Synthesis of monoglycosides, bisglycosides and open-chain ketoacetals from sugar derived exocyclic enol ethers

Abstract

Under acidic conditions, the reaction of pent-4-enofuranosides with various nucleophiles of mostly alcohol origin furnished bisglycosylated products along with open-chain ketoacetals and monoglycosylated products depending upon the reagents and reaction conditions. The reactions appear to proceed via nucleophilic attack at C-1 and/or C-4 of the reaction intermediates.

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Exocyclic vinyl ether derivatives of sugar¹ are formed as intermediates in various biosynthetic pathways, for example during the enzymatic hydrolysis of S-adenosylhomocysteine to adenosine,² enzymatic synthesis of 2-deoxy-scyllo-inosose from D-glucose-6-phosphate,³ formation of dehydroquinate in the shikimic pathway,⁴ the synthesis of nucleoside antibiotic angustmycin A,⁵ and the biomimetic rearrangement to carbocycles⁶ that are key precursors of nucleoside-based natural products neplanocin A and aristeromycin.⁷ Several synthetic reports for these vinyl ethers via dehydrohalogenation of 5-halogeno-furanose derivatives,⁸ Bamford–Stevens rearrangement of 5-tosylhydrazono-furanose derivatives⁹ and Wittig reaction of aldehydes with sugar-based triphenylphosphonium salts¹⁰ have been reported in the literature. Attempts to elaborate the synthetic utility of these ethers in producing glycosides,¹¹ polyethers,¹² spiroketals¹³ and related compounds¹⁴ including heterocycles,¹⁵ carbocyles,¹⁶ and nucleosides¹⁷ using coupling reactions,¹⁸ radical processes¹⁹ and cycloaddition reactions²⁰ have generated molecules of diverse nature. Nevertheless, the chemistry of these systems is less developed as compared to endocyclic vinyl ethers that allow regio- and stereoselective transformation, glycosylation as well as C–C and C-heteroatom bond formations at the anomeric centre.²¹ However, the methods, which take advantage of the nucleophilic character of these ethers for the direct formation of C–C and C–O bonds during organic synthesis are limited to dimerization,²² and opening of epi-sulphonium ion²³ and iodonium ion²⁴ intermediates by nucleophiles. As functionalized tetrahydrofurans are integral components of many biologically significant compounds, the development of more general processes using exocyclic vinyl ethers could find broad application in the synthesis of bioactive molecules.

For a long time, we have been interested in the preparation of various glycoside derivatives via open-chain acetals used as chiral auxiliaries²⁵ towards asymmetric synthesis of natural products or products useful in drug research.²⁶ As a part of that programme, we initiated the present work taking a pent-4-enofuranoside derivative (exocyclic enol ether) as the precursor that could deliver the desired products via nucleophilic attack by alcohols at C-1 and/or C-4 under acidic conditions. The oxocarbenium ions formed at C-1 and C-4 are stabilized, providing scope of nucleophilic attack at these two positions as shown (Fig. 1). We herein report the results of the work.

Fig. 1 A strategy for the synthesis of monoglycosides, bisglycosides and open-chain ketoacetals.

To begin with, the key precursor pent-4-enofuranose derivative 1a,^15a easily prepared from 3-O-benzyl-1,2-O-isopropylidene-5-O-mesyl-xylofuranose,²⁷ was exposed to 5% conc. HCl in methanol for 15 min to afford the monoglycosylated product (MGP) 2a in 45% yield (Scheme 1). Though there was no appreciable change in product formation up to 1 h, continuation of the reaction for 6 h yielded the open-chain acetal (OCA) 3a (65%). Similar results were obtained when 1a was treated with 5% conc. HCl in 2-methoxyethanol furnishing the MGP 2b (42%) and the OCA 3b (65%). But treatment with 5% conc. HCl in benzyl thiol provided the MGP 2c (45%) in 15 min and the bisglycosylated product (BGP) 4a (47%) after 1 h. No OCA product however resulted from this reaction. Reaction of the same starting material with 5% conc. HCl in allyl alcohol, propargyl alcohol, isopropanol or 2-chloroethanol, surprisingly, did not provide any identifiable product in 15 min–1 h. But all of these reactions afforded the OCAs 3c–3f in 52–67% yields after 6 h. In contrast, addition of 5% conc. HCl in ethanol or n-butanol to 1a did not result in any appreciable change in 15 min. However, it afforded the BGPs 4b (53%) and 4c (52%) respectively after 1 h and produced their OCAs 3g (60%) and 3h (61%) after 6 h. Further, reaction of the same precursor with 5% conc. HCl in allyltrimethylsilane, pent-4-ene-1-ol, or n-propanol did not indicate any appreciable change after 15 min, but furnished the BGPs 4d–4f in 52–58% yields when the reaction time was 1 h. Similar reactions of 1b²⁸ with 5% conc. HCl in ethanol, n-butanol, or n-propanol furnished BGPs 4g–4i as the major products in 46–55% yields after 1 h. The product 4i was isolated as its acetate derivative. However, these reactions produced intractable mixture of products after 5–6 h.

Scheme 1 Conversion of pent-4-enofuranose to glycosides and open-chain ketoacetals via the proposed pathway.

