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Transcript of 1 Clark W. Still Career in Review Department of Chemistry, University of Ottawa March 17 th, 2009 By...
1
Clark W. StillCareer in Review
Department of Chemistry, University of OttawaMarch 17th, 2009
By Anik Michelle Chartrand
2
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
3
Graduate Studies
4
His Graduate Work (1969-72)
Diborane Reductions of Oxygen Heterocycles Hydroboration-Oxydation Products of Oxygen
Heterocycles
H3C O H
CH3 OCOCH3
CH3
O
Trichodermin
Early work towards the synthesis of Trichodermin led to a borane oxidation sequence development
O O OH
OBR2 O
O
O
O
OH
O
OBR2
1,2
1,4
Conditions: i) NaBH4, Diglyme, BF3.O(CH2CH3), THF ii) NaOH, H2O2
1 2 3
4
5
6
7W. C. Still and D.J. Goldsmith, J. Org. Chem., 1970, 35 (7), 2282
O
O
4,7-dimethyl-3-chromanone
5
His Graduate Work (1969-72)
Bicyclic Intermediate for Trichothecane Synthesis Exploitation of an Enolate as a Protecting Group Tandem sequence involving bis alkylation
OO
O
CH3
1. Me2CuLi2. MeLi
3. H3O+
O
O
CH3
HO H
9 10
The decarboxylative elimination reaction of β,γ- epoxyacids to make allylic alcohols
O
OO
O
O
H
8
OO
O
CH3
Me2CuLiOO
CH3
O
H
MeLi OHO
CH3
O
H
H3O+OHO
CH3
O
H
9 11 12 10
Still, W.C.; Lewis, A.J.; Goldsmith D.; Tetrahedron Letters, 1971, 18, 1421Still, W.C.; Lewis, A.J.; Goldsmith D.; Tetrahedron Letters, 1973, 48, 4807
6
His Graduate Work (1974-75)
HOH
H
H
CO2H
OH
O O
Gibberellic Acid
Most of his work with Prof. Stork concentrated of the formation of Gibberellic Acids B-C-D ring:
H
H
OOH
C
H
H
Me3SiOOH
C
12
3
LDA (5.5 eq.)HMPA (30%) in THF
-200C
1.
2. TMSCl
12
3
15 16
HO
O
O
HOH
O
O
K, NH3/THF (6:1)
(NH4)2SO4
13 14
Stork, G.; Boeckman, R.K. Jr..; Taber, D.F.; Still W.C. Singh, J. ,JACS, 1979, 101 (23) 7107Stork, G.; Still W.C. Singh, J., Tetrahedron Letters, 1979, 52, 5077
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
Reductive cyclization of Ethynyl ketones
7
Independent Researcher
Vanderbilt University Columbia University
8
His Work at Vanderbilt University (1975-76) Organo cuprates and the development of a new highly selective stereoselective
alkylation agent to produce axial alcohols
t-Bu
O Me3CuLi2
t-Bu
OHCH3
Et2O, - 700C
17 18
Conjugate Addition of trimetylsilyllithium – Axial addition is highly favoured
“ 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.”
O
Me3Si OLi
OMe3Si
Me3SiLi
THF-HMPA
MeOH
Me3SiCl
MeI
OSiMe3Me3Si
OMe3Si
-78oC
H3O
(99%)
(97%)
(99%)19
20
21
22
23
Macdonald, T.L.; Still, W.C.; JACS, 1975, 97(18), 5280 & Still, W.C., J. Org. Chem., 1976, 41(18), 3063
OMe3SiLi
Me3SiLiO
OMe3Si
No reaction
24 25
26
9
His Work at Vanderbilt University (1975-76)
Allyloxy Carbanions:
Cyclization to vinyl oxetans via allyloxycarbanions :
Selective fomation of the more strained oxetane as long as the addition produces the cis ring juncture
O
Cl
sec-BuLiTHF-HMPA, -78oC
O
Cl
O
H
H H
H
and/or
O
27 28 29 30
Still C.W., Tetrahedron Letters, 1976, 25, 2115 & Still, W.C.; Macdonald, T.L.; J. Org. Chem., 1976, 41(22), 3620.
