Total syntheses of naturally occurring seimatopolide A and its enantiomer from chiral pool starting materials using a bidirectional strategy

Article abstract of DOI:10.1021/jo302359h

Enantioselective total syntheses of both enantiomers of the recently isolated decanolide natural product seimatopolide A are described. The C ₂-symmetric building blocks (R,R)-hexa-1,5-diene-3,4-diol (derived from d-mannitol) and its enantiomer (derived from l-(+)-tartrate) serve as key starting materials, which are elaborated in a bidirectional way using a selective mono-cross-metathesis, regio-and stereoselective epoxidation, and regioselective reductive epoxide opening to furnish the first fragment. Both enantiomers of the second fragment, 3-hydroxypent-4-enoic acid, were conveniently obtained through a lipase-catalyzed kinetic resolution and merged with the first fragment via Shiina esterification. An E-selective ring-closing metathesis was used to access the 10-membered lactone. A comparison of the specific optical rotations of synthetic seimatopolides with those reported for the natural product suggests that the originally assigned (3R,6R,7R,9S)- configuration should be corrected to (3S,6S,7S,9R).

Full text of DOI:10.1021/jo302359h

Article
pubs.acs.org/joc
Total Syntheses of Naturally Occurring Seimatopolide A and Its
Enantiomer from Chiral Pool Starting Materials Using a Bidirectional
Strategy
Bernd Schmidt,* Oliver Kunz, and Monib H. Petersen
Institut fuer Chemie (Organische Synthesechemie), Universitaet Potsdam, Karl-Liebknecht-Strasse 24-25, D-14476 Potsdam-Golm,
Germany
S
* Supporting Information
ABSTRACT: Enantioselective total syntheses of both enantiomers of
the recently isolated decanolide natural product seimatopolide A are
described. The C2-symmetric building blocks (R,R)-hexa-1,5-diene-3,4-
diol (derived from D-mannitol) and its enantiomer (derived from L-
(+)-tartrate) serve as key starting materials, which are elaborated in a
bidirectional way using a selective mono-cross-metathesis, regio- and
stereoselective epoxidation, and regioselective reductive epoxide opening
to furnish the first fragment. Both enantiomers of the second fragment, 3-
hydroxypent-4-enoic acid, were conveniently obtained through a lipase-
catalyzed kinetic resolution and merged with the first fragment via Shiina
esterification. An E-selective ring-closing metathesis was used to access the 10-membered lactone. A comparison of the specific
optical rotations of synthetic seimatopolides with those reported for the natural product suggests that the originally assigned
(3R,6R,7R,9S)-configuration should be corrected to (3S,6S,7S,9R).
A comparison with other 10-membered lactones reveals that
this is insofar remarkable, as the majority of these natural
products has the opposite configuration at C9, as illustrated for
herbarumins I and II,3,4 pinolidoxin,4−6 and achaetolide7,8
(Chart 2).9,10
INTRODUCTION
■
Seimatopolides A and B are recently isolated and structurally
characterized metabolites of the fungus Seimatosporium
discosioides. They were discovered through a bioactivity-guided
screening and found to activate the γ-subtype of peroxisome
proliferator-activated receptors (PPAR-γ) with EC50 values in
the micromolar range. As these receptors play an important role
in a manifold of metabolic processes, inter alia regulation of the
glucose level, the more active seimatopolide A was proposed as
a potential candidate for the development of a therapeutic
agent against type-2 diabetes.1,2 On the basis of the NMR
spectroscopic analysis of the Mosher esters of seimatopolides A
and B, Hiep et al. assigned the structures shown below with a
(3R,6R,7R,9S)-configuration for seimatopolide A and a
(3R,6S,9S)-configuration for seimatopolide B (Chart 1).1
Chart 2. Structures of Selected Naturally Occurring
Decanolides
Intrigued by the discrepancy between the C9 configurations
published for seimatopolides A and B and those reported for
many other decanolides, we set out to synthesize both
enantiomers of seimatopolide A from chiral pool starting
materials with reliably assigned absolute configurations. We had
just completed the synthesis of seimatopolide A with the
absolute configuration depicted in Chart 1 and embarked on
the synthesis of its enantiomer, when Reddy et al. published a
synthesis of (+)-seimatopolide A, which relies on a Sharpless
asymmetric dihydroxylation as the crucial enantiodetermining
Chart 1. Originally Assigned Structures of Seimatopolides A
and B
Received: October 24, 2012
Published: November 13, 2012
© 2012 American Chemical Society
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step to establish the absolute configurations at C6 and C7.11
On the basis of their results, these authors concluded that the
structure of seimatopolide A was erroneously assigned and
should be corrected for the naturally occurring laevorotatory
enantiomer to (3S,6S,7S,9R). Herein, we present our syntheses
of (+)- and (−)-seimatopolide, starting from a C2-symmetric
building block, which is elaborated in the sense of a
bidirectional synthesis.
metathesis with 1-undecene (6) required some optimization,
and details are provided in Table 1. In the case of TBS-
protected diene 9a, best results were obtained with 2 mol % of
second generation catalyst A,19 2 equiv of 1-undecene (6)
present from the outset, and slow addition of further 3 equiv of
6 over 30 min (entry 5). For the sterically more demanding
trityl derivative 9b, a larger excess of cross-metathesis partner
was required. Interestingly, significantly improved yields were
obtained by using the Ru-indenylidene catalysts B20 and C,21,22
while the catalyst loading could be reduced to 1 mol % at the
same time (entries 8−10).
In the next step, the cross-metathesis products 4a,b were
subjected to Sharpless epoxidation conditions23 using L-
(+)-diethyl tartrate as chiral ligand. Epoxides 10a and 10b
were obtained as single diastereomers in good to excellent
yields without any complications. The next task was the
regioselective reduction of these epoxides with a hydride source
to establish the required 1,3-diol pattern (Table 2).
Precedence for this regioselectivity in the reduction of epoxy
alcohols exists: Sharpless et al. found that Red-Al often gives
better 1,3- to 1,2-diol selectivities than LiAlH4,24 and Page et al.
described that unsatisfactory regioselectivities can be improved
by addition of methanol, which presumably reduces the
reactivity of the Red-Al.25 Our first experiments gave rather
disappointing results: starting from TBS-protected derivative
10a, the reduction could be accomplished in excellent yield
with 4.0 equiv of Red-Al but with an unsatisfactory 2:1 ratio of
regioisomers, with the undesired 1,2-reduction product 11′
being the major isomer (entry 1). Monitoring the reaction by
TLC revealed that even prior to hydrolytic workup the TBS
group was removed to a significant extent. For these reasons,
we chose acidic workup conditions that would ensure a
quantitative deprotection and yield only the triols 11 and 11′ as
products. Reducing the amount of Red-Al to 2.2 equiv and
lowering the temperature to 0 °C (entry 2) as well as addition
of 1 equiv of methanol (entry 3) resulted in a virtually
unaltered ratio of products. The first experiments with trityl-
protected 10b (entries 4 and 5) were also unsuccessful because
no conversion occurred at ambient temperature after 2 days
and the starting material was recovered. However, at elevated
temperatures, the reduction proceeded slowly to the desired
triol 11, which could be reliably obtained in yields higher than
50% (entry 6). In all experiments using trityl derivative 10b, the
undesired regioisomer 11′ was the minor product. Although
the yield of 11 could not be improved by adding methanol, the
amount of undesired triol 11′ was reduced, resulting in a slight
improvement of the regioselectivity (entries 7−9). Gratifyingly,
separation of 11 and 11′ was easily accomplished by
chromatography. The synthesis of the C5−C9 fragment 12
was completed by protection of the C6−C7-diol moiety as a
propylidene acetal.
RESULTS AND DISCUSSION
■
Retrosynthesis. We envisaged a ring-closing metathesis
(RCM) as a macrocyclization step for the synthesis of
seimatopolide A. The required RCM precursor 1 should, in
turn, be accessible from secondary alcohol 2 and carboxylic acid
3. For the synthesis of alcohol 2, the C2-symmetric (R,R)-hexa-
1,5-diene-3,4-diol (5),12−15 which is available in few steps from
D-mannitol, was considered as a suitable starting material. We
planned to subject 5 or possibly a monoprotected derivative to
mono-cross-metathesis with 1-undecene (6). The resulting
allylic alcohol 4 should then undergo a highly regio- and
diastereoselective epoxidation under Sharpless conditions, and
a subsequent regioselective epoxide opening using a hydride
reagent as a nucleophile should furnish fragment 2. For the
reasons outlined above, it was important to devise routes to
both enantiomers of seimatopolide, and therefore having
convenient access to ent-5 was also essential for the entire
strategy. An ex-chiral-pool synthesis of ent-5 was previously
published by Michaelis and Blechert, starting from L-
(+)-tartrate via reduction of the ester with Dibal-H and double
Wittig olefination.16 In order to obtain both enantiomers of the
second fragment, β-hydroxy carboxylic acid 3, a lipase-catalyzed
kinetic resolution17 of the aldol addition product18 resulting
from ethyl acetate (7) and acrolein (8), was considered as the
most convenient solution (Scheme 1).
