Total Syntheses of Allelopathic 4-Oxyprotoilludanes, Melleolides, and Echinocidins

Article abstract of DOI:10.1021/acs.joc.9b01589

Stereocontrolled total syntheses of allelopathic 4-oxyprotoilludane sesquiterpenes, melleolide, melleolide F, and echinocidins B and D were achieved. The curved 5/6/4 tricyclic system with an angular hydroxy group was built via three key transformations: (1) Me₃Al-catalyzed [2 + 2] cycloaddition of a ketene silyl acetal with a propiolate, (2) reductive ring-opening of a cyclic hemiketal, and (3) the intramolecular Morita-Baylis-Hillman reaction. This synthetic route represents a new and reliable strategy to obtain protoilludanes with several oxy-functional groups.

Full text of DOI:10.1021/acs.joc.9b01589

Article
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/joc
Total Syntheses of Allelopathic 4‑Oxyprotoilludanes, Melleolides,
and Echinocidins
Kazuma Shimoda, Yousuke Yamaoka, Dongeun Yoo, Ken-ichi Yamada, Hiroshi Takikawa,
†
and Kiyosei Takasu*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
*
S Supporting Information
ABSTRACT: Stereocontrolled total syntheses of allelopathic
-oxyprotoilludane sesquiterpenes, melleolide, melleolide F,
4
and echinocidins B and D were achieved. The curved 5/6/4
tricyclic system with an angular hydroxy group was built via
three key transformations: (1) Me Al-catalyzed [2 + 2]
3
cycloaddition of a ketene silyl acetal with a propiolate, (2)
reductive ring-opening of a cyclic hemiketal, and (3) the intramolecular Morita−Baylis−Hillman reaction. This synthetic route
represents a new and reliable strategy to obtain protoilludanes with several oxy-functional groups.
INTRODUCTION
Protoilludane sesquiterpenes, which possess a curved 5/6/4
tricyclic framework with various oxidation states, are found in
Their potential biological and medicinal usefulness along
with the unique framework of protoilludanes has stimulated
enormous synthetic investigations including the racemic and
■
5
,6
1
asymmetric total synthesis. However, the number of reports
nature, generally isolated from fungi. The protoilludane
7
related to the synthesis of 4-oxyprotoilludanes is quite limited.
compounds exhibit a diverse array of biological activities, for
example, antibacterial, antitumor, antifungal, anticonvulsant,
This is due to the high sensitivity of the fused cyclobutanol
moiety during chemical transformations under basic, acidic,
2
and hypnotic. Their activities usually depend on the position,
8
and radical conditions. In 2017, Scheidt and co-workers
stereochemistry, and number of oxy-functional groups. Quite
recently, Gressler and Hoffmeister identified a target protein of
melleolides and elucidated their antifungal action mecha-
reported the first total synthesis of 4-hydroxyprotoilludanes,
3a
3b
amillaridin (3), echinocidins B (4a), and D (4b). The
elegant key steps involve a chiral N-heterocyclic carbene-
catalyzed enal−enone annulation for the construction of the A-
ring in an enantioselective manner and an intramolecular
pinacol-type reductive coupling for the formation of the
2
g
nism. Protoilludanes with an angular hydroxy group at the
C4 position, 4-oxyprotoilludanes, as shown in Figure 1 have
7b
strained cyclobutane ring (C-ring). On the other hand, our
9
group recently reported the total synthesis of paesslerin A (5)
7c
along with its structural revision. The 5/6/4 tricyclic skeleton
with an oxy-function at the C4 position was built by a Tf NH-
2
catalyzed domino reaction involving a [4 + 2] cycloaddition,
isomerization, and [2 + 2] cycloaddition from three
components: cyclopentenone, 2-siloxydiene, and acrylate
(
Scheme 1a). Although the tricyclic core was easily assembled
from readily available materials, introducing the methyl group
at the C2 position and unsaturation of the C2−C3 bond
required long steps, that is, it was very difficult to achieve a
late-stage oxidation of 6 with no decomposition of the fused
cyclobutanol moiety.
To synthesize protoilludanes with higher oxidation states, we
conceived a synthetic route, in which the required oxy-
functional groups are introduced at an early stage. The
retrosynthetic analysis for melleolide (1) is summarized in
Scheme 1b. Compound 1 should be obtained by esterification
of 7 with orsellinic acid. Formation of the B-ring would be
Figure 1. Representative 4-oxyprotoilludanes.
3
been reported as fungi metabolites that regulate plant growth.
Recently, Kawagishi and co-workers reported that melleolide
4
a
4b
(
1) and armillarikin (2), isolated from the honey fungus
Armillaria mellea as an aryl ester of 4-hydroxyprotoilludanes,
inhibit the growth of lettuce and of some mushrooms’ mycelia
at low concentration.
Received: June 14, 2019
3c
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b01589
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The Journal of Organic Chemistry
Article
Scheme 1. Synthetic Strategies to 4-Oxyprotoilludanes: (a)
Our Previous Result to Paesslerin A (5); (b) Retrosynthetic
Analysis for Melleolide (1)
ketene silyl acetal 15, which was obtained with good purity
after aqueous extraction and used in the next step without
further purification. As expected, Me Al-catalyzed [2 + 2]
3
11
cycloaddition of 15 with methyl propiolate nicely proceeded
to give tricyclic ketal 16 as a single diastereomer in excellent
yield. The stereoselectivity in the [2 + 2] cycloaddition can be
rationalized by the selective attack of propiolate at the convex
face of the bicyclic ketene silyl acetal moiety of 15.
Once the A and C framework was constructed, the following
issues were the transformation of the cyclobutenecarboxy
moiety of 16 into the cyclobutanone and the preparation of a
precursor of the IMBH reaction. We envisioned that
conversion of 16 into isocyanate by Curtius rearrangement,
followed by hydrolysis via the corresponding enamine
intermediate, would provide the expected ketone 19 (Scheme
3
). First, carboxylic acid 17 was obtained by basic hydrolysis of
Scheme 3. Preparation of 25 and Rationale for
Stereoselectivity in Reduction of 19
achieved via the intramolecular Morita−Baylis−Hillman
(
IMBH) reaction of 8. This compound could be obtained
10
from 9 by Curtius−hydrolysis combination of the cyclo-
butenecarboxylic acid, followed by oxidation−two carbon
homologation of the primary alcohol moiety. Hemiketal 9
may be readily prepared by a catalytic [2 + 2] cycloaddition of
cyclic ketene silyl acetal 10 with propiolate. Here, we
describe the total synthesis of racemic melleolide and its
related 4-oxyprotoilludanes.
11
RESULTS AND DISCUSSION
We chose lactone 11, which is readily available from the
corresponding bicyclo[3.3.0]ocatanedione, as a starting
material. Scheme 2 summarizes the synthesis of tricyclic
■
12
1
3
Scheme 2. Preparation of Tricyclic Ketal 16
cyclobutene 16 from 11. The gem-dimethyl group of 13 was
introduced by a three-step protocol in good yields as follows:
Wittig reaction of 11 into 12, followed by cyclopropanation of
16. The following Curtius rearrangement using diphenylphos-
phoryl azide gave the desired isocyanate 18 in only low yield
(30%) with poor reproducibility. Careful analysis of the side
products revealed that the 1,4-addition of azide was occurring.
This unusual competing reaction likely proceeds by the release
of strain from the sp -rich cyclobutene ring into the sp -free
cyclobutane. Extensive screening of reaction conditions
resulted in a suitable protocol to obtain 19 in 83% yield
(three steps from 17) by the formation of the corresponding
1
4
1
2, and hydrogenolysis in the presence of PtO (5 mol %)
2
under a H2 atmosphere. Monomethylation of 13 was
performed with the corresponding lithium enolate to give 14
as a mixture of diastereomers in 94% yield. Treatment of 14
2
2
(
diastereomer mixture) with triisopropylsilyl trifluorometha-
nesulfonate (TIPSOTf) in the presence of Et N afforded
3
B
DOI: 10.1021/acs.joc.9b01589
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Article
acyl azide via mixed acid anhydride, followed by rearrangement
and acid hydrolysis.
formyl, and an (ethylthio)carbonyl group, respectively, were
prepared. Although the reaction of nitrile 25b with Me P (neat
3
Then, reduction of cyclobutanone 19 with diisobutylalumi-
num hydride (DIBAL-H) provided cyclobutanol 20 as a single
diastereomer (β-OH isomer). Hydride would attack the keto-
carbonyl group of 19 to avoid the steric hindrance of the bulky
siloxy and methyl groups at the 6/4 ring junctures. The
stereochemistry of the hydroxy group on C5 of 20 was
confirmed by desilylation, followed by acetonide formation
between the C4 and C5 hydroxy groups (see the Supporting
Information). Compound 20 was converted into 21 after
conditions) resulted in complete recovery of the substrate
(Table 1, entry 2), it was found that the aldehyde 25c and
thioester 25d gave the desired tricycles 26c and 26d,
respectively, in good yields (entries 3 and 4). When
nucleophilic catalysts other than Me P were used in the
3
reaction of 25d, no better results were observed. At this stage,
thioester 26d was selected as a suitable intermediate for further
transformation because (1) the preparation of substrate 25c
from 24 requires longer steps than 25d, and (2) the formyl
group would be sensitive under the reaction conditions in the
following transformation.
15
migration of the triisopropylsilyl (TIPS) group by treatment
with NaH (97% yield). Oxidative cleavage of the cyclic
hemiketal 21, followed by Horner−Wadsworth−Emmons
Scheme 4 illustrates the preparation of 26d and the
completion of the total synthesis of melleolide (1). Thioester
(
HWE) reaction, would yield α,β-unsaturated carbonyl
compound 8. Although numerous efforts were attempted,
16
satisfactory results were not obtained. When 21 was treated
with tetrapropylammonium perruthenate (10 mol %) and N-
methylmorpholine-N-oxide, ketoaldehyde 24 (ca. 20%) was
obtained with inseparable byproducts. Thus, the synthetic
strategy was changed to the reductive ring-opening of 21 to
Scheme 4. Completion of the Total Synthesis of Melleolide
(1)
obtain diol 22; when adding LiBH to 21, the reduction
4
proceeded smoothly to afford the corresponding diastereo-
meric diols 22a and 22b in 87 and 5% yields, respectively.
Compound 22 was also obtained from ketone 19 in a single
operation when NaBH4 was used instead of DIBAL-H.
Reduction, silyl migration, and reductive ring-opening
sequentially proceeded albeit in moderate chemical yield
with lower stereoselectivity (50% yield, 22a/22b = 78:22
diastereomeric ratio (dr)), and its regioisomer 23 was also
obtained in 15% yield. Next, oxidation of the two hydroxy
groups of 22 was successful under Swern or Corey−Kim
conditions. A mixture of 22a and 22b diastereomers was
transformed into the ketoaldehyde 24. Subsequent HWE
reaction of 24 gave α,β-unsaturated ester 25a in 69% yield
(
two steps from 22), which was then used for the key IMBH
reaction.
Next, the IMBH reaction of ethyl ester 25a was analyzed.
