, 0.90 mmol) in THF (21 mL)
at 78 °C was added KHMDS (1.28 mL, 0.7 M solution in
toluene, 0.90 mmol) dropwise. The resulting yellow solution
was stirred for 3 min., followed by dropwise addition of a
solution of dienal 15 (114 mg, 0.45 mmol) in THF (14 mL).
The reaction mixture was stirred at 78 °C for 1 h and then
quenched at this temperature by slowly adding a satd. aq.
solution of NH4Cl (45 mL). The mixture was allowed to
warm to ambient temperature, the aqueous phase was
separated and extracted with Et2O (3 times 30 mL). The
combined organic layers were dried with MgSO4, filtered and
evaporated under reduced pressure. The crude product was
purified by dry column vacuum chromatography (SiO2;
eluent: hexanes / MTBE mixtures of increasing polarity) to
give triene 17 (99.4 mg, 0.34 mmol, 76%): pale yellow
1
liquid; H NMR (300 MHz, CDCl3) δ 6.58 – 6.41 (m, 2H),
5.94 – 5.78 (m, 2H), 5.75 – 5.60 (m, 2H), 4.26 (p, J = 6.1 Hz,
1H), 4.06 (dd, J = 8.2, 6.4 Hz, 1H), 3.73 (dd, J = 8.2, 6.4 Hz,
1H), 3.59 – 3.37 (m, 4H), 2.19 (q, J = 7.4 Hz, 2H), 2.10 (q, J
= 7.2 Hz, 2H), 1.69 (p, J = 7.0 Hz, 2H), 1.46 – 1.39 (m, 2H),
1.42 (s, 3H), 1.36 (s, 3H), 0.91 (t, J = 7.3 Hz, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ 135.6, 134.4, 128.1, 127.5, 126.4,
126.0, 109.5, 74.9, 72.0, 71.2, 67.0, 35.2, 29.5, 29.3, 26.9,
25.6, 22.7, 13.9; IR (ATR) v 2929 (m), 1455 (w), 1117 (m),
962 (s); HRMS (ESI) m/z: [M+Na]+ calcd for C18H30O3Na
317.2093; found 317.2087; [α]D25 +6.6 (c 1.0, CHCl3).
5-(Butylsulfonyl)-1-phenyl-1H-tetrazole
(16).
5-
(Butylthio)-1-phenyl-1H-tetrazole:38 1-Butanol (222 mg,
0.27 mL, 3.00 mmol), 1-phenyl-1H-tetrazole-5-thiol (1.07 g,
6.00 mmol) and PPh3 (1.18 g, 4.50 mmol) were dissolved in
THF (120 mL). DIAD (639 mg, 3.15 mmol) was added
dropwise at 0 °C. After 30 min the reaction mixture was
allowed to warm to ambient temperature and stirred for 16 h.
