Synthesis of Highly Oxygenated Bicyclic Carbasugars. Remarkable Difference in the Reactivity of the d-gluco and d-xylo- Derived Trienes

Abstract

2,3,4-Tri-O-benzyl-D-xylopyranose was used as a starting material in the preparation of the corresponding triene, which underwent smooth cyclization to a polyhydroxylated hydrindane, as a single diastereoisomer. The analogous triene prepared from D-glucose did not undergo any cyclization even under high pressure.

1. Introduction

Carbasugars are glycomimetics obtained through a substitution of the endocyclic oxygen atom with a methylene group [1,2]. Due to their similarity to carbohydrates, these compounds often possess interesting biological properties, e.g., they may act as glycosidase inhibitors [3,4,5]. Some of these compounds found an application in medicine; for example, acarbose is commercialized to treat obesity and type 2 diabetes mellitus [6] and validamycin is an antibiotic [7]. Elaboration of the convenient synthetic methods for the preparation of carbobicyclic sugar mimetics is one of the leading trends in our laboratory [8]. We have proposed a useful route to polyhydroxylated decalins (such as 5) from sugar allyltins as shown in Scheme 1 [9]. The model synthesis was initiated from D-gluco-derivative 1, which—upon treatment with mild Lewis acid (preferably ZnCl₂)—afforded dienoaldehyde 2 with the E-configuration across the internal double bond. This compound was converted into phosphonate 3 and—by the Horner-Wadsworth-Emmons (HWE) reaction with the corresponding aldehyde—into triene 4, subsequently cyclized to 5. The methodology proposed in Scheme 1 allowed the preparation of a number of diastereoisomeric polyhydroxylated bicyclic derivatives in optically pure form starting from different sugars: d-glucose, d-mannose, and d-galactose [9,10,11,12].

It is known that polyhydroxylated decalins might have significant biological activity [13,14,15], thus there is an interest in the preparation of such targets. Our methodology, however, starting from organostannanes—being assumed to be highly toxic—cannot be used for the preparation of potential therapeutics. Other, environmentally friendly method(s), for the synthesis of such important derivatives is needed.

We have proposed an efficient method for the stereoselective preparation of sugar dienes with the E or Z geometry across the internal double bond (8-E or 8-Z; Scheme 2) from D-glucosep-derivative 6 (via intermediate 7) [16]. These compounds could be eventually used as convenient precursors for the synthesis of bicyclic carbasugars. Wittig-type reaction of hemiacetal 8 could provide appropriate triene 9 which, via a [4 + 2]-cyclization, should afford carbobicyclic derivatives (e.g., 10; Scheme 2).

However, treatment of compounds 8 (either E or Z) with phosphoranes (Wittig reaction) or phosphonates (HWE reaction) did not give any expected product 9. Further, these hemiacetals did not react even with simplest organometallic species such e.g., Grignard reagents. The only process which could be realized, was the reaction with hydroxylamine providing the corresponding oxime 11 in good yield (Scheme 2).

2. Results and Discussion

Since the intermediate 9 (see Scheme 2) could not be obtained from our diene 8, we changed the concept and design to introduce the diene system at the anomeric position and then the olefinic unit at the terminal position; this triene can be called “inverted” comparing to triene 9. This strategy is exemplified on Scheme 3 for D-glucose derivative 12. We reasoned that this approach would be more profitable, the problems encountered for diene 8 could be avoided, and we would be able to obtain triene 13 in reasonable yield.

This triene should also cyclize to the bicyclic system in the Diels-Alder reaction. This assumption is based on the results of Evans, who presented an efficient and highly diastereoselective cyclization of similar triene with the activating N-acyloxazolidinone unit at the olefinic part (14→15; Scheme 4) [17,18,19].

2.1. Synthesis of Derivatives of D-Glucose with the Diene System Located at the C1

The synthesis of polyhydroxylated trienes in our case was initiated from the easily available di-thioacetal 16, prepared from free glucose according to Yu and coworkers [20]. The OH group at the terminal position in 16 was protected as a TBDPS ether, the carbonyl group at the C1 was regenerated according to reference [21], and the resulting aldehyde 17 was reacted with allyltitanium reagent 18 [22], providing the mixture of silanols 19 with the anticipated [16,22,23] anti-configuration (Scheme 5).

β-Hydroxysilane 19 was subjected to the Peterson olefination under acidic and, independently, basic conditions which should lead to the corresponding dienes with the E or Z-configuration across the internal double bond. However, treatment of 19 with acids (H₂SO₄ or BF₃) did not provide diene 20; the starting material remained unchanged (Scheme 6).

