Synthesis of Highly Enantioenriched Sulfonimidoyl Fluorides and Sulfonimidamides by Stereospecific Sulfur–Fluorine Exchange (SuFEx) Reaction

Article abstract of DOI:10.1002/chem.202002265

Sulfonimidamides present exciting opportunities as chiral isosteres of sulfonamides, with potential for additional directional interactions. Here, we present the first modular enantioselective synthesis of sulfonimidamides, including the first stereoselective synthesis of enantioenriched sulfonimidoyl fluorides, and studies on their reactivity. A new route to sulfonimidoyl fluorides is presented from solid bench-stable, N-Boc-sulfinamide (Boc=tert-butyloxycarbonyl) salt building blocks. Enantioenriched arylsulfonimidoyl fluorides are shown to be readily racemised by fluoride ions. Conditions are developed, which trap fluoride and enable the stereospecific reaction of sulfonimidoyl fluorides with primary and secondary amines (100 % es, es=enantiospecificity) generating sulfonimidamides with up to 99 % ee. Aryl and alkyl sulfonimidoyl fluoride reagents are suitable for mild late stage functionalisation reactions, exemplified by coupling with a selection of complex amines in marketed drugs.

Full text of DOI:10.1002/chem.202002265

Accepted Article
Accepted Article
Title: Synthesis of Highly Enantioenriched Sulfonimidoyl Fluorides and
Sulfonimidamides by Stereospecific SuFEx Reaction
Authors: Stephanie Greed, Edward L. Briggs, Fahima I. M. Idiris,
Andrew J. P. White, Ulrich Lücking, and James Adam Bull
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202002265
Link to VoR: https://doi.org/10.1002/chem.202002265
01/2020

10.1002/chem.202002265
Chemistry - A European Journal
COMMUNICATION
Synthesis of Highly Enantioenriched Sulfonimidoyl Fluorides and
Sulfonimidamides by Stereospecific SuFEx Reaction
Stephanie Greed,[a] Edward L. Briggs,[a] Fahima I. M. Idiris,[a] Andrew J. P. White,[a] Ulrich Lücking[b] and
James A. Bull*[a]
[a]
S. Greed, E. L. Briggs, Dr F. I. M. Idiris and Dr J. A. Bull
Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London W12 0BZ, UK
E-mail: j.bull@imperial.ac.uk
Homepage: http://www3.imperial.ac.uk/people/j.bull
Dr U. Lücking
[b]
Bayer AG, Pharmaceuticals Division, Drug Discovery, Müllerstr. 178, 13353 Berlin, Germany.
Supporting information for this article is given via a link at the end of the document.
Abstract: Sulfonimidamides present exciting opportunities as chiral
isosteres of sulfonamides, with potential for additional directional
interactions. Here we present the first modular enantioselective
synthesis of sulfonimidamides, including the first stereoselective
synthesis of enantioenriched sulfonimidoyl fluorides, and studies on
their reactivity. A new route to sulfonimidoyl fluorides is presented
from solid bench-stable, NBoc-sulfinamide salt building blocks.
Enantioenriched arylsulfonimidoyl fluorides are shown to be readily
racemized by fluoride ions. Conditions are developed which trap
fluoride, and enable the stereospecific reaction of sulfonimidoyl
fluorides with primary and secondary amines (100% es) generating
sulfonimidamides with up to 99% ee. Aryl and alkyl sulfonimidoyl
fluoride reagents are suitable for mild late stage functionalization
reactions, exemplified by coupling with a selection of complex amines
in marketed drugs.
S(VI) Aza-analogues
a) S(VI) Aza-analogues introduce of a new chiral sulfur centre
O
O
O
N
O
O
O
N
S
S
S
S
N
N
Sulfone
Sulfoximine
Sulfonimidamide
Sulfonamide
b) New S(VI) clinical candidates
O
NH
S
F3C
O
N
(R)
HO
N
N
O
N
N
H
Roniciclib
pan-CDK Inhibitor
HN
O
F
NH
N
N
S
(R)
O
S
(S)
NH
N
N
N
H
Ceralasertib
ATR Kinase Inhibitor
F
OMe
BAY1251152
PTEF-b/CDK9 Inhibitor
c) Routes to sulfonimidamides with substitution at sulfur
oxidative
imidation
O
O
N
S
S
OBt
Bolm
Mukaiyama
1965
Cl
Directional interactions are crucial to the development of active
ingredients in pharmaceutical and agrochemical products.
