Baran Group Meeting
08/10/05
Fragmentation Reactions in Synthesis
Background
Ryan Shenvi
Fragmentation
•Heterolytic - governed by "polarity alternation" (Lapworth, A. J. Chem. Soc. 1898,
73, 495): predictable based on these concepts, also by consonance/dissonance
(Evans), conjointment/disjointment (Ho), resonance (see Coulson, C. A., O'Leary, B.,
Mallon, R. B. "Hückel Theory for Organic Chemists" 1978, Academic Press, p.132-33.)
•Homolytic - less predictable, goverened by different rules, energy differences less
directing (see below).
4.2
<
EDISS (kcal/mol)
95.8
~0
<
100
17.3
<
EDISS (kcal/mol)
231.9
27.5
<
Y
X
Y
X
Y
X
Y
d
+ –
fragments
well
– +
+
+
–
–
resists
– + fragmentation
+
d
d
d
NRR',
d = OH, OR, OCOR,
NR(COR), SH, SR, F, Cl, Br, I
a = CHO, COR, CO2H, CO2R, CN, SO2R, NO2, SiR3
Attaching an acceptor gives the adjacent carbon
donor characteristics.
a
a
donor
Attaching a donor gives the adjacent carbon
acceptor characteristics.
d
d
acceptor
•Resources for further reading on polarity alternation:
Lapworth, A. J. Chem. Soc. 1898, 73, 495; Ho, T.-L. Rev. Chem. Interm. 1988, 9,
117; Ho, T.-L. Rev. Chem. Interm. 1989, 11, 157. Ho, T.-L. "Polarity Control for
Synthesis" 1991, Wiley, New York. Ho, T.-L. "Heterolytic Fragmentation of
Organic Molecules" 1993, Wiley, New York; Evans, D. A. "An Organizational
Format for the Classification of Functional Groups. Applications to the Construction of Difunctional Relationships." 2001, Chemistry 206 Handout (Harvard).
Y
X
Y
0.64
Y
1.0
Grob, C. A., et al Helv.
Chim. Acta. 1972, 55, 521.
X
O2N
NO2
O2N
NMe2
NO2
AcO
NR2
X
Required antiperiplanarity (see Prelog, V.
and co-workers, Experientia 1960, 16,
521), must be able to adopt a zig-zag (1)
or W (2) chain conformation. Thus,
tosylate 3 fragments readily, while tosylate
4 does not. Minor deviations in angle
prevent fragmentation, as in brosylate 5,
where the nitrogen lone pair deviates only
20 ° from the desired angle.
Me
Me
H
krel =
Distribution of charge
3.
Cl
Me
Me
N
AcO
•Hydrocarbon chains are essentially homopolar, therefore the introduction of polar
groups affects the chain profoundly.
•Polar groups can be situated in consonant/dissonant (conjoint/disjoint) patterns.
Enderle, H. G. Dissert.
Univ. Basel 1967
X
Cl
X
Operative where there is low nucleofugality
of X and stability of intermediate anion: 1st
order rate constants for X are very similar.
276.7
Y
Operative in substrates where 3° cation is
formed; product ratios (fragmentation,
solvent capture, elimination, cyclization)
insensitive to leaving group; non-participation
of Y in the rate-determining step.
2.
100
249.2
1.
Br
N
Br
1
Me
NMe2
2
N Me
H
OBs
N
N
TsO
OTs
3
4
20 °
5
Cyril A. Grob (1917–2003)
Born in London, studied chemistry at ETH Zürich (PhD, 1943, Leopold
Ruzicka); synthetic studies at Universität Basel on biotin, lysergic acid,
the steroid framework, and sphingosin. An investigation of the reductive
elimination of bromine from 1,4-dibromides in the presence of zinc led in
1955 to the recognition of heterolytic fragmentation as a general reaction
principle. The structural and stereochemical prerequisites for a
fragmentation to occur were investigated with model compounds, and the
fundamental mechanisms of this reaction type were elucidated. In public
Cyril Grob was reserved and he did not particularly enjoy socializing. Only
in intimate circles did he shine as a relaxed, witty, cultured, and kind
person. He fulfilled his social duties efficiently, reliably, and without a fuss.
