Dr.

Pere Romea
Department of Organic Chemistry

Moebius Strip
M. C. Escher, 1963

2. Pericyclic Reactions

Organic Synthesis 2014-2015 Autumn Term

 Introduction: Organic Reactions

The organic reactions can be classified according to their mechanism ...

1. Ionic or polar reactions ...

... the bond-forming or -breaking processes
A B A B
are associated to pair of electrons Nucleophile Electrophile

2. Radical reactions ...

... the bond-forming or -breaking processes
A B A B
are associated to single electrons

3. Pericyclic reactions ...

... the bond-forming or -breaking processes
take place in a concerted way,
+
without the formation of any intermediate
through a cyclic transition state A cycloaddition as a model
2
 Introduction: Key Concepts

A A A
B B B
+

Transition State
A
B

ΔGo

Kinetics

+
B
Thermodynamics

Reactants
Thermal
A
B
Product
... ground electronic state

Reaction coordinate Photochemical

... excited electronic state
Pere Romea, 2014 3
 Pericyclic Reactions: Classes

1. Electrocyclic Reactions ... ... ring formation from an open-chain conjugated system

2. Sigmatropic Rearrangements ... ... intramolecular isomerizations that formally

involve the migration of a
σ bond flanked by one or more π systems

3. Cycloadditions ... ... ring formation from two components,

coming together to form two new σ bonds,
one at each end of both components
+

4. Group Transfer Reactions ...

H H
+
Pere Romea, 2014 4
 Pericyclic Reactions: Concepts

Pericyclic reactions are ...

concerted transformations

proceeding through cyclic transition states without reacting intermediates

in a highly selective manner

Conservation of Orbital Symmetry

A ground-state pericyclic change is symmetry allowed when the

total number of (4q + 2)s and (4r)a component is odd

The Conservation of Orbital Symmetry, Woodward, R. B.; Hoffmann, R. Angew. Chem. Int. Ed. Engl. 1969, 8, 781
Woodward, R. B.; Hoffmann, R. Acc. Chem. Res 1968, 1, 17
5 Pere Romea, 2014
 Pericyclic Reactions: Concepts

Allowed o permesa, if it proceeds easily according to the conservation of orbital symmetry

Forbidden o prohibida, if harsh conditions are required because
the conservation of orbital symmetry rules are not met

A ground-state pericyclic change is symmetry allowed when the

total number of (4q + 2)s and (4r)a component is odd
Suprafacial Antarafacial

Suprafacial Suprafacial Suprafacial

Suprafacial Antarafacial Suprafacial

1 (4q+2)s 1 (4q+2)s 1 (4q+2)s

1 (4q+2)s 0 (4r)a 0 (4r)a
6 Pere Romea, 2014
 Pericyclic Reactions: Concepts

Differents models are used to apply the ideas of the conservation of orbital symmetry

Electronic state correlation diagrams

Frontier Orbitals / HOMO-LUMO (Fukui-Klopman-Salem)
Aromaticity of transition states / Hückel-Moebius (Dewar-Zimmermann)

... The orbital topology plays a crucial role

Ψ4
Ψ3
Ψ2 Ψ3 LUMO
Ψ2
Ψ1 Ψ2 HOMO
Ψ1
Ψ1
7 Pere Romea, 2014
 Pericyclic Reactions: Concepts

Electronic state correlation diagrams

Frontier Orbitals / HOMO-LUMO (Fukui-Klopman-Salem)
Aromaticity of transition states

... with the Diels-Alder reaction, the Claisen rearrangement, and the oxy-Cope rearrangement
providing the majority of reactions that are used “day to day” in the chemistry lab
Anslyn & Dougherty. Modern Physical Organic Chemistry p 878

Look at Química Orgànica III

Chaps. 7/29 Chaps. 34/35 Chap. 6

8 Pere Romea, 2014

 Diels-Alder Reaction

The venerable Diels-Alder reaction: a straightforward route to six-membered rings

The Nobel Prize in Chemistry 1950 ...

