better science through synthesis: new medicinal … · of 11-desmethyl laulimalide, a highly potent...

WENDER GROUP - STANFORD UNIVERSITY

ISCHIA SEPTEMBER 2006 ROCHE LECTURE

BETTER SCIENCE THROUGH SYNTHESIS:

NEW MEDICINAL LEADS BASED ON PHARMACOPHORE TARGETING OFNEW REACTIONS AND ON NOVEL DRUG DELIVERY SYSTEMS

Dept. of Chemistry(H&S); Dept of Molecular Pharmacology(Medical School); Molecular & Genetic Medicine;

Cancer Biology; Clinical Oncology Quantitative ChemicalBiology; Neurobiology; Epithelial Biology; Imaging Institute

SOME RELEVANT LEAD REFERENCESPaul Wender, Nicole Deschamps, Robert Sun "Rh(I )-Catalyzed C-C Bond Activation: Seven-Membered Ring Synthesis bya [6+1] Carbonylative Ring Expansion Reaction of Allenylcyclobutanes " Angewandte Chemie Int. Ed. , 2006, 45(24), 3957.Wender, Croatt, Witulski, “New Reactions and Step Economy: The Total Synthesis of (±)-Salsolene Oxide Based on the TypeI I Transition Metal-Catalyzed Intramolecular [4+4] Cycloaddition” Tetrahedron 2006, 62, 7505-7511.Paul A. Wender,* Michael K. Hilinski, Nicolas Soldermann, Susan Mooberry “Total Synthesis and Biological Evaluationof 11-Desmethyl Laulimalide, a Highly Potent Simplified Laulimalide Analog” Organic Lett. 2006, 1507.Susan L. Mooberry, Deborah A. Randall-Hlubek, Rachel M. Leal, Sayee G. Hegde, Robert D. Hubbard, Lei Zhang and PaulA. Wender “Structure-Function Studies on a New Class of Microtubule Stabilizing Agents Based on Laulimalide” Proc.Natl. Acad. Sci. USA 2004, 101, 8803-8808.Erin A. Clark, Bradley S. Davidson, Paul A. Wender, Susan L. Mooberry “Laulimalide and Synthetic Laulimalide Analogsare Synergistic with Paclitaxel and 2-Methoxyestradiol” Molecular Pharmaceutics 2006, 457-467.Paul Wender, Mitchell P. Croatt, Nicole M. Deschamps "Metal-Catalyzed [2+2+1] Cycloadditions of 1,3-Dienes, Allenes, andCO" Angewandte Chemie Int. Ed. , 2006, 45(15), 2459-2462.Lisa Jones, Elena Goun, Rajesh Shinde, Jonathan Rothbard, C. Contag, P.Wender* “Releasable Luciferin-TransporterConjugates: Tools for the Real Time Analysis of Cellular Uptake and Release” J . Am. Chem. Soc. 2006, 128(20), 6526-6527.Elena Goun, Rajesh Shinde, Karen Dehnert, Angie Adams-Bond, Paul Wender, Chris H. Contag, Benjamin L. Franc“Intracellular Cargo Delivery by an Octaarginine Transporter Adapted to Target Prostrate Cancer Cells Though CellSurface Protease Activation” Bioconjugate Chem. 2006, 17(3), 787-796.Wender, Paul A.; Gamber, Gabriel G.; Williams, Travis J.; Rhodium(I )-Catalyzed [5+2], [5+2], and [5+2+1] Cycl;oadditions:New Reactions for Organic Synthesis in “Modern Rhodium-Catalyzed Organic Reactions” P. Andrew Evans Ed. Wiley-VCHVerlag Gmbh & Co. KgaA, Weinheim pp 263-299, 2005.Wender, P. A.; Gamber, G. G.; Hubbard, R. D.; Pham, S. M.; Zhang, L.; “Multicomponent Cycloadditions: The Four-Component [5+1+2+1] Cycloaddition of Vinylcyclopropanes, Alkynes, and CO” J . Am. Chem. Soc. 2005, 2836-2837.Jonathan B. Rothbard Theodore C. Jessop, Richard S. Lewis, Bryce A. Murray, Paul A. Wender “The Role of MembranePotential and Hydrogen Bonding in the Mechanism of Translocation of Guanidinium-Rich Peptides into Cells” J . Am.Chem. Soc. 2004, 9506-9507.Wender, Paul A.; Baryza, Jeremy L.; Brenner, Stacey E.; Clarke, Michael O.; Craske, Madeleine L.; Horan, Joshua C.; Meyer,Tobias “Function Oriented Synthesis: The Design, Synthesis, PKC Binding and Translocation Activity of a New BryostatinAnalogue” Current Drug Discovery Technologies 2004, 1, 1-11.Samuel, Hearn, Mack, Wender, Rothbard, Kirisits, Mui, Wernimont, Roberts, Muench, Rice, Prigge, Law, McLeod“Delivery of Antimicrobials into Parasites” Proc. Natl. Acad. Sci. USA , 2003, 100, 14281-14286.Paul A. Wender, Dennis J. Mitchell, Kanaka Pattabiraman, Erin Pelkey, Lawrence Steinman, Jonathan B. Rothbard"Molecular Transporters: The Design, Synthesis, and Evaluation of Molecules that Enable or Enhance Cellular Uptake"Proc. Natl. Acad. Sci. USA , 2000, 97, 13003-13008.Jonathan B. Rothbard, Sarah Garlington, Qun Lin, Thorsten Kirschberg, Erik Kreider, P. Leo McGrane, Paul A. Wenderand Paul A. Khavari, Conjugation of Arginine Oligomers to Cyclosporin A Facilitates Topical Delivery and Inhibition ofInflammation, Nature Medicine 2000, 6, 1253-1257.

