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Gareth J. Rowlands Advanced Organic Chemistry Advanced organic 1

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Page 1: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Gareth J. Rowlands

Advanced Organic Chemistry

Advanced organic

1

Page 2: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

Enantioselective synthesis

• Nature yields an enormous variety of chiral compounds• A change in stereochemistry can have profound effects

2

Why is enantioselective synthesis important?

NMe

O HO

H O

(1R,2R,3S,5S)-2-acetyl-8-methyl-8-aza-bicyclo[3.2.1]octan-3-yl benzoate

cocainestimulant

NHN

(S)-3-(1-methylpyrrolidin-2-yl)pyridine

nicotinetoxin / stimulant

OH

O

O

O

AcOMeO2C H

OH

O OHCO2Me

OO O

O

azadiractinanti-feedant

Me CO2H

NH2

(S)-2-aminopropanoic acidL-alanine

mammalian amino acid

Me CO2H

NH2

(R)-2-aminopropanoic acidD-alanine

bacterial cell wall

N

O

O

NHO

OH

(S)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

(S)-thalidomideteratogen (birth defects)

Page 3: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

Chirality and biology

• Enzymes & receptors are invariably chiral• Chiral drugs can interact with these to give two diastereomeric complexes• Imagine the hand below is the enzyme, it can form two very different complexes

depending on the chirality or “handness” of the drug it interacts with...

3

HIV protease + inhibitor Nicotinic receptor

Page 4: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

Chirality and biology II

• As you can imagine, these two complexes can have very different effects• The three drugs above highlight the possible effects of using the “wrong” compound• As a result we must have methods to prepare the correct enantiomers

4

OHNH

OHHN

(R)-1-(isopropylamino)-4-(naphthalen-1-yl)butan-2-ol

(–)-propanololβ-blocker for heart disease

(S)-1-(isopropylamino)-4-(naphthalen-1-yl)butan-2-ol

(+)-propanololcontraceptive

CO2H

NH2

HS

(S)-2-amino-3-mercapto-3-methylbutanoic acid

D-penicillaminetreats chronic arthritus

CO2H

NH2

HS

(R)-2-amino-3-mercapto-3-methylbutanoic acid

L-penicillaminetoxic

NH

HN

OH

Et OH

Et(S,S)-2-[2-(1-Hydroxymethyl-

propylamino)-ethylamino]-butan-1-olEthambutol

tuberculostatic (anti-TB)

NH

HN

OH

EtOH

Et(R,R)-2-[2-(1-Hydroxymethyl-

propylamino)-ethylamino]-butan-1-olcauses blindness

Page 5: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

Revision: terminology

• Stereoisomers - Isomers that differ only by the arrangement of substituents in space• Stereogenic element - the focus of stereoisomerism, be it a stereogenic centre, axis

or plane, within the molecule such that the change of two substituents about this element leads to different stereoisomers

• The easiest to identify are the cis-trans isomers found with sp2 systems• Alkenes should be assigned E or Z using Cahn-Ingold-Prelog rules• We are not going to look at these BUT will see their effects in enolate chemistry

5

B

A C

DA & C have highest priority

alkene = Z

B

A C

DA & D have highest priority

alkene = E

• Imines are treated in a similar manner

NB

A C

A has highest priorityimine = Z or cis

B has highest priorityimine = E or trans

NB

A C

Page 6: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

One stereogenic centre: chirality on an atom• Chiral compounds - simply a molecule (or object) that cannot be superimposed

upon its mirror image• Most obvious example is our hands...

6

Mirror image Left & right hands Non-superimposable

• Chiral centre - In a tetrahedral (Xabcd) or trigonal pyramidal (Xabc) structure, the...atom X to which the four (or three, respectively) substituents abc(d) are attached

Ph Me

OHHP

Ph MeH

chiral centre

Page 7: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

One stereogenic centre: chirality on an atom

Chiral• Mirror images are non-superimposable• Each mirror image is an enantiomer• Only differ by their absolute...configuration or actual 3D shape• Simplistically - 4 different groups• Do not have a plane of symmetry

7

Mirror plane

Mirror plane

rotaterotaterotate rotaterotate

Achiral• Mirror images are superimposable• Compound has a plane of symmetry

R4 R3chiral

R1≠R2≠R3≠R4

R2R1R4 R3achiral

R1=R1≠R3≠R4

R1R1

plane of symmetry running through central

carbon, hydrogen and OHACHIRAL

Me Me

H OH

Page 8: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

Enantiomers & optical rotation

• Each enantiomer has identical physical & chemical properties (in an achiral environment)

• Only differ by how they rotate plane polarised light (rotate in opposite directions• Enantiomers are said to be optically active• Not very useful as value is very unreliable (dependent on solvent & all factors below)• Even sign (+/–) can change depending on concentration!!

