Late-Stage Sulfoximination: Improved Synthesis of the Anticancer Drug Candidate Atuveciclib

Article abstract of DOI:10.1055/s-0037-1610316

An efficient synthesis of racemic atuveciclib was accomplished in five steps with an excellent 51% overall yield, using cheap reagents and mild reaction conditions. The key sulfoximination reaction was realized during the last step of the synthesis from t

Full text of DOI:10.1055/s-0037-1610316

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–E
paper
A
en
T. Glachet et al.
Paper
Synthesis
Late-Stage Sulfoximination: Improved Synthesis of the Anticancer
Drug Candidate Atuveciclib
Thomas Glacheta
Xavier Franckb
Vincent Reboul*a
MeSNa
B(OH)2
O
N
N
0
0
0
0-0
0
0
2-1
4
7
4-4
0
6
5
Cl
N
Cl
O
F
PIDA
a Normandie Université, ENSICAEN, UNICAEN, CNRS, LCMT,
14000 Caen, France
Ammonium
carbamate
Fe/HCl
vincent.reboul@ensicaen.fr
b Normandie Université, CNRS, UNIROUEN, INSA Rouen,
COBRA, 76000 Rouen, France
N
N
O
NH
5 steps
51% overall
yield
S
N
N
H
O2N
F
Cl
Atuveciclib
(BAY-1143572)
Received: 27.08.2018
Accepted after revision: 13.10.2018
Published online: 05.11.2018
Sulfoximines are mainly used as a bioisosteres of car-
boxylic acids,7 amidines,8 alcohols,9 sulfones,10 sulfon-
amides,5,11 sulfoxides, or piperazines.12 The sulfoximine
moiety continues to flourish since it often exhibits favor-
able physicochemical properties, for example,13 metabolic
stability, high aqueous solubility, high passive permeability,
minor decomposition in acidic or basic conditions, and li-
pophilicity comparable to sulfones or amides. Further ap-
plications of sulfoximines in drug discovery are facilitated
by the recent development of safer synthetic methods, es-
pecially from sulfoxides14 and sulfides.15
DOI: 10.1055/s-0037-1610316; Art ID: ss-2018-t0571-op
Abstract An efficient synthesis of racemic atuveciclib was accom-
plished in five steps with an excellent 51% overall yield, using cheap re-
agents and mild reaction conditions. The key sulfoximination reaction
was realized during the last step of the synthesis from the correspond-
ing sulfide.
Key words atuveciclib, sulfoxide, sulfoximine, sulfanenitrile, palladi-
um, cross-coupling
In this context, we recently developed an efficient syn-
thesis of sulfoximines from sulfides using phenyliodine di-
acetate (PIDA) and ammonium carbamate (AC).15c,16 In this
method, we highlighted the importance of methanol, the
solvent of this reaction, which also reacts as a nucleophile
with λ6-sulfanenitrile intermediates to afford the corre-
sponding NH-sulfoximine (Scheme 1). Considering that this
reaction is highly tolerant to a large number of functional
groups and N-heterocycles,17 we reasoned that it could be
applied to the late-stage sulfoximination of atuveciclib.
Despite the early discovery of methionine sulfoximine
(MSO, Figure 1) in the 1950’s,1 as a potent inhibitor of glut-
amine synthetase, sulfoximines appeared only recently in
the life sciences.2 Only one drug containing a sulfoximine
group, sulfoxaflor (insecticide) was marketed in 2013.3 At
the moment, few compounds (Figure 1) are evaluated in
clinical trials (phase 2) for cancer treatment (kinase inhibi-
tors), like AZD6738,4 roniciclib (BAY 1000394),5 and atu-
veciclib (BAY 1143572).6
NH
O
N
S
N
S
O
N
N
PhI(OAc)2
R1
S
OAc
O
NH
OMe
R2
S
R1
R1
+
O
R2
S
NH2COONH4
MeOH, rt, 2 h
R2
λ6-sulfanenitrile
N
N
H
O
F
NH3
MeOH
MeOMe + AcOCH3
Methionine sulfoximine (MSO)
O
Atuveciclib
OH
O
S
R1, R2 = alkyl, aryl
81–96%
NH
R2
R1
N
O
N
O
NH
Scheme 1 Reactive intermediates during the synthesis of NH-sulfox-
F3C
S
N
NH
O
N
imines
HN
S
N
N
H
N
AZD6738
Roniciclib
Atuveciclib is the first potent and highly selective
PTEFb18/CDK9 inhibitor (positive transcription elongation
factor b) to enter clinical trials, making it a promising new
Figure 1 Structure of bioactive sulfoximines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