It is apparent from the results that the nucleophiles (also solvents) can solvate the oxocarbenium ion intermediates A and B, and lower their potential energy. The intermediate B can be more solvated, possibly due to smaller in size and difficult for it to escape from the solvents furnishing less reactivity to the nucleophiles and take longer time (6 h) for the reactions to occur in these solvents (Table 1). 2-Chloroethanol afforded lower yield of its OCA product in comparison to 2-methoxyethanol due to the lesser nucleophilicity of the latter (due to electron-withdrawing inductive effect of Cl). On the other hand, the relatively more hindered intermediate A appeared to be less solvated and thus attack can even take place by allyltrimethylsilane and pent-4-ene-1-ol having comparatively low nucleophilicity affording their BGP within 1 h of the reactions. The reactions in the solvents like ethanol, n-propanol and n-butanol produced their BGPs through this intermediate also. The MGPs formed in methanol, benzyl thiol and 2-methoxyethanol solvents after 15 min are expected to be going through this oxocarbenium ion intermediate.

Table 1 Acid induced reactions^a of pent-4-enofuranoses 1a and 1b to MGPs (2), OCAs (3), and BGPs (4)

Entry	Substrate	Reagent: 5% conc. HCl (vol/vol) in	Products (yield %) after
			15 min	1 h	6 h
a All reactions carried out at rt.b Isolated as acetate derivative.
1	1a	CH3OH	2a (45)		3a (65)
2	1a	MeO(CH2)2OH	2b (42)		3b (65)
3	1a	PhCH2SH	2c (45)	4a (47)
4	1a	CH2=CHCH2OH			3c (63)
5	1a	CH≡CCH2OH			3d (67)
6	1a	(CH3)2CHOH			3e (64)
7	1a	Cl(CH2)2OH			3f (52)
8	1a	CH3CH2OH		4b (53)	3g (60)
9	1a	CH3(CH2)3OH		4c (52)	3h (61)
10	1a	CH2=CHCH2SiMe3		4d (58)
11	1a	CH2=CH(CH2)3OH		4e (52)
12	1a	CH3(CH2)2OH		4f (52)
13	1b	CH3CH2OH		4g (50)
14	1b	CH3(CH2)3OH		4h (55)
15	1b	CH3(CH2)2OH		4i (46)^b

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The structures of all the products were confirmed by ¹H and ¹³C NMR and MS analyses. Anomeric purity of the bisglycosides was provided by their ¹H NMR spectra. The resonance corresponding to the anomeric proton appeared at δ ∼ 5.0 as a doublet (J = ∼5.0 Hz) indicating the presence of only the β-anomer.²⁹ The absence of any detectable amount of the α-anomer was not surprising due to the acid catalyzed attack by nucleophiles at the anomeric carbon from β-face removing the isopropylidene moiety. The relative syn-disposition of the incoming nucleophiles at C-1 and C-4 of BGPs was deduced from the NOESY correlation between one of the methylene protons (2 × multiplets at δ 3.86–3.90 and δ 3.65–3.68) of each ethyl group at C-1 and C-4 of 4g. The methylene carbons (δ 56.8 and 64.2) of the ethyl groups have been identified by HSQC spectrum. The carbon signal at δ 56.8 showed HMBC correlation with the signal at δ 1.40 for the methyl protons at C-4 indicating their propinquity.

Regarding the mechanism of product formation in the reaction, initial protonation of the sugar-derived exocyclic vinyl ether 1a/1b must have furnished the oxocarbenium intermediates. Attack by nucleophiles at C-4 of the intermediate produced the C-4 MGPs. Apparently, because of the steric hindrance induced by the acetonide group of the intermediate the addition occurred across the double bond from the opposite face.^15a Further, under acidic condition the cleavage of the isopropylidene group of the MGPs leading to an oxocarbenium ion and concomitant attack by a variety of nucleophiles at C-1 furnished the BGPs. The other intermediate, upon nucleophilic addition, afforded the OCAs. The OCAs, however, appeared to be generated also from the corresponding BGPs during the progress of the reaction.

In conclusion, sugar-derived exocyclic vinyl ether derivatives are important biosynthetic intermediates in various metabolic pathways in biological processes and could also be regarded as synthetic intermediates for the synthesis of important bioactive molecules. We have demonstrated that the 4-methylidenefuranoside derivative, the key precursor of the reaction, can be utilized to synthesize mono- and bis-glycosides of diverse structures through nucleophilic attack at C-1 and C-4 under acidic condition. Many of these reactions produced open-chain γ-keto acetals as the sole products when the solvents were miscible with conc. HCl. These acetals could be used as chiral auxiliaries in asymmetric synthesis of appropriate organic molecules. On the other hand, immiscible and partially miscible solvents furnished bisglycosides as the major products.

Experimental

General experimental

Melting points were taken in open capillaries and are uncorrected. ¹H and ¹³C NMR spectra were recorded in CDCl₃ as solvent using TMS as internal standard. Mass spectra were recorded using ESI mode. Specific rotations were measured at 589 nm. Pre-coated plates (0.25 mm, silica gel 60 F₂₅₄) were used for TLC. All the solvents were distilled and purified as necessary.

(3aS,5R,6R,6aR)-6-(Benzyloxy)-5-methoxy-2,2,5-trimethyltetrahydrofuro[2,3-d]dioxole (2a). A solution (10 mL) of a mixture of conc. HCl–MeOH (1 : 19) was added to 1a (150 mg, 0.57 mmol) and stirred at room temperature for 15 min. The reaction mixture was neutralized by slow addition of a saturated NaHCO₃ solution, the solvent was evaporated and the product was extracted by DCM (3 × 10 mL). The solvent was washed with water (2 × 5 mL), dried (Na₂SO₄) and concentrated to an oil, which was purified on a silica gel (230–400 mesh) column using petroleum ether–EtOAc (23 : 2) as eluent to furnish 2a (75 mg, 45%) as colourless liquid. [α]²⁵_D + 195.6 (c 0.5 in CHCl₃); ¹H NMR (600 MHz, CDCl₃): δ 1.41 (s, 3H), 1.42 (s, 3H), 1.46 (s, 3H), 3.32 (s, 3H), 3.78 (d, 1H, J = 3.0 Hz), 4.61 (d, 1H, J = 12.0 Hz), 4.78 (t, 1H, J = 3.6 Hz), 4.84 (d, 1H, J = 12.0 Hz), 5.75 (d, 1H, J = 4.8 Hz), 7.29–7.40 (m, 5H); ¹³C NMR (150 MHz, CDCl₃): δ 19.9 (CH₃), 27.8 (CH₃), 28.0 (CH₃), 48.6 (CH₃), 72.2 (CH₂), 86.2 (CH), 88.2 (CH), 103.6 (CH), 105.8 (C), 114.5 (C), 127.9–128.4 (5 × CH), 137.2 (C); ESIMS, m/z: 317 (M + Na)⁺.

