Note
DOI: 10.1002/bkcs.11026
BULLETIN OF THE
N. Lee et al.
KOREAN CHEMICAL SOCIETY
Extending the Synthetic Utilities of the Tandem Cyclic Sulfate
Rearrangement—Opening Process: Synthesis of β-Hydroxy-γ-phenyl-
γ-lactam
*
Nagum Lee, Min Lee Yu, Hyeyeon Jun, and Soo Y. Ko
Department of Chemistry, Ewha Womans University, Seoul 120-750, Korea.
*E-mail: sooyko@ewha.ac.kr
Received October 18, 2016, Accepted November 2, 2016, Published online December 1, 2016
Keywords: γ-lactam, Tandem reaction, Cyclic sulfate rearrangement, Opening
The phenylpropyl skeleton, with O- and/or N-substituents
therefore, one obtains anti-diastereomeric products after the
at each of the three alkyl carbons, is a common structural
feature often found in many bioactive compounds, particu-
larly among those acting on the central nervous system.1
The structural motif may be further derivatized to cyclic
analogs, such as lactones, lactams, oxazolidinones, etc.,
which may find further uses as chiral ligands and
auxiliaries.2
syn-dihydroxylation followed by the tandem process.
Another noteworthy aspect of the process is its environ-
ment friendliness. The simultaneous activations of the C-1/
C-2 diol allows the successive substitutions at C-3 and C-1
(step- and atom-economy), and the tandem process, all
together five steps of reactions, may be executed in a one-
pot operation (pot-economy), lowering the E (environment)
factor (kg waste per kg product).4 So far, we have managed
to employ this tandem process to incorporate O-, O-, N- or
N-, O-, N- heteroatoms at C-1,2,3 of the phenylpropyl skel-
eton, respectively.3
In order to expand the synthetic utility of the tandem
process, we set out to widen the pool of the nucleophiles to
be incorporated at C-3 and C-1. We were particularly keen
on bringing ¯CN into the pool as the one-carbon extension
accomplished by a CN-substitution would lead to a carbon
framework, which is amenable for further transformations.
The synthetic utility of the tandem process would then
stretch far beyond what have previously been accessible via
heteroatom-only substitutions.
Cinnamyl alcohol is an obvious choice of starting mate-
rial that provides the carbon framework for the syntheses of
these compounds. Stereoselective oxidations (epoxidation
or dihydroxylation) pave the way for the introductions of
O-/N-substituents. Issues of regioselections need to be dealt
with in these transformation, which may be tackled either
in the activation steps, in the substitution steps, or in the
protection steps. Issues of diastereoselections (the syn-/anti-
problems) are another matter as they are dependent upon
the cis/trans geometry of the starting cinnamyl alcohol,
which also has bearings on the enantioselectivity if one
chooses to employ the asymmetric oxidation reactions.
Our interests in this area have resulted in a synthetic
pathway in which the key steps include a tandem cyclic
sulfate rearrangement—epoxide opening and another tan-
dem epoxide ring closure—epoxide opening processes
(Scheme 1).3 The starting material (2) is obtained via dihy-
droxylation of an O-silyl protected cinnamyl alcohol. The
two hydroxyl groups at C-1 and C-2 are simultaneously
activated in a single operation to the cyclic sulfate (3).
The silyl-deprotection triggers the first tandem process,
which transposes the activation to C-3, allowing a nucleo-
philic substitution there (3 ! 4 ! 5 ! 6). The second
tandem process gets initiated with an epoxide ring closure,
which allows a second nucleophilic substitution at C-1
(6 ! 7 ! 8). The simultaneous activations of the C-1/C-2
diol in the form of the cyclic sulfate followed by a series of
tandem process transposing the activations first to C-3, then
to C-1 in succession enable regioselective substitutions. As
for the issues of diastereoselections, the configuration at C-2
is inverted and that at C-1 retained through a double inver-
sion in the process. Starting with trans-cinnamyl alcohol,
The first part of the key tandem process (3 ! 6, Scheme
1) is adopted from the cyclic sulfate rearrangement—
5
opening process that we studied earlier, which may be
regarded as a cyclic sulfate-version of the Payne rearrange-
ment.6 In the original work, a fairly wide variety of the
nucleophiles, including ¯CN, were shown to be effective in
the substitutions at C-3. With slight modifications on the
original procedure to use just one equivalent of ¯CN, we
incorporated the one-carbon nucleophile at C-3. An NMR
monitoring (with an internal standard for quantification)
indicated the first part of the tandem process proceeded
well to give the intermediate (6a). We then moved to the
second part of the tandem process (epoxide ring closure—
epoxide opening). Initially, we used the isolated (but not
purified) intermediate, leaving the one-pot procedure to be
worked out later.
When the intermediate (6a) was subjected to the usual
procedure for the second part of the tandem process (¯N3 as
Nu2, ¯OH in aqueous THF), the desired azidonitrile
Bull. Korean Chem. Soc. 2016, Vol. 37, 2091–2093
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library 2091