Combinatorial Chemistry and Synthesis on Solid Support
Burkhard König University of Regensburg
Outline
I. Solid phase synthesis
1. Polymers, resins, supports 2. Linkers 3. Analytical techniques
Solid phase synthesis protocols and automatization
4. Peptide Synthesis
a) Protecting groups (- CO2H, -NH2, side chain= Special topic: Photoremovable protecting groups b) Coupling methods
5. Oligonucleotides 6. Sugars 7. Special topic: Immobilization of catalysts Outline
II. Liquid phase synthesis Polyethylenglycol, Linear Polymers, Isomerization reactions, Metathesis
III. Polymer supported reagents
1. Library synthesis a) in solution, parallel synthesis b) on solid support c) split and combine, one bead one compound 2. Deconvolution and Tagging 3. Dynamic combinatorial Chemistry and virtual libraries
Outline
V. Diversity oriented synthesis (DOS) Principle and examples Molecular complexity
VI. Complexity Generating Reactions Tandem cycloadditions and rearrangements, radical cascade reactions, transition metal catalyzed reactions, mixed tandem reactions, mulit-component reactions
VII. Chemical Diversity Building blocks, functional groups, stereochemistry, molecular framework, examples of diversity from biosynthesis An incomplete list of relevant literature reviews
Current Opinion in Chemical Biology (2000) 4, Issue 4 - available online. Bodanszky, M. (1993). Principles of Peptide Synthesis, 2nd Edition. Springer-Verlag: New York. Schreiber, S. L. (2000). Science 287, 1964-1968. Crowley, J. I., Rapoport, H. (1976). Solid-Phase Organic Synthesis: Novelty or Szostak, J. W. (1997). Introduction: Combinatorial Chemistry. Chemical Fundamental ConceptConcept.. Accounts of Chemical Research 9, 135 - 144. Reviews 97, 347-348. Fréchet, J. M. (1981). Synthesis and Applications of Organic Polymers As Pirrung, M. C. (1997). Spatially Addressable Combinatorial Libraries. Chemical Reviews 97, 473-488. Supports and Protecting Groups. Tetrahedron 37, 663 - 683.
Osborne, S. E., and Ellington, A. D. (1997). Nucleic Acid Selection and the Gait,Gait,M.J.,Ed. M. J., Ed.(1984). Oligonucleotide Synthesis: A Practical Approach. Challenge ooff Combinatorial Chemistry. Chemical Reviews 97, 349-370. IRL Press: Washington, D. C.
Nefzi, A., Ostresh, J. M., and Houghten, R. A. (1997). The Current Status of Letsinger, R. L. (1983). Chemical Synthesis of Oligonucleotides: a Simplified Heterocyclic Combinatorial Libraries. Chemical Reviews 97, 449-472449-472.. Approach. Genetic Engineering 5,191-207.
Pinilla, C., Appel, J., Blondelle, S., Dooley, C., Dorner, B., Eichler, J., Leznoff, C. C. (1974). The Use of Insoluble Polymer Supports in Organic Ostresh, J., and Houghten, R. A. (1995). A Review Of the Utility Of Soluble Chemical Synthesis. Chemical Society Reviews 3,65-85. Peptide Combinatorial Libraries. Biopolymers 37, 221-240. Leznoff, C. C. (1978). The Use of Insoluble Polymer SupportsSupports in General Lam, K. S., Lebl, M., and Krchnak, V. (1997). The Organic Synthesis. Accounts of Chemical Research 11,327-333. ''One-Bead-One-Compound'' Combinatorial Library Method. Chemical Reviews 97, 411-448. Merrifield, B. (1986). Solid Phase Synthesis. Science 232, 341 - 347. Baldwin, J. J., and Henderson, I. (1996). Recent AdvancAdvanceses In the (This is a transcript of Merrifield's NobeNobell Award address.) Generation Of Small-Molecule Combinatorial Libraries - Encoded Split Synthesis and Solid-Phase Synthetic Methodology. Medicinal Research Neckers, D. C. (1978). Solid Phase Synthesis. Chemtech, 108 - 116 Reviews 16, 391-405. Overberger, C. G., Sannes, K. N. (1974). Polymeric Reagents in Organic Lowe, G. (1995). Combinatorial Chemistry.Chemistry. Chemical Society Reviews 24, Synthesis. Angewandte Chemie InternationInternational Edition in English 13, 99 - 104. 329-340. Patchornik, A., Kraus, M. A. (1975). The Use of Polymeric Reagents in Organic Terrett,N.K.,Gardner,M.,Gordon,D.W.,Kobylecki,R.J.,andSteele,J. Sythesis. Pure and Applied Chemistry 43, 503 - 526. (1995). Combinatorial Synthesis - the Design Of Compound Libraries and Their Application to Drug Discovery. Tetrahedron 51, 8135-8173.
Gallop,M.A.,Barrett,R.W.,Dower,W.J.,Fodor,S.P.A.,andGordon,E. M. (1994). Applications Of Combinatorial Technologies to Drug DiscDiscoveryovery .1. Background and Peptide Combinatorial Libraries. Journal Of Medicinal Chemistry 37, 1233-1251.
Gordon, E. M., Barrett, R. W., Dower, W. J., Fodor, S. P. A., and Gallop, M. A. (1994). ApplicatiApplications Of Combinatorial Technologies to Drug Discovery .2. Combinatorial Organic Synthesis, Library Screening Strategies, and Future Directions. Journal Of Medicinal Chemistry 37, 1385-1401.
I. Solid phase synthesis
Synthesis on solid (polymer) support Why should you care about solid-phase synthesis ?
Even if it were the case that the only successful solid-phase chemistries ever performed were the synthesis of oligopeptides and oligonucleotides, it would be difficult to overstate their importance. These advances created entire new areas of research, and have served as the underpinning for almost all modern biochemistry and molecular biology.
Two other primary reasons for caring about solid-phase synthesis:
Its interesting!
It served as the basis for much of the early efforts in combinatorial chemistry.
A little history of solid-phase synthesis
1960's: Solid-phase peptide and oligonucleotide synthesis get started.
1970's: Continued development of 1970's: Synthetic organic chemists solid-phase peptide and oligo begin to explore solid-phase organic synthesis, including the development synthesis. While interesting, no of effective apparati for automated compelling case is made for actually synthesis. bothering to do organic chemistry on solid support, and by 1980 most efforts have stagnated.
1980's (late): Interest in 1980's: Peptide chemists and solid-phase organic synthesis is biologists get interested in figuring out renewed, in both academia and the how to make truly huge numbers of pharmaceutical industry. peptides (and screen them for Adaptation of "modern" synthetic biological activity). This leads to the reactions to the solid-phase development of the firsfirst combinatorial begins. libraries.
1990's: Continued improvements in the rate at which potential drug candidates can be screened (high-throughput screening) lead virtually every major pharmaceutical company to delve into the combinatorialcombinato synthesis of non-peptide, non-oligonucleotide pharmacophores. Bruce Merrifield 1984 Nobel Prize in Chemistry Born July 21, 1921 Benefits often associated with solid-phase synthesis
• Minimized Solubility Problems
• Simplified Purification
• Improved Reaction Yields
• Simplified Manipulation of Small Molar Quantities
• Site Isolation
Why Use Solid Phase Synthesis?
Purification of compounds bound to the solid support from those in solution is accomplished by simple filtration This allows the use of a large excess of reagents, improving the efficiency of many transformations The solid support can be used to compartmentalize library members, permitting the use of split-pool synthesis
S S S S
S S S S SSSS 1. Polymers, resins, supports
Book Chapters
Barany, G., Kempe, M. (1997). The Context of Solid-Phase Synthesis. In: A Practical Guide to Combinatorial Chemistry. Czarnik, A. W., DeWitt, S. H., Eds. (ACS: Washington, DD.. C.) Chapter 3.
Früchtel, J. S., Jüng, G. (1996). Polymer Supported Organic Synthesis: A Review. In: Combinatorial Peptide and Non-Peptide Libraries. Jüng, G., Ed. (VCH: New York) ChapterChapter 2.
Novabiochem (2001). The Combinatorial Chemistry Catalog.
Rapp, W. E. (1996). PEG Grafted Polystyrene Tentacle Polymers: Physico-Chemical Properties and Application to Chemical SynthesisSynthesis..In In Combinatorial Peptide and Non-Peptide Libraries. Jüng, G., Ed. (VCH: New York) Chapter 16.
Rapp, W. E. (1997). Macro Beads as Microreactors: New Solid-Phase Synthesis Methodology.Methodology. In Combinatorial Chemistry. Wilson, S. R.; Czarnick, A. W., Eds. (Wiley&Sons: New York) Chapter 4.
Review Articles
Vaino, A. R. and Janda, K. D. (2000). Solid-Phase Organic Synthesis: A CriCriticaltical Understanding of the Resin. Journal of Combinatorial Chemistry, 2,579-596.
Guillier,F., Orain, D. and Bradley, M. (2000). Linkers and Cleavage Strategies in Solid-Phase Organic Synthesis and ComCombinatorial Chemistry. Chemical Reviews, 100, 2091-2157.
1. Polymers, resins, supports
Typical loading: 1 mmol / g of resin
or 200 pm / bead (for 100 μm aminomethylpolystyrene ~ 5 x 106 beads / g)
1.1 g 1.25 g 1.4 g
(9 wt % substrate) (20 wt % substrate) (29 wt % substrate)
X Y Z
first resin-bound second resin-bound final resin-bound intermediate, MW = 100 intermediate, MW = 250 intermediate, MW = 400 1. Polymers, resins, supports
Polystyrene Resins
= polystyrene/DVB copolymer Cheap; excellent chemical stability; (0.5 - 5% cross-linking) good to ca. 110 - 130 °C at 1% DVB; slightly higher at 2% DVB.
= polystyrene/DVB copolymer Cheap; excellent chemical stability; (8 - 50% cross-linking) remarkable thermal and mechanical stability; very poor swelling characteristics → low loadings. Often called "macroreticulate" resin.
= polystyrene/Kel-F
= PEPS film Polystyrene grafted onto polyethylene film. Improved thermal, mechanical stability, but lower loading.
1. Polymers, resins, supports
Polyamide Resins
= Pepsyn polyamide, Very polar resins; excellent swelling in acopolymerof: DMF, H2O; essentially no swelling in CH2Cl2.
