W. Clark Still
Baran GM 2010-07-10
Jonathan Lockner
HO
O O
H
O
H
O
H O
H
HO O
HO
+i =
O
-
NO2
O
O
H
P2V j bend P3V j nonbonded P4V j CCF
+ - 4 + rij4
rij
rij4
!166.0
'
Gpol,i
rij2
(2+ ij ) 2
% 1( n n
qiq j
G pol = !166.0'1! * - - 2
& $ ) i=1 j=1 (rij + + ij2 e!Dij ) 0.5
Cl
O
host-guest complexes
(podands, corands,
cavitands...)
H
H
N
Cl
Cl
O
Ar# Ar =
O
Electrophoric Tag
Cl
Cl
Cl
H
Cl
Cl
H
Cl
O
O
H H
periplanone B
1979 (Classics I, ch. 13)
F
Cl
H
H
A
B
C
halocarbon encoded libraries
O
peripheral
attack
RESTART
STRAIN ENERGY
MINIMIZATION
Linker
H
Dij =
HO2C
most highly cited papers:
1) "Rapid chromatographic technique..." (flash chromatography)
2) "MacroModel ! An integrated software system for modeling..."
3) "Semianalytical treatment of solvation..."
4) "An internal coordinate Monte Carlo method..."
5) "Direct synthesis of Z-unsaturated esters..."
H
O
+ ij = (+ i+ j ) 0.5
STRAIN ENERGY
CALCULATION
major interests: total synthesis, synthetic methods, macrocyclic stereocontrol,
conformational analysis, computational chemistry, chemically encoded libraries,
host-guest chemistry
O
stretch
+
CONFORMER GENERATION
~170 publications
~21 patents
MacroModel (vers. 1 in 1988; merged with Schrodinger in 1998)
Pharmacopeia (as of 2008, a subsidiary of Ligand Pharma, San Diego)
H
H
H
% 1( q2
algorithms
Gpol = !166.0'1! *
computational chem.
& $) +
G
!166.0
G'pol,i = pol,i1 =
(1! $ ) RvdW,i + , + P1
STRUCTURAL FEATURE
PERCEPTION
DISPLAY
H
O
H
DISPLAY
"
O
monensin
1980 (Classics I, ch. 15)
CHEMIST ENTERS
STRUCTURAL DIAGRAM
H
O
H
H
H
CO2H
Still has spent the past eight years building an airplane in his garage
O
H
1946 -- born (Augusta, GA)
1964 -- graduated from Winter Haven HS (FL)
1969 -- B.S. at Emory (Atlanta, GA)
1972 -- Ph.D. at Emory (w/ David Goldsmith)
1973 -- Postdoc at Princeton (w/ Todd Wipke)
1974-75 -- Postdoc at Columbia (w/ Gilbert Stork)
1975-76 -- Professor at Vanderbilt (Nashville, TN)
1977-98 -- Professor at Columbia (New York, NY)
1999-present? -- Professor Emeritus at Columbia
W. Clark Still
Baran GM 2010-07-10
allyloxy carbanions
#
$
O
R
secBuLi
OSiEt3 THF
"78°C
Li
R'
OSiEt3
RI
secBuLi
THF-HMPA
"78°C
H2O
R
O
H
OH
SiMe3
Me3SiLi
KH
tBu
Et2O
Me3SnLi
THF
O
preisocalamendiol
1977
SiMe3
tBu
note Z,E stereochem
but
Me3SiLi
N.R.
O
a) Me3SnLi
b) Me3SiCl
"we felt that the conformational properties
of the cyclodecadienes and the chemical
reactivity of organotin compounds might
merge to provide a simple solution to the
isomerization problem."