OUTPUTNEW REACTIONS,

CATALYSTS, STRATEGIES

AS INSPIRATION FOR NEW REACTIONS, CATALYSTS, STRATEGIES

NEW THERAPEUTIC LEADSNEW MODES OF ACTION

NEW DRUG DELIVERY SYSTEMS

AS INSPIRATION FOR NEW THERAPEUTIC LEADS, MODES OF ACTION, MATERIALS

OUR RESEARCH FOCUSES ON…*NOVEL STRUCTURES…

INPUT

HO

RCO2 O2CR

H

OH

H

OOH

C

AB

D

PHORBOLO

HO OBz

OAcO OH

O

OAc

HPh

O

OH

NH

O

Ph CB

A D

TAXOL

O O

OOH

RO

E

E

ORH OH

H

OH

O

O

H

H

HO

B

C

A

BRYOSTATIN

H2N

HN

NH

HN

NH

HN

NH

HN

NH

X

O

O

O

O

O

O

O

O

O

HN

NH3

NH2

HN H2N O

H2N NH2

HN

H3N NH2

NH

H3N NH2

HN

H3N NH2

H3N NH2

NH

H3N NH2

HIV TAT 9-MER

O

O

HO

O

OMe

O

O

O

OO

O

MeO

HO

HO

HO

OMe

OH

OH

OH

OMe

HO

APOPTOLIDIN

O

H

O

O

OHO

O

O

OHMeO

B

A

C

RTX

*UNIQUE AND POTENT ACTIVITY, FUNCTION…

*INTEGRATION OF CHEM, BIO, MED

FUNCTION ORIENTED SYNTHESIS

Wender, P.A.; Baryza, J.L.; Brenner, S.E.; Clarke, M.O.; Craske, M.L.; Horan, J.C.; Meyer, T. “ Function Oriented Synthesis:…” Current Drug Discovery Technologies, 2004, 1, 1-11.

•MEDICINAL AGENTS•MATERIALS•CATALYSTS•PROBES

•OVER 200 TOTAL SYNTHESES / YEAR IN ACS JOURNALS ALONE•MAKING MOLECULES IS NO LONGER THE BIGGEST CHALLENGEIN SYNTHESIS•THE MAJOR CHALLENGES NOW ARE TARGET DESIGN &SELECTION & ADVANCING SYNTHESIS TO MAKE SUCH TARGETS …

*Wender, Miller "Toward the Ideal Synthesis: Connectivity Analysis & Multi-Bond FormingProcesses" in Organic Synthesis: Theory and Applications T. Hudlicky (ed.), V. 2, 27, 1993, JAI Press.

Wender, Wright, Handy, "Toward the Ideal Synthesis" Chemistry & Industry, 1997, 765.

IN A PRACTICAL IF NOT IDEAL FASHION

TWO MAJOR PRIORITIES IN CHEMISTRY

•IMAGING TOOLS•DIAGNOSTICS•SENSORS•NANODEVICES

•ENERGY COLLECTION•ENERGY STORAGE•ENERGY CONVERSION•ENVIRONMENTAL

- ONE STEP, 100 % YIELD - READILY AVAILABLE STARTING MATERIALS

- OPERATIONALLY SIMPLE, SAFE AND ENVIRONMENTALLY SOUND - RESOURCE (COST, TIME, MATERIAL, PERSONNEL) EFFECTIVE

THE IDEAL SYNTHESIS AND STEP ECONOMY

*Wender, Miller, "Toward the Ideal Synthesis: Connectivity Analysis and Multi-Bond Forming Processes", in Organic Synthesis: Theory and Applications T. Hudlicky, ed., V. 2, pp 27-66, 1993, JAI Press.

Wender, Dennis Wright, Scott Handy, "Toward the Ideal Synthesis," Chemistry & Industry, 1997, 765.

WHY IS STEP ECONOMY SO IMPORTANT? A 70 step synthesis, even if 100% selective & efficient, is still a 70 step synthesis.70 steps take time, add cost, deplete resources, generate waste (solvent, etc)…


STEP ECONOMY:REDUCES LENGTH, WASTE (SOLVENT, ATOM LOSS!!!), ENVIRONMENTAL IMPACT,DEVELOPMENT & EXECUTION TIME, SEPARATION SCIENCE, EFFORT, COST;

IMPROVES YIELD, SPEED, SCIENTIFIC ADVANCEMENT, SAFETY, RETURN ONINVESTMENT, AND MOST IMPORTANTLY HUMAN ECONOMY

Louis Piaroulli…his cancer was spreading through his bonesand lymph nodes. Traditional chemotherapy hadfailed. Then, doctors tried again with the same chemotherapydrug, but they added bryostatin. Before adding bryostatin, Piaroulli's boneswere riddled with cancer.

"The response was exceptional and dramatic, and we would not have anticipated thisresponse from chemotherapy alone," says Schwartz (Memorial Sloan-Kettering).

BRYOSTATIN: NOVEL STRUCTURE, UNIQUE FUNCTION

Five months after the treatment, there was no trace of the disease.

Underwater TreasuresDoctors Searching for Potential Cancer Cures Beneath the SeaJohn McKenzie abc NEWS“A treasure chest of potential medicine lies in the sponges,algae and coral that live beneath the sea. And doctors thinksome of them may even help cure cancer…” O

O

O

O

O

OH

OH

O

HO

OAc

HO

CO2Me

MeO2C

O

B3

7

1330

19

21

26

11

34

5

2515

17

C

23

1

9A

BRYOSTATIN 1

OO

O

O

O

O

OH

OH

O

H

HO

CO2MeO

SIMPLER BUT FUNCTIONALLY SUPERIOR TARGETS=SHORTER (STEP ECONOMICAL) SYNTHESES

BRYOSTATIN

OO

O

O

O

OH

OH

O

HO

OAc

HO

CO2Me

MeO2C

O

AB

C

SPACER DOMAIN

RECOGNITION DOMAIN

BRYOLOG

A

C

B

Wender, P.A.; Baryza, J.L.; Brenner, S.E.; Clarke, M.O.; Craske, M.L.; Horan, J.C.; Meyer, T. “ Function OrientedSynthesis:…” Current Drug Discovery Technologies, 2004, 1, 1-11.Wender, De Brabander, Harran, Jimenez, Koehler, Lippa, Park, Siedenbiedel, Pettit, Proc. Natl. Acad. Sci., 1998, 6624Wender, Baryza, Bennett, Bi, Brenner, Clarke, Horan, Kan, Lacote, Lippa, Nell, Turner J. Am. Chem. Soc. 2002, 13648

FOS:COMPUTER HOMOLOGYMODELING

RECOGNITION DOMAIN

SIMPLER SPACER DOMAIN

BEYOND NATURAL PRODUCTS: DESIGN A BETTER TARGET

TOWARD A PRACTICAL (MANUFACTURING) SYNTHESIS OF “BRYOLOGS”

O

O

O

O

O

O

OH

OH

O

H

HO

CO2Me

O

H

H

H

17

19

21

25

C

A

B

15

O

OPMB

O

OBn

TBSO

(made in 4 steps)

(5 steps from Me (R)-lactate)

19C

25

21

17

23

22

O

OPMB

OBn

25

23

O

TBSO

19

21

1722

O

20C RING

FORMATION

O

OPMB

OBn

TBSO OMe

O CO2Me

21

17

20

C•DEOXYGENATION•ALKYLIDINATION

7 LLS; 11 O 8 S

I II (19 STEPS)Wender, De Brabander, Harran, Jimenez, Koehler, Lippa, Park,Shiozaki, J . Am. Chem. Soc. , 1998, 4534. Proc. Natl. Acad. Sci.USA , 1998, 6624.

