Skeletal Diversity in Combinatorial Fashion: A New Format for the Castagnoli-Cushman Reaction

Article abstract of DOI:10.1021/acscombsci.7b00118

A new format for the Castagnoli-Cushman reaction of structurally diverse dicarboxylic acids, amines, and aldehydes in the presence of acetic anhydride as dehydrating agent is described. The reaction is distinctly amenable to parallel format: the combinato

Full text of DOI:10.1021/acscombsci.7b00118

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Article
Skeletal Diversity in Combinatorial Fashion: A
New Format for the Castagnoli-Cushman Reaction
Anastasia Lepikhina, Dmitry Dar'in, Olga Bakulina, Evgeny Chupakhin, and Mikhail Krasavin
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.7b00118 • Publication Date (Web): 11 Oct 2017
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Skeletal Diversity in Combinatorial Fashion: A New Format for the
Castagnoli-Cushman Reaction
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Anastasia Lepikhina, Dmitry Dar’in, Olga Bakulina, Evgeny Chupakhin, and Mikhail Krasavin*
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Skeletal Diversity in Combinatorial Fashion: A New Format for the
Castagnoli-Cushman Reaction
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Anastasia Lepikhina,† Dmitry Dar’in,† Olga Bakulina,† Evgeny Chupakhin,‡ and Mikhail
Krasavin†,‡,*
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† Saint Petersburg State University, Saint Petersburg, 199034 Russian Federation
‡ Immanuel Kant Baltic Federal University, Kaliningrad, 236016 Russian Federation
ABSTRACT: A new format for the CastagnoliꢀCushman reaction of structurally diverse
dicarboxylic acids, amines and aldehydes in the presence of acetic anhydride as dehydrating
agent is described. The reaction is distinctly amenable to parallel format: the combinatorial array
of 180 reactions delivered 157 products of >85% purity without chromatographic purification (of
this number, 143 compounds had >94% purity). The new method offers a convenient preparation
of the skeletally and peripherally diverse, leadꢀ and druglike γꢀ and δꢀlactam carboxylic acids
with high diastereoselectivity in combinatorial fashion.
KEYWORDS: diversityꢀoriented synthesis, skeletal diversity, multicomponent reactions,
CastagnoliꢀCushman reaction, cyclodehydration, Schiff bases, phase separation.
INTRODUCTION
The ultimate goal of diversityꢀoriented synthesis (DOS)1 is to be able to control the structural
diversity of the resulting compounds at the skeletal (scaffold) level with the same degree as
combinatorial chemistry allows controlling the diversity of periphery appendages on a given
scaffold. This concept was reduced to practice for the first time over 10 years ago in the seminal
works of Schreiber and Burke.2ꢀ3 The principal strategy underpinning the realization of this
revolutionary approach to sampling the chemical space was in the design of such a common
precursor molecule which would act as a substrate toward numerous sets of reagents and
conditions, delivering a unique molecular scaffold in each case.4 Although the design of such
pluripotent precursors remains the principal challenge, this does not seem to hinder the steady
development of DOS into a routine compound collection enrichment and drug discovery
technology.5
While offering a high degree of peripheral diversity and definitely amenable to parallel format,6
multicomponent reactions tend to deliver redundant skeletons unless the variation in the reagent
space also results in a variable scaffolds. The latter situation is nicely illustrated by the
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employment of different oxocarboxylic acid bifunctional reagents 1 in the Ugi reaction, in which
case a variety of lactam frameworks 2 can be harvested.7 This approach to scaffold diversity,
however, can be seldom exploited in the array format as the reaction conditions need to be
tailored to each type of 1.8 Another multicomponent reaction leading to, primarily, δꢀ and γꢀ
lactams 3 (recently also shown to deliver εꢀlactams9) is the CastagnoliꢀCushman reaction
(CCR)10 of imines 4 (preformed from the respective amines 5 and aldehydes 6) with a variety of
cyclic αꢀCꢀH anhydrides 7. Compounds 3 are based on a saturated (highꢀFsp3),11 relatively
hydrophilic scaffold and are distinctly stereodefined (and can be produced in either trans- or, less
