CH402: Synthetic Chemistry I (Organic) Professor Martin Wills.
synthetic approaches to complex target organic molecules
Structure of course (7 lectures) (underlined/red text indicates the molecule on which
the course will focus, and the examinable/workshop material), there is one handout
and one set of notes on the course with links to references:
1) Introduction to strategy, disconnections, retrosynthesis, protecting groups and
extreme targets which may include palytoxin, vitamin B12, brevitoxin, azadirachtin,
vancomycin.
2) Early classics of total synthesis in organic chemistry, which may include colchicine,
morphine, strychnine, thienamycin and penicillin.
3) Lessons learnt from the synthesis of small important organic molecules which may
include hirsutene, periplanone B, epothilones and prostaglandins.
4) Molecules with a high degree of functionality, which may include avermectin,
erythromycin, amphotericin B, strychnine.
5) Construction of highly complex structures which may include ginkgolide B,
calicheamycin, taxol.
6) The use of cycloadditions in complex molecule synthesis, which may include
FR182877/abyssomicin C , estrone, platensimycin, progesterone, daphniphylline
alkaloids.
7) Enantioselective strategies which may include biotin a-arylpropionic acids, menthol,
1
zaragozic acid, statins.
CH402: Synthetic Chemistry I (Organic), lectures 1-7; Professor Martin Wills.
synthetic approaches to complex target organic molecules
Recommended reading (not essential but if you want to learn more or check anything):
Classics in Total Synthesis; K. C. Nicolaou and E. J. Sorensen, Wiley-VCH 1996. Classics in
Total Synthesis II, K. C. Nicolaou and E. J. Sorensen, VCH 2003.
Molecules that changed the world, K. C. Nicolaou and T. Montagnon, Wiley-VCH, 2008.
The Logic of Chemical Synthesis, E. J. Corey and X.-M. Cheng, Wiley-VCH, 1995.
S. Warren and P. Wyatt, Organic Synthesis: The Disconnection Approach, Wiley, 2nd Edn
2008 and the associated workbook, 2nd Edition 2009.
Catalysis in Asymmetric Synthesis’ by V. Caprio and J. M. J. Williams, Wiley, 2010 (2nd
Edition).
In addition, other annual reviews of progress frequently appear in review journals. For
more detailed reviews of particular areas, you can search the web of knowledge or
Scifinder Scholar for comprehensive literature surveys.
2
CH402: Synthetic Chemistry I (Organic), lectures 1-7; Professor Martin Wills.
Specific requirements and structure of the course:
15 CATS is equivalent to around 150 study hours. There are 10 lectures of 1 h each, three
workshops (1h, 2h, 2h) and a piece of assessed work which would be expected to take
15-20 hours of work. The remaining time is for self-study around the subject.
For the M. Wills section of the course, a number of key references will be provided on
the seven molecules selected for detailed study. These seven molecules and the
associated references represent the main material for the workshops and for the
examinable material.
Key references will be provided for each of the seven targets in bold, and these papers
should be treated as examinable material however - you do not have to learn the
content by heart but should ensure that you understand the reasons for the choice of
strategy and the main mechanisms, particularly with respect to the key steps indicated
for each synthesis.
The assessed task will involve writing an essay about the analysis of a complex synthesis
(which will not be one of the seven highlighted earlier). Further information about this
will be distributed early in the course.
Please note that not all reagents/solvents/conditions are given for each step. In most
3
cases only the KEY reagent is shown.
3
1) Introduction to strategy, disconnections, retrosynthesis, protecting groups and
extreme targets which may include palytoxin, vitamin B12, brevetoxin, azadirachtin,
vancomycin.
Recap: disconnections, synthons, FGIs and reagents.
Target
O
OH
Synthons
O
OH
retrosynthetic
arrow:
O
Actual reagents.
O
O
O
disconnection here
O
Idealised fragments,which you
would buy if you could.
These are what you actually
do the reaction with
O
O
HO
HO
+
NH2
NH2
NO2
H
H
R1
R1
R2
R1
2
R
OH
OH
R1
H
2
R
Ph3P
R2
'Easy' to form but less
stable - tend to do late in
synthesis
C
O
C
N
R1
O
R2
O
R1
O
2
R
Br
'Difficult to form but more
stable - tend to do early in
synthesis to establish C skeleton
C
R1
Cl
O
R2
OH
C
R1
H
BrMg
R2
O
For the trans-alkene
O
For the cis-alkene
O
R2
R
H2 catalyst
R1
R1
2
C
C
But remember there
are no ‘rules’ – the
only limit is your
imagination!
4
Examples of ‘extreme targets’ which have been prepared by total synthesis.
H2NOC
Vitamin B12
Me
Me
H
H2NOC
O
N CNN
Me
Me
H
Co
N
N
Me
NH
HO
Me
O
P
O
O
O H
N
H
NH2
Me
Me
H CONH
2
Me
H
O
O
O
Me
H
H
O
H
O
H
H
H
H Synthesised by Nicolaou
in 1995.
O
H
OH
O
Me
N
O
Synthesised by Woodward
and Eschenmoser 1973.
O
O
O
H
H
O
H
H
H
O
O
O
O
H
Brevetoxin B:
A marine neurotoxin
O
H2NOC
O
HO
NH2
H
H
HO
OH
HO
HO
HO
H2N
OH
Vancomycin,
Antibiotic,
Evans, 1999.
O
O
O
O
N
H
O
HO2C
HO
O
O
OH
OH
O
O
O
O O
OH
O
H
N
N
H
H
OH
O
O Cl
H
N
NH
MeO
O
O
Cl
HO
Azadiractin,
insect antifeedant and
growth disruptor
O
Ley, 2007.
O
NH2
N
H
NHMe
Palytoxin is too big
to fit on this slide –
see the next slide!.
O
5
OH
O
HO
O
Me
H2N
HO
OH
O
OH
OH
O
OH
OH
OH
Palytoxin - toxic marine
natural product.
Synthesised by Kishi in 1994.
HO
OH
HO
OH
OH
OH
OH
O
O
HN
N
H
HO
OH
OH
OH
O
OH
OH
OH
O H
HO
HO
OH
OH
Me
O
HO
HO
Me
O
OH
O
Me
HO
OH
O
HO
OH
Me
OH
H
OH
OH
OH
HO
OH
HO
OH
"Synthesis of Palytoxin from Palytoxin Carboxylic-Acid". E. M. Suh and Y. Kishi, J. Am. Chem. Soc.
1994, 116 (24): 11205–11206. "Total Synthesis of Palytoxin Carboxylic-Acid and Palytoxin Amide".
R. W. Armstrong, J. M. Beau, Y. Kishi et al. J. Am. Chem. Soc. 1989, 111, 7530–7533.
6
Palytoxin – the power of protecting groups.
OPMB
Me
Me
I
PPh3
O
O
Me
PMBO
OPMB
THPO
OPMB
PMBO
OPMB
OPMB
i) (COCl)2, DMSO, Et3N
ii) nBuLi, THF, -78oC.
HO
iii) H2, Pd/C.
iv) TBAF ((Bu)4NF), THF
O
O
OPMB
O
OBz
O
PMBO
OPMB
OPMB
a similar sequence
of transformations.
PMBO
OPMB
Me
OPMB
OMe
O
O
OBz
BzO
BzO
OPMB
O H
OTHP
Me
Me
OPMB
PMBO
Me
O
OPMB
OBz
OPMB
O
OPMB
OPMB
BzO
BzO
O H
Me
BMPO
Me
OMe
OPMB
THPO
Me
OPMB
O H
+
OTBS
OTBS= OSiMe2tBu (sometimes called OTBDMS)
OPMB=CH2C6H4p(OMe) (paramethoxybenzyl)
OTHP=Otetrahydropyran.
OBz= OCOPh (benzoyl)
(in contrast OBn = OCH2Ph; benzyl).
OPMB
OPMB
O
O
Me
OPMB
OH
O
(convert to PPh3)
OBz
A list of protecting groups follows in a couple of slides, along with removal methods.
7
Eribulin – an anticancer drug which arose from the related halichondrin synthesis:
H
H
O
H
O
H
O
O
OH HO
H
O
H O
O
O
O
H
H
H
H
O
O
H
O
O
H
H
O
H
O
H
Halichondrin B - synthesis by Kishi, 1982.
O
H
H2N
OH MeO
H
O
O
H
Eribulinsynthetic anticancer
compound, approved O
in 2010.
H
O
O
H
H
O
O
H
O
Works by binding to
H
microtubules and
hindering mitosis.
O
H
(marketed as
Halaven)
Conclusion of total synthesis:
T. D. Aicher, K. R. Buszek, F. G. Fang,
C. J. Forsyth, S. Ho Jung, Y. Kishi, M.
C. Matelich, P. M. Scola, D. M. Spero
and S. K. Yoon, J. Am. Chem. Soc.
1992, 114, 3162-3164.
D. S. Kim, C. G. Dong, J. T. Kim, H. Guo, J. Huang, P. S.
Tiseni and Y. Kishi, "New syntheses of E7389 C14-C35 and
halichondrin C14-C38 building blocks: double-inversion
approach". J. Am. Chem. Soc. 2009, 131, 15636–15641.