Wender, P. A.; Baryza, J.; Bennett, C.; Bi, C.; Brenner, S. E.; Clarke, M.; Horan, J.; Kan, C.; Lacote, E.; Lippa, Nell, P.; Turner, T. J. Am. Chem. Soc.; 2002, 124, 13648-13649.

(a) NaH, TBDMSCl, THF, rt; (b) (COCl)2, DMSO, Et3N, CH2Cl2, -78°C; (c) 4-chlorobutanol, MeMgCl, -78°C; Mg, THF, reflux; -78°C, THF; 75% 3 steps; (d)(COCl)2, DMSO, Et3N, CH2Cl2, - 78°C; 75%; (e) 5 mol% Ti(Oi-Pr)4, 10 mol% (R)-BINOL, B(OMe)3, allylSnBu3, 4 Å sieves, CH2Cl2, RT; 75%; (f) PTSA, 4 Åsieves, MePh; RT; 80% (g) MMPP, NaHCO3, CH2Cl2, MeOH, 0°C; 75%; (h) 0.1 eq. TPAP, 3 eq. NMO, 4 Å sieves, CH2Cl2, MeCN, 0°C - RT; 81%(i) K2CO3,MeOH, (MeO)(OH)CHCO2Me, - 78°C; 80%; (j) CeCl3∗7H2O, NaBH4, MeOH, -30 ∞C; (k) C7H15CO2H, DIC, DMAP, CH2Cl2, RT; 79% 2 steps; (l)HF/pyridine, THF, RT.; (m) Dess-Martin periodinane, NaHCO3, CH2Cl2, RT; 79% 2 steps; (n) (DHQD)2PYR, K2OsO2(OH)4, K2CO3, K3Fe(CN)6, t-BuOH, H2O,0°C; 90%; (o) TESCl, pyr, CH2Cl2, rt; (p) 1-Br, 2-EtO-ethene, t-BuLi, ZnMe2, -78°C; (q) HF, CH3CN, H2O, rt; (r) 1:3 TBSCl:imidazole, 9:1 CH2Cl2 : DMF;40% 4 steps.

OH OH OTBSO OHOHTBSO OH d,e f

g, h

a-c

17 19

OMgX

XMg

1719

20

20

23

23 23

O

TBSO

19C

25

21

17

23

20

O

TBSO

19C

21

17

20

OMe

O

6 OVERALL

I'

II' (9 STEPS)

O

TBSOOMe

O CO2Me

21

17

20

C

O

O

MeO

CO2Me

O

R

O

OTES

OTES O

O

MeO

CO2Me

O

R

OH

OTBS

OHC

4:1

i j-o p-rC C

2525

20

25

262617 17

15

19

21

$ 0.01 / gram

(18 STEPS)

3 steps, 75%kilogram scale

O

O

O

O

O

O

OH

OH

O

H

HO

CO2Me

O

H

H

H

17

19

21

25

C

A

B

15

TOWARD A PRACTICAL (MANUFACTURING) SYNTHESIS OF “BRYOLOGS”

O Cl

O O

O

O O O OBn

O

OBn

TBDPSO

O

OO O

OBn

TBDPSO

O

OO O

OH

TBDPSO

OO O

O

TBDPSO OH

a b-d e,f

g-i j

O OBn

$

$ OO

O

$

11

1

1

1

1

4

455 3

3

3

5

9

9

9

5

9

5

11

11 11

11

7

6

54

3 2 1

A

10 steps, 25% overall yield

Paul A. Wender, Alexander V. M. Mayweg, Christopher L. VanDeusen Organic Lett. 2003, 277-279

>95:5 es

>95:5 ds >99:1 ds

•LATE STAGE CONVERGENCY•MILD MACROACETALIZATION•COMBINATORIAL SYNTHESIS

2,4,6-Cl3ArCOCl,Et3N, rt, DMAP

81%

1.Amberlyst resin2. cat. Pd(OH)2/C,

H2

88%

Wender, Baryza, Bennett, Bi, Brenner, Clarke, Horan, Kan, Lacote, Lippa, Nell, Turner, J . Am. Chem. Soc.; 2002, 124, 13648.Wender, De Brabander, Harran, Jimenez, Koehler, Lippa, Park, Shiozaki, J . Am. Chem. Soc. , 1998, 4534.Wender, De Brabander, Harran, Jimenez, Koehler, Lippa, Park, Siedenbiedel, Pettit, Proc. Natl. Acad. Sci. USA , 1998, 6624.Wender, Hinkle, Koehler, Lippa, Medicinal Research Reviews, 1999, 388.

A PRACTICAL (MANUFACTURING) SYNTHESIS OF DESIGNED TARGET

BRYOSTATIN

Scale up in progress2nd gen. Synthesis J. Am. Chem. Soc. 2002

BRYOLOG ~ 25 STEPS(BRYOSTATIN > 70 STEPS)

SPACER DOMAIN

RECOGNITION DOMAIN

O O

OOH

O

CO2Me

MeO2COAc

H OH

H

OH

O

O

H

H

HO

O

R

O O O

OOH

O

CO2Me

H H

OBn

H

H

R'

O

R

O O O

OOH

O

CO2Me

H H

H

OH

OH

H

R'

O

R

CHO

OH

R R

OH

O O O

OOH

O

CO2Me

H H

OBn

O

H

H

R'

O

R

CHO

O

R R

O

O

3

3

3

25

25

25

15

15

11

11

3

1

19

26

1

1

AB

C

AB

C

AB

C

AB

C

N

C

NC

Ca2+RACK

Inactive(cytosol) Active

(membrane)

translocation releasespseudosubstrate andactivates protein

C1a C1bC2 PS Kinase GFP

488 nM

508 nM

plasmid

transfection expressionactivation/

translocation

1. encode plasmid for each isozyme

2. express each plasmid independently

REAL TIME EVALUATION OF PKC TRANSLOCATION

J. Baryza, S. Brenner, M. Craske, T. Meyer, P.WenderChemistry & Biology 2004, 1261.

Newton, Chem. Rev. 2001

membrane

B

Cell Sensitivity

MDA-MB-435

MOLT-4

NCI-H460

HCC-2998

K-562

COLO

A549/ATCC

SF-295

SK-MEL-5

CCRF-CEM

SN12C

MDA-MB-231/ATCC

ACHN

LOX

U251

PC-3

EKVX

786-0

HT29

MCF7

HL-60(TB)

