Post on 15-Apr-2017
gareth j rowlands
AND TOTALSYNTHESIS
123.713 A/B
STEREOSELECTIVE
1
why do we need Total Synthesis?
©Wsiegmund@wikimedia commons
O
AcO
H
OH
OBzOHO
O
OHPh
BzHN
AcO O
AcOtaxol
2
©ALTO CONTRASTE . Edgar AVG --BUSY--@flickr
AcHN
O
H2N
CO2Et
Tamiflu®oseltamivir
3
©Whirling Phoenix@flickr
CO2H
OHHO
HO
shikimic acid
CO2EtO
NH
NH2
O
4
© Armed Forces Pest Management Board@flickr
N
N
Cl
N
NHO2N
Imidacloprid(Advantage®)EUR 597 million
5
N
© vermin Inc@flickr
4reactions
6
light-driven molecular motor
Me(ax)
Me(ax)
(3R,3'R)-(P,P)-transstable
Me(eq)
Me(eq)
(3R,3'R)-(M,M)-transunstable
(3R,3'R)-(M,M)-cisunstable
Me(eq)
Me(eq)
(3R,3'R)-(P,P)-cisstable
Me(ax)
Me(ax)
≥ 280 nm
≥ 380 nm
≥ 280 nm
≥ 380 nm
20°C60°C direction of rotation
Feringa, Acc. Chem. Res. 2001, 34, 5047
nanomotor to move objectsrotor
controls direction
anchor
Feringa et al., Nature 2006, 440, 1638
nanomotor to move objects
Feringa et al., Nature 2006, 440, 163x8 real time
9
nanomotor to move objects
Feringa et al., Nature 2006, 440, 163x8 real time
9
O
AcO
H
OH
OBzOHO
O
OHPh
BzHN
AcO O
AcOtaxol
Me(ax)
Me(ax)
AcHN
O
H2N
CO2Et
what property do allthese molecules share?
10
chiralchiral11
course structureLecture 1: introductionLecture 1: problemsLecture 2: catalysisLecture 2: problemsLecture 3: retrosynthesisLecture 3: examplesLecture 4: synthesisLecture 4: assignment
12
recommendedbooks
13
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 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
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?
Through our ‘Organic & Biomolecular Chemistry book of choice’
scheme Organic & Biomolecular Chemistry will regularly highlight
a book from the RSC eBook Collection relevant to your research
interests. Read the latest chapter today by visiting the Organic &
Biomolecular Chemistry website. The RSC eBook Collection o!ers: Over 900 new and existing books Fully searchable Unlimited accessWhy not take a look today? Go online to find out more!
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
14
achiral object
superposable15
achiral compounds
superposable
H OH
16
achiral compounds
symmetryplaneof
Me Me
H OH
17
©DrStarbuck @ Flickr
chiral object
non-superposable18
OH
O
HSNH2H
HO
O
SHH2N H
chiral compounds
non-superposable19
OH
O
HSNH2H
HO
O
SHH2N H
chiral compounds
enantiomers20
OH
O
HSNH2H
HO
O
SHH2N H
a 1:1 mixture of enantiomers
racemateis called a
21
naming:123.202see
CH3HO
O
H NH2
22
CH3HO
O
H NH214
2
3
naming:priorities
groups CH3 NH2 H CO2H1st atom C N H C2nd atom H, H, H O, O, Opriority 3 1 4 2
23
naming:lowest priority
points away
CH3HO
O
H NH2
H3C OH
O
HH2N≡
14
2
3
1 4
2
3
24
naming:
Santiclockwise
Rclockwise
right
1
23
1
2 3
25
NH2
H3C CO2H≡H3C OH
O
HH2N1
4
23
1
23
SSnaming:
finally... (S)-2-aminopropanoic acid26
been taught iswhat you have
