q.org - organic synthesis ii selectivity and control. handout 1

8/10/2019 Q.org - Organic Synthesis II Selectivity and Control. Handout 1

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Organic Synthesis II: Selectivity Control

8 lectures, TT 2011

Dr Martin Smith

O ce: CRL 1

st

oor 30.087

Telephone: (2) 85103

Email: [email protected]

Handout 1

Handouts will be available at:

http://msmith.chem.ox.ac.uk/teaching.html

HN

MeO

H

O


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!Organic Synthesis II: Selectivity & Control. Handout 1

!Selectivity and Control!Definitions:Chemo- and Regio-selectivity!Recap of selective reactions: reductive amination

1,4 vs 1,2 additionElectrophilic aromatic substitution

Nucleophilic aromatic substitution!Stereoselectivity: definitions and recap!Selectivity and disconnection!The finished product: total synthesis of (+-) methyl homosecodaphniphyllate

!Chemo- and Regio-selectivity in oxidation of alcohols!Oxidation as a common functional group interconversion!Oxidation of alcohols: Cr(VI) oxidants!Activated DMSO oxidants: Swern, Moffatt and Parikh-Doering procedures!Application to the generation of bis-aldehydes : (+-) methyl homosecodaphniphyllate!Hypervalent iodine: Dess-Martin periodinane!MnO2and Oppenauer Oxidations!Catalytic Oxidants: TPAP and TEMPO

!Chemo- and Regio-selectivity in reduction of carbonyl derivatives!Selectivity in DIBALH reductions: stopping reactions half-way!Selectivity in (general) hydride reductions

!Using amides as electrophiles: Weinreb amides and examples; the problem of C-acylation!An aside: acylation at carbon - kinetic and thermodynamic control!Kinetic control: use of methylcyanoformate!Selectivity in hydride reducing agents: Lithium Aluminium Hydride

Lithium BorohydrideBorane (and related complexes)NaBH4; modified borohydrides & the Luche reduction

!Organic Synthesis II: Selectivity & Control. Handout 1

!Stereoselectivity in hydride reductions:1,2 stereoinduction (Felkin models and variants)1,3 stereoinduction (1,3-synand 1,3-antidiolsAdditions to cyclohexanones (torsional control)Enantioselectivity in hydride reductionA catalytic asymmetric hydride reduction

!Recap: reduction of alkynes!Dissolving metal reductions: the Birch reduction!Dissolving metal reductions of !,"-unsaturated ketones (and esters)

!Hydrogenation

!Oxidation reactions involving alkenes!Recap: dihydroxylationand allylic alcohol reactions!Osmium-mediated hydroxylation!Allylic alcohol mediated alkene functionalization!Titanium mediated epoxidation: the Sharpless Epoxidation!The Wacker oxidation!Epoxidation vs Baeyer-Villiger!Nucleophilic epoxidation of electron deficient alkenes

!Books & other resources: 1. Oxidation & Reduction in Organic Synthesis (T. J. Donohoe, OUP) 2.Organic Chemistry (Clayden, Greene, Wothers & Warren, OUP)

3.Professor Andrew Myers website (Harvard).http://www.chem.harvard.edu/groups/myers/page8/page8.html4.Molecular Orbitals and Organic Chemical Reactions(I. Fleming, Wiley, 2nd Edn.)

Mechanisms for many oxidation reactions (even well-known ones) are significantly more complexthan drawn throughout this course (and in many cases are not known or understood). Some are

based on factual mechanistic data; some should be treated more as a mnemonic than explanation.


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!Chemo-selectivitySelectivity between two functional groups

!Regio-selectivitySelectivity between different aspects of the same functional group

with nucleophiles

or reducing agents

reaction withperoxy-acids

Whichgroup

reacts?

!What is Selectivity & Control? (and why do we need it?)

O O

OMe

O

O

X

direct or conjugateaddition with nucleophilesor reducing agents

ortho-, para- or meta-with electrophilesand selectivitybetween o-and p-

Wheredoes itreact?

!Chemoselectivity: reactions you have already seen

!Functional groups have different kinds of reactivity

OOH O

Pd/C

H2NaBH4

!Functional groups have similarreactivity

OMe

O O

OMe

OH O

OH

ONaBH4

use nucleophilic

reagentketone-

electrophilicalkene- not

electrophilic

C=C weaker #-

bond than C=O

use catalytic

hydrogenation

ketone- more

electrophilic

ester- less

electrophilic

use selective

reagent

protect more

reactive group


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!Chemoselectivity: reactions you have already seen

!Functional group may react twice (is the product more reactive than the SM?)

Chemoselectivity needed between Starting Material and Product

R1 NH2 R1 NH

R2 R1 N R2

R2

Br R2 Br R2

control?

