Regioselective incorporation of backbone constraints compatible with traditional solid-phase peptide synthesis

Article abstract of DOI:10.1021/co300125m

A protected aldehyde was attached via a two-carbon spacer to a peptide backbone amide nitrogen during a traditional Merrifield solid-phase synthesis. Acid-mediated unmasking of the aldehyde triggered the regioselective formation of cyclic N-acyliminiums between the aldehyde and the neighboring peptide amide nitrogen. In the absence of an internal nucleophile, the cyclic iminiums formed dihydropyrazinones, a six-membered peptide backbone constraint between two peptide amides. In the presence of an internal nucleophile, tetrahydropyrazinopyrimidinediones or tetrahydroimidazopyrazinediones were formed via tandem N-acyliminium ion cyclization-nucleophilic addition. The outcome of this nucleophilic addition was dependent on the substituent on the nitrogen nucleophile.

Full text of DOI:10.1021/co300125m

Research Article
pubs.acs.org/acscombsci
Regioselective Incorporation of Backbone Constraints Compatible
with Traditional Solid-Phase Peptide Synthesis
Agustina La Venia,† Barbora Lemrova,† and Viktor Krchnak*,†,‡
́
̌
́
†Department of Organic Chemistry, Faculty of Science, Institute of Molecular and Translational Medicine, Palacky University, 771 46
Olomouc, 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: A protected aldehyde was attached via a two-
carbon spacer to a peptide backbone amide nitrogen during a
traditional Merrifield solid-phase synthesis. Acid-mediated
unmasking of the aldehyde triggered the regioselective
formation of cyclic N-acyliminiums between the aldehyde
and the neighboring peptide amide nitrogen. In the absence of
an internal nucleophile, the cyclic iminiums formed
dihydropyrazinones, a six-membered peptide backbone con-
straint between two peptide amides. In the presence of an
internal nucleophile, tetrahydropyrazinopyrimidinediones or
tetrahydroimidazopyrazinediones were formed via tandem N-acyliminium ion cyclization-nucleophilic addition. The outcome of
this nucleophilic addition was dependent on the substituent on the nitrogen nucleophile.
KEYWORDS: iminium, bisheterocycles, solid-phase synthesis, regioselectivity
acyliminium ion formation;8 the cyclic N-acyliminium IIa
INTRODUCTION
■
formed with the amide facing the peptide amino terminus
Although peptides possess a wide range of biological activities,
(referred to as westbound)3,9−12 and the iminium IIb formed
they suffer from serious drawbacks as therapeutic agents.
with the amide facing the peptide carboxyl terminus (referred
Peptides are prone to rapid proteolytic degradation; they are
to as eastbound).13 The direction is based on standard peptide/
poorly transported to the brain and are rapidly excreted
protein nomenclature with an N-terminal amino acid on the
through the liver and kidneys, which limits their use as drugs in
left. In the absence of a nucleophile, the intermediates IIa and
clinical practice. Therefore, a significant effort has been
dedicated to overcoming the aforementioned negative charac-
IIb lead to 3,4-dihydropyrazin-2(1H)-ones IIIa and IIIb,
respectively.14,15 Both scenarios were documented in the
teristics by designing and synthesizing peptidomimetics.1−4
literature for simple model compounds that allowed the six-
Victor Hruby describes peptidomimetics as compounds whose
membered ring to close in one direction only.16
essential elements (pharmacophore) mimic a natural peptide or
These cyclic N-acyliminium ions can be transformed into
structures that are more complex. The presence of an internal
nucleophile can trigger a fused-ring formation, and a bicyclic
protein in 3D space but retain the ability to interact with a
biological target, thus producing the same biological effect.2
Several different approaches to peptidomimetics were followed
including amino acid modifications, backbone alterations, the
introduction of global restrictors such as head-to-tail and side-
chain to side-chain cyclization and the synthesis of backbone
system can be formed via tandem N-acylium ion cyclization−
nucleophilic addition.5−7,17,18
Tandem N-acylium ion cyclization−nucleophilic addition
was particularly useful for the synthesis of several peptidomi-
scaffolds. Recent review articles have described these individual
metics in the westbound direction. Baldwin and co-workers19
reported the synthesis of fused ring piperazine derivatives as
bicyclic γ-lactam dipeptide mimetics. Patek’s group9 used
tandem N-acyliminium ion cyclization−nucleophilic addition to
directly access the bi-, tri-, and tetracyclic derivatives of 1-acyl-
3-oxopiperazines (V) (Scheme 2). Kahn and co-workers3,10,11
took advantage of Patek’s solid-phase synthesis9 and prepared
approaches in detail.1−4
Among the numerous potential structural variations, a
straightforward method could allow for rigidifying the peptide
backbone by bridging two neighboring amide nitrogens via a
two-carbon spacer. The formation of a cyclic N-acyliminium
ion from an acyclic intermediate that hosts a protected
aldehyde attached to the amide nitrogen via a two-carbon
spacer could provide a synthetic methodology to facilitate this
bridging, offering access to expanded structural diversity (I,
Scheme 1). Iminium chemistry has been reviewed in in the
literature.5−7 Scheme 1 depicts two possible routes for cyclic N-
Received: October 12, 2012
Revised: December 13, 2012
© XXXX American Chemical Society
A
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Scheme 1. Two Possible Synthetic Routes for Cyclic N-acyliminium
Scheme 2. Reported Iminium Ion Formation in the Westbound Direction
Scheme 3. Reported Iminium Ion Formation in the Eastbound Direction
β-turn mimetics (VII) from a dipeptide containing a β-amino
acid and an α-amino acid (VI). The bicyclic β-turn
peptidomimetics, 1,3,6,8-substituted tetrahydro-2H-pyrazino-
[1,2-a]pyrimidine-4,7-diones, were prepared by Kahn’s group
from a similar linear precursor via tandem cyclization after
cleavage from acetal or olefin linkers.10,11 The aldehyde
function was located on a side chain attached to the amide
nitrogen of the C-terminal amino acid (IV and VI linear
precursors).
