A stereoselective and flexible synthesis to access both enantiomers of N-acetylgalactosamine and peracetylated N-acetylidosamine

Article abstract of DOI:10.3762/bjoc.14.71

Synthetic approaches towards N-acetylgalactosamine (GalNAc) have been attracting considerable interest since this compound is known for its pivotal role in cell-cell interaction and receptor induced cell signaling. Herein, we present a synthetic route in which two of the four stereogenic centers present in the target compound are derived from enantiopure tartaric acid being selectively converted to epoxy alcohols. The key step is the Pd-catalyzed, stereo- and regioselective epoxide opening and subsequent nucleophilic substitution of an azide functionality. This approach enables the synthesis of the naturally D- and unnaturally L-configured GalNAc, as well as both enantiomers of the largely unknown N-acetylidosamine (IdoNAc).

Full text of DOI:10.3762/bjoc.14.71

A stereoselective and flexible synthesis to access both
enantiomers of N-acetylgalactosamine and
peracetylated N-acetylidosamine
Bettina Riedl* and Walther Schmid
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 856–860.
University of Vienna, Institute of Organic Chemistry, Währinger Straße
doi:10.3762/bjoc.14.71
38, A-1090 Vienna, Austria
Received: 08 February 2018
Accepted: 26 March 2018
Published: 13 April 2018
Email:
Bettina Riedl* - bettina.riedl@univie.ac.at
*
Corresponding author
Associate Editor: S. Flitsch
Keywords:
© 2018 Riedl and Schmid; licensee Beilstein-Institut.
License and terms: see end of document.
asymmetric synthesis; carbohydrates; N-acetylgalactosamine;
N-acetylidosamine
Abstract
Synthetic approaches towards N-acetylgalactosamine (GalNAc) have been attracting considerable interest since this compound is
known for its pivotal role in cell–cell interaction and receptor induced cell signaling. Herein, we present a synthetic route in which
two of the four stereogenic centers present in the target compound are derived from enantiopure tartaric acid being selectively con-
verted to epoxy alcohols. The key step is the Pd-catalyzed, stereo- and regioselective epoxide opening and subsequent nucleophilic
substitution of an azide functionality. This approach enables the synthesis of the naturally D- and unnaturally L-configured
GalNAc, as well as both enantiomers of the largely unknown N-acetylidosamine (IdoNAc).
Introduction
N-Acetylgalactosamine (GalNAc, Figure 1) and N-acetyl- lently α-linked to serine or threonine during post-translational
idosamine (IdoNAc) belong to the group of 2-amino-2-deoxy- modifications [3-5]. This glycoconjugate, known as T antigen
sugars, which can be found in a wide range of organisms as nouvelle (Tn antigen), is further modified by the β(1→3) attach-
building blocks of, e.g., glycosaminoglycans, peptidoglycans or ment of galactose leading to the Thomsen–Friedenreich (TF)
lipopolysaccharides [1]. As part of glycoproteins they are antigen [6,7]. These two immunodeterminants are overex-
involved in numerous biological processes. On the one hand, pressed on a high number of different cancer cells, located in
these macromolecules influence the proper folding of newly the breast, lung, colon, liver, prostate and gastric tissues [8].
synthesized proteins in the intracellular compartment of the Furthermore, the TF-antigen region serves as the core region for
endoplasmic reticulum (ER). On the other hand, glycoproteins the ABO and Lewis blood group determinants [9]. The high
serve as ligands for specific extracellular recognition processes importance of GalNAc in diverse biological processes, together
toward, e.g., enzymes, lectins or antibodies [2]. In O-linked with its notable role in drug development, turns this compound
glycoproteins, also known as mucins, GalNAc becomes cova- into an interesting synthetic target. In contrast to the thoroughly
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Beilstein J. Org. Chem. 2018, 14, 856–860.
investigated properties of GalNAc, other stereoisomers have not other approaches, novel synthetic concepts to fill the remaining
been probed for biological or pharmaceutical activity, yet. methodological gaps for accessing the missing isomers of
Highly flexible synthetic routes are required to access and probe 2-amino sugars, as well as new derivatives are still highly
the entire compound class of 2-amino-2-deoxysugars for further desired.
structure–activity relationship studies.
The here presented flexible approach towards GalNAc and
IdoNAc from epoxythreitol 5 is a first step to answer this
request. These molecules can be approached from tartaric
acid (3), which already provides two of the four desired
stereogenic centers. By extending compound 5 via a
Horner–Wadsworth–Emmons (HWE) reaction [15] and subse-
quent stereoselective introduction of the corresponding nitrogen
functionality, a route to four different 2-amino sugar stereoiso-
mers has been elaborated.
Results and Discussion
A synthetic route was developed starting with both the D- and
the L-epoxythreitol 5a and 5b. These isomers have been synthe-
sized from D- (3a) and L-tartaric acid (3b), respectively,
Figure 1: Four possible isomers reachable through the presented ap-
proach.
through an approach that has been published earlier by Iida et
