Chemistry 634: Advanced Organic Chemistry – Synthesis and Reactivity
Problem Set 3
Due Fri, 11/6/15, 5pm
1) Please evaluate the asymmetric reaction (eq 1) reported by Ellman (ACIE, 2008, 47, 5623) for the synthesis of each of
the products shown below. How good of a match is each product to the reaction, and does the disconnection provide a
likely solution to making the product? Please list all factors that might affect the outcome for each particular reaction. If
you do not think the product will likely result from the reaction, can you find other reaction with better precedent that is
more likely to lead to the product cleanly? You may read the paper to answer these questions.
Ph
N
PG
+
(HO)2BR'
R
cat. Rh(acac)(coe)2
cat 1, K3PO4
HN PG
R
N
1
R'
Ph2P
PPh2
NH2
Me
Et
NH2
Me
Et
HN
NH2
Et
Me
Me
Ph
HN
Et
Me
Me
NH2
Me
Et
HN
Me
Ph
Et
HN
Ts
Me
Me
Ts
2) In metalloenamine alkylation, only the syn product (and not the anti) is observed, though in theory both should be
possible. This likely results from the stability of the metalloenamines, as shown. Using FMO analysis, please explain this
observation.
Li
N
R
N
E-X
R
N
Li
E
R
E-X
R
observed, syn product
N
E
not observed, anti product
Explanation:
3) Provide the missing reagents and provide rationale for any stereoselective steps.
Me
Me
Me
Me
O
OBn OH
O
O
OMe
Me
Me
O
OBn OH
O
Me
Me
O
OMe
Me
Me
Synthesis (Missing Reagents):
Stereochemical Rationale:
(3 – continued)
O
5 steps
TBSO
OH
TBSO
H
Me
this enantiomer > 99% ee
Synthesis (Missing Reagents):
Stereochemical Rationale:
4) Enolate oxidation via heteroatom installation is also an important reaction, but was not discussed in class. Given the
example below, provide a mechanistic rationale both for bond formation (arrow-pushing mechanism), as well as the
observed stereochemistry.
O
Me
O
N
O
Bu2BOTf
Et3N, then NBS
O
Me
N
Me
Me
Bn
Arrow-Pushing Mechanism and Stereochemical Rationale:
O
Br
Bn
O
5) Camphor-derived chiral auxiliaries are also important in organic synthesis. Below such an auxiliary (developed by
Helmchen) that is useful for ester synthesis.
a) Build a model of the starting material and draw it in 3D.
b) Using this model and your knowledge of enolate formation, rationalize the stereochemical outcome below.
Me
PhO2S
N
Me
Me
O
Me
O
Me
Me
CyN(i-Pr)Li, THF/HMPA
then
I
Me
PhO2S
N
Me
Me
Me
Me
O
Me
Me
O
Me
dr = 94:6
Stereochemical Rationale:
Me
Me
6) Predict the products from each of the following reactions.
Me
Me OMe
OMe
Br
Br
Br
O
Me
OMe
Me O
Me
O
Me
Me
Me
KOtBu
KOtBu
Me
O
O
KOtBu
N
N
O
O
Me
O
Me OMe
Me
N
O
O
Me
Me O
Me Me
Me
Me
O
Me
Me
O
O
NaHMDS, MeI
NaHMDS, MeI
NaHMDS, MeI
LiHMDS; EtI
LiHMDS; EtI
LiHMDS; EtI
7) For each of the following, predict the product of the reaction and provide a model to explain the
expected stereoselectivity.
O
Me
LDA (kinetic), THF -78°C; then TBSCl
OMe
O
Model to Explain Stereoselectivity:
Me
OMe
O
Me
LDA (kinetic), THF -78°C; then TBSCl
OMe
O
Me
LDA (kinetic), THF/HMPA -78°C; then TBSCl
LDA (kinetic), THF/HMPA -78°C; then TBSCl
OMe
Model to Explain Stereoselectivity:
8) (a) Please propose a synthesis of 1 using 1,3-propane diol and propionic acid as the only sources of carbon in the
product. You may use any other reagents required, including those that contain carbon.
O
OH O
OH
H3C
+
OH
HO
H
H
O
Me
1
single enantiomer
Synthesis:
(b) Please provide a rationale for the stereoselective steps in your synthesis.
Stereochemical Rationale: