timeless methods for radical cyclizations in total...

Timeless Methods for Radical Cyclizations in Total Synthesis

Patricia ZhangMacMillan Group Meeting

Wednesday September 25th, 2013

Radical Cyclizations in Total Synthesis

Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757.

! A little history

! 1900: Moses Gomberg

trivalent carbon (discovery predated electronic theory)

"Ph3C" rather than "Ph3C•"

! 1929: Paneth and Hofeditz

Pb(CH3)4 Pb 4CH3•! in rapid current of H2

+

Paneth, F.; Hofeditz, W. Chem. Ber. 1929, 62, 1335.


Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237-1286.

! A change in the synthetic community's outlook on carbon radicals

! dimerization at diffusion rates! disproportionation! polymerization! extremely reactive

"Unruly & Uncontrollable"

! extremely reactive! neutral species, good for crowded bonds! inert to OH and NH! no !-elimination of OR, NR, etc.! ground state of structures good T.S. models! easy racemic synthesis of radical precursor

"Mild, Neutral and Selective"

Functional Group Transformations

Synthetic Radical Chemistry

! Kolbe oxidation! Hoffman-Loffler-Freytag! Meerwein arylation! NBS bromination! Kharasch reaction! Tin Hydride

! Giese reactions: Intermolecular Additions! Barton's thiohydroxamates: Carbon Radicals! Hart's pyrrolizidine synthesis! Stork's regio- and stereoselective syntheses! Curran's tandem syntheses

then in the 1980s.......


! Goal: General overview of major methods from the 1980s boom

Cyclizations organized by method of radical generation:

The Tin Hydride Method

The Fragmentation Method

The Reduction Method

The Oxidation Method

Showcase power of these methods with examples from today


! The Tin Hydride Method

Initiation:

Bu3SnH

N NMe

MeCN

Me

NCMe

Me Me

CNN22

!+

Me Me

CN+

Me Me

CN+ Bu3Sn

Propagation:

Bu3Sn + R-X R Bu3SnX+

R' + Bu3SnH R'-H + Bu3Sn

AIBN


Bu3SnH, AIBN, !

Raddition orcyclization

R X C C R' H

C C+ R'


! Radical cyclizations follow Baldwin's rules

Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 11 , 6513-6556.

Bu3SnH, AIBN, !

R X

C C

R

C C


! Radical cyclizations follow Baldwin's rules

Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 11 , 6513-6556.

Bu3SnH, AIBN, !

R X

C C

R

C C

boxed structures are allowed


! The Tin Hydride Method

Substrate Trends:


Bu3SnH, AIBN, !R X C C R' H

! Bu3SnH most commonly used reagent to conduct free-radical reactions! Overall reaction: R-X for stronger R-H, Sn-H for stronger Sn-X

! Transferability of X to Bu3Sn• is

! Reactivity of R• to Bu3SnH is

X• + Bu3Sn• Bu3Sn-X I > Br > SePh > "C(S)SMe > Cl > SPh

R• + Bu3Sn•Bu3SnH R-H+ aryl # vinyl > alkyl > allyl # benzyl


! Beckwith's rules


! Cyclizations containing five linking carbons or less prefers exo-mode

! Radicals add to least substituted carbon of olefin if no other geometric constraints

! Bond undergoing homolytic cleavage must lie close to the plane of the radical

! 5-Hexenyl radical ring closures are stereoselective:

1

2

34

56

2-, 4- substituted systems give trans

2-,3-, or 4- substitued systems reflects conformation preference of chair T.S.

1

23

4 5

6

12

3

4 5

6

12

3

45

6

3

12

45

6

R R

RR


! Beckwith's rules






1

2

34

56

1-,3- substituted systems give cis

R

Me

R

Me

R

Me Me

R R R


! Beckwith's rules






1

2

34

56

2-,4- substituted systems give cis

Me Me

Me Me

R

RR

RRR


! Beckwith's rules






1

2

34

56

2-, 4- substituted systems give trans2-,3-, or 4- substitued systems reflects conformation preference of chair T.S.