We reasoned that this resistance to the elimination of silanol might result from the presence of the bulky substituent located at the terminal position (TBDPS ether), so deprotection of this position might solve the problem. Treatment of 19 with fluoride anion not only removed this silyl group but also induced the Peterson olefination providing the Z-diene 21. This Z-diene was thus used to test our hypothesis (shown in Scheme 3) of the convenient preparation of the “inverted” trienes and their subsequent application in the synthesis of bicyclic derivatives via a cyclization reaction as reported by Evans for triene 14 (cf. Scheme 4).

Alcohol 21 was oxidized to the corresponding aldehyde 22 which reacted with phosphonate 23 [24], to afford triene 24 with the E-configuration across the newly created double bond (Scheme 6). This triene was subjected to the cyclization induced by Me₂AlCl; no reaction was, however, noticed. Application of other Lewis acids, as well as, high pressure (10 kbar) also did not give any positive result. This lack of cyclization was very surprising, especially in the context of the results obtained by Evans.

We prepared also two other trienes: 25 and 26 by reaction of aldehyde 22 with appropriate phosphoranes: Ph₃P=CHCO₂Me and Ph₃P=CHCO₂Me. None of the resulting trienes, however, underwent cyclization (Scheme 6).

Why could the cyclization of compounds—similar to those successfully used in Evans’ synthesis—not be realized? Is it a result of only the different configuration across the double bond in a diene system (Z in 24 in our case vs. E in 14 in Evans case)? Or maybe other reasons are responsible for that strange result. This phenomenon is not clear.

We turned, therefore, our attention to shorter analogs being precursors of perhydroindane derivatives.

2.2. Synthesis of Derivatives of D-Xylose with the Diene System at the C1

The synthesis was initiated from known lactone 27 [25], obtained by an oxidation of 2,3,4-tri-O-benzyl-D-xylose. It was reacted with the in situ generated complex of Me₃Al and N,O-dimethylhydroxylamine which provided the Weinreb amide 28. Since this compound was relatively unstable (easily underwent decomposition to 27), it was converted immediately into silylated derivative 29 and then into aldehyde 30. Reactivity of 30 was similar to the previously obtained derivatives. Its conversion into 31 followed the same route as for D-glucose derivatives (depicted in Scheme 1); this silanol (31) was also unreactive under the acidic conditions and underwent conversion into Z-diene 32 with the simultaneous removal of the silyl block upon treatment with fluoride anion (Scheme 7). The configuration of the internal double bond in the diene part was proven by ¹H NMR data in which the coupling constant J = 11.2 Hz was observed (see Scheme 7).

Compound 32 was converted into aldehyde 33 and further into triene 34, with the E-configuration across the newly created double bond (J = 15.9 Hz). Cyclization of this triene induced with Me₂AlCl provided bicyclic compound 35 as a single stereoisomer (Scheme 3); only two olefinic signals at δ = 128.0 and 124.3 ppm were seen in the ¹³C NMR spectrum.

The configuration of the product was assigned by the Nuclear Overhauser Effect (NOE) measurement (Figure 1).

Small NOE values between the H1-H7a and H3-H3a confirmed structure 35 and—at the same time—excluded the alternative one: 35a in which the strong H1-H7a and H3-H3a interaction should have been observed.

3. Materials and Methods

3.1. General

NMR spectra were recorded in CDCl₃ (internal Me₄Si) with a Varian AM-600 (600 MHz ¹H, 150 MHz ¹³C) spectrometer (Sugar Land, TX, USA) at rt. Chemical shifts (δ) are reported in ppm relative to Me₄Si (δ 0.00) for ¹H and residual chloroform (δ 77.00) for ¹³C. All significant resonances (carbon skeleton) were assigned by COSY (¹H-¹H), HSQC (¹H-¹³C), and HMBC (¹H-¹³C) correlations. The relative configuration of the stereogenic centers was assigned on the basis of 1D-NOESY spectra. Mass spectra (ESI) were recorded with an Applied Biosystems 4000 Q-TRAP (low resolution) (Toronto, ON, Canada) and Waters AutoSpec Premier (Waters, Milford, MA, USA) or Waters MALDISynapt G2-S HDMS (high resolution) spectrometers (Manchester, UK). HPLC analyses were conducted on Merck-Hitachi apparatus (Darmstadt, Germany) equipped with Merck LiChrospher 100 RP-18 (250 × 0.4 mm, 5 μm) column and UV detector. Column chromatography was performed on silica gel 60 (70–230 mesh, Merck. Flash chromatography was performed on Buchi glass columns packed with silica gel 60 (230–400 mesh, Merck), using Knauer Smartline system with a Buchi fraction collector. Reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA), Alfa Aesar (Tianjin, China) or ABCR (Karlsruhe, Germany), and used without purification. Thin-layer chromatography was carried out on silica gel 60 F₂₅₄ (Merck). The organic solutions were dried over MgSO₄.

