Synthesis of Erythromycin A

Structure of Erythromycin A

C38H69NO12

Principal investigator	Robert B. Woodward
Publication year	1981
Synthesis type	Total
Number of steps	50 (4 parts)
References	J. Am. Chem. Soc. 1981, 103, 3210. J. Am. Chem. Soc. 1981, 103, 3213. J. Am. Chem. Soc. 1981, 103, 3215.

Part 1 of 4

intermediate structure

+

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NaH

DMSO, THF

RT

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AcOH

H2O

RT

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D-Proline

																	MeCN															

								RT																
							
								See the Aldol Addition
							
								"Also isolated was the C6-epimer (50:50 dr). Both diastereoisomers were obtained as an enantioenriched mixture (36 % ee)."

intermediate structure

MsCl

Pyr

RT

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Al2O3

EtOAc

RT, 12% (5 steps)

"The product was cristallized to optical purity from the enantioenriched mixture."

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NaBH4

MeOH

0 °C

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KH
MeOCH2I

THF

0 °C

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OsO4

Et2O

RT

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TsOH, Me2C(OMe)2

CH2Cl2

0 °C, 74% (4 steps)

intermediate structure

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Part 2 of 4

intermediate structure

CF3CO2H

CH2Cl2

RT

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DMSO, i-Pr2NEt, (CF3CO)2O

CH2Cl2

-60 to 0 °C, 85% (2 steps)

See the Swern Oxidation

intermediate structure

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Part 3 of 4

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Ni (Raney)

EtOH

Reflux

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n-Bu3P , o-NO2PhSeCN
H2O , H2O2

THF

RT

See the Grieco Dehydration

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O3
Me2S

CH2Cl2, MeOH

-78 °C to RT, 80% (3 steps)

intermediate structure

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Part 4 of 4

intermediate structure

+

intermediate structure

MesLi

THF

-50 °C

See the Aldol Addition

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(CF3CO)2O, i-Pr2NEt, DMSO

CH2Cl2

-60 to 0 °C, 76% (2 steps)

See the Swern Oxidation

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KH
AcCl

HMPA, THF

-78 to 0 °C

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NaBH4

MeOH

-20 °C

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MsCl, DMAP

MeOH, Pyr

0 °C

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n-BuLi, BnSH

THF

-50 °C, 85% (4 steps)

See the Michael Addition

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LiAlH4

Et2O

-20 °C

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Ac2O, DMAP

CH2Cl2

0 °C, 92% (2 steps)

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Ni (Raney)

DMF, EtOH

Reflux

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o-NO2PhSeCN , n-Bu3P
H2O , H2O2

THF

RT

See the Grieco Dehydration

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O3
Me2S

CH2Cl2, MeOH

-78 °C to RT, 66% (3 steps)

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i-Pr2NLi, EtCOSt-Bu

THF

-110 °C, 85%

See the Aldol Addition

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(CH2NMe2)2 , t-BuLi
AcOH

THF

-110 °C, 90%

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Na2CO3

MeOH

RT

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DMAP, (PhOCH2CO)2O

CH2Cl2, Pyr

0 °C

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MsCl

Pyr

0 °C

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LiOH, H2O2

H2O, THF

RT, 75% (4 steps)

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LiN3

H2O, HMPA

60 °C, 75%

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PtO2, H2

1 atm

THF

RT

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ClCO2(p-NO2Ph), NaHCO3

CH2Cl2, H2O

RT

See the Schotten-Baumann Reaction

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NH2OH.HCl, KH2PO4

H2O, MeOH

Reflux

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Et3N

CH2Cl2

RT, 70% (4 steps)

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Mesitaldehyde dimethyl acetal, CF3CO2H

CH2Cl2

0 °C, 85%

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EtSLi

HMPA

30 °C

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+

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Et3N

CH2Cl2

0 °C

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PhMe

110 °C, 70% (3 steps)

See the Corey-Nicolaou Macrolactonization

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p-PhBzCl, DMAP

CH2Cl2, Et3N

RT

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NaOH

H2O, i-PrOH, THF

RT, 70% (2 steps)

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CF3CO2H, SiO2

CH2Cl2, H2O

RT, 100%

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+

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AgOTf

CH2Cl2, PhMe

RT, 36%

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+

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Pb(ClO4)2

MeCN

RT

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H2O

MeOH

20% (2 steps)

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Na(Hg)

MeOH

75%

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NCS

Pyr

RT

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AgF

HMPA

70 °C

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H2O

5 °C, 40% (3 steps)

intermediate structure

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