A Short and Efficient Approach for the Total Synthesis of (S)-Zearalenone and (R)-De-O-methyllasiodiplodin by Using Stille and RCM Protocols

Article abstract of DOI:10.1002/ejoc.201501545

A concise, flexible, and linear approach has been devised for the total synthesis of the resorcinylic acid lactones (S)-zearalenone (2) and (R)-de-O-methyllasiodiplodin (4) by using a Stille cross-coupling strategy. The other key steps of the synthesis include a ring-closing metathesis (RCM), a chemoselective reduction of an α,β-unsaturated ketone, and a transesterification reaction.

Full text of DOI:10.1002/ejoc.201501545

DOI: 10.1002/ejoc.201501545
Full Paper
Total Synthesis
A Short and Efficient Approach for the Total Synthesis of (S)-
Zearalenone and (R)-De-O-methyllasiodiplodin by Using Stille
and RCM Protocols
Sujit Kumar Dey,[a,b] Mohammad Ataur Rahman,[a,b] Ahmad Alkhazim Alghamdi,[c]
Basi V. Subba Reddy,[a] and Jhillu S. Yadav*[a]
Abstract: A concise, flexible, and linear approach has been de- thesis include a ring-closing metathesis (RCM), a chemoselect-
vised for the total synthesis of the resorcinylic acid lactones (S)-
zearalenone (2) and (R)-de-O-methyllasiodiplodin (4) by using
a Stille cross-coupling strategy. The other key steps of the syn-
ive reduction of an α,ꢀ-unsaturated ketone, and a transesterifi-
cation reaction.
Introduction
A large number of resorcinylic acid lactones[1] with varying bio-
activities have been isolated from different fungal and plant
sources, and, hence, they have become prominent synthetic tar-
gets for organic chemists worldwide. The first discovered resor-
cinylic acid lactone was radicicol[2] (1), which binds to Hsp90
and alters its function. Hsp90 proteins play an important role
in the regulation of the cell cycle, cell growth, cell survival,
apoptosis, angiogenesis, and oncogenesis. Both zearalenone (2)
and lasiodiplodin (3) are structurally related resorcinylic acid
lactones (RALs), which were isolated from the two different fun-
gal sources Gibberella zeae (Fusarium graminearum)[3] and
Lasiodiplodia theobromae,[4] respectively. These RALs are known
to have a wide range of biological activities such as antibiotic,
estrogenic, uterotropic, antibacterial, antileukemic, antimicro-
bial, and antitumor effects along with being a prostaglandin
synthesis inhibitor.[5,6]
Both 2 and 4 (Figure 1) contain a macrolide core that has an
even-numbered ring (for 2, a 14-membered ring and for 4, a
12-membered ring). They belong to a same class of compounds
as the orsellinic acid (i.e., 2,4-dihydroxy-6-methylbenzoic acid)
family of natural products, and both contain one stereogenic
center with a methyl carbinol moiety. The relative and absolute
stereochemistry of both macrolides have been determined by
total synthesis[7] as well as X-ray crystallography.[6a]
Figure 1. Structures of some naturally occurring RALs.
Inspired by their inherent biological activity, several groups
have been involved in the development of synthetic routes for
both macrolides.[7–9] However, employing a Stille coupling[10] to
construct the styryl C-1′–C-2′ trans-olefin (Scheme 1) found in
both 9 and 14 has not yet been reported. We propose that a
Stille coupling might be a successful tool to construct the styryl
olefin of both RALs. Because of their fascinating structural fea-
tures, we became interested in the development of a concise
synthetic strategy for 2 and 4, which would also be effective
for the total syntheses of other RALs. Following our interests in
the total syntheses of bioactive RALs, we herein report a concise
[a] Centre for Semio-Chemicals, CSIR – Indian Institute of Chemical
Technology,
Hyderabad, India
E-mail: yadavpub@gmail.com
http://www.iictindia.org
[b] Academy of Scientific and Innovative Research,
New Delhi, India
[c] Engineer Abdullah Baqshan for Bee Research, King Saudi University,
Saudi Arabia
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501545.
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approach to the total synthesis of (S)-zearalenone (2) and (R)-
de-O-methyllasiodiplodin (4) by employing Stille and ring-clos-
ing metathesis reactions as the key steps.
Scheme 2. Reagents and conditions: (a) acetone, trifluoroacetic acid (TFA),
trifluoroacetic anhydride (TFAA), room temp., 20 h, 76 %; (b) MeOH, diiso-
propyl azodicarboxylate (DIAD), PPh3, tetrahydrofuran (THF), 0 °C to room
temp., 4 h, 81 %; (c) Tf2O, pyridine (Py), 0 °C, 2 h, 96 %.
The common building block 10 was synthesized according
to a literature procedure.[12] First, commercially available 2,4,6-
trihydroxybenzoic acid (17, Scheme 2) was converted into lact-
one 18 in 76 % yield by using acetone and a mixture of trifluo-
roacetic acid (TFA) and trifluoroacetic anhydride (TFAA). Com-
pound 18 was then subjected to Mitsunobu conditions by us-
ing methanol and a combination of Ph3P and diisopropyl azodi-
carboxylate (DIAD), which resulted in the regioselective O-
methylation of the non-hydrogen bonded phenolic residue to
obtain compound 19 in 81 % yield. The conversion of 19 into
corresponding triflate 10 was readily achieved in 96 % yield
under standard conditions.
With the required starting materials in hand, we attempted
the total synthesis of (S)-zearalenone. Accordingly, stannane 11
was prepared from commercially available 5-hexyn-1-ol (12).
After screening a number of reports in the literature, we found
the Menche protocol[13] was the most suitable to produce the
required trans-vinyl stannane 11 in high yield with excellent
selectivity. The Stille cross-coupling reaction of triflate 10 and
stannane 11 was examined as a method to construct the C-1′–
C-2′ styryl double bond of 2 (Scheme 3). Among various Stille
conditions[14] (see Table 1), we found the best results involved
the treatment of 10 with Pd2(dba)3·CHCl3 (dba = dibenzyl-
ideneacetone, 1 mol-%), 0.08 equiv. of the tri(2-furyl)phosphine
ligand, 3 equiv. of LiCl, and 1.1 equiv. of stannane 11 in N-
methyl-2-pyrrolidone (NMP) at 60 °C to provide the trans-olefin
in 88 % yield (Table 1, Entry 6).
Scheme 1. Retrosynthetic analysis of 2 and 4 (TfO = trifluoromethane-
sulfonate).
Results and Discussion
The retrosynthetic analysis of 2 and 4 is illustrated in Scheme 2.
A close assessment of the structures of (S)-zearalenone (2) and
After the successful optimization of the Stille reaction
(R)-de-O-methyllasodiplodin (4) reveals that precursors to both (Table 1, Entry 6), compound 9 was oxidized by treatment
of them contain similar styryl moieties that can be easily in- with (2,2,6,6-tetramethylpiperidin-1-yl)oxyl/[bis(acetoxy)iodo]-
stalled by a Stille cross-coupling reactions of trans-stannanes benzene (TEMPO/BAIB)[15] to give the corresponding aldehyde
11 and 15, which are directly synthesized from commercially 20 in good yield. Other oxidizing conditions [e.g., pyridinium
available 5-hexyn-1-ol (12) and 4-pentyn-1-ol (16), respectively. chlorochromate (PCC), Dess–Martin periodinane (DMP), and
At a later stage, ring-closing metathesis (RCM) precursors 8 and Swern conditions] afforded aldehyde 20 in poor yield. The Grig-
13 could be obtained by a transesterification[11] with the re- nard reaction of aldehyde 20[16] with vinylmagnesium bromide
quired chiral homoallylic alcohols to convert the lactone into at low temperature furnished allyl alcohol 21 in 90 % yield
the ester moiety and free phenolic residue that is associated (based on recovery of starting material). It is noteworthy that
with both targets. The C-7′–C-8′ bond of 2 and the C-5′–C-6′ the vinyl Grignard reagent only underwent a reaction with the
bond of 4 could be established through a ring-closing meta- aldehyde and did not affect the lactone ring. The secondary
thesis followed by a chemoselective reduction through a 1,4- hydroxy group of 21 was subsequently protected as its silyl
hydride addition to obtain 2 and a catalytic hydrogenation to ether under standard conditions to obtain compound 22 in
give 4.
