Exam 2014, questions and answers PDF

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Drug synthesis...

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Exam paper –Drug Synthesis 2014 Section A (answer all parts) A1. a. Define the following terms: i. Protecting group A group attached, temporarily, to a molecule in order to remove the reactivity of a functional group ii. Resolution (in single enantiomer synthesis) Separation of a racemic mixture into two enantiomers iii. Convergent synthesis A synthesis in which two different routes are followed to form advanced intermediates which are brought together late iv. Chiral pool Use of an available, homochiral natural product as a starting material for sungle enantiomer suynthesis v. Synthetic equivalent reagent or combination of reagents giving the reactivity suggested by a synthon (2 marks each) b. Write synthons and synthetic equivalents for the following disconnections: O

O

CH 3

O

CH3 Met O

O

O

OH

OH

O

CH 3 Met

CH 3

OH

O

O

Br

+ base

OH

O

OH Met

(4 marks each) c. Draw the forward synthesis corresponding to the following retrosynthetic analysis.

O O

O

N Br

O O

O N O

O O

O

O

OH

O

fgi

O

I

fgi + base

O

OH

O

O

O

8 marks for reversing the retrosynthesis correctly with no synthons left in or other retrosynthesis terminology/arrows. 2 marks each for fgi reagents. (14 marks)

Section B (answer 2 questions) 1.

Use retrosynthetic analysis to design a synthesis of the compound shown below. Write the forward synthesis corresponding to your analysis (credit will be given for correct use of retrosynthetic analysis even if a viable synthesis is not designed). Cl H N

1

For B1, 2 and 3 the same scheme is used: a synthesis, designed using retrosynthetic analysis and likely to work gets 30 marks; a synthesis which would not work but reaches the target using good retrosynthesis technique will get 24-29 marks; a partial synthesis will get a maximum of 5 marks for each step presented with the correct synthons, synthetic equivalents and appropriate forward synthesis, max 4 marks for an fgi. (30 marks) 2.

N H

fgi

Use retrosynthetic analysis to design a synthesis of the compound shown below. Write the forward synthesis corresponding to your analysis (credit will be given for correct use of retrosynthetic analysis even if a viable synthesis is not designed).

O

O HO

2

(30 marks) 3. Use retrosynthetic analysis to design a synthesis of the compound shown below. Write the forward synthesis corresponding to your analysis (credit will be given for correct use of retrosynthetic analysis even if a viable synthesis is not designed).

O N H OH

3

(30 marks) 4. Consider the synthesis shown below: a. List all of the possible problems with the synthesis if it was performed on a large-scale. b. Suggest improvements to the synthesis which would allow process scale work.

i. LDA, THF -78

Cl2

O O

ii. BnBr

O

Cl

FeCl3

O

O

O

98%

50% i. conc. HNO3 ii. Na/Hg LiAlH4 Cl

Cl

OH HO

NaNO 2 O

OH

H 2O

Cl

90%

O

NH2

O

O

35%

86% column chromatography

DIAD, Ph3 P, THF

OH O Cl

O

99%

DMF, POCl 3 Cl

O

CrO3

O

Cl

O

78%

99%

Cl

product washed with water 3 x before removing solvent on a rotary evaporator

SOCl2 CH2 Cl 2

O Cl

O

40%

A) 16 marks (one each) for spotting problems: Step 1: poor yield, expensive and dangerous solvent, low temperature Step 3: aggressive conditions, column chromatography and mercury waste Step 4: Low yield Step 5: Dangerous reagent Step 6: Triphenylphosphine oxide waste Step 7: Dangerous reagent Step 8: Chromium waste Step 9: Expensive and ecotoxic solvent, washing with water requires vessel to be drained, rotary evaporator unfeasible, low yield Overall: very long synthesis B) Up to 6 marks for simple substitutions eg toluene for THF or sodium borohydride for lithal. Other 8 for changes to synthesis eg starting with 3-chlorophenol. Many possibilities exist.

(16+14 marks)...