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

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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• 8c Kato A. Asano N. Kizu H. Matsui K. Watson AA. Nash RJ. J. Nat. Prod.  1997,  60:  312 
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• Recent progresses in the use of heterocyclic-derived vinyl phoshpates:
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• The relative stereochemistry of 15 was assigned by NOESY-1D studies which also, together with the coupling constant values, showed that all substituents are axially oriented. There is no large trans-diaxial coupling constant between 2-H and 3-H, 3-H and 4-H, and between 4-H and either of the protons on C-5, as all of them are in equatorial position. Consistently, a strong NOE effect was found between axial 6-H and one of the protons (CH₂OSEM) on the side chain at C-2. In N-protected piperidines analogues to 15, the C-2 substituent is forced towards an axial orientation to relieve the A^(¹,³) strain with the N-protection. See:
• 20a Comins DL. Joseph SP. In Advances in Nitrogen Heterocycles   Vol. 2:  Moody CJ. JAI Press; Greenwich CT: 1996.  p.251-294  
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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).