Combining the petasis 3-component reaction with multiple modes of cyclization: A build/couple/pair strategy for the synthesis of densely functionalized small molecules

Article abstract of DOI:10.1021/co500091f

A build/couple/pair strategy for the synthesis of complex and densely functionalized small molecules is presented. The strategy relies on synthetically tractable building blocks (build), that is, diversely substituted hydrazides, α-hydroxy aldehydes, and boronic acids, which undergo Petasis 3-component reactions (couple) to afford densely functionalized anti-hydrazido alcohols. The resulting scaffolds can subsequently be converted via chemoselective cyclization reactions (pair), including intramolecular Diels-Alder or Ru-alkylidene catalyzed ring-closing metathesis, into sets of structurally diverse heterocycles in good yields in only 3-4 steps.

Full text of DOI:10.1021/co500091f

Research Article
pubs.acs.org/acscombsci
Combining the Petasis 3‑Component Reaction with Multiple Modes
of Cyclization: A Build/Couple/Pair Strategy for the Synthesis of
Densely Functionalized Small Molecules
Thomas Flagstad,† Mette R. Hansen,† Sebastian T. Le Quement,† Michael Givskov,‡,§
and Thomas E. Nielsen*,†,§
†Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark
‡Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of
Copenhagen, DK-2200 Copenhagen, Denmark
§Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore 637551, Singapore
S
* Supporting Information
ABSTRACT: A build/couple/pair strategy for the synthesis of
complex and densely functionalized small molecules is presented.
The strategy relies on synthetically tractable building blocks
(build), that is, diversely substituted hydrazides, α-hydroxy
aldehydes, and boronic acids, which undergo Petasis 3-
component reactions (couple) to afford densely functionalized
anti-hydrazido alcohols. The resulting scaffolds can subsequently
be converted via chemoselective cyclization reactions (pair),
including intramolecular Diels−Alder or Ru-alkylidene catalyzed
ring-closing metathesis, into sets of structurally diverse hetero-
cycles in good yields in only 3−4 steps.
KEYWORDS: Petasis 3-component reaction, intramolecular Diels−Alder reaction, ring-closing metathesis, build/couple/pair,
diversity-oriented synthesis
blocks (build), comprising diverse mono-, di-, and trisub-
n recent years, new synthetic concepts and methodologies
Ihave been proposed for the design and synthesis of stituted hydrazides, α-hydroxy aldehydes and boronic acids, and
molecular screening libraries.1 Challenged by a tendency of
combines the use of robust organic reactions, namely, Petasis 3-
component (couple),6 intramolecular Diels−Alder (IMDA),7
traditional vendor libraries to incorporate simple and relatively
“flat” molecules, as defined by their high content of sp2-
and Ru-alkylidene catalyzed ring-closing metathesis (RCM)
reactions (pair) (Figure 1).8 We have previously reported the
applicability of hydrazides in the Petasis 3-component reaction
(3-CR), and the efficient and selective elaboration of hydrazido
alcohols (I, Figure 1) into oxazolidinones and oxadiazolones by
controlled carbonylation processes (VI and VIII, Figure 1).9
We have also successfully combined Petasis 3-CRs with Ru-
catalyzed cyclizations of simple amines to construct diverse 5-
and 7-membered ring-systems.5f
In a continuous search for screening-relevant molecular
entities, we desired to investigate if an elaboration of these
strategies could further expand the array of accessible
heterocycles from the Petasis 3-CR template, specifically via
strategic positioning of functional groups, such as vinyl and
furyl moieties, which would participate in RCM and IMDA
reactions (II−V and VII, Figure 1).
hybridized carbon,2 evidence suggests that many available
compound collections are not meeting the structural require-
ments of more demanding targets, such as protein−protein
interactions, transcription factors and nucleic acid macro-
molecules.1g Some particularly successful strategies have
heralded molecular diversity as a design parameter to access
target-relevant chemical space. These strategies typically rely on
short synthetic pathways yielding skeletally and stereochemi-
cally diverse molecular scaffolds, frequently drawing upon
structural inspiration from natural products.3 By maximizing the
number of stereogenic carbon atoms in these scaffolds,
emerging trends emphasize that spatially well-defined mole-
cules more smoothly may be elaborated into selective
modulators of biological targets.4 In an effort to meet some
of these challenging goals, diversity-oriented synthesis (DOS)
tactics referred to as build/couple/pair (B/C/P) strategies have
recently been proposed.1e,5
Received: June 11, 2014
We herein report our efforts toward the development of a
Revised: October 28, 2014
synthetic pathway that starts with readily available building
© XXXX American Chemical Society
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Research Article
Scheme 1. Petasis 3-CR: Synthesis of Densely
Functionalized Anti-Hydrazido Alcohols (Couple)
a
Figure 1. Build/couple/pair strategy utilizing the Petasis 3-component
(couple) and cyclization (pair) reactions for the synthesis of densely
functionalized compounds.
In accordance with our previous work,9 the Petasis 3-CR of
hydrazides (1), α-hydroxy aldehydes (2), and both vinyl and
aryl boronic acids (3) proceeded smoothly in MeOH to
provide an array of densely functionalized diastereomerically
pure anti-hydrazido alcohols in good to excellent yields (4{1−
25}, Scheme 1). When using electron-rich 2-furyl boronic acid
yields were typically higher compared to the less electron-rich
vinyl and phenyl boronic acids, and the reactions were generally
promoted using 1,1,1,3,3,3-hexafluoro-propan-2-ol (HFIP) as a
