1
Conjugate (1,4-) addition
Nuc
O
Nuc
R1
Nuc
R2
R1
O
O
∗
R1
R2
∗
∗
R2
E
E
• Nucleophilic attack on C=C bond normally requires electron deficient alkene
• Know as 1,4-addition or conjugate addition
• As enolate formed during reaction - possibility of forming two stereogenic centres
• Substrate control - initial addition to the least hindered face of enone
O
R
E
H
reagent
Nuc
O
electrophile
H
R
Nuc
R
O
yield%
x%de
• Second addition normally occurs from opposite face
123.702 Organic Chemistry
2
Substrate control in total synthesis
O
I
C5H11
+
i. t-BuLi
ii. CuI, PPh3
iii. HMPA
–78°
O
OTBS
O
Si Me
Me t-Bu
OTBS
iv. Ph3SnCl
v.
I
O
CO2Me
O
CO2H
HO
C5H11
TBSO
C5H11
i. Pyr•HF(HF)x
ii. hydrolysis
78%
OH
prostaglandin E2
CO2Me
TBSO
C5H11
OTBS
78%
94%de
• Prostaglandins are technically hormones with very strong physiological effects
• Prostaglandins have been utilised to prevent and treat peptic ulcers, as a
vasodilator, to treat pulmmonary hypertension and induce childbirth / abortion
• This is a synthesis of prostaglandin E2 (PGE2) by M. Suzuki, A. Yanagisawa & R.
Noyori, J. Am. Chem. Soc. 1988, 110, 4718
123.702 Organic Chemistry
3
Diastereoselective conjugate additions
Me
Me
Me
Me
Me
NH
Me
Me
EtMgCl
N
N
S O O
O
S O
O
Oppolzer's
camphor sultam
S
trans conformation
disfavoured
Me
Me
HO
Me
NH
S O
O
O
LiOH
Et
Me
Me
H
N
S O O
O
90% de
Et
Et
O Mg Cl
Mg Cl
O O
Et
cis
conformation
favoured
chelation
restricts rotation
Me
Me H
Me
Me
Me
N
S
H
Et
O Mg Cl
Mg Cl
O O
Et
• Possible to use chiral auxiliary to control 1,4-nucleophilic addition
• Chelation of amide and sultam oxygens to Mg restricts rotation and favours cis
conformation
• Addition occurs from most sterically accessible side
• Chiral auxiliary readily cleaved (& reused) to give enantiomerically pure compound
via diastereoselective reaction
123.702 Organic Chemistry
4
Chiral auxiliary to control two stereocentres
Me
Me
Me
Me
N
1. BuMgCl
2. MeI
Me
Me
H
N
S
S O O
O
Me
Bu
Me
H
Me
H
N
O
Mg L
O O
L
electrophile
approaches from
bottom face
Me
Bu
S O O
O
95% de
Me
I
LiOH
Me
Me
Me
NH
S O
O
+
HO
Me
O
Bu
• It possible to utilise 1,4-addition to introduce two stereogenic centres
• The first addition (BuMgBr) occurs as before to generate an enolate
• The enolate can then be trapped by an appropriate electrophile
• Once again the sultam chiral auxiliary controls the face of addition (of Me)
123.702 Organic Chemistry
5
Alternative chiral auxiliaries I
aldol-like reaction & acid
catalysed elimination
O
Ph
Ph
O
O
1. LDA
Me
N
OH
Ph
R1
R1
N
H
3. CF3CO2H
R1
OMe
NH2
R2–Li
2. R1CHO
OMe
H
OMe
O
CO2H
Ph
Ph
N
Li
OMe
O
Ph
H2O
H3O
R1
H R2
95-99% ee
R2
H
R2
R1
N
OMe
H
R2
N
Li
OMe
hydrolysis
• A second chiral auxiliary is the oxazoline (5-membered ring) of Meyers’
