WuXi AppTec Promotion Exam
(for Assistant Director and above)
March 13, 2015
Note: 1. the answers for >85% of the questions can be found from company training website;
2. 20% of the questions are from Science Seminars.
1. Vorapaxar (brand name Zontivity ) is a protease-activated receptor (PAR-1) antagonist based on the natural product Himbacine . On May 5, 2014, Vorapaxar obtained FDA approval. It is a pharmaceutical treatment for acute coronary syndrome chest pain caused by coronary artery disease. Please design a reasonable synthetic route to prepare Himbacine from compounds A , B, C and other commercially available reagents. (Ref: J. Am. Chem. Soc. 1996, 9812) (18 points
)
Key points: Takai reaction; DA cyclization; epimerization 所属主任：___________
姓名：___________
pound A was identified as a potent S1P1 receptor agonist with good selectivity vs S1P3 receptor. Please provide a synthesis of this compound from compounds B, C and other readily available reagents. (Ref: J. Med. Chem. 2014, 57, 10424−10442) (18 points)
3.Please review the below synthetic scheme for the core synthesis of Daphnilongeranin B and answer the related questions.(Ref: Org. Lett.2011, 1812) (20 points)
Question 1: Please provide structure for intermediate A and mechanism from Compound 2to Compound 3, and explain the stereochemistry (6 points)
Answer:
Question 2: Please provide the conditions for Step 4 (Condition A) and Step 7 (Condition B) (6 points)
Answer: Na2CO3/MeOH;
Question 3: Please explain the stereoselectivity of Step 8 (3 points)
Answer: “H” delivered from less hindered face
Question 4: Please provide a stepwise mechanism for Step 9 (5 points)
Answer:
4.Please review the synthetic scheme below for total synthesis of (+)-Clavilactone A and (-)-Clavilactone B and answer the related questions.(Ref: Org. Lett.2013, 15, 5582) (18 points)
Question 1: Please draw the structures for intermediate A, reagent C and conditions for Step 2B (9 points)
Si(OTf)2/Py, DCM, -78 o C
Answer:, (t-Bu)
Question 2: In Step 3, please explain the reason for stereoselectivity. (4 point)
Answer:
Oxygen atom can’t attack from down side easily.
Question 2: Please provide a stepwise mechanism of Ring Closing Metathesis (5 points)
Answer:
5. Please answer the following questions from recent seminars at Wuxi. (20 points)
Scheme 5-1
Question 1: In his design of total synthesis of Macfarlandin E and Aplyviolene, Professor Larry Overman claimed that a dialdehyde strategy will likely fail. Please have a look at his analysis and propose a mechanism for the formation of B and C from A. (4 points)
Answer:
Scheme 5-2
Question 2: Based on the mechanism from Question 1, what’s the product from above transformation?
(3 points)
Answer:
Scheme 5-3
Question 3: What’s the product from above transformation? (3 points)
Answer:
Scheme 5-4
Question 4: Please provide the mechanism of Step A and the product from step B. (7 points)
Answer:product 3 points; mechanism 4 points
Scheme 5-5
Question 5: What’s the product from above transformation? (3 points)
Answer:
6. English (6 points)
Please translate following words to English
1）过渡金属transition metal
2）抑制剂inhibitor
3）不对称合成asymmetric synthesis
4）亲核试剂nucleophile
5）脂肪族的aliphatic
6 ) 螺环化合物spiro-cyclic compound。