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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
C C
N
H2C X
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
Br
HOOC I
SO3R
OCOR
OH2
NR3
SR2
N2
RO CR2
R2N CR2
Me3C
R2C CR2
H2N NH
HN N
CR2 NR
CR CR
CR N
CR2 O
CO O
N N
RO BR2
1,3 diols: Wharton
enolates: Mander
Marshall
Grob
Eschenmoser
Fragmentations of Chloroamines
Grob, C.A., Angew. Chem. Int. Ed., 1969, 8, 535Hoffmann, R., Helv. Chim. Acta., 1972, 55, 893
N
H
Cl
Me
N
Me
N
Cl
H
Me
NMe
OTsN
H H
Me
Me
HN
H OTs
Me
Me
NMe
Me
NMe2H
H
N
Cl
H Me
N
H
Cl
Me
NMe
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
N
TsO Me
H
N
Me
exclusively trans
N
Me
HTsO
H
N
Me
H
H exclusively cis
N
Me
H
N
Me
H
N
Me
H
OTs
H OTs
H
TsO
no fragmentation products, only elimination and substitution
Fragmentation of Aza-bicyclo-tosylates
Grob, C.A., Angew. Chem. Int. Ed., 1980, 19, 708
N
N
N
NOTs
H
NOTs
NBr
H
H
Reacts 103 times faster than carbon analogue
Reacts 104 times faster than carbon analogue
Reacts 105 times faster than carbon analogue
NH
OTs
NH
NH
OTs
Br
Substitution and
elimination
Decarboxylation Fragmentation
Eschenmoser, A., Angew. Chem. Int. Ed., 1979, 18, 634Eschenmoser, A., Angew. Chem. Int. Ed., 1979, 18, 636
O
baseMe
O
OO
H
CO2HMe
TsO
OO
H
CO2–
MeTsO
O
O
Me
TsO
H
CO2– O
O
Me
H
O
Me
O
O
TsO
CO2–
O
OCO2
–
O
Me Me
O
O
Me
H
H
Decarboxylation Fragmentation
Eschenmoser, A., Angew. Chem. Int. Ed., 1979, 18, 634Eschenmoser, A., Angew. Chem. Int. Ed., 1979, 18, 636
Me
base
O
TsO
O
O
O
Me Me
OO
H
MeTsO
O
TsO
O
CO2–
H
CO2–
H
CO2H
CO2–
OO
H
H
CO2–
Me
O
Me
O
SmI2 Cyclization / Grob Fragmentations
Molander, G. A., et al., J. Org. Chem., 2001, 66, 4511
O
OMs
I
2 SmI2
Sm(iii)O
OMs
CH3
Sm(iii)O
CH3OMs
CH3
O
SmI2 Cyclization / Grob Fragmentations
Molander, G. A., et al., J. Org. Chem., 2001, 66, 4511
O
I
CH3
OMs
O
MsO
H
CH3
O
MsO
H
CH3
CH3
O
Scope of SmI2 Cyclization / Grob Fragmentations
Molander, G. A., et al., J. Org. Chem., 2001, 66, 4511
OMs
O
Me
I
OMs
O
Me
I
CH3
O
Me
O
O
OMs
I
Me
O
Me
O
OMs
MeI
Me
O
69%
42%
86%
51%
O
OMs
MeCl
O
OMs
MeI
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
SmI2 Cyclization / Grob Fragmentations
Molander, G. A., et al., J. Org. Chem., 2001, 66, 4511
OMe
I
OMs
MeONa
Me
I
OMs
O
Sm(III)OH
MeMsO
NaOH
MeMsO
O
Me
Me
O
2.5 eq SmI2
2% NiI2
83%
OH
MeMsO
reflux
88%
2.5 eq SmI2
2% NiI2
92%OSm(III)
MeMsO
SmI2 Cyclization / Grob Fragmentations
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
OMe
I
OMs
1) 2.5 eq SmI2, 2% NiI2
