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

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

References and Notes

• 1 Those authors contributed equally
• 2 Kameda Y. Asano N. Yoshikawa M. Matsui K. J. Antibiot.  1982,  35:  1624 
• 3 Kameda Y. Horii S. J. Chem. Soc., Chem. Commun.  1972,  746 
• 4a Kameda Y. Asano N. Teranishi M. Matsui K. J. Antibiot.  1980,  33:  1573 
• 4b Kameda Y. Asano N. Teranishi M. Yoshikawa M. Matsui K. J. Antibiot.  1981,  34:  1237 
• 4c Asano N. Takeuchi M. Ninomiya K. Kameda Y. Matsui K. J. Antibiot.  1984,  37:  859 
• 5a Ogawa S. Miyamoto Y. Nakajima A. Chem. Lett.  1989,  725 
• 5b Ogawa S. Nakajima A. Miyamoto Y. J. Chem. Soc., Perkin Trans. 1  1991,  3287 
• 6a Chen X. Fan Y. Zheng Y. Shen Y. Chem. Rev.  2003,  103:  1955 
• 6b Mahmud T. Nat. Prod. Rep.  2003,  20:  137 
• 7 Paulsen H. Heiker FR. Angew. Chem., Int. Ed. Engl.  1980,  19:  904 
• 8a Chang Y.-K. Lee B.-Y. Kim D.-J. Lee G.-S. Jeon H.-B. Kim K.-S. J. Org. Chem.  2005,  70:  3299 
• 8b Fukase H. Horii S. J. Org. Chem.  1992,  57:  3651 
• 8c Yoshikawa M. Cha BC. Okaichi Y. Takinami Y. Yokokawa Y. Kitagawa I. Chem. Pharm. Bull.  1988,  36:  4236 
• 8d Nicotra F. Panza L. Ronchetti F. Russo G. Gazz. Chim. Ital.  1989,  119:  577 
• 8e Park TK. Danishefsky SJ. Tetrahedron Lett.  1994,  35:  2667 
• 8f Vasella A. Kapferer P. Sarabia F. Helv. Chim. Acta  1999,  82:  645 
• 8g Tatsuta K. Mukai H. Takahashi M.
  J. Antibiot.  2000,  53:  430 
• 8h Schmidt RR. Kohn A. Angew. Chem., Int. Ed. Engl.  1987,  26:  482 
• 9a Kok SHL. Lee C.-C. Shing TKM. J. Org. Chem.  2001,  66:  7184 
• 9b Shing TKM. Li T.-Y. Kok SHL. J. Org. Chem.  1999,  64:  1941 
• 9c Shing TKM. Kwong CSK. Cheung AWC. Kok SH.-L. Yu Z. Li J. Cheng CHK. J. Am. Chem. Soc.  2004,  126:  15990 
• 10a Ogawa S. Shibata Y. Nose T. Suami T. Bull. Chem. Soc. Jpn.  1985,  58:  3387 
• 10b Knapp S. Naughton ABJ. Dhar TGM. Tetrahedron Lett.  1992,  33:  1025 
• 10c Trost BM. Chupak LS. Lubbers T. J. Am. Chem. Soc.  1998,  120:  1732 
• 10d Chang YK. Lo HJ. Yan TH. Org. Lett.  2009,  11:  4278 
• 11 Garner P. Tetrahedron Lett.  1984,  25:  5855 
• 12 Cram DJ. Kopecky KR. J. Am. Chem. Soc.  1959,  81:  2748 
• 13a Cherest M. Felkin H. Prudent N. Tetrahedron Lett.  1968,  9:  2119 
• 13b Cherest M. Felkin H. Tetrahedron Lett.  1968,  9:  2205 
• 13c Anh NT. Eisenstein OE. Nouv. J. Chim.  1977,  1:  61 
• 13d Anh NT. Top. Curr. Chem.  1980,  88:  145 
• 14a Herold P. Helv. Chim. Acta  1988,  71:  354 
• 14b Garner P. Park JM. Malecki E. J. Org. Chem.  1988,  53:  4395 
• 14c Radunz H.-E. Devant RM. Eiermann V. Liebigs Ann. Chem.  1988,  1103 
• 15 Wipf P. Xu W. Tetrahedron Lett.  1994,  35:  5197 
• 16 Murakami T. Furusawa K. Tetrahedron  2002,  58:  9257 
• 18 Donohoe TJ. Newcombe NJ. Waring MJ. Tetrahedron Lett.  1999,  40:  6881 
• 19 Wei CQ. Jiang XR. Ding Y. Tetrahedron  1998,  54:  12623 
• 20a Corey EJ. Danheiser RL. Chandrasekaran S. Siret P. Keck GE. Gras J.-L. J. Am. Chem. Soc.  1978,  100:  8031 
• 20b Caton MPL. Stuttle KAJ. Tuffin DP. Ansell MF. Eur. J. Med. Chem.  2000,  1099 
• 20c Wu Y. Zhang H. Zhao Y. Zhao J. Chen J. Li L. Org. Lett.  2007,  9:  1199 

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 Na₂SO_4, 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.