1

Reactions of alkenes: stereospecific reactions

• Diastereospecific - reaction permits only one diastereoisomer to be formed
control relative stereochemistry not absolute stereochemistry
• Electrophilic epoxidation via a concerted process is a good example...
H Ph O
m-CPBA
Ar
H Ph
O Ph H Ph H Note: only
O H (E) anti controlling relative
O stereocheimstry
H H O NOT absolute
H Ph
m-CPBA stereochemistry
Ph H H H
Ph Ph Ph Ph
(Z) syn

Iodolactonisation
• Proceeds via an iodonium species followed by intramolecular ring-opening
• Geometry of alkene controls relative stereochemistry

I I I
I2
O
O
Me O H Me O H Me O
Me O H O O
(E) I anti
Me I
I2
O
O H Me O O
(Z) syn
123.702 Organic Chemistry
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Stereoselective reactions
• If there is a pre-existing stereogenic centre then reaction can be stereoselective
• In such reactions two diastereoisomers could be formed but one is favoured
Me Me Me Me
I2 I2
I
OH I
O O O OH O O
O
82% de 88% de

• These cyclisations are probably under thermodynamic control

• This means the reactions are reversible and equilibrate
• Therefore the product is the most stable compound (anti)

• Epoxidation is irreversible and the reaction is under kinetic control

• So how do we explain the following observations...
O O
Me m-CPBA Me Me
+
Me SiMe2Ph Me SiMe2Ph Me SiMe2Ph

>95% <5%

Me Me O O
m-CPBA Me Me Me Me
+
SiMe2Ph SiMe2Ph SiMe2Ph
61% 39%
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Conformations in allylic systems

H H Me H H Me
Me H H H Me if no cis substituent
rotate then only small
H bond Me H
Me energy difference
lowest energy: H slightly higher energy: Me
eclipses plane of alkene eclipses plane of alkene

H Me H Me

X
H H

Me Me H Me Me
cis substituent
H Me H present then only
Me Me high energy: Me–Me ONE conformation
lowest energy: H interaction disfavours
eclipses plane of alkene conformation

• Arguably the lowest energy conformations have greatest separation of (1,3)substituents

• The control of conformation in allyl systems is called allylic strain or A strain

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Stereoselective reactions of alkenes III

• Apply this knowledge to the real system...
X

O O
Me m-CPBA Me Me

Me H SiMe2Ph Me H SiMe2Ph Me H SiMe2Ph

>95% <5%

m-CPBA
m-CPBA
silyl group blocks
X

approach
Me Ph Me Ph H H H
lowest energy H H Si Me H H Si Me Me Me
conformation
Me H Me OH Si Me
Me Me Ph Me
formation of minor
m-CPBA diastereoisomer results
from m-CPBA
approaching alkene in
above conformation or
m-CPBA approaches approaching passed
from unhindered face the silyl group

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Importance of A(1,3) strain

Me Me O O
m-CPBA Me Me Me Me
+
H SiMe2Ph H SiMe2Ph H SiMe2Ph
61% 39%

• The importance of a cis-substituent is made clear by the reduced stereoselectivity

• This is explained as follows...
m-CPBA
X
Ph Me Ph Me
O
lowest energy Me H Si Me Me H Si Me Me Me
conformation H H
gives major product H OH H SiMe2Ph
Me Me 61%

Me Me m-CPBA attacks both conformations low

form least hindered energy -- so mixture of
H SiMe2Ph face products

O
Me H H Me H H O
H Me H Me Me
Me
X

Si Me Si Me H SiMe2Ph
Ph Me Ph Me 39%

m-CPBA
123.702 Organic Chemistry
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Other reactions...
• Epoxidation is not the only stereoselective reaction of alkenes
• Below is an example of hydroboration, a useful reaction that you should be familiar
with...
H Me Me H Me H Me H2O2 H Me H Me
BH3 NaOH