commonly, cis-configuration12), which makes them ideal13 potential starting points (leads) for
medicinal chemistry optimization, should an associated bioactivity be discovered. For a long
time, the range of cyclic anhydrides 7 employable in the CCR14 remained limited to succinic,
glutaric and homophthalic anhydrides. These three have been reported to react under a unified
array chemistry format with imines 4.15 Recently, we added various heteroatomꢀincluding
analogs of glutaric anhydride to the arsenal of reagents for the CCR.16 These, as any other cyclic
anhydride, are prepared via the dehydration of respective dicarboxylic acids 8. This, in principle,
adds an additional chemical operation en route to 3 and an extra set of variables as to the
reaction conditions. Moreover, cyclic anhydrides 7 are hydrolytically prone17 and can convert
back to 8 if not stored with care. Based on these considerations, we decided to investigate if the
reagent space for the CCR could be altered to primary amines (5), carbonyl compounds (6) and
αꢀCꢀH dicarboxylic acids (8). The latter are easier to prepare and handle and can be dehydrated
in situ, which would make the reaction amenable to parallel format for a wider range of cyclic
anhydride components and can potentially eliminate the need to maintain strictly anhydrous
conditions while carrying out the reaction array (Figure 1). Herein, we report on a successful
realization of this strategy.
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Figure 1. Multicomponent reactions generating skeletal product diversity.
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RESULTS AND DISCUSSION
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Cyclic anhydrides 7 are known to enter the CCR under a range of conditions – from room
temperature in polar solvent such as acetonitrile to reflux in highꢀboiling hydrocarbon solvents
such as toluene or xylenes.14 In order to allow conducting combinatorial synthesis of lactams 3
with variety of anhydride precursors 8 (Figure 2), after preliminary experimentation, we selected
highꢀboiling chlorobenzene as the solvent of choice both for the in situ formation of imine 4
from 5 and 6 and for the subsequent reaction of 4 with 8 under dehydrative conditions.
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Table 1. Substrate scope for the new format of the CCR.
Our goal was to minimize the number of manipulations required to preꢀform the imine 4 in situ
and bring it in contact with dicarboxylic acid 8 in presence of an efficient dehydrating agent. To
this end, we tested the formation of 4 in chlorobenzene in presence of 4Ǻ molecular sieves and
1
found it (by H NMR monitoring of the reaction progress) to go to completion after 2 h for
aliphatic amines and after 24 h for anilines. We then attempted adding 8 directly into the solution
of 4 containing molecular sieves followed by addition of acetic anhydride as the dehydrating
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agent. However, after reacting these components at 150 ºC for 16 h (i. e., the conditions we
found previously to be sufficient to achieve full conversion in most of the CCRs) rather
unsatisfactory results in terms of the product yield and purity were obtained. We reasoned that at
higher temperature, molecular sieves could release water (absorbed in the course of formation of
4) which may interfere with the course of the CCR. Simply removing the molecular sieves by
filtration led to a marked improvement of the reaction outcome. Therefore, we adopted this
procedure as the new general protocol (see Experimental Procedures) for the CCR and applied it
to a wide range of substrates 5, 6 and 8 (Table 1).
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It should be noted that the use of acetic anhydride appears to be optimal for the successful
outcome of the reaction. For instance, using thionyl chloride to achieve in situ dehydration of 8
in presence of 4 was found to deliver no CCR product whatsoever, presumably, due to the high
concentration of HCl in the reaction mixture. The same could be the reason for the failed CCR
when oxalyl chloride was tested as the dehydrating agent. The later was recently shown to bring
about efficient cyclodehydration of a range of dicarboxylic acids.18 However, its use in the oneꢀ
pot CCR format discussed herein was ineffective.
