Diastereoselective synthesis of the C14-C29 fragment of amphidinol 3

Article abstract of DOI:10.1039/c3ob41569d

An efficient stereoselective synthesis of the C14-C29 fragment highlighting a coupling reaction between a 1,3-dithiane derivative and an α-branched aldehyde was realized. This highly convergent synthesis involved two chiral pools, l-malic acid and (+)-camphorsulfonic acid, which are the starting compounds to control the six stereogenic centers present in the C14-C29 fragment of amphidinol 3.

Full text of DOI:10.1039/c3ob41569d

Organic &
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Diastereoselective synthesis of the C14–C29 fragment
of amphidinol 3†
Cite this: Org. Biomol. Chem., 2013, 11,
6829
Nicolas Rival,a Gilles Hanquet,*a Charlelie Bensoussan,b Sébastien Reymond,b
Janine Cossyb and Françoise Colobert*a
Received 31st July 2013,
An efficient stereoselective synthesis of the C14–C29 fragment highlighting a coupling reaction between
a 1,3-dithiane derivative and an α-branched aldehyde was realized. This highly convergent synthesis
involved two chiral pools, L-malic acid and (+)-camphorsulfonic acid, which are the starting compounds
to control the six stereogenic centers present in the C14–C29 fragment of amphidinol 3.
Accepted 15th August 2013
DOI: 10.1039/c3ob41569d
www.rsc.org/obc
against human erythrocytes than other well-known antibiotics
such as amphotericin B and filipin III. Biological assays have
Introduction
Dinoflagellates are a rich source of bioactive secondary meta- indicated that amphidinol 3 exhibited different mechanisms
bolites such as brevetoxins, ciguatoxins, maitotoxin, okadaic of action than those for amphotericin B and filipin III, as
acid, and palytoxin,1 which are polyketides with unique struc- pores or lesions in biomembranes are formed depending on
tures frequently present in species implicated in seafood poi- dosage concentrations.11
soning. Recently, amphidinols (AMs),
a
new class of
The syntheses of different fragments of amphidinol 3 have
polyketides, were isolated from dinoflagellates and have been been reported. Polyol,4a,12 pyranyl12b,d,13 and polyenic13e,f,14 frag-
recognized as potent antifungal and hemolytic agents.2 Up to ments have been synthesized and the construction of the most
now, 17 closely related amphidinols have been isolated from advanced fragment C1–C52 was reported by Rychnovsky and co-
dinoflagellates Amphidinium species,3,4 Amphidinium klebsii workers.12b However, no total synthesis has been reported up to
and Amphidinium carterae,2,5 and one of them is amphidinol 3. now. For our part, we have reported one approach towards the
Other related compounds have been extracted from dinofla- pyranyl fragment,13a two approaches to the C53–C67 polyenic
gellates such as luteophanols,6 lingshuiol A,7 and karatungiol8 fragment14a,b as well as two approaches related to the synthesis
showing cytotoxic and antifungal activities. In addition, of the C17–C3012a and C18–C3012b polyol fragments.
carteraol E, an ichthyotoxin, was isolated from Amphidinium
carterae.9
Since we met with difficulties to connect the C17–C30 and
C18–C30 fragments with, respectively, the C1–16 and C1–C17
The amphidinol structures are characterized by a skipped fragments, another disconnection through the C13–C14 bond
polyenic chain and a long irregular polyhydroxy chain, both was envisaged and a new strategy for the synthesis of the frag-
connected by a fragment containing two pyran rings. As the ment C14–C29 (compound A) was designed with full control of
absolute configuration of the stereogenic centers was eluci- the stereogenic centers. Our new retrosynthetic analysis of
dated only for amphidinol 33b,4b,10 isolated in 1996 from amphidinol 3 is reported in Scheme 1 and is based on two dis-
Amphidinium klebsii,4 amphidinol 3 has attracted the attention connections, the C29–C30 and C52–C53 bonds. These two
of synthetic chemists due to its interesting structural features bonds would respectively be built by using a Suzuki–Miyaura15
and its potential antifungal and hemolytic activities related to coupling reaction and a Julia olefination.16 The C1–C29 polyol
its membrane-permeabilizing activity.11 We have to point out fragment would be obtained by using a cross-metathesis17
that amphidinol 3 proved to be a stronger hemolytic agent between fragments C1–C12 and C13–C29 (compound A′), and
the synthesis of the fragment C14–C29 (compound A), bearing
six stereogenic centers, would be achieved by a convergent
aLaboratoire de Synthese et Catalyse Asymetrique, Université de Strasbourg (ECPM),
UMR CNRS 7509, 25 Rue Becquerel, Strasbourg Cedex 02, France.
E-mail: ghanquet@unistra.fr, francoise.colobert@unistra.fr; Tel: +03 68 85 27 46
bLaboratoire de Chimie Organique, ESPCI ParisTech, UMR CNRS 7084,
10 rue Vauquelin, Paris Cedex 05, France
approach involving an optically active β-hydroxyepoxide B,
2-TBS-1,3-dithiane 2, and optically active aldehyde 9. The con-
nection between these three compounds would be realized by
addition of TBS-dithiane 2 to β-hydroxyepoxide B, followed by
addition of the resulting β-silyloxy-dithiane C to aldehyde 9
allowing for the control of the stereogenic center at C24
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob41569d
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Scheme 1 Retrosynthetic analysis of the fragment C14–C29 of AM3, 1 (compound A).
according to a Felkin–Anh model. Aldehyde 9 would be syn- controlled by a diastereoselective 1,2-anti-reduction of the
thesized by using a cross-metathesis between octa-1,7-diene ketone obtained after hydrolysis of the thioketal.
and the enantiomerically pure unsaturated-alcohol 5 which
would be available from Oppolzer’s sultam12b,18 and the opti-
cally active β-hydroxyepoxide B would be accessible from
L-malic acid (Scheme 1).
Results and discussion
We have to point out that the control of the stereogenic The synthesis of aldehyde 9 was planned using a cross-meta-
centers at C20 and C21 would be realized by utilizing AD-mix-α thesis between protected octenol 7 and pentenol 5 (Scheme 2).
for the dihydroxylation of the double bond, resulting from a The access to 518b was achieved starting from Oppolzer’s
cross-metathesis and the stereogenic center at C25 would be sultam, by treatment with NaH followed by addition of
6830 | Org. Biomol. Chem., 2013, 11, 6829–6840
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Scheme 3 Preparation of epoxide 14 (fragment C24–C29).
dependent on the amount of catalyst present in the reaction
medium (Table 1, entries 1, 4 and 5) and when the tempera-
ture was increased, the E/Z ratio of 8 was dramatically
decreased (Table 1, entries 1 and 3). After a Swern oxidation,
the unsaturated alcohol 8 was converted to aldehyde 9 in 94%
yield. Thus, compound 9 was obtained in seven steps with
42% overall yield from Oppolzer’s sultam, which was recycled.
The second fragment, epoxide B, was prepared stereospeci-
fically from L-malic acid in six steps (Scheme 3). L-Malic acid
was fully reduced (BH3·Me2S, B(OMe)3) and the 1,2-diol of the
resulting triol was selectively protected as a ketal (pentan-
3-one, PTSA), leading to 10 (89%) which after transformation of
its primary alcohol to a p-methoxybenzyl ether (NaH, PMBBr,
THF, 0 °C) produced 11 in 95% yield. Acid-catalyzed hydrolysis
of 11 to diol 12 and the subsequent selective transformation of
the primary alcohol to a 2,4,6-triisopropylphenylsulfonate20
produced 13 which, under basic conditions (K2CO3, CH2Cl2,
rt), delivered the optically active epoxide 14 (80%).21 Thus,
epoxide 14 was obtained in 58% overall yield from L-malic
Scheme 2 Synthesis of aldehyde 9 (fragment C14–C24).
Table 1 Screening of the conditions for the preparation of unsaturated
alcohol 8
7
[Ru]-II
(equiv.)
t
Time
(h)
E/Z
Yieldc
(%)
Entry
(equiv.)
(°C)
ratioa
1
2
3
4
5
3
1
3
3
5
0.05
0.05
0.05
25
25
40
25
25
12
12
12
36
168
4.6/1
5/1
1/1
14/1
16/1
60
33
55
40
68b
0.01
3 × 0.005b
All experiments were performed in CH2Cl2 and monitored by GC/MS
until disappearance of 5. a The E/Z ratio was determined by analysis of
the 1H-NMR spectra of the crude material. b 0.5 mol% of [Ru]-II was acid.
added every two days. c Isolated yields.
