total synthesis of (±)-indolizomycin
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Total Synthesis of (±)-Indolizomycin. A presentation by Guillaume Pelletier November 22 th 2012. Structural and biological analysis. - PowerPoint PPT PresentationTRANSCRIPT
Total Synthesis of Total Synthesis of (±)-(±)-IndolizomycinIndolizomycin
A presentation by Guillaume PelletierNovember 22th 2012
N
O OH
MeMe
Indolizomycin
N
O H
(+)-Cyclizidine
Me
OH
MeOH
Structural and biological analysis Structural and biological analysis
A fusion between Streptomyces strains NM16 and NP1-1 produced a particularly active clone SK2-52 which produced Indolizomycin as a potent antibiotic unstable indolizidine.
The particular arrangment of the hemi-aminal functionality (stereochemistry not defined) makes the indolizomycin a very labile molecule even at 25°C!
Total synthesis of the racemic compound was achieved by the Danishefsky group in 1990. Albert I. Meyers’ group intercepted the Danishefsky synthesis with an enantioenriched intermediate in 1999.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.Gomi, S. et al. J. Antibiot. 1984, 37, 1491.
Groaning, M. D.; Meyers, A. I. Tetrahedron Lett. 1999, 40, 4639.
N
O OH
MeMe
Indolizomycin
Retrosynthetic approachRetrosynthetic approach
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
N
O H
(+)-Cyclizidine
Me
OH
MeOH
N
O O
MeMe
TeocJulia coupling
Hemiaminalformation
N
O OTBS
O
Teoc
LiSO2Ph
Me Me
+
Fragmentation
N
O
Teoc
O
N
O
vinylogousMcCluskey
fragmentation
N
OMeO2C
Aza-Robinsonannulation
O
O
O
First steps of the synthesisFirst steps of the synthesis
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
N3 CO2MeBr
CO2Me
NaN3
H2O, Benzene
76%Aldrich
100g/197$
i) PPh3 (1.15 equiv)Benzene, 0°C, 30 min
ii) Bu4NCN (7 mol%)0 °C to rt, 4 h
O
O
O(1.0 equiv)
N
O
OMeO2C
99%
First steps of the synthesisFirst steps of the synthesis
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
N3 CO2MeBr
CO2Me
NaN3
H2O, Benzene
76%Aldrich
100g/197$
i) PPh3 (1.15 equiv)Benzene, 0°C, 30 min
ii) Bu4NCN (7 mol%)0 °C to rt, 4 h
O
O
O(1.0 equiv)
N
O
OMeO2C
99%
1) NaBH4, MeOH 10 °C
2) HCl, MeOH
First steps of the synthesisFirst steps of the synthesis
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
N3 CO2MeBr
CO2Me
NaN3
H2O, Benzene
76%Aldrich
100g/197$
i) PPh3 (1.15 equiv)Benzene, 0°C, 30 min
ii) Bu4NCN (7 mol%)0 °C to rt, 4 h
O
O
O(1.0 equiv)
N
O
OMeO2C
99%
1) NaBH4, MeOH 10 °C
2) HCl, MeOH
N
O
MeO2C
3) AllylTMS (1.25 equiv)then TiCl4 (1.0 equiv), 0°C
4) Lawesson's reagent (0.55 equiv)Benzene
N
S
MeO2C
OMe
85% over 4 steps
« Aza-Robinson » annulation to form « Aza-Robinson » annulation to form the first indolizidinone ringthe first indolizidinone ring
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
N
S
MeO2C
1) 1N NaOH in MeOH
O Cl
O
2)
N-methylmorpholine3) CH2N2, Et2O
N
S
O
N2
77% over 3 steps
« Aza-Robinson » annulation to form « Aza-Robinson » annulation to form the first indolizidinone ringthe first indolizidinone ring
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
N
S
MeO2C
1) 1N NaOH in MeOH
O Cl
O
2)
N-methylmorpholine3) CH2N2, Et2O
N
S
O
N2
77% over 3 steps
Rh(OAc)2 (cat.)Benzene, reflux
N
SH
O
W-2 Raney NiAcetone
N
O
66% over 2 steps
McCluskey fragmentation and McCluskey fragmentation and formation of 9-membered cycleformation of 9-membered cycle
N
O
N
O
Teoc
30% over 3 steps
1) Meerwein salt DCM, 0 °C
2) NaBH4, MeOH0 °C to rt
3) TeocCl, then heat
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
McCluskey fragmentation and McCluskey fragmentation and formation of 9-membered cycleformation of 9-membered cycle
N
O
N
O
Teoc
30% over 3 steps
1) Meerwein salt DCM, 0 °C
2) NaBH4, MeOH0 °C to rt
3) TeocCl, then heat
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
NTeoc
OH
51% over 2 steps
1) aq. 30% H2O2
NaOH-MeOH2) Hydrazine hydrate
MeOH, AcOH, rt
McCluskey fragmentation and McCluskey fragmentation and formation of 9-membered cycleformation of 9-membered cycle
N
O
N
O
Teoc
