With both substrate control and the use of
chiral auxiliaries the stereo-control element
has been part of the substrate.This has
obvious limitations; the must be an existing
stereogenic element or a point of
attachment for the auxiliary. What happens
if we have no stereochemistry in our
molecule? Or we don’t want to add two
steps to our synthesis (attachment/removal
of auxiliary)? We could add the
stereocontrol element to the reagent ...
The molecule above is the primary odour
molecule responsible for the smell of musk
and has been used in perfumes for
thousands of years.
Synthetic muscone saves the poor musk
deer from being slaughtered.
... or in cartoon form ...
The reagent contains the stereochemical
information and its interaction with the
substrate creates diastereomeric transition
states; one will be lower in energy and will
lead to the preferred product.
The advantage of this form of control is
that we no longer require any
stereochemical information in the
One asymmetric synthesis of muscone
involves the conjugate addition (1,4-
addition) of a cuprate to an enone. This
can be achieved in high enantioselectivity
by adding a chiral amino alcohol.
Now, instead of the substrate controlling
which face of a molecule the reagent can
approach, the reagent controls which face
the molecule can approach ...
... the disadvantage is that it can be quite
wasteful; we need a stoichiometric quantity
of the chiral reagent and unless we can
recycle/recover the reagent we are throwing
a lot of chirality away.
Chiral organoboranes have long held a
powerful position in the pantheon of chiral
The reason for this is the easy access to chiral
derivatives from natural ‘chiral pool’ materials
by simple hydroboration coupled to the utility
of these reagents in a number of reactions.
The reagent above is called alpine borane and
is formed from pinene. It is a chiral
This reagent reduces ketones with good
Boron is group 13 so only has 6 valence
electrons in neutral compounds. It is a
Lewis acid. It will coordinate with a lone
pair of electrons on the ketone. The
coordination activates both the ketone,
making the carbonyl more electron
deficient, and activates the reductant.
Rehydridisation of the boron from sp2 to
sp3 lengthens the C–B bond making the
reagent more nucleophilic. Coordination links
substrate and reagent together. The reaction
then proceeds through a boat-like transition
The enantioselectivity (or facial selectivity) is
governed by the minimisation of 1,3-diaxial
interactions across the ring. So the ketone
approaches the borane so that the small
group is parallel to the methyl of the reagent
as shown above.
An example of an analogous reagent being
used in the synthesis of a pharmaceutical
is taken from this synthesis of fluoxetine
This example replaces alpine borane with
(ipc)2BCl (ipc = isopinocampheyl). This
reagent is more sterically demanding
(resulting in higher enantioselectivity) and
more Lewis acidic (higher reactivity) thanks
to the electron-withdrawing chlorine.
The transition state is thought to be the
same as alpine borane. Coordination of the
ketone sets up a boat-like transition state
with the smallest ketone substituent
adopting the pseudo-axial position to
minimise the 1,3-diaxial interactions across
As you can see the reaction is very
Pinene makes an excellent molecule for the
synthesis of these chiral reagents.
It is a cheap and abundant source of chirality
(European pine trees produce a more
enantiomerically enriched sample than North
Hydroboration occurs on the least sterically
hindered face of the alkene (anti the bulky
dimethyl bridge). The boron adds to the least
substituted, more nucleophilic, carbon.
The bulk of pinene means hydroboration
only occurs twice to give (ipc)2BH. This
reagent undergoes disproportionation on
treatment with TMEDA (N,N,N’,N’-
tetramethylethylenediamine) to give
Note how the sign of the optical rotation
changes between the two molecules even
though each contains the same stereogenic
Organoboranes be employed in
enantioselective oxidations as well as
reductions. Good results can be obtained with
cis-alkenes and (ipc)2BH as shown above.
While I will not go through the origin of the
stereoselectivity here you should be able to
start to rationalise it for yourself. First you
need to deduce the favoured conformation of
the two ipc units. Then how they approach the
(ipc)2BH only gives good results with cis-
alkenes; non-bonding interactions prevent it
IpcBH2 gives its best results with trans-
alkenes and trisubstituted alkenes. It is
less sterically demanding, which aids
reactivity, but at a slight cost to
For those of you who are interested this is
the start of understanding the
enantioselectivity in the the hydroboration
There is much ‘harder’ or should that be ‘in
depth’ version of this course on the horizon
(it just takes an awfully long time to
prepare all the diagrams)
Probably the most important use of boron
reagents in asymmetric synthesis is in the
aldol reaction. Here they permit the
formation of a C–C bond and up to two new
stereocentres with remarkably high yields,
diastereo- and enantioselectivity.
(ipc)2BOTf (Tf = triflate = SO2CF3) is
readily prepared from the organoborane.
It is occasionally argued that this an
example of chiral auxiliary control.
As we shall see a chiral enolate is formed
by combining the ketone and reagent. This
is then reacted with the achiral aldehyde.
Personally, as we never isolate the chiral
enolate and the ipc subunit is lost from the
product during work-up I think this is more
a case of chiral reagent ... but it doesn’t
So what is going on?
Why is the reaction so effective?
The first step is the formation of the boron
The geometry of the enolate is of great
importance. Under normal conditions the
Z(O)-enolate (shown above) is favoured.
