Organic Cumulative Exam February 13, 2014 LPSC 239 and LPSC 259

Organic Cumulative Exam
February 13, 2014
LPSC 239 and LPSC 259
Answer only three of the six questions. No more than three question answers will be
graded and any work not to be considered must be clearly marked as such. Clearly
indicate which questions are to be graded on the front of your answer booklet.
Good luck!
!
1. Question based on a previously distributed paper: J. Am. Chem. Soc. 2014, ASAP, DOI:
dx.doi.org/10.1021/ja412290r.
A. What is a Kemp elimination, and why is this reaction historically important to the
field of organic catalysis? [5 points]
B. Describe the key interaction responsible for the catalysis. What is the range of
magnitude for this interaction? Is it stronger or weaker in the transition state? [5
points]
C. Aside from the key interaction, what are three other structural/conformational
factors that the authors probed? Briefly, what are their findings? [7 points]
D. The authors have published a computed reaction coordinate diagram in the
manuscript. Why might this reaction coordinate diagram be flawed and not reflect
reality? What critical intermediate have the authors failed to include? In your
estimation, would satisfactory treatment of this omission change the reaction
coordinate diagram? How would it change? [9 points]
E. In your opinion, does this work merit a publication in the Journal of the American
Chemical Society? Why is this publication in JACS instead of Journal of Organic
Chemistry or Tetrahedron? Substantiate your response with at least 2 points of
argument that discuss the merits and weakness of this manuscript. For your
reference, the four JACS review criteria are significance, novelty, broad interest,
and scholarly presentation. [7 points]
2. The Robertson Group (U of Oxford) recently published a synthesis of pandamarilactone
(Org. Lett. 2014, ASAP; dx.doi.org/10.1021/ol4036424). The synthesis is shown below.
Starting material A was converted into an intermediate B. Intermediate B underwent an acidpromoted isomerization to padamarilactone.
O
6 steps
CN
O
A
B
achiral
N
H2SO4
O
O
O
pandamarilactone
1. Show how to prepare A using simple commercial starting materials.
2. Give the structure of achiral intermediate B.
3. Show how starting material A can be converted into intermediate B (authors used 6 steps
but you can use more if necessary).
4. The authors described the isomerization of B to pandamarilactone as a “biomimetic” step.
Of course, not every synthesis is biomimetic. What aspects of this research could be used
to argue that the step is “biomimetic”? You may suggest other experiments that could
support the claim of biomimicry.
3. 33Pts. Baran and co-workers recently reported a new catalytic reductive
coupling methodology.
J. Am. Chem. Soc. 2014, DOI: 10.1021/ja4117632
A) 6 Pts. Boger et al. set the stage for this development with the shown reaction.
Give the structures of 1 and 2.
J. Am. Chem. Soc. 2009,131, 4904
Fe 2(ox) 3 6H2O
PhSiH 3
O
EtOH/H 2O, rt
Compound 1
C13H 22O2
11%
+
Compound 2
C13H 22O
75%
B) 10 Pts. Baran et al. uses an improved catalyst to solely yield 4. Provide the
structure for compound 4. Redraw the structure and assign the 1H chemical
shifts.
O
Fe(acac) 3 (1.0 eq)
PhSiH 3 (2.5 eq)
EtOH, 60 C
97%
Compound 4
C13H 22O
3
H NMR (600 MHz, CDCl3): δ 2.37 (dd, J = 16.3, 7.2 Hz, 1H), 2.33 (dd, J = 16.3, 7.0 Hz, 1H),
2.16 (s, 3H), 1.62–1.52 (m, 3H), 1.38–1.31 (m, 1H), 1.21–1.13 (m, 2H), 1.04 (s, 3H), 1.02 (s,
3H), 0.91 (s, 3H), 0.67 (ddd, J = 12.7, 7.1, 5.6 Hz, 1H), and 0.14 (d, J = 5.6 Hz, 1H).
13
C NMR (151 MHz, CDCl3): δ 209.7, 44.8, 38.2, 36.0, 32.3, 31.4, 29.88, 29.86, 28.5, 22.6,
21.8, 20.2, and 18.5.
1
C) 13 Pts. Mechanistic studies showed that: Fe(acac)3 and PhSiH3 are needed
for reaction, and that oxygen-free conditions covert 3 to 4 quantitatively.
Using CD3OD or CH3OD as solvent led to incorporation of one sole deuterium
atom adjacent to the ketone.
Please provide a plausible catalytic cycle that explains the product formation
and supports the mechanistic findings.
D) 4 Pts. Synthesis of many diterpenoids can benefit from this reaction. For
rosthorin A (5), show 2 possible connection points. Can you identify and label
the four isoprene units (C5) that make up the natural product?