8

α

light source

polariser plane polarised light

samplecell length l (dm)

readinglight (λ)

Ph CO2H

OHH

(R)-(-)-mandelic acid131-133°C[α]23 –153D

Ph CO2H

HHO

(S)-(+)-mandelic acid131-134°C[α]20 +154D

[α]t = αDl x c

optical rotation

α = observed rotation; l = cell path (dm); c = concentration g/ml (or g/100ml); t = temperature

Page 9: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

Me CO2H

H NH21

2Me CO2H

H NH21

Me CO2H

H NH2

Me NH2

CO2HH

1

2

3Me

H

CO2HNH2 Me NH2

HO2C H ≡

rotate around axis until lowest priority points

away from you

Me CO2H

H NH21

23

4

Defining absolute configuration

• Need to be able to define the absolute configuration of a chiral centre• First assign priorities according to Cahn-Ingold-Prelog rules (highest atomic number)

9

• Next rotate molecule until lowest priority (4) is pointing away from viewer• Draw a line connecting 1 to 3• If line clockwise (right) the (R)• If line anti-clockwise (left) the (S)

Me CO2H

H NH2

alanine

Me CO2H

H NH2

(S)-alanine(S)-2-aminopropanoic acid

Page 10: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

PAr Ph

OMe

1

2 3S

Me Tol

O

1

23

SMe

O

Me

1

23

4SMe

O

Me

PO

MePh

12

3

4

MeO

PO

OMeMe

123

4

PO

OMeMe

12P

O

OMeMe

1

Defining absolute configuration II

10

• Define priorities according to CIP

• Point lowest priority (4) away from viewer

• Draw line from 1 to 3

• Line is anti-clockwise so (S)

PO

OMeMe

(S)-(4-methoxyphenyl)methylphenyl

phosphine oxide

PO

OMeMe

• Define priorities according to CIP

• Point lowest priority (4) away from viewer

• Draw line from 1 to 3

• Line is anti-clockwise so (R)

SMe

O

Me(R)-methyl-4-

methylphenylsulfoxide

Page 11: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

Central chirality at elements other than carbon

• As last two examples indicated it is not just carbon that can have central chirality• Any tetrahedral or pyramidal atom with four (three) different substituents can be chiral• Nitrogen / amines have the potential to be chiral...

11

Chiral Nitrogen compounds

• But rapid pyramidal inversion normally prevents isolation of either enantiomer• If substituents are constrained in a ring then rigid structure prevents inversion• Quaternary ammonium salts (below) can be isolated enantiomerically pure• Racemisation has been observed, presumably via dissociation...

N

N

Me

Me

Tröger's base(5S)-2,8-Dimethyl-6H,12H-5,11-

methano-dibenzo[b,f][1,5]diazocine

R1N R3R2

R1N R3R2

EtNi-PrMe

Ph

Cl

Page 12: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

Central chirality at phosphorus

• Trigonal pyramidal phosphorus (III) is configurationally stable below 200°C• P-chiral phosphines have a rich history as chiral ligands

12

PMe

MeOP Me

MeO

X(S)-cyclohexyl(4-

methoxyphenyl)(methyl)phosphine

• Tetrahedral phosphorus (V) is configurationally stable

PO

O

Pht-Bu

(S)-naphthalen-1-yl tert-butyl(phenyl)phosphinate

Page 13: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

Central chirality at sulfur

• Sulfoxides are tetrahedral; remember they have a lone pair!• Configurationally stable at room temperature• Certain anions (Cl ) can cause racemisation (interconversion of the enantiomers)

13

SMe

O

Me

(R)-1-methyl-4-(methylsulfinyl)benzene

OSS

(R)-S-tert-butyl 2-methylpropane-2-

sulfinothioate

H Ph

NSO

t-Bu

(S)-N-benzylidene-2-methylpropane-2-sulfinamide

• It should be stressed that the definition of a chiral compound is that it cannot be superimposed upon its mirror image• A stereogenic centre (central chirality) is sufficient for the existence of chirality it is not a requirement• Furthermore, as we shall see, not all compounds with a stereogenic centre are chiral!!