- Excerpted from Schiess, P. Angew. Chem. Int. Ed. 2004, 43, 4392.
Requirements of Fragmentation
Representative publications:
•Each member of atomic chain engages in exchanging an electron pair (stereoelectronic implications).
•Three predominant mechanisms operational
C. A. Grob, W. Baumann, Helv. Chim.Acta 1955, 38, 94; C. A. Grob, Angew. Chem. Int. Ed. Engl.
1969, 8, 535; C. A. Grob, Chimia 1971, 25, 87; C. A. Grob, Angew. Chem. Int. Ed. Engl. 1976,15,
569; C. A. Grob, Helv. Chim. Acta 1985, 68, 882. C. A. Grob, Angew. Chem. Int. Ed. Engl. 1982,
21, 87.
Baran Group Meeting
08/10/05
Fragmentation Reactions in Synthesis
0 and 1–Carbon Separations
Ryan Shenvi
Frangomeric Effect
Ratio of the fragmentation and ionization rate constants - kfrag : kion ; estimated by comparing heterosubsituted and homosubstituted analogues (with adjustments made for induction).
1. Examples in natural product synthesis: b-methelenecarboxylation
O
O
H2O
R
OTs
+
O
Dioxane
H
R=
rel
k
O
O
O
[O]
hn
ROH
RO2C
H
H
1
NHAc
22
SMe
39
OMe
84
OH
97
NH2
160
NMe2
1200
Me
H
Grob, C.A. Angew. Chem. Int. Ed. 1976, 15 , 569)
N
HO
H
H
H
O
O
Me
HO
0–carbon separation: (a–d and d–a)
OH
O
HO
H
Me
Me
H
OH
CO2H
Me Me
a d
SiMe3
X
F–
S
R
BF4
X
DIPEA
a H
d
veatchine
Wisener, K. et al. Tetrahedron
Lett. 1968, 6279.
S
R
X = S, NR
Prinzbach, H. et al. Angew Chem. Int. Ed. Engl.
1965, 4, 435.
Hoffmann, R. W. et al. Liebigs Ann. Chem.
1981, 581.
NMe2
110 °C
NMe2
d
NMe2
+
a NMe2
O 1. allene,
OMe
H
H
OMe
hn (300-600 nm)
hexane, -30 °C,
30 min, 72%
H
O
H
H
2. O3, NaHCO3
MeOH, 98%
Me
d
Br
O
Br
H
CO2Me
H
O
OH
Me
O
Me
Me
neotripterifordin
Corey, E.J. et al. J. Am. Chem. Soc.
1997, 119, 9929
2. Variations on a theme
Base
O
O
H
Nefedov, O. et al. Liebigs Ann. Chem. 1967, 707, 217.
Br
gibberellic acid
Yamada, Y. et al. Tetrahedron
Lett. 1989, 30, 971.
stemodin
Piers, E. et al. Chem. Commun.
1982, 80.
O
a
CO2H
Bergman, R.G. et al. J. Am. Chem. Soc. 1970, 92, 2163.
O
O
CO2H
Me
1–carbon separation: (a1a)
Becker, D. et al. J. Org. Chem. 1980, 45, 570.
Becker, D. et al. Chem. Commun. 1975, 377.
Et
Et
For instance:
retro-Claisen reactions
retro-Diekmann
etc.
Et
O
O
a
Nu
1
a
(a1a)
a
O
1
Nu
a
O
Nu
a
O
d
d
COCl
Et
O
Et3N
O
O
H
Snider, B. and co-workers Tetrahedron Lett. 1988, 53, 2356.
O3
O
MeOH,
K2CO3
MeO2C
Baran Group Meeting
08/10/05
Fragmentation Reactions in Synthesis
1 and 2–Carbon Separations
3. Umpolung alternatives
R = P(O)(OEt)2
Ryan Shenvi
1. Halo-deoxygenations
Me
Br
O
Me
O
O
Li
OR
OAc
NH3
Me
H
(EtO)2POCl
O
Funk, R. L. et al. J. Org. Chem.
1983, 48, 2632.
Albizati, K. F. et al. J. Org. Chem.
1989, 54, 4729.
