Olefin Cross metathesis based de novo synthesis of a partially protected L-amicetose and a fully protected L-cinerulose derivative

Article abstract of DOI:10.3762/bjoc.10.102

Cross metathesis of a lactate derived allylic alcohol and acrolein is the entry point to a de novo synthesis of 4-benzoate protected L-amicetose and a cinerulose derivative protected at C5 and C1.

Full text of DOI:10.3762/bjoc.10.102

Olefin cross metathesis based de novo synthesis
of a partially protected L-amicetose and
a fully protected L-cinerulose derivative
Bernd Schmidt* and Sylvia Hauke
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1023–1031.
Institut für Chemie, Organische Synthesechemie, Universität
Potsdam, Karl-Liebknecht-Straße 24–25, 14476 Potsdam-Golm,
Germany
doi:10.3762/bjoc.10.102
Received: 20 December 2013
Accepted: 11 April 2014
Published: 06 May 2014
Email:
Bernd Schmidt* - bernd.schmidt@uni-potsdam.de
Associate Editor: V. M. Dong
* Corresponding author
© 2014 Schmidt and Hauke; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
carbohydrates; de novo synthesis; lactate; metathesis; ruthenium
Abstract
Cross metathesis of a lactate derived allylic alcohol and acrolein is the entry point to a de novo synthesis of 4-benzoate protected
L-amicetose and a cinerulose derivative protected at C5 and C1.
Introduction
Many drugs and bioactive natural products are glycoconjugates, kigamicin B, which carries a D-amicetose disaccharide unit, is
which contain an aglycon part linked through glycosidic bonds shown as a representative example. Another antitumor anti-
to one or more oligosaccharide side chains [1]. While it was biotic is aclacinomycin A, which has been used clinically under
assumed for quite some time that the carbohydrate side chain the name aclarubicin. It is an anthracycline [10] bearing a tri-
merely influences the pharmacokinetics, more recent investi- saccharide side chain consisting of L-rhodosamin, 2,6-
gations led to the conclusion that the oligosaccharide moiety didesoxy-L-lyxose, and L-cinerulose attached to the aglycon
contributes essentially to the mechanisms of action, e.g., aclavinon [11,12]. It was found to be a potent antineoplastic
through molecular recognition of a preferred binding site [2-5], agent with particular activity against different forms of
thereby ensuring the selectivity of a chemotherapeutic agent. leukemia [13] (Figure 1).
Particularly common are side chains composed of deoxy-
genated sugars [6]. For example, the kigamicins are bacterial Desoxy-sugars are sometimes scarcely available from natural
secondary metabolites isolated from Amicolatopsis sp. [7,8] and sources and therefore the chemical syntheses of the monosac-
display both antibiotic and cytotoxic activity [9]. They have a charides [6,14] and their assembly to oligosaccharides [15-17]
polycyclic xanthone aglycone in common, which is glyco- has attracted constant attention for many years. For example,
sylated at the C14–OH group. In Figure 1 the structure of D-amicetose has been obtained from other carbohydrates
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Beilstein J. Org. Chem. 2014, 10, 1023–1031.
Figure 1: Structures of kigamicin B and aclacinomycin A as representative examples for antineoplastic glycoconjugates.