The scans of the NMR data for all compounds are provided as Supplementary Materials.

3.1.1. 2,3,4,5-Tetra-O-benzyl-6-O-tert-butyl-diphenylsilyl-D-glucose 17

To a cooled to 0 °C solution of 2,3,4,5-tetra-O-benzyl-D-glucose propane-1,3-diyl dithioacetal [20] (16; 21.89 g; 34.7 mmol) and imidazole (4.74 g, 69.4 g, 2.0 eq) in methylene chloride (300 mL), tert-butyl-diphenylsilyl chloride (9.6 mL, 37.5 mmol, 1.1 equiv.) was added dropwise within 1 h and the mixture was stirred overnight at room temperature. Water (150 mL) was added, the layers were separated and the organic solution was washed with 1M H₂SO₄ (100 mL) and water (100 mL), dried, concentrated, and the crude product was isolated by column chromatography (hexanes-ethyl acetate 7:1→3:1) to afford the 6-O-protected derivative (27.47 g; 91%) as an oil.

¹H NMR δ: 7.69−7.52 (m, 4H), 7.48−7.15 (m, 26H), 4.88 (d, J = 11.5 Hz, 1H), 4.76−4.57 (m, 5H), 4.49 (d, J = 11.2 Hz, 1H), 4.38 (d, J = 11.5 Hz, 1H), 4.23 (d, J = 4.8 Hz, 1H), 4.07 (t, J = 5.2 Hz, 1H), 3.99−3.91 (m, 2H), 3.85−3.81 (m, 1H), 3.69 (dd, J = 6.2, 4.6 Hz, 1H), 3.54 (dt, J = 5.6, 4.3 Hz, 1H), 2.87−2.74 (m, 1H), 2.77−2.53 (m, 3H), 1.97−1.91 (m, 1H), 1.91−1.81 (m, 1H), 1.10 (s, 9H);

¹³C NMR δ: 138.9, 138.7, 2 × 138.4, 135.9–127.0, 81.9, 79.8, 79.9, 78.4, 75.2, 74.7, 73.8, 72.5, 62.4, 49.5, 30.0, 29.5, 27.0, 26.2, 19.3.

HR-MS: m/z = 868.3647; calcd for C₅₃H₆₀O₅S₂SiNa [M + Na]⁺: 868.3651.

To a solution of the above prepared compound (4.36 g; 5.02 mmol) in MeCN:CH₂Cl₂:H₂O (8:1:1; 50 mL), Dess-Martin reagent (4.47 g, 10.0 mmol, 2.0 eq) was added, the mixture was stirred at room temperature overnight, and concentrated. The residue was purified by column chromatography (hexanes-ethyl acetate 7:1→3:1) affording the title product 17 (3.28 g; 84%) (Figure 2), which was used immediately in the next step.

LR-MS: m/z = 833 [C₅₁H₅₈O₇SiNa (M + MeOH+Na)⁺].

3.1.2. Olefin 19

Generation of the titanium reagent 18: To a cooled to −78 °C solution of allyltrimethylsilane (3.7 g, 32.4 mmol, 10.0 eq) in dry THF (32 mL), a solution of 2.5 M BuLi in hexane (12 mL, 29.1 mmol, 9.0 eq.) was added within 1h with a syringe pump; after another 30 min. the mixture became yellowish. Then, a solution of 1.0 M ClTi(OⁱPr)₃ in methylene chloride (29 mL) was added within 30 min (syringe pump) and the red mixture was stirred for another 30 min.

To such prepared reagent 18, a solution of 17 (2.10 g, 3.19 mmol) in dry THF (6.4 mL) was added within 1h, the mixture was stirred overnight at −78 °C (using immersion cooler with temperature control Huber TC100E, temperature range −100 to +40 °C) and partitioned between water (70 mL) and ether (70 mL). The white precipitate was filtered off and discarded; the organic layer was separated, washed with brine, and concentrated to afford a crude mixture of (anticipated) anti-isomers, pure enough to be used in the next steps (Figure 3).

