Cheletropic ReactionsRuben MartinezBaran Group Meeting

06/01/13

Background"We define as cheletropic reactions those processes in which two σ bonds which terminate at a single atom are made, or broken, in concert."Woodward, R.B.; Hoffman, R. Angew. Chem. Int. Ed. Engl. 1969, 8, 781–853.

Cheletropic reactions are a separate class of pericyclic reactionsthat are subject to orbital symmetry analysis. They must obey theWoodward-Hoffman rules the same way that cycloadditions andsigmatropic rearrangements do.

SO2SO

O

Allowed Ground State ReactionsLinear Nonlinear

4n4n+2

4n4n+2

π electrons

disrotatory

conrotatory

conrotatory

disrotatory conrotatorydisrotatory

Allowed Excited State Reactionconrotatorydisrotatory

Selection rules for cheletropic reactions

Angew. Chem. Int. Ed. Engl. 1969, 8, 781.Sankararaman, S. Pericyclic Reactions; Wiley-VCH: Weinheim, 2005.

Linear approach vs. Non-linear approach

Linear Non-linear

xx

Cheletropic reaction analysis is typically done in the addition direction.Consider fragment "x" to be a single atom that contributes two electrons to the pericyclic transition state. The approach of "x"can be either linear or non-linear. The rotation of the π systemwill be either disrotatory or conrotatory based on the approach of fragment "x"

LUMOHOMO

The HOMO of xpoints directly at the π system.

The HOMO of xapproaches the π system ata skew angle.

LUMOHOMO

Disrotatory ConrotatorySinglet carbene addition to olefins

Only select carbene examples will be discussed here.See K. Chen's GM on carbenes

Singlet carbenes have an unoccupied p orbital andtwo non-bonding electrons in the σ orbital. Only singlet carbenes can participate in cheletropic reactions.

Linear approach Non-linear approach

4-electronHückel forbidden

2-electronMöbius forbidden

2-electronHückel allowed

4-electronMöbius allowed

"The most importatnt cheletropic reaction is the addition of singlet carbenes to make cyclopropanes."

Anslyn and Dougherty

SO2

HH3CCH3H H

H3C HCH3-SO2S

O2

CH3H3CHH H

H3C CH3H-SO2

150 °C 150 °C

J. Am. Chem. Soc. 1966, 88, 2857.J. Am. Chem. Soc. 1966, 88, 2858.

Stereochemical outcome

disrotatory elimination disrotatory elimination

N N N N+

O

C O

Most frequently encountered examples

+

Reactivity general guidline

N N

N N O

C O

CycloreversionOnly

Cycloreversion&

Cycloaddition

OS

O

R1 CR2

singlet carbenes

Cheletropic ReactionsRuben MartinezBaran Group Meeting

06/01/13

SO2 O C6H5

C6H5

The intramolecular Ramberg-Bäcklund reaction: a convenient method for the synthesis of strained bridgehead olefinsBecker, K. B. Helv. Chim. Acta, 1983, 66, 1090.

1.) EtMgBrBr2

2.) t-BuOK, THF, -78 °C

O

PhH, rt95%

Cheletropic elimination of CO and formation of annulenesHelv. Chim. Acta. 1989, 72, 1311.

O

R1 R4

R3R2

OR4

R3

R2

R1 R4

R1

R2

R3

-CO

NP

N

R

R

OTf

+N

PN

R

R

OTfCH2Cl2, rt

40%

R=o-anisyl

Synthesis of new chiral σ2λ2 -phosphenium cationsBuono, G. Tetrahedron Lett. 1999, 40, 4669.

R1, R4 = CO2MeR2, R3 = Ph

90%

NN

O

OMeO

CO2Me

OOMe

MeO2C

O

O

CO2MeOMe

3O O

CO2MeOMe

3

O

MeO CO2Me

Intramolecular [4+1] CycloadditionSpino, C. J. Am. Chem. Soc. 2004, 126, 9926.Evidence: Org. Lett. 2007, 9, 5361.

PhMe, reflux

80%

X

YGe

X

YGe +Δ

X=O,SY=S, NH

N

NGe

N

NGe +Δ

Et

Et

Et

Et

Germanium Analogues of CarbenesChrostowska. A. J. Organomet. Chem. 2009, 694, 43.