1

23

4 5

6

12

3

4 5

6

12

3

45

6

3

12

45

6

R R

RR


! Carbacycle formation with tin hydride


! Cyclizations yielding 5-membered rings are fast

20x faster

+

50x faster

! High regioselectivity for 5-exo


! First application of tin hydride in total synthesis

Bakuzi, P.; Campos, O. O. S.; Bakuzis, M. L. F. J. Org. Chem. 1976, 41, 3261-3264.

Me

OMe

Me

Br

Me

O

Me Me

Me

O

Me Me

Me

OMe

Me

3 : 2

6-exo

62%+

Me

Me Me

Me

Me Me

sativene cocamphene

! 6-membered rings are less general than 5! diminished regioselective and stereoselectivity! more suspectible to reduction before cyclization

+

6x faster

1,5 hydrogen transfer H

H



! Stork improves the 6-exo cyclization

Stork, G.; Baine, N. H. J. Am. Chem. Soc 1982, 104 , 2323-2325.

! vinyl radicals much more reactive to cyclization

!1000x faster


IMe

Me OH

Me Me

Bu3SnH, UV irradiation

72%

no 7-endo product1 : 1 diastereomers

Me Me

Me

Me OH

! more suspectible to reduction and good allylic H atom abstractor! low inversion barrier for vinyl radical

MeO2C CO2Me

Me

Br

MeO2C CO2Me

Br

Me

MeO2C CO2Me

MeMe

75%


! Vinyl radical in the total synthesis of norseychellanone

Stork, G.; Baine, N. H. Tetrahedron Lett. 1985, 26, 5927-5930.

O

MeMe LDA

Br

Me Br

O MeMe

MeBr

O

MeMe

Me

O

MeMe

Me

85:15 !/"norseychellanone

Bu3SnHcat. AIBNirradiation

70%

H2, Pd/C


! Activated olefins to aid 6-endo cyclization

Ladlow, M.; Pattenden, G. Tetrahedron Lett. 1985, 26, 4413-4416.

IMe

Me

O

OMe

OMe

Me

O OMe

MeO

MeMe

Me

Bu3SnH, AIBN

PhH, 85 °C97%

1. TMSI2. Bu3SnH, AIBN

45%

O OH

MeO

MeMe

Me

EWG on "electrophile" lowers LUMO energy

O OH

MeO

MeMe

MeO

alliacolide

Me

Me

O

OMe

OMe

Me


! Activated olefins to aid 6-endo cyclization

Ladlow, M.; Pattenden, G. Tetrahedron Lett. 1985, 26, 4413-4416.

IMe

Me

O

OMe

OMe

Me

O OMe

MeO

MeMe

Me

Bu3SnH, AIBN

PhH, 85 °C97%

1. TMSI2. Bu3SnH, AIBN

45%

O OH

MeO

MeMe

Me

EWG on "electrophile" lowers LUMO energy

O OH

MeO

MeMe

MeO

alliacolide

Me

Me

O

OMe

OMe

Me

mCPBA


! Enones as radical acceptor activators

Giese, B. Angew. Chem. Int. Ed. Engl. 1983, 22, 753-764.

O

Me

O

Me

2500x faster

R C C

SOMO

LUMO

HOMO

! Empirical evidence ! Frontier orbital theory explanation


! The triquinane system

Curran, D.P.; Rakiewicz, D.M. J. Am. Chem. Soc. 1985, 107 , 1448.Curran, D.P.; Chen, M.-H. Tetrahedron Lett. 1985, 26, 4991.

H

Me

MeH

H

Me

hirsutene

H

H

Me

H

!9(12)-capnellene

MeMe

Me

Me H

MeMe

Me

H H

MeMe


Curran, D.P.; Rakiewicz, D.M. J. Am. Chem. Soc. 1985, 107 , 1448.

H

Me

MeH

H

Me

hirsutene

MeMe

Me

H H

MeMe

Me

H H

I

Bu3SnH, AIBN (cat.)

