Post-Ugi Cascade Transformations for Accessing Diverse Chromenopyrrole Collections

Article abstract of DOI:10.1021/acs.orglett.7b03986

Employing a build/couple/pair strategy, a serendipitous one-pot protocol for the diastereoselective construction of diverse collections of chromenopyrroles is described. This methodology features an unprecedented five-step cascade including azomethine ylide generation followed by in situ intramolecular [3 + 2]-cycloaddition. Furthermore, this protocol was extended to access enantiopure chromenopyrroles using amino acids as chiral auxiliary. Moreover, postpairing reactions were employed to increase the diversity and complexity of our pilot compound collections.

Full text of DOI:10.1021/acs.orglett.7b03986

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Post-Ugi Cascade Transformations for Accessing Diverse
Chromenopyrrole Collections
†
,‡
§
†
§
Vunnam Srinivasulu, Scott McN. Sieburth,* Raafat El-Awady, Noor M. Kariem, Hamadeh Tarazi,
∥
,†,§
Matthew John O’Connor, and Taleb H. Al-Tel*
†
§
Sharjah Institute for Medical Research and College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, UAE
‡Department of Chemistry, Temple University, 201 Beury Hall, Philadelphia, Pennsylvania 19122, United States
∥New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island, Abu Dhabi, UAE
*
S Supporting Information
ABSTRACT: Employing a build/couple/pair strategy, a serendipitous one-pot protocol for the diastereoselective construction
of diverse collections of chromenopyrroles is described. This methodology features an unprecedented five-step cascade including
azomethine ylide generation followed by in situ intramolecular [3 + 2]-cycloaddition. Furthermore, this protocol was extended to
access enantiopure chromenopyrroles using amino acids as chiral auxiliary. Moreover, postpairing reactions were employed to
increase the diversity and complexity of our pilot compound collections.
he burgeoning interest in phenotypic screening as an
1a,b
T
alternative tool to target-based screening
has been
validated by a recent FDA study finding that more first-in-class
2a
small molecules were discovered using the former method. In
this context, a great challenge in a phenotypic-screening
campaign is the development of modular synthetic procedures
for the rapid access of complex compound collections possessing
the stereochemical and skeletal diversity needed for compre-
hensive structure−activity relationship (SAR) studies. Privileged
substructure diversity-oriented synthesis (pDOS) is a prominent
tool for generating and identifying small molecules that can
2
,3
Figure 1. Representative bioactive chromenopyrrole structures.
modulate disease-relevant protein functions. Among the
attractive structural options are the chromenopyrrole analogues
exemplified by the marine alkaloids ningalin B (A) and lamellarin
D (B), which display a variety of biological activities including
long reaction times, and expensive catalysts and reagents and
allow low structural variability of the reactants. During our
ongoing studies of efficient one-pot methodologies to prepare
privileged substructures present in biologically significant
4
−6
potential treatments for CNS disorders (Figure 1). Addition-
ally, chromenopyrrole derivatives were also reported to possess
anticancer, antimicrobial, antioxidant, and antileishmanial
1
1
compounds, we encountered an unprecedented cascade
reaction that provides a conceptually distinct approach to the
synthesis of functionalized chromenopyrroles; it is reported here.
The serendipitous cascade reaction was discovered while
attempting the synthesis of the 9-membered ring system,
7
−9
activities.
Owing to their remarkable biological activities, many synthetic
methods have been developed to access chromenopyrrole
8
,10
derivatives (see the Supporting Information).
Strategies to
1
0o
benzo[b,g][1,5]oxazonine 7b (Scheme 1).
The initial
access these scaffolds include 1,3-dipolar cycloaddition via base-
1
0k
synthetic design was inspired by our previous utilization of
catalyzed deprotonation of amino acids;
azomethine ylide
11c
4
g
compound 3a to access complex oxazepine scaffolds. To test
our intramolecular Diels−Alder reaction scheme, the model
substrate 7a was prepared using a four component Ugi protocol.
cycloaddition; a three-component synthesis combining a 4-
aminocoumarin, aldehydes, and nitromethane;
10m
and a Pd(II)-
catalyzed oxidative annulation of 4-aminocoumarins with
1
0n
alkynes.
