Synthesis of the BCDE molecular fragment of azadiradione mediated by titanocene(III)

Article abstract of DOI:10.1021/jo401646g

A practical, short, and diastereoselective synthesis of the azadiradione BCDE fragment from a readily available starting material is described. The key step was the titanocene(III)-promoted tandem cyclization of unsaturated epoxy nitrile.

Full text of DOI:10.1021/jo401646g

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Synthesis of the BCDE Molecular Fragment of Azadiradione
Mediated by Titanocene(III)
A. Fernandez-Mateos,*,† S. Encinas Madrazo,† P. Herrero Teijon,† R. Rabanedo Clemente,†
́
́
R. Rubio Gonzalez,† and F. Sanz Gonzalez‡
́
́
†Departamento de Química Organ
Ciencias,Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
́
ica, Facultad de CC Químicas, and Servicio General de Difraccion
́
de Rayos X, Facultad de
‡
S
* Supporting Information
ABSTRACT: A practical, short, and diastereoselective syn-
thesis of the azadiradione BCDE fragment from a readily
available starting material is described. The key step was the
titanocene(III)-promoted tandem cyclization of unsaturated
epoxy nitrile.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Limonoids are degraded triterpenoids occurring in the
Meliaceae plant family, and they are used in popular medicine
owing to their wide range of biological properties, such as
antifeedant and growth-regulating activities on insects as well as
antibacterial, antifungal, anticancer and antiviral activities and a
number of pharmacological activities in humans.1
The azadiradione and other limonoids isolated from the
Neem tree, Azadirachta indica (A. Juss), are known for their
insect antifeedant activity.2 They are currently displacing
traditional insecticides in integrated pest control, being
biodegradable, bioselective, and very effective at low concen-
tration.1,2 Recent studies have revealed that there is some
interest in the azadirone, a limonoid with cytotoxic activity
against cancer cells.3
Following with our previous studies, we have designed a new
approach with a view to confirming the viability of a cascade
radical cyclization titanocene(III)-based procedure.9 Our
strategy was based on a stereoselective cascade radical
cyclization from an unsaturated epoxy nitrile to a bicyclic
hydroxyketone,10 induced by titanocene chloride. In general,
our cascade started with the known homolytic cleavage of the
oxirane with titanocene chloride, followed by a radical 6-endo
cyclization onto CC and finishing on a nitrile group. The
novelty of this cascade is the termination step. Although radical
cyclization onto nitrile has been considered a slow process, we
have demonstrated the reliability of epoxy nitrile cyclizations
with titanocene chloride by synthesizing cycloalkanones in
good yields.9c The stereochemistry of the adducts is consistent
with the notion of the cyclizations proceeding via a chairlike
transition state. As an outstanding example we have reported a
stereocyclization mode represented by the quadruple cycliza-
tion of I, which is consistent via three 6-endo chairlike
transition-state processes and a further 4-exo cyclization onto
nitrile, providing in good yield (50%) the single diaster-
eoisomer II.10
Despite their significant bioactivity, little synthetic effort has
been invested in these natural products.4 Our research group
has developed a broad range of synthetic methods of “limonoid
structural fragments” constituted by the CDE5 and BCDE6
rings and limonoid analogues.7 Numerous compounds
synthesized by us have shown high insect antifeedant activity,
particularly the fragment consisting of epoxyazadiradione CDE
rings, which has also been found to be active against the AIDS
virus when tested “in vitro”.8
Scheme 1 shows the graphical synthetic sequence of the
target azadiradione BCDE fragment, which consists of five
general steps.
Received: July 31, 2013
Published: September 13, 2013
© 2013 American Chemical Society
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nitrile ( )-6a with m-CPBA produced the epoxy nitrile ( )-7a
chemo and stereoselectively with a small quantity of the isomer
( )-7b. The relative configuration of ( )-7a and ( )-7b was
assigned by analogy with similar epoxyesters, reported by us
elsewhere,5d and from X-ray diffraction of product ( )-12, to
be explored further below.
Scheme 1. General Synthetic Sequence of the Azadiradione
BCDE Fragment
The second step was to address the construction of the CD
rings by cyclization of epoxy nitrile ( )-7a. The tandem radical
cyclization was carried out by reaction of ( )-7a with 2 equiv
of titanocene chloride, generated in situ in THF at room
temperature.10 The hydroxy ketone ( )-8a was obtained as the
only product in 82% yield. The cyclization mechanism is
depicted in Scheme 3: it starts with the homolytic cleavage of
Scheme 3. Mechanism for the Formation of ( )-8a
As starting material we chose the ready available α-ionone 1,
whose cyclohexane ring was to constitute the B ring in our
azadiradione BCDE fragment. The carbonyl function in the
chain of 1 allows adequate elongation and functionalization,
and the endocyclic double bond is located in the best position
to introduce the oxygen atom of the oxirane, which will be the
starting point of the radical cascade cyclization, establishing the
hydroxyl group at C-7. If the cyclization pattern occurs
according to the stereochemical 6-endo/4-exo pattern of our
previous studies, we expect a trans fusion for the first two rings
and a cis fusion for the others. Thus, the relative configuration
of the stereocenters C-8, C-9 and C-13 would be identical to
those of natural limonoids. To complete the synthesis, it would
be necessary to expand and properly functionalize the D ring,
and introduce the E ring.
the oxirane with titanocene chloride, which is followed by a
radical 6-endo cyclization onto CC, and it finishes with a 4-
exo cyclization on the nitrile group.
In the same way, treatment of the epoxy nitrile ( )-7b with
titanocene afforded ( )-8b in 82% yield, as a result of the
radical cyclization (Scheme 4). In both radical cyclizations,
The first general step leading to epoxy nitrile ( )-7
commenced with α-ionone 1, which was converted to
dihydro-α-ionone ( )-2 by a chemoselective hydrogenation
(Scheme 2).11 Subsequent olefination of ( )-2 by the
Scheme 4. Cyclization of Epoxy Nitriles ( )-7a and ( )-7b
with Cp2TiCl
a
Scheme 2. Preparation of Epoxy Nitriles ( )-7a/7b from α-
a
Ionone
a
Key: (i) Cp2TiCl2, Zn, THF, 25 °C; (ii) PCC, CH2Cl2, 25 °C.
three stereocenters are created with complete control of
diastereoselectivity according to the model compound I: trans
for the BC ring fusion and cis for the CD ring fusion, such that
the relative configuration of the carbons C8, C9, and C13 is
identical to the configuration of these carbons in the
azadiradione and other limonoids. The relative configuration
of ( )-8a and ( )-8b was assigned by its chemical correlation
with product ( )-12 (see below). The hydroxy ketones ( )-8a
and ( )-8b only differ in the orientation of the hydroxyl group,
as demonstrated by their oxidation to the same diketone ( )-9.
Regarding these cyclizations, we wished to test the
homologous epoxy nitrile ( )-7c in order to determine its
pattern of cyclization (Scheme 5). If it was the same as with
compounds ( )-7a and ( )-7b, we would be able to dispense
a
Key: (i) H2, Pd/C, Et2NH, EtOAc, 25°C; (ii) EtOOCCH2P(O)-
(OEt)2, NaH, PhCH3, 0 → 25 °C; (iii) DIBAH, PhCH3, −20°C; (iv)
CCl4, PPh3, 80 °C; (v) NaCN, DMSO, 25 °C; (vi) m-CPBA,
NaHCO3, CH2Cl2, −20 °C.
Wadsworth−Emmons method12 furnished the unsaturated
ketoesters ( )-3a (E) and ( )-3b (Z) in a ratio of 91:9.
