Tackling reactivity and selectivity within a strained architecture: Construction of the [6-6-5-7] tetracyclic core of calyciphylline alkaloids

Article abstract of DOI:10.1021/jo300776d

A stereochemically controlled route to the enantiopure [6-6-5-7] tetracyclic core of Calyciphylline A class alkaloids was established, which involves Overman rearrangement, [2 + 2] photochemical cycloaddition, Grob fragmentation, C-N bond-forming nucleophilic displacement, and ring strain-directed hydrogenation as strategic steps.

Full text of DOI:10.1021/jo300776d

Note
pubs.acs.org/joc
Tackling Reactivity and Selectivity within a Strained Architecture:
Construction of the [6−6−5−7] Tetracyclic Core of Calyciphylline
Alkaloids
Chen Xu,† Lu Wang,† Xiaojiang Hao,*,‡ and David Zhigang Wang*,†
†Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University,
Shenzhen University Town, Nanshan District, Shenzhen 518055, China
‡Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China
S
* Supporting Information
ABSTRACT: A stereochemically controlled route to the enantiopure [6−6−5−7] tetracyclic core of Calyciphylline A class
alkaloids was established, which involves Overman rearrangement, [2 + 2] photochemical cycloaddition, Grob fragmentation, C−
N bond-forming nucleophilic displacement, and ring strain-directed hydrogenation as strategic steps.
he Daphniphyllum class alkaloids have in recent years
garnered much attention due primarily to their unusual
identifying an appropriate alcohol protecting group (i.e., P2
group, Scheme 1) that is both easy to manipulate and
compatible with Mannich condensation6 conditions employed
earlier in the sequence for assembling the key precursor 5 for
an enone−alkene [2 + 2] photochemical cycloaddition.7
Challenged by solving these significant problems, a substantially
revised synthetic plan was thus designed and further
experimentally explored. We reported herein the success in
execution of such plans for rapid construction of the critical
[6−6−5−7] tetracycle and with all of the seven stereogenic
centers densely situated on the ring junctions (i.e., C1, C2, C4,
C5, C6, C7, and N8) clearly defined in a way that exactly
corresponds to the absolute configurations found in natural
products.
As shown in Scheme 1, we envisioned that the ring closure of
piperidine A of the tetracycle 1 could be in situ initiated by
liberating the basic nitrogen center in 2 toward an intra-
molecular SN2 displacement of the C9-mesylate. Its immediate
precursor 3 could be furnished through a Grob-type
fragmentation8 on an advanced intermediate 4, which itself
was accessible with an intramolecular [2 + 2] photochemical
cycloaddition event on an allylic amine-tethered enone
substrate 5.2e The assembly of 5 by Mannich condensation of
an appropriately functionalized iminium ion 6 and cyclo-
pentanedione 7 had emerged as a major challenge as its success,
rather unexpectedly, was found (vide infra) to be critically
dependent on the nature of a seemingly remotely positioned
T
structural diversities and stereochemical complexities.1 Driven
by their aesthetical appeal as well as the desire to explore their
so far poorly studied biological utilities, several laboratories
have engaged in chemical synthesis of a certain member of this
remarkable natual product family.2 In this field, Carreira and co-
workers have recently recorded a landmark accomplishment by
completing a highly stereoselective total synthesis of
(+)-daphmanidin E.3
Our own efforts have been focused on Calyciphylline A type
compounds within this family.4 As highlighted in blue in Figure
1, a recurring skeletal motif found among these structures is the
highly stereochemically fused [6−6−5−7] tetracyclic core. It
could thus be recognized that the goal of establishing a
divergent synthetic approach to such diverse targets would be
most economically served by defining an efficient and
stereocontrolled strategy to this tetracycle. A previous
communication2e from our group had disclosed progress
made to build the simpler [5−6−7] tricyclic moiety (i.e.,
rings B−C−D in structure 1 of Scheme 1). Implementation of
the previously uncovered key transformations in the more
elaborated [6−6−5−7] setting had, however, demanded new
strategic planning, as it was subsequently discovered that
substrates-directed double bond hydrogenations within those
tricycles surprisingly led only to an anti-C5-Me-versus-C6-H
orientation (Scheme 1) that is opposite to what is present in
natural products. Furthermore, the attempted piperidine A ring
closure via an intramolecular C9−N bond-forming nucleophilic
displacement event5 was repeatedly hampered by failures in
Received: April 23, 2012
Published: June 12, 2012
© 2012 American Chemical Society
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Figure 1. Calyciphylline A class alkaloids featuring the common [6−6−5−7] tetracyclic core structure.
could apparently be attributed to a strain-releasing-driven retro-
Aldol-type collapse of the keto-ester moiety of 15.15 Reduction
of the ketone carbonyl from its less-hindered face in 15
followed by mesylation of the resultant alcohol 17 readily sets
the stage for base-triggered Grob-fragmentation to give tricyclic
alkene 18, with a remarkable 79% isolated yield over these three
steps.
Scheme 1. Retrosynthetic Strategies
It should be noted that in 16 the C5-Me and C6-H displayed
spatially an anti-orientation (NOESY), which, in conjunction
with our earlier observations in tricyclic alkene model systems
that catalytic hydrogenations failed to deliver the desired (S)-
configuration at the C6 chiral center, hints on the difficulty of
reverting the inherent substrate thermodynamic bias imposed
by saturating the double bond in 18 toward the requiste syn-C5-
Me-versus-C6-H stereochemistry. Hypothetically, a solution to
this problem would invite consideration on crafting 18’s
relatively flat tricyclic skeleton into a much reinforced bowl-
twisted tetracyclic architecture as widely present in Calyciphyl-
line A-class alkaloids. With this design concept in mind, 18 was
next transformed to 20 in very high yield by sequential
protecting group oxidative removal and alcohol mesylation.
