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Synthesis 2012; 44(23): 3688-3692
DOI: 10.1055/s-0032-1317490
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© Georg Thieme Verlag Stuttgart · New York

Synthesis of Both Enantiomers of the Streptomyces Alkaloid 4-epi-SS20846A

Dina Scarpi
a   Dipartimento di Chimica ‘U. Schiff’, Università di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy   Fax: +39(055)4573531   Email: ernesto.occhiato@unifi.it
,
Ottavia Avataneo
b   Dipartimento di Chimica Generale ed Organica Applicata, Università di Torino, Corso Massimo D’Azeglio 48, 10125 Torino, Italy
,
Cristina Prandi
b   Dipartimento di Chimica Generale ed Organica Applicata, Università di Torino, Corso Massimo D’Azeglio 48, 10125 Torino, Italy
,
Paolo Venturello
b   Dipartimento di Chimica Generale ed Organica Applicata, Università di Torino, Corso Massimo D’Azeglio 48, 10125 Torino, Italy
,
Ernesto G. Occhiato*
a   Dipartimento di Chimica ‘U. Schiff’, Università di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy   Fax: +39(055)4573531   Email: ernesto.occhiato@unifi.it
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Further Information

Publication History

Received: 03 August 2012

Accepted after revision: 27 September 2012

Publication Date:
24 October 2012 (online)

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Abstract

The enantiodivergent synthesis of the Streptomyces alkaloid 4-epi-SS20846A was based on a Takai olefination/Suzuki–Miyaura­ coupling sequence for the highly stereoselective introduction of the E,E-pentadienyl side chain on the piperidine skeleton. Optical separation of a key hydroxylated enamide ester, prepared by palladium-catalyzed methoxycarbonylation of a lactam-derived enol phosphate, was successfully achieved by both lipase-catalyzed kinetic resolution and semipreparative HPLC. This approach allowed us to obtain the enantiopure target alkaloid in 35–38% yield over six steps.

Key words

alkaloids - lactams - carbonylation - olefination - cross-coupling

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synthesis.
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  • References

  • 1 Grabley S, Hammann P, Kluge H, Wink J, Kricke P, Zeeck A. J. Antibiot. 1991; 44: 797
    CrossrefSearch in Google Scholar
  • 2 Komoto T, Yano K, Ono J, Okawa J, Nakajima T. JP Kokai 35788, Feb 20, 1986 ; Chem. Abstr. 1986, 105, 132137w.
    • 4a Ripoche I, Canet J.-L, Aboab B, Gelas J, Troin Y. J. Chem. Soc., Perkin Trans. 1 1988; 3485
    • 4b Celestini P, Danieli B, Lesma G, Sacchetti A, Silvani A, Passarella D, Virdis A. Org. Lett. 2002; 4: 1367
      CrossrefSearch in Google Scholar
    • 5a Occhiato EG, Scarpi D, Guarna A, Tabasso S, Deagostino A, Prandi C. Synthesis 2009; 3611
      Thieme Connect
    • 5b Bartali L, Casini A, Guarna A, Occhiato EG, Scarpi D. Eur. J. Org. Chem. 2010; 5831
    • 5c Optical rotation values for (R)-13: [α]D 24 +127.1 (c 0.64, CHCl3); for (2S,4R)-14: [α]D 23 –11.9 (c 0.45, CHCl3).
  • 6 Vink MK. S, Schortinghuis CA, Luten J, van Maarseveen JH, Schoemaker HE, Hiemstra H, Rutjes FP. J. T. J. Org. Chem. 2002; 67: 7869
    CrossrefSearch in Google Scholar
  • 7 The preparation of the lactam-derived enol phosphate and subsequent palladium-catalyzed methoxycarbonylation were carried out as reported in ref. 5b, but the latter at 75 °C and with 80 equivalents of MeOH.
  • 8 Occhiato EG, Scarpi D, Guarna A. Eur. J. Org. Chem. 2008; 524
  • 9 The formation of the unwanted compound 11 is easily revealed by the multiplets at 5.99–5.93 ppm (1 H) and 5.66–5.58 ppm (2 H) assignable to the olefinic protons of 11 in the 1H NMR spectrum of the mixture.
  • 10 Occhiato EG, Casini A, Guarna A, Scarpi D. Eur. J. Org. Chem. 2011; 6544
  • 11 As an alternative to the scalable kinetic resolution, it is possible to also carry out the enantiomeric separation by semipreparative HPLC, which allows 1 mmol of each enantiomer, with ee higher than 99.9%, to be obtained: Chiralpack IC semipreparative column (10 × 250 mm, 5 μm, Daicel, Osaka, Japan), isocratic elution with heptane–EtOH (7:3), flow 4.7 mL/min. Analytical: Chiralpak IC column (4.6 × 250 mm, 5 μm) at 1 mL/min. Retention times: (R)-4 (7.69 min), (S)-4 (12.74 min).
  • 12 Chackalamannil S, Davies RJ, Wang Y, Asberom T, Doller D, Wong J, Leone D, McPhail AT. J. Org. Chem. 1999; 64: 1932
    CrossrefSearch in Google Scholar
  • 13 Takai K, Nitta K, Utimoto K. J. Am. Chem. Soc. 1986; 108: 7408
    CrossrefSearch in Google Scholar
  • 14 Gillis EP, Burke MD. Aldrichimica Acta 2009; 42: 17
    Search in Google Scholar
  • 15 Lee SJ, Anderson TM, Burke MD. Angew. Chem. Int. Ed. 2010; 49: 8860
    CrossrefSearch in Google Scholar
  • 16 Knapp DM, Gillis EP, Burke MD. J. Am. Chem. Soc. 2009; 131: 6961
    CrossrefPubMedSearch in Google Scholar
  • 17 Aldrich 701831. In the 1H NMR (CDCl3) spectrum of the commercial compound, the cis-isomer has diagnostic signals at 6.37 (m) and 5.26 (dq) ppm.
  • 18 In compound 18, as well as in compounds 14–17, the two piperidine ring substituents are axially oriented, as shown by the low coupling constant values for the equatorial protons at C2 and C4 (highest is 6.6 Hz for 2-H in the aldehyde) as well as the lack of NOE effect between 2-H and 4-H with axial 6-H. This is due to the presence of the N-protection which forces the substituent at C2 into an axial orientation to remove the A(1,3) strain with it; see: Comins DL, Joseph SP. In Advances in Nitrogen Heterocycles . Vol. 2. Moody CJ. JAI Press; Greenwich, CT: 1996: 251-294
    CrossrefSearch in Google Scholar
    • 19a Sehat N, Rickert R, Mossoba MM, Kramer JK. G, Yurawecz MP, Roach JA. G, Adlof RO, Morehouse KM, Fritsche J, Eulitz KD, Steinhart K, Ku Y. Lipids 1999; 34: 407
      CrossrefSearch in Google Scholar
    • 19b Dobson G, Christie WW, Nikolova-Damyanova B. J. Chromatogr., B 1995; 671: 197
      Search in Google Scholar