R1 NH2O R2

H

R1 N R2

H

R1 NH

R2

or H2, Pd/C

NaB(CN)H3

!Solution: use reductive amination (more on reduction later)

Chemoselectivity: NaBH3CN only reduces imine, not aldehyde starting material

[NaBH3CN is a less nucleophilic source of hydride than NaBH4due to theelectron-withdrawing nature of the cyanide ligand. As a consequence it will

generally not reduce aldehydes and ketones at neutral pH]

!Regioselectivity: reactions you have already seen

!Conjugate and Direct Addition to Enones

!Electrophilic Aromatic substitution

X X

E

XX

E

EE

E

and/or

OOH

Nu

O Nu

Nu

NuDirect

Conjugate[Michael]

the enone is electrophilicat two different sites

kinetic product

hard nucleophiles

thermodynamic product

soft nucleophiles

choose 'ortho, para-'directinggroup X: Alk, OH, F etc

choose 'meta-'directing group X

COR, NO2etc


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!Stereo-selectivitySelectivity between two (or more!) possible stereochemical outcomes

Examples youve already seen: (I) reduction of cyclohexanones (see course from Dr E. Anderson, HT 2011)

Examples youve already seen: (II) Additions to chiral aldehydes & ketones (Felkin-Anh model)

!What is Selectivity & Control ? (and why do we need it?)

H

tBu

O

H

tBu H

OH

H

tBu OH

H'Hydride'

Which faceis attacked?

equatorialattack

axialattack

"H- "

"H- "

RS

RM

RL

O

HNu

1. Reactive conformation2. Brgi-Dunitz trajectory3. Attack away from RL

and over RS

4. TS is SM-like

PhMe

O

Me

PhMe

OH

Me

LiBH(s-Bu)3

[bulky hydride]

!Disconnections that require selectivity: simple aromatic derivatives

!Selectivity defines strategy in disconnection

Dinocap - fungicide

Order is important(the alternative C-N disconnection prior to the C-C disconnectionwould not lead to appropriate selectivity)

!Reminder of basic principles: where and when to disconnect?

(i) branch points (ii) heteroatoms (iii) functional groups

(iv) simplifying transformations (v) the order of events

(see 1st year course from Prof Gouverneur)

O2N NO2

O

OO2N NO2

OH

O2N NO2

OHOH

C-O

C-C

C-N

directs ortho-for C-C bondformation

para-positionblocked

directs ortho-and para-fornitration

Esterification

FriedelCrafts

(issues?)

Nitration


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!Two group disconnections: Fluconazole

!Selectivity defines strategy in disconnection

!The 1,2 difunctional disconnection

1

2 2

F

F

NN

N

F

NN

N

N

N

N

F

OH O

NH

N

N

F

F

NN

N

O

1

2

F

F

ClO

NH

N

N

F

F

Cl

Cl

O

1,2 di-X

C-Nsulfurylid

C-N1,2 di-X

C-C

FriedelCrafts

least hinderedend attacked

F is o-,p-directing

Deactivating: onlymonoacylation

R2NOH

RSOH

HOOH

XOH

1,2 di-X

OH + X-

!Complex molecule synthesis

!We need to exert control to be able to construct complex molecules efficiently

!Selectivity - as defined by disconnection - offers an opportunity to do this

HN

CO2Me

H

Methyl homoseco-daphniphyllate

!Isolated from the bark of Daphiphyllum macropodum

!Structure confirmed by X-ray crystallography

!Complex architecture contains five fused rings


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!Synthesis of (+/-) methyl homosecodaphniphyllate (IV)

!Final steps:

!A series of simple but selective steps

!Chemo-selectivity, regio-selectivity (and stereoselectivity) areexploited throughout the synthesis to great effect.

!Overall: nine steps - a spectacularly elegant and efficient approach

We will cover the details of many of these steps throughout the course

HN

BnO

H

HN

HO

H

HN

CO2Me

HH2, Pd-C

1. CrO3, H2SO4,H2O, Acetone2. MeOH, H+

Removes benzylprotecting group

and reduces alkene

Chemoselectiveoxidation to acid;

Esterification

!Oxidation is a very common synthetic transformation

!Many functional group transformations are redox reactions

Oxidation = Electrophilic attack = Removal of electrons

!Common 2-electron transformations:

Br Br Br

Br

Br

BrSN2

inversion

Base

-2HBr

bromonium

cation

dibromide product

eliminationelectrophilic attack

Enters as Br+ Leaves as Br-

2 electron oxidation

So functional groups that react readily with electrophiles are easily oxidizedThis includes: alcohols, alkenes, amines and phenols

-2e -2e -2e -2e

R OH R

O R OH

O

alcohol aldehyde acid

R NH2

R NH

R

amine imine nitrile

NH


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HO

R1

Mn

O

O O

MnO

OH

HR1

OMn

OH

OH

R1

O

R1 Mn

OH

OH

Manganate esterallylic/benzylicalcohol

aldehyde/ketone

!MnO2: a selective oxidant for allylic and benzylic alcohols

!Selective for allylic and benzylic alcohols (will not usually oxidize 2 alcohols)

!Selectivity is probably a consequence of a radical mechanism

OH

MnO2

DCM

OH

O

OH

Allylic alcohol oxidized selectively

Mn(IV) Mn(IV) Mn(III) Mn(II)

