Chat with us, powered by LiveChat CHEM 103 UND Characteristics of A Process Route Questions - Uni Pal

DescriptionProblem Set 1 Answer Key
Each question is worth 1 point, for a total of 15 points.
1. Drugs generally arise from three sources: plants, microorganisms, and chemical synthesis.
Which of the following drugs were first derived directly from plants? (select all that apply)
+0.25 points for each correct answer
-0.25 points for each incorrect answer
a.
b.
c.
d.
e.
f.
g.
h.
i.
Caffeine
Methamphetamine
Ephedrine
Penicillin
Salicylic Acid
Morphine
Aspirin
Chloral Hydrate
Heroin
2. Which of the following drugs was originally derived from microorganisms? (check all that
apply)
+1 point for each correct answer
-1 points for each incorrect answer
a.
b.
c.
d.
e.
f.
g.
h.
i.
Caffeine
Methamphetamine
Ephedrine
Penicillin
Salicylic Acid
Morphine
Aspirin
Chloral Hydrate
Heroin
3. Which of the following drugs were first produced via chemical synthesis? (check all that
apply)
+0.25 points for each correct answer
-0.25 points for each incorrect answer
j. Caffeine
k. Methamphetamine
l. Ephedrine
m. Penicillin
n. Salicylic Acid
o. Morphine
p. Aspirin
q. Chloral Hydrate
r. Heroin
Although most drugs are developed by pharmaceutical companies, academic labs can also
develop blockbuster drugs. Using online search engines, answer questions 4–5 pertaining to
Xtandi (enzalutamide) and Erleada (apalutamide), two drugs developed at UCLA by Professor
Michael Jung and co-workers. You’ll get to hear directly from Professor Jung about the
discovery and the development of the drug later in the course!
4. Is Xtandi a small molecule drug or a biological molecule (“biologic”)
+1 points for correct answer
-1 points for incorrect answer
Small molecule
Biological molecule (“biologic”)
5. Using the Anatomical Therapeutic Classification (ATC), what is the pharmacological
subgroup for Erleada?
+1 points for correct answer
-1 points for incorrect answer
ATC Code for Erleada: L02BB05
Pharmacological subgroup for Erleada: L02B, which is Hormone Antagonists and Related
Agents
Acceptable answers:
L02B
L02B Hormone Antagonists and Related Agents
Hormone Antagonists and Related Agents
How are drugs classified?
Anatomical Therapeutic Chemical (ATC)
Classification System
From the World Health Organization (WHO)
NH
Me2N
NH
N
H
NH2
Metformin
ATC Code: A10BA02
Level 1: Anatomical main group – describes the relevant
systems/parts of the body affected
Alimentary tract &
metabolism (“A”)
Level 2: Therapeutic subgroup – describes the ailment
Drugs used in
diabetes (“A10”)
Level 3: Pharmacological subgroup – describes the biological
effect
Blood glucose
lowering drugs
(“A10B”)
Level 4: Chemical subgroup – describes the class of chemical
structures the compound belongs to
Biguanides
(“A10BA”)
Level 5: Chemical substance – name of the compound
Metformin
(“A10BA02”)
6. Assume a company develops five compounds and files an Investigational New Drug
application (IND) for each. One drug dies at the end of phase I, two drugs die at the end of
phase II, and one drug dies at the end of phase III. The fifth drug reaches the market. If a drug
costs $1.2 billion to reach the market, use the pie chart below to determine the cost of
development for the four drugs that failed to complete clinical trials. Assume the “other” and
“approval” costs are a factor only for the fifth drug (post–phase III costs). What are the total
costs of development, in billions of dollars, for all five drug candidates? (round to one decimal
place; e.g., ‘$1.0 billion’) These are the losses that must be offset by the sales of the fifth drug.
+1 points for correct answer
-1 points for incorrect answer
Cost of 1st drug = (0.26+0.07)*($1.2 billion) = $0.396 billion
Cost of 2nd drug = (0.26+0.07+0.10)*($1.2 billion) = $0.516 billion
Cost of 3rd drug = (0.26+0.07+0.10)*($1.2 billion) = $0.516 billion
Cost of 4th drug = (0.26+0.07+0.10+0.26)*($1.2 billion) = $0.828 billion
Cost of 5th drug = 1.0*($1.2 billion) = $1.2 billion
Total cost of all drugs = $0.396 billion + $0.516 billion + $0.516 billion + $0.828 billion + $1.2
billion = $3.456 billion
Acceptable answers:
3.456
3,456,000,000
3.46
3,460,000,000
3.5
3,500,000,000
7. Select the primary roles of the medicinal chemist.
+0.33 points for each correct answer
-0.33 points for each incorrect answer
a. Synthesize many compounds to discover initial hits
b. Optimize route to lead compound
c. Produce large quantities of lead compound for pre-clinical and clinical testing
d. Perform animal testing of target compound
e. Perform biological assays to assess potency [the medicinal chemist is certainly interested in
potency data, but her/his focus is on designing molecules and synthesizing them; it is the job of
the biology team to run the biological assays to assess potency]
f. Filter initial hits to lead compounds
g. Lead optimization
8. Select the primary roles of the process chemist.
+0.5 points for each correct answer
-0.5 points for each incorrect answer
a. Synthesize many compounds to discover initial hits
b. Optimize route to lead compound
c. Produce large quantities of lead compound for pre-clinical and clinical testing
d. Perform animal testing of target compound
e. Perform biological assays to assess potency
f. Filter initial hits to lead compounds
g. Lead optimization
9. Which qualities are most important for a medicinal chemist in selecting a synthetic
route?
