Organoboron-catalyzed regio- and stereoselective formation of β-2-deoxyglycosidic linkages

Article abstract of DOI:10.1021/ol501711v

A borinic acid derived catalyst enables regioselective and β-selective reactions of 2-deoxy- and 2,6-dideoxyglycosyl chloride donors with pyranoside-derived acceptors having unprotected cis-1,2- and 1,3-diol groups. The use of catalysis to promote a β-sel

Full text of DOI:10.1021/ol501711v

Letter
pubs.acs.org/OrgLett
Organoboron-Catalyzed Regio- and Stereoselective Formation of
β‑2-Deoxyglycosidic Linkages
Thomas M. Beale, Patrick J. Moon, and Mark S. Taylor*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: A borinic acid derived catalyst enables
regioselective and β-selective reactions of 2-deoxy- and 2,6-
dideoxyglycosyl chloride donors with pyranoside-derived
acceptors having unprotected cis-1,2- and 1,3-diol groups.
The use of catalysis to promote a β-selective pathway by
enhancement of acceptor nucleophilicity constitutes a distinct
approach from previous work, which has been aimed at
modulating donor reactivity by variation of protective and/or leaving groups.
β-Configured 2-deoxyglycoside linkages are structural elements
of microbial secondary metabolites having important biological
effects, including antitumor, antibiotic, and cardiac activities.1
Their stereoselective synthesis is a challenge: the lack of a
hydroxyl-derived substituent adjacent to the anomeric center
renders many of the established methods for the construction
of equatorially oriented glycosidic bonds relatively unselective,
while the anomeric effect tends to dictate a bias toward α-
configured 2-deoxy glycosides.2 A number of creative solutions,
including alkylations of anomeric alkoxides,3 chiral catalyst-
controlled glycosylations,4 de novo approaches,5,6 and indirect
methods mediated by a removable functional group at C-2 of
the donor,7−10 have been devised. β-Selective couplings of 2-
deoxyglycosyl donors are also possible, either by diastereose-
lective addition to a putative oxacarbenium ion or by an SN2-
type pathway with inversion of configuration of an axially
oriented leaving group. A number of useful protocols have been
reported,11−18 with thorough optimization of factors related to
glycosyl donor (protective group pattern, leaving group,
activation conditions) being a common theme. Herein, we
describe a distinct strategy for promoting β-selective 2-
deoxyglycosylations, using an organoboron catalyst to enhance
acceptor nucleophilicity and thus favor an SN2-type pathway. In
the presence of the catalyst, β-2-deoxyglycosides are formed in
a stereo- and regioselective fashion from readily available α-
glycosyl chlorides, using acceptors having two or three
potentially reactive hydroxyl (OH) groups.
The method for selective β-deoxyglycosylation disclosed here
builds on our discovery that aminoethyl diphenylborinate (1a)
promotes regioselective glycosylations of pyranoside-derived
cis-1,2-diols at the equatorial OH group.19 The dependence of
the reaction outcome on the configuration of the glycosyl
halide starting material, and the observation of first-order
kinetics in the glycosyl donor, acceptor, and catalyst, suggested
that the 1,2-trans stereochemical outcome observed for
protected gluco- or galactopyranosyl halide donors was the
result of an SN2-type displacement of an Ag2O-activated, axially
oriented halide leaving group by a tetracoordinate borinate
ester. We postulated that, for couplings of α-2-deoxyglycosyl
halides, the borinic acid catalyst would not only influence the
regioselectivity of the process by glycosyl acceptor activation
but also provide selective access to the β-configured product by
favoring an SN2-type pathway (Scheme 1).
Scheme 1. Proposal for Organoboron-Catalyzed Preparation
of β-2-Deoxyglycosidic Linkages
Our previous work revealed that, for more reactive “armed”
donors, glycosyl chlorides provided higher levels of regiocontrol
than the corresponding bromides.19a Thus, 3,4,6-tri-O-acetyl-2-
deoxy-α-D-glucopyranosyl chloride (3a, α:β > 20:1), generated
in a straightforward fashion from glycosyl acetate 2a by
treatment with BCl3 in CH2Cl2,20 was selected as the donor to
be used in optimization studies. Mannopyranoside derivative
4a, which we have found to be among the less challenging
pyranoside substrates in terms of regiocontrol,19a,21 was
employed as an acceptor with the aim of minimizing the
complexity of the reaction mixtures at the optimization stage.
