Solid/solution-phase annulation reagents: Single-step synthesis of cyclic amine derivatives

Article abstract of DOI:10.1002/anie.200501665

Spanning the diversity gap: The conversion of primary amines into cyclic derivatives is achieved by using a family of amine-derivatizing reagents, termed SPAn reagents (see scheme). The reagents, which require no further chemical manipulation or activatio

Full text of DOI:10.1002/anie.200501665

Communications
Combinatorial Chemistry
DOI: 10.1002/anie.200501665
Solid/Solution-Phase Annulation Reagents:
Single-Step Synthesis of Cyclic Amine Derivatives
Roland E. Dolle,* Calum MacLeod, Blanca Martinez-
Teipel, William Barker, Pamela R. Seida, and
Torsten Herbertz
Single-step amine-derivatization chemistry is one of the most
powerful and practical streamlined synthetic techniques
available to the medicinal and combinatorial chemist. Acyl-
ation, sulfonylation, ureidoation, heteroarylation, reductive
amination, and alkylation are used extensively to create
libraries of amine derivatives.[1] Researchers involved in drug
discovery particularly appreciate the importance of such high-
throughput chemistries used to create nascent structure–
activity relationships (SARs) and to expand the intellectual
property field around a novel biologically active lead. Amine
derivatization is conveniently carried out in the solution
phase with a scavenger resin(s) to assist in the removal of the
excess derivatizing reagent and/or product purification.[2]
Activated resins have also been developed in which an
amine is treated with a resin-bound functional-group-transfer
reagent suspended in a suitable solvent.[3a] Following filtra-
tion, which removes both the spent and excess reagent, and
solvent evaporation, derivatives are generally produced in
over 75% purity, which is suitable for biological screening.
Examples of this type of reagent are the commercially
available carboxyl- and sulfonyl-activated tetrafluorophenol
(TFP) resins developed by Salvino et al. for amide and
sulfonamide synthesis.[3b]
During the course of a drug-discovery program directed
toward the identification of peripherally restricted k-opioid
receptor agonists, we conducted a high-throughput N-deriva-
tization campaign for diamine I, including the use of TFP
resins, to define the SAR in this region of the pharmacophore
(I!II; X = CO, SO2, HNCO; Scheme 1). In related SAR
studies, conformationally restricted analogues III were pre-
pared by ring-closing metathesis as the method for the
generation of the azepinone ring.[4] In contrast to the hours of
labor required to generate acyclic analogues II by semi-
automated parallel synthesis, the synthesis of cyclic analogues
III required a multistep sequence and several months of labor.
Access to robust reagents to carry out single-step amine
annulations would have accelerated the synthesis and biolog-
ical evaluation of III and related heterocyclic analogues.
However, there are no generally recognized “off-the-shelf”
[*] Dr. R. E. Dolle, Dr. C. MacLeod, Dr. B. Martinez-Teipel, W. Barker,
Dr. P. R. Seida, Dr. T. Herbertz
Department of Chemistry
Adolor Corporation
700 Pennsylvania Drive, Exton, PA 19341 (USA)
Fax : (+1)484-595-1551
E-mail: rdolle@adolor.com
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In light of this experience and the potential for the trouble-
some loading of other reactive esters of interest, an alter-
native method for the generation of the resin-bound reagent
was required. The copper(i)-catalyzed 1,3-dipolar cycloaddi-
tion of azides and terminal alkynes is a robust ligation method
that occurs under very mild reaction conditions.[7] Gmeiner
and co-workers recently employed this approach to create
new amide-backbone[8a,b] and acrylate-based (REM) link-
ers[8c] for solid-phase organic synthesis. With this method-
ology in mind, bromide 7a (5 equiv; prepared from 2-
bromomethylbenzoic acid (1equiv), propargyl alcohol
(3 equiv), N,N’-diisopropylcarbodiimide (1.2 equiv), and
dimethylaminopyridine (cat.) in 48% yield) was added to a
suspension of Merrifield azide resin[8a] in dichloromethane
followed by the addition of excess diisopropylethylamine
(DIEA) and 0.02 equivalents of CuI. The reaction was
monitored by single-bead FTIR (disappearance of absorption
at 2096 cmꢀ1), and resin 2a was obtained in good yield (65%
as determined by elemental analysis) after 20 hours on an
orbital shaker. Importantly, the loading was reproducible
(5 runs, 65–70% yield). Subsequent reaction of 2a with 2,2-
diphenylethylamine (2 equiv) in dimethyl sulfoxide (DMSO)
with excess MP-carbonate (7 equiv; Polymere Labs) under
microwave conditions (1508C for 15 min following a 30-min
temperature ramp-up from 25 to 1508C) afforded the desired
annulated product 4 in 90% crude purity (UV: l1 = 220 nm;
l2 = 254 nm) and 33% yield of the isolated product. It was
subsequently found that both the chloro and iodo ester
analogues of 2 also load efficiently, but only the iodo resin
gave equivalent or higher yields and purity of 4. For this
reason, bromide and iodide were the preferred halogen
leaving groups in the SPAn reagents. Unlike 1, which
spontaneously decomposed to 6 and other unidentified
materials, the resin-bound reagent 2a was stable for months
when stored at ambient temperature and humidity.
