Use of Phenols as Nucleophiles in the Zbiral Oxidative Deamination of N-Acetyl Neuraminic Acid: Isolation and Characterization of Tricyclic 3-Keto-2-deoxy-nonulosonic Acid (KDN) Derivatives via an Intermediate Vinyl Diazonium Ion

Article abstract of DOI:10.1021/acs.joc.9b02279

It is well established that the N-nitrosoamide derived from peracetylated derivatives of N-acetyl neuraminic acid on treatment with a mixture of sodium isopropoxide and trifluoroethanol, followed by the addition of acetic acid, gives an oxidative deamination product, in which the AcN(NO)-C5 bond is replaced with a AcO-C5 bond with the retention of configuration, affording a practical synthesis of 2-keto-3-deoxy-d-glycero-d-galactononulosonic acid (KDN) derivatives. Application of other strong acids, including hydrogen fluoride, thioacetic acid, trifluoromethanesulfonic acid, and hydrogen azide, functions similarly to afford KDN derivatives functionalized at the 5-position. We describe our attempts to extend the range of useful nucleophiles employed in this oxidative deamination process to include phenols and thiophenols, resulting in the discovery of a new branch of the general reaction and the formation of a series of products resulting from substitution of the 5-acetamido group and of the 4-acetoxy group from neuraminic acid. A mechanistic rationale for the formation of these products is advanced according to which, in the absence of acids of pK_a ≤ 8, the intermediate diazonium ion resulting from the elimination of acetic acid and nitrogen from the nitrosoacetamide undergoes elimination of acetic acid from the 4-position to afford a highly electrophilic alkenediazonium ion. Reversible conjugate addition of the nucleophile to the 4-position then initiates the reaction cascade leading to the ultimate products.

Full text of DOI:10.1021/acs.joc.9b02279

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Article
Use of Phenols as Nucleophiles in the Zbiral Oxidative
Deamination of N-Acetyl Neuraminic Acid. Isolation and
Characterization of Tricyclic 3-Keto-2-Deoxy-nonulosonic Acid
(KDN) Derivatives via an Intermediate Vinyl Diazonium Ion
Mohammed Hawsawi, Anura Wickramasinghe, and David Crich
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02279 • Publication Date (Web): 13 Oct 2019
Downloaded from pubs.acs.org on October 21, 2019
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Use of Phenols as Nucleophiles in the Zbiral Oxidative Deamination of N-Acetyl
Neuraminic Acid. Isolation and Characterization of Tricyclic 3-Keto-2-Deoxy-nonulosonic
Acid (KDN) Derivatives via an Intermediate Vinyl Diazonium Ion
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Mohammed Hawsawi, Anura Wickramasinghe, and David Cricha,b,c,d,
a
a,b*
*
a) Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202,
USA
b) Department of Pharmaceutical and Biomedical Sciences, University of Georgia, 250 West
Green Street, Athens, GA 30602, USA
c) Department of Chemistry, University of Georgia, 140 Cedar Street, Athens, GA 30602, USA
d) Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens,
GA 30602, USA
awick@uga.edu; David.Crich@uga.edu
Graphical abstract
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OMe
CO2Me
OMe
OMe
CO2Me
R
N
N
O
Nu
R
O
CO2Me
R
O
AcN
ON AcO
X
nucleophilic
substitution
(pKa~8)
OAc
AcO
alkane diazonium ion
stereoretentive
elimination (pKa~8)
R
O
OMe
O
CO2Me
-naphthol
O
R
OMe
conjugate
addition
N
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N
CO2Me
vinyl diazonium ion
and cyclization
- Formation of highly reactive intermediates
Formation of tricyclic and elimination products
(R = CHOAcCHOAcCH2OAc)
-
Abstract
It is well established that the N-nitrososamide derived from peracetylated derivatives of N-
acetylneuraminic acid on treatment with a mixture of sodium isopropoxide and trifluoroethanol,
followed by addition of acetic acid gives an oxidative deamination product in which the AcN(NO)-
C5 bond is replaced a AcO-C5 with retention of configuration, affording a practical synthesis of
2
-keto-3-deoxy-D-glycero-D-galactononulosonic acid (KDN) derivatives. Application of other
strong acids, including hydrogen fluoride, thioacetic acid, trifluoromethanesulfonic acid and
hydrogen azide, functions similarly to afford KDN derivatives functionalized at the 5-position.
We describe our attempts to extend the range of useful nucleophiles employed in this oxidative
deamination process to include phenols and thiophenols, resulting in the discovery of a new branch
of the general reaction and the formation of a series of products resulting from substitution of the
5
-acetamido group and of the 4-acetoxy group from neuraminic acid. A mechanistic rationale for
the formation of these products is advanced according to which, in the absence of acids of pKa ≤8,
the intermediate diazonium ion resulting from elimination of acetic acid nitrogen from the
nitrosoacetamide undergoes elimination of acetic acid from the 4-position to afford a highly
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electrophilic alkenediazonium ion. Reversible conjugate addition of the nucleophile to the 4-
position then initiates the reaction cascade leading to the ultimate products.
Introduction
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The oxidative degradation of aliphatic amides by thermolysis of their N-nitroso derivatives in the
presence and absence of external carboxylic acids giving rise to the corresponding esters with loss
of nitrogen was first described by White.1-4 An extensive series of studies employing O-labelling
experiments, and variation of solvent, substrate, and external acid demonstrated that under thermal
conditions the reaction proceeds with a preponderance of with retention of configuration when
applied to chiral secondary and tertiary amides leading to the suggestion of a mechanism involving
18
the formation and collapse of a series of two tight ion pairs, following initial N→O migration of
the acyl moiety (Scheme 1).1-4
R3
R3
ON
O
N
N
N
O
N
R3
R1
H
N
O
R1
H
R1
H
O
R2
R2
R2
O
-
N2
R3
R3
O
R1
H
O
O
R1
H
O
R2
R2
Scheme 1. White Mechanism for Oxidative Deamination of N-Nitroso Amides
Among the numerous applications of this reaction some of the more important are in the field of
5
carbohydrate chemistry and in particular in the conversion of the widely available N-acetyl
neuraminic acid (NeuAc, 1) and its derivatives to the less widely available but increasingly
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biologically relevant 3-keto-2-deoxy-nonulsonic acid (KDN, 3) derivatives (Scheme 2).6-8 Indeed,
this has proven to be a pivotal transformation in the synthesis of the pseudaminic acid, glycosides
such as found in the lipopolysaccharides from Pseudomonas aeruginosa and other pathogens.9-11
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AcO
AcN
AcO
OAc
CO2Me
OAc
CO2Me
OAc
AcO
AcO
OAc
AcO
O
O
AcHN
OAc
N
O
1
2

(Ogura) or
i) iPrONa, CF CH OH
3
2
ii) AcOH (Zbiral)
AcO OAc
OAc
AcO
AcO
OMe
OAc
CO2Me
AcO
O
AcO
OAc
+
O
CO Me
2
AcO
AcO
4
3
Scheme 2. Ogura and Zbiral’s NeuAc to KDN Conversion.
