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Synthesis 2024; 56(06): 1026-1034
DOI: 10.1055/a-2186-7116
paper
Emerging Trends in Glycoscience

Tris(pentafluorophenyl)borane-Catalyzed Stereoselective C-Glycosylation of Glycals: A Facile Synthesis of Allyl and Alkynyl Glycosides

Anand Gaurav
a   Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226 031, India
b   Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
,
Zanjila Azeem
a   Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226 031, India
b   Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
,
Pintu Kumar Mandal  ∗
a   Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226 031, India
b   Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
› Author Affiliations

The authors gratefully acknowledge financial support by DST-SERB (CRG/2022/003936), New Delhi, India.
› Further Information
 
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Abstract

In modern advances, tris(pentafluorophenyl)borane (commonly known as BCF) catalyst has risen to prominence owing to its extensive versatility in the use of myriad of organic reactions. An efficient and highly stereoselective α-C-glycosylation strategy is presented by employing a catalytic amount of B(C6F5)3 under mild reaction conditions en route to 2,3-unsaturated C-glycosides. The reaction features a broad functional group tolerance including a variety of glycals coupled with allyltrimethylsilane and trimethylsilylphenylacetylene to access the corresponding 2,3-unsaturated allyl- and alkynyl-C-glycosides with excellent α-selectivity. The reaction proceeds in good to excellent yields via concomitant borane activation of glycal donor under mild conditions.


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Key words

carbohydrate - glycal - tris(penta - fluorophenyl)borane - stereoselective - C-glycosylation - 2,3-unsaturated C-glycosides

Among the numerous carbohydrate-based synthetic building blocks, glycals have been considered as the most versatile chiral synthon, which can be readily functionalized into a broad spectrum of chiral molecules.[1] In this respect, Ferrier rearrangement[2] has represented a vibrant area of research and versatile transformation that produces 2,3-unsaturated glycosides via acid-mediated elimination of the C3 group[3] with concomitant double-bond migration in the presence of O-/N-/S-/C-type nucleophiles.[2b] [4] Most importantly, Ferrier rearrangement of glycals is a well-established reaction in the fields of carbohydrate[1,2b,4] and organic chemistry, which works as an efficient tool to access C-linked pseudo glycals.[5] [6]

The C-glycosides have attracted more attention from chemists[7] owing to their versatility as chiral building blocks and also they are involved as key intermediates during the formation of various functionalized C-saccharides of biological significance and numerous natural products[8] such as halichondrin, spongistatin, palytoxin, etc.[9] Particularly, the synthesis of ‘C-pseudo-glycals’ or 2,3-unsaturated C-glycosides has been encouraged due to the presence of the olefin in these pseudo glycals, which could be further functionalized to access other carbohydrate derivatives and useful chiral molecules[10] in the synthesis of significant pharmaceutical compounds. Further, allyl or alkynyl glycosides are attractive due to the presence of a terminal double or triple bond that is open to easy functionalization[11] leading to other chiral molecules as well as other many carbohydrate derivatives. Specifically, C-alkynyl glycosides are more attractive due to the presence of a triple bond that can be easily converted into other chiral molecules such as ciguatoxin[12] and tautomycin[13] and can be further used upon reaction with azide precursors under CuAAC conditions to achieve glycosyl triazoles[14] as diversely functionalized molecules.

As a result, several reagent systems have been developed to effect the Ferrier glycosylation[5] [6] of glycals to obtain 2,3-unsaturated C-glycosides by strongly Lewis acidic salts derived from transition metals or lanthanides,[5a,b] superacidic conditions,[5q] or the presence of an excess amount of BF3·OEt2 [5r] (Scheme [1a]). Also, Tebbe methylenation[15a] and thermal Claisen rearrangement are another two-step process to synthesize the 2,3-unsaturated C-glycosides elegantly. Additionally, a Pd-metal catalyzed reaction involving a Pd π-allyl intermediate[15b] [c] to construct the glycosidic linkage has been reported by many researchers. In particular, palladium-catalyzed Heck cross-coupling reaction[16] has been employed for the syntheses of Ferrier aryl-C-glycosides by reaction of glycals with aryl halides,[16b] [c] aryl boronic acids,[16d] [e] benzoic acids, and aryl hydrazines.[16g] However, these approaches demand expensive and relatively toxic reagents, moisture-sensitive organometallic compounds, additives, and ligands.

Zoom Image
Scheme 1 Earlier methods and present work for the synthesis of 2,3-unsaturated allyl and alkynyl glycosides

Further, Mukherjee and co-workers[6a] developed a combination of Cu(OTf)2 and ascorbic acid-catalyzed C-glycosylation of unactivated alkynes with glycals (Scheme [1b]). Moreover, silylacetylene,[6b] alkynyltrifluoroborates,[6c] and iodoalkynes[6d] are used as a nucleophile in the presence of stoichiometric amounts of BF3·OEt2 to couple with glycal, affording the Ferrier-type C-alkynylated glycosides (Scheme [1b]). Meanwhile, Shah and co-workers[17] developed a metal-free strategy for glycals to undergo C-alkynylation from unactivated alkynes. The reaction activates terminal alkyne by in situ generation of trimethylsilylacetylene by using TMSOTf as a promoter.

