Glycosyl-Acceptor-Derived Borinic Ester-Promoted Direct and β-Stereoselective Mannosylation with a 1,2-Anhydromannose Donor

Article abstract of DOI:10.1021/acs.orglett.6b00926

β-Stereoselective mannosylations were conducted using a 1,2-anhydromannose donor and mono-ol acceptors in the presence of a glycosyl-acceptor-derived borinic ester. Reactions proceeded smoothly under mild conditions to provide the corresponding β-mannosid

Full text of DOI:10.1021/acs.orglett.6b00926

Letter
pubs.acs.org/OrgLett
Glycosyl-Acceptor-Derived Borinic Ester-Promoted Direct and
β‑Stereoselective Mannosylation with a 1,2-Anhydromannose Donor
Masamichi Tanaka, Junki Nashida, Daisuke Takahashi,* and Kazunobu Toshima*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama
223-8522, Japan
S
* Supporting Information
ABSTRACT: β-Stereoselective mannosylations were con-
ducted using a 1,2-anhydromannose donor and mono-ol
acceptors in the presence of a glycosyl-acceptor-derived
borinic ester. Reactions proceeded smoothly under mild
conditions to provide the corresponding β-mannosides with
high stereoselectivity in moderate to high yields. In addition,
the present glycosylation method was applied successfully to
the total synthesis of acremomannolipin A.
β-Mannosides are components of biologically active natural
products and natural glycans, such as mannans, glycolipids, and
N-linked glycoproteins, which play important roles in biological
activities that include cell signaling, protein folding, and
immune responses. Therefore, efficient syntheses of these
glycosides have attracted much attention.1 However, the
stereoselective synthesis of β-mannosides is difficult due to
both the anomeric effect and steric effect of the axial substituent
at the C2 position.2 To overcome these obstacles, efficient
indirect3 and direct4 methods have been developed. The
intramolecular aglycon delivery (IAD) introduced by Hindsgaul
et al.5 is an example of the indirect method that was extended
by Stork et al.,6 as well as Ito and Ogawa.7 An example of the
direct method is the 4,6-O-benzylidene method reported by
Crich et al.8 Detailed mechanistic studies9 suggested that β-
mannosylation proceeds via SN2-like displacement of the triflate
anion from α-triflate by a glycosyl acceptor or the functionally
indistinguishable β-face attack by a glycosyl acceptor on a
transient contact ion pair (CIP). Subsequently, several 4,6-O-
benzylidene-protected mannosyl donors10 and a 4,6-O-silylene-
protected thiomannosyl donor11 were used successfully for the
stereoselective synthesis of β-mannosides. Recently, Demchen-
ko et al. reported β-stereoselective mannosylation involving
hydrogen-mediated aglycon delivery (HAD) with 3- and/or 6-
O-picoloyl thiomannosyl donors that did not have 4,6-O-
benzylidene protection.12
Scheme 1. (A) Regio- and α-Stereoselective Glucosylation
Using a Glycosyl-Acceptor-Derived Boronic Ester; (B) β-
Stereoselective Mannosylation Using a Glycosyl-Acceptor-
Derived Borinic Ester
report describes a novel direct and β-stereoselective man-
nosylation of 5 and a mono-ol glycosyl acceptor utilizing a
glycosyl-acceptor-derived borinic ester 6 and its application to
the total synthesis of the natural product. The borinic ester 6
was expected to activate 5 without any further additives to
afford the tetracoordinate borinate ester 7 involving an
oxonium cation moiety. Concomitant glycosylation from the
boron-bound oxygen atom in the borinate ester from the same
face should provide β-mannoside 8 (Scheme 1B). This is the
first example of a direct and highly β-stereoselective
mannosylation method using a 1,2-anhydromannose donor.
