Total synthesis of ceratopicanol through tandem cycloaddition reaction of a linear substrate

Article abstract of DOI:10.1002/asia.201200497

Total synthesis of ceratopicanol (1) was achieved with a tandem cycloaddition reaction of allenyl diazo compound 6 via a trimethylenemethane (TMM) diyl intermediate. The TMM diyl mediated [2+3] cycloaddition reaction furnished the consecutive quaternary c

Full text of DOI:10.1002/asia.201200497

DOI: 10.1002/asia.201200497
Total Synthesis of Ceratopicanol through Tandem Cycloaddition Reaction of
a Linear Substrate
[
a]
Sang-Shin Lee, Won-Yeob Kim, and Hee-Yoon Lee*
Abstract: Total synthesis of ceratopicanol (1) was achieved with a tandem cycload-
dition reaction of allenyl diazo compound 6 via a trimethylenemethane (TMM)
diyl intermediate. The TMM diyl mediated [2+3] cycloaddition reaction furnished
the consecutive quaternary carbon centers and showed an unusual diastereoselec-
tivity.
Keywords: diradical · cycladdition
reaction · stereoselectivity · total
synthesis · triquinane
Introduction
and clinical aspects of ceratopicanol were not fully explored
as sesquiterpene hydrocarbons had not shown typical bio-
logical activities, recent reports have indicated that terpenes
including ceratopicanol could be useful as prophylaxis or
Fungi are a source of various natural products that possess
unique structural features. The majority of these natural
products are secondary metabolites that include volatile hy-
drocarbons with diverse structural features. These com-
pounds have been found to be produced as part of a protec-
tion mechanism and communication with other organisms.
Hanssen and Abraham reported the first isolation of the ce-
ratopicane sesquiterpene natural product, ceratopicanol,
[4a,b]
the treatment of pain.
Along with its biological activities, the highly congested
structural feature of ceratopicanol with the cis/anti/cis-line-
arly fused triquinane structure that has five contiguous
chiral carbon atoms, with two consecutive quaternary
carbon centers, has challenged the synthetic chemistry com-
munity. As a result, there have been several reports on the
total synthesis of ceratopicanol. In all the reported total syn-
theses, the consecutive quaternary centers of ceratopicanol
[1]
[2]
from the fungus Ceratosystis Piceae Ha 4/82. Ceratopicane
possesses a linearly fused triquinane structure, which is dif-
ferent to that of the hirsutane or capnellane skeleton
[5]
(
Figure 1). Ceratopicane is biogenetically related to hirsu-
were assembled in a stepwise fashion. We were intrigued
by the structural features of ceratopicanol and became inter-
ested in an efficient total synthesis of ceratopicanol by intro-
ducing the two consecutive quaternary centers simultane-
ously.
tane as one of the proposed intermediate structures in be-
tween humulene to hirsutane is ceratopicane. Recently, an-
other ceratopicane natural product, cucumin H, was isolated
[3]
from Macrocystidia cucumis. While the pharmacological
Recently, we reported a tandem cycloaddition reaction
strategy to triquinanes from linear substrates through a tri-
methylenemethane (TMM) diyl [2+3] cycloaddition reactio-
[6a,b, 7a–i]
n.
Among the reported examples, the tandem cyclo-
addition reaction of 3 produced the complete structure of
ceratopicanol 4 with two consecutive quaternary centers
(
Scheme 1). This outcome was a good model system for the
total synthesis of ceratopicanol using the tandem cycloaddi-
tion reaction strategy from a linear substrate (Scheme 2).
Figure 1. Structure of (+)-ceratopicanol and other sesquiterpene com-
pounds.
[
a] S.-S. Lee, W.-Y. Kim, Prof. Dr. H.-Y. Lee
Department of Chemistry
KAIST
3
73-1 Gusung Dong, Yuseong, Daejeon, 305-701 (Korea)
Fax : (+82)42-350-2810
E-mail: leehy@kaist.ac.kr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200497.
Scheme 1. Tandem cycloaddition reaction of allenyl diazo compound 3.
Chem. Asian J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPER
Results and Discussion
The total synthesis of ceratopicanol started with the prepa-
ration of alkyne 8 and aldehyde 7 (Scheme 4). Swern oxida-
tion of pentynol produced volatile pentynal, which was
treated with an excess amount of isopropenyl Grignard re-
Scheme 2. Synthetic analysis of the total synthesis of ceratopicanol.
While this tandem cycloaddition reaction strategy can con-
struct the ceratopicanol skeleton in a single operation, the
stereoselectivity of the cycloaddition reaction of the TMM
intermediate I has not been explored so far. To the best of
our knowledge, the only report of a diastereoselectivity
study on the TMM cycloaddition reaction to form linearly
fused triquinanes was with substrates bearing the substitu-
ents at different positions in the tether (Scheme 3). Thus,
the total synthesis of ceratopicanol would also provide an
opportunity to understand the stereoselectivity of the cyclo-
addition reaction.
2
Scheme 4. Preparation of the intermediate 11. a) (COCl) (1.2 equiv),
DMSO (1.5 equiv), THF, À788C; Et N (3 equiv), then rt for 4 h; b) iso-
3
propenyl magnesium bromide (11 equiv), THF, À208C, 1 h, 78% (over
2
steps); c) benzyl bromide (1.05 equiv), sodium hydride (1.3 equiv),
[8]
TBAI (0.05 equiv), THF, rt, 12 h, 95%; d) LAH (3.2 equiv), diethylether,
8C, then rt for 24 h, 99%; e) TBDPSCl (1 equiv), imidazole (1.5 equiv),
THF, 08C, then rt for 12 h, 81%; f) (COCl) (1.5 equiv), DMSO
0
2
(2.5 equiv), CH Cl , À788C, 1 h; Et N (5 equiv), then rt for 4 h, 98%;
2
2
3
g) 7 (1.1 equiv), LiHMDS (1.5 equiv), À788C, 1 h, then rt for 2 h, 98%.
agent to afford the alcohol 9 in 78% yield over two steps.
The alcohol 9 was protected as the benzyl ether to form 8.
