Stereoselective Synthesis of Quaternary Pyrrolidine-2,3-diones and β-Amino Acids

Article abstract of DOI:10.1021/acs.orglett.7b01185

A facile, diastereoselective synthesis of highly substituted pyrrolidine-2,3-diones is reported, along with the one-step conversion of these heterocycles to novel β-amino acids and further functionalized derivatives. This method involves an unusually mild, one-pot, three-component cyclization/allylation followed by a Claisen rearrangement to provide unusual pyrrolidinone products that are densely functionalized and contain an all-carbon quaternary stereocenter. The reported reaction sequence is operationally simple, exquisitely diastereoselective, and provides gram-scale access to valuable heterocyclic scaffolds and β-amino acids not readily accessible via existing approaches.

Full text of DOI:10.1021/acs.orglett.7b01185

Letter
pubs.acs.org/OrgLett
Stereoselective Synthesis of Quaternary Pyrrolidine-2,3-diones and
β‑Amino Acids
Nataliia V. Shymanska and Joshua G. Pierce*
Department of Chemistry, College of Sciences, North Carolina State University, Raleigh, North Carolina 27695, United States
S
* Supporting Information
ABSTRACT: A facile, diastereoselective synthesis of highly
substituted pyrrolidine-2,3-diones is reported, along with the
one-step conversion of these heterocycles to novel β-amino
acids and further functionalized derivatives. This method
involves an unusually mild, one-pot, three-component
cyclization/allylation followed by a Claisen rearrangement to
provide unusual pyrrolidinone products that are densely functionalized and contain an all-carbon quaternary stereocenter. The
reported reaction sequence is operationally simple, exquisitely diastereoselective, and provides gram-scale access to valuable
heterocyclic scaffolds and β-amino acids not readily accessible via existing approaches.
itrogen-containing heterocycles are common core scaf-
folds in natural products and pharmaceutical agents. In
particular, five-membered nitrogen-containing heterocycles are
among the most prevalent motifs in bioactive molecules and
represent a key synthetic hurdle for their facile synthesis (Figure
1a). Among the many synthetic approaches to N-heterocycles,
discovery of functionalized and bioactive pyrrolone3a and
quinoline4 heterocycles. In particular, 3-hydroxy-1,5-dihydro-
2H-pyrrol-2-ones (4) have attracted much attention due to their
wide spectrum of biological activities such as anticancer,5
antimicrobial,6 antiviral,3b and protein−protein interaction
inhibitors.7a,b A variety of combinatorial libraries of heterocycles
with general structure 4 have been prepared via multicomponent
approaches (Figure 1b) employing substituted α-oxo esters/
acids (1), aldehydes (2), and amines (3).7−9 Typical conditions
involve polar solvents such as dioxane, THF, or EtOH with less
reactive amine substrates heated in AcOH or DMF in the
presence of TMSCl; unfortunately, aliphatic aldehydes are
scarcely employed and usually provide low yields of pyrrolone
products.5a,7−10 An alternate multicomponent approach11 as well
as asymmetric protocols for the synthesis of 3-hydroxy-1,5-
dihydro-2H-pyrrol-2-ones were also recently described.12 In this
work, we investigated 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones
as high-value building blocks for more densely functionalized
heterocycles and natural products and therefore sought
optimized methods for their preparation.
We recently reported the first total synthesis of the
antimicrobial natural products synoxazolidinones A and B via
an imine acylation/cyclization cascade as a key transformation to
install the 4-oxazolidinone core.13 In this method, acylation of N-
dimethoxybenzylimines derived from aliphatic aldehydes with
arylpyruvic acid chlorides provided 4-oxazolidinone products
exclusively, albeit in moderate yields (Table 1, entries 1 and 2). In
attempts to improve the efficiency of the cyclization to obtain 4-
oxazolidinones, we explored various activated derivatives of
phenylpyruvic acid and identified regioisomeric 1,5-dihydropyr-
rol-2-one products under these alternate conditions (Table 1,
entries 3−5).13 Given the importance of dihydropyrrolones in
medicinal chemistry and our interest in developing these
N
Figure 1. (a) Representative natural product and medicinally relevant
heterocyclic scaffolds. (b) Current approaches to 3-hydroxy-1,5-
dihydropyrrol-2-ones via multicomponent (left) and two-step protocols
(right).
