Oxidative Deamination of N-Acetyl Neuraminic Acid: Substituent Effects and Mechanism

Article abstract of DOI:10.1021/jacs.5b13015

A study of the mechanism of the oxidative deamination of the N-nitroso-N-acetyl sialyl glycosides leading with overall retention of configuration to the corresponding 2-keto-3-deoxy-d-glycero-d-galacto-nonulopyranosidonic acid (KDN) glycosides is described, making use of a series of differentially O-protected N-nitroso-N-acetyl sialyl glycosides and of isotopic labeling studies. No evidence is found for stereodirecting participation by ester groups at the 4- and 7-positions. Comparisons are drawn with oxidative deamination reactions of 4-amino-4-deoxy and 2-amino-2-deoxy hexopyranosides and a common mechanism is formulated involving the intermediacy of 1-oxabicyclo[3.1.0]hexyl oxonium ions following participation by the pyranoside ring oxygen. A minor reaction pathway has been uncovered by labeling studies in the β-thiosialosides that results in the exchange of the 4-O-acetyl group by the glacial acetic acid that serves as external nucleophile in the general oxidative deamination process. A mechanism is proposed for this exchange involving participation by the thioglycoside at the level of an intermediate diazoalkane.

Full text of DOI:10.1021/jacs.5b13015

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Article
Oxidative Deamination of N-Acetyl Neuraminic
Acid: Substituent Effects and Mechanism
Szymon Buda, and David Crich
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b13015 • Publication Date (Web): 05 Jan 2016
Downloaded from http://pubs.acs.org on January 8, 2016
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Oxidative Deamination of NꢀAcetyl Neuraminic Acid:
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Substituent Effects and Mechanism
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Szymon Buda and David Crich*
Department of Chemistry, Wayne State University, Detroit, MI 48202, USA
dcrich@chem.wayne.edu
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RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract. A study of the mechanism of the oxidative deamination of the NꢀnitrosoꢀNꢀacetyl sialyl
glycosides leading with overall retention of configuration to the corresponding 2ꢀketoꢀ3ꢀdeoxyꢀ
Dꢀ
glyceroꢀ ꢀgalactoꢀnonulopyranosidonic acid (KDN) glycosides is described, making use of a series of
D
differentially Oꢀprotected NꢀnitrosoꢀNꢀacetyl sialyl glycosides and of isotopic labelling studies. No
evidence is found for stereodirecting participation by ester groups at the 4ꢀ and 7ꢀpositions.
Comparisons are drawn with oxidative deamination reactions of 4ꢀaminoꢀ4ꢀdeoxy and 2ꢀaminoꢀ2ꢀdeoxy
hexopyranosides and a common mechanism is formulated involving the intermediacy of 1ꢀ
oxabicyclo[3.1.0]hexyl oxonium ions following participation by the pyranoside ring oxygen. A minor
reaction pathway has been uncovered by labelling studies in the βꢀthiosialosides that results in the
exchange of the 4ꢀOꢀacetyl group by the glacial acetic acid that serves as external nucleophile in the
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general oxidative deamination process. A mechanism is proposed for this exchange involving
participation by the thioglycoside at the level of an intermediate diazoalkane.
Introduction.
