Total synthesis of (-)-dihydrosporothriolide utilizing an indium-mediated reformatsky-claisen rearrangement

Article abstract of DOI:10.1021/jo5008948

The asymmetric synthesis of (-)-dihydrosporothriolide (1), a biologically active bis-γ-butyrolactone, is described, that proceeds through a d-proline-catalyzed asymmetric aminooxylation, indium-mediated Reformatsky-Claisen rearrangement of an α,α-dibromoacetate derivative, and diastereoselective dihydroxylation. The route requires no protective group manipulation and allows the concise seven-step synthesis of 1 from n-octanal.

Full text of DOI:10.1021/jo5008948

Note
pubs.acs.org/joc
Total Synthesis of (−)-Dihydrosporothriolide Utilizing an Indium-
Mediated Reformatsky−Claisen Rearrangement
Jun Ishihara,* Hiroaki Tsuru, and Susumi Hatakeyama
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
S
* Supporting Information
ABSTRACT: The asymmetric synthesis of (−)-dihydrosporothriolide (1), a biologically active bis-γ-butyrolactone, is described,
that proceeds through a D-proline-catalyzed asymmetric aminooxylation, indium-mediated Reformatsky−Claisen rearrangement
of an α,α-dibromoacetate derivative, and diastereoselective dihydroxylation. The route requires no protective group manipulation
and allows the concise seven-step synthesis of 1 from n-octanal.
he fused bis-γ-butyrolactones have attracted considerable
attention in the synthetic and biological communities over
sample. To clarify the structural ambiguity, we planned to
synthesize dihydrosporothriolide (1) and confirm its structure
and absolute configuration.
T
the years due to their highly oxygenated compact structures and
wide ranging biological activities.1,2 For example, avenaciolide
exhibits potent antifungal and antibacterial activities3 and inhibits
glutamate transport in rat liver mitochondria.4 The intriguing bis-
γ-butyrolactone skeleton is also found in isoavenaciolide,3
ethisolide,5 and canadensolide,6 numerous syntheses of which
have been reported over the past decades (Figure 1).7−10 In
Recently, we have developed the indium-mediated Reformat-
sky−Claisen rearrangement of α-bromoacetate derivatives that
are applicable to base-sensitive substrates, as exemplified by
Scheme 1.16 We assumed that α-bromoacetate derivative 3
would be initially transformed to α-indium species 4 and then
converted to an indium enolate 5, which would react with a
silylating agent to form silyl ketene acetal 6. Finally Claisen
rearrangement of the silyl ketene acetal 6 would furnish the
product. The feasibility of this method for base-sensitive
substrates makes it complementary to the Ireland−Claisen
Scheme 1. Reformatsky−Claisen Rearrangement vs Ireland−
Claisen Rearrangement
Figure 1. Bis-γ-butyrolactone natural products.
1994, Schulz et al. isolated sporothriolide and discosiolide from
fungi, Sporothrix sp.11,12 Sporothriolide bears a striking
resemblance to canadensolide that differs simply in the length
of the alkyl chain and shows significant antibacterial, fungicidal,
algicidal, and herbicidal activities. It was also revealed that its
hydrogenated product, namely, 3-epi-dihydrosporothriolide13
(2), possesses remarkable antibacterial and herbicidal activities.
In 2010, dihydrosporothriolide (1) was isolated from Xylaria
sp14 and well-characterized by Isaka et al. Before the isolation of
this natural product, the synthesis had appeared in a literature;15
however, the spectral data of natural dihydrosporothriolide were
completely different from those reported for the synthetic
Received: April 22, 2014
© XXXX American Chemical Society
A
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rearrangement and allows a simple access to valuable building
blocks for the synthesis of complex natural products. For
example, Reformatsky−Claisen rearrangement of 3 afforded
carboxylic acid 7 in 64% yield, whereas the reaction of 8 under
Ireland−Claisen conditions did not afford the rearranged
product 7 but the isomerized product 9 (Scheme 1).16b These
results clearly represent a marked advantage of the indium-
mediated Reformatsky−Claisen rearrangement over the com-
mon Ireland−Claisen rearrangement in the reaction of base-
sensitive substrates.
bromopropionyl bromide using pyridine and 4-DMAP afforded
quantitatively compound 12 as a 1:1 mixture. Next, we focused
on the Reformatsky−Claisen rearrangement. When 12 was
exposed to In and InCl3 in the presence of TMSCl and Et3N in
THF−DMPU (1:1) under ultrasonication, the rearranged
product 15 was obtained as a 2:1 diastereomeric mixture in
48% yield, along with debrominated product 16 in 52% yield.
