A Total Synthesis of (±)-Ceratopicanol via Palladium Catalyzed Reductive Cyclization

Article abstract of DOI:10.1002/ejoc.202000769

An efficient total synthesis of ceratopicanol was achieved through successive Pd catalyzed reductive cycloaddition and cyclization reactions. The Pd mediated cyclization reaction to form a triquinane structure demonstrated that a small structural difference changed the reaction pathway either to form different structures or reduced non-cyclized product depending on the reaction conditions.

Full text of DOI:10.1002/ejoc.202000769

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: A total synthesis of (±)-ceratopicanol via palladium catalyzed
reductive cyclization.
Authors: Rira Kim, Sanghyeon Lee, Jaeyeon Lee, and Hee-Yoon Lee
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000769
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01/2020

10.1002/ejoc.202000769
European Journal of Organic Chemistry
FULL PAPER
A total synthesis of (±)-ceratopicanol via palladium catalyzed
reductive cyclization.
Dr. Rira Kim[a], Sanghyeon Lee[a], Jaeyeon Lee[a], and Prof. Dr. Hee-Yoon Lee*[a]
Abstract: An efficient total synthesis of ceratopicanol was achieved
through successive Pd catalyzed reductive cycloaddition and
cyclization reactions. The Pd mediated cyclization reaction to form a
triquinane structure demonstrated that a small structural difference
changed the reaction pathway either to form different structures or
reduced non-cyclized product depending on the reaction conditions.
olefin meta cycloaddition reaction,[5c] squaric acid mediated oxy-
Cope rearrangement,[5d] free radical mediated cyclizaiton,[5b] and
[3+2] cycloaddition reactions of trimethylenemethanes[5h] were
explored to construct the linearly fused triquinane structure with
contiguous quaternary centers. Among these total syntheses, the
seemingly straightforward strategy using tinhydride mediated free
radical cyclization of the enyne compound A, produced
unanticipated product B without the desired triquinane compound
13.[5b] While formation of B was thought to be via well-established
rearrangement of initially formed desired five-membered ring,6
further study strongly indicated that the cyclization occurred
through endo-cyclic closure to form B directly (Figure 2).
Introduction
Discovery of a novel linearly fused triquinane sesquiterpene, (+)-
ceratopicanol in 1988, afforded crucial key to support the
For the construction of a five-membered ring from the 1-hexen-5-
yne, palladium mediated cyclization reaction[7] is the well-known
alternative to free radical mediated cyclization reaction. Thus, we
envisioned that construction of the framework of ceratopicanol 1
could be feasible via palladium catalyzed reaction from A. The
palladium mediated reductive cyclization of A, could serve not
only as the alternative to free radical cyclization reaction but also
as the test ground for influence of seemingly small structural
change that would generate congested quaternary carbon
centers to the cyclization reaction. Herein, we report similarities
and differences of the Pd mediated cyclization reaction from the
radical mediated cyclization reaction as well as a total synthesis
of ceratopicanol.
biogenetic
mechanism
of
hirsutene
and
associated
sesquiterpenoids synthesized through protoilludane cation
rearrangement from humulene.[1] (Figure 1) In addition, it was
recently reported that ceratopicanol and other terpenes might be
useful for prophylaxis or the treatment of pain,[2] and also its
angelate ester showed moderate antifeedant effect on S.
littoralis.[3]
H
H+
H
H
Humulene
Protoilludane cation
H
Hirsutene
H
H
H
H
Bu
ii) H+
AIBN
H
H
3SnH,
i)
+
H
H
OH
H
B
14
Ceratopicanol (1)
H
Pd(0)
R
iH
3S
,
H
Figure 1. Biogenic origin of ceratopicanol and hirsutene.
A
H
13
Along with biogenetic and pharmacological significances,
ceratopicanol is an intriguing and challenging synthetic target due
to its highly congested structural features4 with unusual five
contiguous chiral centers including two consecutive quaternary
carbons in the linearly fused cis, anti, cis-triquinane framework.
For these reasons, there are eight reports of total synthesis and a
formal synthesis.[5] Elegant synthetic strategies such as arene-
Figure 2. Two complimentary cyclization reactions toward ceratopicanol.
For the synthesis of the substrate A, rather than following the
reported synthetic route[5b] we adopted Pd catalyzed cycloaddition
reaction route that eliminated protection-deprotection steps from
the previous synthetic route to A, since compound A could readily
be prepared from bicyclic ketone C that was the known compound
synthesized from commercially available D via Pd mediated
cycloaddition reaction.[8] (Scheme 1)
[a]
Dr. R. Kim, S. Lee, J. Lee, Prof. Dr. H.-Y. Lee*
Department of Chemistry
Korea Advanced Institute of Science and Technology (KAIST),
Daejeon, 34141, Korea
E-mail: leehy@kaist.ac.kr
Homepage: www.org.kaist.ac.kr
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.202000769
European Journal of Organic Chemistry
FULL PAPER
cat
Pd
of TsOH to afford enyne intermediate A, the precursor for
OH
reductive cyclization reaction.
O
A
O
Ceratopicanol
1
O
PPh3MeBr, tBuOK
DIBAL
OMe
OH
3N,
OMe
PhH, 80oC
90%
CH2Cl2
>99%
O
O
H
9
C
O
10
COOMe
TsCl, Et
DMAP
H
O
D
CH2Cl2
80%
C
Scheme 1. Retrosynthesic analysis of ceratopicanol.
TsOH H O
Li
(cat.)
2
OTs
CH2Cl2
99%
DMSO
90%
A
12
11
Results and Discussion
Scheme 3. Preparation of the cyclization precursor.
