Convergent Synthesis of (+)-Carambolaflavone A, an Antidiabetic Agent using a Bismuth Triflate-Catalyzed C-Aryl Glycosylation

Abstract

We describe a convergent total synthesis of carambolaflavone A, a natural flavonoid C-aryl glycoside with significant antihyperglycemic properties. The synthesis features a bismuth triflate-catalyzed stereoselective C-aryl glycosylation of a flavan derivative and an appropriately protected D-fucose derivative as the key step. Inexpensive and non-toxic bismuth triflate provided the best results among various other Lewis acids screened for this C-aryl glycosylation. The method can be utilized for the synthesis of other bioactive C-glycosylflavonoids. The glycosylation partners were synthesized from commercially available (±)-naringenin and D-(+)-galactose, respectively. An oxidative bromination and elimination reaction sequence was utilized to construct the flavone. The natural product is obtained in 13 steps (longest linear sequence) from D-(+)-galactose.

Graphical Abstract

A convergent synthesis of carambolaflavone A, using a bismuth triflate-catalyzed stereoselective C-aryl glycosylation of a flavan derivative, is reported.

Introduction

Diabetes Mellitus is a chronic metabolic disease in which hyperglycemia, or high blood glucose, results from the malfunction of insulin production in the pancreas.^1,2 Type 1 diabetes is characterized by failure of the pancreas to produce enough insulin. In Type 2 diabetes, pancreas produces insulin, but the body is unable to use it effectively.¹ Type 2 diabetes is more common and an estimated 462 million individuals were affected in 2019.^3,4 Diabetes is recognized as a major public health concern around the globe. The disease impacts quality of life and functional capabilities of patients, leading to significant morbidity and premature mortality.^5,6 The prevalence of diabetes is increasing. When not controlled, diabetes can cause serious health risks such as heart attack, stroke, kidney failure, and blindness.^7,8 Currently, there is no cure for diabetes. While insulin is required for treatment of type 1 diabetes, type 2 diabetes can be treated using many types of approved antidiabetic medications in conjunction with a healthy diet and exercise. Many approved drugs have greatly helped to manage the diabetes problem, the majority of drugs are associated with risks and side effects including hypotension, ketoacidosis, kidney injury, and increased susceptibility to fungal and bacterial infection.^9,10 Therefore, development of new, more effective antihyperglycemic agents with fewer side effects is needed for the long-term treatment of this chronic ailment.

Natural products continue to be an important source for structurally diverse and bioactive molecules for drug development.^11,12 The dietary flavonoids, especially their glycosidic derivatives, are ubiquitous in the plant kingdom and are often prevalent in human diets. Both O-glucosides and C-glycosides of flavonoids have shown diverse bioactivity.^13,14 A number of flavonoid glycosides have been shown to possess significant antidiabetic properties.^15,16 Two representative flavonoid glycosides, carambolaflavone A (1, Figure 1) and it’s α-rhamnosyl derivative, carambolaflavone B (2), were isolated from the leaves of the starfruit tree, Averrhoa Carambola, in 2005.^17,18 These carambolaflavones possess C-aryl glycosidic linkage. Preliminary biological studies showed that both compounds can lower acute blood glucose. Further investigation revealed that carambolaflavone A promoted insulin secretion and potentiated glucose-induced insulin secretion in hyperglycemic rats. In addition, carambolaflavone A stimulated glycogen synthesis in rat soleus muscle.¹⁸ This result indicated that carambolaflavones and their structural variants may serve as potential leads for antihyperglycemic drug development.

Figure 1.

Proposed and revised structures of carambolaflavones A and B.

The intriguing bioactivity and structure of carambolaflavone A, generated much interest in synthesis and structural studies. Sun and co-workers reported the total synthesis and structural revision of carambolaflavone A in 2018.¹⁹ The revised structure contains a D-sugar unit connected to the flavone derivative as represented in structure 1b. Their synthetic strategy relies on a Sc(OTf)₃-catalyzed C-aryl glycosylation of an acetophenone derivative, followed by a late stage construction of the flavone system with a Baker-Venkataraman rearrangement.^20,21 As part of our interest in the exploration of chemistry and biology of C-glycosidic flavonoids, we sought to develop a practical and convergent synthesis of (+)-carambolaflavone A. Herein, we report a convergent synthesis of (+)-carambolaflavone A utilizing a bismuth triflate-catalyzed stereoselective C-aryl glycosylation as one of the key steps. We investigated other related Lewis acids for this transformation, but bismuth triflate-catalyzed reaction provided the best results. The flavone and the glycosidic parts were constructed from readily available starting materials. The route is amenable towards the synthesis of derivatives for medicinal chemistry exploration.

Results and discussion

Our synthetic plan for the revised structure of (+)-carambolaflavone A 1b is shown Scheme 1. Carambolaflavone A is a C-aryl glycoside with β-glycosidic linkage in which the large flavonoid segment is in the equatorial position. We planned to assemble (+)-carambolaflavone A by C-glycosylation of appropriately protected flavan derivative 3 and protected D-fucose derivative 4 followed by conversion of the resulting C-glycoside to 1b. The synthesis of flavonoids generally involves condensation of 2-hydroxyacetophenone and benzaldehyde derivative to provide the corresponding 2-hydroxychalcone, the basic skeleton of flavonoids.^22,23 However, direct C-glycosylation of the flavone derivative leads to decomposition of sensitive flavone molecules. Oyama and Kondo previously addressed this issue by direct C-glycosylation of a flavan and perbenzyl glucosyl fluoride as the glycosyl donor in the presence of a BF₃•OEt₂ and DTBMP.²⁴ We planned to investigate direct C-glycosylation of flavan derivative 3 using readily prepared acetate or benzoate derivatives in the presence of metal triflate as the catalyst to provide access to bioactive flavonoids. The majority of previous methodologies for C-glycoside synthesis rely upon scandium triflate-mediated coupling of electrophilic sugar derivatives with glycosyl anions.^25,26 Since carambolaflavone A contains a β-glycosidic linkage with a large flavonoid in the equatorial position, we planned to explore glycosylation conditions under thermodynamic conditions, which would likely provide more stable β-diastereomer. The requisite protected flavan derivative 3 can be synthesized conveniently from commercially available (±)-naringenin 5. The synthesis of D-fucose derivative 4 would be carried out from commercially available and inexpensive D-galactose 6.

Scheme 1.

Retrosynthetic strategy for (+)-carambolaflavone A.

