Formal synthesis of cortistatins

Article abstract of DOI:10.1021/jo102202t

A unified strategy toward the asymmetric facile construction of the [6.7.6.5]oxapentacyclic skeleton of cortistatins is reported, featuring intramolecular Diels-Alder (IMDA), oxidative dearomatization, and an oxy-Michael addition reaction.

Full text of DOI:10.1021/jo102202t

ARTICLE
pubs.acs.org/joc
Formal Synthesis of Cortistatins
Lichao Fang,† Yuan Chen,† Jun Huang,† Lianzhu Liu,† Junmin Quan,† Chuang-chuang Li,*,† and
Zhen Yang*,†,‡
†Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University,
Shenzhen 518055, China
‡Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for
Molecular Science (BNLMS), College of Chemistry, Peking University, Beijing 100871, China
S Supporting Information
b
ABSTRACT: A unified strategy toward the asymmetric facile
construction of the [6.7.6.5]oxapentacyclic skeleton of cortis-
tatins is reported, featuring intramolecular Diels-Alder
(IMDA), oxidative dearomatization, and an oxy-Michael addi-
tion reaction.
’ INTRODUCTION
Cortistatins, isolated from the marine sponge Corticium
simplex in 2006 and 2007, are a novel type of steroidal natural
products.1 Among cortistatins, cortistatins A and J (Figure 1)
exhibit exceedingly potent and selective antiproliferative activity
against human umbilical vein endothelial cells (HUVECs).2
Cortistatins have an unprecedented oxabicyclo[3.2.1]heptane
ring system that lies within a complex tetracarbocyclic skeleton.
Given its fascinating structure and distinguished biological activity,
intensive efforts have been directed toward exploring feasible
strategies for the chemical syntheses of natural products, as ex-
emplified by their recent accomplishments of four total syntheses of
cortistatin A (1),3,11 and two formal total syntheses of cortistatin A
(1),4 as well as a number of studies toward the total synthesis of
cortistatins.5
In our previous communication,5i we reported our developed
Figure 1. Structures of cortistatins.
strategy toward the concise synthesis of the [6.7.6.5]oxapentacyclic
The construction of 13 was expected to be derived from 14
via a nucleophilic addition of water at C-5 in the course of a
hypervalent iodine7-triggered oxidative dearomatization event.8
We also envisaged that 14 could be constructed via the furan-
based IMDA9 promoted by a preorganized, favorable conforma-
tion of substrate 15 (see Scheme 1).10 Precursor 15 could be
conveniently assembled from simpler building blocks 16, 17,
and 18.
We believed the proposed chemistry mentioned above would
allow for rapid access to the elaborated polycyclic ring system in a
highly convergent manner. Herein we report our success in
implementing these synthetic designs for the synthesis of 12, a
key intermediate recently employed in the total syntheses of
cortistatins A, J, K, and L by Myers group.11
core of cortistatins, featuring an intramolecular Diels-Alder (IM-
DA) reaction to synthesize intermediate 10 from 11 (with a dual-
site activated acetylene), and an oxidatively dearomatizative cycliza-
tion to construct 8 from 10 (Figure 2).
When we carried out the proposed strategy toward the total
synthesis of cortistatin J, however, we found out that the removal
of the C1 carboxylate group in intermediate 8 became difficult,
which led us to explore an alternative approach toward its total
synthesis.
To apply retrosynthetic analysis to the second generation of our
total synthesis (Figure 2), compound 12, endowed with suitable
functionalities for further elaboration into the scaffold of cortista-
tins A (1) and J (5), could be derived from 13 through an
intramolecular oxy-Michael reaction. We reasoned that such
cyclization could be a favorable process in consideration of the
fact that the ring strain of 13 would be higher than that of the
cyclized adduct 28.6
Received: November 5, 2010
Published: March 10, 2011
r
2011 American Chemical Society
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Figure 2. Strategies for synthesis of cortistatins.
Scheme 1. Synthesis of D-A Precursor 15
Scheme 2. Optimization of the Key Diels-Alder Reaction
IMDA reaction with 15 as the substrate, the expected cyclization
product could not be formed or in low yield even at elevated
temperature or in the presence of Lewis acids, including TiCl4,
’ RESULTS AND DISCUSSION
Zn(OTf)2, BF3 Et2O, and TMSOTf (Scheme 2).
3
We then speculated that aluminum-based Lewis acids might
have the capability to promote the IMDA of 15, in consideration
of their highly oxygenophilic tendency,14 and of their successful
applications in the Diels-Alder reactions.15 To verify the
analysis, when 15 was treated with the dilute solutions of EtAlCl2
and Et2AlCl at low temperature, to our delight, 23 was obtained
in 51% yield and 10% yield, respectively. This transformation was
actually achieved by way of three reactions, namely Diels-Alder
reaction, aromatization, and TMS-deprotection.
To evaluate the TMS-group effect on the outcome of the
products of the Diels-Alder reaction, we then tested the reaction
with 25 as the substrate. To this end, aldehyde 21 was first treated
with ethynylmagnesium chloride, and the formed secondary
alcohol 24 was oxidized by MnO2 in CH2Cl2, affording 25 in
77% overall yield. We then started to evaluate the Diels-Alder
reaction. In the event, substrate 25 was treated with various Lewis
acids under the conditions listed in Scheme 3, and the results are
Construtions of the Pentacyclic Core Structure 28. Our
synthesis started with the preparation of the precursor 15
(Scheme 1). Synthetically, the easily prepared bicyclic enone
16 and furan-based alkyl iodide 17 were coupled12 under the
conditions listed in Scheme 1, affording 19 in 31% yield as well
as 32% of 16 recovered. This low yield presumably was due to
the competitive β-elimination of iodide 17 under basic
conditions.
To make 20, 19 was first converted into enol triflate, followed
by Pd-catalyzed methoxy carbonylation to give 20 in 76%
combined yield.13 Compound 20 first underwent DIBAL-H
reduction, and then was subjected to the oxidation of MnO2,
affording aldehyde 21 in 85% yield in two steps. Next, aldehyde
21 was treated with the in situ generated lithium trimethylsilyl
acetylene 18. The newly formed propargylic alcohol 22 was
oxidized to 15 in high yield by MnO2-mediated oxidation.
With 15 in hand, we then started to investigate the proposed
furan-based IMDA reaction. However, when we attempted the
listed in Scheme 3. Among the Lewis acids screened, BF3 Et2O
3
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Scheme 3. Alternative Diels-Alder Reaction
Scheme 4. Construction of Pentacyclic Intermediate 28
mediated Diels-Alder reaction gave the best result (47%),
affording 26 as a pair of inseparable diastereoisomers. When
EtAlCl2 and Et2AlCl were utilized as the activating agents to
promote the reactions, 23 and 26 were obtained, and in both
cases, the combined yields are less than 50%. It seemed that the
TMS group was a beneficial substitute for the aromatization step.
We therefore decided to employ 15 as the substrate to do the
Diels-Alder reaction.
