Synthetic studies on azadirachtin: An efficient asymmetric synthesis of the highly functionalized tricyclic decalin part of azadirachtin

Article abstract of DOI:10.1055/s-2000-8224

The detailed examination of intramolecular Diels-Alder reactions of several structurally related trienes led to construction of the desired tricyclic decalin moiety of azadirachtin with the α-hydroxyl groups at C1 and C3 as well as the oxygenated substituent at C8 in the naturally occurring form in good yields.

Full text of DOI:10.1055/s-2000-8224

1894
SPECIAL TOPIC
Synthetic Studies on Azadirachtin: An Efficient Asymmetric Synthesis of the
Highly Functionalized Tricyclic Decalin Part of Azadirachtin
Yuuko Yamamoto,a Jun Ishihara,a Naoki Kanoh,a,b Akio Murai*a
aDivision of Chemistry, Graduate School of Science, Hokkaido University, Sapporo, 060-0810, Japan
Fax +81(11)7062714; E-mail: amurai@sci.hokudai.ac.jp
bPresent address: Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
Received 23 July 2000; revised 9 August 2000
calculations were made by MM2* force-field using the
Abstract: The detailed examination of intramolecular Diels-Alder
parameters devised by Houk4 for the transition state mod-
el of IMDA reactions. The relative energies in the transi-
reactions of several structurally related trienes led to construction of
the desired tricyclic decalin moiety of azadirachtin with the a-hy-
tion states of four possible presumable 1,3-diol adducts
having a methyl group at the dienyl carbon, which consist
of two endo-adducts a and b, and two exo-adducts c and d
are shown in the Table. Based on the energy of the transi-
tion state to 8a having the desired configuration, there is
little difference between other possible diastereoisomers
(entry 1. 8a, 0.0 kcal/mol; 8b, -0.1 kcal/mol, 8c,+0.6
kcal/mol; 8d,+0.7 kcal/mol). Next, the corresponding en-
ergies were compared in the case of the bistriethylsilyl
(di-TES) ether adducts including two endo-adducts 9a
(desired) and 9b, and two exo-adducts 9c and 9d (entry 2).
Different tendencies were seen in this case comparing
with that of the diol (9a, 0.0 kcal/mol; 9b, -1.9 kcal/mol;
9c, -0.29 kcal/mol; 9d, -1.7 kcal/mol). It should be noted
that the undesired endo-adduct 9b as well as an exo-ad-
duct 9d could be preferentially formed rather than the de-
sired endo-compound 9a. Then, we supposed that, if the
two dihydroxy groups could be blocked by some cyclic
protecting group, the conformation in the transition state
might be essentially changed. We calculated the relative
energies in the case of the cyclic carbonate (entry 3). The
desired diastereomeric adduct 10a was calculated to be in
the order of 1.2~7.2 kcal lower in energy than other pos-
droxyl groups at C1 and C3 as well as the oxygenated substituent at
C8 in the naturally occurring form in good yields.
Key words: azadirachtin, insect antifeedant, decalin, cyclic carbon-
ate, intramolecular Diels-Alder reaction
During the course of our synthetic studies on azadirachtin
(1),1 we achieved the intramolecular Diels-Alder
(IMDA) reaction of 2 to 3, and synthesized the function-
alized decalin moiety 42 via a rather lengthy route
(Scheme 1). As a further development, we had planned to
construct the decalin compound having both 1a- and 3a-
OH groups as well as some one-carbon substituent at the
C-8 position beforehand at the stage of the IMDA reac-
tion. As a result, we found the protection of two a-hydrox-
yl groups at C1 and C3 as the cyclic carbonate to be very
effective for stereoselective construction of the highly
functionalized decalin moiety of 1, details of which will
be described herein.
First of all, we calculated the relative energies in the dia-
stereomeric transition structures of the IMDA reactions of
the presumable triene diol, its dimethyl ether, and cyclic
carbonate by MacroModel V6.5.3 Molecular mechanics
O
CO2Me
OH
Me
Me
Me
O
O
O
O
O
14 Me
8
OH
AcO
MeO2C
OH
H
O
1
O
O
O
O
O
O
HO
HO
HO
toluene
210 °C
8
1
3
7
HO
BnO
OMPM
42%
H
H
O
O
O
O
O
Me
Me
Me
Me
3
2
4
Scheme 1
Synthesis 2000, No. 13, 1894–1906 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthetic Studies on Azadirachtin
1895
Table Relative Energies of the Transition Structures in Diels-Alder Reaction of
the Precursory Triene Diol 5, its Di-TES Ether 6, and Its Cyclic Carbonate 7
O
O
O
O
O
O
RO
R1O
RO
R1O
RO
R1O
Me
Me
+
Me
IMDA
H
H
O
O
O
O
O
O
Me
Me
Me
5, 6, 7
a
b
Me
Me
Me
(endo)
(endo)
O
O
O
O
RO
R1O
RO
R1O
Me
Me
+
+
H
H
O
O
O
O
Me
c
d
Me
Me
Me
(exo)
(exo)
triene
adduct
a
b
c
d kcal/mol
entry
1
2
3
5: R = R1 = H
8a-d
0.0
0.0
0.0
-0.1
-1.9
+0.6
+0.7
-1.7
6: R = R1 = TES 9a-d
-0.29
7: R = R1 = -CO-
+7.2
+4.6 +1.2
10a-d
sible diastereomers 10b, 10c, and 10d (10a, 0.0 kcal/mol; ery of 18 (15%). Compound 19 was reduced with
10b,+4.6 kcal/mol, 10c,+1.2 kcal/mol; 10d,+7.2 kcal/ DIBALH to give 20, in 88% yield, which was oxidized to
mol). Although the difference (1.2 kcal/mol) might be not aldehyde 21 with Dess-Martin periodinane. When 21 was
so large between the energies of 10a and 10c, we expected treated with B-allyldiisopinocampheylborane, prepared
to construct the desired endo-compound 10a as the major from (+)-B-chlorodiisopinocampheylborane [(+)-DIP-
adduct, comparing to the cases of the naked diol and its di- chloride] and allylmagnesium bromide in Et2O,6 followed
TES ether. Keeping these calculation results in mind, we by oxidation with H2O2 and NaOH, an allyl alcohol 22
examined experimentally the IMDA reactions using three was obtained in 91% yield. The optical yield of 22 was
optically active precursory trienes, 1,3-diol 11, its di-TES found to be 92%ee by comparing the respective tR in chiral
ether 12, and its 1,3-carbonate 13 (Figure 1), all of which column (DAICEL CHIRALCEL OD, hexane-i-PrOH,
possess the benzyloxymethyl group at the dienyl carbon.
20:1). The absolute configuration of the major alcohol
was deduced to be R by application of the modified Mosh-
er method7 to the respective a-methoxy-a-trifluorome-
thylacetyl (MTPA) esters prepared from 22 with (+)- and
(-)-MTPACl (Et3N, DMAP, CH2Cl2, 25 °C, 2 h, 97-
100% yield). The alcohol 22 was protected to the TMS
ether 23, which underwent dihydroxylation with OsO4
and the subsequent cleavage with NaIO4 to give aldehyde
24 in quantitative yield. Bromofuran 252 was converted to
Preparation of the precursory trienes 11-13 commenced
from diethyl malonate 14 (Scheme 2). Reaction of 14 with
formalin and a base provided diol 15,5 which was convert-
ed to bis-p-methoxyphenyloxymethyl ether 18 in 86%
combined yield for 4 steps. When compound 18 was treat-
ed with DDQ in CH2Cl2-H2O (20:1), a benzylidene acetal
19 and the desired mono-MPM ether 20 were obtained in
19% and 59% yields, respectively, along with the recov-
O
O
O
O
O
O
HO
TESO
O
O
O
OBn
OBn
OBn
O
HO
TESO
O
O
O
O
O
Me
Me
Me
11
12
13
Me
Me
Me
Figure 1 The Precursory Trienes (11, 12, and 13) for IMDA Reactions Examined
Synthesis 2000, No. 13, 1894–1906 ISSN 0039-7881 © Thieme Stuttgart · New York

1896
Y. Yamamoto et al.
SPECIAL TOPIC
O
O
O
O
O
O
O
O
EtO
OEt
RO
OR
a
b
c
e
EtO
HO
OEt
EtO
OEt
O
O
OH
155
Me Me
Me Me
17, R = H
16
14
d
18, R = MPM
PMP
OR
O
O
O
O
MPMO
MPMO
+
OH MPMO
g
H
h
O
O
O
O
O
O
O
Me Me
Me Me
Me Me
Me Me
21
19
20
22, R = H
i
f
23, R = TMS
O
OTIPS
TMSO
O
HO
OH
25
Br
H
j
k, l
MPMO
MPMO
O
O
O
O
O
O
Me Me
Me Me
26, β-OH
27, α-OH
24
m
Reagents and conditions: a) 35% aq HCHO, KHCO3, 25 °C, 1 h;5 b) Me2C(OMe)2, PTS·H2O, acetone, 25 °C, 1 h; c) LiAlH4, Et2O, 25 °C, 1 h;
d) MPMCl, NaH, DMF, 25 °C, 40 min (86% for 4 steps); e) DDQ, CH2Cl2/H2O (20:1), 25 °C, 30 min (19% for 19, 59% for 20, 15% for reco-
vered 18); f) DIBALH, CH2Cl2, 25 °C, 40 min (88%); g) Dess-Martin periodinane, CH2Cl2, 25 °C, 4 h (95%); h) (+)-DIPCl,
CH2 = CHCH2MgBr, Et2O, -78 °C, 1 h, then 21, -93 °C, 1 h; 4M NaOH, 30% aq H2O2, THF, 25 °C, 1.5 h [91% (92%ee)]; i) TMSCl, Et3N,
CH2Cl2, 25 °C, 10 min (96%); j) OsO4 (cat.), NMO, THF/H2O (2:1), 25 °C, 5 h, then NaIO4, 0 °C, 15 min (~100%); k) 25, BuLi, Et2O, -78 °C,
1 h, then 24, TMSCl, -78 °C, 40 min; l) TBAF, THF/AcOH (10:1), 0 °C, 30 min (55% for 26 in 2 steps from 24, 31% for 27 in 2 steps from
24); m) DEAD, PPh3, HCO2H, THF, 25 °C, 30 min; NaHCO3, MeOH/H2O (5:1), 25 °C, 1.5 h (76%)
Scheme 2
the corresponding lithiofuran, which was reacted with 24
TESO
OTES
TESO
OHC
OTES
in the presence of TMSCl and then with TBAF to give a
mixture of anti-26 and syn-diols 27 in 55% and 31%
yields for 2 steps, respectively. By using Mitsunobu’s re-
action,8 anti-diol 26 was transformed into the desired syn-
diol 27 in 76% yield.
a
c
RO
O
O
27
O
O
O
O
O
O
Me
Me
Me
Me
30
28, R = MPM
29, R = H
b
Compound 27 was protected to the di-TES ether 28, of
which the MPM group was detached to afford alcohol 29
(Scheme 3). The aldehyde 30, obtained on tetrapropylam-
monium perruthenate (TPAP) oxidation of 29, was the
common intermediate for further conversion to the
trienes. Compound 30 was subjected to the Takai
reaction9 to give (E)-iodoolefin 31 in 87% yield, which
was led to (E,E)-diene 12 on coupling with (E)-
Bu3SnCH=CHCH2OBn in the presence of Pd(II)10 in 76%
yield. TBAF treatment to 12 provided furanone diol 11,
which, on reaction with triphosgene, was converted
smoothly into the carbonate 13 in 87% yield.