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The sialic acids, a large group of nine carbon sugar acids based on the 2ꢀketoꢀ3ꢀdeoxyꢀDꢀglyceroꢀDꢀ
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galactoꢀnonulopyranosidonic acid framework, are present at the nonꢀreducing end of a myriad of
mammalian cell surface glycans.1ꢀ3 NꢀAcetyl neuraminic acid 1 is the most common member of the
family, but variation at the 5ꢀposition is frequently found with examples including Nꢀglycoyl
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neuraminic, and 2ꢀketoꢀ3ꢀdeoxyꢀDꢀglyceroꢀDꢀgalactoꢀnonulopyranosidonic acid (KDN). The removal of
terminal sialic acid glycosides from cell surface glycans by sialidase enzymes is a key step in the
replication cycle of influenza viruses, giving rise to the importance of the sialidase inhibitors as antiviral
drugs. Increased levels of sialidation in cell surface glycans have led to the development of cancer
vaccine candidates based on tumorꢀassociated carbohydrate antigens (TACAs).1ꢀ4 Modification of the
amido group at the 5ꢀposition of Nꢀamidoneuraminic acid derivatives has proved to be beneficial in the
development of sialidase inhibitors and of carbohydrate antigens with greater antigenicity.5ꢀ9 Such
modifications have typically been achieved by Nꢀdeacetylation of 1, its glycosides and derivatives,
followed by reinstallation of different acyl groups,6ꢀ7,10ꢀ12 or by use of the biosynthetic machinery when
various Nꢀacyl mannosamines are converted enzymatically to the corresponding Nꢀacyl neuraminic
acids13 and eventually their glycosides,14ꢀ15 or by a combination of the biosynthetic and chemical
methods.16 Consequently, modifications are typically limited to amide derivatives or other simple
substitutions that are compatible with the biosynthetic machinery such as the conversion of 2ꢀdeoxy
glucose to 5ꢀdesacetamido neuraminic acid.17
The advent of improved chemical methods for the efficient and stereoselective synthesis of the αꢀ
sialyl glycosides based on the use of 4ꢀO,5ꢀNꢀoxazolidinoneꢀprotected sialyl donors and their Nꢀacetyl
variants18ꢀ22 gave rise to the possibility of the effective chemical synthesis of Cꢀ5 modified sialyl
glycosides provided suitable reactions for postꢀglycosylation removal of the acetamido function could be
identified. Toward this end we have described23ꢀ24 the application of the oxidative deamination of
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neruaminic acid25ꢀ27 and Nꢀacetylneuraminic acid28ꢀ29 to the synthesis of Cꢀ5 modified αꢀsialosides. We
describe here our investigations into the mechanism of stereospecific oxidative deamination of Nꢀnitroso
Nꢀacetyl neuraminic acid glycosides making use of a series of differentially Oꢀprotected derivatives and
isotopic labelling studies. Comparisons are made with oxidative deamination reactions in the 4ꢀaminoꢀ
4ꢀdeoxy and 2ꢀaminoꢀ2ꢀdeoxy hexopyranosides, leading to the formulation of a general mechanism
involving participation by the ring oxygen and the intermediacy of 1ꢀoxabicyclo[3.1.0]hexyl oxonium
ions, whose fate is determined by the substituent pattern. We also describe a minor reaction pathway
found on oxidative deamination of a NꢀnitrosoꢀNꢀacetyl axial sialyl thioglycoside that results in
exchange of the 4ꢀOꢀester with acetic acid from the medium.
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Results
Synthesis. Methyl [methyl (5ꢀacetamidoꢀ5ꢀdeoxyꢀβꢀDꢀglyceroꢀDꢀgalactoꢀ2ꢀnonulopyranosid)onate] 1
was obtained from Nꢀacetylneuraminic acid under standard conditions,30ꢀ31 and was converted by
standard methods to the known derivatives 2-5.30,32ꢀ34
Removal of the isopropylidene group from 4 with trifluoroacetic acid in wet dichloromethane gave the
triol 6, which on acetylation afforded the 4ꢀOꢀsilylꢀ7,8,9ꢀtriꢀOꢀacetyl derivative 7. Treatment with
tetrabutylammonium fluoride then afforded 8, which was converted to the corresponding 4ꢀOꢀbenzyl
ether 9 by reaction with benzyl trichloroacetimidate and TfOH,35 and to the 4ꢀOꢀtꢀbutyloxycarbonyl
derivative 10 by stirring with Boc2O in the presence of trimethylamine and 4ꢀdimethylaminopyridine,
aqueous workꢀup and purification by chromatography over neutral alumina (Scheme 1). It is noteworthy
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that attempted purification of 10 by chromatography over silica gel resulted in an isolated yield of 28%
of the desired product together with 23% of the Nꢀacetyl oxazolidinone 11. This unanticipated
cyclization provides a possible alternative entry into the Nꢀacetyl oxazolidinones, which have found
widespread use in the stereocontreolled synthesis of sialic acid glycosides.20ꢀ22 Isopropylidene cleavage
from 5 gave 12 from which 13 was obtained by acetylation. Subsequent Wittig olefination gave the 4ꢀ
deoxyꢀ4ꢀalkylidene derivative 14 as the Eꢀisomer as determined by the NOE correlation of the vinylic
hydrogen with the H5. Catalytic hydrogenation over palladium charcoal finally gave 15, whose
configuration rests on coupling constant analysis in the H3,H4,H5 spin system in the 1H NMR spectrum
(Scheme 1).