PhH (0.02 M), reflux, 80%

Me

H H

Me

Me

H

Me

MeH

H

MeBu3SnH 5-exo-dig

5-exo-trig


! 1°, 2°, and 3° alkyl radicals have similar reactivities

Curran, D.P.; Rakiewicz, D.M. J. Am. Chem. Soc. 1985, 107 , 1448.Curran, D.P.; Chen, M.-H. Tetrahedron Lett. 1985, 26, 4991.

H

Me

MeH

H

Me

hirsutene

H

H

Me

H

!9(12)-capnellene

MeMe

Me

Me H

MeMe

Me

H H

MeMe

80%

80%


! A common natural product for radical cyclization strategies

CO2HMe

HO

HO OHH

H

(+)-Prostaglandin F2!


! Stork's tandem vicinal difunctionalization strategy

Stork, G.; Sher, P. M.; Chen, H.-L. J. Am. Chem. Soc. 1986, 108 , 6384-6387.

O

TBSO

IOEt Bu3SnCl (0.1 eq.)

NaCNBH3 (2.0 eq.)h!, THF, RT

SiMe3

O

C5H11

O

TBSO

OEt

TBSO

OOEt

TBSO

O

SiMe3

O

C5H11

in situ Bu3SnH

OEt

TBSO

O

SiMe3

O

C5H11

OEt

TBSO

O

O

C5H11

OEt

1. "2. Pd(OAc)2

Giese reaction

58%


! Keck's attempt at PGF2!

O

TBSO

IOEt Bu3Sn

O

C5H11

PhMe, reflux

N NCN NC

TBSO

O

O

C5H11

OEt

SnBu3TBSO

O

O

C5H11

OEt

- Bu3Sn

72%

Keck, G. E.; Burnett, D. A. J. Org. Chem. 1987, 52, 2958.


! The fragmentation method

Keck, G. E.; Yates, J. B. J. Org. Chem. 1982, 47, 3590.

! Keck applies allylation to perhydrohistrionicotoxin synthesis

SnBu3

h!N O

O

Br 2O

N

O

ON

O

SnBu3

N O

O

- Bu3Sn

perhydrohistrionicotoxin

NH

O

Bu

Me


! Intramolecular Keck allylation

Danishefsky, S. J.; Panek, J. S. J. Am. Chem. Soc. 1987, 109 , 917.

N

O

MeO

MeO

SePhN

MeO

MeO

SePh

AcO SnBu3

1. Bu3SnLi2. Ac2O

Bu3SnH

N

MeO

MeO

OAc

N

MeO

MeO

O

3-demethoxyerythratidinone

88%

directed introduction of unsaturation


! Keck allylation for use in scholarisine A

Smith, M. W.; Snyder, S. A. J. Am. Chem. Soc. 2013, 135 , 12964-12967.

OO

Me

NN

scholarisine A

OO

NN

IC-H arylation

OO

CO2Me

ONHR

tandem vicinal difunctionalization

OO

ONHR

X

CO2Me




OO

CO2Me

ONHR

OO

ONHBoc

Br

CO2Me SnBu3

Et3B, PhH,75 °C, air

(3 steps)59%

OO

ONHBoc

CO2Me

OO

ONHBoc

CO2Me

OO

ONHBoc

CO2MeSnBu3




OO

Me

NN

scholarisine A

OO

NN

I Bu3SnH, ACHN, PhMe, !

OO

NN

OO

NN

H

OO

NN

OO

NN

[O]


! Aryl radicals utilized as hydrogen atom abstractors


OO

NN

I Bu3SnH, ACHN, PhMe, !

OO

NN

OO

N

18%

6%

N


! Parker and Fokas: (-)-morphine via radical cyclization and fragmentation

Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114 , 9688-9689.

Br

SPh

OMeONMe

Ts

HO

O

SPhNTs

Me

OH

O

SPhNTs

Me

OH

O

HO

SPh

MeO MeO

MeO

O

HO

MeO

NMe

Ts N TsMe

O

HO

MeO

HH - PhS•

nBu3SnH, AIBN

PhH, reflux

30%

5-exo-trig

6-endo-trig

fragmentation

NMe

(-)-morphine

geometric constraints prevent 5-exo


! Titanium(III)-induced cyclization of epoxyolefins

Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988, 110 , 8561-8562.

