Substrate Control in Addition to
Carbonyls: Felkin, Ahn and Friends
“These observations are, to my knowledge, the first definitive experimental evidence that
further synthesis with asymmetric systems proceeds in an asymmetric manner. Although
this statement does not at all contradict theory, it by no means follows from it”
– Emil Fischer, 1884
How do we set stereocentres?
1. Get them from Nature (i.e. the chiral pool!)
2. Substrate Control:
Cyclic (easier) or acyclic (harder)
Also, substrate directed reactions
3. Chiral Auxiliaries:
e.g. Various oxazolidones, Oppolzer’s sultams, 8-phenylmenthol,
tert-butanesulfinamides, SAMP/RAMP, pseudoephedrine etc.
4. Chiral Reagents:
e.g. Alpine borane, ipc-boranes, BINAL-H, chiral bases…
5. Asymmetric Catalysis:
e.g. SAD/SAE, Jacobsen, CBS, Noyori, Marshall, MacMillian…
Substrate Control?
“Using the inherant stereochemical preferences of the substrate, due to existing
stereocentres, to perform subsequent reactions stereoselectively”
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This is generally easier in cyclic systems as it’s much easier to say where substituents
will be at any one time!
However, it is now know that acyclic systems can react in a highly selective fashion
under certain conditions.
Addition to carbonyl groups with nearby stereocentres is one of the best understood
and most important scenarios and will be the focus of this talk.
But first, a little history!
For substrate directable reactions see: Evans, Hoveyda and Fu, Chem. Rev., 1993, 93, 1307
Cyclic Versus Acyclic Substrates
Krische (2013):
R. B. Woodward (1981):
Cyclic Versus Acyclic Substrates
Krische (2013):
E. J. Corey (1978):
Carbonyl Addition: 1,2-Induction
• The first example of diastereoselective addition to a carbonyl under substrate control
was reported by Emil Fischer in 1889:
“These observations are, to my knowledge, the first definitive experimental evidence that
further synthesis with asymmetric systems proceeds in an asymmetric manner. Although
this statement does not at all contradict theory, it by no means follows from it”
– Emil Fischer, 1884
Early Models
• Fisher came up with a model based on his sugar experiments, but it is now defunct.
• Next came the Cram model (1952):
 Sometimes gives the right answer.
 Bad for systems with electronegative groups in α-position.
 Theoretically flawed (Nu approaches at 90º).
• Cornforth modified it, proposing that minimisation of dipoles was an important
factor when electronegative groups (Rp) were present:
 Sometimes gives the right answer.
 Rationalises observations for electronegative groups.
 Still quite theoretically flawed.
• However, both these models have eclipsing conformations (RL/Rp clashes with R),
which appears counterintuitive on steric grounds!
A Conformational Conundrum
• It was shown by Houk in the 1980’s that for acetaldehyde (and propene/butane) that
the conformer with C-H and C= X ECLIPSING is more stable in the ground state:
If you don’t believe this,
read: Houk et al., J. Am.
Chem. Soc., 1987, 109, 6591.
• The products of addition to such C=X bonds generally prefer to be staggered (like simple
alkanes).
• So, what does the transition state look like?
A Conformational Conundrum
• It was shown by Houk in the 1980’s that for acetaldehyde (and propene/butane) that
the conformer with C-H and C= X ECLIPSING is more stable in the ground state:
If you don’t believe this,
read: Houk et al., J. Am.
Chem. Soc., 1987, 109, 6591.
• However, in a landmark 1986 Science paper, Houk published further studies that showed
that the transition states for addition reactions were product-like i.e. staggered!
“Alkenes or carbonyls have one allylic bond eclipsed with the double bond in the
ground state, but the transition structure conformations are more product-like.
Rotational barriers involving torsional interactions with partially formed bonds are
nearly as large as those involving fully formed bonds. Consequently, the assumption
of staggering in transition states is just as reasonable as the assumption of
staggering in stable molecules.” –Houk, Science, 1986, 231, 1108.
Felkin, Ahn and Friends
• In a seminal Tetrahedron Letter, Felkin proposed the first model for stereoselective
nucleophilic attack on carbonyls with bonds fully staggered (1968):
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Often gives the right answer!
Uses (correct) staggered conformer
Nu approach still at 90 º
Doesn’t work for Aldehydes (R = H)
• For R=H (i.e. aldehydes) then B should be preferred over A on steric grounds:
• Ahn, using studies by Bürgi, Dunitz and Eisenstein improved the model and provided
computational support for it:
 Generally gives the right answer for
aldehydes and ketones
 Uses (correct) staggered conformer
 Nu approaches at ~107 º
 Often gives wrong results with
electronegative atoms in α-position.
Felkin, Ahn and Friends
• Felkin-Ahn results in 1,2-syn products (with respect to RM and the new hydroxyl):
• A little surprisingly, Heathcock observed that the ‘effective substituent size’ for RL was:
MeO > t-Bu > Ph > i-Pr > Et > Me > H
• The reason: the s* C-RL orbital antiperiplanar to the developing bond has a stabilising
effect, which increases with s* C-RL acceptor ability (i.e. electronegativity).
• This general rule is known as the Ahn-Eisenstein hypothesis and is often phrased thus:
“The best acceptor s * orbital is oriented anti-periplanar to the forming bond."