To investigate the hypothesis, 3,4,6-tri-O-benzyl-1,2-anhy-
dromannose (5) and diphenylborinic acid (9a),15 bis(4-
A recent report13 described regioselective and 1,2-cis-α-
stereoselective glycosylations using 3,4,6-tri-O-benzyl-1,2-anhy-
droglucose (1) and diol glycosyl acceptors in the presence of
the corresponding glycosyl-acceptor-derived boronic ester
catalyst 2. In this study, the reactions proceeded smoothly to
provide the corresponding α-glucoside 4 with high stereo- and
regioselectivity in high yield without any further additives under
mild conditions (Scheme 1A). On the basis of previous work,
the mono-ol glycosyl-acceptor-derived borinic ester 6 was
expected to act as an activator of 1,2-anhydromannose 514 to
generate β-mannoside 8 with high stereoselectivity. The present
Received: March 31, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00926
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Organic Letters
Letter
methoxyphenyl)borinic acid (9b),16 and bis(4-fluorophenyl)-
borinic acid (9c)16 were selected as the glycosyl donor and
arylborinic acids, respectively. First, glycosylations of 5 and 6-
O-benzyl-1-hexanol (10) were attempted using catalytic
amounts of 9a-c under different reaction conditions. The
results show that the glycosylation of 5 and 10 using 9a in THF
at −40 °C for 24 h proceeded to give glycoside 12 in 60% yield
with a 42:58 α/β ratio (Table 1, entry 1). To improve β-
Table 1. Glycosylations of 5 and 10 Using Borinic Acids 9a−
c under Several Reaction Conditions
Figure 1. Electrostatic effect of the substituents on the benzene ring in
9b and 9c in the glycosylation of 5 and 10.
ducted at 0 °C for 24 h, the chemical yield of 12 was greater
than those obtained at −20 and −40 °C (Table 1, entries 6−8).
In addition, a reaction time of 24 h gave the greatest yield of 12
with complete β-stereoselectivity (Table 1, entries 8−11).
Thus, glycosylaton of 5 and 10 using 9c in MeCN at 0 °C for
24 h provided the best result, producing 12β in 90% yield as a
single isomer (Table 1, entry 8). These results led to the
proposal of the reaction mechanism shown in Scheme 2. First,
borinic
acid
temp
time
(h)
yield of 12 α/β ratio of
entry
solvent
(°C)
(%)
12
1
9a
9b
9c
9c
9c
9c
9c
9c
9c
9c
9c
THF
−40
−40
−40
−40
−40
−40
−20
0
24
24
24
24
24
24
24
24
3
60
68
64
38
54
73
81
90
73
77
82
42:58
81:19
17:83
α only
α only
8:92
2
THF
3
THF
4
toluene
CH2Cl2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Scheme 2. Proposed Catalytic Cycle for Glycosylation of 5
and 10 Using 9c
5
6
7
β only
β only
β only
β only
β only
8
9
0
10
11
0
6
0
12
stereoselectivity, the electrostatic effect of the substituents on
the benzene ring in the borinic esters was investigated using 9b
and 9c. When 9b, which possesses an electron-donating
methoxy group, was used, undesired α-stereoselectivity was
observed (Table 1, entry 2). In contrast, when 9c, which
possesses an electron-withdrawing fluorine group, was used,
glycoside 12 was obtained in 64% yield with good β-
stereoselectivity, along with recovered 10 in 20% yield (Table
1, entry 3). The anomeric configuration of 12α and 12β was
1
determined by JCH coupling constants, 171 and 155 Hz,
respectively.17 These results suggest that the electron-donating
group in 11b reduces the Lewis acidity of the boron atom,
which causes weak activation of 5 by 11b, and intermolecular
SN2 type substitution of 10 from the α-face of 5 (Figure 1a).
However, the electron-withdrawing group in 11c increases the
Lewis acidity of the boron atom, which causes activation of 5 by
11c, formation of the oxonium cation, and SN1 type
intramolecular nucleophilic attack of the boron-bound oxygen
atom in the borinate ester from the same β-face of the oxonium
cation (Figure 1b).
Next, the solvent effect on glycosylation of 5 and 10 was
examined in the presence of 9c using toluene, CH2Cl2, and
MeCN. The results indicated that complete α-stereoselectivity
occurred when toluene and CH2Cl2 were used (Table 1, entries
4 and 5). In contrast, the reaction proceeded smoothly to
provide 12 in 73% yield with high β-stereoselectivity, along
with recovered 10 in 19% yield, when MeCN was used (Table
1, entry 6). These results indicate that MeCN is the best
solvent for this reaction. Next, the reaction time and reaction
temperature were optimized. When glycosylation was con-
arylborinic acid 9c reversibly binds to mono-ol acceptor 10.