KM12

UACC-257

HCT-116

SF-268

SK-MEL-2

T-47D

UACC-62

OVCAR-3

OVCAR-4

SW-620

IGROVI

SNB-75

UO-31

NCI-H322M

-2

-1

0

1

2

3pico-bryo

nano-bryo

log

(bry

oG

I 50)

- lo

g(a

nalo

gG

I 50)

GROWTH INHIBITION IN HUMAN CANCER CELL LINESStanford / National Cancer Institute USA (Ven Narayanan)

SOME ANALOGS 102-3 BETTER

FUNCTION ORIENTED SYNTHESIS: BETTER, AVAILABLE LEADS

•BRYOLOG AND BRYOSTATIN HAVE SIMILARVIRTUAL STRUCTURES, SOLUTION STRUCTURES, PKC AFFINITIES

•BRYOLOGS ARE GENERALLY MORE POTENT (10-100 FOLD) THAN BRYOSTATIN IN HUMAN CANCER CELL GROWTH INHIBITION

•BRYOLOGS ARE COMPARABLE OR BETTER THAN BRYOSTATIN IN ANIMAL ASSAYS•PICOLOG SYNTHESIS < 30 STEPS, ~ $3K/gm (BRYO $2.3M/ gm); NOW IN SCALE UP

J. Am. Chem. Soc. 2002, 13648•PRE-CLINICAL DEVELOPMENT CANDIDATE

O

O

O

O

O

OH

OH

O

HO

OAc

HO

CO2Me

MeO2C

O

B3

7

1330

19

21

26

11

34

5

2515

17

C

23

1

9A

<30 STEPS>70 STEPS

O

O

O

O

R

O

O

OH

OH

O

H

HO

CO2Me

3

7

13

19

21

26

11

34

5

2515

1723

1

9

O

B

C

A

FOS

Wender, P.A.; Baryza, J.L.; Brenner, S.E.; Clarke, M.O.; Craske, M.L.; Horan, J.C.; Meyer, T.“ FOS” Current Drug Discovery Technologies, 2004, 1, 1-11. Chemistry & Biology 2004, 1261.

STEP ECONOMY

PRACTICAL IMPRACTICALIDEAL

TARGETCOMPLEXITY

[VALUE]

# OF STEPS

STEP ECONOMY AND FUNCTION ORIENTED SYNTHESIS:Wender, Brabander, Harran, Jimenez, Koehler, Lippa, Park, Siedenbiedel, Pettit Proc. Natl. Acad. Sci. USA 1998, 6624;Wender, P.A.; Baryza, J.L.; Brenner, S.E.; Clarke, M.O.; Craske, M.L.; Horan, J.C.; Meyer, T. “ Function OrientedSynthesis” Current Drug Discovery Technologies, 2004, 1, 1-11

FOSDESIGNED

FUNCTIONALANALOG

NEW RXNSTARGET

N

O

13 steps

1-2%

Willstätter & Waser 1911 Reppe & Toepel 1940

Ni (0) cat

70%

H

H

NOW…COMBINE NEW REACTIONS AND FOS…INVENT NEW FUNCTIONAL TARGETS WITH NEW RXNS

PHARMACOPHORE TARGETING WITH NEW REACTIONS

SELECTIVEINHIBITORS

ASMEDICINAL

LEADS

OUTPUTINPUT

DESIGNHIGH

THROUGHPUT IN SILICO

SYNTHESISCOMBI CHEM

FUNCTIONH-T

SCREENS

New reactionsnovel structures

The virtual medicinal chemist

Real time cell &animal assays

•STEP ECONOMY TOKNOWN SCAFFOLDS•STEP ECONOMY TONEW SCAFFOLDS

O

O

O

O

O

OH

OH

O

HO

OAc

HO

CO2Me

MeO2C

O

B3

7

1330

19

21

26

11

34

5

2515

17

C

23

1

9A

O

O

O

O

R

O

O

OH

OH

O

H

HO

CO2Me

3

7

13

19

21

26

11

34

5

2515

1723

1

9

O

B

C

A

>70 steps <25 steps

FOSFOS

NEXTLEVEL?

NEWRXNS SIMPLER

FASTER

N

O

OO

H

R'

CANCER CHEMOTHERAPEUTIC LEADPICOMOLAR ACTIVITY

NEUROPATHIC PAINFEMTOMOLAR ACTIVITY

DESIGNING NEW REACTIONS FOR UNMET NEEDS

TUMOR PROMOTERNANOMOLAR ACTIVITY

OH

OR

H

H

OR'

OHO

OH

O

O

O

H

HO

OH

OH

BzO OH

O

BzO

O

O

O

H

HO OO

O

OMe

OH

R

R

R

R2C/2e

+

4C/4e

6!

THE DIELS-ALDER CYCLOADDITION: A POWERFUL PROCESS FOR 6-MEMBERED RINGS

4+2

Sarel, Breuer J. Am. Chem. Soc. 1959, 6522: Thermal reaction; VCP to CP 51.7kcal/M; Herges in "Chemical Structures”Springer-Verlag, 1988: "vinylcyclopropanes do not react even with the strongest dienophiles..."; Chem. Ber. 1986, 829

XR

R

7+

R

R 2C 5C

DESIGNING NEW REACTIONS: A HOMOLOG OF A [4+2] TO 6 IS A [5+2] TO 7

HEAT ALONE

X

THERMAL REACTION DOES NOT WORK*

DESIGNING NEW REACTIONS: THE [5+2] CYCLOADDITION

THEREFORE, SELECT SUITABLE METAL TO MEDIATE ∏-SYSTEM ACTIVATION(MANY METALS REACT WITH CPs and / or VCPs; must suppress 2+2+2, VCP to CP)

M

H

H H

Ln

M

MLnS

Z

MLn

LnCP 1st

HH

H H

*

MLn

H

H

H

ca. 0°

CP 2nd

Wender, Takahashi, Witulski J. Am. Chem. Soc. 1995, 4720; J. Am. Chem. Soc. 1998, 1940

