Facile Synthesis of Spirocyclic Lactams from β-Keto Carboxylic Acids

Article abstract of DOI:10.1021/acs.orglett.5b01350

A facile synthesis of spirocyclic lactams starting from β-keto carboxylic acids via a one-pot cascade reaction involving a Curtius rearrangement and an intramolecular nucleophilic addition of the enol carbon to the isocyanate intermediate is reported. The same conditions have also been used for the generation of fused cyclic lactams with similar good yields. The synthetic value of this method has been demonstrated by efficient synthesis of tetracyclic spirolactam 8 and pentacyclic spirolactam 9.

Full text of DOI:10.1021/acs.orglett.5b01350

Letter
pubs.acs.org/OrgLett
Facile Synthesis of Spirocyclic Lactams from β‑Keto Carboxylic Acids
Wei Yang,† Xianyu Sun,† Wenbo Yu,† Rachita Rai,† Jeffrey R. Deschamps,‡ Lauren A. Mitchell,‡
Chao Jiang,§ Alexander D. MacKerell, Jr.,† and Fengtian Xue*,†
†Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland 21201,
United States
‡Naval Research Laboratory, Code 6930, 4555 Overlook Avenue, Washington, D.C. 20375, United States
§Department of Pharmaceutical Engineering, School of Chemical Engineering, Nanjing University of Science and Technology,
Nanjing, Jiangsu 210094, China
S
* Supporting Information
ABSTRACT: A facile synthesis of spirocyclic lactams starting
from β-keto carboxylic acids via a one-pot cascade reaction
involving a Curtius rearrangement and an intramolecular
nucleophilic addition of the enol carbon to the isocyanate
intermediate is reported. The same conditions have also been
used for the generation of fused cyclic lactams with similar
good yields. The synthetic value of this method has been demonstrated by efficient synthesis of tetracyclic spirolactam 8 and
pentacyclic spirolactam 9.
Scheme 1. Routes to Spirocyclic β-Keto-lactams
pirocyclic β-keto lactam moieties are widely present in
S
natural and pharmaceutical compounds with a broad
spectrum of biological activities. Spirolactam fusarisentin A,
isolated from fungus Fusarium sp., FN080326, is a potent
inhibitor for acinar morphogenesis, migration, and invasion of
cancer cells.1 Exiguaquinol, a natural product isolated from
Australian sponge Neopetrosia exigua, is a novel antimicrobial
agent that functions by potently inhibiting the Helicobacter
pylori glutamate racemase MurI.2 Phomopsichalasin, the first
cytochalasin-type compound isolated from an endophytic
Phomopsis sp., is known for its antimicrobial and antifungal
activities.3 Synthetic spirolactams have demonstrated promising
antagonistic activities for neuropeptide calcitonin gene-related
peptide (CGRP) receptors as potential treatment for
cerebrovascular disorders.4 In addition, the 1,2,3,4-tetrahydro-
β-carboline (THBC)-based spirolactams have been used
mimetically as somatostatin for somatostatin receptors as
potential treatment of endocrine tumors and acromegaly.5
Because of its unique structural features and great potential
as a multifunctional scaffold in drug discovery,6 the synthesis of
spirocyclic β-keto lactams has attracted long-standing interest.7
Several synthetic methods have been reported. For example,
Cossy and co-workers reported the synthesis of spirocyclic
lactams by a Mn(OAc)3-catalyzed radical cyclization of
unsaturated β-keto carboxamides (Scheme 1).8 Marini and
co-workers synthesized spirolactams via a domino Michael
addition/cyclization process using vinyl selenone as a Michael
acceptor.9 In addition spirolactams have been prepared using
ruthenium-catalyzed ring-closing metathesis10 and palladium-
catalyzed carboxycyclization.10b,11 While these methods found
applications in synthesizing spirocyclic keto-lactams, they
uniformly suffered from major limitations including the lack
of substrate availability, employment of environmental-
unfriendly metal catalysts, harsh reaction conditions, and
multistep synthesis.
The Curtius rearrangement is a commonly used reaction for
the transformation of a carboxylic azide into an isocyanate,12
which can be subsequently attacked by various nucleophiles to
give different products such as carbamate,13 ureas,14 and thio-
urethanes.15 Examples are also known where the isocyanate is
attacked by a nucleophilic carbon to form a new amide bond.16
Of these methods, an activated carbon, through either carbon
metal salts16,17 or reactive methylene, is employed.18 The utility
of the α-carbon of a carbonyl to attack the isocyanate is rarely
explored.19
In the course of our research program on small molecule
therapeutics for diffuse large B-cell lymphoma (DLBCL) and
triple negative breast cancer (TNBC), we are interested in a
practical synthetic method to multisubstituted spirocyclic
Received: May 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01350
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
lactams. Herein, we report a one-step synthesis of spirocyclic β-
keto-lactams using δ-keto acids. To the best of our knowledge,
this is the first example using the α-carbon of a carbonyl to
attack the isocyanate of a Curtius rearrangement product. The
current method broadens the potential application of Curtius
rearrangement and complements the current synthetic methods
for the preparation of spirocyclic lactams.
Scheme 2. Scope of Acids
We first sought to identify optimal conditions for the
generation of 3-acetylpyrrolidin-2-one (2a) from 5-oxohexanoic
acid (1a, Table 1). After a brief survey of solvents, we found
Table 1. Conditions for the Formation of β-Keto-lactam 2a
a
from 5-Oxohexanoic Acid 1a
b
entry
solvent
DCM
base
Et3N
temp (°C)
yield (%)
1
25
50
50
50
50
50
80
80
50
50
50
<5
<5
<5
65
10
31
37
13
<5
<5
<5
2
THF
Et3N
a
A reaction started with 10 mmol of 3b gave 60% yields.
3
DMF
Et3N
4
t-BuOH
1,4-dioxane
