SCH 302 (STEREOCHEMISTRY AND SYNTHESIS OF ORGANIC COMPOUNDS) Tutorial 2 2016 PART B ORGANIC SYNTHESIS 1
QUESTION 1 Relationships between Terms (a) Relate between the terms: i. Asymmetric induction and enantiomeric excess ii. Asymmetric induction is the extent of control of stereoselectivity exerted by an existing chiral centre on the formation of a new chiral centre, while enantiomeric excess is a measure of the purity of a stereoisomer. Note that a chiral auxiliary with a high asymmetric induction leads to a stereoisomer of high enantiomeric excess. Synthon and retron. A synthon is an imaginary fragment or species generated from a bond disconnection during retrosynthetic analysis, while a retron is an intermediate identified in a retrosynthetic analysis and corresponds to a real molecule that can be employed in a synthetic step. 2
QUESTION 1 Rationalization (b) Asymmetric synthesis finds wide application in the field of medicine and cosmetology. (i) Explain the circumstances under which racemic drugs can be approved for therapeutic use. Although it is a strict requirement by regulatory bodies that drugs be produced in enantiomerically pure form, a racemic drug may be acceptable only if it has been determined that both enantiomers of the drug are pharmacological active against the disease targeted for treatment and none of the enantiomers is toxic. 3
QUESTION 1 Rationalization (b)(ii) List any three advantages of the chiral auxiliary approach over the chiral pool approach in asymmetric synthesis. (1) The chiral auxiliary approach is versatile in generating any stereoisomer since both enantiomers of a chiral auxiliary can be employed in a synthesis, whereas the chiral pool approach is limited by the natural stereoisomer. (2) Chiral auxiliaries can be recycled thus reducing the expenses of buying the chiral reagent routinely. (3) The levels of asymmetric induction of the chiral auxilliaries in the reactions are usually high leading to high enantiomeric excess. 4
QUESTION 2 Specific Rotation and Enantiomeric Excess (a) A chemist investigated the two strategies, shown below, of converting (S)-mandelic acid to (S)-methyl mandelate. A sample of 0.5 g of (S)-methyl mandelate obtained in approach (a) dissolved in 1 ml of methanol in a cell of 10cm gave an optical rotation of +60 o, while a similar weight of sample from approach (b) in the same sample cell gave an optical rotation of +72 o. 5
QUESTION 2(a) Calculation of Specific Rotation (a)(i) Determine the specific rotation of the (S)-methyl mandelate from approach (a) and (b) (a)(ii) Considering that enantiopure (S)-methyl mandelate has a specific rotation of +144 o, determine the enantiomeric excess of the mendelate from approach (a) and (b) 6
QUESTION 2(a) Calculation of Enantiomeric Excess (a)(ii) Enantiomeric excess from approach (a) and (b) (a)(iii) Which of the two systems would be preferred in asymmetric synthesis? Method b would be preferred due to its enantiospecificity 7
QUESTION 2 Writing Reaction Mechanisms (Things to Note) Observe the law of preservation of matter (Matter can not be created or destroyed) by balancing the atoms in each elementary step of the reaction mechanism. Also balance the charges in each elementary step of the reaction mechanism. By balancing the charges, you recognize that energy can not be created from nothing. Use curved arrows to show electron movement from an electron-rich site to an electron-deficient site in the reacting species of each elementary 8 step of the reaction mechanism.
QUESTION 2 Writing Reaction Mechanisms (Things to Note) Ensure the valence of atoms is observed. Carbon should have a maximum of four bonds to be neutral. A three bonded carbon should have an appropriate charge based on how it is generated. There should be no pentavelent carbons. In a catalysed reaction, the catalyst will always be part of the first elementary step and will always be regenerated in the last step of the reaction mechanism. Use the reagents you are given to generate any species you need in the mechanism, but do not use any species before you show where and how 9 it comes by.
