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

OH
σ(C–N) → σ*(O–H) N

H H
OH
The hyperconjugative interaction
σ(C–H) → σ*(O–H)
σ(C–N) → σ*(O–H) is responsible
for reducing the electron density
around nitrogen. The present hyperconjugative
interaction σ(C–H) → σ*(O–H)
does not influence the electron
density distribution around
nitrogen. Hence, the basicity of
the nitrogen is retained.

σ(C–N) → σ*(C–CO2Me)
CO2Me
HN HN
OH OH

CO2Me
H
Similarly, the same reasoning could be
applied to the bridged piperidine case. σ(C–C) → σ*(C–CO2Me)
However, σ•(C–CO2Me) is the accepting
orbital in this case. σ(C–H) → σ*(C–CO2Me)
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

σ∗
Me O Attack of alkoxide cannot occur at 180o
O
P 5-Endo-Tet Disfavored
MeO OMe

Bimolecular Reaction leads to product

Me O
Me O Me
O O OMe
P O O O
MeO OMe P P
P
MeO OMe MeO
MeO OMe OMe

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

CN
This Reaction is an acyl silane
variant of the classic Benzoin
Condensation CN
O OTMS
regeneration of
EtO2C SiMe3 CN catalyst O
CN
EtO2C CN

OTMS
O
O
Me EtO2C CN TMS O
H
EtO2C Si Me O
CN
Me
EtO2C CN
OTMS
Apparent 3-endo-tet allowed
via hypervalent silicon species 5-endo-tet allowed via
EtO2C • hypervalent species.
This could also be a bimolecular process N Could also be bimolecular
 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

OH
OH

ACH=CH2 > AOH thus CH=CH2 will be equatorial in most stable conformer.

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%

H
=
H
O Me
O
O

H
H Me
O
O =
O

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?

In this case, the least stable (and hence least abundant) conformer leads to the favored product. This is possible so
long as the two conformers are interconverting rapidly (as you would expect at 440 °ˇC) and that one conformer reacts
faster than the other. This must be the case here. This is an example of the Curtin-Hammett principal at work.
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.

OH OH Minimized syn-pentanes
HO H
H or Me Vinyl group less hindered than
Me Me Me Me grooup.
1 Me Me H
H

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

minimized A1,3 strain minimized A1,3 strain

OH
H H H H
H Me HO Me Me
Me Me Me
H H
Me H
H H
Me
OH no syn-pentane OH
no syn-pentane

The alternative conformations suffer from unavoidable syn-pentane interactions and A1,3 strain. Structure 2 prefers
the termini "trans", while structure 3 prefers termini "cis". On this basis 3 could be incorporated into a β-turn mimic.
H H
H Me H H
Me H Me
Me H
Me H H Me
Me H HO H
syn-pentane Me H
HO A1,3 OH
OH
syn-pentane
A1,3
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.

In polar, protic D2O, hydrophobic effects play a very strong impact on reactivity of the substrates. Thus, the transition
state for epoxidation of nonpolar substrates like 1a is more stable when nonpolar oxidants like 3 are used. In other
words, nonbonding hydrophobic interactions between the oxidant and substrate stabilize the corresponding transition
state in aqueous medium.

Mg2+
CO2
Me N Me
O O
O O
O Me O
H

CO2
CO2 CO2

Aromatic rings are far Isopropyledene methyl groups Aromatic groups can engage
away, low hydrophobic could hydrophobically interact into π-stacking interactions.
stabilization of the TS. with the aromatic substituents thus This TS has maximum stability
stabilizing the TS. in an aqeous environment.
 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

H H
H H

H H H H

H H
H H

H
3 gauche: 2.4 Kcal/mol

H
H H

H H

H
6 gauche: 4.8 Kcal/mol H H

H
H H

H H
H
H
1 flagpole (boat):
6.4 Kcal/mol

H H H H

flagpole
H H
H H
1 syn-pentane + 4 gauche:

6.9 Kcal/mol H H

H H

syn-pentane
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

The cis isomer has 4 possible conformations:

O O H O O O O O
O O O O O
H

O O O

ea/ee ea/ea ee/aa aa/ea

The trans isomer has 5 possible conformations:

O O H O O O
O O O O O O O
O O H O O H
O O
H
O

ee/ee ee/ea ea/ae ae/ea aa/aa

The all axial conformation of the trans isomer is preferred sterically and stereoelectronically.
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

sp
e HO2C
O Me
H Me H
Me Me
Me H e H
O Me
H sp Me O HO2C
HO2C Me O
Me
Me Me H
O O
H H Me H
A
B
Under equilibrating conditions, diastereomer A can adopt a conformation that is clearly favored over both
possiblilites for B. Note the eclipsing methyl/carbonyl interactions (e) and syn-pentane (sp) interactions in the
conformations of diastereomer B.
Acc. Chem. Res. 1994, 27, 9

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

ΔG = -2.3RTLog10K
ΔG = -2.3•1.99 cal/(molK)•353 K•Log10(.24)
ΔG = +1.0 kcal/mol
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

Answer
KNR2

OEt H O
H EtO
CO2Et
O– SN2 KNR2
R
R Br Me
E2
Me Br Me R
Br H
H

minimal A(1,3) strain;

psuedo-equatorial side chains.

(Tetrahedron Lett. 1997, 415)

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 product using your knowledge of acyclic conformational analysis.
O

OTBS OTBS
LDA(2 equiv) O

MeO2C –78 ºC to rt
43% single isomer

LDA Br
O

OTBS
LiO

OMe
H
OTBS
LDA
HO
MeO O

OTBS Chair flip

A1,2 Strain H

OTBS
O Li+

OLi OH

H CO2Me
OMe
Favored

A1,3 Strain

LiO H OMe
MeO2C
O Li+ OH

OTBS
R
H
Disfavored