Synthesis of Azadirachtin

Structure of Azadirachtin

C35H44O16

Principal investigatorSteven V. Ley
Publication year2007
Synthesis typeTotal
Number of steps 79 (3 parts)
References
Angew. Chem. Int. Ed. 2007, 46, 7629. Angew. Chem. Int. Ed. 2007, 46, 7633. Chem. Eur. J. 2008, 14, 10683. Tetrahedron 1995, 51, 2077. J. Chem. Soc. Perkin Trans. 1 1992, 51, 2735. Tetrahedron Lett. 1991, 32, 6187.
Part 1 of 3
intermediate structure
n-Bu2SnO
MeOH
Reflux, 2 h
intermediate structure
MeOCH2Cl
Dioxane
55 °C, 90 min, 93% (2 steps)
intermediate structure
Pyr.SO3, i-Pr2NEt, DMSO
CH2Cl2
0 °C, 30 min
See the Parikh-Doering Oxidation
intermediate structure
AllylMgCl
THF
-78 °C, 30 min, 85% (2 steps)
See the Grignard Reaction
intermediate structure
NaH, BnBr
DMF
0 °C to RT, 19 h, 92%
See the Williamson Ether Synthesis
intermediate structure
NBS
MeCN, Buffer (pH = 7)
RT, 90 min, 58%
intermediate structure
NH4Cl, Zn
EtOH
Reflux, 2 h
intermediate structure
  1. O3
  2. Ph3P
CH2Cl2
-78 °C to RT, 18.5 h
intermediate structure
NMO, n-Pr4N+ RuO4-
4 Å MS
MeCN
RT, 75 min, 76% (3 steps)
See the Ley-Griffith Oxidation
intermediate structure
CF3CO2H
CH2Cl2, H2O
RT, 97%
intermediate structure
TBSCl, Et3N, DMAP
DMF
RT, 3 h, 71%
intermediate structure
  1. TMS2NNa
  2. CS2
  3. MeI
THF
-78 °C, 90 min, 92%
intermediate structure
AIBN, n-Bu3SnH
PhMe
Reflux, 2 h, 100%
See the Barton-McCombie Reaction
intermediate structure
CF3CO2H
CH2Cl2, H2O
RT, 81%
intermediate structure
DMSO, i-Pr2NEt, Pyr.SO3
CH2Cl2
0 °C, 2 h
See the Parikh-Doering Oxidation
intermediate structure
KOt-Bu, Ph3P+CHBr2 Br-
THF
RT, 12 h, 78% (2 steps)
See the Wittig Reaction
intermediate structure
TMSBr
CH2Cl2
0 °C, 30 min, 100%
intermediate structure
Cl3C(=NH)OCH2(p-MeOPh), La(OTf)3
THF
RT, 3 h, 90%
intermediate structure
i-Bu2AlH
CH2Cl2
-78 °C, 2 h, 97%
intermediate structure
Amberlyst 15
3 Å MS
MeCN, MeOH
RT, 16 h, 74% (2 steps)
intermediate structure
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."
intermediate structure
  1. i-PrMgBr
  2. (CH2O)n
THF
45 °C, 5.5 h, 89% (α), 78 % (β)
See the Grignard Reaction
intermediate structure
Ms2O, i-Pr2NEt
CH2Cl2
0 °C, 30 min, 90% (α), 90 % (β)
intermediate structure
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Part 2 of 3
intermediate structure + intermediate structure
(CH2NMe2)2, n-BuLi
THF
-78 to -30 °C, 95 min, 54%
See the Corey-Seebach Reaction
intermediate structure + intermediate structure
KH
THF
0 °C to RT, 90 min, 60%
See the Williamson Ether Synthesis
intermediate structure
Pyr.HF
H2O, MeCN
RT to 35 °C, 34 h, 85%
intermediate structure
Et3N, DMSO, (COCl)2
THF
-78 °C to RT, 23 min, 93%
See the Swern Oxidation
intermediate structure + intermediate structure
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)."
intermediate structure
Cp2TiMe2, Pyr
PhMe, THF
-50 to -35 °C, 3 h
See the Tebbe-Petasis Olefination
intermediate structure
Hydroquinone, i-Pr2NEt
PhMe
85 °C, 4 h, 21% (2 steps)
See the Diels-Alder Reaction
"The yield was 27 % brsm."
intermediate structure
TsOH
H2O, MeCN
RT to 55 °C, 6.5 h, 45%
intermediate structure
DMAP, t-BuCOCl, Pyr
CH2Cl2
45 °C, 72 h, 81%
intermediate structure
NaBH4
MeOH, THF
RT, 90 min, 82%
intermediate structure
MeI, CaCO3
H2O, MeCN
55 °C, 10 h, 98%
intermediate structure
DBU
CH2Cl2
RT, 2.5 h, 100%
intermediate structure
Hg(CF3CO2)2, AcOOH
AcOH, CF3CH2OH
10 °C to RT, 2.5 h, 85%
See the Fleming-Tamao Oxidation
intermediate structure
PhCHO, Pyr.TsOH
Dean-Stark
PhH
Reflux, 24.5 h, 83%
intermediate structure
CeCl3.7H2O, NaBH4
MeOH
0 °C, 10 min, 44%
See the Luche Reduction
