Strategic Approach to the Metamorphosis of γ-Lactones to NH γ-Lactams via Reductive Cleavage and C-H Amidation

Article abstract of DOI:10.1021/acs.orglett.9b02673

A new approach has elaborated on the conversion of γ-lactones to the corresponding NH γ-lactams that can serve as γ-lactone bioisosteres. This approach consists of reductive C-O cleavage and an Ir-catalyzed C-H amidation, offering a powerful synthetic tool for accessing a wide range of valuable NH γ-lactam building blocks starting from γ-lactones. The synthetic utility was further demonstrated by the late-stage transformation of complex bioactive molecules and the asymmetric transformation.

Full text of DOI:10.1021/acs.orglett.9b02673

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Strategic Approach to the Metamorphosis of γ‑Lactones to NH
γ‑Lactams via Reductive Cleavage and C−H Amidation
Hoi-Yun Jung,†,‡ Sukbok Chang,*,‡,† and Sungwoo Hong*,‡,†
†Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
‡Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea
S
* Supporting Information
ABSTRACT: A new approach has elaborated on the conversion of γ-lactones to the
corresponding NH γ-lactams that can serve as γ-lactone bioisosteres. This approach
consists of reductive C−O cleavage and an Ir-catalyzed C−H amidation, offering a
powerful synthetic tool for accessing a wide range of valuable NH γ-lactam building blocks
starting from γ-lactones. The synthetic utility was further demonstrated by the late-stage
transformation of complex bioactive molecules and the asymmetric transformation.
he lactone moiety is a common structural motif present
in a variety of biologically active natural products and
conversion has been studied extensively. The effective general
methods for carrying out the synthesis of the NH-free lactams
from lactones mostly involve three sequential steps that consist
of ring opening of lactone, amination, and intramolecular
cyclization.6 Despite these advances reported in the field thus
far, current methods are often problematic in applications
mainly due to the harsh reaction conditions and/or high
ammonia pressures,6a which limit their utility to the trans-
formation of simple lactone substrates, which are unstable
under hydrolysis conditions. Moreover, the asymmetric version
of lactone-to-lactam conversion has thus far remained out of
reach. With the need for increasing the structural complexity in
medicines, there is a growing demand for new approaches to
the lactone-to-NH lactam conversion to streamline drug
discovery research.
T
pharmaceuticals.1 However, due to the metabolic instability of
lactone rings in various bioactive molecules, their cellular and
in vivo activities are often significantly reduced.2 The NH-free
γ-lactam building block has long been recognized as a
privileged scaffold in medicinal chemistry and can be
considered a bioisostere3 of the γ-lactone moiety. Indeed, the
effectiveness of the lactone-to-lactam replacement has been
well validated in drug discovery.4 For example, dl-3-N-
butylphthalide (dl-NBP, 1a), isolated from the seed of
Apium graveolens Linn, is a γ-lactone-containing drug for the
treatment of ischemic strokes (Figure 1).4c,d However, the low
As outlined in Scheme 1, we envisioned that a new
retrosynthetic analysis using the power of a C−H functional-
ization disconnection approach would enable efficient, direct,
and even enantioselective construction of challenging NH γ-
lactams starting from γ-lactones. Previously, we reported a
straightforward method for preparing γ-lactams by the
intramolecular insertion of Ir-nitrenoids into C−H bonds by
employing 1,4,2-dioxazol-5-ones as useful amidating agents.7d,g
Drawing inspiration from these studies, we speculated that a
synthetically useful lactone-to-NH lactam conversion could be
developed via the combination of reductive C−O cleavage of
the lactone and subsequent direct C−H amidation.7 If
successful, such a powerful synthetic strategy would represent
a convenient platform to convert γ-lactone to NH γ-lactam
scaffold in a predictable and controllable manner. Under the
optimized reaction conditions, we discovered that a wide range
of NH γ-lactams could be formed with high efficiency. The
convenience of this protocol was illustrated by converting an
important class of complex natural products and bioactive
Figure 1. Example of a lactone drug to an NH lactam.
efficacy of dl-NBP has been attributed to its poor aqueous
solubility and metabolic instability.4c,d On the other hand, the
NH γ-lactam derivative 4a was successfully identified as a
bioisostere, which exhibited remarkably improved oral
bioavailability and in vivo antiplatelet aggregation activity.4
With this advantage, the γ-lactone/γ-lactam replacement
presents an attractive strategy for directly accessing NH-free γ-
lactam privileged structures that could improve the phys-
icochemical properties while maintaining or even enhancing
the bioactivity through the formation of new hydrogen bonds
between the lactam NH and the active site of biological
targets.5 Besides, newly synthesized γ-lactam scaffolds are of
high interest for the exploration of chemical space by rapidly
accessing structural diversity, which might have never been
evaluated otherwise. As a result, the lactone-to-NH lactam
Received: July 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02673
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Letter
genolysis to afford the corresponding carboxylic acids in
excellent yield.8a,b Substrates bearing aryl motifs, as exemplified
by phenyl (1b), p-fluorophenyl (1c), p-methoxyphenyl (PMP)
(1d), and naphthyl groups (1e), readily participated in the
reaction and provided the desired products (2b−e). Tricyclic
lactone 1f, easily found in the synthetic phytohormone
strigolactone,9 reacted well to afford the corresponding
carboxylic acid 2f in excellent yield. Further exploration
demonstrated that a series of phthalides containing (hetero)-
arenes, such as phenyl (1g), diphenyl (1h), and thiophene-yl
(1i) could be successfully subjected to these reaction
conditions and generated the corresponding carboxylic acids.