Rh(CO)Cl

R

R

R

Rh(CO)Cl

(CO)ClRh

R

Cl(OC)Rh

R

Rh(CO)Cl

R

RPATHWAY 1

DFT calculations: Zhi-Xiang Yu,Paul Wender, Ken Houk

J. Am. Chem. Soc. 2004, 9154

Ea > 50 kcal/mol

A NEW REACTION: TRANSITION METAL CATALYZED [5+2] CYCLOADDITIONS

O

R

O

R

* ALKYNES (Wender, Takahashi, Witulski J. Am. Chem. Soc. 1995, 4720; J. Am. Chem. Soc, 1998, 10976)

1-10 mol % Rh(PPh3)3Cl

R= H, Me, CO2Me, TMS, Ph 7

80-95 %

5

1-10 mol % AgOTf

t-Bu

E

E

H

E

E

•

92% ee

H

91% ee

t-Bu

1 mol % CAT

PhCH3, 100 °C

3 hH 5 7

96%, only cis

* ALLENES (Wender; Glorius; Husfeld; Langkopf; Love J. Am. Chem. Soc., 1999, 5348; Organic Lett. 2000, 2323)

MeO2C

MeO2CMeO2C

MeO2C

1.0M, PhMe, 110°C, 17h

86-91%, only cis

* ALKENES (J. Am. Chem. Soc. 2001, 123, 179; J. Am. Chem. Soc. 1998, 1940; Tetrahedron 1998, 7203)

0.1 mol % RhCl(PPh3)3

0.1 mol% AgOTf

5R

R= H, Me

7

H

R

(exo selective)

INTERMOLECULAR TRANSITION METAL CATALYZED [5+2] CYCLOADDITIONS

CO2Me

CO2Me

OTBS

MeO2C

MeO2C

O

CO2Me

CH3H3C

MeO2C

O

*ALKYNYL ESTERS

93 %

* HH

O

+

92 % 88 %H

O

IT IS REMARKABLY GENERAL (1-3hr @ 25-40°C for most alkynes)

CAT.; H+

INTERNAL AND TERMINAL ALKYNES

*

79 %

H

H H

H

OCAT.; H+ CAT.; H+

EVEN ACETYLENE*

5 mol % [Rh (CO)2Cl]2,

CDCl3, 40 °C; H+

88 %

ALKYNYL KETONES

OO

2 hr

Wender, P. A.; Rieck, H.; Fuji, M. J. Am. Chem. Soc, 1998, 10976.

*LnRh OTBS

POSSIBLE RESTING STATE OF CATALYST*

CAT.; H+

1.5 hr, 40°C

2.5 hr, 40°C

1.5 hr, 40°C

6 hr, 40°C

OMe OMe

ONE MOLE SCALE

CC ACTIVATION: FROM VCPs to VCBs & A NEW REACTION

Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J. Am. Chem. Soc. 2000, 122, 7815.

R1=R2=HR1=H, R2=Me

95%

78%

A, 3hB, 20h

10 mol % RhCl(PPh3)3, 10 mol % AgOTf

10 mol % RhCl(CO)(PPh3)2, 10 mol % AgOTf

NO

R1

R2

Ts

O

TsN

R1

R2

110°C, tol

catalyst

FIRST [6+2] CYCLOADDITIONS

NEW REACTIONS INSPIRING OTHER NEW REACTIONS:

E

E

O

H

H

E

EH

OH

H

E

E

H

5 mol % [Rh(CO)2Cl]2, 10 mol % P(n-Bu)3,

10 mol % AgOTf

OH

H

E

E

M

86%

8%

-CO

Mechanism: Wender; Correa; Sato; Sun J. Am. Chem. Soc. 2000, 7815:

A NEW THREE COMPONENT CYCLOADDITION:TRANSITION METAL CATALYZED [5+2+1] CYCLOADDITIONS

O

RhLn

O

RhLn

O

+ CO- CO

[5+2] CYCLOADDUCT

[6+2]

THUS FAR, [4+4], [4+2], [5+2], AND [6+2] CYCLOADDITIONS, OVERALL [M+N] CYCLOADDITIONS.COULD A 3rd COMPONENT OF 1, 2, etc ATOMS BE ADDED TO ACHIEVE [M+N+O] CYCLOADDITIONS?

7

8

[5+2]

[6+2] CYCLOADDUCT

[5+2+1] CYCLOADDUCT

[6+2-1] CYCLOADDUCT

NEW REACTIONS BEGET OTHER NEW REACTIONS

A NEW, THREE COMPONENT CYCLOADDITION:TRANSITION METAL CATALYZED [5+2+1] CYCLOADDITIONS

INTRAMOLECULAR [5+2] CYCLOADDITIONS: Wender, Takahashi, W itulski, J. Am. Chem. Soc. 1995 117, 4720.INTERMOLECULAR [5+2] CYCLOADDITIONS: Wender, Rieck, Fuji, J. Am. Chem. Soc, 1998, 120, 10976.

[6+2] CYCLOADDITIONS: Wender, Correa, Sato, Sun, J. Am. Chem. Soc. 2000, 122, 7815. [5+2+1] CYCLOADDITIONS: Wender, Gamber, Zhang, Hubbard, J. Am. Chem. Soc. 2002, 2876.

1-5 mol% [Rh(CO)2Cl]2, dioxane, 60°C, 1-2 atm CO, conc. up to 0.5M; Works with esters, amides, aldehydes, ketones; yields good to excellent; high regioselectivity

1 mol% [Rh(I) cat.

CO

O

OH

+

O

OR 99%

OO

O

OOMe

H+

1 mol% [Rh(I) cat.

CO

O

OH

+H2N

H2N

H2N

O

OR 96%

OO

O

OOMe

H+

NEW SCAFFOLDS

Aldrich

Aldrich

Aldrich

Intramolecular [4+4] cycloaddition of bis dienes (1986)Intramolecular [4+2] cycloaddition of diene-ynes (1989)

Intramolecular [5+2] cycloaddition of VCPs & pi-systems (1995)Intermolecular [5+2] cycloaddition of VCPs & alkynes (1998)Intermolecular [6+2] cycloaddition of VCBs & pi-systems (2000)

Intermolecular [5+2+1] cycloaddition of VCPs, alkynes, CO (2002)

Intermolecular [5+1+2+1] cycloaddition of VCPs, alkynes, 2 CO (2005)

Intramolecular [2+2+1] cycloaddition of alkynes, dienes, CO (Dienyl PK) (2003)

Hetero [5+2] cycloaddition of cyclopropyl imines (2002)

Intramolecular [4+2+1] cycloaddition of dienes, alkynes, CO (2004)

Carbonylative ring expansion [4+2+1]/[6+1] of allenylcyclobutanes (2006)

Intra/intermolecular [5+2]/[4+2] cycloadditions (2001)

