Baran Group Meeting
Dieter Seebach
Biographical Sketch:
-Born in 1937 in Karlsruhe, Germany. Married to
Ingeborg Seebach, with three children.
-B.S. University of Karlsruhe (1961)
-Ph.D. University of Karlsruhe with R. Criegee (1964)
-Postdoctoral fellow and lecturer Harvard University
with E.J. Corey (1964-1965)
-Habilitation at University of Karlsruhe (1966-1969)
-Full professor at Justus Leibig-Universität Giessen
(1971-1977)
-Full professor at Eidgenössische Technische
Hochschule (1977-2003)
- Emeritierte professoren (2003-present)
Dane Holte
Graduate Work: Rudolf Criegee
OOH
Cl
Cl
OH
O
O
H2O2
O
Cl
OOH
Cl
Chem. Ber. 1963, 96, 2704.
O
+
O
R
R
hv
O
R
OTs
R
OTs
R
1. LAH
O
2. p-TsCl
R
http://www.loc.ethz.ch/people/emerit/Seebach
R
O
O
R
Chem. Ber. 1964, 97, 2942.
Author of over 800 papers and mentor of 150 Ph.D. students.
H index = 98, ranked 33rd among living chemists.
Areas of Research:
Umpolung chemistry
Pool of chiral building blocks
Stereoselective transformations
Self-regeneration of stereocenters
Natural product total synthesis
Structure and mechanism of organolithium reagents
Use of organotitanium reagents
TADDOL as a chiral auxiliary
Unnatural amino acids
Peptide chemistry
OOH
OH
Cl H2O2
Postdoctoral Work and Early Career: Umpolung Chemistry
Acyl Anions: Key Precident
O
Ar
O
R–X
ArLi + Ni(CO)4
Ni(CO)3
Li
Ar
R
R"
Be0
O
R
X
O
O
R
R'
BeX
O
OH
R
R'
R"
"After a period of vivid development of new synthetic methods in the past two
O
O
O
O
decades, organic chemists will have to turn increased attention to the
n-BuLi
R'CHO
OH
question of how to achieve selectivities of a degree which are usually
R2N
Hg NR2
Li
R2N
R2N
observed in biochemical processes." D. Seebach (Helv. Chim. Acta 1980,
R'
63, 2451).
Angew. Chem. Int. Ed. 1969, 8, 639.
"It is so sad to find respected colleagues referring to organic chemistry, and
specifically organic synthesis, as a "mature science." There is no way this
SEt
SEt
EtS SEt
LiNH2
R–X
remark can be regarded as anything but an expression of resignation, of selfpitying nostalgia – indeed as evidence of a "drop out" mentality." D. Seebach Me
SEt liq. NH3 Me
SEt
Me
R
(Angew. Chem. Int. Ed. 1990, 29, 1320).
Rec. Trav. Chim. Pays-Bas, 1959, 78, 663.
Substitution of HMPT by the Cyclic Urea DMPU as a Cosolvent for Highly
Reactive Nucleophiles and Bases, Helv. Chim. Acta 1982, 65, 385. (257
citations)
Dieter Seebach
Baran Group Meeting
α-Lithitated Nitrogen
Carbanions of 1,3-Dithianes
Me
n-BuLi
S
S
S
THF, -30 ºC
S
S
TMSCl
base
S
S
Br
Br
Br
S
E+
3
(1 eq. Nu) S
mechanism?
S
Br
n
S
(2
S
D2O
CuII
)
Nu
.
eq S
S
S
S
Angew. Chem. Int. Ed. 1965, 4, 1075.
Angew. Chem. Int. Ed. 1965, 4, 1077.
J. Org. Chem. 1966, 31, 4303.
S
94.5% yield
99.9 ± 0.1 %
S
S
deuterium
incorporation
D
J. Am. Chem. Soc. 1967, 89, 434.
J. Org. Chem. 1968, 33, 300.
n-BuLi
THF, -78 ºC
PhS
(PhS)3CLi
N
THF, -78 ºC LiH2C
N
N
Me
E+
O
N
E
N
O
Angew. Chem. Int. Ed. 1972, 11, 301.