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4
TFA
OX
OX
OMe
OAc
OAc
OMe
TBAF
OBn
XO
AcO
O
O
CO2Me
OTBDMS
6: X = H
CO2Me
AcHN
AcHN
OX
8: X = H, 86%
Ac2O
Boc2O
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: X = Bn, 36%
7: X = Ac,
HN
CCl3
72% 2 steps
10: X = Boc, 43%*
OAc
OAc
OMe
AcO
O
CO2Me
AcN
O
5
O
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TFA
OX
OX
OMe
OAc
OAc
OMe
TBAF
XO
AcO
O
O
CO2Me
CO2Me
AcHN
AcHN
O
Ph3P=CHCO2tBu
CO2tBu
12: X = H
14, 56%
Ac2O
13: X = Ac,
64%, 2 steps
H2, Pd/C
OAc
OAc
OMe
O
AcO
CO2Me
AcHN
CO2tBu
15, 87%
Scheme 1. Synthesis of NeuAc Derivatives Selectively Functionalized at the 4ꢀPosition.
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Benzylation of 4 with sodium hydride and benzyl bromide in DMF gave the 7ꢀOꢀbenzyl derivative 16,
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from which the isopropylidene and silyl groups were removed with acetic acid in methanol yielding 17
and, after acetylation 18 (Scheme 2). Treatment of 1 with diꢀ(tertꢀbutyl)ꢀdichlorosilane and imidazole in
dichloromethane afforded the 8,9ꢀOꢀsilylene derivative 19, which underwent selective installation of the
tertꢀbutyldimethylsilyl group on O4 to give 20. The 7ꢀOꢀBoc group was then installed with Boc2O to
give 21, which on treatment first with TBAF and then acetic anhydride in pyridine afforded 22 (Scheme
2).
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Scheme 2. Synthesis of NeuAc Derivatives Selectively Protected at the 7ꢀPosition.
Benzylation of 3 with sodium hydride and benzyl bromide in DMF gave the 4,7ꢀdiꢀOꢀbenzyl ether 23,
which on removal of the isopropylidene group with toluenesulfonic acid in methanol and subsequent
acetylation gave 24 and 25, respectively (Scheme 3).
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Scheme 3. Synthesis of a NeuAc Derivative Selectively Protected at the 4ꢀ and 7ꢀPositions.
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Influence of Protecting Groups on Stereoselectivity. The series of sialyl glycosides 2, 7, 9, 10, 15,
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18, 22, 23, and 25 were converted to a series of Nꢀnitroso derivatives 26ꢀ34 by treatment with NO+BF4
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in a mixture of pyridine and dichloromethane at ꢀ10 C in essentially quantitative yield and taken
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forward to the next step immediately.23ꢀ24 Exposure to trifluoroethanol and sodium isopropoxide in
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dichloromethane and isopropanol at ꢀ10 C followed by addition of acetic acid under the standard
conditions gave the corresponding KDN derivatives and their epimers at the 5ꢀposition 35ꢀ45 as
reported in Table 1.
Table 1. Influence of Protecting Groups on Stereoselectivity of KDN Formation.a
Product,
Nitrosylated
Entry
Yield, selectivity
Substrate
(KDN:5-epi-KDN)
OAc
OAc
OMe
AcO
AcO
O
CO2Me
AcO
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OAc
35, 56%, 1:0
OAc
OAc
OMe
O
CO2Me
AcO
OBoc
36, 56%, 1:0
OAc
OBoc
OMe
AcO
O
CO2Me
AcN
ON
AcO
28
OAc
OAc
OMe
AcO
O
CO2Me
AcO
OBn
39, 46%, 1:0
OAc
OAc
OMe
OAc
OAc
CO2Me
OTBDMS
40, 52%, 1:0
OMe
AcO
AcO
O
O
CO2Me
AcN
ON
AcO
OTBDMS
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O
OMe
O
OMe
OBn
O
OBn
O
CO2Me
O
O
O
CO2Me
AcN
ON
AcO
OBn
OBn
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43 (eq AcO) and 44 (ax AcO),
40%, 1:1
O
OMe
CO2Me
OBn
O
9b,c
AcN
ON
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OBn
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OAc
OAc
OMe
AcO
O
CO2Me
AcO
10d
CO2tBu
46, 17%, 1:0
a) With the exception of entry 9 all reactions were conducted under a standard set of conditions
involving treatment of the nitrosoamide in CH2Cl2 at ꢀ10 oC with trifluoroethanol and then sodium
isopropoxide in isopropanol followed by addition of glacial acetic acid and warming to 0 oC.
b) The nitrosamide was stored neat at 4 oC in the refrigerator for 12 days. No external reagents were
added.
c) To facilitate isolation from a complex mixture the isopropylidene group was cleaved the initial
product 44 and the residual diol acetylated to give 45.
d) Isolated yield of pure 46 is only 17% owing to difficulties in isolation.