O OBn O H2B OBn O OH OBn

74% de

Attack from the least sterically

O O demanding face of the alkene
H CH2OBn H CH2OBn as it resides in the most
H Me H Me favoured conformation.
H2B H Followed by stereospecific
Me
H2B H
Me
oxidation

preferred
approach Selectivity in addition to cis alkenes

S H L S H L
S H R 1 1
R 3R R
L H S 3
L R1
R1 R1 R1
S = smaller group favoured destabilised by repulsion between C-1 & C-3
L = larger group substituents or A(1,3) strain
123.702 Organic Chemistry
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Directed epoxidation
OH OH OH
reagent
+
O O

reagent: syn t anti

m-CPBA 92 : 8
t-BuO2H, VO(acac)2 98 : 2

• A hydroxyl group can reverse normal selectivity and direct epoxidation

• Epoxidation with a peracid, such as m-CPBA, is directed by hydrogen bonding and
favours attack from the same face as hydroxyl group
• The reaction with a vanadyl reagent results in higher stereoselectivity as it bonds /
chelates to the oxygen

Ar hydrogen
bond O
t-BuO
O
O Me O V O Me V
O O O O O
O H
H Me Me
O
vanadyl acetylacetonate H
H

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Directed epoxidation in acyclic systems

Me Me O O
m-CPBA Me Me Me Me
+
Me H OH Me H OH Me H OH
95 5

hydrogen
Ar bond
Me H H
O O Me Me
O Me H OH
O H H O
H O
Me H H
Me H O O
O
Me H Me
Ar
favoured Me disfavoured
conformation conformation

• Hydroxyl group can direct epoxidation in acyclic compounds as well

• Once again, major product formed from the most stable conformation
• Thus the cis methyl group is very important
• The minor product is formed either via non-directed attack or via the less favoured
...conformation

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Directed epoxidation: effect of C-2 substituent

Me t-BuO2H Me Me
VO(acac)2 Me Me
Me +
O O
H OH OH OH
19 : 1 steric
interaction
Me t-Bu O L
H V
O H O L
favoured disfavoured
conformation as H Me H Me conformation as
only Me & H eclipse O Me Me & Me eclipse
L O
V H
O L
t-Bu H

• The presence of a substituent in the C-2 position (Me) facilitates a highly

diastereoselective reaction
• The preferred conformation minimises the interaction between the two Me (& Me)
groups
• With C-2 substituent (H) there is little energy difference between conformations
• Therefore, get low selectivity
Me
t-BuO2H H
Me Me VO(acac)2 Me Me Me Me O H
+ H too small to
O O H H differentiate
H OH OH OH
O conformations
: L
2.5 1 V
O L
t-Bu 123.702 Organic Chemistry
10

Substrate control in total synthesis

Ph Ph

O VO(acac)2 O
O O O OH OH OTIPS t-BuOOH O O O OH OH OTIPS

O N C1 C13 Me 91% O N C1 C13 Me

Me Me Me Me Me 100% d.e. Me Me Me O Me Me
Bn Bn

• Directed epoxidation from the synthesis of oleandomycin aglcon

• Glycosylated version (R=sugar) is a potent antibiotic from streptomyces antibioticus
• David A. Evans and Annette S. Kim, J. Am. Chem. Soc. 1996, 118, 11323
t-Bu O L
V
O L O
O
H R1 Me
O H
H
Me Me
OH
R2
C13 Me
versus
Me O OR
H C1
H O OR
O R2
Me
H R1 Oleandomycin aglycon
O L (R=H but should be a sugar)
V steric
O L interaction
t-Bu 123.702 Organic Chemistry
11

Stereoselective reactions of alkenes

• Alkenes are versatile functional groups that, as we shall see, present plenty of scope
for the introduction of stereochemistry
• Hydroboration permits the selective introduction of boron (surprise), which itself
can undergo a wide-range of stereospecific reactions
Substrate control
Me H 1. TMEDA H
Me H H Me Me H
BH3 B 2. BF3•OEt2 B
H

Me
(+)-α-pinene (–)-Ipc2BH (+)-IpcBH2

Me Me H
Me H 1. TMEDA Me Me
Me Me Me H
BH3 Me 2. BF3•OEt2 Me
B
BH2
H H H H
Me Me Me

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Hydroboration: reagent control

H
Me H 1. (–)-Ipc2BH Me H H Me
2. H2O2 / NaOH H OH B
Me
Me
Me H
98.4% ee
(–)-Ipc2BH

