Reactivity Umpolung-1
complimentary disconnections
Reactivity Umpolung: reversal of normal polarity
electrophiles become nucleophiles
nucleophiles become electrophiles
O
R
Normal reactivity:
X
c
3
dX
x = heteroatom
d = donor (Nu-)
a = acceptor (E+)
Ready
a
bond
a
d
1
d
b
umpolung
normal
X
or
a
X
MgBr +
R
O
NMe2
OLi
1
4
2
or
O
OEt
R
Br
c
R2 CuLi
+
OEt
Cu
+
Br
RBr
+
O
SLi
Li
1
Outline:
1. electrophilic heteroatoms
2. acyl anions
3. homoenolates
4. the cyclopropane trick
5. sulfone chemistry
R
O
X
X
Li
+
X
X
1
X
b
Br
S + R
S
5
How to make:
a
General Review: ACIEE, 1979, 239
Carey and Sundburg, sec 13.2
Reactivity Umpolung-2
Ready
mCPBA
Electrophilic Heteroatoms
'Rubottom [O]'
General form:
OTMS
Ph
X
X
Y+
X,Y = heteroatoms
Y
Examples
O
NMe2
1. LDA; O2
2. Na2S2O3
O
O
HO
DMDO
NMe2
CO2Et
P'O
69%
OP"
O
PO
OTBS
P'O
OP"
OP"
OP"
Falck, JOC, 1995, 3385
NMe2
1. LiHMDS
2.
HO
Ph
81%
CO2Et
O
O S
O
Wasserman and Lipshutz
TL, 1975, 1731
O
N
O
OH
95% ee
O
O
1. TBSOTf, Et3N
2. DMDO
PO
Oxaziridines
Ph
Ph
O
O O
O
"
O
Rubottom, TL, 1974, 4319
84%
HO O
OTMS
Ph
60%
Electrophile
O2
1. mCPBA
2. HF
O
Mo
O
O
Py O
P(NMe2)3
MoOPH
O
O
LDA; MoOPH
OH
87%
Vedejs, JOC, 1978, 188
Davis, Chem. Rev. 1992, 919
not a general asymmetric method. For racemic, most
commonly used is 'Davis Oxaziridine'
O
TsN
Ph
OH
Reactivity Umpolung-3
Heteroatom exchange: Most commonly with Br, Cl
Aminations (Review: Syn Lett, 1997, 741)
Electrophile
E
N
N
Examples
E
O
R
OH
CO2Me
BnO
Cl
Ready
1. LDA
2.
BOC
N N
BOC
BnO
Br2
OH
R
OH
can you name this rxn?
CO2Me
NHBoc
NHBoc
OH
NH2
Br
OH
Cl
R
O
NH3
O
cat PCl3
α-halo carbonyls are excellent electrophiles (recall SN2 rxn accelerated by
either electron withdrawing or electron releasing groups)
1. H2 Pd/C (-Bn)
2. TFA (-Boc)
3. RaNi, H2
N3O
Br
O
PhO-
Nu
OH
CO2Me
vancomycin
RSH
NH2
HO
CNCl
70%; de > 98%
synthesized from enolate (or equiv) and electrophilic halogen:
Somewhat realated; rarely used; unusual mechanism:
Neber rearrangement
OTs
1. H2N-OH
O
N
NBr
2
TsCl,
Bu
4
Ph
Ph
Ph Toluene/KOH(aq)
Ph
TMS
Include stoltz use of neber in dragmacidin,
JACS, 2005, 5970
O
NCS, NBS, SO2Cl2
O
Cl
O
Li
O
TsCl,
Cl
Cl
Cl
Cl
Cl
O
Ph
H2O
Ph
NH2
Ph
N
Ph
azirine
Maruoka, JACS, 2002, 7640
OH
Br2, Cl2, CuCl2
Lead references: Brummond, TL, 1999, 2231;
enantioselective chlorination: Jorgensen, ACIEE, 2004, 5507
O
Cl
Reactivity Umpolung-4
Ready
Strecker amino acid synthesis: One of the oldest and
most effective ways to make amino acids
Acyl anions are the most sought umpolung reagents
O
O
R
R
Cyanide: Super nucleophile (small, non-basic), can be
converted into amine, aldehyde, acid, ketone.
+ NaCN
Cl
+
KCN
DMSO
CN
Bn
O
N
H
N
H
HO
OPiv
NBn
NHBn
HCN
R
DIBAL
O
CN
O
With keto-imines
R
NBn
LiAlH4
NH2
CO2H
N
O
OH
RMgBr
R
O
N
1 mol%
H3O+
CN
Jacobsen JACS 2002, 10012
CN
DMSO
R
NH2
Recently has become hot topic for asymmetric catalysis.
