Stereoselective Total Syntheses of Leiocarpin A and (-)-Galantinic Acid Starting­ from d-Mannitol

Abstract

Stereoselective total syntheses of leiocarpin A and (-)-galantinic acid, starting from d-mannitol as a chiral synthon, are described. The key steps involve stereoselective allylations, a Grignard reaction to control the required stereogenic centers, and ring-closing metathesis followed by intramolecular Michael addition.

Trees of the genus Goniothalamus of the plant family Annonaceae, which grow in South East Asia, have long been known for their proven use in folk medicine. So far, more than twenty bioactive styryl lactones have been isolated from these plants. [¹] These styryl lactones exhibit pesticidal, teratogenic, embryotoxic, antifungal, antibacterial, and antimalarial activities, and significant-to-marginal cytotoxicity against a broad array of human tumor cell lines, including breast, colon, kidney, and pancreatic carcinoma cells. [²] Because of their unique and intriguing structures and broad spectra of activities, these styryl lactones have attracted the attention of several research groups in recent years. [³] The leiocarpins are a newly discovered series of styryl lactones. Leiocarpin A (1), leiocarpin B (2), and leiocarpin C (3) (Figure  [¹] ) were recently isolated from the ethanolic extract of the stem bark of Goniothalamus leiocapus (Annonaceae) from the south of the Yunnan province in China; these leiocarpins posses cytotoxic activities against several human tumor cell lines. [4a] [b] Leiocarpin A is structurally related to 9-deoxygoniopypyrone 4 (Figure  [¹] ) in regard of the configuration at C-6. [³] Despite the importance of leiocarpin A with respect to its cytotoxic activity, only one synthesis of this compound has been reported. [4c]

Galantinic acid (5) is a constituent of the peptide antibiotic galantin I, isolated from a culture broth of Bacillus pulvifaciens. [5] The originally proposed pyranoid structure 6 for (-)-galantinic acid was later revised to that of 5 by Sakai and Ohfune (Figure  [¹] ). [6] Galantinic acid, which is an unusual amino acid, is an attractive target for synthetic chemists because of its unique structure with dense functionalisation, and also because of its excellent antibacterial activity. A number of synthetic routes to galantinic acid have been reported. [7-¹4] Recently, Bethuel and Gademann [¹³] reported an efficient stereoselective synthesis of galantinic acid starting from protected l-serine and involving a Claisen condensation and an Evans diastereoselective reduction as key steps.

As a continuation of our efforts toward the total syntheses of biologically active natural products, [¹5] we describe a stereoselective total synthesis of leiocarpin A (1) and (-)-galantinic acid (5), starting from d-mannitol-derived (R)-2,3-O -isopropylidineglyceraldehyde [(4R)-2,2-di­methyl-1,3-dioxolane-4-carbaldehyde] as a chiral synthon. For the synthesis of leiocarpin A (1), the key steps involve diastereoselective allylation and phenyl Grignard reactions to control the required stereogenic centers, and ring-closing metathesis followed by the formation of the pyrone ring through intramolecular Michael addition reactions, whereas for the synthesis of (-)-galantinic acid (5), we used diastereoselective allylic additions as a prominent part of the strategy (Scheme  [¹] ).

In our initial attempted synthesis, we performed a zinc-mediated [¹6] stereoselective allylation of (R)-2,3-O-isopropylidineglyceraldehyde (10) [¹7] to give the corresponding homoallylic alcohol as a mixture of diastereomers 9a and 9b (anti/syn = 95:5) in 92% overall yield. The required stereoisomer 9a was protected by treatment with 4-methoxybenzyl bromide and sodium hydride at 0 ˚C to give the ether 13. Hydrolysis of the 2,3-O-isopropylidine moiety of 13 with 1 M hydrochloric acid in tetrahydrofuran at room temperature gave the diol 14, which on subsequent protection with triethylsilyl chloride and imidazole in dichloromethane gave the bistriethylsilyl derivative 15. Selective oxidation of this derivative under Swern conditions [¹8] gave the corresponding aldehyde through domino deprotection of the primary O-triethylsilyl group and subsequent oxidation of the primary alcohol. The aldehyde, without further purification, underwent Grignard reaction with phenylmagnesium bromide, generated in situ from bromobenzene and magnesium in THF at 0 ˚C, to give the benzylic alcohol 8 as a mixture of diastereo­mers 8a and 8b (anti/syn = 9:1) in 76% overall yield for the two steps. The required anti-diastereomer 8a was protected with triethylsilyl chloride, and subsequent 2,3-dichloro-5,6-dicyanobenzo-1,4-quinone (DDQ)-mediated deprotection of the 4-methoxybenzyl ether 16 gave the alcohol 17. The alcohol 17 was acryloylated with acryloyl chloride to give the Grubbs precursor 18, which was then treated with Grubbs’ first-generation catalyst [(PCy₃)₂Cl₂Ru=CHPh (Ru-I)] to give the desired bis(triethylsilyl)-protected 6-epi-goniodiol 7. Finally, the protected 6-epi-goniodiol 7 was deprotected by treatment with tetrabutylammonium fluoride in dichloromethane; a subsequent intramolecular Michael addition reaction in the same pot gave the target leiocarpin A (1) in 86% yield; the spectral and analytical data for this compound were consistent with those reported in the literature (Scheme  [²] ). [4b]

Our attempted at a stereoselective synthesis of (-)-galantinic acid (5) revolved around the generation of the left-hand fragment of galantinic acid containing the 6-amino and the 5- and 7-hydroxy groups. Accordingly, the predominant stereoisomer 9a was protected as its benzyl derivative 19; subsequent hydrolysis of the 2,3-O-isopropylidine moiety with 2 M hydrochloric acid in tetrahydrofuran at room temperature afforded the diol 20, which was subjected to selective protection of the primary alcohol group by treatment with benzyl bromide in the presence of dibutyltin oxide [¹9-²0] in refluxing benzene to produce the dibenzyl derivative 21. This was treated with methanesulfonyl chloride to afford the corresponding mesyl ester 22, which was subsequently heated with excess benzylamine [²¹] at 120 ˚C under solvent-free conditions to afford the desired amino compound 23 in 85% yield. The S_N2 substitution occurred smoothly, even though the mesylate group is flanked by bulky benzylic groups (Scheme  [³] ).

