Automated three-component synthesis of a library of γ-lactams

Article abstract of DOI:10.3762/bjoc.8.206

A three-component method for the synthesis of γ-lactams from commercially available maleimides, aldehydes, and amines was adapted to parallel library synthesis. Improvements to the chemistry over previous efforts include the optimization of the method to a one-pot process, the management of by-products and excess reagents, the development of an automated parallel sequence, and the adaption of the method to permit the preparation of enantiomerically enriched products. These efforts culminated in the preparation of a library of 169 γ-lactams.

Full text of DOI:10.3762/bjoc.8.206

Automated three-component synthesis
of a library of γ-lactams
Erik Fenster1, David Hill1, Oliver Reiser2 and Jeffrey Aubé*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1804–1813.
1Center of Excellence in Chemical Methodologies and Library
Development, the University of Kansas, 2034 Becker Drive, Lawrence
Kansas, 66047, USA and 2Institut für Organische Chemie, Universität
Regensburg, Universitätsstrasse 31, 93053, Regensburg, Germany
doi:10.3762/bjoc.8.206
Received: 18 April 2012
Accepted: 12 September 2012
Published: 19 October 2012
Email:
Jeffrey Aubé* - jaube@ku.edu
This article is part of the Thematic Series "Recent developments in
chemical diversity".
* Corresponding author
Guest Editor: J. A. Porco Jr.
Keywords:
γ-lactam; maleimide; organocatalysis; parallel synthesis; reductive
© 2012 Fenster et al; licensee Beilstein-Institut.
License and terms: see end of document.
amination
Abstract
A three-component method for the synthesis of γ-lactams from commercially available maleimides, aldehydes, and amines was
adapted to parallel library synthesis. Improvements to the chemistry over previous efforts include the optimization of the method to
a one-pot process, the management of by-products and excess reagents, the development of an automated parallel sequence, and the
adaption of the method to permit the preparation of enantiomerically enriched products. These efforts culminated in the preparation
of a library of 169 γ-lactams.
Introduction
In recent years, the rapid access to structurally diverse and com- ring as a target of opportunity in chemical-screening efforts, we
plex small molecules has grown in importance within the previously reported a method to prepare γ-lactams from readily
context of high-throughput screening of biologically relevant available maleimides, aldehydes and amines [12]. The method
targets. The need for such compounds, both as pharmacological involved a three-step stepwise sequence involving an
probes and as starting points for drug-discovery campaigns, has organocatalyzed Michael addition, a reductive amination/
primarily fuelled this interest, while enabling technologies, such intramolecular lactamization, and an epimerization step
as diversity-oriented synthesis (DOS), have improved access to (Scheme 1). It culminated in the preparation of a 43-member
small-molecule libraries [1-5].
library. Although this method permitted relatively easy access
to highly substituted racemic γ-lactams, it required manual
Compounds containing a γ-lactam moiety have been significant manipulations of the intermediate products in each step in the
in the treatment of epilepsy [6,7], HIV [8,9], neurodegenerative form of workups and purifications. Accordingly, we wished to
disease and depression [10,11]. Having identified the lactam develop a streamlined approach that would provide access to
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Scheme 1: Three-step sequence for the preparation of γ-lactams from maleimides, aldehydes and amines. Potential improvements are indicated in
red.
larger numbers and quantities of diverse γ-lactams, preferen- 3–9), we were pleased to find that the use of protected diphenyl-
tially in enantiomerically pure form. Ideally, this would take the prolinol catalyst I at room temperature produced 3{1,1} in high
form of a single-pot process utilizing automation. We now yields and with high enantioselectivity, albeit with low dia-
report improvements to this process, which (1) generates enan- stereoselectivity. Such a low diastereoselectivity was of no
tiomerically enriched compounds, (2) eliminates the need for concern in the originally reported procedure since the final
intermediate purifications, (3) simplifies the method to a three- potassium tert-butoxide promoted epimerization step produced
step one-pot sequence, and (4) allows for the magnification of a racemic mixture of a single diastereomer. In the case of an
the library scale through the use of automation.
