H 3 C. biotin dependent O O. C O + Pi 2 + ADP 3 + H H 2 C C SCoA malonyl-scoa

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1 1 EXAM F SCIETIFIC CULTUE CEMISTY BLEM 1: BISYTESIS F FATTY ACIDS The biosynthesis of fatty acids proceeds by lengthening of a hydrocarbon chain by condensation of two-carbon units derived from acetyl-coenzyme A (noted acetyl-scoa). n 3 C C SCoA acetyl-scoa 3 C C 2 C 2 C n-1 + n CoAS This multi step process requires initially the biosynthesis of an intermediate, the malonyl-scoa, obtained through the reaction of the hydrogenocarbonate ion C 3 with acetyl-scoa. This reaction is coupled to the hydrolysis of AT into AD and the phosphate ion (i). In addition this reaction necessitates the intervention of biotin, a molecule that takes care of the «C 2» part, in order to allow the carboxylation of acetyl-scoa as shown in equation (1): (1) C 3 C SCoA acetyl-scoa biotin dependent + + AT 4 enzyme C + i 2 + AD 3 + C 3 2 C C SCoA malonyl-scoa The first part of this problem deals with the study of the biosynthesis of malonyl-scoa, and then in a second part the transformation sequences resulting in the formation of the hydrocarbon chain of fatty acids will be examined. 1.1 The bioavailability of carbon dioxide depends on its hydration state and the consecutive proton exchange reactions. Carbon dioxide gas, C 2(g), is initially dissolved in water (dissolved C 2 is noted without index) and then hydrated to form dihydrogenocarbonate 2 C 3 which is in turn involved in the acid-base reactions. The rate constants and thermodynamic values given below were measured in water at 300 K. k h = 0,03 s -1 : apparent rate constant of the hydration k d = 30 s -1 : rate constant of the dehydration pk a1 = 3,8 pk a2 = 10, Which form(s) of C 2 hydrated or not is/are predominant at p 7? At neutral p, the dissolution of C 2 in water occurs according to mechanism (a).

2 a) Given that the rate constant of the reaction between the ion C - 3 and a proton 3 + has a value of approximately mol -1 Ls -1, justify the application of a steady state approximation to 2 C 3. b) Deduce the expression for the rate of disappearance of C 2 dissolved in water according to mechanism (a) as a function of k h, k d, K a1 and the concentrations of the different species Given that the standard enthalpy associated to the acid-base reaction corresponding to the constant K a1 is equal to r 1 = 12 kj.mol -1, to which extent is the reaction at equilibrium changed when the temperature is raised? Justify your answer. 2 At p > 8, another mechanism (b) is in competition with the mechanism (a) for the formation of the hydrogenocarbonate ion: The following values are given at 300 K: k b = 8500 mol -1.L.s -1 k b = 2 x 10-4 s Write the rate expression of the disappearance of C 2 dissolved in water according to mechanism (b) Compare the reaction rates of the addition of - to C 2 at p = 8 and of 2 to C 2. ow can you interpret this result? In a biological environment the hydration reaction of dissolved C 2 is catalyzed by the enzyme carbonic anhydrase. This enzyme has a Zn 2+ ion as a metallic cofactor which is coordinated to three imidazole residues of histidine. The active site is schematized below showing the principal protagonists of the reaction: four imidazole residues of histidine (is), three water molecules, and the zinc ion. is is is Zn II is C 2

3 1.1.6 What is the effect of the Zn(II) cation on the acidity of the coordinated water molecule? Explain What is the role of the hydrogen bonding network represented in this scheme? 3 Biotin is a bicyclic compound, as shown below: (C1) (C2) S (C3) Biotine Indicate the absolute configurations of the numbered carbon atoms (C1), (C2) and (C3). Justify your answer Is biotin a chiral molecule? 1.2 C 3 is a very poor electrophile. Therefore, it is necessary to activate this ion in order to carboxylate biotin. C 3 is activated by phosphorylation by AT which results in the formation of a mixed anhydride carboxyphosphate. The biosynthesis of this mixed anhydride proceeds according to the concerted mechanism shown below, with the participation of a Mg 2+ ion: Glu(1) 2 2 Mg(II) Glu(2) Glu(3) Ad Glu(1) Mixed anhydride carboxyphosphate 2 Glu(2) 2 Glu(3) Mg(II) Ad The arrows translate a S2 type nucleophilic attack on the terminal phosphorous atom of AT. Which orbital of this phosphorus atom accepts the electrons of the nucleophile? What is the role of the glutamate residue Glu(1) in this reaction? Explain What is the role of the Mg 2+ ion in this reaction? Explain. The mixed anhydride formed in the reaction of the hydrogenocarbonate ion C 3 with AT transfers then its C 2 group to biotin in order to form the carboxybiotine as shown in the equation below: S 2 S Carboxybiotine

4 During this C 2 group transfer reaction one nitrogen atom of biotin is deprotonated. The pka value of urea in water is > Urea In the active site of the enzyme biotin is activated through the presence of an arginine residue among others as shown below: Arg S Which interactions are possible between the arginine residue and biotin? As a consequence of these interactions, what is the effect on the pka of the first deprotonation of biotin? 1.3 The biosynthesis of fatty acids is catalyzed by an enzymatic complex, the fatty acid synthase. The inhibition of this enzyme may have an important role in a multitude of therapies and in consequence there exists a major interest in the synthesis of new inhibitors. ne of these potential inhibitors is shown below: The synthesis of this type of inhibitor is presented below: Step 1 Step 2 Step 3 1) t-buli rotecting group (G) 2) C 1) t-buli 2)Bu 3 SnCl G Bu 3 Sn G Step 4 Step 5 (h 3 ) 4 d - G deprotection ArCl Ar Ar G Step 6 xidant Ar For the steps 1 and 2, specify briefly the role of each reagent ropose a role played by the palladium complex in step ropose an oxidant for the step 6.

