Post on 18-Jun-2020
Exploring Chemical Space
Shuli Mao04/12/2008
Frontier of Chemistry
Shuli Mao @ Wipf Group Page 1 of 40 4/15/2008
What is chemical space?Chemical space is the space spanned by all possible (i.e. energetically stable)stoichiometrical combinations of electrons and atomic nuclei and topologies (isomers) in molecules and compounds in general.-----wilkipedia
Chemical space is defined as the total descriptor space that encompasses all the small carbon-based molecules that could in principle be created. (Descriptors: molecular mass, liphophilicity and topological features, etc.)-----Dobson, C. M. Chemical space and biology Nature 2004, 432, 824.
Shuli Mao @ Wipf Group Page 2 of 40 4/15/2008
Why we need to explorechemical space?
The estimated number of small carbon-based compounds is on the order of 1060. However, only a minute fraction of this chemical space has been explored. Given thevastness of chemical space, we need to explore chemical space efficiently to find biologically relevant chemical space (space in which biologically active compounds reside).
Lipinski, C; Hopkins, A. Navigating chemical space for biology and medicine Nature 2004, 432, 855.
• To understand biological systems especially in unknown area
• To develop potential drugsFrom 1994 to 2001, only 22 drugs that modulate new targets were approved. So far, less than 500 human proteins have been targeted by current drugs, which is a small portion of human proteins.
Dobson, C. M. Chemical space and biology Nature 2004, 432, 824.
Shuli Mao @ Wipf Group Page 3 of 40 4/15/2008
How to explore chemical space?
(A) Target-Oriented Synthesis(B) Focused Synthesis (Medicinal Chemistry/ Combinatorial Chemistry)(C) Diversity-Oriented Synthesis
Burke, M. D.; Schreiber, S. L. A planning strategy for diversity-oriented synthesisAngew. Chem. Int. Ed. 2004, 43, 46.
Three approaches:
Shuli Mao @ Wipf Group Page 4 of 40 4/15/2008
Comparison of Three Approaches
Thomas, G. L.; Wyatt, E. E.; Spring, D. R. Enriching chemical space with diversity-oriented synthesisCurr Opin Drug Dis Dev 2006, 9, 700.
(A) Target-Oriented Synthesis(B) Focused Synthesis (Medicinal Chemistry/ Combinatorial Chemistry)(C) Diversity-Oriented Synthesis
Shuli Mao @ Wipf Group Page 5 of 40 4/15/2008
Combinatorial Chemistry The rapid synthesis and screening of a large number of different
compounds at the same time - instead of one-at-a-time-manner- toidentify agents with desired functional properties
Shuli Mao @ Wipf Group Page 6 of 40 4/15/2008
Classical VS. Combinatorial ApproachClassical approach: one at a time
Combinatorial approach: many at a time
www.aae.enscm.fr/anciens/94-mc/combchem.htm
Shuli Mao @ Wipf Group Page 7 of 40 4/15/2008
Synthetic Strategies towardsCombinatorial Libraries
Jung, G. Combinatorial Chemistry:synthesis, analysis, screening; 1999
Furka and co-workers pioneered the split-pool synthesis method for the synthesis of large peptide libraries in 1988; this approach is termed divide, couple and recombine synthesis by other workers
(A) Split-pool synthesis
(B) Parallel synthesis
Shuli Mao @ Wipf Group Page 8 of 40 4/15/2008
Split-Pool Synthesis(One-Bead-One-Compound)
Shuli Mao @ Wipf Group Page 9 of 40 4/15/2008
Parallel Synthesis(One-Vessel-One-Compound)
Shuli Mao @ Wipf Group Page 10 of 40 4/15/2008
• Solid-Phase Synthesis
Solid-phase synthesis Solution-phase synthesis
Synthetic Methodology forOrganic Library Construction
Heterogeneous Homogeneous
• Solution-Phase Synthesis
Shuli Mao @ Wipf Group Page 11 of 40 4/15/2008
Solid-Phase Synthesis
Kennedy, J. P.; Williams, L.; Bridges, T. M.; Daniels, R. N.; Weaver, D.; Lindsley, C. W.Application of combinatorial science on modern drug discovery J. Com. Chem. 2008, ASAP.