asymmetric synthesis, however, the initial diasteromeric ratio
would be reflected in the enantiomeric ratio of the final prod-
ucts when the downstream epimerization step is taken into
Results and Discussion
We began by probing the potential for the above-mentioned account; this is illustrated for the limiting case of high facial
improvements to our previously reported method by (a) selectivity with respect to the maleimide component in
exploring the possibility for an asymmetric organocatalyzed Scheme 2. Consequently, higher diastereoselectivity was
reaction in the Michael addition step, (b) combining the indi- required for the synthesis of enantioenriched γ-lactams. Indeed,
vidual three steps, and (c) automating the process to produce a 3{1,1} could be produced with moderate diastereoselectivity
demonstrative 256 member γ-lactam library.
when the reaction was performed at 0 °C over a prolonged
length of time (Table 1, entry 11) [14]. The use other solvents
(THF, acetonitrile) failed to either produce any product
(Table 1, entry 12) or lead to higher diastereoselectivity
Asymmetric organocatalyzed Michael addi-
tion
The success of pyrrolidine as the organocatalyst for the Michael (Table 1, entry 13). We considered that lowering reaction
addition of enolizable aldehydes to maleimides in the original temperatures in chloroform may lead to increased diastereose-
method suggested the possibility of producing chiral γ-lactams lectivities, but concluded that the lengthy reaction times neces-
through the use of a chiral proline-like organocatalysts. In fact, sitated under these conditions would have made the overall
Córdova and co-workers have previously established a protocol process inefficient. Although future work will explore addition-
for such a process [13]. Based on this initial protocol, we al catalysts and reaction conditions to improve this diastereose-
explored the use of various chiral amines in the conjugate addi- lectivity, we elected at this point to explore the additional steps
tion reaction of propionaldehyde (2{1}) to N-phenylmaleimide to produce γ-lactams with the modest enantiomeric enrichment
(1{1}) (Table 1). Although the achiral pyrrolidine was found to in hand.
be an efficient catalyst in the reaction [12], this led to a ~1:1
Combination of three discrete steps into a
mixture of racemic succinimide diastereomers 3{1,1}, even at
lowered temperatures (Table 1, entries 1 and 2). While a single-pot process
number of chiral amines failed to produce any significant We next turned our attention to combining the initial Michael
amounts of the desired succinimide product (Table 1, entries addition step with the remaining reductive amination/lactamiza-
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Table 1: Asymmetric organocatalytic addition of propionaldehyde (2{1}) to N-phenylmaleimide (1{1}).
Entry
Catalyst
Solvent
Temp (°C)
Time (h)
Yield (%)
dr
ee (%)a
1
2
Ab
A
B
C
D
E
F
G
H
I
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
THF
61
rt
2
74
72
1:1.1
1:1.2
—
—
—
—
—
—
—
60
—
—
96
99
—
90
16
12
12
12
12
24
12
12
12
36
12
36
3
61
61
61
61
rt
trace
NR
NR
NR
30
4
—
5
—
6
—
7
1:2.0
—
8
61
61
rt
NR
trace
88
9
—
10
11
12
13
1:2.0
1:4.2
—
I
0
90
I
61
0
NR
72
I
CH3CN
1:2.5
aDetermined by chiral phase HPLC analysis. b30 mol % of the catalyst was used.