However, the desired tricyclic carbocycle 26a was not observed
in the presence of nucleophilic catalysts such as 1,4-
diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyri-
dine (DMAP), Bu P, and Me P, even though a stoichiometric
3
3
amount was used (Table 1, entry 1). This was likely an issue
related to the substrate; thus, the electrophilicity of the β-
carbon was changed by varying the electron-withdrawing group
(
EWG) of 25. Three substrates, 25b−d, with a cyano, a
Table 1. Intramolecular Morita−Baylis−Hillman Reaction
of 25
25d, prepared from 24 with phosphonothioacetate, reacted
with Me P at ambient temperature under neat conditions to
3
afford 26d in 69% yield (Table 1, entry 4). Compound 26d
was transformed into alcohol 27 in high yield. Then, the direct
transformation of the β-alcohol 27 into 30 by the Mitsunobu
reaction was attempted, but no ester product was formed
although simple carboxylic acids, such as benzoic acid, were
used instead of orsellinic acid. The carboxylate nucleophile
would not be able to attack at the sterically crowded concave
face of the tricycle 27. Based on the above, the strategy was
changed to a redox sequence according to Scheidt’s
entry
substrates (EWG)
time (h)
%yield of 26
a
1
25a (CO Et)
24
24
1
0
0
62
69
2
2
3
25b (CN)
25c (CHO)
25d (COSEt)
7b
a
protoilludane synthesis. The Corey−Kim oxidation of 27
provided cyclobutanone 28. Treatment of 28 with NaBH-
4
10.5
a
No better result for the formation of 26 was obtained when
DABCO, DMAP, or Bu P was used instead of Me P.
(OAc) gave the 5α-alcohol 29 in 68% yield along with its
diastereomer 27 (3% yield). The relative stereochemistry of 27
3
3
3
C
DOI: 10.1021/acs.joc.9b01589
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The Journal of Organic Chemistry
Article
1
13
1
and 29 was confirmed by X-ray crystallography. Compound 29
was condensed with nonprotected orsellinic acid to afford ester
relative to tetramethylsilane ( H, 0.00) or CDCl
7
3
( C, 77.0) ( H,
.26), and coupling constants are presented in hertz. Abbreviations
are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br, broad. C peak multiplicity assignments were made based on
distortionless enhancement by polarization transfer data. IR spectra
were recorded on a Shimadzu IRAffinity-1, and the wavenumbers of
3
0. The total synthesis was completed by Fukuyama
1
3
17
reduction of thioester 30 to yield aldehyde 1, from which
the H NMR, C NMR, IR, and high-resolution mass
spectrometry (HRMS) spectra were identical to the reported
1
13
−1
their maximum absorption peaks are presented in cm . High-
3
c,4
ones.
resolution mass spectra were measured on Shimadzu LCMS-IT-TOF
fitted with an ESI. Melting points were determined on the YANACO
micro melting point apparatus. X-ray single-crystal diffraction analyses
were performed on a Rigaku XtaLAB P200 apparatus. All reagents
were purchased from chemical companies and used as received.
Dehydrated solvents were purchased for the reactions and used
without further desiccation unless otherwise mentioned.
Compound 26d can be used as a common intermediate for
the synthesis of several natural protoilludanes (Scheme 5).
Scheme 5. Synthesis of Related Protoilludanes
(
4aR*,7aR*)-Hexahydro-6-methylenecyclopenta[c]pyran-3(1H)-
one (12). To a suspension of methyltriphenylphosphonium bromide
463 mg, 1.3 mmol) in dry tetrahydrofuran (THF) (6.5 mL) was
(
t
added BuOK (1.0 M solution in THF, 0.97 mL, 0.97 mmol) at room
temperature. After the mixture was stirred for 30 min at the same
temperature, a solution of ketone 11 (149 mg, 0.73 mmol) in dry
THF (2.0 mL) was slowly added. After stirring for an additional 3 h,
the resulting mixture was diluted with hexane and filtrated. The
filtered residue was washed with hexane and Et O several times. The
2
filtrate was concentrated in vacuo. The resulting residue was purified
with silica gel column chromatography (hexane/AcOEt = 3:1) to
1
13
afford 12 (82 mg, 74%) as a colorless oil. H and C NMR spectral
20
data were identical to the reported ones.
Cyclopropanation of 12. To a solution of diethylzinc (1.0 M in
hexane, 1.5 mL, 1.5 mmol) in dry CH Cl (1.5 mL) was dropwise
2
2
added trifluoroacetic acid (0.12 mL, 1.5 mmol) at 0 °C, and the
mixture was stirred at the same temperature. After 20 min, to the
mixture was added a solution of CH I (0.12 mL, 1.5 mmol) in dry
2
2
CH Cl (1.0 mL). After stirring for an additional 20 min, a solution of
2
2
olefin 12 (116 mg, 0.76 mmol) in dry CH Cl (1.0 mL) was added.
After warming to room temperature, the mixture was stirred for 4.5 h.
The reaction mixture was quenched with 0.1 N HCl and extracted
2
2
18
Reduction of 1 with NaBH afforded melleolide F (31).
4
Echinocidin D (4b) was obtained by treatment of 26d with
LiAlH4 through reduction and desilylation. Similarly,
twice with Et O. The combined organic layers were washed with
1
9
2
brine, dried over Na SO , and concentrated in vacuo. The residue was
2
4
echinocidin B (4a) was achieved by LiAlH reduction of 29.
4
purified with silica gel column chromatography (hexane/AcOEt =
:1) to afford the corresponding cyclopropane (100 mg, 84%) as a
yellow oil.
The physical data of 4a, 4b, and 31 are consistent with those
3
3a,b,19
reported for the natural products.
R 0.34 (hexane/AcOEt = 3:1).
H NMR: 0.38−0.44 (m, 2H), 0.47−0.56 (m, 2H), 1.40 (dd, J
5.8, 12.8 Hz, 1H), 1.48 (dd, J = 5.8, 12.9 Hz, 1H), 1.73 (dd, J = 8.2,
f
1
CONCLUSIONS
■
=
1
In summary, we completed the first total synthesis of
melleolide (1) in 21 steps with 6.6% overall yield from
known compound 11. The synthetic strategy involved the [2 +
3.4 Hz, 1H), 1.82 (dd, J = 7.9, 12.8 Hz, 1H), 2.43 (dd, J = 7.5, 14.9
Hz, 1H), 2.68 (m, 3H), 4.11 (dd, J = 7.3, 11.3 Hz, 1H), 4.30 (dd, J =
13
5
(
.0, 11.4 Hz, 1H). C NMR: 9.62 (CH ), 10.1 (CH ), 21.6 (C), 34.2
2 2
2
] cycloaddition of a ketene silyl acetal with a propiolate and
CH), 34.3 (CH ), 36.3 (CH), 37.3 (CH ), 41.9 (CH ), 69.7 (CH ),
2 2 2 2
the IMBH reaction for the construction of the tricyclic
skeleton of protoilludanes with oxy-functions. Furthermore,
melleolide F (31) was also synthesized in 22 steps with 5.9%
overall yield, echinocidin B (4a) in 20 steps with 8.6% overall
yield, and echinocidin D (4b) in 17 steps with 16% overall
yield. This synthetic strategy will be useful for the synthesis of
protoilludanes at high oxidation states. The biological
evaluation of the synthetic protoilludanes and of related
analogues is currently under way.
1
73.2 (C). IR (neat): 3071, 2990, 2936, 2855, 1747, 1250, 1080.
+
HRMS−ESI (m/z): [M + K] calcd for C H KO , 205.0625; found,
205.0628.
1
0
14
2
(4aR*,7aR*)-Hexahydro-6,6-dimethylcyclopenta[c]pyran-3(1H)-
one (13). To a solution of the above cyclopropane (3.0 g, 18 mmol)
in AcOH (35 mL) was added PtO (204 mg, 0.90 mmol) at room
temperature. After stirring for 7 h at 90 °C (oil bath) under a H2
atmosphere, the mixture was filtered through a pad of Celite. The
filtered residue was washed with AcOEt several times. After the filtrate
2
was concentrated in vacuo, the residue was diluted with Et O and
2
washed with saturated aqueous NaHCO and brine. The organic layer
3
EXPERIMENTAL SECTION
was concentrated in vacuo. The resulting residue was purified with
silica gel column chromatography (hexane/AcOEt = 5:1−3:1) to
afford 13 (3.1 g, quant.) as white crystals.
■
General. Column chromatography was performed on Fuji Silysia
BW-200 silica gel or Kanto Kagaku Silica Gel 60 N (spherical,
neutral) 100−210 μm. Reactions and chromatography fractions were
analyzed by thin-layer chromatography (TLC) carried out on Merck
Silica Gel 60 F254 or Wako Silica gel 70 F254 TLC Plate-Wako with
visualization by ultraviolet (UV) irradiation at 254 nm, phosphomo-
lybdic acid, anisaldehyde, ninhydrin, and/or potassium permanganate
R 0.39 (hexane/AcOEt = 3:1).
f
1
H NMR: 0.96 (s, 3H), 1.07 (s, 3H), 1.12 (dd, J = 11.6, 11.7 Hz,
1H), 1.35 (dd, J = 11.3, 11.3 Hz, 1H), 1.62 (ddd, J = 2.1, 8.2, 12.3 Hz,
1H), 1.74 (ddd, J = 2.1, 7.5, 12.3 Hz, 1H), 2.33 (dd, J = 5.5, 14.9 Hz,
1H), 2.55−2.65 (m, 2H), 2.66−2.77 (m, 1H), 4.05 (dd, J = 5.0, 11.3
1
13
staining. NMR was recorded on JEOL JNM-LA (500 MHz for H and
Hz, 1H), 4.27 (dd, J = 4.6, 11.5 Hz, 1H). C NMR: 26.4 (CH ), 28.2
3
13
1
25 MHz for C) and measured in CDCl3 unless otherwise
(CH ), 33.6 (CH), 34.6 (CH ), 35.9 (CH), 39.4 (C), 43.1 (CH ),
3
2
2
mentioned. Chemical shifts are presented in parts per million δ
47.9 (CH ), 70.1 (CH ), 173.7 (C). IR (KBr): 3021, 2955, 2866,
2
2
D
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1
740, 1466, 1385, 1246, 1215, 1172, 1083, 756. HRMS−ESI (m/z):
raphy (hexane/AcOEt = 50:1−20:1) to afford 16 (3.96 g, 94% from
14 in two steps) as a colorless oil.
+
[
3
M + K] calcd for C H KO , 207.0782; found, 207.0781. mp: 30−
1
0
16
2
2 °C (from hexane/AcOEt).
4aR*,7aR*)-Hexahydro-4,6,6-trimethylcyclopenta[c]pyran-
(1H)-one (14). To a solution of diisopropylamine (2.2 mL, 15
R 0.52 (hexane/AcOEt = 10:1).
f
1
(
H NMR: 0.89 (s, 3H), 1.05−1.09 (m, 21H), 1.13 (s, 3H), 1.14−
3
1.21 (m, 3H), 1.38 (dd, J = 8.0, 12.5 Hz, 1H), 1.43−1.45 (m, 2H),
n
mmol) in dry THF (20 mL) was added BuLi (1.6 M solution in
hexane, 8.8 mL, 14 mmol) at −78 °C. After the mixture was stirred
for 30 min at the same temperature, to this was added a solution of 13
1.66 (dd, J = 8.5, 12.5 Hz, 1H), 2.09 (ddddd, J = 3.0, 5.0, 8.0, 8.5, 10.5
Hz, 1H), 2.39 (ddd, J = 9.5, 9.5, 10.5 Hz, 1H), 3.48 (dd, J = 3.0, 12.0
Hz, 1H), 3.71 (s, 3H), 3.79 (dd, J = 5.0, 12.0 Hz, 1H), 7.03 (s, 1H).
