β-Stereoselective Mannosylation Using 2,6-Lactones

Article abstract of DOI:10.1021/jacs.6b08874

β-Stereoselective mannosylation using donors bearing the 2,6-lactone moiety is described. In general, glycosylation is a nucleophilic substitution reaction between an alcoholic nucleophile and a sugar moiety containing a leaving group at the anomeric position. Owing to stereoelectronic effects, the reaction tends to proceed via an S_N1 mechanism to afford α-glycosides. We found that the introduction of a 2,6-lactone bridge can circumvent the competing S_N1 reaction, affording β-glycosides with stereoinversion via S_N2(-like) mechanisms. Glycosyl trichloroacetimidates are particularly efficient when activated by a combined catalyst of AuCl₃ and 3,5-bis(trifluoromethyl)phenyl thiourea. In addition, the product stereoselectivity was highly dependent on the concentration of the reaction. Moreover, even when the reaction proceeds via an S_N1 mechanism, the corresponding glycosyl cation appears to present sterically a β-directing nature. Overall, 2,6-lactones were promising structures for achieving β-mannosylations.

Full text of DOI:10.1021/jacs.6b08874

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Communication
#-Stereoselective mannosylation using 2,6-lactones
Yusuke Hashimoto, Saki Tanikawa, Ryota Saito, and Kaname Sasaki
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b08874 • Publication Date (Web): 26 Oct 2016
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β-Stereoselective mannosylation using 2,6-lactones
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Yusuke Hashimoto, Saki Tanikawa, Ryota Saito, Kaname Sasaki*
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Department of Chemistry, Toho University, 2-2-1 Miyama, Funabashi 274-8510 Japan
Supporting Information Placeholder
of the glycosyl cation and the departing anion. However, an
ABSTRACT: β-Stereoselective mannosylation using donors
bearing the 2,6-lactone moiety is described. In general, gly-
cosylation is a nucleophilic substitution reaction between an
alcoholic nucleophile and a sugar moiety containing a leav-
ing group at the anomeric position. Owing to stereoelectron-
ic effects, the reaction tends to proceed via an SN1 mecha-
nism to afford α-glycosides. We found that the introduction
of a 2,6-lactone bridge can circumvent the competing SN1
reaction, affording β-glycosides with stereoinversion via
SN2(-like) mechanisms. Glycosyl trichloroacetimidates are
particularly efficient when activated by a combined catalyst
of AuCl3 and 3,5-bis(trifluoromethyl)phenyl thiourea. In ad-
dition, the product stereoselectivity was highly dependent on
the concentration of the reaction. Moreover, even when the
reaction proceeds via an SN1 mechanism, the corresponding
glycosyl cation appears to sterically present a β-directing
nature. Overall, 2,6-lactones were promising structures for
achieving β-mannosylations.
SN2(-like) reaction at the anomeric position has only been
observed in limited examples, likely due to the intrinsic con-
tribution of the ring-oxygen lone pair blurring the boundary
between SN1 and SN2. Among the classical examples is a het-
erogeneous reaction between a glycosyl halide and a silver
salt.7 As for glucosylation and galactosylation, Taylor et al.
have recently demonstrated reactions proceeding via associ-
ative mechanisms.8 Alternatively, taking advantage of the
electrostatic nature of the protective groups on glycosyl do-
nors has been considered a suitable means to overwhelm the
SN1 reaction. More specifically, the disarming effects9 of elec-
tron withdrawing groups destabilizes the glycosyl cation and
enhances the SN2 pathway.10 Notably, Crich et al. accom-
plished an SN2-like mannosylation employing an α-triflate
with the 4- and 6-oxygen functions tethered (Scheme 1-ii).11
In this case, the 4,6-benzylidene group fixes the geometry
around O5-C5-C6-O6 to maximize the electron withdrawing
nature, increasing the energetic barrier to the glycosyl cati-
on,12 which results in a predominant SN2-like reaction. Addi-
tionally, a 4,6-benzylidene-containing mannosyl cation is
assumed to adopt a B2,5 conformation, which is prone to nu-
cleophilic attack at the β-face.13 Although the chemistry of
4,6-tethered donors has been frequently updated by a num-
ber of groups,14 this chemistry is not free from limitations
with regards to the 4,6-tether and the size of the 2- and 3-
substituents.11a,b In addition, a novel type of donor could
deepen our understanding of the glycosylation mechanism,
and in this context, we herein report the use of 2,6-lactones
to produce 1,2-cis-β-glycosylations (Scheme 1-iii).