O H NH2 N CH2 H C H C N 2 2 H O O
O H N BocHN N CH H 2 O
==PepsynK Pepsyn K Pepsin occluded in keiselguhr (silica) matrix. Excellent longevity; used in continuous flow SPPS. 1. Polymers, resins, supports
Polyamide resins (continued)
= Sparrow amide resin, a copolymer of:
CH3 H H N N N H2N H2C CH3 H2C CH2 CH2 O O O
= Polyhipe, a copolymer of the following in a macroreticulate polystyrene/DVB matrix
CH3 CH3 O N N H2C CH3 H2C OCH3 O O
1. Polymers, resins, supports
Poly(ethylene glycol) - containing resins
= PEG-PS, PEG covalently grafted Lower mechanical and thermal stability onto preformed polystyrene/ than polystyrene, but much better 1% DVB copolymer solvent spectrum. (Resin swells in anything but hexanes.)
= POE-PS (Tentagel), PEG polymerized onto polystyrene/1% DVB copolymer
A couple other resins you might see OH = Polyethylene pins, with a grafted crown of:
n O O
O CH3 HO OH n 1. Polymers, resins, supports
Cellulose
Spot synthesis on paper
Inorganic support materials
Controlled pore glass (CPG); oligonucleotide synthesis
controlled pore ceramics (CPS); high thermal stabilty
1. Polymers, resins, supports
+
2-20mol%
Cl CH3OCH2Cl
SnCl4
Merrifield JACS 1963, 85,2149. Effects of Crosslinking
• Cross-Linking imparts mechanical stability and improved diffusion and swelling properties to the resin
Without cross-linking, each polymer chain can dissolve under thermodynamically favored conditions
Cross-linking can induce some sites of ‘permanent entanglement’ maintaining structural integrity
Introduction of functional groups
Br2, Tl(III) Br
n-BuLi, n-BuLi TMEDA better p- vs o- more convenient regioselectivity
Li Introduction of functional groups
CO2H SCH3
i. CO2 CH3SSCH3 ii. H+
Li
i. O2 – ClPPh2 ii. H
PPh2 OH
For leading references on resin preparations, see the review by Fréchet: Tetrahedron 1981, 37,663.
Structure of resins
Schematic representation of a macroporous solid-phase support Structure of a resin bead......
OH
CH2Cl2
CH2Cl2 OH
CH2Cl2 OH CH2Cl2
10 - 200 μm CH2Cl2 CH2Cl2 Resin Bead
HO Commercially available functional groups grafted onto PS resins OH CH2Cl2 CH2Cl2
Cl NH2 OH
a few Angstroms O O Bead Section Br OH H Mesh size
Tentagel
PEG-Polystyrene graft polymers Swelling of Polymer by Solvent
‘Shrunken’ state
‘Swollen’ state : Permeable to solvent and reagent
Swelling properties
Swelling properties of resins Practical Considerations in Choosing a Solid Support
• Mode of attachment and cleavage of materials from the resin (linker) • Compatibility of the chemistry planned for the library synthesis • The amount of material desired (loading level) • Size - affects efficiency of diffusion within the polymer (reaction rates!)
90 μm (TentaGel) 200 μm (PS) 500 μm (PS) 0.75 mmol/ g 1.05 mmol/ g 1.05 mmol/ g 350 pmol/ bead 4 nmol/ bead 60 nmol/ bead Ca. 180 ng/ bead Ca. 2 μg/ bead Ca. 30 μg/ bead Diffusion Efficiency
2. Linkers
• A linker covalently connects molecules to the solid support, and should provide a means for their chemical attachment and cleavage • Stability of the linker affects the scope of the chemistry that can be employed in the library synthesis
• Many linkers are adapted from protecting group chemistry
Synthetic Steps X Attachment Resin Linker Resin Linker Molecule
Cleavage
Resin Linker Molecule Molecule General structure
Cleavage conditions
Acid-labile benzyl alcohol anchors
Amide linkers Linkers
Benzylic linkers
Acid Labile Linkers
• Many historically important resins (Merrifield, Wang, Sasrin, Sieber, Rink resins) have linkers that are cleaved under acidic conditions • Acidic conditions were intended to prevent racemization of amino acids during solid phase peptide synthesis
X O
X= H, Wang linker: OR O O 50% TFA X= OMe, Sasrin linker: HO R CH2Cl2
O O
N R H 1-3% TFA O Sieber linker: O H NR CH2Cl2 2 Linkers
Cleavage by nucleophiles
Catch and release
Nucleophile Labile Linkers
Kaiser Oxime linker • Advantage: Introduction of diversity in cleavage step
NO2
R NH 1 2 H N R O R R1 N O O
• Difficulty: Often too reactive for common nucleophilic reaction conditions Linkers
Internal nucleophilic cleavage
Linkers
„Traceless“ linkers Traceless Linkers
• This type of linker creates a C-C or a C-H bond at the site of cleavage – C-H bond generation : Si-Ge linker (protonolysis or radical reduction)
Si H TFA
r.t.
NHBn NHBn
Ellman J. et al. JOC, 1995, 60, 6006.
– C-C bond generation
cat. O PCy Cl 3 Ru S S Cl PCy Ph 3 HO N HO N Olefin metathesis OORO OORO
Nicolaou KC et al. ACIEE, 1997, 36, 2097.
Safety-catch linker
Kenner’s sulfonamide linker • A “safety-catch” linker can solve the reactivity problem with a two step cleavage • 1) An activation step that is orthogonal to common functional groups • 2) Cleavage of the activated linker under mild conditions
OO O OO O dilute N O S Br S BnNH2 N R' NR' Bn H R' N i H Pr2NEt, DMSO CN Very stable activation cleavage
Ellman J. et al. JACS, 1996, 118, 3055. Alkylsilyl Linker - Fluoride Labile
• Mild cleavage conditions compatible with various functional groups • Designed for attachment through an alcohol • Compatibile with strong anionic, cationic, oxidative, and reductive conditions
Me Me Me Me B Si * OMe * Tl(OAc) * 3 cat. Pd(PPh3)4 Me Me Me Br / CH Cl Me 2 2 2 NaOH, THF, 40 h Si 1 % Br 96 % 98 % DVB-CL-PS OMe 500- 560 um 127 nmol/ bead 124 nmol/ bead
1. HF-pyr. 6.0 eq. TfOH * THF 2.0 eq. 2,6-lutidine Me Me Me HO NHFmoc Me 2. TMSOMe 1.5 eq. Si O NHFmoc HO NHFmoc 114 nmol/ bead 90 %
Ellman J. et al. JOC, 1997, 62, 6102. Foley MA et al. J. Comb. Chem. 2001, 3, 312.
Photo-labile linker
• Photolytic conditions can be very mild and selective • Dimerization of the support-bound nitroso by-product sometimes hampers further cleavage • Aryl nitro group is incompatible with some organometallic chemistry
Me O Me MeO MeO O R O O hν, 350 nm HO R + O NO2 O N O
Krafft GA et al. JACS, 1988, 110, 301. 2. Linkers - overview
Linkers Cleaved by Moderate Acid Linkers Cleaved by Strong Acid Rink Amide resin (X = NH) Merrifield Resin Rink Acid resin (X = O) O OCH O 3 HF O R HO R
H3CO O O TFA/CH Cl Carbamate resin X R 2 2 O HX R R O N HF H RNH2 PAL resin O
PAM resin O O OCH3 N moderate O H H O O O R HF, CF SO H N R acid 3 3 H2N R N HO R OCH O H 3
Wang resin O BHA resin
O R O O 95% TFA O O CF3SO3H N R HO R H H2N R
DHPP resin Thioester resin O O O O S R O O strong acid moderate O O R N HS R H acid HO R H3C CH3 O
2. Linkers - overview
Linkers Cleaved by Moderate Acid Silicon-based Resins PAB resin SAL resin (X = NH) SAC resin (X = O)
O O O O moderate acid O N N O H HO R H moderate O R X R acid HX R or F– O O (H3C)3Si
Acid-labile carbamate resin O Silyl ether resin R O O N H moderate R R RNH2 Si R' N O acid O moderate acid H R'OH (R, R = Ph, iPr) or F–
Dihydropyran resin Ramage resin O Si(CH ) O O 3 3 O R ArSO3H ROH N F– O CH OH, Δ H 3 O R HO R O
CHA resin Pbs resin
O O O N O tBu H R H Si O O O N N O R m oderate H O F– acid O O
H2N R HO R 2. Linkers - overview
Linkers Cleaved by Weak Acid Linkers Cleaved by Base or Nucleophiles XAL resin (Sieber amide resin) Weinreb amide resin O O R'MgCl O O O N N R H OCH3 R' R O N R H O O O 1% TFA LAH O
CH2Cl2 H N R 2 H R NPE resin
O
SASRIN resin N O H O piperidine O R O HO R NO2 O R 1% TFA O Fm resin O OCH3 CH2Cl2 HO R
R O O O piperidine N O H HO R
Trityl resin (X = H) 2-Chlorotrityl resin (X = Cl)
HMFA resin
O AcOH O O X CH Cl O O 2 2 HO R N piperidine H R O R O HO R
2. Linkers - overview
Photocleavable Linkers α-Methylphenacyl ester resin Linkers Cleaved by Base or Nucleophiles O O Let's not forget Merrifield resin... O R hν HO R O CH3 O R'OH, base O X R R'O R ONb resin (X = O) Nonb resin (X = NH) LAH X=O,S O HO R' O N H hν X R HX R wet CH3CN
NO2 O
Holmes resin (X = O, NH) Finally, a couple derived from early oligo work
O OCH 3 O O O hν N OR H HX R N S NH OH X R H 4 O O ROH NO2 CH3 O
O Geysen resin OR NH OH N 4 H ROH O O O NO2 hν N NH H2N R H wet CH3CN O R
Brown, B. B., Wagner, D. S., and Geysen, H. M. (1995). Molecular Diversity 1,4-12. 2. Linkers - overview
"Traceless" Linkers Ellman's resin Kenner's "safety catch" resin O R O O N O O H strong acid S iCH2N2 O Si N R O H3C H – CH3 R ii HO HO R
Veber's resin SCAL resin O O
O strong acid S S R R H3C CH3 or F– O Si O H3C CH3 O HN R N H O Showalter's resin
i i O Pr Pr (CH ) SiCl, PPh Si 3 3 3 TFA O or H N R R strong acid 2 R (EtO)2P(S)SH or F–
DSB resin
Janda's resin O O CF3 O R N i(CH3)3SiCl, PPh3 H O HO R H3C O Bu3SnH, AIBN, Δ ii TFA O HR N H or Raney Ni, H2 S CH3 R S H3C O Janda, et al. (1996). Tetrahedron Letters 37, 6491-6494.