+0.5 points for each correct answer
-0.5 points for each incorrect answer
a.
b.
c.
d.
e.
Divergent
Diversifiable
Provides the most efficient way to a particular molecule
Scalable
Convergent
10. Which qualities are most important for a process chemist in selecting a synthetic
route?
+0.33 points for each correct answer
-0.33 points for each incorrect answer
f.
g.
h.
i.
j.
Divergent
Diversifiable
Provides the most efficient way to a particular molecule
Scalable
Convergent
11. Which set of targets generally allows for higher selectivity and reduced side effects?
+1 points for correct answer
-1 points for incorrect answer
a. Downstream targets
b. Upstream targets
12. Which of the following are reasons that fluorine is so common in pharmaceutical
compounds?
+0.25 points for each correct answer
-0.25 points for each incorrect answer
a. Improved metabolic stability
b. Increased lipophilicity
c. Increased binding affinity and selectivity
d. Decreased cell membrane penetration
e. Ability to influence the reactivity of neighboring elements
13. Below is a reaction scheme for the conversion of salicylic acid to aspirin (o-acetyl
salicylic acid). What is the atom economy for this reaction? (round to the nearest
percent)
+1 point for correct answer
-1 points for incorrect answer
Acceptable answers:
75
75%
75 percent
14. Which of the following is true about the IC50 value?
+0.33 points for each correct answer
-0.33 points for each incorrect answer
a. The IC50 value is expressed as a molar concentration
b. IC50 values can be used to refer to both inhibitors and agonists
c. The IC50 value is a quantitative tool
d. A lower IC50 value indicates a weaker (less potent) compound
e. A higher IC50 value indicates a weaker (less potent) compound
15. Though it often involves serendipity, drug discovery is a highly systematic process.
Please place the following items in the order they are generally performed.
+1 point for correct order
-1 points for incorrect order
1. Market Analysis
2. Target Selection
3. Assay Development
4. Lead Discovery
5. Lead Optimization
6. Synthetic Route Optimization
7. Scale-up of Synthesis of Drug Lead
8. Animal Trials
9. Phase I
10. Phase II
11. Phase III
12. FDA Approval
13. Phase IV
Problem Set 2 Answer Key
Each question is worth 1 point, for a total of 14 points.
1. What is the role of NADPH in the reaction catalyzed by HMG-CoA reductase?
+1 point for correct answer
-1 points for incorrect answer
a. Oxidant
b. Reductant
c. Acid
d. Electrophile
2. Which of the following pairs of substrates would be suitable for pyrrole synthesis via the
Paal–Knorr condensation reaction? Hint: it may help to draw out the reaction mechanism for
each.
+1 point for each correct answer
-1 points for each incorrect answer
a. A
b. B
c. C
d. D
Paal–Knorr Condensation: Option C
O O
Me +
Ph
Me
Acid
Ph
?
NH2
Ph
Ph
NH2
H+
O O
Me
Ph
Me
Me
H
proton
transfer
O HN
Me
OH
HO
Me
Ph
Ph
OH
N
Ph
Me
N
H 2O
Ph
OH
Me
Ph
Ph
H 2O
OH2
N
Ph
H
Ph
Me
Paal–Knorr Condensation: Option A
Me
O O
Acid
Me
Me
NH2
Me
Me
NH2
H+
O O
Me
H
H
O N
H
O O
Me
Me
?
+
Me
Me
Me
Me
Me
Me
HO
Me
Me
proton
transfer
H
O HN
OH
N
Me
OH
Me
Me
Me
Me
Me
N
OH
Me
Me
H
proton
transfer
OH
Me
Me
Cannot access pyrrole
Me
Me
No hydrogens attached to this carbon!
Deprotonation here cannot occur.
Me
Me
Me
H 2O
Ph
H 2O
Me
N
Ph
Me
Me
Ph
Ph
Ph
Ph
OH
N
Me
Ph
H+
Ph
proton
transfer
H Ph
OH
N
Me
Me
Ph
H
Me
H Ph
O N
OH
H
Me
Ph
Ph
Ph
Ph
H 2O
Me
Ph
Ph
Ph
H
O O
H 2O
H 2O
Me
Me
Me
N
OH
Ph
Paal–Knorr Condensation: Option B
Me
O O
Me
Acid
Me +
NHMe
Me
Me
NHMe
H
O O
H+
O O
Me
?
