Oxidative dearomatization/intramolecular Diels-Alder cycloaddition cascade for the syntheses of (±)-atisine and (±)-isoazitine

Article abstract of DOI:10.1039/c1ob06704d

A convergent and efficient formal synthesis of (±)-atisine has been accomplished. The synthetic strategy is to efficiently construct the bicyclo[2.2.2]octane ring moiety by an oxidative dearomatization/intramolecular Diels-Alder cycloaddition cascade. The first total synthesis of another atisine-type C₂₀-diterpenoid alkaloid, (±)-isoazitine, has also been achieved employing the same strategy.

Full text of DOI:10.1039/c1ob06704d

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PAPER
Oxidative dearomatization/intramolecular Diels–Alder cycloaddition cascade
for the syntheses of ( )-atisine and ( )-isoazitine†
Xiao-Yu Liu, Hang Cheng, Xiao-Huan Li, Qiao-Hong Chen,* Liang Xu and Feng-Peng Wang*
Received 9th October 2011, Accepted 8th November 2011
DOI: 10.1039/c1ob06704d
A convergent and efficient formal synthesis of ( )-atisine has been accomplished. The synthetic strategy
is to efficiently construct the bicyclo[2.2.2]octane ring moiety by an oxidative dearomatization/
intramolecular Diels–Alder cycloaddition cascade. The first total synthesis of another atisine-type
C20-diterpenoid alkaloid, ( )-isoazitine, has also been achieved employing the same strategy.
synthetic target. It can be argued quite successfully that the
Introduction
total synthesis of the diterpenoid alkaloids can be traced back
Diterpenoid alkaloids, featuring polycyclic, highly bridged, and
to the early 1960s when Nagata and co-workers reported the first
total synthesis of atisine.5a So far, four different approaches5 to
Pelletier’s synthetic intermediates (Fig. 1)6 for atisine have been
reported. The major advancement in the synthesis is to efficiently
construct azabicyclo[3.3.1]nonane and bicyclo[2.2.2]octane ring
systems.
Liao and co-workers have developed an efficient method to
construct a bicyclo[2.2.2]octane ring system employing sequential
oxidative dearomatization/intramolecular Diels–Alder (IMDA)
cycloaddition.7 This strategy has been elegantly applied to the for-
mation of highly functionalized bicyclo[2.2.2]octane ring systems
towards the total syntheses of natural products.8 Consequently, we
envisioned assembling the bicyclo[2.2.2]octane ring system of the
key intermediate 3a for diterpenoid alkaloids 1 and 2 by a cascade
of oxidative dearomatization/IMDA cycloaddition.
heavily substituted structures, constitute the largest and most
complex group of terpenoid alkaloids.1 The architectural features,
physiological properties, and pharmacological activities of the
diterpenoid alkaloids pose an alluring target for synthetic chemists
and medicinal chemists.2 Due to the structural diversity and com-
plexity of the diterpenoid alkaloids, their synthesis could prompt
the development of ingenious strategies and new methodology for
complicated natural products.
The diterpenoid alkaloids can be divided into three broad
categories: C20-diterpenoid alkaloids, C19-diterpenoid alkaloids,
and C18-diterpenoid alkaloids.1 The atisine-type C20-diterpenoid
alkaloids, such as atisine (1)3 and isoazitine (2)4 (Fig. 1), possess a
pentacyclic framework, characteristic of azabicyclo[3.3.1]nonane
and bicyclo[2.2.2]octane moieties. The relative simplicity of atisine
coupled with extensive structural data made it an ideal first
Results and discussion
Our retrosynthetic analysis of atisine (1) and isoazitine (2) is
outlined in Scheme 1. The pentacyclic key intermediate 3a for
the targets was proposed to proceed from phenol precursor 5
via the masked ortho-benzoquinone ketal 49 using the oxidative
dearomatization/IMDA cycloaddition cascade. The precursor 5
could be readily generated by a Wittig reaction of aldehyde 7
with phosphonium salt 6. The bicyclo[3.3.1]nonane ring system in
aldehyde 7 may be accessed through the well-established double
Mannich reaction.
Fig. 1 Structures of atisine, isoazitine, and Pelletier’s key synthetic
Aldehyde 7 was prepared as shown in Scheme 2. a-Methylation
of commercially available ethyl 2-oxocyclohexanecarboxylate (8)
using LDA as base provided product 9,10 which was subjected to
double Mannich reaction with benzylamine and formaldehyde to
afford azabicyclic compound 10 in 44% yield over 2 steps. Wittig
methylenation of ketone 10 gave olefin 11 in 77% yield. Reduction
of the ester group in 11 with LiAlH4 followed by protection of the
resulting alcohol provided the MOM ether 12 in 87% yield over
two steps. According to the method reported by Fukumoto,5d
intermediates.
Department of Chemistry of Medicinal Natural Products, Sichuan Univer-
sity, No. 17, Duan 3, Renmin Nan Road, Chengdu, 610041. E-mail: qiao-
hongchen@yahoo.com.cn, wfp@scu.edu.cn; Fax: +86-28-85501368
† Electronic supplementary information (ESI) available: NMR spectra for
two final products and all intermediates. CCDC reference number 834603.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c1ob06704d
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reaction due to the critical correlation between H-14 and H-20 in
its NOESY spectrum (see Electronic Supplementary Information
for details†). This assignment was also confirmed by X-ray
crystallographic analysis of its derivative 19b described below. The
remaining transformations from 17 to 3a were straightforward and
proceeded via ketal 18 in good yields (Scheme 3). The structure
of 3a was established by comparison of its IR data and melting
point with those reported in the literature,6 and by extensive NMR
analyses. Based on the previous work by Pelletier and co-workers,6
the present synthesis of the known compound 3a constitutes a new
formal total synthesis of ( )-atisine.
Scheme 1 Retrosynthetic analysis for ( )-atisine and ( )-isoazitine.
Scheme 2 Construction of A/E ring system.
stereoselective hydroboration of the terminal alkene in 12 was
achieved by the addition of a solution of NaBH4 in diglyme to the
◦
mixture of 12 and BF3·OEt2 in diglyme at -23 C. The resulting
product was oxidized with trimethylamine N-oxide to give the
desired isomer 13 in 82% yield, with trace amounts of the undesired
diastereomer. Conversion of 13 to 7 was easily achieved in 74%
overall yield by a three-step procedure including debenzylation,
selective acylation of the amine and oxidation of the alcohol.
Having made azabicyclo[3.3.1]nonane 7, it was treated
with a Wittig reagent, generated in situ from (2-methoxy-3-
methoxymethoxybenzyl)triphenyl-phosphonium bromide (6) and
t-BuOK, to afford styrene 14 as E isomer in 75% yield. After
removal of the MOM groups and hydrogenation of the alkene, the
phenol was selectively protected as an acetate in the presence of a
primary hydroxyl group, employing the method reported by Ray
et al.11 The double bond between C-9 and C-11 in the precursor
5 was introduced by oxidation of primary alcohol 15 to aldehyde
16 followed by a Wittig methylenation. The acetate in 16 was
hydrolysed by the addition of two equivalents of t-BuOK to the
reaction mixture after the Wittig reaction was completed.