CPh3
N
t-BuLi
Li
Ph2CO
CPh3
N
< 0 ºC
O
N
O
t-BuLi
> 0 ºC
CPh3
Ph O
OH
Ph
52% yield
N
Helv. Chem. Acta 1981, 64, 1337.
Ph
Ph
O
"Any 'trick' by which the polarity pattern [...] is contravened will be termed
umpolung of the normal reactivity in the broadest sense." -D. Seebach
C
SPh
+ PhSLi
Random methods!
CB
MeO
Me
SPh
SPh
Me
LDA
OMe
MeI
PhS
O
Umpolung review, see also: Angew. Chem. Int. Ed. 1979, 18, 239.
Metalated Orthothioformates
(PhS)3CH
Me
N
TMS
E = alkyl halides, ketones,
epoxides, imines, CO2,
double alkylation possible
S
n
Dane Holte
MeO
MeO
SPh
PhS
SPh
SPh
PhS
SPh
Angew. Chem. Int. Ed. 1967, 6, 442.
Angew. Chem. Int. Ed. 1967, 6, 443.
Desulfurization Methods: acidic hydrolysis, transition metal induced hydrolysis
(HgII, CuII, TiIV), oxidative or alkylative hydrolysis (I2, chloramine T, Tl(TFA)3, omesitylenesulfonylhydroxylamine, CAN, SO2Cl2 / SiO2, MeI, Me3OBF4,
FSO3Me), reductive methods (Ca0 / NH3, t-BuOH / hv, Raney Ni, LAH / CuCl2
or ZnCl2 or TiCl4, H2NNH2)
Synthesis, 1977, 357.
[O]
O
CA
O
?
CA
1. CH2(SMe)2,
n-BuLi
CB
SMe HO
2. p-TsCl
3. n-BuLi
SMe
O
H2O
O
OH
Angew. Chem. Int. Ed. 1972, 1, 49.
Br AgClO4
Br
Br
O
TiCl4
1. t-BuLi (2 eq.)
2. DMS
SMe
Helv. Chim. Acta 1974, 107, 847.
Dieter Seebach
Baran Group Meeting
Random methods!
NO2
E+
n-BuLi (2 eq.)
NO2
NR2
dried Alcaligens
eutrophus cells
ROH, ∆
(R)
OR
O
2 eq.
+
H
H
O
t-Bu
Nu1
NO2
Nu
R2 R3
R4
mechanism? R1
R2
Nu2
O
HO
O
OH
O
O
pTsOH
O
LDA
O
OLi
O
THF, -78 ºC
Ph
Ph
RX
up to 50g prepared, a
"multiple coupling reagent"
-preliminary communication, established the
concept of self-regeneration of stereocenters and
use of pivaldehyde
-limited substrate scope
NO2
Nu1
J. Am. Chem. Soc.
1990, 112, 7625.
Self-Regeneration of Stereocenters and Chiral Building Blocks
t-Bu
O
NO2
R3
OCOR
Ph
O
H
NO2
R4
O
NO2
NO2Na
Ph
52% yield
75-90% yield, up to 70g
Since (S)-3-hydroxybutanoates are readily available through yeast reduction
of acetoacetates, this opened up both enantiomers for synthetic use.
Helv. Chim. Acta 1982, 65, 495.
H
THF, HMPT
NO2
+
R1
O
NO2 OH
PhCHO
Chem. Ber. 1986, 119, 575.
"Alcaligens eutrophus is a bacterial species that naturally produces
polyhydroxyalkanoates."
http://en.wikipedia.org/wiki/Alcaligens_eutrophus
OH
NO2Li2
t-BuLi
E
Ti(OEt)4
or H2SO4
n-BuLi
NO2
+
NO2
Angew. Chem. Int. Ed. 1978, 17, 458.
"super-enamine" or, how to make an enamine from a nitro
E
NO2Li2
Dane Holte
Nu2
O
O
O
O
Ph R
Helv. Chim. Acta. 1981, 64, 2704.
No diadduct formation, why? Possibly, the nucleophile reacts simultaneously
with the LUMO of the nitroolefin and σ* of C–OPiv. They note this claim is
lacking in definite evidence, but is compatable with reaction rates and lack of
observed intermediates.
Nu
Formally:
O
NO2
N
O
σ*C–O
OPiv
Helv. Chim. Acta 1984, 67, 261.