Me
Me
Me
Me
Me
H Me
O N
proton
transfer
Me
Me
Me
OH
HO
Me
Me
N
OH
Me
O N
H
OH
Me
proton
transfer
Me
DEAD END
Paal–Knorr Condensation: Option D
O O
Me +
Ph
Acid
N
H
H+
O O
H
O O
Me
Ph
?
N
H
Ph
Me
Ph
H
proton
transfer
O N
Ph
OH
HO
Me
Ph
N
OH
O N
H
OH
Me
proton
transfer
Me
DEAD END
3. What is the first step of the Stetter reaction mechanism?
+1 point for correct answer
-1 points for incorrect answer
a. Nucleophilic Attack
b. Deprotonation
c. Protonation
d. Conjugate Addition
e. Tautomerization
4. Order the following compounds from MOST likely to racemize to LEAST likely to racemize
(based on acidity).
+1 point for all correct
-1 points for incorrect order
Most acidic (pKa ~10): A
Second most acidic (pKa ~20): C
Least acidic (pKa ~50): B
5. True or false: a statin is defined as an inhibitor of HMG-CoA synthase.
+1 point for correct answer
-1 points for incorrect answer
False; it is defined as an inhibitor of HMG-CoA reductase.
6. Match the term with its appropriate description.
+1 point for all correct
-1 points for incorrect
Progestogen – Any steroid hormone that functions in maintaining pregnancy
Progesterone – The most abundant steroid hormone in the body that functions in maintaining
pregnancy
Progestational – Maintaining pregnancy
Progestin – Synthetic steroid hormone that functions in maintaining pregnancy
7.
+1 point for correct answer
-1 points for incorrect answer
a. Substrate A
b. Substrate B; the selectivity of the original reaction comes from the top face of the molecule
being sterically hindered / inaccessible. The presence of an additional methyl group on the top
face (i.e., Substrate A) would result in increased selectivity because the top face would be even
more sterically hindered. The presence of a methyl group on the bottom face (i.e., Substrate B)
would mean that both faces are sterically hindered, and therefore selectivity would be
diminished.
8. Which of the following statements about the Marker Degradation are true?
+0.33 point for each correct answer
-0.33 points for each unselected
A. It gave access to progesterone in large quantity
B. Intermediates in this pathway could be used to access other sex steroids and progestins in
addition to progesterone
C. The starting material in this pathway is a natural product derived from plants
9. What was important about the alkyne motif on norethindrone (structure below)?
+1 point for correct answer
-1 points for incorrect answer
MeHO
H
H
H
H
O
a. It made the progestin a lot less toxic than other derivatives
b. It made this progestin more orally bioavailable than other derivatives
c. It served as a synthetic handle toward further diversification of steroid derivatives
10. How many stereocenters are present in diosgenin (structure below)?
+1 point for correct answer
-1 points for incorrect answer
Me
Me H
Me
Me
O
O
H
H
H
H
HO
Answer: 11 stereocenters present in the molecule
11. How many possible stereoisomers of diosgenin (structure below) are there?
+1 point for correct answer
-1 points for incorrect answer
Me
Me H
Me
Me
O
O
H
H
H
H
HO
Answer: 11 stereocenters present in the molecule, each with 2 different possible orientations
211 = 2048 possible stereoisomers
12. Before the development of the two frontline NRTIs, Lamivudine and Emtricitabine,
what were the drawbacks associated with nucleoside mimic therapeutics? (check all that
apply)
+0.33 points for each correct answer
-0.33 points for each incorrect answer
a. dose-dependent toxicity
b. emergence of resistance
c. nerve damage
d. access to starting materials required for their syntheses
e. racemization under biological conditions
13. What is the main issue with the process route to Tamiflu (structure below)?
+1 point for correct answer
+0 points for incorrect answer
O
Me
Me
CO2Et
HN
Me
O
NH2
a. chromatography purification requirements
b. availability of starting material (shikimic acid became very expensive)
c. pressurized reaction setup required on process scale
d. large amount of toxic byproduct produced
e. low overall yield
14. True or False: a prodrug is a molecule that can be converted in the body into its active
drug form?
+1 points for each correct answer
-1 points for each incorrect answer
True
Problem Set 3 Answer Key
Each Question is worth 1 point, unless stated otherwise, for a total of 15 points
1. What is the main role of a catalyst in a catalyzed chemical reaction?
a. A catalyst lowers the energy of the product in the reaction, increasing the reaction efficiency
b. A catalyst increases the energy of the starting material, allowing for the reaction to proceed.
c. A catalyst is incorporated into the product, enabling the synthesis of new compounds
d. A catalyst provides an alternative reaction pathway with a lower kinetic barrier.
2. Which is the likely product of the Suzuki coupling shown below?
Br
(pin)B
+
OMe
Pd(PPh3)4
K2CO3
?
Me
Br
OMe
OMe
Me
A
Me
B
(pin)B
OMe
OMe
C
Me
D
Me
3. What is the oxidation state of Pd in the following complex (Note – the oxidation state for PdX will
be written as +X in the answers below):
Cl
Ph3P Pd
Ph3P
a. +1
b. +2
c. +3
d. +4
4. What is the total electron count on the following complex?
Ph3P Rh
Ph3P
a. 12 e–
b. 14 e–
c. 16 e–
d. 18 e–
PPh3
Cl
5. You are interested in making the compound on the right, and have the aryl bromide shown on the
left. Which coupling partner would you use for this reaction?