Scheme 1. Retrosynthetic Analysis of Seimatopolide A
The (6S,7S,9R)-C5−C9 fragment (ent-12) was synthesized
from ent-516 via an analogous sequence of steps (Scheme 3). As
the optimization experiments described above revealed that
significantly better results were obtained for almost all steps
with the trityl derivatives, we used only this protecting group
for the sequence leading to ent-12. Obviously, D-(-)- rather than
L-(+)-diethyl tartrate was required for the Sharpless epoxidation
of ent-4b to obtain ent-10b. As expected, all steps proceeded
with yields and selectivities comparable to those previously
obtained for the synthesis of 12.
Synthesis of (6R,7R,9S)-C5−C9 Fragment 12 and Its
Enantiomer (ent-12). To ensure selective mono-cross-meta-
thesis of diene 5 and subsequent OH-directed monoepox-
idation, the introduction of a sterically demanding protecting
group is required (Scheme 2). Therefore, 5 was first converted
into TBS-ether 9a and trityl ether 9b. The subsequent cross-
Synthesis of (3R)-C1−C4 Fragment 3a and Its
Enantiomer (ent-3a). Racemic ethyl 3-hydroxy-4-pentenoate
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Scheme 2. Synthesis of (6R,7R,9S) Fragment 12 from Mannitol-Derived Diene 5
Table 1. Optimization of Cross-Metathesis Conditions
entry
9
catalyst
catalyst loading (mol %)
6 (equiv)
solvent
c (mol·L−1
)
T (°C)
4
yield (%)
1
2
3
4
9a
9a
9a
9a
9a
9b
9b
9b
9b
9b
A
A
A
A
A
A
A
B
C
C
2
2
2
2
2
2
2
2
1
1
5
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0.2
0.5
0.2
0.5
0.2
0.2
0.5
0.2
0.5
0.5
80
40
40
20
20
80
40
40
20
20
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
51
53
58
66
73
53
58
83
74
92
5
5
5
a
5
2 + 3
6
7
5
5
b
8
5 + 5
9
5
8
10
a
b
2 equiv of 6 present from the start, additional 3 equiv added over 30 min. 5 equiv of 6 present from the start, additional 5 equiv added after 1 h.
(rac-13) was synthesized by aldol addition from ethyl acetate
and acrolein following a literature procedure (Scheme 4).18 For
this particular derivative, an enzymatic kinetic resolution was
unknown; however, the analogous tert-butyl ester had been
resolved using Amano lipase PS.17
tested different protocols for this transformation, and the
conditions and results are summarized in Table 3. Using
Steglich’s conditions26 (entry 1), the desired ester 16 was
obtained in 66% yield. With Yamaguchi’s method27 (entry 2), a
slight improvement was observed, and 16 could be isolated in
73% yield. It should be noted that Reddy et al.11 used the same
method in their seimatopolide A synthesis and isolated 16 in
nearly quantitative yield. In our hands, the best results were
obtained with Shiina’s protocol28 (entry 3), using 2-methyl-6-
nitrobenzoic anhydride (MNBA) as coupling reagent, which
led to a yield of 85% of ester 16. Ring-closing metathesis of 16
proceeded without complications using 10 mol % of second
generation catalyst A under high dilution conditions to the fully
protected decanolide 17 in high yield and with exclusive
formation of the E-isomer. From 17, seimatopolide A could be
synthesized either by stepwise deprotection via the inter-
mediate 18 or by global deprotection using a dichloro-
methane−TFA mixture. Similar to Reddy’s results,11 synthetic
seimatopolide A obtained via this route is dextrorotatory, which
is in marked contrast to the sign and value of the specific
rotation reported for natural seimatopolide A (see Chart1).1
We then synthesized (−)-seimatopolide A starting from ent-
12 and ent-3a via the same route (Scheme 6). Comparable
yields were obtained for each synthetic step, and eventually
laevorotatory (3S,6S,7S,9R)-configured seimatopolide A was
isolated.
We chose isopropenyl acetate as acetylating agent and
novozyme 435 as the lipase. Within 48 h, nearly 50%
conversion was reached, and the acetate (S)-14 and the
resolved β-hydroxy ester (R)-13 were isolated in ca. 40% yield.
After protection of the hydroxy group in (R)-13 as a TBS ether
(R)-15, the ethyl ester was hydrolyzed in wet methanol under
mildly basic conditions, furnishing 3a. Cleavage of the acetate
in (S)-14 requires more carefully controlled conditions because,
otherwise, simultaneous hydrolysis of the ethyl ester might
occur. With (S)-13 in hand, the opposite enantiomer ent-3a was
synthesized analogously via silylation and saponification.
Determination of the enantiomeric ratios was accomplished
on the stage of β-hydroxy esters 13 using HPLC on a chiral
stationary phase, after establishing optimum separation
conditions for the racemate rac-13. For (R)-13, the
enantiomeric ratio was reliably better than 97.5:2.5, whereas
for (S)-13 a ratio of enantiomers better than 92.5:7.5 could be
obtained.
Completion of the Synthesis. The synthesis of
seimatopolide A commenced with the esterification of the
C5−C9 fragment 12 and C1−C4 fragment 3a (Scheme 5). We
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Table 2. Regioselective Reduction of Epoxy Alcohols 10a,b
Scheme 4. Synthesis of 3a and Its Enantiomer (ent-3a)
Red-Al
(equiv)
MeOH
(equiv)
yield (%) yield (%)
entry
1
10
conditions
of 11
of 11′
10a
4.0
2.2
3.1
4.0
2.5
4.0
5.5
4.5
6.0
none
none
1.0
THF, 0.5 h,
68 °C
THF, 0.5 h,
0 °C
THF, 0.5 h,
0 °C
THF, 48 h,
20 °C
THF, 48 h,
20 °C
THF, 96 h,
50 °C
THF, 96 h,
50 °C
THF, 48 h,
65 °C
32
67
2
3
4
5
6
7
8
9
10a
10a
10b
10b
10b
10b
10b
10b
29
30
64
65
none
1.0
none
2.0
54
49
53
54
37
29
23
27
2.0
3.0
THF, 96 h,
65 °C
Scheme 3. Synthesis of (6S,7S,9R) Fragment ent-12 from
Tartrate-Derived Diene ent-5
Scheme 5. Synthesis of (+)-(3R,6R,7R,9S)-Seimatopolide A
Comparison of Specific Rotations Reported for
Seimatopolide and Derivatives. Hiep et al.1 reported a
value for the specific rotation of naturally occurring
seimatopolide A with an assigned (3R,6R,7R,9S)-configuration
that differs significantly from the values obtained by Reddy et
al.11 and by us for the synthetic compound with this
configuration. During the preparation of this paper, two further
total syntheses of (3R,6R,7R,9S)-seimatopolide A were
reported.29,30 In both cases, the authors found a negative
specific rotation, as reported for the natural product, which
leads them to the conclusion that their total syntheses
corroborate the originally assigned absolute configuration.31
Specific rotations and assigned configurations of seimatopolide
A isolated from natural sources or obtained via total synthesis
are summarized in Table 4.
This confusing situation prompted us to investigate the
synthesis and characterization of derivatives of both enan-
tiomers of seimatopolide A. Unfortunately, the complete
esterification of seimatopolide A with Mosher’s reagent32 was
unsuccessful in our hands and resulted in complex mixtures of
partially derivatized products, which could not be reliably
compared with the Mosher esters of seimatopolide A derived
from the natural product by Hiep et al.1 We then sought
alternative methods to distinguish between the enantiomers of
seimatopolide A derivatives and provide enantiomer-specific
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check whether or not crystalline derivatives could be obtained
and characterized by single-crystal X-ray structure analysis using
anomalous dispersion. Although complete esterification of all
hydroxy groups is possible and the resulting para-bromoben-
zoates are solids, we were unable to obtain crystals suitable for
crystallographic analysis (Scheme 7).