The total synthesis started with preparation of the intermediate C
from commercially available 3,3-dimethylglutaric anhydride D
using modified procedures from the literature preparation.[8]
(Scheme 2) 3,3-Dimethylglutaric anhydride was reduced twice to
the lactol 3, and Wittig olefination of the lactol 3 produced the
conjugate ester 4. After oxidation of the alcohol of 4 into the
corresponding aldehyde 5, alkynylation using Ohira-Bestmann
reagent[9] produced the alkyne 6. Reduction of the ester followed
by the carbonate formation produced 8, the precursor for the
palladium catalyzed cycloaddition reaction. Palladium catalyzed
tandem ene-cyclization-carbonylation reaction[7b] produced, after
esterification followed by olefin reduction, C.
When the key cyclization reaction was carried out using
Pd2(dba)3•CHCl3 as the catalyst in the presence of triethylsilane,
acetic acid and tri(o-tolyl) phosphine (TOTP) as the ligand
following the conditions reported by Trost, disappointingly, the
reaction was so sluggish that, even after 12 hours, the starting
material A remained and a simple reduction product, terminal
alkene 14 was observed as the major product along with the
desired cyclization product 13 as a minor product and a mixture
of other nonpolar side products which appeared to be β -
elimination products during cyclization reaction judged by GM/MS.
In the Clive’s radical cyclization of A, formation of the 6-endo
cyclized product B was rationalized by direct 6-endo cyclization
rather than the initial 5-exo cyclic radical product that rapidly
rearranged into the 6-endo product via homoallylic radical
rearrangement[10], since the desired 5-exo cyclization product was
not observed at all. The current result also supports the Clive’s
observation in the free radical cyclization reaction that a structural
uniqueness of diquinane precursor A suppressed the usual exo-
cyclic closure of the vinyl radical generated from A. This bias
appeared to be reflected in the Pd mediated hydrogenative
cycloaddition reaction as well. To understand this abnormal
reactivity of A, a simple computational analysis with Gaussian 09
software package, using B3LYP density functional and the 6-
31G(d) basis set, was run to find a unique structural feature of A
that might prevent 5-exo cyclization reaction. (Scheme 4) The
optimized conformation of A showed that the butynyl chain was
located in a pseudo axial position and thus placed either vinyl
radical or vinyl-Pd complex away from the desired reaction center
for five-membered ring formation. This could explain the
preference of 6-endo cyclization over 5-exo cyclization in the free
radical cyclization and low reactivity of Pd mediated cyclization
toward the five-membered ring formation. When we ran the same
analysis on 12 for comparison, the butynyl chain was positioned
at a pseudo-equatorial position that would not block the 5-exo
cyclization. While free radical mediated cyclization reaction of 12
would still form 6-endo cyclization product through rapid
isomerization of initially formed 5-exo cyclization product through
homoallylic radical rearrangement,[11] Pd mediated cyclization
could produce the desired 5-exo cyclization product. (Scheme 4)
O
O
D
O
O
O
2
HO
O
3
DIBAL
NaBH4 MeOH
,
o
CH2Cl2 -78 C
,
Ph3P
rt
THF,
CO2Et
82%
99%
CH2Cl2 reflux
,
95%
(E:Z=94:6)
O
O
CO2Et
P
OMe
OMe
CO2Et
CO2Et
HO
PCC/Celite
N2
O
MeOH
>99%
CH2Cl2
75%
6
DIBAL
5
4
CH2Cl2
99%
O
MeO2CO
OH
O
PPh
40o
,
i) Pd(dba)2
3
ClCO Me,
CO, AcOH,
C
Pyr.
2
OMe
ii) TMS-CHN2
,
CH2Cl2
91%
MeOH, PhH
60%
iii) H2 Pd/C
,
7
8
C
EtOH, 97%
Scheme 2. Stereoselective synthesis of diquinane intermediate C.
With the diquinane intermediate C in hand, the enyne A, precursor
for the Pd catalyzed reductive cyclization was obtained in five step
sequence. (Scheme 3) The ketone of C was transformed into the
corresponding exocyclic olefin using the Wittig reagent at an
elevated temperature to circumvent the steric hindrance to form
9. The ester group was reduced and was activated as a sulfonate
for the acetylide addition reaction, and the final olefin
isomerization was successfully carried out using catalytic amount
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10.1002/ejoc.202000769
European Journal of Organic Chemistry
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Thus, we turned our attention to the intermediate 12, olefinic
isomer and precursor of A. When the Pd mediated reductive
cyclization was carried out under the same reaction conditions, as
we anticipated, the reaction produced the desired product 13
along with 15 (91:9 by GC/MS) in 90% yield and the reaction was
much faster compared to the reaction of A. The two isomeric
substrates A and 12 with only difference in positions of olefins
provided completely different environment for the cyclization
reactions of butenyl radical and Pd complex with the olefins. The
successful cyclization of 12 into the ceratopicane structure
through 5-exo cyclization was quite noteworthy as the
corresponding free radical cyclization formed six-membered ring
exclusively just like in the case of A.
Furthermore, Pd mediated cyclization and free radical mediated
cyclization of 1,5-hexenyne system are complimentary to each
other to form the same products or alternate products as the major
product.
Experimental Section
General procedures. All oxygen or moisture sensitive reactions
were carried out in oven dried glassware under a positive
pressure of argon. Sensitive liquids and solutions were
transferred by syringe or cannula and were introduced through
rubber septa through which a high flow of inert gas was
maintained. Unless otherwise stated, reactions were carried out
at room temperature. Concentration of solutions was
accomplished using a Büchi rotary evaporator with a water
aspirator. This was generally followed by removal of residual
solvents on a vacuum line held at 0.1-1 torr.
Pd
CHCl3
2(dba)3
H
H
H
H
TOTP, Et3SiH
AcOH
+
PhH, 18hr.