Otto Diels Kurt Alder

... for their discovery and development of the diene synthesis

For a review on the Diels-Alder reaction in total synthesis:

Nicolaou, K. C. ACIE 2002, 41, 1668
For a recent view on industrial applications of the Diels-Alder reaction:
Funel, J.-A. ACIE 2013, 52, 3822
Pere Romea, 2014 9
 Diels-Alder Reaction: Key Concepts

The venerable Diels-Alder reaction is a [4πs + 2πs] cycloaddition

diene

dienophile

Remember that an alkyne can also participate in the process

+
Pere Romea, 2014 10
 Diels-Alder Reaction: Kinetics

The kinetics of the reaction depends on electronic … and conformational issues.

O O
k k
+ + O O
Dioxane, 30 °C Dioxane, 30 °C

O O

1
~0

CN
1 3

OMe
NC CN
5 · 10 4 12.3

NC CN
2.25
5 · 10 5
NC Cl
0.1
NC CN
5 · 10 7
NC CN 1350
Cl
Cl
Essential: Cl
~0
Cl
electronically rich diene & electronically poor dienophile Cl
Cl
Complementary character.
For reviews on mechanistic aspects of the Diels-Alder reaction:
11 Sauer,J. ACIEE 1967, 6, 16 ; Sustmann, R. ACIEE 1980, 19, 779
 Diels-Alder Reaction: Kinetics

The kinetics of the reaction depends on electronic and conformational issues.

O O
k
+ O O
Dioxane, 20 °C

O O

skew
1

2.25

~0

cis 3

1350
trans trans

0 90 180 270 360

12 For a conformational analysis on 1,3-butadienes: Squillacote, M. E. JOC 2005, 70, 6564

 Diels-Alder Reaction: Kinetics

Occasionally, the lack of conformational freedom can be useful …

O Medrogestone O O

H H H
BF 3·OEt2
H H H H + H H
O O O
HO
trans conformation unreactive cis conformation reactive

O O
O O
O O

H H
O
Winkley, M.W.; Mitchell, R. D. (American Home Products)
US5428151A, 1995 O
O
13 O Pere Romea, 2014
 Diels-Alder Reaction: Kinetics

In Diels-Alder reactions under Normal electronic demand

diene must be able to achieve the s-cis conformation

s-trans s-cis

diene should contain electrondonating groups (EDG); dienophile, electronwithdrawing groups (EWG)
Me OR NR 2 O
CN COR CO2R NO 2 CO2R
O

Lewis acids catalyze such cycloadditions

O
O
O O O O
+
CH2Cl2, 25 °C

Without AlCl3 t1/2 ∼ 2400 h

With 1 equiv AlCl3 t1/2 < 1 min

Pere Romea, 2014 14
 Diels-Alder Reaction: FMO

The mechanistic pathway of the Diels-Alder reaction can be rationalized through FMO analysis

HOMO

diene dienophile

LUMO

Thermodynamics: broken bonds, 3 π

2σ –2π
new bonds, 2 σ + 1 π

The critical energy difference: E

E (LUMO) - E (HOMO)
The closer the two orbitals are in energy,
the better they interact

Kinetics: As ∆E decreases for

the relevant ground state FMOs,
reaction rate increases EDG
EWG
Neutral Normal
15 electronic demand electronic demand
 Diels-Alder Reaction: Siteselectivity

The HOMO-LUMO interaction and the cyclic transition state

provide outstanding levels of selectivity ...

