Ruth Dorel1, Antonio M Echavarren1. 1. Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology , Av. Països Catalans 16, 43007 Tarragona, Spain.
Abstract
The [3,5,5,7] tetracyclic skeleton of echinopines has been stereoselectively accessed through a gold(I)-catalyzed alkoxycyclization of cyclopropyl-tethered 1,6-enynes. The key bicyclo[4.2.1]nonane core of the enyne precursors was readily assembled by means of a Co-catalyzed [6 + 2] cycloaddition. Furthermore, the attempted alkoxycyclization of 1,5-enyne substrates revealed an uncovered cyclopropyl rearrangement that gives rise to [3,6,5,7] tetracyclic structures.
The [3,5,5,7] tetracyclic skeleton of echinopines has been stereoselectively accessed through a gold(I)-catalyzed alkoxycyclization of cyclopropyl-tethered 1,6-enynes. The key bicyclo[4.2.1]nonane core of the enyne precursors was readily assembled by means of a Co-catalyzed [6 + 2] cycloaddition. Furthermore, the attempted alkoxycyclization of 1,5-enyne substrates revealed an uncovered cyclopropyl rearrangement that gives rise to [3,6,5,7] tetracyclic structures.
Echinopines A and B
(1 and 2) were isolated
in 2008 from the roots of Echinops spinosus and feature an unprecedented [3,5,5,7]-membered-ring tetracyclic
skeleton (Scheme ),
which probably originates biosynthetically from a guaiane precursor.[1] This complex carbon framework holds five contiguous
stereogenic centers, two of them being adjacent quaternary stereocenters.
Despite the fact that no biological activity has been reported to
date for 1 and 2, the unique architecture
of these sesquiterpenes has constituted an appealing challenge for
the synthetic community and several syntheses of echinopines have
been accomplished to date.[2−7] The key feature in all these syntheses is the establishment of the
unique [3,5,5,7] skeleton, and to this aim conceptually very different
ring-forming sequences have been successfully established.[8] However, the assembly of the complex polycyclic
framework of the echinopines skeleton is not easily addressed by conventional
methods, as evidenced by the lengthy existing syntheses, and it is
in most of the cases delayed to one of the last steps of the sequence.
Scheme 1
Strategy for the Gold-Catalyzed Synthesis of the Skeleton of Echinopines
Gold(I) catalysis constitutes
a powerful tool for the construction
of complex polycyclic architectures from relatively simple enyne substrates
under mild reaction conditions.[9−12] A concise synthesis of the complex polycyclic framework
of the echinopines skeleton could easily provide access to structural
analogues for further evaluation of their biological properties. In
this context, we envisioned a gold(I)-catalyzed alkoxycyclization
of cyclopropyl-tethered tricyclic 1,5- (3) or 1,6-enynes
(4) as the key step for the ready access to the tetracyclic
skeleton of echinopines via 5-endo or 5-exo cyclization, respectively
(Scheme ).[13−16] This transformation would stereoselectively lead to echinopine-based
tetracyclic products bearing different groups suited for further functionalization.
Results
and Discussion
Our approach for the synthesis of tricyclic
enynes 3 and 4 relied on a cobalt-catalyzed
[6 + 2] cycloaddition
between cycloheptatriene and an internal alkyne as the key step to
build the bicyclo[4.2.1]nonane core.[17,18] Thus, orthogonally
protected diol5a afforded cycloadduct 6a, which upon monodeprotection and cyclopropanation of the tetrasubstituted
olefin from the less sterically hindered face gave rise to tricyclic
compound 8a (Scheme ). Oxidation of the primary alcohol and subsequent
homologation employing the Ohira–Bestmann reagent provided
1,5-enyne 3a.
Scheme 2
Synthesis of Tricyclic 1,5-Enyne 3a
Initial attempts to perform
the alkoxycyclization of 3a with methanol as the external
nucleophile in the presence of different
cationic gold(I) complexes A–D only
provided methyl ketone 10 as a result of the formal hydration
of the terminal alkyne (Scheme ).[19−22] Moreover, when the reaction was performed under strictly anhydrous
conditions, the corresponding dimethyl acetal 11 could
be isolated, which rapidly decomposed to 10 under ambient
conditions, thus demonstrating that the addition of methanol to the
terminal alkyne of 3a is favored over the attack of the
alkene moiety. Similar results were obtained when other alcohols were
employed as the external nucleophiles.
