Jun Shi
Baran Group Meeting
02/06/2008
Vinyl Sulfone in Synthesis
Vinyl Sulfone:
Preparation of Vinyl Sulfone:
SO2R
1. Good Micheal acceptor
2. 2$ partner in cycloaddtion,
ethylene, acetylene and ketene equivalent
3. nicely crystalline, ease of handling
4. ready removal (desulfonlation)
5. inhibitior of cysteine protease
A. Addtion-Elimination
- ionic
- radical
General Process:
pKa=25
SO2R
SO2R
M+R!-
PhSX
Z
Proctect
[O]
SO2R
X
R!
Regenerate
R!
PhSO2X
SPh
X-R"
1. PhSH
2. [O]
[O]
X
SO2R 1,2-Elimination
R"
R"#
Nucleophilic
SO2R
Eli.
R"
SO2R
O
SO2Ph
Eli.
SO2Ph
OH
or Radical
R!
R!
R!
SPh
PhSCl
1. mCPBA, 99%
99%
Stability of Vinyl Sulfone:
SO2Ph
2. DBU, 97%
Cl
Equilibrium between !,% and ",! unsaturated sulfones,
R
SO2R#
R
99:1
Chem. Rev. 1960, 60, 3840
Interconvension between !,% and ",! unsaturated sulfones
2eq DBU
Et
SO2Tol
Et
SO2Ar
SO2R#
1. PhSeSO2Ar, hv
TL, 1988, 29, 1445
JOC, 1981, 46, 3249
2. H2O2
SO2Tol
94%
JACS, 1964, 86, 3840
For comprehensive reviews: T, 1990, 46, 6951; MRR, 2006, 26, 793; Journal of Sulfur Chemistry, 2005, 26, 163; Phorsphorus, sulfur and silicon and related elements, 1994, 95, 1.
1
Jun Shi
Baran Group Meeting
02/06/2008
Vinyl Sulfone in Synthesis
B. Olefination
D. Organometallic Reagents
- Aldol,
- Wittig,
- Peterson,
- HWE
via organozirconium reagents
Ph
E
Tf
SO2R
SO2R
R1
K2CO3, (CHO)X
Ar
R
SO2Ph
1. BuLi, ArCHO
SO2Ph 2. ClP(O)(OEt)
2
NMeBoc
E
Ar
OL, 2005, 7, 4641
N
Me
>80%
81%
C. Manipulation of acetylenic sulfone
O
R2
R1
OTf
TolSO2Na +
O
O
R2
R1
73%
R3
Al(Hg),
R2
R1
TMS
R
NaBH4
H
H
61%
SO2Ar"
H
JOC, 2001, 60, 74
SO2Tol
Pd2(dba)3
Xantphos
CsCO3
Toluene
60°C
80%
JOC, 2004, 69, 5608
oxidize sulfone carbanion
R
SO2Ph
R3
PhSO2Cl, AlCl3
TMS
SO2Ph
!
C
Li
2 eq Cu(OAc)2
SO2Ph
Phenyl trimethlsilyl ethynyl sulfone as vinyl cation sython, JOC, 1982, 47, 4713
TMS
SO2Ar"
E. Miscellaneous
Base,
TMS
SO2Ph
then acid work up
R3
Ar"SO2Na
ArTe
AcOH, H2O, 80°C
Ar
E+
NHMe
SO2Ph
via palladium catalysis
LHMDS
3. t-BuOK
4. HCl
R
ArTeTeAr
quantitative yield
R1
78%
via organotellurides
SO2R
T.L., 1985, 26, 2849
>70%
SO2Ph
Synlett., 1999, 3, 317
Ar"SO2Cl
OH
R1
Ar
Cp2Zr(H)Cl
H
JOC, 2003, 68, 1958
E+
Addtion of sulfonyl-stabilized carbanion to carbonly compound
Tf
Ph
Cp2Zr(H)Cl
SO2Ar
R
Li
60-85%
SO2Ph
1 eq Cu(OTf)2
SO2Ph
C
SO2Ph
R
>70%
R
R
TL, 1984, 25, 3203
SO2Ph
CAN Mediated Reaction
EtAlCl3, benzene
JOC, 1980, 45, 5015
Me
64%
21%
Me
Me CAN, TolSO2Na, NaI
CH3CN, 0°C
SO2Ar
SO2Ar
SO2Ar
83%
Synthesis, 2002, 2259
Me
SO2Tol
2
Jun Shi
Baran Group Meeting
02/06/2008
Vinyl Sulfone in Synthesis
OLi
Radical-Mediated Alkenylation
R1
R2
R3
2. PhO2S
R4
SO2Ph
tBuON=NOtBu
R1 R2
Ph
R2
R4
R3
SO2Ph
tBuON=NOtBu
R
R4
HO
1. Δ, 95%
1. SOCl2
2. KOH
HO
SO2Ph
2. BnBr, 79%
NH2
Cl
SO2Ph
N
Bn
94%
LDA
80%
SO2Ph
R4
TMS
SO2Ph
N
Bn
JOC, 2003, 68, 9389
N
Radical Addition
ACIEE, 2006, 45, 5847
N
Bn
SO2Et
I
Olefin metathesis
Ph
JOC, 1984, 49, 3898
R3
R3
R4
OTBS
O
PhO2S
R1 R2
R1 R2
Ph
SO2Ph
SO2Ph
R3
Ph
OLi
pTolSO2CN
TMS
R4
55%-72%
R
SO2Ph
R1 R2
JOC, 1980, 45, 4789
R1 R2
CatBH
SO2
100%
R4
R3
SO2Ph
BnON
tBuON=NOtBu
R4
SO2Ph
R1
CatBH
NOBn
R3
Ph
R1 R2
1. CatBH
R3
OH
SO2Me
O
O
Ph
Ph
O
O
tBuOOtBu
SO2Ph
Grubbs II
OTBS
Ph
SO2Ph
ACIEE, 1999, 38, 1943
TL, 42, 2001, 6425
O