To facilitate interpretation Table 1 is organized in order of decreasing electronꢀwithdrawing effect of
their collective protecting group arrays. As observed previously23ꢀ24,29 isolated yields of the oxidative
deamination products are typically in the range of 50% (Table 1). Inspection of each reaction mixture
by mass spectrometry revealed a number of side products typically arising from i) formal elimination of
the nitrosoacetamide function to the give an alkene [M ꢀ AcNHNO]+;28 ii) substitution of the
nitrosoacetamide by trifluoroethoxide [M – AcNNO + CF3CH2O]+; and iii) substitution of the
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nitrosoacetamide by isopropoxide [M – AcNNO + iPrO]+. As the reaction mixtures were complex and
purification of the byproducts tedious, isolation and characterization of such products was not
undertaken. Exceptionally, however, for the tertꢀbutyl ester 34, for which the isolated yield of the
oxidative amination product 46 was only 17% (Table 1, entry 10), a sample of the alkene 47 was
isolated in 6% yield and characterized. In general the KDN derivatives with the equatorial acetoxy
group at C5 are distinguished from their 5’ꢀepiꢀKDN isomers with the axial group on the basis of the
chemical shift and multiplicity of H5, the multiplicity of H4 and the chemical shift of the axial H3 in the
1H NMR spectra. On this basis, the absence of the 5’ꢀepimers in Table 1, entries 1ꢀ6 and 10 was readily
apparent on inspection of the crude reaction mixtures by 1NMR spectroscopy.
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Incorporation of 13C-Labelled Acetic Acid. The oxidative deamination of 26 was also conducted
with acetic acid that was 99% enriched at the carbonyl carbon, resulting in the isolation of 35 carrying
the labelled acetate group at the 5ꢀposition, with no significant loss of label as determined by mass
spectrometry (Scheme 4). The identical experiment was conducted on the nitrosoamide 49, derived
from the corresponding αꢀadamantanyl thioglycoside 48,21,24 with comparable clean and complete
incorporation of the labelled acetate at the 5ꢀposition in the product 50 (Scheme 4). However, with the
isomeric nitrosoamide 51,24 derived from the βꢀadamantanyl thioglycoside 52,21 mass spectrometric
analysis of the crude reaction mixture and of the isolated KDN derivative revealed incorporation of a
second isotopically labelled acetoxy group to the extent of approximately 30% (Scheme 4). Careful
NMR analysis, particularly correlation of the carbonyl C of the minor enriched acetate with H4 in a
HMBC experiment, located this second labelled acetate group at the 4ꢀposition of 53 (Scheme 4). The
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location of the labelled acetate group at the 5ꢀposition of the monolabeled products C1ꢀ35 and 50 was
similarly confirmed by HMBC experiments.
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Scheme 4. Incorporation of 13CꢀLabelled Acetate.
Proton-Deuterium Exchange at the 5-Position. The nitrosylated amide 26 was subjected to the
standard Zbiral conditions23ꢀ24,29 with the difference that all protic solvents and reagents employed were
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deuteriated at the exchangeable position. Thus, a solution of 26 and CF3CH2OD in dichloromethane
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was treated at ꢀ10 C with a solution of sodium isopropoxide in iꢀPrOD followed by addition of
CH3CO2D. Standard work up and chromatographic purification enabled the isolation of the
monodeuterio KDN derivative 35ꢀ5d in which deuterium was fully and selectively incorporated at the 5ꢀ
position (Scheme 5).
Scheme 5. Deuterium Incorporation at the 5ꢀPosition of KDN.
Discussion
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Mechanism of Oxidative Deamination. An mechanistic overview of the oxidative deamination
containing the various hypothetical intermediates is presented in Scheme 6 using the perꢀOꢀacetyl Nꢀ
nitrosoacetamide 26 as example. Trifluoroethoxide generated in situ from trifluoroethanol with sodium
isopropoxide, or added as a prepared salt, serves as a mild nucleophile to bring about the selective
deacetylation of the nitrosoamide 26 to give the hydroxydiazine 55.36 This step may take place either
directly on 26, which is strongly activated because of the presence of the electronꢀwithdrawing nitroso
group, or via the intermediacy of the acetoxydiazene 54 with which it is considered to be in
equilibrium.36 Other nucleophiles that have been used for this purpose in related systems include amine
Nꢀoxides,37 imidazole, and hydroxide.38 On acidification, either by the addition of suitably acidic
nucleophile or by the addition of a Brønsted acid in the presence of a nucleophile,24 protonation and
elimination of water occurs to give the diazonium ion 56 and its conjugate base the diazoalkane 57.36
These level 1 nitrogenous intermediates the undergo loss of molecular nitrogen to give one or other of
the level 2 intermediates, the carbenium ion 58 and the carbene 59. These level two intermediates either
proceed directly to the elimination byproducts28 64 and 65, and the substitution product 35, or are
stabilized in the form of one or more of the level 3 intermediates 60ꢀ63, which ultimately afford the
isolated reaction products. Our goal in initiating this project was to determine the reasons underlying
the stereoretentive nature of the oxidative deamination reaction; accordingly the focus of this discussion
is on the level 2 and level 3 intermediates.
