Wothers. 'Classics in Total Synthesis' by Nicolaou and Sorensen ... aldehydes.
Application of Felkin-Anh and Cram models to the total synthesis monensin ...
Natural Products: Total Synthesis Dr. Paul A. Clarke Room 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 Course In 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 chelation controlled addition to carbonyl groups and to apply it to the stereoselective synthesis of some natural product sub-units
Course Outline Introduction to monensin and historical context.
Kishi’s Synthesis A1,3 strain as a tool for stereocontrol Application of the avoidance of A1,3 strain to the total synthesis monensin
Still’s Synthesis Felkin-Anh model for addition of nucleophiles to chiral aldehydes Cram chelation control model for addition of nucleophiles to chiral aldehydes Application of Felkin-Anh and Cram models to the total synthesis monensin
Introduction and Historical Context
HO 13
O H
9 O
H
H O O H H
OMe
3
O
2 1
CO2H
20
HO 26
monensin
HO
25
Isolated and characterised in 1967, from a strain of Streptomyces cinamonensis. Exhibits broad spectrum anticoccidial activity. Since 1971, it has been used to prevent coccidial infections in poultry and cattle.
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, Claisen rearrangements, additions to carbonyls and aldol reactions arise from studies into the synthesis of polyethers.
Kishi’s Synthesis
Allylic 1,3 (A1,3) Strain
Retrosynthesis O HO
HO H O H
O
H
H
O
OBn HO O
O O
H
H H
OMe
H
H H
OMe O
O
HO
CO2H
CO2Me
HO
HO
MeO
spiroketalisation
aldol condensation OH
CHO OBn
OMe
HO
H
O
MeO
OMe
OH CO2Me O O
H HO
H
O
O
H O
H
H
O H H O HO MeO
carbonyl addtion
H
MeO
O
O
O
O
H H
H H O
O HO
HO MeO
MeO
OMe
Wittig
OMe
CO2Et
O
O
O
O OH
H-W-E reaction H
MeO H
O
H O
O
H H
ring closure
H H O
O O
Ar
HO
H
O
OBz
O
CCl3
O
Ar
O
ring closure
Et
H
H
Wittig
Ar
O H
OH
hydroxy epoxide cyclisation
Et
HO
Claisen rearrangement
OBn
HO
Et
O O
OH
Ar
H
CN
O
O H
H H OH
bromoetherification
MeO
O
bromide displacement
H
OH
Ar
H
OH
carbonyl addition
EtO2C
OBn
Synthesis
CHO
MeO2C OMe OBn
Ph3P 1. LiAlH4, Et2O, 0 oC
1. BuLi, THF, MeI, -78 - 0 oC CN O
CN 2. KOH, MeOH-H2O, reflux
O
2. PCC, CH2Cl2, 25 oC
PhMe, heat O
O
B2H6, THF 0 oC CO2Et
1. LiAlH4, Et2O, 25 oC
OH
then
O
O o
2. BnBr, KH, DMF-THF, 0 C
CO2Et
OBn KOH, H2O2
O
Let's examine the mechansim and stereoselectivity of this reaction
OBn
Synthesis
CHO
MeO2C OMe OBn
Ph OH
1. KH, MeI, DMF-THF, 0 oC OBn
O
1.
OMe
OMe
OH
O
2. H2, 10% Pd/C, MeOH
N C O Et3N, 50 oC
racemic
2. (OMe)2(O)P
(-) - enantiomer
OMe
LiAlH4, Et2O
OMe
1. PCC, CH2Cl2
B2H6, THF, 0 oC
O
O
CO2Me
OH
O
2. resolution 3. LiAlH4
then 10% aq. KOH, H2O2, THF
CO2Me
OH
THf, -78 - -50 oC
OMe OH O
1. BrCH2OMe, PhNMe2, CH2Cl2 OH
2. BnBr, KH, DMF-THF
Examine the stereoselectivity of this reaction
1. O3, MeOH, -78 oC
OMe OBn OMOM
O
2. CH2N2
CHO
MeO2C OMe OBn
O
OMe OBn
MeO
1. HCl, MeOH 2. PCC, CH2Cl2
OMOM
Synthesis
MeO
O
H
Et H
O
OH
Ph
HO
O
PhCHO, CSA, PhMe
OH
O
Et3N AlCl3 - LiAlH4, Et2O
HO
OBn
N C O
HO
OBn
2. resolution 3. LiAlH4
(-) - enantiomer
racemic Et
Et 1. PDC, CH2Cl2
CH3C(OEt)3, EtCO2H HO
Et
2.
