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Synlett 2007(17): 2651-2654  
DOI: 10.1055/s-2007-991059
LETTER
© Georg Thieme Verlag Stuttgart · New York

Nucleophilic Additions and Redox Reactions of Polyhydroxypyrroline N-Oxides on the Way to Pyrrolidine Alkaloids: Total Synthesis of Radicamine B

Pedro Merino*a, Ignacio Delsoa,b, Tomas Tejeroa, Francesca Cardonab, Andrea Goti*b
a Laboratorio de Sintesis Asimetrica, Departamento de Quimica Organica, Instituto de Ciencia de Materiales de Aragon, Universidad de Zaragoza, CSIC, 50009 Zaragoza, Aragon, Spain
Fax: +34(976)762075; e-Mail: pmerino@unizar.es;
b Dipartimento di Chimica Organica ‘Ugo Schiff’ and HeteroBioLab, Università di Firenze, Associated with ICCOM-CNR, Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax: +39(055)4573531; e-Mail: andrea.goti@unifi.it;
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Publication History

Received 5 July 2007
Publication Date:
25 September 2007 (online)

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Abstract

Nucleophilic addition of aryl Grignard reagents to (2R,3R,4R)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-3,4-dihydro-2H-pyrrole 1-oxide afford straightforwardly trihydroxylated ­pyrrolidine alkaloids. Organometallic additions take place with ­complete anti selectivity. In order to gain access to all four dia­stereomers with different configuration at C-2 and C-5, an oxidation-reduction protocol is developed. The high selectivity observed in the nucleophilic addition reaction allowed preparation of natural radicamine B in only two steps and high chemical yield.

Key words

alkaloids - nucleophilic additions - oxidations - nitrones - pyrrolidines

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In their original papers, appeared during the preparation of this manuscript, Gurjar (ref. 5) and Yu (ref. 6) reported the synthesis of the enantiomers of the natural products since they started from ent-5, synthesizing ent-1 and ent-2. Indeed, Yu et al. (ref. 6) revised the configuration of both natural radicamines A and B as those given in Figure [1] .

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Data for 8: [α]D 20 +57 (c 1.11, H2O). 1H NMR (400 MHz, D2O): δ = 3.63 (ddd, J = 8.2, 5.5, 4.1 Hz, 1 H, H5), 3.83 (dd, J = 13.3, 6.3 Hz, 1 H, CH 2OH), 3.88 (dd, J = 13.3, 4.5 Hz, 1 H, CH 2OH), 4.11 (t, J = 7.5 Hz, 1 H, H4), 4.39 (d, J = 9.9 Hz, 1 H, H2), 4.43 (dd, J = 10.0, 6.9 Hz, 1 H, H3), 7.37-7.47 (m, 5 H, Ar). 13C NMR (100 MHz, D2O): δ = 58.1 (CH2OH), 61.9 (C2), 63.2 (C5), 73.7 (C3), 77.5 (C4), 128.3 (Ar), 128.5 (Ar), 130.3 (Ar), 131.3 (Ar). Anal. Calcd for C11H16NO3Cl: C, 53.77; H, 6.56; N, 5.70. Found: C, 53.92; H, 6.74; N, 5.68.