Me
H O
H
O
O
H
MeO2C
O
O
H
Zn
AcOH
OH
O
Me
H O
O
H
N
CO2H
OH
OMe
OMe
Me
MeO2C
KOH
Qian, L. et al. Tetrahedron Lett. 1989, 30, 2089
( )
N
H+
Me
N
(19S)-vindolinine
(19R)-vindolinine
Me
Alternative
Intermediate
CO2Me
N
H
NH
Me
NH
Me
Me
CO2Me
N
R1
O
Nu
R1
Nu
H
Geometry programmed by relative
sterochemistry of L.G.
O
R
Me
H
R
NH2
OSiMe3
Kraus, W. et al. Liebigs Ann. Chem.
1970, 735, 198.
Me
Atta-ur-Rahman, M.; Malik, S.; Albert, K. Z. Naturforsch 1986, B41, 386.
O
NaNH2
MeLi
OTs
CO2Me
N
H
H
R1
OMs
Nu
H
H
H
R2
R2
O
Nu
O
Me
Me
CO2Me
Me
Boeckman, R. K. et al.
J. Am. Chem. Soc. 1989, 111, 2737.
Helpful cueing element for synthesis;
most plausible when E1CB not possible.
O
NH
CO2Me
Also possible if i) E1CB prevented by geometry, or ii) elimination is equilibrating
CO2Me
N
H
H
OMs
n
R2
Me
CO2Me
( )
OMs
H
H
Nu
R1
n
Me
Me
CO2Et
O
O
R2
N
CO2Me O
H
Julia, S. et al. Bull. Soc.
Chim. Fr. 1966, 3490
OMe
MeO2C
NaOMe
Me
OMs
H
Me
CO2H
Me
CO2Et
Me
N
OMe
Hudlicky, T. et al. J. Am. Chem. Soc.
1989, 111, 6691.
H
O
H
NaOH
O
MeO2C
CO2R KOH
N
O
H
O
Corey, E. J. et al. J. Am. Chem. Soc. 1979, 101, 5841. Woodward, R. B. et al. Tetrahedron 1958, 2, 1.
CO2H
Me
O
N
H
Me
2. b-L.G. ketone fragmentations
Me
H
O
Me
4. Other a1a fragmentations
O
Zn
O
OAc
O
OH
O
Br
Na Napth; Me
Br
Br
O
O
Larsen, S. D. et al. J. AM. Chem. Soc.
1977, 99, 8015.
Me
Me
2–carbon separation: (a2d)
Br
a
d
Zn
O d
R
Br
a
OR
Zn
OBz
dO
O
a
O
Nu
d
OR
O
OBz
O
OBz
MeO2C
Nu
a
d
OR
OR
NMe2
MeO
NMe2
Greenlee, M. L. J. Am. Chem. Soc. 1981, 103, 2425.
CH(OMe)2
Baran Group Meeting
08/10/05
Fragmentation Reactions in Synthesis
3 and n–Carbon Separations
Ryan Shenvi
3–carbon separation (a3a, d3d, d3a)
Me
O
CO2Me
MeO2C
MeO2C a
MeO2C
NaOMe
1. PhCH3, D, 90%
2. TFA, MeOH, 96%
CO2Me
O
OTBS
O
O
a
O
20 min
Me
NaOMe
a
2. MeOH,
HCl
78%
Me
Me
OMs
Me
B2H6;
Me
Me
Me
OMOM
H
Me
Me
Me
gymnomitrol
O
12 hr
Me
Me
HO
Extended systems
O
Me
a
NaOMe
O
1. DMDO
100%
Penkett, C. S. et al. Tetrahedron 2004, 60, 2771.
O
Me
O
O
Me
Ganem, B. and co-workers. Tetrahedron Lett. 1987, 28, 6253.
Me
O
O
O
Me
C6H12
7%
CO2Me
MeOH, 97%
hn
254 nm
NaOH
Me
Me
OH
OMs
H
+
H2B
a norpatchoulane
a ketonorcedrene
Deslongchamps, P. Can. J. Chem. 1977, 55, 4117.
Me
OMs
H
Me
H2B
OH
Marshall, J. A. J. Am. Chem. Soc. 1966, 88, 4291.