Scheme 3
Formal Hydration
of 3a
The use of carbonucleophiles such as indole, 1,3-diketones,
and
electron-rich benzenes only resulted in the recovery of unreacted 3a. Nevertheless, when the reaction of 3a was
performed with commercially available gold(I) complex A in the presence of acetic acid, complete conversion of 3a was achieved in 1 h, leading to the formation of rearranged product 12 in up to 61% yield (Scheme ). A closer mechanistic inspection of this transformation
suggested that the gold(I)-catalyzed reaction initially forms intermediate 14 that rearranges to form allyl cation 15, which
is trapped by acetic acid. DFT calculations indicated that the formation
of intermediate 16 that leads to 12 is thermodynamically
favored over the formation of 17, which is predicted
to be the driving force for the rearrangement to take place. This
result further illustrates the influence of the cyclopropane functionality
on the reaction pathways followed in the gold(I)-catalyzed cyclizations
of cyclopropane-tethered 1,5-enynes[23] and
underscores the propensity of the strained tetracyclic system of echinopines
to undergo rearrangements.[6]
Scheme 4
Gold-Catalyzed
Rearrangement of 3a
Values in parentheses correspond
to relative free energies in kcal mol–1 (M06/6-31G(d)
(C, H, P, O) and SDD (Au), solvent = CH2Cl2).
L = PMe3.
Gold-Catalyzed
Rearrangement of 3a
Values in parentheses correspond
to relative free energies in kcal mol–1 (M06/6-31G(d)
(C, H, P, O) and SDD (Au), solvent = CH2Cl2).
L = PMe3.In order to unequivocally
ensure the structure of 12, the acetate moiety was cleaved
to form alcohol 18,
which was converted into the corresponding crystalline p-nitrobenzoate derivative 19, whose structure was confirmed
by X-ray diffraction (Scheme ).[24] In addition, a related system
having one of the double bonds reduced was also examined with the
aim of promoting a rearrangement toward the echinopine skeleton on
the basis of the higher stability of carbocation 24 over 22 predicted by DFT calculations. Thus, 18 could
be selectively hydrogenated in the presence of Crabtree’s catalyst
to give 20, which was converted into tertiary carbocation 22 via triflate 21. Nonetheless, the rearranged
product was not observed and only nonrearranged elimination product 23 was isolated under different reaction conditions.
Scheme 5
Synthesis
of 23 from Acetate 12 and CYLview
Depiction of the X-ray Crystal Structure of 19
Values in parentheses correspond
to relative free energies in kcal mol–1 (M06/6-31G(d),
solvent = CH2Cl2).
Synthesis
of 23 from Acetate 12 and CYLview
Depiction of the X-ray Crystal Structure of 19
Values in parentheses correspond
to relative free energies in kcal mol–1 (M06/6-31G(d),
solvent = CH2Cl2).The
synthesis of the homologous 1,6-enyne 4a commenced
with the cobalt-catalyzed [6 + 2] cycloaddition between cycloheptatriene
and alkyne 25 followed by treatment with N-iodosuccinimide, which afforded vinyl iodide 27 (Scheme ). Kumada cross-coupling
of 27 with (3-(trimethylsilyl)prop-2-yn-1-yl)magnesium
bromide furnished 28, which was treated with HF·py
to give allylic alcohol 29. Cyclopropanation of the tetrasubstituted
olefin followed by deprotection of the terminal alkyne and protection
of the primary alcohol gave rise to tricyclic 1,6-enyne 4a. However, all attempts to perform the alkoxycyclization of 4a in the presence of different gold(I) complexes provided
only traces of the cyclized tetracyclic product and resulted in the
formation of methyl ketone 31 as the major product.
Scheme 6
Synthesis and Formal Hydration of Tricyclic 1,6-Enyne 4a
Aldehydes 9a,b[25] were next employed as the platform
to access a series of tricyclic
1,6-enynes featuring different functionalities at the propargylic
position. Thus, the addition of ethynylmagnesium bromide provided 4b,c as single diastereoisomers and their alkoxycyclization
was investigated using methanol as the external nucleophile in the
presence of a series of gold(I) complexes spanning a range of electrophilicities.