(3aS,5R,6R,6aR)-6-(Benzyloxy)-5-(2-methoxyethoxy)-2,2,5-trimethyltetrahydrofuro [2,3-d][1,3] dioxole (2b). Following the procedure as described for 2a, the reaction was done using 1a (150 mg, 0.57 mmol) and conc. HCl–2-methoxy ethanol (1 : 19) solution (10 mL) at room temperature for 15 min. Work up and purification on a silica gel (230–400 mesh) column using a mixture of petroleum ether–EtOAc (23 : 2) as eluent furnished 2b (80 mg, 42%) as colourless liquid. [α]²⁵_D − 175.9 (c 0.34 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 1.30 (s, 3H), 1.49 (s, 3H), 1.54 (s, 3H), 3.36 (s, 3H), 3.48–3.61 (m, 2H), 3.67–3.80 (m, 2H), 3.97 (s, 1H), 4.56 (d, 1H, J = 11.7 Hz), 4.64 (d, 1H, J = 4.8 Hz), 4.70 (d, 1H, J = 11.7 Hz), 5.94 (d, 1H, J = 4.8 Hz), 7.27–7.38 (m, 5H); ¹³C NMR (75 MHz, CDCl₃): δ 18.3 (CH₃), 26.1 (CH₃), 26.4 (CH₃), 58.9 (CH₃), 60.8 (CH₂), 71.8 (CH₂), 72.1 (CH₂), 83.9 (CH), 87.5 (CH), 106.0 (CH), 112.2 (C), 112.5 (C), 127.5 (2 × CH), 127.8 (CH), 128.4 (2 × CH), 137.5 (C); HRMS (ESI, positive ion) calcd for C₁₈H₂₆NaO₆, m/z 361.1627, found 361.1642.

(3aS,5R,6R,6aR)-6-(Benzyloxy)-5-(benzylthio)-2,2,5-trimethyltetrahydrofuro[2,3-d][1,3] dioxole (2c). A solution of a mixture of conc. HCl–BnSH (1 : 19, 10 mL) was added to 1a (150 mg, 0.57 mmol) and the mixture was stirred at room temperature for 15 min. Usual work up and purification on a silica gel (230–400 mesh) column using a mixture of petroleum ether–EtOAc (93 : 7) as eluent furnished 2c (100 mg, 45%) as yellowish liquid. [α]²⁵_D + 195.6 (c 0.5 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 1.43 (s, 3H), 1.52 (s, 3H), 1.74 (s, 3H), 3.84 (brs, 2H), 3.93 (d, 1H, J = 3.0 Hz), 4.66 (d, 1H, J = 12.0 Hz), 4.75–4.79 (m, 2H), 5.86 (d, 1H, J = 4.5 Hz), 7.20–7.39 (m, 10H); ¹³C NMR (75 MHz, CDCl₃): δ 27.7 (CH₃), 27.9 (2 × CH₃), 31.4 (CH₂), 72.4 (CH₂), 86.8 (CH), 90.9 (CH), 93.1 (C), 104.2 (CH), 114.8 (C), 126.8–129.3 (10 × CH), 137.1 (C), 138.5 (C); HRMS (ESI, positive ion) calcd for C₂₂H₂₆NaO₄S, m/z 409.1449, found 409.1465.

(3R,4R)-3-(Benzyloxy)-4-hydroxy-5,5-dimethoxypentan-2-one (3a). Using the same protocol as described above in 2a the reaction was carried out for 6 h. Work up and purification on a silica gel (230–400 mesh) column furnished 3a (164 mg, 65%) as colourless gummy material using petroleum ether–EtOAc (19 : 1). [α]²⁵_D + 26.3 (c 0.24 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 2.24 (s, 3H), 2.40 (brs, 1H), 3.29 (s, 3H), 3.42 (s, 3H), 3.88 (dd, 1H, J = 2.1, 6.6 Hz), 3.99 (d, 1H, J = 2.7 Hz), 4.40 (d, 1H, J = 6.9 Hz), 4.46 (d, 1H, J = 11.4 Hz), 4.72 (d, 1H, J = 11.4 Hz), 7.32–7.38 (m, 5H); ¹³C NMR (75 MHz, CDCl₃): δ 27.3 (CH₃), 54.1 (CH₃), 55.3 (CH₃), 72.0 (CH), 73.4 (CH₂), 83.7 (CH), 103.5 (CH), 128.2 (CH), 128.4 (2 × CH), 128.5 (2 × CH), 136.9 (C), 209.8 (C); HRMS (ESI, positive ion) calcd for C₁₄H₂₀NaO₅, m/z 291.1208, found 291.1236.

Preparation of 2a and 3a (scale up to 20 fold)

To 1a (3.0 g, 11.4 mmol) was added a mixture of conc. HCl–MeOH (1 : 19) (200 mL) and stirred at room temperature for 15 min. Usual work up and purification yielded 2a (1.6 g, 48%). This reaction was repeated and after 6 h it afforded 3a (3.20 g, 63%) upon work up and purification.