After reacting imines 4 with dicarboxylic acids 8 in presence of a slight excess of acetic
anhydride in chlorobenzene at 150 ºC for 16 h, aqueous potassium bicarbonate solution was
added to neutralize the acetic acid produced in the course of the dehydration of 8 and to convert
product carboxylic acids 3 into respective waterꢀsoluble potassium salts. This allowed extracting
byꢀproducts into an organic solvent (DCM), after which the target products 3 simply precipitated
from the neutralized aqueous phase. All reactions were performed in parallel format in screwꢀ
capped thickꢀwalled tubes equipped with the stirrer; liquidꢀliquid and liquidꢀsolid phase
separation was performed with an aid of a centrifuge, in centrifuge tubes (see Experimental
Procedures). Notably, no specific preꢀcautions were taken to exclude air or moisture.
The results presented in Table 2 clearly show that this convenient synthesis and isolation
protocol led to high purities and mediumꢀtoꢀhigh yields of target carboxylic acids 3 in the
majority of cases among the 180 reactions performed. For some highly lipophilic (cLogP > 4)
products derived from starting material 8{5}, the isolated yields of 3 were initially rather poor,
most likely due to low solubility of the respective carboxylate salts in the aqueous medium.
Hence, an alternative isolation protocol was applied involving simple crystallization of the crude
product mixture, which raised the yields and resulted in high product purities. Interestingly, the
use of 3,3ꢀgemꢀdialkylꢀsubstituted dicarboxylic acids 8{7} and 8{8} resulted in markedly poorer
results: in nearly half the cases, product purities were lower than 85% (in these as well as in
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other similar cases we did not undertake chromatographic purification, considering the overall
high success of this reaction array); in three cases, no product 3 formed at all and in all other
cases when product 3 purity was satisfactory, the isolated yield was quite low. This result is in
line with the previously observed19 lower reactivity of the respective cyclic anhydrides 7, most
likely attributable to the sterically hindered character of the αꢀcarbon atom in the latter which is
a key player14 in the formation of the target lactam framework.
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Table 2. Results (isolated yield,a product purity,b diastereomeric ratio,c cLogPd, isolation
methode) obtained in the combinatorial array of 180 CCRꢀbased syntheses of lactams 3{5,6,8}.
8{1}
8{2}
8{3}
8{4}
8{5}
8{6}
8{7}
8{8}
8{9}
68%
(6.6:1)
[1.87]
93%
(trans)
[1.18]
73%
(8:1)
[2.41]
66%
(15:1)
[2.01]
53%
(9:1)
[2.42]
64%
(8:1)
[1.31]
40%
(10:1)
[2.65]
85%
(8:1)
[2.42]
76%
89%
(5:1)
[2.22]
89%
(6:1)
[1.52]
60%
(5:1)
[2.76]
76%
(trans) (trans)
[2.36]
58%
(3.3:1)
[2.76]
63%
(10:1)
[1.66]
63%
68%
(7:1)
[2.01]
67%
(5:1)
[2.49]
80%
(7:1)
[1.80]
