Chiral phosphoric acid-catalyzed desymmetrizative glycosylation of 2-deoxystreptamine and its application to aminoglycoside synthesis

Article abstract of DOI:10.1039/c7cc05052f

This work describes chiral phosphoric acid (CPA)-catalyzed desymmetrizative glycosylation of meso-diol derived from 2-deoxystreptamine. The chirality of CPA dictates the outcome of the glycosylation reactions, and the use of enantiomeric CPAs results in e

Full text of DOI:10.1039/c7cc05052f

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Chiral phosphoric acid-catalyzed desymmetrizative
glycosylation of 2-deoxystreptamine and its
application to aminoglycoside synthesis†
a
Cite this:DOI: 10.1039/c7cc05052f
Received 29th June 2017,
Accepted 18th July 2017
Jeonghyo Lee, ‡a Alina Borovika,‡b Yaroslav Khomutnyka and Pavel Nagorny
*
DOI: 10.1039/c7cc05052f
rsc.li/chemcomm
This work describes chiral phosphoric acid (CPA)-catalyzed desymme- aminoglycosides.5–7 While the most concise way to desymmetrize
trizative glycosylation of meso-diol derived from 2-deoxystreptamine. 2-DOS is through the direct glycosylation, only enzymatically-
The chirality of CPA dictates the outcome of the glycosylation controlled glycosylations of the C4 position of 2-DOS are known.8
reactions, and the use of enantiomeric CPAs results in either Such transformations provide powerful means for the assembly
C4-glycosylated (67 : 33 d.r.) or C6-glycosylated (86 : 14 d.r.) of aminoglycosides, but at the same time suffer from the
2-deoxystreptamines. These glycosylated products can be con- limited substrate scope, and complementary non-enzymatic
verted to aminoglycosides, and the application of this strategy to methods for the desymmetrizative glycosylation of 2-DOS are
the synthesis of protected iso-neamine and iso-kanamycin B with highly desired.
inverted connection at the C4 and C6 positions is described.
Our group has long-standing interests in developing and
exploring chiral phosphoric acid (CPA)-catalysed reactions
of acetals.9,10 Recently, our group11 along with Toshima and
co-workers12 demonstrated that CPA-catalysed acetal/glycoside
formation might proceed with the recognition of alcohol chirality
in racemic alcohols and carbohydrate-derived diols. Based on
these observations, we surmised that CPA-catalysed glycosylation
of 2-DOS derivative 1 with protected mannose donor 2 might
proceed selectively and lead to desymmetrization of 2-DOS thus
providing key disaccharides a-3A and a-3B. These compounds
could be further used for the assembly of various aminoglycoside
antibiotics and their isomeric forms with the inversed C4/C6
connectivity (Fig. 1B). This manuscript describes our studies on
selective synthesis of a-3A and a-3B through CPA-controlled
desymmetrizative glycosylation of meso-diol 1, and further
functionalization of a-3B to provide isomeric neamine 5 and
kanmycin B derivative 10 that are not readily accessible by
traditional semisynthetic methods.4
Our studies commenced with the synthesis of 2-DOS meso-
derivative 1 (Scheme 1). This substrate can be obtained by direct
derivatization of 2-deoxystreptamine hydrobromide salt that is
readily available by degradation of neomycin B trisulfate.13 This
salt was subjected to a two-step protocol that involves protection
of amines as azides (52% yield),14 and selective TBS-protection of
more reactive C5 hydroxyl group (81% yield) to provide meso-
derivative 1. The azide-based protection of C1 and C3 amines of
1 was selected due to the relatively small steric size and polarity
of the azido group, which is beneficial for the reactivity of 1 in
glycosylation reactions. While the introduction of two azides into
six carbon-containing 2-DOS resulted in a shock-sensitive triol;
Aminoglycosides are a group of carbohydrate-based antibiotics,
which function through binding to specific sites in prokaryotic
ribosomal RNA (rRNA) and affecting the fidelity of protein
synthesis.1 In addition to their antibacterial properties, amino-
glycosides are potent antiviral (HIV) agents and could be employed
to suppress genetic diseases.2 While certain aminoglycosides such
as paromomycin or gentamycin are FDA-approved drugs for the
treatment of bacterial infections, their extensive clinical use has
been curtailed by their toxicity and the rapid increase of amino-
glycoside resistant strains of bacteria.3
Therefore, the design of new modified aminoglycosides with
improved pharmacological properties represents an important
challenge. Despite the extensive interest in this class of natural
products, current approaches to aminoglycosides are often pro-
hibitively long and have significant limitations in the structural
modifications that can be introduced.4 The majority of amino-
glycosides contain an achiral (meso) 2-deoxystreptamine (2-DOS)
subunit that carries glycosylation at either the C4/C5 (i.e.
neomycin B) or C4/C6 (i.e. amikacin) hydroxyl groups (Fig. 1A).