Our first goal was to perform with compounds 9 and 14 a
three components linchpin process exploiting anion relay
chemistry (ARC) starting from linchpin TBS-1,3-dithiane 2 and
propionylchloride. The resulting amide 3 was then alkylated giving access to the C14–C29 fragment of amphidinol 3. Based
with allylbromide giving 4 with an excellent diastereomeric on the precedent of L. Tietze,22 A. B. Smith23 reported that
ratio (dr > 98 : 2) after recrystallisation. After cleavage of the lithiation of silyldithiane followed by alkylation with an
chiral auxiliary, the optically active unsaturated alcohol 5 was epoxide afforded an intermediate oxyanion which upon treat-
isolated in 95% yield, with an enantiomeric excess up to 96%. ment with HMPA undergoes 1,4-Brook rearrangement,23a gen-
The second partner of the cross-metathesis, compound 7, was erating a new reactive dithiane anion which reacts with a
prepared by applying
a mono-hydroalumination/oxidation second different epoxide giving 1,5 diol monoprotected as a
sequence to octa-1,7-diene. The obtained alcohol 6 was then silyl ether. Following this result, we wanted to explore in this
protected as a pivaloyl ester 7. Having 5 and 7 in hand, these process the use of an aldehyde as a second electrophile
two compounds were involved in a cross-metathesis using the instead of an epoxide. The first test has been realized starting
Grubbs catalyst, [Ru]-II.19 A screening of the conditions for the from TBS-1,3-dithiane 2; treatment with t-BuLi in Et2O at
cross-metathesis between 5 and 7 was achieved and the best −78 °C followed by addition of epoxide 14 and HMPA
isolated yield (68%) and E/Z ratio (16/1) in 8 were obtained should give the lithiated species 14a, and then we added
when [Ru]-II was added portionwise (3 × 0.005 equiv.) over one 2-methyl-pentanal as
a model α-branched aldehyde. But
week at 25 °C in CH2Cl2 with the use of an excess of 7 in our hands no trace of coupling product 14b has ever
(5 equiv.) (Table 1, entry 5) and when lower amounts of 7 were been detected showing that the extension of this linchpin
used, lower yields were obtained (Table 1, entries 1 and 2). process with epoxide and aldehyde is not straightforward
Worthy of note is the E/Z ratio of 8 which was highly (Scheme 4).
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Scheme 4 Linchpin process with epoxide 14 and 2-methyl-pentanal.
Scheme 7 Synthesis of 1,3-dithiane 25.
product 19, but in a low yield of 30%. Furthermore, the dia-
stereoisomeric ratio was not satisfactory (dr = 1.7 : 1).
Scheme 5 Preparation of functionalized dithiane 15.
In the course of our study on the addition of dithiane to
Therefore we decided to follow this reaction step by step. aldehydes, a closely related work was published by Brimble
Treatment of epoxide 14 with lithiated TBS-1,3-dithiane in a et al.27 demonstrating that a PMB ether at the δ-position of
mixture of Et2O–HMPA (3/1) at −78 °C afforded, after Brook 1,3-dithiane was interacting with the C–S σ* orbital of the
rearrangement, the optically active 1,3-dithiane 15 in 65% dithiane function,28 lowering dramatically the acidity of the
yield (Scheme 5).
α-hydrogen. This result was confirmed in our case29 and we
With both compounds 9 and 15 in hand, the synthesis of decided to prepare 1,3-dithiane 25 with a PMB protecting
the C14–C29 fragment of amphidinol 3 was undertaken. group of the C27 hydroxyl.
Unfortunately, the addition of 1,3-dithiane 15 to aldehyde 9
Starting from the optically active triol 20 readily prepared
was ineffective when using previously described conditions24 from L-malic acid (Scheme 3), the selective protection of the
(n-BuLi, with or without HMPA in THF at −50 °C). In order to 1,3-diol present in 20 as p-methoxyphenylacetal (PMP acetal)
verify whether the lithiation of 1,3-dithiane 15 was effective, was realized, leading to 21 which was transformed into the
deuterium exchange experiments were performed using iodo derivative 22 (PPh3, Imid. I2, CH2Cl2, rt) in 70% yield
different bases and additives25 and, to our surprise, a low (Scheme 7). After treatment of 22 with lithiated 1,3-dithiane,
metalation or no metalation was observed. Expecting that the 23 was formed in 75% yield. A selective reduction of the six-
TBS ether at the β position of 1,3-dithiane 15 could affect the membered acetal 23 by DIBAL-H30 at −78 °C in CH2Cl2
acidity of the α hydrogen, 1,3-dithiane 16 bearing a MOM pro- afforded the resulting primary alcohol 24 which was then pro-
tecting group instead of a TBS ether was prepared.26 When tected as a TBS ether in quantitative yield (TBSCl, imid., DMF,
deuterium exchange was conducted, it was found that n-BuLi rt). Thus, 1,3-dithiane 25 was prepared stereospecifically in
at −78 °C to 0 °C in THF were the best conditions as 60% deu- seven steps with an overall yield of 40% from L-malic acid.
teration of the dithiane was obtained and when the lithium
anion of dithiane 16 was condensed on aldehyde 17, 18 was (2.5 equiv.), THF, −78 °C to 0 °C, 1 h and then addition of
isolated in 58% yield (Scheme 6).
aldehyde (1 equiv.), −78 °C, 2 h), 26 was obtained with an
By addition of lithiated 25 to aldehyde 9 (n-BuLi
The dithiane anion formed under the previously optimized excellent yield (92%) and with a diastereoselectivity of 2.7 : 1 in
conditions (n-BuLi, −78 °C to 0 °C, THF) was added to the favor of the syn-isomer according to a Felkin–Anh addition
optically active aldehyde 9 to afford the expected coupling mode (Scheme 8). Oxidative cleavage31 of the 1,3-dithiane by
Scheme 6 Addition reactions of 1,3-dithiane 16 to aldehydes 17 and 9.
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Scheme 8 Synthesis of the C14–C29 fragment of amphidinol 3.
phenyliodonium bis(trifluoroacetate) (PIFA) led smoothly to a stereogenic center and the addition of a 1,3-dithiane anion to
mixture of the two diastereoisomeric ketones syn-27 and anti- an α-substituted aldehyde to control the C24 stereogenic
27′ (syn/anti: 2.7/1) which were separated by flash chromato- center according to a Felkin–Anh addition mode. The latter
graphy on silica gel to deliver the optically active ketone 27 coupling required careful optimization of the conditions and
(75%). Ketone 27 was then reduced diastereoselectively by was closely dependent on the protecting groups.
Zn(BH4)2 (Et2O, −78 °C, 72%) affording the anti-1,2-diol which
was protected as an acetonide (2,2-dimethoxypropane, PPTS,
acetone) producing 28 in 70% yield. A Sharpless dihydroxyla-
tion32 applied to 28, using AD-mix-α (CH3SO3NH2, t-BuOH–
Experimental section
H2O, rt), nicely afforded, after 4 days at 0 °C, diol 29 in a 4.7/1 General
diastereoisomeric ratio. After separation by chromatography,
Experimental procedures and spectroscopic and analytical
the resulting optically active diol 29 was isolated in 75% yield
and then protected as an acetonide (2,2-dimethoxypropane,
PPTS, acetone) to afford 30 (85%) with the six stereogenic
centers fully controlled.