The other coupling partner, aldehyde 7, was prepared in
a three-step sequence from 2,2-dimethylsuccinic acid. Re-
duction of the diacid functional groups to the diols and se-
lective monoprotection of the less hindered alcohol with
bulky tert-butyldiphenylsilyl group produced 10. The alcohol
Scheme 3. Diastereoselective cycloaddition reaction of the TMM inter-
mediate.
1
0 was oxidized into aldehyde 7. An addition reaction of the
acetylide anion of 8 with aldehyde 7 furnished the propar-
gylic alcohol 11.
Ceratopicanol could be synthesized from 5, which could
be obtained from diazo compound 6 through the tandem cy-
cloaddition reaction (Scheme 2). The first step of the
tandem cycloaddition reaction sequence would be the for-
mation of the thermally labile pyrazole intermediate II
through a 1,3-dipolar cycloaddition reaction. Then, inter-
Preparation of the precursor 16 for the tandem cycloaddi-
tion reaction from 11 required the introduction of the
methyl group to form the trisubstituted allene moiety from
the propargyl alcohol of 11 (Scheme 5). To introduce the
methyl group and the allene functionality, alcohol 11 was
transformed into methyl carbonate 12. The propargylic car-
mediate II would lose N to generate the TMM diyl inter-
2
[9]
mediate I, which would undergo a [2+3] cycloaddition reac-
tion with the olefin to produce the triquinane 5. The diazo
group of 6 could be generated from the corresponding alde-
hyde. The allenyl compound could be obtained through the
coupling of aldehyde 7 and alkyne 8. The coupling partners,
bonate of 12 was treated with Gilmanꢁs reagent to produce
[10]
the trisubstituted allene 13. The allene compound 13 was
treated with tetrabutylammonium fluoride to give the pri-
mary alcohol 14. Swern oxidation of the alcohol afforded
the aldehyde 15. The aldehyde moiety of 15 could be con-
[11a–e]
7
and 8 can be readily prepared from 2,2-dimethylsuccinic
verted into the diazo functionality with several methods.
acid and pentynol, respectively.
Among these methods, the phenylaziridinyl imine was se-
lected as the precursor of the diazo group because it would
generate the diazo functionality under neutral reaction con-
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Total Synthesis of Ceratopicanol
least four isomeric cycloaddition products in a ratio of
:5:2:1, as judged by GC-MS analysis because all com-
9
pounds showed similar fragmentation patterns with the
same molecular ion peak of the tandem cycloaddition reac-
tion product. As the isomers were not separable by column
chromatography, separation of the isomers was deferred
until after deprotection of the benzyl ether (Scheme 7).
Scheme 5. Preparation of the substrate for the tandem cycloaddition re-
action. a) ClCO
2 2 2
Me (3 equiv), pyridine (5 equiv), CH Cl , 08C, 2 h, then
rt for 2 h, 99%; b) MeMgBr (12 equiv), CuI (12 equiv), LiBr (12 equiv),
0
9
8C, 0.5 h, then rt for 1 h, 97%; c) TBAF (5 equiv), THF, rt for 10 h,
8%; d) (COCl) (1.5 equiv), DMSO (2.5 equiv), CH Cl
, À788C, 1 h;
(5 equiv),then rt for 4 h, 93%; e) N-amino-2-phenylaziridine
1.5 equiv), MeOH, 08C, 0.5 h, then rt for 16 h, 90%
2
2
2
3
Et N
(
Scheme 7. Completion of the total synthesis of ceratopicanol. a) Pd/C
[
12a–c]
(240 mg, 10 wt.% activated carbon), H
2
(60 psi) in a Parr shaker, 36%+
1% of other isomers; b) TPAP (0.1 equiv), NMO (2 equiv), CH Cl , rt,
.5 h, 82%; c) NaBH
ditions.
The aldehyde of 15 underwent condensation
2
1
2
2
[13]
with N-amino-2-phenylaziridine in MeOH to produce al-
lenyl aziridinylimine 16 in good yield.
4
(1.3 equiv), MeOH, À158C, 1 h, 95%. NMO=4-
methylmorpholine N-oxide; TPAP=tetra-n-propylammonium perruthen-
With the precursor 16 in hand, we were ready to explore
the tandem cycloaddition reaction and the diastereoselectiv-
ity of the TMM diyl [2+3] cycloaddition reaction
ate.
(
Scheme 6).
When the tandem cycloaddition reaction product mixture
was subjected directly to the hydrogenation/hydrogenolysis
reaction conditions, two fractions were separated in a 1.7:1
ratio. The major fraction contained ceratopicanol along with
its alcohol epimer 17 (3.7:1 ratio). The ratio of the two iso-
mers was determined by NMR spectroscopy. The structure
of the synthesized ceratopicanol was confirmed by compari-
son of its spectroscopic data with the reported data. The
structure of 17 was confirmed through an oxidation–reduc-
tion sequence that produced ceratopicanol by inversion of
the alcohol stereochemistry of 17.
Contrary to the model case in Scheme 2, the tandem cy-
cloaddition reaction produced an inseparable mixture of at
[2]
The minor fraction also contained a mixture of two epi-
meric alcohols with a ratio of 5:1. The epimeric nature of
the alcohol mixture was confirmed through the oxidation of
the alcohol mixture to a single isomeric ketone. Unfortu-
nately, the exact structure of the minor fraction could not be
deduced firmly owing to the instability of the ketone prod-
uct. The structure of the ketone was tentatively assigned as
the regioisomeric cycloaddition product of 5. This result was
quite different from the result of the cycloaddition reaction
of 3 or A. It was presumed that the efficiency and the selec-
tivity of the cycloaddition reaction were affected by the sub-
stitution patterns, as 3 and A contained quaternary centers
[14]
Scheme 6. Tandem cycloaddition reaction of 16.
in the tether. A Thorpe–Ingold effect
must have influ-
Chem. Asian J. 2012, 00, 0 – 0
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Hee-Yoon Lee et al.
FULL PAPER
enced the selectivity as well as the efficiency of the cycload-
dition reaction.