95 % yield.
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Scheme 3. Reagents and conditions: (a) Pd2(dba)3·CHCl3, LiCl, tri(2-furyl)phosphine, NMP, 60 °C, 3 h, 88 %; (b) TEMPO/BAIB, CH2Cl2, 0 °C to room temp., 2 h,
90 %; (c) vinylmagnesium bromide (3.0 M), THF, –78 °C, 2 h, 90 %; (d) TBSOTf (TBS = tert-butyldimethylsilyl), N,N-diisopropylethylamine (DIPEA), CH2Cl2, 0 °C
to room temp., 30 min, 95 %; (e) (S)-4-penten-2-ol (23), NaH, THF, 0 °C to room temp., 4 h, 75 %; (f) HF·Py, THF, room temp., 12 h, 95 %; (g) DMP, 0 °C to room
temp., 2 h, 92 %.
Table 1. Optimization of Stille cross-coupling between triflate 10 and stannane 11.
Entry
Pd catalyst
Ligand/additive
Solvent
Temperature [°C]
Time [h]
Yield of 9 [%][a,b]
1
2
3
4
5
6
Pd(PPh3)4
Pd(PPh3)Cl2
Pd(PPh3)2Cl2
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
–
CuI
PPh3, LiCl
AsPh3, CuI, LiCl
tri(2-furyl)phosphine
tri(2-furyl)phosphine
NMP
toluene
DMF[c]
DMF
DMF
NMP
100
110
60
80
60
12
12
8
12
6
trace
–
50
60
75
88
60
3
[a] Only the (E) isomer was observed by 1H NMR spectroscopy. [b] Yield was calculated after purification of product by column chromatography. [c] DMF =
N,N-dimethylformamide.
Next, we performed the pivotal base-catalyzed lactone ring- tion of copper(I) hydride, which was generated in situ from
opening/transesterification reaction (under De Brabander's con- CuBr/sodium bis(2-methoxyethoxy)aluminum dihydride (Red-
ditions)[11] by using commercially available (S)-4-penten-2-ol Al).[19] We made several attempts to cleave the O-methyl ether
(23) and non-nucleophilic bases such as sodium hexamethyldis- of 27. Of these, AlI3/tetra-n-butylammonium iodide (TBAI)[20]
ilazide (NaHMDS), LiHMDS, and KHMDS. Among them, NaH af- was the most effective reagent and furnished (S)-zearalenone
forded satisfactory results to furnish 24 in a reasonable yield (2) in a short time as a white crystalline solid in 82 % yield
(75 %). Next, removal of the silyl ether protecting group by us- (Scheme 4).
ing HF·Py in THF afforded compound 25 without any side reac-
After successfully synthesizing (S)-zearalenone (2), we de-
tion because of the presence of different olefins. Allylic alcohol cided to examine the generality of our strategy by carrying out
25 was subsequently oxidized to the corresponding vinyl ket- the total synthesis of (R)-de-O-methyllasiodiplodin (4). In 1990,
one by using DMP[17] to obtain the required RCM precursor 8 the first asymmetric total synthesis of 4 was achieved in 18
(Scheme 3). As expected, the macrocyclic core of 2 was ob- steps and 0.8 % overall yield.[9a] A comparatively shorter route
tained as a single diastereomer in a satisfactory yield (75 %) was published in 1996 by Alois Fürstner and co-workers, which
with trans selectivity by an RCM reaction using Grubbs II cata- involved a more complicated Kolbe–Schmitt reaction.[9b] Al-
lyst.[18] A chemoselective hydride-mediated reduction of enone though Guo and co-workers reported the total synthesis of 4
26 to give 27 was achieved at low temperature by a 1,4-addi- in nine steps and 28.3 % overall yield, they found the final de-
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Scheme 4. Reagents and conditions: (a) Grubbs II, CH2Cl2, reflux, 4 h, 75 %; (b) CuBr/Red-Al, THF, –78 °C to –20 °C, 1 h, 70 %; (c) AlI3, TBAI, benzene, 10 °C,
30 min, 82 %.
methylation step to be relatively low yielding (57 %).[9c] In spite conditions with NiCl2·6H2O/NaBH4
to give 28 in 95 % yield.
[22]
of these results, we herein report the synthesis of 4 from triflate The subsequent oxidation by using TEMPO/BAIB[15] followed by
10 in seven steps and an overall yield of 34.1 %. a one-carbon Wittig homologation furnished compound 29 in
Under similar conditions to those described earlier (Table 1, good yield. Under similar reaction conditions to those de-
Entry 6), the synthesis of 4 began from a Stille cross-coupling scribed earlier (Scheme 3), 29 was then subjected to a sodium
between aromatic triflate 10 and trans-vinyl stannane 15, which hydride mediated transesterification[11] reaction with commer-
was derived from 4-pentyn-1-ol (16), to furnish compound 14 cially available (R)-4-penten-2-ol (30) to give compound 13. The
in 85 % yield (Scheme 5). For the remainder of the synthesis of ring-closing metathesis of 13 with Grubbs II catalyst[18] afforded
4, we followed a similar reaction sequence to that employed macrocycle 31 in a comparatively high yield (80 %) with select-
for 2 such as an oxidation reaction by using TEMPO/BAIB, a ivity for the (E) isomer (E/Z, 4:1). Finally, compound 31 was sub-
Wittig homologation, a transesterification, and an RCM reaction jected to a catalytic hydrogenation by using Pd/C to furnish
by using Grubbs II catalyst. However, the RCM step was rela- saturated product 32, the demethylation of which by using AlI3/
tively low yielding (40 %), probably a result of a competing RCM TBAI[19] afforded (R)-de-O-methyllasiodiplodin (4) as a white
reaction between the terminal olefin and the relatively more solid in 85 % yield (Scheme 6).
reactive styryl olefin.[21] Therefore, we decided to reduce the
The physical characteristics and spectroscopic data of both
styryl double bond of compound 14 prior to the oxidation step. synthetic products 2 and 4 were consistent with those reported
Hence, the olefin was reduced under transfer hydrogenation in the literature (see Supporting Information).[8,9c]
Scheme 5. Reagents and conditions: (a) Pd2(dba)3·CHCl3, LiCl, tri(2-furyl)phosphine, NMP, 60 °C, 3 h, 85 %; (b) NiCl2·6H2O, MeOH, 0 °C, 20 min, 95 %; (c) TEMPO/
BAIB, CH2Cl2, 0 °C to room temp., 2 h, (d) Ph3P+CH3Br–, NaHMDS, THF, 0 °C to room temp., 4 h, 80 % over two steps; (e) (R)-4-penten-2-ol (30), NaH, THF, 0 °C
to room temp., 5 h, 82 %.
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solved in degassed N-methyl-2-pyrrolidone (30 mL), and the result-
ing solution was treated with Pd2(dba)3·CHCl3 (144.9 mg,
0.14 mmol), tri(2-furyl)phosphine (259 mg, 1.12 mmol), and anhy-
drous LiCl (1.68 g, 42 mmol). The solution was stirred at room tem-
perature for 10 min. A solution of stannane 11 (6 g, 15.4 mmol) in
NMP (30 mL) was added dropwise, and the mixture was stirred at
60 °C for 3 h. Upon completion, the reaction mixture was diluted
with a saturated KF solution (50 mL), and the resulting mixture was
extracted with EtOAc (2 × 100 mL). The organic extract was dried
with Na2SO4 and concentrated. Purification of the residue by col-
umn chromatography (EtOAc/PE, 40:60) afforded compound 9
(3.77 g, 88 %) as a colorless liquid; Rf = 0.2 (EtOAc/PE, 40:60). IR
(neat): νmax = 3424, 2936, 1724, 1606, 1280, 1159, 1204, 1064,
˜
962 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.56–1.72 (m, 4 H), 1.70 (s,
6 H), 2.29–2.34 (m, 2 H), 3.68 (t, J = 6.2 Hz, 2 H), 3.85 (s, 3 H), 6.18
(dt, J = 6.8, 15.7 Hz, 1 H), 6.33 (d, J = 2.4 Hz, 1 H), 6.73 (d, J = 2.4 Hz,
1 H), 7.42 (d, J = 15.7 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
25.0, 25.6, 32.0, 32.5, 55.5, 62.7, 100.0, 103.6, 104.9, 108.1, 128.6,
134.7, 144.2, 158.6, 160.3, 164.7 ppm. HRMS (ESI): calcd. for
Scheme 6. Reagents and conditions: (a) Grubbs II, CH2Cl2, reflux, 6 h, 80 %,
E/Z, 4:1; (b) H2, 10 % Pd/C, EtOAc, room temp., 3 h, 90 %; (c) AlI3, TBAI, benz-
ene, 10 °C, 30 min, 85 %.