Intramolecular [2+2+1] cycloaddition of alkenes, dienes, CO (2004)

The allenyl Pauson-Khand [2+2+1] cycloaddition of bis-alkenes, CO (2006)

NEW REACTIONS, THE IDEAL SYNTHESIS, STEP ECONOMY, PHARMACOPHORE TARGETING

Representative New TM Catalyzed Reactions…New Strategies…New Structures…

Intermolecular [3+2] cycloadditions (unpub)Intermolecular [4+2+2] cycloadditions of dienes, alkenes, alkynes (2006)

Intermolecular [2+2+1] cycloaddition of alkenes, dienes, CO (2004)

Intramolecular [4+2] cycloaddition of diene-allenes (1995)

Intramolecular [4+2+2] cycloadditions of dienes, alkenes, alkynes (2006)

Can we exploit thesenew reactions to rapidlyassemble new or novel

FUNCTIONAL molecules

GRAND CHALLENGES: THE BARRIER PROBLEM•Genomics (blueprint)•Proteomics (targets)•Systems Biology (pathways)•Chemogenomics (ligands)

A CHALLENGE AHEAD…

TISSUEBARRIERS

CELLBARRIERS

THERAPY DEPENDS ON BREACHING BARRIERS…

DRUG / PROBE

TARGET

XTRANSPORTER

Varmus, Klausner, et al. “Grand Challenges in Global Health” Science, 2003, 398-399.Jain, R.K. “The Next Frontier of Molecular Medicine: Delivery of Therapeutics” Nature Med. 1998,

“The bilayer provides the basic structure of the membrane and serves as a relativelyimpermeable barrier to the flow of water soluble molecules” …most standard textbooks

BREACHING BIOLOGICAL BARRIERS

TOO POLAR(LIPID BILAYER PROBLEMS)

e.g., RNAi

THE PROBLEM: MOST DRUGS MUST BE BOTH WATER & LIPID SOLUBLE FOR PASSIVE DIFFUSION INTO TISSUES AND CELLS

TOO NON-POLAR(WATER SOLUBILITY PROBLEMS)

e.g., TAXOL

•WATER SOLUBLE•MEMBRANE

IMPERMEABLE

•WATER SOLUBILITY PROBLEMS•MEMBRANE

LOCALIZATION

MANYPOTENTIAL DRUGS

ANDBIOCHEMICAL PROBES

HAVE UPTAKE/SELECTIVITYPROBLEMS

THINKING OUT OF THE log P BOX AND PHYSICAL PROPERTY HOMOGENEITY

Wender, P.; Mitchell, D.; Pattab iraman, K.; Pelkey, E.; Steinman, L.; Rothbard, J. Proc. Natl. Acad. Sci. USA, 2000, 13003Rothbard, Garlington, Lin, Kirschberg, Kreider, McGrane, Wender, Khavari, Nature Medicine 2000, 1253

CELLX

JUST RIGHT

THE LOG P BOX

X

T-D/P

THERAPY DEPENDS ON BREACHING BARRIERS

BARRIER PROBLEMS ARE A MAJOR CAUSE OF HIT-TO-LAUNCH ATTRITIONA POTENTIAL FIX: MOLECULAR TRANSPORTERS

*HIV tat and Antennapedia are transcription factors that cross biological membranes

MEPVDPRLEPWKHPGSQPKTACTTCYCKKCCFHCQVCFTTKALGISYGRKKRRQRRRPPQGSQTHQVSLSKQPTSQPRGDPTGPKE*KKKVERETETDPFD

NATURAL CHEMICAL CODES FOR FACILITATED CELLULAR UPTAKE

*Evolutionary pressures have produced mechanisms to prevent and promote uptake

*This works for the HIV tat protein, the “gold standard” in research - it would have limited use in therapy (cost of goods, metabolism, etc) and - it is not necessarily an optimized system*Design a better transporter; what’s required in tat? Stanford (Engleman, Fathman, Kiley, Rothbard, Wender) -> CellGate

*HIV tat 49-57 is required for translocation (Frankel, Pabo 1988)SIGNIFICANTLY, IT IS CHARGED BUT EXHIBITS FACILITATED UPTAKE

arginine-lysine-lysine-arginine-arginine-glutamine-arginine-arginine-arginine

49 57H2N

HN

NH

HN

NH

HN

NH

HN

NH

X

O

O

O

O

O

O

O

O

O

HN

NH3

NH3

HN H2N O

H2N NH2

HN

H2N NH2

NH

H2N NH2

HN

H2N NH2

H2N NH2

NH

H2N NH2

CHEMICAL CODES FOR CELLULAR UPTAKE

Uptake of Peptide & Peptoid-aca-FITC conjugates into Human Jurkat T Cells

Wender, Mitchell, Pattabiraman, Pelkey, Steinman, Rothbard Proc. Natl. Acad. Sci. USA , 2000, 97, 13003;Rothbard, Garlington, Lin, Kirschberg, Kreider, McGrane, Wender, Khavari, Nature Medicine 2000, 6, 1253-1257;Mitchell, Kim, Steinman, Fathman, Rothbard, J . Pept. Res. 2000, 56(5), 318-325. ; J . Med. Chem. 2002, 3612-3618.* Wender, Jessop, Pattabiraman, Pelkey, VanDeusen Organic Letters 2001, 322

R5 R6 R7 R8 R15 R20 R25 R30R9

CONFOCAL ANALYSISHEAD GROUP TYPE &

TRANSPORTER LENGTH

NN

NN

N

O

O

O

O

O

NO

O

ORN

O

NH

NH

S

O

O

HO

COOHn

HN

H2N NH2

n

HN

H2N NH2

n

HN

H2N NH2

n

HN

H2N NH2

n

HN

H2N NH2

n

HN

H2N NH2

n

HN

H2N NH2

PEPTOID TRANSPORTER

N-hex7

N-hex8

N-hex9

SUPERIOR SYSTEMS

AND

COST OF GOODS*

Mea

nFl

uore

scen

ce

0

1000

K9

NOT SIMPLYCHARGE

Tat49-57

UPTAKE

BACKBONE STEREOCHEMISTRY& POSITION (PEPTOIDS)

Tat49-57

R7 R9 r7 r9

Mea

nFl

uore

scen

ce

0

L

DUPTAKE

STEP ECONOMY THROUGH SYNTHESIS AND FUNCTION GUIDED DESIGN

LINEAR: TARGET OF n UNITS REQUIRES 2n STEPS; THUS EVERY 2 STEPS ADD 1 UNIT

Repeat:7. Make acid8. Make amine9. Couple

XNHRCO[NHRCONHRCO] 6NHCO2Bn9 OPERATIONS OVERALL

NO RESIN, SOLN. SCALABLECOST SAVINGS >100FOLD;

GMP SCALED IN US PHARMA

1. Activate 2. Couple repeat 16 OPERATIONS OVERALL

SEGMENT DOUBLING: A TARGET OF 2n UNITS REQUIRES 3n STEPS THUS AN 8-MER (n=3) REQUIRES ONLY 9 STEPS; THUS EVERY 3 STEPS DOUBLE THE SIZE!