2) MeONa
NaO
H
MeMsO
SmI2 Cyclization / Grob Fragmentations
Peterson, S.L., Meandering Thoughts, 2005, 2, 101
dihedral angle = 72.9° dihedral angle = 173.8°
Relative energy = 1.38 kcal/mol
Me
I
OMs
O2.5 eq SmI2
2% NiI2Sm(III)O
H
MeMsO
Total Synthesis of (+)-Allocyathin
Nakada, M., et al., Org. Lett., 2004, 6, 4897Hasegawa, E., et., al., Tet. Lett., 1998, 39, 4059
Me
Me
Me
MeOH
CHO
Me
Me
Me
MeO–
CO2Me
LDA, then I2
Me
Me
Me
MeO
CO2Me71%
1) LiAlH4
2) MnO2
80%
Me
Me
Me
MeO
CO2Me
I
SmI2, HMPA
-78 °C, 10min
91%Me
Me
Me
MeO
CO2Me
Marshall Fragmentation
Marshall, J.A., JACS, 1966, 88, 4291
Me
O
MeOMs
1) B2H6
2) NaOH
Me
MeOMs
HH2B
OMs
H
H2B
O
O
MeH
H
MeOMs
H2B
H
OMe
H
Synthesis of Allohedycaryol
W ijnberg, J., J. Org. Chem., 1996, 61, 4022
Me
OMe
(+) dihydrocarvone
Me
MeMe
Me
OH
MsO
Me
OH
Me
• 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
Me
NMe
HMePh
1) EVK
2) H2O, HOAc
3) NaOMe
Me
Me
O
Me
1) DDQ
2) DMDOMe
Me
O
Me
O
47% from carvone71%
Me
MeMe
HO
Me
OH
1) t-BuOK
2) NaBH4
3) LiAlH4
67%
Me
MeMe
Me
OH
1) (Me2N)2P(O)Cl
2) Li, EtNH2
1) NBS, KOH
2) PhSeNa3) Ra Ni
Me
MeMe
Me
OH
OH
68%57%
MsCl
Me
MeMe
Me
OH
MsO
99%
1) BH3•THF, 0 °C
2) NaOMe, RT 12hr Me
Me
MsO
BH2OMeMe
Me
OH
H
Me
MeMe
Me
OH
H Me
OH
Me
68%
Me
OH
Me
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
OH
OTs
HO
OTs
OH
OTs
O
O
OHOTs
O
<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
O
OH
MeHO
OH
Me
OH
HO
Me
Me
Me
O
O
Me
OH
Me
OH
HO
Me
Me
Me
HO
HO
HO
HO
O
HOMe
OH
Me
MeHO
HO
iPr
HO
O
HOMe
OH
Me
iPr
HO
O
Me
H+ or HO–HO
HO
OH
HO
Total Synthesis of Ryanodol
Deslongchamps, P., Can. J. Chem., 1979, 57, 3348
H
H
Me
O
Y
Me
Me
Me
OO
R
OH
H
O
H
H
Me
O Me
Me
Me
OO
R
H
O
O
Synthesis of Zaragozic Acid Core
Nagaoka, H., Tet. Lett., 1999, 40, 2777
O
OHHO 13 stepsO
O OBn
OBnBnO
OMsO
OBn
OH O
O
BnO
O
O
OBn
OBnBnO
KHMDS
100 °C5 min
NaBH4, MeOH, RT
then I2, NaHCO3
O
O
BnO
O
O
OBn
OBnBnO
I
43% over 3 steps
O
O
BnO
AcO
AcO
OBn
OBnBnO
I
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
OH
Me
Me
Me
OH
BnO Me
Me
H
H2C
O
MeMe
Me
Me
HOH
O
O
Me
O
BnO
Me
OMe
Br
Me Me• isolated in 1976 from Jatropha microrhiza• active against P-388 lymphocytic leukemia
Synthesis of Jatrophatrione
Paquette, L.A., et al., JACS, 2003, 125, 1567
Me
O
BnO
Me
OMe
Br
Me Me
t-BuLi, CeCl3
80%Me
BnO
Me
Me
Me
OMe
HO
25 g scale
tBuOK
MeMeO
H
H
MeMe
MeO
OMe
[3,3]anionic
oxy-Cope
MeMeO
H
H
MeMe
MeO
OMe
MeI
MeMeO
H
H
MeMe
MeO
OMe
Me
Me
OMe
OMe
Me
Me
Me
BnO
H
OH
Me
Me
Me
OMe
BnO Me
Me
70%
Synthesis of Jatrophatrione
