Construction of N-Boc-2-Alkylaminoquinazolin-4(3H)-Ones via a Three-Component, One-Pot Protocol Mediated by Copper(II) Chloride that Spares Enantiomeric Purity

Article abstract of DOI:10.1002/adsc.202001279

Chiral 2-alkylquinazolinones are key synthetic intermediates, but their preparation in high optical purity is challenging. Thus, a multicomponent procedure integrating anthranilic acids, N-Boc-amino acids, and amines in the presence of methanesulfonyl chl

Full text of DOI:10.1002/adsc.202001279

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DOI: 10.1002/adsc.202001279
Construction of N-Boc-2-Alkylaminoquinazolin-4(3H)-Ones via a
Three-Component, One-Pot Protocol Mediated by Copper(II)
Chloride that Spares Enantiomeric Purity
Xiaoyu Lia and Jennifer E. Goldena,*
a
Department of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705-
2222, USA
E-mail: jennifer.golden@wisc.edu
Manuscript received: October 16, 2020; Revised manuscript received: December 27, 2020;
Version of record online: Februar 3, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001279
© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
class selective inhibitor of PI3Kδ for the treatment of
Abstract: Chiral 2-alkylquinazolinones are key
synthetic intermediates, but their preparation in high
optical purity is challenging. Thus, a multicompo-
some blood cancers.[3] Several quinazolinone-based
PI3K inhibitors[3c,4] appeared afterward, such as the
antiarthritic triamino-pyrimidine 2[5] and the immuno-
nent procedure integrating anthranilic acids, N-Boc-
modulating anti-neoplastic agent, acalisib 3.[6] Ispinesib
amino acids, and amines in the presence of
methanesulfonyl chloride, N-methylimidazole, and
4 is a kinesin spindle protein (KSP) inhibitor that is in
phase II clinical trials for the treatment of neoplastic
copper(II) chloride was developed to mildly afford
diseases.[7] Like ispinesib, quinazolinone 5 features an
N-Boc-2-alkylaminoquinazolin-4(3H)-ones with ex-
N-acylated 2-alkylaminoquinazolinone, but is valued
cellent preservation of enantiomeric purity (>99%
for its anti-inflammatory action due to CXCR3
ee). Copper(II) chloride was essential to retaining
receptor antagonism.[8]
enantiopurity, and reaction component structural
changes were well tolerated, resulting in an effi-
cient, all-in-one procedure that promotes sequential
coupling, lactonization, aminolysis, and cyclization
in good yields. The method was applied to the rapid
assembly of four key intermediates used in the
synthesis of high profile quinazolinones, including
several PI3K inhibitor drugs.
Synthetic approaches to the 2-alkylaminoquinazo-
lin-4(3H)-one core frequently converge to N-Boc
protected intermediates 7 and rely on a dehydrative
procedure incorporating an anthranilic acid, N-Boc-
protected amino acid 6 and an aniline in the presence
of
HOP(OPh)2
or
P(OPh)3
in
pyridine
(Scheme 1).[4b–d,5,9] Alternatively, isobutyl chlorofor-
mate and N-methylmorpholine (NMM) have been used
in place of the phosphite reagents to construct the
quinazolinone core,[8,10] while other methods generate
anthranilamides via peptide coupling, followed by
cyclization using HMDS/I2,[11] TMSCl,[12] or bis
(trimethylsilyl)acet-amide.[13] Preparing anthranil-
amides from 2-nitrobenzoic acids has also been
Keywords: quinazolinone; racemization; copper-
mediated; enantiopurity; PI3 kinase
The quinazolinone framework is a synthetically useful explored[13–14] as a means to afford Boc-protected 2-
intermediate found in a vast number of natural alkylaminoquinazolin-4(3H)-ones 7 with high enantio-
products with a broad spectrum of biological activity.[1] purity via Mumm rearrangement, followed by reduc-
Medicinal chemistry programs centered on this motif tion and cyclization.[15] Nonetheless, many of these
have produced several clinical candidates and ap- methods demonstrated one or more limitations such as
proved drugs featuring a 2-alkylamino-quinazolin- low overall yield, multistage purification, narrow
4(3H)-one core (Figure 1, red highlight). For example, substrate scope, need for synthetically challenging
idelalisib 1 was FDA approved[2] in 2014 as a first-in-
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Scheme 2. Exploratory chemistry leading to 12a formation.
such that, after the addition of aniline, a mixture of
diamide 11a and 12a was observed. Heating of 11a/
12a with TMSCl[12] and NEt3 in dichloromethane
resulted in a 47% yield of quinazolinone 12a and 98%
ee (Table 1, entry 1).