However, some of these reported methods have limitations in terms of substrate scope, and also, most of these procedures involve unconventional reaction operation and tedious workup, harsh reaction conditions, long reaction times, and give unsatisfactory yields. To overcome these issues, recently, organocatalyzed C-glycosylation has been applied as a significant tool by Kancharla and co-workers,[18] relying on an efficient organocatalyst TTBPyHOTf (2,4,6-tri-tert-butylpyridinium triflate salt) for Ferrier-C-rearrangement (Scheme [1c]). Despite the advancements of high-value 2,3-unsaturated C-glycosides, the reports for its construction via an organocatalyzed system are still underdeveloped.

Among the availability of numerous boron-based Lewis acids, tris(pentafluorophenyl)borane [B(C6F5)3, BCF] has frequently and widely used Lewis acid catalyst in organic synthesis.[19] The advantage of BCF catalyst is its air and thermal stability, commercial availability, and performance as an excellent activator, good catalyst, and stoichiometric reagent in synthetic chemistry. Owing to its remarkable properties BCF catalyst indulge in many organic reactions for instance, hydrometallation, alkynylation, allylation, tautomerization, addition or substitution reaction, glycosylation, and so on.[20]

In glycosylation chemistry, BCF activates Schmidt’s trichloroacetimidate donors[21] [22] under mild conditions and provides excellent yields with high stereoselectivity. In this context, we have recently explored the application of B(C6F5)3 in stereoselective C-glycosylation reactions for the generation of biologically appealing 3-glycosyl indoles.[22] In spite of reported applications of B(C6F5)3 in carbohydrate synthesis,[23] its function in C-glycosylation reactions for the generation of high-value 2,3-unsaturated C-glycosides has not yet been reported. In continuation of this work, here we describe the B(C6F5)3-catalyzed highly α-stereoselective synthesis of 2,3-unsaturated C-allyl- and alkynyl glycosides via direct activation of glycals (Scheme [1d]).

At the outset, we started our initial experiments by reacting the triacetylglucal 1a with allylTMS (2a) as starting materials in the presence of BCF catalyst. From our previous experience,[22] the reaction was performed in dichloromethane at room temperature using 10 mol% of the BCF catalyst with the donor/acceptor ratio 1.0/1.2 (Table [1]). Next, refluxing with 10 mol% of BCF, the desired C-glycoside 3a was isolated in a 74% yield in 4 hours with α-selectivity (Table [1], entry 3). Further optimization was executed at 50 °C by varying the solvents such as in dichloroethane (DCE) and acetonitrile. The reaction proceeds in DCE with better efficiency affording the desired product 3a in 85% yield within 30 minutes to that of DCM while acetonitrile affords 3a in slightly lower yield. Next, we moved our attention towards catalyst loading and found that decreasing the catalyst loading below 10 mol% provided a decrease in yields even after 3 hours (entry 6). Further, increasing the catalyst loading up to 20 mol% showed no significant impact during optimization of the reaction conditions (entry 7). Moreover, no reaction was observed when fluoro-substituted phenylboronic acids were employed as promoters instead of BCF (entries 8, 9).

Table 1 Optimization of the Reaction Conditionsa

Entry

Catalyst (mol%)

Solvent

Temp (°C)

Time

Yield (%)b

α:βc

1

BCF (10)

CH2Cl2

25

 6 h

20

α >99

2

BCF (10)

CH2Cl2

25

12 h

30

α >99

3

BCF (10)

CH2Cl2

reflux

 4 h

74

α >99

4

BCF (10)

(CH2Cl)2

50

30 min

85

α >99

5

BCF (10)

CH3CN

50

30 min

70

α >99

6

BCF (5)

(CH2Cl)2

50

 3 h

52

α >99

7

BCF (20)

(CH2Cl)2

50

 1 h

84

α >99

8

(10)

(CH2Cl)2

50

 3 h

NR

–

9

(10)

(CH2Cl)2

50

 3 h

NR

–

a The reaction was conducted with 1a (1.0 equiv), 2a (1.2 equiv), B(C6F5)3 (10 mol%), and solvent (4 mL).

b Isolated yield; NR: no reaction.

c α:β ratio was measured using 1H NMR spectroscopy.