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Scheme 6. Global Mechanism for Oxidative Deamination with Three Levels of Hypothetical
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Intermediates
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The high level of incorporation of C enriched acetic acid in to the product 35 (Scheme 4) under the
typical reaction conditions necessitates an intermolecular process rather than any intramolecular
rearrangement with concomitant loss of nitrogen from 26, 54, or the ion pair 56. If the carbenium ion 58
or one of its stabilized forms 60, 61 and 63 are on the reaction pathway, the complete incorporation of
deuterium at the 5ꢀposition when the reaction is conducted with deuterated reagents (Scheme 5) requires
that the diazonium ion 56 and the diazoalkane 57 be in dynamic equilibrium. Alternatively the
incorporation of deuterium (Scheme 5) can be accommodated by the intermediacy of the carbene 59, or
its stabilized equivalent, the ylid 62. Other carbohydrateꢀbased diazoalkanes generated from Nꢀ
nitroacetamides have been previously shown to participate in typical carbeneꢀtype intermolecular CꢀH
insertions.39ꢀ40 The very high levels of overall retention of configuration typically seen in these
reactions, both past23ꢀ24,28ꢀ29,41 and present (Table 1, entries 1ꢀ6), argue against the formation of the
substitution product 35 directly from the carbenium ion 58 or the carbene 59, although it remains
possible that the elimination products 64 and 65 are formed from 58 or 59 by deprotonation or CꢀH
insertion, respectively. Rather, it is likely that the origin of stereoselectivity lies with the intermediacy
of one or other of the level 3 intermediates formed either directly from the level 1 intermediates 56 and
57 in a concerted manner or via the transient level 2 intermediates 58 and 59.
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Stereodirecting neighboring group participation by esters through the intermediacy of dioxalenium
ions is a wellꢀestablished phenomenon.42ꢀ47 Comparable participation of more remote esters through
sixꢀmembered dioxenium or larger cyclic ions is hotly debated in carbohydrate chemistry,48ꢀ52 but the
premise of dioxenium ions as intermediates in simple systems rests securely on a labelling study.53 In
the present oxidative deamination reaction participation through the dioxenium ion 61 would appear to
be especially favorable in view of the extended zigꢀzag conformation of the side chain54ꢀ60 and the ideal
location it imposes on the 7ꢀOꢀacetyl group. Notwithstanding this precedent, the complete retention of
configuration observed when the 4ꢀO or 7ꢀOꢀacetyl groups are replaced by benzyl ethers or a silyl group
(Table 1, entries 4ꢀ6) excludes the need for ester participation through either a dioxalenium or
dioxenium ion. That the 4ꢀO and 7ꢀOꢀtertꢀbutoxycarbonyl protected systems 27 and 28 (Table 1, entries
2 and 3) also afford the standard substitution products in the typical yields with no indication of the type
of cyclic carbonates50,61 anticipated from Boc participation corroborates this conclusion. Similarly, we
could find no indication of lactone formation62 resulting from participation by the tertꢀbutyl ester 34
(Table 1, entry 10) with loss of the tertꢀbutyl group.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The evidence, therefore, points overwhelmingly toward participation by the ring oxygen as in the
oxabicyclo[3.1.0]hexyl oxonium ion 63. This bicyclic oxonium ion may be formed directly from the
diazonium ion 56, via the intermediacy of the carbenium ion 58, or by protonation of the carbeneꢀ
derived ylid 62 (Scheme 6). Indeed, an early study on the oxidative deamination of 1, under conditions
of simple thermal decomposition, reported the isolation of a ringꢀcontracted furanosyl byproduct such as
would arise from competing nucleophilic ring opening at the 6ꢀposition of 63, albeit neither
characterization data nor a mechanism were advanced.28 Although we have not isolated and
characterized such ring contraction products in the present study, it remains possible that they are
present among the several byproducts formed in minor amounts. Kinetic evidence for the intermediacy
of oxabicyclo[3.1.0]hexyl oxonium ions in the solvolysis of 2ꢀoxaꢀ6ꢀnorbornyl brosylates, in
comparison to that of 2ꢀnorbornyl brosylates, is found in the work of Kirmse and Mrotzeck.63
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When both the 4ꢀOꢀ and 7ꢀOꢀacetyl groups are replaced by less electronꢀwithdrawing benzyl ethers
(32, Table 1, entry 7), minor stereochemical leakage is observed in that the still major equatorial acetate
41 was formed in a 4.5:1 ratio with its axial isomer 42. When additionally the 8ꢀOꢀ and 9ꢀOꢀacetyl
groups are replaced by a less electronꢀwithdrawing isopropylidene group (33, Table 1, entry 8) the