(3R,4R)-3-(Benzyloxy)-4-hydroxy-5,5-bis(2-methoxyethoxy)pentan-2-one (3b). Another set of reaction was performed using 1a (250 mg, 0.95 mmol) and conc. HCl–2-methoxy ethanol (1 : 19) solution (20 mL) at room temperature for 6 h, following the procedure as described in the preparation of 2a. Usual work up and purification by column chromatography over silica gel (230–400 mesh) using petroleum ether–EtOAc (23 : 2) as eluent afforded 3b (219 mg, 65%) as colourless liquid. [α]²⁵_D + 57.1 (c 0.36 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 2.25 (s, 3H), 3.32 (s, 3H), 3.37 (s, 3H), 3.40–3.42 (m, 3H), 3.53 (t, 3H, J = 4.2 Hz), 3.62–3.69 (m, 1H), 3.72–3.80 (m, 1H), 3.87–3.94 (m, 2H), 4.02 (d, 1H, J = 2.1 Hz), 4.47 (d, 1H, J = 11.4 Hz), 4.65 (d, 1H, J = 7.5 Hz), 4.71 (d, 1H, J = 11.4 Hz), 7.32–7.36 (m, 5H); ¹³C NMR (75 MHz, CDCl₃): δ 27.5 (CH₃), 58.9 (2 × CH₃), 65.4 (CH₂), 67.1 (CH₂), 71.5 (CH₂), 71.9 (CH₂), 72.2 (CH), 73.5 (CH₂), 84.2 (CH), 102.8 (CH), 128.0 (CH), 128.4 (2 × CH), 128.4 (2 × CH), 137.3 (C), 210.7 (C); ESIMS, m/z: 379 (M + Na)⁺.

(3R,4R)-5,5-Bis(allyloxy)-3-(benzyloxy)-4-hydroxypentan-2-one (3c). Compound 1a (250 mg, 0.95 mmol) was allylated using conc. HCl–allyl alcohol (1 : 19) solution (20 mL) at room temperature for 6 h, following the procedure as described in the preparation of 2a. Usual work up and purification by column chromatography over silica gel (230–400 mesh) using petroleum ether–EtOAc (19 : 1) as eluent furnished 3c (190 mg, 63%) as colourless liquid. [α]²⁵_D + 70.1 (c 0.23 in CHCl₃); ¹H NMR (600 MHz, CDCl₃): δ 2.24 (s, 3H), 3.89 (dd, 1H, J = 5.4, 12.6 Hz), 3.93 (m, 1H), 4.04 (d, 1H, J = 2.4 Hz), 4.11–4.20 (m, 3H), 4.47 (d, 1H, J = 11.4 Hz), 4.65 (d, 1H, J = 6.6 Hz), 4.71 (d, 1H, J = 11.4 Hz), 5.15 (dd, 1H, J = 1.2, 10.2 Hz), 5.19 (dd, 1H, J = 1.2, 10.2 Hz), 5.24 (dd, 1H, J = 1.2, 16.8 Hz), 5.30 (dd, 1H, J = 1.2, 16.8 Hz), 5.78–5.84 (m, 1H), 5.89–5.95 (m, 1H), 7.32–7.36 (m, 5H); ¹³C NMR (150 MHz, CDCl₃): δ 27.4 (CH₃), 68.0 (CH₂), 68.8 (CH₂), 72.6 (CH), 73.5 (CH₂), 83.7 (CH), 101.2 (CH), 117.4 (2 × CH₂), 128.2–128.5 (5 × CH), 133.9 (CH), 134.1 (CH), 137.0 (C), 209.8 (C); HRMS (ESI, positive ion) calcd for C₁₈H₂₄NaO₅, m/z 343.1521, found 343.1507.

(3R,4R)-3-(Benzyloxy)-4-hydroxy-5,5-bis(prop-2-ynyloxy)pentan-2-one (3d). To 1a (250 mg, 0.95 mmol) was added conc. HCl–propargyl alcohol (1 : 19) solution (20 mL) and the mixture was stirred at room temperature for 6 h, following the procedure as described in the preparation of 2a. Usual work up and purification by column chromatography over silica gel (230–400 mesh) using petroleum ether–EtOAc (19 : 1) as eluent afforded 3d (200 mg, 67%) as colourless liquid. [α]²⁵_D + 36.0 (c 0.31 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 2.22 (s, 3H), 2.50 (brs, 2H), 3.94–4.00 (m, 1H), 4.08 (d, 1H, J = 2.4 Hz), 4.23–4.41 (m, 4H), 4.56 (d, 1H, J = 11.1 Hz), 4.70 (d, 1H, J = 11.1 Hz), 4.92 (d, 1H, J = 6.6 Hz), 7.35–7.61 (m, 5H); ¹³C NMR (75 MHz, CDCl₃): δ 27.4 (CH₃), 54.8 (CH₂), 55.0 (CH₂), 72.6 (CH), 73.6 (CH₂), 75.2 (2 × CH), 78.9 (C), 79.3 (C), 83.4 (CH), 100.2 (CH), 128.2–128.5 (5 × CH), 136.8 (C), 209.9 (C); HRMS (ESI, positive ion) calcd for C₁₈H₂₀NaO₅, m/z 339.1208, found 339.1227.