3. Analytical techniques
Off bead analysis
• Cleavage, then use of conventional analytical techniques (e.g. LC, MS, NMR) • Requires high sensitivity and high throughput format
Example: LC-UV/ MS OH OH S O Ph HO N Ph Kaiser test
On bead analysis
1) Colorimetric methods, Kaiser test
Kaiser test
On bead analysis
1) Colorimetric methods, Kaiser test NMR
On bead analysis
2) MAS-NMR ( Magic angle spinning NMR )
Magic angle rotor (left), rotor spinning at the magic angle (right)
MAS- NMR spectrum (600 MHz)
Si O OMe O
O O O O O
O
Single bead IR
On bead analysis
3) Single-bead FT-IR microspectrometry
OO OO H O HO O O O DIC, DMAP, DMF
Beads in IR cell
Wavelength (cm-1) 4. Peptide Synthesis
Insulin
Protecting groups for -NH2
Benzoyloxycarbonyl group Carbobenzoxy (Cbo) or Z (Zervas) group
Introduction Protecting groups for -NH2
Benzoyloxycarbonyl group Carbobenzoxy (Cbo) or Z (Zervas) group
Cleavage
Protecting groups for -NH2
Tert-Butoxycarbonyl group (Boc)
Introduction
Di-tert-butyl-biscarbonate Pyrocarbonate Protecting groups for -NH2
tert-Butoxycarbonyl group (Boc)
Cleavage
TFA
Protecting groups for -NH2
Fluorenyl-9-methoxycarbonyl group (Fmoc) Introduction: Fmoc-Cl, Fmoc-Suc
Cleavage Protecting groups for -COOH
cleavage All kinds of esters
Protecting groups for -COOH
Carboxyl protecting groups which can be activated for coupling
hydrazide carbamate
transform into azide Protecting groups for side chain functional groups
Guanodinium group
Di-acylation or nitration; No perfect protecting group available
Protecting groups for side chain functional groups
Imidazole H Amino protecting groups Protection often necessary to increase solubility.
cleavage Protecting groups for side chain functional groups
Thiole
Strong nucleophile, easily oxidized – must be protected in peptide synthesis.
cleavage
Protecting groups for side chain functional groups
Hydroxy groups
Protection usually not necessary in peptide synthesis. Exceptions: Large excess of amino acid used; solubility reasons
cleavage Protecting groups for side chain functional groups
Indole, thioether
Protection usually not necessary in peptide synthesis. Caution: Alkylation of thioether by carbenium ion possible
Protecting groups for side chain functional groups
Amides
Protection usually not necessary in peptide synthesis. Exception: Amides with solubility problems; cyclization as side reaction Protecting groups for side chain functional groups
ϖ-Amino- and carboxy groups
Differentiation between α-and ϖ-functional groups necessary
Protecting groups for side chain functional groups
ϖ-Amino- and carboxy groups Special topic: Photocleavable protecting groups and linkers
Norrish-type II: ortho-nitrobenzyl alcohols
C. G. Bochet, J. Chem. Soc., Perkin Trans. 1 2002, 125 - 142.
Photocleavable protecting groups
Norrish-type II: ortho-nitrobenzyl alcohols
C. G. Bochet, J. Chem. Soc., Perkin Trans. 1 2002, 125 - 142. Photocleavable protecting groups
Norrish-type II: ortho-nitrobenzyl alcohols
Different reaction pathway if functional group to be protected is linked in β-position
C. G. Bochet, J. Chem. Soc., Perkin Trans. 1 2002, 125 - 142.
Photocleavable protecting groups
Norrish-type II: ortho-nitrobenzyl alcohols
Protecting group for ketones: Photocleavable protecting groups
Norrish-type II: ortho-nitrobenzyl alcohols Array synthesis:
Photocleavable protecting groups
Norrish-type II: Phenacyl esters
OH
O R
Protection of acids. Fast release trigger for biological stimulants.
C. G. Bochet, J. Chem. Soc., Perkin Trans. 1 2002, 125 - 142. Photocleavable protecting groups
Norrish-type II: Phenacyl esters
Photolabile linkers and resins
F. Guiller, D. Orain, M. Bradley, Chem. Rev. 2000, 100, 2091 - 2157. Photocleavable linkers
F. Guiller, D. Orain, M. Bradley, Chem. Rev. 2000, 100, 2091 - 2157.
Current developments
Selective deprotection by light of different wavelength
C. G. Bochet, J. Chem. Soc., Perkin Trans. 1 2002, 125 - 142. Current developments
M. Kessler, R. Glatthar, B. Giese, C.G. Bochet, Org. Lett. 2003, 5, 1179 - 1181.
Current developments
Selective deprotection by light of different wavelength
M. Kessler, R. Glatthar, B. Giese, C.G. Bochet, Org. Lett. 2003, 5, 1179 - 1181. Current developments
M. Kessler, R. Glatthar, B. Giese, C.G. Bochet, Org. Lett. 2003, 5, 1179 - 1181. Coupling methods
Azide coupling: No racemization, but very slow
Coupling methods
Anhydride and mixed anhydride method
Wrong way ! Coupling methods
sym anhydride method
Maximum yield: 50 % !
Coupling methods
N-Carboxylic acid anhydride method
1,3-Oxazolidin-2,5-dione
Peptide synthesis in aqueous solution
Repeat steps Coupling methods
Carbodiimide method (DCC, EDC)
DCC in situ active Ester formation with additives
Coupling methods
Active esters Synthesis of cyclic peptides
PFP ester ring closure
Coupling methods
Active ester: 8-Chinolyl ester as internal base Coupling methods
In situ formation of active esters
Expensive reagents !
Coupling methods
Segment coupling – native chemical ligation Coupling methods
Segment coupling – native chemical ligation
Synthesis of interleukin 8 (IL-8)
Solution synthesis of large peptides
Sakakibara strategy: Pac = Phenylacyl ester; WSCI = water soluble carbodiimide Solution synthesis of large peptides
Sakakibara strategy: How far can we go?
Purification and characterisation of peptides
Typical analytical methods Solid phase synthesis protocols
Merrifield synthesis
PAM anchor group
PAM anchor Automated peptide synthesis
Protecting group tactics
Boc/Bzl
MBHA = p-methyl benzhydrylamide anchor Protecting group tactics
Fmoc/tBu
Anchor groups in solid phase peptide synthesis
cleavage Racemization during peptide synthesis
Enol formation
Racemization during peptide synthesis
Oxazolon mechanism Racemization during peptide synthesis
Coupling reagents
Biochemical peptide synthesis
Transformation of mRNA into DNA Biochemical peptide synthesis
Schematic procedure for preparation of recombinant proteins
Biochemical peptide synthesis
Recombinant proteins In medicinal chemistry 5. Oligonucleotides
Nucleotides
Nucleosides
Phosphorylated Nucleosides Oligonucleotide
DNA double strand – B DNA DNA double strand – A DNA
Physical parameters of nucleobases Tautomeres ?
Watson – Crick Basenpairing
C - G T - A
Reversed Watson – Crick Basepairing
T - A Wooble Basenpairing
Shifted by one position
U - G Hoogsteen Basenpairing
Watson-Crick hydrogen bond acceptor site
A - T A - T
Oligonucleotide Synthesis
Synthesis of nucleosides Route A
Route A – Hilbert Johnson reaction Route A – Hilbert Johnson reaction
Route A – Silyl Hilbert Johnson reaction Route A – Silyl Hilbert Johnson reaction
reactions at different positions possible
Route A – Silyl Hilbert Johnson reaction (2nd example) Route B
Route C – assembly of the nuclobase
Route to a non-natural Flavin nucleobase Route C
Pseudo-Uridine
Wyosine
Stereoselective synthesis of α-and β-nucleosides
Selective β-nucleoside synthesis Stereoselective synthesis of α-and β-nucleosides
β-nucleoside
Stereoselective synthesis of α-and β-nucleosides
Selective α-nucleoside synthesis Synthesis of nucleotides and oligonucleotides
Chemistry of phosphoric and phosphinic acid esters
Hydrolysis of phosphoric acid triesters Hydolysis of phosphoric acid triesters
Synthesis of phosphoric acid esters Phosphoramidite route
H-Phosphonate route Automated DNA synthesis
First nucleotide in DNA synthesis
Automated DNA synthesis
Each nucleotide addition requires four steps 1. Detritylation 2. Activation and Coupling 3. Capping 4. Oxidation
Repeat steps for next nucleotide Phosphoramidite
Detritylation
The dimethoxy-trityl protecting group of the 5´-OH group needs to be removed, so that the next base can be added. Trichloroacetic acid (TCA) is used as reagent for cleavage. Activation and coupling
Protonation activates the leaving group
Activation and coupling Capping To prevent uncoupled nucleotides from reacting in the next step, which leads to wrong sequence
Oxidation How far can we go ?