Delightfully, exposure of 20 to the action of TMSI16 and Et3N
was found to lead to the formation of the desired structure 21
in 80% isolated yield under very mild conditions.
alcohol protecting group P2.9 It was only after extensive trial-
and-error efforts that we eventually determined 4-methox-
yphenyl10 to be a viable structure compatible with both the
strongly Lewis acidic Mannich reaction promoter and short-
wavelength light employed in subsequent photocycloadditions.
Scheme 2 summarized our experimental explorations leading
to an advanced tetracyclic alkene intermediate 21. Starting from
the known enantiopure diol 8,11 primary alcohol-protected 9
was prepared by the action of tosylation and 4-methoxyphen-
oxide substitution. Imidation of the allylic alcohol with CCl3CN
followed by Overman rearrangement12 under xylene refluxing
conditions converted 9 into allylic trichloroacetamide 10.
Treatment of 10 with MeOH and then HCHO under basic
conditions yielded the hydroxymethylated carbamate 12
through the intermediacy of 11. Mannich unification of 12
with cyclopentanedione was found to be effected by Sn(NTf2)4
leading to structure 13 in 77% isolated yield.13 A range of other
Lewis acids known in the arts6 for promoting Mannich
condensations were also examined but found to be either
inefficient or labile for incurring substantial substrate
decomposition. Acylation of the enol in 13 with acetyl chloride
produced 14 which was next subjected to photolysis with a
medium-pressure Hg lamp emitting light primarily around 254
nm, yielding highly substituted and congested [2 + 2]
cyclobutane product 15 with complete stereochemical control.
It merits attention that this represents a very rare example of
photochemical [2 + 2] cycloadditions on N-tethered substrates
in complex synthesis setting.14 Accompanying 15 was a
diketone byproduct 16 (15:16 = 50:29) whose formation
Indeed, PtO2-promoted catalytic hydrogenation17 of 21 was
found to proceed exclusively from the exposed convex face of
its bowl-twisted skeleton, leading to the target 22 with the
correct C6 stereochemistry (Scheme 3). The syn-C5-Me-versus-
C6-H orientation was clearly manifested by their nuclear
Overhauser effect (NOE) correlation. The reduction was
remarkably facile, completing at room temperature in just 2 h
and with 94% isolated yield. In marked contrast, similar action
on a tricyclic structure 232e produced 24 only very slowly (16
h) with opposite alkene enantiofacial recognition and poor C
C versus CO functionality selectivity, the combined yield of
24 after reoxidation of the alcohol byproduct was 74%. Such an
intriguing discrepancy in both reactivity and stereoselectivity
could most reasonably be rationalized by effects of conforma-
tional shielding as well as ring junction strain that are uniquely
associated with the double bond embedded in the bowl-shaped
architecture of 21.18
In summary, through exploring functionality compatibility
and substrate-reinforced stereoelectronic control, we were able
to solve some critical problems that were, as revealed in simpler
model systems, otherwise impossible to overcome. Our strategy
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Scheme 2. Construction of [6−6−5−7] Tetracyclic Alkene 21
in CHCl3 (80 mL) were added pyridine (4.7 mL, 55.2 mmol), TsCl
(7.9 g, 41.4 mmol) and DMAP (674 mg, 5.5 mmol). The reaction
mixture was stirred for 30 h at room temperature and quenched with
H2O. The aqueous phase was extracted three times with ethyl acetate.
The combined layers were washed with brine (2 × 20 mL) and dried
over Na2SO4. The solvent was removed under vacuum, and the residue
was purified by flash chromatography on silica gel (n-hexane/ethyl
acetate = 2/1) to give an intermediate (5.2 g) in 58% yield as yellow
oil: 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8 Hz, 2H), 7.31 (d, J =
8 Hz, 2H), 5.34 (d, J = 4.4 Hz, 1H), 4.04 (t, J = 6 Hz, 1H), 3.90 (dd, J
= 9.6, 5.2 Hz, 1H), 3.84 (dd, J = 9.4, 5.6 Hz, 1H), 2.45 (s, 3H), 1.92
(dd, J = 11.8, 6 Hz, 1H), 1.80 (br s, 2H), 1.75−1.57 (m, overlapped,
3H), 1.67 (s, 3H), 1.09 (quartet, J = 12 Hz, 1H), 0.84 (d, J = 6.8 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 144.8, 136.5, 132.9, 129.8,
127.8, 123.3, 73.0, 70.7, 36.8, 35.5, 34.5, 29.6, 21.6, 18.7, 13.2; HRMS
calcd for C17H24O4SNa (M + Na+) 347.1293, found 347.1286.
To a solution of p-methoxy phenol (4.36 g, 35 mmol) in DMF (70
mL) at 0 °C was added NaH (1.76 g, 44 mmol) and the mixture
features Overman rearrangement, [2 + 2] photochemical
cycloaddition, Grob fragmentation, C−N bond-forming
nucleophilic displacement, and polycyclic ring strain-directed
hydrogenation as key steps and culminates in construction of
the common [6−6−5−7] tetracyclic core of Calyciphylline A
type alkaloids in a highly efficient and stereocontrolled manner.