(2.0 g, 12 mmol) in dry THF (10 mL). After the resulting mixture
13
C NMR: 13.1 (CH), 18.2 (CH ), 20.4 (CH ), 26.9 (CH ), 29.2
3
3
3
was stirred for 30 min, a mixture of hexamethylphosphoramide (4.5
mL, 26 mmol) and methyl iodide (1.5 mL, 23 mmol) was added at
the same temperature. After stirring for an additional 10 h at room
temperature, the mixture was quenched with saturated aqueous
NH Cl and extracted three times with Et O. The combined organic
(
5
CH ), 34.1 (CH), 36.7 (C), 41.2 (CH), 45.5 (CH ), 47.6 (CH ),
3
2
2
1.0 (CH ), 53.3 (C), 65.5 (CH ), 100.9 (C), 138.3 (C), 156.4
3
2
(CH), 161.9 (C). IR (neat): 2947, 2866, 1728, 1612, 1462, 1281,
+
1
262, 1234, 1049, 883. HRMS−ESI (m/z): [M + Na] calcd for
4
2
C H NaO Si, 445.2745; found, 445.2746.
2
4
42
4
layers were washed with brine, dried over Na SO , and concentrated
2
4
(
2aR*,4aR*,7aS*,7bS*)-2a-Triisopropylsilyloxy-6,6,7b-trimethyl-
in vacuo. The residue was purified with silica gel column
chromatography (hexane/AcOEt = 10:1−3:1) to afford a mixture
of 14a as a less polar diastereomer and 14b as a polar one (2.0 g, dr =
2
a,4,4a,5,6,7,7a,7b-octahydrocyclobuta[b]cyclopenta[d]pyran-2-
carboxylic Acid (17). To a solution of ester 16 (5.7 g, 13 mmol) in
MeCN−H O (90 + 45 mL) was added LiOH·H O (1.1 g, 27 mmol)
2
2
8
:2, 94%) as a yellow oil. The diastereomers could be isolated by Prep
TLC (PTLC), but their stereochemistry was not determined.
14a) R 0.47 (hexane/AcOEt = 3:1).
H NMR: 0.98 (s, 3H), 1.10 (dd, J = 11.5, 12.0 Hz, 1H), 1.11 (s,
H), 1.18 (d, J = 6.5 Hz, 3H), 1.20 (dd, J = 11.0, 12.0 Hz, 1H), 1.63
at room temperature. After stirring for 22.5 h at 60 °C (oil bath), the
reaction mixture was quenched with saturated aqueous NH Cl and
10% aqueous HCl and extracted with AcOEt three times. The
combined organic layers were washed with brine, dried over Na SO ,
4
(
f
1
2
4
3
and concentrated in vacuo. The residue was purified with silica gel
column chromatography (hexane/AcOEt = 10:1−3:1) to afford 17
(
8
2
dd, J = 12.0 Hz, 1H), 1.89 (dd, J = 8.0, 12.0 Hz, 1H), 2.15 (dddd, J =
.0, 8.5, 11.0, 11.5 Hz, 1H), 2.33 (qd, J = 6.3, 11.5 Hz, 1H), 2.59−
(5.20 g, 95%) as a white solid.
.71 (m, 1H), 3.94 (dd, J = 11.0, 12.0 Hz, 1H), 4.31 (dd, J = 6.5, 11.0
R 0.36 (hexane/AcOEt = 3:1).
13
f
Hz, 1H). C NMR: 14.0 (CH ), 26.8 (CH ), 28.6 (CH ), 36.9
1
3
3
3
H NMR: 0.89 (s, 3H), 1.05−1.09 (m, 21H), 1.14 (s, 3H), 1.16−
(
7
CH), 39.3 (CH), 41.0 (C), 41.9 (CH), 42.9 (CH ), 48.1 (CH ),
2 2
1
1
.23 (m, 3H), 1.39 (dd, J = 8.5, 13.0 Hz, 1H), 1.44−1.46 (m, 2H),
.66 (dd, J = 8.5, 13.0 Hz, 1H), 2.10 (ddddd, J = 3.0, 5.0, 8.5, 8.5, 10.0
0.0 (CH ), 176.4 (C). IR (neat): 2936, 2855, 1744, 1458, 1384,
2
+
1
246, 1611, 1107, 1065, 1026. HRMS−ESI (m/z): [M + Na] calcd
Hz, 1H), 2.40 (ddd, J = 9.5, 9.5, 10.0 Hz, 1H), 3.50 (dd, J = 3.0,12.0
Hz, 1H), 3.79 (J = 5.0, 12.0 Hz, 1H), 7.16 (s, 1H). C NMR: 13.0
(
3
1
1
for C H NaO , 205.1199; found, 205.1199.
13
11
18
2
(
14b) R 0.40 (hexane/AcOEt = 3:1).
f
CH), 18.2(CH ), 20.3 (CH ), 26.9 (CH ), 29.2 (CH ), 34.1 (CH),
1
3 3 3 3
H NMR: 0.85−0.95 (m, 4H), 1.04 (s, 3H), 1.13 (d, J = 5.5 Hz,
H), 1.47 (t, J = 5.5 Hz, 1H), 1.53−1.57 (m, 1H), 1.60−1.65 (m,
H), 2.58−2.65 (m, 1H), 2.69−2.77 (m, 2H), 4.11 (d, J = 11.5 Hz,
6.6 (C), 41.0 (CH), 45.5 (CH ), 47.6 (CH ), 53.6 (C), 65.5 (CH ),
2 2 2
1
1
1
00.8 (C), 137.9 (C), 159.2 (CH), 166.6 (C). IR (neat): 2943, 2866,
690, 1620, 1462, 1289, 1265, 1234, 1092, 883, 733. HRMS−ESI (m/
1
3
H), 4.30 (dd, J = 3.5, 11.5 Hz, 1H). C NMR: 12.9 (CH ), 26.0
+
3
z): [M + Na] calcd for C H NaO Si, 431.2588; found, 431.2585.
mp: 109−101 °C.
2
3
40
4
(CH ), 28.0 (CH ), 36.5 (CH), 37.0 (CH), 38.2 (C), 39.8 (CH),
3 3
4
1
3.7 (CH ), 44.0 (CH ), 69.2 (CH ) 176.2 (C). IR (neat): 2939,
2 2 2
744, 1389, 1161, 759. HRMS−ESI (m/z): [M + Na] calcd for
(
2aR*,4aR*,7aS*,7bR*)-2a-Triisopropylsilyloxy-6,6,7b-
+
trimethyloctahydrocyclobuta[b]cyclopenta[d]pyran-2(1H)-one
(19). To a solution of 17 (3.0 g, 7.4 mmol) in THF (75 mL) were
added triethylamine (1.2 mL, 8.9 mmol) and EtOCOCl (0.85 mL, 8.9
mmol) at room temperature. After stirring for 1 h at the same
temperature, to the mixture was added a solution of NaN (507 mg,
7
mixture was diluted with hexane and extracted with hexane three
times. The combined organic layers were washed with brine, dried
over Na SO , and concentrated in vacuo. The crude mixture of the
corresponding acyl azide was obtained as a colorless oil, which was
used in the next step without further purification.
C H NaO , 205.1199; found, 205.1188.
11
18
2
(
4aS*,7aR*)-3-Triisopropylsilyloxy-4,6,6-trimethyl-1,4a,5,6,7,7a-
hexahydrocyclopenta[c]pyran (15). To a solution of 14 (1.8 g, 10
mmol) in dry CH Cl (50 mL) were added triethylamine (2.2 mL, 16
2
2
3
mmol) and TIPSOTf (3.2 mL, 12 mmol) at room temperature, and
the mixture was stirred for 14.5 h at the same temperature. After the
mixture was concentrated in vacuo, the residue was diluted with
hexane, washed with H O and brine, dried over Na SO , and
.8 mmol) in H O (25 mL). After stirring for an additional 1 h, the
2
2
2
4
2
4
concentrated in vacuo. The crude mixture of 15 was obtained as a
pale yellow oil. The material was employed in the next reaction
without further purification.
1
The crude mixture of the above acyl azide was dissolved in toluene
H NMR: 0.99 (s, 3H), 1.04 (s, 3H), 1.05−1.08 (m, 18H), 1.09−
(40 mL), and the solution was stirred for 1 h at 60 °C. The mixture
1
.19 (m, 5H), 1.57 (s, 3H), 1.61 (ddd, J = 1.0, 8.5, 13.0 Hz, 1H), 1.74
was concentrated in vacuo. The crude mixture of the corresponding
isocyanate was obtained as a colorless oil, which was used in the next
step without further purification.
(
ddd, J = 1.0, 6.5, 12.5 Hz, 1H), 2.28−2.35 (m, 1H), 2.45−2.50 (m,
13
1
H), 3.49 (t, J = 10.0 Hz, 1H), 3.84 (dd, J = 4.5, 10.0 Hz, 1H). C
NMR: 12.6 (CH), 13.9 (CH ), 17.7 (CH ), 17.9 (CH ), 29.5 (CH ),
3
3
3
3
The crude mixture of the above isocyanate was dissolved in THF
0.45 (CH ), 36.8 (CH), 38.4 (C), 40.2 (CH ), 47.6 (CH ), 68.7
3
2
2
(150 mL) and 10% aqueous HCl (150 mL). After stirring for 1.5 h at
2
+
60 °C, the mixture was extracted with hexane three times. The
combined organic layers were washed with brine, dried over Na SO ,
and concentrated in vacuo. The residue was purified with silica gel
column chromatography (hexane/AcOEt = 50:1−20:1) to afford 19
(2.3 g, 83% from 17 in three steps) as a colorless oil.
2
0
39
2
2
4
Methyl (2aR*,4aR*,7aS*,7bS*)-2a-Triisopropylsilyloxy-6,6,7b-tri-
methyl-2a,4,4a,5,6,7,7a,7b-octahydrocyclobuta[b]cyclopenta[d]-
pyran-2-carboxylate (16). To a solution of the above 15 and methyl
propiolate (1.0 mL, 12.0 mmol) in dry CH Cl (50 mL) was added a
R 0.52 (hexane/AcOEt = 10:1).
2
2
f
1
solution of Me Al (2.0 M in toluene, 1.0 mL, 2.0 mmol) in dry
H NMR: 1.02 (s, 3H), 1.05−1.09 (m, 25H), 1.23 (septet, J = 7.5
Hz, 3H), 1.54−1.62 (m, 2H), 1.66 (dd, J = 8.0, 14.0 Hz, 1H), 2.18 (d,
J = 15.5 Hz, 1H), 2.33−2.42 (m, 2H), 3.06 (d, J = 15.5 Hz, 1H), 3.39
(dd, J = 6.5, 11.5 Hz, 1H), 3.44 (dd, J = 11.5, 11.5 Hz, 1H).
NMR: 12.7 (CH), 17.9 (CH ), 21.9 (CH ), 31.5 (CH ), 31.7 (CH
35.5 (CH), 36.8 (C), 37.8 (C), 41.7 (CH), 42.1 (CH ), 42.6 (CH ),
3
CH Cl (20 mL) at 0 °C. After stirring for 1 h at room temperature,
2
2
the mixture was quenched with saturated aqueous NaHCO3 and
saturated aqueous potassium sodium tartrate. The resulting mixture
was extracted with hexane three times. The combined organic layers
were washed with brine, dried over Na SO , and concentrated in
1
3
C
),
3
3
3
3
2
4
2
2
vacuo. The residue was purified with silica gel column chromatog-
51.9 (CH ), 61.2 (CH ), 105.6 (C), 202.5 (C). IR (neat): 2947,
2 2
E
DOI: 10.1021/acs.joc.9b01589
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2
866, 1794, 1462, 1246, 1103, 1061, 907, 883, 737. HRMS−ESI (m/
3406, 2928, 2866, 1462, 1366, 1153, 1049, 937, 910, 883. HRMS−
+
+
z): [M + Na] calcd for C H NaO Si, 403.2639; found, 403.2639.
