Download Asymmetric Synthesis: Substrate and Auxiliary Control

Asymmetric Synthesis: Substrate and Auxiliary Control
Lecture 1 – Introduction to stereoselective synthesis
Dr Peter Knipe
[email protected]
Office: 0G.109
1
Course Overview
Course aims – understand the following:
▪
▪
▪
▪
▪
▪
The importance of controlling stereochemistry in synthesis
Theoretical underpinning of asymmetric synthesis
Key stereochemical models (Felkin-Anh, Ireland, Houk, Zimmerman-Traxler)
Substrate control
The concept of chiral auxiliaries
Stereoselective total synthesis of complex molecules
Recommended reading
Much of this course will be taught directly from the primary literature (references given), however the following
texts can provide useful summaries and background information.
Books:
▪
▪
▪
▪
▪
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Organic Synthesis – Strategy and Control (P. Wyatt and S. Warren)
Organic Synthesis – The Disconnection Approach (S. Warren and P. Wyatt)
Stereoselectivity in Organic Synthesis (G. Procter), Oxford chemistry primer
Stereochemistry of Organic Compounds (E. L. Eliel, S. H. Wilen, L. N. Mander)
Organic Chemistry (J. Clayden et al.)
Classics in Total Synthesis (K. C. Nicolaou and E. Sorensen)
Review Articles
▪ Substrate-Directable Organic Reactions, Chem. Rev. 1993, 1307 (Hoveyda, Evans and Fu)
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Course Overview
Lectures
1.
Introduction to stereoselective synthesis
▪ The energetics of stereoselection; methods for analysing stereoisomers
2.
The chiral pool of molecules
▪ Overview of components of the chiral pool; application in total synthesis
3.
Substrate-controlled stereoselective reactions
▪ Models for stereoinduction including Felkin-Anh and Houk
4.
Stereoselective Aldol reactions under substrate and auxiliary control
▪ The Zimmerman-Traxler model; controlling enolate geometry; Evans auxiliary
5.
Other auxiliary-controlled reactions of enolates
▪ Amination, oxygenation and acylation; Oppoltzer and Myers auxiliaries
6.
Chiral auxiliaries on ketones and aldehydes, and asymmetric 1,4-addition reactions
▪ Enders’ SAMP and RAMP, Ellman’s sulfinamide, Corey’s 8-phenylmenthol auxiliaries
7.
Substrate and auxiliary control in pericyclic reactions
▪ Overview of stereospecificity due to Woodward-Hoffmann rules; aspects of stereoselectivity, e.g. endo
rule; use of auxiliaries to control absolute stereochemistry
8.
Stereochemical considerations in retrosynthesis of complex molecules
▪ four case studies: [1] Sorensen’s FR-901483; [2] Zakarian’s pinnatoxin; [3] Ellman’s SC-53116; [4]
Evans’ lepicidin A
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The Importance of Stereochemistry
Why bother controlling stereochemistry?
▪ n stereocentres  up to 2n stereoisomers – control is necessary!
▪ Poor stereocontrol is wasteful (since unwanted stereoisomers are useless)
▪ Different stereoisomers have different properties
diastereoisomers
commercial polystyrene – atactic
non-crystalline, Tg ~ 90 °C
Ziegler-Natta polystyrene – syntactic
Crystalline, Tm ~ 270 °C
▪ In chiral environments such as a cell, enantiomers have different properties too
enantiomers
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Stereochemistry in Organic Molecules – A Brief Summary
▪ Enantiomers have identical physical properties (assuming they are in an achiral environment), e.g.
melting/boiling point, IR and NMR spectra, density, viscosity, etc.
▪ Diastereo(iso)mers have different physical properties.
diastereoisomers (in red)
enantiomers (in blue)
▪ Molecules where mirror image is non-superimposable are chiral
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Representing Stereochemical Information – The Maehr Convention
I will try to follow the Maehr convention:1 wedges indicate absolute stereochemistry, bold
lines indicate relative stereochemistry, i.e.
racemic – bold lines illustrate that OH
groups are syn but both (S,S)- and
(R,R)-enantiomers present
Single (S,S)-enantiomer of the same
(syn) diastereoisomer
Note – this convention is useful but not universally adopted. Exercise caution when using,
and never assume.
1. H. Maehr, J. Chem. Ed. 1985, 114.
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Representing Stereochemical Information - Racemates
What we draw
What we mean
A racemic mixture of the chiral
compound
▪ Ambiguity arises when >1 stereogenic centre is present
What we draw
What we mean
50:50
A poor
representation
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How do stereogenic centres arise?
▪ Stereogenic centres generally arise in molecules when a prochiral intermediate undergoes a reaction. This
can take many guises:
(i)
Nucleophilic addition to a prochiral electrophile
A new stereogenic centre
racemic
(ii)
Electrophilic addition to a prochiral nucleophile
(Re) face
(Si) face
A new stereogenic centre
racemic
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How do stereogenic centres arise?
(iii) Desymmetrization of a prochiral centre
Racemic mixture
This list is by no means exhaustive. Other methods include radical reactions and pericyclic reactions, some of
which we will cover in later lectures.
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Methods for Stereoselective Synthesis
‘Buy in’ stereochemistry
Construct Stereochemistry
Synthesis from the chiral pool
Substrate-controlled
Use existing stereocentres in the substrate (from chiral pool) to
direct formation of new ones.
•
•
•
•
•
Amino acids
Sugars
Hydroxy acids
Terpenes
Alkaloids
Auxiliary-controlled
Use existing stereocentres (from chiral pool) on chiral, cleavable
groups to direct the formation of new stereocentres.
All stereogenic centres in
product are directly derived
from those in chiral pool
starting material
Reagent-controlled
Use existing stereocentres (from chiral pool) on reagent to
direct formation of new stereocentre in substrate.
Catalyst controlled
Use existing stereocentres (from chiral pool) on a catalyst to
direct formation of new stereocentre in substrate.
D-glucose
Resolution
Construct molecule as racemate, then separate enantiomers
using a chiral resolving agent.
negamycin
Ultimately all methods derive from the chiral pool
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Creating non-racemic chiral molecules
▪ All the methods described above required a chiral molecule to be present from the outset (substrate,
reagent, catalyst, etc.). This is an absolute requirement when creating a chiral molecule from achiral starting
materials.
▪ Consider the following reaction:
▪ A new stereogenic centre is created on going from B  C.
▪ In the absence of any other chirality C will be formed racemically
By considering the energetics of the reaction, we can understand why C must be racemic.
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Energetics of Asymmetric Synthesis
(Re)
(Si)
E
ΔG‡(Re)
ΔG‡(Si)
(R)
(S)
To obtain non-racemic product we require ΔΔG‡ ≠ 0
The basis of all asymmetric synthesis is the formation of diastereomeric (rather than enantiomeric) transition states
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Kinetics of Selectivity
▪ In a kinetically-controlled reaction, the difference between activation energies (ΔΔG‡) of the diastereomeric
transition states determines the ratio of stereoisomers formed
B
A
∆𝐺 ‡ ∝ −𝑅𝑇𝑙𝑛(𝑘)
∆∆𝐺 ‡ = −𝑅𝑇𝑙𝑛
𝑘𝐴
𝑘𝐵
▪ Small differences in energy give large selectivities:
For comparison – the energy
required to rotate a single C-C
bond is 12 kJ/mol!