Scheme 2: The transfer of the diastereoselective ratio of 3 to the enantioselectivity of the overall process in the synthesis of γ-lactams 6.
tion and epimerization steps. In the original procedure, the yield (as a 4.5:1 mixture of diastereomers). However, 20% of
reductive amination/lactamization reaction was performed in the succinimide product 7{1,1,1} was also isolated as a single
methylene chloride [12]. However, in order to combine this step diastereomer, resulting from incomplete transamidation.
with the previous Michael addition step, we thought to perform
the reaction in chloroform (Scheme 3). In fact, when the Although the reductive amination occurred readily at room
Michael addition reaction between propionaldehyde (2{1}) and temperature, the lactamization appeared to occur more slowly
N-phenylmaleimide (1{1}) was performed in chloroform at 0 °C than we had anticipated. In investigating individually the reduc-
(using the protected diphenylprolinol catalyst I), followed by tive amination/lactamization step using 3{1,1} with aniline
addition of aniline (4{1}) and sodium triacetoxyborohydride (4{1}) (Table 2), we found that the reaction required heating at
after 36 h, the desired γ-lactam 6{1,1,1} was obtained in 60% 40 °C for at least 8 h for complete lactamization to be achieved
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Beilstein J. Org. Chem. 2012, 8, 1804–1813.
Scheme 3: Combination of the Michael addition step with the reductive amination/lactamization step and of the reductive amination/lactamization step
with the epimerization step.
(Table 2, entry 3). Furthermore, the isolation of succinimide lactamization in the previous step would not necessarily be
7{1,1,1} as a single diastereomer at reduced temperatures required if the reductive amination/lactamization and epimeriza-
(Table 2, entry 1) or reaction times (Table 2, entry 2) seemed to tion steps were combined. Thus, subjecting 3{1,1,1} to the
indicate that the lactamization in forming the syn-diastereomer reductive amination conditions for 2 h at room temperature, fol-
of 6{1,1,1} occurs at a slower rate than that for the anti-diastere- lowed by addition of potassium tert-butoxide (after a solvent
omer.
change from CHCl3 to MeOH) provided the γ-lactam 6{1,1,1}
in 81% (Scheme 3) [15].
However, we found that subjecting succinimide 7{1,1,1} by
itself to potassium tert-butoxide in methanol promoted the Having demonstrated the ability to combine the first two steps
lactamization at room temperature in addition to the final as well as the last two steps, our attention was turned to
epimerization to produce 6{1,1,1} as a single diastereomer combine all three steps in a single-pot process (Scheme 4). At
(Scheme 3). Consequently, it became clear that complete this stage, we also investigated the possibility for removal of
Table 2: Reductive amination/lactamization of 3{1} with aniline (4{1}).
6{1,1,1}
7{1,1,1}
Entry
Temp (°C)
Time (h)
Yield (%)
dr
Yield (%)
1
2
3
rt
8
2
8
45
60
76
1.1:1
1.6:1
2.0:1
40
22
—
40
40
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Beilstein J. Org. Chem. 2012, 8, 1804–1813.
excess reagents and byproducts in order to render the overall Parallel library synthesis
process more efficient for parallel synthesis. If N-phenyl- The combined sequence was next attempted as a rehearsal 2 × 3
maleimide (1{1}) was to be used as a limiting reagent and × 3 validation library by using a Chemspeed Accelerator SLT-
propionaldehyde (2{1}) and aniline (4{1}) were used (with 4{1} 100 synthesizer (Table 3). In general, substrates which varied in
in excess relative to 2{1}), then at the end of the one-pot process their steric and electronic nature were chosen (alkyl and aryl
we should be left with the desired γ-lactam 6{1,1,1} and with groups). By using the three-step single-pot sequence described
only amines (aniline and N-propylaniline) as excess byproducts, above on the Chemspeed platform (0.400 mmol scale), the
which could be removed with a simple aqueous acid wash along resulting 18 crude γ-lactams 6 were subjected to preparative
with the remaining catalyst, borate salts, and potassium tert- HPLC purification. In general, yields in the range of 35–58%
butoxide. Thus, N-phenylmaleimide (1{1}) (1 equiv) was stirred were obtained, with the exception of those reactions that used
with an excess of propionaldehyde (2{1}) (1.5 equiv) in the phenylacetaldehyde 2{2} (yields in the range of 4–12%).