data of the products: reagents and solvents were purchased as
reagent grade and used without further purification. THF was
distilled over sodium benzophenone ketyl. Dichloromethane
was distilled over CaH2 and acetonitrile over P2O5. Flash
column chromatography (FC) was performed using silica gel
60 for preparative column chromatography (40–63 mm), unless
specifically noted otherwise. Demetalled silica gel was pre-
pared according to a published procedure.33 Thin layer
Conclusion
In conclusion, we have reported herein an efficient and conver- chromatography (TLC) was performed on glass sheets coated
gent access to the C14–C29 fragment of amphidinol 3 that with silica gel 60 F254 (otherwise stated), visualization by UV
competes favorably with the previously described synthesis. light or through staining with phosphomolybdic acid, KMnO4
The target molecule 30, which corresponds to the fragment or vanillin. Optical rotations were measured using a polari-
C14–C29 A, was realized in 12 steps from L-malic acid with 9% meter with a sodium lamp and are reported as follows: αD
overall yield by using as the key step a cross-metathesis to (c g per 100 mL solvent). NMR spectra (1H and 13C) were
build the C20–C21 bond, and the addition of a dithiane to an recorded at 300 MHz or 400 MHz. Chemical shifts are reported
epoxide and to an aldehyde to build the C25–C26 and C24– in ppm with the solvent (CDCl3) resonance as the δ 7.26 ppm
C25 bonds, respectively. The control of the six stereogenic (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
centers was realized by using a Sharpless enantioselective s ap = apparent singlet, mc = multiplet center, coupling con-
dihydroxylation to control the C20 and C21 stereogenic stants Hz, integration). Carbon NMR (13C NMR) spectra were
centers, an alkylation of Oppolzer’s sultam to control the C23 also recorded at various field strengths as indicated. Spectra
stereogenic center, a ring-opening of an optically active were recorded in CDCl3 using residual undeuterated solvent
epoxide by a 1,3-dithiane lithium anion to control the C27 (77 ppm) as an internal reference. Infrared (IR) spectra were
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recorded on a diamond ATR spectrometer using neat samples. 3.97 (t, J = 6.6 Hz, 2H), 3.40 (m, 2H), 2.1–1.70 (m, 4H),
Infrared frequencies are reported in wavenumbers (cm−1), and 1.70–1.15 (m, 9H), 1.12 (s, 9H), 0.83 (d, J = 6.7 Hz, 3H);
intensities were determined qualitatively and are reported as 13C NMR (75 MHz) (CDCl3) δ 178.7, 132.1, 128.2, 68.0, 64.4,
strong (s), medium (m) or weak (w). Solid Lewis acids were 38.7, 36.5, 36.0, 32.4, 29.3, 28.6, 28.5, 27.2, 25.7, 16.4; IR
flame-dried in the reaction flask under vacuum and under ν 3389, 2928, 1728, 1284, 1153, 1035, 968.
argon before use.
(S,E)-10-Methyl-11-oxoundec-7-enyl pivalate (9)
Synthesis of oct-7-en-1-ol (6)
DMSO (69.5 μL, 0.98 mmol, 2.4 equiv.) in DCM (1 mL) was
ZrCl4 (637 mg, 2.83 mmol, 0.03 equiv.) was added to a solution
added to a solution of (COCl)2 (42 μL, 0.49 mmol, 1.2 equiv.)
of octa-1,7-diene (10 g, 90.75 mmol, 1 equiv.) in dried hexane
in DCM (2 mL) at −78 °C. The reaction mixture was stirred for
(100 mL) under an argon atmosphere. DIBAL-H (1 M in
30 min at −78 °C and alcohol 8 (116 mg, 0.41 mmol, 1 equiv.)
toluene, 90.75 mL, 90.75 mmol, 1 equiv.) was added dropwise
in DCM (1 mL) was added via cannula into the reaction
at RT (the reaction mixture turning brown) and the reaction
mixture. The reaction mixture was stirred for 30 min, Et3N
mixture was stirred for 7 h at RT. The flask was purged succes-
(283 μL, 2.04 mmol, 5 equiv.) was added to the solution at
sively with dried air (RT, 1 h) and O2 (40 °C, 3 h). The solution
−78 °C and the reaction mixture was warmed to RT over
was treated with H2SO4 (10%, 100 mL), stirred for 1 h at RT,
45 min. Hexane (5 mL) was added to the solution and filtered
and extracted with Et2O (3 × 50 mL). The combined extracts
through a pad of silica, and the silica was washed with a
were washed successively with saturated solutions of NaHCO3
mixture of EtOAc and cyclohexane (EtOAc–cyclohexane 1/5).
and NaCl, dried over Na2SO4, evaporated, and distilled to
The solvents were distilled under vacuum, and the crude 9 was
afford the alcohol 6 as a colorless liquid (6.9 g, 54.4 mmol,
used without any further purification (108 mg, 0.38 mmol,
60%); b.p.: 66–67 °C (8 mmHg) (lit.34 64–66 °C 7 mmHg);
94%); Rf: 0.85 (EtOAc–cyclohexane 1/3); [α]2D5: +11.6° (c = 0.81,
1
Rf: 0.11 (EtOAc–cyclohexane 1/9); H NMR (300 MHz) (CDCl3)
1
CHCl3); H NMR (300 MHz) (CDCl3) δ 9.62 (d, J = 1.4 Hz, 1H),
δ 5.82 (m, 1H), 4.95 (m, 2H), 3.67 (t, J = 6.5 Hz, 2H), 2.07 (m,
5.50–5.30 (m, 2H), 4.02 (t, J = 6.6 Hz, 2H), 2.39 (m, 2H),
2H), 1.58 (m, 2H), 1.50–0.80 (m, 6H); 13C NMR (75 MHz)
2.12–1.94 (m, 3H), 1.58 (m, 2H), 1.42–1.28 (m, 6H), 1.12
(CDCl3) δ 139.0, 114.2, 63.1, 33.7, 32.7, 28.8, 28.8, 25.5; IR
(s, 9H), 1.07 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz) (CDCl3)
ν 3550, 3090, 1640, 920.
δ 204.9, 178.6, 133.4, 126.2, 64.37, 46.3, 38.7, 33.6, 32.4, 29.2,
28.6, 28.5, 27.2, 25.7, 13.0; IR ν 2931, 1725, 1284, 1154, 969;
HRMS ES m/z (M + Na)+: Calcd C17H30NaO3 305.209, found
305.207.
Synthesis of oct-7-enyl pivalate (7)
Alcohol 6 (4.3 g, 33.5 mmol, 1 equiv.) and PivCl (6.07 g,
50.3 mmol, 1.5 equiv.) were stirred in pyridine (150 mL) for
two days. Pyridine was distilled giving a white liquid, which
was diluted in water (100 mL), extracted with EtOAc
(S)-2-(2,2-Diethyl-1,3-dioxolan-4-yl)ethanol (10)35
(3 × 50 mL). The combined extracts were washed with a satu- A solution of L-malic acid (6.0 g, 45 mmol, 1 equiv.) in dry THF
rated solution of NaCl, dried over Na2SO4, filtered, evaporated, (50 mL) was added slowly to a mixture of BMS·THF (30 mL,
and purified by flash chromatography (EtOAc–cyclohexane 5M in THF, 150 mmol, 3.33 equiv.) and trimethyl borate
1/100) affording the protected alcohol 7 as a colorless liquid (15.4 mL, 135 mmol, 3 equiv.) at 0 °C. The reaction mixture
(6.37 g, 30.05 mmol, 90%); Rf: 0.15 (EtOAc–cyclohexane 1/50); was stirred overnight and then quenched with MeOH (50 mL).
1H NMR (300 MHz) (CDCl3) δ 5.78 (m, 1H), 4.94 (m, 2H), 4.02 Solvents were evaporated and the crude was co-evaporated
(t, J = 6.6 Hz, 2H), 2.03 (m, 2H), 1.59 (m, 2H), 1.45–1.20 (m, with MeOH four times. The crude was then purified by chroma-
6H), 1.17 (s, 9H); 13C NMR (75 MHz) (CDCl3) δ 178.6, 138.9, tography (DCM–MeOH 9/1), giving the triol as a colorless oil
114.3, 64.4, 38.7, 33.6, 28.7, 28.6, 28.5, 27.2, 25.7; IR ν 2929, (4.67 g, 44 mmol, 99%).
2858, 1728, 1480, 1460, 1283, 1150, 1034, 994, 909, 771, 726.
p-TsOH (365 mg, 2 mmol, 0.05 equiv.) was added to a
stirred solution of triol (4.50 g, 46 mmol, 1 equiv.) in dry
3-pentanone (80 mL). The reaction mixture was stirred over-
(S,E)-11-Hydroxy-10-methylundec-7-enyl pivalate (8)
7 (6.2 g, 29.24 mmol, 5 equiv.) and 5 (585.7 mg, 5.85 mmol, night at room temperature and then quenched with Et3N
1 equiv.) were stirred in DCM (100 mL) at RT for one week. (0.25 mL). The solvent was removed and the crude was filtered
Grubbs II catalyst (3 × 24.8 mg, 0.087 mmol, 0.015 equiv.) was through a plug of SiO2 with EtOAc–cyclohexane 7/3, giving the
added three times every second day. The reaction mixture was protected 1,2-diol 10, containing less than 1% of the
hydrolyzed with a satd. solution of NaHCO3, the aqueous corresponding protected 1,3-diol as
a pale yellow oil
phase was extracted three times with DCM and the organic (6.5 g, 38.23 mmol, 89%); Rf: 0.30 (EtOAc–cyclohexane 7/3);
layers were dried over Na2SO4, filtered and the solvents were [α]2D5: +2.2° (c = 1.27 CHCl3, lit.36 [α]D27: +2.2°, c = 1.27 in
1
evaporated. The crude was purified by chromatography CHCl3); H NMR (300 MHz) (CDCl3) δ 4.20 (m, 1H), 4.06 (m,
(EtOAc–cyclohexane 1/5) affording the cross-coupling product 1H), 3.74 (td, J = 5.7 Hz, J = 1.2 Hz, 2H), 3.49 (t, J = 8.1 Hz, 1H),
8 as a mixture of E and Z (E/Z 1/16) as a colorless oil (1.12 g, 2.65 (m, 1H), 1.78 (m, 2H), 1.59 (qt, J = 7.5 Hz, 4H), 0.85 (td,
3.97 mmol, 68%); Rf: 0.42 (EtOAc–cyclohexane 1/3); [α]2D5: −2.6° J = 7.5 Hz, J = 3.0 Hz, 6H); 13C NMR (75 MHz) (CDCl3) δ 112.9,
1
(c = 2.31, CHCl3); H NMR (300 MHz) (CDCl3) δ 5.33 (m, 2H), 75.2, 70.1, 60.4, 35.5, 29.9, 29.6, 8.1, 7.9.