30% over 3 steps
1) Meerwein salt DCM, 0 °C
2) NaBH4, MeOH0 °C to rt
3) TeocCl, then heat
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
NTeoc
OH
51% over 2 steps
1) aq. 30% H2O2
NaOH-MeOH2) Hydrazine hydrate
MeOH, AcOH, rt
mCPBADCM, 0 °C
McCluskey fragmentation and McCluskey fragmentation and formation of 9-membered cycleformation of 9-membered cycle
N
O
N
O
Teoc
30% over 3 steps
1) Meerwein salt DCM, 0 °C
2) NaBH4, MeOH0 °C to rt
3) TeocCl, then heat
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
NTeoc
OH
51% over 2 steps
1) aq. 30% H2O2
NaOH-MeOH2) Hydrazine hydrate
MeOH, AcOH, rt
mCPBADCM, 0 °C
84%, >20:1 dr
NTeoc
OH
O
((EE,,EE,,EE)-Triene formation from the allyl )-Triene formation from the allyl functionalityfunctionality
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
NTeoc
OH
O1) TBSOTf, Et3N
DCM, 0°C
2) O3, NaHCO3
MeOH/DCM3) MeOCH=PPh3
NTeoc
OTBS
O
OMe
76% over 3 steps3:2 olefin mixture
((EE,,EE,,EE)-Triene formation from the allyl )-Triene formation from the allyl functionalityfunctionality
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
NTeoc
OH
O1) TBSOTf, Et3N
DCM, 0°C
2) O3, NaHCO3
MeOH/DCM3) MeOCH=PPh3
NTeoc
OTBS
O
OMe
76% over 3 steps3:2 olefin mixture
N
NH
HN
N
(10 mol%)
Piperidine (1 mol%)Tungsten/Iodine lamp (410 nm)
O2, benzene, rtthen PPh3 (1.0 equiv)
NTeoc
OTBS
O
O
69% (only E isomer)
((EE,,EE,,EE)-Triene formation from the allyl )-Triene formation from the allyl functionalityfunctionality
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
NTeoc
OH
O1) TBSOTf, Et3N
DCM, 0°C
2) O3, NaHCO3
MeOH/DCM3) MeOCH=PPh3
NTeoc
OTBS
O
OMe
76% over 3 steps3:2 olefin mixture
N
NH
HN
N
(10 mol%)
Piperidine (1 mol%)Tungsten/Iodine lamp (410 nm)
O2, benzene, rtthen PPh3 (1.0 equiv)
NTeoc
OTBS
O
O
69% (only E isomer)
PhO2S
Me
Me
n-BuLi (1.2 equiv)THF, 78 °C
then Ac2O (3.0 equiv)
(1.2 equiv)Na amalgamMeOH/THF
((EE,,EE,,EE)-Triene formation from the allyl )-Triene formation from the allyl functionalityfunctionality
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
NTeoc
OH
O1) TBSOTf, Et3N
DCM, 0°C
2) O3, NaHCO3
MeOH/DCM3) MeOCH=PPh3
NTeoc
OTBS
O
OMe
76% over 3 steps3:2 olefin mixture
N
NH
HN
N
(10 mol%)
Piperidine (1 mol%)Tungsten/Iodine lamp (410 nm)
O2, benzene, rtthen PPh3 (1.0 equiv)
NTeoc
OTBS
O
O
69% (only E isomer)
PhO2S
Me
Me
n-BuLi (1.2 equiv)THF, 78 °C
then Ac2O (3.0 equiv)
(1.2 equiv)N
Teoc
OTBSO
Me Me
SO2Ph
AcO
86%
Na amalgamMeOH/THF
N
Teoc
OTBSO
Me Me
89%
End GameEnd Game
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
N
Teoc
OTBSO
Me Me
1M HIO4, THF, rt, 8 h
End GameEnd Game
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
N
Teoc
OTBSO
Me Me
1M HIO4, THF, rt, 8 h
N
Teoc
OHO
Me Me
N
Teoc
OO
Me Me
TPAP (1.1 equiv)DCM, rt, 10 min
84%
86%
End GameEnd Game
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
N
Teoc
OTBSO
Me Me
1M HIO4, THF, rt, 8 h
N
Teoc
OHO
Me Me
N
Teoc
OO
Me Me
TPAP (1.1 equiv)DCM, rt, 10 min
84%
86%
N
OHO
MeMe
29%, Indolizomycin
TBAF (3.0 equiv)THF, 0 °C, 1.5 h
Alternative pathway explored Alternative pathway explored previously…previously…
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
N
H
CO2Et
mCPBA (1.0 equiv)DCM, rt, 4 h
N
H
CO2Et
O
Alternative pathway explored Alternative pathway explored previously…previously…
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
N
H
CO2Et
mCPBA (1.0 equiv)DCM, rt, 4 h
N
H
CO2Et
O
N
H
CO2EtO
84%
Alternative pathway explored Alternative pathway explored previously…previously…
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
N
H
CO2Et
mCPBA (1.0 equiv)DCM, rt, 4 h
N
H
CO2Et
O
N
H
CO2EtO
84%
Ac2O (1.1 equiv)DCM, 0 °C to rt
N
CO2Et
OAc
orN
O
O
CO2Et
Alternative pathway explored Alternative pathway explored previously…previously…
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003.Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.
N
H
CO2Et
mCPBA (1.0 equiv)DCM, rt, 4 h
N
H
CO2Et
O
N
H
CO2EtO
84%
Ac2O (1.1 equiv)DCM, 0 °C to rt
N
CO2Et
OAc
orN
O
O
CO2EtN
H
OAc
CO2Et
85%