Commercial suppliers
DNA synthesis: 100 nanomole scale*
Customer's Price per base** Shipping and handling country (no setup fee!) US $ 0.29 per base, no From US $ 1.00 to US $ USA setup fee 18.00 (see "S&H") CAN $ 0.39 per base, From CAN $ 1.00 to Canada no setup fee CAN $ 18 (see "S&H") Nominal charge, could US $ 0.29 per base, no All other countries be as low as US $ 3.00 setup fee (see "S&H")
*Only customers with accounts in good standing are eligible for this scale. All orders at the 100 nmole scale must be placed using our special order form in Microsoft Excel format, please e-mail us your request. 100 nmole (0.1 micromole) synthesis scale will yield typically 0.040-0.150 micromole (40-150 nmole) final product for a regular size, standard purity oligo. Guaranteed minimum 40 nmole for regular size (up to 25-mer) oligos, standard purity (desalted). For longer oligos, 9 OD260 guaranteed minimum (standard purity). Standard purity includes free desalting. All oligos are quantified and three different units of measure are provided to the customer. The relation between these three units is calculated by a computer, but as an approximation for a 20 base long oligo, 50 nmole equals approx. 10 OD260 units or 300 microgram. **Oligos longer than 35 bases, which are ordered without additional purification, will be supplied with no replacement warranty. Synthesis of a synthetic gene
Synthesis of a synthetic gene Synthesis of a synthetic gene
Washington Post, July 17, 2002
Synthesis of phosphate monoesters Pyrophosphates of biological relevance
Synthesis of pyrophosphates Biochemical methods - The principle of PCR
The three major steps:
Denaturation at 94°C Annealing at 54°C Extension at 72°C
Biochemical methods - The principle of PCR Biochemical methods - The principle of PCR
Use of PCR in in vitro random selection
SELEX = systematic evolution of ligands by experimental enrichtment
DNA strand known sequence random sequence Use of PCR in in vitro random selection
Aptamere Intramere Ribozyme
Aptamere Didesoxy DNA sequencing
DNA strand to be sequenced
template strand, labeled with 32P
reaction vessel with didesoxythymidine-5´-triphosphate
reaction vessel with didesoxycytidine-5´-triphosphate
Didesoxy DNA sequencing
Long oligo´s 5´
Yellow = C Green = G Red = T Blue = A
Short oligo´s 3´ Didesoxy DNA sequencing
DNA chips
in complex mixture 6. Sugars
Protecting groups in carbohydrate synthesis Protecting groups in carbohydrate synthesis
Transglycosylation Transglycosylation
OR
OR
Trichloroacetamidate activation
Thermodynamic controlled reaction: α-anomere; anomeric effect
Kinetically controlled reaction: β-anomere
R.R. Schmidt, W. Kinzy, Adv, Carbohydr. Chem. Biochem. 1994, 50, 21. Thioglycosides
Activation of a protected glycoside
Oligosaccharide synthesis
Segement synthesis and coupling Oligosaccharide synthesis
Examples of Solid phase oligosaccharide synthesis
Danishefsky's Strategies for SPS of Oligosaccharides - Cartoon Form HO O Danishefsky, et al. (1995). A Strategy for a Convergent Synthesis of N-Linked O O PO Glycopeptides on a Solid Support. Science 169,202-204. O O PO Danishefsky, et al. (1995). Major Simplifications in OligosaccharideOlig Syntheses Arising from a Solid-Phase Based Method: An Application to the Synthesis of PO PO the Lewis b Antigen. Journal of the American Chemical Society 117,5712- O 5719. PO PO
O O
O O PO O PO O O O PO HO PO PO HO PO O PO PO
PO O O OP PO O O HO PO O PO Etc. O PO HO PO O
PO OH iPr iPr Si OH O i O O Pr O iPr O Si O 1) DMDO, DCM O O i Si( Pr)2Cl O O O i O 2) ZnCl ,THF CH2Cl2, Pr2NEt HO O 2 Home-made DMAP O O O Ph O polystyrene O O derivative O O O O HO HO O O O OH O O iPr O i O Pr O O H3C Si CH O i 3 O Pr iPr O ZnCl ,THF Si O O 2 H O 1) DMDO, DCM O O H O 2) ZnCl ,THF O O 2 O O OH HO O BnO OBn O O iPr O iPr iPr O O BnO O O iPr Si Si HO O OBn BnO O O O Ph O O O O H3C O i O O O O Pr O O O CH3 iPr O Si O O O OH O O O O O HO O HO O O O O H O O O O H O O O HO O O O O O OH HO O O O O Ph O O O O O H3C O O O O O O CH3 BnO OH HO OBn ZnCl2,THF O BnO O O Cleaved from resin by treatment with TBAF/AcOH in MeOH OBn BnO
An example utilizing thioglycoside donors...... The Monomers OTBDPS Solid-Phase Synthesis of a Heptasaccharide Phytoalexin Elicitor BnO O A OAc Nicolaou, et al. (1997). A General and Highly Efficient Solid Phase Synthesis of FmocO SPh Oligosaccharides. Total Synthesis of a Heptasaccharide Phytoalexin Elicitor. OBz OTBDPS Journal of the American ChemicalChemi Society 119, 449 - 450. AcO O AcO OAc BzO O C OAc HO OAc BzO SPh O O O O OBz O O AcO O OH O O OH HO OH O AcO SPh HO HO OH O HO OH OAc B O HO HO OH O HO HO The Iterative HPE Synthesis OH O HO HO HO OH HO HO OTBDPS HO NO2 O BzO O BzO i. HF•Py, THF OBz ii. DMTST, 4AMS, A OTDS O2N O O iii. NEt ,CH Cl I 3 2 2 O BzO O BzO O OTBDPS OH OBz CsCO ,DMF BnO O Home-made polystyrene 3 HO O derivative NO2 OBz i. DMTST, 4AMS, B O BzO O BzO ii. HF•Py, THF OBz OTDS NO2 O O O BzO O BzO hν,THF OBz OH
AcO BnO O O O AcO O > 90% by mass gain O O AcO NO2 OAc OBz i. DMTST, 4AMS, C O BzO O BzO ii. HF•Py, THF OTDS OBz
O O BzO OH 95% BzO OBz OH
BzO O BzO O OAc OBz i. DMTST, 4AMS, A AcO BnO O AcO O AcO O O O ii. NEt3,CH2Cl2 AcO NO O AcO 2 OAc OAc OBz O AcO BzO O BnO O BzO AcO O AcO O O OTBDPS OBz OBz OAc i. hν,THF BzO O O BnO O BzO O ii. Ac O, NEt HO 2 3 O OBz OBz AcO BnO O AcO O BzO O O O AcO NO BzO O 2 i. DMTST, 4AMS, B OAc OBz O OBz OAc BzO O AcO BnO O ii. HF•Py, THF BzO AcO O OBz O O AcO O AcO NO 2 AcO O OAc OBz O OAc O BzO O AcO BzO BnO O AcO O OBz O O AcO OBz OAc O BzO O OH BzO O OAc ca. 20% overall from OBz first resin-bound sugar! BnO O AcO BnO O AcO O AcO O O O O O AcO OBz AcO OAc OAc OBz BzO O O DMTST, 4AMS, B BzO OAc BzO O BzO OBz OBz AcO BnO O AcO O O O AcO NO2 OAc OBz O i. hν,THF BzO O protected solid-phase 95% for two steps BzO oligosaccharide OBz ii. NaOCH3,CH3OH iii. H2,Pd,CH3OH O
2) Strategies Utilizing Support-Bound Acceptors
Glycosyl sulfoxides OTr OH PivO PivO O O O PivO S PivO S Ph PivO PivO O Tf2O, DTBMP o OTr -78 to -60 C PivO O PivO O PivO PivO 1. TFA O PivO S 2. OTr PivO PivO O O O OTr PivO S PivO Ph PivO O PivO O Tf2O, DTBMP o PivO PivO -78 to -60 C O PivO O PivO PivO Cleavage from resin O achieved with: PivO S Hg(OCOCF3)2, water, > 50 % overall yield RT, 5 h PivO O > Coupling efficiency believed to exceed 90%; resin cleavage ~70-75%
Yan, L.; Taylor, C. M.; Goodnow, R.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 6953. Combinatorial Synthesis of a Disaccharide Library Ph Ph Kahne, D., et al. (1996). Parallel Synthesis and Screening of a Solid Phase Ph O O O Carbohydrate Library. Science 274, 1520 - 1522. O O O O AcO O O AcO Ph AcO N3 OPMB OH OH SAr SAr OH OH O O N N3 SAr N3 O 3SAr O Ph O AcO The known antigen for Bauhinia purpurea lectin: O O O OPMB HO O OH AcO SAr O AcO SAr OH NHAc OPMB N3 Ph O O Glycosyl donors: O OPiv AcO S O CO2H PivO OPiv OPiv OPiv NH N3 H NNH O O 2 PEG-PS 2 2 PivO O PivO PivO SOPh PivO PivO SOPh (Tentagel) PivO PivO HOBt, HBTU, NMP DMF SOPh
PivO H3C O SOPh H3C O SOPh OPiv OPiv O SOPh N OPiv PivO OPiv PivO 3 PivO PivO Ph PivO OPiv SOPh SOPh O O OPiv O O CH O O 3 H3C O H3C O OO O H PivO S O N3 OPMB Ph O SOPh O O O O N PivO O O HO S O OPMB N3SOPh TfOH, THF, –65 °C O O O N3 OPiv PivO OPiv OPiv O PivO OPiv O PivO PivO O O SOPh PivO O PivO PivO O PivO PivO SOPh Ph PivO
OPiv i. P(CH3)3,THF PivO OO H ii. AcCl, NEt3, Acylation agents: O O N CH2Cl2 PivO O S O Ac O, iBuCOCl, BuCOCl, PhCOCl, D-Ac-Ala-OH, L-Ac-Ala-OH, MeOCO Cl iii. 20% TFA/CH Cl 2 2 PivO N O 2 2 F 3 iv. LiOH, THF, I O– COCl COCl N CO H S 2 + CH3OH COCl COCl N CO2H
O2N
NO2 OH OH OH OH O H O O O O O O O N OCNCH SCNCH HO O S O 3 H3CSC Cl 3 O H2C OH NHAc O
