Synthetic studies on azadirachtin: Asymmetric synthesis of the tetracyclic decalin part of azadirachtin

Article abstract of DOI:10.1055/s-2000-8223

A synthesis of the tetracyclic decalin part of azadirachtin in the naturally occurring form is described. The key reactions involve the Corey-Bakshi-Shibata (CBS) asymmetric reduction of the ketone, and an intramolecular Diels-Alder (IMDA) reaction.

Full text of DOI:10.1055/s-2000-8223

1878
SPECIAL TOPIC
Synthetic Studies on Azadirachtin: Asymmetric Synthesis of the Tetracyclic
Decalin Part of Azadirachtin
Naoki Kanoh,a,b Jun Ishihara,a Yuuko Yamamoto,a 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
cially the vicinal quaternary centers at C8 and C14
Abstract: A synthesis of the tetracyclic decalin part of azadirachtin
(Scheme 1). Our solution to this bond formation began
with the retrosynthetic transformation, which generates
in the naturally occurring form is described. The key reactions in-
volve the Corey-Bakshi-Shibata (CBS) asymmetric reduction of the
carboxylic acid intermediate 2, which could be traced to
ketene acetal 3 by cleavage of the C8-C14 bond. The Ire-
land ester enolate Claisen rearrangement4 of 3 to 2 would
construct the indicated bond.5 We anticipated that the in-
termediate 3 would arise from the tetracyclic decalin 43b
and tricyclic acetal 5.3c Simplification of 4 led to tetracy-
cle 6, which could be constructed from the precursory
triene 7 via an intramolecular Diels-Alder (IMDA) reac-
tion.6,7 We describe herein in detail a stereocontrolled
enantioselective synthesis of the decalin 4, which embod-
ies the western part of azadirachtin.3a,3b,8
ketone, and an intramolecular Diels-Alder (IMDA) reaction.
Key words: azadirachtin, insect antifeedant, decalin, CBS asym-
metric reduction, intramolecular Diels-Alder reaction
Intensive research on azadirachtin (1),1 isolated from the
seeds of the Indian Neem tree Azadirachta indica A. Juss
(Meliaceae), has revealed its strong antifeedant, insect
growth regulatory, and reproductive effects, although
very little has been known of the biochemical mode of its
action at the cellular level.1b Not surprisingly, its structur-
al complexity and biological activity have attracted much
attention among synthetic chemists.2,3
The preparation of several trienes 7 is summarized in
Schemes 2 and 3, including introduction of the butenolide
group by using the modified Wiesner method9 as well as
Tsuji’s Pd(0)-catalyzed diene formation,10 which provided
From the retrosynthetic perspective, azadirachtin (1) pos-
sesses a number of intriguing structural elements, espe-
O
CO2Me
Me
OR
OR
OR
O
O
O
OH
O
RO
Me
CO2H
O
O
O
O
Me
AcO
14
14
8
8
OH
OR
Me
OH
RO
RO
OR
H
O
H
O
MeO2C
2
1
OR
OR
O
O
O
OR
O
RO
O
HO
OR
OR
+
OR
3
7
O
O
RO
RO
OR
O
RO
O
H
O
H
O
OR
ODEIPS
3
5
4
BnO
O
O
O
O
O
RO
RO
H
O
+
OR
H
Br
O
O
O
O
O
O
Me
Me
Me
Me
Me
Me
6
9
7
8
Retrosynthetic Analysis of Azadirachtin (1)
Scheme 1
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthetic Studies on Azadirachtin
1879
O
O
O
O
Br
O
O
11
EtO
OEt
EtO
OEt
EtO
OEt
a
b
c
O
O
O
O
S
O
O
O
O
12
10
13
O
O
e
h
S
f
H
O
d
RO
OR
RO
OR
16, R = Ac
17, R = H
14, R = H
15, R = Ac
19
g
18, R = acetonide
Reagents and conditions: a) NaOEt, 2-(2-bromoethyl)-1,3-dioxolane (11), EtOH, 55 °C, 1 h (73%); b) NaOEt, CH2=CHCH2I, r.t., 20 min
(95%); c) LiAlH4, Et2O, 0 °C, 4h 40 min; d) Ac2O, Et3N, DMAP (cat.), CH2Cl2, 0 °C; r.t., 35 min (89% for 2 steps); e) HS(CH2)3SH, TiCl4
(cat.), CH2Cl2, 0 °C, 30 min (98%); f) LiAlH4, Et2O, 0 °C, 20 min; g) Me2C(OMe)2, PPTS (cat.), CH2Cl2, r.t., 4.5 h (73% for 2 steps); h) MeI,
CaCO3, MeCN/H2O (11:2), 40 °C, 8 h; r.t., 10 h (71%).
Scheme 2
a triene 29 in high E selectivity (>98:2) in 77% yield. The try 1) gave rise to a mixture of three diastereoisomers
TBDMS group of 29 was removed to an alcohol 30 in 35a-c, the structures of which were assigned after leading
good yield. Finally, alcohol 30 was converted to the silyl to their TBDMS derivatives (36a-c), respectively (vide
ethers 31 and 32 (31; TBDPSCl, imidazole, 78%: 32; infra). The respective thermolysis of the other precursors
TIPSCl, imidazole, 58%), as well as the esters 33 and 34 29, 31-34 afforded the respective adducts as a mixture of
(33; Ac2O, pyridine, 93%: 34; p-bromobenzoyl chloride, four diastereoisomers (entries 2-6). The structures of the
1
pyridine, 91%).
adducts 36a-c were confirmed by their careful H NMR
analyses after being separated to the single isomers by
HPLC, followed by conversion to their p-bromobenzoates
With the requisite trienes in hand, the critical IMDA reac-
tion was then examined (Table 1). Thermolysis of 30 (en-
OH
O
O
O
O
O
OTIPS
c
a
b
O
O
O
O
Br
Br
OTIPS
O
23
20
21
22
O
f
O
O
O
O
O
O
RO
TBDMSO
RO
TBDMSO
d
i
g
H
O
OR
O
O
O
O
O
O
O
O
Me
Me
Me
Me
Me
24, R = H
25, R = TBDMS
Me
Me
Me
27, R = H
28, R = CO2Me
29, R = TBDMS
30, R = H
26
j
e
h
31, R = TBDPS
32, R = TIPS
33, R = Ac
k
34, R = p-BrBz
Reagents and conditions: a) Ref. 11; b) TIPSOTf, Et3N, CH2Cl2, 0 °C, 10 min (92%); c) 22, BuLi, Et2O, -78 °C, 1 h, then 19, -78 °C, 1 h; d)
TBAF, THF, 0 °C, 15 min (56% for 2 steps); e) TBDMSCl, imidazole, DMF, r.t., 10 h (76%); f) OsO4 (cat.), NMO, t-BuOH/THF/H2O (2:2:1),
r.t., 13 h; NaIO4, MeOH/H2O (4:3), 0 °C, 20 min (97%); g) CH2=CHMgBr, THF, -78 °C, 20 min; NaBH4, EtOH, 0 °C, 20 min (56%); h)
ClCO2Me, pyridine, CH2Cl2, 0 °C, 1 h 10 min; r.t., 40 min [~100% (70% conversion)]; i) Pd(PPh3)4 (cat.), Et3N, THF, 55 °C, 40 min (77%,
E:Z = >98:2); j) TBAF, THF, 0 °C, 12 min (98%); k) See experimental.
Scheme 3
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

1880
N. Kanoh et al.
Table 1 Intramolecular Diels-Alder Reactions of Trienes 29-34
SPECIAL TOPIC
O
O
O
O
O
O
O
O
O
O
RO
RO
RO
RO
RO
toluene
a sealed tube
+
+
+
195-205 °C
12-24 h
H
H
H
H
O
O
O
O
O
O
O
O
O
O
Me
Me
Me
Me
(exo)
Me
29 ~ 34
a
c
b
d
Me
Me
Me
Me
Me
(endo)
(endo)
(exo)
triene
30: R = H
product
yielda)
a : b : c : db)
entry
50 : 25 : 25 : NDc)
35 : 45 : 15 : 5
49 : 27 : 23 : 2
1
2
3
4
5
6
72%
81%
35a-c
36a-d
37a-d
38a-d
29: R = TBDMS
31: R = TBDPS
76%
96%d)
42 : 30 : 22 : 5
58 : 14 : 25 : 2
59 : 15 : 24 : 2
32: R = TIPS
33: R = Ac
83%
39a-d
40a-d
34: R = pBrBz
83%
aIsolated yield of diastereo mixture.
bRatio was determined by 1H NMR (400 MHz).
cNot detected.
dYield of crude mixture.
40a-c, the typical NOEs of which are summarized in the
Figure. On the other hand, the structure of 36a was defi-
nitely confirmed by its X-ray diffraction analysis.12 The
structure of 36d was determined by NMR analysis (Fig-
ure). In the respective cases of the adducts obtained from
31, 32, and 33, the structures were deduced from the sim-
ilarity of their pattern for the olefinic and oxygenated me-
thine protons in their 1H NMR spectra to the structurally
established compounds mentioned above.
p-BrBz
H
O
O
H
H
H
H
O
O
O
H
O
H
O
H
H
H
O
O
H
H
H
H
H
H
H
H
O
p-BrBz
The results imply that these starting triene systems are
generally suitable for construction of the trans-decalin
(endo-adducts a and b) rather than the undesired cis-deca-
lin (exo-adducts c and d) (Table 1). Especially, the endo-
adducts having the desired configuration were preferably
formed except in the case of TBDMS-triene 29 (entry 2).
We also attempted Lewis acid-catalyzed IMDA reactions
of 30 using Et2AlCl or EtAlCl2 in CH2Cl2, though the cy-
clization did not occur and only decomposition was ob-
served in both cases.
40a
40b
TBDMS
O
H
p-BrBz
H
O
O
H
O
O
O
H
H
O
H
H
H
H
H
O
H
H
H
H
O
Next, we planned to introduce (R)-OH at the C1 by using
asymmetric reduction of the ketone 44 (Scheme 4). Wein-
reb amidation13 of 42, obtained from 19 in 2 steps, afford-
ed the amide 43 in 98% yield, which was coupled
smoothly with lithiofuran prepared from 22 to give 44 in
93% yield based on the recovered starting material (30%).
The results of CBS reduction of 44 with the Corey reagent
4514 or 4615 followed by TBAF treatment are shown in Ta-
ble 2. Use of 45 (10 mol%) and BH3·THF (1.4 equiva-
lents) afforded (+)-24 in excellent optical purity (93%
ee)16 via 23 (entry 1). The best result in the reduction was
obtained when 30 mol% of 45 and 1.0 equivalent of neat
BH3·SMe2 complex were used (entry 3), in which case the
O
36d
NOE Correlations in Adducts 40a, 40b, 40c, and 36d
40c
Figure
yield and the optical purity16 of the resulting (+)-24
amounted to 100% and 97%, respectively. Prolonged re-
action time and a reduced amount of the catalyst caused
low yield, probably because of an incidental hydrobora-
tion of the terminal olefin portion in 23 (entry 2). When
the modified Corey reagent15 was examined, in which B-
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthetic Studies on Azadirachtin
1881
O
O
O
Me
N
R
a
SPy
b
c
OMe
O
O
O
O
O
O
19, R = H
42
43
41, R = OH
O
OH
O
d
O
e
O
O
O
O
OTIPS
OTIPS
44
(R)-23
O
O
O
O
O
O
HO
HO
HO
g
f
H
O
O
O
O
O
O
Me
Me
Me
Me
(+)-30
Me
(–)-35a
Me
(+)-24
Reagents and conditions: a) NaClO2, NaH2PO4·H2O, 2-methylbut-2-ene, t-BuOH/H2O (3:1), -8 °C, 20 min ~; b) PPh3, 2,2'-dipyridyl disulfide,
CH2Cl2, 25 °C, 1h 20 min (96% for 2 steps); c) N,O-dimethylhydroxylamine hydrochloride, Et3N, CH2Cl2, r.t., 70 min (98%); d) 22, t-BuLi,
Et2O, -78 °C, 10 min, then 43, -78 °C, 30 min (65%); e) 45 (30 mol%), BH3·SMe2 (1.0 equiv), THF, -10 °C, 10 min; f) TBAF, THF, 0 °C,
10 min (~100% for 2 steps) (97% ee); g) toluene, BHT (cat.), autoclave, 210 °C, 2 days (42%)
Scheme 4
butyl oxazaborolidine 46 and catecholborane were used in tylammonium iodide (TBAI), the mixture of the alcohols
toluene at low temperature, both the optical purity and the was converted to an inseparable mixture of 51 and its 4-
isolated yield of the resulting alcohol were unsatisfactory epimer in 93% yield. The p-methoxybenzyl (MPM) group
(entry 4). A combination of catalyst 4 and catecholborane in the mixture of 51 was removed with DDQ18 to afford
also gave an insufficient result (entry 5). According to the (-)-52. The C4-epimer of (-)-52 could be easily separat-
case of racemates shown in Scheme 3, the compound [(+)- ed by silica gel column chromatography at this stage. Me-
24] was converted to the precursory triene (+)-30, which, sylate 53 derived from 52 was then reacted with p-
on heating in toluene at 210 °C for 2 days, was trans- toluenesulfonic acid (PTS) (cat.) in THF-(CH2OH)2 to
formed into the desired adduct (-)-35a [(-)-6, R = H] as cause cleavage of acetonide and cyclization of the tetrahy-
crystals in 42% isolated yield. Separation of (-)-35a from drofuran ring in one step, affording a tetracyclic com-
its diastereomers 35b and 35c was relatively easy.
pound (-)-54 in 83% yield.
