Journal of the American Chemical Society
Article
methyl substituent prevents the optimal orientation of the
reacting N atom in the transition state. Several other types of
substrates engage in slower but still highly enantioselective
reactions. For example, substrates 2k (lacking any additional
electron-donating substituents) and 2l (with 6-phenyl
substitution) each lead to product isolation with 96:4 er, but
with yields of 34% and 32%, respectively. In order to establish
the absolute configuration of the product, we crystallized 2k
for X-ray analysis (see Supporting Information, page 62). The
crystal structure reveals the (S)-absolute stereochemistry of 2k.
Several limitations of the system at its current level of
development are that substrates with electron-withdrawing
substituents at the 6-position, such as CF3 (1m) and F (1n),
do not afford the desired N-oxidation product. A 6-methoxy-
substitution, which might be viewed as an electron-donating
group, was also not explored extensively due to its potential for
inductively electron-withdrawing effects.10 The distance
between the reactive N-atom and the S-center is also critical.
For example, the 4,4′-dipyridyl substrate gave 2p in 23% yield
with 55:45 er; 2,2′-dipyridyl substrate provided 2q in 4% yield
and 65:35 er. Interestingly, substrates 1r and 1s, each with
rather extreme dislocation of the N-atom from the pro-
stereogenic S-atom reacted smoothly and still exhibited
nonzero levels enantiocontrol. Compound 2t, testing the
same question through insertion of an extra methylene unit
between the pyridine ring and the sulfoximine, also gives an
encouraging result, as the product is now observed with a
72:28 er (67% isolated yield). Notably, this spacing of
functional groups in substrate 2t bears analogy to that in
sulfoxaflor (Figure 1D).
the bis-pyridyl-amide,10 the urea N−H of conformer 1k−a
could H-bond with the carbonyl of the proline residue of P9,14
while this peptide resides in a type-II′ β-hairpin conforma-
tion14b to favor the (R)-product of 2k (Figure 3b, I and II).
However, with a methyl amide instead of a methyl ester C-
terminus, an additional H-bond can be formed between the O-
atom of conformer 1k−b and the C-terminal N−H of P11 to
favor the (S)-2k in higher enantiocontrol (Figure 3b, III).
We also tested the kinetic resolution of substrates containing
only a single pyridyl moiety as mechanistic probes, such as
sulfoximines like 4 (Figure 4). Interestingly, the methyl- (4a)
On the basis of the catalyst optimization and scope
investigations described above, we were interested in a better
understanding of the basis of the high enantioselectivity,
including the reversed enantiocontrol observed when using
either a methyl ester vs methyl amide at the C-terminal
position of the catalyst. The crystal structure of 2k shows two
stable conformations within the unit cell (2k−a and 2k−b),
consisting of a vertical pyridine or pyridine N-oxide ring and a
horizontal pyridyl-sulfoximine plane (Figure 3a). Accordingly,
substrate 1k could also adopt either of these two conformers
(1k−a and 1k−b), which likely interconvert rapidly under
reaction conditions. Similar to the proposed binding model for
Figure 4. (A) Kinetic resolution of sulfoximines. 1 (0.2 mmol), P19
(10 mol %), H2O2 (1.0 equiv), DIC (0.5 equiv), CHCl3 (1.0 mL, 0.2
M), 4°C cold room, 2 days, isolated yield, er was determined by chiral
HPLC. (B) A parallel kinetic resolution. Three day reaction time,
combined isolated yield of 5da and 5db, ratio was determined by 1H
NMR.
and phenyl-bearing (4b) sulfoximines gave the product in only
modest enantioselectivity (Figure 4). Considering the poor
reactivity of electron deficient pyridines in this system, we also
attempted the kinetic resolution of unsymmetric bis-pyridyl
substrate 4c to deliver the unsymmetrical sulfoximines (5c). As
expected, 6-Me-pyridine N-oxidized product 5c was obtained
in excellent site-selectivity (only one site-isomer was
observed), with appreciable enantioselectivity (84:16 er).
This observation is in accord with our mechanistic speculation,
and this method can be applied in the asymmetric site-selective
oxidation of the pyridine rings with different electron density.
The X-ray structure of the enantio-enriched 4c shows that the
absolute configuration of 5c is in accord with that observed for
2k.
Of particular note is the possible applicability of our
approach to a combined enantioselective/site-selective prep-
aration of chiral sulfoximines in scaffolds that are particularly
heterocycle rich, containing more than one sp2-hybridized N
atom. Accordingly, we examined substrate 4d, bearing both a
pyridine ring and a quinoline ring, in a parallel kinetic
Figure 3. Speculative and heuristic model for the reversed
enantiomeric outcome using P9 vs P11.
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J. Am. Chem. Soc. 2021, 143, 9230−9235