from analogous linear intermediates during the TFA cleavage of
linear peptides from a solid support.12
The results indicated that the formation of the second fused
ring strongly depended on the direction of cyclization (west or
east), the fused ring size, the type of nucleophile, and the
substituents.
Typically, constrained peptide mimetics have been prepared
in an independent synthesis then incorporated into the peptide.
We describe the synthesis of acyclic precursors during a
traditional Merrifield peptide synthesis and the formation of a
ring system during cleavage from the resin. The cyclic iminium
can be formed in both directions, that is, toward the amino or
the carboxyl terminus; therefore, we evaluated the regiose-
lectivity of the piperazine ring formation and reported the
conditions for the unequivocal synthesis of cyclic iminiums in
either direction. We then addressed the factors influencing the
fused-ring formation in the westbound direction. Cyclization in
the eastbound direction will be reported in a subsequent
communication.
Hruby13 also developed a synthesis for β-turn mimetics via
cyclic acyliminium formation in the opposite direction (the
eastbound direction). In this case, the aldehyde was located on
the amide of the N-terminal amino acid (VIIIa and VIIIb,
Scheme 3). The fused ring IX was formed from the N-(3-
aminopropyl) derivative. Interestingly, no analogous reaction
with a dipeptide precursor has been reported. No ring closure
to the five-membered ring (X) was observed with the olefinic
product (XI) forming instead. Pyrazinopyrimidine moieties
have also been included by Kohn and Zhang into a peptide as
constrained β-turn mimics, which were formed spontaneously
B
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a
Scheme 4. Preparation of the Masked Aldehyde Precursors 4
a
Reagents and conditions: (i) bromoacetic acid, DIC, DIEA, DCM, rt, 2 h; (ii) aminoacetaldehyde dimethylacetal, DIEA, DMF, rt, 2 h; (iii) Fmoc-
α-amino acid, DIC, THF, rt, 16 h or Fmoc-α-amino acid, DIC, N-hydroxybenzotriazole (HOBt), DMF/DCM (1:1), rt, 16 h; (iv) 4-
nitrobenzenesulfonyl chloride, lutidine, DCM, rt, 16 h; (v) glycolaldehyde dimethyl acetal, DIAD, PPh3, THF, 50 °C, 16 h; (vi) mercaptoethanol,
DBU, DMF, rt, 5 min.
a
Scheme 5. Regioselectivity of the Iminium Ion Formation
a
Reagents and conditions: (i) 50% TFA, 10% TES in DCM, rt, 1 h; (ii) 50% TFA in DCM, rt, 1 h.
As an analogy, conformational constraints have been
incorporated into peptides via silylated amino acids with the
subsequent conversion into N-acyliminium ions.20−22 N-Boc-
1,3-oxazinane-masked aldehyde building blocks have been
incorporated into peptides and used to synthesize structurally
diverse bicyclic dipeptide mimetics.23,24 The present work is an
extension of our previous studies.15,18
iminium formation. Cyclic N-acyliminium intermediates were
formed from an aldehyde and a nitrogen atom contained in
different functionalities including the amide, sulfonamide, and
aniline derivatives. Among the various methods for iminium ion
synthesis, the condensation of secondary amides with aldehydes
is regarded as one of the most versatile.17,25−27 The acetal-
protected aldehyde was attached to the peptide backbone
amide nitrogen via a two-carbon spacer. The aldehyde was then
unmasked, and the target compounds were cleaved from the
resin via acid-mediated cleavage to initiate the cyclic N-
acyliminium formation.
The synthesis of the model compounds was carried out using
commercially available polystyrene-1% DVB resin with Rink-
amide28 and BAL29 linkers (Scheme 4). The BAL resin was
reacted with primary amines under reductive amination
conditions to yield polymer-supported secondary amines.30
Two different routes were used to introduce the two-carbon
side-chain with protected aldehydes. The resins labeled 1 were
acylated with bromoacetic acid using in situ-prepared sym-
metrical anhydrides. Then, the α-bromoacylamide resin 2 was
reacted with aminoacetaldehyde dimethyl acetal to yield the
intermediates labeled 3 (Scheme 4, route A).12 A sample of
resin 3 was then reacted with Fmoc-OSu for LC/MS analysis.
In the last synthesis step of the cycle precursor, the secondary
amines 3 were acylated with DIC/HOBt or the in situ-prepared
RESULTS AND DISCUSSION
■
First, we describe the results of experiments focused on the
regioselectivity of cyclic iminium ion formation. Then, we
address the fused-ring formation via tandem N-acyliminium ion
cyclization−nucleophilic addition with respect to the fused ring
size, the type of nucleophile, and its substituents.
