Polymer-supported stereoselective synthesis of (1S,5S)-6-oxa-3,8- diazabicyclo[3.2.1]octanes

Article abstract of DOI:10.1002/ejoc.201300093

We describe a polymer-supported stereoselective synthesis of the (1S,5S)-6-oxa-3,8-diazabicyclo[3.2.1]octane-bridged scaffold by tandem iminium ion cyclization/nucleophilic addition reactions. A series of resin-bound acyclic intermediates bearing different substituents were prepared, and the scope and limitations of the chemical route leading to the bridged scaffold were evaluated. The Thr-derived bridged scaffold was found to be substantially more stable in acid than the Ser-derived scaffold, which was partially transformed into dihydropyrazinones. Substitution at the iminium-forming nitrogen was critical for acid stability, and the N-arylsulfonamides with electron-withdrawing groups yielded the highest purity of the crude products prepared by acid-mediated cleavage. The acid-labile target compounds were synthesized by nucleophile-mediated cleavage from the esterified Wang resin and cyclization in formic acid. The title compounds were prepared by tandem iminium ion cyclization/nucleophilic addition reactions. The scope and limitations of the chemical route leading to the bridged scaffold were evaluated. The Thr-derived bridged scaffold is substantially more stable in acid than the Ser-derived scaffold, which is partially transformed into dihydropyrazinones. Copyright

Full text of DOI:10.1002/ejoc.201300093

Job/Unit: O30093
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Date: 09-04-13 16:50:22
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FULL PAPER
DOI: 10.1002/ejoc.201300093
Polymer-Supported Stereoselective Synthesis of (1S,5S)-6-Oxa-3,8-
diazabicyclo[3.2.1]octanes
[a]
[b]
[b]
[a,b]
ˇ
ˇ
Eva Schütznerová, Allen G. Oliver, Jaroslav Zajícek, and Viktor Krchnák*
Keywords: Peptidomimetics / Heterocycles / Nucleophilic addition / Solid-phase synthesis / Bicyclic compounds
We describe a polymer-supported stereoselective synthesis
of the (1S,5S)-6-oxa-3,8-diazabicyclo[3.2.1]octane-bridged
scaffold by tandem iminium ion cyclization/nucleophilic ad-
dition reactions. A series of resin-bound acyclic intermedi-
ates bearing different substituents were prepared, and the
scope and limitations of the chemical route leading to the
bridged scaffold were evaluated. The Thr-derived bridged
scaffold was found to be substantially more stable in acid
than the Ser-derived scaffold, which was partially trans-
formed into dihydropyrazinones. Substitution at the iminium-
forming nitrogen was critical for acid stability, and the N-
arylsulfonamides with electron-withdrawing groups yielded
the highest purity of the crude products prepared by acid-
mediated cleavage. The acid-labile target compounds were
synthesized by nucleophile-mediated cleavage from the es-
terified Wang resin and cyclization in formic acid.
aloids [tropane (I), Figure 1], a group of over 100 biolo-
gically active compounds that include atropine (II), cocaine
(III), and scopolamine (IV).[9] These bridged bicyclic struc-
tures have pharmacological and clinical uses, for example,
the local anesthetic cocaine acts as a serotonin–norepineph-
rine–dopamine reuptake inhibitor that leads to prolonged
post-synaptic effects. The subsequent high rates of addic-
tion to cocaine have become a worldwide problem.[10] The
structure–activity relationships (SAR) of reuptake inhibi-
tors of the dopamine transporter include tropane and pi-
peridine analogues.[9]
Introduction
Nature is the ultimate source of structural diversity for
drug discovery. Natural products have always played an im-
portant role in traditional medicine and are crucial to the
pharmaceutical chemistry. For example, in cancer treat-
ment, the structures of over 60% of the drugs have a natural
origin.[1,2] The search for novel, biologically active struc-
tures that mimic natural products has become an integral
part of drug discovery. However, recent structural analysis
of the drugs and compound libraries used in high-through-
put screening has revealed significant differences in the
chemical space covered by individual groups of com-
pounds.[3] The existing compound collections typically dis-
play a low frequency of sp3-hybridized carbons and chiral
centers when compared with drugs and natural products.[4]
To fill the gap in chemical space, our ongoing research is
focused on the design and synthesis of compound collec-
tions that are characterized by nature-inspired, nonplanar
structures (i.e., those that include sp3 carbons) and the for-
mation of stereogenic centers with stereocontrol.[5–7]
Figure 1. Bicyclo[3.2.1]octane-derived natural products I–IV.