B
T. Glachet et al.
Paper
Synthesis
O
our
N
N
O
N
N
SNAr
B(OH)2
O
NH
approach
S
+
S
S
H2N
Cl
N
O
N
H
N
N
H
Suzuki then
sulfoximine
introduction
F
Atuveciclib
F
PG: COCF3
A
O
S
Sulfoximine deprotection
and Suzuki (36–40%)
previous work
Cl
NPG
O2N
O2N
S
O
+
MeSNa
H2N
Cl
SNAr
N
N
O
NPG
+
I
B(OH)2
O
NPG
O
S
NH
S
+
+
N
N
B
Cl
N
N
H
S
PG: PMB Ph
N
Br
F
N
Cl
Scheme 2 Retrosynthetic pathways of atuveciclib
approach in cancer therapy. Lücking’s group described two
synthetic strategies (Scheme 2) with 9 steps (A, 16.8% over-
all yield)19 or 6 steps (B, 13.9% overall yield).20 Both synthe-
ses rely on the aromatic substitution reaction with 2,4-di-
chloro-1,2,3-triazine and a Suzuki cross-coupling reaction
with a boronic acid. However, amine I is either obtained
through Bolm’s rhodium-catalyzed imination21 of sulfoxide
(approach A, red disconnection), or through an original pal-
ladium-catalyzed direct α-arylation (approach B, blue dis-
connection) developed by the same group.20 In both syn-
theses, the Suzuki cross-coupling reaction afforded low
yields (36 and 40%).
We reasoned that the sulfoximine function could be re-
sponsible for this low reactivity due to palladium-catalyst
poisoning and therefore propose a late-stage sulfoximina-
tion approach (Scheme 2).22
Our synthesis started (Scheme 3) with the SN2 reaction
of sodium methanethiolate on commercially available ben-
zyl chloride leading to thioether 1 in quantitative yield (no
purification). Next, the nitro group was reduced and, in-
stead of using titanium(III) chloride as described by Lück-
ing, a less toxic and inexpensive Fe/HCl mixture was used.
Aniline 2 was thus obtained in 93% yield and was pure
enough to be used directly in the next step.23 It should be
noted that when the reduction was performed in the pres-
ence of Sn/HCl, it proved to be unsuccessful.24 Next, the nu-
cleophilic aromatic substitution with 2,4-dichloro-1,3,5-
triazine (3) gave thioether 4 in 90% yield after purification
on silica gel. The Suzuki cross-coupling on commercial bo-
ronic acid 5 was then performed using tetrakis(triphenyl-
phosphine)palladium in DME at 100 °C. To our delight, the
desired tricyclic compound 6 was obtained in a satisfactory
81% yield.25 However, surprisingly no reaction occurred
when 2,4-dichloro-1,3,5-triazine (3) and boronic acid 5
were mixed under the same conditions.26
Finally, the last step consisted of the sulfoximination re-
action that was performed using our previously described
conditions:15c PIDA (2.1 equiv), AC (1.5 equiv) in methanol
at room temperature. After 30 minutes, complete conver-
sion was observed and atuveciclib was obtained in 75%
yield on gram scale after purification on silica gel. Hence,
the whole synthetic sequence consisted of only 5 steps with
an excellent 51% overall yield, which competes favorably
with the previous Lücking’s syntheses (6 or 9 steps with
13.8 or 16.8% overall yield, respectively).
