Synthesis of CDE molecular fragments related to sendanin mediated by titanocene(iii)

Article abstract of DOI:10.1039/c2ob25538c

A practical, brief, and diastereoselective synthesis of limonoid CDE fragments from a readily available starting material is described. The key step was the titanocene(iii)-promoted cyclization of unsaturated epoxylactones, readily prepared from α-cyclocitral. In this way, we confirm the viability of our procedure for the synthesis of a limonoid model with different functionalization patterns. We also report the antifeedant activity of epoxylactones 18 and 19, which show significant antifeedant activity against Spodoptera littoralis and Spodoptera frugiperda, two insect species with different feeding ecologies.

Full text of DOI:10.1039/c2ob25538c

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PAPER
Synthesis of CDE molecular fragments related to sendanin mediated by
titanocene(III)†
A. Fernández-Mateos,*a A. I. Ramos Silvo,a R. Rubio Gonzáleza and M. S. J. Simmondsb
Received 12th March 2012, Accepted 30th May 2012
DOI: 10.1039/c2ob25538c
A practical, brief, and diastereoselective synthesis of limonoid CDE fragments from a readily available
starting material is described. The key step was the titanocene(III)-promoted cyclization of unsaturated
epoxylactones, readily prepared from α-cyclocitral. In this way, we confirm the viability of our procedure
for the synthesis of a limonoid model with different functionalization patterns. We also report the
antifeedant activity of epoxylactones 18 and 19, which show significant antifeedant activity against
Spodoptera littoralis and Spodoptera frugiperda, two insect species with different feeding ecologies.
Introduction
Limonoids are degraded triterpenoids occurring in the Meliaceae
plant family, used in popular medicine with a wide range of bio-
logical properties.1 The 12-oxygenated derivatives of limonoids,
such as sendanin and toosendanin (Fig. 1), are promising com-
pounds of interest because of their multiple bioactivities: anti-
cancer, antibotulinum, antiparasitic, antihelmintic, and
antifeedant.2 Moreover, the 12-oxygenated limonoid derivatives
are potential precursors of the C-seco limonoids: salannin and
azadirachtin, considered the most active of the limonoid family
(Scheme 1).2
Fig. 1 Bioactive limonoids.
Despite their significant bioactivity, little synthetic effort has
been invested in these natural products.3 Studies directed
electrocyclization,5a–l dipolar cycloaddition,4j–l and radical
towards the synthesis of related model compounds have been
cascade reactions.5m
conducted to find simple analogues that display similar biologi-
cal activities.4 Most limonoids contain a structural unit of
hydrindane bonded to a heterocycle, constituting the C, D and E
Results and discussion
rings. Work aimed at the hydrindane angular methyl group is
limited, with few ways of accessing a functionalized C ring.
In previous papers, we described the synthesis of model insect
antifeedants related to toosendanin and trichilins, with oxyge-
nated functions at C-11/C-12 position, with the aim of finding
simple analogues with similar biological activity to that of the
archetype.5 We have developed several procedures aimed at the
synthesis of molecular fragments and analogues, based on the
construction of the pentagonal D ring of limonoids by cationic
In connection with these synthetic studies directed towards the
CDE structural fragments of limonoids with functionalization
patterns on C-12, we have designed a new approach with a view
to confirming the viability of the titanocene(III)-based
procedure.6
Our strategy is based on a stereoselective construction of ring
D by a radical cyclization from epoxy lactone A to hydroxy
lactone B, induced by titanocene chloride, in which the oxyge-
nated functions are situated in the correct position and the rela-
tive orientation of the methyl and γ-lactone substituents is the
same (cis) as in natural limonoids. The replacement of the
characteristic furan (ring E) of limonoids by a γ-lactone, is to
confer a more versatile functionality, and for SAR studies.
We carried out a synthesis of several limonoid fragment
analogues, that differ in the functionalization of rings C and D,
following the sequence in Scheme 2.
aDepartamento de Química Orgánica, Facultad de CC. Químicas,
Universidad de Salamanca, Plaza de los Caídos 1–5, 37008
Salamanca, Spain. E-mail: afmateos@usal.es; Fax: (+34) 923294574;
Tel: (+34)923294481
bJodrell Laboratory, Royal Botanic Garden, Kew, Richmond, Surrey, UK
†Electronic supplementary information (ESI) available: 1H and 13C
spectra of all compounds are given as supplementary information. See
DOI: 10.1039/c2ob25538c
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Scheme 3 Reagents and conditions: (a) (EtO)2POCHCOOEt, toluene,
96%. (b) m-CPBA, CH2Cl2, 87%. (c) LiAlH4, ether, 75%.
Scheme 1 Limonoid biogenetic relationship.
Scheme 4 Reagents and conditions: (a) Cp2TiCl, THF, 25 °C.
with respect to the side chain. The stereochemistry of 3 and 4
was assigned by analogy with a similar epoxysulfone, whose
structure has been determined by X-ray.7
The radical cyclization of the epoxy ester 3 was carried out by
reaction with two equivalents of titanocene chloride generated in
situ in THF at room temperature (Scheme 4). The hydroxy ester
5 was obtained as the only product in quantitative yield. In the
same way, the treatment of the epoxy alcohol 4 with titanocene
afforded the unsaturated alcohol 6, in 60% yield, as a result of
the radical cyclization.6
In both radical cyclizations two stereocentres are created with
absolute stereoselectivity; the ring fusion is cis and the cyclopen-
tane substituent orientation is exo. The stereochemistry of the
bicyclic products 5 and 6 was determined by NOE experiments
(Fig. 2).
We suggest the mechanism shown in Scheme 5 to account for
the regio- and stereochemical outcome of this reaction. An
epoxide reductive opening regioselectively originates the tertiary
radical (F, G), the stable chair conformation of this intermediate
determining the stereoselectivity of the cyclization. The radical
thus generated (F, G) is trapped by the double bond via a 5-exo-
trig process. The stereochemistry of the interannular junction,
which proved to be cis, is in accordance with the general guide-
line formation of 6,5-ring fusions by radical cyclization, which
typically proceed with good to excellent cis selectivity. The exo
selectivity found for the cyclopentane ring substituent is appar-
ently in disagreement with the studies reported by RajanBabu
and Fukunaga, which showed that the direction of selectivity in
Scheme 2 C-12 Oxygenated CDE limonoid fragment synthetic plan.