The resulting glycosyl acceptor-derived borinic ester 11c
activates the 1,2-anhydromannose 5 without any further
additives. The oxonium cation intermediate 13c involving a
tetracoordinate borinate ester moiety increases the nucleophil-
icity of the boron-bound oxygen atom, and concomitant
glycosylation from the B−O moiety in the borinate ester affords
the corresponding borinic ester 14c. Finally, an alcohol
exchange reaction between 14c and 10 regenerates the borinic
ester catalyst 11c and provides β-mannoside 12β.
Next, the scope and limitations of this glycosylation method
was investigated using several alcohols. The results indicate that
use of the primary alcohols 15−19 and the secondary alcohol
20 allowed glycosylation to proceed smoothly under mild
conditions to provide the corresponding β-mannosides 23−28
in high yields with excellent β-stereoselectivity in the absence of
any additives (Table 2, entries 1−6). However, when the
secondary alcohol 21 was used, the chemical yield of the
B
DOI: 10.1021/acs.orglett.6b00926
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Organic Letters
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same reaction conditions to the secondary alcohols 22 and 31−
33. The results showed that the corresponding β-mannosides
30 and 34−36 were obtained in moderate yields with complete
β-stereoselectivity (Table 3, entries 2−5). In all cases, the
anomeric configuration of the products was determined by 1JCH
coupling constants. These results indicate that (i) the 1,2-cis-β-
stereoselectivity obtained from this method was consistently
very high and (ii) for secondary alcohols the chemical yield
depended on the chemical structure of the glycosyl acceptor,
probably because of the binding affinity of the glycosyl acceptor
to 9c and because the reactivity of the glycosyl-acceptor-derived
borinic ester toward 5 was strongly influenced by the steric
effects of the glycosyl acceptor.
Finally, the present glycosylation method was applied to the
synthesis of the biologically active natural product, acre-
momannolipin A. Acremomannolipin A has been isolated20
from the extract of the filamentous fungus Acremonium strictum,
as a potential Ca2+ signaling modulator, and two total syntheses
have been reported.21 The synthetic scheme of acremomanno-
lipin A is summarized in Scheme 3. Known mannitol derivative
Table 2. Glycosylations of 5 and Alcohols Using a Catalytic
Amount of 9c
a
entry
acceptor
time (h)
product
yield (%)
α/β ratio
1
2
3
4
5
6
7
8
15
16
17
18
19
20
21
22
4
4
2318
99
β only
β only
β only
β only
β only
β only
β only
β only
24
83
3
25
99
2
2619
27
96
3
86
24
24
24
28
95
29
64
30
trace
a
The acceptors are shown below.
Scheme 3. Total Synthesis of Acremomannolipin A
corresponding β-mannoside 29 was less than those of 23−28.
In addition, when 22 was used, only a trace amount of 30 was
obtained, probably due to the low binding affinities of the
relatively hindered 21 and 22 toward 9c (Table 2, entries 7 and
8). Thus, after mixing 21 and a stoichiometric amount of 9c in
toluene at reflux for 3 h, followed by concentration in vacuo,
glycosylation of 5 in the presence of MS 5 Å in MeCN at 0 °C
for 24 h was examined. The glycosylation proceeded smoothly
to give 29 in 85% yield with complete β-stereoselectivity (Table
3, entry 1). This favorable result led to the application of the
Table 3. Glycosylations of 5 and Several Alcohols Using a
Stoichiometric Amount of 9c
time temp
product
α/β
ratio
recovery yield
(%) of acceptor
entry acceptor (h) (°C) (yield, %)
37 was prepared from D-mannitol according to the reported
procedure22 in three steps. Silylation of 37 followed by removal
of benzyl group gave 38, which was used as a glycosyl acceptor.