Inclusion of chiral moieties can increase complementarity and
hence potency and selectivity of a compound for a biological
target.[1] In contrast to sulfones and sulfonamides, their chiral aza-
analogues, sulfoximines and sulfonimidamides (Fig 1a), have
been underrepresented in the life sciences despite their beneficial
chemical properties.[2,3] They have high chemical and metabolic
stability, and can improve physicochemical properties of a
molecule, such as increased solubility, with the introduction of
both hydrogen bond donor and acceptor capabilities for NH-
derivatives.[4,5] It is notable that sulfoximines have appeared in
several new S(VI) clinical candidates as single enantiomers (Fig
1b).[6,7,8] Sulfonimidamides are less developed in drug discovery,
but present similar potential advantages.[9] However, to date there
are no general methods available to prepare these in
enantioenriched form.
oxidative
chlorination
O
S
2019
N
Johnson
1979
O
N
O
S
N
amine coupling
S
N
Cl
O
O
deoxychlorination
S
Sulfonimidoyl Chloride
susceptible to hydrolysis
and decomposition
N
Chen
2015
Grignard reaction
and chlorination
Grygorenko
2019
O
N
OTf
O
N
S
Tr
S
N
Willis
2017
N
d) Sulfonimidoyl fluorides as sulfonimidamide precursors
coupling with
O
N
N
SuFEx
O
N
O
SOF4
S
S
S
Sharpless
2018
pyrrolidine or
deprotonated amines
N
F
F
F
e) This route
electrophilic
fluorination
O
S
O
S
N
O
S
N
amine coupling
NBoc
Na
F
N
new route to sulfonimidoyl fluorides
full retention of ee at both steps
reaction with unactivated amines
36 examples
high ee and yields up to 96%
late stage functionalisation
Similarly, sulfonyl fluorides have been developed by
Sharpless as click reagents in sulfur-fluorine exchange (SuFEx)
reactions, and are used increasingly as biological probes.[10,11] To
date, application of the chiral sulfonimidoyl fluoride derivatives as
biological probes is limited,[10a,11c] but presents interesting
potential for improved specific directional interactions.
Figure 1. Structure of sulfoximine and sulfonimidamide groups and S(VI) clinical
candidates with asymmetric sulfur centres. Synthetic routes to access
sulfonimidamides typically rely on sulfonimidoyl chloride precursors, alternative
sulfonimidoyl-X species, and this work as a new way to access enantioenriched
sulfonimidoyl fluorides and sulfonimidamides.