presence of the silylated diphenylprolinol catalyst (10 mol %) Although in our previous work aryl acetaldehydes were found
for 36 h at 0 °C, after which an excess of aniline (2 equiv) and to produce decent yields with pyrrolidine [12], similar results
sodium triacetoxyborohydride (2.5 equiv) were added to the were not obtained when the protected diphenylprolinol catalyst
reaction mixture. After being stirred for 6 h at room tempera- I was used. Except for the experiment in Table 3, entry 4,
ture, the chloroform solvent was removed in vacuo, replaced chemical purities >85% were observed for all of the isolated
with methanol, and potassium tert-butoxide (10 equiv) was products. Although most of the reactions proceeded with high
added. After 12 h at room temperature, the methanol solvent diastereoselectivities following the epimerization step (>19:1),
was evaporated in vacuo, the resulting residue was redisolved in this was not the case for all library products prepared during the
methylene chloride, and the solution was washed with 4 N HCl. production run described in the following section, as evident
Following simple filtration through a plug of silica gel, the from small impurities (ca. ≤10%) observable in the 13C NMR
γ-lactam 6{1,1,1} was obtained in 66% yield (with 80% es; spectra of the final products (Supporting Information File 1).
% es = % major enantiomer, corresponding to 60% ee). Overall, Such products were deemed suitable for screening purposes.
the above-mentioned one-pot sequence, in which both workups Finally, enantiomeric purity measurements were obtained for
and purifications are minimized, proved serviceable in the six selected γ-lactam products, which ranged between 62 and
desired parallel-synthesis sequence.
84% es.
Scheme 4: Combination of the Michael addition, the reductive amination/lactamization, and the epimerization step in a single-pot process.
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Table 3: Chemspeed rehearsal 2 × 3 × 3 library of γ-lactams 6.
Entry
Maleimide
Aldehyde
Amine
Product
Yield (%)a
Purity (%)b
es (%)c,d
1
2
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{2}
1{2}
1{2}
1{2}
1{2}
1{2}
1{2}
1{2}
1{2}
2{1}
2{1}
2{1}
2{2}
2{2}
2{2}
2{3}
2{3}
2{3}
2{1}
2{1}
2{1}
2{2}
2{2}
2{2}
2{3}
2{3}
2{3}
4{1}
4{2}
4{3}
4{1}
4{2}
4{3}
4{1}
4{2}
4{3}
4{1}
4{2}
4{3}
4{1}
4{2}
4{3}
4{1}
4{2}
4{3}
6{1,1,1}
6{1,1,2}
6{1,1,3}
6{1,2,1}
6{1,2,2}
6{1,2,3}
6{1,3,1}
6{1,3,2}
6{1,3,3}
6{2,1,1}
6{2,1,2}
6{2,1,3}
6{2,2,1}
6{2,2,2}
6{2,2,3}
6{2,3,1}
6{2,3,2}
6{2,3,3}
45
50
59
10
10
12
58
52
58
50
52
43
5
100
100
100
83.1
100
100
100
96.6
93.7
85.0
85.4
95.7
90.6
100
91.7
100
100
100
62
n.d.
66
3
4
n.d.
n.d.
n.d.
75
5
6
7
8
84
9
n.d.
n.d.
n.d.
71
10
11
12
13
14
15
16
17
18
n.d.
n.d.
n.d.
n.d.
n.d.
74
4
8
35
39
42
aPurified by an automated preparative reverse phase HPLC (detected by mass spectroscopy). bPurity was determined by HPLC with peak area (UV)
at 214 nm. c30 mol % of the catalyst was used. dDetermined by chiral phase HPLC analysis.