Table 3. Esterification Methods Evaluated for the Synthesis
of 16
yield
Scheme 7. Synthesis of Tris-para-bromobenzoates 19 and
ent-19 of Seimatopolides A
3a
(%)
entry (equiv)
method and conditions
of 16
1
1.1
Steglich’s method: DCC (1.1 equiv), DMAP
(20 mol %), CH2Cl2, 20 °C, 16 h
66
2
1.2
Yamaguchi’s method: 2,4,6-trichlorobenzoyl
chloride (1.2 equiv), NEtPri2 (2.2 equiv), DMAP
(25 mol %), CH2Cl2, 20 °C, 16 h
Shiina’s method: MNBA (1.2 equiv), NEtPri2
(2.2 equiv), DMAP (10 mol %), CH2Cl2, 20 °C,
16 h
73
3
1.2
85
Scheme 6. Synthesis of (−)-(3S,6S,7S,9R)-Seimatopolide A
Table 4. Reported Specific Rotations and Assigned Absolute
Configurations for Seimatopolides
Nevertheless, we thought that these derivatives might still be
useful because the para-bromobenzoate moiety should be a
strong chromophore and allow characterization of the
enantiomers by chiroptical methods. For this purpose, circular
dichroism was recorded for both 19 and ent-19 under otherwise
identical conditions. As expected for enantiomers, the CD
spectra are nearly perfect mirror images. While 19, derived
from (+)-seimatopolide, shows a strongly negative Cotton
effect at 254 nm, its enantiomer ent-19 shows a strongly
positive Cotton effect at this wavelength. We predict that a tris-
para-bromobenzoate derivative of naturally occurring seimato-
polide should also have a strongly positive Cotton effect at 254
nm.
assigned
entry
configuration
reported specific rotation
ref
a
1
(3R,6R,7R,9S)
(3S,6S,7S,9R)
(3R,6R,7R,9S)
(3R,6R,7R,9S)
(3R,6R,7R,9S)
(3R,6R,7R,9S)
(3S,6S,7S,9R)
[α]2D6 −188.3 (c 0.05, MeOH)
[α]2D9 −20.8 (c 0.04, MeOH)
[α]2D5 +30.0 (c 0.05, MeOH)
[α]2D5 −143.5 (c 0.05, MeOH)
[α]2D0 −59.3 (c 2.0, MeOH)
[α]2D2 +30.9 (c 0.05, MeOH)
[α]2D2 −27.1 (c 0.05, MeOH)
1
a
2
2,31
b
3
11
b
4
29
b
5
30
c
6
this work
this work
c
7
a
Isolated from natural source and absolute configuration based on
analysis of the corresponding tris-Mosher ester. Synthetic material,
b
with configurations at C6 and C7 established via stereoselective
synthesis. Synthetic material, with configurations at C6 and C7
derived from chiral pool starting materials.
CONCLUSIONS
c
■
In summary, we describe routes to both enantiomers of the
recently discovered naturally occurring decanolide seimatopo-
lide A, starting from C2-symmetric (R,R)- and (S,S)-hexa-1,5-
diene-3,4-diol. As both starting materials are derived from the
well-known chiral pool compounds D-mannitol or L-tartrate, a
reliable assignment of the absolute configuration is possible. A
comparison with the specific rotation reported for the natural
characterization data which might in the future facilitate the
comparison with seimatopolide A derived from the natural
source. To this end, the para-bromobenzoates 19 and ent-19,
respectively, of synthetic (3R,6R,7R,9S)-(+)-seimatopolide A
and (3S,6S,7S,9R)-(−)-seimatopolide A were synthesized to
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(3R,4R,E)-3-(Trityloxy)pentadeca-1,5-dien-4-ol (4b). To a
solution of 9b (500 mg, 1.37 mmol) in CH2Cl2 (2.8 mL) were
added 1-undecene (6, 1.67 g, 10.9 mmol) and Ru catalyst C (9.0 mg, 1
mol %) at room temperature. The solution was stirred for 6 h at room
temperature, and the solvent was evaporated. The residue was purified
by column chromatography on silica (eluent hexanes/MTBE 20:1) to
give 4b (610 mg, 92%) as a colorless oil: [α]2D2 = +15.7 (c 0.57,
CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 7.0, 6H), 7.33−
7.23 (m, 9H), 5.64 (ddd, J = 17.5, 10.5, 8.0, 1H), 5.58 (m, 1H), 5.47
(dd, J = 15.6, 5.8, 1H), 4.87 (dd, J = 10.5, 0.7, 1H), 4.72 (d, J = 17.4,
1H), 3.87 (dd, J = 7.7, 5.8, 1H), 3.77 (dd, J = 5.6, 5.4, 1H), 2.05 (dt, J
= 6.7, 6.7, 2H), 1.87 (d, J = 6.1, 1H), 1.45−1.20 (m, 14H), 0.90 (t, J =
6.3, 3H); 13C NMR (75 MHz, CDCl3) δ 144.8 (0), 136.1 (1), 133.4
(1), 129.1 (1), 128.5 (1), 127.6 (1), 127.1 (1), 117.0 (2), 87.5 (0),
78.8 (1), 73.5 (1), 32.4 (2), 31.9 (2), 29.6 (2), 29.5 (2), 29.3 (2), 29.2
(2), 29.1 (2), 22.6 (2), 14.1 (3); IR (neat) ν 3455 (w), 3058 (m),
2925 (s), 2854 (s), 1597 (w), 1491 (m), 1449 (s); MS (EI) m/z 165
product leads us to the conclusion that naturally occurring
(−)-seimatopolide has most likely a (3S,6S,7S,9R)-configu-
ration, whereas its optical antipode (+)-seimatopolide is
(3R,6R,7R,9S)-configured. Conversion of both enantiomers
into their para-bromobenzoates leads to derivatives which
could be characterized by circular dichroism.
EXPERIMENTAL SECTION
■
General Methods. 1H NMR spectra were obtained at 300, 500, or
600 MHz in CDCl3 or pyridine-d5 with CHCl3 (δ = 7.26 ppm) or
pyridine (δ = 7.22 ppm) as internal standards. Coupling constants (J)
are given in hertz. 13C NMR spectra were recorded at 75, 125, or 150
MHz in CDCl3 or pyridine-d5 with CDCl3 (δ = 77.0 ppm) and
pyridine (δ = 135.9 ppm) as internal standards. The number of
coupled protons was analyzed by DEPT or APT experiments and is
denoted by a number in parentheses following the chemical shift value.
IR spectra were recorded as neat films on NaCl or KBr plates or as
KBr discs. Wavenumbers (ν) are given in cm−1. The peak intensities
are defined as strong (s), medium (m), or weak (w). Low- and high-
resolution mass spectra were obtained by ESI/TOF.
+
(27), 183 (10), 243 (100); HRMS (EI) calcd for C34H42O2 ([M]+)
482.3185, found 482.3180. Anal. Calcd for C34H42O2: C, 84.6%; H,
8.8%. Found: C, 84.4%; H, 8.8%.
(3S,4S,E)-3-(Trityloxy)pentadeca-1,5-dien-4-ol (ent-4b). Fol-
lowing the procedure for 4b, ent-4b was obtained from ent-9b16 (750
mg, 2.1 mmol) as a colorless oil (865 mg, 88%): [α]2D4 = −12.7 (c 0.28,
CH2Cl2). All other analytical data are identical to those reported for
4b.
(3R,4R)-4-(Trityloxy)-hexa-1,5-dien-3-ol (9b). To a solution of
diol 5 (800 mg, 7.1 mmol) in pyridine (5 mL) was added
chlorotriphenyl methane (2.30 g, 8.2 mmol), and the solution was
stirred for 18 h at 65 °C. After cooling to room temperature, water (50
mL) was added and the aqueous layer was extracted three times with
MTBE. The organic layers were washed with aqueous NaHCO3
solution, dried with MgSO4, filtered, and evaporated. The residue
was purified by column chromatography on silica (eluent hexanes/
(1R,2R)-2-(tert-Butyldimethylsilyloxy)-1-((2S,3S)-3-nonyloxir-
an-2-yl)-but-3-en-1-ol (10a). To a solution of Ti(OPri)4 (1.49 mL,
5.0 mmol) in CH2Cl2 (42 mL) was added L-(+)-diethyl tartrate (1.06
mL, 5.9 mmol) at −30 °C. The mixture was stirred at this temperature
for 15 min, and 4a (1.50 g, 4.2 mmol) was added. Stirring at −30 °C
was continued for another 15 min, and tert-butyl hydroperoxide (5.5
M solution in decane, 2.30 mL, 12.6 mmol) was added and the
reaction mixture was then stored in a freezer at −30 °C for 4 days.
