Introduction to Synthesis: Design (CHE686) Spring 2015 Exam #1 3/6/15

Transcription

1 Introduction to ynthesis: Design (CE686) pring 2015 Exam #1 3/6/15 AME: KEY ome Pointers: 1. ELAX!! 2. ead the instructions for each question carefully. Be sure you understand what is required. If you are unsure, PLEAE AK! 3. Don't get stuck on any one problem. They are of varying levels of difficulty, so work through first those problems that you can do easily. 4. Draw your structures cleanly & write neatly. I can't give credit if I can't understand/read what you wrote! Along these lines, be sure any explaination you provide is CLEA. 5. tereochemistry is important! ALWAY show relative stereochemistry, even if the stereocenter will be destroyed by a later transformation. CLEALY depict any stereocenters. Make your bold lines BLD, and the dashed lines DAED. ote that a squiggle or straight line implies a lack of stereoselectivity. Do not indicate stereochemistry where none exists. 6. Don't be afraid to draw conformations and transition states as needed. This may help you to answer the question, and me to assign partial credit. 1. (of 13) 2. (of 15) 3. (of 15) 4. (of 21) 5. (of 16) 6. (of 20) Total: (100)

2 1. (13 points) Identify the two best strategic bond disconnections for the molecule below. For each path clearly show what one bond will be broken retrosynthetically along with the corresponding precursors. emember that functional group manipulations can often help identify a good disconnection. As part of your analysis, identify the reaction you would use to reform each bond in the forward sense. Do not show the forward synthesis. FInally, indicate which of the two disconnections is the better of the two. Clearly explain your reasoning. ote: a. strategic bond disconnection 1: + b. strategic bond disconnection 2: + c. Identify which disconnection is better. Clearly and completely justify your answer. aldol divides target into approximately equal pieces maximize convergency two possible aldol disconnections, but the disconnection shown will allow regioselective enolate generation; the alternative will not 2

3 2a. (15 points) Write a complete, stepwise mechanism for the following transformation. 2 P i. tbuli; Ti(iPr) 4 ii. C A P 2 iii. MeI tbu 2 P 2 P 2 P Ti(iPr) 4 (Pri) 4 Ti P 2 P 2 TiL n MeI Me P 2 TiL n 2 P TiL n 2 P 2b. Justify the stereochemistry of the olefin product. For full credit you will need to: i. Provide a transition state to account for the stereoselective formation of A (show the stereochemistry of this intermediate). ii. Provide a transition state to account for the stereoselective conversion of A to the Z-olefin product. L n Ti P 2 P 2 P 2 2 P Bz 3

4 3. (15 points) The following synthetic plan is basically sound, but will not actually work if executed as written. Identify three of the four problem steps in this synthetic sequence. Explain the nature of each problem (there may be more than one issue in a step), and suggest a modification that would make the route more likely to succeed. Be specific. C 2 Me C 2 Bn C 2 Me ab 4 C 2 2 Bn Pd/C (step 1) (step 2) C 2 Me C 2 C 2 Me C 2 Me LiAl 4 Dess-Martin P 3 (2 equiv) (step 3) (step 4) (step 5) C 2 Me s 4 ; C 2 Me 3 + ai 4 (step 6) (step 7) step 1: Problem: ab 4 will give product with the wrong alcohol stereochemistry (axial attack). olution: Use. Li(sBu) 3 B gives equatorial delivery of hydride, and thus correct alcohol stereochemistry. step 3: Problem: LiAl 4 will reduce both ester and carboxylic acid. olution: Use B 3 to selectively reduce acid in the presence of the ester. step 4: Problem: econdary alcohol will be oxidized as well. olution: Protect secondary alcohol after step 1 (TB, PMB, Bn, MM, etc.). step 6: Problem: These conditions will result in oxidative cleavage of the double bond to regenerate the aldehyde (loss of 1C). olution: Use hydroboration to get terminal alcohol (B 3 ; 2 2, a). 4

5 4. (21 points) Predict the major product formed in each of the following reactions. how all intermediate products. Be sure to address all issues of selectivity. Clearly depict any stereochemistry. a. C 2 Me C 2 Me C 2 Me Boc mcpba ame Boc Boc (1 equiv) b. TB TB Me 2 Bn LiTf 60 C TB TB Me 2 Me 2 TFA Bn TB Bn 5

6 c. C hv, rt Bn Bn mcpba ac 3 Cl Bn d. nbuli C e. Bn 3 PC(I)C 3 I amd I Bn 1. I ZnCl 2 ; tbuli 2. mix, Pd(P 3 ) 4 Bn 6

7 f. a(i) Me 4 B(Ac) 3 g. I 1. Zn, 4 Cl, Δ 2. TBCl, Et 3, DMAP TB 7

8 5. (16 points) how how you would carry out the following transformations in the most efficient manner (e.g. shortest # of steps, fewest side reactions). how all needed reagents and intermediate products. Clearly depict any stereochemistry in both products and intermediates (even if it is lost in later steps). a. PMB Bn Bn Bu 2 BTf, Et 3 ; C Bn Me(Me) Cl AlCl 3 Me PMB(C=)CCl 3 PPT Me PMB EtMgBr PMB b. Me ipr TM TM Me Me C ab 4 BF 3 Et 2 CeCl 3 TM ipr ipr ipr pts 8

9 6. (20 points) Devise a synthesis for the following molecule. how both your retrosynthetic analysis and the forward sequence. Assume common organic reagents are readily available. You may use any simple organic materials of 6 carbons or less. Clearly depict any stereochemistry. retrosynthetic analysis: forward synthesis: C 2 =CMgBr 3 + heat or Lewis acid mcpba 9