MnO2
O
OSiMe3
take-home messages:
• extent of 1,4-addition ! to solvent basicity
• results contrary to HSAB theory predictions
• electron transfer at play (with Me3C and Me3Si)
O
-O
Nu-
acoragermacrone
1977
Nu
Nu
-O
O
dialkylative enone transposition
Me3SiLi
Me3SnLi
O
HO
Group IV anions (C, Si, Sn) 1,2 vs 1,4 addition
OH
tBu
frullanolide
1977
a) LDA
b) HOAc
O
OH
1,4-axial attack
(e- trans. mech)
tBuLi
THF
HMPA
O
Me3Sn
Et2O
O
O
O
RLi
tBuLi
THF
HMPA
O
germacranes
Et2O"HMPA
"20°C
O
I
2) KI3
NaHCO3
CO2Me
OH
RM = MeLi"Me2CuLi ("70°C)
O
c) heat
d) Me2SO4
N
DBU
1) KOH
H
mech?
high yield equatorial methylation of unhindered cyclohexanones
Me3SiLi
O
O
Me (91% yield)
tBu
tBu
2) acryloyl Cl
3) pyrrolidine
OH
OH
RM
tBu
O
a) LDA
b) Et3SiCl
1) Li base
2) NH2NH2
H2O"MeOH
O
secBuLi
THF-HMPA
"78°C
O
O
H
OSiEt3
but
O
O
"methylenic Claisen"
1) NaOOH
R
H
(86%)
O
eudesmanes
why?
#-attack
O
OH
R'
R
OH
OH
R' H3O+
R
OSiEt3
$-attack
Jonathan Lockner
Me3Si
O
O
2) MeLi, Et2O
3) CrO3•2pyr
4) NaOH
OH
SnMe3
OLi
SnMe3
1) Me3SnLi
THF"NH3
iodopentane
stannylation/destannylation
O
cf.
SnBu3 1) nBuLi
O
O
dihydrojasmone
1977
O
H
O
Me3Sn
Bu3SnCH2MOM
1) Bu3SnLi
2) MeCH(Cl)OEt
O
geranyl Cl
O
OEt 2) Li"NH
3
dendrolasin
1978
"Whereas an allyl organometallic may undergo isomerization, the carbinyl carbanion approach...
assures that the geometry of the central trisubstituted double bond is unambiguously retained."
W. Clark Still
Baran GM 2010-07-10
"flash chromatography" 1978 -- "Still demonstrated FC at a Thursday evening seminar to the
department at Columbia - he separated the individual colors in black ball point pen ink faster
with FC than he could run a TLC - it was VERY well received by all"
Jonathan Lockner
"-chelation (5-membered chelate ring) ! Grignard reagents
RMgBr
TBDMSO
H O
Still!Wittig [2,3]-sigmatropic rearrangement
CO2Et
1) KH
Bu3SnCH2I
BuLi
steps
sex attractant
>95% Z
TBDMSO
OBn
MeMgCl
TBDMSO
H O
threo (50:1)
OH
H O
THF
OBn
OAc
2) Ac2O!pyr
OH
O
O
TBDMSO
erythro (50:1)
OH
H O
THF
adjacent sterocenters
OBn
OBn
double Still!Wittig [2,3]
#-chelation (6-membered chelate ring) ! organocuprates
1) KH
Bu3SnCH2I
BuLi
OEE
OH
CHO
2) Ac2O!pyr
3) TsCl
4) LiAlH4
5) H3O+
OH
Me2CuLi
OH
!78 °C
O
>95% Z,Z
O
Me
threo (30:1)
OH
O
HO
muscarine
1980
OBn
OBn
HO
O O
H
O
OH
CHO
configurationally stable Sn/Li alkoxy compounds ! modest stereocontrol for polypropionate synthesis
(5:1, !78 °C)
(8:1, !110 °C)
Me
1) Bu3SnLi
BnO
O
OMOM
O
OMOM
Me
Me
2) MOM-Cl
BnO
O
Me
+
OMOM
BnO
O
HO O
OMOM
HO
H
B
OH
1) thexyl borane
Me
H
monensin
1980 (Classics I, ch. 15)
2) NaOOH
1) Me-M
H O
remote asymmetric induction (via cyclic hydroboration)
a. BuLi
b. Me2SO4
CHO
O
O
H
O
ansa bridge of rifamycin S
1983
SnBu3
BnO
OAc O
H
CO2H
Me
BnO
O
Me
SnBu3 +
2) MOM-Cl
NMe3Cl
H
in t.s., B-H eclipses C=C, while
chain in least strained conformer
96%
8:1 dr
OH
remote sterocenters
application:
TBDMSO
1) borane
(1:1, !78 °C, M = MgBr)
(1:1.4, !78 °C, M = Li)
HO2C
OH OH
steps
O
HO2C
O
2) NaOOH
1:1
Prelog-Djerassi lactonic acid
1981
Me
Me
O
OTHP
BF4
PPh3
KHMDS
THF!HMPA
highly Z-selective Wittig