cosolvent.10
Interestingly, when N′-allylated hydrazides (5) were
subjected to the Petasis 3-CR with 2-furyl boronic acid in
refluxing MeOH, the expected Petasis 3-CR products (6)
rapidly formed before a clean conversion (albeit more slowly)
provided the diastereomerically pure IMDA adducts 7{1} and
7{2} (Scheme 2).
Having confirmed the viability of furyl-functionalized Petasis
3-CR products as IMDA precursors, we next decided to
investigate if the N′-linked double bond could be introduced at
a later synthetic stage, thereby providing a more divergent
approach to the IMDA products. This would also allow for the
use of unsubstituted hydrazides in the Petasis 3-CR. Gratify-
ingly, Petasis 3-CR product 4{12} could be easily allylated with
allyl bromide followed by refluxing in toluene to give IMDA
product 7{1} in acceptable yield (41% over two steps, Scheme
3). Acrylic variants of the scaffold were obtained analogously by
subjecting 4{12} and 4{4} to O-TBS-protection, N-acryloyla-
tion with acryloyl chloride and heating (refluxing toluene),
providing IMDA adducts 11{1} and 11{2} in good yields over
3 steps (51% and 47%, respectively).
The scope of the acryloylation/IMDA sequence was
investigated for a series of furyl-containing Petasis 3-CR
products 4{1−13} and 4{15}. In general, the desired products
(12{1−6} and 12{10−13}) were obtained in decent to good
yields (47−76%). The slightly lower yields observed for the
formation of 12{7−9} (25−44%) presumably reflect the low
solubility of their corresponding starting materials during the
acryloylation step.
a
Reagents and conditions: (a) TBSCl, imidazole, DMF, rt; (b)
b
acryloyl chloride, Et3N, THF, −78 °C. 10% HFIP added as a
cosolvent.
Having established efficient protocols for IMDA reactions of
vinyl and furyl moieties, pairwise reactive diene combinations
were subjected to Ru-catalyzed RCM. For example, when
subjecting the Petasis 3-CR products 4{21−23} and 4{25} to
RCM conditions, three different ring systems (compounds
14{1}, 14{3−4}, and 14{5}) were obtained in good yields
(58−80%, Scheme 6). Unfortunately, despite the use of a range
of different RCM conditions, Petasis 3-CR product 4{20} could
never be converted to the desired 7-membered ring 14{6}.
However, a related ring system could be obtained by
Interestingly, when switching to methacryloyl chloride as the
acryloylating agent (Scheme 5), the reaction of compound 9{2}
provided a mixture of anti diastereomers 13{1} and 13{2} after
IMDA reaction (58% and 14% over 3 steps, respectively).
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Scheme 2. Tandem Petasis 3-CR and Intramolecular IMDA
Reaction (Couple−Pair)
Scheme 4. Sequential Acryloylation and IMDA Reactions
(Pair)
Scheme 3. Functional Group Pairing via IMDA Reaction
a
(Pair)
a
Reagents and conditions: (a) allyl bromide, Et3N, DMF, 60 °C; (b)
toluene, reflux; (c) TBSCl, imidazole, DMF, rt; (d) acryloyl chloride,
Et3N, CH2Cl2, −78 °C.
conversion of acryloylated compound 4{19} to compound
14{2} in good yield (70%), suggesting that the basic N of
4{20} inactivates the metathesis catalyst. Attempts made to
synthesize larger ring systems by RCM of the Petasis 3-CR
products 4{17} and 4{24} were all unfruitful.
Scheme 5. Intramolecular Diels−Alder Reactions (Pair)
Finally, we envisioned that the exocyclic alcohol-moiety in
the IMDA products (originating from the α-hydroxy
aldehydes) could serve as an entry for further skeletalization
reactions. Accordingly, compounds 12{12} and 12{6} were
mesylated and subjected to NaH in a set of commonly used
solvents at room temperature. However, under these conditions
the mesylated compounds 15{1−2} appeared completely
unreactive. This issue was resolved by elevating the temper-
ature, which resulted in the formation of different products
depending on the nature of the solvent. For instance, complex
reaction mixtures were observed when using THF and CH2Cl2,
whereas reactions in toluene or DMF at 80 °C resulted in clean
conversions to either eliminated product 16 (toluene) or
cyclized product 17{1} (DMF). In the same manner,
subjection of mesylate 15{2} to NaH in toluene provided
compound 17{2} as a single enantiomer in good yield (76%).
The stereochemistry of compound 17{2} was assigned via X-
ray crystallography (Figure 2), which provided unambiguous
confirmation of the exo-anti selectivity of the IMDA reaction
and proved that the NaH-mediated cyclization proceeds via
SN2-inversion.
of diverse hydrazides with regio- and stereoselective cyclization
reactions, including ring-closing metathesis and intramolecular
Diels−Alder reactions. Using this strategy, 10 structurally
distinct scaffolds were synthesized in good yields in only 3−4
steps. Functionalized hydrazido alcohols accessed through the
Petasis 3-CR are synthetically versatile templates for sub-
sequent cyclization reactions at several positions, thus
constituting valuable compounds of modular and synthetically
programmable pathways. The presented key cyclization steps of
the pathway take advantage of pairwise reactive functional
groups of a densely functionalized hydrazido alcohol template,
In conclusion, we have shown the feasibility of forming a
collection of structurally diverse heterocycles through a build/
couple/pair pathway that combines the Petasis 3-CR reaction
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Scheme 6. Ring-Closing Metathesis of Diene-Containing
Hydrazido Alcohols (Pair)
AUTHOR INFORMATION
■
a
Corresponding Author
*E-mail: ten@kemi.dtu.dk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Technical University of
Denmark, DSF Center for Antimicrobial Research, Danish
Council for Strategic Research, Danish Council for Independ-
ent Research, and Lundbeck Foundation.
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