5 5 EXAM F SCIETIFIC CULTUE CEMISTY BLEM 2: This exercise deals with the following synthetic pathway: Which base would you adopt to deprotonate the diene 1? Justify your answer Draw the mesomeric forms of the anion resulting from the reaction of the diene 1 with an appropriate base Draw the structure of the compound ropose a mechanism accounting for the transformation 1 3. Justify your choice A compound 3 which is a regioisomer of 3 can form under the reaction conditions. Draw the structure of this compound and indicate which one among 3 and 3 is at the most stable According to your opinion, is it better to work at low or high temperature to preferentially obtain 3? Justify your answer Draw in Cram representation the diol 4 which is required to get the compound ropose a mechanism accounting for the conversion of the compound 3 into the compound ow many chiral centers are contained in the compound 5? ow many stereoisomers of the compound 5 are obtained? Justify your answer.

6 2.3.1 What are the partial charges born by the nitrogen and bromine atoms in the BS molecule? Deduce the reactivity, either electrophilic or nucleophilic, of the bromine atom in this molecule From the answer to the preceding question, draw the intermediate, which is obtained after reaction of the double bond of the compound 5 with BS ropose a mechanism to form the compound 6 from the preceding intermediate Draw the Lewis representation of the borane molecule B 3 (boron atomic number: Z=5) Borane gives a complex with one tetrahydrofurane molecule. Draw its structure and propose an explanation to account for its formation Borane adds onto the double bond of the compound 6 and an alcohol function is introduced in the resulting product at the location of the boron atom during the oxidation step by hydrogen peroxide. ropose a structure for the product Briefly explain the nature of the reactions involved in the transformation of the compound 7 into the product Draw the structure of compound Justify the regioselectivity observed during the reaction with the 9 derivative. 2.6 ropose a reagent to obtain the compound 11. 6

7 7 EXAM F SCIETIFIC CULTUE CEMISTY BLEM 3: Menadione Q is a quinone that is the biological precursor of vitamine K. It can cause very important hemolytical problems for people with a deficiency in glucose-6-phosphate dehydrogenase. This phenomenon is partially inhibited by coumarins. menadione Q 4-hydroxy coumarin Complete the Lewis structure of the two molecules and indicate the hydrogen atoms and all non bonding electron pairs What are the necessary conditions for a molecule to be aromatic? Are menadione and 4- hydroxy coumarin aromatic? Justify your answer. Menadione Q can undergo two successive reduction reactions (a) and (b). The standard redox potentials of the two associated couples, (Q/Q - ) and (Q - /Q 2- ), are given below: (a) Q + e - Q - E (a) = -0,84V (b) Q - + e - Q 2- E (b) = -1,34V Write the Lewis structure of the semiquinonic radical Q - and the hydroquinone Q 2- and indicate the hydrogen atoms, the bonding and non-bonding electron pairs, as well as the charges Write the reaction that is thermodynamically spontaneous between the couples (Q/Q - ) and (Q - /Q 2- ) under standard conditions. Justify your answer Indicate the role of the semiquinonic radical Q - in the couples (Q/Q - ) and (Q - /Q 2- ) in the reaction that you wrote for the preceding question. The hydroquinone Q 2- may be protonated according to the successive equations (c) and (d) below: (c) Q Q K (c) = (d) Q Q K (d) = Calculate the pka values of the acid-base couples Q - /Q 2- and Q 2 /Q Given that the p in biological systems is about 7, as which predominant form exists the hydroquinone (Q 2-, Q - ou Q 2 ) at this p? 3.2 The derivatives of coumarin are compounds that have anticoagulant properties. The echmann reaction allows the access to a large number of compounds with a similar structure. ence, the

8 treatment of 1,3-diol benzene (or resorcinol) A with ethyl 3-oxobutanone (or ethyl acetylacetate) B in the presence of a strong acid results in the formation the 7-hydroxy-4- methylcoumarin C: 8 This synthesis can be decomposed into several steps and the first step is shown below: Justify the regioselectivity of the reaction of B on the aromatic cycle of A Identify the most electrophilic carbon atom in compound B. Justify your answer ropose a mechanism for the formation of the compound D in acidic medium ow many stereoisomers has compound D? Justify your answer. The dehydration step (D E) is followed by an isomerization (E F) as shown below: During the isomerization step E into F a carbocation is formed in acidic medium. Identify this carbocation and justify its exclusive formation compared to the formation of other potential carbocations Indicate the stereochemical relationship that exists between E and F. The last step is the cyclization of F in order to form 7-hydroxy-4- methylcoumarin C.

9 3.2.7 Write the reaction mechanism of the formation of C. 9