Reduction of ( )-3a with DIBAH at −20 °C gave rise to the
alcohol ( )-4, which after hydroxyl substitution afforded the
allylic chloride ( )-5. This compound was transformed into the
unsaturated nitrile ( )-6a by nucleophilic displacement with
sodium cyanide in DMSO. Treatment of the diunsaturated
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a
Scheme 5. Preparation and Cyclization of Epoxy Nitrile
( )-7c
Scheme 6. Expansion of the D Ring
a
a
Key: (i) Ac2O, pyr, DMAP, CH2Cl2; (ii) N2CHCO2Et, BF3·Et2O,
THF; (iii) H2O, DMSO, 180 °C.
The structure of ( )-12, initially assigned on the basis of its
spectroscopic data as a compound with the BCD ring fusion
trans-anti-cis, was subsequently confirmed by X-ray diffraction
analysis (Figure 2).
a
Key: (i) NCCH2CO2Me, NaH, DMF, 25 °C; (ii) H2O, DMSO, 180
°C; (iii) m-CPBA, NaHCO3, CH2Cl2, −20 °C; (iv) Cp2TiCl2, Zn,
THF, 25 °C.
with the ring-expansion step (Scheme 1). The nitrile ( )-7c
was obtained from chloride ( )-5 in three steps: side-chain
elongation to ( )-6b using methyl cyanoacetate anion followed
by desmethoxycarbonylation by the Krapcho method13 to
( )-6c and epoxidation with m-CPBA.
The cyclization of ( )-7c carried out with titanocene
chloride gave the tricyclic hydroxy ketone ( )-8c together
with the unsaturated hydroxy nitrile ( )-8d in 32% and 48%
yield, respectively. It is worth noting the yield difference
between the synthesis of tricyclic products ( )-8a (82%) and
( )-8c (32%) in the radical reaction induced by titanocene
from epoxides ( )-7a and ( )-7c and also the difference in the
cyclization pattern. Thus, whereas in ( )-8a the CD ring fusion
was cis, in ( )-8c the CD ring fusion was trans. The structure of
( )-8c was initially assigned on the basis of its spectroscopic
data as a compound with the BCD ring fusion trans-anti-trans,
and this structure was subsequently confirmed by X-ray
diffraction analysis (Figure 1). Thus, these results prevented
us of using the epoxy nitrile ( )-7c in the synthesis and led us
back to our initial synthesis plan.
Figure 2. X-ray structure of ( )-12.
The target of the fourth main step was the introduction of
the E ring, constituted by the furan ring (Scheme 7). This step
a
Scheme 7. Introduction of the E Ring
a
Key: (i) NH2NH2·H2O, EtOH, reflux; (ii) I2, Et3N, THF, 25 °C; (iii)
(3-fur)SnBu3, Pd (PPh3)4, LiCl, DMSO, 60 °C.
was achieved by a Stille coupling, developed by our group for
similar compounds,15 between vinyl iodide ( )-14, obtained
from ketone ( )-12 through hydrazone ( )-13, and 3-
furyltributylstannane.
The last target in our approach to the synthesis of the
azadiradione BCDE fragment was the ketoacetate ( )-18. The
structural features of this final main stage include the
transformation of the unsaturated D ring into an enone system,
which has been accomplished in three steps (Scheme 8).15
Treatment of the furylketone ( )-15 with 3 equiv of m-CPBA
at −40 °C to avoid the oxidation of the furan afforded, after
attempts of purification through silicagel, an epimeric mixture
of ketones ( )-17a and ( )-17b, at a 6:4 ratio respectively.
Their formation was easily explained in terms of the relief of the
Figure 1. X-ray structure of ( )-8c.
The third step in the synthetic sequence to the azadiradione
BCDE fragment consisted of D ring expansion (Scheme 6).
This was accomplished by reacting acetate ( )-10 with ethyl
diazoacetate,14 followed by desethoxycarbonylation of the
intermediate ( )-11 to give ( )-12 in 77% overall yield.
Attempts to achieve the cyclobutanone ring expansion of
( )-10 with (trimethylsilyl)diazomethane gave a mixture of
products and low yields.
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a
dissolved in methanol, and electrospray was used for ionization. When
required, all solvents and reagents were purified by standard
techniques: tetrahydrofuran (THF) was purified by distillation from
sodium and benzophenone and degassed before use. All air- or
moisture-sensitive reactions were conducted under a positive pressure
of argon, utilizing standard benchtop techniques for the handling of
air-sensitive materials. Chromatographic separations were carried out
under pressure on silica gel using flash column techniques on Merck
silica gel 60 (0.040−0.063 mm). Yields reported are for chromato-
graphically pure isolated products unless otherwise mentioned.
Compound ( )-2. A 10% solution of Pd/C (10.0 g), Et2NH (35.0
mL) and EtOAc (150.0 mL) was stirred under H2 atmosphere for 15
min. After this time, α-ionone 1 (35.0 g, 182.0 mmol) in EtOAc (200.0
mL) was added, and the mixture was stirred at room temperature. The
reaction completion was checked by NMR. After 3 h, the mixture was
filtered through a fritted glass funnel, washed with CHCl3, and
concentrated under reduced pressure. Purification of the residue by
flash chromatography over silica gel with a mixture hexane/Et2O 9:1 as
eluent afforded ( )-2 (colorless oil) (35.9 g, 100%): 1H NMR
(CDCl3, 200 MHz) δ 0.83 (s, 3H), 0.88 (s, 3H), 1.1−1.9 (m, 7H),
1.63 (br s, 3H), 2.09 (s, 3H), 2.43 (m, 2H), 5.32 (br s, 1H) ppm; 13C
NMR (CDCl3, 50 MHz) δ 22.9 (CH2), 23.4 (CH3), 24.3 (CH2), 27.5
(CH3), 27.6 (CH3), 29.8 (CH3), 31.5 (CH2), 32.5 (C), 43.7 (CH2),
48.4 (CH), 120.9 (CH), 135.5 (C), 209.1 (C) ppm; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C13H22NaO 217.1568, found
217.1556.
Scheme 8. Elaboration of D Ring
Compounds ( )-3a and ( )-3b. Triethylphosphonoacetate (22.4
mL, 113.0 mmol) was slowly added to a suspension of 60% NaH (4.1
g, 102.0 mmol) in toluene (34.0 mL) under argon atmosphere and at 0
°C, and the mixture was stirred at the same temperature until the
complete formation of the anion (ca. 30 min). Ketone ( )-2 (20.0 g,
102.9 mmol) was then added dropwise and the new mixture stirred at
room temperature for 15 h, when it was diluted with Et2O and
quenched with water. The aqueous layer was extracted with Et2O, the
mixture of organic extracts was washed with brine and dried over
anhydrous Na2SO4, and the solvent removed under reduced pressure.
Purification of the residue by flash chromatography over silica gel with
a mixture hexane/Et2O 98:2 as eluent afforded ( )-3b (colorless oil)
(2.2 g, 8%) followed by ( )-3a (colorless oil) (22.5 g, 82%).
Data for cis isomer ( )-3b: 1H NMR (CDCl3, 200 MHz) δ 0.85
(s, 3H), 0.96 (s, 3H), 1.0−2.0 (m, 7H), 1.24 (t, J = 7.0 Hz, 3H), 1.70
(s, 3H), 1.85 (s, 3H), 2.48 (m, 1H), 2.76 (m, 1H), 4.11 (q, J = 7.0 Hz,
2H), 5.28 (br s, 1H), 5.59 (s, 1H) ppm; 13C NMR (CDCl3, 50 MHz)
δ 14.3 (CH3), 22.9 (CH2), 23.3 (CH3), 25.1 (CH3), 27.4 (CH3), 27.5
(CH3), 29.2 (CH2), 31.5 (CH2), 32.5 (C), 33.8 (CH2), 49.4 (CH),
59.3 (CH2), 115.8 (CH), 120.2 (CH), 136.2 (C), 160.4 (C), 166.1
(C) ppm.
a
Key: (i) m-CPBA, CH2Cl2, −40 °C; (ii) SiO2; (iii) Et3N, CH3CN;
(iv) TMSOTf, Et3N, −30 °C; (v) PhSeCl, CH2Cl2, −78 °C; (vi) m-
CPBA, CH2Cl2, −78 °C.
strong interaction between the methyl group in C-8 position
and the furan after the regioselective heterolytic cleavage of the
oxirane and the migration of the hydrogen from C-16 to C-17.