Figure 1. Selected 2-alkylaminoquinazolin-4(3H)-ones.
With this result in hand, a systematic study of
reaction parameters was undertaken to optimize the
process. Firstly, we found it was advantageous to run
the reaction without isolation of any intermediates,
hence we optimized the process as a one-pot proce-
dure. The addition of molecular sieves in step 1 was
necessary to avoid hydrolysis of benzoxazinone 10a
(see supplementary Table S1). Increasing the equiva-
lency of NMI in step 2 improved the yield of 12a
without eroding the enantiomeric purity (Table 1,
Scheme 1. General synthetic approaches to N-Boc-quinazoli-
nones.
starting materials, use of sensitizing coupling entries 2–3); however, adding additional quantities of
reagents,[16] or erosion of enantiopurity.
NMI beyond 1.0 equivalent in step 1 reduced the ee
For the purpose of using N-Boc protected 2- value of the product (entries 4–5, Table 1). Exchange
alkylaminoquinazolin-4(3H)-ones as substrates in our of solvent from dichloromethane to dichloroethane,
quinazolinone rearrangement[17] chemistry leading to THF, or acetonitrile with the other reaction parameters
benzamidines, we required a method that would avoid of entry 3 were inferior with respect to both yield and
these issues and efficiently deliver a variety of these optical purity (entries 6–8). Changes to the temperature
quinazolinones with high enantiopurity. We observed in steps 1 or 2, or altering the equivalency of aniline
products of variable optical purity with the phosphite (step 3) or TMSCl/NEt3 (step 4) did not improve the
protocol that was dependent on the substitution pattern enantiomeric purity of the product (Table S1, entries
of the anthranilic acid. With the isobutylchloro- 8–11). As some racemization was still occurring, we
formate/NMM procedure, we obtained low yields of took note of reports showing that this issue in mixed
the desired quinazolinones and significant quantities of anhydride type peptide couplings could be mitigated
side products. Alternatively, we found that the coupling with the addition of CuCl2.[19] The addition of CuCl2
of anthranilic acids with anilines mediated by MsCl (0.25 equiv.) in DCM afforded quinazolinone 12a in
and N-methylimidazole (NMI) was promising 63% yield and >99% ee (Table 1, entry 9). Switch of
(Scheme 2).[18] To survey these conditions, we used solvent to DCE resulted in a slight loss in enantiomeric
anthranilic acid 8a, N-Boc-L-alanine and aniline as purity and yield, though increasing the CuCl2 equiv-
substrates and modulated the reagent stoichiometry, alency and increasing the amount of NMI in step 2
solvent, and temperature.
restored the enantiopurity to >99% (entry 12). This
The reactions were initially monitored by NMR and became important later for some substrates in our
later assessed by TLC and LCMS when purified scope that required heating at a higher temperature
intermediates were in hand. Analysis of the data than what could be accomplished in DCM. Notably,
revealed that a single equivalent of MsCl and NMI we revisited the isobutyl chloroformate/NMM condi-
relative to anthranilic acid resulted in a mixture of acid tions after seeing the copper(II) chloride effect, but
8a, amide 9a and benzoxazinone 10a. Additional only trace amounts of quinazolinone 12a were
MsCl/NMI (1.2 eq. each) facilitated 10a formation
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Table 1. Optimization of quinazolinone 12a formation.[a]
entry
MsCl (equiv.)
NMI (equiv.)