Scheme 3 Formal synthesis of ( )-atisine.
We also investigated the total synthesis of ( )-isoazitine (2)
employing pentacyclic compound 3a as an advanced intermediate.
As illustrated in Scheme 4, Luche reduction (NaBH4, CeCl3)12 of
enone 3a generated two separable isomers 19a and 19b (3 : 2) in
88% overall yield. The configuration of the hydroxyl group at
C-15 of each isomer was confirmed by an X-ray crystallographic
analysis of 19b (Fig. 2).13 Note that the configuration of this allylic
hydroxyl group was always tentatively assigned in the literature
based upon its polarity on alumina according to Pelletier’s view.14
At this point, we investigated the effect of solvents on the ox-
idative dearomatization/IMDA cascade, and found that methanol
was detrimental to IMDA cycloaddition. Consequently, phenol 5
was oxidized with PhI(OAc)2 in the presence of sodium bicar-
bonate using methanol as a solvent. After switching the solvent
from methanol to xylene, the resulting masked ortho-quinone was
subjected to thermal activation (150 ◦C) to provide pentacyclic
compound 17 as a single isomer in 78% yield. Compound 17
was assigned as the intended endo product of the Diels–Alder
Scheme 4 Total synthesis of ( )-isoazitine.
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chromatography was performed using 200–300 mesh silica gel.
All new compounds gave satisfactory spectroscopic data (IR,
1H NMR, 13C NMR, HRMS). Melting points were determined
on a Kofler block (uncorrected); IR spectra were recorded on
a Nicolet 200 SXV spectrometer; HRMS spectra were obtained
with a Bruker BioTOFQ mass spectrometer; NMR spectra were
acquired on a Varian INOVA-400/54 spectrometer, with TMS as
internal standard.
Fig. 2 X-ray crystallographic structure of compound 19b.
Ethyl
3-benzyl-5-methyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-
carboxylate (10). To a solution of diisopropylamine (9.0 mL,
64.6 mmol) in anhydrous THF (125 mL) at 0 ◦C was added
n-BuLi (25.8 mL, 64.6 mmol, 2.5 M solution in hexane), and the
solution was stirred at 0 ◦C for 30 min. To this LDA solution
was added dropwise a solution of 2-oxocyclohexanecarboxylate 8
(5.0 g, 29.4 mmol) in THF (25 mL), and the reaction was allowed
to proceed with stirring at 0 ◦C for an additional 1 h. Methyl
iodide (2.0 mL, 32.3 mmol) was added to the above◦ reaction
mixture, and the reaction was allowed to proceed at 0 C for 30
min prior to being quenched by the addition of saturated NH4Cl
solution (50 mL) and water (50 mL). The subsequent mixture was
extracted with diethyl ether (100 mL ¥ 3). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo to furnish a crude product (9), which was
directly used for the next reaction without further purification. A
mixture of 9, benzylamine (4.8 mL, 44.1 mmol) and formaldehyde
(7.1 mL, 88.1 mmol, 37% aqueous solution) in EtOH (120 mL)
was heated under reflux for 48 h. After removal of the solvent
under reduced pressure, the orange oil was suspended in water
(150 mL), and the subsequent mixture was extracted with CH2Cl2
(80 mL ¥ 3). The organic extracts were washed with brine, dried
over anhydrous Na2SO4, and concentrated to give a residue, which
was subjected to a flash column chromatography on silica gel,
eluting with petroleum ether-EtOAc (100 : 1) to afford compound
10 (4.1 g, 44% over two steps) as a yellow oil. Rf 0.53 (petroleum
ether–EtOAc 20 : 1); IR (film) 2927, 2858, 1735, 1456, 1261, 742,
700 cm-1; 1H NMR (CDCl3, 400 MHz) d 7.36–7.27 (m, 5H),
4.19 (q, J = 7.2 Hz, 2H), 3.49 (s, 2H), 3.20 (dd, J = 11.6, 2.4 Hz,
1H), 3.21–3.12 (m, 1H), 3.03–2.92 (m, 2H), 2.59–2.51 (m, 1H),
2.32 (dd, J = 11.2, 2.4 Hz, 1H), 2.25–2.20 (m, 1H), 2.11–2.06 (m,
1H), 1.86–1.77 (m, 1H), 1.61–1.55 (m, 1H), 1.27 (t, J = 7.2 Hz,
3H), 0.93 (s, 3H); 13C NMR (CDCl3, 100 MHz) d 213.1, 171.1,
138.3, 128.7, 128.4, 127.2, 66.8, 62.1, 62.1, 61.1, 58.8, 46.9, 42.0,
36.8, 20.9, 20.6, 14.1; HRESIMS m/z calcd for C19H25NO3Na
[M+Na]+: 338.1732, found 338.1727.
Consequently, we have confirmed the configuration for the first
time.
The acetamide in 19a was hydrolysed with excess potassium
hydroxide in methanol–water in a sealed tube. After extensive
exploration, it was observed that the secondary amine in 20 can
be selectively oxidized to imine in 65% yield employing Hg(OAc)2
as oxidizing agent at 60 ◦C. Mercuric acetate oxidation of tertiary
amines involves a four-center elimination from the N-mercurated
complex.15 Oxidation of compound 20 might be expected to
undergo at one of the two a-methine positions (C-19 and C-20),
since one of the hydrogens at both positions can be trans to an N-
mercurated complex. The regioselectivity of the mercuric acetate
oxidation at C-19 of 20 is probably because the proton at C-20
is more sterically hindered than the proton at C-19. This can be
supported by the molecular model of compound 20, from which
we can observe that the ring B/C/D system in 20 confers much
more steric hindrance to C-20 relative to C-19. Note when the
reaction was carried out with 2 equivalents of Hg(OAc)2 at 100
◦C, the allylic alcohol in 20 was also oxidized to enone. Thus,
the first total synthesis of ( )-isoazitine (2) was achieved. The
spectroscopic data of synthetic 2 were identical in all aspects to
those of the natural product.16
Conclusions
In summary, a new synthesis of the Pelletier’s intermediate
(3a) for the atisine-type alkaloids has been achieved in 19
steps. A distinctive feature of the synthesis is the application
of an oxidative dearomatization/IMDA cycloaddition cascade
to construct bicyclo[2.2.2]octane moiety. This synthetic strat-
egy, in combination with the well-established construction of
azabicyclo[3.3.1]nonane by a double Mannich reaction,5d enabled
the synthetic route to be convergent and efficient. Furthermore,
the first total synthesis of ( )-isoazitine (2) was achieved in 22
steps using the same strategy. The extension of this strategy to
the synthesis of more complicated hetidine-type and hetisine-
type diterpenoid alkaloids is currently under investigation in our
laboratory.
