A Concise Diastereoselective Approach to the Left-Hand Side of Batzelladine A

Abstract

A highly diastereoselective three-component coupling reaction has been used in a concise approach to the left-hand side of batzelladine A. The stereoselectivity of this reaction, along with related observations described herein, provides insight into the mechanism of this reaction.

Key words

multicomponent reactions - alkaloids - imines - stereoselectivity - isothiocyanates

References and Notes

• For reviews, see:
• 1a Aron ZD. Overman LE. Chem. Commun.  2004,  253 
• 1b Heys L. Moore CG. Murphy PJ. Chem. Soc. Rev.  2000,  29:  57 
• 1c Morris JC. Nicholas GM. Phillips AJ. Nat. Prod. Rep.  2007,  24:  87 
• 2a Patil AD. Kumar NV. Kokke W. Bean MF. Freyer AJ. De Brosse C. Mai S. Truch A. Faulkner DJ. Cartre PB. Breen AL. Hertzberg RT. Johnson R. Westley JW. Potts BCM. J. Org. Chem.  1995,  60:  1182 
• 2b Patil AD. Freyer AJ. Taylor PB. Cartre PB. Zuber B. Johnson R. Faulkner DJ. J. Org. Chem.  1997,  62:  1814 
• 2c Braekman JC. Daloze D. Tavares R. Hajdu E. Van Soest RWM. J. Nat. Prod.  2000,  63:  193 
• 2d Gallimore WA. Kelly M. Scheuer PJ. J. Nat. Prod.  2005,  68:  1420 
• 2e Hua H.-M. Peng J. Dunbar DC. Schinazi RF. de Castro Andrews AG. Cuevas C. Garcia-Fernandez LF. Kelly M. Hamann MT. Tetrahedron  2007,  63:  11179 
• 3a Bewley CE. Ray S. Cohen F. Collins SK. Overman LE. J. Nat. Prod.  2004,  67:  1319 
• 3b Shimokawa J. Iijima Y. Hashimoto Y. Chiba H. Tanaka H. Nagasawa K. Heterocycles  2007,  72:  145 
• 3c Shimokawa J. Ishiwata T. Shirai K. Koshino H. Tanatani A. Nakata T. Hashimoto Y. Nagasawa K. Chem. Eur. J.  2005,  11:  6878 
• 4a Shimokawa J. Shirai K. Tanatani A. Hashimoto Y. Nagasawa K. Angew. Chem. Int. Ed.  2004,  43:  1559 
• 4b Arnold MA. Day KA. Durón SG. Gin DY. J. Am. Chem. Soc.  2006,  128:  13255 
• 5a Cohen F. Overman LE. Ly Sakata SK. Org. Lett.  1999,  1:  2169 
• 5b Nagasawa K. Ishiwata T. Hino T. Koshino H. Hashimoto Y. Nakata T. Org. Lett.  2002,  4:  2921 
• 5c Arnold MA. Durón SG. Gin DY. J. Am. Chem. Soc.  2005,  127:  6924 
• 5d Evans PA. Qin J. Robinson JE. Bazin B. Angew. Chem. Int. Ed.  2007,  46:  7417 
• 6 Snider BB. Chen J. Patil AD. Faulkner DJ. Tetrahedron Lett.  1996,  37:  6977 
• 7a Cohen F. Overman LE. J. Am. Chem. Soc.  2001,  123:  10782 
• 7b Cohen F. Overman LE. J. Am. Chem. Soc.  2006,  128:  2604 
• 8 Collins SK. McDonald AI. Overman LE. Rhee YH. Org. Lett.  2004,  6:  1253 
• For related work, see:
• 9a Black GP. Murphy PJ. Thornhill AJ. Walshe NDA. Zanetti C. Tetrahedron  1999,  55:  6547 
• 9b Louwrier S. Ostendorf M. Tuynman A. Hiemstra H. Tetrahedron Lett.  1996,  37:  905 
• 10a Elliott MC. Long MS. Tetrahedron Lett.  2002,  43:  9191 
• 10b Elliott MC. Long MS. Org. Biomol. Chem.  2004,  2:  2003 
• 11a Tanino H. Nakata T. Kaneko T. Kishi Y. J. Am. Chem. Soc.  1977,  99:  2818 
• 11b Taguchi H. Yazawa H. Arnett JF. Kishi Y. Tetrahedron Lett.  1977,  17:  627 
• 11c Hong CY. Kishi Y. J. Am. Chem. Soc.  1992,  114:  7001 
• 12 Elliott MC. Kruiswijk E. J. Chem. Soc., Perkin Trans. 1  1999,  3157 
• 13 Davies CD. Elliott MC. Wood JL. Tetrahedron  2006,  62:  11158 
• 14 Nishiyama K. Oba M. Bull. Chem. Soc. Jpn.  1987,  60:  2289 
• 18 Duron SG. Gin DY. Org. Lett.  2001,  3:  1551 
• 19a

