Synthesis of Azadirachtin

Structure of Azadirachtin

C35H44O16

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, DMSO, i-Pr2NEt
CH2Cl2
0 °C, 30 min
intermediate structure
AllylMgCl
THF
-78 °C, 30 min, 85% (2 steps)
intermediate structure
BnBr, NaH
DMF
0 °C to RT, 19 h, 92%
intermediate structure
NBS
MeCN, Buffer (pH = 7)
RT, 90 min, 58%
intermediate structure
Zn, NH4Cl
EtOH
Reflux, 2 h
intermediate structure
  1. O3
  2. Ph3P
CH2Cl2
-78 °C to RT, 18.5 h
intermediate structure
n-Pr4N+ RuO4-, NMO
MeCN
RT, 75 min, 76% (3 steps)
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
n-Bu3SnH, AIBN
PhMe
Reflux, 2 h, 100%
intermediate structure
CF3CO2H
CH2Cl2, H2O
RT, , 81%
intermediate structure
Pyr.SO3, DMSO, i-Pr2NEt
CH2Cl2
0 °C, 2 h
intermediate structure
Ph3P+CHBr2 Br-, KOt-Bu
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
MeCN, MeOH
RT, 16 h, 74% (2 steps)
intermediate structure
MeLi.LiBr
THF
-78 to -20 °C, 3 h, 97% (α), 93 % (β)
"The epimers are carried out separately."
intermediate structure
  1. i-PrMgBr
  2. (CH2O)n
THF
45 °C, 5.5 h, 89% (α), 78 % (β)
intermediate structure
Ms2O, i-Pr2NEt
CH2Cl2
0 °C, 30 min, 90% (α), 90 % (β)
intermediate structure
Part 2 of 3
intermediate structure + intermediate structure
n-BuLi, (CH2NMe2)2
THF
-78 to -30 °C, 95 min, 54%
intermediate structure + intermediate structure
KH
THF
0 °C to RT, 90 min, 60%
intermediate structure
Pyr.HF
MeCN, H2O
RT to 35 °C, 34 h, 85%
intermediate structure
(COCl)2, DMSO, Et3N
THF
-78 °C to RT, 23 min, 93%
See the Swern Oxidation
intermediate structure + intermediate structure
LiCl, i-Pr2NEt
DMF
RT, 44 h, 34%
"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
intermediate structure
Hydroquinone, i-Pr2NEt
PhMe
85 °C, 4 h, 21% (2 steps)
"The yield was 27 % brsm."
intermediate structure
TsOH
MeCN, H2O
RT to 55 °C, 6.5 h, 45%
intermediate structure
t-BuCOCl, Pyr, DMAP
CH2Cl2
45 °C, 72 h, 81%
intermediate structure
NaBH4
THF, MeOH
RT, 90 min, 82%
intermediate structure
MeI, CaCO3
MeCN, H2O
55 °C, 10 h, 98%
intermediate structure
DBU
CH2Cl2
RT, 2.5 h, 100%
intermediate structure
AcOOH, Hg(CF3CO2)2
CF3CH2OH, AcOH
10 °C to RT, 2.5 h, 85%
intermediate structure
PhCHO, Pyr.TsOH
PhH
Reflux, 24.5 h, 83%
intermediate structure
NaBH4, CeCl3.7H2O
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
t-BuCOCl, Pyr
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
Dess-Martin Periodinane, Pyr
CH2Cl2
13 °C to RT, 25 min, 90%
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-
THF
RT, 4 h, 93%
intermediate structure
H2Cr2O7.2Pyr
CH2Cl2
RT, 3 h, 88%
intermediate structure
TMS2NLi
THF
0 °C to RT, 100 min, 100%
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
BnBr, Ag2O
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
intermediate structure
SiO2
CH2Cl2
RT, 18 h, 68% (2 steps)
"The yield was 97 % brsm."
intermediate structure
H2, Pd/C
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
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
1,2-Dichlorobenzene
185 °C, 20 min, 86% (α), 83 % (β)
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
TMS2NNa, CS2, MeI
THF
-78 °C, 2 h, 86% (α), 57 % (β)
intermediate structure
n-Bu3SnH, AIBN
PhMe
110 °C, 14 h, 90% (α), 91 % (β)
intermediate structure
MMPP, NaHCO3
MeOH
110 °C, 7 d, 22% (α), 65 % (β)
"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
H2, Pd/C
EtOH
RT, 3 h, 95%
intermediate structure
Ac2O, Et3N, DMAP
CH2Cl2
RT, 4 h, 76%
intermediate structure + intermediate structure
Cs2CO3
PhMe
6 d, 50%
""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
MeOH
RT, 14 h, 81%
intermediate structure
PhSeH, Pyr.TsOH
DCE
Reflux, 4 h
intermediate structure
H2O2, Pyr
CH2Cl2, H2O
0 °C, 10 min, 85% (2 steps)
intermediate structure