48%
68%
(6.6:1) (trans)
[1.87]
75%
(10:1)
[3.08]
88%B
82%
49%
(6:1)
[3.25]
41%
40%
(7:1)
[3.73]
42%
(5:1)
[3.04]
72%
(trans)
[2.63]
60%
(trans)
[1.94]
38%
(trans)
[3.31]
68%
4{1,1}
4{2,1}
4{3,1}
4{1,2}
4{5,1}
4{2,2}
4{4,1}
4{1,3}
[1.70]
82%
(trans) (4.5:1)
[1.00]
60%
(11:1)
[1.31]
46%
(10:1)
[2.62]
71%
[2.56]
86%
(5.5:1) (trans) (trans)
[3.12]
56%
(7:1)
[2.63]
43%
(13:1)
[3.04]
50%
[4.45]
71%
(8:1)
[2.34]
83%
37%
32%
(trans) (4.5:1) (6.5:1) (trans)
[1.84]
67%
[2.14]
47%
(9:1)
[2.30]
[3.91]
[3.39]
13%
[3.39]
17%
(14:1)
[4.28]
15%
[2.77]
48%
(4.3:1)
[4.34]
78%
91%B
(trans) (trans) (4.3:1)
[4.32]
40%
(10:1)
[2.65]
63%B
[2.24]
40%
(10:1)
[2.65]
78%
[3.80]
8%
54%
(trans)
[1.45]
27%
(13:1)
[2.54]
62%
(8:1)
[2.55]
59%
(9:1)
[1.93]
26%
(3.5:1) (3.8:1) (trans)
[2.69]
[3.17]
[2.07]
55%
(trans)
[4.57]
64%
(9:1)
[3.00]
90%
(5:1)
[2.77]
75%
(trans) (trans) (trans)
[3.27]
50%
(trans) (trans) (trans)
[3.04]
63%
[4.56]
74%
[2.48]
95%
61%
(5:1)
[3.80]
30%
44%
(trans) (trans)
[4.28]
[4.32]
65%
[2.24]
81%
[3.18]
69%
4{2,3}
4{5,3}
(8:1)
[1.72]
76%
(10:1)
[2.07]
86%
(14:1)
[1.85]
56%
(8:1)
[2.34]
76%
(trans) (trans)
(4:1)
[3.10]
(trans)
[2.48]
55%
[3.36]
[1.55]
62%B
89%
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(9:1)
[2.96]
60%
(8.5:1)
[3.20]
77%
(8:1)
[3.31]
32%
(8:1)
[3.54]
33%
(trans)
[2.85]
42%
(10:1)
[3.08]
65%
(10:1)
[3.58]
74%
(7:1)
[3.82]
(5.5:1) (trans)
(trans)
[4.88]
63%
(trans)
[5.12]
75%
(trans)
[3.31]
58%
(trans)
[4.71]
58%
(trans)
[3.45]
65%
(trans)
[3.78]
[4.86]
[2.79]
86%
75%B
4{4,3}
4{3,3}
4{4,2}
4{3,2}
4{5,2}
4{6,4}
4{7,5}
4{8,6}
4{9,7}
4{10,8}
(trans) (trans)
[5.10]
90%B
(6:1)
[3.02]
82%
(trans)
[2.89]
75%
52%
(6:1)
(7.5:1) (3.5:1) (7.5:1)
[2.95]
15%
(9:1)
[2.79]
[3.30]
49%
(9:1)
[3.14]
89%
(2:1)
[2.89]
67%
[3.78]
31%
(10:1)
[2.68]
77%
(4:1)
[2.75]
47%
(4:1)
[2.44]
43%
[3.67]
69%
(10:1)
[3.41]
44%
[4.99]
9
89%B
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(trans) (trans)
[4.69]
[2.62]
80%
60%B
(5.5:1) (trans) (trans)
[3.26]
67%
(9:1)
[3.17]
43%
[4.59]
[2.48]
75%
63%
(7.5:1) (7.5:1)
[2.55]
94%
(11:1)
[1.45]
50%
80%B
(trans) (trans)
[2.90]
52%
(11:1)
[1.80]
59%
[4.46]
[2.38]
66%
66%
18%
(8:1)
[2.83]
29%
21%
(6:1)
[3.31]
30%
(5:1)
[3.20]
11%
(trans) (9.3:1) (trans) (trans)
[1.58]
56%
[2.07]
45%
[3.36]
[1.28]
81%
81%
74%
(trans)
[2.10]
77%
(trans) (trans) (trans) (trans) (trans) (trans) (5.3:1)
[1.34]
33%
(trans) (trans) (trans) (6.5:1) (trans) (trans)
[0.69]
48%
(5.5:1) (6.7:1)
[2.37]
33%
[1.69]
52%
[1.47]
32%
[1.96]
60%
[3.25]
75%
[1.17]
79%
[2.72]
8%
(5:1)
[2.07]
(4.3:1) (trans)
[1.04]
48%
[0.82]
42%
(5:1)
[2.50]
38%
(6:1)
[3.67]
[1.31]
78%
[2.59]
[0.52]
81%
[2.55]
[1.45]
75%
(trans)
[3.13]
50%
(trans)
[4.30]
76%B
(8.8:1) (trans) (trans)
[2.99]
37%
(trans) (trans) (trans)
[3.36] [5.44] [3.36]
[2.72]
35%
(15:1)
[3.88]
[4.27]
[2.19]
58%
75%B
(16:1)
[3.54]
aYield (%) of isolated and fully characterized (ESI) product (purity >85% only).