We next focused on stereoselective hydroxylation at the C-3 position. To achieve this, the amine 23 was first protected as its carbamate derivative 11, and subsequent dihydroxylation with osmium tetroxide gave a diol that was cleaved with sodium periodate to give the aldehyde in a pure form in one pot; this sets the stage for chelation-controlled diastereoselective allylation. Thus, the aldehyde was treated with allyl(tributyl)stannane in the presence of magnesium bromide [²²] at 0 ˚C to give the corresponding homoallylic alcohol as a mixture of isomers 12a and 12b in 72% overall yield. The desired major 1,3-anti-addition product 12a was easily separated by column chromatography from the undesired isomer (Scheme  [4] ).

After assembling the three key internal groups with appropriate stereochemistry, our final task was to generate the terminal carboxylic acid. Accordingly, the homoallylic alcohol 12a was treated with a catalytic amount of osmium tetroxide to give the 1,2-diol, which was oxidatively cleaved with NaIO₄ in THF-H₂O (5:1) to afford the aldehyde in one pot. The crude aldehyde was oxidized to the corresponding carboxylic acid 24 in 85% yield by NaClO₂ in the presence of 20% NaH₂PO₄˙2H₂O in t-BuOH. The removal of benzyl and Cbz groups in compound 24 by catalytic­ hydrogenolysis afforded the target compound, (-)-galantinic acid (5) in 86% yield; the spectral and analytical data for the product were consistent with those reported in the literature. [6-7]

In summary, we have developed a simple, convenient, and efficient approach to leiocarpin A (1) and (-)-galantinic acid (5) by a sequence of reactions starting from the three-carbon chiral synthon (R)-2,3-O-isopropylidineglyceraldehyde (10). This approach provides a high stereoselectivity, uses a readily available and inexpensive starting material, and requires simple experimental conditions, making it a useful and attractive approach to the total syntheses of leiocarpin A (1) and (-)-galantinic acid (5).

Melting points were recorded on a Büchi R-535 apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer FTIR 240-c spectrophotometer using KBr optics. ^¹H NMR and ^¹³C NMR spectra were recorded on Gemini-200 (200 MHz), Bruker Avance-300 (300 MHz), and Unity-400 (400 MHz) spectrometers, respectively, in CDCl3 using TMS as internal standard. Mass spectra were recorded on a Finnigan MAT 1020 mass spectrometer operating at 70 eV. Column chromatography was performed using E. Merck 60-120 mesh silica gel. All solvents were distilled, dried over CaH2 and stored under N₂ prior to use. Starting materials and reagents used in the reactions, obtained commercially from Aldrich, Lancaster, and Fluka were used without purification unless otherwise indicated.

(1S)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]but-3-en-1-ol (9a)

To a mixture of activated Zn dust (5.5 g, 84.6 mmol) and anhyd THF (30 mL) under N₂ was added a solution of (R)-2,3-O -isopropylidineglyceraldehyde (10) (5.5 g, 42.3 mmol) in THF (25 mL) at 0 ˚C, followed by allyl bromide (7.15 mL, 84.6 mmol) added dropwise over 10 min. The mixture was then stirred for 4 h at 0 ˚C until the reaction was complete (TLC). The reaction was quenched by addition of sat. aq NH₄Cl (17 mL) at 0 ˚C over 30 min and the mixture was stirred for 1 h then filtered. The filtrate was concentrated in vacuo to give a crude product that was partitioned between H₂O (50 mL) and EtOAc (100 mL). The organic layer was washed with brine (30 mL), dried (anhyd Na₂SO₄), and concentrated. The residue was further purified by column chromatography to give the pure compound 9a as a yellowish oil; yield: 8.3 g (92%); [α]_D ^²5 +5.58 (c = 0.5, MeOH).

IR (neat): 3454 (br, OH), 2986, 1375, 1214, 1064 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 5.90-5.70 (m, 1 H), 5.20-5.00 (m, 2 H), 4.00-3.90 (m, 3 H), 3.75-3.65 (m, 1 H), 2.40-2.20 (m, 2 H), 1.38 (s, 3 H), 1.36 (s, 3 H).

^¹³C NMR (50 MHz, CDCl₃): 134, 118, 109, 88, 71, 65, 38, 27, 25.

MS (EI, 70 eV): m/z (%) = 172 (5) [M]⁺, 157 (10), 141 (13), 101 (70), 59 (35), 43 (100).

(2R,3S)-3-[(4-Methoxybenzyl)oxy]hex-5-ene-1,2-diol (14)

To a solution of acetonide 13 (6 g, 20.5 mmol) in THF (60 mL) was added 1 M HCl (2 mL) at 0 ˚C and the mixture was allowed to warm to r.t., stirred for 6 h, and cooled to 0 ˚C. Solid Na₂CO₃ (0.5 g) was then added in portions to neutralize the mixture. The solvent was removed in vacuo, and the residue was partitioned between H₂O (50 mL) and EtOAc (150 mL). The organic layer was washed with aq NaHCO₃ (50 mL) and brine (20 mL) then dried (Na₂SO₄). Filtration, concentration, and flash chromatography (EtOAc-hexane, 3:7) gave the required product 14 as a pale yellow oil; yield: 4.9 g (95%); [α]_D ^²5 +8.20 (c = 0.4, CHCl₃).

