Lecture1 123713A

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

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

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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

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

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

handed glovesleft rightand

identicalare

51

untilyou add a hand

52

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

Lecture1 123713A

Education

Transcript of Lecture1 123713A