CuCl2 (equiv.)
solvent
12a yield (%)
ee[e] (%)
1
2
3
4
5
6
7
8
1.0[b] +1.2[c]
1.0[b] +1.2[c]
1.0[b] +1.2[c]
2.2[d]
1.0[b] +1.2[c]
1.0[b] +1.5[c]
1.0[b] +2.0[c]
3.0[d]
–
–
–
–
–
–
–
–
0.25
0.25
0.50
0.50
DCM
DCM
DCM
DCM
DCM
DCE
47
57
62
66
57
55
22
36
63
52
45
50
98
98
98
96
97
93
91
93
>99
98
>99
>99
1.0[b] +1.2[c]
1.0[b] +1.2[c]
1.0[b] +1.2[c]
1.0[b] +1.2[c]
1.0[b] +1.2[c]
1.0[b] +1.2[c]
1.0[b] +1.2[c]
1.0[b] +1.2[c]
2.0[b] +1.0[c]
1.0[b] +2.0[c]
1.0[b] +2.0[c]
1.0[b] +2.0[c]
1.0[b] +2.0[c]
1.0[b] +2.0[c]
1.0[b] +2.0[c]
1.0[b] +3.0[c]
THF
CH3CN
DCM
DCE
DCE
DCE
9
10
11
12
[a] 1.0 mmol scale in solvent (0.07 M). Reflux refers to the boiling point of the solvent indicated. Yields reflect isolated product.
[b] Equivalency of reagent added in step 1.
[c] Equivalency of reagent added in step 2.
[d] All MsCl and NMI were added in step 1.
[e] Percent ee determined by chiral HPLC comparison of peak AUCs for each enantiomer obtained by this method. MsCl=
methanesulfonyl chloride; NMI=N-methylimidazole; TMSCl=trimethylsilyl chloride; NEt3 =triethylamine; DCM=dichlor-
omethane; DCE=1,2-dichloroethane; THF=tetrahydrofuran; CH3CN=acetonitrile.
observed when these reagents were switched out for example, quinazolinone 12l was obtained in 41% yield
the MsCl/NMI system in our new protocol.
and 95% ee using DCM and 0.25 equiv. of CuCl2 but
Moving forward with our one-pot protocol, we in DCE and with 0.50 equiv. of CuCl2, 12l was
surveyed a collection of substituted anthranilic acids, obtained in the same yield but with an improved 99%
anilines or benzylamine, and α-substituted, N-Boc ee.
protected amino acids and their associated effects on
Good yields and excellent ee values were observed
yield and enantiomeric purity (Table 2). Substitution of for a variety of anilines and benzyl amine when paired
the anthranilic acid core revealed a 15% better yield with N-Boc- alanine (12g–12k). Notably, for 12k in
for a C5-trifluoromethyl analog 12d compared to a which benzylamine was used in place of an aniline,
C5-methoxy derivative 12c, presumably due to in- fewer equivalents of the amine were required
creased susceptibility of the former case to attack by a (4.0 equiv.) and the cyclization step employing
weakly nucleophilic aniline or stabilization of negative TMSCl/NEt3 was unnecessary, resulting in direct
charge in the intermediates. Nonetheless, anthranilic formation of 12k in 61% yield and >99% ee. This
acids 8a–e were effective substrates, delivering quina- may be due to the greater nucleophilicity of benzyl-
zolinones 12a–e in reasonable yields and excellent amine compared to the use of anilines. The procedure
enantiomeric purity in DCM. When a C6-fluorine atom also tolerated the incorporation of more bulky amino
was present on the anthranilic acid, the corresponding acid side chains such as those in valine, methionine
diamide was not completely converted to quinazoli- and cyclopropylglycine, as shown by the preparation
none 12f in step 4; however, switching to the of quinazolinones 12m–o.
alternative DCE conditions (Table 1, entry 12) permit-
To assess if the protocol was beneficial in the
ted a higher reaction temperature and afforded 12f in synthesis of previously reported N-Boc-2-alkylamino-
30% yield and 98% ee. The relative low yield of 12f quinazolinones, we approached the formal syntheses of
may be due its instability, as C6-halogenated quinazo- four quinazolinone drugs or candidates for which the
linones have been reported to be problematic.[4a] None- requisite N-Boc-quinazolinones were known. Quinazo-
theless, the use of DCE/CuCl2 was beneficial for a few linone 12p,
a
key idelalisib
1
synthetic
other substrates, especially those that employed deacti- intermediate,[3a,14–15] had been reportedly prepared via a
vated anilines or bulky N-Boc protected amino acids, phosphite-mediated strategy, though the yield and
such as those leading to 12j, 12l and 12m. For enantiopurity was not reported (Table 3, entry 1).
