Synthesis of Azadirachtin

C35H44O16
Principal investigator | Steven V. Ley |
---|---|
Publication year | 2007 |
Synthesis type | Total |
Number of steps | 79 (3 parts) |
References |
Part 1 of 3

n-Bu2SnO
MeOH
Reflux, 2 h

MeOCH2Cl
Dioxane
55 °C, 90 min, 93% (2 steps)




NBS
MeCN, Buffer (pH = 7)
RT, 90 min, 58%

NH4Cl,
Zn
EtOH
Reflux, 2 h

- O3
- Ph3P
CH2Cl2
-78 °C to RT, 18.5 h


CF3CO2H
CH2Cl2, H2O
RT, 97%

TBSCl,
Et3N,
DMAP
DMF
RT, 3 h, 71%

- TMS2NNa
- CS2
- MeI
THF
-78 °C, 90 min, 92%


CF3CO2H
CH2Cl2, H2O
RT, 81%



TMSBr
CH2Cl2
0 °C, 30 min, 100%

Cl3C(=NH)OCH2(p-MeOPh),
La(OTf)3
THF
RT, 3 h, 90%

i-Bu2AlH
CH2Cl2
-78 °C, 2 h, 97%

Amberlyst 15
3 Å MS
MeCN, MeOH
RT, 16 h, 74% (2 steps)

MeLi.LiBr
THF
-78 to -20 °C, 3 h, 97% (α), 93 % (β)
"The epimers are carried out separately."


Ms2O,
i-Pr2NEt
CH2Cl2
0 °C, 30 min, 90% (α), 90 % (β)

Part 2 of 3
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Pyr.HF
H2O, MeCN
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)."


Hydroquinone,
i-Pr2NEt
PhMe
85 °C, 4 h, 21% (2 steps)
See the Diels-Alder Reaction
"The yield was 27 % brsm."

TsOH
H2O, MeCN
RT to 55 °C, 6.5 h, 45%

DMAP,
t-BuCOCl,
Pyr
CH2Cl2
45 °C, 72 h, 81%

NaBH4
MeOH, THF
RT, 90 min, 82%

MeI,
CaCO3
H2O, MeCN
55 °C, 10 h, 98%

DBU
CH2Cl2
RT, 2.5 h, 100%


PhCHO,
Pyr.TsOH
Dean-Stark
PhH
Reflux, 24.5 h, 83%

CeCl3.7H2O,
NaBH4
MeOH
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)."

K2CO3
MeOH
RT, 11 h

CH2N2
CH2Cl2
RT

Pyr,
t-BuCOCl
CH2Cl2
RT, 45 min, 95% (2 steps)

TBSOTf,
2,6-Lutidine
CH2Cl2
0 °C, 40 min, 96%

LiOH
EtOH, H2O
60 °C, 5 h

CH2N2
CH2Cl2
RT, 91% (2 steps)


TBSOTf,
Et3N
CH2Cl2
-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)

Zn(BH4)2
THF
-10 °C, 6.5 h

NCCH2CO2H,
TsCl,
Pyr
CH2Cl2
RT, 20 min, 98% (2 steps)

n-Bu4N+ F-
4 Å MS
THF
RT, 4 h, 93%

H2Cr2O7.2Pyr
4 ÅMS
CH2Cl2
RT, 3 h, 88%


DMDO
Acetone
0 °C, 22 min

Pyr.TsOH
MeOH
RT, 5.5 h, 70% (2 steps)

PhCHO,
Pyr.TsOH
PhH
Reflux, 4.5 h, 74%

Ag2O,
BnBr
DMF
RT, 3.5 h, 61%
"Also isolated was the C5-epimer (19 % yield)."

TBSOTf,
Et3N
MeCN
RT, 2 h, 77%


SiO2
CH2Cl2
RT, 18 h, 68% (2 steps)
"The yield was 97 % brsm."

Pd/C,
H2
1 atm
MeOH
RT, 60 min, 60%

"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%

Part 3 of 3
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NaH,
15-Crown-5
0 °C to RT, 4 h, 82% (α), 74 % (β)
"The epimers are carried out separately."

n-Bu4N+ F-
THF
0 °C, 10 min, 90% (α), 100 % (β)


N-TBS-imidazole
DMF
80 °C, 2 h, 91% (α), 86 % (β)

DDQ
CH2Cl2, H2O
RT, 3 h, 91% (α), 95 % (β)

MeI,
TMS2NNa,
CS2
THF
-78 °C, 2 h, 86% (α), 57 % (β)

AIBN,
n-Bu3SnH
PhMe
110 °C, 14 h, 90% (α), 91 % (β)


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."

n-Bu4N+ F-
THF
RT, 60 min, 95%
"The product is also obtained by the degradation of natural azadirachtin."

Pd/C,
H2
1 atm
EtOH
RT, 3 h, 95%

Ac2O,
DMAP,
Et3N
CH2Cl2
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)."

H2,
Pd/C
1 atm
MeOH
RT, 14 h, 81%

Pyr.TsOH,
PhSeH
DCE
Reflux, 4 h

H2O2,
Pyr
CH2Cl2, H2O
0 °C, 10 min, 85% (2 steps)