O
Cl
28
10
His Work at Vanderbilt University (1975-76)
Claisen Variant:
Tin chemistry (stannylation/destannylation) α-Alkoxy Organolithium Reagents
ROH
RO
OR'
RO
OR'
CH2NR2
RH
R'O2C31
32
33
34
O
CH3
CH3
O
H
H
Terpenoid35
R-CHO ROR'
SnBu3
BuLiR
OR'
Li
1) Bu3SnLi
2)R'X
O
HO
ROR'
36 37 38 39
Still, C.W.; Schneider, M.J., JACS, 1977, 99(3), 948 & Still, C.W., JACS, 1978, 100 (5), 1481
11
His Work at Vanderbilt University (1975-76)
Alkylation and oxidation – efficient dialkylative enone transposition
Tri-alkyl tin anions undergo high yield conjugate addition to α,β-enones to give the regiospecific enolate
O
Bu3SnLi
OBu3Sn-78oC, THF
5min, 96%
SnBu3O
2.2 A
Alkylstannanes are smoothly oxidized by chromic anhydride/pyridine to the corresponding ketone
O1.Me3SnLi
2. n-C5H11I
O
SnMe3O
1. MeLi
2. CrO3, Py
3. NaOH90%
89%45 46 47
Still, C.W., JACS, 1977, 99(14), 4836
Bu3Sn OH O OH
CrO3/Py
DCM, R.T.
75%43 44
40 41 42
12
Columbia University (1977-1998) Anionic [2,3]-sigmatropic rearrangements
O
SnBu3
OEE
O
SnBu3
BuLi
OEE
OHOH
48 49
O
Me
R
HH
H
O
Me
H
RH
H
((
Pseudoaxial Pseudoequatorial50 51
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
O
Li
RotationO
Li
O
OH
52 53 54 55
13
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.”
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
Columbia University (1977-1998)
OH
OHH
OHHO
OHO
O
HO
H
COOHOCH3
56
17 asymmmetric centers, 26 carbon backboneTheoretically 131 072 stereoisomers can exist
Monensin – Polyether antibiotic and naturally occurring ionophore
14
Columbia University (1977-1998) Direct Synthesis of Z-unsaturated esters; a useful modification of the Horner-Emmons Olefination
R'P
ORR
1, Base/Solvent
2. O
R2H
R2H
H R'R= Aryl, alkyl R= O-Aryl, O-Alkyl, NR2
Horner- Wittig
Wadsworth-Emmonds
E-alkene
57 58
R'P
ORORO O
HR2
HR2
H R'
Z-alkene
1, Base/Solvent18-crown-6
2.
R = CH2CF3
59 60
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
Still – Gennari Modification
Horner-Wadsworth-Emmons
15
Z-trisubstituted Allylic Alcohols via the Wittig Reaction
(Ph)3P CH2R
R'
R
Trans-selective Olefin synthesis (1965) - Schlosser
R'CHOPhLi (2 eq), ether
HCl/t-BuOK61 62
(Ph)3P CHRR R'
Cis-selective Olefin synthesis (1965) - Schlosser
i) NH3. NaNH2,
ii) R'CHO, Benzene
0oC, 1hr63 64
(Ph)3P CHCH3
O
CH
CH3
P(C6H5)3
H
n-C6H5
CH3
CH2OH
Stereospecific Synthesis of Certain Trisubstituted Olefins (1970) - E.J. Corey
n-C6H13CH
i) n-Buli, THF
-780Cii) CH2O (2eq)
0oC to R.T.
n-C6H13CHOTHF, -780C
65 66 67Schlosser, 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
16
Z-trisubstituted Allylic Alcohols via the Wittig Reaction
OOTHP
Ph3P=CHR
R
CH2CH2CH3
CH(CH3)2
R OTHP
A Direct Synthesis of Z-trisubstitured Allylic Alcohols via the Wittig Reaction
Z:E Yield
60:1
6:1
87%
45%
68 69
PPh3O
OTHP
OH
Application in Synthesis
1.