IR (neat): 3410, 2931, 1612, 1513, 1462, 1301, 1248, 1078, 1034, 821 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 7.18 (d, J = 8.3 Hz, 2 H), 6.81 (d, J = 8.3 Hz, 2 H), 5.90-5.76 (m, 1 H), 5.14-5.05 (m, 2 H), 4.58-3.35 (m, 2 H), 3.77 (s, 3 H), 3.65-3.41 (m, 4 H), 2.69 (br s, 2 H, -OH), 2.39-2.27 (m, 2 H).

LC-MS (EI, 70 eV): m/z (%) = 275.1 (100%) [M + Na]⁺.

(1S,5R)-1-(1-{1,2-Bis[(triethylsilyl)oxy]ethyl}but-3-enyloxy­methyl)-4-methoxybenzene (15)

TESCl (7.3 mL, 45.5 mmol) was added dropwise to a stirred solution of diol 14 (4.6 g, 18.2 mmol) and imidazole (7.4 g, 109.5 mmol) in anhyd CH₂Cl₂ (25 mL) at 0 ˚C under N₂, and the mixture was stirred for 6 h at 0 ˚C to r.t. After completion of the reaction (TLC), the mixture was filtered, the residue was washed with CH₂Cl₂ (2 20 mL), and the organic layer was concentrated. The crude product was diluted with H₂O (50 mL) and extracted with EtOAc (100 mL). The combined organic layers were washed with brine (30 mL), dried (Na₂SO₄), filtered, and concentrated. The residue was purified by column chromatography (EtOAc-hexane, 1:9) to give a colorless liquid; yield: 7.6 g (88%); [α]_D ^²5 -4.08 (c = 0.5, CHCl₃).

IR (neat): 2954, 2878, 1613, 1513, 1461, 1246, 1087, 1009, 739 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 7.18 (d, J = 8.3 Hz, 2 H), 6.78 (d, J = 8.3 Hz, 2 H), 5.89-5.76 (m, 1 H), 5.08-4.98 (m, 2 H), 4.46 (q, J = 17.3, 11.3 Hz 2 H), 3.77 (s, 3 H), 3.75-3.72 (m, 1 H), 3.64-3.59 (m, 1 H), 3.52-3.37 (m, 2 H), 2.34-2.24 (m, 2 H), 0.97-0.92 (m, 18 H), 0.63-0.54 (m, 12 H).

LC-MS (EI, 70 eV): m/z (%) = 503.3 (100%) [M + Na]⁺.

(1R,2R,3S)-3-[(4-Methoxybenzyl)oxy]-1-phenyl-2-[(triethylsilyl)oxy]hex-5-en-1-ol (8a)

A solution of oxalyl chloride (5.0 mL, 58.3 mmol) in CH₂Cl₂ (25 mL) was added dropwise to DMSO (8.2 mL, 116.6 mmol) in CH₂Cl₂ (40 mL) at -78 ˚C. After 15 min, a solution of compound 15 (7.0 g, 14.5 mmol) in CH₂Cl₂ (15 mL) was added, and stirring was continued for 40 min at -78 ˚C and then for 20 min at -40 ˚C. Et₃N (24 mL, 176 mmol) was added at -78 ˚C, and the reaction was allowed to reach r.t. The mixture was diluted with H₂O (50 mL) and extracted with CH₂Cl₂ (150 mL). The organic layer was separated, washed with brine (30 mL), and dried (Na₂SO₄). The crude aldehyde was added to PhMgBr (1.2 equiv) in THF (50 mL) at 0 ˚C and the mixture was stirred for 3 h at 0 ˚C to r.t until the reaction was complete (TLC). The reaction was quenched with sat. aq NH₄Cl (20 mL) at 0 ˚C, and then mixture was concentrated. The crude product was extracted with Et₂O (200 mL), and the organic layer was washed with H₂O (50 mL) and brine (30 mL) then dried (Na₂SO₄), filtered, and concentrated. The residue was purified by column chromatography to give pure compound 8a as a pale yellow oil; yield: 5.1 g (76% overall); [α]_D ^²5 -9.10 (c = 0.4, CHCl₃).

IR (neat): 3452, 2924, 2877, 1708, 1639, 1613, 1513, 1459, 1246, 1085, 1040, 738, 701 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 7.37-7.18 (m, 5 H), 7.12 (d, J = 8.30 Hz, 2 H), 6.77 (d, J = 8.30 Hz, 2 H), 5.86-5.73 (m, 1 H), 5.07-4.97 (m, 2 H), 4.65 (dd, J = 6.79, 2.26 Hz, 1 H), 4.36 (q, J = 10.57 Hz, 2 H), 3.94-3.91 (dd, J = 6.79, 2.26 Hz, 1 H), 3.78 (s, 3 H), 3.51-3.46 (m, 1 H), 2.37 (t, J = 6.79 Hz, 2 H), 0.83 (t, J = 8.30 Hz, 9 H), 0.45-0.35 (m, 6 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 142.9, 129.3, 127.7, 127.6, 127.3, 115.9, 113.4, 79.1, 76.6, 76.2, 70.9, 34.0, 6.9, 4.8.

LC-MS (EI, 70 eV): m/z (%) = 465.3 [M + Na]⁺.

