2-Phenyl-tetrahydropyrimidine-4(1H)-ones - Cyclic benzaldehyde aminals as precursors for functionalised β2-amino acids

Article abstract of DOI:10.3762/bjoc.5.43

Novel procedures have been developed to condense benzaldehyde effectively with β-amino acid amides to cyclic benzyl aminals. Double carbamate protection of the heterocycle resulted in fully protected chiral β-alanine derivatives. These serve as universal precursors for the asymmetric synthesis of functionalised β2-amino acids containing acid-labile protected side chains. Diastereoselective alkylation of the tetrahydropyrimidinone is followed by a chemoselective two step degradation of the heterocycle to release the free β2-amino acid. In the course of this study, an L-asparagine derivative was condensed with benzaldehyde and subsequently converted to orthogonally protected (R)-β2-homoaspartate.

Full text of DOI:10.3762/bjoc.5.43

2-Phenyl-tetrahydropyrimidine-4(1H)-ones – cyclic
benzaldehyde aminals as precursors for
functionalised β2-amino acids
Markus Nahrwold1, Arvydas Stončius1, Anna Penner1, Beate Neumann2,
Hans-Georg Stammler2 and Norbert Sewald*,1
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 43.
1Bielefeld University, Department of Chemistry, Organic and
Bioorganic Chemistry, Universitätsstr. 25, 33615 Bielefeld, Germany
and 2Bielefeld University, Department of Chemistry, Inorganic
Chemistry, Universitätsstr. 25, 33615 Bielefeld, Germany
doi:10.3762/bjoc.5.43
Received: 25 June 2009
Accepted: 28 August 2009
Published: 14 September 2009
Email:
Norbert Sewald* - norbert.sewald@uni-bielefeld.de
Editor-in-Chief: J. Clayden
* Corresponding author
© 2009 Nahrwold et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
β2-amino acids; cyclocondensation; diastereoselective alkylation;
N,N-acetals; peptidomimetics; ring opening; self-regeneration of
stereocentres (SRS)
Abstract
Novel procedures have been developed to condense benzaldehyde effectively with β-amino acid amides to cyclic benzyl aminals.
Double carbamate protection of the heterocycle resulted in fully protected chiral β-alanine derivatives. These serve as universal
precursors for the asymmetric synthesis of functionalised β2-amino acids containing acid-labile protected side chains. Diastereose-
lective alkylation of the tetrahydropyrimidinone is followed by a chemoselective two step degradation of the heterocycle to release
the free β2-amino acid. In the course of this study, an L-asparagine derivative was condensed with benzaldehyde and subsequently
converted to orthogonally protected (R)-β2-homoaspartate.
Introduction
Monosubstituted β-amino carboxylic acids can be classified both in vitro [4,5] and in vivo [6]. As a first biologically active
according to their substitution pattern into α-substituted “β2- example, the β-tetrapeptide Ac-β3hThr-β2hLys-β3hTrp-β3hPhe-
amino acids” and β-substituted “β3-amino acids” [1]. Oligomers NH2 was found to bind to a human somatostatin receptor with
of these β-amino acids are called “β-peptides” and tend to form nanomolar affinity [7-9]. Despite their interesting properties,
distinct and stable secondary structures even at a very short β2-amino acids in particular occur only rarely in nature. Several
chain lengths [2,3]. β-Peptides are metabolically stable peptido- peptidic natural products contain 3-amino-2-methylpropionic
mimetics that have proved to be inert to enzymatic proteolysis acid (β2-homoalanine) as a building block [10]. Examples are
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Beilstein Journal of Organic Chemistry 2009, 5, No. 43.
cryptophycin-1 (a highly cytotoxic depsipeptide produced by resulting olefinic double bond [25-27,31,34,35], and final N,N′-
cyanobacteria Nostoc sp. GSV224 and ATCC53789) [11-14] as protection. Compound 2 proved to be a versatile β2- and β2,2-
well as a class of lipopeptides isolated from various fungi, amino acid precursor. Monoalkylation of 2 takes place in high
comprising topostatin (a topoisomerase I and II inhibitor) [15], yields and with high trans-selectivity. Inversion of the intro-
YM-170320 (an inhibitor of ergosterol biosynthesis) [16], and duced stereogenic centre via diastereoselective protonation [34]
fusaristatins A and B [17].
as well as α,α-dialkylation [36] both proceed smoothly.