Isomerization of ( )-17b to ( )-17a was achieved at 100%
yield by triethylamine treatment. The cis relationship between
the furan and C-13 methyl group was seen in the diamagnetic
shielding effect caused in the methyl group by the furan ring, as
has been observed for related compounds. The structure of
( )-17a was unambiguously confirmed by X-ray crystallo-
graphic analyses (see Supporting Information).
Dehydrogenation of ( )-17a to the target azadiradione
BCDE fragment ( )-18 was accomplished by the known
sequence of selenylation, oxidation, and selenoxide elimination.
Data for trans isomer ( )-3a: 1H NMR (CDCl3, 200 MHz) δ 0.86
(s, 3H), 0.91 (s, 3H), 1.0−2.1 (m, 9H), 1.27 (t, J = 7.2 Hz, 3H), 1.66
(s, 3H), 2.15 (s, 3H), 4.15 (q, J = 7.2 Hz, 2H), 5.30 (br s, 1H), 5.65 (s,
1H) ppm; 13C NMR (CDCl3, 50 MHz) δ 14.3 (CH3), 18.8 (CH3),
22.9 (CH3), 23.3 (CH3), 27.4 (CH3), 27.5 (CH3), 29.1 (CH2), 31.6
(CH2), 32.5 (C), 41.5 (CH2), 48.9 (CH), 59.3 (CH2), 115.4 (CH),
120.6 (CH), 135.7 (C), 160.3 (C), 166.7 (C) ppm; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C17H28NaO2 287.1987, found
287.1969.
CONCLUSION
■
The stereocontrolled total synthesis of the azadiradione BCDE
fragment ( )-18 has been accomplished from α-ionone. The
key feature includes the stereoselective construction of the CD
rings core by titanocene(III)-catalyzed tandem cyclization of
unsaturated epoxy nitrile ( )-7a by a 6-endo/4-exo pattern,
which allows the relative configuration of the C-8, C-9, and C-
13 stereocenters of the hydroxy ketone ( )-8a to be identical
to that of natural limonoids. It is also worth noting the
introduction of the E ring by Stille coupling and the
stereoselective functionalization of the D ring. The procedure
reported here could also allow the enantiospecific synthesis of
azadiradione, diverse molecular fragments, and analogues to be
achieved.
Compound ( )-4. A solution of ( )-3a (5.0 g, 18.9 mmol) in
toluene (189 mL) under argon atmosphere was stirred at −20 °C
while a 1.5 M solution of DIBAH in toluene was added dropwise. The
reaction was stirred at this temperature for 30 min when 37.0 mL of
water was added and the mixture allowed to reach room temperature.
The reaction was then filtered through a fritted glass funnel, the solid
washed with Et2O, and the filtrate dried over anhydrous Na2SO4. After
removal of the solvent under reduced pressure, the residue obtained
was identified as ( )-4 (colorless oil) (4.19 g, 99%) and was used in
EXPERIMENTAL SECTION
■
1
General Methods. Melting points are uncorrected. 1H NMR
spectra were measured at either 200 or 400 MHz, and 13C NMR were
measured at 50 or 100 MHz in CDCl3 and referenced to TMS (1H) or
solvent (13C). HRMS mass spectrometry data were acquired in a
hybrid quadrupole time-of-flight mass spectromer. Samples were
the next reaction without further purification: H NMR (CDCl3, 200
MHz) δ 0.83 (s, 3H), 0.90 (s, 3H), 1.20 (m, 1H), 1.3−1.6 (m, 4H),
1.66 (s, 6H), 1.93 (m, 2H), 2.05 (m, 2H), 4.10 (d, J = 7.0 Hz, 2H),
5.27 (br s, 1H), 5.38 (m, 1H) ppm; 13C NMR (CDCl3, 50 MHz) δ
15.9 (CH3), 22.9 (CH2), 23.4 (CH3), 27.4 (CH3), 27.5 (CH3), 29.4
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(CH2), 31.5 (CH2), 32.5 (C), 40.3 (CH2), 48.9 (CH), 59.3 (CH2),
120.0 (CH), 123.1 (CH), 136.4 (C), 140.3 (C) ppm; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C15H26NaO 245.1881, found
245.1890.
Compound ( )-8a. A solution of Cp2TiCl2 (3.34 g, 13.36 mmol)
and Zn (1.71 g, 26.72 mmol) in THF (27.0 mL) was strictly
deoxygenated with argon until the solution turned green (ca. 15 min).
At the same time, another solution of ( )-7a (1.00 g, 4.05 mmol) in
THF (40.0 mL) was deoxygenated with argon. The epoxide solution
was then added dropwise via canula over the Ti(III) solution, always
maintaining the argon atmosphere. After 15 min, the reaction was
quenched by addition of a saturated aqueous solution of NaH2PO4,
and the resulting mixture, after being stirred for 30 min, was filtered
through a fritted glass funnel. The aqueous layer was extracted with
Et2O, the combined organic extracts were washed with water and brine
and dried over anhydrous Na2SO4, and the solvent was removed under
reduced pressure. The residue was purified by flash chromatography
over silica gel with a mixture hexane/EtOAc 8:2 as eluent to afford
( )-8a (white solid) (830 mg, 82%): mp 72−73 °C; 1H NMR
(CDCl3, 400 MHz) δ 0.86 (s, 3H), 0.92 (s, 3H), 0.95 (s, 3H), 1.05 (m,
1H), 1.20 (s, 3H), 1.2−1.7 (m, 7H), 1.95 (m, 2H), 3.09 (m, 2H), 3.33
(dd, J1 = 4.1 Hz, J2 = 11.3 Hz, 1H) ppm; 13C NMR (CDCl3, 100
MHz) δ 11.7 (CH3), 16.9 (CH2), 21.8 (CH3), 23.1 (CH3), 24.5
(CH2), 27.8 (CH2), 32.5 (CH3), 33.1 (C), 39.0 (C), 40.1 (CH2), 45.6
(CH2), 45.9 (CH), 46.5 (CH), 61.3 (C), 83.9 (CH), 214.5 (C) ppm;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H26NaO2 273.1830,
found 273.1860.
Compound ( )-5. Triphenylphosphine (3.54 g, 13.5 mmol) was
added to a solution of ( )-4 (2.00 g, 9.01 mmol) in CCl4 (12.9 mL),
and the resulting mixture was heated at 80 °C for 150 min. After this
time, the reaction was allowed to cool to room temperature, pentane
was added, and the mixture kept at −18 °C until all the
triphenylphosphine oxide had precipitated (ca. 30 min). The mixture
was then filtered over a fritted glass funnel and the solid washed with
pentane. The filtrate was concentrated under reduced pressure and the
residue obtained identified as ( )-5 (colorless oil) (1.98 g, 92%) and
used in the next reaction without further purification: 1H NMR
(CDCl3, 400 MHz) δ 0.86 (s, 3H), 0.92 (s, 3H), 1.16 (m, 1H), 1.3−
1.6 (m, 4H), 1.66 (s, 3H), 1.72 (s, 3H), 1.94 (m, 2H), 2.07 (m, 2H),
4.01 (d, J = 8.4 Hz, 2H), 5.29 (br s, 1H), 5.53 (m, 1H) ppm; 13C
NMR (CDCl3, 100 MHz) δ: 16.0 (CH3), 22.9 (CH2), 23.5 (CH3),
27.5 (2CH3), 29.2 (CH2), 31.5 (CH2), 32.5 (C), 40.2 (CH2), 44.1
(CH2), 48.8 (CH), 120.2 (CH), 120.3 (CH), 136.3 (C), 144.4 (C)
ppm, HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H25ClNa
263.1542, found 263.1569.
