Asymmetric total synthesis of (+)-didemniserinolipid b via achmatowicz rearrangement/bicycloketalization

Article abstract of DOI:10.1021/jo501142q

A new synthetic strategy was developed for the asymmetric total synthesis of (+)-didemniserinolipid B in 19 linear steps, featuring a highly efficient and enantioselective construction of 6,8-dioxabicyclo[3.2.1]octane (6,8-DOBCO) framework via a rarely explored Achmatowicz rearrangement/bicycloketalization strategy. In addition, the first total synthesis of the proposed (+)-didemniserinolipid C was accomplished with 41.6% yield in 4 steps from a common advanced intermediate 18, and a possible revised structure of (+)-didemniserinolipid C was proposed. The new convergent synthetic strategy greatly expedites the entry to the didemniserinolipids and their analogues for biological activity evaluation.

Full text of DOI:10.1021/jo501142q

Article
pubs.acs.org/joc
Asymmetric Total Synthesis of (+)-Didemniserinolipid B via
Achmatowicz Rearrangement/Bicycloketalization
Jingyun Ren and Rongbiao Tong*
Department of Chemistry, The Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong, China
S
* Supporting Information
ABSTRACT: A new synthetic strategy was developed for the asymmetric total synthesis of (+)-didemniserinolipid B in 19 linear
steps, featuring a highly efficient and enantioselective construction of 6,8-dioxabicyclo[3.2.1]octane (6,8-DOBCO) framework via
a rarely explored Achmatowicz rearrangement/bicycloketalization strategy. In addition, the first total synthesis of the proposed
(+)-didemniserinolipid C was accomplished with 41.6% yield in 4 steps from a common advanced intermediate 18, and a
possible revised structure of (+)-didemniserinolipid C was proposed. The new convergent synthetic strategy greatly expedites the
entry to the didemniserinolipids and their analogues for biological activity evaluation.
mL.2 Interestingly, many simple alkylated 6,8-
INTRODUCTION
Didemniserinolipids A−C (Figure 1) as the first serinolipids
from marine organisms were reported in 1999 by Jimen
■
dioxabicyclo[3.2.1]octanes (6,8-DOBCOs) such as brevicomin,
frontalin, and multistriatin are insect pheromones,3 while many
́
ez and
natural products containing the 6,8-DOBCO moiety were
reported to be biologically active.4 Therefore, further biological
activity evaluation of didemniserinolipids would be desirable,
and consequently their synthetic studies (e.g., total synthesis)
could be of paramount importance.
Not surprisingly, the didemniserinolipids with the structur-
ally interesting and intriguing 6,8-DOBCO core attracted much
interest in the synthetic community (Scheme 1).5 In particular,
Ley’s pioneering synthetic studies culminated in the first total
synthesis and structural revision of didemniserinolipid B, in
which O-sulfate at C31 was identified and the stereochemistry
at C30 was unambiguously determined by chemical synthesis.5a
It was also noteworthy that the second total synthesis of
didemniserinolipid B was elegantly achieved by Burke5b,c and
co-workers through full exploitation of an efficient, nontradi-
tional ketalization/ring-closing metathesis strategy to access the
6,8-DOBCO moiety.
Our interest in didemniserinolipids was triggered by the
central 6,8-DOBCO framework, which was prepared conven-
tionally by intramolecular dehydrative ketalization of a keto
diol.6 We envisioned that such bicyclic ketal core (isolevoglu-
cosenone) could be readily synthesized by oxidative rearrange-
ment (Achmatowicz rearrangement7) of furfuryl diol followed
by dehydrative ketalization (Scheme 1), a process originally
developed by Ogasawara8 for diastereoselective synthesis of
Figure 1. Didemniserinolipids and cyclodidemniserinol trisulfate.
co-workers from the methanol extract of marine tunicate
Didemnum sp.1 The initial methanolic extract indicated a potent
cytotoxic activity against several tumor cell lines, while the
CH2Cl2 partition from this extract was found to have the most
cytotoxic potency (IC50 = 0.25 μg/mL) against tumor cell lines
including P388, A549, and HT29.
Unfortunately, the pure individual didemniserinolipids from
chromatography purification of the CH2Cl2 partition showed
no cytotoxicity in the same assays. In contrast to the lack of
known biological activity for the didemniserinolipids, the
structurally related cyclodidemniserinol trisulfate isolated from
Didemnum guttatum inhibited HIV-1 integrase with an IC50 of
60 μg/mL and MCV topoisomerase with an IC50 of 72 μg/
Received: May 20, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo501142q | J. Org. Chem. XXXX, XXX, XXX−XXX

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Scheme 1. Key Strategies for Synthesis of 6,8-
Dioxabicyclo[3.2.1]octane (6,8-DOBCO)
Scheme 2. Retrosynthetic Analysis of
(+)-Didemniserinolipid B
saccharides. Reduction of the isolevoglucosenone through Pd-
catalyzed hydrogenation and diastereoselective reduction of the
resulting ketone would provide the 6,8-DOBCO moiety of
didemniserinolipids, which is complementary to all previous
synthetic strategies. This rarely explored protocol for the
synthesis of 6,8-DOBCO, however, offers many practical
synthetic benefits including readily accessible substrate (2,5-
disubstituted furan), simple operation, scalability, reproduci-
bility, and high diastereoselectivity.9 One of the most
compelling advantages over previous syntheses is that the
chiral centers (C8, C9, C10, and C13) of 6,8-DOBCO are
derived directly or indirectly from the well-established, highly
enantioselective Sharpless asymmetric dihydroxylation.10 If
successful, such strategy to construct the 6,8-DOBCO would
enable an efficient and modular synthesis of didemniserinoli-
pids, their analogues, and the recently isolated, structurally
closely related siladenoserinols,11 which were found to be
inhibitors of p53−Hdm2 interaction.
To demonstrate the synthetic utility of the Achmatowicz
rearrangement/bicycloketalization (AR/BCK) strategy to
access the 6,8-DOBCO framework in the context of complex
natural products, we elected to undertake the total synthesis of
(+)-didemniserinolipid B (DslB, 1), whose molecular structure
including relative and absolute configurations was revised and
fully confirmed by a previous total synthesis.5 Our key synthetic
strategies are shown in Scheme 2 in a retrosynthetic manner.
Specifically, DslB (1) could be derived from the union of three
functionalized fragments, i.e., serinol derivative (4),5 1,12-
dodecanediol derivative (3), and the 6,8-DOBCO (2), through
Williamson etherification and Julia−Kocienski olefination12/
hydrogenation. The convergence of such design would permit
facile variations of these fragments for potential analogue
preparation. The key 6,8-DOBCO fragment (2) would arise
from hydrogenation and diastereoselective ketone reduction of
the bicyclic acetal 5, which could be provided by the key AR/
BCK sequence of the optically pure furfuryl diol 6. Julia−
Kocienski olefination would be utilized again to introduce the
six-carbon chain (1,6-hexanediol derivative) with trans-alkene
(C8−C9) for Sharpless asymmetric dihydroxylation, which
yielded the key substrate 6 for the AR/BCK sequence.