H
H
~20%
:
1
5
A
13
14
(
)
H
H
Pd
CHCl3
2(dba)3
H
TOTP, Et3SiH
AcOH
+
Reagents and solvents. Unless otherwise noted, all reagents
and solvents were used without additional purification. Exceptions
include: chromatography grade hexane and ethyl acetate were
technical grade and distilled before use; Et2O and THF were
distilled from sodium benzophenone ketyl under nitrogen;
triethylamine were distilled from sodium; dichloromethane was
distilled from P2O5. Benzene and toluene were washed with
concentrated sulfuric acid, water and saturated NaHCO3 solution,
and then dried over sodium for more than 12 h before distillation.
Concentration of alkyllithium solutions was determined by titration
against diphenylacetic acid.
PhH, 2hr.
H
H
H
12
90%
13
:
15
91
9
)
(
H
H
H
H
Amin
12min
Scheme 4. Pd mediated cyclization reactions of two isomers.
Finally, 13 was converted into (±)-ceratopicanol 1 through
Chromatography. Analytical thin layer chromatography (TLC)
was performed on Merck precoated Analytical thin layer
chromatography (TLC) was performed on Merck precoated silica
gel 60 F254 plates. Visualization on TLC was achieved by use of
UV light (254 nm), exposure to iodine vapor, or treatment with
acidic anisaldehyde or ceric ammonium molydate stain followed
by heating. Flash column chromatography was carried out using
Merck 60, 230-400 mesh ASTM.
ozonolysis followed by the known ketone reduction[5h]. (Scheme
5)
OH
O
O3 Me S
NaBH4
;
2
MC/MeOH
60%
(1:1)
MeOH
80%
13
16
ceratopicanol
(1)
Scheme 5. Completion of the synthesis of ceratopicanol.
Physical and spectroscopic measurements. Proton-1 nuclear
magnetic resonance spectroscopy (1H NMR) was recorded on
Bruker Avance 400 (400 MHz), Bruker Ascend 400 (400 MHz), or
Agilent Technologies DD2 (600 MHz). Chemical shifts were
reported in δ units, parts per million (ppm) relative to the singlet
as 7.24 ppm for chloroform-d or 7.15 ppm for benzene-d. The
following abbreviations were used to describe peak patterns when
appropriate: b = broad, s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet. Coupling constant, J, was reported in Hertz
unit (Hz). Carbon-13 nuclear magnetic resonance spectroscopy
(13C NMR) was recorded on Bruker Avance 400 (100 MHz),
Bruker Ascend 400 (100 MHz), or Agilent Technologies DD2 (150
MHz) and was fully decoupled by broad-band decoupling.
Chemical shifts were reported in ppm with the centerline of the
triplet for chloroform-d set at 77.00 ppm or benzene-d set at
Conclusions
We accomplished a total synthesis of ceratopicanol in 7 steps
from the known compound C with overall yield 25.8% (10% from
the commercially available starting material). The current total
synthesis demonstrated not only the efficiency of successive Pd
catalyzed cycloaddition and cyclization reactions in the total
synthesis of natural products but also the importance of
conformation of the substrate for cyclization of 1,5-hexenyne
systems as seemingly minor change in substrate structure could
alter the reactivity of the substrate toward Pd mediated enyne
cyclization reaction as well as free radical cyclization of enynes.
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10.1002/ejoc.202000769
European Journal of Organic Chemistry
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128.00 ppm. Mass spectra were obtained on Bruker Daltonik
micrOTOF-Q Ⅱ high resolution mass spectrometer using
electrospray ionization (ESI) method.
(400 MHz, CDCl3) δ 6.82 (tq, J = 7.8, 1.5 Hz, 1H), 4.17 (q, J = 7.1
Hz, 2H), 3.70 (t, J = 7.5 Hz, 3H), 2.09 (dd, J = 7.8, 1.1 Hz, 2H),
1.81 (d, J = 1.2 Hz, 3H), 1.56 (dd, J = 15.5, 7.7 Hz, 4H), 1.28 (t, J
= 7.1 Hz, 3H), 0.94 (s, 6H). Distinctive proton peak of Z isomer:
5.94 (tq, J = 7.8, 1.5 Hz, 1H), 2.39 (dd, J = 7.7, 1.5 Hz, 2H), 1.90
(d, J = 1.4 Hz, 3H), 13C NMR (100 MHz, CDCl3) δ 168.2 , 138.9,
129.1, 60.4, 59.4, 44.2, 41.2, 27.2, 14.2, 12.5. High Resolution
MS (ESI): Calculated for C7H14O2 [M+Na]+: 237.1461, Found:
237.1444
4,4-Dimethyltetrahydro-2H-pyran-2-one (2). To the solvent of
THF (70 mL) and MeOH (5.9 mL, 140.7 mmol, 2 equiv) was added
sodium borohydride (5.32 g, 140.7 mmol, 2 equiv) at 0 °C very
carefully. The mixture was stirred for 20 min, and 3,3-dimethyl
glutaric anhydride (10 g, 70.3 mmol, 1 equiv.) in THF(30 mL) was
carefully moved dropwise into the mixture by cannula at same
