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AND TOTAL
SYNTHESIS123.702
STEREOSELECTIVE
gareth j rowlands
why do we need Total Synthesis?
©Wsiegmund@wikimedia commons
O
AcO
H
OH
OBzOHO
O
OHPh
BzHN
AcO O
AcOtaxol
©Trois Têtes (TT)@Flickr
NH
H
O O
N
O
O
AsymmetricSynthesis?
why do we need
synthesis of pureenantiomers important
NMe2
Me
PhO
EtO
novradcough-suppressant
Me2NMe
Ph O
EtO
darvonpainkiller
©natashalcd@Flickr
course outline
6lectures
asymmetric synthesis
6lectures
total synthesis
course notes
recommendedbooks
N
umber 16 | 2009
Chem
Com
m
Pages 2053–2224
FEATURE ARTICLE
Toshifumi Dohi and Yasuyuki Kita
Hypervalent iodine reagents as a new
entrance to organocatalystsISSN 1359-7345 COMMUNICATION
Norifumi Fujita, Seiji Shinkai et al.
An organogel system can control the
stereochemical course of anthracene
photodimerization
1359-7345(2009)16;1-0
www.rsc.org/chemcomm
Number 16 | 28 April 2009 | Pages 2053–2224
Chemical Communications
As featured in:
See Debashish Roy, Jennifer N. Cambre
and Brent S. Sumerlin, Chem. Commun.,
2009, 2106.
www.rsc.org/chemcommRegistered Charity Number 207890
By including polymer segments that are sensitive to three di!erent
stimuli, “schizophrenic”, triply-responsive block copolymers were
obtained. RAFT copolymerization with a boronic acid containing
monomer led to block copolymers capable of forming both
micelles and reverse micelles, with the self-assembly being
governed by the temperature, pH, and sugar concentration of the
local environment.
Title: Triply-responsive boronic acid block copolymersShowcasing research from Professor Brent Sumerlin’s
laboratory, Southern Methodist University, USA.
FEATURE ARTICLE
Toshifumi Dohi and Yasuyuki Kita
Hypervalent iodine rea
gents as a new
entrance toorganocata
lystsISSN 1359-7345 COMMUNICATION
Norifumi Fujita, Seiji Shinkai et al.
An organogel system can control the
stereochemical course
of anthracene
photodimerization
1359-7345(2009)16;1-0
www.rsc.org/chemcomm
Number 16 | 28 April 2009 | Pages 205
3–2224
Chemical Communications
Volum
e 7 | Num
ber 9 | 2009 O
rganic & Biom
olecular Chem
istry
Pages 1737–1988
ISSN 1477-0520
www.rsc.org/obc
Volume 7 | Number 9 | 7 May 2009 | Pages 1737–1988
COMMUNICATIONJennifer R. Hiscock et al.Fluorescent carbazolylurea anion receptors
1477-0520(2009)7:9;1-6
www.rsc.org/obcRegistered Charity Number 207890
‘Organic & Biomolecular Chemistrybook of choice’
Why not take advantage of free book chapters from the RSC?
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scheme Organic & Biomolecular Chemistry will regularly highlight
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ISSN 1477-0520
1477-0520(2007)5:1;1-I
www.rsc.org/obc
Volume 5 | Number 1 | 7 January 2007 | Pages 1–188
EMERGING AREAKarina L. Heredia and Heather D. MaynardSynthesis of protein–polymer conjugates
D7903 · ASCAF7 · 351 (5) · 661–804 (2009) · ISSN 1615-4150 · No. 5, March 2009 5/2009
ASC5-Year Impact Factor 2007
5.193The Cutting Edgethat Stays Sharp!
