Organic synthesis II

! Organic Synthesis II: Selectivity & Control. Handout 2.1
! Regioselectivity: a recap
! Reacting the less reactive:

kinetic and thermodynamic approaches
Trianions (and last in, first out)

! Protecting groups for oxygen: Silyl ethers

Benzyl Ethers
Acetal and Ketals
Carbohydrates and protecting groups
Selective cleavage of benzylidene acetals
THP and butanediacetal protecting groups

! Case studies in protection:

Synthesis of a segment of Epothilone, a complex natural product
The synthesis of specifically functionalized carbohydrates

! Synthetic Planning:

Reactivity and control provide synthetic ‘guidelines’

! Books & other resources:

1. Organic Synthesis: The Disconnection Approach
(Warren & Wyatt, Wiley, 2nd Ed., 2008)
2. Classics in total synthesis
(Nicolaou & Sorensen, Wiley, 1996).
3. Protecting groups

(Kocienski, 3rd Ed., Thieme, 2003)

! Organic Synthesis II: Selectivity & Control. Handout 2.2
! Synthetic Planning:

Reactivity and control provide synthetic ‘guidelines’

! Two group disconnections:

Two approaches to Mesembrine
(i) intramolecular Mannich & MVK Michael addition
(ii) Birch Reduction & Cope rearrangement route

! Pattern Recognition:

The Diels Alder reaction
Guanacastepene and a masked D-A disconnection
The intramolecular Diels Alder reaction: Indanomycin
Hetero-Diels Alder reactions: Carpanone

! Two directional synthesis

Total synthesis through bi-directional synthesis

! Pharmaceuticals

Commercial-scale synthesis of Crixivan

! Pericyclic cascades

Colombiasin total synthesis
Vinca alkaloid total synthesis

! Books & other resources:

1. Organic Synthesis: The Disconnection Approach
(Warren & Wyatt, Wiley, 2nd Ed., 2008)
2. Classics in total synthesis
(Nicolaou & Sorensen, Wiley, 1996).
3. Protecting groups
(Kocienski, 3rd Ed., Thieme, 2003)


! Hydrogenation: metallic catalyst+hydrogen
! Reductions of alkenes: usually Pd metal on carbon support (and H2 gas)
H

Pd/C
Ph

Ph

H

H2(g)

E alkene

H

Pd/C
Ph

Ph

Ph

H2(g)

H

Ph

Ph

chiral (but racemic)

Ph

Z alkene

meso-product

Generally: overall stereospecific syn-addition of hydrogen across the alkene
Pd, Pt, Ru, Rh can all be used in hydrogenation processes

! Mechanisms of ‘heterogeneous’ hydrogenation are complex
H2 on catalyst
surface

Alkene on
catalyst surface

Ph
H

Ph

H

syn-reduced
product

Ph

Ph
H

‘half hydrogenated’
state

Ph

H

H

adsorption

H

Ph

H
addition

H
addition

Ph

Ph

H2 (g)
Substrate binds to catalyst surface from one face leading to overall syn-hydrogenation

! Hydrogenation: metallic catalyst+hydrogen
! More substituted alkenes are reduced more slowly
slower
than

R3
R1

R4

slower
than

R3

R1

H

R3

R3

tetra-substituted

tri-substituted

slower
than

R3
R1

H
H

H
R1

H
H

di-substituted

mono-substituted

This can be attributed to steric hindrance to adsorption onto the catalyst surface

! We can also achieve selectivity in hydrogenation
O

H H Me

O
H2 (g)
Pd/C

Alkene is selectively reduced
(C=C ! weaker than C=O !)
Regioselectivity

O

H2 (g)

O

Pd/C
H

H

Syn-addition of hydrogen
Stereoselectivity a consequence of
geometry (less hindered face)

! Birch-type reduction of ",# unsaturated ketones
! Birch-type reductions of ",# unsaturated ketones give enolates as intermediates
Protonation on
oxygen
H OtBu

Na
NH3(l)

O
R1

R2 tBuOH
(1eq.)

Proton transfer
(inter/intramolecular)

O
R1

Na
NH3(l)

OH
R2

R1

H

O

OH

R2 "e " R1

R1

R2

Radical anion

R2

Enolate anion more
stable than other anion

! These enolates can be used as reactive intermediates in ‘tandem’ reaction sequences

O O

O O

O O

1. Li, NH3

1. Li, NH3
2. MeI

2. CN-CO2Me

O

H
EtO2C Me

CO2Et

O O

O
EtO2C

Reduction affords ester enolate that
is alkylated with methyl iodide

H

Reduction affords ketone enolate that is acylated
with methyl cyanoformate (see earlier!)