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(S)-2,2-Diethyl-4-(2-(4-methoxybenzyloxy)ethyl)-1,3-
dioxolane (11)
purified by chromatography (EtOAc–cyclohexane 1/4), giving
the sulfonate 13 as white crystals (1.02 g, 2.14 mmol, 95%);
Rf: 0.2 (EtOAc–cyclohexane 1/4); [α]2D5: −7.3° (c = 1.03, CHCl3);
1H NMR (300 MHz) (CDCl3) δ 7.18 (s, 2H), 7.03 (A2B2, JAB = 8.7 Hz,
Δν = 103.7 Hz, 4H), 4.42 (s, 2H), 4.1 (m, 5H), 3.80 (s, 3H),
3.64 (m, 2H), 2.91 (septet, J = 6.9 Hz, 1H), 1.80 (m, 2H), 1.25
(d, J = 6.6 Hz, 18H); 13C NMR (75 MHz) (CDCl3) δ 159.3, 153.8,
150.8, 129.8, 129.3, 129.1, 123.8, 113.9, 73.0, 72.2, 68.8, 67.4,
55.3, 34.2, 32.6, 29.6, 24.73, 24.71, 23.5; IR ν 3437, 2959, 1614,
1514, 1423, 1337, 1256, 1178, 1072, 1030, 964, 894, 818, 811,
792, 664; HRMS ES m/z (M + Na)+: Calcd for C27H40NaO6S
515.244, found 515.243.
10 (6.5 g, 38.2 mmol, 1 equiv.) was stirred in dry THF (100 mL)
at 0 °C. NaH (60% in mineral oil, 1.83 g, 45.88 mmol,
1.2 equiv.) was added and the reaction mixture was stirred for
30 min at RT. PMB–Br (9.25 mL, 45.88 mmol, 1.2 equiv.) and
Bu4NI (2.1 g, 5.73 mmol, 0.15 equiv.) diluted in dry THF
(100 mL) were added and the reaction mixture was stirred for
6 h at RT. The reaction mixture was hydrolyzed with NH4Cl
(100 mL), and the aqueous phase was extracted three times
with EtOAc (100 mL). The organic phases were washed with a
saturated solution of Na2SO3 and brine, dried with Na2SO4, fil-
tered and evaporated. The crude was purified by chromato-
graphy (EtOAc–cyclohexane 1/4) giving the protected alcohol
11 as a pale yellow oil (10.68 g, 36.3 mmol, 95%); Rf: 0.69
(EtOAc–cyclohexane 1/3); [α]2D5: +8.2° (c = 1.14, CHCl3); 1H NMR
(300 MHz) (CDCl3) δ 6.97 (A2B2, JAB = 8.7 Hz, Δν = 111.5 Hz,
4H), 4.40 (s, 2H), 4.10 (qtd, J = 6.3 Hz, J = 1.5 Hz, 1H), 3.97 (dd,
J = 6.0 Hz, 1H), 3.71 (s, 3H), 3.44 (m, 3H), 1.85 (m, 2H), 1.59
(td, J = 7.5 Hz, J = 4.5 Hz, 4H), 0.86 (t, J = 7.5 Hz, 6H); 13C NMR
(75 MHz) (CDCl3) δ 159.2, 132.0, 129.4, 113.8, 112.3, 74.2, 72.7,
70.3, 66.8, 55.2, 33.7, 30.0, 29.8, 8.3, 8.0; HRMS ES m/z
(M + Na)+: Calcd for C17H26NaO4 317.172, found 317.169.
(S)-2-(2-(4-Methoxybenzyloxy)ethyl)oxirane (14)38
K2CO3 (940 mg, 6.8 mmol, 2 equiv.) was added to a stirred
solution of 13 (1.67 g, 3.4 mmol, 1 equiv.) in dry MeOH. The
reaction mixture was stirred overnight at RT. Solvents were
removed, giving a pale orange solid. The solid was filtered four
times with hot hexane, and the filtrates were dried. The crude
was purified by chromatography (DCM), giving the epoxide 14
as a pale yellow oil (572 mg, 2.73 mmol, 80%); Rf: 0.30 (DCM);
[α]D25: −14.4° (c = 1.0, CHCl3, lit.38 [α]2D7: −13.9°, c = 1.0 in
1
CHCl3); H NMR (300 MHz) (CDCl3) δ 7.07 (A2B2, JAB = 8.4 Hz,
Δν = 114.6 Hz, 4H), 4.46 (s, 2H), 3.80 (s, 3H), 3.59 (t, J = 6.3 Hz,
2H), 3.05 (m, 1H), 2.77 (t, J = 4.8 Hz, 1H), 2.51 (dd, J = 2.7 Hz,
J = 3.0 Hz, 1H), 1.82 (m, 2H); 13C NMR (75 MHz) (CDCl3)
δ 159.2, 130.4, 129.2, 113.8, 72.7, 66.7, 55.3, 50.1, 47.1, 32.6; IR
(ATR) ν 2859, 1612, 1512, 1244, 1173, 1087, 1032, 818.
(S)-4-(4-Methoxybenzyloxy)butane-1,2-diol (12)
PTSA (350 mg, 1.83 mmol, 0.2 equiv.) was added to a solution
of 11 (2.4 g, 9.2 mmol, 1 equiv.) in MeOH (30 mL). The reac-
tion mixture was stirred for 5 h at RT. Water (10 mL) was
added and the reaction mixture was stirred for 4 h at RT. Brine
(50 mL) and EtOAc (50 mL) were added. The aqueous phase (S)-(1-(1,3-Dithian-2-yl)-4-(4-methoxybenzyloxy)butan-2-yloxy)-
was extracted three times with EtOAc and the organic phases (tert-butyl)dimethylsilane (15)
were washed with a saturated solution of NaHCO3 (50 mL),
dried with Na2SO4, filtered and evaporated. The crude was pur-
To a solution of 1-tert-butyl-dimethyl-silyl-(1,3)-dithiane 239
(450 mg, 1.85 mmol, 1 equiv.) in THF (6 mL) at −78 °C was
ified by chromatography (EtOAc–cyclohexane 4/1) giving the
added tert-BuLi (1.7 M in heptane, 1.1 mL, 1.85 mmol,
diol 12 as white crystals (1.84 g, 8.29 mmol, 90%); Rf: 0.15
1 equiv.). The reaction mixture was stirred for 1 h at −50 °C
(EtOAc–cyclohexane 4/1); [α]2D5: −5.2° (c = 2.00, CHCl3, lit.37
and then cooled down to −78 °C. The epoxide 14 (390 mg,
1.85 mmol, 1 equiv.) in THF (6 mL) was added dropwise, and
the reaction mixture was stirred for 1 h at −50 °C and cooled
[α]2D7: −5.2°, c = 2.00 in CHCl3); 1H NMR (300 MHz) (CDCl3)
δ 7.05 (A2B2, JAB = 7.7 Hz, Δν = 109.8 Hz, 4H), 4.24 (s, 2H), 3.85
(m, 1H), 3.78 (s, 3H), 3.60 (m, 2H), 3.51 (AB(ABX), JAX = 3.6 Hz,
down to −78 °C. HMPA (4 mL) was added; the reaction
JBX = 6.3 Hz, JAB = 11.4 Hz, Δν = 42.0 Hz, 2H), 3.16 (s, 2H), 1.72
mixture was stirred at RT for 2 h and quenched with a satu-
rated solution of NH4Cl. The aqueous phase was extracted
twice with dichloromethane (2 × 10 mL) and the organic
phases were washed with brine (10 mL), dried over Na2SO4 and
(m, 2H); 13C NMR (75 MHz) (CDCl3) δ 159.3, 129.93, 129.4,
113.9, 72.9, 71.1, 67.7, 66.6, 55.3, 32.8; IR ν 3256, 2990, 2942,
2863, 1613, 1513.
