Amino acid motifs in natural products: Synthesis of O-acylated derivatives of (2S,3S)-3-hydroxyleucine

Article abstract of DOI:10.3762/bjoc.10.113

(2S,3S)-3-Hydroxyleucine can be found in an increasing number of bioactive natural products. Within the context of our work regarding the total synthesis of muraymycin nucleoside antibiotics, we have developed a synthetic approach towards (2S,3S)-3- hydroxyleucine building blocks. Application of different protecting group patterns led to building blocks suitable for C- or N-terminal derivatization as well as for solid-phase peptide synthesis. With respect to according motifs occurring in natural products, we have converted these building blocks into 3-O-acylated structures. Utilizing an esterification and cross-metathesis protocol, (2S,3S)-3-hydroxyleucine derivatives were synthesized, thus opening up an excellent approach for the synthesis of bioactive natural products and derivatives thereof for structure activity relationship (SAR) studies.

Full text of DOI:10.3762/bjoc.10.113

Amino acid motifs in natural products: synthesis of
O-acylated derivatives of (2S,3S)-3-hydroxyleucine
Oliver Ries1, Martin Büschleb1, Markus Granitzka2, Dietmar Stalke2
and Christian Ducho*1,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1135–1142.
1Department of Chemistry, Institute of Organic and Biomolecular
Chemistry, Georg-August-University Göttingen, Tammannstr. 2,
37077 Göttingen, Germany, 2Department of Chemistry, Institute of
Inorganic Chemistry, Georg-August-University Göttingen,
Tammannstr. 4, 37077 Göttingen, Germany and 3Department of
Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland
University, Campus C2 3, 66123 Saarbrücken, Germany
doi:10.3762/bjoc.10.113
Received: 16 December 2013
Accepted: 04 April 2014
Published: 16 May 2014
This article is part of the Thematic Series "Natural products in synthesis
and biosynthesis".
Email:
Christian Ducho* - christian.ducho@uni-saarland.de
Guest Editor: J. S. Dickschat
* Corresponding author
© 2014 Ries et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
chiral pool; cross metathesis; esterification; β-hydroxy-α-amino acids;
natural products
Abstract
(2S,3S)-3-Hydroxyleucine can be found in an increasing number of bioactive natural products. Within the context of our work
regarding the total synthesis of muraymycin nucleoside antibiotics, we have developed a synthetic approach towards (2S,3S)-3-
hydroxyleucine building blocks. Application of different protecting group patterns led to building blocks suitable for C- or
N-terminal derivatization as well as for solid-phase peptide synthesis. With respect to according motifs occurring in natural prod-
ucts, we have converted these building blocks into 3-O-acylated structures. Utilizing an esterification and cross-metathesis protocol,
(2S,3S)-3-hydroxyleucine derivatives were synthesized, thus opening up an excellent approach for the synthesis of bioactive natural
products and derivatives thereof for structure activity relationship (SAR) studies.
Introduction
Besides the proteinogenic β-hydroxy-α-amino acids serine and potential acylation site for fatty acid side chains such as in A-
threonine, (2S,3S)-3-hydroxyleucine can be found as a substruc- and B-series muraymycin nucleoside antibiotics (Figure 1)
ture of several bioactive natural products. This structural motif [7-9]. In the case of these muraymycin congeners, acylation of
often serves as a 'three-way-junction', as for instance in the 3-hydroxy position with fatty acid side chains, which are
azinothricin [1], citropeptin [2], kettapeptin [3], pipalamycin ω-functionalized in the A-series, leads to a significant increase
[4], dentigerumycin [5], as monosulfuric acid ester [6] or as in biological activity. While non-acylated muraymycins C1 (1c)
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and D1 (1d) showed a minimal inhibitory concentration (MIC) As part of our synthetic studies on muraymycins and their
value of 1 µg/mL (E. coli), the attached unfunctionalized acyl analogues [19-24], including investigations on the unusual
side chain present in muraymycin B6 (1b) led to an increase of ω-functionalized fatty acid motif found in muraymycin A1 (1a)
potency up to MIC = 0.06 µg/mL, which was therefore nearly [25], we identified the need for a highly stereoselective syn-
as active as the most active naturally occurring muraymycin A1 thesis of (2S,3S)-3-hydroxyleucine and its O-acylated deriva-
(1a, MIC = 0.03 µg/mL). For other bacteria such as S. aureus, tives. Efficient synthetic access to such compounds will enable
the presence of the 3-O-acyl motif can even turn biologically the unprecedented preparation of lipidated muraymycins
inactive C- and D-series muraymycins 1c,d into active deriva- bearing the native linkage of the fatty acid moieties, thus poten-
tives 1a,b of the A- and B-series, respectively (Figure 1) [7]. tially leading to novel congeners with improved biological
This significant change in potency might be owed to increased activity. It will also be useful for the synthesis of other natural
lipophilicity and thus to improved cellular uptake, as products containing this amino acid.