The synthesis of a flavan derivative corresponding to 3 from commercially available (±)- naringenin 5 is shown in Scheme 2. Our synthesis of protected flavan derivative involves a modified procedure.^24,27 Compound 5 was reacted with anhydrous K₂CO₃ and benzyl bromide in acetone at 23 °C to 56 °C for 12 h. The resulting monobenzylated derivative was subjected to acylation with acetylchloride in pyridine at 0 °C to 23 °C for 1 h. This has resulted in diacetate derivative 7 in 69% yield over two steps. Diacetate 7 was reacted with NaBH₄ in a mixture (2:1) of dioxane and water at 0 °C for 45 min to furnish a protected flavan derivative 8 as a racemic mixture in 91% yield.

Scheme 2.

Synthesis of flavan derivative 8.

The synthesis of protected D-fucose derivatives is shown in Scheme 3. D-(+)-galactose was reacted with ZnCl₂ and acetone in the presence of a catalytic amount of H₂SO₄ at 23 °C for 15 h to yield diisopropylidene derivative 9 in 93% yield. The primary alcohol was conveniently converted to a primary iodide derivative using iodine and Ph₃P in the presence of imidazole in toluene at 80 °C for 12 h. Hydrogenolysis of the resulting iodide over Pd(OH)₂ in the presence of Et₃N in MeOH at 23 °C for 17 h to furnish fucose derivative 10 in 93% yield over two steps.²⁸ Isopropylidene derivative 10 was heated with 80% aqueous AcOH at 120 °C bath temperature for 3 h to provide the corresponding tetraol. Benzylation of the resulting tetraol using NaH and BnBr in DMF at 0 °C to 66 °C resulted in a mixture (stereoisomeric mixture at the anomeric center) of tetrabenzyl derivative 11 in 75% yield over two steps. Treatment of benzyl acetal 11 with 80% aqueous AcOH at 120 °C for 3 h furnished the corresponding hemiacetal in 74% yield. This was treated with acetic anhydride in pyridine in the presence of a catalytic amount of DMAP at 23 °C to furnish fucose derivative 12 in 63% yield over two steps. The 6-step synthesis uses inexpensive reagents, and it has the potential to be carried out on large scale. Acetate derivative 4 was previously prepared from 6 by a 6-step sequence that used a palladium-catalyzed deallylation as a key step.¹⁹ Stocker and co-workers produced fucose 4 from 6 using a 9-step sequence that utilized a thioglycoside intermediate.²⁹ Hemiacetal derived from 11 was also converted to other glycosyl donors, benzoate 13, and substituted benzoates 14, 15, and 16 in 38–82 % yield (see supporting information).

Scheme 3.

Synthesis of D-fucose derivatives 12-16.

Suzuki previously investigated C-aryl glycosylation reaction that utilizes an electrophilic sugar derivative under thermodynamic conditions using rare earth metal triflates as a Lewis acid catalyst.³⁰ They found Sc(OTf)₃ to be particularly effective. We decided to examine Suzuki conditions first.³⁰ Initially, we examined racemic flavan derivative 8 and a slight excess (1.2 equiv) of acetate glycosyl donor 12 in the presence of metal triflate catalysts (20 mol %) in CH₂Cl₂ at 23 °C for 20 h (Scheme 4). The results are shown in Table 1. As can be seen, the use of Sc(OTf)₃ as the catalyst, resulted in β-C-aryl glycoside 17 in 39% yield (entry 1). Due to the use of racemic favan derivative, we obtained 17 as a 1:1 mixture of inconsequential, inseparable diastereomers. Our subsequent conversion of flavan product 17 to the corresponding flavanone (19, Scheme 5) reveal that β- C-aryl glycoside was formed as a single anomer. We then screened other metal triflates. The use of Fe(OTf)₃ provided slightly lower yields of β-C-aryl glycoside 17 (entry 2). Dy(OTf)₃, Cu(OTf)₃,and Zn(OTf)₂ failed to produce any product and the starting material was recovered (entries 3–5). However, an inexpensive and nontoxic Lewis acid, Bi(OTf)_3, provided β-C-aryl glycoside 17 in 48% yield under the reaction conditions mentioned above (entry 6). Interestingly, bismuth triflate catalyzed C-aryl glycosylation has been little explored.³⁰ To improve yield of the C-aryl glycosylation, we then examined slight excess of the flavan component. The use of 1.5 equivalents of the flavan derivative 8 increased the yield to 72% (entry 7). With this modification, we examined other glycosyl donors. When benzoate derivative 13 was used, β-C-aryl glycoside 17 was obtained in 76% yield (entry 8). Substitution of the benzoate phenyl ring with electron donating or electron withdrawing groups was explored to modulate the C-aryl glycosylation reaction. The results are shown in Table 1 (entries 9–11). The best result was observed when benzoate 13 was used (entry 8). With β-C-aryl glycoside 17 in hand, we then focused our attention to the synthesis of carambolaflavone A.

Scheme 4.

C-aryl glycosylation of flavan derivatives

Table 1.

Lewis acid-catalyzed C-aryl glycosylation of flavan 8 with D-fucose derivatives

Entry	Glycosyl Donor	Flavan 8 (equiv)	Lewis Acid (20 mol%)	Yielda,b
1	12	(1.2)	Sc(OTf)3	39%
2	12	(1.2)	Fe(OTf)3	36%
3	12	(1.2)	Dy(OTf)3	—
4	12	(1.2)	Cu(OTf)2	—
5	12	(1.2)	Zn(OTf)2	—
6	12	(1.2)	Bi(OTf)3	48%
7	12	(1.5)	Bi(OTf)3	72%
8	13	(1.5)	Bi(OTf)3	76%
9	14	(1.5)	Bi(OTf)3	70%
10	15	(1.5)	Bi(OTf)3	75%
11	16	(1.5)	Bi(OTf)3	72%

^aAll reactions were run with 1 equiv of glycosyl donor and 20 mol % metal triflate in CH₂Cl₂ at 23 °C for 20 h.

^bIsolated yield of C-aryl glycosylation product after silica gel chromatography.

Scheme 5.