HO
O
OH
5
OH
O
OH
4. (33 points)
A, B. Suggest reasonable mechanisms for the transformations shown below.
C. The authors suggest this chemistry might be useful in the synthesis of lysergic acid, shown below.
(They do not perform such a synthesis, though.)
Identify (via retrosynthesis) a substrate than could logically be advanced to lysergic acid.
Ref.: Miura, T.; Funakoshi, Y.; Murakami, M. J. Am. Chem. Soc., 2014, ASAP,
http://dx.doi.org/10.1021/ja412663a.
5. Trauner and coworkers recently described the beginning of their efforts to prepare
'polytwistane,' a chiral nanorod with formula (CH)n containing all saturated sp3-hybridized
carbon atoms. The hypothetical polymer is formally constructed by successive addition of
ethylene bridges to the previously known molecule 'twistane' (1) as illustrated below.
Org. Biomol. Chem. 2014, 12, 108.
twistane (1)
ditwistane (2)
tritwistane (3)
polytwistane (4)
(a) According to the von Baeyer nomenclature system, twistane (1) is correctly named as
tricyclo[4.4.0.03,8]decane. Add an appropriate numbering scheme to tricycle 1 and explain
the origin of this systematic name.
(4 points)
(b) Sketch the likely appearance of the 1H and 13C NMR spectra for polytwistane (4).
Cl
Cl
5
Cl
Cl
(a) m-CPBA, CH2Cl2
0 °C to rt, 4 d
O
H
(b) BF3•OEt2, Et3SiH
PhMe, rt, 5 min
6
(3 points)
Cl
Cl
Cl
Cl
(c) In an attempt to access a precursor to tritwistane (3), diene 5 was treated with m-CPBA
followed by BF3•OEt2 and Et3SiH. This reaction sequence gave 6 instead of the desired
product. What was the originally desired product? and provide a mechanism to account for
the formation of 6.
(6 points)
Br
Br2, CHCl3
Br
Br
0 °C, 1 h
7
8, 38%
9, 14%
Br
(d) A dibromide derivative of tritwistane (8) and a rearranged by-product (9) were obtained by
treating diene 7 with bromine. Formulate mechanisms to account for the formation of 8 & 9.
(12 points)
(e) Suggest a synthetic strategy for accessing polytwistane (4). For full credit the approach must
have the possibility of being rendered enantioselective.
(8 points)
6. In Movassaghi's recenty publication in JOC (2014, 79, 473-486) on the trigonoliimines, he explored a variety of
interesting chemistry.
(a) Please provide a reasonable synthetic sequence to convert 1 into 2. Note that all carbons found in 2 come from
the starting material 1.
O
O
O
N
N
steps
O
N
O
O
HO
N
H
N
N
H
1
2
(b) Please provide the complete structures for compounds A, B and 4.
O
O
N
O
Eu(OTf)3
N
O
HO
O
MeCN
72°C
Compound A
C37H28N4O6
1) H2N-NH2•H2O
MeOH, 80°C
2) Ti(OEt)4, THF,
42°C
61% (2 steps)
N
N
H
N
3
N
H
O
Compound B
(-)-isotrigonlimine C (4)
C21H22N4O
THF, rt
C22H22N4O2
NMR Data for Compound 4
1H NMR: 7.95 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.31 (app-dt, J = 9.5, 1.2 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 6.87
(d, J = 2.1 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.77 (app-t, J = 7.1 Hz, 1H), 6.67 (dd, J = 8.6, 2. 2 Hz, 1H), 4.43
(app-td, J = 14.7, 2.8 Hz, 1H), 4.06 (app-dt, J = 12.1, 3.5 Hz, 1H), 3.81 (s, 3H), 3.29-3.22 (m, 2H), 3.11 (app-dt,
J = 16.5, 3.1 Hz, 1H), 2.96 (ddd, J = 16.8, 13.7, 3.4 Hz, 1H), 2.71 (ddd, J = 14.0, 10.5, 5.7 Hz, 1H), 2.39 (ddd, J
= 14.0, 10.1, 5.8 Hz, 1H). 13C NMR: 176.6, 164.0, 158.1, 157.6, 137.8, 135.5, 130.8, 124.8, 124.3, 124.2,
120.2, 119.5, 112.6, 110.6, 110.1, 95.4, 68.0, 56.1, 48.6, 40.7, 35.4, 24.4. (c) Please provide the structure for compound C and a complete mechanism for its formation.
3
1) H2NNH2•H2O
MeOH, 80°C
2) Martin's
sulfurane
CH2Cl2
-78°C
Ph
F3C
CF3
Ph
Ph
O S O
F3C
CF
Ph
3
Martin sulfurane
Compound C
C21H22N4O
N
CH(OiPr)3
PPTS
CH2Cl2
rt
94%
O
N
H
N
N
trigonolimine B (4)