Enantioselective Synthesis of Chiral-at-Sulfur 1,2-Benzothiazines by CpxRhIII-Catalyzed C?H Functionalization of Sulfoximines

Article abstract of DOI:10.1002/anie.201810887

Sulfoximines with stereogenic sulfur atoms are attractive structural motifs in drug discovery. A direct catalytic enantioselective method for the synthesis of sulfur-chiral 1,2-benzothiazines from readily accessible diaryl sulfoximines is presented. Rhodium(III) complexes equipped with chiral cyclopentadienyl ligands and paired with suitable carboxylic acid additives engage in an enantiodetermining C?H activation directed by the sulfoximine group. Subsequent trapping of the rhodacycle with a broad range of diazoketones gives access to S-chiral 1,2-benzothiazines with synthetically highly attractive substitution patterns in good yields and enantioselectivities.

Full text of DOI:10.1002/anie.201810887

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Accepted Article
Title: Enantioselective Access to S-Chiral 1,2-Benzothiazines by
CpxRh(III) Catalyzed C‒H Functionalization of Sulfoximines
Authors: Nicolai Cramer and Yang Sun
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810887
Angew. Chem. 10.1002/ange.201810887
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10.1002/anie.201810887
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Enantioselective Access to S-Chiral 1,2-Benzothiazines by
CpxRh(III)-Catalyzed C‒H Functionalization of Sulfoximines
Yang Sun[a] and Nicolai Cramer*[a]
Abstract: Sulfoximines with stereogenic sulfur atoms are attractive
structural motifs in drug discovery. A direct catalytic enantioselective
method accessing S-chiral 1,2-benzothiazines from readily
accessible diarylsulfoximines is presented. Rhodium(III) complexes
equipped with chiral cyclopentadienyl ligands and paired with
suitable carboxylic acid additives engage in an enantiodetermining
C-H activation directed by the sulfoximine group. Subsequent
trapping of the rhodacycle by a broad range of diazoketones gives
access to S-chiral 1,2-benzothiazines with synthetically highly
Recent synthetic advances have improved the access to
sulfoximines and have largely broadened its available structural
diversity.[11] In particular, Bolm and others demonstrated the
suitability of the sulfoximine moiety to as ortho-directing group
for Rh(III)-catalyzed C-H functionalizations.[12] However, the thin
arsenal of catalytic enantioselective methods to selectively
access optically pure sulfoximines remains a limiting factor.
Besides few approaches by kinetic resolution,[13] only multi-step
strategies focusing on stereoselective imidation or oxidation are
attractive substitution patterns in good yields and enantioselectivities. available.[14] Frequently, enantiopure chiral sulfoximines are
obtained by resolution techniques. Therefore, the development
of catalytic enantioselective sulfoximine syntheses remains a
Over the past decade, the sulfoximine class of compounds
relevant target for asymmetric catalysis.
received a steadily growing interest from the pharmaceutical and
Desymmetrization strategies by the selective C-H
agrochemical industry.[1] Sulfoxmines have a high chemical
functionalization of one C(sp2)-H bond of enantiotopic aryl
stability and can provide several strategic advantages over the
groups have been successfully implemented for the generation
corresponding and ubiquitous sulfone and sulfonamide
of stereogenic carbon atoms (Scheme 1).[15, 16] Examples using
derivatives.[2] Besides the acyclic sulfoximine motif, examplified
this concept to create stereogenic phosphorus[17] or silicon
by roniciclib,[3] ceralasertib,[4] and sulfoxaflor,[5] rigid cyclic
atoms[18] are more scarce. Related methods to access chiral
benzannulated sulfoximine scaffolds such as Lilly’s prazosin
sulfur atomsare to best of our knowledge elusive except a single
analogue,[6] Gö 4962[7] and NSC 287474[8] have recently gained
example for chiral sulfoxides reported by Wang.[19] On the basis
attention. Despite these examples, 1,2,4-benzothiadiazine and
of our findings of creating P-chirality with chiral cyclopentadienyl
1,2-benzothiazines are still underrepresented heterocyclic
(Cpx) rhodium and iridium catalysts, compounds,[17f,h,j] we
scaffolds with significant upside potential for the discovery of
explored the suitability of these for the generation of chiral sulfur
compounds with potential medical applications. A characteristic
atoms of sulfoximines. Herein, we report an asymmetric
annulative C–H functionalization approach of sulfoximines 1
providing an efficient access to S-chiral 1,2-benzothiazines 3.