the use of multicomponent reactions (MCRs) is a powerful tool
to access diversity of substitution in relatively short reaction
sequences.1 In addition to step economy, a particularly appealing
feature of MCRs is the rapid generation of structural diversity
through the utilization of a secondary transformation of the
obtained scaffolds. The increasing power of multicomponent and
cascade reactions can be observed in natural product synthesis,
where bond-forming processes are merged more frequently to
achieve molecular complexity.2
Multicomponent reactions of readily enolizable carbonyls with
various amines and aldehydes (for example, Mannich- and
Doebner-type reactions), supplemented by docking studies and
high-throughput screening approaches, have enabled the
Received: April 21, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01185
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Letter
small molecules.16 Interestingly, rearrangement reactions of 1,5-
dihydro-2H-pyrrol-2-ones remain largely underexplored yet
would provide a significant increase in molecular complexity
and access to quaternary substituted heterocycles.14,17 To
explore the potential of this approach, we proposed the allylation
of 1,5-dihydro-2H-pyrrol-2-one products (11) and optimized a
two-step, one-pot protocol for the synthesis of 3-(allyloxy)-1,5-
dihydro-2H-pyrrol-2-ones (12, Scheme 1). Allylated derivatives
Table 1. Reaction Optimization: Synthesis of Alkyl-
Containing Dihydropyrrolones
a
yield (%)
entry
1
X
R
conditions
8
9
Scheme 1. Substrate Scope of 3-(Allyloxy)-1,5-dihydro-2H-
pyrrol-2-one Synthesis
b
−OH
C5H11 (COCl)2, cat. DMF, THF/
17−40
CH2Cl2, 0 °C
b
2
−OH
C5H11 PyBOP, DIPEA, THF/
24
CH2Cl2, 0 °C
b
b
3
4
−OH
−OH
C5H11 DCC, DMAP, CH2Cl2, 0 °C
C5H11 (CNCl)3, Et3N, MeCN,
6
b
7
40
0 °C
b
b
5
6
7
−OH
C5H11 MeCN, 0 °C
10
60
92
−OMe C5H11 CH2Cl2, 0 °C
−OMe C5H11 CH2Cl2, 0 °C; TBSCl,
c,d
imidazole
e
e
e
8
−OMe C4H9
−OMe cPr
−OMe Ph
MeCN, 0 °C
MeCN, 0 °C
MeCN, 0 °C
83
78
71
9
10
a
b
Isolated yield. 7 was preformed (2,4-DMBA with aldehyde in the
c
presence of MgSO4). Aldehyde and 2,4-DMBA were added to a
solution of ester in CH2Cl2 without MgSO4. 3-OH of 9 was protected
with TBDMS prior to purification. Isolated by filtration.
d
e
12a−o were readily prepared in moderate to high yields, allowing
rapid access to aryl-, alkenyl-, and alkyl-substituted compounds
not easily accessible (Scheme 1).
To explore the potential of 3-(allyloxy)-1,5-dihydro-2H-
pyrrol-2-ones (12) as substrates for sigmatropic rearrangements,
we heated 12b at reflux overnight in toluene and observed full
conversion to 4-allylpyrrolidine-2,3-dione 13b and isolated the
product in quantitative yield following removal of the solvent
(Scheme 2). Importantly, the reaction proceeded in a highly
scaffolds as building blocks, we desired to further explore these
reactions with the aim of overcoming previous limitations in
substrate scope and functional group compatibility.
Although our initial studies focused on activated carboxylic
acid derivatives, full conversion was observed when methyl ester
6 was treated with preformed imine 7 (Table 1, entry 6);
however, varied amounts of dihydropyrrolone product were
isolated after chromatography, pointing to the instability of 9 to
SiO2. Similarly, Guo et al. observed lowered yields of N-tosyl 3-
hydroxy-1,5-dihydro-2H-pyrrol-2-ones after purification.12 To
circumvent the product decomposition, the enol moiety of 9 was
protected as a silyl ether (Table 1, entry 7), which allowed for
isolation of the desired product in 92% yield.
Scheme 2. Synthesis of Novel Pyrrolidine-2,3-dione
Heterocycles Containing All-Carbon Quaternary
a
Stereocenter
At this stage, we sought to avoid preformation of the imines as
well as the need for column purification and therefore explored
the one-pot reaction of the amine, aldehyde, and ester.
Gratifyingly, when imine 7 was formed in the presence of the
ester in acetonitrile (Table 1, entries 8−10), the desired
dihydropyrrol-2-ones precipitated from the reaction mixture
and were isolated by filtration in high yields and excellent purity.
