Conjugate (1,4-) additiongjrowlan/stereo2/lecture9.pdfEnantioselective radical conjugate addition...
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123.702 Organic Chemistry H O R Nuc H yield% x%de electrophile O R Nuc E yield% x%de R 1 ∗ R 2 O Nuc O R reagent O R Nuc R 1 ∗ ∗ R 2 O Nuc E E R 1 R 2 O Nuc Conjugate (1,4-) addition • 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 1 • Second addition normally occurs from opposite face
Transcript of Conjugate (1,4-) additiongjrowlan/stereo2/lecture9.pdfEnantioselective radical conjugate addition...
123.702 Organic Chemistry
H O
R
NucH
yield%x%de
electrophile O
R
NucE
yield%x%de
R1 ∗ R2
ONuc
O
R
reagent O
R
Nuc
R1 ∗ ∗ R2
ONuc
E
E
R1 R2
ONuc
Conjugate (1,4-) addition
• 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
1
• Second addition normally occurs from opposite face
123.702 Organic Chemistry
iv. Ph3SnClv.
I CO2Me
O
TBSOC5H11
OTBS
CO2Me
78%94%de
O
TBSOC5H11
OTBS
O
O+
I C5H11
OTBS
i. t-BuLiii. CuI, PPh3iii. HMPA–78°
SiMe
Met-Bu
Substrate control in total synthesis
• 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
2
i. Pyr•HF(HF)xii. hydrolysis
78%
O
HOC5H11
OH
CO2H
prostaglandin E2
123.702 Organic Chemistry
Me Me
NSO O
OMg
HMe
MgEt
ClEt
Cl
Me Me
NSO O
OMg
MgEt
ClEt
Cl
HMe
Me Me
NHSO
O
HO Me
O Et
LiOH
Me Me
NS O
OO
Et
MeH
90% de
EtMgCl
Me Me
NS O
Me
OO
Me Me
NHS
OO
Oppolzer's camphor sultam
Diastereoselective conjugate additions
• 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
3
trans conformation disfavoured
cis conformation
favouredchelation restricts rotation
123.702 Organic Chemistry
Me Me
NSO O
OMg LL
Bu
MeH
MeI
Me Me
NHSO
O
HO Me
O Bu
Me
+
Me Me
NS O
OO
Bu
MeH
95% de
MeH
Me Me
NS O
Me
OO
1. BuMgCl2. MeI
Chiral auxiliary to control two stereocentres
• 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)
4
electrophile approaches from
bottom face
LiOH
123.702 Organic Chemistry
O
N
Ph
OMe
R1
LiR2
H
O
N
Ph
OMe
R1
LiHR2
O
N
Ph
OMe
R1R2
H
H2O
R2–Li1. LDA2. R1CHO3. CF3CO2H
O
N
Ph
OMe
R1
H
O
N
PhMe
OMe
Alternative chiral auxiliaries I
• 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
5
aldol-like reaction & acid catalysed elimination
hydrolysis
R1CO2H
R2HPh
OH
OMeNH2
H3O
95-99% ee
123.702 Organic Chemistry
NO
O
PhPh
R1
OYbLn
R2
Chiral auxiliary and radical conjugate addition
• 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
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NO
O
PhPh
R1
O
NO
O
PhPh
R1
O R2
R1=Me, PhR2=i-Pr, Et, c-Hex etc
Yb(OTf)3 (1eq), R2–X (5eq), Bu3SnH (2eq), Et3B, O2, 3h, –78°C
81-94%76-96%de
123.702 Organic Chemistry
ZnBr2
O
O
SOZn
MeO
L L
Raney Ni
O
O
H
Ar
O
OS
O
MeO H
Ar
O
O
MgBrO
OS
O
MeO
Sulfoxide-based chiral auxiliary (& total synthesis)
• 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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nuc
O
O
H
O
O
OOMe
MeO
MeO
(–)-podorhizon95% ee
Ar2COCl
123.702 Organic Chemistry
Chiral auxiliaries and total synthesis
• 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
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NPh
Ph
CO2EtBr
O
O
Me
MeMe
+
LiBrEt3N
72%92%de
CO2Et
H N
O
O
Me
Me MePh
Ph
H NH2
HO
O
OH
O
i. HClii. LiOH59%
L-CCG-I
123.702 Organic Chemistry
Enantioselective catalytic conjugate addition
• 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
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O
75%10% ee
O
Et
Et2Zn, Cu(OTf)2 (2%), lig. (4%), tol, 3h, –30°C
O Et2Zn, Cu(OTf)2 (2%), lig. (4%), tol, 3h, –30°C
O
Et94%
>98% ee
OO
P NMe
Ph
MePh
lig.
123.702 Organic Chemistry
Enantioselective radical conjugate addition
• 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
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NO Ph
OO
+ IMe
Me
i. Et3B, O2ii. MgX2
N
O
N
ONO Ph
OO MeMe
90%97%ee
123.702 Organic Chemistry
N
N CO2H
Me
Me
H
CO2Bn
CO2Bn
N
N CO2H
Me
Me
H
CO2Bn
BnOOH
Ph Me
O
BnO OBn
O O
N
NH
CO2HBn
Me
cat. (10%), neat, rt, 165h Ph
Me
CO2BnBnO2C
O
86%99% ee
+
Organocatalysis
• 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
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123.702 Organic Chemistry
N
N
MeO
Me
MeMe
H
X ArH
N
N
MeO
Me
MeMe
H
X
N
N
MeO
Me
MeMe
H
X
NR2
H
X O
H
NR2
N
NH•HCl
Bn
MeO
Me
MeMe
R2N
O
HX
68-90%84-92% ee
+
Organocatalysts II
• 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
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steric hindrance results in predominantly one
conformation
123.702 Organic Chemistry
Organocatalysts III
• 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)
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OTMSO Me R O
HO
HR
OO
Me
N
NH•HCl
Bn
MeO
Me
MeMe
cat. (20%)DCM / H2O
–20 to –70°C, 11–30h77%
syn:anti = 1-31:184-99% ee
+
MeH
O
O CO2Et O
O
CO2EtMe
cat. (20%)KHMDS (20%)
25°C, 24h
80%97% ee
NN
NO
OMe
HBF4
123.702 Organic Chemistry
Mechanism of Stetter reaction
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NN
NO
Ar
NN
N
Ar
Ar2
OHH
NN
N
Ar
HO
OMe
H base
OEt
O
base
O
CO2EtMe
O HN
N
N
Ar
NN
N
Ar
OH
O
Me
O
OEt
MeH
O
O CO2Et
base
O
O
CO2EtMe
• 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
N N
S
F3C
CF3
NH HO O
N
Ph
H
CO2Et
CO2EtH
MeMe
N N
S
F3C
CF3
H HO O
N
Ph
H
N MeMe
HO
O
OEtEtO
H
H
NO2NO2
EtO2C CO2EtNH
NH
S
F3C
CF3
NMeMe
EtO2C CO2Ettoluene, rt, 24h
86%93% ee
+
Organocatalytic bifunctional catalysis
• 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
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123.702 Organic Chemistry
N
N
MeO
Me
MeMe
H
H H
N
N
MeO
Me
MeMe
HPh
RN
Br
BocHN
N
N
MeO
Me
MeMe
HPh
RN
Br
BocNH
Organocatalysis and total synthesis
• 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
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Br N
MeMe
NHBoc
+
O
N
NH
O
Bn t-Bu
Me
i. cat (20mol%)ii. NaBH4
78%90%ee
Br N
MeMe
NBoc
H
OH
Br N
MeMe
N
H
Me
Me
Me
(–)-flustramine B
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