LR-MS: m/z = 915 [C₅₆H₆₈O₆Si₂Na (M + Na)⁺].

3.1.3. Dienoalcohol 21

To a solution of crude 19 obtained above in THF (16 mL) a solution of 1.0 M TBAF in THF (16 mL, 16.0 mmol, 5.0 eq.) was added and the mixture was stirred at room temperature overnight. Then it was concentrated and the residue was subjected to column chromatography (hexane-ethyl acetate, 92:8→36:64) to afford the title product 21 (1.11 g, 73% over two steps) as an oil (Figure 4).

¹H NMR δ: 7.39–7.17 (m, 20H, arom.), 6.51 (ddd, J = 16.6, 11.0 and 10.1 Hz, 1H, H-2), 6.29 (t, J = 11.2 Hz, 1H, H-3), 5.46 (t, J = 10.3 Hz, 1H, H-4), 5.28 (d, J = 16.7 Hz, 1H, H-1), 5.11 (d, J = 10.1 Hz, 1H, H-1′), 4.86 (d, J = 11.4 Hz, 1H, OCH₂Ph), 4.73 (d, J = 11.4 Hz, 1H, OCH₂Ph), 4.68 (d, J = 11.5 Hz, 1H, OCH₂Ph), 4.63–4.57 (m, 3H, H-5 and 2×OCH₂Ph), 4.49 (d, J = 11.6 Hz, 1H, OCH₂Ph), 4.37 (d, J = 11.6 Hz, 1H, OCH₂Ph), 4.33 (d, J = 11.7 Hz, 1H, OCH₂Ph), 3.90 (t, J = 4.9 Hz, 1H, H-8), 3.85 (ddd, J = 12.0, 5.4, and 4.0 Hz, 1H, H-9), 3.77 (ddd, J = 11.7, 6.9, 4.0 Hz, 1H, H-9′), 3.73 (dd, J = 6.1, 4.4 Hz, 1H, H-6), 3.66 (dt, J = 5.5 and 4.0 Hz, 1H, H-7), 2.15 (dd, J = 6.9 and 5.5 Hz, 1H, OH);

¹³C NMR δ: 138.8, 138.7 and 2 × 138.3(quat. benzyl), 134.2 (C-3), 131.9 (C-2), 128.6−127.6 (arom. and C-4), 120.4 (C-1), 81.9 (C-6), 79.7 (C-7), 79.3 (C-8), 75.6 (C-5), 75.2, 74.5, 71.7 and 70.5 (4×OCH₂Ph), 60.8 (C-9).

HR-MS: m/z = 587.2770; calcd for C₃₇H₄₀O₅Na [M + Na]⁺: 587.2773.

3.1.4. Dienoaldehyde 22

To a cooled to 0 °C solution of alcohol 21 (350 mg, 0.62 mmol) and TEMPO (1.0 mg; 6.0 μmol) in dry CH₂Cl₂ (8 mL), trichloroisocyanuric acid (155 mg; 0.66 mmol; 1.1 eq) was added and the mixture was stirred for 15 min. Then it was filtered through short pad of Celite, the filtrate was diluted with Et₂O (6.0 mL) and washed with 5% Na₂S₂O₃ (2.0 mL), 1M NaOH (5 mL), 1M H₂SO₄ (5 mL), and water (3.0 mL). The organic phase was dried and concentrated, and the crude aldehyde was used immediately in the next step (Figure 5).

LR-MS: m/z = 617 [C₃₈H₄₂NO₆Na (M + MeOH + Na)⁺].

3.1.5. Triene 24

To a solution of aldehyde 22 (170 mg, 0.3 mmol) and phosphonate 23 [21] (120 mg, 1.5 eq.) in dry CH₃CN (3 mL), LiBr (40.5 mg, 0.466 mmol, 1.5 eq) was added followed by di-isopropylethylamine (80 μL, 0.466 mmol, 1.5 eq) and the mixture was stirred for 20 h. It was then concentrated and the crude product was purified by column chromatography (hexane 100% then: hexane-ethyl acetate 92:8→36:64) (Figure 6).