ESI (m/z): [M + Na] calcd for C H NaO Si, 407.2952; found,
2
2
40
3
22 45
3
(
2S*,2aS*,4aR*,7aS*,7bR*)-2-Hydroxy-2a-triisopropylsilyloxy-
,6,7b-trimethyldecahydrocyclobuta[b]cyclopenta[d]pyran (20).
To a solution of ketone 19 (21 mg, 55 μmol) in dry CH Cl (1.0
407.2956.
(22b) R 0.56 (hexane/AcOEt = 3:1).
6
f
1
2
2
H NMR: 1.02 (s, 3H), 1.05−1.07 (m, 24H), 1.21 (dd, J = 5.5,
mL) was added diisobutylaluminum hydride (1.0 M in toluene, 0.067
mL, 67 μmol) at −78 °C. After stirring for 2 h at the same
temperature, the reaction mixture was quenched with MeOH and
saturated aqueous potassium sodium tartrate and extracted with
AcOEt three times. The combined organic layers were washed with
brine, dried over Na SO , and concentrated in vacuo. The residue was
13.0 Hz, 1H), 1.26 (s, 3H), 1.27 (dd, J = 7.5, 11.5 Hz, 1H), 1.34 (dd,
J = 12.5, 12.5 Hz, 1H), 1.46 (dd, J = 6.5, 12.5 Hz, 1H), 1.60 (dd, J =
8.5, 13.0 Hz, 1H), 2.10 (dd, J = 9.0, 11.5 Hz, 1H), 2.21 (ddd, J = 6.5,
7.0, 12.5 Hz, 1H), 2.49 (ddddd, J = 5.5, 6.5, 7.0, 8.5, 9.0 Hz, 1H), 3.00
(br, 2H), 3.44 (dd, J = 6.5, 10.0 Hz, 1H), 3.70 (dd, J = 9.0, 10.0 Hz,
1H), 3.82 (d, J = 5.5 Hz, 1H), 4.02 (ddd, J = 5.5, 7.5, 9.0 Hz, 1H).
2
4
1
3
purified with silica gel column chromatography (hexane/AcOEt =
C NMR: 12.0 (CH), 17.9 (CH ), 26.1 (CH ), 30.2 (CH ), 31.3
3 3 3
5
0:1−20:1) to afford 20 (21 mg, 98%) as a white solid.
(
CH ), 35.7 (C), 37.8 (C), 39.3 (CH ), 42.7 (CH ), 43.5 (CH), 44.0
3
2
2
R 0.48 (hexane/AcOEt = 10:1).
(CH), 44.4 (CH ), 63.9 (CH ), 71.2 (CH), 84.4 (CH). IR (neat):
f
2 2
1
H NMR: 0.96 (s, 3H), 1.02 (dd, J = 2.5, 13.5 Hz, 1H), 1.03 (s,
3
391, 2924, 2866, 1462, 1365, 1169, 1092, 1069, 910, 737. HRMS−
+
H), 1.07−1.17 (m, 21H), 1.23 (s, 3H), 1.36 (dd, J = 0.5, 12.0 Hz,
ESI (m/z): [M + Na] calcd for C H NaO Si, 407.2952; found,
2
2
44
3
407.2948.
(
dd, J = 6.0, 12.0 Hz, 1H), 1.99 (td, J = 10.0, 7.0 Hz, 1H), 2.10 (d, J =
(1S*,2R*,3R*)-2-{(1′S*,2′R*)-2-Hydroxymethyl-4,4-dimethylcy-
clopentyl}-3-methyl-2-(triisopropylsilyloxy)cyclobutan-1-ol (23).
To a solution of ketone 19 (1.40 g, 3.7 mmol) in EtOH (75 mL)
4
.0 Hz, 1H), 2.26 (tddd, J = 8.5, 2.5, 7.0, 8.5 Hz, 1H), 3.35 (d, J = 8.5
1
3
Hz, 2H), 3.99 (ddd, J = 0.5, 4.0, 6.0 Hz, 1H). C NMR: 13.1 (CH),
8.1 (CH ), 23.0 (CH ), 31.0 (CH ), 31.5 (CH ), 35.9 (CH), 36.7
1
was added NaBH (696 mg, 18 mmol) at room temperature. After
3
3
3
3
4
(
(
1
C), 36.9 (CH ), 42.4 (CH ), 42.5 (CH ), 44.4 (C), 44.5 (CH), 62.8
stirring for 10 h at 50 °C (oil bath), the reaction mixture was
2
2
2
CH ), 74.4 (CH), 97.6 (C). IR (neat): 3464, 2943, 2866, 1462,
quenched with H O and extracted with Et O three times. The
2
2
2
+
230, 1177, 1061, 883. HRMS−ESI (m/z): [M + Na] calcd for
combined organic layers were washed with brine, dried over Na SO ,
2 4
C H NaO Si, 405.2795; found, 405.2796. mp: 64−66 °C.
and concentrated in vacuo. The residue was purified with silica gel
column chromatography (hexane/AcOEt = 20:1−10:1−3:1) to afford
a mixture of 22a and 22b (709 mg, 50%, dr = 78:22) and 23 (212 mg,
15%) as a colorless oil.
22
42
3
(
2S*,2aS*,4aR*,7aS*,7bR*)-2a-Hydroxy-2-triisopropylsilyloxy-
6
,6,7b-trimethyldecahydrocyclobuta[b]cyclopenta[d]pyran (21).
To a suspension of NaH (60% suspension in oil, 314 mg, 7.8
mmol) in dry THF (30 mL) was slowly added a solution of 20 (1.5 g,
(23) R 0.36 (hexane/AcOEt = 3:1).
f
1
3
.9 mmol) in dry THF (10 mL) at 0 °C. After stirring for 3 h at room
H NMR: 1.02 (s, 3H), 1.07−1.14 (m, 24H), 1.29 (s, 3H), 1.42−
temperature, the reaction mixture was quenched with saturated
1.45 (m, 3H), 1.57 (dd, J = 8.0, 14.0 Hz, 1H), 1.64 (d, J = 13.5 Hz,
1H), 1.98 (dd, J = 5.5, 12.5 Hz, 1H), 2.08−2.13 (m, 1H), 2.18−2.25
(m, 1H), 2.88 (br, 1H), 3.27 (dd, J = 10.5, 10.5 Hz, 1H), 3.59 (dd, J =
aqueous NH Cl and extracted three times with AcOEt. The combined
organic layers were washed with brine, dried over Na SO , and
concentrated in vacuo. The residue was purified with silica gel column
chromatography (hexane/AcOEt = 20:1) to afford 21 (1.46 g, 97%)
as a colorless oil.
4
2
4
1
3
4.0, 10.5 Hz, 1H), 4.12−4.16 (m, 2H). C NMR: 12.0 (CH), 17.8
(CH ), 21.7 (CH ), 31.8 (CH ), 32.4 (CH ), 34.9 (CH ), 36.6 (C),
3
3
3
3
2
41.6 (CH ), 42.9 (CH ), 44.2 (CH), 45.5 (C), 49.1 (CH), 62.8
2
2
R 0.48 (hexane/AcOEt = 10:1).
(CH ), 67.4 (CH), 71.5 (CH). IR (neat): 3387, 2866, 1462, 1381,
f
2
1
H NMR: 0.97 (s, 3H), 1.01 (dd, J = 4.5, 13.5 Hz, 1H), 1.04−1.14
1165, 1138, 1103, 1057, 1030, 910, 883. HRMS−ESI (m/z): [M +
+
(m, 24H), 1.20 (s, 3H), 1.37 (dd, J = 2.0, 11.5 Hz, 1H), 1.42−1.50
(m, 2H), 1.56 (dd, J = 8.0, 13.5 Hz, 1H), 2.01−2.07 (m, 2H), 2.33
(ddddd, J = 4.5, 6.0, 7.5, 8.0, 11.5 Hz, 1H), 3.44 (dd, J = 11.5, 11.5
Na] calcd for C H NaO Si, 407.2952; found, 407.2949.
2
2
44
3
(1S*,2S*)-4,4-Dimethyl-2-{(1′R*,3′S*)-1-methyl-2-oxo-3-
(triisopropylsilyloxy)cyclobutyl}cyclopentane-1-carbaldehyde (24).
Hz, 1H), 3.51 (dd, J = 6.0, 11.5 Hz, 1H), 3.58 (s, 1H), 4.07 (dd, J =
(Swern method) To a solution of (COCl) (0.19 mL, 2.2 mmol) in
2
1
3
2
3
.0, 6.5 Hz, 1H). C NMR: 11.8 (CH), 17.8 (CH ), 21.6 (CH ),
CH
mL, 3.3 mmol) in CH
min, to the mixture was added a solution of 22 (214 mg, 0.56 mol) in
CH Cl (0.50 mL) at the same temperature. After the mixture was
2
Cl
2
(10 mL) was added a solution of dimethyl sulfoxide (0.24
3
3
0.5 (CH ), 31.0 (CH ), 36.6 (CH), 37.2 (C), 39.1 (CH ), 42.0
Cl (5.0 mL) at −78 °C. After stirring for 3
2
2
3
3
2
(
9
CH ), 42.2 (C), 42.3 (CH ), 43.9 (CH), 63.6 (CH ), 73.4 (CH),
2
2
2
7.0 (C). IR (neat): 3564, 2943, 2866, 1462, 1157. HRMS−ESI (m/
2
2
+
z): [M + Na] calcd for C H NaO Si, 405.2795; found, 405.2793.
stirred for 1 h, triethylamine (0.93 mL, 6.7 mmol) was added at −78
°C. After stirring for 6 h at room temperature, the mixture was
quenched with water and extracted with hexane three times. The
combined organic layers were washed with brine, dried over Na SO ,
2
2
42
3
(
1R*,2R*,4S*)-2-{(1′S*,2′R*)-2-Hydroxymethyl-4,4-dimethylcy-
clopentyl}-2-methyl-4-(triisopropylsilyloxy)cyclobutan-1-ol (22a)
and Its 1S* Isomer (22b). To a solution of 21 (500 mg, 1.3
2
4
mmol) in THF (25 mL) was added a solution of LiBH (3.0 M in
and concentrated in vacuo. A crude mixture of aldehyde 24 was
obtained as a pale yellow oil, which was used in the next reaction
giving 25a without further purification.
4
THF, 1.3 mL, 3.9 mmol) at −15 °C. After stirring for 3 h at 0 °C, the
reaction mixture was quenched with saturated aqueous NH Cl and
4
extracted with AcOEt three times. The combined organic layers were
washed with brine, dried over Na SO , and concentrated in vacuo.