2. H3O
85 %99:1 (Z:E)
70 71
No β-oxido Ylide intermediate or n-BuLi required
Counterion effect
Phosphonium fluoroborate Vs
Phosphonium halide
Sreekumar, C.; Darst, K.P.; Still, W.C., J. Org. Chem, 1980, 45(21), 4260
α-santalol
α
α ‘
17
Columbia University (1977-1998) Dichlorocarbene cyclopropanation of allylic alcohols:
OHOH OH
(8:1)
CHCl3,BzN(Et)3Cl
NaOH, 0oC, 4hrs
ClCl
ClCl
HOH
H OH3C
HObserved relative energyCalculated relative energy
0.0 kcal/mol0.0 kcal/mol
0.52 kcal/mol0.60 kcal/mol
72 73 74
This is a Simmons-Smith equivalent that works well in acyclic systems
Synthesis of Alternating Hydroxy- and Methyl-Substituted Hydrocarbons by Oxymercuration of Cyclopropylcarbinols.
OH OH
OR
HgCl LiAlH4
OH
CH3
OH
a) Hg(OR)2
b) NaCl
75 76 77
Mohamadi, F.; Still, W.C., Tetrahedron Letters, 1986, 27(8), 893 &Collum, D.B.; Still, W.C., Mohamadi, F., JACS, 1986, 108(8), 2094
18
Columbia University (1977-1998) A highly stereoselective synthesis of trans epoxides via arsonium Ylides
O
R H
Ph3As
RCH3
H
HO
R= cyclohexyl, > 99% E (84%)R= phenyl, 83% E (61%)
78 79
Remote 1,3-, 1,4-,and 1,5- asymmetric induction. A stereoselective approach to acyclic diols via Cyclic Hydroboration
High stereoselectivity for trans epoxide ≥ 50:1
Still, W.C.; Novack, V. J., JACS, 1981, 103(5), 1283 &Still , W.C..; Darst, K.P., JACS, 1980, 1021(24), 7385
R BH2 H3C
H
B
H
HOH
OH
OH
OH
1)
2) NaOOH
(8:1) 96%+
B
H
H3C
H
H
Major
Minor
80 81
82
83
84
19
Columbia University (1977-1998) Synthesis of Macrocyclic Trichothecanoids: Baccharin B5 and Roridin E
Chemical consequence of conformation in macrocyclic compounds. An effective approach to remote asymmetric induction.
O O
> 95% Trans
89 90
O
O
O
O
98% Cis91 92
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
85 86 87 88
OO H
CH3OO
CH3
OO
HO
O
O
HO CH3
H
H3CH
O
OH
CH3OO
CH3
O
O
O
HO CH3
H
H3CH
OO
H
CH3OO
O
O
O
HO CH3
H
H3CH
O
CH3
OH
CH3OO
O
O
Me2BuSitO CH3
H
H3CH
O
CH3
O
O O
mCPBA
20
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 H HH
Boat-Chair Chair- Chair Boat-Boat
Two eclipsed ethane linkages
Four eclipsed ethane linkages
Transannular repulsion
Still, W.C.; Galynker, I., Tetrahedron, 1981, 37(23), 3981
O O1. LDA, THF
2. MeI, -60oC
95 % Trans93 94
O O1. LDA, THF
2. MeI, -60oC
> 98% Cis95 96
O
H
O
H
H
O
H
O
H H
HH
O
O
O
O
H
H
H
17.8
21.2
17.3
17.9
22.2
19.2
24.922.7
kcal/mol kcal/mol
O
H
O
H
H
O
H
O
H H
HH
O
O
O
O
H
H
H
16.7
18.2
16.9
16.9
18.6
19.8
19.217.2
kcal/mol kcal/mol
H
8-Membered Ring
22
O
O
O
O
O
O
O
O
O
O
O
O
98 % Cis
99% Cis
94% Trans
1. LDA, THF
2. MeI
Me2CuLI
H2, Pd/C
97 98
99 100
101 102
Still, W.C.; Galynker, I., Tetrahedron, 1981, 37 (23), 3981
9-Membered Rings
23
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
24
Periplanone B- Total synthesis and structure of the Sex Excitant Pheromone of the
American Cockroach
Female species of Periplaneta americana, the AmericanCockroach.