Nitrogen-containing heterocyclic systems, particularly
alkaloids, have been the focus of medicinal chemistry for
several decades.[8] The bicyclo[3.2.1]octane moiety is a core
structure in many natural products including tropane alk-
A number of chemical routes lead to tropane-like
bridged bicyclic scaffolds. The densely substituted, bridged
heterocycle V (Figure 2) was prepared from 1,4-diphenyl-
2,6-dioxopiperazine and phenyl hypochlorothioite by di-
polar cycloaddition with formaldehyde.[11] Another bridged
bicycle, methyl 2-oxo-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-
carboxylate VI, which is a conformationally constrained di-
peptide isoster, was prepared from tartaric acid and N-
benzylamino alcohols.[12] Guarna et al.[13] patented an anal-
ogous route for the synthesis of 3-aza-6,8-dioxabicyclo-
[3.2.1]octanes VII from α-amino ketones and α,β-dihydroxy
acid derivatives or α-amino-β-hydroxy acids. Molecumet-
ics[14] patented the synthesis of the fused bicyclic nitroge-
[a] Department of Organic Chemistry, Palacky University,
17. Listopadu 12, 77146 Olomouc, Czech Republic
Fax: +420-585-634-465
Homepage: http://htos.upol.cz/
[b] Department of Chemistry and Biochemistry, 251 Nieuwland
Science Center, University of Notre Dame,
Notre Dame, Indiana 46556, USA
E-mail: vkrchnak@nd.edu
Homepage: http://www.nd.edu/~vkrchnak
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300093.
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FULL PAPER
nous compounds VIII. The synthesis was carried out on the
The acyclic precursors were synthesized on polymer-sup-
solid phase, and acyclic dipeptide aldehydes were cleaved ported amines (resins 1, Figure 3). To expand the diversity
from the resin and concurrently cyclized to the bicyclic de- of the target compounds and address any potential effects
rivatives VIII. The synthesis of (1S,5S)-6-oxa-3,8-diazabicy- from either the immobilization or the amine-containing
clo[3.2.1]octanes (X = O, n = 1) has not been documented, building block, different resin-bound amines were prepared
however, an analogous synthetic route to bridged bicycles on Rink amide,[31] Wang,[32] and backbone amide linker
by the addition of carbon nucleophiles has been re- (BAL)[33] resins by using four types of anchoring: Carbox-
ported.[15]
amide, carboxylate, amine, and ether (Figure 3). The Rink
amide resin 1(1) was used as the starting amine and was
acylated with Fmoc-Tyr(tBu)-OH [resin 1(2)], the BAL
resin was subjected to reductive amination with n-propyl-
amine[34] [1(3)], and the Wang resin was esterified with
Fmoc-Ala-OH followed by cleavage of the Fmoc group by
using piperidine in DMF [1(4)]. Finally, the Wang resin was
also derivatized with 1,3-diaminopropane through a carb-
amate linkage by using the carbonyldiimidazole (CDI) acti-
vation method[35] [1(5)] and with 2-(Fmoc-amino)ethanol
through an ether linkage by using trichloroacetimidate acti-
vation[36] followed by Fmoc cleavage [1(6)].
Figure 2. Synthesis of (1S,5S)-6-oxa-3,8-diazabicyclo[3.2.1]octane.