8
Commonly used protecting groups:
OTMS=OSi(Me)3
OTBS= OSi(Me)2tBu (also called OTBDMS)
ROTHP =
OTPS=OSi(Ph)2tBu (also called OTBDPS)
O
RO
OTIPS=)Si(iPr)3
Silyl group are added using R3SiCl + amine base, removed using fluoride e.g. HF or (Bu)4NF
Ph
(TBAF). TMS can be removed with mild acid.
R2NtBoc =
O
R2NZ =
OPMB=CH2C6H4p(OMe) (paramethoxybenzyl)
O
R2N
R2N
OBn = OCH2Ph (benzyl).
Above are added using ArCH2Br + base, Bn removed by H2/Pd and PMB by using DDQ
(dichlorodicyanoquinone).
OTHP=Otetrahydropyran; added using THPOH and acid, removed with H2O/acid.
OBz= OCOPh (benzoyl) and OAc (acetate): added using anhydride or acid chloride,
removed with H2O/acid.
R2NFMoc =
NtBoc; add with Boc2O, remove with acid (CF3CO2H),
NZ = N(CO)OCH2Ph, add with chloride, remove by hydrogenation.
NFMoc; add via chloride, remove with base.
R2N
O
O
O
O
Vitamin B12 – strategic construction of large units. A very large target can soon be
broken down into smaller ones if a convergent strategy is used.
Vitamin B12
MeO2C
NH2
Me
Me
H
MeO2C
N CNN
Co
Me
Me
H
N
CNN
MeO2C
Me
Albert
Eschenmoser
ETH Zurich
Position of disconnection - or where a bond will be formed
in the synthetic direction.
O
CO2Me
Me
O
O
H
Me
O
MeO2C
CO2Me
Me
Me
H CO Me
2
HO2C
Synthesised by Woodward and
Eschenmoser, et al. 1973 (and
over 100 students and
researchers.
Me
O
O
R B Woodward
(Harvard)
Br
O
O
Me
Me
Me
H CO Me
2
S
Me
HO2C
R. B. Woodward, Pure & Appl.
Chem. 1973, 33, 145, A.
Eschenmoser and C. E. Winter,
Science 1977, 196, 1410. (and
other references).
HN
N
Me
Me
+
CO2Me
and
MeO2C
HO2C
In reverse - remove side chain
(this means it goes in last in the
synthesis).
N
NH
Me
Me
H
O
Me
Me
H
HN
CO2Me
S
Me
Me
HN
S
and
Me
Me
H CO Me
2
10
Brevetoxin B – a marine neurotoxin (‘red tide’ algae blooms)
multiple coupling steps for ring construction – some examples.
OTPS=Si(tBu)Ph2
BnO
K
HO
MeO2C
OTPS
NaH, THF
O
J
H
BnO
H
MeO2C
H
TPSO
H
O
HO
O
MeO2C
OTPS
H
BnO
OTPS
O
J
I
O
H
TPSO
K
O
O
J
BnO
H
OTPS
K
O
OTPS
OBn
H
O
J
H
HO
H
O
H
Camphorsulfonic
acid
OTPS
K
I
O
H
H
H
O
Cl
Cl
MeO2C
MeO2C
ClOC
OBn
Cl
Et3N
E
HO
HO
O
H
H
H
HO
O
A-G section
H
O
O
(EtO)2(O)P
H
O
O
H
iPr2NEt
O
H
H
O
H
O
O
H
H
O
O
H
H
OBn
G
F
then DMAP
H
O
O
OBn
H
O
H
OBn
O
H
O
OBn
O
H
O
H
H
H
You’d be expect to know, or be able to work out, the mechanisms of the reactions.
O
BnO
11
Brevetoxin B – multiple coupling steps for ring construction; synthesis completion.
TBSO
H
H
H
O
O
H
H
O
H
H
O
H
H
O
H
O
O
O
H
H
OTBS
O
O
H
EtS
OH
EtS
O
H
TBSO
O
H
AgClO4 SiO2
Ph3SnH, AIBN
H
H
O
O
H
H
O
H
H
H
H
O
H
O
H
H
O
Note what a variety of cyclisation
methods can be used.
TBSO
H
H
H
H
PPh3
i) nBuLi
ii) acid
H
O
OHC
O
H
OTMS
O
H
EtS
EtS
O
H
O
H
O
OTBS
O
H
O
OTBS
O
O
H
O
H
H
H
O
H
H
H
Reference: ‘The Total Synthesis of Brevetoxin B: A
Twelve-Year Odyssey in Organic Synthesis’ K. C.
Nicolaou, Angew. Chem. Int. Ed. 1996, 35, 588-607.
O
Professor K. C.
Nicolaou, Scripps
Research Institute
(California).
12
Vancomycin – aromatic ether coupling
strategies.
HO
HO
HO
H2N
OH
Vancomycin,
Antibiotic,
Evans, 1999.
O
O
O
O
O
N
H
O
O
H
N
O
NH
HO2C
OP OH
OH
O
H
N
N
H
O
NH2
N
H
NHMe
HO
O
N
H
O
HO2C
HO2C
HO
O
O
NH
OH
OH
N
H
O
O2N
F
OH
O
O
NH2
N
H
NH2
OP
OP
+
PO
H
N
N
H
H
N
NH
O Cl
H
N
O
O
OH
O
Cl
O
Cl
PO
O
OH
OH
HO
P=protecting group.
O Cl
O
Cl
HO
Professor David
Evans, Harvard.
NHMe
O
OP
O
H
N
HO
O
O
NH2
N
H
NHMe
O
Vancomycin is a powerful antibiotic which inhibits the formation of cell walls by
binding to terminal peptide chains.
13
Vancomycin – aromatic ether coupling strategies.
How could this be made?
O2N
F
Cl
HO
O
N
H
CF3
N
H
O
OMe
O
F
OH
O
Cl
O
N
H
O
O
NH
MeHNOC
HO
O
H
N
OH
OH
HO
CF3
OMe
OMe
MeHNOC
H
N
N
H
O
NHP
O
N
H
OH
H
N
NH
O
NH
O
CF3
OBn
OBn
BnO
O2N
F
O
OH
O
N
H
O
deprotect then
add:
+
NO2
O
OH
First step is reductive coupling
MeO
HO
NH
NH
MeO
OMe
O
Cl
O
MeHNOC
MeHNOC
F
Cl O
HO
then
NaBH(OAc)3
OBn
NH
VOF3
BF3.OEt2
AgBF4
CF3CO2H
O
HN
O
NO2
OP
O
H
N
HO
O
NH2
NHMe
N
H
NHMe
O
Two stages of aromatic ether formation.
Total Syntheses of Vancomycin and Eremomycin Aglycons, D. A. Evans, M. R. Wood, B. W. Trotter,
T. I. Richardson, J. C. Barrow, J. L. Katz, Angew. Chem. Int. Ed. 1998, 19, 2700-2704.
14
Azadirachtin – dealing with sensitive functionality. Selected for closer focus.
O
O O
O
O
OMe
O
O
O
O
O
H
AcO
MeO2C
OH
H
OH
O
H
H
HO
MeO2C
CO2Me
OH O
O
OH
O H
H
O
Deprotect OH
Eliminate to
alkene.
O
MeO2C
HO
Azadirachtin,
insect antifeedant and
growth disruptor
Ley, 2007.
add side chain
HO
OBn O
O
O
H
Deprotect OH
and replace with OAc
TBSO
MeO2C
H
OBn OMe
O
O
O H
reduce
‘The Azadirachtin Story, by G. E.
Veitch, A. Boyer and S. V. Ley,
Angew. Chem. Int. Ed. 2008, 47,
9402-9429.
Prepared by S. V. Ley and
Colleagues in 2007.
15
Azadirachtin – dealing with sensitive functionality.
MOMO
AcO
AcO
O
OAc
O
Commercially available carboydrate derivative.
PMBO
OBn
Br
i) DIBAL-H
ii) MeOH, acid
H
O
Br
H
O
PMBO
OBn
Br
OMe
O
O
i) CF3CO2H to remove TBS
O
TBSO
AcO
Br
OBn
OAc
O
O
H
mixture formed but
separation not required.
ii) SO3.py to oxidise.
iii) Ph3PCHBr2, tBuOK
i) MeLi.LiBr.
ii) iPrMgBr
(CH2O)n
iii) Ms2O
iPr2NEt
OPMB
OBn
H O
OMe
O
MsO
A key step - learn mechanism
16
Azadirachtin – Decalin construction.
OMe
OMe
OTBS
HO
CO2Me
then F-
S
H
PhMe2Si
Key step to
learn and
understand.
S
H
MeO2C
The selectivity is reversed if the
silane is not present.
OH
S
O
H
O
pTsOH/H2O
OH
HO
S
H
OH
S
MeO2C
Ph
O
O
H
O
O H
OBn
O
O
H
MeO2C
MeO2C
CN
O
O
S
2.4:1 preference for this isomer.