Moreover, our strategy is also applicable to asymmetric
synthesis of atuveciclib. Indeed, thioether 6 could be easily
transformed into the corresponding enantioenriched sulf-
oxide 7.27 Asymmetric oxidation was performed using
Kagan’s conditions, a titanium-mediated oxidation with cu-
N
N
3
MeSNa
EtOH, rt, 3 h
> 99%
Fe/HCl
93%
N
N
Cl
N
Cl
S
Cl
S
S
DIPEA (2 equiv)
90%
Cl
N
N
O2N
O2N
O
H2N
H
1
2
4
O
PIDA
AC
MeOH
N
N
O
N
N
O
NH
F
B(OH)2
S
S
N
N
H
N
N
5
H
75%
Pd(PPh3)4
DME, 100 °C
81%
F
F
6
(
)-Atuveciclib
CHP
Ti(OiPr)4
(R,R)-DET
> 99%
PIDA
AC
MeOH
O
N
N
O
S
O
N
N
O
NH
S
N
N
H
N
N
68%
H
F
F
7
(S)-Atuveciclib
Scheme 3 Racemic and asymmetric synthesis of atuveciclib
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

C
T. Glachet et al.
Paper
Synthesis
mene hydroperoxide (CHP) in the presence of diethyl (R,R)-
tartrate28 and sulfoxide 7 was isolated in quantitative yield.
Then, the imination reaction into the corresponding atu-
veciclib was achieved using Bull’s metal-free conditions14 in
68% yield and with only 19.8% ee.29 Due to the fact that the
sulfoximination occurs stereospecifically with retention of
configuration, this low enantiomeric excess originates from
a weakly asymmetric sulfoxidation step.30
In conclusion, we have described a short and efficient
racemic synthesis of clinical anticancer drug atuveciclib
with an excellent 51% overall yield, using commercially
available starting material, cheap reagents and featuring a
late-stage sulfoximination. The proof of concept for asym-
metric synthesis was also demonstrated and would need to
be improved.31 Hence, we believe that the late-stage sulfox-
imination approach can be applied to various other mole-
cules provided that the corresponding sulfide is available.
and concentrated to give 0.776 g (93%) of aniline 2 as a brown oil,
which was used without purification in the next step; Rf = 0.7 (pen-
tane/EtOAc, 70:30).
IR (ATR): 3349, 2913, 1618, 1602, 1589 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.09 (t, J = 7.9 Hz, 1 H, ArH), 6.70–6.66
(m, 2 H, ArH), 6.59–6.56 (m, 1 H, ArH), 3.59 (s, 2 H, ArCH2S), 2.00 (s, 3
H, SCH3).
13C{1H} NMR (CDCl3, 101 MHz): δ = 148.6 (Cq), 138.3 (Cq), 128.3 (CAr),
118.2 (CAr), 114.4 (CAr), 112.8 (CAr), 37.3 (CH2), 14.0 (CH3).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C8H12NS: 154.0690; found:
154.0690.
4-Chloro-N-{3-[(methylsulfanyl)methyl]phenyl}-1,3,5-triazin-2-
amine (4)
2,4-Dichloro-1,3,5-triazine (3; 840 mg, 5.6 mmol) was dissolved in
THF/i-PrOH (1:1, 25.5 mL) and the solution was cooled to 0 °C. Then,
DIPEA (1.8 mL, 10.2 mmol) and a solution containing aniline 2 (805
mg, 5.1 mmol) in THF/i-PrOH (1:1, 25.5 mL) were added sequentially.
The resulting solution was stirred at 0 °C for 30 min. Volatiles were
removed under reduced pressure and the crude mixture was purified
by column chromatography (pentane/EtOAc, 70:30) to afford 1.217 g
(90%) of product 4 as a yellow solid; mp 124.7–125.4 °C; Rf = 0.6 (pen-
tane/EtOAc, 70:30).
1H NMR spectra were recorded at 400 MHz or 500 MHz and 13C NMR
spectra were recorded at 101 MHz or 125 MHz on a Bruker DRX400
or Bruker Avance III 500 spectrometer. 19F NMR spectra were record-
ed at 470.5 MHz on a Bruker Avance III 500 spectrometer. IR spectra
were recorded on a PerkinElmer ATR-spectrum one spectrometer.
The high-resolution mass spectrometry (HRMS) analyses were per-
formed using a Xevo G2-XS QTof Waters mass spectrometer equipped
with an electrospray ion source (ESI) operated in positive ion mode.