Among the many chemical routes used for the synthesis
of natural-product-like molecules, the tandem iminium ion
cyclization/nucleophilic addition represents one of the most
versatile methodologies.[16–20] N-Acyliminium pathways
were used in the solid-phase synthesis of piperidines[21] and
2-oxopiperazines,[22] fused benzimidazolopiperazines have
been prepared by the acid-triggered cyclization of iminium
ion intermediates,[23] and N-acyliminium ion chemistry led
to 2,6-bridged piperazines starting from amino acids.[24]
Conformational constraints have been incorporated into
peptides through silylated amino acids with subsequent
conversion into N-acyliminium ions.[25–27] N-Boc-1,3-oxaz-
inane-masked aldehyde building blocks have been incorpo-
rated into peptides and used to synthesize structurally di-
verse bicyclic dipeptide mimetics.[28,29] Finally, diverse
heterocycles have recently been prepared by the acyl-
iminium Pictet–Spengler reaction.[30]
Figure 3. Polymer-supported amines 1(1)–1(6).
We describe herein the polymer-supported stereoselective
synthesis of (1S,5S)-6-oxa-3,8-diazabicyclo[3.2.1]octanes by
using a strategy compatible with the traditional Merrifield
solid-phase synthesis. This strategy has allowed the synthe-
sis of a library of natural-product-like compounds for drug
discovery and the introduction of this bridged scaffold as a
peptide backbone constraint.
Two routes were used to attach the protected aldehyde.
Resin-bound amines 1(1)–1(5) (Figure 3) were acylated with
bromoacetic acid. The protected aldehyde was introduced
by nucleophilic displacement of the bromine with excess
aminoacetaldehyde dimethyl acetal[37,38] to yield resin 2
(Scheme 1, Route I). As an alternative, the protected alde-
hyde was also attached by Route II. The resin-bound
amines 1(5) and 1(6) were treated with 4-nitrobenzenesulf-
onyl chloride (4-Nos-Cl) and the 4-Nos-derivatized poly-
mer-supported amines were subjected to Fukuyama alkyl-
ation[39] with glycolaldehyde dimethyl acetal. The 4-Nos
group was subsequently cleaved. Ultimately, both routes
converged to one family of compounds.
Results and Discussion
Resin-bound acyclic intermediates were prepared on the
The anhydride formed from the reaction of Fmoc-
solid phase by using linkers that allow for base- and/or acid- Ser(tBu)-OH [or Fmoc-Thr(tBu)-OH] and N,NЈ-diisoprop-
mediated cleavage from the resin. The acid-mediated cleav- ylcarbodiimide (DIC)[40] was then treated with the second-
age triggered tandem iminium ion cyclization/nucleophilic ary amine 2 to yield the polymer-supported amide 3. The
addition with concurrent cleavage from the resin to yield piperidine-mediated Fmoc deprotection was followed by re-
(1S,5S)-6-oxa-3,8-diazabicyclo[3.2.1]octanes. The base-me- action of the polymer-supported amines with a series of
diated cleavage released fully protected compounds that reagents to introduce different R3 substituents. Arylsulfonyl
were deprotected and cyclized in solution.