It was quenched with satd. aq. NH4Cl (90 mL) and the
aqueous layer was extracted with Et2O (3 times 60 mL). The
combined organic layers were dried with MgSO4, filtered and
evaporated under reduced pressure. The crude product was
purified by column chromatography (SiO2; eluent: hexanes /
MTBE mixtures of increasing polarity) to give pre-16 (549
mg, 2.34 mmol, 78%): colourless liquid; 1H NMR (300 MHz,
CDCl3) δ 7.59 – 7.52 (m, 5H), 3.39 (t, J = 7.4 Hz, 2H), 1.80
(p, J = 7.4 Hz, 2H), 1.47 (sext., J = 7.4 Hz, 2H), 0.94 (t, J =
(R)-3-(((4E,6E,Z,8E)-Dodeca-4,6,8-trien-1-
yl)oxy)propane-1,2-diol ((4E,6E,8E)-18 and (4E,6Z,8E)-
18). Acetonide 17 (42.5 mg, 0.14 mmol) was dissolved in
MeOH (0.5 mL) and CH2Cl2 (0.5 mL). p-TSA•3H2O (2.52
mg, 10 mol%) was added and the reaction mixture was stirred
at ambient temperature for 4 h. NaHCO3 (100 mg) and water
(2 mL) were added. The aqueous phase was separated and
extracted with EtOAc (5 mL). The combined organic extracts
were dried with MgSO4, filtered and evaporated under
reduced pressure to furnish crude diol 18 (ca. 20 mg, 0.07
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The Journal of Organic Chemistry
mmol, ca. 50%) as a ca. 2 : 3 mixture of (4E,6E,8E)- and
aq. solution of NH4Cl (40 mL) and the aqueous layer was
extracted with Et2O (4 times 30 mL). The combined organic
layers were dried with MgSO4, filtered and evaporated under
reduced pressure. The crude product was purified by dry
column vacuum chromatography (SiO2; eluent: hexanes /
ethyl acetate mixtures of increasing polarity) to give 21 (2.14
1
2
3
4
5
6
7
8
(4E,6Z,8E)-isomers. Selected characteristic NMR-data were
1
obtained from the mixture: H NMR (300 MHz, CDCl3) δ
6.58 – 6.40 (m, 2H, (E,Z,E)-isomer), 6.21 – 5.98 (m, 4H,
(E,E,E)-isomer), 5.91 – 5.77 (m, 2H, (E,Z,E)-isomer), 5.77 –
5.66 (m, 2H, (E,Z,E)- and (E,E,E)-isomer)); 13C NMR data of
(4E,6Z,8E)-18: 13C{1H} NMR (75 MHz, CDCl3) δ 135.8,
134.1, 128.3, 127.4, 126.5, 126.0; 13C{1H} NMR data of
(4E,6E,8E)-18: 13C NMR (75 MHz, CDCl3) δ 134.8, 133.1,
131.5, 131.3, 130.6, 130.6; HRMS (ESI) m/z: [M+H]+ calcd
for C15H27O3 255.1960; found 255.1973.
1
g, 3.60 mmol, 78%): colorless oil; H NMR (300 MHz,
CDCl3) δ 7.73 – 7.64 (m, 6H), 7.63 – 7.55 (m, 3H), 7.47 –
7.35 (m, 6H), 3.94 – 3.85 (m, 1H), 3.84 – 3.74 (m, 2H), 3.71
(d, J = 5.5 Hz, 2H), 3.58 – 3.44 (m, 4H), 2.58 (d (br.), J = 4.5
Hz, 1H), 2.04 (p, J = 7.5 Hz, 2H), 1.76 (p, J = 6.4 Hz, 2H),
1.08 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 153.6, 135.7,
133.3, 133.2, 131.6, 130.0, 129.9, 127.9, 125.3, 72.0, 70.9,
70.4, 65.0, 55.9, 28.1, 27.0, 19.6, 19.4; IR (ATR) v 3562 (s,
broad), 2930 (w), 2858(w), 1340 (m), 1111 (s); HRMS (ESI)
m/z: [M+H]+ calcd for C30H39N4O5SSi 595.2410; found
595.2398; [α]D24 3.2 (c 1.0, CHCl3).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S)-5-((4-((2,2-Dimethyl-1,3-dioxolan-4-
yl)methoxy)butyl)thio)-1-phenyl-1H-tetrazole
(19).