Scheme 5. Oxy-Michael Addition Reaction
Having established the method for the construction of the
[6.7.6.5]tetracyclic core structure 23, we then shifted attention to
investigating the formation of oxabicyclo[3.2.1]heptane core by
directing the intramolecular Michael addition of the C-5 hydro-
xyl group to the Michael receptor in the presence of protic or
Lewis acids. To this end, 23 was first subjected regioselective
hydrogenation3f,16 to give 14 in 60% yield. The selectivity
observed in this reaction might be attributed to the steric effect
of the R-methyl group and also the high stability of the trans
product. After further treatment of 14 with BAIB17(bisacetoxy-
iodobenzene) in the presence of water, 13 was obtained in 36%
yield, together with its diastereoisomer 27 in 24% yield in a ratio
of 1.5:1. 27 could in turn be converted to 14 by Zn-Py/H2O
mediated reductive aromatization.18
We then began to study the formation of the oxabicyclo-
[3.2.1]heptane core of 28 from 13 (Scheme 4). Initially, we
attempted to use Amberlyst-15, Pd-catalyst,19a NaH, and t-
BuOK to promote the expected annulation; however, no desired
product was observed. We then applied NaOAc as the annulating
agent in ethanol19b,c to perform this annulation reaction, and the
expected product 28 was generated in 70% yield. The stereo-
chemistry of 28 was confirmed by the X-ray crystallography
analysis.
products 13a and 27a were obtained in good yields. 13a and 27a
then underwent the oxy-Michael reactions under the conditions
listed in Scheme 2, and the cyclized products 28a and 28b were
obtained in 50% yield and 66% yield, respectively. In addition, 27
could also be annulated, affording product 28c in 76% yield at
elevated temperature (75 °C) (Scheme 5).
Construction of the Functionalized Pentacyclic Core. To
complete the synthesis of key intermediate 12, we started from
exploring the installation of both the alkene group in the central
7-membered ring and the functionalization of the A ring.
We tested various regioselective methods to reduce the ketone
at C-19 of 28, and eventually found out that LiBHEt3 served as an
effective agent to fulfill this conversion. In that event, compound
28 was dissolved in THF, and treated with LiBHEt3 (1.0 equiv)
at -78 °C to regioselectively generate a secondary alcohol of
C-19 in good yield. To form the double bond, the newly formed
Profiling the Scope of the Oxy-Michael Addition Reaction.
To demonstrate the significance of the oxy-Michael addition
reaction as a useful method for the formation of the oxabicyclo-
[3.2.1]heptane core, substrates 13 and 27 were subjected to the
regioselective hydrogenation to remove the double bond at C3
and C4 with Rh(PPh3)3Cl as catalyst. As a result, the desired
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Scheme 6. Synthesis of Key Intermediates 12 and 31
unless otherwise noted. All the chemicals were purchased commercially,
and used without further purification. Anhydrous THF and dioxane
were distilled from sodium-benzophenone, and dichloromethane was
distilled from calcium hydride. Yields refer to chromatographically,
unless otherwise stated.
Experimental Procedures. Synthesis of (1S,7aS)-1-(tert-
butyldimethylsilyloxy)-4-(2-(furan-2-yl)ethyl)-7a-methyl-2,-
3,7,7a-tetrahydro-1H-inden-5(6H)-one (19): To a solution of
DMSO (30 mL) was added NaH (60%, 855 mg, 21.36 mmol), and the
mixture was stirred at 65 °C under N2 for 2 h, and then cooled to 0 °C.
To this solution was added bicyclic enone 16 (5 g, 17.8 mmol) in DMSO
(50 mL) in a dropwise manner, and the formed mixture was then
warmed to room temperature and stirred for an additional 4 h. The
mixture was cooled to 0 °C again, and to this solution was slowly added a
solution of 2-(2-iodoethyl)furan 17 (4.35 g, 19.6 mmol) in 30 mL of
DMSO, and the reaction mixture was then warmed to room temperature
and stirred overnight. The reaction was quenched by addition of a
saturated aqueous solution of NH4Cl (50 mL), and the aqueous layer
was extracted by EtOAc (3 ꢀ 100 mL). The combined organic layer was
dried over Na2SO4. The solvent was removed under vacuum, and the
residue was purified by flash chromatography on silica gel (hexane/
EtOAc = 100/1) to give the desired alkylation product 19 (2.1 g, 31%
yield) as a yellow oil (Rf 0.8 (hexane/EtOAc = 8/1), together with
recovered starting material (1.6 g): 1H NMR (500 MHz, CDCl3) δ 6.25
(dd, J = 2.8, 2.0 Hz, 1H), 5.89 (d, J = 2.9 Hz, 1H), 3.63 (dd, J = 10.2, 7.4
Hz, 1H), 2.69 (t, J = 7.2 Hz, 2H), 2.58-2.43 (m, 2H), 2.38 (ddd, J = 6.7,
5.7, 2.2 Hz, 2H), 2.24-2.09 (m, 2H), 1.97 (ddd, J = 12.7, 5.4, 1.8 Hz,
1H), 1.85 (ddd, J = 15.8, 9.2, 2.3 Hz, 1H), 1.74-1.64 (m, 2H), 1.02 (s,
3H), 0.90 (s, 9H), 0.04 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 197.6,
168.7, 155.1, 140.2, 131.1, 109.7, 105.2, 80.4, 45.0, 33.7, 33.0, 29.4, 26.1,
25.3, 24.3, 17.5, 14.9, -4.9, -5.4; HRMS-ESI Calcd for C22H35O3Si
[M þ Hþ] 375.2350, found 375.2357.
secondary alcohol was first treated with the typical dehydration
agents, such as Py/SOCl2, Burgess reagent,20 p-TSA/CH(OEt)3,21
and Martin’s sulfurane.22 To our surprise, no desired product was
obtained. Gratifyingly, when the alcohol was converted into its
mesylate, followed by treatment with LiBr and Li2CO3 under
elevated temperature,23 the desired elimination product 29 was
obtained in moderate yield. To make the target molecule 12,
compound 29 was regioselectively hydrogenated in the presence
of Wilkinson’s catalyst24 under balloon pressure of hydrogen to give
dienone 30. Dienone 30 was then converted to its corresponding
silyl enol ether, followed by a regio- and stereoselective reaction with
NBS25 to afford the expected product 12 in 80% yield (Scheme 6).
The stereochemistry of compound 12 was also confirmed by its
X-ray crystallography analysis.
Furthermore, after accomplishing the key intermediate 12, we
also did further manipulations of the A ring. According to the
configuration of the bromo in 12, we envisioned that a direct
SN2-type displacement would install the dimethyl amino group
in the desired configuration. Fortunately, when substrate 12 was
treated with dimethyl amino lithium at -78 °C, which was
generated by deprotonation of Me2NH gas in solution, the
desired amino product 31 was generated in good yield. Com-
pound 31 was found to be quite unstable, even in CDCl3 at room
temperature for several hours. Finally, reduction of the ketone
with LiBHEt3 furnished amino alcohol 32 in good yield, although
the configuration of hydroxyl group was found opposite to that of
natural product. This may provide an opportunity for total
synthesis of C(2)-epi-cortistatins.
Synthesis of (1S,7aS)-methyl 1-(tert-butyldimethylsilyl-
oxy)-4-(2-(furan-2-yl)-ethyl)-7a-methyl-2,6,7,7a-tetrahydro-
1H-indene-5-carboxylate (20): To a solution of alkylation com-
pound 19 (749 mg, 2 mmol) in DCM (20 mL) was added 2,4,6-
trimethylpyridine (485 mg, 0.53 mL, 4 mmol) in a dropwise manner,
and the formed mixture was cooled to 0 °C. To this solution was added
trifluoromethanesulfinic anhydride (677 mg, 0.4 mL, 2.4 mmol) slowly,
and the reaction mixture was stirred for an additional 1 h. The reaction
was quenched by addition of a saturated aqueous solution of NH4Cl
(20 mL), and the mixture was extracted by CH2Cl2 (3 ꢀ 30 mL). The
combined organic layer was sequentially washed with 1 N HCl (2 ꢀ
8 mL), water (8 mL), and brine (8 mL), and finally dried over Na2SO4.
The solvent was removed under vacuum, and the residue was used
directly in the next step without purification. It is worthwhile to mention
that the crude product was not stable, even at -20 °C.
To a solution of Pd(OAc)2 (45 mg, 0.2 mmol) and PPh3 (105 mg, 0.4
mmol) in MeOH (6 mL) under N2 was added the fresh made triflate
(dissolved in 4 mL of MeOH) and Hunig’s base (0.5 mL, 3.0 mmol).