Experimental Section
The diastereoselectivity of the TMM cycloaddition reac-
tion of IV was opposite to that of the cycloaddition reaction
of B (Scheme 3). The stereoselectivity of the cycloaddition
reaction of B was clearly explained by the 1,3-diaxial inter-
action between the pseudo-axial substituent and the cyclo-
General Information
NMR spectra were obtained on Bruker DPX400 (400 MHz for H NMR,
1
1
3
100 MHz for C NMR) or Bruker AM300 spectrometers (300 MHz for
1
13
H NMR, 75 MHz for C NMR) in CDCl
3
. Chemical shifts were record-
and coupling constants
ed in ppm relative to internal standard CDCl
3
were reported in Hz. The high-resolution mass spectra were recorded on
VG Autospec Ultima and JMS-700 spectrometers. All reactions were car-
[8]
pentene ring in B-a (Scheme 8). However, the preference
2
ried out in oven-dried glassware under a N atmosphere, and were moni-
tored by TLC analysis using Merck precoated silica gel 60 F254 plates. All
solvents were distilled from the indicated drying reagents straight before
use: Et
dioxane, and N,N-dimethylformamide (DMF; CaH
up procedure involved extraction, drying over MgSO
2
O and THF (Na, benzophenone), CH
2
Cl
2
(P
2
O
5
), and MeCN, 1,4-
). The normal work-
, and evaporation
2
4
of volatile materials in vacuo. Purification by column chromatography
was perfomed using Merck (Darmstadt, Germany) silica gel 60 (230~400
mesh).
2
-Methyl-hept-1-en-6-yn-3-ol (9)
A solution of oxalyl chloride (1.87 mL, 21.40 mmol) in THF (80 mL) was
cooled to À788C, and a solution of dimethyl sulfoxide (DMSO; 1.90 mL,
2
6.75 mmol) in THF (40 mL) was added dropwise over 45 min. A white
Scheme 8. Comparison of transition states leading to cycloaddition reac-
tion products.
precipitate formed as the resulting mixture was stirred at À788C for
4
5 min. A solution of 4-pentyn-1-ol (1.5 g, 17.83 mmol) in THF (40 mL)
was then introduced dropwise over 1 h. After an additional 1 h at À788C,
triethylamine (7.50 mL, 53.50 mmol) was added dropwise over 30 min.
The reaction was stirred at À788C for 1 h, warmed to room temperature,
and stirred for an additional 1 h. Finally, the mixture was filtered, the
filter cake was washed with THF (30 mL), and the aldehyde was used di-
rectly in the subsequent reaction. To this solution cooled to À208C, was
added isopropenyl magnesium bromide (200 mmol) in diethyl ether
between the two plausible transition states of IV was not
obvious. When energies for two plausible transition states,
which led to the formation of 5 and its epimer, were calcu-
[15a,b]
lated by using HF/6-31G* level of theory,
the pseudo-
(
178 mL), prepared from Mg turnings (1.3 g, 53.50 mmol) and 2-bromo-
axial transition state, IV-a was calculated to be more stable
than the pseudo-equatorial transition state IV-e by 1.7 kcal
propene (3.20 mL, 35.66 mmol) by standard techniques using dibromo-
ethane (50 mL) in THF (40 mL), and the resulting reaction mixture was
stirred for 1 h at that temperature, then warmed to room temperature.
À1
mol . Presumably, the lack of the 1,3-diaxial interaction of
After 1 h, the reaction was quenched with saturated NH
the solution was extracted with diethyl ether (2ꢂ100 mL). The combined
organic layers were dried over MgSO , filtered, and evaporated in vacuo.
4
Cl solution, and
the pseudo-axial orientation and the gauche interaction of
the pseudo-equatorial orientation in the allylic conformation
made the pseudo-axial orientation more stable than the
4
The residue was purified by flash column chromatography on silica gel
[16]
pseudo-equatorial orientation.
Interestingly, the similar
(Et O/n-pentane=1:5) to give 1.72 g (13.85 mmol, 78% over 2 steps) of
2
1
reversal in the selectivity was also observed in the TMM cy-
cloaddition reaction for the formation of angularly fused tri-
the alcohol as a colorless oil: H NMR (400 Hz, CDCl
.68 Hz, 1H), 4.80 (d, J=1.41 Hz, 1H), 4.12 (t, J=7.20 Hz, 1H), 2.23–
2.18 (m, 3H), 1.92 (t, J=2.65 Hz, 1H), 1.72–1.69 (m, 2H), 1.67 ppm (s,
3
): d=4.92 (d, J=
0
[17]
quinanes.
13
3
1
1
3
H). C NMR (100 Hz, CDCl ): d=146.8, 111.2, 84.0, 74.3, 68.6, 33.4,
7.5, 14.7 ppm. IR (neat): ~n =3302, 3075, 2952, 2117, 1814, 1435, 1374,
283, 1057, 904 cm
À1
.
Conclusions
[
(1-Isopropenyl-pent-4-ynyl)oxymethyl)benzene (8)
In summary, a total synthesis of ceratopicanol has been ac-
complished in 11 steps for the longest linear sequence with
simultaneous construction of consecutive quaternary centers.
The total synthesis also revealed an unexpected diastereose-
lectivity in the cycloaddition reaction and the influence of
the substitution patterns for the efficiency of the cycloaddi-
tion reaction. The favorable diastereoselectivity for the for-
mation of ceratopicanol could be applied to the asymmetric
total synthesis of ceratopicanol if intermediate 8 is prepared
enantioselectively.
