Synthetic Organic ChemistryFinal Exam (6KM33)

Tuesday,8thApril, 2014,9:00–12:00 (3h)

This is an open-book written exam. The course textbooks (Warren & Wyatt, 2nd Ed.) withpersonal notes and worked exercises, one good general undergraduate textbook (e.g. Organic Chemistry, 7th 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) EXCEPTaccess to the internet is STRICTLY FORBIDDEN. There are four questions in totalincluding 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: 130 points

Explain your answers clearly.

You may write in English or in Dutch.

GOOD LUCK!

Question 1.(48 points, 1 h)

In this courseyou havesynthesizednumerousdifferent alcohol derivatives.

a)Give examples offive different reactions,which result in the formation of an alcohol functional group(e.g. see Question 2, part b). For each reaction, you do not need to write mechanisms; simply write clearly the structures of the starting material(s), product(s) and any other necessary reagents.(15)

Alcohols are extremely versatilebuilding blocks.

b)For the above four syntheses, each starting from alcohol 1, draw the structure of the intermediates after each step, including the most likely product(s)A and C,and suggested,B and D. Where applicable correctly assign all stereo- and geometric isomers.[Note: For B and D, more than one synthetic step may or may not be necessary.](15)

Likewise, simple and inexpensive aromatic building blocks, such as benzene, methoxybenzene (anisole) and toluene are quickly elaborated into a diverse range of richlyfunctionalized benzene AND cyclohexane derivatives.e.g.compound 2, an experimental analgesic, can be disconnected to 3 and 4.

[Note: for parts 1c-e, writeclearly all intermediate structures, and suggested reagents. You do not need to provide mechanisms.]

c)Propose a synthesisof methoxybenzenestarting from benzene?(5)

d)Propose a synthesis of 3 and 4both starting from either benzene or toluene.(10)

e)How would you synthesize2 from3 and 4?(3)

Question 2.(50 points, 1 h)

α,β-unsaturated carbonylsare “chemical chameleons”, which change their reactivity according to their chemical environment.

a)Give examples of five different ways to make an α,β-unsaturated carbonyl functional group in no more than 2 steps.For each reaction sequence you do not need to write mechanisms; simply write clearly the structures of the starting material(s), product(s) and any other necessary reagents.(15)

(Questions 2 cont.)

α,β-unsaturated ketone(enone)5reacts with Grignard reagents at the carbonyl carbon e.g.1,2-addition of n-BuMgBrto form alcohol 6, or with organolithiumcupratesat the β-carbon, e.g. 1,4-Michael addition of methylcuprate en route to ketone7.

b)Provide a detailed curly arrow mechanism for the synthesis of 7?(3)

c)How could you selectively synthesize products 8-10 starting from enone5? Suggest suitable reagents A-C.[Note:Multiple synthetic steps may be required.Write clearly all intermediate structures, and suggested reagents. You do not need to provide mechanisms.](12)

α,β-unsaturated carbonylsalso behave as dienophiles in Diels-Alder reactions.

d)Perform Diels-Alder disconnections on the following five compounds, 11-15, draw the corresponding diene and dienophilereagents.(10)

(Questions 2 cont.)

e)Propose a synthesisof 16 starting from valerolactone. You do not need to provide reaction mechanisms; simply write clearly the structures of the intermediatesformed and reagents used.(10)

Question 3. (based on literature assignment).(32 points, 45mins)

[Citation: BreitlerCarreira, Angew. Chem. Int. Ed., 2013, 52, 11168.]

NOTE: for this question the compound numbers are identical to those used in the citation!

With reference to Scheme 3:

a)Compounds6and 7are not commercially available. Propose a synthesis of6and 7from A and B, respectively?(7)

b)Draw a detailed curly arrow mechanism for the formation of 8 from 6 and 7 over two steps.(5)

c)What would be the expected product be if compound 8 were reacted undercatalytic hydrogenation conditions (e.g.Pd/C/H2)? Explaintherefore why the authors chose to use Na/NH3(l)/EtOH instead.(2)

d)Draw the structure of the compound formed after step e, and provide a detailed curly arrow mechanism for its formation.(3)

e)Briefly discuss thedifferent rolesplayed by EtOH in steps c and g.(2)

With reference to Scheme 3, step h:

f)Briefly explain the stereochemical outcomeforthisreaction.(2)

g)Why do you think that an early attempt at thisreaction using analog C (below) instead of (-)-5did not lead to the anticipated product D?(1)

h)Why was it necessary to use 2,2 equivalents of 2-isopropenylMgBrfor this reaction?(1)

i)Briefly explain how adding lanthanide salt LaCl3.2LiCl to the reaction improvedthe yield of 11.(2)

With reference to Scheme 5:

j)Explain with as much mechanistic detail as possible what is happening in step c, which results inthe formation of the natural product (+)-Crotogoudinfrom 19.(7)

Bonus Question.Total synthesis of Spongistatin 1.

Spongistatin1 is a marine macrolide natural product, which has generated considerable interest in the field due to itspotent 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.

Propose a synthesis of 2from 3 and4ignoring the stereochemistry at the C23 anomeric carbon.