Although the stereochemistry of 15 at the C-2 position was
unclear at this stage, the major isomer of 15 later turned out to
have the desired S-configuration at C-2 based on the X-ray
analysis of 1. It is assumed that compound 15 would be produced
via chairlike transition states (TS-14) of the corresponding silyl
ketene acetals.
Scheme 2 illustrates the retrosynthetic analysis that relies on
our Reformatsky−Claisen protocol. Dihydrosporothriolide (1)
We previously reported that the Reformatsky−Claisen
rearrangement of enantiomerically pure E-compound 17 (98%
ee) and Z-compound 18 (98% ee) provided compounds 19 and
20 in 97% ee and in 94% ee, respectively (Scheme 4).16b Since
Scheme 2. Retrosynthetic Analysis of 1
Scheme 4. Reformatsky−Claisen Rearrangement or Chiral
Substrate16b
would be synthesized by bislactonization of acyclic compound
10, which could be prepared by dihydroxylation of olefin 11.
Compound 11 would be secured by Reformatsky−Claisen
rearrangement of 12 readily available by acylation of allylic
alcohol 13.
Our synthesis of 1 commenced with the enantioselective
preparation of alcohol 13 (Scheme 3). Thus, n-octanal was first
the significant loss of the enantiomeric purity of the substrates
was not detected in these cases, we proposed that the indium-
mediated Reformatsky−Claisen rearrangement would proceed
through a chairlike transition state.
Scheme 3. Attempted Reformatsky−Claisen Rearrangement
On the basis of the aforementioned results, we assumed the
stereochemical course of the rearrangement of 12 as shown in
Scheme 5. Compound 12 would initially react with indium
species to generate α-indium intermediate 21. In the trans-
formation of 21 to indium enolates Z-22 and E-22, conformer
21-B, convertible to E-22, would be disfavored due the steric
repulsion between alkoxy and methyl groups. In contrast,
another conformer 21-A experiences less repulsion so that Z-22
would be favorably generated. After silylation of Z-22, the
resulting Z-23 would undergo the rearrangement via a chairlike
transition state to afford S-15 as a major product.
The production of debrominated product 16 can be explained
by facile protonation of the corresponding α-indium inter-
mediate with the acidic α-proton of 12. Since the Reformatsky−
Claisen rearrangement of 12 provided a considerable amount of
undesired 16, we next selected α,α-dibromopropionate 24 as a
substrate (Scheme 6). To our knowledge, the Reformatsky−
Claisen rearrangement of an α,α-dibromoacyl compound is
unprecedented. Compound 24 was easily available by the
esterification of 13 with α,α-dibromopropionic acid23 using
EDCI and 4-DMAP. Gratifyingly, the rearrangement of 24
proceeded smoothly to provide a 2:1 mixture of carboxylic acids
15 in 80% yield, along with debrominated product 16 in 14%
yield. The mixture of carboxylic acids 15 were esterified with
trimethylsilyl diazomethane in THF−MeOH to afford the
desired ester 25 and its epimer 26 in 56% and 29% yields,
subjected to D-proline-catalyzed asymmetric aminooxylation17
with nitrosobenzene using 1-(2-(dimethylamino)ethyl)-3-phe-
nylurea18 in MeCN−THF (4:1), followed by Horner−Wads-
worth−Emmons olefination19 in one pot. The subsequent
CuSO4-mediated fission20 of the resulting N−O bond afforded
1321 of 95% ee in 50% yield for 3 steps.22 Acylation of 13 with
B
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Scheme 5. Plausible Mechanism of Reformatsky−Claisen Rearrangement of 12
transformed to indium enolate, which affords a mixture of 25
and 26 in the presence of an excess amount of indium species.24
With compound 25 in hand, dihydroxylation of 25 was next
investigated. When 25 was treated with a catalytic amount of
OsO4 and NMO in THF−H2O, dihydroxylation and subsequent
lactonization proceeded to furnish dihydrosporothriolide 1 in
63% yield and monolactone 27 in 35% yield, which was derived
from the minor diastereoisomer of the dihydroxylation products.