As the further functionalization of (-)-35a aimed at the As the next stage, we examined the introduction of 3a-OH
construction of 4, we first attempted to introduce C6- and (Scheme 6). Protection of the hydroxyl group in (-)-54 as
C7-oxygen functionalities (Scheme 5). The hydroxyl its MPM ether, followed by TBAF treatment, provided al-
group of (-)-35a (~100% ee) was protected as its TBDMS cohol (-)-56 in 67% yield for 2 steps, which was oxidized
ether and subjected to dihydroxylation with OsO4 (cat.) with PDC to the ketone (-)-57 in 82% yield. In order to
and N-methylmorpholine N-oxide (NMO) to afford introduce the C3-functional group, we attempted to derive
6a,7a-diol (-)-47 as the major product. The coupling con- a,b-unsaturated ketone 60 from (-)-57 at this stage. After
stant between C5-H and C6-H (9.4 Hz) in the desired (-)- many fruitless attempts, the ketone (-)-57 was trans-
47 indicated that both of these protons occupied axial po- formed into the enol silyl ether (-)-58. When N-phenylse-
sitions. When (-)-47 was refluxed with a catalytic amount lenophthalimide (N-PSP)19 was used as a selenenylation
of PPTS under azeotropic conditions and then with p-anis- reagent for (-)-58, the selenenide 59 was obtained in 18%
aldehyde, the acetonide group was transferred to the yield as well as the enone (+)-60 in 28% yield, which was
C6,C7-position and acetal (-)-48 was provided in 79% thought to be produced by air-oxidation of 59. Oxidative
yield. The p-methoxybenzylidene acetal in (-)-48 was removal of the phenylselenenyl group in 59 was accom-
then opened reductively with NaBH3CN and TfOH in the plished with NaIO4 to afford enone (+)-60 in 87% yield,
presence of MS 3Å to give two alcohols 49 and 50 as an which was oxidized to a,b-epoxy ketone according to the
inseparable 6.2:1 mixture in 80% combined yield. On Miyashita procedure20 in the next step. Treatment of (+)-
treatment with BnBr and NaH in the presence of tetrabu- 60 with t-butyl hydroperoxide (TBHP) in the presence of
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

1882
N. Kanoh et al.
SPECIAL TOPIC
Table 2 Asymmetric Reduction of Ketone 44
O
Ph
Ph
H
N
O
O
+
B
O
O
R
OTIPS
O
O
HO
45, R = Me
46, R = Bu
44
R
conditions
OH
TBAF, THF
O
0 °C, 10 min
R
O
O
Me
O
O
Me
(+)-24
OTIPS
(R)-23
yield a)
(%)
entry
catalyst borane (eq.)
(mol%)
solv.
temp. (°C) / time
BH3 THF (1.4)
BH3 SMe2 (0.7)
THF
THF
57 (93)
1
2
3
4
45 (10)
45 (15)
0 / 40 min
-10 / 25 min
-10 / 10 min
-80 / 41 h
83 (97)
100 (97)
14b) (52)
45 (30) BH3 SMe2 (1.0)
THF
46 (15)
catecholborane
(1.9)
toluene
5
45 (15)
catecholborane
(1.9)
toluene
-80 / 36 h
66 (83)
aValues in parenthesis denote optical purities.
bThe starting material was recovered in 41%.
TBAF afforded an inseparable mixture of a-epoxide 61 ethoxy)borate, Na+[PhSeB(OEt)3]-,21 to afford b-hydroxy
and the recovered 60. Regioselective opening of the ep- ketone (-)-4 in 30% yield for 2 steps as well as the recov-
oxide in 61 was achieved by sodium phenylseleno(tri- ered 60 in 28%. The stereochemistry of the resultant hy-
O
O
O
O
O
O
TBDMSO
RO
TBDMSO
d
c
b
5
7
6
OH
O
H
H
H
O
OH
Me
O
pMP
O
O
O
O
O
Me
Me
Me
Me
Me
(–)-47
(–)-48
(–)-35a, R = H
a
(–)-36a, R = TBDMS
O
O
O
O
O
O
TBDMSO
TBDMSO
TBDMSO
h
e
OH
O
O
H
H
O
H
O
O
Me
Me
BnO
R1O
BnO
OR
OR
Me
Me
51, R = MPM
(–)-52, R = H
(–)-53, R = Ms
49, R = MPM, R1 = H
50, R = H, R1 = MPM
(–)-54
f
g
Reagents and conditions: a) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 90 min (93%); b) OsO4 (cat.), NMO, THF/H2O/t-BuOH (2:1:2),25 °C, 2 days
(73%); c) PPTS, benzene, reflux, 15 min, then p-anisaldehyde, 30 min (79%); d) NaBH3CN, TfOH, MS 3Å, DMF, 25 °C, 1.5 h (80% as an
inseparable 6.2:1 mixture of 49 and 50); e) BnBr, NaH, TBAI, THF, 25 °C, 2 days (93%); f) DDQ, CH2Cl2/H2O (20:1), r.t., 2 h (85%); g)
MsCl, Et3N, CH2Cl2, 0 °C, 2 h (~100%); h) PTS·H2O, (CH2OH)2/THF (1:20), 50 °C, 31 h (83%)
Scheme 5
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthetic Studies on Azadirachtin
1883
O
O
O
O
O
O
RO
TMSO
BnO
O
e
d
c
3
OR1
OMPM
H
O
OMPM
H
O
H
O
BnO
BnO
(–)-54, R = TBDMS, R1 = H
(–)-58
(–)-57
a
b
(–)-55, R = TBDMS, R1 = MPM
(–)-56, R = H, R1 = MPM
O
O
O
O
O
O
O
O
O
PhSe
g
+
O
OMPM
OMPM
H
O
OMPM
H
O
H
O
BnO
BnO
BnO
(+)-60
(–)-59
61
f
O
O
O
H
4.0 Hz
O
O
BnO
O
h
H
H
HO
BnO
OMPM
H
O
2.8 Hz
O
OH
OMPM
H
(–)-4
Reagents and conditions: a) MPMO(C=NH)CCl3, TfOH, Et2O, 25 °C, 4 h (70%); b) TBAF, THF, 0 °C; 25 °C, 1.2 h (95%); c) PDC, MS 3Å,
CH2Cl2, 25 °C, 2 h 20 min (82%); d) LDA, 57, THF, -78 °C, 1 h, then TMSOTf, -78 °C, 25 min [66% (78% based on recovered 57)]; e) N-
PSP, TMSOTf, THF, 0 °C; r.t., 2 h (18% for 59, 28% for 60); f) NaIO4, MeOH/H2O (4:1), r.t., 8 h (87%); g) TBHP, TBAF, DMSO, 25 °C, 30
min; h) Na+[PhSeB(OEt)3]-, AcOH, EtOH, r.t., 20 min (overall 30% for 4).
Scheme 6
1
droxyl group in (-)-4 was confirmed on the basis of H tionalized decalin portion of 1. Concerning the effects of
NMR spectra as shown in Scheme 6.
the alkoxy substituents (OR) adjacent to butenolide dieno-
phile in the respective IMDA reactions, we examined al-
cohol 30, its TBS ether 29, and its acetate 33 as the
modelled trienes by molecular mechanics calculations
(MM2*, MacroModel V6.5)22,23 (Table 3). We found that
our experimental results reflected comparably the respec-
tive calculated data of the transition state models in IMDA
In conclusion, we have constructed the versatile interme-
diate (-)-4, which is equivalent to the decalin fragment of
azadirachtin (1), in the naturally occurring form. The CBS
reduction of ketone 44 and the IMDA reaction of 30 are
the key steps for the first- generation synthesis of the func-
Table 3 Relative Energies of Transition Structures in the IMDA Reactions of 30, 29, and
33 Calculated by MacroModel V6.5 (MM2*)
O
O
O
O
O
O
O
O
O
O
RO
RO
RO
RO
RO
IMDA
+
+
+
H
H
H
H
O
O
O
O
O
O
O
O
O
O
Me
Me
Me
Me
Me
(endo)
30, 29, 33
a
c
b
d
Me
Me
Me
Me
Me
(exo)
(endo)
(exo)
triene
30: R = H
adduct
a
b
c
d kcal/mol
entry
1
2
3
35a-d
36a-d
0.0
0.0
0.0
+0.96 +0.71 +1.40
+0.36 +0.60 +0.25
29: R = TBDMS
33: R = Ac
+0.91
+0.47 +0.58
39a-d
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

1884
N. Kanoh et al.
SPECIAL TOPIC
1H NMR (270 MHz, CDCl3): d = 5.66 (ddt, 1H, J = 17.1, 9.6, 7.6
Hz), 5.11 (br d, 1H, J = 17.1 Hz), 5.09 (br d, 1H, J = 9.6 Hz), 4.86
(t, 1H, J = 4.6 Hz), 4.18 (q, 4H, J = 7.3 Hz), 3.80-4.00 (m, 4H), 2.64
(d, 2H, J = 7.6 Hz), 2.00 (m, 2H), 1.59 (dt, 2H, J = 12.5, 4.6 Hz),
1.24 (t, 6H, J = 7.3 Hz).
reactions except in the case of TBS ether 29. The second-
generation synthesis of the highly functionalized decalin
part will be described in the following paper.24
All anhydrous reactions were conducted in flame-dried glassware
under Ar, unless otherwise stated. All solvents except DMF and
t-BuOH were distilled prior to use. Et2O and THF were distilled
from sodium benzophenone ketyl. Benzene, toluene, pyridine,
MeCN and CH2Cl2 were distilled from CaH2. DMSO was distilled
from CaH2 under reduced pressure (5 Torr). MeOH and EtOH were
distilled from magnesium turnings. t-BuOH and anhyd DMF were
used as received from commercial sources. Chromatography and
extraction were carried out by using reagent-grade solvents. All re-
agents were used as received unless noted. All reactions were mon-
itored by TLC with precoated silica gel plates (E. Merck, Silica gel
60 F254 Art. 5715 and 5554), and compounds were visualized with
UV (254 nm) 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).
HPLC was run with Waters Associates 6000A liquid chromatogra-
phy equipped with Waters Associates R401 differential refractome-
ter. Mps were measured on Yanagimoto Seisakusyo Micro melting
point apparatus (Serial No. 989) and are uncorrected. Optical rota-
tions were recorded on JASCO model DIP-360 digital polarimeter
in appropriate solvents. Low- and high-resolution mass spectra
were obtained on JEOL JMS-DX303, JEOL HX110, JEOL JMS-
AX500, and JEOL JMS-SX102A spectrometers. IR spectra were
measured on Hitachi model 270-30 infrared spectrometer in the not-
HREIMS: calcd. for C15H24O6: 300.1573. Found: 300.1595.
4,4-Dihydroxymethyl-6-(1’,3’-dioxolan-2’-yl)hex-1-ene (14)
A solution of 13 (33 g, 0.11 mol) in Et2O (50 mL) was added over
10 min to a cooled suspension of LiAlH4 (5 g, 0.13 mol) in Et2O
(400 mL). A grey clayey mixture was formed during the addition.
The mixture was stirred at ambient temperature for 100 min, and
then additional amounts of LiAlH4 (total 1.5 g, 39 mmol) were add-
ed over 3 h. To the mixture was slowly added EtOAc until exother-
mic reaction ceased, and 2 M NaOH (20 mL) was added. The
mixture was stirred for further 20 min and filtered through Celite
pad. The filtrate was concentrated and dried in vacuo to afford 14
(24.03 g) as a pale yellow oil. This material was used in the next step
without further purification.
IR (neat): nmax = 3432, 3076, 2888, 1642, 1416, 1230, 1130, 1036,
946, 920, 868 cm-1.
1H NMR (270 MHz, CDCl3): d = 6.81 (ddt, 1H, J = 15.5, 11.2, 7.3
Hz), 5.10 (br d, 1H, J = 15.5 Hz), 5.09 (br d, 1H, J = 11.2 Hz), 4.86
(t, 1H, J = 4.6 Hz), 3.80-4.04 (m, 4H), 3.57 (s, 4H), 2.46 (br s, 2H),
2.03 (br d, 2H, J = 7.3 Hz), 1.42-1.72 (m, 4H).
HREIMS: calcd. for C11H20O4: 216.1362. Found: 216.1352.
1
ed state. H NMR spectra were measured on JEOL JNM-FX270
(270 MHz), JNM-EX400 (400 MHz), and JNM-a400 (400 MHz)
spectrometers. TMS (d = 0.00 ppm) was used as an internal refer-
ence for spectra measured in CDCl3, and residual benzene (d = 7.20
ppm) in C6D6.
4,4-Diacetoxymethyl-6-(1’,3’-dioxolan-2’-yl)hex-1-ene (15)
To a cooled (0 °C) solution of 14 (5.00 g, 23.1 mmol), Ac2O (5.0
mL, 53.0 mmol), and Et3N (10 mL, 71.7 mmol) in CH2Cl2 (30 mL)
was added DMAP (130 mg, 1.06 mmol). The mixture was allowed
to warm to ambient temperature, stirred for 35 min, and then poured
into H2O. The aqueous layer was extracted with CH2Cl2 (2 ¥ 125
mL). The extracts were washed successively with sat. NH4Cl and
brine, dried (MgSO4), and concentrated in vacuo. Purification of the
residue by silica gel column chromatography (70-230 mesh, 150 g,
hexane/EtOAc, 7:1 to 2:1) afforded 15 (6.18 g, 20.6 mmol, 89% for
2 steps) as a colorless oil.
Ethyl 2-Ethoxycarbonyl-4-(1’,3’-dioxolan-2’-yl)butanoate (12)
Diethyl malonate (10, 155 mL, 1.02 mol) was added to a solution of
NaOEt in EtOH (2.36 M, 440 mL, 1.04 mol). The resultant mixture
was heated at 55 °C until the solid melted completely. 2-(2'-Bromo-
ethyl)-1,3-dioxolane (11, 170.6 g, 0.94 mol) was added to the mix-
ture over 35 min. After 25 min, the mixture was concentrated in
vacuo, and extracted with EtOAc (3 ¥ 500 mL). The extracts were
washed with sat. NH4Cl, H2O, and brine, dried (MgSO4), filtered,
concentrated, and distilled in vacuo to afford 12 (178.7 g, 0.69 mol,
73%) as a colorless liquid.
IR (neat): nmax = 3076, 2960, 1746, 1742, 1368, 1232, 1132, 1040,
946, 920, 878 cm-1.
1H NMR (270 MHz, CDCl3): d = 5.75 (ddt, 1H, J = 16.8, 10.2, 7.6
Hz), 5.11 (br d, 1H, J = 10.2 Hz), 5.08 (br d, 1H, J = 16.8 Hz), 4.82
(t, 1H, J = 4.6 Hz), 3.93 (s, 4H), 3.82-3.99 (m, 4H), 2.11 (br d, 2H,
J = 7.6 Hz), 2.06 (s, 6H), 1.56-1.70 (m, 2H), 1.43-1.49 (m, 2H).
Bp = 156-161 °C/3 Torr.
IR (neat): nmax = 2984, 2892, 1734, 1452, 1372, 1258, 1228, 1146,
1028, 946, 860 cm-1.
HREIMS: calcd. for C15H24O6: 300.1573. Found: 300.1565.
1H NMR (270 MHz, CDCl3): d = 4.89 (t, 1H, J = 4.6 Hz), 4.20 (q,
4H, J = 7.3 Hz), 3.81-4.00 (m, 4H), 3.41 (t, 1H, J = 7.6 Hz), 2.03
(m, 2H), 1.72 (m, 2H), 1.27 (t, 6H, J = 7.3 Hz).
