Institutionen för läkemedelskemi

Advanced Organic Chemistry and

Drug Synthesis

Workshops
 Workshop 0

Repetition

1. Välj det alternativ som bäst besvarar frågan eller motsvarar beskrivningen. Ingen
motivering krävs.

a) Vilken av nedanstående radikaler är stablisate?

A B C

b) Vilken av de utritade väteatomerna är ”lättast” att rycka av en stark bas (vilket väte är
surast)?

D E F

c) Vilken av nedanstående molekyler/grupper är mest benängen att agera som en lämnande

grupp?

G H I

d) Vilken reagens bildar en cyklopropan när den få reagera med en alken under svag värme?

J K L

e) Vilken av nedanstående reagens

motsvarar följande synton?

M N O
 f) Hur förhåller sig nedanstående molkyler till varandra

P Enantiomerer Q Identiska R Diastereomerer

2. Vilken/vilka produkter bildas under följande reaktioner? Rita ut produkternas stereostruktur

där så är befogat! Motivera!

a)

b)

c)

d)

e)

f)

g)
h)

3. Föreslå en sannolik mekanism för var och en av reaktionerna nedan!

a)

b)

4. Nedan följer en del syntesen av paklitaxel vilket är ett anticancer läkemedel. Använd den
utritade syntesvägen för att besvara följande frågor.
5. Föreslå syntesmetoder för följande omvandlingar. Valfria organiska och oorganiska
reagens får användas. Reaktionsmekanismerna behöver inte beskrivas. Flera
reaktionssteg kan vara nödvändiga.

a)

b)

c)

a) Hur ser produkt A ut!

b) Ange reagenset/reagensen som döljer sig bakom B!

c) Hur ser produkt C ut!

d) Ange reagenset/reagensen som döljer sig bakom D!

e) Formationen av A har visat sig vara svår då reaktionen är långsam och

upprening av produkten är problematisk. Ange två sätt att underlätta eller
förbättra syntesen av A. Motivera!

6. Nedan ser du en derivat av ethylestrenol, en syntetisk steroid. Analysera molekylen

retrosyntetiskt och föreslå hur den skall syntetiseras utifrån nandralon.
7. Nedan ser du tre syntesförslag (A, B och C) för formation av produkt 1 från alken
1.

a) Kritiskt utvädera alla förslag (dvs identifiera eventuella problem samt för- och
nackdelar)

b) Produkt 1 har visat lovande aktivitet mot HIV-1 och din chef vill att du syntetisera
1 för vidare utveckling? Vilken syntesväg skulle du prova först? Värför?

c) Föreslå en sannolik mekanism för en av reaktionsstegen i A, B eller C.

 Workshop 1

General organic chemistry

Theory: Carey-Sundberg Book A; Chapter 1.1, 1.2.1, 1.2.4, 1.2.5, Chapter 2 (excluding
topics), Chapter 3 (excluding topics)

Workshop 1 (chapters 1–3, Advanced organic chemistry, part A)

Exercise 1
Explain and exemplify if possible the following principles/concepts:

a) Curtin–Hammett principle
b) Hammond’s postulate
c) Pro-R/S
d) Re/Si-face
e) Chirality
f) Thermodynamic versus kinetic reaction control
g) Cram’s rule versus the Felkin–Anh model

Exercise 2
a) Discuss if the compounds below have chiral stereoisomers.

b) For compound III above:

i) Draw all possible stereoisomers.
ii) Assign R/S-configuration at each stereocentra.
iii) Mark two prochiral substituents in one of the stereoisomers.

Exercise 3
Present three different methods for resolving stereoisomers.
Exercise 4
Water-soluble prodrugs (1, Scheme 1) of HIV-1 protease inhibitors were investigated by Kiso
and co-workers. Formation of the inhibitor from the prodrug relies on ON acyl migration
reaction, giving the transition-state structure found in Scheme 1. The effect from the
susbstituent on the rate of formation of the inhibitor is found in Table 1.

a) Draw the structure of the inhibitor X formed from the transition state.

b) Is the proposed mechanism, forming the transition-state, consistent with the trend in
substituent effect on the rate constant? Explain!

c) Draw the configuration of the reaction center in the transition-state structure obtained
after a re-face attack.