A solution of alcohol 9 (400 mg, 3.22 mmol) in THF (10 mL) containing
a catalytic amount of tetrabutylammonium iodide was added to a stirred
suspension of NaH (167 mg of 60% dispersion in mineral oil, 4.19 mmol)
in THF (20 mL). The mixture was stirred for 45 min, and then benzyl
bromide (402 mL, 3.38 mmol) was added dropwise. The resulting suspen-
sion was stirred at room temperature; 12 h later, TLC showed that the al-
cohol had almost disappeared and then EtOAc and H
the reaction mixture. The organic layer was separated and washed with
brine. After drying over MgSO , the solvent was evaporated in vacuo
2
O were added to
4
and the crude product was purified by flash column chromatography on
silica gel (EtOAc/n-hexane=1:20) to afford 658 mg (3.07 mmol, 95%) of
1
the benzylated product as a colorless oil: H NMR (400 Hz, CDCl ): d=
3
7
4
2
.34–7.27 (m, 5H), 4.99 (d, J=1.69 Hz, 2H), 4.50 (d, J=11.66 Hz, 1H),
.70 (d, J=11.66 Hz, 1H), 3.88 (dd, J=8.28, 2.98 Hz, 1H), 2.29–2.24 (m,
1
3
H), 1.92–1.86 (m, 2H), 1.73 (s, 3H), 1.71 ppm (m, 1H). C NMR
): d=144.0, 138.6, 128.3, 127.8, 127.4, 114.0, 84.0, 81.7,
(
100 Hz, CDCl
3
7
1
0.2, 68.4, 32.6, 16.7, 15.0 ppm. IR (neat): ~n =3303, 3030, 2943, 2863,
À1
649, 1453, 1374, 1071, 905 cm
.
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Chem. Asian J. 0000, 00, 0 – 0
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Total Synthesis of Ceratopicanol
4
-(tert-Butyldiphenylsilanyloxy)-2,2-dimethylbutan-1-ol (10)
144.07, 138.6, 135.58, 135.56, 133.03, 132.95, 129.78, 129.76, 128.31, 127.78,
1
7
27.74, 127.74, 127.72, 127.4, 113.99, 113.97, 85.4, 81.94, 81.90, 80.1, 70.5,
0.1, 60.9, 40.7, 38.3, 33.0, 26.7, 24.7, 23.8, 19.0, 16.7, 15.5 ppm. IR (neat):
A solution of 2,2-dimethylsuccinic acid (5.0 g, 34.62 mmol) in dry diethyl
ether (50 mL) was added dropwise to a stirred slurry of lithium alumini-
um hydride (LAH; 4.15 g, 0.11 mol) in dry diethyl ether (150 mL) at
~
À1
1
C
188, 1111, 1028, 904, 823 cm
.
HRMS (EI): m/z calcd for
0
8C. The mixture was stirred at room temperature for 24 h and quenched
sequentially with addition of water (4.20 mL), 10% NaOH solution
8.40 mL), and water (12.60 mL). The slurry was filtered and the inorgan-
ic salts were washed with diethyl ether (2ꢂ50 mL). The combined ethere-
al extracts were dried with MgSO , filtered, and concentrated in vacuo.
The crude diol product (4.06 g, 34.36 mmol, 99%) was used directly with-
37
H
48NaO
3
Si: 591.3270; found: 591.3323.
(
9
-(benzyloxy)-1-(tert-butyldiphenylsilyloxy)-3,3,10-trimethylundec-10-en-5-
yn-4-yl-methyl carbonate (12)
4
2 2
To a solution of alkynol 11 (2.18 g, 3.84 mmol) in CH Cl (25 mL) cooled
1
out further purification: H NMR (400 Hz, CDCl
3
): d=4.02 (s, 2H), 3.62
to 08C was added pyridine (1.55 mL, 19.18 mmol) and methyl chlorofor-
mate (890 mL, 11.51 mmol). After stirring for 2 h, the reaction mixture
was warmed to room temperature, and further stirred for 2 h. The reac-
(
6
t, J=5.90 Hz, 2H), 3.26 (s, 2H), 1.48 (t, J=5.90 Hz, 2H), 0.85 ppm (s,
1
3
H) C NMR (100 Hz, CDCl
3
): d=71.3, 58.7, 42.6, 34.8, 24.8 ppm. IR
À1
(
neat): ~n =3359, 2925, 1652, 1469, 1365, 1159, 1053, 985, 903 cm . Imida-
tion mixture was diluted with CH
2
Cl
2
and washed with 1N HCl, H
2
O,
zole (1.96 g, 28.84 mmol) and TBDPSCl (5.0 mL, 19.23 mmol) were
added to a solution of the diol (2.27 g, 19.23 mmol) in THF (45 mL).
and brine. The organic layer was dried over MgSO
removed in vacuo. The crude product was purified using flash column
4
, and the solvent was
After 24 h, the reaction was quenched with sat. NaHCO
was extracted with diethyl ether (3ꢂ50 mL), dried over MgSO
and the solvent was removed under reduced pressure. The residue was
3
. The solution
, filtered,
chromatography on silica gel (EtOAc/n-hexane=1:20 to 1:10) to give
2.40 g (3.83 mmol, 99%) of the carbonate product as a colorless oil:
4
1
3
H NMR (400 Hz, CDCl ): d=7.68–7.66 (m, 4H), 7.41–7.24 (m, 11H),
purified by flash column chromatography on silica gel (EtOAc/n-
5.00–4.97 (m, 1H), 4.48 (d, J=11.65 Hz, 1H), 4.23 (dd, J=11.60, 2.20 Hz,
1H), 3.86–3.84 (m, 1H), 3.76 (s, 3H), 3.73 (t, J=6.12 Hz, 2H), 2.29 (t,
J=7.32 Hz, 2H), 1.87–1.83 (m, 1H), 1.75–1.73 (m, 1H), 1.73 (s, 3H),
hexane=1:4) to give 5.54 g (15.54 mmol, 81%) of the protected alcohol
1
as a colorless oil: H NMR (400 Hz, CDCl
3
): d=7.69 (dd, J=7.44,
1
3
1
6
0
1
2
1
3
.50 Hz, 4H), 7.46–7.38 (m, 6H), 3.72 (t, J=5.70 Hz, 2H), 3.37 (d, J=
1.70–1.64 (m, 2H), 1.05 (s, 9H), 0.96 ppm (s, 6H). C NMR (100 Hz,
CDCl ): d=155.3, 144.0, 138.6, 135.5, 133.81, 133.79, 129.5, 128.3, 127.74,
.51 Hz, 2H), 3.25 (brs, 1H), 1.55 (t, J=5.75 Hz, 2H), 1.07 (s, 9H),
3
1
3
.90 ppm (s, 6H). C NMR (100 Hz, CDCl
3
): d=135.5, 133.0, 129.8,
127.60, 127.44, 113.9, 87.4, 82.00, 81.88, 76.2, 75.8, 70.22, 70.19, 60.5, 54.7,
40.34, 40.30, 37.21, 37.20, 32.7, 26.8, 23.3, 23.0, 19.1, 16.7, 15.4 ppm. IR
(neat): ~n =3070, 2957, 2857, 1754, 1441, 1428, 1390, 1341, 1264, 1190,
27.7, 71.6, 61.0, 41.9, 35.0, 26.7, 25.0, 19.0 ppm. IR (neat): ~n =3443, 3071,
957, 1959, 1890, 1823, 1589, 1471, 1427, 1391, 1362, 1308, 1264, 1188,
À1
À1
111, 939, 890, 822 cm . HRMS (EI): m/z calcd for C22
H
32NaO
2
Si:
1145, 1110, 1029, 998, 952, 904, 823 cm . HRMS (EI): m/z calcd for
79.2069; found: 379.2096.
