Nickel-catalyzed stereoselective formation of α-2-deoxy-2-amino glycosides

Article abstract of DOI:10.1021/ja903123b

(Chemical Equation Presented) The development of a new method for the stereoselective synthesis of α-2-deoxy-2-amino glycosides is described. This methodology relies on the nature of the cationic nickel catalyst, generated in situ from L_nNiCl₂ and AgOTf, to direct the anomeric stereoselectivity. The new glycosylation reaction is highly α-selective and proceeds under mild conditions with 5-10 mol % of the nickel catalyst loading at ambient temperature. This new method has been applied to both D-glucosamine and galactosamine trichloroacetimidate donors as well as an array of primary, secondary, and tertiary alcohol nucleophiles to provide the desired glycoconjugates in good yields with excellent α-selectivity. Mechanistic studies of the present reaction are underway and will be reported in due course. Copyright

Full text of DOI:10.1021/ja903123b

Published on Web 06/04/2009
Nickel-Catalyzed Stereoselective Formation of r-2-Deoxy-2-Amino Glycosides
Enoch A. Mensah and Hien M. Nguyen*
Department of Chemistry and Biochemistry, Montana State UniVersity, Bozeman, Montana 59717
Received April 19, 2009; E-mail: hmnguyen@chemistry.montana.edu
Scheme 1a
The R-2-deoxy-2-amino glucosides and galactosides are the struc-
tural units found within a variety of biologically important glycoconju-
gates.1-5 The stereoselective synthesis of R-1,2-cis-glycosides of
D-glucosamine and D-galactosamine is challenging because it requires
a nonassisting neighboring group effect at the C(2)-amino functionality
on the glycosyl donor to direct the R-selectivity.6 Early work in this
area employs the C(2)-azide functionality on the glycosyl donor as a
nonparticipatory group.7 However, the stereochemical outcome can
be difficult to predict and often resulted in moderate R-selectivity.4b
In 2001, Kerns reported an elegant strategy utilizing a glycosyl donor
incorporated with the C(2)-oxazolidinone group.8a This approach
requires 2 equiv of the activating reagent (PhSOTf), and undesired
N-glycosylation8b and sulfenylation8a are also observed in the reaction.
Later, Schmidt reported the conjugate addition of alcohols to C(2)-
nitro-galactals in the presence of t-BuOK to afford R-2-deoxy-2-nitro-
galactosides in good yields.9 Gin has recently reported the opening of
aziridine with C(1)-hemiacetal nucleophiles to form R-O-glycosyl
serine conjugates in good diastereoselectivity.10 Despite the variety
of methods available, selective synthesis of R-2-dexoy-2-amino gly-
cosides continues to be a challenge because each of the above
methodologies has its own advantages and disadvantages.
The use of para-methoxybenzylidene as the protecting group for
the C(2)-nitrogen on glycosyl bromide was investigated over 40 years
ago.11 However, its use was complicated due to the low stability of
the Schiff base as well as the multistep synthesis required for the
preparation of glycosyl bromide. Additionally, the stereochemical
outcome of the coupling process depends on the nature of the promoters
as well as the alcohol acceptors. For instance, utilizing stoichiometric
amounts of HgCN provides the desired glucosides selectively either
as the R-isomers12 or as the ꢀ-isomers13 depending on the nature of
the alcohol acceptors. In contrast, the use of AgOTf (2 equiv) as a
promoter provides glucosides exclusively as ꢀ-isomers.13 On the other
hand, the n-pentenyl glycoside approach provides R-glucoside in
moderate yield.14 In this communication, we report the use of C(2)-
para-methoxybenzylideneamino trichloroacetimidates 5 and 6 as the
donors (Scheme 1) for the stereoselective synthesis of R-2-deoxy-2-
amino glycosides. This strategy relies on the nature of the ligand on
nickel to control the R-selectivity. This method requires only a catalytic
amount of the cationic nickel catalyst to activate trichloroacetimidate
donors at ambient temperature. Furthermore, its application is wide-
spread to a variety of alcohol nucleophiles.
a (i) p-Anisaldehyde, NaOH (1 M); (ii) Ac2O, DMAP, pyridine; (iii) NH3
in MeOH, THF; (iv) Cl3C-CN, DBU, CH2Cl2.