TESO
OTES
I
d
e
f
g
O
12
11
13
O
O
O
Me
Me
31
Reagents and conditions: a) TESCl, imidazole, DMF, 25 °C, 2.5 h
(84%); b) DDQ, CH2Cl2/H2O (19:1), 25 °C, 30 min (~100%);
c) TPAP, NMO, MS 4A, CH2Cl2, 25 °C, 30 min (91%); d) CrCl2,
CHI3, THF, 25 °C, 2 h (87%); e) (E)-Bu3SnCH=CHCH2OBn,
Pd(MeCN)2Cl2, DMF, 26 °C, 3 h (76%); f) TBAF, HOAc, THF,
26 °C, 3 h (99%); g) (Cl3CO)2CO, pyridine, CH2Cl2, 0 °C, 20 min
(87%)
The IMDA reactions using three kinds of trienes 11, 12,
and 13 having a benzyloxymethyl substituent at the re-
spective diene parts were examined under thermal condi-
tions [toluene, 2,6-di-t-butyl-4-methoxyphenol (BHT),
sealed tube, 200 °C, 27 h] (Scheme 4). Thermolysis of
1a,3a-diol 11 provided two endo-decalin adducts 32 and
Scheme 3
Synthesis 2000, No. 13, 1894–1906 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthetic Studies on Azadirachtin
1897
O
O
O
O
RO
RO
OBn
OBn
a
11
+
RO
RO
H
H
O
O
O
O
Me
Me
Me
Me
32, R = H (29%)
33, R = H (26%)
b
b
34, R = TES (81%)
35, R = TES (66%)
O
O
O
O
TESO
TESO
OBn
OBn
a
12
+
TESO
TESO
H
H
O
O
O
O
Me
Me
Me
Me
35 (59%)
36 (23%)
O
O
O
O
O
O
RO
O
O
O
O
O
OBn
OBn
OBn
O
O
a
c
+
13
RO
H
H
O
H
O
O
O
O
Me
Me
Me
Me
Me
38 (14%)
Me
c
37 (67%)
32 (~100%)
39, R = H (54%)
d
40, R = TES (~100%)
Reagents and conditions: a) toluene, BHT, a sealed tube, 200 °C, 27 h; b) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 30 min; c) K2CO3, CH2Cl2,
MeOH, 25 °C, 30 min; d) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 30 min
Scheme 4 Intramolecular Diels-Alder Reactions of Trienes 11-13
33 in 29% and 26% yields, respectively. The structure of which provided the di-TES ether 40 quantitatively, which
the desired adduct 32 was deduced from the NOE experi- was not identical to 36 in its 1H NMR.
1
ments and the coupling constants in the H NMR spec-
trum of the corresponding di-TES ether 34 (Figure 2). The
Apart from the functional groups at C1 and C3, there
could be four possible adducts, starting from these trienes
structure of the other adduct 33 was also determined from
11-13, e.g., three of which include two endo-adducts
1
the H NMR spectral data of the corresponding di-TES
(consisting of a pair of 32 and 37 as well as 33 and 35) and
ether 35. Next, the reaction using di-TES-ether 12 afford-
one exo-adduct 38. These structures have already been as-
ed two adducts as an inseparable 2.5:1 mixture in 82%
signed by the mutual correlation and NMR spectral dis-
1
combined yield. However, the major peaks in the H
cussion. Accordingly, the tentative structure of the
NMR spectrum of the mixture were found to be superim-
residual minor product 36 starting from 12 could be as-
signed as another exo-adduct by elimination without any
posable with those of 35. The minor adduct itself was
structurally not deduced, but the tentatively assigned
supporting spectral data.
structure was proposed as 36 (vide infra). Furthermore,
It is noteworthy that the stereochemistry of the products in
these addition reactions depended upon the functional
groups at C1 and C3; 1,3-diol 11 led to an almost 1:1 mix-
ture of two endo-adducts. The corresponding di-TES ether
the cyclic carbonate 13 in question was heated under the
same conditions as the above reactions. The structure of
the major adduct, obtained in 67% isolated yield, was as-
signed as 37 having the exactly desired configurations
12 gave endo-35 and exo-36 in a 2.5:1 mixture. Surpris-
from the spectral data, whereas that of the minor product
ingly, in the case of the 1,3-cyclic carbonate 13, the endo-
(14%) was revealed to be an exo-adduct 38 judging from
addition occurred predominantly to afford the major ad-
duct 37 with the desired configurations in excellent yield
(67%). Notably, these results indicated that the experi-
mental results of diol 11, di-TES ether 12, and carbonate
its 1H NMR spectral data (Figure 2). The major compound
37 was saponified with K2CO3 to give the diol, which was
identical with 32 (vide ante) (Scheme 4). The minor ad-
duct 38 was led to the diol 39 under the same conditions,
Synthesis 2000, No. 13, 1894–1906 ISSN 0039-7881 © Thieme Stuttgart · New York

1898
Y. Yamamoto et al.
SPECIAL TOPIC
H
H
H
H
O
H
H
O
O
1 OTES
H
3
H
2
2
9
TESO
H
1
OBn
9
3
H
8
H
O
H
O
TESO
OBn
H
8
H
O
O
TESO
O
34, JH1-2, JH2-3 = ~3 Hz
35, JH1-2aq, JH2aq-3 = ~9 Hz
H
H
H
H
O
O
H
O
O
H
O
O
H
1 H
H
2
H
1
9
2
9
H
H
3
H
3
H
8
O
O
H
O
O
8
OBn
H
OBn
H
O
O
O
O
37, JH1-2, JH2-3 = ~3 Hz
38, JH1-2, JH2-3 = ~3Hz
Figure 2 NOE Experiments and Coupling Constants in 1H NMR of 34, 35, 37, and 38
13 reflected those of the calculation rather exactly (Table sition of the decalin. Accordingly, we attempted further
1). Eventually, we were able to succeed in efficient con- IMDA reactions with other trienes 41 and 42 having an
struction of the highly functionalized tricyclic decalin alkoxycarbonyl group at C8 in place of the benzyloxyme-
compound 37, having the asymmetric carbons with all the thyl group, though the respective HOMO energies of the
desired configurations. Thus, we confirmed the efficiency diene parts might be lowered to some extent compared
of the 1,3-diol carbonate group for the IMDA reactions.
with those of the above-mentioned benzyloxymethyl
groups (Scheme 5). The aldehyde 30 was subjected to
Horner-Emmons reactions12 using methyl and ethyl (E)-
diethylphosphonocrotonates, followed by desilylation, to
afford alkoxycarbonyl (E,E)-dienyl diols 43 and 44 in
In order to realize the connection of the decalin part with
the tricyclic dihydrofuran alcohol of the right side1c in 1
by the Ireland-Claisen rearrangement,11 the carboxylic
acid is indispensable as the functional group at the C8 po-
TESO
OHC
OTES
HO
OH
MeO2C
MeO2C
EtO2C
a
O
O
O
O
O
O
O
O
Me
Me
Me
Me
30
43
O
b
O
O
O
c
O
O
O
Me
Me
41
O
O
O
HO
O
OH
EtO2C
d
O
O
O
O
O
O
O
Me
Me
Me
Me
44
42
Reagents and conditions: a) LDA, (E)-(EtO)2P(O)CH2CH=CHCO2Me, THF, 0 °C, 30 min; TBAF, HOAc, THF, 25 °C, 4 h (63% for 2 steps);
b) (Cl3CO)2CO, pyridine, CH2Cl2, 0 °C, 20 min (79%); c) LDA, (E)-(EtO)2P(O)CH2CH=CHCO2Et, THF, 0 °C, 30 min; TBAF, HOAc, THF,
25 °C, 4 h (56% for 2 steps); d) (Cl3CO)2CO, pyridine, CH2Cl2, 0 °C, 15 min (~100%)
Scheme 5
Synthesis 2000, No. 13, 1894–1906 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthetic Studies on Azadirachtin
1899
63% and 56% yields for 2 steps, respectively. These diols
were converted to the respective cyclic carbonates 41 and
42 in 79% and ~100% yields, respectively.
O
O
O
O
O
O
O
O
O
CO2Me
CO2Me
O
O
a
41
+
When a solution of the triene 41 in toluene was heated at
200 °C in a sealed tube, a longer time (67 h) was required
for completion of the reaction (Scheme 6). The products
consisted of both endo-adducts 45 and 46 in 40% and 14%
yield, respectively. The structures of these products were
deduced by their 1H NMR spectral analyses involving the
coupling constants and NOE experiments (Figure 3). In
order to clarify the mutual relationship between the prod-
ucts, the adduct 46 was heated under the same heat condi-
H
H
O
O
O
Me
Me
Me
Me
a
45 (40%)
46 (14%)
(76%)
3.2 : 1
O
O
O
O
O
O
O
O
1
tions as above (toluene, 200 °C, 67 h). The H NMR
CO2Et
CO2Et
spectrum of the reaction residue revealed the product to be
a 3.2:1 mixture of 45 and 46 in 76% combined yield. Like-
wise, heat treatment of another triene 42 led to formation
of both endo-adducts 47 and 48 in 30% and 12%, respec-
tively,1d the structures of which were assigned by compar-
O
O
b
42
+
H
H
O
O
O
O
Me
Me
Me
48 (12%)
Me
1
ison with those of the methyl esters in their H NMR
47 (30%)
spectra (Figure 3). The relative stability of 45 or 47 having
an axial ethoxycarbonyl group suggests that the B-ring
takes a boat conformation on the basis of the respective
coupling constants JH8-9 in 47 and 48, though those in 45
and 46 could not be detected for superimposition of the
peaks. These stereochemistries were also supported by the
X-ray analysis of 47.13 In this way, the cases of alkoxycar-
bonyl substituents led to exclusive formation of endo-ad-
ducts having correct configurations, but of neither
unnatural endo- nor exo-adducts. There might be some
conformational influence arising from the alkoxycarbonyl
substituents attached at the diene parts in the respective
transition states.
Reagents and conditions: a) toluene, BHT (cat.), a sealed tube,
200 °C, 67 h; b) toluene, BHT (cat.), a sealed tube, 200 °C, 60 h
Scheme 6 Intramolecular Diels-Alder Reactions of Trienes 41, 42
In conclusion, we were able to establish a more efficient
synthetic route to the tricyclic decalin fragment of aza-
dirachtin 1 in the naturally occurring form. The key step
in our second-generation synthesis involves the IMDA re-
actions of several substituted trienes having 1,3-diol cy-
clic carbonates. Our results were found to be parallel to
the results of calculation of the transition structures in the
respective cases by MM2*. Further conversion of these
O
H
H
O
H
O
H
O
O
O
2
9
2
1
9
1
3
H
3
H
O
H
O
8CO2Me
H
H
H
O
O
8
H
H
CO2Me
O
O
O
O
45, JH1-2, JH2-3 = ~3 Hz
46, JH1-2, JH2-3 = ~3 Hz
H
H
O
H
H
O
O
O
O
O
H
H
H
H
2
2
9
1
9
1
H
H
3
3
O
O
CO2Et
H
H
H
O
O
8
H8
H
H
CO2Et
O
O
O
O
47, JH1-2, JH2-3 = ~3 Hz
JH8-9 = 0.9 Hz
48, JH1-2, JH2-3 = ~3 Hz
JH8-9 = 8.2 Hz
Figure 3 NOE Experiments and Coupling Constants in 1H NMR of 45, 46, 47, and 48
Synthesis 2000, No. 13, 1894–1906 ISSN 0039-7881 © Thieme Stuttgart · New York

1900
Y. Yamamoto et al.
SPECIAL TOPIC
IR (neat): nmax = 2988, 2940, 1744, 1394, 1374, 1248, 1224, 1148,
adducts having the benzyloxymethyl or alkoxycarbonyl
groups at the C8 positions to the corresponding carboxylic
1100, 1078, 1052 cm-1.
acids is now in progress in our laboratory in order to com- 1H NMR (300 MHz, CDCl3): d = 4.29 (s, 4H), 4.24 (q, 4H, J = 7.1
bine with another tricyclic dihydrofuran alcohol1c aimed
at formation of the C8-C14 bond via Ireland-Claisen
rearrangement11 as the most crucial stage in the total syn-
thesis of 1.
