InCl3 catalyzed highly diastereoselective [3 + 2] cycloaddition of 1,2-cyclopropanated sugars with aldehydes: A straightforward synthesis of persubstituted bis -tetrahydrofurans and perhydrofuro[2,3- b ]pyrans

Article abstract of DOI:10.1021/ol402192f

A mild and efficient strategy for the construction of persubstituted bis-tetrahydrofuran and perhydrofuro[2,3-b]pyran derivatives has been developed. Persubstituted cyclization products were obtained in good to excellent yields. The [3 + 2] cycloaddition of 1,2-cyclopropanated sugars with aldehydes in the presence of InCl₃ is highly diastereoselective.

Full text of DOI:10.1021/ol402192f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
InCl Catalyzed Highly Diastereoselective
3
000–000
[
1
3 þ 2] Cycloaddition of
,2-Cyclopropanated Sugars with
Aldehydes: A Straightforward Synthesis
of Persubstituted Bis-Tetrahydrofurans
and Perhydrofuro[2,3‑b]pyrans
Xiaofeng Ma, Qin Tang, Jun Ke, Xinglong Yang, Jichao Zhang, and Huawu Shao*
Natural Products Research Centre, Chengdu Institute of Biology, Chinese Academy of
Sciences, Chengdu, 610041, China, and University of Chinese Academy of Sciences, China
shaohw@cib.ac.cn
Received August 2, 2013
ABSTRACT
A mild and efficient strategy for the construction of persubstituted bis-tetrahydrofuran and perhydrofuro[2,3-b]pyran derivatives has been
developed. Persubstituted cyclization products were obtained in good to excellent yields. The [3 þ 2] cycloaddition of 1,2-cyclopropanated sugars
3
with aldehydes in the presence of InCl is highly diastereoselective.
Perhydrofuro[2,3-b]pyran or furan scaffolds maintain a
widespread presence in a host of pharmaceuticals and
The [3 þ n] (n = 2, 3, and 4) cycloaddition of Donorꢀ
Acceptor (DꢀA) cyclopropanes provided a large number
of five-, six-, seven-membered carbo- and heterocycles that
1ꢀ4
biologically active natural products.
The complex skel-
6
etons combined with excellent bioactivity continually
stimulate many organic and medicinal chemists to develop
creative strategies for the construction of such fused-cycle
exhibit interesting biological and medicinal properties.
Among them, the [3 þ 2] cycloadditions between cyclo-
propanes 1,1-diester and carbonyl compounds have been
extensively used to construct substituted tetrahydrofurans
5
motifs. Although many achievements have been reported,
novel synthetic routes suitable for the highly diastereoselective
construction of such structural motifs are still highly desired.
6
b,7,8
(THFs).
using DꢀA cyclopropanes to construct the perhydrofuro-
2,3-b]pyrans or bis-THF were reported, especially using
In sharp contrast to these, very few examples
[
(
1) (a) Che, Y.-S; Gloer, J. B.; Scott, J. A.; Malloch, D. Tetrahedron
monodonorꢀmonoacceptor cyclopropanes as starting
Lett. 2004, 45, 6891. (b) Enomoto, M.; Nakahata, T.; Kuwahara, S.
Tetrahedron 2006, 62, 1102.
9
materials.
(
2) (a) Ghosh, A. K.; Chapsal, B. D.; Weber, J. T.; Mitsuya, H. Acc.
Furthermore, due to their widespread occurrence, low-
price, multifunctional groups, and multichiral centers,
carbohydrates offer anirresistible platform for asymmetric
Chem. Res. 2008, 41, 78. (b) Ghosh, A. K.; Anderson, D. D.; Weber,
I. T.; Mitsuya, H. Angew. Chem., Int. Ed. 2012, 51, 1778.
(
3) Eom, K. D.; Raman, J. V.; Kim, H.; Cha, J. K. J. Am. Chem. Soc.
003, 125, 5415.
