Polymer-supported stereoselective synthesis of tetrahydro-2 H -oxazolo[3,2- a ]pyrazin-5(3 H)-ones from N -(2-Oxo-ethyl)-derivatized dipeptides via eastbound iminiums

Article abstract of DOI:10.1021/co3001567

Polymer-supported N-(2-oxo-ethyl)-derivatized Ser/Thr/Cys-containing dipeptides were synthesized and subjected to acid-mediated tandem N-acylium ion cyclization-nucleophilic addition to yield tetrahydro-2H-oxazolo[3,2-a]pyrazin- 5(3H)-ones. The reaction conditions and building-block combinations for stereoselective synthesis of the newly formed asymmetric carbon were developed. The synthesis was fully compatible with solid-phase peptide synthesis, and the products serve as conformationally constrained peptidomimetics. The traceless synthesis of bicycles is also reported as part of this work.

Full text of DOI:10.1021/co3001567

Research Article
pubs.acs.org/acscombsci
Polymer-Supported Stereoselective Synthesis of
Tetrahydro‑2H‑oxazolo[3,2‑a]pyrazin-5(3H)‑ones from N‑(2-Oxo-
ethyl)-Derivatized Dipeptides via Eastbound Iminiums
Agustina La Venia,†,§ Bohumil Dolensky,‡ and Viktor Krchnak*,†,§
́
̌
́
†Department of Organic Chemistry, Faculty of Science, Palacky University, 17. Listopadu 12, 771 46 Olomouc, Czech Republic
́
‡Department of Analytical Chemistry, Institute of Chemical Technology, Prague, Technicka
́
5, 166 28 Praha, Czech Republic
§Department of Chemistry and Biochemistry, 251 Nieuwland Science Center, University of Notre Dame, Notre Dame, Indiana
46556, United States
S
* Supporting Information
ABSTRACT: Polymer-supported N-(2-oxo-ethyl)-derivatized
Ser/Thr/Cys-containing dipeptides were synthesized and
subjected to acid-mediated tandem N-acylium ion cycliza-
tion−nucleophilic addition to yield tetrahydro-2H-oxazolo-
[3,2-a]pyrazin-5(3H)-ones. The reaction conditions and
building-block combinations for stereoselective synthesis of the newly formed asymmetric carbon were developed. The
synthesis was fully compatible with solid-phase peptide synthesis, and the products serve as conformationally constrained
peptidomimetics. The traceless synthesis of bicycles is also reported as part of this work.
KEYWORDS: fused heterocycles, iminium, solid-phase synthesis, stereoselectivity
Oxygen has previously served as an internal nucleophile in the
preparation of five-,21−23 six-,24 and seven-membered rings.25,26
Analogous 6 + 5 fused heterocycles that contain a 2-
oxopiperazine ring have also been synthesized using a one-pot
strategy in solution.22 Oxazolo[3,2-a]pyrazin-5-ones (VI) have
also been prepared from 3-aza-1,5-diketoacids (IV) and amino
alcohols (V) (Scheme 2).23
We have already reported the polymer-supported synthesis of
6-oxa-3,8-diazabicyclo[3.2.1]octan-2-ones (VII)6 and
tetrahydropyrazino[2,1-b][1,3]oxazine-4,7(6H,8H)-diones
(VIII)5 via westbound tandem N-acylium ion cyclization−
nucleophilic addition using Ser and Thr as key building blocks to
provide the oxygen internal nucleophile (Scheme 3). Here, we
describe the expansion of this chemistry for the synthesis of
tetrahydro-2H-oxazolo[3,2-a]pyrazin-5(3H)-ones (IX). In addi-
tion to Ser and Thr, we also included Cys and compared the
results with O- and S-nucleophiles. Although the synthesis of
oxazolo[3,2-a]pyrazin-5-ones has already been reported,23 we
used a different synthetic strategy and prepared compounds with
different substitution patterns. The synthetic route reported here
allows the incorporation of bicyclic scaffolds as a peptide
constraint during traditional peptide synthesis.