Compound under construction is covalently attached to a swollen insoluble solid support (usually aresin bead) by a linker that can be cleaved under specific conditions with an appropriate reagent togive the target compound in solution later on.
Shuli Mao @ Wipf Group Page 12 of 40 4/15/2008
Solid-Phase Peptide Synthesis (SPPS)
“Merrifield’s publication of SPPS method completely revolutionized the field, both from the perspective of accelerating research and discovery, and also because of its now widespread use for the manufacture of peptides for use as active pharmaceutical ingredients (APIs).”
Verlander, M. Industrial applications of solid-phase peptide synthesis-a status reportInt. J. Pep. Res. Ther. 2007, 13, 75.
Peptide APIs: yearly sales in excess of $12 billion with a growth rate of ~4% and majority (>50%) are prepared via SPPS
Leuprolide: a blockbuster drug with worldwide sales in excess of $2 billion/yearis prepared via SPPS
Leuprolide
Shuli Mao @ Wipf Group Page 13 of 40 4/15/2008
Microwave-Assisted SPPS
Katritzky, A. R. Microwave-assisted solid-phase peptide synthesis utilizing N-Fmoc-protected (α-aminoacyl)benzotriazoles Chem. Bio. Drug. Des. 2007, 70, 465.
Easy reagent separation; Eliminates losses of product during filtration,recrystallization;Completion of reaction by excess reagents;Each step can be monitored by Nihydrin test
MW heating used to minimize reaction time, improve peptide yield and reduce epimerization problem
Shuli Mao @ Wipf Group Page 14 of 40 4/15/2008
O
H
O
I
EtP -Ph3I, nBuLi
O
1) TMSOTf2) PTSA
O OO
OHC
O
1) Ph3PCH2OMeCl
2) pyr id in ium p- to luenesulfonate
CHO
O
OH
O
3- br omofur an
nBuLi
1) O2, EtiPr2N,
r os ebengal, hv
2) Grubss 2ndGen cat
OH
O
HO
O
Solid-Phase Synthesis of DysidiolideAnalogs as Phosphastase Inhibitors
Waldmann et al Natural products are biologically validated starting points in structure space forcompound library development: solid-phase synthesis of dysidiolide-derived phosphatase inhibitorsAngew. Chem. Int. Ed. 2002, 41, 307.
Overall yield: 14% (11 steps);average yield: 84% per step
Employment of structural frameworks of biologically active natural products as a guilding principle for library development
endo:exo= 91:9endo:endo’ = 95:5dr = 87:4:8.9:0.1
Shuli Mao @ Wipf Group Page 15 of 40 4/15/2008
Solution-Phase Synthesis
A + B (excess) P + B (excess) + Byproduct XTag S
P
Tag S
B
X
Kennedy, J. P.; Williams, L.; Bridges, T. M.; Daniels, R. N.; Weaver, D.; Lindsley, C. W.Application of combinatorial science on modern drug discovery J. Com. Chem. 2008, ASAP.
Tag Method of Phase Separation
Polymer Filtration
Ionizable grouppH adjusted LLE orion-exchange SPE
Fluorous tag 3-Phase LLE (heavy) orfluorous SPE (light)
Scavenging reagents were used to form either covalent or ionic bond with excess reagents or reaction byproduct;In general terms, scavenging can be considered a ‘phase-switching” technique, wherein a chemoselective reactionIs employed to switch the phase of one product relative to another by virtue of a “tag” attached to the scavenging reagent.
Shuli Mao @ Wipf Group Page 16 of 40 4/15/2008
Solution-Phase SynthesisUsing Fluorous Tag
Kasahara, T.; Kondo, Y. Fluorous-tagged indolylboron for the diversity-oriented synthesis of biologically-attractive bisindole derivatives Chem. Commun. 2006, 891.
