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