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Energetics of Asymmetric Synthesis – influence of a chiral catalyst
No longer enantiomeric TS’s
(Si)
(Re)
E
(R)
(S)
chiral
catalyst
Stereocentres in catalyst make transition states diastereomeric so ΔG‡(Re) < ΔG‡(Si)
The same argument holds for existing stereocentres in the substrate or reagent
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Methods for Controlling Stereochemistry
1.
Substrate control
Controls new stereocentre
formation
existing stereocentre
2.
Auxiliary control [really just a special case of (1)]
add auxiliary
existing stereocentre
overall transformation
cleave auxiliary
Controls new stereocentre
formation
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Methods for Controlling Stereochemistry
3.
Reagent Control [Prof. Stevenson’s Course]
Controls new stereocentre
formation
existing stereocentre(s) on reagent
4.
Catalyst Control [Prof. Stevenson and Dr Tchabanenko’s courses]
Controls new stereocentre
formation
existing stereocentre on catalyst
We need models to understand how stereochemistry in the
substrate/auxiliary/reagent/catalyst determines the new
stereochemistry in the product
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Determining Enantiomeric Composition
▪ For a chiral molecule we quantify the ratio of enantiomers by the enantiomeric excess (ee)
▪ Normally we would just look at NMR to determine the ratio of two compounds, but NMR spectra of
enantiomers are identical, as are all other physical and chemical properties.
▪ The analogous diastereomeric ratio (dr) can be used to describe the diastereoselectivity of a reaction
To differentiate between enantiomers we must place them in a chiral environment, so they become
diastereomeric
Methods:
1.
2.
3.
Optical rotation measurements
Advanced NMR methods
Chiral chromatography (GC and HPLC)
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Determining ee by optical rotation measurements
▪ Optical rotation (α) is the amount by which a substance will rotate plane-polarized light passing through it.
▪ Normally quoted as:
[𝛼]20
𝐷 =
[α] = observed rotation / degrees
L = path length of cell (dm)
c = concentration (g/100 mL)
20 = indicates measurement was at 20 °C
D = indicates measurement was at the D-line of
sodium (λ = 589 nm)
[𝛼]
× 100
𝐿×𝑐
▪ A single enantiomer of a compound will generally have a characteristic [𝛼]20
𝐷 value. If the value is positive,
this may be called the (+)-enantiomer.
▪ The opposite enantiomer will always give an equal [𝛼]20
𝐷 value of the opposite sign, and would be called the
(−)-enantiomer since it gives a negative value.
▪ If the value of [α]max (i.e. the optical rotation of either pure enantiomer) is known, you can calculate the
‘optical purity’ (same as ee) of a mixture according to:
𝑂𝑝𝑡𝑖𝑐𝑎𝑙 𝑝𝑢𝑟𝑖𝑡𝑦 % = 𝛼
𝑜𝑏𝑠. /
𝛼
𝑚𝑎𝑥.
× 100
▪ Note – this method is extremely sensitive to the presence of other chiral impurities in the sample. Many
incorrect ee’s have been published!
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Determining ee by NMR
1. Chiral shift reagents (CSRs)
Normally a chiral (single enantiomer) Lewis acid – binds to the two enantiomers in question and creates
difference local environments.
+
2:1
Example of a CSR
integrate peaks to obtain ratio of enantiomers
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Harry Stone Mosher
Determining ee by NMR
2. Form diastereomeric derivatives
One of the most common methods is to form Mosher’s ester derivatives of chiral alcohols.
Mosher’s Acid (MTPA)
(S)
(R)
e.g.
a mixture of enantiomers –
same NMR spectra
Very convenient – can just take a 19F NMR and work out ratio of CF3 groups in the two diastereomeric
derivatives (spectrum is very simple, much easier than 1H)
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Determining ee by chromatography
▪ This is the most general and most commonly used method for determining ee
S
S
Column packed with
chiral stationary phase
Detector
Typically measures
UV/vis absorbance
▪ GC (gas chromatography) – mobile phase is gas; HPLC (high performance liquid chromatography) – mobile
phase is liquid)
S
Typical HPLC/GC
R Enantiomers separated
trace
Software integrates peaks to give
relative abundance
y-axis = UV
absorbance
A typical chiral stationary phase for HPLC –
derived from chiral pool sugars
Time axis 
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Determining Absolute Configuration
1. Single Crystal X-Ray Diffraction
This is the gold standard for determining absolute stereochemistry
X-ray diffraction pattern
2. Circular Dichroism (CD)
•
Historically needed a ‘heavy’
(2nd row or lower) atom to get
absolute stereochemistry
•
New machines can do this even
with all 1st row elements
Crystal structure
Chiral molecules induce ellipticity
[θ] in circularly-polarized light
•
Enantiomers have equal and
opposite effects
•
Empirical rules (e.g. the octant
rule) and computation can
predict absolute
stereochemistry from
appearance of CD spectrum
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Determining Absolute Configuration
3a. Chemical Degradation/Interrelation
convert the molecule of interest into another molecule whose stereochemistry is already known
This is the classical way to determine the absolute configuration of molecules.
Before the absolute stereochemistry of anything was known, this method was used to relate stereochemistry
to D-glyceraldehyde, which was used as a standard for comparison.
D-glyceraldehyde
L-glyceraldehyde
D = dextrorotatory – rotates plane
polarized light clockwise
L = levorotatory – anticlockwise
Natural sugars are D
Natural amino acids are L
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Determining Absolute Configuration
3b. Total Synthesis
e.g. (-)-tedanalactam,1 a potent fungicide
isolated from a marine sponge
[𝛼]30
𝐷 = −8.9
Sharpless asymmetric
dihydroxylation
(Prof. Stevenson’s module)
[𝛼]30
𝐷 = +8.5
94% ee
94% ee
[𝛼]30
𝐷 = −7.6
91% ee
91% ee
1. J. Org. Chem 2009, 6378
Naturally-occurring enantiomer
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Lecture 1 – Key Facts
Energetic basis for asymmetric synthesis
Generate diastereomeric transition states that are different in energy
Methods for generating molecules as a single stereoisomer
Substrate, auxiliary, reagent and catalyst control
Determining enantiomeric excess
NMR, chromatography, optical rotation
Determining absolute configuration
X-ray, CD, chemical methods
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Asymmetric Synthesis: Substrate and Auxiliary Control
Lecture 2 – The chiral pool of molecules
Last lecture:
-
Introduction to asymmetric reactions
Energetics of asymmetric synthesis
Analysing stereoisomers
Dr Peter Knipe
[email protected]
Office: 0G.109
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The Chiral Pool
The collection of naturally-occurring compounds that exist as single enantiomers, and are cheap and abundant.
