Clark W. Still
Career in Review
Department of Chemistry, University of Ottawa
March 17th, 2009
By Anik Michelle Chartrand
1
Who Is He ?
 1946 - Born in Augusta, Georgia
 1964 - Graduated from Winter Haven High
School in Polk Country, FL
 1969- B.Sc. At Emory University
 1972- Ph.D. At Emory University – Advisor was David
Goldsmith
 1973- Postdoc at Princeton University (computer related)
 1974/75- Postdoc at Columbia University with Gilbert Stork
 1975/76- Professor at Vanderbilt University in Nashville, TN
 1977 to 98 - Professor at Columbia University in NY, NY
 1999 – Professor Emeritus, Columbia University in NY, N
2
Graduate Studies
3
His Graduate Work (1969-72)
O
H3C
O
CH3
CH3
H
O
O
OCOCH3
4,7-dimethyl-3-chromanone
Trichodermin
 Diborane Reductions of Oxygen Heterocycles
 Hydroboration-Oxydation Products of Oxygen
Heterocycles
Early work towards the synthesis
of Trichodermin led to a borane
oxidation sequence development
O
O
O
O
BR2
H
O
O
O
1,2
4
1,4
1
2
O
3
Conditions: i) NaBH4, Diglyme,
BF3.O(CH2CH3), THF
ii) NaOH, H2O2
W. C. Still and D.J. Goldsmith, J. Org. Chem., 1970, 35 (7), 2282
OBR2
6
O
5
7
4
OH
His Graduate Work (1969-72)
O
 The decarboxylative elimination reaction of β,γ- epoxyacids
to make allylic alcohols
O
O
H
O
8
O
 Bicyclic Intermediate for Trichothecane Synthesis
 Exploitation of an Enolate as a Protecting Group
 Tandem sequence involving bis alkylation
O
O
O
Me2CuLi
H
O
9
HO
11
CH3
Still, W.C.; Lewis, A.J.; Goldsmith D.; Tetrahedron Letters, 1971, 18, 1421
Still, W.C.; Lewis, A.J.; Goldsmith D.; Tetrahedron Letters, 1973, 48, 4807
1. Me2CuLi
2. MeLi
O
O
9
H
CH3
O
O
O
CH3
MeLi
O
H
HO
3. H3O+
O
10
H3O+
HO
H
CH3
CH3
O
O
O
12
O
10
CH3
5
His Graduate Work (1974-75)
H
O
HO
O
OH
H
H
CO2H
Gibberellic Acid
Most of his work with Prof. Stork concentrated of the formation of Gibberellic Acids B-C-D ring:
 Reductive cyclization of Ethynyl ketones
H
O
O
H
(NH4)2SO4
O
OH
K, NH3/THF (6:1)
O
O
13
14
 Unusual regiospecificity in the enolization of a ketone as the result of a difference
in energy to achieve the best overlap of an alpha hydrogen
H
H
1
O
2
C
3
H
15
OH
1. LDA (5.5 eq.)
HMPA (30%) in THF
0
-20 C
2. TMSCl
Stork, G.; Boeckman, R.K. Jr..; Taber, D.F.; Still W.C. Singh, J. ,JACS, 1979, 101 (23) 7107
Stork, G.; Still W.C. Singh, J., Tetrahedron Letters, 1979, 52, 5077
1
Me3SiO
2
C
3
H
OH
16
6
Independent Researcher
Vanderbilt University
Columbia University
7
His Work at Vanderbilt University (1975-76)
 Organo cuprates and the development of a new highly selective stereoselective
alkylation agent to produce axial alcohols
O
t-Bu
OH
CH3
Me3CuLi2
Et2O, - 700C
t-Bu
18
17
“ In contrast to the numerous highly stereoselective reducing agents which have
been developed, the ability of reagents for the addition of unhindered alkyl
nucleophiles to ketones with high stereoselectivity is limited.”
 Conjugate Addition of trimetylsilyllithium – Axial addition is highly favoured
O
Me3SiLi
24
Me3Si
O
25
O
Me3SiLi
O
Me3SiLi
19
THF-HMPA
o
-78 C
Me3Si
MeOH
21
Me3Si
(99%)
O
H3O
20
OLi
No reaction
26
Macdonald, T.L.; Still, W.C.; JACS, 1975, 97(18), 5280 & Still, W.C., J. Org. Chem., 1976, 41(18), 3063
Me3SiCl
22
Me3Si
(99%)
OSiMe3
MeI
23
Me3Si
O
(97%)
8
His Work at Vanderbilt University
(1975-76)
Allyloxy Carbanions:
 Cyclization to vinyl oxetans via allyloxycarbanions :
O
Cl
27
sec-BuLi
THF-HMPA, -78oC
O
Cl
28
H
H
O
O
and/or
H
29
H
30
Selective fomation of the more strained oxetane as long
as the addition produces the cis ring juncture
O
Cl
28
9
Still C.W., Tetrahedron Letters, 1976, 25, 2115 & Still, W.C.; Macdonald, T.L.; J. Org. Chem., 1976, 41(22), 3620.