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.
OO
O1
2
3
45 6
78
910
106
Still, W.C., JACS, 1979, 101(9), 2493
Periplanone B – First Diastereomer
O
O O
RH
O
O
OR
O OAc
O R
OR
HO
Me3SiO OAc
OR
Me3Sn
OOH
RO
1. LDA, THF, 0oC
2., -78oC
3. Ac2O, -78oC
2. Me3SiCl, -78oC
1. Me2CuLi, Et2O,
0OC, 30 min.2. mCPBA (1.5 eq)
1
5
67
8
1
5
67
8
74% from 107
1.KH, 18-Crown-6THF, 1hr, 70oC
2. Me3SiCl, mCPBA
-78oC
1. Me3SnLi (1.1 eq); 5min.
Sn ( )4(1 eq.)
PhLi (4 eq), Et2O, 0oC57%
103 104 105
106 107 108
C-5 and C-6 Diaxial coupling (10Hz); C-7 and C-8 trans coupling (16 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
25
26
Peripheral AttackX
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
Periplanone B – Stereocontrol Approach
27
OOH
RO
OOTBDMS
RO
OO
SI
OTBDMS
RO
O
O1. Me2-t-BuSiCl
2. t-BuOOH, Triton B, THF, 66%
NaH, , THF, DMSO
-5oC, 75%109 110 111
OTBDMSO
O
OO
O
OH
HO
Ha
HbH
O
1. H20.HOAc (1:1)
25oC, 15 minutes
2. o-NO2C6H4SeCN,
Bu3P, THF, 5 min,
0oC3.H2O2, THF, 18h, 25oC
68%
1.TBAF, THF
2. PCC, DCM
112 113
Spectral comparison with authentic Periplanone-B
concludes they are Unidentical
Periplanone B – First Diastereomer
R=O
28
OH
HO
H
HH
O
HOH
HO
Ha
HbO
Periplanone B
7
8
9a
9b
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
Periplanone B – First Diastereomer
First Disatereomer
29
OOH
RO
OOTBDMS
RO
OOH
RO
O
O1. Me2-t-BuSiCl
2. t-BuOOH, Triton B, THF, 66% 4. t-BuOOH,
Vo(acac)2, benzene 95%
3. TBAF, THF
1.Me3SiCH2MgCl, Et2O2. KH, THF, 62%
109 110 114
2. H20.HOAc (1:1)
25oC, 15 min.
1. o-NO2C6H4SeCN,
Bu3P, THF, 5 min,
0oC
2.H2O2, THF, 18 h, 25oC
1. PCC, DCM
O
HO
O
O
OO
O
OH
HO
H
HH
O115 116
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
Periplanone B – Second Diastereomer
R=O
30
Periplanone B -Third Diastereomer Construction of the stereoisomeric C-2 – C-3 cis epoxide:
Desired epoxide is the more hindered one.