The Chemistry of Organic Germanium, Tin and Lead Compounds, John Wiley and Sons, Chichester, 2002 (Chapter 1)

via:

[4+1]N2

BrBr

Na2Te Te 500 °C

Tellurium Extrusion: Synthesis of BenzocyclobuteneMacNicol, D.D. Tetrahedron Lett. 1975, 24, 1893.

"moderate yield" 74%

N

N

NPh

SHEt

Bn

DMAD

N

N S

NPh

CO2MeCO2Me

Et

Bn

N

N

SCO2Me

Et

BnCO2Me

N CPh78%

CH2Cl2, 30 °C

An unprecedented tandem 1,3-dipolar cycloaddition-cheletropic elimination:a facile approach to novel push-pull olefinsCheng, Y. Org. Biomol. Chem. 2007, 5, 1282.

Sequential cycloaddition-cycloreversion and a strange caged structureHoward, J. A. K. Tetrahedron, 1993, 49, 4699.

PhPh

Ph

Ph

ClClCl

Cl

ClClCl

Cl Cl

Cl

O

Ph

Ph Ph

Ph

Ph

PhPh

Ph Ph

Ph

Ph Ph

ClCl Cl

Cl

Cl

Cl

ClCl

ClO

Ph

Ph

PhPh

Cl

Cl Cl

ClCl

Cl

ClCl

ClClCO [π2s+π2a+ σ2a]

bromobenzene, 160 °C, 48h40%

Cheletropic ReactionsRuben MartinezBaran Group Meeting

06/01/13

Tandem Cope-cheletropic reaction: a new molecular rearrangmentMai, D. Chem. Comm. 1996, 1181.

O

O

O

O

O

O

O

O

H

H

heat

N

S

NH

Me

CO2Et

retro-Cheletropic ene Reactions with 2-carbena-1,3-dioxolane as the chelefugeVidal, A.; Sanchez-Andrada, P. Tetrahedron 2011, 67, 5590.

NPh

Ph

CO2EtEtO2CN C C

Ph

Ph

O

O

SCO2Et

NO

OC

N OMe

H

H

N

S

N

CO2Et

OO H

6π electrocyclicring closure

Arretro-cheletropic

ene reaction OO CO2 H2C CH2+

PhMe, 160 °C, 24 h

PhMe, reflux, 1 h

O N O

O

Ph

PhPh

Ph

N O

Ph

Ph

hυ-CO

NO

NOhυ-CO

Nitric oxide cheletropic traps (NOCTs)Ingold, K.U. J. Am. Chem. Soc. 1994, 116, 2767.Korth, H.G. Angew. Chem. Int. Ed. Engl. 1997, 36, 1501.

fluorescent non-radical products

reduction

O

O

O

hυ-CO

hυ-CO2 O + CO

O

O

O

O

O

O

OO

O

O

O

O

O

CF3

CF3

CF3

CF3

CF3

CF3

CF3

CF3

hυ hυ

-CO2

Ar matrix

Ar matrix Ar matrix

Phenanthryne and bis-benzyne Murata, S. J. Org. Chem. 1995, 60, 2344.Yabe, A. J. Am. Chem. Soc. 2002, 124, 4512.

Ar matrix

hυ+CO

89%

44%

55%

CO

Ohυ-CO

12h, rt

"magic dust"

characterized by IR

J. Am. Chem. Soc. 1966, 88, 582.Chem. Commun. 1994, 2155.

-197 °C

Cheletropic ReactionsRuben MartinezBaran Group Meeting

06/01/13

Applications in Total Synthesis

SO2

K.C.N.'s idea: intramolecular trapping of o-quinodimethanes

Oppolzer, W. Synthesis 1978, 11, 793.

Inspiration from W. Oppolzer

Cheletropic extrusion of SO2: The search for a diene equivalent

H

n 1,5-hydride shift

CH3

nPotential problem

The methylstyrene side product was observed in only a small (unspecified) amount.

n= 2,3 n= 2,3

Stereoselective Synthesis of the Taxane Ring System.

H

O HH

H

O HO

+

Winkler. J.; Houk, K. J. Org. Chem. 1997, 62, 2957.