The desired alkoxycyclization products could only be detected from
the reactions carried out in the presence of phosphine–gold(I)
complexes, whereas gold(I) complexes bearing NHC and phosphite ligands
gave complex mixtures.[26] Cationic gold(I)
complex B provided the best results, and the use of the
alcohol as the solvent proved to be optimal for the alkoxycyclization
of enynes 4b,c to afford regio- and stereoselectively
tetracyclic products 32a–c, which
feature the [3,5,5,7] tetracyclic skeleton of echinopines (Scheme ). While the reaction
of 4b with methanol provided 32a as a single
regioisomer, the analogous reaction of 4c gave rise to
a 5:1 mixture of regioisomers. Nonetheless, changing the external
nucleophile from methanol to allyl alcohol in the reaction of 4c resulted in the exclusive formation of 32c as the sole isomer. The structure of tetracycles 32a–c could be confirmed from the X-ray crystal
structure of 32a.[24]
Scheme 7
Synthesis
and Alkoxycyclization of 4b,c and CYLview
Depiction of the X-ray Crystal Structure of 32a
Interestingly, the propargylic
alcohol of enynes 4b,c was substituted by
a second molecule of alcohol in
the gold(I)-catalyzed cyclization process. In order to elucidate the
order of events in this transformation, the closely related system 34 in which the 1,3-diene had been reduced to the corresponding
alkane was submitted to the optimized reaction conditions for the
gold(I)-catalyzed alkoxycyclization (Scheme ). However, after 2 h only hydroxyketone 35 and unreacted 34 were detected from the crude
mixture and no substitution of the propargylic alcohol was observed.[26] This result supports a catalytic cycle in which
the propargylic alcohol in 4b,c is eliminated
after the cyclization of the enyne by the attack of a molecule of
methanol to intermediate 36, which generates α,β-unsaturated
gold(I) carbene intermediate 37.[27] The attack of a second molecule of alcohol to 37 forms 38, which releases tetracycles 32 by protodeauration
(Scheme ).
Scheme 8
Synthesis
of 34 and Gold(I)-Catalyzed Reaction under
the Optimized Alkoxycyclization Reaction Conditions
Scheme 9
Catalytic Cycle for the Alkoxycyclization of 4b,c
Ketoenynes 4d,e were also prepared
by
direct oxidation of 4b,c, and their alkoxycyclization
under the optimized reaction conditions provided mixtures of the two
possible regioisomeric products 39a′,b′ and 39a″,b″,[28] which could be separated by preparative chromatography
(Scheme ). Water
could also be used as the external nucleophile to afford inseparable
mixtures of regioisomeric allylic alcohols 39c′,d′/39c″,d″ in moderate yields.
Scheme 10
Synthesis and Alkoxycyclization of 4d,e
Conclusion
In summary, the [3,5,5,7] tetracyclic core
of echinopines can be
readily accessed through the gold(I)-catalyzed alkoxycyclization of
tricyclic cyclopropyl-tethered 1,6-enynes bearing an O functionality
at the propargylic position, giving access to functionalized echinopine
analogues as single stereoisomers. Furthermore, the cyclization of
1,5-enyne 3a uncovered an unexpected migration of the
cyclopropane functionality, thus providing access to the complex natural-product-like
[3,6,5,7] tetracycle 12.
Experimental
Section
General Remarks
Chemicals and solvents for chromatography
were used as received. Solvents used in reactions under an inert atmosphere
were dried by passing through an activated alumina column on a solvent
purification system. Analytical thin-layer chromatography was carried
out using TLC-aluminum sheets with 0.2 mm of silica gel (Merck FG254)
with UV light as the visualizing agent or an acidic solution of vanillin
in ethanol as the developing agent. Purifications by chromatography
were carried out using flash grade silica gel (SDS Chromatogel 60
ACC, 40–60 mm). Preparative TLC was performed on 20 cm ×
20 cm silica gel plates. Organic solutions were concentrated under
reduced pressure on a rotary evaporator. NMR spectra were recorded
at 298 K on 300, 400, and 500 MHz devices. 1H and 13C chemical shifts (δ) are given in ppm relative to
TMS, and coupling constants (J) in Hz. Mass spectra
were recorded employing TOF mass analyzers (ESI, APCI). Melting points
were determined by observation of the fusion of the solids placed
in a capillary, through a magnifying glass. Crystal structure determinations
were carried out using a diffractometer equipped with an APPEX 2 4K
CCD area detector, an FR591 rotating anode with Mo Kα radiation,
Montel mirrors as the monochromator, and a Kryoflex low temperature
device (T = −173 °C). Full-sphere data
collection was used with ω and φ scans. Programs used:
data collection APEX-2, data reduction Bruker Saint V/.60A, and absorption
correction SADABS. Structure solution and refinement: crustal structure
solution was achieved using direct methods as implemented in SHELXTL
and visualized using the program XP. Missing atoms were subsequently
located from difference Fourier synthesis and added to the atom list.