The mechanism for enolate formation
involves activation of the carbonyl group by
coordination to the boron followed by
The aldol reaction then proceeds through
the classic Zimmerman-Traxler chair-like
Coordination of the boron enolate with the
the aldehyde activates both the electrophile
(Lewis acid activation) and the nucleophile
(rehybridisation of boron from sp2 to sp3
lengthens the B–O bond feeding electrons
towards the oxygen).
+2.3 kcal mol–1
+1.4 kcal mol–1
The geometry of the enolate fixes the
position of the enolate substituents and
the methyl group must be pseudo-axial.
The orientation of the aldehyde can change
but, as you should be aware, its substituent
will adopt the pseudo-equatorial position to
minimise 1,3-diaxial interactions.
The only choice is which face of the
aldehyde is attacked (re or si) ...
... this is controlled by the pinene units.
The favoured conformation of two pinenes
is that shown above.
In many respects the most important
pinene is the pseudo axial pinene. The
equatorial pinene is only playing a support
role. The axial pinene wants to minimise
1,3-diaxial interactions so the hydrogen
atom is directed towards the ring ...
This slide tries to demonstrate the various
conformations of the reagent based on
minimising 1,3-diaxial interactions (and
thus fixing the conformation of the axial
Once the conformation of the boron
reagent has been sorted we then have to
look at the constituents of the chair-like
transition state. The enolate has an axial
substituent. To minimise non-bonding
interactions this will be orientated away
from the methyl of the pinene. So the
aldehyde must approach from the same
face as this methyl group. Thus the enolate
attacks the si face of the aldehdye.
If you want to find an example of this sort
of chemistry in action look for the work of
Paterson, he has undertaken some
remarkable total syntheses that are often
built on the power of the aldol reaction ...
This example is from the synthesis of
laulimalide, a marine natural product.
This example is of the challenging acetate
aldol (a methyl ketone so there is no
substituent on the enolate). Such examples
frequently have lower stereoselectivities than
the normal propionate examples ... the
influence of the methyl substituent on the
transition state is surprisingly important.
Anyways, this example shows how the reagent
can control diastereoselectivity in a complex
Boron reagents have found considerable
use in enantioselective allylation and
crotylations, a powerful route to
Hopefully you can already see the similarity
between these reagents and the aldol
reaction ... conceptually, a methylene group
has replaced the oxygen of the enolate
otherwise everything is the same ...
Coordination of substrate and reagent
activates both the electrophile and the
A six-membered Zimmerman-Traxler chair-
like transition state is formed.
The ligands on the boron will control the
enantioselectivity while the geometry of the
crotyl alkene will control the
As with the aldol reaction. The position of
the alkene substituents is fixed (like the
enolate substituents). The only option we
have is the aldehyde substituent.
It will adopt the pseudo-equatorial position
in preference to the pseudo-axial
conformation in order ...
... to minimise unfavaourable 1,3-diaxial
The geometry of the alkene will control the
diastereoselectivity of the reaction.
Hopefully you can see that the E-alkene
results in formation of ...
... the anti product (RE is on the opposite
face of the product to the hydroxyl group)
while the Z-alkene results in the formation
of the syn product.
This stereospecificity is key Type 1
crotylations and boron-mediated aldol
If you do not understand it see me.
Now we need to look at controlling the
Once again this can be achieved with the
use of pinene derivatives.
These are readily formed by hydroboration
followed by addition of the appropriate
As expected (see aldol reaction) the Z-
crotyl reagent results in the formation of
the syn product.
Remember: geometry of the alkene
controls the relative stereocehmistry or
The pinene subunit controls the absolute
stereochemistry or enantioselectivity.
The reaction proceeds through the
Zimmerman-Traxler chair-like transition
The aldehyde will be orientated so that its
substituent is equatorial.
The crotyl reagent is bulkier than the
aldehyde (CH2 vs. O) so the favoured
conformation has it away from the methyl
groups of the pinene (or the aldehyde
approaches from the same face as the
The use of allyl/crotyl pinene-derived boranes is
known as the Brown allylation or crotylation.
Changing the geometry of the alkene will result
in the formation of the anti diastereomer. The
absolute stereochemistry (the hydroxyl
stereocentre) will remain the same.
These reagents give good enantio- and
diastereoselectivities but are moisture sensitive
so require careful handling (prepare on day of
Tartaric acid derivatives are known as the
Roush reagents. These give slightly
reduced stereoselectivities compared to the
Brown reagents but are easier to use.
As we can see, they follow the same
principles with the reaction proceeding
through a closed chair-like transition state
so the geometry of the alkene controls
diastereoselectivity and the tartrate
controls absolute stereoselectivity ...
... the control of the absolute
stereochemistry is thought to be control by
an electronic effect rather than simple
The aldehyde approaches anti to the lower
ester in order to minimise the interactions
of the oxygen lone pair of electrons.
There are many asymmetric allylation/
crotylation reagents available.
Amongst the most successful of the new
generation are the silicon based reagents of
An example of the use of these is found in
the synthesis of this potential drug
... these reagents operate in the same
manner as the boranes we have just
covered. The reactions proceed through a
closed chair-like transition state. The
geometry of the alkene controls the relative
stereochemistry (syn or anti) while the
diamine (a common, easily accessible,
‘chiral pool’ material) controls the absolute
These reagents are air-stable solids and are
commercially available. More information
can be found in:
J. Am. Chem. Soc. 2011, 133, 6517