Stereospecific [3+2] cycloaddition of 1,2-cyclopropanated sugars and ketones catalyzed by SnCl4: An efficient synthesis of multi-substituted perhydrofuro[2,3-b]furans and perhydrofuro[2,3-b]pyrans

Article abstract of DOI:10.1039/c3cc48963a

Stereospecific [3+2] cycloaddition of 1,2-cyclopropanated sugars and ketones catalyzed by SnCl₄ is described. The method offers multi-substituted perhydrofuro[2,3-b]furans (bis-THFs) and perhydrofuro[2,3-b] pyrans containing a quaternary carbon chiral center in good to excellent yields.

Full text of DOI:10.1039/c3cc48963a

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Stereospecific [3+2] cycloaddition of
1,2-cyclopropanated sugars and ketones
catalyzed by SnCl4: an efficient synthesis of
multi-substituted perhydrofuro[2,3-b]furans
and perhydrofuro[2,3-b]pyrans†
Cite this: Chem. Commun., 2014,
50, 3505
Received 24th November 2013,
Accepted 6th February 2014
DOI: 10.1039/c3cc48963a
Xiaofeng Ma,a Jichao Zhang,a Qin Tang,a Jun Ke,a Wei Zoub and Huawu Shao*a
www.rsc.org/chemcomm
Stereospecific [3+2] cycloaddition of 1,2-cyclopropanated sugars glycosides,5 ring expanded oxepanes6 or other carbohydrate based
and ketones catalyzed by SnCl4 is described. The method offers multi- heterocyclic compounds.7 The [3+2] cycloaddition of cyclopropanated
substituted perhydrofuro[2,3-b]furans (bis-THFs) and perhydrofuro- carbohydrates has, however, been much less mentioned.8
[2,3-b]pyrans containing a quaternary carbon chiral center in good
Perhydrofuro[2,3-b]pyran (and furan) derivatives are broadly
found in a large number of structurally complex and bioactive
compounds including novaxenicins A, B, C, stemona alkaloids,
to excellent yields.
Much effort has been devoted to the discovery and study of euplotin C,9 communiol D,10 asteltoxin,11 and TMC-114.12 Among
new stoichiometric or catalytic reactions that employed vicinal them, TMC-114 has been approved by the FDA (called darunavir)
donor–acceptor (D–A) cyclopropanes in recent years.1 These for AIDS treatment.
powerful and versatile synthons fascinated the synthetic and
Owing to the great structural diversity and the wide-range of
pharmaceutical chemists not only because they could react with a biological activities of perhydrofuro[2,3-b]pyrans (furans), the
wide range of nucleophiles and electrophiles.1b In the presence of construction of these subunits continues to attract the interest
Lewis acid, the doubly activated cyclopropanes could also form of both synthetic and pharmaceutical chemists.9–12 In this context,
1,3-zwitterionic intermediates which can be trapped by an array and in continuation of our previous work on the synthesis of
of unsaturated bonds including carbonyl, imine, nitrone and so carbohydrate derivatives, we envisioned that the multi-substituted
on, to form five-, six-, seven-membered carbocycles and hetero- 5/6 or 5/5 fused bicyclic compounds would be used as analogues
cycles via [3+n] (n = 2, 3, 4) cycloaddition.1a,c Among them, the of the natural products to work as potential botanical pesticides,
[3+2] cycloaddition between cyclopropanes and carbonyl com- antifreezes, waterproof agents, antiemetic and antifungal agents.9c–e
pounds, especially, the aldehydes,2 are undoubtedly the strongest Also, they may be tested as potential glycosidase inhibitors.13
and particularly versatile ones, since they offer a powerful strategy Recently, starting from 2-C-branched sugar, we developed a NIS-
for highly stereoselective construction of tetrahydrofurans (THFs). promoted intramolecular cyclization to synthesize 2-substituted
Due to the pioneering studies of Johnson and co-workers in 2005,2j perhydrofuro[2,3-b]pyrans.9c In continuation of our studies on the
the [3+2] cycloaddition of D–A cyclopropanes and aldehydes development of new synthetic methodologies, herein, we report
has been extensively investigated.2 By contrast, only very little our results on synthesis of 2,2,3-tri-substituted perhydrofuro-
research has been conducted in applying the less reactive [2,3-b] pyrans (furans) via [3+2] cycloaddition of cyclopropanated
ketones, especially, the nonsymmetrical ketones, as the reaction sugars and ketones (Scheme 1). With excellent diastereoselectivity
partners for this cycloaddition.3
and compatibility of a wide range of functional groups, this reaction
Furthermore, D–A cyclopropanated carbohydrates, which com- offers an example that utilizes [3+2] cycloaddition between cyclo-
bine the high reactivity of cyclopropanes together with those of propanes and ketones to construct multi-substituted perhydrofuro-
multi-functional groups and multi-chiral-centres associated with [2,3-b]pyrans and bis-THFs, which contain a quaternary carbon
sugars,4 were also extensively used to synthesize 2-C-branched
a Natural Products Research Centre, Chengdu Institute of Biology, Chinese Academy