trait of sulfoximines is their stereogenic sulfur atom.[9] Embedded
in a rigid cyclic structure, this provides the additional benefit of a
directed and functionalizable exit vector.[10]
Scheme 1. Enantioselective C–H functionalization strategies for the creation
of stereogenic carbon, phosphorus and sulfur atoms by desymmetrization.
Figure 1. Biologically active molecules with a sulfoximine functionality.
DG=directing group.
[a]
Y. Sun, Prof. Dr. N. Cramer
The envisaged functionalization / cyclization sequence was
Laboratory of Asymmetric Catalysis and Synthesis
EPFL SB ISIC LCSA, BCH 4305
CH-1015 Lausanne (Switzerland)
E-mail: nicolai.cramer@epfl.ch
investigated and optimized with diphenyl sulfoximine (1a) and
ethyl diazo acetylacetate (2a) as the prototype substrate
combination (Table 1). First, our most general chiral Cpx
ligands[20] were surveyed (Entries 1-7). Under the initial
Homepage: http://isic.epfl.ch/lcsa
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201810887
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conditions (toluene at 100 °C), disubstituted version Rh1-Rh3
gave modest selectivities and yields (Entries 1-3). Fully
pentasubstituted versions Rh4 resulted in an increased yield
(Entry 4). Complexes having trisubstituted Cpx ligands were
directly used at the +III-oxidation state (Entries 5 and 6). Rh5
provided with sodium benzoate as additive 3aa in 80:20 e.r. and
78 % yield at 50 °C (Entry 5). Notably, the trisubstituted ligands
led to the opposite major enantiomer compared to the di- and
pentasubstituted congeners. Moreover, the transformation was
found to be sensitive to the carboxylic acid / carboxylate additive
(Entries 7-14). A brief evaluation showed that tert-leucine
derived acid A4[17h] performed best and gave 3aa in 95 % yield
with 87.5:12.5 e.r. in the matching combination (Entry 13). The
mismatched enantiomer A5 was less efficient, but still gave the
same major enantiomer of 3aa (Entry 14). Switching the solvent
from toluene to tBuOH allowed for a reaction temperature of
35 °C and additionally increased the enantioselectivity of 3aa to
95.5:4.5 (Entries 15-16). The added K3PO4 can be omitted by
increasing the acid additive from 5 to 30 mol%. The use of TFE
caused a significant reduction in the enantioselectivity which
dropped to 70:30 e.r. (Entry 17). Notably, HFIP was found to
have an even more profound effect on the selectivity, giving the
opposite enantiomer of 3aa majorly with 28.5:71.5 e.r. (Entries
18, 19). The very high sensitivity of the enantioselectivity in this
transformation towards external effects like solvents and
additives besides the direct influence of the chiral Cpx ligands
opens opportunities but poses as well some caution flags in
terms of robustness.
10
11
12
13
14
Rh5
Rh5
Rh5
Rh5
Rh5
A1
A2
A3
A4
A5
A4
A4[j]
A4
A4
A4
toluene
toluene
toluene
toluene
toluene
tBuOH
tBuOH
TFE
50
50
50
50
50
35
35
35
35
35
89
88
80.5:19.5
81:19
75
87:13
95
87.5:12.5
71.5:28.5
95.5:4.5
96:4
82
15[e,f] Rh5
16[h,i] Rh5
17[e,i] Rh5
18[e,i] Rh5
19[i] Rh5
99 (92)[g]
92[g]
95
70:30
HFIP
94
28.5:71.5
32.5:67.5
HFIP
85
[a] Conditions: 0.05 mmol 1a, 0.05 mmol 2a, 5 mol% Rh (2.5 mol% dimer), 5
mol% additive, 50 mol% NaSbF6, 0.2 M in solvent. [b] Determined by 1H-NMR
with an internal standard. [c] Determined by HPLC with a chiral stationary
phase. [d] for 6 h. [e] with 50 mol% K3PO4. [f] for 48 h. [g] isolated yield. [h]
0.1 mmol scale. [i] for 30 h. [j] with 30 mol% A4. TFE=2,2,2-trifluoroethanol;
HFIP=hexafluoroisopropanol.