The possibility of desymmetrizing 2-DOS has attracted signifi-
cant attention as the obtained desymmetrized derivatives can be
used to provide a direct access to a wide range of functionalized
a University of Michigan, Chemistry Department, 930 N. University Avenue,
Ann Arbor, MI 48103, USA. E-mail: nagorny@umich.edu
b Bristol-Myers-Squibb Co. 1 Squibb Dr. New Brunswick, NJ 08901, USA
† Electronic supplementary information (ESI) available: Experimental procedures
and 1H and 13C NMR spectra for compounds 1–9. See DOI: 10.1039/c7cc05052f
‡ Equally contributing authors.
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Table 1 Optimization of desymmetrizative glycosylation of protected
2-deoxystreptamine 1 and functionalized mannose 2a
Conversion,
% (yield, %)
Diastereoselectivity
(a-3A : a-3B)
Entry Catalyst Ar1, Ar2
=
1
2
3
4
5
6
7
8
(PhO)2PO2H
(S)-2,4,6-(iPr)3-C6H2
(S)-3,5-Cl2-C6H3
(S)-2,5-(CF3)2-C6H3
(S)-3,5-(CN)2-C6H3
(S)-3,5-F2-C6H3
Decomposition N/A
No rxn
o25
o25
o25
37
N/A
50 : 50
26 : 74
50 : 50
33 : 67
42 : 58
60 : 40
30 : 70
50 : 50
26 : 74
58 : 42
25 : 75
14 : 86
67 : 33
(S)-(1H)-(4-Ph)-1,2,3-triazolyl o25
(R)-3,5-(CF3)2-C6H3
(S)-3,5-(CF3)2-C6H3
(R)-Ar1 = C6F5, Ar2 = H
(S)-Ar1 = C6F5, Ar2 = H
(R)-C6F5
52
25
9
10
11
12
13
14
15
o25
34
30
61
(S)-C6F5
(S)-3,5-(SF5)2-C6H3
(R)-3,5-(SF5)2-C6H3
88 (74)
62 (51)
a
Conditions: donor 2 (1.5 equiv.), acceptor 1 (1 equiv.), catalyst (10 mol%),
DCM (0.2 M) 4 Å MS, 40 1C for 3 days; d.r. was determined by NMR
analysis of the crude mixture.
Fig. 1 Application of desymmetrizative glycosylation to synthesis of
aminoglycosides.
synthesis of natural aminoglycosides such as kanamycin B.15
To test the inherent selectivity of the glycosylation reaction, the
mixture of 1 and 2 was subjected to catalytic quantities of
TMSOTf. While the formation of B1 :1 mixture of disaccharides
a-3A and a-3B was indeed observed, the substantial quantities
of other isomeric disaccharides inseparable from a-3A and a-3B
complicated further analysis.
Similarly, the attempts to promote the reaction by using
diphenylphosphoric acid as the catalyst (Table 1, entry 1), did
not result in clean formation of a-3A or a-3B, but rather led to
decomposition of the starting materials. To our delight, BINOL-
backbone-containing CPAs16 were found to be significantly
better catalysts of this glycosylation;11,12,17,18 however, strong
dependence of the catalytic activity on the nature of the 3,30-aryl
substituents was observed. Thus, CPAs without electron with-
drawing group on their backbones (entry 2) failed to promote
Scheme 1 Preparation of 2-deoxystreptamine derivative 1. aConditions:
(a) HBr (conc.), reflux; (b) 1H-imidazole-1-sulfonyl azideꢀH2SO4, CuSO4,
K2CO3, 52% yield; (c) TBSOTf, 2,6-lutidine, THF, r.t., 81% yield.
the C5 TBS-protected derivative 1 was found to be stable to the glycosylation reaction at all. However, more acidic catalysts
detonation by heat or shock (refer to SI for further details).
with electron withdrawing 3,30-aryl groups did promote the for-
With the meso-derivative 1 in hand, the catalyst-controlled mation of inseparable mixtures of a-3A and a-3B with variable
glycosylation of 1 with trichloroacetimidate 2 was investigated selectivities (entries 3–15). Remarkably, the use of (S)-CPA with
next (Table 1). The mannose-derived trichloroacetimidates Ar = 3,5-(SF5)2C6H3 resulted in a-3B as the main product
undergo a-selective glycosylations, which is required for the (86 : 14 d.r., 74% yield, entry 14). Finally, the use of enantiomeric
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Scheme 2 Stereochemical assignment of products 3 and synthesis of
protected iso-neamine 5a. aConditions: (a) TBAF, THF, 4 Å MS, 82% yield;
(b) NaH, BnBr, DMF, 40 1C, 84% yield; (c) DDQ, DCM/H2O, (10 : 1), 0 1C to
r.t. overnight, 67% yield; (d) Tf2O, pyridine, DCM, ꢁ15 1C; (e) NaN3, DMF,
40 1C, 30% yield (2 steps). bTransformations a–e were carried on 86 : 14
mixture of a-3B : a-3A the mixture was separated after the first step (a) and
only deprotected a-3B was advanced to 5.