Page 14: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

HO2C

H

CO2H

HD-Fecht acid

(S)-spiro[3.3]heptane-2,6-dicarboxylic acid

Axial chiralityAxial chirality - Nonplanar arrangement of four groups about an axis

14

Spiro-compounds

CO2H

H

HO2C

HL-Fecht acid

(R)-spiro[3.3]heptane-2,6-dicarboxylic acid

Mirror

axis of chirality

CO2H

H

H CO2H

CO2H

H

HHO2C

Mirror

Viewed along axis

OO

O

O

O

O

olean(R)-1,7-

dioxaspiro[5.5]undecaneattracts male olive flies

olean(S)-1,7-

dioxaspiro[5.5]undecaneattracts female olive flies

Mirror

axis of chirality

RH2C OR

CH2R

OR1

2

34

anti-clockwise = (S)

Page 15: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

Axial chirality II

Axial chirality and atropisomerismAtropisomers - stereoisomers resulting from restricted rotation about a single bondMostly commonly found in hindered biaryls

15

AllenesMirror

CCl

H Cl

HC

Cl

HCl

H(R)-1,3-dichloropropa-

1,2-diene(S)-1,3-dichloropropa-

1,2-diene

axis of chirality

Mirror

PPh2

PPh2

(R)-(+)-BINAP(R)-2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen

-1-yl)naphthalene

Ph2PPh2P

(S)-(-)-BINAP(S)-2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen

-1-yl)naphthalene

axis of chirality

Page 16: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

Axial chirality III• Atropisomerism is not just found in biaryl compounds• Any molecule in which rotation is restricted sufficiently to allow isolation of each

isomer can be chiral...

16

MeOCHO

NOMeO

CHO

NO

Xrotation around

central bond

• Atropisomerism is found in nature• Vancomycin is an anti-bacterial• Kotanin is from rice mold

OO

MeO

Me

MeO

Me OMe

O

OMe

O

kotanin

NH

HN

HN

NH

HN

NH

NHMe

Me

Me

OO

O

O

O

HO OHOH

O O

O

NH2

OHHO

O

Cl

Cl

O

HOHO

OH

OOMe

NH2OH

Me

HO2CO

Vancomycin

Page 17: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

Helicity

• Molecules that twist like a helix, propeller or screw• Right-handed helix is denoted P (clockwise as you travel away from viewer)• Interestingly, [8]helicene racemises (1:1 mixture of enantiomers) readily at 293°C!

17

P [8]helicene M [8]helicene

Mirror

Page 18: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

Planar chirality• Planar chirality - chirality resulting from the arrangement of out-of-plane groups

with respect to a plane, called the chiral plane• In [2.2]paracyclophane the more substituted benzene ring is considered the chiral

plane

18

NH2

(R)-4-amino[2.2]para-cyclophane

H2N

(S)-4-amino[2.2]para-cyclophane

Mirror

NH2

plane of chirality

Page 19: Advanced Organic Chemistry - Massey Universitygjrowlan/stereo/lecture1.pdfAdvanced organic Chirality and biology II • As you can imagine, these two complexes can have very different

Advanced organic

Planar chirality II• Probably the most important planar chiral compounds are ferrocene derivatives• These have found considerable use in enantioselective catalysis

19

Fe PPh2

PhFePh2P

Ph

(S)-2-phenyl-1-(diphenylphosphanyl)

ferrocene

(R)-2-phenyl-1-(diphenylphosphanyl)

ferrocene

Mirror

• An interesting example of planar chirality is found in some (E)-cycloalkenes

H

H

(R)-(E)-cyclooctene

H

H

(S)-(E)-cyclooctene

Mirror