药明康德有机合成2013年3月晋升测试题I (1)

Question 4: What effect is responsible for the high diastereoselectivity observed in the methylation of ketone 6? (3 points)
答 题 时 请 勿 超 越 此 虚 线 ， 谢 谢 ！
4. Please review the below synthetic scheme for the first total synthesis of (±)-oxerine and answer the
related questions. (Ref: Tetrahedron, 1994, 50, 13575.)
Question 3:
When the mixture of 4A & 4B react with P-tolSH, only 5A was obtained as major product.
Compound 4B was observed to be converted into 4A under this basic condition.
(14 points)
[Step a] ?
N
Br
N
1
O
b. NaBH4, MeOH c. PhCH2Br, NaH
OTHP d. Pd ()), TMSC CH
Br 2
OBn OTHP
N
( )-3
TMS
e. p-TsOH, MeOH f. TBAF, THF
OBn
g. PPh3, NBS, CH2Cl2
1. Crizotinib (PF-02341066) is a potent and selective c-MET/ALK dual inhibitor. It has gained FDA
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approval for ALK-positive cancers. Please design reasonable synthetic route to prepare racemic
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！
Question 4: Please propose the mechanism for step 9;
(5 points)
答
题
时
请
勿
6. Please review the below synthetic scheme and answer the related questions.
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(Ref: J. Org. Chem., 2012, 77, 4017)
5. Please review the below synthetic scheme and answer the related questions.
(Ref: Org. Lett., 2012, 14, 4886)
(18 points)
OTES
O
H CO2Et
1
L-Selectride THF, - 80 oC
2）异吲哚啉
3）环加成
4）亲核试剂
5）硼氢化钠
6）脱水
7) 偶合常数
答
8）核磁共振题Fra bibliotek时请
勿
超
越
此
虚
线
， 谢
谢
！
2. Lorcaserin, a selective Serotonin 5-HT2c Receptor agonist, was approved by FDA for the treatment of Obesity in 2012. Dr. Graeme Semple (Vice President of Arena Pharmaceuticals) discussed in details about the discovery, SAR and synthesis of Lorcaserin during his visiting seminar at WuXi. Please answer below questions. (15 points)
Please provide a rationale on how this racemization occurred
(5 points)
答
题
时
请
勿
超
越
此
虚
线
， 谢
谢
Question 4: Please provide the structure of compound 7.
！
(3 points)
(12 points)
越
此
虚
线
， 谢
谢
！
Question 1: Please provide reaction conditions for Steps 2 and 3;
(4 points)
Question 2: Please explain the stereo-selectivity for Step 2;
Question 1: Design a reasonable synthesis route for Lorcaserin started from compound 1 (10 points)
答
题
时
请
勿
超
越
此
虚
Question 2: Describe the strategy & methods to obtain enantiomeric pure Lorcasrin in
Step 1
OTES H CO2Et 4
1. Swern oxidation 2. MePPh3Br, nBuLi
Step 4/5
NaHMDS, CS2 MeI, THF, - 78 oC
Step 2 2
1. DiBAL-H, DCM
H CO2Et 5
2. Swern oxidation 3. CH2=CHMgBr, DCM
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manufacturing scales
(5 points)
，
谢
谢
！
3. During his WX visit, Professor Yujiro Hayashi discussed many new methodologies developed in his group and their applications in the natural product synthesis (WX Science Seminar series #9, Nov 02th 2012). Please study below scheme and answer the related questions. (18 points)
Scheme 3-1: High Efficient Synthesis of (-)-oseltamivir
答
题
时
请
Question 1: The author used catalyst 1 in the preparation of enantiomeric enriched compound 2.
OH h. SmI2, THF/HMPA, -78oC
N
N
4
OBn 5 CH2
i, O3
OBn
N O
6
j, MeMgBr
OBn
答
N
( )-Oxerine
题
HO CH3
时
( )-7
请
勿
超
Question 1: What’s the condition for Step a? (3 points)
越
此
虚
(4 points)
答
Question 3: Please draw mechanism for Step 5;
(4 points)
题
时
请
勿
超
越
此
虚
线
， 谢
谢
！
7. English (8 points) Please translate following words to english
1）重结晶
WuXi AppTec Promotion Exam
(for Assistant Director and above)
March 1, 2013
Note: 1. the answers for >85% of the questions can be found from company training website; 2. 30% of the questions are from Science Seminars.
Step 6/7/8
Bu3SnH, AIBN Toluene, refulx
Step 3 3
H OH
6
Grubbs II catalyst Step 9
H OH 7
Dess-martin oxidation Step 10
HO 8
Question 1: Please draw the products from steps 1 and 2;
(4 points)
Question 2: Please explain the stereochemistry of step 1;
(4 points)
答
题
时
请
勿
超
越
Question 3: Please propose the mechanism for step 3;
(5 points)
此
虚
线
， 谢
勿
Please provide an explanation on the origin of enantioselectivity