Regioselectivity. As mentioned previously, the N-(2-oxo-
ethyl)-derivatized peptides can, in principle, form N-acylimi-
nium species in two directions (Scheme 1): toward the peptide
amino terminus (referred to as westbound, intermediate IIa)
and toward the carboxyl peptide terminus (eastbound direction,
intermediate IIb). Cyclization in either direction is viable, and
both directions of the N-acyliminium ion formation have been
reported in model compounds that allowed only one direction
of cyclization.9,12−14
We evaluated the regioselectivity of cyclic iminium formation
on model compounds that allowed both directions of cyclic
C
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a
Scheme 6. Effect of the N-substituent on the Regioselectivity
a
Reagents and conditions: (i) 50% TFA in DCM, rt, 1 h.
a
Scheme 7. Regioselectivity of Iminium Formation and Demonstration of Eastbound Viability
a
Reagents and conditions: (i) 50% TFA, 10% TES in DCM, rt, 1 h; (ii) mercaptoethanol, DBU, DMF, rt, 5 min; (iii) Fmoc-α-amino acid, DIC,
HOBt, DMF/DCM (1:1), rt, 16 h; (iv) 50% piperidine in DMF, rt, 20 min; (v) 4-nitrobenzenesulfonyl chloride, lutidine, DCM, rt, 4 h.
1
symmetrical anhydrides of different amino acids including
Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Phe-OH, Fmoc-Val-OH,
Fmoc-Ile-OH, Fmoc-Glu(Ot-Bu)−OH, and Fmoc-Lys(Boc)−
OH. A ∼10 mg sample of resin 4 was reacted with Fmoc-OSu,
and the product was released from the resin to analyze the
completion of the acylation reaction.
An alternative strategy to introduce the masked aldehyde was
based on Fukuyama N-alkylation31 (Scheme 4, route B). This
route involved the sulfonylation of resin-bound amines (Rink
resin 1b or generic resin-bound amine 1c) with 4-nitro-
benzenesulfonyl (4-Nos) chloride followed by the Fukuyama
variation of a Mitsunobu N-alkylation with glycolaldehyde
dimethyl acetal to produce resin 5. The corresponding diethyl
acetal did not provide the expected N-alkylated species; only
starting material was detected in all cases. The final Nos-group
cleavage of 5 produced a secondary resin-bound amine that was
then acylated with the Fmoc-protected amino acids to yield
resin 4, as previously described.
On the basis of these strategies, three different model
systems (Models A−C shown in Schemes 5−7, respectively)
were synthesized using traditional peptide chemistry, and the
regioselectivity of the iminium formation was evaluated. The
first polymer-supported tetrapeptide 6 could form both cyclic
N-acyliminium regioisomers: toward the peptide carboxyl
terminus (eastbound) or toward the peptide amino terminus
(westbound cyclization) (Model A, Scheme 5). Under TFA
exposure, the cyclic N-acyliminium was formed exclusively in
the westbound direction to yield only a single regioisomer, as
confirmed by H and 13C NMR analyses. Triethylsilane (TES)
present in the cleavage cocktail reduced the iminium to 1,4-
substituted-piperazinone (7).14 The cyclic iminium was formed
with sulfonamide. We extended the peptide backbone by one
amino acid and synthesized pentapeptide 8 to form the
iminium with amide (two Tos groups prevented the formation
of a fused ring). Only one regioisomer (9) was detected,
isolated, and characterized, demonstrating the same west
directional preference. Next, we extended the peptide toward
the amino terminus and synthesized three tetrapeptides on the
Rink-amide resin, 4-Nos-Ala-Gly-Ala-N-(2-oxo-ethyl)-Ala-NH-
Resin, 4-Nos-Ala-Ala-Ala-N-(2-oxo-ethyl)-Ala-NH-Resin, and
4-Nos-Ala-Lys-Ala-N-(2-oxo-ethyl)-Ala-NH-Resin, and ob-
served only regioselective westbound formation of the
piperazinone derivatives.
To further evaluate the potential effect of the amide type and
N-substituent on the regioselectivity of the iminium ion
formation, we prepared model compounds 10a−c (Model B,
Scheme 6). The N-propyl carboxyl-terminal amide (10)
provided increased nucleophilicity and steric accessibility
when compared with the previous model compounds. We
also introduced different N-substituents including urethane,
sulfonamide, and aryl derivatives and found that neither the
type of secondary amide nor the substituents influenced the
regioselectivity. We observed the exclusive formation of west
regioisomers (11a−c) in all cases.
Finally, the third model system also documented the
westbound-directed cyclization route; the linear precursor 14,
D
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a
Scheme 8. Synthesis of 6 + 6 Fused Rings
a
Reagents and conditions: (i) 50% piperidine in DMF, 15 min, rt; (ii) Fmoc-β-Ala-OH, DIC, HOBt, DMF/DCM (1:1), rt, 16 h; (iii) for R4 = 1,2:
benzenesulfonyl chlorides, lutidine, DCM, rt, 16 h; for R4 = 4: Cbz-Cl, DIEA, DCM, rt, 16 h; for R4 = 5: 4-fluoro-2-nitrobenzotrifluoride, DIEA,
DMSO, rt, 16 h; for R4 = 6: 1-fluoro-2-nitrobenzenes, DMSO, 50 °C, 16 h; for R4 = 7: 1-fluoro-2-nitrobenzenes, DMSO, 50 °C, 16 h followed by
SnCl2, DIEA, and DMF saturated with N2, rt, 16 h; for R4 = 8, 9: carboxylic acid or Fmoc-AA, DIC, HOBt, DMF/DCM (1:1), rt, 16 h; for R4 = 10:
2-bromo-1-p-tolyl-ethanone, DIEA, DMF, rt, 16 h; for R4 = 11: (N)-2-hydroxyethylphthalimide, DIAD, PPh3, THF, rt, 16 h; (iv) 50% TFA in DCM,
1 h.
with the ability to cyclize in both directions, reacted via the
west-iminium ion exclusively to generate the 1,4-disubstituted-
3,4-dihydro-1H-pyrazin-2-one 15 as the sole product (Model
C, Scheme 7). A similar substrate (12) that allowed iminium
formation toward the east direction only was also examined.