¹H NMR δ: 7.46 (d, J = 15.6, 1H, H-10), 7.35–7.16 (m, 21H, arom. and H-9), 6.51 (ddd, J = 16.7, 11.3 and 10.1 Hz, 1H, H-2), 6.27 (t, J = 11.2 Hz, 1H, H-3), 5.45 (dd, J = 11.1 and 9.7 Hz, 1H, H-4), 5.25 (d, J = 16.7 Hz, 1H, H-1), 5.09 (d, J = 10.1 Hz, 1H, H-1′), 4.84 (d, J = 11.5 Hz, 1H, OCH₂Ph), 4.67–4.59 (m, 3H, 2×OCH₂Ph and H-5), 4.56 (d, J = 11.7 Hz, 1H, OCH₂Ph), 4.55–4.47 (m, 2H, 2×OCH₂Ph), 4.38–4.30 (m, 3H, OCH₂Ph and 2×H-13), 4.24 (dd, J = 6.8 and 5.6 Hz, 1H, H-8), 4.14 (d, J = 11.4 Hz, 1H, OCH₂Ph), 3.97 (qdd, J = 11.1, 8.9 and 7.1 Hz, 2H, 2×H-14), 3.81 (dd, J = 5.6 and 4.2 Hz, 1H, H-7), 3.74 (dd, J = 6.3 and 4.2 Hz, 1H, H-6);

¹³C NMR δ: 164.5 (C-12), 153.3 (C-11), 147.6 (C-9), 138.9, 138.7, 138.4 and 137.9 (quat. benzyl), 134.1 (C-3), 132.1 (C-2), 128.6−127.3 (arom. and C-4), 122.3 (C-10), 120.2 (C-1), 82.0 (C-7), 81.6 (C-6), 79.2 (C-8), 75.5 (C-5), 75.3, 74.2, 71.4, 70.4 (4×OCH₂Ph), 62.1 (C-13), 42.7 (C-14).

HR-MS: m/z = 696.2922; calcd for C₄₂H₄₃NO₇Na [M + Na]⁺: 696.2937.

3.1.6. Triene 25

Aldehyde 22 (45 mg) and Ph₃P=CHCO₂Me (54 mg; 2.0 eq.) were dissolved in dry benzene and stirred at room temperature for 16 h. The mixture was concentrated and the product was isolated by column chromatography (hexanes-ethyl acetate, 3:1→2:1) as a colorless oil in 74% yield (36.5 mg) (Figure 7).

¹H NMR δ: 7.43–7.18 (m, 20H), 7.01 (dd, J = 15.8, 6.6 Hz, 1H, H-9), 6.45 (ddd, J = 16.7, 11.2, 10.0 and 6.0 Hz, 1H, H-2), 6.26 (t, J = 11.2 Hz, 1H, H-3), 6.01 (d, J = 15.9 Hz, 1H, H-10), 5.45 (t, J = 10.3 Hz, 1H, H-4), 5.26 (d, J = 16.7 Hz, 1H, H-1), 5.09 (d, J = 10.0 Hz, 1H, H-1′), 4.82 (d, J = 11.5 Hz, 1H, OCH₂Ph), 4.63 (m, 2H, 2×OCH₂Ph), 4.59–4.53 (m, 2H, OCH₂Ph and H-5), 4.51 (d, J = 11.3 Hz, 1H, OCH₂Ph), 4.46 (d, J = 11.5 Hz, 1H, OCH₂Ph), 4.32 (d, J = 11.7 Hz, 1H, OCH₂Ph), 4.15 (m, 2H, OCH₂Ph and H-8), 3.81 (s, 3H, OMe), 3.79 (dd, J = 5.6 and 4.4 Hz, 1H, H-7), 3.73 (m, 1H, H-6);

¹³C NMR δ: 166.3 (C-11), 146.0 (C-9), 138.7, 138.4, 138.1 and 137.8 (quat. benzyl), 133.9 (C-3), 131.8 (C-2), 128.5−127.3 (arom. and C-4), 123.3 (C-10), 120.2 (C-1), 81.6 and 81.5 (C-6 and C-7), 78.8 (C-8), 75.2 (OCH₂Ph), 75.1 (C-5), 74.1, 71.1,and 70.3 (3×OCH₂Ph), 51.7 (OMe).

HR-MS: m/z = 641.2886; calcd for C₄₀H₄₂O₆Na [M + Na]⁺: 641.2879.

3.1.7. Triene 26

This triene was prepared analogously as 25 from aldehyde 22 (47 mg) and Ph₃P=CHCOMe (55 mg; 2.0 eq) as a colorless oil in 76% yield (36.5 mg) (Figure 8).