toluene
t-BuOH
toluene
t-BuOH
t-BuOH
t-BuOH
Et3N
showed a similar configuration to that of compound 4b
(Supporting Information). The products containing halogen
substituents can be used to construct more complex structures
through cross-coupling reactions. When cyclohexanone-based
starting material 3-(2-oxocyclohexyl)propanoic acid (3i) and 3-
(1-tetralone-2yl)propanoic acid (3j) were used, only a trace
amount of compound 4i and modest yields of spirocyclic keto-
lactam 4j were obtained.
To explain the different yields obtained for spirolactams 4a−
b vs 4i−j, the geometric preferences of the isocyanate
intermediates 4a′, 4b′, 4i′, and 4j′ were studied using molecular
dynamics (MD) simulations. The isocyanates were described
by the CHARMM General Force Field (CGenFF).20 The gas-
phase MD runs for the four compounds were performed using
the CHARMM program.21
The probability distributions of the distance of C1−C2 for the
four isocyanates from the MD simulations are shown in Figure
1. As compared to isocyanate 4i, isocyanate 4a showed
enhanced sampling at shorter C1−C2 distances, indicated by
the higher peak around 3.5 Å and lower peak around 4.5 Å.
This may allow for a higher production rate during the reaction
when the two carbons covalently bond together for the five-
membered ring moieties. With an additional phenyl ring, the
distance probability distributions are changed moderately.
5
Et3N
6
Et3N
7
Et3N
8
Et3N
9
DMAP
Cs2CO3
K2CO3
10
11
a
A mixture of 1a (1.0 mmol), DPPA (1.0 mmol) and base (1.0 mmol)
b
in 5.0 mL of solvent was stirred for 16 h. Isolated yields.
that the most promising yields of compound 2a were obtained
when using t-BuOH as the solvent in the presence of Et3N at
50 °C for 16 h (entry 4), whereas no obvious formation of 2a
was detected in solvents such as DCM, THF, and DMF
(entries 1−3). The chemical structure of compound 2a was
confirmed by its X-ray single crystal structure (Table 1).
Decreased yields were observed when the reaction was carried
out in either toluene or 1,4-dioxane (entries 5 and 6). Reactions
that were performed at 80 °C resulted in significantly decreased
yields, indicating that higher temperature was detrimental
(entries 7 and 8). Other bases were also tested, and no obvious
product was formed when using bases such as carbonate and
DMAP (entries 9−11).
With the optimal reaction conditions in hand, we next
examined the generality of this reaction (Scheme 2). When
using 3-(2-oxocyclopentyl)propanoic acid (3a) as the starting
material, the cyclization reaction went smoothly to afford
spirolactam 2-azaspiro[4.4]nonane-1,6-dione (4a) in good
yields. Similar yields of spirolactam 4b were obtained when
3-(1-oxo-2,3-dihydro-1H-inden-2-yl)propanoic acid (3b) was
used as the starting material. Gram-scale quantities of 4b were
prepared using this method with no obvious loss of the yields.
The chemical structure of compound 4b was confirmed by X-
ray crystallography (Scheme 2). Substitution of the phenyl ring
was studied using 3-(1-indanone-2yl) propanoic acids 3c−h as
the substrates. Our results indicated that both electron-
donating and -withdrawing substituents on the phenyl ring
were tolerated and the desired products 4c−h were isolated in
good yields. X-ray crystal structures of spirolactam 4c and 4f
Figure 1. Probability distributions of the C1−C2 distance for
isocyanates 4a′, 4b′, 4i′, and 4j′ for MD simulations.
B
DOI: 10.1021/acs.orglett.5b01350
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
However, compared to isocyanate 4j, isocyanate 4b still showed
increased sampling at shorter C1−C2 distances around 3.5 Å.
These results suggest that additional short interactions in the
five-membered ring isocyanate intermediates led to their higher
yields.
To further broaden the scope of this method, we studied a
series of reactions using 2-(3-oxocyclopentyl) acetic acid and 2-
(3-oxocyclohexyl) acetic acid derivatives (5a−e) as the starting
material to synthesize the fused cyclic β-keto-lactams (6a−e).
As shown in Scheme 3, under the same optimal conditions,
Figure 2. X-ray single crystal structure of compound 7.
Scheme 3. Scope of Acids for Fused Cyclic β-Keto-lacatms
readily available β-keto carboxylic acids. The differences in
yields for compounds 4a and 4b vs 4i and 4j are due to
increased sampling of the shorter isocyanate carbon to ring
carbon distances as evidenced by MD simulations. The value of
the method has been shown in the preparation of compounds
7−9 in high yields. Further asymmetric control of the
generation of the quaternary carbon center of spirolactams is
being investigated.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and spectral data for new compounds. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01350.
substrates 5a−c reacted smoothly to give the corresponding
products 6a−c in modest to good yields. When the 3-
oxocyclohexyl substrates 5d and 5e were used, the desired
products 6d and 6e were obtained in 70% and 66% yields,
respectively.
Since these small and rigid spirocyclic and fused keto-lactams
contain multiple functional groups, they have potential as
precursors in diversity-oriented synthesis (DOS) to build novel
drug-like compounds. As shown in Scheme 4, diastereoselective
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: fxue@rx.umaryland.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Maryland Computer-Aided Drug
Design Center, the Leukemia Research Foundation, and the
Samuel Waxman Cancer Research Foundation for their support
of this work. The X-ray crystallographic work was supported by
NIDA through Interagency Agreement No. Y1-DA1101 with
the Naval Research Laboratory (NRL).
Scheme 4. Synthesis of Compounds 7−9
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