Received: June 12, 2014
© XXXX American Chemical Society
A
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The effects of varying the reaction conditions are summarized
in Table 1.
also evident under these optimized conditions (entry 9).
Although we anticipated that heteroboraanthracene-derived
catalysts such as 1b and 1c might give rise to more nucleophilic
borinates and thus provide enhanced β-selectivity relative to
1a,22 they in fact provided inferior results (entries 10, 11). The
use of Ag2CO3 in place of Ag2O provided a lower yield and
marginally poorer β-selectivity (entry 12).
Table 1. Evaluation of Reaction Conditions for
Regioselective and β-Selective Coupling of 3 and 4a
The optimal conditions were applied to couplings of 2-
deoxyglucopyranosyl or -galactopyranosyl donors with a variety
of acceptors containing cis-1,2- or 1,3-diol motifs suitable for
activation by organoboron catalyst 1a (Table 2). In each case,
either HPLC or 1H NMR spectroscopic analysis of the
unpurified reaction mixture was employed to determine the
1
β:α selectivity. The magnitude of the 1H−13C J coupling
constant and/or 3J coupling constants (H1−H2ax, H1−H2eq),23
as well as the chemical shift of the anomeric hydrogen,17d were
consistent with the assignment of β stereochemistry for the
major disaccharide product. Isolated yields of the β-anomer
after purification by silica gel chromatography are shown, for
the two-step protocol starting from the peracetylated 2-
deoxypyranosides. The corresponding α-configured disacchar-
ides, along with the products of glycosyl chloride hydrolysis,
accounted for the remainder of the mass balance; only in the
case of 5f and 5g were regioisomeric 2-deoxyglycosides evident
(20% and 15% yield, respectively).
a
b
entry
solvent
yield
β:α
1
2
3
4
5
6
7
CH3CN (0.10 M)
toluene (0.10 M)
THF (0.10 M)
44
6
1.6:1
2.2:1
4.6:1
9:1
61
27
55
44
72
iPr2O (0.10 M)
CH2Cl2 (0.10 M)
CH2Cl2 (0.20 M)
CH2Cl2 (0.05 M)
5.7:1
4.9:1
7.3:1
We sought to extend the method to the formation of β-2,6-
dideoxy linkages, which are particularly prevalent in bioactive
natural products. Diphenylborinate 1a was found to promote β-
selective reactions of 2-deoxy-L-rhamnopyranosyl chloride 3c
with a range of acceptors, as depicted in Table 3. To investigate
whether there was a matching/mismatching effect between
donor and acceptor,24 glycosylations of both enantiomers of
methyl β-arabinopyranoside were carried out. Similar yields and
β:α selectivities were obtained for diastereomeric disaccharides
6d and 6e. A control experiment revealed that, in the absence
of catalyst 1a, disaccharide 6a was obtained in 4% yield (4.3:1
β:α) under the conditions of Table 3.
Uncatalyzed reactions
8
9
CH3CN (0.10 M)
CH2Cl2 (0.05 M)
26
18
1:9
2:1
Variation of catalyst/Ag(I) salt
entry
variation from entry 5
yield
β:α
10
11
12
catalyst 1b (10 mol %)
catalyst 1c (10 mol %)
Ag2CO3
22
41
27
1.3:1
1:1.6
4.6:1
a
Combined yield of α and β anomers, over two steps from 2a (0.05
mmol scale), as determined by HPLC analysis of the unpurified
reaction mixture. Determined by HPLC analysis of the unpurified
b
reaction mixture.
The effects of varying the protective groups of the glycosyl
donor are depicted in Scheme 2. Replacement of the ester
protective groups with less electron-deficient benzyl ethers was
expected to favor ionization of the glycosyl chloride,25 and thus
to have a deleterious effect on the stereoselectivity of the
organoboron-catalyzed reaction. Mono- and dibenzylated 3d
and 3e were synthesized from the corresponding anomeric
hemiacetals using the Ghosez reagent,26 as reactions of the 1-
OAc pyranosides with BCl3 proved ineffective for accessing
these more labile donors.27 As shown in Scheme 2, the use of
the more electron-rich, “armed” deoxyglycosyl chloride donors
resulted in lower yields of disaccharide products (with glycosyl
donor hydrolysis being the major side reaction) and also
adversely affected the β:α ratio, consistent with the mechanistic
hypothesis outlined in Scheme 1.