stereoselectivity of the reaction is fully compromised and the equatorial and axial acetates 43 and 44,
respectively, are formed in equimolar quantities. These observations support the existence of an
equilibrium between carbenium ion 66 and oxabicyclo[3.1.0]hexyl oxonium ions 67 (Scheme 7) with
the latter favored under typical conditions in the presence of multiple electronꢀwithdrawing protecting
groups. With only two remote electronꢀwithdrawing esters to destabilize it, as in 32, the carbenium ion
is sufficiently populated to cause erosion of stereoselectivity. In the complete absence of electronꢀ
withdrawing esters, the carbenium ion is sufficiently stable that it dominates the stereochemical outcome
of the reaction. The very high degree of retention of configuration observed with the branched carbon
analog 34 (Table 1, entry 1) indicates that the presence of three electronꢀwithdrawing esters in the side
chain is sufficient to compensate for the replacement of the C4ꢀO bond by the more electronꢀdonating Cꢀ
C bond such that the oxonium ion mechanism is still favored for substitution.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Equilibrating Carbenium and Bridged Oxonium Ions and the Influence of Protecting
Groups.
In an attempt to prepare and store larger quantities of Nꢀnitrosoamides, 33 was accessed on 400 mg
o
scale and stored as a solid in the refrigerator at 4 C. On examination after 12 days the sample was
found to have decomposed to give the typical mixture of substitution and elimination products as
determined by mass spectrometry. Inspection of the NMR spectra of the crude mixture of products
revealed the substitution product to consist exclusively of the 5ꢀepiꢀKDN derivative 44, which was
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isolated as the derivative 45 in 38% yield after removal of the isopropylidene group and acetylation
(Table 1, entry 10). Because it takes place in the solid phase, this rearrangement necessarily arises by an
intramolecular process and most likely involves passage through an ion pair related to the level 1
intermediate 56 (Scheme 6) with concerted displacement of nitrogen by the incoming acetate. The
possibility of an intramolecular SN2 process at the level of the Zꢀisomer of the acetoxydiazene related to
54, formally a 6ꢀendoꢀtet process,64 is considered unlikely on the grounds of the endocyclic restriction
test.65ꢀ66 It is noteworthy that the corresponding peracetyl N-nitrosoamide 26 did not undergo
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
decomposition on standing in the refrigerator at 4 C for one month, thereby reaffirming the role of
protecting groups on the stability of the nitrosoamides.
Comparison
with
the
4-Deoxy-4-acetamidoglucopyranoside
and
2-Deoxy-2-
acetamidoglucopyranoside Series. Comparison with older studies on the oxidative deamination of 4ꢀ
and 2ꢀacetamidopyranosides is instructive. Nitrous acidꢀpromoted deamination of methyl 4ꢀaminoꢀ4ꢀ
deoxyꢀαꢀ
D
ꢀglucopyranoside gives methyl αꢀ
D
ꢀglucopyranoside as the major product together with
methyl βꢀ
Lꢀaltrofuranoside and 4,5ꢀanhydroꢀ
Dꢀgalactose, all of which are suggestive of the involvement
of the ring oxygen and of a bicyclic oxonium ion intermediate (Scheme 8). A further product of this
ꢀxylofuranoside, arises from the migration of C2.67 Although product
reaction, 3ꢀdeoxyꢀ3ꢀCꢀformyl αꢀ
D
distributions were substrate and protecting group dependent, comparable products were observed in the
nitrous acidꢀmediated deamination of methyl 4ꢀaminoꢀ4ꢀdeoxyꢀ2,3ꢀOꢀisopropylideneꢀαꢀ
rhamnopyranoside.68 Methyl 4ꢀaminoꢀ4,6ꢀdideoxyꢀ
D
D
ꢀ
ꢀ
D
ꢀmannopyranoside is also reported to give
rhamnopyranose on nitrous acid deamination and hydrolysis.69 On the other hand, methyl 4ꢀaminoꢀ4,6ꢀ
dideoxyꢀ2,3ꢀOꢀisopropylideneꢀαꢀ ꢀtalopyranoside, with an axial amine at the 4ꢀposition, does not
D
undergo ring contraction to a significant extent under the same conditions, implying the absence of
participation by the ring oxygen, but gives mainly the products of substitution with inversion of
configuration.68 The analogous dependence on configuration is observed in the NOꢀmediated
deamination of the 4ꢀaminoꢀ4ꢀdeoxyglycopyranoside residues of various bacterial oligosaccharides.70
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1
2
3
4
5
6
7
8
9
10
Scheme 8. Deamination Reactions in the 4ꢀAminoꢀ4ꢀdeoxyglucose Series
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The ring contraction of 4ꢀOꢀsulfonyl derivatives of rhamnopyranose in the presence of azide in DMF
at reflux also is known to give the 5,6ꢀdideoxyꢀ5ꢀazidoꢀtalofuranose skeleton as the major product
requiring overall inversion at C4 and retention (double inversion) at C5.71ꢀ73 As with the deamination
reactions, this ring contraction with inversion of configuration at C4 in suggests participation by the ring
oxygen leading again to an intermediate oxabicyclo[3.1.0]hexyl oxonium ion (Scheme 9).