Winkler's retrosynthetic analysis:

I SO O

2 steps fromknown diene alcohol

LHMDS, THF-78 C, 57% brsm

O2S PhMe, reflux50 min, 80%

O

ZnCl2 (2 equiv)

DCM, rt63%

H

O H

BF3-Et2O (6 equiv)

5 mM in PhMe

H

O HH

"It is interesting to note that neither Lewis acid is capable of catalyzing both Diels-Alder reactions."

82%

SO2

TsO

+

OO1.) KH

DME, 25 °C, 15 h

2 equiv. 1 equiv.

O

SO22.) AcOH-THF-H2O

45 °C, 24 h77%,1:1 mixture

separated by chromatographyDBP, 210 °C, 8 h

OO

HH

H

85%

Synthesis of estra-1,3,5,(10)-trien-17-one Nicolaou, K.C. J. Org. Chem. 1980, 45, 1463.

-The examples presented here will consist of the three main cheletropic reactionsseen in total synthesis. Cheletropic reactions involving Fischer carbenes will not bediscussed here beyond examples of the Simmons-Smith cyclopropanation. For an in depth presentation and discussion of Fischer carbenes see K. Chen's group meeting on Fischer carbenes.

SO2

Early studies on the formation of cyclobutareneCava, M.P. J. Am. Chem. Soc. 1959, 81, 4266.

Δ

-The first report of this type of reactivity dates back to 1913. This topic remainedunexplored until it was returned to in 1935.Staudinger, H. German Patent 506,839; [Chem. Abstr. 1913, 25, 522]Staudinger, H. Chem. Ber. 1935, 68B, 455.

Cheletropic ReactionsRuben MartinezBaran Group Meeting

06/01/13

OMeOMe

OMeTBSO

H7

9

12

OOMe

OHO

H7

9

12

AgO, 6M HNO3

1,4-dioxane, rt, 3 h<1% desired product

+

Second generation:

many by-productslacking the

diene system

The solution:

OMeOMe

OMeTBSO

H7

9

12

SO2

rt, 20 min91%

OMeOMe

OMeTBSO

H7

SO2

H9

12

AgO6M HNO3

1,4-dioxanert, 3h

OOMe

OHO

H7

SO2

H9

12

85 %

180 °C, 20 min

PhMe

O

O

OH

H

H9

10

11

12

2

78

1

89%exclusive endo product

HOcolombiasin A

BBr3cyclooctene

DCM-78 °C, 30 min

43% brsm

Total Synthesis of Colombiasin ANicolaou, K.C. Angew. Chem. Int. Ed. 2001, 40, 2482.Full paper: Chem. Eur. J. 2001, 7, 5359.

O

O

OH

H

Hcolombiasin A

910

11

12

2

78

1

OMeOMe

OMeTBSO

H7

9

12

OOMe

OHO

H7

9

12

AgO, 6M HNO3

1,4-dioxane, rt, 3 h27%

"numerous unidentified by-products"

+

First generation:

Total Synthesis of (+)-Rishirilide BPettus, T. R. R. J. Am. Chem. Soc. 2006, 128, 15625.

OH

Me

HO OHO

OHHO

(+)-rishirilide B

O

OBn

1.) SO2, hυ2.) MeOH, p-TsOH

SO2

OMe

OBn

ZnO155 °C

OMe

OO

O

O

OO

O

stepsOBn

OMe

Diel-Alder andβ-elimination

O

OO

O

DDQsteps

O

O

O

CO2Me

OH

O

O

O

CO2Me

NHR

R = CO2Me

O OH

OS O

O

MeO2H2CN

H

An "almost" cheletropic elimination of SO3 from 11-gorgiacerolGaich, T.; Mulzer, J. Org. Lett. 2012, 14, 2834.

Burgess' reagentPhH, reflux

O

O

O

CO2Me

O SO2NHCO2Me

40%

Cheletropic ReactionsRuben MartinezBaran Group Meeting

06/01/13

O O

O

O

O

H

OH

eremantholide A

O O

O

Br

O

O

HI

TMS2SNaOMe

THF, 0 °C50%

O O

O

O

O

HS

O O

O

O2S O

O

H

O O

O

O

O

HS

O

O

6N HCl-THF25 °C, 10 h

oxoneMeOH-H2O25 °C, 6h

Amberlyst-15DCM, 25 °C, 4h

99%

1.) LiHMDSTHF, - 78 °C

2.) Cl3CCCl320 °C, 1 h

57%

1.) (Et)3COKHMPA

DME, 70 °C5 min

2.) 6N HCl-THF25 °C, 4h

70 % over two steps

steps

A Novel application of the Ramberg-Bäcklund Rearrangement to a Highly StereoselectiveSynthesis of (+)-Eremantholide ABoeckman, R. K. J. Am. Chem. Soc. 1991, 113, 9682.