Compound ( )-6a. Over a stirred solution of ( )-5 (2.94 g, 12.25
mmol) in 41.0 mL of DMSO was added powdered NaCN (900 mg,
18.38 mmol), and the mixture was stirred at room temperature for 5 h.
After this time, the reaction was diluted in Et2O and quenched with
water. The aqueous layer was extracted with Et2O, the combined
organic extracts were washed abundantly with water and brine and
dried over anhydrous Na2SO4, and the solvent was removed under
reduced pressure. The residue was purified by flash chromatography
over silica gel with a mixture hexane/Et2O 9:1 as eluent to afford
Compound ( )-8b. A solution of epoxide ( )-7b (113 mg, 0.45
mmol) in THF (4.5 mL) was made to react with a Ti(III) solution,
prepared with Cp2TiCl2 (373 mg, 1.50 mmol) and Zn (191 mg, 3.00
mmol) in THF (3.0 mL), in exactly the same way described for the
above epoxide. The residue obtained after the work up was purified by
flash chromatography over silica gel with a mixture hexane/EtOAc 8:2
as eluent to afford ( )-8b (yellow oil) (94 mg, 82%): 1H NMR
(CDCl3, 200 MHz) δ 0.90 (s, 3H), 0.94 (s, 3H), 0.94 (s, 3H), 1.23 (s,
3H), 1.2−1.7 (m, 7H), 1.95 (m, 2H), 2.75 (dd, J1 = 6.3 Hz, J2 = 9.7
Hz, 1H), 2.89 (dd, J1 = 6.3 Hz, J2 = 17.5 Hz, 1H), 2.97 (dd, J1 = 9.7
Hz, J2 = 17.5 Hz, 1H) 3.41 (br s, 1H) ppm; 13C NMR (CDCl3, 50
MHz) δ 17.4 (CH2), 18.2 (CH3), 22.0 (CH3), 23.9 (CH3), 25.3
(CH2), 25.7 (CH2), 33.0 (CH3, C), 34.2 (CH2), 36.5 (CH), 37.9 (C),
41.3 (CH), 43.9 (CH2), 61.1 (C), 72.4 (CH), 214.3 (C) ppm.
Compound ( )-9. To a suspension of PCC (39 mg, 0.18 mmol)
and SiO2 (38 mg) in CH2Cl2 (1.0 mL) was added a solution of ( )-8a
(30 mg, 0.12 mmol) in CH2Cl2 (1.0 mL). After 2 h of stirring at room
temperature, the reaction was passed through a small column of SiO2
using CH2Cl2 as eluent. Removal of the solvent at reduced pressure
1
( )-6a (yellow oil) (1.61 g, 81%): H NMR (CDCl3, 400 MHz) δ
0.86 (s, 3H), 0.91 (s, 3H), 1.13 (m, 1H), 1.3−1.6 (m, 4H), 1.66 (s,
3H), 1.67 (s, 3H), 1.94 (m, 2H), 2.06 (m, 2H), 3.02 (d, J = 6.9 Hz,
2H), 5.15 (m, 1H), 5.29 (br s, 1H) ppm; 13C NMR (CDCl3, 100
MHz) δ 16.1 (CH2), 16.4 (CH3), 22.9 (CH2), 23.4 (CH3), 27.4
(CH3), 27.5 (CH3), 29.2 (CH2), 31.5 (CH2), 32.5 (C), 39.9 (CH2),
48.9 (CH), 111.3 (CH), 118.5 (C), 120.3 (CH), 136.2 (C), 143.0 (C)
ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H25NNa
254.1885, found 254.1876.
Compounds ( )-7a and ( )-7b. A mixture of ( )-6a (1.00 g,
4.33 mmol) and NaHCO3 (400 mg, 4.76 mmol) in CH2Cl2 (21.6 mL)
under argon atmosphere was cooled to −20 °C, and m-CPBA (820
mg, 4.76 mmol) was added. The reaction was stirred at that
temperature for 90 min and then quenched with a 10% aqueous
solution of Na2S2O3. The mixture was then allowed to reach room
temperature, the aqueous layer was extracted with CH2Cl2, the
combined organic extracts were washed with a saturated aqueous
solution of NaHCO3 and brine and dried over anhydrous Na2SO4, and
the solvent was removed under reduced pressure. Purification of the
residue by flash chromatography over silica gel with a mixture of
hexane/Et2O 8:2 as eluent afforded ( )-7a (colorless oil) (749 mg,
70%) and ( )-7b (colorless oil) (56 mg, 5%).
1
afforded ( )-9 (yellow oil) (30 mg, 98%): H NMR (CDCl3, 200
MHz) δ 0.97 (s, 3H), 1.15 (s, 3H), 1.18 (s, 3H), 1.21 (s, 3H), 1.2−1.9
(m, 7H), 2.24 (dt, J1 = 3.9 Hz, J2 = 14.5 Hz, 1H), 2.53 (dd, J1 = 6.6 Hz,
J2 = 9.8 Hz, 1H), 2.75 (ddd, J1 = 5.5 Hz, J2 = 14.5 Hz, J3 = 14.5 Hz,
1H), 3.00 (dd, J1 = 6.6 Hz, J2 = 18.2 Hz, 1H), 3.17 (dd, J1 = 9.8 Hz, J2
= 18.2 Hz, 1H) ppm; 13C NMR (CDCl3, 50 MHz) δ 17.1 (CH3), 17.8
(CH2), 21.1 (CH3), 23.5 (CH3), 24.3 (CH2), 31.6 (CH3), 32.8 (C),
34.9 (CH2), 39.4 (CH), 40.7 (CH2), 45.2 (CH2), 47.8 (C), 48.5
(CH), 61.2 (C), 213.8 (C), 215.6 (C) ppm; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C16H24O2Na 271.1669, found 271.1677.
A similar procedure applied to ( )-8b (41 mg, 0.16 mmol) also
afforded ( )-9 (39 mg, 96%).
1
Data for isomer ( )-7a: H NMR (CDCl3, 400 MHz) δ 0.80 (s,
Compound ( )-6c. To a suspension of NaH (159 mg, 3.96
mmol) in DMF (1.4 mL) at 0 °C was added ethyl cyanoacetate (0.45
mL, 4.2 mmol) dropwise, and the mixture was stirred at room
temperature for 30 min. A solution of ( )-5 (680 mg, 2.83 mmol) in
DMF (1 mL) was then added, and the reaction was stirred at 70 °C.
After 7 h at this temperature, the mixture was cooled to room
temperature and was quenched with water and an aqueous 2 N
solution of HCl. The aqueous layer was extracted with Et2O, and the
combined organic extracts were washed with water and brine and dried
over anhydrous Na2SO4. Removal of the solvent under reduced
pressure furnished an oil which was diluted in DMSO (8.3 mL) and
water (1.5 mL), and then NaCl (316 mg, 5.4 mmol) was added. The
mixture was stirred at 180 °C for 3 h. The reaction was then allowed to
reach room temperature, EtOAc was added, the mixture was washed
abundantly with water and brine and dried over anhydrous Na2SO4,
and the solvent was removed under reduced pressure. The residue was
3H), 0.88 (s, 3H), 1.26 (m, 1H), 1.31 (s, 3H), 1.46 (m, 3H), 1.69 (s,
3H), 1.88 (m, 3H), 2.03 (m, 1H), 2.30 (m, 1H), 2.93 (br s, 1H), 3.02
(d, J = 7.0 Hz, 2H), 5.20 (m, 1H) ppm; 13C NMR (CDCl3, 100 MHz)
δ 16.1 (CH2), 16.4 (CH3), 21.9 (CH2), 25.7 (CH2), 26.8 (CH2), 26.9
(CH3), 27.2 (CH3), 27.7 (CH3), 31.4 (C), 39.9 (CH2), 46.8 (CH),
59.4 (C), 60.1 (CH), 111.3 (CH), 118.5 (C), 143.1 (C) ppm; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C16H25NNaO 270.1834, found
270.1836.