Conclusions
17H23O5 [M + H]+ 307.15400; found 307.15331.
In summary, a concise, efficient, and linear synthesis of the two
resorcinylic acid lactones (S)-zearalenone (2) and (R)-de-O-
methyllasiodiplodin (4) has been accomplished in 10 steps (in
19.1 % overall yield) and 7 steps (34.1 % overall yield), respec-
tively. The present synthesis involves Stille, transesterification,
chemoselective reduction, and ring-closing metathesis reac-
tions. Our strategy is a viable route to synthesize analogues of
2 and 4 as well as other RALs.
C
(E)-6-(7-Methoxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-
5-yl)hex-5-enal (20): To a stirred solution of alcohol 9 (4 g,
13.0 mmol) in CH2Cl2 (40 mL) were added sequentially [bis(acet-
oxy)iodo]benzene (5.06 g, 15.7 mmol) and TEMPO (409 mg,
2.6 mmol). After stirring at room temperature for 2 h, a saturated
aqueous solution of Na2S2O3 (20 mL) and diethyl ether (100 mL)
were added. The isolated organic phase was washed with saturated
aqueous NaHCO3 (10 mL) followed by H2O (10 mL). The combined
aqueous phases were extracted with diethyl ether (2 × 50 mL), and
the combined organic extracts were washed with brine (2 × 20 mL),
dried with Na2SO4, and filtered. The filtrate was concentrated under
reduced pressure, and the resulting residue was purified by flash
chromatography (EtOAc/PE, 25:75) to provide aldehyde 20 (3.58 g,
90 %) as a yellow liquid; Rf = 0.3 (EtOAc/PE, 30:70). Aldehyde 20
was immediately used in the Grignard reaction.
Experimental Section
General Methods: All reactions that required anhydrous conditions
were conducted in a flame-dried glass apparatus under nitrogen.
THF was freshly distilled from sodium/benzophenone ketyl prior to
use. N-methyl-2-pyrrolidone and CH2Cl2 were freshly distilled from
CaH2, and benzene was dried azeotropically by using a Dean–Stark
apparatus. Anhydrous methanol was obtained by distillation from
magnesium alkoxide and stored under nitrogen over activated mo-
lecular sieves (4 Å). Reactions were monitored by TLC analysis using
silica plates with fluorescent indicator (254 nm). Unless otherwise
mentioned, all column chromatography was done with 60–
120 mesh silica gel. All commercially available reagents were pur-
chased and typically used as supplied. The 1H and 13C NMR spectro-
scopic data were recorded in Fourier transform mode at the field
strength specified (300, 400, or 500 MHz for 1H NMR and 75, 100,
or 125 MHz for 13C NMR). Chemical shifts (δ) are reported in ppm
and referenced to residual CHCl3 (δ = 7.26 ppm) for 1H NMR and
CDCl3 (δ = 77.16 ppm) for 13C NMR. Data are reported as follows:
chemical shift, multiplicity [s (singlet), d (doublet), t (triplet), q (quar-
tet), quintet (quint), m (multiplet), br. (broad), app (apparent), ABq
(AB quartet)], coupling constant, number of protons, assignment.
Ratios of diastereomers (dr) were obtained from 1H NMR (400 MHz)
spectra, which were obtained with a signal/noise ratio of >200:1.
Infrared spectra were recorded with an FTIR instrument, and the
values are reported as the frequency of absorption (cm–1). Melting
points were recorded with a melting point instrument. Optical rota-
tions were measured with a polarimeter that was equipped with a
sodium lamp (589 nm, D line) and a 2 dm, 2 mL quartz sample cell.
The values are reported as [α]D (concentration in g 100 mL–1 sol-
vent). For high resolution mass spectra, the ion mass/charge (m/z)
ratios are reported as values in atomic mass units.
(E)-5-(6-Hydroxyocta-1,7-dien-1-yl)-7-methoxy-2,2-dimethyl-
4H-benzo[d][1,3]dioxin-4-one (21): To a stirred solution of 20
(3.5 g, 11.5 mmol) in THF (30 mL) was added dropwise vinylmagne-
sium bromide (3.0
M solution in THF, 7.7 mL, 23.0 mmol) at –78 °C.
The reaction mixture was stirred at same temperature for 2 h and
then quenched with an aqueous saturated solution of NH4Cl
(20 mL). The organic layer was separated, and the aqueous portion
was extracted with EtOAc (50 mL). The combined organic extracts
were washed with water (2 × 10 mL) and brine (20 mL) and then
dried with Na2SO4. The filtrate was concentrated in vacuo, and the
resulting residue was purified by column chromatography (EtOAc/
PE, 25:75) to afford pure ( )-21 (3.09 g, 90 %) and recovered com-
pound 20 (350 mg); Rf = 0.2 (EtOAc/PE, 30:70). IR (neat): νmax
=
˜
3426, 2932, 2854, 1725, 1605, 1571, 1277, 1159, 1036, 915 cm–1. H
NMR (500 MHz, CDCl3): δ = 1.59–1.69 (m, 4 H), 1.70 (s, 6 H), 2.27–
2.35 (m, 2 H), 3.85 (s, 3 H), 4.12–4.18 (m, 1 H), 5.11 (dt, J = 1.5,
10.3 Hz, 1 H), 5.24 (dt, J = 1.5, 17.2 Hz, 1 H), 5.85–5.93 (m, 1 H), 6.18
(dt, J = 6.8, 15.7 Hz, 1 H), 6.33 (d, J = 2.7 Hz, 1 H), 6.73 (d, J = 2.7 Hz,
1 H), 7.42 (d, J = 15.7 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
24.6, 25.6, 32.7, 36.3, 55.5, 72.9, 100.0, 103.6, 104.9, 108.1, 114.6,
128.6, 134.7, 141.1, 144.2, 158.6, 160.2, 164.7 ppm. HRMS (ESI): calcd.
for C19H24O5Na [M + Na]+ 355.15160; found 355.15083.
1
(E)-5-{6-[(tert-Butyldimethylsilyl)oxy]octa-1,7-dien-1-yl}-7-
methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (22): Anhy-
drous DIPEA (3.1 mL, 18 mmol) was added at 0 °C to a solution of
allylic alcohol 21 (2 g, 6.02 mmol) in dry dichloromethane (DCM,
20 mL) at 0 °C, and the mixture was stirred at 0 °C under N2. After
(E)-5-(6-Hydroxyhex-1-en-1-yl)-7-methoxy-2,2-dimethyl-4H-
benzo[d][1,3]dioxin-4-one (9): Triflate 10 (5 g, 14 mmol) was dis-
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15 min, TBSOTf (1.7 mL, 7.22 mmol) was added dropwise, and the
mixture was stirred at room temp. for 30 min, whereupon TLC analy-
sis indicated complete consumption of starting material. The reac-
tion was then quenched with H2O (10 mL), and the mixture was
extracted with DCM (2 × 20 mL). The organic extracts were com-
bined and washed with brine (50 mL), dried with Na2SO4, and fil-
tered. The filtrate was concentrated under reduced pressure, and
the resulting residue was purified by flash column chromatography
(EtOAc/PE, 7:93) to give 22 (2.55 g, 95 %) as a yellow liquid; Rf = 0.5
H), 3.81 (s, 3 H), 4.12–4.16 (m, 1 H), 4.38 (dd, J = 7.1, 14.3 Hz, 1 H),
5.1–5.14 (m, 2 H), 5.15–5.17 (m, 1 H), 5.21–5.28 (m, 2 H), 5.78–5.93
(m, 3 H), 6.37 (d, J = 2.7 Hz, 1 H), 6.4 (d, J = 2.7 Hz, 1 H), 6.97 (d,
J = 15.4 Hz, 1 H), 11.74 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 19.6, 25.0, 32.8, 36.5, 40.2, 55.3, 71.8, 73.1, 99.6, 108.1, 114.7,
118.1, 131.5, 132.0, 133.0, 141.1, 143.5, 163.8, 164.9, 170.7 ppm.