Alcohol 10 (1.20 g, 5.87 mmol), 1-phenyl-1H-tetrazole-5-
thiol (2.09 g, 11.7 mmol) and PPh3 (2.30 g, 8.81 mmol) were
dissolved in THF (225 mL) and cooled to 0 °C. DIAD (1.26
g, 1.23 mL, 6.22 mmol) was added dropwise and the reaction
mixture was stirred at ambient temperature for 16 h. It was
quenched with satd. aq. solution of NH4Cl (100 mL) and the
aqueous layer was extracted with Et2O (3 times 60 mL). The
combined organic layers were dried with MgSO4, filtered and
evaporated under reduced pressure. The crude product was
purified by dry column vacuum chromatography (SiO2;
eluent: hexanes / MTBE mixtures of increasing polarity) to
give 19 (1.70 g, 4.67 mmol, 80%): pale yellow oil; 1H NMR
(300 MHz, CDCl3) δ 7.60 – 7.48 (m, 5H), 4.23 (p, J = 6.0 Hz,
1H), 4.03 (dd, J = 8.2, 6.5 Hz, 1H), 3.69 (dd, J = 8.2, 6.5 Hz,
1H), 3.58 – 3.45 (m, 3H), 3.45 – 3.36 (m, 3H), 1.90 (p, J =
6.8 Hz, 2H), 1.72 (p, J = 6.5 Hz, 2H), 1.39 (s, 3H), 1.33 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 154.4, 133.8, 130.2,
129.9, 123.9, 109.5, 74.8, 72.1, 70.9, 66.9, 33.2, 28.6, 26.9,
26.1, 25.5; IR (ATR) v 2985 (w), 2867 (w), 1597 (w), 1499
(s), 1241 (m); HRMS (EI) m/z: [M+] calcd for C17H24N4O3S
364.1569; found 364.1564; [α]D23 +8.9 (c 1.0, CHCl3).
(R)-1-((tert-Butyldiphenylsilyl)oxy)-3-(4-((1-phenyl-
1H-tetrazol-5-yl)sulfonyl)butoxy)-propan-2-yl 4-((tert-
butyldiphenylsilyl)oxy)benzoate (23).26 Alcohol 21 (1.28 g,
2.15 mmol), acid 22 (1.62 g, 4.30 mmol) and PPh3 (1.13 g,
4.30 mmol) were dissolved in THF (60 mL) and cooled to 0
°C. DIAD (870 mg, 0.85 mL, 4.30 mmol) was added
dropwise and the reaction mixture was stirred at ambient
temperature for 16 h. The reaction was quenched by addition
of satd. aq. solution of NH4Cl (50 mL) and the aqueous layer
was extracted with Et2O (3 time 40 mL). The combined
organic layers were dried with MgSO4, filtered and
evaporated under reduced pressure. The crude product was
purified by dry column vacuum chromatography (SiO2;
eluent: hexanes / MTBE mixtures of increasing polarity) to
give sulfone 23 (1.47 g, 1.54 mmol, 72%): pale yellow oil;
1H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 8.7 Hz, 2H), 7.74
– 7.66 (m, 6H), 7.64 – 7.57 (m, 7H), 7.49 – 7.30 (m, 9H),
7.29 – 7.22 (m, 3H), 6.78 (d, J = 8.7 Hz, 2H), 5.27 (p, J = 4.9
Hz, 1H), 3.86 (d, J = 4.7 Hz, 2H), 3.78 – 3.62 (m, 4H), 3.57
– 3.44 (m, 2H), 2.01 (p, J = 7.4 Hz, 2H), 1.73 (p, J = 6.2 Hz,
2H), 1.12 (s, 5H), 1.02 (s, 5H); 13C{1H} NMR (75 MHz,
CDCl3) δ 165.8, 160.0, 153.6, 135.7, 135.6, 133.4, 133.3,
133.2, 132.4, 132.4, 131.7, 131.5, 130.3, 129.8, 129.8, 128.0,
127.8, 127.8, 125.2, 123.1, 119.7, 73.1, 70.5, 69.5, 62.8, 55.9,
28.2, 26.9, 26.6, 19.6, 19.6, 19.4; IR (ATR) v 2931 (w), 1714
(m), 1603 (m), 1259 (s), 1112 (s), 700 (s); HRMS (ESI) m/z:
[M+Na]+ calcd for C53H60N4NaO7SSi2 975.3613; found
975.3626; [α]D25 7.8 (c 1.0, CHCl3). Analytical data match
those previously reported in the literature,26 except for the
(R)-3-(4-((1-Phenyl-1H-tetrazol-5-
yl)sulfonyl)butoxy)propane-1,2-diol (20). To a solution of
19 (1.91 g, 5.24 mmol) in CH2Cl2 (120 mL) at 0 oC was added
m-CPBA (2.69 g, 15.7 mmol, 70 wt-% suspension in water)
in portions. The reaction mixture was stirred at ambient
temperature for 16 h. The reaction was quenched by addition
of satd. aq. solution of Na2S2O3 (80 mL), the aqueous layer
was separated and extracted with CH2Cl2 (3 times 60 mL).
