A neighboring group participation strategy: Direct and highly diastereoselective synthesis of 2-substituted and 2,2-bisubstituted perhydrofuro[2,3-b]pyran derivatives

Article abstract of DOI:10.1039/c4ob00642a

Treatment of methyl 2-C-formylmethyl-2-deoxy-β-d-glucopyranoside (5) or methyl 2-C-acetylmethyl-2-deoxy-β-d-glucopyranoside (1) with H ₂SO₄-HOAc-Ac₂O gave 2-acetoxyl-4,5- bis(benzyloxy)-6-[(benzyloxy)methyl]hexahydrofuro[2,3-b]pyran (6) and acetyl 2-C-acetylmethyl-2-deoxy-α-d-glucopyranoside (7) respectively, which were further reacted with nucleophiles in the presence of TMSOTf and offered a series of 2-substituted and 2,2-disubstituted perhydrofuro[2,3-b]pyran derivatives in high yield with excellent diastereoselectivity. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00642a

Organic &
Biomolecular Chemistry
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PAPER
A neighboring group participation strategy:
direct and highly diastereoselective synthesis of
2-substituted and 2,2-bisubstituted perhydrofuro-
[2,3-b]pyran derivatives†
Cite this: Org. Biomol. Chem., 2014,
12, 7381
Xiaofeng Ma,a,b Qin Tang,a,b Jun Ke,a,b Jichao Zhang,a,b Xinglong Yang,a,b
Xudong Shena,b and Huawu Shao*a
Treatment of methyl 2-C-formylmethyl-2-deoxy-β-D-glucopyranoside (5) or methyl 2-C-acetylmethyl-
2-deoxy-β-D-glucopyranoside (1) with H2SO4–HOAc–Ac2O gave 2-acetoxyl-4,5-bis(benzyloxy)-6-[(benzyl-
oxy)methyl]hexahydrofuro[2,3-b]pyran (6) and acetyl 2-C-acetylmethyl-2-deoxy-α-D-glucopyranoside
(7) respectively, which were further reacted with nucleophiles in the presence of TMSOTf and offered a
series of 2-substituted and 2,2-disubstituted perhydrofuro[2,3-b]pyran derivatives in high yield with excel-
lent diastereoselectivity.
Received 27th March 2014,
Accepted 30th July 2014
DOI: 10.1039/c4ob00642a
www.rsc.org/obc
these cases, much attention has been paid to the synthesis of
Introduction
3-substituted perhydrofuro[2,3-b]pyrans. Installation of
a
The perhydrofuro[2,3-b]pyran scaffolds constitute the core heteroatom substituent or an active functional group at the
structural elements which are prevalent in a large number of C(2) position of perhydrofuro[2,3-b]pyran, however, still rep-
naturally occurring biological active products.1 Recent research resents a great challenge.
also revealed that they would be used as potential HIV-1 pro-
On the other hand, the use of neighboring group partici-
tease inhibitors.2 Among the myriad of elegant approaches to pation for regio- and stereo-chemical control is ubiquitous in
construct perhydrofuro[2,3-b]pyrans,3 intramolecular cycliza- organic chemistry.8 Nowhere is this strategy more extensively
tions are particularly attractive with regard to stereoselectivity exploited than in carbohydrate chemistry.9 Neighboring group
and chemoselectivity.4 To this end, several different intramole- participation of a 2-O-carboxylate ester is the most reliable
cular cyclization strategies have been introduced to achieve the method for stereoselective construction of the 1,2-trans glyco-
synthesis of substituted perhydrofuro[2,3-b]pyrans. Particu- sidic bond. Generally, in this strategy, a 2-O-carboxylate ester
larly, the use of 3-halogeno-2-allyloxy-perhydropyrans as sub- and an anomeric leaving group must be installed first
strates via radical cyclization to synthesize 3-substituted (Scheme 1(A)). Then, in the presence of a promoter, the
perhydrofuro[2,3-b]pyrans have been extensively studied and
used to construct a number of complex natural or unnatural
products.5 Furthermore, in 2003, Yus and co-workers success-
fully synthesized 2,2-dialkyl-substituted perhydrofuro[2,3-b]-
pyrans via the oxidation–cyclization of methylidenic diols.6
Very recently, Chandrasekaran and co-workers achieved the
synthesis of 3-idio-perhydrofuro[2,3-b]pyrano-γ-butyrolactones
and 3-idio-perhydrofuro[2,3-b]pyrans via NIS-mediated ring
opening of 1,2-cyclopropanated sugar derivatives.7 In most of
aNatural Products Research Center, Chengdu Institute of Biology, Chinese Academy
of Sciences, Chengdu 610041, China. E-mail: shaohw@cib.ac.cn;
Fax: (+)86-28-82890288
bThe University of Chinese Academy of Sciences, Beijing 10049, China
†Electronic supplementary information (ESI) available. CCDC 851788. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ob00642a
Scheme 1 (A) The neighboring group participation strategy in the syn-
thesis of 1,2-trans-glycosides. (B) The construction of perhydrofuro[2,3-b]-
pyrans via a neighboring group participation strategy.
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leaving group is activated, followed by its departure with the (Scheme 2, path b) vs. a 6/5 fused bicyclic oxocarbenium ion
help of the oxygen of the pyran-ring to form an oxonium ion. (Scheme 2, path c), however, we only obtained the fused-cyclic
Then, the carbonyl group attacked the oxonium ion forming a products in high yield with only one diastereoisomer (when
more stable acetoxonium ion. An alcohol can attack the TMSCN was used as a nucleophile, two diastereoisomers were
anomeric center of the acetoxonium ion from only one face to obtained). Furthermore, it is well established that the neigh-
provide 1,2-trans glycoside (Scheme 1(A), path a). An unavoid- boring group participation is not a predominant factor in the
able by-product associated with this reaction is 1,2-sugar synthesis of C-glycosides,13 interestingly, our research demon-
orthoester derived from the attack of the alcohol to the acet- strated that it is possible to use neighboring group partici-
oxonium ion (Scheme 1(A), path b).