With the optimized reaction conditions in hand, the scope and generality of this method were established with variously protected glucal, galactal, rhamnal, and disaccharide glycals, and the results are presented in Scheme [2]. A variety of masked glycals with acetyl, methyl, ethyl, benzoyl, benzyl, and allyl protecting groups performed efficiently in the designed methodology. It was found that all the reactions proceeded efficiently yielding the allyl glycosides 3a–j in good to excellent yields with >99% α-selectivity. Also, a disaccharide such as maltal performed well in the designed protocol, leading to 3k in 75% yield with lowered α-selectivity of up to α:β 90:10. Next, we subjected the optimized protocol to deoxysugar 3,4-di-O-acetyl-l-rhamnal and the reaction afforded the desired C-glycoside 3l in 88% yield with excellent stereoselectivity (α >99) (Scheme [2]).

Zoom Image
Scheme 2 Reaction of allylTMS with various glycals

Encouraged by these results, we steered our attention to trimethylsilylphenylacetylene as nucleophile to obtain alkynyl glycosides, since these compounds have significant synthetic utility for the construction of various natural products and biologically active molecules. So, we tested the current protocol with glucal and galactal derivatives with trimethylsilylphenylacetylene under standardized reaction conditions (Scheme [3]). As expected, the reaction proceeded to its logical end within 30 minutes leading to desired glycosides 5a–c in high yields (83–85%) with excellent stereoselectivity. However, in the case of disaccharide the selectivity was the same as aforementioned for alkynyl glycoside 5d and lowered up to α:β 90:10. Moreover, the substrate scope of trimethylsilylphenylacetylene was investigated. The methyl (Me)-, methoxy (OMe)-, and fluoro (F)-substituted alkyne acceptor performed well in the designed protocol, affording 5e, 5f, and 5g alkynyl glycosides in good yields, respectively. The structure and stereochemical outcome of compound 5e were identified via NMR analysis and also by comparison with the reported data.[6a] [17] There are cross peaks between H-1 and βH-6 in the NOE spectrum of 5e (see Supporting information), which verified that the reaction is completely α-selective.

Zoom Image
Scheme 3 Substrate scope of alkynyl glycosides

Based on the present result and reported literature studies, a plausible mechanistic path is depicted in Scheme [4]. It is supported from the literature[24] that the allylic rearrangement is effectively processed by BCF, which could act as a Lewis acid to work on deactivated glycals 1a and generate an oxocarbenium ion. Next, the active nucleophiles such as allyltrimethylsilane or trimethylsilylacetylene attack at C-1 in a stereoselective manner from α-phase to give the corresponding 2,3-unsaturated C-glycosides with exclusive α-selectivity. The stereochemical outcome of the products clearly preferred an α-face nucleophilic approach owing to steric and a favorable anomeric effect.[25]

Zoom Image
Scheme 4 Proposed mechanism of designed protocol

In conclusion, we have established a convenient and highly catalytic efficient tris(pentafluorophenyl)borane (BCF) system for the C-glycosylation of glycals to access 2,3-unsaturated allyl/alkynyl glycosides under mild reaction conditions. Pleasingly, the designed protocol applies to a wide range of glycals such as per-O-benzylated, benzoylated, methylated, allylated, ethylated, and acetylated donors which coupled with allyltrimethylsilane and trimethylsilylphenylacetylene to achieve functionalized Ferrier C-glycosides in good to excellent yields. Mostly, the reaction proceeds in a stereoselective manner providing exclusive α-anomer preferred by steric and anomeric effect. However, in the case of disaccharide lowered selectivity was observed. The reported methodology lays out the advantage of easy availability of starting material and eco-friendly catalytic system, which features a relative inertness, stability, and strong Lewis acid character, involved in frequent organic reactions. We believe that further exploration of BCF-catalyzed glycosylation finds its applicability and broaden the advancement of glycochemistry in the future.

All reactions were carried out under an argon atmosphere with anhydrous solvents under anhydrous conditions in oven-dried round-bottom flasks, unless otherwise noted. Reagents were purchased at the highest commercial quality available and used without further purification, unless otherwise stated. Reactions were monitored by TLC carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as the visualizing agent also by warming ceric sulfate [2% Ce(SO4)2 in 5% H2SO4 in EtOH]-sprayed plates on a hot plate. Silica gel 230–400 mesh was used for column chromatography. 1H NMR spectra were recorded in CDCl3 on a Bruker AV 400 (400 MHz) spectrometer. 13C{1H} NMR spectra were recorded in CDCl3 on a Bruker 400 (100 MHz) and Bruker 300 (75 MHz) spectrometer. Chemical shifts are reported relative to CDCl3 (δ = 7.26) for 1H NMR and CDCl3 (δ = 77.0) for 13C{1H} NMR. Coupling constants are given in hertz (Hz). Structural assignments were made with additional information from gCOSY, gHSQC, and DEPT-135 experiments. High-resolution mass spectra (HRMS) were recorded as ESI-HRMS on Q-TOF mass spectrometer. Either protonated molecular ions [M + H]+, sodium adducts [M + Na]+, or ammonium adducts [M + NH4]+ were used for empirical formula confirmation. Commercially available grades of organic solvents are used for column chromatography for purifications. The known compounds 1a–l [26] showed characterization data in full agreement with previously reported data.