His Work at Vanderbilt University
(1975-76)
 Claisen Variant:
CH3
R
O
H
32 OR'
R
OH
31
H
R
H
CH3 O
R'O2C
O
35
Terpenoid
34
R
O
33 OR'
CH2NR2
 Tin chemistry (stannylation/destannylation)
 α-Alkoxy Organolithium Reagents
R-CHO
1) Bu3SnLi
2)R'X
36
OR'
R
SnBu3
37
BuLi
R
O
OR'
OR'
HO
R
Li
38
39
10
Still, C.W.; Schneider, M.J., JACS, 1977, 99(3), 948 & Still, C.W., JACS, 1978, 100 (5), 1481
His Work at Vanderbilt University
(1975-76)
 Tri-alkyl tin anions undergo high yield conjugate addition to α,β-enones to give
the regiospecific enolate
Bu3SnLi
40
o
O -78 C, THF
5min, 96%
Bu3Sn
41
SnBu3
O
O
42
2.2 A
 Alkylstannanes are smoothly oxidized by chromic anhydride/pyridine to the
corresponding ketone
CrO3/Py
Bu3Sn
DCM, R.T.
OH
O
75%
43
OH
44
 Alkylation and oxidation – efficient dialkylative enone transposition
O
O
1. MeLi
2. CrO3, Py
1.Me3SnLi
2. n-C5H11I
SnMe3
90%
45
Still, C.W., JACS, 1977, 99(14), 4836
46
3. NaOH
89%
O
47
11
Columbia University (1977-1998)
 Anionic [2,3]-sigmatropic rearrangements
OH
OEE
O
OH
BuLi
O
OEE
SnBu3
SnBu3
49
48
H
R
H
O
R
(
H
H
O
50
Pseudoaxial
(
H
Me
H
Me
51
Pseudoequatorial
OH
Li
Rotation
O
O
Li
52
53
O
54
Still, C.W.; McDonald J.H. III; Collum, D.B.; Mitra, A., Tetrahedron Letters, 1979, 7, 593 &
Still, C.W.; Kahn, M.; Mitra, A., J. Org. Chem., 1978, 43(14), 2923
55
12
Columbia University (1977-1998)
 Rapid Chromatographic Technique for Preparative Separation of
moderate resolution
“ We have recently developed a substantially faster technique
for the routine purification of a products which we call
flash chromatography.”
 Monensin – Polyether antibiotic and naturally occurring ionophore
HO
O
O
H O
H
OCH3
COOH
H
56
17 asymmmetric centers, 26 carbon backbone
Theoretically 131 072 stereoisomers can exist
H
H O
HO
O
OH
1) Still, C.W.; Kahn, M.; Mitra, A., J. Org. Chem., 1978, 43(14), 2923 2) Still, W. C.; Dongwei, J. Org. Chem.,
1988, 53, 4643 3) Still, W.C.; MacDonald, J.H.III; Collum, D.B.; JACS, 1980, 102(6), 2117 4) Still, W.C.;
MacDonald, J.H.III; Collum, D.B.; JACS, 1980, 102(6), 2118 5)Still, W.C.; MacDonald, J.H.III; Collum, D.B.; JACS,
1980, 102(6), 2120
13
Columbia University (1977-1998)
 Direct Synthesis of Z-unsaturated esters; a useful modification of the
Horner-Emmons Olefination
Horner-Wadsworth-Emmons
O
R P
R
57
1, Base/Solvent
R'
2.
O
H
H
R'
H
R= Aryl, alkyl
R= O-Aryl, O-Alkyl, NR2
R2
Horner- Wittig
Wadsworth-Emmonds
58
R2
E-alkene
Still – Gennari Modification
O
RO P
RO
59
R'
1, Base/Solvent
18-crown-6
2.
O
R2
H
H
R'
R2
H
R = CH2CF3
60
Z-alkene
14
Still, W.C., JACS, 1979, 101(9), 2493 & Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9), 2495
Z-trisubstituted Allylic Alcohols via
the Wittig Reaction
Trans-selective Olefin synthesis (1965) - Schlosser
(Ph)3P CH2R
61
R'CHO
PhLi (2 eq), ether
HCl/t-BuOK
R'
R
62
Cis-selective Olefin synthesis (1965) - Schlosser
(Ph)3P CHR
63
i) NH3. NaNH2,
ii) R'CHO, Benzene
0oC, 1hr
R
R'
64
Stereospecific Synthesis of Certain Trisubstituted Olefins (1970) - E.J. Corey
(Ph)3P CHCH3
65
n-C6H13CHO
THF, -780C
O
n-C6H13CH
CH P(C6H5)3
CH3
66
Schlosser, M; Christmann, K.F. Angew. Chem. Intl, Ed., 1966, 5(1), 126 &
Schlosser, M; Christmann, K.F,; Muller, G., Angew. Chem. Intl, Ed., 1966, 5 (17), 667 &
Corey, E.J.; Yamamoto, H.; JACS, 1970, 92(1), 226
i) n-Buli, THF
-780C
ii) CH2O (2eq)