SMe
Pd(PPh3)4
CuI, Et3N
Br
+
CF3
?
CF3
Me
SMe
SMe
A
B
SMe
SMe
C
(pin)B
BrZn
D
6. Select the incorrrect description for oxidative addition:
a. Breaks substrate σ bond
b. Forms two new M–L σ bonds
c. The catalyst is regenerated in this step
d. Metal oxidation state increases by two
Ln
PdII
Ln
PdX
X
R
Reductive elimination
Ln
Oxidative addition
PdII
Ln
PdII
R
X
Transmetalation
M
X
M
R
7. Fill in the label for the missing blank on the catalytic cycle (step 2).
8. What oxidation state is the palladium reduced to at the beginning of the catalytic cycle (labeled
as X)?
a. It’s not reduced
b. 2
c. 1
d. 0
9. The role of the base in a Suzuki Miyaura cross-coupling is to…
a. Accelerate Oxidative Addition
b. Accelerate transmetalation
c. Regenerate the Catalyst
d. Deprotonate the Nucleophile
10. What is the name of the following reaction?
Br
S
Pd(PPh3)4 (5 mol%)
CsF (4 equiv)
O
+
Me3Si
Me
O
S
1,2-dichloroethane (0.1 M)
75 ºC, 12 h
Me
(63% yield)
Org. Synth. 2021, 98, 68-83
Hiyama Coupling
Name of the reaction: –––––––––––––––––––––––––––––––––––––––
11. Which of the following CANNOT be X for the reaction scheme shown below?
X
+
PdCl2(PPh3)2 (cat.)
CuI (cat.)
Et3N, 23 ºC
a. Br
b. I
c. F
d. OTf
12. What is the role of the pi alkyne-Cu(I) complex?
a. Makes the terminal proton of the alkyne more acidic to allow to form the copper acetylide
b. Reduces the Pd(II) to Pd(0)
c. Oxidatively inserts into aryl halide bond
d. It has no role
13. Which of the following nucleophiles does not classify as a Suzuki–Miyaura cross-coupling
reaction partner?
a. boric acid
b. boronic acid
c. organotrifluoroborate salt
d. borane
e. boronic ester
14. True or False: A stronger nucleophile leads to faster transmetalation.
a. True
b. False
Problem Set 4 Answer Key
Each Question is worth 1 point, unless stated otherwise, for a total of 15 points
1. The following reaction was used to form the macrocycle of lissodendoric acid A. How would you
classify this reaction?
H
O
CO2tBu
O
Grubbs 2nd Generation
Catalyst
N
O
H
O
NHBoc
CO2tBu
N
NHBoc
a. Cross metathesis
b. Asymmetric Hydrogenation
c. Ring-closing metathesis
d. Ruthenium-catalyzed amination
2. What was the main advantage of using Buchwald–Hartwig amination conditions?
a. Eliminates the use of strong base
b. Avoids the use of aminostannanes
c. Increases catalyst loading
d. Readily available starting materials
3. What is the biggest challenge associated with using aliphatic alcohols or amines?
a. Beta-hydride elimination
b. The alcohol or amine is not as nucleophilic as aryl alcohols or amines.
c. Aliphatic alcohols/amines are difficult to find
d. Aliphatic alcohols/amines shut down the Pd catalyst
4. What is the result of the following intermediate undergoing beta hydride elimination?
PdII
H
H
O
Ph
H
Ln PdII
O
Ph
PdII
H
OH
O
Ln
Ph
PdII
Ph
Ph
a.
b.
c.
d.
O
5. What is a major challenge with using Schrock’s Molybdenum-based olefin metathesis
catalysts?
a. Competitive alkene isomerization
b. Incompatibility with strically-hindered substrates
c. Poor functional group tolerance
d. Low Reactivity
6. What is the driving force that pushes ring-closing metathesis reactions forward?
a. Release of ethylene
b. Retro [2+2] cycloaddition
c. Generation of the +metallocyclobutane
d. Regeneration of the metal carbene
7. How would you classify the following olefin?
HO
Me
Me
a. Type 1
b. Type 2
c. Type 3
d. Type 4
8. Polydispersity is a characteristic of Ring-Opening Polymerization that describes the range of
lengths of the polymers formed. Higher polydispersitiy refers to a broader range of lengths, while
lower polydispersity refers to a a narrower range of lengths.
TRUE
9. Use the selectivity principles of Sharpless Asymmetric Epoxidation of allylic alcohols to
determine whether (+) or (–) DET was used to access the following product.