DisfavouredAntiperipheral attack
needed
favouredperipheral attack
NOT WANTED
Alternate tactic was chosen – construction of the C-5 – C-7 conjugated diene :
O ORH
HH O
HH H OR
32
5
7
6
s-trans
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
31
OOTBDMS
RO
OOTBDMS
OOTBDMS
OH
H1. H20.HOAc (1:1)
25oC, 15 minutes
2. o-NO2C6H4SeCN,
Bu3P, THF, 0oC3.H2O2, THF, 18h, 25oC
54%
BuOOH, KH
THF, -20oC
74%4:1117 118 119
O
SI OTBDMS
OH
H
O
OH
H
O
O
HH H
O
O
O
NaH, , THF, DMSO
-5oC, 69%
1.TBAF, THF
2. PCC, DCM81%
120 121
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
Periplanone B -Third Diastereomer
R=O
32
Columbia University (1977-1998) An internal Coordinate Monte Carlo method for searching conformational Space
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
Chang, G.; Guida, W.C.; Still, W.C., JACS, 1989, 111 (8), 3075
Begin with Randominitial Structure Energy Minimize
Reconnect ring closures
Energy within desired
bounds
Pass constraint
test 2?
Apply random variations to
chosen coordinates
Choose coordinates to be varies
Open ringclosures
Choose new starting
geometry
Search complete?
Save Structure
Duplicate of previousstructure?
Passconstraint
Test 1?
Yes
No
Yes
No Yes
Yes No
Yes
No
Done. Order structuresby energy and output
to file.
Recover previousstarting geometry
Complex Synthetic chemical libraries indexed with molecular tags
HOOC
NO2
O O
O
OArn
Cl
Cl
Cl
Cl
Cl
Cl
ClCl
Cl
FCl
Ar =
Linker Electrophoric Tag
A new generation of Fluorescent chemosensors demonstrate improved analyte detection sensitivity and photobleaching resistance.
F
Q
ANALYTE
F
Q
ANALYTE
Columbia University (1977-1998)
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 &Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, 279 (5352), 851 33
Complex Synthetic Chemical Libraries Indexed with Molecular Tags
Spacially segrated arrays Only small libraries
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 34
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.
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
HOOC
NO2
O O
O
OAr
Cl
Cl
Cl
Cl
Cl
Cl
H
Cl
H
Cl
Cl
H
F
H
Cl
nAr =
Linker 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
37
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
O OH
Cl
Cl
Cl
Cl
Cl
O O
Cl
Cl
Cl
Cl
Cl MeO COY
n n
Tn TnA : Y = OHTnB : Y = Cl TnC : Y = CHN2
Halophenol derivativeChemically inert & Analysis by ECGC
Vanillic Acid derivative
Nestler, H.P.; Barlett, P.A.; Still, W.C., J. Org. Chem., 1994, 59(17), 4723
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 analyteo Redout mechanism – signals binding.
F
Q
ANALYTE
F
Q
ANALYTE
Chemosensor for tripeptides in CHCl3.Function as synthetic analogs of the antigen-binding site of immunoglobulins
FET signal transduction system
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
38
39
Chemosensors
OCNH
HNCOOCNH
HNCOOC CO2
N
NH
NH
OCNH
HNCOOCNH
HNCOOC CO2
Q
F
F
NH
NH
OC
OC
CO
CO
HN
HN
O NH
NHO
NPhOCHN
N
CHO
Q
PhOCHN
F
Chemosensor A
Chemosensor B
Q = COC6H4N=NC6H4NMe2
F = (CH2)2NH-SO2C10H6NMe2
Dabcyl N-hydrosuccinamide ester
Dansyl sulfonamide of ethanolamine
40
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 chemosensorCan 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
41
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
42
Dansyl fluorofore moiety
Known to undergo photobleaching
New Fluorencent Chemosensors with Improved Photobleaching Resistance
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
43
Dansyl vs Acridone Moiety Replacement of the dansyl fluorophore moiety with an acridone derivative
NMe2
SO2ClH2N
OH
NH
O
N
O
NMe2
SO2NHOH
N
O
SO2NH
OH
N
O
SO2Cl
H2NOH
iPr2EtN
Dansyl Fluorophore moiety:
Acridone Fluorophore moiety:
1. NaH, DMF
2. MeI
85%
1. ClSO3H
2. NaHCO3 aq
65%
iPr2EtN80%
122 123
124 125 126
127Rothman, 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
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
New Fluorencent Chemosensors with Improved Photobleaching Resistance
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
45
Conclusion Still was clearly ahead of his time
- Total synthesis - Methodology- Computational chemistry - Chemical biology etc..