To examine the possibilities of the synthetic project, in par-
ticular the transformation of the epoxy alcohol A into the diol B,
two simple model compounds were selected as substrates: the
epoxy ester 3 and the epoxy alcohol 4 (Scheme 3). Both com-
pounds were obtained, in two and three steps respectively, from
the aldehyde 1, readily available in turn from α-cyclocitral.4j
Olefination of 1 to the conjugated ester 2 and further epoxida-
tion afforded, chemo- and stereoselectively, the epoxy ester 3,
which after selective reduction with lithium aluminium hydride
afforded the epoxy alcohol 4. In both epoxides, the oxirane is cis
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Fig. 2 NOE values of compounds 5 and 6.
Scheme 6 Reagents and conditions: (a) 2-(2-bromoethyl)-1,3-dioxo-
lane, Li, THF, 65%. (b) AcOH–THF–H2O, reflux, 100%. (c) γ-butyro
lactonylidene triphenyl phosphorane, DME, 41%. (d) m-CPBA, CH2Cl2,
89%.
Scheme 5 Stereochemistry of cyclizations.
the reactions of cyclohexyl radicals with alkenes with a chain
substituent depends on the orientation of the alkenyl side chain.
For rigid cyclohexyl conformers with an equatorial acceptor side
chain, the endo product isomer predominates, while the exo
product is the major isomer with an axial acceptor side chain.8
In our case, the side chain acceptor is equatorial, but the exo
selectivity is evident from Scheme 5, which clearly shows that
the intermediate G, which would afford the endo product, is dis-
favoured with respect to the intermediate F, due to the severe
non-bonded interaction between the side chain and the axial
methyl group.
The success of radical cyclization experiments with models 3
and 4 from the regio- and stereochemical points of view is suit-
able for the construction of a hydrindane with substituents in the
correct place, and the same relative orientation of the angular
methyl group and the cyclopentane side chain as in limonoid
CDE structural fragments. It is worth noting that the cyclization
of the ester 3 is a better model for synthesis than that of alcohol
4, because the yield of cyclic product is higher. This must be due
to the nucleophilic character of the initial radical. The addition
of this radical to the allylic alcohol system of 4 is slower because
the non-cyclic side product 7 was obtained in 20% yield.
The next target in our approach to the synthesis of a limonoid
model was the epoxy lactone 12. The structural features of this
cyclization substrate include the conjugated double bond in the
side chain as a radical acceptor, the γ-lactone as an E ring precur-
sor, and the hydroxyl group geminal to the side chain as a
Scheme 7 Reagents and conditions: (a) Cp2TiCl, THF, 25 °C.
precursor of the cyclopentane double bond present in limonoid
models.
The preparation of epoxy lactone 12 was achieved in four
steps from the readily available trimethylcyclohexenone 8, as
depicted in Scheme 6: the Barbier reaction to introduce the side
chain was followed by ketal deprotection, olefination and epoxi-
dation. While the olefination only afforded one isomer, the
hydroxy lactone 11, oxidation with m-CPBA gave a mixture of
two epoxide isomers α/β, 12a/12b, in a 3 : 1 ratio respectively;
the structural assignation is based on the syn director effect of
the hydroxyl group and the stereochemistry of the subsequent
reaction products.
Synthesis of the α/β isomers 12a and 12b allowed us to
observe their different behaviour against titanocene chloride. The
reaction of each isomer was carried out separately (Scheme 7).
The major isomer 12a, which features a trans relationship
between the oxirane and the side chain, reacts with Cp2TiCl in
THF at room temperature to afford exclusively the bicyclic diol
lactone 13a, with B/C junction rings in trans orientation, in 75%
yield. This is a rare and relevant stereoselective 5-exo cyclization
of a cyclohexyl radical to afford a 6,5-trans ring fusion.9 The
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Fig. 3 NOE values of lactones 13a and 13b.
Scheme 9 Reagents and conditions: (a) m-CPBA, CH2Cl2, 98%. (b)
Dess–Martin reagent, CH2Cl2, 90%.
Desilylation of compound 15 with PPTS afforded the hydroxy
lactone 16 in quantitative yield.
Fragment 17, related to azadiradione, was obtained through
the allylic oxidation of 15 with chromium trioxide–dimethylpyr-
azole. The δ values in the 13C NMR of compound 17 are in
agreement with those described by us for related compounds.5j
The epoxy alcohol 18 was obtained quantitatively by reaction
of the unsaturated hydroxy lactone 16 with m-chloroperbenzoic
acid (Scheme 9). The oxidation is endocyclic and directed by the
hydroxyl group. Dess-Martin oxidation of 18 afforded the ketone
19 in 90% yield.
The structural assignation of the epoxides was based on
experience gained with analogous compounds described by us
elsewhere, in which oxidation with m-CBPA always afforded the
endo-epoxide isomer 18.4d,h,k,n,5d,i,j Additionally, the γ-effect in
the 13C NMR was considered.4d,h,k,n,5d,i,j The difference in the
chemical displacement of the γ-carbon between 18 and 16 was
as expected (6.7 ppm) for these compounds. The shielding effect
of the lactone ring on the protons of the angular methyl group
confirmed the cis relationship between both groups in epoxy lac-
Scheme 8 Reagents and conditions: (a) TBDMSCl, imidazole, DME,
85%. (b) SOCl2, pyr, 90%. (c) PPTS, EtOH, 98%. (d) , CH2Cl2, 68%.
minor isomer 12b, which matches the cis relationship between
the oxirane and the side chain in the former models 3 and 4,
reacts with Cp2TiCl in THF at room temperature to afford exclu-
sively the bicyclic diol lactone 13b, with the B/C junction rings
in cis orientation, in 70% yield. Stereochemical assignments
were based on NOE studies. Some representative data are shown
in Fig. 3.