Methods for the synthesis of sulfonimidamides have
developed significantly in recent years including powerful NH
transfer methods.[12] A valuable disconnection for divergent
synthesis is formation of the S–N bond, by coupling an
electrophilic S-source with amines.[13,14] Several methods proceed
via the sulfonimidoyl chloride, including recent powerful methods
developed by Chen[15] and Willis (Fig 1c).[16] However,
1
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10.1002/chem.202002265
Chemistry - A European Journal
COMMUNICATION
a) Route to racemic sulfonimidamides via sulfonimidoyl fluoride
sulfonimidoyl chlorides are typically unstable and decompose
under basic, aqueous or reductive conditions, requiring in situ
generation and amine coupling.[5] Alternative sulfonimidoyl
reagents have been developed as more stable sulfonimidamide
precursors.[17-19] Sharpless has used SOF4 gas to generate stable
N-aryl sulfonimidoyl fluoride reagents which were reacted with
pyrrolidine or lithium amide reagents (Fig 1d).[20] It is notable that
none of the methods described to date have been amenable to
the preparation of enantioenriched derivatives.[21]
Procedure B
NEt3
piperidine
O
S
Procedure A
Selectfluor
O
S
NBoc
F
O
NBoc
N
S
NBoc
Na
THF
80 ºC, 24 h
77%
DMF
0 ºC to rt, 24 h
98%
2a
3a
1a
b) Using enantioenriched starting material
Fluorination
Amine coupling
(S)-1a
(R)-2a
(R)-3a
8% ee
>99% ee
81% ee
racemization
observed
near complete
racemization
d) Hypothesis: racemization from nucleophilic
attack of fluoride ion on sulfonimidoyl fluoride
c) Loss of ee with reaction progress
Enantioenriched sulfonimidoyl fluorides have been unknown
until very recently. Zuilhof isolated the first example of an
enantioenriched sulfonimidoyl fluoride, generated by the reaction
of a racemic sulfonimidoyl chloride with KF, followed by
separation of the enantiomers by chiral HPLC.[22] Notably these
reagents reacted with phenols in the presence of DBU, without
requiring silylation, but underwent racemisation ascribed to the
base. Using sodium phenolate provided enantioenriched
sulfonimidates in a rapid reaction.
O
NBoc
O
NBoc
F
S
S
Ar
Ar
F
F
O
NBoc
F
F
(R)-2a
S
Ar
fluoride ion retained ee
entry
source
of (R)-2a (%)
1
2
3
-
93
0
99
TBAF
KF
Scheme 1. A new route to sulfonimidamides via sulfonimidoyl fluorides was
developed, however racemization was observed in both fluorination and amine
coupling steps, understood to be from sulfonimidoyl fluoride racemization. For
details on Procedures A & B, see SI. For 1d, reactions were performed on a
0.1 mmol scale in THF (0.3 M) at rt for 3 h. Retained ee given by %ee(R)-2a
Here we describe a method to prepare highly enantioenriched
sulfonimidoyl fluorides from bench-stable sulfinamide salts, and
their use in the synthesis of a diverse range of enantioenriched
sulfonimidamides by stereospecific SuFEx reaction (Fig 1e). The
first stereocontrolled synthesis of sulfonimidoyl fluorides is
reported. Fluoride ions are demonstrated to cause racemization
of the sulfonimidoyl fluorides, which is avoided by fluoride trapping.
The mild coupling reagents allow the use of neutral primary and
secondary amines, and the methodology is exemplified in the
functionalization of amine containing drug compounds, showing
the potential for its use to rapidly prepare novel chemical entities
and diverse chemical libraries.[23] A readily removed NBoc-
protecting group on the imide nitrogen is employed, which also
increased the electrophilicity of the sulfonimidoyl fluoride.
product/%ee(R)-2a SM
.
We proposed that degenerate nucleophilic attack of fluoride
ions in solution on the sulfonimidoyl fluoride center was causing
the racemization (Scheme 1d). To explore this hypothesis, two
fluoride ion sources, TBAF and KF, were added to the
sulfonimidoyl fluoride (R)-2a in THF at rt for 3 h. In the absence
of a soluble fluoride ion source (Entry 1), a small amount of
racemization occurred, presumably as a result of elimination of
fluoride ions from the starting material. A soluble fluoride source
(TBAF, Entry 2) caused the complete racemization of the
sulfonimidoyl fluoride whereas the highly insoluble, inorganic KF
did not release fluoride ions into solution and may, in fact, have
complexed with F– present to prevent racemization (Entry 3).[26,27]
By analogy with sulfonyl fluorides, we envisaged a new route
to sulfonimidoyl fluorides through fluorination of sulfinamide
salts.[24,25] Initially, racemic p-tolyl sulfinamide salt 1a was
prepared from the corresponding NBoc-sulfoximine by elimination
of acrylate (see SI). Pleasingly, sulfonimidoyl fluoride 2a was
formed in high yield and excellent purity using Selectfluor, after a
simple aqueous workup (Scheme 1a, Procedure A). Furthermore,
we developed conditions for the reaction 2a with 11 examples of
primary and secondary amines (Procedure B; e.g. piperidine,
77% yield 3a in Scheme 1a. See SI for further examples).