We believed that the success disclosed here would help
establish an enabling and supportive platform on which
diversity-oriented syntheses of this family of fascinating natural
products could be convergently tackled. Continued efforts
toward total syntheses of some members in this class are
currently being pursued and will be reported in due course.
EXPERIMENTAL SECTION
■
(1S,5S)-5-((S)-1-(4-Methoxyphenoxy)propan-2-yl)-2-methyl-
cyclohex-2-enol (9). To a solution of alcohol 811 (4.7 g, 27.6 mmol)
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Scheme 3. Construction of [6−6−5−7] Tetracyclic Core 22: Remarkable Conformational Strain-Driven Reactivity and
Stereoselectivity
stirred for 1 h. Then the solution of the above-prepared intermediate
(9.5 g, 29.3 mmol) in DMF (30 mL) was added into the mixture via
syringe, and the reaction was warmed to room temperature. After
being stirred for 16 h, the mixture was poured into ice−water (100
mL). The aqueous phase was extracted with Et2O (3 × 80 mL). The
combined organic layers were washed with H2O (3 × 80 mL) and
dried over Na2SO4. The solvent was removed under vacuum, and the
residue was purified by flash chromatography on silica gel (n-hexane/
trichloroacetamide 10 (2.2 g, 5.23 mmol) and Na2CO3 (1.1 g, 10.34
mol). Then the reaction was conducted in the sealed tube at 150 °C
for 4 h and cooled to room temperature. The mixture was quenched
with H2O (10 mL), diluted with Et2O (3 × 20 mL), washed with H2O
(1 × 30 mL) and brine (1 × 30 mL), dried over anhydrous Na2SO4,
and concentrated. The residue was purified by flash chromatography
on silica gel (n-hexane/ethyl acetate = 8/1) to give 11 (1.45 g) in 82%
yield as white solid: 1H NMR (400 MHz, CDCl3) δ 6.80 (s, 4H), 5.50
(s, 1H), 4.49 (d, J = 9.6 Hz, 1H), 4.27 (br s, 1H), 3.86−3.79 (m, 1H),
3.74 (s, 3H), 3.71−3.62 (m, overlapped, total 4H), 2.07 (dd, J = 11.8,
4.8 Hz, 1H), 1.96 (d, J = 15.5 Hz, 1H), 1.90−1.77 (m, 3H), 1.64 (s,
3H), 1.25−1.15 (m, 1H), 0.95 (d, J = 7 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 156.9, 153.7, 153.2, 134.2, 124.9, 115.4, 114.6, 71.5,
55.7, 52.0, 51.9, 37.2, 35.7, 35.4, 27.7, 19.4, 13.4; HRMS calcd for
C19H28NO4 (M + H+) 334.2018, found 334.2024; mp 128.1−128.5
°C.
1
ethyl acetate = 5/1) to give 9 (6.9 g) in 85% yield as white solid: H
NMR (400 MHz, CDCl3) δ 6.80 (s, 4H), 5.45 (d, J = 4.4 Hz, 1H),
4.20−4.10 (m, 1H), 3.88−3.80 (m, 1H), 3.79−3.70 (m, overlapped,
4H), 2.14 (dd, J = 8, 2 Hz, 1H), 2.0−1.70 (m, overlapped, 4H), 1.73
(s, 3H), 1.54 (br s, 1H), 1.30−1.20 (m, 1H), 1.00 (d, J = 6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 153.7, 153.3, 136.4, 124.1, 115.4,
114.6, 71.5, 71.1, 55.7, 37.2, 36.0, 35.3, 30.0, 18.8, 13.8; HRMS calcd
for C17H24NaO3 (M + Na+) 299.1623, found 299.1616; mp 58.1−58.5
°C.
M e t h y l ( H y d r o x y m e t h y l ) ( ( 1 R , 5 R ) - 5 - ( ( S ) - 1 - ( 4 -
methoxyphenoxy)propan-2-yl)-2-methylcyclohex-2-enyl)-
carbamate (12). To a solution of 11 (390 mg, 1.2 mmol) in t-BuOH
(12 mL) at room temperature was added t-BuOK (650 mg, 5.85
mmol) followed by (HCHO)n (351 mg, 11.7 mmol). The resulting
yellow suspension was stirred for 1.5 h at room temperature, and then
satd NH4Cl (10 mL) was added. The resulting mixture was extracted
with ethyl acetate (2 × 10 mL), and the combined organic layers were
washed first with water (30 mL) and then with brine (30 mL) and
dried over Na2SO4. The solvent was removed under reduced pressure
to give a colorless oil, which was purified by silica gel flash column
chromatography (n-hexane/ethyl acetate = 8/1) to give 12 (169 mg)
in 54% yield as a colorless oil (based on 102 mg starting material
2,2,2-Trichloro-N-((1R,5R)-5-((S)-1-(4-methoxyphenoxy)-
propan-2-yl)-2-methylcyclohex-2-enyl)acetamide (10). To a
solution of allylic alcohol 9 (2.89 g, 10.5 mmol) in dry CH2Cl2 (50
mL) was added DBU (2 mL, 15.8 mmol), and the solution was cooled
to 0 °C. To this solution was added 2,2,2-trichloroacetonitrile (2 mL,
21 mmol) over 20 min. After being stirred at 0 °C for 1 h, the reaction
mixture was quenched with satd NH4Cl solution. The organic layer
was washed with satd NH4Cl solution (×2), passed through a column
packed with anhydrous Na2SO4 and silica gel (to remove polymeric
products), and evaporated under reduced pressure to give crude
trichloroacetimidate, which was used for the following step without
any purifications. To a solution of the crude imidate in xylene (105
mL) was added powdered anhydrous K2CO3 (2 g), and the mixture
was heated at reflux temperature for 6 h with vigorous stirring. After
being cooled to room temperature, the mixture was filtered through a
pad of Super-Cel, and the precipitate was washed with toluene. The
solvent was removed under vacuum, and the residue was purified by a
flash chromatography on silica gel (n-hexane/ethyl acetate = 8/1) to
1
recovered): H NMR (400 MHz, CDCl3) δ 6.80 and 6.79 (each s,
total 4H), 5.63 (br s, 1H), 4.95−4.88 (m, 1H), 4.87 and 4.60 (each br
s, total 1H), 4.25 (t, J = 10 Hz, 1H), 3.86−3.65 (m, overlapped, 8H),
3.65−3.55 and 2.86−2.75 (each m, total 1H), 2.01−1.75 (m,
overlapped, 6H), 1.52 (s, 3H), 0.96 (d, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3 some peaks double due to amide conformational
isomers) δ 157.7, 153.7, 153.7, 153.3, 132.9, 132.7, 127.2, 115.5, 114.6,
71.6, 68.6, 67.9, 57.1, 55.7, 52.9, 52.7, 37.4, 37.4, 35.7, 35.5, 33.8, 33.5,
27.7, 27.4, 19.7, 19.5, 13.4, 13.3; HRMS calcd for C20H29NNaO5 (M +
Na+) 386.1943, found 386.1936.