On the other hand, the Sharpless asymmetric dihydroxylation led
to more satisfying results. Thus, upon reaction of 25 with Super-
AD-mix25,26 using (DHQD)2PHAL as a chiral ligand in aqueous
t-BuOH at 0 °C, diastereoselective dihydroxylation occurred
preferentially to give 1 and 2727 in 84% and 11% yields,
respectively. The characterization data of the synthetic material
matched the reported data for natural dihydrosporothriolide in
all respects. In addition, recrystallization of synthetic sample
from hexane and ethyl acetate provided crystals suitable for X-ray
analysis, which clearly indicates its stereostructure. At this stage,
we unambiguously confirmed the absolute structure of
dihydrosporothriolide to be 1 as demonstrated by Isaka et al.14
In the case of minor rearranged product 26, the dihydrox-
ylation with super-AD-mix β provided 3-epi-dihydrosporothrio-
lide 2 in 64% yield along with other unidentified compounds.
The structure of 2 was determined by NMR spectra (COSY, and
NOESY).28 It was found that treatment of 2 with DBU in
CH2Cl2 at room temperature for 24 h furnished a 3:1 mixture of
1 and 2 that was chromatographically separable. This result
shows that epimer 2 can be also converted to dihydrosporo-
thriolide.
Scheme 6. Synthesis of Dihydrosporothriolide 1
In summary, we have achieved the concise asymmetric
synthesis of (−)-dihydrosporothriolide (1) in 17% overall yield
in seven steps starting from n-octanal, thereby confirming its
absolute structure. The synthesis illustrates the synthetic utility
of our indium-mediated Reformatsky−Claisen rearrangement
applicable to base-sensitive substrates. It should be highlighted
that the synthetic route requires no protecting group
manipulation.
respectively. The reaction of α,α-dibromo compound 24
afforded clearly a better result than the reaction of α-monobromo
compound 12. It is assumed that, compared to the α-bromo
enolate derived from 12, the lower nucleophilicity of the enolate
generated from 24 would retard the protonation to decrease the
yield of undesired product 16. It is also assumed that ester 12
containing an acidic α-proton can serve as a proton donor,
leading to the production of 16, whereas compound 24 has no
such acidic proton at the α-position. It should be noted that the
corresponding α-bromocarboxylic acid was not detected as a
rearranged product in this particular case. This result shows that
the rearranged α-bromocarboxylic acid would be rapidly
EXPERIMENTAL SECTION
■
General. Tetrahydrofuran was purified by filtration through a
column of activated alumina under an argon atmosphere.29 Dichloro-
methane (CH2Cl2), pyridine, and triethylamine (Et3N) were distilled
C
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from calcium hydride. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi-
dinone (DMPU) was distilled under reduced pressure from calcium
hydride. Methanol (MeOH) was distilled from sodium. Unless
otherwise noted, reagents were commercially available and used without
further purification. Normal reagent-grade solvents were used for flash
chromatography and extraction. InCl3 was flame-dried for 1 min under
reduced pressure prior to use. The ultrasonic cleaner with 120 W, 38
kHz, was used for ultrasonication. All reactions were monitored by TLC
with precoated silica gel plates (0.25 mm thickness). Visualization was
achieved via UV light, a 5.6% ethanolic p-anisaldehyde solution
containing 5.6% of concentrated H2SO4-heat, and 10% ethanolic
phosphomolybdic acid solution-heat. Column chromatography was
performed using silica gel (particle size 100−210 μm), and flash
chromatography was performed using silica gel (particle size 40−50
μm). Melting points were measured in open capillary tubes and are
uncorrected. IR spectra were measured on a Fourier transform infrared
Methyl (4S,E)-4-((2-Bromopropanoyl)oxy)dec-2-enoate (12).