Retired at 53 years old – Emeritus professor at Columbia University
Never got an NIH grant
Now building planes as a hobby.....
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
46
Prof. Louis Barriault
Graduate students Jason PoulinMinaruzamanKassandra LepackFrancis BarabéChristiane Grisé-BardEric Beaulieu (Past)Marie-Christine Brochu (Past)Steve Arns (Past)
Undergrads
Anne-Catherine BédardGrabriel BellavanceJean-Francois Vincent-RocanOlivier GagnéPatrick Lévesque (Past)
47
Monensine
17 asymmmetric centers, 26 carbon backbone theoretically 131 072 stereoisomers can exist Polyether antibiotics constitute a growing class of naturally occurring ionophores.
OH
OHH
OHHO
OHO
O
HO
H
COOHOCH3
Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117
48
Retrosynthetic Pathway
Ph3P
COOHOOOHC H
OHO
OO
XH
H
OO
Br
CHO
COOCH3
OR
OCH3 OHO
H
H
OR`R``O
OHO RO
OH
OHH
OHHO
OHO
O
HO
H
COOHOCH3
Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117
49
Monensin- Chromic Acid Degradation
OH
OHH
OHHO
OHO
O
HO
H
COOHOCH3
CrO3
HOAc
O
COOH
OCH3
O
H
OH
OHH
OHOO
O
Why degradation ? : Called relay synthesis Structure proof of advanced synthetic intermediates
Ex: Stereochemistry
Dongwei, C.;Still, W.C.; J.Org. Chem., 1988, 53, 4641
50
Monensin – Further Degradation
O
COOH
OCH3
O
HO
OCH3
O
H
O OBz O
COOCH3
OH
OCH3
OBz CHO
COOCH3
OSiEt3
OCH3
1.EtO2CCl, Et3N NaBH4, Ether
4h, 25oC
2.Benzyl chloromethylether, i-Pr2NEt
LiOH, H2O,1. Protection2. Hydrogenation
3. OxidationTHF, 0oC
Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117
51
Monensin- Retrosynthetic Scheme
Ph3P
COOHOOOHC H
OHO
OO
XH
H
OO
Br
CHO
COOCH3
OR
OCH3 OHO
H
H
OR`R``O
OHO RO
OH
OHH
OHHO
OHO
O
HO
H
COOHOCH3
Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117
52
Monensin- Further Degradation
OH
OH
H
OH
OO
OH
O H
H
OH
OO
OO
OH
O HH
OHHO
OO
OH
OHH
OHO
Br
O
O
OH
p-TsOH, HC(OMe3)3
HO
25oC, 60%
1.MeLi (1.2 eq)THF, -78oC
2.Ph3PCH3Br, Buli, THF, 73%
NBS,p-TsOH,DCM, 96%
Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117
53
OH
OHH
O
O O
O
OH
OH
O O
I
H
OH
OH
OH
H
O
1. NIS DCM
OHO
H
O O
O
OH
HOH
O O
1.excess MeLi, Et2O, 80%
2. CrO3.2Py, DCM10h
74 %
1.excess MeLi, Et2O, 80%
2. CrO3.2Py, DCM10h
1. Dibal,tol., -78oC2. Ph3PCH3Br, BuLi, THF84%
0oC, 94 %
(4:1)
1.PhCO2H, DBU,DMF
2. LAH, Et2O40%
3. p-TsOH
OH
OHH
OHOO
O O
Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117
Monensin- Further Degradation
54
Ph3P
COOHOOOHC H
OHO
OO
XH
H
OO
Br
CHO
COOCH3
OR
OCH3 OHO
H
H
OR`R``O
OHO RO
OH
OHH
OHHO
OHO
O
HO
H
COOHOCH3
Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117
Monensin- Retrosynthetic Scheme
55
Forward Synthesis
CHO
O
OBz
COOCH3
O
OCH3
OBz
CHO
COOCH3
OCH3
O
OCH3
O
H
COOCH3
OSiEt3
OCH3
OO Si1.