The combined organic layers were washed with satd. aq.
solution of NaHCO3, dried with MgSO4, filtered and
evaporated under reduced pressure. The crude product was
purified by filtration through a pad of silica gel to give
20
specific rotation (reported value:26 [α]D 7.8 (c 1.0,
1
sulfone 20 (1.68 g, 4.71 mmol, 90%): pale yellow oil; H
CHCl3)).
NMR (300 MHz, CDCl3) δ 7.74 – 7.52 (m, 5H), 3.90 – 3.75
(m, 3H), 3.70 (dd, J = 11.3, 3.9 Hz, 1H), 3.60 (dd, J = 11.4,
5.7 Hz, 1H), 3.56 – 3.43 (m, 4H), 2.70 (s (br.), 2H), 2.06 (p,
J = 7.4 Hz, 2H), 1.79 (p, J = 6.8, 6.4 Hz, 2H); 13C{1H} NMR
(75 MHz, CDCl3) δ 153.5, 133.1, 131.6, 129.9, 125.2, 72.5,
70.8, 70.4, 64.0, 55.8, 27.9, 19.6; IR (ATR) v 3401 (s, broad),
2873 (w), 1598 (w), 1497 (m), 1338 (s), 1149 (s); HRMS
(ESI) m/z: [M+H]+ calcd for C14H21N4O5S 357.1233; found
357.1215; [α]D24 1.5 (c 1.0, CHCl3).
(S)-1-((tert-Butyldiphenylsilyl)oxy)-3-(4-((1-phenyl-
1H-tetrazol-5-yl)sulfonyl)butoxy)-propan-2-ol (21). Diol
20 (1.64 g, 4.60 mmol) was dissolved in DMF (60 mL). A
solution of imidazole (611 mg, 8.97 mmol) and TBDPSCl
(1.35 g, 1.27 mL, 4.92 mmol) in DMF (25 mL) was added
dropwise at 0 °C. The reaction was stirred at ambient
temperature for 16 h. The reaction was quenched with satd.
Hex-1-en-3-yl but-3-enoate (26).47 Alcohol 25 (1.56 g,
15.6 mmol), DMAP (281 mg, 2.30 mmol) and 3-butenoic
acid (1.61 g, 1.60 mL, 18.7 mmol) were dissolved in Et2O
(160 mL). The solution was cooled to 0 °C and DCC (3.85 g,
18.7 mmol) was added. The reaction was stirred at 20 °C for
36 h. The reaction mixture was cooled to 0 °C, filtered and
washed with Et2O. The filtrate was washed with aq. HCl (1
M) and a satd. aq. solution of NaHCO3. The organic phase
was dried with MgSO4, filtered and evaporated under
reduced pressure. The crude product was purified by column
chromatography (SiO2; eluent: hexanes / MTBE mixtures of
increasing polarity) to give 26 (2.46 g, 14.7 mmol, 94%): pale
1
yellow liquid; H NMR (300 MHz, CDCl3) δ 5.93 (ddt, J =
17.0, 9.7, 6.9 Hz, 1H), 5.77 (ddd, J = 17.0, 10.5, 6.4 Hz, 1H),
5.32 – 5.09 (m, 5H), 3.09 (d, J = 7.0 Hz, 2H), 1.73 – 1.46 (m,
2H), 1.40 – 1.25 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C{1H}
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NMR (75 MHz, CDCl3) δ 170.9, 136.6, 130.5, 118.6, 116.7,
(R)-1-((tert-Butyldiphenylsilyl)oxy)-3-(((4E,6Z,8E)-
dodeca-4,6,8-trien-1-yl)oxy)propan-2-yl 4-((tert-
1
2
3
4
5
6
7
8
75.0, 39.6, 36.4, 18.4, 13.9; IR (ATR) v 2961 (m), 1736 (s),
