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?

Through our ‘Organic & Biomolecular Chemistry book of choice’

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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