muraymycins inhibit the transmembrane protein MraY (translo-
case I), an enzyme involved in peptidoglycan formation with its Several synthetic approaches towards (2S,3S)-3-hydroxy-
active site located on the cytosolic side of the membrane [10- leucine have been established utilizing for instance diastereo-
14]. For previously reported SAR studies on muraymycins and selective aldol reactions [26-28], Sharpless epoxidation [29],
their analogues, the fatty acid side chain was either neglegted or asymmetric hydrogenation [30] and dynamic kinetic resolution
replaced with a structurally distinct lipophilic mimic [15-17]. [31]. However, in contrast to these routes, we desired to
Mansour and co-workers found a direct relation of the develop a synthesis of O-acylated (2S,3S)-3-hydroxyleucine
lipophilicity of semi-synthetic muraymycin C1 analogues and derivatives which should be easily scalable and would enable
their biological activity [18]. They thus also postulated that the O-acylation after construction of the stereocenters with only
lipid structure might be involved in transporting the molecule to few changes in the protecting group pattern. The most
the active site of the target enzyme. The most recent SAR promising strategy to achieve these goals appeared to be a vari-
investigation on synthetic muraymycin analogues conducted by ation of the ex-chiral pool synthesis developed by Zhu and
Ichikawa et al. also supported the proposal of increased co-workers [32]. They have utilized the stereocenter of D-serine
membrane penetration resulting from the lipophilic moiety [17]. in a diastereoselective Grignard addition to protected D-serinal
However, they employed simple lipophilic amino acids as as the key step of their route. In addition, we also envisaged to
surrogates of the naturally occurring O-acylated (2S,3S)-3- establish a facile strategy to introduce structural diversity in the
hydroxyleucine motif. This led to antibacterially active com- O-acyl moiety, ideally by the late-stage derivatization of an
pounds, but one of it showed a ca. 30-fold reduction of according precursor.
inhibitory potency towards the target enzyme MraY as
compared to non-lipidated muraymycin D2 containing Results and Discussion
L-leucine instead of (2S,3S)-3-hydroxyleucine. This result high- Utilizing the aforementioned synthetic strategy developed by
lighted the significance of the native linkage of the lipophilic Zhu and co-workers [32], we have employed their 7-step syn-
moiety to the muraymycin scaffold.
thesis of a stereoisomerically pure amino alcohol as the key
intermediate. According to the previously reported protocol,
D-serine (2) was transformed into protected derivative 3
(4 steps, 59% overall yield, Scheme 1). Alcohol 3 was then
oxidized to a D-serinal derivative with limited stability, which
was immediately converted into alcohol 4 by diastereoselective
Felkin–Anh type Grignard addition with isopropyl magnesium
chloride (50% yield over 2 steps from 3, dr > 95:5). However,
we could not confirm that the use of diethyl ether as co-solvent
in the Grignard reaction would suppress the reformation of
alcohol 3 as the competing Grignard reduction product, as it had
been claimed by Zhu and co-workers in their initial report [32].
It was therefore decided to attempt the recycling of alcohol 3,
which was obtained in varying amounts, for another round of
oxidation and Grignard addition. The enantiomeric purity of
reisolated 3 was determined by HPLC analysis as its racemiza-
tion can readily occur via silyl migration under the basic reac-
tion conditions (see Supporting Information File 2 for HPLC
Figure 1: Structures of muraymycins A1, B6, C1 and D1 1a–d.