3) Bidirectional Glycosylation Strategy BnO Generation of a small carbohydrate library...... O O O Monomers H BnO N BnO O O O O BnO H BnO O CCl3 N O O O O HO BnO HO O acceptor bound SEt NH O BnO BnO OMe HO O BnO OH BnO TMSOTf BnO SEt O BnO O BnO OMe O BnO NH O OH OBn O Couple with HO O O each monomer BnO O O O BnO BnO O BnO O O OBn BnO O O BnO H O O N O O donor bound BnO SEt NIS/TMSOTf BnO O 1. AcOH/H O O 2 THPO O products obtained as O O mixture of anomers BnO OBn OMe BnO OBn O BnO O NH 6 compounds total BnO SEt O OBn O BnO O NIS/TMSOTf OBn O BnO O BnO BnO O O BnO O BnO O O 1. NaOMe O O BnO O BnO OBn OBn OMe 2. H2/Pd BnO BnO O O HO OBn OH O O O O HO O O BnO O NaOMe, MeOH HO O O OH OMe BnO HO OH BnO HO BnO O O Boons and Zhu in "Solid Support Oligosaccharide Synthesis and BnO O Combinatorial Carbohydrate Libraries," P. Seeburger, ed.; Wiley BnO O Interscience, New York, pp. 201-211. O O O O Solid-Phase Chemical/Enzymatic Oligosaccharide Synthesis Wong, C.-H., et al. (1994). Solid-Phase Chemical Enzymatic Synthesis of Glycopeptides and Oligosaccharides. Journal of the American Chemical H H Society 116,1135-1136. N N NHBoc O N H O Bn O O α-chymotrypsin OH HO OH H H O NH O NH2 O N (Gly)6NHBoc OH OH Si Si HO HO2C O O O O O O AcHN HO NHAc controlled-pore glass HO O OH 65% O O H H N N NHBoc O N H O O NH2 O O O OH H N NHBoc O NH HO N H HO Bn O O α-1,3-fucosyltransferase HO NHAc OH HO OH H GDP-Fucose OH OH O NH HO HO2C O O AcHN HO NHAc O O HO O OH H H >95% N N NHBoc β-1,4-galactosyltransferase O N H O Bn O O O O O O– O– NH OH H OH O O N NHBoc OH P P 55% OH O NH O O O O N O OH HO N O O HO OH O H HO NHAc Bn O O OH UDP-Gal HO OH HO OH HO OH H OH OH O NH HO HO2C O O AcHN O NHAc α-2,3-sialyltransferase HO O OH H3C O NH HO OH 2 OH H HO C O– N HO OH HO 2 O AcHN P O O N O HO O 35% CMP-NeuAc + 20% des-NeuAc HO OH +45% starting material 7. Special topic: Immobilization of catalysts
SEPARATION OF CATALYST? R P R HOMOGENEOUS P P C CATALYST P C P PURITY OF PRODUCTS P R P R
BIPHASIC SYSTEMS EASIER RECYCLING
P P R • Hydrophylic P P R • Hydrophobic NON-MISCIBLE R P P LIQUID PHASES • Fluorinated C • Ionic liquids C • Supercritical fluids
SEPARATION OF CATALYST? R P R HOMOGENEOUS P P C CATALYST P C P PURITY OF PRODUCTS P R P R
BIPHASIC SYSTEMS EASIER RECYCLING
P P R P P P R P R R NON-MISCIBLE R SOLID P P P LIQUID PHASES CATALYST P C C P P C C R P R IMMOBILIZATION METHODS
STRONG INTERACTION WEAK INTERACTION *LM ML* [ML*]
COVALENT ADSORPTION SUPPORT SUPPORT BOND [ML*]
[ML*] ML*
+ [ML*]
ELECTROSTATIC ENTRAPMENT [ML*] INTERACTION SUPPORT + [ML*]
+ [ML*]
TYPES OF SUPPORTS
highly cross-linked linear cross-linked inorganic polymer polymer polymer
example polystyrene (PS) PS-DVB (0.5-3%) PS-DVB (>5%) silica
solubility soluble swellable insoluble insoluble solvent dependent dependent independent? independent
mass transport no little potential potential problems
separation difficult filtration filtration filtration
number of high high high high anchoring points IMMOBILISATION BY COVALENT BOND FORMATION (I) ORGANIC POLYMERS
Grafting
P XY+ C* P Z C* R R L*(C*) M
P XY+ L* P Z L*
Polymerisation P X P Precursor
Ligand synthesis in solid phase
SOLUBLE POLYMER SUPPORTS
HOMOGENEOUS SOLUBILIZATION IN ULTRAFILTRATION REACTION A NON-MISCIBLE PHASE Price of membranes
CHANGE OF INSOLUBILIZATION OF CHANGE OF SOLVENT TEMPERATURE THE SUPPORTED CATALYST
O N COOH 1. Anionic polymerisation H O H2CCH2 H(CH2CH2)nCH2OH N COOPE 2. CO2 H 3. Me2SBH3 polymeric ligand (PL) Run %yield %ee
(PL)4Rh2 1 58 98 OCOCHN2 toluene reflux O 3 58 83 7 58 61 O RECOVERING BY CENTRIFUGATION AT ROOM TEMPERATURE IMMOBILISATION OF HYDROGENATION CATALYSTS: POLYMERISATION
CH CH3 3 CH CH CH C CH2CH CH2C 2 2 NaPPh 0,92 [Rh(C2H4)Cl]2 0,08 0,92 2 0,08 CATALYST O O O O 86% e.e. OO OO OH OH (homog. 81% e.e.) reusable in the absence of air Ph PCH CH2PPh2 TsOCH2 CH2OTs 2 2
CH3 CH3 CH2CH CH2C CH2C 0,05 0,85 0,10 TEST REACTION O O Ph2P N O O O COOH COOH H2 R O MeOH OH O Ph NHCOMe Ph NHCOMe Ph2P 90% e.e. ACA
IMMOBILISATION OF HYDROGENATION CATALYSTS: GRAFTING
Ph2 Tentagel (n= 60) P ACA HYDROGENATION spacer + - Rh (cod)BF4 H MeOH: no reaction O N N PPh2 EtOH: 90% ee, no reusable PS O n O O Benzene/MeOH: 97% ee, reusable once
TEST REACTION H PS N O COOMe O PPh2 + THF/MeOH Ru (cod) H2
PPh2 97% ee OH (rec. 90% ee) COOMe R EXAMPLES OF GRAFTING ONTO POLYMERS: AMINOALCOHOLS
Ph TEST REACTION Me OH CHO N OH PS ZnEt2 S Me 5-10% cat. 80-89% e.e. (R)
PS
N P Me MeN Me OH 92% e.e. (S) R Ph O 1 R2 OH
Merrifield (R1=R2=H): Synthesis in solid phase PS N Ph up to 69% ee Ph HO Barlos (R1=Ph, R2=o-Cl-Ph): Grafting 96% e.e. 94% ee
EXAMPLES OF GRAFTING ONTO POLYMERS: Mn(salen)
TEST REACTIONS O O O NN Mn M-CPBA, NMO P O O O O Cl 4% catal. -78ºC-rt
O MeO OH n n m MeO-PEG Ph P styrene dhnapht yield %ee yield %ee NCPS MeOPEG 62 57 70 76 (non-cross-linked PS) OH NCPS 76 51 69 73
cross-linker JandaJel 81 51 71 79 in JandaJel Merrifield 61 35 69 78 OO Me 82 52 75 84 SYNTHESIS OF THE LIGAND IN SOLID PHASE
CHO NNH2 NN OH OH O t P P O OH HO Bu tBu tBu P O tBu But
TEST REACTION Ph Ph O M-CPBA, NMO NN Mn O O tBu P O OAc tBu But Porous PS 61% ee Gel-type PS 66% ee Porous polymethacrylate 91% ee
POLYMERISATION OF TADDOLS
Ar Ar TEST REACTION O O O OH H Catalyst in the NO main chain O OH COR Ar Ar 1) styrene/DVB i CATALYSTS Ph Ph 2) Ti(O Pr)2Cl2
O OH
conv. endo/exo %ee O OH Catalyst in the cross-linking points Ar=Ph 63 87/13 30 Ar=2-napht 92 87/13 56 30 81/19 6 OTHER CATALYSTS FOR HYDROGEN TRANSFER
O TEST REACTION NH2 P N H N i H Ph O PrOH OH SO2 Ph Ph KOH Ph Grafting
[Ru(p-cymene)Cl2]2 H NH2 N Support method conv. %ee SO2 Ph Ph PS grafting 88 91 Polymerisation tentagel grafting 955 + PS polym. 23 84 PS polym. 73 91
[Ir(cod)Cl]2
IMMOBILISATION BY COVALENT BOND FORMATION (II) INORGANIC SOLIDS
O O O Si(OR)4 Si L*-M-L (RO)3Si L*-M-L M L* O O
O O Si(OR) OH 4 O L-M-L* (RO)3Si L* Si L* OH O O
O Grafting (ligand or catalyst) L*-M-L O Ligand synthesis in solid phase “Polymerisation” (sol-gel synthesis) INORGANIC SUPPORTS FOR COVALENT IMMOBILIZATION
SILANOL O SiO quartz GROUPS Si 2 O O OH O OH Si OH Si O O O OH O Si OH isolated geminal O silicaS O O vicinal Si OSiMe O 3 O • Precipitation (hydrolysis) "end-capped"
• Pyrolysis SiCl4 (vapour) MESOPOROUS CRYSTALLINE SILICAS
• Surface area • Porosity (size and distribution) • Silanol density
Surfactant Control of pore size (template) (25-100 Å, narrow distribution)
GRAFTING THROUGH THE METAL CENTRE
Cl Cl Al Al Et2AlCl SILICA + Et O O O (-)-menthol
TEST REACTION Enantioselectivity similar to that obtained with the analogous in CHO -50OC + CHO homogeneous phase. < 15% cat. (2 equivalents of menthol are needed for better selectivities) 31% ee POSSIBILITIES FOR SILICA FUNCTIONALIZATION
OR OH O Si + (RO)3Si-R' OH O R' functionalized group
-(CH2)3-NHR Alkylation Imine or amide formation NH2 -(CH ) -SH Alkylation 2 3 Radical addition -(CH2)3-X (Cl, Br, I) -(CH2)11-Br Reaction with amines or alcohols CH2Cl (formation of secondary amines, O O ethers, ureas, carbamates, sulfonamides) -(CH2)3-NCO
SO2Cl Radical addition -(CH2)n-CH=CH2 (0 ≤ n ≤ 6) -(CH2)2-Ph Aromatic electrophilic substitution
HYDROGENATION CATALYSTS ON SILICA
Ph2 PPh2 P OEt + - H a) silica/toluene O H Rh (cod)BF4 (EtO)3Si N N Si N N b) [Rh(cod)2]BF4 O PPh2 PPh2 O O
TEST REACTION S D loading conv (min) % e.e. (m2/g) (nm) (μmol/m2) COOMe H COOMe 2 S 310 14 0.18-0.63 100 (20-30) 91.7-93.5 100 (14-23) 92.1-94.5 Ph NHCOCH3 Ph NHCOCH3 370 10 0.22 99 (26) 92.5 590 4.4 0.31 99 (90) 89.3 No interactions between cationic species 33 (114) 86.8
Deactivation with small pores (pore blocking?) DIHYDROXYLATION CATALYSTS ON SILICA
O O Si S S Si O O OMe N MeO N N N OO
MeO OMe
N N + OsO4 Loss of Os
MeO
O OMe Si O N Problem of toxicity O N O N TEST REACTION N N OH N K3[Fe(CN)6]/K2CO3 O Ph Ph Ph t Ph O N BuOH/water N Si O OH O OMe 77-88% yield MeO 99% e.e.