To a solution of compound 13 (202 mg, 1.01 mmol) in CH2Cl2 (5 mL)
were added pyridine (0.19 mL, 2.35 mmol), 4-dimethylaminopyridine
(12.2 mg, 0.100 mmol), and 2-bromopropionyl bromide (0.12 mL, 1.15
mmol). The reaction mixture was stirred at 0 °C for 13 h. The mixture
was diluted with brine (10 mL), extracted with Et2O (10 mL × 3), dried,
and concentrated. The residue was subjected to chromatography (SiO2
15 g, hexanes−AcOEt, 10:1) to furnish a 55:45 diastereomeric mixture
of 12 (347 mg, 1.01 mmol, ∼100%) as a colorless oil; Rf = 0.63
(hexanes−AcOEt, 5:1); IR (neat): 2929, 2858, 1729, 1665, 1435, 1312,
1273, 1219, 1157 cm−1; 1H NMR (400 MHz, CDCl3): δ = 6.88 (dd, J =
5.5, 15.9 Hz, 0.55H), 6.86 (dd, J = 5.5, 15.9 Hz, 0.45H), 6.05 (dd, J = 1.6,
15.6 Hz, 0.55H), 6.04 (dd, J = 1.7, 15.6 Hz, 0.55H), 6.00 (dd, J = 1.7,
15.6 Hz, 0.45H), 5.43 (q, J = 6.4 Hz, 1H), 4.40 (q, J = 7.1 Hz, 0.55H),
4.39 (q, J = 6.9 Hz, 0.45H), 3.75 (s, 3H), 1.85 (d, J = 7.1 Hz, 1.65H), 1.84
(d, J = 6.9 Hz, 1.35H), 1.76−1.70 (m, 1H), 1.40−1.24 (m, 8H), 0.88 (d,
J = 6.8 Hz, 3H; 13C NMR (100 MHz, CDCl3): δ = 169.3, 144.8, 144.7,
121.4, 121.3, 73.9, 73.8, 60.3, 51.7, 51.7, 39.8, 39.8, 33.6, 33.6, 31.5, 31.5,
28.8, 28.8, 24.7, 24.6, 22.6, 22.4, 21.5, 21.5, 14.1, 14.0; MS (EI): m/z (%)
= 336, 334, 255, 199; HRMS−EI: m/z calcd for C14H2381BrO4:
336.0759; found: 336.0746 (M+).
1
spectrometer in neat state. The H NMR and 13C NMR spectra were
measured using CDCl3 as solvent, and chemical shifts are reported as δ
values in parts per million (ppm) based on internal (CH3)4Si or solvent
peak (1H NMR 7.26 ppm, 13C 77.0 ppm). Splitting patterns were
designated as “s, d, t, q, m, and br”, indicating “singlet, doublet, triplet,
quartet, multiplet, and broad”, respectively. Optical rotations were
recorded on a digital polarimeter using CHCl3 as solvent. HRMS spectra
were taken in EI (dual focusing sector field). All reactions were carried
out under anhydrous conditions and an argon atmosphere, unless
otherwise noted.
(2R,S,3R,E)-3-(Methoxycarbonyl)-2-methylundec-4-enoic
Acid (15) and Methyl (S,E)-4-(Propionyloxy)dec-2-enoate (16)
from 12. A mixture of TMSCl (0.5 mL, 3.9 mmol) and Et3N (0.5 mL,
3.5 mmol) was centrifuged at 3000 rpm for 5 min. The supernatant
(0.23 mL, containing 1.4 mmol of TMSCl and 1.3 mmol of Et3N) was
added to a mixture of dried InCl3 (100 mg, 0.454 mmol) and In (52 mg,
0.454 mmol) in THF (1.0 mL). To a stirred mixture was added a
solution of 12 (76 mg, 0.227 mmol) in DMPU (1.0 mL), and the
reaction mixture was stirred at 10−30 °C for 2 h under ultrasonication.
The stirring mixture was diluted with AcOEt (20 mL × 2) and washed
with 3 M HCl (10 mL × 3) and brine (10 mL). The organic layer was
dried over MgSO4 and concentrated. The residue was purified by
chromatography (SiO2 5 g, hexane−AcOEt, 5:1 to 3:1) to afford a
diastereomeric mixture 15 (28 mg, 0.109 mmol, 48%) as a 2:1
diastereomeric mixture as a colorless oil and 16 (30 mg, 0.117 mmol,
52%) as a colorless oil; 15: Rf = 0.15 (hexanes−AcOEt, 3:1); IR (neat):
Methyl (S,E)-4-hydroxydec-2-enoate (13). To a solution of D-
proline (166 mg, 1.44 mmol) and nitrosobenzene (1.03 g, 9.63 mmol) in
MeCN (20 mL) and THF (5 mL) were added 1-(2-(dimethylamino)-