BocNHRCO2H

HCl•NH2RCO2Bn

BocNHRCHCONHRCHCO2Bn3

$

$

1

2

4

5

BocNHRCONHRCO2H

HCl•NH2RCONHRCO2Bn

BocNHRCONHRCONHRCONHRCO2Bn6

G G -G2G -G2 -G3 -G4 -G5 -G6 -G7 -G8 G -G2 -G3 -G4 -G5 -G6 -G7-G8

Wender, Jessop, Pattabiraman, Pelkey, VanDeusen Organic Letters 2001, 3229.Wender, Mitchell, Pattabiraman, PelkeySteinman, Rothbard Proc. Natl. Acad. Sci. USA , 2000, 13003

MOLECULAR TRANSPORTERS FOR CELLULAR UPTAKE

NN

NN

N

O

O

O

O

O

NO

O

ORN

O

NH

NH

S

O

O

HO

COOHn

HN

H2N NH2

n

HN

H2N NH2

n

HN

H2N NH2

n

HN

H2N NH2

n

HN

H2N NH2

n

HN

H2N NH2

n

HN

H2N NH2

PEPTOID TRANSPORTERS

Proc. Natl. Acad. Sci. USA , 2000, 13003

RXRXRXRXRXRXRSPACED

ARG-TRANSPORTERSJ. Med. Chem. 2002, 3612

OLIGOARGININE TRANSPORTERS

Nature Medicine 2000,1253

NH2O

O

NH

NH

n

TFA

NHH2N

R

OLIGOCARBAMATE TRANSPORTERS

J. Am. Chem. Soc. 2002 13382

nX

NH

O

S

NH

HN

OO

NH

4

ARBOREAL DENDRIMER TRANSPORTERS

Organic Lett. 2005, 4815

SW NANOTUBE TRANSPORTERS

J. Am. Chem. Soc. 2004, 6850

AND OTHERS…

DRUG--LINKER--HN

NH

HN

NH

HN

NH

HN

NH

XO

O

O

O

O

O

O

O

HN

HN

H2N NH2

NH

H2N NH2HN

H2N NH2

H2N NH2

NH

H2N NH2

HN

H2N NH2

HN

H2N NH

HN

H2N NH2

THE MEMBRANE BARRIERSinger-Nicolson (Science 1972) fluid mosaic modelVereb, Damjanovich, et al. (PNAS 2003) Dynamically structured mosaic model

“The bilayer provides the basic structure of the membrane and serves asa relatively impermeable barrier to the flow of water soluble molecules” …

Variations of this statement are found in most standard textbooks

WHY ARGININE AND NOT LYSINE?

ARGININE

0

200

400

600

800

mean

flu

orescen

ce

DiMe-R8Me-R8

R8

ARE HYDROGEN BONDSTHAT IMPORTANT?

Rothbard, Jessop, Lewis, Murray, Wender J. Am. Chem. Soc. 2004, 9506-9507.

HN

H2N

O

N

N N

8

NH

O

R"

R"

5NH

S

Fluorescein

H

H

H

TFA

O

P

O

O O

R R' MEMBRANE

OP

O

O

O

R

R'

REPLACE "H"

WITH METHYL

A

B

N

H H

N

N

HH

R H

NON-POLAR MEMBRANE NON-POLAR MEMBRANE

EXTRACELLULAR

POLAR MILIEU

POLAR

GROUP

POLAR

GROUP

LESS

POLAR

COMPLEX

O

P

O

O O

R R'

N

H H

N

O

P

O

N

O O

R R'

HH

R H

LYSINEN

R H

EXTRACELLULAR

POLAR MILIEU

POLAR

GROUP

POLAR

GROUP

LESS

STABLE

COMPLEX

H H

NON-POLAR MEMBRANENON-POLAR MEMBRANE

O

P

O

O O

R R'

N

R H

H H

O

P

O

O O

R R'

TRANSPORTER-PEPTIDE CARGO UPTAKE INTO HEART TISSUE

PEPTIDE DELIVERY TO PREVENT ISCHEMIC DAMAGE

PRECONDITIONING : BRIEF EPISODES OF ISCHEMIA DECREASE NECROSIS DURING PROLONGED ISCHEMIARACK PEPTIDES SIMULATE PRECONDITIONING WHEN INJECTED INTO CELLS BUT CANNOT ENTER BY DIFFUSION

HO2C-DYGIPDAHC-SS-CR7-CONH2RACK-TRANSPORTER CONJUGATE

HO2C-DYGIPDAHC-SHRACK PEPTIDE

(“DRUG”)

HS-CR7-CONH2TRANSPORTER

+

•THE RACK PEPTIDE ITSELFMUST BE MICROINJECTEDINTO CELLS•TRANSPORTER RACKCONJUGATE WORKSWITHOUT INJECTION

RACKCS-

SCTat

RACKCS-

SCR7

50%

78%

NO

TRMT

CREATINE

PHOSPHOKINASE

RELEASE

DAMAGE

PROTECTION

BASIS FOR NEWCOMPANY, 2003

L. Chen, L. Wright, C-H. Chen, S. F. Oliver, P. A. Wender,* D. Mochly-Rosen*CHEMISTRY & BIOLOGY, 2001, 1123

TRANSPORTER ENABLED DRUG UPTAKE IN HUMAN SKINPaul Wender, Dennis Mitchell, Kanaka Pattabiraman, Erin Pelkey, Lawrence Steinman, Jonathan RothbardProc. Natl. Acad. Sci. USA , 2000, 13003-13008; Jonathan Rothbard, Sarah Garlington, Qun Lin, ThorstenKirschberg, Erik Kreider, P. Leo McGrane, Paul Wender, Paul Khavari, Nature Medicine 2000, 1253-1257

HUMAN TRIALS ESTABLISHED SAFETY AND THERAPEUTIC LEVELS OF CONJUGATE: T-L-CsA -> T-L + CsA (pH based release)

ASSAY NEEDED TO QUANTIFY RELEASE IN ANIMALS

UPTAKE OF BIOTINYLATED CYCLOSPORIN (A) AND BIOTINYLATED CYCLOSPORIN TRANSPORTER CONJUGATE(C) IN HUMAN SKIN GRAFTED ON IMMUNE DEFICIENT MICE. PANELS B AND D ARE CONTROLS USING PROPIDIUMIODIDE TO VISUALIZE ALL CELLS.