The reaction mixture was saturated with CO for 30 min, then heated to
50 °C for 48 h. The reaction was quenched by filtration of the mixture
through a plug of Celite and washed with diethyl ether (3 ꢀ 20 mL). The
solvent was removed under vacuum, and the residue was purified by flash
chromatography on silica gel (hexane/EtOAc = 100/1) to give the
desired methyl ester 20 (625 mg) in 76% yield as colorless oil in 2 steps:
Rf 0.8 (hexane/EtOAc = 10/1); 1H NMR (500 MHz, CDCl3) δ 7.29 (d,
J = 1.1 Hz, 1H), 6.25 (dd, J = 2.9, 2.0 Hz, 1H), 5.98 (d, J = 2.9 Hz, 1H),
5.81 (s, 1H), 3.95 (dd, J = 8.6, 7.8 Hz, 1H), 3.74 (s, 3H), 3.00-2.88 (m,
1H), 2.84-2.76 (m, 3H), 2.58-2.34 (m, 4H), 1.88-1.80 (m, 1H), 1.29
(td, J = 12.0, 6.2 Hz, 1H), 0.92 (s, 9H), 0.89 (s, 3H), 0.07 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 170.0, 156.7, 147.0, 141.7, 141.6, 127.0,
124.9, 110.9, 105.9, 83.0, 52.2, 46.4, 39.6, 34.5, 29.3, 29.2, 26.7, 25.9,
’ CONCLUSION
In summary, we have developed an asymmetric synthesis
of oxabicyclo[3.2.1]heptane core via a furan-based IMDA reac-
tion and an intramolecular oxy-Michael addition as the key steps.
The work described herein demonstrates the usefulness of our
strategy for the synthesis of the key intermediate 12, which can be
used for the syntheses of cortistatins, as well as other analogues.
’ EXPERIMENTAL SECTION
Materials and Methods. All reactions were carried out under a
nitrogen atmosphere with dry solvents under anhydrous conditions,
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18.9, 16.0, -3.6, -3.9; HRMS-ESI calcd for C24H37O4Si [M þ Hþ]
417.2456, found 417.2463.
134.5, 134.1, 129.79, 128.8, 118.9, 118.6, 110.1, 105.4, 105.3, 105.1, 89.7,
82.2, 82.1, 62.2, 61.4, 45.8, 45.6, 38.6, 38.6, 33.9, 28.0, 27.7, 26.3, 26.2,
25.9, 22.1, 22.0, 18.1, 15.2, 15.0, -0.15, -0.16, -4.48, -4.79; HRMS-
ESI calcd for C28H44O3NaSi2 [M þ Naþ] 507.2721, found 507.2712.
Synthesis of 1-((1S,7aS)-1-(tert-butyldimethylsilyloxy)-4-
(2-(furan-2-yl)ethyl)-7a-methyl-2,6,7,7a-tetrahydro-1H-in-
den-5-yl)-3-(trimethylsilyl)prop-2-yn-1-one (15): To a solution
of propagylic alcohol 22 (350 mg, 0.72 mmol) in CH2Cl2 (10 mL) was
added activated MnO2 (88%, 711 mg, 7.2 mmol) at room temperature,
and the mixture was stirred at the same temperature overnight. The
reaction was quenched by filtration of the mixture through a plug of
Celite, and washed with CH2Cl2 (3 ꢀ 30 mL). The filtrate was
concentrated under vacuum to give the crude alkynyl ketone product
15 (317 mg) in 91% yield as a yellow oil: Rf 0.8 (hexane/EtOAc = 10/1);
1H NMR (500 MHz, CDCl3) δ 7.29 (d, J = 1.0 Hz, 1H), 6.26 (dd, J =
3.0, 1.9 Hz, 1H), 6.00 (d, J = 3.0 Hz, 1H), 5.96 (s, 1H), 3.95 (dd, J = 8.8,
7.7 Hz, 1H), 3.15-3.03 (m, 1H), 2.98-2.87 (m, 1H), 2.79 (dd, J = 14.8,
6.7 Hz, 3H), 2.61-2.46 (m, 2H), 2.40 (dd, J = 16.9, 9.0 Hz, 1H), 1.91
(dd, J = 12.5, 4.6 Hz, 1H), 1.34-1.28 (m, 1H), 0.92 (s, 9H), 0.89 (s,
3H), 0.23 (s, 9H), 0.06 (d, J = 2.3 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ 178.1, 154.8, 146.0, 142.8, 140.0, 131.6, 126.5, 109.4, 104.4, 102.6,
98.1, 81.1, 44.7, 38.2, 32.7, 27.8, 27.1, 25.1, 24.5, 17.3, 14.5, -1.5, -5.2,
-5.5; HRMS-ESI calcd for C28H43O3Si2 [M þ Hþ] 483.2745, found
483.2752.
Synthesis of (1S,7aS)-1-(tert-butyldimethylsilyloxy)-4-(2-
(furan-2-yl)ethyl)-7a-methyl-2,6,7,7a-tetrahydro-1H-inde-
ne-5-carbaldehyde (21): To a solution of methyl ester 20 (680 mg,
1.63 mmol) in DCM (15 mL) was added DIBAL (1.0 M in toluene,
3.4 mL, 3.4 mmol) at -78 °C slowly over 5 min, and the formed mixture
was stirred at the same temperature for 15 min. The reaction was
quenched by addition of a saturated solution of sodium potassium
tartrate (30 mL), and the mixture was stirred until a clear solution was
obtained. The mixture was extracted with CH2Cl2 (3 ꢀ 30 mL), and the
combined organic layer was dried over Na2SO4. The solvent was
removed under vacuum, and the residue was purified by flash chroma-
tography on silica gel (hexane/EtOAc = 6/1) to give a primary alcohol
(571 mg) in 90% yield as a colorless oil: Rf 0.4 (hexane/EtOAc = 5/1);
1H NMR (300 MHz, CDCl3) δ 7.36 - 7.27 (m, 1H), 6.26 (dd, J = 3.0,
1.9 Hz, 1H), 5.94 (d, J = 3.0 Hz, 1H), 5.46 (s, 1H), 4.05 (d, J = 12.1 Hz,
1H), 3.94 (dd, J = 14.5, 7.1 Hz, 2H), 2.78-2.67 (m, 2H), 2.61 (dd, J =
14.9, 7.6 Hz, 2H), 2.42 (dd, J = 10.1, 5.6 Hz, 2H), 2.31 (d, J = 6.0 Hz,
2H), 2.04 (s, 1H), 1.89-1.77 (m, 1H), 1.29 (s, 1H), 0.94 (s, 9H), 0.90
(s, 3H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 155.5, 146.0, 140.9,
134.9, 128.8, 117.6, 110.0, 105.3, 82.1, 62.1, 45.6, 38.4, 33.9, 27.9, 26.0,
25.8, 25.6, 18.0, 15.0, -4.6, -4.9; HRMS-ESI calcd for C23H36O3NaSi
[M þ Naþ] 411.2326, found 411.2326.
To a solution of the primary alcohol made above (350 mg, 0.9 mmol)
in CH2Cl2 (10 mL) was added activated MnO2 (88%, 886 mg, 9 mmol)
at room temperature, and the formed mixture was stirred at the same
temperature overnight. The reaction was quenched by filtration of the
mixture through a plug of Celite and washed with CH2Cl2 (2 ꢀ 10 mL).