Chemoselectivity (Siteselectivity): rich diene / poor dienophile

CHO
CHO
CHO +

O O O
CN
CN CN
+
CN CN
CN
O O O
16% 62%

16 Pere Romea, 2014

 Diels-Alder Reaction: Regioselectivity

Regioselectivity: ortho-para rule

EDG EDG EWG EDG
EWG EWG
meta ortho
EWG
EWG
EDG EWG EDG EWG EDG
meta
para
EWG

NEt 2 NEt 2
CO2Me
CO2Me EtO EtO
CO2Me

CO2Me
Single product Single product

CO2Me
CO2Me
Lewis acids improve the regioselectivity +
CO2Me
para meta
Without Lewis acid, 120 °C, 6 h 70 : 30
Pere Romea, 2014 1 eq AlCl3, 20 °C, 3 h 95 : 5 17
 Diels-Alder Reaction: Stereoselectivity

Stereoselectivity: endo rule

HOMO
LUMO

O H
H endo
O
O
O
O O

O HOMO
LUMO O
O
O exo
H O
H
O
O

18 Pere Romea, 2014

 Diels-Alder Reaction: Stereoselectivity

Kinetic vs Thermodynamic Control

ΔΔG
E
If equilibrium cannot be reached
under the experimental conditions,
the endo isomer predominates

Kinetic Control
O

O ΔΔG°
O Instead,
O O
the exo isomer predominates
H H
at equilibrium
O O

H O H O
Thermodynamic Control
exo endo
19 Pere Romea, 2014
 Diels-Alder Reaction: Stereoselectivity

O O
Endo stereoselectivity is excellent with
O
planar dienophiles
O O

Exo diastereomers are preferred + +

100 °C R X
R X
with α substituted dienophiles endo X R exo

R X endo : exo

H CN 55 : 45
H COOMe 71 : 29
H CHO 71 : 29
Me CN 16 : 84
Me COOMe 32 : 68
Me CHO 24 : 76

Lewis acids improve

+ +
H CO2Me
endo stereoselectivity CO2Me
CO2Me H
endo exo
endo : exo
CH2Cl2, 0 °C 80 : 20

20 C6H 6, SnCl 4, 25 °C 95 : 5 Pere Romea, 2014

 Diels-Alder Reaction in Synthesis

Classical syntheses by Woodward took advantage of Diels-Alder reaction ...

O O O
Me Me H
Me
Δ MeO
+ H
O
MeO 86% MeO
H H H
O O
HO Cholesterol
endo TS
Woodward, R. B. JACS 1952, 74, 4223

... even with dienes containing EWG groups ...

O O
H H
Δ OCOAr
+ O N
MeO2C
90% OMe
H H H
O CO2Me O O CO2Me N CO2Me
H
endo TS MeO Reserpine

Woodward, R. B. JACS 1956, 78, 2023, 2657

For a review on quinones as dienophiles in Diels-Alder reaction:
Moody, C. J. ACIE 2014, 53, 2056 21 Pere Romea, 2014
 Diels-Alder Reaction in Synthesis

In fact, electronrich dienes containing R3SiO substituents are very useful ...

EWG
EWG EWG

TMSO TMSO O

OMe EWG OMe

EWG EWG

TMSO TMSO O

Danishefsky’s diene

BzO BzO BzO OH

H H O O
OTBS OTBS O
Δ TFA
+ HO 2C N
R OH H
O OMe O OMe dr 11:1 83% O O
Platensimycin

Pere Romea, 2014

Matsuo, J.-i. OL 2010, 10, 4049 22
 Diels-Alder Reaction in Synthesis

Intramolecular Diels-Alder (IMDA) reactions are very efficient ...