Ethyl
3-benzyl-5-methyl-9-methylene-3-azabicyclo[3.3.1]
nonane-1-carboxylate (11). To a suspension of Ph3PCH3Br (11.9
g, 33.3 mmol) in anhydrous THF (150 mL) was slowly added
n-BuLi (13.3 mL, 33.3 mmol, 2.5 M solution in hexane) at -20 ◦C,
and the mixture was stirred for 30 min at 0 ◦C. A solution of
10 (7.0 g, 22.2 mmol) in anhydrous THF (50 mL) was added
to the above Wittig reagent, and the reaction mixture was kept
stirring for 2 h at room temperature prior to being quenched
by the addition of saturated NH4Cl solution (150 mL). The
subsequent mixture was extracted with CH2Cl2 (100 mL ¥ 3), the
combined organic layers were washed with brine and dried over
anhydrous Na2SO4, and the organic solvents were removed in
vacuo. The crude residue was purified via chromatography eluting
with petroleum ether–EtOAc (100 : 1) to afford alkene 11 (5.3 g)
Experimental
General procedures
All reactions were carried out under argon unless otherwise stated.
All the chemicals were purchased from commercial sources and
were used without further purification. THF, toluene, and xylene
were distilled from sodium–benzophenone; dichloromethane was
distilled from calcium hydride; methanol was distilled from
Mg/I2; diglyme was distilled from calcium hydride. Column
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as a colorless oil in 77% yield. Rf 0.60 (petroleum ether–EtOAc
30 : 1); IR (film) 3029, 2959, 2923, 1727, 1456, 1248, 1033, 893,
699 cm-1; 1H NMR (CDCl3, 400 MHz) d 7.34–7.25 (m, 5H), 4.76
(s, 1H), 4.56 (s, 1H), 4.23–4.15 (m, 2H), 3.41 (s, 1H), 3.40 (s, 1H),
3.13–3.04 (m, 1H), 3.03 (d, J = 11.2 Hz, 1H), 2.80 (d, J = 10.4 Hz,
1H), 2.65 (dd, J = 10.8, 2.0 Hz, 1H), 2.28–2.19 (m, 1H), 1.97 (d,
J = 10.8 Hz, 1H), 1.96–1.93 (m, 1H), 1.83–1.78 (m, 1H), 1.60–1.46
(m, 2H), 1.29 (t, J = 7.2 Hz, 3H), 0.98 (s, 3H); 13C NMR (CDCl3,
100 MHz) d 174.6, 155.1, 139.1, 128.6, 128.3, 126.8, 102.5, 67.1,
63.0, 62.4, 60.5, 51.7, 41.0, 38.1, 35.7, 25.4, 21.3, 14.2; HRESI
m/z calcd for C20H28NO2 [M+H]+: 314.2120, found 314.2116.
NMR (CDCl3, 400 MHz) d 7.34–7.23 (m, 5H), 5.15 (br.s, 1H,
exchangeable with D2O), 4.59, 4.58 (AB, J = 6.4 Hz, 2H), 3.80
(dd, J = 11.6, 5.2 Hz, 1H), 3.68 (br.d, J = 10.0 Hz, 1H), 3.47–3.39
(m, 2H), 3.25–3.45 (m, 2H), 3.32 (s, 3H), 2.49–2.41 (m, 1H), 2.34–
2.19 (m, 4H), 1.65–1.49 (m, 4H), 1.37–1.30 (m, 2H), 0.97 (s, 3H);
13C NMR (CDCl3, 100 MHz) d 138.0, 128.9, 128.4, 127.1, 96.8,
74.8, 62.8, 60.6, 58.2, 55.8, 55.5, 50.5, 41.9, 38.1, 36.6, 34.2, 27.8,
20.1; HRESI m/z calcd for C20H32NO3 [M+H]+ 334.2382, found
334.2384.
3-Acetyl-1-((methoxymethoxy)methyl)-5-methyl-3-azabicyclo
[3.3.1]nonane-9-carbaldehyde (7). To a solution of 13 (3.5 g,
10.5 mmol) in anhydrous MeOH (70 mL) were added Pd–C (3.0
g) and anhydrous ammonium formate (3.2 g, 50.7 mmol), and
the mixture was refluxed for 10 min. After being cooled down
to room temperature and filtered through Celite, the filtrate was
concentrated to give a crude product. To a stirred solution of
above crude amine in CH2Cl2 (50 mL) were added saturated
NaHCO3 (50 mL) and acetyl chloride (3.85 mL, 51.0 mmol), and
the subsequent mixture was stirred overnight at room temperature.
After being basified with ammonium hydroxide (25% v/v), the
aqueous layer was extracted with CH2Cl2 (2 ¥ 50 mL). The
combined organic phases were washed with water and brine, dried
over anhydrous Na2SO4, and evaporated to give a residue, which
was directly employed in the next step.
To a solution of the residue in dry CH2Cl2 (150 mL) was added
NaHCO3 (5.0 g, 59.5 mmol) and Dess–Martin periodinane (5.2 g,
12.3 mmol) and the mixture was stirred for 1 h at 0 ◦C prior to being
quenched by the addition of saturated Na2S2O3. The mixture was
extracted with CH2Cl2 (100 mL ¥ 2). The organic extracts were
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. Flash chromatography (petroleum ether–EtOAc = 1 : 2)
of the crude residue afforded aldehyde 7 (2.2 g, 74% over three
steps) as a colorless oil. Rf 0.20 (petroleum ether–EtOAc 1 : 1);
IR (film) 3406, 2954, 2921, 1716, 1622, 1457, 1151, 1042 cm-1;
1H NMR (CDCl3, 400 MHz, some signals exist as a pair due to
the presence of rotamers) d 10.02 (d, J = 3.2 Hz, 1H), 4.55/4.54,
4.53/4.52 (AB, J = 6.8 Hz, 2H), 4.38 (d, J = 14.0 Hz, 1H), 3.76/3.44
(dd, J = 13.2, 2.4 Hz, 1H), 3.22/2.87 (dd, J = 14.0, 2.4 Hz, 1H),
3.58–3.48 (m, 1H), 3.36–3.26 (m, 1H), 3.32/3.31 (s, 3H), 2.23 (dd,
J = 11.2, 4.8 Hz, 1H), 2.13 (s, 3H), 1.92–1.84 (m, 1H), 1.73–1.63
(m, 3H), 1.60–1.39 (m, 3H), 0.95 (s, 3H); 13C NMR (CDCl3, 100
MHz, signals for the rotamers are included) d 204.4, 204.3, 169.7,
96.7, 96.6, 73.7, 60.1, 60.0, 55.6, 55.5, 53.2, 50.2, 49.5, 44.4, 40.8,
40.5, 38.7, 38.2, 35.2, 34.9, 34.1, 33.5, 26.0, 25.9, 22.4, 19.8; HRESI
m/z calcd for C15H26NO4 [M+H]+ 284.1862, found 284.1860.
3-Benzyl-1-((methoxymethoxy)methyl)-5-methyl-9-methylene-3-
azabicyclo[3.3.1]nonane (12). To a suspension of LiAlH4 (114
mg, 3.0 mmol) in dry THF (8 mL) at 0 ◦C was slowly added a
solution of 11 (785 mg, 2.5 mmol) in anhydrous THF (12 mL),
and the mixture was stirred for 1 h at the same temperature.
After sequential addition of H2O (115 mL), 15% aqueous NaOH
solution (115 mL), and H2O (345 mL), the resulting mixture was
filtered through Celite eluting with CH2Cl2. The filtrate was dried
over anhydrous Na2SO4 and concentrated to give a residual oil,
which was used directly for the next step.