al. (Scheme 1) [16]. Here, tartaric acid predefines the configura-
tion at C4 and C5 of the target compounds 5a and 5b. After the
Several strategies for the synthesis of 2-amino sugars have been C4-chain of tartaric acid has been extended by two carbon
published so far. In one exemplary straightforward approach, atoms resulting in compounds 4a and 4b, two new stereo-
GalNAc was prepared by inverting the stereogenic center at the centers have been introduced by Sharpless epoxidation [17,18].
C-4 position of N-acetylglucosamine (GlcNAc) [10]. However, We applied this approach for the epoxidation of 4a with
the necessity of using a 2-amino sugar as starting material L-diethyl tartrate (L-DET) directing the reaction towards the
reduces the flexibility of this approach. Another strategy intro- D-galacto-configured epoxythreitol 5a. Alternatively, epoxida-
duces the nitrogen at C-2 [11] via the 2-iodoxybenzoic acid- tion of 4b with D-DET was used to access L-galacto-config-
mediated generation of an oxazolidinone ring, selectively ured epoxythreitol 5b.
leading to C2–C3 syn-products [12]. A third approach features
E-selective Julia olefination of (R)- or (S)-2,3-isopropylidene- A procedure by Miyashita et al. [19] for nucleophilic substitu-
glyceraldehyde with a second chiral building block containing tion of epoxides by an azide functionality was applied for the
the amine function, followed by dihydroxylation [13,14]. presented approach. Therefore, 5a and 5b had to be converted
Despite the compounds already available through these and first to the unsaturated esters 6a and 6b (Scheme 2) [20,21].
Scheme 1: Sharpless epoxidation to gain D-galacto- 5a and L-galacto-configured epoxythreitol 5b.
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Beilstein J. Org. Chem. 2018, 14, 856–860.
Scheme 2: Reagents and conditions: a) i) (COCl)2, DMSO, Et3N, DCM, ii) triethyl phosphonoacetate, NaH, DCM; b) TMSN3, Pd(PPh3)4, EtOH;
c) i) DOWEX H+, MeOH; ii) O3, dimethyl sulfide, DCM/MeOH; iii) Ac2O, DMAP, pyridine; d) H2, Pd/C, Ac2O; e) MeOH/H2O/Et3N (10:10:1).
These compounds were reacted with trimethylsilyl azide mation of the aldehyde by the oxidation of the methylene func-
(
TMSN3) under Pd0 catalysis. With this protocol, the azide was tionality. Consequently, intramolecular hemiacetal formation
introduced under double inversion of the stereocenter on C4, re- resulted immediately in the cyclization of the unprotected azido
sulting in the desired cis-selective epoxide opening and there- sugar, which was peracetylated to yield compounds 8a and 8b.
fore, galacto-configured azido alcohols 7a and 7b (≥95% de) The azide function was reduced with H2 and Pd/C in acetic an-
[
22]. Initial limitations in reaction size and yield could have hydride to gain the fully acetylated amino sugars 2a and 2b. In
been overcome by switching the solvent from THF, as de- the final step, the compounds were deprotected using a mixture
scribed in the Miyashita protocol, to EtOH. This improvement of MeOH/H2O/Et3N to yield D-GalNAc (1a) and L-GalNAc
can be explained by a protonation of TMSN3 causing the in situ (1b).
generation of highly reactive HN3 (Scheme 3). Additionally, no
acidic work-up, as described by Miyashita et al., was necessary As proof of concept, this approach was additionally adapted for
to gain the free alcohol on C5, which corroborates the proposed the synthesis of peracetylated D-N-acetylidosamine 2c. There-
mechanism.
fore, the epoxidation of 4a was performed with D-DET instead
of L-DET, resulting in D-epoxythreitol 5c (Scheme 4). Per-
The protecting groups were cleaved by the use of acidic ion forming the presented, optimized reaction sequence resulted in
exchange (DOWEX H+). Subsequent ozonolysis caused the for- the formation of peracetylated D-IdoNAc 2c.
Scheme 3: Proposed mechanism of the Pd-catalyzed azide substitution of 6a in protic solvent.
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Beilstein J. Org. Chem. 2018, 14, 856–860.
Scheme 4: Approach towards peracetylated D-IdoNAc 2c, reactions and conditions: a) Ti(OiPr)4, t-BuOOH, D-DET, DCM; b) i) (COCl)2, DMSO,
Et3N, DCM, ii) triethyl phosphonoacetate, NaH, DCM; c) TMSN3, Pd(PPh3)4, EtOH; d) i) DOWEX H+, MeOH; ii) O3, dimethyl sulfide, DCM/MeOH;
iii) Ac2O, DMAP, pyridine; e) H2, Pd/C, Ac2O.
3
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Varki, A.; Cummings, R. D.; Esko, J. D.; Stanley, P.; Hart, G. W.;
Aebi, M.; Darvill, A. G.; Kinoshita, T.; Packer, N. H.; Prestegard, J. H.;
Schnaar, R. L.; Seeberger, P. H., Eds. Essentials of Glycobiology, 3rd
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Conclusion
The presented synthetic route was successfully used to prepare
both, D- and L-GalNAc, from non-carbohydrate starting materi-
als over 9 steps with overall yields of 22% and 12%, respective-
ly. Our approach combines the Sharpless epoxidation and
Pd-catalyzed azide substitution, both, highly stereoselective
protocols resulting in an advantageous flexibility. Therefore,
this route can also be adapted for the synthesis of the rarely
known D- and L-IdoNAc. As a proof of concept, the synthesis
of the peracetylated D-IdoNAc was performed (Scheme 4,
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