o
0 C to R.T.
H
CH3
n-C6H5
CH2OH
67
15
Z-trisubstituted Allylic Alcohols via
the Wittig Reaction
A Direct Synthesis of Z-trisubstitured Allylic Alcohols via the Wittig Reaction
 No β-oxido Ylide intermediate or n-BuLi required
α
OTHP
O
Ph3P=CHR
R
OTHP
α ‘ 68
Counterion effect
69
R
Z:E
Yield
CH2CH2CH3
60:1
87%
CH(CH3)2
6:1
45%
Phosphonium fluoroborate
Vs
Phosphonium halide
Application in Synthesis
OTHP
PPh3
1. O
OH
2. H3O
70
85 %
99:1 (Z:E)
71
Sreekumar, C.; Darst, K.P.; Still, W.C., J. Org. Chem, 1980, 45(21), 4260
α-santalol
16
Columbia University (1977-1998)
 Dichlorocarbene cyclopropanation of allylic alcohols:
OH
OH
CHCl3,BzN(Et)3Cl
OH
NaOH, 0oC, 4hrs
Cl
Cl
72
73
H
O
This is a Simmons-Smith
equivalent that works
well in acyclic systems
H3C
H
H
Observed relative energy
Calculated relative energy
Cl
Cl
(8:1)
74
0.0 kcal/mol
0.0 kcal/mol
O
H
0.52 kcal/mol
0.60 kcal/mol
 Synthesis of Alternating Hydroxy- and Methyl-Substituted Hydrocarbons by
Oxymercuration of Cyclopropylcarbinols.
OH
OH
OH
a) Hg(OR)2
HgCl
b) NaCl
75
CH3
LiAlH4
OH
OR
76
Mohamadi, F.; Still, W.C., Tetrahedron Letters, 1986, 27(8), 893 &
Collum, D.B.; Still, W.C., Mohamadi, F., JACS, 1986, 108(8), 2094
77
17
Columbia University (1977-1998)
 A highly stereoselective synthesis of trans epoxides via arsonium Ylides
R
H
Ph3As
O
78
O
R
H
CH3
High stereoselectivity
for trans epoxide ≥ 50:1
79 H
R= cyclohexyl, > 99% E (84%)
R= phenyl, 83% E (61%)
 Remote 1,3-, 1,4-,and 1,5- asymmetric induction. A stereoselective approach to acyclic
diols via Cyclic Hydroboration
H
1) R BH2
H3C
2) NaOOH
OH
H
B
Major
H
81
80
H
H
H3C
B
H
82
Still, W.C.; Novack, V. J., JACS, 1981, 103(5), 1283 &
Still , W.C..; Darst, K.P., JACS, 1980, 1021(24), 7385
OH
83
+
(8:1) 96%
OH
Minor
OH
84
18
Columbia University (1977-1998)
 Synthesis of Macrocyclic Trichothecanoids: Baccharin B5 and Roridin E
O
H
H3C
H
H
O
H3C
H
O
O
O
O
O
O
O
HO
O
O
O
O
CH3
HO
H
H3C
O
H
O
O
O
O
O
O
H
O
CH3
CH3
H
HO
O
O
CH3
CH3
H
H3C
O
O
CH3
mCPBA
O
O
O
O
CH3
H
O
HO
CH3
CH3
CH3
H
O
CH3
OH
Me2BuSitO
CH3
85
86
87
88
 Chemical consequence of conformation in macrocyclic compounds. An effective approach
to remote asymmetric induction.
O
O
O
89
90
> 95% Trans
Still, W.C.; Gennari, C.; Noguez, J.A..; Pearson, D.A., JACS, 1984, 106(1), 260 &
Still, W.C.; Galynker, I., Tetrahedron, 1981, 37 (23), 3981
91
O
O
O
92
98% Cis
19
Macrocycles
 Stereochemical control - acyclic and macrocyclic natural products rely on some form of
absolute stereochemical control to set up remote diastereometric relationship
 Readily available enantiomerically pure S.M.
 Resolution of an intermediate
 Asymetric induction by enantiomerically pure reagent
 Still’s alternative – pre-existing substrate chirality, which may be quite distant from the
reaction site, to direct the stereoselectivity of the reaction.