Methyl ((2-Hydroxy-5-oxocyclopent-1-en-1-yl)methyl)-
((1R,5R)-5-((S)-1-(4-methoxyphenoxy)propan-2-yl)-2-methyl-
cyclohex-2-en-1-yl)carbamate (13). To a solution of the 12 (300
mg, 0.83 mmol) in 8 mL of CH3CN were successively added under an
argon atmosphere 1,3-cyclopentanedione (162 mg, 1.65 mmol) and
Sn(NTf2)4·9DMSO (242 mg, 0.12 mmol, 15 mol %). The reaction
mixture was stirred at ambient temperature for 4 h, and then the
solution was quenched with a 5% aqueous solution of NaHCO3 and
the aqueous phase was extracted three times with ethyl acetate. The
combined organic layers were washed with brine and dried over
Na2SO4. The solvent was removed under vacuum, and the resulting
1
give 10 (2.2 g) in 50% yield as a white solid: H NMR (400 MHz,
CDCl3) δ 6.80 (s, 4H), 6.45 (dd, J = 9.6 Hz, 1H), 5.62−5.58 (m, 1H),
4.62−4.50 (m, 1H), 3.83 (dd, J = 9.2, 6 Hz, 1H), 3.74 (s, 3H), 3.72
(dd, J = 9.2, 6 Hz, 1H), 2.13 (dd, J = 12, 5.6 Hz, 1H), 2.09−1.82 (m,
overlapped, 4H), 1.66 (s, 3H), 1.32 (quartet, J = 12 Hz, 1H), 0.98 (d, J
= 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 153.8, 153.2,
132.6, 126.3, 115.4, 114.6, 92.9, 71.4, 55.7, 52.3, 37.2, 35.1, 34.4, 27.5,
19.2, 13.3; HRMS calcd for C19H25Cl3NO3 (M + H+) 420.0900, found
420.0887; mp 88.9−89.3 °C.
Methyl (1R,5R)-5-((S)-1-(4-Methoxyphenoxy)propan-2-yl)-2-
methylcyclohex-2- enylcarbamate (11). Trimethoxymethane (1.1
mL) and p-toluensulfonic acid (101 mg, 0.58 mmol) were placed in a
sealed tube. DMF (27.5 mL) and MeOH (6.4 mL) were added, and
the mixture was stirred at reflux temperature for 1 h. After being
cooled to room temperature, the mixture was added with
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Note
residue was purified by flash chromatography on silica gel (n-hexane/
ethyl acetate = 4/1) to give 13 (283 mg) in 77% yield as yellow oil: 1H
NMR (400 MHz, CDCl3) δ 12.14 (s, 1H), 6.85−6.75 (m, 4H), 5.73
(s, 1H), 4.64 (br s, 1H), 3.81−3.69 (m, overlapped, 2H), 3.77(s, 3H),
3.72 (s, 3H), 3.69−3.59 (m, 2H), 2.48 (br s, 2H), 2.40−2.30 (m, 2H),
2.10−1.68 (m, overlapped, 6H), 1.49 (s, 3H), 0.93 (d, J = 6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 203.3, 189.4, 160.8, 153.6, 153.4,
131.4, 128.7, 115.3, 114.9, 114.6, 71.4, 58.0, 55.7, 53.8, 37.2, 35.3, 34.0,
33.7, 31.3, 26.9, 19.4, 13.2; HRMS calcd for C25H34NO6 (M + H+)
444.2386, found 444.2386.