pation to highly selectively construct a fused-ring by slightly
Furthermore, it is well established that the 2-C-branched changing the structure of the substrate. Besides, these carbo-
(acetylmethyl or acetonyl) sugars are the C2-carbon isosteres hydrate-based fused-cyclic compounds could be used to mimic
of the 2-O-acetyl-sugars or 2-N-acetamido sugars,10 and the the transition state geometry of glycosidases or glycosyltrans-
2-C-branched sugars have been widely used in glyco- ferases,14 thus they can be further tested as potential small-
biology.10d–f Inspired by the neighboring group participation molecule inhibitors of glycosidases or glycosyltransferases.15
phenomenon and due to our continued interest in the con- Finally, this method furnished the products containing a
struction of 2-C-branched glycoside,11 it was assumed that the chiral quaternary carbon center in a stereoselective manner,
perhydrofuro[2,3-b]pyran derivatives would be obtained from which is perceived as a challenging problem in organic syn-
the nucleophilic capture of the bicyclic oxocarbenium ion, thesis.16 These features make it an exceedingly efficient and
which could be generated through the attack of the 2-carbonyl practical method for synthesis of 2-substituted and 2,2-disub-
oxygen of the 2-formylmethyl or 2-acetylmethyl to the anomeric stituted perhydrofuro-[2,3-b]pyran derivatives.
center (Scheme 1(B)). By this strategy, recently, we have
reported a highly stereoselective synthesis of 2-O/N substituted
perhydrofuro[2,3-b]pyran derivatives from p-tolyl 2-formyl-
methyl-2-deoxy-D-thioglucopyranoside.11c Mechanistic studies
demonstrated that the formation of 2-O/N substituted per-
hydrofuro[2,3-b]pyran derivatives was partially through a SN2-
type reaction. Furthermore, we also successfully constructed
the 2,2-disubstituted perhydrofuro[2,3-b]pyran (and furan)
derivatives starting from 1,2-cyclopropanated sugars via ring-
opening-recyclization–addition in the presence of BiCl3.12 As a
continuation of these studies, herein, we describe the syn-
thesis of 2-C-substituted and 2,2-disubstituted perhydrofuro-
[2,3-b]pyran derivatives using 2-formylmethyl/2-acetylmethyl
instead of 2-O-acetyl as a participating group, and the for-
mation of 2,2-disubstituted perhydrofuro[2,3-b]pyran deriva-
tives was a SN1-type reaction.
Results and discussion
Initially, we selected the methyl 2-C-acetylmethyl-2-deoxy-β-D-
glucopyranoside 111h and allyltrimethylsilane 2 as the model
substrates to screen reaction conditions, the results are sum-
marized in Table 1. As shown in Table 1, when 2.0 equiv. of
TMSOTf and BF3·OEt2 were used at −78 °C to r.t., we obtained
the bicyclic compound 3 in 75% and 62% yield respectively
(Table 1, entries 1 and 2). In contrast, some other Lewis acids
including ZnCl2, AlCl3, and FeCl3 only gave disappointing
Table 1 Optimal of the reaction conditionsa
The potential advantage of this approach over the previous
methods was that the products could be further converted to
other fused-ring derivatives conveniently due to the presence
of allyl, carbonyl and cyano groups. Also, both the chemo-
selectivity and stereoselectivity are excellent, and there may
be three different reaction pathways for nucleophiles keto
carbonyl (Scheme 2, path a) vs. anomeric oxocarbenium ion
Entry
Promoter
Solvent
T
Productb
1c
TMSOTf
BF3·OEt2
ZnCl2
AlCl3
FeCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CHCl3
Et2O
−78 °C to r.t. (15 h)
−78 °C to r.t. (15 h)
−78 °C to r.t. (15 h)
−78 °C to r.t. (15 h)
−78 °C to r.t. (15 h)
−78 °C to r.t. (15 h)
−40 °C to r.t. (2 h)
−40 °C to r.t. (18 h)
−40 °C to r.t. (18 h)
−40 °C to r.t. (18 h)
−40 °C to r.t. (18 h)
−40 °C to r.t. (18 h)
−40 °C to r.t. (18 h)
−40 °C to r.t. (18 h)
3 (75%)
3 (62%)
NR
Trace
Decomposed
3 (54%)
3 (84%)
4
4
4
4
4
4
4
2c
3c
4c
5c
6c
BiCl3
7d
8
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
9
10d
11d
12d
13d
14d
Toluene
THF
DMF
Acetone
a All reactions were performed with methyl-glucoside 1 (0.1 mmol),
allyltrimethylsilane 2 (0.2 mmol), 4 Å M.S. 100 mg. b Isolated yield.
c 2.0 equiv. of promoter were used. d 0.8 equiv. of promoter was used.
Scheme 2 The different reaction pathways between acetyl 2-C-acetyl-
methyl-α-D-glucopyranoside and nucleophiles.
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results (Table 1, entries 3–5). Interestingly, when we conducted
the reaction in the presence of 2.0 equiv. of BiCl3 in CH2Cl2 at
−78 °C to r.t., we also obtained the 2,2-disubstituted perhydro-
furo[2,3-b]pyran derivative in 54% yield (Table 1, entry 6).12
Further optimization of the reaction conditions showed that
the solvent has a great influence on this reaction. For example,
we obtained the fused bicyclic product in 84% yield when the
reaction was carried out in CH3CN in the presence of 0.8 equiv.
of TMSOTf (Table 1, entry 7); however, other solvents such as
CH2Cl2,17 CHCl3, Et2O, toluene, THF, DMF and acetone only
isomerized methyl 2-C-acetylmethyl-2-deoxy-β-D-glucopyranoside
(1) to the methyl 2-C-acetylmethyl-2-deoxy-α-D-glucopyranoside
(4) (Table 1, entries 8–14). In all cases, we could not avoid the
presence of α-D-glucopyranoside 4 even when the reaction was
carried out at −40 °C to r.t. for two days.