Paquette, L.A., et al., J. Org. Chem., 1999, 64, 3244Paquette, L.A., et al., J. Org. Chem., 1999, 64, 3255
OH
Me
Me
Me
OMe
BnO Me
MeOH
Me
Me
Me
OH
BnO Me
Me
H
5 steps
54%
1) MsCl
2) KOtBu
85%Me
O
MeMe
Me
Me
BnOH
Me
MeCH3SO2O
H
H
BnO
H
Me
O HMe
H2C
O
MeMe
Me
Me
HOH
O
O
5 steps8 % yield
Synthesis of Coraxeniolide-A
Leumann, C.J., J. Org. Chem., 2000, 65, 9069
O
O
Me
Me
H
Me
H
O
MeOH
Me
H
O
MeOTs
OH
MeO
MeO
O
• From the xenicane family• Isolated in 1981 from a pink coral
H
Me
H
Me
Me
caryophyllene
Synthesis of Coraxeniolide-A
Leumann, C.J., et al., J. Org. Chem., 2000, 65, 9069Grieco, P.A., J. Am. Chem. Soc., 1991, 113, 5488
MeO
O
1) NaBH4
2) TBSCl
3) LiAlH4
MeOTBS
HO
O
Hg(OAc)2
MeOTBS
O
69%80%
Mg(ClO4)2[1,3]
(supra/antara)
MeOTBS
O
H
83%
1) CH(OMe)3
2) m-CPBA3) LiCN4) KOH
45%
MeOTBS
MeO
MeO
CNOH
Synthesis of Coraxeniolide-A
Leumann, C.J., et al., J. Org. Chem., 2000, 65, 6069
MeOTBS
MeO
MeO
CNOH
1) TMSCl
2) DIBAl-H
3) NaBH4
MeOTBS
MeO
MeOOTMS
HO66%
1) K10 clay
2) TBAF3) TsCl
MeOTs
OH
OMeO77%
1) HCl
2) Ag2CO3
3) TsCl
MeOTs
OH
OO
DIBAl-H
MeOTs
OH
OHO
56%
98%
Synthesis of Coraxeniolide-A
Leumann, C.J., et al., J. Org. Chem., 2000, 65, 6069
MeOTs
OH
OMeO
MeOTs
OH
OO
MeOTs
OH
OHO
NaH, DMSO
RT, 20min O
Me
H
O
MeO
H
NaH, DMSO
RT, 20min
NaH, DMSO
RT, 10min
O
Me
H
O
O
H
O
Me
H
O
HO
H
89%
71%
88%
2.2:1 at C3
3
1.2:1 at C3
3
Synthesis of Coraxeniolide-A
Leumann, C.J., et al., J. Org. Chem., 2000, 65, 6069
MeOTs
OH
OMeO
NaH, DMSO
RT, 20min O
Me
H
O
MeO
H
89%
2.2:1 at C3
3
O
OTsH
O
Me
OMe
H O
H
O
Me
OMe
H
E-olefin is only isolated product
Synthesis of Coraxeniolide-A
Leumann, C.J., et al., J. Org. Chem., 2000, 65, 6069
O
Me
H
O
HO
H
1) TBSCl
2) Tebbe
3) TBAF
4) Ag2CO3
52%
O
Me
HO
H
LDA,
Me
MeBr
50% 1:5.7 dr
O
Me
HO
H
Me
Me
N
HN N
O
Me
HO
H
Me
Me
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
O
O
O
O
OH
O
O
O
OAcO
OH
O
2) K2CO3, MeOH
Fragmentation of Isotwistane
Me Me1) MsCl
95%
O
O
O
O
O
OBn
7 steps
73% O
TIPSO
TIPSO
O
O
OEt
O
N2
1) Rh2(piv)4, PhH, 50 °C
2) NaH, BrCH2CO2MeO
TIPSO
TIPSO
O
OO
OMeO
OEt
Construction of Quaternary Sterecenter
46%
Synthesis of Trisubstituted Olefins
Siddall, J.A, JACS , 1968, 90, 6224
HO
Me
MeOH
Me
1) mcpba
2) LiAlH4
3) TsCl
4) NaH, THF, RT
OH
Me
Me Me
O
Me
MeO
1) MeLi2) TsCl3) NaH, THF, RT
Me O
Me Me
O
Me
Me O
Me MeMe
O
Synthesis of (-)–Epibatidine
Evans, D.A., Org. Lett., 2001, 19, 3009
HN
TESO
O
H
N
Cl
NOO
O
Bn
1) Sm(OTf)3, MeOH
2) BOC2O, NEt3, DMAP
82%
N
TESO
O
H
N
Cl
OMeO
O
tBuO
TBAFC
N
HN
Cl
O
OH
OMe
4 steps44%
HO