ethyl)-3-phenylurea (298 mg, 1.44 mmol) and octanal (2.25 mL, 14.4
mmol) at 0 °C, and the mixture was stirred for 12 h. To the mixture were
added trimethyl phosphonoacetate (3.5 mL, 21.6 mmol), LiCl (916 mg,
21.6 mmol), and DBU (2.5 mL, 16.9 mmol) at 0 °C. After stirring for 6
h, the mixture was diluted with saturated aqueous NH4Cl (30 mL) and
extracted with AcOEt (30 mL × 3). Organic extracts were washed with
brine (20 mL), dried over Mg2SO4, and concentrated. The residue was
diluted with MeOH (40 mL), and CuSO4·5H2O (479 mg, 1.92 mmol)
was added. After stirring at room temperature for 10 h, CuSO4·5H2O
(480 mg, 1.92 mmol) was added again. The mixture was diluted with
saturated aqueous NH4Cl (20 mL), extracted with AcOEt (30 mL × 3),
and washed with brine (20 mL). Drying over Mg2SO4, concentration,
and flash chromatography (SiO2 100 g, hexanes−AcOEt, 5:1 to 3:1)
afforded compound 13 (952 mg, 4.75 mmol, 50%) as a colorless oil;
[α]2D8 +22.3 (c 1.00, CHCl3) {lit. for the enantiomer, [α]2D0 −20.2 (c 1.0,
CHCl3), 93% ee;21a [α]D20 −22.4 (c 1.03, CHCl3)21b}; Rf = 0.25
(hexanes−AcOEt, 4:1); IR (neat): 3439, 2936, 2858, 1731, 1689, 1437,
1313, 1173, 1042, 981, 927, 862, 724, 610 cm−1; 1H NMR (400 MHz,
CDCl3): δ = 6.96 (dd, J = 4.9, 15.6 Hz, 1H), 6.04 (dd, J = 1.7, 15.6 Hz,
1H), 4.32 (q, J = 4.9 Hz, 1H), 3.75 (s, 3H), 1.73 (dd, J = 1.7, 15.6 Hz,
1H), 1.61−1.55 (m, 2H), 1.43−1.24 (m, 8H), 0.88 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ = 167.1, 150.7, 119.4, 70.9, 51.5, 36.5,
31.6, 29.0, 25.0, 22.4, 13.9; MS (EI): m/z (%) = 200, 171, 115, 87;
HRMS−EI: m/z calcd for C11H20O3: 200.1413; found: 200.1413 (M+).
MTPA Esters of 13. To a solution of 13 (5 mg, 0.025 mmol) in
CH2Cl2 (1.0 mL) were added pyridine (0.5 mL), 4-dimethylaminopyr-
idine (2 mg, 0.018 mmol), and (R)-(−)-α-methoxy-α-trifluoromethyl-
phenylacetyl chloride (14 μL, 0.0748 mmol). After stirring at rt for 10 h,
the mixture was evaporated and the residue was subjected to
chromatography (SiO2 1 g, hexanes−AcOEt, 10:1) to furnish (S)-
MTPA ester (11 mg, 0.025 mmol, ∼100%) as a colorless oil.
1
2928, 2856, 1737, 1711, 1458, 1435, 1164, 970, 411 cm−1; H NMR
(400 MHz, CDCl3): δ = 5.70−5.58 (m, 1H), 5.45 (dd, J = 9.0, 14.9 Hz,
0.67H), 5.27 (dd, J = 9.3, 15.1 Hz, 0.33H), 3.70 (s, 2H), 3.68 (s, 1H),
3.17 (t, J = 9.0 Hz, 1H), 2.94−2.86 (m, 1H), 2.06−1.98 (m, 2H), 1.40−
1.25 (m, 8H), 1.18 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ = 173.8, 173.2, 137.0, 136.3, 125.0, 124.1, 124.1,
52.0, 52.0, 51.9, 51.6, 42.1, 40.9, 32.4, 32.3, 31.6, 28.9, 28.7, 28.6,
22.5,15.0, 14.6, 14.0, 14.0; MS (EI): m/z (%) = 256, 183; HRMS−EI:
m/z calcd for C14H24O4: 256.1671; found: 256.1669 (M+); 16: [α]D29
−13.0 (c 0.35, CHCl3); Rf = 0.58 (hexanes−AcOEt, 5:1); IR (neat):
2930, 2858, 1731, 1665, 1462, 1435, 1310, 1274, 1176, 1082, 851, 725
cm−1; 1H NMR (400 MHz, CDCl3): δ = 6.86 (dd, J = 5.2, 15.6 Hz, 1H),
5.92 (dd, J = 1.5, 15.6 Hz, 1H), 5.40 (q, J = 5.7 Hz, 1H), 3.74 (s, 3H),
2.37 (q, J = 7.6 Hz, 2H), 1.85−1.63 (m, 2H), 1.30−1.26 (m, 8H), 1.16
(t, J = 7.6 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ = 173.5, 166.5, 146.0, 120.9, 72.2, 51.6, 33.8, 31.5, 28.9, 27.7,
24.6, 22.5, 14.0, 9.0; MS (EI): m/z (%) = 256, 199, 183; HRMS−EI: m/
z calcd for C14H24O4: 256.1675; found: 256.1659 (M+).