  There is precedent for the deoxygenation of a secondary alcohol in the presence of an S-methylisothiourea, see ref. 19b. While we have been able to successfully S-methylate compound 25, the subsequent xanthate formation proved troublesome, and these studies are ongoing.

• 19b Buenger GS. Nair V. Synthesis  1990,  962 

15

( Z )-Methyl [3-Methoxycarbonylamino)-3-phenyl-2-pyrrolidin-2-ylidene]propionate (16)
Methyl N-phenylmethylenecarbamate (15, 62 mg, 0.38 mmol) was added to a solution of (Z)-pyrrolidin-2-ylidene-acetic acid methyl ester (11, 54 mg, 0.38 mmol) in CH₂Cl₂ (5 mL). The resulting solution was stirred at r.t. overnight, concentrated in vacuo, and purified by flash column chromatography (eluent: hexane-EtOAc, 2:1; R _f = 0.4) to give the title compound (78 mg, 67%) as a colourless oil. HRMS: m/z calcd for C₁₆H₂₁N₂O₄ [M]: 305.1501. Found: 305.1515 [MH⁺]. ^¹H NMR (400 MHz, CDCl₃): δ = 8.27 (1 H, br s, NH), 7.21-7.18 (4 H, m, J = 4.2 Hz, arom. CH), 7.14-7.08 (1 H, m, arom. CH), 5.91 (1 H, app. br d, J = 9.4 Hz, NH), 5.11 (1 H, d, J = 10.0 Hz, CHPh), 3.65 (3 H, s, Me), 3.54-3.50 (2 H, m, CH₂N), 3.42 (3 H, s, Me), 3.05 (1 H, ddd, J = 16.8, 8.6, 6.9 Hz, one of CH₂), 2.70 (1 H, ddd, J = 16.8, 8.8, 7.1 Hz, one of CH₂C=C) and 2.00-1.94 (2 H, m, CH₂). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 169.7 (C=O), 166.2 (C=O), 157.1 (C=CCO₂Me), 143.2 (arom. C), 128.0 (arom. CH), 126.3 (arom. CH), 125.8 (arom. CH), 90.1 (C=CCO₂Me), 53.6 (CH), 52.0 (CH₃), 50.1 (CH₃), 47.5 (CH₂), 31.5 (CH₂), 21.7 (CH₂). MS (TOF AP⁺): m/z (%) = 305 (22) [MH⁺], 230 (100), 195 (43).

16

( Z )-Ethyl 3-(Cyanoamino)-2-(pyrrolidin-2-ylidene)oct-anoate (18)
Cyanamide (16 mg, 0.4 mmol) was added to a solution of hexanal (48 µL, 0.4 mmol) in dry CH₂Cl₂ (4 mL) under N₂, and the resulting suspension was stirred at 25 ˚C for 30 min. A solution of (Z)-pyrrolidin-2-ylidene-acetic acid ethyl ester (17, 60 mg, 0.4 mmol) in CH₂Cl₂ (2 mL) was added, and the resulting mixture was stirred at 25 ˚C for 3 h. The solvent was then removed in vacuo to afford the title compound as a pale yellow gum (94 mg, 87% crude yield). ^¹H NMR (500 MHz, CDCl₃): δ = 8.26 (1 H, br s, NH), 4.37 (1 H, br s, NHCN), 4.00-4.18 (2 H, m, CO₂CH₂), 3.75 (1 H, app. q, J = 7.4 Hz, CHNHCN), 3.50 (2 H, app. t, J = 7.0 Hz, CH ₂NH), 2.78 (1 H, ddd, J = 16.1, 9.1, 7.0 Hz, one of CH₂C=C), 2.58 (1 H, ddd, J = 16.1, 9.2, 6.9 Hz, one of CH₂C=C), 1.89-2.03 (2 H, m, pyrrolidine CH ₂CH₂NH), 1.64-1.85 (2 H, m, CH ₂CHNHCN), 1.14-1.26 [9 H, m, (CH₂)₃ and CO₂CH₂CH ₃], 0.81 (3 H, t, J = 6.9 Hz, CH ₃CH₂-alkyl). ^¹³C NMR (125 MHz, CDCl₃): δ = 169.0 (ester C=O), 166.0 (C=CCO₂Et), 117.3 (NHCºN), 88.3 (C=CCO₂Et), 59.0 (CO₂ CH₂), 47.3 (CHNHCN), 35.2 (CH₂NH), 31.6 (CH₂C=C), 31.5 (CH₂CHNHCN), 26.6 (CH₂CH₂NH), 22.5 (CH₂) 22.4 (CH₂), 21.6 (CH₃ CH₂-alkyl), 14.6 (CO₂CH₂ CH₃), 13.9 (CH₃CH₂-alkyl).