Least-squares refinement on F2 using all
measured intensities was carried out using the program SHELXTL. All
non-hydrogen atoms were refined including anisotropic displacement
parameters.
NaH (60% in mineral oil, 1.89 g, 47.2 mmol)
was added to a solution of 4-((tert-butyldimethylsilyl)oxy)but-2-yn-1-ol[29] (8.60 g, 42.9 mmol) in anhydrous THF (210 mL)
under argon at 0 °C. The resulting suspension was stirred for
30 min, and then methyl iodide (3.2 mL, 51.5 mmol) was slowly added.
The reaction mixture was warmed to room temperature and then stirred
for 1.5 h. After it was diluted with Et2O (100 mL), the
mixture was washed with a saturated solution of NH4Cl (150
mL) and water (150 mL), the aqueous layers were extracted with Et2O (2 × 100 mL), and the combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced
pressure. The product was obtained after purification by flash chromatography
(cyclohexane/EtOAc 95/5) as a clear oil (8.00 g, 37.3 mmol, yield
87%). 1H NMR (400 MHz, CDCl3): δ 4.38
(t, J = 1.8 Hz, 2H), 4.15 (t, J =
1.8 Hz, 2H), 3.40 (s, 3H), 0.93 (s, 9H), 0.14 (s, 6H). 13C NMR (101 MHz, CDCl3): δ 85.1, 80.6, 60.0, 57.6,
51.7, 25.8, 18.3, −5.2. HRMS (ESI+): m/z calcd for C11H22NaO2Si
[M + Na]+, 237.1281; found, 237.1278.
Synthesis of 6
CoBr2 (306.1
mg, 1.40 mmol), Zn (366.1 mg, 5.60 mmol), and ZnI2 (1.79
g, 5.60 mmol) were suspended in anhydrous 1,2-dichloroethane (20 mL)
under argon. Then P(OiPr)3 (0.69 mL, 2.80
mmol) was added, followed by cycloheptatriene (4.36 mL, 41.98 mmol)
and a solution of 5(30) (27.99
mmol) in dry 1,2-dichloroethane (8 mL). The resulting mixture was
stirred at 50 °C for 16 h and then filtered through a pad of
Celite and concentrated under reduced pressure. Purification of the
resulting crude by flash chromatography (cyclohexane/EtOAc 1/0 to
95/5) afforded compounds 6.
TBAF
(1.0 M in THF, 22.8
mL, 22.8 mmol) was added to a solution of 6 (11.4 mmol)
in anhydrous THF (200 mL) at 0 °C under argon. The mixture was
stirred at room temperature for 2 h and then diluted with Et2O (100 mL) and washed with saturated solution of NH4Cl
(150 mL) and water (150 mL). The aqueous layers were extracted with
Et2O (2 × 100 mL), and the combined organic layers
were dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification by flash chromatography (cyclohexane/EtOAc
7/3) afforded products 7.
Diiodomethane (0.61 mL,
7.57 mmol) and ZnEt2 (1.0 M in hexanes, 15.75 mL, 15.75
mmol) were added to a solution of 7 (6.30 mmol) in anhydrous
CH2Cl2 (210 mL) at 0 °C. The resulting
mixture was warmed to room temperature and stirred until TLC analysis
showed complete disappearance of the starting material (5–12
h). The reaction mixture was quenched by the slow addition of a saturated
aqueous Na/K-tartrate solution (100 mL), and after it was stirred
for 30 min the organic layer was separated, the aqueous layer was
extracted with CH2Cl2 (100 mL), and the combined
organic phases were dried over MgSO4 and concentrated under
reduced pressure. Purification by flash chromatography (cyclohexane/EtOAc
7/3) afforded products 8.