1
Data for isomer ( )-7b: H NMR (CDCl3, 200 MHz) δ 0.71 (s,
3H), 0.81 (s, 3H), 1.03 (m, 1H), 1.32 (s, 3H), 1.49 (m, 3H), 1.67 (s,
3H), 1.82 (m, 3H), 2.13 (m, 1H), 2.27 (m, 1H), 2.86 (br s, 1H), 3.01
(d, J = 0.7 Hz, 2H), 5.19 (m, 1H) ppm; 13C NMR (CDCl3, 50 MHz)
δ 16.1 (CH2), 16.4 (CH3), 19.8 (CH3), 21.5 (CH2), 22.6 (CH3), 25.6
(CH2), 27.7 (CH3), 31.8 (C), 33.8 (CH2), 41.3 (CH2), 49.3 (CH),
60.0 (C), 60.8 (CH), 111.9 (CH), 118.4 (C), 142.2 (C) ppm.
9575
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1
purified by flash chromatography over silica gel with a mixture hexane/
EtOAc 9:1 as eluent to afford ( )-6c (yellow oil) (318 mg, 46% from
( )-5): H NMR (CDCl3, 200 MHz) δ 0.85 (s, 3H), 0.91 (s, 3H),
(colorless oil) (1.6 g, 99%): H NMR (CDCl3, 200 MHz) δ 0.84 (s,
3H), 0.90 (s, 3H), 0.99 (s, 3H), 1.15 (s, 3H), 1.0−2.0 (m, 10H), 1.96
(s, 3H), 2.93 (m, 2H), 4.58 (dd, J1 = 5.1 Hz, J2 = 10.2 Hz, 1H) ppm;
13C NMR (CDCl3, 50 MHz) δ 12.2 (CH3), 16.8 (CH2), 20.8 (CH3),
21.6 (CH3), 23.2 (CH3), 23.9 (CH2), 24.3 (CH2), 32.2 (CH3), 32.8
(C), 38.0 (C), 39.6 (CH2), 44.6 (CH2), 44.9 (CH), 46.6 (CH), 60.8
(C), 84.4 (CH), 169.9 (C), 212.5 (C) ppm; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C18H28NaO3 315.1936, found 315.1940.
Compound ( )-11. To a solution of ( )-10 (1.54 g, 5.27 mmol)
in Et2O (16.0 mL) were added BF3·OEt2 (1.0 mL, 7.90 mmol) and
ethyl diazoacetate (0.8 mL, 7.90 mmol). The reaction was stirred in
the dark at room temperature, under argon atmosphere for 24 h, and
then quenched with an aqueous 2 N solution of HCl. The aqueous
layer was extracted with Et2O, the combined organic extracts were
washed with water and brine and dried over anhydrous Na2SO4, and
the solvent was removed under reduced pressure. Purification of the
residue by flash chromatography over silica gel with a mixture hexane/
EtOAc 9:1 as eluent afforded ( )-11 (pale yellow solid) (1.69 g,
85%): mp 107−109 °C; 1H NMR (CDCl3, 200 MHz) δ 0.80 (s, 3H),
0.82 (s, 3H), 0.87 (s, 3H), 1.03 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.2−
1.7 (m, 11H), 2.08 (s, 3H), 2.50 (m, 1H), 3.23 (t, J = 9.8 Hz, 1H),
4.18 (q, J = 7.1 Hz, 2H), 4.63 (dd, J1 = 5.4 Hz, J2 = 10.7 Hz, 1H) ppm;
13C NMR (CDCl3, 50 MHz) δ 10.9 (CH3), 13.9 (CH3), 18.5 (CH2),
21.4 (CH3), 21.9 (CH3), 24.5 (2CH2), 26.7 (CH3), 32.6 (CH2), 32.7
(C), 33.1 (CH3), 39.1 (CH2), 40.9 (C), 50.1 (C), 52.1 (2CH), 54.3
(CH), 61.2 (CH2), 84.2 (CH), 169.3 (C), 170.1 (C), 212.5 (C) ppm;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C22H34NaO5 401.2304,
found 401.2302.
1
1.0−2.2 (m, 11H), 1.64 (s, 3H), 1.66 (s, 3H), 2.33 (m, 2H), 5.13 (br s,
1H), 5.28 (br s, 1H); 13C NMR (CDCl3, 50 MHz) δ 16.3 (CH3), 17.5
(CH2), 22.9 (CH2), 23.3 (CH3), 23.9 (CH2), 27.3 (CH3), 27.4 (CH3),
29.5 (CH2), 31.5 (CH2), 32.5 (C), 40.2 (CH2), 48.9 (CH), 117.6
(CH), 119.7 (C), 120.0 (CH), 136.4 (C), 139.8 (C); HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C17H27NNa 268.2041, found
268.2050.
Compound ( )-7c. A solution of ( )-6c (542 mg, 2.21 mmol)
and 204 mg (2.43 mmol) of NaHCO3 in CH2Cl2 (4.5 mL) under
argon atmosphere was cooled to −20 °C, and 420 mg (4.46 mmol) of
m-CPBA was added. The reaction was stirred at −10 °C for 90 min
and then was quenched with a 10% aqueous solution of Na2S2O3. The
mixture was then allowed to reach room temperature, the aqueous
layer was extracted with CH2Cl2, the combined organic extracts were
washed with a saturated aqueous solution of NaHCO3 and brine and
dried over anhydrous Na2SO4, and the solvent was removed under
reduced pressure. Purification of the residue by flash chromatography
over silica gel with a mixture hexane/Et2O 8:2 as eluent afforded
( )-7c (pale yellow oil) (208 mg, 36%): 1H NMR (CDCl3, 400 MHz)
δ 0.79 (s, 3H), 0.87 (s, 3H), 1.31 (s, 3H), 1.66 (s, 3H), 0.9−2.0 (m,
11H), 2.35 (m, 2H), 2.91 (br s, 1H), 5.17 (br s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 16.2 (CH3), 17.6 (CH2), 19.3 (CH3), 22.0
(CH2), 23.7 (CH2), 25.9 (CH2), 26.8 (CH2), 26.9 (CH3), 27.7 (CH3),
33.0 (C), 39.3 (CH2), 46.8 (CH), 59.5 (C), 60.1 (CH), 119.6 (C),
119.8 (CH), 139.9 (C); HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C17H27NNaO 284.1990, found 284.1982.
Compound ( )-12. A solution of ( )-11 (1.69 g, 4.47 mmol) in
DMSO (4.5 mL) and water (0.2 mL, 8.94 mmol) was stirred at 180 °C
for 3 h. The reaction was then allowed to cool to room temperature
and diluted with EtOAc, the mixture was washed with an aqueous 1 N
solution of HCl and brine and dried over anhydrous Na2SO4, and the
solvent was removed under reduced pressure. The residue was purified
by flash chromatography over silica gel with a mixture of hexane/
EtOAc 8:2 as eluent to afford ( )-12 (white solid) (1.23 g, 90%): mp
Compound ( )-8c. A solution of Cp2TiCl2 (657 mg, 2.63 mmol)
and Zn (230 mg, 3.6 mmol) in 5.3 mL of THF was strictly
deoxygenated with argon until the solution turned green (ca. 15 min).