1249 (m), 1170 (s), 918 (s); HRMS (ESI) m/z: [M+Na]+ calcd
for C10H16NaO2 191.1048; found 191.1044. Analytical data
match those previously reported in the literature.47
butyldiphenylsilyl)oxy)benzoate (24). To a solution of 23
(618 mg, 0.648 mmol) in THF (15 mL) at 78 °C was
KHMDS (0.93 mL, 0.7 M solution in toluene, 0.648 mmol)
added dropwise. The resulting yellow solution was stirred for
3 min.. A solution of aldehyde 28 (40.2 mg, 0.324 mmol) in
THF (12 mL) was added dropwise and the reaction mixture
was stirred at 78 °C for 1 h. Satd. aq. solution of NH4Cl (30
mL) was added dropwise at 78 °C and the mixture was
allowed to warm to ambient temperature. The aqueous phase
was extracted with Et2O (3 times 30 mL) and the combined
organic layers were dried with MgSO4, filtered and
evaporated under reduced pressure. The crude product was
purified by dry column vacuum chromatography (SiO2;
eluent: hexanes / MTBE mixtures of increasing polarity) to
give TBDPS-protected bretonin B 24 (143 mg, 0.168 mmol,
52%): colourless oil; 1H NMR (500 MHz, CDCl3) δ 7.81 (d,
J = 8.8 Hz, 2H, H2’’), 7.74 – 7.70 (m, 4H, Ph), 7.65 – 7.61
(m, 4H, Ph), 7.47 – 7.42 (m, 2H, Ph), 7.41 – 7.23 (m, 10H,
Ph), 6.78 (d, J = 8.8 Hz, 2H, H3’’), 6.47 (dd, Jtrans = 14.8, 10.4
Hz, 2H, H5, H8), 5.86 (dd, J = 10.8, 10.8 Hz, 1H, H6/7), 5.82
(dd, J = 10.8, 10.8 Hz, 1H, H6/7), 5.70 (dt, J = 15.1, 7.3 Hz,
1H, H9), 5.65 (dt, J = 15.1, 7.3 Hz, 1H, H4), 5.28 (p, J = 5.0
Hz, 1H, H2’), 3.89 (d, J = 4.6 Hz, 2H, H3’), 3.72 (dd, J = 5.3,
1.6 Hz, 2H, H1’), 3.52 – 3.41 (m, 2H, H1), 2.15 (q, J = 7.2
Hz, 2H, H3), 2.10 (q, J = 7.2 Hz, 2H, H10), 1.70 – 1.60 (m,
2H, H2), 1.49 – 1.38 (m, 2H, H11), 1.12 (s, 9H, OSiC(CH3)3),
1.02 (s, 9H, CarOSiC(CH3)3), 0.92 (t, J = 7.4 Hz, 3H, H12);
13C{1H} NMR (125 MHz, CDCl3) δ 165.8 (C=O), 160.0
(C4’’), 135.7 (Ph), 135.6, 134.6 (C4, C9), 133.5 (Ph), 132.4
(Ph), 131.7 (C2’’), 130.3 (Ph), 129.8 (Ph), 129.8 (Ph), 128.1
(Ph), 127.8, 127.8 (C6, C7), 127.6 (Ph), 126.3, 126.1 (C5,
C8), 123.3 (C1’’), 119.7 (C3’’), 73.3 (C2’), 71.1 (C1), 69.1
(C1’), 62.8 (C3’), 35.2 (C10), 29.6 (C3), 29.5 (C2), 26.9
(SiC(CH3)3), 26.6 (SiC(CH3)3), 22.7 (C11), 19.6
(SiC(CH3)3), 19.4 (SiC(CH3)3), 13.9 (C12); IR (ATR) v 3072
(w), 2957 (m), 2931 (m), 1716 (m), 1603 (m), 1508 (m), 1428
(m), 125 9 (s), 1164 (m), 1112 (s), 911 (m), 735 (m) 700 (s);
HRMS (ESI) m/z: [M+Na]+ calcd for C54H66NaO5Si2
873.4341; found 873.4348; [α]D24 8.1 (c 1.0, CHCl3).