55%
SO2Tol
Reactions of Vinyl Sulfones
A. Michael Addtion
- Hard nucleophiles: competing reaction between metalation and conjugatea addtion
R1
hv, AIBN
O
O
O
R1
O
R2
57%
steps
SO2Tol
R1
O
SO2Tol
R3
R2
R2
R4
X
80-90%
H+, heat
R1
- Soft nucleophiles: sp3 functionalized nucleophiles, the trans product in excess
sp functionalized anion, the cis product predominated
potassium anions were more reactive
R2
Chem. Lett. , 1988, 813
Y
N
R4
R3
X=NHY
O
R1
R4
R2
R3
X=OH
3
Jun Shi
Baran Group Meeting
02/06/2008
Vinyl Sulfone in Synthesis
D. Metallation
B. Cycloaddition
- [2+2]
- [2+3]
- [2+4]
Form the vinyl transition metal complex
Et
TMS
R1
Pd(PPh3)4, dppe
SO2Ph
Cp
H
R2
70%
PhO2S
OAc
Cp
R3
R1
THF, RT
SO2Ph
H
Zr
R3
R2
R1
E+
ZrCp2SO2Ph
R2
ACIEE, 2002, 41, 1410
R3
E
75-90%
JACS, 1982, 104, 3733
E. Miscellaneous
Ph
C. Asymmetric Reactions
- Asymmetric Dihydroxylation, T, 2003, 59, 7973
Ph
Ph
Ph
O
Br
SO2Tol
nBuLi
-78°C to RT
81%
TolO2S
O
JACS, 2004, 126, 1624,
OSiMe3
O
+
R1
R2
SiMe3
N
N
LHMDS
N
S
O2
R2
R1
N
SiMe3
Ph
R1
R2
OL, 2003, 5, 2789
- Catalytic Enantioselective Reduction, ACIEE, 2007, 46, 5955
Desulfonlation of Vinyl sulfone
A. Reductive Desulfonylation
General process: dissolving metal or metal amalgams, e.g. Al(Hg)
SO2Ph
2 mol% Ni(acac)2
R
2 eq nBuMgCl
R′
SO2Ph
R
Me
T., 1987, 43,859
R
R′
Na2S2O4, DMF
H
H2O, NaHCO3
R
T.L., 1982, 23, 3265
Me
4
Jun Shi
Baran Group Meeting
02/06/2008
Vinyl Sulfone in Synthesis
B. Tin-based Methods
S
SO2Ph
R
xylene
SnBu3
R
R!
R!
R
reflux
2-lithiodithiane
R!
JCS, CC, 1983, 619
MeO
OMe
SO2Ph
1. Bu3SnLi
TMS
2. TMSCl
MeO
83%
nBu3B, THF,
Reflux
MeO
Bu
70%
1% Fe(acac)3
60%
(±)-Magnofaragesin
T.L., 1982, 23, 2469
Total Synthesis of dl-Morphine, JOC, 1988, 53, 4694
Ph
OTBS
Applications in Total Synthesis
OMe
Br
nBu3Sn
1. nBu3P
DEAD, 85%
OH
H
2.2 nBuLi
-78°C
SO2Ph
O
PhICN(OTf)
OMe
OMe
MeO
DCM, RT
OMe
59%
OH
45%
OMe
O
MeO
OMe
O
9 Steps
O
O
PhSO2Na
MeO
OMe
Br
PhO2S
SO2Ph
IPh(OTf)
MeO
Br
2. HF, 95%
Br
Total Synthesis of (±)-Magnofaragesin, OL, 2006, 8, 3659
MeO
MeO
OMe
OH
MeO
Ar
Ph
1.8eq PhMgBr
tBuO2S
O
OMe
Bull. Soc. Chem. Jpn., 1974, 47, 503
Ph
OAc
1. Mg, HgCl2
EtOH MeO
2. TBAF
O
C. Alkylative Desulphonlation
70%
SO2Ph
TBSO
OMe
HO
R
Chem. Lett., 1983, 1457
SO2Me
OMe
1. nBuLi, -100°C
veratraldehyde
2. Ac2O, Py
TMS
R
O
MeO
OMe
SnBu3
R
MeO
2. NaBH4
3. TBSOTf
lutidine
76%
MeO
89%
SO2Ph
TBSO
1. MeI, CaCO3
MeCN-H2O
O
THF, -100°C
Addition functionality into the unsaturated product
SO2Ph
SO2Ph
S
SO2Ph
Bu3SnLi
O OH
OH
MeN
dl-Morphine
SO2Ph
5
Jun Shi
Vinyl Sulfone in Synthesis
Baran Group Meeting
02/06/2008
Total Synthesis of dl-Cephalotaxine, JACS, 1990, 112, 9601
1.
O
O
O
O2S
O
O
then BrCH2CH=CH2
HMPA
84%
Li
O
O
O
O
O
O
O
SO2Ph
O
O
O
tBuLi,
-78°C to RT
O
77%
O
O
N
O
O
O
1. p-TsOH
2. NH2OH, nBuNIO4
O
71%
O
The synthesis of natural product is analogous to building a pyramid. One needs to forge
a strong base before being in a position to complete the structure. The analog extends to
further to the merit of the excercise- those pyramids which have been carefully crafted will
provide further benefit to all who follow.
Phillips. L. Fuchs
O
O
O
O
O
O
O
N
O
O
O
O
O
O
O
O
N
O
O
N
O
O
9 steps
40%
O
N
O
HO
O
O
O
O
MeO
dl-Cephalotaxine
6