At the same time, another solution with of ( )-7c (208 mg, 0.80
mmol) in THF (8.0 mL) was deoxygenated with argon. The epoxide
solution was then added dropwise via canula over the Ti(III) solution,
always maintaining the argon atmosphere. After 15 min, the reaction
was quenched by addition of a saturated aqueous solution of
NaH2PO4, and the resulting mixture, after being stirred for 30 min,
was filtered through a fritted glass funnel. The aqueous layer was
extracted with Et2O, the combined organic extracts were washed with
water and brine and dried over anhydrous Na2SO4, and the solvent
was removed under reduced pressure. The residue was purified by
flash chromatography over silica gel with a mixture hexane/EtOAc 8:2
as eluent to afford ( )-8c (white solid) (67 mg, 32%), followed by
( )-8d (101 mg, 48%).
1
101−105 °C; H NMR (CDCl3, 200 MHz) δ 0.78 (s, 3H), 0.82 (s,
3H), 0.86 (s, 3H), 0.97 (s, 3H), 1.0−2.5 (m, 14H), 2.06 (s, 3H), 4.63
(dd, J1 = 4.4 Hz, J2 = 11.2 Hz, 1H) ppm; 13C NMR (CDCl3, 50 MHz)
δ 10.3 (CH3), 18.5 (CH2), 19.3 (CH2), 21.4 (CH3), 21.9 (CH3), 24.6
(CH2), 27.9 (CH3), 31.7 (CH2), 32.7 (C), 33.0 (CH3), 33.9 (CH2),
39.2 (CH2), 41.0 (C), 49.1 (C), 52.3 (CH), 55.9 (CH), 84.2 (CH),
170.1 (C), 220.8 (C) ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C19H30NaO3 329.2093, found 329.2085.
Compound ( )-13. Triethylamine (0.5 mL, 3.4 mmol) and
hydrazine monohydrate (1.2 mL, 24.2 mmol) were added to a solution
of ( )-12 (200 mg, 0.065 mmol) in EtOH (6.5 mL), and the mixture
was refluxed for 30 h. After this time, the reaction was allowed to cool
to room temperature and the solvent removed under reduced pressure.
The residue was then dissolved in CH2Cl2, washed with water until
neutral pH was reached and then with brine, and dried over anhydrous
Na2SO4 and the solvent removed under reduced pressure. The residue
was identified as the hydrazone ( )-13 (pale yellow oil) (189 mg,
97%), and the product used in the next reaction without further
1
Data for ( )-8c: mp 108−110 °C H NMR (CDCl3, 400 MHz) δ
0.82 (s, 3H), 0.84 (s, 3H), 0.96 (s, 3H), 0.97 (s, 3H), 1.2−2.4 (m,
15H), 3.36 (dd, J1 = 4.5 Hz, J2 = 11.0 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ 12.1 (CH3), 17.1 (CH3), 18.6 (CH2), 20.9 (CH3), 21.7
(CH2), 28.4 (CH2), 32.7 (C), 32.9 (CH3), 33.2 (CH2), 35.6 (CH2),
40.2 (CH2), 43.3 (C), 48.7 (C), 55,5 (CH), 57.7 (CH), 80.1 (CH),
221.2 (C); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H28NaO2
287.1987, found 287.1980.
Data for ( )-8d: 1H NMR (CDCl3, 400 MHz) δ 0.70 (s, 3H), 0.90
(d, J = 6.4 Hz, 3H), 0.96 (s, 3H), 0.8−2.0 (m, 15H), 2.32 (m, 2H),
3.95 (t, J = 8.0 Hz, 1H), 4.68 (dd, J1 = 1.0 Hz, J2 = 6.5 Hz, 1H), 5.17
(d, J = 1 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 17.4 (CH2), 19.1
(CH3), 19.6 (CH3), 22.8 (CH2), 23.0 (CH2), 29.5 (CH3), 32.8 (CH),
33.3 (CH2), 35.4 (CH2), 35.7 (CH2), 36.2 (CH2), 38.5 (C), 52.1
(CH), 73.8 (CH), 104.5 (CH2), 119.7 (C), 150.9 (C); HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C17H29NO 263.2249, found 263.2268.
Compound ( )-10. To a stirred solution of ( )-8a (1.35 g, 5.40
mmol) in CH2Cl2 (5.4 mL) and pyridine (0.6 mL, 8.10 mmol) were
added Ac2O (0.76 mL, 8.10 mmol) and a catalytic amount of DMAP.
After 20 h at room temperature, the mixture was poured into water
and stirred for 30 min. The aqueous layer was then extracted with
Et2O, the combined organic extracts were washed with water, an
aqueous 2 N solution of HCl, an aqueous 5% solution of NaHCO3,
and brine and dried over anhydrous Na2SO4, and the solvent was
removed under reduced pressure. The residue was identified as ( )-10
1
purification: H NMR (CDCl3, 200 MHz) δ 0.70 (s, 3H), 0.76 (s,
3H), 0.83 (s, 3H), 0.97 (s, 3H), 1.1−2.7 (m, 14H), 3.29 (dd, J1 = 4.0
Hz, J2 = 11.0 Hz, 1H) ppm.
Compound ( )-14. To a solution of the hydrazone ( )-13 (189
mg, 0.61 mmol) in THF (4.2 mL) at room temperature were added
Et3N (0.9 mL, 6.38 mmol) and iodine (242 mg, 0.96 mmol)
portionwise, and the reaction was stirred until gas evolution ceased.
The reaction was then dissolved in Et2O and quenched with water.
The aqueous layer was extracted with Et2O, the combined extracts
washed with an aqueous 2 N solution of HCl, an aqueous 10%
solution of Na2S2O3, an aqueous saturated solution of NaHCO3, and
brine and dried over anhydrous Na2SO4, and the solvent was removed
under reduced pressure. Purification of the residue by flash
chromatography over silica gel with a mixture hexane/Et2O 98:2 as
eluent afforded ( )-14 (white solid) (257 mg, 100%): mp 103−104
°C; 1H NMR (CDCl3, 400 MHz) δ 0.87 (s, 3H), 0.91 (s, 3H), 0.93 (s,
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Featured Article
3H), 1.01 (s, 3H), 1.1−1.7 (m, 9H), 1.86 (m, 1H), 2.02 (s, 3H), 2.35
(m, 1H), 2.45 (m, 1H), 4.58 (dd, J1 = 4.4 Hz, J2 = 11.5 Hz, 1H), 5.93
(s, 1H) ppm; 13C NMR (CDCl3, 100 MHz) δ 11.6 (CH3), 17.9
(CH2), 21.6 (2CH3), 24.6 (CH2), 29.6 (CH3), 32.3 (CH3), 32.5
(CH2), 33.3 (C), 35.9 (CH2), 39.7 (CH2), 40.6 (C), 48.3 (CH), 51.2
(C), 54.8 (CH), 84.8 (CH), 111.0 (C), 136.7 (CH), 170.5 (C) ppm;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C19H29O2NaI 439.1103,
found 439.1102.