temperature. The resulting mixture was allowed to warm to room
temperature and stirred for 3h. After the 3,3-dimethyl glutaric
anhydride disappeared on TLC plate(stained by PMA), the 1N HCl
(68 mL, 210 mmol, 3 equiv) was added very slowly to the mixture
cooled to 0 °C. The reaction mixture was stirred for 3 h at room
temperature, again. Then, it was quenched by saturated sodium
bicarbonate and distilled water, and the aqueous layer was
extracted three times with diethyl ether after addition of brine. The
extracts were dried over MgSO4, filtered and concentrated in
vacuo. The organic residue was purified by flash column
chromatography on silica gel (eluent, Et2O/ Hx 1:1) to give lactone
2 (7.38 g, 82%) as oil. 1H NMR (400 MHz, CDCl3) δ 4.32 (t, J =
Ethyl (E)-2,5,5-trimethyl-7-oxohept-2-enoate (5). To the
solution of alcohol 4 (10 g, 46.6 mmol, 1 equiv) in DCM (100 mL)
was added pyridinium chlorochromate(PCC, 20.9 g, 97 mmol, 2
equiv) and celite (20.9 g) at 0°C. The mixture was warmed to room
temperature and stirred for 2 h. The crude mixture was filtered
with DCM and diethyl ether, and the filtrate was concentrated in
vacuo. The organic residue was purified by flash column
chromatography on silica gel (eluent, EtOAc/ Hexane 1:10) to give
aldehyde 5 (7.41 g, 75%) as oil. 1H NMR (400 MHz, CDCl3) δ 9.81
(t, J = 2.8 Hz, 1H), 6.79 (tq, J = 8.1, 1.6 Hz, 1H), 4.17 (q, J = 7.1
Hz, 2H), 2.29 (d, J = 2.8 Hz, 2H), 2.20 (dd, J = 7.8, 1.0 Hz, 2H),
1.81 (dd, J = 1.6, 0.9 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.09 (s,
6H).13C NMR (100 MHz, CDCl3) δ 202.6, 167.9, 137.2, 130.1,
60.5, 54.5, 41.1, 34.5, 27.4, 14.2, 12.6. High Resolution MS
(ESI): Calculated for C12H20O3 [M+Na]+: 235.1305, Found:
235.1302
6.1 Hz, 1H), 2.27 (s, 1H), 1.65 (t, J = 6.1 Hz, 1H), 1.04 (s, 3H). 13
C
NMR (100 MHz, CDCl3) δ 171.5, 66.5, 44.1, 35.9, 29.7, 28.8. High
Resolution MS (ESI): Calculated for C7H12O2 [M+Na]+: 151.0730,
Found: 151.0727
4,4-Dimethyltetrahydro-2H-pyran-2-ol (3). To a evacuated
lactone 2 (6.6 g, 51.6 mmol, 1 equiv) in DCM(20 mL) was added
diiosbutylaluminum hydride (DIBAL 1M in DCM, 103 mL, 103
mmol, 2 equiv) at -78°C over 1 h. The resulting mixture was stirred
for 2 h at -78°C. To quench the reaction mixture, Rochell salt and
distilled water was added at -78°C and stirred until the cloudy
solution became clear at 0°C. After then, and the aqueous layer
was extracted with diethyl ether and also, ethyl acetate, two times.
The extracts were dried over MgSO4, filtered and concentrated in
vacuo. The organic residue was purified by flash column
chromatography on silica gel (eluent, Et2O/ pentane 2:3) to give
Ethyl (E)-2,5,5-trimethyloct-2-en-7-ynoate (6). To the solution
of aldehyde 4 (3 g, 13.7 mmol, 1equiv) and dimethyl(1-diazo-2-
oxopropyl)-phosphonate(Bestmann reagent, 2.9mL, 19.2 mmol,
1.4 equiv) in MeOH (7 mL) was added potassium carbonate(4.54
g, 32.9 mmol, 2.4 equiv) at 0 oC. The reaction mixture was
warmed to room temperature and stirred for 4 h. Then, it was
quenched by saturated sodium bicarbonate and distilled water,
and the aqueous layer was extracted three times with diethyl ether
after addition of brine. The extracts were dried over MgSO4,
filtered and concentrated in vacuo. The organic residue was
purified by flash column chromatography on silica gel (eluent,
EtOAc/ Hx 1:10) to give alkyne 6 including esterificated byproduct
(ethylester(a) : methylester(b) = 2 : 1, >99%, 2.2 g) as oil. 1H NMR
(400 MHz, CDCl3) δ 6.79 – 6.71 (m, 1H), 4.13 (q, J = 7.1 Hz, 2H),
2.18 – 2.12 (m, 2H), 2.05 (d, J = 2.7 Hz, 2H), 1.96 (t, J = 2.7 Hz,
1H), 1.79 (dq, J = 1.6, 0.8 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 0.96
(s, 6H). Distinctive methyl ester peak: 3.68 (s, 1H), 13C NMR (100
MHz, CDCl3) δ 168.0, 138.2, 129.6, 81.9, 70.3, 60.3, 39.6, 34.5,
31.6, 26.6, 14.2, 12.5. Methyl ester : δ 168.4, 138.6, 129.3, 81.9,
70.3, 51.6, 39.6, 34.5, 30.2, 26.6, 12.5. High Resolution MS
(ESI): Calculated for C13H20O2 [M+Na]+: 231.1356, Found:
231.1331n
1
lactol 3 (6.7 g, >99%) as oil. H NMR (300 MHz, CDCl3) δ 4.87
(dd, J = 8.4, 2.6 Hz, 1H), 4.11 (s, 1H), 3.87 (dt, J = 11.9, 4.2 Hz,
1H), 3.60 (td, J = 11.4, 2.8 Hz, 1H), 1.54 (dt, J = 13.2, 2.1 Hz, 1H),
1.41 (ddd, J = 13.3, 10.8, 4.6 Hz, 1H), 1.28 – 1.15 (m, 2H), 0.97
(s, 3H), 0.95 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 93.1 , 61.3,
44.9, 37.8, 31.6, 29.6, 26.0.
