31
Natural Products: Natural Products: Total Synthesis Total Synthesis Dr. Paul A. Clarke Room C170
Natural Products: Natural Products: Total SynthesisTotal Synthesis
Dr. Paul A. ClarkeRoom C170
Resources
‘Organic Chemistry’ by Clayden, Greeves, Warren and Wothers.
‘Classics in Total Synthesis’ by Nicolaou and Sorensen
http://www.york.ac.uk/res/pac/teaching/natprods.html
Scope of the CourseScope of the CourseIn the limited time available we will look at how synthetic
chemists have been inspired by complex natural products to developed new methods for acyclic
stereocontrol in order to synthesise these, and other, entities in the laboratory.
Particular emphasis will be placed on understanding the retrosynthetic strategies employed and the
stereoselectivity of the key reactions which are used to install the stereogenic centres in the target molecule.These points will be illustrated by the consideration of
the total syntheses of the polyether antibiotic monensin.
Learning Objectives
1) To appreciate the general strategies used by synthetic chemists for the total synthesis of monensin.
2) To understand the concept of A1,3 strain and to apply it to the stereoselective synthesis of some natural product sub-units.
3) To understand the concept of Felkin-Anh and chelationcontrolled addition to carbonyl groups and to apply it to the stereoselective synthesis of some natural product sub-units
Course OutlineIntroduction to monensin and historical context.
Kishi’s SynthesisA1,3 strain as a tool for stereocontrol
Application of the avoidance of A1,3 strain to the total synthesis monensin
Still’s SynthesisFelkin-Anh model for addition of nucleophiles to chiral aldehydesCram chelation control model for addition of nucleophiles to chiral
aldehydesApplication of Felkin-Anh and Cram models to the total synthesis monensin
Introduction and Historical ContextIntroduction and Historical Context
Isolated and characterised in 1967, from a strain of Streptomycescinamonensis. Exhibits broad spectrum anticoccidialactivity.Since 1971, it has been used to prevent coccidial infections in poultry and cattle.
O
O
OOO
CO2H
OMe
H
HO
HH
HO
H
H
HO1
2
3
9
13
20
25
26monensin
Monensin assumes a cyclic structure which is maintained by two intramolecular hydrogen bonds between the terminal C-1 CO2H and the C-25 and C-26 OH groups.Monensin’s exterior is hydrocarbon-like, but its interior is rich in Lewis-basic O atoms, and its cyclic conformation make it ideal for the complexation and transportation of metal ions through biological membranes.
It is difficult to overestimate the role that polyether antibiotics, particularly monensin, have played in the development of acyclic stereocontrol. In fact much of our understanding of factors controlling acyclic stereoselectivity for such fundamental processes as hydroboration, epoxidation, halocyclisations, Claisenrearrangements, additions to carbonyls and aldol reactions arise from studies into the synthesis of polyethers.
KishiKishi’’ss SynthesisSynthesis
Allylic 1,3 (A1,3) Strain
O
O
OOO
CO2H
OMe
H
HO
HH
HO
H
H
HO O
O
O
CO2Me
OMe
H
HO
HH
MeO
H
H
HO
OBn HO
O
CHO
CO2Me
OMe
H
OBn
O
O
O
HH
MeO
H
H
HO
HO
O
O
MeO
HO
OH
O
O
O
HH
MeO
H
H
HO
OO
O
OMe
OH
O
O
O
HH
MeO
H
H
HO
MeO
spiroketalisation aldol condensation
carbonyl addtion
Retrosynthesis
OO
O
OMe
OH
OHO
Ar
H
H
O
O
O
HH
MeO
H
H
HO
MeO
OBn
Et
HO
CNO
OO
Ar
H
H
OH
OO
OMe
HO OH
OOO
Ar
H H
H
H
OBz
CCl3O
Ar
Et
O
OHH
CO2EtO
OHOO
Ar
H H
H
H
EtO2C
Et
OBn
H-W-E reaction
ring closure
bromide displacement
bromoetherification
Wittig
Wittig hydroxy epoxide
cyclisation
ring closure
carbonyl addition
Claisen rearrangement
CNO
CHOMeO2C
OMe OBn
CO2EtO
CNO
O OBn
OO
CO2EtPh3P
O OBn
OH
Synthesis
1. BuLi, THF, MeI, -78 - 0 oC
2. KOH, MeOH-H2O, reflux
1. LiAlH4, Et2O, 0 oC
2. PCC, CH2Cl2, 25 oC
PhMe, heat
1. LiAlH4, Et2O, 25 oC
2. BnBr, KH, DMF-THF, 0 oC
B2H6, THF 0 oCthen
KOH, H2O2
Let's examine the mechansim and stereoselectivity of this reaction
O OBn
OH
(OMe)2(O)P CO2Me
O
OMe OH
OH
CHOMeO2C
OMe OBn
O
OMe
CO2Me
O OH
OMe
O
OMe OBn
OMOM
CHOMeO2C
OMe OBn
PhN C O
O
OMe
OH
O OH
OMe
O
MeO
OMe OBn
OMOM
Synthesis
1. KH, MeI, DMF-THF, 0 oC
2. H2, 10% Pd/C, MeOH
racemic (-) - enantiomer
Et3N, 50 oC1.