A. Conformations – Transannular non bonded repulsions and high-energy torsional
arrangements must be minimized
H
Boat-Chair
Two eclipsed
ethane linkages
HH
H
Chair- Chair
Boat-Boat
Four eclipsed Transannular
repulsion
ethane linkages
Still, W.C.; Galynker, I., Tetrahedron, 1981, 37(23), 3981
20
8-Membered Ring
O 1. LDA, THF
O
2. MeI, -60oC
95 % Trans
93
94
kcal/mol
H
kcal/mol
H
H
17.8
H
O
17.9
16.7
O
O
22.2
18.2
O
17.3
H
H
19.2
16.9
O
H
H
O
O
24.9
O
19.8
H
17.2
O
H
18.6
H
H
22.7
H
H
H
H
16.9
O
O
O
H
O
O
H
H
O
96
kcal/mol
H
H
O
2. MeI, -60oC
> 98% Cis
95
kcal/mol
21.2
O 1. LDA, THF
H
H
O
19.2
9-Membered Rings
1. LDA, THF
O
O
2. MeI
O
O
97
98
98 % Cis
Me2CuLI
O
O
O
O
100
99% Cis
99
H2, Pd/C
O
O
O
101
O
102
94% Trans
Still, W.C.; Galynker, I., Tetrahedron, 1981, 37 (23), 3981
22
Peripheral vs Antiperipheral Attack
 3D Structure – sp2 centers are perpendicular to the plane of the ring
Cis-cyclohexene
Cis- cyclooctene
Cis- cyclodecene
 2 faces of π-system are sterically different
 Peripheral attack preferred
Still, W.C.; Galynker, I., Tetrahedron, 1981, 37 (23), 3981
23
Periplanone B- Total synthesis and structure
of the Sex Excitant Pheromone of the
American Cockroach
 Female species of Periplaneta americana, the American
Cockroach.
 In the early 70’s Persoons et al. Isolated two extremely
active compounds, periplanones-A (-20 pg) and -B (-200 pg).
 Periplanone-B was characterized spectrally and
tentatively assigned a germacranoid structure.
Still reported highly stereoselective syntheses of three of
the four possible diastereomers.
O
O
2
3
1
10
9
O
4
5
6
7
8
106
24
Still, W.C., JACS, 1979, 101(9), 2493
Periplanone B – First Diastereomer
O
O
OAc
O
103
O
R
1. LDA, THF, 0 C
O
2.
, -78oC
H
3. Ac2O, -78oC
1. Me2CuLi, Et2O,
O
0 C, 30 min.
2. mCPBA (1.5 eq)
74%
from 107
O
R
Sn (
)4(1 eq.)
PhLi (4 eq), Et2O, 0oC
106
C-5 and C-6 Diaxial coupling (10Hz);
C-7 and C-8 trans coupling (16 Hz)
R
105
1
8
O
104
7
5
Me3Sn
HO
6
OAc
2. Me3SiCl, -78oC
O R
O
1
Me3SiO
1. Me3SnLi (1.1 eq);
5min.
o
7
6
8
5
O
107
R
O
1.KH, 18-Crown-6
THF, 1hr, 70oC
OH
2. Me3SiCl, mCPBA
-78oC
RO
57%
108
Still, W.C., JACS, 1979, 101(9), 2493 &
Adams, M.A.; Nakanishi, K.; Still, W.C.;
25
Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9), 2495
Periplanone B – Stereocontrol
Approach
X
Peripheral
Attack
 Diastereomers synthesis:
 1-5 Cyclodecadienes have a well defined conformation
 Olefinic linkage perpendicular to plane of ring.
 Attack from less hindered peripheral face of the π system
Still, W.C., JACS, 1979, 101(9), 2493 &
Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9), 2495
26
Periplanone B – First Diastereomer
O
OH
O
O
O
I
S
OTBDMS
1. Me2-t-BuSiCl
RO
2. t-BuOOH, Triton B,
THF, 66%
109
R=
O
110
NaH, , THF, DMSO
-5oC, 75%
111
RO
RO
O
1. H20.HOAc (1:1)
25oC, 15 minutes
2. o-NO2C6H4SeCN,
Bu3P, THF, 5 min,
o
OTBDMS
O
0 C
o
3.H2O2, THF, 18h, 25 C
68%
OTBDMS
O
1.TBAF, THF
O
2. PCC, DCM
112
O
O
H
O
O
H
Hb
H
O
113
O
Ha
Spectral comparison with
authentic Periplanone-B
concludes they are
Unidentical
27
Periplanone B – First Diastereomer
H
O
O
H
7
O
8
H
H 9b
H
O
O H
H
H 9a
First Disatereomer
Hb
O
Ha
Periplanone B
300-MHz NMR strongly suggest :
 Only difference is the configuration of the isopropyl group.
