Organic & Biomolecular Chemistry
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this enantiopure compound, a stated research goal of the
World Health Organisation, was recently reported via
different resolution starting from the racemate.12
a
Conclusions
The present approach extends the already-powerful CDC
methodology through the use of the PMP protecting group.
This modification preserves the high-yielding one-pot nature
of the coupling reaction, but allows for the downstream
elaboration of the CDC products. In the event that chiral,
enantioenriched amines are employed, it has been shown that
protecting group removal does not compromise the enantio-
meric excess of the CDC reaction product, as illustrated by a
new synthesis of enantioenriched praziquantel, an important
drug. Given the ease of protection and deprotection
involved in the use of the PMP group in CDC reactions, it is
expected that its adoption in preference to the phenyl group
will lead to a broader range of applications for CDC reactions
in synthesis.
Fig. 1 1H NMR spectrum of compound 6b, showing assignments of key
proton environments derived from 2D experiments and the unusual difference
in chemical shift of protons attached to carbon C3 (highlighted in green).
A sample of this novel 9-methyl PZQ analog was biologically
evaluated against adult schistosomes but was found to be in-
active (IC50 > 25 µg mL−1, ESI†). Though the sample is
obviously a mixture of four isomeric compounds, this result
implies that methylation at the 9-position is not tolerated,
adding to the literature on the high sensitivity of this com-
pound to structural change.11
The facile synthesis and handling of chiral primary amine
10a suggested this compound could be resolved, which would
broaden the usefulness of these CDC reaction products, par-
ticularly if the subsequent removal of the PMP group did not
epimerise the benzylic stereocentre. A search for a suitable
resolving agent began with a derivative of tartaric acid.12 To
navigate the multiple factors involved in optimising a resolu-
tion, a statistically-based Design of Experiments (DoE) protocol
was used.13 A Box–Behnken design was adopted as an efficient
method for a system in which it can be assumed that the
optimum result is within the experimental factor space defined
by the choice of variable extremes. The factors chosen in this
DoE search were concentration of amine (0.05 to 0.2 M wrt
amine), solvent ratio (1 : 1 to 6 : 1 isopropanol–water), time (6 to
24 h) and temperature (0 °C to rt). A three-level Box–Behnken
design (i.e., three different values for each variable) incorporat-
ing these factors was implemented (see ESI†) giving optimal
values (5 : 1 isopropanol–water, at temperatures between 12 and
20 °C for 24 h) for the resolution of compound 8.
Subjecting amine 10a to these resolution conditions gave
an enantioenrichment of 62% ee which could be increased to
95% ee by recrystallisation from minimal 8 : 1 isopropanol–
water. Pleasingly when this enantioenriched sampled was sub-
jected to the PMP removal no loss of enantiomeric excess was
observed. To date, literature examples of PMP amine deprotec-
tions on chiral substrates have suggested, but not conclusively
shown, retention of stereochemical integrity.14
Acknowledgements
We thank the Australian Research Council and the UNICEF/
UNDP/World Bank/WHO Special Programme for Research and
Training in Tropical Diseases (TDR) for funding (LP0883419),
and the Agnes Campbell Foundation and the Lamberton
Foundation as well as an Australian Postgraduate Scholarship
(to A. S.-K. T.).
Notes and references
‡Characterisation was in agreement with the literature.9
§The ratio was found to be 72 : 28 according to the integrals of peaks obtained
in the HPLC spectrum at 270 nm, suggesting that the diastereoisomers probably
have different extinction coefficients.
1 (a) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111,
1215–1292; (b) C. J. Scheuermann, Chem.–Asian J., 2010,
5, 436–451; (c) C.-J. Li, Acc. Chem. Res., 2009, 42, 335–
344.
2 (a) M. Ghobrial, M. Schnürch and M. D. Mihovilovic, J. Org.
Chem., 2011, 76, 8781–8793; (b) M. Ghobrial,
K. Harhammer, M. D. Mihovilovic and M. Schnürch, Chem.
Commun., 2010, 46, 8836–8838; (c) H. Richter and O. García
Mancheño, Eur. J. Org. Chem., 2010, 4460–4467;
(d) C. Dubs, Y. Hamashima, N. Sasamoto, T. M. Seidel,
S. Suzuki, D. Hashizume and M. Sodeoka, J. Org. Chem.,
2008, 73, 5859–5871; (e) N. Sasamoto, C. Dubs,
Y. Hamashima and M. Sodeoka, J. Am. Chem. Soc., 2006,
128, 14010–14011.
The amine could be taken through to enantiopure PZQ,
upon which it was found that the (S)-enantiomer had been
produced. This enantiomer is the undesirable, biologically
inactive enantiomer of the drug that is responsible for the
racemate’s bitter taste.15 Repetition of the procedure using
the antipode of the resolving agent allowed for the synthesis of
the active (R)-enantiomer of PZQ in 97% ee. The preparation of
3 A. S.-K. Tsang and M. H. Todd, Tetrahedron Lett., 2009, 50,
1199–1202.
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