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2,3-Sigmatropic Rearrangements in Organic Synthesis
October 25, 2006
Matt Haley
Crimmins Group
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Sigmatropic Rearrangements-concerted pericyclic reactions traditionally thought to be governed by orbital symmetry
-a group attached by a sigma bond migrates to the terminus of an adjacent pi-electron system
2,3-sigmatropic rearrangements:
-can be defined as a thermal isomerization that proceeds through a six-electron, five-membered
cyclic transition state
-thermally allowed sigmatropic process according to the Woodward-Hoffman Rule*
XY
XY Y
X
5-membered cyclic transition state
2,3-sigmatropic rearrangements discussed:
-2,3-Wittig rearrangements
-Mislow-Evans rearrangement
-Additional 2,3 rearrangements
*Chem. Rev. 1986, 86, 885-902
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2,3-Wittig Rearrangement(anionic)
O O O
O
G
Me
G = C CH
C Me
n-BuLi
THF, -85 CGHO
Me
99% ee99% ee
O
G
G = Ph
C CH
C TMS
n-BuLi
THF, -85 CGHO
Me
95~98% ee100% ee100% ee
Me
Chem. Rev. 1986, 86, 885-902
erythro
threo
A general trend is observed that E-alkenes
show threo selection and Z-alkenes show
Erythro selection. Exceptions include
Substrates where G = CO2H and Ph
-regiospecific carbon-carbon bond formation and allylic transposition of oxygen function
-generation of specific olefin geometries
-stereoselective creation of vicinal chiral centers
-transfer of chirality
-competition is seen with 1,2-shift, dependent on substrate structure and rxn
temperatureDiastereoselection Study
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O
G
Me
O
G
Me
GHO
Me
GHO
Me
O
H
H
GMe
H
O
H
G
HMe
H
O
H
G
HH
Me
O
H
H
GH
Me
threoerythro
Diastereoselectivity:Proposed Transition States
Chem. Rev. 1986, 86, 885-902
Nakai and Mikami Marshall, Houk, and Wu
J. Org. Chem.1990, 55, 1421-1423
endo exo
Transition structure based onMP2/6-31+G computations:
sterics place substituents
preferentially in the exo position-acceptors like carbonyls
and electropositive groups
like silyl ethers prefer endo
position
Cation plays large role
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Piers, et al. Organic Letters,2000, 2, 1407-1410
Me
OH
H
Me
Me KH, Bu3SnCH2I
Me
O
H
Me
Me
SnBu3
-diterpenoid from the cyathane family
-characterized by Ayer and Taube in 1972
-anti-fungal and promotes synthesis of nerve growth factor
M e
HO
1. Me 2NNH 22. CSA (equil.)
71% (2 s teps)
Me
HN
N
1 . K D A ,
2. AcOH, NaOAc, H 2O
69% (2 steps)
M e3Ge
Me
HO
Me 3GeI
1 . Na O M e , 6 6 %2. LDA, MeI, 85%
3 . N IS ,9 0 %4. BuLi, 86%
Me
OH
H Me
CHO
O
Me
HO
Me
H
Sarcodonin G
Me
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Piers, et al. Organic Letters,2000, 2, 1407-1410
Me
O
H
Me
Me BuLi
88% (2 steps)
H
Me
O
H
Me
Me
Me
O
H
Me
Me
Me
H
Me
Mequench
HOH H
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Mislow-Evans(neutral)
Acc. Chem. Res.1974, 7, 147-155
SO
SO O
S
R RR
R3P:
O
-it is proposed that the rearrangement proceeds exclusively through a concerted mechanism
-equilibrium lies largely to the left, sulfonate not detectable by NMR
-increased heating can result in 1,3-shift of sulfoxide:
S Ph
O
!