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chromatograms and for the synthesis of the racemic reference). Zhu and co-workers had based their stereochemical assignment
After one oxidation–addition sequence we could isolate 3 with of 5 on the 1H NMR coupling constants of a cyclic derivative of
an enantiomeric purity of er = 99:1. Use of the obtained alcohol this amino alcohol. We were able to confirm the postulated
in a second oxidation–addition sequence followed by subse- stereochemical outcome of the Grignard addition by X-ray
quent HPLC analysis of reduction product 3 demonstrated a crystallography as (2R,3S) for the amino alcohol and thus, due
decrease in enantiomeric purity to er = 78:22 though. On the to altered priorities, (2S,3S) for the corresponding amino acid,
basis of these results, we desisted from the use of this alcohol in respectively. The absolute configuration was deduced assuming
a third oxidation–addition cycle. It was concluded that the recy- the integrity of the stereocenter at the 2-position, which had
cling of the Grignard reduction product is in principle feasible, been derived from D-serine (2). As neither 4 nor 5 gave crys-
but that one should always check its enantiomeric purity prior to tals suitable for X-ray analysis, the 3-hydroxy group of 4 was
a repetition of the oxidation–addition sequence. Finally, the acylated with levulinic acid, leading to ester 6 in 82% yield
previously reported hydrogenolytic debenzylation of 4 [32] (Scheme 1) which crystallized upon removal of residual solvent
provided amino alcohol key intermediate 5 in quantitative yield under reduced pressure. Hence, a single crystal of 6 was
for the deprotection step and in 29% overall yield over 7 steps obtained, and X-ray crystal structure analysis unambiguously
from D-serine (2, Scheme 1). It should be noted that Garner's confirmed the relative configuration (Figure 2; see Supporting
aldehyde is often used instead of acyclic D-serinal derivatives Information File 1 for crystallographic data). Levulinyl ester 6
for the addition of nucleophiles to amino acid-derived alde- crystallizes in the orthorhombic space group P212121 with one
hydes [33,34]. However, Zhu and co-workers have pointed out molecule in the asymmetric unit. The Flack parameter [35]
that Garner’s aldehyde surprisingly furnishes the syn diastereo- refined to x = −0.05(8) and confirmes the stereocenters to have
mer as the major product from its reaction with isopropyl the proposed (2R,3S)-configuration.
magnesium chloride [32], thus discouraging its use for the
preparation of anti-configured (2S,3S)-3-hydroxyleucine.
Figure 2: Molecular structure of levulinyl ester 6. Anisotropic displace-
ment parameters are depicted at the 50% probability level. Atom color
code: carbon = black, oxygen = red, nitrogen = blue, silicon = grey,
and hydrogen = white. The other hydrogen atoms are omitted for
clarity.
In their synthesis of (2S,3S)-3-hydroxyleucine, Zhu and
co-workers cyclized amino alcohol 5 towards an oxazolidinone,
with the carbonyl group simultaneously providing O- and
N-protection [32]. Removal of this protecting group required
harsh reaction conditions though (conc. HCl, reflux, 40 h) and
yielded the unprotected amino acid as the hydrochloric salt.
However, in the case of our envisaged synthesis of 3-hydroxy-
leucine building blocks suitable for further derivatization as
well as incorporation into natural products and their analogues,
Scheme 1: Synthesis of stereoisomerically pure amino alcohol 5 [32]
and of derivative 6 suitable for X-ray crystallography.
we were in need for a more versatile protecting group pattern.
We therefore investigated different carbamates as protecting
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groups for the amino functionality, leading to the secondary
alcohol functionality being selectively accessible for further
conversions. We discovered that we were in need for a
protecting group reducing the basic character of the amino
group as an oxidation of the silyl-deprotected amino alcohol to
the corresponding acid was not possible, probably due to the
basicity of the amino group (reactions not displayed).
For the synthesis of a C-protected building block, 5 was
converted with Boc anhydride to yield Boc-protected amino
alcohol 7 in 79% yield (Scheme 2). After removal of the silyl
group, a selective oxidation of the primary alcohol in presence
of the unprotected 3-hydroxy group unfortunately could not be
achieved (reactions not displayed). It was therefore decided to
introduce an N,O-acetal moiety by transformation of 7 into the
dimethyloxazolidine 8, a reaction which required careful opti-
mization though (Scheme 2, Table 1). Using boron trifluoride
and 2,2-dimethoxypropane (2,2-DiMP), as known from the syn-
thesis of the structurally related Garner's aldehyde [33,34], led
to an unwanted cleavage of the silyl ether and furnished a mix-
ture of the desired product 8, the TBDMS cleavage product 9
and the corresponding O,O-acetal 10 (Table 1, entry 1). Hence,
further reaction conditions using different acid catalysts and
solvents were investigated. Changing the catalyst to pyridinium
p-toluenesulfonate (PPTS) only led to small amounts of the pro-
duct after prolonged reaction times and could not suppress the
formation of the O,O-acetal (Table 1, entries 2 and 3). The use
of racemic camphorsulfonic acid (CSA) in toluene and acetone,
respectively, resulted in the formation of 8 in moderate to good
yields (Table 1, entries 4–6). Finally, when 2,2-DiMP was used
as solvent with catalytic amounts of CSA in the presence of
magnesium sulfate, 8 could be isolated in a very good yield of
93% (Table 1, entry 7). After TBAF-mediated cleavage of the
silyl ether, the resultant primary alcohol 9 (obtained in 80%
Scheme 2: Synthesis of (2S,3S)-3-hydroxyleucine building blocks
13a,b useful for N-derivatization and of the protected muraymycin
tripeptide unit 15a,b.