TMS
d
O
Me
hn
O
a
Me
SiO2
O
Et2O
N2
O
TMS
MeO
H
N
H
H
O
H
O
H
O
O
Cl
N
O
MeO2C
Cl
N
POCl3
N
H
Et
N
N
Et
MeO2C
Et
MeO2C
Ireland, R. E. et al. J. Org. Chem. 1984, 49, 1003.
Me
Me
OH OMe
Me
Me
H
H
H OH
Cl
d
Me
Me
KOt-Bu
H
BnO
Me
H OH
Me
Me
MeI, 70% BnO
H
(25 g scale)
Me
Me
Me
BnO
Me
H
Me
OMe
MeO2C
OH d
Me
H
O
BnO
Me
H Me
Me
BnO H
H Me
H
Me
MsO
O
MeO2C
Me
jatrophatrione
Paquette, L. A. et al. J. Am. Chem. Soc. 2003, 125, 1567.
N
H
Et
MeO2C
Takano, S. et al. J. Am. Chem. Soc. 1979, 101, 6414.
d
d
H
Me
N
N
H
Et
Me
O
Me
HO H
N
H
H
Cl
N
NaBH4
Me
H
1. MsCl
2. KOt-Bu
O
N
Me
O H
Me
N2
CO2t-Bu
O
O
OH
Me
O
Me
Corey, E. J. et al. J. Am. Chem. Soc. 1987, 109, 4717.
Tf2O
H
OBn
2,6-lutidine,
CH2Cl2, O
-78 °C
Me
H
H
OBn
Et
Baran Group Meeting
08/10/05
Fragmentation Reactions in Synthesis
Example Syntheses
Ryan Shenvi
Examples of fragmentation reactions in synthesis
Et
O
O
O
O
tryptamine
Et3N, THF,
0 °C, 83%
O
1. POCl3, PhH, D;
NaBH4, 83%
N
H
O 2. CH2O, MeOH
N
H
O
Me 1. LDA, THF,
H
H
O
hn,
C6H12
Me
DMPU, -78 °C
H
O
N
H
HCl/Et2O; H2O
73% ~1 : 1 dr
O
H N
OMOM
OMe
2. DMSO, BuLi,
THF, 0 °CÆ50 °C;
Zn, NaOH, H2O
O
Me
1. LDA; n-BuONO,
THF, 42%
2. NaBH4, EtOH;
TsCl, py, 69%
H N
N
H
Et
HCl
H
N
H
H
H
NC
O
tacamonine
2. POCl3, Py,
0 °C, 63%
3. Pd/C, H2,
MeOH, 78%
H N
O
Me
H
CHO
N
H
OMOM
Corex
Filter
O
Me
1. i-Pr2NMgI, THF,
0Æ50 °C
2. Swern
76% (2 steps)
O
1. MeMgBr, THF,
-10 °C, 66%
H N
NaOMe;
Me
H
Me
Me
NC
Me
1. LDBB, THF, -78 °C
2. PPh3, Im, I2
2. LDA, THF, MeI
44% (4 steps)
I
Ho, T.-L. et al. Tetrahedron, 2002, 58, 4969.
Me
1. LiBF4, MeCN/H2O
OMOM
O
Me
Me
MOMO
n-BuLi, THF
-100 °C
Me
Cl
Me
O3, MeOH; Me2S
O
MeO
72%
3. TsCl
4. KOt-Bu
5. H3O+
33% (5 steps)
OMe
Me
Me
O
1. 9-BBN, H2O2
2. NaH, BnI
(+)-limonene
N
OHC
Me
Me
Me
O
HO
1. Ac2O
Me
2. H2, Pd/C
1. hn, 90%
3. TsCl, NaI
4. KOt-Bu
2. TMSI
75%
OBn
OTBS
55%
OTBS
p-TsOH
OMe
O
Me
85%
O
Me
Me
OBn
(+)-ligudentatol
Haddad, N. et al. Tetrahedron Lett. 1997, 34, 6087.
OBn
Me
68%
Me
Me2CuLi,
THF, 0 °C
Me
NTf2
Me
84%
Me
Me
Me
Me
Me
(–)-isocomene
1. Li
2. PCC
3. MeOH, K2CO3
HO
TfO
Me
OBn
Rawal, V. H. et al. Pure & Appl. Chem. 1996, 68, 675.