INTRODUCTION
■
Several compound collections commonly used for high-
throughput screening in drug discovery have been analyzed
and their structural features have been compared with current
drugs and natural products. The analysis revealed statistically
significant deficiencies of specific features. In addition to limited
diversity, the compound decks suffered from a low frequency of
sp3 carbons (compound “flatness”) and mostly absence of
asymmetric carbons.1−3 Specifically, only 6% of compounds were
prepared by asymmetric synthesis.1 To enhance structural
diversity and enrich the screening decks with compounds
possessing underrepresented features, our ongoing research is
focused on the development of synthetic routes to heterocycles
with 3D topography and formation of asymmetric carbons with
full stereocontrol.4−7
Tandem N-acylium ion cyclization−nucleophilic addition is a
powerful strategy for synthesis of diverse fused ring systems,8−10
including conformational constraints in peptides.11−14 Typically,
a cyclic iminium is formed from an aldehyde attached via a two-
carbon spacer to an amide nitrogen (I, Scheme 1). The cyclic
iminium can be formed in two directions: either toward the
peptide amino terminus (II) (referred to as westbound) or
toward the peptide carboxyl terminus (eastbound, iminium III).5
The directions are based on the standard peptide/protein
nomenclature with the N-terminal amino acid on the left side.
Cyclizations in both directions have been reported in the
literature;15 however, the westbound direction has been used
more frequently.16−18 When both directions of iminium
formation are possible, the westbound direction is favored.5 In
the eastbound cyclization direction, N, O, S, and C internal
nucleophiles have been used to close the fused ring.19−21
RESULTS AND DISCUSSION
■
The solid-phase synthesis of acyclic precursors 5 that contain O-
and S-nucleophiles was performed using traditional peptide
synthesis protocols (Scheme 4). Rink amide resin (1) was
Received: December 22, 2012
Revised: February 8, 2013
Published: February 15, 2013
© 2013 American Chemical Society
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Research Article
Scheme 1. Eastbound and Westbound Directions of Iminium Formation
O(1,4,1), 7-S(1,2,1), 8-S(1,5,1), 8-S(1,3,1), 8-O(1,3,1), 8-
O(1,5,1), and 9-S(1,5,1). First, the chemical shifts were
unambiguously assigned to individual atoms based on gCOSY,
gHSQC, and gHMBC NMR spectra. Subsequent analyses of the
NOE interactions (NOESY1D spectra) enabled estimation of
the absolute configuration at C8a. Specifically, the NOE
interactions between the substituents at C6 and the hydrogen
at C8a were decisive (Figure 2). The configurations of the other
compounds were derived based on the similarity of their
characteristic signals (chemical shifts and size of interaction
constants; see Table S1 in the Supporting Information).
Scheme 2. Synthesis of Oxazolo[3,2-a]pyrazin-5-ones
Scheme 3. Reported and New Solid-Phase Syntheses of Fused
Rings using Ser and Thr (Shown in Red) as Key Building
Blocks
The effect of individual factors was evaluated on a set of model
compounds with the 4-Nos group in the R3 position. The
stereochemistry of the fused ring was influenced by the chirality
of the amino acids, the character of the R2 side chain, and the
presence of Ser, Thr, or Cys derivatives (Table 1). The results
indicated that the stereocontrol was mainly directed by the (S)-
configuration of the first amino acid (Ser, Thr, or Cys), which
favored the formation of the new stereocenter with an (S)-
configuration. This stereocontrol was evident in substrates with
no substituent at the R2 position, such as 5-O(1,1,1) (entry 1)
and 5-S(1,1,1) (entry 13), both of which formed with high
stereoselectivity. However, the stereo-outcome was also strongly
influenced by the nature of the R2 group. Figure 1 portrays a
model compound with the R2 originating from L-amino acids and
where the nucleophilic attack occurred through the same face of
the R2 group. As evident in the figure, the stereoselectivity
decreased because of the steric hindrance. In contrast, the D-
amino acid-derived model exhibited a synergic effect, which
reinforced the controlled direction of the second ring closure.