This directed us to examine fluoride trapping strategies (See
SI). Firstly, in the fluorination step, changing the solvent to ethanol,
being polar and protic, resulted in full preservation of ee. However,
the yield of the fluorination was much reduced, presumably from
the protonation of the sulfinamide salt causing reduced
nucleophilicity of the sulfur center. The introduction of potassium
acetate as a soluble inorganic base resulted in an increased yield
for this step with no loss of ee (Table 1, (S)-1a to (R)-2a).
While this route demonstrated the proof of concept, a key aim
for this project was in the development of an efficient strategy to
Preventing racemization of the sulfonimidoyl fluoride in the
amine coupling step required more extensive optimization (Table
1, (R)-2a–(R)-3a). A selection of trapping additives was examined
(Entries 2-6). A typical organic fluoride ion scavenger, TMS-Cl
shut down the reactivity and resulted in almost complete recovery
of starting material. The addition of water resulted in an increased
yield, however, there was only a small increase in es observed.
Soluble inorganic salts were investigated to precipitate insoluble
fluoride salts.[26] Adding KBr was not beneficial, whereas LiCl
gave complete preservation of ee. The use of more soluble LiBr
resulted in complete preservation of ee and an increase in yield.
Changing the solvent had a lesser effect on ee than in the
fluorination step and alcohol solvents caused a significant amount
of sulfonimidate formation (Entries 7-8). However, changing the
solvent to MeCN resulted in an increased yield (Entry 9), and
enantioenriched
sulfonimidamides.
The
corresponding
enantioenriched salt (S)-1a was formed from commercial (S)-(+)-
p-toluenesulfinamide (S)-4 (Table 1; (S)-4 to (S)-1a). However,
when using the enantioenriched sulfinamide salt, a significant loss
of ee occurred in both fluorination and coupling steps (Scheme
1b). Monitoring the reduction of ee over the course of the SuFEx
reaction showed sulfonimidoyl fluoride (R)-2a rapidly racemized
(Scheme 1c, see SI for additional data). Sulfonimidamide (R)-3a
retained a low ee and was proven to be configurationally stable
under the reaction conditions.
2
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10.1002/chem.202002265
Chemistry - A European Journal
COMMUNICATION
Procedure D
NEt3 (2.0 equiv)
LiBr (2.0 equiv)
when combined with LiBr resulted in the formation of an
enantioenriched sulfonimidamide in excellent yield (Entry 10).
O
O
S
NBoc
F
NBoc
S
H
N
N
+
MeCN
80 ºC, 24 h
Table 1. Optimization of amine coupling for retention of ee and yield
(R)-2a
(R)-3a-u
O
O
O
NBoc
NBoc
NBoc
nBuLi then
Boc2O
O
S
O
S
O
S
S
S
S
NaH
N
H
N
H
N
NBoc
Na
NH2
NHBoc
THF
25 ºC, 1 h
quant. , >99% ee
THF
–78 ºC to 0 ºC, 3 h
62%, >99% ee
(R)-3b
81%, 99% ee
(R)-3c
78%, 99% ee
(R)-3a
96%, >99% ee
(S)-4
(S)-5
NEt3 (2.0 equiv)
piperidine (2.0 equiv)
additive (2.0 equiv)
(S)-1a
Procedure C
Selectfluor
KOAc
O
NBoc
O
O
NBoc
NBoc
O
O
S
NBoc
F
NBoc
N
S
S
S
S
N
H
N
H
N
H
solvent
80 ºC, 24 h
EtOH
0 ºC to rt, 24 h
quant, >99% ee
(R)-3d
60%, 98% ee
(R)-3e
62%, 95% ee
(R)-3f
76%, >99% ee
(R)-2a
(R)-3a
Yield (%)a
Entry
Solvent
Additive
% esc
O
NBoc
O
O
NBoc
N
NBoc
N
(R)-2a
(R)-3a
Totalb
S
S
S
N
H
1
2
THF
THF
-
TMS-Cl
H2O
KBr
LiCl
LiBr
-
30
75
6
52
1
82
76
83
77
42
75
33
72
82
96
87
8
(R)-3g
68%, 97% ee
(R)-3h
86%, 96% ee
(R)-3i
54%, 99% ee
n.d.