(1R,2S,3S)-3-[(4-Methoxybenzyl)oxy]-1-phenyl-1,2-bis[(tri­ethylsilyl)oxy]hex-5-ene (16)

TESCl (3.5 g, 22.9 mmol) in anhyd CH₂Cl₂ (10 mL) was added dropwise to a stirred solution of alcohol 8a (4.6 g, 10.4 mmol) and imidazole (2.8 g, 41.6 mmol) in anhyd CH₂Cl₂ (20 mL) at 0 ˚C under N₂. The mixture was stirred for 4 h at 0 ˚C to r.t. When the reaction was complete (TLC), the mixture was filtered, the residue was washed with CH₂Cl₂ (20 mL), and the combined organic layers were concentrated. The crude product was diluted with H₂O (30 mL) and extracted with EtOAc (125 mL). The combined organic layers were washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated to give a residue that was purified by column chromatography (EtOAc-hexane, 1:9) to give compound 16 as a yellowish oil; yield: 4.8 g (85%); [α]_D ^²5 +4.80 (c = 1.2, CHCl₃).

IR (neat): 2954, 2878, 1612, 1513, 1459, 1245, 1089, 1008, 737 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 7.31-7.19 (m, 5 H), 7.16 (d, J = 8.3 Hz, 2 H), 6.78 (d, J = 8.3 Hz, 2 H), 5.91-5.76 (m, 1 H), 5.08-4.96 (m, 2 H), 4.47-4.44 (m, 2 H), 4.32 (d, J = 11.3 Hz, 1 H), 3.90 (m, 1 H), 3.79 (s, 3 H), 3.66-3.60 (m, 1 H), 2.40-2.29 (m, 2 H), 0.81 (t, J = 8.3 Hz, 9 H), 0.75 (t, J = 8.3 Hz, 9 H); 0.48-028 (m, 12 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 128.8, 127.2, 127.1, 126.8, 115.4, 112.9, 78.6, 76.1, 75.7, 70.4, 33.5, 6.4, 4.3.

LC-MS (EI, 70 eV): m/z (%) = 579.3 (100%) [M + Na]⁺.

(1R,2S,3S)-1-Phenyl-1,2-bis[(triethylsilyl)oxy]hex-5-en-3-ol (17)

DDQ (1.8 g, 8.1 mmol) was added portionwise to a stirred solution of 16 (3.8 g, 6.8 mmol) in CH₂Cl₂- H₂O (19:1) at 0 ˚C. The mixture was stirred for 30 min until the reaction was complete (TLC) and then solid NaHCO₃ (0.84 g, 10 mmol) was added. The mixture was then filtered and washed with H₂O (10 mL) and brine. The solvent was removed in vacuo, and the residue was partitioned between H₂O (30 mL) and CH₂Cl₂ (50 mL). The organic layer was washed with H₂O (20 mL) and brine (20 mL), dried (Na₂SO₄), filtered, and concentrated to give a residue that was purified by flash chromatography (EtOAc-hexane, 2:8) to give the required alcohol 17 as a yellowish oil; yield: 2.7 g (90%); [α]_D ^²5 +12.0 (c = 0.4, CHCl₃).

IR (neat): 3432, 2923, 2853, 1638, 1459, 1238, 1063, 1007, 736 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 7.32-7.23 (m, 5 H), 5.92-5.72 (m, 1 H), 5.21-5.08 (m, 2 H), 4.59 (d, J = 6.6 Hz, 1 H), 3.81-3.74 (m, 1 H), 3.70-3.71 (m, 1 H), 2.23-2.02 (m, 2 H), 0.89-0.78 (m, 18 H), 0.50-0.29 (m, 12 H).

LC-MS (EI, 70 eV): m/z (%) = 459.2 (100%) [M + Na]⁺.

(1R,2S,3S)-1-Phenyl-1,2-bis[(triethylsilyl)oxy]hex-5-en-3-yl Prop-2-enoate (18)

Et₃N (2.0 mL, 15.0 mmol) was added dropwise over 15 min to a solution of alcohol 17 (2.2 g, 5.0 mmol) in anhyd CH₂Cl₂ (10 mL) at 0 ˚C, and the mixture was stirred for 30 min at 0 ˚C. Acryloyl chloride (0.45 mL, 5.5 mmol) in anhyd CH₂Cl₂ (5 mL) was added dropwise at 0 ˚C, and the mixture was stirred at 0 ˚C to r.t. for 6 h. When the reaction was complete (TLC), the mixture was quenched with sat. aq NaHCO₃ (5 mL) at 0 ˚C and then diluted with CH₂Cl₂ (20 mL). The organic layer was washed with H₂O (10 mL) and brine (10 mL), dried, and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc-hexane, 1:9) to give the required product 18 as a yellow oil; yield: 2.2 g (92%).

^¹H NMR (200 MHz, CDCl₃): δ = 7.31-7.15 (m, 5 H), 6.38 (dd, J = 17.3, 2.2 Hz, 1 H), 6.08 (dd, J = 17.3, 10.5 Hz, 1 H), 5.82-5.74 (m, 2 H), 5.47-5.42 (m, 1 H), 5.07-4.95 (m, 2 H), 4.41 (d, J = 8.3 Hz, 1 H), 3.89 (m, 1 H), 2.54-2.41 (m, 2 H), 0.85 (t, J = 8.3 Hz, 9 H), 0.76 (t, J = 8.3 Hz, 9 H), 0.49-0.41 (m, 6 H), 0.30-0.20 (m, 6 H).