HPLC separations were achieved with Waters Alliance system, using
Chiralpak IC column. Melting points were determined using a Gallen-
Kamp melting point apparatus. Compounds 1, 2, and atuveciclib were
previously described, and their spectroscopic data are in agreement
with those reported in the literature.6,20
IR (ATR): 3090, 2953, 1543, 1512, 1488, 1377, 1013, 796 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 8.57–8.51 (m, 1 H, HetArH), 7.60–7.47
(m, 3 H, ArH and NH), 7.34 (t, J = 7.8 Hz, 1 H, ArH), 7.13 (d, J = 7.8 Hz, 1
H, ArH), 3.69 (s, 2 H, ArCH2S), 2.03 (s, 3 H, SCH3).
13C{1H} NMR (CDCl3, 101 MHz): δ = 167.7 (CHetAr), 166.9 (Cq), 164.1
(Cq), 139.7 (Cq), 136.6 (Cq), 129.3 (CAr), 125.9 (CAr), 121.6 (CAr), 120.0
(CAr), 38.2 (CH2), 15.0 (CH3).
HRMS (ESI-QTOF): m/z [M + H]+ calcd C11H1235ClN4S: 267.0471;
found: 267.0472.
4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(methylsulfanyl)meth-
1-[(Methylsulfanyl)methyl]-3-nitrobenzene (1)
yl]phenyl}-1,3,5-triazin-2-amine (6)
Sodium methanethiolate (3.5 g, 49.5 mmol) was added in three por-
tions to a stirred solution of 1-(chloromethyl)-3-nitrobenzene (5.0 g,
29.1 mmol) in EtOH (60 mL) at –15 °C. The cold bath was removed
and the solution was stirred at r.t. for 3 h. The reaction mixture was
diluted with brine and extracted with EtOAc (3 × 20 mL). The com-
bined organic layers were washed with H2O, dried (MgSO4), filtered,
and concentrated under reduced pressure to give 5.33 g (>99%) of
thioether 1 as a yellow oil, which was used without purification in the
next step; Rf = 0.9 (pentane/EtOAc, 70:30).
A degassed mixture containing chloride 4 (267 mg, 1 mmol), 4-fluo-
ro-2-methoxyphenylboronic acid (5; 255 mg, 1.5 mmol), Pd(PPh3)4
(173 mg, 0.15 mmol), and aq 2 M K2CO3 (1.0 mL, 2 mmol) in 1,2-DME
(6 mL) was heated under N2 atmosphere at 100 °C for 90 min in a
sealed tube. After cooling, the mixture was diluted with EtOAc and
washed with brine. The organic phase was dried (MgSO4), filtered,
and the volatiles were removed under reduced pressure. The crude
mixture was purified by column chromatography (pentane/EtOAc,
70:30) to give 290 mg (81%) of compound 6 as a yellow solid; mp
101.5–104.5 °C; Rf = 0.3 (pentane/EtOAc, 70:30).
IR (ATR): 1522, 1350 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 8.18 (s, 1 H, ArH), 8.11 (d, J = 8.0 Hz, 1
H, ArH), 7.66 (d, J = 8.0 Hz, 1 H, ArH), 7.50 (t, J = 8.0 Hz, 1 H, ArH), 3.75
(s, 2 H, ArCH2S), 2.01 (s, 3 H, SCH3).
13C{1H} NMR (CDCl3, 101 MHz): δ = 148.4 (Cq), 140.6 (Cq), 134.9 (CAr),
129.4 (CAr), 123.7 (CAr), 122.1 (CAr), 37.8 (CH2), 15.0 (CH3).
IR (ATR): 3285, 2911, 1616, 1550, 1420, 1237, 798 cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 8.83 (br s, 1 H, HetArH), 7.99–7.60 (m,
4 H, ArH and NH), 7.31 (t, J = 7.8 Hz, 1 H, ArH), 7.06 (d, J = 7.8 Hz, 1 H,
ArH), 6.78–6.74 (m, 2 H, ArH), 3.93 (br s, 3 H, ArOCH3), 3.68 (s, 2 H,
ArCH2S), 2.01 (s, 3 H, SCH3).
