Advanced organic
Me
Me Ph
Me
O
OOH
H Me98% deMe
Me
Me
OO
MgO
H
L L
Me
Me Ph
Me
O
OO
H
MeMgBr–78°C
Stereoselective reactions of the carbonyl group• We have seen many examples of substrate control in nucleophilic addition to the
carbonyl group (Felkin-Ahn & chelation control)• If molecule does not contain a stereogenic centre then we can use a chiral auxiliary • The chiral auxiliary can be removed at a later stage
1
• Opposite diastereoisomer can be obtained from reduction of the ketone• Note: there is lower diastereoselectivity in the second addition as the nucleophile,...‘H–’ is smaller
Me
Me Ph
Me
O
OO
Me
KBH(i-OPr)3
Me
Me Ph
Me
O
OOH
Me H90% de
Me
Advanced organic
HO OHMe
MeLiAlH4
Me
Me Ph
Me
O
OO
Me
RMgBr–78°C
Me
Me Ph
Me
O
O
OHMe
Me
Chiral auxiliary in synthesis
• The chiral auxiliary, 8-phenylmenthol, has been utilised to form the pheromone, frontalin
2
O3–78°C
O
O
Me
Me
(–)-frontalin100% ee
Advanced organic
RSO
Tol
HO H
R Me
HO HRaney Ni
70% de
OS O Al
RTol
H
i-Bui-Bu
AlHi-Bu i-Bu
DIBAL
R Me
HO HRaney NiR
SO
Tol
HO H
80% de
RS O Li
OTol
AlH3HLiAlH4
RS
O O
Tol
Sulfoxides as chiral auxiliaries
• Underrated chiral auxiliary - easily introduced, performs many reactions & can be readily removed
• One auxiliary can give either enantiomer of product• Selectivity dependent on whether reagent can chelate two groups
3
lithium can chelate 2 oxygens
hydride directed to si face
oxygens are not directly tethered
dipoles directed in opposing directions
Advanced organic
RL RS
OHH+
Me
Me
Me
B OH
Me
Me
Me RSRL
+RL RS
O
Me
Me
BHMe
alpine borane®
Me
Me
Me
+ BH O
(+)-α-pinene 9-BBN•THF
Chiral reagents• Clearly, chiral reagents are preferable to chiral auxiliaries in that they function
independent of the substrate’s chirality or on prochiral substrates• A large number have been developed for the reduction of carbonyls• Most involve the addition of a chiral element to one of our standard reagents
4
(CH2)4Me
Oalpine borane®
small group as linear
(CH2)4Me
OHH
86% ee
proceeds via boat-like transition state
selectivity governed by 1,3-diaxial interactions
can be reused
Advanced organic
Chiral reagents II• Alpine-borane is very good for reactive carbonyls (aldehydes, conjugated ketones
etc)• It is less efficient with other ketones so a more Lewis acidic variant has been
developed• Addition of the chloride makes the boron more electrophilic• Transition state similar to previous slide
• And here is another...