LDA, THF, -110oC
2. MgBr2, 85 %
3. H5IO6, MeOH
4. i) KN(TMS)2 ii) (CH3)2SO4
50%
1.H2, Pd/c, THF
2. CrO3.2Py, DCM 90%
Al
-78oC, THF
1. LiOH, THF, H2O2. CH2N2
3. Et3SiOClO3, ACN, Py
O3, MeOH
Me2S, Py
95%COOCH3
OSiEt3
OCH3
O
O
OTMS
HO
OBz
BrMg
O
OO
H
OBz
OTMS
HO
HOH
O O
O COOHH
OO
Br
H
OOCOOH
HOOC HOH p-TsOH, 85%
1. BH3, THF
2. H3O+3.BnOMeCl, iPr2Et 75%
1. MeMgBr (1 eq),
THF, -78oC
2. t-BuMe2SiCl, DMF, im
THF, -78oC
1.
2. Li, NH3, -78oC
70%
1. NBS, Ph3P
71%Collum, D.B.; McDonald, J.H.III; Still, W.C., JACS, 1980, 102(6), 2118
56
COOBzCOOBz O
O
I
H
OO
OH
H
O
O
CHO
H
1. O3, AcOH, -78oC
2. Jones, -78oC to 0oC
3. Pb(OAC)4, Cu(OAC)2,
Bn, 80oC, 80%
1. KOH, MeOH, H2O
2.I2, ACN, -15oC89%
1. BzOK,
THF,-200C2.10% Pd/C, Et2O, 84%
1. LiALH4, Et2O2.(CH3)2CO, CuSO4 p-TSOH3.CrO3.Py.HCl, DCM 80%
THPOCHO
O O O OCOOH
Ph3P
O
O1. , LDA, THF,
-78oC
2. PTSA, reflux, 8hrs 50%
1. 5% Rh/Al2O3
Et2O, -10oC
HI conc., 130oC10 min thenPPh3 (1.2 eq)
1300C, 3h
Collum, D.B.; McDonald, J.H.III; Still, W.C., JACS, 1980, 102(6), 2118
Forward Synthesis
57
O
O
CHO
H
COOHPh3P
PyrS
O
O
OH
H
H
O
O
O H
HOOC
HO
O
O
OH
H
H AcOCF3
O
O
H
I
HO
ONaH, Me2SO, 250C
18hr, 70%
KI3, NaHCO3
H2O, 87%
DCM, 25oC50%
1. Jones ox.
2. 2-PyrSH, COCl2 Et3N
Collum, D.B.; McDonald, J.H.III; Still, W.C., JACS, 1980, 102(6), 2118
Forward Synthesis
58
OO
Br
H
O
O
O
OH
H
H
SP
yr
OH
OHH
OHHO
OHO
O
HO
H
COOHOCH3
OH
OHH
OHHOO
OH
OHH
OMeBzO
O
H
O
HO
H
COOMe
OCH3SiEt3
OH
CHO
COOMe
OSiEt3
OCH3
LDA, -78oC,
THF ; MgBr275%
1. 10% Pd/C, H2, Et2O2. p-TsOH, DCM, Et2O, H2O3. NaOH, H2O, MeOH
Collum, D.B.; McDonald, J.H.III; Still, W.C., JACS, 1980, 102(6), 2120
Forward Synthesis