Comparison of Resin Types

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Comparison of Resin Types
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Bound Reagent Development Strategy

• Major classes and important reactions
• Acids and Bases
• Scavengers
• Reductive Amination
• Common Reagents for Amide Synthesis
• Oxidizing agents
• Palladium Catalyst Scavenger

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Polymer-Supported Acids and Bases
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General Acid Resin MP-TsOH - Example

• Resin-bound toluenesulfonic acid equivalent
• high-loaded 3.5 4.5 mmol/g
• Cation exchange resin
• Macroporous backbone
• Scavenges amines, basic compounds
• Purification via Catch and Release purification

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Catch and Release Purification

• Sulfonic acid media
• Catch amines/ amine salts - afford product as
  free amine
• Flow-through process facilitated in cartridges.
  Release with NH3/MeOH

Protocol 1. Condition cartridge with THF or
DCM 2. Apply sample solution 3. Wash cartridge
with organic solvent 4. Elute product with 2M NH3
/ MeOH solution
1
2
3
Catch amine
Non basic impurities
4
6
PS-TBD Polymer Supported Base

• Polymer-supported bicyclic guanidine (1,5,7-
  triazabicyclo 4.4.0dec-5-ene)
• Stronger base than PS-DIEA, PS-NMM - pKa approx.
  13 15
• Deprotonates moderately acidic hydrogens
• PS-TBD applications include Alkylation,
  esterification and de-halogenation

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PS-TBD- Resin Bound Base
Catch and Release

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Polymer-Bound Reagents Schematic

• Remove spent and excess reagent by filtration
• Perform one-pot multi-step reactions
• Mix incompatible functionalities
• Eliminate problems with small molecule reagents
• Toxicity, byproducts difficult to eliminate, odor

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Argonaut Polymeric Reagents
0020821n.ppt
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Reductive Amination

• Reductive amination of carbonyl compounds is a
  very powerful tool in synthesizing diverse series
  of amines
• Resin-bound reagents and scavengers simplify
  purification of product amine
• Excess substrate and reaction byproducts are
  removed by filtration
• Excellent for lead generation, validation, 25 of
  compounds in the drug database are amines or
  amine derivatives1
• Borohydride-based reducing agents are most
  popular- MP-(OAc)3BH, MP-CNBH3, MP-BH4 (with
  PS-DEAM scavenger)

1.Brown, A. R. Rees, D. C. Rankovic, Z.
Morphy, J. R. J. Am. Chem. Soc. 1997, 119, 3288.
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Resins for Reductive Amination
MP-Triacetoxyborohydride
MP-Borohydride

• Macroporous resin
• Inert scaffold for the chemical reagent
• Efficient reagent delivery
• Removed by simple filtration
• Limited swelling
• Ease of use and handling
• Stable to storage

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Reductive Amination Summary

• MP-BH(OAc)3
• Tolerates acid-sensitive groups ketals, acetals
• Secondary amines isolated as acetate
• Tertiary amines as free base
• MP-BH3CN
• Requires acetic acid
• Similar reactivity and scope
• MP-BH4 /Ti(iOPr)4
• Suppresses over-alkylation with reactive
  carbonyls
• Enables use of
• sterically hindered carbonyls e.g. adamantyl
  ketones
• enolizable ketones including acetophenone
• Titanium isopropoxide scavenged by PS-DEAM

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Bound Coupling Reagents / Amide synthesis

• Polymer-supported reagents for coupling / amide
  synthesis
• Simplify purification - exploit polymer-bound
  intermediates
• Combine diverse sets of carboxylic acids with
  amines
• Excellent for lead generation, validation,
  analogue series
• PS-DMAP - General Acylation catalyst,
  Acylation/Sulfonation via catch and release
• PS-Carbodiimide One-step amide synthesis
• Scavenging may be required
• Active ester resins Two-step process
• PS-HOBt (HL), RGT-ACTU/ PS-HOBt (HL)
• Amine used as limiting reagent -gt amides in
  high purity
• Reactive intermediate can be stored

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Amide Synthesis PS-Carbodiimide

• Coupling agent
• Bound variant of DCC
• Tether to polystyrene backbone increases
  activity
• Stable

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Active Ester Resins
PS-HOBt(HL)

• Two-step synthesis
• Couple acid with the resin to make the bound
  active ester
• Amine acylation
• Approach
• Both steps in a single reactor, or
• Prepare active ester in bulk and split out
• Synthesize a series of amides from one bound
  active ester

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Synthesis of Amides with PS-HOBt (HL)

• Remove byproducts from active ester preparation
  by filtration, solvent washing
• Generate pure product with amine as limiting
  reagent

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Amides From PS-HOBt Complex Molecules
Used aminoester hydrochlorides Kulkarni, B.A.
Roth, G.P. Lobkovsky, E. Porco,Jr. J.A. J.
Comb. Chem. 2002, 4, 56.