The filtrate was concentrated under vacuum, and the residue was purified
by flash chromatography on silica gel (hexane/EtOAc = 15/1) to give the
desired aldehyde 21 (327 mg) in 94% yield as a light yellow oil: Rf 0.7
(hexane/EtOAc = 5/1); 1H NMR (500 MHz, CDCl3) δ 9.93 (s, 1H),
7.30 (d, J = 1.1 Hz, 1H), 6.25 (dd, J = 2.9, 1.9 Hz, 1H), 6.06 (s, 1H), 5.95
(d, J = 2.9 Hz, 1H), 3.98 (dd, J = 8.8, 7.7 Hz, 1H), 3.09 (dd, J = 14.0, 7.1
Hz, 1H), 2.98-2.89 (m, 1H), 2.86-2.78 (m, 2H), 2.60-2.48 (m, 2H),
2.45 (d, J = 9.0 Hz, 1H), 2.25-2.14 (m, 1H), 1.87 (dd, J = 12.5, 5.4 Hz,
1H), 1.21 (dd, J = 12.6, 7.0 Hz, 1H), 0.92 (s, 9H), 0.88 (s, 3H), 0.06 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 191.0, 153.7, 147.0, 146.6, 141.1,
133.5, 126.6, 110.0, 106.1, 81.6, 45.5, 38.8, 32.6, 29.1, 25.6, 24.8, 20.3,
17.8, 15.1, -4.7, -5.0; HRMS-ESI calcd for C23H35O3Si [M þ Hþ]
387.2350, found 387.2343.
Synthesis of 1-((1S,7aS)-1-(tert-butyldimethylsilyloxy)-
4-(2-(furan-2-yl)ethyl)-7a-methyl-2,6,7,7a-tetrahydro-1H-
inden-5-yl)-3-(trimethylsilyl)prop-2-yn-1-ol (22): To a solution
of trimethylsilyl acetylene 18 (245 mg, 0.36 mL, 2.49 mmol) in THF
(10 mL) was added n-BuLi (2.5 M in hexane, 1 mL, 2.49 mmol)
at -78 °C in a dropwise manner, and the mixture was stirred at the same
temperature for 30 min. To this solution was added a solution of
aldehyde 21 (320 mg, 0.83 mmol) in THF (10 mL), and the formed
mixture was stirred at the same temperature for 40 min. The reaction was
quenched by addition of a saturated aqueous solution of NH4Cl
(20 mL). The mixture was extracted by EtOAc (3 ꢀ 30 mL), and the
combined organic layer was dried over Na2SO4. The solvent was
removed under vacuum, and the residue was purified by flash chroma-
tography on silica gel (hexane/EtOAc = 15/1) to give the desired
propagylic alcohol 22 (381 mg) in 95% yield as a pair of diastereoi-
somers: Rf 0.4 (hexane/EtOAc = 10/1); 1H NMR (300 MHz, CDCl3) δ
7.33 (ddd, J = 6.3, 1.7, 0.7 Hz, 1H), 6.27 (ddd, J = 4.9, 3.1, 1.9 Hz, 1H),
5.97 (d, J = 2.9 Hz, 1H), 5.52 (d, J = 2.6 Hz, 1H), 5.24 (dd, J = 12.1, 3.7
Hz, 1H), 4.00-3.87 (m, 1H), 2.84-2.69 (m, 2H), 2.69-2.55 (m, 2H),
2.54-2.32 (m, 4H), 1.87 (dd, J = 12.0, 3.7 Hz, 1H), 1.32 (dd, J = 13.1,
7.1 Hz, 1H), 0.92 (s, 9H), 0.88 (s, 3H), 0.17 (d, J = 4.2 Hz, 9H), 0.07 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 155.6, 155.4, 146.2, 141.1, 141.0,
Synthesis of dienone-phenol 23: To a solution of the crude
alkynyl ketone 15 (410 mg, 0.85 mmol) made above in CH2Cl2
(140 mL) was slowly added EtAlCl2 (0.9 M in heptane, 1.4 mL, 1.3
mmol) at -78 °C, and the mixture was stirred at the same temperature
for 10 min. After worming to °C, the mixture was stirred for an additional
1 h. The reaction was quenched by addition of a saturated solution of
sodium potassium tartrate (50 mL), and the formed water layer was
extracted with CH2Cl2 (3 ꢀ 60 mL), then the combined organic layer
was dried over Na2SO4. The solvent was removed under vacuum, and
the residue was purified by flash chromatography on silica gel (hexane/
EtOAc = 10/1) to give the desired dienone-phenol product 23 (177 mg)
in 51% yield as a light yellow solid: Rf 0.2 (hexane/EtOAc = 5/1). This
procedure was applied to the other Lewis acid-catalyzed reactions
1
described in the text. H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 2.7
Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.92 (dd, J = 8.1, 2.7 Hz, 1H), 6.23 (s,
1H), 6.00 (s, 1H), 4.04-3.95 (m, 1H), 3.05-2.80 (m, 4H), 2.64-2.37
(m, 4H), 1.92 (dd, J = 12.5, 5.0 Hz, 1H), 1.30 (d, J = 5.7 Hz, 1H), 0.92 (s,
9H), 0.89 (s, 3H), 0.06 (d, J = 3.7 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ 197.0, 155.1, 147.8, 145.1, 140.5, 135.0, 132. 8, 129.4, 126.4, 119.3,
116.6, 81.9, 45.7, 39.0, 33.5, 32.4, 30.2, 25.87, 25.1, 18.0, 15.0, -4.6, -4.8;
HRMS-ESI calcd for C25H35O3Si [M þ Hþ] 411.2350, found
411.2351.
Synthesis of 1-((1S,7aS)-1-(tert-butyldimethylsilyloxy)-4-
(2-(furan-2-yl)ethyl)-7a-methyl-2,6,7,7a-tetrahydro-1H-in-
den-5-yl)prop-2-yn-1-ol (24): To a solution of aldehyde 21 (1160
mg, 3.0 mmol) in THF (30 mL) was added ethynyl magnesium chloride
(0.6 M in THF/toluene, 10 mL, 6.0 mmol) at 0 °C in a dropwise
manner, and the mixture was stirred at the same temperature for 30 min.
The reaction was quenched by addition of a saturated aqueous solution
of NH4Cl (20 mL), and the formed mixture was extracted by EtOAc
(3 ꢀ 40 mL). The combined organic layer was dried over Na2SO4. The
solvent was removed under vacuum, and the residue was purified by flash
chromatography on silica gel (hexane/EtOAc = 15/1) to give propagylic
alcohol 24 (1126 mg) in 91% yield as a pair of diastereoisomers: Rf 0.5
(hexane/EtOAc = 5/1); 1H NMR (300 MHz, CDCl3) δ 7.41-7.30 (m,
1H), 6.28 (ddd, J = 4.9, 3.1, 1.9 Hz, 1H), 5.97 (d, J = 3.0 Hz, 1H), 5.62-
5.46 (m, 1H), 5.33-5.16 (m, 1H), 3.95 (t, J = 7.8 Hz, 1H), 2.74 (td, J =
8.2, 3.1 Hz, 2H), 2.63 (dd, J = 7.4, 4.4 Hz, 2H), 2.52-2.31 (m, 5H),
1.93-1.81 (m, 1H), 1.37-1.26 (m, 1H), 0.96-0.87 (m, 12H), 0.07 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 155.4, 155.2, 146.0, 145.9, 141.2,
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141.1, 134.0, 133.5, 129.9, 128.8, 119.2, 119.0, 110.1, 105.5, 105.4, 83.3,
83.0, 82.1, 82.0, 73.2, 73.1, 61.6, 60.8, 45.6, 45.5, 38.5, 38.4, 33.7, 28.0,
27.6, 26.2, 26.0, 25.8, 21.9, 21.8, 18.0, 15.1, 15.0, -4.5, -4.8; HRMS-ESI
calcd for C25H36O3NaSi [M þ Naþ] 435.2326, found 435.2332.