However, complete hydrolysis of the alkylated N,N-acetal
β3-Homoamino acids can be synthesised by Arndt–Eistert requires refluxing in concentrated aqueous mineral acid. There-
homologation of the corresponding proteinogenic α-amino acids fore, precursor 2 can only be applied for the synthesis of target
[18-20]. Contrary to that, no procedure is known yet to enantio- compounds without acid labile functional groups. Seebach et al.
specifically convert α-amino acids into their partly circumvented this problem by cleaving α-alkylated imino
β2-homologues – although this goal has been achieved diaste- esters of tetrahydropyrimidine-4-ones to corresponding
reoselectively under auxiliary control [21,22]. A vast number of β2-amino acid methyl esters under markedly milder acidic
synthetic approaches to β2-(homo)amino acids have been conditions [37].
developed so far, but the majority of these procedures are
limited to α-alkyl substituted β2-amino acids – mostly due to Nevertheless, a derivative of 2 being cleavable under neutral or
harsh conditions of auxiliary cleavage or limited substrate toler- slightly basic conditions was still unknown. Such a precursor
ance [10,23,24]. Diastereoselective total synthesis starting from would allow the synthesis of β2-amino acids containing e.g.
N-acylated Evans’ type auxiliaries turned out to be the only tert-butyl protected side chain functions. Amino acids protected
universal route to β2-analogues of the 20 most common like that are particularly suitable for solid phase peptide
proteinogenic α-amino acids. (For a recent overview on synthesis and are thus highly desirable. Our novel ring cleavage
β2-amino acid syntheses see ref. [23].)
concept includes the protection of both ring-nitrogen atoms as
carbamates (Scheme 1C). Similar to the cleavage conditions of
The tetrahydropyrimidine-4(H)-one 2 developed by Juaristi et Evans’ auxiliaries (Scheme 1B) [38], the tetrahy-
al. [25,26] and Konopelski et al. [27,28] represents a chiral dropyrimidinone ring could now be regioselectively opened by
cyclic β-alanine derivative that serves as a straightforward treatment with lithiumhydroperoxide. If the original C2-tert-
β2-amino acid precursor (Scheme 1A). Following the principle butyl function was additionally substituted by a phenyl group
of self regeneration of stereogenic centres (SRS) proposed by through replacement of pivalaldehyde by benzaldehyde, this
Seebach [29], condensation of L-asparagine and pivalaldehyde structural modification would facilitate a final release of the
yields N,N′-acetal 1, which is converted to 2 by subsequent β2-amino acid by hydrogenolysis of all remaining benzyl-type
oxidative decarboxylation [25,28,30-33], hydrogenation of the N-protective groups.
Scheme 1: Selectively cleavable β2-amino acid precursors: Structures and reactivities of 2-tert-butyl-tetrahydropyrimidine-4(1H)-ones (A), N-acylated
Evans auxiliaries (B), and novel Cbz-protected 2-phenyl-tetrahydropyrimidine-4(1H)-ones (C).
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Beilstein Journal of Organic Chemistry 2009, 5, No. 43.
Results and Discussion
Cyclocondensation of benzaldehyde and β-amino acid amides
to 2-phenyl-tetrahydropyrimidine-4(1H)-ones is problematic,
since acyclic resonance stabilised Schiff bases are preferen-
tially formed. Consequently, one pot cyclisation protocols
employing conditions such as KOH in protic solvents deliver
the desired six-membered ring only in unsatisfactory yields [30,
39]. An alternative approach to cyclise benzaldehyde-derived
imines consists of a 4-DMAP catalysed N-acylation reaction
with acyl chlorides and usually affords the target compounds in
moderate yields [39,40].