(1S,2R,6S)-6-{2-Phenyl-1,2-bis[(triethylsilyl)oxy]ethyl}-5,6-dihydro-2 H -pyran-2-one (7)

A solution of diolefin 18 (1.8 g, 3.6 mmol) in anhyd CH₂Cl₂ (20 mL) was added dropwise over 1 h to a refluxing solution of ruthenium catalyst Ru-I (630 mg, 0.72 mmol) in anhyd degassed CH₂Cl₂ (780 mL), and then the mixture was refluxed until the starting material was consumed (10 h, TLC). Removal of the solvent in vacuo and column chromatography of the residue on silica gel (EtOAc-hexane, 1:9) gave the required lactone 7 as a pale yellow oil; yield: 1.6 g (85%); [α]_D ^²5 +20.00 (c = 0.5, CHCl₃).

IR (neat): 3445, 2923, 2853, 1738, 1633, 1461, 1482, 1244, 1085, 737 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 7.29-7.23 (m, 5 H), 6.91-6.84 (m, 1 H), 5.95 (dd, J = 9.82, 2.26 Hz, 1 H), 4.63 (m, 1 H), 4.51 (d, J = 6.04 Hz, 1 H), 4.06 (dd, J = 6.79, 2.26 Hz, 1 H) 2.79-2.68 (m, 1 H), 2.35-2.25 (m, 1 H), 0.81 (m, 18 H), 0.48-0.39 (m, 12 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 163.4, 144.9, 144.5, 127.1, 127.0, 126.4, 119.9, 76.9, 76.6, 28.8, 5.9, 3.9.

LC-MS (EI, 70 eV): m/z (%) = 485.2 [M + Na]⁺.

Leiocarpin A (1)

A 1.0 M solution of TBAF in THF (1.2 mL) was added to a stirred solution of lactone 7 (200 mg, 0.43 mmol) in THF at 0 ˚C. The mixture was stirred for 8 h at 0 ˚C to r.t. until the reaction was complete (TLC). The solvent was removed in vacuo, and then the residue was partitioned between H₂O (5 mL) and CH₂Cl₂ (10 mL). The organic layer was washed with H₂O (5 mL) and brine (5 mL), dried (Na₂SO₄), filtered, and concentrated. The residue was purified by flash chromatography (EtOAc-hexane, 4:6) to give the target compound 1 as a colorless solid; yield: 87 mg (86%); [α]_D ^²5 -94.9 (c = 0.4, CHCl₃).

IR (KBr): 3437, 2924, 2854, 1716, 1631, 1459, 1379, 1274, 1080, 758 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 7.44-7.27 (m, 5 H), 4.89 (br s, 1 H), 4.44 (m, 1 H), 4.39 (d, J = 9.82 Hz, 1 H), 3.52 (dd, J = 9.82, 3.02 Hz, 1 H), 2.96 (d, J = 18.88 Hz, 1 H), 2.86 (dd, J = 18.88, 5.28 Hz, 1 H), 2.22 (br s, 2 H).

^¹³C NMR (75 MHz, CDCl₃): 168.8, 137.7, 128.7, 128.6, 127.3, 77.1, 74.4, 72.5, 65.8, 36.5, 22.6.

LC-MS (EI, 70 eV): m/z = 257.1 [M + Na]⁺.

(4R)-4-[(1S)-1-(Benzyloxy)but-3-en-1-yl]-2,2-dimethyl-1,3-dioxolane (19)

A solution of alcohol 9a (5.5 g, 31.9 mmol) in anhyd THF (20 mL) was added to a stirred solution of NaH (1.53 g, 38.3 mmol) in anhyd THF (40 mL) at 0 ˚C under N₂, and the mixture was stirred for 20 min. BnBr (4.6 mL, 38.3 mmol) was added, and the mixture was stirred for 4 h at r.t. The reaction was then quenched with ice-cold H₂O (20 mL) at 0 ˚C, and the mixture was concentrated and then diluted with H₂O (50 mL). The aqueous layer was extracted with EtOAc (3 × 30 mL), and the combined organic layers were washed with brine (30 mL), dried (Na₂SO₄), and concentrated. The residue was further purified by column chromatography to give pure compound 19 as a yellowish oil; yield 7.5 g (90%). [¹6f]

(2R,3S)-3-(Benzyloxy)hex-5-ene-1,2-diol (20)

To a stirred solution of acetonide 19 (1.0 g, 3.81 mmol) in THF (15 mL) was added 2 M HCl (1 mL) at 0 ˚C. The mixture was stirred for 3 h at r.t. then cooled to 0 ˚C and neutralized with solid NaHCO₃ (0.168 g, 2 mmol). The solvent was removed in vacuo and diluted with H₂O (20 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with aq NaHCO₃ and brine, then dried (Na₂SO₄) and concentrated. The residue was further purified by flash chromatography (EtOAc-hexane, 3:7) to give pure 20 as a yellowish oil; yield: 0.76 g (90%). [¹6f]

(2R,3S)-1,3-Bis(benzyloxy)hex-5-en-2-ol (21)

Bu₂SnO (2.065 g, 8.30 mmol) and Bu₄NI (696 mg, 1.89 mmol) were added to a stirred solution of compound 20 (1.67 g, 7.55 mmol) in benzene (150 mL) at r.t. The flask was then fitted with a Dean-Stark trap (filled with 4-Å molecular sieves) and a reflux condenser. The trap was filled with benzene, and the mixture was heated to reflux until H₂O evolution appeared to be complete. The mixture was cooled to r.t., and BnBr (1.08 mL, 9.04 mmol) was added. The resulting yellow solution was refluxed for 18 h. The mixture was then diluted with Et₂O (50 mL) and washed with 10% Na₂S₂O₃ (50 mL). The layers were separated, and the aqueous phase was extracted with Et₂O (3 × 50 mL). The combined organic layers were washed with H₂O (30 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give ether 21 as a colorless oil; yield: 2.06 g (88%). [¹6f]