Synthesis of (+)-carambolaflavone A

The synthesis of (+)-carambolaflavone A is shown in Scheme 5. Our synthesis required the conversion of flavan to flavone derivative. Compound 17 was reacted with acetic anhydride in pyridine at 23 °C for 22 h to afford the corresponding acetate derivative. Benzylic oxidation of the resulting flavan derivative with ceric ammonium nitrate (CAN) in aqueous acetonitrile at 23 °C for 2 h furnished flavanone derivative 18 in 38% yield over two steps.²⁴ For the subsequent dehydrogenation reaction, flavanone 18 was subjected to oxidative bromination followed by elimination reaction with Ph₃P·HBr in DMSO at 80 °C for 10 h as described by Das and co-workers.³¹ These conditions provided protected flavone derivative 19 in 52% yield. For removal of protecting groups, flavone 19 was saponified with 1 M LiOH aqueous solution in methanol at 23 °C for 2 h. The resulting phenol derivative was exposed to hydrogenolysis to remove the benzyl protecting groups. This was carried out in a mixture (8:1) of ethanol and ethyl acetate in the presence of 10% Pd-C under a hydrogen-filled balloon at 23 °C for 2 h. This has provided synthetic (+)-carambolaflavone A (1b) in 50% yield after silica gel chromatography over two-steps. An analytical sample was prepared after HPLC purification using a semipreparative C-18 column. The spectroscopic data and optical rotation [α]_D²³ = +59 (c 0.1, MeOH) of our synthetic (+)-carambolaflavone A is in complete agreement with the previously reported data.^18,19

Experimental

All chemical and reagents were purchased from commercial suppliers and used without further purification unless otherwise noted. Solvents (THF, CH₂Cl₂, and MeCN) were purchased in anhydrous, unstabilized form and were purified using a solvent purification system. Other solvents were purchased and used as is. Reactions were run under an argon atmosphere unless noted otherwise. Magnetic stirring was used for all reactions. Glassware used in reactions was oven-dried unless otherwise noted. Reactions were heated using an oil bath on a hot plate equipped with a temperature probe. TLC analysis was conducted using glass-backed thin-layer silica gel chromatography plates (60 Å, 250 μm thickness, F-254 indicator, 2 × 5 cm). Compound spots were visualized by using a combination of shortwave UV (254 nm) and/or various stains (Phosphomolybdic acid, KMnO₄, or 2,4-dinitrophenylhydrazine) followed by heating on a hot plate. Flash chromatography was done using 230–400 mesh, 60 Å silica gel. ¹H NMR spectra were recorded on 400 or 800 MHz spectrometers. ¹³C NMR spectra were recorded on 100 or 200 MHz spectrometers. Chemical shifts are reported in parts per million and referenced to the deuterated residual solvent peak (CDCl₃, 7.26 ppm for ¹H and 77.16 ppm for ¹³C). NMR data are reported as δ value (chemical shift), J-value (Hz), and integration, where s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplet, dd = doublet doublets, and so on. Optical rotations were recorded on a Perkin Elmer 34l polarimeter. Low resolution mass spectra (LRMS) spectra were recorded using a quadrupole LCMS under positive electrospray ionization (ESI+). High-resolution mass spectrometry (HRMS) spectra were recorded at the Purdue University Department of Chemistry Mass Spectrometry Center. These experiments were performed under ESI+ and positive atmospheric pressure chemical ionization (APCI+) conditions using an Orbitrap XL Instrument.

4-(5-Acetoxy-7-(benzyloxy)-4-oxochroman-2-yl)phenyl acetate (7).

To a flask was added (±)-naringenin 5 (109 mg, 0.4 mmol), K₂CO₃ (61 mg, 0.44 mmol), and acetone (1 mL). The mixture was placed under argon and benzyl bromide (72 μL, 0.6 mmol) was added dropwise. The mixture was then heated to reflux and stirred overnight. The reaction was cooled to 23 °C and quenched with 2 mL of 1 M citric acid. The acetone was removed in vacuo and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The solid material was then washed with diethyl ether to afford the title compound (113 mg, 79%) as an amorphous white solid.

To a flask containing above benzyl derivative (58 mg, 0.16 mmol) was added 0.5 mL of pyridine and cooled to 0 °C. Acetyl chloride (56 μL,0.8 mmol) was then added dropwise. The reaction was warmed to 23 °C and stirred for 1 h. The reaction was then concentrated in vacuo and subsequently partitioned between sat. aq. NaHCO₃ solution and ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The crude material was subjected to Silica gel chromatography (30% EtOAc/hexanes) to afford 7 (62 mg, 87% yield) as a white foam. R_f = 0.22 (30% EtOAc/hexanes). ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 3.8 Hz, 5H), 7.15 (d, J = 8.6 Hz, 2H), 6.49 (d, J = 2.5 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 5.45 (dd, J = 13.4, 2.8 Hz, 1H), 5.07 (s, 2H), 2.99 (dd, J = 16.7, 13.4 Hz, 1H), 2.72 (dd, J = 16.7, 2.9 Hz, 1H), 2.39 (s, 3H), 2.31 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 188.7, 169.6, 169.4, 164.7, 164.2, 152.0, 151.0, 136.1, 135.5, 128.9, 128.6, 127.6, 127.5, 122.1, 108.2, 105.6, 100.5, 79.1, 70.7, 45.1, 21.2.

4-(7-(benzyloxy)-5-hydroxychroman-2-yl)phenyl acetate (8).

To a flask was added 7 (27 mg, 0.06 mmol) which was dissolved in 0.6 ml of a 2:1 mixture of 1,4-dioxane/water. The reaction was cooled to 0 °C and to it was added NaBH₄ (5 mg, 0.12 mmol). The reaction was stirred for 1 h and quenched with 1 mL of a saturated NH₄Cl solution. The organics were removed in vacuo and the resultant aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo to afford the crude product. The crude was then subjected to Silica gel chromatography (20% EtOAc/hexanes) to afford 8 (21 mg, 91%) as a white foam. R_f = 0.25 (5% EtOAc/45% hexanes/50% CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.45 – 7.28 (m, 7H), 7.13 – 7.07 (m, 2H), 6.20 (d, J = 2.4 Hz, 1H), 6.08 (d, J = 2.4 Hz, 1H), 5.01 – 4.96 (m, 3H), 4.80 (s, 1H), 2.76 – 2.62 (m, 2H), 2.31 (s, 3H), 2.21 (dddd, J = 13.7, 5.9, 3.6, 2.4 Hz, 1H), 2.01 (dtd, J = 13.8, 10.3, 6.4 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 169.5, 158.3, 156.5, 154.38, 150.1, 139.0, 136.9, 128.5, 127.8, 127.4, 127.1, 121.5, 102.0, 95.5, 95.3, 69.1, 29.3, 21.1, 18.8.