2 - ( ( ( M e t h o x y c a r b o n y l ) ( ( 1 R , 5 R ) - 5 - ( ( S ) - 1 - ( 4 -
methoxyphenoxy)propan-2-yl)-2-methylcyclohex-2-en-1-yl)-
amino)methyl)-3-oxocyclopent-1-en-1-yl Acetate (14). To a
solution of 13 (324 mg, 0.73 mmol) in 4 mL of CH2Cl2 at 0 °C were
added consecutively triethylamine (0.3 mL, 2.19 mmol) and acetyl
chloride (150 μL, 2.19 mmol). After being stirred at 0 °C for 1.5 h, the
reaction mixture was quenched by addition of satd NH4Cl, and the
aqueous phase was extracted three times with ethyl acetate. The
combined organic layers were washed with brine and dried over
Na2SO4. The solvent was removed under vacuum, and the resulting
residue was purified by flash chromatography on silica gel (n-hexane/
ethyl acetate = 2/1) to give 14 (337 mg) in 95% yield as yellow oil: 1H
NMR (400 MHz, CDCl3) δ 6.79 (s, 4H), 5.62 (br s, 1H), 4.88 and
4.69 (each br s, total 1H), 4.12−3.95 (m, 1H), 3.70−3.40 (m,
overlapped, 9H), 2.85−2.70 (m, 2H), 2.50−2.31 (m, 2H), 2.15 and
2.12 (each s, total 3H), 1.99−1.68 (m, overlapped, total 6H), 1.49 (s,
3H), 0.93 (d, J = 5.6 Hz, 3H); 13C NMR (100 MHz, CDCl3 some
peaks double due to amide conformational isomers) δ 205.1, 176.8,
175.8, 166.8, 153.7, 153.3, 132.9, 127.7, 126.4, 115.3, 114.6, 71.5, 61.9,
57.6, 57.3, 55.8, 52.6, 37.4, 36.5, 35.8, 34.2, 34.0, 32.0, 31.3, 28.1, 27.5,
27.1, 19.4, 13.8, 13.4; HRMS calcd for C27H36NO7 (M + H+)
486.2492, found 486.2482.
23.4, 13.7, 13.6; HRMS calcd for C25H34NO6 (M + H+) 444.2386,
found 444.2380.
(2aR,2a1R,4R,5aS,5bS,8R,8aS)-Methyl 5b-Acetoxy-8-hy-
droxy-4-((S)-1-(4-methoxyphenoxy)propan-2-yl)-2a1-
methyldecahydrocyclopenta[1,4]cyclobuta[1,2,3-cd]indole-
2(1H)-carboxylate (17). To a solution of 15 (188 mg, 0.39 mmol) in
MeOH (10 mL) at 0 °C was added NaBH4 (30 mg, 0.77 mmol). The
reaction mixture was stirred for 2 h at 0 °C and then quenched by satd
NH4Cl. The aqueous phase was extracted three times with ethyl
acetate. The combined organic layers were washed with brine and
dried over Na2SO4. The solvent was removed under vacuum, and the
residue was purified by flash chromatography on silica gel (n-hexane/
ethyl acetate = 2/1) to give 17 (181 mg) in 95% yield as colorless oil:
1H NMR (500 MHz, CDCl3) δ 6.79 (s, 4H), 4.17 (dd, J = 10.8, 7.5
Hz, 1H), 3.82−3.76 (m, 2H), 3.74 (s, 3H), 3.71−3.68 (m, overlapped,
1H), 3.67 (s, 3H), 3.61 (t, J = 6 Hz, 1H), 3.43 (d, J = 12 Hz, 1H), 2.44
(dd, J = 14, 8 Hz, 1H), 2.32 (t, J = 9 Hz, 1H), 2.15−2.10 (m, 1H),
2.02 (s, 3H), 2.02−1.70 (m, 5H), 1.58−1.50 (m, 1H), 1.50−1.49 (m,
1H), 1.35 (s, 3H), 1.32−1.26 (m, 1H), 0.91 (d, J = 7 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 170.1, 156.4, 153.8, 153.5, 115.6, 114.7,
83.4, 76.7, 71.7, 64.8, 58.6, 55.8, 52.2, 50.1, 48.8, 43.3, 37.8, 36.3, 32.0,
31.1, 29.0, 23.5, 21.4, 21.2, 13.3; HRMS calcd for C27H38NO7 (M +
H+) 488.2648, found 488.2634.
(2a1R,6aS,8R,9aR)-Methyl 8-((S)-1-(4-Methoxyphenoxy)-
propan-2-yl)-2a1-methyl-6-oxo-2,2a1,4,5,6,6a,7,8,9,9a-decahy-
dro-1H-cyclohepta[cd]indole-1-carboxylate (18). To a stirred
solution of 17 (181 mg, 0.37 mmol) in pyridine (10 mL) were added
methanesulfonyl chloride (0.3 mL, 3.7 mmol) and DMAP (44 mg,
0.36 mmol). The reaction mixture was stirred for 1.5 h at room
temperature, diluted with ethyl acetate (10 mL), and washed
consecutively with satd NH4Cl (2 × 5 mL) and brine (2 × 5 mL).
The organic layer was dried with Na2SO4 and concentrated to yield
mesylate which was carried on to the next step. The mesylate was
dissolved in MeOH (5 mL) and stirred with K2CO3 (305 mg, 2.2
mmol) overnight at room temperature. The reaction mixture was
filtered, evaporated, diluted with water (5 mL), and extracted with
ethyl acetate before drying over Na2SO4. The solvent was removed
under vacuum, and the residue was purified by flash chromatography
on silica gel (n-hexane/ethyl acetate = 4/1) to give 18 (129 mg) in
Synthesis of 15 and 16. A solution of 14 (60 mg, 0.12 mmol) in
acetonitrile (90 mL) in a photoreaction vessel (quartz) was degassed
by bubbling N2 through the solution for 15 min. The resulting solution
was then irradiated (10 W medium pressure lamp, 254 nm) for 1 h at
0 °C under nitrogen atmosphere. Evaporation of volatiles and
purification by flash chromatography (n-hexane/ethyl acetate = 4/1)
to give 15 (30 mg) in 50% yield as yellow oil and 16 (15 mg) in 29%
yield as yellow oil.