• It can be prepared from carboxylic acids (normally in 3 steps) or from condensation
•
of the amino alcohol and a nitrile
As can be seen excellent enantiomeric excesses can be achieved via a highly
diastereoselective reaction
123.702 Organic Chemistry
6
Chiral auxiliary and radical conjugate addition
O
O
O
R1
N
Yb(OTf)3 (1eq), R2–X
(5eq), Bu3SnH (2eq),
Et3B, O2, 3h, –78°C
81-94%
76-96%de
Ph
Ph
O
O
R2
O
R1
N
Ph
Ph
R1=Me,
R2=i-Pr,
Ph
Et, c-Hex etc
Ln
O
O
Yb
O
R2
R1
N
Ph
Ph
• Radicals once thought to be too reactive to allow diastereoselective reactions
• Clearly not true - oxazolidinone auxiliary
• Rare-earth Lewis acids give superior results
• Use of Et3B & O2 as radical initiator allows the use of low temperatures
123.702 Organic Chemistry
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Sulfoxide-based chiral auxiliary (& total synthesis)
L L
Zn
O
O
O
O
S
ZnBr2
O
O
MeO
MgBr
S
MeO
O
O
S
O
O
H
MeO
Ar
O
Raney Ni
nuc
O
MeO
O
O
O
Ar2COCl
H
MeO
OMe
O
H
O
Ar
(–)-podorhizon
95% ee
O
• Sulfoxide is a good chiral auxiliary; not only does it introduce a stereocentre but it
•
•
•
•
activates the alkene by addition of an extra electron-withdrawing group
Sulfoxide substituent blocks the bottom face & is readily removed
Simple substrate control instals aryl group on opposite face to substituent
(–)-Podorhizon is a member of the anticancer podophyllotoxin family of compounds
This synthesis is by G. H. Posner, T. P. Kogan, S. R. Haines, L. L. Frye, Tetrahedron
Lett. 1984, 25, 2627
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Chiral auxiliaries and total synthesis
Ph
Me
N
Ph
Ph
CO2Et
Me
O
+
Br
Me
LiBr
Et3N
H N
72%
92%de
O
Me
Me
Ph
CO2Et
O
O
Me
i. HCl
ii. LiOH
59%
H NH2
OH
HO
O
O
L-CCG-I
• L-CCG-I (L-carboxycyclopropylglycine-I) is a conformationally restrained analogue of
•
L-glutamic acid (there are four possible stereoisomers of L-CCG)
L-Glutamic acid is the most abundant excitatory neurotransmitter in our bodies; it is
thought to be involved in cognitive functions like learning and memory in the brain
and possibly with umami, one of the five basic human tastes
• This synthesis is by Subhash P. Chavan, Pallavi Sharma, Rasapalli Sivappa, Mohan
M. Bhadbhade, Rajesh G. Gonnade and Uttam R. Kalkote, J. Org. Chem. 2003, 68,
6817
123.702 Organic Chemistry
9
Enantioselective catalytic conjugate addition
O
Et2Zn, Cu(OTf)2 (2%),
lig. (4%), tol, 3h, –30°C
O
Ph
O
O
Et
Me
P N
Me
Ph
94%
>98% ee
lig.
• Much effort has been expended trying to develop enantioselective catalysts for
•
•
conjugate addition
Whilst many are very successful for certain substrates, few are capable of acting on
a wide range of compounds
The system above gives excellent enantioselectivities for cyclohexenone but...