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General Glycosylation Procedures for the Prepration of 2,3-Unsaturated Allyl- and Alkynyl- C-glycosides 3a–l, 5a–g

A solution of glycal 1a–l (0.5 mmol, 1 equiv.) and allyltrimethylsilane (2a) or the respective trimethylsilylphenylacetylene 4 (0.6 mmol, 1.2 equiv.) in anhyd dichloroethane (5 mL) was taken in a screwed cap vial followed by the addition of catalyst B(C6F5)3 (10 mol%). The reaction mixture was stirred at 50 °C for 1 h. After completion of the reaction, the reaction was quenched by the addition of Et3N (0.1 mL). The crude reaction mixture was concentrated in a rotavapor. The resulting crude reaction mixture was purified by silica gel (100–200 mesh) column chromatography (hexane/EtOAc) to afford the corresponding 2,3-unsaturated allyl- and alkynyl-C-glycosides 3a–l, 5a–g.


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((2R,3S,6R)-3-Acetoxy-6-allyl-3,6-dihydro-2H-pyran-2-yl)methyl Acetate (3a)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (8:1); yield: 107.9 mg (85%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 5.95–5.92 (m, 1 H), 5.86–5.79 (m, 2 H), 5.16–5.10 (m, 3 H), 4.28 (td, J = 5.7, 3.0 Hz, 1 H), 4.24 (dd, J = 11.8, 6.6 Hz, 1 H), 4.16 (dd, J = 11.9, 3.4 Hz, 1 H), 3.97 (td, J = 6.4, 3.5 Hz, 1 H), 2.51–2.43 (m, 1 H), 2.36–2.29 (m, 1 H), 2.09 (s, 6 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 170.8, 170.4, 133.9, 132.8, 123.7, 117.6, 71.4, 69.8, 65.0, 62.9, 37.9, 21.1, 20.8.

HRMS (ESI): m/z [M + NH4]+ calcd for C13H22NO5: 272.1498; found: 272.1503.


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(2R,3S,6R)-6-Allyl-2-((benzoyloxy)methyl)-3,6-dihydro-2H-pyran-3-yl Benzoate (3b)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (10:1); yield: 156.8 mg (83%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 8.07–8.00 (m, 2 H), 7.59–7.50 (m, 2 H), 7.45–7.36 (m, 4 H), 6.03–5.99 (m, 1 H), 5.98–5.94 (m, 1 H), 5.92–5.82 (m, 1 H), 5.49–5.46 (m, 1 H), 5.17–5.06 (m, 2 H), 4.60–4.45 (m, 2 H), 4.41–4.35 (m, 1 H), 4.33–4.28 (m, 1 H), 2.57–2.49 (m, 1 H), 2.42–2.35 (m, 1 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 166.4, 166.0, 134.1, 133.3, 133.2, 133.1, 129.9, 129.8, 129.7, 128.4, 128.3, 123.8, 117.6, 74.5, 70.1, 65.9, 63.9, 37.9.

HRMS (ESI): m/z [M + NH4]+ calcd for C23H26NO5: 396.1805; found: 396.1808.


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(2R,3S,6R)-6-Allyl-3-(benzyloxy)-2-((benzyloxy)methyl)-3,6-dihydro-2H-pyran (3c)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (12:1); yield: 134.7 mg (77%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 7.33–7.25 (m, 10 H), 5.92 (ddd, J = 12.2, 7.1, 5.1 Hz, 1 H), 5.89– 5.81 (m, 2 H), 5.09 (dd, J = 16.3, 14.2 Hz, 2 H), 4.60 (dd, J = 11.9, 5.3 Hz, 2 H), 4.52 (d, J = 12.2 Hz, 1 H), 4.48 (d, J = 11.6 Hz, 1 H), 4.26–4.22 (m, 1 H), 4.00–3.98 (m, 1 H), 3.85–3.81 (m, 1 H), 3.70–3.63 (m, 2 H), 2.52–2.48 (m, 1 H), 2.34–2.27 (m, 1 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 138.3, 138.2, 134.6, 131.2, 128.4, 128.3, 127.9, 127.8, 127.7, 127.6, 125.6, 117.3, 73.4, 72.1, 71.4, 71.0, 70.0, 69.3, 38.1.

HRMS (ESI): m/z [M + NH4]+ calcd for C23H30NO3: 368.2226; found: 368.2221.


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(2R,3S,6R)-6-Allyl-3-methoxy-2-(methoxymethyl)-3,6-dihydro-2H-pyran (3d)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (10:1); yield: 70.3 mg (71%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 5.93 (td, J = 10.5, 3.4 Hz, 1 H), 5.90–5.80 (m, 2 H), 5.14–5.06 (m, 1 H), 4.25–4.21 (m, 1 H), 3.75–3.68 (m, 2 H), 3.61–3.54 (m, 2 H), 3.41 (s, 3 H), 3.40 (s, 3 H), 2.51–2.43 (m, 1 H), 2.34–2.27 (m, 1 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 134.5, 131.3, 124.9, 117.3, 72.0, 71.7, 70.9, 59.3, 56.4, 38.1.