Ahn-Eisenstein: Electronic Considerations
• Nucleophilic attack can be very sensitive to small electronic effects:
• Phenyl is smaller than cyclohexyl, so why is the reaction more diastereoselective?
• The slightly lower energy of the s* Csp2–Csp3 orbital exerts a significant effect!
“The best acceptor s * orbital is oriented anti-periplanar to the forming bond."
Other Factors
• Unsurprisingly, bigger nucleophiles give better selectivity (branched enolates are
especially good).
• However, counter ions and the nature of the nucleophile can be important for high
selectivity:
• The Felkin-Ahn model can also be used to predict the outcome of certain SN2’
reactions.
A Notable Exception: Borane Reagents
• The Felkin-Ahn model gives good results in many cases, but the borane reduction of
ketones usually gives the anti-Felkin diastereomer:
• This is due to the “non-spherical” nucleophile and the nature of its approach:
1,2-Chelation Control – Cram Model
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Normal diastereoselectivity can be reversed by carrying out reactions under chelation
control
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This normally entails the use of Zn-, Al- or Ti-based reagents/Lewis acids, however
hydrogen bonds can also be used.
These reactions are highly solvent dependent (more polar usually means a better dr).
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An example of 1,2-chelation control
• Silicon protecting groups usually negate chelation, EXCEPT for reactions with certain
Zinc (e.g. ZnR2) or Aluminium (e.g. Me2AlCl or MeAlCl2) nucleophiles/Lewis acids
1,3-Induction: Reetz Cyclic Model
• Bidentate Lewis acids can catalyse the addition of nucleophiles to b-alkoxycarbonyls
with good diastereoselectivity
• These reactions are thought to proceed through cyclic transition states:
“The reactions mediated by BF3•OEt2… represent the real surprise” –Reetz
1,3-Induction: Evans Polar Model
• Surprisingly, stereoinduction remains good even for monodentate Lewis Acids!
• Reetz proposed an acyclic model to explain this stereoinduction but it has now been
superseded by the newer Evans Polar Model:
• Note that both chelate and polar models favour 1,3-anti products.
• Non-coordinating (i.e. alkyl) substituents poorly induce diastereoselectivity.
Multiple Stereocentres
• As stated earlier: 1,2-stereoinduction favours syn products (Felkin-Ahn Model); 1,3induction (whether cyclic or not) favours anti products.
• Thus, for molecules with α- and β-stereocentres, these effects can potentially reinforce
or interfere with each other.
• For the Non-Reinforcing α,β-syn case: large nucleophiles react under Felkin-Ahn control;
small nucleophiles tend to react under 1,3-control (to give anti-Felkin products).
• For the Reinforcing α,β-anti case excellent diastereomeric induction (often >99:1) is
usually observed, almost irrespective of the nucleophile or subsituents.
Key reference: Evans et al., J. Am. Chem. Soc., 2001, 123, 10840.
Felkin-Ahn meets Zimmerman-Traxler
• In a simple aldol reaction, the major diastereomer formed depends on the geometry of
the enolate, which is transferred to the product via a simple cyclic transition state.
• However, additional stereocentres in the two components can also influence the
reaction outcome, and their effects must be considered if present.
Combining Models
• First, let’s consider an adjacent stereocentre on the enolate component.
• (Z)-enolates with α-stereocentres generally form all syn products:
• Conversely, (E)-enolates with α-stereocentres generally form syn-anti products:
Combining Models
• Aldehydes with a-stereocentres give anti-syn (Felkin) products with (E)-enolates…
• …and syn-anti (Anti-Felkin) products with (Z)-enolates:
Roush (only!), J. Org. Chem., 1991, 56, 4151.
Combining Models
Evans et al., J. Am. Chem. Soc. 1995, 117, 9073.
Conclusions
“The on-going development of chemical reactions of ever increasing selectivity coupled
with an evolving sophistication in the tenets of synthesis design now provide one with the
basic tools to design and execute rationally the laboratory synthesis of an impressive array
of organic structure. Without question, the prime activating function for the contruction of
carbon-carbon bonds is the carbonyl function” – Evans, 1984
• Even in acyclic systems, there are many tricks that can be used to perform highly
diastereoselective reactions using simple non-chiral reagents in conjuction with the
existing stereocentres present.
• This talk has only covered a few simple cases for 1,2- and 1,3-asymmetric induction in
addition of nucleophiles to carbonyl compounds but sometimes up to 1,6-induction is
routinely used (see for example Paterson, J. Org. Chem., 2005, 70, 150)!
Possible Reading
Books:
• Classics in Stereoselective Synthesis by Carreira and Kvaerno
• Modern Physical Chemistry by Anslyn and Dougherty
• Strategy and Control by Wyatt and Warren
Reviews/Lectures
• “Around and Beyond Cram's Rule” A. Mengel and O. Reiser, Chem. Rev., 1999, 99, 1191.
• “Structural, mechanistic, and theoretical aspects of chelation controlled carbonyl
addition reactions.” M. Reetz, Acc. Chem. Res., 1993, 26, 462.
• D. A. Evans’ Harvard Chem 206 Lectures, particularly 1-7, 17, 21 and 22.