Hz), 1.41 (s, 6H), 1.27 (t, 6H, J = 7.1 Hz).
LRMS (FD): m/z = 261 (M++1, 2.88%), 245 (100), 200 (6.5).
5,5-Dihydroxymethyl-2,2-dimethyl-1,3-dioxane (17)
To Et2O (350 mL) was slowly added LiAlH4 (8.19 g, 173 mmol) at
0 °C. A solution of 16 (24.8 g) in Et2O (150 mL) was added to the
suspension at 0 °C over 45 min. The mixture was stirred at 25 °C for
1 h. To the mixture were slowly added H2O (8.2 mL), 4 M NaOH
(8.2 mL), and H2O (24.6 mL), and the mixture was filtered through
a Celite pad and washed with EtOAc (2 L). The filtrate was concen-
trated in vacuo to afford crude 17 (15.4 g) as colorless needles; mp:
124-128 °C.
All anhydrous reactions were conducted in flame-dried glassware
under Ar, unless otherwise stated. All solvents except acetone,
DMF, and MeOH were distilled prior to use. Et2O, THF, and tolu-
ene were distilled from sodium benzophenone ketyl. CH2Cl2 was
distilled from CaH2. MeOH, acetone, and anhyd DMF were used as
received from commercial sources. Chromatography and extraction
were carried out by using normal reagent grade solvents. All re-
agents were used as received unless otherwise noted. All reactions
were monitored by TLC with precoated silica gel plates (E. Merck,
Silica gel 60 F254 Art. 5715), and compounds were visualized with
UV light and/or ethanolic p-anisaldehyde (p-anisaldehyde-96%
H2SO4-EtOH, 1:1:18). For chromatography, was utilized silica gel
(YMC, YMCGEL SIL-60-230/70W and SIL-60-400/230W), alu-
mina (INC, INC Alumina N, Act. 1), or PTLC (E. Merck, Silica gel
60 F254 Art. 5744). Mps were measured on Yanagimoto Seisakusyo
Micro melting point apparatus (Serial No. 989) and are uncorrected.
Optical rotations were recorded on JASCO model P-1020 digital
polarimenter in appropriate solvents. Low- and high-resolution
mass spectra were obtained on JEOL JMS-AX500 and/or JMS-
SX102A spectrometers. IR spectra were measured on Hitachi mod-
el 270-30 infrared spectrometer in the noted state. 1H NMR spectra
were measured on JEOL JNM-AL-300 (300 MHz) or JNM-a400
(400 MHz) spectrometers. Chemical shifts (d) are reported ppm;
coupling constants (J) are reported in Hz. Splitting patterns were de-
signed as "s, d, t, q, m, and br"; these symbols indicate "singlet, dou-
blet, triplet, quartet, multiplet, and broad", respectively. TMS
(d = 0.00 ppm) was used as an internal reference for spectra mea-
sured in CDCl3, and residual benzene (d = 7.20 ppm) in C6D6.
IR (KBr): nmax = 3404, 2982, 2936, 2880, 1458, 1386, 1372, 1250,
1198, 1148, 1086, 1046, 878 cm-1.
1H NMR (300 MHz, CDCl3): d = 3.77 (d, 4H, J = 5.3 Hz), 3.74 (s,
4H), 2.05 (t, 2H, J = 5.3 Hz), 1.42 (s, 6H).
LREIMS: m/z = 161 (M+-Me, 100%), 71 (27), 59 (62), 43 (60).
HREIMS: calcd. for C7H13O4: 161.0814. Found: 161.0840.
5,5-Bis-p-methoxybenzyloxymethyl-2,2-dimethyl-1,3-dioxane
(18)
To DMF (200 mL) was added NaH (12.2 g, a 60% oil suspension,
305 mmol) at 0 °C. A solution of 17 (15.4 g) in DMF (150 mL) was
added to the resulting suspension at 0 °C, and the mixture was
stirred at 25 °C for 30 min, and then allowed to cool to 0 °C.
MPMCl (23.4 mL, 173 mmol) was then added, and the mixture was
stirred at 25 °C for 40 min. Sat. NH4Cl (100 mL) was added, and the
mixture was extracted with Et2O (3 ¥ 500 mL) and then with EtOAc
(2 ¥ 200 mL). The combined extracts were washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo. Purification of the
residue by silica gel column chromatography (230/70W, 900 g, hex-
ane/EtOAc, 5:1) afforded 18 (35.1 g, 86% for 4 steps) as a colorless
oil.
Diethyl 2,2-Dihydroxymethylmalonate (15)5
IR (neat): nmax = 2992, 2936, 2860, 1612, 1586, 1512, 1464, 1369,
1301, 1247, 1200, 1172, 1083, 1035, 934, 830 cm-1.
To a solution of 35% aqueous formaldehyde (18 mL, 206 mmol)
and KHCO3 (1 g, cat.) was added diethyl malonate (14, 15 mL, 98.4
mmol) via syringe at 20 °C. After stirring at 25 °C for 1 h, the mix-
ture was diluted with sat. NH4Cl (50 mL), and then extracted with
EtOAc (8 ¥ 300 mL). The extracts were washed with brine, dried
(MgSO4), filtered through a Celite pad, and concentrated in vacuo
to afford crude 155 (22.8 g) as a colorless oil.
1H NMR (300 MHz, CDCl3): d = 7.20 (d, 2H, J = 8.8 Hz), 6.85 (d,
2H, J = 8.8 Hz), 4.41 (s, 4H), 3.79 (s, 6H), 3.76 (s, 4H), 3.45 (s, 4H),
1.39 (s, 6H).
LREIMS: m/z = 401 (M+-Me, 2.98%), 295 (67), 237 (28), 161 (45),
121 (100).
HREIMS: calcd. for C23H29O6: 401.1964. Found: 401.1982.
IR (neat): nmax = 3488, 2984, 2904, 1728, 1470, 1450, 1392, 1372,
1306, 1222, 1160, 1096, 1042, 860 cm-1.
5-Hydroxymethyl-5-p-methoxybenzyloxymethyl-2,2-dimethyl-
1,3-dioxane (20)
1H NMR (300 MHz, CDCl3): d = 4.26 (q, 4H, J = 7.1 Hz), 4.11 (d,
4H, J = 7.1 Hz), 2.82 (t, 2H, J = 7.1 Hz), 1.29 (t, 6H, J = 7.1 Hz).
LREIMS: m/z = 221 (M++1, 3.44%), 189 (67), 175 (20), 143 (50),
To a solution of 18 (15.0 g, 36.1 mmol) in CH2Cl2 (280 mL) and
H2O (14 mL) was added DDQ (8.36 g, 35.7 mmol) at 25 °C and the
mixture was stirred for 30 min. The reaction was quenched with sat.
NaHCO3 (30 mL), and the mixture was extracted with Et2O
(3 ¥ 300 mL) and then EtOAc (2 ¥ 200 mL). The combined extracts
were washed with brine, dried (MgSO4), filtered, and concentrated
in vacuo. Purification of the residue by silica gel chromatography
(230/70W, 800 g, hexane/EtOAc, 9:1 to 3:1) afforded 20 (6.26 g,
59%) as a colorless oil, acetal 19 (1.97 g, 19%) as a white solid, and
recovered 18 (2.30 g, 15%).
127 (100).
HREIMS: calcd. for C9H17O6: 221.1025. Found: 221,1037.
5,5-Diethoxycarbonyl-2,2-dimethyl-1,3-dioxane (16)
To a stirred solution of 155 (22.8 g) in acetone (330 mL) were added
2,2-dimethoxypropane (25.5 mL, 206 mmol) and p-toluenesulfonic
acid monohydrate (PTS·H2O) (1.44 g, cat.) at 0 °C, and the mixture
was warmed to 25 °C and stirred for 1 h. The reaction was quenched
with sat. NaHCO3 (50 mL), and the mixture was extracted with
Et2O (5 ¥ 200 mL). The extracts were washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo to afford crude 16
(24.9 g) as a colorless oil.
20
IR (neat): nmax = 3462, 2992, 2938, 2867, 1613, 1586, 1513, 1455,
1371, 1302, 1247, 1201, 1173, 1153, 1081, 1037, 829, 453 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.23 (d, 2H, J = 8.6 Hz), 6.88 (d,
2H, J = 8.6 Hz), 4.46 (s, 2H), 3.81 (s, 3H), 3.71 (s, 4H), 3.66 (d, 2H,
Synthesis 2000, No. 13, 1894–1906 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthetic Studies on Azadirachtin
1901
J = 5.9 Hz), 3.54 (s, 2H), 2.37 (t, 1H, J = 6.0 Hz), 1.41 and 1.40 (s,
each 3H).
1H NMR (300 MHz, CDCl3): d = 7.24 (d, 2H, J = 8.8 Hz), 6.88 (d,
2H, J = 8.8 Hz), 5.94-5.81 (m, 1H), 5.12-5.05 (m, 2H), 4.50 and
4.43 (d, each 1H, J = 11.0 Hz), 3.91 (s, 2H), 3.80 (s, 3H), 3.78 and
3.61 (d, each 1H, J = 9.5 Hz), 3.37 and 3.54 (d, each 1H, J = 12.0
Hz), 3.59-3.53 (m, 1H), 2.80 (d, 1H, J = 7.7 Hz), 2.21-2.04 (m, 2H),
1.41 and 1.37 (s, each 3H).
HREIMS: calcd. for C16H24O5: 296.1623. Found: 296.1639.
Acetal 19
Mp: 111 °C.
IR (KBr): nmax = 2991, 2972, 2939, 2856, 1614, 1517, 1459, 1382,
HREIMS: calcd. for C19H28O5: 336.1927. Found: 336.1924.
1317, 1251, 1207, 1162, 1105, 1060, 1031, 831 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.36 (d, 2H, J = 8.6 Hz), 6.88 (d,
2H, J = 8.6 Hz), 5.37 (s, 1H), 4.30 (d, 2H, J = 12.0 Hz), 4.13 (s, 2H),
3.80 (s, 3H), 3.64 (d, 2H, J = 12.0 Hz), 3.49 (s, 2H), 1.43 (s, 6H).
(1’R)-5-p-Methoxybenzyloxymethyl-2,2-dimethyl-5-(1’-trime-
thylsilyloxybut-3’-enyl)-1,3-dioxane (23)
To a solution of 22 (2.04 g, 6.16 mmol) in CH2Cl2 (100 mL) were
added Et3N (3.5 mL, 25.2 mmol) and TMSCl (1.55 mL, 12.2 mmol)
at 0 °C and the mixture was stirred at 25 °C for 10 min. The solution
was mixed with sat. NH4Cl (5 mL) and extracted with CH2Cl2
(3 ¥ 100 mL). The extracts were washed with brine, dried (MgSO4),
filtered, and concentrated in vacuo. Purification of the residue by
silica gel chromatography (230/70W, 150 g, hexane/EtOAc, 20:1,
10:1) afforded 23 (2.39 g, 96%) as a colorless oil.
LREIMS: m/z = 294 (M+, 9.1%), 135 (7.2), 83 (100).
HREIMS: calcd. for C16H22O5: 294.1466. Found: 294.1467.
Conversion of 19 to 20
To a solution of 19 (8.31 g, 28.3 mmol) in CH2Cl2 (150 mL) was
added DIBALH (60 mL, 0.95 M in CH2Cl2, 57.0 mmol) at 0 °C and
the mixture was stirred at 25 °C for 40 min. The reaction was
quenched with MeOH (10 mL) and 4 M NaOH (50 mL), the mixture
was extracted with Et2O (3 ¥ 100 mL) and the extracts were washed
with brine, dried (MgSO4), filtered, and concentrated in vacuo. Pu-
rification of the residue by silica gel chromatography (230/70W,
400 g, hexane/EtOAc, 3:1 to 1:1) afforded 20 (7.37 g, 88%) as a col-
orless oil.