Overall, the results of the validation efforts demonstrated both produced either lowered or zero amounts of material in the reac-
the success of the one-pot automated method, as well as the tions for which these were utilized, with no discrepancy of the
scope of substrates suitable for a larger library set. With these substitution on the aryl ring. Additionally, 3-pycolylamine 4{8}
considerations, we planned for a 4 × 8 × 8 = 256 member yielded little or no material in the reactions for which it was
library of γ-lactams 6 on the Chemspeed platform with the used. With these exceptions, the process, in general, yielded
conditions evaluated in the rehearsal library. A number of products in the 15–70% range.
maleimides 1, aldehydes 2 and amines 3 were chosen
(Scheme 5) based on differences in their structure and polarity. Conclusion
Using the validated conditions, the Chemspeed was In summary, our previously reported method for the three-
programmed to run four sets of 4 maleimides × 2 aldehydes × component preparation of γ-lactams from commercially avail-
8 amines (64 compounds each) for a total of 256 attempted able maleimides, aldehydes and amines was improved and
syntheses. Upon completion of the four 64-compound runs, the adapted to automated parallel library synthesis. Improvements
reaction mixtures were purified by preparative HPLC, which to the chemistry over the previous method include the introduc-
afforded 169 compounds that met our goals of quantities tion of asymmetry in the form of an organocatalyzed Michael
>20 mg and purities >90%, in each case starting with addition, the removal of the main by-products and excess
0.400 mmol of maleimides 1 [16]. Further analysis of the results reagents by using an aqueous acid wash, and the optimization
showed that the arylacetaldehydes (2{2}, 2{6} and 2{7}) for a one-pot process. These efforts allowed the efficient use of
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Beilstein J. Org. Chem. 2012, 8, 1804–1813.
Scheme 5: Chemspeed 4 × 8 × 8 library of γ-lactams 6.
automation for parallel library synthesis, culminating in the in pH 9.8 buffered aqueous ammonium formate to 100% aceto-
preparation of a library of 169 γ-lactams.
nitrile at 1.0 mL·min−1 flow rate). Methylene chloride, acetoni-
trile, methanol and tetrahydrofuran were purified by using an
Innovative Technology Pure-Solv 400 solvent purification
system. Chloroform was purified by distillation over calcium
Experimental
General
All single-vessel reactions were performed under an argon hydride. The maleimides 1, the aldehydes 2, the amines 3 and
atmosphere in flame-dried glassware. The glass syringes and the chiral amine organocatalyst (A–I) were purchased from the
stainless-steel needles used for handling anhydrous solvents and Aldrich Chemical Co. and used without further purification.
reagents were oven dried, cooled in a desiccator, and flushed Melting points were performed by using an Optimelt (MPA100)
with dry nitrogen prior to use. Plastic syringes were flushed automated melting-point system (Sanford Research Systems)
with dry nitrogen before use. Thin-layer chromatography (TLC) and are uncorrected. Optical rotations of samples were
was performed on Analtech Uniplate Silica Gel GHLF 250 μm performed by using a Rudolph Research Analytical Autopol IV
precoated TLC plates. All library syntheses using automated automatic polarimeter at 589 nm. Infrared (IR) spectra were
technology were performed by using a Chemspeed Accelerator obtained using a Perkin-Elmer Spectrum 100 FT-IR spectrom-
SLT-100 Automated Synthesizer under an argon atmosphere in eter with a UATR application. Chiral HPLC measurements
vacuum dried (50 °C, 9 mmHg) 13 mL reactor vessels. Parallel were performed on a Shimadzu SCL-10A system with a SPD-
evaporations were performed by using a GeneVac EZ-2 plus 10AV UV–vis detector and hexane/isopropanol as the solvent
evaporator. Automated preparative reverse-phase HPLC purifi- mobile phase. Proton nuclear magnetic resonance (1H NMR)
cation was performed by using a Waters 2767 Mass Directed and carbon nuclear magnetic resonance (13C NMR) spectra
Fractionation system (2767 sample manager, 2525 Binary were recorded in deuterochloroform by using a Bruker AV-400
Pump, 515 Make-up pump) with a Waters ZQ quadrapole spec- or a Bruker DRX-500. Chemical shifts are reported in parts per
trometer and detected by UV (270 nm, Waters Xterra MS C-18 million (ppm) and are referenced to the centerline of deute-
column, 19 × 150 mm, elution with the appropriate gradient of rochloroform (δ 7.24 ppm 1H NMR, 77.0 ppm 13C NMR).
acetonitrile in pH 9.8 buffered aqueous ammonium formate at Coupling constants are given in hertz (Hz). Low-resolution
18 mL·min−1 flow rate). Purity was determined by reverse- mass spectra (MS) and high-resolution mass spectra (HRMS)
phase HPLC with peak area (UV) at 214 nm by using a Waters were recorded on a Waters LCT Premier TOF spectrometer for
Alliance 2795 system (Waters Xterra MS C-18 column, 4.6 × electrospray ionization (ESI).