Within the whole plan for the limonoid fragment synthesis,
lactones 13a and 13b are very important intermediates. The
lactone ring, which constitutes the E limonoid ring, is likely to
be converted into unsaturated lactone, lactol, and furan, all
present in certain natural limonoids. The steps required to obtain
the limonoid fragments from 13a–b are a selective dehydration
of the tertiary alcohol, followed by epoxidation to afford com-
pounds related to sendanin, or by allylic oxidation to obtain
compounds related to azadiradione.
The dehydration step was carried out on 14a–b with thionyl
chloride in almost quantitative yield, after protection of the sec-
ondary alcohol using the corresponding t-butyl dimethyl silyl
ether. The sequence was accomplished separately for 13a and
13b, as shown in Scheme 8. The only product obtained from
either 14a or 14b was the unsaturated lactone 15. It should be
noted that although so far only one enantiomer has been drawn
for convenience for each compound, it is really a racemic
mixture. Therefore in this situation we have represented lactone
15 as an enantiomer, when it is really a racemic mixture. We
chose the enantiomer most similar to the target natural limonoid.
1
tones 18 and 19, which appear in H NMR at 0.82 and 0.90,
respectively. The δ values in the 13C NMR of compounds 18 and
19 are in agreement with the endo-epoxides described by us
elsewhere.4d,h,k,n,5d,i,j
Both hydroxy lactone 18 as 19 are structural fragments related
to the limonoids sendanin and toosendanin.
Biological results
Larvae of the African leafworms Spodoptera littoralis and
Spodoptera frugiperda were used to assess the antifeedant
activity of our molecular fragments.10 In the series of model
compounds related to toosendanin, the racemic epoxy lactones
18 and 19 exhibited similar antifeedant values when compared
with the phenyl (ring E) fragment (Fig. 4).4n
Conclusions
A new synthetic approach to 18 and 19, CDE fragments of limo-
noids related to sendanin, has been achieved from trimethyl-
cyclohexenone in nine and ten steps, with overall yields of 14%
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dried (Na2SO4), and filtered. After removal of the solvent, the
crude product was purified by flash chromatography.
(E)-Ethyl 5-(2,6,6-trimethylcyclohex-2-enyl)-pent-2-enoate 2.
A dry three-necked flask equipped with stirrer, condenser, and
dropping funnel was purged with argon and charged with a 60%
dispersion oil of sodium hydride in mineral oil (117 mg,
2.91 mmol) and dry toluene (0.9 mL). To this stirred mixture at
25 °C was added dropwise triethyl 2-phosphonoacetate (0.6 mL,
3.06 mmol), and the mixture was stirred for 30 min at room
temperature to ensure complete reaction. To this nearly clear sol-
ution was added dropwise the aldehyde 1 (500 mg, 2.78 mmol)
in toluene (0.6 mL). The mixture was stirred for an additional
16 h and diluted with ether, and water was then added dropwise.
The organic layer was separated, and the aqueous phase was
extracted with ether. The combined extracts were washed with
brine and dried (Na2SO4), the solvent was evaporated and the
residue was chromatographed on silica gel. Elution with hexane–
ether (97 : 3) gave unsaturated ester 2 as a colorless oil (671 mg,
96%): 1H NMR (δ): 0.87 (3H, s), 0.91 (3H, s), 1.28 (3H, t, J = 7
Hz), 1.4–2.1 (7H, m), 1.65 (3H, br s), 2.21 (2H, m), 4.18 (2H, q,
J = 7 Hz), 5.31 (1H, br s), 5.80 (1H, dt, J = 1.6 Hz, J′ = 15.6
Hz), 6.95 (1H, dt, J = 6.8 Hz, J′ = 15.6 Hz) ppm; 13C NMR (δ):
14.2, 22.9, 23.3, 27.3, 27.5, 29.4, 31.5, 32.5, 32.6, 48.9, 59.9,
120.6, 121.2, 135.9, 149.2, 166.5 ppm; IR: 2934, 1724,
1655 cm−1; MS EI, m/z (relative intensity): 250 (M+, 1), 235 (2),
204 (1), 162 (5), 137 (13), 114 (19), 95 (10), 81 (100), 67 (12),
55 (20); HRMS: for C16H26O2 + Na: 273.1830, found.
273.1833.
Fig. 4 Antifeedant index of the compounds tested in choice bioassays
at 100 ppm. [Antifeedant index = [(C − T)/(C + T)]% of compounds
tested in choice bioassavs with glass discs (control (C) vs. treatment (T),
n = 20].
and 12.5% respectively. The required D ring was formed by the
titanocene(III)-promoted cyclization of unsaturated epoxy lac-
tones, with total stereoselectivity. The versatility of the method
allows it to be applied to the synthesis of more complicated
limonoids. The racemic lactones 18 and 19 showed significant
antifeedant activity against larvae of the African leafworms
Spodoptera littoralis and Spodoptera frugiperda.
Experimental section
General methods
1
Melting points are uncorrected. H 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), except where indicated otherwise. IR spectra were
recorded for neat samples on NaCl plates, unless otherwise
noted. Standard mass spectrometry data were acquired using a
GC-MS system in EI mode with a maximum m/z range of 600.
When required, all solvents and reagents were purified by stan-
dard techniques: tetrahydrofuran (THF) was purified by distilla-
tion from sodium and benzophenone and was degassed before
use. All reactions were conducted under a positive pressure of
argon, using 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). The yields reported
are for chromatographically pure isolated products unless other-
wise mentioned.
(E)-Ethyl 5-((1S*,2S*,6R*)-1,3,3-trimethyl-7-oxa-bicyclo [4.1.0]-
heptan-2-yl)pent-2-enoate 3. To a stirred solution of 2 (200 mg,
0.8 mmol) in CH2Cl2 (6 mL) was added m-CPBA (138 mg,
0.8 mmol) and Na2CO3 (6.7 mg, 0.08 mmol). The reaction
mixture was stirred under argon at room temperature for 3 h.
Then, Na2SO3 (10%) was added and the resulting heterogeneous
mixture was vigorously stirred for 15 min. The organic layer was
separated and the aqueous phase was extracted with CH2Cl2.