Sugars (carbohydrates)
C5
α-Amino acids (and amino alcohols after reduction)
C4
ribose
alanine
erythrose
C6
tryptophan
C3
glucose
glyceraldehyde
isoleucine
Hydroxy-acids
Terpenes
mandelic acid
menthol
carvone
lactic acid
camphor
tartaric acid
citronellal
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Synthesis from the chiral pool - polypeptides
▪ Nature’s proteins and polypeptides are almost universally formed from L-amino acids.
▪ Chemists form polypeptides by solid phase peptide synthesis (SPPS).
▪ This would quickly get out of hand if we didn’t use chiral pool L-amino acids as starting materials!
desired
product
A racemic synthesis would give a theoretical yield of
1
where n is the number of amino acids in the
2𝑛
peptide. For a decapeptide (n = 10) theoretical yield
is 0.09%
waste
Chiral pool asymmetric synthesis:
100% theoretical yield
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Carbohydrates for chiral pool synthesis
Disadvantages
▪ Overfunctionalized with OH groups –
chemoselectivity difficult
▪ Too many stereocentres
▪ Little chemodiversity (only OH and C=O F.G.s)
▪ Syntheses often require multiple inelegant
protection/deprotection and redox steps.
Key features (e.g. D-glucose)
▪ Only D-sugars are cheap
• α/β indicates relative
stereochemistry
between anomeric
carbon (C1) and sidechain
• Pyranose/furanose
indicates ring size
Different
representations
α-D-glucose
pyranose
α-D-glucose
furanose
Different stereo
and regioisomers
β-D-glucose
pyranose
See Joe Vyle’s course for more in-depth
β-D-glucose
furanose
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Key reactions of carbohydrates
Use acetal chemistry to achieve chemoselective protection (and ‘freezing out’ of one isomeric form)
•
•
MeO prefers α anomer
PhCHO selective for 6membered ring – traps out
pyranose
•
Excess RSH traps out openchain form
•
Acetone selective for 5membered acetonide –
traps out α-furanose
Protected glyceraldehyde
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An extremely useful building block
Synthesis from carbohydrates – (+)-galanthamine
From D-glucose
Primary alcohols
manipulated
selectively over
secondary
Synthesis
surplus to
requirement
Skeletal rearrangement
No new carbon atoms
See Tetrahedron Letters 2007, 48, 6267 for full synthesis
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Amino acids for chiral pool synthesis
Advantages
Disadvantages
▪ Easy to manipulate NH2 or CO2H selectively.
▪ Can be prone to racemization/epimerization
under basic conditions.
▪ Wide variety of useful side-chains, including
alcohols, amines and carboxylic acids.
▪ Only L-stereoisomers are cheap
Key Reactions
Reduction
Substitution with retention
α-lactone
Amino acid  ketone (for more examples see http://tinyurl.com/h4tsjag)
Stable at low T
No over-addition
(similar to DIBAL
reduction)
Weinreb amide
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Synthesis from the pool of amino acids
Look for oxidation patterns that match chiral pool molecule (i.e. where heteroatoms are attached
A simple example:
A much more complex example:
threonine
several chiral
pool SM options
(both have been
reported)
erythrose
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Chiral pool synthesis of thienamycin
▪ Hanessian (the godfather of chiral pool synthesis) chose threonine as the starting point:1
[1] J. Org. Chem. 1990, 55, 3098
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Chiral pool synthesis of thienamycin
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Chiral pool synthesis of thienamycin
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The new chiral pool
▪ New synthetic methods mean that some other chiral molecules are now extremely cheap, and are now
considered as a new chiral pool.
This (and the previous page) is not an exhaustive list – representative examples of each class are given only.
Virtually every chiral molecule ever made by chemists in an enantio-enriched (non-racemic) form ultimately
derives its chirality from chiral pool molecules.
37
Where does the chiral pool come from?
▪ So far we have only been able to create non-racemic products when the SM/catalyst/reagent has been nonracemic.
▪ When simple organic molecules first formed on earth they were achiral or racemic. Nothing yet existed as a
single enantiomer.
What processes could lead to a bias towards one enantiomer of amino acids/sugars etc.?
What is the origin of homochirality on earth?
This is one of the greatest unsolved problems in chemistry.
Theory 1 – Asymmetric Autocatalysis
Autocatalysis – the product of a reaction is a catalyst for its own synthesis – a feedback mechanism that can
enhance an initially extremely low ee:
e.g. the Soai reaction
initial ee very low
final ee very high
It is plausible that a stochastic excess of one enantiomer could have arisen in the early earth, and catalysed its
own amplification.
However, the autocatalytic reaction that would lead to amino acids and/or sugars is yet to be discovered.
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Where does the chiral pool come from?
Theory 2 – Physical Separation of Enantiomers
Some (5-10%) of compounds preferentially crystallize as a single enantiomer rather than a racemate.
e.g. racemic ammonium sodium tartrate (Louis Pasteur)
In a reversible reaction where the product partially crystallizes, this preference can lead to high enantiomeric
excesses from racemic starting materials1 through a process called Viedma Ripening.
Theory 3 – Astronomical Sources
(a) ‘Seeding’ of chirality from comets etc. – this just shifts the problem to another location.
(b) Chiral light sources – circularly polarized radiation from e.g. neutron stars2,3
remaining SM has 1.98% ee
towards (S)-enantiomer
[1] Nature Comms. 5, 5543; [2] J. Am. Chem. Soc 1977, 99, 3622; [3] J. Orig Life Evol Biosph. 2001, 31, 167.
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Lecture 2 – Key Facts
The chiral pool
sugars
amino acids
hydroxy acids
terpenes
Chiral pool syntheses
Peptide synthesis, key reactions of amino acids and carbohydrates, total synthesis
General strategy – look for oxidation/heteroatom substitution patterns matching chiral pool molecules
The new chiral pool
Epoxides and diamines
40
Asymmetric Synthesis: Substrate and Auxiliary Control
Lecture 3 – Substrate-controlled stereoselective reactions
Last lecture: the chiral pool
-
Overview of classes of molecule in
the chiral pool
Using chiral pool molecules in
synthesis
The origin of homochirality on Earth
Dr Peter Knipe
[email protected]
Office: 0G.109
41
Substrate-controlled addition to carbonyl groups
In many cases, nucleophilic addition to a ketone/aldehyde leads to a new stereogenic centre:
If the substrate and reagent are achiral, the product will be racemic.
We must explain the following:
racemic
anti
syn
racemic
racemic
Why is the anti product favoured?
Why does the bias increase as the size of R increases?
Note: if a single enantiomer of the SM had been used, both anti and syn diastereoisomers would be single enantiomers!
42
Addition to aldehydes and ketones with α-stereocentres – model development
Donald Cram (1952)1
“…that diastereomer will predominate which would be formed by the approach of the
entering group from the least hindered side of the double bond when the rotational
conformation of the C-C bond is such that the double bond is flanked by the two least bulky
groups attached to the adjacent asymmetric centre.”
Assumptions
- The nucleophile approaches at 90° angle
- The metal-coordinated carbonyl behaves as a larger group than R (hence RL points away from carbonyl)
Cram was the first to identify the importance of the relative size of substituents at the α-carbon, but this is
an incomplete explanation.
