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123.702 Organic Chemistry
bX
c
HR2
dR
a
bX
c
HR2
dR
aX
R
R2
da b
c
heatX
R2
R3R1
X
R1 R3
R2
[3,3]-Sigmatropic rearrangements
• A class of pericyclic reactions whose stereochemical outcome is governed by the geometric requirements of the cyclic transition state
• Reactions generally proceed via a chair-like transition state in which 1,3-diaxial interactions are minimised
• Many similarities to the aldol reaction Absolute stereochemistry - controlled by existing stereocentre (destroyed in rct)Relative stereochemistry - controlled by alkene / enolate geometry
1
X
R1 R3
R2
X
R2
R
dcb
a
123.702 Organic Chemistry
H
Me
MePh
H Me
PhMe
91%
H
Ph
MeMe
Me H
MePh
9%
Me
Me
Ph
Cope rearrangement
• A very simple example of a substrate controlled [3,3]-sigmatropic rearrangement is the Cope rearrangement
• To minimise 1,3-diaxial interactions phenyl group is pseudo-equatorial • Note: the original stereocentre is destroyed as the new centre is formed• This process is often called ‘chirality transfer’
2
1,3-diaxial interactions disfavoured
123.702 Organic Chemistry
Claisen rearrangements
• One of the most useful sigmatropic rearrangements is the Claisen rearrangement and all it’s variants
3
Claisen rearrangement
Johnson-Claisen rearrangement
Eschenmoser-Claisen rearrangement
OH +OEt Hg+ O O
H
heat
OH +Me OMe
MeO OMe H+ O
OMe
O
OMe
heat
OH +Me NMe2
MeO OMe H+ O
NMe2
O
NMe2
heat
Ireland-Claisen rearrangement
OH +Me O Me
O O Et3N
Me
O
O
O
OSiR3
O
OSiR3
heatR3SiClbase
123.702 Organic Chemistry
Me
Me
OMe
NMe2
Me NMe2
MeO OMe
Me
Me
OH MeH2
Lindlar cat.
MeNMe2
Me
Me O
≡
MeMe
Me
NMe2
O HMe
Me
O
Me
NMe2
Me NMe2
MeO OMeNaNH3 Me
Me
OH
MeMe
Me
Me
OH
Me
Me
Me
OH
‘Enantioconvergent’ synthesis
• Both enantiomers of initial alcohol can be converted into the same enantiomer of product
• This process (Eschenmoser-Claisen) shows the importance of alkene geometry
4
SET reduction gives most stable alkene
heterogeneous hydrogenation leads to syn addition of H2
O
H NMe2
i-Pr
Me
O
H NMe2
i-Pr
Me
HH
Me2N
O
H Me
Hi-PrMe2N
O
H Me
Hi-Pr
same configuration
MeH
Me
NMe2
O Me
≡
123.702 Organic Chemistry
O
H
H
OSiR3MeMe O
H
H
OSiR3MeMe
O
OSiR3Me
Me
1. LDA, THF/HMPA2. R3SiCl
O
MeMe
OSiR3
O
H
Me
OSiR3Me
H
O
OSiR3Me
MeO
H
Me
OSiR3Me
H
1. LDA, THF2. R3SiCl
O
MeOSiR3
Me
O
MeMe
O
Ireland-Claisen reaction
• Enolate geometry controls relative stereochemistry• Therefore, the enolisation step controls the stereochemistry of the final product• As we saw earlier it is relatively easy to control enolate geometry...