The methoxy group is not a good leaving group, which
may lead to its isomerization.18 Therefore, we further opti-
mized the substrate by changing the methoxy group to the
acetoxyl group. Interestingly, when methyl 2-C-formylmethyl-2-
deoxy-3,4,6-tri-O-benzyl-glucopyranoside (5) was treated with
H2SO4–HOAc–Ac2O,19 we only obtained the fused-ring product
6, while under the same reaction conditions methyl 2-C-acetyl-
Table 2 The synthesis of 2-substituted and 2,2-disubstituted perhydro-
furo[2,3-b]pyransa
Yieldb
(%)
Entry Donor Nu
Product
1
6
75
2
6
85
3
6
TMSCN (11)
62
24
4
5
7
7
89
81
methyl-2-deoxy-3,4,6-tri-O-benzyl-glucopyranoside
(1)
was
transformed to acetyl 2-C-acetylmethyl-2-deoxy-3,4,6-tri-O-
benzyl-glucopyranoside (7) smoothly (Scheme 3).
As desired, started from 6, the fused-ring products were
obtained in high yield as a single diastereoisomer except when
TMSCN was used as a nucleophile. Inspired by the initial
success, under the optimal reaction conditions, acetyl 2-C-acetyl-
methyl-2-deoxy-3,4,6-tri-O-benzyl-glucopyranoside (7) was further
treated with 0.8 equiv. of TMSOTf in the presence of nucleo-
philes. The nucleophiles included allyltrimethylsilane (2) and
its analogue 9, silyl enol ether derivates (15, 17, 19, and 21)
and TMSCN (11), the results are summarized in Table 2. Satis-
factorily, the coupling reaction between 7 and the nucleophiles
could proceed smoothly to furnish the 2,2-disubstituted per-
hydrofuro[2,3-b]pyrans in excellent yield with high stereo-
6
7
7
7
92
95c
8
7
86
selectivity. However, when TMSCN was employed as
a
nucleophile, two isomers were obtained. The low selectivity of
nucleophilic attack exhibited by trimethylsilyl cyanide can be
explained by the high reactivity of the nucleophile, and
smaller steric hindrance presented by this nucleophile may
bring about the lower stereoselectivity as well.20
9
7
7
95
58
10
TMSCN (11)
32
a All reactions were carried out using 2.0 equiv. nucleophile, 0.8 equiv.
TMSOTf in CH3CN at −40 °C to r.t. with 100 mg of 4 Å M.S. unless
otherwise noted. b Isolated yield. c A pair of inseparable
diastereoisomers (1 : 1) were obtained due to the prochiral centre of
the substituted cyclohexanone as determined by 1H NMR.
Scheme 3 Synthesis of acetate from methyl 2-C-branched-glycoside.
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The stereochemistry of the products was first confirmed by phile which attacked the anomeric carbon from α (path-2) or
the extensive NMR experiments (1H-NMR, 13C-NMR, and β (path-1) face to form six–five fused-ring oxocarbenium ion
NOESY) of compounds 3, 8, 12, 18, 23 and 24 and further intermediates INT1 or INT2 respectively.22 The DFT calcu-
determined by X-ray crystallographic analysis of compound 25 lations23 on the B3LYP/6-31+G** level showed that INT1 is
(hydrogenation loss of the benzyl product of 3) (Scheme 4) 8.7 kcal mol−1 more stable than INT2. Therefore, the major
(Fig. 1).21
ring oxocarbenium ion is INT1. For the 2-acetoxyl-perhydro-
Based on the results of the experiments, a plausible mech- furo[2,3-b]pyran 6, in the presence of TMSOTf, it can form the
anism is proposed for the formation of perhydrofuro[2,3-b]- INT1 directly. Thus, after the formation of INT1, theoretically,
pyrans (Scheme 5). Starting from acetyl 2-C-acetylmethyl- the nucleophiles can approach the INT1 from either the
2-deoxy-3,4,6-tri-O-benzyl-glucopyranoside 7, TMSOTf co- concave or convex face to produce the endo- or exo-products
ordinated to the carbonyl oxygen atom of OAc and enhanced respectively. However, the calculation demonstrated the
its leaving ability, followed by its departure with the assistance concave face is more sterically hindered than the convex
of oxygen from the pyranoid ring formed the 2-C-branched face,22 thus the major products of this reaction are exo-
monocyclic pyran oxocarbenium ion. Subsequently, the carbo- products, which are consistent with the experimental
nyl oxygen of the ketone served as an intramolecular nucleo- observations.
It is worth mentioning that in our previous report, we
observed that the p-tolyl 2-C-formylmethyl-2-deoxy-3,4,6-tri-O-
benzyl-β-D-glucopyranoside can be used to synthesize
2-O/N substituted perhydrofuro[2,3-b]pyran partially through a
SN2-type reaction.11c However, in this study, when acetyl
2-C-acetylmethyl-2-deoxy-3,4,6-tri-O-benzyl-α-D-glucopyranoside
was employed as the starting material, the 2,2-di-substituted
perhydrofuro[2,3-b]-pyran can still be obtained in high yield
with excellent diastereoselectivity, and this is a SN1-type reac-
tion, which means that the reaction proceeds in the different
mechanisms by using various substrates.
Scheme 4 The hydrogenation loss of benzyl of products 3.
Conclusions
In summary, a highly stereoselective synthesis of 2-substituted
and 2,2-disubstituted perhydrofuro[2,3-b]pyran derivatives
using 2-C-branched (formylmethyl or acetylmethyl)-2-deoxy-
D-glucosides as starting material has been developed. The
strategy takes full advantage of the classical neighboring group
participation phenomenon using carbonyl (formylmethyl or
acetylmethyl) as the participating group to form the fused-ring
products in good to excellent yield with excellent diastereo-
selectivity. Mechanistic studies demonstrated that the for-
mation of 2,2-disubstituted perhydrofuro[2,3-b]pyrans from
Fig. 1 X-ray crystal structure of 25.
acetyl
2-C-acetylmethyl-2-deoxy-3,4,6-tri-O-benzyl-α-D-gluco-
pyranoside through a SN1-type reaction to produce the pyran
oxocarbenium ion, followed by intramolecular attack by the
oxygen atom of ketone gave cis-5/6-fused ring oxocarbenium
ions preferentially, which were further trapped by the nucleo-
philes from the less sterically hindered convex face to afford
the products.
