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Synlett 2009(6): 913-916  
DOI: 10.1055/s-0028-1088202
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Chemistry of Lactam-Derived Vinyl Phosphates: Stereoselective Synthesis of (+)-Fagomine

Laura Bartalia, Dina Scarpia, Antonio Guarnaa, Cristina Prandib, Ernesto G. Occhiato*a
a Dipartimento di Chimica Organica ‘U. Schiff’, Università di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
Fax: +39(055)4573531; e-Mail: ernesto.occhiato@unifi.it;
b Dipartimento di Chimica Generale e Chimica Organica, Università di Torino, Via P. Giuria 7, 10125 Torino, Italy
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Publication History

Received 17 December 2008
Publication Date:
16 March 2009 (online)

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Chemistry of Lactam-Derived Vinyl Phosphates: Stereoselective Synthesis of (+)-FagomineSynlett 2010; 2010(05): 839-839
DOI: 10.1055/s-0029-1219556

Abstract

The synthesis of (+)-fagomine, based on the Pd-catalyzed methoxycarbonylation reaction of a lactam-derived vinyl phosphate and the stereoselective hydroboration-oxidation of the enamine double bond, is presented. The target product is obtained in 23% overall yield in eight steps from a known lactam.

Key words

palladium - carbonylation - stereoselective hydrobo­r­ations - piperidine alkaloids - (+)-fagomine

    References and Notes

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12

Typical Procedure
To a solution of KHMDS (5.85 mL of a 0.5 M solution in toluene, 2.93 mmol) in THF (15.5 mL), cooled at -78 ˚C and under nitrogen atmosphere, was added a solution of 8 (687 mg, 2.34 mmol) in THF (6 mL) and the resulting mixture was stirred for 1.5 h. Afterward a solution of (PhO)2P(O)Cl (605 µL, 2.93 mmol) in THF (5 mL) was added, stirring was continued for 1 h at -78 ˚C before allowing the temperature to rise to 0 ˚C. Then, a 10% NaOH aq soln (47 mL) was added, the mixture was extracted with Et2O (3 × 40 mL), washed with 10% NaOH (30 mL), and dried over anhyd K2CO3 for 30 min. After filtration and evaporation of the solvent (without heating and leaving a small volume of solvent), the crude phosphate was chromatographed (EtOAc-n-hexane, 1:2, +1% Et3N, R f = 0.26) on a short layer of SiO2 (3.5 cm of SiO2 in a column with internal diameter of 3 cm) to give 9 (1.044 g, 85%) as a pale yellow oil. ¹H NMR (200 MHz, CDCl3): δ = 7.40-7.16 (m, 12 H), 6.86 (d, J = 8.8 Hz, 2 H), 5.25 (t, J = 2.9 Hz, 1 H), 4.43 (s, 2 H), 4.07-3.96 (m, 1 H), 3.79 (s, 3 H), 3.84-3.72 (m, 1 H), 3.55 (s, 3 H), 3.35 (td, J = 12.8, 2.6 Hz, 1 H), 2.09-1.92 (m, 1 H), 1.87-1.68 (m, 1 H). ¹³C NMR (50 MHz, CDCl3): δ = 159.0 (s), 154.1 (s), 150.4 (s, 2 C), 141.1 (s), 129.7 (d, 4 C), 129.5 (s), 129.1 (d, 2 C), 125.5 (d, 2 C), 120.0 (d, 4 C), 113.8 (d, 2 C), 98.8 (d), 69.7 (d), 68.5 (t), 55.3 (q), 53.3 (q), 42.8 (t), 29.7 (t). MS: m/z = 525 (1) [M+], 121 (100).
Phosphate 9 (1.044 g, 1.99 mmol) was immediately dissolved in DMF (6 mL), Ph3P (123 mg, 0.47 mmol) and Pd(OAc)2 (53 mg, 0.24 mmol) were added, and the solution was stirred 10 min under a CO atmosphere (balloon). Then Et3N (649 µL, 4.68 mmol) and MeOH (3.8 mL, 93.6 mmol) were added and stirring was continued at 50 ˚C (external bath) for 2 h under static CO pressure. The solution was diluted with H2O (46 mL) and extracted with Et2O (4 × 46 mL), washed with brine (30 mL), and dried over Na2SO4. After filtration and evaporation of the solvent, the oily residue was chromatographed (EtOAc-n-hexane, 1:2, R f = 0.27) to give 10 (633 mg, 95%) as a thick pale yellow oil. Spectroscopic and analytical data as reported. [4]

