NAME__________________________ 4-Digit ID:__________________________

Heterocyclic Chemistry

Prof. Phil S. Baran

Department of Chemistry
Scripps Research

OPENING!
VERY TherapeuticsTM*
“Laughter is the best medicine”

Congratulations! You are just about to earn your PhD in chemistry from Wow
Research. Invigorated by all of the content in heterocycles, you have decided to
go to industry and interview on site at VERY Therapeutics. Your industry hosts,
Max and Tucker have an action-packed schedule where you will interact with all
departments at VERY Therapeutics. They heard how miserably challenging your
classes (especially heterocycles) at Wow research were and are eager to grill you.
In order to protect intellectual property, the legal department of the company
requests that you provide only your FINAL answers in the most LEGIBLE
handwriting possible. Take synthetic routes back to SIMPLE starting materials

You have until 5:00 pm PDT before they bring in the next candidate.

Question 1 : _________________/ 45

Question 2 : _________________/ 45

Question 3 : _________________/ 60

Question 4 : _________________/ 40

Question 5 : _________________/ 60

Question 6 : _________________/ 30

Question 7 : _________________/ 15

Question 8 : _________________/ 55

BONUS QUESTION :_________________/ 45

TOTAL : _________________/ 350 + 45

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NAME__________________________ 4-Digit ID:__________________________

Examples of simple starting materials (not limited to):

O X/EWG/EDG
O
X EDG/EWG Cl
N N
X/EWG/EDG

Examples of not simple starting materials (not limited to):

O O R
R/X S
Me
OMe R/X N N
R
N
R N R
R N R/X H
Me SH R

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NAME__________________________ 4-Digit ID:__________________________

Question #1: (45 points total, 15 points each) Medicinal Chemistry – The MedChem
team at VERY Therapeutics is working to study anti-aging in the context memes so that
memes never die. They have identified the following hits and want to perform SAR studies
at the specified positions to hopefully advance one to lead status. Provide a Med Chem
FORWARD ROUTE WITH SUGGESTED REAGENTS to the following cores that
allows for diverse R groups. Ar groups are aryl/hetaryl and R can be either alkyl or
aryl. Cross coupling is allowed in Med Chem.

O R Ar
R
R Ar N N
N R O O
R
R N O N N N R
O R H R
Ar R
A B C

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NAME__________________________ 4-Digit ID:__________________________

Question #2: (45 points total, 5 points each) Radiochemistry Group – The
radiochemistry group is studying ADME properties of several different molecules.
Specifically, they want to see whether or not these compounds have a long t1/2 in the
funny bone. Provide quick FORWARD ROUTES WITH SUGGESTED REAGENTS to
the following radiolabeled compounds using the building blocks below:
!!!!

**
Spicy molecules OMe O O O

MeO * OMe *
H OH *
Cl Cl H 2N
NH2
*
H H

O O O
* CO
*
CO2
*
KCN

*
Me OH *
H NMe2 Me * OH
*
MeI
*
NH3

A)
H
Ph N
Me

B)
Me

Me O

S
*
N

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NAME__________________________ 4-Digit ID:__________________________

C)
Me S
* I

OMe
O

D)
Me N

*
O

E)
H
N

N
*

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NAME__________________________ 4-Digit ID:__________________________

F)

N *
* Me

G)

*
N N
O

H)
N

N
*

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NAME__________________________ 4-Digit ID:__________________________

I)

*
N
SMe

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NAME__________________________ 4-Digit ID:__________________________

Question #3: (60 points total, 20 points each) Medicinal Chemistry – The Med Chem
team at Very Therapeutics is in the early stages of a new program directed towards
relieving stress in students taking hard exams. They have identified the following
molecule from a library screen as being uniquely effective in reducing stress, so much so
that simply proposing a synthesis of it has therapeutic effects.