Pseudo-axial in X: (J7-8 = 5, J8-9a = 7.5, J8-9b= 2 Hz)
Pseudo-equatorial (Periplanone B) : (J7-8 = 10, J8-9a = 10, J8-9b= 5.5 Hz
Still, W.C., JACS, 1979, 101(9), 2493 &
Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9), 2495
28
Periplanone B – Second Diastereomer
O
OH
O
O
OTBDMS
1. Me2-t-BuSiCl
RO
2. t-BuOOH, Triton B,
THF, 66%
109
R=
1. PCC, DCM
O
O
1. o-NO2C6H4SeCN,
Bu3P, THF, 5 min,
0oC
2. H20.HOAc (1:1)
25 C, 15 min.
110
1.Me3SiCH2MgCl, Et2O
2. KH, THF, 62%
3. TBAF, THF
4. t-BuOOH,
RO
Vo(acac)2, benzene
95%
O
114
O
O
o
RO
OH
O
HO
115
2.H2O2, THF, 18 h, 25oC
O
O
O
116
O
H
O
H
H
H
O
H
 NMR of 116 is very different than Periplanone B
 Transannular -O- interaction is replaced by a more severe -CH2- interaction
Still, W.C., JACS, 1979, 101(9), 2493 &
Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9), 2495
29
Periplanone B -Third Diastereomer
 Construction of the stereoisomeric C-2 – C-3 cis epoxide:
Desired epoxide is the more hindered one.
Disfavoured
Antiperipheral attack
needed
favoured
peripheral attack
NOT WANTED
 Alternate tactic was chosen – construction of the C-5 – C-7 conjugated diene :
H
2
3
5
O
H
7
6
O
H
OR
H
H
s-trans
H
OR
New conformation exposes opposite face to peripheral attack
Still, W.C., JACS, 1979, 101(9), 2493 &
Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9), 2495
30
Periplanone B -Third Diastereomer
O
RO
OTBDMS
1. H20.HOAc (1:1)
O
o
25 C, 15 minutes
BuOOH, KH
2. o-NO2C6H4SeCN,
Bu3P, THF, 0oC
3.H2O2, THF, 18h, 25oC
54%
117
R=
OTBDMS
H
O
H
THF, -20oC
74%
4:1
118
O
OTBDMS
119
O
O
I
S
NaH, , THF, DMSO
-5oC, 69%
H
O
H
OTBDMS
H
1.TBAF, THF
2. PCC, DCM
81%
O
120
O
H
O
O
O
O
H
H O
H
121
 Comparison of (±) – 121 with Periplanone–B showed they were identical
Still, W.C., JACS, 1979, 101(9), 2493 &
Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9), 2495
31
Columbia University (1977-1998)
 An internal Coordinate Monte Carlo method for searching conformational Space
Pass
constraint
Test 1?
Yes
Yes
Duplicate
of previous
structure?
No
Begin with Random
initial Structure
Reconnect
ring closures
Energy Minimize
Yes
Pass
constraint
test 2?
Energy
within desired
bounds
No
Save
Structure
Yes
No
Apply random
variations to
chosen coordinates
Choose
coordinates
to be varies
Open ring
closures
Choose
new starting
geometry
Search
complete?
No
Yes
Recover previous
starting geometry
Done. Order structures
by energy and output
to file.
 Random Search for finding the low-energy
conformations of molecules
 Was the first to create a software available and
and fairly easy to use for the general public
32
Chang, G.; Guida, W.C.; Still, W.C., JACS, 1989, 111 (8), 3075
Columbia University (1977-1998)
 Complex Synthetic chemical libraries indexed with molecular tags
Cl
O
HOOC
O
O
n
Ar
Cl
Cl
Cl
Cl
Ar =
O
Cl Cl
NO2
Cl
Cl
F
Cl
Linker
Electrophoric Tag
 A new generation of Fluorescent chemosensors demonstrate improved analyte detection
sensitivity and photobleaching resistance.
F
F
ANALYTE
Q
ANALYTE
Q
Nestler, H.P.; Barlett, P.A.; Still, W.C., J. Org. Chem., 1994, 59(17), 4723 &
Ohlmeyer, M.H.J.; Swanson, R.N.; Dillard, L.W.; Reader, J.C.;Asouline, G.;Kobayashi, R.; Wigler, M.;Still, W.C., Proc. Natl. Acad. Sci. USA,
1993, 90(23), 10922 & Rothman, J.H.; Still, W.C., Bioorg.& Med. Chem. Letters, 1999, 9(4), 509 &
33
Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, 279 (5352), 851
Complex Synthetic Chemical Libraries
Indexed with Molecular Tags
 Spacially segrated arrays
Only small libraries
 Multivalent synthesis methods
Moderate complexity library is produced
 Pooling of multiple reagents during synthesis
 Pool is identified to have interesting properties
 Resynthesized with lower and lower complexity till one compound is identified
 NOT practical for construction of massive libraries.
Split synthesis
 On solid particles (ex. Beads)
 Each bead has a product from a single reaction sequence bound to it
 Selection of a bead with desirable property followed by ID of substrate by analytic method.
 Only for compounds that can be readily elucidated by micro scale sequencing.
 Co-synthesis method
Co-synthesis of a sequencable tag encoding the steps and reagents used in each step.