O
HO
a. (+)-DET
b. (–)-DET
10. Which of the following is not true about chirality at phosphorous?
a. Phosphorous is tetrahedral
b. The lone pair counts as a substituent
c. Requires 10 kcal/mol to pyramidally invert at room temperature
d. Is below nitrogen on the periodic table
Week 5 Homework Answer Key
Each question is worth 1 point, for a total of 15 points
1. What types of transition-metal catalyzed reactions are most often used in the
pharmaceutical industry?
a. Hydrogenations
b. Oxidations
c. Cross-couplings
d. Olefin metathesis
2. What are the top 3 transition-metal catalyzed reactions used in drug discovery?
a. Suzuki–Miyaura cross-coupling
b. Kumada cross-coupling
c. Sonogashira coupling
d. Buchwald–Hartwig amination
e. Heck reaction
3. Crizotinib is an anti-cancer drug approved for treatment of non-small cell
carcinoma. What transition metal-catalyzed reaction can be utilized to make the
C–C bond highlighted in red?
NH
N N
a. Sonogashira coupling
b. Heck reaction
Cl
Me
c. Suzuki–Miyaura coupling
O
Cl
F
N
NH2
d. Buchwald–Hartwig coupling
4. Valsartan is a medication used to treat high blood pressure, heart failure and
diabetic kidney disease. Which bond was formed via a Suzuki–Miyaura crosscoupling reaction?
O
Me
B
CO2H
Me
N
Me
a. Bond A
C
A
b. Bond B
c. Bond C
d. Bond D
N
N
N N
D
Me
5. The structure below is an intermediate in route to olopatadine, a medication
used to decrease the symptoms of allergic conjunctivitis and allergic rhinitis (hay
fever). Which key bond was formed via a Sonogashira coupling?
A
OH
Br
NMe2
a. Bond A
O
O
CO2H
C
b. Bond B
B
c. Bond C
d. Bond D
Olopatadine
D
CO2Me
Intermediate in route to olopatadine
6. A Merck group discovered the molecule below as a potent mCluR antagonist
that could be potentially used to treat schizophrenia. The synthesis employed a
Negishi coupling to furnish the desired product. What organonucleophile was
used in this coupling?
O
O
Me
+
N
Me
?
Br
Pd2(dba)2
Xantphos
Me
55 °C, 6 h
Me
Me F
N
N
N N
(89% yield)
Me F
Me F
(Br)ClZn
BrMg
F
N
F
N
N N
N N
Me F
(OH)2B
F
N
N
N N
N N
7. What is the oxidation of PEPPSI-IPr?
iPr
iPr
N
F
(Br)ClZn
Me
N
a. 1
iPr
iPr
Cl Pd Cl
b. 2
N
c. 3
d. 4
Cl
PEPPSI-IPr
F
F
8. Otsuka identified the compound below as a potential treatment for tuberculosis.
Which bond was formed via a Buchwald–Hartwig amination?
A
N
O2N
a. Bond A
D
Me
b. Bond B
N
N
O
O
c. Bond C
d. Bond D
B
C
9. Predict the product of the following Buchwald–Hartwig amination in the
synthesis of diclofenac analogs.
Et
Cl
NH2
Pd2(DBA)3-BINAP
I
+
Cs2CO3, toluene
110 °C
Cl
Cl
Cl
NH2
H
N
Cl
I
Et
Cl
Et
Et
H
N
Cl
Cl
Cl
?
10. Predict the product for the following Kumada cross-coupling reaction to access
an intermediate in route to Diflunisal, a nonsteroidal anti-inflammatory drug.
OMe
Br
Pd(PPh3)4
+
F
?
THF, 80 °C
F
(91% yield)
MgBr
OMe
F
MgBr
OMe
OMe
F
Br
F
F
F
F
Br
11. The reaction below is a step in the synthesis of eletriptan, used to treat
migraines. What is the name of the overall reaction?
O O
S
N
+ Br
Me
N
H
a. Heck reaction
b. Buchwald–Hartwig amination
c. Sonogashira cross-coupling
d. Kumada cross-coupling
Pd(OAc)2
P(o-Tol)3
O O
S
N
Me
NEt3, CH3CN
N
H
Intermediate in route
to eletriptan
12. Consider the following catalytic cycle. What oxidation state is palladium in after
the first oxidative addition step?
a. 0
b. 1
c. 2
d. 3
e. 4
N
Br
O O
S
N
Me
Intermediate in route
to eletriptan
Me bromoindole
Name this step
in question 13
N
H
Oxidative
addition
Pd(0)
N
H
Br
O O
S
N
Pd?
Me
Intermediate 1
N
N
H
Me
Pd?
O O
S
N
H
Intermediate 4
O
S
?
Br
O
N
Pd?
Me
Intermediate 3
Insertion
N
H
Intermediate 2
π complex
13. Consider the catalytic cycle from Question 12. What is the last step of the cycle
(intermediate 4→ product)?
a. Transmetalation
b. Nucleophilic aromatic substitution
c. Oxidative addition
d. Reductive elimination
14. Consider the catalytic cycle from Questions 12 and 13. Identify Intermediate 3
(after insertion of Pd to intermediate 2).