The SN2-SN1 borderline poses a critical problem in stere-
oselective transformations1 and has cast a shadow over the
field of glycosylation. In particular, the construction of the
1,2-cis-β-glycosidic linkages (e.g. β-mannosylation) remains
puzzling due to the absence of neighboring group participa-
tion, and as such, significant efforts have been put into estab-
lishing current methodologies.2 In terms of diastereoselectiv-
ity in the SN1 system, the Woerpel and Deslongchamps mod-
els have helped us to understand its origin.3 Chemical man-
nosylations via an SN1 mechanism are postulated to proceed
through a glycosyl cation in a half-chair conformation, oth-
Scheme 1. Mechanistic overview in mannosylations.
4
erwise known as H3,4 as illustrated in Scheme 1-i. Nucleo-
philic addition to the cation is favored from the α-face as the
generating lone pair of the ring oxygen is expected to be an-
tiperiplanar to the incoming nucleophile, which induces the
4
most stable conformer, C1. Attack at the β-face, however, is
1
predicted to produce a skew-boat conformer, S3, due to
pseudoaxial attack, and as such, this route is disfavored.
Overall, glycosylation via an SN1 mechanism tends to produce
α-glycosides. Thus, to construct β-mannosidic linkages via an
SN1 mechanism, the oxocarbenium ions must be distorted,3b,5
the
nucleophile
must
be
delivered
(pseudo-
)intermolecularly,6 or the α-face must be shielded by remote
participation.5a An alternative strategy involves the stereoin-
version of an α-nucleofuge via an SN2 or SN2-like reaction,
where nucleophilic attack occurs against the contact ion pair
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We carried out the glycosylation reaction of primary sugar
alcohol 6a with donors 5a–c as outlined in Table 1. With the
appropriate configurations and conditions, diethyl phos-
phites21 and iodides22 have been reported to behave as leav-
ing groups with partial stereoinversion. The reaction using
phosphite 5aα proceeded stereoselectively to give the corre-
sponding β-glycoside with an anomeric ratio of 9:1. Further-
more, α-glycosyl iodide 5bα proceeded with perfect β-
stereoselectivity, although the reaction rate was rather slow.
As shown in entry 3, the stereoselectivity decreased when
using an anomeric mixture, i.e., 5bαβ, suggesting that this
reaction proceeded with partial stereoinversion. Trichloroa-
cetimidate 5cα resulted in an even faster reaction with good
β-stereoselectivity in the presence of a AuCl3 and 3,5-
bis(trifluoromethyl)phenyl thiourea co-catalyst system.
Again, a poorer stereoselectivity was observed when the β-
imidate 5cβ was employed. These promising results prompt-
ed us to further investigate the substrate scope and concen-
tration effects of the reaction using 5cα (Table 2).
Examples of SN2-like mannosylation reactions are limited,
and the SN1 mechanism yields predominantly α-
stereoselectivity via the 4H3-glycosyl cation, as outlined in
part i. In contrast, the 4,6-tethered α-triflates result in an
SN2(-like) reaction, and their glycosyl cations direct β-
stereoselectivity via the B2,5-conformer (part ii). We herein
demonstrate β-stereoselective mannosylation reactions using
2,6-lactones (part iii). The donors employed result in an
SN2(-like) reaction, and the distorted glycosyl cations direct
β-stereoselectivity.
We speculated that the nO-O-C1-X geometry should have a
significant effect on the SN1-reaction rate. When nO and C-X
Table 1. Glycosylation of 6a with 2,6-lactones 5a–c.
4
are antiperiplanar, as in C1, the X group should leave rela-
tively easily, while a less effective overlap will likely retard
the SN1 reaction, favoring an SN2-reaction. In addition, the
carbonyl group at the O-2 position should function as an
electron withdrawing group.15 Based on these speculations,
we designed and prepared a series of glycosyl donors con-
taining 2,6-lactones. The conformation bridged by the 2,6-
lactone moiety should be restricted to a conformation be-
Entry
Donor
X
Conditions
Yield(α:β ratio)
1a
2
3
-OP(OEt)2
-I
TMSOTf
91% (1:9)
5aα
5bα
5bαβ
5cα
5cβ
5
2
tween S1, 2,5B, and SO, which lessens the nO-
σ*
C-X
overlap
iPr2NEt, Ph3PO
iPr2NEt, Ph3PO
AuCl3, (ArFNH)2CS
AuCl3, (ArFNH)2CS
37% (β only)
18% (1:2.3)
78% (1:16)
48% (1:1)
compared with 4C1. As outlined in Scheme 2, 2,6-lactones are
easily prepared in a few steps from allyl mannoside 1, which
itself could be easily prepared by Fischer glycosylation.16
-I (α:β = 2:1)
-OC(NH)CCl3
-OC(NH)CCl3
4
5
n
Compound 1 was subjected to Bu2SnO-catalyzed O-3 selec-
tive benzylation,17 with the subsequent TEMPO oxidation
leading to the desired 2,6-lactone 3 under anhydrous condi-
tions to permit ring-closure. The O-4 position could then be
either benzylated18 or silylated to give 4a or 4b, respectively.