O
MeO2C
S
PhMe2Si
PhMe2Si
H
Ph
Tebbe
reagent
S
S
O
OMe
OMe
O
Diels-Alder
reaction
S
PhMe2Si
H
OMe
OMe
O
CO2Me
PhMe2Si
O
O
CO2Me
S
CO2Me
OMe
OMe
O
OH
Br
PhMe2Si
S
OMe
OMe
MeO2C
TESO
H
H
H
O
O H
OBn
O
TESO
MeO2C
H
O
O H
17
Azadirachtin – synthesis completion.
All steps except the last one in this sequence are key material to study and understand.
MeO2C
TESO
MsO
OBn
O
H
H
O
O H
ii) 185oC, or
gold catalyst.
H
H
TESO
MeO2C
H
O
O H
MeO2C
Radical
cyclisation
Bu3SnH, AIBN,
toluene, 100oC.
HO
MeO2C
H
OBn
O
H
O
O
O
O H
MeS
H O
H
H
O
OBn .
O
S
OBn OMe
O
O
O H
MeO2C
OBn OMe
O
H
TBSO
H
i) add TBSCl
OPMB
HO
OBn OMe ii) DDQ, DCM
iii) CS2, base
O
O
then MeI.
TBSO
MeO2C
OBn .
O
H
HO
MeO2C
OPMB
OBn OMe
MeO2C
MeO2C
HO
OBn
O
O
O
i) TBAF; removes
TES groups.
MeO2C
TESO
NaH, [15-crown-5], 0oC
H
TESO
MeO2C
OPMB
OBn OMe
O
O H
HO
OBn O
O
OBn OMe
epoxidise
O
H
O
TBSO
MeO2C
H
O
O
O H
18
2) Early classics of total synthesis in organic chemistry, which may include colchicine,
morphine, strychnine, thienamycin and penicillin.
Colchicine,
various biological
properties,
MeO
Strychnine
Toxic alkaloid.
Woodward 1954.
HO
OMe
OMe
MeO
O
Morphine,
Analgesic, O
Gates 1952.
H
H
NMe
H
N
H
HO
NH
N
H
O
H
H
O
O
Thienamycin
Antibiotic.
OH
H H
Penicillin V
Antibiotic.
Sheehan 1957.
H H H
N
S
PhO
O
O
O
CO2H
Me
N
H H H
N
S
HO2C
S
N
N
Cephalosporin C
Antibiotic.
NH2
CO2H
NH2
O
N
OAc
O
HO2C
Tropinone
Precursor to more
complex alkaloids including
atropine, cocaine etc
Robinson 1917.
O
19
Tropinone: A classic synthesis.
Sir Robert
Robinson.
Nobel Prize
1947.
Tropinone A small but important alkaloid and precursor of other drug molecules.
Robinson 1917.
Me
N
O
NMe
MeNH2
O
O
O
The power of basic
condensation reactions.
O
Try to draw the mechanism
Ca2
An actual synthesis:
+
O
+ MeNH2
?
Me
N
O2C
O
CO2H
O2C
HO2C
CO2H
OH
Me
N
(-2 CO2)
O
NMe
NaOH then
HCl
O
O
CO2H
CO2H
NMe
NMe
O
O
H
H
OH
CO2H
OH H
CO2H
PhD Manchester 1910,
Sydney 1912-1915,
Manchester 1915-1920,
Director of Research at
the British Dyestuffs
Corporation 1920-21,
StAndrews 1921-1922,
Manchester 1922-1928,
London 1928-1930,
Oxford 1930-1955.
CO2H
Birch, A. J. (1993). "Investigating a Scientific Legend: the Tropinone Synthesis of Sir Robert Robinson, F.R.S".
Notes and Records of the Royal Society of London, 1993, 47, 277–296.
20
Colchicine; Deceptively simple but actually very challenging.
An early synthesis of colchicine (Eschenmoser et al 1959):
HO
i) Me2SO4
ii) H2 Pd/C
MeO
HO
iii) LiAlH4
iv) H3PO4
MeO
OH
OH O
Purpurogallin (available
starting material)
CO2Me
Et3N
i)
ii) MeI
O
OH
MeO
MeO
(step i) proceeds via
initial OH alkylation)
O
OMe
Cl
O
o
175 C
tBuOK
tBuOH
MeO
MeO
OMe
CO2Me
O
O
i) H2SO4 then
MeO
CH2N2.
MeO
O
Cl
MeO
CO2Me
OMe
CO2Me
Cl
MeO
O
OMe
H CO2Me
O
H
O
Many steps.
MeO
MeO
CO2Me
OMe
MeO
MeO
OMe
CO2Me
O
Colchicine,
i) N bromo
MeO
O
succinamide,
NH
(PhCO2)2
MeO
ii) NH3, EtOH.
OMe
iii) KOH, EtOH.
OH iv) CH2N2
O
racemic
v) Ac2O
OMe
BBC Science news 12th Sept 2011: ‘The native British Autumn crocus, is recorded
in early herbal guides as a treatment for inflammation. This is because it contains
the potent chemical colchicine, which is known to have medicinal properties,
including anti-cancer effects.’ (reporting on anew drug delivery method).
Features in MT
course CH408
21
Colchicine
A more recent synthesis of colchicine (Graening and Schmalz, 2005):
O
MeO
MeO
OH
MeO
Enantioselective
reduction using
chemical
MeO
catalyst.
O
TMS
I
2 steps.
MeO
TMS
I
OMe
MeO
OMe
MeO
OTBS
i) L-selectride
(H- source)
OH
ii) TMSOf then
K2CO3, MeOH.
MeO
OMe
I
OMe
i) iPrMgCl O
DMSO,
(CF3CO)2O
then Et3N.
OTBS
O
ii) iBuOCOCl then
CH2N2.
OTBS
O
MeO
MeO
OTBS
MeO
OMe
OH
[Rh2(OAc)4]
reflux
O
O
MeO
OMe
N2
O
O
(last steps are from Banwell synthesis)
MeO
OTBS
MeO
OMe
O
OH
i) MeI, K2SO4, ii) TBAF.
iii) Zn(N3)2.py DIAD, PPh3 *
iv) PPh3, H2O.
v) Ac2O, pyridine.
* Mitsunobu reaction
Colchicine,
MeO
O
NH
MeO
OMe
enantiomerically pure.
O
OMe
Total synthesis of colchicine in comparison:
By: Graening, Timm; Schmalz, Hans-Guenther , Angew Chem Int Ed. 2004, 43, 3230-3256.
22
Synthesis of Penicillins and related antibiotics.
Penicillin V
Antibiotic.
Sheehan 1957.
H H H
N
S
PhO
O
Thienamycin
Antibiotic.
OH
H H
N
Cephalosporin C
Antibiotic.
S
N
O
NH2
NH2
O
CO2H
CHO
+ H N
2
O
O
PhO
CO2H
H
S
HN
amide
formation
OAc
O
O
CO2H
OH
N
O
OH
S
H H H
N
S
PhO
CO2H
H
HN
O
O
O
O
H
N
OtBu
H H
N
N
O
HS
H
N
O
HO2C
CO2H
O
Penicillin V
a synthesis that
uses classical
condensations
and amide
formations.
H H H
N
S
HO2C
CO2H
Mechanistic challenge:
H H H
N
S
R
O
O
N
O
penicillin core
[O]
H H H
N
S
R
N
OAc
O
CO2H
cephalosporin core
CO2H
John S Sheehan
From Time Magazine, March 1957; ‘After nine years of dogged work, Chemist John C. Sheehan of M.I.T. 23
announced last week that he had discovered a practical method of synthesizing penicillin V.’
The synthesis would not compete with microbiological methods for Pencillin, but allows analogues to be made.
Morphine and related alkaloids.
Morphine,
Analgesic, O
Gates 1952.
H
MeO
AcO
HO
Codeine
Heroin,
O
H
H
H
O
NMe
NMe
H
H
H
Ph
O
NH
HN
Pd
PPh2 Ph2P
CO2Me
Morphine,
Cl3C
O
Analgesic,
+
Trost, 2002.
O
(an asymmetric
synthesis)
(racemic)
Br
MeO
Palladium catalysed
asymmetric allylation
OH
Professor Barry
Trost (Stanford).
O
MeO
MeO
O
Br
CO2Me
O
Br
CN
H
H
MeO
H
Ph
O
O
Combination of Pdcatalysed asymmetric
reactions and coupling
reactions.
H
HO
AcO
HO
NMe
Pd-catalysed
intramolecular
Heck reaction.
Pd(OAc)2
diphosphine
"Enantioselective Synthesis
of (-)-Codeine and (-)Morphine", Trost, B.M.;
Tang, W. J. Am. Chem. Soc.
2002, 124, 14542.
HO
MeO
Cyclise NMe
onto alkene
O
H
CN
H
O
H
HO
H
NHMe then remove
OMe->OH
O
H
NMe
H
H
24
HO
Morphine
Strychnine – selected for closer analysis.
