Stereoselectivity of D-psicofuranosylation influenced by protecting groups of psicofuranosyl donors

Article abstract of DOI:10.3987/COM-15-S(T)39

We synthesized several types of novel D-psicofuranosyl acetate derivatives, and investigated their use as glycosyl donors in scandium triflate-catalyzed D-psicofuranosylation reactions. Psicofuranosylation demonstrated unique stereoselectivities depending

Full text of DOI:10.3987/COM-15-S(T)39

HETEROCYCLES, Vol. 93, No. 1, 2016
55
HETEROCYCLES, Vol. 93, No. 1, 2016, pp. 55 - 61. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 31st August, 2015, Accepted, 1st October, 2015, Published online, 16th October, 2015
DOI: 10.3987/COM-15-S(T)39
STEREOSELECTIVITY
OF
D-PSICOFURANOSYLATION
INFLUENCED BY PROTECTING GROUPS OF PSICOFURANOSYL
DONORS†
Takashi Yamanoi*,1 Yoshiki Oda,2 Toshiaki Ishiyama,3 and Mikio
Watanabe3
1Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado,
Saitama 350-0295, Japan: yamanoi1119@gmail.com; 2Technology Joint
Management Office, Tokai University, 4-1-1 Kitakaname, Hiratsuka, Kanagawa
259-1292, Japan; 3Department of Chemistry, School of Science, Tokai University,
4-1-1 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan
†Dedicated to Professor Dr. Lutz F. Tietze on his 75th birthday
Abstract – We synthesized several types of novel D-psicofuranosyl acetate
derivatives, and investigated their use as glycosyl donors in scandium
triflate-catalyzed
D-psicofuranosylation
reactions.
Psicofuranosylation
demonstrated unique stereoselectivities depending on the protecting groups of
psicofuranosyl donors. The donor having a 3,4-isopropylidene group afforded
β-psicofuranosides with high stereoselectivities. Donors having a C3 benzoyloxy
group demonstrated low stereoselectivities with no neighboring group
participation. This study also discusses the stereoselectivities of
psicofuranosylation based on the conformers of the glycosyl oxocarbenium ion
intermediates as influenced by the protecting groups of the psicofuranosyl donors.
We also compared the neighboring group participation of the glycosyl donors
bearing
a
C3 benzoyloxy group during D-psicofuranosylation and
D-fructofuranosylation.
The glycosylation reaction is a very important technique for synthesizing biologically active sugar chains
and glycosides.1 In recent years, considerable recent attention has been focused on the development of
efficient and stereoselective furanosylation reactions.2 We are interested in studying the

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HETEROCYCLES, Vol. 93, No. 1, 2016
ketofuranosylation reactions using protected D-fructose and D-psicose. We have previously reported
highly reactive scandium triflate (Sc(OTf)3)-catalyzed ketofuranosylation reactions using appropriately
protected D-fructofuranosyl acetates and D-psicofuranosyl acetates as the glycosyl donors.3
BzO
OAc
OBz
BzO
O
5 mol% Sc(OTf)3
O
BzO
OH
BzO
+
+
OBz
PhMe, CaSO4
94%
O
BzO
3
BzO
1
D only
BzO
BzO
O
OAc
O
O
5 mol% Sc(OTf)3
OH
OBz
OBz
OBz
OBz
CH2Cl2, CaSO4
81%
BzO
BzO
3
2
DꢀE= 32/68
Scheme 1. D-Fructofuranosylation and D-psicofuranosylation reactions using phenethyl alcohol (3)
The fructofuranosylation of 1,3,4,6-tetra-O-benzoyl-D-fructofuranosyl acetate (1) afforded
α-fructofuranosides with high stereoselectivity, whereas the psicofuranosylation of 1,3,4,6-tetra-O-
benzoyl-D-psicofuranosyl acetate (2) produced psicofuranosides with α/β anomeric ratios of ca. 30/70.
Scheme 1 shows the fructofuranosylation and psicofuranosylation reactions using phenethyl alcohol (3)
as the glycosyl acceptor. These results suggest that α-fructofuranosides were successfully obtained
through the neighboring group participation of the C3 benzoyloxy group of 1; however, the C3
benzoyloxy group of 2 did not significantly contribute to increasing the β-stereoselectivity during the
psicofuranosylation reaction. This prompted us to investigate the unique stereoselectivity of
psicofuranosylation, and to explore stereoselective psicofuranosylation, through the use of several types
of psicofuranosyl acetate derivatives as the glycosyl donors.
We designed and synthesized several D-psicofuranosyl acetate derivatives (4-7) as the novel glycosyl
donors. The syntheses of 4-7 are shown in Scheme 2. 3,4-Di-O-benzoyl-1,6-di-O-tert-butyldimethylsilyl-
D-psicofuranosyl acetate (4), 1,3,4,6-tetra-O-benzyl-D-psicofuranosyl acetate (5), 1,6-di-O-tert-
butyldimethylsilyl-3,4-O-isopropylidene-D-psicofuranosyl acetate (6), and 1,3,4-tri-O-benzoyl-6-O-
benzyl-D-psicofuranosyl acetate (7) were synthesized in good yields.
We then investigated D-psicofuranosylation reactions using 4-7 (Scheme 3). Phenethyl alcohol (3) and
2,3,4-tri-O-benzyl-α-D-glucopyranoside (8) were used as the glycosyl acceptors, and Sc(OTf)3 was used
as the activator. The reactions of 4-7 with 1 equiv. of alcohol (3 or 8) using 5 mol% Sc(OTf)3 in the
presence of dry CaSO4 in toluene or dichloromethane for 1-3 h afforded the corresponding
D-psicofuranosides in good yields. These results are summarized in Table 1.