(+)-Bretonin B (6). HF•pyridine complex (0.62 mL,
⁓70% HF and 30% pyridine) was added dropwise to a
solution of 24 (138 mg, 0.163 mmol) and dry pyridine (1.27
mL) in THF (8 mL) at 20 °C. After 2 h the reaction mixture
was filtered through a pad of silica gel, eluted with Et2O. The
crude product was purified by dry column vacuum
chromatography (SiO2; eluent: hexanes / MTBE mixtures of
increasing polarity) to give (+)-bretonin B (6) (45.7 mg,
0.122 mmol, 75%): colourless oil; 1H NMR (600 MHz,
CDCl3) δ 7.86 (d, J = 8.7 Hz, 2H, H2’’), 6.79 (d, J = 8.8 Hz,
2H, H3’’), 6.48 (ddt, J = 15.1, 10.4, 1.4 Hz, H5/8), 6.45 (ddt,
J = 15.1, 10.4, 1.4 Hz, H5/8), 5.86 (dd, J = 10.8, 10.8 Hz,
H6/7), 5.81 (dd, J = 10.8, 10.8 Hz, H6/7), 5.69 (dt, J = 15.1,
7.3 Hz, 1H, H4/9), 5.65 (dt, J = 15.1, 7.3 Hz, 1H, H4/9), 5.22
(p, J = 4.6 Hz, 1H, H2’), 4.00 – 3.95 (m, 2H, H3’), 3.80 (dd,
J = 10.7, 5.0 Hz, 1H, H1’), 3.75 (dd, J = 10.7, 4.8 Hz, 1H,
H1’), 3.58 – 3.45 (m, 2H, H1), 2.21 – 2.11 (m, 2H, H3), 2.10
– 2.02 (m, 2H, H10), 1.72 – 1.64 (m, 2H, H2), 1.45 – 1.36
(m, 2H, H11), 0.90 (t, J = 7.1 Hz, 3H, H12); 13C{1H} NMR
(75 MHz, CDCl3) δ 166.6 (C=O), 161.1 (C4’’), 135.8, 134.0
(C4, C9), 132.2 (C2’’), 128.3, 127.4 (C6, C7), 126.6, 126.0
(C5, C8), 121.7 (C1’’), 115.5 (C3’’), 73.2 (C2’), 71.4 (C1),
70.5 (C1’), 63.3 (C3’), 35.1 (C10), 29.5 (C3), 29.3 (C2), 22.6
Ethyl (2Z,4E)-octa-2,4-dienoate (27).17 To a solution of
26 (500 mg, 2.97 mmol) in degassed dry CH2Cl2 (30 mL) was
added second generation Grubbs’ catalyst A (75.6 mg, 3.0
mol%) at 40 °C. The reaction mixture was stirred at this
temperature until the starting material was fully consumed,
as indicated by TLC (ca. 2 h). The solution was cooled to 0
°C and NaHMDS (1 M solution in THF, 3.56 mL, 3.56
mmol) was added. The reaction was warmed to ambient
temperature and stirred for 3 h. Meerwein’s salt [Et3O]BF4
(845 mg, 4.46 mmol) was added and the reaction mixture was
stirred for another 3 h. The solution was filtered through
celite and washed with CH2Cl2. The solvent was evaporated
under reduced pressure and the crude product was purified by
column chromatography (SiO2; eluent: hexanes / MTBE
mixtures of increasing polarity) to give 27 (400 mg, 2.38
mmol, 80%): pale yellow liquid; 1H NMR (300 MHz, CDCl3)
δ 7.36 (ddm, J = 15.2, 11.3 Hz, 1H), 6.54 (t, J = 11.3 Hz, 1H),
6.06 (dt, J = 14.9, 7.0 Hz, 1H), 5.56 (dd, J = 11.4, 0.9 Hz,
1H), 4.18 (q, J = 7.2 Hz, 2H), 2.18 (q, J = 7.0 Hz, 2H), 1.47
(sext., J = 7.3 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 0.92 (t, J =
7.4 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 166.7, 145.6,
145.5, 127.2, 115.7, 60.0, 35.2, 22.1, 14.5, 13.9; IR (ATR) v
2961 (m), 1713 (m), 1422 (w), 1178 (s); HRMS (EI) m/z:
[M+] calcd for C10H16O2 168.1150; found 168.1156.