Attempts to remove water (MgSO4, sieves, etc.) during the
reaction led to lower yields and byproduct formation. Notably,
the reactions are extremely rapid and likely proceed via an initial
acid−base reaction between the enol and basic imine, addition of
the resulting enolate to the iminium ion, and subsequent ring
closure and loss of methanol. The lack of an additional activating
carbonyl on the pyruvate fragment, the mild nature of these
reactions and the use of electron-rich and aliphatic imines make
this process distinct from existing MCRs toward this substrate
class.7−12
With a high-yielding, three-component reaction to form our
target heterocycle in hand, we planned to leverage these scaffolds
as building blocks for more functionalized molecules. Synthetic
transformations of 1,5-dihydro-2H-pyrrol-2-ones14 have pre-
viously provided entry to other complex structures such as α-keto
γ-lactams,15a natural products,15b and related biologically active
a
Reaction conditions: (a) toluene, 110 °C, quantitative yield; (b) 5
mol % (Pdη3C3H5Cl)2, R-(+)-BINAP, 10 mol %, tBuOK, allylOAc,
toluene, 0 °C to rt, 30 min, 13h (95%) and 13j (93%).
B
DOI: 10.1021/acs.orglett.7b01185
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Letter
diastereoselective fashion providing only one observed diaster-
eomer. The preference of the allyl moiety to approach from the
least hindered face, opposite to the substituent at C5, was
confirmed by X-ray analysis of 13b. It should be noted that under
thermal conditions the rearrangement proceeded slowly with an
average reaction time of 12−18 h. Other pyrrolidine-2,3-diones
(except 13j) were also obtained quantitatively after evaporation
of toluene and no purification was required. Thermal rearrange-
ment of substrate 12j bearing an alkenyl moiety proceeded with a
color change to deep green even at lower temperatures,
accompanied by low yields of product 13j (10−18%) following
purification. This prompted us to explore an alternate, Pd-
catalyzed Tsuji−Trost allylation of 3-hydroxy-1,5-dihydro-2H-
pyrrol-2-ones as a rapid strategy to form pyrrolidine-2,3-diones
containing a quaternary stereocenter in cases where thermal
rearrangement was not feasible.18 Standard conditions of Tsuji−
Trost type allylation (Pd−allyl dimer catalyst, P-ligand, and base)
applied toward 11j proceeded at 0 °C, and full conversion was
achieved in 30 min resulting in 93% yield of 13j (same relative
stereochemistry observed in Claisen rearrangement, confirmed
by NMR).19,20 Pyrrolone 13h could also be isolated as a single
diastereomer in 95% yield after isolation and purification via this
approach.
The 4-allylpyrrolidine-2,3-dione products 13a−o possess a
novel dione-substituted heterocyclic core and share structural
similarity with isatins, a class of privileged scaffolds21 contained in
natural products and drug candidates.22 Previous extensive
exploration into the reactivity of isatins (nucleophilic addition to
C3 carbonyl, oxidations, spiro-annulations, etc.) has provided
useful insights into the potential reactivity of pyrrolidine-2,3-
diones, albeit the isatin scaffold bears a fused aromatic ring.22c We
explored ring modifications of the pyrrolidine-2,3-dione
products to evaluate the potential to further functionalize these
scaffolds. Our preliminary investigations were centered around
functionalization of the alkene and ketone groups (Scheme 3).
We further envisioned exploration of ring opening reactions of
4-allylpyrrolidine-2,3-diones for the synthesis of novel β2,2,3
-
amino acids (Scheme 4). A multitude of methods exist for the
Scheme 4. Synthesis of Novel β2,2,3-Amino Acids and β-
Lactam Derivatives
synthesis of monosubstituted β-amino acids at the β2 and/or β3
positions;23 however, only few reports describe the preparation
of disubstituted β2,2- or β3,3-derivatives as this substitution
pattern requires the synthetically challenging formation of a
quaternary stereocenter.24 In most cases, limitations in the
synthesis of the starting materials lead to a lack of versatility in the
achievable substitution pattern. Given the considerable chemical
and biological potential of β-amino acids, the development of
rapid and scalable approaches to access their novel derivatives is
of high importance.
A demonstration of the conversion of commercially available
materials to complex, quaternary-substituted β-amino acids is
shown in Scheme 4. The three-component reaction of methyl
ester, aldehyde, and 2,4-dimethoxybenzylamine (2,4-DMBA)
afforded 1,5-dihydro-2H-pyrrol-2-ones 11b,d,h which were
isolated by filtration. One-pot allylation with allyl bromide
followed by removal of dimethoxybenzyl substituent using TFA
in DCM (1:1 v/v) furnished allyl vinyl ethers 15b,d,h in good
yields; importantly, gram quantities of products could be
obtained. Claisen rearrangement in refluxing toluene followed
by purification provided 4-allylpyrrolidine-2,3-dione 18b,d,h as
single diastereomers. At this stage, the separation of enantiomers
could be achieved by conversion of 18d to ketimine
diastereomers followed by column separation and removal of
chiral auxiliary (see the Supporting Information) if desired.