4) (a) Ghosh, K.; Chapsal, B. D.; Baldridge, A.; Steffey, M. P.;
Walters, D. E.; Koh, Y.; Amano, M.; Mitsuya, H. J. Med. Chem. 2011,
2
(
(6) Lewis acid activated donorꢀacceptor cyclopropanes have been
largely reported; for reviews, see: (a) Reissig, H.-U.; Zimmer, R. Chem.
Rev. 2003, 103, 1151. (b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61,
321. (c) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051. (d)
De Simone, F.; Waser, J. Synthesis 2009, 3353. (e) Xiao, Y.-N.; Zhang,
J.-L, Cyclization of Cyclopropane- or Cyclopropene-Containing Com-
pounds in Handbook of Cyclization Reactions; Ma, S.-M., Ed.; Wiley-
VCH: Weinheim, 2010; Vol. 2, p 733.
5
1
4
4, 622. (b) Ghosh, A. K.; Anderson, D. D. Future Med. Chem. 2011, 3,
181. (c) Ma, X.-F.; Tian, Q.; Tang, Q.; Shao, H.-W. Org. Lett. 2011, 13,
276and references therein. (d) Ma, X.-F; Tang, Q.; Ke, J.; Zhang, J.-C;
Wang, C.; Wang, H.-B.; Li, Y.-X.; Shao, H.-W. Chem. Commun. 2013,
9, 7085.
5) For selected examples on the construction of perhydrofuro[2,3-
b]pyrans and bis-THFs, see refs 4c, 4d and references therein.
4
(
1
0.1021/ol402192f r XXXX American Chemical Society

synthesis. They also provide the key functional subunits
for rational drug designs. Cyclopropanated carbohy-
drates, the combination of cyclopropanes and carbohy-
drates within a single molecule, have also been widely used
there have been no reported cycloaddition reactions of
cyclopropanated carbohydrates under catalysis condi-
tions until this report.
Given the important role of the substituted perhydro-
furo[2,3-b]pyrans (and bis-THFs), the lack of utility of
cyclopropanated carbohydrates in both Lewis acid and
transition metal catalyzed cycloadditions, and as part of
our continuing interest in the synthesis of carbohydrate
1
0
11,12
to synthesize branched glycosides, oxepanes,
some other natural products or carbohydrate-based fused
and
1
3
ring compounds. The [3 þ n] cycloaddition of 1,2-cyclo-
propanated sugar, which would be an efficient method to
synthesize carbohydrate-based carbo- and heterocyclic
4
c,10c,10d,14
analogues,
we disclose herein our results on an
6b,10b
compounds, however, still remains almost unknown.
In 2003, excellent work was reported by Pagenkopf and
InCl catalyzed [3 þ 2] cycloaddition of cyclopropanated
3
15,16
sugars and aldehydes.
This reaction offers a mild,
1
3
co-workers, which involved the [3 þ 2] cycloaddition of
carbohydrate-based cyclopropanated ester with nitriles.
This method offered densely functionalized 3,4-dihydro-
efficient method to generate multisubstituted perhydrofuro-
[2,3-b]pyrans (and bis-THFs) in high yield with excellent
diastereoselectivity (Scheme 1). To our knowledge, this is
the first successful example that utilizes the [3 þ 2] cycload-
dition between cyclopropanes and CdX (X = C, N, O)
compounds to synthesize multisubstituted perhydrofuro-
2H-pyrroles in high stereoselectivity; however, stoichiometric
TMSOTf was required. To the best of our knowledge,
[
2,3-b]pyrans and bis-THFs.
(
7) For some recent publications involving aldehydes, see: (a) Xing,
S.-Y.; Pan, W.-Y.; Liu, C.; Ren, J.; Wang, Z.-W. Angew. Chem., Int. Ed.
