Synthetic Organic Chemistry Final Exam Resit (6KM33) Thursday, 26th June, 2014, 9:00 12:00 (3 h)

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1 Synthetic rganic Chemistry Final Exam Resit (6KM33) Thursday, 26th June, 2014, 9:00 12:00 (3 h) This is an open-book written exam. The course textbooks (Warren & Wyatt, 2 nd Ed.) with personal notes and worked exercises, one good general undergraduate textbook (e.g. rganic Chemistry, 7 th Ed. Bruice) and a copy of the literature assignment with personal notes are all permitted. Additional books and material are also allowed (but not necessary) EXCEPT access to the internet is STRICTLY FRBIDDEN. There are four questions in total including one bonus question. The first three questions are compulsory. The bonus question is optional. Maximum no. points per question, and recommended time are highlighted in yellow. Maximum no. points for exam: 100 points Explain your answers clearly. You may write in English or in Dutch. GD LUCK! Question 1.(33 points, 1 h) Protecting groups are frequently used to improve the chemo and regioselectivity of a synthesis. Carbonyls (1) are commonly protected as either 1,3 dioxanes (2) or analogous 1,3 dithianes (3) under acid catalyzed conditions. a) Draw a curly arrow mechanism for the formation of 1,3 dithiane 3 from 1,3 propanedithiol and 1.(3) Interestingly, 1,3 propanedithiol reacts with propargylic ketones (e.g. 4) under basic conditions to form keto 1,3 dithianes (e.g. 5). b) Propose a detailed curly arrow mechanism for the formation of 5 from 4 and 1,3 propanedithiol under the basic conditions described above.(6)

2 Under the same conditions, propargylic ketone 7 does not form 8, but instead undergoes a tandem Michael addition intramolecular aldol reaction to form 9. c) Draw the structure for 9 and a detailed mechanism for its formation.(6) d) Propose a detailed synthesis of 7 starting from (12) e) Therefore, propose a synthesis of 8 starting from (6) Question 2.(33 points, 1 h) Amines are important functional groups in chemistry and biology. a) Describe five different ways to introduce an amine functional group into a molecule in no more than 2 steps. For each reaction sequence you do not need to write mechanisms; simply write the structures of the starting material(s), product(s) and any other necessary reagents.(15) α,β unsaturated carbonyls are synthetic versatile building blocks, e.g. for the synthesis of 2 and 3 starting from α,β unsaturated ketone (enone) 1. b) Briefly explain the difference in reactivity between MeMgBr and Me 2 CuLi towards 1, for the synthesis of 2 and 3, respectively.(2)

3 Note: For parts c) and d) multiple synthetic steps may be required. Write clearly all intermediate structures, and suggested reagents. You do not need to provide reaction mechanisms. c) ow could you selectively synthesize products 4 6 starting from enone 5? Suggest suitable reagents A C.(12) d) ow could you convert 6 into 7? Suggest suitable reagents, D.(4) Question 3. (based on literature assignment).(34 points, 45 mins) Citation: Breitler & Carreira, Angew. Chem. Int. Ed., 2013, 52, Note: compound numbers are identical to those used in the article! With reference to Scheme 3: a) Draw a detailed curly arrow mechanism for the formation of 8 from 6 and 7 over steps a and b.(4) b) What would be the expected product if compound 8 were reacted under catalytic hydrogenation conditions (e.g.pd/c/ 2 )? Explain therefore why the authors chose to use Na/N 3 (l)/et instead.(2) Cyclopropane 14 was formed in step j as one of a separable 4.4:1 mixture of two diastereomers. c) Draw the structure of the other diastereomer formed in step j.(2) d) With reference to the structure of compound 12 explain why diastereomer 14 is formed in preference to other possible diastereomers.(3)

4 The carbon at position 1 in compound 14 (above) is prochiral. e) What do you think is meant by prochiral in this case. Refer to the structure of 14 in your answer.(2) f) The other diastereomer hypothetically formed during step k is 15a (see above, but not shown in article). Provide a mechanism for the formation of 15a from 14 in step k, and explain why you think 15 is formed, and not 15a.(4) g) Is step k a sterespecific or stereoselective reaction? Briefly explain your answer.(3) With reference to Scheme 4: The synthesis of 17 from 16 occurs in a yield of 80% and generates two diastereromers in a ratio (d.r.) of 7.7:1. The structure of the major diastereomer is shown in Scheme 4. h) Draw the full structure of TBS in compound 16.(2) i) Draw the structure of the the minor diastereomer formed in Scheme 4.(2) j) With reference to the reaction mechanism proposed in Scheme 4, explain why diastereomer 17 is formed in preference to other possible diastereomers.(3) With reference to Scheme 5: k) Describe and explain what is happening in step c, providing as much mechanistic detail as possible.(7)

5 Bonus Question. Total synthesis of Spongistatin 1. Spongistatin 1 is a marine macrolide natural product, which has generated considerable interest in the field due to its potent antitumour properties and outstanding structural beauty. In one reported synthesis of 1, the CD spiroketal fragment 2 was synthesized from chiral enantiomerically pure epoxides 3 and 4. Cl Ac B A Ac 16 F C 23 D Me E 28 spongistatin (1) 16 C S 23 D S 28 2 PMB? Cl PMB Propose a synthesis of 2 from 3 and 4 ignoring the stereochemistry at the C23 anomeric carbon.