chlorides in the presence of a base produced the sulfon-
2
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Polymer-Supported Synthesis of Oxadiazabicyclooctanes
Scheme 1. Polymer-supported stereoselective synthesis of (1S,5S)-6-oxa-3,8-diazabicyclo[3.2.1]octane 6. Reagents and conditions:
(i) bromoacetic acid (2 equiv.), DIC (1 equiv.), DCM, 5 min, then N-ethyl-N,N-diisopropylamine (DIEA; 1 equiv.), room temp., 1 h;
(ii) aminoacetaldehyde dimethyl acetal, DIEA, DMF, room temp., 2 h; (iii) Fmoc-amino acid (2 equiv.), DIC (1 equiv.), THF, room
temp., overnight; (iv) 4-nitrobenzenesulfonyl chloride, 2,6-lutidine, DCM, room temp., overnight; (v) glycolaldehyde dimethyl acetal, PPh3,
DIAD, anhydrous THF, 0 to 50 °C, overnight, repeat; (vi) 2-mercaptoethanol, DBU, DMF, room temp., 5 min; (vii) Fmoc-Ser(tBu)-OH
(1 equiv.), HOBt (1 equiv.), DIC (1 equiv.), DCM/DMF (1:1), room temp., overnight; (viii) 50% piperidine in DMF, room temp., 20 min;
(ix) arylsulfonyl chloride, 2,6-lutidine, DCM, room temp., overnight; (x) 50% TFA in DCM, room temp., 90 min; (xi) TFA/H2O (95:5),
room temp., 90 min.
amide resin 4. N-Alkylation was carried out after activation
with 4-Nos-Cl followed by reaction with 2-nitrobenzyl
alcohol and N-(2-hydroxyethyl)phthalimide under Mitsu-
nobu conditions.[41] The 4-Nos group was subsequently
cleaved by treatment with mercaptoethanol and 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU).[39,42] The N-arylation was
performed with 4-fluoro-3-nitrobenzofluoride in the pres-
ence of a base.[43] N-Acylation was carried out with 4-meth-
oxybenzoic acid, 4-trifluoromethylbenzoic acid, and Fmoc-
Pro-OH by using conventional peptide coupling techniques
Figure 4. ORTEP drawing of the X-ray crystal structure of com-
with N-hydroxybenzotriazole (HOBt) and DIC.[44] The final
pound 6(1,1,6). Thermal displacement ellipsoids are depicted at the
50% probability level.
cyclization of the resin-bound acyclic precursor 4 was en-
abled by the acid-mediated cleavage of the hydroxy and al-
dehyde protecting groups concurrent with cleavage from the
resin with a 50% TFA solution in dichloromethane (DCM; why this product was formed; the enamide 7 could have
Route I) or 5% water in TFA (Route II). The acid-assisted been formed from iminium 5[45,46] or the partially decom-
cleavage typically yielded two products, (1S,5S)-6-oxa-3,8- posed target bridged compound 6 present in the cleavage
diazabicyclo[3.2.1]octane 6 and 3,4-dihydropyrazin-2(1H)- cocktail. We tested the effect of acid concentration and ex-
one 7 (Scheme 1).
posure time on the ratio of 6 and 7 by using two model
The structure of the bridged compound 6 was confirmed compounds 4(1,1,3) (R1 = CH2CONH2, R2 = H, R3
=
by analysis of its 1D and 2D H and 13C NMR spectra pTos; for numbering of the building blocks, see Table 1) and
(COSY, HSQC, and HMBC). In addition, compound 4(4,1,4) (R1 = CH2COOH, R2 = H, R3 = 4-methoxy-2-ni-
6(1,1,6) was crystallized from an acetonitrile/DMSO solu- trophenylsulfonyl). The results are summarized in Table 1.
tion and its structure was determined by X-ray analysis A longer reaction time or higher TFA concentration shifted
1
(Figure 4).
the ratio of 6/7 in favor of the enamide 7 (entries 1–4).
These results indicated that bicycle 6 suffered acid-medi-
The presence of dihydropyrazinone 7 in the crude reac-
tion mixture following the acid-mediated cleavage of the ated transformation into enamide 7 and that milder condi-
acyclic intermediate from the resin prompted us to explore tions were required to increase the yield of target com-
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Table 1. Effect of the cleavage conditions on the ratio of products enamide 7 is formed from the bridged compound 6. En-
6/7 from resins 4(4,1,4) and 4(1,1,3).
amide 7 was also formed when 8(4,1,4) was exposed to 10%
6(4,1,4)/7(4,1,4)[a]
6(1,1,3)/7(1,1,3)
TFA (entry 8). In contrast, treatment of the polymer-sup-
ported precursor 4(4,1,4) with formic acid for 1 h followed
by sodium hydroxide cleavage from the resin yielded only
bridged compound 6. However, only 17% of the tBu pro-
tecting group was cleaved (entry 9). Thus, mildly acidic con-
ditions could not be used for on-resin tBu deprotection and
subsequent cyclization.
