14-pericyclic rxns 4 harvard
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Pericyclic ReactionsTRANSCRIPT
Chem 206D. A. Evans Pericyclic Reactions: Part–4
D. A. EvansFriday,October 20, 2006
! Reading Assignment for week:
Carey & Sundberg: Part A; Chapter 11Concerted Pericyclic Reactions
Chemistry 206
Advanced Organic Chemistry
Lecture Number 14
Pericyclic Reactions–4
! [3,3] Sigmatropic Rearrangements: Introduction
! Cope Rearrangements & Variants
! Claisen Rearrangements & Variants
K. Houk, Transition Structures of Hydrocarbon Pericyclic RxnsAngew Chem. Int. Ed. Engl. 1992, 31, 682-708
K. Houk, Pericyclic Reaction Transition States: Passions & Punctilios, Accts. Chem. Res. 1995, 28, 81-90
Angew Chem. Int. Ed. Engl. 1992, 31, 682-708
http://www.courses.fas.harvard.edu/colgsas/1063! Other Reading Material:
! Problems of the Day:
[3,3] Sigmatropic Rearrangements
Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5, Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope) Chapter 7.2, Claisen
S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen)
S. R. Wilson, Organic Reactions 1993, 43, 93 (oxy-Cope)
T. S. Ho, Tandem Organic Reactions 1992, Chapter 12 (Cope, Claisen)
Paquette, L. A. (1990). “Stereocontrolled construction of complex cyclic ketones by oxy-Cope rearrangement.” Angew. Chem., Int. Ed. Engl. 29: 609.
Predict the stereochemical outcome of this Claisen rearrangement
diastereoselection>87:13
144 °C, 6h
CMe3
O
Et
CMe3
O
Et
H3O+ quench
Schreiber, JACS 1984, 106, 4038
Me
Me
OH
HMe
O
HMe
KH, ! THF
Provide a mechanism for the indicated fransformation
Ireland, JOC 1983, 48, 1829
Database Problem numberDatabase Problem number 117: Key words: Rearrangement + 117: Key words: Rearrangement + ClaisenClaisen
In a recent article, MacMillan and Yoon (JACS 2001, 123, 2448) reported the complex rearrangement illustrated below.
Part A. Provide a mechanism for this overall transformation. In answering this question, you should illustrate those transition states where stereocenters are generated and where stereochemcal information is relayed.
Part B. From your answer in Part A, illustrate the stereochemical relationships in the diamide product A.
Me
R2N
R2N
ClMe
OYb(OTf)3
CH2Cl2, R3N R2N NR2
O
Me
Me
Me
O
diastereoselection >95:5
several equivA
S
O
Ar
O
O
SAr
H Cl Cl
Provide a mechanism for the indicated transformation that accounts for the observed stereochemical outcome (JACS, 1984, 7643).
OC
Cl
Cl
Database Problem numberDatabase Problem number 195: Key words: Rearrangement + 195: Key words: Rearrangement + ClaisenClaisen
Introduction to [3, 3]-Sigmatropic RearrangementsD. A. Evans Chem 206
General Reviews:
S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen)
T. S. Ho, Tandem Organic Reactions 1992, Chapter 12 (Cope, Claisen)
Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5, Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope) Chapter 7.2, Claisen
S. R. Wilson, Organic Reactions 1993, 43, 93 (oxy-Cope)
•
•
‡
?
X & Z = C, O, N etc
Cope Rearrangement, Ea = 33.5 kcal/mol Claisen Rearrangement Ea = 30.6 kcal/mol
X
Z Z
X
X
Z
X
Z
X XOO
The Reaction Energetics Goldstein, JACS 1972, 94, 7147
!G523‡ = 46.3
‡
‡
!G523‡ = 40.5
E
X XX
X
X
The Boat and Chair geometries for these transition structures are well defined.
Relative Energy !G°: 0 + 5.3 kcal/mol
+ 5.8 kcal/mol0Relative Energy !!G‡:
The CopeTransition States
‡X
CHAIR BOAT
BOATCHAIR
The FMO Analysis (Fleming page 101)
Bring two allyl radicals together to access for a possible bonding interaction between termini.
