Pitt CHEM 2320 - Total Synthesis of the Putative Structure of Stemonidine

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Total Synthesis of the Putative Structureof Stemonidine: The Definitive Proof ofMisassignmentFrancisco Sa´nchez-Izquierdo, Pilar Blanco, Fe´lix Busque´, Ramo´n Alibe´s,Pedro de March, Marta Figueredo,* Josep Font, and Teodor Parella†UniVersitat Auto`noma de Barcelona, Departament de Quı´mica,08193 Bellaterra, [email protected] February 26, 2007ABSTRACTThe total synthesis of the putative structure of theStemonaalkaloid stemonidine has been completed. The key transformations include a1,3-dipolar cycloaddition of a chiral nitrone derived from (S)-prolinol and a spirolactonization process involving the generation of the criticalstereocenter. The NMR data of the synthetic material do not match those reported for the natural product. It is concluded that the structureassigned to stemonidine is incorrect, and it must be reassigned as stemospironine.The extracts of several plants of the Stemonaceae family havelong been used in Chinese and Japanese traditional medicinefor the treatment of respiratory disorders, as antihelminticsand also as insecticides.1Significant constituents of theseextracts are a series of structurally related alkaloids, whichmay be responsible for their medicinal properties. Nowadays,around 90 Stemona alkaloids are known, whose structureswere elucidated by X-ray analysis, spectroscopic techniques,and/or chemical correlation, but there is a continuous flowin the literature of new reports describing the isolation ofpreviously unknown members of the family. All the Stemonaalkaloids are polycyclic, and most of them present a centralpyrrolo[1,2-a]azepine system as a common characteristicstructural feature. The majority also incorporates at least onesubstructure of R-methyl-γ-butyrolactone, which can belinked to the azabicyclic core in a spiro or fused manner oras a substituent. Considering their structural diversity, Pilliand co-workers have recently classified the Stemona alkaloidsin eight groups,1awhereas Greger has suggested a differentclassification in only three groups taking into account theirbiosynthetic connections.1bOne of these groups, thetuberostemospironine1aor croomine1btype, concurs in bothclassifications and is characterized by the inclusion of a spiro-γ-lactone at C9of the basic azabicyclic nucleus (Figure 1).In 1982, Xu and co-workers assigned to stemonidine, analkaloid isolated from the roots of Stemona tuberosa, thestructure depicted as 1, on the basis of its1H NMR data.2Later on, the same group revised the former stereochemicalassignment and proposed the new structure that is depictedas 2.3More recently, Williams and co-workers completedthe first synthesis of (-)-stemospironine and found that itsspectral and physical data matched those reported for thenatural material, whose structure had been unequivocallyestablished by X-ray analysis.4They also found that the13CNMR spectra of synthetic stemospironine and natural ste-monidine were virtually identical; the authors did not excludethe possibility of the two compounds being spirocyclicdiastereomers. Herein, we describe the total synthesis and†Servei de Ressona`ncia Magne`tica Nuclear, Universitat Auto`noma deBarcelona. 08193-Bellaterra, Spain.(1) For recent reviews, see: (a) Pilli, R. A.; Rosso, G. B.; de Oliveira,M. C. F. In The Alkaloids; Cordell, G. A., Ed.; Elsevier: New York, 2005;Vol. 62, pp 77-173. (b) Greger, H. Planta Med. 2006, 72, 99.(2) Xu, R.; Lu, Y.; Chu, J.; Iwashita, T.; Naoki, H.; Naya, Y.; Nakanishi,K. Tetrahedron 1982, 38, 2667.(3) He, X.; Lin, W.; Xu, R. Huaxue Xuebao 1990, 48, 694.(4) (-)-Stemospironine: Williams, D. R.; Fromhold, M. G.; Early, J.D. Org. Lett. 2001, 3, 2721.ORGANICLETTERSxxxxVol. 0, No. 0A-D10.1021/ol070486p CCC: $37.00 © xxxx American Chemical SocietyPAGE EST: 4Published on Web 03/31/2007NMR data of the putative structure of stemonidine 2, whichare definitive proof of the incorrect original assignments ofthe natural product.The challenging molecular architecture of the Stemonaalkaloids has attracted considerable interest among syntheticorganic chemists, and several total syntheses have beenpublished, although they are limited to a quite small numberof targets.4-12We designed a strategy in which the azabi-cyclic core was generated at an early stage of the sequenceand the R-methyl-γ-butyrolactone and other specific frag-ments were then incorporated, with the aim of developing aflexible approach, with some intermediates being commonprecursors of various alkaloids (Scheme 1).13A main advan-tage of this methodology is the high antifacial selectivityaccomplished in the 1,3-dipolar cycloadditions of nitronessuch as 6 to electron-deficient olefins of type 5, deliveringisoxazolidine adducts 4 with relative trans configuration ofthe stereogenic centers at C3and C9a, as required for thetarget alkaloids.13b,14Previously, we have reported the one-step preparation of(S)-5-hydroxymethyl-1-pyrroline N-oxide, 7, by treatment ofL-prolinol, 8, with dimethyldioxirane in acetone at lowtemperature and its isolation in 32% yield.14aAlthough thisstraightforward methodology competed favorably with otherpreparations of related nitrones in terms of brevity and yield,difficulties associated with the purification of 7 and scaling-up of the procedure led us to temporarily abandon its useand explore different alternatives. However, recent reportsdisclosing a new protocol for in situ dioxirane reactions15led us to reinvestigate the possibility of preparing the requirednitrone by direct oxidation of a prolinol derivative. Hence,the TBDPS derivative ofL-prolinol 9 was prepared16andtreated with Oxone under different reaction conditions(Scheme 2). As the best result, it was found that 2.1 equivof the oxidant in THF-CH3CN (1:4) in the presence of(5) (+)-Croomine: (a) Williams, D. R.; Brown, D. L.; Benbow, J. W.J. Am. Chem. Soc. 1989, 111, 1923. (b) Martin, S. F.; Barr, K. J. J. Am.Chem. Soc. 1996, 118, 3299.(6) (()-Stenine: (a) Chen, C.-Y.; Hart, D. J. J. Org. Chem. 1990, 55,6236. (b) Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515. (c) Golden, J.E.; Aube´, J.Angew. Chem., Int. Ed. 2002, 41, 4316. (-)-Stenine: (d) Wipf,P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106. (e)Morimoto, Y.; Iwahashi, M.; Nishida, K.; Hayashi, Y.; Shirahama, H.Angew. Chem., Int. Ed. Engl. 1996, 35, 904.(7) (()-Stemoamide: (a) Kohno, Y.; Narasaka, K. Bull. Chem. Soc. Jpn.1996, 69, 2063. (b) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 1997, 119,3409. (-)-Stemoamide: (c) Williams,


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Pitt CHEM 2320 - Total Synthesis of the Putative Structure of Stemonidine

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