Scheme 1.

Table 1. Rate constants for the conversion of prodrug 1 to active inhibitor X.

Prodrug R Rate constant (s-1)
1a H 3.81×10-4
1b NO2 44.0×10-4
1c Cl 7.24×10-4
1d CH3 2.65×10-4
1e OCH3 1.73×10-4

Exercise 5
Give three examples on how to acquire clues to the reaction mechanism of a reaction.

Exercise 6
Listed below are the results of four different mechanistic investigations. Convert each result
to specific information of the transition state of the reaction.

a) The reaction is highly endothermic.

b) The Hammet’s reaction constant is large and positive.
c) A clear inverse secondary kinetic isotope effect was found.
d) The reaction rate is significantly higher in polar solvent compared to non-polar solvent.
Exercise 7
Order the list of acids according to increasing acid strength. The pKa values do not need to be
listed but the order must be motivated!

Benzoic acid, 3-nitrobenzoic acid, 3-metoxybenzoic acid, 3-fluorobenzoic acid, acetic acid,
trifluoroacetic acid.
 Workshop 2

Nucleophilic Substitutions
Additions and Eliminations

Theory:
Organic Chemistry, Clayden, Chapter 10 (NS at carbonyl), 15 (NS), 17 (Eli), 19 (El add), 36
(Neighbouring group participation/carbocation rearrangements).
Carey-Sundberg Book A; Chapter 4 (excluding 4.1.5, 4.4.5), Chapter 5 (excluding 5.4, 5.9.5)
(Questions 1-7).
Book B Chapter 3 (excluding 3.5), Chapter 4 (excluding 4.1.6, 4.2.2, 4.2.3, 4.6) (Questions 8-
12)

Key concepts

 Nucleophilic substitutions: Mechanism, structural and solvent effects.

 Neighbouring group participation
 Structure and stability of carbocations
 Rearrangements involving carbocations.
 Elimination reactions: Mechanism, classification and selectivity
 Addition reactions involving alkenes and alkynes

Self studies/preparations:

A. Summarize what you learned about leaving groups, nucleophilicity and solvent
effects in substitution reactions (Chapter 4.1-4.2 A)
B. Discuss carbocation rearrangement (mechanisms) and carbocation stabilization
(Chapter 4.4 A, 3.4 A).
Self studies
C. Describe and compare the use of mercuration (oxymercuration) of alkenes and
organoboranes as synthetic intermediates in organic synthesis (Chapter 5.6 A, 5.7
A, 4.1.3 B and 4.5 B).

Problems:

1. The relative order in reaction rate of the two competitive substitutions reactions below is
solvent dependent (Chapter 4.2.2 A and 3.8.2 A).

a) Which one is fastest in DMSO and in MeOH, respectively?

b) This reaction could also be performed in a chlorobenzene/water two-phase system. What
is the benefit of using tetraalkylphosphonium salt reagents in this case?
2. Rank the stability of the following carbocations (Chapter 4.4 A and 3.4 A).

3. Suggest a mechanism for the following transformation (Chapter 4.4 A, 3.4 A and 10.1.2 B).

4. Give the product/products (consider stereochemistry) expected to be formed under the

specified reaction conditions (Chapter 5.1 A and 4.1 B).

5. Discuss what product/products would expected to be formed from the two E-alkenes below
under bromination and chlorination conditions, respectively (Chapter 5.3 A).

6. The mechanism and outcome of eliminations are often influenced by the leaving group.
Deduce the elimination mechanism from the primary isotope effect and Hammet -values of
different leaving groups in the 2-phenylethyl system (shown below). Hint: Consider what
kH/kD-values close to 2 and close to 7 means, as well as a positive value.
Also, discuss the location of the transition state, i.e. which one is most E1cb-like. Explain
your reasoning (Chapter 3.5 A, 3.6 A and 5.10.1-3 A).
 X kH/kD 
Br 7.11 2.1
OSO2C7H7 5.66 2.3
+
S(CH3)2 5.07 2.7
+
N(CH3)3 2.98 3.7