Review:Transition Metal-Catalysed, Direct and Site-Selective N1-, C2- or C3-Arylation
of the Indole Nucleus: 20 Years of Improvements
Lionel Joucla, Laurent Djakovitch
journals
lecture oneterminology
substrate controland
©DrStarbuck @ Flickr
chiral object
non-superposable
chiral objectnon-superposable
OH
O
HSNH2H
HO
O
SHH2N H
chiral compounds
non-superposable
OH
O
HSNH2H
HO
O
SHH2N H
chiral compounds
enantiomers
achiral object
superposable
achiral compounds
superposable
H OH
achiral compounds
symmetryplaneof
Me Me
H OH
naming:123.202see
CH3HO
O
H NH2
CH3HO
O
H NH214
2
3
naming:priorities
groups CH3 NH2 H CO2H
1st atom C N H C
2nd atom H, H, H O, O, O
priority 3 1 4 2
naming:lowest priority
points away
CH3HO
O
H NH2
H3C OH
O
HH2N≡
14
2
3
1 4
2
3
1
23
1
2 3
naming:
Santiclockwise
Rclockwise
right
NH2
H3C CO2H≡H3C OH
O
HH2N1
4
23
1
23
SSnaming:
finally... (S)-2-aminopropanoic acid
PO
OMeMe
H Ph
NSO
t-Bu
N
NRu
NN
NN
non-carbon-basedchiral compounds
principalssame
chiralityof
other forms axial
OO
OO
O
O
O
O©MonkeyBoy69@flickr
chiralityof
other forms
©mugley@flickr
PPh2PPh2
Ph2PPh2P
axial
chiralityof
other forms helical
P [8]helicene M [8]helicene
chiralityof
other forms
planar
Fe PPh2
PhFePh2P
Ph
compoundswith
enantiomers
stereocentres2or more
OH
NH2
OH
NH2
compoundswith
diastereoisomers
stereocentres2or more
OH
NH2
OH
NH2
OH
NH2
OH
NH2
compoundswithstereocentres2or more
enantiomers
OH
NH2
OH
NH2
stereocentres2
compounds4
OH
NH2
OH
NH2
OH
NH2
OH
NH2
stereocentres3
compounds8
HOCHO
OH OH
OH
HOCHO
OH OH
OH
HOCHO
OH OH
OH
HOCHO
OH OH
OH
HOCHO
OH OH
OH
HOCHO
OH OH
OH
HOCHO
OH OH
OH
HOCHO
OH OH
OH
stereocentresn
compounds2n
generalisation!thisisa !
HO2C CO2HOH
OHHO2C CO2H
OH
OH
HO2C CO2HOH
OHHO2C CO2H
OH
OH
stereocentres2
compounds3
HO2C CO2HOH
OHHO2C CO2H
OH
OH
HO2C CO2HOH
OHHO2C CO2H
OH
OH
stereocentres2
compounds3
diastereoisomers
HO2C CO2HOH
OHHO2C CO2H
OH
OH
HO2C CO2HOH
OHHO2C CO2H
OH
OH
stereocentres2
compounds3
enantiomers
stereocentres2
compounds3
identicalmeso
HO2C CO2HOH
OHHO2C CO2H
OH
OH
HO2C CO2HOH
OHHO2C CO2H
OH
OH
compoundsmeso
HO2C
OH
CO2H
HOHO2C CO2H
OH
OH
≡
symmetry
compoundsmeso
achiralplaneof
HO
HO2C
OH
CO2H
properties
enantiomersidenticalhave
NH2
NH2
NH2
H2N
mp = 41-45°Cmp = 40-43°C
propertiesdifferenthave
diastereoisomers NH2
NH2
mp = 41-45°Cbp = 221°C
NH2
NH2
difference between
diastereoisomers
synthesis asymmetric to
key
©brittanyculver@flickr
how do we measure
purity?