13

We have already shown that generation of the enolate from a 4-silyloxy-substituted lactam causes both elimination of silanol (TBSOH) and migration of the silyl group to the enolate O atom. Thus, the phosphate has to be prepared from the lactam with a PMB-protected 4-OH group, see ref. [4] .

14

When the reaction is complete, before proceeding with the extractions, the pale brown solid was filtered under vacuum through a layer of Celite washing with CH2Cl2.

17

Typical Procedure
To a solution of 12 (266 mg, 0.81 mmol) in anhyd Et2O (23 mL), cooled at -78 ˚C, was added dropwise a solution of DIBAL-H (1.78 mL of a 1 M solution in n-hexane, 1.78 mmol) under stirring and nitrogen atmosphere. After 1 h, the reaction mixture was heated to 0 ˚C and left under stirring for 30 min. Then sat. aq NH4Cl (3.5 mL) was added, and the mixture was diluted with 11 mL of CH2Cl2. Then it was filtered through a Celite layer, the phases were separated, and the aqueous one was extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Chromatography (SiO2, eluant EtOAc-n-hexane 1:3, R f = 0.25) afforded 13 (177 mg,) in 73% yield as a colorless oil; [α]D ²0 +149.3 (c 0.35, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 5.15 (d, J = 4.1 Hz, 1 H), 4.31-4.26 (m, 1 H), 4.19-4.13 (m, 1 H + 1 H), 3.82 (ddd, J = 12.9, 5.0, 3.8 Hz, 1 H), 3.76 (s, 3 H), 3.40 (ddd, J = 12.9, 9.4, 4.7 Hz, 1 H), 1.81-1.77 (m, 2 H), 0.88 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 154.7 (s), 139.4 (s), 115.9 (d), 65.0 (t), 62.1 (d), 53.2 (q), 40.8 (t), 32.3 (t), 25.9 (q, 3 C), 18.1 (s), -4.4 (q), -4.6 (q). MS: m/z = 301 (0.5) [M+], 244 (100). Anal. Calcd for C14H27NO4Si: C, 55.78; H, 9.03; N, 4.65. Found: C, 55.44; H, 8.94; N, 4.39.

18

Compound 14.
Chromatography (SiO2): eluant: EtOAc-n-hexane (1:12 then 1:6), R f = 0.46; [α]D ²² +126.1 (c 0.49, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 5.24 (d, J = 3.5 Hz, 1 H), 4.67 (s, 2 H), 4.50 (d, J = 13.1 Hz, 1 H, part of an AB system), 4.39 (d, J = 13.1 Hz, 1 H, part of an AB system), 4.19 (m, 1 H), 3.89 (ddd, J = 12.9, 5.5, 3.7 Hz, 1 H), 3.72 (s, 3 H), 3.66-3.60 (m, 2 H), 3.39 (ddd, J = 12.9, 9.2, 4.3 Hz, 1 H), 1.83-1.78 (m, 2 H), 0.96-0.92 (m, 2 H), 0.88 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H), 0.02 (s, 9 H). ¹³C NMR (100 MHz, CDCl3): δ = 154.2 (s), 137.0 (s), 115.0 (d), 93.9 (t), 68.0 (t), 65.3 (t), 62.7 (d), 52.8 (q), 41.5 (t), 33.2 (t), 25.9 (q, 3 C), 18.1 (s),18.0 (t), -1.4 (q, 3 C), -4.4 (q), -4.6 (q). MS: m/z = 431 (1) [M+], 228 (37), 73 (100). Anal. Calcd for C20H41NO5Si2: C, 55.64; H, 9.57; N, 3.24. Found: C, 55.31; H, 9.62; N, 3.02.