39 5
C H50NaO Si: 649.3325; found: 649.3352.
4
-(tert-Butyldiphenysilanyloxy)-2,2-dimethylbutyraldehyde (7)
(9-benzyloxy-3,3,6,10-tetramethylundeca-4,5,10-trienyloxy)(tert-
butyl)diphenylsilane (13)
To a solution of oxalyl chloride (1.65 mL, 18.86 mmol) in CH
cooled at À788C was added DMSO (2.23 mL, 31.43 mmol) in CH
10 mL) dropwise. The reaction mixture was stirred for 15 min and the
solution of alcohol 10 (4.48 g, 12.57 mmol) in CH Cl (10 mL) was added
by cannula over 5 min. After the solution was stirred for 30 min, triethyl-
amine (8.80 mL, 62.86 mmol) was added, and the reaction mixture was
stirred for 1 h, then allowed to warm to room temperature for 4 h. Water
2
Cl
2
(40 mL)
2
Cl
2
To a well stirred mixture of lithium bromide (2.35 g, 26.99 mmol) and
copper iodide (5.14 g, 26.99 mmol) in THF (135 mL) at 08C was added
methyl magnesium bromide (9.0 mL of 3m ethereal solution,
26.99 mmol), and the solution was stirred for 30 min. The carbonate 12
(1.41 g, 2.25 mmol) in THF (10 mL) was added dropwise. The progress of
the reaction was followed by TLC until completion (5 min to 1 h). The
mixture was then poured into a saturated aqueous solution of ammonium
(
2
2
(
50 mL) was added, and the aqueous layer was extracted with additional
CH Cl (60 mL). The organic layers were combined, washed with saturat-
ed NaCl solution (100 mL), and dried over MgSO . The filtrate was con-
4
chloride, extracted with ether, dried over MgSO , and the solvent was re-
moved in vacuo. The crude product was purified using flash chromatogra-
2
2
4
centrated in vacuo, and the residue was purified by flash column chroma-
phy on silica gel (EtOAc/n-hexane=1:20) to afford 1.24 g (2.19 mmol,
97%) of the substituted allene product as a colorless oil: H NMR
(400 Hz, CDCl ): d=7.67–7.63 (m, 4H), 7.40–7.24 (m, 11H), 4.95–4.89
3
1
tography on silica gel (EtOAc/n-hexane=1:10) to give the aldehyde
1
(
4.35 g, 12.27 mmol, 98%) as a white solid: H NMR (400 Hz, CDCl
3
):
d=9.54 (s, 1H), 7.63 (dd, J=7.65, 1.49 Hz, 4H), 7.42–7.35 (m, 6H), 3.63
(m, 1H), 4.89 (s, 1H), 4.87–4.85 (m, 1H), 4.48 (d, J=11.80 Hz, 1H), 4.23
(d, J=11.80 Hz, 1H), 3.71 (t, J=7.13 Hz, 3H), 2.10–1.92 (m, 1H), 1.88–
1.84 (m, 1H), 1.75–1.72 (m, 1H), 1.67 (d, J=3.99 Hz, 3H), 1.63 (m, 2H),
(
t, J=6.16 Hz, 2H), 1.78 (t, J=6.11 Hz, 2H), 1.05 (s, 6H), 1.02 ppm (s,
H). C NMR (100 Hz, CDCl ): d=205.4, 135.6, 133.4, 129.7, 127.7, 60.2,
3
1
3
9
4
2
4.5, 40.6, 26.7, 21.6, 19.0 ppm. IR (neat): ~n =2961, 2928, 2855, 2360,
1.57 (s, 3H), 1.55–1.54 (m, 1H), 1.03 (s, 9H), 0.92 (d, J=2.32, 3H),
À1
13
341, 1734, 1711, 1459, 1428, 1109, 1085, 1056, 990, 824 cm
.
0.90 ppm (s, 3H). C NMR (100 Hz, CDCl
3
): d=198.64, 198.60, 144.60,
1
44.56, 138.8, 135.5, 134.1, 129.5, 128.3, 127.78, 127.75, 127.55, 127.4,
9
5
-Benzyloxy-1-(tert-butyldiphenylsilanyloxy)-3,3,10-trimethylundec-10-en-
-yn-4-ol (11)
113.74, 113.69, 101.28, 101.22, 100.88, 100.78, 82.86, 82.81, 69.9, 61.4, 45.2,
34.03, 34.00, 31.8, 31.6, 30.1, 28.76, 28.70, 28.05, 27.97, 26.9, 19.6, 19.1,
1
6.62, 16.60 ppm. IR (neat): ~n =3070, 3030, 2957, 2857, 1960, 1650, 1496,
To a solution of alkyne 8 (845 mg, 3.94 mmol) in THF (30 mL) cooled to
À788C was added LiHMDS (5.90 mL of 1.0m solution in THF,
À1
1
455, 1428, 1390, 1362, 1308, 1188, 1153, 1110, 997, 939, 902, 823 cm
.