4,4-Diacetoxymethyl-6-(1’,3’-dithian-2’-yl)hex-1-ene (16)
To a cooled (0 °C) solution of 15 (21.9 g, 73.0 mmol) and propane-
1,3-dithiol (9.0 mL, 89.6 mmol) in CH2Cl2 (150 mL) was added
TiCl4 (2.0 mL, 18.2 mmol) over 5 min via syringe. After 13 min, an
additional amount of TiCl4 (2.0 mL, 18.2 mmol) was added to the
mixture and the mixture was stirred for an additional 9 min. The re-
action was quenched with sat. NaHCO3 (30 mL). The mixture was
allowed to warm to r.t., poured into H2O (100 mL), and extracted
with EtOAc (2 ¥ 300 mL). The extracts were washed successively
with H2O and brine (100 mL each), dried (MgSO4), filtered, and
concentrated in vacuo. Purification of the residue by silica gel col-
umn chromatography (70-230 mesh, 500 g, hexane/EtOAc, 7:1 to
2:1) afforded 16 (24.65 g, 71.2 mmol, 98%) as a pale yellow oil.
HREIMS: calcd. for C12H20O6: 260.1260. Found: 260.1227.
4,4-Diethoxycarbonyl-6-(1’,3’-dioxolan-2’-yl)hex-1-ene (13)
To a solution of NaOEt in EtOH (1.26 M, 50 mL, 63 mmol) was
added a solution of 12 (13 g, 50 mmol) in EtOH (20 mL) and the
mixture was stirred for 30 min. Allyl iodide (6 mL, 65.7 mmol) was
added dropwise. After 20 min, the reaction was quenched with sat.
NH4Cl (4 mL), and then concentrated in vacuo. The residue was di-
luted with H2O, extracted with EtOAc (2 ¥ 300 mL), and the ex-
tracts were washed successively with H2O and brine, dried
(MgSO4), filtered, and concentrated in vacuo. Purification by silica
gel column chromatography (70-230 mesh, 100 g, hexane/EtOAc,
5:1) afforded 13 (14.2 g, 47.3 mmol, 95%) as a pale yellow oil.
IR (neat): nmax = 2936, 1738, 1426, 1366, 1246, 1042, 910, 870 cm-1.
1H NMR (270 MHz, CDCl3): d = 5.74 (ddt, 1H, J = 16.5, 10.2, 7.6
Hz), 5.13 (br d, 1H, J = 10.2 Hz), 5.10 (br d, 1H, J = 16.5 Hz), 3.98
IR (neat): nmax = 3080, 2984, 2884, 1734, 1664, 1450, 1370, 1270,
1210, 1192, 1146, 1034 cm-1.
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthetic Studies on Azadirachtin
1885
(t, 1H, J = 6.3 Hz), 3.92 (s, 4H), 2.80-2.94 (m, 4H), 2.10 (br d, 2H,
J = 7.6 Hz), 2.07 (s, 6H), 1.54-1.93 (m, 6H).
HREIMS: calcd. for C11H17O3 (M+-Me): 197.1178. Found:
197.1161.
HREIMS: calcd. for C16H26O4S2: 346.1273. Found: 346.1284.
4-Bromo-2-triisopropylsilyloxyfuran (22)
To a cooled (0 °C) solution of 4-bromofuran-2(5H)-one (21)11
(31.51 g, 193.3 mmol) in CH2Cl2 (200 mL) were added Et3N (31
mL, 222.4 mmol) and TIPSOTf (55 mL, 204.6 mmol). The solution
was stirred for 10 min, diluted with Et2O (200 mL), and washed suc-
cessively with sat. NH4Cl and sat. NaHCO3 (50 mL each). The or-
ganic layer was diluted further with Et2O (100 mL), washed with
H2O and brine (50 mL each), dried (MgSO4), filtered, and concen-
trated in vacuo. Purification of the residue by silica gel column
chromatography (70-230 mesh, 250 g, hexane) afforded 22 (56.95
g, 178.5 mmol, 92%) as a pale yellow liquid.
4,4-Dihydroxymethyl-6-(1’,3’-dithian-2’-yl)hex-1-ene (17)
To a cooled (0 °C) suspension of LiAlH4 (4.09 g, 107.6 mmol) in
Et2O (100 mL) was added a solution of 16 (11.29 g, 32.63 mmol) in
Et2O (100 mL) dropwise over 21 min. The mixture was stirred at
0 °C for 1.5 h, mixed with H2O (4 mL), and stirred for 30 min. 4 M
NaOH (4 mL) was added and the mixture was stirred for 30 min,
and H2O (8 mL) was added again. The mixture was stirred at 25 °C
for 1 h, and filtered through Celite pad. The filtrate was concentrat-
ed in vacuo to afford 17 (7.17 g) as white crystals. This material was
used in the next step without further purification; mp: 86-88 °C.
IR (neat): nmax = 3168, 2952, 2872, 1614, 1466, 1358, 1272, 1100,
IR (CHCl3): nmax = 3632, 3460, 3076, 1640, 1426, 1278, 1036, 922,
958, 920 cm-1.
866 cm-1.
1H NMR (270 MHz, CDCl3): d = 6.83 (d, 1H, J = 1.3 Hz), 5.24 (d,
1H, J = 1.3 Hz), 1.18-1.31 (m, 3H), 1.09 (d, 18H, J = 6.9 Hz).
1H NMR (270 MHz, CDCl3): d = 5.81 (ddt, 1H, J = 16.5, 10.9, 7.6
Hz), 5.12 (br d, 1H, J = 16.5 Hz), 5.11 (br d, 1H, J = 10.9 Hz), 3.99
(t, 1H, J = 6.9 Hz), 3.58 (br s, 4H), 2.80-2.94 (m, 4H), 1.51-2.18 (m,
10H).
HREIMS: calcd. for C13H23BrO2Si: 318.0651. Found: 318.0651.
2,2-Dimethyl-5-{3’-[furan-2’’(5’’H)-on-4’’-yl]-3’-hydroxypro-
pyl}-5-(prop-2’’’-enyl)-1,3-dioxane (24)
HREIMS: calcd. for C12H22O2S2: 262.1062. Found: 262.1066.
To a cooled (-78 °C) solution of 22 (1.60 g, 5.02 mmol) in Et2O (10
mL) was added BuLi (1.64 M in hexane, 2.5 mL, 4.10 mmol) and
the mixture was stirred for 1 h. To the resultant solution was added
a solution of 19 (0.70 g, 3.30 mmol) in Et2O (2 mL) along with Et2O
rinse (2 mL). The solution was stirred for 1 h, then mixed with sat.
NH4Cl (5 mL). The aqueous layer was extracted with EtOAc
(3 ¥ 10 mL). The extracts were washed with H2O and brine (10 mL
each), dried (MgSO4), filtered, and concentrated in vacuo to afford
23 (2.11 g) as a yellowish brown oil. This material was dissolved in
THF (10 mL), and cooled to 0 °C. TBAF (1.0 M in THF, 5 mL, 5.0
mmol) was added to the solution. The mixture was stirred for 15
min, poured into sat. NH4Cl (10 mL), and extracted with EtOAc
(3 ¥ 10 mL). The extracts were washed with H2O and brine (5 mL
each), dried (MgSO4), filtered, and concentrated in vacuo. Purifica-
tion of the residue by silica gel chromatography (70-230 mesh, 40
g, hexane/EtOAc, 2:1 to 1:2) afforded 24 (551 mg, 1.86 mmol, 56%
for 2 steps) as a brown oil.
2,2-Dimethyl-5-(prop-2’-enyl)-5-[3’’-(1’’’,3’’’-dithian-2’’’-yl)]-
1,3-dioxane (18)
A solution of 17 (7.17 g), 2,2-dimethoxypropane (5 mL, 40.6
mmol), and PPTS (359 mg, 1.43 mmol) in CH2Cl2 (100 mL) was
stirred at 25 °C. After 4 h, an additional amount of 2,2-dimeth-
oxypropane (1.0 mL, 8.13 mmol) was added and the mixture was
stirred for further 30 min, and then mixed with sat. NaHCO3 (10
mL). The organic layer was washed successively with H2O and
brine (10 mL each), dried (MgSO4), filtered, and concentrated in
vacuo. Purification of the residue by silica gel column chromatog-
raphy (70-230 mesh, 100 g, hexane/EtOAc, 7:1 to 4:1) afforded 18
(7.22 g, 23.9 mmol, 73% for 2 steps) as a colorless oil.
IR (neat): nmax = 2992, 2940, 2860, 1456, 1424, 1372, 1202, 1156,
1092, 914, 834 cm-1.
1H NMR (270 MHz, CDCl3): d = 5.76 (ddt, 1H, J = 9.6, 17.5, 7.5
Hz), 5.12 (br d, 1H, J = 17.5 Hz), 5.11 (br d, 1H, J = 9.6 Hz), 3.98
(t, 1H, J = 6.3 Hz), 3.56 (s, 4H), 2.80-2.94 (m, 4H), 2.17 (br d, 2H,
J = 7.5 Hz), 2.06 (m, 1H), 1.50-1.92 (m, 5H), 1.40 (s, 6H).
IR (neat): nmax = 3432, 2940, 2864, 1778, 1748, 1640, 1454, 1374,
1262, 1198, 1094, 924, 893, 832 cm-1.
1H NMR (270 MHz, CDCl3): d = 5.98 (br s, 1H), 5.71 (ddt, 1H,
J = 16.5, 10.2, 7.9 Hz), 5.12 (br d, 1H, J = 10.2 Hz), 5.11 (br d, 1H,
J = 16.5 Hz), 4.88 (br s, 2H), 4.63 (br t, 1H, J = 5.6 Hz), 3.64 (d, 2H,
J = 11.9 Hz), 3.52 (d, 2H, J = 11.9 Hz), 2.06 (d, 2H, J = 8.2 Hz),
1.47-1.85 (m, 4H), 1.42 (s, 3H), 1.39 (s, 3H).
HRMS (FAB): calcd. for C16H25O5 (M++H): 297.1702. Found:
297.1728.
HREIMS: calcd. for C15H26O2S2: 302.1375. Found: 302.1397.
3-[2’,2’-Dimethyl-1’,3’-dioxa-5’-(prop-2’’-enyl)]propanal (19)
To a stirred suspension of 18 (19.91 g, 65.9 mmol) and CaCO3
(13.19 g, 131.8 mmol) in MeCN (600 mL) and H2O (110 mL) was
added MeI (55 mL, 0.883 mol). The mixture was stirred at 40 °C for
8 h, then allowed to cool to r.t. for 10 h. The mixture was concen-
trated in vacuo to a volume of approx. 100 mL. The concentrate was
extracted with Et2O (3 ¥ 300 mL), and the extracts were washed
successively with 10% aq Na2S2O3, H2O, and brine (50 mL each).
The combined aqueous layers were extracted again with Et2O
(3 ¥ 100 mL). All organic extracts were combined, dried (MgSO4),
filtered, and concentrated in vacuo. Purification of the residue by
silica gel chromatography (70-230 mesh, 100 g, hexane/Et2O, 1:1)
afforded 19 (9.90 g, 46.7 mmol, 71%) as a pale yellow oil.
(R)-Alcohol (+)-24
To a cooled (-10 °C) solution of oxazaborolidine 4514 (1.0 M in tol-
uene, 0.30 mL, 0.30 mmol) in THF (5 mL) was added BH3·SMe2
complex (approx. 10.1 M, 0.1 mL, 1.05 mmol), and the solution was
stirred for 10 min. A solution of 44 (449.6 mg, 1.00 mmol) in THF
(2.5 mL) along with THF wash (2.5 mL) were added and the mix-
ture was stirred at -10 °C for 10 min. The reaction was quenched by
cautious addition of sat. NH4Cl (2 mL). The mixture was allowed to
warm to r.t., and concentrated in vacuo. The aqueous residue was
extracted with Et2O (3 ¥ 5 mL). The extracts were washed with H2O
and brine (3 mL each), dried (MgSO4), filtered, and concentrated in
vacuo. This material was dissolved in THF (5 mL) and cooled to
0 °C. TBAF (1.0 M in THF, 1.0 mmol) was added and the solution
was stirred at 0 °C for 10 min, and then sat. NH4Cl (10 mL) was
added. The mixture was concentrated in vacuo. The aqueous residue
was extracted with EtOAc (3 ¥ 5 mL). The extracts were washed
IR (neat): nmax = 2992, 2940, 2864, 2720, 1726, 1640, 1454, 1372,
1256, 1198, 1156, 1098, 1078, 1034, 998, 920, 830 cm-1.
1H NMR (270 MHz, CDCl3): d = 9.79 (t, 1H, J = 1.7 Hz), 5.72 (ddt,
1H, J = 16.0, 10.9, 7.6 Hz), 5.11 (d, 1H, J = 10.9 Hz), 5.10 (d, 1H,
J = 16.0 Hz), 3.63 (d, 2H, J = 11.9 Hz), 3.55 (d, 2H, J = 11.9 Hz),
2.46 (dt, 2H, J = 1.7, 7.9 Hz), 2.10 (br d, 2H, J = 7.6 Hz), 1.73 (m,
2H), 1.41 (s, 3H), 1.40 (s, 3H).
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

1886
N. Kanoh et al.
SPECIAL TOPIC
with brine (5 mL), dried (MgSO4), filtered, and concentrated in vac-
uo. Purification of the residue by silica gel chromatography (70-230
mesh, 10 g, hexane/EtOAc, 1:1 to 1:2) afforded (+)-24 (306.2 mg,
1.00 mmol, ~100% for 2 steps) as a brown oil; [a]D24 +4.2 (c 1.47,
CHCl3). The optical purity of this material (97% ee) was determined
by the modified Mosher method.16
(150 mL), and the mixture was concentrated in vacuo. The residue
was extracted with EtOAc (3 ¥ 200 mL), and the extracts were
washed with brine (100 mL). The brine layer was extracted again
with EtOAc (100 mL). The combined extracts were dried (MgSO4),
filtered, and concentrated in vacuo to afford an inseparable mixture
of 26 and 27, which was dissolved in EtOH (200 mL) and cooled to
0 °C. To the solution was added NaBH4 (491.2 mg, 13.0 mmol), and
the mixture was stirred for 20 min. The reaction was quenched by
slow addition of sat. NH4Cl (50 mL). The mixture was concentrated
in vacuo, poured into H2O (100 mL), and extracted with EtOAc (3
x 200 mL). The extracts were washed with brine (100 ml), dried
(MgSO4), filtered, and concentrated in vacuo. Purification of the
residue by silica gel chromatography (70-230 mesh, 250 g, hexane/
EtOAc, 4:1 to 1:2) afforded 27 (as a 1:1 mixture of diastereomers,
10.27 g, 23.3 mmol, 56% for 2 steps) as a pale yellow oil.
