Chiral Synthesis Jointly done by: Lin Wan Shi, Serene Loo, Sadia Riaz, Eran Sim, G. Girish from Temasek Junior College, Singapore

Amazing discoveries We found out that the main gist of all the experiments carried out by the undergraduates was “Chiral Synthesis”, aka “Enatioselective Synthesis” aka “Asymmetric Synthesis”. Especially important in the pharmaceutical field Manufacturing of drugs

A brief introduction Chiral Synthesis is essentially organic synthesis which introduces 1 or more new desired elements of Chirality It is especially important in the pharmaceutical field because different enatiomers have different biological activity (e.g. Side Effects of drugs)

Chirality Asymmetric Property Each isomer would be a mirrored- reflection of each the other, in a molecule. Mirror image would however, be unable to be superimposed on the original isomer. Example: Bromochlorofluoromethane (bottom picture)

Analogy A physical analogy : Our human hands The left hand is a non-super imposable mirror image of the right hand; no matter how the two hands are oriented, it is impossible for all the major features of both hands to coincide.

Drug Analogy Simple analogy would be in any kind of medicinal drug. The compound in the drug would be chiral, meaning that each isomer would have a mirror image (but not similar) other side. Use of drug (chiral) would commonly arouse a certain side effect. This side effect would be the so called “unwanted side of the molecule”.

Reactant (researched on) C 12 H 24 B 2 O 4 Scientific Name: Bis(pincolato)diboron Applications: Imipenem

Undergraduate students were trying to break the Boron-Boron bond of the reactant, which would thus allow the boron to attack another reactant and form a new product. Reactant is achiral. Introduction of chiral catalyst Product formed would be chiral Info about Task

Catalyst

The Reactant… Bis (pinacolato) diboron: C 12 H 24 B 2 O 4 Mass:

Properties… Description: White Solid Melting point ( o C): 135 – 140 Stability: Stable under normal temperatures and pressure Incompatibilities: Strong oxidizing agents Decomposition: Carbon monoxide, Carbon dioxide and oxides of Boron.

Solubility: Soluble in aromatic hydrocarbons, ethers and chlorinated hydrocarbons Stability: Thermally stable and does not react readily with atmospheric moisture Formula weight: gmol-1 Purity: 98% Properties…

Role of C 12 H 24 B 2 O 4 in Organic Chemistry Preferred over other diborons as borylated products derived from it and itself can be handled in ordinary conditions, exhibit high stability towards hydrolysis, hence aiding reaction work scope and purification Undergoes coupling reactions with aryl halides and allyl acetates, in the presence of Pd catalysts, to give aryl and allyl boronates. Borylation of alkanes and arenes through Rh- and Ir- mediated C-H activation

Generation of gem-diborylated alkenes Reagent to prepare boronic acids and its esters Imipenem (an intravenous b-lactam antibiotic which inhibit cell wall synthesis of gram-positive and gram-negative bacteria) Role of C 12 H 24 B 2 O 4 in Organic Chemistry

Usefulness of Bis(Pinacolato) Diboron via Palladium Catalysis  Bis (Pinacolato) Diboron is transformed into an arylboronate through palladium catalysis  This allows for inclusion of an aromatic fragment containing functional groups which are not compatible with organometallic routes to form arylboronates.  Important factors which influences the reaction: catalyst, base and solvent.  Base: A weak base does no promote further reaction of the arylboronate to a biaryl.  Catalyst: Choosing catalyst ligands can control reaction rate and remove undesired byproducts formed during the reaction

Usefulness of Bis(Pinacolato) Diboron via Palladium Catalysis  Solvent: In times where reaction is difficult, the scope of reaction can be increased by using microwave assistance with an imidazolium ligand for the specific catalyst (e.g. palladium)  Direct borylation of arenas through transition metal mediated C-H activation is now very popular as rhodium and iridium catalysts under thermal conditions insert into the arene C-H bond, at times rather selective.  Formation of the boron-carbon bond and elimination of the arylboronate completes the reactions.  One iridium catalyst is able to work at ambient temperature with high turnover numbers.

The Reaction… The reaction involves the breaking of a double bond from the molecule: And the single bond between in bis(pinacolato) diboron molecule. In the presence of catalysts, the C=CH attacks the B-B forming a new single bond between Boron and Carbon and a new double bond between CH 2 and C. Ph-C=CH=CH 2

To illustrate the mechanism… Ph-C=CH=CH 2 Breaking of double bond Breaking of single bond

Chemical reactions involving Bis (pinacolato) Diboron & simple organic compounds Note: The Reagents, R, Catalysts, C, and Solvents, S, that are involved in the reactions are represented above the arrow

Reaction 22

Reaction 96

Reaction 103

Reaction 106

Reaction 107

Reaction 112

Reaction 113

Reaction 123

Reaction 124

Reaction 222

Reaction 227

Reaction 234

Reaction 238

Reaction 240

Reaction 475

Reaction 1381