After this time, FeSO4 (3.20 g) was dissolved in an aqueous solution of
tartaric acid (15 wt %, 50 mL) and added to the reaction mixture at
−30 °C. The mixture was allowed to warm to room temperature and
filtered through a pad of Celite, extracted three times with MTBE, and
washed with brine. The organic layers were dried with MgSO4, filtered,
and evaporated. The residue was purified by column chromatography
on silica (eluent hexanes/MTBE 10:1) to give 10a (1.26 g, 81%) as a
ethyl acetate 12:1) to give 9b (2.10 g, 89%) as a colorless oil: [α]D24
=
38.4 (c 0.35, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.70−7.59 (m,
6H), 7.43−7.28 (m, 9H), 6.16 (ddd, J = 17.2, 10.7, 4.7, 1H), 5.77
(ddd, J = 18.2, 10.5, 8.0, 1H), 5.32 (d, J = 17.4, 1H), 5.29 (d, J = 10.5,
1H), 5.02 (d, J = 10.5, 1H), 4.90 (d, J = 17.4, 1H), 4.08 (dd, J = 7.6,
5.7, 1H), 3.87 (ddm, J = 5.0, 5.0, 1H), 2.13 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 144.7 (0), 137.0 (1), 135.6 (1), 129.0 (1), 127.6 (1),
127.1 (1), 117.2 (2), 115.7 (2), 87.6 (0), 78.4 (1), 73.0 (1); IR (neat)
ν 3445 (m), 3026 (m), 1959 (w), 1447 (m), 1033 (s), 699 (s); MS
(ESI) m/z 105 (13%), 165 (38%), 243 (100%), 357 ([M + H]+, 2%);
HRMS (ESI) calcd for C25H25O2 ([M + H]+) 357.1855, found
357.1857. Anal. Calcd for C25H24O2: C, 84.2%; H, 6.8%. Found: C,
84.3%; H, 7.2%.
1
colorless oil and as a single diastereomer, as determined by H NMR
spectroscopy of the crude reaction mixture: [α]2D4 = −2.0 (c 0.84,
1
CH2Cl2); H NMR (300 MHz, CDCl3) δ 5.87 (ddd, J = 17.1, 10.5,
(3S,4S)-4-(Trityloxy)hexa-1,5-dien-3-ol (ent-9b). Following the
procedure for 9b, ent-9b was obtained from diol ent-5 (300 mg, 2.6
mmol) as a colorless oil (800 mg, 86%): [α]2D7 = −42.7 (c 0.30,
CH2Cl2). All other analytical data are identical to those reported for
9b.
6.2, 1H), 5.29 (dd, J = 17.2, 1.4, 1H), 5.19 (dd, J = 10.4, 1.2, 1H), 4.27
(ddd, J = 6.2, 4.1, 1.3, 1H), 3.32 (ddd, J = 5.7, 5.7, 4.2, 1H), 2.93 (dt, J
= 6.3, 2.2, 1H), 2.77 (dd, J = 5.8, 2.2, 1H), 2.40 (d, J = 5.7, 1H), 1.70−
1.20 (m, 16H), 0.92 (s, 9H), 0.87 (t, J = 6.5, 3H), 0.11 (s, 3H), 0.07 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 137.5 (1), 116.5(2), 74.8 (1),
74.2 (1), 57.9 (1), 57.3 (1), 31.9 (2), 31.7 (2), 29.5 (2), 29.5 (2), 29.4
(2), 29.3 (2), 25.9 (2), 25.8 (3), 22.6 (2), 18.2 (0), 14.1 (3), −4.3 (3),
−5.0 (3); IR (neat) ν 3448 (m), 2928 (s), 2856 (s), 1644 (w), 1472
(m), 1361 (m), 1253 (s); MS (ESI) m/z 353 (100), 371 (57, [M +
H]+); HRMS (ESI) calcd for C21H43O3Si+ ([M + H]+) 371.2981,
found 371.2950. Anal. Calcd for C21H42O3Si: C, 68.1%; H, 11.4%.
Found: C, 67.8%; H, 11.3%.
(1S,2R)-1-((2S,3S)-3-Nonyloxiran-2-yl)-2-(trityloxy)-but-3-en-
1-ol (10b). To a solution of Ti(OPri)4 (1.67 mL, 5.6 mmol) in
CH2Cl2 (60 mL) was added L-(+)-diethyl tartrate (1.12 mL, 6.7
mmol) at −30 °C. The mixture was stirred at this temperature for 15
min, and 4b (2.25 g, 4.7 mmol) was added. Stirring at −30 °C was
continued for another 15 min, and tert-butyl hydroperoxide (5.5 M
solution in decane, 2.70 mL, 14.1 mmol) was added and the reaction
mixture was then stored in a freezer at −30 °C for 4 days. After this
time, FeSO4 (3.60 g) was dissolved in an aqueous solution of tartaric
acid (15 wt %, 100 mL) and added to the reaction mixture at −30 °C.
The mixture was allowed to warm to room temperature and filtered
through a pad of Celite, extracted three times with MTBE, and washed
with brine. The organic layers were dried with MgSO4, filtered, and
evaporated. The residue was purified by column chromatography on
silica (eluent hexanes/MTBE 10:1) to give 10b (2.20 g, 94%) as a
(3R,4R,E)-3-(tert-Butyldimethylsilyloxy)pentadeca-1,5-diene-
4-ol (4a). To a solution of 9a15 (550 mg, 2.2 mmol) in CH2Cl2 (4.4
mL) were added 1-undecene (6, 0.66 g, 4.4 mmol) and second
generation catalyst A (37 mg, 2 mol %) at room temperature. After
stirring the solution for 5 min, a solution of 1-undecene (6, 1.00 g, 6.6
mmol) in CH2Cl2 (4.4 mL) was added dropwise over a period of 30
min. After stirring the reaction mixture for an additional 15 min, the
reaction was quenched with ethylvinyl ether (0.2 mL) and the solvent
was evaporated. The residue was purified by column chromatography
on silica (eluent hexanes/MTBE 20:1) to give 4a (563 mg, 73%) as a
colorless oil: [α]2D4 = −4.8 (c 0.96, CH2Cl2); H NMR (300 MHz,
1
CDCl3) δ 5.80 (ddd, J = 17.1, 10.5, 6.5, 1H), 5.70 (ddt, J = 15.4, 6.7,
1.0, 1H), 5.41 (ddd, J = 15.4, 6.5, 1.4, 1H), 5.22 (dd, J = 17.2, 1.2, 1H),
5.16 (dd, J = 10.4, 1.1, 1H), 3.94 (ddd, J = 6.3, 6.2, 1.1, 1H), 3.86 (dd,
J = 6.3, 6.2, 1H), 2.55 (br s, 1H), 2.04 (dt, J = 6.8, 5.9, 2H), 1.45−1.20
(m, 14H), 0.94−0.86 (m, 12H), 0.08 (s, 3H), 0.05 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 138.0 (1), 133.9 (1), 128.5 (1), 116.6 (2), 77.8
(1), 75.7 (1), 32.4 (2), 31.9 (2), 29.6 (2), 29.5 (2), 29.3 (2), 29.2 (2),
29.1 (2), 25.8 (3), 22.7 (2), 18.2 (0), 14.1 (3), −4.1 (3), −4.9 (3); IR
(neat) ν 3567 (m), 3466 (m), 2925 (s), 2856 (s), 1645 (w), 1472 (m),
1361 (m), 1253 (s); MS (ESI) m/z 337 (100), 355 (2, [M + H]+),
377 (2, [M + Na]+); HRMS (ESI) calcd for C21H43O2Si+ ([M + H]+)
355.3032, found 355.3009.