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Table 2. Method substrate scope, yields and enantiomeric
purity of N-Boc-2-alkylaminoquinazolinones.[a]
Table 3. Comparison of yield and %ee using various methods
to generate N-Boc-quinazolinone 12p.
entry 8f, method
ref
9c
12p 12p
yield ee
X
(%)[a] (%)[b]
1
2
3
NH2 P(OPh)3/pyridine
aniline, 70 C, 8 h
NH2 P(OPh)3/pyridine
aniline, 70 C, 8 h
NO2 SOCl2 coupling,
not reported
°
9c[d] 30
15 36
94
[c]
°
97–98[e]
Mumm rearrangement,
reduction/cyclization
4
5
NH2 See Table 2,
this 33
work
>99
>99
one pot, DCE,
1 mmol scale[c]
NH2 See Table 2,
one pot, DCE,
this 43
work
10 mmol scale
[a] Isolated yields.
[b] Percent ee determined by chiral HPLC comparison of peak
AUCs for each enantiomer.
[c] Reactions run on 1.0 mmol scale.
[d] Procedure from ref. 9c for 12p was reproduced in our lab and
resulting yields and %ee of 12p are reported (see SI).
[e] Ref. 15 reported a 98% ee in the main manuscript but 97% ee
in the SI for 12p.
copper(II) chloride-mediated strategy afforded 12p in
33% yield and 99% ee on a 1 mmol scale, and in 43%
yield on a 10 mmol scale without loss of enantiomeric
purity (>99% ee, entry 5).
The high stereofidelity of the method was further
demonstrated in the formal synthesis of acalisib 3
(Scheme 3). Using our protocol in DCM, anthranilic
acid 8g was converted into quinazolinone 12q (56%
yield, >99% ee) which was deprotected with TFA to
afford amine 13a in 88% yield and >99% ee. The
transformation of 13a to acalisib 3 has been
reported,[6a] though the yields and enantiopurity of 13a
prepared by that method were not provided. Nonethe-
less, the final enantiopurity of acalisib 3 was reported
as >99% ee after proceeding through a four-step
protocol. We converge to the same intermediate 13a
using the one-pot procedure with a reasonable 49%
yield and excellent enantiopurity.
[a] Reactions run on 1.0 mmol scale/0.07 M. Performed in DCM
and with CuCl2 (0.25 equiv.) unless otherwise noted; reflux
refers to DCM boiling point unless DCE was used. Yields
reflect isolated product. Percent ee determined by chiral
HPLC comparison of peak AUCs for each enantiomer
obtained by this method.
[b] Used DCE/CuCl2 (0.50 equiv.); reflux refers to DCE boiling
point.
[c] Used BnNH2 (4.0 equiv.) and step 4 was unnecessary.
Using their published[9c] protocol, we generated
For both the formal synthesis of ispinesib 4 and that
12p in 30% yield and 94% ee (entry 2). The generation of CXCR3 antagonist 5, isobutyl chloroformate and N-
of quinazolinone 12p by Mumm rearrangement of an methylmorpholine were combined with the necessary
imidoyl chloride, followed by reduction and cycliza- anthranilic acid and aniline to generate N-Boc quinazo-
tion was reported to occur in 36% yield and 97–98% linones 12r and 12s, respectively (Scheme 3). Using
ee.[15] Using anthranilic acid 8f (X=NH2), our one-pot, our protocol in DCE, the reaction of anthranilic acid
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Scheme 3. Formal syntheses of acalisib 3, ispinesib 4 and
quinazolinone 5 using the one-pot procedure on a 1.0 mmol
scale (0.07 M). Yields reflect isolated product and %ee was
determined by chiral HPLC comparison of peak AUCs.
8e, N-Boc-D-valine, and benzylamine proceeded with-
out the need of step 4 and expeditiously afforded 12r,
the key intermediate in the synthesis of ispinesib 4,
with 98% ee and in a 41% yield.[7,10] Quinazolinone
Scheme 4. Control experiments revealing need for CuCl2.