Based on the observations described herein, we suggest
the mechanism presented in Scheme 3 for the formation of
the bridged bicycle 6 and its acid-mediated transformation
into enamide 7. The initial formation of the oxonium spe-
cies 9 was adopted from the mechanism proposed for acetal
deprotection under anhydrous conditions.[50]
Entry Cleavage cocktail
1
2
50% TFA/DCM,
30 min
50% TFA/DCM,
overnight
78:22
36:64
39:61
22:78
3
4
100% TFA, 30 min
95%TFA/water,
30 min
63:37
67:33
28:72
27:73
5
6
NaOH, 30 min
NaOH, 30 min then
formic acid, 1 h
NaOH, 30 min then
formic acid, overnight
NaOH, 30 min then
10% TFA, 1 h
95% of 8(4,1,4)
n.a.[b]
n.a.
99:1
7
8
9
58:42[c]
75:25
n.a.
n.a.
n.a.
formic acid, 1 h, then
0.5 m NaOH, 30 min
99:1[d]
[a] The relative ratio of products 6/7 was estimated from the LC
traces at 240 nm. [b] n.a.: not applicable. [c] Contains an O-formyl
derivative. [d] Only 17% of tBu was cleaved.
pound 6. Cleavage from the Rink amide resin typically re-
quires exposure to TFA and a milder acid such as formic
acid (FA), often used to trigger the tandem iminium ion
cyclization/nucleophilic addition reaction,[47–49] does not
completely cleave the products from the Rink amide resin.
However, formic acid does cleave the OtBu protecting
group of Ser and unmasks the aldehyde in solution. Model
experiments indicated that a solution of Fmoc-Ser(tBu)-OH
in FA contain Fmoc-Ser-OH (50%), Fmoc-Ser(O-formyl)-
OH (43%), and Fmoc-Ser(tBu)-OH (7%) after 1 h, which
corresponds to 93% cleavage of the tBu group. We synthe-
sized model compound 4(4,1,4) immobilized on the Wang
resin through an ester linkage (Scheme 2). We then cleaved
the protected intermediate 8(4,1,4) from the resin 4(4,1,4)
with 0.5 m NaOH and isolated the highly pure product
8(4,1,4) (entry 5). When 8(4,1,4) was exposed to formic acid
for 1 h, the bridged compound 6 was formed exclusively
(entry 6). Treatment of 8(4,1,4) with formic acid overnight
led to 42% of the enamide 7 (entry 7), thus confirming that
Scheme 3. Suggested mechanism for the formation and transforma-
tion of bridged bicycle 6.
The study next focused on the acid lability of bicycle 6
as a function of its substitution pattern. To study the sta-
bility of the diversely substituted target compound 6 in the
acid-based cocktail typically used for its release from acid-
labile linkers, we prepared a series of compounds on the
Rink amide resin. The substituent R3 was expected to be
the factor determining the ratio 6/7 because this substituent
Table 2. Correlation of the ratio of bridged 6 to the Hammett con-
stant σ of the substituents on the aromatic rings of R3 from the
sulfonamides.