010, 49, 3215. (b) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li,
2
W.; Johnson, J. S. J. Am. Chem. Soc. 2008, 130, 8642. (c) Parsons, A. T.;
Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 3122. (d) Pohlhaus, P. D.;
Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 16014. (e) Schneider, T. F.;
Kaschel, J.; Dittrich, B.; Werz, D. B. Org. Lett. 2009, 11, 2317. (f) Brand,
C.; Rauch, G.; Zanoni, M.; Dittrich, B.; Werz, D. B. J. Org. Chem. 2009,
Scheme 1. Lewis Acid (LA) Catalyzed Cycloaddition Reaction
of 1,2-Cyclopropanated Sugars with Aldehydes
7
1
4, 8779. (g) Smith, A. G.; Slade, M. C.; Johnson, J. S. Org. Lett. 2011,
3, 1996. (h) Campbell, M. J.; Johnson, J. S.; Parsons, A. T.; Pohlhaus,
P. D.; Sanders, S. D. J. Org. Chem. 2010, 75, 6317. (i) Parsons, A. T.;
Campbell, M. J.; Johnson, J. S. Org. Lett. 2008, 10, 2541. (j) Yang, G.-S.;
Shen, Y.; Li, K.; Sun, Y.-X.; Hua, Y.-Y. J. Org. Chem. 2011, 76, 229. (k)
Xing, S.-Y.; Li, Y.; Li, Z.; Liu, C.; Ren, J.; Wang, Z.-W. Angew. Chem.,
Int. Ed. 2011, 50, 12605. (l) Benfatti, F.; de Nanteuil, F.; Waser, J. Org.
Lett. 2012, 14, 386. (m) Bai, Y.; Tao, W.-J.; Ren, J.; Wang, Z.-W. Angew.
Chem., Int. Ed. 2012, 51, 4112. (n) Haubenreisser, S.; Hensenne, P.;
Schr o€ der, S.; Niggemann, M. Org. Lett. 2013, 15, 2262.
Our preliminary investigation focused on the cycloaddi-
tion reaction of cyclopropanated sugar (1a) and benzalde-
hyde (2a). Afterseveral parameterswere screened (Table S1,
Supporting Information), the product 3aa was obtained
in 86% isolated yield (dr = 18:1) in the presence of 20 mol %
(8) For the reactions between cyclopropanes and ketones, see: (a)
Martins, E. O.; Gleason, J. L. Org. Lett. 1999, 1, 1643. (b) Sugita, Y.;
Kawai, K.; Yokoe, I. Heterocycles 2000, 53, 657. (c) Shi, M.; Xu, B.
Tetrahedron Lett. 2003, 44, 3839. (d) Gupta, A.; Yadav, V. K. Tetra-
hedron Lett. 2006, 47, 8043. (e) Benfatti, F.; de Nanteuil, F.; Waser, J.
Chem.;Eur. J. 2012, 18, 4844.
InCl in toluene at 0ꢀ4 °C for 2 h. Subsequently, to
3
investigate the generality of this reaction, under the
optimized reaction conditions, the influence of various
substituents on the phenyl ring was first studied (Table 1).
The results indicated that the stereoselectivity of the [3 þ 2]
cycloaddition was not very sensitive to the electron density
of the phenyl ring. Both electron-donating (Table 1, entry 2)
and electron-withdrawing groups (Table 1, entries 4ꢀ11)
provided good results. A strong electron-withdrawing
group (Table 1, entries 8ꢀ11) also provided cycloaddition
products in high diastereoselectivity but induced a significant
variation in yield. The position of substituents on the phenyl
ring also had a negligible effect on the diastereoselectivity
(3ad and 3ag vs 3ah; 3ak vs 3al). Then, heteroaromatic
aldehydes were subjected to the [3 þ 2] cycloaddition with
cyclopropanated sugar 1a, and it was found that 2-furalde-
hyde and 2-thenaldehyde furnished the perhydrofuro[2,3-b]-
pyrans in high yield with excellent stereoselectivity
(Table 1, entries 12, 13); however, 2-pyridylaldehyde did
not achieve the conversion (Table 1, entry 16). In addition,
(
9) For examples using [3
þ
2] cycloaddition to synthesize
tetrahydrofuro[2,3-b][1]benzonpyranones, see: Sugita, Y.; Kawai, K.;
Yokoe, I. Heterocycles 2001, 55, 135 and ref 8b.