Manipulation at the C-1 position gave glycosyl donors 5a–d
(see Supporting Information for details), with the glycosyl
iodide 5b being stable to silica gel column chromatography.
Although the intermediacy of glycosyl iodides has been dis-
cussed,19 they have rarely been isolated, with the exception of
the disarmed per-O-acetylated glucose.20 Therefore, the unu-
sual stability of 5b may indicate that the 2,6-lactone system
exhibits the desired disarming effect.
aR1OTMS 6a’ was used instead of R1OH (6a). ArF = 3,5-
Bis(trifluoromethyl)phenyl
Recently, Crich et al. clearly demonstrated that the stere-
oselectivity of glycosylation reactions is highly dependent on
substrate concentration where either triflate or trichloroace-
timidate are the leaving group.13b,23 Indeed, our glycosylation
reaction exhibits a clear tendency towards improved β-
stereoselectivity in more concentrated solutions, indicating
that β-glycosides result from SN2(-like) reactions while α-
glycosides are formed via an SN1 mechanism. This trend was
observed in the reaction with glycosyl acceptors 6a–e. Inter-
estingly, 5d, which has a sterically demanding TBS substitu-
ent, afforded good β-stereoselectivity (entry 6). Moreover,
the obtained glycosides 7a could be converted to mannosides
8 by gentle reduction with NaBH4, or to mannuronates 9 by
solvolysis, as shown in Scheme 3.
Scheme 2. Preparation of 2,6-lactones.
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Table 2. Substrate scope and the effect of concentra-
tion on β-stereoselectivity.
Entry Donor
Yield (α:β ratio)
99% (1:>99)
1
2
3
4
5
6
7
8
1
10α (α only)
R2OH (1.2eq.) 6a-e
AuCl3 (0.1 eq.)
(ArFNH)2CS (0.1eq.)
O
2
98% (1:>99)
10αβ (α:β = 1:1)
O
O
O
O
O
BnO
CH2Cl2, -78–0o
CCl3
C
BnO
R1O
R1O
O
OR2
With respect to the co-catalyst, we were inspired to use
NH
5cα: R1 = Bn
5d : R1 = TBS
7a-f
the combined AuCl3 and the thiourea catalyst based on
Schmidt et al.’s glucosylation and galactosylation reactions
(where AuCl3 functions via acid-base catalysis)27 and by re-
cent findings on the thiourea in glycosylations.28 We ob-
served that β-stereoselectivity was diminished in the absence
of both thiourea and AuCl3 (Table 4). Compared to TMSOTf
(entries 1 and 3), AuCl3 alone induced β-stereoselectivity,27
while thiourea promoted such selectivity. However, thiourea
appeared not to participate in the reaction with TMSOTf
(entry 4). Indeed, 1H and 19F NMR experiments clearly
showed that the addition of AuCl3 desymmetrized the thiou-
rea (Figure 1). In addition, we observed activation of the do-
nor in the presence of AuCl3 and thiourea, which contrasts
with Schmidt et al.’s observation that AuCl3 alone does not
affect the imidate donor.27 Although the function of the thi-
ourea moiety in glycosylation reactions has recently been
discussed,28 in our case, we expect that the gold binds to
sulfur and enhances the acidity of a single thiourea N-H
group. As interactions also appeared to take place between
the hydroxy moiety and the thiourea, further studies are re-
quired to gain a better understanding of the reaction mecha-
nisms involved.29
α
OMe
OH
O
Ph
O
BnO
HO
BnO
Ph
O
O
O
O
O
O
9
O
HO
BnO
BnO
O
HO
BnO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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29
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OMe
OMe
OAll
6b
6c
6d
6e
entry donor R2OH, glyco-
side
yield (α:β ratio) a
0.1 M
1.5 M
1
6a, 7a
6b, 7b
6c, 7c
6d, 7d
6e, 7e
6a, 7f
78% (1:16)
83% (1:6.9)
77% (1:10)
88% (1:3.0)
7% (1:10)
52% (1:8.0)
93% (1:>99)
81% (1:10)
93% (1:>99)
93% (1:47)
25% (1:12)
70% (1:12)
5cα
5cα
5cα
5cα
5cα
5dα
2
3
4
5
6
aThe α:β ratios were determined by HPLC based on authentic
samples. The α-anomers of 7b–e were prepared separately by
alternative routes, and the other glycosides were isolated
1
from each reaction. Since the JCH values at the anomeric
Table 4. Glycosylation reactions in the presence and
absence of thiourea.
position are different from those of typical glycosides (179.0
Hz for 7aα and 169.6 Hz for 7aβ),24 the anomeric configura-
tion was confirmed by NOE correlations between H-1 and H-
3 (see, Scheme S1 in Supporting Information).