Analytical data match those previously described in the
literature.17
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(2Z,4E)-Octa-2,4-dienal (28). A solution of ester 27 (421
mg, 2.50 mmol) in CH2Cl2 (25 mL) was cooled to 0 °C.
DIBAl-H (5.0 mL, 1 M solution in hexane, 5.00 mmol) was
added slowly, the reaction was allowed to warm to ambient
temperature and stirred for 10 min.. Brine (15 mL) and a
minimum amount of aq. HCl (1 M) were then added and the
aqueous layer was extracted with CH2Cl2 (3 times 30 mL).
The combined organic layers were washed with satd. aq.
solution of NaHCO3 and brine, dried with MgSO4, filtered
and evaporated under reduced pressure. The crude product
was immediately redissolved in CH2Cl2 (25 mL) and the
solution was cooled to 0 °C. Dess- Martin-periodinane
(DMP)29 (2.13 g, 5.00 mmol) was added and the reaction was
stirred at 20 °C for 2 h. It was quenched by addition of satd.
aq. solutions of NaHCO3 and Na2S2O3 (1 : 1 (v/v)). The
aqueous layer was extracted with CH2Cl2 (3 times 30 mL),
dried with MgSO4, filtered and evaporated under reduced
pressure. The crude product was purified by dry column
vacuum chromatography (SiO2; eluent: hexanes / MTBE
mixtures of increasing polarity) to give aldehyde 28 (305.2
mg, 2.46 mmol, 98%): yellowish liquid; 1H NMR (300 MHz,
CDCl3) δ 10.17 (d, J = 7.9 Hz, 1H), 7.04 (ddm, J = 14.4, 12.0
Hz, 1H), 6.92 (dd, J = 12.0, 10.7 Hz, 1H), 6.17 (dt, J = 14.4,
7.1 Hz, 1H), 5.78 (dd, J = 10.5, 8.0 Hz, 1H), 2.21 (q, J = 7.2
Hz, 2H), 1.50 (sext., J = 7.3 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 190.5, 148.1, 147.1,
125.9, 124.6, 35.2, 22.0, 13.8; IR (ATR) v 2960 (m), 1664
(s), 1634 (s), 1229 (m), 953 (m); HRMS (ESI) m/z: [M+H]+
calcd for C8H13O 125.0966; found 125.0962. (2Z,4E)-Octa-
2,4-dienal (28) was reported to be a volatile oxidation
product of sunflower oils and detected by GC-MS, but no
other analytical data of this compound have previously been
reported.48
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The Journal of Organic Chemistry
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Misale, A.; Niyomchon, S.; Maulide, N.