 Oligonucleotide and oligopeptide tags are used
Problem = tag is labile, can associate selectively with biological receptors.
34
Ohlmeyer, M.H.J.; Swanson, R.N.; Dillard, L.W.; Reader, J.C.;Asouline, G.;Kobayashi, R.; Wigler, M.;Still, W.C., Proc. Natl. Acad. Sci. USA, 1993, 90(23), 10922
Complex Synthetic chemical libraries
indexed with molecular tags
 Chemically encoded combinatorial library
 Synthesis on microsphere beads (like in split method)
 Each step tagging molecules are attached to the beads
 Encodes both the step number and reagent used in that step = Binary record
 No co-synthesis required (tags not connected)
 20 tags = 1 048 576 different syntheses
Cl
HOOC
O
NO2
O
n O
Cl
Ar
Cl
Cl
Cl
Cl
F
Ar =
Cl
O
Cl
Linker
H
H
H
H
Cl
Cl
Electrophoric Tag
Ohlmeyer, M.H.J.; Swanson, R.N.; Dillard, L.W.; Reader, J.C.;Asouline, G.;Kobayashi, R.; Wigler, M.;Still, W.C., Proc. Natl. Acad. Sci. USA,
1993, 90(23), 10922
35
Result Analysis
Peptide library beads stained with mAb 9E10.
GC of tags from EQKLISEEDLGGGG-Bead
Ohlmeyer, M.H.J.; Swanson, R.N.; Dillard, L.W.; Reader, J.C.;Asouline, G.;Kobayashi, R.; Wigler, M.;Still, W.C., Proc. Natl. Acad. Sci. USA,
1993, 90(23), 10922
36
General Method for Molecular Tagging of
Encoded Combinatorial Libraries
 Requires no particular tag-attaching functional group other than what already
makes up the polymer matrix
 New tagging reagent = tag plus linker
Vanillic Acid derivative
Cl
Cl
Cl
O
Cl
n
OH
Cl
Cl
Cl
O
Cl
Cl
n
O
MeO
COY
Cl
Tn
TnA : Y = OH
TnB : Y = Cl
TnC : Y = CHN2
Halophenol derivative
Chemically inert & Analysis by ECGC
Nestler, H.P.; Barlett, P.A.; Still, W.C., J. Org. Chem., 1994, 59(17), 4723
37
Fluorescent, Sequence-Selective Peptide
Detection by Synthetic Small molecules
Chemosensors are small molecules that signal the presence of analytes, and typically have
two components:
o Receptor – site that selectively binds an analyte
o Redout mechanism – signals binding.
F
F
ANALYTE
Q
Chemosensor for tripeptides in CHCl3.
Function as synthetic analogs of the
antigen-binding site of immunoglobulins
Rothman, J.H.; Still, W.C., Bioorg.& Med. Chem. Letters, 1999, 9(4), 509 &
Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, 279 5352), 851
ANALYTE
Q
FET signal transduction system
38
Chemosensors
N
PhOCHN
OCNH
O
HNCO
CO2
OC
OCNH
NH
F
HNCO
CO
OC
NH
NH
Q
F
CHO
N
HN
NH
OCNH
HNCO
CO2
OC
OCNH
HN
NH
OC
CO
F
HNCO
Q
O
Chemosensor A
N
H
N
PhOCHN
Chemosensor B
Q = COC6H4N=NC6H4NMe2
Dabcyl N-hydrosuccinamide ester
F = (CH2)2NH-SO2C10H6NMe2
Dansyl sulfonamide of ethanolamine
39
Fluorescent, Sequence-Selective Peptide
Detection by Synthetic Small molecules
Fluorescence spectra of chemosensor A and B with Peptides P1 and P2
 Demonstrate the sequence selective optical detection of peptides
 By small molecules chemosensor
Can be extended to solid state libraries
Rothman, J.H.; Still, W.C., Bioorg.& Med. Chem. Letters, 1999, 9(4), 509 &
Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, 279 (5352), 851
40
New Fluorencent Chemosensors with
Improved Photobleaching Resistance
Photobleaching : is the photochemical destruction of a fluorophore.
•Major problem with chemosensors that report binding via fluorescence trough UV
FRET ( fluorescence resonance energy transfer) interaction
 The level of fluorescence that escapes quenching is proportional
to the binding strength
 Photobleaching is a significant source of detection error.