[a]D22 -3.1 (c 1.91, CHCl3).
IR (neat): nmax = 3076, 2992, 2956, 2904, 2868, 1644, 1616, 1516,
1458, 1370, 1302, 1252, 1202, 1174, 1038, 934, 840 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.24 (d, 2H, J = 8.6 Hz), 6.87 (d,
2H, J = 8.6 Hz), 5.85-5.71 (m, 1H), 5.05-5.00 (m, 2H), 4.48 and
4.39 (d, each 1H, J = 12.0 Hz), 3.92-3.83 (m, 3H), 3.80 (s, 3H),
3.76-3.44 (m, 4H), 2.37-2.29 (m, 1H), 2.17-2.07 (m, 1H), 1.40 and
1.37 (s, each 3H), 0.097 (s, 9H).
5-Formyl-5-p-methoxybenzyloxymethyl-2,2-dimethyl-1,3-diox-
ane (21)
HREIMS: calcd. for C22H36O5Si: 408.2333. Found: 408.2332.
To a solution of 20 (2.21 g, 7.45 mmol) in CH2Cl2 (100 mL) was
added Dess-Martin periodinane (9.69 g, 23.0 mmol) at 25 °C and
the mixture was stirred at 25 °C for 4 h. The reaction was quenched
with sat. Na2S2O3 (10 mL) and sat. NaHCO3 (10 mL), and then ex-
tracted with CH2Cl2 (3 ¥ 100 mL). The extracts were washed with
brine, dried (MgSO4), filtered, and concentrated in vacuo. Purifica-
tion of the residue by silica gel chromatography (230/70W, 100 g,
hexane/EtOAc, 3:1) afforded 21 (2.04 g, 95%) as a colorless oil.
(1’R)-5-p-Methoxybenzyloxymethyl-2,2-dimethyl-5-(1’-trime-
thylsilyloxy-3’-oxopropyl)-1,3-dioxane (24)
To a solution of 23 (110 mg, 0.27 mmol) in THF (2.4 mL) and H2O
(1.2 mL) were added N-methylmorpholine N-oxide (NMO) (65.4
mg, 0.54 mmol) and OsO4 (1.2 mL, 0.02 M in t-BuOH, 0.024
mmol) at 25 °C and the mixture was stirred at 25 °C for 5 h. Phos-
phate buffer (pH 7.5, 1 mL) was added and the mixture was allowed
to cool to 0 °C. NaIO4 (99.1 mg, 0.46 mmol) was added and the
mixture was stirred at 0 °C for 15 min. Sat. Na2S2O3 (2 mL) was
added, and the mixture was extracted with Et2O (3 ¥ 10 mL). The
extracts were washed with brine, dried (MgSO4), filtered, and con-
centrated in vacuo. Purification of the residue by alumina chroma-
tography (6%wet alumina, 6 g, hexane/EtOAc, 20:1, 10:1) afforded
24 (112 mg, ~100%) as a colorless oil.
IR (neat): nmax = 2992, 2938, 2867, 1716, 1516, 1372, 1250, 1200,
1172, 1154, 1082, 1036, 832 cm-1.
1H NMR (300 MHz, CDCl3): d = 9.71 (s, 1H), 7.19 (d, 2H, J = 8.6
Hz), 6.87 (d, 2H, = 8.6 Hz), 4.41 (s, 2H), 4.11 and 3.88 (d, each 2H,
J = 12.0 Hz), 3.80 (s, 3H), 3.54 (s, 2H), 1.41 and 1.40 (s, each 3H).
HREIMS: calcd. for C16H22O5: 294.1468. Found: 294.1485.
[a]D22 -2.5 (c 0.58, benzene).
(1’R)-5-(1’-Hydroxybut-3’-enyl)-5-p-methoxybenzyloxymethyl-
2,2-dimethyl-1,3-dioxane (22)
IR (neat): nmax = 2992, 2956, 2904, 2868, 1730, 1614, 1514, 1458,
1372, 1302, 1252, 1202, 1174, 1088, 1036, 868 cm-1.
To a solution of (+)-DIPCl (4.42 g, 13.8 mmol) in Et2O (40 mL) was
added CH2=CHCH2MgBr (12.2 mL, 1.0 M in Et2O, 12.2 mmol) at
-78 °C. After stirring at -78 °C for 1 h, the mixture was allowed to
cool to -93 °C. A solution of 21 (2.05 g, 6.96 mmol) in Et2O (30
mL) was added, and the mixture was stirred at -93 °C for 1 h. Sat.
NH4Cl (10 mL) was added and the mixture was extracted with Et2O
(3 ¥ 100 mL). The extracts were washed with brine, dried (MgSO4),
filtered, and concentrated in vacuo. To the solution of the residue in
THF (50 mL) were slowly added 4 M NaOH (10 mL) and 30% H2O2
(10 mL) at 0 °C and the mixture was stirred at 25 °C for 1.5 h, treat-
ed with sat. Na2S2O3 (10 mL) at 0 °C, and then extracted with
EtOAc (3 ¥ 50 mL). The extracts were washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo. Purification of the
residue by silica gel chromatography (400/230W, 100 g, hexane/
EtOAc, 10:1, 5:1) afforded 22 (2.13 g, 91%, 92%ee) as a colorless
oil.
1H NMR (300 MHz, CDCl3), d = 9.73 (dd, 1H, J = 2.3, 1.2 Hz),
7.22 (d, 2H, J = 8.6 Hz), 6.87 (d, 2H, J = 8.6 Hz), 4.43 and 4.36 (d,
each 1H, J = 12.0 Hz), 4.42-4.40 (m, 1H), 3.84-3.63 (m, 4H), 3.81
(s, 3H), 3.48 and 3.41 (d, each 1H, J = 9.3 Hz), 2.76 (ddd, 1H,
J = 17.0, 4.0, 1.2 Hz), 2.61 (ddd, 1H, J = 17.0, 7.5, 2.3 Hz), 1.39 and
1.38 (s, each 3H), 0.10 (s, 9H).
HREIMS: calcd. for C21H34O6Si: 410.2124. Found: 410.2165.
(1’R,3’R)-5-{1’,3’-Dihydroxy-3’-[furan-2’’(5’’H)-on-4’’-yl]pro-
pyl}-5-p-methoxybenzyloxymethyl-2,2-dimethyl-1,3-dioxane
(26) and (1’R,3’S)-5-{1’,3’-Dihydroxy-3’-[furan-2’’(5’’H)-on-4’’-
yl]propyl}-5-p-methoxybenzyloxymethyl-2,2-dimethyl-1,3-di-
oxane (27)
To a stirred solution of bromofuran 252 (5.60 g, 17.6 mmol) in Et2O
(60 mL) was added BuLi (9.6 mL, 1.56 M in hexane, 14.8 mmol) at
-78 °C and the mixture was stirred at -78 °C for 1 h. A solution of
24 (1.83 g, 4.50 mmol) and TMSCl (1.2 mL, 9.48 mmol) in Et2O
(40 mL) was added and the mixture was stirred at -78 °C for 40
[a]D22 +13.0 (c 1.13, benzene).
IR (neat): nmax = 3508, 3076, 2992, 2940, 2868, 1642, 1614, 1588,
1516, 1458, 1371, 1302, 1250, 1202, 1176, 1152, 1080, 1036, 914,
832 cm-1.
Synthesis 2000, No. 13, 1894–1906 ISSN 0039-7881 © Thieme Stuttgart · New York

1902
Y. Yamamoto et al.
SPECIAL TOPIC
min. The mixture was diluted with sat. NH4Cl (10 mL) and extract-
ed with Et2O (3 ¥ 70 mL). The extracts were washed with brine,
dried (MgSO4), filtered, and concentrated in vacuo. To the solution
of the crude residue in THF (40 mL) and HOAc (4 mL) was added
TBAF (31 mL, 1.0 M in THF, 31 mmol), and the mixture was
stirred at 0 °C for 30 min. The mixture was treated with sat. NH4Cl
(10 mL), and extracted with EtOAc (3 ¥ 100 mL). The extracts were
washed with sat. NaHCO3, brine, dried (MgSO4), filtered, and con-
centrated in vacuo. Purification of the residue by silica gel chroma-
tography (400/230W, 100 g, hexane/EtOAc, 3:1 to 1:2) afforded 26
(1.04 g, 55% for 2 steps) as well as 27 (0.577 g, 31% for 2 steps) as
colorless oils.
1.78-1.68 (m, 1H), 1.37 and 1.36 (s, each 3H), 1.03-0.90 (m, 18H),
0.74-0.54 (m, 12H).
IR (neat): nmax = 2956, 2912, 2876, 1782, 1754, 1516, 1462, 1372,
1250, 1200, 1174, 1130, 1076, 1036, 830 cm-1.
HREIMS: calcd. for C34H58O8Si2: 650.3670. Found: 650.3667.
(1’R,3’S)-5-{1’,3’-Bistriethylsilyloxy-3’-[furan-2’’(5’’H)-on-4’’-
yl]propyl}-5-hydroxymethyl-2,2-dimethyl-1,3-dioxane (29)
To a solution of 28 (63.4 mg, 0.098 mmol) in CH2Cl2 (1.5 mL) and
H2O (0.08 mL) was added DDQ (47.4 mg, 0.20 mmol), and the mix-
ture was stirred at 25 °C for 30 min. Sat. NaHCO3 (1 mL) was added
and the mixture was extracted with EtOAc (3 ¥ 5 mL). The extracts
were washed with brine, dried (MgSO4), filtered, and concentrated
in vacuo. Purification of the residue by silica gel chromatography
(230/70W, 2.5 g, hexane/EtOAc, 7:1, 3:1) afforded 29 (52.6 mg,
~100%) as a colorless oil.
26
[a]D25 +6.0 (c 0.80, CHCl3).
IR (neat): nmax = 3448, 2992, 2944, 2872, 1780, 1746, 1614, 1516,
1456, 1374, 1304, 1250, 1202, 1178, 1142, 1076, 1034, 832 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.22 (d, 2H, J = 8.6 Hz), 6.90 (d,
2H, J = 8.6 Hz), 5.93 (d, 1H, J = 1.5 Hz), 4.90-4.88 (m, 1H), 4.83-
4.81 (m, 2H), 4.53 and 4.39 (d, each 1H, J = 12.0 Hz), 3.92-3.76 (m,
4H), 3.82 (s, 3H), 3.71 and 3.54 (d, each 1H, J = 9.3 Hz), 3.66 and
3.48 (d, each 1H, J = 12.0 Hz), 1.88-1.78 (m, 1H), 1.66 (ddd, 1H,
J = 14.0, 7.1, 1.5 Hz), 1.39 and 1.38 (s, each 3H).
[a]D25 +3.6 (c 0.53, CHCl3).
IR (neat): nmax = 3504, 2960, 2916, 2880, 1782, 1754, 1464, 1374,
1242, 1202, 1168, 1084, 1034, 828 cm-1.
1H NMR (300 MHz, CDCl3): d = 5.99 (s, 1H), 4.89 (s, 2H), 4.80-
4.75 (m, 1H), 4.66 (dd, 1H, J = 6.6, 3.8 Hz), 3.96 (d, 1H, J = 12.0
Hz), 3.81-3.75 (m, 2H), 3.63-3.52 (m, 3H), 2.50-2.47 (m, 1H), 2.10
(ddd, 1H, J = 14.0, 7.9, 4.0 Hz), 1.93-1.84 (m, 1H), 1.40 and 1.36
(s, each 3H), 1.02-0.92 (m, 18H), 0.74-0.58 (m, 12H).
