http://www.courses.fas.harvard.edu/~chem206/
N
S
S
O
O H
RS RACHO
MeO
MeO N
O
O
S
O
Et
CO2Me
RS
RA
RS RA
N
CO2Me
O
O
MeO
MeO
NH
S
O
Chem 206D. A. Evans
Matthew D. Shair Wednesday, November 20, 2002
Reading Assignment for this Week:
Ambiphilic Functional Groups–2: Sulfur-Based Activating Groups
Chemistry 206
Advanced Organic Chemistry
Lecture Number 27
Ambiphilic Functional Groups–2
Sulfur-Based Activating Groups
a73 Sulfur-Ylides
a73 Sulfur-Stabilized Carbanions: Structure
a73 Sulfone-Based Transformations
a73 Pummerer Rearrangement
Relevant Background Reading
General:
General:
Julia:
Electrophilic Properties:
SO2 Extrusion:
Ramberg-B?cklund Rxn:
Triflones:
Sulfoximides:
Simpkins, N.S. Sulphones in Organic Synthesis,
Pergamon Press, New York, 1993.
Magnus, P.D. Tetrahedron 1977, 33, 2019.
Kocienski, P.J. Chem. Ind.(London) 1981, 548.
Trost, B.M. Bull.Chem. Soc. Jpn. 1988, 61, 107.
Vogtle, F.; Rossa, L. ACIEE 1979, 18, 515.
Paquette, L.A. Org. Reactions 1977, 25, 1.
Hendrickson, J.B. Org. Prep. Proc. Int. 1977, 175.
Johnson, C.R. Tetrahedron 1984, 40, 1225
Cume Question, 1998: The stereoselective construction of trans olefins throughcarbanion-mediated condensation processes has still not been rendered general. One
transformation that may be used in certain circumstances is the "one-step" Juliatransformation illustrated below. Provide a mechanism for this transformation.
1
LiN(iPr)2
THF-78 to 25 °C +
+
+ SO2
"Chemical Chameleons: Organosulfones as Synthetic Building Blocks"B. M. Trost, Bull. chem. Soc. Japan, 1988, 61, 107-124 (handout) Ac2O/HOAc
70%
The cruel mechanistic problems that you should be prepared for in Chem 206
Padwa et al. JOC 1996, 61, 4888
Carey & Sundberg: Part A; Chapter 7Carbanions & Other Nucleophilic Carbon Species
Carey & Sundberg: Part B; Chapter 2Reactions of Carbon Nucleophiles with Carbonyl Compounds
S
CH3
CH3
CH3
S CH3
R
R
S
R
R
CH3S
R
R
O N
N
N
N
NH2
OHOH
SHO
Me
NH2
O
S CH2
R
R
S CH3
R
R
S
R
R+
+
+
+ +
+
Me I
S CH3CH3
SCH3 CH3
O
S
O
CH3CH3
O
Na H
O
NH2
S
Me
HO
OH OH
NH2
N
NN
N
O
O
P
RO
O– O
S
O
R CH3
O
S CH3
L
L
L
R2S C(+)
CH4
NH3
HOH
SN2
S
O
O –
R
L S:
L
L
Me Nu
Me Nu
H H
Me Nu
D. A. Evans Chem 206
Relevant Background Reading
pKa (~56)
pKa 31
pKa (~41)
Sulfide
Sulfoxide
Sulfone
Sulfonium Salt
pKa (DMSO)
~ 18
~ 31
(45)
~35
Sulfonium Salt: pKa ~ 18
Reactions of Sulfonium Ylids
a73 Synthesis: SN2a71a71 + I –
S-Adenosylmethionine
SN2
+ a71 a71a73 Deprotonation: –
pKa ~ 38pKa ~ 18
Sulfur-Based Functional Groups-1
Bordwell, F. G.; Zhang, X.-M. Acc. Chem. Res. 1993, 26, 510-17. Good LG
Excellent LG
a71a71
a71a71
SN2 +Nu:+
+ Nu: +SN2
+(+) Nu:+
a73 Leaving Group Potential:
Acidities of Sulfur-based Functional Groups
General:
General:
Julia:
Electrophilic Properties:
SO2 Extrusion:
Ramberg-B?cklund Rxn:
Triflones:
Sulfoximides:
Simpkins, N.S. Sulphones in Organic Synthesis,
Pergamon Press, New York, 1993.
Magnus, P.D. Tetrahedron 1977, 33, 2019.
Kocienski, P.J. Chem. Ind.(London) 1981, 548.