To the primary alcohol, obtained from the above reaction,
were sequentially added anhydrous CH2Cl2 (15 mL), DIPEA
(1.75 mL, 10.0 mmol), and MOMCl (381 mL, 5.0 mmol) at 0 ◦C,
and the reaction mixture was warmed to room temperature and
stirred overnight. After being poured into water, the phases were
separated and the aqueous layer was extracted with CH2Cl2 (10 mL
¥ 2). The combined organic extracts were washed with brine,
dried over anhydrous Na2SO4, and concentrated in vacuo. The
crude residue was purified via flash chromatography, eluting with
petroleum ether–EtOAc (100 : 1) to yield ether 12 as a colorless oil
(679 mg, 87% over two steps). Rf 0.65 (petroleum ether–EtOAc
30 : 1); IR (film) 3028, 2923, 1458, 1372, 1150, 1109, 1038, 917,
893, 699 cm-1; 1H NMR (CDCl3, 400 MHz) d 7.33–7.25 (m, 5H),
4.76 (s, 1H), 4.64 (s, 1H), 4.62 (s, 2H), 3.50–3.43 (m, 2H), 3.42,
3.30 (ABq, J = 13.2 Hz, 2H), 3.37 (s, 3H), 3.12–3.04 (m, 1H), 3.02
(d, J = 10.4 Hz, 1H), 2.77 (d, J = 10.0 Hz, 1H), 2.06 (d, J = 10.4
Hz, 1H), 2.00–1.95 (m, 1H), 1.88 (d, J = 10.4 Hz, 1H), 1.82–1.77
(m, 1H), 1.55–1.38 (m, 3H), 0.95 (s, 3H); 13C NMR (CDCl3, 100
MHz) d 157.6, 139.4, 128.6, 128.2, 126.7, 100.2, 96.8, 74.3, 67.1,
63.4, 63.2, 55.2, 41.9, 41.5, 38.4, 36.6, 25.3, 21.4; HRESI m/z calcd
for C20H30NO2 [M+H]+ 316.2277, found 316.2284.
(3-Benzyl-1-((methoxymethoxy)methyl)-5-methyl-3-azabicyclo-
[3.3.1]nonan-9-yl)methanol (13). To a stirred mixture of olefin 12
(1.5 g, 4.8 mmol) and BF3·OEt2 (2.4 mL, 19.0 mmol) in anhydrous
diglyme (35 mL) was slowly added a solution of NaBH4 (540 mg,
1-(9-(2-Methoxy-3-(methoxymethoxy)styryl)-1-((methoxy-
methoxy)methyl)-5-methyl-3-azabicyclo[3.3.1]nonan-3-yl) ethan-
one (14). To a stirred suspension of 6 (10.6 g, 20.3 mmol) in
anhydrous THF (40 mL) was slowly added a solution of t-BuOK
(2.3 g, 20.3 mmol) in anhydrous THF (40 mL) under argon at 0 ◦C,
and the mixture was stirred at the same temperature for 30 min.
A solution of 7 (2.3 g, 8.13 mmol) in THF (40 mL) was added
dropwise to the above Wittig reagent, and the reaction mixture
was stirred at 35 ◦C for 9 h prior to being quenched with aqueous
NH4Cl (40 mL). The resulting mixture was extracted with CH2Cl2
(80 mL ¥ 3). The combined extracts were washed with brine, dried
over anhydrous Na2SO4, and concentrated in vacuo to furnish
a residue, which was subjected to column chromatography on
◦
14.3 mmol) in diglyme (35 mL) at -23 C under argon, and the
mixture was stirred for 13 h at the same temperature. The mixture
was allowed to warm to room temperature prior to the addition
of Me3NO·2H2O (3.7 g, 33.3 mmol). The subsequent reaction
mixture was heated at 120 ◦C for 7 h before being cooled down to
0 ◦C. After the addition of 10% ammonium hydroxide (50 mL), the
mixture was extracted with diethyl ether (60 mL ¥ 3). The organic
layers were washed with brine, dried, and concentrated to give
a residue, which was subjected to flash chromatography column
(petroleum ether–EtOAc = 10 : 1 to 5 : 1) to deliver alcohol 13
(1.3 g, 82%) as a colorless oil. Rf 0.33 (petroleum ether–EtOAc
5 : 1); IR (film) 3426, 2924, 2855, 1459, 1217, 1106, 1045 cm-1; 1H
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silica gel, using petroleum ether–acetone (6 : 1) as eluent, to afford
styrene 14 (2.70 g, 75%) as a white solid. m.p. 128–129 ◦C; Rf 0.46
(petroleum ether–acetone 3 : 1); IR (film) 2955, 2924, 1643, 1468,
1262, 1152, 1040 cm-1; 1H NMR (CDCl3, 400 MHz, some signals
are described as a pair due to the presence of amide rotamers)
d 7.08–6.96 (m, 3H), 6.76/6.73 (d, J = 16.0 Hz, 1H), 6.32/6.29
(d, J = 16.0 Hz, 1H), 5.22 (s, 2H), 4.54, 4.52/4.51 (AB, J = 6.4
Hz, 2H), 4.38/4.26 (d, J = 13.6 Hz, 1H), 3.80 (s, 3H), 3.66/3.40
(d, J = 13.2 Hz, 1H), 3.51 (s, 3H), 3.30/3.27 (s, 3H), 3.25–3.20
(m, 2H), 3.19 (d, J = 13.2 Hz, 1H), 2.76 (br.d, J = 14.0 Hz, 1H),
2.19/2.16 (s, 1H), 2.13/2.12 (s, 3H), 2.10–2.04 (m, 1H), 1.87–1.74
(m, 3H), 1.60–1.54 (m, 2H), 0.83/0.81 (s, 3H); 13C NMR (CDCl3,
100 MHz, all signals for the amide rotamers are listed) d 169.8,
150.6, 131.6, 128.4, 128.3, 127.6, 124.2, 119.8, 115.4, 115.3, 96.8,
96.7, 95.1, 75.1, 74.6, 61.0, 56.2, 55.2, 53.0, 52.8, 52.2, 49.3, 47.9,
44.3, 40.7, 40.5, 38.2, 37.6, 35.2, 34.9, 34.1, 33.4, 27.1, 22.5, 20.2;
HRESI m/z calcd for C25H37NO6Na [M+Na]+ 470.2519, found
470.2514.