5
4
.92 mmol). After stirring for 30 min, a solution of aldehyde 7 (1.54 g,
9
-benzyloxy-3,3,6,10-tetramethylundeca-4,5,10-trien-1-ol (14)
.34 mmol) in THF (10 mL) was added. The mixture was stirred for 1 h
at À788C and slowly warmed to room temperature. After stirring for 2 h,
saturated ammonium chloride solution was added, and the mixture was
extracted with diethyl ether (2ꢂ40 mL). The combined ethereal extracts
were dried over MgSO , and the solvent was removed in vacuo. The
4
crude product was purified using flash column chromatography on silica
To a stirred solution of silyl-protected alcohol 13 (1.24 g, 2.19 mmol) in
THF (30 mL) was added TBAF (11 mL of 1m solution in THF,
10.94 mmol) at room temperature. After stirring for 10 h at room temper-
ature, the reaction mixture was diluted with diethyl ether (30 mL), and
water was added (30 mL). The organic layer was washed with 1N HCl,
gel (EtOAc/n-hexane=1:10) to yield 2.23 g (3.91 mmol, 99%) of the al-
2 4
H O, and brine, dried over MgSO , filtered, and concentrated in vacuo.
The residue was purified by flash column chromatography on silica gel
1
kynol as a colorless oil: H NMR (400 Hz, CDCl
3
): d=7.70–7.66 (m,
4
4
H), 7.42–7.38 (m, 6H), 7.38–7.24 (m, 5H), 4.97 (d, J=6.46 Hz, 2H),
.49 (d, J=11.73 Hz, 1H), 4.23 (d, J=11.73 Hz, 1H), 4.07 (s, 1H), 3.85
(EtOAc/n-hexane=1:4) to give 705 mg (2.15 mmol, 98%) of the free al-
1
cohol as a colorless oil: H NMR (400 Hz, CDCl
3
): d=7.32–7.23 (m, 5H),
(
1
1
dd, J=8.09, 5.41 Hz, 1H), 3.72–3.66 (m, 2H), 2.29 (t, J=7.30 Hz, 2H),
4.97–4.95 (m, 2H), 4.92 (s, 1H), 4.48 (d, J=11.81 Hz, 1H), 4.23 (d, J=
11.81 Hz, 1H), 3.74 (t, J=6.90 Hz, 1H), 3.66 (t, J=7.19 Hz, 2H), 2.03–
1.99 (m, 1H), 1.89–1.87 (m, 1H), 1.78–1.74 (m, 1H), 1.70 (s, 3H), 1.66 (d,
.90–1.85 (m, 2H), 1.72 (s, 3H), 1.70–1.67 (m, 1H), 1.45–1.39 (m, 1H),
1
3
3
.04 (s, 9H), 0.95 ppm (s, 6H). C NMR (100 Hz, CDCl ): d=144.12,
Chem. Asian J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Hee-Yoon Lee et al.
FULL PAPER
J=1.65, 3H), 1.64–1.1.56 (m, 4H), 0.99 (s, 3H), 0.98 ppm (s, 3H).
C NMR (100 Hz, CDCl ): d=198.75, 198.69, 144.56, 144.50, 138.7,
3
chromatography to give 30.7 mg (0.14 mmol, 36%) of the alcohol as an
oil (3:1 diastereomeric mixture).
1
3
1
8
3
28.3, 127.80, 127.77, 127.4, 113.88, 113.84, 101.29, 101.27, 101.16, 101.13,
2.89, 82.80, 69.94, 69.92, 60.2, 45.46, 45.43, 34.11, 34.09, 31.81, 31.69,
0.14, 30.10, 28.63, 28.60, 28.2, 19.68, 19.62, 16.59, 16.56 ppm. IR (neat):
The crude product was purified with flash column chromatography (n-
hexane/EtOAc=10:1) to give 15.5 mg of ceratopicanol (32%): H NMR
1
(
400 Hz, CDCl
3
): d=3.72–3.68 (m, 1H), 2.50–2.48 (m, 1H), 2.35–2.32 (m,
~
n=3385, 3068, 3031, 2956, 2864, 2361, 2340, 1961, 1497, 1454, 1372, 1151,
1
1
1
H), 2.16 (dd, J=13.79, 9.52 Hz, 1H), 1.90–1.86 (m, 1H), 1.67 (ddd, J=
À1
1
068, 1027, 987, 902, 817 cm
.
3.0, 8.4, 1.3 Hz, 1H), 1.60–1.50 (m, 1H), 1.50–1.32 (m, 5H), 1.23 (dd, J=
3.0, 4.8 Hz, 1H), 1.08 (dd, J=13.8, 6.8 Hz, 1H), 1.04 (s, 6H), 0.88 (s,
1
3
9
-benzyloxy-3,3,6,10-tetramethylundeca-4,5,10-trienal (15)
3H), 0.87 ppm (s, 3H). C NMR (100 Hz, CDCl
3
): d=82.6, 58.8, 54.9,
5
1.2, 48.8, 44.2, 41.9, 41.7, 40.8, 39.5, 31.5, 30.6, 28.5, 23.9, 21.2 ppm. IR
To a solution of oxalyl chloride (105 mL, 1.21 mmol) in CH
2
Cl
2
(10 mL)
À1
(
neat): ~n =3364, 2948, 2866, 1460, 1374, 1312, 1065, 1032, 989 cm
.
cooled at À788C was added DMSO (143 mL, 2.01 mmol) dropwise. The
HRMS (EI): m/z calcd for C15 26NaO: 245.1881; found: 245.1876.
H
reaction mixture was stirred for 10 min and the solution of alcohol 14
(
264 mg, 0.80 mmol) in CH
After the solution was stirred for 15 min, triethylamine (560 mL,
.02 mmol) was added, and the reaction mixture was stirred for 5 min
and then allowed to warm to room temperature. Water (10 mL) was
added, and the aqueous layer was extracted with CH Cl (10 mL). The
organic layers were combined, washed with saturated brine (10 mL), and
dried over MgSO . The filtrate was concentrated in vacuo, and the resi-
2 2
Cl (3 mL) was added by cannula over 5 min.