Next, the glycosylation of 38 and 5 was carried out using a
catalytic amount of 9c in MeCN at 0 °C for 6 h, which resulted
in a 99% yield of the desired β-mannoside 39 (1JCH = 157 Hz)
with excellent β-stereoselectivity. These results also demon-
strate the high efficiency and generality of the glycosylation
method. In addition, acylation with octanoyl chloride in
pyridine gave 40. Removal of the benzyl groups in 40 followed
by acylation with hexanoyl chloride gave 42. Finally,
deprotection of TBS and the acetonide groups in 42 furnished
acremomannolipin A. The 1H NMR, 13C NMR, optical
rotation, and HRMS (ESI-TOF) data for an analytical sample
1
2
3
4
5
21
22
31
32
33
24
24
6
0
0
29 (85)
30 (61)
34 (58)
35 (57)
36 (56)
β only
β only
β only
β only
β only
−
39
40
23
31
−40
0
24
24
a
0
a
MeCN/THF = 4/1 was employed as a solvent.
C
DOI: 10.1021/acs.orglett.6b00926
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Organic Letters
Letter
(9) (a) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217−11223.
(b) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435−436.
(c) Crich, D. J. Carbohydr. Chem. 2002, 21, 663−686. (d) Crich, D.;
Chandrasekera, N. S. Angew. Chem., Int. Ed. 2004, 43, 5386−5389.
of synthetic acremomannolipin A were identical to those
reported.
In conclusion, the first direct and highly β-stereoselective
mannosylation of 1,2-anhydromannose and mono-ol acceptors
was developed utilizing a glycosyl-acceptor-derived borinic ester
under mild conditions. The use of di(4-fluoro)phenylborinic
acid (9c) in MeCN was effective for glycosylations with several
mono-ol acceptors. Furthermore, this glycosylation method was
applied successfully to the total synthesis of acremomannolipin
A. Detailed mechanistic studies of this method, application to
other types of acceptors, and synthetic studies of other
biologically active compounds using the present method are
now in progress.
(e) Huang, M.; Garrett, G. E.; Birlirakis, N.; Bohe,
Chem. 2012, 4, 663−667. (f) Huang, M.; Retailleau, P.; Bohe,
Crich, D. J. Am. Chem. Soc. 2012, 134, 14746−14749. (g) Adero, P. O.;
Furukawa, T.; Huang, M.; Mukherjee, D.; Retailleau, P.; Bohe, L.;
́
L.; Crich, D. Nat.
́
L.;
́
Crich, D. J. Am. Chem. Soc. 2015, 137, 10336−10345. (h) Hosoya, T.;
Kosma, P.; Rosenau, T. Carbohydr. Res. 2015, 401, 127−131.
(10) (a) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435−436.
(b) Weingart, R.; Schmidt, R. R. Tetrahedron Lett. 2000, 41, 8753−
8758. (c) Kim, K. S.; Kim, J. H.; Lee, Y. J.; Lee, Y. J.; Park, J. J. Am.
Chem. Soc. 2001, 123, 8477−8481. (d) Crich, D.; Smith, M. J. Am.
Chem. Soc. 2001, 123, 9015−9020. (e) Tsuda, T.; Sato, S.; Nakamura,
S.; Hashimoto, S. Heterocycles 2003, 59, 509−515. (f) Tanaka, S.;
Takashina, M.; Tokimoto, H.; Fujimoto, Y.; Tanaka, K.; Fukase, K.
Synlett 2005, 2325−2328. (g) Kim, K. S.; Fulse, D. B.; Baek, J. Y.; Lee,
B.-Y.; Jeon, H. B. J. Am. Chem. Soc. 2008, 130, 8537−8547.
(11) Heuckendorff, M.; Bendix, J.; Pedersen, C. M.; Bols, M. Org.
Lett. 2014, 16, 1116−1119.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00926.
(12) Pistorio, S. G.; Yasomanee, J. P.; Demchenko, A. V. Org. Lett.
2014, 16, 716−719.
(13) Nakagawa, A.; Tanaka, M.; Hanamura, S.; Takahashi, D.;
Toshima, K. Angew. Chem., Int. Ed. 2015, 54, 10935−10939.
(14) Manabe, S.; Marui, Y.; Ito, Y. Chem. - Eur. J. 2003, 9, 1435−
1447.