After treatment with TFA, resin 12 generated the double cycle
13, proving that the formation of eastbound iminium was
feasible in the absence of a west-iminium path.
In conclusion, we demonstrated that the N-(2-oxo-ethyl)-
derivatized peptides were regioselectively converted either to
3,4-dihydropyrazin-2(1H)-one upon the acid-mediated depro-
tection of the aldehyde or to piperazin-2-one in the presence of
the reducing agent TES. This conclusion was supported by our
recently published synthesis of 3,4-dihydropyrazin-2(1H)-ones
and piperazin-2-ones from polymer-supported acyclic inter-
mediates via N-acyl iminiums.15 Thus, this synthesis can
incorporate a six-membered peptide backbone constraint
during traditional Merrifield solid-phase peptide synthesis.
Tandem N-acylium Ion Cyclization−Nucleophilic
Addition. The second part of this study focused on the
formation of a fused ring via an internal nucleophile. The
tandem N-acyliminium ion cyclization−nucleophilic addition
was studied using two ring sizes (five and six-membered rings)
and an internal N-arylsulfonyl, N-acyl, N-aryl, N-alkyl, or
carbamate nitrogen nucleophile.
6 + 6 Fused Rings. To study the formation of 6 + 6 fused
rings, common intermediates 4 (Scheme 4) were acylated using
Fmoc-β-Ala-OH, followed by Fmoc group cleavage and N-
derivatization with a wide variety of functional groups in the R4
position to evaluate the influence of the different nitrogen
nucleophiles on the acyliminium reaction (resin 16, Scheme 8,
Table 1). Exposure to TFA caused cleavage from the resin, and
the deprotection of the aldehyde triggered the formation of
iminium ions, which could undergo nucleophilic addition to
form the target hexahydro-pyrazino[1,2-a]pyrimidine-4,7-dio-
nes 17 or enamides 18.13 The crude products were analyzed
1
using LC/MS and/or H NMR spectroscopy. To assess the
effect of the cleavage cocktail, several analytical samples were
also exposed to 5% water in TFA and neat formic acid. These
cleavage cocktails yielded the same major products observed
with 50% TFA in DCM.
N-arylsulfonyl Derivatives. Both the Tos (16(1,1,1,1),
16(2,1,1,1), 16(2,2,1,1)) and 4-Nos derivatives (16(2,1,1,2),
16(2,2,1,2)) provided clean conversions to the fused-ring
systems 17 with no detectable formation of enamides. The
purity of the crude compounds was high, >90% as determined
by LC/MS traces at 240 nm. The NMR spectra indicated that
E
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e
Table 1. Evaluation of the Internal Nitrogen Nucleophile during 6 + 6 Ring Formation
F
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Table 1. continued
a
b
The relative ratio of products 17:18 was estimated from the LC traces at 240 nm and/or from the crude 1H NMR spectrum. The total yield after
c
HPLC purification of the products prepared in a 6- to 10-step synthesis. These compounds were unstable and decomposed during purification; the
d
products were identified in the 1H NMR of the crude preparations through their characteristic olefinic protons. Inseparable mixture of isomers 17
e
1
and 18; the ratio of 17:18 was calculated from the H NMR spectra. NI stands for not isolated.
the nucleophilic addition proceeded with full stereocontrol of
the newly formed asymmetric carbon. The 4-Nos group was
chosen because it could be easily removed.31,32
N-carbamates. The polymer-supported Fmoc derivatives
(16(2,2,1,3)) and Cbz derivatives (16(2,1,1,4), 16(2,2,1,4))
formed a mixture of products with the bisheterocycles 17 as the
major products in the case of Fmoc derivatives. The Cbz
derivatives primarily yielded the enamides 18. Replacing Gly
with Ala appeared to have a little effect.
N-aryl Derivatives. The reaction outcome with the N-aryl
model compounds (possessing low basicity, pKa 19−31) was
dependent on the aromatic substituents. The electron-deficient
aromatic rings yielded only the enamides (18(2,1,1,5),
18(2,2,1,5)) or a mixture of products (16(2,3,1,6)), while the
electron-donating substituents promoted the nucleophilic
addition and generated the fused products in good yields
(16(2,1,1,7), 17(2,3,1,7)).