The combined organic extract was washed with sat. NaHCO3
and brine. Removal of the solvent afforded a crude residue,
which was purified by flash chromatography. Eluting with
hexane–Et2O (90 : 10) furnished epoxide 3 (185 mg, 87%), as a
colourless oil. 1H NMR (δ): 0.80 (3H, s), 0.88 (3H, s), 1.28 (3H,
t, J = 7 Hz), 1.32 (3H, s), 1.4–2.5 (9H, m), 2.94 (1H, br s), 4.17
(2H, q, J = 7 Hz), 5.85 (1H, dt, J = 1.5 Hz, J′ = 15.6 Hz), 7.00
(1H, dt, J = 7 Hz, J′ = 15.6) ppm; 13C NMR (δ): 14.2, 22.0,
26.0, 26.8 (2), 27.2, 27.6, 31.4, 31. 7, 46.7, 59.1, 60.0 (2C),
121.3, 149.3, 166.6 ppm; IR: 2957, 1723, 1655, 1196 cm−1; MS
EI, m/z (relative intensity): 266 (M+, 1), 251 (1), 233 (1), 205
(2), 153 (81), 125 (32), 95 (27), 81 (48), 69 (40), 55 (100);
HRMS: for C16H26O3 + Na, 289.1780, found. 289.1782.
General procedure 1 (GP1)
A mixture of Cp2TiCl2 (2.20 mmol) and Zn (6.60 equiv) in
strictly deoxygenated THF (10 mL) was stirred at room tempera-
ture until the red solution turned green. In a separate flask, the
epoxy compound (1 mmol) was dissolved in strictly deoxyge-
nated THF (10 mL). The green Ti(III) solution was slowly added
via cannula to the epoxide solution. After 30 min, an excess of
saturated NaH2PO4 was added, and the mixture was stirred for
20 min. The mixture was filtered to remove insoluble titanium
salts. The product was extracted into ether, and the combined
organic layers were washed with saturated NaHCO3 and brine,
(E)-5-((1S*,2S*,6R*)-1,3,3-Trimethyl-7-oxa-bicyclo[4.1.0] heptan-
2-yl) pent-2-en-1-ol 4. LiAlH4 (17 mg, 0.4 mmol) was added to
a solution of the unsaturated ester 3 (106 mg, 0.4 mmol) in
diethyl ether (2.3 ml). The reaction mixture was vigorously
stirred at room temperature under argon for 1 h, after which it
was quenched with Na2SO4·10H2O. The resulting mixture was
filtered, and then the filtrate was evaporated under reduced
pressure to afford unsaturated alcohol 4 as a colorless oil (67 mg,
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1
75%): H NMR (δ): 0.80 (3H, s), 0.88 (3H, s), 1.2–2.4 (9H, m),
brine. Removal of the solvent afforded a crude residue, which
1.33 (3H, s), 2.93 (1H, br s), 4.08 (2H, d, J 4.8 Hz), 5.71 (2H,
m) ppm; 13C NMR (δ): 22.0, 26.8 (2), 27.0, 27.3, 27.7, 31.4,
31.8, 46.6, 59.5, 60.0, 63.8, 128.9, 133.6 ppm; IR: 3447, 2930,
1456 cm−1; HRMS: for C14H24O2 + Na, 247.1674, found.
247.1672.
was purified by flash chromatography. Eluting with hexane–Et2O
(80 : 20) gave the alcohol 9 as a colorless oil (7.9 g, 65%). H
NMR (δ): 0.93 (3H, s), 0.95 (3H, s), 1.1–2.1 (9H, m), 1.71 (3H,
s), 3.90 (4H, m), 4.81 (1H, t, J = 3.9 Hz), 5.38 (1H, br s) ppm;
IR: 3516, 2961, 1451. 1142 cm−1; HRMS: for C14H24O3 + Na,
263.1623, found. 263.1624.
1
Reaction of 3 with Cp2TiCl
(E)-3-(3-(1-Hydroxy-2,6,6-trimethylcyclohex-2-enyl) propyli-
dene)-dihydrofuran-2(3H)-one 11. A solution of 9 (3.88 g,
16.2 mmol) in a mixture of 3 : 1 : 1 AcOH–THF–H2O (40.4 mL)
was stirred under argon at reflux for 3 h. Then, the mixture was
cooled to room temperature and an aqueous solution of 5%
NaHCO3 was added to quench the reaction. The organic layer
was separated and the aqueous phase was extracted with ether.
The combined organic extracts were washed with saturated
NaHCO3 and brine. Removal of the solvent afforded a mixture
of lactols 10 as a colorless oil (3.16 g, 100%), which where used
According to GP1, reaction of 3 (67 mg, 0.25 mmol) with
Cp2TiCl followed by flash chromatography (hexane 8 : 2 diethyl
ether) furnished ethyl 2-((1S*,3aS*,7R*,7aS*)-7-hydroxy-4,4,7a-
trimethyl-octahydro-1H-inden-1-yl)acetate 5 as a colorless oil
1
(65 mg, 98%): H NMR (δ): 0.83 (3H, s), 0.89 (3H, s), 0.99
(3H, s), 1.2–2.6 (10H, m), 1.23 (3H, t, J = 7 Hz), 2.10 (1H, dd,
J = 9 Hz, J′ = 15.6 Hz), 2.90 (1H, dd, J = 4 Hz, J′ = 15 Hz),
3.58 (1H, dd, J = 5 Hz, J′ = 11 Hz), 4.10 (2H, q, J = 7 Hz) ppm;
13C NMR (δ): 14.2, 23.5, 24.3, 24.7, 27.6, 31.2, 32.7 (2C), 37.4,
38.0, 38.3, 48.1, 57.9, 60.0, 78.2, 174.7 ppm; IR: 3476, 2947,
1738, 1032 cm−1; MS EI, m/z (relative intensity): 268 (M+, 1),
250 (1), 235 (3), 211 (12), 168 (100), 123 (63), 93 (35), 81 (80),
69 (32), 55 (67); HRMS: for C16H28O3 + Na, 291.1936, found.
291.1933.