[1] J. Am. Chem. Soc., 1952, 74, 5828
43
The Bürgi-Dunitz attack trajectory
▪ One of the assumptions of the Cram model was the 90° angle of approach of the nucleophile
▪ Crystallographers Hans Beat Bürgi and Jack Dunitz discovered (1974) that this is not the case:1,2
X-ray crystal structures of a range of amino-ketones – studied approach angle of amines into ketone carbonyl groups
[1] J. Am. Chem. Soc. 1973, 95, 5065; [2] Tetrahedron 1974, 30, 1563.
44
The Felkin-Anh (Felkin-Nguyen) Model
The generally accepted model for addition to carbonyl groups with an α-stereogenic centre:
Learn and never forget!
major
product
Can now explain LiAlH4 reaction 3 slides ago…
45
The polar Felkin-Anh model
▪ How can we explain the following result:
Which is the large group?
Implies NBn2 >> CHMe2
The high selectivity can’t be explained by sterics alone – these groups are about the same size  stereoelectronics
C-X σ*
C=O π*
New, lower energy LUMO
▪ The polar Felkin-Anh model – heteroatoms tend to behave as the large group in the Felkin-Anh model
•
•
Heteroatom (N) perpendicular  2
reactive conformations
Lowest energy approach is past the
small group (H, not CHMe2)
46
The Cram chelate model
▪ Another result to explain:
Felkin polar model gives wrong stereochem
anti
Tet. Lett. 1980, 21, 1031
▪ Chelation is key. Leads to an alternative transition state:
▪ When working out whether to use chelation model or polar Felkin model, need to play close attention to
the reagent: Sn, Al, Mg, Ti, Zn are good chelators; Li, K, Na much less likely to form chelates
▪ For Dave Evans’ (Harvard) much more in-depth discussion of stereochemical control in addition to C=O, see
tinyurl.com/zjbwnqq
For
▪ many more examples of chelate control, see Chem. Rev. 1999, 99, 1191.
47
Selecting a model for carbonyl 1,2-stereoinduction
Heteroatom (O/N/S etc)
at α-position?
NO
Felkin-Anh Control
YES
Is the metal likely to form
a chelate through the
heteroatom?
YES
NO
Polar Felkin Control
Cram Chelate Control
48
Auxiliary control of 1,2-addition
▪ In all the above cases an existing stereocentre has directed the approach of the nucleophile
▪ What if we want to control stereochemistry of attack in an achiral/prochiral molecule?
Options
- Chiral source of allyl anion (Reagent control)
- Asymmetric catalyst
- Chiral auxiliary approach
Target molecule
major diasteromer
(24:1 d.r.)
chelation
reductive
removal of
auxiliary
Chem. Lett. 1987, 341
chelation places
isobutyl group on
upper face
Nucleophile attacks
lower face
49
Carbonyl 1,3-Stereocontrol?
▪ All the models (Felkin Anh, polar Felkin, Cram chelate) discussed so far have been examples of 1,2steroinduction
▪ Can a stereogenic centre at the 3-position give control?
Models
Felkin-Anh
Polar Felkin
Chelation
2
1
?
3
2
1
Evans–Saksena Reaction
JACS 1988, 3560
Narasaka-Prasad Reaction
Tet. Lett. 1987, 28, 155
50
1,3-Stereocontrol Models
Evans–Saksena Reaction
Narasaka-Prasad Reaction
half-chair
Fürst-Plattner
attack
Intramolecular reaction  anti-product
Intermolecular reaction  syn-product
51
Aside – Fürst Plattner control
twist-boat
chair
In the Narasaka-Prasad Reaction
chair
twist-boat
52
Carbonyl 1,3-Stereocontrol – beyond borane reductions
▪ By the use of chelating Lewis acids it is possible to achieve 1,3 stereocontrol in other nucleophilic additions
to carbonyl groups, not just borane reductions:
JACS 1988, 3560
Ti chelates to β-alkoxy group
and C=O
Fürst Plattner attack on halfchair
Note: ‘flat’ drawing gives correct result too
– Me blocks upper face so attack lower face
(but doesn’t fully explain nuances)
53
Stereocontrol in alkenes
▪ Alkenes adjacent to a stereogenic centre may also undergo stereoselective addition reactions:
Why is the anti- product favoured over syn?
Why does the alkene geometry have such a large effect?
consider 1,3-allylic (A1,3) strain:
trans
cis
For a review see Chem. Rev. 1989, 1841.
Science 1986, 231, 1108
54
Stereocontrol in Alkenes – Stereoelectronic Effects
▪ The Houk Model is highly effective when one α-substituent is a silane:
new HOMO
C=C π
J. Chem. Soc. Perkin Tran. 1 1992, 3363
Electron-rich C-Si σ-bond raises energy of C=C π bond (HOMO) in this conformation only
 Conformation with RS (here H) inside is both low in energy and most reactive
C=C π
C-Si σ
C-Si σ
▪ The reverse effect is sometimes observed for electronegative α-substituents (particularly oxygen) – called
the inside alkoxy effect:
C-O σ*
C=C π
JACS 1984, 3880
new HOMO
Electron-poor C-O σ-bond lowers energy of C=C π bond
(HOMO) except when placed ‘inside’ (orthogonal to π system)
 Conformation with OMe inside is most reactive
reactive conformer
55
Long Range Stereocontrol – a World Record
An example of [1,61]
stereocontrol, i.e. 61
bonds between existing
stereocentre and site of
reaction!
Stereochemistry
‘transmitted’ through
helical structure
See Angew. Chem. Int. Ed. 2014, 53, 3315 for an excellent discussion
56
Lecture 3 – Key Facts
1,2-Stereocontrol in addition to carbonyl groups
Felkin-Anh control, the polar variant, and the Cram chelate model
1,3-stereocontrol in carbonyl reduction
Evans-Saksena and Narasaka-Prasad reductions
?
Stereocontrolled reactions of alkenes
3
2
1
E+
The Houk model
57
Asymmetric Synthesis: Substrate and Auxiliary Control
Lecture 4 – Stereoselective Aldol reactions under substrate and auxiliary control
Last lecture: substrate-controlled
stereoselective reactions
-
Felkin-Anh and Houk models
1,2- and 1,3 control in ketone
reduction
Dr Peter Knipe
[email protected]
Office: 0G.109
58
The Aldol Reaction
▪ Need to explain the following stereochemical outcomes
Major product
anti
syn
Why is there selectivity at all?
Why do the two reactions above produce different stereoisomers of the product?
59
The Zimmerman-Traxler Model
Aldol reactions generally react through a closed, chair-like transition state called the Zimmerman-Traxler
model:
aldehyde substituent
equatorial
cis-enolate
cis-enolate
no choice of axial/equatorial
syn-product
aldehyde substituent
equatorial
trans-enolate
trans-enolate
no choice of axial/equatorial
anti-product
To control the stereochemistry of the aldol reaction, we must first control the E/Z stereochemistry of the enolate
60
Aside – A-values as a measure of steric bulk
- A Value (–ΔG°) = Free energy difference between
equatorial and axial substituent on a cyclohexane ring.
