Synthesis of Spinosyn A

Structure of Spinosyn A

C41H65NO10

Principal investigatorWilliam R. Roush
Publication year2004
Synthesis typeTotal
Number of steps 39 (5 parts)
References
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11955.
Part 1 of 5
intermediate structure + intermediate structure
TBSOTf
4 A MS
CH2Cl2
RT, 15 min, 84%
intermediate structure
n-Bu4N+ F-
THF
0 °C to RT, 75 min, 84%
intermediate structure
Pyr, Dess-Martin Periodinane
CH2Cl2
0 °C to RT, 2.5 h, 92%
See the Dess-Martin Oxidation
intermediate structure
CBr4, Ph3P
CH2Cl2
0 °C, 35 min, 94%
See the Wittig Reaction
intermediate structure
  1. KHCO3 , O3
  2. Ph3P
CH2Cl2, MeOH
-78 °C to RT
intermediate structure
Ph3P=CHCO2Me
CH2Cl2
RT, 12 h, 82% (2 steps)
See the Wittig Reaction
intermediate structure
i-Bu2AlH
CH2Cl2
-78 °C, 75 min, 89%
intermediate structure
i-Pr2NEt, DMSO, Pyr.SO3
CH2Cl2
0 °C, 20 min
See the Parikh-Doering Oxidation
"The crude aldehyde was used in the next step (see part 3)"
intermediate structure
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Part 2 of 5
intermediate structure
Et3N, (4-MeOPh)CH2Br, TMS2NK
THF
-78 °C to RT, ON, 91%
intermediate structure
  1. BH3.Me2S , 2-Methyl-2-butene
  2. NaHCO3 , H2O2 , H2O
THF
0 °C to RT, 6 h, 85%
intermediate structure
Pyr.SO3, i-Pr2NEt, DMSO
CH2Cl2
0 °C, 20 min, 91%
See the Parikh-Doering Oxidation
intermediate structure
Special reagent
Et2Zn
PhMe
0 °C to RT, 76 h, 94%
intermediate structure
TESOTf, 2,6-Lutidine
CH2Cl2
0 °C, 1 h, 94%
intermediate structure
Special reagent
n-BuLi
THF
-78 °C, 3 h, 96%
See the Weinreb Ketone Synthesis
intermediate structure
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Part 3 of 5
intermediate structure + intermediate structure
Ba(OH)2
H2O, THF
RT, 8 h, 93% (2 steps)
See the Horner-Wadsworth-Emmons Reaction
intermediate structure
AcOH
H2O, THF
RT, 2 h, 100%
intermediate structure
Special reagent
EDC.MeI, DMAP
CH2Cl2
RT, 90 min, 98%
See the Steglich Esterification
intermediate structure
Special reagent
Tl2CO3, Pd(PPh3)4
H2O, THF
RT, 2 h, 82%
See the Suzuki Coupling
intermediate structure
Pyr.SO3, i-Pr2NEt, DMSO
CH2Cl2
0 °C, 25 min
See the Parikh-Doering Oxidation
intermediate structure
LiCl, i-Pr2NEt
MeCN
RT, 12 h, 55%
See the Diels-Alder Reaction
See the Horner-Wadsworth-Emmons Reaction
"Also produced were 2 other diastereomers (20% yield)"
intermediate structure
Me3P
t-AmylOH
RT, 6 h, 100%
intermediate structure
DDQ
CH2Cl2, Buffer (pH = 7)
0 °C, 4 h, 100%
intermediate structure
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Part 4 of 5
intermediate structure
(PhO)2P(O)N3, DEAD, Ph3P
THF
0 °C, 2 h, 82%
See the Mitsunobu Reaction
intermediate structure
K2CO3, K3Fe(CN)6, K2OsO2(OH)4, (DHQD)2Pyr
H2O, t-BuOH
0 °C, 7 h, 96%
See the Sharpless Asymmetric Dihydroxylation
"86:14 d.r."
intermediate structure
Imidazole, TBSCl
DMF
RT, 4 h
intermediate structure
AcOH
H2O, THF
RT, 55 h, 62% (2 steps)
"86:14 d.r."
intermediate structure
Pyr.SO3, i-Pr2NEt, DMSO
CH2Cl2
0 °C, 15 min, 66%
See the Parikh-Doering Oxidation
"93:07 d.r."
intermediate structure
DDQ
CH2Cl2, Buffer (pH = 7)
0 °C, 4 h
intermediate structure
Ac2O, DMAP, Et3N
CH2Cl2
RT, 12 h
intermediate structure
n-Bu4N+ F-
THF
0 °C, 1 h
intermediate structure
Ac2O, DMAP, Et3N
CH2Cl2
RT, 18 h, 87% (4 steps)
intermediate structure
AcOH, (CH2NH2)2
THF
RT, 24 h, 78%
intermediate structure
DBU, Cl3CCN
CH2Cl2
0 °C, 1.5 h, 100%
intermediate structure
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Part 5 of 5
intermediate structure + intermediate structure
TMSOTf
CH2Cl2
-78 °C, 1 h, 97%
intermediate structure
Guanidinium nitrate, NaOMe
CH2Cl2, MeOH
RT, 2 h, 95%
intermediate structure
SnCl2, PhSH, Et3N
THF
RT, 15 min, 92%
intermediate structure
NaOAc, NaBH3CN, CH2O, AcOH
H2O, MeOH
RT, 55 min, 87%
intermediate structure
TCDI, DMAP
PhMe
65 °C, 2 h
intermediate structure
AIBN, n-Bu3SnH
Dioxane
100 °C, 20 min, 35%
See the Barton-McCombie Reaction
intermediate structure
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