5
123.702 Organic Chemistry
Substrate control in Ireland-Claisen rearrangement
• In a similar fashion to the Cope rearrangement we saw earlier, the Ireland-Claisen rearrangement occurs with ‘chirality transfer’
• Initial stereogenic centre governs the conformation of the chair-like transition state• Largest substituent will adopt the pseudo-equatorial position
• Once again, the relative stereochemistry is governed by the geometry of the enolate
6
O
Me Me
OHO
91% ee
1. LHMDS2. TMSCl
H
O
OTMS
H
Me
OTMS
Me
H
O
OTMS
H
Me
OTMS
Me
HO2CMe
OTMS
Me98% syn91% ee
methyl group is pseudo-equatorial
123.702 Organic Chemistry
Auxiliary controlled rearrangement in total synthesis
• (–)-Malyngolide is an antibiotic isolated from the blue-green marine algae Lyngbya majuscula
• This synthesis utilises Enders' RAMP hydrazone as a chiral auxiliary to set up the quarternary centre
• Dieter Enders & Monika Knopp Tetrahedron 1996, 52, 5805
7
NN
OMe
O
O LiTMP NN
OMe
O
OLi LiAlH4 N
N
OMe
OHO
OMe
OHMe
( )7
(–)-malyngolide
123.702 Organic Chemistry
O
OHMe
Me96% ee
warmO
O
Me
R*2B
MeEt3NTol / hexane
–78°C
O
OHMe
Me>97% ee
warmO
OMe
Me
R*2Bi-Pr2NEtCH2Cl2–78°C
O
OMe
Me
+ NBN
Ph Ph
ArO2S SO2Ar
Br
Chiral reagent control in the Ireland-Claisen rearrangement
• Funnily enough, it is possible to carry the reaction out under “reagent” control • Although, it could be argued that this is just a form of temporary auxiliary control!• Enolate formation (enolate geometry) governs relative stereochemistry
8
123.702 Organic Chemistry
The use of a chiral reagent in total synthesis
• Dolabellatrienone is a marine diterpenoid isolated from gorgonian octocorals such as Eunicea calyculata and other marine organisms
• This synthesis of dolabellatrienone relies on boron enolate chemistry to establish the stereochemistry of the final molecule
• E. J. Corey & Robert S. Kania, J. Am. Chem. Soc. 1996, 118, 1229
9
O
Me
MeMe
O
NBN
Ph Ph
Br
SO2O2S
CF3F3C
F3CCF3 Me Me
CO2HH
Me
Me Me
HMe
O
Me
Medolabellatrienone
Ni-Pr
N(i-Pr)2
(i-Pr)2N
86%>98%ee
123.702 Organic Chemistry
Chiral catalyst control in the Ireland-Claisen rearrangement
• It is also possible to perform the reactions under chiral catalyst control• Presumably, the Lewis acid coordinates to the oxygen & influences the reactive
conformation thus controlling enantioselectivity
10
O
Ph
SiMe
MeMe
HO
SiMe3
Ph
O
Ph
SiMe3
MeAl(OR*)2
OO
Al Me
SiMe2t-Bu
SiMe2t-Bu
MeAl(OR*)2 =
123.702 Organic Chemistry
H
Me
O
H H
H H
Me
HO
H H
H
MeMe
≡ HO
Me
98%de98%ee
Me
OBuLi–85°CMe
Me
H
H
HO
H H
Me
H
≡ HO
Me
98%deH
H
O
H H
Me
H
O
MeBuLi–85°C
11
2
2 3
1
12
2 3
O Z H HO ZO Z Base O Z
2,3-Wittig rearrangement
• Useful rearrangement allowing good 'chirality transfer'• Requires method for formation of anion - either acidic proton (Z=electron
withdrawing group) or metal-functional group exchange• Driving force is stability of alkoxide (although other elements can be used...)
• Transition state debatable but useful model is the 'envelope' based on chair
11
• Largest substituents adopt pseudo-equatorial position
123.702 Organic Chemistry
Enantioselectivity in the 2,3-Wittig rearrangement
• Reagent control utilising boron reagent seen in both aldol & Claisen reactions• Chiral catalysis is far less developed in this area• One example is given below:
12
O
Me
CO2Me+
NBN
Ph Ph
PhO2S
Br
SO2Ph
Et3N O
Me
R2BO OMe
MeO
MeO OBN
NSO2
O2S
Ph
Ph
Ph
Ph
≡ HO
Me
CO2Me
66%de96%ee
O
ArR2*RNPh(CH2)2
OO
Ar
cat (20mol%)MeOH, rt, 5d
75%60%ee (dr 2:1)
Ph(CH2)2
O
OH
Ar
NH N
123.702 Organic Chemistry
[2,3]-aza-Wittig reaction in total synthesis
• Aza-Wittig reaction is less common as normally no driving force• Here relief of ring-strain accelerates reaction• Utilised in the synthesis of indolizidine 209B from Dendrobates pumilio or the
strawberry poison dart frog by Jens Åhman & Peter Somfai, Tetrahedron, 1995, 51, 9741
13
C5H11
Me
NCO2t-Bu
LDA
97%
N
C5H11
H
H
MeHLiO
Ot-Bu
NH
C5H11 CO2t-Bu
Me
NC5H11
Me
indolizidine 209B
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