Organic Cumulative Examination (October 7, 2010)
Daesung Lee
1. (15 points) Recently, a large scale synthesis of 3-benzyl-3-azabicyclo[3.1.1]heptan-6-one, a
promising building block for medicinal chemistry, was reported (Org. Lett. 2010, 12, 4372). This
practical synthesis involves a two-step operation as shown below. Provide detailed step-by-step
electron pushing mechanism for both Step A and Step B.
Step A
OMe OMe
O
+
Step B
MeO
OMe
Me3SiCl
N
Ph
O
TFA
N
CH3CN
N
Ph
Ph
2. m-CPBA (meta-chloroperbenzoic acid) is one of the most convenient reagents to convert an
alkene to the corresponding epoxide, which can be converted to trans-1,2-diol.
Step A
CO2H
O
m-CPBA
Step B
OH
1. heat
OH
+
CH2Cl2
Cl
racemic
2. NaOH
Step C
racemic
(a) (10 points) Provide detailed a step-by-step electron pushing mechanism for Step A.
(b) (5 points) Provide a mechanism and the product of Step B.
1
In contrast the m-CPBA-mediated epoxidation and subsequent transformations, the following
reaction selectively generated cis-1,2-diol.
Step A
Step B
1.0 eq H2O
1 M, NaOH
O
OH
O
O
+
60 °C
CHCl3, 40 °C
O
OH
C14H14O5
1.2 equiv.
(c) (15 points) Provide detailed a step-by-step electron pushing mechanism for Step A
and the structure of product in the box (the role of added water is critical).
(d) (5 Points) As shown below, peroxides 1–3 showed significantly different reaction
rates for their epoxidation. Provide any plausible explanation of this reactivity
difference.
1
2
3
3. (15 Points) For the total synthesis of an acetogenin class of natural product trilobaci, Kim and
coworkers utilized selenium ion induced transannular cyclization to form the required bistetrahydrofuran moiety as shown below (J. Am. Chem. Soc. 2010, 132, 12226). Provide a
reasonable reaction mechanism for this remarkable stereospecific process.
PhSe Ha
Hb
O
Hc
R1
O
Hd
PhSeCl, r.t.
R2
83%
Cl
Hd
R1
Hc
2
O
Hb Ha
O
R2
4. N-Heterocyclic carbene (NHC)-catalyzed reactions have emerged as powerful synthetic tools.
Among many variations, Lupton et al. described a rearrangement process of enolcinnamate for
the synthesis of dihydropyranone (J. Am. Chem. Soc. 2009, 131, 14176; Org. Lett. 2010, ASAP,
DOI: 10.1021/ol101983h).
Ar N
(10 mol%)
O
Ph
Cl
N Ar
O
KOtBu (20 mol%)
tol, reflux, 16h
O
Ph
O
86%
(a) (5 Points) Draw a typical form of N-heterocyclic carbene (NHC) involved in this reaction.
(b) (10 Points) Provide a detailed electron-pushing mechanism for the reaction above.
5. Sometimes unexpected structures show up in the literature, and you should be very careful
whether you believe them or not because they are not always correct. One of this example
appeared on recent issue of J. Am. Chem. Soc. (2010, 132, 12565). The authors refer the
mechanism for this transformation as “Formal” [4 + 2] cycloaddition. I was very surprised by
the structure and until I check the X-ray structure in the Supporting Information I was not
convinced with this structural assignment.
O
OEt
3 mol% LAuNTf2
OEt
O
Formal
OX
[4 + 2] Cycloaddition
OX
X=H
(10 Points) Indeed, the structure was correct but I still think that this is very unusual structure.
Explain why the product structure is unusual.
3
6. (10 Points) Xylopyranosyl isocyanide favors seemingly less stable conformation A over B. On
the other hand, the corresponding xylopyranosyl urea favors conformation D over C. Briefly
explain these conformational behaviors.
NC
OAc
O
OAc
O
AcO
AcO
NC
OAc
OAc
A ( 1C4 )
B ( 4C1 )
63 : 37
O
OAc HN
N
AcO
AcO
O
O
OAc
OAc
OAc
C ( 1C 4 )
D ( 4C1 )
15 : 85
4
H
N
N
O