OMe
OMe
H
N3
O
OMe
NaN3,
O
O
RO2SO
O
DMF,
O
O
O
O
O
Scheme 9. Ring Contraction of a Rhamnosyl 4ꢀOꢀSulfonate
Nitrosylation of Nꢀacetylꢀβꢀ ꢀglucosamine tetraacetate gives an isolable Nꢀnitroso acetamide that on
standing undergoes decomposition to give βꢀ ꢀglucose pentaacetate, by a process considered to involve
D
D
rearrangement to the diazoacetate and subsequent SNi, possibly with participation by the ring oxygen.74ꢀ
75
On standing in chloroform NꢀacetylꢀNꢀnitrosoꢀαꢀDꢀglucosamine tetraacetate, but not its βꢀanomer,
similarly affords βꢀ
Dꢀglucose pentacetate leading to the suggestion of neighboring group participation
and ultimate migration by the axial anomeric acetate.76 Alternatively, treatment of NꢀacetylꢀNꢀnitrosoꢀαꢀ
or βꢀDꢀglucosamine tetraacetate with potassium isopropoxide followed by acetylation gives 3,4,5ꢀtriꢀOꢀ
acetylꢀ1,2ꢀdideoxyꢀ
Dꢀerythroꢀpentꢀ1ꢀynitol by a process considered to involve diazoalkane formation,
loss of nitrogen to give the carbene, hydrogen migration and C1ꢀC2 bond cleavage (Scheme 10).74ꢀ75 In
aqueous acetone both anomers of NꢀacetylꢀNꢀnitrosoꢀ
D
ꢀglucosamine tetraacetate undergo ring
ꢀmannose (chitose)
contraction with inversion of configuration at C2 to give triacetylꢀ2,5ꢀanhydroꢀ
D
implying transannular attack by the ring oxygen and the intermediacy of an oxabicyclo[3.1.0]hexyl
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oxonium ion (Scheme 10).76 NꢀAcetylglucosamine and its glycosides undergo the analogous
rearrangement on Nꢀnitrosylation;77 the process has been employed in the depolymerization of
glycoaminoglycans70 and in the cleavage of ring I from the aminoglycoside antibiotic paromomycin.78
1
2
3
4
5
6
7
8
9
OAc
O
OH
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
KOH,
AcO
AcO
HO
HO
OAc
OH
iPrOH
NAc
N2
ON
Neat
i) -N2
ii) C-H insert.