through ethanethiolysis and subsequent Ni-catalyzed desulfuriz- alkynols, which yields the glycal of amicetose or its epimer
ation [18,19], by reduction of the corresponding aldonolactone rhodinose, respectively [33]. An approach to amicetose (and a
[20], or by conversion of a protected mannopyranoside into the few other 6-desoxy sugars) involves the formation of an enan-
2,3-unsaturated enopyranoside and subsequent hydrogenation tiopure β,γ-unsaturated δ-valerolactone via ring closing
and reductive 6-deoxygenation [21,22]. Successful de novo metathesis (RCM). The RCM product is subsequently converted
approaches [14] to both enantiomers of amicetose include an into L-amicetose in four steps [34]. Unfortunately, the steps
Achmatowicz rearrangement–hydrogenation sequence, starting determining the configuration at C4 proceed in both cases with
from enantiomerically pure 2-(1-hydroxyethyl)furan [23-25], a virtually no diastereoselectivity, although the resulting epimers
sequence comprising perdeuteration of an alkynoate derived were conveniently separated by chromatography. We have
from L-threonine (giving a 2,2,3,3-tetradeuterated amicetose) recently established two different metathesis based routes to
[26], enantioselective hydroboration of hetero Diels–Alder L-amicetose [35] or L-amicetal [36], respectively, which both
adducts [27], stereoconservative diazotation of L-glutamic acid use enantiomerically pure L-ethyl lactate (1) as the starting ma-
[28,29], diastereoselective addition of methylmagnesium bro- terial (Scheme 1). The synthetic routes rely on the highly
mide to enantiopure 2-benzyloxyhex-5-enal [30], oxidative de- diastereoselective two-step conversion of ethyl lactate to allylic
gradation of aromatics and subsequent lactonization [31], and a alcohol 2 [36,37] and further to the RCM precursor 3, which
two-carbon homologation of an enantiopure C4-building then undergoes RCM-isomerization to L-amicetal 4 [36]. Alter-
block with a metallated sulfone [32]. A combinatorial natively, we have used 2 as a substrate for a cross metathesis
biosynthetic approach to D- and L-amicetose has also recently reaction with methyl acrylate under isomerization-free condi-
been established by combining different sugar biosynthesis tions to furnish enoate 5, which underwent cyclization to the
genes [5].
lactone 6 after hydrogenation. Reduction of 6 with DIBAL-H
eventually yields a protected L-amicetose 7 [35]. To avoid the
Comparatively few transition metal mediated or -catalyzed reac- last step of the sequence, we envisaged a cross metathesis with
tions have hitherto been used for the synthesis of 2,3,6- acroleine, rather than methyl acrylate, to give enal 8 which
tridesoxy sugars such as amicetose. An example is the should undergo spontaneous lactol formation after hydrogena-
W-promoted cycloisomerization of lactaldehyde derived tion and desilylation. However, compared to cross metathesis
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Beilstein J. Org. Chem. 2014, 10, 1023–1031.
Scheme 1: RCM-isomerization approach to L-amicetal 4 and alternative CM approaches to L-amicetose.
reactions with methyl acrylate literature precedence for the use decided to test the phosphine free catalyst B. This and related
of acroleins as CM partner is significantly smaller [38-44].
catalysts [56], comprising a hemilabile ortho-isopropoxy substi-
tuted alkylidene ligand, are particularly suited for cross
In this contribution we report a de novo synthesis of a protected metathesis reactions [57,58]. Indeed, even at ambient tempera-
L-amicetose, using a cross metathesis reaction of allyl alcohol 2 ture and without any rate accelerating additive, a good yield of
with acrolein, and the elaboration of the cross metathesis prod- 86% was obtained (Table 1, entry 4), which could be improved
uct 8 to a fully protected acyclic cinerulose derivative. We are to quantitative by increasing the reaction temperature to 40 °C
aware of only one previous de novo synthesis of DL-cinerulose, (Table 1, entry 5). Reducing the catalyst loading to 2.5 mol % is
which used an Achmatowicz rearrangement of 2-(1-hydroxy- possible, but at the expense of isolated yield of product
ethyl)furan [45].
(Table 1, entry 6). We have previously used the Umicore M51
catalyst (C) [49] for cross metathesis reactions and discovered
that high selectivities and rates of conversion can be accom-
Results and Discussion
The three second generation catalysts A [46], B [47,48] and C plished even with comparatively low catalyst loadings [59,60].
[49,50] were initially tested for the cross metathesis of 2 and For the cross metathesis of 2 and acroleine, C gave signifi-
acrolein (Table 1). We started with the most common catalyst, cantly better yields than A, but was found to be inferior to B
the second generation Grubbs’ catalyst. In order to suppress (Table 1, entries 7–9).
undesired double bond isomerization reactions [51,52] we tried
to avoid high reaction temperatures, which may cause catalyst In the following step we decided to protect the hydroxy group at
decomposition to isomerization active species. This phenom- C4 first to avoid any complications arising from the formation
enon has often been observed for second generation catalysts of a furanose after hydrogenation of the C–C double bond.
