Chirality And Stereoisomers - Dr. Neufeldt

Post-BACON Quiz3. In the 1950’s the ‘wonder drug’ thalidomide was prescribed to pregnant women for the treatment of morning sickness, but was halted because ___________________________________

• The (S) enantiomer of the drug caused birth defects.

• The (R) enantiomer of the drug caused brain damage.

• The US government redirected their attention to space exploration.

• Both enantiomers of the drug caused birth defects.

Post-BACON Quiz4. What hypothesis has come about, at least in part, because of the discovery of chiral amino acids in the Murchison meteorite, which landed in Australia in 1969?

• The universe is most likely expanding

• Natural amino acids are D-amino acids

• Homochirality originated on Earth

• The origins of homochirality might be extraterrestrial

Post-BACON Quiz1. Which of the following compounds smells like lemons and is the enantiomer of a compound that smells like oranges?

Pre-BACON Quiz1. Which of the following compounds smells like lemons and is the enantiomer of a compound that smells like oranges?

Pre-BACON Quiz3. In the 1950’s the ‘wonder drug’ thalidomide was prescribed to pregnant women for the treatment of morning sickness, but was halted because ___________________________________

• The (S) enantiomer of the drug caused birth defects.

• The (R) enantiomer of the drug caused brain damage.

• The US government redirected their attention to space exploration.

• Both enantiomers of the drug caused birth defects.

BACON at UCLA – Chirality and Stereoisomers Page 4 of 16 Assign the absolute configuration in (–)-limonene:

• R

• S

BACON at UCLA – Chirality and Stereoisomers Page 12 of 16 Synthesis of Pharmaceuticals              Chiral reagents and catalysts can be used nowadays to make molecules of interest with control of absolute stereochemistry, but enzymes can also be used for this purpose.  One important drug that can be synthesized on kilogram scale using an enzyme is (+)-naproxen, which is an anti-inflammatory drug used by millions of people around the world. In this reaction, the lipase enzyme only reacts with one of the enantiomers of the racemic methyl ester. This gives (+)-naproxen and the unreacted (­–) enantiomer of the substrate. Identify the stereochemistry of (+)-naproxen:

• R

• S

• Impossible to determine

Pre-BACON Quiz2. Which of the following correctly describes the enantiomer of “meth”, the drug frequently seen in the hit TV show “Breaking Bad”?

• It is another drug that is just as dangerous as “meth”.

• It is one of the ingredients used in the artificial sweetener Equal.

• It provides evidence of extraterrestrial life.

• It is used in an over-the-counter medicine to help alleviate nasal congestion.

Pre-BACON Quiz4. What hypothesis has come about, at least in part, because of the discovery of chiral amino acids in the Murchison meteorite, which landed in Australia in 1969?

• The universe is most likely expanding

• Natural amino acids are D-amino acids

• Homochirality originated on Earth

• The origins of homochirality might be extraterrestrial

BACON at UCLA – Chirality and Stereoisomers Page 6 of 16 (–)-Aspartame can be made from L-aspartic acid and L-phenylalanine methyl ester. Identify the absolute configuration of the two chiral centers. 

• Blue = R; Red = S

• Blue = R; Red = R

• Blue = S; Red = S

• Blue = S; Red = R

Page 1 of 16Here is a quick refresher for stereochemistry:

Page 2 of 16 Here is a quick refresher of enantiomers and diastereomers:

Page 3 of 16           Although enantiomers have the same physical properties (e.g.. melting point, boiling point, density, and solubility), they will usually interact differently with other chiral molecules. A common example of this involves the taste and smell receptors in the tongue and nose, respectively.          Two famous examples involve the compounds limonene and carvone. The (–) enantiomer of limonene is recognized as an lemon smell, while the (+) enantiomer is recognized as a orange smell. Also, while (–)-carvone has a spearmint smell, (+)-carvone has a dill or caraway smell. 

Page 4 of 16 - SOLUTIONS Assign the absolute configuration in (–)-limonene:a. Rb. SExplanation: The correct answer is B (S configuration) – the explanation is shown below.

Page 5 of 16           Another interesting example involves the artificial sweetener Equal and its key ingredient aspartame. Aspartame was first discovered in the 1960s and is now a common ingredient in consumer products, such as candy and soft drinks. Did you know that only one enantiomer of aspartame is used as a sweetener? The (­–)-enantiomer of aspartame is sweet, but the (+)-enantiomer of aspartame is bitter. The difference in taste comes from the two enantiomers interacting differently with our chiral taste receptors. 

Page 6 of 16 – SOLUTIONS Identify the absolute configuration of the two chiral centers. a. Blue = R; Red = Sb. Blue = R; Red = Rc. Blue = S; Red = Sd. Blue = S; Red = RExplanation: The correct answer is C – the explanation is shown below. Make sure the lowest priority substituent (often hydrogen) is facing back when assigning R or S configuration. 

Page 7 of 16 Artificial sweeteners have long been a controversial topic. Are they safe? Do they cause cancer?  Check out this video to learn more! 

Page 8 of 16Breaking BACONIn addition to having different interactions with taste and smell receptors, enantiomers will often have different biological properties. One striking example of this involves the Schedule II drug, methamphetamine (aka “meth”), which has received much attention from the hit TV show “Breaking Bad”. Methamphetamine systematically destroys the body and causes memory loss and psychotic behavior. It can also lead to heart and brain damage. It is estimated that nearly 500 metric tons of amphetamine-type stimulants are produced each year with over 24 million abusers worldwide. While methamphetamine is a very dangerous, highly addictive drug, its enantiomer levomethamphetamine is commonly used as a vasoconstrictor and helps to alleviate nasal congestion when used in small doses. Levomethamphetamine can be found in the popular over-the-counter medicine Vick’s Vapor Inhaler. 