EPOXIDATION CATALYSTS ON SILICA
Synthesis of the ligand TEST REACTION in solid phase O R MCPBA R Ph Ph Ph NMO Ph (-78ºC) N N Mn O O tBu Cl R cat. time conv (%) % e.e. N H homog. 45 min 97 84 heterog. 4 h 92 89 OMe Me homog. 45 min 81 43 Si O O heterog. 4 h 74 56
MCM-41 IMMOBILIZATION WITH FORMATION OF THE SUPPORT
SILICA O O Si Si(OEt)3 O x = 0-3 NH NH x Si(OEt) Low surface area 4 Rh(cod)Cl Rh(cod)Cl (3-11 m2g-1) H O NH 2 NH O Si Si(OEt)3 O O SILICA
TEST REACTION x time (d) conv (%) % e.e. O OH homog. 5 95 26 iPrOH 0 5 75 58 S KOH 1 7 60 10 3 8 20 15 3 7 30 98 Npht-COCH3
IMMOBILIZATION BY ELECTROSTATIC INTERACTION
L L + - CATIONIC L* M L* X + + L* M L* - EXCHANGE + X L L
SOLID SOLUTION SOLID SOLUTION
CHARGE SITUATION H2
G+ L + M M + H + L* M L*
L
metal ligand neutral TYPES OF INORGANIC SUPPORTS
CLAYS MICROPOROUS MESOPOROUS ZEOLITES CRYSTALLINE Pores: 4-10 Å ~ 10 Å SILICAS
Pores: 25-100 Å Supermicropores by partial destruction Interlamellar space AlO6 of the structure octahedra SiO4 tetrahedra Isomorphous substitutions: Al
T HYDROTALCITES - - O T [Mg0.75Al0.25(OH)2](CO3)0.125 exchangeable + + + octahedral cations + layer - exchangeable anions - - +
TYPES OF ORGANIC SUPPORTS
HYBRID MATERIALS
POLYMERS Grafted organic groups SO3Na
X m (RO)3Si 1) Grafting p n Si + 2) Transformation OOO Silica (X SO3Na) SILICA SO3Na Composites
CF2 CF2 Variations: CF2 SO3H CF2 CF2 CF2 Silica CF CF • Main chain: -(CF2)n- SO3H 2 2 CF SO H + 2 3 • Cross-linking: nature and degree synthesis CF2 CF2 + Si(OR)4 CF2 SO3H • Charged group: -COONa, -NR3 nafion-silica nanocomposite THE EXCHANGE PROCESS
+ - + [L*-M] X + support Na+ support [L*-M] +Na+X-
+ - L* +M+X- + support Na+ L* + support M+ +NaX
• Complex and leaving salt in solution IMPORTANCE • Possible coordination to M: deplacement of chiral ligand OF SOLVENT • Compatible with support: swelling
HYDROGENATION WITH CLAY-IMMOBILIZED CATALYSTS
HECTORITE COOH R = H COOH H2 + 70% e.e. Ph 100% conv (1-6 h) EtOH R NHCOCH3 R NHCOCH3 5 cycles N PPh2 Rh(cod) R = Ph EFFECT OF hectorite 49% e.e. PPh2 N SUPPORT nontronite 0% e.e.
Ph
HECTORITE
EFFECT OF % e.e. MeOH EtOH iPrOH H Me +
A SOLVENT AND Homog.: 15 32 56 NH 2 2
.
IMMOBILIZATION Heterog.: 64 88 84 7 PPh2 2 Fe Rh(cod) COOBu COOBu PPh2 H2
COOBu COOBu IMMOBILIZATION ON CATIONIC SUPPORTS
HYDROTALCITE AS SUPPORT
- OH H OH SO3 - 2 SO3 100% e.e.
P + Cl Ru Cl- P COOMe COOMe H 2 48% e.e. - SO3 COOMe COOMe - SO3
Big size of the complex Unclear points: Exchange on the external • Need for a MgAl hydrotalcite surface of the hydrotalcite • Possibility of reuse
IMMOBILISATION WITHOUT LIGAND-SUPPORT BOND
• Adsorption on the surface Hydrophylic or hydrophobic interactions Supported liquid phase
• Entrapment into the pore system “Ship-in-a-bottle” method Entrapment between polymer chains IMMOBILIZATION BY ADSORPTION
P CF3 COOCH H 3 HYDROGEN Rh(cod) S COOCH3 2 BOND O O O hexane NHCOCH3 P NHCOCH3 H H H 99% e.e. OOO
SILICA
O O 12 PPh H COOCH3 HYDROPHOBIC 2 COOCH3 2 A tBuCO N
C INTERACTION I L water Ph I Rh(COD)BF4 NHCOCH3 S Ph NHCOCH3 PPh2 93% e.e. O O 12
SUPPORTED LIQUID PHASE
Organic Porous
Glass catalyst particle COOH H2 COOH
MeO MeO (S)-naproxen
Glass
SO3Na H2O
P SO3Na Ru 2Cl Hydrophilic phase: ethyleneglycol P SO3Na Hydrophobic phase: CHCl3/cyclohexane (1:1) Results: tof 24 h-1, 88% e.e. (r.t.) SO3Na H2O 96% e.e. (3ºC) Organic Phase ENTRAPMENT INTO ZEOLITES “ship-in-a-bottle” synthesis
channel
Ligand components Mn2+ are small enough to enter the zeolite (zeolite supercage) channels
CHO
R2 OH H H
H2N NH2 R1
H H
N + N Mn Complex is too
R2 O O R2 large to leave And to be accommodated? R1 R1
ENTRAPMENT INTO MEMBRANES
Me Me cross-linked polysiloxane Si O Si (membrane Me Me form) n P "curing" P + Rh(cod) Rh(cod) "SWELLING" OSiMe H 2 OTf OTf P Si P OSiMe H 2 SOLVENT HMe2SiO OSiMe2H EFFECT
Entrapment of Mn(salen) solvent swelling solubility leaching OH PhCl 173 21 100 O H2 Et O 240 7 90 COOCH COOMe 2 3 acetone 15 90 62 90-93% e.e. MeOH 2 162 54 heptane 235 0.3 12 CONCLUSIONS
pro contra Ligand modification Versatility (effect on e.e.) COVALENT BOND Metal leaching Ligand retention (possible )
Ionic character ELECTROSTATIC Ligand leaching (possible )
Simplicity Leaching and ADSORPTION solubility Without ligand modification Complex size ENTRAPMENT
Swelling and leaching
References
BOOKS
• Chiral Catalyst Immobilization and Recycling; D. E. De Vos, I. F. J. Vankelecom, P. A. Jacobs, Eds.; Wiley- VCH: Weinheim, 2000. • Comprehensive Asymmetric Catalysis; E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Eds.; Springer-Verlag: Berlin-Heidelberg, 1999; chapters 37 and 38. • D. C. Sherrington, P. Hodge. Synthesis and Separations using Functional Polymers; Wiley: New York, 1988. • W. T. Ford. Polymeric Reagents and Catalysts; ACS Symposium Series 308, American Chemical Society: Washington, 1986.
•H.-U. Blaser, Tetrahedron: Asymmetry 1991, 3, 843. • S. J. Shuttleworth, S. M. Allin, P. K. Sharma, Synthesis 1997, 1217. •L. Pu, Tetrahedron: Asymmetry 1998, 9, 1457. REVIEWS • L. Canali, D. C. Sherrington, Chem. Soc. Rev. 1999, 28, 85. • Y. R. de Miguel, J. Chem. Soc. Perkin Trans. 1 2000, 4213. • S. J. Shuttleworth, S. M. Allin, R. D. Wilson, Synthesis 2000, 1035. • Y. R. de Miguel, E. Brulé, R. G. Margue, J. Chem. Soc. Perkin Trans. 1 2001, 3085. • B. Clapham, T. S. Reger, K. D. Janda, Tetrahedron 2001, 57, 4637. II. Liquid phase synthesis
Dickerson, Tobin J.; Reed, Neal N.; Janda, Kim D. Chem. Rev. 2002, 102, 3325.
Polyglycerol
Haag, R. et. al. J. Comb. Chem., 2002, 4, 112; Haag, R. Chem. Eur. J., 2001, 7, 327 Soluble Polymers
Janda, K. D. Chem. Rev., 1997, 97, 489-509. Janda, K. D. Chem. Rev., 2002, ASAP.
LPS supported synthesis of Prostaglandins
Janda, K. D. JACS., 1997, 119, 8724-8725. PEG-Supported Sulfoxide for Swern Oxidations
Harris, J. M, etc. J. Org. Chem., 1998, 63, 2407.
Chemical Tagging Fluorous Method: A solution phase method
Luo, Z.; Zhang, Q.; Oderaotoshi, Y.; Curran, D. P. Science 2001, 291, 1766-1769.
Starter Library of Mappicine Analogs
Luo, Z.; Zhang, Q.; Oderaotoshi, Y.; Curran, D. P. Science 2001, 291, 1766-1769. Automated High Throughput Purification
www.biotage.com
Wilcox’s Precipitons
Bosanac, T.; Yang, J.; Wilcox, C. S. Angew. Chem. Int. Ed. 2001, 40, 1875-1879. Bosanac, T.; Wilcox, C. S. J. Am. Chem. Soc. 2002, 124, 4194-4195. ROM Polymerization
1st-G: Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110. 2nd-G Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956.
Features of Phase Trafficking via ROMP Impurity Trapping: Chromatography Free Mitsunobu Reaction
Barrett, A. G. M., et. al. Org. Lett. 2000, 2, 2999. Barrett, A. G. M. Chem. Bev. 2002, ASAP.
Synthesis of ROMPgel Activated Esters
Barrett, A. G. M., et. al. Org. Lett. 2000, 2, 261-264. Acylation of Amines Using ROMPgel Supp. Esters
Barrett, A. G. M., et. al. Org. Lett. 2000, 2, 261-264.
Polymer supported Tosmic Reagent
NC
Barrett, A. G. M., et. al. Org. Lett. 2001, 3, 271-273. Polymer supported Tosmic Reagent
Barrett, A. G. M., et. al. Org. Lett. 2001, 3, 271-273.
Sequestration of Excess Amine
Barrett, A. G. M., et. al. Org. Lett. 2000, 2, 2663-2666. Bolm ROM-Polymer Catalyst
Bolm, C.; Dinter, C. L.; Seger, A.; Hocker, H.; Brozio, J. J. Org. Chem. 1999, 64, 5730-5731.
Radical Reactions on Soluble ROMP Supports
O O
OR Bu3SnH OR ZnCl , Et B, O Br 2 3 2 o CH2Cl2, -78 C >90:1 de n n Bu3Sn H O AIBN, PhH H O Ph Ph Ph Ph O O 80oC O O O R = N Br Br O O O O O H H O Precipitate from tin salts n with cold MeOH Precipitate from tin salts with cold MeOH
Enholm, E. J.; Gallagher, M. E. Org. Lett. 2001, 3, 3397-3399. Enholm, E. J.; Cottone, J. S. Org. Lett. 2001, 3, 3959-3962. Capture-ROMP-Release: Synthesis of Amino Acids
Mukherjee, S.; Poon, K. W. C.; Flynn, D. L; Hanson, P. R., Tetrahedron Lett. 2003, 44, 7187-7190. III. Polymer supported reagents
Reviews on polymer-bound reagents
Polymer-supported organic catalysts Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. Rev. 2003, 103, 3401
Recent advances in asymmetric C-C- and C-heteroatom bond forming reactions using polymer-bound catalysts Bräse, S.; Lauterwasser, F.; Ziegert, R. E. Adv. Synth. Catal. 2003, 345, 869
Whole issue dedicated to polymer-bound reagents Chem. Rev. 2002, 102, No. 10
*New tools and concepts for modern organic synthesis Ley, S. V.; Baxendale, I. R. Nature Reviews: Drug Discovery 2002, 1, 573
Functionalized polymers – emerging versatile tools for solution-phase chemistry and automated parallel synthesis Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew. Chem. Int. Ed. Engl. 2001, 40, 650
Multi-step organic synthesis using solid-supported reagents and scavengers: a new paradigm in chemical library generation Ley, S.V. et al. J. Chem. Soc., Perkin Trans. 1 2000, 3815
Solid-supported reagents in organic synthesis Drewry, D. H.; Coe, D. M.; Poon, S. Med. Res. Rev. 1999, 19, 97
Solution-phase chemical library synthesis using polymer-assisted purification techniques Parlow, J. J.; Devraj, R. V.; South, M. S. Curr. Opin. in Chem. Biol. 1999, 3, 320
Functionalized polymers: Recent developments and new applications in synthetic organic chemistry Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis 1997, 1219.