5-{3’-tert-Butyldimethylsilyloxy-3’-[furan-2’’(5’’H)-on-4’’-
yl]propyl}-5-(2’’’-propenyl)-2,2-dimethyl-1,3-dioxane (25)
A solution of 24 (559.7 mg, 1.89 mmol), TBDMSCl (327.3 mg,
2.17 mmol), and imidazole (155.3 mg, 2.28 mmol) in DMF (2 mL)
was stirred at 25 °C for 10 h. Purification of the mixture by silica gel
chromatography (70-230 mesh, 40 g, hexane/EtOAc, 5:1 to 1:1) af-
forded 25 (588.2 mg, 1.43 mmol, 76%) as a colorless oil.
IR (neat): nmax = 2992, 2932, 2856, 1780, 1752, 1642, 1454, 1372,
1260, 1198, 1092, 1030, 916, 884, 836 cm-1.
IR (neat): nmax = 3464, 2932, 2856, 1780, 1752, 1642, 1464, 1372,
1258, 1146, 1084, 936, 838 cm-1.
1H NMR (270 MHz, CDCl3): d = 5.93 (dt, 1H, J = 2.0, 1.5 Hz), 5.69
(ddt, 1H, J = 16.9, 10.8, 7.7 Hz), 5.10 (br d, 1H, J = 10.8 Hz), 5.08
(br d, 1H, J = 16.9 Hz), 4.80 (d, 2H, J = 1.5 Hz), 4.63 (br t, 1H,
J = 6.2 Hz), 3.60 (dd, 2H, J = 11.6, 1.7 Hz), 3.50 (d, 2H, J = 11.6
Hz), 2.07 (d, 2H, J = 7.7 Hz), 1.37-1.67 (m, 4H), 1.40 (s, 3H), 1.38
(s, 3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.04 (s, 3H).
1H NMR (270 MHz, CDCl3): d = 5.94 (m, 1H), 5.88 (ddd, 1H,
J = 17.3, 11.6, 6.9 Hz), 5.24 (dt, 1H, J = 17.3, 0.9 Hz), 5.09 (dt, 1H,
J = 11.6, 0.8 Hz), 4.81 (m, 2H), 4.66 (m, 1H), 4.41 (m, 1H), 3.55-
3.76 (m, 4H), 1.30-1.67 (m, 6H), 1.42 (s, 3H), 1.41 (s, 3H), 0.92 (s,
9H), 0.10 (s, 3H), 0.05 (s, 3H).
HRMS (FAB): calcd. for C22H39O5Si (M++H): 411.2567. Found:
411.2560.
HRMS (FAB): calcd. for C23H40O6Si: 440.2594. Found: 440.2565.
Allyl Alcohol (+)-27
TBS Ether (+)-25
[a]D23 +13.0 (c 1.32, CHCl3).
[a]D22 +14.2 (c 0.98, CHCl3).
5-{3’-tert-Butyldimethylsilyloxy-3’-[furan-2’’(5’’H)-on-4’’-
yl]propyl}-5-(2’’’-methoxycarbonyloxybut-3’’’-en-1’’’-yl)-2,2-
dimethyl-1,3-dioxane (28)
5-{3’-tert-Butyldimethylsilyloxy-3’-[furan-2’’(5’’H)-on-4’’-
yl]propyl}-5-(2’’’-oxopropyl)-2,2-dimethyl-1,3-dioxane (26)
To a cloudy solution of 25 (188.8 mg, 0.46 mmol) and NMO (65.0
mg, 0.56 mmol) in THF (2.5 mL) and H2O (1.25 mL) was added
OsO4 (19.7 mM in t-BuOH, 2.5 mL, 0.049 mmol), and the solution
was stirred at 25 °C for 13 h. The excess oxidizer was quenched by
adding NaHSO3 (175 mg). The mixture was stirred for an additional
5 h, filtered through Celite pad, and concentrated in vacuo to afford
diol (244.5 mg) as a pale yellow oil. This material was dissolved in
MeOH (4 mL) and cooled to 0 °C. A solution of NaIO4 (121.0 mg,
0.566 mmol) in H2O (3 mL) was added, and the mixture was stirred
at 0 °C for 20 min, filtered through Celite pad, and concentrated in
vacuo. The residue was poured into H2O (10 mL), and extracted
with EtOAc (3 ¥ 30 mL). The extracts were washed with brine (10
mL), dried (MgSO4), filtered, and concentrated in vacuo. Purifica-
tion of the residue by silica gel chromatography (70-230 mesh, 4 g,
hexane/EtOAc, 3:1 to 1:1) afforded 26 (184.6 mg, 0.45 mmol, 97%
for 2 steps) as a colorless oil.
To a cooled (0 °C) solution of 27 (758.5 mg. 1.70 mmol) and pyri-
dine (0.70 mL, 8.65 mmol) in CH2Cl2 (10 mL) was carefully added
methyl chloroformate (0.52 mL, 6.73 mmol) over 16 min. The mix-
ture was stirred at 0 °C for 70 min, then allowed to warm to r.t. over
40 min. The reaction was quenched with sat. NH4Cl (10 mL), and
the mixture was extracted with Et2O (3 ¥ 30 mL). The extracts were
washed with brine (10 mL), dried (MgSO4), filtered, and concen-
trated in vacuo. Purification of the residue by silica gel column
chromatography (230-400 mesh, 23 g, hexane/EtOAc, 4:1 to 1:1)
afforded 28 (as a 1:1 mixture of diastereomers, 604.0 mg, 1.20
mmol, 70%) as a pale yellow oil followed by recovered 27 (233.0
mg, 0.53 mmol, 30%).
28
IR (neat): nmax = 2956, 1780, 1754, 1446, 1264, 1094, 838, 778 cm-1.
1H NMR (270 MHz, CDCl3): d = 5.97 (dt, 1/2H, J = 1.5, 1.0 Hz),
5.94 (q, 1/2H, J = 1.0 Hz), 5.79 (ddt, 1H, J = 5.5, 10.0, 16.5 Hz),
5.29 (br d, 1H, J = 16.5 Hz), 5.15-5.33 (m, 2H), 4.86 (m, 2H), 4.74
(m, 1/2H), 4.60 (m, 1/2H), 3.76 (s, 3H), 3.48-3.66 (m, 4H), 1.48-
1.80 (m, 6H), 1.39 (s, 3H), 1.37 (s, 3H), 0.92 (s, 9/2H), 0.91 (s, 9/
2H), 0.11 (s, 3H), 0.06 (s, 3/2H), 0.05 (s, 3/2H).
IR (neat): nmax = 2992, 2932, 2856, 1780, 1752, 1644, 1464, 1374,
1260, 1200, 1086, 1026, 938, 836 cm-1.
1H NMR (270 MHz, CDCl3): d = 9.88 (t, 1H, J = 1.8 Hz), 5.93 (m,
1H), 4.79 (d, 2H, J = 1.5 Hz), 4.62 (br t, 1H, J = 4.4 Hz), 3.69 (d,
2H, J = 11.5 Hz), 3.65 (d, 2H, J = 11.5 Hz), 2.58 (d, 2H, J = 1.8
Hz), 1.35-1.70 (m, 4H), 1.42 (s, 3H), 1.41 (s, 3H), 0.91 (s, 9H), 0.04
(s, 3H), 0.09 (s, 3H).
HRMS (FAB): calcd. for C25H43O8Si (M++H): 499.2728. Found:
499.2747.
HRMS (FAB): calcd. for C21H36O6Si: 412.2281. Found: 412.2254.
Methyl Carbonate (+)-28
[a]D24 +8.6 (c 1.13, CHCl3).
Aldehyde (+)-26
[a]D23 +14.6 (c 1.01, CHCl3).
(1’’’E)-5-(Buta-1’’’,3’’’-dien-1’’’-yl)-5-{3’-tert-butyldimethylsil-
yloxy-3’-[furan-2’’(5’’H)-on-4’’-yl]propyl}-2,2-dimethyl-1,3-di-
oxane (29)
To a warmed (40 °C) solution of Pd(PPh3)4 (2.48 g, 2.15 mmol) and
Et3N (5.5 mL, 39.5 mmol) in THF (300 mL) was added a solution
of 28 (9.85 g, 19.8 mmol) in THF (30 mL) via cannula along with
THF wash (30 mL). The solution was warmed to 55 °C over 40 min,
allowed to cool to r.t., filtered through a short column of Florisil,
5-{3’-tert-Butyldimethylsilyloxy-3’-[furan-2’’(5’’H)-on-4’’-
yl]propyl}-5-(2’’’-hydroxybut-3’’’-en-1’’’-yl)-2,2-dimethyl-1,3-
dioxane (27)
To a cooled (-78 °C) solution of 26 (17.28 g, 41.9 mmol) in THF
(250 mL) was added vinylmagnesium bromide (1.0 M soln in THF,
47.0 mL, 47.0 mmol) over 5 min, and the mixture was stirred at
-78 °C for 14 min. The reaction was quenched with sat. NH4Cl
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthetic Studies on Azadirachtin
1887
and concentrated in vacuo. Purification of the residue by silica gel
column chromatography (70-230 mesh, 150 g, hexane/EtOAc, 5:1)
afforded 29 (6.44 g, 15.2 mmol, 77%) as a pale yellow oil.
IR (neat): nmax = 2948, 2868, 1782, 1754, 1466, 1674, 1198, 1080,
1032, 882 cm-1.
1H NMR (400 MHz, C6D6): d = 6.25 (dt, 1H, J = 17.1, 10.5 Hz),
5.95 (dd, 1H, J = 10.5, 15.9 Hz), 5.87 (t, 1H, J = 1.3 Hz), 5.16 (dd,
1H, J = 17.1, 1.5 Hz), 5.13 (dd, 1H, J = 15.9, 1.8 Hz), 5.04 (dd, 1H,
J = 10.5, 1.5 Hz), 4.53 (dt, 1H, J = 17.6, 1.3 Hz), 4.43 (br s, 1H),
4.32 (d, 1H, J = 17.6 Hz), 3.60 (dd, 2H, J = 3.3, 11.7 Hz), 3.43 (d,
2H, J = 11.7 Hz), 1.25-1.75 (m, 4H), 1.44 (s, 3H), 1.29 (s, 3H),
0.88-1.05 (m, 21H).
IR (neat): nmax = 2992, 2952, 1780, 1754, 1644, 1474, 1372, 1256,
1198, 1080, 1008, 838 cm-1.
1H NMR (270 MHz, CDCl3): d = 6.28 (dt, 1H, J = 17.6, 11.1 Hz),
6.02 (dd, 1H, J = 11.1, 16.8 Hz), 5.94 (m, 1H), 5.37 (d, 1H, J = 16.8
Hz), 5.19 (br d, 1H, J = 17.6 Hz), 5.09 (br d, 1H, J = 11.1 Hz), 4.80
(d, 2H, J = 2.3 Hz), 4.66 (m, 1H), 3.78 (d, 2H, J = 12.3 Hz), 3.55 (d,
2H, J = 12.3 Hz), 2.50-2.75 (m, 4H), 1.42 (s, 3H), 1.39 (s, 3H), 0.92
(s, 9H), 0.10 (s, 3H), 0.05 (s, 3H).
HREIMS: calcd. for C26H44O5Si: 464.2958. Found: 464.2953.
(1’’’E)-5-{3’-Acetoxy-3’-[furan-2’’(5’’H)-on-4’’-yl]propyl}-5-
(buta-1’’’,3’’’-dienyl)-2,2-dimethyl-1,3-dioxane (33)
A solution of 30 (11.6 mg, 37.7 mmol), Ac2O (35 mL, 0.37 mmol),
and pyridine (45 mL, 0.56 mmol) in CH2Cl2 (1 mL) was stirred at
25 °C for 10 h, and then concentrated in vacuo. Purification of the
residue by silica gel chromatography (70-230 mesh, 2 g, hexane/
EtOAc, 3:1 to 2:1) afforded 33 (12.3 mg, 35.1 mmol, 93%) as a pale
yellow oil.
HREIMS: calcd. for C23H38O5Si: 422.2488. Found: 244.2462.
Triene (-)-29
[a]D19 -1.9 (c 1.20, benzene).
(1’’’E)-5-(Buta-1’’’,3’’’-dienyl)-5-{3’-[furan-2’’(5’’H)-on-4’’-yl]-
3’-hydroxypropyl}-2,2-dimethyl-1,3-dioxane (30)
To a cooled (0 °C) solution of 29 (1.46 g, 3.45 mmol) in THF (30
mL) was added TBAF (1.0 M in THF, 3.8 mL, 3.8 mmol). The so-
lution was stirred at 0 °C for 12 min, and then poured into sat.
NH4Cl (20 mL). The separated aqueous layer was extracted with
EtOAc (2 ¥ 40 mL). The extracts were washed with H2O and brine
(20 mL each), dried (MgSO4), filtered, and concentrated in vacuo.
Purification of the residue by silica gel chromatography (70-230
mesh, 25 g, hexane/EtOAc, 2:1 to 1:2) afforded 30 (1.04 g, 3.37
mmol, 98%) as a yellow oil.
IR (neat): nmax = 2940, 1782, 1756, 1646, 1456, 1374, 1234, 1158,
1080, 832 cm-1.
1H NMR (400 MHz, C6D6): d = 6.23 (dt, 1H, J = 17.0, 10.3 Hz),
5.91 (dd, 1H, J = 10.3, 16.0 Hz), 5.61 (m, 1H), 5.30 (br t, 1H,
J = 5.9 Hz), 5.14 (br d, 1H, J = 17.0 Hz), 5.08 (d, 1H, J = 16.0 Hz),
5.03 (br d, 1H, J = 10.3 Hz), 4.03 (m, 2H), 3.58 (dd, 2H, J = 11.7,
2.2 Hz), 3.39 (d, 2H, J = 11.7 Hz), 1.59-1.64 (m, 2H), 2.00 (s, 3H),
1.44 (s, 3H), 1.30-1.44 (m, 2H), 1.29 (s, 3H).
IR (neat): nmax = 3448, 2944, 2868, 1780, 1746, 1642, 1454, 1374,
HREIMS: calcd. for C19H26O6: 350.1730. Found: 350.1713.
1260, 1198, 1080, 896, 830 cm-1.