sulfone 9 using KHMDS as the base at −78 °C provided a E/Z
mixture of alkene 10 in 90% yield with good E/Z selectivity (E/
Z = 9/1), which could not be separated by flash column
chromatography on silica gel and was directly used for
Sharpless asymmetric dihydroxylation with AD mix-β to
enantioselectively install the vicinal diol of furan (−)-6 (97%
ee by HPLC) in 84% yield. It was noted that the desired,
enantiomerically pure 6 was easily separated from the
undesired, minor diastereomer derived from the Z-isomer of
10 through flash column chromatography on silica column. The
AR/BCK sequence of furan (−)-6, to our delight, was
effectively promoted by m-CPBA and then CSA to provide
the desired bicyclic acetal (−)-5 as a single diastereomer in 72%
yield on a multigram scale (>6.4 g obtained). Pd-catalyzed
chemoselective hydrogenation of enone 5 using EtOAc as the
optimal solvent for 2 h gave the ketone 11 in excellent yield
(87% yield). Chemo- and diastereoselective reduction of
ketone 11 to alcohol 12a was found to be very challenging
because delivery of hydride from the less hindered convex gave
the pseudo-equatorial alcohol (12b) as the major undesired
product (Table 1, entries 2−7), except in case of K-selectride
(Table 1, entry 1) where it produced a 1:1 mixture of
diastereomers in excellent yield. After two cycles of recovery of
the undesired 12b via Dess−Martin periodinane (DMP)
oxidation14 and K-selectride reduction, 12a could be obtained
in 54% overall yield from ketone 11. It should be noted that
Mitsunobu inversion15 of the secondary alcohol of 12b under
various conditions resulted in a complex mixture. Alternatively,
reduction of enone (−)-5 with various reducing agents
followed by palladium-catalyzed saturation of the double
bond did not provide better diastereoselectivity or yields of
12a (see Supporting Information). Compound 12a was then
converted to aldehyde 2 in two steps via TBS silylation and
DIBAL-H reduction. Julia−Kocienski olefination of aldehyde 2
with the 12-carbon sulfone 3 was promoted by LiHMDS in
THF at −78 °C to provide the alkene 14 as inconsequent 2:1
E/Z isomers. Removal of the PMB protecting group with DDQ
in a pH 7.0 buffered solution gave the alcohol 15, which was
RESULTS AND DISCUSSION
■
Our synthesis (Scheme 3) began with preparation of aldehyde
8 by Vilsmeier−Haack formylation13 of the commercial furan 7
with 90% yield. Julia−Kocienski olefination of aldehyde 8 with
B
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Scheme 3. Asymmetric Total Synthesis of (+)-Didemniserinolipid B
a
of 16 in methanol at room temperature saturated the double
bond on the side chain and simultaneously removed the
protecting benzyl group. The resulting primary alcohol was
oxidized with Dess−Martin periodinane (DMP) to yield the
aldehyde 17, which upon treatment of the in situ generated
stabilized phosphonate anion underwent Horner−Wadsworth−
Emmons olefination16 to provide the conjugate ester 18 as a
single trans-isomer. Global deprotection of 18 with 1.0 N HCl
in ethanol and protection of the resulting amino group with
FmocCl provided the known DslB precursor 19 (>200 mg
synthesized with 2.31% yield in 17 steps), which was further
elaborated to DslB by following the protocols developed by Ley
and co-workers.5a It should be noted that the sulfation of 19 in
our hand was still not efficient (10−27% yield) after many
unsuccessful attempts. Nonetheless, we eventually achieved the
third total synthesis of DslB using a unique Achmatowicz
rearrangement/bicycloketalization strategy. The spectroscopic
data of our synthetic DslB were in good agreement with those
reported previously for natural and synthetic DslB.17
Table 1. Diastereoselective Reduction of Ketone 11
temp
ratio
yield
(total, %)
entry
[H−]
K-selectride
(°C)
(12a/12b)
1
2
3
4
5
6
7
−78
−78
−78
rt
1/1
<1/20
1/3
81
89
79
52
81
50
71
NaBH4
LiAlH(Ot-Bu)3
SmI2/i-PrOH
CBS/BH3
1/5
−20
rt
<1/20
<1/20
<1/20
(R)-alpine/BH3
(S,S)-Ru*
Et3N/HCO2H
rt
a
1
The diastereomeric ratio was determined by H NMR of the crude
products, isolated yield. CBS: Corey−Bakshi−Shibata catalyst. (S,S)-
Ru*: RuCl(p-cymene)[(S,S)-Ts-DPEN].
subjected to mesylation followed by Williamson etherification
with serinol derivative 4. Under the condition developed
previously for Williamson etherification of similar substrates,5
the union of the functionalized 6,8-DOBCO (15) and serinol
derivative 4 proceeded efficiently to provide compound 16 with
the full-carbon side chain of DslB. Pd-catalyzed hydrogenation
In addition, we have attempted to synthesize didemniser-
inolipid C from the advanced intermediate 18 (Scheme 4). To
this end, 18 was elaborated in a 4-step sequence including
C
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Ethyl 3-(5-Formylfuran-2-yl)propanoate (8). To a solution of
N,N-dimethylformamide (DMF, 8.10 g, 110 mmol) in dry CH2Cl2 (50
mL) at 0 °C was added phosphorus oxychloride (POCl3, 15.4 g, 100
mmol). After 30 min, ethyl 3-(furan-2-yl)propanoate 7 (8.40 g, 50.0
mmol) was added to this solution slowly. After the completion of
addition, the reaction mixture was allowed to warm to room
temperature and stirred for additional 6 h. Then the reaction was
quenched by addition of saturated aqueous Na2CO3 solution (100
mL). The organic fractions were collected, and the aqueous phase was
extracted with CH2Cl2 (3 × 80 mL). The combined organic fractions
were washed with water and brine, dried over Na2SO4, and
concentrated under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel (hexane/EtOAc
= 4:1) to afford the desired product 8 (8.64 g, 45.0 mmol, 90% yield)
as a yellow oil. The analytical data were identical to those reported in
the literature.7b 1H NMR (400 MHz, CDCl3): δ 9.49 (s, 1H), 7.13 (d,
J = 3.5 Hz, 1H), 6.26 (d, J = 3.5 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H),
3.03 (t, J = 7.4 Hz, 2H), 2.68 (t, J = 7.4 Hz, 2H), 1.21 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 176.9, 171.7, 161.3, 151.9,
109.0 (2 × C), 60.6, 31.8, 23.6, 14.0.
Scheme 4. Total Synthesis of the Proposed
(+)-Didemniserinolipid C
reduction with DIBAL-H, Pinnick oxidation, global depro-
tection with 1 N HCl and neutralization with NaHCO3 to
furnish didemniserinolipid C (DslC, 20) in 41.6% overall yield.
5-(6-(Benzyloxy)hexylsulfonyl)-1-phenyl-1H-tetrazole (9). To
a solution of 1,6-hexane-diol (11.8 g, 100 mmol) in dry THF (100
mL) at 0 °C was added sodium hydride (NaH, 4.40 g, 110 mmol, ca.
60 wt %) slowly. After 30 min at 0 °C, benzyl bromide (BnBr, 17.1 g,
100 mmol) and tetrabutylammonium iodide (TBAI, 3.90 g, 10.0
mmol) were added to this solution dropwise. After the completion of
addition, the reaction mixture was allowed to warm to room
temperature and stirred for additional 10 h. Then reaction was
quenched by addition of saturated aqueous NH4Cl solution (100 mL).
The organic phase was collected, and the aqueous phase was extracted
with EtOAc (3 × 80 mL). The combined organic fractions were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The resulting residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 4:1) to afford the
desired monobenzylated alcohol (11.4 g, 54.5 mmol, 55% yield) as a
colorless oil. To a solution of the alcohol (10.0 g, 48.0 mmol) in THF
(400 mL) at 0 °C were added PPh3 (26.3 g, 96.0 mmol), 1-phenyl-1H-
tetrazole-5-thiol (PTSH, 17.8 g, 96.0 mmol), and diisopropyl
azodicarboxylate (DIAD, 20.2 g, 96.0 mmol). The reaction mixture
was stirred at room temperature for 6 h and then evaporated directly
in vacuo. The residue was dissolved in saturated aqueous NH4Cl (100
mL) and extracted with CH2Cl2 (3 × 100 mL). The combined organic
fractions were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel (hexane/EtOAc
= 10:1) to afford the desired sulfide product (16.1 g, 43.2 mmol, 90%
yield) as a colorless oil. To a solution of the sulfide obtained above
(16.1 g, 43.2 mmol) in CH2Cl2 (500 mL) at 0 °C were added
NaHCO3 (20.0 g, 240 mmol) and 3-chloroperbenzoic acid (m-CPBA,
19.5 g, 96.0 mmol, ca. 85 wt %). The reaction mixture was stirred
overnight at room temperature. The reaction was quenched by
addition of saturated aqueous Na2SO3 solution (100 mL). The organic
phase was collected, and the aqueous phase was extracted with CH2Cl2
(3 × 100 mL). The combined organic fractions were washed with
saturated aqueous NaHCO3 solution and brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography on silica gel
(hexane/EtOAc = 5:1) to afford the desired sulfone product 9 (18.3 g,
45.0 mmol, 82% yield) as a colorless oil. IR (neat, cm−1): 3029, 2859,
1
Unfortunately, the H- and 13C NMR spectra of our synthetic
DslC was not consistent with those reported for the natural
DslC. This finding suggested that the structure of natural DslC
might be incorrectly proposed. We suspected that DslC might
have the O-sulfate on the side chain, similar to the
corresponding side chain for DslB identified by Ley et al.
