Key words 1,3-dipolar cycloaddition - spirochromanones - glycosyl heterocycles - azomethine
ylide - pyrrolidines
Cyclic glycosides are important as enzyme inhibitors and as chiral synthons that are
suitable for the synthesis of many natural products.[1 ] Enormous amounts of work on carbohydrate-based heterocycles has shown a diverse
range of biological properties such as anticancer,[2 ] antitumor,[3 ] anti-influenza (H1N1),[4 ] antimicrobial,[5 ] and anti-HIV activity.[6 ] The formation of heterocycles from carbohydrates is a much studied area in the synthetic
organic field.[7 ] However, five-membered heterocycles with one nitrogen atom in the ring are less
readily available directly from carbohydrates. The most relevant approach for the
synthesis of unnatural five-membered heterocycles from carbohydrates is by means of
a 1,3-dipolar cycloaddition reaction.[8 ] 1,3-Dipolar cycloadditions of sugar-derived compounds allow the synthesis of pyrrolidines,
pyrrolizidines, isoxazoles, imidazoles, and imadazolidines.[9 ]
4-Chromanone is a privileged structure, and chromanones are important intermediates
in organic synthesis.[10 ] Spirochromanone derivatives have been found to exhibit a wide range of biological
properties such as anti-inflammatory, antioxidant,[11 ] antitubercular,[12 ] antidiabetic[13 ] and antimicrobial activities.[14 ] Recent reports show that spirochromanone derivatives have been found to have a
strong acetyl-CoA carboxylase (ACC) inhibiting effect (Figure [1 ]).[15 ]
Figure 1 Representatives of bioactive spirochromanones
Molecular hybridization is the combination of two or more pharmacophores linked or
fused with each other to create a new molecule, with each component enriching the
biological properties when compared to the individuals.[16 ] The potential applicability of 4-chromanone and carbohydrate scaffolds to such a
strategy has led us to synthesize some new sugar-fused spirochromanone derivatives
by using 1,3-dipolar cycloaddition chemistry.
The synthetic utility of carbohydrate scaffolds as dipolarophiles (azide, nitrone
and nitrile oxide) has been well exploited in 1,3-dipolar cycloaddition chemistry,[17 ] but the use of a carbohydrate scaffold as a dipole has not been well exploited.
With a view to study the carbohydrate scaffold as an azomethine ylide, as well as
in continuation of our endeavor towards the synthesis of novel heterocycles using
1,3-dipolar cycloaddition reactions,[18 ] we report herein the synthesis of novel sugar-fused spirochromanono heterocycles
by a one-pot, three-component 1,3-dipolar cycloaddition of azomethine ylides, obtained
from glucose aldehyde and a range of secondary amino acids, with 3-arylidene chroman-4-ones.
As shown in Scheme [1 ], the construction of a spiro-pyrrolidine ring system (A) was envisaged from a 1,3-cycloaddition
reaction involving an azomethine ylide (B) with an external olefin (C), while templates
for such cycloaddition could be conveniently realized from 4-chromanone (E) and sugar
aldehyde (D).
Scheme 1 Retrosynthetic approach for the synthesis of sugar-fused spirochromanono heterocycles
The synthesis began with the known O -benzyl sugar aldehyde 3 and various 3-arylidene chroman-4-ones as starting materials, which were prepare
according to reported procedures.[19 ]
[20 ]
O -Benzyl tethered sugar aldehyde 3 , when reacted with sarcosine 2 and 3-arylidene chroman-4-ones 1a –c in refluxing toluene under Dean–Stark conditions, yielded novel glycosyl spirochromanonopyrrolidines
5a –c through cycloaddition reaction of azomethine ylide generated from sugar aldehyde
and sarcosine with 3-arylidene chroman-4-ones (Scheme [2 ]). That the benzyloxy group elimination had occurred during the reaction was confirmed
by mass spectrometry and NMR spectroscopic analysis of the product. The cycloadduct
5b revealed a peak in the mass spectrum at m /z 519 instead of the expected m /z 627, which indicates the elimination of the benzyloxy group. This was further confirmed
from the 1 H NMR spectrum, which revealed the absence of a signal due to the benzylic protons
(CH2 Ph). Furthermore, only three protons were observed in the furanose moiety. Based on
the above observations, the structure of the compound was assigned as the alkenyl
sugar-fused chromanono pyrrolidine 5b .[21 ]
Scheme 2 Synthesis of sugar-fused spirochromanono pyrrolidines
The IR spectrum of product 5b exhibited a peak at 1679 cm–1 characteristic of a chromanone carbonyl carbon. The absorption bands at 1554 and
1350 cm–1 were attributed to the nitro group.