Scheme 1. Amine derivatization leading to k-opioid receptor
agonists.[4]
reagents for high-throughput amine annulation. An explor-
atory chemical-technology program was initiated to address
this gap in methodology, and so develop reagents for rapid
amine annulation. Approaches were sought to produce
monocyclic, bicyclic, spirocyclic, and polycyclic ring systems
from primary amines in one step that would be amenable to
semiautomated library production in a manner analogous to
the acyclic derivatization protocols. The acronym SPAn,
derived from solid/solution-phase annulation, collectively
refers to the technology, reagents, and products thereof. The
first examples of this conceptually new family of SPAn
reagents, which yield five-, six-, and seven-membered hetero-
cycles from primary amines, are introduced.
A tandem N-alkylation/intramolecular acylation reaction
that yields an isoindolinone was selected as the prototypical
annulation reaction to be investigated (1/2!3!4;
Scheme 2).[5] The results of the initial solution-phase experi-
Given the success of this first annulation reaction, the
chemistry was expanded to include homologue 2b and the
preparation of a 20-member library of isoindolinones 8 and
isoquinolones 9 (Table 1). A range of primary amine sub-
strates was successfully annulated in a single step, including
substituted alkyl- A1, A4; alkylaryl- A2, A9; heteroarylalkyl-
A3, A6–8; and heterocycloalkylamines A5 and the sterically
demanding 6b-naltrexamine (A10). An average yield of 30%
and a purity of greater than 90% was obtained following
chromatographic purification.
To explore the scope of the SPAn chemistry in terms of
ring sizes that may be obtained, iodo esters 10a–d were
synthesized (Scheme 3). Reaction of the resins with a
representative amine, phenoxyethylamine (A1), under the
reaction conditions defined above afforded pyrrolidinone
(11c; 29%) and piperidinone (11d; 24%; Scheme 4). Azetid-
inone (11a) and azepinone (11b) were not detected in the
crude reaction mixtures. Seven-membered-ring annulation
products were obtained, however, provided that a conforma-
tional constraint biased the system toward cyclization. For
example, reagents 10m–o, in which the acyl and haloalkyl
groups are ortho-disposed on an aromatic ring, furnished
11m, 11n, and 11o (21, 23, and 12%, respectively) upon
annulation of A1.
Scheme 2. Annulation strategy for isoindolinone 4.
ments with assorted esters 1 and 2,2-diphenylethylamine in a
range of solvents under both thermal and microwave reaction
conditions were unsatisfactory. As a result, our attention
turned to the employment of a cyclorelease strategy[6] and the
preparation of resin-bound reagent 2. The dilemma that
immediately surfaced with this approach was the efficient
loading of acid 5. Direct coupling of 5 to Wang resin by
employing a range of coupling reagents and reaction con-
ditions resulted in capricious loading, even when 5 was used in
large excess. Substantial amounts of lactone 6 formed, which
is a testament to the reactivity and instability of this material.
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Table 1: Isoindolinone 8 and isoquinolone 9 library from SPAn reagents
2a,b.
(phenyl) or alkyl (ethyl) groups furnishes substituted pyrro-
lidinones 11e,f and piperidinones 11g–i (A1; 23–62% yield).
This result is significant for two reasons: First, the chemical
reactivity of the SPAn reagents was expanded to include
displacement of less-reactive nonbenzylic halogen centers in
the tandem alkylation/intracyclization process. Second, the
unique three-dimensional disposition of the ring function-
alities present in 11e–i permits a thorough interrogation of
biological space. The differential display of the chemical
functionalities by the annulation products is ideal for the
development of a SAR against a given molecular target.