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1
colorless oil and as a single diastereomer, as determined by H NMR
spectroscopy of the crude reaction mixture: [α]2D2 = +24.0 (c 0.31,
CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 6.8, 6H), 7.33−
7.23 (m, 9H), 5.77 (ddd, J = 16.9, 10.2, 7.3, 1H), 4.97 (d, J = 10.2,
1H), 4.95 (d, J = 16.9, 1H), 4.12 (dd, J = 7.1, 5.2, 1H), 3.33 (ddd, J =
7.1, 4.2, 2.6, 1H), 2.95−2.90 (m, 2H), 1.86 (d, J = 4.1, 1H), 1.60−1.20
(m, 16H), 0.90 (t, J = 6.4, 3H); 13C NMR (75 MHz, CDCl3) δ 144.5
(0), 135.7 (1), 129.0 (1), 127.7 (1), 127.2 (1), 116.7 (2), 87.8 (0),
76.7 (1), 70.4 (1), 58.0 (1), 55.4 (1), 31.9 (2), 31.6 (2), 29.5 (2), 29.5
(2), 29.5 (2), 29.3 (2), 25.9 (2), 22.6 (2), 14.1 (3); IR (neat) ν 3446
(m), 3058 (m), 3023 (m), 2926 (s), 2854 (s), 1597 (w), 1491 (m),
1449 (s), 1220 (m); MS (EI) m/z 165 (20), 243 (100); HRMS (EI)
calcd for C34H42O3+ ([M]+) 498.3134, found 498.3128. Anal. Calcd for
C34H42O3: C, 81.9%; H, 8.5%. Found: C, 81.6%; H, 8.9%.
was quenched by addition of aqueous NaHCO3 solution (20 mL), and
the aqueous layer was extracted three times with MTBE (20 mL). The
organic layers were dried with MgSO4, filtered, and evaporated. The
residue was purified by column chromatography on silica (eluent
hexanes/MTBE 3:1) to give 12 (481 mg, 91%) as a colorless oil: [α]D27
= +6.2 (c 0.40, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 5.79 (ddd, J
= 17.3, 10.2, 7.2, 1H), 5.35 (dd, J = 17.2, 0.9, 1H), 5.25 (dd, J = 10.2,
0.7, 1H), 3.04 (dd, J = 8.5, 7.3, 1H), 3.96−3.80 (m, 2H), 2.35 (br s,
3H), 1.67 (m, 2H), 1.52−1.20 (m, 22H), 0.87 (t, J = 6.5, 3H); 13C
NMR (75 MHz, CDCl3) δ 135.0 (1), 118.9 (2), 108.9 (0), 82.3 (1),
77.9 (1), 68.9 (1), 37.8 (2), 37.6 (2), 31.9 (2), 29.6 (2), 29.6 (2), 29.5
(2), 29.3 (2), 27.3 (3), 26.9 (3), 25.6 (2), 22.6 (2), 14.0 (3); IR (neat)
ν 3441 (w), 2924 (s), 2854 (s), 1461 (m), 1374 (s), 1223 (s); MS
(ESI) m/z 223 (100), 241 (40), 299 ([M + H]+, 18); HRMS (ESI)
+
calcd for C18H35O3 ([M + H]+) 299.2586, found 299.2577. Anal.
(1R,2S)-1-((2R,3R)-3-Nonyloxiran-2-yl)-2-(trityloxy)-but-3-en-
1-ol (ent-10b). Following the procedure for 10b and replacing L-
(+)-diethyl tartrate by D-(−)-diethyl tartrate, ent-10b was obtained
from ent-4b (600 mg, 1.2 mmol) as a colorless oil (543 mg, 88%):
[α]2D2 = −23.9 (c 0.44, CH2Cl2). All other analytical data are identical
to those reported for 10b.
Calcd for C18H34O3: C, 72.4%; H, 11.5%. Found: C, 72.2%; H, 11.9%.
(R)-1-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-
undecan-2-ol (ent-12). Following the procedure for 12, ent-12 was
obtained from ent-11 (150 mg, 0.58 mmol) as a colorless oil (151 mg,
87%): [α]2D3 = −5.8 (c 0.41, CH2Cl2). All other analytical data are
identical to those reported for 12.
(3R,4R,6S)-Pentadec-1-ene-3,4,6-triol (11) and (3R,4R,5R)-
Pentadec-1-ene-3,4,5-triol (11′). To a solution of 10b (500 mg,
1.0 mmol) in THF (10 mL) was added methanol (0.122 mL, 3.0
mmol) at 0 °C. To this mixture was added Red-Al (3.3 M solution in
toluene, 1.80 mL, 6.0 mmol), and the reaction mixture was stirred for
4 days at 65 °C. After cooling to ambient temperature, 1 M HCl (aq.,
10 mL) was added and the aqueous layer was extracted three times
with MTBE. The organic layers were dried with MgSO4, filtered, and
evaporated. The crude residue was diluted in DCM (20 mL), p-
toluenesulfonic acid (17.2 mg, 10 mol %) was added, and the reaction
mixture was stirred for 1 h at room temperature. The reaction was
quenched by addition of aqueous NaHCO3 solution (20 mL), and the
aqueous layer was extracted three times with MTBE (20 mL). The
organic layers were dried with MgSO4, filtered, and evaporated. The
residue was purified by column chromatography on silica (eluent
hexanes/MTBE 1:1) to give 11 (139 mg, 54%) and 11′ (70 mg, 27%)
as white solids. Analytical data for (3R,4R,6S)-pentadec-1-ene-3,4,6-triol
(11): mp 76 °C; [α]2D3 = +13.4 (c 0.37, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 5.83 (ddd, J = 17.1, 10.5, 6.6, 1H), 5.32 (d, J = 17.2, 1H),
5.23 (d, J = 10.5, 1H), 3.98 (dd, J = 6.6, 6.6, 1H), 3.90 (m, 1H), 3.78
(m, 1H), 3.20 (br s, 3H), 1.70−1.20 (m, 18H), 0.87 (t, J = 6.4, 3H);
13C NMR (75 MHz, CDCl3) δ 137.2 (1), 117.6 (2), 76.3 (1), 71.8 (1),
69.1 (1), 38.6 (2), 37.6 (2), 31.9 (2), 29.6 (2), 29.6 (2), 29.5 (2), 29.3
(2), 25.7 (2), 22.6 (2), 14.1 (3); IR (neat) ν 3321 (m), 2954 (m),
2919 (s), 2850 (m), 1468 (w), 1064 (m); MS (ESI) m/z 281 ([M +
Na]+, 100); HRMS (ESI) calcd for C15H30O3Na+ ([M]+) 281.2093,
found 281.2069. Analytical data for (3R,4R,5R)-pentadec-1-ene-3,4,5-
triol (11′): mp 89 °C; [α]2D3 = +17.1 (c 0.44, CH2Cl2); 1H NMR (300
MHz, CDCl3) δ 5.92 (ddd, J = 17.2, 10.6, 5.6, 1H), 5.37 (dd, J = 17.3,
1.4, 1H), 5.25 (dd, J = 10.6, 1.3, 1H), 4.40 (m, 1H), 3.76 (dq, J = 4.9,
4.6, 1H), 3.42 (dd, J = 3.5, 3.2, 1H), 3.29 (br s, 1H), 2.97 (br s, 2H),
1.57−1.20 (m, 18H), 0.88 (t, J = 6.4, 3H); 13C NMR (75 MHz,
CDCl3) δ 137.5 (1), 116.8 (2), 75.1 (1), 73.9 (1), 72.3 (1), 32.9 (2),
31.9 (2), 29.6 (2), 29.6 (2), 29.6 (2), 29.3 (2), 25.9 (2), 22.7 (2), 14.1
(3); IR (neat) ν 3330 (m), 2919 (s), 2851 (m), 1463 (w), 1069 (m);
MS (ESI) m/z 281 ([M + Na]+, 100); HRMS (ESI) calcd for
C15H30O3Na+ ([M]+) 281.2093, found 281.2108.
Ethyl 3-Hydroxypent-4-enoate (rac-13).18 To a solution of
diisopropylamine (7.7 mL, 55 mmol) in THF (200 mL) was added n-
butyllithium (2.5 M in hexane, 22 mL, 55 mmol) at −78 °C. The
solution was stirred for 15 min, ethylacetate (4.9 mL, 50 mmol) was
added, and the reaction mixture was stirred for 45 min at −78 °C. To
the solution was added acrolein (3.4 mL, 50 mmol), and the mixture
was stirred for another 15 min at −78 °C. The reaction was quenched
by addition of aqueous NH4Cl solution (50 mL), and the aqueous
layer was extracted three times with MTBE. The organic layers were
washed with brine, dried with MgSO4, filtered, and evaporated. The
residue was purified by column chromatography on silica (eluent
hexanes/MTBE 8:1) to give rac-13 (6.4 g, 89%) as a colorless oil. All
analytical data are identical to those reported below for (R)-13.