Experimental section
General information
All reactions sensitive to air or moisture were carried out under
a nitrogen or argon atmosphere with anhydrous solvents. All
reagents were purchased from commercial suppliers and used
without further purification unless otherwise noted. Thin-layer
Scheme 5 Plausible mechanism for the synthesis of perhydrofuro[2,3-
b]pyrans from 2-C-branched sugar.
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chromatography was performed using silica gel GF254 pre- ESI-HRMS: m/z calcd for C32H36NaO7 [M + Na]+: 555.2359;
coated plates (0.20–0.25 mm thickness) with a fluorescent indi- found: 555.2349.
cator. Visualization on TLC was achieved by UV light (254 nm)
and a typical TLC indication solution (10% sulfuric acid–
ethanol solution). Column chromatography was performed on
General procedures for synthesis of 2-C-branched
perhydrofuro[2,3-b]pyrans
silica gel 90, 200–300 and 300–400 mesh. Optical rotations To a stirring solution of 6 or 7 (0.1 mmol) in anhydrous
were measured with a Perkin Elmer M341 Digital Polarimeter. CH3CN (1 mL) containing 100 mg of 4 Å M.S. at −40 °C and
1H and 13C NMR (600 and 150 MHz, respectively) spectra were under a N2 atmosphere was added nucleophiles (0.2 mmol).
recorded on a Bruker Avance 600 spectrometer. 1H NMR Then trimethylsilyl triflate (14.8 μL, 0.08 mmol) was added
chemical shifts are reported in ppm (δ) relative to tetramethyl- dropwise. The reaction mixture was stirred at −40 °C for 1.5 h,
silane (TMS) with the solvent resonance employed as the and then for 0.5 h at rt. The yellow mixture was diluted with
internal standard (CDCl3, δ 7.26 ppm; CD3OD, δ 3.31 ppm). CH2Cl2 (10 mL), and neutralized with a saturated NaHCO3
Data are reported as follows: chemical shift, multiplicity (s = solution (10 mL). The organic layer was collected, and the
singlet, d = doublet, t = triplet, q = quartet, m = multiplet), aqueous layer was re-extracted with further CH2Cl2 (2 ×
coupling constants (Hz) and integration. 13C NMR chemical 10 mL). The combined organic phases were dried over anhy-
shifts are reported in ppm from tetramethylsilane (TMS) with drous Na2SO4 and concentrated to give an orange syrup. The
the solvent resonance as the internal standard (CDCl3, crude material was slightly diluted with CH2Cl2 (0.2 mL) and
δ 77.0 ppm; CD3OD, δ 49.0). ESI-HRMS spectra were recorded purified by silica gel flash column chromatography (petroleum
on BioTOFQ.
ether–ethyl acetate, 8 : 1).
(3aR,4R,5S,6R,7aR)-2-Acetoxyl-4,5-bis(benzyloxy)-6-[(benzyloxy)-
(2R,3aR,4R,5S,6R,7aR)-2-Allyl-4,5-bis(benzyloxy)-6-[(benzyl-
methyl]-hexahydrofuro[2,3-b]pyran (6). Methyl 2-C-formyl- oxy)methyl]-hexahydrofuro[2,3-b]pyran (8). Obtained as a col-
methyl-2-deoxy-3,4,6-tri-O-benzyl-glucopyran 5 (0.9 g, 1.8 mmol) orless syrup (39.2 mg, 78%); [α]2D0 +70.6 (c 0.30, CHCl3);
was dissolved in 34 mL HOAc, and 20 mL Ac2O was added. The 1H NMR (600 MHz, CDCl3) δ 7.38–7.19 (m, 15H), 5.80–5.67 (m,
mixture was cooled to 0 °C, and then 27 μL H2SO4 was added. 1H), 5.45 (d, J = 4.5 Hz, 1H), 5.12–5.01 (m, 2H), 4.88 (d, J =
The mixture was stirred at 0 °C until all of 5 disappeared (about 11.5 Hz, 1H), 4.78 (d, J = 10.9 Hz, 1H), 4.68 (d, J = 11.6 Hz, 1H),
0.5 h). The reaction mixture was poured into ice water with vig- 4.65 (d, J = 12.0 Hz, 1H), 4.63 (d, J = 10.7 Hz, 1H), 4.55 (d, J =
orous stirring, and extracted with CH2Cl2 (20 mL × 3). The com- 12.1 Hz, 1H), 4.15 (dq, J = 12.0, 6.1 Hz, 1H), 3.82 (dd, J = 18.8,
bined organic phase was washed successively with saturated 7.9 Hz, 2H), 3.74 (t, J = 8.9 Hz, 1H), 3.70 (dd, J = 10.4, 1.4 Hz,
NaHCO3, saturated NaCl, and dried with Na2SO4. The crude 1H), 3.54 (t, J = 8.6 Hz, 1H), 2.32 (dt, J = 12.8, 6.4 Hz, 2H), 2.21
product was purified by flash column chromatography.
(dt, J = 13.4, 6.5 Hz, 1H), 1.88 (dd, J = 12.5, 5.8 Hz, 1H),
Compound 6 obtained as colorless syrup; yield: 95%. 1.71–1.64 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 138.5, 138.3,
[α]2D0 +67.5 (c 0.29, CHCl3); 1H NMR (600 MHz, CDCl3) 138.1, 133.9, 128.5, 128.4, 128.4, 128.1, 127.9, 127.8, 127.7,
δ 7.40–7.12 (m, 15H), 6.84 (t, J = 4.5 Hz, 1H), 6.34 (d, J = 127.6, 117.5, 101.5, 80.7, 77.9, 76.6, 74.6, 74.4, 73.6, 72.2, 68.8,
3.2 Hz, 1H), 4.96 (d, J = 11.0 Hz, 1H), 4.83 (d, J = 10.7 Hz, 1H), 44.3, 40.7, 33.8; ESI-HRMS: m/z calcd for C32H36NaO5
4.71 (d, J = 11.0 Hz, 1H), 4.66 (d, J = 12.0 Hz, 1H), 4.60 (d, J = [M + Na]+: 523.2460; found: 523.2455.