HRMS (ESI): m/z [M + NH4]+ calcd for C11H22NO3: 216.1594; found: 216.1597.


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((2R,3R,6R)-3-Acetoxy-6-allyl-3,6-dihydro-2H-pyran-2-yl)methyl Acetate (3e)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (8:1); yield: 106.7 mg (84%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 6.05 (dd, J = 10.3, 2.8 Hz, 1 H), 6.01–5.96 (m, 1 H), 5.90–5.79 (m, 1 H), 5.17–5.10 (m, 2 H), 5.07 (dd, J = 5.0, 2.6 Hz, 2 H), 4.38–4.33 (m, 1 H), 4.24–4.18 (m, 2 H), 4.16–4.12 (m, 1 H), 2.48–2.41 (m, 1 H), 2.33–2.63 (m, 1 H), 2.08 (s, 3 H), 2.87 (s, 3 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 170.7, 170.5, 134.8, 133.9, 112.0, 117.7, 74.4, 72.3, 68.0, 63.9, 62.9, 36.8, 20.9, 20.8.

HRMS (ESI): m/z [M + NH4]+ calcd for C13H22NO5: 272.1498; found: 272.1505.


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(2R,3R,6R)-6-Allyl-2-((benzoyloxy)methyl)-3,6-dihydro-2H-pyran-3-yl Benzoate (3f)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (7:1); yield: 151.2 mg (80%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 8.08–8.05 (m, 2 H), 8.04–8.01 (m, 2 H), 7.58–7.52 (m, 2 H), 7.45–7.39 (m, 4 H), 6.17–6.13 (m, 1 H), 6.12–6.09 (m, 1 H), 5.93–5.82 (m, 1 H), 5.43–5.41 (m, 1 H), 5.15–5.09 (m, 1 H), 5.08–5.505 (m, 1 H), 4.61 (dd, J = 11.5, 7.7 Hz, 1 H), 4.51 (dd, J = 11.5, 4.7 Hz, 1 H), 4.47–4.39 (m, 1 H), 2.53–2.46 (m, 1 H), 2.37–2.31 (m, 1 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 166.3, 166.1, 135.0, 133.9, 133.2, 133.1, 129.8, 129.7, 128.4, 128.3, 122.2, 117.7, 72.3, 68.5, 64.6, 63.7, 36.9.

HRMS (ESI): m/z [M + NH4]+ calcd for C23H26NO5: 396.1805; found: 396.1811.


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(2R,3R,6R)-6-Allyl-3-(benzyloxy)-2-((benzyloxy)methyl)-3,6-dihydro-2H-pyran (3g)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (12:1); yield: 127.7 mg (73%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 7.34–7.32 (m, 4 H), 7.31–7.27 (m, 6 H), 5.97–5.92 (m, 2 H), 5.91–5.81 (m, 1 H), 5.15–5.07 (m, 2 H), 4.61 (ABq, J = 11.9 Hz, 2 H), 4.61 (ABq, J = 11.9 Hz, 2 H), 4.32–4.29 (m, 1 H), 4.13–4.09 (m, 1 H), 3.89–3.87 (m, 1 H), 3.79–3.70 (m, 1 H), 2.47–2.39 (m, 1 H), 2.31–2.24 (m, 1 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 138.6, 138.4, 134.4, 133.3, 128.3, 127.8, 127.7, 127.6, 127.5, 124.0, 117.4, 73.5, 71.8, 71.2, 70.8, 68.8, 68.5, 37.5.

HRMS (ESI): m/z [M + NH4]+ calcd for C23H30NO3: 368.2226; found: 368.2228.


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(2R,3R,6R)-6-Allyl-3-methoxy-2-(methoxymethyl)-3,6-dihydro-2H-pyran (3h)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (10:1); yield: 70.3 mg (71%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 6.03–5.96 (m, 2 H), 5.90–5.79 (m, 1 H), 5.15–5.07 (m, 1 H), 4.32–4.28 (m, 1 H), 4.07–4.03 (m, 1 H), 3.67–3.65 (m, 1 H), 3.60–3.59 (m, 1 H), 3.58 (br s, 1 H), 3.41 (s, 3 H), 3.39 (s, 3 H), 2.48–2.47 (m, 1 H), 2.33–2.26 (m, 1 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 134.2, 133.4, 123.5, 117.4, 71.8, 71.3, 70.9, 70.4, 59.2, 56.5, 37.6.

HRMS (ESI): m/z [M + NH4]+ calcd for C11H22NO3: 216.1594; found: 216.1596.