(10) For reviews, see: (a) Yin, J.; Linker, T. Org. Biomol. Chem. 2012,
1
1
0, 2351. (b) Cousins, G. S.; Hoberg, J. O. Chem. Soc. Rev. 2000, 29,
65and ref 6b. Some other examples: (c) Tian, Q.; Dong, L.; Ma, X.-F.;
Xu, L.-Y.; Hu, C.-W.; Zou, W.; Shao, H.-W. J. Org. Chem. 2011, 76,
045. (d) Tian, Q.; Xu, L.-Y.; Ma, X.-F.; Zou, W.; Shao, H.-W. Org.
Lett. 2010, 12, 540. (e) Sridhar, P. R.; Kumar, P. V.; Seshadri, K.;
Satyavathi, R. Chem.;Eur. J. 2009, 15, 7526. (f) Beyer, J.; Skaanderup,
P. R.; Madsen, R. J. Am. Chem. Soc. 2000, 122, 9575. (g) Beyer, J.;
Madsen, R. J. Am. Chem. Soc. 1998, 120, 12137.
1
(
11) (a) Hewitt, R. J.; Harvey, J. E. J. Org. Chem. 2010, 75, 955. (b)
Ganesh, N. V.; Raghothama, S.; Sonti, R.; Jayaraman, N. J. Org. Chem.
010, 75, 215. (c) Ganesh, N. V.; Jayaraman, N. J. Org. Chem. 2009, 74,
39. (d) Batchelor, R.; Harvey, J. E.; Northcote, P. T.; Teesdale-Spittle,
P.; Hoberg, J. O. J. Org. Chem. 2009, 74, 7627. (e) Ganesh, N. V.;
Jayaraman, N. J. Org. Chem. 2007, 72, 5500.
2
7
(12) (a) Hoberg, J. O.; Bozell, J. Tetrahedron Lett. 1995, 36, 6831. (b)
Hoberg, J. O. J. Org. Chem. 1997, 62, 6615. (c) Batchelor, R.; Hoberg,
J. O. Tetrahedron Lett. 2003, 44, 9043.
(13) Yu, M.; Pagenkopf, B. L. J. Am. Chem. Soc. 2003, 125, 8122.
(14) (a) Ma, X.-F.; Tang, Q.; Ke, J.; Wang, H.-B.; Zou, W.; Shao,
H.-W. Carbohydr. Res. 2013, 366, 55. (b) Wang, H.-B.; Luo, H.-R.; Ma,
X.-F.; Zou, W.; Shao, H.-W. Eur. J. Org. Chem. 2011, 4834. (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.; Ektha-
watchai, S.; Chen, C. S.; Wu, S. H.; Zou, W. J. Org. Chem. 2005, 70,
3
(15) For selected recent reviews on InCl , see: (a) Auge, J.; Lubin-
Germain, N.; Uziel, J. Synthesis 2007, 1739. (b) Yadav, J. S.; Antony, A.;
George, J.; Subba Reddy, B. V. Eur. J. Org. Chem. 2010, 591.
4
726. (f) Wang, Z.; Shao, H.-W.; Lacroix, E.; Wu, S. H.; Jennings, H. J.;
Zou, W. J. Org. Chem. 2003, 68, 8097. (g) Zhao, J.-Z.; Wei, S.-Q.; Ma,
X.-F.; Shao, H.-W. Green Chem. 2009, 11, 1124. (h) Zhao, J.-Z.; Wei,
S.-Q.; Ma, X.-F.; Shao, H.-W. Carbohydr. Res. 2010, 345, 168. (i) Luo,
H.-R.; Zou, W.; Shao, H.-W. Carbohydr. Res. 2009, 344, 2454.
3
(16) For the cycloaddition involved in InCl , see: (a) Yadav, J. S.;
Subba Reddy, B. V.; Rao, R. S.; Kumar, S. K.; Kunwar, A. C. Tetra-
hedron 2002, 58, 7891. (b) Yadav, J. S.; Subba Reddy, B. V.; Kondaji, G.
Synthesis 2003, 1100.