• The two compounds formed previously, mono- & diisopinocampheylborane are

common reagents for the stereoselective hydroboration of alkenes
• Ipc2BH is very effective for cis-alkenes but less effective for trans
• IpcBH2 gives higher enantiomeric excess with trans and trisubstituted alkenes

Me Me
Me 1. (+)-IpcBH2 H Me H
2. H2O2 / NaOH Me
BH2
H HO
H H
66% ee (+)-IpcBH2

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Hydrogenation: enantioselective catalysis

MeO
H H2(g)
H H
[((S)-DIPAMP)RhL2]
MeO CO2H L=solvent MeO CO2H P P

NHAc H NHAc
AcO AcO OMe
95% ee
(S,S)-DIPAMP

• One of the most important industrial reactions; above example produces amino acids
• Variety of diphosphines can be used
• It is essential that there is a second coordinating group (here the amide)
• On coordination, two diastereoisomeric complexes are formed
• The stability / ratio of each of these is unimportant
• It is their reactivity we are concerned with...
Ar
O
MeO MeO MeO
HO2C N Me
H Ar
P P P P P O Ar P
Rh Rh O Rh
L L
HO2C N Me Me
OMe OMe H OMe N
H
CO2H

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Mechanism for catalytic hydrogenation

Ph Ar Ar
O Ph Ar
P Ar P P O Ar P
Ar Rh O Ph Ar Rh Ph
HO2C N Me
HO2C N Me H Me N CO2H
H + [DIPAMPRhL2] H

H2 H2
slow oxidative fast
addition
oxidative addition fast
complex more
reactive
insertion H H
Ph Ph
H Ar P P O Ar H
Rh O Ar Ar Rh
One complex more reactive
HO2C N
P Me Me N
P CO2H
Ar H H Ar
Ph Ph

reductive
elimination

L L
Ph H Ar Ar H Ar Ar H Ph Ar
H Ar
P O P H O O H P O P
Ar Rh Ph H H Ar Rh Ph
HO2C N Me HO2C N Me Me N CO2H Me N CO2H
H H H H
H minor enantiomer major enantiomer H
123.702 Organic Chemistry
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Enantioselective hydrogenation in action

O [(R)-MeO-BIPHEP-RuBr2] O
MeO 60psi H2, 50°C, THF/H2O MeO
98%e.e.
t-BuO2C CO2Na t-BuO2C CO2Na

O
MeO
H Ph
O N
MeO P Ph
O O MeO P Ph
CO2H Ph

candoxatril (R)-MeO-BIPHEP

• Used in the synthesis of candoxatril, a potent atrial natriuretic factor (ANF)

potentiator (cardiovascular drug developed by Pfizer)
• Process used on a 2 metric ton-scale
• Michel Bulliard, Blandine Laboue, Jean Lastennet, and Sonia Roussiasse, Org.
Process Res. Dev., 2001, 5, 438
123.702 Organic Chemistry
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Organocatalytic hydrogenation
Me
O N
t-Bu
Me O
N H Me O
Bn
H2 Cl3CO2
H H
H H
NC MeO2C CO2Me NC
89%; 96% ee

Me N i-Pr
H
catalyst 10%
hydrogen source 1eq

HE Me δ+ O Me
O Me N H N
δ– i-Pr
N H HE
Ar Bn N t-Bu
O
Bn N t-Bu H N Me
N H H
Me Ph
H
Ar H
Me Me Me
Ar Me Me

• A recent development is the use of small organic molecules to achieve hydrogenation

• Inspire by nature
• Based on the formation of a highly reactive iminium ion (this is the basis of many
organocatalytic reactions)
123.702 Organic Chemistry
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Sharpless Asymmetric Epoxidation (SAE)

Me Me
(+)-DIPT, Ti(Oi-Pr)4, TBHP
O
OH OH
must be 92% ee
allylic alcohol
Me Me
(–)-DET, Ti(Oi-Pr)4, TBHP
Me Me
O
OH OH
Me Me
>90% ee