150 mm, elution with a linear gradient of 5% acetonitrile in
pH 9.8 buffered aqueous ammonium formate to 100% acetoni- General procedure for the asymmetric organocat-
trile at 1.0 mL·min−1 flow rate). Purity was determined by alyzed Michael addition of aldehyde 2{1} to
reverse-phase HPLC with peak area (UV) at 214 nm by using a maleimide 1{1} to produce 3{1,1} (Table 1)
Waters Alliance 2795 system (Waters Xterra MS C-18 column, Propionaldehyde (2{1}) (31.2 μL, 0.433 mmol, 1.5 equiv) was
4.6 × 150 mm, elution with a linear gradient of 5% acetonitrile added to a solution of N-phenylmaleimide (1{1}) (50.0 mg,
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Beilstein J. Org. Chem. 2012, 8, 1804–1813.
0.289 mmol, 1.0 equiv) in chloroform (3 mL) at 0 °C, followed 2-((3S,4R)-4-Methyl-2-oxo-1-phenylpyrrolidin-3-yl)-N-
by the appropriate chiral amine (A–I) (0.0289 mmol, 0.1 equiv) phenylacetamide (6{1,1,1}) (major syn diastereomer):
and the reaction mixture was stirred at the appropriate tempera- 1H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 7.62–7.53 (m, 4H),
ture for the appropriate length of time listed in Table 1. Water 7.42–7.36 (m, J = 8.0 Hz, 2H), 7.32–7.24 (m, 2H), 7.22–7.16
was added upon completion of the reaction and the resulting (m, J = 9.2, 5.5 Hz, 1H), 7.10–7.03 (m, J = 7.4 Hz, 1H), 4.05
mixture was extracted with methylene chloride (3 × 5 mL). The (dd, J = 9.6, 6.0 Hz, 1H), 3.43 (dd, J = 9.7, 0.9 Hz, 1H),
methylene chloride extracts were combined, dried over sodium 3.29–3.22 (m, J = 7.8, 5.4 Hz, 1H), 3.00–2.93 (m, 1H),
sulfate and concentrated in vacuo to yield a yellow liquid. The 2.82–2.74 (m, 1H), 2.51 (dd, J = 15.3, 5.3 Hz, 1H), 1.09 (d, J =
crude liquid was purified by column chromatography (2/3 ethyl 3.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.4, 170.0,
acetate–hexane) to yield the succinimide 3{1,1} as a clear color- 139.2, 138.4, 129.0, 128.9, 125.2, 123.9, 120.3, 119.8, 54.9,
less liquid composed of a mixture of two diastereomers, which 44.7, 35.1, 30.7, 14.9; IR (neat): 3465, 3263, 2932, 2855,
were separated by further chromatographic purification.
1660 cm−1; MS (ESI+) m/e 309.2 [M + H]+; HRMS (ESI+)
calcd for C19H21N2O2 [M + H]+: 309.1603; found: 309.1606.