[53]. For these reasons, phenol was used as a rate accelerating Benzoyl was chosen as a protecting group, because of its
additive. Phenols are believed to coordinate to the Ru and stabi- UV-activity, its orthogonality to the TBS group at C5–OH and
lize the catalytically active 14-electron species, resulting in a its stability under hydrogenation conditions. Interestingly,
retarded catalyst decomposition [54,55]. In the presence of attempted benzoylation in pyridine resulted exclusively in the
5 mol % of A and 0.5 equiv of phenol, however, the yield of formation of furan 10 (Table 2, entry 1). We reasoned that pyri-
cross metathesis product 8 was very low at ambient tempera- dine initiates an E/Z-isomerization of the enal through nucleo-
ture (Table 1, entry 1). Heating the mixture to reflux in philic attack at the β-position, followed by lactol formation,
dichloromethane resulted in a comparably low yield (Table 1, benzoylation of the lactol and finally elimination of benzoic
entry 2), whereas a significant improvement could be observed acid. Replacing pyridine as a solvent by dichloromethane and
in toluene at 80 °C (Table 1, entry 3). We thought that the yield using NEt(iPr)2 as an HCl-scavenger led indeed to a suppres-
could not be further increased with catalyst A and therefore sion of the formation of furan 10, but the desired benzoate 9
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Beilstein J. Org. Chem. 2014, 10, 1023–1031.
Table 1: Catalyst screening for CM of allyl alcohol 2 and acrolein.
entry
catalyst
cat. loading
additive (equiv)
solvent
T/°C
yield of 8
1a
2a
3
A
A
A
B
B
B
C
C
C
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
2.5 mol %
5 mol %
5 mol %
2.5 mol %
phenol (0.5)
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
25 °C
40 °C
80 °C
25 °C
40 °C
40 °C
40 °C
80 °C
80 °C
25%
20%
68%
86%
99%
76%
65%
80%
65%
phenol (0.5)
phenol (0.5)
4
–
–
–
–
–
–
5
6
7
8
9
aAllylic alcohol 2 was recovered in 21% yield (entry 1) and in 12% yield (entry 2), respectively.
Table 2: C4–OH protection as benzoate.
entry
reagents and conditions
product
yield
1
benzoyl chloride (1.5 equiv), pyridine (0.4 M), 65 °C, 12 h
10
9
47%
<20%
82%
2a
3
benzoyl chloride (2.6 equiv), NEt(iPr)2 (3.0 equiv), CH2Cl2, 40 °C, 12 h
benzoic acid (1.8 equiv), DCC (1.8 equiv), DMAP
(0.1 equiv), CH2Cl2, 20 °C, 12 h
9
aStarting material 8 was recovered in ca. 80% yield.
was obtained in yields lower than 20%, along with ca. 80% of modification [62] of Stryker’s reagent [63], which we had
recovered starting material 8 (Table 2, entry 2). Benzoate 9 was previously used successfully for the conjugate reduction of a
eventually obtained in high yields from benzoic acid using related enoate [35], failed completely in this case and resulted
Steglich’s esterification [61] (Table 2, entry 3).
only in the isolation of unreacted starting material. For these
reasons we resumed to a hydrogenation catalyzed by Pd/C, in
With enal 9 in hands, selective hydrogenation of the C–C spite of the well-known capricious nature of these transforma-
double bond had to be accomplished in the next step. Lipshutz’ tions [64].
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Beilstein J. Org. Chem. 2014, 10, 1023–1031.
With a commercial sample of Pd on charcoal (10 wt %) a The benzoate scrambling was completely suppressed by
plethora of products was detected, four of which could be avoiding highly nucleophilic alkoxide intermediates, which was
isolated and identified as the hydrogenated acetal 11, the methyl achieved with acidic deprotection conditions. Thus, treating the
ether 13, and the two desilylated products 14 and 15 (Table 3, mixture of 11 and 12 with trifluoroacetic acid in
entry 1). Literature precedence exists for the Pd/C-induced dichloromethane at ambient temperature resulted in desilyla-
dealkoxylation of acetals [65] and for desilylation reactions of tion and acetal cleavage, giving 4-benzoyl protected L-amice-
silyl ethers [66]. With in situ generated Pd/C (obtained from tose 16 as an anomeric mixture in 65% yield (Scheme 3).