6a (1.2equiv.)
5cα
7aβ
CH2Cl2, MS 4A
-78–0oC
Scheme 3. Derivatization of the obtained glycosides.
Entry Activator
(ArFNH)2CS
O
NaBH
NaOMe
4
OH
O
Yield (α:β ratio)
HO
BnO
BnO
OH
O
7aβ
MeO
BnO
OR2
MeOH, 25o
10min, 82%
C
MeOH, 25 o
20 min, 76%
C
OR2
BnO
−
+
−
+
8a
9
1
AuCl3
86% (1:5)
78% (1:16)
64% (1:2)
94% (1:2)
a
1JCH for C-1ʹ was 158.4 Hz, which confirmed the anomeric
2
3
4
AuCl3
configuration of 7aβ.24
TMSOTf
TMSOTf
We then attempted to gain some insight into the mecha-
nisms of these reactions. Although it is clear that β-
stereoselectivity, at least partially, arises from an SN2(-like)
mechanism, we examined the nature of the glycosyl cation.
Thus, we chose to carry out C-glycosylation via the glycosyl
cation (Table 3), as C-allylation has been used to probe steric
effects originating from glycosyl cations.3a,25 The reaction
yielded β-C-glycosides with perfect stereoselectivity irrespec-
tive of the leaving group geometry, indicating that the glyco-
syl cation has a β-directing nature when electrostatics and
hydrogen bonding are ignored. This also explains why β-
trichloroacetimidate did not exhibit α-stereoselective proper-
ties (Table 1, entry 5). Thus, a partial SN2(-like) reaction
should yield the α-glycosides and the residual SN1 reaction
will produce β-glycosides.26
Figure 1. NMR experiments.
Table 3. C-allylation of glycosyl phosphate 10.
TMS
TMSOTf
CH Cl2, -78–0°C BnO
O
O
O
O
O
O
BnO
BnO
2
In summary, we successfully developed and employed gly-
cosyl donors bearing a 2,6-lactone moiety in 1,2-cis-β-
OPO(OPh) 2
BnO
10
11
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(10) (a) H., E. A. E. S.; Conrad, S. Bull. Chem. Soc. Jpn. 1986, 59, 1581–
glycosylation reactions. The reactions proceeded mainly with
concentration-dependent stereoinversion, more specifically
via SN2-like mechanisms, with the glycosyl cation generated
from the donor being sterically β-directing. This methodolo-
gy can serve an alternative route to those using 4,6-tethered
donors, and is expected to contribute to a wider understand-
ing of the SN2-SN1 borderline, in particular in the field of car-
bohydrate chemistry. Detailed mechanistic studies and ap-
plication to other types of donors are now in progress.
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ASSOCIATED CONTENT
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(12) Jensen, H. H.; Nordstrom, L. U.; Bols, M. J. Am. Chem. Soc. 2004,
126, 9205–9213.
Full experimental procedures, spectral data for all unknown
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) (a) Heuckendorff, M.; Bendix, J.; Pedersen, C. M.; Bols, M. Org.
Lett. 2014, 16, 1116–1119; (b) Huang, M.; Retailleau, P.; Bohe, L.; Crich,
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S.; Manabe, S.; van Gunsteren, W. F.; Hunenberger, P. H. J. Chem.
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AUTHOR INFORMATION
Corresponding Author
kaname.sasaki@sci.toho-u.ac.jp
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful to Prof. Hidetoshi Yamada (Kwansei Univer-
sity) for helpful discussions. This work was financially sup-
ported by a JSPS Grant-in-Aid for Scientific Research B
(JP16KT0061) and the Nagase Foundation.
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10089–10092; (c) Balmond, E. I.; Coe, D. M.; Galan, M. C.;
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(29) We also tried to prepare 2,6-anhydrosugar with α-
trichloroacetimidate to elusidate which of the disarming effect of
carbonyl group at O-2 and the conformational effect is dominant,
but only β-trichloroacetimidate 12 could be prepared.
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