Synthesis of 1-((1S,7aS)-1-(tert-butyldimethylsilyloxy)-4-
(2-(furan-2-yl)ethyl)-7a -methyl-2,6,7,7a-tetrahydro-1H-in-
den-5-yl)prop-2-yn-1-one (25): To a solution of propagylic alcohol
24 (95 mg, 0.23 mmol) in CH2Cl2 (6 mL) was added activated MnO2
(88%, 227 mg, 2.3 mmol) at room temperature, and the mixture was
stirred overnight. The reaction mixture was filtered off through a silica
gel pad and washed through with CH2Cl2 (3 ꢀ 20 mL). The filtrate was
removed under vacuum, and the residue was purified by flash chroma-
tography on silica gel (hexane/EtOAc = 20/1) to give alkynyl ketone 25
(80 mg) in 85% yield: Rf 0.5 (hexane/EtOAc = 10/1); 1H NMR (500
MHz, CDCl3) δ 7.29 (dd, J = 1.7, 0.7 Hz, 1H), 6.26 (dd, J = 3.0, 1.9 Hz,
1H), 6.00 (dd, J = 4.9, 1.8 Hz, 2H), 3.96 (dd, J = 8.9, 7.6 Hz, 1H), 3.31 (s,
1H), 3.11-3.01 (m, 1H), 2.91 (dt, J = 12.3, 8.0 Hz, 1H), 2.86-2.75 (m,
3H), 2.65-2.55 (m, 1H), 2.50 (ddd, J = 17.0, 7.5, 3.6 Hz, 1H), 2.40 (dd,
J = 17.0, 9.0 Hz, 1H), 1.91 (dd, J = 12.6, 4.4 Hz, 1H), 1.31 (td, J = 12.5,
5.7 Hz, 1H), 0.92 (s, 9H), 0.89 (s, 3H), 0.06 (d, J = 1.8 Hz, 6H); 13C
NMR (75 MHz, CDCl3) δ 179.2, 155.3, 146.5, 144.4, 140.7, 131.7,
128.0, 110.1, 105.2, 82.5, 81.7, 79.8, 45.3, 38.9, 33.3, 28.4, 27.9, 25.7,
25.2, 18.0, 15.2, -4.6, -4.9; HRMS-ESI calcd for C25H35O3Si [M þ
Hþ] 411.2350, found 411.2357.
CDCl3) δ 197.0, 157.0, 155.1, 141.9, 133.6, 131.5, 129.0, 118.8, 116.1,
80.2, 49.8, 42.8, 33.6, 33.5, 32.4, 31.4, 26.0, 25.8, 22.5, 18.0, 11.1, -4.5,
-4.8; HRMS-ESI calcd for C25H37O3Si [M þ Hþ] 413.2506, found
413.2502.
Synthesis of tertiary alcohol 13: To a solution of enone-phenol
14 (100 mg, 0.24 mmol) in CH3CN (20 mL) and H2O (5 mL) was
slowly added iodobenzene diacetate (116 mg, 0.36 mmol) at 0 °C, and
the mixture was stirred at the same temperature for 40 min. The reaction
was quenched by addition of a saturated solution of NaHCO3 (20 mL),
the mixture was extracted with EtOAc (3 ꢀ 30 mL), and the combined
organic layer was then dried over Na2SO4. The solvent was removed
under vacuum, and the residue was purified by flash chromatography on
silica gel (hexane/EtOAc = 6/1) to give the desired tertiary alcohol 13
(37 mg) in 36% yield (Rf 0.2 (hexane/EtOAc = 3/1), together with its
diastereoisomer 27 (25 mg) in 24% yield (Rf 0.3 (hexane/EtOAc = 3/
1)). For tertiary alcohol 13: 1H NMR (500 MHz, CDCl3) δ 6.83 (d, J =
10.0 Hz, 1H), 6.15 (d, J = 1.8 Hz, 1H), 6.07 (dd, J = 10.0, 1.9 Hz, 1H),
3.75 (s, 1H), 3.68 (t, J = 8.1 Hz, 1H), 2.48-2.26 (m, 5H), 2.17 (ddd, J =
13.9, 5.2, 3.1 Hz, 1H), 2.12-1.99 (m, 2H), 1.88-1.79 (m, 1H), 1.75
(dd, J = 11.6, 6.9 Hz, 1H), 1.62-1.46 (m, 2H), 1.28 (dd, J = 21.2, 9.8 Hz,
1H), 0.87 (s, 9H), 0.64 (s, 3H), 0.01 (d, J = 5.1 Hz, 6H); 13C NMR (125
MHz, CDCl3) δ 194.8, 185.9, 161.2, 159.3, 151.3, 134.4, 125.9,
125.6, 80.1, 70.1, 48.9, 43.1, 38.5, 32.8, 31.1, 27.5, 25.8, 24.0, 22.5,
18.0, 11.1, -4.5, -4.8; HRMS-ESI calcd for C25H37O4Si [M þ Hþ]
429.2456, found 429.2453. For tertiary alcohol 27: 1H NMR (500 MHz,
CDCl3) δ 6.89 (d, J = 10.0 Hz, 1H), 6.50 (d, J = 1.7 Hz, 1H), 6.11 (dd,
J = 10.0, 1.7 Hz, 1H), 3.77-3.67 (m, 1H), 2.69 (d, J = 10.5 Hz, 1H),
2.52-2.44 (m, 1H), 2.33 (d, J = 11.7 Hz, 3H), 2.13 (ddd, J = 29.9, 14.9,
7.5 Hz, 3H), 2.04 (d, J = 12.1 Hz, 1H), 1.87 (dd, J = 12.7, 7.6 Hz, 1H),
1.83-1.75 (m, 1H), 1.63 (s, 2H), 0.90 (s, 9H), 0.80 (s, 3H), 0.04 (d, J =
4.6 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 195.0, 187.0, 160.8, 156.5,
152.2, 136.0, 128.2, 126.1, 81.0, 71.3, 49.8, 43.9, 39.1, 33.9, 32.1, 28.3,
26.8, 24.7, 22.8, 19.0, 12.1, -3.6, -3.9; HRMS-ESI calcd for
C25H37O4Si [M þ Hþ] 429.2456, found 429.2465.
Synthesis of dienone 26: To a solution of alkynyl ketone 25 (30
mg, 0.073 mmol) in CH2Cl2 (12 mL, 0.006 M) at -78 °C was slowly
added BF3 Et2O (48% BF3, 29 μL, 0.11 mmol), and the mixture was
3
stirred at the same temperature for 1 h. The reaction was quenched by
addition of a saturated solution of NaHCO3 (10 mL), and the formed
mixture was extracted with CH2Cl2 (3 ꢀ 20 mL). The combined organic
layer was dried over Na2SO4. The solvent was removed under vacuum,
and the residue was purified by flash chromatography on silica gel
(hexane/EtOAc = 15/1) to give dienone product 26 (14 mg) in 47%
yield: Rf 0.3 (hexane/EtOAc = 10/1); 1H NMR (500 MHz, CDCl3) δ
6.72 (dd, J = 10.7, 6.1 Hz, 1H), 6.21 (dd, J = 12.6, 3.1 Hz, 1H), 6.12 (d,
J = 10.7 Hz, 1H), 5.97 (dd, J = 21.6, 1.8 Hz, 1H), 5.58 (d, J = 15.1 Hz,
1H), 3.87-3.72 (m, 1H), 3.52-3.39 (m, 1H), 2.95 (ddd, J = 38.6, 14.9,
5.1 Hz, 1H), 2.87-2.75 (m, 1H), 2.58 (d, J = 13.5 Hz, 1H), 2.50 (dd, J =
13.4, 5.0 Hz, 1H), 2.41 (ddd, J = 16.2, 7.4, 3.4 Hz, 1H), 2.27 (ddd, J =
30.6, 22.4, 11.3 Hz, 1H), 2.00 (dd, J = 18.4, 5.2 Hz, 1H), 1.67 (dd, J =
12.6, 4.4 Hz, 1H), 1.21 (td, J = 12.4, 5.5 Hz, 1H), 0.88 (d, J = 2.8 Hz, 9H),
0.80 (s, 3H), 0.01 (dd, J = 6.7, 2.6 Hz, 6H); 13C NMR (125 MHz,
CDCl3) δ 202.7, 202.4, 155.3, 155.2, 150.3, 150.1, 146.4, 145.1, 142.0,
140.7, 132.5, 132.4, 131.2, 130.5, 123.6, 123.5, 120.7, 120.2, 109.6, 109.4,
109.2, 108.9, 81.9, 81.7, 45.6, 45.3, 38.4, 33.5, 33.0, 28.5, 27.3, 26.2, 26.0,
25.8, 25.4, 24.3, 18.0, 15.3, 14.8, -4.6, -4.5, -4.8, -4.9; HRMS-ESI
calcd for C25H35O3Si [M þ Hþ] 411.2350, found 411.2346.