((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4’,5’-d]pyran-5-yl)methanol (9).

To a flask was added ZnCl₂ (12.1 g, 88.8 mmol) and acetone (120 mL). To the stirring mixture was added a few drops of concentrated H₂SO₄ until a clear solution was observed. To the mixture was added D-(+)-galactose 6 (10.0 g, 55.5 mmol) and the reaction was stirred at 23 °C for 15 h. The reaction was quenched by addition of sat. aq. NaHCO₃, and then it was filtered through celite with acetone. The filtrate was concentrated under reduced pressure to remove acetone. The remaining material was extracted with EtOAc and then with 10% MeOH/CH₂Cl₂. The organics were dried over Na₂SO₄, filtered, concentrated under reduced pressure, and purified by column chromatography on Silica gel (50% EtOAc/hexanes) to afford 9 (13.5 g, 93%) as a colorless oil. R_f = 0.40 (50% EtOAc/hexanes). ¹H NMR (400 MHz, CDCl₃) δ 5.53 (d, J = 5.0 Hz, 1H), 4.58 (dd, J = 7.9, 2.5 Hz, 1H), 4.30 (dd, J = 5.2, 2.5 Hz, 1H), 4.28 – 4.20 (m, 1H), 3.89 – 3.76 (m, 2H), 3.71 (dt, J = 11.4, 5.4 Hz, 1H), 2.43 (d, J = 7.9 Hz, 1H), 1.50 (s, 3H), 1.42 (s, 3H), 1.30 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 109.5, 108.8, 96.4, 71.6, 70.8, 70.7, 68.3, 62.3, 26.1, 26.0, 25.0, 24.4.

(3aR,5R,5aS,8aS,8bR)-2,2,5,7,7-pentamethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4’,5’-d]pyran (10).

To a flask was added 9 (500 mg, 1.90 mmol) which was dissolved in toluene (8 mL). The flask was heated to 80 °C and to it was added triphenylphosphine (600 mg, 2.28 mmol), imidazole (642 mg, 4.8 equiv), and iodine (965 mg, 3.8 mmol) portion-wise over 0.5 h. The reaction was stirred for 13 h and cooled to 23 °C. The organics were washed sequentially with saturated Na₂S₂O₄ and water. The organics were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. Filtration through a plug of Silica (20% EtOAc/hexanes) afforded the iodide (654 mg, 93%) as an amorphous white solid. ¹H NMR (400 MHz, CDCl₃) δ 5.54 (d, J = 5.0 Hz, 1H), 4.61 (dd, J = 7.9, 2.5 Hz, 1H), 4.40 (dd, J = 7.9, 1.9 Hz, 1H), 4.30 (dd, J = 5.0, 2.5 Hz, 1H), 3.95 (td, J = 7.0, 1.9 Hz, 1H), 3.32 (dd, J = 10.0, 6.8 Hz, 1H), 3.21 (dd, J = 10.0, 7.1 Hz, 1H), 1.54 (s, 3H), 1.44 (s, 3H), 1.35 (s, 3H), 1.33 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 109.7, 109.0, 96.9, 71.7, 71.3, 70.7, 69.1, 26.2, 26.1, 25.0, 24.6, 2.5.

To a solution of the above iodide (212 mg, 0.57 mmol) in methanol (10 mL) was added NEt₃ (0.8 mL, 5.74 mmol) and 20% Pd(OH)₂ (40 mg, 20% w/w). The reaction was placed under a 60 psi atmosphere of hydrogen and reacted for 17 h. The apparatus was depressurized and the reaction was filtered through a plug of celite. The filtrate was concentrated in vacuo and filtered through a plug of Silica gel (20% EtOAc/hexanes) to afford 10 (131 mg, 93%) as a clear oil. R_f = 0.55 (20% EtOAc/hexanes). ¹H NMR (400 MHz, CDCl₃) δ 5.51 (dd, J = 5.1, 2.1 Hz, 1H), 4.58 (dt, J = 7.9, 2.3 Hz, 1H), 4.28 (dt, J = 4.7, 2.2 Hz, 1H), 4.07 (dt, J = 7.9, 2.1 Hz, 1H), 3.91 (dq, J = 8.9, 5.2 Hz, 1H), 1.51 (d, J = 2.1 Hz, 3H), 1.46 (d, J = 2.1 Hz, 3H), 1.38 – 1.34 (m, 3H), 1.32 (d, J = 2.1 Hz, 3H), 1.25 (dd, J = 6.5, 2.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 109.1, 108.4, 96.7, 73.7, 71.1, 70.5, 63.6, 26.2, 25.1, 24.6, 16.1.

(3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-ol (11).

To a flask was added diacetonide 10 (474 mg, 1.94 mmol) and a solution of 80% AcOH/H₂O (24 mL). The mixture was refluxed (oil bath heat source, 120 °C) for 3 h and then concentrated under reduced pressure (rotary evaporator, water bath set to 40 °C). Toluene was added to the residue and removed under reduced pressure three times to remove trace acetic acid and water. The residue was dissolved in 20% MeOH/CH₂Cl₂, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford D-(+)-fucose as a white foam that was used without further purification. R_f = 0.20 (20% MeOH/CH₂Cl₂).

To a flame-dried flask was added a solution of the above crude D-(+)-fucose (1.94 mmol) in dry DMF (10 mL). The mixture was cooled to 0 °C prior to addition of 60% NaH (621 mg, 15.5 mmol) and benzyl bromide (1.85 mL, 15.5 mmol). The mixture was stirred under argon at 0 °C for 20 min and then it was allowed to warm up and stir at 23 °C for 2.5 h. The mixture was then diluted in EtOAc, washed with water, 1M HCl, sat. aq. NaHCO₃, and brine. The organics were dried over Na₂SO₄, filtered, concentrated under reduced pressure, and purified by column chromatography on Silica gel (5–10% EtOAc/hexanes) to afford the tetra-benzylated fucose 11 as a yellow oil (758 mg, 75% over 2-steps) and as an inseparable mixture of anomers that were not extensively characterized. R_f = 0.50 (20% EtOAc/hexanes).

(3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl acetate (12).

