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AND TOTAL
SYNTHESIS
123.702
gareth j rowlands
why d o we n ee d Total Synthesis?
AcO O OH
AcO
BzHN O
Ph O H
OH OH AcO O
taxol OBz
©Wsiegmund@wikimedia commons
do we need
why
Asymmetric
Synthesis?
O
H
N
O
O N O
H
enantiomers important
Me
Me
NMe2
Me2N
O Ph
O Ph O
Et O
novrad
cough-suppr Et
essant darvon
painkiller
course outline
6 asymmetric synthesis
lectures
6 total synthesis
lectures
©natashalcd@Flickr
course no
tes
recommended
books
ume 7 |
ber 9 | 20 Num
09
Number
16 | 2009
www.rs
c.org/obc
s 2053 –2224
ril 20 09 | Page
16 | 28 Ap
Number
ic ations
Volume Commun
Chemical
7 | Num
ber 9 | 7 May
2009 | Pa
ges 1737 comm
–1988 .org/chem
www.rsc
5/2009
ChemCo
D7903 · ASCAF7 · 351 (5) · 661–804 (2009) · ISSN 1615-4150 · No. 5, March 2009
mm
journals Showca si
laborato
ng re search fr
ry, Southe
rn Metho
di st
sor Brent
U ni
Sumerlin
om Profes versity, USA.
ers
’s
c acid bloc
k copoly
m
As feature
d in:
Chemical
www.rsc.org
Communication
/chemcomm
s
Number
16 | 28 April
2009 | Pages 2053–2224
e boroni
ip ly-responsiv
Title : Tr e different
ve to thre
are sensiti lymers we
re
er se gm ents that oc k co po
ng polym bl
By includi sponsive ntaining
ph re ni c”, triply-re a bo ro nic acid co
hizo tion with th
stimuli, “sc forming bo
ARTICLE Kita 09)16;1-0
polymeriza
FEATURE Yasuyuki a new
TION et al. Dohi and as 1359-7345(20
ISSN 1359-7345 COMMUNICA Seiji Shinkai Toshifumi reagents
Fujita, control the Hypervalent iodine sts
Norifumi system can to organocataly
capable of
An organogel al course of anthracene entrance
. RAFT co
stereochemiczation
photodimeri
Pages 20
nt carbaz Fu nt len
receptor olylurea Norifumi gel system can co racene Hyperva catalysts
s to organo
m
an th
ion An organo ical course of an entrance
mcom
.org/che
stereochem zation
www.rsc
eri
photodim
53–2224
er 207890
Ch arity Numb
Registered
1477-052
0(2009)7
:9;1-6
Review:
Transition Metal-Catalysed, Direct and
ASC
5-Year Impact Factor 2007
Site-Selective N1-, C2- or C3-Arylation
5.193 of the Indole Nucleus:
The Cutting Edge
that Stays Sharp! 20 Years of Improvements
Lionel Joucla, Laurent Djakovitch
lecture one
terminology
and
substrate control
chiral object
©DrStarbuck @ Flickr
non-superposable
chiral object
non-superposable
chiral compounds
O O
HS OH HO SH
H NH2 H2N H
non-superposable
chiral compounds
O O
HS OH HO SH
H NH2 H2N H
enantiomers
achiral object
supe r p o sa b l e
achiral compounds
H OH
supe r p o sa b l e
achiral compounds
H OH
Me Me
plane of
symmetry
O
CH3
HO
H NH2
naming:
see1
23.202
O
3
2 CH3
HO
H
4
NH
1
2
priorities priority 3 1 4 2
O O
3 3
HO
2 CH3
≡ H3C 2
OH
H NH2 H2N H
4 1 1 4
naming:
lowest priority
points away
3 2 2 3
1 1
S R
anticlockwise clockwise
right
naming:
3 2
O
3
H3C CO2H
2
H3C
OH
1
H2N H 4 NH2
1
S S
naming:
finally... (S)-2-aminopropanoic acid
O
S
t-Bu N
N
H Ph N N
Ru
non-carbon-based N N
chiral compounds N
O
P
Me OMe
same principals
other forms axia
of chirality
l
O O
O O
O O
O O
©MonkeyBoy69@flickr
other forms axia
of chirality
l
PPh2
PPh2
Ph2P
Ph2P
©mugley@flickr
other forms helic
of chirality
al
P [8]helicene M [8]helicene
other forms
of chirality Ph Ph
Fe PPh2 Ph2P Fe
lanar
p
compounds with
2 stereocentres
or more
OH OH
NH2 NH2
enantiomers
compounds with
2 stereocentres
or more
OH OH
NH2 NH2
OH OH
NH2 NH2
diastereoisomers
compounds with
2 stereocentres
or more
OH OH
NH2 NH2
enantiomers
2 stereocentres
OH OH
NH2 NH2
OH OH
NH2 NH2
4
compounds
3 stereocentres
OH OH OH OH
CHO CHO CHO CHO
HO HO HO HO
OH OH OH OH OH OH OH OH
OH OH OH OH
CHO CHO CHO CHO
HO HO HO HO
OH OH OH OH OH OH OH OH
8
compounds
n stereocentres
2n
compounds
this
is
a
!
generalisation!