10.7 Hz, 1H), 4.52 (d, J = 12.0 Hz, 1H), 3.85–3.78 (m, 3H), 3.68
(2R,3aR,4R,5S,6R,7aR)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]-
(d, J = 10.2 Hz, 2H), 2.30–2.23 (m, 1H), 2.21–2.16 (m, 1H), 2.12 2-(2-methylallyl)-hexahydrofuro[2,3-b]pyran (10). Obtained as
(s, 3H), 1.97–1.93 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 168.8, a colorless syrup (43.7 mg, 85%); [α]D20 +74.6 (c 0.30, CHCl3);
138.1, 138.1, 137.9, 128.5, 128.4, 128.0, 127.9, 127.9, 127.8, 1H NMR (600 MHz, CDCl3) δ 7.37–7.20 (m, 15H), 5.46 (d, J =
127.8, 92.5, 89.5, 80.2, 79.0, 75.4, 75.0, 73.7, 73.1, 68.3, 40.3, 4.6 Hz, 1H), 4.88 (d, J = 11.6 Hz, 1H), 4.79 (d, J = 11.2 Hz, 2H),
30.3, 20.9, 20.8; ESI-HRMS: m/z calcd for C31H34NaO7 4.69 (d, J = 11.2 Hz, 2H), 4.65 (d, J = 12.0 Hz, 1H), 4.64 (d, J =
[M + Na]+: 541.2204; found: 541.2204.
10.8 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H), 4.23 (dq, J = 12.6,
Acetyl-2-C-acetonyl-2-deoxy-3,4,6-tri-O-benzyl-D-gluco- 6.3 Hz, 1H), 3.82 (dd, J = 15.5, 6.4 Hz, 2H), 3.75 (t, J = 8.9 Hz,
pyranoside (7). Compound 7 was synthesized following a 1H), 3.70 (d, J = 8.8 Hz, 1H), 3.54 (t, J = 8.6 Hz, 1H), 2.33 (dd,
similar procedure to compound 6, and obtained as colorless J = 13.9, 6.5 Hz, 2H), 2.08 (dd, J = 14.0, 6.4 Hz, 1H), 1.88 (dd,
syrup; yield: 98%. [α]2D0 +79.5 (c 0.28, CHCl3); 1H NMR J = 12.8, 5.9 Hz, 1H), 1.70 (s, 3H), 1.68–1.62 (m, 1H); 13C NMR
(600 MHz, CDCl3) δ 7.38–7.15 (m, 15H), 6.20 (d, J = 2.8 Hz, (150 MHz, CDCl3) δ 142.0, 138.5, 138.3, 138.1, 128.4, 128.4,
1H), 4.95 (d, J = 11.3 Hz, 1H), 4.79 (d, J = 10.7 Hz, 1H), 4.66 (d, 128.4, 128.1, 127.9, 127.8, 127.7, 127.6, 112.6, 101.3, 80.6, 77.9,
J = 12.1 Hz, 1H), 4.60 (d, J = 11.2 Hz, 1H), 4.59 (d, J = 10.7 Hz, 75.8, 74.4, 74.4, 73.6, 72.2, 68.8, 44.8, 44.3, 34.4, 22.9;
1H), 4.53 (d, J = 12.1 Hz, 1H), 3.86–3.85 (m, 1H), 3.84–3.81 (m, ESI-HRMS: m/z calcd for C33H38NaO5 [M + Na]+: 537.2617;
1H), 3.80 (dd, J = 8.1, 2.9 Hz, 1H), 3.67 (dd, J = 11.0, 1.4 Hz, found: 537.2621.
1H), 3.64 (dd, J = 10.8, 8.4 Hz, 1H), 2.64–2.54 (m, 2H),
(2R,3aR,4R,5S,6R,7aS)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]-
2.26–2.14 (m, 1H), 2.08 (s, 3H), 2.04 (d, J = 7.7 Hz, 3H); 13C 2-cyano-hexahydrofuro[2,3-b]pyran (12). Obtained as a color-
NMR (150 MHz, CDCl3) δ 206.1, 169.2, 138.2, 138.0, 137.9, less syrup (30.1 mg, 62%); [α]2D0 +85.1 (c 0.12, CHCl3); H NMR
1
128.5, 128.4, 128.3, 127.9, 127.9, 127.8, 127.8, 127.7, 127.7, (600 MHz, CDCl3) δ 7.38–7.20 (m, 15H), 5.46 (d, J = 4.3 Hz,
93.1, 79.9, 79.2, 75.0, 74.9, 73.6, 68.4, 41.2, 40.7, 29.8, 20.9; 1H), 4.92 (d, J = 11.7 Hz, 1H), 4.77 (d, J = 11.0 Hz, 1H), 4.69 (d,
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J = 11.7 Hz, 1H), 4.65 (dd, J = 8.3, 2.8 Hz, 2H), 4.62 (d, J = 2H), 3.68 (dd, J = 8.2, 4.8 Hz, 2H), 3.19 (d, J = 2.5 Hz, 2H),
4.2 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H), 3.94 (d, J = 9.2 Hz, 1H), 2.47–2.41 (m, 1H), 2.34 (dd, J = 13.6, 8.4 Hz, 1H), 2.02 (dd, J =
3.83 (dd, J = 14.2, 5.9 Hz, 2H), 3.75 (d, J = 8.9 Hz, 1H), 3.72 (d, 13.6, 5.8 Hz, 1H), 1.44 (s, 3H). 13C NMR (150 MHz, CDCl3)
J = 10.4 Hz, 1H), 2.40–2.33 (m, 2H), 2.18 (d, J = 13.8 Hz, 1H); δ 198.6, 138.3, 138.2, 138.1, 137.5, 133.2, 128.6, 128.5, 128.4,
13C NMR (150 MHz, CDCl3) δ 138.2, 138.0, 137.9, 128.6, 128.5, 128.3, 128.0, 127.9, 127.9, 127.8, 127.8, 127.6, 100.5, 80.8, 79.8,
128.4, 128.1, 127.9, 127.8, 127.7, 119.0, 103.3, 79.9, 77.4, 75.0, 77.1, 73.6, 73.5, 73.2, 72.0, 69.2, 49.7, 43.6, 38.4, 28.6.
74.4, 73.6, 72.9, 68.4, 63.0, 42.8, 32.8; ESI-HRMS: m/z calcd for ESI-HRMS: m/z calcd for C38H40NaO6 [M + Na]+: 615.2717;
C32H31NNaO5 [M + Na]+: 508.2100; found: 508.2094.
found: 615.2717.
(2S,3aR,4R,5S,6R,7aS)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]-
(2R,3aR,4R,5S,6R,7aR)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]-
2-cyano-hexahydrofuro[2,3-b]pyran (13). Obtained as a colorless 2-(1-cyclohexanon-2-yl)-2-methylhexahydro-furo[2,3-b]pyran (18).
1
syrup (11.6 mg, 24%); H NMR (600 MHz, CDCl3) δ 7.38–7.29 Colorless syrup, 54.2 mg, yield: 95%, [α]2D0 +75.9 (c 0.48,
1
(m, 13H), 7.20 (d, J = 7.3 Hz, 2H), 5.59 (d, J = 4.7 Hz, 1H), 4.81 CHCl3); H NMR (600 MHz, CDCl3) δ 7.38–7.20 (m, 15H), 5.41
(d, J = 11.9 Hz, 1H), 4.70 (d, J = 11.1 Hz, 1H), 4.64–4.61 (m, (dd, J = 7.4, 5.2 Hz, 1H), 4.81 (dd, J = 11.5, 3.5 Hz, 1H),
3H), 4.58–4.53 (m, 2H), 3.80 (d, J = 9.1 Hz, 1H), 3.75 (dd, J = 4.78–4.72 (m, 1H), 4.69 (t, J = 11.2 Hz, 1H), 4.63 (d, J = 12.2 Hz,
13.9, 10.0 Hz, 2H), 3.69–3.67 (m, 1H), 3.44 (t, J = 7.3 Hz, 1H), 1H), 4.58 (dd, J = 14.3, 11.2 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H),
2.48 (s, 1H), 2.24 (dt, J = 22.0, 7.5 Hz, 2H).
3.90 (dd, J = 12.5, 5.8 Hz, 1H), 3.79 (td, J = 10.3, 3.4 Hz, 1H),
(2S,3aR,4R,5S,6R,7aR)-2-Allyl-4,5-bis(benzyloxy)-6-[(benzyloxy)- 3.74–3.66 (m, 3H), 2.53 (ddd, J = 57.9, 12.6, 4.7 Hz, 1H),
methyl]-2-methylhexahydrofuro[2,3-b]pyran (3). Obtained as a 2.41–2.25 (m, 4H), 2.13–1.99 (m, 3H), 1.93 (s, 1H), 1.71–1.55
colorless syrup (45.8 mg, 89%); [α]2D0 +46.2 (c 0.41, CHCl3); (m, 3H), 1.40 (s, 1H), 1.30 (s, 1H), 1.26 (dd, J = 8.4, 5.8 Hz, 1H).
1H NMR (600 MHz, CDCl3) δ 7.41–7.29 (m, 15H), 5.88–5.77 (m, 13C NMR (150 MHz, CDCl3) δ 211.6, 211.5, 138.4, 138.4, 138.2,
1H), 5.50 (d, J = 5.1 Hz, 1H), 5.12 (t, J = 12.2 Hz, 2H), 4.83 (d, 138.2, 138.1, 128.5, 128.4, 128.4, 128.1, 128.0, 127.9, 127.9,
J = 11.8 Hz, 1H), 4.75 (d, J = 11.1 Hz, 1H), 4.69 (d, J = 11.8 Hz, 127.8, 127.8, 127.6, 101.6, 100.5, 82.1, 81.4, 81.2, 80.7, 77.6,
1H), 4.68 (d, J = 12.2 Hz, 1H), 4.58 (t, J = 11.8 Hz, 2H), 3.95 (dt, 74.2, 74.0, 73.9, 73.6, 72.1, 69.1, 69.0, 62.2, 60.6, 44.6, 44.0,
J = 8.9, 3.0 Hz, 1H), 3.82 (dd, J = 10.7, 3.6 Hz, 1H), 3.79 (dd, J = 43.5, 43.4, 40.3, 36.1, 29.3, 29.2, 28.9, 28.3, 28.1, 25.4, 25.3,
8.9, 6.9 Hz, 1H), 3.74 (dd, J = 10.6, 2.5 Hz, 1H), 3.70 (t, J = 23.6. ESI-HRMS: m/z calcd for C36H42NaO6 [M
6.9 Hz, 1H), 2.49–2.42 (m, 1H), 2.30–2.21 (m, 2H), 2.01 (dd, J = 593.2874; found: 593.2870.
+
Na]+:
13.3, 8.4 Hz, 1H), 1.77 (dd, J = 13.3, 5.4 Hz, 1H), 1.29 (s, 3H);
(2R,3aR,4R,5S,6R,7aR)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]-
13C NMR (125 MHz, CDCl3) δ 138.4, 138.2(2), 128.4(2), 128.0, 2-[(2,2-dimethyl-propionyl)methyl]-2-methylhexahydrofuro[2,3-b]-
127.9(2), 127.8(2), 127.6, 118.2, 100.6, 80.9, 80.2, 77.4, 73.7, pyran (20). Colorless syrup, 49.2 mg, yield: 86%, [α]2D0 +68.7
73.5, 73.3, 71.9, 69.2, 47.0, 43.9, 38.0, 27.7; ESI-HRMS: m/z (c 0.42, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.37–7.20 (m,
calcd for C33H38NaO5 [M + Na]+: 537.2617; found: 537.2611.
15H), 5.46 (d, J = 5.0 Hz, 1H), 4.78 (d, J = 11.5 Hz, 1H), 4.72 (d,
(2R,3aR,4R,5S,6R,7aR)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]- J = 11.1 Hz, 1H), 4.67 (d, J = 11.5 Hz, 1H), 4.63 (d, J = 12.1 Hz,
2-methyl-2-(2-methylallyl)-hexahydrofuro[2,3-b]pyran (14). 1H), 4.56 (d, J = 11.3 Hz, 1H), 4.53 (d, J = 12.3 Hz, 1H), 3.90
Obtained as a colorless syrup (42.8 mg, 81%); [α]2D0 +52.1 (dd, J = 6.2, 2.7 Hz, 1H), 3.78 (dd, J = 10.6, 3.6 Hz, 1H),
(c 0.17, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.37–7.19 (m, 3.76–3.72 (m, 1H), 3.72–3.66 (m, 2H), 2.84 (d, J = 17.4 Hz, 1H),
19H), 5.44 (d, J = 5.1 Hz, 1H), 4.86 (s, 1H), 4.78 (d, J = 11.8 Hz, 2.68 (d, J = 17.4 Hz, 1H), 2.44–2.37 (m, 1H), 2.25 (dd, J = 13.8,
1H), 4.70 (d, J = 11.4 Hz, 2H), 4.64 (d, J = 11.8 Hz, 1H), 4.64 (d, 8.3 Hz, 1H), 2.01 (dd, J = 13.8, 4.9 Hz, 1H), 1.36 (s, 3H), 1.12 (s,
J = 12.1 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H), 4.52 (d, J = 12.6 Hz, 9H). 13C NMR (150 MHz, CDCl3) δ 214.2, 138.3, 138.2, 128.5,
1H), 3.89 (dt, J = 8.9, 2.9 Hz, 1H), 3.79–3.73 (m, 2H), 3.70 (dd, 128.4, 128.4, 128.0, 127.9, 127.9, 127.8, 127.8, 127.6, 100.5,
J = 10.6, 2.5 Hz, 1H), 3.66 (t, J = 6.8 Hz, 1H), 2.42 (dd, J = 13.5, 80.3, 80.2, 77.4, 73.8, 73.5, 73.5, 72.1, 69.1, 47.8, 44.7, 43.9,
6.4 Hz, 1H), 2.20 (d, J = 13.5 Hz, 1H), 2.13 (d, J = 13.4 Hz, 1H), 38.9, 27.9, 26.2. ESI-HRMS: m/z calcd for C36H44NaO6
2.05–2.00 (m, 1H), 1.80 (s, 3H), 1.76 (dd, J = 13.2, 5.6 Hz, 1H), [M + Na]+: 595.3030; found: 595.3049.
1.26 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 142.7, 138.5, 138.2,
(2R,3aR,4R,5S,6R,7aR)-2-[(Acetyl)methyl]-4,5-bis(benzyloxy)-
128.4, 128.4, 128.3, 128.0, 127.9, 127.9, 127.8, 127.7, 127.6, 6-[(benzyloxy)methyl]-2-methylhexahydrofuro[2,3-b]pyran (22).
114.7, 100.5, 81.5, 80.1, 76.8, 73.7, 73.5, 73.3, 71.9, 69.2, 49.9, Colorless syrup, 47.8 mg, yield: 95%, [α]2D0 +43.1 (c 0.54,
1
43.8, 38.9, 27.8, 24.3; ESI-HRMS: m/z calcd for C34H40NaO5 CHCl3); H NMR (600 MHz, CDCl3) δ 7.37–7.20 (m, 15H), 5.47
[M + Na]+: 551.2773; found: 551.2768.
(d, J = 5.1 Hz, 1H), 4.77 (d, J = 11.8 Hz, 1H), 4.70 (d, J =
(2R,3aR,4R,5S,6R,7aR)-2-[(Benzoyl)methyl]-4,5-bis(benzyloxy)- 11.1 Hz, 1H), 4.64 (t, J = 11.8 Hz, 2H), 4.54 (d, J = 11.0 Hz, 2H),
6-[(benzyloxy)methyl]-2-methyl-hexahydro-furo[2,3-b]pyran (16). 4.53 (d, J = 12.1 Hz, 1H), 3.89 (dt, J = 8.6, 3.0 Hz, 1H), 3.77 (dd,
Colorless syrup, 54.5 mg, yield: 92%, [α]2D0 +30.1 (c 0.25, J = 10.7, 3.8 Hz, 1H), 3.75–3.72 (m, 1H), 3.70 (dd, J = 10.7,
1
CHCl3); H NMR (600 MHz, CDCl3) δ 7.95 (d, J = 7.4 Hz, 2H), 2.5 Hz, 1H), 3.66 (t, J = 6.7 Hz, 1H), 2.66 (d, J = 14.9 Hz, 1H),
7.56 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.37–7.27 (m, 2.56 (d, J = 14.9 Hz, 1H), 2.46–2.40 (m, 1H), 2.17 (s, 3H), 2.14
13H), 7.20 (d, J = 6.5 Hz, 2H), 5.41 (d, J = 5.1 Hz, 1H), 4.74 (d, (dd, J = 13.6, 8.4 Hz, 1H), 1.90 (dd, J = 13.6, 5.6 Hz, 1H), 1.34
J = 11.6 Hz, 1H), 4.68 (d, J = 11.1 Hz, 1H), 4.64 (d, J = 11.7 Hz, (s, 3H). 13C NMR (150 MHz, CDCl3) δ 207.4, 138.3, 138.1,
1H), 4.61 (d, J = 12.1 Hz, 1H), 4.52 (d, J = 11.0 Hz, 1H), 4.51 (d, 138.1, 128.5, 128.4, 128.4, 128.1, 127.9, 127.9, 127.9, 127.8,
J = 12.2 Hz, 1H), 3.89 (dt, J = 8.5, 3.0 Hz, 1H), 3.78–3.70 (m, 127.6, 100.6, 79.9, 79.8, 77.1, 73.7, 73.5, 73.3, 72.0, 69.1, 54.8,
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43.6, 38.8, 31.9, 28.0. ESI-HRMS: m/z calcd for C33H38NaO6
[M + Na]+: 553.2551; found: 553.2561.
Notes and references
(2R,3aR,4R,5S,6R,7aR)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]-
1 Selected examples: (a) M. E. Rateb, W. E. Houssen,
M. Schumacher, W. T. A. Harrison, M. Diederich, R. Ebel
and M. Jaspars, J. Nat. Prod., 2009, 72, 1471–1476;
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(e) G. E. Veitch, E. Beckmann, B. J. Burke, A. Boyer,
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T. S. Kam, Tetrahedron, 2011, 67, 3830–3838.
2-cyano-2-methylhexahydrofuro[2,3-b]pyran
(23). Colorless
syrup, 25.3 mg, yield: 58%, [α]2D0 +49.5 (c 0.69, CHCl3); 1H NMR
(600 MHz, CDCl3) δ 7.40–7.27 (m, 14H), 7.23–7.19 (m, 2H),
5.60 (d, J = 5.5 Hz, 1H), 4.72 (d, J = 12.0 Hz, 1H), 4.65–4.59 (m,
3H), 4.54 (d, J = 12.1 Hz, 1H), 4.50 (d, J = 11.2 Hz, 1H),
3.84–3.80 (m, 1H), 3.76–3.70 (m, 2H), 3.68 (dd, J = 10.7, 2.6 Hz,
1H), 3.53 (t, J = 5.8 Hz, 1H), 2.68–2.60 (m, 1H), 2.41 (dd, J =
13.7, 8.1 Hz, 1H), 1.95 (dd, J = 13.7, 7.2 Hz, 1H), 1.56 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 138.0, 137.9, 137.7, 128.6, 128.5,
128.4, 128.3, 128.1, 127.9, 127.9, 127.7, 121.2, 101.6, 77.5, 76.4,
73.5, 73.4, 72.7, 72.7, 72.3, 69.0, 41.6, 39.8, 26.3; ESI-HRMS:
m/z calcd for C31H33NNaO5 [M + Na]+: 522.2251; found:
522.2256.
(2S,3aR,4R,5S,6R,7aR)-4,5-Bis(benzyloxy)-6-[(benzyloxy)methyl]-
2-cyano-2-methylhexahydrofuro[2,3-b]pyran
(24). Colorless
syrup, 14 mg, yield: 32%, 1H NMR (600 MHz, CDCl3)
δ 7.36–7.27 (m, 13H), 7.22 (d, J = 6.7 Hz, 2H), 5.51 (d, J =
4.6 Hz, 1H), 4.93 (d, J = 11.6 Hz, 1H), 4.78 (d, J = 11.1 Hz, 1H),
4.70 (d, J = 11.7 Hz, 1H), 4.64 (d, J = 12.9 Hz, 1H), 4.62 (d, J =
12.1 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H), 4.27–4.25 (m, 1H),
3.97–3.94 (m, 2H), 3.82 (dd, J = 10.8, 3.2 Hz, 1H), 3.75–3.69 (m,
2H), 2.43–2.37 (m, 1H), 2.10 (dd, J = 6.8, 2.8 Hz, 1H), 2.04 (dd,
J = 14.8, 8.0 Hz, 1H), 1.61 (s, 3H). 13C NMR (150 MHz, CDCl3)
δ 138.3, 138.0, 137.9, 128.7, 128.6, 128.5, 128.4, 128.4, 128.2,
128.0, 127.9, 127.8, 127.7, 121.6, 102.6, 80.2, 77.6, 75.1, 74.4,
73.6, 72.9, 72.6, 68.4, 44.7, 40.8, 28.3. ESI-HRMS: m/z calcd for
C31H33NNaO5 [M + Na]+: 522.2251; found: 522.2271.
Synthesis of (2S,3aR,4R,5S,6R,7aR)-4,5-dihydroxy-6-(hydroxy
methyl)-2-methyl-2-propanyl-hexahydrofuro[2,3-b]pyran (25).
To a solution of 3 (0.26 g, 0.51 mmol) in MeOH (10 mL) were
added 10% Pd-C (0.026 g) and HCOOH (0.5 mL). The mixture
was stirred at 50 °C under an atmosphere of H2 overnight. The
mixture was cooled to room temperature, filtered over diato-
maceous earth, and concentrated in vacuo, purified by silica
gel flash column chromatography (ethyl acetate–MeOH =
20 : 1) to afford compound 25 (0.11 g, 0.46 mmol, 90%) as a
colourless solid; [α]D20 +30.9 (c 0.14, CHCl3); 1H NMR (600 MHz,
MeOH-d4): δ 5.36 (d, J = 4.5 Hz, 1H), 3.78 (dd, J = 11.9, 2.6 Hz,
1H), 3.74 (dd, J = 11.9, 4.9 Hz, 1H), 3.64 (ddd, J = 9.4, 4.8,
2.6 Hz, 1H), 3.56 (t, J = 8.8 Hz, 1H), 3.35 (t, J = 9.1 Hz, 1H),
2.10–2.05 (m, 1H), 2.02 (dd, J = 13.1, 7.6 Hz, 1H), 1.97 (dd, J =
13.2, 2.2 Hz, 1H), 1.49 (ddd, J = 16.3, 11.0, 4.8 Hz, 2H), 1.39
(ddd, J = 16.4, 12.2, 6.2 Hz, 2H), 1.35 (s, 3H), 0.93 (t, J = 7.3 Hz,
3H); 13C NMR (150 MHz, MeOH-d4): δ 100.8, 80.5, 74.5, 74.0,
69.9, 61.3, 45.3, 45.2, 38.5, 26.5, 17.3, 13.5; ESI-HRMS: m/z
calcd for C12H22NaO5[M + Na]+: 269.1359 found: 269.1362.
2 (a) K. Ghosh, B. D. Chapsal, A. Baldridge, M. P. Steffey,
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576–579; (b) D. Sarkar and R. V. Venkateswaran, Tetra-
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5 (a) H. M. R. Hoffmann, Angew. Chem., Int. Ed. Engl., 1992,
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Acknowledgements
We are grateful for the financial support from the National
Science Foundation of China (21372215).
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