3-(2-(3-Acetyl-1-formyl-5-methyl-3-azabicyclo[3.3.1]nonan-9-
yl)ethyl)-2-methoxyphenyl acetate (16). To a stirred solution
of 15 (2.04 g, 5.06 mmol) in CH2Cl2 (100 mL) were added
NaHCO3 (4.5 g, 53.5 mmol) and Dess–Martin periodinane (3.4
g, 8.02 mmol) at 0 ◦C. After being stirred for 2 h at room
temperature, the reaction was quenched with saturated aqueous
Na2S2O3. The aqueous layer was extracted with CH2Cl2 (60 mL ¥
2). The combined organic extracts were washed with brine, dried
over anhydrous Na2SO4, and concentrated to give a residue, which
was chromatographed on silica gel (petroleum ether–acetone =
4 : 1) to afford 16 (1.85 g, 91%) as an off-white foam. Rf 0.50
(petroleum ether–acetone 3 : 2); IR (film) 3424, 2957, 2924, 2854,
1766, 1717, 1639, 1465, 1265, 1196, 1008 cm-1; 1H NMR (CDCl3,
400 MHz, some signals appear as pairs due to the presence of
amide rotamers) d 9.23/9.10 (s, 1H), 7.05–6.91 (m, 3H), 4.47/4.18
(d, J = 14.0 Hz, 1H), 3.76 (s, 3H), 3.60/3.09 (d, J = 13.6 Hz,
1H), 3.35/3.31 (d, J = 12.8 Hz, 1H), 2.92/2.62 (d, J = 14.0 Hz,
1H), 2.72–2.56 (m, 2H), 2.33 (s, 3H), 2.08 (s, 3H), 1.83–1.67 (m,
3H), 1.65–1.57 (m, 3H), 1.52–1.44 (m, 1H), 1.35–1.18 (m, 2H),
0.97/0.95 (s, 3H); 13C NMR (CDCl3, 100 MHz, all signals for
the amide rotamers are listed) d 203.7, 203.5, 170.0, 169.0, 149.8,
143.7, 135.9, 135.8, 127.8, 124.1, 121.8, 61.1, 52.2, 50.8, 50.0, 47.1,
45.8, 44.0, 43.4, 40.9, 40.4, 40.2, 33.8, 33.0, 32.1, 32.0, 31.6, 31.5,
28.3, 28.0, 25.5, 25.4, 22.4, 20.9, 19.5, 19.4; HRESI m/z calcd for
C23H32NO5 [M+H]+ 402.2280, found 402.2283.
3-(2-(3-Acetyl-1-(hydroxymethyl)-5-methyl-3-azabicyclo [3.3.1]-
nonan-9-yl)ethyl)-2-methoxyphenyl acetate (15). The mixture of
styrene 14 (2.70 g, 6.04 mmol) and concentrated HCl (15 mL) in
MeOH (70 mL) was heated at 50 ◦C for 30 min. After addition of
25% ammonium hydroxide (25 mL) at 0 ◦C, the organic solvent was
removed under reduced pressure, and the residue was extracted
with CH2Cl2 (80 mL ¥ 3). The organic extracts were washed with
water and brine, dried over anhydrous Na2SO4, and concentrated
to give a white amorphous powder. To a solution of the crude
product obtained above in MeOH (120 mL) was added Pd–C
(500 mg), and the reaction was allowed to proceed with stirring in
the presence of hydrogen atmosphere at room temperature for
2 h. After removal of insoluble material by filtration through
Celite, the filtrate was concentrated to generate a residue. Isopropyl
alcohol (85 mL) was added to this residue, and then a solution of
NaOH (762 mg, 19.0 mmol) in H2O (5 mL) and Ac2O (1.80 mL,
19.0 mmol) were added to the mixture. The reaction was kept
to proceed with stirring at room temperature for 3 h before
removing organic solvent. The residue was dissolved in water and
basified with 25% ammonium hydroxide, and the resulting mixture
was extracted with CH2Cl2 (60 mL ¥ 3). The combined organic
extracts were washed with brine, dried with anhydrous Na2SO4,
and concentrated to yield a residue, which was chromatographed
over silica gel eluting with petroleum ether–acetone (2 : 1) to afford
acetate 15 (2.04 g, 85% over three steps) as a white amorphous
powder. Rf 0.35 (petroleum ether–acetone 3 : 2); IR (film) 3392,
1-(9-(3-Hydroxy-2-methoxyphenethyl)-1-methyl-5-vinyl-3-aza-
bicyclo[3.3.1]nonan-3-yl)ethanone (5). To
a
suspension of
Ph3PCH3Br (3.8 g, 10.6 mmol) in dry THF (30 mL) was slowly
added a solution of t-BuOK (1.2 g, 10.6 mmol) in THF (30 mL) at
0 ◦C, and the mixture was stirred at 0 ◦C for 30 min. To this mixture
was slowly added a solution of aldehyde 16 (1.7 g, 4.24 mmol) in
THF (30 mL), and the subsequent reaction mixture was warmed
up to room temperature and stirred for an additional 3 h prior to
the addition of another portion of t-BuOK (950 mg, 8.48 mmol).
The reaction was allowed to proceed with stirring for 2 h at 35 ◦C
prior to being quenched by addition of saturated NH4Cl solution.
After extracting the resulting mixture with CH2Cl2 (50 mL ¥
3), the combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and concentrated to give a residue. The
residue was purified by column chromatography on silica gel with
petroleum ether–acetone (5 : 1) as eluent to furnish phenol 5 (1.06
g, 70%) as a white solid. m.p. 137–139 ◦C; Rf 0.42 (petroleum
ether–acetone 3 : 2); IR (film) 3197, 2957, 2925, 2854, 1618, 1586,
1
1
2956, 2923, 2853, 1766, 1620, 1463, 1374, 1198, 1011 cm-1; H
1468, 1276, 1008, 753 cm-1; H NMR (CDCl3, 400 MHz, some
NMR (CDCl3, 400 MHz, some signals exist as a pair due to the
presence of amide rotamers) d 7.05–7.02 (m, 2H), 6.94–6.91 (m,
1H), 4.10 (t, J = 13.2 Hz, 1H), 3.86/3.52 (d, J = 10.8 Hz, 1H),
3.80 (s, 3H), 3.37–3.32 (m, 1H), 3.29–3.23 (m, 1H), 3.07/2.98 (dd,
J = 13.2, 2.0 Hz, 1H), 2.76–2.63 (m, 2H), 2.59/2.46 (d, J = 13.6
Hz, 1H), 2.35 (s, 3H), 2.07/2.05 (s, 3H), 1.87–1.72 (m, 3H), 1.69–
1.49 (m, 5H), 1.38–1.30 (m, 1H), 0.91/0.89 (s, 3H); 13C NMR
(CDCl3, 100 MHz, all signals for the amide rotamers are listed) d
169.7, 169.6, 169.2, 149.8, 143.7, 136.8, 136.6, 128.2, 128.0, 124.2,
121.6, 121.4, 68.3, 67.9, 61.1, 52.4, 48.4, 47.3, 45.3, 44.6, 43.5, 41.0,
40.8, 39.2, 38.5, 35.1, 34.9, 34.5, 33.8, 32.4, 32.2, 25.9, 25.4, 25.2,
22.4, 20.8, 20.3, 20.2; HRESI m/z calcd for C23H34NO5 [M+H]+
404.2437, found 404.2446.
signals exist as pairs due to the presence of amide rotamers) d 6.94
(t, J = 8.0 Hz, 1H), 6.82 (dd, J = 8.0, 1.6 Hz, 1H), 6.67 (dd, J = 8.0,
1.6 Hz, 1H), 5.92/5.90 (br.s, 1H), 5.69/5.64 (t, J = 7.2 Hz, 1H),
5.10–4.90 (m, 2H), 4.43/4.20 (d, J = 14.0 Hz, 1H), 3.79 (s, 3H),
3.52/3.32 (d, J = 13.2 Hz, 1H), 3.23/3.10 (dd, J = 13.2, 2.0 Hz,
1H), 2.74/2.61 (d, J = 14.0 Hz, 1H), 2.70–2.54 (m, 2H), 2.11/2.10
(s, 3H), 1.86–1.41 (m, 8H), 1.27–1.22 (m, 1H), 0.98 (s, 3H); 13C
NMR (CDCl3, 100 MHz, all signals for the amide rotamers are
listed) d 169.7, 149.1, 145.2, 135.4, 128.6, 128.4, 124.8, 121.4,
113.7, 112.4, 112.1, 61.9, 52.2, 49.1, 46.9, 49.0, 43.9, 41.0, 40.8,
40.7, 40.2, 38.9, 38.9, 34.4, 33.7, 32.5, 32.4, 27.3, 27.2, 25.8, 22.4,
20.5; HRESI m/z calcd for C22H32NO3 [M+H]+ 358.2382, found
358.2374.