N
H
CO2H
H
O
H
H+
O
N
O
E
1. LDA
2.
E+
O
N
O
HBr
E
N
H
CO2H
Greatly expanded electrophile substrate scope, and "any new type of
transformation of amino acids without extensive loss of enantiomeric purity is
bound to be synthetically useful." -D. Seebach
J. Am. Chem. Soc. 1983, 105, 5390.
Pop Quiz! Which Baran Lab synthesis
Tetrahedron, 1984, 40, 1313.
features the use of this reaction sequence?
Helv. Chim. Acta 1987, 70, 237.
Helv. Chim. Acta 1987, 70, 1149.
Dieter Seebach
Baran Group Meeting
But why do we get this stereoselectivity in the Michael addition or
hydrogenation? Not steric, based on these observations:
SRS and Chiral Building Blocks (Cont.)
Me
O
O
1. MeNH2
Br
H2N
Br 2. NH3
O
N
H
Me
*
Δ
E
O O
OH
Me
Bu
O
N
N
H
O
N
H
O
LDA
MeI
O
OLi
PhSeCl
H2O2, py.
O
O
85% yield
95% ds
O
+
O THF, -75 ºC
BuCuLi
O
O
O
O
O
O
94% yield
>95% ds
from A
O
82% yield
"chiral acetoacetic acid"
O
SePh
83% yield from A
1. LDA, DMPU
2. MeI
55% yield O
O
O
BuCuLi
O
O
Bu
O
O
"high ds"
"chiral glycine"
H2, PtO2
O
CO2H
Me
N
2. E+
O
H+
O
O
O
Ph
Tetrahedron, 1988, 44, 5277.
OH
N
H
resolution
HCl (0.75M)
DOWEX 50WX8 1. LDA
CO2H
1. even methyl group leads to "high ds"
OH
allows for the preparation of isotopically
labeled, (R)-, and unnatural amino acids
H2N
O
N
then, H+
Dane Holte
Helv. Chim. Acta. 1986, 69, 1147.
2. photochemical reactions occur
with low / opposite selectivty
3. directing group is sterically remote
in crystal structures of compounds
and related structures
H
Re
t-Bu
O
O
O Si
So what is it? Nucleophiles should attack the less electron-rich face of the πsystem. This predicts the selectivity, if the oxygens are between sp2 and sp3
hybridization (crystal structures) then the Re lone pair is larger than the Si lone
pair and/or the sp2 electrons are angled downward "away" from the out-of
plane disposition of the acetal carbon. Probably not ground-state
pyramidalization, although it correlates. J. Am. Chem. Soc. 1988, 110, 4763.
see also: Angew. Chem. Int. Ed. 1996, 35, 2708.
α,α,α',α'-tetraaryl-2,2-disubstituted 1,3-dioxolane-4,5dimethanol (TADDOL) Chemistry
The number of publications each year with references to TADDOLs can be
determined from the bar graph below (based on CAS search conducted in
February, 2000).
Dieter Seebach
Baran Group Meeting
Dane Holte
General TADDOL Synthesis: As of 2000, 297 TADDOLs have been prepared.
O
HO
HO
CO2Me
R1
H
R1
R2
CO2Me H2O, org.
solvent, Δ
R2
O
O
H
H
CO2Me
RMgBr (6 eq.)
CO2Me
R R
R1
O
OH
R2
O
OH
H
PhMe, 0 ºC → rt
MeO
O
R R
Angew. Chem. Int. Ed. 2001, 40, 92.
TADDOL uses
MeO
CO2Et
HO
N
HO
CO2Et
NH HO
N
LAH
HO
N
ZnEt2 (1 eq.),
A (1 eq.),
HO
N
Et2O, -75 ºC → rt
O
O
Pr
LAH
Ph
OH
Pr
Ph
no ee reported, but
optically active!
Chem. Ber. 1980, 113, 1691.
Ph Ph
t-Bu
H
O
OH
O
OH
Ph Ph
3. PhCHO
4. KF/H2O
OH
Ph
Me
yields typically 75–90 %
ee ranges from 7–91 %
3:97 er, 86 %
OH
(R)
96:4 er, 53 %
Angew. Chem. Int. Ed. 1991, 30, 99.