61
Smith, M. B.; March, J. Advanced Organic Chemistry 5th Ed. Chapter 4 (A Values page 173-5)
Controlling enolate geometry
Lithium enolates
The Ireland Model for enolization
Base
cis
trans
LDA
LiTMP
33
14
67
86
LiTMP + HMPA
92
8
HMPA binds Li+ - prevents chelate formation  open TS
1,2-strain
 cis enolate
Note that this is guidance only – can be overturned by changes in substrate. e.g. if Et is changed to tBu,
LiTMP alone favours the cis enolate, since 1,2-strain defeats 1,3 in the Ireland TS
62
‘Soft’ enolization with boron
▪ For geometrically defined boron enolates can use ‘soft’ enolization (Lewis acid + weak base)
bulky
halide LG
small
trans-selective
small
OTf LG
bulky
cis-selective
63
Diastereoselective Aldol reaction in practice – Ebelactone synthesis
TS-1
TS-2
H rather than Me/RL oriented
towards L groups to minimize
diaxial interaction
TS-2
TS-1
equatorial
equatorial
J. Org. Chem. 1995, 60, 3288
Aldehyde approaches
enolate via Me, not RL group
64
Aldol Reaction - Summary
▪ Draw a chair and place aldehyde substituent (R3) equatorial:
▪ Notes:
▪ Enolate stereochemistry governed by Ireland model, or determined using ‘soft’ enolization methods
▪ (Z)-enolates give syn products; (E)-enolates give anti products
▪ Increasing the sizes of R1 and R3 will increase selectivity in the example above
▪ Boron enolates give higher diastereocontrol because the B-O bond is much shorter (~1.4 Å) than the
Li-O bond (~1.9 Å) leading to a tighter transition state
65
Aldol reactions with existing stereogenic centres
▪ Dealing with chiral ketones or aldehydes in aldol reactions requires you to combine both ZimmermanTraxler transition state and Felkin-Anh considerations. E.g.
1. Enolate formation
OAr group small – Me equatorial (1,2-allylic
strain) rather than equatorial (1,3 diaxial
strain with iPr)
66
Aldol reactions with existing stereogenic centres
▪ Dealing with chiral ketones or aldehydes in aldol reactions requires you to combine both ZimmermanTraxler transition state and Felkin-Anh considerations. e.g.
2. Aldol Reaction – ZT transition state – 2 possible versions
minor TS
Enolate
geometry
retained
Aldehyde equatorial
2 diastereomeric transition states – Felkin Anh tells us
which is preferred
67
Mukaiyama Aldol Reactions
In the above cases the metal enolate was formed in situ. In the Mukaiyama aldol reaction, an enol silane is preformed, and induced to react through use of a Lewis acid:
formed by trapping enolate
with TMS-Cl
JACS 1995, 117, 9598
68
Controlling absolute stereochemistry in enolate reactions
So far we have encountered two situations:
1.
Achiral starting materials producing racemic products (sometimes diastereoselectively)
2.
Chiral starting materials producing non-racemic chiral products (diastereoselectively), e.g. previous slide
What if we want chiral and non-racemic products from achiral starting materials?
Options:
1. Use chiral Lewis acid catalysts (A)
2. Use a chiral counter-ion (X+)
3. Install chiral group at R as a single enantiomer temporarily – this is the chiral auxiliary
approach
(not an exhaustive list – other strategies exist)
69
Chiral Auxiliaries in Aldol Reactions
▪ Chiral auxiliary aldol strategy:
But what is Xc?
70
Oxazolidinones as auxiliaries
Evans’ Auxiliary
Available as either
enantiomer
▪ Installing the auxiliary:
Variants replace CH2Ph
with Ph or i-Pr.
other ways of activating acid may be used
(e.g. DCC, POCl3, TFAA, etc…)
▪ Removing the auxiliary:
if alcohol desired
if acid desired
LiOOH generated in situ – better selectivity
than LiOH for desired carbonyl group
David A. Evans
Harvard
71
Auxiliary-directed alkylation – overall enantioselective reaction
single enantiomer
Org. Syn., 1993, coll. vol. 8, 339
>97% d.r.
remaining minor diastereomer separated by chromatography
Step (i):
Step (ii):
72
Aldol Reactions with the Evans Auxiliary
▪ More complicated – now the electrophile is prochiral, so possible to form even more diastereoisomers
▪ Use Zimmerman-Traxler model to predict which diastereomer is favoured
major product arises from TS where auxiliary
substituent (Bn) is directed away from the ring
conformation of auxiliary
determined by dipole repulsion
with the aldehyde
Aldehyde equatorial in both cases
73
Evans Aldol Reactions – Practice Problem
▪ Predict the major diastereomeric product of the following reaction:
74
Oxazolidinone auxiliary-directed aldol reactions in synthesis
Glucolipsin A
Aldehyde equatorial
(Z)-enolate  syn aldol
Dipoles opposed
Auxiliary substituents directed
away from aldehyde
J. Org. Chem. 2004, 69, 459
75
Auxiliary-Directed anti-Aldol Reactions
▪ So far the Evans auxiliary-controlled Aldol reaction has given syn products
▪ What if we need anti? – 2 methods: chelation control and external Lewis acid catalysis
1. Chelation control for anti-Aldol
TMSCl required to release
Lewis acid catalyst (Mg2+),
otherwise this stays
attached to product
chair
+2.5 kcal/mol
76
J. Am. Chem. Soc., 2002, 124, 392
Auxiliary-Directed anti-Aldol Reactions
2. External Lewis Acid Catalysis
When an extra Lewis acid is added to the
electrophile it leads to an open (i.e. acyclic)
transition state
J. Org. Chem. 1991, 5747
Minimizes gauche interactions in TS
Large Lewis acids (e.g. Et2AlCl)
Small Lewis acids (e.g. SnCl4, TiCl4)
77
Lecture 4 – Key Facts
The Zimmerman-Traxler model for Aldol Reactions
Controlling enolate geometry
trans-selective
cis-selective
The Ireland model, boron enolates
The Evans auxiliary for stereocontrolled Aldol reactions
78
Asymmetric Synthesis: Substrate and Auxiliary Control
Lecture 5 – Other auxiliary-controlled reactions of enolates
Last lecture: Stereoselective Aldol reactions
under substrate and auxiliary control
-
Zimmerman-Traxler model
Evans’ oxazolidinone chiral auxiliary
Dr Peter Knipe
[email protected]
Office: 0G.109
79
Reformatsky-type Reactions – An Alternative Way to form Enolates
You do not need to know the mechanism for the reductive
formation of the Sn enolate (see Chem. Lett. 1982, 161 if interested)
Tet. Lett. 1989, 5821
80
Auxiliary Directed Enolate Reactions – Amination
For stereoselective introduction
of nitrogen α- to carbonyl – need
electrophilic source of nitrogen.
electrophilic nitrogen reagent
e.g. Azidation
JACS, 1987, 109, 6881
Other electrophilic sources of N
81
Auxiliary Directed Enolate Reactions – Oxygenation
Need an electrophilic source of oxygen
electrophilic oxygen reagent
94:6 d.r.