Antitumor Insulin receptor activator
SO2Cl
C8F17
1) 3-Iodoindole, 88%
2) PdCl2(dppf )2,HBpin, 88%
NBsRf8
BP in Pd(PPh3)4,
Tl2CO 3, quant
O
O
Br
OMeB r
MeO
O
O
B r
OMe
MeO
NBsRf8
1) Pd(PPh3) 4,Tl2CO3
2) CsF
88% ( 2 steps)
O
O
OMe
MeO
NBsRf8
NTIPS
BPin
HN
1) MeI, Cs2CO3, 96%
2) Mg, NH4Cl, 95%
O
O
OMe
MeO
NH
MeN
Shuli Mao @ Wipf Group Page 17 of 40 4/15/2008
Solution-Phase SynthesisUsing Fluorous Tag
Solid-phase synthesis of bisindole derivatives is hard to monitor, fluorous synthesis made it easier; Pd-catcoupling is used consecutively; New sulfonamide type tag (Rf8-Bs) was developed.
Shuli Mao @ Wipf Group Page 18 of 40 4/15/2008
Comparison of Combinatorial Libraryand DOS Library
• Combinatorial library: (a) Tens of thousand to millions of compounds; (b) Structures are not very complex (c) May have a specific target
• DOS library: (a) Tens to hundreds of compounds; (b) Most have cyclic architectures with many stereocenters and
resemble natural product; (c) DOS are utilized as small-molecule chemical probes for
understanding cellular processes and are not biased toward aspecific biological target
Shuli Mao @ Wipf Group Page 19 of 40 4/15/2008
Diversity-Oriented Synthesis-1st Example
Tempest, P. A.; Armstrong, R. W. Cyclobutenedione derivatives on solid support: toward multiple corestructure libraries J. Am. Chem. Soc. 1997, 119, 7607.
Shuli Mao @ Wipf Group Page 20 of 40 4/15/2008
Diversity-Oriented Synthesis
Tan, D. S.; Foley, M. A.; Shair, M. D.; Schreiber, S. L. Stereoselective synthesis of over two million compounds having structural features both reminiscent of natural products and compatible with miniaturized cell-based assays J. Am. Chem. Soc. 1998, 120, 8565.
Shuli Mao @ Wipf Group Page 21 of 40 4/15/2008
Diversity-Oriented Synthesis
• Appendage diversity• Stereochemical diversity• Skeleton diversity
DOS aims at generating natural product-like compounds that are (a) easy to access,(b) rich in dense, chiral functional groups, and (c) rich in stereochemically and three-dimentional, skeletally diverse architectures.
Shuli Mao @ Wipf Group Page 22 of 40 4/15/2008
Appendage Diversity
• Using coupling reactions to attach different appendages to acommon molecular skeleton
• A split-pool synthesis can be used when a molecular skeleton hasmultiple reactive sites with potential for orthogonal functionalization
Shuli Mao @ Wipf Group Page 23 of 40 4/15/2008
Appendage Diversity
Tan, D. S.; Foley, M. A.; Shair, M. D.; Schreiber, S. L. Stereoselective synthesis of over two million compounds having structural features both reminiscent of natural products and compatible with miniaturized cell-based assays J. Am. Chem. Soc. 1998, 120, 8565.
Shuli Mao @ Wipf Group Page 24 of 40 4/15/2008
Appendage Diversity
Lindsley, C. W.; Chan, L. K.; Goess, B. C.; Joseph, R.; Shair, M. D. Solid-phase biomimetic synthesis of carpanone-like molecules J. Am. Chem. Soc. 2000, 122, 422.
Four substituents can be varied.
Shuli Mao @ Wipf Group Page 25 of 40 4/15/2008
Limitations of Appendage Diversity
Compounds having a common molecular skeleton display chemicalinformation similarly in 3D space, thus limiting the pool of potentialbinding partners to only those macromolecules with acomplementary 3D binding surface
Shuli Mao @ Wipf Group Page 26 of 40 4/15/2008
Stereochemical Diversity
• Increase the number of relative orientations of potentialmacromolecule-interacting elements in small molecules
• Require powerful reagents that can override substrate bias anddeliver diastereomeric products with very high selectivity
Chavez, D. E.; Jacobsen, E. N. Catalyst-controlled inverse-electron-demand hetero-Diels-Alder reactionsIn the enantio- and diastereoselective synthesis of iridoids natural products Org. Lett. 2003, 5, 2563.
