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performed on each substrate. However, this was outside of the
scope of our investigation, therefore we tested the best condi-
tions for the model substrate to evaluate their applicability to
rac-1b–g.
In the presence of catalyst IV, the chiral electron-rich p-me-
thoxyphenyl and the electron-poor p-chlorophenyl substituted
oxazinones 1b and 1c were obtained with excellent enantio-
meric excess, and the corresponding chiral esters 3b and 3c
were obtained with 90 and 80% ee, respectively (Table 8, en-
tries 1 and 2).
into consideration that the selectivity factor decreases slightly
(S factor: 45 (entry 2) vs. 41 (entry 3)). This first DoE (entry 3)
served as preliminary campaign to gain insights into the condi-
tions of the reaction. This information was then analysed and
exploited to design the second DoE (entry 4), which allowed
a remarkable S factor of 98 to be achieved, thus facilitating
this kinetic resolution (53% conversion, 1a: 99.6% ee; 3a:
88% ee).
Conclusion
The presence of a bromine atom in the meta-position of the
aromatic ring affected both the enantioselectivity and the reac-
tion rate (Table 8, entries 3 and 4). Sterically more demanding
aliphatic iso-propyl and tert-butyl residues influenced the effi-
ciency of the squaramide catalyst IV; after 24 and 18 h, oxazi-
nones (S)-1e–f could be obtained with only 66 and 72% ee, re-
spectively (entries 5 and 6). The enantiomeric excess of the
corresponding esters were respectively 89 and 81%. Moderate
results were obtained in the kinetic resolution of iso-butyl oxa-
zinone rac-1g in the presence of squaramide-derived catalyst
IV (entry 7). A short screening showed that better results can
be achieved by using catalyst V and working with a 0.4m solu-
tion. With the new conditions, oxazinones (S)-1e–f could be
obtained with 99 and 92% ee, respectively, after 27 and 48 h.
Esters (R)-3e–f were obtained in 83 and 90% ee, respectively
(entries 8 and 9).
The optimisation of the kinetic resolution of rac-1a was per-
formed by applying two rational screening designs on four cat-
alysts and five solvents and other variables (catalyst loading,
solution concentration, equivalents of nucleophile 2 and tem-
perature). The first screening design allowed the identification
of two catalysts and two possible solvents as the most promis-
ing conditions to yield simultaneously both the starting materi-
al 1a and the allyl ester product 3a with the highest enantio-
meric excess. The second screening (DSD design) allowed the
optimised reaction conditions to be established, reaching
99.6% ee for oxazinone (S)-1a and 88% ee for the product (R)-
3a at 53% conversion (catalyst IV selectivity factor S=98). The
reaction was performed on 1 gram scale of starting-material
without the need for a glove-box. We also confirmed that the
established conditions could be a good starting point for the
kinetic resolution of a number of substituted oxazinones rac-
1b–g.
It was shown, using a previously reported kinetic resolution
as a model reaction, that a rational approach such as DoE, can
be a powerful tool with which to optimise asymmetric reac-
tions. Statistic treatment should also be encouraged for adop-
tion by organic chemists in academia. Carlson and Carlson
stated that “statistics is always secondary to chemistry in the
domain of organic synthesis. It does not matter how statistical-
ly significant an analysis turns out to be if the chemistry does
not afford the desired results. Therefore, any conclusion from
a model must be confirmed by an experiment.”[19]
Table 9 compares the results obtained by following the dif-
ferent approaches. A comparison between entry 1 (results
from Berkessel et al.,[9] for which first-generation chiral thiour-
eas were employed) and the best results from Table 1 (for
which second-generation Cinchona alkaloid-derived bifunction-
al thioureas were employed) showed that the second-genera-
tion chiral thioureas were superior (S factor: 45 (entry 2) vs. 35
(entry 1)). The first DoE experiment (reported in the Supporting
Information) served as an “information gathering” process. The
enantiomeric excess of chiral products 1a–3a are apparently
much better with respect to Table 1, but it should be taken
Table 9. Comparison of the results for the various approaches towards
the kinetic resolution of racemic 2,4-diphenyl-4,5-dihydro-1,3-oxazin-6-
one rac-1a to give allyl ester 3a.
Acknowledgements
Entry[a] Method
ee 1a ee
Conv. S[d]
M.B. acknowledges financial contribution for this work from
“Progetto di Ateneo 2011–2013”, Sapienza Universitꢄ di Roma,
and Chiesa Valdese Italiana, ottopermillevaldese.org. Support
from COST action ORCA (ORganoCAtalysis) 0905 is gratefully
acknowledged.
[%][b] 3a [%][c]
[%][b]
1
2
previous results (ref. [9])
preliminary catalyst screening results
(Table 1)
99 86
88 88
57
50
35
45
3
4
first DoE experiment: custom design
(see the Supporting Information)
definitive screening design (Table 6)
>99 79
56
53
41
98
Keywords: design of experiments
organocatalysis · squaramides · thioureas
· kinetic resolution ·
99.6 88
[a] Reaction conditions: see the Supporting Information and ref. [9]
[b] Enantiomeric excess was determined by HPLC analysis on a chiral sta-
tionary phase. [c] The conversion was determined by HPLC analysis on
a chiral stationary phase by comparison with the peak areas of stock sol-
utions of the oxazinone rac-1a in toluene. Quantification was based on
UV detection at l=230 nm. [d] Selectivity factor defined by the Kagan
equation assuming first-order reaction and neglecting possible nonlinear
effects: S factor=ln[(1ꢀC)(1ꢀeestarting material)]/ln[(1ꢀC)(1+eestarting material)].[2f]
´
Weiner, W. Szymanski, D. B. Janssen, A. Minnaard, B. L. Feringa, Chem.
[2] For reviews on kinetic resolution, see: a) C. E. Mꢀller, P. R. Schreiner,
Chem. Eur. J. 2014, 20, 1 – 9
7
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