Reactions of alkenes: stereospeciﬁc reactions

123.702 Organic Chemistry

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...

1

PhH

PhH

Om-CPBA

syn

PhH

HPh

Om-CPBA

anti

Ph

HH

Ph(Z)

Ph

PhH

H(E)

Ph HPhH

OOOH

Ar

Note: only controlling relative

stereocheimstry NOT absolute

stereochemistry

I

Me O Osyn

OOH

Me I2

(Z)

I

Me O O H

I

Me O OantiI

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

OOHMe

I2

(E) OOHMe

I


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

2

OOH

MeI2

O

IMe

O82% de

O

Me

OH

I2

OI

Me

O88% 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...

Me SiMe2Ph

Me

Me SiMe2Ph

MeO

Me SiMe2Ph

MeO

m-CPBA +

>95% <5%

Me m-CPBA +

61% 39%

MeO

MeOMe Me Me

SiMe2Ph SiMe2Ph SiMe2Ph


Conformations in allylic systems

• Arguably the lowest energy conformations have greatest separation of substituents• The control of conformation in allyl systems is called allylic strain or A(1,3) strain

3

Me

MeH

if no cis substituent then only small

energy difference

HH H

MeMe

H

HH H

HMe

Melowest energy: H

eclipses plane of alkeneslightly higher energy: Me eclipses plane of alkene

rotate bond

Me

MeMeH

cis substituent present then only

ONE conformation

MeH H

MeMe

HMeH H

HMe

Melowest energy: H

eclipses plane of alkenehigh energy: Me–Me

interaction disfavours conformation

HH H

HMe

Me

HH H

MeMe

H

H HMe

HH

Me

MeMe

HMe

Me

HX


Stereoselective reactions of alkenes III• Apply this knowledge to the real system...

4

m-CPBA

>95%Me

Me

H SiMe2Ph

O

MeH H

HSi

Me

MeMe

Ph

OMeH H

HSi

Me

MeMe

Ph

Me

Me m-CPBA

H SiMe2Ph

m-CPBAX

lowest energy conformation

silyl group blocks approach

X

m-CPBA approaches from unhindered face

<5%Me

Me

H SiMe2Ph

O

HMe

HMe

H

Si MePh Me

m-CPBA

formation of minor diastereoisomer results

from m-CPBA approaching alkene in above conformation or

approaching passed the silyl group


m-CPBA

m-CPBA

HMe H

MeH

SiPh

MeMe

O

39%

Me

H SiMe2Ph

OMe

HMe H

HSi

Me

MePh Me

O61%

Me

H SiMe2Ph

OMe

Me

H SiMe2Ph

Me

HMe H

HSi

Me

MePh Me

HMe H

MeH

SiPh

MeMe

Importance of A(1,3) strain

• The importance of a cis-substituent is made clear by the reduced stereoselectivity• This is explained as follows...

5

Me m-CPBA+

61% 39%

H SiMe2Ph

Me

H SiMe2Ph

OMe

H SiMe2Ph

OMe Me Me

X

m-CPBA attacks form least hindered

face

X

lowest energy conformation

gives major product HMe H

HSi

Me

MePh Me

HMe H

MeH

SiPh

MeMe

both conformations low energy -- so mixture of

products


H2B HH2B

H CH2OBnMeH

Me

OH CH2OBn

MeHMe

O

H

H2O2NaOH

OBn

H Me

O

H Me

OH74% de

Me

OBn

H Me

O

BH3

OBn

H Me

O

H Me

H2B

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...

6

R

R1

HS

LL R1

RS H

S = smaller groupL = larger group

R

R1

SL

HR

R1

LH

S

favoured destabilised by repulsion between C-1 & C-3 substituents or A(1,3) strain

13

13

preferred approach Selectivity in addition to cis alkenes

Attack from the least sterically demanding face of the alkene as it resides in the most favoured conformation. Followed by stereospecific oxidation


Directed epoxidation

• 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

7

OHreagent

OH

O

reagent:m-CPBAt-BuO2H, VO(acac)2

OH

O+

syn9298

t::

anti82

H

OO

HO

OH

Ar hydrogen bond O

VO OO O MeMe

Me Mevanadyl acetylacetonate

O

H

OV

t-BuO O


MeMe H

HO

Me

HOO

OH

Ar

Me Me

Me OHHm-CPBA Me Me

Me OHH

OMe Me

Me OHH

O+

95 5

Directed epoxidation in acyclic systems

• 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

8

• The minor product is formed either via non-directed attack or via the less favoured...conformation

hydrogen bond

favoured conformation

O

MeMe H H

OH

HO

O

Me

Ardisfavoured

conformation

MeMe H

HOH

Me

O


Directed epoxidation: effect of C-2 substituent

• 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

9

• With C-2 substituent (H) there is little energy difference between conformations• Therefore, get low selectivity