4
Acknowledgements
2
2
This research was supported by Basic Science Research Program through
the National Research Foundation of Korea (NRF) funded by the Minis-
try of Education, Science and Technology (KRF-2008-314-C00198).
4
due was purified by flash column chromatography on silica gel (EtOAc/
n-hexane=1:10) to give 244 mg (0.75 mmol, 93%) of the aldehyde as
1
a colorless liquid: H NMR (400 Hz, CDCl
3
): d=9.75 (t, J=3.03 Hz,
1
4
H), 7.32–7.24 (m, 5H), 5.08–5.05 (m, 1H), 4.97 (d, J=1.40 Hz, 1H),
.97 (s, 1H), 4.48 (d, J=11.81 Hz, 1H), 4.22 (d, J=11.81 Hz, 1H), 3.74 (t,
[
[
[
1] R. Kramer, W.-R. Abraham, Phytochem. Rev. 2012, 11, 15–37.
2] P. Hanssen, W.-R. Abraham, Tetrahedron 1988, 44, 2175–2180.
3] V. Hellwig, J. Dasembrock, S. Schumann, W. Steglich, K. Leonhardt,
T. Amke, Eur. J. Org. Chem. 1998, 73–79.
J=6.51 Hz, 1H), 2.30–2.28 (m, 2H), 2.03–2.00 (m, 1H), 1.93–1.90 (m,
H), 1.77–1.74 (m, 1H), 1.70 (s, 3H), 1.65 (d, J=1.06 Hz, 3H), 1.61–1.57
1
1
3
(
3
m, 1H), 1.12 ACHTUNGTRENNUNG( s, 3H), 1.11 ppm (s, 3H). C NMR (100 Hz, CDCl ): d=
[
4] a) J. M. McPartland, J. Am. Osteopath. Assoc. 2004, 104, 244–249;
b) T. T. Bothma, J. H. Rossouw, A.-M. Richard, J. P. Cronje, WO/
2
1
3
03.3, 198.72, 198.68, 144.45, 144.38, 138.68, 128.2, 127.73, 127.70, 127.3,
13.86, 113.81, 102.44, 102.32, 100.26, 100.17, 82.72, 82.62, 69.9, 54.8,
4.35, 34.33, 31.69, 31.53, 30.0, 28.70, 28.68, 28.66, 19.52, 19.49, 16.5 ppm.
2
007/066350, 2007.67.
[
5] a) G. Mehta, S. R. Karra, J. Chem. Soc. Chem. Commun. 1991,
1367–1368; b) D. L. J. Clive, S. R. Magnuson, Tetrahedron Lett.
IR (neat): ~n =3068, 3031, 2959, 2865, 2731, 2360, 1963, 1721, 1649, 1497,
1
À1
454, 1371, 1323, 1070, 1028, 903, 815 cm
.
1
995, 36, 15–18; c) B. Christophe, C. Michel, J. Michel, J. Org.
Chem. 1996, 61, 3576–3577; d) L. A. Paquette, F. Geng, J. Am.
Chem. Soc. 2002, 124, 9199–9203; e) T. Anger, O. Graalmann, H.
Schçder, R. Gerke, U. Kaiser, L. Fitjer, M. Noltemeyer, Tetrahedron
1998, 54, 10713–10720; f) C. Mukai, M. Kobayashi, I. J. Kim, M. Ha-
naoka, Tetrahedron 2002, 58, 5225–5230; g) C. H. Oh, C. Y. Rhim,
M. Kim, D. I. Park, A. K. Gupta, Synlett 2005, 2694–2696.
N-(9-benzyloxy-3,3,6,10-tetramethylundeca-4,5,10-trienylidene)-2-
phenylaziridin-1-amine (16)
To the solution of aldehyde 15 (220 mg, 0.67 mmol) in MeOH (3 mL)
cooled to 08C with an ice-bath was added N-amino-2-phenylaziridine
(
1.0 mL of 1.0m solution in MeOH, 1.00 mmol). After stirring for 16 h,
the mixture was concentrated in vacuo. The crude product was purified
by flash column chromatography on silica gel (EtOAc/n-hexane=1:5) to
[6] a) H.-Y. Lee, Y. J. Kim, J. Am. Chem. Soc. 2003, 125, 10156–10157;
b) H.-Y. Lee, B. G. Kim, Y. K. Yoon, W. Y. Kim, T. Kang, J. Am.
Chem. Soc. 2011, 133, 18050–18053.
afford 267 mg (0.61 mmol, 90%) of the aziridinylimine as a pale yellow
1
oil: H NMR (400 Hz, CDCl
3
): d=7.97 (t, J=6.23 Hz, 1H), 7.33–7.24 (m,
[7] For reviews, see: a) G. Koebrich, H. Heinemann, J. Chem. Soc.
Chem. Commun. 1969, 493–494; b) W. T. Borden, Diradicals, Wiley-
Interscience, New York, 1982, pp. 151–194; c) M. G. Lazzara, J. J.
Harrison, M. Rule, E. F. Hilinski, J. A. Berson, J. Am. Chem. Soc.
1982, 104, 2233–2243; d) J. C. Tripp, C. H. Schiesser, D. P. Curran, J.
Am. Chem. Soc. 2005, 127, 5518–5527; e) I. Shinohara, M. Okue, Y.
Yamada, H. Nagaoka, Tetrahedron Lett. 2003, 44, 4649–4652; f) E.
Piers, A. M. Kaller, Tetrahedron Lett. 1996, 37, 5857–5860; g) F.
Saitoh, M. Mori, K. Okamura, T. Date, Tetrahedron 1995, 51, 4439–
4446; h) W. F. Bailey, A. D. Khanolkar, K. V. Gavaskar, J. Am.
Chem. Soc. 1992, 114, 8053–8060; i) B. G. Christensen, R. G. Stra-
chan, N. R. Trenner, B. H. Arison, R. Hirschman, J. M. Chemerda, J.
Am. Chem. Soc. 1960, 82, 3995–4000.