7. Predict the structure of the product(s) of the following reactions (Chapter 5.1 A and 5.10.1-
2 A).

8. Predict the structure of the product(s) of the following reactions and show the reaction
mechanism (Chapter 3.1-3.4 B and 4.1-4.2 B).

a)

b)
 c)

9. Give a reaction mechanism that would explain the following observations and reactions.
(Chapter 3.1 B and 4.3 A).

10. Suggest synthetic methods for the following transformations (Chapter 3.1-2 B, 3.4 B
and 4.4-4.5 B).

a)

b)
11 The synthetic route to BILN 2061 is shown below. BILN 2061 was the first protease
. inhibitor of hepatitis C showing proof-of-concept in clinical trials, but was later
stopped due to cardiac toxicity in animals after long-term use. (Chapter 3.1 B, 3.4 B
and 7.4 A).

AA B

Step 4
CC

a) Suggest two different synthetic methods for transformation A.

b) Suggest a synthetic method for transformation B.

c) Suggest a synthetic method for transformation C.

d) What kind of reaction is performed in Step 4 (hint! Out of current topics)

e) Draw the structure of BILN 2061.

 Workshop 3

Carbanions and other nucleophilic carbon species.

Reactions of carbonyl compounds

Theory: Carey-Sundberg Book A; Chapter 6, Chapter 7, Book B Chapter 1, Chapter 2

(excluding 2.1.5, 2.5).
Clayden 20, 25, 26

Key concepts

 C-H acidity; Structural effects

 Enolates; Formation, kinetic vs thermodynamic
 Acetal hydrolysis; structural effects
 Reactions involving enols, enolates, enamines, imines; alkylations,
acylations, condensations, conjugate (Michael) additions, halogenations
 Wittig olefination; selectivity

1. Predict the order of increasing thermodynamic acidity in each series of

compounds. Explain the basis of your prediction.

Chapter 6.1 and 6.3.

a)

b) O
O
N NO2 S

c) O O O O O O O O

CF3

2. Indicate which proton is the most acidic in each of the following molecules.
Explain your reasoning.

Chapter 6.1, 6.3 and 1.1

 b) c)
a)

O
d) S S e)

3. Draw all possible enolates. Indicate which you expect will be favored in a
kinetically controlled deprotonation and which you expect will be the most
stable enolate.

Chapter 6.3 and 1.1

O
a) O b)

O
d)
c) O

4. Arrange the following acetals/ketals in order of stability towards hydrolysis to

the corresponding aldehydes or ketones. Explain your reasoning.

Chapter 7.2

a)
O O O O O O
Cl
H H H
 b)

O O O O O O
H H H

c)
O O O O O O
H H H
O

5. Give the expected structure for the products of the following reactions.
Chapter 1.2, 2.1, 2.2, 2.4, 4.3
O
1M NaOH
a) H C8H14O
80oC

O
b) 5% Na2CO3
C10H14O
100oC
O

O O
Br2
c)
OH
NaOAc

O
Cl Cl2
d)
NaOAc

O O
e) O
1.) 1 equiv LiNH2/NH3
O
2.) MeI
 HO O
O
f) 1.) 2 equiv LiNH2/NH3
O
2.) MeI

O N
g) 1.) H Cat. H+

2.) BnBr
3.) H2O

h) O O
1.) NaOEt, EtOH
O
2.) BnBr
3.) NaOH, H2O
4.) HCl, Heat

6. Suggest synthetic methods for the following transformations

Chapter 1.2, 2.1, 2.2, 2.3

Br O
O
a)

Br O
O
b)

O O O
c)
O O OH

O
O
d)

