Extended Piperidine-Piperidinone Protein Interface Mimics

Article abstract of DOI:10.1021/acs.joc.5b00300

Minimalist structures, H and I, were designed as protein interface mimics. Attributes of these chemotypes are (i) greater rigidity than conventional peptides, (ii) chiral and nonplanar heterocyclic backbones that are less prone to the hydrophobic aggregation effects, and (iii) potential to be prepared with a variety of side chains corresponding to natural amino acids. Intermediates, however, in the oligo(pyrrolidinone-piperidine)s H syntheses were vulnerable to epimerization. The origins of this epimerization were determined, then the study was focused on oligo(piperidinone-piperidine) compounds I. Mimics I were prepared via iterative couplings; a penta(piperidinone-piperidine) was prepared in this way. A series of lower homologues of this pentamer were crystallized and studied (single crystal X-ray), and four of them were used in a circular dichroism (CD) study. Thus, an estimate of 36 ? for the N-to-C distance of a typical conformation of the penta(piperidinone-piperidine) was made. CD spectra of four progressively longer oligomers allowed assignment of elipticity changes around 300 nm that can be attributed to increased conformational ordering of the longer oligomers in solution. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b00300

Article
pubs.acs.org/joc
Extended Piperidine−Piperidinone Protein Interface Mimics
Dongyue Xin, Arjun Raghuraman, and Kevin Burgess*
Department of Chemistry, Texas A & M University, Box 30012, College Station, Texas 77842, United States
S
* Supporting Information
ABSTRACT: Minimalist structures, H and I, were designed as protein interface
mimics. Attributes of these chemotypes are (i) greater rigidity than conventional
peptides, (ii) chiral and nonplanar heterocyclic backbones that are less prone to
the hydrophobic aggregation effects, and (iii) potential to be prepared with a
variety of side chains corresponding to natural amino acids. Intermediates,
however, in the oligo(pyrrolidinone-piperidine)s H syntheses were vulnerable to
epimerization. The origins of this epimerization were determined, then the study
was focused on oligo(piperidinone−piperidine) compounds I. Mimics I were
prepared via iterative couplings; a penta(piperidinone−piperidine) was prepared
in this way. A series of lower homologues of this pentamer were crystallized and
studied (single crystal X-ray), and four of them were used in a circular dichroism
(CD) study. Thus, an estimate of 36 Å for the N-to-C distance of a typical
conformation of the penta(piperidinone−piperidine) was made. CD spectra of
four progressively longer oligomers allowed assignment of elipticity changes around 300 nm that can be attributed to increased
conformational ordering of the longer oligomers in solution.
In our view, the hidden potential of so-called minimalist
mimics is they also populate conformations other than the
targeted secondary structure.8,9 We coined the term universal
mimics to describe small molecules simultaneously populating
conformations that resemble more than one secondary
structure. This led us to appreciate that minimalist mimics in
some situations can resemble regions of a PPI interface but not
any particular secondary structure. This was enlightening
because it forced us to realize that mimicry of secondary
structures is not the real issue in designing small molecules to
perturb PPIs.
In response, we conceived the Exploring Key Orientations
(EKO) strategy. Briefly, in EKO, each set of three residues on a
protein at a crystallographically characterized PPI interface is
categorized in terms of six Cartesian coordinates corresponding
to the three sets of Cα and Cβ atoms. Similarly, each kinetically
and thermodynamically accessible conformation of a minimalist
mimic of a PPI interface, an interface mimic, can be
characterized in the same way, regardless of whether it
resembles a secondary structure or not.
Papers from our laboratories have reported on the minimalist
mimics G.10 We were intrigued by the fact that small changes to
the backbone structure G must affect the accessible
conformations of these molecules and, therefore, the types of
protein−ligand interface regions they can resemble.11 However,
if the compounds are not synthetically accessible, then it will be
impossible to test their effects in a cellular environment. Our
group has shown that mimics G can be prepared with a variety
of amino acid side chains, but not without limitations.10
INTRODUCTION
■
Minimalist mimics of peptides and proteins are organic scaffolds
that (i) access fewer conformations than peptides (are
“semirigid”) and (ii) display three or more amino acid side
chains. Motivation for studies of minimalist mimics stems from
their potential to perturb protein−protein interactions (PPIs).
Noncovalent interaction energies at protein interfaces tend to
be dominated by side chain to side chain interactions.1
A
minimalist mimic that presents side chains in orientations
corresponding to one PPI component, called here the protein−
ligand, has the potential to displace that ligand and bind to the
other partner in the PPI, the protein−receptor.
Figure 1 shows illustrative minimalist mimics (A,2 B,3 C,4 D,5
E,6 F7) reported since this area was reviewed in 2011.8 For any
particular PPI, a minimalist mimic scaffold has potential only if
it is synthetically accessible with amino acid side chains
corresponding to the protein−ligand at the interface region.
The main shortcoming of designing generic secondary structure
mimics is that secondary structures at PPI interfaces are usually
distorted, and many interfaces do not involve secondary
structures at all. This makes it difficult to decide where to
overlay the mimic on the interface region and, therefore, which
amino acids side chains should be incorporated.
If the appropriate region of overlay can be determined, the
scaffold has to be made presenting those particular side chains.
Mimic A has been formed from amino acids and is attractive in
this regard. Sheet mimics D−F have so far been prepared only
with methyl side chains, but there is potential to construct D
and E from a variety of amino alcohols. Preparation of mimics
B, C, and F with a variety of genetically encoded amino acid
side chains would be more challenging.
Received: February 9, 2015
© XXXX American Chemical Society
A
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Figure 2. This paper focuses on minimalist mimics H and I,
conceptually derived from G.
prepare, and they were easily converted to piperidine-
functionalized tetramic acid esters 2.13 The first chromato-
graphic separation was required only at this stage; hence, these
monomers were conveniently prepared in gram amounts
(Scheme 1). Throughout this paper, compounds are numbered
according to the scaffold with lower case one-letter codes
Scheme 1. Preparation of Pyrrolidine−Piperidines 4
Figure 1. Recent examples of minimalist mimics.