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ACTU A New Coupling Agent
ACTU (2-Chloro-1,1,3,3-tetramethyluronium
hexachloroantimonate)

• Precursor to PS-HBTU
• Stable, crystalline solid
• Forms active ester yields in 100 DMF

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Amide Synthesis with PS-HOBt(HL) and ACTU

• Remove byproducts and DMF from bound active ester
  by filtration and solvent washing
• Generate pure product with amine as limiting
  reagent

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Racemization Study Comparison
Coupling of (L)cbz-Phenylglycine with (L)-Valine
methyl ester
The reactions were carried out at 0 C in DCMDMF
(91)
Carpino, L.A. J. Am. Chem. Soc. 1993, 115, 4397
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Amide Synthesis Reagent Comparison

• PS-Carbodiimide - Coupling Agent
• One-step amide synthesis
• Scavenging may be required
• Rearrangement to acylisourea can be problematic
• Active Esters (PS-HOBt)
• Two-step process
• Amine limiting reagent in acylation, affords
  high purity amides
• Storable reactive intermediate

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PS-Carbodiimide Coupling vs. Acylurea Formation

• In some cases, acylisourea rearranges to
  unreactive acylurea
• HOBt additive converts acylisourea to reactive
  HOBt ester prior to rearrangement

2 equiv PS-Carbodiimide, 1.5 equiv acid, 1.7
equiv HOBt stirred in DCM 10 min, r.t. Add 1
equiv amine, stir r.t. 16 h. Scavenge HOBt with 5
equiv PS-Trisamine or MP-Carbonate 2h, filter.
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Oxidizing Agent for Alcohols

• Selective reagent for alcohol oxidation with
  simple protocol for product purification
• Aldehydes and ketones are versatile building
  blocks
• Sometimes unstable in storage
• Synthesize reactive carbonyls for use in
  multi-step syntheses
• Current methods with bound reagents have
  drawbacks
• Reagents leach toxic heavy metals e.g., chromium,
  osmium, lead
• Perruthenate resins have low loading

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Bound Oxidizing Agent MP-TsO-TEMPO

• MP-TsO-TEMPO is a bound oxoammonium sulfonate
• Oxidation of benzylic, allylic, acetylenic and
  cyclic secondary alcohols
• Stable
• Resin is a mixture of active oxoammonium and
  reduced hydroxylammonium species

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Activation of MP-TsO-TEMPO

• Simple, rapid procedure
• Oxidation of the hydroxylammonium species by
  DCDMH
• Chlorine-based oxidant removed by washing before
  use
• Contains only the active oxoammonium species
• Capacity 1.0 mmol/g

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MP-TsO-TEMPO Oxidation of Activated Alcohols

• Reactions in ACN or DCM
• 2 equiv of MP- TsO-TEMPO at rt
• No liquid liquid extraction or column
  chromatography

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Traditional Chemistry PS-Triphenylphosphine
Mitsunobu Reaction
Wittig Reaction
Scavenging of Alkyl Halides
Chlorination
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Polymer-Bound Triphenylphosphine-Pd(0)

• Bound Catalyst for Suzuki type Cross- Coupling
  Reactions
• Simplified product isolation
• Insensitive to air, light and moisture
• Easy Handling
• Shelf-stable at room temperature
• Capacity 0.1 mmol/g

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PS-TPP-Pd Catalyst for Suzuki Coupling

• 0.5 mol of PS-TPP-Pd used
• Reactions performed under air, no inert
  conditions required
• Reaction scale 1.0 mmol
• DME EtOH H2O 2 2 1
• Purification Partition water/DCM silica pad
• Products isolated in high purity and yield
• Low palladium level in products (lt 60 ppm)

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PS-TPP-Pd Suzuki Coupling Data Set
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Suzuki Coupling Using N-Heterocyclic Halides

• Products isolated in high purity and yield by
  MP-TsOH catch and release
• Partition with water/DCM prior to catch and
  release
• Reaction scale 1.0 mmol

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PS-PPh3-Pd / MP-BH4 Deprotection of N-Alloc

• 2 mol of PS-PPh3-Pd and 3 eq MP-BH4used
• Reactions performed at rt under air, no inert
  conditions required
• Reaction scale 1.0 mmol
• DCM MeOH H2O 5 4 1
• Isolation Filter through Na2SO4 plug,
  concentrate
• Products isolated in high purity and yield
• Low palladium level in products (lt 100 ppm)

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Reductive Deprotection of N-Alloc Scope Studies