To a flask containing the above tetra-benzylated fucose (900 mg, 1.72 mmol) was added 1M H₂SO₄ (1.4 mL), followed by glacial acetic acid (11 mL). The mixture was then heated to 80 °C and kept at that temperature for 4 h. The reaction was cooled to 23 °C and the acetic acid was removed in vacuo. The remaining liquid was then dissolved in DCM and extracted with a sat. aq. NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography on Silica gel (30% EtOAc/hexanes) to afford hemiacetal (540 mg) as a white solid and as a 2.2:1 mixture of inseparable anomers. R_f = 0.45 (40% EtOAc/hexanes). ¹H NMR (400 MHz, CDCl₃) δ 7.45 – 7.28 (m, 23H), 5.31 (t, J = 2.9 Hz, 1H), 4.99 (ddd, J = 14.3, 11.3, 2.3 Hz, 2H), 4.89 – 4.62 (m, 8H), 4.18 – 4.04 (m, 2H), 3.95 (dt, J = 9.9, 2.5 Hz, 1H), 3.79 (ddd, J = 9.6, 7.4, 1.9 Hz, 1H), 3.68 (d, J = 3.1 Hz, 1H), 3.63 – 3.49 (m, 2H), 1.22 (dd, J = 6.4, 2.0 Hz, 1H), 1.17 (dd, J = 6.5, 2.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 138.8, 138.6, 138.4, 138.3, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.7, 127.6, 127.6, 97.8, 91.9, 82.5, 80.9, 79.1, 77.4, 76.5, 76.4, 75.1, 74.8, 74.8, 73.5, 73.2, 73.0, 70.7, 66.7, 17.0, 16.8.

To a flask was added hemiacetal (89 mg, 0.20 mmol), pyridine (1.5 mL), and Ac₂O (0.5 mL). The mixture was stirred at 23 °C for 18 h. The mixture was then diluted in EtOAc, washed with water, 1M HCl, sat. aq. NaHCO₃, and brine. The organic layer was dried over Na₂SO₄, filtered, concentrated under reduced pressure, and purified by flash chromatography on Silica gel (15% EtOAc/hexanes) to yield the acetate 12 (82 mg, 85%) as a white solid and as a 2:1 (β:α) mixture of inseparable anomers. R_f = 0.60 (30% EtOAc/hexanes). ¹H NMR (400 MHz, CDCl₃) δ 7.45 – 7.30 (m, 46H), 6.43 (d, J = 3.7 Hz, 1H), 5.60 (d, J = 8.1 Hz, 2H), 5.03 (dd, J = 11.6, 1.8 Hz, 3H), 4.90 (dd, J = 11.6, 6.9 Hz, 3H), 4.83 – 4.70 (m, 12H), 4.21 (dd, J = 10.1, 3.8 Hz, 1H), 4.06 – 3.91 (m, 4H), 3.75 (dd, J = 2.9, 1.3 Hz, 1H), 3.68 – 3.61 (m, 6H), 2.15 (s, 3H), 2.07 (s, 6H), 1.22 (d, J = 6.4 Hz, 6H), 1.19 (d, J = 6.5 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 169.7, 169.6, 138.8, 138.5, 138.4, 138.4, 138.3, 138.1, 128.5, 128.5, 128.4, 128.3, 128.3, 128.1, 127.9, 127.8, 127.8, 127.7, 127.6, 127.6, 127.5, 94.3, 90.9, 79.0, 78.1, 77.4, 76.0, 75.3, 75.0, 74.8, 73.3, 73.3, 73.2, 71.5, 69.2, 21.3, 21.1, 16.8.

(3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl benzoate (13).

To a flame-dried flask was added hemiacetal 11 (251 mg, 0.58 mmol) and pyridine (3.0 mL). The mixture was cooled to 0 °C prior to addition of benzoyl chloride (201 μL, 1.73 mmol). The mixture was then allowed to warm to 23 °C and stir under argon for 23 h. The mixture was then diluted in EtOAc, washed with brine, dried over Na₂SO₄, filtered, concentrated, and purified by column chromatography on Silica gel using 5% EtOAc/10% CH₂Cl₂/hexanes to afford benzoate 13 (254 mg, 82%) as a colorless syrup and as a mixture of anomers 2.6:1 (β:α). R_f = 0.20 (5% EtOAc/10% CH₂Cl₂/hexanes). ¹H NMR (400 MHz, CDCl₃) δ 8.16 – 8.01 (m, 11H), 7.66 – 7.55 (m, 6H), 7.52 – 7.19 (m, 68H), 6.62 (d, J = 3.6 Hz, 1H), 5.85 (d, J = 8.1 Hz, 3H), 5.04 (dd, J = 11.6, 2.4 Hz, 4H), 4.95 – 4.68 (m, 20H), 4.30 (dd, J = 10.1, 3.6 Hz, 1H), 4.21 – 4.04 (m, 5H), 3.80 – 3.64 (m, 9H), 1.23 (d, J = 6.4 Hz, 8H), 1.18 (d, J = 6.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 171.6, 165.2, 138.8, 138.4, 138.4, 138.4, 138.3, 133.9, 133.5, 133.3, 130.3, 130.2, 130.0, 129.5, 129.4, 128.7, 128.6, 128.5, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8, 127.8, 95.1, 91.8, 83.0, 78.8, 78.1, 76.2, 75.5, 75.4, 75.1, 74.9, 73.3, 73.2, 71.8, 69.6, 16.9. HRMS (ESI) m/z: [M+Na]⁺ Calcd for C₃₄H₃₄O₆Na⁺ 561.22476; Found 561.22344.

(2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl 4-methoxybenzoate (14).

To a flame-dried flask was added hemiacetal 11 (60 mg, 0.14 mmol) and pyridine (1.0 mL). The mixture was cooled to 0 °C prior to addition of 4-methoxybenzoyl chloride (71 mg, 0.41 mmol). The mixture was then allowed to warm to 23 °C and stir under argon for 16 h. The mixture was then diluted in EtOAc, washed with brine, dried over Na₂SO₄, filtered, concentrated, and purified by column chromatography on Silica gel using 15% EtOAc/hexanes to afford benzoate derivative 14 (52 mg, 66%) as a colorless syrup and as the α anomer. ¹H-NMR analysis of the crude mixture showed a mixture of anomers 1:7 (β:α). The minor β anomer was present in small amount and contaminated with an inseparable impurity, and therefore it was not isolated. α anomer R_f = 0.60 (30% EtOAc/hexanes). [α]_D²³ = +80.7 (c 0.87, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 8.03 – 7.98 (m, 2H), 7.47 – 7.25 (m, 15H), 6.97 – 6.91 (m, 2H), 6.60 (d, J = 3.6 Hz, 1H), 5.05 (d, J = 11.5 Hz, 1H), 4.92 (d, J = 11.9 Hz, 1H), 4.85 – 4.70 (m, 4H), 4.30 (dd, J = 10.1, 3.6 Hz, 1H), 4.15 – 4.04 (m, 2H), 3.88 (s, 3H), 3.78 (dd, J = 2.9, 1.3 Hz, 1H), 1.18 (d, J = 6.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.9, 163.7, 138.8, 138.5, 138.3, 132.0, 128.5, 128.4, 128.4, 128.0, 127.8, 127.7, 127.7, 122.6, 113.8, 91.4, 78.9, 75.6, 75.1, 73.3, 73.1, 69.4, 55.6, 16.9. HRMS (ESI) m/z: [M+Na]⁺ Calcd for C₃₅H₃₆O₇Na⁺ 591.23532; Found 591.23521.