These results are analogous, albeit accentuated by the
conformational rigidity of the cyclic derivatives, to SAR
information that may be obtained when traditional acyclic
derivatization is performed. The swath of chemical space
occupied by the SPAn products is assessed visually by
examination of the overall topography of all of the annulation
products listed in Scheme 4 (Figure 1a). The importance of
shape sampling in relation to biological activity is illustrated
in the derivatization of 6b-naltrexamine (A10) with reagents
2a,b. The a-phenylpyrrolidinone derivative 8j exhibits a
Ki value of 1.6 nm against the m-opioid receptor, whereas Ki =
Amine
SPAn
reagent
Annulation
product
Yield
[%][a]
2-phenoxyethylamine
A1 2a
8a
9a
8b
9b
8c
9c
8d
9d
8e
9e
8 f
9 f
8g
9g
8h
9h
8i
32
32
29
30
24
32
24
36
42
30
61
26
40
25
21
22
45
31
2b
A2 2a
2b
A3 2a
2b
2-(4-chlorophenyl)ethyl-
amine
(pyridin-3-yl)methylamine
2-(N-morpholino)ethyl-
amine
4-amino-(N-Boc-piperidine) A5 2a
2b
(thiophen-2-yl)methylamine A6 2a
2b
(5-methylfuran-2-yl)methyl- A7 2a
amine
A4 2a
2b
2b
A8 2a
2b
A9 2a
2b
(5-methylisoxazol-3-yl)-
methylamine
(S)-methylbenzylamine
9i
2a
A10
8j
9j
33
17
2b
[a] Yield of isolated product, as purified by HPLC.
Figure 1. a) The collective topology of SPAn products given in
Scheme 4 indicates dense interrogation of chemical space. The phe-
noxyamide linkage was kept fixed and low-energy conformations of the
side chains of 11c–p were calculated by using the MMFF94x forcefield
in the molecular operating environment (MOE; Chemical Computing
Group). The structures were aligned with respect to the atoms making
up the phenoxyamide linker. b) Graphical comparison of electrostatic
potential surfaces of 11c,d versus 11j,k,p, as derived from HF/3-21g*
calculations by using Spartan ’04. The electrostatic potential values
range from ꢀ67 (red) to 37 kcalmolꢀ1 (blue). The phenoxyethyl group
is replaced with a methyl group for clarity.
Scheme 3. Additional selected examples of SPAn reagents.
The introduction of substituents into these reagents adds
elements of stereochemical and shape diversity in the
annulation products. SPAn reagents 10e–i with pendent aryl
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other non-lactams have also been devel-
oped by us, thus increasing the molecular
diversity of the cyclic derivatives obtained.
Application of SPAn chemistry in the
context of finding new lead compounds
and SAR development will be reported
subsequently.[10]
Received: May 13, 2005
Published online: August 3, 2005
Keywords: amines · annulation ·
.
combinatorial chemistry · cycloaddition ·
heterocycles
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[2] S. Bhattacharyya, Curr. Opin. Drug Dis-
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Scheme 4. Use of SPAn reagents for cyclic amine derivatization.
Krolinkowski, T. Herpin, M. Gardyan, G.
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56 nm for the a-phenylpiperidinone derivative 9j at this
receptor. The increase in ring size by a single methylene unit
causes a remarkable 35-fold decrease in binding affinity.
Replacement of the methylene carbon atoms in 10b,c by a
heteroatom generates reagents 10j,k which afford morpho-
linone 11j (A1; 29%) and piperazinone 11k (A1; 21%).
These cyclic and related heteroatom-containing derivatives
11n–p, give rise to electrostatic potential (EP) surfaces,
distinct from their carbon congeners.[9] This result is again
evident upon visual inspection of the EP surfaces generated
for 11j,k,p and carbon congeners 11c,d (Figure 1b). The
complementarity of the EP surface and molecular shape are
two mutually inclusive determinants for high-affinity binding.
Both of these molecular attributes are readily probed by
employing the annulation chemistry.
A new family of reagents for amine derivatization, termed
SPAn reagents, enables the single-step conversion of primary
amines to cyclic derivatives. The annulation protocol,
together with existing protocols for the preparation of
amides, sulfonamides, ureas, and other acyclic derivatives in
one step (Scheme 4), represents a powerful ensemble for
streamlined synthesis. Resin loading, a major obstacle in
reagent preparation, was overcome through the 1,3-dipolar
cycloaddition reaction of solution-prepared propargyl esters
and Merrifield azide resin. The reagents require no further
chemical manipulation or activation for their use and display
excellent shelf stability. Microwave heating was essential to
obtain the annulation products as discrete compounds 11c–p
or in a library format (2a,b!8/9a–j, respectively). Tandem
N-alkylation/intramolecular acylation is utilized in this report
as the annulation manifold to yield heterocyclic lactams.
Reagents that afford cycloalkylamines, diazaspirocycles, and
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[10] The authors wish to acknowledge P. C. Kambhampati, D.
Subrahmanyam, V. S. Ponnapalli, L. M. Kolukuluri, Y. Deraje,
and M. R. Motatipally, of GVK Biosciences PVT, Ltd., Hyder-
abad, India, for their assistance in the preparation of propargyl
esters, the details of which will be reported separately.
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