Synthesis of Putative Uniflorine A Andrew S. Davis,† Stephen G. Pyne,*,† Brian W. Skelton,‡ and Allan H. White‡ Department of Chemistry, University of Wollongong, Wollongong, New South Wales, 2522, Australia, and Department of Chemistry, University of Western Australia, Crawley, Western Australia, 6009, Australia
[email protected] Received February 2, 2004
A diastereoselective synthesis of the putative structure of the natural product uniflorine A has been achieved by using the Petasis borono-Mannich reaction and ring-closing metathesis as key steps. The NMR data of the synthetic material did not match that reported for the natural product. The structure of the final synthetic product was unequivocally determined by single-crystal X-ray study of its pentaacetate derivative. Thus it was concluded that the proposed structure of uniflorine A is incorrect. The polyhydroxylindolizidine alkaloid uniflorine A was isolated in 2000 from the leaves of the tree Eugenia uniflora L.1-3 The water-soluble extract of these leaves has been used as an antidiabetic agent in Paraguayan traditional medicine. Uniflorine A was found to be an inhibitor of the R-glucosidases maltase and sucrase, with IC50 values of 12 and 3.1 µM, respectively. The structure of uniflorine A was deduced from NMR analysis to be that shown as structure 1.1 The proposed structure of uniflorine A is similar to that of castanospermine 2, except for the stereochemistry at C-1 and the extra hydroxyl substitution at C-2. As part of our program concerned with the synthesis of polyhydroxylated indolizidine and pyrrolizidine alkloids4-6 we have developed a short and efficient synthesis of 1, which is reported here. Our retrosynthetic analysis of 1 (Scheme 1) suggested that the target compound could be acquired from the precursor 3 using a ring-closing metathesis (RCM) reaction7-9 and N-alkylation to prepare the five- and sixmembered rings of 1, respectively. The 1,2-anti amino alcohol 3 would be expected to be readily obtained from the boronic acid-Mannich reaction (Petasis reaction)10 †
University of Wollongong. University of Western Australia. (1) Matsumura, T.; Kasai, M.; Hayashi, T.; Arisawa, M.; Momose, Y.; Arai, I.; Amagaya, S.; Komatsu, Y. Pharm. Biol. 2000, 38, 302307. (2) Arisawa, M.; Hayashi, T.; Momose, Y. Food Style 21 2001, 5, 69-73. (3) Momose, Y. Japanese Kokai Tokkyo Koho 2000, 7 pp (JP 2000072770, CAN 132:203147). (4) Lindsay, K. B.; Tang, M.; Pyne, S. G. Synlett 2002, 731-734. (5) Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774-7780. (6) Tang, M.; Pyne, S. G. J. Org. Chem. 2003, 68, 7818-7824. (7) For the application of the ring-closing metathesis reaction to the synthesis of aza-sugars see refs 4-6 and: (a) Huwe, C. M.; Blechert, S. Tetrahedron Lett. 1995, 36, 1621-1624. (b) Overkleeft, H. S.; Pandit, U. K. Tetrahedron Lett. 1996, 37, 547-550. (c) Huwe, C. M.; Blechert, S. Synthesis 1997, 61-67. (d) White, J. D.; Hrnciar, P.; Yokochi, A. F. T. J. Am. Chem. Soc. 1998, 120, 7359-7360. (e) Lindstrom, U. M.; Somfai, P. Tetrahedron Lett. 1998, 39, 7173-7176. (f) Ovaa, H.; Stragies, R.; van der Marcel, G. A.; van Boom, J. H.; Blechert, S. Chem. Commun. 2000, 1501-1502. (g) Subramanian, T.; Lin, C.-C.; Lin, C.C. Tetrahedron Lett. 2001, 42, 4079-4082. (h) Klitze, C. F.; Pilli, R. A. Tetrahedron Lett. 2001, 42, 5605-5608. (i) Chandra, K. L.; Chandrasekhar, M.; Singh, V. K. J. Org. Chem. 2002, 67, 4630-4633. (j) Buschmann, N.; Ru¨ckert, A.; Blechert, S. J. Org. Chem. 2002, 67, 4325-4329. ‡
FIGURE 1. Proposed structure of uniflorine A (1) and the structure of castanospermine (2).
SCHEME 1.