The oxidative deamination protocol was first applied to NeuAc by Ogura and coworkers who
relied on simple White-type thermal degradation of the N-nitroso amide 2, obtaining a KDN
derivative 3 and, albeit without supporting spectral data, the product of a ring contraction 4 with
inversion of configuration at the site of reaction (Scheme 2).12 It was Zbiral and Schreiner,
however, who developed practical conditions for the NeuAc to KDN conversion involving the
stepwise treatment of the N-nitroso amide with sodium isopropoxide and trifluoroethanol followed
6
rapidly by acetic acid. The Zbiral laboratory also observed the formation of and characterized the
6
ring contraction product (Scheme 2). In our laboratory we modified the Zbiral conditions to render
them compatible with NeuAc thioglycosides, leading to a ready preparation of a KDN donor and
7
ultimately to the highly stereocontrolled synthesis of KDN-a-glycosides. We further modified
the Zbiral conditions to permit replacement of the previously ubiquitous acetic acid nucleophile
by thioacetic acid, hydrogen fluoride, triflic acid, and levulinic acid derivatives, leading to the
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formation of the corresponding desacetamido acetylthio, trifloxy, fluoro, and levulinoxyl
derivatives, each with retention of configuration.8, 13 We also demonstrated the compatibility of
the reaction with NeuAc di- and trisaccharides and its potential for application in the development
of improved aminoglycoside antibiotics.13, 14 The very high levels of retention of configuration in
these reactions prompted us to probe the reaction mechanism, leading to the exclusion of
participation by the neighboring esters and the invocation of participation by the pyranoside ring
oxygen via a 1-oxabicyclo[3.1.0]hexanium-type intermediate 10,15 which also satisfactorily
accounts for the formation of the ring contraction product observed by the early workers in the
field (Scheme 3). Although unusual, such 1-oxabicyclo[3.1.0]hexane-type intermediates have
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been invoked by Corey and coworkers in the course of a total synthesis of glabrescol, and by
17
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19
20
Stevens, Hanessian, Horton, and Cassinelli in a variety of pyranoside to furanoside ring
2
1
22
contractions. Equivalent 1-thiabicyclo[3.1.0]hexanium and 1-azabicyclo[3.1.0]hexanium are
also widely postulated in the literature.
OAc
OAc
OMe
OAc
OAc
OMe
AcO
CF3CH2ONa
AcO
O
O
2
CO Me
CO2Me
N
N
AcN
ON
OAc
OAc
O
5
6
HX
OAc
OAc
OMe
OAc
OAc
OMe
+ H
- H
AcO
AcO
O
O
CO2Me
CO2Me
N2
N
OAc
OAc
N
X
7
8
-
N2
AcO
OMe
CO2Me
OAc
OAc
OMe
OAc
AcO
O
AcO
O
CO2Me
OAc
H
OAc
H
X
10
X
9
AcO OAc
X
OMe
CO2Me
AcO
O
OAc
OAc
OMe
AcO
O
CO2Me
X
AcO
OAc
4
11
ring contraction
substitution with retention
HX = HO2CR, HSAc, HF, HO3SCF3,
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Scheme 3. Proposed Mechanism of Zbiral Reaction and Ring Contraction
Continuing our earlier studies on the use of alternative nucleophiles to the original acetic acid with
the goal of preparing novel NeuAc derivatives with which to probe and exploit structural
differences between sialic acid binding proteins of different origins, we turned to the use of phenols
as nucleophiles. As we report, a series of structurally interesting derivatives were formed albeit
not the simple 5-O-aryl KDN ones initially envisaged. Rather, cine-substitution occurs leading to
the formation of a series of vinyl ethers and, in the case of ambient nucleophiles such as β-naphthol,
the formation of structurally unusual tricyclic systems. These products shed further light on the
mechanism of the Zbiral reaction in the presence of weakly acidic nucleophiles and invoke the
formation of a little studied class of electrophile, the vinyl diaozonium ions,23-30 as intermediates.
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Results
Methyl (methyl 4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-(N-nitrosoacetamido)-D-glycero-β-D-
galacto-non-2-ulopyranosid)onate 5 was prepared according to a procedure reported in the
literature7, 15 from commercially available N-acetylneuraminic (NeuAc) by nitrosylation of the
corresponding amide 12 with nitrosyl tetrafluoroborate (NOBF ) and pyridine in dichloromethane
4
at – 10 C; it was used immediately for the oxidative deamination without further purification. The
deamination reactions were typically affected by treatment of the nitrosoamide 5 with sodium
trifluoroethoxide in the presence of 18-crown-6 in anhydrous dichloromethane at – 10 C, as
1
5
described previously, followed after 10 mins (sufficient time for the consumption of 5) by
addition of an excess of the putative nucleophile. After stirring for a further 5 mins the reactions
were quenched by addition of aqueous sodium bicarbonate, washed with aqueous sodium
hydroxide to remove the excess nucleophile, and then subjected to chromatographic purification
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to afford the products (Table 1). Under these conditions the use of levulinic acid as nucleophile
afforded the typical substitution product 13 with retention of configuration in 31% isolated yield,
accompanied by the regioisomeric elimination products 14 and 15 in 34% combined yield (Table
1
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, entry 1). Replacement of the carboxylic acid nucleophile by phenol resulted in the isolation of
the disubstitution product 16, in which the acetoxy group at the 4-position was substituted by
phenol with retention of configuration in addition to replacement of the nitrosoamide at the 5-
position with inversion of configuration (Table 1, entry 2). Additionally, enol ether 17 was isolated
from this reaction in 31% yield. The use of β-naphthol as nucleophile on the other hand afforded
the tricyclic product 18 in 57% yield along with the azo dye 19 in 13% yield (Table 1, entry 3).
Returning to simple monocyclic phenols, the use of p-methoxyphenol afforded 36% of the enol
ether 20 (Table 1, entry 4), whereas that of p-nitrophenol gave 9% of the typical substitution
product 21 and 9% of the elimination product 22 (Table 1, entry 5). The use of 3,5-
dimethoxyphenol on the other hand resulted in the isolation of the tricyclic adduct 23 in 34% yield
(Table 1, entry 6). Turning to the use of heteroaromatic phenols as nucleophiles, attempted use of
2
7
-quinolinol gave only the elimination products 14 and 15 in 86% combined yield (Table 1, entry
), whereas 3-quinolinol afforded 24 and 25 in 21 and 12% yield, respectively (Table 1, entry 8).
With the use of 6-quinolinol on the other hand the pattern of reactivity seen with β-naphthol and
,5-dimethoxyphenol was again observed with the isolation of the tricyclic product 26 in 53%
3
yield (Table 1, entry 9). This latter reaction was conducted in the poorly nucleophilic
hexafluoroisopropanol31, 32 as solvent owing to the limited solubility of the nucleophile in the more
typical dichloromethane. The same pattern was reverted to with 5-hydroxyindole resulting in the
isolation of the tricyclic product 27 in 3% yield when the reaction was conducted at -10 °C (Table
1, entry 10), and in 27% yield when the reaction temperature was lowered to -40 °C (Table 1, entry
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1
1). The formation of 27 was accompanied by that of the elimination products 14 and 15 in 35%
and 7% combined yield at -10 and -40 °C, respectively (Table 1, entries 10 and 11), while 9% of
the azo dye 28 was also isolated from the reaction at the lower temperature (Table 1, entry 11).
