Chem 335 A01: Page 1
UNIVERSITY OF VICTORIA
CHEMISTRY 335, A01
SYNTHETIC METHODS IN ORGANIC CHEMISTRY
FINAL EXAM — APRIL 22, 2009
NAME:
KEY
STUDENT ID:______________
INSTRUCTOR: FRASER HOF
TOTAL MARKS = 70
DURATION: 3 HOURS (9:00 AM – 12:00 PM)
THIS EXAMINATION PAPER HAS 9 PAGES, INCLUDING THIS COVER PAGE. COUNT THE
NUMBER OF PAGES IN THIS EXAMINATION PAPER BEFORE YOU START TO WRITE, AND
REPORT ANY DISCREPANCY IMMEDIATELY TO THE INVIGILATOR.
QUESTIONS ARE TO BE ANSWERED IN THE SPACE PROVIDED ON THE EXAM FORM.
Chem 335 A01: Page 2
1. (26 marks total) Fill in the boxes with the missing reagents, starting materials, or products (1 mark
each). For boxes with reaction products, show only the majo stereoisomer produced by the given
reaction and indicate whether it is achiral, racemic, or a single enantiomer (0.5 marks each).
a)
O
Ph3P
OMe
H
OMe
achiral
b)
O
S
P2S5
O
achiral
c)
H2N
C
N
O
CO2Me
NaCNBH3
H
H
N
C
N
CO2Me
O
Cl
O
H N N N
O
N
N
NH
N N
C
N
CO2Me
N
CO2Me
sing. ent.
d)
Et3N,
Cl
B
O
O
O
B
Ph
H
O
achiral
OH
(±)
Chem 335 A01: Page 3
Problem 1 continued...
e)
Li, NH3
O
O
O
O
f)
O
H2N NH2
∆
O
N
N
N
Ph
N
Ph
achiral
g)
1) LDA, –78 °C
2)
O
O
O
OH
H
(±)
h)
O
OH
OH
O
O
I2, NaHCO3
NaOH, H2O
O
I
O
(±)
achiral
i)
O
LiAlH4
O
O
OH OH
H
Ph
pTsOH, O
Ph
H
O
O
Chem 335 A01: Page 4
Problem 1 continued...
j)
sing. ent.
O
O
O
O
N
MeO
O
O
1) BuLi
2) BnBr
LiOMe
Ph
N
O
O
Ph
O
NH
2 products
sing. ent.
k)
Br
N3
MeO
MeO
CuCl,
NaN3
N
N
MeO
N
Pr
achiral
2. (4 marks) a) Give the mechanism for this reaction, including all proton transfers and intermediates. b)
State why it proceeds at site X and not at site Y. Use a diagram to illustrate your point.
Y
OMe
1 eq.
Cl
Cl
H2N
N
N
∆
Cl
N
H
OMe
1 pt. for neg. charge onto ring nitrogen
1 pt. for rest of mechanism
1 pt. for picture of meta attack
1 pt. for description of why it's bad
X
B
Cl
H 2N
N
H H
N
Cl
R
Cl
N
Nu
Cl
R
BH+
H
N
Cl
N
Cl
Cl
R
N
Nu
Cl
Cl
N
Cl
- negative charge can't be localized on ring nitrogen
- reaction less favorable
N
Cl
N
H
R
Chem 335 A01: Page 5
3. (4 marks each, 8 marks total) ANSWER ONLY TWO OF THE THREE PARTS. Give the
product of the reaction. Explain the origin of the observed stereoselectivity in one short phrase, and draw
3D stereochemical diagrams of starting materials and products to illustrate your point.
a)
Me
RS
O
O
–
K+
H B
R'
Me
RS
3
(K-selectride)
"H–"
O
R'
HO
Large = equatorial attack
Me
O
R'
RS
H RS
O
Me
O
R'
OH
b)
OMe
R
OMe
O
OH
Zn(BH4)2
N
N
Zn2+
Me2N
O
iPr
O
Me2N
R
H
H
H–
R
iPr
HO NMe2
H
H
R
iPr
HO H
R
iPr
H
NMe2
c)
mCPBA
O
more hindered by methyls
O
less hindered by methyls
Chem 335 A01: Page 6
4. (8 marks) The following building block A is used in the synthesis of Viagra. Plan the synthesis of A
from acyclic starting materials with 5 or fewer carbon atoms. Whether you go in the forward or reverse
direction, clearly indicate the reagents and conditions that would be required for each reaction in the
forward direction.