cationic Pd(PhCN)2(OTf)2,16 the reaction proceeded sluggishly at 0
°C to give the desired disaccharide 8 in poor yield with moderate
diastereoselectivity (entry 1). Warming the reaction to 25 °C shortened
the reaction time and increased the yield (entry 2). Switching to the
cationic nickel catalyst improved the yield and the R-selectivity, and
8 was isolated in 95% yield with R:ꢀ ) 8:1 (entry 4).17 We then
investigated the nature of the ligands on nickel to influence the
anomeric selectivity. The more electron-withdrawing substituted ben-
zonitrile ligands decreased the reaction time and increased the
R-selectivity (entries 5 and 6). On the other hand, the more electron-
rich ligands increased the reaction time (entries 7 and 8). These results
clearly demonstrate the efficiency of the nickel method, with the
formation of disaccharide 8 with excellent R-diastereoselectivity. It
has been reported that coupling of the C(2)-azide donor derivative of
5 with 7 provided a 2:1 mixture of R- and ꢀ-isomers.18
Glycosylation of alcohol acceptor 9 with 5 has been attempted under
Lewis acid conditions.13 The reaction did not occur in the presence of
TMSOTf as a promoter, and the use of BF3 ·OEt2 resulted in only a
trace amount of the desired disaccharide 10. Encouraged by the results
Table 1. Selective Formation of R-Disaccharide 8a
entry
catalyst
loading
temp
time
yieldb R:ꢀc
The straightforward synthesis of 5 and 6 commenced with D-
glucosamine (1) and D-galactosamine (2), respectively. Exposure of 1
and 2 to p-anisaldehyde and NaOH followed by acetylation provided
3 and 4 in good yields (Scheme 1).15 Chemoselective 1-O-deacetylation
with NH3 in MeOH and subsequent treatment of the resulting
hemiacetals with trichloroacetonitrile in the presence of DBU afforded
trichloroacetimidates 5 and 6. With these donors in hand, our attention
was focused on the glycosylation reactions.
1
2
3
4
5
6
7
8
Pd(PhCN)2(OTf)2
Pd(PhCN)2(OTf)2
Pd(PhCN)2(OTf)2
Ni(PhCN)4(OTf)2
Ni(4-CF3-PhCN)4(OTf)2 5 mol % 25 °C
Ni(4-F-PhCN)4(OTf)2 5 mol % 25 °C
Ni(4-MeOPhCN)4(OTf)2 5 mol % 25 °C
Ni(dppe)(OTf)2 5 mol % 25 °C
5 mol %
0 °C 15 h 41%
5:1
4:1
5:1
8:1
5 mol % 25 °C
7 mol % 25 °C
5 mol % 25 °C
6 h 60%
4 h 63%
4 h 95%
3 h 90% 10:1
3 h 93% 10:1
6 h 76% 10:1
7 h 95%
8:1
Initial experiments were performed with trichloroacetimidate 5 as
the donor and primary alcohol of galactoside 7 as the acceptor (Table
1). Upon treatment of both coupling partners 5 and 7 with 5 mol % of
a The reactions were performed with 5-7 mol % of Pd(PhCN)2-
(OTf)2 or 5 mol % of LnNi(OTf)2 which was generated in situ from
c
LnNiCl2 and AgOTf. b Isolated yield. 1H NMR ratio.
9
8778 J. AM. CHEM. SOC. 2009, 131, 8778–8780
10.1021/ja903123b CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope
obtained in Table 1, we decided to explore the feasibility of the cationic
nickel method with both coupling partners 5 and 9 (Scheme 2). The
reaction proceeded smoothly to provide disaccharide 10 in 77% yield
with excellent diastereoselectivity (R:ꢀ ) 20:1). Compared to other
glycosylation methods,13,19 this chemistry is more R-selective. For
instance, coupling of 9 with glycosyl bromide derivative of 5 in the
presence of AgOTf (1.5 equiv) as a promoter provided the ꢀ-isomer
of 10 as the major product (R:ꢀ ) 1:9).13 On the other hand,
glycosylation of 9 with C(2)-oxazolidinone thioglycoside donor
afforded glycoconjugate in 81% yield with R:ꢀ ) 3:1.19
Scheme 2
The scope of this new coupling method was further examined with
a number of primary, secondary, and tertiary alcohols 11-16 (Table
2). The desired glucosides 17-22 were isolated in good yields with
excellent R-selectivity (entries 1-6). For instance, glycosylation of
primary alcohol 11 with C(2)-benzylideneamino donor 5 under nickel-
catalyzed conditions provided disaccharide 17 in 78% yield with R:ꢀ
) 15:1 (entry 1). On the other hand, coupling of 11 with the C(2)-
azide derivative of 5 yielded a 8:1 mixture of R- and ꢀ-isomers.18 In
the case of glycosyl acceptor 13, the nickel-catalyzed glycosylation
reaction provided disaccharide 19 in 97% yield exclusively as R-isomer
(entry 3). Under the Kochetkov’s C(2)-azide thiocyanate donor,
glycosylation of 13 also afforded exclusively the R-coupling product,
albeit in lower yield (72%).20 With use of dihydrocholesterol 14 as a
nucleophile, the glycoconjugate 20 was obtained in 85% yield with
R:ꢀ ) 11:1 (entry 4). Under the Oscarson’s oxazolidinone conditions,
the coupling product was obtained exclusively as the ꢀ-isomer when
dihydrochlolesterol was employed as a glycosyl acceptor.21 The
R-isomer, however, could be obtained when a significant amount of
AgOTf (0.4 equiv) was employed in the reaction.21 Under nickel-
catalyzed conditions, coupling of L-threonine 15 with 5 provided
glycopeptide 21 with R:ꢀ )10:1 (entry 5). In contrast, a 2.5:1 mixture
of R- and ꢀ-isomers was obtained when C(2)-azide donor was
employed in the coupling process.22 Overall, the nickel-catalyzed
glycosylation with C(2)-benzylideneamino glycosyl donor 5 provided
a practical approach to get access to a variety of glycoconjugates with
high R-selectivity. Additionally, it does not require PhSEt as a putative
nucleophile (the azide method)18 or a large quantity of AgOTf (the
oxazolidinone method)21 to improve the R-selectivity. It only requires
a catalytic amount of cationic nickel catalyst (5-10 mol %) to activate
glycosyl donor 5, leading to the formation of the coupling products
with excellent R-selectivity.