III. Polymer supported reagents
Conventional synthesis
Reagent A +B AB
Solid phase synthesis
Reagent AAB+B
Synthesis using a solid-supported reagent
Reagent A +B AB Different types of polymer-bound reagents
Reagents Scavengers Reage nt Quenching reagents substrate product Capture-and-release reagents
Scav eng er + + + Scav eng er
substrates product product
Capturing rea gen t
Release Capturing rea gen t product
Solid Phase Reagent and Scavenger Resins
Attaching reagents to the solid phase instead of substrates provides similar advantages: - Ease of purification allows the use of excess reagents
Reagent + Reagent Filter Starting Product Clean Material Product
Excess reagents can be removed by use of a solid phase-bound “scavenger” that reacts with or binds the excess reagent
Excess + Reagent 1) Scavenger Reagent Starting Product Clean Material 2) Filter Product + Scavenger Reagent Advantages
Compared to solution phase chemistry
Easy workup / can be automated
Toxic or volatile reagents can be immobilized
Two incompatible reagents can be used at the same time (’wolf and lamb’)
Excess reagent can be used
Advantages
Compared to solid phase chemistry
Easier to develop chemistry Easier to analyze intermediates (solution) Convergent synthesis possible
A B
E C D Disadvantages
Slower reaction in some cases Leaching of metal More expensive
Solid supports
Polystyrene Other organic polymers (polyamides etc.) Soluble polymeric supports (PEG, dendrimers) Silica Zeolites Glass Graphite Cellulose Polystyrene
Microporous polystyrene (1-4% cross-linked) Macroporous polystyrene (30-50% cross-linked) Hybrids (PS/PEG)
O O OH n
Soluble polystyrene Plugs of microporous polystyrene
How are the reagents/scavengers attached to the resin?
Covalent binding by: LiPPh2 Cl PPh2 - reaction with a derivatized resin - co-polymerization of the Functionalized + + reagent with styrene and polymer divinylbenzene PPh2
NaCN NM e3 Forming an ion-pair NM e3 Cl CN
Entrapment, reagent enclosed in a polystyrene network Polymer-Bound Reagents
Reagent
substrate product
Some examples: Oxidation Reduction Nucleophilic reactions Carbon-carbon bond formation Amide bond formation
Resin-Supported Reagents
Review: Ley, S. V. et al. J. Chem. Soc., Perkin Trans. 1 2000, 3815-4195. Scavenger Resins
Reagents for Oxidation
NMe3 RuO 4
X N OsO4 O N Cl O Ph 2 PCoPPh3 Cl SiO2 CrO3
2- NMe3 Cr2O7 SiO2 KMnO4 2
NMe3 IO4 Reagents for Oxidation COH CO
PSP = polymer supported perruthenate
KRuO4 NMe3 RuO4 NMe3 Cl ultrasound PSP
H PSP, O2 toluene O OH > 99% 75 - 85 oC
as above H 83 % H15C7 OH H15C7 O
Hinzen, B., Lenz, R., Ley, S. V. Synthesis, 1998, 977
Reagents for Oxidation COH CO
Polymer-bound sulfoxide for Swern oxidation
O O O HO S t-BuOOH OH + O S DMAP, DIC O S H O
H Ph O sulfoxide Ph O OH O 71 % (COCl)2, Et3N
OH O as above 82 %
Cole, Stock, Kappel Bioorg. Med. Chem. Lett. 2002, 12, 1791 Liu, Y.; Vederas, J. C. J. Org. Chem. 1996, 61, 7856 Reagents for Oxidation COH CO
Poly(vinylpyridinium dichromate)
n n + CrO3
N NNN N 2- Cr2O7 cross-linking agent H
OH PDC O
98%
OH PDC O 93%
Fréchet, J. M. J.; Darling, P.; Farrall, M. J. J. Org. Chem. 1981, 46, 1728
Reagents for Oxidation HO OH CC CC
Dihydroxylation & oxidative cleavage of alkenes CO+ OC
L[OsO4]
OH N OsO4 HO C8H17 C8H17 Me3NO 90%
Cl O NNOsO4 H H NaIO4 65% O
Nagayama, S.; Endo, M.; Kobayashi, S. J. Org. Chem. 1998, 63, 6094 Cainelli, G.; Contento, M.; Manescalchi, F.; Plessi, L. Synthesis 1989, 45 Reagents for Oxidation O CC Epoxidation
O O O
CF3 PS or Tentagel
CO N N O O Ru N N C OOH O
S OOH O
Reagents for Oxidation O CC Epoxidation
Oxon O
SO4H
80%
O SO4H
80%
Pande, C. S.; Jain, N. Synth. Commun. 1989, 19, 1271 Reagents for Oxidation O O
n Epoxidation & oxidation of amines
O
oxirane
82%
NH2 NO2 oxirane
83%
oxirane
N N 83% O
Shiney, A.; Rajan, P. K. ; Sreekumar, K. Polymer International 1996, 41, 377
Reagents for Oxidation
N N Mn Asymmetric epoxidation OOCl O
Ph Ph O
Mn-salen
NaOCl, 4-PPNO O 37% (94% ee)
4-PPNO = 4-phenylpyridine-N-oxide
Smith, K.; Liu, H.-C. Chem. Commun. 2002, 886 Reagents for Reduction CO COH
NMe (CN)BH NMe3 BH4 3 3
BH BH4 4 DMF NH3 H N Pd H2 N
PPh3 BH4
NZn(BH4)2
Reagents for Reduction CO COH
BH4 BH4 O NH3 N H2 OH H MeOH 100%
O OH
NMe BH MeO 3 4 MeO H NiCl2, MeOH H N N MeO MeO 88% Epimaritidine
Rajasree, K.; Devaky, K. S. J. Appl. Polym. Sci. 2001, 82, 693; Ley, S. V. Schucht, O.; Thomas, A. W.; Murray, P. J. J. Chem. Soc., Perkin Trans 1 1999, 1251 Reagents for Reduction
CO CNH2 Reductive amination
O N NMe3 BH4 HN + H H2N H 94%
Yoon, N. M.; Kim, E. G.; Son, H. S., Choi, J. Synth. Commun. 1993, 23, 1595
Scavengers can be used to remove excess aldehyde or excess amine:
NH2 NCO
Reagents for Reduction CBr CH Dehalogenation
Bu Bu Sn H
NH2 NH2
N N N N Br N N SnH N N HO HO O O H H H H H H H H OH OH OH OH 87%
Gerlach, M.; Jordens, F.; Kuhn, H.; Neumann, W. P. Peterseim, M J. Org. Chem. 1991, 56, 5971 Applications
Reagents for oxidation and reduction O H NMe RuO Cl NMe3 BH4 OH 3 4 O
Cl N Cl N Cl N
OH TBDMSO 1) NMe3 OH NO2 NMe2 NO2
CH NO 3 2 Cl N CH3SO2Cl Cl N 2) TFA
O OH N OMs
NMe3 BH4 N
CH3SO2Cl NO Cl N 2 NO NO Cl N 2 Cl N 2
OMs Several steps and N Cl polymer-bound reagents. H NMe3 BH4 N
NH Cl N 2 Epibatidine, purity > 90% Habermann, J.; Ley, S. V.; Scott, J. S. J. Chem. Soc. Perkin Trans. 1 1999, 1253
Amide Formation O O + R' C H N C R OH 2 R NR' H
O O O O O OH O O OR1 HO R S N 1 S N R2R3NH R2 N N NR H N PyBrOP H N 1 N N R3
N PF PyBrOP = P 6 N Br N
Pop, I. E.; Deprez, B. P.; Tartar, A. L. J. Org. Chem. 1997, 62, 2594 ’Wolf and Lamb’
O 1) Ph Ph Li O H N O Ph Ph NO2 N
Ph Me 2) SO NH NH THF 3 3 2 Ph
Reagents that are incompatible in solution can be used together when bound to a solid phase.
Cohen, B. J.; Kraus, M. A.; Patchornik, A. J. Am. Chem. Soc. 1977, 99, 4165; J. Am. Chem. Soc. 1981, 103, 7620
Polymer-bound Nucleophiles
Nucleophilic substitution CX CNu
NMe3 Nu
Nu = OAr,CN,SAr, N3, NaCO3, NCO, SePh, NO2, NCS
Br NMe3 CN C N
72%
Gordon, M.; DePamphilis, M. L.; Griffin, C. E. J. Org. Chem. 1963, 28, 698 Carbon-Carbon Bond Formation
Horner-Wadsworth-Emmons CO CC
O O NMe OH CN H 3 P CN + EtO EtO Cl Cl 99% O O O NMe3 OH O P + EtO OEt H OEt EtO 93%
PASSflow reactor used:
Soledenko, W.; Kunz, U.; Jas, G.; Kirschning, A. Bioorg. Med. Chem. Lett. 2002, 12, 1833.
Metathesis
Cross Metathesis
R 1 R 2 catalyst R 1 + + CM
R 2 Ring Closing Metathesis
+ RCM
Ring Opening Metathesis Polymerization R [M] R R [M] ROMP R n R Metathesis Catalysts R1 R2 1 + +
R2
Schrock type Grubbs type
L R Cl Ru Cl N L
Mo RO Ph L = phosphine or carbene OR
Metathesis reactions are often difficult to purify as the catalyst (typical 10 – 20 mol%) contaminates the product.