BocHN
H
N
Cl3 steps
73%
92:8 diastereoselectivity
H
N
Cl
NH
Synthesis of Germacranes
Mander, L.N., J. Org. Chem., 1977, 42, 3984
OMe
O
OAc
tulipinolide
*
*
*
**
*
*
*
*
O
CO2H
OMe
OMe
ArO2SO
MeCO2
Me
H
O
O
LDAArSO2
OLiMeO
Me
O
O
MeCO2
O
O
Synthesis of Sericenine
Honan, M.C., J. Org. Chem., 1985, 50, 4326
TsO
MeO2CH
MeO 1) LDA, ZnCl2
2)
Me
O
OTHP
TsO
MeO2CH
MeO
MeOH
OTHP p-TsOH
TsO
MeO2CH
Me
O
Me18%
77%
KHMDS
43%
Me
CO2Me
O
Me
OTsO
Me
MeOOK
MeO2C
O
Me
Me
H
O
Me
Me
O –MeO
Me
O
Me
O –MeO
Me
CO2Me
O
Me
:NHTMS2
Synthesis of (E,E)-Germacranes
W ijnberg, J. B., J. Org. Chem., 1997, 62, 7336
R
R
KHMDS
TsO
MeO2CH
Me
O
Me
Me
CO2Me
O
Me
KHMDS
TsO
MeO2CH
Me
R
sericenine
TsO
R
Me
1) BH3•THF
Me
OH
Me
Me
MeMe
Me
OH
MsO
allohedycaryol
2) NaOMe
1) BH3•THF
2) NaOMe
Synthesis of (E,E)-Germacranes
W ijnberg, J. B., J. Org. Chem., 1997, 62, 7336
MsO
OHCH
Me
OH
Me
Me
MsO
OHCH
Me
OH
Me
Me
OHCOH
Me
Me Me
Me
CHO Me
O
Me
MsO
OHCH
Me
OTMS
Me
Me
MsO
OHCH
Me
OTMS
Me
Me
OHCOTMS
Me
Me
[3,3]
OHCH
Me
OTMS
Me
Me
Synthesis of (E,E)-Germacranes
W ijnberg, J. B., J. Org. Chem., 1997, 62, 7336
MsO
OHCH
Me
Me
Me
KHMDS
CHO Me
Me
Me
CHO
Me
MeHNTMS2
MsO
OHCH
Me
Me
Me
1) NaO-t-amyl
CH2OH Me
Me
2) Red-Al
MsO
OHCH
Me
Me
Me
OTES
1) NaO-t-amyl
2) Red-AlCH2OH Me
Me
OTES
TBAF
CH2OH Me
Me
OH
15-hydroxyhedycaryol
Synthesis of Imidoyl Cyanides
De Kimpe, N., et al., Tet. Lett., 2001, 42, 3921
H
NR
1) Br2
2) KCNN
R
NC
BrNaH
CN
NR
N
R
Br
BrN
R
Br
NC
KCN
N
R
Br
NC N
R
NC
Br
NaH
N
R
NCBrCN
NR
Synthesis of Imidoyl Cyanides
De Kimpe, N., et al., Tet. Lett., 2001, 42, 3921
H
N
R
1) Br2
2) KCNN
R
NC
Br
NaHCN
N
R
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
H
Cl
Me
N
Me
• These types of fragmentation reactions are useful for the synthesis of medium size rings containing olefins
O
OMs
I
Me
O
Me
86%
• 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
H2C
O
MeMe
Me
Me
HOH
O
O
O
O
BnO
AcO
AcO
OBn
OBnBnO
I
• These types of fragmentation reactions can also be used in the synthesis of other interesting functional groups
N
R
NC
BrNaH
CN
NR
Conclusions
•Stereoelectronic requirements for fragmentation reactionsN
H
Cl
Me
N
Me
• These types of fragmentation reactions are useful for the synthesis of medium size rings containing olefins
O
OMs
I
Me
O
Me
86%
• 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
H2C
O
MeMe
Me
Me
HOH
O
O
O
O
BnO
AcO
AcO
OBn
OBnBnO
I
• These types of fragmentation reactions can also be used in the synthesis of other interesting functional groups
N
R
NC
BrNaH
CN
NR