Longer 1º alkyl zincs also react with high er.
Angew. Chem. Int. Ed. 1991, 30, 1008.
A
Variation in –Ar affects enantioselectivity/ new (easier) procedure.
O
Ar
H
Ar
OH
RCHO
OH
H
Ar
ZnEt2 (1.2 eq.),
B (0.1 eq.),
Ti(Oi-Pr)4 (1.2 eq.),
PhMe, -76 ºC → rt
Ar
OH
Ph (S)
85:15 er
PhCHO
Et2O
OH
R (S)
yields: 70 – 95 %
er: up to 99.5:0.5
Angew. Chem. Int. Ed. 1991, 30, 1321.
B, Ar = napthyl
Helv. Chim. Acta. 1987, 70, 954.
"I am convinced that only in the area of transition metal organic chemistry are
there new reactions waiting to be discovered." D. Seebach (Angew. Chem.
Int. Ed. 1990, 29, 1320).
(S)
MeO
Ph Ph
Ph Ph
H
H
O O
O
O
Ti
O
O
O O
H
H
Ph Ph
Ph Ph
O
1. TiCl(i-OPr)3
2. MeLi
(R)
up to
99:1 er, 89 %
OH
ZnEt2 (1.2 eq.),
A (0.1 eq.),
Ti(Oi-Pr)4 (1.2 eq.),
PhMe or Et2O, -75 ºC → rt MeO
O
HO
OH
ZnEt2 (1.2 eq.),
A (0.05–2 eq.)
Ph Ph
H
O
OH
O
OH
H
Ph Ph
+ EtMgBr (3 eq.)
PhCHO
THF
OH
Ph (R)
21:79 er
heterogenous conditions: -105 ºC
Also includes method for ketone → 3º alcohol
Angew. Chem. Int. Ed. 1992, 31, 84.
Baran Group Meeting
Dieter Seebach
Dane Holte
There are a lot of words on this page, so here's a picture:
Oi-Pr
O
O
Zurich, photo taken from http://www.sambaum.ch/
i-PrO
H
O
Oi-Pr
Ti
Oi-Pr
O
H
Based on the strange previous experiments, several control studies led to the
following conclusions about the addition of Et2Zn to PhCHO in the presence
of chiral titanates.
1. more highly hindered chiral titanates are more active catalysts than Ti(iOPr)4
2. with increasing bulkiness of the α-substituents in the dioxolanedimethanols, the efficiency of the chiral catalyst increases in the order
hydrogen < alkyl < Ph < β-napthyl
3. when the steric hidrance becomes too large, as in the α-napthyl derivative,
the rate and enantioselectivity of the reaction decreases
4. the Ti-complexes with less hindering dioxolane-dimethanol groups, such
as bis gem-dimethyl, do not successfully compete as catalysts with Ti(i-OPr)4
5. the enantioselectivity is higher with substoichiometric amounts of the
TADDOLate-Ti complex in the presence of excess Ti(i-OPr)4 than it is with
equimolar amounts of the chiral complex alone
2. As the reaction proceeds, new chiral titanate catalysts are being formed.
The original catalyst I is in equilibrium with titanates containing the product
alkoxy ligands (II and III) and these newly formed titanates give rise to altered
selectivites. This was confirmed experimentally by exchanging the alkoxy
groups and subjecting to reaction conditions. Addition of excess Ti(i-OPr)4
restrores selectivity by funtioning as a pool for product alkoxides, as a means
to reconstitute the original catalyst.
O
PhCHO + Et2Zn
O
Ti
*
O
+
O
EtZn
O
O
Ti
*
O
O
Ph
Ph
Ph
O
*
I
O *
O
I
O
+
Ph
O *
O
*
Ti
O
OTi(i-OPr)3
EtZn
O
II
*
+
Ti
*
What mechanistic conclusions can we (ie. Dieter Seebach) draw?
