药明康德有机合成2014年8月晋升测试题I

WuXi AppTec Promotion Exam

(for Assistant Director and above)

August 22, 2014

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. Phenanthoindolizine and phenanthroquniolizidine alkaloid natural products have attracted great interest owing to their range of biological activities, including (-)-tylocrebine 1 which was advance to clinical trials (although it failed owing toxicity on the CNS). Please provide a synthesis of

(-)-tylocrebine (including the proper stereochemistry) from compound A and other readily available reagents. (Ref: J. Org. Chem., 2014, 3348) (18 points ) OM e

M e O M e O M e O CHO OM e M e O M e

O M e O

N H

(-)-tyl ocre bi ne A

工号：___________ 姓名：___________ 所属主任：___________

2.Levofloxacin (Levaquin(US)) is a broad spectrum antibiotic of the fluoroquinolone drug class. Please provide a synthesis of Levofloxacin from readily available compounds A and B (Ref: J. Chem. Eng. Chin. Univ. 2005, 708) (16 points)

CO2H

F

F

F F

NH2

OH

2

H

L evo fl oxac i n A B

3. Please review the below synthetic scheme for the total synthesis of (±)-Przewalskin B and answer the related questions. (Ref: J. Org. Chem., 2014, 79, 2746) (24 points )

O

O

89% (d .r . 12.5:1)

1) KOH ,

N 2H 4.H 2O

di e thyl ene gly co l ;) H O

H O

OTBS

e ,

2M e 1) N a BH 4, C e Cl 3.7H 2O ) ,

ea ()2(),

H

O P OEt

O OEt TBSO

CHO

a 2,

2P l ki B

1

St e p 1

A

St e p 2

2

St e p 3St e p 4

3

4

St e p 7

St e p 8

8

9

Question 1: Please provide structure for intermediate A and explain the diastereoselectivity (4 points)

Question 2: Please provide the conditions for Step 5 (B ) and Step 8 (C ) (4 points)

Question 3: What’s the “name reaction” of Step 4; instead of the two step sequence (Steps 3,4), please suggest an alternative to make compound 4 from compound 2 (4 points)

Question 4: Please provide a stepwise mechanism from Step 6 (4 points)

Question 5: In Step 7, please explain why Luche conditions are necessary in the reduction of this α,β-unsaturated ketone 6? (4 points)

Question 6: Please provide a stepwise mechanism from Step 9 (4 points)

4. Please review the below synthetic scheme for the total synthesis of (+)-Lasonolide A and answer the related questions. (Ref: Angew. Chem. Int. Ed., 2003, 4779) (16 points )

O

O

OH

O

O O

O

O

O Ph O

Ph

O z

Ph

O z

Ph

z

wern

B

O

O 2iP r

2r

, , -PhCHO (3 e q )

, TFA 4 e q d .. 51

wern

B O

O

2iP r

iP r

, e , -o A

B

1)

Pd/C , H 22) TBSCl 3 TESOTf D -M ti (+)-L asono lid e A

1

23

4

567

8

9

10

11

12

St e p 1

St e p 2

St e p 3

St e p 4

St e p 5

St e p 7

St e p 8St e p 9

St e p 10

Question 1: Please provide the structure of compound A and the conditions for Step 7 (B ) and Step 9 (C ). (6 points)

Question 2: Please draw the other diastereomer of Step 3 and explain why compound 5 is the major product. (5 points)

Question 3: Please propose a reasonable mechanism for Step 10. (5 points)

5. Please answer the following questions from recent seminars at Wuxi. (20 points )

Scheme 5-1 N

R N R F AgF 2

Question 1: What is the mechanism for above direct fluorination? (3 points)

Scheme 5-2

N O

N

Ni H

PR 2O Al O M e M e Ni (COD )2(R 2N )2P (O )H

AlM e 3

Question 2: What’s the product from above transformation? (3 points)

Scheme 5-3 CO 2M e

O

DMAP O

I F 3CS

Question 3: What’s the product from above transformation? (3 points)

Scheme 5-4 O

O OH

O SiE t 31) DiBAlH 2) TBSCl , py 90%O O OTBS

SiE t 3OH 17:1 d e

Question 4: What is the predicted stereochemistry of the product and propose a reasonable

mechanism to explain your reasoning? (5 points)

Scheme 5-5

O

OA c

O OA c

O tB u

B n NH 2,

THF ,

N tB u

B n

B n HN

CO 2H

Question 5: The above dioxabicyclo[3.2.1] can react quickly with primary amines to form pyrroles.

Please provide a stepwise mechanism for this transformation. (6 points)

6. English (6 points )

Please translate following words to Chinese

1) Diastereomer 2) Funnel 3) carbocation 4) cyclobutanone 5) epoxidation

6) Intermolecular cyclization

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