Similarly, D-galactosamine substrate 6 was found to be a viable
donor, and glycoconjugates 23-28 were obtained with excellent
R-selectivity. Notably, the efficiency of the reaction is illustrated by
the ability to provide O-threonine conjugate 27 in 74% yield with R:ꢀ
) 14:1 (entry 5). Under the oxazolidinone method, coupling of
threonine afforded glycopeptide as a 1:1 mixture of R- and ꢀ-isomers.8
On the other hand, the C(2)-azide glycosyl bromide donor provided
glycopeptide in 60% yield with R:ꢀ ) 4:1.23
The efficacy of this nickel-catalyzed R-glycosylation was further
explored with other N-substituted benzylidene derivatives on trichlo-
roacetimidate donors (Table 3). Coupling of 7 with the C(2)-
benzylideneamino donor provided disaccharide 29 in 92% yield with
R:ꢀ ) 10:1 (entry 1). On the other hand, switching to the electron-
a 5 mol % of Ni(II) catalyst was employed. b 10 mol % of Ni (II)
e
catalyst was employed. c Dihydrocholesterol. d Isolated yield. 1H NMR
ratio.
withdrawing N-substituted benzylidenes shortened the reaction time
from 3 to 1 h, and the coupling products 30 and 31 were still obtained
with similar yields and R-selectivity (entries 2 and 3).
A possible mechanism for the cationic nickel-catalyzed reaction
reported herein is shown in Scheme 3. Reversible coordination of
LnNi(OTf)2 to both C(1)-trichloroacetimidate nitrogen and C(2)-
benzylidene imine of donor 32 forms a seven-membered ring complex
33. It is hypothesized that hydrogen bonding between the external
oxygen nucleophile and trichloroacetamide facilitates ionization of
species 33 to produce complex 34. Subsequent ligand exchange
followed by dissociation of trichloroacetamide provides ion-pair 35.
The intermediate 35 then recombines in a stereoelectronically favored
mode to form a five-membered ring complex 36. Dissociation of the
nickel catalyst from complex 36 yields R-product 37.
To verify that the presence of the external oxygen nucleophile is
necessary for the facile ionization of a seven-membered ring complex
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C O M M U N I C A T I O N S
Table 3. Other N-Substituted Benzylidene Derivativesa
ature. Mechanistic studies of the present reaction are currently
underway and will be reported in due course.
Scheme 5
.
entry
X
time
disaccharide
yieldb
R:ꢀc
1
2
3
H
CF3
F
3 h
1 h
1 h
29
30
31
92%
87%
96%
10:1
9:1
9:1
a The reactions were performed with 5 mol % of Ni(4-F-PhCN)4-
c
(OTf)2 in CH2Cl2 (0.2 M). b Isolated yield. 1H NMR ratio.
Acknowledgment. This work is dedicated to Professor Paul
Grieco on the occasion of his 65th birthday and with gratitude for
his mentorship. We thank Montana State University for financial
support and Ms. Shannon Atkins for the generous gift of 13.
Scheme 3
Supporting Information Available: Experimental procedure and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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Scheme 4
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C(2)-benzylideneamino trichloroacetimidate donors can be easily
prepared in four steps starting from commercially available D-
glucosamine and D-galactosamine. These glycosyl donors are able to
couple to primary, secondary, and tertiary alcohols to provide access
to a variety of glycoconjugates with excellent R-selectivity. The
diastereoselectivity of the current nickel-catalyzed reaction depends
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