O O O
e)
O O HO
 f) O
O
O
O O
O
O

7. Predict the product formed in the following reactions.

Chapter 2.1, 2.2, 2.3, 2.4, 2.6

a) O
O
1.) NaOEt
O + O
O
2.) H+
O

b) O
CH3NO2
H
NaOH, MeOH

c) O O
NaOEt, EtOH
O + O O

d) O
1.) KOMe
O +
O 2.) K2CO3, MeOH
O
heat

e) 1.) PPh3
Br
2.) BuLi
3.) PhCHO

f) O + O
O
PPh3 +
- H
 Workshop 4

Aromaticity and the reactions of benzene and its derivatives

Carey -Sundberg Book A, Chapter 8, Clayden 7, 21, 22, 24, 29, 30

Key concepts

 Aromaticity, homoaromaticity, heterocycles

 Electrophilic aromatic substitutions; substituent effects
 Nucleophilic aromatic substitutions; substituent effects
 Reactivity of 5- and 6-membered heterocycles
 Directed ortho lithiation and lithiation of heterocycles
 Heterocycle synthesis; Fischer indole and Hantzsch pyridine

1. What is Hückels rule of aromaticity? How does it relate to molecular orbital theoey?

2. What is homoaromaticity?

3. What structural elements are commonly found in heterocycles?

4. A single resonance structures is shown below. Consider other resonance stuctures and
indentify those that would be expected to make a major stabilising contribution to the
molecule in question.

5. Predict whether or not the following structures would show strong delocalisation and
stabilisation (aromatic), weak stabilisation by conjugation (nonaromatic), or strong
destabilisation (antiaromatic) relative to acyclic structures. Explain.

a)

b)
 c)

6. In the electrophilic aromatic substitution reaction what functional groups are activators,
deactivators, ortho/para and meta directors? Why?

7. Although N,N-dimethylaniline is extremely reactive towards electrophilic aromatic

substitution and is readily substituted by weak electrophiles this reactivity is greatly
diminished by introduction of an alkyl substituent in an ortho position. Explain.

8. Propose a structure for the products of the following reactions

a)

b)

c)

d)

9. Suggest a synthetic route to the following target compounds using the starting materials
indicated on the left.
 a)

b)

10. Compare and contrast the reactivity of 5- and 6-membered aromatic heterocycles
towards electrophilic and nucleophilic substitution.

11 Propose a structure for the products of the following reactions

a)

b)

c)

d)

12. Bumetanide, developed by Roche, is a drug that is used to treat heart failure.
Analyse the molecule retrosynthetically and propose a synthetic route to the molecule
starting from toluene.
13. Propose a mechanism for the following transformation.
 Workshop 5

Reductions and Oxidations

Theory: Advanced Organic Chemistry, CS, Chapter 5B and 12B. Clayden 23

Key concepts

 Oxidation and reduction, fundamental theory

 Mechanisms and reagents
 Reactivity and Selectivity
 Environmental aspects on reaction protocols
 Catalytic approaches
 Oxidation and reductions of heteroatoms
 Homogeneous and heterogeneous protocols

1. a) Give the reactants/reagents need to achieve transformations A-G below. Suggest a

reasonable mechanism to explain these reactions. If there are similar procedures to
achieve the same transformation, give these as well.
HINT: If more than one step is required, think about the order in which the
reactions should be done.
Useful chemicals: PCl5, hexane, MnO2, H2O2 etc..
b) Give the mechanism and thermodynamic driving force for the reaction. This is an
example of a named reaction – what is it called? This is not essential information
but it can be useful to remember!
HINT: Acid-base properties and nucleophilicity ar important concepts. Bromoform
is a byproduct formed in the reaction.

O NaOH, Br2 O
R R
OH
2. a) Fill in the missing products/reactants/reagents needed to complete the following
synthesis (A-E). Be prepared to discuss mechanisms and selectivity for each step.
HINT: A borohydride is formed in step 1 in the synthesis of V. The first step in the
synthesis of D is a DHP protection. VI is in equilibrium with a linear compound –
what is it? Step E is a Wittig reaction with a final deprotection.

b) Give an example of a Swern oxdation including its mechanism. What are the
advantages of this reaction compared to other oxidation methods (e.g. Cr(VI) based
methods)? Give some examples of electrophile that can be used in this reaction
(HINT: These reactions may have different names)
3. a) What reduction method should be used to complete the following step in the
synthesis of an asthma drug (leukotrienreceptor antagonist)? Justify your choice
based on reactivity, chemoselectivity and chirality.

b) Give at least three different methods to prepare aldehydes from carboxylic acids,
esters and nitriles.
HINT: You can use more than one reaction step and sometimes a clever functional
group interconversion (FGI) can be very useful!