Metathesis
Mechanism
R 1 [M ] CH 2
R2
R 1
[M] [M]
R R 1 2 R 1
[M] R2
R 1 Polymer-Bound Metathesis Catalysts
Barrett’s ”boomerang” catalysts
PC y3 PC y3 CH Cl Cl 2 2 Cl + Ru Ru + Cl reflux Cl Ph Ph L L
L1 = PCy3 L2 = IMes
P N N
PCy 3 IMes
Ahmed, M.; Arnauld, T.; Barrett, A. G. M.; Braddock, D. C.; Procopiou, P. A. Synlett 2000, 1007
Polymer-Bound Metathesis Catalysts
Barrett’s ”boomerang” catalysts
R PC y3 R PC y Cl 3 Ru + Cl Cl Ru L Cl L
PC y PC y3 Ph 3 R Cl Cl Ru Ru + Cl Cl Ph L L unstable Polymer-Bound Metathesis Catalysts
Recycling of Barrett’s catalyst
PC y3 Ru Cl Cl CO2Et IMes CO2Et
CO2Et 1-octene, PPh3 CO2Et
Cycle 123456
% Conversion 100 100 100 88 43 7
More Metathesis Catalysts
O
Blechert NN Mes Mes
Cl Ru Ph Cl PCy2 PCy Ph 3 Cl Ru Ph Cl
PEG PCy2 Grubbs O
Cl Ru Cl PCy3 Lamaty Enantioselective Olefin Metathesis
iPr tBu
N Hoveyda / Schrock O Mo iPr O
tBu
O O 5 mol% catalyst H benzene, RT, 24 h
meso compound 90% conversion, 95% ee
Suzuki Reaction
Palladium-catalyzed coupling of an aryl/alkenyl halide with a boronic acid/ester.
B B Pd-cat. X + (RO)2B
A A or or or
X + (RO)2B A B B A or
B A Suzuki Reaction
1 2 R R 1 L2 R X Pd(0) Mechanism
L L2 2 1 R1 Pd R2 R Pd X
R'ONa
' R OB(OR")2 L2 R1 Pd OR' NaX
2 R B(OR")2
Carbon-Carbon Bond Formation
Suzuki coupling Pd cat. CX+ (HO)2B C CC sp2 sp2
LiPPh2 PdLn
Cl PPh2 Ph2P[Pd]
Pd source: Pd(PPh3)4 PdCl2 Pd(CH3CN)2Cl2 Pd(dba)2 Na2PdCl4
Jang, S. Tetrahedron Lett. 1997, 38, 1793; Fenger, I.; Le Drian, C. Tetrahedron Lett. 1998, 39, 4287 Suzuki Coupling Pd cat. CX+ (HO)2B C CC sp2 sp2
{Pd}
Na2CO3 B(OH)2 + Br N N toluene/water reflux 90 - 95 %
{Pd} Bu Bu Br Hex NaOEt + benzene Hex o B O 80 C O 84 %
Suzuki Coupling: Other Catalysts
Pd cat. CX+ (HO)2B C CC sp2 sp2
O Si Si O O O
PEG N H HN NH
Uozumi PPh2 S[Pd] Zhang Hayashi Pd Cl O Cy2 P [Pd] Buchwald Pd(OAc)2 or Pd2(dba)2 Stille Coupling
O O Br 1) cat. LiCl, NMP Pd cat. MeO O + R 2) NaOMe R SnBu 3
Ar 2 O O P Pd cat. = Pd Pd P O O Ar 2
Advantages: Tin reagents are toxic – easier to handle if bound to a solid support. Tin byproducts often contaminate product in solution reactions.
The Pauson-Khand Reaction
R 1 O
Co 2(CO )8 + R 1
R 2 R 2 The Pauson-Khand Reaction
On solid phase
O
O Co 2(CO) 8 benzene 80 oC, 6 h
ester O hydrolysis HO
Schore, N. E.; Najdi, S. D. J. Am. Chem. Soc. 1990, 112, 441
The Pauson-Khand Reaction
Mechanism
RL RL Co2(CO)8 - CO R RS RL RS S Co(CO) - 2 CO Co(CO)3 3 Co Co (CO)3 (CO)2
R R R L L alkene RS insertion RS Co(CO)3 CO insertion Co(CO)3 CO Co(CO)2 CO Co(CO)3
R R
R L (CO)3Co(CO)3 R R reductive Co S L R RS RL S Co(CO)3 elimination -Co2(CO)6 Co(CO)3 O O
O R R The Pauson-Khand Reaction
Using polymer-bound cobalt carbonyl
Ph2 P Ph2 Co (CO )3 Co (CO )4 PCo(CO)3
P Co (CO )4 Ph THF, RT 2 1 + 2
Co (CO) PPh2 + 2 8
1,4-dioxane Ph2 P Co (CO ) 75 oC 3
P Co (CO )3 Ph2 3
Comely, A.C.; Gibson, S. E.; Hales, N. J. Chem. Commun. 2000, 305
The Pauson-Khand Reaction
Ph2 P Using polymer-bound cobalt carbonyl Co(CO)3 Co(CO) P 3 Ph2 3
CO 50 mbar, 3 TsN O TsN 70 oC, THF, 24 h
61%
Et O 2C Et O 2C as above O
Et O 2C Et O 2C 49% The Pauson-Khand Reaction
Using polymer-bound promotors
O
N + OSMe 1 O 2
O H 1, THF, RT R R + or 2, DCE, Δ Co2(C O)6 H R = Ph, tBu, Me2(OH)C 74 - 99% yield
Kerr, W. J. et al, Chem. Comm. 2000, 1467; 1999, 2551.
References
Reviews on polymer-bound organometallic reagents:
Recent advances in asymmetric C-C and C-heteroatom bond forming reactions using polymer-bound catalysts Bräse, Lauterwasser, Ziegert Adv. Synth. Catal. 2003, 345, 869-929
Preparation of polymer-supported ligands and metal complexes for use in catalysis Leadbeater, Marco Chem. Rev. 2002, 102, 3217-3273
Recoverable catalysts and reagents using recyclable polystyrene-based supports McNamara, Dixon, Bradley Chem. Rev. 2002, 102, 3275-3300
Soluble polymers as scaffolds for recoverable catalysts and reagents Dickerson, Reed, Janda Chem. Rev. 2002, 102, 3325-3344
Functionalized polymers – Emerging versatile tools for solution-phase chemistry and automated parallel synthesis Kirschning, Monenschein, Wittenberg Angew. Chem. Int. Ed. Engl. 2001, 40, 650-579
Multi-step organic synthesis using solid-supported reagents and scavengers: a new paradigm in chemical library synthesis Ley et al. J. Chem. Soc., Perkin Trans 1 2000, 3815-4195 Scavengers
+ +
substrates product
Scav eng er
+ Scav eng er
product
Scavengers
O O acidic S OH OH
CH3 basic N N CH3
NH2
nucleophilic NH2 N
NH2 O electrophilic NC O H Scavengers
Application
1) R1X 1) R2X HN N HN N NMe2 BEMP NH N Cl Cl R1 2) 2) NH2 NH2
R2 N N
N Cl R1
N N P BEM P = NN
Xu, W.; Mohan, R.; Morrissey, M. M. Bioorg. Med. Chem. Lett. 1998, 8, 1089
Capture and Release
Capturing reagent + Capturing reagent
substrates product Release + contaminants
product Capture and Release
Tamoxifen library
R1 O O B B R3 X O O R2 R1 R2 Pt(PPh ) Pd(dppf)Cl , base 3 4 O B B O 2 O O
R 1 R1 I R1 1) O N Si R R2 R 2 + H 2 B O 2) 30% TFA in CH2Cl2 O
R3 R3 R3 + R3 + regioisomer regioisomer 5 x 5 library
Brown, S. D.; Armstrong, R. W. J. Org. Chem. 1997, 62, 7076
Capture and Release
Synthesis of β-amino alcohols
OH O O O N Cl H O NH2 OH NaH
Impurities
OH O O OH
NH2 Capture and Release
Synthesis of β-amino alcohols using polymer-bound borane
OH O O 1) O N Cl O NH2 O BY 2 NaH 2) HBY2
HCl
O BH O N HBY2 = PEG H OH
2
Hori, M.; Janda, K. D. J. Org. Chem. 1998, 63, 889
Capture-Release Alkylation Utilizing Resin-Bound Sulfonyl Chloride
Rueter, J. K.; Nortey, S. O.; Baxter, E. W.; Leo, G. C.; Reitz, A. B. Tetrahedron Lett. 1998, 39, 975-978. Capture Activation-Release: Solid-Supported DCT for Amide Synthesis
Masala, S.; Taddei, M. Org. Lett. 1999, 1, 1355-1357.
An Example of Solid Phase Reagents and Scavengers
An extremely efficient three step reductive amination and triflation is accomplished by the use of solid phase reagents and scavengers
RuO OH 4 HO HO NMe O MeO 3 MeO H NH2 MeO MeO N MeO BH4 H
NMe3 MeO
HO
Tf2O, NN MeO N Tf MeO 98 % 3 steps
Ley SV et al. J. Chem. Soc. Perkins. Trans. I 1999, 63, 6625. Application: Sildenafil (Viagra™)
Pr OE t H2N O N O + H N S 2 N N O OH N O 1 2
OE t Pr O N S N N O HN N N O Sildenafil (ViagraTM)
Pr =
Baxendale, I. R.; Ley, S. V. Bioorg. Med Chem. Lett. 2000, 10, 1983
Sildenafil, building block 1
1) OEt OH HN N O O O O EtN(i- Pr)2 S S N O Cl 2) Et2SO4 OH O OH N crude 1 Sildenafil, building block 2
O Pr N OEt Pr O NH 2NH Me Pr N Br NH NH EtO 2 N H BEMP O + NM e3 CN cat. H+
H N O MnO2 N 1) BEMP Pr N OEt Pr N OEt N N 2) NH3/MeOH NC O Pr NH 2 CN O CN O NH 2 2
N N P BEMP = NN
Sildenafil (Viagra™)
OEt OEt O O O S O HOBt N 2 S O O N N O OH PyBrOP N N N NCO crude 1 N
OEt OEt Pr O O NH2 Pr N O EtOH/NaOEt S S N N N o O O HN N MW 10 min/120 C HN N N N N O O Sildenafil
PF 6Br PyBrOP = N P N HOBt = N N N N HO Natural Products via Supported Reagents
Baxendale, I. R.; Ley, S. V.; Piutti, C. Angew. Chem., Int. Ed. 2002, 41, 2194-2197 Baxendale, I. R.; Brusotti, G.; Matsuoka, M.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 2002, 143-154 Baxendale, I. R.; Lee, A.-L.; Ley, S. V. Synlett 2001, 1482-1484 Habermann, J.; Ley, S. V.; Scott, J. S. J. Chem. Soc., Perkin Trans. 1 1999, 1253-1255 Ley, S. V.; Schucht, O.; Thomas, A. W.; Murray, P. J. J. Chem. Soc., Perkin Trans. 1 1999, 1251-1252.
Epothilone
For a total synthesis of epothilone using S polymer-bound reagents, see: Storer, R. I.; Takemoto, T.; Jackson, P. N S.; Ley, S. V. Angew. Chem. Int. Ed. 2003, 42, 2521 H O O OH O
O OH