1
for further reaction without any purification; H NMR (δ: 0.81
(3H, s), 0.89 (3H, s), 0.96 (6H, s), 1.2–2.2 (16H, m), 1.63 (3H,
s), 1.76 (3H, s), 5.30 (1H, br s), 5.38 (1H, br s), 5.61 (2H, br s)
ppm; IR: 3410, 2972, 2917, 1723 cm−1
.
A solution of lactol 10 (882 mg, 4.50 mmol), benzoic acid
(112 mg, 0.92 mmol), and γ-butyro-lactonylidene triphenyl
phosphorane (4.27 g, 12.35 mmol) in dry DME (40 mL) was
stirred at reflux for 2 d under argon. When the reaction was com-
plete the solvent were evaporated in vacuo and the residue was
purified by flash chromatography (3 : 7 hexane–ethyl acetate) to
Reaction of 4 with Cp2TiCl
According to GP1, reaction of 4 (52 mg, 0.23 mmol) with
Cp2TiCl followed by flash chromatography (hexane 80 : 20
diethyl ether) furnished (3S*,3aS*,4R*,7aS*)-3a,7,7-trimethyl-3-
vinyl-octahydro-1H-inden-4-ol 6 as a colorless oil (21 mg,
1
give 11 as a colorless oil (487 mg, 41%), H NMR (δ): 0.95
(3H, s), 0.97 (3H, s), 1.5–2.4 (8H, m), 1.74 (3H, br s), 2.87 (2H,
dt, J = 2.7 Hz, J′ = 6 Hz), 4.36 (2H, t, J = 7.4 Hz), 5.45 (1H, br
s), 6.71 (1H, m) ppm; 13C NMR (δ): 19.5, 22.6, 23.0, 24.3,
25.1, 26.9, 34.2, 35.8, 37. 8, 65.5, 77.1, 124.4, 125.1, 137.0,
141.5, 171.4 ppm; IR: 3511, 2922, 1751, 1678 cm−1; MS EI,
m/z (relative intensity): 264 (M+, 3), 246 (8), 231 (6), 208 (17),
139 (92), 125 (52), 112 (74), 95 (100), 79 (34); HRMS: for
C16H24O3 + Na, 287.1623, found. 287.1624.
1
60%). H NMR (δ): 0.83 (3H, s), 0.92 (3H, s), 1.09 (3H, s),
1.2–2.0 (10H, m), 3.50 (1H, dd, J = 6 Hz, J′ = 10 Hz), 4.96 (1H,
dd, J = 2 Hz, J′ = 9.5 Hz), 5.08 (1H, dd, J = 2 Hz, J′ = 17 Hz),
5.95 (1H, ddd, J = 17 Hz, J′ = 9.5 Hz, J′′ = 9.6 Hz) ppm; 13C
NMR (δ): 23.6, 24.3, 25.2, 27.7, 30.5, 32.7 (2C), 37.9, 46.6,
49.9, 58.1, 78.6, 114.7, 143.4 ppm; IR: 3447, 2953, 1456,
1042 cm−1; MS EI, m/z (relative intensity): 208 (M+, 3), 194 (3),
175 (10), 139 (49), 93 (58), 69 (36), 55 (73), 41 (100). HRMS:
for C14H24O + Na, 231.1725, found. 231.1726. Eluting with
hexane–Et2O (5 : 95) furnished (1R*,3S*)-3-(5-hydroxypentyl)-
4,4-dimethyl-2-methyl-ene-cyclohexanol 7 as a colorless oil
Epoxidation of 11
To a stirred solution of 11 (304 mg, 1.15 mmol) in CH2Cl2
(6 mL) was added m-CPBA (198 mg, 1.15 mmol) and Na2CO3
(1.6 mg, 0.015 mmol). The reaction mixture was stirred under
argon at room temperature for 150 min. Then, Na2SO3 (10%)
was added and the resulting heterogeneous mixture was vigor-
ously stirred for 15 min. The organic layer was separated and the
aqueous phase was extracted with CH2Cl2. The combined
organic extract was washed with sat. NaHCO3 and brine.
Removal of the solvent afforded a crude residue, which was
purified by flash chromatography. Eluting with hexane–Et2O
(4 : 6) furnished (E)-3-(3-((1R*,2R*,6R*)-2-hydroxy-1,3,3-tri-
methyl-7-oxa-bicyclo[4.1.0]heptan-2-yl)-propylidene)-dihydro-
furan-2(3H)-one 12b as a white solid (78 mg, 24%), m.
1
(10 mg, 20%): H NMR (δ): 0.69 (3H, s), 0.95 (3H, s), 1.2–1.7
(13H, m), 3.64 (2H, t, J = 6.4 Hz), 3.96 (1H, br s), 4.70 (1H, br
s), 5.17 (1H, br s) ppm; 13C NMR (δ): 25.4, 26.1, 28.0, 29.5,
29.6, 30.3, 32.7, 33.3, 35.7, 51.6, 63.0, 73.8, 104.6, 150. 9 ppm;
IR: 3398, 2964 cm−1; MS EI, m/z (relative intensity): 208
(M+–H2O, 3), 193 (4), 175 (3), 122 (52), 107 (100), 91 (30), 79
(37), 55 (57), 41 (91); HRMS: for C14H26O2 + Na, 249.1830,
found. 249.1835.
1-(2-(1,3-Dioxolan-2-yl)ethyl)-2,6,6-trimethylcyclohex-2-enol 9.
To a stirred suspension of Li (1.24 g, 117 mmol) in THF
(64 mL) was added a solution of 2-(2-bromoethyl)-1,3-dioxolane
(1.37 mL, 76.1 mmol) and 2,6,6-trimethyl-2-cyclohexenone
(7 g, 50.7 mmol). The resulting mixture was stirred under argon
for 1 h at room temperature, and then 2 M HCl was added at
0 °C, and the heterogeneous mixture stirred for 5 min. The
organic layer was separated and the aqueous phase was extracted
with ether. The combined organic extracts were washed with
1
p. 130 °C, H NMR (δ): 0.80 (3H, s), 0.91 (3H, s), 1.1–2.1 (8H,
m), 1.43 (3H, s), 2.63 (1H, d, J = 1.5 Hz), 2.90 (1H, m), 3.17
(1H, br s), 4.38 (2H, t, J = 7.5 Hz), 6.77 (1H, m) ppm; 13C
NMR (δ): 21.3, 21.5, 21. 8, 24.1, 25.1, 26.4, 28.5, 31.2, 37.2,
62.1, 65.0, 65.3, 73.1, 124.9, 141.3, 171.2; IR: 3511, 2934,
1744, 1678 cm−1; MS EI, m/z (relative intensity): 280 (M+, 5),
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5620–5628 | 5625

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264 (6), 223 (7), 205 (9), 149 (100), 126 (29), 109 (31), 95 (37),
81 (47); HRMS: for C16H24O4 + Na, 303.1572, found.