1
82% yield as colorless oil: H NMR (500 MHz, CDCl3) δ 6.80−6.71
(m, 4H), 5.71 (d, J = 19.5 Hz, 1H), 4.27 and 4.19 (each d, J = 16.5 and
15.0 Hz, total 1H), 3.91 (t, J = 15 Hz, 1H), 3.75 and 3.74 (each s, total
3H), 3.69 and 3.67 (each s, total 3H), 3.81−3,71 (m, overlapped, 2H),
3.70−3.63 and 3.53 (overlapped and dd, J = 10, 5.5 Hz, total 1H),
2.71−2.61 (m, 2H), 2.53−2.39 (overlapped, 2H), 2.29−2.19 (m, 1H),
2.05 and 1.90 (each dt, J = 13, 2.5 Hz and 13, 2.5 Hz, total 1H), 1.87−
1.77 (m, 1H), 1.76−1.70 (m, 1H), 1.70−1.55 (overlapped, 1H), 1.40
(pentet, J = 12.5 Hz, 1H), 1.20 and 1.19 (each s, total 3H), 1.10−0.92
(m, 1H), 0.94 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3 some
peaks double due to amide conformational isomers) δ 213.0, 155.4,
155.1, 154.0, 153.9, 153.3, 140.8, 140.0, 121.4, 121.2, 115.6, 155.6,
114.8, 71.7, 71.7, 65.8, 65.7, 60.3, 55.8, 52.4, 52.3, 50.1, 49.7, 45.1,
44.5, 42.3, 37.5, 37.3, 37.3, 33.2, 32.4, 30.5, 30.2, 29.7, 27.0, 27.0, 24.0,
13.8, 13.7; HRMS calcd for C25H34NO5 (M + H+) 428.2437, found
428.2412.
(2aR,2a1R,4R,5aS,5bS,8aR)-Methyl 5b-acetoxy-4-((S)-1-(4-
m e t h o x y p h e n o x y ) p r o p a n - 2 - y l ) - 2 a 1 - m e t h y l - 8 -
oxodecahydrocyclopenta[1,4]cyclobuta[1,2,3-cd]indole-2(1H)-
carboxylate (15): 1H NMR (500 MHz, CDCl3) δ 6.79 (s, 4H), 3.81
(dd, J = 9, 6 Hz, 1H), 3.76−3.69 (m, overlapped, 2H), 3.73 (s, 3H),
3.645 (s, 3H), 3.49 (dd, J = 10, 2 Hz, 1H), 3.42 (d, J = 12.5 Hz, 1H),
2.74−2.65 (m, 1H), 2.50−2.29 (m, overlapped, 4H), 2.21 (br s, 1H),
2.06 (s, 3H), 1.87−1.77 (m, overlapped, 2H), 1.68−1.52 (m, 3H),
1.12 (s, 3H), 0.94 (d, J = 7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
214.8, 170.4, 155.9, 153.8, 153.4, 115.5, 114.7, 80.5, 71.4, 64.1, 63.0,
55.8, 52.2, 50.8, 48.9, 47.3, 38.7, 38.2, 35.4, 31.1, 26.8, 21.5, 21.2, 21.0,
13.6; HRMS calcd for C27H36NO7 (M + H+) 486.2492, found
486.2494.
(2aR,2a1R,6aS,8R,9aR)-Methyl 8-((S)-1-(4-methoxyphenoxy)-
propan-2-yl)-2a1-methyl-3,6-dioxododecahydro-1H-
cyclohepta[cd]indole-1-carboxylate (16): 1H NMR (400 MHz,
CDCl3) δ 6.82−6.72 (m, 4H), 4.15 and 4.08 (each dd, J = 12, 8.8 Hz
and J = 11.8, 9.2 Hz, total 1H), 3.70−3.89 (m, overlapped, 3H), 3.75
(s, 3H), 3.69 and 3.66 (each s, total 3H), 3.73−3.70 and 3.58 (m,
overlapped and dd, J = 14, 5.6 Hz, total 1H), 3.48 and 3.44 (each dd, J
= 11, 9.2 Hz and J = 11.6, 8.8 Hz, total 1H), 3.19 (td, J = 13.2, 4 Hz,
1H), 2.72−2.56 (m, overlapped, 2H), 2.51−2.39 (m, 1H), 2.34 (dt, J =
12, 4 Hz, 1H), 2.23−2.15 and 2.08−1.98 (each m, total 1H), 1.97−
1.87 (m, 1H), 1.82−1.76 (m, 1H), 1.69−1.62 (m, overlapped, 2H),
1.29−1.11 (m, 1H), 0.51 (d, J = 6.8 Hz, 3H), 0.88 (s, 3H); 13C NMR
(100 MHz, CDCl3 some peaks double due to amide conformational
isomers) δ 210.7, 210.6, 206.3, 205.9, 155.1, 153.9, 153.0, 115.5, 115.4,
114.7, 71.4, 71.3, 66.2, 66.1, 60.5, 55.8, 52.4, 51.4, 50.4, 43.7, 43.2,
42.9, 42.2, 38.3, 37.3, 36.2, 36.1, 33.5, 323.0, 32.2, 28.5, 28.2, 23.5,
(2a1R,6aS,8R,9aR)-Methyl 8-((S)-1-Hydroxypropan-2-yl)-2a1-
methyl-6-oxo-2,2a1,4,5, 6,6a,7,8,9,9a-decahydro-1H-
cyclohepta[cd]indole-1-carboxylate (19). To a solution of 18
(160 mg, 0.37 mmol) in CH3CN/H2O = 4:1 (2.5 mL) at 0 °C was
added CAN (410 mg, 0.75 mmol). After being stirred for 30 min, the
reaction was quenched with brine (2 mL), and the aqueous layer was
extracted with ethyl acetate (3 × 2 mL). The combined organic
portion was dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography on silica gel (n-
hexane/ethyl acetate = 1/2) to give 19 (120 mg) in 99% yield as
yellow oil: 1H NMR (400 MHz, CDCl3) δ 5.73 and 5.70 (each d, J =