OBn
EtO2C
o
140 C
o
THF, 0 C
MgBr
Johnson orthoester Claisen rearrangement Will look at the mechanism of this reaction BrMg
OMe Et
1. o
Et2O, 0 C Ar 2. CrO3, H2SO4, H20 - acetone 3. BCl3
O
OH
Ar =
Et
1. LiAlH4, Et2O
OMe
OBn
CHO 2. PCC, CH2Cl2
OBn
Synthesis
H
Ar
O
Et H
O
OH
O
1. TsCl, py, 0 oC
O Ar
OH
Et
Et
mCPBA, CH2Cl2, aq. NaHCO3
Et
OMe
Ar =
MeO
O
Ar
OH
o
2. LiAlH4, Et2O, 0 C
H
Et H
OH
MeO
7:2 mix of epimers in favour of this one
OH
cf. radical course yr 3
OsO4, NaIO4, H2O - dioxane O
H
CSA, CH2Cl2
5-exo cyclisation
Examine the selectivity in this reaction
Ar
O
H
O
Et H O
OH
Synthesis
MeO H
O
Et H
O H
H
O
OH
OMe
Ar =
OMe
Ph3P Ar H
O
Ar Et H
O
OH
O
H
Et H
OH
DMSO
O
Ar H
O
Et H
OH
KO2, 18-cr-6, DMSO
NBS, MeCN
Ar
Ar H
O
Et H
O H
H
O
Et H
O H
Br
OH
bromoetherification. Let's examine the selectivity 1. Cl3CCOCl, py, 0 oC 2. OsO4, py, THF
1. NaOMe, MeOH
Ar H
3. BzCl, py, CH2Cl2 4. CrO3, H2SO4, H2O-acetone
O
Et H
O H O
O
CCl3
O
OBz
2. (CH3O)3CH, MeOH, CSA, CH2Cl2
MeO H
O
Et H O H
H
O
OH OMe
HO
Synthesis
H O
O H
H
O O H H
OMe
O
Li, EtOH, NH3 (l)
HO
CO2H
MeO
HO
H
O
Et H
O H
H
O
OH OMe
1. (CH3O)3CH, MeOH, CSA, CH2Cl2 2. O3, MeOH, -78 oC MeO H
O
Et H
O H
H
O
OH OMe
OHC
3. MgBr2, CH2Cl2-H2O
O
O
H
O
Et H O H
H
O
OH OMe
Me
1. O3, MeOH, -78 oC
MeMgBr, Et2O O OH
OHH
O
Et H
O H
H
O
OH OMe
Me
Re-face addition Full explanation of stereoselectivity will be given later in the course MeLI, THF, -78 oC O
OHH
O
Et H
O H H
O
OH OMe
O 2. conc. HCl, MeOH
O
H
O
Et H O H
H
O
OH OMe
Synthesis
HO H O
O H
H
O O H H
OMe
O HO
CO2H
HO
8:1 mix of diastereomers in favour of this one CHO i
Pr2NMgBr, THf, -78 oC
OBn OMe
O
OHH
O
Et H
O H
H
OH
O
O
OMe
CO2Me
OBn
aldol reaction Explain stereoselectivity later in course
HO 1. H2, 10% Pd/C, MeOH - AcOH 2. CSA, H2O, CH2Cl2 - Et2O 3. 1N NaOH - MeOH
H O H
O
H
O O H H
OMe
O CO2Na
HO HO
spiroketalisation Explanation of the selectivity
HO
OMe CO2Me
OHH
O
Et H
O H
H
O
OH OMe
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 hydroboration reactions. 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.