Although these protocols are useful methods for the synthesis
Received: December 22, 2017
of chromeno[4,3-b]pyrroles, they require multistep reactions,
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03986
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Zinc Bromide Unexpected Cascade Leading to the
Formation of Tricyclic Chromeno[4,3-b]pyrrole 8a
Scheme 2. Proposed Mechanism for the Formation of
Chromenopyrrole Systems
Unfortunately, subjecting 7a to a broad set of catalysts and
reaction conditions failed to induce formation of Diels−Alder
product 7b, leading only to recovery of 7a or formation of
complex reaction products. Nevertheless, we were delighted to
oxazolidinone IV should deliver the second azomethine ylide V.
Subsequent 1,4-proton migration proceeds to give the
chromenopyrrole final product 8a with the most stable cis ring
fusion. The fact that no reaction occurs in the absence of the
find that using ZnBr catalysis gave a single, yet unexpected,
ZnBr catalyst provides corroboration for the hypothesis that the
2
2
product. Extensive spectroscopic analysis unambiguously iden-
tified this compound as chromeno[4,3-b]pyrrole 8a, isolated in
initial step involves O-acylation reaction leading to the
oxazolidinone intermediate III through the proposed azome-
thine yilde intermediate. Many additional experiments in which
65% yield. This sequence has turned out to be a general approach
to these structures, and here we report its successful employment
with functionalized carboxylic acids, amines, isocyanides, and
Michael acceptors to generate a set of diversely substituted
chromenopyrroles (see Scheme 3).
As described in Scheme 1, our synthetic plan contemplated
the same coupling was attempted in the absence of ZnBr led
only to the recovery of the Ugi product, with no evidence of the
cyclized product 8a.
The stereochemistry around 8a was elucidated using 1D- and
2D-NMR spectroscopy. The chemical shift of the pyrrolidyl
2
12
systems of type 8a, which were to be constructed by utilizing a
methine proton (H ) in 8a appeared at δ 4.50 ppm as a doublet (J
a
13
build/couple/pair strategy. In this, the build stage begins with
the synthesis of compound 3a obtained by reacting 2-
hydroxybenzaldeyde (1), with trans-4-bromobutenoate (2)
= 8.0 Hz), consistent with cis ring fusion. The two protons at the
pyrrolidylbenzopyran ring fusion also showed strong reciprocal
NOESY interactions, unambiguously confirming a cis relation-
ship (Figure 1, SI). To understand the stereochemistry obtained
for 8a, one needs to consider its two most accessible
conformations A and B (Figure 2, SI). The structural elements
in conformer C (59 kcal/mol) are such that steric bias is minimal
and more conducive, favoring the formation of the cis product
after 1,4-proton rearrangement. The situation is precisely
reversed in intermediate D (177 kcal/mol), where the potential
for substantive steric compression is obvious. Therefore,
intermediate C should be thermodynamically more relevant
intermediate furnishing the cis product.