Synthesis of diketone 28: To a solution of tertiary alcohol 13
(100 mg, 0.233 mmol) in EtOH (50 mL) was added NaOAc 3H2O
3
(317 mg, 2.33 mmol) at room temperature, and the mixture was stirred
at 50 °C for 36 h. After cooling to room temperature, the reaction was
quenched by the addition of water (30 mL) and EtOH (30 mL), the
mixture was extracted with EtOAc (3 ꢀ 30 mL), and the combined
organic layer was dried over Na2SO4. The solvent was removed under
vacuum, and the residue was purified by flash chromatography on Al2O3
(hexane/EtOAc = 10/1) to give the desired diketone 28 (70 mg) in 70%
1
yield as a light yellow solid: Rf 0.8 (hexane/EtOAc = 3/1); H NMR
(500 MHz, CDCl3) δ 6.86 (d, J =10.1 Hz, 1H), 6.49 (d, J =1.75 Hz, 1H),
6.32 (dd, J = 10.1, 1.8 Hz, 1H), 3.67 (t, J =7.9 Hz, 1H), 2.50 (dd, J =13.2,
3.6 Hz, 1H), 2.18-2.10 (m, 3H), 2.04-1.92 (m, 3H), 1.79-1.72 (m,
3H), 1.59-1.54 (m, 3H), 1.09-1.03 (m, 1H), 0.89 (s, 9H), 0.74 (s,
3H), 0.03 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 199.2, 186.8, 153.9,
148.5, 130.9, 124.5, 88.3, 82.2, 78.8, 64.3, 51.1, 45.9, 39.6, 36.7, 31.4,
27.7, 26.7, 21.0, 20.3, 19.0, 12.8, -3.5, -3.9; HRMS-ESI calcd for
C25H37O4Si [M þ Hþ] 429.2456, found 429.2468.
The procedure for other Lewis acids-catalyzed reactions was similar
to the one mentioned above.
Synthesis of enone-phenol 14: To a solution of Pd/BaSO4
(5% wt/wt, 52 mg, 0.049 mmol) in dried EtOAc (120 mL) was added
dienone-phenol 23 (200 mg, 0.49 mmol), and the mixture was stirred
under balloon pressure of H2 atmosphere at room temperature for 3 h.
The reaction was quenched by filtration through Celite, and washed with
EtOAc (3 ꢀ 30 mL). The solvent was removed under vacuum, and the
residue was purified by flash chromatography on silica gel (hexane/
EtOAc = 10/1) to give the desired enone-phenol 14 (120 mg) in 60%
Synthesis of diketone 28a: To a solution of Wilkinson’s catalyst
(9 mg, 0.01 mmol) in dried benzene (4 mL) was added a solution of the
tertiary alcohol 13 (45 mg, 0.1 mmol) in benzene (3 mL), and the
reaction mixture was stirred at room temperature under balloon pressure
of H2 overnight. The mixture was then filtered off through a silica gel
pad and washed with EtOAc (3 ꢀ 10 mL). The solvent was removed
under vacuum, and the residue was purified by flash chromatography
on silica gel (hexane/EtOAc = 4/1) to give a tertiary alcohol (33 mg) in
73% yield.
1
yield as a light yellow solid: Rf 0.5 (hexane/EtOAc = 3/1); H NMR
(500 MHz, CDCl3) δ 7.44 (d, J = 2.6 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H),
6.92 (dd, J = 8.1, 2.6 Hz, 1H), 3.73-3.61 (m, 1H), 3.03-2.91 (m, 1H),
2.83-2.69 (m, 2H), 2.51 (dd, J = 19.2, 10.9 Hz, 3H), 2.32 (d, J = 11.2
Hz, 1H), 2.05 (dt, J = 8.8, 6.6 Hz, 1H), 1.88 (dd, J = 12.4, 7.4 Hz, 1H),
1.82-1.73 (m, 1H), 1.64-1.51 (m, 2H), 1.30 (td, J = 12.0, 8.0 Hz, 1H),
0.90 (s, 9H), 0.70 (s, 3H), 0.04 (d, J = 6.2 Hz, 6H); 13C NMR (125 MHz,
To a solution of the tertiary alcohol (20 mg, 0.046 mmol) made above
in EtOH (10 mL) at room temperature was added NaOAc 3H2O (63
3
mg, 0.46 mmol), then the mixture was stirred at 75 °C for 12 h. The
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ARTICLE
reaction was quenched by addition of water (10 mL) and EtOH, and the
mixture was concentrated under vacuum to remove the ethanol. The
remaining water layer was extracted with EtOAc (3 ꢀ 10 mL), and the
combined organic layer was then dried over Na2SO4. The solvent was
removed under vacuum, and the residue was purified by flash chromatog-
raphy on Al2O3 (hexane/EtOAc = 8/1) to give diketone 28a (10 mg) in
50% yield: Rf 0.7 (hexane/EtOAc = 3/1); 1H NMR (300 MHz, CDCl3) δ
6.35 (d, J = 1.1 Hz, 1H), 3.74-3.59 (m, 1H), 2.72-2.55 (m, 1H), 2.55-
2.38 (m, 2H), 2.34-2.07 (m, 4H), 2.07-1.82 (m, 3H), 1.72 (dd, J = 16.7,
7.5 Hz, 3H), 1.52 (d, J = 10.1 Hz, 4H), 1.14-1.00 (m, 1H), 0.90 (d, J = 3.7
Hz, 9H), 0.73 (s, 3H), 0.03 (d, J = 1.2 Hz, 6H); 13C NMR (125 MHz,
CDCl3) δ 198.8, 198.6, 154.2, 124.8, 84.9, 81.4, 80.2, 63.3, 50.4, 45.0, 37.7,
36.2, 36.1, 33.4, 30.5, 26.6, 25.8, 20.1, 19.4, 18.1, 11.9, -4.56, -4.8; HRMS-
ESI calcd for C25H39O4Si [M þ Hþ] 431.2612, found 431.2606.
Synthesis of tertiary alcohol 28b: To a solution of Wilkinson’s
catalyst (8 mg, 0.009 mmol) in dried benzene (3 mL) was added a
solution of tertiary alcohol 27 (38 mg, 0.09 mmol) in benzene (3 mL),
and the mixture was stirred at room temperature under balloon pressure
of H2 overnight. The reaction was worked up by filtration of the reaction
mixture through a silica gel pad and washed with EtOAc (3 ꢀ 10 mL).
The solvent was removed under vacuum, and the residue was purified by
flash chromatography on silica gel (hexane/EtOAc = 4/1) to give a
dienone (31 mg) in 82% yield.
manner, and then the mixture was stirred at the same temperature for 20
min. The reaction was quenched by addition of a saturated solution of
sodium chloride (15 mL), then the mixture was first extracted with
EtOAc (3 ꢀ 20 mL) and the combined organic layer was then dried over
Na2SO4. The solvent was removed under vacuum, and the residue was
used directly in the next step without further purification.