Shuli Mao @ Wipf Group Page 27 of 40 4/15/2008
Shang, S.; Iwadare, H.; Macks, D. E.; Ambrosini, L. M.; Tan, D. S. A unified synthetic approach to polyketides having both skeletal and stereochemical diversity Org. Lett. 2007, 9, 1895.
Stereochemical Diversity
BnO
R1
OH
OMe
OMe
a: R1= H
b: R1 = Me
C p 2T iC
l 2
i -BuMgBr
Re d-A l
B nO
R1
OH
OMe
OMe
BnO
R1
OH
OMe
OMe
m -CPBA
Sharp lessepoxidation
BnO
R1
OH
OMe
OMe
O
BnO
R1
OH
OMe
OMe
O
ally lic alco hol epoxyols 1,3-diols
BnO
R1
OH
R2OMe
OMeOH
BnO
R1
O H
R2OMe
OMeOH
n -BuLi; Me3Al
MeMgCl, CuCl
Dess -Martinoxidation
Dess -Martinoxidation
NaBH(O Ac) 3anti -1 ,3-d iol
ORsy n -1 ,3-d io lnot shown
BnO
R1
O
OMe
OMe
BnO
R1
O
OMe
OMe
enones
BnO
R1
O
OMe
OMe
O
BnO
R1
O
OMe
OMe
O
epoxyketones
SmI2
hydroxyketo nes
BnO
R1
O
OMe
OMeOH
Shuli Mao @ Wipf Group Page 28 of 40 4/15/2008
Skeletal Diversity
• Products with many distinct molecular skeletons are particularlyeffective at achieving a diverse display of chemical functionality in3D space
• Differentiating processes Strategy 1: Pluripotent functional group strategy Strategy 2: Multiple group pairing strategy
• Folding processes
Shuli Mao @ Wipf Group Page 29 of 40 4/15/2008
Differentiating Processes
• Using different reagents to transform a common substrate with thepotential for diverse reactivity
Strategy 1: Pluripotent functional group strategyStrategy 2: Multiple group pairing strategy
Shuli Mao @ Wipf Group Page 30 of 40 4/15/2008
Pluripotent Functional Group Strategy
Wyatt, E. E.; Fergus, S.; Galloway, W.; Bender, A.; Fox, D. J.; Plowright, A. T.; Jessiman, A. S.; Welch, M.; Spring, D. R. Skeletal diversity construction via a branching synthetic strategy Chem. Commun. 2006, 3296.
Shuli Mao @ Wipf Group Page 31 of 40 4/15/2008
Pluripotent Functional Group Strategy
Wyatt, E. E.; Fergus, S.; Galloway, W.; Bender, A.; Fox, D. J.; Plowright, A. T.; Jessiman, A. S.; Welch, M.; Spring, D. R. Skeletal diversity construction via a branching synthetic strategy Chem. Commun. 2006, 3296.
(a) C6H6, Rh2(O2CCF3)4, 70%; (b) RCCH, Rh2(OAc)4, [BuCCH, 57%]; (c) RNH2, NaOH then MeOH, H2SO4, [MeNH2, 35%]; (d) dienophile [DMAD, 59%]; (e) C5H6, 92%
Shuli Mao @ Wipf Group Page 32 of 40 4/15/2008
Pluripotent Functional Group Strategy
Phenotypic screening showed that a high number of the compounds modulate the growth of pathogenic strains of methicillin resistant Staphylococcus aureus (MRSA): 100 µM (29%), 50 µM (6%), 25 µM (4%), 10 µM (2%). The most active ones have MIC 3.56 and 6.05 µg/mL.
(a) Rh2(OAc)4, furan, then I2, 60% (91%); (b) DMAD, 84% (88%); (c) LDA, RCOR’, then Rh2(OAc)4; 8: 49% (90%);9: 68% (97%); (d) PhCHO, PhNH2, then DMAD, Rh2(OAc)4, dr = 20:1, 51% (80%); (e) Guanidine carbonate 62% (96%);(f) Resorcinol, H2SO4, 74% (95%); (g) NH2OH, 77% (89%); (h) Thiophene-2-carboxaldehyde, guanidine carbonate,Then 3-formylchromone, 43% (98%) Yield and purity (in brackets)
Shuli Mao @ Wipf Group Page 33 of 40 4/15/2008
Multiple Group Pairing Strategy
Comer, E.; Rohan, E.; Deng, L.; Porco, J. A., Jr. An approach to skeletal diversity usingfunctional group pairing of multifunctional scaffolds Org. Lett. 2007, 9, 2123.