of Sciences, Chengdu, China. E-mail: shaohw@cib.ac.cn; Fax: +86-028-82890288
b Institute for Biological Sciences, National Research Council of Canada,
100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada
† Electronic supplementary information (ESI) available: General procedures,
spectral data and other supplementary information. See DOI: 10.1039/c3cc48963a
Scheme 1 [3+2] Cycloaddition of 1,2-cyclopropanated sugars and ketones.
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Table 1 SnCl4 catalyzed [3+2] cycloaddition between 1,2-cyclopropanated
sugar 1a and ketonesa,b
Table 2 [3+2] Cycloaddition between 1,2-cyclopropanated sugar 1b and
ketonesa,b
a
All reactions were performed with cyclopropanated sugar 1b (0.1 mmol),
ketones 2 (0.4 mmol), SnCl4 (0.02 mmol), in CH2Cl2 (1 mL) at 0 1C to 4 1C.
b
Isolated yield.
N-methyl-isatin was employed in the reaction, we obtained a
spirocycle oxindole framework (3ah), which is a privileged
structural motif in a large number of natural products and
biologically active molecules,16 in 79% yield.
The scope of the [3+2] cycloaddition of cyclopropanated sugar
and ketones was further extended to 1,2-cyclopropanated sugar
1b, and the results are provided in Table 2. The cyclopropanated
sugar 1b is also the suitable substrate for the [3+2] cycloaddition.
Under the standard reaction conditions, perhydrofuro[2,3-b]-
pyran derivatives were obtained in good to excellent yields.
Consistent with the previous results, all of the reactions only
offered a single diastereoisomer.
Given the importance of the bis-THF framework and the
difficulties in the [3+2] cycloadditions of cyclopropanes with ketones,
we then turned our attention to furanosyl 1,2-cyclopropanated
carbohydrate to synthesize multi-substituted perhydrofuro
[2,3-b]furans (bis-THFs) and further investigate the generality of the
cycloaddition. Thus, starting from furanosyl 1,2-cyclopropanated
sugar 1c and a series of aromatic, aliphatic, and heteroaromatic
ketones, we successfully synthesized a range of bis-THF bearing
multiple contiguous stereocenters, including a quaternary carbon
chiral center (Table 3).
a
All reactions were performed with cyclopropanated sugar 1a
(0.1 mmol), ketones 2 (0.4 mmol), SnCl4 (0.02 mmol), in CH2Cl2
(1 mL) at 0 1C to 4 1C. Isolated yield.
b
chiral center.14 To the best of our knowledge, this is the first
successful example that utilizes acetyl-1,2-cyclopropaned sugars
and ketones as starting materials for the [3+2] cycloaddition.15
Initial studies were performed with Lewis acid in CH2Cl2 using
cyclopropanated sugar 1a and acetophenone 2a as model sub-
strates to screen the reaction conditions. Then, 20 mol% SnCl4 in
CH2Cl2 at 0–4 1C was chosen as the optimal condition for the [3+2]
cycloaddition. Under these conditions, the cycloaddition product
3aa was obtained in 80% yield as a single diastereoisomer.
Subsequently, the scope of the methodology was evaluated.
The results are summarized in Table 1. Initially, various sub-
stituted acetophenone with different substitution patterns and
electronic properties were examined. Gratifyingly, it was found
that the stereoselectivity of the [3+2] cycloaddition was not very
sensitive to various substrates. In all cases, electron-rich (3ab) and
electron-poor substituted acetophenones (3ac–3ae) achieved the
products in good to excellent yields, and each product was isolated
as a single diastereoisomer. A strong electron-withdrawing group
(3ae) also provided the cycloaddition product in high diastereo-
selectivity, but led to a slightly reduced yield. Propiophenone was
also a suitable substrate for this reaction, which offered the fused-
ring product in 80% yield (3af). Heteroaromatic ketone such as
2-acetylfuran (3ag) was tolerated, while basic 4-acetylpyridine
enabled the reaction to proceed with no conversion, only the
starting material was recovered. Then, symmetric (3ai, 3aj) and
asymmetric (3ak–3am) aliphatic ketones were subjected to
the [3+2] cycloaddition of cyclopropanated sugar 1a, and the
2,2-di-alkyl-substituted fused-ring products were achieved in good
to excellent yields and high stereoselectivity. Especially, when
Table 3 SnCl4 catalyzed [3+2] cycloaddition between 1,2-cyclopropanated
sugar 1c and ketonesa,b
a
All reactions were performed with cyclopropanated sugar 1c (0.1 mmol),
ketones 2 (0.4 mmol), SnCl4 (0.02 mmol), in CH2Cl2 (1 mL) at 0 1C to 4 1C.
b
Isolated yield.
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Notes and references
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perhydrofuro[2,3-b]pyrans catalyzed by SnCl4.
¨
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This work was supported by the National Science Founda-
tion of China (21372215 and 20972151).
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