1. Due to steric hindrance to coordination, there exists fast dynamics of
ligand exchange at the Ti-site in the bulky TADDOLate complex. The Ticenter bearing four isopropyl groups achieves the preferred stable
hexacoordination by aggregation and undergoes ligand exchange more
slowly than the TADDOL titanate.
x
-aggregates or solvated,
higher coordinated Ti
-slow lignad exchange
-steric hindrance to
coordination
-fast dynamics of
ligand exchange
On the Mechanism
Ti Oi-Pr
Oi-Pr
EtZn
O
+
O
O
*
O
Ti
O
O
O
I
*
III Ph
These results are a demonstration of the ligand acceleration effect. In this
case, the acceleration is clearly related to a structural feature, the steric
hindrance to coordination of the metal center.
Large portions of this slide quoted and paraphrased from:
Helv. Chim. Acta. 1992, 75, 2171.
Dieter Seebach
Baran Group Meeting
42% yield, 95:5 er
85% yield, 5:95 er
OH
Ph (R)
Et2Zn + PhCHO
Ph Ph
Ph Ph
H
H
O O
O
O
Ti
O
O
O O
H
H
Ph Ph
Ph Ph
OH
Dane Holte
Meanwhile, Dieter Seebach had other plans for TADDOL...
TADDOL Based Dendrimers and Polymers
While TADDOL works well in terms of enantioselectivity, and yields are good,
separation of TADDOL from products is not always simple.
Ph Ph
Ph (S)
H
O
O
Oi-Pr
Ti
Oi-Pr
O
O
H
Ph Ph
This is weird. BUT! Crystal structures of (TADDOL)2Ti show Ti center too
hindered for conversion to pentacoordinate ligand sphere necessary for
reaction. Perhaps the spiro-titanate does not catalyze the reaction, but is
some less hindered species formed in situ. "In view of this suspicion, the
reversal of the steric course [...] is much less discomforting to us [...] than
when we first observed it."
H
A Possible Model
Oi-Pr
O
Et
Ph
O
Zn
i-Pr
Et
Ph
Ph
O
O
Ti
O
Ph
H
O
Ph
Ph
O
Ti
Ph
O
Ti
O
Oi-Pr
O
O-iPr
Et
Zn
Oi-Pr
Et
Helv. Chim. Acta. 1992, 75, 2171.
For an expanded substrate scope see: Tetrahedron, 1994, 50, 4363.
In addition to Seebach's seminal investigations, TADDOL ligands have been
utilized as enantioselective oxidizing/reducing agents, Lewis acids in [4+2],
[3+2], and [2+2] cycloadditions, chiral doping agent in liquid crystals, chiral
inclusion compounds, and enantiomeric H–bond acceptors. TADDOL and
derivatives have been studied with Li, B, Mg, Al, Si, Cu, Zn, Ce, Ti, Zr, Mo, Rh,
Ir, Pd, and Pt.
Ph Ph
Angew. Chem. Int. Ed. 2001, 40, 92.
Merrifield
resin
O
OH
O
O
Ph
OH
Ph
O
OH
O
OH
Ph Ph
Dieter Seebach
Baran Group Meeting
O
Total Syntheses
O
Bu
Li
S
S
O
N
OLi
S
OEt
S
Bu
S
O
NMe2
O
O
O
O
Bu
OH
O
Bu
O
OH
O
O
O
2. n-BuLi
3. DMF
S
O
O
S
S
S
1.
CHO
S
OMe
O
2. HBr / AcOH
workup
80% overall
NaNO2,
R=H
AcOH
R = NO
100% yield
OH
O
MeO
Cl , NEt3
Ph
NH
MeO
2. NaOCl
55%
yield
O
over two steps
O
O
S
CO2Me
S
60% yield
OH
S
NH
HO
1. Raney-Ni
2. LAH
MeO
MeO
PPh3, DEAD
O
Li
Ph3P
2. HCl, H2O
3. LiOH, MeOH, H2O
O
S
R
62% yield (92% brsm)
S
OMe
Ph
N
MeO
O
O
N N THF, -78 ºC
Angew. Chem. Int. Ed. 1974, 13, 77.
1.
O
C
O
O
(–)-pestalotin
I
N
MeO
O
Br
1.
MeO
O
O
O
1. LDA (2 eq.)
MeO
H+
63% yield
named
reaction?