(2R,3S)-1,3-Bis(benzyloxy)hex-5-en-2-yl Methanesulfonate (22)

MeSO₂Cl (0.86 mL, 11.06 mmol) was added to a stirred solution of compound 21 (3.15 g, 10.06 mmol) and DIPEA (5.24 mL, 15.09 mmol) in anhydrous CH₂Cl₂ (15 mL) at 0 ˚C. The mixture was stirred for 3 h then neutralized with K₂CO₃ (1.65 g, 12 mmol). The resulting mixture was stirred for 15 min then washed with H₂O (2 × 15 mL), and extracted with CH₂Cl₂ (2 × 25 mL). The combined organic layers were washed with brine (20 mL), dried (Na₂SO₄), and concentrated. The residue was further purified by column chromatography EtOAc-hexane, 2:8) to give pure compound 22 as a pale yellow oil; yield: 3.2 g (82%); [α]_D ^²5 +2.0 (c = 0.2, CHCl₃).

IR (neat): 3030, 2922, 2858, 1454, 1353, 1174, 1097, 919, 741, 698 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 7.45-7.18 (m, 10 H), 5.90-5.73 (m, 1 H), 5.16-5.06 (m, 2 H), 4.88-4.83 (m, 1 H), 4.64-4.44 (m, 4 H), 3.79-3.69 (m, 3 H), 2.96 (s, 3 H), 2.48-2.14 (m, 2 H).

MS (EI, 70 eV): m/z (%) = 413.1 [M + Na]⁺.

(2S,3S)-N -Benzyl-1,3-bis(benzyloxy)hex-5-en-2-amine (23)

A mixture of compound 22 (2.5 g, 6.41 mmol) and BnNH₂ (10.5 mL, 96.15 mmol) was heated to 120 ˚C. After 12 h, the mixture was cooled to r.t. and diluted with EtOAc. The resulting mixture was washed with aq NaHCO₃ and brine, dried (Na₂SO₄) and concentrated. The residue was further purified by column chromatography (EtOAc-hexane, 1:8) to give compound 23 as a yellowish oil; yield: 2.0 g (85%); [α]_D ^²5 +7.5 (c = 0.1, CHCl₃).

IR (neat): 3063, 3029, 2923, 2853,1454, 1095, 913, 738, 698 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 7.45-7.06 (m, 15 H), 5.92-5.62 (m, 1 H), 5.19-4.96 (m, 2 H), 4.63-4.32 (m, 4 H), 3.89-3.71 (m, 2 H), 3.65-3.45 (m, 3 H), 2.92-2.83 (m, 1 H), 2.59-2.22 (m, 2 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 140.7, 138.5, 138.2, 135.4, 134.3, 129.6, 128.9, 128.4, 128.3, 128.2, 128.1, 127.7, 127.6, 127.5, 127.4, 126.7, 116.8, 78.9, 73.1, 72.2, 69.5, 58.4, 52.0, 35.0.

MS (ESI, 3.5 kV): m/z (%) = 402.2 [M + 1]⁺.

HRMS (EI): m/z [M + 1]⁺ calcd for C₂₇H₃₂NO₂: 402.2433; found: 402.2438.

Benzyl Benzyl[(2S,3S)-1,3-bis(benzyloxy)hex-5-en-2-yl]carbamate (11)

Compound 23 (1.3 g, 3.25 mmol) was dissolved in EtOH-H₂O (10:1; 10 mL) and the mixture was stirred at 0 ˚C. NaHCO₃ (1.09 g, 13 mmol) and CbzCl (0.56, 3.9 mmol) were added, and the mixture was stirred for 3 h at 0 ˚C and then diluted with H₂O (20 mL). The resulting mixture was concentrated and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (20 mL), dried (Na₂SO₄), and concentrated. The residue was further purified by column chromatography (EtOAc-hexane, 2:8) to give compound 11 as yellowish oil; yield: 1.48 g (90%); [α]_D ^²5 -4.5 (c = 0.1, CHCl₃).

IR (neat): 3064, 3030, 2922, 2853, 1697, 1454, 1243, 1103, 914, 736, 697 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 7.33-6.99 (m, 20 H), 5.96-5.65 (m, 1 H), 5.14-4.89 (m, 4 H), 4.69-4.41 (m, 4 H), 4.35-4.17 (m, 3 H), 4.12-4.05 (m, 1 H), 3.92-3.65 (m, 1 H), 3.56-3.33 (m, 1 H), 2.44-2.21 (m, 2 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 139.4, 137.9, 136.5, 134.3, 134.1, 128.2, 128.0, 127.7, 127.6, 127.4, 127.0, 126.5, 117.4, 78.5, 72.8, 72.5, 69.2, 67.2, 59.4, 49.7, 35.8.

MS (ESI, 3.5 kV): m/z (%) = 536.2 [M + 1]⁺, 558.2 [M + Na]⁺.

HRMS: m/z [M + Na]⁺ calcd for C₃₅H₃₇NO₄Na: 558.2620; found: 558.2620.