no selectivity for cyclopentenone
O
Et2Zn, Cu(OTf)2 (2%),
lig. (4%), tol, 3h, –30°C
O
Et
75%
10% ee
123.702 Organic Chemistry
10
Enantioselective radical conjugate addition
O
O
O
N
i. Et3B, O2
ii. MgX2
Me
Ph
+
I
O
O
Me
O
O
Me
N
Me
Ph
O
N
N
90%
97%ee
• Not unsurprisingly, once stereoselective conjugate radical additions with auxiliaries
•
•
had been developed, the enantioselective catalytic variant rapidly followed
Effectively, this is a chiral Lewis acid catalysed reaction
Most work in this area has been pioneered by Sibi
123.702 Organic Chemistry
11
Organocatalysis
Me
N
O
O
Bn
O
+
Ph
Me
BnO
OBn
N
H
CO2H
cat. (10%),
neat, rt, 165h
CO2Bn
BnO2C
Ph
O
Me
86%
99% ee
Me
Me
N
CO2H
N
Me
H
N
N
BnO
H
O
CO2Bn
CO2H
Me
CO2Bn
H CO Bn
2
• New small molecule organic catalysts are now achieving remarkable results
• Enone is activated by formation of the charged iminium species
• The catalyst also blocks one face of the enone allowing selective attack
123.702 Organic Chemistry
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Organocatalysts II
O
Me
N
X
Bn
NR2
O
Me
X
Me
N
H•HCl Me
+
H
O
H
R2N
O
O
Me
N
Me
H
H
X
X
H
Me
N
Me
Me
Me
N
Me
Me
O
Me
N
N
68-90%
84-92% ee
Me
Me
N
NR2
Me
H
X
Ar
H
steric hindrance results
in predominantly one
conformation
• A range of reactions can be achieved, including enantioselective Friedel-Crafts
• Catalyst ensures that the enone reacts via one conformation
• Must use electron rich aromatic substrates
123.702 Organic Chemistry
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Organocatalysts III
O
Me
N
Bn
H
+
TMSO
O
Me
R
O
Me
Me
N
H•HCl Me
O
O
cat. (20%)
DCM / H2O
–20 to –70°C, 11–30h
Me
O
R
H
77%
syn:anti = 1-31:1
84-99% ee
• Possible to introduce two stereogenic centres with good diastereoselectivity and
•
enantioselectivity
An interesting reaction is the Stetter reaction - this is the conjugate addition of an
acyl group onto an activated alkene and proceeds via Umpolung chemistry (the
reversal of polarity of the carbonyl group)
OMe
cat. (20%)
KHMDS (20%)
25°C, 24h
O
Me
H
O
CO2Et
O
Me
N N
CO2Et
O
80%
97% ee
N
O
H
BF4
123.702 Organic Chemistry
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Mechanism of Stetter reaction
O
O
Me
Me
Ar
CO2Et
H
N N
O
O
N
CO2Et
O
N
Me
Ar
N
Ar
N N
base
O H
N
CO2Et
OH
H
N
base
Ar2
O
Ar
N N
N N HO
OEt
N
O
Ar
O
H
N
OEt
OH
O
base
O
Me
Me
• The Stetter reaction is analogous to the activity of thiamine (vitamin B1) in our bodies
and the reaction is thus biomimetic
123.702 Organic Chemistry
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Organocatalytic bifunctional catalysis
CF3
S
F3C
NO2
+
EtO2C
CO2Et
N
H
N
H
Me
N
EtO2C
CO2Et
Me
NO2
toluene, rt, 24h
86%
93% ee
CF3
CF3
S
F3C
S
H
N H
N Me
H
H
Me
O
O
H O
N
O
H
EtO
Ph
F3C
N
OEt
N
N
H
H
O
O
N
N
H
Ph
Me
Me
H
CO2Et
CO2Et
• The thio(urea) moiety acts as a Lewis acid via two hydrogen bonds
• The amine both activates the nucleophile and positions it to allow good selectivity
123.702 Organic Chemistry
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Organocatalysis and total synthesis
O
Me
N
NHBoc
Me
O
Br
N
Bn
N
H
t-Bu
NBoc
+
Me
N
Br
i. cat (20mol%)
ii. NaBH4
Me
78%
90%ee
Me
N
Me
Me
N
H
Ph
Me
H
BocHN
H
Me
Me
(–)-flustramine B
O
Me
Me
Me
N
Me
Me
Me
N
N
Br
Me
N
O
N
H
Me
O
H
Me
OH
Me
Me
Me
N
Ph
H
BocN
H
RN
RN
H
Br
Br
• Beautiful example of enantioselective conjugate addition in total synthesis
• From the synthesis of a marine alkaloid from the Bryozoa, Flustra foliacea by Joel F.
Austin, Sung-Gon Kim, Christopher J. Sinz, Wen-Jing Xiao, and David W. C.
MacMillan, PNAS 2004, 101, 5482
123.702 Organic Chemistry