(3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl 2,4-dimethoxybenzoate (15).

To a flame-dried flask was added hemiacetal 11 (49 mg, 0.11 mmol) and pyridine (0.75 mL). The mixture was cooled to 0 °C prior to addition of 2,4-dimethoxybenzoyl chloride (68 mg, 0.34 mmol). The mixture was then allowed to warm to 23 °C and stir under argon for 16 h. The mixture was then diluted in EtOAc, washed with brine, dried over Na₂SO₄, filtered, concentrated, and purified by column chromatography on Silica gel using 5% EtOAc/CH₂Cl₂ to afford benzoate derivative 15 (35 mg, 52%) as a colorless syrup and as a mixture of anomers 2.1:1 (β:α). R_f = 0.70 (5% EtOAc/CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J = 9.4 Hz, 2H), 7.86 (d, J = 8.6 Hz, 1H), 7.41 – 7.22 (m, 47H), 6.60 (d, J = 3.6 Hz, 1H), 6.51 – 6.43 (m, 6H), 5.81 (d, J = 8.1 Hz, 2H), 5.03 (dd, J = 11.6, 5.7 Hz, 3H), 4.94 – 4.68 (m, 17H), 4.26 (dd, J = 10.0, 3.6 Hz, 1H), 4.15 – 4.01 (m, 4H), 3.88 – 3.84 (m, 15H), 3.80 (s, 3H), 3.74 (dd, J = 2.9, 1.3 Hz, 1H), 3.71 – 3.63 (m, 6H), 1.21 (d, J = 6.4 Hz, 6H), 1.16 (d, J = 6.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 164.9, 164.7, 164.2, 163.5, 162.3, 161.8, 139.0, 138.6, 138.4, 134.8, 134.4, 128.6, 128.5, 128.5, 128.4, 128.3, 128.1, 128.0, 127.8, 127.7, 127.6, 127.6, 112.3, 111.2, 104.8, 104.6, 99.0, 98.9, 94.5, 90.9, 83.0, 79.0, 78.3, 77.7, 76.4, 75.6, 75.2, 75.0, 74.9, 73.4, 73.2, 72.9, 71.6, 69.3, 56.0, 55.9, 55.6, 16.9. HRMS (ESI) m/z: [M+Na]⁺ Calcd for C₃₆H₃₈O₈Na⁺ 621.24589; Found 621.24447

(3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl 4-nitrobenzoate (16).

To a flame-dried flask was added hemiacetal 11 (61 mg, 0.14 mmol) and pyridine (0.75 mL). The mixture was cooled to 0 °C prior to addition of 4-nitrobenzoyl chloride (78 mg, 0.42 mmol). The mixture was then allowed to warm to 23 °C and stir under argon. A thick slurry formed, so CH₂Cl₂ (0.5 mL) was added. Stirring under argon at 23 °C was continued for 18 h. The mixture was then diluted in EtOAc, washed with water, washed with brine, dried over Na₂SO₄, filtered, concentrated, and purified by column chromatography on Silica gel using 15% EtOAc/hexanes to afford benzoate derivative 16 (31 mg, 38%) as a mixture of anomers 1.7:1 (β:α). R_f = 0.80 and 0.70 (30% EtOAc/hexanes). ¹H NMR (400 MHz, CDCl₃) δ 8.31 – 8.23 (m, 5H), 8.17 – 8.12 (m, 5H), 7.43 – 7.26 (m, 31H), 7.24 – 7.17 (m, 9H), 6.61 (d, J = 3.6 Hz, 1H), 5.83 (d, J = 8.0 Hz, 2H), 5.04 (dd, J = 11.5, 3.9 Hz, 3H), 4.92 – 4.68 (m, 14H), 4.30 (dd, J = 10.1, 3.7 Hz, 1H), 4.15 (dd, J = 9.5, 8.0 Hz, 2H), 4.12 – 4.05 (m, 1H), 4.01 (dd, J = 10.1, 2.7 Hz, 1H), 3.79 (dd, J = 2.9, 1.3 Hz, 1H), 3.77 – 3.67 (m, 5H), 1.23 (d, J = 6.4 Hz, 5H), 1.19 (d, J = 6.5 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 163.5, 163.4, 150.9, 150.8, 138.5, 138.4, 138.3, 138.2, 138.1, 135.8, 134.9, 131.3, 131.0, 128.7, 128.6, 128.6, 128.5, 128.5, 128.4, 128.1, 128.0, 127.9, 127.9, 127.8, 127.8, 127.7, 123.7, 123.6, 95.5, 93.0, 83.1, 78.7, 77.7, 75.9, 75.4, 75.4, 75.2, 75.0, 73.5, 73.3, 73.1, 72.0, 70.0, 16.9. HRMS (ESI) m/z: [M+Na]⁺ Calcd for C₃₄H₃₃NO₈Na⁺ 606.20984; Found 606.20940.

4-(7-(benzyloxy)-5-hydroxy-6-((2S,3S,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl acetate (17).