evaporated. The crude was purified by flash chromatography
(EtOAc–cyclohexane 1/9) giving the dithiane 15 as an orange
oil (533 mg, 1.20 mmol, 65%); Rf: 0.5 (EtOAc–cyclohexane 1/4);
(S)-2-Hydroxy-4-(4-methoxybenzyloxy)butyl 2,4,6-
triisopropylbenzenesulfonate (13)
Dried Et3N (470 μL, 3.4 mmol, 1.5 equiv.) was added to a solu- [α]2D5: +8.1° (c = 1.02 (CHCl3); 1H NMR (300 MHz) (CDCl3) δ
tion of 12 (500 mg, 2.25 mmol, 1 equiv.) in dry DCM at RT. 7.08 (A2B2, JAB = 8.6 Hz, Δν = 116.0 Hz, 4H), 4.43 (s, 2H), 4.10
The sulfonyl chloride (1.05 g, 3.34 mmol, 1.5 equiv.) was then (m, 2H), 3.82 (s, 3H), 3.52 (t, J = 6.6 Hz, 2H), 2.82 (m, 4H), 1.90
added; the reaction mixture was allowed to warm to RT and (m, 6H), 0.90 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H); 13C NMR
stirred for 36 h. The reaction mixture was hydrolysed with (75 MHz) (CDCl3) δ 159.1, 130.6, 129.3, 113.8, 72.7, 66.4, 66.3,
water (2 mL) and stirred for 1 h at RT. The organic phases were 55.3, 43.9, 42.9, 37.3, 30.5, 30.1, 26.0, 25.9, 18.0, −4.5, −4.6; IR
washed consequently with water (10 mL), H2SO4 1 M (10 mL), ν 2929, 2855, 2118, 1613, 1513, 1463, 1360, 1248, 1172, 1094,
water (10 mL) and NaHCO3 (10 mL). The organic phases were 1039, 928, 835, 775; HRMS ES m/z (M + Na)+: Calcd for
dried over Na2SO4, filtered and evaporated. The crude oil was C22H38NaO3S2Si 465.192, found 465.192.
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(S)-2-(4-((4-Methoxybenzyl)oxy)-2-(methoxymethoxy)butyl)-
1,3-dithiane (16)
2H), 4.10 (m, 1H), 3.80 (s, 3H), 3.58 (t, J = 6.6 Hz), 3.38 (s, 3H),
3.0–2.55 (m, 4H), 2.37–2.17 (m), 2.08–1.78 (m), 1.76–1.50 (m),
1.50–1.25 (m), 1.12–0.82 (mixt. of d and t, 6H).
To a solution of 1,3-dithiane (689 mg, 5.74 mmol, 3 equiv.)
in THF (5 mL) at −78 °C was added n-BuLi (1.55 M in hexane,
(10S,E)-11-Hydroxy-11-(2-((S)-4-((4-methoxybenzyl)oxy)-
2-(methoxymethoxy)butyl)-1,3-dithian-2-yl)-10-methylundec-
7-en-1-yl pivalate (19)
7.4 mL, 11.48 mmol,
6 equiv.) and DMPU (1.4 mL,
11.48 mmol, 6 equiv.). The reaction mixture was stirred for 2 h
at 0 °C. The reaction mixture was then cooled down to −78 °C.
The epoxide 14 (402 mg, 1.91 mmol, 1 equiv.) in THF (5 mL)
was added dropwise, and the reaction mixture was stirred for
1.5 h at −78 °C and then for 1 h at −10 °C. The reaction was
quenched with 10 mL of satd. NH4Cl. The aqueous phase was
then extracted with EtOAc (3 × 10 mL), the organic phases were
washed with satd. NH4Cl (2 × 10 mL), brine (10 mL), dried over
Na2SO4 and evaporated. The crude was purified by chromato-
graphy (cyclohexane–EtOAc 4/1) giving alcohol as a pale yellow
oil (520 mg, 1.59 mmol, 83%).
To a solution of alcohol (500 mg, 1.52 mmol, 1 equiv.)
in DMF (20 mL) were added DIPEA (2.1 mL, 12.12 mmol,
8 equiv.), n-Bu4NI (565 mg, 1.52 mmol, 1 equiv.) and MOM–Cl
(460 μL, 6.08 mmol, 4 equiv.). The reaction mixture was stirred
for 16 h at 50 °C and then quenched with 10 mL of satd.
NH4Cl. The aqueous phase was then extracted with EtOAc
(3 × 10 mL) and organic phases were washed with satd. NH4Cl
(2 × 10 mL), brine (10 mL), dried over Na2SO4 and evaporated.
The crude was purified by chromatography (cyclohexane–
EtOAc 9/1) affording the protected alcohol 16 as a colorless oil
(520 mg, 1.39 mmol, 92%); Rf: 0.31 (EtOAc–cyclohexane 1/4);
[α]2D5: +2.2° (c = 0.96, CHCl3); 1H NMR (300 MHz) (CDCl3)
n-BuLi (1.6 M in hexane, 240 μL, 0.38 mmol, 2.2 equiv.) was
added to
a stirring solution of dithiane 16 (130 mg,
0.347 mmol, 2 equiv.) in dry THF (5 mL) at −78 °C and the
solution turned yellow. The reaction mixture was stirred for
1 h at 0 °C, turned into a pale yellow solution and then cooled
down to −78 °C. The aldehyde 9 (49 mg, 0.173 mmol, 1 equiv.)
in THF (1 mL) was added via cannula into the solution and
the reaction mixture was stirred for 1 h at −78 °C. The reaction
mixture was hydrolyzed by a satd. solution of NaHCO3, and the
aqueous phase was extracted three times with EtOAc. The
organic layers were washed with brine, dried over Na2SO4, and
filtered and the solvents were removed. The crude was purified
by chromatography (EtOAc–cyclohexane 5/95) affording the
desired coupling product 19 as a mixture of stereoisomers
(dr = 1/1.7) as a pale yellow oil (34 mg, 0.051 mmol, 30%);
1
Rf: 0.52 (EtOAc–cyclohexane 3/7); H NMR (300 MHz) (CDCl3)
δ 6.99 (A2B2, JAB = 8.6 Hz, Δν = 120.7 Hz, 4H), 5.36 (m, 2H),
4.75–4.58 (m, 2H), 4.36 (s, 2H), 4.02 (m, 1H), 3.96 (t, J = 6.6 Hz,
2H), 3.76 (m, 1H), 3.73 (s, 3H), 3.51 (t, J = 6.6 Hz, 2H), 3.31/
3.30 (s, 3H), 2.90–2.45 (m, 4H), 2.40–1.7 (m, 7H), 1.54 (m, 4H),
1.26 (m, 8H), 1.12 (s, 9H), 1.00 (d, J = 6.8 Hz, 3H), 0.91 (d,
J = 6.7 Hz, 3H).
δ 7.05 (A2B2, JAB = 8.7 Hz, Δν = 116.9 Hz, 4H), 4.62 (AB, JAB
=
6.9 Hz, Δν = 6.2 Hz, 2H), 4.41 (s, 2H), 4.15 (dd, J = 5.7 Hz, J =
5.7 Hz, 1H), 3.99 (m, 1H), 3.78 (s; 3H), 3.52 (t, J = 6.3 Hz, 2H),
3.36 (s, 3H), 2.82 (m, 4H), 1.95 (m, 6H); 13C NMR (75 MHz)
(CDCl3) δ 159.1, 130.4, 129.3, 113.8, 96.3, 72.9, 72.6, 66.3, 55.7,
55.3, 43.6, 40.9, 35.0, 30.3, 30.0, 25.7; IR (ATR) ν 2931, 1512,
1244, 1093, 1030, 916, 818; HRMS ES m/z (M + Na)+: Calcd for
C18H28NaO4S2 395.132, found 395.132.