Part A: Please provide a FORWARD ROUTE WITH SUGGESTED REAGENTS to the

compound below.
O

N
O Me
N
MeO

N N
NH2

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NAME__________________________ 4-Digit ID:__________________________

Question #3 (continued):
Part B: Oops. That appeared to have the opposite effect… The computational chemists
have suggested that adjusting the scaffold slightly will turn the compound from an agonist
to an antagonist of the biological target. Please provide a FORWARD ROUTE WITH
SUGGESTED REAGENTS to the compound below.

N
O Me
N
MeO

N N
NH2

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NAME__________________________ 4-Digit ID:__________________________

Question #3 (continued):
Part C: Oh jeez. That still didn’t work. In vivo studies failed to demonstrate efficacy.
Academic consultant, Bill Pharan, thinks making some scaffold changes, yet again, may
solve this conundrum. He also thinks that the aniline may lead to tox problems… but we
will cross that bridge when we get there. Please provide a FORWARD ROUTE WITH
SUGGESTED REAGENTS to the compound below.
O

N
Me O
N
MeO

N N
NH2

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NAME__________________________ 4-Digit ID:__________________________

Question #4: (40 points total, 10 points each). During your lunch break, you overhear
a few Very Therapeutics scientists, Hucker and Pax, discussing some bizarre reactions
they found on the internet. Intrigued, and looking to make a killer impression, you go out
of your way to insert yourself into their conversation and tell them exactly how these
reactions work. PLEASE PROVIDE REASONABLE MECHANISMS FOR THE
FOLLOWING REACTIONS.

Part A:
Me
OH
Me N CN xylene, 190 ºC
nBu N O
nBu H

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NAME__________________________ 4-Digit ID:__________________________

Part B:
Me
Me
PPh3 (cat) CO2Me
MeO2C N
• CHCl3, rt
MeO2C
N
CO2Me H

Part C:

O
NC CN H 2N CN
N Et3N Ph
S N
S O CHCl3
O
O
Ph

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NAME__________________________ 4-Digit ID:__________________________

Part D:
DMB DMB DMB
HN NH
N
• O DMB
N N N N N N N
H 2N Ph + NH
MeO CN N Ph MeO MeO CN
N N
H DCM, r.t.

MeO

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NAME__________________________ 4-Digit ID:__________________________

Question #5. (60 points total, 15 points each). Medicinal Chemistry – At Very
Therapeutics, fused heterocycles are no laughing matter. Isolated from dead crickets at
comedy clubs, such molecules have been shown to improve the delivery of terrible jokes.
Unfortunately, no one at Very Therapeutics knows how to make them. Show them who is
boss by demonstrating you know how to make these systems by breaking either ring!
Propose TWO RETROSYNTHESES for each of the following compounds. One that
disconnects ring A and one that disconnects ring B. Please take your retrosyntheses
back to mono or difunctionalized heterocycles with SIMPLE substituents (ex: Halogen,
Nitrile, Ester, Hydroxyl, Methyl, etc).

A)
O

A S N B
MeO2C A B
N O
H

B)

HN
A HO B
A B
N N

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NAME__________________________ 4-Digit ID:__________________________

Question #5 (continued):
C)
A B
A B CO2Et
Cl N S

D)
Me

O Me H
A N Me B
N
A B
N Me

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NAME__________________________ 4-Digit ID:__________________________

Question #6: (30 points) Process Chemistry – The process team, exhausted from a long
and brutal cage match with the medicinal chemists, are unable to come up with a
manufacturing route to the following clinical candidate. Eager to help, you check your
pockets for some transition metals to make it easy but unfortunately you spent it all on
late-stage stoichiometric couplings in your PhD. Desperate to make a good impression,
you still jump at the opportunity to help! Propose a process friendly
RETROSYNTHESIS for the following molecule. No metal mediated cross coupling
reactions allowed.
O
O
Me O
Me N
N H
N Me
Me N N
Me
Me O O
Me

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NAME__________________________ 4-Digit ID:__________________________

Question #7: (15 points total) Awkward hallway encounter – On your way out of the
process team interview, you bump into someone who graduated from your current lab.
Gee, chemistry is a small world! Pretending like all those times they grilled you on
mechanisms totally didn’t happen you stop and chat for a bit. Quickly, you find yourself
drawn into a deep discussion about what the best way to build their scaffold is. Now it is
your turn to teach them a lesson in synthetic strategy. Please provide a FORWARD
ROUTE WITH SUGGESTED REAGENTS to the compound below.