Ethyl (E)-7-hydroxy-2,5,5-trimethylhept-2-enoate (4). To a
solution of lactol 3 (6.7 g, 51.6 mmol, 1 equiv) in DCM (150 mL)
was added 1-Carboethoxy-ethylidenetriphenylphosphorane (23 g,
63 mmol, 1.2 eqiuv). The reaction mixture was stirred for 20 h
under the reflux condition (40°C). After then, water was poured
into the mixture, and the aqueous layer was extracted three times
with dimethylchloride (DCM) after addition of brine. The extracts
were dried over MgSO4, filtered and concentrated in vacuo. The
organic residue was purified by flash column chromatography on
silica gel (eluent, Et2O/ pentane 2:3) to give stereoisomeric
mixture alcohol 4 (10.5 g, 95%) as oil in ratio of 94:6(E:Z). 1H NMR
(E)-2,5,5-Trimethyloct-2-en-7-yn-1-ol (7). To the solution of
alkyne 6 (a and b) (1.23 g, 6.1 mmol, 1 equiv) in diethylether(12
mL) was added DIBAL (1M in DCM, 17 mL, 17 mmol, 2.8 equiv)
at -78 °C carefully. The resulting mixture was stirred for 2 h at
room temperature. To quench the reaction mixture, Rochell salt
and distilled water was added at 0 °C and stirred until the cloudy
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10.1002/ejoc.202000769
European Journal of Organic Chemistry
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solution became clear. After then, and the aqueous layer was
extracted with diethyl ether (Et2O) three times. The extracts were
dried over MgSO4, filtered and concentrated in vacuo. The
organic residue was purified by flash column chromatography on
silica gel (eluent, EtOAc/ hexane 1:10 to 1:5) to give alcohol 7
(1.04 g, >99%) as oil. 1H NMR (400 MHz, CDCl3) δ 5.43 (tq, J =
7.7, 1.4 Hz, 1H), 3.99 (s, 2H), 2.07 – 1.99 (m, 4H), 1.96 (t, J = 2.7
Hz, 1H), 1.67 – 1.61 (m, 3H), 0.94 (s, 6H). 13C NMR (100 MHz,
CDCl3) δ 136.9, 122.0, 82.6, 69.9, 69.0, 38.7, 34.3, 31.3, 26.5,
13.8. High Resolution MS (ESI): Calculated for C11H18O
[M+Na]+: 189.1250, Found: 189.1226
ether, and the filtrate was evacuated in vacuo. The organic
residue was purified by flash column chromatography on silica gel
(eluent, EtOAc/ Hexane 1:20) to afford C (141 mg, 91%) as oil. 1H
NMR (400 MHz, C6D6) δ 3.25 (s, 3H), 2.63 (m, 1H), 2.52 (dd, J =
18.4, 10.2 Hz, 1H), 2.43 (m, 1H), 2.33 – 2.17 (m, 2H), 1.74 (dd, J
= 18.4, 6.6 Hz, 1H), 1.57 (ddd, J = 13.0, 8.1, 1.7 Hz, 1H), 1.24
(ddd, J = 12.7, 7.4, 1.7 Hz, 1H), 1.00 (s, 4H), 0.91 – 0.83 (m, 7H),
0.79 (s, 3H). 13C NMR (100 MHz, C6D6) δ 219.4, 171.1, 51.0, 49.7,
49.4, 49.0, 43.7, 43.6, 42.9, 40.3, 35.1, 29.8, 28.3, 19.6. High
Resolution MS (ESI): Calculated for C14H22O3 [M+Na]+: 261.1461,
Found: 261.1447
(E)-Methyl (2,5,5-trimethyloct-2-en-7-yn-1-yl) carbonate (8).
To a solution of primary alcohol 7 (907 mg, 5.4 mmol, 1 equiv) in
DCM (27 mL) was added pyridine (0.87 mL, 10.8 mmol, 2 equiv)
and methyl choloroformate (0.84 mL, 10.8 mmol, 2 equiv) at 0°C.
The reaction mixture was warmed to temperature and stirred for
2h. The crude mixture was concentrated in vacuo. The organic
residue was purified by flash column chromatography on silica gel
(eluent, EtOAc/ Hexane 1:10) to give allylchloroformate 8 (1.1 g,
91%) as oil. 1H NMR (400 MHz, CDCl3) δ 5.53 (tq, J = 7.8, 1.3 Hz,
1H), 4.52 (s, 2H), 3.76 (s, 3H), 2.08 – 2.01 (m, 4H), 1.96 (t, J =
2.6 Hz, 1H), 1.67 (s, 3H), 0.95 (s, 6H). 13C NMR (100 MHz, CDCl3)
δ 155.7, 131.7, 126.6, 82.4, 73.9, 70.00, 54.7, 38.8, 34.4, 31.4,
26.5, 14.0. High Resolution MS (ESI): Calculated for C13H20O3
[M+Na]+: 247.1305, Found: 247.1272
Methyl 2-(-1,5,5-trimethyl-2-methyleneoctahydropentalen-1-
yl)acetate (9). To a solution of methyltriphenylphosphonium
bromide (525.1 mg, 1.47 mmol, 2.5 equiv), flame dried, in distilled
toluene (3.5 mL) was added potassium tert-butoxide (141.4 mg,
1.26 mmol, 2 equiv). To generate ylide, the mixture was stirred for
30 min under reflux condition (80°C) for about 30 min, appearing
yellow color. After then, the solution was allowed to cool to room
temperature, and a solution of ketone C (147 mg, 0.6 mmol, 1
equiv) in distilled toluene (3.5 mL) was moved into the solution via
cannula. The reaction mixture was stirred for 1h under reflux
condition (at 80°C). Then, it was quenched by saturated
ammonium chloride and distilled water, and the aqueous layer
was extracted three times with ethyl acetate after addition of brine.