((4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl)methanol (21)
p-Anisaldehyde dimethyl acetal (5.75 mL, 33.74 mmol,
0.95 equiv.) and PTSA (337 mg, 1.77 mmol, 0.05 equiv.) were
added to a stirring solution of (S)-butane-1,2,4-triol 20 (3.78 g,
35.5 mmol, 1 equiv.) in dry DMF (75 mL) at RT. The reaction
mixture was stirred under vacuum (15 mbar) until the reaction
was complete (1 h). Et2O (75 mL) was added and the organic
phase was then washed three times with a satd. solution of
NaHCO3, a satd. solution of NH4Cl and finally brine. The
organic phase was dried over Na2SO4, filtered and evaporated.
1-(2-((S)-4-((4-Methoxybenzyl)oxy)-2-(methoxymethoxy)butyl)-
1,3-dithian-2-yl)-2-methylpentan-1-ol (18)
n-BuLi (1.6 M in hexane, 375 μL, 0.56 mmol, 3.75 equiv.) was The crude was purified by chromatography (EtOAc–cyclo-
added over three minutes to a solution of dithiane 16 (112 mg, hexane 2/8 and then 6/4) affording the protected diol 21 as a
0.30 mmol, 2 equiv.) at −78 °C. The reaction mixture was pale yellow oil (6.94 mg, 29.1 mmol, 82%); m.p.: 43–45 °C;
stirred and then warmed to 0 °C over 1 h. 2-Methylvaleralde- Rf: 0.22 (EtOAc–cyclohexane 1/4); [α]2D5: +7.8° (c = 1.3, CH3Cl,
1
hyde 17 (19 μL, 0.15 mmol, 1 equiv.) was added via cannula to lit.40 [α]D27: +7.2°, c = 1.3, CHCl3); H NMR (300 MHz) (CDCl3)
the stirring solution of 2-lithiodithiane at −78 °C and the reac- δ 7.15 (A2B2, JAB = 8.7 Hz, Δν = 156.9 Hz, 4H), 5.50 (s, 1H), 4.28
tion mixture was stirred for 1 h at −78 °C. The reaction (ddd, J = 11.1 Hz, J = 4.8 Hz, J = 0.9 Hz, 1H), 3.98 (m, 2H), 3.80
mixture was hydrolyzed with a satd. solution of NH4Cl, and the (s, 3H), 3.67 (m, 2H), 2.11 (t, J = 6.3 Hz, 1H), 1.91 (qd, J =
aqueous layer was extracted three times with EtOAc. Organic 12.9 Hz, J = 5.1 Hz, 1H), 1.43 (m, 1H); 13C NMR (75 MHz) (CDCl3)
layers were washed with brine, dried over Na2SO4, filtered, and δ 160.0, 131.0, 127.5, 113.6, 101.2, 77.6, 66.6, 65.6, 55.3, 26.8;
concentrated. The crude material was purified by chromato- IR ν 3433, 2930, 2856, 1614, 1517, 1244, 1172, 1101, 1067,
graphy (EtOAc–cyclohexane 1/9 and then 1.5–8.5) affording 1027, 825, 777.
product 18 as a mixture of 4 diastereoisomers as a colorless oil
(4S)-4-(Iodomethyl)-2-(4-methoxyphenyl)-1,3-dioxane (22)
(41.5 mg, 0.088 mmol, 58%); Rf: 0.12 (EtOAc–cyclohexane 1/9);
1H NMR (300 MHz) (CDCl3) δ 7.08 (A2B2, JAB = 8.7 Hz, Δν = Triphenylphosphine (1.20 g, 4.59 mmol, 1.03 equiv.) and imid-
120.3 Hz, 4H), 4.97–4.6 (mixt. of AB, 2H), 4.44 (mixt. of AB, azole (364 mg, 5.35 mmol, 1.2 equiv.) were stirred in DCM
6836 | Org. Biomol. Chem., 2013, 11, 6829–6840
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(10 mL) at 0 °C. Iodine (1.16 g, 4.59 mmol, 1.03 equiv.) was corresponding alcohol 24 as
a
colorless oil (160 mg,
added at 0 °C (the solution turned dark brown) and the reac- 0.47 mmol, 94%); Rf: 0.36 (EtOAc–cyclohexane 1/1); [α]2D5:
tion mixture was stirred for 40 min at RT. Alcohol 21 (1.0 g, −11.2° (c = 1.00, CHCl3); 1H NMR (300 MHz) (CDCl3) δ 7.08
4.46 mmol, 1 equiv.) in DCM (10 mL) was added via cannula (A2B2, JAB = 8.4 Hz, Δν = 119.2 Hz, 4H), 4.52 (AB, JAB = 11.1 Hz,
into the stirring solution and the reaction mixture was stirred Δν = 12.6 Hz, 2H), 4.10 (m, 1H), 3.93 (m, 1H), 3.80 (s, 3H), 3.74
for 12 h at RT. The reaction mixture was hydrolyzed with a (m, 2H), 2.83 (m, 4H), 2.0 (m, 6H); 13C NMR (75 MHz) (CDCl3)
satd. solution of NaHCO3 and a satd. solution of Na2SO3. The δ 159.3, 130.3, 129.7, 113.9, 74.4, 71.3, 60.1, 55.3, 43.9, 40.0,
aqueous phase was extracted three times with Et2O, and the 36.3, 30.4, 30.3, 25.9; IR ν 3434, 2934, 1612, 1513, 1247,
organic phases were dried over Na2SO4, filtered and evapor- 1174, 1034, 821, 772; HRMS ES m/z (M + Na)+: Calcd for
ated. The crude was filtered through a pad of silica (EtOAc– C16H24NaO3S2 351.106, found 351.103.
cyclohexane 1/4) affording the desired compound 22 as a color-
(S)-(4-(1,3-Dithian-2-yl)-3-((4-methoxybenzyl)oxy)butoxy)-
(tert-butyl)dimethylsilane (25)
less oil (31 mg, 0.148 mmol, 70%); Rf: 0.89 (EtOAc–cyclohexane
1/1) [α]2D5: +33.6° (c = 1.03, CHCl3); 1H NMR (300 MHz) (CDCl3)
δ 7.16 (A2B2, JAB = 8.4 Hz, Δν = 161.5 Hz, 4H), 5.48 (s, 1H), 4.27 TBSCl (462 mg, 3.06 mmol, 1.5 equiv.) and imidazole (347 mg,
(m, 1H), 3.94 (m, 2H), 3.80 (s, 3H), 3.27 (AB(ABX), JAX = 6.0 Hz, 5.1 mmol, 2.5 equiv.) were added to a stirring solution of
JBX = 6.0 Hz, JAB = 9.9 Hz, Δν = 29.3 Hz, 2H), 1.82 (m, 2H); alcohol 24 (700 mg, 2.04 mmol, 1 equiv.) in dry DMF (10 mL)
13C NMR (75 MHz) (CDCl3) δ 158.9, 130.8, 126.4, 112.5, 100.1, at RT and the reaction mixture was stirred overnight. Et2O
75.3, 65.5, 54.1, 30.1, 6.8.
(15 mL) was added to the solution and the organic phase was
washed three times with a satd. solution of NaHCO3, once
with a satd. solution of NH4Cl and with brine. The organic
phase was dried over Na2SO4, filtered and evaporated. The
(4S)-4-((1,3-Dithian-2-yl)methyl)-2-(4-methoxyphenyl)-
1,3-dioxane (23)
1,3-Dithiane (3.28 g, 27.3 mmol, 2.44 equiv.) was dissolved in crude was purified by chromatography giving the protected
THF/HMPA (10 mL/0.25 mL) and the solution was cooled alcohol 25 as a colorless oil (840 mg, 1.84 mmol, 90%); Rf: 0.27
down to −30 °C. t-BuLi (1.7 M in hexane, 16.0 mL, 27.3 mmol, (EtOAc–cyclohexane 5/95); [α]2D5: −17.6° (c = 1.07 in CHCl3);
2.44 equiv.) was added dropwise and the solution turned dark 1H NMR (300 MHz) (CDCl3) δ 7.08 (A2B2, JAB = 8.7 Hz, Δν =
yellow. The reaction mixture was stirred for 1.5 h at −30 °C 121.2 Hz, 4H), 4.49 (AB, JAB = 10.8 Hz, Δν = 10.8 Hz, 2H), 4.14
and 22 (3.74 g, 11.2 mmol, 1 equiv.) in THF (5 mL) was added (dd, J = 9.0 Hz, J = 5.7 Hz, 1H), 3.86 (m, 1H), 3.80 (s, 3H), 3.69
via cannula to the reaction mixture at −78 °C. The reaction (td, J = 6.6 Hz, J = 2.4 Hz, 2H), 2.81 (m, 4H), 1.85 (m, 6H), 0.89
mixture was stirred for 45 min at −78 °C, turned dark brown, (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz) (CDCl3) δ 159.2, 131.0,
and was hydrolyzed with a satd. solution of NH4Cl. The 129.5, 113.8, 72.8, 71.4, 59.4, 55.3, 44.0, 40.6, 37.6, 30.4, 30.1,
aqueous layer was extracted three times with Et2O, dried over 26.0, 25.9, 18.2, −5.3, −5.3; IR (ATR) ν 2929, 1612, 1513, 1246,
Na2SO4, filtered and evaporated. The crude was then purified 1172, 1089, 1035, 832, 774; HRMS ES m/z (M + H)+: Calcd for
by chromatography giving the corresponding dithiane 23 C22H39O3S2Si 443.210, found 443.210.