Key step here is the transformation
Of A to B.
N
Strychnine
Toxic alkaloid.
first by Woodward
1954.
The synthesis here is
by Overman 1995.
H
N
H
O
H
H
H
N
O
HN
OtBu
H
H
OH
NR2 =
N
NMe
O
NMe
NR2
N
HO
NR2
H
HO
NR2
OtBu
A
N
H
HO
NR2
OtBu
H
OtBu
L Overman
N
N
HO2C
N
CO2H
H
H
O
NR2
OtBu
B
N
H H
HO
H
H
H
O
N
Ac2O, NaOAc, AcOH
O
H
H
H
O
Wieland-Gumlich aldehyde.
S. D. Knight, L. E. Overman and G. Pairaudeau, J. Am. Chem. Soc. 1993, 115, 9293–9294 . 25
Key steps are from A to C (via B).
Shibasaki synthesis of strychnine
Strychnine
Shibasaki synthesis
2002..
CO2Me
O
I
Asymmetric
catalyst
H
CO2Me
+
CO2Me
O
CO2Me
EtS
HO
OTIPS
EtS
i) Tf2O
O
O
NO2
H
EtS
ii)
EtS
OPMB
OSEM
H
OPMB
OH
H
N
Zn, MeOH
NH4Cl
O
NO2
NH2
H
OSEM OPMB
A
EtS
EtS
N
EtS
N
EtS
DMTSF
H
O
NH2
N
H
H
OSEM OPMB
B
C
OSEM OPMB
N
N
EtS
H
N
Ac H
HO
H
E
OTIPS
N
Ac H
HO
(undefined
reagent which
supplies
equivalent of
H+)
H
remove
TIPS
OTIPS
steps
N
D
H
OSEM OPMB
N
oxidation
of alcohol
NiCl2, NaBH4
N
EtS
as before
H
N
Ac H
HO
Strychnine
H
H
O
T. Ohshira, Y. Xu, R. Takita, S. Shimizu, D. Zhong and M. Shibasaki, J. Am. Chem. Soc, 2002,
124, 14546-14547.
Strychnine synthesis by Vanderwal, 2011.
Strychnine
Synthesis byVanderwal and Martin, 2011.
longest linear sequence of six steps!
Chem. Sci. 2011, 2, 649-651.
O2N
N
H
N
H
Key step
N
O
N
H H
O
O
TMS
O
N
NaHMDS, NMP
then CuBr.SMe2
5-10% yield.
O
O
OH
N
N
H H
O
NH
Pd(PPh3)4
THF, 0.02M
80oC
N
H
NO2
81% based on pyridinium
salt, 100% recovery of excess
s.m.
N
KOtBu
N
OH
Br
TMS
iPrNEt2 69%
N
H H
O
HO2C
CO2H
H
N
H H
HO
N
H
H
O
H
Wieland-Gumlich aldehyde.
N
Ac2O, NaOAc, AcOH
H
(known process)
O
D. B. C. Martin and C. D. Vanderwal, Chemical Science, 2011, 2, 649-651.
H
H
O
27
Strychnine synthesis by Andrade, 2010.
Strychnine
Approach to closely related
akuammicine by Andrade et al, 2010.
O
O
MgSO4
Br
O
NBn
Br
O
N
H
N
H
+
MeO
OTMS
CO2Me
A
O
NBn
NBn
DBU
(base)
N
CO2Me
B
N
H H
C
i) Reduction of
the C=O bond.
ii) debenzylation
N
NaBH3CN
AcOH
NaOMe,
MeOH
(epimerises)
OTBS
N
H
H H
MeO2C
CO2Me
D
K2CO3
N
DIBAL-H,
toluene
(known
process)
H
N
H H
HO
OH
Pd(PPh3)4
PPh3, Et3N
N
H H
N
H
N
H
H
MeO2C
I
OTBS
CO2Me iii)
OTBS
N
Br
I
E
NBn
AgOTf
N
H
O
Br
NBn
Cl
BnNH2
N
H
Key steps are from A to
C and from D to E.
Strychnine
H
O
H
Wieland-Gumlich aldehyde.
G. Sirasani, T. Paul, W. Dougherty Jr., S. Kassel and R. B Andrade, J. Org. Chem. 2010, 75, 3529-3532.
28
3) Lessons learnt from the synthesis of small important organic molecules which may
include hirsutene, periplanone B, epothilones and prostaglandins.
Periplanone B
Pheromone
O
O
Hirsutene.
H
O
S
O
H
Epothilone A
Anti cancer
1996/7.
HO
N
H
O
O
Prostaglandins (E2 illustrated)
Various biological functions.
O
CO2H
HO
OH
O
Grandisol
male cotton boll weevil pheromone
OH
OH
CH3
29
Intramolecular epoxide opening reactions
The synthesis of Grandisol, the pheromone of the male cotton boll weevil, and
closely-related compounds, has been achieved in a very concise synthesis using
a key epoxide-opening step. The high level of ring strain provides a means for
the synthesis of similarly strained targets:
OMe
OMe
I. Petschen, A. Parrilla, M. P.
Bosch, C. Amela, A. A. Botar, F.
Camps and A. Guerrero, Chem.
Eur. J. 1999, 11, 3299-3309
O
O
CN
CN
NaOMe
O
O
base
OMe
OMe
4-exo-tet
O
O
H
mCPBA =
O O
H
Cl
HO
O
CN
O
CN
OH
'steps'
CH3
Grandisol
(racemic product is formed,
but this is the correct
diastereoisomer)
30 30
Hirsutene – radical cyclisation approach by Curran.
H
Hirsutene.
I
I
H
Li Naphthalenide
(reduces bromide)
OTHP
O
H
H
H
H
OTHP
i) sulphonic acid
ii) LiAlH4
O
H
H
HO
CO2H
then CuBr.SMe2
Br
H
H
(CF3SO2)2O
pyridine.
nBu4N
OH
I
I
TMS
Li
H
H
I
H
H
Radical
cyclisation
I
H
H
H
H
nBu3SnH
AIBN
H
H
D. P. Curran and D. M. Rakiewicz, Tetrahedron 1985, 41, 3943-58.
D. P. Curran and D. M. Rakiewicz, Donna M, J. Am. Chem. Soc. 1985, 107, 1448-9.
31
Periplanone B. – approach by Still.
OEE =
O
O
HO
O
O
Li
KH, 18-C-6
TMSCl
Et2O
EEO
EEO
TMSO
mCPBA
EEO
OH
TMSO O
i)TBSCl,
imidazole, DMF
O
EEO
ii) tBuOOH
EEO
EEO
Periplanone B
Pheromone - Still 1979.
OTBS
O
H2C
O
EEO
SMe2
OTBS
O
DMSO/THF
O
O
O
O
EEO
W. C. Still, J. Am. Chem. Soc. 1979, 101, 2493-2495. M. A. Adams, K. Nakanishi, W. C. Still,
E. V. Arnold, J. Clardy, C. J. Persoons, J. Am. Chem. Soc. 1979, 101, 2495- 2498.
32
Prostaglandins – approach by Corey.
A classic synthetic approach:
Prostaglandins (E2 illustrated)
Various biological functions.
MeO
KOH, H2O
MeO
DMSO
MeO
+
Cl
Cu(II)
Cl
CN
HO
mCPBA
O
O
CN
O
O
O
O
O
O
NaOH, H2O
MeO
KI3
I
OMe
HO
O
OMe
HO
HO
P(O)(OMe)2
OH
O
O
O
O
N aH, DME
HO
THPO
O
OTHP
O
Ph3P
+ base
CO2H
CO2H
then oxidation.
HO
OH
E. J. Corey, N. M. Weinshenker, T. K. Schaaf J. Am. Chem. Soc. 1969, 91, 5675-5677.
This process has been significantly developed by Corey since the initial report.
33
Discussed in MT
course for binding metathesis
And structural
variation but not
synthesis.
Epothilones - This to be the focus of Section 3.
Epothilone A R=H
Epothilone B R=Me
(a very extensive range
now discovered and
prepared by synthesis)
Anti cancer
Epothilone C R=H
Epothilone D R=Me R
O R
S
S
OH
N
O
OH
N
O
O
OH
O
O
OH
O
In the biological synthesis, the compounds are produced by polyketide synthase multienzyme
complexes which pass the growing chain from domain to domain until an intramolecular
cyclisation completes the synthesis and releases the product from the enzyme. The epoxidation
is the last step after this cyclisation. Epothilones can be prepared by cloning and expressing the
genecluster in myxococcus xanthus.
First isolated in early 1990s from soil bacterium Sorangium cellusum and found to
possess antfungal activity. In 1993, they were found to possess antitumour activity in a
screen run by MSD. Epothilone B was even more active than taxol and share the same
binding site on tubulin. First synthesised in 1996-7. Can be prepared by fermentation
processes. Tubulin is a polymeric, tube-shaped protein which for the ‘mititic spindle
when cells divide – this controls the correct separation of DNA into the daughter cells.