LREIMS: m/z = 515 (M+-Me, 6.4%), 485 (2.7), 443 (5.1), 369 (25),
271 (24), 227 (100).
HREIMS: calcd. for C22H30O8: 422.1940. Found: 422.1974.
27
[a]D24 -10.7 (c 0.53, CHCl3).
IR (neat): nmax = 3460, 2992, 2940, 2868, 1780, 1752, 1614, 1516,
1456, 1374, 1302, 1250, 1202, 1176, 1140, 1080, 1032, 832 cm-1.
HREIMS: calcd. for C25H47O7Si2: 515.2860. Found: 515.2869.
1H NMR (300 MHz, CDCl3): d = 7.23 (d, 2H, J = 8.6 Hz), 6.90 (d,
2H, J = 8.6 Hz), 5.90 (d, 1H, J = 1.5 Hz), 4.86-4.85 (m, 3H), 4.57
and 4.41 (d, each 1H, J = 12.0 Hz), 4.05-4.02 (m, 1H), 3.91-3.65
(m, 4H), 3.82 (s, 3H), 3.53 (d, 1H, J = 9.3 Hz), 3.48 (d, 1H, J = 12.0
Hz), 1.71-1.61 (m, 2H), 1.40 and 1.38 (s, each 3H).
(1’R,3’S)-5-Formyl-5-{1’,3’-bistriethylsilyloxy-3’-[furan-
2’’(5’’H)-on-4’’-yl]propyl}-2,2-dimethyl-1,3-dioxane (30)
To a solution of 29 (91.2 mg, 0.17 mmol) in CH2Cl2 (2 mL) were
added NMO (41.5 mg, 0.34 mmol), MS 4Å (50 mg), and TPAP
(0.55 mg, 0.016 mmol), and the mixture was stirred at 25 °C for 30
min. The mixture was filtered through a Celite pad, and concentrat-
ed in vacuo. Purification of the residue by silica gel chromatography
(230/70W, 5 g, hexane/EtOAc, 10:1) afforded 30 (82.7 mg, 91%) as
a colorless oil.
HREIMS: calcd. for C22H30O8: 422.1941. Found: 422.1966.
Conversion of 26 to 27
To a solution of 26 (28.6 mg, 0.068 mmol) in THF (1 mL) were add-
ed PPh3 (32 mg, 0.12 mmol), DEAD (0.016 mL, 0.10 mmol), and
HCOOH (0.005 mL, 0.13 mmol) at 25 °C and the mixture was
stirred at 25 °C for 30 min. The mixture was concentrated in vacuo.
To the solution of the crude residue in MeOH (1 mL) and H2O (0.2
mL) was added NaHCO3 (34.4 mg, 0.410 mmol) at 0 °C, and the
mixture was stirred at 25 °C for 1.5 h. The mixture was diluted with
sat. NH4Cl (1 mL), and then extracted with EtOAc (3 ¥ 3 mL). The
extracts were washed with brine, dried (MgSO4), filtered, and con-
centrated in vacuo. Purification of the residue by preparative TLC
(PTLC) (hexane/EtOAc, 1:3) afforded 27 (22 mg, 76% from 26) as
a colorless oil.
[a]D23 -1.1 (c 1.96, CHCl3).
IR (neat): nmax = 3108, 2948, 2912, 2892, 2736, 1786, 1756, 1646,
1460, 1418, 1374, 1312, 1240, 1200, 1162, 1094, 1036, 886 cm-1.
1H NMR (300 MHz, CDCl3): d = 9.78 (s, 1H), 5.96 (s, 1H), 4.92-
4.77 (m, 2H), 4.71-4.67 (m, 1H), 4.14-3.99 (m, 4H), 3.87 (d, 1H,
J = 12.0 Hz), 2.18-1.97 (m, 1H), 1.87-1.78 (m, 1H), 1.40 and 1.37
(s, each 3H), 1.00-0.93 (m, 18H), 0.68-0.57 (m, 12H).
LREIMS: m/z = 513 (M+-Me, 2.1%), 483 (0.9), 441 (9.7), 411 (47),
227 (29), 171 (100).
(1’R,3’S)-5-{1’,3’-Bistriethylsilyloxy-3’-[furan-2’’(5’’H)-on-4’’-
yl]propyl}-5-p-methoxybenzyloxymethyl-2,2-dimethyl-1,3-di-
oxane (28)
HREIMS: calcd. for C25H45O7Si2: 513.2704. Found: 513.2722.
(1’R,3’S,1’’’E)-5-{1’,3’-Bistriethylsilyloxy-[furan-2’’(5’’H)-on-
4’’-yl]propyl}-5-(2’’’-iodoethenyl)-2,2-dimethyl-1,3-dioxane
(31)
To a solution of 27 (0.557 g, 1.32 mmol) in DMF (10 mL) were add-
ed imidazole (1.35 g, 19.5 mmol) and TESCl (1.77 mL, 10.6 mmol),
and the mixture was stirred at 25 °C for 2.5 h. The mixture was di-
luted with sat. NH4Cl (3 mL), and extracted with Et2O (3 ¥ 10 mL).
The extracts were washed with brine, dried (MgSO4), filtered, and
concentrated in vacuo. Purification of the residue by silica gel chro-
matography (230/70W, 30 g, hexane/EtOAc, 20:1, 5:1) afforded 28
(0.719 g, 84%) as a colorless oil.
To a stirred suspension of CrCl2 (0.313 g, 2.42 mmol) in THF (2
mL) was added a solution of 30 (83.7 mg, 0.16 mmol) and CHI3
(0.331 g, 0.82 mmol) in THF (3 mL) at 0 °C, and the mixture was
warmed to 25 °C. The mixture was stirred at 25 °C for 2 h, diluted
with H2O (3 mL), and extracted with Et2O (3 ¥ 5 mL). The extracts
were washed with brine, dried (MgSO4), filtered, and concentrated
in vacuo. Purification of the residue by silica gel column chroma-
tography (400/230W, 5 g, hexane/EtOAc, 20:1, 10:1) afforded 31
(90.0 mg, 87%) as a colorless oil.
[a]D24 -6.2 (c 0.55, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.21 (d, 2H, J = 8.6 Hz), 6.90 (d,
2H, J = 8.6 Hz), 5.89 (br s, 1H), 4.77-4.75 (m, 2H), 4.70-4.66 (m,
1H), 4.42 and 4.37 (d, each 1H, J = 12.0 Hz), 3.89-3.64 (m, 5H),
3.81 (s, 3H), 3.46 (s, 2H), 2.17 (ddd, 1H, J = 14.0, 7.3, 4.6 Hz),
[a]D23 +18.8 (c 1.75, CHCl3).
Synthesis 2000, No. 13, 1894–1906 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthetic Studies on Azadirachtin
[a]D22 -0.40 (c 1.54, CHCl3).
1903
IR (neat): nmax = 3064, 2956, 2912, 2876, 1782, 1754, 1460, 1416,
1374, 1344, 1242, 1198, 1136, 1076, 1036, 886 cm-1.
IR (neat): nmax = 3436, 3112, 2992, 2940, 2872, 1780, 1742, 1640,
1498, 1456, 1376, 1308, 1260, 1198, 1150, 1112, 1074, 1028, 890
cm-1.
1H NMR (300 MHz, CDCl3): d = 7.38-7.29 (m, 5H), 6.24 (dd, 1H,
J = 15.0, 10.0 Hz), 6.05 (dd, 1H, J = 16.0, 10.0 Hz), 5.97-5.96 (m,
1H), 5.83 (dt, 1H, J = 15.0, 5.8 Hz), 5.40 (d, 1H, J = 16.0 Hz), 4.90-
4.89 (m, 3H), 4.52 (s, 2H), 4.48-4.35 (m, 2H), 4.07-3.74 (m, 6H),
3.75 (br s, 1H), 1.87-1.73 (m, 2H), 1.45 and 1.41 (s, each 3H).
1H NMR (300 MHz, CDCl3): d = 6.43 (d, 1H, J = 15.4 Hz), 6.23 (d,
1H, J = 15.4 Hz), 5.99 (s, 1H), 4.87 (s, 2H), 4.76-4.71 (m, 1H), 4.04
(dd, 1H, J = 7.1, 3.3 Hz), 3.89 (d, 1H, J = 12.0 Hz), 3.83, 3.71, and
3.64 (d, each 1H, J = 12.0 Hz), 1.92-1.74 (m, 2H), 1.40 and 1.35 (s,
each 3H), 1.02-0.93 (m, 18H), 0.68-0.58 (m, 12H).
LREIMS: m/z = 637 (M+-Me, 2.0%), 565 (5.6), 425 (5.5), 385 (56),
227 (100).
HREIMS: calcd. for C26H46IO6Si2: 637.1878. Found: 637.1876.
HRMS (FD): calcd. for C25H32O7: 444.2148. Found: 444.2125.
(1E)-3-Benzyloxy-1-tributylstannylprop-1-ene
(1’R,3’S,1’’’E,3’’’E)-5-(5’’’-Benzyloxypenta-1’’’,3’’’-dienyl)-5-
{1’,3’-dihydroxy[furan-2’’(5’’H)-on-4’’-yl]propyl}-2,2-dimeth-
yl-1,3-dioxane 1’,3’-Carbonate (13)
NaH (1.5 g, a 60% oil suspension, 37.5 mmol) was added to THF
(200 mL) at 0 °C. To the suspension was added a solution of (2E)-
3-tributylstannylprop-2-enol (9.01 g, 25.9 mmol) in THF (50 mL)
at 0 °C. The mixture was stirred at 25 °C for 30 min and cooled to
0 °C. BnBr (3.7 mL, 31.1 mmol) and tetrabutylammonium iodide
(TBAI) (2.0 g, 5.41 mmol) were added and the mixture was stirred
at 25 °C for 4 h. Sat. NH4Cl (100 mL) was added and the mixture
was extracted with Et2O (3 ¥ 200 mL). The extracts were washed
with brine, dried (MgSO4), filtered, and concentrated in vacuo. Pu-
rification of the residue by silica gel chromatography (230/70W,
300 g, hexane/EtOAc, 40:1, 20:1) afforded the benzyl ether (10.7 g,
95%) as a colorless liquid.
To a solution of 11 (40.0 mg, 0.09 mmol) in CH2Cl2 (2 mL) was
added pyridine (0.03 mL, 0.36 mmol) at 0 °C. A solution of triph-
osgene (39.5 mg, 0.13 mmol) in CH2Cl2 (1 mL) was added, and the
mixture was stirred at 0 °C for 20 min. The mixture was diluted with
sat. NH4Cl (1 ml), and then extracted with EtOAc (3 ¥ 5 mL). The
extracts were washed with brine, dried (MgSO4), filtered, and con-
centrated in vacuo. Purification of the residue by PTLC (hexane/
EtOAc, 1:2) afforded 13 (36.7 mg, 87%) as a colorless oil.
[a]D21 -10.7 (c 0.78, CHCl3).
IR (neat): nmax = 2996, 2936, 2872, 1750 (br), 1648, 1456, 1376,
1H NMR (300 MHz, CDCl3): d = 7.35-7.28 (m, 5H), 6.24 (d, 1H,
J = 18.0 Hz), 6.08 (dt, 1H, J = 18.0, 4.9 Hz), 4.52 (s, 2H), 4.06 (d,
2H, J = 4.9 Hz), 1.58-1.25 (m, 18H), 0.89 (t, 9H, J = 7.2 Hz).
1246, 1198, 1146, 1114, 1078, 1032, 888 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.38-7.26 (m, 5H), 6.24 (dd, 1H,
J = 15.0, 10.0 Hz), 6.15 (s, 1H), 6.07 (dd, 1H, J = 16.0, 10.0 Hz),
5.90-5.81 (m, 1H), 5.46-5.25 (m, 3H), 4.95 (s, 2H), 4.53 (s, 2H),
4.17-4.01 (m, 4H), 3.77 (d, 2H, J = 15.0 Hz), 2.42-2.37 (m, 1H),
2.05-1.96 (m, 1H), 1.48 and 1.43 (s, each 3H).