Me OH OH
Me CO2i-Pr CO2Et
OH i-PrO2C EtO2C
Me O
OH OH
TBHP (+)-DIPT (–)-DET

• Sharpless asymmetric epoxidation was the first general asymmetric catalyst

• There are a large number of practical considerations that we will not discuss
• Suffice to say it works for a wide range of compounds in a very predictable manner
• Compounds must be allylic alcohols
• Second example shows that this limitation allows highly selective reactions

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Sharpless Asymmetric Epoxidation II

Ti(Oi-Pr)4 R2 R3
D-(–)-DET if you want “O” on top its
unnatural isomer TBHP
O on your kNuckles so you
“O” OH use Negative (–)-DET
R1

R2
R3 place alkene using your left hand,
vertical and the index finger is
R1
alcohol in bottom the alkene and your
OH right corner thumb the alcohol

Ti(Oi-Pr)4 R2 R3
“O” TBHP if you want “O” on top its
D-(+)-DET O on your Palm so you use
natural isomer OH Positive (+)-DET
R1

• SAE is highly predictable -- the mnemonic above is accurate for most allylic alcohols
• To understand where this comes from we must look at the mechanism
• A simplified version of the basic epoxidation is given below
TiL4 Ot-Bu t-Bu
O Ot-Bu L
+ L L Ot-Bu
O L Ti L Ti
TBHP L Ti Ti O
L L O
+ O O O
O O
HO
activation of
peroxide 123.702 Organic Chemistry
19

Mechanism of SAE
CO2Et CO2Et
i-Pr i-Pr
i-Pr O i-Pr O
O O
O O O O O O
i-Pr i-Pr
Ti(Oi-Pr)4 + Ti CO2Et Ti t-BuO2H Ti CO2Et Ti CO2Et
(+)-DET OEt
O O O O O O
i-Pr
O O O O
t-Bu
EtO EtO
Active species thought to be 2 x Ti
bridged by 2 x tartrate HO
Reagents normally left to ‘age’
before addition of substrate thus R
allowing clean formation of dimer
CO2Et CO2Et
i-Pr O i-Pr O
O O
O O O O O O
i-Pr i-Pr
HO Ti CO2Et Ti E Ti CO2Et Ti E
O
O O O O O O
R
O O O O
R R
t-Bu t-Bu
EtO EtO
must deliver “O” from lower face
123.702 Organic Chemistry
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R2 OH good substrates
R2 OH high yields and ee's >90%
R1

R3 R3
normally good • SAE works for a wide range of
OH R2 OH
ee's >90% allylic alcohols
R1 R1
few examples
• Only cis di-substituted alkenes
appear to be problematic

R3 problematic
slow reactions
moderate ee's,
OH especially with bulky R3

• Example below shows that SAE can over-ride the inherent selectivity of a substrate
• Furthermore, it demonstrates the concept of matched & mismatched
• When the catalyst & substrate reinforce each other spectacular (or matched) results
are achieved
Me Me Me
Me Me Me
conditions O O
O +
O O OH O OH
OH
O O
t-BuO2H, VO(acac)2 2.3 : 1
t-BuO2H, Ti(Oi-Pr)4, (+)-DET 1 : 22
t-BuO2H, Ti(Oi-Pr)4, (–)-DET 99 : 1
123.702 Organic Chemistry
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Use of SAE in synthesis

SAE Red-Al OH
(+)-DIPT O [NaAlH2(OCH2CH2OMe)2]
Ph OH Ph OH
89% Ph OH
>98%e.e. H

MsCl
CF3
1. NaH
2. ArCl OH MeNH2 OH
O
Ph NHMe Ph OMs
Ph NHMe
fluoxetine

• Fluoxetine is a commercial anti-depressant (better known as Sarafem® or Prozac®)

• Can be synthesized in a number of methods
• One involves the use of the SAE reaction...
• Y. Gao and K. B. Sharpless, J. Org. Chem., 1988, 53, 4081
• Yun Gao, Robert M. Hanson, Janice M. Klunder, Soo Y. Ko, Hiroko Masamune, and
K. Barry Sharpless, J. Am. Chem. Soc., 1987, 109, 5165
123.702 Organic Chemistry
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Kinetic resolution
R3 R
racemic mixture
R2 OH
R1

slow fast
steric hindrance
(–)-DET, Ti(Oi-Pr)4,
TBHP

R2 R2
R3 R3
R H
R1 R1
OH OH

H R
if reaction goes to
if allylic alcohol is desired use 0.6eq TBHP 100% completion you
if epoxy alcohol is desired use 0.45eq TBHP get a 1:1 mixture of
diastereoisomers
R3 R R3 R
O
R2 OH R2 OH
R1 R1