O2Cp2TiCl

CO2MeMeO2C

Cp2(Cl)TiO Ti(Cl)Cp2

HO Me

CO2MeMeO2C

CO2MeMeO2C

85:15 cis:trans

68%

H3O+

Cp2(Cl)TiO

CO2MeMeO2C

Cp2(Cl)TiO

CO2MeMeO2C


! Epoxides as !-alkoxy radical cyclization precursors

Velasco, J. et. al. J. Org. Chem. 2013, 78, 5482-5491.

N

HO

HO

N

N NH

O

NH2

EntecavirAntiviral agent against Hepatitis B

BMS patent to expire in 2015 in U.S.

OTBS OAc

O

20 mol% Cp2TiCl2, 10 mol% IrCl(CO)(PPh3)2

Mn (2 eq.), collidine, TMSCl, H2 (4 bar), THF, 4 hr. RT58% AcO

HOOTBS


! Epoxides as !-alkoxy radical cyclization precursors

Velasco, J. et. al. J. Org. Chem. 2013, 78, 5482-5491.

OTBS OAc

OAcO

HOOTBS

Cp2TiCl2

1/2 M 1/2 MCl2

Cp2TiCl

AcO

TBSO

OTiIIILn

AcO

LnTiIIIOOTBS

AcO

LnTiIIIOOTBS

LnTiIII

IrCl(CO)(PPh3)2, H2, collidine, TMSCl


! The reductive method


R-Xe-

R + X-R' R

R'

e-

RR'

H+

RR'

H

anionic chemistry


! The reductive method more commonly used to generate ketyl radicals


R'

R'

e-

R'

H+

R'

H

anionic chemistry

O

R R

R = H, alkyl

R R

O

RR

O

RR

SmI2 O

OH

RR


! The triquinane system using SmI2

Fevig, T. L.; Elliott, R. L.; Curran, D. P. J. Am. Chem. Soc. 1988, 110 , 5064-5067.

H

H

Me

hypnophilin

Me

Me H

MeMe

Me

H H

MeMe

O

O

Me

Me

OH


! The triquinane system using SmI2

Fevig, T. L.; Elliott, R. L.; Curran, D. P. J. Am. Chem. Soc. 1988, 110 , 5064-5067.

Me

Me

Me

Me

MeMe

H

Me

MeH

H

Me

MeMe

Me

H H

MeMe

Me

H H

O

SmI2, THF/DMPU

69%

Me

H H

Me

Me

H

Me

MeH

H

Me

O

O

OSmI2

O

O

O

O

O

O

OOSmI2

SmI2

O

OHO


! Kilburn's stereoselective synthesis of paeonilactone B via a SmI2 cyclization

Boffey, R. J.; Wittingham, W. G.; Kilburn, J. D. J. Chem. Soc., Perkin Trans. 1, 2001, 487-496.

OMe

OH

SmI2, HMPA, tBuOH

THF, 0 to RT63% Me

OSmIIILn

H

OH

H

Me

OSmIIILn

H

OOSmIIILn

MeH

O

10:1 diastereomers

O

O

H

H

MeHO

O

O

H

H

MeHO

HMPA thought to cooridnate to SmIII to add bulk and induce stereoselectivity


! SmI2 for macrocyclizations in Diazonamide A

Nicolaou, K. C. et. al. ACIEE 2003, 42, 1753.

O

N

Me

Me

Cbz O

NBn

N MOM

N

O

NOMe

SmI2, DMA

O

N

Me

Me

Cbz HO

NBn

N MOM

N

O

H2N

40-45%

NH

NH

N

O

NO

O

O

HN

MeMe

HN

O

Me Me

HO Cl

Cl

diazonamide A


! SmI2 for macrocyclizations in Diazonamide A

Nicolaou, K. C. et. al. ACIEE 2003, 42, 1753.

O

N

Me

Me

Cbz O

NBn

N MOM

N

O

NOMe

SmI2, DMA

O

N

Me

Me

Cbz HO

NBn

N MOM

N

O

H2N

40-45%

O

N

Me

Me

Cbz O

NBn

N MOM

N

O

NOMe

SmI2

I2Sm


De Mesmaeker, A. et. al. Tetrahedron Lett. 1989, 30, 6307-6310.