(1’R,3’S,1’’’E,3’’’E)-5-(5’’’-Benzyloxypenta-1’’’,3’’’-dienyl)-5-
{1’,3’-bistriethylsilyloxy[furan-2’’(5’’H)-on-4’’-yl]propyl}-2,2-
dimethyl-1,3-dioxane (12)
LRMS (FD): m/z = 471 (M++1, 57%), 445 (11), 379 (100), 91 (97).
To a solution of Pd(MeCN)2Cl2 (3.0 mg, 0.012 mmol) in DMF (1
mL) were added a solution of 31 (90.0 mg, 0.14 mmol) in DMF (1.5
mL) and then a solution of (E)-Bu3SnCH=CHCH2OBn (75.4 mg,
0.17 mmol) in DMF (1 mL), and the mixture was stirred at 26 °C for
3 h. The mixture was diluted with H2O (3 mL), and extracted with
Et2O (3 ¥ 5 mL). The extracts were washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo. Purification of the
residue by silica gel chromatography (400/230W, 5 g, hexane/
EtOAc, 10:1) afforded 12 (69.9 mg, 76%) as a colorless oil.
HRMS (FD): calcd. for C26H31O8: 471.2019. Found: 471.2035.
Intramolecular Diels-Alder (IMDA) Reaction of 11
To a thick wall glass tube (f 10 ¥ 120 mm, 2 mm in thickness) was
added a solution of 11 (13.6 mg, 0.031 mmol) and BHT (1 mg, cat.)
in toluene (2 mL). The tube was sealed under Ar and heated at
200 °C for 27 h, and then allowed to cool to 25 °C. The reaction
mixture was concentrated in vacuo to afford the mixture of adducts.
Purification of the residue by PTLC (hexane/EtOAc, 1:3) afforded
32 (3.9 mg, 29%) and 33 (3.5 mg, 26%) as colorless oils.
[a]D22 +20.8 (c 2.19, CHCl3).
IR (neat): nmax = 2956, 2912, 2876, 1782, 1756, 1456, 1416, 1372,
1342, 1310, 1242, 1198, 1074, 1004, 884 cm-1.
32
[a]D22 +6.6 (c 0.17, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.38-7.26 (m, 5H), 6.23 (dd, 1H,
J = 15.0, 10.0 Hz), 6.05 (dd, 1H, J = 16.0, 10.0 Hz), 5.98 (s, 1H),
5.78 (dt, 1H, J = 15.0, 6.0 Hz), 5.52 (d, 1H, J = 16.0 Hz), 4.87 (br s,
2H), 4.75 (dd, 1H, J = 8.8, 5.7 Hz), 4.52 (s, 2H), 4.13 (dd, 1H,
J = 7.1, 2.9 Hz), 4.06 (d, 1H, J = 6.0 Hz), 3.90-3.85 (m, 2H), 3.68
(dd, 1H, J = 12.0, 2.2 Hz), 3.59 (d, 1H, J = 12.0 Hz), 1.93-1.59 (m,
2H), 1.40 and 1.34 (s, each 3H), 1.01-0.88 (m, 18H), 0.70-0.56 (m,
12H).
IR (neat): nmax = 3464, 2992, 2932, 1768, 1456, 1374, 1320, 1260,
1228, 1198, 1162, 1092, 1074, 1030, 838 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.35-7.27 (m, 5H), 6.13-6.09 (m,
2H), 4.61-4.52 (m, 3H), 4.09-3.65 (m, 9H), 3.39 (d, 1H, J = 8.8 Hz),
3.27 (d, 1H, J = 12.0 Hz), 2.93-2.91 (m, 1H), 2.66-2.60 (m, 2H),
2.29-2.24 (m, 1H), 2.10-2.05 (m, 1H), 1.47 and 1.37 (s, each 3H).
LRMS (FD): m/z = 445 (M++1, 95%), 429 (100), 215 (6.9), 91 (17).
HRMS (FD): calcd. for C37H60O7Si2: 672.3878. Found: 672.3861.
HRMS (FD): calcd. for C25H33O7: 445.2226. Found: 445.2223.
(1’R,3’S,1’’’E,3’’’E)-5-(5’’’-Benzyloxypenta-1’’’,3’’’-dienyl)-5-
{1’,3’-dihydroxy[furan-2’’(5’’H)-on-4’’-yl]propyl}-2,2-dimeth-
yl-1,3-dioxane (11)
33
[a]D23 +7.2 (c 0.10, CHCl3).
IR (neat): nmax = 3476, 2992, 2932, 2872, 1752(br), 1456, 1380,
To a solution of 12 (121 mg, 0.18 mmol) in THF (3 mL) were added
HOAc (0.07 mL, 0.91 mmol) and TBAF (0.72 mL, 1.0 M in THF,
0.72 mmol), and the mixture was stirred at 26 °C for 3 h. The mix-
ture was diluted with sat. NH4Cl (1 mL), and extracted with EtOAc
(3 ¥ 5 mL). The extracts were washed with sat. NaHCO3, brine,
dried (MgSO4), filtered, and concentrated in vacuo. Purification of
the residue by silica gel chromatography (230/70W, 5 g, hexane/
EtOAc, 1:2) afforded 11 (0.079 g, 99%) as a colorless oil.
1266, 1168, 1080, 1032, 434 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.35-7.28 (m, 5H), 6.33-6.24 (m,
1H), 6.13-6.09 (m, 1H), 4.60 and 4.54 (d, each 1H, J = 12.0 Hz),
4.22 (d, 1H, J = 9.0 Hz), 4.13-4.08 (m, 1H), 3.99-3.53 (m, 10H),
2.92 (d, 1H, J = 8.6 Hz), 2.19-2.13 (m, 2H), 1.84-1.76 (m, 1H), 1.69
(br s, 1H), 1.43 and 1.39 (s, each 3H).
Synthesis 2000, No. 13, 1894–1906 ISSN 0039-7881 © Thieme Stuttgart · New York

1904
Y. Yamamoto et al.
SPECIAL TOPIC
LRMS (FD): m/z = 445 (M++1, 48%), 429 (100), 390 (3.4), 279
(8.2), 215 (7.8), 91 (17).
mol%) in toluene (5 mL). The tube was sealed under Ar and heated
at 200 °C for 27 h, and then allowed to cool to 25 °C. The mixture
was concentrated in vacuo to afford the mixture of adducts. Purifi-
cation of the residue by PTLC (hexane/EtOAc, 1:2) afforded 37
(24.9 mg, 67%) and 38 (5.1 mg, 14%) as colorless oils.
HRMS (FD): calcd. for C25H33O7: 445.2226. Found: 445.2249.
Silylation of 32
37
To a solution of 32 (3.9 mg, 0.0088 mmol) in CH2Cl2 (0.8 mL) were
added 2,6-lutidine (0.017 mL, 0.14 mmol) and TESOTf (0.016 mL,
0.071 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min.
The mixture was diluted with sat. NH4Cl (1 mL), and extracted with
Et2O (3 ¥ 3 mL). The extracts were washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo. Purification of the
residue by PTLC (hexane/EtOAc, 3:1) afforded 34 (4.8 mg, 81%)
as a colorless oil.
[a]D22 +19.0 (c 0.51, CHCl3).
IR (neat): nmax 3020, 1780, 1732, 1390, 1374, 1320, 1264, 1216,
1182, 1114, 1086, 1036, 756 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.38-7.26 (m, 5H), 6.20-6.09 (m,
2H), 5.17-5.16 (m, 1H), 4.59-4.58 (m, 1H), 4.54 and 4.49 (d, each
1H, J = 12.0 Hz), 3.98-3.66 (m, 7H), 3.38 (dd, 1H, J = 12.0, 1.2
Hz), 3.24 (d, 1H, J = 9.4 Hz), 2.70-2.64 (m, 1H), 2.53-2.45 (m,
1H), 2.35-2.26 (m, 2H), 1.46 and 1.38 (s, each 3H).
[a]D21 +12.2 (c 0.24, CHCl3).
IR (neat): nmax = 2952, 2928, 2876, 1772, 1228, 1184, 1162, 1110,
HRMS (FD): calcd for C26H30O8: 470.1941. Found: 470.1935.
1084, 1004, 734 cm-1.
38
1H NMR (300 MHz, C6D6): d = 7.41-7.19 (m, 5H), 6.10-6.07 (m,
1H), 5.94-5.90 (m, 1H), 4.49 and 4.44 (d, each 1H, J = 11.0 Hz),
4.34-4.33 (m, 1H), 4.10-4.04 (m, 1H), 3.95 (d, 1H, J = 12.0 Hz),
3.78 (dd, 1H, J = 8.8, 6.8 Hz), 3.67 (d, 1H, J = 12.0 Hz), 3.62-3.57
(m, 2H), 3.49 (d, 1H, J = 9.2 Hz), 3.40 (d, 1H, J = 8.6 Hz), 3.22 (d,
1H, J = 9.2 Hz), 2.92 (d, 1H, J = 12.0 Hz), 2.77 and 2.62 (br s, each
1H), 1.75-1.70 (m, 1H), 1.52-1.47 (m, 1H), 1.43 and 1.29 (s, each
3H), 1.07-0.94 (m, 18H), 0.80-0.62 (m, 12H).
[a]D21 -57.0 (c 0.10, CHCl3).
IR (neat): nmax = 2992, 2932, 2872, 1752 (br), 1456, 1380, 1266,
1168, 1080, 1032, 434 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.36-7.27 (m, 5H), 5.92-5.87 (m,
1H), 5.70-5.65 (m, 1H), 5.11-5.10 (m, 1H), 4.63 and 4.53 (d, each
1H, J = 12.0 Hz), 4.40-4.38 (m, 1H), 4.26 (d, 1H, J = 12.0 Hz),
4.13 (d, 1H, J = 9.7 Hz), 4.01-3.75 (m, 5H), 3.69 (dd, 1H, J = 9.3,
6.0 Hz), 2.95-2.89 (m, 1H), 2.89 (d, 1H, J = 12.0 Hz), 2.45-2.37
(m, 2H), 2.11-2.06 (m, 1H), 1.44 and 1.40 (s, each 3H).
HRMS (FD): calcd. for C37H60O7Si2: 672.3877. Found: 672.3865.
HRMS (FD): calcd. for C26H30O8: 470.1941. Found: 470.1920.
Silylation of 33
To a solution of 33 (3.4 mg, 0.0077 mmol) in CH2Cl2 (1 mL) were
added 2,6-lutidine (0.017 mL, 0.15 mmol) and TESOTf (0.016 mL,
0.071 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min.
The mixture was diluted with sat. NH4Cl (1 mL), and extracted with
Et2O (3 ¥ 3 mL). The extracts were washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo. Purification of the
residue by PTLC (hexane/EtOAc, 3:1) afforded 35 (3.4 mg, 66%)
as a colorless oil.
Saponification of the Carbonate Part of 37
To a solution of 37 (4.8 mg, 0.010 mmol) in CH2Cl2 (0.6 mL) and
MeOH (1 mL) was added K2CO3 (17.8 mg, 0.13 mmol) at 0 °C and
the mixture was stirred at 0 °C to 25 °C for 30 min. The mixture
was treated with sat. NH4Cl (1 mL), and extracted with EtOAc
(3 ¥ 3 mL). The extracts were washed with brine, dried (MgSO4),
filtered, and concentrated in vacuo. Purification of the residue by
PTLC (hexane/EtOAc, 1:4) afforded the diol (4.5 mg, ~100%) as a
colorless oil, 1H NMR data of which were identical with those of 32.