1H NMR (270 MHz, C6D6): d = 6.26 (dt, 1H, J = 16.7, 9.7 Hz), 5.98
(br dd, 1H, J = 15.9, 10.5 Hz), 5.56 (br s, 1H), 5.15 (d, 1H, J = 16.7
Hz), 5.15 (d, 1H, J = 16.7 Hz), 5.04 (d, 1H, J = 10.3 Hz), 4.15 (d,
1H, J = 16.0 Hz), 4.13 (d, 1H, J = 16.0 Hz), 3.75 (m, 1H), 3.61 (dd,
2H, J = 3.2, 11.3 Hz), 3.43 (m, 2H), 1.50-1.70 (m, 2H), 1.45 (s, 3H),
1.31 (s, 3H), 1.05-1.30 (m, 2H).
(1’’’E)-5-{3’-p-Bromobenzoyloxy-3’-[furan-2’’(5’’H)-on-4’’-
yl]propyl-5-(buta-1’’’,3’’’-dienyl)-2,2-dimethyl-1,3-dioxane (34)
Pale yellow oil.
IR (neat): nmax = 2940, 1782, 1756, 1728, 1592, 1400, 1374, 1266,
1198, 1102, 1012, 848 cm-1.
1H NMR (400 MHz, C6D6): d = 7.72 (br d, 2H, J = 8.6 Hz), 7.25 (d,
2H, J = 8.6 Hz), 6.23 (dt, 1H, J = 17.2, 10.4 Hz), 5.91 (dd, 1H,
J = 10.4, 16.0 Hz), 5.68 (m, 1H), 5.53 (br t, 1H, J = 5.5 Hz), 5.12 (d,
1H, J = 17.2 Hz), 5.09 (d, 1H, J = 16.0 Hz), 5.02 (br d, 1H, J = 10.4
Hz), 4.10 (m, 2H), 3.58 (br d, 2H, J = 11.7 Hz), 3.40 (br d, 2H,
J = 11.7 Hz), 1.52-1.73 (m, 2H), 1.39 (s, 3H), 1.31-1.50 (m, 2H),
1.27 (s, 3H).
HREIMS: calcd. for C17H24O5: 308.1623. Found: 308.1618.
Alcohol (+)-30
[a]D22 +1.1 (c 2.30, benzene).
(1’’’E)-5-(Buta-1’’’,3’’’-dienyl)-5-{3’-tert-butyldiphenylsilyloxy-
3’-[furan-2’’(5’’H)-on-4’’-yl]propyl}-2,2-dimethyl-1,3-dioxane
(31)
HREIMS: calcd. for C24H27BrO6: 490.0991. Found: 490.0998.
A solution of 30 (35.0 mg, 0.11 mmol), TBDPSCl (45 mL, 0.17
mmol), and imidazole (16.4 mg, 0.24 mmol) in DMF (0.5 mL) was
stirred at 25 °C for 42 h. Purification of the mixture by silica gel
chromatography (70-230 mesh, 5 g, hexane/EtOAc, 7:1 to 3:1) af-
forded 31 (46.0 mg, 0.089 mmol, 78%) as a colorless oil.
Diels-Alder Adducts 35a, 35b, and 35c
To a thick wall glass tube (f 10 x 90 mm, 2 mm in thickness) was
added a solution of 30 (33.2 mg, 0.11 mmol) in toluene (2 mL)
along with toluene wash (0.5 mL). The tube was sealed under Ar,
heated at 200 °C for 12 h, and then allowed to cool to r.t. The mix-
ture was concentrated in vacuo to afford a mixture of Diels-Alder
adducts, which was separated by HPLC (Develosil 60-3 column,
hexane/EtOAc, 1:3, 3 mL/min, RI) to afford 35b (tR = 11.7 min, 4.8
mg, 14.5%, contaminated with 13% of 35c) as white crystals fol-
lowed by 35c (tR = 12.2 min, 6.8 mg, 20.5%, contaminated with
26% of 35b) as a colorless oil and 35a (tR = 14.4 min, 12.2 mg, 37%,
contaminated with 5% of 30). These adducts were led to their
TBDMS-derivatives (TBDMSOTf, 2,6-lutidine, CH2Cl2, 0 °C to
r.t.) and identified by their 1H NMR spectra.
IR (neat): nmax = 2940, 1780, 1752, 1434, 1372, 1260, 1198, 1112,
1078, 1008, 702 cm-1.
1H NMR (400 MHz, C6D6): d = 7.26-7.73 (m, 10H), 6.22 (dt, 1H,
J = 16.8, 10.6 Hz), 5.88 (dd, 1H, J = 10.6, 16.0 Hz), 5.78 (q, 1H,
J = 1.2 Hz), 5.13 (dd, 1H, J = 0.8, 16.8 Hz), 5.04 (d, 1H, J = 16.0
Hz), 5.03 (dd, 1H, J = 0.8, 10.6 Hz), 4.41 (br t, 1H, J = 5.2 Hz), 4.37
(dd, 1H, J = 1.6, 17.6 Hz), 4.11 (br d, 1H, J = 17.6 Hz), 3.55 (dd,
2H, J = 7.2, 11.6 Hz), 3.39 (dd, 1H, J = 1.6, 11.6 Hz), 3.32 (dd, 1H,
J = 1.6, 11.6 Hz), 1.28-1.75 (m, 4H), 1.43 (s, 3H), 1.29 (s, 3H), 1.12
(s, 9H).
Adduct (-)-35a
HREIMS: calcd. for C33H42O5Si: 546.2801. Found: 546.2794.
A 300 mL autoclave (SUS 316) containing (+)-30 (4.69 g, 15.2
mmol), toluene (200 mL), and BHT (41.4 mg, 0.19 mmol) was heat-
ed under Ar at 210 °C for 2 days. The reaction mixture was allowed
to cool to r.t., and concentrated in vacuo. Purification of the residue
by silica gel chromatography (230-400 mesh, 200 g, hexane/EtOAc,
(1’’’E)-5-(Buta-1’’’,3’’’-dienyl)-2,2-dimethyl-5-{3’-[2’’(5’’H)-
furanon-4’’-yl]-3’-triisopropylsilyloxypropyl}-1,3-dioxane (32)
Colorless oil.
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

1888
N. Kanoh et al.
SPECIAL TOPIC
HREIMS: calcd. for C23H38O5Si: 422.2489. Found: 422.2515.
2:1 to 1:2) afforded a mixture of 35b and 35c (1.77 g, 38%) as white
crystals, followed by (-)-35a (1.97 g, 42%) as white crystals, which
was recrystallized from benzene to afford colorless prisms. (-)-35a
p-Bromobenzoates 40a, 40b, 40c, and 40d
Thermolysis of 34 (16.9 mg, 34.4 mmol) in toluene (1.5 mL) was
performed as described above, and the crude mixture was purified
by silica gel chromatography (70-230 mesh, 2 g, hexane/EtOAc, 5:1
to 3:1) to afford a mixture of adducts 40a, 40b, 40c, and 40d (14.1
mg, 83%) as white crystals. The ratio of these isomers was estimat-
ed to be 59:15:24:2 by comparing the integration of olefinic protons
and C1 proton of 400 MHz NMR spectra. 40d
Mp: 185-188 °C.
[a]D22 -14.8° (c 1.02, CHCl3).
IR (KBr): nmax = 3456, 2948, 2880, 1766, 1458, 1374, 1202, 1160,
1036, 832, 734 cm-1.
1H NMR (400 MHz, CDCl3): d = 6.18 (dt, 1H, J = 9.4, 3.2 Hz), 6.11
(m, 1H), 4.30 (d, 1H, J = 8.6 Hz), 3.92 (d, 1H, J = 11.6 Hz), 3.87
(dd, 1H, J = 1.6, 12.0 Hz), 3.66 (m, 1H), 3.64 (d, 1H, J = 8.6 Hz),
3.38 (dd, 1H, J = 1.6, 11.6 Hz), 3.21 (dd, 1H, J = 1.6, 12.0 Hz), 2.83
(dd, 1H, J = 0.8, 9.2 Hz), 2.57 (dd, 1H, J = 6.8, 19.0 Hz), 2.51 (dt,
1H, J = 14.4, 3.2 Hz), 2.43 (br, 1H, OH), 2.25 (m, 1H), 1.79-1.89
(m, 2H), 1.66 (m, 1H), 1.45 (s, 3H), 1.38 (s, 3H), 1.12 (ddt, 1H,
J = 2.0, 3.6, 14.0 Hz).
1H NMR (400 MHz, C6D6) for the olefinic and C1 protons: d = 5.46
(m, 1H), 5.20 (m, 1H), 4.90 (dd, 1H, J = 4.9, 11.7 Hz).
The adducts 40a, 40b, and 40c were separated as single isomers by
HPLC (Develosil 60-3 column, hexane/EtOAc, 3:1, 3 mL/min, RI).
40a
tR = 12.8 min; white crystals; mp: 235-237 °C.
HREIMS: calcd. for C17H24O5: 308.1623. Found: 308.1643.
IR (KBr): nmax = 2988, 2952, 1774, 1720, 1590, 1486, 1400, 1578,
1270, 1202, 1176, 1156, 1102, 1072, 1062, 1038, 1026, 1010, 990,
854, 832, 756 cm-1.
Adducts 36a, 36b, 36c, and 36d
Thermolysis of 29 (56.4 mg, 0.134 mmol) in toluene (3 mL) was
performed as described above. The resultant mixture of adducts was
separated by HPLC (Develosil 60-3 column, hexane/EtOAc, 5:1, 3
mL/min, RI) to afford a 3:1 mixture of 36b and 36c (tR = 10.2 min,
27.7 mg, 49%) as white crystals, followed by 36a (tR = 11.7 min,
15.9 mg, 28%) as white crystals, and 36d (tR = 14.2 min, 2.5 mg,
4%) as a colorless oil. The adducts 36a, 36b, and 36c were led to
their p-bromobenzoyl derivatives 40a, 40b, and 40c, respectively,
and these structures were identified by 1H NMR spectra.
1H NMR (400 MHz, C6D6): d = 7.90 (br d, 2H, J = 8.8 Hz), 7.17 (br
d, 2H, J = 8.8 Hz), 5.80 (dt, 1H, J = 9.5, 2.9 Hz), 5.68 (ddt, 1H,
J = 9.5, 6.9, 2.9 Hz), 4.67 (dd, 1H, J = 11.4, 3.7 Hz), 3.96 (d, 1H,
J = 9.2 Hz), 3.55 (d, 1H, J = 11.7 Hz), 3.46 (dd, 1H, J = 1.8, 11.7
Hz), 3.37 (d, 1H, J = 9.2 Hz), 3.06 (dd, 1H, J = 1.5, 11.7 Hz), 2.93
(dd, 1H, J = 1.5, 11.7 Hz), 2.40 (ddd, 1H, J = 16.2, 6.9, 1.1 Hz),
2.33 (dt, 1H, J = 13.9, 3.7 Hz), 2.29 (dd, 1H, J = 9.5, 1.1 Hz), 1.92
(dq, 1H, J = 13.6, 3.7 Hz), 1.72 (ddq, 1H, J = 16.2, 9.5, 2.9 Hz),
1.42 (s, 3H), 1.27 (s, 3H), 1.25 (m, 1H), 1.20 (q, 1H, J = 2.9 Hz),
0.74 (br t, 1H, J = 13.9 Hz).
36d
White crystals; mp: 113-115 °C.
HREIMS: calcd. for C24H27BrO6: 490.0991. Found: 490.0971.
IR (KBr): nmax = 2932, 2856, 1772, 1258, 1198, 1156, 1086, 1040,
996, 968, 836, 772 cm-1.
40b
tR = 11.1 min; white crystals; mp: 217-218.5 °C.
1H NMR (400 MHz, C6D6): d = 5.51 (ddd, 1H, J = 3.4, 6.2, 10.2
Hz), 5.28 (ddd, 1H, J = 3.4, 7.4, 10.2 Hz), 3.71 (d, 1H, J = 11.4 Hz),
3.65 (d, 1H, J = 8.6 Hz), 3.62 (dd, 1H, J = 11.4, 2.0 Hz), 3.61 (d,
1H, J = 8.6 Hz), 3.39 (dd, 1H, J = 2.4, 11.4 Hz), 3.18 (dd, 1H,
J = 4.8, 11.2 Hz), 2.96 (dd, 1H, J = 2.4, 11.4 Hz), 2.63 (dt, 1H,
J = 14.0, 3.2 Hz), 2.51 (dd, 1H, J = 11.4, 2.0 Hz), 2.17 (ddd, 1H,
J = 2.0, 6.2, 17.4 Hz), 1.82 (ddt, 1H, J = 11.4, 17.4, 3.4 Hz), 1.52 (s,
3H), 1.43 (m, 1H), 1.35 (m, 1H), 1.29 (s, 3H), 1.07 (s, 9H), 0.87 (d,
1H, J = 7.4 Hz), 0.70 (br dt, 1H, J = 14.0, 2.0 Hz.), 0.14 (s, 3H),
0.06 (s, 3H).
IR (KBr): nmax = 2988, 2936, 1762, 1724, 1590, 1398, 1374, 1272,
1202, 1174, 1158, 1114, 1094, 1068, 1032, 1012, 998, 848, 754
cm-1.
1H NMR (400 MHz, C6D6): d = 7.65 (br d, 2H, J = 8.4 Hz), 7.21 (br
d, 2H, J = 8.4 Hz), 5.87 (ddd, 1H, J = 9.5, 3.3, 2.9 Hz), 5.71 (ddt,
1H, J = 9.5, 6.6, 2.9 Hz), 4.96 (br s, 1H), 3.72 (d, 1H, J = 11.7 Hz),
3.48 (br d, 1H, J = 11.7 Hz), 3.31 (d, 1H, J = 9.5 Hz), 3.29 (br d, 1H,
J = 9.5 Hz), 3.11 (dd, 1H, J = 1.5, 11.7 Hz), 3.05 (dd, 1H, J = 1.5,
11.7 Hz), 2.61 (dd, 1H, J = 8.3, 1.3 Hz), 2.53 (ddd, 1H, J = 15.7,
6.6, 1.3 Hz), 2.17 (ddd, 1H, J = 13.6, 3.3, 3.0 Hz), 2.07 (dt, 1H,
J = 3.3, 2.9 Hz), 1.82 (ddq, 1H, J = 15.7, 8.3, 2.9 Hz), 1.75 (dq, 1H,
J = 15.7, 3.3 Hz), 1.43 (s, 3H), 1.30 (s, 3H), 1.28 (m, 1H), 1.09 (br
t, 1H, J = 13.6 Hz).
HREIMS: calcd. for C23H38O5Si: 422.2488. Found: 422.2497.
