NOTE: These are just a few more exercises for you to practice.

It does not mean that the Final exam

will have the same number of questions in each group nor that the content of the Final will be the
same as depicted here!

1. Provide the reagent(s) and/or the structure of the major organic product(s) in each of the following
reactions. Show stereochemistry for chiral compounds.

a. (Note: the second step, with PCC, is used to regenerate the carbonyl group which can be reduced under
the conditions employed for the first step, specially, if too much sodium metal is used.)

Straight forward reduction of an alkyne with dissolved metal to give the corresponding E-alkene. Role of
PCC is explained

b.

Step (i) is a Clemmensen reduction and step (ii) is a Friedel-Crafts alkylation with carbocation
rearrangement:
c. Note how the Wittig reagent used gives rise to the E-alkene, in the first step.

Given the way the final product was drawn, it would be best to do a retrosynthetic analysis on the product
to figure out which enantiomer of diethyl tartarate (DET) had to be used for the asymmetric Sharpless
epoxidation

d.

Alkylation of the α-position via enamine formation followed by hydrolysis to give the ketone back. Wolff-
Kishner reduction (or Clemmensen reduction) to remove the ketone group.

e.

OH i. DMP, CH2Cl2
ii.
Ph3P

KOtBu, THF
Oxidation of the primary alcohol to aldehyde using Dess-Martin periodane (DMP) followed by Wittig
reaction to give the Z-alkene (beware of the Wittig reagent employed and how it can give rise to either
the E- or Z-alkene as the major product!).

f. (Note: TBSCl is a silicon-based reagent which is widely used to protect alcohols due to the formation of
the strong Si – O bond. Tetrabutylammonium fluoride (TBAF) is used to remove the silicon group and
regenerate the free OH. TBAF works as a source of “F−“ and the Si – F bond is even more stable than the Si
– O bond). Adapted from: Tamura, O., et. al., Org. Lett., 2017, 19, 6320-6323.

OMe
OH OH
TBSCl, imidazole O
HO OH HO OH O OH
OH OTBS
O O OTBS
O

O
SO3H
NaH

Ph Br

O i. (COCl)2, DMSO O
O OBn ii. NEt3 O OBn
TBAF
OH
O O OTBS
O O

O
Ph3P
OMe

O O i. (COCl)2, DMSO O
O LiAlH4 O ii. NEt3 O
OBn OBn OBn

OH O
O CO2Me O O

The roles of TBSCl and TBAF were explained, and the respective products given. The first set of reagents
were not shown in class but, if you put some thought into it and did a little bit of arrow pushing you could
figure that they will give rise to an acetal according to the mechanism:
Why did that alcohol and not any of the others attacked? Because, even though all hydroxyl groups are
secondary, that one is the least sterically hindered. Furthermore, the acetal will form preferably between
the two syn hydroxyl groups as shown below:

OH circled in bue always syn

regardless of conformation
OH TBSO OH
OH H
HO OH HO OH
H OH H
OTBS O O H
O OTBS H H
H
H OH
most stable chair conformation pink OH can not form a
5-membered ring in this
conformation
They could in the most stable conformation
but, it is slower than the syn hydroxyl groups
O
O
OH
O
OTBS

The second step is alkylation of the remaining hydroxyl group (Bn stands for Benzyl which is a –CH 2Ph
group); TBAF, as mentioned, removes the TBS group regenerating the primary alcohol and then it’s a series
of Swern Oxidation, Wittig, reduction and Swern Oxidation again.

g.

Note that none of the reagents given affects the carbon chain. They only manipulate functional groups.
Therefore, the reagent must have the same number of carbons. Doing the retrosynthetic analysis, you
get:
Note how the tertiary alcohol does not get oxidized by chromic acid because, there are no hydrogens in
its carbon.

h.

From the first step you form a highly electrophilic iminium ion which can be easily reduced with sodium
borohydride to the corresponding amine, just like you saw for reductions of carbonyl compounds with
hydride sources:

2. Propose a synthetic route (sequence of reactions) to prepare the following compounds. Be sure to
write out each reaction in your route showing the starting compound and intermediate and specific
reaction conditions (more than one step will be required).

Note: there may be other options in this question. If you found a different way but are unsure if it would
work as well feel free to shoot us an email
a.