#

(2R,3R,6R)-6-Allyl-3-ethoxy-2-(ethoxymethyl)-3,6-dihydro-2H-pyran (3i)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (9:1); yield: 79.1 mg (70%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 5.99–5.96 (m, 1 H), 5.92 (dd, J = 10.3, 2.4 Hz, 1 H), 5.90–5.79 (m, 1 H), 5.14–5.07 (m, 2 H), 4.31–4.27 (m, 1 H), 4.06–4.02 (m, 1 H), 3.76–3.74 (m, 1 H), 3.69–3.60 (m, 3 H), 3.59–3.49 (m, 3 H), 2.47–2.39 (m, 1 H), 2.31–2.24 (m, 1 H), 1.21 (t, J = 7.1 Hz, 3 H), 1.19 (t, J = 7.1 Hz, 3 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 134.4, 132.8, 124.4, 117.3, 71.7, 71.1, 69.2, 68.9, 66.8, 64.8, 37.5, 15.6, 15.2.

HRMS (ESI): m/z [M + NH4]+ calcd for C13H26NO3: 244.1907; found: 244.1911.


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(2R,3R,6R)-6-Allyl-3-(allyloxy)-2-((allyloxy)methyl)-3,6-dihydro-2H-pyran (3j)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (10:1); yield: 90.0 mg (72%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 5.99–5.95 (m, 2 H), 5.94–5.79 (m, 3 H), 5.31–5.28 (m, 1 H), 5.27–5.24 (m, 1 H), 5.19–5.07 (m, 4 H), 4.32–4.28 (m, 1 H), 4.15–3.99 (m, 5 H), 3.82–3.80 (m, 1 H), 3.68 (dd, J = 10.2, 5.3 Hz, 1 H), 3.64 (dd, J = 10.2, 7.2 Hz, 1 H), 2.47–2.39 (m, 1 H), 2.31–2.24 (m, 1 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 135.1, 134.8, 134.3, 133.2, 124.0, 117.3, 116.9, 116.8, 72.4, 71.8, 71.1, 70.0, 68.7, 68.5, 37.5.

HRMS (ESI): m/z [M + NH4]+ calcd for C15H26NO3: 268.1907; found: 268.1910.


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(2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-(((2R,3S,6R)-2-(acetoxymethyl)-6-allyl-3,6-dihydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl Triacetate (3k)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (2:1); yield: 203.2 mg (75%, α:β = 10:1); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 5.94–5.89 (m, 1 H), 5.88–5.78 (m, 1 H), 5.77–5.74 (m, 1 H), 5.46 (dd, J = 10.1, 9.6 Hz, 1 H), 5.31 (d, J = 3.4 Hz, 1 H), 5.17–5.10 (m, 2 H), 5.09–5.04 (m, 1 H), 4.85 (dd, J = 6.8, 3.9 Hz, 1 H), 4.29–4.23 (m, 4 H), 4.14–4.04 (m, 3 H), 3.95–3.91 (m, 1 H), 2.49–2.42 (m, 1 H), 2.35–2.29 (m, 1 H), 2.09 (s, 6 H), 2.07 (s, 3 H), 2.04 (s, 3 H), 2.02 (s, 3 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 170.8, 170.6, 170.2, 170.1, 169.6, 134.0, 132.9, 123.4, 117.6, 94.3, 71.5, 70.8, 70.1, 69.9, 69.8, 68.4, 67.9, 63.3, 61.8, 37.8, 20.8, 20.7, 20.6.

HRMS (ESI): m/z [M + NH4]+ calcd for C25H38NO3: 560.2338; found: 560.2344.


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(2S,3R,6S)-6-Allyl-2-methyl-3,6-dihydro-2H-pyran-3-yl Acetate (3l)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (15:1); yield: 86.2 mg (88%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 5.95–5.92 (m, 1 H), 5.91–5.82 (m, 1 H), 5.80–5.76 (m, 1 H), 5.16–5.09 (m, 1 H), 4.90–4.87 (m, 1 H), 4.23–4.18 (m, 1 H), 3.96–3.89 (m, 1 H), 2.48–2.41 (m, 1 H), 2.35–2.28 (m, 1 H), 2.09 (s, 3 H), 1.24 (d, J = 6.6 Hz, 3 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 170.8, 134.3, 133.4, 122.9, 117.4, 69.8, 69.5, 68.7, 38.4, 21.2, 16.9.

HRMS (ESI): m/z [M + NH4]+ calcd for C11H20NO3: 214.1438; found: 214.1444.


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((2R,3S,6S)-3-Acetoxy-6-(phenylethynyl)-3,6-dihydro-2H-pyran-2-yl)methyl Acetate (5a)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (8:1); yield: 33.5 mg (85%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 7.46–7.44 (m, 2 H), 7.35–7.31 (m, 3 H), 5.99 (ddd, J = 10.2, 3.5, 1.9 Hz, 1 H), 5.84 (dt, J = 10.2, 1.9 Hz, 1 H), 5.35 (ddd, J = 8.8, 3.9, 1.9 Hz, 1 H), 5.21 (dt, J = 3.6, 1.9 Hz, 1 H), 4.27 (d, J = 3.9 Hz, 2 H), 4.22–4.19 (m, 1 H), 2.11 (s, 3 H), 2.10 (s, 3 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 170.9, 170.3, 131.8, 129.2, 128.8, 128.3, 125.5, 122.2, 86.7, 84.7, 70.0, 64.8, 64.5, 63.1, 21.0, 20.8.