Therefore, the identical sulfation protocol was applied to the
synthetic proposed DslC; however, we could not isolate any
desired product. Alternatively, DslB was subjected to
saponification, which unfortunately resulted in decomposition,
and no desired DslC could be detected by NMR. More
synthetic work is needed to reach a conclusion for the true
structure of the natural DslC.
CONCLUSION
■
We have developed a new synthetic strategy for the asymmetric
total synthesis of (+)-didemniserinolipid B with 0.62% yield in
19 steps from commercially available materials, featuring a
novel Achmatowicz rearrangement/bicycloketalization strategy
for the construction of the key 6,8-dioxabicyclo[3.2.1]octane
substructure. The first total synthesis of the proposed structure
of (+)-didemniserinolipid C was accomplished with 41.6% yield
in 4 steps from a common advanced intermediate 18 and a new
possible structure for (+)-didemniserinolipid C was proposed.
Most importantly, the new, convergent synthetic strategy would
greatly expedite the entry to the didemniserinolipids and their
analogues for biological activity evaluation. Further application
of the new Achmatowicz rearrangement/bicycloketalization
strategy to the 6,8-DOBCOs in total synthesis of siladenoser-
inols is ongoing and will be reported in a due course.
EXPERIMENTAL SECTION
■
NMR spectra were recorded on a 400 MHz spectrometer (400 MHz
for H, 100 MHz for 13C). Chemical shifts are reported in parts per
1
million (ppm) as values relative to the internal chloroform (7.26 ppm
for 1H and 77.16 ppm for 13C). Infrared (IR) spectra were recorded as
neat samples (liquid films on KBr plates). HRMS spectra were
recorded with a TOF detector (LD+: MALDI ionization). Normal
phase HPLC was used to determine enantiomeric excess of chiral
compounds with eluents of hexane/i-PrOH. Reactions were carried
out in oven- or flame-dried glassware under a nitrogen atmosphere,
unless otherwise noted. Tetrahydrofuran (THF) was freshly distilled
before use from sodium using benzophenone as indicator. Dichloro-
methane (DCM) was freshly distilled before use from calcium hydride
(CaH2). All other anhydrous solvents were dried over 3 or 4 Å
molecular sieves.
1
2360, 2341, 1737, 1595, 1340, 1151, 1100, 763, 689. H NMR (400
MHz, CDCl3): δ 7.70−7.68 (m, 2H), 7.65−7.56 (m, 3H), 7.39−7.31
(m, 4H), 7.31−7.25 (m, 1H), 4.50 (s, 2H), 3.81−3.64 (m, 2H), 3.47
(t, J = 6.3 Hz, 2H), 2.02−1.89 (m, 2H), 1.68−1.59 (m, 2H), 1.57−
1.37 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 153.5, 138.5, 133.0,
131.4, 129.7 (2 × C), 128.4 (2 × C), 127.6 (2 × C), 127.5, 125.1 (2 ×
C), 72.9, 69.9, 55.9, 29.3, 27.9, 25.6, 21.9. HRMS (TOF, LD+) m/z
calcd for C20H24N4O3SNa, [M + Na]+ 423.1467, found 423.1461.
Ethyl 3-(5-(7-(Benzyloxy)hept-1-enyl)furan-2-yl)propanoate
(10). To a solution of sulfone 9 (12.3 g, 30.0 mmol) in dry THF (200
mL) at −78 °C was added potassium bis(trimethylsilyl)amide
D
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Article
(KHMDS, 0.5 M in toluene, 84.0 mL, 42.0 mmol) slowly. The
reaction mixture was stirred at −78 °C for 30 min, and the aldehyde 8
(8.67 g, 45.0 mmol) was added very slowly. After the completion of
addition, the reaction mixture was stirred at −78 °C for additional 2 h.
Then, the reaction was quenched by addition of saturated aqueous
NH4Cl (50 mL). The organic phase was collected, and the aqueous
phase was extracted with Et2O (3 × 100 mL). The combined organic
fractions were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel (hexane/EtOAc
= 20:1) to afford the desired alkene product 10 (10.0 g, 27.0 mmol,
90% yield, ratio of E/Z isomers 9/1) as a pale yellow oil. IR (neat,
cm−1): 2926, 2853, 2360, 2341, 1734, 1647, 1373, 732, 696. 1H NMR
(400 MHz, C6D6): δ 7.33 (d, J = 7.4 Hz, 2H), 7.19 (t, J = 7.5 Hz, 2H),
7.11 (t, J = 7.3 Hz, 1H), 6.32−6.18 (m, 1H), 6.11 (d, J = 15.8 Hz, 1H),
5.94 (d, J = 3.2 Hz, 1H), 5.88 (d, J = 3.2 Hz, 1H), 4.35 (s, 2H), 3.90
(q, J = 7.1 Hz, 2H), 3.30 (t, J = 6.4 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H),
2.40 (t, J = 7.5 Hz, 2H), 2.03 (dt, J = 6.8, 7.2 Hz, 2H), 1.60−1.50 (m,
2H), 1.37−1.29 (m, 2H), 1.25−1.19 (m, 2H), 0.90 (t, J = 7.1 Hz, 3H).
13C NMR (100 MHz, C6D6): δ 171.7, 153.6, 152.6, 139.5, 130.2, 128.5
Hz, 2H), 2.64−2.47 (m, 2H), 2.33 (t, J = 7.5 Hz, 2H), 1.71−1.59 (m,
4H), 1.47−1.38 (m, 4H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 194.8, 172.8, 150.1, 138.6, 128.3 (2 × C), 127.6 (2 ×
C), 127.5, 126.2, 104.3, 84.3, 75.8, 72.9, 70.1, 60.6, 33.9, 29.6, 29.4,
27.2, 25.9, 25.5, 14.2. HRMS (TOF, LD+) m/z calcd for C23H30O6Na,
[M + Na]+ 425.1940, found 425.1948.
Ethyl 3-((1R,7R)-7-(5-(Benzyloxy)pentyl)-2-oxo-6,8-
dioxabicyclo[3.2.1]octan-5-yl)propanoate ((+)-11). To a solution
of enone (−)-5 (6.48 g, 16.1 mmol) in ethyl acetate (EtOAc, 50 mL)
was added Pd/C (0.85 g, 0.81 mmol, 10.0 wt % Pd on activated
carbon) under N2 (g) at room temperature. The reaction flask was
flushed by H2 (balloon) for 10 min, then the gas outlet was closed, and
the reaction mixture was stirred under H2 (balloon, 1 atm) atmosphere
at room temperature for 2 h before filtration through Celite. The
solvent (EtOAc) was removed under reduced pressure, and the
resulting residue was purified by flash column chromatography on
silica gel (hexane/EtOAc = 8:1) to afford (+)-11 (5.65 g, 14.0 mmol,
87% yield) as yellow oil. [α]2D0 = +18.4 (c 0.95, CHCl3). IR (neat,
cm−1): 3445, 2936, 2858, 2360, 1732, 1635, 1365, 1027, 737, 698. 1H
NMR (400 MHz, CDCl3): δ 7.36−7.29 (m, 4H), 7.29−7.23 (m, 1H),
4.49 (s, 2H), 4.20−4.10 (m, 2H), 4.08 (s, 1H), 4.01 (t, J = 6.7 Hz,
1H), 3.46 (t, J = 6.4 Hz, 2H), 2.55−2.36 (m, 4H), 2.23−2.13 (m, 2H),
2.13−2.02 (m, 2H), 1.63−1.56 (m, 2H), 1.51−1.29 (m, 6H), 1.25 (t, J
= 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 205.8, 173.2, 138.6,
128.3 (2 x C), 127.6 (2 x C), 127.5, 108.4, 83.9, 78.9, 72.9, 70.1, 60.5,
34.5, 34.4, 32.4, 31.4, 29.6, 28.2, 25.9, 25.3, 14.2. HRMS (TOF, LD+)
m/z calcd for C23H32O6Na, [M + Na]+ 427.2097, found 427.2099.