Research described in this paper covers a brief investigation of
the pyrrolinones−piperidine mimics H and more extensive
work on the piperidinones−piperidines I,11,12 particularly with
respect to repeated application of the coupling chemistry used
to prepare these molecules and some characteristics of the
extended systems that are formed (Figure 2).
Scaffolds G−I have different conformational ensembles that
orient the three side chains on each scaffold in different ways.
Each scaffold will therefore overlay on different types of PPI
interfaces, as determined using massive screening of the PDB
with the data mining routine we developed as part of the EKO
strategy. Illustrative data regarding what PPI interfaces EKO
predicts will be impacted by scaffolds H and I are given in the
Supporting Information (section E). This paper concerns
attempts to make scaffold H and more successful syntheses of
scaffolds I that are flexible with respect to the side chains that
can be incorporated.
RESULTS AND DISCUSSION
■
Exploratory Studies On Pyrrolidinone−Piperidine
Oligomers H. Synthesis of the chiral center pyrrolidines G
necessitated SN2 displacement of a triflate from an enantiomeri-
cally enriched, N-protected, 3-hydroxypyrrolidine; this was not
a reaction that proceeded cleanly from starting material to
product.10 Superficially, syntheses of mimics H appeared to be
more facile because reductive amination to give the diamines 1
does not introduce a chiral center. Diamines 1 were easy to
B
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Table 1. Optimization of Coupling the Piperidines 2a with the Tetramic Acids 3a
entry
activating reagent
base
additive
epimerization by 13C NMR
isolated yield (%)
a
c
1
2
TBTU
HBTU
PyBOP
TFFH
EDCI
EDCI
EDCI
EDCI
EDCI
EDCI
EDCI
EDCI
TEA
n.d.
10
a
a
a
a
a
a
TEA
TEA
TEA
TEA
TEA
TEA
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
10%
none
n.d.
n.d.
23
3
complex mixture
4
<10
5
30
6
HOBt
HOAt
HOAt
HOAt
HOAt
HOAt
45
7
59
b
8
KF
40
b
9
Li2CO3
39
b
b
10
11
12
13
Cs2CO3
86
KHCO3
74
b
KHCO3
oxyma16
complex mixture
10
b
EDCI
KHCO3
N-hydroxysuccinimide
a
b
c
2.0 equiv of TEA. 5.0 equiv of the base. Not determined.
relating their side chains to the parent amino acids (e.g., f for
Phe, s for Ser, s′ for the −CH2OtBu, t for CH2CH(OH)Me,
and t′ for CH2CH(OBn)Me; named from N- to C-terminus,
just as in peptides).
Surprisingly, it proved to be difficult to couple the
piperidines 2 with tetramic acids 3, as compared with the
pyrrolidines used in syntheses of scaffolds G. Considerable
optimization of these reaction conditions was required, as
documented in Table 1 and in a study of similar β-enamino
ester syntheses from our lab.14 The highlighted conditions
(entry 11: EDCI, KHCO3, HOAt15) afforded the scaffold with
two side chains, 4aa, more efficiently than any other set of
conditions studied.
were observed: one of these was formed in even greater
amounts when the experiment was repeated with aged (partially
racemized) 2s′. The fact that a significant amount of the fourth
possible stereoisomer was not observed in the experiments
involving optically pure 3a indicates epimerization of the 2s′
fragment dominates. A possible reason for this is inductive
stabilization of the enolate from 2s′ that would not affect 3a or
the N-terminal part of product 4as′.
At this stage, it became clear that the targeted pyrrolidi-
none−piperidine oligomers H were too stereochemically
delicate, especially if they contained side chains that somehow
promoted epimerization. Consequently, we decided to focus
our efforts on the piperidinone−piperidine systems I featured
in the next section. Nevertheless, we were able to synthesize the
three-side-chain system 5aaa without epimerization (reaction
2).
A major difficulty arose when the optimized conditions that
gave 4aa without epimerization were applied to make 4as′ and
4 fs′; ∼15 and 30% epimerization was observed (by 13C NMR
and analytical HPLC), respectively (reaction 1). A series of
experiments were undertaken to determine which of the two
chiral centers was most vulnerable to epimerization (SI, Figure
S2). First, it was established that compound 2s′ is basic enough
to mediate its own racemization when stored as a concentrated
oil at room temperature overnight. Evidence for this assertion
was from an experiment in which “aged” 2s′ was coupled with
racemic tetramic acid 3a, resulting in four stereoisomeric
products that could be separated via analytical HPLC with a
chiral support (Chiralpak AD). When freshly prepared 2s′ was
coupled with optically pure tetramic acid 3a, three products
Recently, we devised a strategy called Exploring Key
Orientations on Secondary structures (EKOS). EKOS matches
side chain orientations of a large number of accessible
conformations of a minimalist mimic with sets of similar
parameters in common secondary structures; this relates the
conformations of the mimics in solution to the secondary
structures they resemble most closely in terms of side chain
C
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orientation.9b Application of the EKOS routine indicated
accessible conformations of 5aaa contain some that overlay
on a sheet-turn-sheet motif more accurately than any of the
conformers matched the other common secondary structures
(310-, α-, π-helices; parallel and antiparallel β-sheets; and β-
strands). Figure 3 shows the same overlay with conventional
atom colors on the left and the ideal sheet-turn-sheet motif
highlighted in purple on the right.
Scheme 2. Synthesis of the Piperidinones−Piperidine Mimic
12fffff with 10 Linked Rings
Figure 3. Overlay of 5aaa on an ideal sheet-turn-sheet motif.
Piperidinone−Piperidine Oligomers I. Our laboratory
has reported syntheses of compounds 6,11 and applied them to
perturb PPIs involved in oligomerization of α-antithrombin.12
The purpose of the current study was to see if the iterative
coupling chemistry used to prepare compounds 6 could be
applied to form extended systems and to elucidate some
characteristics of the products formed (Figure 4).
Solid state structures of 13gg, 9af, and 14-Bn′-faf reveal that
these molecules crystallize as conformers that have different
dihedral angles for the linkages marked with red arrows in
Figure 5. Rotation around bonds associated with these red
arrows has a profound effect on the side chain orientations.