Toa solutionofthecrude alcohol madeabove, Et3N (486 mg, 0.67 mL,
4.8 mmol), and DMAP (20 mg, 0.16 mmol) in CH2Cl2 (15 mL) was
slowly added a solution of MsCl (183 mg, 0.12 mL, 1.6 mmol) in CH2Cl2
(5 mL) at 0 °C, and the mixture was stirred at the same temperature for
1 h. The reaction was quenched with a saturated solution of NaHCO3
(15 mL). The mixture was first extracted with CH2Cl2 (3 ꢀ 20 mL), and
the combined organic layer was then dried over Na2SO4. The solvent was
removed under vacuum, and the residue was purified by fast flash
chromatography (<20 min) on silica gel (hexane/EtOAc = 3/1) to give
a crude mesylate: Rf 0.5 (hexane/EtOAc = 2/1); HRMS-ESI calcd for
C26H41O6SiS [M þ Hþ] 509.2388, found 509.2394.
To a solution of the crude mesylate made above in dried DMF (5 mL)
was added LiBr (139 mg, 1.6 mmol) and Li2CO3 (118 mg, 1.6 mmol) at
room temperature, then the mixture was stirred at 100 °C for 20 h. The
reaction was quenched by addition of a saturated solution of sodium
chloride (30 mL). The mixture was extracted with EtOAc (3 ꢀ 15 mL),
and the combined organic layer was washed with brine (2 ꢀ 8 mL) and
dried over Na2SO4. The solvent was removed under vacuum, and the
residue was purified by flash chromatography on silica gel (hexane/
EtOAc = 5/1) to give the cyclohexatrienone 29 (19 mg) in 28% yield for
3 steps: Rf 0.65 (hexane/EtOAc = 3/1); 1H NMR (300 MHz, C6D6) δ
6.45 (d, J = 10.2 Hz, 1H), 6.20 (dd, J = 10.0, 1.9 Hz, 1H), 5.94 (s, 1H),
5.50 (d, J = 2.0 Hz, 1H), 3.45-3.30 (m, 1H), 2.07 (dd, J = 21.2, 9.2 Hz,
1H), 1.99-1.90 (m, 1H), 1.86 (dd, J = 11.7, 7.2 Hz, 1H), 1.81-1.71 (m,
1H), 1.63 (ddd, J = 10.6, 7.7, 5.2 Hz, 3H), 1.58-1.51 (m, 1H), 1.45 (dd,
J = 10.0, 5.8 Hz, 3H), 1.18 (s, 1H), 0.99 (s, 9H), 0.90 (s, 1H), 0.71 (s,
3H), 0.02 (d, J = 1.0 Hz, 6H); 13C NMR (75 MHz, C6D6) δ 185. 8,
157.6, 154.5, 146.7, 129.9, 119.8, 119.1, 86.3, 81.8, 75.3, 47.8, 43.9, 37.3,
36.2, 30.8, 29.1, 28.9, 26.1, 19.7, 18.3, 11.1, -4.3, -4.7; HRMS-ESI calcd
for C25H36O3NaSi [M þ Naþ] 435.2326, found 435.2330.
To a solution of tertiary alcohol 27a (38 mg, 0.088 mmol) in EtOH
(20 mL) was added NaOAc 3H2O (120 mg, 0.88 mmol) at room
3
temperature, and the mixture was stirred at 90 °C for 36 h. The reaction
was quenched by addition of water (15 mL) and EtOH, and the formed
mixture was concentrated under vacuum. The remaining water layer was
extracted with EtOAc (3 ꢀ 20 mL), and the combined organic extract
was dried over Na2SO4. The solvent was removed under vacuum, and
the residue was purified by flash chromatography on Al2O3 (hexane/
EtOAc = 10/1) to give diketone 28b (25 mg) in 66% yield: Rf 0.8
(hexane/EtOAc = 3/1); 1H NMR (300 MHz, CDCl3) δ 6.44 (d, J = 1.1
Hz, 1H), 3.57 (t, J = 8.3 Hz, 1H), 2.74-2.56 (m, 1H), 2.50 (ddd, J =
14.0, 7.3, 3.3 Hz, 2H), 2.36-2.09 (m, 4H), 2.09-1.95 (m, 1H), 1.95-
1.75 (m, 3H), 1.75-1.63 (m, 3H), 1.57-1.43 (m, 1H), 1.35 (dd, J =
12.5, 7.0 Hz, 2H), 1.12 (td, J = 13.5, 7.2 Hz, 1H), 0.93 (s, 3H), 0.93-
0.79 (m, 9H), 0.03 (d, J = 4.2 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ
201.4, 198.7, 152.6, 125.5, 82.2, 81.6, 81.3, 59.3, 48.0, 43.3, 36.8, 36.2,
35.5, 34.1, 33.9, 29.9, 25.8, 24.7, 18.8, 18.1, 12.1, -4.5, -4.8; HRMS-ESI
calcd for C25H39O4Si [M þ Hþ] 431.2612, found 431.2613.
Synthesis of dienone 30: To a solution of Wilkinson’s catalyst (9
mg, 0.01 mmol) in dried benzene (4 mL) was added a solution of
cyclohexatrienone 29 (40 mg, 0.1 mmol) in benzene (3 mL) at room
temperature, then the mixture was stirred under balloon pressure of H2
atmosphere overnight. The reaction was quenched by filtration through
a Celite pad and washed with EtOAc (3 ꢀ 10 mL). The filtrate was
removed under vacuum, and the residue was purified by flash chroma-
tography on silica gel (hexane/EtOAc = 5/1) to give the desired dienone
30 (30 mg) in 75% yield: Rf 0.6 (hexane/EtOAc = 3/1); 1H NMR (500
MHz, CDCl3) δ 5.92 (d, J = 2.2 Hz, 1H), 5.54 (s, 1H), 3.66 (t, J = 8.3 Hz,
1H), 2.53 (ddd, J = 18.7, 14.9, 8.6 Hz, 2H), 2.48-2.38 (m, 2H), 2.07
(ddd, J = 14.5, 12.7, 6.6 Hz, 5H), 1.93 (dd, J = 11.8, 7.6 Hz, 1H), 1.84-
1.77 (m, 2H), 1.66 (dd, J = 11.1, 6.0 Hz, 2H), 1.31-1.20 (m, 3H), 0.90
(s, 9H), 0.83 (s, 3H), 0.03 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
198.6, 160.4, 157.8, 119.7, 118.6, 84.1, 81.6, 78.1, 47.9, 43.9, 36.2, 35.7,
35.5, 33.6, 30.6, 30.5, 29.1, 25.8, 19.6, 18.1, 10.9, -4.4, -4.9; HRMS-ESI
calcd for C25H39O3Si [M þ Hþ] 415.2663, found 415.2661.
Synthesis of diketone 28c: To a stirred solution of tertiary
alcohol 27 (50 mg, 0.117 mmol) in EtOH (25 mL) was added
NaOAc 3H2O (159 mg, 1.17 mmol) at room temperature, and the
3
mixture was stirred at 75 °C for 20 h. The reaction was quenched by
addition of water (15 mL) and EtOH, and the formed mixture was
concentrated and removed under vacuum. The remaining water layer
was extracted with EtOAc (3 ꢀ 15 mL), and the combined extract was
dried over Na2SO4. The solvent was removed under vacuum, and the
residue was purified by flash chromatography on Al2O3 (hexane/EtOAc
= 10/1) to give diketone 28c (38 mg) as a light yellow solid in 76% yield:
Rf 0.9 (hexane/EtOAc = 3/1); 1H NMR (500 MHz, CDCl3) δ 6.91 (d,
J = 10.0 Hz, 1H), 6.59 (s, 1H), 6.31 (d, J = 10.0 Hz, 1H), 3.58 (t, J = 8.3
Hz, 1H), 2.32 (dd, J = 12.7, 5.1 Hz, 1H), 2.27-2.18 (m, 1H), 2.08 (td,
J = 12.7, 6.3 Hz, 1H), 1.91 (ddd, J = 16.8, 10.8, 3.8 Hz, 2H), 1.85-1.75
(m, 3H), 1.66 (d, J = 9.7 Hz, 2H), 1.54 (s, 1H), 1.40 (dd, J = 12.6, 7.0 Hz,
1H), 1.13 (dd, J = 14.3, 11.5 Hz, 1H), 0.92 (s, 3H), 0.89 (s, 9H), 0.02 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 200.8, 186.1, 151.2, 148.3, 129.3,
124.5, 84.6, 81.4, 78.8, 60.2, 47.5, 43.3, 36.7, 36.0, 34.0, 29.8, 25.8,
24.5, 18.8, 18.1, 12.2, -4.5, -4.8; HRMS-ESI calcd for C25H37O4Si
[M þ Hþ] 429.2456, found 429.2458.