Ethyl 3-((1S,2S,7R)-7-(5-(Benzyloxy)pentyl)-2-hydroxy-6,8-
dioxabicyclo[3.2.1]octan-5-yl)propanoate ((+)-12a). To a sol-
ution of ketone (+)-11 (5.60 g, 14.0 mmol) in dry THF (50 mL) at
−78 °C was added K-selectride (1.0 M in toluene, 28 mL, 28.0 mmol)
slowly. After the completion of addition, the reaction mixture was
stirred at −78 °C for 2 h. Then, the reaction was quenched by addition
of saturated aqueous NH4Cl (50 mL). The organic phase was
collected, and the aqueous phase was extracted with Et2O (3 × 100
mL). The combined organic fractions were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography on silica gel
(hexane/EtOAc = 4:1) to afford the desired alcohol product (+)-12a
(2.40 g, 5.90 mmol, 42% yield) as a pale yellow oil and pseudo-
equatorial alcohol (+)-12b (2.21 g, 5.45 mmol, 39% yield), which was
recycled to afford (+)-12a in two steps as follows. To a solution of
recycled pseudo-equatorial alcohol (+)-12b (2.1 g, 5.0 mmol) in dry
CH2Cl2 (20 mL) at 0 °C were added NaHCO3 (2.2 g, 25 mmol) and
Dess−Martin periodinane (DMP, 4.2 g, 10 mmol). The reaction
mixture was stirred for 2 h at 0 °C. Then, the reaction was quenched
by addition of saturated aqueous NaHCO3 (50 mL). The organic
phase was collected, and the aqueous phase was extracted with CH2Cl2
(3 × 100 mL). The combined organic fractions were washed with
brine, dried over Na2SO4, and concentrated under reduced pressure.
The resulting residue was purified by flash column chromatography on
silica gel (hexane/EtOAc = 10:1) to afford the desired ketone product
(+)-11 (1.8 g, 4.4 mmol, 90% yield) as a pale yellow oil. To a solution
of ketone (+)-11 (1.8 g, 4.4 mmol) in dry THF (20 mL) at −78 °C
was added K-selectride (1.0 M in toluene, 8.8 mL, 8.8 mmol) slowly.
After the completion of addition, the reaction mixture was stirred for 2
h at −78 °C. Then the reaction was quenched by addition of saturated
aqueous NH4Cl (50 mL). The organic phase was collected, and the
aqueous phase was extracted with Et2O (3 × 100 mL). The combined
organic fractions were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel (hexane/EtOAc
= 4:1) to afford the desired alcohol product (+)-12a (0.68 g, 1.7
mmol, 38% yield) as a pale yellow oil and pseudo-equatorial alcohol
(+)-12b (0.65 g, 1.6 mmol, 37% yield). After two cycles of recovery
pseudo-equatorial alcohol (+)-12b, desired (+)-12a could be obtained
in 54% overall yield (3.1 g, 7.5 mmol) from ketone (+)-11. (+)-12a:
[α]2D0 = +27.0 (c 1.00, CHCl3). IR (neat, cm−1): 3629, 2935, 2858,
(2 × C), 127.6 (2 × C), 127.5, 119.2, 101.1, 107.2, 72.9, 70.4, 60.1,
33.0, 30.1, 29.6, 29.2, 26.4, 23.9, 14.1. HRMS (TOF, LD+) m/z calcd
for C23H30O4, [M]+ 370.2144, found 370.2152.
Ethyl 3-(5-((1S,2R)-7-(Benzyloxy)-1,2-dihydroxyheptyl)furan-
2-yl)propanoate ((−)-6). To a solution of alkene 10 (10.0 g, 27.0
mmol) in t-BuOH/H2O (1/1, 100 mL/100 mL) solution at 0 °C were
added sequentially K2CO3 (11.0 g, 81.0 mmol), K3Fe(CN)6(26.0 g,
81.0 mmol), (DHQD)2PHAL(0.21 g, 0.27 mmol), K2OsO4·(H2O)2
(99 mg, 0.27 mmol), and MeSO2NH2(2.6 g, 27 mmol). The reaction
mixture was stirred at 0 °C for 4 days. The reaction was quenched by
addition of saturated aqueous Na2SO3 (50 mL). The organic phase
was collected, and the aqueous phase was extracted with CH2Cl2 (3 ×
100 mL). The combined organic fractions were washed with brine,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The resulting residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 2:1) to afford the
desired diol (−)-6 (9.16 g, 22.7 mmol, 84% yield, 97 ee %) as a yellow
oil. HPLC data: Daicel CHIRALPAK AD-H Column, 10% i-PrOH in
hexane, t1 = 12.6 min (98.31%), t2 = 13.9 min (1.69%). [α]2D0 = −6.1 (c
0.80, CHCl3). IR (neat, cm−1): 3421, 3030, 2859, 2360, 1733, 1455,
1
1186, 1097, 1019, 789, 737, 698. H NMR (400 MHz, CDCl3): δ
7.36−7.29 (m, 4H), 7.29−7.25 (m, 1H), 6.18 (d, J = 3.1 Hz, 1H), 5.96
(d, J = 3.1 Hz, 1H), 4.48 (s, 2H), 4.37 (d, J = 6.2 Hz, 1H), 4.13 (q, J =
7.1 Hz, 2H), 3.85 (dd, J = 10.4, 7.0 Hz, 1H), 3.44 (t, J = 6.6 Hz, 2H),
2.94 (t, J = 7.5 Hz, 2H), 2.82 (br s, 1H), 2.62 (t, J = 7.6 Hz, 2H), 1.59
(dd, J = 13.5, 6.7 Hz, 2H), 1.53−1.44 (m, 1H), 1.44−1.31 (m, 5H),
1.24 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 172.4, 154.0,
152.7, 138.5, 128.3 (2 × C), 127.5 (2 × C), 127.4, 108.3, 106.0, 73.2,
72.8, 71.0, 70.2, 60.5, 32.7, 32.6, 29.5, 26.0, 25.3, 23.4, 14.1. HRMS
(TOF, LD+) m/z calcd for C23H32O6Na, [M + Na]+ 427.2097, found
427.2089.
Ethyl 3-((1R,7R)-7-(5-(Benzyloxy)pentyl)-2-oxo-6,8-
dioxabicyclo[3.2.1]oct-3-en-5-yl)propanoate ((−)-5). To a sol-
ution of diol (−)-6 (9.0 g, 22 mmol) in CH2Cl2 (50 mL) was added 3-
chloroperbenzoic acid (m-CPBA, 5.4 g, 27 mmol, ca. 85 wt %) at 0 °C.
The reaction mixture was stirred at 0 °C for 2 h, and then CSA (5.1 g,
22 mmol) was added. The reaction mixture was stirred at 0 °C for
additional 20 min. Then the reaction was quenched by addition of
saturated aqueous Na2S2O3 (30 mL) and NaHCO3 solution (30 mL).
The organic phase was collected, and the aqueous phase was extracted
with CH2Cl2 (3 × 50 mL). The combined organic fractions were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The resulting residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 5:1) to afford the
desired product (−)-5 (6.5 g, 16 mmol, 72% yield) as a yellow oil.