(R)-Ethyl 3-Hydroxypent-4-enoate ((R)-13) and (S)-Ethyl 3-
Acetoxy-pent-4-enoate ((S)-14). To a solution of rac-13 (1.44 g,
10.0 mmol) in toluene (50 mL) were added novozyme 435 (100 mg)
and isopropenyl acetate (1.1 mL, 10.0 mmol), and the reaction
mixture was stirred for 48 h at room temperature. After this time, the
mixture was filtered through a pad of Celite, washed three times with
MTBE, and the solvent was evaporated. The residue was purified by
column chromatography on silica (eluent hexanes/hexane 8:1) to give
(R)-13 (608 mg, 42%, >95% ee (HPLC)) and acetate (S)-14 (771 mg,
41%) as colorless oils. (R)-Ethyl 3-hydroxypent-4-enoate ((R)-13): [α]D23
= +4.6 (c 0.31, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 5.86 (ddd, J
= 17.1, 10.4, 5.5, 1H), 5.29 (dd, J = 17.2, 1.3, 1H), 5.12 (dd, J = 10.5,
1.2, 1H), 4.51 (ddm, J = 6.2, 5.6, 1H), 4.14 (q, J = 7.1, 2H), 3.09 (br s,
1H), 2.56 (dd, J = 16.1, 2.5, 1H), 2.47 (dd, J = 16.2, 6.9, 1H), 1.25 (t, J
= 7.1, 3H); 13C NMR (75 MHz, CDCl3) δ 172.1 (0), 138.9 (1), 115.2
(2), 68.9 (1), 60.7 (2), 41.2 (2), 14.1 (1); IR (neat) ν 3452 (m), 2984
(m), 1721 (s), 1371 (m), 1173 (s); MS (ESI) m/z 122 (100%), 127
(28%), 167 ([M + Na]+, 32%); HRMS (ESI) calcd for C7H12O3Na
([M + Na]+) 167.0694, found 167.0696. Anal. Calcd for C7H12O3: C,
58.3%; H, 8.4%. Found: C, 57.9%; H, 8.3%. (S)-Ethyl 3-acetoxy-pent-4-
enoate ((S)-14): [α]2D3 = −6.9 (c 0.86, CH2Cl2); H NMR (300 MHz,
1
CDCl3) δ 5.82 (ddd, J = 17.0, 10.4, 6.3, 1H), 5.61 (dt, J = 7.0, 6.3,
1H), 5.28 (d, J = 17.2, 1H), 5.18 (d, J = 10.5, 1H), 4.13 (q, J = 7.1,
2H), 2.67 (dd, J = 15.6, 7.8, 1H), 2.56 (dd, J = 15.6, 5.8, 1H), 2.03 (s,
3H), 1.22 (t, J = 7.1, 3H); 13C NMR (75 MHz, CDCl3) δ 169.6 (0),
169.6 (0), 135.1 (1), 117.3 (2), 70.7 (1), 60.6 (2), 39.4 (2), 20.9 (3),
14.1 (1); IR (neat) ν 3087 (m), 2986 (m), 2935 (m), 1739 (s), 1373
(m), 1232 (s); MS (ESI) m/z 127 (100%), 187 ([M + H]+, 70%);
HRMS (ESI) calcd for C9H15O4 ([M + H]+) 187.0970, found
187.0959.
(S)-Ethyl 3-Hydroxypent-4-enoate ((S)-13). To a solution of
acetate (S)-14 (1.0 g, 5.4 mmol) in ethanol (20 mL) was added
concentrated HCl (aq.) (0.1 mL), and the mixture was heated to reflux
for 10 h. After this time, saturated NaHCO3 solution (50 mL) was
added and the aqueous layer was extracted three times with MTBE.
The organic layers were dried with MgSO4, filtered, and evaporated.
(3S,4S,6R)-Pentadec-1-ene-3,4,6-triol (ent-11) and
(3S,4S,5S)-pentadec-1-ene-3,4,5-triol (ent-11′). Following the
procedure for 11, ent-11 was obtained from ent-10b (500 mg, 1.0
mmol) as a colorless solid (140 mg, 55%), along with the regioisomer
ent-11′ (58 mg, 22%). (3S,4S,6R)-Pentadec-1-ene-3,4,6-triol (ent-11):
[α]2D2 = −12.2 (c 0.39, CH2Cl2). (3S,4S,5S)-Pentadec-1-ene-3,4,5-triol
(ent-11′): [α]2D2 = −7.5 (c 0.41, CH2Cl2). All other analytical data are
identical to those reported for 11 and 11′, respectively.
(S)-1-((4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-unde-
can-2-ol (12).11 To a solution of 11 (460 mg, 1.8 mmol) in CH2Cl2
(50 mL) were added 2,2-dimethoxy propane (0.65 mL, 5.34 mmol)
and p-toluenesulfonic acid (31 mg, 10 mol %) at room temperature.
The solution was stirred for 30 min at room temperature. The reaction
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The residue was purified by column chromatography on silica (eluent
hexanes/hexane 3:1) to give (S)-13 (740 mg, 95%, >85% ee (HPLC))
as colorless oil: [α]2D3 = −4.7 (c 1.09, CH2Cl2). All other analytical data
are identical to those reported for (R)-13.
solution, and the aqueous layer was extracted three times with MTBE
(20 mL). The organic layers were washed with aqueous NaHCO3
solution and aqueous NH4Cl solution and dried with MgSO4, filtered,
and evaporated. The residue was purified by column chromatography
on silica (eluent hexanes/MTBE 20:1) to give 16 (223 mg, 73%) as a
colorless oil.
(R)-Ethyl 3-(tert-Butyldimethylsilyloxy)-pent-4-enoate ((R)-
15). To a solution of (R)-13 (620 mg, 4.3 mmol) in CH2Cl2 (40
mL) were added imidazole (439 mg, 6.5 mmol) and tert-
butyldimethylsilyl chloride (713 mg, 4.7 mmol) at 0 °C. The solution
was stirred for 12 h at room temperature. After this time, water (50
mL) was added and the aqueous layer was extracted three times with
MTBE. The organic layers were dried with MgSO4, filtered, and
evaporated. The residue was purified by column chromatography on
silica (eluent hexanes/MTBE 10:1) to give (R)-15 (1.04 g, 94%) as a
Shiina’s Method: A solution of 3a (117 mg, 0.50 mmol), MNBA
(176 mg, 0.50 mmol), ethyl diisopropylamine (0.181 mL, 1.05 mmol),
and DMAP (5.1 mg, 10 mol %) in CH2Cl2 (2 mL) was stirred for 20
min at room temperature. To this mixture was added 12 (126 mg, 0.42
mmol) in CH2Cl2 (4 mL), and the solution was stirred for 5 h at room
temperature. The reaction was diluted with MTBE (20 mL), quenched
by addition of water, and the aqueous layer was extracted three times
with MTBE (20 mL). The organic layers were washed with aqueous
NaHCO3 solution and aqueous NH4Cl solution and dried with
MgSO4, filtered, and evaporated. The residue was purified by column
chromatography on silica (eluent hexanes/MTBE 20:1) to give 16
colorless oil: [α]2D2 = +5.7 (c 0.37, CH2Cl2); H NMR (300 MHz,
1
CDCl3) δ 5.83 (ddd, J = 16.9, 10.3, 6.1, 1H), 5.22 (d, J = 17.2, 1H),
5.06 (d, J = 10.3, 1H), 4.57 (dt, J = 6.7, 6.3, 1H), 4.14 (m, 2H), 2.51
(dd, J = 14.5, 7.6, 1H), 2.43 (dd, J = 14.5, 5.3, 1H), 1.25 (t, J = 7.1,
3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 171.0 (0), 140.4 (1), 114.5 (2), 70.9 (1), 60.3 (2), 43.8 (2),
25.7 (3), 18.1 (0), 14.2 (1), −4.4 (3), −5.1 (3); IR (neat) ν 2957 (m),
2930 (m), 2858 (m), 1737 (s), 1252 (m), 1178 (m); MS (ESI) m/z
196 (100%), 259 ([M + H]+, 5%); HRMS (ESI) calcd for C13H27O3Si
([M + H]+) 259.1729, found 259.1752.
(182 mg, 85%) as a colorless oil: [α]2D7 = +0.8 (c 0.33, CH2Cl2); H
1
NMR (300 MHz, CDCl3) δ 5.84 (ddd, J = 16.9, 10.3, 6.1, 1H), 5.77
(ddd, J = 17.3, 10.3, 7.4, 1H), 5.37 (d, J = 17.1, 1H), 5.25 (d, J = 10.1,
1H), 5.22 (dd, J = 17.1, 1.4, 1H), 5.06 (dd, J = 10.4, 1.3, 1H), 5.00 (tt,
J = 7.4, 6.0, 1H), 4.57 (dd, J = 8.0, 7.7, 1H), 3.67 (dm, J = 8.4, 1H),
2.55 (dd, J = 15.0, 6.8, 1H), 2.42 (dd, J = 15.0, 6.3, 1H), 1.85−1.50 (m,
4H), 1.40−1.20 (m, 20H), 0.90−0.85 (m, 12H), 0.06 (s, 3H), 0.05 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 170.4 (0), 140.3 (1), 135.0 (1),
119.0 (2), 114.6 (2), 108.9 (0), 82.8 (1), 77.4 (1), 72.1 (1), 70.6 (1),
43.8 (2), 36.7 (2), 34.5 (2), 31.9 (2), 29.5 (2), 29.5 (2), 29.3 (2), 27.3
(3), 26.9 (3), 25.8 (3), 25.0 (2), 22.6 (2), 18.1 (0), 14.0 (3), −4.5 (3),
−4.9 (3); IR (neat) ν 2927 (s), 2856 (m), 1736 (s), 1371 (m), 1250
(s), 1174 (s); MS (ESI) m/z 453 (100), 511 ([M + H]+, 75); HRMS
(ESI) calcd for C29H55O5Si+ ([M + H]+) 511.3819, found 511.3825.