This supports the assertion that minimalist mimics have the
potential to adopt conformers that can overlay on more than
one ideal secondary structure or interface region. Compounds
13gg, 9af, and 14-Bn′-faf have 3, 4, and 5 piperidinone/
piperidine rings, and they measure (N- to C-termini) 11.2, 15.1,
and 17.5 Å, respectively. Those dimensions correspond to 3.73,
3.77, and 3.50 Å, respectively, per piperidinone or piperidine
ring, and the difference between these figures (0.27 Å) reflects
the extent of kinking or curvature in the overall conformation.
None of these solid state conformations overlay very well on
ideal secondary structures, but within this series, 13gg and 9af
are the most extended (cf sheet structures), and 14-Bn′-faf is
most helical. Compound DDDDD-12fffff was not crystallized,
but the solid state data suggests this compound might have N-
Figure 4. Scaffold 6 with various side chain functionalities.
Syntheses Of Extended Systems I. Compound 7 in
Scheme 2 is analogous to an N-protected, C-activated amino
acid. That Scheme illustrates how iterative couplings under
elevated temperature and mildly basic conditions were suitable
for synthesis of 12fffff with five repeating units derived from
Phe. Supporting Information Figure S1 shows the MALDI MS
of this product has a single ion at the predicted m/z of 1507.8
for M + H (plus 1529.8 for M + Na, and 1545.8 for M + K).
This product is considerably less polar than typical peptides,
being soluble in dichloromethane, methanol, and DMSO.
Some Properties of the Extended Piperidinone−
Piperidine Systems I. Three intermediates (9af, 13gg, and
14-Bn′-faf) were isolated11 and crystallized in the course of the
synthetic studies described above. Representations from X-ray
crystal structures of those compounds are shown in Figure 5.
D
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Figure 5. Scaffolds 13gg, 9af, and 14-Bn′-faf were characterized via single crystal X-ray studies;11 consequently, the N-to-C dimensions of 12fffff
were estimated to be around 36 Å.
to-C dimensions of (10 × 3.50) to (10 × 3.77), or around 36 Å
in the solid state.
state structures of three compounds of intermediate lengths in
this series showed they tend to adopt extended conformations
and provided evidence to suggest a 36 Å longitudinal
dimension for the pentamer 12fffff. CD studies of milestone
intermediates in this synthesis indicates the conformational
ensemble tends toward progressively more ordered structures
in solution.
CD spectra of minimalist mimics are rarely informative
because it is unusual to have a series that represents systematic
changes to the scaffold structure.17 However, in this particular
study, several oligo(piperidinone−piperidine)s of different
lengths were available, and this facilitated meaningful
correlations of elipticities with structure. Figure 6a shows UV
spectra of compounds represented by the generic structure J (n
= 1 is 9ff; n = 2, 10fff; n = 3, 11ffff; and, n = 4, 12fffff; D
configuration throughout). Absorbance maxima at ∼290−310
nm (MeOH) are attributed to additive effects of the enamide
chromophores (red box on J); more absorbance correlates with
higher values of n. If the compounds were nonrandomly
distributed among stereoisomeric secondary structures (e.g.,
right- and left-handed helices), then increased molar elipticities
would be expected as n increases. Figure 6b shows that molar
elipticities in the 290−310 nm wavelength region do, in fact,
increase with n, implying some degree of ordering in solution.
EXPERIMENTAL SECTION
■
General Procedures. All reactions were carried out under
nitrogen atmosphere with dry solvents under anhydrous
conditions. Glassware was dried in an oven at 140 °C for a
minimum of 6 h prior to use. Dry solvents were obtained by
passing the previously degassed solvents through activated
alumina columns. Reagents were purchased at a high
commercial quality (typically 97% or higher) and used without
further purification unless otherwise stated. Flash chromatog-
raphy was performed using silica gel (230−600 mesh).
Analytical thin layer chromatography (TLC) was carried out
on Merck silica gel plates with QF-254 indicator and visualized
CONCLUSION
by UV or potassium permanganate stains. H and 13C spectra
1
■
This study has demonstrated mimics I are easier to prepare as a
single stereoisomer than the closely related oligomers H.
Solution phase syntheses of mono-, di-, tri-, tetra-, and
pentaoligo(piperidinone−piperidine)s were convenient. Solid
were recorded on a 300 or 400 MHz spectrometer and were
calibrated using residual nondeuterated solvent as an internal
reference. Chemical shifts (δ) are reported in parts per million,
and coupling constants (J) are given in Hz. The following
E
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General Procedure for the Syntheses of 2. NaBH-
(OAc)3 (6.36 g, 30.0 mmol) was added portionwise to a
solution of L-alanine tert-butyl ester hydrochloride (1.82 g, 10.0
mmol), benzyl 4-oxopiperidine-1-carboxylate (2.33 g, 10.0
mmol), triethylamine (1.39 mL, 10.0 mmol) in 1,2-dichloro-
ethane (70.0 mL) at 0 °C (ice bath) under nitrogen in a round-
bottom flask. The ice bath was removed, and after stirring at 27
°C for 24 h, CH2Cl2 (100 mL) was added. The mixture was
washed with saturated NaHCO3 solution (3 × 100 mL) and
then with brine (100 mL). The organic layer was separated,
dried over anhydrous MgSO4, and concentrated in vacuo to
give the reductive amination product 3.48 g (96% yield) as a
colorless oil.
The product from the previous step (2.90 g, 8.0 mmol) was
dissolved in dry dioxane (70.0 mL) in a round-bottom flask and
heated to 100 °C under nitrogen atmosphere. Bestmann’s ylide
(recrystallized from PhMe, 5.32 g, 17.6 mmol, 2.2 equiv) was
added in one portion, then 10 mL of TFA solution (0.4 M in
dry dioxane) was added dropwise over 10 min. The reaction
1
was monitored by H NMR spectroscopy. After completion of
the reaction (3 h), the solvent was removed under reduced
pressure. The resulting oil was dissolved in dichloromethane
and filtered through a thin layer of silica gel (∼1 cm). The silica
gel was further washed with 9:1 dichloromethane/ethyl acetate.
The solvent was removed under reduced pressure to give the
cyclized product contaminated with Ph3PO.