12s, which was used to prepare[8] CXCR3 antagonist 5 racemization, and isolation of the ring closing reaction
and was generated using isobutyl chloroformate/NMM with diamide 11a and TMSCl/NEt3 showed no loss of
in 30% yield over 4 steps (no reported %ee), was enantiopurity in the absence of copper(II) chloride to
instead assembled using our one-pot protocol in DCM form 12a (panel 4). Collectively, these results point to
in 66% yield and >99% ee. Ultimately, these four key the sensitivity of benzoxazinone 10a and the diamide
quinazolinone intermediates (12p, 12r, 12s, and 13a) forming reaction (step 3, Scheme 2) as the source of
were successfully generated using the one-pot protocol loss of enantiomeric purity and the point at which
and resulted in excellent enantiomeric purity and yields CuCl2 is needed to prevent it.
that are reasonable when considering the number of
Given that metal-coordination with the equivalent
steps otherwise required to make them. These formal nitrogen atom in quinazolinones has been
syntheses, taken together with the quinazolinone characterized,[20] we reasoned that the CuCl2 may
collection shown in Table 2, underscore the utility of coordinate the benzoxazinone core nitrogen atom in
this method in preserving the enantiopurity of the 10a, as shown in Scheme 5 (intermediate A). Reaction
desired quinazolinone products.
between mesyl chloride and NMI forms HCl which
Last, several control experiments were carried out can further activate the benzoxazinone carbonyl toward
to determine the point at which racemization occurred nucleophilic addition of the aniline, followed by
(Scheme 4). The conversion of anthranilic acid 8a to elimination to form ring-opened intermediate C. Loss
benzoxazinone 10a in DCE without CuCl2 was of the amide-nitrogen coordinated copper species can
arrested after step 2 (Scheme 4, panel 1). Isolation and ultimately afford vis-amide 11a. Alternatively, when
characterization revealed that 10a was obtained in an copper(II) chloride was not present, we proposed that
86% yield, >99% ee, and showed no racemization the stereocenter may be compromised by an alternative
occurring in the first two steps.
pathway en route to the formation of the bis-amide
Treatment of isolated benzoxazinone 10a (>99% intermediate, in accordance with the results shown in
ee) with aniline in DCE with and without copper (II) Scheme 4. We took note of a report[4a] from Patel and
chloride showed erosion of enantiomeric purity in the co-workers who, while generating quinazolinone PI3K
absence of the additive (Scheme 4, panel 2). Formation inhibitors, proposed a mechanism by which the
of diamide 11a from acid 8a did not reveal quinazolinones formed a nitrilium ion that ultimately
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Scheme 5. Proposed role of CuCl2 in attenuating racemization.
led to ring opening and bis-amide formation. In the aminolysis, and cyclization occurs in one-pot without
case of the benzoxazinone 10a, we propose that a the need for isolation of intermediates and affords
structurally similar nitrilium ion intermediate may products in modest to good yields and excellent
form by virtue of the uncoordinated imine-like nitro- enantiopurities. Moreover, when benzylamine was
gen atom that fragments the activated ring to generate employed in place of the aniline component, diamide
nitrilium ion E in the absence of copper(II) chloride. In cyclization occurred spontaneously, thus obviating the
the key step leading to racemization, loss of the acidic need for the TMSCl/NEt3 step. The utility and
propargylic-like proton may generate a benzenamine F enantiopurity-preserving feature of the transformation,
that could be intercepted by an intramolecular 6-endo- including the Boc-deprotection step leading to 13a that
dig cyclization involving the nearby carboxylic acid retained the enantiopurity with high fidelity, was
group to afford benzoxazinylidene G. Attack of the further demonstrated by the rapid formal syntheses of
aniline on the carbonyl of G would be expected to quinazolinone-based drugs, idelalisib 1, acalisib 3, and
afford an intermediate H that, upon ring opening and ispinesib 4 and bioactive quinazolinone 5.
subsequent tautomerization, would generate racemized
bis-amide 11a’. This rationale accounts for the
observed racemization leading to 11a’ in the absence
Experimental Section
of CuCl2 and the stabilization of the stereocenter when General Procedures A (DCM/0.25eq. CuCl2) and B
the reagent is used. Further, this mechanistic proposal (DCE/0.50eq. CuCl2) for the Synthesis of Quinazo-
underscores the importance of using the non-basic linones 12
reagent, N-methylimidazole, as part of the amide
coupling. As noted earlier, adding CuCl2 to the
previously reported isobutyl chloroformate/NMM con-
ditions failed to improve reaction yield or preserve
enantiopurity. In light of the proposed mechanism, this
made sense as the N-methyl morpholine reagent would
be expected to preferentially coordinate the copper(II)
chloride over the substrate 10a.
