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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