Benzyl Benzyl[(2S,3S,5R)-1,3-bis(benzyloxy)-5-hydroxyoct-7-en-2-yl]carbamate (12a)

To a solution of compound 11 (0.7 g, 1.30 mmol) in acetone-H₂O (3:1, 10 mL) were added OsO₄ (0.5 mol%) and NMO (0.46 g, 3.92 mmol) at r.t. The mixture was stirred for 6 h, and then the reaction was quenched with solid NaHSO₄ (0.94 g, 7.84 mmol) and the mixture was stirred for 15 min. Solid particles were separated by filtration and the filtrate was dried (Na₂SO₄) and concentrated. The residue was dissolved in THF-H₂O (4:1, 10 mL), and NaIO₄ (0.84 g, 3.92 mmol) was added. After 30 min, the mixture was filtered, dried (Na₂SO₄), and concentrated to give the crude aldehyde. A solution of this crude aldehyde (0.6 g, 1.1 mmol) in anhydrous CH₂Cl₂ (15 mL) was treated with MgBr₂˙Et₂O (0.53 g, 3.31 mmol) and allyl(tributyl)stannane (0.51 mL, 1.65 mmol) at 0 ˚C, and the mixture was stirred for 3 h. The mixture was then washed with 2 M HCl solution (5 mL) and extracted with CH₂Cl₂ (2 × 25 mL). The combined organic layers were dried (Na₂SO₄) and concentrated. The residue was purified by flash column chromatography (silica gel) to give compound 12a as yellowish oil; yield: 0.40 g (64%); [α]_D ^²5 - 6.2 (c = 0.75, CHCl₃).

IR (neat): 3453(br, OH), 3063, 3030, 2920, 2854, 1692, 1452, 1414, 1241, 1067, 913, 734, 696 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 7.40-6.98 (m, 20 H), 5.85-5.53 (m, 1 H), 5.20-4.92 (m, 4 H), 4.71-3.92 (m, 8 H), 3.83-3.65 (m, 1 H), 3.55-3.24 (m, 2 H), 2.19-1.94 (m, 2 H), 1.67-1.45 (m, 2 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 157.0, 139.1, 136.4, 134.6, 128.8, 128.7, 128.3, 128.2, 128.1, 128.0, 127.8, 127.6, 127.4, 127.0, 126.6, 117.7, 77.0, 73.0, 72.7, 69.1, 67.8, 67.2, 60.0, 50.0, 42.5, 37.5..

LC-MS (EI, 70 eV): m/z (%) = 580.3 [M⁺ + 1], 602.3 [M + Na]⁺.

HRMS: m/z calcd for [M + Na]⁺ C₃₇H₄₁NO₅Na: 602.2882; found: 602.2854.

(3S,5S,6S)-6-[Benzyl(benzyloxycarbonyl)amino]-5,7-bis(ben­zyloxy)-3-hydroxyheptanoic Acid (24)

To a solution of compound 12a (0.5 g, 0.86 mmol) in acetone-H₂O (3:1, 5 mL) were added OsO₄ (0.5 mol%) and NMO (0.30 g, 2.59 mmol) at r.t. The mixture was stirred for 6 h, and the reaction was quenched with solid NaHSO₄ (0.62 g, 5.18 mmol) and the mixture was stirred for 15 min. Solid particles were separated by filtration, and the filtrate was dried (Na₂SO₄) and concentrated. The residue was dissolved in THF/H₂O (4:1, 5 mL), and NaIO₄ (0.55 g, 2.59 mmol) was added. After 30 min, the mixture was filtered, dried (Na₂SO₄), and concentrated to give the crude aldehyde. To a solution of this crude aldehyde (0.43 g, 0.74 mmol) in t-BuOH (5 mL) were added NaClO₂ (0.73 g, 8.14 mmol) and 20% aq Na₂H₂PO₄˙2H₂O (5 mL) at 0 ˚C, and the mixture was stirred for 4 h at r.t. The mixture was then diluted with EtOAc (5 mL) and washed with 5 M aq NaH₂PO₄ (1 mL). The organic layer was dried (Na₂SO₄) and concentrated, and residue was purified by flash column chromatography (silica gel) to afford compound 24 as a yellowish oil; yield: 0.43 g (85%); [α]_D ^²5 -6.0 (c = 0.23, CHCl₃).

IR (neat): 3435(br, OH), 3029, 2923, 2854, 1693, 1454, 1243, 1103, 738, 697 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 7.63-7.06 (m, 20 H), 5.13 (br s, 2 H), 4.79-4.04 (m, 9 H), 3.74-3.37 (m, 2 H), 2.51-2.24 (m, 2 H), 1.80-1.46 (m, 2 H).

^¹³C NMR (50 MHz, CDCl₃): δ = 157.2, 138.8, 137.5, 136.2, 128.4, 128.2, 128.0, 127.8, 127.7, 127.6, 127.0, 126.8, 77.1, 73.1, 72.8, 70.1, 69.0, 67.5, 59.8, 49.9, 41.5, 37.2.

LC-MS (EI, 70 eV) (ESI, 3.5 kV): m/z (%) = 620.3 [M + Na]⁺.

HRMS: m/z = [M + Na]⁺ calcd for C₃₆H₃₉NO₇Na: 620.2624; found: 620.2646.

(-)-Galantinic Acid (5)

To a solution of acid 24 (0.23 g, 0.38 mmol) in MeOH (10 mL) was added 10% Pd/C (0.01 g) under a H₂ atmosphere (0.1 mPa), and the mixture was stirred for 8 h. The mixture was then filtered and concentrated to give a residue that was purified on Dowex 50W×4, eluting with 1 M aq NH₃, to give a colorless solid; yield: 0.06 g (86%); [α]_D ^²5 -28.2 (c = 0.5, H₂O).

IR (KBr): 3448, 2923, 2851, 1637, 1458, 1215, 759 cm^-¹.

