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

Pedro Merino; Ignacio Delso; Tomas Tejero; Francesca Cardona; Andrea Goti

doi:10.1055/s-2007-991059

LETTER

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

Pedro Merino*^a, Ignacio Delso^a,b, Tomas Tejero^a, Francesca Cardona^b, 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;

Abstract

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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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Referenzen

References and Notes

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See also ref. 5 and 6.

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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.

<A NAME="RG23207ST-10">10</A> Marradi M. Cicchi S. Delso I. Rosi L. Tejero T. Merino P. Goti A. Tetrahedron Lett. 2005, 46: 1287

<A NAME="RG23207ST-11A">11a</A> Goti A. Cicchi S. Fedi V. Nannelli L. Brandi A. J. Org. Chem. 1997, 62: 3119

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<A NAME="RG23207ST-12">12</A> Semiempirical calculations (PM3) demonstrated a slightly higher stability of 15 (ΔH_f = -80.60 kcal/mol), with respect to 14 (ΔH_f = -79.21 kcal/mol)

<A NAME="RG23207ST-13">13</A> Cicchi S. Marradi M. Goti A. Brandi A. Tetrahedron Lett. 2001, 42: 6503

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.

<A NAME="RG23207ST-15">15</A> Yu Y. Singh SK. Liu A. Li T.-K. Liu LF. LaVoice EJ. Bioorg. Med. Chem. 2003, 11: 1475

<A NAME="RG23207ST-16">16</A> Merino P. Revuelta J. Tejero T. Cicchi S. Goti A. Eur. J. Org. Chem. 2004, 776

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.