TBS Ether (-)-36a
A solution of (-)-35a (113.8 mg, 0.37 mmol), 2,6-lutidine (90 mL,
0.83 mmol) and TBDMSOTf (130 mL, 0.57 mmol) in CH2Cl2 (2
mL) was stirred for 2.5 h. H2O (2 mL) was added and the mixture
was diluted with Et2O (20 mL). Usual workup afforded (-)-36a
(144.7 mg, 0.34 mmol, 93%) as white crystals.
HREIMS: calcd. for C24H27BrO6: 490.0991. Found: 490.0979.
40c
tR = 11.6 min; white crystals; mp: 217-219 °C.
IR (KBr): nmax = 2996, 2928, 1776, 1724, 1592, 1380, 1316, 1270,
1252, 1230, 1202, 1186, 1140, 1124, 1102, 1076, 1060, 1038, 1012,
824, 754 cm-1.
Mp: 127-130 °C.
[a]D24 -27.8 (c 1.42, CHCl3).
1H NMR (400 MHz, C6D6): d = 7.76 (br d, 2H, J = 8.8 Hz), 7.20 (br
d, 2H, J = 8.8 Hz), 5.56 (m, 1H), 5.27 (dt, 1H, J = 9.6, 2.8 Hz), 4.81
(dd, 1H, J = 4.8, 11.2 Hz), 4.17 (d, 1H, J = 9.4 Hz), 3.76 (d, 1H,
J = 9.4 Hz), 3.44 (d, 1H, J = 11.6 Hz), 3.42 (dd, 1H, J = 1.6, 11.6
Hz), 3.29 (d, 1H, J = 11.6 Hz), 3.28 (dd, 1H, J = 11.6, 1.6 Hz), 2.24
(br dt, 1H, J = 15.6, 6.4 Hz), 2.14 (t, 1H, J = 6.8 Hz), 2.07 (br s, 1H),
2.04 (m, 1H), 1.78 (m, 1H), 1.74 (m, 1H), 1.40 (s, 3H), 1.28 (s, 3H),
1.17 (m, 1H), 1.06 (m, 1H).
IR (KBr): nmax = 2952, 2856, 1770, 1466, 1374, 1260, 1206, 1160,
1106, 1050, 836, 776 cm-1.
1H NMR (400 MHz, CDCl3): d = 5.82 (dt, 1H, J = 9.6, 3.0 Hz), 5.74
(ddt, 1H, J = 7.0, 9.6, 3.0 Hz), 4.01 (d, 1H, J = 8.6 Hz), 3.69 (d, 1H,
J = 11.6 Hz), 3.50 (dd, 1H, J = 1.8, 11.6 Hz), 3.28 (d, 1H, J = 8.6
Hz), 3.17 (dd, 1H, J = 4.8, 11.2 Hz), 3.11 (dd, 1H, J = 2.0, 11.6 Hz),
2.99 (dd, 1H, J = 2.6, 11.6 Hz), 2.59 (dd, 1H, J = 7.0, 16.0 Hz), 2.49
(d, 1H, J = 9.2 Hz), 2.40 (dt, 1H, J = 13.8, 3.8 Hz), 1.83 (m, 1H),
1.48 (s, 3H), 1.44 (ddt, 1H, J = 14.0, 4.8, 3.8 Hz), 1.29 (s, 3H), 1.29
(m, 1H), 1.20 (q, 1H, J = 3.0 Hz), 1.01 (s, 9H), 0.65 (ddt, 1H,
J = 1.8, 3.8, 13.8 Hz), 0.08 (s, 3H), 0.02 (s, 3H).
HREIMS: calcd. for C24H27BrO6: 490.0991. Found: 490.1003.
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthetic Studies on Azadirachtin
1889
S-(2-Pyridyl)-3-[2’,2’-dimethyl-5’-(prop-2’’-enyl)-1’,3’-dioxan-
5’-yl]propanthioate (42)
and brine (100 mL each). The combined aqueous layers were ex-
tracted again with EtOAc (100 mL). The extracts were combined,
dried (Na2SO4), filtered, and concentrated in vacuo. Purification of
the residue by silica gel chromatography (70-230 mesh, 400 g, hex-
ane/EtOAc, 40:1 to 1:3) afforded 44 (19.62 g, 43.5 mmol, 65%),
followed by the recovered 43 (contaminated with 9% of 2(5H)-fura-
none, 6.07 g, 20.35 mmol, 30%).
To the cooled (-8 °C) solution of 19 (9.65 g, 45.5 mmol), 2-methyl-
but-2-ene (48.0 mL, 453 mmol), and NaH2PO4·2H2O (10.17 g, 65.2
mmol) in t-BuOH (120 mL) and H2O (40 mL) was added NaClO2
(>86% purity, 7.21 g, >68.6 mmol) in several sequential portions,
and the solution was stirred at -8 °C for 1 h and then at 25 °C for 30
min. The reaction was quenched by addition of 10% NaHSO3 (20
mL), and the mixture was concentrated in vacuo. The aqueous resi-
due was extracted with Et2O (4 ¥ 100 mL), and the extracts were
washed with brine (30 mL). The combined aqueous layers were ex-
tracted again with CH2Cl2 (2 ¥ 30 mL), and the extracts were
washed with brine (6 mL). All organic extracts were combined,
dried (MgSO4), filtered, and concentrated in vacuo to afford the
crude acid 41 (12.11 g) as white crystals, which was dissolved in
CH2Cl2 (300 mL). To the stirred solution were added 2,2'-dipyridyl
disulfide (11.08 g, 50.3 mmol) and PPh3 (13.89 g, 53.0 mmol), and
the solution was stirred at 25 °C for 80 min. Then, H2O (40 mL) was
added, and the aqueous layer was extracted with CH2Cl2 (30 mL).
The extracts were washed with brine (30 mL), dried (MgSO4), fil-
tered, and concentrated in vacuo. Purification of the residue by sili-
ca gel chromatography (70-230 mesh, 200 g, hexane/EtOAc, 7:1 to
2:1) afforded 42 (14.06 g, 43.8 mmol, 96% for 2 steps) as a yellow
oil.
Diols (-)-47
A solution of (-)-36a (1.16 g, 2.74 mmol), OsO4 (19.7 mM in
t-BuOH, 12 mL, 0.39 mmol), and NMO (370.8 mg, 3.17 mmol) in
THF (12 mL) and H2O (6 mL) was stirred at 25 °C for 2 days.
NaHSO3 (1.07 g) was added and the mixture was stirred at 25 °C for
1 h, and then filtered through Celite pad, which was washed with
THF (100 mL). The filtrate was concentrated in vacuo. Purification
of the residue by silica gel chromatography (230-400 mesh, 40 g,
hexane/EtOAc, 2:1 to 1:3) afforded 6a,7a-diol (-)-47 (915.2 mg,
2.00 mmol, 73%) as white crystals and 6b,6b-diol (248.2 mg, 0.54
mmol, 20%) as a colorless oil.
(-)-47
Mp: 121-124 °C.
[a]D22 -13.2 (c 0.65, CHCl3).
IR (KBr): nmax = 3448, 2936, 1772, 1636, 1466, 1378, 1256, 1104,
972, 838 cm-1.
IR (neat): nmax = 3072, 2988, 2872, 1818, 1716, 1642, 1574, 1454,
1372, 1258, 1198, 1040 cm-1.
1H NMR (400 MHz, CDCl3): d = 5.30 (br s, 1H), 4.43 (dd, 1H,
J = 9.4, 4.4 Hz), 4.38 (d, 1H, J = 9.2 Hz), 4.09 (d, 1H, J = 9.2 Hz),
3.92 (ddd, 1H, J = 4.4, 3.2, 8.3 Hz), 3.77 (d, 1H, J = 12.4 Hz), 3.70
(d, 1H, J = 12.4 Hz), 3.56 (d, 1H, J = 12.4 Hz), 3.53 (d, 1H, J = 12.4
Hz), 3.45 (dd, 1H, J = 4.4, 11.6 Hz), 3.12 (br, 1H), 2.46 (t, 1H,
J = 7.2 Hz), 2.20 (ddd, 1H, J = 7.2, 8.3, 15.6 Hz), 1.80 (ddd, 1H,
J = 3.2, 7.2, 15.6 Hz), 1.79 (d, 1H, J = 9.4 Hz), 1.50-1.75 (m, 3H),
1.42 (s, 6H), 1.09 (dt, 1H, J = 4.0, 13.6 Hz), 0.36 (s, 9H), 0.06 (s,
6H).
1H NMR (270 MHz, C6D6): d = 8.37 (br dd, 1H, J = 1.7, 6.6 Hz),
7.58 (br d, 1H, J = 7.9 Hz), 7.00 (dt, 1H, J = 1.7, 7.9 Hz), 6.52 (br
dd, 1H, J = 4.6, 6.6 Hz), 5.53 (ddt, 1H, J = 17.8, 10.6, 7.6 Hz), 4.99
(br d, 1H, J = 17.8 Hz), 4.98 (br d, 1H, J = 10.6 Hz), 3.32 (d, 2H,
J = 11.5 Hz), 3.29 (d, 2H, J = 11.5 Hz), 2.43 (m, 2H), 1.92 (br d,
2H, J = 7.6 Hz), 1.69 (m, 2H), 1.37 (s, 3H), 1.34 (s, 3H).
HRMS (FAB): calcd. for C17H24NO3S (M++H): 322.1477. Found:
322.1449.
HRMS (FAB): calcd. for C23H41O7Si (M++H): 457.2622. Found:
457.2652.
Weinreb Amide 43
A solution of 42 (5.83 g, 18.1 mmol), N,O-dimethylhydroxylamine
hydrochloride (1.96 g, 20.1 mmol), and Et3N (2.8 mL, 20.1 mmol)
in CH2Cl2 (50 mL) was stirred at 25 °C for 70 min. The mixture was
washed successively with 1 M NaOH (3 ¥ 10 mL), H2O (10 mL),
and brine (10 mL). The combined aqueous layers were extracted
with Et2O (10 mL), and the extracts were dried (MgSO4), and con-
centrated in vacuo. Purification of the residue by silica gel chroma-
tography (70-230 mesh, 100 g, hexane/EtOAc, 2:1 to 1:1) afforded
43 (4.81 g, 17.7 mmol, 98%) as a pale yellow oil.
p-Methoxybenzylidene Acetal (-)-48
To a solution of (-)-47 (795.1 mg, 1.74 mmol) in benzene (30 mL)
was added PPTS (19.6 mg, 78.0 mmol), and the solution was re-
fluxed for 15 min with azeotropic removal of H2O (Dean-Stark). p-
Anisaldehyde (0.3 mL, 2.47 mmol) was added and the mixture was
stirred under the same conditions for further 30 min. Then, the so-
lution was allowed to cool to r.t., diluted with Et2O (20 mL), washed
successively with sat. NaHCO3, H2O, and brine (2 mL each), dried
(MgSO4), filtered, and then concentrated in vacuo. Purification of
the residue by silica gel chromatography (230-400 mesh, 30 g, hex-
ane/EtOAc, 8:1 to 6:1) afforded (-)-48 (792.5 mg, 1.38 mmol,
79%) as a colorless amorphous solid.
IR (neat): nmax = 2992, 2940, 2868, 1668, 1456, 1418, 1388, 1260,
1198, 1090, 998, 832 cm-1.
1H NMR (270 MHz, C6D6): d = 5.79 (ddt, 1H, J = 17.8, 9.2, 7.9 Hz),
5.12 (br d, 1H, J = 17.8 Hz), 5.11 (br d, 1H, J = 9.2 Hz), 3.70 (s,
3H), 3.60 (s, 4H), 3.18 (s, 3H), 2.42 (m, 2H), 2.21 (br d, 2H, J = 7.9
Hz), 1.67 (m, 2H), 1.41 (s, 3H), 1.40 (s, 3H).
Mp: 141-143 °C.
[a]D27 -28.5 (c 1.07, CHCl3).
IR (neat): nmax = 2936, 2856, 1772, 1616, 1464, 1384, 1252, 1164,
HREIMS: calcd. for C14H25NO4: 271.1784. Found: 271.1803.
1076, 1034, 978, 894, 834 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.40 (m, 2H, Jortho = 8.8 Hz), 6.90
(m, 2H, Jortho = 8.8 Hz), 5.38 (s, 1H), 4.39-4.45 (m, 3H), 4.05 (br d,
1H, J = 11.6 Hz), 4.00 (m, 1H), 3.85 (dd, 1H, J = 10.8, 2.8 Hz), 3.81
(s, 3H), 3.67 (d, 1H, J = 9.2 Hz), 3.58 (dd, 1H, J = 11.6, 2.8 Hz),
3.50 (dd, 1H, J = 4.4, 11.2 Hz), 2.84 (dt, 1H, J = 14.6, 3.2 Hz), 2.58
(br d, 1H, J = 7.2 Hz), 2.17 (br dd, 1H, J = 4.4, 13.0 Hz), 1.83 (m,
1H), 1.74 (dt, 1H, J = 7.2, 13.0 Hz), 1.66 (m, 1H), 1.61 (d, 1H,
J = 8.8 Hz), 1.45 (s, 3H), 1.38 (s, 3H), 1.18 (br t, 1H, J = 14.6 Hz),
0.86 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H).
3-[2’,2’-Dimethyl-5’-(prop-2’’-enyl)-1’,3’-dioxan-5’-yl]-1-(2’’’-
triisopropylsilyloxyfuran-4’’’-yl)-1-oxopropane (44)
To a cooled (-78 °C) solution of t-BuLi (1.62 M solution in pentane,
92.0 mL, 149.0 mmol) in Et2O (200 mL) was added a solution of 22
(23.69 g, 74.3 mmol) in Et2O (50 mL) over 20 min, and the mixture
was stirred for 20 min. To a cooled (-78 °C) and vigorously stirred
solution of 43 (18.28 g, 67.4 mmol) in Et2O (250 mL) was trans-
ferred the lithiofuran solution, prepared above, via thick cannula (f
2 mm) over 10 min, and the mixture was stirred for 30 min. The re-
action was quenched by addition of sat. NH4Cl (100 mL), and the
mixture was allowed to warm to r.t. The aqueous layer was extract-
ed with EtOAc (100 mL), and the extracts were washed with H2O
HRMS (FAB): calcd. for C31H47O8Si (M++H): 575.3040. Found:
575.3070.
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

1890
N. Kanoh et al.
SPECIAL TOPIC
Alcohols 49 and 50
tography (230-400 mesh, 30 g, hexane/EtOAc, 8:1 to 2:1) afforded
(-)-52 (488.5 mg, 0.89 mmol, 85%) as a colorless viscous oil and
(4S)-epimer of (-)-52 (92.3 mg, 0.17 mmol, 15%) as a colorless oil.