O O O O O
BnO O O O
N O Δ BnO N BnO N
O
O O
73%
O
O O

Conrotatory ring opening

MeO 2C
MeO 2C H O N
Δ O H
TBDPSO TBDPSO H
HO O
70% H H
H Et
Et
H Et
Antibiotic X-14547A

Nicolaou, K. C. JOC 1985, 50, 1440

23 Pere Romea, 2014

 Diels-Alder Reaction in Synthesis

TOTAL SYNTHESIS of COLOMBIASIN A

Poor dienophile
Rich diene O O OMe
H
OMe 30 mol% L 2TiCl2 OMe 1) K 2CO3, MeI OMe
+
TBSO PhMe, –60 to –10 °C 2) 2% TFA O
TBSO
H
O 85% O 80% OMe

Lewis acids catalyze DA

Excellent site-, regio- and endo-selectivity

OMe O O
OMe OMe OMe O
OMe
1) SO2, rt Δ
TBSO TBSO TBSO
H 2) HNO 3, AgO H H HO
OMe O O H
O
72% 89%
SO2 H

Chelotropic reaction IMDA O

100% endo-selectivity OH

H
Nicolaou, K. C. CEJ 2001, 7, 5359 O
24 H
 [3,3] Sigmatropic Rearrangements

2
1 3
σ σ Cope
1' 3'
2'

MO MO O
Oxy-Cope
M: H, Na, K, SiR 3

O O
Claisen

OM OM OH

O O O
Ireland-Claisen
M: H, Na, K, SiR 3

For a review on Claisen rearrangement and variants, see Martín Castro, A. M. Chem. Rev. 2004, 104, 2939
For a review on sigmatropic rearrangements, see Jones, A. C.; Stoltz, B. M. ACIE. 2014, 53, 2556
25
 [3,3] Sigmatropic Rearrangements: Orbital Analysis

This is symmetry allowed ... ... the FMO approach takes into account
two allyl radicals in the TS

σ2s

π2s

π2s Ψ3

3 (4q+2)s Ψ2

0 (4r)a
Ψ1

Bonding
interaction Bonding interaction

Bonding interaction Bonding interaction

26 Pere Romea, 2014

 [3,3] Sigmatropic Rearrangements: Boat- versus Chair-like Transition States

Boat-like TS Chair-like TS

kcal mol–1
ΔG523 = 46.3
ΔG523 = 40.5

Stereoselectivity?

Goldstein, M. J. JACS 1972, 94, 7147

Pere Romea, 2014 27
 [3,3] Sigmatropic Rearrangements: Stereoselectivity

The C3–C4 relative configuration determines the geometry of the resultant alkenes ...

1 3

6
(E,E)
4

1 3
(E,E) / (Z,Z) 9:1
6
4
6 1
3
(Z,Z)
4

1 3
1 3
6
(E,Z)
6 4
4

28 Pere Romea, 2014

 [3,3] Sigmatropic Rearrangements: Stereoselectivity

The geometry of the alkenes determines the C3–C4 relative configuration ...

1 3

6 4
1 3

6 4
1
6
4 3

1 3
1
3
6 4
6 4

29 Pere Romea, 2014

 Cope Rearrangement in Synthesis

The application of the Cope rearrangement in synthesis is restricted to those situations in which the
equilibrium is ruled by the stability of the resultant products, as …
H H

H H
Strain-Release Cope rearrangements

O O

ß-Himachalene
H Δ, xilè
90%
Me

Piers, J. CAJ 1983, 61, 1226, 1239

H H H H H H
ethylene, Grubbs II
PhH, 50 °C Δ
H H
H H H H 74% H H
O O H
O Metathesis (ROM) O
O
see Chapter 3
(–) Asteriscanolide
Snapper, M. L. JACS 2000, 122, 8071
30 Pere Romea, 2014
 Oxy-Cope Rearrangement

… but it is the origin of a wide array of variants, as the Oxy-Cope rearrangement…

H H

però
H OH OH O

... in which the use of alkoxides increases the reaction rate

X T t1/2
OX
H 66 °C –
OX H Li 66 °C –
THF H Na 66 °C 1.2 h
MeO
K 66 °C 1.4 min
OMe
K 10 °C 11 h

For a review on oxy-Cope rearrangement, Paquette, L. A. Tetrahedron 1997, 53, 13971