1
4
1
2
0H), 5.00 (d, J=2.26 Hz, 1H), 5.00–4.97 (m, 1H), 4.93–4.91 (m, 1H),
.48 (d, J=11.85 Hz, 1H), 4.23 (d, J=11.80, 1H), 3.73 (t, J=7.12 Hz,
H), 3.00 (m, 1H), 2.40 (d, J=7.79 Hz, 1H), 2.29 (d, J=4.79 Hz, 1H),
.21 (d, J=6.24 Hz, 2H), 2.15–1.95 (m, 1H), 1.88–1.86 (m, 1H), 1.78–1.76
(
(
m, 1H), 1.70 (s, 3H), 1.66 (s, 3H), 1.60 (m, 1H), 1.04 (s, 3H), 1.03 ppm
1
3
s, 3H). C NMR (100 Hz, CDCl
3
): d=198.76, 198.74, 198.71, 161.80,
1
1
1
3
1
1
8
61.76, 144.52, 144.46, 138.73, 138.62, 128.28, 128.24, 127.74, 127.72,
27.33, 127.1, 126.4, 113.82, 113.76, 101.76, 101.64, 100.72, 100.71, 100.63,
00.59, 82.79, 82.77, 82.72, 77.3, 77.0, 76.7, 69.9, 44.9, 43.61, 43.59, 40.1,
4.90, 34.89, 31.73, 31.57, 30.0, 28.48, 28.46, 28.42, 27.98, 27.94, 27.92,
9.61, 19.57, 16.58, 16.57 ppm. IR (neat): ~n =3065, 3031, 2958, 2361, 1963,
807, 1648, 1606, 1497, 1455, 1372, 1311, 1186, 1070, 1028, 990, 904,
À1
13 cm
.
[8] L. Van Hijfte, R. D. Little, J. L. Petersen, K. D. Moeller, J. Org.
Chem. 1987, 52, 4647–4661.
[
9] H. Gilman, R. G. Jones, L. A. Woods, J. Org. Chem. 1952, 17, 1630–
634.
Cycloaddition reaction of 16 and synthesis of (Æ)-Ceratopicanol (1)
A solution of aziridinylimine 16 (235 mg, 0.53 mmol) in toluene (53 mL,
1
[10] D. Regꢃs, M. M. Afonso, M. L. Rodrꢄguez, J. A. Palenzuela, J. Org.
Chem. 2003, 68, 7845–7852.
1
0 mm) was heated in an oil bath (ca. 1258C) for 18 h. The reaction mix-
ture was cooled to room temperature, and the solvent was removed in
vacuo. The residue was purified by column chromatography on silica gel
[11] a) M. Regitz, G. Mass, Diazo Compounds: Properties and Synthesis,
Academic Press, London, 1986, pp. 65–198; b) M. E. Furrow, A. G.
Myers, J. Am. Chem. Soc. 2004, 126, 12222–12223; c) V. K. Aggar-
wal, E. Alonso, I. Bae, G. Hynd, K. M. Lydon, H. J. Palmer, M.
Patel, M. Porcelloni, J. Richardson, R. A. Stenson, J. R. Studley, J.-
L. Vass, C. L. Winn, J. Am. Chem. Soc. 2003, 125, 10926–10940;
d) S. Kim, C. M. Cho, Tetrahedron Lett. 1995, 36, 4845–4848; e) H.
Kçnig, H. Metzger, K. Seelert, Chem. Ber. 1965, 98, 3724.
(
EtOAc/n-hexane=1:10) to give the cyclized product (123 mg,
0
0
.40 mmol, 75%) as a colorless oil. The cyclized product (120 mg,
.39 mmol) underwent hydrogenolysis with a shaker-type Parr Hydroge-
2
nator under H (60 psi), Pd/C (240 mg of 10 wt.% activated carbon), in
EtOH (5 mL) for 12 h. The mixture was filtered over a Celite pad, and
evaporated in vacuo. The crude product was purified by flash column
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Chem. Asian J. 0000, 00, 0 – 0
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Total Synthesis of Ceratopicanol
[
12] a) A. Padwa, H. Ku, J. Org. Chem. 1980, 45, 3756; b) A. G. Schultz,
J. P. Dittami, K. K. Eng, Tetrahedron Lett. 1984, 25, 1255; c) G. B.
Jones, C. J. Moody, A. Padwa, J. M. Kassir, J. Chem. Soc. Perkin
Trans. 1 1991, 1721.
[15] a) Gaussian 98 (RevisionA.6), M. J. Frisch, G. W. Trucks, H. B.
Schlegel, J. A. Pople, Gaussian, Pittsburgh, 1998; b) A. D. French,
A.-M. Kelterer, G. P. Johnson, M. K. Dowd, C. J. Cramer, J.
Comput. Chem. 2001, 22, 65–78.
[
13] R. K. Mueller, R. Joos, D. Felix, J. Schreiber, C. Wintner, A. Es-
chenmoser, Organic Synthesis; John Wiley & Sons, New York, 1988,
Collect Vol. VI, 56.
[16] R. W. Hoffmann, Chem. Rev. 1989, 89, 1841–1860.
[17] Y. Yoon, T. Kang, H. Y. Lee, Chem. Asian J. 2011, 6, 646–651.
Received: June 4, 2012
Published online: && &&, 0000
[
14] M. E. Jung, G. Piizzi, Chem. Rev. 2005, 105, 1735–1766.
Chem. Asian J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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FULL PAPER
Total Synthesis
Sang-Shin Lee, Won-Yeob Kim,
Hee-Yoon Lee*
&&&& — &&&&
Total Synthesis of Ceratopicanol
through Tandem Cycloaddition Reac-
tion of a Linear Substrate
When they all add up: Total synthesis
of ceratopicanol was achieved by using
a tandem cycloaddition reaction of
allenyl diazo compound 6 via a trime-
thylenemethane (TMM) diyl inter-
mediate. The TMM diyl mediated
[2+3] cycloaddition reaction furnished
the consecutive quaternary carbon cen-
ters and showed an unusual diastereo-
selectivity.
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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ÝÝ These are not the final page numbers!