B
Org. Lett., Vol. XX, No. XX, XXXX

derivatives, we then focused on the synthesis of substituted
perhydrofuro[2,3-b]furans (bis-THFs) via a similar strat-
egy. Based on this, the furanosyl 1,2-cyclopropanated
Table 1. InCl Catalyzed [3 þ 2] Cycloaddition between
3
a
1
,2-Cyclopropanated Pyranoses 1a, 1b and Aldehydes
17
ketone 1c was prepared, and the scope of the [3 þ 2]
cycloaddition under the standard conditions was further
investigated (Scheme 2). Therefore, a series of substituted
1ꢀ3
bis-THFs, which possess a wide occurrence in medicine,
were obtained from furanosyl 1,2-cyclopropanated ketone
c. While the yield of the reaction is moderate, nonetheless,
the diastereoselectivity is still excellent. Cycloadditions of
,2-cyclopropanated ketone 1c with linear aliphatic and
1
products
T
yield
b
c
entry
1
R
(3)
(h)
(%)
dr
1
1
2
3
4
5
6
7
8
9
1a Ph (2a)
3aa
3ab
3ad
3ae
3af
2
86
87
75
72
65
85
83
47
51
47
55
93
81
90
82
0
18:1
branched aliphatic aldehydes were exceptionally interest-
ing because the products all had similar substituents and
stereochemistry as Asteltoxin, which is a latent inhibitor of
1a 4-MeC
1a 4-BrC
6
H
4
(2b)
(2d)
2
>20:1
20:1
6
H
4
4
1a 4-ClC
1a 2,4-Cl
1a 3-BrC
1a 2-BrC
6
H
4
6
(2e)
4
20:1
3
oxidative phosphorylation.
2
C
H
4
(2f)
5
20:1
6
H
6
H
4
4
(2g)
3ag
3ah
3ai
4
20:1
(2h)
4
17:1
1a 4-NO
2
C
6
H
4
(2i)
(2j)
16
13
14
14
2
13:1
1a 4-CNC
6
H
4
3aj
19:1
Scheme 2. [3 þ 2] Cycloaddition between 1,2-Cyclopropanated
aꢀc
1
0
1a 4-FC
1a 3-FC
6
H
H
4
(2k)
(2l)
3ak
3al
20:1
Lyxose 1c and Aldehydes
11
6
4
19:1
12
13
14
15
16
17
18
19
20
21
22
23
24
25
1a 2-furyl (2m)
1a 2-thienyl (2n)
1a n-Pr (2o)
3am
3an
3ao
3ap
ꢀ
20:1
2
>20:1
>20:1
>20:1
ꢀ
1
1a i-Pr (2p)
1
1a 2-pyridyl (2q)
1b Ph (2a)
24
2
3ba
3bb
3bc
3bd
3be
3bm
3bn
3bo
3bp
71
82
85
74
81
81
64
86
70
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
1b 4-MeC
1b 4-MeOC
1b 4-BrC
1b 4-ClC
6
H
4
(2b)
(2c)
2
6
H
4
2
6
H
4
(2d)
(2e)
4
6
H
4
4
1b 2-furyl (2m)
1b 2-thienyl (2n)
1b n-Pr (2o)
4
4
2
1b i-Pr (2p)
2
a
Reaction conditions: cyclopropanated sugar 1a or 1b (0.1 mmol),
aldehyde (0.4 mmol), InCl (0.02 mmol), toluene (1 mL), 0 to 4 °C.
3
b
c 1
Yield of isolated product. The dr was determined by H NMR.
a
Reaction conditions: cyclopropanated sugar 1c (0.1 mmol), alde-
the linear aliphatic aldehyde (Table 1, entry 14) and
branched aliphatic aldehyde (Table 1, entry 15) were also
suitable substrates for the reaction, which offered the 2-al-
kyl-substituted perhydrofuro[2,3-b]pyrans in good yield
and stereoselectivity.
b
hyde (0.4 mmol), InCl
3
(0.02 mmol), toluene (1 mL), 0 to 4 °C. Yield of
c
isolated product. Unless otherwise noted dr >20:1.
All products generated in the study have a similar coupl-
ing constant (for furan[2,3-b]pyrans J(H7a,H3a) = 4.0ꢀ5.1
Hz, for furan[2,3-b]furans J(H6a,H3a) = 5.1ꢀ5.9 Hz), which
Having successfully achieved the synthesis of glucose-
based perhydrofuro[2,3-b]pyrans, we next explored the
generality of the reaction by using galactose derivatives.
