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Synlett 2010(5): 761-764  
DOI: 10.1055/s-0029-1219354
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Organocatalytic Approach to Enantiopure 2,6-Disubstituted Tetrahydropyranols

Stephen Hanessian*, Xueling Mi
Department of Chemisty, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, QC, H3C 3J7, Canada
e-Mail: stephen.hanessian@umontreal.ca;
Further Information

Publication History

Received 24 November 2009
Publication Date:
26 January 2010 (online)

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Abstract

A method is described for the synthesis of cis-2,6-disubstituted tetrahydropyranols related to ring A of ambruticin S. An organocatalytic and metal-free aldol condensation was utilized as a key step between appropriate carbonyl-containing precursors resulting in high diastereoselection and 24% overall yield for seven steps.

Key words

organocatalysis - tetrahydropyranol - aldol reaction - ambruticin S - Michael-type cyclization

21

Procedure for the d -Proline-Catalyzed Aldol Product 3
A solution of 2 (349 mg, 2.0 mmol) in DMF solution (2.0 mL) was added slowly over the course of 18 h to a stirring suspension of 1 (1.63 g, 6.0 mmol), d-proline (69 mg, 0.6 mmol) in DMF solution (3.0 mL) at 4 ˚C. After stirring at 4 ˚C for 18 h, the resulting solution was diluted with Et2O (25 mL) and washed successively with H2O (15 mL) and brine (15 mL). The combined aqueous layers were then re-extracted with 3 portions of CH2Cl2 (20 mL). The organic layers were then combined, dried over Na2SO4, concen-trated, and purified with flash column chromatography (silica gel, EtOAc-hexanes = 1:4) to afford the desired aldol product 3 as a colorless oil (134 mg, 15%).
¹H NMR (400 MHz, CDCl3): δ = 9.65 (d, J = 1.2 Hz, 1 H), 7.02 (dt, J = 15.6, 7.6 Hz, 1 H), 5.91 (d, J = 15.6 Hz, 1 H), 4.15 (dd, J = 4.8, 1.2 Hz, 1 H), 4.03 (dd, J = 10.8, 5.2 Hz, 1 H), 3.80 (dt, J = 6.4, 4.8 Hz, 1 H), 3.74 (s, 3 H), 2.66-2.59 (m, 1 H), 2.51-2.43 (m, 1 H), 0.94 (s, 9 H), 0.90 (s, 9 H), 0.13 (s, 6 H), 0.10 (s, 6 H). ¹³C NMR (100 MHz, CDCl3): δ = 201.20, 166.26, 144.64, 123.28, 77.69, 75.59, 69.97, 51.10, 34.84, 25.45, 25.39, 17.84, 17.64, -4.62, -4.85, -4.89,
-5.39. ESI-MS: m/z calcd for C21H43O6Si2 [M + H]+: 446.3; found: 446.3.

22

Procedure for the d -Proline-Catalyzed Aldol Product 7
To a solution of d-proline (35 mg, 0.30 mmol) in DMF (2 mL) were added 2,2-dimethyl-1,3-dioxan-5-one (6, 650 mg, 5.0 mmol) and aldehyde 1 (272 mg, 1.0 mmol), and the resulting reaction mixture was stirred at 4 ˚C for 3 d. Then sat. NH4Cl solution (2 mL) and Et2O (5 mL) were added with vigorous stirring and the layers separated. The organic phase was combined, washed with brine (4 mL), dried over Na2SO4, concentrated, and purified with flash column chromatography (silica gel, EtOAc-hexanes = 1:4) to afford the desired aldol product 7 as a colorless oil (242 mg, 60%).
¹H NMR (400 MHz, CDCl3): δ = 6.94 (dt, J = 15.6, 7.6 Hz, 1 H), 5.92 (d, J = 15.6 Hz, 1 H), 4.30 (ABq, J = 17.2 Hz, 1 H), 4.13 (m, 1 H), 4.09 (ABq, J = 17.2 Hz, 1 H), 3.77 (m, 1 H), 3.74 (s, 3 H), 3.06 (d, J = 9.6 Hz, 1 H), 2.66 (ddt, J = 15.2, 7.6, 0.8 Hz, 1 H), 2.42 (ddt, J = 14.8, 7.6, 1.2 Hz, 1 H), 1.49 (s, 3 H), 1.46 (s, 3 H), 0.92 (s, 9 H), 0.12 (d, J = 1.6 Hz, 6 H). ¹³C NMR (100 MHz, CDCl3): δ = 209.39, 166.31, 144.26, 123.23, 100.40, 73.66, 71.50, 69.62, 66.66, 51.14, 36.57, 25.54, 24.24, 23.43, 17.80. [α]D ²0 +80.6 (c 2.2, CHCl3). ESI-MS: m/z calcd for C19H35O7Si [M + H]+: 403.2; found: 403.2.