RCN

RCOOH RCHO

RCOOMe
4. a) Fill in the missing products/reactants/reagents needed to complete the following
synthesis. Be prepared to discuss mechanisms and selectivity for each step. HINT:
The final product is a drug for the treatment of asthma and heart disease
(thromboxane receptor antagonist). Aromaticity and conjugation are excellent
driving forces. Step 2 (H2O, H+) after the Li, NH3 reaction is hydrolysis of an enol
ether. Product II is formed as two diastereomers (why is this) that are then
separated via crystallization. Acrylonitrile is a good Michael acceptor.

b) Describe 'Wilkinsons catalyst' with reference to reaction mechanism, selectivity

and reactivity.

c) Give some advantages/disadvantages of homogeneous hydrogenation catalysts

compared to heterogeneous catalysts.
5. Describe the concept of ozonolysis. Give the general mechanism for the ozonolysis of
alkenes and describe how the reaction outcome can be controlled through careful choice
of the reaction conditions. Consider the aromatic transition state, O-O bonds and formal
charges. What is favored/disfavored? What is an ozonide?

6. a) Fill in the missing products/reactants/reagents needed to complete the following

synthesis (A-E). Be prepared to discuss mechanisms and selectivity for each step. .
HINT: steric hindrance, ring strain, carbocation stability, electronic effects. B is a
monoacetate – which one? CH3CONHBr (bromoacetamide) is a Br+ reagent

b) Describe the mechanism for oxidation using Dess-Martin and TEMPO.

c) Compare the methods from B with Swern and Cr(VI) methods considering:
i) reactivity; ii) greeness, toxicity; iii) atom economy
7. Give the reagents/reactants A-C and the structure of intermediate D. Could ozone be
used to form the final products? Show the mechanism for the transformation of D into
the final product.

O
COOH
COOH O
A

C
D

B
IO4-
OH

OH
 Workshop 6

Organometallic chemistry with focus on lithium- and magnesium chemistry and

palladium catalysis in organic and medicinal synthesis

Theory: Carey-Sundberg Book B, Chapter 7 (excluding 7.3.2-7.3.4 and 7.4), Chapter 8,

Chapter 9.1.1, 9.2.1, 9.2.2. Clayden pages 668-677, 858-865, Chapter 40.

Key concepts

 Generation and reactivity of organolithium/organomagnesium reagents; Metalation,

halogen-metal exchange
 Palladium-catalyzed reactions; π-allyl species, carbonylations, Heck reactions, cross-
couplings, aminations and amidations.
 Generation and reactivity of organosilanes; addition of allylic silanes with aldehydes
and ketones.

1. The first part of this workshop (5A) is an introductory lecture on palladium and
transition metal chemistry. The notes can be found on stadium.

The second part of the workshop is based on the discussion of the questions below.

2. Predict the outcome of the following reaction. Suggest a method to prepare the starting
silyl ether.
Chapter 3.5.1, 7.1.2, 9.2.1

3. Predict the outcome of the following reaction.

Chapter 7.2.2.2

4. Predict the outcome of the following reaction.

Chapter 7.2.2.2, 7.1.2

5. These unsaturated alcohols can be made from reactions of organometallic reagents and
readily available starting materials. Show how they would be prepared?
Chapter 7.2.2.
 a.

b.

6. Predict the stereochemical outcome of the following reaction and indicate the basis of
your prediction.
Clayden 858-865

7. A short synthetic sequence involving functionally substituted organometallic

compounds as key reagents can effect the following synthetic transformation. Suggest a
reaction sequence.
Chapter 7.2.2.

8. Predict the product of the following reactions.

Chapter 8.2

a.

b.