[a]
[b]
[c]
Resin
Substituent
σpara
σortho
σsum
Amount of 6[d] [%]
4(1,1,2) 4-OMe
4(1,1,3) 4-Me
4(1,1,4) 2-NO2, 4-OMe
4(1,1,5) 2-NO2
4(1,1,2) 4-NO2
4(1,1,7) 2-NO2, 4-CF3
4(1,1,8) 2,4-diNO2
–0.27
–0.17
–0.27
–
0.78
0.54
0.78
–
–
0,51
0,51
–
–0.27
–0.17
0.24
0.51
0.78
1.05
1.28
44
62
83
90
89
95
99
0.51
0.51
Scheme 2. Acid- and base-mediated cleavage of 4(4,1,R3). Reagents
and conditions: (i) 0.5 m NaOH in MeOH/THF (1:1), room temp.,
30 min; (ii) 50% TFA in DCM, room temp., 1 h; (iii) formic acid,
room temp., 1 h.
[a] Values from refs.[51,52] [b] Calculated by using σortho
=
[53]
0.65σpara
.
[c] Sum of the corresponding ortho and para con-
stants.[54] [d] Based on the relative amount of product 6, estimated
from the LC traces at 240 nm.
4
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Polymer-Supported Synthesis of Oxadiazabicyclooctanes
is directly linked to the nitrogen atom involved in the for- pounds were prepared with different R3 groups and in-
mation of the cyclic iminium. Thus, the first set of com- cluded N-arylsulfonyl, N-alkyl, N-aryl, and N-acyl deriva-
Table 3. Synthesized derivatives of (S)-3-(hydroxymethyl)-3,4-dihydropyrazin-2(1H)-one 7 and (1S,5S)-6-oxa-3,8-diazabicyclo[3.2.1]octane
6.
[a] The relative ratios of products 6/7 were estimated from the LC traces at 240 nm. [b] Yield [%] after HPLC purification based on initial
loading of the resin. NI, not isolated. Cleavage protocol A: 50% TFA in DCM, 1.5 h; B: 5% water in TFA, 1.5 h; C: 0.5 m NaOH in
THF/MeOH (1:1) 30 min, isolation, then formic acid, 1 h.
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tives. Table 3 summarizes the influence of the R3 substitu- ylsulfonyl and 2,4-dinitrophenylsulfonyl derivatives were
ent on the ratio of the final products 6 and 7 (as well as the prepared as a result of the high purity of their correspond-
R groups numbering).
ing bicycles (6). To document the compatibility of this
The urethane derivative [R3 = Fmoc; 4(1,1,1)] formed method with peptide synthesis, we extended the R1 chain
both products, with enamide 7 being the major component. by one amino acid towards the C terminus and prepared
The sulfonamides afforded various ratios of both products; the Gly-Tyr-NH2 derivative as a terminal amide [4(2,1,4)]
the relative quantity of bicycle 6 increased with increasing and the Gly-Ala-OH compound as a terminal carboxylate
electron-withdrawing nature of the substituents present on [4(4,1,4)]. To obtain compounds with alcohol and amine
the aromatic ring (OMe Ͻ Me Ͻ OMe + NO2 Ͻ NO2 ≈ terminal groups, N-(2-hydroxyethyl) [4(6,1,4)] and N-(2-
CF3 + NO2 ≈ 2NO2) and the trend corresponds to the aminopropyl) [4(5,1,4)] resins were prepared. No com-
Hammett constants of the substituents (Table 2).
pounds exhibited significant variation in their 6/7 ratios,
The N-acyl derivatives, including pTos-Pro [4(1,1,9)], 4- thus proving the expected independence of the R1 group on
methoxybenzoyl [4(1,1,10)] and 4-trifluoromethylbenzoyl the acid stability.