HRMS (ESI): calcd. for C21H29O5 [M + H]+ 361.20095; found
361.20105.
(S,E)-Pent-4-en-2-yl 2-Hydroxy-4-methoxy-6-(6-oxoocta-1,7-
dien-1-yl)benzoate (8): A solution of the alcohol 25 (100 mg,
0.277 mmol) in CH2Cl2 (8 mL) under argon was cooled to 0 °C, and
then Dess–Martin periodinane (176 mg, 0.415 mmol) was added.
The resulting solution was stirred at room temperature for 2 h. The
mixture was filtered through Celite, and the filter cake was thor-
oughly washed with DCM (2 × 10 mL). The filtrate was washed with
water (5 mL) and brine (5 mL) and then dried with Na2SO4. The
DCM was evaporated under reduced pressure, and the residue was
purified by flash column chromatography (EtOAc/PE, 10:90) to give
enone 8 (91.2 mg, 92 %) as a colorless liquid; Rf = 0.5 (EtOAc/PE,
(EtOAc/PE = 20:80). IR (neat): νmax = 2931, 2855, 1730, 1605, 1573,
˜
1275, 1159, 1035, 835, 775 cm–1
.
1H NMR (500 MHz, CDCl3): δ =
0.03 (s, 3 H), 0.06 (s, 3 H), 0.89 (s, 9 H), 1.49–1.57 (m, 4 H), 1.69 (s, 6
H), 2.25–2.30 (m, 2 H), 3.84 (s, 3 H), 4.10–4.14 (m, 1 H), 5.02 (ddd,
J = 1.2, 1.6, 10.3 Hz, 1 H), 5.14 (dt, J = 3.0, 17.1 Hz, 1 H), 5.80 (ddd,
J = 6.1, 10.3, 17.1 Hz, 1 H), 6.32 (d, J = 2.6 Hz, 1 H), 6.74 (d, J =
2.6 Hz, 1 H), 7.43 (d, J = 15.7 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = –4.8, –4.4, 18.2, 24.7, 25.6, 25.8, 33.0, 37.5, 55.5, 73.6,
100.0, 103.7, 104.8, 108.0, 113.5, 128.3, 135.1, 141.7, 144.2, 158.6,
160.1, 164.6 ppm. HRMS (ESI): calcd. for C25H38O5NaSi [M + Na]+
469.23807; found 469.23736.
20:80). [α]D25 = +19.18 (c = 0.44, CHCl3). IR (neat): νmax = 2929, 1646,
˜
1608, 1573, 1257, 1159, 964, 770 cm–1
.
1H NMR (400 MHz, CDCl3):
(S)-Pent-4-en-2-yl 2-{(E)-6-[(tert-Butyldimethylsilyl)oxy]octa-1,7-
dien-1-yl}-6-hydroxy-4-methoxybenzoate (24): Sodium hydride
(60 % dispersion in mineral oil, 358 mg, 8.96 mmol) was slowly
added to a magnetically stirred solution of homoallylic alcohol 23
(481 mg, 5.6 mmol) in dry THF (8 mL) at 0 °C under nitrogen. The
mixture was stirred at room temperature for 1 h and then cooled
again to 0 °C. Acetonide 22 (500 mg, 1.12 mmol) in THF (5 mL) was
slowly added to the mixture, which was then allowed to stir at room
temperature for 4 h. Upon completion of the reaction, the solution
was treated with a saturated aqueous solution of NaHCO3 (10 mL)
and ethyl acetate (20 mL). The separated organic phase was washed
with brine (1 × 10 mL), dried with Na2SO4, and filtered. The filtrate
was concentrated under reduced pressure, and the resulting residue
was purified by flash column chromatography (EtOAc/PE, 5:95) to
give compound 24 (398 mg, 75 %) as a yellow oil; Rf = 0.5 (EtOAc/
δ = 1.37 (d, J = 6.3 Hz, 3 H), 1.79–1.87 (m, 2 H), 2.24 (ddd, J = 1.3,
7.9, 14.6 Hz, 2 H), 2.39–2.53 (m, 2 H), 2.66 (t, J = 7.3 Hz, 2 H), 3.82
(s, 3 H), 5.09–5.13 (m, 1 H), 5.16 (dd, J = 1.4, 3.1 Hz, 1 H), 5.26 (dd,
J = 6.2, 12.3 Hz, 1 H), 5.76–5.90 (m, 3 H), 6.23 (dd, J = 1.2, 17.6 Hz,
1 H), 6.37 (dd, J = 10.5, 17.6 Hz, 1 H), 6.38 (d, J = 2.5 Hz, 1 H), 6.43
(d, J = 2.5 Hz, 1 H), 6.99 (d, J = 15.5 Hz, 1 H), 11.71 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 19.6, 23.4, 32.3, 38.9, 40.2, 55.3,
71.8, 99.7, 104.0, 108.1, 118.2, 128.0, 131.3, 132.0, 133.3, 136.5, 143.3,
163.8, 164.9, 170.7 ppm. HRMS (ESI): calcd. for C21H27O5 [M + H]+
359.18530; found 359.18533.
(S,5E,11E)-16-Hydroxy-14-methoxy-3-methyl-3,4,9,10-tetra-
hydro-1H-benzo[c][1]oxacyclotetradecine-1,7(8H)-dione (26): A
stirred solution of diene 8 (70 mg, 0.195 mmol) in CH2Cl2 (50 mL)
was purged with argon, and Grubbs II catalyst (14.8 mg,
0.017 mmol) was added. The reaction mixture was then heated at
reflux for 4 h under argon. After this time, the reaction was cooled
and diluted with EtOAc (20 mL), and the resulting mixture was
washed with H2O (2 × 10 mL) and brine (10 mL), dried with Na2SO4,
and concentrated. The crude product was purified by column chro-
matography (EtOAc/PE, 12:88) to furnish unsaturated macrocycle 26
PE, 10:90). [α]D25 = +21.41 (c = 0.24, CHCl3). IR (neat): νmax = 2929,
˜
2855, 1647, 1256, 1159, 1032, 835, 772 cm–1
.
1H NMR (400 MHz,
CDCl3): δ = 0.03, (s, 3 H), 0.05 (s, 3 H), 0.90 (s, 9 H), 1.36 (d, J =
6.3 Hz, 3 H), 1.51–1.58 (m, 4 H), 2.15–2.23 (m, 2 H), 2.37–2.52 (m, 2
H), 3.81 (s, 3 H), 4.01–4.14 (m, 1 H), 5.03 (dt, J = 1.3, 10.4 Hz, 1 H),
5.09–5.14 (m, 2 H), 5.25 (dd, J = 6.2, 12.3 Hz, 1 H), 5.74–5.91 (m, 3
H), 6.37 (d, J = 2.7 Hz, 1 H), 6.4 (d, J = 2.7 Hz, 1 H), 6.95 (d, J =
15.5 Hz, 1 H), 11.76 (d, J = 0.8 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = –4.8, –4.4, 18.2, 19.6, 24.8, 25.8, 33.1, 37.7, 40.2, 55.3,
71.8, 73.7, 99.6, 104.0, 108.1, 113.6, 118.1, 131.4, 132.3, 133.3, 141.6,
143.7, 163.8, 164.9, 170.8 ppm. HRMS (ESI): calcd. for C27H42O5NaSi
[M + Na]+ 497.26937; found 497.26865.