To a flame-dried flask was added a solution of sugar 12 (254 mg, 0.47 mmol) in CH₂Cl₂ (9.4 mL). To the solution was added flavan 8 (276 mg, 0.71 mmol). After the flavan was dissolved, Bi(OTf)₃ (62 mg, 0.09 mmol) was added. The mixture was stirred under argon at 23 °C for 20 h, and then it was diluted in EtOAc and washed with saturated aq. NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and purified by column chromatography on Silica gel (20% EtOAc/hexanes) to afford 17 (281 mg, 74%) as a white foam and as a 1:1 inseparable mixture of diastereomers due to the inconsequential stereocenter from the racemic starting material 8. R_f = 0.40 (25% EtOAc/hexanes). ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J = 6.8 Hz, 1H), 7.47 – 7.42 (m, 2H), 7.42 – 7.26 (m, 16H), 7.22 – 7.16 (m, 3H), 7.13 – 7.07 (m, 4H), 6.11 (d, J = 4.4 Hz, 1H), 5.11 (dd, J = 12.0, 2.6 Hz, 1H), 5.05 – 4.74 (m, 7H), 4.57 (dd, J = 10.8, 1.9 Hz, 1H), 4.29 (q, J = 9.6 Hz, 1H), 4.18 (dd, J = 10.8, 3.7 Hz, 1H), 3.77 – 3.59 (m, 3H), 2.88 – 2.64 (m, 2H), 2.30 (d, J = 3.0 Hz, 3H), 2.20 (ddd, J = 11.5, 5.9, 2.8 Hz, 1H), 2.09 – 1.91 (m, 1H), 1.21 (dd, J = 6.3, 2.9 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 169.5, 156.3, 156.2, 155.8, 155.7, 155.4, 150.3, 139.4, 138.9, 138.7, 137.5, 128.5, 128.4, 128.4, 128.2, 128.1, 128.0, 127.6, 127.6, 127.5, 127.4, 127.3, 121.7, 105.9, 105.8, 103.9, 103.8, 93.2, 93.1, 84.4, 78.4, 78.3, 77.4, 76.7, 75.1, 74.4, 74.3, 72.7, 70.5, 29.8, 29.7, 21.3, 19.3, 19.2, 17.5. HRMS (ESI) m/z: [M+Na]⁺ Calcd for C₅₁H₅₀O₉Na⁺ 829.3347; Found 829.3351.

4-(5-acetoxy-7-(benzyloxy)-4-oxo-6-((2S,3S,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)chroman-2-yl)phenyl acetate (18).

To a flask was added compound 17 (215 mg, 0.27 mmol). The starting material was dissolved in pyridine (4 mL) and then acetic anhydride (2 mL) was added. The mixture was stirred under argon at 23 °C for 22 h, and then it was diluted in EtOAc, washed 3X with 1.0M HCl, once with saturated aq. NaHCO₃, and once with brine. The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and purified by column chromatography on Silica gel (25% EtOAc/hexanes) to afford the diacetal derivative (218 mg, 96%) as a white foam and as a 1:1 inseparable mixture of diastereomers due to the inconsequential stereocenter from racemic 8. R_f = 0.70 (40% EtOAc/hexanes). ¹H NMR (400 MHz, CDCl₃) δ 7.44 – 7.26 (m, 19H), 7.21 – 7.17 (m, 3H), 7.07 (tdd, J = 9.2, 4.2, 2.2 Hz, 4H), 6.39 (d, J = 2.0 Hz, 1H), 5.08 – 4.76 (m, 8H), 4.65 – 4.59 (m, 2H), 4.28 – 4.18 (m, 1H), 3.71 (d, J = 2.9 Hz, 1H), 3.66 (ddd, J = 9.3, 4.1, 3.0 Hz, 1H), 3.60 – 3.51 (m, 1H), 2.61 – 2.47 (m, 2H), 2.30 (d, J = 1.2 Hz, 3H), 2.18 – 2.10 (m, 1H), 1.98 (d, J = 6.2 Hz, 3H), 1.18 (d, J = 6.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 169.8, 169.5, 156.8, 156.7, 156.0, 155.9, 150.4, 149.6, 149.5, 139.1, 139.0, 138.9, 138.8, 137.3, 129.1, 128.5, 128.3, 128.0, 128.0, 127.8, 127.6, 127.6, 127.6, 127.3, 127.3, 127.2, 127.2, 121.7, 113.1, 113.0, 109.3, 109.1, 99.4, 85.3, 85.2, 78.6, 77.3, 75.6, 74.8, 74.6, 74.5, 73.2, 72.9, 70.9, 29.6, 29.1, 21.2, 20.6, 20.5, 19.7, 17.3. HRMS (ESI) m/z: [M+Na]⁺ Calcd for C₅₃H₅₂O₁₀Na⁺ 871.3453; Found 871.3462.

To a flask was added diacetate derivative (214 mg, 0.25 mmol). The starting material was dissolved in a solution of 20% H₂O/MeCN (17 mL), and then ammonium cerium(IV) nitrate (2.07 g, 3.78 mmol) was added. The mixture was stirred at 23 °C for 2 h, and then it was diluted in EtOAc and H₂O, extracted twice with EtOAc, dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and purified by column chromatography on Silica gel (30% EtOAc/hexanes) to afford 18 (86 mg, 40%) as a pale yellow foam and as a 1:1 inseparable mixture of diastereomers due to the inconsequential stereocenter from racemic 8. R_f = 0.45 (40% EtOAc/hexanes). ¹H NMR (400 MHz, CDCl₃) δ 7.46 – 7.28 (m, 17H), 7.23 – 7.11 (m, 6H), 7.09 – 7.02 (m, 2H), 6.39 (d, J = 2.7 Hz, 1H), 5.40 (d, J = 13.3 Hz, 1H), 5.02 (q, J = 9.5 Hz, 3H), 4.84 (d, J = 16.2 Hz, 3H), 4.74 (d, J = 11.8 Hz, 1H), 4.63 (d, J = 10.8 Hz, 1H), 4.52 (t, J = 9.5 Hz, 1H), 4.30 (d, J = 11.7 Hz, 1H), 3.71 (s, 1H), 3.65 (d, J = 9.4 Hz, 1H), 3.54 (d, J = 6.6 Hz, 1H), 2.97 (q, J = 14.6 Hz, 1H), 2.69 (d, J = 16.6 Hz, 1H), 2.31 (s, 3H), 2.04 (s, 3H), 1.18 (d, J = 6.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 188.7, 188.2, 170.2, 169.4, 163.5, 163.4, 163.1, 151.3, 160.0, 139.0, 139.0, 138.9, 138.7, 136.1, 136.1, 135.9, 129.1, 128.7, 128.5, 128.3, 128.1, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.6, 127.4, 127.3, 127.2, 122.1, 116.1, 116.0, 108.7, 98.7, 98.6, 85.33, 85.28, 79.1, 79.0, 78.2, 77.3, 75.6, 74.9, 74.8, 74.7, 72.7, 72.63, 71.0, 45.5, 45.3, 21.2, 20.8, 17.3. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₅₃H₅₁O₁₁⁺ 863.3426; Found 863.3435.