Pd(OAc)2 and charcoal according to Felpin’s protocol) [67] an
improved selectivity was observed as the cleavage of the silyl With a view towards L-cinerulose, formally the C4-oxidation
groups could be suppressed. However, reductive dealkoxyla- product of L-amicetose, we started from cross metathesis prod-
tion of the acetal remained a problem and the combined yield of uct 8 which was first oxidized using Dess–Martin periodinane
the desired products 11 and 12 was still unsatisfactory (Table 3, [69]. The α,β-unsaturated γ-keto aldehyde 21 was obtained in a
entry 2). This situation changed when we used Pd(OH)2 on very high yield of 90%, and subsequently subjected to hydro-
charcoal (10 wt %) as hydrogenation catalyst, which resulted in genation conditions using a commercial sample of Pd/C
the exclusive formation of acetal 11 and aldehyde 12 in 83% (10 wt %, “batch 1”). We were pleased to find that the expected
combined yield (Table 3, entry 3).
cinerulose derivative 22 could be isolated in analytically pure
form in 85% yield (Scheme 4).
For the deprotection of 11 and 12 a desilylation initiated by
TBAF, followed by acidic hydrolysis was investigated first. To our great dismay, we found that this result could not be
With isolated acetal 11, these conditions induced a scrambling reproduced with a different batch of commercial Pd/C
of the benzoate and led to a mixture of the desired pyranose 16 (10 wt %, “batch 2”), purchased from the same supplier. As can
and the furanose 17. Facile migration of carboxylates upon be seen from Table 4, entry 1, the second batch of Pd/C
TBAF-mediated desilylation of a vicinal alcohol has previously catalyzes under otherwise identical conditions a chemoselective
been observed by us in a different context [68]. We assume that acetalization of the aldehyde, leading to 23 which was isolated
this process starts with a nucleophilic attack of the alkoxylate in 52% yield. A similar result was obtained with Pd(OH)2/C
18 at the ester carbon, giving a five membered intermediate 19 (Table 4, entry 2). In situ formed Pd on charcoal [67], prepared
(Scheme 2).
from 0.5 mol % of Pd(OAc)2 as a precursor, gave an insepa-
Table 3: Hydrogenation of benzoyl protected enal 9.
entry
reagents and conditions
11
12
13
14
15
1
2
Pd/C (10 wt %; 1.6 mol %), H2 (1 bar), methanol, 20 °C, 12 h
31%
28%
–
16%
16%
–
8%
–
Pd(OAc)2 (1 mol %), activated charcoal (9 mol %), H2 (1 bar),
methanol, 20 °C, 12 h
9%
trace
3a
Pd(OH)2/C (10 wt %; 1.2 mol %), H2 (1 bar), methanol, 20 °C, 12 h
51%
32%
–
–
–
aProducts 11 and 12 were obtained as an inseparable mixture, yields are estimated from 1H NMR spectrum.
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Beilstein J. Org. Chem. 2014, 10, 1023–1031.
Scheme 2: Two step desilylation–acetal hydrolysis.
Scheme 3: Deprotection of 11 and 12 to L-amicetose derivative 16.
Scheme 4: Synthesis of a cinerulose-TBS ether 22.
Table 4: Chemoselective acetalization of oxidation product 21.
entry
reagents and conditions
yield of 23
1
2
3
4
Pd/C (“batch 2”, 10 wt %; 2.2 mol %), H2 (1 bar), methanol, 20 °C, 12 h
Pd(OH)2/C (10 wt %; 1,7 mol %), H2 (1 bar), methanol, 20 °C, 12 h
52%
43%
Pd(OAc)2 (0.5 mol %), activated charcoal (9 mol %), H2 (1 bar), methanol, 20 °C, 12 h
Pd(OAc)2 (1.0 mol %), activated charcoal (9 mol %), H2 (1 bar), methanol, 20 °C, 12 h
34%a
82%
aEstimated from 1H NMR spectrum (21 and 23 were obtained as an inseparable mixture in ca. 90% combined yield).