As expected from the previous analysis, we observed full
stereocontrol for the Ser derivatives with R2 = H or a small alkyl
group, such as methyl. The stereocontrol was independent of the
absolute configuration of the second amino acid (R2 substituent)
because of insignificant steric repulsion (e.g., substrates 5-
O(1,1,1), 5-O(1,2,1), and 5-O(1,3,1), entries 1 to 3). However,
the stereochemistry of the newly formed chiral carbon was
influenced by the presence of bulkier alkyl groups (such as
isopropyl, entries 6 and 7) in the R2 position and was dependent
on the R2 chirality. We observed complete stereochemical
control for the compound with the (R)-configuration (8-
O(1,5,1), entry 7), whereas the opposite (S)-configuration (L-
Val, entry 6) unfavorably influenced the stereochemistry and
resulted in the formation of a mixture of diastereomers (6-
O(1,4,1) and 7-O(1,4,1) as well as the enamide 10(1,4,1)). In
addition, the exchange of 4-Nos for 2-Nos at R3 hindered the
formation of major stereoisomer 6 and produced a small amount
of 7 as well (entry 4, substrate 5-O(1,2,2)).
acylated with Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, and
Fmoc-Cys(Trt)-OH (resin 2), followed by acylation with a set of
L- and D-α-amino acids (3) to evaluate the effect of their chirality
and the R2 substituent on the stereochemistry of the target
compounds. The protected aldehyde was incorporated via the
Fukuyama variation27 of the Mitsunobu reaction28 with
glycolaldehyde dimethyl acetal on 4-nitrobenzenesulfonyl (4-
Nos) derivatized resin (4)4 to obtain the resin-bound acyclic
substrates 5.
Upon acid-mediated unmasking of protection groups and
cleavage of the acyclic intermediates from the resin, the cyclic N-
acyliminium ions were formed. The presence of O- or S-
nucleophiles facilitated the formation of the fused ring, and two
diastereomers were formed depending on the direction of the
nucleophilic attack. The new chiral carbon (C8a) was formed
either with an (S)-configuration (diastereomer A, compounds 6
and 8) or the opposite configuration (R) (diastereomer B,
compounds 7 and 9) (Figure 1).
The polymer-supported precursors prepared using Thr as the
C-terminal amino acid incorporated a methyl group and an
additional stereocenter, which disfavored the stereoselectivity of
the reaction and led to a mixture of products (entries 9 to 12).
The probable reason for this decreased selectivity was the
presence of bulkier side chains in close proximity to the internal
nucleophile. This proximity influenced the stereoselectivity in a
The absolute configuration of the new chiral center at C8a was
unambiguously assigned using the NMR spectra of compounds
6-O(1,1,1), 6-O(1,2,1), 6-O(1,2,2), 6-O(1,4,1), 6-O(2,2,1), 7-
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a
Scheme 4. Polymer-Supported Synthesis of Ser/Thr/Cys Bicyclic Compounds
a
Reagents and conditions: (i) piperidine (50% v/v), DMF, rt, 20 min; (ii) Fmoc-AA, HOBt, DIC, DCM, rt, 16 h; (iii) 2-methylbenzenesulfonyl
chloride (2-Nos-Cl) or 4-methylbenzenesulfonyl chloride (4-Nos-Cl), lutidine, DCM, rt, 16 h; (iv) glycolaldehyde dimethyl acetal, DIAD, PPh3,
anhydrous THF, 50°C, 16 h; (v) TFA (50%), DCM, rt, 2−3 h; (vi) mercaptoethanol, DBU, DMF, rt, 10 min. Note: individual compounds are
identified by a number followed by the type of nucleophile (O or S) (e.g., 6-O(R1,R2,R3)). For R numbering, see Table 1.
Figure 2. Decisive NOE interactions (red) and the coupling interactions
(blue) for assignment of the absolute configuration at C8a using 8-
Figure 1. Formation of diastereomers A and B [for (S)-R2 series].
S(1,5,1) and 9-S(1,5,1).
manner similar to that of bulkier side chains on L-amino acids
(R2) (entry 6). Surprisingly, an opposite effect for R2 was
observed: only the combination of Thr with L-Ala in the second
position resulted in significant stereocontrol (entry 10, 6-
O(2,2,1)).