Like Taxol, epothilones bind to the tubulin in the microtubules and interfere with their
operation, thus preventing mitosis. Like many anticancer drugs, epothilones are highly
cytotoxic. More information on biological action in M. Tosin’s CH408 course.
34
Epothilones – synthetic strategies.
Strategies towards epothilones:
Make bond by metathesis
epoxidation - late in synthetic
direction.
R O
R
condensation?
S
S
HO
N
O
O
OH
O
HO
N
Create with
aldol reaction.
O
O
OH
O
Create with
aldol reaction.
Make bond by
macrolactonisation
Semisynthesis represents
A viable approach to new analogues.
The majority are made by derivatisation.
Note the amide version too.
Key review: J. Mulzer, K.-H. Altmann, Höfle, R. Müller and K. Prantz, COMPTES RENDUS
CHIMIE. 2008, 11, 1336-1368.
35
Epothilones – metathesis approach.
Nicoloau 1996 synthesis:
S
OTBS=OSiMe2(tBu)
(remove with Fluoride F-)
N
OH
O TBSO
+
2 eq. LDA HO
O
OH
-78oC
(aldol)
O
OH
O TBSO
Grubbs
metathesis
catalyst
S
HO
EDCI
DMAP
O
S
HO
N
N
O
O TBSO
O
(3:2 with other
trans isomer)
O (1.2:1 E:Z)
Key Step
O TBSO
Epothilone C
Epothilone A
S
HF/pyridine
HO
N
O
O
OH
O
O
O
S
DMDO
HO
O
N
O
O
O
OH
(3:1 ratio)
O
36
Epothilones – alkyne metathesis approach.
Key steps are the conversion of A to
B, and B to C
i) Acid (hydrolyse
acetal)
ii) TBSOTf
iii) Acid
Furstner synthesis, 2001.
O
HO
EtO
OH
O
O
OTBS
O
O
iv) PDC
LDA, THF
O
(prepared by an
asymmetric
hydrogenation)
O
O
S
A
HO
O
OH
HO
HO
OH
N
O
DCC, DMAP,
DCM, 81%
O
O
S
HO
N
O
O
OH
O
Mo-based (Schrock)
metathesis catalyst.
S
N
OH
B
O
Lindlar catalyst
quinoline
1 atm H2
S
HO
N
O Epothilone C
HF, Et2O
C
O
OH
O
37
Epothilones – Aldol approach.
Prof Samuel Danishefsky,
Columbia University and the
Memorial Sloan-Kettering
Cancer Center (New York)
Key step is conversion of A to B.
An early but ingenious intramolecular aldol reaction approach by Danishefsky:
S
I
9-BBN
N
BR2
TBSO
O
OMe
TPSO
S
O
TBSO
PdCl2(dppf), CsCO
3
Ph3As
N
iii) TBSOTf
O
pTsOH
TPSO
OMe
S
TBSO
N
i) KHMDS
ii) HF.py
O
A
O
S
i) Oxidation.
ii) Deprotection
HO
N
O Epothilone C
O
OH
OTBS O
B
O
OH
O
38
Epothilones – lactonisation approach.
A large scale industrial synthesis of a
synthetic epothilone analogue now in
clinical trials as anti-cancer drug.
Ph 3P
S
i) NaHMDS
N
S
O
OTBS
THPO
ii) pTsOH
iii) Swern oxidation.
N
(note-E:Z mixture is
formed but unwanted
isomer is isomerised
to required one)
O
OTBS
LDA, ZnCl2
S
HO
O
O
N
O
OTBS
O
S
HO
N
O TBSO
A
O
Deprotection of
acetal/TBS and
oxidation to acid.
O
O
O
'i) Yamaguchi lactonisation'
ii) HF-py
iii) DMDO (7:1)
HO
S
N
O
OH
OH
O
OH
O
ZK-EPO
(sagopilone).
B
Key step is the Aldol reaction from A to B.
39
4) Molecules with a high degree of functionality, which may include avermectin,
erythromycin, amphotericin B and strychnine (covered in part 2).
Avermectin (B1a illustrated)
Insecticides.
1986,87..
MeO
O
O
Me
O
O
O
O
O
Me
HO
Me
H
Erythromycin
aglycone
OH
Me
OH
O
(in the full
molecule, two
carbohydrates
are attached
to OHs *)
Me
H
OH
MeO
OH *
O
Me
OH
H
Amphtericin B
Antifungal.
1987.
OH *
O
O
OH
Me
Strychnine
Toxic alkaloid.
Woodward 1954.
OH
OH
O
N
OH
H
HO
O
OH HO
HO
OH
O
N
CO2H
O
O
O
HO
NH2
H
H
H
O
OH
40
Avermectins - retrosynthesis.
Avermectin (B1a illustrated)
Insecticides.
MeO
H
O
H
O
O
O
O
MeO
O
H
O
OH
O
H
H
O
OH
MeO
OH
O
O
O
MeO
O
O
O
O
O
O
O
OH
OH
O
H
OH
First discovered when a scientist notice a healthy patch of grass
on a golf course! Analysis of the sample produced a bacteria
which produced the Avermectins. These act as insecticides and
as treatment for internal and external parasites in livestock.
Almost no toxicity to humans.
41
Avermectin – Hanessian route.
TBSO
Synthesis by
Hanessian
(to aglycone):
HO
H
i) nBuLi to acetylene then
add lactone.
O
O
+ TMSO
H
H
O
O
BnO
H
TBSO
O
O
H
H
H
SO2Ph
H
O
OH
CO2H
OH
Couple fragments
then deprotect.
O
H
H
HO
O
O
O
H
O
DCC, DMAP
Completion requires
addition of sugars and
double bond rearrangement
S. Hanessian, A. Ugolini, D. Debé, P. J. Hodges and C.
André, J. Am. Chem. Soc. 1986, 108, 2776-2778.
H
O
OH
O
H
OH
OTMS
base, then SOCl2 then
reductive eimination
(Julia olefination)
OTBS
OTBS
HO
TMS
CO2Me
O
O
OTBS
O
O
O
PhO2S
i) (PhS)2, PPh3
ii) mCPBA.
H
OTBS
OTBS
H
O
ii) Pd/ BaSO4 H2.
iii) BF3.Et2O.
iv) TBAF.
OH
Professor Stephen
Hanessian (University of
Montreal).
42
Amphotericin B – focus of this section. Key disconnections and approach.
Amphtericin B
Antifungal.
1987.
OH
OH
O
HO
O
OH HO
HO
OH
O
O
HO
OH
CO2H
O
OH
NH2
OP
OMe
HO
O
OP PO
PO
OH
OP
O
OP
CO2Me
MeO
MeO P
PO
O
O
O
X
O
form alkenes here
PO
OP
NP2
P=protecting group
X=leaving group.
43
Key step is the WadsworthEmmons reaction.
Amphotericin B – focus of this section. Nicolaou approach.
First step;- Sharpless asymmetric epoxidation.
O
O
OH
Ph
O
Ph
O
O
OH
OH
Ph
Ph
O
O
OH
Ring open epoxide then
oxidise to CHO
then PPh3P=CHCO2Me
then reduce to alcohol
HO
O
Ph
Ph
O
OH
O
OTBS
O
Ph
OH
O
OH
Steps
RedAl
HO
O
O
Ph
Ph
OSi(tBu)Ph2
Ph
O
HO
OH
OH
O
O
Ph2(But)SiO
OH
MeO OMe
O
BnO
P
H
O
O
HO
O
+
OTBS
O
O
O
O
i) WadsworthEmmons
O
ii) further conversions
Both could be made by starting from each enantiomer
of the sugar xylose, however the favoured method involved
a Sharpless allylic epoxidation
OMe
O
OTBS
O
O
OTBS O
CO2Me
MeO
MeO P
O
O
K. C. Nicolaou, R. A. Daines, J. Uenishi, W. S. Li, D. P. Paphatjis and T. K. Chakraborty, J. Am. Chem.
44
Soc. 1988, 110, 4672-4685. (the completion is described in the two papers which follow this).
Amphotericin B completion of the synthesis.
Key step is the Intramolecular
cyclisation reaction of A to B.
OH
HO
PO
O
O
OMe
O
OTBS
O
O
O
OTBS O
CO2Me
MeO
MeO P
O
Couple fragments together
using DCC and DMAP.
O
O
O
PO
O
OMe
O
OTBS
O
O
P=protecting group
X=leaving group.
A
DBU, LiCl or K2CO3.
OTBS O
O
O
MeO
MeO
CO2Me
O
O
PO
P
O
OMe
O
O
O
OH
O
ii) add
OH
AcO
HO
O
OH HO
HO
OH
O
CO2H
OTBS O
O
i) Reduce C=O,
deprotect
OH
OTBS
O
CO2Me
B
NH
CCl3
X
O
OTBS
N3
iii) complete
O
O
HO NH2
OH
45
A. M. Szpilman, D. M. Cereghette,
N. R. Wurtz, J. M. Manthorpe and
E. M. Carreira, Angew. Chem. Int.
Ed. 2008, 47, 4335-4338
Amphotericin B; Carrerira synthesis of polyol structure:
O
O
OTBS
OtBu O
Enantiomers
O
O
(EtO)2(O)P
H
BnO
O
H
CO2Et
N2
O
BnO
O
O
O
N-methyl
ephedrine
(chiral directing
agent).