Methyl (S,E)-4-((2,2-Dibromopropanoyl)oxy)dec-2-enoate
(24). To a solution of compound 13 (125 mg, 0.625 mmol) in THF
(6 mL) were added EDCI (356 mg, 1.86 mmol), 4-dimethylaminopyr-
idine (22.5 mg, 0.186 mmol), and 2,2-dibromopropionic acid (427 mg,
1.86 mmol). After the reaction mixture was stirred at room temperature
for 6 h, EDCI (128 mg, 0.67 mmol) and 4-DMAP (11.3 mg, 0.093
mmol) were added, and stirring was continued at room temperature for
an additional 6 h. The mixture was diluted with sat. NH4Cl (10 mL),
extracted with Et2O (10 mL × 3), dried, and concentrated. The residue
was subjected to chromatography (SiO2 10 g, hexanes−AcOEt, 20:1) to
furnish 24 (232 mg, 0.560 mmol, 90%) as a colorless oil; [α]2D7 −0.4 (c
1.06, CHCl3); Rf = 0.66 (hexanes−AcOEt, 4:1); IR (neat): 2930, 2857,
1
Analogously, (R)-MTPA ester was also prepared. H NMR difference
in ppm ((S)-Mosher ester − (R)-Mosher ester, 400 MHz, CDCl3): δ
H3; 6.86−6.80 = +0.06, H2; 5.99−5.86 = +0.13, H4; 5.61−5.59 = +0.02,
H3; 3.75−3.73 = +0.02, H5; 1.69−1.74 = −0.05.
1
1736, 1665, 1436, 1378, 1261, 1173, 1119, 1068, 977, 593 cm−1; H
NMR (400 MHz, CDCl3): δ = 6.91 (dd, J = 4.9, 15.6 Hz, 1H), 6.13 (dd, J
= 1.7, 15.6 Hz, 1H), 5.47 (q, J = 5.9 Hz, 1H), 3.76 (s, 3H), 2.66 (s, 3H),
D
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1.80−1.75 (m, 2H), 1.44−1.24 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H); 13
C
8H), 1.45 (d, J = 7.6 Hz, 3H), 0.89 (t, J = 6.6 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ = 176.8, 174.7, 82.4, 78.3, 49.0, 38.3, 31.5, 28.9, 28.8,
25.3, 22.5, 17.1, 14.0; MS (EI): m/z (%) = 240, 222, 194; HRMS−EI:
m/z calcd for C13H20O4: 240.1362; found: 240.1343 (M+).
NMR (100 MHz, CDCl3): δ = 166.3, 165.9, 144.1, 121.5, 51.7, 51.6,
37.1, 33.5, 31.5, 29.8, 24.6, 22.4, 14.0; MS (EI): m/z (%) = 416, 414, 412,
385, 383, 381, 263, 261, 183; HRMS−EI: m/z calcd for C14H2281Br2O4:
415.9844; found: 415.9835 (M+).
27. [α]2D7 +16.8 (c 0.33, CHCl3); Rf = 0.55 (hexanes−AcOEt, 2:1); IR
(neat): 3460, 2929, 2857, 1772, 1738, 1437, 1378, 1262, 1176, 1005, 727
cm−1; 1H NMR (400 MHz, CDCl3): δ = 4.45 (d, J = 9.1 Hz, 1H), 3.78 (s,
3H), 3.67 (brs, 1H), 3.19 (t, J = 9.1 Hz, 1H), 3.01−2.94 (m, 1H), 1.75
(brs, 1H), 1.67−1.60 (m, 2H), 1.57−1.44 (m, 2H) 1.37 (d, J = 7.0 Hz,
3H), 1.30−1.26 (m, 6H), 0.89 (t, J = 6.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ = 176.9, 171.4, 80.9, 70.9, 52.6, 48.7, 39.1, 34.0, 31.6, 29.0,
25.5, 22.5, 14.6, 14.0: MS (EI): m/z (%) = 272, 238, 210, 183, 158:
HRMS−EI: m/z calcd for C14H24O5: 272.1624; found: 272.1632 (M+).