as a white solid (2.74 g, 8.4 mmol, 75%); Rf: 0.42 (EtOAc–cyclo-
(10S,E)-11-(2-((S)-4-((tert-Butyldimethylsilyl)oxy)-
2-((4-methoxybenzyl)oxy)butyl)-1,3-dithian-2-yl)-11-hydroxy-
10-methylundec-7-en-1-yl pivalate (26)
hexane 1/4); [α]2D5: +44.21° (c = 1.03, CHCl3); 1H NMR
(300 MHz) (CDCl3) δ 7.16 (A2B2, JAB = 8.7 Hz, Δν = 159.0 Hz,
4H), 5.48 (s, 1H), 4.26 (td, J = 9.9 Hz, J = 4.5 Hz, 1H), 4.15
(m, 2H) 3.95 (td, J = 12.0 Hz, J = 2.4 Hz, 1H), 3.80 (s, 3H), 2.85 n-BuLi (1.6 M in hexane, 1.21 mL, 0.76 mmol, 2.5 equiv.) was
(m, 4H), 2.11 (m, 2H), 1.88 (m, 3H), 1.52 (m, 1H); 13C NMR added dropwise to a stirring solution of dithiane 25 (337 mg,
(75 MHz) (CDCl3) δ 159.9, 131.3, 127.8, 113.5, 101.0, 73.1, 66.8, 0.76 mmol, 2.5 equiv.) in THF (7 mL) at −78 °C and the reac-
55.3, 42.8, 41.7, 31.3, 30.2, 29.8, 26.0; IR (ATR) ν 2926, 1611, tion mixture was stirred for 1 h at −10 °C. The freshly prepared
1517, 1428, 1301, 1246, 1172, 1138, 1088, 1030, 1013, 969, 835, aldehyde 9 (86 mg, 0.304 mmol, 1 equiv.) in THF (5 mL) was
818, 768; HRMS ES m/z (M + Na)+: Calcd for C16H22NaO3S2 added dropwise via cannula to the reaction mixture at −78 °C
349.090, found 349.091.
and the reaction mixture was stirred for 2 h at −78 °C. The
reaction mixture was hydrolyzed by a satd. solution of NaHCO3
and the aqueous layer was extracted three times with EtOAc.
(S)-4-(1,3-Dithian-2-yl)-3-((4-methoxybenzyl)oxy)butan-1-ol (24)
DIBAL-H (1 M toluene, 3.0 mL, 3.0 mmol, 6 equiv.) was added The organic phases were washed with brine, dried over
dropwise to a solution of 23 (169 mg, 0.5 mmol, 1 equiv.) in Na2SO4, filtered and evaporated; the crude was purified by
DCM (12 mL) at −40 °C and the reaction mixture was stirred chromatography (EtOAc–cyclohexane 1/9) affording the coup-
for 4 h at −40 °C until the starting material disappeared on ling product 26 as a mixture of non-separable diastereoisomers
TLC. The reaction mixture was hydrolyzed with a satd. solution (r.d. 1/2.7) as a pale yellow oil (210 mg, 0.29 mmol, 92%); Rf:
of sodium tartrate and the solution was stirred until the two 0.65 (EtOAc–cyclohexane 1/4); 1H NMR (300 MHz) (CDCl3)
phases were clear. The aqueous layer was extracted three times δ 7.05 (A2B2, JAB = 8.4 Hz, Δν = 117.9 Hz, 4H), 5.42 (m, 2H),
with DCM, organic phases were washed with brine, dried over 4.52 (AB, JAB = 10.5 Hz, Δν = 46.5 Hz, 2H), 4.45 (AB, JAB
=
Na2SO4, filtered and evaporated. The crude was purified 10.5 Hz, Δν = 17.1 Hz, 2H), 4.03 (t, J = 6.6 Hz, 2H), 3.99 (m, 1H),
by chromatography (EtOAc–cyclohexane 3/7) affording the 3.79 (s, 3H), 3.74 (m, 3H), 3.58 (d, J = 4.5 Hz, 1H), 2.73 (m, 4H),
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2.28 (m, 3H), 1.88 (m, 8H), 1.60 (m, 2H), 1.32 (m, 6H), 1.42 layers were washed with brine, dried over Na2SO4, filtered, and
(s, 9H), 1.04 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H), 0.91 evaporated. The crude was purified by chromatography
(s, 9H), 0.07 (s, 6H), 0.06 (s, 6H), 13C NMR (75 MHz) (CDCl3) (EtOAc–cyclohexane 1/9) giving the protected 1,2-diol 28 as a
δ 178.6, 132.0, 130.9, 113.8, 113.7, 74.8, 74.7, 70.7, 64.4, 59.7, colorless oil (16.0 mg, 0.024 mmol, 71%); Rf: 0.64 (EtOAc–
59.6, 41.3, 40.4, 38.7, 37.6, 33.8, 33.6, 30.2, 29.6, 28.8, 28.6, cyclohexane 1/3); [α]2D5: −22.6° (c = 1.01, CHCl3); 1H NMR
27.3, 26.9, 26.0, 25.9, 25.8, 25.6, 25.0, 24.6, 18.3, 15.7, 15.6, (300 MHz) (CDCl3) δ 7.05 (A2B2, JAB = 6.6 Hz, Δν = 117.7 Hz,
−5.26, −5.29; IR ν 3460, 2929, 2856, 1726, 1514, 1248, 4H), 5.34 (m, 2H), 4.43 (AB, JAB = 8.4 Hz, Δν = 28.5 Hz, 2H),
1155, 1091, 1036, 834, 775; HRMS ES m/z (M + Na)+: Calcd 4.11 (m, 1H) 4.09 (t, J = 5.1 Hz, 2H), 3.79 (s, 3H), 3.65 (m, 4H),
C30H68NaO6S2Si 747.412, found 747.406.
2.05–1.70 (m, 5H), 1.70–1.50 (m, 6H), 1.43 (s, 3H), 1.25
(m, 6H), 1.23 (s, 3H) 1.19 (s, 9H), 0.99 (d, J = 4.8 Hz, 3H), 0.89
(s, 9H), 0.04 (s, 6H); 13C NMR (75 MHz) (CDCl3) δ 178.6, 159.4,
132.6, 131.0, 129.4, 127.2, 113.8, 107.4, 81.9, 74.4, 73.4, 70.7,
64.4, 59.8, 55.3, 38.7, 37.0, 34.1, 33.1, 32.5, 29.7, 29.4, 28.3,
(10S,11R,14S,E)-16-((tert-Butyldimethylsilyl)oxy)-11-hydroxy-
14-((4-methoxybenzyl)oxy)-10-methyl-12-oxohexadec-7-en-
1-yl pivalate (27)
Dithiane 26 (30 mg, 0.041 mmol, 1 equiv.) was dissolved in 28.6, 28.4, 27.2, 26.0, 25.8, 18.3, 16.7, −5.2; IR ν 2929, 1729,
CH3OH (0.2 mL), water (0.2 mL) and THF (2 mL). PIFA (27 mg, 1514, 1461, 1249, 1158, 1091, 837, 775; HRMS ES m/z
0.06 mmol, 1.5 equiv.) was added, the reaction mixture was (M + Na)+: Calcd C39H68NaO7Si 699.463, found 699.458.