H O Me

H

O

OV

t-Bu

H Me

LL

MeMe

OHH

t-BuO2HVO(acac)2 Me

MeMe

Me

O OOH OH19 1

+

:

disfavoured conformation as Me & Me eclipse

steric interaction

favoured conformation as

only Me & H eclipse

H O H

Me

O

OV

t-Bu

H Me

LL

Me Me

H OH

t-BuO2HVO(acac)2 Me Me

O OOH OH

2.5 1

+

:

Me Me H O H

Me

O

OV

t-Bu

H H

LL

H too small to differentiate

conformations


H O H

R2

O

OV

t-Bu

H R1

LL

H O R2

H

O

OV

t-Bu

H R1

LL

versus

Substrate control in total synthesis

• 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

10

C13 MeNO

BnMe

O

Me

O OH

Me

OH OTIPS

MeMe

Ph

O O

MeNO

BnMe

O

Me

O OH

Me

OH OTIPS

MeMe

Ph

O O

O

VO(acac)2t-BuOOH

91%100% d.e.

C1 C1 C13

C13

OHMe

O

OO

Me

OR

ORMe

O

Me

Me

Me

C1

Oleandomycin aglycon(R=H but should be a sugar)

steric interaction


BHMe

H

H

HBH2

HMeMe Me

1. TMEDA2. BF3•OEt2

Me

1. TMEDA2. BF3•OEt2

Me

(+)-IpcBH2

H

BHMe

HH Me

B

HMeMe Me

H

H

Me

Me MeH

BH3

BH3

(–)-Ipc2BH

Me

MeMeMe

(+)-α-pinene

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 reactionsSubstrate control

11


Hydroboration: reagent control

• 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

12

Me

Me

1. (–)-Ipc2BH2. H2O2 / NaOH

MeMe

OHHH

H 98.4% ee

BHMe

HH Me

(–)-Ipc2BH

Me

H

1. (+)-IpcBH22. H2O2 / NaOH

H

HOH

Me

66% eeH

BH2

HMeMe Me

(+)-IpcBH2


P P

OMe

MeO

RhO

Me NH

CO2H

ArP P

OMe

MeO

Rh O

MeNH

HO2C

Ar

Hydrogenation: enantioselective catalysis

• 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...

13

HCO2H

NHAc

MeO

AcO

H2(g)[((S)-DIPAMP)RhL2]

L=solvent MeO

AcO

CO2H

H NHAc

H H

95% ee(S,S)-DIPAMP

P P

OMe

MeO

P P

OMe

MeOO

MeNH

HO2C

Ar

RhL L


ArPHPh

Rh

H

PAr Ph

O

MeNH

HO2C

Ar

Mechanism for catalytic hydrogenation

14

L

PhPP

Ar

Ph Ar

Rh O

MeNH

HO2C

ArH

H

ArP P

Ph

ArPh

Rh O

MeNH

HO2C

Ar

H2slow

L

ArP P

Ph

ArPh

RhO

Me NH

CO2H

ArH

H

ArP H

Ph

Rh

H

PArPh

O

Me NH

CO2H

Ar

ArP P

Ph

ArPh

RhO

Me NH

CO2H

Ar

H2fast

O

MeNH

HO2C

ArHHH

minor enantiomer

O

Me NH

CO2H

ArHHH

major enantiomer

O

MeNH

HO2C

Ar

+ [DIPAMPRhL2]

oxidative addition fastcomplex more

reactive

oxidative addition

insertion

reductive elimination

One complex more reactive


Enantioselective hydrogenation in action

• 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

15

MeOO

t-BuO2C CO2Na

[(R)-MeO-BIPHEP-RuBr2]60psi H2, 50°C, THF/H2O

98%e.e.