(C11), 13.9 (C12); IR (ATR) v 3329 (s, broad), 2929 (m),
2871 (m), 1711 (m), 1687 (m), 1608 (m), 1593 (m), 1272 (s),
1165 (m), 1114 (m), 851 (w), 700 (w); HRMS (ESI) m/z:
Cyclobutenes: At a Crossroad between Diastereoselective Syntheses of
Dienes and Unique Palladium-Catalyzed Asymmetric Allylic Substitutions.
Acc. Chem. Res. 2016, 49, 2444-2458.
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2
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4
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22
[M+H]+ calcd for C22H31O5 375.2171; found 375.2158; [α]D
(13)
Souris, C.; Frébault, F.; Patel, A.; Audisio, D.; Houk,
+4.5 (c 1.0, CHCl3). All analytical data match those
previously reported by Bach and coworkers.26 Isomerization
to all-E-configured bretonin A was observed upon standing
at ambient temperature (signals emerging in the region of
6.07 – 5.98 ppm in the 1H-NMR-spectrum).
K. N.; Maulide, N. Stereoselective Synthesis of Dienyl-Carboxylate
Building Blocks: Formal Synthesis of Inthomycin C. Org. Lett. 2013, 15,
3242-3245.
(14)
Kajikawa, T.; Iguchi, N.; Katsumura, S. Olefin
metathesis in carotenoid synthesis. Org. Biomol. Chem. 2009, 7, 4586-
4589.
(15)
Zhang, Y.; Arpin, C. C.; Cullen, A. J.; Mitton-Fry,
ASSOCIATED CONTENT
Supporting Information
M. J.; Sammakia, T. Total Synthesis of Dermostatin A. J. Org. Chem. 2011,
76, 7641-7653.
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Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T. The
Total Synthesis of the Oxopolyene Macrolide RK-397. Angew. Chem. Int.
Ed. 2007, 46, 1066-1070.
The Supporting Information is available free of charge on the ACS
Publications website at...
(17)
Schmidt, B.; Audörsch, S.; Kunz, O. Stereoselective
Copies of 1H and 13C NMR spectra for all new compounds (PDF)
Synthesis of 2Z,4E-Configured Dienoates through Tethered Ring Closing
Metathesis. Synthesis 2016, 48, 4509-4518.
AUTHOR INFORMATION
(18)
Schmidt, B.; Audörsch, S. Stereoselective Total
Synthesis of Atractylodemayne A, a Conjugated 2(E),8(Z),10(E)-Triene-
4,6-diyne. Org. Lett. 2016, 18, 1162–1165.
Corresponding Author
(19)
Bracegirdle, S.; Anderson, E. A. Recent advances in
*E-mail: bernd.schmidt@uni-potsdam.de
the use of temporary silicon tethers in metal-mediated reactions. Chem. Soc.
Rev. 2010, 39, 4114-4129.
ORCID
(20)
Č usak, A. Temporary Silicon-Tethered Ring-
Bernd Schmidt: 0000-0002-0224-6069
Notes
The authors declare no competing financial interest.
Closing Metathesis: Recent Advances in Methodology Development and
Natural Product Synthesis. Chem. Eur. J. 2012, 18, 5800-5824.
(21)
Hanson, P. R. Modular Synthesis of Novel Macrocycles Bearing α , β -
Unsaturated Chemotypes through Series of One-Pot, Sequential
Protocols. Chem. Eur. J. 2016, 22, 6755-6758.
Javed, S.; Bodugam, M.; Torres, J.; Ganguly, A.;
a
ACKNOWLEDGMENTS
Financial support by the Deutsche Forschungsgemeinschaft (DFG
grant Schm1095/6-2) is gratefully acknowledged. We thank Triin
Tikk for technical assistance.
(22)
Quinn, K. J.; Hu, Y.; Miller, P. J.; Walsh, R. T.;
Caporello, M. A.; Maliszewski, M. L.; Markowski, J. H. Synthesis of the
non-adjacent bis(tetrahydrofuran) core of squamostanin C by silicon-
tethered, size-selective triple ring-closing metathesis. Tetrahedron Lett.
2019, 60, 1773-1776.
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