To a mixture of (-)-48 (792.5 mg, 1.38 mmol), MS 3Å (activated
by heating at 200 °C for 4 h, 1.54 g) and NaBH3CN (1.73 g, 27.5
mmol) in DMF (30 mL) was added TfOH (2.1 mL, 27.3 mmol) over
5 min, maintaining the temperature below 25 °C. The mixture was
stirred at the same temperature for 90 min, and then cooled to 0 °C.
The reaction was quenched by slow addition of sat. NaHCO3 (50
mL). The mixture was extracted with EtOAc (4 ¥ 50 mL), and the
extracts were washed with brine (30 mL), and concentrated in vac-
uo. Residual DMF was removed under high vacuum (<1 Torr) at
35 °C. Purification of the residue by silica gel chromatography (70-
230 mesh, 20 g, hexane/EtOAc, 5:1 to 3:1) afforded 49 (contaminat-
ed with 14% of 50, 640.0 mg, 1.10 mmol, 80%) as white crystals;
mp: 59 °C.
(-)-52
[a]D23 -17.0 (c 0.71, CHCl3).
IR (neat): nmax = 3544, 2936, 1776, 1458, 1384, 1256, 1106, 1072,
976, 838 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.28-7.38 (m, 5H), 4.81 (dd, 1H,
J = 6.4, 9.0 Hz), 4.53 (d, 1H, J = 11.6 Hz), 4.41 (d, 1H, J = 11.6
Hz), 4.38 (d, 1H, J = 13.6 Hz), 3.99 (d, 1H, J = 12.2 Hz), 3.95 (m,
1H), 3.89 (d, 1H, J = 13.6 Hz), 3.48 (d, 1H, J = 9.8 Hz), 3.43 (dd,
1H, J = 4.8, 11.2 Hz), 3.26 (br d, 1H, J = 12.2 Hz), 3.15 (d, 1H,
J = 9.8 Hz), 2.97 (br, 1H, OH), 2.17 (dd, 1H, J = 4.0, 13.6 Hz), 1.94
(d, 1H, J = 9.0 Hz), 1.75 (dd, 1H, J = 7.2, 13.4 Hz), 1.68 (m, 1H),
1.36-1.64 (m, 3H), 1.46 (s, 3H), 1.28 (s, 3H), 0.84 (s, 9H), 0.06 (s,
3H), 0.04 (s, 3H).
49
IR (KBr): nmax 3472, 2940, 1772, 1616, 1516, 1472, 1372, 1252,
1172, 1032, 972, 840 cm-1.
HRMS (FAB): calcd. for C30H47O7Si (M++H): 547.3091. Found:
547.3081.
1H NMR (400 MHz, CDCl3): d = 7.23 (m, 2H, Jortho = 8.8 Hz), 6.88
(m, 2H, Jortho = 8.8 Hz), 4.53 (dd, 1H, J = 6.4, 8.8 Hz), 4.47 (d, 1H,
J = 9.6 Hz), 4.44 (d, 1H, J = 11.2 Hz), 4.43 (d, 1H, J = 11.2 Hz),
3.96 (m, 1H), 3.92 (d, 1H, J = 9.2 Hz), 3.91 (d, 1H, J = 9.2 Hz), 3.81
(s, 3H), 3.74 (br d, 1H, J = 11.6 Hz), 3.49 (br d, 1H, J = 11.6 Hz),
3.43 (dd, 1H, J = 5.2 Hz), 3.25 (d, 1H, J = 8.8 Hz), 2.67 (br, 1H),
2.52 (d, 1H, J = 6.8 Hz), 2.16 (dt, 1H, J = 14.4, 2.8 Hz), 2.12 (dd,
1H, J = 15.6, 6.0 Hz), 1.74 (d, 1H, J = 8.8 Hz), 1.40-1.80 (m, 3H),
1.43 (s, 3H), 1.26 (s, 3H), 1.17 (dt, 1H, J = 4.0, 14.4 Hz), 0.84 (s,
9H), 0.07 (s, 3H), 0.04 (s, 3H).
Mesylate (-)-53
To a cooled (0 °C) solution of (-)-52 (488.5 mg, 0.89 mmol) in
CH2Cl2 (20 mL) were added Et3N (0.30 mL, 2.15 mmol) and MsCl
(0.14 mL, 1.81 mmol), and the mixture was stirred at 0 °C for 1.5 h.
Sat. NaHCO3 (10 mL) was added and the separated aqueous layer
was extracted with Et2O (3 ¥ 20 mL). The extracts were washed
with sat. NH4Cl, H2O, and brine (8 mL each), dried (MgSO4), fil-
tered, and concentrated in vacuo. Purification of the residue by sili-
ca gel chromatography (230-400 mesh, 2 g, hexane/EtOAc, 5:1 to
3:1) afforded (-)-53 (634.0 mg) as a pale yellow viscous oil, which
was used for the next step. An analytical sample was completely
dried in vacuo.
HREIMS: calcd. for C31H48O8Si: 576.3118. Found: 576.3143.
Benzyl Ether 51
To a stirred solution of a 6.2:1 mixture of 49 and 50 (640.8 mg, 1.11
mmol) in THF (20 mL) were added successively NaH (60% in oil,
91.3 mg, 2.05 mmol), TBAI (24.8 mg, 67.1 mmol), and BnBr (0.26
mL, 2.19 mmol) at 25 °C, and the mixture was stirred for 1 day. To
the mixture were added additional NaH (95.0 mg, 2.37 mmol),
TBAI (34.9 mg, 94.5 mmol), and BnBr (0.26 mL, 2.19 mmol), and
the mixture was stirred for another 1 day, then cooled to 0 °C. Sat.
NH4Cl (2 mL) was added and the mixture was concentrated in
vacuo. H2O (5 mL) was added to the aqueous residue, and the mix-
ture was extracted with EtOAc (3 ¥ 30 mL). The extracts were
washed with brine (5 mL), dried (MgSO4), filtered, and concentrat-
ed in vacuo. Purification of the residue by silica gel chromatography
(230-400 mesh, 15 g, hexane/EtOAc, 20:1 to 1:1) afforded 51 [con-
taminated with 14% of (4S)-isomer, 690.3 mg, 1.04 mmol, 93%] as
a colorless viscous oil.
(-)-53
[a]D23 -11.3 (c 1.85, CHCl3).
IR (neat): nmax = 2936, 1772, 1358, 1260, 1176, 1074, 968, 840 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.29-7.39 (m, 5H), 4.84 (dd, 1H,
J = 6.8, 9.2 Hz), 4.48 (d, 1H, J = 11.7 Hz), 4.47 (d, 1H, J = 11.7
Hz), 4.44 (d, 1H, J = 9.5 Hz), 4.34 (d, 1H, J = 9.3 Hz), 4.29 (d, 1H,
J = 9.5 Hz), 3.93 (ddd, 1H, J = 11.7, 6.8, 4.6 Hz), 3.84 (d, 1H,
J = 9.3 Hz), 3.43 (d, 1H, J = 10.3 Hz), 3.42 (m, 1H), 3.35 (d, 1H,
J = 10.3 Hz), 2.97 (s, 3H), 2.54 (br d, 1H, J = 6.2 Hz), 2.16 (br dd,
1H, J = 13.6, 4.6 Hz), 1.87 (d, 1H, J = 9.2 Hz), 1.37-1.76 (m, 5H),
1.41 (s, 3H), 1.22 (s, 3H), 0.84 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H).
HREIMS: calcd. for C31H48O9Ssi: 624.2788. Found: 624.2798.
IR (neat): nmax = 2936, 2856, 1772, 1358, 1260, 1176, 1074, 968,
840 cm-1.
Tetracycle (-)-54
A solution of (-)-53 (634.0 mg containing 76 mg of EtOAc, 0.89
mmol), PTS·H2O (50.0 mg, 0.26 mmol) in (CH2OH)2 (1 mL) and
THF (20 mL) was stirred and heated under reflux for 31 h. The mix-
ture was allowed to cool to r.t., and sat. NaHCO3 (5 mL) was added.
The mixture was concentrated in vacuo and the aqueous layer was
extracted with EtOAc (4 ¥ 20 mL). The extracts were washed with
brine (5 mL), dried (MgSO4), filtered, and concentrated in vacuo.
Purification of the residue by silica gel chromatography (230-400
mesh, 20 g, hexane/EtOAc, 2:1 to EtOAc) afforded (-)-54 (360.3
mg, 0.74 mmol, 83% for 2 steps) as white crystals.
1H NMR (400 MHz, CDCl3): d = 7.23-7.35 (m, 7H), 6.86 (m, 2H,
Jortho = 8.8 Hz), 4.84 (dd, 1H, J = 7.2, 9.0 Hz), 4.33-4.48 (m, 5H),
3.90 (d, 1H, J = 9.6 Hz), 3.88 (m, 1H), 3.79 (s, 3H), 3.60 (d, 1H,
J = 9.2 Hz), 3.48 (d, 1H, J = 9.2 Hz), 3.41 (dd, 1H, J = 4.8, 11.2
Hz), 3.38 (d, 1H, J = 10.2 Hz), 3.36 (d, 1H, J = 10.2 Hz), 2.51 (d,
1H, J = 6.8 Hz), 2.10 (dd, 1H, J = 4.0, 12.4 Hz), 2.00 (d, 1H, J = 9.0
Hz), 1.39-1.77 (m, 5H), 1.43 (s, 3H) 1.22 (s, 3H), 0.84 (s, 9H), 0.04
(s, 3H), 0.03 (s, 3H).
HRMS (FAB): calcd. for C38H55O8Si (M++H): 667.3666. Found:
667.3635.
Mp: 188-190 °C.
[a]D24 -2.5 (c 0.12, CHCl3).
Alcohol (-)-52
IR (KBr): nmax = 3540, 2952, 1774, 1160, 1096, 1050, 866, 834
To a solution of a mixture of 51 and its (4S)-epimer (690.3 mg, 1.04
mmol) in CH2Cl2 (20 mL) and H2O (1 mL) was added DDQ (352.4
mg, 1.55 mmol), and the mixture was stirred at 25 °C for 1.5 h. The
mixture was diluted with Et2O (30 mL), washed with sat. NaHCO3,
H2O, and brine (6 mL each), filtered through Celite pad, and con-
centrated in vacuo. Purification of the residue by silica gel chroma-
cm-1.
1H NMR (400 MHz, CDCl3): d = 7.30-7.39 (s, 5H), 4.55 (d, 1H,
J = 11.9 Hz), 4.49 (d, 1H, J = 11.9 Hz), 4.29 (d, 1H, J = 9.2 Hz),
4.27 (1H, m), 4.20 (d, 1H, J = 8.1 Hz), 4.02 (d, 1H, J = 9.2 Hz), 3.84
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthetic Studies on Azadirachtin
1891
(dd, 1H, J = 2.6, 12.1 Hz), 3.61 (dd, 1H, J = 4.8, 11.0 Hz), 3.38 (br
d, 1H, J = 8.1 Hz), 3.33 (br d, 1H, J = 8.8 Hz), 3.24 (dd, 1H, J = 8.8,
1.1 Hz), 2.42 (ddd, 1H, J = 3.7, 6.6, 14.7 Hz), 2.37 (dd, 1H, J = 6.6,
11.7 Hz), 2.17 (d, 1H, J = 12.1 Hz), 2.08 (dt, 1H, J = 13.4, 2.9 Hz),
2.01 (br, 1H, OH), 1.72 (dq, 1H, J = 14.3, 4.4 Hz), 1.56 (m, 1H),
1.47 (m, 1H), 1.29 (dt, 1H, J = 4.4, 13.4 Hz), 0.86 (s, 9H), 0.06 (s,
3H), and 0.05 (s, 3H).
Ketone (-)-57
To a suspension of (-)-56 (82.2 mg, 0.17 mmol) and MS 3Å (three
spatula-full, approx. 35 mg) in CH2Cl2 (3 mL) was added PDC (94.4
mg, 0.25 mmol), and the suspension was stirred at 25 °C for 2 h 20
min. The mixture was extracted with Et2O (15 mL) and usual work-
up afforded (-)-57 (67.3 mg, 0.18 mmol, 82%) as a colorless oil.
[a]D23 -23.2 (c 1.00, CHCl3).
HRMS (FAB): calcd. for C27H41O6Si (M++H): 489.2672. Found:
489.2694.
IR (neat): nmax = 2876, 1786, 1716, 1616, 1516, 1458, 1368, 1302,
1252, 1174, 1098, 920, 822 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.31-7.41 (m, 5H), 7.23 (m, 2H,
Jortho = 8.6 Hz), 6.87 (m, 2H, Jortho = 8.6 Hz), 4.66 (d, 1H, J = 11.7
Hz), 4.59 (d, 1H, J = 11.9 Hz), 4.56 (d, 1H, J = 11.7 Hz), 4.54 (d,
1H, J = 11.9 Hz), 4.24 (d, 1H, J = 10.3 Hz), 4.15 (d, 1H, J = 10.3
Hz), 4.07 (d, 1H, J = 8.2 Hz), 4.03 (m, 1H), 3.98 (d, 1H, J = 2.9,
12.1 Hz), 3.81 (s, 3H), 3.55 (s, 2H), 3.46 (d, 1H, J = 8.2 Hz), 2.79-
2.88 (2H, m), 2.74 (d, 1H, J = 12.1 Hz), 2.28-2.41 (m, 3H), 1.78 (dt,
1H, J = 5.5, 13.6 Hz), 1.41 (ddd, 1H, J = 2.2, 13.2, 15.0 Hz).
MPM Ether (-)-55
To a cooled (0 °C) suspension of (-)-54 (317.5 mg, 0.65 mmol) and
p-methoxybenzyl 2,2,2-trichloroacetimidate (0.2 mL, 0.96 mmol)
in Et2O (20 mL) was added TfOH (32.5 mM in Et2O, 50 mL, 1.63
mmol, 0.25 mol%), and the mixture was allowed to warm to r.t. over
1 h. Additional p-methoxybenzyl 2,2,2-trichloroacetimidate (0.1
mL, 0.48 mmol) was added and the mixture was stirred for further
3 h. Sat. NaHCO3 (5 mL) was added and the aqueous layer was ex-
tracted with Et2O (2 ¥ 20 mL). The extracts were washed with brine
(8 mL), dried (MgSO4), filtered, and concentrated in vacuo. Purifi-
cation of the residue by silica gel chromatography (230-400 mesh,
20 g, hexane/EtOAc, 6:1 to 3:1) afforded (-)-55 (278.0 mg, 0.46
mmol, 70%) as a colorless oil.