13C{1H} NMR (CDCl3, 101 MHz): δ = 171.4 (Cq), 166.3 (CHetAr), 165.6 (d,
J = 208.8 Hz, Cq), 163.6 (Cq), 160.5 (Cq), 139.5 (Cq), 138.0 (Cq), 133.5
(Cq), 129.2 (CAr), 124.8 (CAr), 122.0 (CAr), 120.9 (CAr), 119.3 (CAr), 107.7
(d, J = 21 Hz, CAr), 100.3 (d, J = 25.5 Hz, CAr), 56.4 (CH3), 38.4 (CH2), 15.0
(CH3).
HRMS (ESI-QTOF): m/z [M]+ calcd for C8H9NO2S: 183.0354; found:
183.0351.
3-[(Methylsulfanyl)methyl]aniline (2)
Iron powder (3.27 g, 54.6 mmol) and few drops of concd HCl were
added to a stirred solution of nitrobenzene 1 (1.00 g, 5.46 mmol) in
EtOH/H2O (4:1, 15 mL) at r.t. The mixture was stirred for 3 h at reflux.
After filtration through Celite 545, the residue was washed with
EtOH. Then, the combined organic layers were dried (MgSO4), filtered,
19F NMR (CDCl3, 470.5 MHz): δ = –105.5 (m, 1 F).
HRMS (ESI-QTOF): m/z [M + H]+ calcd C18H18FN4OS: 357.1185; found:
357.1187.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

D
T. Glachet et al.
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Synthesis
(rac)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimi-
(S)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimi-
doyl)methyl]phenyl}-1,3,5-triazin-2-amine [(±)-Atuveciclib]
doyl)methyl]phenyl}-1,3,5-triazin-2-amine [(S)-Atuveciclib]
To a flask containing a stir bar was added successively, sulfide 6 (1.019
g, 2.86 mmol), ammonium carbamate (335 mg, 4.29 mmol), and
MeOH (15 mL). PIDA (1.936 g, 6.01 mmol) was added in one portion
and the reaction mixture was stirred at r.t. for 30 min (open flask to
the atmosphere). The solvent was removed under reduced pressure
and the crude mixture was purified by flash chromatography on silica
gel (CH2Cl2/MeOH, 95:5) to afford 0.825 g (75%) of atuveciclib as an
off-white solid with spectral data identical with those described;6,20
mp 167–168 °C; Rf = 0.3 (CH2Cl2/MeOH, 95:5).
To a flask was added successively sulfoxide 7 (74.5 mg, 0.2 mmol),
ammonium carbamate (21.9 mg, 0.28 mmol), and MeOH (1 mL). PIDA
(67.6 mg, 0.21 mmol) was added in one portion and the reaction mix-
ture was stirred at r.t. for 30 min (flask open to the atmosphere). After
completion, the solvent was removed under reduced pressure and the
crude was purified by flash chromatography on silica gel (CH2Cl2/
MeOH, 95:5) to give 53 mg (68%) of atuveciclib as an off-white solid;
mp 167–168 °C.
An ee of 19.8% was determined by HPLC [Chiralpak IC column, 1:1
IR (ATR): 3258, 2923, 1546, 1420, 1279, 1194, 1025, 1006, 955, 803
heptane/i-PrOH, λ = 275 nm, tR = 30.6 min (S) and tR = 37.5 min (R)].
cm–1
.
1H NMR (CDCl3, 500 MHz): δ = 8.78 (br s, 1 H, HetArH), 8.16–7.73 (m,
4 H, ArH and ArNHAr), 7.38 (t, J = 7.8 Hz, 1 H, ArH), 7.13 (d, J = 7.8 Hz,
1 H, ArH), 6.78–6.73 (m, 2 H, ArH), 4.40 and 4.27 (AB system, JAB = 13.0
Hz, 2 H, ArCH2S), 3.91 (br s, 3 H, ArOCH3), 2.96 (s, 3 H, SCH3).
13C{1H} NMR (CDCl3, 101 MHz): δ = 172.0 (Cq), 166.3 (Cq), 165.7 (d, J =
250.1 Hz, Cq), 163.6 (Cq), 160.4 (Cq), 138.7 (Cq), 133.9 (CHetAr), 129.7
(Cq), 129.4 (CAr), 126.3 (CAr), 122.9 (CAr), 122.0 (d, J = 2.9 Hz, CAr), 121.1
(CAr), 107.7 (d, J = 21 Hz, CAr), 100.3 (d, J = 25.5 Hz, CAr), 64.0 (CH2),
56.4 (CH3), 41.6 (CH3).