O O
S
O
S O
N
PdII
N
PdII
Me
Me
N
H
N
H
O O
S
N
Br
N
PdII
Me
PdII
Me
N
H
N
H
15. The synthesis of Eniluracil, an orally available chemotherapeutic, employs a
Sonogashira cross-coupling. What electrophile was used in the reaction to form
the bond highlighted in red?
SiEt3
+
?
NEt3, EtOAc
O
O
N
H
O
N
H
O
HN
(Br)ClZn
HN
N
H
O
B(OH)2
HN
O
O
HN
O
I
HN
O
Pd(PPh3)2Cl2
CuI
I
O
N
H
N
H
SiEt3
Quiz 1 Answer Key
Each question is worth 1 point, for a total of 5 points
1. Dopamine (A) and its binding at the dopamine receptor have been intensely studied. Trans2-(3,4-methylene-dioxyphenyl)cyclopropylamine (B) is an agonist for the receptor, whereas
the cis isomer is inactive. Based on this information, would compound C or D be a better
agonist for the dopamine receptor?
+1 point for correct answer
+0 points for incorrect answer
Compound C
Compound D (contains the same functional groups and “linker length” present in Dopamine)
2. Estimate the IC50 value for a compound with the following dose–response curve.
+1 point for correct answer
+0 points for incorrect answer
a. 3 μM
b. 4 μM (0.5 points, remember IC50 is expressed as the actual concentration at which a
biological process is inhibited by 50%!)
c. 5 μM
d. 1,000 μM
e. 10,000 μM (correct answer, +1 point)
f. 100,000 μM
3. Like any measurement, activity data from screening a library has many sources of error.
Which of the following would be true if partial evaporation of the solvent in the stock
solution of a library member occurred?
+1 point for correct answer
+0 points for incorrect answer
a. Activity would be overreported (potential false positive)
b. Activity would be underreported (potential false negative)
4. Assume the following two molecules exhibit identical bioactivity and pharmacokinetics.
In considering which to promote to lead status in a drug discovery program, which would
be the more desirable choice?
+1 point for correct answer
+0 points for incorrect answer
Compound A (compound A has fewer stereocenters and thus is considerably less complex, so
its synthesis will likely be shorter, whereas more elements of selectivity would be needed for the
synthesis of Compound B)
Compound B
5. The amounts of material needed for the synthesis of o-acetyl salicylic acid (aspirin) are
shown below. The bulk of the material is solvents required for precipitations,
recrystallizations, and rinses. If the reaction produces 120 g of o-acetyl salicylic acid
(aspirin), what is the E-Factor for this reaction? Round to the nearest whole number.
+1 point for correct answer
+0 points for incorrect answer
Answer: 30 (+/- 1 accepted)
E factor = mass of total waste / mass of product
Mass of total waste = mass of total material used – mass of product
(100 g salicylic acid + 1.082 g/mL x 200 mL acetic anhydride + 1.685 g/mL x 1 mL phosphoric
acid + 1.000 g/mL x 2.8 L x 1000 mL/1L water + 0.789 g/mL x 700 mL ethanol) – 120 g product
= 100 g salicylic acid + 216.4 g acetic anhydride + 1.685 g phosphoric acid + 2,800 g water +
552.3 g ethanol – 120 g product
= 3670.4 g – 120 g
= 3550.4 g waste material
Mass of product = 120 g
E factor = 3550.4 g/120 g = 29.6 = ~30
Quiz 2 Answer Key
Each question is worth 1 point, for a total of 5 points
1. True or false: there has been a net increase in deaths per year as a result of cardiovascular
disease in the US from the early 1980s to 2011.
False
2. How many HIV drugs were on the market in 1994, 14 years after the first cases of HIV were
reported?
a. 0
b. 1
c. 2
d. 3
e. 4
f. >4
3. Match the HIV drug with its structure.
A – AZT (Zidovudine)
B – Lamivudine
C – Dolutegravir
D – DDC (Zalcitabine)
E – Emtricitabine
F – DDI (Didanosine)
4. Indicate the final bond formed in the synthesis of remdesivir via Gilead’s process route (as
explained in lecture). As you can see, the route is highly convergent!
Answer: Bond C
5. During the H1N1 pandemic in 2009, it was found that adults who were hospitalized were 25%
less likely to die if given Tamiflu. Which of the following general steps in the influenza viral life
cycle does Tamiflu inhibit?
a. Step 1: Attachment
b. Step 2: Penetration
c. Step 3: Uncoating
d. Step 4: Biosynthesis
e. Step 5: Assembly
f. Step 6: Release
Quiz 3 – Answer Key
1. Which coupling would be best suited to effect the following transformation?
Pd-catalyzed
cross-coupling
O
I
O
O
Me
Me
O
a. Suzuki–Miyaura Coupling
b. Negishi Coupling
c. Hiyama Coupling
d. Kumada Coupling
2. Predict the product of the following Suzuki–Miyaura coupling:
O
O
Pd(OAc)2 (2 mol%)
PCy3•HBF4 (4 mol%)
B(OH)2
Me
+
Me
K2CO3 (5 equiv)
MeOH, ball-milling (30 Hz)
99 min
Cl
J. Org. Chem., 2016, 81, 10049-10055
3. Predict the product of the following Mizoroki–Heck coupling:
Br
+
Pd cat. (0.01 mol%)
CO2Me
MeO2C
NaCO3 (5 equiv)