Review: Chem Rev. 2003, 2795
70%
Cl
NH2
+ NaCN + NH4Cl
R
NBn
Ar
CN
ee's 88-95 for 3- or 4-substituted Ar
R
CN
R
Ph
%ee
99
iPr
97
tBu
99
nPent
96
Reactivity Umpolung-5
Ready
Hydrocyanation of aldehydes and ketones
Strecker Rxn with quinolines (Reissert Rxn)
O
Tol P
Tol
O
Tol P
Tol
Cl Al
O
O
Cl Al
N
R
O
R
O
CN
N
0.1 equiv
R
CN
N
ee
96
97
98
97
S
N
O
Ph P
Ph
O
72%, 89%ee
H
R
Ph
Ph(CH2)2
Hexyl
Shibasaki, JACS, 1999, 2641
MeO
CN
yields > 85%
TMSCN
0.4 equiv Bu3PO
O
O
O
TMSO
O
O
91% , 85%ee
CN
MeO
CN
H
O
Me2N
O
N
R
TMSCN
Cl
N
Tol
P
Tol
O
O
Tol
P
Tol
O
O
O
O
O
99%, 91%ee
RO Ti
RO
O
R
R'
O
O
TMSO
CN
R
R'
TMSCN
70-90% yield
Propose:
TMSO CN
O
P
TMSO
CN
TMSO
CN
Me3Si
X
N
N
Cl Al
O
O
X= H, 92% ee
Cl, 92% ee
91% ee
Shibasaki, JACS, 2000, 7412
85% ee
Reactivity Umpolung-6
Increasing the acidity of the formyl proton
O
RO
R
H
RO
EWG
R
Nature uses carbenes:
EWG
NH2
R
H
KCN
+
KOH
Ph
H
O
NC OH
OH
Ph
Ph
O
N
S
Ph
OH
O
O
H
HCN
R
OEt
CN
Stork, JACS, 1971, 5286
O
OH
TsO
R
NH2
O
O
OH
S
OPP
N
R'
PO
HO
N
HO
HO
NH2
-RCHO
R
OH
+
N
N
S
OPP
N
enamine intermediate
R
OP
R'CHO
Related Chemistry:
R'
NR2
R
OH
R'
R=Me; R' = n-hex (85%)
iPr (80%); allyl (76%)
1. LDA
2. KOH
R
R
O
N
R'
NC
OH
α-keto acid or Ketose substrate
OEt
O
OPP
N
O
1. LDA
2. R'X
3. NaOH
S
Vitamin B1 (thiamine)
HO
O
N
Ph Coenzyme: thiamine pyrophosphate
Ph
Cyanomethyl ethers
..
N
OPP
H
R
Base
N
O
NC OH Ph
NH2
+
N
Benzoin condensation
Ready
CN
Review: Chem. Soc. Rev
2000, 359
NH2
N
OH
OH
N
N
OH
HO
R'
S
OPP
OH
O
ketose product
Reactivity Umpolung-7
In the lab: Review: Org. Rxn. 1991, 407; ACIEE 2004, 1326
Benzoin reaction
Catalytic homoenolate generation
Bode, JACS, 2004, 14370
H Cl-
enantioselective version:
O
N N Ph
+
O
O
N
tBu
H
Ar
(10 mol%)
KO Bu (10 mol%)
O
O
DBU (8 mol %)
THF/tBuOH
1
Ar
Ar2
d.r. ~4:1
Ar
Ar
KCN (30 mol%)
18-C-6 (10 mol%)
Mes N
O
1
Ar
O
Ar1
OH
Mes
N+
2
Ar
SiEt3
CN
N Mes
Ar2
Ar1 O
-
Ar
O
O
Problem: crossed benzoin gives mixture of homo and
hetero dimers.
Soln: Acyl silanes
+ RCHO
N Mes
O
80-95% ee
Enders, ACIEE,
2002, 1743
SiEt3
Ar2
1
OH
O
Mes N
+
O
+
t
Ar
Ar
Ready
N
OH
N
Ar1 Mes +
Mes
Brook
O
Ar
OSiEt3
R
R
Ar
OSiEt3
CNO-
OSiEt3
Ar
Ar1 OH
CN
Ar
Johnson, ACIEE, 2003, 2534
2
N
OH
Mes
Mes
N
Mes
N+
O
OH
Ar1 Mes
N
Mes
N
Reactivity Umpolung-7a
catalytic Sila-Stetter Reaction
Schiedt, JACS, 2004, 2314
30 mol%
S
HO
O
O
+
Ar
SiMe2R R'
R = Me or Ph
R''
Rovis, JACS, 2002, 10298
O
Br-
N
+
CH3
DBU, iPrOH
CH3
R'
O
Ar
O
Ar
R''
O
CHO
S
O
Ar
N
R'
DBU
CO2Et
O
94% ee
94% y
SiMe2R
S
OH
quaternary stereocenters with activated catalyst:
Rovis, JACS, 2004, 8876
O
BF4
N
F
N
N
F
SiR3
O
CO2Et
OCH3
O
R''
Ar
N
N
O
R'
N
BF4
N
O
+
Ready
Ar
R''
N+
O-
S
O
CHO
CH3
F
LiHMDS
CO2Et
F
CO2Et
F
CH3
99% ee
95% y
opposite
enantiomers!