O
N
H2N
N
H2N
A
H2, Pd/C
O
N
H2N
O
HNO3
N
H2N
N
NH3 (or stepwise) O
N
MeO
N
N
O2N
NaH, MeI
O
MeO
O
O
O
H2NNH2
O
MeO
OH
LDA, H
MeO
O
PCC
O
O
MeO
H
N
N
O
1pt. per step (0.5 reagent, 0.5 product, total 7)
1pt. for consideration of cross-reactivity of amines and PG's
Chem 335 A01: Page 7
5. (10 marks) The intermediate A from question 4 is reacted with an acid chloride under basic
conditions to give key Viagra precursor B. Give the detailed mechanism for this reaction. Explicitly
show all starting materials, proton transfers, intermediates, and byproducts.
Cl
NaOH
THF
∆
O
N
H 2N
O
O
N
N
HN
EtO
N
N
H 2N
OEt
A
B
O
H 2N
H
O
N
H 2N
H
N
N
H
N
N
O
HO H
O
H
N
H2N
N
N
HN
–O
Cl
HO–
HO–
O
Cl
Ar
N
N
H
HN
O
N
Cl–
Ar
Ar
HO H
O
HN
HO
N
Ar
H
O–
S
HO H
N
N
HN
–O
N
Ar
H
N
HO–
O
N
HN
N
N
OEt
+ H2O
+ HO–
N
HN
N
1 mark for each step (7)
1 mark for byproducts
1 mark for the oath
1 mark for reasonable arrows
(moving charge onto carbonyl oxygen not
necessary for full marks)
N
HN
O
Ar
Chem 335 A01: Page 8
6. (3 marks) The epoxidation reaction shown below does not proceed. Show why this is the case with a
detailed 3D diagram of the starting material that explicitly shows the orbitals involved in this reaction.
NaOH
OH
O
I
Nu can't reach backside of σ* orbital
O–
1pt. chair with I equatorial
1pt. σ* orbital picture
1pt. "can't reach"
σ*
I
7. (3 points) The CBZ protecting group, pictured below protecting a simple amino ester, is a common
protecting group for amines. Based on your knowledge of the reactivity of related groups, indicate
which conditions should be used for deprotecting the amine, and show which two byproducts would be
produced.
2 byproducts
= CBZ
H2, Pd/C
O
MeO2C
N
H
O
MeO2C
1pt. each thing (3)
NH2
+
O
C
O
Chem 335 A01: Page 9
8. (8 marks) Plan the synthesis of the cholesterol absorption blocker Zetia (pictured below, left). You
have the three key building blocks A, B, and C available to you. Whether you picture the synthesis in
the forward or retro direction, include reagents and conditions above each arrow.
You must control the stereochemistry at all three stereocenters, but this is a special day in the lab and
you get to use Group 9’s special reagent “magic” as an additive to a normal reaction that will provide
absolute stereocontrol in the formation of ONE of the three stereocenters. For the other two make it
clear how you are setting the stereochemistry, without resorting to magic.
OH
OH
OH
H2N
O
F
N
F
O
HO2C
A
Zetia
F
O
B
C
F
TBAF
asymmetric reduction!
OTBS
OTBS
OH
O
(+)-CBS
BH3
F
F
N
N
O
O
F
F
1. LDA
2. A
diastereoselective
Michael addition (facial
selectivity)
OTBS
O
DCC
Et3N
O
O
OH
TBS-Cl
Et3N
OH
OTBS
OTBS
C, NaCNBH3
MAGIC
N
HN
OH
O
F
1 pt. per step (0.5 reagent, 0.5 product, total 6)
1 extra pt. for each stereocontrol step (total 2)
- no penalty for choosing (–)-CBS instead of (+)
O
O
OH
F