[a]D21 -4.3 (c 0.17, CHCl3).
IR (neat): nmax = 2956, 2924, 2876, 1762, 1458, 1418, 1378, 1266,
1240, 1206, 1174, 1110, 1074, 1042, 840 cm-1.
Saponification of the Carbonate Part of 38
1H NMR (300 MHz, CDCl3): d = 7.38-7.28 (m, 5H), 6.94-6.19 (m,
1H), 6.02-5.97 (m, 1H), 4.62 and 4.54 (d, each 1H, J = 11.0 Hz),
4.30 (dd, 1H, J = 12.0 Hz, 4.2 Hz), 4.17 (d, 2H, J = 12.0 Hz), 4.03-
3.97 (m, 2H), 3.75-3.69 (m, 1H), 3.64 (dd, 1H, J = 12.0, 4.2 Hz),
3.51-3.44 (m, 1H), 3.27-3.24 (m, 2H), 2.74 (d, 1H, J = 8.4 Hz),
2.60 (br s, 1H), 1.93-1.86 (m, 1H), 1.78 (br s, 1H), 1.69-1.60 (m,
1H), 1.40 and 1.38 (s, each 3H), 1.07-0.83 (m, 18H), 0.67-0.51 (m,
12H).
To a solution of 38 (4.8 mg, 0.01 mmol) in CH2Cl2 (0.5 mL) and
MeOH (1 mL) was added K2CO3 (15 mg, 0.11 mmol) at 0 °C and
the mixture was stirred at 25 °C for 30 min. The mixture was treated
with sat. NH4Cl (1 mL), and extracted with EtOAc (3 ¥ 3 mL). The
extracts were washed with brine, dried (MgSO4), filtered, and con-
centrated in vacuo. Purification of the residue by PTLC (hexane/
EtOAc, 1:4) afforded 39 (2.2 mg, 54%) as a colorless oil.
[a]D22 -48.2 (c 0.11, CHCl3).
HRMS (FD): calcd. for C37H60O7Si2: 672.3877. Found: 672.3858.
IR (neat): nmax = 3450, 2988, 2944, 2876, 1750, 1448, 1372, 1300,
The peaks in the 1H NMR spectrum of 35 were superimposed with
those of the major peaks corresponding to the major adduct from the
starting triene 12 (vide infra).
1248, 1198, 1152, 1126, 1032, 886 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.38-7.26 (m, 5H), 6.01-5.87 (m,
2H), 5.27 (dd, 1H, J = 12.0, 4.0 Hz), 5.05-4.97 (m, 3H), 4.21-3.45
(m, 10H), 2.61-2.46 (m, 2H), 2.37-2.29 (m, 1H), 1.95 (br s, 1H),
1.76-1.66 (m, 1H), 1.36 (s, 6H).
IMDA Reaction of 12
To a thick wall glass tube (f 10 ¥ 120 mm, 2 mm in thickness) was
added a solution of 12 (10.3 mg, 0.015 mmol) and BHT (1 mg, cat.)
in toluene (1.5 mL). The tube was sealed under Ar and heated at
200 °C for 27 h. The mixture was allowed to cool to 25 °C and con-
centrated in vacuo to afford the mixture of adducts. Purification of
the residue by PTLC (hexane/EtOAc, 3:1) afforded a 2.5:1 mixture
(8.4 mg) of 35 and 36 as a colorless oil in 82% combined yield.
LRMS (FD): m/z 445 (M++1, 97%), 429 (100), 91 (23).
HRMS (FD): calcd. for C25H33O7: 445.2226. Found: 445.2224.
Silylation of 39
To a solution of 39 (2.2 mg, 0.005 mmol) in CH2Cl2 (0.8 mL) were
added 2,6-lutidine (0.012 mL, 0.10 mmol) and TESOTf (0.011 mL,
0.05 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min.
The mixture was diluted with sat. NH4Cl (1 mL), and extracted with
Et2O (3 ¥ 3 mL). The extracts were washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo. Purification of the
IMDA Reaction of 13
To a thick wall glass tube (f 10 ¥ 180 mm, 2 mm in thickness) was
added a solution of 13 (36.7 mg, 0.078 mmol) and BHT (3 mg, 20
Synthesis 2000, No. 13, 1894–1906 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthetic Studies on Azadirachtin
1905
residue by PTLC (hexane/EtOAc, 3:1) afforded 40 (3.7 mg, ~100%)
as a colorless oil.
[a]D24 -12.3 (c 0.19, CHCl3).
J = 15.0 Hz), 5.80 (d, 1H, J = 16.0 Hz), 5.48-5.44 (m, 1H), 5.26
(dd, 1H, J = 12.0, 3.1 Hz), 4.96-4.95 (m, 2H), 4.17 (dd, 1H,
J = 12.0, 2.7 Hz), 4.04 (d, 1H, J = 12.0 Hz), 3.85-3.74 (m, 2H),
3.75 (s, 3H), 2.47-2.41 (m, 1H), 2.00-1.96 (m, 1H), 1.49 and 1.44
(s, each 3H).
IR (neat): nmax = 2998, 2946, 2876, 1750, 1432, 1372, 1248, 1198,
1142, 1126, 1032, 888 cm-1.
LRMS (FD): m/z = 409 (M++1, 78%), 393 (56), 320 (100).
1H NMR (300 MHz, CDCl3): d = 7.33-7.26 (m, 5H), 6.24-6.17 (m,
1H), 5.90-5.87 (m, 1H), 4.70 (dd, 1H, J = 11.0, 7.0 Hz), 4.54 (s,
2H), 4.10 (d, 1H, J = 12.0 Hz), 4.04 (d, 1H, J = 12.0 Hz), 3.95-3.87
(m, 2H), 3.77-3.72 (m, 1H), 3.51-3.33 (m, 4H), 2.69 (br s, 1H),
2.50 (br s, 1H), 2.27, (br s, 1H), 2.20-2.06 (m, 1H), 1.73-1.69 (m,
1H), 1.35 (s, 6H), 0.98-0.86 (m, 18H), 0.67-0.52 (m, 12H).
HRMS (FD): calcd. for C20H25O9: 409.1498. Found: 409.1476.
Ethyl (1’R,3’S,2E,4E)-5-{1’,3’-Dihydroxy-[furan-2’’(5’’H)-on-
4’’-yl]propyl-2’’’,2’’’-dimethyl-1’’’,3’’’-dioxan-5’’’-yl}penta-2,4-
dienoate (44)
To a solution of i-Pr2NH (0.07 mL, 0.52 mmol) in THF (0.8 mL)
was added BuLi (0.33 mL, 1.50 M in hexane, 0.51 mmol) at 0 °C
and the mixture was stirred at 0 °C for 30 min. Ethyl 4-dieth-
ylphosphonocrotonate (0.16 mL, 0.58 mmol) was added and the
mixture was stirred at 0 °C for 30 min. A solution of 30 (74.7 mg,
0.14 mmol) in THF (2 mL) was added and the mixture was stirred
at 0 °C for 30 min. The mixture was diluted with sat. NH4Cl (1 mL),
and then extracted with EtOAc (3 ¥ 5 mL). The extracts were
washed with brine, dried MgSO4, filtered, and concentrated in vac-
uo. To a solution of the residue in THF (1 mL) were added HOAc
(0.056 mL, 0.72 mmol) and TBAF (0.55 mL, 1.0 M in THF, 0.55
mmol), and the mixture was stirred at 25 °C for 4 h. The mixture
was diluted with sat. NH4Cl (1 mL), and then extracted with EtOAc
(3 ¥ 3 mL). The extracts were washed with sat. NaHCO3 and brine,
dried (MgSO4), filtered, and concentrated in vacuo. Purification of
the residue by silica gel chromatography (400/230W, 5 g, hexane/
EtOAc, 2:3) afforded 44 (31.1 mg, 56% for 2 steps) as a white amor-
phous solid.
HRMS (FD): calcd. for C37H60O7Si2: 672.3877. Found: 672.3866.
The 1H NMR spectrum of 40 was not superimposable with that of
the minor adduct 36 from the starting triene 12 (vide ante).
Methyl (1’R,3’S,2E,4E)-5-{1’,3’-Dihydroxy-[furan-2’’(5’’H)-on-
4’’-yl]propyl-2’’’,2’’’-dimethyl-1’’’,3’’’-dioxan-5’’’-yl}penta-2,4-
dienoate (43)
To a solution of i-Pr2NH (0.096 mL, 0.68 mmol) in THF (1.5 mL)
was added BuLi (0.45 mL, 1.50 M in hexane, 0.68 mmol) at 0 °C
and the mixture was stirred at 0 °C for 30 min. Methyl 4-dieth-
ylphosphonocrotonate (0.164 g, 0.69 mmol) was added and the
mixture was stirred at 0 °C for 30 min. A solution of 30 (0.125 g,
0.24 mmol) in THF (3 mL) was added and the mixture was stirred
at 0 °C for 30 min. The solution was mixed with sat. NH4Cl (2 mL)
and extracted with EtOAc (3 ¥ 7 mL). The extracts were washed
with brine, dried MgSO4, filtered, and concentrated in vacuo. To a
solution of the residue in THF (6 mL) were added HOAc (0.092 mL,
1.18 mmol) and TBAF (0.95 mL, 1.0 M in THF, 0.95 mmol), and
the mixture was stirred at 25 °C for 4 h. The mixture was diluted
with sat. NH4Cl (2 mL), and extracted with EtOAc (3 ¥ 5 mL). The
extracts were washed with sat. NaHCO3 and brine, dried MgSO4,
filtered, and concentrated in vacuo. Purification of the residue by
silica gel chromatography (400/230W, 5 g, hexane/EtOAc, 2:3) af-
forded 43 (0.057 g, 63% for 2 steps) as a white amorphous solid.
[a]D21 -2.1 (c 0.18, CHCl3).
IR (neat): nmax = 3456, 2988, 2944, 2876, 1780, 1750, 1640, 1448,
1372, 1300, 1250, 1198, 1154, 1076, 1032, 886 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.26-7.17 (m, 1H), 6.21 (dd, 1H,
J = 16.0, 10.0 Hz), 5.98-5.84 (m, 3H), 4.90-4.89 (m, 3H), 4.49-
4.45 (m, 1H), 4.25-3.76 (m, 7H), 3.10-3.08 (m, 1H), 1.82-1.76
(m, 2H), 1.45 and 1.43 (s, each 3H), 1.36-1.24 (m, 3H).
LRMS (FD): m/z = 397 (M++1, 100%), 381 (94), 363 (13), 308
(36), 290 (21), 182 (44).
[a]D21 -2.5 (c 0.26, CHCl3).
IR (neat): nmax = 3456, 2992, 2952, 2876, 1780, 1750, 1642, 1618,
1440, 1376, 1342, 1300, 1252, 1200, 1154, 1110, 1078, 1030, 884
cm-1.
HRMS (FD): calcd. for C20H29O8: 397.1863. Found: 397.1859.
1H NMR (300 MHz, CDCl3): d = 7.22 (dd, 1H, J = 15.0, 11.0 Hz),
6.22 (dd, 1H, J = 16.0, 11.0 Hz), 5.97-5.87 (m, 3H), 4.93-4.89 (m,
3H), 4.46 (dd, 1H, J = 9.2, 3.1 Hz), 4.05 (dd, 1H, J = 12.0, 2.0 Hz),
3.94 (d, 1H, J = 12.0 Hz), 3.85-3.74 (m, 2H), 3.76 (s, 3H), 2.57-
2.52 (m, 1H), 1.84-1.70 (m, 2H), 1.45 and 1.43 (s, each 3H).
LRMS (FD): m/z = 383 (M++1, 94%), 367 (100), 324 (23), 294 (31),
242 (47), 168 (53).