In sharp contrast, it was observed to be difficult to selectively
cleave the Calkoxy−O bond in nonbenzylic lactones by
conventional Pd-catalyzed hydrogenolysis. Because a Lewis
acid can promote Calkoxy−O bond activation with olefins,8c,d we
wondered whether it could invoke the catalytic hydrogenation
reactivity by exploiting the effect of a series of Lewis acids. To
our delight, the reductive ring-opening of nonbenzylic lactones
was successfully achieved by adding a catalytic amount of metal
triflates, where Hf(OTf)4 was found to be most efficient in this
reaction, and the desired products were readily obtained8d (see
the Supporting Information for details). After systematic
variation of different reaction parameters, the optimal
conditions were identified and then applied to a variety of
nonbenzylic lactones to investigate the scope of the reaction.
The lactone substrates bearing various alkyl substituents,
including methyl (1j), dimethyl (1k), benzyl (1l), and heptyl
Scheme 1. Approaches to NH-Free γ-Lactam Synthesis from
γ-Lactones
molecules containing γ-lactone cores into the corresponding
valuable NH γ-lactam analogues. Moreover, the utility of this
powerful transformation was further demonstrated in the
successful asymmetric formation from a racemic γ-lactone.
Based on the above considerations, we explored the
feasibility of our proposed ideas by initially testing the Pd-
catalyzed reductive cleavage of the C−O bond of various
simple substrates containing γ-lactones, as shown in Table 1.
The benzylic lactones could readily undergo catalytic hydro-
Table 1. Scope of the Lactone-to-NH Lactam Conversion
a
Conditions A: 1 mol % Pd/C and 1 (2 mmol) in MeOH at rt under 1 atm H2 for 1−12 h. Conditions B: 0.5 mol % Pd/C, 2 mol % Hf(OTf)4, and
1 (2 mmol) without solvent at 135 °C under 1 atm H2 for 12 h. Conditions B′: 10 mol % Pd/C, and 10 mol % Hf(OTf)4 and 1 (1 mmol) in
b
c
d
e
MeOH (1 mL) at 60 °C under 1 atm H2 for 12 h. 10 mol % Pd/C. 5 mol % Pd/C. 10 mol % Pd/C in AcOH at 90 °C for 4 h. nBuOH at 120
f
g
h
°C. Conditions C: 3 (0.1 mmol), Ir catalyst (2 mol %), and NaBArF4 (2 mol %) in CH2Cl2 (1.2 mL) at 35−50 °C. 10 mol % Ir catalyst. 5 mol %
i
j
Ir catalyst. 80 °C for 48 h. Tetrachloroethane at 35 °C for 24 h.
B
DOI: 10.1021/acs.orglett.9b02673
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Organic Letters
Letter
(1n) groups, proceeded well under conditions B to afford the
desired products (2j−l and 2n) in modest to good yields. In
addition, expanding the scope to a spiro-lactone 1m was also
feasible in an alcoholic solvent, giving rise to ester, and
subsequent hydrolysis produced the corresponding carboxylic
acid 2m.
With various 1,4,2-dioxazol-5-ones accessed from carboxylic
acids and esters,7d we next examined the reaction scope of the
intramolecular C−H amidation catalyzed by the Ir catalysts
displayed in Figure 2. Dioxazolones containing benzylic C−H
lactamization (4n) at an aliphatic secondary C−H bond
adjacent to the heptyl position with >96:4 er by employing Ir
catalyst III bearing a chiral hydrogen-bond donor ligand.7g
To further test the generality of this approach, the synthetic
applicability to medicinally relevant molecules and polycyclic
natural products was also investigated as summarized in
Scheme 2. A natural product, dl-NBP (1a) was initially
subjected to conditions B′ using methanol as the solvent;
however, the reactivity turned out to be poor. Remarkably, the
use of ethyl acetate as the solvent notably enhanced the C−O
bond cleavage reaction, and we were successfully able to obtain
the carboxylic acid (2a), which was readily converted to the
dioxazolone. Subsequently, Ir catalyst I was employed to
transform the dioxazolone (3a) to the desired lactam 4a. Next,
we turned to desmotoroposantonin acetate, a sesquiterpene
lactone derivative that is known to have immunosuppressive
effects,11 and the corresponding carboxylic acid (2o) was
obtained in excellent yield via the established hydrogenolysis
procedure. The subsequent C−H amidation of the dioxazolone
derivative resulted in 78% yield of the lactam product 4o. (R)-
(+)-Sclareolide is another sesquiterpene lactone that has been
extracted from various plants,12 which has been used as a
starting material for the synthesis of bioactive derivatives,
especially as an antifungal agent.12 Exposing this natural
product to conditions B′, we obtained the methyl ester, and
subsequent hydrolysis gave the carboxylic acid (2p) in 96%
two-step yield. During the Lewis acid promoted lactone
cleavage, the stereochemistry of the tertiary carbon was
inverted, where the methyl group is in the equatorial position,
as confirmed by NOESY NMR studies (see the SI for details).