(48.5 mg, 75 %) as a white solid; Rf = 0.2 (EtOAc/PE, 10:90). [α]D25
=
–138.2 (c = 0.03, CHCl3). IR (KBr): νmax = 3420, 2925, 2853, 1658,
˜
1
1610, 1256, 1205, 701 cm–1. H NMR (400 MHz, CDCl3): δ = 1.41 (d,
J = 6.5 Hz, 3 H), 1.78–1.89 (m, 1 H), 2.01–2.15 (m, 2 H), 2.28 (ddd,
J = 3.5, 6.9, 13.2 Hz, 1 H), 2.31–2.42 (m, 2 H), 2.81–2.93 (m, 2 H),
3.83 (s, 3 H), 5.55–5.63 (m, 1 H), 5.83 (ddd, J = 4.6, 9.1, 15.4 Hz, 1
H), 6.17 (d, J = 16.1 Hz, 1 H), 6.41 (d, J = 2.5 Hz, 1 H), 6.49 (d, J =
2.5 Hz, 1 H), 6.94 (d, J = 15.4 Hz, 1 H), 7.02 (ddd, J = 6.2, 8.5, 16.2 Hz,
1 H), 11.51 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.2, 25.9,
31.2, 34.6, 36.4, 55.4, 70.0, 99.9, 104.0, 108.4, 132.5, 133.1, 136.4,
142.7, 143.4, 164.1, 164.9, 170.2, 203.2 ppm. HRMS (ESI): calcd. for
C19H23O5 [M + H]+ 331.15400; found 331.15441.
(S)-Pent-4-en-2-yl 2-Hydroxy-6-[(E)-6-hydroxyocta-1,7-dien-1-
yl]-4-methoxybenzoate (25): In a 10 mL round-bottom plastic
tube, a stirred solution of 24 (300 mg, 0.632 mmol) in dry THF
(5 mL) was cooled to 0 °C, and a solution of HF·Py (0.2 mL) in THF
(0.7 mL) was added. The reaction was stirred at room temperature
for 12 h and then quenched at 0 °C by pouring it into a solution of
saturated aqueous NaHCO3 (10 mL). The product was extracted into
ethyl acetate (3 × 10 mL), and the combined organic extracts were
washed with a saturated aqueous solution of CuSO4 (10 mL) and
(S,E)-16-Hydroxy-14-methoxy-3-methyl-3,4,5,6,9,10-hexahydro-
1H-benzo[c][1]oxacyclotetradecine-1,7(8H)-dione (27): A solu-
water (10 mL) and then dried with MgSO4. After concentration of tion of sodium bis(2-methoxyethoxy)aluminum hydride in benzene
the organic extracts, the crude product was purified by column
(Vitride or Red-Al, 70 % solution, 0.11 mL, 0.36 mmol) was added
dropwise to a suspension of cuprous bromide (38 mg, 0.27 mmol)
chromatography (EtOAc/PE, 30:70) to afford 25 (216 mg, 95 %) as a
colorless liquid; Rf = 0.2 (EtOAc/PE, 30:70). [α]D25 = +32.06 (c = 0.44, in dry THF (2 mL) at 0 to –5 °C under argon. The resulting brown-
CHCl3). IR (neat): νmax = 3077, 2931, 2856, 1647, 1574, 1255, 1159,
black suspension was stirred at 0 °C for 0.5 h and then cooled to
–78 °C. To this mixture at –78 °C was added by syringe a solution
of 26 (30 mg, 0.090 mmol) in THF (3 mL). After 10 min, the solution
˜
1115, 835, 775 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.36 (d, J =
6.2 Hz, 3 H), 1.51–1.64 (m, 4 H), 2.20–2.26 (m, 2 H), 2.39–2.52 (m, 2
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was stirred at –20 °C for 1 h and then quenched by the addition of
5-(5-Hydroxypentyl)-7-methoxy-2,2-dimethyl-4H-benzo[d]-
water (3 mL). The resulting mixture was poured into a saturated [1,3]dioxin-4-one (28): NiCl2·6H2O (81 mg, 0.34 mmol) was added
aqueous ammonium chloride solution (10 mL). Ether (20 mL) was
added, and the blue (copper) aqueous solution was separated. The
ether layer was washed with water (2 × 3 mL), concentrated and
to a stirred solution of conjugated alkene 14 (1 g, 3.42 mmol) in
MeOH (10 mL) at 0 °C. Then, NaBH4 (259 mg, 6.84 mmol) was added
portionwise. The reaction was stirred for 20 min and then quenched
purified by column chromatography (EtOAc/PE, 10:90) to afford by the addition of a saturated solution of NH4Cl (5 mL). The mixture
compound 27 (20.9 mg, 70 %) as a white solid; Rf = 0.2 (EtOAc/PE, was concentrated to obtain a residue, which was extracted with
10:90). [α]D25 = –160.8 (c = 0.1, CHCl3). IR (KBr): νmax = 3451, 2924, EtOAc (3 × 5 mL). The combined organic layers were washed with
˜
2852, 1646, 1607, 1257, 1211, 1160, 770 cm–1 1H NMR (500 MHz, brine (5 mL), dried with anhydrous Na2SO4, and concentrated under
.
CDCl3): δ = 1.39 (d, J = 6.1 Hz, 3 H), 1.45–1.82 (m, 6 H), 2.10–2.24
(m, 3 H), 2.32–2.42 (m, 1 H), 2.60 (ddd, J = 3.2, 5.8, 12.3 Hz, 1 H),
2.85 (ddd, J = 1.9, 12.0, 18.6 Hz, 1 H), 3.82 (s, 3 H), 4,97–5.04 (m, 1
H), 5.68 (ddd, J = 3.5, 10.5, 15.1 Hz, 1 H), 6.40 (d, J = 2.6 Hz, 1 H),
6.46 (d, J = 2.6 Hz, 1 H), 7.02 (dd, J = 1.8, 15.2 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 20.8, 22.3, 30.9, 34.7, 36.6, 42.9, 55.4,
73.3, 77.2, 99.9, 103.5, 108.2, 132.3, 143.3, 164.0, 165.6, 211.0 ppm.
HRMS (ESI): calcd. for C19H25O5 [M + H]+ 333.16965; found
333.16910.
reduced pressure. The crude reaction mixture was purified by silica
gel column chromatography (EtOAc/PE, 40:60) to provide the corre-
sponding saturated compound 28 (955 mg, 95 %) as a clear oil; Rf =
0.4 (EtOAc/PE, 40:60). IR (neat): νmax = 3427, 2933, 2857, 1728, 1612,
˜
1279, 1160, 966, 855 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.43–1.50
(m, 2 H), 1.59–1.66 (m, 4 H), 1.69 (s, 6 H), 3.05 (app t, J = 7.8 Hz, 2
H), 3.65 (d, J = 6.5 Hz, 2 H), 3.83 (s, 3 H), 6.30 (d, J = 2.4 Hz, 1 H),
6.47 (d, J = 2.4 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.1,
21.1, 24.1, 24.7, 27.2, 30.8, 31.0, 33.6, 55.2, 75.0, 98.8, 105.1, 110.5,
148.5, 163.7, 165.6, 171.9 ppm. HRMS (ESI): calcd. for C16H23O5 [M
+ H]+ 295.15400; found 295.15303.