The extracts were dried over MgSO4, filtered and concentrated in
vacuo. The organic residue was purified by flash column
chromatography on silica gel (eluent, EtOAc/ Hx 1:30 to 1 : 20) to
give methylene diquinane 9 (128.6 mg, 90%) as oil. 1H NMR (600
MHz, C6D6) δ 4.87 – 4.85 (m, 1H), 4.81 – 4.79 (m, 1H), 3.33 (s,
3H), 2.75 (ddt, J = 15.8, 10.1, 2.6 Hz, 1H), 2.47 – 2.36 (m, 2H),
2.26 (d, J = 13.3 Hz, 1H), 2.18 (d, J = 13.3 Hz, 1H), 1.86 – 1.81
(m, 1H), 1.67 (ddd, J = 12.7, 8.4, 2.3 Hz, 1H), 1.23 (s, 3H), 1.02 –
0.92 (m, 6H), 0.84 (s, 3H). 13C NMR (100 MHz, C6D6) δ 171.3,
157.1, 106.2, 53.7, 50.7, 49.6, 47.1, 46.0, 43.4, 40.18 , 40.16 ,
37.7, 29.4, 27.4, 19.9. High Resolution MS (ESI): Calculated for
C15H24O2 [M+Na]+: 259.1669, Found: 259.1638.
Methyl 2-(1,5,5-trimethyl-2-oxo-1,2,4,5,6,6a- hexahydropental
en-1-yl)acetate (S1). A flask, containing (E)-carbonate 8 (451.6
mg, 2.03 mmol, 1 equiv), Pd(dba)2 (116.7 mg, 0.2 mmol, 0.1
equiv.) and triphenylphosphine (106.5 mg, 0.41 mmol, 0.2 equiv)
was evacuated and then filled with CO gas. After addition of
degassed acetic acid (10 mL), carbon monoxide was bubbled
through the mixture. The reaction mixture was stirred for 21 h
under CO (1 atm) at 40°C. Then, acetic acid was removed under
reduced pressure, and the residue was filtered with ethyl acetate
through celite. The solution was concentrated in vacuo to afford
diastereoisomeric carboxylic acids, followed by treated with TMS-
diazomethane (2 M in ether, 2 mL, 2 equiv) in MeOH (5 mL) and
benzene (5 mL), and stirred for 1 h. The crude mixture was
concentrated in vacuo. The organic residue was purified by flash
column chromatography on silica gel (eluent, EtOAc/ Hexane
1:10) to S1 (288 mg, 60%) as oil. 1H NMR (400 MHz, C6D6) δ 5.68
(s, 1H), 3.25 (s, 3H), 3.18 – 3.10 (m, 1H), 2.63 (d, J = 16.2 Hz,
1H), 2.47 (d, J = 16.2 Hz, 1H), 1.95 (d, J = 18.5 Hz, 1H), 1.83 (d,
J = 18.5 Hz, 1H), 1.50 (dd, J = 12.2, 8.2 Hz, 1H), 1.03 (t, J = 12.2
Hz, 1H), 0.91 (s, 3H), 0.87 (s, 3H), 0.81 (s, 3H). 13C NMR (100
MHz, C6D6) δ 211.4, 186.2, 171.8, 121.7, 55.0, 50.9, 49.2, 42.1,
40.8, 40.4, 40.1, 30.3, 29.9, 20.4. High Resolution MS (ESI):
Calculated for C14H20O3 [M+Na]+: 259.1305, Found: 259.1286
2-(1,5,5-Trimethyl-2-methyleneoctahydropentalen-1-yl )etha
n-1-ol (10). To the solution of methyl acetate 9 (128 mg, 0.54
mmol, 1 equiv) in DCM (5 mL) was added DIBAL (1M in DCM, 1.5
°
mL, 1.5 mmol, 3 equiv) at -78 C carefully. The resulting mixture
was stirred for 2 h at room temperature. To quench the reaction
°
mixture, Rochell salt and distilled water was added at 0 C and
stirred until the cloudy solution became clear. After then, and the
aqueous layer was extracted with ethyl acetate three times. The
extracts were dried over MgSO4, filtered and concentrated in
vacuo. The organic residue was purified by flash column
chromatography on silica gel (eluent, EtOAc/ hexane 1:5) to give
1
alcohol 10 (106.8 mg, 95%) as oil. H NMR (300 MHz, C6D6) δ
4.82 (d, J = 1.7 Hz, 1H), 4.69 (d, J = 1.8 Hz, 1H), 3.46 (t, J = 7.0
Hz, 2H), 2.69 (ddt, J = 15.7, 10.4, 2.6 Hz, 1H), 2.52 – 2.32 (m,
1H), 2.18 (dt, J = 11.6, 7.9 Hz, 1H), 1.78 (dd, J = 15.9, 2.4 Hz,
1H), 1.68 (ddd, J = 12.6, 8.7, 2.3 Hz, 1H), 1.67 – 1.54 (m, 1H),
1.35 (dt, J = 13.6, 6.7 Hz, 2H), 1.17 (ddd, J = 12.2, 7.2, 2.3 Hz,
1H), 0.98 (s, 3H), 0.95 (d, J = 3.8 Hz, 1H), 0.91 (s, 4H), 0.84 (s,
Methyl 2-(1,5,5-trimethyl-2-oxooctahydropentalen-1-yl) aceta
te (C). To a solution of S1 (153.8 mg, 0.65 mmol, 1 equiv) in
ethanol (3.25 mL) was added Pd /C (10%, 76.9 mg). The reaction
mixture was stirred for overnight at room temperature under H2
gas (1 atm). The resulting mixture was filtered through celite with
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3H). 13C NMR (100 MHz, C6D6) δ 158.3, 105.7, 59.9, 54.9, 49.7,
46.6, 44.1, 43.2, 40.5, 40.0, 37.5, 29.3, 27.3, 19.4 High
Resolution MS (ESI): Calculated for C14H25O [M+H]+: 209.1900,
Found: 209.1900.