OTBS

TMSH

OTBS

H

+ 1.) hυ2.) CO70%

OTBS

HSO2

TMS H

H H 1.) t-BuOk, -105 °C2.) NCS (1 equiv.)

3.) t-BuOK, 105 °C65%

HKNH(CH2)3NH2

THF, rt71%

OTBS

TMSH

inseparable mixture

1.) HF/MeCN2.) Et3SiH/TFA

38%

OH

TMSHH

H Pb(OTFA)4

TFA80%

OH

HO

H

H H

estradiol

Total Synthesis of Ampelopsin DSnyder, S. A. J. Am. Chem. Soc. 2009, 131, 1753.

Ramberg–Bäcklund Reaction

SR1

LG

R2

O O

HBase

SR1

LG

R2

O O SO O

R1 R2

SO O

R1 R2

R1 R2

R2R1

+ +

(Z)

(E)

OH

MeO OMe

OMe

MeO

OMe

1.) p-TsOHHS

OMesteps

2.) m-CPBA

OMe

MeOS

MeOOMe

OMe

OMe

O

O

Total Synthesis of (+)-EstradiolRigby, J. H. J. Am. Chem. Soc. 1999, 121, 8237.

O2S

TMSC CH Co2(CO)6+

1.) PhMe, reflux30%

O2S

2.) Br2, Et3N70%

O2S

(MeCN)3Cr(CO)3

(CO)3Cr85%THF

TMS TMS

O2S

(CO)3CrTMS

SO2

SR1

LG

R2

O O

The reaction was first discovered in 1940 but no further work was published until 1950.

OH

OH

Br

BrO2S

Cl TBDPSO

TBDPSO

1.) Na2SAl2O32.) mCPBA

1.) MeLi2.)TBAF

3.) SO2Cl24.) mCPBA

Early studies toward the synthesis of the enediyne moeity of calicheamicinNicolaou, K. C. J. Am. Chem. Soc. 1992, 114, 7360.

Cl

TBDPSO

TBDPSO

Cheletropic ReactionsRuben MartinezBaran Group Meeting

06/01/13

Total Synthesis of Ampelopsin D continued

OH

HO

HOOH

OH

OH

1.) t-BuOH, aq. KOH

CCl480 °C

2.) BBr3

40% over two steps

ampelopsin D

Me H H

H HO NH

O

hirsutellone B

O

OH

Total Synthesis of Hirsutellone BNicolaou, K. C. Angew. Chem. Int. Ed. 2009, 48, 6870.

OMe

MeOS

MeOOMe

OMe

OMe

O

O

Me

OH H

H H

O

IAcS

1.) NaOMesteps

2.)H2O2Na2WO4

Me H H

H HO O

S OO

Me H H

H HO O

CF2Br2,KOH/Al2O3

DCM, t-BuOH,0 °C to rt

steps

Directed Heterodimerization: Stereocontrolled Assemblyvia Solvent-Caged Unsymmetrical Diazene FragmentationMovassaghi, M. J. Am. Chem. Soc. 2011, 133, 13002.

NN

NN

NN

CO2Me

CO2Me

CO2MeBnO2C

MeO2CH

MeO2C

H

NN

NN

CO2Me

CO2Me

CO2MeBnO2C

MeO2CH

MeO2C

H

NN

CO2Me

CO2Me

CO2Me

H

HNSONa

OO

oxalyl chloride

DMFN

NCO2Me

CO2Me

CO2Me

H

HNSO

OCl

NN

BnO2C

MeO2CH

MeO2C

NH2

DMAP, Et3NCH2Cl2

NN

NN

HN

HN

CO2Me

CO2Me

CO2MeBnO2C

MeO2CH

MeO2C

H

SOO

NCS, BEMP

NN

NN

CO2Me

CO2Me

CO2MeBnO2C

MeO2CH

MeO2C

H

hυt-BuOH

"...the first example of directed and stereoselective C–C bond construction fusing two different cyclotryptamine fragments at vicinal quaternary stereocenters."

