Chiral (Stoichiometric) Reagents
• So far we have looked at the use of chiral substrates that either include all the necessary stereocentres or are used to control the introduction of new stereocentres
• Ideally we would like to control the introduction of chirality regardless of any already possessed by the substrate
• This can be achieved with chiral reagents
• Today we will look at reactions that utilise stoichiometric quantities of a chiral reagent
Substrate
R Substrate
R Chiral Reagent
Chiral Reducing Reagents
• Many different means to reduce ketones selectively have been devised
• Two of the more common are given below:
C8H17
O
CO2Me O
O Al H OEt Li
C8H17
OH
CO2Me
O Li O Et H Al
R O
C8H17 O
+
• Proposed transition state model
• ethoxide forms bridge to allow 6-membered transition state
• unsaturated group is equatorial
• orientation of BINOL system controls carbonyl approach
• BINOL (1,1'-bi-2-naphthol) IS chiral (honest)
• Due to restricted rotation around the central bond it has axial chirality
OH OH
HO HO
the two forms are not superposable
• utilised in the synthesis of a beetle pheromone
B
RL RS O
+
H B O
RS RL
RL RS OH
• largest substituent adopts pseudo-equatorial
conformation
• smallest group has 1,3-interaction
• derived from pinene and 9-BBN
• A boron alternative
H
The Aldol Reaction
• Previously we saw the use of a chiral auxiliary to control the stereochemistry
• Now an example where the reagent is used to control the stereochemistry
O
+ OP
O
(–)-DIP-Cl, Et3N PO
PO OP
O OH
• (–)-DIP-Cl = (–)-IpcCl = (–)-B-chlorodiisopinocampheylborane derived from pinene
• Proposed transition state
B O O R
H PO
• reduce diaxial interaction between R and methyl group
• adopts pseudo-equatorial position to reduce 1,3-diaxial
ring strain
• proceeds via the boron enolate (cf chiral auxiliaries)
Carbonyl Allylation Reactions
O O B R
H
PO
R2
R2 OH
O R
H
PO R
O OH
≡
OP work-upH2O2
oxiditive O–B cleavage
• Formation of C–C bonds one of the most important reactions
• Nucleophilic addition to carbonyls (as above) one of the classsic ways of achieving this
• The enantioselective allylation of aldehydes has been intensely studied by Brown and Roush
• Boron reagents have once again proved very amenable
Brown Allylation and Crotylation
BOMe
2
MgBr
K
BF3•OEt2
B
2
B
2 BH3•SMe2
MeOH
allyl nucleophile
Z-crotyl nucleophile
• hydroboration (2nd year)
• boron adds to least substituted end and least
hindered face
• can readily form E-crotyl reagent
as well
• again boron a Lewis acid aids organisation
• (–)-Ipc-OMe
• (+)-Ipc-allyl
B
2
Et2O, -78 ˚C
+
O OH
• Proceeds via a chair-like 6-membered transition state
• I recommend that you practice drawing those chairs
• The crotyl variant behaves in the same manner except two stereocentres are formed
B O
H B
O H
OBR2
≡
work-up
• allyl group orientated away from methyl groups
• aldehyde approaches opposite side
• largest substituent adopts psuedo-equatorial
conformation
• boron useful due to Lewis acid properties which activiate aldehyde
• co-ordination also sets-up 6-ring
B
2
Et2O, -78 ˚C
+
O OH
B O H
OH H
≡
OH H H• chiral auxiliary / pinene groups control absolute stereochemistry (the face the
aldehyde approaches from)
• geometry of alkene controls relative stereochemistry between alcohol and methyl
• Pinene derivatives give excellent selectivity
• But they are problematic to handle
• Require preparation directly prior reaction
• Roush developed tartrate derived analogues which are much more stable
• Z-alkene gives syn product
O O O
B O O
CO2iPr
CO2iPr
+ toluene, -78 ˚C
4 Å sieves O
O OH
O B O
O CO2iPr CO2iPr H
R H
O B O
O CO2iPr CO2iPr H
R H
R
OBR22
≡
work-up
• relative stereochemistry anti with E-alkene
• aldehyde approaches from least hindered side of tartrate
• Tartrate readily available in both enantiomers
• Considerably more easy to handle than the Brown variant
• Slightly worse enantioselectivities in certain cases
Asymmetric Deprotonation Epoxides
• Prochiral epoxides can be transformed into enantiomerically enriched allylic epoxides
O OH
conditions
Ph N
Li Ph
NLi N
Base Conditions Yield (e.e.)
THF, reflux
THF, 0 ˚C
65 % (31 %)
77 % (92 %)
Proposed mechanism
O O OH
OH
(R)-disfavoured (S)-favoured
H O
N Li N
H O
N Li N
Vs
•confusing: but remember base in
same position in both pictures but
• bulk of epoxide
"below" paper along with pyrrolidine
O O
OTBS
NLi
N OH
OTBS benzene, 4 ˚C
O
OH
• Can be used to form useful synthetic building blocks
Ketones
• Chiral bases can be used to desymmetrise prochiral ketones
• Used in the preparation of enantiomerically enriched silyl enol ethers
O O O
NLi Ph Ph
TMSCl, -94 ˚C O
O O
OTMS O
OH HO
OH HN
O O
• enantiotopic positions
• remember plane of symmetry makes it prochiral
showdomycin
O
tBu
N MeN
Ph LiNiPr
+ TMSCl, THF,
HMPA, -78 ˚C
OTMS
tBu
• The same concept can be used for the kinetic resolution of racemic ketones
O
tBu N
MeN
Ph LiN
+
tBu
TMSCl, THF, HMPA, -105 ˚C
O
tBu +
OTMS tBu
45 % 90 % e.e.
51 % 94 % e.e.
• One enantiomer reacts considerably faster
• Maximum yield would be 50 % (or e.e. drops)
"Chiral Anions"
O N
Li Ph Ph
OLi O
CO2Me
90 % 67 % e.e.
15 min., 0 ˚C
CO2, MeI, Et2O, -196 to -80 ˚C
• Chiral base used in the asymmetric reactions of achiral enolates
• Enantiomerically pure lithium amide is non-covalently associated with achiral enolate
• Behaves like a chiral auxiliary (without being bound to the molecule!)
• racemate
Asymmetric Horner-Wadsworth-Emmons Reaction
• Many other possible chiral reagents
• An interesting example is an asymmetric reaction that forms an sp2 centre!
• Asymmetric as desymmetrises a prochiral substrate
What have we learnt?
• Asymmetric reagents can be used to instal chirality to a molecule
• It is possible to use a reagent to control the selectivity of carbonyl reduction
• Chiral boron reagents are readily formed and are excellent for addition reactions to carbonyls
• Chiral lithium amides are good bases for desymmetrisation or resolution reactions
• An asymmetric Wittig reaction can be readily achieved even though it forms an sp2 centre
O
tBu
+
N P N O
Ph
1. BuLi 2. AcOH
tBu Ph