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Table 1. Application of Levulinic Acid and of Phenols as Nucleophiles in the Zbiral Reactiona
AcO
AcO
AcN
OMe
O
CO2Me
i) CF3CH2ONa,
OMe
CO2Me
OAc
AcO
AcO
OAc
AcO
NOBF , py
4
18-c-6, CH Cl , -10 °C
2
2
Products
O
AcHN
CH Cl , -10 °C
2
2
ii) Nucleophile
ON AcO
12
5
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
0
1
2
3
4
5
6
7
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9
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1
2
3
4
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Entry Nucleophileb
pKa
Products (% yield)c
4.6033
AcO
OAc
AcO
OMe
CO Me
AcO
OMe
CO Me
1
Levulinic Acid
OMe
OAc
AcO
AcO
OAc
AcO
AcO
O
O
CO Me
O
2
O
2
2
O
Me
AcO
O
AcO
14 + 15, 34%; 14:15 = 1:2.5
13, 31%, eq only
9.9834
AcO
OMe
2
3
Phenol
OAc
AcO
OMe
CO2Me
AcO
AcO
OAc
O
CO Me
2
O
OPh
PhO
PhO
OH
17, 31%
16, 33%
9.535
R
β-Naphthol
O
OMe
O
R
O
OMe
N
CO Me
2
N
AcO
CO Me
2
(
R = CHOAcCHOAcCH OAc)
(
R = CHOAcCHOAcCH OAc)
2
2
18, 57%
19, 13%
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1
0
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
10.2134
7.1534
9.5
AcO
4
5
4-Methoxyphenol
4-Nitrophenol
OMe
CO2Me
AcO
OAc
O
4
-MeOC H O
6
4
20, 36%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
AcO
AcO
OMe
CO Me
OMe
O
CO Me
OAc
OAc
AcO
AcO
4
O
2
2
O
AcO
-O NC H O
2
6 4
O N
21, 9%
2
22, 9%
MeO
R
O
6
3,5-Dimethoxyphenol
O
OMe
CO Me
MeO
2
(
R = CHOAcCHOAcCH OAc)
2
23, 34%
7.8636
AcO
7
8
2-Hydroxyquinoline
3-Hydroxyquinoline
AcO
OMe
OMe
OAc
AcO
AcO
OAc
AcO
O
CO Me
O
CO Me
2
2
AcO
14 + 15, 86%; 14:15 = 2.5:1
8.0336
AcO
OMe
AcO
AcO
OMe
AcO
OAc
O
OAc
O
O
CO2Me
CO2Me
O
N
N
24, 21%
2
5, 12%
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2
3
4
5
6
7
8
9
9d
8.8736
R
O
6-Hydroxyquinoline
O
OMe
N
CO Me
2
(
R = CHOAcCHOAcCH OAc)
2
26, 53%
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
R
O
1
1
0
5-Hydroxyindole
5-Hydroxyindole
-
-
O
AcO
OMe
CO2Me
AcO
OMe
O
CO2Me
AcO
OAc
AcO
AcO
OAc
OMe
CO2Me
R = CHOAcCHOAcCH2OAc)
O
HN
AcO
4 + 15, 35%; 14:15 = 1:1.3
(
1
2
7, 3%
1e
R
O
AcO
OMe
CO2Me
AcO
OMe
CO2Me
N
AcO
OAc
OAc
AcO
OMe
O
CO2Me
AcO
OAc
AcO
AcO
AcO
O
OMe
CO2Me
R = CHOAcCHOAcCH2OAc)
7, 27%
O
O
HN
N
N
AcO
4 + 15, 7%; 14:15 = 1:1.3
(
OH
1
28, 9%
2
a) Unless otherwise stated all reactions were conducted at -10 °C in dichloromethane. b) Nucleophiles were employed in 10-20 fold
excess as detailed in the Supporting Information. c) The elimination products 14 and 15 are the major side products in all reactions as
determined by inspection of the crude reaction mixtures by mass spectrometry and NMR spectroscopy, albeit they were not isolated
and quantified in every case. d) 6-Hydroxyquinoline was added as a solution in hexafluoroisopropanol. e) This reaction was
performed at – 40 C.
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2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Attention was next turned to the use of thiophenols as nucleophiles. With the parent, the direct substitution
product 29 was isolated in 23% yield and retention of configuration (Table 2, entry 1), accompanied by
the reduction product 30 in 19% yield. The use of 2-aminothiophenol on the other hand gave 58% of the
substitution product 31, but in the form of a 3:1 axial:equatorial mixture of isomers (Table 2, entry 2),
together with the reduction product 30 in 20% yield. Finally, the use of 2-mercaptonaphthalene as
nucleophile gave the substitution with retention product 32a in 30% yield, contaminated with a minor
amount of the stereoisomer 32b (25%), and the reduction product 30 (13%) (Table 2, entry 3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Application of Thiophenols in the Zbiral Reactiona
Entry Nucleophileb
pKa
6.6
Products (% yield)c
3
5
AcO
1
Thiophenol
OMe
OAc
AcO
AcO
OMe
O
CO Me
AcO
OAc
AcO
AcO
AcO
O
CO Me
2
PhS
2
OAc
29, 23%
3
0, 19%
OMe
CO Me
AcO
S
OMe
CO2Me
2
2-Aminothiophenol
6.5937
OAc
AcO
OAc
O
O
2
AcO
NH2
AcO
3
0, 20%
31, 58%; ax:eq = 1:3
2-Mercaptonaphthalene 5.935
AcO
OMe
AcO
OMe
OAc
OAc
AcO
AcO
OMe
O
CO2Me
3
AcO
CO2Me
AcO
OAc
AcO
O
O
CO2Me
S
S
OAc
OAc
32a + 32b, 25%; ax:eq = 1:4
3
2a, 30%
30, 13%
a) All reactions were conducted at -10 °C in dichloromethane. b) Nucleophiles were employed in 10-20
fold excess as detailed in the Supporting Information. c) The elimination products 14 and 15 are the
major side products in all reactions as determined by inspection of the crude reaction mixtures by mass
spectrometry and NMR spectroscopy, albeit they were not isolated and quantified in this series of
reactions.
Structural Elucidation
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3
1
2
3
While the structures of the direct substitution products 13, 21, 29, 23, 31 and 32, the elimination products
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
4 and 15, and the reduction product 30 follow directly from the H-NMR spectra and require no further
discussion, the elucidation of some of the unexpected products deserves comment. The structure of the
disubstitution product 16 follows directly from analysis of the 3JH,H coupling constants and nOe contacts
around the pyranose ring. Thus, the 3JH4,H5 and 3JH5,H6 coupling constants of 4.5 and 2.0 Hz, respectively,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
for a spectrum recorded in CDCl owing to the co-incidence of H’s 5 and 6 in CDCl , are indicative of the
3
3
all cis-nature of the substituents at C’s 4, 5, and 6, and are supported by the nOe correlation between H’s
and 6. The structure of the tricyclic product 18 was determined by X-ray crystallography (Fig 1) of a
4
crystal obtained from diethyl ether. In the crystal the pyranose ring adopts a conformation best described
as approximating to the 3,6B boat. This 3,6B conformation also predominates in solution as indicated by
3
the observed pattern of J scalar couplings in the H , H , H , H spin system (Table 3) as well as by nOe
3
a,b
4
5
6
interactions measured between one of the H3 protons and the aromatic proton peri to the ring junction.
Figure 1: X-ray crystallographic structure of product 18 (CCDC 1941624)
It is noteworthy in view of the current interest in the influence of side chain conformation on the reactivity
of glycosyl donors,11, 38, 39 that the side chain of 18 adopts what is effectively the gauche,gauche-
conformation (gg)40, 41 similar to that found in NeuAc itself.42-48 In this regard, it is also of interest to note
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4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
that the side chain of 16, with the axial substituent at C5 and J of 5.6 Hz, does not take up the gg-
6
,7
3
2
42-48
conformation, which is characterized by J of ~ 2 Hz in the standard C chair conformation.