HETEROCYCLES, Vol. 93, No. 1, 2016
57
TBSO
OH
OAc
BzO
BzO
OH
TBSO
OAc
BnO
OAc
O
O
e)
O
O
O
b)
OTBS
BzO OBz
OBz
OBz
OBz
BzO OBz
OBn
OTBS
BzO
BnO OBn
BzO OBz
d)
5
2
4
j)
a)
f)
OH
TBSO
OH
O
OH
O
TBSO
HO
O
BnO
OH
O
p)
OTBS
BzO
O
c)
O
OTBS
OH
OBn
OBz
O O
HO OH
HO OH
BnO OBn
BzO OBz
D
-Psicose
k)
i)
g)
q)
OAc
TBSO
O
O
BnO
O
O
HO
HO
O
O
BnO
O
O
h)
O
l)
O
OTBS
OH
OBn
BnO OBn
O
O O
O O
HO OH
O O
6
m)
OH
BnO
OAc
BnO
OH
O
BnO
O
O
o)
n)
OBz
OBz
OH
BzO OBz
HO OH
BzO OBz
7
a) BzCl, Py/CH2Cl2, 67%, b) BuLi, Ac2O/THF, -30 ºC, 75%, c) TBSCl, imidazole/DMF, 97%, d) BzCl, Py/CH2Cl2, 98%, e) BuLi,
Ac2O/THF, -30 ºC, 83%, f) prop-2-en-1-ol, Sc(OTf)3/CH2Cl2, 87%, g) NaOMe/MeOH, quant., h) BnBr, NaH/DMF, 98%, i)
PdCl2/MeOH-H2O, 51%, j) BuLi, Ac2O/THF, -30 ºC, 82%, k) acetone, TsOH, l) BnBr, NaH/DMF, 84%, m) 3M HCl aq./THF, reflux, 50%,
n) BzCl, Py/CH2Cl2, 98%, o) BuLi, Ac2O/THF, -30 ºC, 73%, p) acetone, PPTS, 98%, q) BuLi, Ac2O/THF, -30 ºC, 75%
Scheme 2. Synthetic routes toward D-psicofuranosyl acetate derivatives (4-7)
R4O
OAc
R4O
OR
O
5 mol% Sc(OTf)3
Solvent, CaSO4
O
+
ROH
OR1
OR2
OR1
OR2
R3O
R3O
4: R1= R4= TBS; R2= R3= Bz
5: R1= R2= R3= R4= Bn
6: R1= R4= TBS; R2= R3= Isopropylidene
7: R1= R2= R3= Bz; R4= Bn
MeO
O
OBn
OBn
OBn
O
O
R4O
R4O
O
O
HO
O
ROH
BnO
BnO
Product
OR1
OR2
HO
OR1
R3O
OMe
OR2
R3O
BnO
3
8
Scheme 3. D-Psicofuranosylation reaction of 4, 5, 6, or 7 with alcohol 3 or 8