N-acyl Compounds. The presence of the nonbasic amide
functionality did not lead to the fused ring system; the
G
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a
Scheme 9. Synthesis of 5 + 6 Fused Rings
a
Reagents and conditions: (i) piperidine, DMF, 15 min, rt; (ii) Fmoc-α-amino acid, DIC, HOBt, DMF/DCM (1:1), rt, o/n; (iii) for R4 = 1, 2:
benzenesulfonyl chlorides, lutidine, DCM, rt, 16 h; for R4 = 5: 4-fluoro-2-nitrobenzotrifluoride, DIEA, DMSO, rt, 16 h; for R4 = 7: 1-fluoro-2-
nitrobenzenes, DMSO, 50 °C, 16 h, followed by SnCl2, DIEA, DMF saturated with N2, rt, 16 h; for R4 = 8, 13, 14 (twice): carboxylic acid or Fmoc-
AA, DIC, HOBt, DMF/DCM (1:1), rt, 16 h; (iv) 50% TFA in DCM, 1 h.
enamides were isolated as the only products (18(2,1,1,8),
18(2,2,1,8), 18(2,1,1,9), 18(2,2,1,9)). Despite forcing different
conditions, including high temperature, extended reaction
times, and the use of trifluoroacetic anhydride or formic acid,
no formation of the fused heterocycle was observed.
N-H and N-alkyl Compounds. The acyclic resin-bound
substrates with strongly basic amine functionalities (pKa higher
than 40) formed the enamides exclusively (18(2,1,1,10),
18(2,2,1,10), 18(2,1,1,11), 18(2,2,1,11), 18(2,1,1,12), and
18(2,2,1,12)), most likely because of the protonation of the
amino group.
N-arylsulfonyl Derivatives. We prepared model sulfona-
mides with tosyl and nosyl chlorides (sulfonamides, Table 2)
and evaluated the effect of amino acids (R2 and R3 substituents)
on the ratio of the fused-ring compounds to the enamides.
Unlike the previously described six-membered ring formation,
this outcome was highly influenced by the types of arylsulfonyl
group and amino acid. The N-Tos derivatives prepared using
Fmoc-Gly-OH (no Cα substituent in R1) (19(1,1,2,1),
19(2,1,2,1), and 19(2,1,6,1)) formed both the fused hetero-
cycles 20 and the enamides 21. However, the Cα-substituted
amino acids (Ala, (19(2,2,2,1), and 19(2,2,6,1))) formed the
fused ring predominantly (>99:1). Moreover, Ser and Thr with
or without the t-butyl protected hydroxyl group formed the
fused west ring through the amino group and not the hydroxyl
group (potential six-membered ring formation). In contrast, the
Nos derivatives produced a mixture of products in all cases
examined. The presence of a Cα substituent (R2 ≠ H) favored
the second cyclization, and the proportion of bicyclic products
increased independently of the electronic and steric character-
istics of the R2 group (compare the substrate 19(2,1,2,2) with
substrates 19(2,2,2,2), 19(2,2,5,2), 19(2,4,1,2), 19(2,4,2,2),
19(2,5,1,2), 19(2,5,2,2), 19(2,6,1,2), 19(2,7,2,2), and
19(2,7,5,2)).
5 + 6 Fused Rings. To form a five-membered fused ring,
resin 4 was acylated overnight with Fmoc-protected amino
acids (both L- and D-) via DIC activation in the presence of
HOBt at ambient temperature, although the reaction time was
reduced to 1 h for unprotected Fmoc-Ser-OH (Scheme 9). The
final derivatization using standard reaction conditions generated
sulfonamides, urethanes, amides, and N-aryl derivatives 19 and
enabled us to evaluate the effect of the N-substituent on the
reaction outcome. After treating resin 19 with a TFA solution
(50% in DCM), the crude products were analyzed using LC/
1
MS and/or H NMR spectroscopy. As in the previous study,
the iminium ion could either undergo nucleophilic addition to
form the target fused five-membered ring 20 or elimination to
produce enamide 21. We observed that the formation of
enamide 21 strongly depended on both the N-R4 substituent
and the type of amino acids (R2 and R3).
The formation of an asymmetric carbon during the tandem
N-acylium ion cyclization−nucleophilic addition was stereo-
selective; we isolated only one diastereoisomer (20(2,2,2,1),
20(2,2,2,2), 20(2,2,5,2), 20(2,4,1,2), and 20(2,4,2,2)) when a
H
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Table 2. Evaluation of Internal Nitrogen Nucleophiles in a 5 + 6 Double Ring
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Table 2. continued
a
The relative ratio of the products 20:21 was estimated from the LC traces at 240 nm and/or from the crude 1H NMR spectra. NC stands for not
b
calculated because of overlap. NI stands for not isolated; The total yield after HPLC purification of the products prepared in a 6- to 10-step
synthesis. Mixture of diastereoisomers. This sample produced a mixture of diastereoisomers, but only one was isolated. These compounds were
unstable and decomposed during purification; the products were identified in the H NMR spectra of the crude preparations through their
c
d
e
1
characteristic olefinic protons.
chiral amino acid was present in the first ring of the target
structure (R2 ≠ H). This was independent of the nature of the
second amino acid (the R3 influence). The spatial arrangement
of the iminium salt enabled the formation of a fused ring from
J
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only one side without any dependence on the east ring, and we
obtained the optically pure compounds 20(2,2,2,1),
20(2,2,2,2), 20(2,2,5,2), 20(2,4,1,2), and 20(2,4,2,2). The
configuration of the new chiral carbon was determined using
the two ring systems exhibited analogous trends; however, the
six-membered rings were formed more efficiently than the five-
membered rings (Table 3). The observed favored six-
the Karplus equation33 with coupling constants from the H
1
Table 3. Bicycle and Enamide Formation As a Function of
NMR spectra or the 2D NOE experiments to verify that all
structures were the S isomers. However, when the chiral amino
acid was present only in the second cycle (e.g., 19(2,1,2,1) with
Fmoc-Gly-OH as the first amino acid), a mixture of
diastereoisomers was formed as indicated by NMR (see
substrates 19(1,1,2,1), 19(2,1,2,1), and 19(2,1,2,2)). The
ratio of diastereoisomers was 65:35 in favor of isomer 19.