¹H NMR δ: 7.36–7.19 (m, 20H, arom.), 6.78 (dd, J = 16.3, 6.5 Hz, 1H, H-9), 6.46 (dt, J = 16.2, 10.6 Hz, 1H, H-2), 6.28 (t, J = 11.1 Hz, 1H, H-3), 6.18 (d, J = 16.2 Hz, H-10), 5.45 (t, J = 10.4 Hz, 1H, H-4), 5.27 (d, J = 16.7 Hz, 1H, H-1), 5.11 (dd, J = 10.0 and 1.7 Hz, 1H, H-1′), 4.85 (d, J = 11.4 Hz, 1H, OCH₂Ph), 4.64–4.56 (m, 4H, 3×OCH₂Ph and H-5), 4.53 (d, J = 11.4 Hz, 1H, OCH₂Ph), 4.45 (d, J = 11.6 Hz, 1H, OCH₂Ph), 4.32 (d, J = 11.7 Hz, 1H, OCH₂Ph), 4.18 (d, J = 11.6 Hz, 1H, OCH₂Ph), 4.15 (ddd, J = 6.5 and 5.3 Hz, 1H, H-8), 3.81 (t, J = 4.8 Hz, 1H, H-7), 3.70 (dd, J = 6.3 and 4.3 Hz, 1H, H-6), 2.11 (s, 3H, H-12);

¹³C NMR δ: 198.2 (C-11), 144.7 (C-9), 138.6, 138.3, 138.1 and 137.8 (quat. benzyl), 134.1 (C-3), 132.6 (C-10), 131.7 (C-2), 128.5−127.4 (arom. and C-4), 120.3 (C-1), 81.7 and 81.6 (C-6 and C-7), 79.3 (C-8), 2 × 75.3 (C-5 and OCH₂Ph), 74.0, 71.3, 70.3 (3×OCH₂Ph), 26.9 (C-12).

HR-MS: m/z = 625.2936; calcd for C₄₀H₄₂O₅Na [M + Na]⁺: 625.2930.

3.1.8. Weinreb Amide 29

To a cooled to 0 °C suspension of MeNHOMe x HCl (5.85 g, 60.0 mmol, 3.0 eq) in dry CH₂Cl₂ (175 mL), a 2M solution of Me₃Al in toluene (30 mL, 60 mmol, 2 eq.) was added dropwise during 30 min. by a syringe pump. The mixture was stirred for an additional 30 min., then lactone 27 (8.37 g, 20 mmol) in dry CH₂Cl₂ (25 mL) was added within 30 min. by a syringe pump, and the mixture was stirred at room temperature for 3 h. Aqueous H₂SO₄ (1M solution, 100 mL) was carefully added and the organic phase was separated, washed with water (100 mL), brine (100 mL), and dried.

Imidazole (4.08 g, 60 mmol, 3.0 eq) was added to this containing crude 28 and the resulting mixture was cooled to 0 °C. A solution of tert-butyldiphenylchlorosilane (7.8 mL, 30.0 mmol, 1.5 eq.) in CH₂Cl₂ (20 mL) was added dropwise within 1 h by a syringe pump and the mixture was stirred for additional 16 h. Aqueous H₂SO₄ (1M solution, 50 mL) was carefully added, the organic phase was separated, washed with water (100 mL), brine (100 mL), dried, and the crude product was purified by column chromatography (hexanes-ethyl acetate: 13:1→7:1) to give the title product 29 (12.35 g, 86% over two steps) as a colorless oil (Figure 9).

¹H NMR δ: 7.49–7.42 (m, 3H, arom.), 7.36–7.22 (m, 15H, arom.), 7.18–7.15 (m, 2H, arom.), 4.78–4.71 (m, 2H, 2×OCH₂Ph), 4.60–4.51 (m, 4H, H-5 and 3×OCH₂Ph), 4.35 (d, J = 11.4 Hz, 1H, OCH₂Ph), 3.72–3.65 (m, 3H, H-2, H-3 and H-4), 3.62 (s, 3H, OCH₃), 3.41 (m, 1H, H-4′), 3.15 (bs, 3H, NCH₃), 1.07 [s, 9H, OSiPh₂C(CH₃)₃];

¹³C NMR δ 170.4 (C-1), 138.5, 138.3 and 138.0 (quat. benzyl), 135.8, 133.3, 129.6 and 129.3−126.5 (arom.), 82.3 (C-3), 79.6 (C-4), 76.1 (C-2), 74.2, 73.3 and 71.6 (3×OCH₂Ph), 61.4 (OCH₃), 32.8 (NCH₃), 26.8 [OSiPh₂C(CH₃)₃], 18.8 [OSiPh₂C(CH₃)₃].