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1411–1417 | 1415
©

View Online
14-Acetyl-11,11-dimethoxy-8-methyl-3,4,4a,5,6,7,8,8a,9,10-
decahydro-3,10a-ethano-4b,8-(methanoiminomethano) phenan-
52.6, 51.8, 51.3, 51.2, 49.1, 47.4, 46.8, 44.3, 44.2, 42.3, 42.1, 41.9,
41.1, 40.8, 40.1, 39.9, 37.7, 37.4, 37.1, 33.2, 32.4, 29.6, 29.5, 28.0,
27.4, 26.7, 26.4, 25.9, 23.9, 22.5, 21.0, 17.7; HRESI m/z calcd for
C24H38NO3 [M+H]+ 388.2852, found 388.2844.
thren-12-one (17). To a stirred mixture of PIDA (102 mg,
0.317 mmol) and NaHCO3 (44 mg, 0.523 mmol) in MeOH
(16 mL) was added a solution of 5 (75 mg, 0.210 mmol) in
MeOH (16 mL) at 0 ◦C, and the mixture was stirred at the same
temperature for 30 min. After addition of xylene (150 mL) to
the resulting mixture, methanol was cautiously removed under
reduced pressure at room temperature. The resulting solution
was heated at 150 ◦C in a sealed tube for 4 h. The solvent
was then evaporated off, and the residue was chromatographed
over silica gel with petroleum ether–EtOAc (1 : 1) to afford
pentacyclic compound 17 (63 mg) as a white solid in 78% yield.
m.p. 172–174 ◦C; Rf 0.38 (petroleum ether–EtOAc 1 : 2); IR (film)
14-Acetyl-8-methyl-2-methylenedecahydro-3,10a-ethano-4b,8-
(methanoiminomethano)phenanthren-1(5H)-one (3a). A solution
of p-TsOH (17 mg, 0.099 mmol) in acetone (0.6 mL) was added to a
stirred mixture of 18 (25 mg, 0.065 mmol) in acetone (2.4 mL) and
H2O (0.3 mL). The reaction was allowed to proceed with stirring
at room temperature for 30 min prior to being quenched with
aqueous NaHCO3 (1 mL). The mixture was extracted with CH2Cl2
(5 mL ¥ 3). The organic extracts were washed with brine, dried over
anhydrous Na2SO4, and concentrated to give a residue, which was
subjected to flash chromatography, eluting with petroleum ether–
acetone (6 : 1), to give 3a (21 mg) as a white solid in 95% yield.
m.p. 150–153 ◦C; Rf 0.50 (petroleum ether–acetone 3 : 1); IR (film)
1
2955, 2923, 2851, 1729, 1636, 1461, 1376, 1092 cm-1; H NMR
(CDCl3, 400 MHz, some signals exist as pairs due to the presence
of amide rotamers) d 6.25–6.11 (m, 2H), 4.15/4.02 (d, J = 14.0
Hz, 1H), 3.46/3.45 (s, 3H), 3.33/3.32 (s, 3H), 3.28 (d, J = 13.2 Hz,
1H), 3.25–3.07 (m, 2H), 2.70/2.59 (d, J = 14.0 Hz, 1H), 2.18–1.97
(m, 3H), 2.05/2.03 (s, 3H), 1.83–1.71 (m, 4H), 1.70–1.59 (m,
2H), 1.52–1.42 (m, 4H), 1.18–1.14 (m, 1H), 0.88/0.86 (s, 3H);
13C NMR (CDCl3, 100 MHz, all signals for the amide rotamers
are listed) d 203.6, 203.3, 169.4, 140.2, 139.5, 126.2, 125.7, 95.8,
55.6, 55.5, 52.5, 52.4, 49.4, 49.3, 48.5, 48.4, 48.3, 47.3, 44.2, 43.8,
43.1, 41.0, 40.7, 39.2, 37.6, 36.9, 33.1, 32.4, 25.9, 25.8, 25.6, 25.4,
22.5, 22.4, 20.9, 17.7; HRESI m/z calcd for C23H34NO4 [M+H]+
388.2488, found 388.2481.
1
2926, 2869, 1709, 1643, 1460, 1279 cm-1; H NMR (CDCl3, 400
MHz, some signals exist as pairs due to the presence of amide
rotamers) d 5.97/5.94 (s, 1H), 5.25/5.23 (s, 1H), 4.52/4.15 (d,
J = 13.6 Hz, 1H), 3.66/3.32 (d, J = 12.8 Hz, 1H), 3.60/3.15 (dd,
J = 12.8, 2.0 Hz, 1H), 3.10/2.66 (d, J = 13.6 Hz, 1H), 2.81–2.77
(m, 1H), 2.18–2.12 (m, 1H), 2.11/2.08 (s, 3H), 1.95–1.58 (m, 10H),
1.53–1.23 (m, 6H), 1.02–0.98 (m, 1H), 0.87/0.86 (s, 3H); 13C NMR
(CDCl3, 100 MHz, all signals for the amide rotamers are listed)
d 203.2, 202.6, 169.6, 146.5, 145.9, 118.0, 117.6, 52.5, 49.1, 49.0,
47.4, 46.6, 44.5, 43.4, 43.2, 41.7, 40.9, 40.6, 39.7, 39.6, 38.6, 37.9,
35.7, 33.2, 32.5, 28.8, 28.6, 27.9, 27.5, 26.2, 25.9, 25.8, 25.0, 24.9,
22.5, 20.8, 17.2, 17.1; HRESI m/z calcd for C22H32NO2 [M+H]+
342.2433, found 342.2426.
1-(1,1-Dimethoxy-8-methyl-2-methylenedodecahydro-3,10a-
ethano-4b,8-(methanoiminomethano)phenanthren-14-yl) ethanone
(18). To a solution of 17 (50 mg, 0.129 mmol) in MeOH (5 mL)
was added Pd–C (5 mg), and the reaction mixture was stirred
under an atmosphere of hydrogen at room temperature for 2 h.
The mixture was filtered through Celite rinsing with EtOAc. The
solvent was removed under reduced pressure to afford a white
solid.