26
O
O
O
NBoc
NBoc
NBoc
3
THF
77
44
31
56
33
66
73
96
87
S
S
S
N
N
N
4
THF
33
11
19
-
13
O
(R)-3j
93%, 97% ee
(R)-3k
93%, 97% ee
(R)-3l
88%, >99% ee
5
THF
>99
>99
45
6
THF
O
O
O
NBoc
N
NBoc
N
NBoc
N
S
S
S
7
EtOH
iPrOH
MeCN
MeCN
MeCN
F
8
-
6
29
O
OH
F
(R)-3o
56%, 99% ee
(R)-3m
35%, 97% ee
(R)-3n
75%, 99% ee
9
-
9
28
O
O
10
11
LiBr
LiI
-
>99
>99
O
NBoc
NBoc
NBoc
S
S
S
N
N
N
-
NBoc
N
N
N
O
N
a Reactions performed on 0.1 mmol scale. aYields determined by 1H-NMR using
1,3,5-trimethoxybenzene as internal standard. Isolated yields in parentheses.
Sum of preceding two columns. es, enantiospecificity, given by %ee(R)-
(R)-3p
74%, 97% ee
(R)-3q
69%, >99% ee
(R)-3r
75%, 98% ee
b
c
F
O
NBoc
3a/%ee(R)-2a. For details on Procedure C, see SI.
(R)-3t
45%
single diastereomer
S
O
NBoc
N
Ph
Ph
N
H
S
N
With the optimized conditions in hand, the amine scope of the
reaction was explored (Scheme 2). Pleasingly, both primary and
secondary amines were suitable in this reaction with complete
enantiospecificity in all cases. Aliphatic, benzylic and allylic
amines were all coupled in good yields ((R)-3b–(R)-3g). Acyclic
and cyclic secondary amines reacted in excellent yields ((R)-3h–
(R)-3l). Ketones and gem-difluoro substituents were all well
O
NBoc
(R)-3u
43%
single diastereomer
(R)-3s
75%, 98% ee
from Desipramine
S
N
H
Scheme 2. Amine scope using the p-tolyl sulfinamide salt. Reactions performed
on 0.25 mmol scale. Coupling reaction performed using (R)-2a (95–99% ee)
with no loss of ee in this step.
tolerated
Chemoselective reactivity was observed with 6-piperidinol to form
sulfonimidamide (R)-3o without significant competing
sulfonimidate formation. Finally, more highly functionalized
piperidines and piperazine heterocycles were coupled in good
yield under the mild conditions ((R)-3p–(R)-3s), including the drug
desipramine. Treating (R)-2a with both enantiomers of
a-methylbenzylamine gave different single diastereoisomer
products ((R)-3t and (R)-3u).
on
the
amine
substrate
((R)-3m–(R)-3n).
Sulfonimidamide (R)-3h was determined to be (R)-
stereochemistry by single crystal X-ray diffraction analysis
(Scheme 3; CCDC 1991431). This indicates inversion in the
substitution reaction. Nucleophilic substitution with inversion at
the sulfur center has precedent with sulfonimidoyl chlorides and
sulfonimidates,[14,21,28] and more recently in the nucleophilic attack
of phenols on sulfonimidoyl fluorides.[22] Fluorination is presumed
to occur with retention of the configuration similar to prior studies
on chlorination (S changing to R due to priority change).[29]
3
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10.1002/chem.202002265
Chemistry - A European Journal
COMMUNICATION
O
O
derivatization, as exemplified in a Suzuki–Miyaura cross-coupling
to give enantioenriched biphenyl derivative (R)-10.