31 Pere Romea, 2014
 Oxy-Cope Rearrangement in Synthesis

O O H O
Guaiane
Δ, 120 °C
OH 42% O OH

Zografos, A. L. OL 2013, 15, 152

O
TESO O O O
O O O
TESO
O O O
toluè, 120 °C, 1 h O O
O > 95%
CO2H CP-263,114

... we may thus conclude that qualitatively the strain we have built into lactone spiroketal results in a similar acceleration than the anion effect.
In addition, this reaction is in principle an equilibrium process and it is noteworthy that the equilibrium overwhelmingly favors the desired
bridged-head double bond. Leighton, J. L. JACS 1999, 121, 890

OMe OMe
OMe OMe N OMe
OMe
OMe t-BuOK, 18-crown-6 OMe
Cl Cl Cl
OH THF, 0 °C O HO O
R 92% R O
MeO
Acutumine
Castle, S. L. JOC 2009, 74, 9082
32 Pere Romea, 2014
 Claisen and Ireland-Claisen Rearrangements

... and finally the Claisen and Ireland-Claisen rearrangements are favored

X X X ΔH (kcal mol –1 )

O Δ O H –16
OH –31

~ 30
~ 20
Claisen Ireland - Claisen
H OR

O ~ 20 O
~ 30

H OR

O O

33 Pere Romea, 2014

 Ireland-Claisen Stereoselectivity

Assuming that both Z- and E-enolates can be prepared stereoselectively

and that the Ireland-Claisen proceeds through a chair-like transition state,
three and erythro relative configurations are accessible ...

SiR 3
SiR 3 O
SiR 3 O
O
Z O E
O O

(±) O
O
Threo
O
O
SiR 3 SiR 3 SiR 3
O O O
E
E Z
O O O Z

(±)
Erythro

... and the absolute configuration can also be controlled by the introduction of stereocenters
Pere Romea, 2014 34 McIntosh, M. C. Tetrahedron 2002, 58, 2905, and refs therein
 Ireland-Claisen Rearrangement in Synthesis

O O OTBS dr 96:4 83% O O OTBS

MeO

LDA, Et 3N, TMSCl

CH2N 2, Et 2O, 0 °C
THF, –78 °C

OTMS

E enolate O OTMS
O OTBS
O O OTBS
O R
Δ, 4 h
OTMS

O
O O OH

Ebelactone A

Pere Romea, 2014 35 Paterson, I JOC 1995, 60, 3288

 Ireland-Claisen Rearrangement in Synthesis

O OMe dr > 97:3 90% OMe

HO
OTBS OTBS

LHMDS, TBSCl
LiAlH 4, Et 2O, 0 °C to rt
4:1 THF/DMPU, –78 °C to rt

OTBS OTBS
Z enolate O OMe OTBS O OMe
R
O
OTBS OTBS

O OMe
O
Herboxidiene HO O
H H
OH

Pere Romea, 2014 36 Romea, P. & Urpí, F. OL 2011, 13, 5350

 Ireland-Claisen Rearrangement in Synthesis

O t-Bu
O
O
O dr 90 : 10 70% O
t-Bu O OTBS OH
BnO
O

LHMDS, TBSCl
THF/HMPA, –78 °C to rt

OTBS OTBS
Z enolate
O R O
t-Bu O OTBS O R t-Bu O OTBS

O OTBS O
Olefina E

O O
PivO
HO
O
Daphnicyclidin A
H O
H
O N
N
H
H
Pere Romea, 2014 37 Iwabuchi,Y. OL 2009, 11, 1833
 Ireland-Claisen Rearrangement in Synthesis

TBSO
OTMS
TBSO
O
O E enolate
LDA, TMSCl, Et 3N
O
THF, –78 °C
OPMB
OPMB Z olefin

dr 94 : 6 85%

OPMB Δ
O TMS
H O
TBSO
HO
TBSO OPMB O
H H R
Me

O
O OH
4-Hydroxydictyolactone

Williams, D. R. JACS 2009, 131, 9038

38 Pere Romea, 2014