[α]2D0 = −23.2 (c 0.74, CHCl3). IR (neat, cm−1): 3030, 2937, 2361,
1
1734, 1700, 1372, 1229, 1093, 1028, 899, 737, 698. H NMR (400
MHz, CDCl3): δ 7.38−7.31 (m, 4H), 7.29 (dd, J = 9.0, 4.2 Hz, 1H),
6.96 (d, J = 9.8 Hz, 1H), 6.04 (d, J = 9.8 Hz, 1H), 4.51 (s, 2H), 4.32
(s, 1H), 4.25−4.08 (m, 2H), 3.80 (t, J = 6.6 Hz, 1H), 3.48 (t, J = 6.4
1
2361, 1733, 1366, 1235, 1114, 1027, 736, 698. H NMR (400 MHz,
CDCl3): δ 7.34 (dd, J = 7.1, 5.8 Hz, 4H), 7.28 (dd, J = 8.5, 3.8 Hz,
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1H), 4.49 (s, 2H), 4.18−4.07 (m, 2H), 4.04 (s, 1H), 3.92−3.83 (m,
1H), 3.59 (s, 1H), 3.46 (t, J = 6.5 Hz, 2H), 2.53−2.35 (m, 3H), 2.13−
1.92 (m, 3H), 1.87−1.75 (m, 1H), 1.69−1.52 (m, 5H), 1.48−1.37 (m,
4H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 173.5,
138.5, 128.3 (2 × C), 127.5 (2 × C), 127.4, 108.3, 82.3, 78.0, 72.8,
70.1, 66.1, 60.3, 34.9, 31.5, 30.6, 29.6, 27.6, 25.9, 25.37, 24.9, 14.1.
HRMS (TOF, LD+) m/z calcd for C23H34O6Na, [M + Na]+ 429.2253,
found 429.2246.
purified by flash column chromatography on silica gel (hexane/EtOAc
= 4:1) to afford the desired product PMB-protected alcohol (9.9 g, 31
mmol, 61% yield) as a colorless oil. To a solution of the alcohol (9.9 g,
31 mmol) in THF (200 mL) at 0 °C were added PPh3 (9.7 g, 37
mmol), 1-phenyl-1H-tetrazole-5-thiol (PTSH, 6.6 g, 37 mmol), and
diisopropyl azodicarboxylate (DIAD, 7.4 g, 37 mmol). The reaction
mixture was stirred at room temperature for 6 h and then evaporated
directly in vacuo. The residue was dissolved in saturated aqueous
NH4Cl (100 mL) and extracted with CH2Cl2 (3 × 100 mL). The
combined organic fractions were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography on silica gel
(hexane/EtOAc = 10:1) to afford the desired sulfide product (12 g, 25
mmol, 81% yield) as a colorless oil.To a stirred solution of the sulfide
(10.9 g, 24.8 mmol) in CH2Cl2 (200 mL) were added NaHCO3 (10.4
g, 124 mmol) and 3-chloroperbenzoic acid (m-CPBA, 10.0 g, 49.6
mmol, ca. 85 wt %) at 0 °C. The reaction mixture was stirred
overnight at room temperature. The reaction was quenched by
addition of saturated aqueous Na2SO3 solution (100 mL), and reaction
mixture was extracted with CH2Cl2 (3 × 100 mL). The combined
organic fractions were washed with saturated aqueous NaHCO3
solution and brine, dried over Na2SO4, and concentrated under
reduced pressure. The resulting residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 5:1) to afford the
desired sulfone product 3 (9.9 g, 19 mmol, 78% yield) as a colorless
oil. IR (neat, cm−1): 3067, 2926, 2853, 1718, 1653, 1558, 1420, 1340,
Ethyl 3-((1S,2R,7R)-7-(5-(Benzyloxy)pentyl)-2-hydroxy-6,8-
dioxabicyclo[3.2.1]octan-5-yl)propanoate ((+)-12b). [α]D20
=
+21.4 (c 0.95, CHCl3). IR (neat, cm−1): 3445, 2970, 2858, 2360,
1
1733, 1647, 1419, 1026, 697. H NMR (400 MHz, CDCl3): δ 7.37−
7.31 (m, 4H), 7.31−7.25 (m, 1H), 4.49 (s, 2H), 4.21−4.17 (m, 1H),
4.17−4.06 (m, 2H), 3.91 (s, 1H), 3.88 (t, J = 4.8 Hz, 1H), 3.47 (t, J =
6.5 Hz, 2H), 2.51−2.34 (m, 2H), 2.08−1.97 (m, 3H), 1.91 (t, J = 5.7
Hz, 1H), 1.79 (br s, 1H), 1.68−1.58 (m, 6H), 1.49−1.36 (m, 4H),
1.24 (t, J = 6.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 173.7, 138.5,
128.3 (2 × C), 127.6 (2 × C), 127.4, 107.3, 80.8, 75.8, 72.8, 70.2, 66.2,
60.3, 34.9, 34.2, 30.8, 29.6, 27.9, 26.4, 25.9, 25.4, 14.2. HRMS (TOF,
LD+) m/z calcd for C23H34O6Na, [M + Na]+ 429.2253, found
429.2256.
3-((1R,2S,7R)-7-(5-(Benzyloxy)pentyl)-2-(tert-butyldimethyl-
silyloxy)-6,8-dioxabicyclo[3.2.1]octan-5-yl)propanal ((+)-2). To
a solution of (+)-12a (1.9 g, 4.7 mmol) in dry DMF (20 mL) at 0 °C
were added imidazole (1.4 g, 9.3 mmol) and tert-butyldimethylsilyl
chloride (TBSCl, 0.63 g, 9.3 mmol). After the completion of addition,
the reaction mixture was allowed to warm to room temperature and
stirred overnight. The reaction was quenched by addition of water (60
mL). The organic fraction was collected, and the aqueous phase was
extracted with CH2Cl2 (3 × 80 mL). The combined organic fractions
were washed with saturated aqueous NaHCO3 solution and brine,
dried over Na2SO4, and concentrated under reduced pressure. The
resulting residue was purified by flash column chromatography on
silica gel (hexane/EtOAc = 10:1) to afford the desired product ester
(2.0 g, 3.8 mmol, 82% yield) as a colorless oil. To a solution of ester
(2.0 g, 3.8 mmol) in CH2Cl2 (50 mL) at −78 °C was added
diisobutylaluminum hydride solution (DIBAL-H, 1.0 M, 4.2 mL, 4.2
mmol) dropwise. After stirring at −78 °C for 2 h, the reaction was
quenched by addition of saturated aqueous Rochelle salt (sodium
potassium tartrate) solution (50 mL). The organic phase was
collected, and the aqueous phase was extracted with CH2Cl2 (3 ×
20 mL). The combined organic fractions were washed with brine,
dried over Na2SO4, and concentrated under reduced pressure. The
resulting residue was purified by flash column chromatography on
silica gel (hexane/EtOAc = 5:1) to afford desired aldehyde (+)-2 (1.5
g, 3.1 mmol, 80% yield) as a yellow oil. [α]2D0 = +11.1 (c 0.90, CHCl3).
IR (neat, cm−1): 3444, 2930, 2856, 2360, 1724, 1646, 1635, 1363,
1
1152, 1074, 916, 819, 761, 717. H NMR (400 MHz, CDCl3): δ 7.70
(dd, J = 7.7, 1.5 Hz, 2H), 7.65−7.57 (m, 3H), 7.27 (d, J = 8.5 Hz, 2H),
6.88 (d, J = 8.5 Hz, 2H), 4.45 (s, 2H), 3.81 (s, 3H), 3.78−3.68 (m,
2H), 3.45 (t, J = 6.7 Hz, 2H), 1.95 (dt, J = 12.1, 7.8 Hz, 2H), 1.66−
1.55 (m, 2H), 1.55−1.45 (m, 2H), 1.40−1.23 (m, 14H). 13C NMR
(100 MHz, CDCl3): δ 169.7, 159.1, 133.7, 133.0, 131.4, 130.7, 130.2,
129.8, 129.7, 129.2, 128.2, 125.0, 113.7, 72.4, 70.2, 56.0, 55.2, 29.7,
29.5 (3 × C), 29.4, 29.1, 28.9, 28.1, 26.1, 21.9. HRMS (TOF, LD+) m/
z calcd for C27H38O4N4SNa, [M + Na]+ 537.2511, found 537.2524.