Ethoxycarbonyl Triene Cyclic Carbonate 42
To a solution of 44 (29.2 mg, 0.074 mmol) in CH2Cl2 (2.5 mL) were
added pyridine (0.018 mL, 0.22 mmol) and then a solution of tri-
phosgene (35.5 mg, 0.12 mmol) in CH2Cl2 (1.5 mL) at 0 °C, and the
mixture was stirred at 0 °C for 15 min. Then, the mixture was dilut-
ed with sat. NH4Cl (1 mL), and extracted with EtOAc (3 ¥ 3 mL).
The extracts were washed with brine, dried (MgSO4), filtered, and
concentrated in vacuo. Purification of the residue by PTLC (hexane/
EtOAc, 1:3) afforded 42 (32.9 mg, ~100%) as a white amorphous
solid.
HRMS (FD): calcd. for C19H27O8: 383.1706. Found: 383.1692.
Methoxycarbonyl Triene Cyclic Carbonate 41
[a]D21 -19.1 (c 0.32, CHCl3).
To a solution of 43 (21.6 mg, 0.057 mmol) in CH2Cl2 (2 mL) were
added pyridine (0.014 mL, 0.17 mmol) and a solution of triphos-
gene (23.2 mg, 0.076 mmol) in CH2Cl2 (1 mL), and the mixture was
stirred at 0 °C for 20 min. Then, the mixture was diluted with sat.
NH4Cl (1 mL), and extracted with EtOAc (3 ¥ 3 mL). The extracts
were washed with brine, dried (MgSO4), filtered, and concentrated
in vacuo. Purification of the residue by PTLC (hexane/EtOAc, 1:3)
afforded 41 (18.0 mg, 79%) as a white amorphous solid.
IR (neat): nmax = 2988, 2944, 2876, 1780, 1750, 1710, 1648, 1448,
1372, 1300, 1248, 1198, 1152, 1126, 1032, 886 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.18 (dd, 1H, J = 15.0, 11.0 Hz),
6.26-6.15 (m, 2H), 5.93 (d, 1H, J = 15.0 Hz), 5.79 (d, 1H, J = 16.0
Hz), 5.47-5.44 (m, 1H), 5.27 (dd, 1H, J = 12.0, 3.1 Hz), 4.96-4.89
(m, 2H), 4.21 (q, 2H, J = 7.1 Hz), 4.18-4.14 (m, 1H), 4.05 (d, 1H,
J = 12.0 Hz), 3.82 (dd, 1H, J = 12.0, 2.6 Hz), 3.81 (d, 1H, J = 12.0
Hz), 2.47-2.40 (m, 1H), 2.00-1.95 (m, 1H), 1.49 and 1.44 (s, each
3H), 1.30 (t, 3H, J = 7.1 Hz).
[a]D21 -26.3 (c 0.71, CHCl3).
IR (neat): nmax = 2996, 2952, 2880, 1752, 1714, 1646, 1618, 1440,
1378, 1352, 1306, 1250, 1198, 1148, 1128, 1034, 888 cm-1.
LRMS (FD): m/z = 423 (M++1, 1.85%), 407 (65), 363 (21), 334
(100).
1H NMR (300 MHz, CDCl3): d = 7.19 (dd, 1H, J = 15.0, 10.0 Hz),
6.22 (dd, 1H, J = 16.0, 11.0 Hz), 6.17-6.15 (m, 1H), 5.94 (d, 1H,
Synthesis 2000, No. 13, 1894–1906 ISSN 0039-7881 © Thieme Stuttgart · New York

1906
Y. Yamamoto et al.
SPECIAL TOPIC
IMDA Reaction of 41
(d, 1H, J = 5.3 Hz), 3.36 (dd, 1H, J = 9.3, 1.3 Hz), 2.70-2.69 (m,
1H), 2.50 (dt, 1H, J = 16.0, 4.1 Hz), 2.31 (br d, 1H, J = 16.0 Hz),
1.45 and 1.38 (s, each 3H), 1.29-1.25 (m, 3H).
LRMS (FD): m/z = 423 (M++1, 2.2%), 409 (64), 393 (100).
To a thick wall glass tube (f 10 ¥ 120 mm, 2 mm in thickness) was
added a solution of 41 (14.0 mg, 0.034 mmol) and BHT (2 mg, 20
mol%) in toluene (2 mL). The tube was sealed under Ar and heated
at 200 °C for 67 h, and then allowed to cool to 25 °C. The mixture
was concentrated in vacuo to afford the mixture of adducts; the 1H
NMR spectrum of which revealed a 3.7:1 mixture of 45 and 46. Pu-
rification of the residue by PTLC (hexane/EtOAc, 1:2) afforded 45
(5.6 mg, 40%) and 46 (1.9 mg, 14%) as white amorphous solids.
48
Mp: 189-191 °C.
IR (neat): nmax = 2928, 2856, 1780, 1742, 1454, 1378, 1260, 1116,
1078, 1036, 928, 888 cm-1.
1H NMR (300 MHz, CDCl3): d 6.64 (dt, 1H, J = 9.3, 3.1 Hz), 6.21
(dt, 1H, J = 9.7, 3.7 Hz), 5.22-5.21 (m, 1H), 4.65-4.64 (m, 1H),
4.29 (q, 2H, J = 7.2 Hz), 4.13 (d, 1H, J = 13.0 Hz), 4.09-3.76 (m,
4H), 3.63 (d, 1H, J = 8.2 Hz), 3.42 (dd, 1H, J = 12.0, 1.8 Hz), 3.24-
3.21 (m, 1H), 2.53 (dt, 1H, J = 15.0, 4.0 Hz), 2.33 (br d, 1H,
J = 15.0 Hz), 2.05 (br s, 1H), 1.48 and 1.40 (s, each 3H), 1.34 (t, 3H,
J = 7.2 Hz).
45
Mp: 242-247 °C (gradually melted).
[a]D20 -58.9 (c 0.055, CHCl3).
IR (KBr): nmax = 3020, 2316, 1780, 1742, 1558, 1480, 1196, 1174,
1114, 968, 834 cm-1.
1H NMR (300 MHz, CDCl3): d = 6.32 (dd, 1H, J = 9.5, 3.3 Hz),
6.27-6.21 (m, 1H), 5.12-5.10 (m, 1H), 4.57-4.56 (m, 1H), 4.04-
3.96 (m, 2H), 3.76 (s, 3H), 3.90-3.74 (m, 4H), 3.67 (d, 1H, J = 7.0
Hz), 3.36 (dd, 1H, J = 12.0, 1.7 Hz), 2.70-2.69 (m, 1H), 2.54-2.47
(m, 1H), 2.34-2.29 (m, 1H), 1.45 and 1.38 (s, each 3H).
LRMS (FD): m/z = 423 (M++1, 1.9%), 407 (2.7), and 393 (100).
Acknowledgement
LRMS (FD): m/z = 409 (M++1, 69%), 393 (100).
Financial support for this work was provided in part by a Grant-in-
Aid for Scientific Research from the Ministry of Education, Sci-
ence, Sports, and Culture, Japan (09780516, J. I.). We thank Prof.
T. Inabe at Hokkaido University for permission to use the X-ray dif-
fractometer.
HRMS (FD): calcd for C20H25O9: 409.1498. Found: 409.1488.
46
[a]D20 +39.6 (c 0.025, CHCl3).
IR (KBr): nmax = 3020, 1780, 1732, 1390, 1374, 1320, 1264, 1216,
1182, 1114, 1086, 1036, 756 cm-1.
1H NMR (300 MHz, CDCl3): d = 6.66-6.61(m, 1H), 6.25-6.19 (m,
1H), 5.22-5.20 (m, 1H), 4.66-4.63 (m, 1H), 4.04 (d, 1H, J = 12.0
Hz), 3.83 (s, 3H), 3.95-3.76 (m, 4H), 3.63 (d, 1H, J = 8.2 Hz), 3.42
(dd, 1H, J = 12.0, 1.8 Hz), 3.27-3.24 (m, 1H), 2.55-2.49 (m, 1H),
2.34-2.29 (m, 1H), 2.15 (br s, 1H), 1.48 and 1.40 (s, each 3H).
References
(1) a) Kanoh, N.; Ishihara, J.; Murai, A. Synlett 1995, 895.
b) Kanoh, N.; Ishihara, J.; Murai, A. Synlett 1997, 737.
c) Ishihara, J.; Fukuzaki, T.; Murai, A. Tetrahedron Lett.
1999, 40, 1907.
d) Ishihara, J.; Yamamoto, Y.; Kanoh, N.; Murai, A.
Tetrahedron Lett. 1999, 40, 4387.
(2) Kanoh, N.; Ishihara, J.; Yamamoto, Y.; Murai, A. the previous
paper.
(3) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caulfield, C.; Chang, G.; Hendrickson, T.; Still,
W. C. J. Comput. Chem. 1990, 11, 440.
(4) Raimondi, L.; Brown, F. K.; Gonzalez, J.; Houk, K. N. J. Am.
Chem. Soc. 1992, 114, 4796.
(5) Block, P. Org. Synth., Coll. Vol. 5, 1973, 381.
(6) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105,
2092.
(7) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092.
LRMS (FD): m/z = 409 (M++1, 44%), 393 (100).
HRMS (FD): calcd. for C20H25O9: 409.1498. Found: 409.1493.
Equilibration between 46 and 45
To a thick wall glass tube (f 10 ¥ 120 mm, 2 mm in thickness) was
added a solution of 46 (3.7 mg, 0.009 mmol) and BHT (1 mg, cat.)
in toluene (1.2 mL). The tube was sealed under Ar and heated at
200 °C for 67 h. The mixture was allowed to cool to 25 °C and con-
centrated in vacuo to afford a 3.2:1 mixture of 45 and 46 (2.8 mg,
76%) as determined from its 1H NMR spectrum.
IMDA Reaction of 42
To a thick wall glass tube (f 10 ¥ 120 mm, 2 mm in thickness) was
added a solution of 42 (16.4 mg, 0.038 mmol) and BHT (2 mg, 20
mol%) in toluene (2 mL). The tube was sealed under Ar and heated
at 200 °C for 60 h, and then allowed to cool to 25 °C. The mixture
was concentrated in vacuo to afford the mixture of adducts. Purifi-
cation of the residue by PTLC (hexane/EtOAc, 1:3) afforded 47 (5.0
mg, 30%) as white crystals and 48 (2.0 mg, 12%) as a white solid.
(8) Mitsunobu, O. Synthesis 1981, 1.
(9) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(10) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813.
(11) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94,
5897.
Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem.
Soc. 1976, 98, 2868.
Ireland, R. E. Aldrichimica Acta 1988, 21, 59.
(12) Wadsworth, W. S. Jr. Org. React. (New York) 1977, 25, 73.
(13) The bond lengths and angles of the crystal of 47 are
summarized as supporting information.
47
Mp: 228-230 °C.
[a]D21 -65.0 (c 0.16, CHCl3).
IR (neat): nmax = 3020, 2932, 1780, 1758, 1720, 1388, 1376, 1300,
1214, 1174, 1120, 1076, 1064, 834, 826 cm-1.
1H NMR (300 MHz, CDCl3): d = 6.33-6.22 (m, 2H), 5.12-5.11 (m,
1H), 4.57-4.56 (m, 1H), 4.26-4.16 (m, 2H), 4.02 (d, 1H, J = 7.4
Hz), 3.98 (d, 1H, J = 7.3 Hz), 3.88 (d, 1H, J = 9.3 Hz), 3.87 (t, 1H,
J = 9.2 Hz), 3.81 (d, 1H, J = 0.9 Hz), 3.76 (d, 1H, J = 9.3 Hz), 3.65
Article Identifier:
1437-210X,E;2000,0,13,1894,1906,ftx,en;E10600SS.pdf
Synthesis 2000, No. 13, 1894–1906 ISSN 0039-7881 © Thieme Stuttgart · New York