• Both enantiomers should be epoxidised from same face

• But rate of epoxidation is different
• If sufficient rate difference then stop the reaction at 50% conversion
123.702 Organic Chemistry
23

Kinetic resolution II
Me3Si Me3Si Me3Si
(+)-DIPT, Ti(Oi-Pr)4,
TBHP O
OH OH + OH
rate of epoxidation
C5H11 (S) : (R) ~700 : 1 C5H11 C5H11
(R/S) >95% ee (R) >95% ee

• Kinetic resolution normally works efficiently

• The problem with kinetic resolution is that is can only give a maximum yield of 50%
• Desymmetrisation of a meso compound allows 100% yield
• Effectively, the same as two kinetic resolutions, first desymmetrises compound
second removes unwanted enantiomer
• ee of desired product increases with time (84% ee 3hrs ➔ >97% 140hrs)

OH
FAST
slow
FAST O slow
wanted
OH
OH O
(–)-DIPT
H
O O
meso OH
slow readily
OH FAST removed
H
O
O
123.702 Organic Chemistry
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Desymmetrisation in synthesis
NHPh
OH (–)-DIPT, Ti(Oi-Pr)4, OH PhNCO
TBHP pyr O O

1hr = 93%e.e. O
OBn OBn 2hr = 95%e.e. OBn OBn O
3hr = >97%e.e. OBn OBn

BF3•OEt2

O
OH
HO OH O
OH O
HO2C O

OH OBn OBn
KDO HO

• Desymmetrisation has been used in many elegant syntheses

• Here is the synthesis of KDO, a key component of the cell wall lipopolysaccharide
(LPS) of Gram-negative bacteria forming the necessary linkage between the
polysaccharide and lipid A regions
• David B. Smith, Zhaoyin Wang and Stuart L. Schreiber, Tetrahedron, 1990, 46, 4793.
• Stuart L. Schreiber, Thomas S. Schreiber, and David B. Smith, J. Am. Chem. Soc.,
1987, 109, 1525 123.702 Organic Chemistry
25

Jacobsen-Katsuki epoxidation
• SAE is a marvelous reaction but suffers certain limitations
substrate must be an allylic alcohol
cis-disubstituted alkenes are poor substrates
• (salen)Mn catalysts with bleach (NaOCl) are good for these substrates

(S,S)-cat (2-15%) O
L S Ph CO2Me Me O CN
L S NaOCl, pH 11
O Me
L = larger group O O
O
S = smaller group O
94% ee ≥95% ee 97% ee

H
O
H H
N Cl N
Mn N N
Mn
t-Bu O O t-Bu O
H O

t-Bu t-Bu manganese(IV) oxo

species active oxidant
(S,S)-Mn(salen)

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26

Jacobsen-Katsuki oxidation in synthesis

N OH CHBn OH
H
N N
N
CONHt-Bu O
Indinavir
(Merck / HIV treatment)

(salen)Mn cat H2SO4

NaOCl, R3N+–O– MeCN
OH
O
2000kg scale
MeCN

OH H2O OH
O
Me
NH2 N N C
Me

• This example demonstrates the industrial potential of such catalytic systems

• Indinavir is an HIV protease inhibitor marketed by Merck as Crixivan®
• "Industrial Syntheses of the Central Core Molecules of HIV Protease Inhibitors"
Kunisuke Izawa and Tomoyuki Onishi, Chem. Rev., 2006, 106, 2811
123.702 Organic Chemistry
27

Organocatalytic epoxidations
cat.
oxone, K2CO3
DME / H2O, –15°C Me
Me Ph
Ph O
100%; 86% ee

F
F

O O
O
F
F
cat.