This is
6
,7
5
presumably due to the strong dipolar and steric (syn-pentane-type) interactions that would exist between
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
the C5-O5 and C7-O7 bonds in such a conformation.8
The structures and solution conformations of the bicyclic products 23, 26, and 27 are assigned by analogy
to that of 18 and the close homology of the coupling constants in the H3a,b, H , H , H spin system (Table
4
5
6
3
3
). In each of the tricyclic products 18, 23, 26, and 27 the J coupling constant between the pseudo-axial
bowsprit H3 and H4 is at the upper limit (12.9-13.5 Hz) of the usual range seen for a pair of coupled
trans-diaxial spins in a saturated aliphatic systems lacking direct electronegative substituents.49
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5
1
2
3
Table 3. Diagnostic Chemical shifts and Coupling Constants for 16, 18, 23, 26, and 27.a
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
Chemical Shifts (δ, ppm)b
Coupling Constants (Hz)
3J3pa,4
3J3pe,4
3J4,5
3J5,6
3J6,7
2J3pa,pe
Product
H3pa
2.55
2.77
1.90
1.79
1.92
2.02
H3pe
2.47
2.57
2.86
2.63
2.78
2.72
H4
H5
H6
H7
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
1
1
1
2
2
2
6
6c
8
3
6
7
4.52
4.61
3.87
3.47
3.88
3.77
3.14
3.01
4.94
4.70
4.99
4.82
3.13
3.18
4.21
4.03
4.21
4.12
4.99
5.16
5.69
5.59
5.68
5.67
8.9
3.2
3.4
5.0
5.4
5.1
5.5
3.7
4.5
9.2
9.1
8.9
8.8
-
5.3
5.7
5.1
4.6
5.0
5.0
14.9
14.8
14.9
14.9
14.9
14.9
8.8
2.0
9.4
9.4
9.3
9.4
13.5
12.9
13.4
12.8
a) All spectra were recorded in CDCl unless otherwise stated. b) H3pa and H3pe refer to the pseudo-axial and pseudo-equatorial protons at
3
C3, respectively. c) Recorded in C D .
6
6
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1
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3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
13
The usual H and C spectroscopic methods did not allow unambiguous distinction between two possible
regioisomers for the enol ethers 17, 20, and 24 owing to the multiplicity of long range coupling constants
spanning the alkene. Ultimately, taking 20 as a representative example, the structure was assigned
following treatment with ethylene glycol in dichloromethane in the presence of p-toluenesulfonic acid at
room temperature when the cyclic ketal 33 was isolated in 42% yield (Scheme 4). The isolated nature of
the two methylene spin systems in this ketal clearly points to 33 as the structure and not the alternative
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
5, and thus to 20 as the structure of the enol ether as opposed to 34. Further confirmation of the structure
of 20 was obtained on treatment with ethylene glycol and p-toluenesulfonic acid in wet methanol at room
temperature when the enone 36 was isolated in 55% yield (Scheme 4). The structures of 17, and 24 follow
from the close homologies of their NMR spectra with those of 20. The structures of the azo dyes 19 and
2
8 follow directly from their mass and NMR spectra, and their intense yellow colors with λmax 380 nm
-
1
-1
-1
-1
(
acetonitrile, ε = 8699 M cm ) and 365 nm (dichloromethane, ε = 2391 M cm ), respectively, in the
UV/visible spectra recorded.
MeO
O
AcO
OMe
CO2Me
AcO
OAc
MeO C
O
2
O
HOCH CH OH, pTSA
O
2
2
AcO
4
-MeOC6H4O
2 2
CH Cl , rt
AcO
2
0
33, 42%
AcO
AcO
OMe
CO2Me
AcO
OMe
CO2Me
OAc
AcO
OAc
O
AcO
-MeOC6H4O
34 (eliminated from consideration)
2 2
HOCH CH OH
O
O
O
4
pTSA, CH2Cl2, rt
35, not formed
AcO
OMe
CO2Me
HOCH2CH2OH, pTSA
AcO
OAc
O
AcO
AcO
OAc
O
2
CO Me
O
4
-MeOC6H4O
20
MeOH, H2O, rt
3
6, 55%
Scheme 4. Structural Elucidation of 20.
Discussion
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7
1
2
3
The results are best interpreted in terms of a new branch of the mechanism we advanced previously for
the Zbiral reaction. Thus, reaction of the N-nitrosoacetamide 5 with trifluoroethoxide leads to the
formation of a diazonium ion 7, which undergoes reversible deprotonation to the diazoalkane 8. Evidence
for the formation of the diazonium ion as a discrete intermediate in this process is now provided in the
form of the azo dyes 19 and 28, which are the typical products of the reaction of diazonium ions with β-
naphthols and related phenols. The reversibility of the deprotonation was previously established through
the use of deuterioacetic acid as nucleophile, which resulted in the formation of monodeuterio-KDN with
selective introduction of a deuterium atom in the 5-position.15
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
0
The pKa of the methyldiazonium ion (pKa~10) and, by extrapolation, that of the diazonium ion 7, with
its electron-withdrawing and acidity-enhancing β-C-O bonds, is such that with carboxylic acids and more
acidic species as reaction partner the diazonium ion – diazoalkane equilibrium strongly favors the
diazonium ion and, following loss of nitrogen, the heretofore standard substitution and elimination
products (Scheme 2). With less acidic reaction partners such as the phenols employed here we postulate
that the diazoalkane 8 undergoes β-elimination of the acetoxy group from the 4-position to give the α,β-
unsaturated diazonium ion 37, a member of the little-studied class of alkenediazonium ions (Scheme 5).
This strongly electrophilic species can be considered to populate at least the two half-chair conformers
O
2
2
3
7- H and 37- H , and related boat conformers, with 37- H undergoing kinetic Michael addition from
2 O O
the β-face past the minimally sterically demanding methoxy group to afford the new diazoalkane 38
directly in a chair conformation. Under thermodynamic conditions a process of reversible additions and
eliminations leads to the eventual introduction of the nucleophile in the equatorial position, presumably
O
by bottom face attack on 37- H leading directly to the observed chair conformation, but possibly by
2
2
bottom face attack on 37- H and subsequent conformational equilibration.
O
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8
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
OMe
OMe
O
CO2Me
O
CO Me
2
R
OMe
R
R
N2
N2
O
N
OAc
N
CO Me
2
8
37-2HO
O
37- H
2
+ H
Nu
Nu
-
H
OMe
OMe
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OMe
Nu
O
R
O
CO2Me
R
CO2Me
R
O
CO2Me
N2
N
N
Nu
39 (thermodynamic)
OAc
N
N
38 (kinetic)
7
Scheme 5. Mechanism of Substitution at C4
With phenol as nucleophile, the thermodynamic mode of addition is observed and is followed by
protonation of the diazoalkane from the α-face by a second molecule of phenol giving a contact
ion pair (CIP) 41, which collapses with loss of nitrogen and inversion of configuration to give the
observed product 16 (Scheme 6). α-Face protonation of 40 to give 41 is consistent with the
protonation of diazoalkane 8, returning diazonium ion 7 (Scheme 3), established in our earlier
studies by deuterium labelling experiements.15 In the case of the more acidic nucleophiles
classically employed in the Zbiral reaction, invertive collapse of the analogous CIP is retarded by
the reduced nucleophilicity of the anion, leading to participation by the ring oxygen and overall
substitution with retention of configuration at the 5-position (Scheme 3). Finally, loss of nitrogen
from 41 followed by, or in concert with, deprotonation affords the enol ether 17 (Table 1, entry 2).
p-Methoxyphenol and 3-quinolinol follow a similar path to phenol itself with the enol ethers 20,
2
4 and 25 as major isolated products (Table 1, entries 4 and 8). p-Nitrophenol on the other hand
is considerably more acidic than phenol such that reprotonation of the diazonium ion 37 is
competitive with elimination and the standard substitution product 21 is formed at least in a minor
amount (Table 1, entry 5).