[4(1,1,11)], completely decomposed to enamide 7 when pre-
The synthesis of the N-(2-hydroxyethyl) derivative
pared on the Rink amide resin and cleaved by using 50% 4(6,1,4) deserved further attention because it behaved dif-
TFA in DCM (Table 3). Thus, the acid-labile bridged com- ferently. The LC–MS analysis of the crude Fmoc derivative
pound 6 was synthesized on the Wang ester linker followed 4(6,1,1) revealed the presence of one major product (purity
by cleavage of the protected linear precursor with 0.5 m Ͼ5%) when using the conventional cleavage cocktail of
NaOH in THF/MeOH for 30 min and cyclization by using 50% TFA in DCM. However, the mass spectrum indicated
formic acid in solution. The N-acyl derivatives exhibited the the presence of a species with m/z = 427, which formally
same trend in stability as the N-sulfonyl derivatives: The 4- corresponds to the potential methoxy derivative 13 or 14
methoxy derivative 4(4,1,10) partially decomposed to the (Scheme 4). Attempts to purify and characterize the puta-
enamide, whereas the 4-trifluoromethylbenzoyl compound tive methoxy derivatives and determine their structures
4(4,1,13) was stable under these conditions. The NMR were unsuccessful because the product was unstable and de-
spectra of the N-acyl derivatives indicated the formation of composed. The use of a cleavage cocktail containing 5%
rotamers. The presence of two rotamers is manifested by water in 95% TFA yielded a product with the expected
1
the existence of two singlet lines in the H NMR spectra, molecular ion in the mass spectrum (m/z = 395). Thus, we
corresponding to the Ala methyl protons. We present the continued with the synthesis, prepared the sulfonamide
NMR spectra of the major rotamers in the Supporting In- 4(6,1,4), and cleaved the product by using 5% water in 95%
formation. In addition, the 1H NMR spectra of the N-acyl- TFA. The product was isolated and fully characterized as
ated target compounds show broad, unresolved peaks for the expected bridged compound 6.
both methines at room temperature. Therefore the spectrum
Owing to the instability of the putative N-acyl methoxy
of the derivative 6(4,1,13) was measured at an elevated tem- derivatives 13 and 14, we prepared the simpler N-pTos
perature (50 °C).
Although two strong electron-withdrawing groups (CF3
and NO2) are present on the aromatic ring, the N-aryl de-
rivative 4(3,1,12) yielded only the corresponding enamide 7;
the 1H NMR spectrum revealed the presence of characteris-
tic olefin resonances. The N-alkylated precursors decom-
posed during cleavage from the resin and neither product
could be identified.
To obtain target compounds with three points of diversi-
fication, we introduced methyl as the R2 group into the mo-
lecule and synthesized 4(R1,2,R3) resins with Fmoc-
Scheme 4. Potential products formed by cleavage of the resin-
Thr(tBu)-OH. The presence of the methyl group signifi-
cantly increased the acid stability of bridged scaffold 6,
which was formed almost exclusively, including the N-acyl
and N-aryl derivatives 6(1,2,10), 6(1,2,11), and 6(1,2,12).
The derivative 6(1,2,11) with N-terminal Pro documents the
incorporation of the bridged constraint into a peptide.
Having addressed the effects of the R2 and R3 groups on
the outcome of the reaction, we focused on the importance
of the R1 group on the formation of bicycle 6. We prepared
several R1-derivatized compounds with 4-methoxy-2-ni-
trophenylsulfonyl because this R3 group led to the forma-
tion of both the enamide 7 and bicycle 6 and allowed the
effect of the R1 substituent on the formation of the bicycle
bound compound 4(6,1,1). Reagents and conditions: (i) TES, 50%
TFA in DCM, room temp., 30 min; (ii) 50% TFA in DCM, room
temp., 30 min.
Scheme 5. Alternate cyclization route. Reagents and conditions:
to be assessed. In addition, 4-trifluoromethyl-2-nitrophen- (i) TES, 50% TFA in DCM, room temp., 1 h.
6
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Polymer-Supported Synthesis of Oxadiazabicyclooctanes
for 1 h. The solution was then diluted with water (1 mL) and puri-
fied by semi-preparative reversed-phase HPLC. All products were
characterized by LC–MS, HRMS, and 1H and 13C NMR spec-
troscopy.
model compound 15, for which only one mode of cycliza-
tion[55] was possible (Scheme 5). The synthesis was carried
out on resin 1(6) [R1 = N-(2-hydroxyethyl)]. Cleavage of the
4-Nos group was followed by reaction with pTos-Cl to yield
resin 15. After cleavage from the resin with 50% TFA in
DCM, product 17 was isolated and its structure was con-
firmed by NMR spectroscopy and HRMS.