(3R,4R)-3-(Benzyloxy)-5,5-diisopropoxy-4-hydroxypentan-2-one (3e). Compound 1a (250 mg, 0.95 mmol) was treated with conc. HCl–i-PrOH mixture (1 : 19, 20 mL) at room temperature for 6 h, following the procedure as described in the preparation of 2a. Usual work up and purification by column chromatography over silica gel (230–400 mesh) using petroleum ether–EtOAc (19 : 1) as eluent gave 3e (195 mg, 64%) as colourless liquid. [α]²⁵_D + 16.5 (c 0.27 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 1.14–1.25 (m, 12H), 2.24 (s, 3H), 2.48 (d, 1H, J = 5.7 Hz), 3.77–3.97 (m, 3H), 4.06 (d, 1H, J = 3.0 Hz), 4.52 (d, 1H, J = 11.4 Hz), 4.66 (d, 1H, J = 11.4 Hz), 4.71 (d, 1H, J = 6.0 Hz), 7.32–7.41 (m, 5H); ¹³C NMR (75 MHz, CDCl₃): δ 21.9 (CH₃), 22.8 (CH₃), 23.2 (CH₃), 23.4 (CH₃), 27.4 (CH₃), 69.1 (CH), 70.1 (CH), 73.3 (CH, CH₂), 83.7 (CH), 98.8 (CH), 128.0–128.6 (5 × CH), 137.2 (C), 209.9 (C); HRMS (ESI, positive ion) calcd for C₁₈H₂₈NaO₅, m/z 347.1834, found 347.1851.

(3R,4R)-3-(Benzyloxy)-5,5-bis-(2-chloroethoxy)-4-hydroxypentan-2-one (3f). A mixture of conc. HCl–chloro ethanol (1 : 19, 20 mL) was added to 1a (250 mg, 0.95 mmol) and the mixture was stirred at room temperature for 6 h, following the procedure as described in the preparation of 2a. Usual work up and purification by column chromatography over silica gel (230–400 mesh) using petroleum ether–EtOAc (19 : 1) as eluent produced 3f (220 mg, 64%) as colourless liquid. [α]²⁵_D + 107.1 (c 0.16 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 2.25 (s, 3H), 2.52 (brs, 1H), 3.50–3.57 (m, 2H), 3.66 (t, 3H, J = 5.4 Hz), 3.81–3.99 (m, 4H), 4.47 (d, 1H, J = 11.4 Hz), 4.65 (d, 1H, J = 7.2 Hz), 4.75 (d, 1H, J = 11.4 Hz), 7.36 (s, 5H); ¹³C NMR (75 MHz, CDCl₃): δ 27.4 (CH₃), 42.8 (CH₂), 43.2 (CH₂), 66.3 (CH₂), 67.7 (CH₂), 72.0 (CH), 73.3 (CH₂), 83.4 (CH), 101.8 (CH), 128.2 (CH), 128.4 (2 × CH), 128.5 (2 × CH), 136.8 (C), 209.9 (C); HRMS (ESI, positive ion) calcd for C₁₆H₂₂Cl₂NaO₅, m/z 387.0742, found 387.0760.

(3R,4R)-3-(Benzyloxy)-5,5-diethoxy-4-hydroxypentan-2-one (3g). The reaction was carried out following the procedure as described for 2a, using the same protocol at room temperature for 6 h. Work up and purification by column chromatography over silica gel (230–400 mesh) using petroleum ether–EtOAc (19 : 1) as eluent afforded 3g (170 mg, 60%) as colourless liquid. [α]²⁵_D + 153.1 (c 0.31 in CHCl₃); ¹H NMR (600 MHz, CDCl₃): δ 1.12 (t, 3H, J = 7.2 Hz), 1.22 (t, 3H, J = 7.2 Hz), 2.25 (s, 3H), 2.40 (d, 1H, J = 4.2 Hz), 3.34 (quint, 1H, J = 7.2 Hz), 3.59–3.65 (m, 1H), 3.66–3.76 (m, 2H), 3.85 (brt, 1H, J = 3.0 Hz), 4.01 (d, 1H, J = 2.4 Hz), 4.46 (d, 1H, J = 11.4 Hz), 4.53 (d, 1H, J = 6.6 Hz), 4.72 (d, 1H, J = 12.0 Hz), 7.29–7.36 (m, 5H); ¹³C NMR (150 MHz, CDCl₃): δ 15.2 (CH₃), 15.4 (CH₃), 27.4 (CH₃), 63.1 (CH₂), 63.7 (CH₂), 72.6 (CH), 73.4 (CH₂), 83.8 (CH), 102.0 (CH), 127.9, 128.1, 128.2, 128.4, and 128.5 (5 × CH), 137.0 (C), 209.8 (C); HRMS (ESI, positive ion) calcd for C₁₆H₂₄NaO₅, m/z 319.1521, found 319.1493.

(3R,4R)-3-(Benzyloxy)-5,5-dibutoxy-4-hydroxypentan-2-one (3h). The reaction was carried out using 1a (250 mg, 0.95 mmol) and conc. HCl–n-BuOH (1 : 19) solution (20 mL) at room temperature for 6 h, following the procedure as described in the preparation of 2a. Work up and purification by column chromatography over silica gel (230–400 mesh) using petroleum ether–EtOAc (93 : 7) as eluent gave 3h (205 mg, 61%) as colourless liquid. [α]²⁵_D + 153.1 (c 0.31 in CHCl₃); ¹H NMR (600 MHz, CDCl₃): δ 0.90 (t, 3H, J = 7.8 Hz), 0.92 (t, 3H, J = 7.8 Hz), 1.30–1.39 (m, 4H), 1.44–1.49 (m, 2H), 1.55–1.59 (m, 2H), 2.25 (s, 3H), 3.28 (dd, 1H, J = 6.6, 15.6 Hz), 3.54 (dd, 1H, J = 6.6, 15.6 Hz), 3.61–3.68 (m, 2H), 3.87 (dd, 1H, J = 3.0, 7.2 Hz), 4.04 (d, 1H, J = 2.4 Hz), 4.46 (d, 1H, J = 11.4 Hz), 4.53 (d, 1H, J = 6.6 Hz), 4.70 (d, 1H, J = 11.4 Hz), 7.28–7.36 (m, 5H); ¹³C NMR (150 MHz, CDCl₃): δ 13.8 (2 × CH₃), 19.3 (2 × CH₂), 27.4 (CH₃), 31.8 (CH₂), 31.9 (CH₂), 67.1 (CH₂), 67.9 (CH₂), 72.6 (CH), 73.4 (CH₂), 83.8 (CH), 102.0 (CH), 128.3 (CH), 128.4 (2 × CH), 128.5 (2 × CH), 137.1 (C), 210.0 (C); HRMS (ESI, positive ion) calcd for C₂₀H₃₂NaO₅, m/z 375.2147, found 375.2125.