•
•
‡
bonding
bonding
It is evident that synchronous bonding is possible in this rearrangement
The nonbonding allyl MO
!2
Chem 206D. A. Evans The Doering–Roth Experiments
Meso isomer
The Geometry of the transltion state (boat vs chair) can be analyzed via the rearrangement of substituted 1,5-dienes:
Threo isomer
Doering/Roth Experiments: Tetrahedron 18, 67, (1962):
Me
Me
Me
Me Me
Me
MeMe
Me
Me
Predictions:
Threo isomer
! Measure product composition from rearrangement of each diene isomer
less favored
trans-trans
cis-cis
favored Me
Me
H
HH
H
Me
Me
Me
Me
H
HH
H
Me
Me
trans-cisdisfavored
Me
H
MeHMe
HMe
Predictions:
Meso isomer
disfavoredtrans-trans
trans-cis
Me
H
Me
HH
Me
H
Me
Me
Me
HHH
H
MeMe
favored
favored
Results:
Threo isomer
The Resultstrans-trans:
90%Me
Me
H
H HMe
Me
H
less favored cis-cis:
10%
Me
Me
H
H H
H
Me
Me
disfavoredtrans-cis:
< 1%Me H
MeH H Me
H
Me
disfavored
trans-cis: 99.7%
trans-trans: 0.3%
favored
Results:
Meso isomer
Me Me
HH H H
Me
Me
Me
H
Me
H H
Me
H
Me
!!G‡
~ 5.7 kcal/mol
The Boat and Chair geometries for these transition structures are well defined.
Relative Energy !G°: 0 + 5.3 kcal/mol
+ 5.8 kcal/mol0Relative Energy !!G‡:
The CopeTransition States
‡X
CHAIR BOAT
BOATCHAIR
Strain–Accelerated Cope RearrangementsD. A. Evans Chem 206
equilibrium stongly favors this isomer
Reese Chem. Commun. 1970, 151960 °C
120 °C Vogel Annalen 1958, 615, 1
Brown Chem. Commun. 1973, 3195-20 °C
Ring Strain can be employed to drive the Cope process:
H
H
H
H
H
H
‡20 °C
! !!
Bullvalene: Ea = 13.9 kcal/mol
At 100 °C one carbon is observed in nmr spectrum
Carey, Vol 1, page 630–631
Ring Strain can be employed to drive the Cope process:
W. von E. Doering's Bullvalene
EtNH2/THF LDA
LDA
"quantitative"
1.5 equiv
! Ring extension via divinylcyclopropane rearrangement
–
heatxylene
90%
!-himachalenePiers, Can J. Chem. 1983, 61, 1226, 1239
Me
Me
Me
Me
MeP
O(EtO)2
O
P
O
(EtO)2 Cl
Me
Me
MeO
MeMeMe
O
I
O
Me
Me
Me
Me
(PhS)Cu
O Me
Me
Me
Me
Me
Me
Li (Ph3)3RhCl
H2
MeI
Li+
Wharton J. Org. Chem. 1973, 38, 4117
Vogel Angew. Chem. Int. Ed. 1963, 2, 739
favored
! Position of Equilibrium dictated by ring strain issues:
H
H
H
H
Energetically, how much does tautomerization give you?
Marvell, Tet. Lett. 1970, 509
90%
3h
220 °C
! However, tautomerism can shift the equilibrium:
OH
H
OH O
keq ~ 10+5
The Anionic Oxy-Cope RearrangementD. A. Evans Chem 206
!G‡O – = !G‡
OH + 2.3RT [ pka TS – pka SM]
+ 2.3RT [18 – 29] (in DMSO)= !G‡OH!G‡
O –
!G‡O – = !G‡
OH + 1.4 [– 11]
= !G‡OH – 15 kcal/mol at 298 K (in DMSO)!G‡
O –
No Rxn66 °C
10 +12 rate acceleration
!!G‡estimate = 15 kca mol -1
!!G‡experiment = 13 kca mol -1
(HMPT)10 °C
4.4 min–O- +K
11 hrs
66 °C
1.4 min
1.2 hrs
no rxn
(66 yrs)
Half-life
66 °C
Documentation of Alkoxy Substituent Effect
OX
MeO
XO
MeO
OMe
OX
H
H
THF
–OK
–OK
–ONa
–OLi
–OH
–OX
THF
Maximal rates are observed under conditions where reactant is maximally destabilized
Origin of the Rate Effect ‡
‡
Effect probably comes from bothreactant destabilization
& transition state stabilization
~ 15 kcal/mol–
HO
– O
HO
– O
!
"!"
‡
!GOH!G‡
OH
!G‡O – !GO –
‡
pka (SM) pka (TS)
??
HO HOHO
– O – O– O
Evans, Golob, JACS 1975, 97, 4765.
‡
Accelerated Cope Rearrangements
k1
k2k2
k1= 10 + 10 10 + 17
Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5,
Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope)
"Recent applications of anionic oxy-Cope rearrangements."
Paquette, L. A. Tetrahedron 1997, 53, 13971-14020
HO HOHO
– O – O
O
A priori Estimate of the Acceleration (DAE)
Chem 206D. A. Evans Anionic Substituent Effects: Bond Homolysis
ketyl
+ •CR3
DI!I
+ •CR3
Substituent Effects in Bond Homolysis
HO C CR3
–O C•
C•HO
C CR3–O
B •A
DI
DI – DII = 2.3 RT [pka (A) – pka (B)]
pKa = 9.2pKa = 10.7
Acidities of these radicals are known in H2O, Hayon, Accts.