bProduct purity range: >94%, 85–94%, <85% (not isolated), no product.
cRatio of trans(major) : cis(minor)ꢀconfigured lactams 3 according to integration of characteristic
signals in the 1H NMR spectrum (shown in round parentheses).
dCalculated using ACD Labs 10.0 software (shown in square parentheses).
eMethod A – throughout unless noted (xx%B) otherwise.
The selection of product structures obtained in >94% purity using the approach described (Figure
2) clearly demonstrate the power of the CCR in controlling both the periphery and skeletal
diversity of the respective lactams 3, now in combinatorial fashion. As we did not set any
conscious boundaries to the physicochemical properties of the reagents 5, 6 and 8 utilized in the
described array, we were also curious to see if the 157 products obtained in >85% purity from
the 180 combinatorial reactions (87% success rate) conform to the rules of drugꢀ20 and leadꢀ
likeness.21 As it can be seen from Figure 3, only three compounds lie outside of the ruleꢀofꢀfive
(Ro5 of Lipinski’s rules of druglikeness) boundaries and a good number of products 3 fall within
rather strict limits of ruleꢀofꢀthree (or leadꢀlikeness). At the same time, the highly hydrophilic
area (cLogP<3) is quite substantially populated.
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CO2H
CO2H
CO2H
CO2H
O
O
N
N
O
Me
O
N
N
F
F
7
OMe
8
9
3{5,3,1}
76% (dr 9:1)
3
{1,1,2}
3{1,2,1}
66% (dr 15:1)
OMe
3{5,2,2}
OMe
89% (dr 5:1)
67% (dr 7.5:1)
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S
N
CO2H
O
CO2H
O
CO2H
O
O
N
O
N
Me
Me
OMe
3
{3,3,4}
52% (dr 6:1)
3{3,1,3}
3{4,3,3}
42% (dr 10:1)
MeO
MeO
46% (dr 10:1)
CO2H
F
S
N
CO2H
CO2H
CO2H
O
O
N
O
N
O
N
F
OMe
Me
MeO
3{1,3,8}
3{2,1,7}
3
3
{2,2,4}
57% (trans)
{7,5,7}
29% (dr 5:1)
44% (trans)
41% (dr 4.5:1)
SO2Me
SO2Me
SO2Ph
N
CO2H
N
CO2H
N
CO2H
CO2H
S
O
N
O
N
O
N
O
N
CO2Me
F
3{6,4,8}
21% (dr 6:1)
3{9,7,6}
81% (trans)
3{4,2,6}
75% (trans)
3
{10,8,5}
75% (trans)
F
SO2Ph
N
CO2H
CO2H
CO2H
O
N
O
N
O
N
OMe
F
OMe
3{8,6,9}
77% (trans)
NO2
MeO
OMe
3{3,2,9}
58% (trans)
3
{5,1,5}
91% (trans)
Figure 2. Representative lactams 3{5,6,8} obtained in this work.
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Figure 3. Drugꢀ and leadꢀlikeness (MW/cLogP) of the lactams
3 obtained in this work.