triethylamine (0.18 mL, 1.29 mmol). The mixture was then cooled to
−30 °C, and trimethylsilyl trifluoromethanesulfonate (0.18 mL, 1.29
mmol) was added. The reaction was stirred at this temperature for 14
h, quenched by addition of an aqueous 5% solution of NaHCO3, and
allowed to reach room temperature. The aqueous layer was extracted
with Et2O, and the combined organic extracts were washed with water,
an aqueous 5% solution of NaHCO3, and brine and dried over
anhydrous Na2SO4. Removal of the solvent under reduced pressure
afforded an oil (108 mg) that was immediately diluted in CH2Cl2 (4.7
mL). Pyridine (79 μL, 0.98 mmol) was added, and the mixture was
cooled to −78 °C. Then, a solution of PhSeCl (163 mg, 0.85 mmol) in
CH2Cl2 (7.6 mL) was added dropwise. The mixture was stirred at the
same temperature for 45 min and then quenched with a saturated
aqueous solution of NaHCO3. The aqueous layer was extracted with
Et2O, and the combined organic extracts were washed with a saturated
aqueous solution of NaHCO3 and brine, and dried over anhydrous
Na2SO4. Removal of the solvent under reduced pressure afforded 195
mg of a solid that were again diluted in of CH2Cl2 (8.8 mL) and
cooled to −78 °C. A solution of m-CPBA (51 mg, 0.3 mmol) in
CH2Cl2 (2.8 mL) was added dropwise, and the mixture was stirred at
−78 °C for 3 h. It was then quenched by addition of an aqueous
saturated solution of Na2S2O3, and after being stirred for additional 30
min, the aqueous layer was extracted with Et2O, the combined organic
extracts were washed with water, a saturated aqueous solution of
NaHCO3, and brine and dried over anhydrous Na2SO4, and the
solvent was removed under reduced pressure. Purification of the
residue by flash chromatography over silica gel with a mixture hexane/
EtOAc 8:2 as eluent afforded ( )-18 (white solid) (65 mg, 68%): mp
Compound ( )-15. To a flask with vinyl iodide ( )-14 (500 mg,
1.20 mmol), under argon atmosphere, were added anhydrous LiCl
(153 mg, 3.10 mmol) and Pd(PPh3)4 (27.8 mg, 0.024 mmol), followed
by a solution of 3-(tributylstannyl)furan16 (645 mg, 1.80 mmol) in
DMSO (10 mL). This mixture was heated for 24 h at 60 °C, cooled to
room temperature, and diluted with Et2O. The resulting solution was
washed with an aqueous 5% solution of NH3 and water until neutral
pH was reached and with brine and dried over anhydrous Na2SO4 and
the solvent removed under reduced pressure. Purification of the
residue by flash chromatography over silica gel with a mixture of
hexane/EtOAc 8:2 as eluent afforded ( )-15 (pale yellow solid) (389
1
mg, 91%): mp 95−97 °C; H NMR (CDCl3, 400 MHz) δ 0.87 (s,
3H), 0.92 (s, 3H), 0.97 (s, 3H), 1.23 (s, 3H), 1.3−1.8 (m, 9H), 1.90
(m, 1H), 2.05 (s, 3H), 2.50 (m, 2H), 4.61 (dd, J1 = 4.4 Hz, J2 = 11.5
Hz, 1H), 5.64 (s, 1H), 6.54 (s, 1H), 7.34 (s, 1H), 7.38 (s, 1H) ppm;
13C NMR (CDCl3, 100 MHz) δ 11.7 (CH3), 18.5 (CH2), 21.6 (CH3),
21.7 (CH3), 24.7 (CH2), 29.9 (CH3), 31.3 (CH2), 32.3 (CH3), 33.2
(CH2), 33.3 (C), 39.8 (CH2), 40.8 (C), 48.1 (CH), 49.3 (C), 59.6
(CH), 85.0 (CH), 110.3 (CH), 120.9 (C), 125.5 (CH), 137.9 (CH),
142.3 (CH), 142.4 (C), 170.6 (C) ppm; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C23H32O3Na 379.2244, found 379.2256.
1
134−136 °C; H NMR (CDCl3, 200 MHz) δ 0.91 (s, 3H), 0.97 (s,
Compound ( )-17. A mixture of ( )-15 (110 mg, 0.31 mmol)
and NaHCO3 (78 mg, 0.93 mmol) in CH2Cl2 (5.2 mL) under argon
atmosphere was cooled to −40 °C, and m-CPBA (160 mg, 0.93
mmol) was added. After being stirred at that temperature for 6 h, the
reaction was quenched with a 10% aqueous solution of Na2S2O3. The
mixture was then allowed to reach room temperature, the aqueous
layer was extracted with CH2Cl2, the combined organic extracts were
washed with a saturated aqueous solution of NaHCO3 and brine and
dried over anhydrous Na2SO4, and the solvent was removed under
reduced pressure. Purification of the residue by flash chromatography
over silica gel with a mixture of hexane/EtOAc 9:1 as eluent afforded
the ketones ( )-17a (white solid) (43 mg, 37%) and ( )-17b (pale
yellow oil) (31 mg, 27%).
3H), 1.04 (s, 3H), 1.34 (s, 3H), 1.2−2.0 (m, 9H), 2.12 (s, 3H), 3.38
(s, 1H), 4.75 (dd, J1 = 4.8 Hz, J2 = 11.0 Hz, 1H), 6.06 (s, 1H), 6.24 (s,
1H), 7.42 (m, 2H) ppm; 13C NMR (CDCl3, 50 MHz) δ 17.6 (CH2),
20.2 (CH3), 21.5 (CH3), 21.9 (CH3), 25.0 (CH2), 27.8 (CH3), 31.7
(CH2), 32.9 (CH3), 33.4 (C), 39.8 (CH2), 43.7 (C), 44.2 (CH), 48.8
(C), 60.8 (CH), 78.7 (CH), 111.5 (CH), 118.8 (C), 127.2 (CH),
141.8 (CH), 142.9 (CH), 170.6 (C), 192.1 (C), 206.7 (C) ppm;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C23H30O4Na 393.2036,
found 393.2049.
ASSOCIATED CONTENT
■
Data for isomer ( )-17a: mp 171−173 °C; 1H NMR (CDCl3, 200
MHz) δ 0.76 (s, 3H), 0.89 (s, 3H), 0.93 (s, 3H), 1.06 (s, 3H), 1.1−2.0
(m, 10H), 2.06 (s, 3H), 2.61 (m, 2H), 3.49 (s, 1H), 4.63 (dd, J1 = 4.8
Hz, J2 = 10.8 Hz, 1H), 6.15 (s, 1H), 7.26 (s, 1H), 7.38 (s, 1H) ppm;
13C NMR (CDCl3, 50 MHz) δ 12.1 (CH3), 17.6 (CH2), 21.4 (CH3),
21.9 (CH3), 24.5 (CH2), 28.2 (CH3), 32.9 (CH3, C), 35.8 (CH2), 39.3
(CH2), 40.1 (CH2), 40.9 (C), 43.8 (C), 52.2 (CH), 53.3 (CH), 53.6
(CH), 85.1 (CH), 111.4 (CH), 118.1 (C), 141.4 (CH), 142.5 (CH),
170.6 (C), 218.8 (C) ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C23H32O4Na 395.2193, found 395.2174.
S
* Supporting Information
Copies of 1H and 13C NMR spectra for all described
compounds and X-ray data for ( )-8c, ( )-12, and ( )-17a.
This material is available free of charge via the Internet at
http://pubs.acs.org. Crystallographic data of compounds
( )-8c, ( )-12, and ( )-17a have been deposited with the
Cambridge Crystallographic Data Centre with the following
deposition numbers: CCDC 950577 for ( )-12, CCDC
950578 for ( )-17a, and CCDC 950579 for ( )-8c.