in benzene (5.9 mL) was added acetic acid (6.7 μL, 0.117 mmol,
1 equiv) at room temperature. The resulting mixture was stirred
until the solution color changed from purple to yellow. (Generally,
it takes about 10 min) After then, to the solution was added
triethylsilane (47 μL, 0.29 mmol, 2.5 equiv) slowly, and the
reaction mixture was stirred till purple color appeared again. The
resulting mixture was filtered with pentane through silica pad and
concentrated under reduced pressure. The organic residue was
purified by flash column chromatography on silica gel (eluent,
pentane) to give triquinane 13 (22.9 mg, 90%) as oil.1H NMR (400
MHz, CD2Cl2) 4.66 (td, J = 2.1, 1.1 Hz, 1H), 4.61 (td, J = 2.4, 1.0
Hz, 1H), 2.50 – 2.39 (m, 1H), 2.38 – 2.29 (m, 2H), 2.29 – 2.19 (m,
1H), 1.84 (dd, J = 12.9, 8.5 Hz, 1H), 1.55 – 1.42 (m, 2H), 1.37 –
1.30 (m, 1H), 1.30 – 1.26 (m, 1H), 1.22 (dd, J = 8.0, 2.0 Hz, 1H),
1.20 – 1.13 (m, 1H), 1.00 (dd, J = 12.5, 8.2 Hz, 1H), 0.93 (s, 3H),
2-(1,5,5-Trimethyl-2-methyleneoctahydropentalen-1-yl)ethyl-
4-methylbenzenesulfonate (11). To a stirred solution of alcohol
10 (104.17 mg, 0.5 mmol, 1 equiv) in DCM (5 mL) was added p-
toluenesulfonyl chloride (114.4 mg, 0.5 mmol, 1.2 equiv),
triethylamine (83.7 μL, 0.6 mmol, 1.2 equiv) and 4-dimethyl-
aminopyridine (DMAP, 18.3 mg, 0.15 mmol, 0.3 equiv). The
resulting mixture was stirred for 15 h at room temperature. Then,
it was quenched by saturated ammonium chloride (sat.NH4Cl)
and distilled water, and the aqueous layer was extracted three
times with ethyl acetate (EtOAc) after addition of brine. The
extracts were dried over MgSO4, filtered and concentrated in
vacuo. The organic residue was purified by flash column
chromatography on silica gel (eluent, EtOAc/ Hx 1:15) to give
tosylated product 11 (145.07mg, 80%) as oil. 1H NMR (400 MHz,
CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.9 Hz, 2H), 4.80 –
4.69 (m, 1H), 4.60 – 4.49 (m, 1H), 3.96 (dddd, J = 26.7, 9.9, 8.9,
6.1 Hz, 2H), 2.60 – 2.44 (m, 2H), 2.43 (s, 3H), 2.22 (dt, J = 11.5,
7.8 Hz, 1H), 1.82 – 1.75 (m, 1H), 1.75 – 1.67 (m, 2H), 1.66 – 1.58
(m, 1H), 1.58 – 1.55 (m, 1H), 1.20 (ddd, J = 12.1, 7.2, 2.3 Hz, 1H),
0.89 (s, 3H), 0.87 – 0.80 (m, 2H), 0.78 (s, 3H), 0.74 (s, 3H). 13
C
NMR (100MHz, CD2Cl2) δ 162.9, 102.6, 57.4, 54.1, 52.2, 48.3,
47.0, 42.4, 41.7, 41.0, 38.4, 29.8, 28.9, 26.6, 22.4, 18.6. High
Resolution MS (ESI): Calculated for C16H27 [M+H]+: 219.2107,
Found: 219.2106.
3a,5,5,7a-Tetramethyldecahydro-1H-cyclopenta[a]pentalen-1
-one (16). A stirred solution of triquinane 13 (21 mg, 0.096 mmol)
in DCM/MeOH (1 mL/1 mL) was saturated with ozone for 5 min at
-78°C. The resulting mixture was quenched with dimethylsulfide
(0.2 mL) and allowed to warm to room temperature for 2 h. The
solvent was evaporated under reduced pressure. The residue
was purified by flash column chromatography on silica gel (eluent,
EtOAc/Hx 1 : 20) to give ketone 16 (12.7 mg, 60%) as oil. 1H NMR
(600 MHz, CD2Cl2) δ 2.50 (pd, J = 8.9, 5.0 Hz, 1H), 2.46 – 2.40
(m, 1H), 2.22 (ddd, J = 19.1, 9.0, 4.8 Hz, 1H), 2.14 – 2.05 (m, 1H),
1.93 (dd, J = 13.6, 9.3 Hz, 1H), 1.66 – 1.57 (m, 2H), 1.54 (ddd, J
= 13.4, 9.4, 4.8 Hz, 1H), 1.31 – 1.27 (m, 2H), 1.11 (dd, J = 13.6,
5.0 Hz, 1H), 1.03 (dd, J = 12.6, 8.4 Hz, 1H), 0.94 (s, 3H), 0.89 (s,
3H), 0.82 (s, 3H), 0.78 (s, 3H).13C NMR (150 MHz, CDCl3) δ 223.6,
61.1, 55.8, 51.5, 49.5, 43.3, 43.2, 42.2, 41.8, 35.1, 34.5, 29.4,
26.8, 18.8, 17.9. High Resolution MS (ESI): Calculated for
C15H24O [M+Na]+: 243.1719, Found: 243.1687
0.95 (s, 3H), 0.92 – 0.88 (m, 1H), 0.87 (s, 3H), 0.83 (s, 3H). 13
C
NMR (100 MHz, CDCl3) δ 155.8, 144.6, 133.3, 129.7, 127.8,
106.5, 68.3, 54.3, 49.3, 46.1, 42.9, 40.0, 39.8, 38.9, 37.1, 29.1,
27.1, 21.6, 19.1. High Resolution MS (ESI): Calculated for
C21H30O3S [M+Na]+: 385.1808, Found: 385.1850.