(2S,3R,4R,5R)-4-(Benzyloxy)-2,5-bis-(benzylthio)-5-methyl-tetrahydrofuran-3-ol (4a). The same reaction was carried out using 1a (250 mg, 0.95 mmol) and conc. HCl–BnSH (1 : 19) solution (20 mL) at room temperature for 1 h, following the procedure as described in the preparation of 2a. Subsequent work up and purification by column chromatography over silica gel (230–400 mesh) using petroleum ether–EtOAc (23 : 2) as eluent afforded 4a (200 mg, 47%) as yellowish liquid; [α]²⁵_D − 16.5 (c 0.12 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 1.73 (s, 3H), 2.54 (brd, 1H J = 7.5 Hz), 3.71 (d, 1H, J = 3.3 Hz), 3.77–3.91 (m, 4H), 4.06–4.11 (m, 1H), 4.60 (d, 1H, J = 12.0 Hz), 4.66 (d, 1H, J = 12.0 Hz), 4.83 (d, 1H, J = 6.0 Hz), 7.26–7.36 (m, 15H); ¹³C NMR (150 MHz, CDCl₃): δ 24.2 (CH₃), 33.0 (CH₂), 35.1 (CH₂), 72.2 (CH₂), 80.6 (CH), 86.9 (CH), 89.1 (CH), 93.5 (C), 127.1–129.0 (15 × CH), 137.4 (C), 137.5 (C), 137.8 (C); HRMS (ESI, positive ion) calcd for C₂₆H₂₈NaO₃S₂, m/z 475.1378, found 475.1366.

(2R,3R,4R,5S)-4-(Benzyloxy)-2,5-diethoxy-5-methyl-tetrahydrofuran-3-ol (4b). As described in 2a, compound 1a (250 mg, 0.95 mmol) was dissolved in conc. HCl–EtOH (1 : 19) solution (20 mL) and the reaction mixture was stirred at room temperature for 1 h. Work up and purification on a silica gel (230–400 mesh) column using a mixture of petroleum ether–EtOAc (19 : 1) as eluent to furnish 4b (150 mg, 53%) as colourless liquid. [α]²⁵_D + 72.7 (c 0.33 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 1.21 (t, 3H, J = 6.9 Hz), 1.41–1.46 (m, 6H), 3.53–3.61 (m, 2H), 3.64–3.74 (m, 2H), 3.76 (d, 1H, J = 3.6 Hz), 4.62 (d, 1H, J = 12.0 Hz), 4.79 (t, 1H, J = 4.2 Hz), 4.84 (d, 1H, J = 12.0 Hz), 5.77 (d, 1H, J = 4.5 Hz), 7.28–7.41 (m, 5H); ¹³C NMR (75 MHz, CDCl₃): δ 15.7 (2 × CH₃) 21.1 (CH₃), 56.8 (CH₂), 63.7 (CH₂), 72.0 (CH₂), 86.3 (CH), 88.2 (CH), 103.6 (CH), 105.9 (C), 127.8–128.3 (5 × CH), 137.37 (C); HRMS (ESI, positive ion) calcd for C₁₆H₂₄NaO₅, m/z 319.1521, found 319.1509.

(2R,3R,4S,5R)-4-(Benzyloxy)-2,5-dibutoxy-5-methyl-tetrahydrofuran-3-ol (4c). Treatment of 1a (250 mg, 0.95 mmol) with conc. HCl–n-BuOH (1 : 19) solution (20 mL) at room temperature for 1 h, following the procedure as described in the preparation of 2a and subsequent work up and purification by column chromatography over silica gel (230–400 mesh) using petroleum ether–EtOAc (19 : 1) as eluent furnished 4c (175 mg, 52%) as colourless liquid. [α]²⁵_D + 14.5 (c 0.22 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 0.89–0.95 (m, 6H), 1.30–1.65 (m, 11H, including a ‘s, 3H’ at δ 1.42), 3.44–3.65 (m, 3H), 3.67–3.85 (m, 1H), 3.91 (d, 1H, J = 5.7 Hz), 4.02–4.16 (m, 1H), 4.67 (d, 1H, J = 12.0 Hz), 4.72 (d, 1H, J = 11.7 Hz), 4.98 (d, 1H, J = 4.8 Hz), 7.28–7.41 (m, 5H); ¹³C NMR (75 MHz, CDCl₃): δ 13.9 (2 × CH₃), 19.3 (CH₂), 19.4 (CH₂), 20.2 (CH₃), 31.5 (CH₂), 32.1 (CH₂), 61.1 (CH₂), 68.6 (CH₂), 72.0 (CH₂), 75.7 (CH), 87.1 (CH), 100.4 (CH), 107.9 (C), 127.5–128.3 (5 × CH), 138.0 (C); HRMS (ESI, positive ion) calcd for C₂₀H₃₂NaO₅, m/z 375.2147, found 375.2125.