Anal. Calcd for C29H54O5Si: C, 68.2%; H, 10.7%. Found: C, 68.1%; H,
11.0%.
(S)-((R)-1-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-
undecan-2-yl)-3-(tert-butyldimethylsilyloxy)pent-4-enoate
(ent-16). Following the procedure for 16 (Shiina’s method), ent-16
was obtained from ent-12 (133 mg, 0.45 mmol) and ent-3a (123 mg,
0.54 mmol) as a colorless oil (185 mg, 81%): [α]2D3 = −2.1 (c 0.49,
CH2Cl2). All other analytical data are identical to those reported for
16.
(S)-Ethyl 3-(tert-Butyldimethylsilyloxy)-pent-4-enoate ((S)-
15). Following the procedure for (R)-15, (S)-15 was obtained from
(S)-13 (390 mg, 2.7 mmol) as a colorless oil (663 mg, 95%): [α]D22
=
−5.1 (c 0.54, CH2Cl2). All other analytical data are identical to those
reported for (R)-15.
(R)-3-(tert-Butyldimethylsilyloxy)-pent-4-enoic acid (3a).11
To a solution of (R)-15 (500 mg, 1.93 mmol) in methanol (5 mL)
and water (1 mL) was added K2CO3 (534 mg, 3.86 mmol) at room
temperature. The reaction mixture was stirred for 5 h under reflux.
After cooling to room temperature, HCl (aq.) (1 M, 10 mL) was
added, and the aqueous layer was extracted three times with MTBE.
The organic layers were dried with MgSO4, filtered, and evaporated.
The residue was purified by column chromatography on silica (eluent
hexanes/hexane 3:1) to give 3a (405 mg, 91%) as a colorless oil: [α]D22
= −7.6 (c 0.61, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 5.85 (ddd, J
= 16.8, 10.3, 6.1, 1H), 5.25 (dd, J = 17.1, 1.3, 1H), 5.11 (dd, J = 10.3,
1.2, 1H), 4.57 (dt, J = 6.8, 6.1, 1H), 2.57 (dd, J = 14.9, 7.2, 1H), 2.51
(dd, J = 14.9, 5.5, 1H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 176.6 (0), 139.7 (1), 115.2 (2), 70.6 (1),
43.3 (2), 25.7 (3), 18.1 (0), −4.4 (3), −5.2 (3); IR (neat) ν 2956 (m),
2930 (m), 2858 (m), 1711 (s), 1253 (m), 1085 (m); MS (ESI) m/z
231 ([M + H]+, 100%); HRMS (ESI) calcd for C11H23O3Si ([M +
H]+) 231.1416, found 231.1418. Anal. Calcd for C11H22O3Si: C,
57.4%; H, 9.6%. Found: C, 57.1%; H, 9.8%.
(3aR,5S,9R,11aR,E)-9-(tert-Butyldimethylsilyloxy)-2,2-di-
methyl-5-nonyl-4,5,8,9-tetrahydro-3aH-[1,3]dioxolo[4,5-d]-
oxecin-7-(11aH)-one (17).11 To a solution of 16 (185 mg, 0.36
mmol) in CH2Cl2 (360 mL) was added second generation catalyst A
(31 mg, 10 mol %), and the solution was stirred at 40 °C for 4 h. The
solvent was evaporated, and the residue was purified by column
chromatography on silica (eluent hexanes/MTBE 40:1) to give 17
1
(S)-3-(tert-Butyldimethylsilyloxy)-pent-4-enoic acid (ent-3a).
Following the procedure for 3a, ent-3a was obtained from (S)-15 (500
mg, 1.93 mmol) as a colorless oil (400 mg, 90%): [α]2D2 +7.2 (c 0.51,
CH2Cl2). All other analytical data are identical to those reported for
3a.
(R)-((S)-1-((4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-
undecan-2-yl)-3-(tert-butyl-dimethylsilyloxy)pent-4-enoate
(16).11 Steglich’s Method: To a solution of 12 (38 mg, 0.13 mmol) in
dichloromethane (5 mL) were added 3a (33 mg, 0.14 mmol),
dicyclohexylcarbodiimide (29 mg, 0.14 mmol), and DMAP (3.2 mg,
20 mol %) at 0 °C. The mixture was allowed to warm to room
temperature and stirred for 1 day. The solution was filtered and
washed three times with dichloromethane. The combined organic
layers were washed with 1 M HCl (aq.) and with aqueous NaHCO3
solution, dried with MgSO4, filtered, and evaporated. The residue was
purified by column chromatography on silica (eluent hexanes/MTBE
20:1) to give 16 (44 mg, 66%) as a colorless oil.
(161 mg, 92%) as a colorless oil: [α]2D7 = +15.2 (c 0.37, CH2Cl2); H
NMR (300 MHz, CDCl3) δ 5.90 (dd, J = 15.4, 2.4, 1H), 5.66 (ddd, J =
15.4, 9.3, 1.6, 1H), 4.92 (dt, J = 7.6, 6.4, 1H), 4.66 (m, 1H), 4.06 (dd, J
= 8.9, 8.7, 1H), 3.62 (dd, J = 8.6, 8.4, 1H), 2.56 (d, J = 3.5, 1H), 2.05
(d, J = 5.2, 1H), 1.86 (m, 1H), 1.60−1.20 (m, 22H), 0.92 (s, 9H), 0.87
(t, J = 6.5, 1H), 0.10 (s, 3H), 0.06 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 168.4 (0), 137.5 (1), 123.3 (1), 107.9 (0), 84.3 (1), 81.8
(1), 72.5 (1), 67.8 (1), 45.3 (2), 36.8 (2), 36.1 (2), 31.9 (2), 29.4 (2),
29.2 (2), 27.0 (3), 27.0 (3), 25.8 (3), 25.2 (2), 22.6 (2), 18.3 (0), 14.0
(3), −4.9 (3), −5.2 (3); IR (neat) ν 2927 (s), 2856 (m), 1738 (s),
1371 (m), 1253 (s), 1157 (s); MS (ESI) m/z 144 (100), 293 (50),
483 ([M + H]+, 74); HRMS (ESI) calcd for C27H51O5Si+ ([M + H]+)
483.3506, found 483.3474.
(3aS,5R,9S,11aS,E)-9-(tert-Butyldimethylsilyloxy)-2,2-di-
methyl-5-nonyl-4,5,8,9-tetrahydro-3aH-[1,3]dioxolo[4,5-d]-
oxecin-7(11aH)-one (ent-17). Following the procedure for 17, ent-
17 was obtained from ent-16 (160 mg, 0.31 mmol) as a colorless oil
(145 mg, 96%): [α]2D3 = −15.7 (c 0.28, CH2Cl2). All other analytical
data are identical to those reported for 17.