Pd/C (10 wt %; 0.85 g, 0.10 equiv Pd) was carefully added to
a stirred solution of the crude cyclization product in methanol
(60 mL) under nitrogen at 25 °C. The reaction was evacuated,
refilled with N2, and placed under an atmosphere of H2 (1 atm,
balloon) for 10 h. The reaction mixture was purged with N2
and filtered over a pad of Celite under a gentle vacuum
(SAFETY NOTE: Do not let the pad run dry). The Celite pad
was washed with methanol (2 × 15 mL), and the combined
filtrates were concentrated. The residue was purified by flash
chromatography (SiO2, 3−5% MeOH/CH2Cl2 containing 1%
Et3N) to afford the product 2a (1.37 g, 68%) as a white solid.
(S)-4-(tert-Butoxy)-5-methyl-1-(piperidin-4-yl)-1H-pyrrol-
2(5H)-one (2a). White solid, 1.37 g, 68% yield over two steps;
1
mp = 130.5−131.0 °C; H NMR (300 MHz, CDCl3) δ 4.96
(1H, s), 4.01−3.81 (2H, m), 3.18−3.04 (2H, m), 2.71−2.56
(3H, m), 1.83−1.61 (4H, m), 1.39 (9H, s), 1.29 (3H, d, J = 6.9
Hz); 13C NMR (75 MHz, CDCl3) δ 172.2, 171.8, 95.2, 81.4,
56.6, 49.6, 46.3, 46.2, 32.9, 31.0, 27.4, 18.7. HRMS (ESI-TOF):
m/z calcd for C14H24N2O2 [M + H]+ 253.1916; found
253.1908.
Figure 6. a UV; and, b CD spectra of J (n = 1 is 9ff; n = 2, 10fff; n = 3,
11ffff; and, n = 4, 12fffff) in MeOH. UV spectra were recorded at 20
μM, and CD at 200 μM.
(S)-5-Benzyl-4-(tert-butoxy)-1-(piperidin-4-yl)-1H-pyrrol-
2(5H)-one (2f). White solid, 0.83 g from L-phenylalanine tert-
butyl ester hydrochloride (1.03 g, 4.00 mmol), 63% yield over
abbreviations were used to explain the multiplicities: s = singlet,
d = doublet, t = triplet, q = quartet, dd = double doublet, dq =
double quartet, m = multiplet, br = broad. HRMS were
obtained using ESI or MALDI ionization. Melting points were
recorded on an automated melting point apparatus and are
uncorrected.
All the HPLC analyses were carried out with UV detection
monitored at 254 nm. Analytical reversed phase HPLC analyses
were performed with a 150 × 4.6 mm C-18 column using
gradient conditions (10−90% acetonitrile in water, flow rate =
0.75 mL/min). Chiralpak AD (250 × 4.6 mm i.d.) column was
utilized for the chiral HPLC analysis (hexanes: isopropyl
alcohol 85:15, flow rate = 1 mL/min).
1
three steps; mp = 218.8−219.6 °C; H NMR (300 MHz,
CDCl3) δ 7.25−7.13 (5H, m), 5.30−5.22 (1H, br), 4.92 (1H,
s), 4.16 (1H, t, J = 5.1 Hz), 3.64−3.52 (1H, m), 3.28−3.18
(2H, m), 3.09 (1H, dd, J = 5.1, 14.4 Hz), 3.00 (1H, dd, J = 5.1,
14.4 Hz), 2.78−2.59 (2H, m), 2.35−2.04 (2H, m), 1.89−1.69
(2H, m), 1.28 (9H, s); 13C NMR (75 MHz, CDCl3) δ 174.0,
170.6, 136.0, 129.4, 128.1, 126.7, 96.8, 82.0, 61.6, 50.7, 45.6,
45.5, 36.9, 30.1, 29.7, 27.3. HRMS (ESI-TOF): m/z calcd for
C20H28N2O2 [M + H]+ 329.2229; found 329.2220.
(S)-5-((1H-Indol-3-yl)methyl)-4-(tert-butoxy)-1-(piperidin-
4-yl)-1H-pyrrol-2(5H)-one (2w). White solid, 1.12 g from L-
tryptophan tert-butyl ester hydrochloride (1.48 g, 5.00 mmol),
UV spectra were recorded on a UV spectrometer using a 10
mm quartz cuvette at 20 μM in MeOH. Circular dichroism
spectra were recorded on a CD spectrometer using a 2 mm
quartz cuvette at 200 μM in MeOH.
1
61% yield over three steps; mp = 197.9−198.4 °C; H NMR
(300 MHz, CDCl3) δ 8.82 (1H, br), 7.58 (1H, d, J = 6.6 Hz),
F
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7.32 (1H, d, J = 6.6 Hz), 7.16−7.03 (3H, m), 4.83 (1H, s), 4.29
(1H, t, J = 4.2 Hz), 3.38−3.19 (2H, m), 3.19−3.04 (2H, m),
2.66−2.53 (2H, m), 2.53−2.32 (1H, br), 2.05−1.69 (4H, m),
1.07 (9H, s); 13C NMR (75 MHz, CDCl3) δ 174.0, 170.7,
135.5, 128.1, 122.2, 121.6, 118.8, 118.6, 111.1, 108.7, 96.6, 81.6,
60.7, 50.9, 46.4, 46.3, 32.3, 31.4, 26.8, 25.4. HRMS (ESI-TOF):
m/z calcd for C22H29N3O2 [M + H]+ 368.2338; found
368.2324.
(1H, d, J = 2.1 Hz), 6.19 (1H, s), 4.91 (1H, s), 4.60 (1H, s),
4.26 (1H, t, J = 5.1 Hz), 4.00 (1H, q, J = 6.3 Hz), 3.89−3.77
(1H, m), 3.44−3.06 (4H, m), 2.83−2.64 (2H, m), 2.12−1.54
(4H, m), 1.28 (3H, d, J = 6.3 Hz), 1.23 (9H, s); 13C NMR (75
MHz, CDCl3) δ 176.1, 173.8, 170.9, 169.5, 135.8, 127.7, 122.2,
121.8, 119.0, 118.4, 111.4, 109.3, 96.4, 90.4, 81.9, 61.3, 52.2,
50.4, 48.1, 47.8, 30.3, 28.7, 27.1, 26.6, 20.4. HRMS (ESI-TOF):
m/z calcd for C27H34N4O3 [M + H]+ 463.2709; found
463.2692.