303.1571. Eluting with hexane–Et2O (2 : 8) furnished a white
solid identified as (E)-3-(3-((1S*,2R*,6S*)-2-hydroxy-1,3,3-tri-
methyl-7-oxa-bicyclo[4.1.0]heptan-2-yl)propylidene)-dihydro-
furan-2(3H)-one 12a (209 mg, 65%), m.p. 100–104 °C; 1H
NMR (δ): 0.84 (3H, s), 0.92 (3H, s), 1.0–2.0 (8H, m), 1.38 (3H,
s), 2.53 (1H, m), 2.94 (1H, m), 2.98 (1H, br s), 4.37 (2H, t, J =
7.5 Hz), 6.77 (1H, m) ppm; 13C NMR (δ): 21.6, 21.9, 22.1,
23.7, 25.1, 25.6, 30.0, 33.9, 36.6, 60.8, 61.1, 65.3, 75.7, 125.3,
141.2, 171.4 ppm; IR: 3520, 1741, 1675 cm−1; MS EI, m/z (rela-
tive intensity): 280 (M+, 3), 262 (3), 219 (7), 181 (10), 153 (20),
125 (74), 112 (100), 95 (67), 81 (57); HRMS: for C16H24O4 +
Na, 303.1572, found. 303.1570.
(125 mg, 85%), which was used for further reaction without any
purification; H NMR (δ): 0.06 (3H, s), 0.16 (3H, s), 0.86 (9H,
s), 0.93 (3H, s), 1.03 (6H, s), 1.1–2.2 (12H, m), 4.20 (3H, m)
ppm.
1
To a stirred solution of the alcohol 14a (123 mg, 0.31 mmol) in
CH2Cl2 (2 mL) and pyridine (0.04 mL, 0.63 mmol), at 0 °C was
added SOCl2 (0.06 ml, 0.94 mmol). After 75 min at this temp-
erature, the mixture was poured into ice water and stirred for an
additional 20 min at room temperature. The two-phase system
was extracted with ether. The combined ethereal extracts were
washed with 2 N HCl, 5% NaHCO3, water and brine, dried
(Na2SO4) and concentrated in vacuo to give the silyloxy ester 15
1
as a white solid (105 mg, 90%), m.p. 55 °C; H NMR (δ): 0.02
(3H, s), 0.05 (3H,s), 0.86 (12H, s), 1.08 (3H, s), 1.11 (3H, s),
1.9–2.3 (8H, m), 2.62 (1H, dd, J = 9 Hz, J′ = 18 Hz), 2.97 (1H,
m), 4.22 (3H, m), 5.34 (1H, br s), ppm; 13C NMR (δ): −5.0,
−4.3, 16.2, 19.0, 26.0 (3C), 26.2, 28.4, 29.6, 31.5, 32.6, 33.3,
33.4, 39.7, 42.5, 52.2, 66.1, 71.7, 119.0, 155.9, 178.2 ppm; IR:
2930, 1775, 1080 cm−1; MS EI, m/z (relative intensity): 363
(M+–Me, 3), 321 (100), 246 (34), 161 (73), 119 (44), 91 (30),
75 (54), 55 (30), 41 (35); HRMS: for C22H38O3Si + Na,
401.2488, found. 401.2489.
Reaction 12a with Cp2TiCl
According to GP1, reaction of 12a (175 mg, 0.62 mmol) with
Cp2TiCl followed by flash chromatography (hexane 7 : 3 diethyl
ether) furnished
a white solid identified as ethyl 3-
((1R*,3aR*,7S*,7aS*)-3a,7-dihydroxy-4,4,7a-trimethyloctahy-
dro-1H-inden-1-yl)dihydrofuran-2(3H)-one 13a (131 mg, 75%),
1
m.p. 150–156 °C, H NMR (δ): 0.95 (3H, s), 1.03 (3H, s), 1.07
From compound 13b. A mixture of the hydroxy ester 13b
(28 mg, 0.10 mmol), tert-butyldimethylsilyl chloride (66 mg,
0.43 mmol), and imidazole (59 mg, 0.85 mmol) in dry DMF
(1 mL) was stirred for 2 d under argon at 25 °C, poured into ice
water, and extracted with hexane. The extract was washed with
water and brine, dried (Na2SO4) and concentrated in vacuo. The
residue was filtered though a small pad of silica gel, and concen-
trated to yield the silyloxy alcohol 14b, as a colorless oil
(34 mg, 86%), which was used for further reaction without any
(3H, s), 1.2–1.9 (7H, m), 2.08 (1H, m), 2.24 (1H, m), 2.45 (1H,
m), 2.80 (1H, m), 2.89 (1H, m), 3.70 (1H, dd, J = 3 Hz, J′ = 5.5
Hz), 4.14 (1H, m), 4.30 (1H, dt, J = 2.6 Hz, J′ = 9 Hz) ppm; 13
C
NMR (δ): 18.4, 23.6, 24.2, 25.7, 26.3, 27.7, 32.3, 35.8, 37.1,
41.8, 43.7, 51.0, 66.6, 75.8, 85.2, 180.8 ppm; IR: 3464, 2943,
1739, 1215 cm−1; MS EI, m/z (relative intensity): 264
(M+–H2O, 2), 249 (8), 231 (4), 213 (7), 195 (6), 178 (21),
123 (31), 97 (100), 86 (45), 55 (52), 43 (84); HRMS: for
C16H26O4 + Na, 305.1729, found. 305.1731.