O
O
O R
R H
H R
R H
H

• As with most chemical reactions, epoxidation has seen a move towards ‘greener’
chemistry and the use of catalytic systems that do not involve transition metals
• A number of systems exist, notably the catalysts of Shi & Armstrong
• Most are based on the in situ conversion of ketones to the active, dioxirane
species, that actually performs the epoxidation
123.702 Organic Chemistry
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Organocatalytic epoxidations in synthesis

cat (5mol%),
O O
oxone (1eq), NaHCO3, O
dioxane/H2O
OMe OMe
89%
MeO 77% ee MeO

O
O S
O N
NMe2
O MeO
O AcO O
diltiazem

• Tanabe Seiyaku Co. utilise organocatalysis in the synthesis of diltiazem-L®, a blood

pressure reducing agent
• T. Furutani, R. Imashiro, M. Hatsuda and M. Seki, J. Org. Chem. 2002, 67, 4599
123.702 Organic Chemistry
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Sharpless Asymmetric Dihydroxylations (SAD)

K2OsO2(OH)4, K3Fe(CN)6,
K2CO3, MeSO2NH2, t-BuOH, OH
CO2Et H2O, 0°C, (DHQD)2-PHAL CO2Et
C5H11 C5H11
OH
99% ee

• Looks complicated but isn’t too bad...

• The active, catalytic, oxidant is K2OsO2(OH)4 - OsO4 is too volatile & toxic
• K3Fe(CN)6 is the stoichiometric oxidant
• K2CO3 & MeSO2NH2 accelerate the reaction
• Normally use a biphasic solvent system
• And the two ligands are...
Et Et Et Et
N N N N N N N N
O O O O
H H H H
MeO OMe MeO OMe

N N N N
(DHQD)2-PHAL (DHQ)2-PHAL

• Ligands are pseudo-enantiomers (only blue centres are inverted; red are not)
• They act if they were enantiomers (see slide 26)
• Coordinate to the metal via the green nitrogen 123.702 Organic Chemistry
30

Sharpless Asymmetric Dihydroxylation II

K2OsO2(OH)4, K3Fe(CN)6, K2OsO2(OH)4, K3Fe(CN)6,
OH K2CO3, MeSO2NH2, t-BuOH, K2CO3, MeSO2NH2, t-BuOH, OH
H2O, 0°C, (DHQD)2-PHAL H2O, 0°C, (DHQ)2-PHAL
Ph Ph Ph
Ph Ph Ph
OH OH
98.8% ee >99.5% ee

• Reaction works on virtually all alkenes

• Exact mechanism not known but...
• It is relatively predictable (but not as predictable as the SAE)
(DHQD)2PHAL
OsO4

small steric
barrier
S M
attractive area -
attracts flat, aromatic
substituents or large, L H large steric
hydrophobic aliphatic barrier
groups

OsO4
(DHQ)2PHAL

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Sharpless asymmetric dihydroxylation in synthesis

OsO4, K3Fe(CN)6, K2CO3, OH
Me MeSO2NH2, t-BuOH, H2O, Me
Me Me
0°C, (DHQD)2-PHAL Me TsOH O
HO
O 96% O 90% O
O O
95% ee Me
exo-Brevicomin

• The simple example above shows the power of the SAD reaction in synthesis
• exo-Brevicomin is the aggregation pheromone of several timber beetles
• Interestingly, endo-brevicomin inhibits the aggregation of the southern pine beetle
• John A. Soderquist and Anil M. Ranel, Tetrahedron Lett., 1993, 34, 5031
123.702 Organic Chemistry
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The Sharpless aminohydroxylation reaction

AcNHBr, LiOH,
O K2OsO2(OH)4, AcNH O
HCl.NH2 O
(DHQ)2-PHAL HCl, H2O
Ph Oi-Pr Ph Oi-Pr
Ph Oi-Pr
OH
OH
regioselectivity >20:1
94% ee

AcO O
Me OH
O Ph O Me
Me
Ph N O
H Me
OH
H O
HO AcO
taxol OBz

• A variant has now been developed that permits aminohydrodroxylation

• Used in the semi-synthesis of paclitaxel (Taxol®), an anti-carcinogen
• G. Li and K.B. Sharpless, Acta Chem. Scand., 1996, 50, 649
123.702 Organic Chemistry