MeO
1. (Me)2SO4, K2CO3
2. HgCl2, HgO, 66 ºC
Al
H H
resolve
O
S
OH
CHO
then,
O
80% yield
NMe2
O
H2N
MeO
ONa
Bu
95% yield
Bu
Dane Holte
N
C
O
Ph
3. O
O
O
OH
O
O
CHO
N
HO
CHO
MeO
MeO
N
Ph
O
55% over
three steps
O
Pd/C, 180 ºC,
4 hr, "poor yield"
HgO, BF3⋅OEt2
70% yield
NH
O
O
O
O
MeO
(–)-Pyrenophorin
MeO
O
O
Angew. Chem. Int. Ed. 1977, 16, 264.
N CHO
LAH
N
MeO
MeO
O
(±)-macrostomine
O
N
O
Tet. Lett. 1980, 21, 1927.
O
Dieter Seebach
Baran Group Meeting
O (+)-gloeosporone
Total Syntheses (cont.)
t-BuO2C
OEE
H
OH
O
O
O
O
O
S
C5H11
acetylide
S
OTHP
O
O
O
O
N
S
O
Me
Me2N
C5H11
(+)-conglobatin
Me
CO2H
Tet. Lett. 1984, 25, 5881.
O
O
J. Am. Chem. Soc. 1987, 109, 6176.
CO2Me
HOH2C
Me
OTBDMS
Liebigs Ann. Chem. 1986, 2081.
TBDMSO
CO2Et
OMe
O
Et
HO
O
OH
O
O
OH
OH
O
O
(+)-11,11'-di-O-methylelaiophylidene
OH
Ph3C
Et
O
CO2Et
CO2Me
HN
HN
(+)-myxovirescine M2
HO
S
OH
H
OH
I
OH
OTf
O
J. Am. Chem. Soc.
1985, 107, 5292.
OH
EtO2C
O
O
OH
O
CO2H
O
O
MeO
OH
both stereocenters originate
from: Br
S
OTHP
Ph3P
MeO2C
C5H11
OH
S
S
O
HO2C
S
dithiane
alkylation
N
C
S
C5H11 alkylation
O
O
Lactonization under
Mitsunobu conditions
O
C5H11
O
Tet. Lett. 1982, 23, 159.
Schöllkopf oxazole
synthesis
O
O
(–)-grahamimycin A1
CO2H
N
OTBS
O
O
+
OH
O
O
HO
O
O
Dane Holte
CO2Et
MeO2C
OH
Liebigs Ann. Chem.
1986, 1281.
OBn
MPMO
Helv. Chim. Acta. 1991, 74, 2112.
Br
O
O
S
Dieter Seebach
Baran Group Meeting
OH
Me
O
OLi
+
CO2H
O
"How we drifted into peptide chemistry and where we have arrived at"
MeO OMe
I
On a Visit to Sandoz: Find a more sensative method for detecting cyclosporin
A. Seleno-derivative allows for HPLC analysis with a detection limit of 5 ng.
Me
Me
88% yield
O
O
(+)-frontalin
LAH
O
O
Me
O
O
O
MeO OMe
Me
Dane Holte
N
N
(S)
(S)
O
Liebigs Ann. Chem. 1983, 1930.
O
O
NH
SeCl
(S)
O
cyclosporin A
HN
O
N
(S)
N
HN
(S)
O
"Thus, we have excised a single proton from
a peptide chain of molecular mass 1200 and
replaced it by a side-chain substituent."
N
(R)
O
(S)
O
NH
(S)
O
(S)
(S)
(S)
H
N
(S)
O
HN
N
OH
O
N
(S)
(S)
(R)
N
(S)
O
HN
O
H
N
(R)
O
O
NapSe
O
HN
N
(S)
O
O
(S)
N
(S)
N
HN
(S)
O
N
O
(R)
O
Led to work within the Seebach group on
peptide enolates, stablization of peptides in
THF with lithium salts, direct thionations of
peptides with Lawesson's reagent, and
cyclosporin as an ionophore.
Started a research program called "chemical
modification of peptides. Work on poly(3hydroxybutyrate) led them to consider βamino acids, especially interesting was their
propensity to form helices.
Tetrahedron, 2004, 62, 7455.
Acc. Chem. Res. 2008, 41, 1366.