In summary, we have devised an efficient means of
assembling N-Boc-protected 2-alkylaminoquinazolin-
4(3H)-ones which are valuable intermediates in syn-
thetic processes leading to bioactive natural product
derivatives, promising lead compounds and marketed
drugs. Faced with a need to generate an array of these
intermediates reliably and with high enantiomeric
purity, we developed a MsCl/NMI/CuCl2 mediated
protocol that incorporates commercially available,
substituted anthranilic acids, N-Boc-amino acids, and
amines. Notably, the peptide coupling, lactonization,
Procedure A (DCM/0.25eq. CuCl2). To the mixture of Boc-L
or D amino acid (1.00 mmol), anhydrous CuCl2 (34 mg,
0.25 mmol) and 4 Å MS (140 mg) in anhydrous DCM (15 mL)
°
under N2 and cooled to À 20 C was added dropwise N-
methylimidazole (NMI) (80 μL, 1.00 mmol) and MsCl (77 μL,
°
1.00 mmol). After being stirred at À 20 C for 1 h, anthranilic
acid or substituted anthranilic acid 8 (1.00 mmol) was added
°
into the reaction mixture and stirred at À 20 C for 1.5 h. Then,
MsCl (93 μL, 1.20 mmol) and NMI (160 μL, 2.00 mmol) was
°
added dropwise into the reaction mixture at À 20 C and slowly
°
heated to 40 C in parallel synthesizer heating mantle for 1.5 h.
After being cooled to rt, aniline or substituted aniline
(6.00 mmol) was added dropwise into the reaction mixture and
heated to reflux in a parallel synthesizer heating mantle for
16 h. Subsequently, triethylamine (2.37 mL, 17.00 mmol) and
TMSCl (1.91 mL, 15.00 mmol) was added dropwise into the
°
reaction mixture at 0 C and slowly heated to reflux in Parallel
synthesizer heating mantle for 24 h. The reaction mixture was
diluted with DCM (100 mL), washed with 1 M HCl, saturated
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aqueous Na2CO3, and brine in turn, dried over Na2SO4, and
filtered, then the solvent was evaporated under reduced
pressure. The residue was purified by flash chromatography to
afford 12.
Med. Chem. 2016, 59, 9228–9242; b) S. Perreault, J.
Chandrasekhar, Z.-H. Cui, J. Evarts, J. Hao, J. A. Kaplan,
A. Kashishian, K. S. Keegan, T. Kenney, D. Koditek, L.
Lad, E.-I. Lepist, M. E. McGrath, L. Patel, B. Phillips, J.
Therrien, J. Treiberg, A. Yahiaoui, G. Phillips, J. Med.
Chem. 2017, 60, 1555–1567; c) M. Wei, X. Zhang, X.
Wang, Z. Song, J. Ding, L.-H. Meng, A. Zhang, Eur. J.
Med. Chem. 2017, 125, 1156–1171; d) A. Thakur, G. J.
Tawa, M. J. Henderson, C. Danchik, S. Liu, P. Shah,
A. Q. Wang, G. Dunn, M. Kabir, E. C. Padilha, X. Xu,
A. Simeonov, S. Kharbanda, R. Stone, G. Grewal, J.
Med. Chem. 2020, 63, 4256–4292.
Procedure B (DCE/0.50eq. CuCl2). To the mixture of Boc-L
or D amino acid (1.00 mmol), anhydrous CuCl2 (68 mg,
0.50 mmol) and 4 Å MS (140 mg) in anhydrous DCE (15 mL)
°
under N2 cooled to À 20 C was added dropwise NMI (80 μL,
1.00 mmol) and MsCl (77 μL, 1.00 mmol). After being stirred
°
at À 20 C for 1 h, anthranilic acid or substituted anthranilic acid
8 (1.00 mmol) (137 mg, 1.00 mmol) was added into the reaction
°
mixture and stirred at À 20 C for 1.5 h. Then, MsCl (93 μL,
1.20 mmol) and NMI (240 μL, 3.00 mmol) was added dropwise
[5] L. Patel, J. Chandrasekhar, J. Evarts, A. C. Haran, C. Ip,
J. A. Kaplan, M. Kim, D. Koditek, L. Lad, E.-I. Lepist,
M. E. McGrath, N. Novikov, S. Perreault, K. D. Puri,
J. R. Somoza, B. H. Steiner, K. L. Stevens, J. Therrien, J.
Treiberg, A. G. Villaseñor, A. Yeung, G. Phillips, J. Med.