DMF
NO2
NO2
J. Org. Chem., 2009, 74, 4882-4885.
4. What is this process called in the Sonogoshira coupling?
a. Transmetalation
b. Ligand exchange
b. Beta hydride elimination
d. Coordination
R1
X
Ln
R1
PdII
X
R2
CuI
X
Et3NH
LnPd0
Et3N
Pd cycle
Cu cycle
CuIX
H
Ln
R1
R1
PdII
CuI
R2
5. What is the electron count of the following transition metal complex:
Cl
PCy2Ph
Ni
PhCy2P
Me
a.18
b.17
c.14
d.16
X
H
R2
R2
R2
Quiz 4
Answer Key
1. What are the advantages of using Shrock’s catalyst in comparison to Grubb’s catalyst (select
all that apply)?
a. Schrock’s catalyst is more reactive
b. Schrock’s catalyst has good functional group tolerance
c. Schrock’s catalyst also works for alkynes
d. There are several generations of Schrock’s catalyst that enable different reactivities
2. Which is the least activated alkene to undergo strain-promoted ring opening metathesis
polymerization?
a.
b.
c.
d.
3. In Curran’s synthesis of (20R)-Homocamptothecin, a Sharpless asymmetric epoxidation was
used to introduce chirality. What is the product formed from the following reaction?
TMS
N
OMe
Ti(Oi-Pr)4, TBHP
L-(+)-DET
OMOM
Me
?
DCM, –20 °C, 2h
OH
TMS
N
OMe
TMS
N
OMe
OMOM
A
Me
OH
TMS
N
OMOM
O
Me
OH
OMe
OH
TMS
N
OMe
OMOM
OMOM
C
Me
O
B
Me
D
O
OH
4. What is the product of the following Buchwald–Hartwig coupling?
F
Pd0, base
OTf
+
HN
O
O
a.
F
O
N
b.
O
N
c.
OTf
HN
d.
O
N
OH
5. Enantiomers have all the same physical and chemical properties except when they are in
a ______ environment?
a. Racemic
b. Chiral
c. Stressful
d. Crystalline
Midterm Answer Key (Questions 1–13)
For all single answer questions:
+1 for correct
-1 for incorrect
1. Which of the following is the current most used drug in the world?
a. Aspirin
b. Caffeine
c. Penicillin
d. Tamiflu
2. Which of the following is a natural product whose derivatives have been linked to the opioid
crisis?
a. Methamphetamine
b. Taxol
c. Morphine
d. Heroin
3. Which of the following are responsibilities of the medicinal chemist?
+0.33 for each correct
-0.33 for each incorrect
a. Devise a synthetic route that provides rapid access to compounds for testing
b. Synthesize many derivatives in order to optimize a lead compound
c. Develop a biological assay to determine potency
d. Collaborate with a biology team to develop structure–activity relationships (SAR) for a
compound of interest
e. Perform animal testing to assess activity in vivo
4. Which of the following lead discovery techniques generally requires a higher potency for a
compound to be registered as a “hit”?
a. Fragment-based screening
b. Traditional library screening
5. A single enantiomer of a drug is often more active than a racemic mixture. As we observed in the
case of thalidomide, the opposite enantiomer can even lead to harmful side effects. Because of this,
the synthesis and testing of stereochemically pure compounds is now preferred when possible, in
addition to pharmacokinetic evaluation.
Which of the following molecules is more likely to racemize, resulting in loss of stereochemistry?
F3C H
H 3C H
O
O
vs.
A
B
Correct answer: A
6. Which of the following compounds is more likely to racemize?
Me
H
Me
H
O
vs.
O
O
O
A
B
Correct answer: A
7. Telescoping synthesis, which is often described as “one-pot” synthesis, allows for multiple steps
to be performed in a single reaction flask. This is a highly desirable feature for a process chemist!
Müller and co-workers published the following one-pot reaction, where (i–iii) indicate the order of
addition of reagents. Which bonds found in the product are formed under these conditions?
OH
Br
i. Pd(PPh3)2Cl2 (cat.)
CuI (cat.)
N
+
NC
ii.
Note: The isomerization below can occur readily.
O
O
OH
R1
O
R2
O
R1
(R1 and R2 are carbon substituents)
Bn
Me
N
S
HO
(cat.)
iii. H2N
acid
NC
(59% yield, one pot)
R2
Which bonds are formed?
G
H
A
O
I
F
N
B
E
D
C
NC
Correct answer: C, B, F, and I. This is a Sonogashira–isomerization / Stetter / Paal–Knorr
reaction cascade. See below for a breakdown of the transformations involved and bonds
formed.
+0.25 for each correct
-0.25 for each incorrect
Bond C
OH
Pd(PPh3)2Cl2 (cat.)
CuI (cat.)