Trost, B.M. Bull.Chem. Soc. Jpn. 1988, 61, 107.
Vogtle, F.; Rossa, L. ACIEE 1979, 18, 515.
Paquette, L.A. Org. Reactions 1977, 25, 1.
Hendrickson, J.B. Org. Prep. Proc. Int. 1977, 175.
Johnson, C.R. Tetrahedron 1984, 40, 1225
Ar S
O
CH3
Ar S
O
O
CH3
S
O
O
CH2–Li–[TMEDA]
Ar S
O
CH2–Li
Ar S
O
O
CH2–Li
Li Li
Ar S
O
CH2
El
Ar S
O
O
CH2
El
S
O
C–Li
Me
Li
Li
Li
Chem 206
Sulfone- & Sulfoxide Based Carbanions: Structure
X-ray Structures of Metallated Sulfones & Sulfoxides
LDA El(+)
a73 Sulfone- and sulfoxide-stabilized carbanions are extremely useful carbon
nucleophiles in organic synthesis.
However, until recently little information was available on the solid state structures of these species:
LDA El(+)
"The Structure of Lithium Coumpounds of Sulfones, Sulfoximides, Sulfoxides,
Thioethers, 1,3 Dithianes, Nitriles, Nitro Compounds, and Hydrazones."
Boche, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 277.
Here are several examples taken from the Boche review:
Gais, etal. Angew. Chem. Int. Ed. 1985, 24, 859
Boche, etal. Angew. Chem. Int. Ed. 1986, 25, 1101
+ TMEDA
a73 The Li counterions are not associated with the charged carbon.
a73 The carbanions are largely trigonal.
D. A. Evans, K. Scheidt
S
O
C–Li
Me
Li
Li
Li
S
O
O
CH–Li
Li
Li
D. A. Evans, K. Scheidt Chem 206X-ray Structures of Phenylsulfinyl Carbanions
Boche, etal. Angew. Chem. Int. Ed. 1986, 25, 1101 Boche, etal. Angew. Chem. Int. Ed. 1985, 24, 573
+ TMEDA+ TMEDA
CH2
O –
S
Me
Me
S
Me
Me
CH2
O –
C
H
H
S
Me
Me
C
H
H
S
Me
Me
S
Me
Me
O –SMe
Me
S
Me
Me O –
S CH2
Me
Me
S CH2
R
R
S CH3
R
R
+
+
+
+ –
+
++
+
+
O
O
R2S C
CH2
O
R2S C
Me Br
Me
Me
BrMe Ph:S
O
O –
H2O2
S PhMe
Me
O O
Me
SMe Ph
O
CH2 R2S C
O
O
R2S C
R2S C
OLi
S PhMe
Me
O O
S
OO
Me
Me Ph
Li
S
OO
Me
Me Ph
S PhMe
Me
O O
R2SO2 C
BuLi
H2O2
HIO4
R2SO2 C
S PhMe
Me
O
O SMe
Me O
Ph
D. A. Evans Chem 206Sulfur-Based Functional Groups-2
–
(+)
(–)
Reactivity Pattern: Nonalternate
(± )a73 Reactions with ketones:
"Twenty-five Years of Dimethylsulfoxonium Methylide (Corey's Reagent).",
Gololobov, Y. G.; Lysenko, V. P.; Boldeskul, I. E. Tetrahedron 1987, 43, 2609.
Nonalternate reactivity pattern revealed in consecutive reactions (+)
(+)
(–)
Reactions of Sulfonium Ylids: Conjugate Addition
a71 a71 –
Sulfinate esternot observed(Sulfinate anion)
PhS: –
Synthesis:
Reactions of Sulfones
Good review article: Magnus, Tetrahedron 1977, 33, 2019-2045.
Will function as LG ??
1,2- vs 1,4-addition ????