Therefore, treatment of 1,2-cyclopropanated galactose 1b
with aromatic (Table 1, entries 17ꢀ21), heteroaromatic
suggested the fused ring systems have [2,3-b]-cis-bicyclic
1a,4
stereochemistry.
1
The structure of bicycles was deter-
17
1
1
minedby the H NMR, Hꢀ H COSY, and NOESY and
18
was further confirmed by X-ray crystallographic analysis
of compound 3bb.
(
Table 1, entries 22 and 23), linear aliphatic (Table 1, entry 24),
and branched aliphatic (Table 1, entry 25) aldehydes in
the presence of InCl (20 mol %) smoothly afforded the
3
desired cycloaddition products in good yield with excellent
diastereoselectivity. Compared to the cyclopropanated glu-
cose, the yields of the reaction between 1,2-cyclopropanated
galactose and aldehydes are slightly reduced, which can
be rationalized by the high reactivity of the cyclopropa-
nated galactose, leading to some other byproducts as
detected by TLC.
After successful construction of persubstituted perhy-
drofuro[2,3-b]pyrans from 1,2-cyclopropanated pyranose
(
17) See the Supporting Information for details.
(18) CCDC 914931 (3bb) contains the supplementary crystallo-
graphic data for this study. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/ data_request/cif.
(
19) (a) Qu, J.-P.; Liang, Y.; Xu, H.; Sun, X.-L.; Yu, Z.-X.; Tang, Y.
Chem.;Eur. J. 2012, 18, 2196. (b) Morra, N. A.; Morales, C. L.; Bajtos,
B.; Wang, X.; Jang, H.; Wang, J.; Yu, M.; Pagenkopf, B. L. Adv. Synth.
Catal. 2006, 348, 2385. (c) Takasu, K.; Nagao, S.; Ihara, M. Adv. Synth.
Catal. 2006, 348, 2376. (d) M u€ ller, P.; Bernardinelli, G.; Allenbach,
Y. F.; Ferri, M.; Grass, S. Synlett 2005, 1397. (e) Shen, Z.-L.; Wang,
S.-Y.; Chok, Y. K.; Xu, Y.-H.; Loh, T. P. Chem. Rev. 2013, 113, 271.
1
0c
Org. Lett., Vol. XX, No. XX, XXXX
C

Based on the results of the experiments, a plausible
mechanism is proposed for the InCl -catalyzed [3 þ 2]
Alternatively, after InCl coordinated to the keto-car-
3
bonyl of cyclopropane, aldehydes can act as a nucleophile
7
to assist the cyclopropane ring opening (pathway B).
3
bꢀd
cycloaddition between 1,2-cyclopropanated sugars and
aldehydes (Scheme 3). First, InCl coordinated to the
This pathway could form the intermediate B mainly due to
steric hindrance. For pyranosyl cyclopropane ketones,
both of the two pathways perhaps exist in our reaction
system. However, forthefuranosyl cyclopropane, wefavor
pathway A over pathway B due to the lack of equilibrium
between intermediate B and C.
3
keto-carbonyl of the cyclopropane and induced the
ring opening of cyclopropane to form zwitterionic
intermediate A, which is expected to form the indium
1
9
enolate (pathway A). Subsequently, aldehydes trapped
the anomeric oxocarbenium ion from either the β- or
1
3
R-face producing the intermediate B and C respectively.
Therefore, for the furanosyl 1,2-cyclopropanated lyx-
ose, after InCl activated the cyclopropane, the ring open-
3
ing of 1,2-cyclopropane followed and formed a furan-
based zwitterionic intermediate E, in which the C3-OBn
group resided in a pseudo axial position and the alkox-
ymethyl group at C-4 and the C-branch in C-2 were in a
pseudo equatorial position. Then, aldehydes approached
intermediate E via an inside attack model, followed by
recyclization through an aldol-type reaction process as
shown in Scheme 4, to obtain the bis-THF products.