Dess–Martin periodinane
(2.67 g, 6.30 mmol) was added to a solution of 8 (4.85
mmol) in CH2Cl2 (50 mL). After the addition
of 1 drop of water the resulting suspension was stirred at room temperature
for 1 h and then washed with a 1/1 mixture of a saturated solution
of Na2S2O3/Na2CO3 (40 mL). The organic layer was dried over MgSO4, filtered,
and concentrated under reduced pressure. The product was obtained
after purification by flash chromatography (cyclohexane/EtOAc 7/3).
A dry two-neck round-bottom flask equipped
with a condenser was charged with activated magnesium tunings (583
mg, 24.0 mmol) that were covered with anhydrous THF (100 mL). Dibromoethane
(0.1 mL) was added, followed by trimethylsilylpropargyl bromide (2.0
mL, 12.12 mmol). The reaction mixture was heated at 50 °C for
1 h and then cooled to room temperature and transferred via cannula
to a second two-neck round-bottom flask containing a solution of 27 (1.23 g, 2.40 mmol) and Pd(PPh3)4 (138.7 mg, 0.12 mmol) in anhydrous THF (30 mL). The resulting mixture
was stirred at 50 °C for 2 h and then cooled to room temperature,
poured on brine (100 mL), and extracted with Et2O (2 ×
100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification
by flash chromatography (cyclohexane/EtOAc 95/5) afforded 28 as a yellow oil that was directly taken to the next step due to
its low stability. 1H NMR (400 MHz, CDCl3):
δ 7.72–7.67 (m, 4H), 7.47–7.36 (m, 6H), 6.27–6.18
(m, 1H), 6.17–6.09 (m, 1H), 5.83–5.71 (m, 2H), 4.33
(d, J = 12.8 Hz, 1H), 4.20 (d, J = 13.0 Hz, 1H), 3.42 (t, J = 7.0 Hz, 1H), 3.36
(t, J = 7.0 Hz, 1H), 2.95 (d, J =
19.4 Hz, 1H), 2.85 (d, J = 18.6 Hz, 1H), 2.26 (dtt, J = 11.3, 6.7, 1.2 Hz, 1H), 1.61 (d, J =
11.3 Hz, 1H), 1.08 (s, 9H), 0.16 (s, 9H). 13C NMR (101
MHz, CDCl3): δ 140.2, 139.7, 135.6, 135.6, 135.0,
133.7, 133.6, 129.9, 129.6, 129.6, 127.7, 127.7, 124.4, 124.1, 104.8,
85.0, 58.5, 46.6, 45.0, 30.3, 26.8, 19.2, 17.2, 0.1. To a solution
of 28 (646.0 mg, 1.30 mmol) in THF (12 mL) in a Teflon
flask was added HF·py (70% weight, 0.31 mL, 12.1 mmol), and the
resulting mixture was stirred at room temperature for 16 h. The reaction
was quenched by the slow addition of a saturated solution of NaHCO3 (10 mL), and the product was extracted with Et2O (2 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification
by flash chromatography (cyclohexane/EtOAc 8/2) afforded the product
as a yellow oil (528.1 mg, 1.06 mmol, yield over two steps 44%). 1H NMR (400 MHz, CDCl3): δ 6.31–6.19
(m, 2H), 5.87–5.78 (m, 2H), 4.29 (d, J = 12.7
Hz, 1H), 4.19 (d, J = 12.7 Hz, 1H), 3.37 (d, J = 7.2 Hz, 1H), 3.34 (d, J = 7.2 Hz, 1H),
3.17 (d, J = 19.3 Hz, 1H), 3.11 (d, J = 19.1 Hz, 1H), 2.27 (dtt, J = 11.4, 6.7, 1.2 Hz,
1H), 1.61 (d, J = 11.4 Hz, 1H), 0.18 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 139.8, 139.4,
135.1, 131.5, 124.7, 124.5, 104.4, 85.4, 57.3, 46.7, 45.4, 30.1, 17.2,
0.0. HRMS (ESI+): m/z calcd for
C16H22NaOSi [M + Na]+, 281.1332;
found, 281.1322.