Chem. Res. 1974, 7, 114
HO C•C•
H
H
HO HO C•
Ph
Ph(H2O)
In DMSO, ΔD = 2.3 RT [ 29 – 18] ~15 kcal/mol
(Evans, Goddard, JACS 1979, 101, 1994)
!D+16.5 kcal/mol
(BDE = 91.8 expt)
BDE = 74.2BDE = 79.0BDE = 80.6BDE = 90.7
! Substituent Effect based on ab initio calculations
C H
H
H
HO NaO C
H
H
H C H
H
H
KO –O C
H
H
H
– –
[3,3]
[1,3]
––
– –
[1,2]
–
[2,3]
–
–
ene
–
Substituent Effects in Molecular Rearrangements
Y
R
X X
Y X
R
X X
R
X
R
R
YX YX
R
H
X
H
X
– –
– –
–
–
Y X Y X
C
C
Y X
C
CC
Y X
C
X
CC
CC
X
– •
•–
–
R •
– •X C H
X CCX
CX
R–H
Anionic Oxy-Cope Rearrangement: Applications Chem 206D. A. Evans
75%
Jung, JACS 1980, 102, 2463
Jung, JACS 1978, 100, 4309
KH, THFLevine, JOC 1981, 46, 2199
KH, THF
Gadwood, JOC, 1982, 47, 2268
MeO OMe
O OH
OMeMeO
MgX
HO
OMeOMe
H
H
H
OH
O
Me
Me
OH
Me
Me
O
NaH
50 °C
50 % yield
poitediol
Gadwood, JACS, 1986, 108, 6343dactylol
Me
O
HH
OH
MeHMe
OH
OMe H
HC CLi
HMeMe
OH
Me
MeMe
OH
MeMe H
OH
200 µg from 75,000 virgin female cockroaches
Periplanone-B Synthesis
MeH
OO
Me
H2C
Me
Me
OO
O
H
O
Still, JACS 1979, 101, 2493
OH
MeH
ROH2C
Me
ROH2C
Me
Me
OR
! THF
KH
2 stepsSchreiber, JACS 1984, 106, 4038
Me
Me
OH
H
OR
Me
Me
Me
O
HMe
KH
! THF
Synthesis of (+)-CP-263,114: Shair, JACS 2000, 122, 7424-7425.
O
OO
O
O
O
CO2H
Me
O
Me
H
XMgO
MeO2C
R
R
H
CH2OR
H
H
XMgO
C
R
R
H
CH2OR
HOOMe
O R
R
H
CH2OR
H
O[3,3]
–78!23 °C
Dieckmann 53%
Chem 206D. A. Evans The Claisen Rearrangement
There is good thermodynamic driving force for this reaction.
Bonds Broken: C-C! (65 kcal mol-1) & C-O" (85 kcal mol-1)
Bonds Made: C-O! (85 kcal mol-1) and C-C" (85 kcal mol-1)
#H ~ –20 kcal mol-1
! The Reaction:
! General Reviews:
S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen)Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5, Ch 7.2Ziegler, Accts. Chem. Res. 1977, 10, 227 (Claisen)Bennett, Synthesis 1977, 589 (Claisen)Blechert, Synthesis 1989, 71 (HeteroCope)R. K. Hill, Asymmetric Synthesis vol 3, Ch 8, p503 (chirality transfer)Ziegler, Chem Rev. 1989, 89, 1423 (Claisen)
R
O O
R
#
(Benson estimates)
~ 20
! Themodynamics of Claisen Variants:Substituent !H (kcal mol-1)
X = H
X = OH
X = NH2 –30
–31
–16
~ 20 kcal/mol
~ 30
~ 30 kcal/mol
Heteroatom substitution at the indicated position increases exothermicity as well as reaction rate
H
OO
X X
H
O
O
OR
OR
O
O
Recognition Pattern for Organic Synthesis: An Enforced SN2'
Claisen –SN2'
R
R
X
O
R
R
O
R
O
R
Stereochemical outcome is syn and controlled by hydroxyl stereocenter
2
2
1
1
Control of stereocenter 2 evolves into a decision how toestablish the hydroxyl-bearing stereocenter
O
R
X
O
X
R
X
O
R
XO
R
R
O
180-200 oC
Rearrangements of Aryl Allyl Ethers: Traditional Applications
77%
65%
E:Z = 6.7:1
91%
180-200 oC Cope
O OH
OH
O MeMe
MeMe
N
O Me
Me
O
H
Me Me
Me Me
MeMe
OH
MeO OH
Me
N
Chem 206D. A. Evans The Claisen Rearrangement-2
! Endocyclic Olefins: Ireland, JOC 1983, 48, 1829
diastereoselection>87:13
144 °C, 6h
CMe3
O
Et
Me3C
H CH2
H
Et
O
For endocyclic olefins, overlap between developing sigma and pi bonds required. Best overlap for forming chair geometry. As shown below, bring a radical up to either face of the allylic radical. As the bond is formed, overlap must be maintained. Path A evolves into a chair conformation while Path B evolved into a boat conformation.