(3R,3aS,6R,6aR)-6-Hexyl-3-methyltetrahydrofuro[3,4-b]-
furan-2,4-dione (3-epi-dihydrosporothriolide) (2). To an ice-
cooled solution of 26 (27.0 mg, 0.10 mmol) in t-BuOH-H2O (1:1, 1.0
mL) were added super-AD-mix-β prepared by mixing K3Fe(CN)6 (98
mg, 0.3 mmol), K2CO3 (41 mg, 0.3 mmol), (DHQD)2PHAL (8 mg,
0.01 mmol), K2OsO2(OH)4 (0.4 mg, 0.001 mmol), and MeSO2NH2
(9.5 mg, 0.1 mmol). After stirring at room temperature for 25 h,
Na2S2O3·5H2O (160 mg) was added, and stirring was continued for 30
min. Then, the mixture was diluted with 1 M HCl (5 mL) and diethyl
ether (5 mL), and the mixture was stirred for an additional 90 min. The
reaction mixture was filtered through Celite cake, and the filtrate was
concentrated to half volume. The mixture was extracted with AcOEt (5
mL × 3), dried, and concentrated. The residue was subjected to flash
chromatography (SiO2 5 g, hexanes−AcOEt, 4:1) to provide 3-epi-
dihydrosporothriolide (15.4 mg, 0.064 mmol, 64%) as a colorless solid.
3-epi-Dihydrosporothriolide (2): mp 77−78 °C (recrystallized from
hexanes−AcOEt, 1:2); [α]D23 +15.4 (c 0.48, CHCl3) {lit. [α]D −22.06 (c
0.5, CHCl3)15,28}; Rf = 0.21 (hexanes−AcOEt, 2:1); IR (neat): 2927,
2860, 1785, 1459, 1344, 1200, 1020, 946, 896, 787, 680, 579, 405 cm−1;
1H NMR (400 MHz, CDCl3): δ = 5.02 (dd, J = 4.2, 6.0 Hz, 1H), 4.51
Dimethyl (2S,3R)-2-Methyl-3-((E)-oct-1-en-1-yl)succinate (25)
and Dimethyl (2R,3R)-2-Methyl-3-((E)-oct-1-en-1-yl)succinate
(26). A mixture of TMSCl (0.5 mL, 3.9 mmol) and Et3N (0.5 mL, 3.5
mmol) was centrifuged at 3000 rpm for 5 min. The supernatant (0.25
mL, containing 0.98 mmol of TMSCl and 0.89 mmol of Et3N) was
added to a mixture of dried InCl3 (112 mg, 0.506 mmol) and In (52 mg,
0.506 mmol) in THF (2.0 mL). To a stirred mixture was added a
solution of 24 (104 mg, 0.253 mmol) in DMPU (2.0 mL), and the
reaction mixture was stirred at 10−30 °C for 1.5 h under ultrasonication.
The stirring mixture was diluted with 2 M HCl (10 mL), extracted with
Et2O (10 mL × 3), and washed with brine (10 mL). The organic layer
was dried over MgSO4 and concentrated. The residue was purified by
chromatography (SiO2 5 g, hexane−AcOEt, 10:1 to 2:1) to afford a
diastereomeric mixture of 15 (51.9 mg, 0.202 mmol, 80%) and 16 (9.2
mg, 0.036 mmol, 14%).