Me
BF4
AsPh3
O
OTHP
83% yield
(>97% Z)
R
H
KHMDS
THF!HMPA
H
O
R
Me
H
>50:1 trans:cis
Corey!Chaykovsky
using arsonium ylide
W. Clark Still
Baran GM 2010-07-10
germacranes (continued)
H
"
O OR
H H
periplanone B
1979 (Classics I, ch. 13)
Me
Me
H H
H
H
Me
H
H
O
O
OR
steps
H
O
H
HO
BzO
H9e
OH steps
H
O
OH
O
H
OH
trichodermol
1980
7
O
O
H2C
Me
O
H
H
Me
O
Me
OR
O
2% aq
O H2SO4
H9a
O
H
Grob
O
O
O
H
THF
0°C
2) NaOH
EtOH
acetone
45°C
H
OH
Favorski
macrocyclic
stereocontrol
H2C
NaH
steps
OR
8
Me
EEO
1) tBuOOH
Triton B
EtO2C
O
O
BzO OMs
O
O
O
peripheral
attack
H
trichothecanes (cf. his PhD work at Emory with Goldsmith)
O
O
Jonathan Lockner
HO
H
H
O
H
O
O
O
O
H
O
O
verrucarin A
1981
O
O
O
roridin E
1984
O
H
O
O
O
O
Me
H
H
O
O
H
HO
O
baccaharin B5
1984
HO
O
O
O
H
O
H
HO
"The [epoxidation] reaction... cleanly establishes four new asymmetric
centers of which two appear to be controlled by the conformation of the
macrocycle."
RO
RO
HO
O
O
H
O
H
O
1) H+
RO
2) B!V [O]
3) NaBH4
OH
O
O
mCPBA
O
OH
O
O
(74%)
O
O
O
O
O
O
1) K2CO3-MeOH
2) Collins [O]
HO
3) DBU
4) NaBH4
5) H2-Pd(OH)2
O
O
remote epoxide gives modest diast.
during CrCl2 macrocyclization
O
O
O
OH
O
O
O
O
OH
eucannabinolide
1983
O
O
O
steps
OH
OH
sapon;
HOAc
(94%)
HO
asperdiol
1983
O
3
3-deoxyrosaranolide
1984
11 kinetically-controlled reactions on
a 16-membered macrolide were used
to establish 7 of the 9 stereocenters
O
O
O
cf. monensin
O
HO
HO
W. Clark Still
Baran GM 2010-07-10
macrocyclic stereocontrol
host-guest chemistry, computational chemistry, and combinatorial chemistry...
Me2CuLi
BF3
O
39
OH OH
H
steps
O
Moving beyond monensin (a natural podand ionophore), Still's group investigated a variety
of host structural motifs. Design considerations included: ease of synthesis, incorporation
of symmetry elements (to minimize conformational heterogeneity), organic solvent vs.
water solubility, flexible vs. rigid binding pockets, appropriate donor-acceptor motifs,
hydrophobicity/hydrophilicity...
34
39
34 O
!78 °C
(92%)
O
O
O
Early on, progress appears to have been slow. Computational limitations needed to be
overcome by either (a) waiting for hardware to improve or (b) writing code that would get
the job done in less CPU time but without significant sacrifice in quality of simulation
results. So, there was plenty of coding and debugging going on in the Still lab during the
80s and 90s.
most stable conformer
EtMgBr
CHCl3
O 43
!30 °C
(69%)
H
39
H
O
O 43
steps
34
34 OH
H
39
H
O
30
C30-C43 segment of palytoxin
1982
1) NBS
2) (MeO)3P
DEAD
OH
2) Mukaiyama
dehydration
O
O
O
CO2H
O
O
3) PS-SnH
4) sapon.
O
OH
H
N
R
N
N
R
N
H
thromboxane A2
1985
6
OH
I
CO2H
HO
However, at some point, there seems to have been a transition (or at least a major tilt in
emphasis) from rational design to "irrational synthesis" ! the emergence of split/mix library
generation, chemical encoding, fluoresence assays. One can make judicious use of both
enterprises, of course.
In any case, it strikes me that Still was a pioneer in all of the above...
macrocyclic "chemocontrol"
1) Corey!