HRMS (ESI): m/z [M + H]+ calcd for C18H19O5: 315.1232; found: 315.1224.


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((2R,3R,6S)-3-Acetoxy-6-(phenylethynyl)-3,6-dihydro-2H-pyran-2-yl)methyl Acetate (5b)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (8:1); yield: 133.5 mg (85%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 7.45–7.43 (m, 2 H), 7.36–7.29 (m, 3 H), 6.15 (dd, J = 10.0, 3.7 Hz, 1 H), 6.06 (ddd, J = 10.0, 5.3, 1.8 Hz, 1 H), 5.26 (dd, J = 3.6, 1.8 Hz, 1 H), 5.12 (dd, J = 5.3, 2.3 Hz, 1 H), 4.44 (ddd, J = 7.4, 5.3, 2.4 Hz, 1 H), 4.31 (dd, J = 11.5, 5.3 Hz, 1 H), 4.22 (dd, J = 11.5, 7.3 Hz, 1 H), 2.09 (s, 3 H), 2.07 (s, 3 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 170.7, 170.4, 132.0, 131.8, 128.8, 128.4, 122.5, 122.1, 86.9, 84.1, 69.7, 64.4, 63.4, 62.9, 20.9, 20.8.

HRMS (ESI): m/z [M + H]+ calcd for C18H19O5: 315.1232; found: 315.1226.


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((2R,3R,6S)-3-(Benzoyloxy)-6-(phenylethynyl)-3,6-dihydro-2H-pyran-2-yl)methyl Benzoate (5c)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (10:1); yield: 181.7 mg (83%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 8.08–8.06 (m, 2 H), 8.03–8.01 (m, 2 H), 7.57–7.28 (m, 11 H), 6.26–6.19 (m, 2 H), 5.44 (dd, J = 4.4, 2.3 Hz, 1 H), 5.33 (d, J = 1.9 Hz, 1 H), 4.73–4.64 (m, 2 H), 4.55 (dd, J = 11.0, 4.6 Hz, 1 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 166.3, 166.0, 133.3, 133.1, 132.2, 131.8, 129.8, 129.7, 129.6, 128.7, 128.5, 128.3, 122.7, 122.1, 86.8, 84.4, 70.3, 64.6, 64.1, 63.6.

HRMS (ESI): m/z [M + H]+ calcd for C28H23O5: 439.1540; found: 439.1528.


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(2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-(((2R,3S,6S)-2-(acetoxymethyl)-6-(phenylethynyl)-3,6-dihydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl Triacetate (5d)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (2:1); yield: 237.7 mg (79%, α:β = 10:1); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 7.49–7.46 (m, 2 H), 7.36–7.31 (m, 3 H), 5.98–5.89 (m, 1 H), 5.78 (td, J = 10.2, 1.6 Hz, 1 H), 5.46 (dd, J = 10.2, 9.4 Hz, 1 H), 5.32 (d, J = 3.9 Hz, 1 H), 5.17–5.15 (m, 1 H), 5.08 (dd, J = 10.2, 9.6 Hz, 1 H), 4.86 (dd, J = 10.3, 3.9 Hz, 1 H), 4.44 (dd, J = 12.2, 2.4 Hz, 1 H), 4.35–4.30 (m, 1 H), 4.29–4.24 (m, 2 H), 4.14–4.05 (m, 3 H), 2.12 (s, 3 H), 2.09 (s, 3 H), 2.08 (s, 3 H), 2.03 (s, 3 H), 2.02 (s, 3 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 170.8, 170.6, 170.2, 170.1, 169.6, 131.9, 129.3, 128.8, 128.3, 125.0, 122.2, 94.5, 86.7, 84.6, 70.8, 70.5, 69.9, 69.9, 69.8, 68.2, 68.1, 64.4, 63.4, 61.7, 20.9, 20.7, 20.6.

HRMS (ESI): m/z [M + H]+ calcd for C30H35O13: 603.2072; found: 603.2063.