HR-MS: m/z = 740. 3387; calcd for C₄₄H₅₁NO₆SiNa [M + Na]⁺: 740.3383.

3.1.9. 2,3,4-Tri-O-benzyl-5-O-tert-butyl-diphenylsilyl-D-xylose 30

To a cooled to 0 °C solution of amide 29 (2.94 g, 4.10 mmol, 1.0 eq.) in dry Et₂O (41 mL), LiAlH₄ (0.19 g, 5.12 mmol, 1.25 eq.) was added in three portions within 15 min., and the mixture was stirred for 1 h. Aqueous H₂SO₄ (1M solution, 20 mL) was added, the organic phase was separated, washed with water (20 mL) and brine (20 mL), dried, and concentrated. The crude product was purified by column chromatography (hexanes→hexanes-ethyl acetate: 68:32) to give the aldehyde 30 (2.05 g, 76%) as a colorless oil (Figure 10). This product was used immediately in the next step.

LR-MS: m/z = 713 [C₄₃H₅₀O₆SiNa (M + MeOH + Na)⁺].

3.1.10. Silanol 31

This compound was prepared analogously as 19, from 30 (2.79 g, 4.23 mmol) as a colorless oil as a mixture of (anticipated) two anti-isomers (Figure 11).

LR-MS: m/z = 795 [C₄₈H₆₀O₅Si₂Na (M + Na)⁺].

3.1.11. Dienoalcohol 32

This compound was prepared, analogously as 21, from 31. It was purified by column chromatography (hexanes→hexanes-ethyl acetate: 36:64) to give title dienalcohol 32 as a colorless oil (1.36 g, 72% over two steps) (Figure 12).

¹H NMR δ: 7.37–7.22 (m, 15H, arom.), 6.58 (ddd, J = 16.7, 11.2 and 10.1 Hz, 1H, H-2), 6.27 (t, J = 11.2 Hz, 1H, H-3), 5.53 (t, J = 10.3 Hz, 1H, H-4), 5.29 (d, J = 16.7 Hz, 1H, H-1), 5.16 (d, J = 10.2 Hz, 1H, H-1′), 4.78 (d, J = 11.4 Hz, 1H, OCH₂Ph), 4.73 (d, J = 11.4 Hz, 1H, OCH₂Ph), 4.64–4.55 (m, 4H, H-5 and 3×OCH₂Ph), 4.35 (d, J = 11.7 Hz, 1H, OCH₂Ph), 3.72 (ddd, J = 11.3, 6.6 and 4.2 Hz, 1H, H-8), 3.69–3.65 (m, 2H, H-6 and H-7), 3.55 (ddd, J = 11.4, 5.6 and 3.5 Hz, 1H, H-8′), 2.12 (t, J = 6.3 Hz, 1H, OH);

¹³C NMR δ: 138.6, 138.4 and 138.1 (quat. benzyl), 133.8 (C-3), 132.0 (C-2), 128.8−127.8 (arom. and C-4), 120.2 (C-1), 82.1 (C-6 or C-7), 79.7 (C-6 or C-7), 75.2 (OCH₂Ph), 74.8 (C-5), 72.8 and 70.6 (2×OCH₂Ph), 61.7 (C-8).

HR-MS: m/z = 467.2180; calcd for C₂₉H₃₂NO₄Na [M + Na]⁺: 467.2188.

3.1.12. Triene 34

Alcohol 32 (244 mg, 0.55 mmol) was oxidized as described for 22 and the resulting product was purified by column chromatography (hexanes 100%→hexanes-ethyl acetate: 1:2) to afford the corresponding aldehyde 33 (204 mg, 84%) as an oil. LR-MS: m/z = 497 [C₃₀H₃₄O₅Na (M + MeOH + Na)⁺].

This aldehyde (96 mg, 0.216 mmol) was reacted with phosphonate 23 analogously as for 22. The crude product was purified column chromatography (hexanes 100%→hexanes-ethyl acetate: 90:10→20:80) to give the title triene 34 as a colorless oil (87.3 mg, 73%) (Figure 13).

