Stereoelectronic Requirements of Fragmentation Reactions...

Stereoelectronic Requirements of Fragmentation Reactionsand Applications in Synthesis

Key W ords: Grob, Fragmentation, Marshall, W harton, Nucleofuge, Electrofuge

Grob, C.A., Angew. Chem. Int. Ed., 1967, 6, 1Grob, C.A., Angew. Chem. Int. Ed., 1969, 8, 535

A B C D X

N C C C X

Scott PetersonEvans Group Seminar, March, 2005

Types of Fragmentation Reactions

A B C D X A B C D X

Electrofugal Middle Groups Nucleofugal

A B C D X

HO CR2 CR2 CR2 Cl

HOOC I

RO CR2

R2N CR2

R2C CR2

H2N NH

CR2 NR

RO BR2

1,3 diols: Wharton

enolates: Mander

Marshall

Eschenmoser

Fragmentations of Chloroamines

Grob, C.A., Angew. Chem. Int. Ed., 1969, 8, 535Hoffmann, R., Helv. Chim. Acta., 1972, 55, 893

mixture of other products

Frangomeric Effect: kf : ki

For all cases studied, kf : ki > 102

Some as high as 105

Fragmentation of Amino-Tosylates

Grob, C.A., Angew. Chem. Int. Ed., 1969, 8, 535

TsO Me

exclusively trans

H exclusively cis

no fragmentation products, only elimination and substitution

Fragmentation of Aza-bicyclo-tosylates

Grob, C.A., Angew. Chem. Int. Ed., 1980, 19, 708

Reacts 103 times faster than carbon analogue

Substitution and

elimination

Decarboxylation Fragmentation

Eschenmoser, A., Angew. Chem. Int. Ed., 1979, 18, 634Eschenmoser, A., Angew. Chem. Int. Ed., 1979, 18, 636

baseMe

CO2HMe

CO2–

CO2– O

CO2–

Decarboxylation Fragmentation

Eschenmoser, A., Angew. Chem. Int. Ed., 1979, 18, 634Eschenmoser, A., Angew. Chem. Int. Ed., 1979, 18, 636

CO2–

SmI2 Cyclization / Grob Fragmentations

Molander, G. A., et al., J. Org. Chem., 2001, 66, 4511

2 SmI2

Sm(iii)O

CH3OMs

Scope of SmI2 Cyclization / Grob Fragmentations

complex mixtures

Reaction Conditions:

2.5 eq SmI2 freshly prepared from Sm0 and CH2I2

2 mol% NiI2

THF, -10 °C to 0 °C for 1 hour

Sm(III)OH

2.5 eq SmI2

2% NiI2

reflux

2.5 eq SmI2

2% NiI2

92%OSm(III)

Peterson, S.L., Meandering Thoughts, 2005, 2, 101

Ground statedihedral angle = 143.8°

Possible transition statedihedral angle = 175.4°

Relative energy = 6.50 kcal/mol

1) 2.5 eq SmI2, 2% NiI2

2) MeONa

Peterson, S.L., Meandering Thoughts, 2005, 2, 101

dihedral angle = 72.9° dihedral angle = 173.8°

Relative energy = 1.38 kcal/mol

O2.5 eq SmI2

2% NiI2Sm(III)O

Total Synthesis of (+)-Allocyathin

Nakada, M., et al., Org. Lett., 2004, 6, 4897Hasegawa, E., et., al., Tet. Lett., 1998, 39, 4059

MeO–

LDA, then I2

CO2Me71%

1) LiAlH4

2) MnO2

SmI2, HMPA

-78 °C, 10min

Marshall Fragmentation

Marshall, J.A., JACS, 1966, 88, 4291

1) B2H6

2) NaOH

Synthesis of Allohedycaryol

W ijnberg, J., J. Org. Chem., 1996, 61, 4022

(+) dihydrocarvone

• Regioisomer of (+)-hedycaryol• Isolated from F. communis L. (giant fennel)•!Toxic to livestock• Widespread in the Mediterranean area

Synthesis of Allohedycaryol

W ijnberg, J., J. Org. Chem., 1996, 61, 4022

1) EVK

2) H2O, HOAc

3) NaOMe

1) DDQ

2) DMDOMe

47% from carvone71%

1) t-BuOK

2) NaBH4

3) LiAlH4

1) (Me2N)2P(O)Cl

2) Li, EtNH2

1) NBS, KOH

2) PhSeNa3) Ra Ni

68%57%

1) BH3•THF, 0 °C

2) NaOMe, RT 12hr Me

BH2OMeMe

Wharton Fragmentation of 1,3 Diols

W harton, P.S., J. Org. Chem., 1961, 26, 4781W harton, P.S., J. Org. Chem., 1963, 28, 3217W harton, P.S., J. Org. Chem., 1965, 30, 3254

<6%, probably from ionization and elimination

Ryanodol to Anhydroryanodol

W eisner, K. Adv. Org. Chem., 1972, 8, 295Deslongchamps, P.., Can. J. Chem., 1979, 57, 3348W eisner, K., Tet. Lett., 1967, 3, 221

H+ or HO–HO

Total Synthesis of Ryanodol

Deslongchamps, P., Can. J. Chem., 1979, 57, 3348

Synthesis of Zaragozic Acid Core

Nagaoka, H., Tet. Lett., 1999, 40, 2777

OHHO 13 stepsO

OBnBnO

100 °C5 min

NaBH4, MeOH, RT

then I2, NaHCO3

OBnBnO

43% over 3 steps

OBnBnO

1) AcOH, H2O

2) AcCl, pyr

Synthesis of Jatrophatrione

Paquette, L.A., et al., J. Org. Chem., 1999, 64, 3244Paquette, L.A., et al., JACS, 2003, 125, 1567