(S,E)-14,16-Dihydroxy-3-methyl-3,4,5,6,9,10-hexahydro-1H-
benzo[c][1]oxacyclotetradecine-1,7(8H)-dione (2): To a stirred so-
lution of AlI3 in benzene [prepared in situ from Al (48.6 mg,
5-(Hex-5-en-1-yl)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]di-
2.25 mmol) and I2 (320 mg, 1.26 mmol) in anhydrous benzene oxin-4-one (29): To a stirred solution of alcohol 28 (500 mg,
(3 mL) at 80 °C for 1 h] was added 27 (12 mg, 0.036 mmol) in
anhydrous benzene (1 mL) at 10 °C. The reaction mixture was stirred
for 30 min then quenched by the addition of solutions of aqueous
NH4Cl (2 mL) and aqueous Na2S2O5 (2 mL). The resulting mixture
was extracted with EtOAc (3 × 5 mL), and the combined organic
1.7 mmol) in CH2Cl2 (8 mL) were added sequentially [bis(ace-
toxy)iodo]benzene (657 mg, 2.04 mmol) and TEMPO (53 mg,
0.34 mmol). The resulting mixture was stirred at room temperature
for 2 h, and then a saturated aqueous solution of Na2S2O3 (5 mL)
and diethyl ether (20 mL) were added. The isolated organic phase
layers were dried with Na2SO4 and concentrated in vacuo. The resi- was washed with a saturated aqueous solution of NaHCO3 (5 mL)
due was purified by flash column chromatography on silica gel followed by H2O (5 mL). The combined aqueous layers were ex-
(EtOAc/PE, 30:70) to afford (S)-zearalenone (2, 9.3 mg, 82 %) as a tracted with diethyl ether (2 × 20 mL), and the combined organic
white crystalline solid; Rf = 0.2 (EtOAc/PE, 30:70), m.p. 161–163 °C. extracts were washed with brine (10 mL), dried with Na2SO4, and
[α]D20 = –160.8 (c = 0.1, CHCl3). IR (KBr): νmax = 3417, 2924, 2853, filtered. The filtrate was concentrated under reduced pressure, and
˜
1709, 1646, 1259, 1022, 803, 702 cm–1
.
1H NMR (500 MHz, CDCl3):
the resulting residue was purified by flash column chromatography
on silica gel (EtOAc/PE, 30:70) to provide the corresponding alde-
δ = 1.38 (d, J = 6.1 Hz, 3 H), 1.45–1.81 (m, 6 H), 2.11–2.24 (m, 3 H),
2.33–2.440 (m, 1 H), 2.58–2.67 (m, 1 H), 2.85 (ddd, J = 2.6, 12.2, hyde (471 mg) as a yellow liquid, which was immediately used in
18.6 Hz, 1 H), 3.68 (t, J = 6.4 Hz, 1 H), 4.96–5.03 (m, 1 H), 5.68 (ddd,
the next step. To the stirred solution of the Ph3P+CH3Br– (1.74 g,
J = 3.6, 10.5, 15.5 Hz, 1 H), 6.35 (d, J = 2.6 Hz, 1 H), 6.41 (d, J = 4.32 mmol) in anhydrous THF was added NaHMDS (3.6 mL,
2.6 Hz, 1 H), 7.01 (dd, J = 1.8, 15.5 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 20.8, 20.9, 22.2, 32.2, 34.7, 36.6, 42.9, 73.4, 102.4, 103.7,
3.6 mmol) dropwise at 0 °C. After 30 min, the previously prepared
aldehyde (471 mg) was added at the same temperature, and the
108.4, 132.4, 133.1, 143.9, 160.6, 165.4, 171.3, 211.5 ppm. HRMS mixture was stirred at room temperature for 4 h. The reaction was
(ESI): calcd. for C18H23O5 [M + H]+ 319.15400; found 319.15412.
quenched with cold water, and the resulting mixture was extracted
with ethyl acetate (3 × 5 mL). The combined organic extracts were
washed with brine (5 mL), dried with anhydrous Na2SO4, and con-
centrated in vacuo. Purification by column chromatography (EtOAc/
PE, 10:90) gave pure compound 29 (394 mg, 80 % from 28) as a
(E)-5-(5-Hydroxypent-1-en-1-yl)-7-methoxy-2,2-dimethyl-4H-
benzo[d][1,3]dioxin-4-one (14): Triflate 10 (2 g, 5.6 mmol) was
dissolved in degassed NMP (15 mL), and the resulting solution was
treated with Pd2(dba)3·CHCl3 (58 mg, 0.056 mmol), tri(2-furyl)phos-
phine (104 mg, 0.45 mmol), and anhydrous LiCl (705 mg,
16.8 mmol). The solution was stirred at room temperature for
10 min, and then a solution of stannane 15 (1.8 g, 6.17 mmol) in
NMP (12 mL) was added dropwise. The resulting solution was
stirred for 3 h and then diluted with a saturated KF solution (20 mL).
The mixture was extracted with EtOAc (2 × 50 mL). The organic
extract was dried with Na2SO4 and concentrated. Purification of the
residue by flash chromatography (EtOAc/PE, 40:60) afforded com-
pound 14 (1.39 g, 85 %) as yellow oil; Rf = 0.3 (EtOAc/PE, 40:60). IR
colorless liquid; Rf = 0.5 (EtOAc/PE, 10:90). IR (neat): νmax = 2928,
˜
1
1729, 1611, 1577, 1277, 1059, 911 cm–1. H NMR (500 MHz, CDCl3):
δ = 1.45–1.52 (m, 2 H), 1.57–1.64 (m, 2 H), 1.69 (s, 6 H), 2.09 (dd,
J = 7.1, 14.5 Hz, 2 H), 3.06 (app t, J = 7.7 Hz, 2 H), 3.83 (s, 3 H), 4.91–
4.94 (m, 1 H), 5.00 (ddd, J = 1.5, 3.3, 17.2 Hz, 1 H), 5.77–5.86 (m, 1
H), 6.29 (d, J = 2.4 Hz, 1 H), 6.46 (d, J = 2.4 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 24.9, 28.1, 29.7, 32.9, 33.7, 54.8, 98.5, 104.0,
111.5, 113.6, 138.2, 149.3, 158.4, 159.3, 164.0 ppm. HRMS (ESI): calcd.
for C17H22O4Na [M + Na]+ 313.14103; found 313.13998.
(neat): νmax = 3426, 2996, 2939, 1724, 1605, 1279, 1160, 967,
(R)-Pent-4-en-2-yl 2-(Hex-5-en-1-yl)-6-hydroxy-4-methoxy-
benzoate (13): Sodium hydride (60 % dispersion in mineral oil,
165 mg, 4.13 mmol) was slowly added to a magnetically stirred
solution of homoallylic alcohol 30 (223 mg, 2.6 mmol) in dry THF
(5 mL) at 0 °C under nitrogen. The mixture was stirred for 1 h at
room temperature and then cooled again to 0 °C. Acetonide 29
(151 mg, 0.520 mmol) in THF (3 mL) was added slowly to the mix-
ture, which was then allowed to stir at room temperature for 5 h.
Upon completion of the reaction, the solution was treated with a
˜
856 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.70 (s, 6 H), 1.77 (AB
quint, J = 6.4, 7.1 Hz, 2 H), 2.38 (ddd, J = 1.3, 7.1, 14.3 Hz, 2 H), 3.72
(t, J = 6.4 Hz, 2 H), 3.8 (s, 3 H), 6.16 (dt, J = 7.0, 15.7 Hz, 1 H), 6.33
(d, J = 2.6 Hz, 1 H), 6.7 (d, J = 2.6 Hz, 1 H), 7.40 (dd, J = 1.3, 15.7 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 25.5, 29.3, 31.6, 55.5, 61.9,
100.0, 103.6, 104.9, 108.2, 128.9, 134.2, 144.1, 158.6, 160.3,
164.8 ppm. HRMS (ESI): calcd. for C16H21O5 [M + H]+ 293.13835;
found 293.13754.