(+)
poorer leaving group than:
a71 a71 –more nucleophilic
than:
pKa ~ 25
Reactions of Sulfones
(+)
(+)
(–)
+
R2SO2 C
Li
S PhMe
Me
O O
S O
O
Me
Me Ph
Li
Li
SO2PhMe
Me
MeMe
R2SO2 C
Me
CO2R
Br
Me
OEtMe
O
O
R2SO2 C
Me Me
Me
Me SO2Ph
CO2R
Me
H
Me
Me
OLi
OEt
Me
Me
SO2Ph
OMe
Me
SO2Ph
Me
Me
–O
CO2EtMe
Me H
H
Me Me
R SO2Ph
MeO
TBDPSO
PhO2S
Me
OH
Me
MEMO
MEMO
Me
SO2Ph
Me
BuLi
Me
X
Me
MEMO
OTBS
Me Me
H
O
S
S
Me
PMBO
SO2PhR
El
R2SO2 C
Me
CO2H
Me
Me
MeMe
R2SO2 C
TBDPSO
MeO
O
S
S
Me
PMBO
H
MeOH
Na(Hg)
TBDPSO
MeO
O
S
S
SO2Ph
Me
PMBO
TBDPSO
MeO
HO
S
S
SO2Ph
Me
PMBO
Me
OTBS
MeI
El
R H
D. A. Evans, P. Carter Chem 206Sulfur-Based Functional Groups-3
Industrial synthesis developed by M. Julia
trans chrysanthemic acid
However!! Not observed
–PhSO2 –
1,2-addition
(+)
(+)
Alkoxide not sufficiently nucleophilic to
displace PhSO2– anion.
(–)
(–) (+)
El(+)
The Sulfone group may also be readily removed reductively:
Synthesis of Vitamin A: Julia & Co-workers, Bull. Soc. Chim. Fr. 1985, 130
(–) KOH/MeOH
(+)
(+)
1. MsCl, TEA2. PhSLi, THF, RT
3. mCPBA
Fragment Coupling with Sulfonyl Carbanions
X= SO2Ph
X = H
Li wire, Na2HPO4
THF/HMPA/tBuOH 50% yield
2 eq. nBuLiTHF/HMPA;
then add iodide
65 - 85% yield
Heathcock, C.H.; et al.
J.Org.Chem. 1988, 53, 1922.
TFAA, DMSO; NEt3
CH2Cl2, -78 oC
Smith, A.B. III; et al.Tet.Lett. 1989, 30, 6963.
77% yield
Al-Hg, aq. THFReflux
90% yield
Me MeHO
OH
O
MeMe
OHMeO
2C
CO2Me
OH
OHMe
O
O
O
OO
On-Pr
H
BuLi
OPhO2S OPhO2S OPhO2S O O
I
MeMe
OSO
2Ph
O
SO2Ph
El
–SO2PhR
2SO2 C
ROH
OElOEl
OR
O
O
O
O
O
COOH
OO
Me
H
OHH
H
Me
OH
Me
H
Me
H
OHMe
OH H
R2SO2 C
O
O
Me
HO H
Me
n-BuLi, DMPU
OPhO2S
OBn
H OSO2Ph RH O O
I
MeMe
O OTf
OTBDMS
C Ring HH O
SO2Ph
N–iPh
O
H
MeMe OPMB
OTBDMS
Li
O
NHPh
O
H
Me
Me
OPMB
OTBDMSO
OTBDMS
C Ring HH OH
O
O
Me
MeH
N
H O H
N O
HOOC
HO
O
OBnO
Me
HO
MeH
H
C
D. A. Evans, T. Dunn Chem 206Sulfur-Based Functional Groups-4
Functionalization of cyclic Ethers
–
El(+)
Lewis acid
+
(–)
(+)
Ley et al, Synlett, 1992, 395; Ley et. al, Tetrahedron, 1992, 48, 7899
Total Synthesis of Routiennocin (CP-61,405)
Routiennocin
68% yield
1.) Addition of iodide,
-78o C → RT
2.) H+, H2O
+–
Total synthesis of Okadaic Acid
n-BuLi, DMPU
THF, -78o C
Ley et al, J. Chem. Soc., Perkin Trans. 1, 1998, 3907.
90% yield
1.) Addition of
iodide,
-78o C to RT
2.) CSA, MeOH
+
Evans et al, JACS. 1999, 121, 7540-7552.
87% yield
Bryostatin 2
Total synthesis of Bryostatin 2
THF, -78oC
OPMB
OTES
H
H
H
O OTESMeMeOO
HO
H
Me
DEIPSO H O
O
H
Me
H
H OH
MeH
TBSO
Me H
O
OTES
Me
O
OMeTESO
Si
t-Bu
Me
t-Bu
21 3
1
SO2PhR BuLi
SO2Ph
R R'
OH
OAc
R'R
SO2Ph
Ac2O
Na(Hg)
R2
R1
SO2RX X
R1
R2
SO2Ar
OAc
OAc
SO2Ar OAc
MeOH
R2
R1
R R'
R1
R2
R'
R
PhO2S Li
OTBDPS
Me Me
Me
Me
O
OMe
Me
CHO
H Me H MeOTBS
MeOO
H Me
OCH2OCH2CCl3
O
H
Me
H
OH
HDEIPSO
Me
CHOMe
TBSO
OPMB
TESO Me
Si
O
O
OTES H
O MeOTES
HMeO
H
H
O
t-Bu
t-Bu
Me
PhSO2
Me
TESO
O
HO
Me
Me
O
OMe
Me H Me H MeOTBS
MeOO
OTBDPS
Me Me
D. A. Evans, P. Carter Chem 206Sulfur-Based Functional Groups-5: Julia Olefin Synthesis
Problem: Work out the mechanism of reduction step.