Procedure C
S
S
NH2
NBoc
Na
Retention at
sulfur centre
(S)-4
(S)-1a
Moreover, additional racemic aryl and alkyl sulfinamide salts
1c–1h were prepared (See SI). These were converted to new
sulfonimidoyl fluorides 2c–2h with Selectfluor and coupled with
O
O
S
NBoc
F
NBoc
Procedure D
S
N
(R)-3h
Inversion of
sulfur centre
piperidine
sulfonimidamides
to
form
a
collection
Scheme
of
5).
NBoc-protected
Electron-rich
absolute configuration
by X-ray crystallography
(3z–3aj,
(R)-2a
(R)-3h
methoxyphenyl (3ab), and electron-poor pyridine derivatives
(3ac) were successfully employed. Alkyl sulfinamide salts were
also successfully converted to piperidine sulfonimidamides 3ad
and 3ae. Procedure A (DMF) was more suitable for the
fluorination step with the alkyl derivatives. The SuFEx reaction
with methylsulfonimidoyl fluoride 2h was demonstrated with
several amines, including the marketed drugs primaquine,
desipramine and amoxapine (3ah-3aj).
Scheme 3. From the commercially available (S)-enantiomer of the sulfinamide
salt building block, the fluorination-amine coupling sequence was proven to
occur with overall inversion of the sulfur centre from crystal structure analysis,
rationalized to occur in the amine coupling step.
To exemplify
a general approach to enantioenriched
sulfinamides, we targeted 4-bromophenylsulfonimidoyl fluoride
(R)-2b, exploiting enantioselective sulfoxide oxidation as the
asymmetric step (Scheme 4).
O
S
O
Selectfluor
O
S
NBoc
F
amine
NBoc
N
S
NBoc
Na
Procedure
A or C
Procedure
B or D
ligand 1
VO(acac)2
OMe
H2O2
O
3z-aj
1c-h
2c-h
methyl acrylate
NaOAc
SH
S
S
OMe
O
S
NBoc
N
O
S
NBoc
N
O
S
NBoc
O NBoc
O
THF:H2O
rt, 24 h
CHCl3
0 ºC
O
Br
Br
N
S
Br
N
N
6
7
8
92%
68%, 99% ee
F
MeO
BocNH2
PhI(OAc)2, Rh2(OAc)4
MgO
O
3z
3aa
3ab
3ac
84%d
(2f 68%a)
O
S
NBoc
5 M NaOH
in MeOH
d
d,e
d
74
%
48
%
88
%
OMe
S
NBoc
(2c 54%a)
(2d 88%c)
(2e quantc)
CH2Cl2
40 ºC, 24 h
O
Na
CH2Cl2
C
Br
Br
25 º
, 4 h
O
NBoc
N
O
NBoc
O
NBoc
N
O
NBoc
(S)-9
87%, 99% ee
(S)-1b
90%, 99% ee
S
S
S
S
Me
N
Me
Me
N
O
NBoc
O
Procedure C
Selectfluor
KOAc
Procedure D
amine
NEt3, LiBr
NBoc
O
S
NBoc
F
S
3ad
3ae
3af
3ag
73%
N
b
b
b
32%d
81
(2h 47%a)
%
81%
(2g 90%a (86%c))
EtOH
0 ºC to rt, 24 h
MeCN
80 ºC, 24 h
Br
Br
(R)-2b
quant, 92% ee
Cl
N
O
N
O
NBoc
O
NBoc
NBoc
N
H
N
S
S
S
Me
Me
N
N
Me
N
H
O
NBoc
O
S
NBoc
O
S
NBoc
N
N
S
O
N
H
N
H
OMe
3aj
45%b
from Amoxapine
3ah
58%
3ai
71%b
Br
Br
Br
(R)-3v
62%, 92% ee
(R)-3w
(R)-3x
87%, 90% ee
from Primaquine
from Desipramine
PhB(OH)2
Pd(dtbpf)Cl2
75%, 90% ee
conditions
S
O
S
NBoc
Scheme 5. Scope of varying sulfinamide salt building blocks in fluorination and
SuFEx amine coupling reactions. For reaction conditions and equivalents, see
SI. a) Procedure A; b) Procedure B; c) Procedure C; d) Procedure D. e)
Competing SNAr reactivity gave reduced yield of 3aa.