Still’s Synthesis
Felkin-Anh and Cram Chelation Models for the Addition of Nucleophiles to Carbonyl Groups
Retrosynthesis spiroketalisation
aldol condensation O
HO
HO H O
O H
H
H
O
OTES HO O
O O
H
H H
OMe
H
H H
OMe O
O
HO
CO2H
CO2Me
HO
HO
MeO
CHO H OTES
O
O
OMe
carbonyl addition
OMe
OHC
CO2Me
OMe CO2Me
C-C bond formation
carbonyl addition O
H TESO
H
O
O
ring closure
PyS
H O O O
H H
H H
HO MeO
H O
O
O
Br
O O
O
H H
O O
O HO MeO
Retrosynthesis OMe
BOMO
OHC
OMe
CO2Me
BOMO
OH
CO2Me
CHO
CO2H
aldol condensation
carbonyl addition Br
OTBS
OTBS CO2H
O
O
OBOM
HO
HO2C O
OBOM
OH
PyS H
O
O O
ring closure
H
O
O H
I
H O O
CO2H O
O
O
O
Wittig
HO Ph3P
iodolactonisation O
O
I
HO2C
CHO
Synthesis
1. LDA, THF; then
OHC
OH
MgBr2, -110 oC
O
OTES OMe
OTMS
BnO
OTMS
CO2Me
O
2. BnO
CHO 85%
Aldol Reaction 5:1 mix in favour of syn diastereomer. We will discuss this selectivity
OMe O
1. H5IO6, MeOH 2. KN(SiMe3)2 then Me2SO4 50%
Et2AlO
BnO
OMe
OMe O
OHC 2. CrO3.2Py, CH2Cl2 90%
H
O
O
OMe
OHC 2. Et3SiOClO3, MeCN, py OMe
3. O3, MeOH, -78 oC, Me2S, py >95%
THF, -78 oC
OTES OMe
1. LiOH, THF/H2O then CH2N2
OMe
Cram-Felkin-Anh addition gives this as major diastereomer in 3:1 ratio We shall look at this selectivity
AlEt2
OMe O
1. H2, 10% Pd/C
CO2Me
Synthesis
Br Me2C(OMe)2, TsOH
CO2H
O
O
CO2H
O H
HO2C
85%
OH
O
1. BH3.THF, then H2O 2. BnOCH2Cl, iPr2NEt
O
75%
OTBS
1. MeMgBr, THF, -78 oC
OTBS MgBr
O 2. TBSCl, DMF, imidazole O
O
OBOM
OBOM
THF, -78 oC
HO
Chelation control 50:1 mix of epimers We shall examine this selectivity O Br OTBS
HO
OH
1.
TsOH, CuSO4
2. NBS, PPh3, 71%
O
O
OBOM
1. Li, NH3 (l), -78 oC 70%
Synthesis 1. O3, acetone, -78 oC then CrO3, H2SO4, H2O 0 oC
H
H PyS O
CO2Bn
O
H O
2. Pb(OAc)4, Cu(OAc)2, PhH O
O
H2, 10% Pd/C, Et2O
O O
H
CO2Bn
84%
2. I2, MeCN, -15 oC
CO2Bn
80 oC 73% yield on 80% conv
BnOK, THF, -20 oC I
1. KOH, MeOH, H2O
1. LiAlH4, Et2O HO H
O
O
O
2. acetone, TsOH, CuSO4 3. CrO3.py.HCl, CH2Cl2, 80%
I NaH, DMSO, 25 oC
Ph3P
KI3, NaHCO3, H2O, 87%
O
O
O HO2C
I
70%
O
HO2C
O O
AgCO2CF3, CH2Cl2, 50%
H
O
CHO
iodolactionisation we will look at the selectivity 1. CrO3, H2SO4, H2O
HO
H
H
H
H
O 2. 2-pySH, COCl2, Et3N
H O
PyS O
O
O
H O O
O
O
CHO
Synthesis
H
H O
Br
H O
O
Et
H O O
1. Mg, THF
Br
2. CuI.Bu3P, THF, -78 oC
O
3. O
O
O
H
H
O
EtMgBr, THF, -78 oC, 70%
H
H
H O
O
O
PyS O
O
Et
H O O
H
H
O
O
OH
O
NBS, TsOH, CH2Cl2, 0 oC
O Br
H
Br
O
H O
Et
O
H O O
O
OH Et
1. MeSO2Cl, Et3N, CH2Cl2, 0 oC
H
H
H O
H
chelation control we shall look at the selectivity of this reaction
OH
O
2. CF3CH2OH, NaOAc, 60 oC
H O O
67%
HO
Synthesis
H O
O H
H
O
H
1. BnOCH2Li, THF, -78 oC
H
O H H
OMe
O
Br
H O
Et
O
2. HC(OMe)3, TsOH, 80%
H O O
O HO
CO2H
HO
H O
Br
H O
Et
1. Zn(Cu), NaI, DMF, 60 oC 2. Et3SiOClO3, py, MeCN
H O
o
H O
3. O3, CH2Cl2, -78 C, Me2S, py
OMe
H
H O
O
H O
O
Et
H O
TES
OMe
BnO
BnO
3:1 mix of diastereomers from the aldol reaction O 1. LDA, THF, -78 oC, MgBr2
HO
1. H2, Pd/C, Et2O 2. TsOH, CH2Cl2, Et2O, H2O
H OTES OTES OMe
2. OHC
CO2Me
H
O
H
H
O 3. NaOH, H2O, MeOH
O
TES
H H
OMe 75%
HO
O H
O
H
O O H H
OMe
O
O CO2Me
BnO
CO2Na MeO
HO HO
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.