(S)-4-(tert-Butoxy)-5-(tert-butoxymethyl)-1-(piperidin-4-
yl)-1H-pyrrol-2(5H)-one (2s′). Colorless oil, 0.91 g from O-tert-
butyl-L-serine tert-butyl ester hydrochloride (1.27 g, 5.00
(S)-4-(tert-Butoxy)-5-(tert-butoxymethyl)-1-(1-((S)-2-meth-
yl-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)piperidin-4-yl)-1H-pyr-
rol-2(5H)-one (4as′). Colorless oil, 100.4 mg from 2s′ (130.0
1
mmol), 56% yield over three steps; H NMR (300 MHz,
1
CDCl3) δ 4.96 (1H, s), 3.97−3.82 (2H, m), 3.67 (1H, dd, J =
2.4, 9.3 Hz), 3.39 (1H, dd, J = 5.1, 9.3 Hz), 3.18−3.03 (2H, m),
2.64−2.51 (3H, m), 2.08−1.82 (2H, m), 1.79−1.58 (2H, m),
1.38 (9H, s), 1.11 (9H, s); 13C NMR (75 MHz, CDCl3) δ
172.9, 168.2, 96.9, 81.4, 72.9, 62.0, 61.2, 50.5, 46.6, 46.4, 32.1,
31.2, 27.4, 27.3. HRMS (ESI-TOF): m/z calcd for C18H32N2O3
[M + H]+ 325.2491; found 325.2479.
General Procedure for the Syntheses of 4. To a stirred
solution of 2a (126.2 mg, 0.5 mmol), 3a (113.1 mg, 1.0 mmol),
and HOAt (149.7 mg, 1.1 mmol) in dry dichloromethane (5
mL) under nitrogen in a round-bottom flask, KHCO3 (0.25 g,
2.5 mmol) and EDCI (210.9 mg, 1.1 mmol) were added, and
the resulting yellow mixture was stirred at room temperature
for 10 h. After the reaction was complete, dichloromethane (10
mL) was added to precipitate the urea byproduct. The solvent
was decanted, and the dark red solid was washed twice with
dichloromethane (2 × 10 mL). The organic solution was
combined and evaporated under reduced pressure. The residue
was purified by flash chromatography (SiO2, 3−5% MeOH/
CH2Cl2) to afford the product 4 (128.4 mg, 74% yield) as a
colorless oil.
(S)-4-(tert-Butoxy)-5-methyl-1-(1-((S)-2-methyl-5-oxo-2,5-
dihydro-1H-pyrrol-3-yl)piperidin-4-yl)-1H-pyrrol-2(5H)-one
(4aa). Colorless oil, 128.4 mg, 74% yield; 1H NMR (300 MHz,
CDCl3) δ 6.46 (1H, s), 4.95 (1H, s), 4.66 (1H, s), 4.16 (1H, q,
J = 6.3 Hz), 4.09−3.95 (1H, m), 3.83 (1H, q, J = 6.6 Hz),
3.59−3.40 (2H, m), 3.00−2.83 (2H, m), 1.99−1.66 (4H, m),
1.38 (9H, s), 1.33 (3H, d, J = 6.3 Hz), 1.28 (3H, d, J = 6.6 Hz);
13C NMR (75 MHz, CDCl3) δ 175.9, 172.3, 171.9, 169.4, 95.1,
90.8, 81.6, 56.7, 52.3, 49.2, 48.0, 47.8, 31.2, 28.9, 27.4, 20.5,
18.7. HRMS (ESI-TOF): m/z calcd for C19H29N3O3 [M + H]+
348.2287; found 348.2284.
(S)-5-Benzyl-4-(tert-butoxy)-1-(1-((S)-2-methyl-5-oxo-2,5-
dihydro-1H-pyrrol-3-yl)piperidin-4-yl)-1H-pyrrol-2(5H)-one
(4af). Colorless oil, 145.9 mg from 2f (164.0 mg, 0.5 mmol)
and 3a (113.1 mg, 1.0 mmol), 69% yield; 1H NMR (300 MHz,
CDCl3) δ 7.31−7.09 (5H, m), 6.17 (1H, s), 4.88 (1H, s), 4.65
(1H, s), 4.16−4.08 (2H, m), 3.62−3.38 (3H, m), 3.11 (1H, dd,
J = 4.8, 14.7 Hz), 2.92 (1H, dd, J = 5.4, 14.7 Hz), 2.85−2.70
(2H, m), 2.20−2.14 (1H, m), 2.02−1.96 (1H, m), 1.83−1.79
(1H, m), 1.72−1.67 (1H, m), 1.38−1.26 (12H, m); 13C NMR
(75 MHz, CDCl3) δ 175.8, 173.7, 170.3, 169.4, 136.2, 129.2,
128.2, 126.9, 96.8, 90.8, 81.9, 61.7, 52.2, 51.1, 48.1, 47.8, 37.3,
29.8, 29.1, 27.3, 20.5. HRMS (ESI-TOF): m/z calcd for
C25H33N3O3 [M + H]+ 424.2600; found 424.2605.
mg, 0.4 mmol) and 3a (90.5 mg, 0.8 mmol), 60% yield; H
NMR (300 MHz, CDCl3) δ 6.14 (1H, s), 4.99 (1H, s), 4.66
(1H, s), 4.15 (1H, q, J = 6.6 Hz), 4.10−3.95 (1H, m), 3.92
(1H, dd, J = 2.1, 6.6 Hz), 3.66 (1H, dd, J = 2.4, 9.6 Hz), 3.59−
3.39 (2H, m), 3.28 (1H, dd, J = 6.9, 9.6 Hz), 3.00−2.81 (2H,
m), 2.34−2.00 (2H, m), 1.82−1.59 (2H, m), 1.41 (9H, s), 1.34
(3H, d, J = 6.6 Hz), 1.14 (9H, s); 13C NMR (75 MHz, CDCl3)
δ 176.1, 172.8, 169.6, 168.1, 96.7, 90.2, 81.8, 73.4, 62.7, 62.3,
52.3, 49.9, 48.2, 47.9, 30.2, 28.7, 27.5, 27.4, 20.5. HRMS (ESI-
TOF): m/z calcd for C23H37N3O4 [M + H]+ 420.2862; found
420.2878.