82
Auxiliary Directed Enolate Reactions – Other Electrophiles
Previous examples can be summarized by:
electrophile
Many electrophiles possible
“ Br+ ”
Tet. Lett. 1987, 28, 1123
“ PhS+ ”
Tet. Lett. 1994, 35, 3991
“ F+ ”
Tet. Lett. 1992, 33, 1153
83
Auxiliary Directed Enolate Reactions – Acylation
Need an electrophilic acyl group
J. Am. Chem. Soc. 1984, 106, 1154
96:4 d.r.
Question: why doesn’t the product epimerize?
Doesn’t happen
Find out why in two
slides time
84
The β-Ketoimide Aldol Reaction
Can also access these substrates by
oxidation of the ‘normal’ aldol product:
conditions
TiCl4, iPr2EtN
syn,syn
Sn(OTf)2, Et3N
anti,syn
Bu2B(OTf), Et3N
anti,anti
JACS 1990, 112, 866.
85
Why don’t β-ketoimide aldol substrates epimerize?
loss of stereochemistry
in reality deprotonation only
occurs here
would expect this to be most
acidic  epimerization
formed
not formed
86
Ti, Sn and B β-ketoimide Aldol Reactions
The difference in stereochemisty is due to the chelation preferences of the Lewis acid metal:
1,3-steric clash
anti,syn
JACS 1990, 112, 866
major
minor
Me inwards –
1,3-clash
syn,syn
The boron acetate aldol stereochemical outcome (next slide) is poorly understood – see Tetrahedron 1992, 48, 2127
87
β-Ketoimide Aldol – Stereoselective reduction
Combine with stereoselective reductions (lecture 3) to form structures that appear throughout biology:
set in initial aldol
determined by auxiliary +
enolate geometry
set by β-ketoimide aldol:
enolate geometry +
choice of Ti/Sn/B
set by stereoselective
reduction
88
β-Ketoimide Aldol – Use in total synthesis
▪ Retrosynthesis
89
Evans’ total synthesis of 6-deoxyerythronolide B
‡A
‡B
‡C
‡D
C1-C7 fragment
You should now be able to understand and reproduce all the following transition states relating to this synthesis:
‡A
‡B
‡C
‡D
Bulky CR2
Small OR
90
Designing Chiral Auxiliaries
▪ When creating a chiral auxiliary the following criteria should be considered:
1.
Ease of synthesis
(in practice don’t even need to perform reduction
– amino alcohols are commercially available)
2.
Available as both enantiomers
100 g for £68
3.
Easily added and removed from substrate
4.
Provides high levels of stereoselectivity
50 g for £50*
91
Oppoltzer’s Auxiliary
Wolfgang Oppoltzer pioneered the use of camphorsultam as an auxiliary for asymmetric synthesis:
Wolfgang Oppoltzer
University of Geneva
‘The Baron’
Synthesis
Oppoltzer’s Auxiliary
both enantiomers
available
Installation
Review: Tet. Asym. 2014, 25, 1061
Removal
(+ many other methods, e.g. LiAlH4 gives alcohol product)
92
Alkylation of Oppoltzer Enolates
94
Oppoltzer’s Auxiliary – Stereochemical Model
Boron
Not:
enolate pointed towards
bulky bridged carbocycle
JACS 1990, 112, 2767
Tin
In both cases the aldehyde is equatorial and approaches from the bottom face of the enolate to avoid the
bulky gem-dimethyl group
95
Myers’ Auxiliary
Andy Myers introduced pseudoephedrine as a chiral auxiliary for enolate reactions
=
Andrew G. Myers
Harvard
Installation
JACS 1997, 6496; Angew. Chem. Int. Ed. 2012, 4568
Removal
96
Myers’ Auxiliary – Stereochemical Model
Enolization
Alkylation
Stereochemistry
97
Myers’ Auxiliary in Aldol Reactions
Few examples of pseudoephedrine in aldol reactions, but its close analogue pseudoephenamine has been
reported:
pseudoephedrine
pseudoephenamine
Aldol Reaction (Angew. Chem. Int. Ed. 2014, 4642 and Angew. Chem. Int. Ed. 2012, 4568)
Stereochemistry
Enolization
Aldol
98
Amino Acids from Amino Acids – Schollkopf’s Auxiliary [also co-discoverer of Wittig reaction!]
Desired Reaction
glycine
(achiral)
artificial αamino acids
Use another amino acid as an auxiliary!
Stereochemistry:
Angew. Chem. Int. Ed. 1981, 20, 798
99
Lecture 5 – Key Facts
Electrophilic substitution of Evans enolates
The β-ketoimide aldol reaction
Boron, tin and titanium enolate reactions
Oppoltzer and Myers auxiliaries
100
Asymmetric Synthesis: Substrate and Auxiliary Control
Lecture 6 – Chiral auxiliaries on ketones and aldehydes, and asymmetric 1,4addition reactions
Last lecture: Other auxiliary-controlled
reactions of enolates
-
Amination, oxygenation, acylation and
other electrophiles
β-ketoamide Aldol reactions
Oppoltzer, Myers and Schollkopf
auxiliaries
Dr Peter Knipe
[email protected]
Office: 0G.109
101
Chiral Auxiliaries for Ketone Alkylation
So far we have looked at auxiliaries in reactions involving enolates of carbonyl groups at the carboxylic acid
oxidation level (primarily amides) – the ester/amide linkage is useful for attaching auxiliaries since it is an
easily-manipulated bond, but not generally involved in the reaction of interest (i.e. enolate attack onto
electrophile).
Acid oxidation level:
Problem: How can we install an auxiliary into a ketone?
Solution: convert divalent oxygen to trivalent nitrogen
102
SAMP and RAMP – Ketone Auxiliaries
Dieter Enders introduced a class of auxiliaries based on proline called SAMP and RAMP (for (S) and (R)
versions):
Synthesis
Org. Synth. 1987, 65, 173.
103
SAMP and RAMP installation and removal
Installation
Removal
reductive
oxidative
hydrolytic
104
SAMP and RAMP – Stereochemical Models
SAMP
enolization
Electrophile approach
RAMP would give opposite stereochemistry
SAMP and RAMP are also effective in Aldol reactions, but stereochemical outcome not well understood
Review: Tetrahedron 2002, 58, 2253
105
Stereocontrolled Chemistry of Imines – Ellman’s Auxiliary
So far we have mostly considered placing a chiral auxiliary on a nucleophilic molecule – it is also possible to
induce stereoselectivity by placing an auxiliary on the electrophile
control this
stereocentre
Desired reaction
Ellman’s Auxiliary
Auxiliary strategy
chiral equivalent of
For comprehensive reviews see Chem. Rev. 2010, 110, 3600 and Chem. Soc. Rev.2009, 38, 1162.
106
Ellman’s Auxiliary
Synthesis of the Ellman Auxiliary
Installation
Removal
107
Asymmetric Reduction using Ellman’s Auxiliary
NaBH4
• Chelation by
boron
• Closed TS
• t-Bu equatorial
JOC 2006, 71, 6859.