Yamaguchi’s Method: To a solution of 3a (166 mg, 0.72 mmol),
2,4,6-trichlorobenzoyl chloride (0.113 mL, 0.72 mmol), and 12 (180
mg, 0.60 mmol) in THF (10 mL) were added ethyl diisopropylamine
(0.228 mL, 1.32 mmol) and DMAP (18.3 mg, 25 mol %). The
solution was stirred for 4 h at room temperature. The reaction was
diluted with MTBE (20 mL), quenched by addition of aqueous NH4Cl
(3aR,5S,9R,11aR,E)-9-Hydroxy-2,2-dimethyl-5-nonyl-4,5,8,9-
tetrahydro-3aH-[1,3]dioxolo[4,5-d]oxecin-7(11aH)-one (18). To
a solution of 17 (80 mg, 0.17 mmol) in THF (2 mL) was added TBAF
(62 mg, 0.20 mmol), and the solution was stirred for 1 h at room
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The Journal of Organic Chemistry
Article
temperature. The reaction was quenched by addition of water, and the
aqueous layer was extracted three times with MTBE. The combined
organic layers were dried with MgSO4, filtered, and evaporated. The
residue was purified by column chromatography on silica (eluent
hexanes/MTBE 1:1) to give 18 (52 mg, 87%) as a colorless oil: [α]D28
= +22.8 (c 0.20, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 5.91 (dd, J
= 15.9, 2.3, 1H), 5.63 (dd, J = 15.9, 9.2, 1H), 5.05 (dt, J = 9.8, 6.4,
1H), 4.71 (m, 1H), 4.06 (dd, J = 8.8, 8.6, 1H), 3.64 (dd, J = 8.8, 8.6,
1H), 2.63 (dd, J = 12.1, 2.3, 1H), 2.52 (dd, J = 12.1, 3.7, 1H), 2.07 (d,
J = 15.3, 1H), 1.89 (m, 1H), 1.60−1.20 (m, 22H), 0.87 (t, J = 7.0,
1H); 13C NMR (75 MHz, CDCl3) δ 169.9 (0), 136.8 (1), 123.2 (1),
108.2 (0), 84.0 (1), 81.7 (1), 73.0 (1), 67.3 (1), 44.4 (2), 37.0 (2),
36.0 (2), 31.8 (2), 29.4 (2), 29.4 (2), 29.3, 29.2, 27.0 (3), 26.9 (3),
25.2 (2), 22.6 (2), 14.0 (3); IR (neat) ν 3454 (m), 2924 (s), 2855
(m), 1730 (s), 1371 (m), 1233 (s), 1156 (s); MS (ESI) m/z 369 ([M
+ H]+, 100); HRMS (ESI) calcd for C21H37O5+ ([M + H]+) 369.2641,
found 369.2652.
131.7, 131.6, 131.4, 131.0, 131.0, 128.6, 128.5, 128.4, 128.3, 122.4,
77.4, 75.3, 72.8, 68.3, 41.1, 39.5, 36.7, 31.8, 29.5, 29.4, 29.4, 29.2, 24.8,
22.6, 14.1; IR (neat) ν 2924 (s), 2854 (m), 1713 (s), 1589 (m), 1398
(m), 1261 (s), 1100 (s); HRMS (ESI) calcd for C39H42O879Br3+ ([M +
H]+) 875.0430, found 875.0397.
(2R,4S,5S,8S,E)-2-Nonyl-10-oxo-3,4,5,8,9,10-hexahydro-2H-
oxecine-4,5,8-triyl Tris(4-bromobenzoate) (ent-19). Following
the procedure for 19, ent-19 was obtained from (3S, 6S, 7S, 9R)-
(-)-seimatopolide A (12 mg, 0.037 mmol) as a white solid (29 mg,
90%): [α]2D2 +114.7 (c 0.17, CH2Cl2). All other analytical data are
identical to those reported for 19.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
General experimental details, analytical data, copies of H and
13C NMR spectra for all new compounds, copies of HPLC
chromatograms for compound rac-13 and its separate
enantiomers, and copies of the UV spectrum, the individual
CD spectra, and superimposed CD spectra for 19 and ent-19.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(+)-(3R, 6R, 7R, 9S)-Seimatopolide A.11 Global deprotection of
compound 17: To a solution of 17 (150 mg, 0.31 mmol) in DCM (10
mL) was added TFA (2.5 mL) at 0 °C, and the solution was stirred for
24 h at room temperature. The reaction was quenched by addition of
aqueous NaHCO3 solution (30 mL), and the aqueous layer was
extracted three times with MTBE. The combined organic layers were
dried with MgSO4, filtered, and evaporated. The residue was purified
by column chromatography on silica (eluent hexanes/ethyl acetate
1:4) to give (+)-(3R,6R,7R,9S)-seimatopolide A (75 mg, 74%) as a
white solid. Stepwise deprotection of compound 18: To a solution of 18
(85 mg, 0.23 mmol) in THF (2 mL) were added water (0.5 mL) and
TFA (2 mL) at 0 °C, and the solution was stirred for 16 h at room
temperature. The reaction was quenched by addition of aqueous
NaHCO3 solution (30 mL), and the aqueous layer was extracted three
times with ethyl acetate. The combined organic layers were dried with
MgSO4, filtered, and evaporated. The residue was purified by column
chromatography on silica (eluent hexanes/ethyl acetate 1:2) to give
(+)-(3R,6R,7R,9S)-seimatopolide A (71 mg, 94%) as a white solid:
AUTHOR INFORMATION
Corresponding Author
*E-mail: bernd.schmidt@uni-potsdam.de.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was generously supported by the Deutsche
Forschungsgemeinschaft (DFG Grant Schm1095/6-2). We
thank Evonik Oxeno for generous donations of solvents and
Umicore (Hanau, Germany) for generous donations of
metathesis catalysts M2 and M51. We thank Dr. Werner
Fudickar for recording UV and CD spectra, and Prof. Pablo
Wessig for helpful discussions.
[α]2D2 = +30.9 (c 0.05, MeOH); H NMR (600 MHz, pyridine-d5) δ
1
6.46 (ddd, J = 15.7, 9.5, 1.0, 1H), 6.14 (dd, J = 15.7, 3.1, 1H), 5.14 (dt,
J = 6.8, 6.5, 1H), 4.96 (m, 1H), 4.40 (dd, J = 9.1, 9.1, 1H), 3.97 (dd, J
= 8.7, 8.5, 1H), 2.86 (dd, J = 11.6, 3.2, 1H), 2.73 (dd, J = 11.6, 3.9,
1H), 2.34−2.24 (m, 2H), 1.67 (m, 1H), 1.57 (m, 1H), 1.40−1.15 (m,
14H), 0.86 (t, J = 7.1, 1H); 13C NMR (150 MHz, pyridine-d5) δ 170.8,
136.8, 128.3, 79.9, 77.4, 73.7, 67.5, 44.9, 42.5, 37.7, 32.4, 30.2, 30.2,
30.1, 29.9, 25.8, 23.3, 14.6; IR (neat) ν 3344 (m), 2927 (s), 2857 (m),
1667 (s), 1448 (m), 1195 (s), 1138 (s); MS (ESI) m/z 329 ([M +
H]+, 14), 351 ([M + H]+, 21), 359 (100); HRMS (ESI) calcd for
C18H32O5Na+ ([M + Na]+) 351.2147, found 351.2169.
(−)-(3S,6S,7S,9R)-Seimatopolide A. Following the procedure for
the global deprotection of RCM product 17, (−)-(3S, 6S, 7S, 9R)-
seimatopolide A was obtained from ent-17 (145 mg, 0.29 mmol) as a
white solid (70 mg, 74%): [α]2D2 = −27.1 (c 0.05, MeOH). All other
analytical data are identical to those reported for (+)-(3R,6R,7R,9S)-
seimatopolide A.
(2S,4R,5R,8R,E)-2-Nonyl-10-oxo-3,4,5,8,9,10-hexahydro-2H-
oxecine-4,5,8-triyl Tris(4-bromobenzoate) (19). To a solution of
(3R,6R,7R,9S)-(+)-seimatopolide A (11 mg, 0.034 mmol) in pyridine
(0.5 mL) and CH2Cl2 (0.5 mL) was added 4-bromobenzoyl chloride
(75 mg, 0.34 mmol), and the solution was stirred for 5 h under reflux.
The reaction mixture was diluted with MTBE (10 mL), and the
organic layer was washed with 1 M HCl (aq.) (10 mL), followed by
aqueous NaHCO3 solution (10 mL). The organic layers were dried
with MgSO4, filtered, and evaporated. The residue was purified by
column chromatography on silica (eluent hexanes/MTBE 5:1) to give
19 (24 mg, 81%) as a white solid: [α]2D1 −101.3 (c 0.11, CH2Cl2); 1H
NMR (300 MHz, CDCl3) δ 7.95 (d, J = 8.5, 2H), 7.73 (d, J = 8.5, 2H),
7.67 (d, J = 8.6, 2H), 7.61 (d, J = 8.5, 2H), 7.47 (d, J = 8.5, 2H), 7.41
(d, J = 8.6, 2H), 6.30 (dd, J = 15.3, 3.4, 1H), 5.92 (d, J = 3.2, 1H),
5.80−5.70 (m, 2H), 5.35 (dd, J = 9.1, 8.8, 1H), 5.05 (dt, J = 7.0, 6.5,
1H), 2.84 (dd, J = 12.6, 2.1, 1H), 2.72 (dd, J = 12.6, 3.9, 1H), 2.25 (m,
1H), 2.00 (d, J = 16.1, 1H), 1.70−1.17 (m, 16H), 0.87 (t, J = 6.9, 1H);
13C NMR (75 MHz, CDCl3) δ 168.5, 164.8, 164.8, 164.3, 135.1, 131.9,
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