Table 1: Optimization of the reaction of 7 to dimethyloxazolidine 8.
Entry
Reaction conditions
Yield [%] (compound)
1
2
3
4
5
6
7
9 equiv 2,2-DiMP, 0.1 equiv BF3·Et2O, acetone, rt, 23 h
9 equiv 2,2-DiMP, 0.1 equiv PPTS, acetone, rt, 4 d
19 (8), 19 (9), 30 (10)a
76 (7), 21 (8)
mixture (8)/(9)b, 9 (10)
79 (8)
10 equiv 2,2-DiMP, 0.3 equiv PPTS, THF, rt, 17 h
26 equiv 2,2-DiMPc, 0.02 equiv CSA, MS 3 Å, toluene, 80 °C, 17 h
20 equiv 2,2-DiMPd, 0.02 equiv CSA, MS 3 Å, toluene, 80 °C, 15 h
30 equiv 2,2-DiMP, 0.03 equiv CSA, acetone, reflux, 16 h
0.15 equiv CSA, MgSO4, 2,2-DiMP, 50 °C, 24 h
74 (7), 20 (8)
60 (8)
93 (8)
a10:
bnot separated; c2,2-dimethoxypropane (2,2-DiMP) was added in two portions; d2,2-DiMP was added at once.
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yield) was oxidized to carboxylic acid 11 by ruthenium(III)- the silyl ether (product 18, 95% yield) and oxidation of the pri-
catalyzed periodate oxidation in 82% yield. Subsequent protec- mary alcohol to carboxylic acid 19 in 65% yield (49% over 3
tion of the acid functionality furnished 2-(trimethylsilyl)ethyl steps from 17). The potential of 19 to serve as a universal
(TMSE) and benzyl esters 12a and 12b (yields 72% and 84%, building block for C-terminal derivatization was demonstrated
respectively). Finally, acidic deprotection afforded the desired by the following transformations. Acid 19 was reacted with 1,1-
building blocks 13a,b suitable for N-derivatization, with the diethoxy-3-aminopropane (20) under standard EDC/HOBt
compounds not being fully purified. In order to demonstrate the coupling conditions to afford amide 21 in 77% yield, followed
synthetic versatility of these 3-hydroxyleucine derivatives, they by concomitant acidic cleavage of the N,O- and O,O-acetal
were coupled with urea dipeptide 14 [36], thus providing protecting groups leading to building block 22 in 89% yield
protected derivatives 15a,b of the full-length peptide unit of (Scheme 3). Aldehyde 22 can be used for the connection of the
C-series muraymycins in yields of 51% and 88%, respectively, (2S,3S)-3-hydroxyleucine motif of C-series muraymycins (such
over 2 steps from 12a,b. It is expected that 15a,b can serve as as muraymycin C1 (1c), Figure 1) to the nucleoside moiety by
useful building blocks in the total synthesis of muraymycins reductive amination (reactions not displayed), as demonstrated
and their analogues.
before in our syntheses of simplified muraymycin analogues
[21,22].
Following the synthesis of building blocks 13a,b suitable for
N-derivatization, it was also desired to obtain (2S,3S)-3- N-Cbz-protected acid 19 was also used for a methodical study
hydroxyleucine derivatives suitable for C-terminal coupling regarding the acylation of the 3-hydroxy group. Therefore, 19
reactions. We therefore chose a Cbz group as amino protecting was converted into benzyl ester 23 (70% yield) followed by
group. Treatment of amino alcohol 5 with Cbz chloride acidic cleavage of the acetonide to yield building block 24 in
furnished protected derivative 16 in 74% yield (Scheme 3). In 71% yield (Scheme 4). Acylation reactions were carried out
analogy to the aforementioned synthetic route, 16 was then with DIC as coupling reagent and catalytic amounts of DMAP.
cyclized with 2,2-DiMP to the corresponding dimethyloxazoli- Based on this protocol, esterification reactions with octanoic
dine 17 (79% yield), followed by TBAF-mediated cleavage of acid (25) and 6-methylheptanoic acid (26, vide infra) yielded
the acylated (2S,3S)-3-hydroxyleucine derivatives 27 and 28 in
63% and 94% yield, respectively. The latter compound might
Scheme 3: Synthesis of (2S,3S)-3-hydroxyleucine building block 19
useful for C-derivatization and of aldehyde 22, a synthetic building
block for C-series muraymycins.