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saturated aqueous solution of NaHCO3 (8 mL) and ethyl acetate
(10 mL). The separated organic phase was washed with brine (1×
(362 mg, 1.42 mmol) in anhydrous benzene (3 mL) at 80 °C for 1 h]
was added 32 (12 mg, 0.040 mmol) in anhydrous benzene (1 mL)
10 mL), dried with Na2SO4, and filtered. The filtrate was concen- at 10 °C. The reaction was stirred for 30 min then quenched by the
trated under reduced pressure, and the resulting residue was puri-
fied by flash column chromatography on silica gel (EtOAc/PE, 10:90)
to give compound 13 (134.8 mg, 82 %) as a yellow oil; Rf = 0.5
addition of solutions of aqueous NH4Cl (2 mL) and aqueous
Na2S2O5 (2 mL). The mixture was extracted with EtOAc (3 × 6 mL),
and the combined organic layers were dried with Na2SO4 and con-
centrated in vacuo. The residue was purified by flash column chro-
(EtOAc/PE, 10:90). [α]D25 = –13.22 (c = 0.64, CHCl3). IR (neat): νmax
=
˜
1
3446, 2929, 2855, 1646, 1579, 1255, 1158, 1047, 931 cm–1. H NMR matography (EtOAc/PE, 30:70) to afford 4 (9.4 mg, 85 %) as a white
(400 MHz, CDCl3): δ = 1.38 (d, J = 6.3 Hz, 3 H), 1.41–1.50 (m, 2 H),
solid; Rf = 0.3 (EtOAc/PE, 30:70). [α]D25 = +26.82 (c = 0.20, CHCl3). IR
1.52–1.60 (m, 2 H), 2.08 (ddt, J = 7.2, 14.3, 1.2 Hz, 2 H), 2.38–2.55 (KBr): νmax = 2924, 2854, 1640, 1460, 1260, 1096, 1019, 3358 cm–1
.
˜
(m, 2 H), 2.76–2.98 (m, 2 H), 3.80 (s, 3 H), 4.94 (d quin, J = 1.1. 1H NMR (500 MHz, CDCl3): δ = 1.36 (d, J = 6.2 Hz, 3 H), 1.39–1.71
10.1 Hz, 1 H), 5.00 (ddd, J = 1.6, 3.5, 17.1 Hz, 1 H), 5.09–5.14 (m, 2
H), 5.30 (ddd, J = 6.3, 12.6, 18.8 Hz, 1 H), 5.75–5.87 (m, 2 H), 6.27
(d, J = 2.7 Hz, 1 H), 6.33 (d, J = 2.7 Hz, 1 H), 11.9 (s, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 19.5, 29.1, 31.5, 33.8, 36.7, 40.2, 55.2,
71.6, 98.8, 104.9, 110.6, 114.5, 118.2, 133.2, 138.7, 147.6, 163.7, 165.6,
170.9 ppm. HRMS (ESI): calcd. for C19H27O4 for [M + H]+ 319.19039;
found 319.19019.
(m, 10 H), 1.75–1.82 (m, 1 H), 1.88–1.97 (m, 1 H), 2.50 (td, J = 5.8,
11.6 Hz, 1 H), 3.50 (td, J = 3.9, 11.6 Hz, 2 H), 6.22 (d, J = 2.7 Hz, 1
H), 6.27 (d, J = 2.7 Hz, 1 H), 11.96 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 20.0, 21.1, 24.0, 24.6, 27.2, 29.6, 30.7, 31.0, 33.5, 75.1,
101.3, 105.5, 110.7, 149.4, 160.0, 165.3, 171.8 ppm. HRMS (ESI): calcd.
for C16H23O4 [M + H]+ 279.15909; found 279.15908.
(R)-14-Hydroxy-12-methoxy-3-methyl-3,4,7,8,9,10-hexahydro-
1H-benzo[c][1]oxacyclododecin-1-one (31): A stirred solution of
diene 13 (50 mg, 0.157 mmol) in CH2Cl2 (40 mL) was purged with
argon, and Grubbs II catalyst (1.3 mg, 0.001 mmol) was added. The
Acknowledgments
S. D. and M. A. R. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi for the financial assistance in the
reaction mixture was then heated at reflux for 6 h under argon. form of a fellowship. J. S. Y. thanks CSIR and the Department of
After this time, the mixture was cooled and then diluted with EtOAc
(20 mL). The resulting solution was washed with H2O (2 × 10 mL)
and brine (10 mL), dried with Na2SO4, and concentrated. The crude
product was purified by column chromatography on silica gel
(EtOAc/PE, 10:90) to furnish the unsaturated macrocycle 31
(36.4 mg, 80 %; separable diastereomeric mixture; E/Z, 4:1) as a yel-
low liquid; Rf = 0.4 (EtOAc/PE, 10:90). [α]D25 = +3.67 (c = 0.32, CHCl3).
Science and Technology (DST), New Delhi for the Bhatnagar
and J. C. Bose fellowships, respectively. This work was partly
funded by the XII Five Year plan programme (CSC-0108) under
the title “Organic Reactions in Generating Innovative and Natu-
ral scaffolds” (ORIGIN) sponsored by CSIR, New Delhi.
IR (neat): νmax = 2927, 2854, 1645, 1578, 1256, 1158, 1040, 834,
˜
Keywords: Total synthesis · Natural products · Macrocycles ·
Cross-coupling · Metathesis · Transesterification
1
712 cm–1. H NMR (400 MHz, CDCl3): δ = 1.39 (d, J = 6.1 Hz, 3 H),
1.47–1.62 (m, 6 H), 1.92–2.89 (m, 4 H), 3.79 (s, 3 H), 5.07–5.14 (m, 1
H), 5.37 (ddd, J = 4.7, 10.7, 16.1 Hz, 1 H), 5.52 (ddd, J = 5.8, 10.7,
16.1 Hz, 1 H), 6.28 (d, J = 2.7 Hz, 1 H), 6.32 (d, J = 2.7 Hz, 1 H), 12.1
(s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.9, 27.7, 29.8, 35.5,
55.2, 72.6, 98.8, 104.5, 110.7, 125.6, 133.0, 148.6, 163.8, 165.8,
171.6 ppm. HRMS (ESI): calcd. for C17H23O4 [M + H]+ 291.15909;
found 291.15817.
[1] a) S. Omura (Ed.), Macrolide Antibiotics, Academic Press, New York, 1984;
b) E. A. Cauladours, P. M. Anastasia, A. B. Emmanuel, Org. Lett. 2004, 6,
977–980; c) R. M. Garbaccio, S. J. Danishefsky, Org. Lett. 2000, 2, 3127–
3129; d) J. S. Yadav, S. Das, J. S. Reddy, N. Thrimurtulu, A. R. Prasad,
Tetrahedron Lett. 2010, 51, 4050–4052.
[2] a) N. Winssinger, S. Barluenga, Chem. Commun. 2007, 22–36; b) N. Wins-
singer, J. G. Fontaine, S. Barluenga, Curr. Top. Med. Chem. 2009, 9, 1419–
1435; c) E. A. Couladouros, A. P. Mihou, E. A. Bouzas, Org. Lett. 2004, 6,
977–980.
[3] M. Stob, R. S. Baldwin, J. Tuite, F. N. Andrews, K. G. Gillette, Nature 1962,
196, 1318.
[4] a) D. C. Aldridge, S. Galt, D. Giles, W. B. Turner, J. Chem. Soc. C 1971,
1623–1627; b) R.-Y. Yan, C.-Y. Li, Y.-C. Lin, G.-T. Peng, Z.-G. She, S.-N. Zhou,
Bioorg. Med. Chem. Lett. 2006, 16, 4205–4208.
[5] a) E. Keinan, S. C. Sinha, A. Sinhabachi, J. Chem. Soc. Perkin Trans. 1 1991,
3333–3339; b) S. A. Hitchcock, G. Pattenden, J. Chem. Soc. Perkin Trans. 1
1992, 1323–1328; c) K. C. Nicolaou, N. Winssinger, J. Pastor, F. Murphy,
Angew. Chem. Int. Ed. 1998, 37, 2534–2537; Angew. Chem. 1998, 110,
2677, and references cited therein.
[6] a) K. H. Lee, N. Hayasi, M. Okano, I. Hall, R. Y. Wu, Phytochemistry 1982,
21, 1119–1121; b) A. Fürstner, G. Seidel, N. Kindler, Tetrahedron 1999, 55,
8215–8230.