! Oxidation of enolates and enol ethers (electron rich alkenes)
! Birch reduction-enolate oxidation sequence
H

O

1. Li, NH3
tBuOH
2. Et3SiOTf

Me

OSiEt3

H
Me

Oxidation of silyl enol ethers:
the Rubottom reaction

2. Bu4N+F-

H

Protonation occurs to afford
cisoid-ring system. Silicon traps
on oxygen (hard electrophile)

HO

1. m-CPBA

H
Me

H

H

Oxidation from top face
(opposite bicyclic ring system)
Strong Si-F bond in desilylation

! Dioxiranes are alternative oxidizing agents for these materials
Weak O-O bond

OTBS

O
O

Dimethyldioxirane ‘DMDO’
Weak O-O bond
Electrophilic oxidising
agent - v. mild
Biproduct is acetone

O

BnO

OTBS
OTBS

O

O

PMBO

sulfonic acid

PMBO

OTBS

BnO

OTBS
OTBS

Rubottom reaction via: (I) epoxidation (ii) epoxide
cleavage via oxonium formation (iii) silyl migration
‘Protecting groups’:TBS = tert-butyl dimethylsilyl, Bn = benzyl
PMB = para-methoxybenzyl (see later in the course)

O


! Oxidation of enolates and enol ethers (electron rich alkenes)
! Oxaziridines can be used to perform similar transformations
Generation of
potassium enolate

O

N

Me

RO2S

OTBS
1. KHMDS, THF

Oxaziridine (chiral but rac)
Weak N-O bond
Electrophilic oxidising
agent - v. mild

O

H

2. Oxaziridine

O

Me

HO
O

H

OTMS

OTBS

O
OTMS

Oxidation of enolate
with oxaziridine

! Stereochemical information can be transmitted with chiral dioxiranes

O

O

chiral dioxirane
catalyst (10 %)

O
O

O

Ph

Ph

O
Ph

Oxone, pH 10.5

Ph

O
O

Oxone is the reoxidant
(2:1:1 mixture of
KHSO5, KHSO4, K2SO4)

Dioxirane (non-racemic)
Weak O-O bond
Can be made catalytic
with a reoxidant

97:3 ratio of
enantiomers

! Selective oxidations of alkenes
! For alkenes there are essentially two modes of oxidation:
O

allylic oxidation

C=C oxidation

R1

H

R1

H

R1

O

O

! C=C oxidations: Recap - OsO4 oxidation of alkenes
[Os(VIII)]
[Os(VIII)]

R2

NMO

O

O
O Os
concerted
O

OsO4

R1

[Os(VI)]

O

R1

syn addition

R1

O
O Os
O

R2

R2

Re-oxidation
Overall: syn-stereospecific
dihydroxylation of an alkene

O
NMO =

OH

R1

R2

N

O

OH

H2O

O
+ HO Os
OH
[Os(VI)]

Generally: dihydroxylation from
the least hindered face

O

Compare with Woodward and Prevost methods for dihydroxylation
(see Dr E. Anderson Course HT 2011)


! Selective oxidations of alkenes
! The dihydroxylation reaction is accelerated by amines (catalysis)
[Os(VIII)]
L

[Os(VIII)]

O Os

OsO4

R1
R2

O

O
O

R1

NMO
R3N (=L)

[Os(VI)]

concerted
R1

syn addition
R2

L
O
O Os O
O

O

OH

H2O

+ HO Os O +
OH
[Os(VI)]

OH

R1
R2

R2

L

Re-oxidation

! We can transfer chirality from the amine to permit asymmetric dihydroxylation
Os(VIII)

Et
N

H

H

N N
O Et

O

tBuOH-H O
2

N
H

H

MeO
N

reoxidant
(DHQD)2-PHAL

OMe

HO

OH

Ratio of enantiomers: 99:1
Selective for most
electron-rich alkene

N

L = Amine ligand ‘(DHQD)2-PHAL’

! Recap: allylic alcohol alkene oxidations (see Dr Anderson course, HT 2011)
! Allylic epoxidation: m-CPBA-mediated
OAc

OAc

OH

Ar

OH
O

m-CPBA

m-CPBA

O

O

H

O
H

O

O

Major diastereoisomer
Sterics: least hindered face
is oxidized

Major diastereoisomer
Intramolecular H-bond stabilizes TS
and directs oxidation

H

! Allylic functionalization: Vanadium and Zinc mediated process
OH

OH
VO(acac)2
tBuOOH

OH

tBu

O

O
O

OH
Zn

O
V OR

CH2I2

O

Major diastereoisomer
Alcohol-directed epoxidation

H

Major diastereoisomer
Hydroxyl-directed
cyclopropanation

H
H

I

Zn
O
H


! Allylic alcohol reactions: Sharpless asymmetric epoxidation

! Reactions directed by the allylic alcohol are faster & more selective
tBuOOH

(>1 eq.)
Ti(OiPr)4 (10 mol%)

M

X

CO2Et

EtO2C

H
R1

O

OH

OH

O

97:3 ratio of
enantiomers

OH
(10 mol%)

OH

OH

Chirality transferred from the diethyl tartrate to the product

! The complex formed by the reagents is, well…..complex
EtO2C
tBuOOH,

iPr

O

Ti(OiPr)4

OH

iPr

CO2Et

EtO2C

E

iPr

O

iPr

O

O

R

Ti CO2Et Ti CO2Et
O

O

HO
O
O

iPr

O

O

Ti CO2Et Ti
O

O

O

O
O

O
O

O

OH

O

O

L-(+)-diethyltartrate

tBu

tBu

EtO

EtO

[L-(+)DET]

R

Alkene coordinates to complex
and is epoxidized

! Allylic alcohol reactions: Sharpless asymmetric epoxidation
! Luckily there is a mnemonic to work out which enantiomer is produced
D-(-)-DET delivers oxygen to top