^¹H NMR (400 MHz, D₂O): δ = 4.26-4.17 (m, 1 H), 3.94-3.89 (m, 1 H), 3.78 (dd, J = 4, 12 Hz, 1 H), 3.64 (dd, J = 7, 12 Hz, 1 H), 3.18 (ddd, J = 4, 7, 7 Hz, 1 H), 2.59-2.44 (m, 2 H), 1.68-1.55 (m, 2 H).

LC/MS (EI, 70 eV): m/z (%) = 194.1 [M + 1]⁺, 216.1 [M + Na]⁺.

HRMS: m/z [M + Na]⁺ calcd for C₇H₁₅NO₅Na: 216.0847; found: 216.0839.

Acknowledgment

D.S. and K.V.P. thank CSIR, New Delhi, for the award of fellowships.

References and Notes

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References and Notes

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  Search in Google Scholar
• 1b Sam TW. Saw-Yeu C. Matsjeh S. Gan EK. Razak D. Mohamed AL. Tetrahedron Lett.  1987,  28:  2541 
  Search in Google Scholar
• 1c Talapatra SK. Basu D. Goaiwami S. Talapatra B. Indian J. Chem. Sect. B: Org. Chem. Incl. Med. Chem.  1985,  24:  29 
  Search in Google Scholar
• For reviews on the cytotoxic activity and other bioactivity of styryl lactones see:
• 2a Mereyala HB. Joe M. Curr. Med. Chem. Anti-Cancer Agents  2001,  1:  293 
  Search in Google Scholar
• 2b Blázquez MA. Bermejo A. Zafra-Polo MC. Cortes D. Phytochem. Anal.  1999,  10:  161 
  Search in Google Scholar
• 2c Mohd Ridzuan MAR. Ruenruetai U. Noor Rain A. Khozirah S. Zakiah I. Trop. Biomed.  2006,  23:  140 
  Search in Google Scholar
• 3a Surivet JP. Vatele JM. Tetrahedron Lett.  1998,  39:  7299 
  Search in Google Scholar
• 3b Prasad KR. Dhaware MG. Synlett.  2007,  1112 
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  Search in Google Scholar
• 3d Dixon DJ. Ley SV. Tate EW. J. Chem. Soc., Perkin Trans. 1  1998,  3125 
• 3e Tate EW. Dixon DJ. Ley SV. Org. Biomol. Chem.  2006,  4:  1698 
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• 3f Banwell MG. Coster MJ. Edwards AJ. Karunaratne OP. Smith JA. Welling LL. Willis AC. Aust. J. Chem.  2003,  56:  585 
  Search in Google Scholar
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• 3h Ramachandran PV. Chandra JS. Reddy MVR. J. Org. Chem.  2002,  67:  7547 
  Search in Google Scholar
• 3i Viroleaud MA. Bressy C. Piva O. Tetrahedron Lett.  2003,  44:  8081 
  Search in Google Scholar
• 3j Nakashima K. Kikuchi N. Shirayama D. Miki T. Ando K. Sono M. Suziki S. Kawase M. Kondoh M. Sato M. Tori M. Bull. Chem. Soc. Jpn.  2007,  80:  387 
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• 3k Prasad KR. Dhaware MG. Synlett  2007,  1112 
• 3l Yamshita Y. Saito S. Kobayashi S. J. Am. Chem. Soc.  2003,  125:  3793 
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• 3m Chen J. Lin G.-Q. Wang Z.-M. Liu H.-Q. Synlett  2002,  1265 
• 3n Tsubaki M. Kanai K. Nagase H. Honda T. Tetrahedron  1999,  55:  2493 
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• 3o Surivet JP. Vatele JM. Tetrahedron  1999,  55:  13011 
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• 3q Prasad KR. Gholap SL. Tetrahedron Lett.  2007,  48:  4679 
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• 3r Chen J. Lin GQ. Wang ZM. Liu HQ.   , 
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  CrossrefSearch in Google Scholar
• 10 Kiyooka S. Goh K. Nakamura Y. Takesue H. Hena MA. Tetrahedron Lett.  2000,  41:  6599 
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• 11 Moreau X. Campagne J. Tetrahedron Lett.  2001,  42:  4467 
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• 12 Raghavan S. Ramakrishna Reddy S. J. Org. Chem.  2003,  68:  5754 
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• 13 Bethuel Y. Gademann K. Synlett  2006,  1580 
  Thieme Connect
• 14 Kumar P. Pandey SK. Kandula SV. Tetrahedron Lett.  2004,  45:  5877 
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• 15a Nagaiah K. Sreenu D. Srinvasa Rao R. Yadav JS. Tetrahedron Lett.  2007,  48:  7173 
  Search in Google Scholar
• 15b Praveen Kumar S. Nagaiah K. Tetrahedron Lett.  2007,  48:  1391 
  Search in Google Scholar
• 15c Praveen Kumar S. Nagaiah K. Chorgade MS. Tetrahedron Lett.  2006,  40:  7149 
  Search in Google Scholar
• 16a Marton D. Stivanello D. Tagliavini G. J. Org. Chem.  1996,  61:  2731 
  Search in Google Scholar
• 16b Christian P. Jean LL. J. Org. Chem.  1985,  50:  910 
  Search in Google Scholar
• 16c Molas P. Matheu MI. Castillón S. Tetrahedron Lett.  2004,  45:  3721 
  Search in Google Scholar
• 16d Miranda LSM. Meireles BA. Costa JS. Pereira VLP. Vasconcellos MLAA. Synlett  2005,  869 
• 16e Paterson I. Anderson EA. Dalby SM. Genovino J. Lim JH. Moessner C. Chem. Commun.  2007,  1852 
• 16f Radha Krishna P. Ramana Reddy VV. Srinivas R. Tetrahedron  2007,  63:  9871 
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