O
R'
OH
N
Ar
S
Ar
N
OSiR3
N
CHO
CH3
No Rxn
Ar
No Rxn
F
F
SiMe2R
Ph
O
F
O
O
SiMe2R
N
N
Ph
S
O
Ar
BF4
O
R''
LiHMDS
F
F
O
CH3
99% ee
63% y
Reactivity Umpolung-7b
Isonitriles
Ugi Four-component coupling (U4CC)
R
N
C
Versitile C1 synthons; often act as acyl anion
Passerini Rxn:
R
N
C
O
+
R'
+
R''
H+
O
R'
OH
O2CR''
R'
N
+ R'
R'
N
NR'''
R'''NH2
R
OH
N
R'''
NHR'''
O2CR''
acyl migration
R'
NHR'
NHR'''
R''CO2H
R'
N
+ R'
N
R'
Has been applied extensively for library synthesis:
O
an enantioselective version has appeared
X
OH
Cat.
RCHO
R'
+
R''
H+
+
O
protected amino acid
OCOR''
NHR'
R'
SiCl4
+
O
O
R''
acyl migration
+
O
OH
OH
R'
tBu
N
+
Ready
NHtBu
R'
Y
1
CO2H R
+
R2
NO2
Ar
O +
O
R3
+
NC
NH3Cl
O
cat =
R
O
N
P N
N
2
*
Propose silyl cation
lewis acid:
O
O Si +Cl
Cl
Cl
tol
naphthyl
2-furyl
c-hex
JACS,
2003, 7825
ee
99
99
92
64
O
2
O R1 R
X
Y
N
NO2
O
R3
NH
Fe, AcOH
2
O
X
R1 R
N
Ar
O
Y
N
Ar
R3
NH
Reactivity Umpolung-7c
Ready
Isonitriles as linchpins (first as E+, then as Nu-)
U4CC in synthesis:
OCH3
OMOM
BnO
H3C
1. 2 SmI2
OCH3
CH3
O
2.
+
NH2
I
BocHN
OTBDPS
O
O
OMOM
NC
OMOM
O
H3C
PMP
NH
NHBoc
BnO
N
N
O
O
O
O
TBDPSO
I
H3C
OBn
OCH3
O
H3C
90%
CH3
OH
+
3. H3O
O
2 SmI2
Cl
BnO
SmX2
(Barbier reaction)
I
Ar
N
C
OBn
OCH3
Ar
N
O
OH
HO
OCH3
CH3
NH
H3CO
O
AcO
H3C
HO
S
O
BnO
N
C
CO2H
NH
O
TBDPSO
Cl + H3C
CH3CHO
O
H3C
BnO
BnO
R
N
SmX2
Ar
H
N
H3O+
CH3
N
O
O
OH
Ecteinascidin 743
Antiproliferative (IC50 = 0.2 - 1 nM)
Fukuyama, JACS, 2002, 6552
OH
Ito, JOC, 1993, 1458
BnO
O
Ar
N
C
Reactivity Umpolung-8
Dithiane anions
R
S
BuLi
S
R
S
E+
Li
R
S
sample products:
E
S
Ready
R
S
E
OTBS SS OH
O
O
BnO
Corey, Seebach, JOC, 1975, 231
R
E
H
Me
Et-I
74%
% yield
85
83
Ph
iPr-I
iPr-I
H
PhCHO
n-pent
O
OP
65%
95
Vinyl thioether anions
77
R
O
SEt
R'
S
S
O
R
3. HMPA,
TBS
S
O
O
R
Li
sample products:
OLi
S
R
sBuLi
THF/HMPA R'
1. E+
SEt 2. HgII, H2O
Li
S
R
OTBS
S
O
Ph
n-C8H17
R
O
O
Ph
n-C8H17
OH
R'
Stable until addn
of HMPA
How?
SEt
HO
Smith,III, JACS, 2003, 14435
E
R'
An extension: dithianes as linchpins
1. tBuLi
2.