Page 9 of 16Racemic vs Enantiopure Drugs  It is often the case that enantiomers will have different effects on our bodies. However, in other cases, one enantiomer may be ‘active’, while the other enantiomer has no physiological effect. This allows pharmaceutical companies to sell some drugs as racemic mixtures. Notable examples include Ritalin (treatment of ADHD) and Zyrtec (treatment of allergies), although enantiopure versions have also been made for competitive purposes. In other cases, racemic drugs and their enantiopure versions have been marketed for very different purposes. For example, Imovane (racemic) was originally developed in the 1980’s as an antipsychotic. However, decades later, scientists found that a single enantiomer of this compound, branded as Lunesta, combats insomnia. 

Page 10 of 16 One of the most famous examples of the importance of stereochemistry and medicines is the story of thalidomide. In 1957, racemic thalidomide was marketed as a drug for the treatment of morning sickness and was viewed as a ‘wonder drug’ for pregnant women.  However, reports soon surfaced of children being born with abnormalities.  The drug was quickly recalled, but over 10,000 babies were born with birth defects, including mental illnesses and badly deformed or completely missing limbs. The drug is thought to have claimed the lives of over 2,000 children. What went wrong?  Although the (R)-enantiomer of thalidomide was useful for the treatment of morning sickness, it turns out that the (S)-enantiomer is a teratogen and caused the birth defects.  You might wonder if one can use the (R)-enantiomer of thalidomide as a drug. Unfortunately, this does not work either because thalidomide readily racemizes under physiological conditions to produce an equal mixture of R and S enantiomers. Even recently, scientists have been trying to get around this stereochemistry problem. 

Page 11 of 16 Nobel Prize in Chemistry           Given the importance of chirality, chemists have put forth exhaustive efforts to develop reactions that give one enantiomer of a given compound, instead of racemic mixtures.  Three heroes in the field are Professor K. Barry Sharpless, Dr. William S. Knowles, and Professor Ryoji Noyori. They shared the 2001 Nobel Prize in Chemistry for their “development of catalytic asymmetric synthesis.” Their work has been important in the syntheses of several drugs, including Dr. Knowles’ catalytic asymmetric synthesis of L-DOPA, a precursor to adrenaline. Other notable syntheses include (–)-menthol, fosfomycin (anti-biotic), and amphotericin B (anti-fungal). 

Page 12 of 16 – SOLUTIONS Synthesis of Pharmaceuticals  Identify the stereochemistry of (+)-naproxen:a. Rb. Sc. Impossible to determineExplanation: The correct answer is B – the explanation is shown below. Make sure the lowest priority substituent (often hydrogen) is facing back when assigning R or S configuration. 

Page 13 of 16 Origins of Life Biomolecules such as proteins and DNA are assembled from chiral amino acid and sugar building blocks, respectively. Amino acids in nature predominately exist in the L-configuration. Although not abundant, D-amino acids like D-glutamic acid, D-glutamine, and D-alanine are found in the peptidoglycan layer of bacterial cell walls. Also, D-serine is a neurotransmitter synthesized in the brain from L-serine. Sugars, such as glucose and deoxyribose, naturally exist in the D-configuration. Many unnatural sugars have been made, including L-glucose, which tastes the same as D-glucose but cannot be broken down into energy in the body. L-deoxyribose has also been made and used to study ‘mirror-image DNA’.

Page 14 of 16 The fact that DNA and proteins are always made with the same sense of chirality falls under a topic called homochirality, which has intrigued scientists for more than half a century.  What is the origin of our homochirality?  The answer is still unknown, but there are several theories. One of the most provocative ideas is that the chirality source is extraterrestrial.  This thinking has largely been inspired by the discovery of chiral amino acids in the Murchison meteorite, a >1000 kg meteorite that landed in Australia in 1969. Click here for more information about the origin of biological homochirality.Click here to learn about another interesting theory called asymmetric autocatalysis. 

Page 15 of 16 Space exploration / Mars Rovers For centuries people have speculated about the existence of extraterrestrial life and questioned if life could exist on other planets.  Mars has been a target for investigation due to its proximity and relative similarity to Earth.On January 24, 2014, NASA reported that its “Mars rovers” would be searching for evidence of life, including water, organic compounds, and chirality. Although chirality has not yet been detected on Mars, such a finding would suggest that life could exist beyond the planet Earth. Click here for more information on Mars rover investigation.Learn more about the Mars Rover missions by watching this National Geographic video.  

Page 16 of 16 Stereochemistry in Video Games?           Believe it or not, there is a video game that features stereochemistry!  In the first-person shooter game, “Mass Effect” an alien species based on D-amino acids, tries to destroy the human race. The aliens cannot consume any L-amino acid-based foods because it has no nutritional value to them and may cause a fatal allergic reaction. Since L-amino acids are more abundant in the universe, the aliens want to kill off all of the humans to increase the amount of the D-amino acids in the universe. Some of the food for D-amino acid-based sapients is even referred to as “dextro rations”. The game is available on Xbox 360 and PlayStation 3.