Good sulfone review: Trost, Bull Chem. Soc. Japan, 1988, 61, 107-124.
Elimination is stepwise; therefore, not stereospecific
major
R'CHO
Julia Trans Olefin Synthesis: Julia Olefination - Ionomycin 1. add RCHO, -78oC;
add Ac2O, -78oC to R.T.
2. Na/Hg, EtOAc/MeOH, -30oC
70% yield86:14 olefin mixture
Evans, et al.
JACS 1990, 112, 5290.
Review: Kocienski etal. Phosphorus & Sulfur 1985, 24, 97-127
Kochenski, J. Chem. Soc Perkin Trans I, 1978, 834
Na(Hg)
? or –
a54
++ e-?+ e-
The reduction step is not stereosecific Cytovaricin Synthesis: JACS 1990, 112, 7001
Free acid must be used to prevent loss of C
4 OH in 2nd step
C21 OH deprotection
21
C=C construction
Reactions accomplished:
overall yield, 66%
Ac2O, pyr
6% Na(Hg)-40 °C
2 LiNEt2, THF
+
C39–C46 Synthon
Me
Br
MeO
O
HH O
O N
O
Me
HH
H
HO
H
CH2
Me
O
MeO
OHH N
O
H
H
O
O
H
HO
H
Me
46
38
33
19
1
4
9
13
Br
OMe
S
S
N
OO
Br
OMe
CH3
I
NaHMDS
CH3
I
O
H
Br
OMe
CH3
I
O–Na
S
O O
S
N
NaHMDSRCHO
SO2
S
NNaO
Br
OMe
CH3
I
Br
OMe
CH3
I
A
C
O2SN
N
N N
Ph
R
CH3
I
O–Na
S
O
O
SN
R
C
O2S
Ph
NN
N N
R
C
O2S
C4H9
NN
N N
Ph
H R'
O Me
OR
KHMDS
KHMDS
OHC
C9H19OHC
KHMDS
–60 °C→rt
–60 °C→rt
–60 °C→rt
CH3
I
O
S
O
O
S
N
R
C4H9
C9H19Ph
R'
Me
OR
R
S
NNaO
SO2
CH3
I
O
S
O
O
S
N
R
R
CH3
I
D. A. Evans, P. Carter Chem 206Sulfur-Based Functional Groups-5: Julia Olefin Synthesis-2
Phorboxazole B Synthesis
THF, -78?C - rt
75%
E/Z = >95:5
Evans, Smith, Fitch, Cee JACS 2000, 122, 10033-10046.
disconnection
Julia Construction
Mechanism??
The Mechanism:
Olefin stereochemistry could be established in the formation of A.
Recent Modifications of the Julia Process:
Kocienski, SynLett 2000, 3, 365-366.
E/Z: 99:1 (75%)
R = Ph: E/Z: 29:71 (70%)
R = tBu: E/Z: <1:99 (95%)
E/Z: >10:1 (64%)
Metternich, JOC 1999, 54, 9632
(RS)2 C(–)(RS)2 C(+)
C–G(–)
C–E(+)
C–G(–)
C–E(+)
O C
R
El
El
R
S
S
C
El
R
O2N
O C
R
El
+ N
– O
– O
R
R
T2
T2
+ N
R
R
O
– O
H
C: –
O
R
+ N
H
R
– O
– O
S
S
R
Li
C:
O
R1
Li
R
S
S
C:
O
R1
R–Li
R1 C
O
MgCl
R1 C
O
C
O
R1
S
S
R
H
T2
T1
+H2O
–H2O
C Cl
O
R1
RCHO
R1 C
O
R2
SH
SH
Chem 206Sulfur-Based Functional Groups-5
Operational equivalents to the carbonyl anion are useful in synthesis
Carbonyl anions are not normally accessible via aldehyde deprotonation
carbonyl anion
not feasible !! Why??Mg0
+ R2:
R2:+
Consider the two possible polar disconnections of the C–R2 bond of the ketone
shown below:
Carbonyl Anions: A useful Reversed Polarity Equivalent
pKa ~ 39
Construction Step
Reactivity Patterns:
Equivalent Synthons
El
H3O +
El
1,3-Dithianes as Carbonyl Anion Equivalents
The overall set of reactions which establishes the equivalency of the hypothetical carbonyl anion 1 and its equivalent synthon 2 is shown below:
Dithianes anions highly nucleophilic (indiscriminate): Nitonate anions higly discriminating
pKa 18
Nitronate Anions are also useful Carbonyl Anions
Equivalent Synthons
Construction Step
HO –
nitronate anion highly stablized(–)
(±)
Nef Reaction
1
2
D. A. Evans, N. Finney
+
+
El+
El+
Ar S R
O
Ar S R
O
TFAA
H+
Ar S R
OH
H
Ar S R
OTFA
H
–H2O
–TFAOH
Ar S R
H
Ar S R
H
+TFAO–
–ArSH
+H2O O R
H
Ar S R
OTFA
N
S
O
O
RHN
CO2Bn
S
Ar O
O
N
N
O
S
H Et
R
Ph
O
TsOH
?