2.8 and J = 3 Hz, total 1H), 4.23 (ddd, J = 35, 28, 3 Hz, 1H), 3.90 (td,
J = 13.2, 1.2 Hz, 1H), 3.68 (s, 3H), 3.63 and 3.58−3.50 (dd and
overlapped, J = 10, 7 Hz, total 1H), 3.57−3.42 (m, 2H), 2.71−2.60
and 2.48−2.35 (m, total 2H), 2.49 (td, J = 15, 4.5 Hz, 1H), 2.29−2.18
6311
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The Journal of Organic Chemistry
Note
(m, 1H), 2.05−1.96 and 1.90−1.80 (each m, total 1H), 1.72−1.47
(overlapped, total 4H), 1.36−1.27 (m, 1H), 1.19 and 1.18 (each s,
total 3H), 1.09−0.92 (m, 1H), 0.85 and 0.84 (each d, J = 8 and 8 Hz,
total 3H); 13C NMR (100 MHz, CDCl3 some peaks double due to
amide conformational isomers) δ 213.5, 213.4, 155.3, 155.1, 140.5,
139.7, 121.4, 121.2, 65.7, 65.7, 60.2, 60.2, 52.5, 52.4, 50.0, 49.7, 45.0,
44.4, 42.4, 39.98, 39.92, 36.7, 36.5, 30.2, 29.8, 27.1, 27.0, 23.7, 13.4,
13.1; HRMS calcd for C18H28NO4 (M + H+) 322.2018, found
322.2023.
(2aR,2a1S,6aS,8R,9aR)-Methyl 8-Isopropyl-2a1-methyl-6-ox-
ododecahydro-1H-cyclohepta[cd]indole-1-carboxylate (24).
To a solution of carbamate 23 (42 mg, 0.14 mmol) in MeOH (2
mL) was added PtO2 (16 mg, 0.07 mmol). Then the reaction was
stirred under hydrogen atmosphere (1 atm) for 16 h. The solvent was
removed under vacuum, and the resulting residue was purified by flash
chromatography on silica gel (n-hexane/ethyl acetate = 8:1) to give
the mixture of compound 24 and corresponding alcohol. The crude
products were treated with DMP (170 mg, 0.42 mmol) and NaHCO3
(70 mg, 0.84 mmol) in CH2Cl2 (2 mL) for 3 h. The reaction was
quenched with satd Na2S2O3/NaHCO3 = 1:1 (2 mL), and the aqueous
layer was extracted with ethyl acetate (3 × 2 mL). The combined
organic portion was washed with H2O (2 mL) and brine (2 mL) and
dried over Na2SO4. The solvent was removed under vacuum, and the
resulting residue was purified by flash chromatography on silica gel (n-
hexane/ethyl acetate = 8:1) to give 24 (32 mg) in 74% yield as
(2a1 R,6aS,8R,9aR)-Methyl 2a1-Methyl-8-((S)-1-
( ( m e t h y l s u l f o n y l ) o x y ) p r o p a n - 2 - y l ) - 6 - o x o -
2,2a1,4,5,6,6a,7,8,9,9a-decahydro-1H-cyclohepta[cd]indole-1-
carboxylate (20). To a solution of 19 (120 mg, 0.373 mmol) in
CH2Cl2 (4 mL) at 0 °C were added Et3N (160 μL) and methylsufonyl
chloride (60 μL), and then the mixture was warmed to room
temperature. After the mixture was stirred for 2 h, the reaction was
quenched with brine (4 mL), and the aqueous layer was extracted with
ethyl acetate (3 × 3 mL). The combined organic portion was washed
with brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography on silica gel (n-
hexane/ethyl acetate = 1.5/1) to give 20 (142 mg) in 95% yield as
yellow oil: 1H NMR (400 MHz, CDCl3) δ 5.69 (d, J = 11.6 Hz, 1H),
4.27−3.82 (m, overlapped, 4H), 3.65 and 3.64 (each s, total 3H), 3.59
and 3.48 (each dd, J = 11, 5.2 Hz and J = 11, 5.2 Hz, total 1H), 2.96
and 2.95 (each s, total 3H), 2.70−2.58 (m, 2H), 2.44 (td, J = 12.6, 3.2
Hz, 1H), 2.40−2.32 (m, 1H), 2.27−2.14 (m, 1H), 2.02−1.93 and 1.84
(m and dt, J = 12.8, 2.4 Hz, total 1H), 1.74 (pentet, J = 6 Hz, 1H),
1.70−1.61 (m, 1H),1.49−1.38 (m, 1H), 1.38−1.25 (m, 1H), 1.56 (s,
3H), 0.98−0.92 (m, 1H), 0.89 (d, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3 some peaks double due to amide conformational
isomers) δ 212.7, 212.6, 155.1, 154.9, 140.2, 139.4, 121.5, 121.3, 72.1,
72.0, 65.3, 65.3, 59.9, 52.3, 52.2, 49.9, 49.5, 44.8, 44.2, 42.2, 37.2, 37.2,
36.8, 36.5, 32.8, 31.9, 30.2, 29.8, 26.8, 26.8, 23.6, 23.5, 13.4; HRMS
calcd for C19H30NO6S (M + H+) 400.1794, found 400.1777.