(R)-2-((S)-2,5-Dioxo-1-phenylpyrrolidin-3-yl)propanal
(3{1,1}) (major diastereomer):
+74.0 (c 1.10, CHCl3); 2-((3S,4S)-4-Methyl-2-oxo-1-phenylpyrrolidin-3-yl)-N-
1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 7.47 (m, 2H), 7.39 phenylacetamide (6{1,1,1}) (minor anti diastereomer):
(m, 1H), 7.35–7.23 (m, 2H), 3.36 (m, 1H), 3.13 (m, 1H), 2.98 1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 7.62–7.51 (m, 4H),
(dd, J = 18.5, 9.7 Hz, 1H), 2.51 (m, 1H), 1.30 (d, J = 7.6 Hz, 7.41–7.33 (m, 2H), 7.30–7.22 (m, J = 10.3, 5.5 Hz, 2H),
3H); 13C NMR (100 MHz, CDCl3) δ 201.4, 177.5, 175.0, 131.8, 7.22–7.12 (m, J = 7.4 Hz, 1H), 7.10–6.98 (m, J = 7.4 Hz, 1H),
129.1, 128.6, 126.4, 46.9, 39.4, 31.5, 9.7; IR (neat): 2971, 2940, 3.79 (dd, J = 9.4, 8.0 Hz, 1H), 3.42 (t, J = 9.5 Hz, 1H), 2.85 (dd,
1774, 1701 cm−1; MS (ESI+) m/e 232.1 [M + H]+; HRMS J = 14.7, 7.7 Hz, 1H), 2.72–2.61 (m, J = 12.6, 11.2, 8.8 Hz,
(ESI+) calcd for C13H14NO3 [M + H]+: 232.0974; found: 1H), 2.55 (dd, J = 14.7, 3.9 Hz, 1H), 2.33–2.14 (m, 1H), 1.22
232.0988.
(d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.7,
169.4, 138.7, 138.3, 128.8, 128.7, 125.0, 123.7, 120.1, 119.6,
(S)-2-((S)-2,5-Dioxo-1-phenylpyrrolidin-3-yl)propanal 54.1, 48.1, 37.7, 33.7, 16.6; IR (neat): 3460, 3265, 2932, 2855,
(3{1,1}) (minor diastereomer): +43.3 (c 0.80, CHCl3); 1657 cm−1; MS (ESI+) m/e 309.2 [M + H]+; HRMS (ESI+)
1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 7.47 (m, 2H), 7.39 calcd for C19H21N2O2 [M + H]+: 309.1603; found: 309.1590.
(m, 1H), 7.28 (m, 2H), 3.26–3.15 (m, J = 13.0, 6.5 Hz, 1H),
3.10–3.00 (m, 1H), 2.87 (dd, J = 18.1, 9.6 Hz, 1H), 2.54 (dd, J (S)-1-Phenyl-3-((R)-1-(phenylamino)propan-2-yl)pyrroli-
= 18.1, 5.6 Hz, 1H), 1.33 (d, J = 7.8 Hz, 3H); 13C NMR dine-2,5-dione (7{1,11}): 1H NMR (400 MHz, CDCl3) δ
(100 MHz, CDCl3) δ 201.8, 177.6, 175.1, 132.0, 129.0, 128.5, 7.50–7.33 (m, 3H), 7.24–7.08 (m, 4H), 6.79–6.67 (m, J =
126.5, 46.8, 40.6, 31.5, 11.2; IR (neat): 2973, 2941, 1773, 7.3 Hz, 1H), 6.67–6.52 (m, J = 7.5 Hz, 2H), 3.82 (s, 1H),
1701 cm−1; MS (ESI+) m/e 232.1 [M + H]+; HRMS (ESI+) 3.42–3.26 (m, 1H), 3.26–3.09 (m, 2H), 2.92 (dd, J = 18.5,
calcd for C13H14NO3 [M + H]+: 232.0974; found: 232.0985. 9.6 Hz, 1H), 2.63 (dd, J = 18.5, 5.0 Hz, 1H), 2.63–2.50 (m, J =
5.0 Hz, 1H), 1.09 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
General procedure for the reductive amination/
CDCl3) δ 178.5, 175.6, 147.8, 131.8, 129.3, 129.1, 128.6,
lactamization of 3{1,1} with aniline (4{1}) (Table 2)
126.6, 117.9, 112.9, 46.9, 42.4, 34.3, 31.3, 15.0; IR (neat):
Aniline (4{1}) (38.4 μL, 0.422 mmol, 1.5 equiv) and sodium 3380, 2974, 2950, 1775 cm−1; MS (ESI+) m/e 309.2 [M + H]+;
triacetoxyborohydride (119 mg, 0.562 mmol, 2.0 equiv) were HRMS (ESI+) calcd for C19H21N2O2 [M + H]+: 309.1603;
added to a solution of succinimide 3{1,1} (65.0 mg, found: 309.1595.
