CUME January 29, 2015
Cumulative Examination
•Answer 3 out of the 6 questions.
•Clearly specify which three questions you wish to be graded.
CUME January 29, 2015
Question 1
JOC 2015, 80, 1034-1041
Zheng and co-workers reported the formal synthesis of securinine.
(a) Please provide complete structures (including stereochemistry) for compounds A-E.
(b) Explain the regioselectivity in the coupling reaction of 1 and 2 to make A.
(c) Provide a viable mechanism for the conversion of E into 3.
(d) Provide a viable synthetic sequence to convert 3 into 4. You must use actual reagents
and conditions to receive any credit.
O
MgI
TBSO
BnO
N
PMB
1
2
CH2Cl2, -20°C;
O
Et3SiH, BF3•Et2O
CH2Cl2, -78°C to rt
92% overall
Compound E
C16H25BrN2O3
TPAP, NMO
Mol Sieves
CH2Cl2
Compound A
C23H29NO4
N
3
OH
O
steps
CAN
MeCN/H2O (9:1)
86%
1) DIBAL-H, THF
BF3•Et2O
SmI2 / t-BuOH
75%, 3:1 dr
Compound D
C16H27BrN2O3
2) Pd/C
HCO2H, MeOH
85%
1) SmI2
MeOH/THF
75% (2 steps)
2) TFA, CH2Cl2, 0°C
then K2CO3, MeCN
93%
H
Ph3P, CBr4
CH2Cl2, 83%;
O
H
O
N
(-)-securinine (4)
Compound B
C15H20BrNO2
Boc2O
DMAP, Et3N
CH2Cl2
92%
Compound C
C20H28BrNO4
CUME January 29, 2015
Question 2
Science, 2002, 22, 2245–2247
Question is based on a previously distributed paper:.
(a) What is "Fourier transform-ion cyclotron resonance spectrometry" and how is it
relevant to the science? [6 points]
(b) Explain three critical features of the substrates that allowed the experiments to be
performed efficiently and accurately. State what they are and briefly describe their
importance. [6 points]
(c) Reproduce the reaction coordinate curves of a gas phase reaction and compare that to
the solution reaction. Label what part of the curve represents the starting material,
association complex, transition state, and the product. There is a qualitative difference
in the shapes of the curves. Explain why this exists. [7 points]
(e) What is the magnitude of steric effects in solution and gas phase? Why is there a
difference? In other words, according to the authors, what is the origin of "steric"
effects in SN2 reactions? [7 points]
(f) Why is a Monte Carlo simulation critical to reproduce experimental barriers in these
cases? Why couldn't you use an implicit solvation model? [7 points]
CUME January 29, 2015
Question 3
Angew. Chem. Int. Ed. 2015, ASAP; doi:10.1002/anie.201410375
This question is based a recent report from Wang and Gevorgyan. The paper describes a
new method for the synthesis of substituted salicylic acids.
(a) The authors comment on several previous methods available for the synthesis of
substituted salicyclic acids. Describe/show 2 methods for the synthesis of this
functional group.
OH
CO2H
salicyclic acid
(b) The key reaction reported is the conversion of 1 to 2. Give a plausible mechanism for
this transformation, and be sure to account for the role of each of the reagents (DCE
is the solvent).
O
tBu
Si
OH
tBu
1
tBu
Pd(OAc)2 (10 mol%)
AgOAc (3 equiv)
CO, CF3CH2OH (3 equiv)
DCE (0.25 M), 95 oC, 18h
tBu
H
N
O
O
O
CO2H
(20 mol%)
tBu
Si
O
tBu
O
2
(c) Based on your mechanism, what is the source of the oxygen atom indicated by the
arrow? Design/show a labeling experiment that tests this hypothesis. Comment on
any potential concerns with the labeling experiment: is it possible a labeling
experiment could give you incorrect mechanistic information? How else could you
probe the mechanism?
CUME January 29, 2015
Question 4
Nature Chemistry 2015 | DOI: 10.1038/NCHEM.2141
Denmark et. al. introduced a novel method for the syn-dichlorination of alkenes, which
can be useful for the synthesis of chlorosulfolipids like malhamensilipin A. (isolated by Bill
Gerwick at OSU: J. Nat. Prod. 1994, 57, 524; 2010, 73, 279).
PhSeSePh (5 mol%)
BnEt 3NCl (3.0 equiv.)
1 (1.3 equiv.)
