Synthesis of Taxol

Structure of Taxol

C47H51NO14

Principal investigatorTeruaki Mukaiyama
Publication year1999
Synthesis typeTotal
Number of steps 61 (linear)
References
Chem. Eur. J. 1999, 5, 121.
Part 1 of 1
intermediate structure
H2SO4, NaNO2
H2O
0 °C to RT, 5.5 d
intermediate structure
H2SO4, HC(OMe)3
MeOH
60 °C, 30 min, 88% (2 steps)
intermediate structure
Imidazole, TBSCl
DMF
0 °C, 6 h, 82%
intermediate structure
TfOH, Cl3C(=NH)OBn
Et2O
RT, 10 h, 100%
intermediate structure
i-Bu2AlH
Hexane(s)
-78 °C, 60 min, 95%
intermediate structure
i-PrCO2Me, i-Pr2NLi
Et2O
-78 °C, 65%
See the Aldol Addition
"Also isolated was the C3-epimer (20 % yield)."
intermediate structure
Cl3C(=NH)OCH2(p-MeOPh), TfOH
CH2Cl2
0 °C, 3 h, 75%
"99 % yield based on 76 % conversion."
intermediate structure
i-Bu2AlH
Hexane(s)
-78 °C, 60 min, 92%
intermediate structure
(COCl)2, DMSO, Et3N
CH2Cl2
-78 °C to RT, 75 min, 97%
See the Swern Oxidation
intermediate structure + intermediate structure
MgBr2.OEt2
PhMe
-15 °C, 75 min, 71%
See the Mukaiyama Aldol Addition
"87 % yield based on 88 % conversion. Also isolated was the C2-epimer (16 % yield)."
intermediate structure
2,6-Lutidine, TBSOTf
CH2Cl2
0 °C, 60 min, 100%
intermediate structure
i-Bu2AlH
PhMe
-78 °C, 60 min
intermediate structure
(COCl)2, DMSO, Et3N
CH2Cl2
-78 °C to RT, 75 min, 94% (2 steps)
See the Swern Oxidation
intermediate structure
MeMgBr
Et2O
-78 °C, 100 min, 99%
See the Grignard Reaction
intermediate structure
(COCl)2, DMSO, Et3N
CH2Cl2
-78 °C to RT, 45 min, 97%
See the Swern Oxidation
intermediate structure
  1. TMS2NLi
  2. TMSCl
THF
-78 °C, 90 min
intermediate structure
NBS
THF
0 °C, 30 min, 100% (2 steps)
intermediate structure
  1. TMS2NLi
  2. MeI
HMPA, THF
-78 °C, 2.5 h, 100%
intermediate structure
HCl
H2O, THF
0 °C, 60 min, 83%
intermediate structure
Et3N, DMSO, (COCl)2
CH2Cl2
-78 °C to RT, 75 min, 95%
See the Swern Oxidation
intermediate structure
SmI2
THF
-78 °C, 20 min, 70%
See the Reformatsky Reaction
intermediate structure
Ac2O, DMAP
Pyr
RT, 90 min, 87%
intermediate structure
DBU
PhH
60 °C, 90 min, 91%
intermediate structure + intermediate structure
CuCN, t-BuLi
Et2O
-78 to 0 °C, 2 h, 92%
See the Michael Addition
"99 % yield base on 93 % conversion."
intermediate structure
HCl
H2O, THF
0 °C, 97%
intermediate structure
NMO, n-Pr4N+ RuO4-
4 Å MS
CH2Cl2
0 °C, 30 min, 92%
See the Ley-Griffith Oxidation
intermediate structure
NaOMe
MeOH, THF
0 °C, 90%
See the Aldol Addition
"Also isolated was the C4-epimer (8 % yield)."
intermediate structure
AlH3
PhMe, THF
-78 °C, 2 h, 94%
intermediate structure
2,2-Dimethoxypropane, Camphorsulfonic acid
CH2Cl2
RT, 60 min, 100%
intermediate structure
DDQ
CH2Cl2, H2O
RT, 60 min, 97%
intermediate structure
H2Cr2O7.2Pyr
CH2Cl2
RT, 16 h, 90%
"94 % yield based on 96 % conversion."
intermediate structure
s-BuLi, 4-Iodobutene
Cyclohexane, PhH
-23 to 0 °C, 85 min, 96%
intermediate structure
n-Bu4N+ F-
THF
50 °C, 60 min, 100%
intermediate structure
Imidazole, CyMeSiCl2
DMF
RT, 15 min, 99%
intermediate structure
MeLi
HMPA, THF
-78 °C, 30 min, 96%
intermediate structure
NMO, n-Pr4N+ RuO4-
4 Å MS
CH2Cl2, MeCN
0 °C to RT, 60 min, 80%
See the Ley-Griffith Oxidation
intermediate structure
PdCl2
DMF, H2O
RT, 3.5 h, 98%
See the Wacker Oxidation
intermediate structure
TiCl2, LiAlH4
THF
0 °C to Reflux, 40 min, 43-71%
See the Pinacol Coupling
intermediate structure
Na
NH3, THF
-78 to -45 °C, 2 h, 100%
See the Birch Reduction
intermediate structure
n-Bu4N+ F-
THF
RT, 5 min, 100%
intermediate structure
Pyr, Triphosgene
CH2Cl2
-45 °C, 70 min, 100%
intermediate structure
Ac2O, DMAP
PhH
0 to 35 °C, 10 h, 84%
intermediate structure
HCl
H2O, THF
60 °C, 10 h
intermediate structure
TESCl
Pyr
0 °C to RT, 40 min, 83% (2 steps)
intermediate structure
NMO, n-Pr4N+ RuO4-
4 Å MS
CH2Cl2
RT, 60 min, 76%
See the Ley-Griffith Oxidation
intermediate structure
DMAP, TCDI
PhMe
100 °C, 8 h
intermediate structure
P(OMe)3
110 °C, 5 h, 53% (2 steps)
See the Corey-Winter Olefin Synthesis
intermediate structure
NaOAc, HCrO3Cl.Pyr, Celite
PhH
95 °C, 7 h, 78%
intermediate structure
K(s-Bu)3BH
THF
-23 °C, 4 h, 87%
intermediate structure
TESOTf
Pyr
-23 °C, 10 min, 98%
intermediate structure
CuBr, BzOOt-Bu
Dark
MeCN
-23 to 50 °C, 14 h, 62%
See the Wohl-Ziegler Reaction
"Also isolated was the desired exocyclic allylic bromide (15 % yield, see next step)."
intermediate structure
CuBr
MeCN
50 °C, 100 min, 69%
"The yield was 92 % yield brsm."
intermediate structure
Pyr, OsO4
Et2O, THF
RT, 17 h, 92%
"96 % yield based on 96 % conversion."
intermediate structure
DBU
PhMe
50 °C, 105 min, 42%
"81 % yield based on 52 % conversion."
intermediate structure
Ac2O, DMAP
Pyr
RT, 13 h, 91%
intermediate structure
PhLi
THF
-78 °C, 15 min, 94%
intermediate structure
Pyr.HF
THF
RT, 60 min, 96%
intermediate structure
TESCl
Pyr
RT, 30 min, 87%
"92 % yield based on 95 % conversion."
intermediate structure + intermediate structure
DMAP, DPTC
PhMe
73 °C, 4 h, 66%
intermediate structure
H2, Pd(OH)2/C
1 atm
EtOH
RT, 23 h, 76%
intermediate structure
Pyr.HF
THF
RT, 72 h, 100%
intermediate structure
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