OtBu
O
OtBu
O
TBSO
i) H2, Pd/C, MeOH
ii) TBSCl, Imidazole
O
O
Zn(OTf)2,
O
+
K2CO3, MeOH
O
OtBu
O
O
HO
BnO
TBSO
O
O
BnO
O
O
O
OtBu
O
O
The key step is conversion of A to B.
TBSO
i) LiAlH4, THF
ii) TEMPO, NaOCl
BnO
N
O
O
B
XN=chiral auxiliary group
O
O
O
XN
O
O
HO
MeO
(Bu3Sn)2O, tBuOCl.
i) LiOOH
ii) MeOH,
EtOAc
O
XN
O
O
O
A
TBSO
O
HO
OH
MeO
iii) HONH2.HCl, py
BnO
N
TBSO
BnO
iii) Mo(CO)6
MeCN/water
O
O
OH
O
O
O
MeO
OH
CO2Me
46
O
Amphotericin B; Krische iterative polyol synthesis:
Aspirational approach to polyol synthesis - how could this be done:
OH
OH
OH
O
O
OH
OH
O
O
O
O
O
O
OH
Answer - it can (Krische synthesis of (+)-Roxaticin (related to amphotericin B) from 2010:
Repeat twice
with S-enantiomer
of chiral catalyst.
10 mol%
O
O
Cl R enantiomer
Ph2
P
of catalyst.
OMe
>99% ee with a 30:1
OMe
preference for this
isomer over the meso.Protect the diol
then
OH OH
Cl
Ir
Ph2P
OH
OH
O2 N
OH
O
OH
Cl
oxidise alcohols.
OAc Cs2CO3, 110oC
H
H
Ir
Ir
O
- OAc
Ir
(abbreviated
catalyst)
OAc
OAc
OH
H
H
H
Ir
O
H
OH
O
Ir
H
H
OH
O
Ir
OH
OH
+
H
Ir
OAc
47
Amphotericin B; Krische iterative polyol synthesis:
Key step is conversion of A to B.
Next steps in the synthesis:
Elimination
OH
O
O
O
O
O
O
OH
OH
O
O
O
O
O
O
Grubbs
metathesis
catalyst
PMBO
Ir catalyst again
OAc
3 eq.
O
O
O
O
HO
O
B
O
O
O
O
O
O
OH
O
PMBO
O
A
O
O
O
PMBO
O
(+) Mycotocin A
O
HO
O
O
Michael Krische
University of Texas
at Austin.
Added in 3 stages.
S. B. Han, A. Hassan, I. S. Kim and M. J. Krische, J. Am. Chem. Soc. 2010, 132, 15559-15561.
48
5) Construction of highly complex structures which may include ginkgolide B,
calicheamycin, taxol.
O
HO
Calicheamicin - anticancer molecule
NHCO2Me
MeSSS
O
I
O
S
O
OMe
O
OH
OMe
MeO
O
O
H
N
O
HO
O
NHO
H
H
Nicolaou, 1992
Ginkgo tree in
Kew gardens.
O
MeO
HO
AcO
NHBz O
O
OH
Ph
O
OH
HO
H
Taxol - anti cancer molecule
O
AcO
O
Nicolaou, Holton 1994
Ph
Features in MT course,
Including biosynthesis,
Semisynthesis and binding.
O
O
Ginkgolide B
1988
O
O
HO
H
HO
O H
O
H
HO
O
O
49
Calicheamycin – intramolecular cyclisation.
Calicheamicin - anticancer molecule enediyne component.
O
O
N
O
O
Et3SiO
O
N
Et3SiO
CO2Me
O
MeO
O
SiMe3
O
Mo(CO)6,
then K2CO3
O
NH2
Et3SiO
H
MeO
O
O
Me3Si
O
i) Pyridine +
O
COCl
COCl
ii) SiO2
iii) Ac2O
O
O
O
NHCO2Me
O
H
ii) MeNHNH2
iii) (Cl2CO)3
pyridine.
H
OMs
BzO
RO
O
O
NHCO2Me
Et3SiO
NaBH4
i) SiO2 pyridine
O
DIBAL-H
PhCOCl
O
KN(SiMe3)2 MeO
(base)
O
then MsCl/pyridine
O
O
Nphth
Et3SiO
O
H
MeO
Et3SiO
O
Nphth
Et3SiO
O
N
Nphth =
H
HO
NHCO2Me
MeSSS
RO
H
Chemistry and Biology of Natural and Designed Enediynes, K.C. Nicolaou, A.L. Smith, E.W. Yue,
Proc. Natl. Acad. Sci. USA 1993, 90, 5881-5888.
50
Alleviates asthma symptoms
(and other medicinal properties)
Ginkgolide B.
MeO
E J Corey
(Harvard)
i) Pd coupling to
O
O
O
O
TfO
ii) (cHex)B)2H,
iii) AcOH, H2O2.
iv) 1N HCl.
MeO
O
O
O
i) (COCl)2
ii) nBu3N, heat.
Ph3COOH
NaOH
H
(BaeyerVilliger)
O
(via a [2+2]
cycloaddition)
H
H
O
O
O
several
steps
MeO
O
O
OMe
O
several
steps
O
OH
OH
MeO
CSA
O
HO
H
HO
O H
O
(acid)
O
O
H
O
O
E. J. Corey, M. C. Kang, M. C. Desai, A. K. Ghosh and I. N. Houpis
J. Am. Chem. Soc., 1988, 110, 649–651
O
H
HO
O
O
51
Nicolaou route: Key step is
conversion of A to B.
Taxol – selected for close analysis.
AcO
AcO
CN
TBSO
Cl
130oC
CN
N NHSO2Ar
Cl
O
O
O
OH
+
O
(Diels-Alder)
CO2Et
OH
O
O
PhB(OH)2 90oC
EtO2C
O
A
O
BPh
O CO2Et
B
Ph
O
(Endo TS)
O
O
O
O
HO
OH
OH
EtO2C OH
OH
B
OTBS
O
Features in MT course,
Including biosynthesis,
Semisynthesis and binding.
O
O
HO
EtO2C
O CO2Et
B
Ph
O
H
H
OBn
O
O
CO2Et
O
OH
O
HO
‘The Conquest of Taxol’, K. C. Nicolaou and R. K. Guy, Angew. Chem. Int. Ed. 1995, 34, 2079-2090.
52
Key steps are conversion of A to B, and
of C to D.
Taxol – Nicolaou route.
O
TBSO
i) nBuLi
(shapiro reaction)
H
O
A
OBn
O
N NHSO2Ar
HO
O
TBSO
OBn
O
H
O
O
O
C
OTES
HO
HO
O
Ph
O
H
AcO
O
OTES
Removal of silyl groups
(use fluoride).
O
O
O
D
AcO
NHBz O
O
OH
Ph
Ph
H
O
BzN
O
O
O
O
AcO
OBn
TiCl3.DME
Zn-Cu
McMurry
Coupling
H
O
O
HO
OH
O
OTBS
OBn
B
OTBS
ii)
O
OH
HO
H
O
O
AcO
O
Ph
53
AcO
AcO
NHBz O
O
NHBz O
O
OH
Ph
O
N
OH
Ph
O
O
O
O
HO
Me
H
O
O
AcO
HO
O
AcO
SO2
O
O
CO2Me
Ph
H
AcO
Ph
water soluble Taxol prodrugs.
NEt2
Bioactive fluorescent taxoid.
O
AcO
NHBz O
O
H
N
O
Ph
O
O
OH
HO
S
O2
NEt2
H
O
O
AcO
O
Ph
Taken from:
‘The Conquest of Taxol’, K. C. Nicolaou and R. K. Guy, Angew. Chem. Int. Ed. 1995, 34, 2079-2090.
O
Taxol - Holton route.
Key step is conversion of A to B.
OTES
OTES
O
O
OH
OH
O
A
OTES
OTES
OTES
H
O
O
H+
H+
OH
O
OTES
HO
O
NHBz O
O
OH
O
OH
HO
H
AcO
OTES
O
Professor Robert
Holton, Florida
State University.
AcO
Ph
Ph
O
B
BzN
O
HO
O
Ph
H
O
AcO
HO
H
O
O
AcO
O
Ph
R. A. Holton, H.-B. Kim, C. Somoza, F. Liang, R. J. Biediger, P.D. Boatman, M. Shindo, C. C. Smith, S.
Kim, H. Nadizadeh, Y. Suzuki, C. Tao, P. Vu, S. Tang, P. Zhang, K. K. Murthi, L. N. Gentle and J. W. Liu,55
J. Am. Chem. Soc. 1994, 116, 1599-1600.
Key steps are conversion of
A to B and C to D.