(Alternative method, the Corey−Kim method) To a solution of N-
chlorosuccinimide (28 mg, 0.21 mmol) in toluene (0.50 mL) was
added dimethyl sulfide (18 μL, 0.25 mmol) at −20 °C, and the
resulting mixture was stirred for 35 min at the same temperature. To
this was added a solution of a mixture of 22a and 22b (20 mg, 53
μmol) in toluene (0.50 mL) at −20 °C. After the mixture was stirred
for 40 min, triethylamine (58 μL, 0.42 mmol) was added. After
stirring for 1 h at 0 °C, the mixture was quenched with water and
extracted with hexane three times. The combined organic layers were
washed with brine, dried over Na SO , and concentrated in vacuo. A
2
4
The residue was purified with silica gel column chromatography
(
hexane/AcOEt = 10:1−3:1) to afford a mixture of 22a and 22b (460
mg, 92%, dr = 95:5) as a colorless oil. 22a and 22b could be isolated
by PTLC.
(
22a) R 0.60 (hexane/AcOEt = 3:1).
f
1
H NMR: 1.00 (s, 3H), 1.05−1.14 (m, 24H), 1.24 (s, 3H), 1.33
dd, J = 12.0, 12.5 Hz, 1H), 1.39 (dd, J = 6.0, 13.0 Hz, 1H), 1.44 (dd,
(
J = 7.0, 12.5 Hz, 1H), 1.47 (dd, J = 1.5, 12.5 Hz, 1H), 1.54 (dd, J =
2
4
7
7
.5, 13.0 Hz, 1H), 1.92 (dd, J = 6.0, 12.5 Hz, 1H), 2.17 (ddd, J = 7.0,
.5, 12.0 Hz, 1H), 2.33 (ddddd, J = 6.0, 6.5, 7.5, 7.5, 8.5 Hz, 1H), 3.10
crude mixture of 24 was obtained as a pale yellow oil, which was used
for the preparation of 25b and 25d without further purification.
1
(br, 1H), 3.37 (dd, J = 8.5, 11.0 Hz, 1H), 3.72 (dd, J = 6.5, 11.0 Hz,
H NMR: 1.02 (s, 3H), 1.04−1.14 (m, 21H), 1.17 (s, 3H), 1.30
1
H), 3.96 (d, J = 6.0 Hz, 1H), 4.39 (ddd, J = 1.5, 6.0, 7.5 Hz, 1H).
(dd, J = 7.0, 12.0 Hz, 1H), 1.33 (dd, J = 12.0, 12.5 Hz, 1H), 1.38 (s,
3H), 1.56 (ddd, J = 0.5, 8.5, 14.0 Hz, 1H), 1.74 (dd, J = 7.0, 12.0 Hz,
1H), 1.91 (dd, J = 4.5, 14.0 Hz, 1H), 2.42 (dd, J = 10.0, 12.0 Hz, 1H),
2.54 (ddd, J = 7.0, 8.5, 12.5 Hz, 1H), 3.01 (dddd, J = 3.0, 4.5, 8.5, 8.5
1
3
C NMR: 11.8 (CH), 17.8 (CH ), 18.9 (CH ), 30.7 (CH ), 31.4
3
3
3
(
4
CH ), 36.5 (C), 39.4 (CH ), 41.7 (CH ), 44.2 (CH ), 44.5 (CH),
3 2 2 2
5.3 (C), 49.9 (CH), 63.4 (CH ), 68.0 (CH), 72.3 (CH). IR (neat):
2
F
DOI: 10.1021/acs.joc.9b01589
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Hz, 1H), 4.81 (dd, J = 7.0, 10.0 Hz, 1H), 9.84 (d, J = 3.0 Hz, 1H). 13
C
1
H NMR: 1.04−1.13 (m, 24H), 1.17 (s, 3H), 1.26 (s, 3H), 1.40−
NMR: 11.9 (CH), 17.7 (CH ), 22.1 (CH ), 30.1 (CH ), 30.2 (CH ),
1.50 (m, 3H), 1.67 (dd, J = 7.0, 11.5 Hz, 1H), 1.81 (dd, J = 7.0, 13.5
Hz, 1H), 2.36−2.43 (m, 1H), 2.46 (dd, J = 10.0, 11.5 Hz, 1H), 3.06−
3.12 (m, 1H), 4.82 (dd, J = 7.0, 10.0 Hz, 1H), 6.07 (dd, J = 8.0, 15.5
Hz, 1H), 6.95 (dd, J = 9.5, 15.5 Hz, 1H), 9.55 (d, J = 8.0 Hz, 1H).
NMR: 11.9 (CH), 17.7 (CH ), 21.7 (CH ), 30.4 (CH ), 31.2 (CH ),
36.3 (CH ), 37.5 (C), 42.7 (CH ), 45.1 (CH), 46.5 (CH ), 46.8
(CH), 59.0 (C), 80.7 (CH), 132.1 (CH), 159.4 (CH), 193.8 (CH),
213.5 (C). IR (neat): 2947, 2866, 1782, 1690, 1462, 1177, 995.
HRMS−ESI (m/z): [M + Na] calcd for C H NaO Si, 429.2795;
found, 429.2793.
3
3
3
3
3
6.3 (CH ), 37.9 (C), 39.5 (CH ), 43.1 (CH ), 46.7 (CH), 53.5
2 2 2
(
CH), 58.3 (C), 80.4 (CH), 203.5 (CH), 213.0 (C).
Ethyl (E)-3-[(1S*,2S*)-4,4-Dimethyl-2-{(1′R*,3′S*)-1-methyl-2-
1
3
C
oxo-3-(triisopropylsilyloxy)cyclobutyl}cyclopentyl]acrylate (25a).
To a suspension of NaH (60% suspension in oil, 20 mg, 0.50
mmol) in dry toluene (5.0 mL) was added triethyl phosphonoacetate
3
3
3
3
2
2
2
(0.1 mL, 0.5 mmol) in dry toluene (0.50 mL) at 0 °C. After stirring
+
for 30 min at room temperature, the resulting mixture was turned to a
colorless solution (solution A). To a solution of the crude of 24 in dry
toluene (0.50 mL) was added solution A (2.6 mL) at room
temperature. After stirring for 1 h at the same temperature, the
2
4
42
3
(S)-Ethyl (E)-3-[(1S*,2S*)-4,4-Dimethyl-2-{(1′R*,3′S*)-1-methyl-
2-oxo-3-(triisopropylsilyloxy)cyclobutyl}cyclopentyl]prop-2-ene-
thioate (25d). Starting from 22 (2.4 g, 6.3 mmol as a mixture of 22a
mixture was quenched with saturated aqueous NH Cl and extracted
4
22
and 22b in a 92:8 ratio) and (EtO) POCH COSEt (1.6 g, 6.6
with hexane three times. The combined organic layers were washed
with brine, dried over Na SO , and concentrated in vacuo. The
2
2
mmol), 25d was prepared according to the same procedure as the
synthesis of 25a. The crude residue of 25d was purified by silica gel
column chromatography (hexane/AcOEt = 40:1−20:1) to afford 25d
2
4
residue was purified with silica gel column chromatography (hexane/
AcOEt = 20:1) to afford 25a (186 mg, 78% from 22) as a colorless
(
2.27 g, 78% from 22) as a white solid.
oil.1
R 0.50 (hexane/AcOEt = 10:1).
H NMR: 1.01 (s, 3H), 1.03−1.14 (m, 21H), 1.16 (s, 3H), 1.27 (s,
f
1
H NMR: 1.02 (s, 3H), 1.04−1.13 (m, 21H), 1.16 (s, 3H), 1.26 (s,
3
1
1
1
7
1
1
3
H), 1.28−1.31 (m, 4H), 1.42 (dd, J =3.5, 14.0 Hz, 1H), 1.46 (dd, J =
2.0, 12.0 Hz, 1H), 1.67 (dd, J = 7.0, 12.0 Hz, 1H), 1.76 (dd, J = 8.0,
4.0 Hz, 1H), 2.29 (ddd, J = 6.5, 8.0, 12.0 Hz, 1H), 2.52 (dd, J = 10.0,
2.0 Hz, 1H), 2.94 (dddd, J = 3.5, 6.5, 8.0, 10.5 Hz, 1H), 4.18 (qd, J =
.0, 11.0 Hz, 1H), 4.22 (qd, J = 7.0, 11.0 Hz, 1H), 4.77 (dd, J = 7.0,
3
(
1
H), 1.29 (t, J = 7.5 Hz, 3H), 1.31 (dd, J = 7.0, 12.5 Hz, 1H), 1.43
dd, J = 3.5, 14.0 Hz, 1H), 1.46 (t, J = 12.5 Hz, 1H), 1.68 (dd, J = 7.0,
2.5 Hz, 1H), 1.77 (dd, J = 8.0, 14.0 Hz, 1H), 2.31 (td, J = 7.0, 12.5
Hz, 1H), 2.51 (dd, J = 10.0, 12.5 Hz, 1H), 2.91 (dddd, J = 3.5, 7.0,
.0, 10.5 Hz, 1H), 2.95 (qd, J = 7.5, 15.5 Hz, 1H), 2.97 (qd, J = 7.5,
15.5 Hz, 1H), 4.77 (dd, J = 7.0, 12.0 Hz, 1H), 6.04 (d, J = 15.5 Hz,
H), 6.89 (dd, J = 10.5, 15.5 Hz, 1H). C NMR: 11.9 (CH), 14.7
CH ), 17.8 (CH ), 22.2 (CH ), 23.1 (CH ), 30.7 (CH ), 31.4
CH ), 35.8 (CH ), 37.6 (C), 42.7 (CH ), 44.6 (CH), 46.2 (CH ),
6.7 (CH), 58.7 (C), 80.9 (C), 128.0 (CH), 146.0 (CH), 189.9 (C),
214.0 (C). IR (neat): 2943, 1782, 1667, 1462, 1173, 995. HRMS−
ESI (m/z): [M + Na] calcd for C H NaO SSi, 489.2829; found,
8
0.0 Hz, 1H), 5.76 (d, J = 15.5 Hz, 1H), 6.97 (dd, J = 10.5, 15.5 Hz,
H). 13C NMR: 11.9 (CH), 14.2 (CH ), 17.7 (CH ), 22.2 (CH ),
3
3
3
13
1
0.8 (CH ), 31.4 (CH ), 35.7 (CH ), 37.5 (C), 42.7 (CH ), 44.6
3
3
2
2
(
(
4
3
3
3
2
3
(
CH), 46.4 (CH ), 46.5 (CH), 58.7 (C), 60.3 (CH ), 80.9 (CH),
2
2
3
2
2
2
1
1
20.6 (CH), 150.0 (CH), 166.5 (C), 214.1 (C). IR (neat): 2947,
782, 1716, 1466, 1261, 1157, 995, 760. HRMS−fast atom
+
bombardment (m/z): [M + H] calcd for C H O Si, 451.3238;
2
6
47
4
+
2
6
46
3
found, 451.3244.
E)-3-[(1S*,2S*)-4,4-Dimethyl-2-{(1′R*,3′S*)-1-methyl-2-oxo-3-
triisopropylsilyloxy)cyclobutyl}cyclopentyl]acrylonitrile (25b).
4
89.2827. mp: 118−121 °C.