! Radical cyclizations in sugar chemistry

O

OBn

OBn

BnO O

O

OBn

SePhOBn

BnO O

Bu3SnH, AIBN, 90%Me

O

OBn

SO2PhOBn

BnO O

Et3B, Bu3SnH, RT, 72%

O

OBn

OBn

BnO O

MeSmI2, HMPA, 78%

O

OBn

SePhOBn

BnO NH

O

OBn

OBn

BnO NH

Me

Sinay, P. et. al. Tetrahedron Lett. 1992, 33, 8065-8068.Czernecki, S.; Ayadi, E.; Xie, J. Tetrahedron Lett. 1996, 37, 9193-9194.


De Mesmaeker, A. et. al. Tetrahedron Lett. 1989, 30, 6311-6314.

! Tethered alkene and alkyne radical acceptors

Stork, G.; Suh, H. S.; Kim G. J. Am. Chem. Soc. 1991, 113 , 7054-7056.

O SePh

OOMeMeO

OMe

SiMe

MePh

1. Bu3SnH, AIBN2. TBAF

73%

O

OHOMeMeO

OMePh

E:Z >20:1

O SePh

OBnOBnO

OBn

OMe

Bu3SnH, AIBN

89%

O

OBnBnO

OBn

OOMe

MeO

OBnBnO

OBnOTBDMS

OMe

Me H


! 9-endo cyclization for !"C-disaccharides

Xin, Y. C.; Mallet, J.-M.; Sinay, P. J. Chem. Soc., Chem. Commun. 1993, 864-865.

O

OSePhBnO

BnOBnO

SiMe Me

O

O

OBn

OBnOMe

1. Bu3SnH, AIBN2. HF, THF

40%

O

OHBnO

BnOBnO

O

OH

OMe

BnOBnO

! 8-endo cyclization for #"C-disaccharides

O

OSePhBnO

BnO OBn

SiO

Me Me

O

OBn

OBn

OMe

1. Bu3SnH, AIBN2. TBAF

45%

O

OHBnO

BnO OBn

OOBn

OMe

HO

OBn

6, 2' adduct

3, 2' adduct


! 5-exo SmI2 cyclization for C-disaccharides

Mazeas, D.; Skrydstrup, T.; Doumeix, O.; Beau, J.-M. Angew. Chem. Int. Ed. Engl. 1994, 33, 1383-1386.

1. SmI2, THF2. TBAF, THF3. Pd/C, H24. Ac2O, Py

48%

! no HMPA makes SmI2 weaker reductant! LUMO !* of SO2Ar lowered with 2-pyridine! less toxic conditions

O SO2PyrOSi

MeMe

O

BnOBnOOMe

OBn

OBn

BnOBnO

OOBn

BnOBnO

O

OMeAcOAcOAcO

AcO


Wilcox, C. S.; Gaudino, J. J. J. Am. Chem. Soc. 1986, 108 , 3104-3105.

OH

OHOHHO

HO

carba-D-fructo-furanose

MeO2CBnO OBn

Br2HC OHOBn

O

OBn

HO

BnO

OBn

commercially available

t-BuO2CBnO OBn

OBnHO

t-BuO2CHC PPh3

DCM, 92%

2:3 E:Z

MeO2CBnO OBn

OBnO

1. Me2SO, (COCl)2, NEt3, 96%2. TFA, DCM, 0 °C, 93%

1. LDA2. CH2Br23. LDA, CH2N2

78%

5 equiv. Bu3SnH, PhH, RT85%

OHOBn

BrHC

OBnOBn

MeO2C OBn

OHOBnMeO2C

BnOH


Wilcox, C. S.; Gaudino, J. J. J. Am. Chem. Soc. 1986, 108 , 3104-3105.