5
Me
Me
Me HBCl
2(+)-Ipc2BCl
+
OMe
Me
Me
Me
H OH
98% ee
MeMe
Me
O
+B MeMe
H
MeMe
Me
H OH
>99% ee
Advanced organic
Binol derivative of LiAlH4
• Reducing reagent based on BINOL and lithium aluminium hydride• Selectivity is thought to arise from a 6-membered transition state (surprise!!)• Largest substituent (RL) adopts the pseudo-equatorial position and the small
substituent (RS) is axial to minimise 1,3-diaxial interactions
6
MeSnBu3
O 1. (S)-BINAL–H2. MOM–Cl
MeSnBu3
OMOMH
93% ee
OOAlOEt
H
Li(R)-BINAL–H
O
Et
Al
H O
LiORS
O
RL
Advanced organic
Ph H
OH OH
95% ee
MgBrTi
OO
MeMe
OO Ph
Ph
PhPh
HH
Ti
OO
MeMe
Cl OO Ph
Ph
PhPh
HH
Chiral reagents: allylation
• Stereoselective reactions other than reduction can be performed with chiral reagents• In the above reaction the standard Grignard reagent is reacted with the titanium
complex to give the chiral allylating reagent• Note: the chirality is derived from tartaric acid (again)
7
Advanced organic
OHREH
RZ
H
RR
OH
RERZ
B
OL
RER
RZ
H L
B
OL
REH
RZ
H L
H R
vs
R
OB
RZ RE
L L
OB
RRZ
RE
L L
R
O+ B RE
RZ
L
L
Chiral allyl boron reagents
• Allyl boron reagents have been used extensively in the synthesis of homoallylic alcohols
• Reaction always proceeds via coordination of Lewis basic carbonyl and Lewis acidic boron
• This activates carbonyl as it is more electrophilic and weakens B–C bond, making the reagent more nucleophilic
• Funnily enough, reaction proceeds by a 6-membered transition state
8
• Aldehyde will place substituent in pseudo-equatorial position (1,3-diaxail strain)• Therefore alkene geometry controls the relative stereochemistry (like aldol rct)
E-alkene gives anti productZ-alkene gives syn product
disfavoured
H2O2NaOH
R
OH
RZ RE
Advanced organic
OH
Me
H
H
EtB
O
Me
H
H
MeMe
Me
MeMe
MeEt
Me
Me
B
2
Me
Me+
O
Et HEt
Me
OH
92% ee
Chiral allyl boron reagents II
• Reagent is synthesized from pinene in two steps• Gives excellent selectivity but can be hard to handle (make prior to reaction)
• Remember pinene controls absolute configurationGeometry of alkene controls relative stereochemistry
9
crotyl group orientated away from pinene methyl groups
substituent pseudo-equatorial
Advanced organic
Other boron reagents
• A number of alternative boron reagents have been developed for the synthesis of homoallylic alcohols
• These either give improved enantiomeric excess, diastereoselectivity or ease of handling / practicality
• Ultimately, chiral reagents are wasteful - they need at least one mole of reagent for each mole of substrate
• End by looking at chiral catalysts
10
Me
Me
B
2
Me
RZ
RE
attacks on si face of RCHO
B
RZ
RE
O
O
i-PrO2C
i-PrO2C
attacks on si face of RCHOtartaric acid derivative
B
RZ
RE
N
N
Ph
Ph
attacks on re face of RCHO
Ts
Ts
Advanced organic
Catalytic enantioselective reduction
• An efficient catalyst for the reduction of ketones is Corey-Bakshi-Shibata catalyst (CBS)
• This catalyst brings a ketone and borane together in a chiral environment• The reagent is prepared from a proline derivative• The reaction utilises ~10% heterocycle and a stoichiometric amount of borane and
works most effectively if there is a big difference between each of the substituents on the ketone
• The mechanism is quite elegant...
11
OOMe
MeO
CBS catalyst (10%)BH3•THF
MeO
MeO
OHH
93% ee
NB O
HPhPh
MeCBS catalyst
proline derivative
BH3 NB O
HPhPh
MeH3B
active catalyst
Advanced organic
Ph
Ph
OBNB
HO
MeH
H
RL
RS
RL RS
O
Ph
Ph
OBNB
HO
MeH
H
RL
RS
NB O
HPhPh
MeH3B
BH3•THFNB O
HPhPh
Me
• interaction of amine & borane activates borane• it positions the borane
• it increases the Lewis acidity of the endo boron
coordination of aldehyde activates
aldehyde and places it close to the borane
chair-like transition statelargest substituent is pseudo-equatorial
catalyst turnover
Mechanism of CBS reduction
12
RL RS
H OH
Advanced organic
MeON
MeMe Me
ZnOZn
C5H11
C5H11
Ar
H
Me
C4H9
MeON
MeMe Me
ZnOZn
C5H11
C5H11
H
Ar
Me
C4H9
vs.Me
ON
MeMe Me
MeZn
ZnC5H11
C5H11C5H11
OH
O+ C5H11 Zn C5H11
(–)-DAIB (2%) OC5H11
H OH
>95% ee
Catalytic enantioselective nucleophilic addition
• There are now many different methods for catalytic enantioselective reactions• Here are just a few examples...• Many simple amino alcohols are known to catalyse the addition of dialkylzinc
reagents to aldehydes• Mechanism is thought to be bifunctional - one zinc becomes the Lewis acidic
centre and activates the aldehyde• The second equivalent of the zinc reagent actually attacks the aldehyde• Once again a 6-membered ring is involved and 1,3-diaxial interactions govern
selectivity
13
MeOHNMe2
MeMe
(–)-DAIB
disfavoured
Advanced organic
Catalytic chiral Lewis acid mediated allylation
• A variety of chiral Lewis acids can be used to activate the carbonyl group• These can result in fairly spectacular allylation reactions (higher ee than this example)• A problem frequently arises with crotylation • Often the reactions proceed with poor diastereoselectivity favouring either the syn
or anti diastereoisomer regardless of geometry of the starting crotyl reagent• This is because the reactions proceed via an open transition state• (just to confuse you most actually favour syn! I use this example as the comparisons
were easy to find...)