(R)-3y
80%
single diast.
from duloxetine
O
NBoc
N
S
N
O
Br
(R)-10
91%, 90% ee
Scheme 4. Preparation enantioenriched 4-bromophenyl sulfonimidamides.
Ligand (S)-(–)-2-(N-3,5-diiodosalicyliden)amino-3,3-dimethyl-1-butanol.
Stereochemistry of 8 assigned based on prior literature.[30] Suzuki conditions =
PhB(OH)2 (1.5 equiv), K2CO3 (2 equiv), Pd(dtbpf)Cl2 (10 mol%), MeCN:H2O (1:1,
0.2 M), 80 °C, 2 h.
Finally, the NBoc protecting-group was readily removed on
both tertiary and secondary enantioenriched sulfonimidamide
substrates with TFA in CH2Cl2 (Scheme 6). Treating (R)-3a and
(R)-3f with TFA effected deprotection with no racemization to give
NH-sulfonimidamides (R)-11 and (R)-12.
1
=
Catalytic enantioselective oxidation of sulfide 7 gave sulfoxide
8 in 68% yield and 99% ee (S).[30] Rh-catalyzed NBoc transfer to
form the sulfoximine (S)-9,[31] which has been shown to occur with
retention of ee, and elimination of methyl acrylate from gave the
bench-stable sulfinamide salt (S)-1b. The elimination occurred
with preservation of ee, as indicated by re-protonation of a sample
of the salt. This provides a new approach to enantioenriched
sulfinamide salts. Treatment of (S)-1b with Selectfluor gave
fluoride (R)-2b with 92% ee. Reaction of (R)-2b with amines gave
high yields and maintained high ee ((R)-3v–(R)-3x). Using the
O
O
NBoc
N
NH
N
TFA (10 equiv)
S
S
CH2Cl2 (0.1 M)
25 ºC, 4 h
89%, >99% ee
(R)-3a
(R)-11
O
N
O
NBoc
TFA (10 equiv)
S
S
NH2
N
H
CH2Cl2 (0.1 M)
25 ºC, 4 h
84%, 98% ee
(R)-3f
(R)-12
Scheme 6. NBoc-deprotection of primary and secondary sulfonimidamide.
Sample of (R)-3f used had 98% ee, with NBoc-deprotection occurring with
complete preservation of ee.
enantiopure drug compound duloxetine yielded
a single
diastereoisomer product (R)-3y. Moreover, the 4-bromophenyl
substituent of (R)-3x was shown to be a suitable handle for further
4
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10.1002/chem.202002265
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In conclusion, we have reported a new, practical method to
access sulfonimidamides from bench-stable sulfinamide salt
building blocks by a SuFEx reaction of sulfonimidoyl fluorides. We
describe the first facile route to enantioenriched sulfonimidamides,
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diverse array of sulfonimidamides. The methodology can be
applied to the late stage functionalization of drug molecules all in
good to excellent yields, which has the potential to accelerate the
preparation of novel chemical entities and diverse chemical
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Acknowledgements
We gratefully acknowledge The Royal Society [University
Research Fellowship, UF140161 (to J. A. B.), URF appointed
grant RG150444, and URF enhancement grant, RGF\EA\180031],
and EPSRC [CAF to J.A.B. (EP/J001538/1), DTA Studentships
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5
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10.1002/chem.202002265
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
H
N
O
O
O NBoc
NBoc
N
F+
S
S
S
NBoc
Na
F
stereospecific
with LiBr
up to 99% ee
Stereocontrolled synthesis provides highly enantioenriched sulfonimidoyl fluorides for SuFEx chemistry. Enantiospecific S–N bond
formation is achieved with inversion by preventing fluoride promoted racemization. A diverse array of sulfonimidamides are synthesized
using primary and secondary amines including complex amine containing drugs.
Institute and/or researcher Twitter usernames: @jamesabull
6
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