(
(
S)-Ethyl (2S*,2aS*,4aS*,7aS*,7bR*)-2a-Hydroxy-6,6,7b-tri-
(
21
methyl-2-triisopropylsilyloxy-2,2a,4a,5,6,7,7a,7b-octahydro-1H-
Starting from 22 (20 mg, 53 μmol) and (EtO) POCH CN (9.0
2
2
cyclobuta[e]indene-3-carbothioate (26d). Thioester 25d (500 mg,
mg, 50 μmol), 25b was prepared according to the same procedure as
the synthesis of 25a. The crude residue of 25b was purified by silica
gel column chromatography (hexane/AcOEt = 40:1−20:1) to afford
1
.1 mmol) was dissolved in Me P (0.50 mL, 4.8 mmol) at room
3
temperature. The mixture was stirred for 10.5 h at the same
temperature. The mixture was concentrated in vacuo to give the
residue, which was purified with silica gel column chromatography
hexane/AcOEt = 40:1−20:1) to afford 26d (346 mg, 69%) as a
colorless oil.
2
5b (8.0 mg, 38% from 22) as a colorless oil.
R 0.32 (hexane/AcOEt = 10:1).
f
(
1
H NMR: 1.02 (s, 3H), 1.04−1.13 (m, 21H), 1.15 (s, 3H), 1.25 (s,
3
=
=
H), 1.31−1.42 (m, 3H), 1.72 (dd, J = 7.0, 12.0 Hz, 1H), 1.78 (dd, J
R 0.64 (hexane/AcOEt = 10:1).
f
8.0, 14.0 Hz, 1H), 2.32 (ddd, J = 6.5, 7.0, 12.5 Hz, 1H), 2.44 (dd, J
10.0, 12.0 Hz, 1H), 2.89−2.95 (m, 1H), 4.80 (dd, J = 7.0, 10.0 Hz,
1
H NMR: 1.00 (s, 3H), 1.05−1.11 (m, 21H), 1.13−1.20 (m, 3H),
1
1
(
=
.25 (t, J = 7.5 Hz, 3H), 1.28 (s, 3H), 1.33 (dd, J = 12.5, 13.0 Hz,
H), 1.42 (dd, J = 7.0, 13.0 Hz, 1H), 1.43 (d, J = 13.0 Hz, 1H), 1.58
dd, J = 1.5, 13.5 Hz, 1H), 1.82 (dd, J = 5.5, 13.5 Hz, 1H), 1.87 (dd, J
8.5, 13.5 Hz, 1H), 2.00 (td, J = 7.0, 12.5 Hz, 1H), 2.67 (tdd, J = 1.5,
.0, 8.5 Hz, 1H), 2.86 (qd, J = 7.5, 13.5 Hz, 1H), 2.92 (qd, J = 7.5,
13.5 Hz, 1H), 3.54 (s, 1H, OH), 4.32 (d, J = 5.5 Hz, 1H), 6.58 (d, J =
.5 Hz, 1H). C NMR: 12.0 (CH), 14.5 (CH ), 17.9 (CH ), 22.3
CH ), 23.2 (CH ), 31.76 (CH ), 31.85 (CH ), 36.9 (CH ), 37.7
C), 39.2 (CH), 41.8 (CH ), 44.2 (C), 44.7 (CH), 47.4 (CH ), 71.1
1
3
1H), 5.30 (d, J = 16.0 Hz, 1H), 6.77 (dd, J = 10.5, 16.0 Hz, 1H). C
NMR: 11.9, 17.7, 18.0, 21.8, 30.5, 31.3, 36.0, 37.5, 42.5, 45.9, 46.2,
4
2
6.6, 58.6, 80.9, 99.1, 117.4, 156.8, 213.3. IR (neat): 2947, 2866,
222, 1782, 1462, 1176, 995. HRMS−ESI (m/z): [M + Na] calcd
+
7
for C H NNaO Si, 426.2799; found, 426.2797.
24
41
2
(
E)-3-[(1S*,2S*)-4,4-Dimethyl-2-{(1′R*,3′S*)-1-methyl-2-oxo-3-
triisopropylsilyloxy)cyclobutyl}cyclopentyl]acrolein (25c). To a
solution of ester 25a (264 mg, 0.59 mmol) in dry CH Cl (5.0
13
1
3 3
(
(
(
(
3 2 3 3 2
2
2
2
2
mL) was added diisobutylaluminum hydride (1.0 M in toluene, 2.9
mL, 2.9 mmol) at −78 °C. The mixture was stirred for 1 h at the same
temperature and then quenched with MeOH and saturated aqueous
potassium sodium tartrate. The mixture was extracted with AcOEt
three times. The combined organic layers were washed with brine,
dried over Na SO , and concentrated in vacuo to give a crude product
C), 74.2 (CH), 139.7 (C), 142.1 (CH), 193.2 (C). IR (neat): 3526+,
2
943, 2866, 1670, 1462, 1145, 880. HRMS−ESI (m/z): [M + Na]
calcd for C H NaO SSi, 489.2829; found, 489.2828.
2
6
46
3
(
2S*,2aS*,4aS*,7aS*,7bR*)-2a-Hydroxy-6,6,7b-trimethyl-2-trii-
sopropylsilyloxy-2,2a,4a,5,6,7,7a,7b-octahydro-1H-cyclobuta[e]-
2
4
indene-3-carbaldehyde (26c). Aldehyde 25c (166 mg, 0.41 mmol)
of the corresponding diol, which was used in the next reaction without
further purification. To a solution of the crude diol in dimethyl
sulfoxide (6.0 mL) was added 2-iodoxybenzoic acid (492 mg, 1.76
mmol) at room temperature. After stirring for 2.5 h at the same
temperature, the mixture was quenched with water and extracted with
hexane three times. The combined organic layers were washed with
brine, dried over Na SO , and concentrated in vacuo. The residue was
was dissolved in Me P (0.40 mL, 3.9 mmol) at room temperature.
3
The mixture was stirred for 1 h at the same temperature. The mixture
was concentrated in vacuo to give the residue, which was purified with
silica gel column chromatography (hexane/AcOEt = 20:1) to afford
26c (103 mg, 62%) as a colorless oil.
R 0.44 (hexane/AcOEt 10:1).
f
1
H NMR: 0.99 (s, 3H), 1.00 (s, 3H), 1.07−1.16 (m, 21H), 1.27
2
4
purified with silica gel column chromatography (hexane/AcOEt =
(dd, J = 12.5, 12.5 Hz, 1H), 1.32 (s, 3H), 1.43 (dd, J = 6.5, 12.5 Hz,
1H), 1.47 (d, J = 12.5 Hz, 1H), 1.59 (dd, J = 2.5, 13.0 Hz, 1H), 1.79
(dd, J = 5.5, 12.5 Hz, 1H), 1.95 (dd, J = 9.0, 13.0 Hz, 1H), 2.07 (ddd,
2
0:1) to afford 25c (166 mg, 70% from 25a) as a colorless oil.
Rf 0.56 (hexane/AcOEt = 3:1).
G
DOI: 10.1021/acs.joc.9b01589
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mixture was quenched with saturated aqueous NaHCO and extracted
3
with AcOEt three times. The combined organic layers were washed
with brine, dried over Na SO , and concentrated in vacuo. The
2
4
(
CH ), 31.6 (CH ), 37.1 (CH ), 37.8 (C), 39.6 (CH), 42.0 (CH ),
residue was purified with silica gel column chromatography (hexane/
AcOEt = 3:1) to afford 29 (291 mg, 68%) as a white solid.
3
3
2
2
4
1
1
4
3.6 (C), 44.6 (CH), 46.9 (CH ), 70.0 (C), 73.9 (CH), 139.4 (C),
2
53.6 (CH), 193.3 (CH). IR (neat): 3526, 2943, 2866, 1697, 1462,
R 0.28 (hexane/AcOEt = 3:1).
f
+
1
149, 1041. HRMS−ESI (m/z): [M + Na] calcd for C H NaO Si,
H NMR: 1.01 (s, 3H), 1.02 (s, 3H), 1.20 (s, 3H), 1.27−1.33 (m,
5H), 1.45 (dd, J = 7.0, 12.5 Hz, 1H), 1.55 (dd, J = 2.0, 13.5 Hz, 1H),
1.88 (dd, J = 8.5, 11.5 Hz, 1H), 1.92 (dd, J = 9.5, 13.5 Hz, 1H), 2.14
(ddd, J = 7.0, 7.5, 12.5 Hz, 1H), 2.63 (br, 1H, OH), 2.86 (tdd, J = 2.0,
7.5, 9.5 Hz, 1H), 2.94 (qd, J = 7.5, 13.5 Hz, 1H), 2.97 (qd, J = 7.5,
13.5 Hz, 1H), 3.80 (br, 1H, OH), 4.41 (t, J = 8.5 Hz, 1H), 6.98 (d, J
2
4
42
3
29.2801; found, 429.2802.
S-Ethyl (2S*,2aS*,4aS*,7aS*,7bR*)-2,2a-Dihydroxy-6,6,7b-tri-
methyl-2,2a,4a,5,6,7,7a,7b-octahydro-1H-cyclobuta[e]indene-3-
carbothioate (27). To a solution of 26d (200 mg, 0.43 mmol) in
THF (10 mL) were added NH F (36 mg, 0.97 mmol) and tetra-n-
butylammonium fluoride (1.0 M in THF, 0.77 mL, 0.77 mmol) at 0
4
1
3
= 2.0 Hz, 1H). C NMR: 14.5 (CH ), 22.0 (CH ), 23.5 (CH ), 31.2
3 3 2
°
C. The mixture was stirred for 1 h at the same temperature,
quenched with saturated aqueous NH Cl, and extracted with AcOEt
(CH ), 31.6 (CH ), 34.5 (CH ), 36.7 (C), 37.8 (C), 39.7 (CH), 41.7
3 3 2
4
(CH ), 43.8 (CH), 46.8 (CH ), 76.1 (CH), 136.1 (C), 145.9 (CH),
2
2
three times. The combined organic layers were washed with brine,
dried over Na SO , and concentrated in vacuo. The residue was
purified with silica gel column chromatography (hexane/AcOEt =
198.1 (C). IR (neat): 3449, 2947, 2866, 1643, 1447, 1377, 1204,
+
2
4
1080, 980, 768. HRMS−ESI (m/z): [M + Na] calcd for
C H NaO S, 333.1495; found, 333.1498. mp: 80−82 °C.
1
7
26
3
5
:1−3:1) to afford 27 (120 mg, 91%) as a white solid.