Nicolaou
Jonathan Lockner
O
I
O
N
HN
H
O
N
NO2 H O2N
O
O2N
I
O
O
N
N O
O
I
O
N
OH
H
N
thromboxane B2
A
Br
CO2Me Bu3SnH
O
O
compare:
CO2Me
O
H
N
O
OH
OH
N
H
O
O
H
N
A
Still!Gennari modification of Horner!Emmons olefination
kinetic elimination prior to isomerization gives Z isomer
R
H
KHMDS, 18-crown-6
THF, !78 °C
O
N
H
O O
S
N
H
O O
S
HN
H
N
H
N
HN
S
O O
O
(CF3CH2)2P(O)CH2CO2Et
O
H
EtO
R
Z-selective Horner!Emmons
cf. Ando's reagent: (PhO)2P(O)CH2CO2Et
Boc
H
Boc
S
O O
N
H
N
R
peptide guest
A
O
H
N
O
NO2
O
O
B
O
NH
H
H
N
H
N
O
N
H
O
H
N
N
H
O
B
N
H
A
L
NH
CH2
CH2
R
N
O O
OR
Cu2+
N
N
R'
R'
N
W. Clark Still
Baran GM 2010-07-10
Cl
HO2C
O
NO2
Linker
N
O
Cl
Cl
O
Ar
Cl
H
H
Ar =
Cl
O
Cl
Cl
Cl
Electrophoric Tag
A
Cl
Cl
F
H
H
B
C
halocarbon encoded libraries
Jonathan Lockner
"results suggest that designs for the most selective receptors should aspire to
total conformational homogeneity, not just conformationally well-defined
functionality in the binding site. It is also instructive to note that increasing the
flexibility of our receptor resulted in a decrease in binding of the otherwise
selectively bound guests. Thus while flexible receptors may adapt their structures to
fit a guest, there is a price in binding energy as well as in selectivity which must be
paid."
Tet Lett 1993
Separate Beads into 3 Groups
OH
Step 1
A+
1% T1
T1
O A
OH
OH
C+
1% T1 + 1% T2
B+
1% T2
T2
O B
T1
T2
O C
Mix Beads and Separate into 3 Groups
T1
Split synthesis encoded
with multiple tagging
molecules (T1-T4)
O A
T2
O B
T1
T2
O C
Step 2
O A
T2
O B
T1
T2
O C
X+
1% T3
T1
T3
T2
T3
T1
T2
T1
O A
T2
O B
T1
T2
O C
Z+
1% T3 + 1% T4
Y+
1% T4
O AX
T1
T4
O BX
T2
T4
O CX
T3
Equilibrate ligand library
with host (or vice-a-versa):
manually "cherry-pick" the
highly colored beads
T1
O AY
T1
T3
O BY
T2
T3
O AZ
"simple, host-like molecules can bind peptides with significant sequence-selectivity.
Thus the prognosis is good for creating synthetic small molecules with binding
properties similar to those of natural antibodies.
"combinatorial synthesis and screening offers an effective approach to many
chemical problems where too little is known for a deterministic solution. It also
provides an important tool for testing specific hypotheses via batteries of
measurements that can be applied in single experiments and thus to test hypotheses
in many different contexts.
"We are now using it to find small-molecule receptors for particular peptide substrates
via preparation of encoded combinatorial libraries of receptors. In these libraries, we
use what we know about effective peptide receptors to design a relevant, basic
receptor structure and then vary that structure combinatorially to make up for what we
do not know about binding a particular substrate."
Acc Chem Res 1996
T4
T1
T2
O CY
T4
O BZ
performing conformational searches:
T4
T1
T2
O CZ
T3 T4
molecular geometry is described in mathematical terms via a coordinate system:
e.g. torsion angles, Cartesian coordinates, matrices of internuclear distances
variations of coordinates may be systematic, random (stochastic), or a mixture thereof
e.g. Monte Carlo (coined by physicists at LANL) techniques are random
select a force field (AMBER*, MM2, MM3, etc.)
choose a solvation model (GB/SA developed by Still et al. is industry standard)
Decode: in this case, the
halocarbon tags are
amenable to GC analysis
other problem-specific algorithms may or may not be included
e.g. applying a frozen atom approximation in order to limit extent of variations
run the search, interpret the results of the simulation