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HETEROCYCLES, Vol. 93, No. 1, 2016
Table 1. D-Psicofuranosylation reaction of 4, 5, 6, or 7 with alcohol 3 or 8
Entrya)
1b)
Donor
ROH
Solvent
PhMe
Temp./ ºC
Yield /%
α/β ratio
α
rt
rt
rt
rt
94
94
81
72
1
3
8
3
8
2b)
PhMe
α
1
3c)
2d)
2d)
CH2Cl2
CH2Cl2
32/68
25/75
4c)
5
PhMe
PhMe
CH2Cl2
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
0
72
82
75
65
81
78
78
56
77
76
63
42/58
40/60
5/95
6/94
4/96
8/92
53/47
53/47
25/75
β
4
7
5
5
5
5
5
5
5
6
6
3
3
3
3
3
3
3
3
8
3
8
6
0
7
rt
8
rt
9
0
10
11
12
13
14e)
15e)
-10
-20
-78
0
0
0
β
a) Molar ratio; Donor: ROH: Sc(OTf)3= 1: 1: 0.05. Reaction time= 3 h. b) See Ref. 3a. c) See Ref. 3b. d) 2 is poorly soluble in PhMe.
e) Reaction time= 1 h.
As for the anomeric ratios of the produced psicofuranosides, the reactions with 4 and 7 gave anomeric
mixtures with α/β ratios of 42/58 and 40/60 (entries 5 and 6), respectively. Judging from these anomeric
ratios, it seems as though the neighboring group participation of the C3 benzoyloxy group of 4 and 7 did
not occur in the same manner as 2. In contrast, the reactions with 5 or 6, bearing a benzyl or
isopropylidene group4 at the C3 position proceeded without the neighboring group participation in high
β-stereoselectivities (entries 7-9, 14, and 15). However, the β-stereoselectivity of the reaction with 5 was
low at low temperatures (entries 11 and 12). In particular, the reaction with 6 stereoselectively afforded
only β-psicofuranosides (entries 14 and 15).
Next, we discuss the stereoselectivities of psicofuranosylation with a focus on the conformers of the
glycosyl oxocarbenium ion intermediates influenced by the protecting groups of the psicofuranosyl
donors.5 The glycosyl oxocarbenium ion from 2, 4, or 7 could exist as two conformers (A and B), as
shown in Scheme 4. The formation of 2,3-cyclic oxocarbenium conformer C from conformer A through
the neighboring group participation of the C3 benzoyloxy group is disfavored as conformer C has a
C2-C3 eclipsed conformation with severe strain between the pseudoaxially oriented C3 group and the C2

HETEROCYCLES, Vol. 93, No. 1, 2016
59
group. Formation of a 2,3-cyclic oxocarbenium ion intermediate from conformer B is also disfavored due
to the 1,3-diaxial interaction. Based on the anomeric ratios of the produced psicofuranosides, it seems as
though stereospecific 1,2-cyclic oxocarbenium conformer D from 2 or 7 was not formed as a result of the
C1 benzoyloxy group. Therefore, it was concluded that the stereoselectivity of psicofuranosylation with 2,
4, or 7 is poor as the stereospecific glycosyl oxocarbenium ion intermediates were not formed, as shown
in E.
In contrast, conversion of 1 to 2,3-cyclic oxocarbenium ion intermediate G via an oxocarbenium
conformer F is favorable because conformer G has a stable C2–C3 staggered conformation.
Consequently, the SN2 attack of alcohols toward G occurs to stereoselectively produce
α-fructofuranosides.
R4O
OR1
+
R3O
O
O
R4O
2
3
OR1
ax
R3O
O
O
+
O
O
Ph
C2-C3 Eclipsed comformation
C
A
Ph
2 (or 4, 7)
OR4
OR4
Ph
BzO
O
+
OR1
3
O
+
R O
O
2
O
ax
O
R3O
1
O
D
1,3-Diaxial interaction
Ph
B
ROH
O
R4O
R3O
+
2 (or 4, 7)
DꢀandꢀE-Mixture of psicofuranoside
OR1
O
ROH
O
Ph
E
Ph
BzO
BzO
+
+
BzO
O
OBz
O
O
O
2
OBz
D-Fructofuranoside
1
3
O
Ph
O
BzO
ROH
G
F
C2-C3 Staggered comformation
Scheme 4. Speculated glycosyl intermediates influenced by the C3 benzoyloxyoxy group