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((2R,3R,6S)-3-Acetoxy-6-(p-tolylethynyl)-3,6-dihydro-2H-pyran-2-yl)methyl Acetate (5e)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (8:1); yield: 139.4 mg (85%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J = 8.1 Hz, 2 H), 7.12 (d, J = 8.1 Hz, 2 H), 6.14 (dd, J = 10.0, 3.7 Hz, 1 H), 6.04 (ddd, J = 10.0, 5.3, 1.8 Hz, 1 H), 5.26 (dd, J = 3.6, 1.8 Hz, 1 H), 5.11 (dd, J = 5.3, 2.3 Hz, 1 H), 4.44 (ddd, J = 7.4, 5.3, 2.4 Hz, 1 H), 4.31 (dd, J = 11.5, 5.3 Hz, 1 H), 4.21 (dd, J = 11.5, 7.3 Hz, 1 H), 2.35 (s, 3 H), 2.09 (s, 3 H), 2.07 (s, 3 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 170.8, 170.5, 138.9, 132.2, 131.7, 129.1, 122.3, 119.0, 87.1, 83.4, 69.7, 64.5, 63.4, 62.9, 21.5, 20.9, 20.8.

HRMS (ESI): m/z [M + H]+ calcd for C19H21O5: 329.1384; found: 329.1389.


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((2R,3R,6S)-3-Acetoxy-6-((4-methoxyphenyl)ethynyl)-3,6-dihydro-2H-pyran-2-yl)methyl Acetate (5f)

Synthesized according to general procedure on a 0.5 mmol scale; eluent: hexane/EtOAc (8:1); yield: 142.7 mg (83%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 7.38 (d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.14 (dd, J = 10.0, 3.7 Hz, 1 H), 6.05 (ddd, J = 10.0, 5.3, 1.8 Hz, 1 H), 5.25 (dd, J = 3.6, 1.8 Hz, 1 H), 5.11 (dd, J = 5.3, 2.3 Hz, 1 H), 4.44 (ddd, J = 7.4, 5.3, 2.4 Hz, 1 H), 4.31 (dd, J = 11.5, 5.3 Hz, 1 H), 4.22 (dd, J = 11.5, 7.3 Hz, 1 H), 3.81 (s, 3 H), 2.09 (s, 3 H), 2.07 (s, 3 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 170.8, 170.5, 159.9, 133.4, 132.3, 130.5, 122.3, 113.9, 82.7, 69.6, 64.5, 63.4, 62.9, 55.3, 20.9, 20.8.

HRMS (ESI): m/z [M + Na]+ calcd for C19H20O6Na: 367.1152; found: 367.1155.


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((2R,3R,6S)-3-Acetoxy-6-((4-fluorophenyl)ethynyl)-3,6-dihydro-2H-pyran-2-yl)methyl Acetate (5g)

Synthesized according to general procedure on a 0.5 mmol scale, eluent: hexane/EtOAc (8:1); yield: 132.8 mg (80%, α >99); colorless jelly.

1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 5.7 Hz, 1 H), 7.40 (d, J = 5.7 Hz, 1 H), 7.02 (t, J = 8.7 Hz, 2 H), 6.14 (dd, J = 10.0, 3.7 Hz, 1 H), 6.06 (ddd, J = 10.0, 5.3, 1.8 Hz, 1 H), 5.25 (dd, J = 3.6, 1.8 Hz, 1 H), 5.12 (dd, J = 5.3, 2.3 Hz, 1 H), 4.42 (ddd, J = 7.4, 5.3, 2.4 Hz, 1 H), 4.31 (dd, J = 11.5, 5.3 Hz, 1 H), 4.22 (dd, J = 11.5, 7.3 Hz, 1 H), 2.35 (s, 3 H), 2.09 (s, 3 H), 2.07 (s, 3 H).

13C{1H} NMR (100 MHz, CDCl3): δ = 170.8, 169.4, 163.8 (J C,F = 248 Hz), 133.8, 133.7, 131.9, 122.6, 118.2 (J C,F = 8 Hz), 115.8 (J C,F = 22 Hz), 115.6 (J C,F = 22 Hz), 85.8, 83.9, 69.7, 64.3, 63.3, 62.8, 20.9, 20.8.

19F NMR (376 MHz, CDCl3): δ = 110.0 (s).

HRMS (ESI): m/z [M + H]+ calcd for C18H18FO5: 333.1133; found: 333.1145.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

A. G. thanks the National Fellowship for other backward classes (NF-OBC) (ICMR), New Delhi for providing a JRF Fellowship. Z. A. thanks CSIR, New Delhi for providing a fellowship. The authors gratefully acknowledge SAIF Division of CSIR-CDRI for providing the spectroscopic and analytical data. CDRI communication no. 10677.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2186-7116.
  • Supporting Information

Corresponding Author

Pintu Kumar Mandal
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute
BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226 031
India   

Publication History

Received: 05 September 2023

Accepted after revision: 05 October 2023

Accepted Manuscript online:
05 October 2023

Article published online:
14 November 2023

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Zoom Image
Scheme 1 Earlier methods and present work for the synthesis of 2,3-unsaturated allyl and alkynyl glycosides
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Scheme 2 Reaction of allylTMS with various glycals
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Scheme 3 Substrate scope of alkynyl glycosides
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Scheme 4 Proposed mechanism of designed protocol