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Data for 15: [α]D 20 +45 (c 0.41, H2O). 1H NMR (400 MHz, D2O): δ = 3.86-3.96 (m, 3 H, H5, CH 2OH), 4.35 (t, J = 3.3 Hz, 1 H, H4), 4.41 (d, J = 5.9 Hz, 1 H, H2), 4.49 (dd, J = 5.9, 3.1 Hz, 1 H, H3), 7.40-7.50 (m, 5 H, Ar). 13C NMR (100 MHz, D2O): δ = 56.9 (CH2OH), 62.9 (C2), 67.6 (C5), 74.5 (C3), 79.8 (C4), 128.4 (Ar), 129.4 (Ar), 130.0 (Ar), 132.1 (Ar). Anal. Calcd for C11H16NO3Cl: C, 53.77; H, 6.56; N, 5.70. Found: C, 53.70; H, 6.62; N, 5.79.
Data for 16: [α]D 20 +78 (c 0.54, H2O). 1H NMR (400 MHz, D2O): δ = 3.64 (ddd, J = 8.4, 4.8, 3.5 Hz, 1 H, H5), 3.85 (dd, J = 12.2, 8.6 Hz, 1 H, CH 2OH), 3.95 (dd, J = 12.2, 5.0 Hz, 1 H, CH 2OH), 4.11 (dd, J = 3.4, 1.3 Hz, 1 H, H4), 4.37 (dd, J = 3.3, 1.2 Hz, 1 H, H3), 4.85 (d, J = 3.3 Hz, 1 H, H2), 7.34-7.40 (m, 5 H, Ar). 13C NMR (100 MHz, D2O): δ = 59.4 (CH2OH), 64.8 (C5), 67.5 (C2), 75.9 (C3), 76.6 (C4), 127.5 (Ar), 128.9 (Ar), 129.1 (Ar), 130.3 (Ar). Anal. Calcd for C11H16NO3Cl: C, 53.77; H, 6.56; N, 5.70. Found: C, 53.88; H, 6.59; N, 5.83.
Data for 17: [α]D 20 +27 (c 0.10, H2O). 1H NMR (400 MHz, D2O): δ = 3.90 (dd, J = 12.0, 8.2 Hz, 1 H, CH 2OH), 3.98 (dd, J = 12.1, 5.1 Hz, 1 H, CH 2OH), 3.98-4.06 (m, 1 H, H5), 4.30-4.34 (m, 1 H, H2), 4.46 (dd, J = 4.3, 1.3 Hz, 1 H, H4), 4.81-4.85 (s, 1 H, H3), 7.34-7.43 (m, 5 H, Ar). 13C NMR (100 MHz, D2O): δ = 58.3 (CH2OH), 62.5 (C2), 64.0 (C4), 75.0 (C3), 77.4 (C5), 127.8 (Ar), 128.8 (Ar), 129.1 (Ar), 131.3 (Ar), 132.1 (Ar). Anal. Calcd for C11H16NO3Cl: C, 53.77; H, 6.56; N, 5.70. Found: C, 53.85; H, 6.40; N, 5.45.

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Data for 2·HCl: [α]D 20 +81 (c 0.25, H2O). 1H NMR (400 MHz, D2O): δ = 3.57 (ddd, J = 4.0, 6.2, 8.5 Hz, 1 H, H5), 3.81 (dd, J = 6.2, 12.6 Hz, 1 H, CH 2OH), 3.86 (dd, J = 4.0, 12.6 Hz, 1 H, CH 2OH), 4.08 (t, J = 7.7 Hz, 1 H, H4), 4.31 (d, J = 10.2 Hz, 1 H, H2), 4.37 (dd, J = 7.5, 10.2 Hz, 1 H, H3), 6.87 (d, J = 8.7 Hz, 2 H, ArH), 7.32 (d, J = 8.7 Hz, 2 H, ArH). 13C NMR (100 MHz, D2O): d = 58.2 (CH2OH), 61.6 (C2), 62.8 (C4), 73.6 (C3), 77.1 (C5), 116.2 (Ar), 122.9 (Ar), 130.2 (Ar), 157.1 (Ar). Anal. Calcd for C11H16NO4Cl: C, 50.48; H, 6.48; N, 5.63. Found: C, 58.29; H, 6.73; N, 5.80.
Data for 2: [α]D 20 +74 (c 0.29, H2O) [Lit. for natural compound: +72 (c 0.10, H2O);3a Lit. for synthetic enantiomer: -69 (c 0.20, H2O)5 and -72.7 (c 0.17, H2O)6]. 1H NMR (400 MHz, D2O): δ = 2.83-2.91 (m, 1 H, H5), 3.35 (pseudo t, J = 9.9 Hz, 1 H, CH 2OH), 3.40-3.56 (m, 3 H, CH 2OH + H4 + H3), 3.73 (pseudo t, J = 7.8 Hz, 1 H, H2), 6.92 (d, J = 8.0 Hz, 2 H, ArH), 6.37 (d, J = 8.0 Hz, 2 H, ArH). 13C NMR (100 MHz, D2O): d = 62.3 (C2), 63.5 (CH2OH), 63.8 (C4), 78.4 (C3), 82.9 (C5), 116.7 (Ar), 126.1 (Ar), 128.8 (Ar), 165.7 (Ar). Anal. Calcd for C11H15NO4: C, 58.66; H, 6.71; N, 6.22. Found: C, 58.50; H, 6.90; N, 6.31.