60
HETEROCYCLES, Vol. 93, No. 1, 2016
For compound 6, we speculated that cyclic acetal, isopropylidene would transform the oxocarbenium
conformer into C4-endo envelope conformer H. Nucleophilic α-attack of the alcohol forms disfavored
C2–C3 eclipsed product I, and its β-attack forms a favored C2–C3 staggered product J. Therefore,
formation of the staggered product, i.e., β-psicofuranoside, would be expected, as shown in Scheme 5.
OR4
OR
O
2
3
O
O
OR1
-Attack
I
ROH
R4O
C2-C3 Staggered product
4
+
O
(-Psicofuranoside)
O
6
2
OR1
1
O
ROH
O
OR1
R4O
2
3
H
-Attack
OR
O
O
J
C2-C3 Eclipsed product
(-Psicofuranoside)
Scheme 5. Speculated glycosyl intermediate from 6
In summary, we investigated Sc(OTf)3-catalyzed D-psicofuranosylation reactions using several types of
novel D-psicofuranosyl acetate derivatives as the glycosyl donors.6 Psicofuranosylation demonstrated
unique stereoselectivities influenced by the protecting groups of psicofuranosyl donors. We discussed the
stereoselectivities of psicofuranosylation with a focus on the glycosyl oxocarbenium ion intermediates
from the psicofuranosyl donors.
ACKNOWLEDGEMENT
We thank Fushimi Pharmaceutical Co., Ltd. for the gifts of D-psicose and
1,2:3,4-di-O-isopropylidene-β-D-psicofuranose.
REFERENCES AND NOTES
1. H. Pellissier, Tetrahedron, 2005, 61, 2947.
2. a) N. Oka, R. Kajino, K. Takeuchi, H. Nagakawa, and K. Ando, J. Org. Chem., 2014, 79, 7656; b) A.
Ishiwata and Y. Ito, J. Am. Chem. Soc., 2011, 133, 2275.
3. a) T. Yamanoi, N. Misawa, and M. Watanabe, Tetrahedron Lett., 2007, 48, 6458; b) T. Yamanoi, T.
Ishiyama, Y. Oda, S. Matsuda, and M. Watanabe, Heterocycles, 2010, 81, 1141; c) T. Yamanoi, N.
Misawa, S. Matsuda, M. Watanabe, and Y. Oda, Heterocycles, 2012, 86, 919.

HETEROCYCLES, Vol. 93, No. 1, 2016
61
4. Uenishi et al. also reported the stereoselective β-psicofuranosylation using the donor haiving a
3,4-isopropylidene group. See. J. Uenishi and A. Ueda, Heterocycles, 2009, 77, 1297.
5. See. For example: a) C. H. Larsen, B. H. Ridgway, J. T. Shaw, and K. A. Woerpel, J. Am. Chem.
Soc., 1999, 121, 12208; b) D. M. Smith, M. B. Tran, and K. A. Woerpel, J. Am. Chem. Soc., 2003,
125, 14149; c) A. Ishiwata, H. Akao, and Y. Ito, Org. Lett., 2006, 8, 5525.
6. A typical psicofuranosylation procedure: To a stirred suspension of Sc(OTf)3 (2.5 mg, 0.005 mmol)
and 3 (12 μL, 0.1 mmol) in toluene (3 mL) was added 6 (50 mg, 0.1 mmol) in the presence of
anhydrous CaSO4 (ca. 50 mg) under an Ar atmosphere and stirred for 1 h. The reaction was then
quenched by the addition of a saturated aqueous NaHCO3 solution (5 mL). The reaction mixture was
extracted with EtOAc, and the organic layer was washed with water and a saturated aqueous NaCl
solution. After the organic layer was dried over anhydrous Na2SO4, the solvent was evaporated
under reduced pressure. The crude product was purified using a preparative silica gel TLC (PTLC;
EtOAc/hexane = 1/20) to give the desired psicofuranoside (43 mg, 76%) as amorphous. [α]2D6 -10.7
1
(c 2, CHCl3). H NMR:  0.06 (6H, s, Si(CH3)2), 0.07 (6H, s, Si(CH3)2), 0.88 (18H, s, SiC(CH3)3),
1.31 (3H, s, CH3), 1.44 (3H, s, CH3), 2.79 ~ 2.89 (2H, m, CH2CH2Ph), 3.55 ~ 3.60 (2H, m, H-6),
3.64 ~ 3.68 (1H, m, CHaHbCH2Ph), 3.76 ~ 3.86 (1H, m, CHaHbCH2Ph), 3.79 (1H, d, J = 11.0 Hz,
H-1a), 3.85 (1H, d, J = 11 Hz, H-1b), 4.07 (1H, t, J = 7.6 Hz, H-5), 4.49 (1H, d, J = 5.5 Hz, H-3),
4.66 (1H, d, J = 5.5 Hz, H-4), 7.12 ~ 7.29 (Ph), 13C NMR:  −5.5 (Si(CH3)2), −5.3 (Si(CH3)2), −5.2
(Si(CH3)2), 18.4 (SiC(CH3)3), 25.1 (CH3), 25.8 (SiC(CH3)3), 25.9 (SiC(CH3)3), 26.6 (CH3), 36.4
(CH2CH2Ph), 59.3 (C-1), 61.7 (CH2CH2Ph), 64.2 (C-6), 82.5 (C-4), 84.7 (C-3), 86.6 (C-5), 110
(C-2), 112.1 (C(CH3)2), 126.2 ~ 138.9 (Ph). Anal. calcd for C29H52O6Si2⋅0.25 H2O: C, 62.49; H,
9.49. found: C, 62.67; H, 9.69.