Scheme 3: Protection and deprotection of 4. a) Boc2O, DMAP,
CH3CN, 16 h, rt; b) 1. n-BuLi, THF, −78 °C, 30 min; 2. Cbz-Cl, rt, 16 h;
c) H2, 10% Pd/C, abs. THF, 4 h, rt.
We chose Nα-Cbz-protected β-alanine amide (3) as starting
material for the synthesis of the 2-phenyltetrahydropyrimidine-
4(1H)-one rac-4 to circumvent the difficulty of cyclising stabil-
ised benzyl imines. Cyclocondensation was successfully carried In contrast to the reported separation of racemic 2-tert-butyl-
out under two different reaction conditions (Scheme 2). On the tetrahydropyrimidine-4(H)-ones [37], attempts to resolve
one hand, 3 was reacted with benzaldehyde or with the corres- 2-phenyl-tetrahydropyrimidine-4(1H)-ones rac-4 and rac-5 via
ponding dimethylacetal in refluxing toluene in the presence of a HPLC on chiral phases (Chiralcel OD®, Chiralpak AD®,
catalytic amount of p-TsOH. The water or methanol formed elution with i-PrOH/hexane) were not successful. Interestingly,
during condensation was distilled azeotropically from the reac- the N1-Cbz-protective group of 4 can be chemoselectively
tion mixture. An even more effective method turned out to be cleaved by carefully monitored hydrogenolysis on 10% Pd/C in
the BF3·Et2O-mediated condensation of 3 with benzaldehyde or dry THF solution. The pure fully deprotected tetrahy-
benzaldehyde dimethylacetal. Since the Lewis acid serves both dropyrimidinone rac-7 was obtained after recrystallisation from
as activating agent and as irreversible water/methanol trapping ethyl acetate. Although 7 proved to be stable under inert gas
agent, two equivalents of it are necessary to drive the reaction to atmosphere, prolonged contact to air moisture results in slow
completion. The 2-phenyl-tetrahydropyrimidine-4-one rac-4 hydrolysis of the aminal. Attempts to obtain diastereomeric
obtained by either of the two methods can be purified by crys- salts of 7 failed. This result corresponds well to the finding that
tallisation or chromatography. Compound 4 proved to be stable salts of N1-uncapped tetrahydropyrimidinones are generally
to air moisture at room temperature. Despite the success in unstable [34] – unlike the stable salts of five membered
condensing 3 and benzaldehyde (dimethylacetal), all attempts to imidazolidinone rings [42].
condense 3 with closely related acetophenone dimethylketal did
not lead to any cyclisation product.
Finally, enantiopure 2-phenyltetrahydropyrimidine-4(1H)-ones
were successfully synthesised via a chiral pool approach by
condensing Cbz-L-Asn-OAll (8) with benzaldehyde
dimethylacetal (Scheme 4). Compared to the respective cyclisa-
tion reaction starting from 3, complete conversion of 8 required
a larger excess of BF3·Et2O, most probably due to the larger
number of Lewis basic functions present in the starting material.
Starting at −30 °C, the temperature of the reaction mixture had
to be raised to −15 °C to enhance the solubility of the starting
material as well as to increase the otherwise very low reaction
rate. Cyclocondensation afforded the trans-configured major
product (2R,6S)-9 and the cis-configured minor diastereomer
Scheme 2: Cyclocondensation of Cbz-βAla-NH2 (3) and benzalde-
hyde. a) [p-TsOH], toluene, reflux, Dean–Stark trap, 3 h; b) BF3·Et2O
(2.0 equiv), CH2Cl2, rt, 16 h.