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9
1
2
3
4
5
6
7
8
9
OMe
O
PhOH
R
O
CO Me
2
OMe
N
R
N2
OPh
40
N
CO Me
2
OMe
O
CO Me
O
37- H
2
R
2
PhOH
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
PhO
- N , H
2
17
OMe
O
CO Me
OMe
CO Me
R
R
O
2
2
N2
OPh
OPh
H
PhO
OPh
1 (CIP)
1
6
4
Scheme 6. Formation of Disubstitution Product 16.
With the less aromatic ambident nucleophile β-naphthol, and analogously the other electrophilic
aromatic substitution prone phenols, the kinetic Michael addition product 42 is trapped by
intramolecular proton transfer, possibly from the rearomatized phenol as shown or possibly as a
part of the rearomatization process, leading a zwitterion 43 that undergoes ring closure with loss
of nitrogen and inversion of configuration leading to the tricyclic product 18 (Scheme 7). 2-
Quinolinol, which exists predominantly in the quinolinone form, is both more acidic and only very
weakly nucleophilic resulting in predominant formation of the elimination products 14 and 15
(
Table 1, entry 7).
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0
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
OMe
CO Me
-naphthol
2
HO
R
OMe
N2
O
R
O
CO Me
2
2
3
7- H
O
N
N
4
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R
O
O
O
OMe
CO Me
OMe
R
O
2
CO Me
2
18
N2
43 (zwitterion)
Scheme 7. Formation of Tricyclic Product 18.
With the more acidic thiophenols as reaction partners, the acidity of the reaction medium is
sufficient that the initial diazonium ion – diazoalkane equilibrium strongly favors the former such
that the prototypical simple substitution with retention of configuration (Scheme 3) is the
predominant reaction pathway. The observation of minor amounts of the substitution with
inversion in this series suggests, however, that direct displacement of nitrogen from the diazonium
ion by the sulfur-based nucleophile is in competition with participation by the ring oxygen. The
formation of the reduction product 30 in the presence of thiophenol most likely arises either from
single electron transfer from the thiophenate to the diazonium ion 7, followed by loss of molecular
nitrogen and hydrogen atom transfer to the ensuing alkyl radical 44 from the thiophenol (Scheme
8
), consistent with the established mechanism of reduction of arenediazonium ions by
thiophenols.51 Alternatively, diazonium ion 7 and thiophenate may combine to give the
arylthiodiazene 45, that undergoes homolytic scission to afford radical 44, followed by trapping
with thiophenol (Scheme 8). Either way, the isolation of the reduction product 30 constitutes
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further evidence in support of the existence of the diazonium ion 7 as a discrete intermediate in
the Zbiral chemistry.
AcO
OMe
CO2Me
AcO
OMe
CO2Me
PhS
OAc
SET
- N2
AcO
OAc
AcO
O
O
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
OAc
OAc
44
+
PhS
7

, - N2
PhSH
AcO
OMe
CO2Me
AcO
OMe
AcO
OAc
AcO
PhS
OAc
O
O
CO2Me
N
N
OAc
OAc
3
0
4
5
PhSSPh
Scheme 8. Mechanism for the formation of the Reduction Product 30.
Finally we return to the substitution of the ester at the 4-position with retention of configuration
observed during our earlier studies on the mechanism of the classical Zbiral reaction with
carboxylic acids as nucleophiles.15 Thus it was found through the use of C-enriched acetic acid
as nucleophile, and confirmed with the use of levulinic acid, that in addition to the substitution of
the acetamido group with retention of configuration in the β-thioglycoside 46 up to 30% of the
13
1
3
ester at the 4-position also underwent substitution with retention of configuration as in C -47
2
(Scheme 9).
OAc
OAc
SAda
i) CF CH OH,
AcO
3
2
O
OAc
OAc
SAda
CO2Me
O
NaOiPr, iPrOH,
X
O
AcO
o
Y
O
CH Cl , -10 C
CO Me
2
2
13
13
13
AcN
ON
2
C -47: X = CH CO, Y = Ac
C -47: X = Y = CH313CO
1
3
OAc
ii) CH313CO H
2
2
46
13
13
C -47 + C -47 = 55%
1
2
13
13
C -47 : C -47 = 2.5:1
1
2
OAc
OAc
CO Me
OAc
OAc
OMe
2
AcO
AcO
O
O
SAda
CO Me
2
AcN
ON
AcN
ON
OAc
OAc
4
8
5
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 9. Substitution at the 4- and 5-Positions in the Axial Thioglycoside 46 as Revealed by
Isotopic Labelling.
This previously unobserved substitution of the ester at the 4-position only occurred with the β-
thioglycoside 46, and not with its α-anomer 48 or the simple methyl glycoside 5 prompting us to
write a mechanism involving reversible ring closure by the thioether onto C5 at the level of the
diazoalkane followed by a reversible series of acyl migrations and cleavages.15 In the light of the
results described in this Article, it is clear that a more likely mechanism involves reversible
displacement of the acetoxy group from the 4-position of the diazoalkane 49 by the thioether
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
Scheme 10) resulting in overall substitution with retention of configuration. Displacement of the
acetoxy group from the 4-position by the thioether is facilitated by the presence of the neighboring
diazoalkane resulting in what is effectively an allylic displacement.
Ada
OAc
OAc
SAda
OAc
OAc
S
- AcO
+ AcO
AcO
AcO
O
O
CO Me
CO2Me
2
N
OAc
N
N
N
50
49
Scheme 10. Likely Mechanism for Acetoxy Substitution at the 4-Position
Conclusion
Attempted use of phenols as nucleophiles in the Zbiral oxidative deamination of N-nitroso-N-
acetylneuraminic acid has resulted in the discovery of a new branch of this valuable reaction. In
effect, with nucleophiles of pKa≥8 the intermediate diazoalkane is favored over its protonated
form, the diazonium ion, and instead suffers elimination of the acetoxy group from the 4-position
to give an alkenediazonium ion. This highly electrophilic species undergoes reversible conjugate
addition of the phenolic nucleophiles resulting ultimately in the 4,5-disubstituted products. When
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the nucleophile is β-naphthol or other highly electron-rich phenols nucleophilic attack takes place
on carbon rather than oxygen ultimately affording a series of structurally unusual tricyclic ulosonic
acid derivatives. When the more acidic thiophenols, capable of protonating the intermediate
diazoalkane, are employed as nucleophiles, the reaction follows the classical Zbiral-like path with
the introduction of the nucleophile at the 5-position largely with retention of configuration.