L-selectride
• Open TS
• t-Bu in least
hindered
conformation
• H- approaches via
lone pair
108
Nucleophilic Addition to Ellman Imines – Closed TS
Grignard reagents work extremely well:
syn
Solvent effect
Tet. Lett. 2002, 43, 923/
THF
Et2O
CH2Cl2
syn:anti
50:50
62:38
97:3
Closed TS
Ethereal solvents bind Mg – competing open TS
109
More Nucleophilic Additions
Allylation
Tetrahedron 1999, 55, 8883
Enolate Addition
•
•
•
•
Enolate geometry – Ireland Model
TS: same as Zimmerman-Traxler
Conformation of auxiliary locked by
chelation to Ti
Favoured TS – tBu pointing away
from enolate
not
JOC 2002, 67, 7819
110
Chiral Enamines from Ellman’s Imines
Ellman imines with an adjacent CH can be deprotonated to form the nucleophilic imine
•
•
•
chiral enamine
Transmetallation for better
chelation control
J. Am. Chem. Soc. 2003, 125, 11276
Zimmerman-Traxler
S=O chelates to metal
Et equatorial
tBu pointing outwards
111
Ellman Auxiliary in Total Synthesis
tBu directed outwards
RCM
Me3Al activates imine and
allows E/Z isomerization
J. Am. Chem. Soc. 2004, 126, 15652
112
Asymmetric Conjugate Additions
Desired reaction
Stereoselective 1,4-addition?
Pioneering Work – E. J. Corey – introduced 8-phenylmenthol as a chiral alcohol to control 1,4-addition to esters1
Installation
or any other
esterification
procedure
= R*OH
Removal
8-phenylmenthol
[1] JACS 1975, 97, 6908; [2]
113
8-Phenylmenthol in Asymmetric Conjugate Additions
soft, non-basic nucleophile
selective for 1,4-addition
Stereocontrol
Amines and thiols also make effective nucleophiles in this reaction
Helv. Chim. Acta 1981, 64, 2808.
114
The Oppoltzer Auxiliary in Asymmetric 1,4-Addition
Chem. Pharm. Bull. 1992, 40, 2579
Stereochemistry
1,4-addition
- Li chelates to S=O and C=O
- Upper face blocked by dimethyl bridge
- 1,4-addition on lower face
Enolate protonation
- PhS now blocks lower face
- Kinetic protonation occurs preferentially
on upper face
115
Evans’ Auxiliary in Asymmetric 1,4-Addition
Metal (e.g. Mg2+) chelates auxiliary and carbonyl
Alkene oriented away from bulky auxiliary
Nuc approaches away from benzyl group
J. Org. Chem. 1993, 58, 766
116
Chiral Sulfinamides in Asymmetric 1,4-Addition
Tet. Lett. 1984, 25, 2627
However, auxiliary is not easily installed:
5 steps
Ideally an auxiliary should add only 2 steps to the synthesis – one
to install and one to remove
117
Asymmetric Reduction
For α,β-unsaturated systems, this is just a special case of asymmetric 1,4-addition where the nucleophile is Hbulky to prevent 1,2-reduction
JOC 1995, 60, 6198
stereoselective protonation
Pyridines
protonation causes
conformational
locking via H-bonding
reduction away
from iPr group
118
Lecture 6 – Key Facts
Enders’ SAMP and RAMP
Ellman’s Sulfinamide auxiliary
Closed and open transition states; in aldol reactions
Asymmetric 1,4-addition
Corey’s 8-phenylmenthol auxiliary; other auxiliaries previously encountered
119
Asymmetric Synthesis: Substrate and Auxiliary Control
Lecture 7 – substrate and auxiliary control in pericyclic reactions
Last lecture: Chiral auxiliaries on ketones
and aldehydes, and asymmetric 1,4-addition
reactions
-
Enders’ SAMP and RAMP
Ellman’s sulfinamide
Corey’s 8-phenylmenthol for asymmetric
1,4-addition
Dr Peter Knipe
[email protected]
Office: 0G.109
120
Control in the Diels-Alder Reaction - Stereospecificity
Diels Alder reactions are pericyclic and thus governed by the Woodward-Hoffmann (WH) Rules.
diene
dienophile
Simultaneously stereospecific, stereoselective and regioselective, e.g.
1. Stereospecificity - there is no choice – the mechanism dictates the stereochemistry entirely (e.g. a cis
dienophile will always give a syn cyclohexene product
dienophile stereochemistry reflected in product
Orbital symmetry and the WH rules
tell us that the diene and dienophile
must come together in a suprafacial
manner  this requires an
‘envelope’ transition state
diene stereochemistry reflected in product
121
Control in the Diels-Alder Reaction – Stereoselectivity and the endo Rule
2. Stereoselectivity – a preference for a particular stereoisomer, but not an absolute requirement
In Diels-Alder the dienophile
normally approaches in an
endo orientation
(due to secondary orbital
overlap, or electrostatic
repulsion in the alternative exo
geometry)
not
But either geometry is WH allowed, and both can occur. Very substrate dependent.
122
Control in the Diels-Alder Reaction – Regioselectivity
3. Regioselectivity – a preference for a particular regioisomer, but not an absolute requirement
Primary orbital interaction is between the diene HOMO and the dienophile LUMO
Regioselectivity arises through preferential interaction between the largest orbital coefficients on the HOMO
and LUMO – use resonance to determine these
vs.
HOMO largest here
LUMO largest here
123
Diels-Alder Reactions
Dienophiles and 1,4-acceptors are similar (both electron-poor alkenes) – if auxiliaries work for 1,4-addition,
they will also work for Diels-Alder reactions.
α
4 new stereogenic
centres in 1 step!
[4+2]
OBn points away
from dienophile
Stereospecific
(Woodward-Hoffmann
Rules)
and stereoselective
(endo rule)
α
enantiomers
Major
diastereoisomer
but racemic
β
β
Envelope TS
EWG underneath
Enantiomeric TS’s  racemic product
diene (endo)
If R is chiral, TS’s become diastereomeric – can achieve selectivity for α vs. β
124
Corey’s Auxiliary-Controlled Diels-Alder Reaction
Corey used the 8-phenylmenthol auxiliary we have already encountered:
89% yield
Sole product
combine with
Diels-Alder TS
diene exclusively approaches
front face of dienophile
JACS 1975, 97, 6908.