1
purification; H NMR (δ): 0.06 (3H, s), 0.13 (3H, s), 0.88 (9H,
s), 1.01 (3H, s), 1.05 (6H, s), 1.1–2.2 (12H, m), 4.25 (3H, m)
ppm.
Reaction 12b with Cp2TiCl
To a stirred solution of the alcohol 14b (34 mg, 0.09 mmol) in
CH2Cl2 (0.5 mL) and pyridine (0.03 mL, 0.52 mmol), at 0 °C
was added SOCl2 (0.03 ml, 0.35 mmol). After 12 h at this temp-
erature, the mixture was poured into ice water and stirred for an
additional 20 min at room temperature. The two-phase system
was extracted with ether. The combined ethereal extracts were
washed with 2 N HCl, 5% NaHCO3, water and brine, dried
(Na2SO4) and concentrated in vacuo to give the silyloxy ester 15
(32 mg, 95%).
According to GP1, reaction of 12b (76 mg, 0.27 mmol) with
Cp2TiCl followed by flash chromatography (hexane 7 : 3 diethyl
ether) furnished ethyl 3-((1R*,3aR*,7R*,7aR*)-3a,7-dihydroxy-
4,4,7a-trimethyloctahydro-1H-inden-1-yl)dihydrofuran-2(3H)-
one 13b as a colorless oil (46 mg, 60%), 1H NMR (δ): 0.89 (3H,
s), 1.02 (3H, s), 1.06 (3H, s), 1.3–2.5 (10H, m), 2.66 (1H, m),
3.05 (1H, m), 4.02 (1H, br s), 4.48 (1H, m), 4.84 (1H, m) ppm;
13C NMR (δ): 17.5, 24.5, 25.0, 25.6, 27.2, 28.7, 29.6, 30.1,
37.9, 39.3, 40.2, 49.8, 67.5, 72.9, 87.3, 181.7 ppm; IR: 3422,
2926, 1750, 1365 cm−1; MS EI, m/z (relative intensity): 264
(M+–H2O, 3), 246 (9), 231 (13), 203 (4), 178 (46), 161 (48),
145 (31), 123 (49), 105 (31), 86 (78), 55 (63), 41 (100); HRMS:
for C16H26O4 + Na, 305.1729, found. 305.1727.
3-((1S*,7R*,7aS*)-7-Hydroxy-4,4,7a-trimethyl-2,4,5,6,7,7a-
hexahydro-1H-inden-1-yl)dihydro furan-2(3H)-one 16. To a sol-
ution of the silyloxy compound 15 (16 mg, 0.04 mmol) in EtOH
(0.5 mL) was added PPTs (20 mg, 0.08 mmol). The reaction
mixture was refluxed for 48 h under argon, and then concentrated
to afford a residue, which was dissolved in H2O and extracted
with Et2O. The combined organic extracts were washed with
brine, and dried with Na2SO4. Removal of the solvent afforded a
3-((1R*,7R*,7aS*)-7-(tert-Butyldimethylsilyloxy)-4,4,7a-trimethyl-
2,4,5,6,7,7a-hexahydro-1H-inden-1-yl) dihydrofuran-2(3H)-one 15
From compound 13a. A mixture of the hydroxy ester 13a
(105 mg, 0.37 mmol), tert-butyldimethylsilyl chloride (231 mg,
1.49 mmol), and imidazole (209 mg, 3.07 mmol) in dry DMF
(1 mL) was stirred for 7 d under argon at 25 °C, poured into ice
water, and extracted with hexane. The organic layer was washed
with water and brine, dried (Na2SO4) and concentrated in vacuo.
The residue was filtered though a small pad of silica gel, and
concentrated to yield silyloxy alcohol 14a as a colorless oil
1
colorless oil identified as 16 (11 mg, 98%): H NMR (δ): 1.06
(3H, s), 1.11 (3H, s), 1.12 (3H, s), 1.1–2.4 (9H, m), 2.77 (2H,
m), 3.99 (1H, t, J = 3 Hz), 4.24 (1H, m), 4.33 (1H, dt, J = 3 Hz,
J′ = 8 Hz), 5.44 (1H, br s) ppm; 13C NMR (δ): 18.3, 25.9, 28.9,
29.3, 31.1, 32.6, 33.0, 33.5, 39.3, 42.9, 51.4, 66.9, 70.8, 120.2,
156.4, 180.3 ppm; IR: 3511, 2930, 2857, 1750 cm−1; MS EI,
m/z (relative intensity): 264 (M+, 3), 246 (21), 161 (100), 145
5626 | Org. Biomol. Chem., 2012, 10, 5620–5628
This journal is © The Royal Society of Chemistry 2012

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1
(51), 121 (62), 105 (52), 91 (36), 77 (29), 55 (39); HRMS: for
C16H24O3 + Na, 287.1623, found. 287.1622.
a colorless oil (10 mg, 90%), H NMR (δ): 0.90 (3H, s), 1.31
(3H, s), 1.33 (3H, s), 1.5–2.7 (10H, m), 2.98 (1H, dt, J = 5 Hz,
J′ = 9 Hz), 3.44 (1H, br s), 4.20 (1H, dd, J = 7 Hz), 4.31 (2H,
dt, J = 3.8 Hz, J′ = 8.2 Hz), ppm; 13C NMR (δ): 17.5, 26.7,
27.3, 28.1 (2C), 32.4, 36.2, 36.6, 36.9, 38.9, 54.1, 55.7, 65.8,
73.5, 178.1, 213.5 ppm; IR: 2928, 2857, 1771, 1717 cm−1; MS
EI, m/z (relative intensity): 278 (M+, 4), 263 (6), 249 (18), 223
(19), 207 (32), 177 (99), 149 (24), 133 (38), 91 (45), 77 (40), 55
(100), HRMS: for C16H24O4 + Na, 301.1416, found. 301.1418.