¹H NMR δ: 7.46 (d, J = 15.9, 1H, H-9), 7.35–7.16 (m, 16H, arom. and H-8), 6.51 (ddd, J = 16.7, 11.3 and 10.1 Hz, 1H, H-2), 6.27 (t, J = 11.2 Hz, 1H, H-3), 5.45 (dd, J = 11.1 and 9.7 Hz, 1H, H-4), 5.25 (d, J = 16.7, 1H, H-1), 5.09 (d, J = 10.1 Hz, 1H, H-1′), 4.74 (d, J = 11.5 Hz, 1H, OCH₂Ph), 4.67 (d, J = 11.3 Hz, 1H, OCH₂Ph), 4.58–4.30 (m, 6H, H-5, H-12, H-12′ and 4×OCH₂Ph), 3.97 (m, 2H, H-13 and H-13′), 3.81−3.74 (m, 2H, H-6 and H-7);

¹³C NMR δ: 164.3 (C-10), 153.1 (C-11), 147.4 (C-8), 138.9, 138.7 and 138.1 (quat. benzyl), 134.0 (C-3), 132.1 (C-2), 128.5−127.2 (arom. and C-4), 122.5 (C-9), 120.1 (C-1), 82.0 and 79.8 (C-6 and C-7), 75.5 (×OCH₂Ph), 75.0 (C-5), 72.4 and 70.4 (2×OCH₂Ph), 62.1 (C-12), 42.7 (C-13).

HR-MS: m/z = 553.2456; calcd for C₃₄H₃₅NO₆Na [M + Na]⁺: 553.2464.

3.1.13. Bicyclic Compound 35

To a cooled to −30 °C solution of 34 (39.6 mg, 7.86–10⁻² mmol) in dry CH₂Cl₂ (1.0 mL) a 1.0 M solution of Me₂AlCl (118 μL, 0.118 mmol, 1.5 eq.) was carefully added and the mixture was stirred for 5 h. Then the mixture was concentrated and the crude product was purified by preparative TLC (n-heptane-MTBE: 6:4) to give the cyclic product 35 as colorless oil (26.9 mg, 68%) (Figure 14).

¹H NMR δ: 7.44–7.16 (m, 15H, arom.), 5.82–5.76 (m, 1H, H-4), 5.68–5.62 (m, 1H, H-5), 4.69–4.58 (m, 4H, 4×OCH₂Ph), 4.59–4.51 (m, 2H, 2×OCH₂Ph), 4.34 (td, J = 9.0 and 6.8 Hz, 1H, H-10), 4.28 (td, J = 9.1 and 7.0 Hz, 1H, H-10′), 4.03 (t, J = 5.0 Hz, 1H, H-2), 3.99–3.85 (m, 3H, H-7, H-11 and H-11′), 3.75 (t, J = 5.5 Hz, 1H, H-3), 3.60 (t, J = 5.6 Hz, 1H, H-1), 2.94 (brs, 1H, H-3a), 2.64 (q, J = 7.2 Hz, 1H, H-7a), 2.26 (dtd, J = 17.8, 4.2 and 2.0 Hz, 1H, H-6), 2.08 (dtd, J = 17.8, 3.8 and 1.9 Hz, 1H, H-6′);

¹³C NMR δ: 175.4 (C-8), 152.8 (C-9), 138.5, 138.4 and 138.3 (quat. benzyl), 128.4−127.5 (arom. and C-4), 124.3 (C-5), 90.3 (C-2), 88.5 (C-3), 83.4 (C-1), 72.0, 71.9 and 71.5 (3×OCH₂Ph), 61.8 (C-10), 42.7 (C-11), 2 × 40.4 (C-3a and C-7a), 36.9 (C-7), 25.8 (C-6).

HR-MS: m/z = 553.2478; calcd for C₃₄H₃₅NO₆Na [M + Na]⁺: 553.2464.

Configuration was established on the basis of 1D NOE (see Figure 1 in the text).

4. Conclusions

We have proposed a convenient and simple route to optically pure bicyclic carbasugar derivatives from D-xylose derivative. The methodology is based on the introduction of the Z-diene system at the anomeric position of a sugar and an olefinic unit at the terminal position. The so obtained triene underwent smooth and highly stereoselective cyclization providing the bicyclic derivative a good yield. The analogous triene prepared from the D-glucose derivative did not, however, undergo any cyclization even under high pressure. We do not know yet the reason for such peculiar behavior.

It is very likely that our methodology leading to bicyclic sugar mimetics can be applied to other simple sugars containing 5-carbon atoms in the chain. Very problematic, however, is the application of our methodology to hexoses.