Scheme 3. Plausible Mechanism of InCl
Cycloaddition between Cyclopropanated Pyranoses and Aldehydes
3
Catalyzed [3 þ 2]
2
3
Scheme 4. Plausible Mechanism of InCl3 Catalyzed [3 þ 2]
Cycloaddition between 1,2-Cyclopropanated Lyxose and
Aldehydes
Then, intermediate B isomerizes to C via zwitterionic A
In summary, we have developed a novel [3 þ 2] cycload-
2
0
due to the anomeric effect, and intermediate C was
ultimately recyclized via transient state D, through an
intramolecular aldol-type reaction to form the bicyclic
dition reaction catalyzed by InCl using 1,2-cyclopropa-
3
nated sugars as a new type of reagent. The cycloaddition
between cyclopropanated sugars and aldehydes is efficient
and provides a general method to construct substituted
perhydrofuran[2,3-b]pyrans and bis-THFs. This method
offers several advantages, i.e., excellent diastereoselectiv-
ity, a large range of functional group compatibility, and
simplicity in operation, making it a useful and attractive
strategy for the synthesis of some natural products and
other carbohydrate analogues. Further investigations of
the scope of this reaction and of the biological activities of
these compounds will be undertaken.
2
1,22
compound.
(
20) (a) Lu, S.-R.; Lai, Y.-H.; Chen, J.-H.; Liu, C.-Y.; Tony Mong,
K. K. Angew. Chem., Int. Ed. 2011, 50, 7315. (b) Chao, C.-S.; Lin, C.-Y.;
Mulani, S.; Hung, W. C.; Tony Mong, K. K. Chem.;Eur. J. 2011, 17,
12193.
(
21) For some other aldol-type reactions involved in DꢀA cyclopro-
panes and carbonyls, see: (a) Shimada, S.; Hashimoto, Y.; Sudo, A.;
Hasegawa, M.; Saigo, K. J. Org. Chem. 1992, 57, 7126. (b) Shimada, S.;
Hashimoto, Y.; Nagashima, T.; Hasegawa, M.; Saigo, K. Tetrahedron
1
1
993, 49, 1589. (c) Shimada, S.; Hashimoto, Y.; Saigo, K. J. Org. Chem.
993, 58, 5226. (d) Reissig, H.-U.; Holzinger, H.; Glomsda, G. Tetra-
hedron 1989, 45, 3139. (e) Reissig, H.-U.; Reichelt, I.; Lorey, H. Liebigs
Ann. Chem. 1986, 1924. (f) Reissig, H.-U. Tetrahedron Lett. 1981, 22, 2981.
Acknowledgment. This work was supported by the
Chinese Academy of Sciences (Hundreds of Talents
Program) and the National Science Foundation of China
(22) It is also possible that after the ring opening of the cyclopropanes,
the aldehydes reacted with the formed zwitterionic via an aldol-type reaction
to form the oxygen anions, which were further reacted with the anomeric
oxonium ion to generate the fused-ring products, as Yokoe and co-workers
reported (see ref 9). However, in this case, the electron poor aldehydes
should react faster than the electron rich aldehydes. Thus, this process can be
ruled out. Whereas, if the aldehydes reacted with the anomeric oxonium ion
to generate another oxonium ion first, then the produced intermediate
carried out the intramolecular aldol-type reaction; the rate-limiting step for
this reaction would be the reaction between the aldehyde and the oxoium
ion. This coincides with the results of our experiments.
(20972151 and 21372215).
Supporting Information Available. Experimental pro-
cedures; characterization data for all new compounds;
1
1
Hꢀ H COSY for 3an; and NOESY for 3an, 3bn, and 3cb.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) (a) Hou, D.; Taha, H. A.; Lowary, T. L. J. Am. Chem. Soc. 2009,
31, 12937. (b) Smith, D. M.; Tran, M. B.; Woerpel, K. A. J. Am. Chem.
1
Soc. 2003, 125, 14149. (c) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.;
Woerpel, K. A. J. Am. Chem. Soc. 1999, 121, 12208.
The authors declare no competing financial interest.
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