0.281 mmol, 1.0 equiv) in chloroform (3 mL) and the reaction
mixture was stirred at the appropriate temperature for the appro- General procedure for the combination of the
priate length of time listed in Table 2. A 1 N aqueous solution Michael addition, the reductive amination/lactamiza-
of sodium hydroxide (3 mL) was added and the reaction mix- tion, and the epimerization step in a single-pot
ture was extracted with methylene chloride (3 × 2 mL). The process to produce γ-lactam 6{1,1,1} (Scheme 4)
methylene chloride extracts were combined, dried over sodium A 0.400 M solution of propionaldehyde (2{1}) in chloroform
sulfate and concentrated in vacuo to yield a yellow liquid. The (1.50 mL, 0.600 mmol, 1.5 equiv) was added to a 0.400 M solu-
crude liquid was purified by column chromatography (1/1 ethyl tion of N-phenylmaleimide (1{1}) in chloroform (1.00 mL,
acetate-hexane) to yield 6{1,1,1} as a clear colorless liquid 0.400 mmol, 1.0 equiv) at 0 °C, followed by a 0.100 M
composed of a mixture of two diastereomers and 7{1,1,1} as a solution of (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol
clear colorless liquid.
trimethylsilyl ether (0.40 mL, 0.040 mmol, 0.10 equiv), and the
1811

Beilstein J. Org. Chem. 2012, 8, 1804–1813.
reaction mixture was stirred at 0 °C for 36 h. A 1.00 M solution
of aniline (4{1}) (0.80 mL, 0.800 mmol, 2.0 equiv) was added
followed by sodium triacetoxyborohydride (212 mg,
1.00 mmol, 2.5 equiv) and the reaction mixture was stirred at
room temperature for 6 h. The chloroform solvent was removed
in vacuo, methanol (10 mL) was added followed by potassium
tert-butoxide (449 mg, 4.00 mmol, 10.0 equiv), and the reac-
tion mixture was stirred at room temperature for 12 h. The
methanol solvent was removed in vacuo, a 4.0 N aqueous solu-
tion of hydrochloric acid (5.0 mL, 20 mmol, 50.0 equiv) was
added, and the reaction mixture was extracted with methylene
chloride (3 × 2 mL). The methylene chloride extracts were
combined, dried over sodium sulfate and concentrated in vacuo
to yield a yellow liquid. The crude liquid was purified by
column chromatography (1/1 ethyl acetate-hexane) to yield
81.4 mg (66%) of a single diastereomer of 6{1,1,1} as a clear
colorless liquid. The ee of the product was determined by chiral
HPLC analysis to be 80% (Chiralpak AD column, 80/20
hexane/isopropanol).
Supporting Information
Supporting Information File 1
Results for the four 4 × 2 × 8 libraries using an automated
synthesizer, full characterization data for representative
compounds, and copies of 1H and 13C NMR spectra for
representative compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-206-S1.pdf]
Acknowledgements
The authors are grateful to Ben Neuenswander for carrying out
the purification of the libraries and to the National Institutes of
General Medical Sciences for financial support through the
University of Kansas Chemical Methodologies and Library
Development center (P50 GM69663).
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14.This should ultimately produce lactams with ~80% es.
15.We observed a decrease in the enantiomeric purities, reflective of the
diastereomeric ratio of the succinimide, as we had anticipated
(Scheme 3).
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Beilstein J. Org. Chem. 2012, 8, 1804–1813.
16.The standards for compound purity and quantity are based on those
requested from the National Institutes of Health's Molecular Library
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