Although we have restricted ourselves in this Article to the use of phenols and thiophenols as
nucleophiles, we anticipate that this new class of substitution reactions, which complements
existing methods for substitution and inversion at the 4-position of N-acetylneuraminic acid,52-56
will afford entry into a broad spectrum of unusual ulosonic acid derivatives with potential for
exploitation in medicinal chemistry.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Experimental Section
General. All reactions were performed using oven-dried glassware under an atmosphere
of argon. All reagents and solvents were purchased from commercial suppliers and were used
without further purification unless otherwise specified. Chromatographic purifications were
performed on silica gel (230-400 mesh) columns (20-50 g) of silica gel per gram of crude
compound). Reactions were monitored by analytical thin-layer chromatography on pre-coated
glass backed plates (w/UV 254) and visualized by UV irradiation (254 nm) or by staining with
2
5% H SO in EtOH or ceric ammonium molybdate (CAM) solution. Specific rotations were
2 4
measured on an automatic polarimeter with a path length of 100 mm in the solvent specified.
Concentrations are given in g/100 mL. High resolution mass spectra (HRMS) were recorded with
an electrospray ionization (ESI) source coupled to a time-of-flight (TOF) mass analyzer or with
1
13
19
an electron impact (EI) source coupled to a TOF mass analyzer. H, C, F, spectra were recorded
on a 400, 500 or 600 MHz spectrometer. NMR solvents were used without purification. Chemical
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1
1
1
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1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
shifts are given in ppm (δ) and coupling constants (J) are given in Hz. Multiplicities are given as
singlet (s), broad singlet (br s), doublet (d), triplet (t), doublet of doublets (dd), triplet of doublets
(td), multiplet (m), apparent quartet (app q), apparent pentet (app p), etc. Spectral assignments
were made by a combination of COSY, HSQC and HMBC spectra.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General Procedure of oxidative deamination. Using the quantities described in the individual
experiments, sodium 2,2,2-trifluoroethoxide and 18-crown-6 were dissolved in anhydrous CH Cl
2
2
under Ar and cooled to -10 C. The solution was added to the nitrosyl sialoside (0.1 M solution in
anhydrous CH Cl ) at -10 C under Ar. The mixture was stirred for 5 min at -10 C. The
2
2
nucleophile (10-20 equiv) dissolved in the solvent described under Ar at -10 C was added to the
reaction mixture in one portion. After stirring for 5 min, the reaction was quenched by addition of
saturated NaHCO solution and diluted with DCM. The reaction mixture was washed with NaOH
3
(1M) to remove excess phenolic nucleophile. The organic layer was washed with brine, dried over
anhydrous Na SO , and concentrated under reduced pressure to afford the crude product which
2
4
was purified by column chromatography over silica gel.57
Methyl (methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-β-D-galacto-non
2-ulopyranosid)onate (12). Compound 12 (6 g, 95%) was obtained by a literature procedure15
over two steps as a white solid from N-acetylneuraminic acid (20 g, 64.7 mmol).
Methyl
(methyl
4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-(anti/syn-N-nitrosoacetamido)-D-
glycero-β-D-galacto-non-2-ulopyranosid)onate (5). A solution of compound 12 (330 mg, 0.7
mmol) in dry dichloromethane (7 mL) was treated with dry pyridine (0.5 mL, 6.5 mmol, 10 equiv)
and cooled to -10 °C. After stirring for 15 min, crushed nitrosyl tetrafluoroborate (382 mg, 3.0
mmol, 5 equiv) was added in one portion. The reaction mixture was stirred at -10 °C until TLC
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showed complete conversion (4-5 h). The mixture was diluted with cold dichloromethane (3 mL)
and washed with cold 1N HCl, saturated NaHCO and brine. The organic layer was dried over
3
anhydrous Na SO and concentrated under 10 °C to obtain 5 as a yellowish foam which was carried
2
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
forward for next reaction without further purification.15
Methyl (methyl 4,7,8,9-tetra-O-acetyl-3-deoxy-5-O-levulinyl-D-glycero-β-D-galacto-non-2-
ulopyranosid)onate (13) and a mixture of Methyl (methyl 4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
β-D-arabino-non-4-en-2-ulopyranosid)onate (14) and Methyl (methyl 4,7,8,9-tetra-O-acetyl-
3
,5-dideoxy-β-D-ribo-non-5-en-2-ulopyranosid)onate (15). The nitrosyl sialoside 5 (267 mg,
0
.5 mmol) in CH Cl (5 mL) was deaminated using the general procedure for oxidative
2
2
deamination with sodium 2,2,2-trifluoroethoxide (122 mg, 1 mmol), 18-crown-6 (291 mg, 1.1
mmol) in CH Cl (2.5 mL) and levulinic acid (1.16 g, 10 mmol, 20 eq) in CH Cl (5 mL) to afford
2
2
2
2
1
3 after column chromatography over silica gel eluting with (hexane/ethyl acetate 3:1), as colorless
crystals from methanol/CH Cl (88 mg, 31%) and an inseparable mixture of 14 and 15 as a
2
2
colorless oil (1:2.5 ratio, 75 mg, 34%).
20
o
1
Compound 13; colorless crystals, m.p. = 132-134 C; [α] – 5.7 (c 0.4, CH Cl ). H NMR (400
D
2
2
MHz, CDCl ) δ 5.34 – 5.19 (m, 3H, H8, H7 and H4), 4.87 (t, J = 9.9 Hz, 1H, H5), 4.65 (dd, J =
3
12.6, 2.4 Hz, 1H, H9), 4.09 (dd, J = 12.5, 6.7 Hz, 1H, H9’), 4.00 (dd, J = 10.1, 2.2 Hz, 1H, H6),
3
.75 (s, 3H, CH ), 3.21 (s, 3H, CH ), 2.79 – 2.69 (m, 1H, H3e), 2.61 – 2.35 (m, 4H, CH CH ), 2.11
3 3 2 2
(
s, 3H, CH ), 2.05 (s, 3H, CH ), 2.02 (s, 3H, CH ), 1.98 (s, 3H, CH ), 1.97 (s, 3H, CH ), 1.77 (dd,
3 3 3 3 3
1
3
1
J = 13.0, 11.5 Hz, 1H, H3a). C { H} NMR (101 MHz, CDCl ) δ 205.9, 171.7, 170.6, 170.2,
3
1
70.0, 167.2, 98.9, 70.9, 70.1, 68.7, 67.8, 67.6, 62.1, 52.7, 51.4, 37.9, 37.8, 37.0, 29.7, 28.0, 21.0,
+
2
0.9, 20.8, 20.7. HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H NaO 585.1795; Found:
2
4
34
15
585.1792.
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3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
1
4 and 15 (1:2.5 mixture); colorless oil; HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H NaO
19 26
12
4
69.1322; Found: 469.1322.
1
Compound 15; H NMR (400 MHz, CDCl ) δ 5.51 (m, 1H, H8), 5.46 (m, 1H, H7), 5.25 (m, 1H,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H4), 5.07 (dq, J = 4.4, 1.1 Hz, 1H, H5), 4.36 (dd, J = 12.1, 3.0 Hz, 1H, H9), 4.30 (dd, J = 12.1, 7.1
Hz, 1H, H9’), 3.75 (s, 3H, CH ), 3.36 (s, 3H, CH ), 2.31 (dd, J = 14.1, 3.6 Hz, 1H, H3), 2.16 (dd,
3
3
J = 14.2, 5.3 Hz, 1H, H3’), 2.11 (s, 3H, CH ), 2.04 (s, 3H, CH ), 2.03 (s, 3H, CH ), 1.96 (s, 3H,
3
3
3
1
3
1
CH ). C { H} NMR (101 MHz, CDCl ) δ 170.8, 170.1, 170.0, 169.3, 167.7, 149.8, 99.2, 98.0,
3
3
7
0.4, 70.3, 63.0, 61.9, 52.7, 52.2, 34.6, 21.1, 20.9, 20.9.