Me

N Me
O
N

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NAME__________________________ 4-Digit ID:__________________________

WOW! Great news! You have been

hired by Very Therapeutics. You have
blown them away with your creative
answers and quick thinking.

In fact, they were so impressed that they

have made you Vice President of
Chemistry right away!

As VP, you must oversee the following

project from start to finish.

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NAME__________________________ 4-Digit ID:__________________________

Question #8: (55 points total)

Part A: (10 points) Medicinal Chemistry – Your medicinal chemistry team has identified
the following scaffold as being a potent FUN-1 agonist. Help them make it in a modular
way. Please provide a FORWARD ROUTE WITH SUGGESTED REAGENTS to the
compound below. The route should allow for rapid diversification at the variable
positions (Ar1, Ar2, Ar3, and R).

R3
Ar1
NHR1

N N

R2

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NAME__________________________ 4-Digit ID:__________________________

Question #8 (continued):
Part B: (35 points) Process Chemistry – Congratulations, your FUN-1 agonist has been
moved up to Phase III by the FDA after demonstrating efficacy and safety in a small
patient population. The advisory panel also loved how the structure has one of each
heterocycle. Pretty as it is, the required dose is quite high as we did not hear any laughing
during this exam. As a result, the manufacturing route needs to be incredible scalable
and not reliant on costly cross coupling chemistry (say that 5 times fast). Propose a
process friendly FORWARD SYNTHESIS WITH SUGGESTED REAGENTS. You may
not use any metal mediated cross coupling reactions.
CF3

Me N N
O NH O O

S HN OMe
NH
N N

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NAME__________________________ 4-Digit ID:__________________________

Part C: (10 points) Radio Chemistry – Quantitative biology wants to track ADME of your
FUN-1 agonist. The radiochemistry team has a bit of an unorthodox definition of what fun
means and suggested 14C labelling the pyridine OR the quinoline. Exercising good
executive leadership skills, you kindly listen to their suggestion and trust their judgement.
Propose a RETROSYNTHESIS ONLY for each of the following CARBON labelled
compound below. You only have to label ONE ring carbon on either ring at any
position. You pick. You may only use molecules in the box from problem 2.
CF3 CF3

Me N N Me N N
O NH O O NH O
O O
OR
S HN OMe S HN OMe
NH *N N
NH
N N
*
O O

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NAME__________________________ 4-Digit ID:__________________________

BONUS: (45 points total, 5 points each) Wow what a day. Like Gilgamesh standing
on the city wall, you ponder whether or not the journey was worth it all. Turns out it was
because you are the VP of Very Therapeutics in your late 20’s. While you are waiting for
your brand new Tesla to charge, you think back to heterocycles and wonder if you still
got it. You also wonder you even are remembering the structures correctly… Propose
RETROSYNTHESES of the following molecules.

A)
Br

H 2N N NH2

B)
NH2
O
O
N NH

H 2N NH2
Cl

C)
O
O

NH

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NAME__________________________ 4-Digit ID:__________________________

D)
Me

N
H
N

E)
MeO

Br
O
S

MeO

F)
Me

O
N H
H

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NAME__________________________ 4-Digit ID:__________________________

G)

Me N

Me
HN

H)
MeO2C
OTBS
HN

BnO N
H

I)

F3C O Me
MeO

N
HN

CN

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