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Azadirachtin
"The work reported herein represents the conclusion of a 22-year synthesis journey"
C35H44O16
| Author | Steven V. Ley |
|---|---|
| Publication year | 2007 |
| Synthesis type | Total synthesis |
| Number of steps | 79 (3 parts) |
| References |
Browse hundreds of other total syntheses.
Part 1 of 3
n-Bu2SnO
MeOH
Reflux, 2 h
Reflux, 2 h
MeOCH2Cl
Dioxane
55 °C, 90 min, 93 % (2 steps)
55 °C, 90 min, 93 % (2 steps)
NBS
MeCN, Buffer (pH = 7)
RT, 90 min, 58 %
RT, 90 min, 58 %
Zn, NH4Cl
EtOH
Reflux, 2 h
Reflux, 2 h
O3, Ph3P
CH2Cl2
-78 °C to RT, 18.5 h
-78 °C to RT, 18.5 h
CF3CO2H
CH2Cl2, H2O
RT, 97 %
RT, 97 %
TBSCl, Et3N, DMAP
DMF
RT, 3 h, 71 %
RT, 3 h, 71 %
TMS2NNa, CS2, MeI
THF
-78 °C, 90 min, 92 %
-78 °C, 90 min, 92 %
CF3CO2H
CH2Cl2, H2O
RT, 81 %
RT, 81 %
TMSBr
CH2Cl2
0 °C, 30 min, 100 %
0 °C, 30 min, 100 %
Cl3C(=NH)OCH2(p-MeOPh), La(OTf)3
THF
RT, 3 h, 90 %
RT, 3 h, 90 %
i-Bu2AlH
CH2Cl2
-78 °C, 2 h, 97 %
-78 °C, 2 h, 97 %
Amberlyst ® 15
3 Å MS
MeCN, MeOH
RT, 16 h, 74 % (2 steps)
Selectivity : 66:34 α/β
3 Å MS
RT, 16 h, 74 % (2 steps)
Selectivity : 66:34 α/β
MeLi.LiBr
THF
-78 to -20 °C, 3 h, 97 % (α), 93 % (β)
See the Fritsch-Buttenberg-Wiechell Rearrangement
The epimers are carried out separately.
-78 to -20 °C, 3 h, 97 % (α), 93 % (β)
See the Fritsch-Buttenberg-Wiechell Rearrangement
The epimers are carried out separately.
Ms2O, i-Pr2NEt
CH2Cl2
0 °C, 30 min, 90 % (α), 90 % (β)
0 °C, 30 min, 90 % (α), 90 % (β)
Part 2 of 3
+ 
+ 
Pyr.HF
MeCN, H2O
RT to 35 °C, 34 h, 85 %
RT to 35 °C, 34 h, 85 %
+ 
LiCl, i-Pr2NEt
DMF
RT, 44 h, 34 %
See the Horner-Wadsworth-Emmons Reaction
The yield was 67 % brsm. Also isolated was the Z-isomer (13 % yield).
RT, 44 h, 34 %
See the Horner-Wadsworth-Emmons Reaction
The yield was 67 % brsm. Also isolated was the Z-isomer (13 % yield).
Hydroquinone, i-Pr2NEt
PhMe
85 °C, 4 h, 21 % (2 steps)
See the Diels-Alder Reaction
The yield was 27 % brsm.
85 °C, 4 h, 21 % (2 steps)
See the Diels-Alder Reaction
The yield was 27 % brsm.
TsOH
MeCN, H2O
RT to 55 °C, 6.5 h, 45 %
RT to 55 °C, 6.5 h, 45 %
t-BuCOCl, Pyr, DMAP
CH2Cl2
45 °C, 72 h, 81 %
45 °C, 72 h, 81 %
NaBH4
THF, MeOH
RT, 90 min, 82 %
RT, 90 min, 82 %
MeI, CaCO3
MeCN, H2O
55 °C, 10 h, 98 %
55 °C, 10 h, 98 %
DBU
CH2Cl2
RT, 2.5 h, 100 %
RT, 2.5 h, 100 %
PhCHO, Pyr.TsOH
Dean-Stark
PhH
Reflux, 24.5 h, 83 %
Dean-Stark
Reflux, 24.5 h, 83 %
NaBH4, CeCl3.7H2O
MeOH
0 °C, 10 min, 44 %
See the Luche Reduction
Also isolated was the C8-epimer (53 % yield).
0 °C, 10 min, 44 %
See the Luche Reduction
Also isolated was the C8-epimer (53 % yield).
+ 
Pyr, DMAP
CH2Cl2
RT to 30 °C, 21 h, 43 %
Also isolated was the corresponding diastereoisomer (44 % yield).
RT to 30 °C, 21 h, 43 %
Also isolated was the corresponding diastereoisomer (44 % yield).