E
iPr

O
iPr

O

O
O

O

HO

Ti CO2Et Ti
O

O

O
O

O

Arrange substrate
with hydroxyl
group to left

O
R

R

HO
R

tBu

L-(+)-DET delivers oxygen to bottom

EtO

! Examples:
Me
Me
Me

Me
OH

Ti(OiPr)4
(-)-DET
tBuOOH

Me

Me

O

Chemoselective
oxidation of allylic alkene

OH

Me
Me

Highly enantioselective
oxidation of alkene


! Wacker Oxidation
! Mild method for oxidation of terminal alkenes
O

PdCl2, H2O
R1

CuCl2, O2

Generally gives this
regiochemistry of oxidation

R1

! Generalized mechanism:
Pd(II)
Cl

Cl

Cl

Pd

H2O

L
R1

Cl
Pd

R1
effective
oxypalladation

!-complex
electrophilic Pd(II)

Pd Cl

R1

L

L
Cl
OH Pd
H

L

HO H

R1

L

"-hydride
elimination

!-complex
Pd-H readdition

L Cl
Pd
OH
L
H
R1

O

R1

Elimination

Pd(0)

Reoxidation with Cu(II)

Attack of nucleophile (in this case H2O) is regioselective for the most substituted position
Probably a consequence of charge stabilization in the TS (compare with attack of water on
bromonium ions) but also a preference to put the bulky Pd in the least hindered position

! Oxidation of the allylic position
! The second of our two modes of reactivity:
O

allylic oxidation

C=C oxidation

R1

H

R1

H

R1

O

O

! Oxidation in the allylic position is often a rearrangement process
H

O

OCrO(OH)

O
Cr
O

Cr(VI)
Ene reaction

OH

O
Cr
OH
O
2,3-sigmatropic
shift

and/
or

-Cr(IV)
or Cr(II)
Cr(IV)
Disproportionation?

O

Allylic alcohol often
oxidized in-situ

! Selenium dioxide can also be used: ‘Riley Oxidation’
H

O

O
Se
O

Se

Can be made catalytic in Se
with tBuOOH reoxidant

OH

O
and/
or

Se
O

Se(IV)

OH

O

Se(II)

-Se(II)
or Se(0)


! Chemoselectivity in Oxidation
! Epoxidation vs Baeyer-Villiger: a comparison
Epoxidation

Baeyer-Villiger
(–)
O

O
H

H

R
O O

H O
O

R
O O
(–)

(+)

O

LUMO
O-O "*

HOMO
C=C !

R

O

RCO3H

O

HOMO
C-C !
O

O

(+) O

O

O
(+)

+ RCO2H

+ RCO2H

H O(–)

LUMO
O-O !*

R

O (–)

Comparison: Though epoxidation is electrophilic attack on an
alkene and Baeyer-Villiger rearrangement is nucleophilic attack on
a C=O group, the slow steps both use the O-O !* as the LUMO
CF3CO3H is the best peroxy acid for both reactions.

So difficult to achieve chemoselectivity by choice of reagent

! Oxidation: Epoxidation vs Baeyer-Villiger

! A delicate balance - take each case on its merits!
O

O

RCO3H

H

O

O

RCO3H
!max: 1715 cm-1

• Normal ketone

H

O

• Alkene is trisubstituted so more nucleophilic

O

H

H
RCO3H

MeO

MeO

!max: 1745 cm-1

• very strained ketone - strain
relieved in slow step

mCPBA

O

NaHCO3
CH2Cl2

H
O

• alkene is only disubstituted
and only slightly strained

O
O

• Nothing wrong with
epoxidation!

• strained ketone - strain relieved in slow step

• alkene is disubstituted and only slightly strained

Note regioselectivity in Baeyer-Villiger oxidation:
more substituted carbon atom migrates with
retention of configuration

O
O

H

!max: 1780 cm-1


! Oxidation: Epoxidation vs Baeyer-Villiger of conjugated enones
! Chemo-selectivity and regioselectivity
pKa H2O : 15.6
pKa H2O2: 11.8
O

O

O

O

H2O2
Ph

H2O2

Ph

NaOH

O
O

HOAc

O

new, high
H energy HOMO

Ph
True reagent:

True reagent:

O O
!-effect:
raises HOMO (kinetic)
increases acidity
(thermodynamic)

O

O

O

H

O

O

normal peroxyacetic acid

H

normal B-V: alkene is
better migrating group

! Mechanism:
O OH

O

O

O

Ph

better nucleophile
than base
high energy HOMO

OH

O

O

Ph

Ph

weak O–O bond means
bad leaving group OK

! Regioselectivity: recapitulation of previous examples
! Generation of functionalized aromatic compounds
Cl
Cl

NO2

SR

PhSH
Base

Cl

NO2

NO2

HNO3
H2SO4

Me

Only the ortho-leaving group
is substituted

O2 N

NO2

Me

Combination of directing effects
lead to specific nitration

! Elimination processes
E1 elimination

OH
H2SO4

E2 elimination

Me

NaOH

Me

Br
This geometry is the major product:
consequence of lower TS energy
(consider steric effects in intermediate
cation & relate to TS energy)

This geometry is the major product:
H and Br must be antiperiplanar.
This reaction is stereospecific


! Complex materials are polyfunctional: selectivity?
! Functional groups may have the same type of reactivity:
OH

O

NaBH4

O

O

OMe

O
OMe

use selective

reagent

ketone - more
electrophilic

OH
protect more
reactive group

ester - less
electrophilic

! How do we access a kinetically less reactive functional group?
HO
O

O

OH

O

H+

OMe

1. LiBH4

O

O

OMe

Ketone more electrophilic than
ester: exploit in temporary
blocking group formation

2.