MeOO

t-BuO2C CO2Na

MeOO

HN

OCO2H

O

O

candoxatril

MeOMeO

PP

PhPh

PhPh

(R)-MeO-BIPHEP


N

Ar

H

N

t-BuBn

O Me

HMe

N NH

ArMe

H

PhMe

OH

Me MeMe

NMe

i-PrE

EH

H

Hδ–

δ+

N

Ar Me

H

N

t-BuBn

O Me

Me

H

O

NC

NH2

N

Bnt-Bu

OMe

Cl3CO2

NH

MeO2C

Me i-Pr

CO2MeH H

H

O

NC

H Me

89%; 96% ee

catalyst 10%hydrogen source 1eq

Organocatalytic hydrogenation

• 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)

16


Me

Me

MeOH

Me

OH

(–)-DET, Ti(Oi-Pr)4, TBHPMe

Me

MeOH

O

>90% ee

(+)-DIPT, Ti(Oi-Pr)4, TBHP Me

OHO

92% ee

Me

Me

MeOH

Me

OH

Sharpless Asymmetric Epoxidation (SAE)

• 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

17

EtO2CCO2Et

OH

OH(–)-DET

i-PrO2CCO2i-Pr

OH

OH(+)-DIPT

Me O

MeMe

OH

TBHP

• Compounds must be allylic alcohols• Second example shows that this limitation allows highly selective reactions

must be allylic alcohol


OTi

Ot-BuLL

OO

Ot-Bu

OTi

LL

O

t-BuO

OTi

LL

OTi

OLL

Ot-BuTiL4

TBHP+

+

HO

Sharpless Asymmetric Epoxidation II

• 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

18

if you want “O” on top its on your kNuckles so you

use Negative (–)-DET

if you want “O” on top its on your Palm so you use

Positive (+)-DET

using your left hand, the index finger is

the alkene and your thumb the alcohol

R1

R2 R3

OHO

Ti(Oi-Pr)4TBHP

R1

R2 R3

OHO

Ti(Oi-Pr)4TBHP

R3

R1

R2

OH

D-(–)-DET unnatural isomer

“O”

“O”D-(+)-DET

natural isomer

place alkene vertical and

alcohol in bottom right corner

activation of peroxide


E

OO

O

TiO

O O

O

O

TiO

O

CO2Et

CO2Et

i-Pr

i-Pr

EtOt-Bu

R

HO

RO E

OO

O

TiO

O O

O

O

TiO

O

CO2Et

CO2Et

i-Pr

i-Pr

EtOt-Bu

R

HO

R

t-BuO2H CO2Et

OO

O

TiO

O O

O

O

TiO

O

CO2Et

CO2Et

i-Pri-Pr

i-Pr

EtOt-Bu

OO

O

TiO

O O

O

O

TiO

O

CO2Et

CO2Et

i-Pri-Pr

i-Pr

i-Pr

OEt

EtO

Ti(Oi-Pr)4 +(+)-DET

Mechanism of SAE

19

Active species thought to be 2 x Ti bridged by 2 x tartrate

Reagents normally left to ‘age’ before addition of substrate thus allowing clean formation of dimer

must deliver “O” from lower face


• SAE works for a wide range of allylic alcohols

• Only cis di-substituted alkenes appear to be problematic

20

R2 OHR2 OH

R1good substrates

high yields and ee's >90%

OHR1

R3

R2 OHR1

R3normally good

ee's >90%few examples

OH

R3 problematicslow reactionsmoderate ee's,

especially with bulky R3

OHO

O

MeMe

OHO

O

MeMe

OHO

O

MeMe

O O

conditions

t-BuO2H, VO(acac)2t-BuO2H, Ti(Oi-Pr)4, (+)-DETt-BuO2H, Ti(Oi-Pr)4, (–)-DET

+

2.3199

:::

1221

• 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


MeNH2

Ph NHMe

OH1. NaH2. ArCl

MsCl

Ph OMs

OH

Red-Al[NaAlH2(OCH2CH2OMe)2]

Ph OHH

OHSAE(+)-DIPT

89%>98%e.e.

Ph OHO

Use of SAE in synthesis

• 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

21

Ph OH

Ph NHMe

O

CF3

fluoxetine


R2 OHR1

R3 RO

R

R3

R1

R2

OHH

H

R3

R1

R2

OHR

R2 OHR1

R3 R

(–)-DET, Ti(Oi-Pr)4, TBHP

Kinetic resolution

• 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

22

R2 OHR1

R3 R

if allylic alcohol is desired use 0.6eq TBHPif epoxy alcohol is desired use 0.45eq TBHP

slowsteric hindrance fast

racemic mixture

if reaction goes to 100% completion you

get a 1:1 mixture of diastereoisomers


H

OH

Kinetic resolution II

• 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)

23

Me3Si

C5H11

OH

(+)-DIPT, Ti(Oi-Pr)4, TBHP

Me3Si

C5H11

OH

Me3Si

C5H11

OH+O

>95% ee (R) >95% ee(R/S)

rate of epoxidation (S) : (R) ~700 : 1

OH

O

OH(–)-DIPT

FAST

FASTslow

slow

OH

O wanted

OH

O Omesoreadily

removed

OHH

H

OH

O

slow

OHH

O

FASTslowFAST


OH

OBnOBn

(–)-DIPT, Ti(Oi-Pr)4, TBHP

1hr = 93%e.e.2hr = 95%e.e.