( ( 1 R , 2 S , 7 R ) - 7 - ( 5 - ( B e n z y l o x y ) p e n t y l ) - 5 - ( 1 5 - ( 4 -
methoxybenzyloxy)pentadec-3-enyl)-6,8-dioxabicyclo[3.2.1]-
octan-2-yloxy)(tert-butyl)dimethylsilane ((+)-14). To a solution
of sulfone 3 (2.9 g, 5.6 mmol) in dry THF (20 mL) at −78 °C was
added lithium bis(trimethylsilyl)amide (LiHMDS, 1.0 M in THF, 6.2
mL, 6.2 mmol) slowly. The reaction mixture was stirred at −78 °C for
30 min, and the aldehyde (+)-2 (1.34 g, 2.80 mmol) was added very
slowly. After the completion of addition, the reaction mixture was
stirred at −78 °C for additional 2 h. Then, the reaction was quenched
by addition of saturated aqueous NH4Cl (20 mL). The organic phase
was collected, and the aqueous phase was extracted with Et2O (3 × 20
mL). The combined organic fractions were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography on silica gel
(hexane/EtOAc = 10:1) to afford the desired alkene product (+)-14
(1.76 g, 2.30 mmol, 82% yield, ratio of E/Z isomers 2/1) as a pale
yellow oil. [α]2D0 = +20.9 (c 0.60, CHCl3). IR (neat, cm−1): 3048, 2927,
1
1028, 834, 774. H NMR (400 MHz, CDCl3): δ 9.76 (s, 1H), 7.38−
7.31 (m, 4H), 7.31−7.24 (m, 1H), 4.50 (s, 2H), 3.93 (s, 1H), 3.84−
3.74 (m, 1H), 3.60 (s, 1H), 3.47 (t, J = 6.4 Hz, 2H), 2.56 (t, J = 7.1
Hz, 2H), 2.07 (qd, J = 14.8, 7.4 Hz, 2H), 1.98−1.83 (m, 2H), 1.63 (dt,
J = 13.7, 6.8 Hz, 2H), 1.59−1.45 (m, 4H), 1.45−1.35 (m, 4H), 0.90 (s,
9H), 0.07 (d, J = 2.4 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 202.5,
138.6, 128.3 (2 × C), 127.6 (2 × C), 127.5, 108.0, 83.1, 78.1, 72.9,
70.2, 66.7, 37.4, 35.0, 30.9, 29.7, 29.2, 26.0, 25.9, 25.8, 25.5, 18.2 (3 ×
C), −4.6, −4.7. HRMS (TOF, LD+) m/z calcd for C27H44O5SiNa, [M
+ Na]+ 499.2856, found 499.2870.
1
2854, 2360, 1810, 1541, 1437, 1248, 1099, 1172, 868, 774. H NMR
(400 MHz, CDCl3): δ 7.27 (d, J = 4.3 Hz, 3H), 7.23−7.12 (m, 4H),
6.80 (d, J = 7.9 Hz, 2H), 5.36−5.26 (m,2H), 4.43 (s, 2H), 4.36 (s,
2H), 3.87 (s, 1H), 3.73 (s, 1H), 3.73 (s, 3H, overlap), 3.53 (s, 1H),
3.44−3.32 (m, 4H), 2.14−2.03 (m, 2H), 1.99−1.75 (m, 4H), 1.74−
1.62 (m, 2H), 1.62−1.44 (m, 6H), 1.41−1.31 (m, 4H), 1.29−1.14 (m,
18H), 0.84 (s, 9H), 0.02 (d, J = 2.0 Hz, 6H). 13C NMR (100 MHz,
CDCl3): δ 138.7, 138.6, 130.8, 130.5, 130.2, 129.7, 129.2, 128.3 (2 ×
C), 127.6 (2 × C), 127.5, 113.7 (2 × C), 108.8, 83.0, 77.7, 72.9, 72.4,
70.4, 70.1, 66.9, 55.2, 37.2, 35.2, 32.6, 30.5, 29.8, 29.7, 29.6 (3 × C),
29.5, 29.4, 29.3, 29.2, 26.1 (3 × C), 26.0, 25.9, 25.5, 18.3, −4.6 (2 ×
C). HRMS (TOF, LD+) m/z calcd for C47H76O6SiNa, [M + Na]+
787.5309, found 787.5331.
5-(12-(4-Methoxybenzyloxy)dodecylsulfonyl)-1-phenyl-1H-
tetrazole (3). To a solution of 1,12-dodecan-diol (10.0 g, 50.0 mmol)
in dry THF (100 mL) at 0 °C, was added NaH (2.4 g, 60 mmol, ca. 60
wt %) slowly. After 30 min at 0 °C, 4-methoxybenzyl chloride
(PMBCl, 8.6 g, 55 mmol) and tetrabutylammonium iodide (TBAI, 1.8
g, 5.0 mmol) were added sequentially to this solution dropwise. After
the completion of addition, the reaction mixture was allowed to warm
to room temperature, and then the reaction was heated to reflux for 10
h. The reaction was quenched by addition of saturated NH4Cl aqueous
solution (100 mL). The organic phase was collected, and the aqueous
phase was extracted with EtOAc (3 × 80 mL). The combined organic
fractions were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The resulting residue was
15-((1R,2S,7R)-7-(5-(Benzyloxy)pentyl)-2-(tert-butyldime-
thylsilyloxy)-6,8-dioxabicyclo[3.2.1]octan-5-yl)pentadec-12-
en-1-ol ((+)-15). To a solution of (+)-14 (1.76 g, 2.30 mmol) in dry
CH2Cl2 (20 mL) at 0 °C were added 2,3-dichloro-5,6-dicyano-p-
benzoquinone (DDQ, 0.626 g, 2.76 mmol) and buffer (pH = 7.0)
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solution (2 mL). After the completion of addition, the reaction
mixture was allowed to warm to room temperature and stirred for 2 h.
The reaction was quenched by addition of saturated sodium thiosulfate
(20 mL). The organic fractions were collected, and the aqueous phase
was extracted with CH2Cl2 (3 × 30 mL). The combined organic
fractions were washed with saturated aqueous NaHCO3 solution and
brine, dried over Na2SO4, and concentrated under reduced pressure.
The resulting residue was purified by flash column chromatography on
silica gel (hexane/EtOAc = 4:1) to afford the desired product (+)-15
atmosphere (balloon, 1 atm) was stirred at room temperature for 2
h before filtration through Celite. The solvent was removed under
reduced pressure, and the resulting residue was purified by flash
column chromatography on silica gel (hexane/EtOAc = 8:1) to afford
the desired alcohol (0.67 g, 0.87 mmol, 87% yield) as yellow oil. To a
solution of the alcohol (0.67 g, 0.87 mmol) in dry CH2Cl2 (10 mL) at
0 °C were added NaHCO3 (0.37 g, 4.35 mmol) and Dess−Martin
periodinane (DMP, 0.74 g, 1.7 mmol). The reaction mixture was
stirred at 0 °C for 2 h. Then, the reaction was quenched by addition of
saturated aqueous NaHCO3 (10 mL). The organic phase was
collected, and the aqueous phase was extracted with CH2Cl2 (3 ×
10 mL). The combined organic fractions were washed with brine,
dried over Na2SO4, and concentrated under reduced pressure. The
resulting residue was purified by flash column chromatography on
silica gel (hexane/EtOAc = 4:1) to afford the desired aldehyde (+)-17
(0.51 g, 0.66 mmol, 76% yield) as a pale yellow oil. [α]2D0 = +13.5 (c
0.65, CHCl3). IR (neat, cm−1): 2927, 2854, 2361, 1731, 1646, 1387,
(1.12 g, 1.75 mmol, 76% yield, E/Z = 2/1) as a colorless oil. [α]D20
=
+11.0 (c 0.50, CHCl3). IR (neat, cm−1): 2927, 2854, 2360, 2341, 1734,
1
1608, 1489, 1252, 1058, 868, 774. H NMR (400 MHz, CDCl3): δ
7.36−7.30 (m, 4H), 7.30−7.24 (m, 1H), 5.42−5.32 (m, 2H), 4.49 (s,
2H), 3.93 (s, 1H), 3.84−3.74 (m, 1H), 3.68−3.56 (m, 3H), 3.46 (t, J =
6.4 Hz, 2H), 2.25−2.07 (m, 2H), 2.03−1.85 (m, 4H), 1.77−1.69 (m,
2H), 1.67−1.49 (m, 6H), 1.46−1.35 (m, 4H), 1.35−1.25 (m, 18H),
0.91 (s, 9H), 0.07 (d, J = 2.0 Hz, 6H). 13C NMR (100 MHz, CDCl3):
δ 138.5, 130.4, 130.1, 129.7, 129.2, 128.3 (2 × C), 127.5 (2 × C),
127.4, 108.7, 108.7, 83.0, 83.0, 77.8, 77.7, 77.2, 72.8, 70.2, 66.8, 62.9,
37.2, 35.1, 32.7, 32.6, 30.5, 30.4, 29.6, 29.5, 29.4, 29.3, 29.2, 29.0, 27.1,
26.0 (3 × C), 25.9, 25.7, 25.4, 20.7, 18.2, −4.6, −4.7. HRMS (TOF,
LD+) m/z calcd for C39H68O5SiNa, [M + Na]+ 667.4734, found
667.4735.