employing a traditional S 2 reaction (Scheme 1). The couple
N
stage then involves the use of an Ugi-multicomponent reaction
(MCR), which combines the key building block 3a with
commercially available components (e.g., 4a, 5a, and 6a) leading
to dipeptides of type 7a. The reactive functionalities present in
compound 7a were then paired through a tandem acylation/
azomethine yilde formation/cycloaddition process. To optimize
the conditions for this serendipitous cascade, many Lewis and
Bronsted acids were screened as possible promoters of the
desired reaction, including, Sc(OTf) , TFA, and AcOH. With the
3
first two, in a variety of solvents and at a range of temperatures
under anhydrous conditions, no significant clean reaction
occurred. When catalytic or equimolar quantities of acetic acid
were used, substantial decomposition was observed. Ultimately,
With successful reaction conditions defined, the generality of
the method was evaluated by preparation of a broad set of
analogues of 8a, shown in Scheme 3. All of the amine and acids
tested led to the expected products. Altering the aromatic
substitutions on the methylamine and the phenylacetic acid was
readily accommodated (8b−e). Changing the benzylamine
component to an aniline derivative also gave the product, with
a changed skeleton, but in reduced yield, perhaps because of the
reduced nucleophilicity of the amine (8f, 8g). Alternatively,
increased steric congestion around the azomethine ylide with the
N-phenyl substitution could be lowering the yields for 8f and 8g
(Scheme 2). Changing the nitrogen substitution to 2-phenethyl
(8h) or isopentyl (8j) also led to good yields. The latter two cases
also carried n-alkyl substitution in place of the aryl acetic acid
component. Changing the starting phenyl acetic acid to 2-indole
(8i) led to the expected product albeit in modest yield.
it was discovered that ZnBr in dichloroethane (DCE) under
2
MW conditions provided the ideal conditions to promote the
desired cascade. Thus, we were delighted to observe the efficient
and diastereoselective formation of tricyclic chromenopyrrole 8a
in 65% yield by using 30 mol % of ZnBr under microwave
2
irradiation at 170 °C.
We then turned our attention to propose a plausible
mechanistic pathway of this cascade (Scheme 2). First,
coordination of the metal salt ZnBr , in I, catalyzes the O-
2
acylation by the tertiary amide leading to the tetrahedral
intermediate II. Rearrangement of the latter followed by
abstraction of the benzylic proton by the expelled strong base
t-BuNH group led to the generation of azomethine ylide III.
Consequently, intramolecular [3 + 2]-cyclization (as we have
assumed, Scheme 2) should deliver the highly strained
intermediate IV. Expulsion of the carbon dioxide from the
As a further step in building stereodefined products, the amino
acid phenylalanine was included in this study (Scheme 4). This
would have the advantage of potentially controlling absolute
stereochemistry. Both D- and L-phenylalanine (9a and 9b) were
B
DOI: 10.1021/acs.orglett.7b03986
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Preparation of Various Polysubstituted
Chromenopyrroles
Scheme 5. Post-Pairing Reaction Leading to Tetrasubstituted
Chromenopyrroles
using this chemistry is apparent when comparing the structure of
1
2 with the important cholesterol-lowering drug Lipitor.
A second postpairing application, the synthesis of the novel
compounds, tetrahydrobenzo[f]chromeno[4,3-b]indol-7-ol de-
rivatives, is shown in Scheme 6 using 3,4,5-trimethoxy- and 4,5-
Scheme 6. Post-Pairing Reaction Leading to
Tetrahydrobenzo[f ]chromeno[4,3-b]indol-7-ol Systems
Scheme 4. One-Pot Synthesis of Enantiomerically Pure
Chromenopyrroles
dimethoxyphenylacetic acids as the acid component in the Ugi
coupling step. Subjecting substrates 13a and 13b to 50 mol % of
ZnBr at 170 °C under microwave irradiation for 40 min gave
2
directly 15a and 15b in 59% and 45% yield, respectively.
Cyclization to give an additional ring by Friedel−Crafts acylation
was not a significant pathway even with electron-rich products
such as indole 8i; however, with the additional Lewis acid the
pentacyclic products 15 could be produced, presumably through
intramolecular Friedel−Crafts acylation of the di- and
trimethoxybenenes (for a proposed mechanism, see Scheme 3,
SI).
A third version of this reaction cascade provided a more direct
synthesis of pyrroles. Substituting a propargyl unit for the 4-
substituted butenoate, propynyl and butynyl substrates 16a and
used as the amine, as well as L-3,4-dimethoxyphenylalanine (9c),
in the initial Ugi coupling step. The additional steric hindrance
on the amine was well tolerated in the reaction sequence, yielding
the product in 39−43% yield. The three amines all gave a mixture
of two diastereomers (10a−c and 11a−c). In each case, the
mixture of 10 and 11 was formed in a ratio of ca. 7:3. The relative
stereochemistry between the phenylalanine starting reagent,
which remains untouched in the reaction sequence, and the
stereochemistry of the pyrrolidine−pyran ring fusion was proved
using NMR spectroscopic analysis relationship (see Figure 3, SI).