Surprisingly, the presence of the opposite stereochemistry
(R) in the R3 position obtained through the introduction of D-
Ala or D-Val as the second amino acid strongly hindered the
second cyclization, leading to the enamides 21 as the major
products (21(2,2,3,2) and 21(2,2,4,2)) likely because of steric
effects.
N-carbamates. Resin-bound Fmoc derivatives provided only
minor quantities of the fused ring compounds (substrates
19(2,1,1,3), 19(2,1,2,3), 19(2,1,5,3), and 19(2,2,5,3)) except
for the Ser- and Thr-substituted compounds in the R2 position
(19(2,1,7,3) and 19(2,2,7,3)). However, in this case the
presence of an alcohol group allowed the closure of the second
ring through the oxygen nucleophile to form the 6 + 6
tetrahydropyrazino[2,1-b][1,3]oxazine-4,7(6H,8H)-diones
22(2,1,7,3) and 22(2,2,7,3) (Figure 1).
N-substituent
derivative
6 + 6 bicycle enamide 5 + 6 bicycle enamide
N-arylsulfonyl
>99%
30−75%
1−99%
<1%
<1%
15−70%
1−6%
1−99%
<1%
85−30%
99−94%
99−1%
>99%
N-carbamates
70−25%
99−1%
>99%
N-aryl derivatives
N-acyl compounds
N-H compounds
<1%
>99%
<1%
>99%
membered ring formation followed Baldwin’s rules.34 In both
cases, the nature of the R4 group was critical to defining the
final destination of the iminium salt. In both the 6 + 6 and 6 + 5
fused rings, the second cyclization was strongly promoted by
the N-terminal sulfonamide groups. Furthermore, both the 6 +
6 and 6 + 5 bisheterocycles were produced with full
stereocontrol of the newly formed asymmetric carbon when a
chiral carbon was present at the R2 position. The N-aryl
derivatives formed the double cycle only when an electron-
donating substituent was present, while the N-alkyl and N-acyl
acyclic precursors did not form a second ring. The N-
Arylsulfonyl derivatives of compounds prepared using Ser and
Thr formed five-membered rings via a nitrogen nucleophile,
while the N-Fmoc and N-acyl derivatives closed six-membered
rings via an oxygen nucleophile, thus enabling selection
between the competitive cyclizations by choosing the
appropriate N-substituent.
EXPERIMENTAL PROCEDURES
■
Acylation with Bromoacetic Acid (Resin 2). Resin 1a
was a commercial Rink resin (loading = 0.6 mmol/g), and the
Fmoc protecting group was cleaved by a 20-min exposure to
50% piperidine in DMF. Resin 1b was prepared from a BAL
resin according to the reported procedure.30 A fritted
polypropylene reaction vessel charged with resin 1a or 1b (1
g) was washed 3 times with DCM. A solution of bromoacetic
acid (700 mg, 5 mmol) was made in 10 mL of DCM in a fritted
syringe, and DIC (386 μL, 2.5 mmol) was added. The
precipitated N,N′-di-i-propylurea (DIU) was filtered after 10
min shaking, the DIEA (436 μL, 2.5 mmol) was added, and the
solution was placed in the syringe with resin 1a or 1b. The resin
slurry was shaken at ambient temperature for 4 h and then
washed 5 times with DCM. The completion of the acylation to
obtain resin 2 followed using the bromophenol blue test.
Reaction with Aminoacetaldehyde Dimethylacetal
(Resin 3). A fritted polypropylene reaction vessel charged
with resin 2 (1 g) was washed 3 times with DCM and 3 times
with DMF. An aminoacetaldehyde dimethylacetal (1.09 mL, 10
mmol) and DIEA (1.74 mL, 10 mmol) solution in 10 mL of
DMF was added. The resin slurry was shaken at ambient
temperature for 2 h and then washed 3 times with DMF and 3
times with DCM.
Figure 1. Six +6-membered rings: tetrahydropyrazino[2,1-b][1,3]-
oxazine-4,7(6H,8H)-diones.
N-aryl Compounds. The outcome of the N-aryl derivatives
was in good agreement with the 6-membered ring formation.
The N-aryl iminium ions formed the double-fused ring with the
electron-rich aryl groups (20(2,1,2,7)), or lost a proton and
yielded an enamide with the electron-deficient aromatic rings
(21(2,2,2,5)).
N-acyl Compounds. Model compounds prepared with an N-
acyl substituent provided results analogous to the previous six-
membered ring formation in which only the enamides 21 were
detected except for those substrates with Ser or Thr as the
second amino acid (19(2,2,6,14) and 19(2,2,7,14)). These
exceptions produced the heterofused rings 22(2,2,6,14) and
22(2,2,7,14) through the participation of oxygen as an internal
nucleophile. Because the fused ring 20 was not formed, the
enamide 21 was incorporated as a six-membered peptide
backbone constraint during the traditional Merrifield solid-
phase peptide synthesis.