Scheme 3 Application to the synthesis of isomeric kanamycin B derivative
10a. aConditions: (a) TBAF, THF, Å MS, 82% yield; (b) 4 (1 equiv.), 8 (1.5 equiv.)
TMSOTf (15 mol%), DCM/Et2O (1:1, 0.25 M), 0 1C, 66% yield; (c) Ac2O, DMAP
(10 mol%), pyridine, r.t., 89% yield; (d) DDQ, DCM/H2O (10:1), 0 1C to r.t.
overnight, 86% yield; (e) Tf2O, 2,6-lutidine, DCM, ꢁ78 1C, 1 h, then NaN3
(20 equiv.) in DMSO, 90 1C, overnight, 16% yield.
(R)-CPA overturned the selectivity and favoured a-3A product
(67 : 33 d.r., 51% yield, entry 15).
The a-C1 configuration of 3A and 3B could be conveniently glycosylation of the C4 position. The product 7 was subjected to
confirmed by observing the J(C1–H) to be 173 and 169 Hz glycosylation with trichloroacetimidate 8 to provide trisaccharide
(cf. ESI†), which is consistent with the values typically observed 9 as a single diastereomer and regioisomer in 66% yield, and the
for the a-mannosides (B170 Hz) and inconsistent with the J(C1–H) observed J(H1–H2) = 3 Hz for the new anomeric stereocenter of 9
for the b-mannosides (B160 Hz). However, the proposed con- was consistent with the a-configuration.
nectivity (i.e. C4- vs. C6) required further validation (Scheme 2).
The formation of protected iso-kanamycin B (10) was com-
This was achieved by converting the 86 : 14 mixture of a-3B and pleted by oxidizing the trisaccharide with DDQ to remove the
a-3A into molecule 5 and comparing it with the known neamine PMB groups in the mannose subunit (86% yield). The resultant
derivative 6. The synthesis of 5 from a-3B commenced with diol was subjected to bis-triflation and azide substitution to yield
subjecting a-3B to TBAF to remove C5-TBS group (82% yield), compound 10. While the bis-triflation proceeded smoothly, the
reprotecting the resultant diol as a benzyl ether (84% yield), and displacement of the C2-triflate of mannose subunit with sodium
removing of the PMB protecting groups on mannose subunit by azide19 was found to be sluggish and provided the desired
DDQ (67% yield) to provide disaccharide 4. Diol 4 was subjected protected iso-kanamycin B in only 16% yield (2 steps).
to a two-step protocol that included converting the mannose
The plausible reaction intermediates for the formation of
subunit to 2,6-bis-triflate, which was subjected to nucleophilic a-3A and a-3B are proposed in Fig. 2. Our prior mechanistic and
substitution with sodium azide in DMF to provide desired theoretical studies of CPA-catalyzed regioselective glycosylation
derivative 5 in 30% yield (2 steps). The 1H and 13C NMR spectra of 6-dEB and oleandomycin-derived macrolactones20 identified
for the synthetic derivative 5 were distinctly different from the covalently linked anomeric phosphates such as 11A as viable
corresponding spectra of known natural neamine derivative reaction intermediates. However, considering that the exclusive
613 supporting the glycosylation at the C6 position of 2-DOS formation of a-3A and a-3B from a-2 is observed in these studies,
in a-3B.
the formation of an oxocarbenium-based ion pair 11B cannot be
The stereoselective synthesis of disaccharide a-3B offered an ruled out.
intriguing possibility of converting this substrate to isomeric
In conclusion, we were able to demonstrate that chiral
kanamycin B with reverse connectivity of the sugars at the C4 phosphoric acids catalyze desymmetrizative glycosylation of
and C6 position (Scheme 3). The direct functionalization of 2-deoxystreptamine-derived meso-diol 1 with mannose trichloro-
kanamycin B to form this derivative represents a significant acetimidate donor 2. While the evaluated achiral acids could not
challenge, while the desymmetrizative functionalization of promote this glycosylation selectively, the (S)-enantiomer of CPA
2-DOS would provide a more straightforward access to amino- (Ar = 3,5-(SF5)2-C6H3) catalysed diastereoselective formation of
glycosides of this type.4 Thus, the synthesis of iso-kanamycin B the C6 glycosylated product a-3B in 86: 14 d.r. This transforma-
commenced with the cleavage of the C5 TBS group of a-3B that tion was accomplished on significant scale (0.3 g of a-3B), and is
resulted in diol 7 (70% yield) along with the regioisomeric of utility for the preparation of functionalized aminoglycosides.
product arising from the deprotection of a-3A (12% yield). This Thus, intermediate a-3B was converted into the isomeric pro-
deprotection was necessary as the TBS group obstructed the tected aminoglycosides neamine and kanamycin B with reversed
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applications of this transformation as well the investigation
of the reaction mechanism are the subjects of ongoing studies
by our laboratory.
This work was partially funded by the National Science
Foundation CAREER Award (CHE-1350060 to PN) and NSF GRFP
(DGE 0718128 to AB). PN is the Sloan Foundation and Amgen
Young Investigator Fellow.
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