125
Corey’s Auxiliary-Controlled Diels-Alder – Use in Total Synthesis of Prostaglandin E1
(TS on previous slide)
enolate
hydroxylation
Oxidative diol
cleavage
Reductive
auxiliary removal
prostaglandin E1
Baeyer-Villiger /
lactam hydrolysis
JACS 1975, 97, 6908
iodolactonization
126
Evans’ Auxiliary in Diels-Alder Reactions
Auxiliary blocks one face of dienophile (analogous
to Evans alkylation):
Benzyl auxiliary gives even better control –due to πstacking stabilizing conformation
This interaction is exploited in catalytic asymmetric Diels-Alder
reactions, see Prof. Stevenson’s course and JACS 2002, 122, 4243
[work by Jorgensen, Macmillan]
Angew. Chem. Int. Ed. 1987, 26, 1184; JACS 1988, 110, 1238
127
Evans-Directed Diels-Alder in Total Synthesis – (-)-stenine
Parikh-Doering
Masamune-Roush modified HornerWadsworth-Emmons reaction
Diene approaches
top of dienophile
IMDA
Intramolecular
Diels-Alder
endo
chelated auxiliary
blocks lower face
ACIE 1996, 35, 904
128
(-)-stenine
Oppoltzer’s Auxiliary in Diels-Alder Reactions
Stereocontrol1
In total synthesis2
[1] Helv. Chem. Acta 1989, 72, 123
[2] Tet. Lett. 1988, 29, 5885
(-)-Pulo’upone
129
Diels-Alder Reactions – Auxiliary on the Diene
You encountered Danishefsky’s Diene in Level 3 pericyclic course – a highly active, electron-rich diene that
forms cyclohexanones:
Major product
endo but
racemic
Danishefsky’s
diene
Rawal’s Asymmetric version:
‘diastereoconvergent’
points forwards in approach underneath
Ester always avoids clash with Ph group
Rawal auxiliary
JACS 1999, 121, 9562
points backwards in approach from above
130
Asymmetric [2+2] Cycloadditions
[2+2]-cycloadditions are generally thermally forbidden (by the Woodward-Hoffmann Rules) and generally
require photochemical activation
e.g.
A
Desired
reaction
Auxiliary Strategy
chiral equivalent of A
sensitizer
ethylene approaches convex face of curved bicyclic molecule
JACS 1986, 108, 306
131
Auxiliary Controlled Thermal [2+2]-cycloadditions of ketenes
π2s
From CHM3002
[2+2] cycloadditions of
ketenes are allowed due to
participation of the ketone –
actually a [2+2+2]
cycloaddition
(4q+2)s = 1
(4r)a = 0
Total = 3
π2a
Odd 
allowed
π2a
Thermal [2+2]
one carbon
ring expansion
JACS 1987, 109, 4752
JACS 1979, 101, 4003
radical
elimination
JACS 1968, 90, 1582
132
Auxiliary Controlled [3+2] Cycloadditions
[3+2] cycloadditions – isoelectronic to Diels-Alder ([4+2]) cycloadditions
JOC 1992, 57, 6527.
Potential strategies:
- Chiral auxiliary on 1,3-dipole
- Auxiliary on alkene
- Chiral catalyst
133
Electrocyclic Reactions
Electrocyclic reactions are pericyclic reactions; stereospecific as dictated by the Woodward-Hoffmann Rules.
2π
4π
6π
8π
Thermal (4n) reactions
are disrotatory
Thermal (4n+2)
reactions are
conrotatory
π2s
π4a
π6s
π8a
disrotatory
conrotatory
disrotatory
conrotatory
134
Asymmetric Electrocyclic Reactions – Torquoselectivity
Although reactions are stereospecific, they produce racemic products:
The aim of chiral auxiliaries and catalysts in controlling electrocyclic reactions is to
bias torquoselectivity by making transition states diastereomeric rather than enantiomeric
135
Auxiliary Control in 4π Electrocyclizations
Eur. J. Org. Chem. 2008, 2960
The
Staudinger
beta-Lactam
synthesis
CH2OBn moves towards H on auxiliary
In diastereomeric TS moves towards CMe
conrotatory
Chem. Comm. 2003, 1380
The Nazarov
Reaction
Ph points away in πstacked conformation
136
Auxiliary Control in 6π and 8π Electrocyclic Reactions
6π
Org. Lett. 2010, 12, 5768
95 %
9:1 d.r.
Disrotatory
R and H move away from Bn group
Org Lett. 2005, 7, 4475
8π
conrotatory
helical TS
for 8π
reactions
disrotatory
Ar moves outwards
R points away
137
Lecture 7 – Key Facts
Stereospecificity and stereo- and regioselectivity of cycloaddition reactions
Diels-Alder: envelope TS; endo rule; use resonance to determine regiochemistry
Auxiliary use including Rawal, Corey, Oppoltzer and Evans
Other cycloadditions: [2+2], [3+2]
Electrocyclic Reactions
Stereochemical selection rules based on electron count (Woodward-Hoffmann)
Concept of torquoselectivity
Auxiliary use including Evans and Rawal
138
Asymmetric Synthesis: Substrate and Auxiliary Control
Lecture 8 – stereochemical considerations in retrosynthesis of
complex molecules
Last lecture: substrate and auxiliary control
in pericyclic reactions
-
-
Stereospecificity and the WoodwardHoffmann rules
Stereo- and regioselectivity in Diels-Alder
reactions
Auxiliary controlled absolute
stereochemistry in Diels-Alder and
electrocyclic reactions
Dr Peter Knipe
[email protected]
Office: 0G.109
139
Synthesis Design
Guidelines (not rules!) for synthesis design
1.
Use two-group disconnections (i.e. reactions that install 2 required bonds at once, e.g. Diels-Alder)
2.
Disconnect molecule at the middle
3.
Disconnect at branch points
4.
Disconnect rings from chains
5.
Disconnect to recognisable starting points
6.
Use symmetry where possible
7.
Use a convergent (rather than linear) approach
8.
Analyse oxidation states and potential functional-group interconversions (FGIs)
9.
Look for key structural features/patterns (e.g. cyclohexene  Diels-Alder)
10. Install most reactive functional group last
Read Organic Synthesis – The Disconnection Approach (Warren and Wyatt)
140
Chiral Pool – Sorensen’s synthesis of FR-901483 – Retrosynthetic Strategy
Retrosynthesis reveals that the core can be formed from 2 x tyrosine
 Chiral pool synthesis is appropriate
Angew. Chem. Int. Ed. 2000, 39, 4593.
141
Sorensen’s synthesis of FR-901483
142
Sorensen’s synthesis of FR-901483
other potential products
143
Retrosynthetic Strategy – When to use Auxiliaries
Key intermediate
in the synthesis of
pinnatoxin
existing
stereocentres
too far away to
help
Both ‘R’ groups on esters above could be replaced by chiral (e.g. Evans) auxiliaries
Tet. Lett. 2007, 48, 6845
144
Synthesis of key pinnatoxin intermediate
145
Ellman’s Auxiliary Approach to SC-53116
Org. Lett. 2004, 6, 3621
146
Synthesis of SC-53116
Plausible TS model
147
Synthesis of SC-53116
SC-53316
148
Diels-Alder Reactions in Complex Molecule Synthesis
JACS 1993, 115, 4497
149
Synthesis of the Southern Fragment of Lepicidin A
Southern fragment
150
Cross-Coupling and Diels-Alder Reactions in the synthesis of Lepicidin A
Control experiment
diene approaches from opposite face of dienophile as benzyl group
 auxiliary overturns innate reactivity
151
Course Overview
Substrate control
Auxiliary control
Reagent control
Evans
Felkin-Anh
Oppoltzer
Ireland enolate model
Myers
Catalyst control
Houk
Ellman
Zimmerman-Traxler
Enders
+ others…
Nucleophilic addition to carbonyl
Aldol
Electrophilic addition to enolates
1,4-addition
… Prof. Stevenson’s lectures
Imine/enamine chemistry
Reactions
Pericyclic reactions
152