(R)-14-Hydroxy-12-methoxy-3-methyl-3,4,5,6,7,8,9,10-octa-
hydro-1H-benzo[c][1]oxacyclododecin-1-one (32): To a solution
of olefin 31 (20 mg, 0.068 mmol) in of EtOAc (1.5 mL) was added a
catalytic amount of 10 % Pd/C under an inert atmosphere. The reac-
tion flask was purged with hydrogen and then closed under a posi-
tive pressure of hydrogen. The progress of the reaction was moni-
tored by TLC analysis. Upon completion, the reaction mixture was
filtered through a small pad of Celite, and the filtrate was concen-
trated under reduced pressure. Purification of the crude residue by
silica gel column chromatography (EtOAc/PE, 10:90) to afforded sat-
urated product 32 (17.9 mg, 90 %) as a colorless oil; Rf = 0.5 (EtOAc/
PE, 10:90). [α]D25 = +21.41 (c = 0.24, CHCl3). IR (KBr): νmax = 2924,
˜
1
2854, 1644, 1612, 1416, 1253, 1208, 1157, 1040, 813 cm–1. H NMR
(400 MHz, CDCl3): δ = 1.36 (d, J = 6.2 Hz, 3 H), 1.39–1.69 (m, 10 H),
1.73–1.89 (m, 1 H), 1.88–1.99 (m, 1 H), 2.46–2.55 (m, 1 H), 3.30 (td,
J = 4.2, 12.8 Hz, 2 H), 3.80 (s, 3 H), 6.29 (d, J = 2.7 Hz, 1 H), 6.33 (d,
J = 2.7 Hz, 1 H), 11.99 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
20.1, 21.1, 24.1, 24.7, 27.2, 30.8, 31.0, 33.6, 55.2, 75.0, 98.8, 105.1,
110.5, 148.5, 163.7, 165.6, 171.9 ppm. HRMS (ESI): calcd. for
C17H25O4 [M + H]+ 293.17474; found 293.17412.
[7] D. Taub, N. N. Girotra, R. D. Hoffsommer, C. H. Kuo, H. L. Slates, S. Weber,
N. L. Wendler, Tetrahedron 1968, 24, 2443–2461.
[8] For selected previous approaches to the synthesis of (S)-zearalenone,
see: a) T. Takahashi, H. Ikeda, J. Tsuji, Tetrahedron Lett. 1981, 22, 1363–
1366; b) S. A. Hitchcock, G. Pattenden, Tetrahedron Lett. 1990, 31, 3641–
3644; c) G. Solladie, M. C. Maestro, A. Rubio, C. Pedregal, M. C. Carreno,
J. L. Garcia Ruano, J. Org. Chem. 1991, 56, 2317–2322; d) A. Kalivretenos,
J. K. Stille, L. S. Hegedus, J. Org. Chem. 1991, 56, 2883–2894; e) K. C.
Nicolaou, N. Wissinger, J. Pastor, F. Murphy, Angew. Chem. Int. Ed. 1998,
37, 2534–2537; Angew. Chem. 1998, 110, 2677; f) E. J. Corey, K. C. Nicol-
(R)-12,14-Dihydroxy-3-methyl-3,4,5,6,7,8,9,10-octahydro-1H-
benzo[c][1]oxacyclododecin-1-one (4): To a stirred solution of AlI3
in benzene [prepared in situ from Al (54 mg, 2.0 mmol) and I2
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Full Paper
aou, J. Am. Chem. Soc. 1974, 96, 5614–5616; g) S. Masamune, S. Kamata,
W. Schilling, J. Am. Chem. Soc. 1975, 97, 3515–3516; h) A. Fürstner, O. R.
Thiel, N. Kindler, B. Bartkowska, J. Org. Chem. 2000, 65, 7990–7995; i) C.
Napolitano, P. McArdle, P. V. Murphy, J. Org. Chem. 2010, 75, 7404–7407;
j) J. S. Yadav, P. V. Murthy, Synthesis 2011, 2117–2124, and references
cited therein.
[13]
[14]
M. Altendorfer, A. Raja, F. Sasse, H. Irschik, D. Menche, Org. Biomol. Chem.
2013, 11, 2116–2139.
a) V. Farina, B. Krishnan, J. Am. Chem. Soc. 1991, 113, 9585–9595; b) T.
Nemoto, T. Ohshima, M. Shibasaki, Tetrahedron 2003, 59, 6889–6897; c)
J. K. Stille, Angew. Chem. Int. Ed. Engl. 1986, 25, 508–524; Angew. Chem.
1986, 98, 504; d) A. B. Smith, G. R. Ott, J. Am. Chem. Soc. 1998, 120,
3935–3948; e) J. M. Saa, G. Martorell, A. Garcia-Raso, J. Org. Chem. 1992,
57, 678–685; f) A. Fürstner, T. Dierkes, O. R. Thiel, G. Blanda, Chem. Eur. J.
2001, 7, 5286–5298.
A. D. Mico, R. Margarita, L. Parlanti, A. Vescovi, G. Piancatelli, J. Org. Chem.
1997, 62, 6974–6977.
G. Nagaraju, A. Srikrishna, Synlett 2012, 23, 123–127.
[9] For selected previous approaches to the synthesis of (R)-de-O-methyl-
lasiodiplodin, see: a) G. Solladié, A. Rubio, M. C. Carreño, J. G. Ruano,
Tetrahedron: Asymmetry 1990, 1, 187–198; b) A. Fürstner, N. Kindler, Tetra-
hedron Lett. 1996, 37, 7005–7008; c) C. S. Jiang, R. Zhou, J. X. Gong, L.-L.
Chen, T. Kurtán, X. Shen, Y. W. Guo, Bioorg. Med. Chem. Lett. 2011, 21,
1171–1175, and references cited therein.
[10] a) W. J. Scott, G. T. Crisp, J. K. Stille, Org. Synth. 1993, 8, 97; W. J. Scott,
G. T. Crisp, J. K. Stille, Org. Synth. 1990, 68, 116; b) D. Milstein, J. K. Stille,
J. Am. Chem. Soc. 1979, 101, 4992–4998; c) D. Milstein, J. K. Stille, J. Am.
Chem. Soc. 1978, 100, 3636–3638.
[11] a) B. Thirupathi, D. K. Mohapatra, RSC Adv. 2014, 4, 8027–8030; b) L.
Wang, Y. Gao, J. Liu, C. Cai, Y. Du, Tetrahedron 2014, 70, 2616–2621; c) Y.
Gao, J. Liu, L. Wang, M. Xiao, Y. Du, Eur. J. Org. Chem. 2014, 2092–2098;
d) M. Liniger, C. Neuhaus, T. Hofmann, L. Fransioli-Ignazio, M. Jordi, P.
Drueckes, J. Trappe, D. Fabbro, K.-H. Altmann, ACS Med. Chem. Lett. 2011,
2, 22–27; e) P. W. Betteridge, J. R. Carruthers, R. I. Cooper, K. Prout, D. J.
Watkin, J. Appl. Crystallogr. 2003, 36, 1487; f) A. Bhattacharjee, O. R. Se-
quil, J. K. De Brabander, Tetrahedron Lett. 2000, 41, 8069–8073.
[12] P. Srihari, B. Mahankali, K. Rajendraprasad, Tetrahedron Lett. 2012, 53, 56–
58.
[15]
[16]
[17]
a) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156; b) D. B.
Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277–7287.
M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1, 953–956.
[18]
[19] H. J. Bestmann, M. Schmidt, Tetrahedron Lett. 1985, 26, 6171–6174.
[20] J. S. Yadav, N. Thrimurthulu, K. U. Gayathri, B. V. S. Reddy, A. R. Prasad,
Tetrahedron Lett. 2008, 49, 6617–6620.
[21] F. Calo, J. Richardson, A. G. M. Barrett, Org. Lett. 2009, 11, 4910–4913,
and references cited therein.
[22] T. Satoh, K. Nanba, S. Suzuki, Chem. Pharm. Bull. 1971, 19, 817–820.
Received: December 9, 2015
Published Online: February 23, 2016
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