Chem. 2016, 59, 3532–3548.
[6] a) K. D. Puri, J. B. Evarts, B. Lannutti, N. A. Giese,
(Calistoga Pharmaceuticals Inc.), PCT Int. Appl. WO
2010/123931 A1, 2010; b) A. A. P. Kater, S. H. Tonino,
M. Spiering, M. E. D. Chamuleau, R. Liu, A. H. Ade-
woye, J. Gao, L. Dreiling, Y. Xin, J. K. Doorduijn, M. J.
Kersten, Blood Cancer J. 2018, 8, 16.
°
°
into the reaction mixture at À 20 C and slowly heated to 40 C
in Parallel synthesizer heating mantle for 1.5 h. After being
cooled to rt, aniline or substituted aniline (6.00 mmol) was
added dropwise into the reaction mixture and heated to reflux in
Parallel synthesizer heating mantle for 16 h. Subsequently,
triethylamine (2.37 mL, 17.00 mmol) and TMSCl (1.91 mL,
15.00 mmol) was added dropwise into the reaction mixture at
°
0 C and slowly heated to reflux in Parallel synthesizer heating
mantle for 24 h. The reaction mixture was diluted with DCM
(100 mL), washed with 1 M HCl, saturated aqueous Na2CO3,
and brine in turn, dried over Na2SO4, and filtered, then the
solvent was evaporated under reduced pressure. The residue
was purified by flash chromatography to afford 12.
[7] L. Sorbera, J. Bolos, N. Serradell, M. Bayes, Drugs
Future 2006, 31, 778–787.
[8] M. Johnson, A.-R. Li, J. Liu, Z. Fu, L. Zhu, S. Miao, X.
Wang, Q. Xu, A. Huang, A. Marcus, F. Xu, K. Ebsworth,
E. Sablan, J. Danao, J. Kumer, D. Dairaghi, C. Lawrence,
T. Sullivan, G. Tonn, T. Schall, T. Collins, J. Medina,
Bioorg. Med. Chem. Lett. 2007, 17, 3339–3343.
[9] a) N. Yamazaki, F. Higashi, Tetrahedron Lett. 1972, 13,
5047–5050; b) G. Rabilloud, B. Sillion, J. Heterocycl.
Chem. 1980, 17, 1065–1068; c) A. Boruah, S. Hosahalli,
S. K. Panigrahi, (Aurigene Discovery Technologies
Limited), PCT Int. Appl. WO 2014/106800 A2, 2014.
[10] G. Bergnes, E. Ha, G. Yiannikouros, P. Kalaritis, B. E.
Yonce, K. A. Welday, (Cytokinetics, Inc.), PCT Int. Appl.
WO 2003/070701 A2, 2003.
Acknowledgements
J.E.G. gratefully acknowledges funding from the National
Institutes of Health (R01AI118814 and U19AI142762). We
thank the UW-Madison Medicinal Chemistry Center and the
Analytical Instrumentation Center in the UW-Madison School
of Pharmacy for use of instrumentation related to chiral HPLC,
NMR, HRMS, and polarimetry.
References
[1] a) D. I. S. P. Resende, P. Boonpothong, E. Sousa, A.
Kijjoa, M. M. M. Pinto, Nat. Prod. Rep. 2019, 36, 7–34;
b) I. Khan, A. Ibrar, W. Ahmed, A. Saeed, Eur. J. Med.
Chem. 2015, 90, 124–169; c) U. A. Kshirsagar, Org.
Biomol. Chem. 2015, 13, 9336–9352; d) M. Demeu-
nynck, I. Baussanne, Curr. Med. Chem. 2013, 20, 794–
814; e) J. P. Michael, Nat. Prod. Rep. 2003, 20, 476–493.
[2] A. Markham, Drugs 2014, 74, 1701–1707.
[11] U. A. Kshirsagar, S. B. Mhaske, N. P. Argade, Tetrahe-
dron Lett. 2007, 48, 3243–3246.
[12] J. B. Evarts, B. Lannutti, H. Webb, (Gilead Calistoga
Llc), PCT Int. Appl. WO 2013/082540 A1, 2013.