C CH2C H
R
H2CH
H
Me3C
H
Me3C
R
H
Me3C H
H2C
AB
•
R•
R•
ratio 75:25
heat
ratio 52:48
heat
! Exocyclic Olefins: House, JOC 1975, 40, 86
for exoocyclic olefins, overlap between developing sigma and pi bonds is equally good from either olefin diastereoface. In this instance, steric effects dominate & this systemshows a modest preference for "equatorial attack." A related case is provided below.
O
OEt
H
Me3C
O
CMe3
Me3C
H
OEt
O
OEt
H
Me3C
CMe3
O
Me3C
H
O
O
H
H
(review) S. H. Pines, Organic Reactions 1993, 43, 1
Synthesis of Allyl Vinyl Ethers
-EtOH
75%
Watanabe, Conlon, JACS 1957, 79, 2828
Bronsted acids can also serve as catalysts
96%
Use of Tebbe's Reagent: Evans, Grubbs, J. Am. Chem. Soc. 1980, 102, 3272.
(solvent)
AcOHgOH O
OEt
O
OPh
O CH2
Ph OCH2
Cp2Ti
Cl
AlMe2
OEt
Hg(OAc)2
X = H
Claisen
The Ireland approach to the bicyclic acid A: JOC 1962, 27, 1118
Me
HO
Me Me
O
X
O
MeMe
HO
H
MeMe
HO
Me Me
OH
A
!
The new stereocenter (!) introduced via the rearrangement had the wrong configuration!
53% overall
OH
MeMeHO
Me Me
H
HOMe Me
O
H
H
MeMe
Me
H
O
OH
H
Hg(OAc)2
EtOCH=CH2
Chem 206D. A. Evans The Claisen Rearrangement: Stereoselective Olefin Synthesis
!G‡a - !G‡
e = 1.5 kcal/mol
Consider the following rearrangement:
a‡
e‡
ka
ke
Claisen Rearrangement as vehicle for stereoselective olefin synthesis
O
Me
O
H
Me
H
Me
O
Me
CHO
MeCHO
!!G‡ = +1.5 kcal/mol
Faulkner & Perrin (Tet. Lett. 2783 (1969) have made the correlation between
!!G‡ for rearrangement & !G° for the corrresponding cyclohexane# equilibria:
O
Me
HMe
H
O
!G° = +1.75 kcal/mol
H
Me H
Me
#Note: The A-value of 2-methyl-tetrahydropyran is +2.86 kcal/mol (Lecture No. 6)
Faulkner, JACS 1973, 95, 553
91:990:10Et–Et–
Me– iPr– 93:07 94:6
91:990:10Et–Me–
(E):(Z) predicted(E):(Z) found
110 °C
(Z)(E)
They then suggest that there is a good correlation between cyclohexane "A-values" &
!!G‡ for the rearrangement process. Their case is fortified by the following expamples:
R2
O CHO
R2
CHOR2
R1 R1 R1
R2R1
Faulkner, Tet Let 1969, 3243
Johnson, JACS 1970, 92, 741
Faulkner, JACS 1973, 95, 553
>98:2
110 °C
110 °C
(E):(Z) found
90:10
>99:1Me–
>99:1
(E)
(Z)
The R2!X interaction should destabilize a‡ as X gets progressively larger.
ke
ka
e‡
a‡
Faulkner suggests that the installation of other substituents on Claisen transition states will lead to enhanced reaction diastereoselection:
R2
R2
O
R2
H
R2
H
O
R2
O
X
X
X
O
O
Me
Me
MeMe
Me
X
X
Me2N–
X
H–
MeO–
For R2 = Et
‡
! Another comparison: (DAE) M. DiMare, Ph. D. Harvard University, 1988
97:3
94:6
97.5:2.580
130
-78!+55
T, °C
LDA, TMSCl
HC(OMe)3, H+
Y = H, Eschenmoser
Y = H, Johnson
Y = Ac, Ireland
(E):(Z) ratioconditionsprocedure
OPMB
Me
Et
OY
Me
O
Et
OPMBX
Me
O
Et
X
R
MeO–
TMSO–
Me2N–
X
MeC(OMe)2NMe2