17

Methyl (5 S )-1,2,3,5,6,7-Hexahydro-3-(9- tert -butyl-diphenylsilyloxynonyl)-5-hydroxy-1-thioxo-pyrrolo[1,2- c ]pyrimidine-4-carboxylate (25) Trimethylsilyl isothiocyanate (62 µL, 0.45 mmol) was added to a solution of aldehyde 26 (183 mg, 0.45 mmol) in dry CH₂Cl₂ (3 mL) under N₂, and the resulting brown solution was stirred for 30 min at 25 ˚C. A solution of alkylidene-pyrrolidine 24 (70 mg, 0.45 mmol) in CH₂Cl₂ (2 mL) was then added, and the reaction was stirred for 3 h. The reaction was quenched with ca. 0.1 M aq NaOH solution (20 ml) and the layers separated. The aqueous layer was washed with CH₂Cl₂ (3 × 25 mL), the combined organic layers dried with Na₂SO₄, and the solvent removed in vacuo. The resulting orange gum was purified by column chromatography (eluent: hexane-EtOAc, 2.5:1; R _f = 0.55) to give the title compound (79 mg, 29%) as a yellow gum. HRMS: m/z calcd for C₃₄H₄₉N₂O₄SiS [M]: 609.3182. Found: 609.3196 [MH⁺]. IR (CH₂Cl₂): ν_max = 3401, 3205, 2883, 1675, 1629, 1531, 1462, 1416, 1324 and 1255 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.70-7.55 (4 H, m, arom. CH), 7.41-7.28 (6 H, m, arom. CH), 6.99 (1 H, br s, NH), 5.20 (1 H, br s, OH), 5.10 (1 H, app. t, J = 8.0 Hz, CHOH), 4.24 (1 H, app. dt, J = 7.8, 3.8 Hz, CHNH), 4.06 (1 H, ddd, J = 11.6, 8.8, 3.3 Hz, one of CH₂NCS), 3.89 (1 H, ddd, J = 11.6, 9.0, 8.0 Hz, one of CH₂NCS), 3.65 (3 H, s, CO₂CH₃), 3.58 (2 H, t, J = 6.5 Hz, CH ₂OTBDPS), 2.40-2.33 (1 H, m, one of CH ₂CHOH), 2.00-1.95 (1 H, m, one of CH ₂CHOH), 1.54-1.40 (6 H, m, 3 × CH₂) and 1.36-1.10 [19 H, m, 5 × CH₂ and ((CH ₃)₃C]. ^¹³C NMR (125 MHz, CDCl₃): d = 175.3 (C=S), 166.2 (C=O), 153.2 (C=CCO₂Me), 139.8 (arom. C), 134.6 (arom. CH), 128.5 (arom. CH), 126.6 (arom. CH), 99.6 (C=CCO₂Me), 71.2 (CHOH), 63.0 (CH₂OTBDPS), 51.2 (CO₂ CH₃), 50.9 (CH-alkyl), 48.7 (CH₂NC=S), 36.1 (pyrrolidine CH₂CHOH), 31.6 (CH₂CH-NH), 28.8 (CH₂), 28.6 (CH₂), 28.4 (CH₂), 28.2 (CH₂), 28.1 (CH₂), 25.9 [(CH₃)₃C], 24.8 (CH₂), 23.0 (CH₂), 18.2 [(CH₃)₃ C]. MS (ES⁺): m/z (%) = 609 (25) [MH⁺], 577 (32), 279 (100). [a]_D -30 (c 1, CH₂Cl₂).