Download PDF
Synlett 2008(13): 2028-2032  
DOI: 10.1055/s-2008-1077969
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Christopher D. Daviesb, Mark C. Elliott*a, Joseph Hill-Cousinsa, Misbah-ul A. Khanc, Tahir Maqboola,c, John L. Wooda
a School of Chemistry, Cardiff University, Main College Building, Park Place, Cardiff, CF10 3AT, UK
Fax: +44(29)20874030; e-Mail: elliottmc@cardiff.ac.uk;
b AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
c Department of Chemistry, Faculty of Science, The Islamia University of Bahawalpur, Pakistan
Further Information

Publication History

Received 12 May 2008
Publication Date:
15 July 2008 (online)

    Permissions and Reprints All articles of this category

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

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): νmax = 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).