"Also isolated was the C8-epimer (53 % yield)."
intermediate structure + intermediate structure
Pyr, DMAP
CH2Cl2
RT to 30 °C, 21 h, 43%
"Also isolated was the corresponding diastereoisomer (44 % yield)."
intermediate structure
K2CO3
MeOH
RT, 11 h
intermediate structure
CH2N2
CH2Cl2
RT
intermediate structure
Pyr, t-BuCOCl
CH2Cl2
RT, 45 min, 95% (2 steps)
intermediate structure
TBSOTf, 2,6-Lutidine
CH2Cl2
0 °C, 40 min, 96%
intermediate structure
LiOH
EtOH, H2O
60 °C, 5 h
intermediate structure
CH2N2
CH2Cl2
RT, 91% (2 steps)
intermediate structure
Pyr, Dess-Martin Periodinane
CH2Cl2
13 °C to RT, 25 min, 90%
See the Dess-Martin Oxidation
intermediate structure
TBSOTf, Et3N
CH2Cl2
-15 to -5 °C, 3 h
"The starting material was recovered and recycled."
intermediate structure
  1. O3
  2. Ph3P
CH2Cl2
-78 °C to RT, 13 h, 85% (2 steps)
intermediate structure
Zn(BH4)2
THF
-10 °C, 6.5 h
intermediate structure
NCCH2CO2H, TsCl, Pyr
CH2Cl2
RT, 20 min, 98% (2 steps)
intermediate structure
n-Bu4N+ F-
4 Å MS
THF
RT, 4 h, 93%
intermediate structure
H2Cr2O7.2Pyr
4 ÅMS
CH2Cl2
RT, 3 h, 88%
intermediate structure
TMS2NLi
THF
0 °C to RT, 100 min, 100%
See the Michael Addition
intermediate structure
DMDO
Acetone
0 °C, 22 min
intermediate structure
Pyr.TsOH
MeOH
RT, 5.5 h, 70% (2 steps)
intermediate structure
PhCHO, Pyr.TsOH
PhH
Reflux, 4.5 h, 74%
intermediate structure
Ag2O, BnBr
DMF
RT, 3.5 h, 61%
"Also isolated was the C5-epimer (19 % yield)."
intermediate structure
TBSOTf, Et3N
MeCN
RT, 2 h, 77%
intermediate structure
H2CN+Me2 I-
CH2Cl2
35 °C, 48 h
See the Mannich Reaction
intermediate structure
SiO2
CH2Cl2
RT, 18 h, 68% (2 steps)
"The yield was 97 % brsm."
intermediate structure
Pd/C, H2
1 atm
MeOH
RT, 60 min, 60%
intermediate structure
"The experimental details for this step doesn't seem to be reported anywhere. The product is also obtained by the degradation of natural azadirachtin."
intermediate structure
TESOTf, i-Pr2NEt
CH2Cl2
-60 to 0 °C, 2.5 h, 71%
intermediate structure
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Part 3 of 3
intermediate structure + intermediate structure
NaH, 15-Crown-5
0 °C to RT, 4 h, 82% (α), 74 % (β)
"The epimers are carried out separately."
intermediate structure
n-Bu4N+ F-
THF
0 °C, 10 min, 90% (α), 100 % (β)
intermediate structure
μW
1,2-Dichlorobenzene
185 °C, 20 min, 86% (α), 83 % (β)
See the Claisen Rearrangement
intermediate structure
N-TBS-imidazole
DMF
80 °C, 2 h, 91% (α), 86 % (β)
intermediate structure
DDQ
CH2Cl2, H2O
RT, 3 h, 91% (α), 95 % (β)
intermediate structure
MeI, TMS2NNa, CS2
THF
-78 °C, 2 h, 86% (α), 57 % (β)
intermediate structure
AIBN, n-Bu3SnH
PhMe
110 °C, 14 h, 90% (α), 91 % (β)
intermediate structure
Special reagent
NaHCO3, MMPP
Sealed tube
MeOH
110 °C, 7 d, 22% (α), 65 % (β)
See the Prilezhaev Reaction
"The yield were 67% (α) and 93 % (β) brsm."
intermediate structure
n-Bu4N+ F-
THF
RT, 60 min, 95%
"The product is also obtained by the degradation of natural azadirachtin."
intermediate structure
Pd/C, H2
1 atm
EtOH
RT, 3 h, 95%
intermediate structure
Ac2O, DMAP, Et3N
CH2Cl2
RT, 4 h, 76%
intermediate structure + intermediate structure
Cs2CO3
PhMe
6 d, 50%
See the Yamaguchi Esterification
""Heated in a sealed tube"."
intermediate structure
NaBH4, CeCl3.7H2O
MeOH
0 °C, 4 h, 49%
See the Luche Reduction
"Also isolated was the C3-epimer (43 % yield)."
intermediate structure
H2, Pd/C
1 atm
MeOH
RT, 14 h, 81%
intermediate structure
Pyr.TsOH, PhSeH
DCE
Reflux, 4 h
intermediate structure
H2O2, Pyr
CH2Cl2, H2O
0 °C, 10 min, 85% (2 steps)
intermediate structure
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