X-ray crystallographic analysis (CCDC 1905934): recrystallization
R 0.40 (hexane/AcOEt = 3:1).
from hot hexane gave colorless platelets suitable for X-ray crystal
structural analysis: triclinic P1; a = 8.372 (6), b = 9.957 (7), c =
f
1
H NMR: 1.00 (s, 3H), 1.02 (s, 3H), 1.28 (t, J = 7.5 Hz, 3H), 1.29
̅
(
1
(
t, J = 12.5 Hz. 1H), 1.31 (s, 3H), 1.44 (dd, J = 7.0, 12.5 Hz, 1H),
.48 (dd, J = 0.5, 13.0 Hz, 1H), 1.58 (dd, J = 1.5, 13.0 Hz, 1H), 1.78
dd, J = 6.0, 13.0 Hz, 1H), 1.92 (dd, J = 9.0, 13.0 Hz, 1H), 2.04 (ddd,
10.205 (6); α = 94.49 (5), β = 102.94 (5), γ = 99.05 (5); V = 813.1
(10), Z = 2, D = 1.27.
x
Compound 30. To a solution of 29 (100 mg, 0.322 mmol) in 1,2-
dichloroethane (2.0 mL) were added DMAP (197 mg, 1.61 mmol),
EDCI·HCl (309 mg, 1.61 mmol), and orsellinic acid (271 mg, 1.61
mmol) at room temperature. After stirring for 25.5 h at 60 °C (oil
bath), the reaction mixture was quenched with saturated aqueous
J = 7.0, 7.5, 12.5 Hz, 1H), 2.76−2.79 (m, 1H), 2.91 (qd, J = 7.5, 13.5
Hz, 1H), 2.95 (qd, J = 7.5, 13.5 Hz, 1H), 3.32 (br, 1H, OH), 3.96−
1
3
3
.98 (m, 1H), 4.18 (s, 1H, OH), 6.84−6.85 (m, 1H). C NMR: 14.5
(
(
(
(
CH ), 22.5 (CH ), 23.3 (CH ), 31.5 (CH ), 31.7 (CH ), 35.7
3 3 2 3 3
CH ), 37.7 (C), 39.6 (CH), 41.9 (CH ), 43.5 (C), 44.5 (CH), 47.1
CH ), 71.2 (C), 73.0 (CH), 138.0 (C), 144.8 (CH), 195.6 (C). IR
neat): 3464, 2943, 1651, 1454, 1138, 910. HRMS−ESI (m/z): [M +
Na] calcd for C H NaO S, 333.1495; found, 333.1497. mp: 108−
NH
4
Cl and extracted with AcOEt three times. The combined organic
SO , and concentrated
2
2
layers were washed with brine, dried over Na
2
2
4
in vacuo. The residue was purified with silica gel column
chromatography (hexane/AcOEt = 3:1), followed by HPLC (YMC
Multiple Preparative HPLC LC-forte/R, YMC-GPC T2000) to afford
30 (94 mg, 62%) as a white solid.
+
17
26
3
1
10 °C.
X-ray crystallographic analysis (CCDC 1905933): recrystallization
from hot hexane gave colorless platelets suitable for X-ray crystal
R 0.76 (hexane/AcOEt = 1:1).
f
1
structural analysis: monoclinic, P2 /c; a = 11.968 (2), b = 12.136 (3),
H NMR: 0.92 (t, J = 7.5 Hz, 3H), 1.00 (s, 3H), 1.01 (s, 3H), 1.32
(s, 3H), 1.35 (dd, J = 12.5, 13.0 Hz, 1H), 1.49 (dd, J = 7.0, 12.5 Hz,
1H), 1.55 (dd, J = 2.5, 13.5 Hz, 1H), 1.66 (dd, J = 9.0, 11.0 Hz, 1H),
1.96 (dd, J = 9.5, 13.5 Hz, 1H), 1.98 (dd, J = 9.0, 11.0 Hz, 1H), 2.23
(ddd, J = 7.0, 7.0, 12.5 Hz, 1H), 2.38 (s, 3H), 2.56 (qd, J = 7.5, 13.5
Hz, 1H), 2.60 (qd, J = 7.5, 13.5 Hz, 1H), 2.92 (dddd, J = 1.5, 2.5, 7.0,
9.5 Hz, 1H), 4.89 (s, 1H, OH), 5.60 (br, 1H, OH), 5.70 (dd, J = 9.0,
9.0 Hz, 1H), 6.16 (d, J = 2.0 Hz, 1H), 6.25 (d, J = 2.0 Hz, 1H), 7.00
1
c = 11.618 (3); β = 95.415 (2); V = 1680.0 (7), Z = 4, D = 1.23.
x
S-Ethyl (2aS*,4aS*,7aS*,7bR*)-2a-Hydroxy-6,6,7b-trimethyl-2-
oxo-2,2a,4a,5,6,7,7a,7b-octahydro-1H-cyclobuta[e]indene-3-car-
bothioate (28). To a solution of N-chlorosuccinimide (123 mg, 0.92
mmol) in toluene (5.0 mL) was added a solution of dimethyl sulfide
(1.0 M in toluene, 1.1 mL, 1.1 mmol) at −20 °C. After the mixture
was stirred for 40 min at the same temperature, to this was added a
solution of 27 (191 mg, 0.62 mmol) in toluene (5.0 mL). After the
resulting mixture was stirred for 40 min, triethylamine (0.26 mL, 1.9
mmol) was added. The mixture was stirred for an additional 1 h at 0
1
3
(d, J = 1.5 Hz, 1H), 11.75 (s, 1H, OH). C NMR: 13.9 (CH ), 21.6
3
(CH ), 23.1 (CH ), 24.4 (CH ), 31.0 (CH ), 31.4 (CH ), 32.3
3
2
3
3
3
(CH ), 37.7 (C), 37.9 (C), 39.6 (CH), 41.7 (CH ), 43.4 (CH), 46.6
2
2
°
C, quenched with water, and extracted with hexane three times. The
(CH ), 76.6 (CH), 76.9 (C), 101.1 (CH), 105.1 (C), 111.3 (CH),
134.4 (C), 144.1 (C), 145.9 (CH), 160.7 (C), 165.4 (C), 170.8 (C),
2
combined organic layers were washed with brine, dried over Na SO ,
2
4
and concentrated in vacuo. The residue was purified with silica gel
column chromatography (hexane/AcOEt = 10:1−5:1) to afford 28
196.2 (C). IR (neat): 3356, 2951, 1651, 1447, 1311, 1257, 1099, 733.
+
HRMS−ESI (m/z): [M + Na] calcd for C25
H32NaO S, 483.1812;
6
(
165 mg, 87%) as a white solid.
found, 483.1809. mp: 190−193 °C.
R 0.40 (hexane/AcOEt = 3:1).
Melleolide (1). To a solution of 30 (20 mg, 43 μmol) in CH
Cl
2
2
f
1
H NMR: 1.05 (s, 3H), 1.06 (s, 3H), 1.22 (s, 3H), 1.28 (t, J = 7.5
(5.0 mL) were added Pd/C (10 wt %, 46 mg, 43 μmol), MgSO
4
(105
Hz, 1H), 1.36 (t, J = 13.0 Hz, 1H), 1.59 (dd, J = 7.0, 13.0 Hz, 1H),
.65 (dd, J = 2.0, 13.5 Hz, 1H), 2.05 (dd, J = 9.5, 13.5 Hz, 1H), 2.41
d, J = 16.0 Hz, 1H), 2.48 (ddd, J = 7.0, 7.5, 13.0 Hz, 1H), 2.79 (d, J
mg, 0.868 mmol), and triethylsilane (35 μL, 0.22 mmol) at room
temperature. After stirring for 1.5 h at the same temperature, the
mixture was filtered through a pad of Celite. The filtered residue was
1
(
=
=
16.0 Hz, 1H), 2.92 (dddd, J = 2.0, 2.5, 7.5, 9.5 Hz, 1H), 2.94 (qd, J
7.5, 13.5 Hz, 1H), 2.97 (qd, J = 7.5, 13.5 Hz, 1H), 4.61 (s, 1H,
washed with Et O several times. The filtrate was concentrated in
2
vacuo to give the residue, which was purified with silica gel column
chromatography (hexane/AcOEt = 3:1) to afford melleolide (1) (15
mg, 88%) as a white solid.
1
3
OH), 7.01 (d, J = 2.5 Hz, 1H). C NMR: 14.5 (CH ), 20.4 (CH ),
3
3
3.4 (CH ), 31.2 (CH ), 31.6 (CH ), 36.5 (C), 38.4 (C), 39.8 (CH),
2 3 3
2.0 (CH), 42.6 (CH ), 46.5 (CH ), 51.7 (CH ), 86.3 (C), 131.9
R 0.16 (hexane/AcOEt = 3:1).
f
2
2
2
1
H NMR: 1.00 (s, 3H), 1.03 (s, 3H), 1.29 (dd, J = 13.0, 13.0 Hz,
1H), 1.33 (s, 3H), 1.50 (dd, J = 7.0, 12.5 Hz, 1H), 1.58 (dd, J = 9.0,
11.5 Hz, 1H), 1.59 (dd, J = 3.0, 13.5 Hz, 1H), 2.02 (dd, J = 9.5, 13.5
Hz, 1H), 2.07 (dd, J = 8.5, 11.5 Hz, 1H), 2.28 (ddd, J = 7.0, 7.0, 13.0
Hz, 1H), 2.28 (s, 3H), 3.03 (dddd, J = 2.0, 3.0, 7.0, 9.5 Hz, 1H), 4.47
(s, 1H, OH), 5.66 (dd, J = 8.5, 9.0 Hz, 1H), 6.14 (d, J = 2.0 Hz, 1H),
6.14 (br, 1H, OH), 6.20 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H),
2
866, 1782, 1636, 1450, 1377, 1173, 1103, 764. HRMS−ESI (m/z):
+
[
M + Na] calcd for C H NaO S, 331.1338; found, 331.1336. mp:
17 24 3
8
3−85 °C.
(
S)-Ethyl (2R*,2aS*,4aS*,7aS*,7bR*)-2,2a-Dihydroxy-6,6,7b-tri-
methyl-2,2a,4a,5,6,7,7a,7b-octahydro-1H-cyclobuta[e]indene-3-
carbothioate (29). To a solution of 28 (426 mg, 1.4 mmol) in
CH Cl (30 mL) was added sodium triacetoxyborohydride (1.5 g, 6.9
1
9.47 (s, 1H), 11.64 (s, 1H, OH). H NMR (CD Cl ): 0.99 (s, 3H),
2
2
2
2
mmol) at 0 °C. After stirring for 7.5 h at room temperature, the
1.02 (s, 3H), 1.26 (dd, J = 13.0, 13.5 Hz, 1H), 1.30 (s, 3H), 1.49 (dd,
H
DOI: 10.1021/acs.joc.9b01589
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
J = 7.0, 13.0 Hz, 1H), 1.59 (dd, J = 2.5, 13.5 Hz, 1H), 1.61 (dd, J =
135.5 (C). IR (neat): 3672, 3279, 2924, 2870, 1717, 1458, 1261,
+
9
1
2
1
1
.0, 11.5 Hz, 1H), 2.02 (dd, J = 9.5, 13.5 Hz, 1H), 2.04 (dd, J = 8.5,
1.5 Hz, 1H), 2.25−2.30 (m, 1H), 2.29 (s, 3H), 3.03 (dddd, J = 2.0,
.5, 7.0, 9.5 Hz, 1H), 4.36 (s, 1H, OH), 5.64 (dd, J = 8.5, 9.0 Hz,
H), 5.76 (s, 1H, OH), 6.16 (d, J = 2.0 Hz, 1H), 6.20 (d, J = 2.0 Hz,
1069. HRMS−ESI (m/z): [M + Na] calcd for C H NaO ,
1
5
24
3
275.1618; found, 275.1617. mp: 155−158 °C. All of the spectral
data except for the melting point were identical to the reported
3a
ones.
1
3
H), 6.83 (d, J = 2.0 Hz, 1H), 9.45 (s, 1H), 11.62 (s, 1H, OH).
C
Melleolide F (31). To a solution of 1 (14 mg, 35 μmol) in MeOH
NMR: 21.2 (CH ), 24.5 (CH ), 31.0 (CH ), 31.5 (CH ), 33.0
(3.0 mL) was added NaBH (4.0 mg, 11 μmol) at room temperature.