H+,

O

H2O

OH

Ester now only electrophilic group.
Can be reduced selectively, and then blocking group
can be removed to regenerate ketone

The use of ‘protecting groups’ can allow us to perform selective transformations
but they add length and complexity to many synthetic routes
(we have to put them on and then take them off too!)

! Reacting the less reactive group
! Functional group reactivity can be a thermodynamic or kinetic phenomenon
Thermodynamic
product in base

Amino alcohol has two
reactive functional groups

Thermodynamic
product in acid

Treat with base

HO

PhCOCl

Ph

N

Et3N

O

PhCOCl

HO

H+

HN

Ph

O
HN

O
Treat with acid

! The most stable product predominates under the reaction conditions

HO

H+

O

N

Ph
O

Ph

Amides are thermodynamically
more stable than esters:
predominates in base

H+
OH

H+

O

N
Ph

HN
O

O
Ph

H2N
O

Basic nitrogen is
protonated in acid: unable
to function as nucleophile


! Reacting the ‘less’ reactive group
! Accessing challenging patterns of reactivity
pKa = 25
H

H

H

H

These pKa values suggest that we
cannot make the requisite anion by
selective deprotonation
(as the terminal C-H is a lot more acidic)
pKa = 35 ish

How do we access an
anion like this?

! A solution: make a tri-anion to allow access to the less reactive position
…then the next
most acidic

H

Li

Li

H

BuLi

2 BuLi

O

Li

OH

then H+
H

Li

Li

Remove two most
acidic protons…

H

Anion reactivity:
last in, first out

Intermediate in the
synthesis of estrone

! Protecting groups for oxygen
! Blocking groups allow access to the less reactive functional group
In principle:

In practice:

Li

OH

C-C

O

OH

H

Li

O

Li
Not the
desired
material

Br

Br
Simple disconnection; exploits
acidity of alkyne

Br

Strongly basic lithium reagent
deprotonates alcohol

A solution is to use a protecting group to block the reactivity of the alcohol functional group

! Silyl ethers are effective and versatile protecting groups for alcohols
Shortened to ‘TBS’
tBu

Me
Si

OH

Br

Cl

Me

N

NH

Me
O

tBu

Si

Li

Me

Imidazole is a weak base and
nucleophilic catalyst

O

TBS
Bu4NF

OH

Br
Bu4NF is a source of F-


! Protecting groups for oxygen
! Mechanisms: Silyl protection…..
tBu

Me
Imidazole is nucleophilic
and weakly basic

N

N

Me

NH

pKa imidazole = 7.6

Me

Si

Me
N

Imidazole is
regenerated….

tBu

Me

-HCl

Si
Cl

pKa ROH
= 16 ish

O

OH
R1

R2

tBu

Si

N

Me

R1

NH

R2

Simplified: silicon can form fivevalent ‘ate’ complexes’

…and also
functions as a base

! …..and deprotection: Si-F is a strong bond (142kcal mol-1; Si-O 112kcal mol-1)
‘ate’ complex

O
R1

tBu

Si

Me

F Bu4N

R1

Si

Bu4N

Si Me
O
F

Me
R2

tBu

F

Me
OH

O Bu4N

R2

R1

‘TBAF’ (tetrabutylammonium fluoride) is
an organic-soluble fluoride source

Sources of fluoride:
HF.pyridine
TBAF
TBAT

tBu

Me
Me

R1

R2

R2

Bu4N

Strong Si-F bond

F
Ph
Ph Si Ph
F

Silyl ethers are generally removed by treatment with fluoride or under acidic conditions
but can also be hydrolysed under basic condition (sodium hydroxide)

! Protecting groups for oxygen
! Different groups on the silicon change the nature of the group:
Me
O

Me

Me

Si

O

Me

R1

R2

trimethylsilyl
'TMS' group

R1

iPr

tBu

Si

O

Me
R2

t-butyldimethylsilyl

'TBS' group

R1

Ph t
Bu
Si
O
Ph

iPr

Si

iPr

R2

R1

..and many other
variations too; steric

and electronic effects
influence stability

R2

triisopropylylsilyl
'TMS' group

t-butyldiphenylsilyl

'TBDPS' group

acid

1

20000

700000

5000000

base/F-

1

20000

100000

20000

Rates (1/krel)
[bigger = slower]

! Exploiting the different steric environments of alcohols; selectivity in protection
Two alcohols:
one 1˚ and one 2˚
TBSCl is capable of
reacting with both
(3˚ alcohols usually inert)

OH
CO2Me
OH

TBSCl
imidazole
DMF, -10˚C

OTBS
CO2Me
OH

Selective protection of 1˚ alcohol:
less sterically hindered & faster reacting

Similar selectivity for hydrolysis reactions too: 1˚ hydrolysed faster than 2˚

! Protecting groups for oxygen
! ….and selectivity in deprotection
OTIPS

Silyl ethers are generally stable to
weak acid and base, and oxidizing
and reducing conditions
(except TMS: very labile!)