Gold(I) complex (0.002 mmol) was added to a solution of 4a (0.1 mmol) in MeOH (1 mL), and the resulting mixture was stirred
at room temperature for 2 h before the addition of 1 drop of Et3N. Then the volatiles were removed under reduced pressure,
and purification by column chromatography afforded the product in
22–47% yield. 1H NMR (400 MHz, CDCl3):
δ 5.98–5.83 (m, 2H), 5.77–5.69 (m, 2H), 4.09 (d, J = 10.6 Hz, 1H), 3.37 (d, J = 10.4 Hz,
1H), 3.01 (d, J = 16.1 Hz, 1H), 2.76 (t, J = 7.2 Hz, 1H), 2.73 (t, J = 6.7 Hz, 1H),
2.18 (s, 3H), 2.14 (d, J = 16.0 Hz, 1H), 2.04–1.95
(m, 1H), 1.71 (d, J = 13.0 Hz, 1H), 0.91 (s, 9H),
0.79 (d, J = 5.7 Hz, 1H), 0.21 (d, J = 5.7 Hz, 1H), 0.06 (s, 3H), 0.06 (s, 3H). 13C NMR (101
MHz, CDCl3): δ 208.9, 136.6, 136.5, 125.2, 125.1,
63.1, 43.7, 42.9, 41.8, 41.0, 35.6, 30.2, 26.4, 25.9, 18.3, 13.9,
−5.2, −5.4. HRMS (ESI+): m/z calcd for C20H32NaO2Si
[M + Na]+, 355.2064; found, 355.2056.
Synthesis of 4b,c
Ethynylmagnesium
bromide (0.5 M in THF, 8.07 mL, 4.04 mmol) was added to a solution
of 9 (3.67 mmol) in anhydrous THF (37 mL) at 0 °C.
After it was stirred at room temperature for 30 min, the reaction
mixture was diluted with Et2O (15 mL) and quenched by the
addition of saturated NH4Cl aqueous solution (50 mL). The
aqueous layer was extracted with Et2O (2 × 40 mL),
the combined organic phases were dried over MgSO4, filtered,
and concentrated under reduced pressure, and the resulting crude was
purified by column chromatography (cyclohexane/EtOAc 7/3).
Gold(I) complex B (3.1 mg, 0.002 mmol)
was added to a solution of 4b,c (0.1 mmol)
in ROH (1 mL), and the resulting suspension was stirred at room temperature
for 2 h before the addition of 1 drop of Et3N. Then the
volatiles were removed under reduced pressure and the resulting crude
was purified by column chromatography to afford tetracycles 32.
Dess–Martin
periodinane (524.3 mg, 1.24 mmol) was added to a solution of 33 (200 mg, 0.95 mmol) in CH2Cl2 (10
mL). After the addition of 1 drop of water the resulting suspension
was stirred at room temperature for 15 min and then washed with a
1/1 mixture of saturated solution of Na2S2O3/Na2CO3 (20 mL). The organic layer was
dried over MgSO4, filtered, and concentrated under reduced
pressure. The product (33′) was obtained after
filtration through a pad of silica gel as a colorless oil and directly
submitted to the next step. 1H NMR (500 MHz, CDCl3): δ 9.44 (s, 1H), 3.86 (dd, J = 10.2, 1.3
Hz, 1H), 3.54 (d, J = 10.2 Hz, 1H), 3.39 (s, 3H),
2.66 (ddd, J = 7.3, 4.4, 2.7 Hz, 1H), 2.51–2.41
(m, 2H), 1.97–1.88 (m, 1H), 1.64–1.40 (m, 9H), 1.37
(dd, J = 4.9, 1.3 Hz, 1H). 13C NMR (126
MHz, CDCl3): δ 200.7, 71.6, 58.9, 45.5, 43.1, 39.5,
38.1, 30.2, 29.6, 27.8, 25.5, 24.3, 23.4. Ethynylmagnesium bromide
(0.5 M in THF, 2.01 mL, 1.00 mmol) was added to a solution of aldehyde 33′ (190 mg, 0.91 mmol) in anhydrous THF (9 mL) at
0 °C. After it was stirred at room temperature for 30 min, the