(S)-1-(1-((S)-2-Benzyl-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)-
piperidin-4-yl)-4-(tert-butoxy)-5-(tert-butoxymethyl)-1H-pyr-
rol-2(5H)-one (4 fs′). Colorless oil, 45.5 mg from 2s′ (130.0
1
mg, 0.4 mmol) and 3f (151.4 mg, 0.8 mmol), 23% yield; H
NMR (300 MHz, CDCl3) δ 7.33−7.18 (5H, m), 5.22 (1H, s),
5.01 (1H, s), 4.73 (1H, d, J = 2.4 Hz), 4.28 (1H, dd, J = 4.5, 9.9
Hz), 4.13−3.99 (1H, m), 3.95 (1H, dd, J = 2.4, 6.9 Hz), 3.73−
3.46 (3H, m), 3.34−3.27 (1H, m), 3.16 (1H, dd, J = 2.7, 7.8
Hz), 3.09−2.89 (2H, m), 2.55 (1H, dd, J = 9.6, 13.8 Hz), 2.21−
2.09 (2H, m), 1.88−1.67 (2H, m), 1.42 (9H, s), 1.14 (9H, s);
13C NMR (75 MHz, CDCl3) δ 175.2, 172.8, 168.1, 167.6,
137.1, 129.0, 128.8, 127.1, 96.8, 91.9, 81.8, 73.4, 62.8, 62.4,
57.7, 50.0, 48.5, 48.1, 41.3, 30.2, 28.7, 27.5, 27.4. HRMS (ESI-
TOF): m/z calcd for C29H41N3O4 [M + H]+ 496.3176; found
496.3163.
(S)-4-(tert-Butoxy)-5-methyl-1-(1-((S)-2-(2-(methylthio)-
ethyl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)piperidin-4-yl)-1H-
pyrrol-2(5H)-one (4ma). Light yellow oil, 50.9 mg from 2a
(126.2 mg, 0.5 mmol) and 3m (173.2 mg, 1.0 mmol), 25%
1
yield; H NMR (300 MHz, CDCl3) δ 6.45 (1H, s), 5.00 (1H,
s), 4.78 (1H, d, J = 1.5 Hz), 4.33−4.29 (1H, m), 4.11−3.98
(1H, m), 3.87 (1H, q, J = 6.6 Hz), 3.60−3.42 (2H, m), 3.04−
2.91 (2H, m), 2.60 (2H, t, J = 7.8 Hz), 2.12 (3H, s), 2.10−1.71
(6H, m), 1.44 (9H, s), 1.32 (3H, d, J = 6.6 Hz); 13C NMR (75
MHz, CDCl3) δ 176.0, 172.4, 171.9, 167.7, 95.2, 92.4, 81.7,
56.7, 55.6, 49.2, 48.3, 48.1, 33.8, 31.2, 30.4, 28.9, 27.4, 18.7,
15.7. HRMS (ESI-TOF): m/z calcd for C21H33N3O3S [M +
H]+ 408.2321; found 408.2314.
Procedure for the Syntheses of 5aaa. Compound 4aa
(277.7 mg, 0.5 mmol) was treated with TFA/Et3SiH (97:3, 2.5
mL) at 25 °C. The reaction was stirred in a vented capped flask
until complete disappearance of starting material (monitored by
NMR spectroscopy, ∼ 1 h). Toluene (10 mL) was added, and
the reaction mixture was concentrated in vacuo. Toluene (2 ×
10 mL) was used to azeotrope residual TFA. The crude oil was
dissolved in dichloromethane (4 mL) and filtered through a
thin layer of silica gel (∼0.5 cm) to remove some polar
impurities. The silica gel was washed with 5% MeOH/CH2Cl2
five times (5 × 5 mL). The organic fractions were combined,
and the solvent was removed in vacuo to give the deprotected
(S)-5-((1H-Indol-3-yl)methyl)-4-(tert-butoxy)-1-(1-((S)-2-
methyl-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)piperidin-4-yl)-1H-
pyrrol-2(5H)-one (4aw). Light yellow oil, 145.5 mg from 2w
(183.5 mg, 0.5 mmol) and 3a (113.1 mg, 1.0 mmol), 63% yield;
1H NMR (300 MHz, CDCl3) δ 9.05 (1H, s), 7.53 (1H, d, J =
7.8 Hz), 7.34 (1H, d, J = 7.5 Hz), 7.16−7.04 (2H, m), 7.01
G
DOI: 10.1021/acs.joc.5b00300
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
4aa as a white solid. The white solid was dried under high
vacuum and used directly in the next step without further
purification.
8H); 13C NMR (101 MHz, CDCl3) δ 166.4, 166.2, 165.7,
155.2, 153.7, 138.4, 137.7, 136.8, 129.3, 129.2, 128.8, 128.7,
128.5, 128.0, 127.9, 126.9, 126.8, 94.6, 93.1, 67.2, 55.7, 52.2,
51.6, 51.5, 50.4, 46.0, 45.7, 43.9, 43.8, 39.5, 39.2, 31.1, 30.8,
30.1, 29.8, 29.7, 28.6; HRMS (ESI-TOF): m/z calcd for
C43H50N4O5 [M + H]+ 703.3859; found 703.3849.
To a stirred solution of 2a (75.6 mg, 0.3 mmol), deprotected
4aa from previous step, and HOAt (89.8 mg, 0.66 mmol) in dry
dichloromethane (2 mL) under nitrogen, KHCO3 (150 mg, 1.5
mmol) and EDCI (126.5 mg, 0.66 mmol) were added, and the
resulting yellow mixture was stirred at room temperature for 16
h. After the reaction was complete, dichloromethane (4 mL)
was added to precipitate the urea byproduct. The solvent was
decanted, and the light red solid was washed twice with
dichloromethane (2 × 3 mL). The organic solution was
combined and evaporated under reduced pressure. The residue
was purified by flash chromatography (SiO2, 4−6% MeOH/
CH2Cl2) to afford the product 5aaa.