OH
OAc
O
N
AcO
AcO
OAc
O
OH
HO
HO
N
AcO
Ac2O
OAc
O
OAc
OAc
AcO
OAc
AcO
AcO
OAc
OAc
O
AcO
AcO
OAc
OAc
NAc
ON
OAc
O
OAc
O
CHCl3
-only
AcO
AcO
AcO
AcO
O
O
H2O, Me2CO
AcO
O
OAc
O
AcO
CHO
AcO
AcO
OAc
AcO
OAc
Scheme 10. Deamination Reactions in the Glucosamine Series
Overall, a consistent pattern emerges in which a tetrahydropyran carrying an equatorial leaving group
undergoes transannular participation by the ring oxygen with inversion of configuration to give an 1ꢀ
oxoabicyclo[3.1.0]hexyl oxonium ion (Scheme 11). In most cases participation by the ring oxygen
predominates over participation by ester substituents on the tetrahydropyran framework. The
subsequent chemistry of the 1ꢀoxoabicyclo[3.1.0]hexyl oxonium ion is dictated by the reaction
conditions and above all by the substituent pattern. Nucleophilic attack at the bridgehead carbon leads
to the substitution product with overall inversion of configuration, whereas nucleophilic attack in the
smaller bridge affords ring contraction products. The partitioning between these two pathways depends
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on the overall substituent pattern, the nucleophile, and the reaction conditions. In the sialic acid series,
with the larger more heavily substituted side chain in the small bridge, attack at the bridgehead
predominates (Table 1 and Scheme 6). Conversely, in the 4ꢀaminoglucosyl series and related
compounds (Schemes 8 and 9) with a smaller and less electronꢀwithdrawing side chain in the small
bridge, ring contraction is more common. In the 2ꢀaminoglucosyl series (Scheme 10), the small bridge
is the anomeric carbon and ring contraction is facilitated by the presence of glycosidic oxygen.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
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26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 11. 1ꢀOxabicyclo[3.1.0]hexyl Oxonium Ion Formation and Opening.
Influence of the anomeric Substituent and Configuration. Finally we return to the formation of
the doubly labelled KDN derivative 13C2-53 identified as byproduct on use of 13Cꢀlabelled acetic acid as
nucleophile in the oxidative deamination of the βꢀthiosialoside 51, and the absence of comparable
products in the reactions of the epimeric substrate 48 or the Oꢀglycoside 26 (Scheme 4). We suggest
that incorporation of the label at the 4ꢀposition is best explained by the series of equilibria outlined in
Scheme 12. Thus the diazoalkane A, whose formation is dictated by the deuterium incorporation
experiment (Scheme 6), exists in equilibrium with the zwitterion C arising from participation by the ring
axial thioglycoside. O→N Acetate transfer then occurs via a sixꢀmembered cyclic transition state from
O4 to give the Nꢀacyl diazene C, which undergoes deacetylation on reaction with the labelled acetic acid
present in the reaction mixture to give D and 13Cꢀlabelled acetic anhydride. The reverse process returns
either A or 13C1-A depending on which of the two carbonyl groups in the mono 13Cꢀlabelled acetic
anhydride serves as electrophile. With the label introduced at O4, 13C1-A then enters the standard
13
mechanism in parallel with its isotopomer A leading overall to the formation of 13C2-53 and C1-53,
respectively.
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SAda
CO2Me
SAda
1
2
3
4
5
6
7
8
R
R
CO2Me
O
O
OAc
O
N
N
N
N
N
O
A
13C1-A
SAda
CO2Me
SAda
CO2Me
N
N
O
N
O
9
R
R
O
OAc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
13C1-B
B
SAda
CO2Me
SAda
N
N
O
N
CO2Me
N
O
R
R
O
Ac
O
O
13C1-C
C
O
AcOH
SAda
CO2Me
OH
N
O
N
R
OH
O
+
D
OAc
Scheme 12. Incorporation of 13CꢀLabelled Acetate at O4 in the Axial Thioglycoside 53.
Conclusion. The stereoretentive oxidative deamination of the NꢀnitrosoꢀNꢀacetyl sialyl glycosides
derives its stereospecificity from participation by the pyranosyl ring oxygen through the intermediacy of
a 1ꢀoxabicyclo[3.1.0]hexyl oxonium ion and not via participation by esters at either the 4ꢀ or 7ꢀ
positions. In general the oxidative deamination of the sialic acids and the 4ꢀaminoꢀ4ꢀdeoxyꢀ and 2ꢀ
aminoꢀ2ꢀdeoxy glycopyranosides proceeds through a common pathway with the differences in product
distribution, mainly substitution verses ring contraction, determined by the substituents at the level of
the 1ꢀoxabicyclo[3.1.0]hexyl oxonium ion intermediate. A minor reaction pathway in the βꢀ
thiosialosides has been identified by isotopic labelling studies in which the 4ꢀOꢀacetate undergoes
exchange with external acetic acid in the medium, for which a mechanism is proposed.
Acknowledgments
We thank the NIH (GM62160) for support of this work, and acknowledge support from the NSF
(MRIꢀ084043) for the purchase of the 600 MHz NMR spectrometer in the Lumigen Instrument Center at
Wayne State University.
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Supporting Information Available. Full experimental details and copies of H and 13C NMR
1
1
2
3
spectra for all new compounds. This information is available free of charge via the internet at
4
5
6
http://pubs.acs.org.
7
8
References
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