(2S,3S,4S,5R)-2,5-Diallyl-4-(benzyloxy)-5-methyltetrahydrofuran-3-ol (4d). To 1a (150 mg, 0.57 mmol) were added allyltrimethylsilane (10 mL) and conc. HCl (0.5 mL) and the reaction mixture as stirred at room temperature for 60 min. following the procedure as described in 2a. Work up and purification on a silica gel (230–400 mesh) column using a mixture of petroleum ether–EtOAc (19 : 1) as eluent afforded 4d (95 mg, 58%) as colourless liquid. [α]²⁵_D + 27.8 (c 0.43 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 1.22 (s, 3H), 2.27–2.48 (m, 4H), 3.66–3.69 (m, 1H), 3.99–4.17 (m, 2H), 4.54–4.71 (m, 2H), 4.98–5.23 (m, 4H), 5.74–5.94 (m, 2H), 7.29–7.36 (m, 5H); ¹³C NMR (75 MHz, CDCl₃): δ 20.2 (CH₃), 33.6 (CH₂), 45.6 (CH₂), 72.4 (CH₂), 77.3 (CH), 77.4 (CH), 82.9 (C), 89.2 (CH), 117.1 (CH₂), 118.5 (CH₂), 127.3–128.6 (5 × CH), 134.0 (CH), 134.7 (CH), 138.2 (C); ESIMS, m/z: 311 (M + Na)⁺.

(2R,3R,4R,5S)-4-(Benzyloxy)-5-methyl-2,5-bis(pent-4-enyloxy)tetrahydrofuran-3-ol (4e). The reaction was carried out using the protocol, viz. 1a (250 mg, 0.95 mmol), conc. HCl–4-penten-1-ol (1 : 19) solution (20 mL) and stirring at room temperature for 1 h, following the procedure as described in the preparation of 2a. Work up and purification by column chromatography over silica gel (230–400 mesh) using petroleum ether–EtOAc (19 : 1) as eluent afforded 4e (185 mg, 52%) as colourless liquid. [α]²⁵_D + 34.5 (c 0.21 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 1.42 (s, 3H), 1.60–1.77 (m, 4H), 2.09–2.25 (m, 4H), 3.45–3.92 (m, 5H), 4.03–4.13 (m, 1H), 4.67 (d, 1H, J = 12.0 Hz), 4.72 (d, 1H, J = 12.0 Hz), 4.96–5.05 (m, 5H), 5.74–5.86 (m, 2H), 7.27–7.45 (m, 5H); ¹³C NMR (75 MHz, CDCl₃): δ 20.2 (CH₃), 28.6 (CH₂), 29.1 (CH₂), 30.2 (CH₂), 30.3 (CH₂), 60.8 (CH₂), 68.2 (CH₂), 72.0 (CH₂), 75.8 (CH), 87.1 (CH), 100.4 (CH), 107.9 (C), 114.7 (CH₂), 114.9 (CH₂), 127.5–128.3 (5 × CH), 137.9 (CH), 138.0 (C), 138.2 (CH); HRMS (ESI, positive ion) calcd for C₂₂H₃₂NaO₅, m/z 399.2147, found 399.2150.

(2R,3R,4R,5S)-4-(Benzyloxy)-5-methyl-2,5-dipropoxy-tetrahydrofuran-3-ol (4f). Treatment of 1a (250 mg, 0.95 mmol) with conc. HCl–n-PrOH (1 : 19) solution (20 mL), at room temperature for 60 min, following the procedure as described in the preparation of 2a, followed by work up and purification by column chromatography over silica gel (230–400 mesh) using petroleum ether–EtOAc (19 : 1) as eluent furnished 4f (160 mg, 52%) as colourless liquid. [α]²⁵_D + 86.7 (c 0.26 in CHCl₃); ¹H NMR (600 MHz, CDCl₃): δ 0.91 (t, 3H, J = 7.2 Hz), 0.94 (t, 3H, J = 7.2 Hz), 1.42 (s, 3H), 1.53–1.59 (m, 2H), 1.60–1.66 (m, 2H), 2.73 (d, 1H, J = 10.8 Hz), 3.42–3.48 (m, 2H), 3.49–3.52 (m, 1H), 3.75–3.79 (m, 1H), 3.92 (d, 1H, J = 5.4 Hz), 4.12 (quint, 1H, J = 4.8 Hz), 4.68 (d, 1H, J = 12.0 Hz), 4.72 (d, 1H, J = 12.0 Hz), 4.99 (d, 1H, J = 5.4 Hz), 7.27–7.36 (m, 5H); ¹³C NMR (150 MHz, CDCl₃): δ 10.6 (CH₃), 10.6 (CH₃), 20.3 (CH₃), 22.7 (CH₂), 23.2 (CH₂), 63.0 (CH₂), 70.4 (CH₂), 72.0 (CH₂), 75.8 (CH), 87.2 (CH), 100.4 (CH), 107.9 (C), 127.5 (2 × CH), 127.6 (CH), 128.3 (2 × CH), 138.1 (C); HRMS (ESI, positive ion) calcd for C₁₈H₂₈NaO₅, m/z 347.1834, found 347.1881.