Taxol - An approach to the CD ring by
G Audran et al. 2008:
MeO
O
O
Ph3P
O
OMe
O
CSA,
MeOH
O
OH
O
LiAlH4
KOtBu
MeO
O
OMe
MeO
H
OMe
MeO
OMe
OTBS
OMe
O O H
HO
MeO
OMe
OTBS
OTBS
OsO4, NMO
SeO2, TBHP
H
H
PMB
OMe
H
O
PMB
O
H
OH
A
PMB
O
H
HO
OH
HO
B
MeO
OMe
OTBS
DBU (base)
PMB
O
C
HO
HO
H
OMe
OMe
OTBS
H
MeO
MeO
(with inversion)
H
H
OMs
PMB
O
D
HO
OTBS
i) BnBr, NaH
ii) DDQ
iii) TPAP
(oxidation)
O
P. Bremond, G. Audran and H. Monti, J. Org. Chem. 2008, 73, 6033-6036.
H
H
O
BnO
O
56
6) The use of cycloadditions in complex molecule synthesis, which may include FR182877,
estrone, platensimycin, progesterone, daphniphyllum alkaloids, abyssomicin C.
O
Hexacyclinic acid-
FR 182877
HO
AcO
H
H
H
OH
H
H
HO2C
Estrone
hormone
1952
OH
H
O
H
H
H
H
HO
Progesterone
hormone
1952
O
HO
O
H
O
O
O
H
H
O
H
H
H
H
H
H
O
Platensimycin
inhibitor of fatty acid
biosyntheisis
OH
Cholesterol
biosynthesis and
statins etc in MT
course with
discussion of
biosynthesis.
O
O
O
HO2C
O
O
N
H
OH
O
Daphiphylium
alkaloid
H
HN
57
Estrone – Vollhardt synthesis.
O
O
SiMe3
CpCo(CO)2
Me3Si
H
H
Me3Si
SiMe3
O
O
Me3Si
O
Estrone
hormone
1952
H
Me3Si
H
Me3Si
H
Me3Si
K. Peter Vollhardt,
Berkeley.
H
H
H
H
HO
K. Peter C. Vollhardt, Angew. Chem. Int.
Ed. 1984, 23, 539-556.
58
Progesterone – W. S. Johnson, 1971.
William
Summer
Johnson
(Stanford)
H
OH
O
O
O
O
O
O
O
H
H
H
H
H
H
aq K2CO3
O
O
O3
Progesterone
aq. KOH
O
H
Note this is a racemic
synthesis.
H
O
H
H
H
H
O
W. S. Johnson, M. B. Gravestock and B. E. McCarry, "Acetylenic bond participation in biogenetic-like
59
olefinic cyclizations. II. Synthesis of dl-progesterone". J. Am. Chem. Soc. 1971, 93, 4332–4.
Estrone, progesterone - Pattenden approach.
Professor Gerry
Pattenden,
Nottingham.
Me
Me
SePh
Another clever racemic
but stereoselective approach by
Pattenden:
Me
nBu3SnH
AIBN, heat
isomeric
mixture denoted by
Me
Me
O
Me
Me
Me
Me
H
H
.
H
O
O
A. Batsanov, L. Chen, G. B. Gill and G. Pattenden
J. Chem. Soc., Perkin Trans. 1, 1996, 45-55.
60
Endiandric acids:
K. C. Nicolaou’s research group achieved a direct synthesis of endiandric acid A in
the laboratory. This was achieved by the reduction of the two alkyne groups in the
molecule below by Lindlar catalyst (cis- alkenes are formed selectively) which then
formed the product upon heating in toluene. A pretty impressive ‘one-pot’
reaction.
Ph
MeO2C
H2
Lindlar catalyst
(Pd/CaCO3, + Pb or quinine poison)
Ph
H
100oC
(not isolated)
MeO2C
Ph
H
H
Toluene
H
H
MeO2C
Endiandric acid A
(methyl ester derivative)
K. C. Nicolaou, N. A. Petasis and R. E. Zipkin, J. Am. Chem. Soc. 1982, 104, 5560-5562.
61
Further applications of Diels-Alder reactions - alkaloid synthesis:
CHO
+
DielsAlder
OBn
MeO P
MeO
CHO
O
O
N
H
O
O
N
H
Bn=CH2Ph
OBn
nPr
base
(Wadsworth-Emmons)
regio and stereo-controlled
O
nPr
O
H2, Pd/C
(removes CO2Bn
and reduces alkene)
nPr
H+ (catalytic)
O
N
H
NH2
OBn
H
H
Pumiliotoxin C
('poison arrow' toxin)
NaBH4
(reduces C=N
N
H
not isolated
nPr
N
H H H
R. Kartika and R. E. Taylor, Richard Chemtracts 2006, 19, 385-390.
62 62
Daphniphyllum alkaloids.
CHO
OH
CO2tBu
MsCl, DBU
CHO
CO2tBu
DIBAL-H
Swern oxidation
O
O
O
i) NH3
H
O
ii) AcOH
H
Daphniphylium
alkaloid
H
O
HN
HN
G. A. Wallace and C. H. Heathcock, "Further Studies of the Daphniphyllum Alkaloid Polycyclization
Cascade," J. Org. Chem. 2001, 66, 450-454
63
FR182877 – selected
for close analysis.
Sorensen Approach –
inspired by biosynthetic
route:
TESO
TESO
OTES
O
OTES
Pd2dba3
i) KHMDS, PhSeBr
ii) mCPBA, DCM.
O
OtBu
OtBu
OCO2Me
O
Eric Sorensen
Princeton University
TESO
HO
H
OTES
OTES
O
H
O
HH
OTMS
B
OH
H
iii) EDC/DMAP
H
O
FR 182877
i) Sulfonic acid. H
ii) TFA/DCM
H
OtBu
OtBu
A
OTMS
O
TESO
Key step
is from
A to B.
OTMS
H
O
H
H
O
O
OTMS
H
O
H
64
D. A. Vosberg, C. D. Vandewall and E. J. Sorensen, . J. Am. Chem. Soc. 2002, 124, 4552-4553.
FR182877 – anticancer
Compound, selected
for close analysis.
TBSO
Br
NMe(OMe)
i) Pd(PPh3)4
Br
OTBS
base
O
+
ii) steps.
B(OH)2
Evans Approach
(to (-) enantiomer)
OTMS
OTBS
TBSO
TBSO
Different (Suzuki)
coupling step
between fragments but
same cyclisation
approach:
OTBS
O
O
then CsCO3
OEt
Br
OH
O
OTBS
OTBS
O
B
A
Key step
is from TBSO
A to B.
(-) FR 182877
TBSO
OTBS
H
Diels-Alder
E
Br
OTBS
I2, PPh3
OEt
i) Ph2Se2O3
ii) SO3 py TEA.
H
H
Br
OTBS
OTBS
O
H
HH
OEt
OEt
Br
H
O
Steps
O
H
H
OEt
OTBS
H
50oC, 6h.
O
TBSO
H
O
OTBS
D. A. Evans and J. T. Starr, Angew. Chem. Int. Ed.. 2002, 41,1787-1790.
H
O
OTBS
65
Abyssomicin C – selected for close analysis. Again a Diels-Alder approach by Sorensen. This
compound inhibits growth of gram positive bacteria including MRSA and the vancomycin
resistant strain. It blocks an early stage in the biosynthesis of tetrahydrofolate – a process
important to bacteria but not humans.
i) LDA, THF
+
O
O
ii) TBSOTf, base
OTES
iii) Swern oxidation:
Me2S(O), (COCl)2, Et3N
OTBS O
OTES
(selective for OTES group)
O
O
Key step
is from
A to B.
LDA, toluene
OTBS O
A
O
O
O
OMe
Deprotonation to form the
vinyllithium is proposed.
i) Dess-Martin Periodinate (oxidant)
OTBS O
B
OH
OMe
ii) Sc(OTf)3, DCM (elimination).
O
O
O
O
OMe
C. W. Zapf, B. A. Harrison, C. Drahl and S. J. Sorenson, Angew. Chem. Int. Ed.. 2005, 44,6533-6537. 66
O
Abyssomicin C –
synthesis completion.
O
A
O
O
O
OMe
O
O
Diels-Alder
cycloaddition
O
O
Key step
is from
A to B.
OMe
OMe
Toluene,
100oC
O
O
O
O
O
O
O
O
O
O
O
OMe
LiCl
DMSO
pTsOH, LiCl,
MeCN
O
O
B
H
O
OH
O
O
O
O
O
Abyssomicin C
Antibacterial natural
product.
OH
67
Abyssomicin C –
synthesis by Nicolaou.
Approach depends on early synthesis of bicyclic
part then coupling to aldehyde, and a metathesis:
i) tBuLi then
O
Key step
is from
A to B.
O
O
O
PMBO
A
ii) DDQ
OTES
OH
O
HO
O
B
O
OTES
i) HCl. MeOK
HO
(remove TES)
ii) Grubbs
metathesis
catalyst
OH
O
oxidation
O
O
OH
K. C. Nicolaou and S. T. Harrison. J. Am. Chem. Soc. 2007, 129, 429-440.
O
O
O
O
O
Abyssomicin C
Antibacterial natural
product.