In the subsequent intramolecular C−H amidation reaction of
dioxazolone 3p, two adjacent tertiary C−H bonds were found
to react to produce 4-membered and 5-membered lactams: γ-
lactam 4p and spiro-β-lactam 4p′ were confirmed by nuclear
magnetic resonance (NMR) and X-ray diffraction (XRD)
analysis.
Figure 2. Ir catalysts used for the intramolecular C−H amidation.
bonds were readily converted to the corresponding γ-lactams
in high yields. The cyclization of substrates bearing phenyl, 4-
fluorophenyl, PMP, and naphthyl groups provided γ-lactams
(4b−e) in moderate to high yields. A tricyclic γ-lactam (4f),
which is a building block of strigolactam,10 could be
constructed from a secondary benzylic C−H bond in the
indane ring. A series of dioxazolones prepared from phthalides
containing (hetero)arenes, such as phenyl, diphenyl, and
thiophene, could be successfully subjected to these reaction
conditions to generate the corresponding isoindolines (4g−i).
The optimal conditions were then applied to a variety of
nonbenzylic lactones to investigate the scope of the reaction.
The amidation of nonactivated secondary C−H bonds of
methyl, dimethyl, and benzyl groups was successful and
resulted in the corresponding products (4j−l). The tertiary C−
H bond in the cyclohexyl group reacted well under conditions
C to afford spiro-lactam 4m. Motivated by these findings, we
next investigated the lactone-to-NH lactam conversion in an
asymmetric version and successfully achieved enantioselective
This strategy was then applied to develop a novel γ-lactam-
containing inhibitor accessible from a bioactive γ-lactone
scaffold. After screening chemical libraries in our group, spiro-
lactone 1q was identified as a new hit against bromodomain
(BRD) 2-1 to regulate uncontrolled gene transcription.13 To
Scheme 2. Late-Stage Transformation of γ-Lactones into the NH γ-Lactams
a
b
c
d
e
Run in dry ethyl acetate at 70 °C. 5 mol % Pd/C was used. Run in AcOH at 60 °C (97% yield). 20 mol % Hf(OTf)4 was used. 10 mol % Ir
f
catalyst was used. 5 mol % Ir catalyst was used.
C
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Letter
the best of our knowledge, BRD inhibitors bearing a steroid
scaffold have not yet been reported. To identify more potent
BRD inhibitors, we investigated the binding mode of a newly
identified inhibitor, spiro-lactone 1q, in the active site of BRD
2-1 employing the crystal structure (PDB 2DVQ) as a
template.14 Interestingly, our docking studies revealed that
the NH lactam ring could confer favorable binding forces by
serving as a hydrogen-bond donor with the carboxylate side
chain of ASP160 as presented in Figure 3. Based on this
chemical transformations that can streamline the overall drug
discovery process.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02673.
Experimental procedure and characterization of new
compounds (1H and 13C NMR spectra) (PDF)
Accession Codes
CCDC 1940644, 1940963, 1940966, and 1941110 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Figure 3. Calculated binding mode of 4q at the active site of BRD 2-1
(PDB 2DVQ). Each dotted line indicates a hydrogen bond.
*E-mail: hongorg@kaist.ac.kr.
*E-mail: sbchang@kaist.ac.kr.
ORCID
structural analysis, we wondered whether the lactone-to-NH
lactam conversion might improve the potency by establishing
an additional H-bond. Using the developed synthetic strategy,
NH γ-lactam compound 4q was successfully obtained starting
from 1q, and its structure was confirmed by the X-ray
crystallographic analysis (Scheme 2). The inverted spiro-
lactone 1r was also prepared15 as a control compound.
Intriguingly, newly synthesized NH lactam 4q showed
improved inhibitory activity against BRD 2-1 (IC50 value of
79 μM)16 when compared to those of the original lactone 1q
and 1r, as enumerated in Table 2. This result illustrates that
the novel scaffold 4q has the potential to be a good starting
point from which more potent BRD inhibitors can be derived.
Hoi-Yun Jung: 0000-0003-4111-850X
Sukbok Chang: 0000-0001-9069-0946
Sungwoo Hong: 0000-0001-9371-1730
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported financially by the Institute for
Basic Science (IBS-R010-A2). We thank Dr. Dongwook Kim
(IBS) for XRD analysis and single-crystal X-ray diffraction
experiments with synchrotron radiation were performed at the
BL2D-SMC in the Pohang Accelerator Laboratory.
Table 2. BRD 2-1 Inhibition Activity
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