In summary, the use of a borinic acid derived catalyst enables
regio- and stereoselective glycosylations of pyranoside-derived
cis-1,2- and 1,3-diols, using both 2-deoxy and 2,6-dideoxygly-
cosyl chloride donors. Enhancement of acceptor nucleophilicity
to promote a β-selective pathway constitutes a distinct
approach from previous work, which has been focused on
modulating donor reactivity by variation of protective and/or
leaving groups.28 The protocol is most efficient when
peracetylated deoxyglycosyl halides are used. While potentially
limiting the types of products that may be accessed by this
approach, these peracetylated donors offer advantages in terms
Under the standard conditions for glycosylation catalyzed by
1a (CH3CN solvent, 1 equiv of Ag2O as a halide abstracting
reagent/base, 23 °C), disaccharide 5a was obtained as a single
regioisomer, but as a mixture of anomers (β:α = 1.6:1, entry 1).
It should be noted that, in the absence of the catalyst, the α
anomer was obtained selectively under these conditions (β:α =
1:9, entry 8). This latter result is consistent with previous work:
inversion of configuration of an α-2-deoxyglycosyl halide or
sulfonate generally requires a good leaving group (X = I,16
Br17a,d or OSO2R15), most often in combination with other
features that favor an SN2-type pathway, such as benzylidene
protection of the donor, low temperature, and/or the use of an
acceptor-derived alkoxide. 2-Deoxyglycosyl chlorides (activated
by AgOTf in CH2Cl2) have been shown to provide α-
configured products, although modest, acceptor-dependent
levels of β-selectivity have been obtained using a benzylidene-
protected donor.17c In any case, the results shown in entries 1
and 8 of Table 1 clearly indicate that the organoboron catalyst
has a significant effect on the stereochemical outcome of this
glycosylation. To improve upon the result obtained in the
presence of the catalyst, solvents of lower polarity and/or Lewis
basicity than acetonitrile were examined (entries 2−5), with
optimal results being obtained in dichloromethane at a
concentration of 0.05 M (entry 7). Enhancements in yield
and β-selectivity compared to the uncatalyzed reaction were
B
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Table 2. Organoboron-Catalyzed Regioselective and β-
Selective Reactions of 2-Deoxyglycopyranosyl Donors
Table 3. Organoboron-Catalyzed Construction of β-2,6-
Dideoxy Linkages
a
Determined by HPLC analysis of unpurified reaction mixtures.
Determined by H NMR analysis of unpurified reaction mixtures.
b
1
c
Isolated yields of β-anomers after purification by silica gel
chromatography, from reactions carried out on 0.1 mmol of 2c.
d
Isolated as a 4.9:1 β:α mixture.
Scheme 2. Organoboron-Catalyzed Glycosylations Using
a
Benzyl-Protected 2-Deoxyglucopyranosyl Donors
a
Determined by HPLC analysis of unpurified reaction mixtures.
b
c
Determined by 1H NMR analysis of unpurified reaction mixtures. A
regioisomer (20%) was identified by 1H NMR analysis of the
unpurified reaction mixture. A regioisomer (15%) was identified by
HPLC analysis of the unpurified reaction mixture. Isolated yields of β-
a
Isolated yields from reactions carried out on 0.1 mmol scale of 2d/2e
d
are listed.
e
anomers after purification by silica gel chromatography, from reactions
carried out on 0.1 mmol of 2a/2b.
C
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data for all new
compounds, including NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mtaylor@chem.utoronto.ca.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by a Personnel Award from the Heart
and Stroke Foundation of Canada (T.M.B.). Additional support
was provided by NSERC (Discovery Grants Program, Canada
Research Chair to M.S.T.), Boehringer Ingelheim (Canada)
Ltd., the Canada Foundation for Innovation, the Province of
Ontario, and the University of Toronto. M.S.T. is a Fellow of
the A. P. Sloan Foundation. P.J.M. was supported by a
scholarship from the University of Ottawa. NMR facilities were
funded by the CFI (Project No. 19119) and the Province of
Ontario.
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Supporting Information.
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