To a solution of 15 (51.9 mg, 0.202 mmol) in THF (1 mL) and
MeOH (2 mL) was added timethylsilyldiazomethane (2.0 M solution in
hexane; 0.3 mL, 0.6 mmol) at 0 °C, and the mixture was stirred at 0 °C
for 1 h. The mixture was concentrated and purified by flash
chromatography (SiO2 5 g, hexanes−AcOEt, 20:1) to give compound
25 (30.5 mg, 0.113 mmol, 56%) as a colorless oil and compound 26
(15.6 mg, 0.058 mmol, 29%) as a colorless oil; 25: [α]2D8 +63.4 (c 0.81,
CHCl3); Rf = 0.62 (hexanes−AcOEt, 4:1); IR (neat): 2953, 2927, 2856,
1
1735, 1458, 1434, 1259, 1192, 1157, 1067, 970 cm−1; H NMR (400
MHz, CDCl3): δ = 5.58 (d, J = 15.1, 6.8 Hz, 1H), 5.41 (dd, J = 9.5 15.1
Hz, 1H), 3.70 (s, 3H), 3.64 (s, 3H), 3.19 (t, J = 8.8 Hz, 1H), 2.89 (ddd, J
= 7.0, 8.8, 13.9 Hz, 1H), 2.04−1.97 (m, 2H), 1.31−1.25 (m, 8H), 1.15
(d, J = 6.8 Hz, 3H), 0.86 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ = 174.6 173.1, 135.7, 124.6, 52.5, 51.8, 51.5, 42.5, 32.3, 31.6,
29.0, 28.8, 22.5, 15.2, 14.0; MS (EI): m/z (%) = 270, 256, 238, 210, 183;
HRMS−EI: m/z calcd for C15H26O4: 270.1831; found: 270.1825 (M+);
26: [α]2D8 +103.0 (c 0.38, CHCl3); Rf = 0.57 (hexanes−AcOEt, 4:1); IR
(dt, J = 4.2, 6.4 Hz, 1H), 3.45 (dd, J = 6.2, 10.0 Hz, 1H), 3.06 (dq, J =
10.0, 7.6 Hz, 1H), 1.94−1.78 (m, 2H), 1.56−1.26 (m, 8H), 1.47 (d, J =
7.6 Hz, 3H), 0.89 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ =
176.7, 172.0, 81.5, 77.9, 44.6, 36.6, 31.5, 28.9, 28.7, 25.3, 22.4, 13.9, 10.9:
MS (EI): m/z (%) = 240, 194, 98: HRMS−EI: m/z calcd for C13H20O4:
240.1362 ; found: 240.1364 (M+).
1
(neat): 2954, 2928, 1736, 1459, 1434, 1195, 1165, 970, 772 cm−1; H
NMR (400 MHz, CDCl3): δ = 5.64 (d, J = 15.1, 6.8 Hz, 1H), 5.26 (dd, J
= 9.6 15.1 Hz, 1H), 3.67 (s, 3H × 2), 3.22 (t, J = 9.5 Hz, 1H), 2.88−2.80
(m, 1H), 2.03 (q, J = 7.2 Hz, 2H), 1.36−1.26 (m, 8H), 1.13 (d, J = 7.1
Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ =
175.6, 173.9, 136.7, 124.3, 51.9, 51.9, 51.8, 41.1, 32.4, 31.6, 28.9, 28.7,
22.5, 14.7, 14.0; MS (EI): m/z (%) = 270, 256, 238, 210, 183; HRMS−
EI: m/z calcd for C15H26O4: 270.1831; found: 270.1830 (M+).
(3S,3aS,6R,6aR)-6-Hexyl-3-methyltetrahydrofuro[3,4-b]-
furan-2,4-dione (Dihydrosporothriolide) (1) and Methyl
(2S,3S,4S)-2-((S)-1-Hydroxyheptyl)-4-methyl-5-oxotetra-
hydrofuran-3-carboxylate (27). To an ice-cooled solution of 25
(27.0 mg, 0.10 mmol) in t-BuOH-H2O (1:1, 1.0 mL) were added super-
AD-mix-β prepared by mixing K3Fe(CN)6 (98 mg, 0.3 mmol), K2CO3
(41 mg, 0.3 mmol), (DHQD)2PHAL (8 mg, 0.01 mmol), K2OsO2-
(OH)4 (0.4 mg, 0.001 mmol), and MeSO2NH2 (9.5 mg, 0.1 mmol).
After stirring at room temperature for 16 h, Na2S2O3·5H2O (150 mg)
was added, and stirring was continued for 30 min. Then, the mixture was
diluted with 1 M HCl (5 mL) and diethyl ether (5 mL), and the mixture
was stirred for an additional 90 min. The reaction mixture was filtered
through Celite cake, and the filtrate was concentrated to half volume.
The mixture was extracted with AcOEt (5 mL × 3), dried, and
concentrated. The residue was subjected to flash chromatography (SiO2
5 g, hexanes−AcOEt, 4:1) to provide dihydrosporothriolide (20.1 mg,
0.084 mmol, 84%) as a colorless solid and compound 27 (2.9 mg, 0.011
mmol, 11%) as a colorless oil.
ASSOCIATED CONTENT
■
S
* Supporting Information
X-ray analysis of dihydrosporothriolide and H and 13C NMR
1
spectra of synthetic intermediates and dihydrosporothriolide. X-
ray crystalllographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jishi@nagasaki-u.ac.jp.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Grant-in-Aid for Scientific
Research (C) (24590011).
■
REFERENCES
■
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Dihydrosporothriolide (1). mp 90−91 °C (recrystallized from
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1
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F
dx.doi.org/10.1021/jo5008948 | J. Org. Chem. XXXX, XXX, XXX−XXX