3-((1S*,7R*,7aS*)-7((tert-Butyldimethylsilyl)oxy)-4,4,7a-trimethyl-
2-oxo-2,4,5,6,7,7a-hexahydro-1H-inden-1-yl) dihydrofuran-2(3H)-
one 17. A suspension of CrO3 (107 mg, 1.07 mmol) in CH2Cl2
(1 ml) was added 3,5-dimethylpyrazole (107 mg, 1.07 mmol)
under argon at −25 °C. After 15 min, a solution of the com-
pound 15 (32 mg, 0.09 mmol) in CH2Cl2 (1 ml) was added
dropwise. The reaction mixture was stirred for a further 3 h, and
2 M NaOH (0.8 ml, 1.6 mmol) was added, and stirring was con-
tinued for a further 10 min at 0 °C. Then, it was allowed to
warm to room temperature, the organic layer was separated and
the aqueous phase was extracted with CH2Cl2. The combined
extracts were washed with 2 M HCl, water, dried (Na2SO4) and
filtered. Removal of the solvent afforded a crude residue, which
was purified by flash chromatography. Eluting with hexane–Et2O
References
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1
(4 : 6) furnished ketone 17 as a colorless oil (24 mg, 68%), H
NMR (δ): 0.06 (3H, s), 0.08 (3H, s), 0.86 (9H, s), 1.20 (3H, s),
1.24 (3H, s), 1.30, (3H, s), 1.6–2.6 (7H, m), 3.63 (1H, d, J = 4.5
Hz), 3.96 (1H, d, J = 3.8 Hz), 4.20 (1H, dd, J = 2.1 Hz, J′ = 8.3
Hz), 4.40 (1H, dt, J = 2.8 Hz, J′ = 8.9 Hz), 5.89 (1H, s) ppm;
13C NMR (δ): −5.3, −4.3. 18.0, 23.4, 25.4, 25.8 (3C), 26.7,
28.3, 31.2, 33.3, 35.4, 36.6, 52.7, 53.2, 66.5, 71.6, 126.5, 178.2,
191.4, 206.8 ppm; IR: 2926, 1778, 1690 cm−1; MS EI, m/z (rela-
tive intensity): 392 (M+, 6), 355 (100), 263 (6), 177 (38), 75
(43); HRMS: for C22H36O4Si + Na, 415.2281, found. 415.2283.
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Jpn., 1998, 56, 1014; (b) B. Heasley, Eur. J. Org. Chem., 2011, 19. Syn-
thesis of azadiradione: (c) E. J. Corey, J. G. Reid, A. G. Myers and
R. W. Hahl, J. Am. Chem. Soc., 1987, 109, 918–919; (d) E. J. Corey and
R. W. Hahl, Tetrahedron Lett., 1989, 30, 3023–3026; (e) D. C. Behenna
and E. J. Corey, J. Am. Chem. Soc., 2008, 130, 6720–6721. Synthesis of
azadirachtin: (f) S. V. Ley, A. A. Denholm and A. A. Wood, Nat. Prod.
Rep., 1993, 10, 109–157; (g) G. E. Veitch, A. Boyer and S. V. Ley,
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Chem., Int. Ed., 2008, 47, 34–37. Synthetic dumsin studies:
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3((1aR*,3S*,3aR*,4R*,7aS*)-4-Hydroxy-3a,7,7-trimethylocta-
hydroindeno[1,7a-b]oxiren-3-yl)-dihydrofuran-2(3H)-one 18. To
a stirred solution of 16 (11 mg, 0.04 mmol) in CH2Cl2 (1 mL)
was added m-CPBA (7 mg, 0.04 mmol). The reaction mixture
was stirred under argon at room temperature for 120 min. Then,
Na2SO3 (10%) was added and the resulting heterogeneous
mixture was vigorously stirred for 15 min. The organic layer was
separated and the aqueous phase was extracted with CH2Cl2.
The combined organic extract was washed with sat. NaHCO3
and brine. Removal of the solvent afforded a crude residue,
which was purified by flash chromatography. Eluting with
hexane–Et2O (4 : 6) furnished epoxide 18 as a colorless oil
Azadiradione study:
(l) A. Fernández-Mateos, A. López Barba,
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González and C. Tapia Hernández, Tetrahedron, 1997, 53, 14131–14140.
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50, 1309–1313; (b) T. Tokoroyama, Y. Fukuyama and Y. Kotsuji,
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1990, 38, 1400–1403; (d) A. Fernández-Mateos and J. A. de la Fuente,
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(g) A. Fernández-Mateos and A. López Barba, J. Org. Chem., 1995, 60,
3580–3585; A. Fernández-Mateos, G. Pascual Coca, R. Rubio González
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la Fuente, J. J. Marugán, S. S. Cross, A. Fernández-Mateos, S. García
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1
(11 mg, 98%), H NMR (δ): 0.82 (3H, s), 1.10 (3H, s), 1.19
(3H, s), 1.6–2.5 (11H, m), 3.35 (1H, br s), 4.17 (1H, br s), 4.19
(1H, m), 4.34 (1H, dt, J = 2.5 Hz, J′ = 8.3 Hz), ppm; 13C NMR
(δ): 17.4, 26.3, 26.5, 27.6, 28.7, 31.0, 31.7, 33.2, 36.2, 38.8,
45.8, 54.5, 66.4, 71.6, 73.2, 178.5; IR: 3505, 2928, 1763,
1458 cm−1; MS EI, m/z (relative intensity): 280 (M+, 2), 262 (7),
247 (18), 229 (14), 177 (58), 139 (53), 119 (37), 95 (44), 86
(47), 55 (100), HRMS: for C16H24O4 + Na, 303.1572, found.
303.1575.
(1aR*,3S*,3aS*,7aS*)-3a,7,7-Trimethyl-3-(2-oxotetrahydro-
furan-3-yl)hexahydroindeno[1,7a-b]oxiren-4(5H)-one 19. To
a solution of the epoxy-alcohol 18 (11 mg, 0.04 mmol) in
CH2Cl2 (0.6 mL) were added Dess–Martin reagent (20 mg,
0.05 mmol). The reaction mixture was stirred under argon at
room temperature for 20 h, after which it was diluted with
CH2Cl2. The solution was washed with 5% NaHCO3, 10%
Na2SO3, and brine, dried (Na2SO4). Removal of the solvent
afforded a crude residue, which was purified by flash chromato-
graphy. Eluting with hexane–Et2O (2 : 8) furnished ketone 19 as
This journal is © The Royal Society of Chemistry 2012
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