(2R,3R,4R,5S)-4-(Allyloxy)-2,5-diethoxy-5-methyl-tetrahydrofuran-3-ol (4g). Compound 1b (250 mg, 1.18 mmol) was treated with a solution (20 mL) of conc. HCl–EtOH (1 : 19) at room temperature for 1 h, following the procedure as described in the preparation of 2a followed by work up and purification by column chromatography over silica gel (230–400 mesh) using petroleum ether–EtOAc (23 : 2) as eluent furnished 4g (145 mg, 50%) as colourless liquid. [α]²⁵_D + 160.3 (c 0.18 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 1.18 (t, 3H, J = 6.9 Hz), 1.26 (t, 3H, J = 6.9 Hz), 1.38 (s, 3H), 2.76 (d, 1H, J = 10.5 Hz), 3.51–3.70 (m, 3H), 3.82–3.93 (m, 2H), 4.03–4.11 (m, 1H), 4.15 (t, 2H, J = 5.4 Hz), 5.00 (d, 1H, J = 5.1 Hz), 5.19 (d, 1H, J = 10.5 Hz), 5.32 (d, 1H, J = 17.4 Hz), 5.86–5.99 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 15.1 (CH₃), 15.6 (CH₃), 20.0 (CH₃), 56.8 (CH₂), 64.2 (CH₂), 71.1 (CH₂), 75.9 (CH), 87.3 (CH), 100.3 (CH), 108.0 (C), 117.0 (CH₂), 134.4 (CH); HRMS (ESI, positive ion) calcd for C₁₂H₂₂NaO₅, m/z 269.1365, found 269.1382.

(2R,3R,4R,5S)-4-(Allyloxy)-2,5-dibutoxy-5-methyl-tetrahydrofuran-3-ol (4h). A solution (20 mL) of conc. HCl–n-BuOH (1 : 19) was added to 1b (250 mg, 1.18 mmol) and the mixture was stirred at room temperature for 1 h, following the procedure as described in the preparation of 2a. Work up and purification by column chromatography over silica gel (230–400 mesh) using petroleum ether–EtOAc (19 : 1) as eluent furnished 4h (195 mg, 55%) as colourless liquid. [α]²⁵_D + 21.3 (c 0.37 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 0.92 (t, 3H, J = 7.5 Hz), 0.95 (t, 3H, J = 7.2 Hz), 1.32 (s, 3H), 1.13–1.42 (m, 4H), 1.47–1.66 (m, 4H), 3.45–3.75 (m, 3H), 3.78–3.84 (m, 2H), 4.01–4.10 (m, 1H), 4.14–4.16 (m, 2H), 4.96 (d, 1H, J = 5.1 Hz), 5.20 (d, 1H, J = 10.5 Hz), 5.32 (dd, 1H, J = 1.5, 17.1 Hz), 5.86–5.99 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 13.9 (CH₃), 14.0 (CH₃), 19.3 (CH₂), 19.4 (CH₂), 20.2 (CH₃), 31.6 (CH₂), 32.1 (CH₂), 61.2 (CH₂), 68.6 (CH₂), 71.1 (CH₂), 75.8 (CH), 87.0 (CH), 100.4 (CH), 107.9 (C), 117.0 (CH₂), 134.4 (CH). HRMS (ESI, positive ion) calcd for C₁₆H₃₀NaO₅, m/z 325.1991, found 325.1980.

(2R,3R,4R,5S)-2-Acetoxy-4-allyloxy-5-methyl-2,5-dipropoxy-tetrahydrofuran (4i). To 1b (250 mg, 1.18 mmol) was added a mixture of conc. HCl–n-PrOH (1 : 19) (20 mL) at room temperature for 1 h, following the procedure as described in the preparation of 2a and subsequent work up and purification led to an inseparable mixture (230 mg). To a solution of the mixture in pyridine (8 mL) at 0 °C, was added Ac₂O (0.17 mL, 1.8 mmol) and the solution was stirred at 0 °C for 60 min and then at 25 °C for 6 h. The solvent was removed, crushed ice was added to the residue and the crude product was extracted with DCM (3 × 20 mL). The solvent was successively washed with 1(N) HCl (10 mL), a saturated NaHCO₃ solution (2 × 15 mL), brine (2 × 15 mL), dried (Na₂SO₄), and evaporated to a residue, which was purified by column chromatography on silica gel (230–400 mesh) using petroleum ether–EtOAc (24 : 1) as eluent to afford 4i (170 mg, 46%) as colourless liquid. [α]²⁵_D + 30.5 (c 0.28 in CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ 0.86–0.96 (m, 6H), 1.39 (s, 3H), 1.57 (q-like, 4H, J = 6.9 Hz), 2.11 (s, 3H), 3.45–3.57 (m, 3H), 3.64–3.73 (m, 2H), 4.06–4.22 (m, 2H), 4.99 (dd-like, 1H, J = 1.8, 4.8 Hz), 5.13 (d, 1H, J = 4.8 Hz), 5.16–5.34 (m, 2H), 5.82–5.97 (m, 1H). ¹³C NMR (75 MHz, CDCl₃): δ 10.5 (CH₃), 10.6 (CH₃), 20.7 (CH₃), 21.5 (CH₃), 22.6 (CH₂), 23.3 (CH₂), 63.3 (CH₂), 70.2 (CH₂), 71.3 (CH₂), 77.0 (CH), 83.1 (CH), 97.9 (CH), 106.5 (C), 117.1 (CH₂), 134.2 (CH), 170.6 (C). HRMS (ESI, positive ion) calcd for C₁₆H₂₈NaO₆, m/z 339.1784, found 339.1809.

Acknowledgements

S N D thanks CSIR, Govt. of India for providing a Senior Research Fellowship to him and P K K, a student of NIPER-Kolkata, is grateful to Indian Institute of Chemical Biology for giving him laboratory facility.

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C-NMR spectra of all new compounds; NOESY, HSQC and HMBC spectra of 4g. See DOI: 10.1039/c4ra03340j

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