1
Data for isomer ( )-17b: H NMR (CDCl3, 200 MHz) δ 0.86 (s,
3H), 0.93 (s, 3H), 0.95 (s, 3H), 1.34 (s, 3H), 1.2−1.7 (m, 9H), 2.04
(s, 3H), 2.13 (dd, J1 = 4.7 Hz, J2 = 11.7 Hz, 1H), 2.50 (dd, J1 = 5.0 Hz,
J2 = 18.8 Hz, 1H), 2.61 (dd, J1 = 11.9 Hz, J2 = 18.8 Hz, 1H), 3.33 (s,
1H), 4.65 (dd, J1 = 5.3 Hz, J2 = 10.6 Hz, 1H), 6.23 (s, 1H), 7.30 (s,
1H), 7.39 (s, 1H) ppm; 13C NMR (CDCl3, 50 MHz) δ 12.2 (CH3),
17.4 (CH2), 21.5 (CH3), 21.7 (CH3), 24.6 (CH2), 26.7 (CH2), 30.9
(CH3), 32.3 (CH3), 33.2 (C), 39.3 (CH2), 39.8 (CH2), 41.1 (C), 42.1
(C), 45.5 (CH), 51.8 (CH), 57.7 (CH), 85.3 (CH), 111.5 (CH),
117.3 (C), 141.3 (CH), 142.4 (CH), 170.6 (C), 215.7 (C) ppm.
Epimerization of ( )-17b to ( )-17a. Triethylamine (1.2 mL,
8.70 mmol) was added to a solution of ( )-17b (115 mg, 0.31 mmol)
in CH3CN (24.0 mL), and the mixture was stirred at 45 °C for 90 min.
It was the allowed to cool to room temperature, and the solvent
removed under reduced pressure. The residue obtained was identified
as ( )-17b (115 mg, 100%).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: afmateos@usal.es. Fax: (+34) 923294574. Tel: (+34)
923294481.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work from the Junta de Castilla y
́
Leon (SA200A12-1) is gratefully acknowledged. We also thank
́
the Ministerio de Ciencia y Tecnologia of Spain for the
fellowships to R.R.C. and S.E.M and the Universidad de
Salamanca for the fellowship to P.H.T.
Compound ( )-18. Over a solution of ( )-17a (96 mg, 0.26
mmol) in CH2Cl2 (1.3 mL) under argon atmosphere was added
9577
dx.doi.org/10.1021/jo401646g | J. Org. Chem. 2013, 78, 9571−9578

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REFERENCES
■
(1) (a) Dreyer, D. L. Prog. Chem. Org. Nat. Prod. 1968, 26, 190−244.
(b) Taylor, D. A. H. Prog. Chem. Org. Nat. Prod. 1984, 45, 1−102.
(c) Champagne, D. E.; Koul, O.; Isman, M. B.; Scudder, G. G. E;
Towers, G. H. N. Phytochemistry 1992, 31, 377−394. (d) Akhila, A.;
Rani, K. Prog. Chem. Org. Nat. Prod. 1999, 78, 48−149. (e) Roy, A.;
Saraf, S. Biol. Pharm. Bull. 2006, 29, 191−201. (f) Manners, G. D. J.
Agric. Food Chem. 2007, 55, 8285−8294. (g) Qin-Gang, T.; Xiao-
Dong, L. Chem. Rev. 2011, 111, 7437−7522.
(2) Brahmachari, G. ChemBioChem 2004, 5, 408−421.
(3) Nanduri, S.; Thunuguntla, S. S. R.; Nyavanandi, V. K.; Kasu, S.;
Kumar, P. M.; Ram, P. S.; Rajagopal, S.; Kumar, R. A.; Deevi, D. S.;
Rajagopalan, R.; Venkateswarlu, A. Bioorg. Med. Chem. Lett. 2003, 13,
4111−4115.
(4) Reviews on limonoid synthesis: (a) Tokoroyama, T. J. Synth. Org.
Chem. Jpn. 1998, 56, 1014−1025. (b) Heasley, B. Eur. J. Org. Chem.
2011, 19. Synthesis of azadiradione: (c) Corey, E. J.; Reid, J. G.;
Myers, A. G.; Hahl, R. W. J. Am. Chem. Soc. 1987, 109, 918−919.
(d) Corey, E. J.; Hahl, R. W. Tetrahedron Lett. 1989, 30, 3023−3026.
(e) Behenna, D. C.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 6720−
6721. Synthesis of azadirachtin: (f) Ley, S. V.; Denholm, A. A.; Wood,
A. A. Nat. Prod. Rep. 1993, 10, 109−157. (g) Veitch, G. E.; Boyer, A.;
Ley, S. V. Angew. Chem., Int. Ed. 2008, 47, 9402−9429.
(5) (a) Fernan
55, 1349−1354. (b) Fernan
Alonso, J. J.; Rubio Gonzalez, R.; Simmonds, M. S. J.; Blaney, W. M.
Tetrahedron 1998, 54, 14989−14998. (c) Fernandez-Mateos, A.;
Herrero Teijon, P.; Pascual Coca, G.; Rubio Gonzalez, R.; Simmonds,
M. S. J. Tetrahedron 2010, 66, 7257−7251. (d) Fernandez-Mateos, A.;
Ramos Silvo, A. I.; Rubio Gonzalez, R.; Simmonds, M. S. J. Org.
Biomol. Chem. 2012, 10, 5620−5628.
(6) Fernandez-Mateos, A.; Martín de la Nava, E. M.; Rubio Gonzal
R. J. Org. Chem. 2001, 66, 7632−7638.
(7) Fernandez-Mateos, A.; Pascual Coca, G.; Rubio Gonzal
Tetrahedron 2005, 61, 8699−9704.
(8) de la Fuente, J. A.; Marugan, J. J.; Cross, S. S.; Fernan
A.; García, S.; Menendez, A. Bioorg. Med. Chem. Lett. 1995, 14, 1471−
1474.
(9) (a) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116,
986−997. (b) Gansauer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem. Soc.
́
dez-Mateos, A.; de la Fuente, J. A. J. Org. Chem. 1990,
́
dez-Mateos, A.; Pascual Coca, G.; Perez
́
́
́
́
́
́
́
́
́
ez,
ez, R.
dez-Mateos,
́
́
́
́
́
̈
1998, 120, 12849−12859. (c) Fernan
́
dez-Mateos, A.; Mateos Buron
́
,
L.; Rabanedo Clemente, R.; Ramos Silva, A. I.; Rubio Gonzal
́
ez, R.
Synlett 2004, 1011−1014. (d) Gansauer, A.; Lauterbach, T.; Narayan,
̈
S. Angew. Chem., Int. Ed. 2003, 42, 5556−5573. (e) Barrero, A. F.;
́
Quilez del Moral, J. F.; Sanchez, E. M.; Arteaga, J. F. Eur. J. Org. Chem.
2006, 1627−1641. (f) Justicia, J.; Alvarez Cienfuegos, L.; Campana, A.
̃
G.; Miguel, D.; Jakoby, V.; Gansauer, A.; Cuerva, J. M. Chem. Soc. Rev.
̈
2011, 40, 3525−3537.
(10) Fernan
́
dez-Mateos, A.; Herrero Teijon
́
, P.; Rabanedo Clemente,
R.; Rubio Gonzal
2722.
ez, R.; Sanz Gonzalez, F. Synlett 2007, 17, 2718−
́ ́
(11) Paquette, L. A.; Maleczka, R. E. J. Org. Chem. 1992, 57, 7118−
7122.
(12) Wadsworth, W. S.; Emmons, W. D. Organic Synthesis; Wiley:
New York, 1973; Collect. Vol. V, p 547.
(13) Krapcho, A. P. Synthesis 1982, 805−822.
(14) Liu, H. J.; Ogino, T. Tetrahedron Lett. 1973, 49, 4937−4940.
(15) Fernan
́ ́
dez-Mateos, A.; Pascual Coca, G.; Rubio Gonzalez, R.;
Tapia Hernan
́
dez, C. J. Org. Chem. 1996, 61, 9097−9102.
(16) Pinhey, J. T.; Roche, E. G. J. Chem. Soc., Perkin Trans. 1 1988, 8,
2415−2421.
9578
dx.doi.org/10.1021/jo401646g | J. Org. Chem. 2013, 78, 9571−9578