HREIMS: calcd. for C29H32O7: 492.2148. Found: 492.2184.
TMS Enol Ether (-)-58
To a cooled (-78 °C) solution of LDA, which was prepared by mix-
ing i-Pr2NH (0.10 mL, 0.71 mmol) and BuLi (1.63 M in hexane,
0.34 mL, 0.55 mmol) in THF (2 mL) at 0 °C for 30 min, was added
a solution of (-)-57 (90.7 mg, 0.18 mmol) in THF (1 mL) along
with THF wash (1 mL). The mixture was stirred at -78 °C for 1 h,
TMSOTf (0.14 mL, 0.72 mmol) was added dropwise, and stirring
was continued for 20 min. Sat. NH4Cl (3 mL) was added and the
mixture was allowed to warm to 25 °C. The organic layer was sep-
arated, and the aqueous layer was extracted with EtOAc (4 ¥ 4 mL).
The extracts were washed with brine (2 mL), dried (MgSO4), fil-
tered, and concentrated in vacuo. Purification of the residue by sili-
ca gel chromatography (230-400 mesh, 2 g, hexane/EtOAc, 2:1 to
1:2) afforded (-)-58 (68.8 mg, 0.12 mmol, 66%) followed by the re-
covered (-)-57 (13.9 mg, 0.028 mmol, 15%).
[a]D20 -18.9 (c 0.49, CHCl3).
IR (neat): nmax = 2932, 1776, 1614, 1516, 1472, 1366, 1252, 1178,
1102, 1032, 838 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.26-7.39 (m, 7H), 6.89 (m, 2H,
Jortho = 8.4 Hz), 4.72 (d, 1H, J = 12.0 Hz), 4.59 (d, 1H, J = 12.0 Hz),
4.56 (d, 1H, J = 11.4 Hz), 4.49 (d, 1H, J = 11.4 Hz), 4.28 (d, 1H,
J = 9.0 Hz), 4.19 (d, 1H, J = 7.8 Hz), 4.03 (m, 1H), 4.01 (d, 1H,
J = 9.0 Hz), 3.85 (dd, 1H, J = 2.4, 12.2 Hz), 3.81 (s, 3H), 3.60 (dd,
1H, J = 4.4, 10.8 Hz), 3.37 (d, 1H, J = 7.8 Hz), 3.31 (d, 1H, J = 9.0
Hz), 3.20 (d, 1H, J = 9.0 Hz), 2.26-2.39 (m, 2H), 2.28 (d, 1H,
J = 12.2 Hz), 2.08 (dt, 1H, J = 13.2, 2.4 Hz), 1.70 (m, 1H), 1.58 (m,
1H), 1.37 (ddd, 1H, J = 2.4, 12.4, 14.4 Hz), 1.26 (dt, 1H, J = 4.4,
13.2 Hz), 0.86 (s, 9H), 0.06 (s, 3H), and 0.04 (s, 3H).
(-)-58
[a]D17 -33.3 (c 1.70, CHCl3).
HRMS (FAB): calcd. for C35H49O7Si (M++H): 609.3247. Found:
609.3278.
IR (neat): nmax = 2956, 2868, 1780, 1636, 1614, 1516, 1458, 1302,
1214, 1174, 1114, 1094, 1024, 962, 920, 874, 750 cm-1.
1H NMR (270 MHz, C6D6): d = 7.18-7.30 (m, 7H), 6.85 (d, 2H,
J = 8.9 Hz), 4.73 (d, 1H, J = 11.9 Hz), 4.57 (d, 1H, J = 11.9 Hz),
4.50 (dd, 1H, J = 2.3, 5.0 Hz), 4.34 (d, 1H, J = 7.6 Hz), 4.24 (d, 1H,
J = 12.2 Hz), 4.20 (d, 1H, J = 12.2 Hz), 4.07 (s, 2H), 3.74-3.80 (m,
2H), 3.62 (d, 1H, J = 7.6 Hz), 3.34 (s, 3H), 3.11 (d, 1H, J = 8.8 Hz),
3.03 (d, 1H, J = 12.9 Hz), 3.01 (d, 1H, J = 8.8 Hz), 2.76 (dd, 1H,
J = 5.9, 12.2 Hz), 2.26 (m, 1H), 2.05 (dd, 1H, J = 5.0, 16.8 Hz), 1.81
(dd, 1H, J = 2.3, 16.8 Hz), 1.07 (m, 1H), and 0.21 (m, 9H).
Alcohol (-)-56
To a cooled (0 °C) solution of (-)-55 (275 mg, 0.45 mmol) in THF
(8 mL) was added TBAF (1.0 M soln in THF, 0.90 mL, 0.90 mmol).
The mixture was stirred at 0 °C for 13 min, and allowed to warm to
25 °C over 1.2 h. Sat. NH4Cl (5 mL) was added and the mixture was
concentrated in vacuo. The aqueous residue was extracted with
EtOAc (4 ¥ 10 mL). The extracts were washed with brine (5 mL),
dried (MgSO4), filtered, and concentrated in vacuo. Purification of
the residue by silica gel chromatography (70-230 mesh, 6 g, hexane/
EtOAc, 5:1 to 1:2) afforded (-)-56 (212 mg, 0.43 mmol, 95%) as a
colorless oil.
HREIMS: calcd. for C32H40O7Si: 564.2543. Found: 564.2568.
Phenylseleno Ketone (-)-59 and Enone (+)-60
[a]D22 -4.6 (c 0.82, CHCl3).
To a cooled (0 °C) solution of (-)-58 (12.9 mg, 22.8 mmol) and N-
PSP (10.7 mg, 35.4 mmol) in THF (2 mL) was added TMSOTf
(0.001 mL, 5.17 mmol). The mixture was stirred at 0 °C for 30 min,
and allowed to warm to 25 °C over 35 min. Additional TMSOTf
(0.004 mL, 20.7 mmol) was added to the mixture, and the solution
was stirred for another 35 min. H2O (2 mL) was added and the mix-
ture was concentrated in vacuo. The residue was extracted with
EtOAc (4 ¥ 3 mL); the extracts were washed with brine (1 mL),
dried (MgSO4), filtered, and concentrated in vacuo. Purification of
the residue by silica gel chromatography (230-400 mesh, 400 mg,
hexane/EtOAc, 2:1 to 1:1) afforded the crude mixture of (-)-57,
(-)-59, and (+)-60. Further purification of the mixture by HPLC
(Develosil 60-3 column, hexane/EtOAc, 1:2, 3 ml/min, UV, 254
nm) afforded (-)-59 (contaminated with 13% of (+)-60, 2.9 mg, to-
IR (neat): nmax = 3448, 2932, 1774, 1616, 1516, 1456, 1302, 1248,
1180, 1096, 954, 822 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.24-7.39 (m, 7H), 6.88 (m, 2H,
Jortho = 8.4 Hz), 4.71 (d, 1H, J = 11.6 Hz), 4.58 (d, 1H, J = 11.6 Hz),
4.56 (d, 1H, J = 12.4 Hz), 4.49 (d, 1H, J = 12.4 Hz), 4.27 (d, 1H,
J = 9.2 Hz), 4.17 (d, 1H, J = 8.4 Hz), 4.06 (d, 1H, J = 9.2 Hz), 4.05
(br s, 1H), 3.87 (dd, 1H, J = 2.8, 13.0 Hz), 3.81 (s, 3H), 3.70 (dd,
1H, J = 4.8, 11.2 Hz), 3.37 (d, 1H, J = 8.4 Hz), 3.31 (d, 1H, J = 8.8
Hz), 3.21 (d, 1H, J = 8.8 Hz), 2.47 (dd, 1H, J = 5.4, 12.0 Hz), 2.36
(ddd, 1H, J = 14.2, 5.4, 3.5 Hz), 2.30 (d, 1H, J = 13.0 Hz), 2.10 (dt,
1H, J = 13.6, 2.3 Hz), 1.62-1.77 (m, 2H), 1.24-1.44 (m, 2H).
HREIMS: calcd. for C29H34O7: 494.2304. Found: 494.2288.
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

1892
N. Kanoh et al.
SPECIAL TOPIC
tal 21%) as a colorless oil, and pure (+)-60 (2.6 mg, 0.0063 mmol,
28%) as a colorless oil.
luted with EtOAc (8 mL), and washed with brine (1 mL). The brine
layer was extracted with EtOAc (1 mL), and the extracts were fil-
tered, and concentrated in vacuo. Purification of the residue by sili-
ca gel chromatography (230-400 mesh, 400 mg, hexane/EtOAc, 2:1
to 1:1) afforded (+)-60 (0.7 mg, 1.4 mmol, 27% overall) as a color-
less oil and (-)-4 (0.8 mg, 1.57 mmol, 50%) as a colorless oil.
(-)-59
tR = 8.4 min; [a]D21 -7.9 (c 0.14, CHCl3) [this sample was contami-
nated with 13% of (+)-60].
IR (neat): nmax = 2932, 1782, 1714, 1614, 1516, 1458, 1368, 1250,
(-)-4
1176 cm-1.
[a]D20 -14.0 (c 0.10, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.54 (m, 2H, Jortho = 8.1 Hz), 7.16-
7.38 (m, 10H), 6.88 (m, 2H, Jortho = 8.4 Hz), 4.87 (dd, 1H, J = 6.6,
12.8 Hz), 4.64 (d, 1H, J = 11.8 Hz), 4.56 (d, 1H, J = 11.8 Hz), 4.48
(d, 1H, J = 11.6 Hz), 4.46 (d, 1H, J = 11.6 Hz), 4.26 (d, 1H, J = 10.6
Hz), 4.25 (d, 1H, J = 10.6 Hz), 4.03 (m, 1H), 3.95 (dd, 1H, J = 2.6,
11.7 Hz), 3.82 (s, 3H), 3.80 (m, 1H), 3.56 (d, 1H, J = 9.6 Hz), 3.54
(d, 1H, J = 9.6 Hz), 3.39 (d, 1H, J = 8.4 Hz), 2.95 (dd, 1H, J = 5.8,
12.8 Hz), 2.80 (d, 1H, J = 11.7 Hz), 2.49 (dd, 1H, J = 6.6, 12.8 Hz),
2.38 (ddd, 1H, J = 3.6, 5.8, 14.8 Hz), 2.04 (t, 1H, J = 12.8 Hz), 1.43
(ddd, 1H, J = 2.2, 12.8, 14.8 Hz).
IR (neat): nmax = 3416, 2928, 1780, 1718, 1614, 1516, 1458, 1248,
1176, 1082, 1028, 832 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.20-7.43 (m, 7H), 6.86 (m, 2H,
Jortho = 8.8 Hz), 4.73 (d, 1H, J = 11.8 Hz), 4.59 (d, 1H, J = 11.8 Hz),
4.56 (d, 1H, J = 11.8 Hz), 4.51 (d, 1H, J = 11.8 Hz), 4.46 (m, 1H),
4.23 (d, 1H, J = 10.4 Hz), 4.14 (d, 1H, J = 10.4 Hz), 4.04 (m, 1H),
4.02 (d, 1H, J = 8.4 Hz), 3.95 (dd, 1H, J = 2.8, 12.4 Hz), 3.90 (d,
1H, J = 8.4 Hz), 3.80 (s, 3H), 3.56 (d, 1H, J = 9.4 Hz), 3.52 (d, 1H,
J = 9.4 Hz), 3.37 (d, 1H, J = 12.4 Hz), 3.15 (dd, 1H, J = 4.0, 16.4
Hz), 2.90 (dd, 1H, J = 5.8, 12.8 Hz), 2.51 (dd, 1H, J = 2.8, 16.4 Hz),
2.35 (ddd, 1H, J = 4.0, 5.8, 14.8 Hz), 1.42 (ddd, 1H, J = 2.4, 12.8,
14.8 Hz).
LRMS (FAB): m/z = 491 (1.0%, M+-PhSe), 93 (100).
(+)-60
tR = 10.2 min; [a]D21 +27.9 (c 0.38, CHCl3).
HRMS (FAB): calcd. for C29H31O8 (M+-H): 507.2019. Found:
507.2064.
IR (neat): nmax = 2876, 1782, 1686, 1616, 1516, 1248, 1174, 1102,
1078, 1022, 840 cm-1.
1H NMR (400 MHz, CDCl3): d = 7.28-7.39 (m, 3H), 7.23-7.27 (m,
2H), 7.23 (m, 2H, Jortho = 8.6 Hz), 7.12 (d, 1H, J = 9.9 Hz), 6.87 (m,
2H, Jortho = 8.6 Hz), 6.13 (d, 1H, J = 9.9 Hz), 4.68 (d, 1H, J = 11.6
Hz), 4.57 (d, 1H, J = 11.6 Hz), 4.51 (d, 1H, J = 11.9 Hz), 4.49 (d,
1H, J = 11.9 Hz), 4.18 (d, 1H, J = 10.3 Hz), 4.11 (d, 1H, J = 10.3
Hz), 4.09 (m, 1H), 4.09 (d, 1H, J = 7.9 Hz), 3.97 (dd, 1H, J = 2.6,
12.5 Hz), 3.80 (s, 3H), 3.66 (d, 1H, J = 7.9 Hz), 3.48 (d, 1H, J = 9.0
Hz), 3.40 (d, 1H, J = 9.0 Hz), 3.12 (d, 1H, J = 12.5 Hz), 2.75 (dd,
1H, J = 5.9, 12.8 Hz), 2.41 (ddd, 1H, J = 4.0, 5.9, 15.0 Hz), 1.48
(ddd, 1H, J = 2.2, 12.8, 15.0 Hz).
Acknowledgement
Support for this research was provided by the Japan Society for the
Promotion of Science (JSPS) through a JSPS research fellowship
for young scientists to N. K. We kindly thank Dr. K. Kinoshita and
Ms. K. Yamashita (Institute for Life Science Research, Asahi Che-
mical Industry, Co. Ltd.) as well as Prof. T. Inabe for the X-ray ana-
lysis of 36a. We are also grateful to Prof. M. Miyashita (Hokkaido
University) for helpful discussions.
HREIMS: calcd. for C29H30O7: 490.1992. Found: 490.1982.
References
Enone (+)-60
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To a stirred solution of (-)-59 [contaminated with 13% of (+)-60,
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mg, 121.6 mmol) at 25 °C, and the mixture was stirred for 8 h. The
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Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
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Article Identifier:
1437-210X,E;2000,0,13,1878,1893,ftx,en;E10500SS.pdf
Synthesis 2000, No. 13, 1878–1893 ISSN 0039-7881 © Thieme Stuttgart · New York