Ph S
O
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J. Org. Chem.1989, 54, 2779-2780
There is a very high E-olefin selectivity when there issubstitution to the sulfoxide (substitution at R1)
R1 X
H
R3R2
SOR4
R1
R2
X
H
OsR4
R3
R1 > R2
R1 OSR4
X
R3
R2
Olefin Geometry
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Synthesis of the Imine Ring System of Pinnatoxins
OO
OH
Me
N
Me
OHO M e
H
R
Me
Pinnatoxins: A: R = CO2H C: R =
B: R =CO2
-
NH3+
CO2-
NH3+
-pinnatoxins structurally elucidated by Uemura et al. in 1995
-structurally unique cyclic imine, stable to aqueous acids
Organic Letters, 2005, 7, 1629-1631
O
OPMBO
OAc
N
Me
Me
O O
O
PivO
PMBO
SO
O
O
O
PMBO
PivO Me
Me
OH
cascade Claisen-Mislow-Evans
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Construction of Cascade Reaction Precursor
Organic Letters, 2005, 7, 1629-1631
from ascorbic acid
O
HO
OHO
1. LAH, 98%
2. NaH, PivCl3. I2, Ph3P, ImH, 74% (2 steps) PivO
IA
O
O
O
TIP S O
MgBr1. , 9 3 %
2. OsO4, N a I O43. TP AP, N MO, 68% (2 s teps)
O O
OOTIPS
O
1. LDA; Et2Zn ;A , DMPU
2. PhNTf2, KHMDS
80% (2 steps )O O
OOTIPS
TfO
PivO
1. P MBOCH2C H 2C H 2ZnX, Pd0
, 7 5 %
2. TBAF, 91%
3. Swern
4. (S)-methyl p-tolyl sulfoxide, LDA
5. TMSCl, KHMDS
6. LDA, 65% (4 steps)
O O
OOTIPS
TfO
Piv O
O O
O
Piv O
PMBO
SO
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O
Me
HO H
O
O
O
H
OMe
H
Me
MeH
M e
M eH
TBDPSO
O
HO
Me
H
Me
MeH
M e
M eH
Ph3
PO
H
OH
O TMS
O
OTBS
TIPSO
H
Me
H
+
(+)-Milbemycin D
-milbemycins first reported in 1975 by Mishima
-among the most potent antiparasitic and insecticidal agents known
-notable synthetic challenges include spiroketal moiety and hexahydrobenzofuran
Crimmins et al. J. Am. Chem. Soc.1996, 118, 7513-7528
Additional 2,3-Sigmatropic RearrangementsSynthesis of (+)-Milbemycin D
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O
1. P h3P=CHCO2Et, 98%2. LAH
3. TB SCl, 95% (2 steps)
TBSO
H C C C H O1 . , 9 8 %2 . LA H , 9 8 %
M e
OTBS
Me
O TBSOH OH
+
1. SAE
2. Swern3. MeMgCl
4. Swern
73% (4 steps)Me
O TBS
M e
OTBSO O
+O O
1.5 : 1
M e
OTBSO
O
LD A , T M S C l
M e
OTBSOTMS
TMSO
mC P B A
60% (2 steps)
M e
OTBSO
TMSO
HO PhSeCl, 7 8%O
OR
H
OH
H
M e
SePh
OTBS
Preparation of 2,3-Rearrangement Precursor
Crimmins et al. J. Am. Chem. Soc.1996, 118, 7513-7528
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O
MeMe
H
O
Bakkenolide A
Additional 2,3-Sigmatropic Rearrangements ContdSynthesis of Bakkenolide A
-Approximately 50 bakkanes isolated from plants to date
-they are sesquiterpenoids possessing a cis-hydrindane skeleton
with two quat. centers
-biological activities include selective cytotoxicity, antifeedant effectsand inhibition of platelet aggregation
Organic Letters, 2004, 6, 3345
J. Am. Chem. Soc.1977, 99, 5453
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Me
Me
O
CHSnC 4H9
Cl
KotBu84%
Me
O
CHSnC4H 9
Me
KOH
78%
M e
O
M eM e
O
M e
+
OsO4, NaIO4
46 %
only syn pdt
taken on
M e
O
OM e
Me
O
O
Me 1. K O t Bu , 6 3 %
2. H 2/ Pd - C , 9 3 %O
H
Me
M e
L i
H
Me
M e
HO60%
PB r3
H
Me
M eBr
Synthesis of Bakkenolide A
H
MeMe
Br S
O
O
HN HN C
S
SCH3
NaH
75% (2 steps) H
Me
Me
SSCH3
NNHTs
J. Am. Chem. Soc.1977, 99, 5453
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H
Me
Me
SSCH 3
NNHTs
H
Me
Me
SSCH3
N
TsN
H
Me
Me
S
N
T sN
SCH 3H
Me
Me
S
N
Ts N
SCH 3 H
Me
Me
SCH3
S
NaH
62%
2,3-Sigmatropic RearrangementSynthesis of Bakkenolinde A
H
MeMe
SCH 3
S
HgO, HgCl2, H 2O
H
MeMe
SCH 3
O
H2SeO3 O
MeMe
H
O
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Additional Interesting 2,3 Rearrangements
SeAr*
Ar=
Fe
NMe2
Me
N
OMe
Ts
mCPBA or
Ti(OiPr)2, DIPT Me O H
Ph SeR
NHTs
*
R = OH , tBuOCl, then TsNHLi 90% ee
Angew. Chem. Int. Ed.2000, 39, 3740
NN2
O
( )m
( )n Cu(acac)2
C6H6, refluxN
H
O( )m
( )n
NO
N2
Cu(acac)2
C6H6, refluxN
O
H
J. Chem. Soc., Perkin Trans. 1.2001, 3325