1-Hydroxy-8-methyl-2-methylenedodecahydro-3,10a-ethano-
4b,8-(methanoiminomethano)phenanthren-14-yl)ethanone
(19).
To a solution of 3a (60 mg, 0.176 mmol) in MeOH (5 mL) was
added CeCl3·7H2O (462 mg, 1.24 mmol) and NaBH4 (47 mg,
1.24 mmol) at 0 ◦C, and the mixture was stirred at 0 ◦C for 30
min. After quenching the reaction by addition of aqueous NH4Cl
(2 mL) and aqueous NaHCO3 (2 mL), the mixture was extracted
with CH2Cl2 (8 mL ¥ 3). The extracts were washed with brine,
dried over anhydrous Na2SO4, and concentrated to give a residue,
which was purified via chromatography over silica gel, eluting
with petroleum ether–EtOAc (1 : 1), to afford a pair of epimers
19a (30 mg) and 19b (23 mg) in 88% overall yield.
n-BuLi (0.23 mL, 0.57 mmol, 2.5 M solution in hexane) was
added dropwise to a stirred suspension of Ph3PCH3Br (243 mg,
0.68 mmol) in anhydrous toluene (4 mL) at 0 ◦C under argon,
and the reaction mixture was stirred for 30 min. A solution of the
white solid obtained above in anhydrous toluene (4 mL) was slowly
added to the reaction mixture at 0 ◦C, and the reaction was allowed
◦
to proceed with heating at 100 C for 8 h prior to being cooled
19a: white solid; m.p. 170–172 ◦C; Rf 0.43 (petroleum ether–
EtOAc 1 : 2); IR (film) 3392, 2924, 2853, 1622, 1461, 1377, 1063,
895 cm-1; 1H NMR (CDCl3, 400 MHz, some signals exist as
pairs due to the presence of amide rotamers) d 5.12/5.09 (s, 1H),
5.07/5.04 (s, 1H), 4.45/4.14 (d, J = 14.0 Hz, 1H), 3.62 (br.s,
1H), 3.58/3.31 (d, J = 12.8 Hz, 1H), 3.57/3.14 (dd, J = 12.8,
2.0 Hz, 1H), 3.07/2.66 (d, J = 13.6 Hz, 1H), 2.37–2.34 (m, 1H),
2.12/2.09 (s, 3H), 2.04–1.87 (m, 2H), 1.80–1.72 (m, 2H), 1.68–
1.54 (m, 6H), 1.51–1.31 (m, 5H), 1.28–1.17 (m, 2H), 1.13–1.03 (m,
1H), 0.87/0.86 (s, 3H); 13C NMR (CDCl3, 100 MHz, all signals for
the amide rotamers are listed) d 169.5, 156.5, 155.8, 110.3, 109.7,
76.8, 76.6, 52.6, 49.2, 47.5, 47.0, 42.1, 41.1, 40.8, 39.9, 39.8, 39.2,
38.9, 37.4, 37.3, 36.7, 36.1, 33.2, 32.5, 31.3, 31.2, 28.3, 28.0, 27.4,
26.4, 25.9, 26.0, 22.5, 20.9, 17.5; HRESI m/z calcd for C22H34NO2
[M+H]+ 344.2590, found 344.2589.
to 0 ◦C. The reaction was then quenched by addition of saturated
NH4Cl solution (5 mL), and the resulting mixture was extracted
with CH2Cl2 (5 mL¥ 3). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and concentrated to give
a residue, which was purified by flash chromatography on silica gel
(petroleum ether–acetone = 12 : 1) to afford 18 (38 mg, 76% over
two steps) as a white powder. Rf 0.68 (petroleum ether–acetone
3 : 1); IR (film) 2924, 2853, 1647, 1460, 1377, 1116 cm-1; 1H NMR
(CDCl3, 400 MHz, some signals exist as pairs due to the presence of
amide rotamers) d 5.20/5.18 (s, 1H), 5.11/5.08 (s, 1H), 4.43/4.15
(d, J = 13.2 Hz, 1H), 3.56/3.31 (s, 1H), 3.35/3.34 (s, 3H), 3.29/3.28
(s, 3H), 3.12 (d, J = 12.8 Hz, 1H), 3.07/2.63 (d, J = 13.6 Hz, 1H),
2.38–2.36 (m, 1H), 2.11/2.08 (s, 3H), 1.94–1.86 (m, 2H), 1.81–1.38
(m, 14H), 1.37–1.17 (m, 1H), 1.11–1.06 (m, 1H), 0.86/0.85 (s, 3H);
13C NMR (CDCl3, 100 MHz, all signals for the amide rotamers
are listed) d 169.5, 169.4, 149.7, 149.3, 112.6, 112.2, 102.3, 102.1,
19b: white needles were crystallized from EtOAc; m.p. 172–
173 ◦C; Rf 0.37 (petroleum ether–EtOAc 1 : 2); IR (film) 3461,
1416 | Org. Biomol. Chem., 2012, 10, 1411–1417
This journal is
The Royal Society of Chemistry 2012
©

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1
2928, 2867, 1624, 1443, 1278, 1048, 894 cm-1; H NMR (CDCl3,
d 169.0, 156.6, 109.7, 77.0, 55.7, 47.6, 41.5, 38.9, 38.4, 37.6, 37.5,
36.4, 36.2, 31.1, 28.5, 27.1, 26.3, 23.8, 20.3, 19.7; HRESI m/z calcd
for C20H30NO [M+H]+ 300.2327, found 300.2330.
400 MHz, some signals exist as pairs due to the presence of amide
rotamers) d 5.11/5.08 (s, 1H), 5.05/5.02 (s, 1H), 4.48/4.16 (d, J =
13.6 Hz, 1H), 3.63 (br.s, 1H), 3.62/3.32 (d, J = 13.2 Hz, 1H),
3.61/3.15 (dd, J = 13.2, 2.0 Hz, 1H), 3.11/2.66 (d, J = 13.6 Hz,
1H), 2.36–2.33 (m, 1H), 2.12/2.09 (s, 3H), 1.95 (dt, J = 12.8, 5.6
Hz, 1H), 1.80–1.55 (m, 9H), 1.52–1.33 (m, 5H), 1.21–1.08 (m, 2H),
1.07–1.01 (m, 1H), 0.88/0.86 (s, 3H); 13C NMR (CDCl3, 100 MHz,
all signals for the amide rotamers are listed) d 169.5, 156.3, 155.6,
109.6, 109.2, 79.8, 79.6, 52.6, 49.7, 47.4, 46.6, 47.2, 47.0, 41.8, 41.1,
40.8, 39.9, 39.8, 37.7, 37.0, 35.7, 35.6, 33.8, 33.6, 33.3, 32.5, 27.5,
27.4, 27.0, 26.0, 22.5, 20.9, 20.7, 20.6, 17.6, 17.5; HRESI m/z calcd
for C22H34NO2 [M+H]+ 344.2590, found 344.2582.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 30873147) for financial support of this research. We
thank Dr Jesu´s G. D´ıaz (Universidad de La Laguna, Spain) for
offering the original NMR spectra of natural isoazitine and Dr
Jun-Biao Chang (Zhengzhou University, China) for assisting with
X-ray analysis.
