Synthesis of Erythromycin A

Structure of Erythromycin A

C38H69NO12

Principal investigator	Pierre Deslongchamps
Publication year	1985
Synthesis type	Formal
Number of steps	43 (linear)
References	Can. J. Chem. 1985, 63, 2810. Can. J. Chem. 1985, 63, 2814. Can. J. Chem. 1985, 63, 2818.

Part 1 of 1

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+

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n-BuLi
TMSCl

THF

-78 to 0 °C, 4 h, 80%

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Lindlar Catalyst, H2

Cyclohexane

15 °C, 30 h, 100%

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TMSOTf

CH2Cl2

-78 °C, 5 h, 84%

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Pyr.TsOH

CH2Cl2

Reflux, 40 h, 84%

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SeO2, Pyr

Xylene(s)

140 °C, 5 h

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HCrO3Cl.Pyr

3 Å MS

CH2Cl2

RT, 60% (2 steps)

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CuBr , MeLi
Bz2O2

Et2O

-78 to 0 °C, 45 min, 75%

See the Michael Addition

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MeMgBr

Et2O

-78 °C, 60 min, 63%

See the Grignard Reaction

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K2CO3

MeOH

RT, 60 min, 94%

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LiCl

DMSO, H2O

170 °C, 70 min, 83%

See the Krapcho Decarboxylation

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i-PrN(Cy)Li
PhSeBr

DME

-78 °C, 90 min, 89%

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H2O2, Pyr

CH2Cl2, H2O

RT to 45 °C, 86%

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Pd/C

Xylene(s)

138 °C, 2 h, 100%

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LiAlH4

THF

0 °C to RT, 2 h, 90%

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DMAP, (EtCO)2O

Pyr

RT, 60 min, 99%

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i-Pr2NEt, MeOCH2Cl

CH2Cl2

50 °C, 4 h, 90%

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i-Pr2NLi
TBSCl

HMPA, THF

-78 °C, 2.5 h

See the Ireland-Claisen Rearrangement

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KHCO3, KI3

H2O, MeOH

0 °C to RT, 15.5 h, 65% (2 steps)

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Ni (Raney), NaHCO3, H2

3.5 atm

EtOH, H2O

RT, 24 h, 60%

"Also isolated was the C6-epimer (25 % yield)."

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LiAlH4

THF

0 °C to RT, 65 min, 90%

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TBDPSCl, Imidazole

DMF

RT, 60 min, 95%

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BzCl

Pyr

70 °C, 24 h, 78%

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TMS2NK
BnBr

THF

0 °C to RT, 20 min, 92%

See the Williamson Ether Synthesis

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n-Bu4N+ F-

THF

70 °C, 2 h, 95%

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HCrO3Cl.Pyr, NaOAc

3 Å MS

CH2Cl2

RT, 30 min, 85%

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i-Pr2NLi, EtCO2Me, Cp2ZrCl2

THF

-78 °C to RT, 2 h, 60%

See the Aldol Addition

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HCl

H2O, MeOH

RT, 8 h, 93%

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K2CO3

MeOH

RT, 2 h, 95%

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ClCO2Ph, Pyr

CH2Cl2

0 °C, 30 min, 92%

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Imidazole

Xylene(s)

100 °C, 40 min, 98%

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TsOH

AcOH, CF3CO2H

70 °C, 30 min, 81%

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HCl

Acetone, H2O

RT, 24 h, 68%

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DMAP, Ac2O

CH2Cl2

RT, 20 h, 74%

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NaBH4

MeOH, THF

RT, 90 min, 48%

"Also isolated was the C9-epimer (24% yield)."

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MsCl

Pyr

0 °C, 20 h, 100%

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LiN3

HMPA

60 °C, 60 min, 91%

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PtO2, H2

THF

RT, 3 h, 100%

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PhH

Reflux, 5 d, 76%

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LiI

Pyr

Reflux, 5 d

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NaOH

H2O, MeOH

RT, 70 h

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CH2N2

Et2O

RT, 10 min, 60% (3 steps)

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Pd/C, H2

EtOAc

RT, 11.5 h, 85%

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Remaining...

1.1% (14 Steps)

"See: J. Am. Chem. Soc. 1981, 103, 3215."

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