Benzyl 4-((R)-2-benzyl-4-(4-((R)-2-benzyl-4-(4-((R)-2-ben-
zyl-4-methoxy-6-oxo-3,6-dihydropyridin-1(2H)-yl)piperidin-1-
yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)piperidin-1-yl)-6-oxo-
3,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate (DDD-
10fff). DD-9ff (351.3 mg, 0.5 mmol) was deprotected with
general procedure B, and the product was coupled with D-7f
(220.5 mg, 0.5 mmol) using general procedure A to give DDD-
1
10fff as a light yellow oil. 268.8 mg, 55% yield; H NMR (400
MHz, CDCl3) δ 7.43−7.05 (m, 20H), 5.18 (s, 3H), 5.05 (s,
1H), 5.06 (s, 1H), 4.76−4.48 (m, 3H), 4.35 (br, 2H), 3.74−
3.63 (m, 10H), 3.12−2.76 (m, 12H), 2.55 (dd, J = 16.8, 5.6 Hz,
1H), 2.33−2.13 (m, 5H), 2.00−1.61 (m, 12H); 13C NMR (101
MHz, CDCl3) δ 166.4, 166.2, 165.7, 155.2, 153.7, 153.6, 138.4,
138.3, 137.7, 136.8, 129.3, 129.2, 128.8, 128.7, 128.7, 128.5,
128.0, 127.9, 126.9, 126.9, 126.8, 94.6, 93.1, 92.9, 67.2, 55.7,
52.2, 52.0, 51.6, 51.5, 50.9, 50.4, 46.0, 45.7, 45.7, 43.9, 43.8,
39.5, 39.2, 39.1, 31.1, 30.8, 30.2, 30.1, 29.8, 29.6, 28.8, 28.5;
HRMS (ESI-TOF): m/z calcd for C60H70N6O6 [M + H]+
971.5435; found 971.5437.
(S)-4-(tert-Butoxy)-5-methyl-1-(1-((S)-2-methyl-1-(1-((S)-2-
methyl-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)piperidin-4-yl)-5-
oxo-2,5-dihydro-1H-pyrrol-3-yl)piperidin-4-yl)-1H-pyrrol-
2(5H)-one (5aaa). Colorless oil, 64.6 mg, 41% yield over two
1
steps; H NMR (300 MHz, CDCl3) δ 5.74 (1H, s), 4.97 (1H,
s), 4.77 (1H, s), 4.71 (1H, d, J = 1.8 Hz), 4.18 (1H, q, J = 6.3
Hz), 4.12−3.91 (3H, m), 3.86 (1H, q, J = 6.3 Hz), 3.59−3.33
(4H, m), 3.06−2.84 (4H, m), 2.19−1.68 (8H, m), 1.42 (9H, s),
1.35 (6H, d, J = 6.3 Hz), 1.30 (3H, d, J = 6.6 Hz); 13C NMR
(75 MHz, CDCl3) δ 175.7, 172.8, 172.4, 171.9, 169.3, 167.6,
95.2, 92.3, 90.8, 81.7, 56.8, 54.3, 52.1, 49.6, 49.3, 48.3, 48.1,
48.0, 47.9, 31.3, 31.0, 29.0, 28.7, 27.4, 21.1, 20.6, 18.6. HRMS
(MALDI-TOF): m/z calcd for C29H43N5O4 [M + H]+
526.3388; found 526.3384.
General Procedure A for Coupling Reaction. Anhy-
drous KHCO3 powder (4.00 g, 40.0 mmol, 40.0 equiv) was
added to a 0.5 M solution of D-8f (300.5 mg, 1.0 mmol, 1.0
equiv) in CH2Cl2. The vinyl chloride D-7f (439.0 mg, 1.0
mmol, 1.0 equiv) was then added as a 0.5 M solution in CH2Cl2
to the reaction mixture. While stirring at room temperature, the
solvent was removed with nitrogen. The resulting solid was
heated to 120 °C under N2. After 24 h, 2 mL of anhydrous 1,4-
dioxane was added, stirred for 10 min and then removed with
nitrogen. The mixture was kept at 120 °C under N2 for another
24 h. After the reaction finished, the mixture was cooled to
room temperature. CH2Cl2 (20 mL) was added, and the
inorganic solids were removed by filtration. The solution was
concentrated to give the crude product. The product was
purified by flash chromatography (SiO2, 3−5% MeOH/
CH2Cl2) to afford the product DD-9ff.
Benzyl 4-((R)-2-benzyl-4-(4-((R)-2-benzyl-4-(4-((R)-2-ben-
zyl-4-(4-((R)-2-benzyl-4-methoxy-6-oxo-3,6-dihydropyridin-
1(2H)-yl)piperidin-1-yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)-
piperidin-1-yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)piperidin-1-
yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate
(DDDD-11ffff). DDD-10fff (194.9 mg, 0.2 mmol) was
deprotected with general procedure B, and the product was
coupled with D-7f (175.6 mg, 0.4 mmol) using general
procedure A to give DDDD-11ffff as a light yellow oil. 99.6 mg,
1
41% yield; H NMR (400 MHz, CDCl3) δ 7.44−7.08 (m,
25H), 5.19 (s, 3H), 5.10−5.02 (m, 3H), 4.79−4.47 (m, 4H),
4.35 (br, 2H), 3.80−3.61 (m, 13H), 3.14−2.76 (m, 16H), 2.55
(dd, J = 16.8, 5.8 Hz, 1H), 2.39−2.16 (m, 7H), 2.03−1.57 (m,
16H); 13C NMR (101 MHz, CDCl3) δ 166.4, 166.3, 166.2,
165.7, 155.2, 153.7, 153.6, 138.4, 138.3, 138.3, 137.7, 136.8,
129.2, 129.2, 128.8, 128.7, 128.7, 128.5, 128.0, 127.9, 126.9,
126.9, 126.8, 94.6, 93.1, 92.9, 92.9, 67.2, 55.7, 52.2, 52.0, 51.7,
51.6, 50.9, 50.9, 50.3, 46.0, 46.0, 45.8, 45.7, 43.9, 43.8, 39.5,
39.2, 39.2, 31.0, 30.8, 30.2, 30.1, 29.9, 29.8, 29.7, 28.8, 28.6;
HRMS (MALDI-TOF): m/z calcd for C77H90N8O7 [M + Na]+
1261.6824; found 1261.6881.