1
1365, 1089, 834, 774. H NMR (400 MHz, CDCl3): δ 9.77 (s, 1H),
4.12−3.96 (m, 2H), 3.96−3.88 (m, 2H), 3.85−3.76 (m, 1H), 3.60 (s,
2H), 3.52−3.36 (m, 2H), 3.35−3.18 (m, 1H), 2.48−2.43 (m, 2H),
2.00−1.79 (m, 2H), 1.76−1.64 (m, 4H), 1.58−1.38 (m, 29H), 1.36−
1.18 (m,18H), 0.90 (s, 9H), 0.07 (s, 6H). 13C NMR (100 MHz,
CDCl3): δ 202.1, 109.3 (2 × C), 83.1 (2 × C), 77.4 (2 × C), 71.4 (2 ×
C), 66.9 (2 × C), 56.5, 43.7, 37.6, 35.1, 30.3, 29.8, 29.6 (6 × C), 29.5
(4 × C), 29.4 (4 × C), 28.4, 26.1, 25.9, 25.8 (3 × C), 25.2, 23.0, 21.9,
18.2, −4.7, −4.6. HRMS (TOF, LD+) m/z calcd for C43H81O8NSiNa,
[M + Na]+ 790.5629, found 790.5644.
(4S)-tert-Butyl 4-((15-((1R,2S,7R)-7-(5-(Benzyloxy)pentyl)-2-
(tert-butyldimethylsilyloxy)-6,8-dioxabicyclo[3.2.1]octan-5-yl)-
pentadec-12-enyloxy)methyl)-2,2-dimethyloxazolidine-3-car-
boxylate ((+)-16). To a solution of alcohol (+)-15 (1.12 g, 1.75
mmol) in CH2Cl2 (20 mL) at 0 °C were added N,N-diisopropylethyl-
amine (DIPEA, 0.44 g, 3.4 mmol), 4-(dimethylamino)pyridine
(DMAP, 20 mg, 0.17 mmol), and methanesulfonyl chloride (MsCl,
0.30 g, 2.6 mmol) slowly. The reaction was allowed to warm to room
temperature. After 4 h, the reaction was quenched by addition of
saturated aqueous NH4Cl solution (20 mL). The organic phase was
collected, and the aqueous phase was extracted with CH2Cl2 (3 × 20
mL). The combined organic fractions were washed with brine, dried
over anhydrous Na2SO4, and concentrated under reduced pressure.
The resulting crude product (0. 94 g, 1.3 mmol, 78% yield E/Z = 2/1)
as a yellow oil was used directly for the Williamson etherification
without further purification. To a solution of serinol derivative 4 (0.60
g, 2.6 mmol) in dry DMSO (5 mL) were added NaH (0.12 g, 2.9
mmol, ca. 60 wt %) and the mesylate (0.94 g, 1.3 mmol). The reaction
was allowed to warm to room temperature. After 24 h, the reaction
was quenched by addition of saturated aqueous NH4Cl solution (10
mL). The organic phase was collected, and the aqueous phase was
extracted with CH2Cl2 (3 × 10 mL). The combined organic fractions
were washed with water and brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel (hexane/EtOAc
= 4:1) to afford the desired product (+)-16 (0.86 g, 1.1 mmol, 77%
yield E/Z = 2/1) as a yellow oil. [α]2D0 = +23.3 (c 0.55, CHCl3). IR
(neat, cm−1): 2928, 2855, 2360, 2341, 1828, 1792, 1365, 1207, 1102,
867, 735. 1H NMR (400 MHz, CDCl3): δ 7.37−7.30 (m, 4H), 7.29 (s,
1H), 5.43−5.33 (m, 2H), 4.50 (s, 2H), 4.11−3.96 (m, 2H), 3.95−3.87
(m, 2H), 3.85−3.75 (m, 1H), 3.60 (s, 2H), 3.51−3.43 (m, 4H), 3.44−
3.36 (m, 1H), 3.33−3.27 (m, 1H), 2.22−2.09 (m, 2H), 2.05−1.89 (m,
4H), 1.71−1.36 (m, 27H), 1.35 1.20 (m, 18H), 0.91 (s, 9H), 0.07 (s,
6H). 13C NMR (100 MHz, CDCl3): δ 138.6, 130.5, 130.2, 129.7,
129.4, 128.3 (2 × C), 127.6, 127.4, 108.7, 83.0, 77.7, 73.0, 71.8, 71.5,
70.1, 67.0, 37.3, 35.2, 32.4, 30.9, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2,
28.5, 28.4, 27.1, 26.0, 25.9, 25.6, 25.5, 20.2, 18.3, −4.6, −4.7. HRMS
(TOF, LD+) m/z calcd for C50H87O8NSiNa, [M + Na]+ 880.6099,
found 880.6103.
(4S)-tert-Butyl 4-((15-((1R,2S,7R)-2-(tert-Butyldimethylsily-
loxy)-7-((E)-7-ethoxy-7-oxohept-5-enyl)-6,8-dioxabicyclo-
[3.2.1]octan-5-yl)pentadec-12-enyloxy)methyl)-2,2-dimethy-
loxazolidine-3-carboxylate ((+)-18). To a solution of NaH (61 mg,
1.5 mmol, ca. 60 wt %) in THF (5 mL) at 0 °C was added triethyl
phosphonoacetate (0.32 g, 1.3 mmol). After 30 min of stirring at 0 °C,
a solution of aldehyde (+)-17 (0.51 g, 0.66 mmol) in THF (1 mL) was
added dropwise at 0 °C. After the reaction mixture was stirred at 0 °C
for 2 h, the reaction was quenched by addition of saturated aqueous
NH4Cl solution (5 mL). The organic phase was collected, and the
aqueous phase was extracted with EtOAc (3 × 5 mL). The combined
organic fractions were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel (hexane/EtOAc
= 10:1) to afford a single E isomer (+)-18 (0.44 g, 0.52 mmol, 80%
yield) as a yellow oil. [α]D20 = +14.3 (c 0.65, CHCl3). IR (neat, cm−1):
2927, 2855, 2360, 1721, 1702, 1655, 1463, 1388, 1365, 1257, 1176,
1089, 834, 774. 1H NMR (400 MHz, CDCl3): δ 6.95 (dt, J = 15.5, 7.0
Hz, 1H), 5.80 (d, J = 15.6 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.10−
3.95 (m, 2H), 3.92 (d, J = 6.2 Hz, 2H), 3.83−3.71 (m, 1H), 3.60 (s,
1.5H), 3.53−3.35 (m, 2.5H), 3.35−3.24 (m, 1H), 2.19 (dd, J = 13.5,
6.8 Hz, 2H), 2.02−1.75 (m, 2H), 1.74−1.36 (m, 30H), 1.36−1.14 (m,
24H), 0.91 (s, 9H), 0.07 (d, J = 3.3 Hz, 6H). 13C NMR (100 MHz,
CDCl3): δ 171.0, 166.6, 148.9, 121.4 (2 × C), 109.24, 83.0, 80.3, 77.5,
71.3, 70.0, 66.8, 60.3, 60.0 (2 × C), 37.5, 35.0, 32.0, 30.2, 29.8, 29.7 (3
× C), 29.6 (3 × C), 29.5, 29.4, 28.4, 27.8, 26.7, 26.1, 26.0, 25.9 (5 ×
C), 25.1, 24.4, 22.8, 21.0, 18.3, 14.2, 14.1, −4.6, −4.7. HRMS (TOF,
LD+) m/z calcd for C47H87O9NSiNa, [M + Na]+ 860.6048, found
860.6066.