K2CO3
MeOH
RT, 11 h
RT, 11 h
CH2N2
CH2Cl2
RT
RT
t-BuCOCl, Pyr
CH2Cl2
RT, 45 min, 95 % (2 steps)
RT, 45 min, 95 % (2 steps)
TBSOTf, 2,6-Lutidine
CH2Cl2
0 °C, 40 min, 96 %
0 °C, 40 min, 96 %
LiOH
EtOH, H2O
60 °C, 5 h
60 °C, 5 h
CH2N2
CH2Cl2
RT, 91 % (2 steps)
RT, 91 % (2 steps)
TBSOTf, Et3N
CH2Cl2
-15 to -5 °C, 3 h
The starting material was recovered and recycled.
-15 to -5 °C, 3 h
The starting material was recovered and recycled.
O3, Ph3P
CH2Cl2
-78 °C to RT, 13 h, 85 % (2 steps)
-78 °C to RT, 13 h, 85 % (2 steps)
Zn(BH4)2
THF
-10 °C, 6.5 h
-10 °C, 6.5 h
NCCH2CO2H, TsCl, Pyr
CH2Cl2
RT, 20 min, 98 % (2 steps)
RT, 20 min, 98 % (2 steps)
n-Bu4N+ F-
4 Å MS
THF
RT, 4 h, 93 %
4 Å MS
RT, 4 h, 93 %
H2Cr2O7.2Pyr
4 ÅMS
CH2Cl2
RT, 3 h, 88 %
4 ÅMS
RT, 3 h, 88 %
DMDO
Acetone
0 °C, 22 min
0 °C, 22 min
Pyr.TsOH
MeOH
RT, 5.5 h, 70 % (2 steps)
Selectivity : 82:18 S/R
RT, 5.5 h, 70 % (2 steps)
Selectivity : 82:18 S/R
PhCHO, Pyr.TsOH
PhH
Reflux, 4.5 h, 74 %
Selectivity : 75:25 S/R
Reflux, 4.5 h, 74 %
Selectivity : 75:25 S/R
BnBr, Ag2O
DMF
RT, 3.5 h, 61 %
Also isolated was the C5-epimer (19 % yield).
RT, 3.5 h, 61 %
Also isolated was the C5-epimer (19 % yield).
TBSOTf, Et3N
MeCN
RT, 2 h, 77 %
RT, 2 h, 77 %
SiO2
CH2Cl2
RT, 18 h, 68 % (2 steps)
The yield was 97 % brsm.
RT, 18 h, 68 % (2 steps)
The yield was 97 % brsm.
H2, Pd/C
1 atm
MeOH
RT, 60 min, 60 %
Selectivity : 80:20 α/β
1 atm
RT, 60 min, 60 %
Selectivity : 80:20 α/β
The experimental details for this step doesn't seem to be reported anywhere. The product is also obtained by the degradation of natural azadirachtin.
TESOTf, i-Pr2NEt
CH2Cl2
-60 to 0 °C, 2.5 h, 71 %
-60 to 0 °C, 2.5 h, 71 %
Part 3 of 3
+ 
NaH, 15-Crown-5
0 °C to RT, 4 h, 82 % (α), 74 % (β)
The epimers are carried out separately.
The epimers are carried out separately.
n-Bu4N+ F-
THF
0 °C, 10 min, 90 % (α), 100 % (β)
0 °C, 10 min, 90 % (α), 100 % (β)
N-TBS-imidazole
DMF
80 °C, 2 h, 91 % (α), 86 % (β)
80 °C, 2 h, 91 % (α), 86 % (β)
DDQ
CH2Cl2, H2O
RT, 3 h, 91 % (α), 95 % (β)
RT, 3 h, 91 % (α), 95 % (β)
TMS2NNa, CS2, MeI
THF
-78 °C, 2 h, 86 % (α), 57 % (β)
-78 °C, 2 h, 86 % (α), 57 % (β)
n-Bu3SnH, AIBN
PhMe
110 °C, 14 h, 90 % (α), 91 % (β)
110 °C, 14 h, 90 % (α), 91 % (β)
MMPP, NaHCO3
Sealed tube
110 °C, 7 d, 22 % (α), 65 % (β)
See the Prilezhaev Reaction
The yield were 67% (α) and 93 % (β) brsm.
n-Bu4N+ F-
THF
RT, 60 min, 95 %
The product is also obtained by the degradation of natural azadirachtin.
RT, 60 min, 95 %
The product is also obtained by the degradation of natural azadirachtin.
H2, Pd/C
1 atm
EtOH
RT, 3 h, 95 %
1 atm
RT, 3 h, 95 %
Ac2O, Et3N, DMAP
CH2Cl2
RT, 4 h, 76 %
RT, 4 h, 76 %
+ 
NaBH4, CeCl3.7H2O
MeOH
0 °C, 4 h, 49 %
See the Luche Reduction
Also isolated was the C3-epimer (43 % yield).
0 °C, 4 h, 49 %
See the Luche Reduction
Also isolated was the C3-epimer (43 % yield).
H2, Pd/C
1 atm
MeOH
RT, 14 h, 81 %
1 atm
RT, 14 h, 81 %
PhSeH, Pyr.TsOH
DCE
Reflux, 4 h
Reflux, 4 h
H2O2, Pyr
CH2Cl2, H2O
0 °C, 10 min, 85 % (2 steps)
0 °C, 10 min, 85 % (2 steps)