3hr = >97%e.e.

OH

OBnOBnO

O

OBnOBnO

O

NHPhPhNCO

pyr

BF3•OEt2

HOOBn

OO

O

OBn

O

OH

OHOH

OH

HO2C

HO

KDO

Desymmetrisation in synthesis

• 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

24


Jacobsen-Katsuki epoxidation• SAE is a marvelous reaction but suffers certain limitations

substrate must be an allylic alcoholcis-disubstituted alkenes are poor substrates

• (salen)Mn catalysts with bleach (NaOCl) are good for these substrates

25

NNMn

OOt-Bu

t-Bu t-Bu

t-Bu

HHCl

(S,S)-Mn(salen)

H

H

NN

O OMn

O

manganese(IV) oxo species active oxidant

L S

L = larger groupS = smaller group

(S,S)-cat (2-15%) NaOCl, pH 11 L S

O

O

OO

Ph CO2Me

O

O CNMe

MeO

94% ee ≥95% ee 97% ee


Jacobsen-Katsuki oxidation in synthesis

• 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

26

(salen)Mn catNaOCl, R3N+–O–

O2000kg scale

H2SO4MeCN OH

OH

N CMe

N

O

Me

OH

NH2

H2O

MeCN

N

NN

HN

OH CHBn

CONHt-Bu

OH

O

Indinavir(Merck / HIV treatment)


Organocatalytic epoxidations

• 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

27

PhMe

cat.oxone, K2CO3

DME / H2O, –15°CPh

MeO

100%; 86% ee

O

F

F

cat.F

F

OO

RH

H

OO

RR

H

HO

R


Organocatalytic epoxidations in synthesis

• 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

28

MeO

OMe

O cat (5mol%), oxone (1eq), NaHCO3,

dioxane/H2O

89%77% ee MeO

OMe

OO

O

O

O

O

O

NS

AcO O

NMe2MeO

diltiazem


Sharpless Asymmetric Dihydroxylations (SAD)

• 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...

29

C5H11CO2Et

K2OsO2(OH)4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH,

H2O, 0°C, (DHQD)2-PHALC5H11

CO2EtOH

OH99% ee

• 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

N

HO

N

MeO

EtN

HO

N

OMe

EtNN

(DHQD)2-PHAL

N

HO

N

OMe

N

HO

N

MeO

N NEt Et

(DHQ)2-PHAL


Sharpless Asymmetric Dihydroxylation II

• Reaction works on virtually all alkenes• Exact mechanism not known but...• It is relatively predictable (but not as predictable as the SAE)

30

PhPh

PhPh

OH

OHPh

PhOH

OH98.8% ee >99.5% ee


H2O, 0°C, (DHQ)2-PHAL


H2O, 0°C, (DHQD)2-PHAL

small steric barrier

large steric barrier

attractive area - attracts flat, aromatic substituents or large, hydrophobic aliphatic

groups

H

MS

L

OsO4

(DHQD)2PHAL

OsO4(DHQ)2PHAL


Me

OO

Me OsO4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH, H2O,

0°C, (DHQD)2-PHAL Me

OO

Me

HO

OH

96%95% ee

TsOH

90% O

O

Me

Me

exo-Brevicomin

Sharpless asymmetric dihydroxylation in synthesis

• 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

31


The Sharpless aminohydroxylation reaction

• 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

32

Ph Oi-Pr

O

Ph Oi-Pr

OAcNH

OHregioselectivity >20:1

94% ee

Ph Oi-Pr

OHCl.NH2

OH

HCl, H2O

AcNHBr, LiOH, K2OsO2(OH)4, (DHQ)2-PHAL

ONH

Ph

O OPh

OH

Me

OBz

Me

Me

AcO OHMe

H OAcO

O

HOtaxol

Documents

Reactions of alkenes: stereospeciﬁc reactions