[13] D. Xi, T. Wang, X. Feng, S. Wu, T. Zhang, L. Wang,
(Sunshine Lake Pharma Co., Ltd., Calitor Sciences, Llc),
PCT Int. Appl. WO 2016/14960 A1, 2016.
[3] a) K. W. Fowler, D. Huang, E. A. Kesicki, H. C. Ooi,
A. R. Oliver, F. Ruan, J. Treiberg, (Icos Corporation),
PCT Int. Appl. WO 2005/113556 A1, 2005; b) A. E.
Garces, M. J. Stocks, J. Med. Chem. 2019, 62, 4815–
4850; c) M. W. D. Perry, R. Abdulai, M. Mogemark, J.
Petersen, M. J. Thomas, B. Valastro, A. Westin Eriksson,
J. Med. Chem. 2019, 62, 4783–4814.
[4] a) L. Patel, J. Chandrasekhar, J. Evarts, K. Forseth, A. C.
Haran, C. Ip, A. Kashishian, M. Kim, D. Koditek, S.
Koppenol, L. Lad, E.-I. Lepist, M. E. McGrath, S.
Perreault, K. D. Puri, A. G. Villaseñor, J. R. Somoza,
B. H. Steiner, J. Therrien, J. Treiberg, G. Phillips, J.
[14] N. Mekala, S. R. Buddepu, S. K. Dehury, K. M. V. R.
Moturu, S. K. V. Indukuri, U. R. Vasireddi, A. R. Parimi,
RSC Adv. 2018, 8, 15863–15869.
[15] P. Zhichkin, E. Kesicki, J. Treiberg, L. Bourdon, M.
Ronsheim, H. C. Ooi, S. White, A. Judkins, D. Fairfax,
Org. Lett. 2007, 9, 1415–1418.
[16] K. J. McKnelly, W. Sokol, J. S. Nowick, J. Org. Chem.
2020, 85, 1764–1768.
[17] a) V. A. Jaffett, A. Nerurkar, X. Cao, I. A. Guzei, J. E.
Golden, Org. Biomol. Chem. 2019, 17, 3118–3128;
b) C. E. Schroeder, S. A. Neuenswander, T. Yao, J.
Aubé, J. E. Golden, Org. Biomol. Chem. 2016, 14, 3950–
Adv. Synth. Catal. 2021, 363, 1638–1645
1644
© 2021 The Authors. Advanced Synthesis & Catalysis
published by Wiley-VCH GmbH

COMMUNICATIONS
asc.wiley-vch.de
3955; c) C. E. Schroeder, T. Yao, J. Sotsky, R. A. Smith, [19] a) T. Miyazawa, T. Donkai, T. Yamada, S. Kuwata, Int.
S. Roy, Y.-K. Chu, H. Guo, N. A. Tower, J. W. Noah, S.
McKellip, M. Sosa, L. Rasmussen, L. H. Smith, E. L.
White, J. Aubé, C. B. Jonsson, D. Chung, J. E. Golden,
J. Med. Chem. 2014, 57, 8608–8621.
J. Pept. Protein Res. 1992, 40, 49–53; b) T. Miyazawa,
T. Otomatsu, T. Yamada, S. Kuwata, Tetrahedron Lett.
1984, 25, 771–772; c) S.-Y. Han, Y.-A. Kim, Tetrahedron
2004, 60, 2447–2467.
[18] a) L. Mao, Z. Wang, Y. Li, X. Han, W. Zhou, Synlett [20] M. M. Aly, Y. A. Mohamed, K. A. M. El-Bayouki, W. M.
2011, 2011, 129–133; b) B. Li, J. Zhang, Y. Xu, X. Yang,
L. Li, Tetrahedron Lett. 2017, 58, 2374–2377; c) N. R.
Gangarapu, E. K. Reddy, A. M. Sajith, S. Yellappa, K. B.
Chandrasekhar, ChemistrySelect 2017, 2, 7706–7710.
Basyouni, S. Y. Abbas, Eur. J. Med. Chem. 2010, 45,
3365–3373.
Adv. Synth. Catal. 2021, 363, 1638–1645
1645
© 2021 The Authors. Advanced Synthesis & Catalysis
published by Wiley-VCH GmbH