CONCLUSION
■
N-(2-Oxoethyl)-derivatized peptides formed the N-acylimi-
niums toward the peptide amino terminus, referred to here as
westbound cyclization. In the absence of the westbound amide
nitrogen, the N-acyliminium ions were formed toward the
peptide carboxyl terminus (eastbound cyclization). The fused 6
+ 6 and 6 + 5 bisheterocycles were formed via internal
nucleophilic addition to cyclic iminium ions. The formation of
Quantification of Resin Loading. A ∼10 mg resin sample
was reacted with Fmoc-OSu (169 mg, 0.5 mmol) in 1 mL of
DCM for 30 min at ambient temperature. The resin was
washed 5 times with DCM, dried, precisely weighed, and the
product was cleaved from the resin with TFA:TES:DCM
(5:1:4) for 30 min. The cleavage cocktail was evaporated by a
stream of nitrogen, and the cleaved compounds extracted into 1
K
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ACS Combinatorial Science
Research Article
mL of MeOH. These samples of Fmoc derivatives of 3 were
analyzed using LC/MS, and the analyses were compared with
that of the standard (Fmoc-Ala-OH; concentration 1 mg/mL).
The loading of the resin was determined using the external
standard method.
solution in DCM (1.5 mL), and both syringes were cooled in a
freezer for 30 min. The DIEA solution was then added to the
resin suspension, and the resulting mixture was shaken
overnight at room temperature. The resin was next washed 5
times with DCM, and the completion of the reaction was
confirmed using the bromophenol blue test.
Acylation with Fmoc-Amino Acid (Resin 4). A fritted
polypropylene reaction vessel charged with resin 4a or 4b (250
mg) was washed 3 times with DCM and 3 times with DMF.
The Fmoc protecting group was cleaved with 50% piperidine in
DMF as previously described. The resin was washed 3 times
with DMF and 3 times with DCM. The Fmoc-amino acid (0.4
mmol) was dissolved in 1 mL of DMF and 1 mL of DCM.
Then, HOBt (61.2 mg, 0.4 mmol) and DIC (63 μL, 0.4 mmol)
were added, and the solution was added to the resin. The
reaction slurry was shaken at ambient temperature for 1 h
(Fmoc-Ser-OH) or overnight (for other amino acids), and then
the resin was washed 5 times with DCM. A sample of the resin
was reacted with Fmoc-OSu, followed by product cleavage with
50% TFA and analysis using LC/MS as previously described.
Sulfonylation with 4-Methyl-benzenesulfonyl Chlor-
ide (Resins 5, 13), or 2- or 4-Nitrobenzenesulfonyl
Chloride (Resins 5, 15, 16, 19). A fritted polypropylene
reaction vessel charged with resin 1b, 1c, or 4 (250 mg) was
washed 3 times with DCM and 3 times with DMF. The Fmoc
group was cleaved with 20% piperidine in DMF as previously
described above, and the resin was washed 3 times with DMF
and 3 times with DCM. A solution of 4-methylbenzenesulfonyl
chloride (190 mg; 1 mmol) or 2-nitrobenzenesulfonyl chloride
(222 mg; 1 mmol) and DIEA (174 μL; 1 mmol) in 2 mL of
DCM was added to the resin, and the reaction slurry was
shaken at ambient temperature overnight. The resin was then
washed 5 times with DCM. A sample of resin was reacted with
Fmoc-OSu, the product cleaved with 50% TFA and analyzed by
LCMS as previously described.
Sulfonylation with 2- or 4-Nitrobenzenesulfonyl
Chloride Followed by the Fukuyama Variation of the
Mitsunobu N-alkylation with Glycolaldehyde Dimethyl
Acetal (Resins 5, 12). Resins 1b, c (330 mg) were
sulfonylated as previously described and washed 3 times with
anhydrous THF. A solution of Ph3P (260 mg, 1 mmol) and
glycolaldehyde dimethyl acetal (100 μL, 1 mmol) in anhydrous
THF (5 mL) was added to the swollen resin which was
contained in a fritted polypropylene reaction vessel. This vessel
was connected to another syringe containing DIAD (200 μL, 1
mmol) in anhydrous tetrahydrofuran (THF, 4 mL), and both
syringes were cooled in a freezer for 30 min. The DIAD
solution was then added to the resin suspension, and the
resulting mixture was shaken at room temperature for 30 min
and then at 50 °C overnight. The resin was washed 3 times
with THF, once with MeOH, and 3 times with DCM. A sample
of resin was treated with TFA:TES:DCM (5:1:4), and the
liberated products were analyzed using LCMS as previously
described.
Arylation with 4-Fluoro-2-nitrobenzotrifluoride (10c,
16, 19) or with 1-Fluoro-2-nitrobenzene (16, 19). A fritted
polypropylene reaction vessel charged with acylated resin 4
(250 mg) was washed 3 times with DCM and 3 times DMF.
The Fmoc protecting group was cleaved with 20% piperidine in
DMF as previously described, and the resin was washed 3 times
with DMF and 3 times with DCM. A solution of 4-fluoro-2-
nitrobenzotrifluoride (700 μL, 5 mmol) or 1-fluoro-2-nitro-
benzotrifluoride (530 μL, 5 mmol) and DIEA (870 μL, 5
mmol) in 5 mL of DMSO was added to the resin, and the
reaction slurry was shaken overnight at ambient temperature
(for 4-fluoro-2-nitrobenzotrifluoride) or at 80 °C (for 1-fluoro-
2-nitrobenzotrifluoride). The resin was next washed 3 times
with DMSO and 3 times with DCM. The completion of the
reaction was confirmed using the bromophenol blue test.