OTIPS
LiOH
EtOH/H2O

MeO
OTBS

O

MeO

90˚C

They are removed with strong
acids (inc. Lewis acids), strong
base and fluoride

OH

O

Selective removal of 1˚ TBS group
rather than 2˚ TIPS group

! Benzyl ethers: alternative protecting groups for oxygen
Br

Generally stable to
acids, bases and
fluoride

H2 (gas)
R1

OH

R1

NaH, DMF

O

R1

Pd/C

Made by the classical Williamson
ether synthesis

OH

Orthogonal to silyl
ethers

Removed by hydrogenation
Pd common, but Ru, Rh, Pt also

It is important to recognize that protecting groups are a (somewhat) necessary evil
which can help or hinder efficiency in synthesis.
Their use must be considered in the overall strategic approach to a synthesis

! Protecting groups for oxygen: acetals and ketals
! Acetals can be used to protect ketones or to protect diols
O

1. LiBH4

O

O

OH

O

2. H+, H2O

OMe

O
Acetone

HO
OH

H+

CH3
Ketone masked as an acetal to allow for
reduction of less reactive functional group

O
CH3

Protect diol as a ketal
with acetone and acid

! Acetal groups you are likely to come across
OMe
For alcohols
Generally
n= 0, 1
For 1,2 and
1,3 diols

H3C CH3
O
R1

O
n

O
R2

‘acetonide’

R1

O
n

O
R2

‘benzylidene’

R1

O
n

O

O

R1

R2

‘p-methoxy

benzylidene’

Tetrahydropyranyl
‘THP’

Reminder: acetals are generally made and hydrolysed under acidic conditions


! Protecting groups for oxygen: acetals and ketals
! Under thermodynamic control aldehydes select for 1,3-diols; ketones for 1,2 diols
Ph

OH
O

Aryl group
equatorial in chair

O

O

OH

O
O

O

O

HO

Ph

OH

PhCHO/H+

OH

HO

OH

major
OH
O

Ph
H

major

OH

D-Mannitol

O
O

Me

[used as a sweetener;
derived from mannose]

O

O

OH

Me2CO/H+

Me ) ( H

minor

minor
Disfavoured by 1,3 diaxial
interactions

! Selectivity in action: ketones
1,3 diol
1,2 diol

OH
HO
2

1

OH

O

Acetone

3

O

TsOH

2

Choice of 1,2 or 1,3
protection

OH
HO

1

O

O

1

3

85%

Ketone used in protection:
1,2 diol protection

15%

! Protecting groups for oxygen: acetals and ketals
! Selectivity in action: aldehydes

Lewis acid catalyst
can be used instead
of a Brønsted acid
catalyst

H
N

OH
3

OH
1

New stereocentre: puts
group equatorial in
chair conformer

ZnCl2

OH

H
N

PhCHO

2

OBn

N

O

O

3

1

OH
2

OBn

N

aldehyde used in

protection:
1,3 diol protection

Choice of 1,2 or 1,3
protection

! Acetals and ketals can be made under kinetic control too:
2-methoxy propene is more reactive than acetone
in the formation of acetonides

OMe

OH
HO
HO

OH
O
D-Glucose

HO

OH

TsOH
DMF

HO

HO

O
O

OMe

OH

OH

O

HO

OH
O

OH TsOH
DMF

OH
HO
HO

D-Galactose
Ketone selects 1,3 diol: the 1˚ alcohol is the most nucleophilic
and reaction occurs there first
This selectivity relies on preventing equilibration to thermodynamic products

O

O

O


! Protecting groups for oxygen: acetals and ketals
! kinetic and thermodynamic control can affect carbohydrate ring size
Carbohydrates are hemiacetals
5- (furan) and 6- (pyran) ring systems exist in equilibrium

Most stable

SLOW

HO

OH

Fastest formed

OH
O

HO
O

OH

OH

HO

OMe

O

equilibrium
ratio

1

HO

O
4

OMe

O
O

HO
OH

HO

O
Thermodynamic

Acetone

HCl, MeOH

OH
OH

HO

bond
rotation

HO

OH

TsOH
DMF

HO

O
Kinetic

OH
O

O

HO

HO

Furan system is probably most
stable as 6-ring protected suffers
from 1,3-diaxial interactions

Interconversion of 5- and 6-ring
systems slower than protection
under kinetic conditions

Very difficult to protect diequatorial diols with acetals using the groups we have seen so far

! Protecting groups for oxygen
! Benzylidene acetals can be regioselectively cleaved
OR'
RO
MeO

OBn
OH

O

OR'