Supporting Information (see footnote on the first page of this arti-
cle): Materials and methods, product characterization data, 1H and
13C NMR spectra, and crystallographic data.
Acknowledgments
Conclusions
This research was supported by the Department of Chemistry and
Biochemistry, University of Notre Dame, the Grant Agency of the
Czech Republic (GACR) (project number P207/12/0473), the Euro-
pean Social Fund (project number CZ.1.07/2.3.00/20.0009) and the
Ministry of Education, Youth and Sport of the Czech Republic
(project number ME09057). The authors gratefully appreciate the
use of the NMR facility at the University of Notre Dame.
We have developed a polymer-supported, stereoselective
synthesis of the (1S,5S)-6-oxa-3,8-diazabicyclo[3.2.1]octane
bridged scaffold by tandem iminium ion cyclization/nucleo-
philic addition reactions. The 7-methyl derivatives prepared
by using Thr were acid-stable, whereas the Ser-derived com-
pounds suffered a partial acid-mediated transformation
into enamides. Substitution at the iminium-forming nitro-
gen was critical for the acid stability of these target com-
pounds. The N-arylsulfonamide derivatives bearing elec-
tron-withdrawing groups were stable, whereas the N-acyl
derivatives were substantially more acid labile and were pre-
pared by the hydroxide-mediated hydrolysis of their acyclic
precursors from the Wang ester resin followed by cycliza-
tion with formic acid in solution. The synthesized com-
pounds will serve as scaffolds for the construction of com-
pound libraries and as peptide backbone-constrained
peptidomimetics.
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Experimental Section
General: The solid-phase syntheses were carried out in plastic reac-
tion vessels (syringes, each equipped with a porous disc). The vol-
ume of the wash solvent was 10 mL per 1 g of resin. The resin
slurry was washed by shaking with fresh solvent for at least 1 min
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Acid-Mediated Cleavage, Cyclization, and Isolation (6, 7, and 17):
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Route I) or with 95% TFA in water (3 mL, v/v; Route II) for
90 min. The TFA solution was collected, the resin was washed three
times with 50% TFA in DCM (3 mL), and the combined extracts
were evaporated in a stream of nitrogen. The residual material was
analyzed by LC–MS. The products were purified by semi-prepara-
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MS, HRMS, and H and 13C NMR spectroscopy.
Hydrolysis from the Wang Resin, Cyclization, and Isolation
[8(4,R2,R3)]: The resin 4(4,R2,R3) (250 mg) was washed three times
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Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O30093
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Date: 09-04-13 16:50:22
Pages: 9
E. Schütznerová, A. G. Oliver, J. Zajícˇek, V. Krchnˇák
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Published Online: ᭿
8
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Job/Unit: O30093
/KAP1
Date: 09-04-13 16:50:22
Pages: 9
Polymer-Supported Synthesis of Oxadiazabicyclooctanes
Polymer-Supported Synthesis
ˇ
E. Schütznerová, A. G. Oliver, J. Zajícek,
V. Krchnˇák* ...................................... 1–9
Polymer-Supported Stereoselective Syn-
thesis of (1S,5S)-6-Oxa-3,8-diazabicyclo-
[3.2.1]octanes
The title compounds were prepared by tan-
dem iminium ion cyclization/nucleophilic
addition reactions. The scope and limi-
tations of the chemical route leading to the
bridged scaffold were evaluated. The Thr-
derived bridged scaffold is substantially
more stable in acid than the Ser-derived
scaffold, which is partially transformed
into dihydropyrazinones.
Keywords: Peptidomimetics / Heterocycles /
Nucleophilic addition / Solid-phase syn-
thesis / Bicyclic compounds
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