TFAA
R N R
O
R
H+ –H2O O R
H
+H2O
–R2NHR N R
OH
R H
R
N RR
H
MeO
MeO N
O
O
S
O
Et
CO2Me
S
Ar O
N
N
O
S
H Et
R
Ph
N
S
O
RHN
CO2Bn
OAc
N
N
O
H Et
R
PhS
N
CO2Me
O
O
MeO
MeO
S
Ar O
Chem 206The Pummerer Rearrangement
Basic Transformation:
D. A. Evans
De Lucchi, Miotti, et al. (1991). “The Pummerer reaction of sulfinyl compounds.” Organic Reactions 1991, 40: 157.
Grierson, and Husson (1991). Polonovski- and Pummerer-type Reactions and the Nef Reaction. Comprehensive Organic Synthesis. Trost and Fleming. Oxford, Pergamon
Press. 6: 909.
Padwa, A., D. E. Gunn, et al. “Application of the Pummerer reaction toward the synthesis of complex carbocycles and heterocycles.” Synthesis 1997 1353-1377.
Carreno, “Applications of sulfoxides to asymmetric synthesis of biologically active compounds.” Chem. Reviews 1995 95, 1717-1760.
The Pummerer Rearrangement facilitates the transformation of a sulfinyl → aldehyde
transformation. The rearrangement may be initiated by either a Bronsted acid or an
anhydride such as trifluoroacetic anhydride (TFAA). With the latter reagent, the
transformation occurs at room temperature.
Leading References
The Related Polonovski Reaction:
Regioselectivfity: Depends on the relative kinetic acidy of the protons
Transformations Mediated by the Pummer Rearrangement
86%
81%
P. Magnus et al. Accts Chem Res. 1984, 17, 35
Ac2O/HOAc
>80%
Ac2O/HOAc
70%
The cruel mechanistic problems that you should be prepared for in Chem 206
Padwa et al. JOC 1996, 61, 4888
Kita, Y. and N. Shibata (1996). “Asymmetric pummerer-type reactions induced by O-silylated ketene acetals.” Synlett(4): 289-296.
MeO
MeO N
O
O
S
O
Et
CO2Me
N
CO2Me
O
O
MeO
MeO NMe
H N
S Et
OO
Me
S EtO
O
N
O CO2MeMeO
OMe
Ac
H
S Et
O
N
O CO2MeMeO
OMe
N
O CO2MeMeO
OMe
O
SEtH
N
O CO2MeMeO
OMe
O
SEt
O SEt
COOCH3N
OMe
OMe
O
N
O
COOCH3
O
MeO
MeO
NMe
H N
S Et
OO
Me
H
N
N
Et
O
SMe
H
HMe
OAc
OAc
NMe
N
Et
O
SMe
H
N
H N
S Et
OMe
Me
NMe
H N
S Et
OMe
Chem 206The Pummerer RearrangementD. A. Evans
Ac2O/HOAc
70%
Padwa et al. JOC 1996, 61, 4888
Endo [4+2]
Pummerer
Endo [4+2]
Product
Pummerer
Mechanism??
TsOH, THF
78 %
Exam 3, 2000: Question 5 (11 points). An interesting rearrangement which also
results in the construction of this same ring system (Question 4) has been reported by Langlois & coworkers ( J.Org. Chem. 1985 , 50 , 961). This rearrangement is illustrated
below. Provide a mechanism for this transformation.
Pummerer
Pummerer
Product