OH

OHOHHO

HO

carba-D-fructo-furanose

MeO2CBnO OBn

Br2HC OHOBn

OHO

OBnBnO

OBn

commercially available

t-BuO2CBnO OBn

OBnHO

t-BuO2CHC PPh3

DCM, 92%

2:3 E:Z

MeO2CBnO OBn

OBnO

1. Me2SO, (COCl)2, NEt3, 96%2. TFA, DCM, 0 °C, 93%

1. LDA2. CH2Br23. LDA, CH2N2

78%

5 equiv. Bu3SnH, PhH, RT85%

OHOBn

BrHC

OBnOBn

MeO2C OBn

OHOBnMeO2C

BnOH


! The oxidative method

O

RH

R'

OH

RR'

M+n

-H+O

RR'

O

RR'

R" O

RR'

R"M+n

M+n-1+

O

RR'

R" product

! Chemical oxidation

! Electrochemical oxidationKolbe electrolysis

2 R-CO2- 2 [ R-CO2•] 2 R• R-R-e- -CO2



! Oxidative quadruple cyclization to prepare tetracyclic diterpenes

Snider, B.B.; Kiselgof, J. Y.; Foxman, B. M. J. Org. Chem. 1990, 112 , 4003-4008.

O

Me

MeMn(OAc)3, Cu(OAc)2

MeOH, RT, 3 h35%

Me

OMe CO2Et

Me

H

H

CO2EtMe

Me

Me CO2Et

Me O

H

H

isosteviol

Me

Me

Me

H

H

beyer-15-ene-3,9-diol

HO

HO


! Oxidative quadruple cyclization by Snider

Snider, B.B.; Kiselgof, J. Y.; Foxman, B. M. J. Org. Chem. 1990, 112 , 4003-4008.

O

Me

MeMn(OAc)3, Cu(OAc)2

MeOH, RT, 3 h35%

Me

OMe CO2Et

Me

H

H

CO2EtMe

O

Me

CO2Et Me Me

O

Me

CO2Et Me Me

O

Me

CO2Et Me Me

O

Me

CO2Et Me Me

O

Me

CO2Et Me Me

Mn(III)Cu(II)

* only other epimer isolated


OPh

O

Me

Me

HO

OH

Me

MeMe

Me

Me

Mn(OAc)3, Cu(OAc)2, AcOH, RT, 3 hrs

OMeMe O

O

HOMe

Me

Me

Me MeH

H

garcibracteatone

OO

O Me

Me

Me MeH

HO

Me

Me

Me

OO

O

Me

Me

Me

Me MeH

Me

Me

HOOO

O

HOMe

Me

Me

Me MeH

MeMe

OMeMe O

O

HOMe

Me

Me

Me MeH

H

Pepper, H. P.; Lam, H. C.; Bloch, W. M.; George, J. H. Org. Lett. 2012, 14 , 5162-5164.


! The oxidative method


OPh

O

Me

Me

HO

OH

Me

MeMe

Me

Me Mn(OAc)3, Cu(OAc)2, AcOH, RT, 3 hrs

OMeMe O

O

HOMe

Me

Me

Me MeH

H

garcibracteatone14%

OMeMe O

O

HOMe

Me

MeH

H

Me Me5-epi-garcibracteatone

8%

! 4 C-C bonds formed! no protecting groups! 5 stereocenters formed! biomimetic pathway


OPh

O

Me

Me

HO

OH

Me

MeMe

Me

Me

Mn(OAc)3, Cu(OAc)2, AcOH, RT, 3 hrs

OMeMe O

O

HOMe

Me

Me

Me MeH

H

garcibracteatone

OO

O Me

Me

Me MeH

HO

Me

Me

Me

OO

O

Me

Me

Me

Me MeH

Me

Me

HOOO

O

HOMe

Me

Me

Me MeH

MeMe

OMeMe O

O

HOMe

Me

Me

Me MeH

H



! So what is "radical" now?

! Total syntheses with radical cyclizations method in the last year:

! No photoredox radical cyclization in total synthesis yet

! Radical cyclization still primarily for carbon-carbon bond formations

! Many use fragmentation method - for functional handle after

! Total syntheses with tandem radical cyclization in the last year:

Tin Reagent: 8 reported Reduction: 6 reported Oxidation: 6 reported

Tandem: 5

timeless methods for radical cyclizations in total...

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