Lewis acid or
Brønsted acid,
hydride donor

RO

DIBALH
Bu2BOTf
/BH3.THF

Lewis acid or
Brønsted acid,
hydride donor

O

MeO

O

O

OR'
RO

OH

TFA/Et3SiH
NaBH3CN/HCl MeO
AlCl3/BH3.NMe3

1˚ alcohol product
Generally with
Lewis acids

OBn

O

2˚ alcohol product
Generally with
strong protic acids

! Mechanism with Lewis acid
Coordinates to least
hindered end

Reduces oxonium-type
intermediate
benzyl ether

O
O

O

O
O

DIBALH

DIBALH is
Lewis acidic

O

O
R

Al

H
R

O

OBn
O
R

Al

H
R

Intramolecular delivery
of hydride

O

OH

1˚ alcohol
product

! Protecting groups for oxygen: acetals and ketals
! A special sort of ketal can be used for trans- diols
OH
HO
MeO

O

OMe

OH
O

HO
HO
HO

OH

OMe

O

Diequatorial diol

MeOH,

CH2OH

HO

O
O

O
H+

OMe

HO

O

MeO

OMe

OMe

OMe

O

OH
O

O

CH2OH

Product populates chair conformation

OMe groups axial for maximum
anomeric effect (stabilizing!)

Mannose-derived: 4 alcohols (3 x 2˚
alcohol and 1 x 1˚ alcohol)

! The tetrahydropyranyl (THP) group is an acetal protecting group for alcohols
Mixture of diastereoisomers
(for chiral R1)

H
R1

Acetals: made
& hydrolyzed
in acid

H

OH

usually
TsOH

O

O

O

R1

HO

'dihydropyran'

O

R1

THPO

Oxonium-type
intermediate

R1

often abbreviated
like this

! Protecting groups: Case study I
! A fragment of a complex natural product: Epothilone
S
Me

O
N

12

Me

chiral
aldehyde

13

Me
Epothilone
Anti-cancer

OP1

OH

15

Me

O

Me
O

OH

OP1

12

15

13

OP2

OP3

vinyl
metal

O

M

Me

M

O
Allyl
metal

O

! Synthesis exploits orthogonal protecting group strategy
Use oxygen to direct
addition to aldehyde

OBn

chelation
controlled
allylation

Bn and TBS groups not
usually cleaved by oxidation

OBn

Me
O
Choose benzylic
protecting group

TBSCl
imidazole

O3, PPh3

97% yield
OH

OBn

OBn

O

98% yield

OTBS
Silicon protecting group:
orthogonal to Bn

OTBS


! Protecting groups: Case study I
! A fragment of a complex natural product: Epothilone
mix of diastereoisomers
Ratio = 3:2

OBn

OBn

Selective removal of Si group
(Bn not touched by fluoride)

O BrMg
89% yield

OBn

OBn

1. TBAF
2. TsOH,

1. O3, PPh3

OTBS

TBSO

OH

O

O

O

O

94% yield
(2 steps)

98% yield
(2 steps)

Stereocentre 1,3- to aldehyde so
difficult to control facial
selectivity of addition

O

2. K2CO3
MeOH

MeO OMe

Selective protection of diol(s)
Bn not touched by acid

! Protecting groups are not always spectators: final step epimerization
O

OBn
O

O
O

K2CO3

O

R

H

O

O

K2CO3
O

MeOH

R

H

MeOH

H

Desired diastereoisomer
Groups equatorial on ketal chair
Thermodynamically most stable
Predominates at equilibrium

OBn

H

O

O
O

O

R

O

O

O

H

Undesired diastereoisomer
One group axial on ketal chair
Thermodynamically less stable

Enolate
intermediate

! Protecting groups: Case study II
! Carbohydrate targets often require access to specific functional groups
OBn
O

5

HO

OH

OH
OH

4

O

HO

OH

4

OH

5

HO

Need access to
C-2 and C-3

HO

O

N3

4
5

OH

MeO

OH

O

Need access to C-1 and
C4 (with inversion)

D-Glucose

! D-Glucose is a polyfunctional material
HO

OH
1 x hemiacetal
3 x 2˚ alcohol
1 x 1˚ alcohol

HO

OH

4
5

HO

O

OH

Pyran
(2 diastereomers)

HO
O

4

OH
5

CH2OH

HO
HO

OH
4

O

OH
Open-chain
aldehyde

OH
5

OH
Furan
(2 diastereomers)

Must consider the position of these equilibria in carbohydrate manipulations


! Protecting groups: Case study II
! Carbohydrate targets: examples of chronic protection!
Thermodynamic
ketal formation

OH
HO

OH

4
5

HO

O

OH

Acetals hydrolyzed
and made in acid

4

O

2. NaH

BnBr

OBn

OBn

O

1. Acetone
TsOH

O

Pyran with axial C-1 group:
Anomeric effect

1. MeOH
HCl

HO

5

2. PhCHO
ZnCl2

O

5

MeO

NaH
PrBr

OBn
O

OBn

5

HO

CF3CO2H

OH

4

O

O

Benzyl ether
untouched in acid

Ph

O

4

O

O

H2O

OH

O

5

MeO

Ph

O

4

O

O

Strong acid hydrolyses acetals
& ketals; ethers left untouched

This is an extreme example of the use of protecting groups: we should aim to minimize their
use through the application of chemoselective transformations where possible.