(E)-Ethyl 7-((1R,2S,7R)-5-(15-((R)-2-(((9H-Fluoren-9-yl)-
methoxy)carbonylamino)-3-hydroxypropoxy)pentadec-3-
enyl)-2-(tert-butyldimethylsilyloxy)-6,8-dioxabicyclo[3.2.1]-
octan-7-yl)hept-2-enoate ((+)-19). A solution of (+)-18 (0.44 g,
0.52 mmol) in EtOH (5 mL) and 1 N HCl (1 mL) was stirred at 45
°C for 12 h. The mixture was concentrated under reduced pressure.
The resulting residue was purified by flash column chromatography on
silica gel (CH2Cl2/MeOH = 5:1) to afford the desired product (0.31 g,
0.50 mmol, 96% yield) as a yellow oil. To a solution of the product
obtained (0.19 g, 0.31 mmol) in dioxane/H2O (2 mL/2 mL) were
added K2CO3 (0.21 g, 1.5 mmol) and 9-fluorenylmethoxycarbonyl
chloride (FmocCl, 0.39 g, 1.5 mmol). After the reaction mixture was
stirred for 4 h, the reaction was quenched by addition of saturated
aqueous NH4Cl solution (5 mL). The organic phase was collected,
(4S)-tert-Butyl 4-((15-((1R,2S,7R)-2-(tert-Butyldimethylsily-
loxy)-7-(5-oxopentyl)-6,8-dioxabicyclo[3.2.1]octan-5-yl)-
pentadec-12-enyloxy)methyl)-2,2-dimethyloxazolidine-3-car-
boxylate ((+)-17). To a solution of alkene (+)-16 (0.86 g, 1.1 mmol)
in methanol (MeOH, 5 mL) was added Pd/C (53 mg, 0.050 mmol, ca.
10.0 wt % Pd on activated carbon) under N2 atmosphere at room
temperature. The reaction flask was flushed by H2 gas for 10 min, then
the gas outlet was closed, and the reaction mixture under H2
G
dx.doi.org/10.1021/jo501142q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
and the aqueous phase was extracted with CH2Cl2 (3 × 2 mL). The
combined organic fractions were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography on silica gel
(hexane/EtOAc = 1:1) to afford desired protected product (+)-19
(0.21 g, 0.25 mmol, 80% yield) as a yellow oil. [α]2D0 = +20.6 (c 0.60,
CHCl3). IR (neat, cm−1): 3440, 2971, 2360, 2341, 2067, 1737, 1720,
1438, 1228, 1216. 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 7.5 Hz,
2H), 7.60 (d, J = 7.3 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4
Hz, 2H), 6.95 (dt, J = 15.5, 7.0 Hz, 1H), 5.81 (d, J = 15.8 Hz, 1H),
5.47 (d, J = 5.6 Hz, 1H), 4.40 (d, J = 6.5 Hz, 2H), 4.26−4.14 (m, 3H),
4.05 (s, 1H), 3.92−3.80 (m, 3H), 3.72 (br s, 1H), 3.68−3.56 (m, 3H),
3.44 (t, J = 6.3 Hz, 2H), 2.21 (dd, J = 13.8, 6.8 Hz, 2H), 2.04−1.92 (m,
2H), 1.84−1.72 (m, 1H), 1.73−1.60 (m, 2H), 1.61−1.36 (m, 12H),
1.36−1.17 (m, 24H). 13C NMR (100 MHz, CDCl3): δ 166.6, 156.4,
148.8, 143.8 (2 × C), 141.2, 127.5 (2 × C), 126.9 (2 × C), 125.0,
124.9 (2 × C), 121.3, 119.8 (2 × C), 109.5, 82.3, 77.6, 71.7, 71.2, 66.7,
66.1, 63.6, 60.1, 51.7, 47.1, 46.3, 37.4, 34.9, 31.9, 30.0, 29.7, 29.6 (3 ×
C), 29.5 (3 × C), 29.4, 29.3, 27.7, 25.9, 25.0, 24.9 (2 × C), 22.8, 14.1.
HRMS (TOF, LD+) m/z calcd for C48H71O9NNa, [M + Na]+
828.5027, found 828.5051.
desired product (+)-DslC (6.4 mg, 0.012 mmol, 63%) as a yellow oil.
[α]2D0 = +10.5 (c 0.08, CHCl3). IR (neat, cm−1): 3514, 3452, 2926,
1
2855, 2360, 2340, 1700, 1677, 1630,1461, 1386, 1033, 836, 799. H
NMR (400 MHz, CD3OD): δ 7.10−6.81 (m, 1H), 5.84 (d, J = 15.7
Hz, 1H), 4.00 (s, 1H), 3.91−3.88 (m, 1H), 3.77−3.71 (m, 2H), 3.64−
3.56 (m, 4H), 3.52−3.48 (m, 2H), 2.23 (d, J = 6.8 Hz, 2H), 2.04−1.96
(m, 2H), 1.82 (dd, J = 21.0, 6.2 Hz, 2H), 1.66−1.58 (m, 6H), 1.49−
1.42 (m, 6H), 1.34−1.25 (m, 22H). 13C NMR (100 MHz, CD3OD): δ
151.1, 131.2, 121.8, 110.4, 83.7, 79.2, 72.8, 68.8, 66.6, 60.4, 52.1, 36.3,
33.1, 30.8 (4 × C), 30.7 (4 × C), 30.6 (3 × C), 30.5 (3 × C), 30.1,
29.1, 27.2, 26.3. HRMS (TOF, LD+) m/z calcd for C31H58O7N, [M +
H]+ 556.4213, found 556.4219.
ASSOCIATED CONTENT
* Supporting Information
■
S
Tables of NMR data comparison of our synthetic (+)-didem-
niserinolipid B with those reported in the literature and copies
1
of H and 13C NMR spectra of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(+)-Didemniserinolipid B ((+)-1). According to the procedure
reported by Ley et al.,5a to a solution of the (+)-19 (20 mg, 0.025
mmol) in dry DMF (0.4 mL) was added sulfur trioxide pyridine
complex (SO3·Py, 4.8 mg, 0.050 mmol). The reaction was stirred
under microwave irradiation at 110 °C for 2 h. The reaction was
concentrated under reduced pressure to afford crude product as a
yellow oil. The crude product was dissolved in DMF/piperidine (0.4
mL/0.1 mL), and the resulting solution was stirred at room
temperature for 2 h. The reaction was concentrated under reduced
pressure, and the residue was purified by flash column chromatography
on silica gel (CH2Cl2/MeOH = 4:1) to afford (+)-didemniserinolipid
B as a yellow oil. This reaction was carried out for several times with
isolated yields ranging from 10% (1.7 mg, 2.5 μmol) to 27% (4.6 mg,
6.8 μmol). HRMS (TOF, LD+) m/z calcd for C33H60NO10SNa, [M +
H]+ 686.3914, found 686.3904. Other spectroscopic data were listed in
the Supporting Information and compared with those reported in the
literature.
AUTHOR INFORMATION
Corresponding Author
*E-mail: rtong@ust.hk.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was financially supported by The Hong Kong
University of Science and Technology (HKUST R9309) and
Research Grant Council of Hong Kong (GRF ECS 605912 and
GRF 605113).
REFERENCES
■
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I
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