CHEMISTRY 335, A01 SYNTHETIC METHODS IN ORGANIC CHEMISTRY FINAL EXAM APRIL 22, 2009 NAME: KEY STUDENT ID:

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1 UIVESITY VICTIA Chem 335 A01: Page 1 CEMISTY 335, A01 SYTETIC METDS I GAIC CEMISTY IAL EXAM APIL 22, 2009 AME: KEY STUDET ID: ISTUCT: ASE TTAL MAKS = 70 DUATI: 3 US (9:00 AM 12:00 PM) TIS EXAMIATI PAPE AS 9 PAGES, ICLUDIG TIS CVE PAGE. CUT TE UMBE PAGES I TIS EXAMIATI PAPE BEE YU STAT T WITE, AD EPT AY DISCEPACY IMMEDIATELY T TE IVIGILAT. QUESTIS AE T BE ASWEED I TE SPACE PVIDED TE EXAM M.

2 Chem 335 A01: Page 2 1. (26 marks total) ill in the boxes with the missing reagents, starting materials, or products (1 mark each). or boxes with reaction products, show only the majo stereoisomer produced by the given reaction and indicate whether it is, racemic, or a single enantiomer (0.5 marks each). a) 3 P Me Me b) P 2 S 5 S c) 2 C 2 Me C acb 3 C C 2 Me C 2 Me sing. ent. C C 2 Me d) Et 3, B B (±)

3 Problem 1 continued... e) Chem 335 A01: Page 3 Li, 3 f) 2 2 g) 1) LDA, 78 C 2) (±) h) I 2, ac 3 a, 2 I (±) i) LiAl 4 pts,

4 Problem 1 continued... Chem 335 A01: Page 4 j) sing. ent. 1) BuLi 2) BnBr LiMe Me k) 2 products sing. ent. Me Br 3 a 3 Me Cu, Me Pr 2. (4 marks) a) Give the mechanism for this reaction, including all proton transfers and intermediates. b) State why it proceeds at site X and not at site Y. Use a diagram to illustrate your point. Y 1 eq. 2 Me Me 1 pt. for neg. charge onto ring nitrogen 1 pt. for rest of mechanism 1 pt. for picture of meta attack 1 pt. for description of why it's bad X B B + 2 u u - negative charge can't be localized on ring nitrogen - reaction less favorable

5 Chem 335 A01: Page 5 3. (4 marks each, 8 marks total) ASWE LY TW TE TEE PATS. Give the product of the reaction. Explain the origin of the observed stereoselectivity in one short phrase, and draw 3D stereochemical diagrams of starting materials and products to illustrate your point. a) S Me ' K + B (K-selectride) 3 S Me ' " " Large = equatorial attack S Me ' S Me ' b) Me Zn(B 4 ) 2 Me Me 2 ipr Me 2 Zn 2+ ipr Me 2 ipr ipr Me 2 c) mcpba more hindered by methyls less hindered by methyls

6 Chem 335 A01: Page 6 4. (8 marks) The following building block A is used in the synthesis of Viagra. Plan the synthesis of A from acyclic starting materials with 5 or fewer carbon atoms. Whether you go in the forward or reverse direction, clearly indicate the reagents and conditions that would be required for each reaction in the forward direction. 2 2 A 2, Pd/C (or stepwise) Me a, MeI Me PCC Me 2 2 Me LDA, 1pt. per step (0.5 reagent, 0.5 product, total 7) 1pt. for consideration of cross-reactivity of amines and PG's Me

7 Chem 335 A01: Page 7 5. (10 marks) The intermediate A from question 4 is reacted with an acid chloride under basic conditions to give key Viagra precursor B. Give the detailed mechanism for this reaction. Explicitly show all starting materials, proton transfers, intermediates, and byproducts. 2 2 A a T Et B Et 2 2 Ar 2 Ar Ar Ar Ar S Ar Et mark for each step (7) 1 mark for byproducts 1 mark for the oath 1 mark for reasonable arrows (moving charge onto carbonyl oxygen not necessary for full marks)

8 Chem 335 A01: Page 8 6. (3 marks) The epoxidation reaction shown below does not proceed. Show why this is the case with a detailed 3D diagram of the starting material that explicitly shows the orbitals involved in this reaction. I a u can't reach backside of σ* orbital I σ* 1pt. chair with I equatorial 1pt. σ* orbital picture 1pt. "can't reach" 7. (3 points) The CBZ protecting group, pictured below protecting a simple amino ester, is a common protecting group for amines. Based on your knowledge of the reactivity of related groups, indicate which conditions should be used for deprotecting the amine, and show which two byproducts would be produced. Me 2 C = CBZ 2, Pd/C 2 byproducts Me 2 C 2 + C 1pt. each thing (3)

9 Chem 335 A01: Page 9 8. (8 marks) Plan the synthesis of the cholesterol absorption blocker Zetia (pictured below, left). You have the three key building blocks A, B, and C available to you. Whether you picture the synthesis in the forward or retro direction, include reagents and conditions above each arrow. You must control the stereochemistry at all three stereocenters, but this is a special day in the lab and you get to use Group 9 s special reagent magic as an additive to a normal reaction that will provide absolute stereocontrol in the formation of E of the three stereocenters. or the other two make it clear how you are setting the stereochemistry, without resorting to magic. Zetia 2 2 C A B C TBA asymmetric reduction! TBS (+)-CBS B 3 TBS diastereoselective Michael addition (facial selectivity) 1. LDA 2. A TBS C, acb 3 MAGIC TBS DCC Et 3 TBS TBS- Et 3 1 pt. per step (0.5 reagent, 0.5 product, total 6) 1 extra pt. for each stereocontrol step (total 2) - no penalty for choosing ( )-CBS instead of (+)