REAL TIME QUANTIFICATION OF TISSUE PENETRATION, CELL UPTAKE,RELEASE & INTRACELLULAR FUNCTION IN TRANSGENIC MICE

Rothbard, Garlington, Lin, Kirschberg, Kreider, McGrane, Wender, Khavari Nature Medicine 2000, 1253.L. Jones, E. Goun, R. Shinde, J. Rothbard, C. Contag, P. Wender* J. Am. Chem. Soc. 2006, 128(20), 6526.

Luc-RL-Trans (Luciferin-Releasable Linker-Transporter)

Luc-RL-Trans

Stratum corneum

Luc-RL-Trans

Cell membrane

Luc + RL + Trans

Intracellrelease

luciferase

Light

Animalscan be re-used!

STRATUM CORNEUM

area of application

EPIDERMIS

DERMIS

DESIGN STRATEGY FOR REAL TIME DERMAL UPTAKE

S

N

S

N

O

COOH

O

O

SS

NHAc

O

N

H

H2N

O

NH

NH2

H2N

8

F3C

O

O

Conjugate Vehicle: propylene glycol, ethanol,buffered water

GSH(mM)

GSH(mM)

GSH(mM)

GSH(mM)

GSH(mM)

GSH(mM)

GSH(mM)

GSH(mM)

GSH(µM)

S

N

S

N

HO

COOH

Conjugate

GSH103> in cell

S

O O

S

N

S

N

O

COOH

O

O

SH

L L L L

LLLL

L hv•Comp radiolabeling

LIGHT

L. Jones, E. Goun, R. Shinde, J. Rothbard, C. Contag, P. Wender* J. Am. Chem. Soc. 2006, 128(20), 6526.

SYNTHESIS OF NEW BIO-RELEASABLE CONJUGATES

R8-CARBONATE 5 SYNTHESIS: 3 STEPS, OVERALL YIELD 40%

1. 2-aldrithiol, MeOH, 97%; 2. i) Phosgene,pyr, tol, ii) Luciferin, NaOH, H2O, 70%; 3.AcHN-Cys-arg8-CONH2, DMF, 59%

SH

O

O

S S

NN

S

N

S

O

OS S

N

S

N

S

NHAc

O

NH

r8 CONH2O O

+ 8 TFA

HO1-2 3

HO2C HO2C

•C67 H124 N36 O15 S4

•NO PROTECTING GROUPS•GENERAL AND SCALABLE

L. Jones, E. Goun, R. Shinde, J. Rothbard, C. Contag, P. Wender* J. Am. Chem. Soc. 2006, 128(20), 6526.

March 25 all buffers 37oC

5 minute pulsewells seeded with 30,000 cells/well pH 6.9/7.4

0

250,000

500,000

750,000

1,000,000

1,250,000

1,500,000

1,750,000

2,000,000

2,250,000

2,500,000

2,750,000

3,000,000

0 200 400 600 800 1000 1200 1400 1600 1800 2000

time (seconds)

Flu

x (

ph

oto

ns/s

eco

nd

)

50mM r8 carbonate 6 HBS

25mM r8 carbonate 6 HBS

50mM r8 carbonate 6 K+HBS

25mM r8 carbonate 6 K+HBSLuc-RL(SS)-Trans

Luc + RLSH + HS-Trans

GSH (in cell)

REAL TIME QUANTIFICATION OF CELL UPTAKE IN TRANSFECTED PC3M CELLS

Luc-RL(SS)-Trans

Cell Entry

Light

Luciferase

Phot

ons/s

ec

March 25

0

250,000

500,000

750,000

1,000,000

1,250,000

1,500,000

1,750,000

2,000,000

2,250,000

2,500,000

2,750,000

3,000,000

3,250,000

3,500,000

3,750,000

4,000,000

0 200 400 600 800 1000 1200 1400 1600 1800 2000

time (seconds)

Flu

x (

photo

ns/s

econd)

50mM luciferin HBS 1 minute



50mM luciferin K+HBS 1 minute



POINTS OF IMPORTANCE:•UPTAKE & RELEASE ARE RAPID•UPTAKE/RELEASE DOSE DEPENDENT•UPTAKE IS INHIBITED BY K+•UPTAKE/RELEASE MAX. IN MINUTES•SIGNAL FROM CONJUGATE IS ~ ALLFROM BIORELEASE•UPTAKE/RELEASE IS REPRODUCIBLE•UPTAKE OF LUCIFERIN SHOWSDIFFERENT KINETICS

Phot

ons/s

ec

Time (seconds)

Luciferin

Luciferin-RL(SS)-conjugate

K+ inhibition

uptake

L. Jones, E. Goun, R. Shinde, J. Rothbard, C. Contag, P.Wender* J. Am. Chem. Soc. 2006, 128(20), 6526.

FUNCTION ORIENTED SYNTHESIS


•MEDICINAL AGENTS•MATERIALS•CATALYSTS•PROBES

•OVER 200 TOTAL SYNTHESES / YEAR IN ACS JOURNALS ALONE•MAKING MOLECULES IS NO LONGER THE BIGGEST CHALLENGEIN SYNTHESIS•THE MAJOR CHALLENGES NOW ARE TARGET DESIGN &SELECTION & ADVANCING SYNTHESIS TO MAKE SUCH TARGETS …

*Wender, Miller "Toward the Ideal Synthesis: Connectivity Analysis & Multi-Bond FormingProcesses" in Organic Synthesis: Theory and Applications T. Hudlicky (ed.), V. 2, 27, 1993, JAI Press.

Wender, Wright, Handy, "Toward the Ideal Synthesis" Chemistry & Industry, 1997, 765.

IN A PRACTICAL IF NOT IDEAL FASHION

TWO MAJOR PRIORITIES IN CHEMISTRY

•IMAGING TOOLS•DIAGNOSTICS•SENSORS•NANODEVICES

•ENERGY COLLECTION•ENERGY STORAGE•ENERGY CONVERSION•ENVIRONMENTAL

better science through synthesis: new medicinal … · of 11-desmethyl laulimalide, a highly potent...

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