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Beilstein J. Org. Chem. 2014, 10, 1023–1031.
rable mixture of starting material 21 and acetal 23 in a 1.7:1 via this procedure, 1H NMR spectroscopical analysis was
ratio (Table 4, entry 3). By increasing the amount of catalyst possible. The data suggest that cinerulose exists in CDCl3 as a
precursor to 1 mol %, conversion to acetal 23 was complete, 2:1 mixture of acyclic aldose 27 and lactol 28 (Scheme 5).
and this product could be isolated in 82% yield (Table 4, entry
4).
Although the Pd(II)-catalyzed acetalization of aldehydes,
including enals, is known [70], we are not aware of examples
where Pd-catalysts immobilized on charcoal have been used for
this transformation. Most likely the acetalization is catalyzed by
residual Pd2+ via Lewis-acidic carbonyl activation. It is known
that the reduction to Pd(0) is almost never complete, even if
hydrogen is present [71,72].
At this stage we decided to reinvestigate the hydrogenation step,
starting from acetal 23, using fresh samples of catalyst which
have not been used previously for the acetalization (Table 5).
Scheme 5: Deprotection of 24.
With in situ prepared Pd/C (Table 5, entry 1) a major amount of
starting material 23 was recovered and minor quantities of
hydrogenated products 24 and 26, as well as desilylated starting Conclusion
material 25 were detected. With commercial Pd/C (10 wt %, In summary, we showed that an allylic alcohol, available
“batch 2”) (Table 5, entry 2) the starting material was fully diastereoselectively from enantiomerically pure L-lactate in few
consumed and only hydrogenated products 24 and 26 could be steps, is a useful starting material for a metathesis based syn-
detected in a 1:2 ratio, but unfortunately the isolated yields were thesis of protected L-amicetose and L-cinerulose. It undergoes a
only mediocre. As for the hydrogenation of benzoate 9 clean and high yielding cross metathesis reaction with acrolein,
(Table 3), best results were reproducibly obtained with Pd(OH)2 however, the most commonly used second generation Grubbs’
on charcoal (Table 5, entry 3), leading to an isolated yield of catalyst is not the ideal initiator for this particular transforma-
84% of a double protected cinerulose derivative 24.
tion. Significantly better results were obtained with two
different phosphine free catalysts comprising a hemilabile
All attempts to isolate cinerulose were hampered by the high alkoxy substituted benzylidene ligand, even at only moderately
volatility of the product. To accomplish complete deprotection elevated temperatures. The acrolein cross metathesis product
of the precursor, compound 24 was first treated with TBAF can be converted into the 4-benzoate of L-amicetose via
trihydrate in THF, followed by treatment with diluted aqueous benzoylation, Pd-catalyzed hydrogenation and global deprotec-
HCl. Although only small amounts of material were obtained tion, whereas a cinerulose derivative protected at C1 as a
Table 5: Hydrogenation of acetal 23.
entry
reagents and conditions
24
25
26
1a
2
Pd(OAc)2 (1.0 mol %), activated charcoal (9 mol %), H2 (1 bar), methanol, 20 °C, 12 h
Pd/C (10 wt %; 2.2 mol %), H2 (1 bar), methanol, 20 °C, 12 h
7%
16%
n.d.
n.d.
7%
19%
84%
38%
n.d.
3
Pd(OH)2/C (10 wt %; 1.0 mol %), H2 (1 bar), methanol, 20 °C, 12 h
aStarting material 23 (49%) was recovered.
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9. Lu, J.; Kunimoto, S.; Yamazaki, Y.; Kaminishi, M.; Esumi, H.
Cancer Sci. 2004, 95, 547–552.
dimethyl acetal and at C5–OH as a TBS ether becomes avail-
able via Dess–Martin oxidation, Pd-catalyzed acetalization and
Pd-catalyzed hydrogenation. Notably, our results underline once
again that apparently trivial olefin hydrogenation reactions
catalyzed by commercial “Pd/C” can be capricious and very
difficult to reproduce, unless the specific properties of the cata-
lyst used and the conditions for its preparation are documented
by the supplier. Unfortunately, this is very often not the case
and the catalytic activities of apparently identical catalysts
which are often designated just as “10 wt % Pd on carbon” may
vary dramatically.
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