Oxazatricyclic Noradamantanes:  Stereocontrolled Synthesis of Functionalized Scopolines, Related Cage Molecules, and Drug Leads

Pascual, María Vidal; Proemmel, Steffen; Beil, Winfried; Wartchow, and Rudolf; Hoffmann, H. M. R.

doi:10.1021/ol048603t

Cited by 23 publications

(6 citation statements)

References 20 publications

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“…We decided to form the six‐membered hemiacetal at a late stage in the synthesis from A . For the construction of the seven‐membered ring with the oxygen bridge (the so‐called dioxa analogue of noradamantane2), [4+3] cycloaddition between a furan and a silyloxyallyl cation with a π‐donating alkoxy substituent was thought to be a straightforward approach 2. 3 As there are two tetrahydrofuran rings in A , two types of cycloaddition are possible: C + D (route a) and G + F (route b).…”

Section: Methodsmentioning

confidence: 99%

Stereoselective Total Synthsis of (±)‐Urechitol A

Sumiya¹,

Ishigami²,

Watanabe³

2010

Angewandte Chemie

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Urechitol A (1) was isolated from the methanolic root extract of Pentalinon andrieuxii by Peaea-Rodríguez and co-workers in 2009.[1] P. andrieuxii is a plant used commonly in Yucatecan traditional medicine for the treatment of cutaneous eruptions derived from leishmaniasis, an infectious disease caused by protozoan parasites of the Leishmania genus. The relative stereochemistry of 1 has been elucidated unambiguously by X-ray crystallographic analysis (Scheme 1). This compound has a novel and very unique structure, incorporating a highly functionalized cycloheptane ring with two oxygen bridges. Although urechitol A itself exhibited no biological activity, its unique tetracyclic structure prompted us to investigate its synthesis.Our synthetic strategy toward 1 is shown in Scheme 1. We decided to form the six-membered hemiacetal at a late stage in the synthesis from A. For the construction of the sevenmembered ring with the oxygen bridge (the so-called dioxa analogue of noradamantane [2] ), [4+3] cycloaddition between a furan and a silyloxyallyl cation with a p-donating alkoxy substituent was thought to be a straightforward approach. [2, 3] As there are two tetrahydrofuran rings in A, two types of cycloaddition are possible: C + D (route a) and G + F (route b). In both cycloadducts (B and E, respectively), the oxygen functionalities and double bonds were expected to be located in the required positions for further transformations leading to urechitol A. However, a preliminary investigation indicated that the cycloaddition between C (R 2 = allyl) and D (R 1 = CO 2 Me) afforded a product with both undesired regioand stereochemistry. Therefore, route b was adopted for the synthesis of urechitol A, as described below.Our synthesis started from the key [4+3] cycloaddition reaction between known compounds 2[4] and 3 [3b] ; the product (4) was obtained as a sole regio-and stereoisomer in a moderate yield (Scheme 2). For the reaction, TiCl 4[3a] was used as a Lewis acid instead of the more generally used TMSOTf, [3b] and the reaction was carried out at a relatively lower concentration (0.1m) relative to that of the standard reaction conditions (1m) [3b] to avoid the generation of unidentified by-products. The allylic alcohol was then oxidized into the unstable epoxy alcohol 5 under Sharpless conditions [5] in the presence of NaHCO 3 as a basic additive, which prevented the decomposition of the product during the Scheme 1. Synthetic strategies for urechitol A (1). TMS = trimethylsilyl. Scheme 2. a) TiCl 4 , EtNO 2 , NaHCO 3 , À78 8C, 46 %; b) [VO(acac) 2 ], TBHP, NaHCO 3 , CH 2 Cl 2 , RT, 47 %; c) TsOH·H 2 O, MeOH, 40 8C, 67 % of 6 and 28 % of 7; d) TBSCl, imidazole, DMF, RT, 74 %; e) TPAP, NMO, M.S. 4 , CH 2 Cl 2 , RT, quant. Bn = benzyl, TES = triethylsilyl, Et = ethyl, acac = acetylacetonate, TBHP = tert-butylhydroperoxide, Ts = para-toluenesulfonyl, Me = methyl, TBS = tert-butyldimethylsilyl, DMF = N,N-dimethylformamide, TPAP = tetra-n-propylammonium perruthenate, NMO = 4-methylmorpholine N-oxide, M.S. = molecular ...

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Section: Methodsmentioning

confidence: 99%

Stereoselective Total Synthsis of (±)‐Urechitol A

Sumiya¹,

Ishigami²,

Watanabe³

2010

Angewandte Chemie

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“…[45][46][47] The direct methylation of amino piperidine compound 14 was not achievable for the reasons described before. 18 Reactions of amino piperidine 14 with p-anisaldehyde and formaldehyde under reductive conditions in DCM gave compound 16.…”

Section: 39mentioning

confidence: 99%

Chiral Pool Synthesis of N-Cbz-cis-(3R,4R)-3-methylamino-4-methylpiperidine from L-Malic acid

Hao¹,

Liu²,

Zhang³

et al. 2013

Bulletin of the Korean Chemical Society

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“…Compounds containing the 8-oxabicyclo[3.2.1]octane framework have shown broad utility as chiral building blocks for synthesis of polyketides, see: Coste & Gerber-Lemaire (2005); Meilert et al (2003); Schwenter & Vogel (2001); Gerber-Lemaire & Vogel (2003); Gerber & Vogel (1999; Re et al (2009); Pascual et al (2004); Derwick (1998). For the inhibitory activity of calystegines and other tropane alkaloids against several glycosidase enzymes, see: Asano et al (2000); Drager (2004).…”

Section: Related Literaturementioning

confidence: 99%

“…Compounds containing the 8-oxabicyclo[3.2.1]octane framework are important precursors in the field of biologically active compounds. They have shown broad utility as chiral building blocks for synthesis of polyketides (Coste & Gerber-Lemaire, 2005;Meilert et al, 2003;Schwenter & Vogel, 2001;Gerber-Lemaire & Vogel, 2003), C-linked disaccharides (Gerber & Vogel, 1999;Gerber & Vogel, 2001), calystegines (Re et al, 2009;Pascual et al, 2004;Derwick, 1998) and other natural products. Calystegines and other tropane alkaloids show remarkable inhibitory activities against several glycosidase enzymes, in comparison with other alkaloidal glycosidase inhibitors (Asano et al, 2000;Drager, 2004).…”

Section: S1 Commentmentioning

confidence: 99%