9. A number of syntheses of medium- and large-ring compounds which involve

transition-metal reagents have been described. Suggest an organometallic reagent or
metal complex which could bring about the following conversion.
Chapter 8.2.1
10. The following synthetic transformation can be accomplished by use of organometallic
reagents and/or catalysts. Indicate a sequence of reactions which would permit the
synthesis to be completed.
Chapter 8.2

11. The following reactions are accomplished with a palladium catalyst. Write a detailed
mechanism for the reactions. The number of equivalents of each reagent which is used
is given in parentheses.
Chapter 8.2.1, 8.2.2,

a)

b)

12. Give a mechanism for the following reaction.

Chapter 8.2.3
 Workshop 7

Cycloadditions and Rearrangements

Theory: Organic Chemistry, Chapters 34, 35 (excluding electrocyclic reactions) and 36.

Key concepts

 Diels Alder reaction; selectivity.

 1,3 dipolar cycloadditions
 [3,3]-sigmatropic rearrangements
 Carbocation rearrangements.

1. Predict the major regioisomer that is formed in the following reactions. Motivate your
answer

2. The reaction between 2-allylindolin-3-on2 A och ylid B at 0°C give rise to product C. When
compound C is heated in toluene product D is formed.

a) Give the structure of ylid B

b) Give the structure of D and explain its fomation

3. Complete the missing products and reagents. Briefly comment on the regio- and
stereoselectivity of the reactions. Give a mechanism for one of the reactions.
4 Consider the following reaction

a) What product is formed in the first step?

b) Suggest a reasonable mechanism for the transformation that occurs in step
2

5 Suggest a reasonable mechanism for the following reaction

 Workshop 8

Stereoselective, diastereoselective and asymmetric reactions

Theory: Organic Chemistry, Chapters 32 (excluding fused bicyclic compounds) 33 and 41.

Key concepts

 Stereochemical control in six-membered rings

 Selectivity in cyclohexene epoxides
 Diastereoselective additions to carbonyl groups
 Stereoselective aldol reactions
 Stereoselective reactions of acyclic alkenes
 Asymmetric enolate alkylation
 Asymmetric epoxidation/dihydroxylation

1. Predict the major stereoisomer that is formed in the following reactions. Motivate your
answer.

2 Explain how the stereochemistry and regioselectivity of these reactions is controlled.

3 Explain the stereochemical outcome of the following reactions. Draw the most stable
conformation of the ketone and show the path of the incoming nucleophile.

4 Explain the stereochemical outcome of the following reactions. Draw the lowest energy
transition state leading to the product.
 Workshop 9

Multi-Step Reactions and Drug Synthesis

Theory: All of the above.

Sundberg Book B Chapter 3.5, Clayden Chapter 23

Key concepts

 Synthesis and use of protecting groups.

 Retrosynthesis
 Multistep synthesis
 Selectivity in action

1 Choose a known drug substance, derivative or biologically active substance and give a
powerpoint presentation of a synthetic route for its preparation (min 5 steps). Include an
in depth discussion of one of the reactions used in your synthesis. Include also a
number of questions for your classmates.
Some useful places (besides google) to find information are: The Journal of Medicinal
Chemistry, Organic Process and Research Development, Reference books on Drug
Synthesis (there are a number of these available through the library and Molbase.
Let me know if you have any trouble gaining access to journal articles, patents etc.

2. Choose two protecting groups for the alcohol, amine, carbonyl and carboxylic acid
groups. Present one or two synthetic methods for their installation and removal and
identify any orthogonal groups.

3. Below is a synthetic route for the preparation of enalapril, an antihypertensive ACE

inhibitor. Identify and fill in the missing reagents.

4. Below is one of many synthetic routes for the preparation of rofecoxib, a COX2
inhibitor launched by Merck in 1999. Identify and fill in the missing intermediates and
reagents.
5. Below is an important intermediate in the synthesis of a number of antibacterial and
antifungal natural products. Analyse the molecule retrosynthetically and propose a
synthetic route for its preparation, starting from molecule A.

6. Efavirenz is a reverse transcriptase inhibitor, marketed by Merck and DuPont, used in

the treatment of HIV-1.
Analyse the molecule retrosynthetically and propose a synthetic route for its
preparation. Only a general strategy for control of the stereochemistry is required.
7. Below is a synthetic route for the preparation of Butorphanol, a synthetic analgesic.
Identify and fill in the missing intermediates and reagents. Keep in mind the
stereochemical outcome of each transformation.