Cys-derived substrates exhibited an analogous chemoselectiv-
ity in the outcome of the final product (entries 13 to 18).
However, when the mixture of both fused diastereomers was
produced, we observed a lower selectivity toward stereoisomers 6
and 8 than that observed with Ser-derived compounds (compare
substrates 5-S(1,2,1) (entry 14), 5-S(1,2,2) (entry 16), and 5-
S(1,5,1) (entry 18) with 5-O(1,2,1) (entry 2), 5-O(1,2,2)
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Table 1. Effect of Derivatization (R1, R2, and R3) on Product Distribution
a
b
entry
substrate
R1
R2
R3
ratio 6:7:10 or 8:9:11
total yield (%)
1
2
3
4
5
6
5-O(1,1,1)
5-O(1,2,1)
5-O(1,3,1)
5-O(1,2,2)
5-O(1,2,3)
5-O(1,4,1)
H
H
H
H
H
H
H
4-Nos
99:<1:0
99:<1:0
99:<1:0
85:15:0
6-O(1,1,1) 10%
6-O(1,2,1) 75%
8-O(1,3,1) 67%
6-O(1,2,2) 27%
17 52%
(S)-CH3
4-Nos
(R)-CH3
4-Nos
(S)-CH3
2-Nos
c
(S)-CH3
4-Nos-Ala
4-Nos
95% of 17
d
(S)-CH(CH3)2
50:22:28
6-O(1,4,1) 35%
7-O(1,4,1) 28%
d
10(1,4,1) 26%
7
5-O(1,5,1)
5-O(1,6,1)
5-O(2,1,1)
5-O(2,2,1)
5-O(2,3,1)
5-O(2,4,1)
H
H
(R)-CH(CH3)2
(S)-CH2STrt
H
4-Nos
4-Nos
4-Nos
4-Nos
4-Nos
4-Nos
99:<1:0
8-O(1,5,1) 40%
12 29%
e
8
95% of 12
9
(R)-CH3
(R)-CH3
(R)-CH3
(R)-CH3
52:32:16
99:<1:0
6-O(2,1,1) 20%
6-O(2,2,1) 66%
8-O(2,3,1) 33%
6-O(2,4,1) 27%
7-O(2,4,1) 8%
6-S(1,1,1) 11%
6-S(1,2,1) 13%
7-S(1,2,1) 12%
8-S(1,3,1) 12%
6-S(1,2,2) 14%
7-S(1,2,2) 12%
6-S(1,4,1) 11%
7-S(1,4,1) 10%
8-S(1,5,1) 45%
10
11
12
(S)-CH3
(R)-CH3
83:17:00
48:27:25
(S)-CH(CH3)2
13
14
5-S(1,1,1)
5-S(1,2,1)
H
H
H
4-Nos
4-Nos
99:<1:0
52:48:0
(S)-CH3
15
16
5-S(1,3,1)
5-S(1,2,2)
H
H
(R)-CH3
(S)-CH3
4-Nos
2-Nos
99:<1:0
57:43:0
17
18
5-S(1,4,1)
5-S(1,5,1)
H
H
(S)-CH(CH3)2
(R)-CH(CH3)2
4-Nos
4-Nos
54:46:0
88:22:0
9-S(1,5,1) 12%
a
1
The relative ratio of products was estimated from LC traces at 240 nm or structures confirmed in the crude preparation by H NMR; major
b
products were isolated by HPLC and were fully characterized. Total yield after purification by HPLC of products prepared in a 6- to 9-step
synthesis. NA: not applicable, westbound cyclization (see Scheme 6). Products obtained as an inseparable mixture (see Scheme 5). NA: not
applicable, sulfur-aldehyde reaction.
c
d
e
Scheme 5. Regioselectivity of Products with N-Terminal Cys and Ser
(entry 4), and 5-O(1,5,1) (entry 7), respectively). The less
efficient stereocontrol in those reactions that involved sulfur as
the internal nucleophile was ascribed to its pronounced
nucleophilicity and larger size, which allowed the formation of
the more thermodynamically stable diastereomer in a greater
ratio. Nevertheless, a positive effect on stereoselectivity for the D-
amino acids (R2) was also significant in both model compounds
(5-S(1,3,1), entry 15, and 5-S(1,5,1), entry 18). The increased
nucleophilicity of sulfur was also expressed in the complete
absence of the enamides in all of the tested cases.