We next investigated the scope of the developed
transformation (Scheme 2). A variety of para-substituted diary
sulfoximines 1 underwent efficient C–H functionalization and
allowed for the synthesis of annulated sulfoximines 3 in a highly
enantioselective fashion. Substrates with either electron-
donating groups (1b) or those with electron-withdrawing groups
(1c-1f) reacted well and gave the corresponding cyclized
products 3 in excellent yields and good enantioselectivities.
Table 1. Optimization of the enantiotopic functionalization of sulfoximine 1a.[a]
Entry Rh
Additive
(BzO)2
(BzO)2
(BzO)2
(BzO)2
NaOBz
NaOBz
HOBz
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
T [° C]
100
100
100
100
50
yield [%][b]
e.r.[c]
1[d]
2[d]
3[d]
4[d]
5
Rh1
75
35
48
99
78
14
93
99
87
54:46
23:77
24:76
35:65
80:20
81:19
78:22
74:26
61:39
Rh2
Rh3
Rh4
Rh5
Rh6
Rh5
Rh5
Rh5
6
50
7
50
Scheme 2. Scope of the sulfoximine substrates. Conditions: 0.1 mmol 1, 0.1
mmol 2a, 2.5 μmol Rh5, 30 μmol A4, 50 μmol NaSbF6, 0.2 M in tBuOH at
35 °C for 30-72 h.
8
NaOAc
NaOPiv
50
9
50
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Sulfoximine substrates with meta-substituted aryl groups
underwent selective functionalization at the more accessible
ortho C-H group and gave product 3ga and 3ha. Ortho-
substitution does not compromise the yield but influences the
selectivity and caused a reduction in e.r. of 3ia. Besides R2
being the standard ethyl ester, benzyl ester bearing diazo
compound 1b reacts equally well, allowing to determine the
absolute configuration by X-ray crystallography[21] (Scheme 3). A
ten-fold increase in scale resulted in 83 % yield 94:6 e.r.
Replacing the ester by a phosphonate gave cyclized product
3ac. A p-tosyl group reacted in high yields and selectivities at
60 °C (3ad). While the enantioselectivity is somewhat lower, the
obtained particular substitution pattern is synthetically attractive.
The substituent R1 offers a broad variability. For instance, alkyl
groups, a cyclopropyl unit (3al), aromatic and heteroaromatic
moieties (3ah-3ak) as well as a styryl unit (3ae) can be used for
the cyclization with very little influence on the reaction outcome.
Uniformly, high yields and selectivities are obtained. The
reaction with diazo ethyl formyl acetate (R1=H) gives rise to 3af
with a free 3-position at the ring. Notably, besides the described
acceptor/acceptor substituted diazo species, diazo ketones
without an additional electron-withdrawing group participated
very well in the enantioselective annulation. For instance, diazo
ketones having aryl or benzyl groups as the R2 substituent can
be used. These provide cyclized product 3am, 3an and 3ao in
good yields and selectivities. Moreover, diazoacetophenone
(R2=H) gives rise to 3ap with a free 4-position at the ring.
observed the formation of products 5 and 6 in virtually the same
yield. The observed enantiomeric ratios were for 93.5:6.5 for the
phenyl functionalization and 90:10 for the p-tolyl activation,
indicating a smooth parallel kinetic resolution.
Scheme 4. Parallel kinetic resolution of racemic diaryl sulfoximine rac-4.