Baran Group Meeting
Dieter Seebach
β-amino acids
"A search for the answers to the following two questions has taken us into
the world of β- and γ-peptides: What happens if the oxygen atoms in a 3helix of a polymeric chain are composed of (R)-3-hydroxybutanoic acid are
replaced by NH units? What happens if one or two CH2 groups are
introduced into each amino acid building block in the chain of a peptide or
protein, thereby providing homologues of proteinogenic α-amino acids?"
The use of β-amino acids led to structural variety in secondary structure
(linear, helices, sheets, and hairpins) formed. To date, five have been
characterized (four below):
Dane Holte
Synthetically...
Many of these unnatural amino acids are now available, but if they aren't (and
when they weren't) the Seebach group (and others) developed routes:
R
PG
CH2N2
X
N
H
Arndt-Eistert
homologation
O
R
PG
KCN
OMs
N
H
R
O
H2N
OH
β3-amino
acids
Kolbe
reaction
OR
Li
LiO
R
R
MeX
O
Fmoc
OR
N
H
O
R
OR
O
R
Biologically...
- Do not bind to active sites of peptidases; proteolytically stable
- Metabolically stable in mammals
- In one case, biodegradation by enviornmental microorganisms was shown
- Bioactivity has been shown: inhibition of an intestinal transport protein,
antibiotic and hemolytic activities, and binding to DNA and RNA
- one β−peptide has shown the ability to cross the blood-brain-barrier
- no toxic effects!
- this has led to a search for polypeptide mimics
Ph
O
N
H
OH
β2,3-amino acids
OR
HO2C
(PhO)2PO–N3
CO2R
Curtius
degradation
O
O
R
Ph * N
Li
Davies Method
R
- Secondary structures can be seen in as few as six residues.
- Have been designed and found using molecular modeling programs.
OH
R
Fmoc
O
PG
N
O
*
Ph
Ph
R
H2N
OH
O
N
H
X
β2-amino acids
Evans
methodology
Actual peptide coupling to build up polypeptides is the same as with α-amino
acids.
Tetrahedron, 2004, 62, 7455.
Acc. Chem. Res. 2008, 41, 1366.
Dieter Seebach
Baran Group Meeting
Dane Holte
"As the last major project of our group before retirement of D.S. (with concomitant necessary reduction of the research-group size) we joined forces and made
essentially everybody (from advanced lab course students, through masters thesis candidates, the last PhD students all the way to the post-doctoral coworkers) part of a team to synthesize all-β2-eicosapeptide with the 20 proteinogenic amino acid side chains. The reason for embarking on this adventure,
which eventually turned out to be a 159-step synthesis..."
O
H2N
O
N
H
O
N
H
HN
N
H H N NH
2
O
N
H
O
N
H
O
O
N
H
NH2 O
H
N
H
HO
O
O
N
H
HO
O
N
H
O
N
H
OH
O
N
H
HS
O
N
H
O
H
O
N
H
O
N
H
O
N
H
HN
NH2
NH2
HO
N
H
N
Why?
1. Prove that it is possible to make all β2-amino acids
2. Find ways to avoid epimerization in coupling
3. Learn something about secondary structures of β2-peptides
4. Because "there was an atmosphere of sportive ambition in the group"
Seebach's "Magic" Stain, the OG procedure:
Found in the experimental information of: "Optisch aktive Alkohole
aus 1,3-Dioxan-4-onen: eine praktikable Variante der
enantioselektiven Synthese unter nucleophiler Substitution an AcetalZentren," Helv. Chim. Acta 1987, 70, 448.
O
O
N
H
HO
O
N
H
O
O
N
H
H
O
N
SMe
Tetrahedron, 2004, 62, 7455.
Acc. Chem. Res. 2008, 41, 1366.
Questionable methodology award goes to:
n-BuLi
O
OMe
Me2N
NMe2
OMe
OH
Bu
14% optical yield
optical yield: ratio of the optical
purity of pdt to that of the precursor...
-120 ºC
Entwicklung durch Besprühen mit einer Lsg. aus 25 g
Phosphormolybdänsäure, 10 g Ce(SO)4·H2O, 60 ml konz. H2SO4 und
940 ml H2O und nachfolgendes Erhitzen.
25 g polymolybdic acid
10 g cerium (IV) sulfate
60 ml conc. H2SO4
940 ml H2O
Angew. Chem. Int. Ed. 1969, 8, 982.
O
H