药明康德有机合成2015年3月晋升测试题I_Answer

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: