A novel and highly stereoselective synthesis of 2-substituted perhydrofuro[2,3-b]pyran derivatives

Article abstract of DOI:10.1021/ol201622t

An effective and facile method for the synthesis of 2-substituted perhydrofuro[2,3-b]pyran derivatives is described. The cyclization of 2-C-aldehydo-2-deoxy-d-thioglucoside in the presence of N-iodosuccinimide (NIS) is highly stereoselective. 2-Substitute

Full text of DOI:10.1021/ol201622t

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4276–4279
A Novel and Highly Stereoselective
Synthesis of 2-Substituted
Perhydrofuro[2,3-b]pyran Derivatives
Xiaofeng Ma,† Qiang Tian,† Qin Tang,† Jinzhong Zhao,†,‡ and Huawu Shao*,†
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of
Sciences, Chengdu 610041, China, and Shanxi Agriculture University, Taigu Shanxi
030801, China and Graduate School of Chinese Academy of Sciences, China
shaohw@cib.ac.cn
Received June 16, 2011
ABSTRACT
An effective and facile method for the synthesis of 2-substituted perhydrofuro[2,3-b]pyran derivatives is described. The cyclization of 2-C-
aldehydo-2-deoxy-D-thioglucoside in the presence of N-iodosuccinimide (NIS) is highly stereoselective. 2-Substituted cyclization products were
obtained in good to excellent yields.
Perhydrofuro[2,3-b]pyran subunits have been found in a
variety of biologically important natural products such
as tetrahydroaplysulphurin-1;1 novaxenicins A, B, C;2
penifulvin A, B, C;3 stemona alkaloids;4 euplotin C;5
azadirachtin;6 and cadlinolide A, B.7 A range of methods
have been developed for the synthesis of these fascinating
motifs.8 Classical routes include reactions such as radical
cyclization,8aꢀc intramolecular dehydration,8d double in-
tramolecular cyclizations from an acyclic precursor,8e N-
iodosuccinimide (NIS) mediated ring opening of 1,2-cyclo-
propanated sugar derivatives,8f or the hetero-DielsꢀAlder
reaction.8gꢀi While these methods havecontributed greatly
to this area, the highly stereoselective installation of a
heteroatom substituent or an active functional group at
the C(2) of perhydrofuro[2,3-b]pyrans still represents a great
challenge.
(6) (a) Veitch, G. E.; Beckmann, E.; Burke, B. J.; Boyer, A.; Maslen,
S. L.; Ley, S. V. Angew. Chem., Int. Ed. 2007, 46, 7629. (b) Veitch, G. E.;
Beckmann, E.; Burke, B. J.; Boyer, A.; Ayats, C.; Ley, S. V. Angew.
Chem., Int. Ed. 2007, 46, 7633. (c) Denholm, A. A.; Jennens, L.; Ley,
S. V.; Wood, A. Tetrahedron 1995, 51, 6591. (d) Beckmann, E.; Boyer,
A.; Veitch, G. E.; Ley, S. V. Angew. Chem., Int. Ed. 2009, 48, 1317.
(7) Tischler, M.; Andersen, R. J.; Choudhary, M. I.; Clardy, J. J. Org.
Chem. 1991, 56, 42.
(8) For representative examples, see: (a) Yamazaki, O.; Yamaguchi,
K.; Yokoyama, M.; Togo, H. J. Org. Chem. 2000, 65, 5440. (b) Yanada,
R.; Koh, Y.; Nishimori, N.; Matsumura, A.; Obika, S.; Mitsuya, H.;
Fujii, N.; Takemoto, Y. J. Org. Chem. 2004, 69, 2417. (c) Marco-
Contelles, J.; Ruiz-Caro, J. Carbohydr. Res. 2001, 335, 71. (d) Duhamel,
P.; Deyine, A.; Dujardin, G.; Ple, G.; Poirier, J. M. J. Chem. Soc. Pak. 1
1995, 2103. (e) Alonso, F.; Lorenzo, E.; Melendez, J.; Yus, M. Tetra-
hedron 2003, 59, 5199. (f) Haveli, S. D.; Sridhar, P. R.; Suguna, P.;
Chandrasekaran, S. Org. Lett. 2007, 9, 1331. (g) Evans, D. A.; Olhava,
E. J.; Johnson, J. S.; Janey, J. M. Angew. Chem., Int. Ed. 1998, 37, 3372.
(h) Evans, D. A.; Johnson, J. S. J. Am. Chem. Soc. 1998, 120, 4895. (i)
Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122,
1635.
(9) (a) Tian, Q.; Xu, L. Y.; Ma, X. F.; Zou, W.; Shao, H. W. Org. Lett.
2010, 12, 540. (b) Tian, Q.; Dong, L.; Ma, X. F.; Xu, L. Y.; Hu, C. W.;
Zou, W.; Shao, H. W. J. Org. Chem. 2011, 76, 1045. (c) Shao, H. W.;
Wang, Z. R.; Lacroix, E.; Wu, S. H.; Jennings, H. J.; Zou, W. J. Am.
Chem. Soc. 2002, 124, 2130. (d) Shao, H. W.; Ekthawatchai, S.; Wu,
S. H.; Zou, W. Org. Lett. 2004, 6, 3497. (e) Shao, H. W.; Ekthawatchai,
S.; Chen, C. S.; Wu, S. H.; Zou, W. J. Org. Chem. 2005, 70, 4726. (f)
Wang, Z.; Shao, H. W.; Lacroix, E.; Wu, S. H.; Jennings, H. J.; Zou, W.
J. Org. Chem. 2003, 68, 8097.
† Chengdu Institute of Biology.
‡ Shanxi Agriculture University.
(1) Rateb, M. E.; Houssen, W. E.; Schumacher, M.; Harrison,
W. T. A.; Diederich, M.; Ebel, R.; Jaspars, M. J. Nat. Prod. 2009, 72,
1471.
(2) Bishara, A.; Rudi, A.; Goldberg, I.; Benayahu, Y.; Kashman, Y.
Tetrahedron 2006, 62, 12092.
(3) Gaich, T.; Mulzer, J. Org. Lett. 2010, 12, 272.
(4) (a) Sastraruji, T.; Chaiyong, S.; Jatisatienr, A.; Pyne, S. G.; Ung,
A. T.; Lie, W. J. Nat. Prod. 2011, 74, 60. (b) Sastraruji, K.; Sastraruji, T.;
Pyne, S. G.; Ung, A. T.; Jatisatienr, A.; Lie, W. J. Nat. Prod. 2010, 73,
€
935. (c) Bruggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen,
M. D.; Schwink, L.; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284. (d)
Kende, A. S.; Smalley, T. L.; Huang, H. J. Am. Chem. Soc. 1999, 121,
7431. (e) Ye, Y.; Velten, R. F. Tetrahedron Lett. 2003, 44, 7171.
(5) Guella, G.; Callone, E.; Mancini, I.; Uccello-Barretta, G.; Balzano,
F.; Dini, F. Eur. J. Org. Chem. 2004, 1308.
r
10.1021/ol201622t
Published on Web 07/20/2011
2011 American Chemical Society

Traditionally, 2-O-acyl groups have been used as neigh-
boring assistant groups for the stereoselective construction
of 1,2-trans glycosides and the synthesis of 1,2-sugar
orthoesters. In continuation of our previous work in the
stereoselective synthesis of C-glycosides,9 we conceived
that 2-O-acetyl could be replaced with a 2-formylmethyl
group, and an appropriate leaving group was installed at
anomeric carbon; under the help of a promoter, this might
generate fused perhydrofuro[2,3-b]pyran ring systems by
trapping six-five fused ring oxonium ion intermediates
(Scheme 1). Herein, we report our recent attempts to effect
this transformation.
Table 1. Reaction of Thioglucosides 1, 2, 3 with MeOHa
entry
donor
promoterb
yieldc (%)
5/6d
1
1
1
1
1
1
1
1
1
1
1
2
3
NISþAgOTf
32
2:1
3:1
/
2
NIS þ TMSOTf
53
3
CuBr2þ Bu4NBr
trace
85
4
NIS þ TfOH
NIS
3:1
5:1
3:1
/
5
92
6
NBS
NCS
I2
92
Scheme 1. Proposed Synthetic Route for 2-Substituted
Perhydrofuro[2,3-b]pyran Derivatives
7
trace
83
8
1:2
1:1
1:3
1:1
/
9
Br2
69
10
11
12
ICl
89
NIS
83
NIS
trace
a All reactions were performed with thioglucosides 1, 2, or 3 (0.1
mmol), MeOH 4 (0.2 mmol), promoter 0.15 mmol, in CH2Cl2 (2 mL)
at ꢀ30 °C - rt for 1 h. b For NIS promoted reactions, 0.15 mmol NIS and
5 mol % additive were used; while for CuBr2 pomoted reaction, 0.35 mmol
CuBr2 and 0.22 mmol Bu4NBr were used. c Isolated yield. d Values were
determined by 1H NMR.
A preliminary experiment was performed with p-tolyl
thioglucopyranoside 1 and MeOH 4 as model substrates,
and the reaction was mediated by NIS in the presence of
5% mmol AgOTf in CH2Cl2 at ꢀ30 °C, whereafter the
reactants were warmed to room temperature for 1 h. To
our delight, the desired perhydrofuro[2,3-b]pyran derivatives
5 and 6 were obtained in 32% combined yield (Table 1,
entry 1). The stereochemistries of 5 and 6 were exten-
sively studied by 1H NMR, 1Hꢀ H COSY, and NOESY
1
(Figure 1), and the structure of 5 was further unambigu-
ously determined by X-ray crystallography (Figure 2).
With this promising result in hand, the reaction conditions
were then optimized. By choosing the additive TMSOTf,
the yield was increased to 53% (Table 1, entry 2). CuBr2
and Bu4NBr as promoters afforded an unsatisfactory
result (Table 1, entry3). The presence of TfOH provided
a good result (Table 1, entry 4). In order to reveal optimal
conditions for this transformation, p-tolyl thioglucopyra-
noside 1 and MeOH were directly treated with thiophilic
reagents including NIS, NBS, NCS, I2, Br2, and ICl
(Table 1, entries 5ꢀ10). It was found that all of these
thiophilic reagents promoted the reaction except for NCS.
NBS, I2, and ICl furnished the bicyclo-products in high
yield but with lower stereoselectivity. By way of contrast,
when NIS was employed as a promoter, the perhydrofuro-
[2,3-b]pyran derivative was obtained in excellent yield with
good diastereoselectivity (Table 1, entry 5). Further screen-
ing of the glycosyl donors with phenyl thioglucopyrano-
side 2 and ethyl thioglucopyranoside 3 (Table 1, entries 11
and 12) indicated that the p-tolyl thioglucopyranoside 1
was the best substrate for this NIS-promoted reaction.
Figure 1. Key NOEs of perhydrofuro[2,3-b]pyran derivatives
5 and 6.
To investigate the scope of the reaction, a number of
primary, secondary, and tertiary alcohols; hydroxyben-
zenes; and TMSN3 were reacted with p-tolyl thioglucopyr-
anoside 1 (Table 2). The NIS-promoted reaction shows
wide applicability for the synthesis of various alkyl or aryl
O-substituted perhydrofuro[2,3-b]pyran derivatives (Table 2).
When simple alcohols and hydroxybenzenes were used as
nucleophiles, the desired perhydrofuro[2,3-b]pyran deriva-
tives were formed in 68ꢀ83% yields (Table 2, entries 1,
4ꢀ9), while, with i-PrOH 9 and t-BuOH 11 (Table 2,
entries 2, 3) as nucleophiles, the reactions were not complete,
giving lower conversions (70%, 60% respectively), but with
good yields. Altering the reaction conditions by elevating
the reaction temperature, increasing the quantity of NIS to
2 equiv, and using the acceptors as solvent gave similar
results. When monosaccharides25 and 27 (Table 2, entries 10
and 11) were used as nucleophiles, the perhydrofuro-
[2,3-b]pyran derivatives 26 and 28 were obtained in high
yields. Interestingly, when TMSN3 29 (Table 2, entry 12)
Org. Lett., Vol. 13, No. 16, 2011
4277

Table 2. Cyclization Reaction of 2-C-Acetaldehyde-D-
thioglucoside 1 with Different Nucleophilesa
Figure 2. X-ray crystal structure of 5 (CCDC 828091). The
hydrogen atoms are deleted for clarity.
was employed as a nucleophile the N3-substituted per-
hydrofuro[2,3-b]pyran derivative 30 was formed in 78%
yield. This result is of particular significance because this
compound is an analogue of Thiamet-G, which exhibits
excellent O-GlcNAcase inhibition activity.10
On the basis of the above results, a plausible mechanism
is proposed for the formation of hemiketal under the NIS-
mediated conditions (Scheme 2). First, the thiophilic NIS
coordinates to the anomeric sulfur atom to give a tolylthio-
nium cation. This is followed by the generation of a six-five
fused ring oxocarbenium ion via participation of the carbo-
nyl oxygen of the 2-acetaldehyde. Then, the resulting highly
reactive five-membered oxocarbenium ion intermediate is
trapped by nucleophiles, giving the fused ring products.11
The stereoselectivity of the NIS-promoted reaction can be
rationalized by evaluation of the face selectivity in the
transition state. In order to accommodate the optimal
chair conformer of the six-membered ring, we propose
that the five-membered ring oxocarbenium ion adopts an
(10) (a) Yuzwa, S. A.; Macauley, M. S.; Heinonen, J. E.; Shan, X. Y.;
Dennis, R. J.; He, Y. A.; Whitworth, G. E.; Stubbs, K. A.; McEachern,
E. J.; Davies, G. J.; Vocadlo, D. J. Nat. Chem. Biol. 2008, 4, 483. (b)
Macauley, M. S.; Vocadlo, D. J. Biochim. Biophys. Acta, Gen. Subj.
2010, 1800, 107. (c) Martinez-Fleites, C.; He, Y.; Davies, G. J. Biochim.
Biophys. Acta, Gen. Subj. 2010, 1800, 122.
(11) It is presumed that initial activation of sulfur by iodization
released succinimide anion, and then with the assistance of oxygen from
the acetaldehyde and/or pyranoid ring oxygen-assisted departure of
TolSI, generated the six-five fused ring or monocyclic pyran oxocarbe-
nium ions. The nucleophiles attacked the six-five fused ring oxocarbe-
nium ions and would offer the perhydrofuro[2,3-b]pyrans. However, if
the nucleophiles intercepted the pyran oxocarbenium species, the gly-
cosylation products will be obtained. Because the intramolecular reac-
tions are faster than the intermolecular reactions, it is no surprise that,
under our reaction conditions, the major products were perhydrofuro-
[2,3-b]pyrans. In some cases, the presence of the glycosylation reaction
would complicate the reaction which resulted in the decrease of the yield
(Table 1, entry 12). In addition, it is possible that more than one
accessible bicyclic oxocarbenium ion was formed in which the steric
hindrance from the sugar backbone had been partially reduced; there-
fore, the nucleophiles had almost equal opportunity to attack the
oxocarbenium ions from the two faces which did not influence the yield,
but would decrease the stereoselectivity. For different species of bicyclic
oxocarbenium ions, see: (a) Whitfielda, D. M.; Nukada, T. Carbohydr.