OO
OO
O
O
O
O©MonkeyBoy69@flickr
not entirely true
chiral
four different groupsbut does not have
27
chiralityofother forms
©mugley@flickr
PPh2PPh2
Ph2PPh2P
axial
28
chiralityofother forms helical
P [8]helicene M [8]helicene
29
chiralityofother forms
planar
Fe PPh2
PhFePh2P
Ph
30
compoundswith
enantiomers
stereocentres2or more
OH
NH2
OH
NH2
31
compoundswith
diastereoisomers
stereocentres2or more
OH
NH2
OH
NH2
OH
NH2
OH
NH2
32
stereocentres2
compounds4
OH
NH2
OH
NH2
OH
NH2
OH
NH2
33
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
34
stereocentresn
compounds2n
35
HO2C CO2HOH
OHHO2C CO2H
OH
OH
HO2C CO2HOH
OHHO2C CO2H
OH
OH
stereocentres2
compounds3
36
HO2C CO2HOH
OHHO2C CO2H
OH
OH
HO2C CO2HOH
OHHO2C CO2H
OH
OH
stereocentres2
compounds3
diastereoisomers37
HO2C CO2HOH
OHHO2C CO2H
OH
OH
HO2C CO2HOH
OHHO2C CO2H
OH
OH
stereocentres2
compounds3
enantiomers38
stereocentres2
compounds3
identicalmeso
HO2C CO2HOH
OHHO2C CO2H
OH
OH
HO2C CO2HOH
OHHO2C CO2H
OH
OH
39
compoundsmeso
HO2C
OH
CO2H
HOHO2C CO2H
OH
OH
≡
40
symmetry
compoundsmeso
achiralplaneof
HO
HO2C
OH
CO2H
41
practicedrawing
molecules & manipulating
42
properties
enantiomersidenticalhave
NH2
NH2
NH2
H2N
mp = 41-45°Cmp = 40-43°C
43
propertiesdifferenthave
diastereoisomers NH2
NH2
mp = 41-45°Cbp = 221°C
NH2
NH2
44
difference betweendiastereoisomers
synthesis asymmetric to
key
45
©brittanyculver@flickr
how do we measurepurity?
46
NH2NH2
NH2H2N
NH2NH2
=
80% 20% 60%eeenantiomeric excess (ee)
47
NH2NH2
NH2H2N
=
80% 20%
4 : 1
enantiomeric ratio (er)
80 : 20
48
NH2NH2
NH2NH2
80% 20%diastereoisomeric excess 60% de
diastereoisomeric ratio 4 : 1 dr
diastereoisomeric ratio 80 : 20 dr49
©brittanyculver@flickr
how do we measureee?
50
handed glovesleft rightand
identicalare
51
untilyou add a hand
52
samethe
©David Reeves from Flickr
chemistry
diastereoisomersneed
53
samethechemistry
diastereoisomersneed...
R S
R
R R SR
R S54
OH
Ph CO2H
DCC, DMAPOMeF3C iPr
O H
OPh
F3C OMe
iPr
O H
OPh
F3C OMe
covalent
Mosher’s acid73JACS512, 73JOC2143 & 91JACS4092
derivatisation
55
HO2CCO2H
OTol
OTol
O2CCO2H
OTol
OTol
S diastereoisomer is insoluble
NaOH
(–)-propranololβ-blocker
OOH
NH
OOH
NH2
OOH
NHionic (salt)derivatisation
56
©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
57
key isdiastereoisomeric
transition states58
7
=97.5 2.5 95%:
er ee
δ𝚫G‡ = 8.3 kJ mol-1 at 0°C
59
one substituentCH3
CH3
H
CH3
H
95%equatorial
more stable by8 kJmol–1
5%axial
disfavoured
60
analysis
F
HHF
HHF
HHH
FH
conformational
useful starting point61
H3C H
PhO
HEt
...although one conformation of a molecule is more stable than other possible conformations, this does not mean that the molecule is compelled to react a s i f i t w e r e i n t h i s conformation or that it is rigidly fixed in any way.
“
..”D.H.R. Barton, Experientia 1950, 6, 316
62