Reduction with Tin(II) Chloride Dihydrate (Resins 16,
19). Tin(II) chloride dihydrate (912 mg, 4 mmol) was
dissolved in 3 mL of DMF saturated with N2, and DIEA
(700 μL, 4 mmol) was added. The solution was added to resin
10 (250 mg), and the reaction slurry was shaken overnight at
ambient temperature for 2 h, or 2 times overnight (16, 19).
Finally, the resin was washed 3 times with DMF and 3 times
with DCM.
Alkylation with 2-Bromo-1-p-tolyl-ethanone (Resin
16). A fritted polypropylene reaction vessel charged with
acylated resin 4 (250 mg) was washed 3 times with DCM and 3
times with DMF. The Fmoc protecting group was cleaved with
20% piperidine in DMF as previously described, and the resin
was washed 3 times with DMF and 3 times with DCM. The
resultant resin was sulfonylated as previously described above
and then washed 3 times with DMF. A solution of 2-bromo-1-
p-tolyl-ethanone (320 mg, 1.5 mmol) and DIEA (525 μL, 3
mmol) in 3 mL of DMF was added. The resin slurry was
shaken overnight at ambient temperature, then washed 3 times
with DMF and 3 times with DCM. The completion of the
reaction was confirmed using the bromophenol blue test.
Finally, the nosyl group was removed by treating the resin with
a solution of mercaptoethanol (105 μL, 1.5 mmol) and DBU
(75 μL, 0.5 mmol) in DMF (2.5 mL) at ambient temperature
for 10 min. The resin was then washed 3 times with DMF and
3 times with DCM.
Alkylation with (N)-2-hydroxyethylphthalimide (Resin
16). Acylated resin 4 (250 mg) was Fmoc deprotected and
sulfonylated as previously described. The resin was then washed
3 times with anhydrous THF. A solution of Ph3P (230 mg, 0.9
mmol) and (N)-2-hydroxyethylphthalimide (169 mg, 0.9
mmol) in anhydrous THF (5 mL) was next added to the
swollen resin contained in a fritted polypropylene reaction
vessel. This vessel was connected to another syringe containing
DIAD (180 μL, 0.9 mmol) in anhydrous THF (3 mL), and
both syringes were cooled in a freezer for 30 min. The DIAD
solution was then added to the resin suspension, and the
resulting mixture was shaken overnight at room temperature.
Finally, the resin was washed 3 times with THF, once with
MeOH, and 3 times with DCM.
Reaction with Benzyloxycarbonyl (Cbz) Chloride
(Resin 16). A fritted polypropylene reaction vessel charged
with resin 4 (250 mg) was washed 3 times with DCM and 3
times with DMF. The Fmoc group was cleaved with 20%
piperidine in DMF as previously described, and the resin was
washed 3 times with DMF and 3 times with DCM. A solution
of carbobenzoxy chloride (60 μL, 0.42 mmol) in DCM (2 mL)
was added to the swollen resin contained in a fritted
polypropylene reaction vessel. This vessel was connected to
another syringe containing a DIEA (75 μL, 0.42 mmol)
Acylation with p-Methoxybenzoic Acid (Resin 19). A
fritted polypropylene reaction vessel charged with acylated
L
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ACS Combinatorial Science
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resin 4 (250 mg) was washed 3 times with DCM and 3 times
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washed 3 times with DMF and 3 times with DCM. A solution
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was added. The precipitated N,N′-di-i-propylurea (DIU) was
filtered after 10 min of shaking, and the solution was added to
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for 1 h, except the Ser- and Thr-containing resins, which had
reaction times of 2 h. The TFA solution was then collected, and
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ASSOCIATED CONTENT
* Supporting Information
■
S
Analytical data of individual compounds and copies of NMR
spectra associated with this article. This material is available free
of charge via the Internet at http://pubs.acs.org.
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Iminium Ion Cyclization. Chem. Rev. 2004, 104, 2311−2352.
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Synthesis of a bicyclic gama-laclam dipeptide analogue. Tetrahedron
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AUTHOR INFORMATION
Corresponding Author
*E-mail: vkrchnak@nd.edu.
■
Funding
This research was supported by the Department of Chemistry
and Biochemistry, University of Notre Dame, by the projects
P207/12/0473 from GACR, CZ.1.07/2.3.00/20.0009 from the
European Social Fund, and ME09057 from the Ministry of
Education, Youth and Sport of the Czech Republic.
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tics:New Electroauxiliaries and the Use of a Chemical Oxidant for
Introducing N-Acyliminium Ions into Peptides. Org. Lett. 2003, 5,
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Notes
The authors declare no competing financial interest.
(22) Sun, H.; Martin, C.; Kesselring, D.; Keller, R.; Moeller, K. D.
Building Functionalized Peptidomimetics:Use of Electroauxiliaries for
Introducing N-Acyliminium Ions into Peptides. J. Am. Chem. Soc.
2006, 128, 13761−13771.
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ACKNOWLEDGMENTS
We gratefully appreciate the use of the NMR facility at the
University of Notre Dame.
■
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