! Synthetic planning, reactivity and control
! How do we approach the synthesis of complex materials?
OMe
MeO

Strategy

Tactics
Control

The plan, as defined
by disconnection

O

Which reagents and
methods we use

N
H Me

! The basics of synthetic planning: some ‘guidelines’ to consider
OMe

1. Use two-group disconnections

MeO

2. Disconnect at branch points
3. Disconnect rings from chains
4. Disconnect to recognisable starting materials
5. Use symmetry elements if possible
6. Analyse oxidation states and potential FGIs
7. Chemoselectivity is key to efficiency

O
O

Li

N
Me

Three simple fragments:
How do we choose this approach?


! Look for two-group disconnections
! Case study I: Mesembrine; two obvious two-group disconnections
OMe

OMe

MeO

OMe

MeO
C-N

C-C

1,3-di X

1,3-di X

HN

O

MeO

N
H Me

O

Me

N
Me

O

! Both disconnections are viable: examine C-C disconnection first
MeO

MeO

MeO
Disconnect:
Branch point
Rings from chains

C-C

C-C

O

Li
N
Me

O

Aryl lithium made by
Halogen-metal
exchange

OMe

OMe

OMe

N

Me

N
Me

O

Methyl vinyl ketone
Common 4-carbon building block

! Look for two-group disconnections
! Putting it together:
OMe
MeO

MeO
OMe

2 eq tBuLi

MeO

MeO

MeO

MeO

H+

THF, -78˚C

HO

O

Br

Li

Need two eq. BuLi
(one for reaction, one to
destroy tBu-Br formed)

-H2O
N
Me

N
Me

t

high b.p.
solvent

N
Me

OH

OH
heat

OMe
MeO

O

OMe
MeO

N
H Me

O

E1 elimination

OMe
MeO

N
Me

Intramolecular
Mannich

O

methyl vinyl
ketone

MeO
MeO

N
Me

This enolate
unproductive

O

N
Me


! Look for two-group disconnections
! Mesembrine disconnection II (more complex!)
Call this group
ʻArʼ for clarity
OMe

OMe

MeO

OMe

MeO
C-N

FGI

reductive
amination

[ox]

HN

O

MeO

Pattern for [3,3]:
Two alkenes three
bonds apart

O

O

O

Me
Cope
[3,3]

Ar

Ar

FGI
[red]

MeO

MeO

O

CO2NR2

CO2NR2

Add EWG for selectivity
over other arene
ʻcontrol groupʼ

Ar

Easier to
functionalize next
to carbonyl

Birch reductionalkylation?

! Look for two-group disconnections

! Mesembrine final steps:
Enol ether
hydrolysis

Non-conjugated
diene formed

Ar 1. Li, NH (l)
3
tBuOH (1 eq )
MeO

CONR2

Br

1. Regioselectivity in Birch
directed by EDG and EWG
2. Less electron-rich arene
reduced preferentially

Ar

1. HCl
MeO

2.
CONR2

Ar

Ar

2. 140˚C

O3, Me2S
O

O

O
CONR2

Stereospecific Cope rearrangement
[alkene transposed onto same face]

CONR2

Reductive amination
[reduce intermediate imine,
not aldehyde]

MeNH2
NaBH3CN

OMe

OMe
MeO

MeO

Ar
2 steps
O

O

N
H Me

O
R2NOC
To remove
ʻcontrol groupʼ

N
H Me

R2NOC

HN
Me

Intramolecular
1,4-addition


! Pattern recognition: the Diels-Alder reaction
! Simplest pattern: 6-ring containing an alkene

O

OMe

FGI

Simplest D-A pattern

OMe

D-A

FGI to reveal D-A pattern

Remember: we generally need EDG on the diene
and EWG on the dienophile to accelerate the reaction
(this lowers the HOMO-LUMO gap, in the FMO treatment)

! and don’t forget models for the actual reaction:
CH3

!4s
H3C
O

O
O

!2s
HOMO diene

LUMO dienophile
In FMO terms

[4q+2]s =1; [4r]a = 0
Total=1: Allowed
(by Woodward-Hoffman)

O

O
Endo-TS favoured
(2˚ orbital overlap)
Kinetic product

H3C

H
H
O

H

H

H3C H H

H

Draw product in
same orientation as

the starting material

…but no obvious
disconnection

O

H

OH

6

AcO

OH

1

MeO2C

3

MeO2C

6

O

O

reconnect

1

C-O

3

CO2Me

MeO2C
MeO2C
Baeyer
Villiger

OR
CO2Me

OR

CO2Me

HOMO diene
LUMO dienophile
In FMO speak

Diels
Alder

MeO2C
MeO2C

6-ring with alkene
highlighted

O

FGI
ketone enol ether

MeO2C
MeO2C

O

Rotate to flat and
transcribe
stereochemistry

! Complex natural product example disconnection: Guanacastepene

O

O
O

! Pattern recognition: the Diels-Alder reaction

6-ring looks promising

for Diels-Alder….