2 stereocentres
OH OH
HO2C HO2C
CO2H CO2H
OH OH
OH OH
HO2C HO2C
CO2H CO2H
OH OH
3
compounds
2 stereocentres
OH OH
HO2C HO2C
CO2H CO2H
OH OH
OH OH
HO2C HO2C
CO2H CO2H
OH OH
3
diastereoisomers compounds
2 stereocentres
OH OH
HO2C HO2C
CO2H CO2H
OH OH
OH OH
HO2C HO2C
CO2H CO2H
OH OH
3
enantiomers compounds
2 stereocentres
OH OH
HO2C HO2C
CO2H CO2H
OH OH
OH OH
HO2C HO2C
CO2H CO2H
meso
OH OH
3
identical compounds
meso
compounds
OH
HO OH
HO2C
CO2H ≡ HO2C CO2H
OH
meso
compounds
HO OH
HO2C CO2H
achiral
of
plane
symmetry
enantiomers NH2 NH2
NH2 H2N
have identical
properties mp = 41-45°C
mp = 40-43°C
diast e reo isom ers NH2 NH2
NH2 NH2
have different
properties mp = 41-45°C
bp = 221°C
difference between
dia stereoisomers
key
toasymmetric
synthesis
ow e measure
h do w
purity?
©brittanyculver@flickr
=
NH2 NH2 NH2
NH2 H2N NH2
80% 20%
enantiomeric ratio (er)
NH2 NH2
NH2 NH2
80% 20%
diastereoisomeric excess 60% de
diastereoisomeric ratio 4 : 1 dr
ow e measure
h do w
ee?
©brittanyculver@flickr
left and right
handed gloves
arei
d
entical
you
til
un add a hand
chem istry
thesam
e
need
©David Reeves from Flickr diastereoisomers
chem istry
thesam R S
e
R R R S
need..
R S
diastereoisom ers
covalent
derivatisation O
Ph
O H
OH DCC, F3C OMe
F3C OMe DMAP
iPr
Ph CO2H O
Ph
O H
F3C OMe
iPr
Mosher’s acid
7 3 J O C 2 1 4 3 & 9 1 J A C S 40 92
73JACS512,
OTol
HO2C
OH CO2H OH
O O OTol
OTol O2C
NH NH2 CO2H
OTol
S diastereoisomer is insoluble
NaOH
OH
O
ionic (salt) NH
derivatisation
(–)-propranolol
β-blocker
temporary
interactions
O
O O
Si O
Si O H
O
O O Si N
Si O Me
Si O Si NO2
O Me O
O
NO2
silica chiral amine
chiral
©Pere Tubert Juhé@flickr ch rom atography
asymmetric
©Tony the Misfit@flickr
synthesis
O
O
H H
n-C4H9 O O
canadensolide3
2, 971 0 06, 6
©simpologist@flickr Tetrahderon, 2
substrate O
O
H H
control n-C4H9 O O
OH O
n-C4H9
OMe
OBn
O
OSiMe3 TiCl4 100%
n-C4H9
H OH O
OMe 77%
OBn n-C4H9
OMe
OBn
0%
100% de
©SarahWynne@flickr
C
ram
helation Cln
ontrol Ti
BnO O
n-C4H9
Me3SiO
H H
MeO
Bürghi-Dunitz angle
OR
R
Nu RR
Nu Nu
repulsion
R R
C O C O
R R
π π*
C
ram
helation
ontrol
M
O O Nu OH
L M Z L
R R R
Z S S L Z S
Nu
C
ram
helation
ontrol
M
O O Nu OH
L M Z L
R R R
Z S S L Z S
Nu
L Z Z
O O OH L
Nu OH
Nu
Z S Nu S L S L Z S
R R R R
Me
HO
O OH O
MeO
Me
HO
Me
HO OH OH
Me
Me O
Me
OMe
preswinholide 7
, 943
ron , 1 9 9 5 , 51
Tetra h de
©Ed Bierman@flickr
this isn’t the right sponge!
substrate
control
Me
t-Bu
O H Me
t-Bu Si t-Bu
O
O O
Me t-Bu Si Me
O OH
Me O TiCl4 Me
Me
94% Me O
95% de Me
OMe
OMe
Me3Si Me
why
Felkin-Ahn
model
O M S O
L L
Nu M H Nu
H S Nu
Felkin-Ahn
H OH
model Ph
Et
O Me H
EtMgBr 25%
Ph
H HO H
Me H Ph
Et
Me H
75% (50% de)
Felkin-Ahn
model
O Ph
O
Ph
H
≡
Me H Me H
H
draw
first...
Newman projection
Felkin-Ahn
model
Ph
O Ph O OH Me O
H Ph Ph
Me H Me H H Me HH
H
rotate
group
large
perpendicular
Felkin-Ahn model
Me O Me OH
Ph Ph
HH Et H
Et H
HO H Me OH
Ph
Et ≡ Et Ph
Me H H H
notthe whole
O
story
Ph
SMe
Zn(BH4)2 LiEt3BH
H OH HO H
iPr iPr
Ph Ph
SMe SMe
chelation
control
Zn
MeS O
iPr
H3B H H Ph
no
chelation
O iPr
MeS
Ph H H BEt3
electronegative element
perpendicular
carbonyl
sterics electronics
©Capt Kodak@flickr
substrate
control
O
n-C4H9
H OH O
TiCl4 n-C4H9
OBn
OMe
OSiMe3 OBn
OMe