reaction mixture was diluted with Et2O (15 mL) and quenched
by the addition of saturated NH4Cl aqueous solution (50
mL). The aqueous layer was extracted with Et2O (2 ×
40 mL), the combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure, and the resulting
crude was purified by column chromatography (cyclohexane/EtOAc 7/3)
to afford 34 as a colorless oil (208.9 mg, 0.89 mmol,
yield over two steps 98%). 1H NMR (500 MHz, CDCl3): δ 4.87 (dd, J = 5.2, 2.2 Hz, 1H), 3.81
(d, J = 10.4 Hz, 1H), 3.70 (d, J = 10.3 Hz, 1H), 3.48 (d, J = 5.3 Hz, 1H), 3.36
(s, 3H), 2.51 (d, J = 2.2 Hz, 1H), 2.42 (ddd, J = 7.7, 5.3, 2.4 Hz, 1H), 2.31 (ddd, J = 7.8, 6.1, 1.9 Hz, 1H), 2.08–2.01 (m, 1H), 1.86–1.79
(m, 1H), 1.78–1.71 (m, 1H), 1.70–1.61 (m, 1H), 1.57–1.42
(m, 4H), 1.40–1.32 (m, 2H), 0.94 (d, J = 4.7
Hz, 1H), 0.82 (d, J = 4.7 Hz, 1H). 13C
NMR (126 MHz, CDCl3): δ 84.5, 74.0, 72.8, 61.1, 58.4,
42.1, 41.5, 38.7, 35.8, 29.6, 29.1, 29.0, 25.2, 24.5, 16.4. HRMS (ESI+): m/z calcd for C15H22NaO2 [M + Na]+, 257.1512; found, 257.1514.
Synthesis of 4d,e
Dess-Martin
periodinane (478.8 mg, 1.13 mmol) was added to a solution of 4b,c (0.87 mmol) in CH2Cl2 (9 mL). After the addition of 1 drop of water, the resulting suspension
was stirred at room temperature for 1 h and then washed with a 1/1
mixture of a saturated solution of Na2S2O3/Na2CO3 (40 mL). The organic layer was
dried over MgSO4, filtered, and concentrated under reduced
pressure. The product was obtained after purification by flash chromatography
(cyclohexane/EtOAc 7/3).
Gold(I) complex B (3.1
mg, 0.002 mmol)[31] was added to a solution
of 4d,e (0.1 mmol) in ROH (1 mL) or a 2/1
dioxane/H2O
mixture (2 mL), and the resulting suspension was stirred at room temperature
for the appointed time before the addition of 1 drop of Et3N. Then the volatiles were removed under reduced pressure and purification
by preparative TLC afforded the tetracyclic products 39′/39″.
(1aR*,2S*,3aS*,4S*,6aS*,7R*)-7-Hydroxy-1a-(methoxymethyl)-5-methylene-1a,2,3,3a,4,5-hexahydro-2,4-prop[1]enocyclopropa[c]pentalen-6(1H)-one (39c′) and (1aR*,2R*,3aS*,4S*,6aS*,9S*)-9-hydroxy-1a-(methoxymethyl)-5-methylene-1a,2,3,3a,4,5-hexahydro-4,2-prop[1]enocyclopropa[c]pentalen-6(1H)-one (39c″)
(1aR*,2S*,3aS*,4S*,6aS*,7R*)-1a-((Benzyloxy)methyl)-7-hydroxy-5-methylene-1a,2,3,3a,4,5-hexahydro-2,4-prop[1]enocyclopropa[c]pentalen-6(1H)-one (39d′) and (1aR*,2R*,3aS*,4S*,6aS*,9S*)-1a-((benzyloxy)methyl)-9-hydroxy-5-methylene-1a,2,3,3a,4,5-hexahydro-4,2-prop[1]enocyclopropa[c]pentalen-6(1H)-one (39d″)
Authors: Alberto Martínez; Patricia García-García; Manuel A Fernández-Rodríguez; Félix Rodríguez; Roberto Sanz Journal: Angew Chem Int Ed Engl Date: 2010-06-21 Impact factor: 15.336
Authors: Eloísa Jiménez-Núñez; Mihai Raducan; Thorsten Lauterbach; Kian Molawi; César R Solorio; Antonio M Echavarren Journal: Angew Chem Int Ed Engl Date: 2009 Impact factor: 15.336
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