H


! Pattern recognition: the Diels-Alder reaction
! …and the actual synthesis:
D-A: EDG on diene…
Trap to form silyl
enol ether

O

OSiMe3

1. LDA

Me3SiO

CO2Me

2. TMSCl

CO2Me
CO2Me

then H+
O

OH

O

MeO2C

O

MeOH, H+

mCPBA
MeO2C

MeO2C

…EWG on
dieneophile

MeO2C

Kinetic enolate
formation (not
extended enolate)

CO2Me

MeO2C

MeO2C

Hydrolyze

enol ether

MeO2C
Baeyer-Villiger:
most substituted
group migrates

Note: the six membered ring that we start with is not the one that ends up in the product
(as a consequence of the oxidative cleavage in the B-V reaction)

! Pattern recognition: the Diels-Alder reaction
! Intramolecular Diels-Alder
Intramolecular
D-A pattern
Disconnects two rings
Simplest D-A pattern

! Example: Indanomycin (an antibiotic ionophore)
O

H
CO2H

O

N
H H

OEt
PO

PO

O
H

EtO2C

H

H

1. Electronics: best with EDG on diene and EWG on dienophile
(or vice versa; an ʻinverse electron demandʼ Diels Alder
2. Stereochemistry: alkene geometry is key (stereospecific)
3. Endo vs exo: must consider length of ‘tether’
4. Intramolecular better than intermolecular (and so the ‘rules’
are less stringent for substituent effects)


! Pattern recognition: the Diels-Alder reaction
! Synthesis plan: consider functional groups; employ appropriate tactics
allylic alcohol
Wittig

trans-alkene with EWG

EtO2C
Wittig
(and FGI)

PO
Part of
SM

stereocentre to control
absolute configuration

trans-trans alkene

! Synthesis:
OEt
OEt

P

EtO2C
TBSO

TBSCl
OH

imidazole

TBSO

O
O

EtO2C

NaH

O
Protects open
chain 1˚alcohol

Horner-Wadsworth-Emmons
ʻextendedʼ phosphonate anion
trans-alkene

O
OH

! Pattern recognition: the Diels-Alder reaction
! Final steps and intramolecular Diels Alder
Only removes
silyl group

Reduces ester to
1˚ alcohol
TBSO

TBSO

1. DIBALH
2. Et3N

EtO2C

1. Bu4NF

O
MEMO

2. Swern

MEMO

OMe
O

An acetal-type protecting
group ʻMEMʼ

Selective oxidation
to aldehyde

Cl

Ph3P

Major Isomer TS
H

H

H

H

OMEM
CO2Et

Minor Isomer TS
Clashing with alkene
hydrogen disfavours

O

OEt
H

H
H

Major: endo-TS
Least hindered

MEMO

toluene

H
H

Stabilized ylide
trans-alkene

EtO2C

110˚C

MEMO
EtO2C

CO2Et

H

OMEM
CO2Et

MEMO
H


! Symmetry and the Diels-Alder reaction
! Extension of the simple D-A pattern: hetero Diels-Alder reactions
O

O

O

Simplest D-A pattern

O

Simple hetero D-A pattern: useful for O, N

! How symmetry can help (I): Carpanone
Patterns to recognize in this case:

H

H

O

O
H
O

H

O

O
H
O

O
O

H
O

O
O

O

O
O

O

Carpanone
6 rings, 5 stereocentres

O

O

O

Unsaturated 6-membered ring
Heteroatom in the ring
Hetero-Diels Alder?

Material is dimeric
Two ʻmonomericʼ skeletons
outlined

! Symmetry and the Diels-Alder reaction
! Disconnection:

H

O

O

Diels
Alder

O C-C

O

H
O

O

O
O

O
O

[ox]

O
O

O

O
O

O

OH

O

! Synthesis: one step (!)
Only this
stereochemistry
produced

O
O

PdCl2
OH

O

O

O

H

O

O
H

O

O

O

O

O
O
O

Palladium(II) probably generates this
delocalized radical

Radical dimerization is FAST
(diffusion controlled)

O
O
O

Carpanone
6 rings, 5 stereocentres


! Symmetry as an aid to disconnection
! Symmetry & ‘two directional’ synthesis
O

H

H

C-C

H

EtO2C
C-C
H

H

N

N

H

EtO2C

CO2Et
C-N

H
N

Dieckmann

H

CO2Et
P

N

P

1,4-addition

H

A hint of symmetry (but
nothing obvious)

Symmetrical
intermediate

! Disconnection of starting material
EtO2C

CO2Et
P

N

O

O

C-C

P

P

N

Symmetrical
intermediate

C-N

P

OH

FGI
[ox]

Maintain symmetry
Two-directional elaboration

! Symmetry as an aid to disconnection
! Total synthesis (I): requires a desymmetrization
Mitsonobu reaction
(N nucleophile)

O

Dihydroxylation and
in situ diol cleavage

NH
O

OH

O

N

OsO4

O

O

N

O

NaIO4

PPh3, DEAD
THF

O

HWE olefination
gives transalkene

Cleaves phthalimide
group to liberate
nucleophilic nitrogen

O
EtO
EtO P

NaH

Imide reactivity
is ketone-like
(so is reduced
with NaBH4 )

O
CO2Et
H

H
N

EtO2C
KOtBu
benzene
Li metal

H

Dieckmann (non-selective; afford
mixture of regioisomers). Li
removes EtOH from equilibrium

CO2Et

H

H

NaBH4;

N
H

then AcOH
80˚C
EtO2C

Key step: facilitates double
intramolecular 1,4-addition to give
only this diastereoisomer

CO2Et

O

O

N

O
CO2Et