The 1 H NMR spectrum of 5b showed a sharp singlet at δ = 2.40 ppm for the N -methyl protons. The H4 proton of the pyrrolidine ring was observed as a singlet at
δ = 3.77 ppm, which clearly shows the regioselectivity of the cycloadduct. The H5
proton was observed to resonate as a doublet of doublets at δ = 3.41 (J = 3.6, 9.3 Hz), which strongly supports the structure of the proposed regioisomer.
Two well-separated doublets at δ = 3.93 and 4.27 ppm with a coupling constant of 12.3 Hz
corresponded to the CH2 protons of the chromanone moiety.
In the 1 H-1 H COSY spectrum of 5b , the proton at δ = 5.91 ppm showed a correlation with the proton at δ = 5.09 ppm.
Additionally, the proton at δ = 5.09 ppm showed a correlation with the proton at δ
= 5.14 ppm in addition to that with the proton at δ = 5.91 ppm. Hence, we could assign
the signals at δ = 5.14 ppm to H2 and δ = 5.14 ppm to H3. The stereochemistry of the
cycloadduct 5b was deduced on the basis of 2D NOESY experiments. There is no NOESY correlation between
H4 and H5 of 5b , which at least supports trans stereochemistry.
The 13 C NMR spectrum of 5b showed a signal at δ = 57.5 ppm for the spiro carbon and the signal at δ = 39.3 ppm
correlated to the N -methyl group (Figure [2 ]). In the DEPT 135 spectrum of 5b the N -CH2 carbon resonated at δ = 60.1 ppm and the O -CH2 carbon of the chromanone moiety showed a negative signal at δ = 68.3 ppm. The furanose
ring attached to the pyrrolidine carbon showed a peak at δ = 64.5 ppm and the peak
at δ = 48.2 ppm correlating to the benzyl attached pyrrolidine ring carbon were confirmed
by DEPT-135 and 1 H-13 C correlation. The furanose ring carbons showed signals at δ = 104.7, 101.4, 81.3,
and 156.0 ppm, respectively, which were confirmed by DEPT-135 and 1 H-13 C correlation. The peak at δ = 192.1 ppm corresponds to the chromanone carbonyl group.
Moreover, the cycloadduct 5b exhibited a peak at m /z 519.3 [MH+ ] in the mass spectrum. All these spectroscopic features support the conclusion that
the cycloaddition proceeded in a highly regioselective manner, with elimination affording
a single regioisomer. The benzyloxy group elimination in the above reaction is well
supported by previous reports.[22 ]
Figure 2 Key NMR assignments in compound 5b
Encouraged by this result, we extended the reaction of 3-arylidene chroman-4-ones
1a –c to different azomethine ylides generated from cyclic amino acids proline 6 , pipecolinic acid 7 , thiazolidine-4-carboxylic acid 10 , and sugar aldehyde 3 under the optimized conditions to give glycosyl spirochromanono pyrrolizidines/thiolizidines
(8a –c , 9a –c , and 11a –c ) in good yields (Table 1). The reaction gave a single product in all cases, as evidenced
by TLC analysis. The cycloaddition was found to be highly regioselective and the O -benzyl group was found to be eliminated in all cases (Scheme [3 ] and Scheme [4 ]).[23 ] The structure and regiochemistry of the cycloadducts were established by IR, 1 H, 13 C, DEPT-135, 2D NMR spectroscopic and mass spectrometric studies as described for
5b .
Scheme 3 Synthesis of sugar-fused spirochromanono pyrrolizidines
Scheme 4 Synthesis of sugar-fused spirochromanono thiolizidines
The reaction was investigated in a series of solvent systems such as acetonitrile,
methanol, and toluene to establish the best reaction conditions. Among the solvents
used, toluene was found to be the best in terms of better yields and short reaction
time (Table 1).
Table 1 Cycloaddition Reaction of O -Benzyl Tethered Sugar Aldehyde and Cyclic/Acyclic Amino Acid with 3-Arylidene Chroman-4-ones
in Different Solvents
Compound
Toluene
Methanol
Acetonitrile
Time (h)
Yield (%)
Time (h)
Yield (%)
Time (h)
Yield (%)
5a
8
64
9
48
9
42
5b
8
66
9
43
9
49
5c
8
62
9
49
9
48
8a
8
64
9
47
9
51
8b
8
65
9
51
9
45
8c
8
61
9
46
9
44
9a
8
60
9
46
9
41
9b
8
62
9
50
9
49
9c
8
62
9
41
9
44
11a
8
61
9
42
9
41
11b
8
67
9
40
9
42
11c
8
67
9
43
9
47
In conclusion, the synthetic utility of a carbohydrate scaffold as an azomethine ylide
in 1,3-dipolar cycloaddition reaction has been studied and a series of sugar-fused
spirochromanono heterocycles has been synthesized.