2. resolution3. LiAlH4
1. PCC, CH2Cl2
2.
THf, -78 - -50 oC
LiAlH4, Et2O B2H6, THF, 0 oC
then 10% aq. KOH, H2O2, THF
1. BrCH2OMe, PhNMe2, CH2Cl2
2. BnBr, KH, DMF-THF
1. O3, MeOH, -78 oC
2. CH2N2
Examine the stereoselectivity of this reaction
1. HCl, MeOH2. PCC, CH2Cl2
HO OH
MeOO O OHHEtH
MgBr
EtHO OBn
Et
Et
OHOAr
OMeBrMg
OO
Ph
OMe
EtO2C
Et
OBn
HO OBn N C OEt3N
HO OBn
CHO
Et
OBn
Synthesis
PhCHO, CSA, PhMe AlCl3 - LiAlH4, Et2O
racemic
2. resolution3. LiAlH4
(-) - enantiomer
1. PDC, CH2Cl2
2.THF, 0 oC
CH3C(OEt)3, EtCO2H
140 oC
Johnson orthoester Claisen rearrangementWill look at the mechanism of this reaction
1. LiAlH4, Et2O
2. PCC, CH2Cl2
2. CrO3, H2SO4,H20 - acetone
3. BCl3
Ar =Et2O, 0 oC
1.
MeOO O OHHEtH
Et
OHOAr
OMeSynthesis Ar =
mCPBA, CH2Cl2, aq. NaHCO3
Et
OHOAr
O
Examine the selectivity in this reaction
1. TsCl, py, 0 oC
2. LiAlH4, Et2O, 0 oC
Et
OHAr
O
H
CSA, CH2Cl2
ArO OHHEtH
OsO4, NaIO4, H2O - dioxane
MeOO O OHHEtH
7:2 mix of epimers in favour of this one
5-exo cyclisationcf. radical course yr 3
ArO O OHHEtH
MeOO OHEtH
OH H OMe
OH
ArO OH OHEtH
Ph3P
ArO OHEtH H
Br
DMSO
ArO OHEtH H
OO
OBzO
CCl3
OMe
ArO OHHEtH
ArO OHEtH H
OH
MeOO OHEtH
OH H OMe
OH
SynthesisAr =
NBS, MeCN
bromoetherification. Let's examine the selectivity
KO2, 18-cr-6, DMSO
1. Cl3CCOCl, py, 0 oC2. OsO4, py, THF
3. BzCl, py, CH2Cl24. CrO3, H2SO4, H2O-acetone
1. NaOMe, MeOH
2. (CH3O)3CH, MeOH, CSA, CH2Cl2
MeOO OHEtH
OH H OMe
OH
O
OOO
CO2H
OMe
H
HO
HH
HO
H
H
HOO
O OHEtHO
H H OMeOH
O
MeOH
OH
O OHEtHO
H H OMeOH
O OH
MeOO OHEtH
OH H OMe
OH
O OHEtHO
H H OMeOHOHC O
MeO
O OHEtHO
H H OMeOHOO
Synthesis
Li, EtOH, NH3 (l)
1. (CH3O)3CH, MeOH, CSA, CH2Cl22. O3, MeOH, -78 oC
3. MgBr2, CH2Cl2-H2O
MeMgBr, Et2O
Re-face additionFull explanation of stereoselectivity
will be given later in the course
1. O3, MeOH, -78 oC
2. conc. HCl, MeOH
MeLI, THF, -78 oC
CHO
CO2Me
OMe
OBn
O OHEtHO
H H OMeOH
O OH
O
OOO
CO2H
OMe
H
HO
HH
HO
H
H
HOO
O
OOO
CO2Na
OMe
H
HO
HH
HO
H
H
HOO
O OHEtHO
H H OMeOH