To facilitate our selective ring opening concept, the N3-nitrogen (2S,6S)-9 in a ratio of 64 : 36 (28% de). Both compounds were
of 4 had to be protected as a carbamate. While the introduction obtained as colourless thick oils after separation by column
of a Boc-protecting group was straightforwardly carried out chromatography. Since the cyclisation reaction was carried out
under mild conditions by reaction of 4 with Boc2O/DMAP in under kinetic control, its moderate trans-selectivity contrasts to
acetonitrile [41], comparative Cbz-protection required more the high cis-selectivity observed for the thermodynamically
drastic conditions, i.e. deprotonation of 4 with n-BuLi and controlled cyclocondensation of potassium asparaginate and
subsequent reaction with Cbz-Cl (Scheme 3).
aliphatic aldehydes [25,27,28,31,34,35].
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Beilstein Journal of Organic Chemistry 2009, 5, No. 43.
Scheme 4: Synthesis of enantiopure 2-phenyl-tetrahydropyrimidine-4(1H)-ones. a) PhCH(OMe)2, BF3·Et2O (6.0 equiv), CH2Cl2, −30 °C → −15 °C,
16 h; b) 1. [Pd(PPh3)4], morpholine, THF, rt, 1 h; 2. DIB, I2, CH2Cl2, rt, 4 h, then BF3·Et2O, rt, 1 h; c) Ni(OAc)2·4H2O/NaBH4, MeOH/THF, 0 °C,
10 min; d) Boc2O, DMAP, CH3CN, 16 h, rt.
En route to the target compound (R)-4, the allyl ester (2R,6S)-9 serves as a highly active hydrogenation catalyst, whereas an
was cleaved in a Pd(0)-catalysed reaction [43]. In accordance excess of NaBH4 serves as hydrogen source [45,46]. The reac-
with a literature procedure, the intermediate carboxylic acid was tion reaches completion within ten minutes at 0 °C – virtually
directly subjected to an oxidative decarboxylation [30]. The without formation of by-products. A similar procedure has
iodoalkene 10 was obtained by reaction of the free carboxylic formerly been employed by Bella et al. for the reduction of
acid with diacetoxyiodosobenzene (DIB) in the presence of α-halogenated, α,β-unsaturated lactones [47].
iodine and BF3·Et2O. The absolute configuration of the highly
crystalline compound 10 was determined in the course of an The racemic fully protected heterocycle rac-5 as well as the
X-ray analysis [44]. The six-membered heterocycle of 10 shows enantiopure compound (S)-5 derived from (R)-4 were both used
a flattened boat- to envelope-like conformation. Five of the six a starting materials for diastereoselective alkylation experi-
ring atoms are almost coplanar while the C2-atom and the ments. Attempts to enolise 5 at −78 °C by reaction with
pseudoaxial C2-phenyl group are situated above the plane NaHMDS or LiHMDS, followed by addition of benzyl bromide
(Figure 1).
did not lead to any alkylation product. Instead, the starting
material was re-isolated. Addition of sodium iodide to the reac-
tion mixture for an in situ conversion of the alkyl bromide to the
alkyl iodide [48] did not increase reactivity. The alkylation
reaction started to proceed only after warming the lithium
enolate solution to −55 °C, but still remained incomplete after
20 h reaction time. By adding DMPU as co-solvent [49], the
alkylation was typically complete within 16 h at −55 °C. The
alkylation products 11a-d were obtained in good yields and
with high diastereomeric excesses around 90% (see Scheme 5).
However, none of the diastereomeric mixtures was separable by
column chromatography on silica gel. Although in general no
α,α-dialkylation products were detected by ESI-mass spectro-
metry, HPLC-analysis of 11d revealed the existence of a less
polar by-product (see Supporting Information File 1), which
Figure 1: X-ray crystal structure of 10 [44].
In order to convert the iodinated dihydropyrimidinone 10 into
the fully saturated tetrahydropyrimidinone (R)-4, selective
hydrodehalogenation and reduction of the double bond had to
be accomplished. Chemoselective reduction of 10 was carried
out by reaction with sodium borohydride in the presence of
Ni(OAc)2. The “nickel boride” formed as black precipitate
Scheme 5: Diastereoselective alkylation of 5.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 43.
could probably be explained by additional side chain alkylation may nevertheless account for the decrease in reactivity and
of 11d.
diastereoselectivity being observed for alkylations of 5
compared to alkylations of 2.
