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2,3-Sigmatropic Rearrangements in Organic Synthesis
October 25, 2006
Matt Haley
Crimmins Group
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
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 rxntemperature
Diastereoselection Study
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 substituentspreferentially in the exo positionπ-acceptors like carbonyls
and electropositive groupslike silyl ethers prefer endo position
Cation plays large role
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
Me
HO
1. Me2NNH22. CSA (equil .)
71% (2 s teps)
Me
HN
N
1. KDA,
2. A cOH, NaOAc, H2O
69% (2 steps )
Me3Ge
Me
HO
Me3GeI
1. NaOMe, 66%2. LDA , MeI, 85%3. NIS , 90%4. BuLi , 86%
Me
OH
H Me
CHO
O
Me
HO
Me
H
Sarcodonin G
Me
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
Completion of Sarcodonin G
Piers, et al. Organic Letters, 2000, 2, 1407-1410
Me
H
Me
Me
HO
1. KH, PMBCl, 96%
2. OsO4, NaIO4, 65%3. NaH, (EtO)2CO, 74%
Me
H
Me
MeO H
PMBO
CO 2E t
TBAF; CH2I2
78%
Me
H
Me
MeO
PMBO
CO 2E t
I
SmI2
CO 2E t
O
Me
PMBO
Me
H Me
1. DIBAlH2. DMP
86% (2 steps)
CO2Et
O
Me
PMBO
Me
H
CHO
O
Me
PMBO
Me
H
H
1. piper id ine, P hSeCl
2. KIO4, 78% (2 steps)
3. DBN, 95%4. DDQ , 91%
CHO
O
Me
HO
Me
HMe Me Me
Mislow-Evans(neutral)
Acc. Chem. Res. 1974, 7, 147-155
SO
SO O
S
R R R
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:
SPh
O
!Ph
S
O
J. Org. Chem. 1989, 54, 2779-2780
There is a very high E-olefin selectivity when there is substitution β 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
Synthesis of the Imine Ring System of Pinnatoxins
OO
OH
Me
N
Me
OHO Me
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
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
TIPS O
MgB r1. , 93%
2. OsO4, NaIO43. TPAP, NMO , 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. PMBOCH2CH2CH2ZnX, Pd0, 75%
2. TBAF, 91%
3. Swern
4. (S )-methyl p- to lyl s ul fox ide, LDA
5. TMSCl, KHMDS
6. LDA, 65% (4 steps)
O O
OOTIPS
TfO
PivO
O O
O
PivO
PMBO
SO
O O
O
PivO
PMBO
SO
(EtO)3P, s-collidine
MeOCH2OCH2CH2OH
150 °C, 15h, ~90%
O
O
O
PMBO
PivO Me
Me
OH
Cascade Claisen-Mislow-Evans
OO
O
SR1
R2
A r(O)
O
O
O
PMBO
P ivO Me
Me
S OA r O
O
O
PMBO
P ivO Me
Me
SO
A r
O
O
O
PMBO
PivO Me
Me
SO
ArO
O
O
PMBO
PivO Me
Me
OH
(EtO)3P:
Organic Letters, 2005, 7, 1629-1631
O
OPMBO
OAc
N
Me
Me
can be done in microvave in 20 min with ~10% yield hit
O
Me
HO H
OO
O
H
OMe
H
Me
MeH
Me
MeH
TBDPSOO
H
OMe
H
Me
MeH
Me
MeH
Ph3P
O
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
O
1. Ph3P=CHCO2Et, 98%2. LAH
3. TBSCl, 95% (2 steps )
TBSO
HC CCHO1. , 98%2. LAH, 98%
Me
OTBS
Me
O TBSOH OH
+
1. SAE2. Swern3. MeMgCl4. Swern
73% ( 4 steps)Me
O TBS
Me
OTBSO O
+O O
1.5 : 1
Me
OTBSO
O
LDA , TMSCl
Me
OTBSOTMS
TMSO
mCPBA
60% (2 steps )Me
OTBSO
TMSO
HO PhSeCl, 78%O
OR
H
O
H
H
Me
SePh
OTBS
Preparation of 2,3-Rearrangement Precursor
Crimmins et al. J. Am. Chem. Soc. 1996, 118, 7513-7528
O
OR
H
O
H
H
Me
SePh
OTBS
H2O2
66% ( 2 steps)
O
OR
H
OH
H
Me
Se
OTBS
Ph
O
O
H
O
OTMS
OTBS
O
H
Me
Se
PhO
OR
H
OH
H
Se
OTBS
PhO
Me
wor kupO
H
O
O TMS
O TBS
HO
H
Me
O
H
O
OTMS
OTBS
HO
H
Me
O
HOTMS
O
OTBS
TIPSO
H
Me
HTBDPSO
OHO Me
H
Me
MeH
Me
MeH
Ph3P
+
1. MeLi -LiBr
2. I2
(73% 2 steps )
O
H
TBDPSO
O
HO Me
H
Me
MeH
Me
MeH
O TMST IPSO
Me
H OTBS
O
Me
HO H
OO
O
HO Me
H
Me
MeH
Me
MeH
OH
Crimmins et al. J. Am. Chem. Soc. 1996, 118, 7513-7528
Rearangement and Endgame
O
MeMe
H
O
Bakkenolide A
Additional 2,3-Sigmatropic Rearrangements Cont’dSynthesis 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 effects and inhibition of platelet aggregation
Organic Letters, 2004, 6, 3345J. Am. Chem. Soc. 1977, 99, 5453
Me
Me
O
CHSnC4H9
Cl
KotBu84%
Me
O
CHSnC4H9
Me
KOH
78%
Me
O
MeMe
O
Me
+
OsO4, NaIO4
46%
only s yn pdt
taken on
Me
O
OMe
Me
O
O
Me 1. KOtBu, 63%
2. H2/Pd-C, 93%O
H
Me
Me
Li
H
Me
Me
HO60%
PB r3
H
Me
MeBr
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
H
Me
Me
SSCH3
NNHTs
H
Me
Me
SSCH3
N
TsN
H
Me
Me
S
N
T sN
SCH3H
Me
Me
S
N
TsN
SCH3 H
Me
Me
SCH3
S
NaH
62%
2,3-Sigmatropic RearrangementSynthesis of Bakkenolinde A
H
MeMe
SCH3
S
HgO, HgCl2, H2O
H
MeMe
SCH3
O
H2SeO3 O
MeMe
H
O
Additional Interesting 2,3 Rearrangements
SeAr*
Ar=
Fe
NMe2
Me
N
OMe
Ts
mCPBA or
Ti(OiPr)2, DIPT Me OH
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
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