Scheme 4: Synthesis of O-acylated (2S,3S)-3-hydroxyleucine deriva-
tives 27 and 28.
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serve as a building block for the synthesis of muraymycin B6 conditions, e.g., by olefin cross metathesis. Therefore, amino
(1b) and also muraymycin B7 (as well as derivatives thereof) as alcohol 5 was Fmoc-protected (product 34, 84% yield), fol-
the 6-methylheptanoyl moiety is a constituent of these natural lowed by esterification of the 3-hydroxy group with acryloyl
products. It represents the first example of a synthetically chloride (35), thus furnishing acrylate 36 in 94% yield
obtained O-acylated 3-hydroxyleucine moiety of a naturally (Scheme 6). After acidic cleavage of the silyl ether in 93% yield
occurring muraymycin.
[40], the resultant primary alcohol 37 was oxidized using
catalytic amounts of TEMPO and trichlorocyanuric acid
The preparation of O-acylated derivative 28 required the syn- (TCCA) as stoichiometric oxidant to provide (2S,3S)-3-
thesis of 6-methylheptanoic acid (26) though. This branched hydroxyleucine derivative 38, a potential building block for
carboxylic acid was obtained starting from commercially avail- SPPS and post-synthetic modification of the peptide, in 85%
able 4-methylpentanoic acid (29, Scheme 5). Esterification with yield.
methanol (product 30, 99% yield) and reduction of the ester
with lithium borohydride afforded primary alcohol 31 in 68%
yield. A direct reduction of acid 29 with lithium aluminum
hydride was also investigated, but resulted in a moderate yield
of 32% only (reaction not displayed). One-pot Swern oxidation
to the corresponding aldehyde and subsequent Wittig reaction
with stabilized Wittig reagent 32 led to α,β-unsaturated ester 33
in 85% yield. After simultaneous reduction of the double bond
and cleavage of the benzyl ester by catalytic hydrogenation,
6-methylheptanoic acid (26) could be obtained in 92% yield for
the final step (Scheme 5).
Scheme 5: Synthesis of 6-methylheptanoic acid (26).
Scheme 6: Synthesis of Fmoc-protected building blocks 38 and 41
suitable for SPPS, with late-stage side chain diversification by olefin
metathesis.
With respect to the (2S,3S)-3-hydroxyleucine motif occurring in
several different peptidic natural products (vide supra), we also
investigated the synthesis of N-Fmoc-protected building blocks
In order to demonstrate the feasibility of the olefin cross
metathesis approach for the late-stage diversification of the acyl
side chain, acid 38 was transformed into benzyl ester 39 in 97%
yield (Scheme 6). Subsequent treatment with commercially
available 1-octene and Grubbs 2nd generation catalyst [41]
afforded lipidated (2S,3S)-3-hydroxyleucine derivative 40 in
63% yield without any observed homo-coupling of the amino
potentially suitable for solid-phase peptide synthesis (SPPS). It
is well established that O-acylated β-hydroxy-α-amino acids can
be used in Fmoc-strategy peptide syntheses without migration
of the acyl unit [37-39]. Based on these findings, we have
desired to develop a method for the modification of the acyl
side chain of a previously incorporated O-acylated β-hydroxy-
α-amino acid building block at a very late stage and under mild
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acid. Amino acid 40 was then debenzylated under standard Acknowledgements
hydrogenation conditions with concomitant reduction of the O. R., M. B. and C. D. thank the Deutsche Forschungsgemein-
double bond, thus leading to lipidated amino acid building schaft (DFG, SFB 803 "Functionality controlled by organiza-
block 41 suitable for SPPS in 75% yield for the final step. tion in and between membranes") and the Fonds der Chemis-
chen Industrie (FCI, Sachkostenzuschuss) for financial support.
Conclusion
M. G. and D. S. thank the Danish National Research Founda-
In summary, we have developed a divergent approach for the tion (DNRF)-funded Center for Materials Crystallography
synthesis of several (2S,3S)-3-hydroxyleucine building blocks (CMC).
employing stereoisomerically pure amino alcohol 5 [32].
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