Oxidative ring opening of the pyrrolidine-2,3-dione was achieved
by treatment of 18b,d,h with 1 M NaOH and 30% hydrogen
peroxide to furnish β-amino acids 19b,d,h, which could be
isolated by filtration after acidic work up or easily purified by
reversed-phase flash chromatography. Slow evaporation from
wet methanol allowed for crystallization of 19d, the structure of
which was confirmed by X-ray analysis (Scheme 4). In addition,
19d was readily converted to the corresponding β-lactam 20d in
good yield, highlighting one potential application of the β-amino
acids.
Scheme 3. Conversion of 4-Allylpyrrolidine-2,3-diones to
Cyclic Alkene Derivatives via Ring-Closing Metathesis
Reactions
In summary, we have optimized a protocol for the preparation
of alkyl-substituted 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones in
high yield. Subsequent Claisen rearrangement of allyl ether
derivatives of these heterocycles enabled access to novel
pyrrolidine-2,3-dione heterocycles containing a quaternary
stereocenter. We have demonstrated that straightforward
transformations of pyrrolidine-2,3-diones at the alkene and
ketone moieties can provide rapid access to N-containing
polycyclic scaffolds. Importantly, we found that 4-allyl-
pyrrolidine-2,3-diones could be converted to β2,2,3-amino acids
Initially, to take advantage of the alkenes already present in
substrate 13a, seven-membered alkene 14 was prepared via ring-
closing metathesis (RCM) in good yield by employing the first-
generation Grubbs’ catalyst. Incorporation of an additional allyl
moiety was also explored, and addition of allylmagnesium
bromide to 15d followed by RCM provided bicyclic γ-lactams 16
and 17 in 67% yield (Scheme 3).
C
DOI: 10.1021/acs.orglett.7b01185
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01185.
Experimental procedures; characterization of products; 1H
(13) Shymanska, N. V.; An, I. H.; Pierce, J. G. Angew. Chem., Int. Ed.
2014, 53, 5401.
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(b) Merchant, J. R.; Shah, R. J.; Bhandarkar, R. M. Recueil des Travaux
Chimiques des Pays-Bas 1962, 81, 131.
and 13C NMR spectra (PDF)
X-ray crystallographic data for compound 13b (CIF)
X-ray crystallographic data for compound 19d (CIF)
(15) (a) Bender, D. R.; Brennan, J.; Rapoport, H. J. Org. Chem. 1978,
43, 3354. (b) Dagoneau, D.; Xu, Z.; Wang, Q.; Zhu, J. Angew. Chem., Int.
Ed. 2016, 55, 760.
(16) (a) Zhuang, C.; Miao, Z.; Wu, Y.; Guo, Z.; Li, J.; Yao, J.; Xing, C.;
Sheng, C.; Zhang, W. J. Med. Chem. 2014, 57, 567. (b) Castellano, T. G.;
Neo, A. G.; Marcaccini, S.; Marcos, C. F. Org. Lett. 2012, 14, 6218.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jgpierce@ncsu.edu.
ORCID
Joshua G. Pierce: 0000-0001-9194-3765
Notes
(18) (a) Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95, 292.
(b) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6,
4387.
The authors declare no competing financial interest.
(19) (a) Trost, B. M.; Brennan, M. K. Org. Lett. 2006, 8, 2027.
(b) Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44,
308.
(20) We cannot rule out Pd-catalyzed allylation on the enol oxygen
followed by a subsequent Pd-catalyzed Claisen rearrangement:
(a) Keith, J. A.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Oxgaard, J.;
Stoltz, B. M.; Goddard, W. A. J. Am. Chem. Soc. 2007, 129, 11876.
(b) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343.
(c) Cao, T. C.; Linton, E. C.; Deitch, J.; Berritt, S.; Kozlowski, M. C. J.
Org. Chem. 2012, 77, 11034.
ACKNOWLEDGMENTS
■
We are grateful to the NIH (1R01GM110154) and NSF (CHE
1454845) for generous support of this work and to North
Carolina State University for support of our program. Mass
spectrometry data were obtained at the NC State Mass
Spectroscopy Facility. We thank Dr. Roger Sommer (NC
State) for X-ray analysis of 13b and 15d. We also acknowledge
Dr. Daniel Comins (NC State) for helpful discussions and
Materia, Inc., for generous donation of metathesis catalysts.
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