Cheletropic ReactionsRuben MartinezBaran Group Meeting

06/01/13

OO

OBzO

O

O

OBzO

O

hυ, pyrex filter

cyclohexane 15-30 °C

83%

1.) H2 (3 atm) Pd/C (10%)

Olongifolene

O

PtO2

HOAc, rt, 18h96%

Et2O, 35 °C, 60 h78%

2.) selective Wittig

olefination

Zn-Ag, CH2I2

Total synthesis of (±)longifoleneOppolzer, W. J. Am. Chem. Soc. 1978, 100, 2583.

3 steps

3 steps

Simple synthetic route to the limonoid systemCorey, E.J. J. Am. Chem. Soc. 1987, 109, 918.

H

H

O

O

H

O

O

H

O

HOHR

variousorganocopper

reagents

unreacted S.M. 1,2-addition

+

"The most obvious approach" gave poor results

13

O

HOHH

13

Hydroxyl directed Simmons-Smith

1.) Zn-Ag, CH2I2

O

H2.) PDC

OLi, NH3

-78 °C, 15 min

O

H

O

H

Enantioselective total synthesis of oleanolic acid, erythrodiol, β-amyrin, and other pentacyclic triterpenes from a common intermediate Corey, E.J. J. Am. Chem. Soc. 1993, 115, 8873.

H

H

1312

17

18Et2Zn, CH2I2PhMe, rt, 8h

56%

H

H

BzO BzO

H

HTBSO

1.) PhCO2O-t-Bu, CuBrPhCl, 115 °C, 4h

51%

11

2.) aq. NaOH, MeOH-THF

95%H

HBzO

CH2OH

-78 °C, 2 h93%

H

HBzO

CH2OHLi, NH3-THF

H

β-amyrin

erythrodiol

oleanolic acid

R4R1

R2 R3

R1R2

R4R3

EtZnI

R1R2

R4R3

CH2

Zn IEt

ZnEt2 + CH2I2 EtZnCH2I

EtI

Simmons-Smith cyclopropanationFirst discovered in 1944. Many asymmetric modificationshave been throughout the years. The most notable beingthe Charette asymmetric modification.

For an excellent review on stereoselective cyclopropanation reactions see: Chem. Rev. 2003, 103, 977.

Cheletropic ReactionsRuben MartinezBaran Group Meeting

06/01/13

Total Synthesis of (±)-TaxusinKuwajima, I. J. Am. Chem. Soc. 1996, 118, 9186.

HH

AcO

OAcOAc

OActaxusin

H

TESO

OBnOBn

HO

1.) Et2Zn, CH2I2Et2O, rt, 6h

H

TESO

OBnOBn

O

2.) PDC85%

1.) Li, NH3t-BuOH

2.) MeOH91%H

HO

OHOH

OH

4 steps

steps

OHO OZn(CH3CHI)2•DME

86%Me

HO

Total Synthesis of (+)-AmbruticinJacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772.Regioselective, asymmetric cyclopropanation

O

OMe

Me

O

MeOO

maoecrystal V

Total Synthesis of (±)-Maoecrystal VDanishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860.

O

O

O

OH

O

OMOM

2.) CH2I2, Zn/Ag

O

O

O

OH

OMOE

1.) Lombardo reagent

O

O

O

O

PCCO

O

O

O

OO

H2, PtO2

AcOH

40% 76%

75%

steps

O

Me

OH

CO2H

OH

(+)-ambruticin

Highly Enantioselective Simmons-Smith Fluorocyclopropanation of Allylic Alcohols

R1R2

R3

OH

∗∗

R1

O ZnEtBO

OBu

R2R3

i.) Et2Zn

OB O

CONMe2

CONMe2

Bu

F

R2 R1

R3 OH

transZnFF

I

ZnIF

F

ICHF2IZnEt-EtI

halogen scrambling

OB O

CONMe2

CONMe2

Bu

Charette A. B. J. Am. Chem. Soc. 2013, 135, 7819.

State of the art in cyclopropanation