4-(5-acetoxy-7-(benzyloxy)-4-oxo-6-((2S,3S,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)-4H-chromen-2-yl)phenyl acetate (19).

To a flame-dried flask was added triphenylphosphine hydrobromide (66 mg, 0.19 mmol) and an argon balloon was attached. To the flask was added dry DMSO (1.7 mL) dropwise. The solid fumed vigorously upon initial addition of DMSO. After complete addition of DMSO, the flask was swirled for several minutes to dissolve the solid completely. To another flame-dried flask was added compound 18 (83 mg, 0.10 mmol). The DMSO solution was quickly added by syringe to the flask containing 18, which was then equipped with a reflux condenser and an argon balloon. The mixture was heated at 80 °C for 10 h under argon, and then it was cooled to 23 °C, diluted with EtOAc, washed with saturated aq. NH₄Cl, dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and purified by column chromatography on Silica gel (40% EtOAc/hexanes) to afford 19 (43 mg, 52%) as a colorless syrup. R_f = 0.15 (40% EtOAc/hexanes). [α]_D²³ = +17.5 (c 1.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 8.4 Hz, 2H), 7.45 – 7.30 (m, 15H), 7.25 (d, J = 8.6 Hz, 2H), 7.18 – 7.10 (m, 3H), 7.01 (dd, J = 6.5, 3.0 Hz, 2H), 6.80 (s, 1H), 6.55 (s, 1H), 5.18 – 5.03 (m, 3H), 4.97 (d, J = 9.9 Hz, 1H), 4.83 (s, 2H), 4.76 (d, J = 11.4 Hz, 1H), 4.69 – 4.56 (m, 2H), 4.25 (d, J = 11.4 Hz, 1H), 3.74 (d, J = 2.9 Hz, 1H), 3.69 (dd, J = 9.2, 2.7 Hz, 1H), 3.58 (t, J = 6.4 Hz, 1H), 2.35 (s, 3H), 2.11 (s, 3H), 1.20 (d, J = 6.2 Hz, 3H).¹³C NMR (100 MHz, CDCl₃) δ 176.4, 170.2, 169.1, 161.2, 160.7, 158.1, 153.1, 150.2, 138.8, 138.7, 135.8, 129.1, 129.1, 128.8, 128.5, 128.4, 128.3, 128.0, 128.0, 127.7, 127.6, 127.6, 127.3, 127.2, 122.4, 119.6, 98.1, 85.3, 78.0, 75.6, 74.9, 74.8, 72.7, 71.2, 21.3, 20.9, 17.4. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₅₃H₄₉O₁₁⁺ 861.3269; Found 861.3279.

Carambolaflavone A (1b).

To a flask was added 19 (33 mg, 0.04 mmol). To the flask was added MeOH (1.5 mL) and 1.0M LiOH (1.5 mL). The mixture was stirred at 23 °C for 2 h, and then it was acidified by addition of 1.0M HCl and extracted twice with a 10% MeOH/CH₂Cl₂ solution. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to yield the crude deacetylated compound 7-(benzyloxy)-5-hydroxy-2-(4-hydroxyphenyl)-6-((2S,3S,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)-4H-chromen-4-one as a yellow solid (28 mg) that was used without further purification.

Above deacetylated compound was then dissolved in a solution of 20% EtOAc/EtOH and 10% Pd/C (14 mg, 50% w/w) was added. The flask was evacuated under vacuum and then flushed with hydrogen gas. This was repeated twice more before the mixture was left to stir under a balloon of hydrogen (1 atm) at 23 °C for 18 h. The mixture was then diluted in MeOH and filtered through celite. The celite was rinsed several times with MeOH. The yellow filtrate was then concentrated under reduced pressure and purified by column chromatography on Silica gel (10% MeOH/CH₂Cl₂). Further purification by reversed phase HPLC on a YMC-Pack C18 column (ODS-A 250 × 20 mm, 5 μm particle size, 12 nm pore size, 75% H₂O/MeCN as eluent, 10 mL/min flowrate, monitored at 220 nm wavelength, used 200 μL injection volumes, retention time = 30 min) was carried out to yield Carambolaflavone A 1b (8 mg, 50% over 2 steps) as a yellow solid. R_f = 0.40 (15% MeOH/CH₂Cl₂). [α]_D²³ = +59.0 (c 0.1, MeOH). ¹H NMR (800 MHz, CD₃OD) δ 7.86 (d, J = 8.3 Hz, 2H), 6.93 (d, J = 8.3 Hz, 2H), 6.61 (s, 1H), 6.52 (s, 1H), 4.14 (t, J = 9.6 Hz, 1H), 3.79 (q, J = 6.5 Hz, 1H), 3.75 (d, J = 3.0 Hz, 1H), 3.60 (dd, J = 9.4, 3.0 Hz, 1H), 1.30 (d, J = 6.4 Hz, 3H). ¹³C NMR (200 MHz, CD₃OD) δ 184.1, 166.3, 165.1, 162.9, 161.2, 158.8, 129.5, 123.1, 117.1, 109.7, 105.1, 103.8, 95.8, 76.5, 76.3, 75.6, 73.4, 70.9, 17.3. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₂₁H₂₁O₉⁺ 417.1180; Found 417.1173.

Conclusions

In summary, we have accomplished an enantioselective synthesis of the revised structure of carambolaflavone A. Our convergent synthesis required 13 synthetic steps from the commercially available D-(+)-galactose. The synthesis features efficient conversion of (+)-galactose to a number of D-fucose-derived glycosyl donors. The key C-aryl glycosylation was carried out with a catalytic amount of inexpensive and nontoxic bismuth-triflates to provide the desired β-glycosidic linked C-aryl derivative in good yield and diastereoselectivity. We have also investigated a number of other related Lewis acids based on Sc, Fe, Dy, Cu and Zn, however, Bi(OTf)₃ showed the best results. Such Bi(OTf)₃ catalyzed C-arylation reaction has not been explored previously. We examined the scope and utility of this reaction using a number of glycosyl donors. The benzoate derivative showed the best result. The current synthesis of (+)-carambolaflavone is amenable to a variety of structural derivatives for optimization of antidiabetic properties. Further research is in progress in our laboratory.