stirred for one minute, and the reaction mixture was hydro-
(7S,8S,10S)-10-((4R,5S)-5-((S)-4-((tert-Butyldimethylsilyl)oxy)-
2-((4-methoxybenzyl)oxy)butyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-
7,8-dihydroxyundecyl pivalate (29)
lyzed with a satd. solution of Na2SO3. The aqueous phase was
extracted three times with EtOAc. Organic phases were dried
over Na2SO4, filtered, and evaporated. The crude was purified
by chromatography (EtOAc–cyclohexane 5/95) giving the AD-mix-α (31 mg) and CH3SO2NH2 (2 mg) were added to a
ketone as a single diastereoisomer 27 (19.6 mg, 0.030 mmol, solution of alkene 28 (16 mg, 0.022 mmol, 1 equiv.) in
75%); Rf: 0.59 (EtOAc–cyclohexane 1/4); [α]2D5: −19.8° (c = 1.01, t-BuOH–H2O (0.5/0.5 mL) at RT and the reaction mixture was
1
CHCl3); H NMR (300 MHz) (CDCl3) δ 7.02 (A2B2, JAB = 8.7 Hz, stirred at RT for 6 days. The reaction was stopped by addition
Δν = 106.4 Hz, 4H), 5.45 (m, 2H), 4.45 (AB, JAB = 11.1 Hz, Δν = of sodium sulfite and the yellow color disappeared. The
9.17 Hz, 2H), 4.14 (m, 2H), 4.03 (t, J = 6.6 Hz, 2H), 3.79 (s, 3H), aqueous phase was extracted three times with EtOAc, the
3.69 (t, J = 5.7 Hz, 2H), 3.41 (d, J = 4.8 Hz, 1H), 2.70 (AB(ABX), organic layers were washed with brine, dried over Na2SO4, fil-
JAX = 7.5 Hz, JBX = 4.8 Hz, JAB = 16.2 Hz, Δν = 72.6 Hz, 2H), 2.0 tered and evaporated. The crude was purified by chromato-
(m, 6H), 1.65 (m, 4H), 1.33 (m, 6H), 1.19 (s, 9H), 0.89 (s, 9H), graphy (EtOAc–cyclohexane 1/4) affording the 1,2-diol 29 as a
0.66 (d, J = 6.3 Hz, 3H), 0.04 (s, 6H); 13C NMR (75 MHz) mixture of diastereoisomers (dr = 4.7/1) as a colorless oil
(CDCl3) δ 211.4, 179.1, 159.2, 133.0, 130.3, 129.4, 127.9, 113.7, (12.0 mg, 0.017 mmol, 77%); Rf: 0.05 (EtOAc–cyclohexane 1/3);
78.7, 72.5, 71.7, 64.4, 59.2, 55.2, 43.7, 38.7, 37.2, 36.4, 32.5, [α]2D5: −19.1° (c = 0.45, CHCl3); 1H NMR (300 MHz) (CDCl3)
29.7, 29.4, 28.8, 28.6, 27.2, 25.9, 25.8, 18.2, 12.6, −5.3; IR ν δ 7.01 (A2B2, JAB = 8.7 Hz, Δν = 109.7 Hz, 4H), 4.40 (AB, JAB
=
2929, 2856, 1727, 1514, 1462, 1249, 1156, 1092, 836, 776; 11.1 Hz, Δν = 25.9 Hz, 2H), 4.17 (m, 1H) 4.09 (t, J = 6.3 Hz,
HRMS ES m/z (M + Na)+: Calcd C36H62NaO7Si 657.416, found 2H), 3.75 (s, 3H), 3.68 (m, 4H), 3.48 (m, 1H), 3.27 (m, 1H),
657.416.
2.05–1.55 (m, 13H), 1.40 (s, 3H), 1.25 (m, 6H), 1.20 (s, 3H) 1.14
(s, 9H), 1.00 (d, J = 6.3 Hz, 3H), 0.84 (s, 9H), 0.00 (s, 6H);
13C NMR (75 MHz) (CDCl3) δ 178.8, 159.2, 131.9, 129.4, 113.8,
107.8, 82.5, 75.3, 74.5, 73.35, 71.88, 70.6, 64.4, 59.8, 55.3,
38.80, 38.0, 37.1, 33.6, 29.7, 29.4, 29.3, 28.3, 28.6, 28.1, 27.3,
(S,E)-10-((4R,5S)-5-((S)-4-((tert-Butyldimethylsilyl)oxy)-
2-((4-methoxybenzyl)oxy)butyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-
undec-7-en-1-yl pivalate (28)
Zn(BH4)2 (260 μL, 0.183 mmol mL−1, 0.047 mmol, 1 equiv.) 26.0, 25.6, 18.3, 16.1, −5.2; IR (ATR) ν 3445, 2931, 2857, 2324,
was added dropwise to a solution of the ketone 27 (32 mg, 1728, 1514, 1463, 1249, 1158, 1093, 1039, 836, 776.
0.047 mmol, 1 equiv.) in Et2O (2 mL) at −78 °C. The reaction
6-((4S,5S)-5-((S)-2-((4R,5S)-5-((S)-4-((tert-Butyldimethylsilyl)-
mixture was stirred for 2 h at −78 °C. The reaction mixture
oxy)-2-((4-methoxybenzyl)oxy)butyl)-2,2-dimethyl-1,3-dioxolan-
4-yl)propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)hexyl pivalate (30)
was hydrolyzed with water (5 mL). The aqueous phase was
extracted three times with Et2O and the organic phases
were washed with brine, dried over Na2SO4, filtered and evapo- To a solution of 29 (9.0 mg, 0.012 mmol, 1 equiv.) in acetone
rated. The crude was purified by chromatography (EtOAc– (1 mL) were added PPTS (0.3 mg, 0.001 mmol, 0.1 equiv.) and
cyclohexane 1/9) affording the trans 1,2-diol as a single 2,2-DMP (15 mL, 0.12 mmol, 10 equiv.) at room temperature.
diastereoisomer (r.d. > 98/2) as a colorless oil (22.7 mg, The reaction mixture was stirred for 12 h and hydrolyzed with
0.033 mmol, 72%).
a satd. solution of NaHCO3. The aqueous phase was extracted
PPTS (0.9 mg, 0.003 mmol, 0.1 equiv.) was added to a solu- three times with EtOAc, and the organic layers were dried over
tion of 1,2-diol (22.7 mg, 0.034 mmol, 1 equiv.) in 2,2-DMP Na2SO4, filtered and concentrated. The crude was purified by
(1 mL) at RT. The reaction mixture was stirred overnight at RT chromatography (EtOAc–cyclohexane 1/9) affording the com-
and hydrolyzed with a satd. solution of NaHCO3. The aqueous pound 30 as a colorless oil (8.0 mg, 0.010 mmol, 85%); Rf: 0.48
layer was extracted three times with EtOAc, and the organic (EtOAc–cyclohexane 1/4); [α]2D5: −0.13° (c = 0.15 in CHCl3);
6838 | Org. Biomol. Chem., 2013, 11, 6829–6840
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1H NMR (300 MHz) (CDCl3) δ 7.05 (A2B2, JAB = 8.7 Hz, Δν =
118.5 Hz, 4H), 4.44 (AB, JAB = 11.1 Hz, Δν = 39.9 Hz, 2H), 4.17
(m, 1H) 4.04 (t, J = 6.6 Hz, 2H), 3.79 (s, 3H), 3.76–3.55 (m, 5H),
3.46 (m, 1H), 2.05–1.55 (m, 11H), 1.44 (s, 3H), 1.36 (s, 3H),
1.35 (s, 3H), 1.32 (s, 3H) 1.25 (m, 6H), 1.19 (s, 9H), 1.04 (d, J =
6.6 Hz, 3H), 0.88 (s, 9H), 0.00 (s, 6H); 13C NMR (75 MHz)
(CDCl3) δ 178.6, 159.1, 131.1, 129.3, 113.7, 108.1, 107.5, 82.5,
81.3, 77.2, 74.6, 73.5, 70.4, 64.3, 59.9, 55.3, 38.7, 37.6, 37.2,
33.6, 32.5, 31.9, 29.7, 29.4, 29.3, 28.9, 28.6, 28.1, 27.4, 27.3,
27.2, 26.10, 26.0, 25.9, 25.7, 18.3, 16.1, 14.1, −5.2; IR (ATR) ν
2927, 2855, 1730, 1514, 1462, 1248, 1157, 1093, 836, 775;
HRMS ES m/z (M + Na)+: Calcd C42H74NaO9Si 773.499, found
773.497.
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Acknowledgements
We are grateful to the Centre National de la Recherche Scienti-
fique (CNRS), the Ministère de l’Education Nationale et de la
Recherche, and the Agence Nationale pour la Recherche (ANR
program 08-BLAN-0262-01, Amphi 3) for financial support and 11 (a) T. Houdai, S. Matsuoka, N. Morsy, N. Matsumori,
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