3
3
3
3
4
(
(
1
1
CH ), 37.5 (C), 38.0 (C), 40.3 (CH), 41.6 (CH ), 44.0 (CH), 46.5
After stirring for 1 h at the same temperature, the mixture was
2
2
CH ), 75.1 (C), 77.1 (CH), 101.4 (CH), 105.1 (C), 111.3 (CH),
quenched with saturated aqueous NH
three times. The combined organic layers were washed with brine,
dried over Na SO , and concentrated in vacuo. The residue was
Cl and extracted with AcOEt
4
2
37.3 (C), 143.3 (C), 158.7 (CH), 160.6 (C), 165.4 (C), 170.7 (C),
96.1 (CH). 13C NMR (CD Cl ): 21.3 (CH ), 24.7 (CH ), 31.2
2
2
3
3
2
4
(
(
1
CH ), 31.7 (CH ), 33.1 (CH ), 37.8 (C), 38.2 (C), 40.8 (CH), 42.0
purified with silica gel column chromatography (hexane/AcOEt =
1:1) to afford melleolide F (31) (13 mg, 90%) as a white solid.
3
3
2
CH ), 44.4 (CH), 46.8 (CH ), 75.6 (C), 77.5 (CH), 101.5 (CH),
2
2
05.6 (C), 111.5 (CH), 137.7 (C), 144.1 (C), 159.2 (CH), 160.9
R 0.42 (hexane/AcOEt = 1:1).
f
1
(C), 165.9 (C), 171.2 (C), 196.7 (CH). IR (neat): 3371, 2951, 1647,
H NMR (acetone-d ): 0.99 (s, 3H), 1.00 (s, 3H), 1.24 (s, 3H),
6
+
1
447, 1312, 1258, 1096. HRMS−ESI (m/z): [M + Na] calcd for
1.39 (dd, J = 7.0, 12.5 Hz, 1H), 1.47 (dd, J = 12.5, 12.5 Hz, 1H), 1.51
(dd, J = 1.5, 13.0 Hz, 1H), 1.70 (dd, J = 9.0, 11.0 Hz, 1H), 1.87 (dd, J
= 8.5, 13.0 Hz, 1H), 1.94 (dd, J = 8.5, 11.0 Hz, 1H), 2.21 (ddd, J =
7.0, 8.0, 12.5 Hz, 1H), 2.39 (s, 3H), 2.78−2.82 (m, 1H), 4.04 (d, J =
12.5 Hz, 1H), 4.13 (br, 1H, OH), 4.32 (dd, J = 1.0, 12.5 Hz, 1H),
4.92 (br, 1H, OH), 5.64 (dd, J = 8.5, 9.0 Hz, 1H), 5.78 (s, 1H), 6.23
C H NaO , 423.1778; found, 423.1777. mp: 188−190 °C. All of the
observed spectral data were identical to the reported ones (see the
Supporting Information).
23
28
6
4
Echinocidin D (4b). To a suspension of LiAlH (8.0 mg, 0.21
4
mmol) in dry Et O (0.50 mL) was added a solution of 26d (10 mg,
2
1
21 μmol) in Et O (0.50 mL) at 0 °C. After stirring for 5.5 h at room
(d, J = 2.5 Hz, 1H), 6.26 (dd, J = 0.5, 2.5 Hz, 1H). H NMR
2
temperature, the reaction mixture was quenched with saturated
aqueous potassium sodium tartrate and extracted with AcOEt three
times. The combined organic layers were washed with brine, dried
over Na SO , and concentrated in vacuo. The residue was purified
(CD OD): 1.01 (s, 3H), 1.03 (s, 3H), 1.23 (s, 3H), 1.36 (dd, J = 7.5,
3
12.5 Hz, 1H), 1.44 (dd, J = 12.5, 12.5 Hz, 1H), 1.51 (dd, J = 1.5, 13.5
Hz, 1H), 1.70 (dd, J = 9.0, 11.5 Hz, 1H), 1.88 (dd, J = 8.5, 13.5 Hz,
1H), 1.93 (dd, J = 9.0, 11.5 Hz, 1H), 2.19 (ddd, J = 7.0, 7.5, 12.5 Hz,
1H), 2.37 (s, 3H), 2.75−2.78 (m, 1H), 3.97 (d, J = 13.5 Hz, 1H),
4.27 (d, J = 13.5 Hz, 1H), 5.57 (dd, J = 9.0, 9.0 Hz, 1H), 5.76 (s, 1H),
2
4
with silica gel column chromatography (hexane/AcOEt = 1:3) to
afford echinocidin D (4) (4.2 mg, 78%) as a white solid.
1
3
R 0.20 (hexane/AcOEt = 1:3).
6.14 (d, J = 2.5 Hz, 1H), 6.17 (d, J = 2.5 Hz, 1H). C NMR
(CD OD): 22.2 (CH ), 24.3 (CH ), 32.2 (CH ), 32.3 (CH ), 33.7
), 38.9 (C), 39.8 (C), 40.2 (CH), 42.4 (CH ), 45.8 (CH), 48.8
), 49.1 (C), 49.5 (C), 64.2 (CH ), 77.9 (C), 78.9 (CH), 101.7
f
1
H NMR: 0.98 (s, 3H), 1.02 (s, 3H), 1.26 (s, 3H), 1.36 (dd, J =
3
3
3
3
3
1
1
2.5, 13.0 Hz, 1H), 1.38 (dd, J = 6.5, 12.5 Hz, 1H), 1.40 (dd, J = 1.0,
3.0 Hz, 1H), 1.48 (dd, J = 2.0, 13.5 Hz, 1H), 1.82 (dd, J = 9.0, 13.5
(CH
(CH
2
2
2
2
Hz, 1H), 1.84 (dd, J = 6.5, 13.0 Hz, 1H), 1.99 (ddd, J = 6.5, 7.0, 13.0
Hz, 1H), 2.60 (ddd, J = 2.0, 7.0, 9.0 Hz, 1H), 2.94 (br, 1H, OH), 3.23
(CH), 105.7 (CH), 112.5 (CH), 132.6 (CH), 144.7 (C), 163.9 (C),
172.3 (C). IR (neat): 3302, 2951, 1643, 1450, 1315, 1258, 760.
+
(
(
br, 1H, OH), 3.85 (br, 1H, OH), 3.94 (dd, J = 1.0, 6.5 Hz, 1H), 4.07
d, J = 12.0 Hz, 1H), 4.30 (dd, J = 1.0, 12.0 Hz, 1H), 5.60 (d, J = 1.0
HRMS−ESI (m/z): [M + Na] calcd for C23
H30NaO
6
, 425.1935;
1
found, 425.1932. mp: 184−186 °C. H NMR and IR spectral data
were identical to the reported ones.
19
13
Hz, 1H). C NMR: 22.2 (CH ), 31.9 (CH ), 32.0 (CH ), 35.8
3
3
3
(
(
(
7
2
CH ), 37.9, (C), 38.7 (CH), 41.8 (CH ), 44.0 (C), 45.0 (CH), 47.7
2
2
CH ), 65.3 (CH ), 72.7 (C), 73.2 (CH), 134.1 (CH), 134.5 (C). IR
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b01589.
2
2
■
neat): 3395, 2928, 2866, 1450, 1389, 1362, 1192, 1138, 1022, 910,
*
S
+
33. HRMS−ESI (m/z): [M + Na] calcd for C H NaO ,
1
5
24
3
75.1618; found, 275.1616. mp: 87−89 °C. All of the spectral data
3b
except for the melting point were identical to the reported ones.
Echinocidin B (4a). To a suspension of LiAlH (12 mg, 0.32
Stereochemical characterization of 20, comparison of
4
mmol) in dry Et O (0.50 mL) was added a solution of 29 (10 mg, 32
spectral data between isolated natural products and
2
1
13
μmol) in Et O (0.50 mL) at 0 °C. After stirring for 1 h at room
2
synthetic compounds, H NMR and C NMR spectra
of new compounds, and X-ray crystallography (PDF)
Crystallographic data for 27 (CCDC 1905933) (CIF)
Crystallographic data for 29 (CCDC 1905934) (CIF)
temperature, the reaction mixture was quenched with saturated
aqueous potassium sodium tartrate and extracted with AcOEt three
times. The combined organic layers were washed with brine, dried
over Na SO , and concentrated in vacuo. The residue was purified
2
4
with silica gel column chromatography (hexane/AcOEt = 1:3) to
afford echinocidin B (3) (6.0 mg, 78%) as a white solid.
AUTHOR INFORMATION
Corresponding Author
E-mail: kay-t@pharm.kyoto-u.ac.jp. Tel: +81 75 753 4553.
■
*
R 0.08 (hexane/AcOEt = 1:3).
f
1
H NMR: 0.98 (s, 3H), 0.99 (s, 3H), 1.18 (s, 3H), 1.28 (dd, J =
2.5, 12.5 Hz, 1H), 1.34−1.40 (m, 2H), 1.41 (ddd, J = 2.0, 13.0, 13.0
Hz, 1H), 1.81 (dd, J = 8.5, 13.0 Hz, 1H), 1.90 (dd, J = 8.5, 11.0 Hz,
1
Fax: +81 75 753 4604.
1
1
1
1
H), 2.05−2.12 (m,1H), 2.70−2.73 (m, 1H), 4.27 (d, J = 12.0 Hz,
ORCID
H), 4.30 (dd, J = 8.5, 8.5 Hz, 1H), 4.44 (d, J = 12.0 Hz, 1H), 5.68 (s,
Kiyosei Takasu: 0000-0002-1798-7919
Present Address
1
H). H NMR (CD OD): 0.99 (s, 3H), 1.01 (s, 3H), 1.12 (s, 3H),
3
.34 (dd, J = 7.0, 12.5 Hz, 1H), 1.37 (dd, 9.0, 10.5 Hz, 1H), 1.40 (dd,
†
Graduate School of Pharmaceutical Sciences, Tokushima
J = 12.5, 12.5 Hz, 1H), 1.46 (dd, J = 2.0, 13.0 Hz, 1H), 1.75 (dd, J =
University, Shomachi, Tokushima 770-8505, Japan (K.Y.).
Notes
The authors declare no competing financial interest.
8
1
1
1
.5, 10.5, 1H), 1.85 (dd, J = 9.0, 13.0 Hz, 1H), 2.09 (ddd, J = 7.0, 7.0,
2.5 Hz, 1H), 2.70 (dddd, J = 2.0, 2.0, 7.0, 9.0 Hz, 1H), 4.16 (td, J =
.0, 12.5, 1H), 4.24 (dd, J = 8.5, 9.0, 1H), 4.32 (td, J = 1.0, 12.5 Hz,
1
3
H), 5.72−5.73 (m, 1H). C NMR: 21.8 (CH ), 31.7 (CH ), 32.0
3
3
(
(
1
CH ), 35.9 (CH ), 37.1 (C), 38.0 (C), 39.1 (CH), 41.6 (CH ), 44.5
CH), 45.5 (CH ), 65.2 (CH ), 76.4 (CH), 77.7 (C), 133.5 (C),
3
2
2
ACKNOWLEDGMENTS
■
2
2
33.9 (CH). 1 C NMR (CD OD): 22.6 (CH ), 32.2 (CH ), 32.3
3
We thank JSPS KAKENHI Grant Number JP16H05073,
JP19H03350, MEXT KAKENHI Grant Number JP16H01147,
JP18H04406 in Middle Molecular Strategy, and AMED
3
3
3
(
(
CH ), 36.3 (CH ), 38.3 (C), 38.9 (C), 40.3 (CH), 42.6 (CH ), 46.0
CH), 48.7 (CH ), 64.6 (CH ), 76.4 (CH), 78.5 (C), 134.3 (CH),
3
2
2
2
2
I
DOI: 10.1021/acs.joc.9b01589
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Platform for Supporting Drug Discovery and Life Science
Research.
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