General Procedure B For Cbz Deprotection. Pd/C (10
wt %; 53 mg, 0.10 equiv Pd) was carefully added to a stirred
solution of DD-9ff (351 mg, 0.5 mmol) in 5 mL methanol (0.1
M) under nitrogen at 25 °C. The reaction was placed under an
atmosphere of hydrogen (1 atm, balloon) for 12 h. After 12 h,
the flask was purged with N2. The reaction mixture was filtered
over a Celite pad and concentrated to afford the Cbz
deprotected product. The product was used in the next step
without further purification.
Benzyl 4-((R)-2-benzyl-4-(4-((R)-2-benzyl-4-(4-((R)-2-ben-
zyl-4-(4-((R)-2-benzyl-4-(4-((R)-2-benzyl-4-methoxy-6-oxo-
3,6-dihydropyridin-1(2H)-yl)piperidin-1-yl)-6-oxo-3,6-dihydro-
pyridin-1(2H)-yl)piperidin-1-yl)-6-oxo-3,6-dihydropyridin-
1(2H)-yl)piperidin-1-yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)-
piperidin-1-yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)piperidine-
1-carboxylate (DDDDD-12fffff): DDDD-11ffff (75.1 mg, 0.06
mmol) was deprotected with general procedure B, and the
product was coupled with D-7f (88.5 mg, 0.2 mmol) using
general procedure A to give DDDDD-12fffff as a light yellow
oil. 27.6 mg, 31% yield; 1H NMR (400 MHz, CDCl3) δ 7.49−
7.07 (m, 30H), 5.21−5.17 (m, 3H), 5.10−5.02 (m, 4H), 4.77−
4.49 (m, 5H), 4.35 (br, 2H), 3.77−3.62 (m, 16H), 3.15−2.79
(m, 20 H), 2.56 (dd, J = 16.9, 5.6 Hz, 1H), 2.37−2.15 (m, 9H),
2.09−1.61 (m, 20H); 13C NMR (101 MHz, CDCl3) δ 166.4,
166.3, 166.2, 165.7, 155.2, 153.7, 153.6, 138.4, 138.3, 138.3,
137.7, 136.8, 129.3, 129.2, 128.8, 128.7, 128.7, 128.5, 128.0,
Benzyl 4-((R)-2-benzyl-4-(4-((R)-2-benzyl-4-methoxy-6-
oxo-3,6-dihydropyridin-1(2H)-yl)piperidin-1-yl)-6-oxo-3,6-di-
hydropyridin-1(2H)-yl)piperidine-1-carboxylate (DD-9ff).
White foamy solid, 454.3 mg from coupling of D-7f and D-8f
1
with general procedure A, 65% yield; H NMR (400 MHz,
CDCl3) δ 7.40−7.20 (m, 12H), 7.18−7.04 (m, 3H), 5.16 (s,
3H), 5.06 (s, 1H), 4.77−4.61 (m, 1H), 4.59−4.50 (m, 1H),
4.33 (br, 2H), 3.75−3.60 (m, 7H), 3.14−2.71 (m, 8H), 2.54
(dd, J = 16.9, 5.6 Hz, 1H), 2.34−2.09 (m, 3H), 1.99−1.55 (m,
H
DOI: 10.1021/acs.joc.5b00300
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(13) (a) Bestmann, H. J. Angew. Chem., Int. Ed. 1977, 16, 349.
(b) Schobert, R.; Dietrich, M.; Mullen, G.; Urbina-Gonzalez, J.-M.
Synthesis 2006, 3902. (c) Schobert, R. Org. Synth. 2005, 82, 140.
(14) (a) Xin, D.; Burgess, K. Org. Lett. 2014, 16, 2108. (b) Li, X.;
Taechalertpaisarn, J.; Xin, D.; Burgess, K. Org. Lett. 2015, 17, 632.
(15) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
(16) Subiros-Funosas, R.; Prohens, R.; Barbas, R.; El-Faham, A.;
Albericio, F. Chem.Eur. J. 2009, 15, 9394.
127.9, 126.9, 126.9, 126.8, 94.6, 93.1, 92.9, 67.2, 55.7, 52.2,
52.0, 51.7, 51.5, 51.0, 50.9, 50.4, 46.0, 45.8, 45.7, 43.9, 43.8,
39.5, 39.2, 39.2, 31.0, 30.2, 30.1, 29.8, 29.7, 28.8, 28.5; HRMS
(MALDI-TOF): m/z calcd for C94H110N10O8 [M + Na]+
1529.8398; found 1529.8406.
ASSOCIATED CONTENT
■
S
* Supporting Information
(17) Driver, R. W.; Hoang, H. N.; Abbenante, G.; Fairlie, D. P. Org.
Lett. 2009, 11, 3092.
1
Copies of H and 13C NMR spectra for all new compounds.
Procedures for quenched molecular dynamics and EKOS
analysis. Detailed procedure and analysis for epimerization
study in the synthesis of 4as′ with NMR and HPLC. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: burgess@tamu.edu
■
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
■
Financial support for this project was provided by the National
Institutes of Health (GM087981), and the Robert A. Welch
Foundation (A-1121) and the High Impact Research (HIR
(UM.C/625/1/HIR/MOHE/MED/17 and UM.C/625/1/
HIR/MOHE/MED/33) from the Ministry of Higher Educa-
tion, Malaysia. TAMU/LBMS-Applications Laboratory pro-
vided mass spectrometric support. The NMR instrumentation
at Texas A&M University was supported by a grant from the
National Science Foundation (DBI-9970232) and the Texas
A&M University System. We thank Dr. J. Reibenspies at
TAMU for the crystallographic analysis.
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I
DOI: 10.1021/acs.joc.5b00300
J. Org. Chem. XXXX, XXX, XXX−XXX