8-Methyl-2-methylenedodecahydro-3,10a-ethano-4b,8-(meth-
anoiminomethano)phenanthren-1-ol (20). A mixture of 19a (20
mg, 0.058 mmol) and KOH (170 mg, 3.03 mmol) in MeOH (2 mL)
and H2O (0.3 mL) was heated at 110 ◦C in a sealed tube for 48 h.
After removing the solvent, the residue was partitioned in water
(5 mL) and CH2Cl2 (5 mL). The aqueous layer was extracted with
CH2Cl2 (5 mL ¥ 2), and the combined organic extracts were washed
with water and brine, and dried over Na2SO4. The solvents were
evaporated off, and the residue was chromatographed on silica gel
eluting with petroleum ether–acetone (3 : 2) to give 20 (resin, 12
mg, 71%). Rf 0.22 (petroleum ether–acetone 3 : 2); IR (film) 3387,
Notes and references
1 For recent reviews, see: (a) F. P. Wang, Q. H. Chen and X. Y. Liu, Nat.
Prod. Rep., 2010, 27, 529–570; (b) F. P. Wang and X. T. Liang, in The
Alkaloids: Chemistry and Biology, ed. G. A. Cordell, Elsevier Science,
New York, 2002, vol. 59, pp. 1–280; (c) F. P. Wang, Q. H. Chen and X.
T. Liang, in The Alkaloids: Chemistry and Biology, ed. G. A. Cordell,
Elsevier Science, New York, 2009, vol. 67, pp. 1–78; (d) F. P. Wang and
Q. H. Chen, in The Alkaloids: Chemistry and Biology, ed. G. A. Cordell,
Elsevier Science, New York, 2010, vol. 69, pp. 1–577.
2 E. C. Cherney and P. S. Baran, Isr. J. Chem., 2011, 51, 391–405.
3 (a) S. W. Pelletier and W. A. Jacobs, J. Am. Chem. Soc., 1954, 76, 4496–
4497; (b) S. W. Pelletier, R. Aneja and K. W. Gopinath, Phytochemistry,
1968, 7, 625–635.
1
2925, 2855, 1661, 1461, 1377, 1077, 895 cm-1; H NMR (CDCl3,
4 J. G. D´ıaz, J. G. Ruiz and G. de la Fuente, J. Nat. Prod., 2000, 63,
1136–1139.
400 MHz) d 5.08 (s, 1H), 5.02 (s, 1H), 3.59 (s, 1H), 3.28 (dd, J =
12.8, 2.4 Hz, 1H), 2.96 (d, J = 13.2 Hz, 1H), 2.83 (dd, J = 13.2, 2.4
Hz, 1H), 2.62 (d, J = 13.2 Hz, 1H), 2.31 (br.s, 1H), 2.21–1.92 (m,
4H), 1.75–1.52 (m, 7H), 1.48–1.36 (m, 3H), 1.23–1.14 (m, 2H),
1.07–1.01 (m, 1H), 0.93–0.85 (m, 1H), 0.73 (s, 3H); 13C NMR
(CDCl3, 100 MHz) d 156.7, 126.4, 76.9, 52.6, 50.0, 46.1, 40.8,
39.8, 39.7, 37.4, 36.6, 36.3, 32.6, 31.5, 28.0, 27.5, 26.5, 26.2, 23.5,
17.5; HRESI m/z calcd for C20H32NO [M+H]+: 302.2484, found
302.2493.
5 (a) W. Nagata, T. Sugasawa, M. Narisada, T. Wakabayashi and Y.
Hayase, J. Am. Chem. Soc., 1963, 85, 2342–2343; (b) S. Masamune, J.
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6 (a) S. W. Pelletier and W. A. Jacobs, J. Am. Chem. Soc., 1956, 78, 4144–
4145; (b) S. W. Pelletier and P. C. Parthasarathy, Tetrahedron Lett.,
1963, 4, 205–208.
7 Y. K. Chen, R. K. Peddinti and C. C. Liao, Chem. Commun., 2001,
1340–1341.
8 For a recent review, see: (a) S. P. Roche and J. A. Porco Jr., Angew.
Chem., Int. Ed., 2011, 50, 4068–4093. For the applications in the total
synthesis of natural products, see: (b) H. Y. Shiao, H. P. Hsieh and C.
C. Liao, Org. Lett., 2008, 10, 449–452; (c) K. C. Nicolaou, Q. Y. Toh
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9 For a review, see: D. Magdziak, S. J. Meek and T. R. R. Pettus, Chem.
Rev., 2004, 104, 1383–1430.
10 S. N. Huckin and L. Weiler, J. Am. Chem. Soc., 1974, 96, 1082–1087.
11 V. Srivastava, A. Tandon and S. Ray, Synth. Commun., 1992, 22, 2703–
2710.
8-Methyl-2-methylene-1,2,3,4,4a,5,6,7,8,8a,9,10-dodecahydro-
3,10a-ethano-4b,8-(methanoazenometheno)phenanthren-1-ol (( )-
isoazitine, 2). To a stirred solution of 20 (7.8 mg, 0.026 mmol) in
dioxane (0.6 mL) was added Hg(OAc)2 (10.0 mg, 0.031 mmol), and
the reaction mixture was heated at 60 ◦C for 2 h. After addition of
water (2 mL) and CH2Cl2 (2 mL), the mixture was basified with
25% ammonium hydroxide. The aqueous phase was extracted with
CH2Cl2 (3 mL ¥ 2), and the organic extracts were washed with
brine, dried over anhydrous Na2SO4, and concentrated to give a
residue, which was subjected to flash chromatography on silica gel,
eluting with petroleum ether–EtOAc (2 : 1), to afford ( )-isoazitine
(2) (5.0 mg) as an oil in 65% yield. Rf 0.42 (petroleum ether–EtOAc
1 : 1); IR (film) 3301, 2925, 2854, 1661, 1461, 1376, 1077, 1020, 895
12 J. L. Luche, J. Am. Chem. Soc., 1978, 100, 2226–2227.
13 The crystallographic data of compound 19b can be found in the
electronic supplementary information. Deposition Number is CCDC
834603.
1
cm-1; H NMR (CDCl3, 400 MHz) d 7.44 (br.s, 1H), 5.11 (br.s,
14 S. W. Pelletier, Tetrahedron, 1961, 14, 76–112.
1H), 5.05 (br.s, 1H), 3.93 (br.d, J = 19.2 Hz, 1H), 3.62 (s, 1H), 3.43
(dd, J = 19.2, 2.8 Hz, 1H), 2.34 (br.s, 1H), 2.17–2.11 (m, 1H), 1.74–
1.49 (m, 9H), 1.39–1.34 (m, 1H), 1.29–1.20 (m, 2H), 1.16–1.11 (m,
1H), 1.07 (s, 3H), 1.04–0.90 (m, 4H); 13C NMR (CDCl3, 100 MHz)
15 N. J. Leonard and D. E. Morrow, J. Am. Chem. Soc., 1958, 80, 371–375.
16 See Electronic Supplementary Information (ESI) for a comparison
of the 1H and 13C NMR spectra of natural isoazitine and synthetic
isoazitine.
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