Rothman, J.H.; Still, W.C., Bioorg.& Med. Chem. Letters, 1999, 9(4), 509 &
Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, 279 (5352), 851
41
New Fluorencent Chemosensors with
Improved Photobleaching Resistance
Dansyl fluorofore moiety
Known to undergo photobleaching
Rothman, J.H.; Still, W.C., Bioorg.& Med. Chem. Letters, 1999, 9(4), 509 &
Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, 279 (5352), 851
42
Dansyl vs Acridone Moiety
 Replacement of the dansyl fluorophore moiety with an acridone derivative
Dansyl Fluorophore moiety:
SO2NH
SO2Cl
H2N
OH
OH
iPr2EtN
NMe2
NMe2
122
123
Acridone Fluorophore moiety:
O
O
1. NaH, DMF
N
H
124
2. MeI
85%
O
SO2Cl
1. ClSO3H
N
125
2. NaHCO3 aq
65%
N
126
H2N
OH
iPr2EtN
80%
O
SO2NH
N
Rothman, J.H.; Still, W.C., Bioorg.& Med. Chem. Letters, 1999, 9(4), 509 &
Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, 279 (5352), 851
OH
127
43
New Fluorencent Chemosensors with
Improved Photobleaching Resistance
Receptor binding saturation experiment.
 Receptor is now more resistant to fluorophore photobleaching.
 No significant change in binding saturation characteristics
 Acridone exhibits increased fluorescence upon binding
Rothman, J.H.; Still, W.C., Bioorg.& Med. Chem. Letters, 1999, 9(4), 509 &
Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, 279 (5352), 851
44
Conclusion
 Still was clearly ahead of his time
- Total synthesis
- Computational chemistry
- Methodology
- Chemical biology etc..
 3 most cited papers (from a total of 190 publications):
1) Still W.C.; Kahn M., Mitra A., Rapid Chromatographic Technique for Preparative
Separations with Moderate Resolutions, J. Org. Chem., 1978, 43(14), 2923
Times Cited: 7419
2) Mohamadi F.; Richards N.G.J; Guida W.C.; Still, W.C., Macromodel -an Intergrated
Software System for Modeling Organic and bioorganic Molecules Using Molecular
Mechanics, J. Comp. Chem., 1990, 11(4), 440
Times Cited: 2788
3) Still, W.C.; Tempczyka, A.; Hawley R.C. Semianalytical Treatment of Solvation for
Molecular Mechanics and Dynamics, JACS, 1991, 112(16), 6127
Times Cited: 1511
 Retired at 53 years old – Emeritus professor at Columbia University
 Never got an NIH grant
 Now building planes as a hobby.....
45
Prof. Louis Barriault
Graduate students
Jason Poulin
Minaruzaman
Kassandra Lepack
Francis Barabé
Christiane Grisé-Bard
Eric Beaulieu (Past)
Marie-Christine Brochu (Past)
Steve Arns (Past)
Undergrads
Anne-Catherine Bédard
Grabriel Bellavance
Jean-Francois Vincent-Rocan
Olivier Gagné
Patrick Lévesque (Past)
46
Monensine
HO
O
O
H
OCH3
COOH
H O
H
H O
H
HO
O
OH
17 asymmmetric centers, 26 carbon backbone
 theoretically 131 072 stereoisomers can exist
 Polyether antibiotics constitute a growing class of naturally occurring ionophores.
47
Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117
Retrosynthetic Pathway
HO
O
O
H O
H
OHC
H
Ph3P
O
OH
HO
O
H
OR
O RO
COOCH3
H
X
CHO
OCH3
COOH
O
H
H O
OCH3
COOH
O
H
H
O
H O
H
O
H O
O
Br
H O
OR`
R``O
O
O
48
Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117
Monensin- Chromic Acid Degradation
HO
O
O
H
OCH3
COOH
H O
CrO3
H
H O
H
HO
HOAc
COOH
O
H
O
O
OH
OCH3
O
O
H O
H
H O
H
O
O
Why degradation ? :
 Called relay synthesis
 Structure proof of advanced synthetic intermediates
 Ex: Stereochemistry
49
Dongwei, C.;Still, W.C.; J.Org. Chem., 1988, 53, 4641
Monensin – Further Degradation
COOH
O
H
1.EtO2CCl, Et3N
NaBH4, Ether
O
4h, 25oC
OCH3
2.Benzyl
chloromethylether,
i-Pr2NEt
O
OBz
O
O
H
O
LiOH, H2O,
THF, 0oC
OCH3
OBz
OH
1. Protection
2. Hydrogenation
OCH3 3. Oxidation
COOCH3
CHO
OSiEt3
OCH3
COOCH3
50
Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117
Monensin- Retrosynthetic Scheme
HO
O
O
H O
H
OHC
H
Ph3P
O
OH
HO
O
H
OR
O RO
COOCH3
H
X
CHO
OCH3
COOH
O
H
H O
OCH3
COOH
O
H
H
O
H O
H
O
H O
O
Br
H O
OR`
R``O
O
O
51
Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117
Monensin- Further Degradation
O
O
O
O
H
HO
H
O
HO
H
O
H
H
O
O
OH
p-TsOH, HC(OMe3)3
25oC, 60%
O
H
O
H
H
O
O
H O
1.MeLi (1.2 eq)
THF, -78oC
2.Ph3PCH3Br,
Buli, THF,
73%
H
H
H
NBS,
p-TsOH,
DCM, 96%
O
O
Br
O
H O
O
O
O
H
H O
H
O
O
52
Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117
Monensin- Further Degradation
O
O
H O
O
1.excess MeLi,
Et2O, 80%
H
H O
H
O
O
H
O
O
O
H
1.excess MeLi, O
Et2O, 80%
H
H O
2. CrO3.2Py, DCM
10h
O
H O
O
2. CrO3.2Py, DCM
10h
1. Dibal,
tol., -78oC
2. Ph3PCH3Br,
BuLi, THF
84%
I
H
O
H
O
O
1.PhCO2H,
DBU,DMF
2. LAH, Et2O
40%
3. p-TsOH
H
O
O
74 %
OH
H
O
H
O
H
O
O
1. NIS DCM
O
0oC, 94 %
(4:1)
H
HO
H
O
O
O
53
Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117
Monensin- Retrosynthetic Scheme
HO
O
O
H O
H
OHC
H
Ph3P
O
OH
HO
O
H
OR
O RO
COOCH3
H
X
CHO
OCH3
COOH
O
H
H O
OCH3
COOH
O
H
H
O
H O
H
O
H O
O
Br
H O
OR`
R``O
O
O
54
Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117
Forward Synthesis
1.