Synthesis of bromo ketone 12: To a solution of dienone 30 (40
mg, 0.1 mmol) in THF (8 mL) at 0 °C was added Et3N (304 mg,
0.42 mL, 3 mmol) and TMSOTf (333 mg, 0.27 mL, 1.5 mmol) in a
dropwise manner, then the reaction mixture was stirred at 0 °C for
30 min. To this solution was added a solution of N-bromosuccinimide
(36 mg, 0.2 mmol) in THF (5 mL) slowly, and the formed mixture
was stirred for 1 h. The reaction was quenched by addition of a
saturated solution of sodium chloride (15 mL). The mixture was first
extracted with EtOAc (3 ꢀ 15 mL), and the combined organic layer was
then dried over Na2SO4. The solvent was removed under vacuum,
and the residue was purified by flash chromatography on silica gel
Synthesis of cyclohexatrienone 29: To a solution of diketone
28 (70 mg, 0.16 mmol) in THF (10 mL) was added lithium triethylbor-
ohydride (1 M in THF, 0.16 mL, 0.16 mmol) at -78 °C in a dropwise
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The Journal of Organic Chemistry
ARTICLE
(hexane/EtOAc = 6/1) to give the desired bromo ketone 12 (38 mg) in
80% yield: Rf 0.5 (hexane/EtOAc = 5/1); 1H NMR (500 MHz, CDCl3) δ
5.92 (d, J = 2.0 Hz, 1H), 5.61 (s, 1H), 4.59 (dd, J = 2.4, 1.2 Hz, 1H), 3.65 (t,
J = 8.3 Hz, 1H), 2.93 (dd, J = 15.0, 4.6 Hz, 1H), 2.59-2.36 (m, 4H), 2.37-
2.27 (m, 1H), 2.09 (td, J = 11.4, 5.9 Hz, 1H), 2.03-1.94 (m, 1H), 1.94-
1.86 (m, 1H), 1.84-1.76 (m, 2H), 1.67-1.52 (m, 3H), 1.24 (d, J = 4.9 Hz,
1H), 0.90 (s, 9H), 0.85 (s, 3H), 0.03 (s, 6H); 13C NMR (125 MHz, CDCl3)
δ191.0, 160.2, 158.8, 119.4, 116.5, 83.4, 81.5, 76.0, 47.7, 44.7, 43.9, 41.2, 37.3,
36.2, 30.6, 30.0, 29.2, 25.8, 19.4, 18.0, 10.9, -4.5, -4.9; HRMS-ESI calcd for
C25H38O3SiBr [M þ Hþ] 493.1768, found 493.1757.
’ ACKNOWLEDGMENT
The project was supported by the Fund of State Key Labora-
tory of Phytochemistry and Plant Resources in West China and
the National Science Foundation of China (Grant Nos.
20852002 and 20902007). We also thank the National Science
and Technology Major Project “Development of key technology
for the combinatorial synthesis of privileged scaffolds”
(2009ZX09501-012), the National Basic Research Program of
China (973 Program, Grant No. 2010CB833201), and the
Scientific Research Foundation for the Returned Overseas Chi-
nese Scholars, Ministry of Education of China, the Shenzhen Basic
Research Program (Nos. JC200903160352A and JC201005260097A).
Synthesis of amino alcohol 32: To a saturated solution of
Me2NH gas in THF [prepared by addition of a aqueous solution of
Me2NH HCl (10 g, 122.7 mmol) in H2O (20 mL) to sodium hydroxide
3
solid (10 g, 250 mmol) in a dropwise manner, and the generated gas was
passed through a drying tube containing sodium hydroxide into THF
(5 mL)] was added n-BuLi (2.5 M in hexane, 0.65 mL, 1.62 mmol)
at -78 °C in a dropwise manner, and the mixture was stirred at the same
temperature for 1 h. To this solution was added a solution of bromo ketone
12 (40 mg, 0.081 mmol) in THF (3 mL) in a dropwise manner, and the
formed mixture was stirred for an additional 20 min. The reaction was
quenched by addition of a saturated solution of NH4Cl (2 mL) and added
water (10 mL). The mixture was extracted with EtOAc (3 ꢀ 15 mL), then
the combined organic layer was dried over Na2SO4. The solvent was
removed under vacuum, and the residue (amino ketone) was used directly
in the next step. It is worthwhile to mention that the formed amino
ketone was unstable at room temperature for 13C NMR analysis: Rf 0.4
(CH2Cl2/MeOH = 5/1); 1H NMR (500 MHz, CDCl3) δ 5.90 (d, J =
2.1 Hz, 1H), 5.52 (s, 1H), 3.66 (t, J = 8.3 Hz, 1H), 3.48 (dd, J = 13.8, 4.2
Hz, 1H), 2.52 (s, 1H), 2.46-2.36 (m, 5H), 2.18 (dd, J = 11.8, 4.0 Hz,
1H), 2.15-1.99 (m, 4H), 1.92 (dd, J = 11.7, 7.7 Hz, 1H), 1.71-1.61 (m,
4H), 1.56 (s, 1H), 0.90 (s, 9H), 0.84 (s, 3H), 0.02 (d, J = 12.9 Hz, 6H);
HRMS-ESI calcd for C27H44NO3Si [M þ Hþ] 458.3085, found
458.3101.
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1
white solid: Rf 0.2 (CH2Cl2/MeOH = 5/1); H NMR (500 MHz,
CDCl3) δ 5.71 (d, J = 1.7 Hz, 1H), 5.31 (d, J = 5.3 Hz, 1H), 4.68 (s, 1H),
3.62 (t, J = 8.2 Hz, 1H), 3.09 (d, J = 10.8 Hz, 1H), 2.82 (s, 6H), 2.44 (d,
J = 13.4 Hz, 1H), 2.40-2.22 (m, 2H), 2.04 (dd, J = 17.5, 11.1 Hz, 2H),
2.01-1.89 (m, 3H), 1.82 (dt, J = 19.5, 8.5 Hz, 2H), 1.74 (dd, J = 12.5, 3.9
Hz, 1H), 1.65-1.56 (m, 2H), 1.52 (s, 1H), 1.15 (td, J = 13.0, 4.8 Hz,
1H), 0.88 (s, 9H), 0.79 (s, 3H), 0.02 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 150.1, 144.0, 118.5, 115.8, 83.9, 81.6, 78.1, 63.1, 62.9,
47.9, 43.9, 41.3, 37. 5, 36.4, 31.6, 30.8, 30.6, 28.6, 25.8, 19.6, 18.0,
10.9, -4.5, -4.9; HRMS-ESI calcd for C27H46NO3Si [M þ Hþ]
460.3241, found 460.3235.
’ ASSOCIATED CONTENT
1
S
Supporting Information. Experimental procedure, H
b
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: chuangli@pku.edu.cn; zyang@pku.edu.cn.
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