1
colorless oil: H NMR (500 MHz, CDCl3) δ 3.64 and 3.63 (each s,
total 3H), 3.58−3.48 and 3.38 (m and dd, J = 11, 6 Hz, total 2H), 3.11
and 3.05 (each t, J = 11 Hz and J = 10.5 Hz, total 1H), 2.65 (ddd, J =
19.6, 6.5, 2.5 Hz, 1H), 2.64−2.56 (m, 1H), 2.46−2.34 (m, 2H), 2.12−
2.07 and 1.96−1.90 (m, total 1H), 1.87−1.60 (m, 4H), 1.49−1.40 (m,
2H), 1.29 (ddd, J = 24.8, 12.3, 2 Hz, 1H), 1.23−1.12 (m, 1H), 1.05−
0.94 (m, 1H), 0.98 and 0.97 (each s, total 3H), 0.86−0.82 (m, 6H);
13C NMR (125 MHz, CDCl3 some peaks double due to amide
conformational isomers) δ 214.2, 155.4, 155.1, 66.6, 66.5, 60.3, 60.2,
52.2, 52.1, 50.1, 49.8, 42.2, 42.2, 41.6, 41.5, 40.8, 39.2, 38.3, 32.3, 32.3,
32.0, 31.4, 29.3, 29.1, 26.2, 22.8, 22.3, 22.2, 19.6, 19.5, 19.5, 19.4;
HRMS calcd for C18H30NO3 (M + H+) 308.2226, found 308.2220.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and procedures, compound character-
1
ization data, and copies of H, 13C, and 2D NMR spectra for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(2R,3S,11S,11aR,11bR)-3,11a-Dimethyl-3,4,6,8,9,11,11a,11b-
octahydro-1H-2,11-methanocyclohepta[a]indolizin-10(2H)-
one (21). To a solution of 20 (20 mg, 0.05 mmol) in CH2Cl2 (1.5
mL) was added TMSI (30 mg, 0.15 mmol). The mixture was stirred at
room temperature for 4 h, quenched with satd Na2S2O3 (aq), and
extracted with CH3OH/CH2Cl2 = 1:9 (8 × 2 mL). The combined
organic portion was washed with brine and dried over Na2SO4, filtered,
and concentrated in vacuo. The crude product was dissolved in 1.5 mL
of CH2Cl2 and 50 μL Et3N added. After being stirred for 16 h, the
mixture was purified by flash chromatography on silica gel (CH2Cl2/
MeOH/Et3N = 100:5:1) to give 21 (10 mg) in 80% yield as a colorless
AUTHOR INFORMATION
Corresponding Author
*E-mail: (D.Z.W.) dzw@pkusz.edu.cn; (X.H.) haoxj@mail.kib.
ac.cn.
■
Notes
The authors declare no competing financial interest.
1
oil: H NMR (400 MHz, CDCl3) δ 6.19 (ddd, J = 7.2, 3.0, 2.8 Hz,
ACKNOWLEDGMENTS
■
1H), 4.08 (dt, J = 13.6, 2.8 Hz, 1H), 3.77 (s, 1H), 3.37 (d, J = 13.6 Hz,
1H), 3.25 (d, J = 13.6 Hz, 1H), 3.17 (dd, J = 13.4, 5.6 Hz, 1H), 2.71−
2.55 (m, overlapped, 3H), 2.50−2.40 (m, 1H), 2.30−2.22 (m, 1H),
2.21−2.13 (m, 2H), 2.15−1.90 (m, 1H), 1.90−1.71 (m, 1H), 1.64 (dd,
J = 16, 4.4 Hz, 1H), 1.49−1.37 (m, 1H), 1.32 (d, J = 7.2 Hz, 3H), 1.26
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 210.5, 139.0, 129.3, 66.8,
59.5, 55.7, 48.6, 41.1, 39.8, 32.5, 27.7, 26.3, 25.5, 23.6, 18.3, 16.9;
HRMS calcd for C16H24NO (M + H+) 246.1858, found 246.1852.
(2R,3S,6aS,11S,11aS,11bR)-3,11a-Dimethyldecahydro-1H-
2,11-methanocyclohepta[a]indolizin-10(2H)-one (22). To a
solution of 21 (4.5 mg, 0.018 mmol) in MeOH (1 mL) was added
PtO2 (2 mg, 0.009 mmol). Then the reaction was stirred under
hydrogen atmosphere (1 atm) for 2.5 h. The solvent was removed
under vacuum, and the resulting residue was purified by flash
chromatography on silica gel (CH2Cl2/MeOH/Et3N = 100:5:1) to
We thank the National Science Foundation of China (Grant
Nos. 20872004 and 20972008 to D.Z.W. and 20672120 to
X.J.H), the National “973 Project” from the State Ministry of
Science and Technology, the Shenzhen Bureau of Science,
Technology and Information, and the Shenzhen “Shuang Bai
Project” for generous financial support. We also thank Mr. Bo
Zhang for experimental assistance and Dr. Zheng Xiang for
helpful discussions.
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