O
OBz
O Si
OBz
O
CHO
CHO
O
LDA, THF, -110oC
OCH3
2. MgBr2, 85 %
3. H5IO6, MeOH
4. i) KN(TMS)2
ii) (CH3)2SO4
50%
COOCH3
1.H2, Pd/c, THF
2. CrO3.2Py, DCM
90%
Al
OCH3
-78oC, THF
COOCH3
O
OSiEt3
OSiEt3
O3, MeOH
Me2S, Py
95%
OCH3
OCH3
COOCH3
COOCH3
O
HOOC
COOH
O O
H
p-TsOH, 85%
OH
O
O
COOH
H
1. BH3, THF
1. LiOH, THF, H2O
2. CH2N2
O
Collum, D.B.; McDonald, J.H.III;
Still, W.C., JACS, 1980, 102(6), 2118
O
O
H
3. Et3SiOClO3, ACN,
Py
OCH3
OTMS
O
O
H
1. MeMgBr (1 eq),
THF, -78oC
OBz 2. t-BuMe2SiCl,
DMF, im
O
2. H3O+
3.BnOMeCl, iPr2Et
75%
Br
H
O
O
H
O
OBz
OTMS 1.
BrMg
1. NBS, Ph3P
71%
HO
H
OH
THF, -78oC
2. Li, NH3, -78oC
70%
55
Forward Synthesis
COOBz
1. O3, AcOH, -78oC
2. Jones, -78oC to 0oC
3. Pb(OAC)4, Cu(OAC)2,
Bn, 80oC, 80%
1. KOH, MeOH, H2O
o
COOBz 2.I2, ACN, -15 C
89%
CHO
O
O H
1.
THPO
CHO 2. PTSA, reflux, 8hrs
50%
1. LiALH4, Et2O
2.(CH3)2CO, CuSO4
p-TSOH
3.CrO3.Py.HCl, DCM
80%
1. 5% Rh/Al2O3
O
2
o
O Et O, -10 C
1. BzOK,
THF,-200C
2.10% Pd/C,
Et2O, 84%
O
I
O
O , LDA, oTHF,
-78 C
O
H
O
H
O
O
OH
HI conc., 130oC
10 min then
PPh3 (1.2 eq)
0
O 130 C, 3h Ph3P
COOH
56
Collum, D.B.; McDonald, J.H.III; Still, W.C., JACS, 1980, 102(6), 2118
Forward Synthesis
CHO
O
COOH
Ph3P
O H
NaH, Me2SO, 250C
O
O
KI3, NaHCO3
O H
18hr, 70%
H
O H
H2O, 87%
I
O
HOOC
O
O
HO
PyrS
H
O
H
H
1. Jones ox.
O
2. 2-PyrSH, COCl2
Et3N
O
H
O
H
H
AcOCF3
O
DCM, 25oC
50%
O
57
Collum, D.B.; McDonald, J.H.III; Still, W.C., JACS, 1980, 102(6), 2118
SPy
r
Forward Synthesis
Br
CHO
O
O
O
O HO
H
H
H
O
H
H O
OSiEt3
H
H O
H
O
OCH3
O
COOMe
O
75%
HO
HO
O
O
H
OCH3
COOH
H O
OH
LDA, -78oC,
THF ; MgBr2
H
H
H O
H
HO
1. 10% Pd/C, H2, Et2O
2. p-TsOH, DCM, Et2O, H2O
3. NaOH, H2O, MeOH
O
OH
H
O
O
SiEt
3
OCH
3
COOMe
H
H O
H
BzO
O
OMe
58
Collum, D.B.; McDonald, J.H.III; Still, W.C., JACS, 1980, 102(6), 2120