11 11
7 5 9 7 5
8 4 HO2C 4
6 8 6
10
9 3 HO 1 3
10 1 2 2

O3
NaBH4
DMS

Na2Cr2O7
H2SO4, H2O
HO
O
O
O
O

First thing to note is that the carbon chain was not affected (look at the numbering). Therefore, you are
only changing the functional groups in your molecule. It is also evident that one of the rings was opened
and since you have a double bond in one of them, that’s the one you need to focus on. The only method
you learned to cleave C=C double bonds is ozonolysis thus, that’s going to be your first step. Remember
that ozonolysis of alkenes gives rise to aldehydes/ketones. You did not learn any direct method from going
to aldehyde to carboxylic acid but, you learned that if you treat primary alcohols with aq. Acidic chromic
acid, they will get oxidized all the way to carboxylic acid via aldehyde hydrate (see below). Therefore,
treatment of an aldehyde with such conditions will give rise to the desired carboxylic acid. The last step is
chemioselective reduction of the ketone to alcohol. Remember that sodium borohydride is not a strong
enough source of hydrides to reduce carboxylic acids.

b.

Note that you lost a carbon atom. There are two ways you could achieve this transformation based on the
chemistry you learned in this course.
Route #1:

In this route you lose the carbon atom in the ozonolysis step. The only tricky step is that you had to do a
E2 elimination of the hydroxyl group. If you went for E1, you would most likely have a Wagner-Meerwein
rearrangement taking place:

Route #2:

OH H

PCC or
PCC or
Swern or
Swern or
DMP or
DMP
Collin's
O
OH

xs Br2
NaOH, heat
LiAlH4
O

OH + CHBr3

haloform reaction

In this route, you lose one carbon in the haloform reaction and note how the last step, you can not use
Collin’s reagent for the oxidation otherwise you go back to the carboxylic acid.
c.

Again, you do not have any change in the carbon skeleton so, you only need to manipulate functional
groups. It’s a pretty straight forward anti-Markovnikov hydration followed by oxidation.

d.

In here, you have increased the number of carbons in the final product by 3. Furthermore, you also added
two extra carbonyl groups (one ketone and one ester). Looking at the relative positions of the carbonyl
groups you have:

There is a 1,3 relationship between two of the carbonyls (Claisen or Claisen-type

condensation) and a 1,5 relationship (Michael addition).

Your starting material is a decent Michael acceptor (α,β-unsaturated ketone) 1,3-

dicarbonyl compounds can act as good Michael donors. Since there is an ester in our
product and we concluded that the 1,3-dicarbonyl relationship in the product could arise from a Claisen
(or Claisen-type) condensation, what if the Michael donor looks like this:

Let us add these two together, under basic conditions and see if we get to the
product (Note: your base must match the alkoxide groups of the di-ester so, you
need to use NaOMe as a base). The synthesis comes as follows:

For completeness sakes, the mechanism is depicted in the following page:

3. Provide a step-by-step mechanism for each of the following conversions.

a.

Hg(OAc)2
OH H2SO4

tautomerization

OH

AcOHg
OH

H
O
HgOAc OH

H H
AcOHg
highly reactive intermediary,
lots of ring strain because of
double bond

Note that no other nucleophiles were given so, the hydroxyl group already present had to act as such.
b.

O
O
O i. NaBH4, MeOH
O
ii. H2O
O

OH
H
H B H
H
H2 O
O

O O O
O
O O
O H

Chemioselective reduction of the ketone by sodium borohydride followed by intramolecular

esterification.

c.

Attack from the Nitrogen in blue, gives rise to the blue regioisomer; attack from the Nitrogen in red gives
rise to the red isomer. The mechanism is depicted in the next page.

The key steps are: (i) attack of the nitrogen takes place to the most electron deficient carbonyl carbon (i.e.
the ketone); (ii) the 5-membered rings are formed sequentially i.e. you do not form the imine and then
the amide giving a large 8-membered ring with concomitant contraction to two fused 5-membered rings.
It is statistically more likely that the molecule will adopt the required conformation to form a 5-membered
ring than it is to form an 8-membered ring (faster, lower activation energy, kinetics) and 5-membred rings
are less strained than 8-membered rings (thermodynamics).
d. (Note: BF3∙OEt2 is a strong Lewis acid which, is being used as a catalyst to speed up the reaction. The
Lewis acid reversibly coordinates to the Oxygen atom of the α,β-unsaturated aldehyde activating this
substrate. You do not need to show this activation in your mechanism). Adapted from Kulkarni, K. A.,
Reddy, D. S., et. al. Org. Lett., 2018, 20, 7003-7006.

Straight forward Diels-Alder reaction followed by intramolecular aldol condensation.

e.

This reaction is called a Pictet-Spengler reaction. Even though we did not learn this specific reaction in
class, we did learn all of the key steps that take place in this reaction which are: (i) nitrogen addition to
carbonyl (more precisely aldehydes, to form imines); (ii) electrophilic aromatic substitution (in this case
with an heteroaromatic system) and; (iii) carbocation rearrangements. The mechanism is depicted below.
The red path is the most accepted path. However, when the indole-Nitrogen has electron withdrawing
groups attached to it, the black path can also be accepted.