An additional step can be added to this reaction cascade,
adding tetrasubstituted pyrrole products to the set of compounds
that can be prepared with this chemistry. The reaction is shown
in Scheme 5 with 8h as the substrate. Polycyclic dihydropyrrole
1
6b were prepared. While the alkynes lack the activating
electron-withdrawing ester, they nevertheless underwent cyclo-
addition with the postulated azomethine ylid intermediate to give
1
7a and 17b, respectively, in very reasonable yields (Scheme 7).
These successful reactions are indicative of the broad
applicability of this preparative chemistry.
Scheme 7. Synthesis of Tetrasubstituted Chromenopyrroles
8
h was subjected to similar conditions used to prepare it, but
doubling the amount of ZnBr . Under these conditions, the
2
phenol ether underwent elimination, and isomerization gave the
pyrrole in 62% yield (for a proposed mechanism, see Scheme 2,
SI). The potential for preparing medically important products
C
DOI: 10.1021/acs.orglett.7b03986
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Organic Letters
Letter
To gain insight into the drug-likeness of the synthesized
compounds, we have calculated the relevant molecular
descriptors for prediction of standard physicochemical param-
eters linked to the oral bioavailability and drug-likeness pattern
according to the Lipinski “rule of five”. Most of the compounds
are compliant with the Lipinski rules attributed to the nature of
lead drug candidates (for discussion and calculated parameters,
see the SI).
In summary, the novel one-pot cascade methodology
described above is a broadly reliable and versatile tool for the
synthesis of a range of polysubstituted chromenopyrrole
scaffolds. The substrate scope is large and the diastereoselectivity
and the isolated yields are high under a single set of reaction
conditions, suggesting that diverse targeted libraries should be
readily synthesized using this protocol. Gratifyingly, in situ
intramolecular generation of a transient azomethine ylides avoids
the need for the more exotic approaches described in the
literature. Furthermore, the methodology provided access to
enantiomerically pure products when amino acids were used as
the reaction partners, hence increasing the 3D-diversity of our
pilot compound collection. In addition, the use of postpairing
transformations increased the complexity of our small library.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03986.
Previous approaches, stereochemical analysis, druglike
properties, mechanisms, characterization data, and NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*
E-mail: scott.sieburth@temple.edu.
E-mail: taltal@sharjah.ac.ae.
2
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*
S.; Pal, G.; Das, A. R. RSC Adv. 2013, 3, 8637. (n) Peng, S.; Wang, L.;
Huang, J.; Sun, S.; Guo, H.; Wang, J. Adv. Synth. Catal. 2013, 355, 2550.
ORCID
(o) Huang, J.; Du, X.; Van Hecke, K.; Van der Eycken, E. V.; Pereshivko,
Taleb H. Al-Tel: 0000-0003-4914-9677
Notes
P.; Peshkov, V. A. Eur. J. Org. Chem. 2017, 2017, 4379.
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Wirth, D. F.; Li, L.; Naumov, P.; O’Connor, M. J.; Al-Tel, T. H. Chem. -
Eur. J. 2017, 23, 4137. (b) Srinivasulu, V.; Janda, K. D.; Abu-Yousef, I. A.;
O’Connor, M. J.; Al-Tel, T. H. Tetrahedron 2017, 73, 2139.
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E. V. Chem. Soc. Rev. 2015, 44, 1836. (b) Pelish, H. E.; Peterson, J. R.;
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by generous grants from Al Jalila
Foundation, UAE (Grant No. AJF201531) and the Research
Funding Department, University of Sharjah-UAE (Grants Nos.
15011101007 and 15011101002).
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