NH2NH2
NH2H2N
NH2NH2
=
80% 20% 60%eeenantiomeric excess (ee)
NH2NH2
NH2H2N
=
80% 20%
4 : 1
enantiomeric ratio (er)
NH2NH2
NH2NH2
80% 20%diastereoisomeric excess 60% de
diastereoisomeric ratio 4 : 1 dr
©brittanyculver@flickr
how do we measure
ee?
handed glovesleft rightand
identicalare
untilyouadd a hand
samethe
©David Reeves from Flickr
chemistry
diastereoisomersneed
samethechemistry
diastereoisomersneed...
R S
R
R R SR
R S
OH
Ph CO2H
DCC, DMAPOMeF3C iPr
O H
OPh
F3C OMe
iPr
O H
OPh
F3C OMe
covalent
Mosher’s acid73JACS512, 73JOC2143 & 91JACS4092
derivatisation
HO2CCO2H
OTol
OTol
O2CCO2H
OTol
OTol
S diastereoisomer is insoluble
NaOH
(–)-propranololβ-blocker
OOH
NH
OOH
NH2
OOH
NHionic (salt)derivatisation
©Pere Tubert Juhé@flickr
temporary interactions
chiral chromatography
SiN
H
ONO2
NO2
SiOSi
Si OO
O
O
OSi
OSiO
O
O
O
O
MeMe
silica chiral amine
asymmetricsynthesis
©Tony the Misfit@flickr
©simpologist@flickr
canadensolideTetrahderon, 2006, 62, 9713
O
O
O
On-C4H9
H H
n-C4H9 H
O
OBnOMe
OSiMe3
n-C4H9
OH
OBnOMe
O
TiCl4
77%n-C4H9
OH
OBnOMe
O100%
0%100% de
substrate control
O
O
O
On-C4H9
H H
©SarahWynne@flickr
Controlhelationram
n-C4H9H
BnOO
H
ClnTi
MeO
Me3SiO
angle
RR
R
O
R
C ORR
Nu
C ORR
NuNu
π π*
repulsion
Bürghi-Dunitz
LR
O
Z S
MR
OZ
M
S LNu
LR
Nu OH
Z S
Controlhelationram
Controlhelationram
L
SZ
LR
O
Z S
MR
OZ
M
S LNu
LR
Nu OH
Z S
O
R
Z
LS
O
RNu
L
SZR
Nu OH
Z
LSNu
OH
R
©Ed Bierman@flickr this isn’t the right sponge!
preswinholideTetrahderon, 1995, 51, 9437
OMe
OMe
Me
HO
HOMe
Me
OH OHMe
MeO
OOH
MeHO
O
OMe
OMe
Me
OSiO
Me
MeH
Ot-Bu
t-Bu
Me3Si Me
TiCl4
94%95% de
OMe
OMe
Me
OSiO
Me
Me
OHt-Bu
t-BuMe
substrate control
why
modelFelkin-Ahn
L
M
SH
O
Nu
L
S
M H
O
NuNu
modelFelkin-Ahn
PhH
O
Me H
EtMgBr
PhEt
Me H
PhEt
Me H
H OH
HO H25%
75% (50% de)
modelFelkin-Ahn
PhH
O
Me H
Ph
HMe
O
H
≡
first...Newmanprojection
draw
modelFelkin-Ahn
Ph
HMe
O
H
HPh
Me
O
H
PhH
Me
O
H
PhMe
H
O
H
perpendicular
rotatelarge group
Felkin-Ahn
PhMe
H
O
HEtPh
Me
H
OH
Et H
PhMe
H
OHEt
H≡Ph
EtMe H
HO H
model
Ph
O
SMeLiEt3BH
PhiPr
SMe
HO H
PhiPr
SMe
H OH
Zn(BH4)2
not the whole
story
iPr
MeS
H Ph
OZn
HH3B
chelationcontrol
perpendicularelementelectronegative
MeS
iPr
HPh
O
H BEt3
carbonyl
chelationno
©Capt Kodak@flickr
sterics electronics
substratecontrol
n-C4H9 H
O
OBn
OMe
OSiMe3
n-C4H9
OH
OBnOMe
OTiCl4