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CONCLUSIONS
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We have described a novel format for the CastagnoliꢀCushman reaction which relies on the
arsenal of structurally diverse dicarboxylic acids which is much more readily available compared
to the respective cyclic anhydrides (the latter are also hydrolytically prone that limits their
storage and mandates special handling). The reaction is distinctly amenable to parallel format
and clearly offers a simultaneous control of over the periphery groups and the skeleton. The
latter consideration aligns this method with the spirit of diversityꢀoriented synthesis. No
chromatographic purification was employed to obtain the products and yet 157 compounds were
obtained in >85% purify from 180 reactions, of which number 143 compounds had purity of
>94%, clearly attesting to the high combinatorial efficiency of the method. The compounds
obtained are within the limits of druglikeness and a large portion thereof – within the leadꢀlike
property space. This makes these compounds useful tools for the interrogation of biological
targets, which would offer ample room for medicinal chemistry optimization should any
promising biological activity be discovered.
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EXPERIMENTAL PROCEDURES
General Procedure (Method A) for the Synthesis of Lactams 3. Amine
5 (10 mmol) and
aldehyde (10 mmol) were combined in chlorobenzene (20 mL). Activated 4Ǻ molecular sieves
6
(0.8 g) were added and the mixture was shaken for 2 h (for aliphatic amines) or 24 h (for
aromatic amines) at room temperature. The molecular sieves were filtered off and equal volume
(2 mL, 1 mmol) of the imine
4
solution thus obtained was added to thickꢀwalled, screwꢀcapped
(0.9 mmol). Acetic
tubes equipped with a magnetic stirrer, containing dicarboxylic acids
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anhydride (1.1 mmol) was added to each reaction vessel. The latter were capped and heated
under stirring at 150 ºC for 16 hours. Upon cooling of the reaction tubes to ambient temperature,
5% aqueous KHCO3 solution (6 mL) was carefully added to each tube (gas evolution!). The
reaction mixtures were transferred to 15 mL centrifuge tubes and the reaction vessels were
additionally rinsed with dichloromethane (1 mL) and 5% aqueous KHCO3 solution (2 mL). The
vials were vigorously shaken for 30 min and then centrifuged at 4700 rpm for 5 min to ensure
efficient phase separation. The lower (dichloromethane) layer was carefully removed by a pipette
and the pH of the aqueous layer was carefully adjusted to 3.0 with concentrated HCl (gas
evolution!). The mixtures containing thick product precipitates were centrifuged at 5 ºC and
4700 rpm for 20 min. The supernatant was decanted and the solid residue was washed with water
(5 mL), separated by a repeat centrifugation and dried at 70 ºC. If oilꢀlike residues were obtained
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at this point, these were extracted with ethyl acetate, the extracts were dried over anhydrous
MgSO4 and evaporated to dryness.
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General Procedure (Method B) for the Synthesis of Lactams 3. This method is identical to
Method A except for the product isolation procedure. Reaction mixtures obtained were
evaporated to dryness. Dichloromethane (5 mL) was added and the resulting solutions were
chilled to 5 ºC overnight. The resulting precipitate was filtered off and airꢀdried. If the
precipitate did not form, dichloromethane was evaporated and the residue was triturated with
hexane (12 mL) and the solid thus formed was dried in vacuo.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
10.1021/acscombsci.xxxxxxx. Characterization and full spectroscopic data (1H, 13C NMR,
HRMS) of compounds
3 (PDF).
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: m.krasavin@spbu.ru
ORCID
Olga Bakulina: 0000ꢀ0002ꢀ4930ꢀ0739
Dmitry Dar’in: 0000ꢀ0002ꢀ0413ꢀ7413
Mikhail Krasavin: 0000ꢀ0002ꢀ0200ꢀ4772
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This research was supported by the Russian Scientific Fund (project grant 14ꢀ50ꢀ00069). We are
grateful to the Research Centre for Magnetic Resonance and the Centre for Chemical Analysis
and Materials Research of Saint Petersburg State University Research Park for the analytical
data.
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