To this point, model compounds with aliphatic R2 side chains
were investigated, but we became interested in the outcome of
these reactions when R2 contained a more complex functional
group, particularly nucleophiles. To evaluate the competition
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Scheme 6. Westbound Cyclization Favored
and regioselectivity of different internal nucleophiles, Ser and
Cys were introduced as N-terminal amino acids. In the case of Ser
incorporation (R2 = (S)-CH2Ot-Bu), however, the Mitsunobu
reaction with glycolaldehyde dimethyl acetal did not provide
satisfactory conversion. In contrast, the Cys-derived substrate 5-
O(1,6,1) (entry 8) was obtained successfully. Interestingly, acid
treatment yielded the olefin 12 as the major product through
reaction of the sulfur with the aldehyde, and the fused ring
compound was not detected (Scheme 5). To independently
prove the observed regiochemistry, we prepared model
compounds using C-terminal Gly (13a, 13b) (Scheme 5).
None of these polymer-supported substrates formed the
acyliminium intermediate under acidic conditions. Furthermore,
the Cys-containing dipeptide 13a yielded an analogous
compound, similar to the previous case; the main product was
the unsaturated compound 14. Interestingly, methoxythiomor-
pholine 15 was also isolated as a minor product. Moreover, resin-
bound Ser derivative 13b yielded a mixture of diastereomers of
16.
Scheme 7. Synthesis of Model Compounds for Cyclization
with O-Nucleophiles via a Traceless Approach
Incorporation of tetrahydro-2H-oxazolo[3,2-a]pyrazin-
5(3H)-ones as peptide mimetics during traditional Merrifield
peptide synthesis by simple extension of the peptide was not
possible. The addition of one amino acid to the dipeptide N-
terminus followed by 4-Nos derivatization (5-O(1,2,3), entry 5,
Table 1) opened the possibility of westbound iminium formation
(Scheme 6).5 The olefin 17 was produced exclusively, whereas
the presence of 6 + 5 fused rings was not detected. This problem
can be solved through modification of the synthetic strategy and
will be the subject of a future study.
Table 2. Compounds Prepared with O-Nucleophiles using A
and B Synthetic Routes
Encouraged by the smooth preparation of the 6 + 5 ring system
with oxygen nucleophiles, we modified the synthetic scheme and
synthesized fused bicycles in a traceless manner.29 Although the
previous synthetic route was designed to incorporate the bicycles
during peptide synthesis as peptidomimetics, the following route
enabled access to these bicycles with no trace of a linker on the
products. We evaluated the scope and limitation of this solid-
phase synthesis with two different immobilizations of amino
alcohols. Route A (Scheme 7) involved the attachment of the
precursor via the oxygen nucleophile to Wang resin using Fmoc-
2-aminoethanol with trichloroacetimidate activation.30 Route B
involved the application of the amide nitrogen for immobiliza-
tion. BAL resin underwent reductive amination with 1-
aminopropanol. Both routes continued with acylation of the
polymer-supported amines with bromoacetic acid followed by
reaction with aminoacetaldehyde dimethyl acetal. The derivati-
zation of the resin-bound secondary amines by Tos-Cl and 4-
fluoro-3-nitrobenzotrifluoride was the last synthetic step on the
solid phase. Both the sulfonamide (Tos) and N-aryl (4-
trifluoromethyl-2-nitroaryl) derivatives provided 5 + 6 as well
as 6 + 6 fused heterocycles in excellent purity and yield (Table 2).
Gratifyingly, the formation of the elimination product was not
observed.