19

Typical Procedure
To a solution of 14 (77 mg, 0.18 mmol) in anhyd THF (8.4 mL), under nitrogen atmosphere and cooled at -78 ˚C, was added a solution of BH3˙THF (612 µL of a 1.0 M solution in THF, 0.612 mmol). After 5 min, the flask was submerged in an ice bath and left at 0 ˚C for 22 h. Then, under vigorous stirring, Me3NO (trimethylamine N-oxide, 162 mg, 2.16 mmol) was added and, after mounting a condenser, the reaction was heated at 65 ˚C (external bath) for 2 h. After cooling, EtOAc (16 mL) was added, the organic layer was washed with brine (2 × 8 mL) and dried over anhyd Na2SO4. Chromatography (EtOAc-n-hexane, 1:3, R f = 0.22) afforded 15 (56 mg, 70%) as a colorless oil; [α]D ²² -1.4 (c 0.175, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 4.65 (d, J = 6.6 Hz, 1 H, part of an AB system), 4.61 (d, J = 6.6 Hz, 1 H, part of an AB system), 4.41 (br m, 1 H), 3.99 (dd, J = 10.7, 8.8 Hz, 1 H), 3.90 (br d, J = 13.3 Hz, 1 H), 3.89-3.86 (m, 1 H), 3.69 (s, 3 H), 3.70-3.67 (m, 1 H), 3.66-3.49 (m, 1 H + 2 H), 3.20 (td, J = 13.3, 2.5 Hz, 1 H), 2.01 (m, 1 H), 1.42 (br dd, J = 13.7, 2.3 Hz, 1 H), 0.95-0.90 (m, 2 H), 0.89 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H), 0.00 (s, 9 H). ¹³C NMR (100 MHz, CDCl3): δ = 157.3 (s), 94.4 (t), 68.7 (d), 68.4 (d), 65.0 (t), 64.5 (d), 57.3 (t), 52.7 (q), 34.3 (t), 27.9 (t), 25.7 (q, 3 C), 18.1 (s), 17.9 (t), -1.5 (q, 3 C), -5.0 (q), -5.1 (q). MS: m/z = 449 (0.1) [M+], 244 (85), 156 (53), 73 (100). Anal. Calcd for C20H43NO6Si2: C, 53.41; H, 9.64; N, 3.11. Found: C, 53.05; H, 9.32; N, 2.88.

21

Typical Procedure
A suspension of 15 (55 mg, 0.12 mmol) in 2 N HCl (aq) was refluxed for 18 h. After cooling at r.t., it was washed with Et2O (5 × 10 mL), concentrated, and triturated with CHCl3 to give 1˙HCl (22 mg, 100%) as pale yellow solid after 12 h under vacuum; [α]D ²³ +12.3 (c 0.38, H2O); lit. [¹0f] [α]D ²0 +12.9 (c 0.93, H2O). ¹H NMR (400 MHz, D2O): δ = 3.97 (dd, J = 12.5, 3.1 Hz, 1 H, part of an ABX system), 3.91 (dd, J = 12.5, 5.1 Hz, 1 H, part of an ABX system), 3.75 (ddd, J = 14.0, 10.1, 4.7 Hz, 1 H), 3.56 (pseudo t, J = 10.1 Hz, 1 H), 3.48 (br d, J = 12.1 Hz, 1 H), 3.19-3.10 (m, 1 H + 1 H), 2.27-2.22 (m, 1 H), 1.81-1.74 (m, 1 H). ¹³C NMR (100 MHz, D2O): δ = 70.9 (d), 70.1 (d), 60.9 (d), 58.2 (t), 42.4 (t), 29.1 (t).