Chem 206 Due: Friday, Sept.

29th
Problem Set 2: Conformational Analysis Name:_________________________
General Instructions: Neatly, in the space allocated, provide concise answers to the following questions using clear
three-dimensional representations for all relevant structures. Address stereochemical and stereoelectronic issues
where appropriate.

Question 1. The given below pairs of hydroxylated piperidines exhibit substential differences in pKa. These pKa
differences could be attributed to stereoelectronic effects. Using FMO theory, provide an explanation that accounts
for the different basicity of the diastereomeric piperidines below. Be sure to include 3D drawings to your
explaination and clearly identify the interacting orbitals.

OH HN CO2Me
N N OH HN
OH
CO2Me
OH

pKa 8.73 pKa 10.2 pKa 8.2 pKa 9.2

Question 2. For each of the following two transformations please provide a plausible reaction mechanism. Be
sure to dicuss the relevant issues regarding orbital overlap requirements.

O OMe
MeO
A. Δ
(MeO)3P + H MeO P
O

O OTMS
O
B. H KCN (cat.) O
+
EtO2C SiMe3
EtO2C
Question 3.

Part A. Draw the two chair conformers of the vinylcyclohexanol shown below. Based on A values,
predict which of the two is the most stable.

OH

Part B. Vinylcyclohexanols undergo retro-ene reactions at high temperatures as shown below. Sketch out 3-
D transition states leading to the two products.
H

O Me

440 °C 62%
H
O H Me

O
38%

Part C. Assuming A values are valid at 440 °C, can these be used to account for the product distribution? If
not, can you think of another explanation?
Question 4. The structural unit of β-turns is present in many proteins and bioactive peptides and has important
implications for both structure and function. As such, the synthesis of β-turn mimics has been an intensive area of
research. While most solutions to creating such turns have relied on covalent linkages, Hoffmann and coworkers
have developed an approach based on acyclic conformational preferences (Angew. Chem. Int. Ed. Engl. 1997, 36,
1745-1747).
Part A. Please provide a clear 3-dimensional representation of the lowest energy conformer of 1.

HO
Me Me
1

Part B. Based on your analysis of 1 please draw the low energy conformations of 2 and 3, and comment on
which structure you think could be used as a β-turn mimic. Note: A β-turn is a structural feature that creates a U-
turn in a peptide, bringing the termini into proximity.

Me Me Me Me
OH OH
HO HO
Me Me 2 Me Me 3
Question 5. The following epoxidation studies performed in aqeous medium have been reported by Breslow and
Biscoe. It was noted that cinnamates 1a have similar epoxidation rate as crotonates 2a if MMPP is used for
epoxidation. However, the oxidation of styrenes 1a is faster if dimethyldioxyrane (DMDO) and oxaziridinium 3 are
used as epoxidizing agents.

O O Oxidant O O
O O

Ar O Me O NaHCO3/D2O Ar O Me O
1a 2a 1b 2b
O

Ar MMPP (1b:2b) DMDO (1b:2b) Oxaziridinium 3 (1b:2b) OH

O Mg2+

p-CF3Ph 16:84 22:78 92.7:7.3 CO2 MMPP

2

Ph 44:56 61:39 96.5:3.5

Me Me

N Me
2-Naphthyl 47:53 68:32 99.8:3.2 O O
O
DMDO BF4-
3

Using 3D drawings of the epoxidation transition states, eplain why oxaziridinium 3 shows the highest selectivity
for the cinnamic acid epoxidation and MMPP--the lowest.
Question 6. Draw all possible diastereomers of this tricyclic ring system in 2D and 3D. Based on your 3D
drawings, rank each structure in terms of energy. Clearly identify all gauche-butane and syn-pentane interactions.

H H

H H

2D Structure Corresponding 3D Structure

Question 7. The dispiroketal (Dispoke) protecting group is of great utility for the selective protection of 1,2-
diols. Provide a 3-D representation of the expected product for the acid-catalyzed reaction of bis-dihydropyran
1 with ethylene glycol.

HO O
OH
O O
O O
CSA, CHCl3, reflux
O

1
aa/aa
Question 8.

Part A. Rationalize the selectivity observed in the following thermodynamic cyclization:

Me Me Me Me
Me Me Me Me
H+
HO2C HO2C
HO2C CO2H O O
80 ˚C O O
OH H H
Me Me Me Me

A/B =4.2:1 A B

Part B. Assuming that equilibration between A and B is complete, calculate the energy difference between A and
B.
Me Me Me Me

HO2C HO2C
O O O O
H H
Me Me Keq = 0.24 Me Me
at 353 K
A B
Question 9. Two new stereocenters have been generated in the illustrated transformation shown below. Based
on your knowledge of conformational analysis, provide a mechanism for this transformation that predicts the
stereochemistry of the product.

O O
EtO
Me
EtO 2 equiv
KNR2 Me
Br
R
R
Br
Question 10. The following cascade alkylation was employed by Stork and coworkers during their synthesis of
histrionicotoxin alkoloids. Please propose a mechanism with clear 3D drawings that accounts for the formation of
the indicated product and explains the diastereoselectivity.
O
OTBS OTBS
LDA(2 equiv) O
MeO2C –78 ºC to rt
43% single isomer

Br
O