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Synlett 2012(6): 913-916  
DOI: 10.1055/s-0031-1290614
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Concise Synthetic Approach to (+)-Valienamine Starting from Garner’s Aldehyde

Bing Zhoua,, Zhi Luoa,, Sui Linb, Yuanchao Li*a
a Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Road Zu Chong Zhi, Zhangjiang Hi-Tech Park,Shanghai 201203, P. R. of China
Fax: +86(21)50807288; e-Mail: ycli@mail.shcnc.ac.cn;
b Fujian Institute of Medical Sciences, Fuzhou 350001, P. R. of China
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Publication History

Received 15 December 2011
Publication Date:
15 March 2012 (online)

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Abstract

A synthesis of (+)-valienamine was achieved starting from Garner’s aldehyde in ten steps and 23% overall yield. A unique feature of the synthetic route is that an acyclic precursor was constructed, using diastereoselective antireductive coupling reaction of alkyne and Garner’s aldehyde as the key step, which was then cyclized in an intramolecular aldol reaction to form the valienamine skeleton.

Key words

(+)-valienamine - Garner’s aldehyde - diastereoselective - hydrozirconation-transmetalation - intramolecular aldol reaction

17

Procedure for the Synthesis of 6
To an ice-cooled stirred suspension of Cp2Zr(H)Cl (5.05 g, 19.6 mmol) in THF (50 mL) under argon protection was added tert-butyl(but-3-ynyloxy)dimethylsilane (3.61 g, 19.6 mmol), the mixture was stirred at r.t. for 1 h, and then cooled to 0 ˚C. To the resulting orange solution was added aldehyde 7 (2.25g, 9.8 mmol) in THF (35 mL) followed by ZnBr2 (552 mg, 2.45 mmol, dried under vacuum for 1 h before use), and the mixture was stirred for 24 h at r.t. The mixture was diluted with EtOAc (100 mL) and aq potassium sodium
(+)-tartrate (5.7 g, 19.6 mmol), and stirred for 10 min. The resulting suspension was filtered off and washed thoroughly with EtOAc (100 mL). The combined filtrate was transferred into a separatory funnel and successively washed with H2O and brine. The aqueous phase was extracted with EtOAc (2 × 200 mL), and the combined organic layers were dried over anhyd Na2SO4. The mixture was concentrated and purified by silica gel chromatography to afford 6 (3.625 g, 84%) as a colorless oil: [α] D ²0 -27.0 (c 1.2, CHCl3). ¹H NMR (300 MHz, CDCl3): δ = 5.72 (m, 1 H), 5.49 (dd, J = 15.0, 6.0 Hz, 1 H), 4.02 (m, 4 H), 3.61 (t, J = 6.0, 2 H), 2.26 (m, 2 H), 1.48 (s, 15 H), 0.86 (s, 9 H), 0.01 (s, 6 H). ¹³C NMR (100 MHz, CDCl3): δ = 153.8, 130.6, 128.7, 94.1, 80.7, 73.6, 64.7, 62.7, 61.9, 35.9, 28.2, 28.2, 28.2, 26.3, 25.8, 25.8, 25.8, 24.5, 18.1, -5.4, -5.4. IR (film): 3454, 2931, 2858, 1699, 1473, 1387, 1255, 1174, 1097, 837, 775 cm-¹. MS (EI): m/z (%) = 415 (0.04)[M+], 100 (64.29), 57 (100.00). HRMS (EI): m/z calcd for C21H41NSiO5 [M+]: 415.2754; found: 415.2765.

21

Procedure for the Synthesis of 11
To a suspension of 3 (40 mg, 0.09 mmol) and CeCl3˙7H2O (52 mg, 0.135 mmol) in MeOH (3 mL) was added NaBH4 (4 mg, 0.1 mmol) at 0 ˚C. The mixture was stirred for 15 min, and the solvent was removed under reduced pressure. Then, H2O (3 mL) was added to the residue, which was then extracted with EtOAc (3 × 6 mL). The organic layer was washed with H2O (3 mL) and brine (3 mL), dried (Na2SO4), filtered, and and the solvent was removed under reduced pressure to give the colorless oil, which was directly dissolved in CH2Cl2 (4 mL), and TFA (2 mL) was added. The mixture was stirred for 4 h at 0 ˚C. Then, the solvent was removed in vacuum to give the crude product 1, which was dissolved in pyridine (2 mL) and Ac2O (1 mL) containing a catalytic amount of DMAP. The mixture was stirred at r.t. for 24 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with sat. NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, and filtered. Concentration of the filtrate followed by chromatography gave pentaacetate 11 (23 mg, 68% over 3 steps) as a white solid; mp 91-93 ˚C; [α]D ²0 +20.0 (c 0.075, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 2.02 (s, 6 H), 2.06 (s, 3 H), 2.07 (s, 6 H), 4.39 and 4.64 (ABq, J = 13.2 Hz, 2 H), 5.02-5.11 (m, 2 H), 5.36 (br d, J = 6.8 Hz, 1 H), 5.45 (dd, J = 10.0, 6.4 Hz, 1 H), 5.70 (br d, J = 8.4 Hz, 1 H), 5.89 (dd, J = 5.2, 1.2 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 20.7, 20.8, 20.8, 20.8, 23.3, 44.9, 62.9, 68.5, 69.0, 71.2, 126.1, 134.3, 169.9, 170.0, 170.2, 170.3, 170.4. IR (film): 3363, 3269, 2924, 2850, 1743, 1649, 1556, 1469, 1371, 1223, 1024 cm-¹. MS (EI): m/z (%) = 385 (0.67) [M+], 326 (100.00), 223 (57.20), 164 (68.60). HRMS (EI): m/z calcd for C17H23NO9 [M+]: 385.1373; found: 385.1370.