1
Compound 14 was identified in the mixture by the following diagnostic signals; H NMR (400
MHz, CDCl ) δ 5.43 (dd, J = 6.1, 2.5 Hz, 1H, H8), 5.33 – 5.29 (m, 2H, H7 and H5), 4.58 (ddd, J
3
= 12.6, 2.4, 1.3 Hz, 1H, H9), 4.51 (dq, J = 4.7, 2.5 Hz, 1H, H6), 4.19 (ddd, J = 12.5, 5.9, 1.3 Hz,
13
1
1
H, H9’), 3.78 (s, 3H, CH ), 3.24 (s, 3H, CH ), 2.68 (ddd, J = 17.0, 3.9, 2.4 Hz, 1H, H3. C { H}
3 3
NMR (101 MHz, CDCl ) δ 170.7, 170.4, 169.9, 168.5, 168.0, 144.5, 110.0, 98.1, 70.7, 70.1, 69.2,
3
62.4, 52.7, 51.5, 34.8, 21.0, 20.9, 20.7.
Methyl
(methyl
7,8,9-tri-O-acetyl-3-deoxy-4,5-di-O-phenyl-D-glycero-β-D-gulo-non-2-
ulopyranosid)onate (16) and Methyl (methyl 7,8,9-tri-O-acetyl-3,5-dideoxy-4-O-phenyl-β-D-
arabino-non-4-en-2-ulopyranosid)onate (17). The nitrosyl sialoside 5 (200 mg, 0.4 mmol) in
CH Cl (4 mL) was deaminated using the general procedure for oxidative deamination with
2
2
sodium 2,2,2-trifluoroethoxide (90 mg, 0.7 mmol), 18-crown-6 (195 mg, 0.7 mmol) in CH Cl (2
2
2
mL) and phenol (188 mg, 2 mmol, 5 eq) in CH Cl (1 mL) followed by column chromatography
2
2
over silica gel eluting with (hexane/ethyl acetate 1:1) to afford 16 (71 mg, 33%) and 17 (56 mg,
1%).
3
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o
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Compound 16: colorless oil, [α] – 32.4 (c 0.25, CHCl ). H NMR (600 MHz, C D ) δ 7.29 –
D
3
6
6
7
.23 (m, 4H, ArH), 7.09 (dt, J = 7.7, 1.1 Hz, 2H, ArH), 7.04 (t, J = 7.3 Hz, 1H, ArH), 6.96 (t, J =
7.3 Hz, 1H, ArH), 6.87 (d, J = 8.5 Hz, 2H, ArH), 5.19 (td, J = 5.8, 3.7 Hz, 1H, H8), 4.99 (t, J = 5.3
Hz, 1H, H7), 4.52 (dt, J = 8.9, 3.7 Hz, 1H), 4.20 (dd, J = 12.3, 3.6 Hz, 1H, H9), 4.14 (dd, J = 12.2,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
.3 Hz, 1H, H9’), 3.56 (s, 3H, CH ), 3.48 (s, 3H, CH ), 3.17 – 3.12 (m, 2H, H6 and H5), 2.55 (dd,
3 3
J = 14.9, 8.9 Hz, 1H, H3a), 2.47 (dd, J = 14.9, 3.2 Hz, 1H, H3e), 2.07 (s, 3H, CH ), 2.04 (s, 3H,
3
1
CH ), 2.02 (s, 3H, CH ). H NMR (600 MHz, C D ) δ 7.28 – 7.26 (m, 2H, ArH), 7.08 (dt, J = 8.6,
3
3
6
6
7
.3 Hz, 4H, ArH), 6.99 – 6.96 (m, 2H, ArH), 6.84 (tt, J = 7.3, 1.2 Hz, 1H, ArH), 6.78 (tt, J = 7.4,
1.2 Hz, 1H, ArH), 5.36 (ddd, J = 6.2, 5.7, 3.6 Hz, 1H, H8), 5.16 (t, J = 5.7 Hz, 1H, H7), 4.61 (ddd,
J = 8.8, 4.6, 3.4 Hz, 1H, H4), 4.20 (dd, J = 12.3, 3.6 Hz, 1H, H9), 4.15 (dd, J = 12.2, 6.3 Hz, 1H,
H9’), 3.26 (s, 3H, CH ), 3.24 (s, 3H, CH ), 3.18 (dd, J = 5.7, 2.1 Hz, 1H, H6), 3.01 (dd, J = 4.5,
3
3
2
.0 Hz, 1H, H5), 2.77 (dd, J = 14.8, 8.8 Hz, 1H, H3a), 2.57 (dd, J = 14.8, 3.4 Hz, 1H, H3e), 1.65
1
3
1
(s, 3H, CH ), 1.63 (s, 3H, CH ), 1.57 (s, 3H, CH ). C{ H} NMR (151 MHz, CDCl ) δ 170.6,
3
3
3
3
1
6
70.1, 169.7, 168.3, 157.4, 154.4, 129.8, 129.7, 123.3, 122.1, 118.8, 116.0, 101.3, 71.6, 70.6, 70.5,
1
3
1
1.6, 57.4, 54.1, 52.8, 50.4, 37.1, 20.9, 20.8, 20.8. C{ H} NMR (151 MHz, C D ) δ 169.8, 169.6,
6
6
169.3, 168.1, 158.1, 155.1, 129.9, 129.9, 128.2, 128.1, 127.9, 123.3, 122.1, 119.3, 116.6, 101.8,
7
2.6, 71.2, 71.0, 61.7, 57.6, 54.4, 52.1, 50.2, 37.4, 20.4, 20.2, 20.1. ESI-HRMS Calcd. for
+
(C H NaO ) :([M+Na] ) m/z: 597.1948; found: 597.1943.
2
9
34
12
2
0
o
1
Compound 17: colorless oil, [α] – 32.1 (c 0.26, CHCl ). H NMR (600 MHz, CDCl ) δ 7.32 (t,
D
3
3
J = 7.9 Hz, 2H, ArH), 7.12 (t, J = 7.4 Hz, 1H, ArH), 6.98 (d, J = 7.7 Hz, 2H, ArH), 5.44 (dd, J =
.2, 2.3 Hz, 1H, H8), 5.26 (dd, J = 6.4, 2.7 Hz, 1H, H7), 4.69 (t, J = 1.9 Hz, 1H, H5), 4.57 (dd, J
12.5, 2.4 Hz, 1H, H9), 4.48 (p, J = 2.6 Hz, 1H, H6), 4.21 (dd, J = 12.5, 6.1 Hz, 1H, H9’), 3.83
(s, 3H, CH ), 3.31 (s, 3H, CH ), 2.65 (ddd, J = 17.2, 3.7, 2.2 Hz, 1H, H3), 2.54 (dd, J = 17.2, 2.6
6
=
3
3
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1
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2
2
2
2
2
2
2
2
2
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3
3
3
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5
5
5
5
6
13
1
Hz, 1H, H3’), 2.08 (s, 3H, CH ), 2.04 (s, 3H, CH ), 2.03 (s, 3H, CH ). C { H} NMR (151 MHz,
3
3
3
CDCl ) δ 170.8, 170.0, 169.9, 168.4, 154.6, 151.0, 129.8 (2 carbons), 124.4, 120.2 (2 carbons),
3
99.4, 98.5, 71.3, 70.2, 69.4, 62.5, 52.8, 51.6, 34.5, 21.0, 20.9, 20.9. ESI-HRMS Calcd. for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(
C H NaO ) :([M+Na] ) m/z: 503.1529; found: 503.1529.