Funding Information
This research was supported by Conseil Régional de Normandie,
CNRS, Normandie Université, LabexSynorg (ANR-11-LABX-0029), and
European FEDER funding.
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Supporting Information
19F NMR (CDCl3, 470.5 MHz): δ = –105.2 (m, 1 F).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610316.
S
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p
p
orti
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HRMS (ESI-QTOF): m/z [M + H]+ calcd C18H19FN5O2S: 388.1243;
found: 388.1245.
References
4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfinyl)meth-
yl]phenyl}-1,3,5-triazin-2-amine (7)
(1) (a) Bentley, H. R.; Whitehead, J. K. J. Chem. Soc. D 1950, 2081.
(b) Bentley, H. R.; McDermott, E. E.; Pace, J.; Whitehead, J. K.;
Moran, T. Nature 1950, 165, 150.
(2) Lücking, U. Angew. Chem. Int. Ed. 2013, 52, 9399.
(3) Arndt, K. E.; Bland, D. C.; Irvine, N. M.; Powers, S. L.; Martin, T.
P.; McConnell, J. R.; Podhorez, D. E.; Renga, J. M.; Ross, R.; Roth,
G. A.; Scherzer, B. D.; Toyzan, T. W. Org. Process Res. Dev. 2015,
19, 454.
Diethyl (R,R)-tartrate (82.5 mg, 0.4 mmol), Ti(Oi-Pr)4 (56.8 mg, 0.2
mmol), and three drops of H2O were added to a suspension of 6 (71.3
mg, 0.2 mmol) in toluene (3 mL) at 54 °C. The mixture was stirred for
1 h at 54 °C, the temperature was then adjusted to 30 °C, and subse-
quently DIPEA (26 mg, 0.2 mmol) and cumene hydroperoxide (84% in
cumene, 61 mg, 0.4 mol) were added. The solution was extracted
with NH4OH (28% of NH3, 3 × 20 mL). Subsequently, Et2O (20 mL) was
added to the combined aqueous extracts. Then the pH of the aqueous
phase was adjusted to 7 with AcOH, the layers were separated, and
the aqueous layer was extracted with an additional portion of Et2O
(20 mL). To the combined organic solutions was added aq 1 M NaOH
(100 mL) and the solution was left to stir for 1 h. After separation, the
organic phase was dried (MgSO4), filtered, and the volatiles were re-
moved under reduced pressure. The crude was purified by column
chromatography (CH2Cl2/MeOH, 95:5) to give the 74.5 mg (>99%) of
sulfoxide 7 as a yellow solid; mp 51.1–54.1 °C; Rf = 0.4 (CH2Cl2/MeOH,
95:5).
(4) Foote, K. M.; Lau, A.; Nissink, J. W. M. Future Med. Chem. 2015, 7,
873.
(5) Lücking, U.; Jautelat, R.; Krüger, M.; Brumby, T.; Lienau, P.;
Schäfer, M.; Briem, H.; Schulze, J.; Hillisch, A.; Reichel, A.;
Wengner, A. M.; Siemeister, G. ChemMedChem 2013, 8, 1067.
(6) Lücking, U.; Scholz, A.; Lienau, P.; Siemeister, G.; Kosemund, D.;
Bohlmann, R.; Briem, H.; Terebesi, I.; Meyer, K.; Prelle, K.;
Denner, K.; Bömer, U.; Schäfer, M.; Eis, K.; Valencia, R.; Ince, S.;
von Nussbaum, F.; Mumberg, D.; Ziegelbauer, K.; Bert, K.;
Choidas, A.; Nussbaumer, P.; Baumann, M.; Schultz-Fademrecht,
C.; Rühter, G.; Eickhoff, J.; Brands, M. ChemMedChem 2017, 12,
1776.
IR (ATR): 3259, 3095, 2964, 1544, 1419, 1399, 1279, 1156, 1026, 955,
831, 803 cm–1
.