BnO Me

Me Me• isolated in 1976 from Jatropha microrhiza• active against P-388 lymphocytic leukemia

Paquette, L.A., et al., JACS, 2003, 125, 1567

t-BuLi, CeCl3

25 g scale

[3,3]anionic

oxy-Cope

BnO Me

Paquette, L.A., et al., J. Org. Chem., 1999, 64, 3244Paquette, L.A., et al., J. Org. Chem., 1999, 64, 3255

BnO Me

5 steps

1) MsCl

2) KOtBu

MeCH3SO2O

5 steps8 % yield

Synthesis of Coraxeniolide-A

Leumann, C.J., J. Org. Chem., 2000, 65, 9069

• From the xenicane family• Isolated in 1981 from a pink coral

caryophyllene

Leumann, C.J., et al., J. Org. Chem., 2000, 65, 9069Grieco, P.A., J. Am. Chem. Soc., 1991, 113, 5488

1) NaBH4

2) TBSCl

3) LiAlH4

MeOTBS

Hg(OAc)2

MeOTBS

69%80%

Mg(ClO4)2[1,3]

(supra/antara)

MeOTBS

1) CH(OMe)3

2) m-CPBA3) LiCN4) KOH

MeOTBS

Leumann, C.J., et al., J. Org. Chem., 2000, 65, 6069

MeOTBS

1) TMSCl

2) DIBAl-H

3) NaBH4

MeOTBS

MeOOTMS

1) K10 clay

2) TBAF3) TsCl

OMeO77%

1) HCl

2) Ag2CO3

3) TsCl

DIBAl-H

NaH, DMSO

RT, 20min O

NaH, DMSO

RT, 20min

NaH, DMSO

RT, 10min

2.2:1 at C3

1.2:1 at C3

NaH, DMSO

RT, 20min O

2.2:1 at C3

E-olefin is only isolated product

1) TBSCl

2) Tebbe

3) TBAF

4) Ag2CO3

50% 1:5.7 dr

80% 3:1 dr

coraxeniolide-A

Progress Towards the Synthesis of CP-263,114

W ood, J. L., Org. Lett., 2001, 16, 2431W ood, J. L., Tet., 2002, 58, 6545

2) K2CO3, MeOH

Fragmentation of Isotwistane

Me Me1) MsCl

7 steps

1) Rh2(piv)4, PhH, 50 °C

2) NaH, BrCH2CO2MeO

Construction of Quaternary Sterecenter

Synthesis of Trisubstituted Olefins

Siddall, J.A, JACS , 1968, 90, 6224

1) mcpba

2) LiAlH4

3) TsCl

4) NaH, THF, RT

1) MeLi2) TsCl3) NaH, THF, RT

Me MeMe

Synthesis of (-)–Epibatidine

Evans, D.A., Org. Lett., 2001, 19, 3009

1) Sm(OTf)3, MeOH

2) BOC2O, NEt3, DMAP

4 steps44%

Cl3 steps

92:8 diastereoselectivity

Synthesis of Germacranes

Mander, L.N., J. Org. Chem., 1977, 42, 3984

tulipinolide

ArO2SO

LDAArSO2

OLiMeO

Synthesis of Sericenine

Honan, M.C., J. Org. Chem., 1985, 50, 4326

MeO2CH

MeO 1) LDA, ZnCl2

MeO2CH

OTHP p-TsOH

MeO2CH

O –MeO

:NHTMS2

Synthesis of (E,E)-Germacranes

W ijnberg, J. B., J. Org. Chem., 1997, 62, 7336

MeO2CH

sericenine

1) BH3•THF

allohedycaryol

2) NaOMe

1) BH3•THF

2) NaOMe

CHO Me

OHCOTMS

CHO Me

MeHNTMS2

1) NaO-t-amyl

CH2OH Me

2) Red-Al

1) NaO-t-amyl

2) Red-AlCH2OH Me

CH2OH Me

15-hydroxyhedycaryol

Synthesis of Imidoyl Cyanides

De Kimpe, N., et al., Tet. Lett., 2001, 42, 3921

1) Br2

2) KCNN

NCBrCN

Synthesis of Imidoyl Cyanides

De Kimpe, N., et al., Tet. Lett., 2001, 42, 3921

1) Br2

2) KCNN

R Piperdine Imidoyl Cyanide

cycloHexyl 80 % 77 %

(CH2)2Ph 71 % 0 %

sec-Bu 70 % 74 %

cycloPentyl 77 % 15 %

i-Pr 78 % 82 %

t-Bu 83 % 76 %

Conclusions

•Stereoelectronic requirements for fragmentation reactionsN

• These types of fragmentation reactions are useful for the synthesis of medium size rings containing olefins

• These types of fragmentation reactions typically occurunder very mild conditions (usually RT, with base) and

have shown utility in the synthesis of complex natural products

OBnBnO

• These types of fragmentation reactions can also be used in the synthesis of other interesting functional groups

Conclusions

•Stereoelectronic requirements for fragmentation reactionsN

• These types of fragmentation reactions are useful for the synthesis of medium size rings containing olefins

• These types of fragmentation reactions typically occurunder very mild conditions (usually RT, with base) and

have shown utility in the synthesis of complex natural products

OBnBnO

• These types of fragmentation reactions can also be used in the synthesis of other interesting functional groups

Stereoelectronic Requirements of Fragmentation Reactions...

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