O OH
CO2Me
OMe
OBn
HO
Synthesis
iPr2NMgBr, THf, -78 oC
aldol reactionExplain
stereoselectivity later in course
1. H2, 10% Pd/C, MeOH - AcOH2. CSA, H2O, CH2Cl2 - Et2O
3. 1N NaOH - MeOH
spiroketalisationExplanation of the selectivity
8:1 mix of diastereomers in favour of this one
Summary of Kishi’s Synthesis
The first total synthesis of monensin by Kishi is one of the great achievements in acyclic stereocontrol. Retrosynthetic analysis allowed the molecule to be divided into two sectors to be unified by a crossed aldol reaction. The left hand sector containing vicinal stereocentres is set up under the guiding influence of a pre-existing seterocentre by the use of two hydroborationreactions. While the right hand sector possesses both vicinal and remote stereocentres which are set up using a combination of stereo-defining principles. However, the main highlight of Kishi’s synthesis is the use of the avoidance of allylic 1,3 strain as a stereocontrolling factor, and he used it to install 6 out of the 17 stereogenic centres present in monensin.
StillStill’’s Synthesiss Synthesis
Felkin-Anh and Cram ChelationModels for the Addition of
Nucleophiles to Carbonyl Groups
O
O
OOO
CO2H
OMe
H
HO
HH
HO
H
H
HO
CHO
CO2Me
OMe
OTES
O
O
O
HH
MeO
H
H
HO
TESO
O
O O
OMe
H
O
OH
H
H
O O O
O
O
O
CO2Me
OMe
H
HO
HH
MeO
H
H
HO
OTES HO
O
OHC CO2Me
OMe
O O
Br
O
O
PyS
HH
MeO
H
HO
O
spiroketalisation aldol condensation
carbonyl addition
Retrosynthesis
ring closure
carbonyl addition
C-C bond formation
O
OHC CO2Me
OMe
O O
Br
O
O
PyS
H
H
O
H
O
O
OI
O
O
H
CO2Me
OMeBOMO
HO OBOM
OTBS
CHO
BOMO
HO
O
O
O
OBOM
OTBS
O
I
OO
CHO
CO2H
OH
HO2C
Ph3P
HO2CCO2H
OH
CO2H
aldol condensation
Retrosynthesis
carbonyl addition
ring closure
iodolactonisationWittig
OHC CO2Me
OMeOTESOTMS
O
BnOCHO
BnO OMe
OMe O
OHCOMe
OMe O
OMe
OMe OEt2AlOO
OMe
OH
BnOOTMS
OH O
OHC CO2Me
OMeOTES
AlEt2
Synthesis1. LDA, THF; then MgBr2, -110 oC
2.
85%
Aldol Reaction5:1 mix in favour of syn diastereomer.