OH
68
7) Enantioselective strategies which may include biotin, a-arylpropionic acids,
menthol, zaragozic acid, statins (nb statins and zaragozic acids mentioned in MT
course).
O
Ibuprofen
Biotin
NH
HN
CO2H
HO
Lovastatin
(Mevacor)
.....Chlesterol-lowering.
H
H
CO2H
S
O
O
O
O
H
O
O
OH
AcO
OH
L-menthol
HO2C
HO2C
O
OH
O
CO2H
Ph
69
A total synthesis of Biotin.
Ph
H2N
O
O
O
NH
H
OEt
.
NH
i) DIBAL,
ii) BnNH(OH).HCl
O
N
PhCH3
H
H
O
S
heat
OEt
2
S
S
L-cysteine
mehyl ester dimer
Ph
O
O
Ph
O
NH
O
NH
N
H
O
Zn, AcOH
then
N
H
H
H
S
S
EtO
N
NH
H
H
O
ClCO2Me,
Na2CO3.
H
S
O
O
O
Biotin
N
Ph
N
HN
Ph
H
H
Ba(OH)2
dioxane/
H2O
OH
O
N
Ph
3 steps
H
H
S
OH
CO2H
H
H
H
H
S
NH
HN
S
CO2H
OH
E. G. Baggiolini, H. L. Lee, G. Pizzolato, M. R. Uskoković, J. Am. Chem. Soc. 1982, 104, 6460.
70
note how the left hand structure is unambigouslink chiral centres through a normal bond (i.e. not a wedge or dash)
H
H
S
H
H
H
S
OH
Confusing
OH
a-Arylpropionic acids
Asymmetric hydrogenation:
Ibuprofen
CO2H
{Ru(DUPHOS)]+
CO2H
H2
Asymmetric hydrocyanation:
Ibuprofen
Rh/diphosphine
CO2H
HCN
Several classes of asymmetric catalysts can do this.
71
Zaragozic acid synthesis – key asymmetric dihydroxylations.
O
Zaragozic acid A/Squalestatin S1
Chlesterol-lowering.
O
OH
PMBO
AcO
HO2C
HO2C
O
OH
AD-mix 
Ph
O
CO2H
PMBO
MeO
PMBO
(performs an
asymmetric
dihydroxylation
DDQ, H2O
OSEM
OSEM
O
MeO
O
O
HO
PMBO
Then use 2-methoxy
propene and acid to
form acetal.
OSEM
O
O
O
OsO4, NMO
N
O
O
OH
OH
OH
HO
OH
OH
OSEM
O
O
O
OSEM
O
O
O
O
NMO=
O
O
BnO2C
oxidations
esterifications
O
O
O
CO2Bn
OTMS
O
O
O
72
Zaragozic acid synthesis – continued.
BnO2C
CO2Bn
OTMS
O
O
O
BnO2C
OTBS
Li
Ph
S
O
S
CO2Bn
OTMS
HO
O
O
OTBS
Ph
O
O
O
S
S
OTBS
i) 2% HCl/ MeOH
(removes TMS)
BnO2C
CO2Bn
O
O
ii) Hg(ClO4)2, CaCO3
O
Ph
OH
1.8% HCl/MeOH
OH
O
O
O
HO
Zaragozic acid A/Squalestatin S1
Chlesterol-lowering.
O
OH
OH
AcO
OTBS
MeO2C
BnO2C
O
OH
O
CO2Me
Ph
several
steps.
HO2C
HO2C
O
OH
O
CO2H
Ph
Reference: a) K. C. Nicolaou. E. W. Yue, Y. Naniwa, F. DeRiccardis, A. Nadin, J. E. Leresche. S.
LaGreca. Z. Yang, Angew. Chem. Int. Ed. 1994, 33, 2184. b) K. C. Nicolaou, A. Nadin, J. E. Leresche,
73
S . LaCreca, T. Tsuri. E. W. Yue, Z. Yang, Angew. Chem. Int. Ed. 1994, 33. 2187.
Menthol is prepared through an ene reaction: This uses a mild Lewis acid. The chirality of
the product comes entirely from the single chiral centre of the starting material, itself
made by an asymmetric isomerisation reaction.
H
Ph2
P
Rh
NMe2
NMe2
PPh2
H+/H2O
[Rh/S-BINAP]
Isomerisation (not a reduction!)
H2, Pd/C
ZnBr2
O
(catalyst)
O
ZnBr2
OH
OH
H
L-menthol
ZnBr2
O
O
via
H
H
This method was developed by Takasago, developed in collaboration with R. Noyori – BASF have a similar
74 74
strategy. S.-I. Inoue, H. Takaya, K. Tani, S. Otsuka, T. Saito and R. Noyori, J. Am. Chem. Soc. 1990, 112, 4897.
Statins - selected for closer attention.
R=Me; Lovastatin (Mevacor) HO
R=H; Mevastatin (Compactin)
Chlesterol-lowering drugs
O
HO
O
Simvastatin (Zocor)
O
O
O
O
O
H
H
H
O
hydrolysis
of ester.
R
R
The above compounds are natural products isolated by fermentation - they work by
ring opening to the 3,5-dihydroxy acid, which inhibits fatty acid (and cholesterol)
biosynthesis (see M. Tosin course CH404 for more information on this).
HO
O
HO
OH
OH
(CoA)S
O
OH
Mevaldic acid hemithioacetalintermediate in cholesterol biosynthesis
note relationship
to chlesterolsynthesis]
intermediate shown
on left
OH
OH
O
R
OH
OH
R
F
OH
F
OH
OH
OH
N
O
S
O
OH
N
O
Atorvastatin (Lipitor)
N
Fluvastatin (Lescol)
OH
OH
N
OH
O
pFC6H4
Rosuvastatin (Crestor)
N
Ph
OH
O
PhHN
O
75
HO
Synthetic approaches to statins; An early
approach to compactin from M. Hirama and
M. Uei.
O
O
O
O
H
H
O
O
O
i)
OMe
O
P
OMe
OMe
O
P(O)(OMe)2
OMe
ii) Ac2O
iii) Na/Hg
OTBS
OTBS
OTBS
OBn
OBn
MeO
O
MeO
O
Bakers' yeast
O
O
O
O3 then
OH
O
Me2S
O
O
M. Hirama and M. Uei, J. Am. Chem. Soc. 1982, 104, 4251-4253.
76
OBn
Key steps are from
A to B and B to C.
OBn
O
O
O
OBn
O
O
O
O
P(O)(OMe)2
O
H
O
+
reflux
NaH
chlorobenzene
THF
OTBS
A
O
OTBS
H
OTBS
B
C
O
O
HO
R
R
O
O
O
O
H
H
O
SOCl2
O
H
OH
H
H
Other isomers are formed and
separated by chromatography.
H
R
Last steps include i) deprotection of the OBn to OH, then oxidation, ii) deprotection
iii) cyclisation to the lactone
Hirama and Uei, J. Am. Chem. Soc. 1982, 104, 4251-4253.
77
Synthetic approaches (+)-dihydrocompactin
where remote stereocontrol is achieved.
OH
OTMS
OH
OTMS
O
O
H
i) Al(OTf)3/ TfOH
ii) H2O, HCl
49% for 3 steps.
9:1 mixture of isomers.
iii) K2CO3/MeOH
H
B
A
TMSO
TMSO
TMSO
Key step is from
A to B.
O
O
O
O
O
H
H
+
stereochemistry
controlled at
this step.
H
by
H
deprotonation
by OTMS H
adding to C=O
1 : 1 mixture formed
T. Sammakia, D. J. Johns, G. Kim and M. A. Berliner, J. Am. Chem. Soc. 2005, 127, 6504-6505.
78
Synthetic approaches (+)-dihydrocompactin – completion of synthesis.
OH
OCPh3
OH
Br
O
i) Add side chain
ii) ZnBr2 (remove Tr).
iii) Dess-Martin
periodinate.
O
i) Ph3CCl,
py
O
H
OH
H
ii) L-selectride
(reduce C=O).
iii) BrCOCH2Br, py
H
Key step is from
A to B.
H
py=pyridine
HO
O
O
O
O
O
O
O
H
O
Br
O
SmI2
H
(reductive coupling)
A
B
H
H
T. Sammakia, D. J. Johns, G. Kim and M. A. Berliner, J. Am. Chem. Soc. 2005, 127, 6504-6505.
79
Statins - An approach to a subunit involving
organocatalysis and a metathesis.
O
TMS
Key step is from
A to B.
NMe
OTMS
Ph
O
N
H
+
O
O
O
O
O
O
O
AIBN
nBu3SnH
TMS
TMS
Br
O
one
step
A
O
H
H
TMS
TMS
(radical
cyclisation)
Pd(PPh3)4
Br
B
Br
O
OH
O
OH
OH
H
OH
H
TMS
steps
O
SnBu3
TMS
LiAlH4
Grubbs
metathesis
H
DCM, reflux
J. Robichaud and F. Tremblay, Org. Lett. 2006, 8, 597-600.
80