Res. 2007, 342, 1291. (b) Mydock, L. K.; Demchenko, A. V. Org. Biomol.
a All reactions were carried out using 1.5 equiv of NIS and 1.2 equiv of
acceptor in 2 mL CH2Cl2 unless otherwise noted. b Isolated yield. c 3.0 equiv
of acceptor was used. d Conversion rate 70%. e Conversion rate 60%.
ꢀ
Chem. 2010, 8, 497. (c) Bohe, L.; Crich, D. Chim. C. R. 2011, 14, 3. (d)
Crich, D. Acc. Chem. Res. 2010, 43, 1144.
(12) (a) Larsen, C.; Ridgway, B.; Shaw, J.; Woerpel, K. A. J. Am.
Chem. Soc. 1999, 121, 12208. (b) Smith, D. M.; Tran, M. B.; Woerpel,
K. A. J. Am. Chem. Soc. 2003, 125, 14149.
envelope conformation, with the CdOþ-unit connected to
the flattened portion of the envelope,12 which produces a
4278
Org. Lett., Vol. 13, No. 16, 2011

Scheme 2. Plausible Mechanism of NIS-Promoted Cyclization
via Oxocarbenium Ion Intermediates
Scheme 3. Modification of Perhydrofuro[2,3-b]pyran
Derivatives
synthesis of the 2-C-substituted perhydrofuro[2,3-b]pyran
derivatives 33 and 34. Under the standard allylation condi-
tions, 5 was treated with allyltrimethylsilane and 2-methyl
allyltrimethylsilane in the presence of TMSOTf in CH3CN
(Scheme 3),14 providing 2-C-substituted perhydrofuro[2,3-
b]pyran derivatives in high yield and diastereoselectivity.15
In conclusion, we have developed an effective and facile
method for the highly stereoselective synthesis of 2-sub-
stituted perhydrofuro[2,3-b]pyran derivatives by NIS-me-
diated cyclization of 2-C-aldehydo-D-thioglucoside. In the
future, this method may also be expanded to other ana-
logues.
convex and concave face. Theoretically, the nucleophile can
approach the cation from either the convex face (path a)
orthe concaveface (pathb), which willleadtothe products
in two different conformations. However, the concave face
is blocked by the sugar backbone.13 Therefore, compared
with its concave face, the convex face of this six-five fused
ring oxocarbenium ion is less sterically hindered, which
facilitates the nucleophile to capture the electrophilic
oxocarbenium ion from the convex face to offer the major
product 31.
Acknowledgment. We are grateful for the financial
support from the Chinese Academy of Sciences (Hun-
dreds of Talents Program) and the National Science Foun-
dation of China (20972151).
Meanwhile, modification of these 2-heteroatom substi-
tuted fused ring building blocks was demonstrated by the
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds
and 1H, 1HꢀCOSY, NOESY for 5, 6, and 33. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Other convex face attack examples, see: (a) Chen, S.; Patrick,
B. O.; Scheffer, J. R. J. Org. Chem. 2004, 69, 2711. (b) Beignet, J.;
Tiernan, J.; Woo, C. H.; Kariuki, B. M.; Cox, L. R. J. Org. Chem. 2004,
69, 6341. (c) Banoub, J.; Boullanger, P.; Potier, M.; Descotes, G.
Tetrahedron Lett. 1986, 27, 4145.
(14) The reactions were carried out using 0.10 mmol of 5, 0.08 mmol
of TMSOTf, and 0.20 mmol of nucleophiles in 1.0 mL of acetonitrile.
(15) The stereochemistry of the product 33 was determined by
extensive 1H NMR and NOESY studies.
Org. Lett., Vol. 13, No. 16, 2011
4279