Cl
R
N+
BF 4F
R
Me 3SiCl (2.0 equiv.)
solvent, rt
Cl
1
(a) What is the active catalyst? Please propose a catalytic cycle for the selenium catalyzed
syn dichloronation of alkenes! Note oxidation stages of metals involved, type of
reactions, and possible competing reactions. [12 points]
(b) Malhamensilipin A’s structure was re-assigned in 2010 by J-based configurational
analysis (JBCA) and Mosher’s analysis.
(i) Use the given heteronuclear couplings and NOE correlations of derivative 2 to
draw Newman projections for C-11 to C-15. Assign the relative configuration in
wedge/dash notation! [12 points]
Cl
OH
C7H15
11
14
Cl
C11 2
Cl
Cl
Cl
7
C12 C13 C14
C15
H12-H10
H12-H14
H13-H15
H14-H16
H17-H15
H14-H11
H14-H12
H16-OH14
H15-H16
H12-OH14
H15-OH14
H16-H14
H15-H13
NOE
CUME January 29, 2015
Question 4 (continued)
Nature Chemistry 2015 | DOI: 10.1038/NCHEM.2141
(ii) Esterification of 2 with R- and S-2-methoxy-2-trifluoromethylphenylacetic acid
(MTPA) revealed the absolute configuration at C-14. δH(S-R) values are given in
small numbers below. Please assign the absolute configuration at C-14! Redraw
2 and use the wedge/dash notation and note S/R at each stereocenter. [9
points]
CUME January 29, 2015
Question 5
Carbohydr. Res., 2015, 402, 77-80
Biopolymers, 2013, 99, 686-696
Prof. Saludes, in his Jan. 15, 2015 seminar, described an oligopeptide designed to
penetrate the cell wall based on a derivative of sialic acid and arginine.
(a) Outline the synthesis of the sialic acid glycal 9 used as a building block, and the
innovation his student applied to shorten the 7-step synthesis to 4 steps.
(b) Describe what must be done to 9 to allow its use in solid-phase synthesis of the
oligopeptide.
(c) Describe the physiologic function of the arginine units in the oligopeptide.
(d) Describe the physiologic benefit of using this sialic acid derivative, rather than another
α-amino acid.
(e) Describe the structural benefit of using this sialic acid derivative.
(f) Prof. Saludes noted that current understanding of the oligopeptide structure depended
exclusively on NMR and circular dichroism studies. Describe what each method is
capable of establishing, regarding particularly secondary and tertiary structure of the
oligopeptide.
(g) Describe the structural features that interfere with successful solution of a single-crystal
X-ray crystallographic structure, and explain why classical approaches you might use
to rectify the problems may either not work or not, in the end, be of much value based
on the project goals.
CUME January 29, 2015
Question 6
Angew. Chem., Int. Ed. 2015, 54, 1223
Maimone recently reported the synthesis of the polycyclic diterpene (+)-chatancin.
(a) PhMe, Δ
(b) Tf2O, Et3N, CH2Cl2
(c) cat. Pd(OAc)2
Ph3P, i-Pr2NEt
CO (1 atm)
MeOH, MeCN
?
+
O
O
O
OSiMe3
CHO
O
O
2
1
3
H
H
H
+
O
PhMe
H
CO2Me
O
6
O
O
100 °C
CO2Me
90%
dr = 1:1
O
5
O
4
O
CO2Me
H
?
cat. H+
H
OH
H
O
CO2Me
8
C21H30O3
IR: ν = 1715, 1685 cm–1
(+)-chatancin (7)
(a) Suggest reagents and conditions to prepare ketone 3 from (S)-dihydrofarnesal 1 and
silyl ketene acetal 2. More than one step may be required. [5 points]
(b) Write detailed mechanisms for the multistep conversion of ketone 3 into α-pyranone
4. [15 points]
(c) Mild thermolysis of 4 results in an intramolecular Diels-Alder reaction that yields
diastereomeric cyclohexenes 5 and 6. Account for the formation of these two isomers
and explain why alternate isomers are not formed from this cycloaddition reaction. [10
points]
(d) (+)-Chatancin (7) is acid sensitive and decomposes to compound 8 when exposed to
overly acidic (or Lewis acidic) conditions. Provide a likely structure for compound 8
and suggest reagents and reaction conditions for the conversion of cycloadduct 5 into
(+)-chatancin (7). [3 points]