(7) Barnes, A. C.; Hairsine, P. W.; Matharu, S. S.; Ramm, P. J.; Taylor,
J. B. J. Med. Chem. 1979, 22, 418.
1H NMR (500 MHz, CDCl3): δ = 8.81 (br s, 1 H, HetArH), 7.94–7.63 (m,
4 H, ArH and ArNHAr), 7.36 (t, J = 7.9 Hz, 1 H, ArH), 7.03 (d, J = 7.9 Hz,
1 H, ArH), 6.79–6.74 (m, 2 H, ArH), 4.05 and 3.94 (AB system, JAB = 14.0
Hz, 2 H, ArCH2S), 3.92 (br s, 3 H, ArOCH3), 2.49 (s, 3 H, SCH3).
13C{1H} NMR (125 MHz, CDCl3): δ = 171.9 (Cq), 166.0 (d, J = 254.1 Hz,
Cq), 165.8 (Cq), 163.4 (Cq), 160.4 (Cq), 138.6 (Cq), 134.0 (CHetAr), 130.6
(Cq), 129.7 (CAr), 125.6 (CAr), 122.0 (CAr), 121.9 (CAr), 120.6 (CAr), 107.7
(d, J = 22 Hz, CAr), 100.3 (d, J = 25.2 Hz, CAr), 60.2 (CH2), 56.4 (CH3), 37.4
(CH3).
(8) Selected examples: (a) Cheng, Y.; Dong, W.; Wang, H.; Bolm, C.
Chem. Eur. J. 2016, 22, 10821. (b) Le, T.-N.; Diter, P.; Pégot, B.;
Bournaud, C.; Toffano, M.; Guillot, R.; Vo-Thanh, G.; Magnier, E.
Org. Lett. 2016, 18, 5102. (c) Pandya, V.; Jain, M.; Chakrabarti,
G.; Soni, H.; Parmar, B.; Chaugule, B.; Patel, J.; Jarag, T.; Joshi, J.;
Joshi, N.; Rath, A.; Unadkat, V.; Sharma, B.; Ajani, H.; Kumar, J.;
Sairam, K. V. V. M.; Patel, H.; Patel, P. Eur. J. Med. Chem. 2012, 58,
136.
19F NMR (470.5 MHz, CDCl3): δ = –105.2 (m, 1 F).
HRMS (ESI-QTOF): m/z [M + H]+ calcd for C18H18FN4O2S: 373.1134;
(9) Selected examples: (a) Lu, D.; Sham, Y. Y.; Vince, R. Bioorg. Med.
Chem. 2010, 18, 2037. (b) Raza, A.; Sham, Y. Y.; Vince, R. Bioorg.
Med. Chem. Lett. 2008, 18, 5406. (c) Nishimura, N.; Norman, M.
H.; Liu, L.; Yang, K. C.; Ashton, K. S.; Bartberger, M. D.; Chmait,
found: 373.1135.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

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T. Glachet et al.
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Synthesis
S.; Chen, J.; Cupples, R.; Fotsch, C.; Helmering, J.; Jordan, S. R.;
Kunz, R. K.; Pennington, L. D.; Poon, S. F.; Siegmund, A.; Sivits,
G.; Lloyd, D. J.; Hale, C.; St. Jean, D. J. J. Med. Chem. 2014, 57,
3094.
(19) Lücking, U.; Bohlmann, R.; Scholz, A.; Siemeister, G.; Gnoth, M.
J.; Bömer, U.; Kosemund, D.; Lienau, P.; Rüther, G.; Schulz-
Fademrecht, C. PCT Int. Appl WO 2012160034, 2012.
(20) Sirvent, J. A.; Bierer, D.; Webster, R.; Lücking, U. Synthesis 2017,
49, 1024.
(21) Okamura, H.; Bolm, C. Org. Lett. 2004, 6, 1305.
(22) Sulfoximines are good ligands for transition metals: (a) Bolm,
C.; Kaufmann, D.; Zehnder, M.; Neuburger, M. Tetrahedron 1996,
37, 3985. (b) Okamura, H.; Bolm, C. Chem. Lett. 2004, 33, 482.
(c) Cadierno, V.; Díez, J.; García-Garrido, S. E.; Gimeno, J.;
Pizzano, A. Polyhedron 2010, 29, 3380. (d) Lemasson, F.; Gais,
H.-J.; Runsink, J.; Raabe, G. Eur. J. Org. Chem. 2010, 2157.