CONCLUSION
■
We have developed a robust polymer-supported synthetic route
allowing access to fused tetrahydro-2H-oxazolo[3,2-a]pyrazin-
5(3H)-one heterocycles and their sulfur analogs via eastbound
tandem N-acylium ion cyclization−nucleophilic addition. The
effect of amino acids and their chirality on the stereochemical
outcome was studied, and compounds with full stereocontrol of
the newly formed asymmetric carbon were synthesized. The
synthesized compounds will serve as scaffolds for the
construction of compound libraries and as peptide backbone-
constrained peptidomimetics.
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Research Article
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(15) Kim, J. H.; Lee, Y. S.; Kim, C. S. Synthesis of Praziquantel via N-
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2285.
EXPERIMENTAL PROCEDURES
■
Individual steps of the solid-phase synthesis of compounds 5, the
cleavage of target compounds from the resin, and the HPLC
purification are described in a previous paper5 and in the
Supporting Information.
(16) Kohn, W. D.; Zhang, L. Solid-Phase Synthesis of Peptide-
Heterocycle Hybrids Containing a Tripeptide-Derived 6,6-Fused
Bicyclic Subunit. Tetrahedron Lett. 2001, 42, 4453−4457.
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Diversity at the I Position. Tetrahedron Lett. 2001, 42, 1237−1239.
(18) Eguchi, M.; Lee, M. S.; Nakanishi, H.; Stasiak, M.; Lovell, S.;
Kahn, M. Solid-Phase Synthesis and Structural Analysis of Bicyclic β-
Turn Mimetics Incorporating Functionality at the i to i + 3 Position. J.
Am. Chem. Soc. 1999, 121, 12204−12205.
(19) Min, B. J.; Gu, X.; Yamamoto, T.; Petrov, R. R.; Qu, H.; Lee, Y. S.;
Hruby, V. J. Synthesis of a Novel Benzyl-octahydropyrazino[1,2-
a]pyrimidin-6-one Derivative As a Convenient Internal Bicyclic
Peptidomimetic. Tetrahedron Lett. 2008, 49, 2316−2319.
(20) Piergentili, A.; Del Bello, F.; Gentili, F.; Giannella, M.; Quaglia,
W.; Vesprini, C.; Thomas, R. J.; Robertson, G. M. Solution-Phase
Synthesis of ICG-001, a [beta]-Turn Peptidomimetic Molecule
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ASSOCIATED CONTENT
■
S
* Supporting Information
Analytical data of individual compounds, tabulated NMR
characteristics (Table S1), and copies of NMR spectra associated
with this article. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: vkrchnak@nd.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(21) Amat, M.; Santos, M. M. M.; Bassas, O.; Llor, N.; Escolano, C.;
Gomez-Esque, A.; Molins, E.; Allin, S. M.; McKee, V.; Bosch, J.
Straightforward Methodology for the Enantioselective Synthesis of
Benzo[a]- and Indolo[2,3-a]quinolizidines. J. Org. Chem. 2007, 72,
5193−5201.
This research was supported by the Department of Chemistry
and Biochemistry, University of Notre Dame, by the projects
P207/12/0473 from GACR and CZ.1.07/2.3.00/20.0009 from
the European Social Fund. We gratefully appreciate the use of the
NMR facility at the University of Notre Dame.
(22) Ciofi, L.; Morvillo, M.; Sladojevich, F.; Guarna, A.; Trabocchi, A.
Skeletal Diversity by Sequential One-Pot and Stepwise Routes Using
Morpholine Ester Scaffolds. Tetrahedron Lett. 2010, 51, 6282−6285.
(23) Bencsik, J. R.; Kercher, T.; O’Sullivan, M.; Josey, J. A. Efficient,
Stereoselective Synthesis of Oxazolo[3,2-a]pyrazin-5-ones: Novel
Bicyclic Lactam Scaffolds from the Bicyclocondensation of 3-Aza-1,5-
keto acids and Amino Alcohols. Org. Lett. 2003, 5, 2727−2730.
(24) Airiau, E.; Spangenberg, T.; Girard, N.; Schoenfelder, A.;
Salvadori, J.; Taddei, M.; Mann, A. A General Approach to Aza-
Heterocycles by Means of Domino Sequences Driven by Hydro-
formylation. Chem.Eur. J. 2008, 14, 10938−10948.
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