Obtained by Cinchona catalyzed enantioselectiveMichael addition
Skeletal diversity was achieved by chemoselectiveactivation of different pairs of functional groups
Shuli Mao @ Wipf Group Page 34 of 40 4/15/2008
Folding Processes
• Transform substrates having different appendages that pre-encodeskeletal information (called σ elements) into products having distinctmolecular skeletons using common reaction conditions
Shuli Mao @ Wipf Group Page 35 of 40 4/15/2008
Santra, S.; Andreana, P. R. A one-pot, microwave-influenced synthesis of diverse small molecules bymulticomponent reaction cascades Org. Lett. 2007, 9, 5035.
Folding Processes
O
OHR2
R4-NCR1-CHO NH2-R3
MW
300 W20min
N
N
O
O
R1R4
R3
R2
Protic
O
N
R2
O
R1
O
NHR4
S
R2
H
N
O
R3
OHN
H
R4
Protic
Aprotic
Shuli Mao @ Wipf Group Page 36 of 40 4/15/2008
Mechanism
H2NY
XO
HO CO2Et
R4-NC OHC-t -Bu
Acyclic Ugi Product
Pathway A Pathway B
R4 = t-Bu
X = OH; Y = OMe
R4 = BnX = OMe; Y = H
microwave; protic solvent
OH
MeO
N O
OEt
O
t-Bu
O
t-BuHN 5-exo
N
N
O
O
BnH
t -Bu
OEtO
OMe
Michael aza-Michael
6-exo
O
MeO
N O
OEt
O
t-Bu
O
t-BuHN
N
N
O
O
Bn t-Bu
OEtO
OMe
N
Y
X
O
O
OEt
t-Bu
O
HN
R4
B
A
Shuli Mao @ Wipf Group Page 37 of 40 4/15/2008
Mechanism
SCHO
Bn-NC
H2N
OMeO
HO CO2Et
m ic rowav e
aprotic s olvent
N
OMeO
OBnHN
S
E tO 2C
H
S
CO2Et
H
N
O
OMe
OBnHN
H
Shuli Mao @ Wipf Group Page 38 of 40 4/15/2008
Build/Couple/Pair (B/C/P) Strategy
Nielsen T. E.; Schreiber, S. L Towards the optimal screening collection: a synthesis strategyAngew. Chem. Int. Ed. 2008, 47, 48.Mitchell, J. M.; Shaw, J. T. A structurally diverse library of polycyclic lactams resulting from systematic Placement of proximal functional groups Angew. Chem. Int. Ed. 2006, 45, 1722.
R1O
N
OA r
OMe
Couple
A l- cat
N
OAr
R1
CO2MeH
H
Build
R2Br
Couple
Phos phazene
base
N
OAr
R1
CO2Me
H
R2
Me3P , DBU
Pair P air Pair P airR1=H, R2=N3 R1=CH2N3, R
2=H R
1=H, R
2=CH2N3 R1=NH2, R
2=H
N
OA r
Ph
H
NH
O
N
O
A r
NH
OPh
H N
OA r
Ph
H
NH
O
N
O
A r
Ph
H
NH
O
Al-catalyzed Asy Suga-Ibata reaction
Al-cat
Shuli Mao @ Wipf Group Page 39 of 40 4/15/2008
ConclusionTOS, focused synthesis and DOS are all important approaches to explore chemical space. They all play very important role in studying biological systemsand discovering drugs.
“Although no longer in the spotlight and heralded as the savior of the drug industry, combinatorial chemistry is alive and well: actually, combinatorial science is more prevalent and widespread than ever before.”-----Craig W. Lindsley
DOS is a new and challenging field, the development of it will lead to the discovery of new chemistry as well as new entities in the chemical space; however, whether it is the most efficient and successful way or not needs to be evaluated in the future.
Shuli Mao @ Wipf Group Page 40 of 40 4/15/2008