Interestingly, alkylation of 5 turned out to be syn-selective,
whereas literature known alkylations of the closely related
compound 2 selectively afford anti-configured alkylation
products [25,26,35]. First hints at the stereochemical outcome
of the alkylation reaction were deduced by comparing 1H NMR
spectra of compounds 11a-d with those of literature known
N3-methylated alkylation products 12 and 14 (Figure 2) [36].
Overall, chemical shifts and coupling constants are quite similar
for both types of compounds, indicating an analogous ring
conformation in CDCl3 solution. In case of 11d, 3J-coupling
constants within the ABX-system of the three protons at C5 and
C6 parallel those of the syn-configured compound cis-12, but
not those of the anti-configured compound trans-12 [36]. The
high value of the 3JAX-coupling constant of around 10 Hz does
not significantly change after removing the N3-Boc-protective
group, as exemplified by compounds 11b/13.
Figure 3: Supposed enolate conformations.
The decisive influence of N-acyl substituents within cyclic five- To release the tert-butyl protected β2-homoaspartate, its
and six-membered N,N-and N,O-acetals on the stereochemical precursor 11d was regioselectively degraded in a two step
course of alkylations and ring closure reactions is a long known procedure (Scheme 6). Treatment of 11d with LiOH/H2O2 in
and frequently observed phenomenon (for an overview, see ref. THF/H2O afforded the ring opening product 15. Although 15
[50]). The at first sight surprising differences in stereochemical can be purified by column chromatography, it turned out to be
outcome of alkylations of 2 and 5 could be explained by only moderately stable and slowly degraded to Cbz-(R)-
comparing their proposed enolate conformations (see Figure 3). β2hAsp(Ot-Bu)-OH, benzaldehyde and tert-butyl carbamate
In case of 2-Li, the pseudo-axial C2-tert-butyl function effect- upon prolonged exposure to air moisture. Therefore, unpurified
ively shields one diastereotopic face, thereby enforcing an elec- 15 was directly converted to the free amino acid by means of
trophilic attack at the opposite side of the ring [26]. In contrast hydrogenation. Subsequent Fmoc-protection afforded the ortho-
to that, the sterically less demanding C2-phenyl group within gonally protected target compound Fmoc-(R)-β2hAsp(Ot-Bu)-
5-Li does not completely shield its diastereotopic half room. OH (16). The specific rotation of the (R)-configured compound
Instead, the opposite face is more efficiently shielded by the 16 in CHCl3 showed a value of −1.2, whereas Seebach et al.
two bulky N1- and N3-urethanes. This hypothesis is supported report a value of +1.4 for the corresponding (S)-enantiomer
by the fact that alkylation of the N3-Cbz-protected heterocycle [51]. Thus, the determined optical activity of 16 corresponds
rac-6 resulted in a decreased diastereoselectivity compared to well to its expected enantiomeric excess of 89% and doubt-
reactions of the N3-Boc-protected compound 5 (results not lessly confirms the anticipated stereochemistry of the alkyla-
shown here). The steric hindrance caused by the C2-phenyl ring tion reaction.
Figure 2: Comparison of coupling constants (C5–C6-ABX system) within the 1H-NMR spectra of literature known compounds trans-12 and cis-12 (A)
[36] to those of alkylation products 11a–d and 13 (B).
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Beilstein Journal of Organic Chemistry 2009, 5, No. 43.
Scheme 6: Selective ring opening of the heterocycle 11d and isolation of orthogonally protected β2-homoaspartate 16. a) LiOH/H2O2, THF/H2O, 0 °C
→ rt, 5 h, then aq. Na2SO3, 20 min; b) H2, 10% Pd/C, MeOH, rt, 16 h; c) FmocOSu, NaHCO3, acetone/H2O, rt, 4 h.
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