We will discuss this selectivity
1. H5IO6, MeOH
2. KN(SiMe3)2 then Me2SO450%
1. H2, 10% Pd/C
2. CrO3.2Py, CH2Cl290%
THF, -78 oC
Cram-Felkin-Anh addition gives this as major diastereomer in 3:1 ratio
We shall look at this selectivity
1. LiOH, THF/H2O then CH2N2
2. Et3SiOClO3, MeCN, py
3. O3, MeOH, -78 oC, Me2S, py>95%
O O
Br
HO2CCO2H
OH
Me2C(OMe)2, TsOH
O
OBOMOO
OTBS
OBOM
MgBr
OTBS
OHHO
O
O O
Br
OTBS
OBOMHO
O O
CO2HO
H
Synthesis
85%
1. BH3.THF, then H2O
2. BnOCH2Cl, iPr2NEt
75%
1. MeMgBr, THF, -78 oC
2. TBSCl, DMF, imidazoleTHF, -78 oC
Chelation control 50:1 mix of epimers
We shall examine this selectivity
1. Li, NH3 (l), -78 oC
70%
1. TsOH, CuSO4
2. NBS, PPh3, 71%
OOPyS
H
H
O
H
O
CO2Bn
OI
O CO2Bn
OH O
HOO
H
Ph3P
HO2C
I
CHOO
O
OO
HO2C
HO
O
H
O
OH
HOO
PySH
H
O
H
O
CO2Bn
OO
OI
H
O
CHOO
O
Synthesis1. O3, acetone, -78 oC thenCrO3, H2SO4, H2O 0 oC
2. Pb(OAc)4, Cu(OAc)2, PhH80 oC 73% yield on 80% conv
1. KOH, MeOH, H2O
2. I2, MeCN, -15 oC
BnOK, THF, -20 oC H2, 10% Pd/C, Et2O
84%
1. LiAlH4, Et2O
2. acetone, TsOH, CuSO43. CrO3.py.HCl, CH2Cl2, 80%
NaH, DMSO, 25 oC
70%
KI3, NaHCO3, H2O, 87%
iodolactionisation we will look at the selectivity
AgCO2CF3, CH2Cl2, 50% 1. CrO3, H2SO4, H2O
2. 2-pySH, COCl2, Et3N
O O
Br
OOH
H H
O
OBr
O EtH
OOPyS
H
H
O
H
O
O OOO
H
H H
OEt OH
OOH
H H
O
OBr
O EtH
O OOO H
H H
OO
OHOO H
H H
OEt OHOBr
Synthesis
1. Mg, THF2. CuI.Bu3P, THF, -78 oC
3.
EtMgBr, THF, -78 oC, 70%
chelation controlwe shall look at the
selectivity of this reaction
NBS, TsOH, CH2Cl2, 0 oC 1. MeSO2Cl, Et3N, CH2Cl2, 0 oC
2. CF3CH2OH, NaOAc, 60 oC
67%
OOH
H H
OBr
O EtH
BnO
OMe
O
OOO
CO2H
OMe
H
HO
HH
HO
H
H
HOO
OHC CO2Me
OMeOTES
O
O
O
CO2Me
OMe
H
HO
HH
MeO
H
H
BnO
OTESO
O
TES
OOH
H H
O
OBr
O EtH
OOH
H H
O O EtH
BnO
OMeO
TES
O
OOO
CO2Na
OMe
H
HO
HH
HO
H
H
HOO
Synthesis1. BnOCH2Li, THF, -78 oC
2. HC(OMe)3, TsOH, 80%
1. Zn(Cu), NaI, DMF, 60 oC2. Et3SiOClO3, py, MeCN
3. O3, CH2Cl2, -78 oC, Me2S, py
1. LDA, THF, -78 oC, MgBr2
2.
75%
1. H2, Pd/C, Et2O2. TsOH, CH2Cl2, Et2O, H2O
3. NaOH, H2O, MeOH
3:1 mix of diastereomers from the aldol reaction
Summary of Still’s Synthesis
The second total synthesis of monensin by Still is truly one of the great achievements in acyclic stereocontrol and natural product synthesis. Retrosynthetic analysis diveded the molecule into three units of comparable complexity, which allowed for a highly convergent synthesis of the natural product. Of particular note is the fact that only the methyl groups at carbons 4, 18 and 22 are derived from the chiral pool. All other stereogenic centres are fashioned through substrate controlled reactions. A particular highlight of this synthesis is the extensive use of chelation controlled reactions to set the majority of the stereogenic centres present in monensin. This must rank as one of the most impressive total syntheses of the late 20th century.
Course Summary
In this course we have discussed and illustrated the use of acyclic stereocontrol in the total synthesis of the polyether antibiotic monensin. Of particular importance is the avoidance of allylic 1,3 strain employed by Kishi in his synthesis, and the use of Felkin-Anh and Cram chelation control for the installation of stereogenic centres in Still’s synthesis.
An understanding of these principles and an ability to apply them in the construction of natural product fragments is expected.