1-(But-3-yn-1-yl)-1,5,5-trimethyl-2-methylene octahydropenta
lene (12). To a stirred solution of compound 11 (80 mg, 0.22 mmol,
1 equiv) in DMSO (2.2 mL) was added lithium acetylide (stabilized
with ethylenediamine, 90 wt%, 101.3 mg, 1.1 mmol, 5 equiv). The
reaction mixture was stirred for 3.5 h at room temperature. Then,
it was quenched by distilled water, and the aqueous layer was
extracted three times with hexane after addition of brine. The
extracts were dried over MgSO4, filtered and concentrated in
vacuo. The organic residue was purified by flash column
chromatography on silica gel (eluent, pentane) to give alkyne 12
(42.8 mg, 90%) as oil. 1H NMR (400 MHz, C6D6) δ 4.76 – 4.70 (m,
1H), 4.54 – 4.49 (m, 1H), 2.56 (ddt, J = 15.5, 10.3, 2.6 Hz, 1H),
2.46 (dddd, J = 15.9, 10.6, 7.5, 2.5 Hz, 1H), 2.26 – 2.14 (m, 1H),
2.03 – 1.80 (m, 2H), 1.80 (t, J = 2.7 Hz, 1H), 1.78 – 1.68 (m, 1H),
1.64 (ddd, J = 12.6, 8.5, 2.3 Hz, 1H), 1.50 (ddd, J = 13.5, 11.2,
5.3 Hz, 1H), 1.45 – 1.32 (m, 1H), 1.16 (ddd, J = 12.0, 7.2, 2.4 Hz,
1H), 0.87 (s, 3H), 0.88 – 0.80 (m, 2H), 0.80 (s, 3H), 0.77 (s, 3H).
(±)-Ceratopicanol (1). A stirred solution of ketone 95 (10 mg,
0.045 mmol, 1 equiv) in MeOH (1mL) was added sodium
°
borohydride (5.1 mg, 0.135, 3 equiv) at 0 C. The solution was
allowed to warm to room temperature and stirred for 2 h. Then,
the reaction mixture was quenched with 1N hydrochloric acid and
distilled water at 0°C, and the aqueous layer was extracted three
times with diethyl ether (Et2O) after addition of brine. The extracts
were dried over MgSO4, filtered and concentrated in vacuo. The
13C NMR (150 MHz, CD2Cl2) δ 156.3, 105.5, 85.0, 67.0, 53.9, 49.0, organic residue was purified by flash column chromatography on
47.1, 42.8, 39.6, 39.6, 39.5, 36.9, 28.5, 26.5, 17.9, 13.5 . High
Resolution MS (ESI): Calculated for C16H25 [M+H]+: 217.1951,
Found: 217.1944.
silica gel (eluent, Et2O/ Hx 1:20) to give ceratopicanol (1) (8.1 mg,
80%) as amorphous solid. 1H NMR (600MHz, CDCl3) δ 3.70 (t, J
= 7.9 Hz, 1H), 2.49 (dq, J = 15.6, 8.4 Hz, 1H), 2.34 (dt, J = 11.7,
8.2 Hz, 1H), 2.16 (dd, J = 13.8, 9.6 Hz, 1H), 1.89 (dtd, J = 11.8,
7.5, 4.0 Hz, 1H), 1.67 (ddd, J = 12.9, 8.5, 1.5 Hz, 1H), 1.56 (ddd,
J = 13.2, 9.2, 4.3 Hz, 1H), 1.45 – 1.28 (m, 5H), 1.21 (dd, J = 12.9,
5.6 Hz, 1H), 1.07 (d, J = 7.0 Hz, 1H), 1.04 (s, 6H), 0.88 (s, 3H),
0.87 (s, 3H). 13C NMR (150 MHz,CDCl3) δ 82.6, 58.8, 55.0, 51.2,
3a,5,5,7a-Tetramethyl-1-methylenedecahydro-1H-cyclopenta
[a]pentalene (13). To a solution of diquinane 12 (25.5 mg, 0.12
mmol, 1 equiv), Pd2(dba)3•CHCl3 (5.4 mg, 0.006 mmol, 0.05
equiv) and tri(o-tolyl)phosphine (3.5 6mg, 0.012 mmol, 0.1 equiv)
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P. Hu, H. M. Chi, K. C. Debacker, X. Gong, J. H. Keim, I. T. Hsu, S. A.
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48.8, 44.2, 42.0, 41.7, 40.9, 39.6, 31.6, 30.6, 28.6, 23.9, 21.3.
High Resolution MS (ESI): Calculated for C15H26O [M+Na]+:
245.1876, Found: 245.1850
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1368; b) D. L. J. Clive, S. R. Magnuson, Tetrahedron Lett. 1995, 36, 15-
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Acknowledgements
Keywords: triquinane • cyclization • free radical • Pd catalysis •
total synthesis
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
Pd
CHCl3
Et
2(dba)3
H
H
H
TOTP, 3SiH
AcOH
An efficient total synthesis of
ceratopicanol was achieved
through successive Pd catalyzed
reductive cycloaddition and
cyclization reactions. The Pd
mediated cyclization reaction to
Total Synthesis
PhH, 2hr.
Rira Kim[a], Sanghyeon Lee[a],
Jaeyeon Lee[a], and Hee-Yoon
Lee*[a]
H
H
H
5:1
9:1
>20%
+
H
Pd
CHCl3
Et
2(dba)3
TOTP, 3SiH
AcOH
PhH, 2hr.
Page No. – Page No.
H
form
a
triquinane structure
small
90%
A total synthesis of (±)-
demonstrated that
a
Ceratopicanol
ceratopicanol via palladium
catalyzed reductive cyclization
structural difference changed the
reaction pathway either to form
different structures or reduced
non-cyclized product depending
on the reaction conditions.
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