OTBS SS OH OTBS
O
O
97
99
H
TBS
O
OTBS
R'
S
S
R
Li
+
Br
O
Br
52%
Yamamoto, JACS, 1973, 2694
Reactivity Umpolung-9
conjugate addn.
Homoenolate equivalents
" M
O "
CO2Et
O
O
O
Br
Tol
1. E+
2. hydrolysis
O
Ready
CN
O
O
MgBr
O
O
Tol
CuBr-DMS
CO2Et
NC
O
58%
E
MgBr
available from aldrich
TL, 2003, 737
OH
X
examples:
CHO
1.
γ
O
O
O
Roush, JACS,
1978, 3599
2. HCl
Many examples. Few work well.
Selectivity (α vs. γ) usually poor
OMe
O
N
HO
nC3H7
1. s-BuLi
2. E+
E
OMe
O
Ph
O
α M
MgBr
C6H13n
Ph
OMe
O
MgBr
77%
N
O
nC3H7
79%
Evans, JACS, 1974, 5560
H2 Pd/C
90%
Bosch, JOC, 2003, 1919
N
nC3H7
OMe
OH
72%
Reactivity Umpolung-10
Ready
homoenolates, cont.
Seebach:
1. s-BuLi
2. E+
OTES
E
OTES
SH
Yield (%)
E
Me
Et
95
83
Allyl
68
1. 2 BuLi
TMEDA
2. E+
3. MeI
E+ = n-alkyl Br
EtCHO
PhCHO
c-pentanone
Still, JACS, 1974, 5561
Review: Tet, 1983, 205
1.
Ph
H
N
N
Boc
N
Ar
H
2. E+
sBuLi
Boc
N
Ar
Ph
E
E+
% yield
% ee
Me
73
95
Allyl
72
94
77
98
O
Review: ACIEE, 1997, 2282
SMe
E
yields = 65-95
α:γ = 1:3 - 1:4
Reactivity Umpolung-11
CO2Me
CO2Me
The Cyclopropane Trick
O
X
X Y
X Y
OMe
O
Wenkert, JOC, 1978, 1267
O
O
O-
E
E
O
O
1. Acid
2. Base
Y
+
X
O-
N
with cyclopropane
Y
+
CO2Me
Base
NH2
cyclopropanes convert even to odd, odd to even:
normal reactivity mode
Ready
OEt
O
O
O
TMSO
TiCl4
TiIV
(a homoenolate equivalent)
EtO
Nu
Nu
O
O
O2N
H
examples
CO2Me
CO2Me
CO2Me
CO2Me
CHO
NaH
DMSO
CO2Me
CO2Me
CO2Me
84%
CO2Me
O
Danishefsky
JACS, 1974, 1256
NO2
O
EtO
OH
Kuwajima, JACS, 1977, 7360
O
Reactivity Umpolung-12
Ready
OMe
Br
Sulfones
sulfones display amphoteric reactivity pattern:
they can be either electrophilic or nucleophilic
MeO
OMe
Li
O
HO
+
SO2Ph
R
MsCl;
Note: leaving group β to lithium, but no
cyclopropene formed from eilimination
HO
SO2Ph
Base, E+
SH
R
PhO2S
[O]
E
R
E
LDA, then 1
O
O
OTBS
O
Corey, TL, 1975, 3685
S
O
OTBS
OTf
(85% yield)
OBn O
O
O
O
1
OTBS
OBn O
O
O
O
X
O
O
OTBS
O
LDA, MoOPH
40% yield
X = H, SO2Ph
X=O
Masamune, TL, 1988, 451
Reactivity Umpolung-13
Ready
Spiroketal synthesis
OTBS
OP' OP
SO2Ph
nBuLi; epoxide; BF3 Et2O
OTIPS
MeO
nBuLi; -78oC
PhO2S
O
PhO2S
O
O
O
O
O
rt
C-SO2Ar is nucleophilic
then electrophilic
O
OH
CSA
O
OTBS
OP' OP
PhO2S
O
OH
OMe
OH
OTIPS
75%, 4:1
1. nBuLi; CH2I2-iPrMgBr
2. OsO4, Pyr
3. NaIO4, pH7
OH
O
O
O
O
OH
76%
Ley, TL, 1986, 5277
Perkin, 1991, 25
Strategies &Tactics in Organic Synthesis, 1991, 237
PO
69%
MeO
+
SO2Ph
1. BuLi
2. Swern [O]
PO
SO2Ph
MeO
77%
O
S
O
S
OP
S
OP' S
OTBS
OP' OP
O
Al-Hg, ∆
90%
OH
OMe
OTIPS
Schreiber, JACS, 1993, 7906
PO
Smith, III, TL, 1989, 6963
MeO
S
O
OP
S