2
3
28
11
Methyl (methyl 7,8,9-tri-O-acetyl-3,4-dideoxy-4-C,5-O-(naphthalen-1,2-diyl)-D-glycero-β-D-
talo-non-2-ulopyranosid)onate (18) and Methyl (methyl 4,7,8,9-tetra-O-acetyl-3,5-dideoxy-
5-(2-hydroxynaphthalen-1-diazenyl)-D-glycero-β-D-galacto-non-2-ulopyranosid)onate (19).
The nitrosyl sialoside 5 (534 mg, 1 mmol) in CH Cl (10 mL) was deaminated using the general
2
2
procedure for oxidative deamination with sodium 2,2,2-trifluoroethoxide (244 mg, 2 mmol), 18-
crown-6 (582 mg, 2 mmol) in CH Cl (5 mL) and 2-naphthol (2.88 g, 20 mmol, 20 eq) in Et O (10
2
2
2
mL) to afford, after flash chromatography over silica gel eluting with (hexane/ethyl acetate 1:1),
1
8 as white crystals (282 mg, 57%) from diethyl ether, and 19 as deep yellow crystals (81 mg,
3%) from methanol/CH Cl .
1
2
2
Compound 18: white crystals, m.p. = 107-109 °C; [α]20 – 116.0 (c 1.0, CHCl ). H NMR (400
o
1
D
3
MHz, CDCl ) δ 7.81 (d, J = 8.2 Hz, 1H, ArH), 7.69 (d, J = 8.8 Hz, 1H, ArH), 7.53 (dd, J = 8.0,
3
1
.2 Hz, 1H, ArH), 7.46 (ddd, J = 8.3, 6.7, 1.2 Hz, 1H, ArH), 7.32 (ddd, J = 8.1, 6.7, 1.3 Hz, 1H,
ArH), 7.10 (d, J = 8.8 Hz, 1H, ArH), 5.69 (dd, J = 6.0, 5.1 Hz, 1H, H7), 5.47 (td, J = 6.0, 2.7 Hz,
H, H8), 4.94 (t, J = 9.2 Hz, 1H, H5), 4.48 (dd, J = 12.3, 2.7 Hz, 1H, H9), 4.35 (dd, J = 12.3, 6.0
Hz, 1H, H9’), 4.21 (dd, J = 9.4, 5.1 Hz, 1H, H6), 3.92 (s, 3H, CH ), 3.87 (ddd, J = 13.5, 9.2, 5.0
1
3
Hz, 1H, H4), 3.31 (s, 3H, CH ), 2.86 (dd, J = 14.9, 5.0 Hz, 1H, H3pe), 2.18 (s, 3H, CH ), 2.10 (s,
3
3
1
3
1
3
H, CH ), 2.09 (s, 3H, CH ), 1.90 (dd, J = 14.9, 13.5 Hz, 1H, H3pa). C{ H} NMR (101 MHz,
3 3
CDCl ) δ 170.8, 170.2, 169.9, 169.3, 157.1, 130.4, 130.0, 129.8, 129.1, 127.2, 123.4, 122.1, 119.8,
3
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1
12.5, 99.4, 80.0, 70.6, 69.8, 69.6, 61.8, 53.0, 51.7, 37.1, 34.1, 21.0, 20.9. ESI-HRMS Calcd. for
+
(C H O Na) :([M+Na] ) m/z: 553.1686; found: 553.1686.
2
7
30 11
Compound 19: deep yellow crystals; m.p. = 163-165 °C; [α] 2D 0 – 21.6 (c 0.7, CHCl ). H NMR
o
1
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
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4
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4
4
4
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5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
400 MHz, CDCl ) δ 8.47 (d, J = 8.3 Hz, 1H, ArH), 7.75 (d, J = 9.2 Hz, 1H, ArH), 7.65 (d, J = 7.9
3
Hz, 1H, ArH), 7.53 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H, ArH), 7.38 (ddd, J = 8.1, 7.1, 1.3 Hz, 1H, ArH),
6
1
1
.98 (d, J = 9.3 Hz, 1H, ArH), 5.86 (ddd, J = 11.2, 10.0, 5.1 Hz, 1H, H4), 5.42 (td, J = 6.1, 2.4 Hz,
H, H8), 5.35 (dd, J = 6.5, 1.9 Hz, 1H, H7), 4.60 (dd, J = 12.5, 2.5 Hz, 1H, H9), 4.44 (dd, J = 10.4,
.9 Hz, 1H, H6), 4.18 – 4.07 (m, 1H, H9), 4.00 (t, J = 10.2 Hz, 1H, H5), 3.83 (s, 3H, CH ), 3.32
3
(s, 3H, CH ), 2.66 (dd, J = 12.9, 5.1 Hz, 1H, H3), 2.13 (s, 3H, CH ), 2.02 (s, 3H, CH ), 1.94 (s,
3
3
3
1
3
1
3H, CH ), 1.83 (s, 3H, CH ), 1.26 – 1.22 (m, 1H, H3’). C{ H} NMR (101 MHz, CDCl ) δ 170.7,
3
3
3
1
9
70.1, 169.7, 169.5, 167.4, 161.9, 138.1, 133.3, 129.7, 128.5, 128.4, 128.0, 125.1, 122.5, 121.3,
9.0, 70.4, 70.2, 69.5, 68.9, 67.5, 62.1, 52.8, 51.5, 36.7, 21.0, 20.8, 20.7, 20.7. UV/vis λmax = 380
-1
-1
+
nm (acetonitrile, ε = 8699 M cm ). ESI-HRMS Calcd. for (C H N O Na) :([M+Na] ) m/z:
2
9
34
2
13
6
41.1959; found: 641.1964.
Methyl (methyl 7,8,9-tri-O-acetyl-3,5-dideoxy-4-O-(4-methoxyphenyl)-β-D-arabino-non-4-
en-2-ulopyranosid)onate (20) The nitrosyl sialoside 5 (267 mg, 0.5 mmol) in CH Cl (5 mL) was
2
2
deaminated using the general procedure for oxidative deamination with sodium 2,2,2-
trifluoroethoxide (122 mg, 1 mmol), 18-crown-6 (291 mg, 1.1 mmol) in CH Cl (2.5 mL) and 4-
2
2
methoxyphenol (1.24 g, 10 mmol, 20 eq) in CH Cl (5 mL) to afford, after flash column
2
2
chromatography over silica gel eluting with (toluene/ethyl acetate 3:1), 20 as a colorless oil (92
2
0
o
1
mg, 36%); [α] – 10.9 (c 0.7, CH Cl ). H NMR (600 MHz, CDCl ) δ 6.93 – 6.87 (m, 2H, ArH),
D
2
2
3
6
.87 – 6.80 (m, 2H, ArH), 5.42 (td, J = 6.2, 2.3 Hz, 1H, H8), 5.23 (dd, J = 6.3, 2.7 Hz, 1H, H7),
4.56 (dd, J = 12.5, 2.4 Hz, 1H, H9), 4.51 (t, J = 1.9 Hz, 1H, H5), 4.45 (dt, J = 5.3, 2.6 Hz, 1H, H6),
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