Br
+
NC
OH
O
Isomerization
NC
NC
Sonogashira Coupling
Bond F
Bond I
Bond B
O
O
O
Bn
Me
O
N
NH2
acid
N
NC
S
HO
O
O
Paal–Knorr
Condensation
NC
(cat.)
Stetter Reaction
8. In the one-pot reaction from Question 7, which bond is formed first?
Correct answer: C
9. Which of the following amines (A or B) would likely be problematic if used in a Paal–Knorr
condensation with dicarbonyl C?
O
CN
O O
Ph
vs.
NH2
NH2
A
B
Me
C
a. Amine A
b. Amine B
The aldehyde of amine A would likely be problematic, as it could serve as an electrophile in
the reaction. Example of undesired reactions that could occur:
A could condense onto another molecule of A:
O
NH2
O
NH2
In the case that the Paal–Knorr reaction happens, A could react with the pyrrole product:
O
O O
O
O
Ph
+
NH2
Me
Ph
NH2
N
Me
The –CN substituent is less reactive, and was therefore used in the synthesis of Lipitor.
10. Remdesivir has been receiving consistent attention in the media for its use as a treatment for
COVID-19. Which general step of the viral life cycle does remdesivir inhibit?
a. Step 1: Attachment
b. Step 2: Penetration
c. Step 3: Uncoating
d. Step 4: RNA Replication
e. Step 5: Assembly
f. Step 6: Release
11. Which of the following would likely be unsuitable candidate(s) for the treatment of HIV by
inhibition of integrase, based on the known pharmacophore for integrase inhibition?
F
Me
F
N
O
N
O
N
N
OH
O
O
O
O
NH
O
N
O
O
N
N
OH
N
OH
OH
N
O
O
O
O
A
B
C
D
E
a. A
b. B (only 1 carbonyl present à cannot effectively chelate both Mg2+ ions in the active site)
c. C (no linker present à cytosine residue in the enzyme active site is too far away to
engage in interaction with C)
d. D (linker is present, but the rigid double bond geometry renders it inflexible)
e. E (no aromatic group present at the end of the linker chain à cannot engage in key p–p
interaction with cytosine residue in the active site)
12. The annual production of hydrocortisone (a topical treatment for various skin conditions) and
related pharmaceutical corticoids has been estimated at 300 tons. Assuming these compounds are
produced with a typical pharmaceutical E-Factor of 25, how many tons of waste are generated by
corticoid production each year, in tons? (do not include units in your response; only the number).
E-Factor = (total waste)/(weight of product)
25 = (total waste)/(300 tons)
25 * (300 tons) = 7,500 tons
13. The birth of the Pill marked a major paradigm shift in family planning around the world. Which of
the four ‘lead discovery’ sources that we have discussed was harnessed in the development of
norethindrone?
a. Traditional library screening
b. Fragment-based screening
c. Virtual screening
d. Natural products
Midterm Answer Key Q14-20
14. Which of the following is not a requirement for nucleophilic aromatic substitution?
a. Ring must contain powerful electron-withdrawing group
b. Ring must contain a leaving group
c. The leaving group must be either ortho or para to the electron-withdrawing group
d. The leaving group must be meta to the electron-withdrawing group
15. Which of the following trends is incorrrect for the oxidative addition step in the catalytic
cycle?
a. The more electron rich the transition metal center, the slower the oxidative addition is.
b. The more sterically hindered the substrate or transition metal complex is, the less favorable
oxidative addition is.
c. The stronger the aryl-halide bond, the slower the oxidative addition is.
d. Electron-withdrawing groups on the aryl ring of the electrophile increase the rate of
oxidative addition.
16. Which factor influences the regioselectivity of insertion in the Mizoroki–Heck reaction?
a. Electronics of the R group on the alkene substrate
b. Electronics of the palladium catalyst
c. Stability of the resulting product
d. Steric bulk of the palladium catalyst
17. Which named reaction would be the best to form the bond highlighted in red for the
compound shown below?
Me
N
a. Negishi coupling
b. Suzuki–Miyaura coupling
c. Sonogashira coupling
d. Mizoroki–Heck coupling
Me
Me
N
18. What is the role of the base in the Suzuki–Miyaura cross-coupling?
a. Make the nucleophile more nucleophilic
b. Help with oxidative addition
c. Slow down transmetalation
d. Make the aryl halide more electrophilic
19. Place in order of most electrophilic C–X bond to least electrophilic:
TfO
Cl
TfO
OMe
Cl
NO2
NO2
C
B
A
OMe
D
a. B>A>C>D
b. A>B>C>D
c. B>C>A>D
d. A>B>D>C
20. What is the name of the following reaction?
Note: This is a unique modification that allows for the omission of a traditionally essential
reagent.
O
Pd
Me2
N
N
Me2 O
+
Ar
Br
a. Mizoroki–Heck coupling
b. Sonogashira coupling
c. Suzuki–Miyaura coupling
d. Buchwald–Hartwig coupling
(1 mol%)
Cs2CO3 (2 equiv)
DMF, 23 ºC, 20 h
Ar

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