Mechanistically, the transformation very likely proceeds by the
pathway proposed by Bolm for the corresponding achiral
reaction (Scheme 5).[12b] Coordination of the sulfoximine to the
RhIII center initiates ortho-C-H activation by
a concerted
metalation deprotonation.[22] Coordination of the diazo species
leads to formation of carbenoid intermediate D, which in turn
undergoes subsequent insertion and protonation to produce
ketone E. An off-cycle cyclocondensation delivers 1,2-
benzothiazine 3. However, the mechanism of the
enantioselection remains a complex question with several
interplaying variables. Theoretically, for transformations with a
trapping step after the enantiodetermining step (A→B), the
observed enantioselectivities of the products 3 should be
completely independent of the intercepting reagent, unless the
enantiodetermining step has some reversible character. Indeed,
most used diazo compounds are very reactive interceptors and
react fast enough so that the potential reversibility of the C-H
activation by the CMD-pathway becomes rather negligible.
However, the lower selectivity of difficult diazo compounds such
as phosphonate 2c and ketone 2g implicates reversibility which
can become an issue for the development of related
transformations with less reactive trapping agents. The
pronounced responsiveness of the enantioselectivity towards
solvents and especially the solvent may be linked to a potential
ambiguity in the catalyst-substrate binding and orientation. The
initial coordination of the rhodium to the free sulfoximine
directing group classically suggested[12a] to occur via its
deprotonated nitrogen atom (A1). However, depending on the
reaction conditions, the metal center may alternatively initiate
cyclometalation from a coordination of the oxygen atom as for
A3 (or the non-deprotonated NH-group, A2). Mono-cationic Cp*
metal complexes of group 9 metals with a single carboxylate
were found to be typically most suited for non-deprotonatable
directing groups (A3-mode) whereas neutral bis-carboxylate
bound congeners are superior for deprotonable directing groups
(A1-mode). With all other factors constant, a switch from N- to
O-coordination would result in an inversion of the attacked
enantiotopic aryl group (C2) and consequently lead to ent-3. The
exact catalyst binding and enantioselection warrants further
detailed computational studies which could provide valuable
insights for the development of related transformations.
Scheme 3. Scope of the diazo compounds in the sulfoximine functionalization.
Conditions: 0.1 mmol 1a, 0.1 mmol 2, 2.5 μmol Rh5, 30 μmol A4, 50 μmol
NaSbF6, 0.2 M in tBuOH at 35 °C for 24-72 h.
A parallel kinetic resolution of racemic sulfoximines bearing two
different aromatic groups was attempted next (Scheme 4).
Substrate 4 having a minimal steric and electronic bias, we
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Scheme 5. Suggested mechanism and their potentially critical steps for the
enantioselectivity.
In conclusion, we have developed an enantiotopic C-H
functionalization of sulfoximines resulting in a stereogenic sulfur
atom. The enantio-determining activation step is enabled by a
combination of a Rh(III) complex bearing a chiral Cpx ligand.
Carboxylic acid additives were found to have a profound effect
on the selectivity. A matching chiral carboxylic acid additive
interacts synergistically and enhances the selectivity. The
transformation proceeds with high enantioselectivity for
a
diverse range of sulfoximines. broad range of diazo
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This work is supported by the Swiss National Science
Foundation (no 157741).
Keywords: Asymmetric Catalysis • C‒H Activation • Chiral
Cyclopentadienyl • Sulfoximine • Rhodium
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This article is protected by copyright. All rights reserved.

10.1002/anie.201810887
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Yang Sun, Nicolai Cramer*
Page No. – Page No.
Enantioselective Access to S-Chiral
1,2-Benzothiazines by CpxRh(III)
Catalyzed C‒H Functionalization of
Sulfoximines
Sulfoximines with stereogenic sulfur atoms are attractive structural motifs in drug
discovery.
A
catalytic enantioselective method accessing S-chiral 1,2-
benzothiazines is reported. CpxRhIII catalysts paired with suitable carboxylic acid
additives engage in enantiodetermining C-H activation. Trapping of the rhodacycle
by a broad range of diazoketones yields S-chiral 1,2-benzothiazines with
synthetically highly attractive substitution patterns in good yields and
enantioselectivities.
This article is protected by copyright. All rights reserved.