1
Experimental methods and details; synthetic details, H
and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(15) Lee, D.; Newman, S. G.; Taylor, M. S. Org. Lett. 2009, 11,
5486−5489.
*E-mail: dtak@applc.keio.ac.jp.
*E-mail: toshima@applc.keio.ac.jp.
Notes
(16) Mori, Y.; Kobayashi, J.; Manabe, K.; Kobayashi, S. Tetrahedron
2002, 58, 8263−8268.
(17) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293−
297.
The authors declare no competing financial interest.
(18) Chayajarus, K.; Chambers, D. J.; Chughtai, M. J.; Fairbanks, A. J.
Org. Lett. 2004, 6, 3797−3800.
(19) Nicotra, F.; Panza, L.; Ronchetti, F.; Russo, G.; Toma, L. J.
Chem. Soc., Perkin Trans. 1 1987, 1319−1324.
(20) Sugiura, R.; Kita, A.; Tsutsui, N.; Muraoka, O.; Hagihara, K.;
Umeda, N.; Kunoh, T.; Takada, H.; Hirose, D. Bioorg. Med. Chem. Lett.
2012, 22, 6735−6739.
(21) (a) Tsutsui, N.; Tanabe, G.; Kita, A.; Sugiura, R.; Muraoka, O.
Tetrahedron Lett. 2013, 54, 451−453. (b) Sun, P.; Wang, P.; Zhang, Y.;
Zhang, X.; Wang, C.; Liu, S.; Lu, J.; Li, M. J. Org. Chem. 2015, 80,
4164−4175.
(22) Vidyasagar, A.; Sureshan, K. M. Eur. J. Org. Chem. 2014, 2014,
2349−2356.
ACKNOWLEDGMENTS
■
This research was supported in part by the MEXT-supported
Program for the Strategic Research Foundation at Private
Universities, 2012−2016, from the Ministry of Education,
Culture, Sports, Science and Technology of Japan (MEXT).
REFERENCES
■
(1) (a) Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W.,
Sinay, P., Eds; Wiley-VCH: Weinheim, 2000; Vols. 1−4. (b)
̈
Glycoscience, Chemistry and Chemical Biology; Fraser-Reid, B. O.,
Tatsuta, K., Thiem, J., Eds; Springer: Berlin, 2001.
(2) (a) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155−173.
(b) Demchenko, A. V. Synlett 2003, 1225−1240.
(3) For selected reviews, see: (a) Jung, K.-H.; Muller, M.; Schmidt, R.
̈
R. Chem. Rev. 2000, 100, 4423−4442. (b) Cumpstey, I. Carbohydr. Res.
2008, 343, 1553−1573. (c) Ishiwata, A.; Lee, Y. J.; Ito, Y. Org. Biomol.
Chem. 2010, 8, 3596−3608. For selected recent examples, see:
(d) Partridge, K. M.; Bader, S. J.; Buchan, Z. A.; Taylor, C. E.;
Montgomery, J. Angew. Chem., Int. Ed. 2013, 52, 13647−13650.
(e) Ishiwata, A.; Kaeothip, S.; Takeda, Y.; Ito, Y. Angew. Chem., Int. Ed.
2014, 53, 9812−9816.
(4) For selected reviews, see: (a) Gridley, J. J.; Osborn, H. M. I. J.
Chem. Soc., Perkin Trans. 1 2000, 1471−1491. (b) Crich, D. J. Org.
Chem. 2011, 76, 9193−9209. (c) Nigudkar, S. S.; Demchenko, A. V.
Chem. Sci. 2015, 6, 2687−2704. For a selected recent example, see:
(d) Zhu, Y.; Yu, B. Chem. - Eur. J. 2015, 21, 8771−8780.
(5) Barresi, F.; Hindsgaul, O. J. Am. Chem. Soc. 1991, 113, 9376−
9377.
(6) Stork, G.; Kim, G. J. Am. Chem. Soc. 1992, 114, 1087−1088.
(7) Ito, Y.; Ogawa, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 1765−
1767.
(8) (a) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 4506−4507.
(b) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198−1199. (c) Crich,
D.; Sun, S. Tetrahedron 1998, 54, 8321−8348.
D
DOI: 10.1021/acs.orglett.6b00926
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