23

Procedure for 8 To a solution of 7 (350 mg, 0.87 mmol) in MeOH (9 mL) was added NaBH4 (66 mg, 1.74 mmol) at -20 ˚C. The resulting reaction mixture was stirred at -20 ˚C for 2 h until TLC showed consumption of starting material, followed by treatment of ice water. The aqueous layer was then extracted with EtOAc (3 × 10 mL). The organic phase was combined, dried over MgSO4, concentrated, and purified with flash column chromatography (silica gel, EtOAc-hexanes = 1:2) to afford 8 as a colorless oil (211 mg, 80%). ¹H NMR (400 MHz, CDCl3): δ = 6.93 (dt, J = 15.6, 7.2 Hz, 1 H), 5.92 (d, J = 15.6 Hz, 1 H), 4.11 (dd, J = 8.0, 4.8 Hz, 1 H), 3.92 (dd, J = 11.2, 5.6 Hz, 1 H), 3.79 (m, 1 H), 3.76 (s, 3 H), 3.74 (m, 1 H), 3.64 (dd, J = 11.2, 9.6 Hz, 1 H), 3.46 (m, 1 H), 2.58 (ddt, J = 15.2, 7.6, 0.8 Hz, 1 H), 2.43 (m, 1 H), 1.48 (s, 3 H), 1.38 (s, 3 H), 0.94 (s, 9 H), 0.15 (s, 6 H). ¹³C NMR (100 MHz, CDCl3): δ = 166.25, 143.62, 123.28, 98.12, 76.44, 71.20, 67.90, 67.10, 62.95, 51.16, 37.03, 28.44, 25.46, 19.26, 17.87, -4.32, -4.96. [α]D ²0 +10.6 (c 2.0 in CHCl3). ESI-MS: m/z calcd for C19H38O7Si [M + H]+: 405.2; found: 405.2.

24

Procedure for 9
A solution of H2SO4 (0.1 M in MeOH, 0.68 mL) was added to a solution of 8 (138 mg, 0.34 mmol) in anhyd MeOH (3.4 mL), and this reaction mixture was heated under reflux for 3 h. The reaction was cooled to r.t. and the solvent removed in vacuo. The resultant residue was redissolved in MeOH (3.4 mL) and the solution heated under reflux for 3 h. This process was repeated for 3 times, then stirred overnight at r.t., at which time NaOMe (0.5 M in MeOH, 0.96 mL) was added. The mixture was heated under reflux for an additional 24 h. The solution was then cooled to r.t. and H2SO4 (0.1 M in MeOH) was added until the solution was strongly acidic (pH ca. 1). The solution was stirred for 2 h at r.t., and sat. aq NaHCO3 was added until the mixture was neutral. The insoluble salts were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting oil was purified by flash chromatography (silica gel, MeOH-EtOAc = 1:10) to provide compound 9 as a white solid
(58 mg, 68%).
¹H NMR (400 MHz, CD3OD): δ = 3.89-3.84 (m, 2 H), 3.73-3.70 (m, 2 H), 3.69 (s, 3 H), 3.64-3.56 (m, 2 H), 3.24 (dd, J = 9.6, 4.8 Hz, 1 H), 2.55 (d, J = 3.2 Hz, 1 H), 2.53 (d, J = 1.6 Hz, 1 H), 2.02 (ddd, J = 12.8, 5.6, 1.6 Hz, 1 H), 1.36 (q, J = 12.8 Hz, 1 H). ¹³C NMR (100 MHz, CD3OD): δ = 171.48, 78.92, 73.16, 71.85, 71.70, 62.33, 50.44, 39.43, 38.01. [α]D ²0 -6.89 (c 2.8, MeOH). ESI-MS: m/z calcd for C10H19O7 [M + H]+: 251.1; found: 251.1.

25

Procedure for 5
To a solution of 9 (50 mg, 0.2 mmol) in THF and H2O (3 mL, v/v 2:1) was added NaIO4 (51 mg, 0.24 mmol) at 0 ˚C, and the resulting solution was stirred for 15 min at 0 ˚C, followed by addition of EtOAc. The solution was filtered through a Celite pad and washed with EtOAc. The EtOAc filtrate was then washed with sat. Na2S2O3 (3 mL), dried over MgSO4, and concentrated under vacuum. The crude aldehyde was then dissolved in MeOH (2 mL), to which NaBH4 (30 mg, 0.8 mmol) was added in one portion at 0 ˚C. The resulting solution was then stirred at 0 ˚C for 30 min, followed by treatment of ice water. The aqueous layer was extracted with EtOAc (3 × 5 mL), dried over MgSO4, filtered, and concentrated under vacuum. The crude triol was then purified with flash column chromatography (silica gel, MeOH-EtOAc = 1:9) to provide 5 ¹³e as a white solid (32 mg, 72%).
¹H NMR (400 MHz, CD3OD): δ = 3.92-3.81 (m, 2 H), 3.69 (s, 3 H), 3.59-3.55 (m, 2 H), 3.20 (d, J = 1.6 Hz, 1 H), 2.61 (dd, J = 15.6, 7.2 Hz, 1 H), 2.51 (dd, J = 15.6, 5.6 Hz, 1 H), 2.04 (ddd, J = 12.8, 5.2, 2.0 Hz, 1 H), 1.36 (q, J = 12.8 Hz, 1 H). ¹³C NMR (100 MHz, CD3OD): δ = 176.33, 82.77, 73.16, 72.63, 71.04, 62.98, 52.80, 41.85, 39.77. ESI-MS: m/z calcd for C9H17O6 [M + H]+: 220.1; found: 220.1.