(23) Chen, X. Y.; Buschmann, H.; Bolm, C. Synlett 2012, 23, 2808.
(24) Holland, H. L.; Brown, F. M.; Larsen, B. G. Tetrahedron: Asymme-
try 1995, 6, 1561.
(25) The Pd(OAc)2-catalyzed ligand-free and aerobic Suzuki reaction
did not occur: Liu, C.; Ni, Q.; Hu, P.; Qiu, J. Org. Biomol. Chem.
2011, 9, 1054.
(26) Wang, C.; Zhang, J.; Tang, J.; Zou, G. Adv. Synth. Catal. 2017, 359,
2514.
(27) Mahony, G. E. O.; Kelly, P.; Lawrence, S. E. ARKIVOC 2011, (i), 1.
(28) (a) Brunel, J.-M.; Diter, P.; Duetsch, M.; Kagan, H. B. J. Org. Chem.
1995, 60, 8086. (b) Cotton, H.; Elebring, T.; Larsson, M.; Li, L.;
Sörensen, H.; Von Unge, S. Tetrahedron: Asymmetry 2000, 11,
3819.
(29) The enantiomers were separated using chiral HPLC and accord-
ing to specific rotation measurement, the major enantiomer is
(S)-atuveciclib.
(10) Selected examples: (a) Kahraman, M.; Sinishtaj, S.; Dolan, P. M.;
Kensler, T. W.; Peleg, S.; Saha, U.; Chuang, S. S.; Bernstein, G.;
Korczak, B.; Posner, G. H. J. Med. Chem. 2004, 47, 6854.
(b) Walker, D. P.; Zawistoski, M. P.; McGlynn, M. A.; Li, J.-C.;
Kung, D. W.; Bonnette, P. C.; Baumann, A.; Buckbinder, L.;
Houser, J. A.; Boer, J.; Mistry, A.; Han, S.; Xin, L.; Guzman-Perez,
A. Bioorg. Med. Chem. Lett. 2009, 19, 3253. (c) Steinkamp, A.-D.;
Wiezorek, S.; Brosge, F.; Bolm, C. Org. Lett. 2016, 18, 5348.
(11) Selected example: Steinkamp, A.-D.; Seling, N.; Lee, S.;
Boedtkjer, E.; Bolm, C. Med. Chem. Commun. 2015, 6, 2163.
(12) Sirvent, J. A.; Lucking, U. ChemMedChem 2017, 12, 487.
(13) Frings, M.; Bolm, C.; Blum, A.; Gnamm, C. Eur. J. Med. Chem.
2017, 126, 225.
(14) Zenzola, M.; Doran, R.; Degennaro, L.; Luisi, R.; Bull, J. A. Angew.
Chem. Int. Ed. 2016, 55, 7203.
(15) Simultaneously, three groups worked on this synthesis, includ-
ing ours: (a) Xie, Y.; Zhou, B.; Zhou, S.; Zhou, S.; Wei, W.; Liu, J.;
Zhan, Y.; Cheng, D.; Chen, M.; Li, Y.; Wang, B.; Xue, X.; Li, Z.
ChemistrySelect 2017, 2, 1620. (b) Tota, A.; Zenzola, M.;
Chawner, S. J.; John-campbell, S. S.; Carlucci, C.; Romanazzi, G.;
Degennaro, L.; Bull, J. A.; Luisi, R. Chem. Commun. 2017, 53, 348.
(c) Lohier, J.-F.; Glachet, T.; Marzag, H.; Gaumont, A.-C.; Reboul,
V. Chem. Commun. 2017, 53, 2064.
(16) Marzag, H.; Schuler, M.; Tatibouët, A.; Reboul, V. Eur. J. Org.
Chem. 2017, 896.
(17) The reaction conditions were compatible with various hetero-
cycles. See reference 14.
(30) Kagan’s conditions usually work for liquid substrate and aro-
matic/alkyl thioether. The poor asymmetric induction in our
case might be due to the nature of starting material (solid and
alkyl/alkyl thioether).
(31) Currently, (R)-atuveciclib is obtained via chiral preparative
HPLC separation. See reference 19.
(18) PTEFb is a heterodimer of CDK9, which is exclusively involved in
transcriptional regulation of RNA polymerase II.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E