Hydrogen abstraction is faster for allylic/benzylic alcohols(the radical that is produced is delocalized and hence more stable)

!MnO2: a selective oxidant for allylic and benzylic alcohols

MnO2is a heterogeneous oxidant: workup is generally just filtration

!Selective for allylic and benzylic alcohols (will not usually oxidize 2 alcohols)

!The aldehyde products can be used in situwith other reagents (MnO2is v. mild)

MnO2

CH2Cl2

Bu3Sn OH Bu3Sn O

Mild conditions; can retain vinyl stannane group

aldehyde formed in-situ, condenses with amineto form intermediate imine

NaBH4reduction of imine faster in polarprotic solvent (MeOH)

Oxidant (MnO2) compatible with reductant (NaBH4) in same vessel

MnO2, CH2Cl2NaBH4, 4 sieves

amine

then methanol

OH NN [red]


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!Intramolecular (Dieckmann) condensation can offer a solution to C-acylation

!Thermodynamic control

Note: The final enolization is reversible, but the equilibrium lies over to the RHS

Irreversiblealkylation

!Regioselectivity through thermodynamic control

EtOEtO

O

EtO OEt

O

O

CO2EtH

EtO OEt

O

EtO2C

O

Cannot form astable enolate

Can form astable enolate

CO2Et

O

CO2Et

O

CO2Et

OH Me

O

OEt

CO2Et

EtO EtO MeI

!Enolate stability can control regiochemistry of C-acylation

!Acylation at Carbon - Kinetic vs thermodynamic

Note: The final enolization is reversible, but the equilibrium lies over to the RHS

Kinetic productThermodynamic product

!With reversible enolization conditions we get equilibration between all species

O O

O

CO2Me

O

CO2Me

O

CO2

Me

O

CO2

Me

H

This enolate destabilized byinteraction with aromatic

C-H bond - precludesplanarity

No such destabilizinginteraction - more stable

enolate

O OO

CO2Me

CO2Me

NC OMe

O

LDA, -78C

MeO OMe

O

NaH, 0C


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!Diastereoselectivity with hydrides: 1,3-stereoinduction

!1,3-syn diols may be generated by using a Lewis acid to favor intermolecularhydride delivery from the least hindered face:

OH O

R1 R2B

O

OR1

R

R

R2

R3B, MeOH

NaBH4

H-

OH OH

R1 R2

!1,3-anti diols may be generated by using intramolecular delivery of thehydride nucleophile

1,3-synBoron isLewis acidic

Chair-like TSaxial attack of hydride

OH O

R1 R2

OH OH

R1 R2H

BO

H

R1

HH

OAc

OAc

OH

R2

Me4NBH(OAc)3

Boron isLewis acidic

Chair-like TSput substituents pseudo-equatorial

Intramolecular delivery

1,3-anti

!Diastereoselectivity with hydrides

!Size matters: addition to cyclohexanones (see Dr E. Anderson course HT 2011)

LiAlH4

Small H-9:1, axial/equat. attack

Na(s-Bu)3BH

Big H-96:4, equat./axial attack

So equatorial attack appears to be favoured, as it does not require the hydride to approachacross the ring (where 1,3-diaxial interactions hinder trajectory)

!Why is axial attack then favoured for small hydrides (nucleophiles)?

O

H

H

axial

equatorial

Equatorial: O moves towardsC-H, leading to highertorsional strain in the TS

Axial: O moves away fromC-H, leading to lowertorsional strain in the TS

HH O

LargeHydride

SmallHydride

'Axialattack'

'Equatorialattack'

H-

H-

HH

HH

OH

H

H

OH


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!Reduction of alkynes (recap of 1st year material)

!Overall cis addition of hydrogen across the alkyne: hydrogenation

!Overall trans addition of hydrogen across the alkyne: dissolving metal

Isolated alkenes are not usuallyreduced under these conditions

Anion adopts trans-configuration

R1 R2 R

1 R2H2(g)

Lindlarcatalyst

cis alkene

H H

hydrogen oncatalyst surface

H H

R1

R2

Na

NH3(l)R1

R2

N

H

HH

R1R2

HNH3(l)

R1R2

HNH3(l)

R1R2

H

H

Na

NH3(l)

LUMO

C C*

!Dissolving metal reductions: The Birch reduction

!The Birch reduction can be used to partially reduce aromatic rings

H H

H H

Na, NH3(l), EtOH Kinetic product is non-conjugated diene

!The regiochemistry of the reduction depends on substitution

A range of metals can beused: Li, Na, K (sometimes

even Ca and Mg)

Na, NH3(l), EtOH

OMe OMeH

H

HH

Na, NH3(l), EtOH

CO2H

H H

H CO2H

Electron-donating groups (OR,

NR2, alkyl) give rise to thisorientation of reduction

Electron-withdrawing groups (CO2H,

CO2R, COR, CONR2, CN, Ar) give riseto this orientation of reduction


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q.org - organic synthesis ii selectivity and control. handout 1

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