14
Ph H
O+ SnBu3
cat. (5%), DCM, rt, 7h
Ph
OHH
88%62% ee
Rh N
OO
N
Bn Bn
Cl
Cl
cat. derived from amino acid (via the alcohol)
Ph H
O+ SnBu3
cat. (10%), DCM, rt, 72h
Ph
OHHMe
Me E : Z95 : 5
2 : 98
anti (ee) : syn (ee)71 (57) : 29 (8)63 (60) : 37 (7) SnBu3
R H
OM
open transition state
Advanced organic
Catalytic chiral Lewis base mediated allylation
• An alternative strategy is the use of Lewis bases to activate the crotyl reagent• Reaction proceeds via the activation of the nucleophile to generate a hypervalent
silicon species• This species coordinates with the aldehyde, thus activating the aldehyde and
allowing the reaction to proceed by a highly ordered closed transition state• As a result good diastereoselectivities are observed and the geometry of
nucleophile controls the relative stereochemistry
15
R H
O+ SiCl3RE
RZ
Lewis base catalyst (LB)R
OHH
RE RZ
Si
OREH
RZR
LBClLB
Cl Cl
NP
NHH N
MeNMe
PN
NOO HH
( )5
RE = Me86% ee
anti/syn 99/1
RZ = Me95% ee
syn/anti >19/1
Ph N Ph
OH
Me Me
RE = Me98% ee
anti/syn >99/1
RZ = Me98% ee
syn/anti 40/60
NMe O
NMe O
RE = Me86% ee
anti/syn 97/3
RZ = Me84% ee
syn/anti 99/1
Advanced organic
O
Ph Ph92% ee
85% de (trans)
SEt Et
PhPh
O
Ph H
O
SEt Et
Ph
Ph Br
SEt Et
cat. (10%)NaOH
Organocatalysts
• As we have seen with many stereoselective reactions, small organic molecules are now finding considerable use as enantioselective catalysts
• Above is a simple example of epoxide formation• The reaction proceeds by SN2 displacement of the bromide by the sulfide and
subsequent deprotonation to give the reactive ylide • Nucleophilic attack & cyclisation give the epoxide and regenerate the sulfide catalyst
16
Advanced organic
N
R
O O
Ar
N
H
BocH
NO2R+Ar
N
H
Boc
cat. (10%) ArNO2
HN
R
P(O)Ph2
90% ee90% de
NH HNHH
N NH
OTf
Organocatalysts II
• Acts as a ‘chiral proton’• Protonation of the imine forms a highly electrophilic species• Aza-Henry reaction can then proceed to give the new amine
17
Advanced organic
NMe
Me
N N
S
F3C
CF3
H HO
N
R
HO
Ar
NDpp
H
N N
S
F3C
CF3
H HO O
N
H
H
N MeMe
H
R
NO2R +Ar
N
H
P(O)Ph2
cat. (10%)DCM, rt
ArNO2
HN
R
P(O)Ph2
76% ee
NH
NH
S
F3C
CF3
NMeMe
Bifunctional organocatalysts
• Thio(urea) acts as a Lewis acid to activate & position the nitro substrate• Pendent amine functionality deprotonates the nitro α-C–H and presumably an
electrostatic interaction shields the bottom face of the nitro enolate
18