QUESTION 2 Writing Reaction Mechanisms (Things to Note) The species written should be consistent with the nature (acidity) of the reaction media: i. Any species generated in an acidic media (or acid-catalysed conditions) should either be neutral or positively charged. There should be no negatively charged species in this media ii. Any species generated in a basic media (or base-catalysed conditions) should either be neutral or negatively charged. There should be no positively charged species in this media iii. In neutral media, either neutral, positively charged or negatively charged species can be 10
QUESTION 2(a) Reaction Mechanisms (a)(iv) Propose the reaction mechanisms of the two pathways to establish the basis for the differences in enantiomeric excess of the two pathway. Note that Method (a) is in acidic media and Method (b) is in neutral media. Observe the requirements of each media in writing the reaction mechanism. 11
QUESTION 2(b) Reaction Mechanism for Method (a) 12
QUESTION 2(a) Reaction Mechanism for Method (a) 13
QUESTION 2(a) Reaction Mechanism for Method (b) Since the reaction media is neutral, the reaction mechanism can accommodate neutral, positively and negatively charged species. 14
QUESTION 2(b) Reaction Mechanisms (b) Using a reasonable and stepwise reaction mechanism, rationalize for the difference in the outcome of the reactions below: Note that the reaction is acid catalysed and therefore in acidic media and any proposed reaction mechanism should observe the requirements of an acidic media. 15
QUESTION 2(b) Reaction Mechanism for Deprotection 16
QUESTION 2(b) Reaction Mechanism for Glceric Acid Protection Note that there is no resonance stabilization similar to that observed in the cleavage of the BOC group 17
QUESTION 2(c) Reaction Mechanism for Diazotization-Hydrolysis (c) The natural amino acid L-alanine can be converted to L-lactic according to reaction shown below. Propose a reasonable and stepwise reaction mechanism to account for the observed stereochemical outcome. Note that the reaction is acidic media and therefore the reaction mechanism must observe the requirements of the acidic media 18
QUESTION 2(c) Reaction Mechanism for Diazotisation Hydrolysis 19
QUESTION 2(c) Reaction Mechanism for Diazotization Hydrolysis 20
QUESTION 2(c) Reaction Mechanism for Diazotization Hydrolysis 21
QUESTION 3 The Value of Organic Synthesis (a) Does synthesis have any role to play in pest control? Highlight any example(s) Pest control is the management of pests perceived to be detrimental to human health, the ecology or the economy (agriculture). There are different strategies in pest control ranging from the use of pesticides (herbicides, insecticides, fungicides etc.), repellents, attractants (pheromones), antifeedants and biological control. The role of organic synthesis in pest control would be in the synthesis of pesticides, repellents, attractants or antifeedants. 22
QUESTION 3 The Value of Organic Synthesis (Examples) a) The synthesis of the racemic pheromone (1,7- dioxaspiro[5,5]-undecane), of the olive fruit fly can allow for its use in combination with an appropriate insecticide. b) An insect repellent (Deet) is used to control mosquitoes and ticks. Their use together in integrated pest management (IPM) programmes is even more eco-friendly. 23
QUESTION 3 Organic Synthesis b) D is the alarm pheromone of the myrmicine ants. It can be synthesized based on the partial scheme shown below: (i) Deduce the structures of the missing intermediate compounds (A-C) in this synthesis and of the pheromone D. Indicate stereochemistry where relevant 24
QUESTION 3 Synthetic Pathway Deducing the structures of the missing intermediate compounds (A-C) and the pheromone D. 25
QUESTION 3 Retrosynthetic Pathway (ii) Propose a retrosynthetic pathway for the pheromone that is consistent with synthetic scheme above. Identify the key steps in the synthesis (steps that address stereochemistry and generate key functional groups of the target molecule). These key steps must be addressed in the retrosynthetic pathway. Do not just list every step in the synthetic scheme. 26
CAT 2 ORGANIC SYNTHESIS THURSDAY, 7 TH APRIL 2016 8.00 9.00 AM CHEMLAB 1 27
SCH 302: STEREOCHEMISTRY AND SYNTHESIS OF ORGANIC COMPOUNDS WEDNESDAY, 13 TH APRIL 2016 2.00 4.00 PM BOTANY LAB 1 SCHOOL OF BIOLOGICAL SCIENCES 28