Retrosynthetic Analysis of 1
of L-xylose, allylamine, and (E)-styrene boronic acid, followed by chemo- and regioselective N- and O-protection reactions. (8) For the application of the ring-closing metathesis reaction to the synthesis of 2,5-dihydropyrroles from dienes see: (a) Huwe, C. M.; Velder, J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 23762378. (b) Furstner, A.; Fursterner, A.; Picquet, M.; Bruneau, C.; Dixneuf, P. H. Chem. Commun. 1998, 1315-1316. (c) Cerezo, S.; Cortes, J.; Moreno-Manas, M.; Pleixats, R.; Roglans, A. Tetrahedron 1998, 54, 14869-14884. (d) Furstner, A.; Ackermann, L. Chem. Commun. 1999, 95-96. (e) Bujard, M.; Briot, A.; Gouverneur, V.; Mioskowski, C. Tetrahedron Lett. 1999, 40, 8795-8788. (f) Furstner, A.; Liebl, M.; Hill, A. F.; Wilton-Ely, J. D. E. T. Chem. Commun. 1999, 601-602. (g) Ackermann, L.; Furstner, A.; Weskamp, T.; Kohl, F. J.; Hermann, W. A. Tetrahedron Lett. 1999, 40, 4787-4790. (h) Ahmed, M.; Barrett, A. G. M.; Braddock, D. C.; Cramp, S. M.; Procopiou, P. A. Tetrahedron Lett. 1999, 40, 8657-8662. (i) Evans, P. A.; Robinson, J. E. Org. Lett. 1999, 1, 1929-1931. (j) Hunt, J. C. A.; Laurent, P.; Moody, C. J. Chem. Commun. 2000, 1771-1772. (9) For RCM reactions on related acyclic N-protected dienes see: (a) Huwe, C. M.; Kiehl, O. C.; Blechert, S. Synlett 1996, 67-8. (b) Agami, C.; Couty, F.; Rabasso, N. Tetrahedron Lett. 2000, 41, 4113-4116. (c) Martı´n, R.; Moyano, A.; Perica`s, M. A.; Riera, A. Org. Lett. 2000, 2, 93-95. (d) Agami, C.; Couty, F.; Rabasso, N. Tetrahedron 2001, 57, 5393-5401. (e) Fustero, S.; Navarro, A.; Pina, B.; Soler, Juan G.; Bartolome, A.; Asensio, A.; Simon, A.; Bravo, P.; Fronza, G.; Volonterio, A.; Zanda, M. Org. Lett. 2001, 3, 2621-2624.
10.1021/jo049806y CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/02/2004
J. Org. Chem. 2004, 69, 3139-3143
3139
Davis et al. SCHEME 2a
a Reagents and conditions: (a) (E) PhCHdCHB(OH) , allyl2 amine, EtOH, rt, 16 h; ion exchange, 73%; (b) (Boc)2O, Et3N, MeCN, DMF, 0 °C (4 h) then rt (14 h), 51%; (c) TrCl, pyridine, rt, 18 h, 68%; (d) Grubbs’ catalyst, DCM, reflux, 18 h, 86%; (e) K2OsO4‚2H2O, NMO, acetone/water, rt, 30 h, 88%; (f) NaH, BnBr, n-Bu4NI, THF, 50 °C, 3 d, 76%; (g) TFA, anisole, DCM, 0 °C, 2 h, 10 (37%) and 11 (54%); (h) PPh3, CBr4, NEt3, CH2Cl2, 0 °C, 2 h, 54%; (i) PdCl2, H2 (1 atm), MeOH, rt, 2 h; ion exchange then recrystallization, 63% (j) Ac2O, pyridine, rt, 4 h, 88%.
In the event, the requisite Petasis reaction gave the desired amino-tetraol 4 in 73% yield as a single diastereomer after purification by ion-exchange chromatography (Scheme 2). The amino-tetraol 4 was converted to its N-Boc derivative 5 (51% yield) and then the primary alcohol was regioselectively protected as its O-trityl compound 6 (68% yield). A RCM reaction of 6 with Grubbs’ first generation catalyst (benzylidene bis(tricyclohexylphosphine)dichlororuthenium, 10 mol %) smoothly gave the 2,5-dihydropyrrole 7 in 86% yield. Osmium(VIII)-catalyzed syn-dihydroxylation (DH) of 7 furnished the pentaol 8 as a single diastereomer in 88% yield. The stereochemical outcome of this DH reaction was expected due to the stereodirecting effect of the C-2 substituent in 74,5 and was later confirmed from the single-crystal X-ray analysis of the pentaacetate derivative of 1 (12, see Supporting Information). The pentaol 8 was readily converted to its penta-O-benzyl derivative 9 in 76% yield under standard conditions.11 Selective liberation of the (10) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798-11799.
3140 J. Org. Chem., Vol. 69, No. 9, 2004
SCHEME 3
secondary amino and primary hydroxyl groups of 9 was achieved by exposure of 9 to TFA in the presence of anisole, as a cation scavenger, at room temperature.12 Surprisingly, this reaction gave a mixture of the desired amino-alcohol 10 (37%) and the indolizidine 11 (54%) (Scheme 2). When this reaction was performed at 0 °C a mixture of 10 and the monodeprotected trityl derivative of 9 was obtained. Treatment of this compound or 10 with TFA/anisole at room temperature gave only a very poor yield (
