Tandem Radical Cyclizations Initiated with α-Carbonyl Radicals:  First Total Synthesis of (+)-Paniculatine

Sha, Chin-Kang; Lee, Fang‐Kun; Chang, C. C. K.

doi:10.1021/ja992315o

Cited by 86 publications

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“…The Evans laboratory recently reported an elegant total synthesis of a similar alkaloid ring system (clavolonine) 10. Additionally, numerous other total syntheses of structural different lycopodium alkaloids have been reported over the past decade by Bosch,11 Chang,12 Comins,13 Dake,14 Johnston,15 Liao,16 Mukai,17 Overman,18 Sarpong,19 Siegel,20 Toste,21 Takahashi22 and Takayama 23. Herein, we disclose a full account of our work towards the alkaloid lycopodine.…”

Section: Introductionmentioning

confidence: 99%

Development of an Enantioselective Route toward the Lycopodium Alkaloids: Total Synthesis of Lycopodine

Carter

2010

J. Org. Chem.

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Synthesis of a C15-desmethyl tricycle core of lycopodine has been accomplished. Key steps in the synthetic sequence include organocatalytic, intramolecular Michael addition of a keto sulfone and a tandem 1,3-sulfonyl shift / Mannich cyclization to construct the tricyclic core ring system. Synthetic work towards this natural product family led to the development of N-(p-dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide – an organocatalyst which facilitiates enantioselective, intramolecular Michael additions. A detailed mechanistic discussion is provided for both the intramolecular Michael addition and the sulfone rearrangement. Finally, the application of these discoveries to the enantioselective total synthesis of alkaloid lycopodine is described.

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Section: Introductionmentioning

confidence: 99%

Development of an Enantioselective Route toward the Lycopodium Alkaloids: Total Synthesis of Lycopodine

Carter

2010

J. Org. Chem.

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“…Lycopodium alkaloids [1][2][3] isolated from club mosses of the genus Lycopodium (Lycopodiaceae) exhibit fascinating complex structures and have attracted the attention of synthetic organic chemists [4][5][6][7][8][9][10] as well as pharmacologists because of such potent biological activities as an inhibitory effect on acetylcholinesterase. 11) Recent extensive studies on the chemical constituents in Lycopodium plants have resulted in the isolation of a number of new alkaloids having novel and diverse structures.…”

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confidence: 99%

Ten New Lycopodium Alkaloids Having the Lycopodane Skeleton Isolated from Lycopodium serratum THUNB.

et al. 2003

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(10), having lycopodine-related structures, were isolated from the club moss Lycopodium serratum THUNB. and their structures were elucidated on the basis of spectroscopic analysis and/or chemical transformation.Key words alkaloid; Lycopodium; structure elucidation; X-ray crystal structure; NMR; chemical transformation Lycoposerramine-G (2) was obtained as a colorless amorphous powder. HR-FAB-MS analysis gave m/z 280.1893 (MϩH) ϩ (D Ϫ2.0 mmu) and established the molecular formula as C 16 H 25 NO 3 , which was one oxygen atom less than 1 described above. The 1 H-and 13 C-NMR (Table 1) spectra of 2, which resembled those of 1 except for the chemical shifts of the carbons adjacent to nitrogen, indicated that 1 was an N-oxide derivative of 2. Actually, when 2 was treated with one equivalent of m-CPBA, lycoposerramine-F (1) was obtained in 63% yield, thereby establishing the structure of the new alkaloid as formula 2.Lycoposerramine-H (3) was obtained as colorless prisms (mp 227-228°C, sublimation). HR-FAB-MS analysis gave m/z 262.1809 (MϩH) ϩ (D ϩ0.2 mmu) and established the molecular formula as C 16 H 23 NO 2 , which indicated that 3 had one extra unsaturated number compared to common lycopodine-type alkaloids.1 H-and 13 C-NMR spectra (see Table 1) as well as DEPT spectra suggested the presence of one ketone, a trisubstituted olefin bearing a methyl group, one sp 3 quaternary carbon, four sp 3 methines (one of which had a hydroxyl function), and seven sp 3 methylenes. 1 H-1 H COSY and HMQC spectra revealed connectivities as shown by the bold line in Fig. 3. Further, allyl couplings between the olefinic proton (d 5.35, H-8) and methyl protons (d 1.58, H-16) and methylene protons (d 1.98, 2.70, H-14), as well as homoallyl coupling between the methyl protons (H-16) and the methine proton (d 2.52, H-7), indicated the presence of a double bond at the C-8 (d 121.6)-C-15 (d 135.9) position of the lycopodine skeleton. The location of the secondary hydroxyl group was inferred from the HMBC cross-peaks between the proton at d 3.78 (d, Jϭ2.7 Hz) and the carbonyl carbon (d 212.4, C-5) and the methine carbon at d 38.7 (C-4). The structure including the stereochemistry of the secondary hydroxyl group at C-6 was determined by X-ray analysis as formula 3 (Fig. 3). This is the first example of a lycopodine-type alkaloid that has a double bond at the C-8-C-15 position.Lycoposerramine-I (4) showed a molecular ion peak at m/z 261 and the molecular formula, C 16 H 23 NO 2 , which was established by HR-FAB-MS [m/z 262.1802 (MϩH) ϩ , D Ϫ0.5 mmu], was identical with that of 3 described above. Comparison of its1 H-and 13 C-NMR spectra (see Table 1) with those of 3 suggested that the two alkaloids were isomers at the position of the secondary hydroxyl group. The chemical shifts at C-10 (d 35.5), C-11 (d 69.2), and C-12 (d 44.6) in 4 as well as the HMBC cross-peak (Fig. 4) between the low-field proton (d 4.34) and the quaternary carbon at C-13 (d 59.7) indicated that the hydroxyl group existed at the C-11 position. The stereochemistry...

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“…Several other notable alkaloids syntheses have been reported in which carbocyclizations play the pivotal role and introduction of nitrogen is secondary, for example Sha's syntheses of (-)-dendrobine [76] and (+)-paniculatine [77], and Clive's synthesis of (2)-fredericamycin [78]. It is not meant to be a comprehensive review, but focusses on syntheses in which nitrogen plays a clear role in the cyclization process, either as an attenuator of radical reactivity (Sections 4.1.2 and 4.1.3), a tether (Section 4.1.4), or a radical acceptor (Section 4.1.5).…”

Section: Discussionmentioning

confidence: 99%

Radical Cyclizations in Alkaloid Synthesis

Hart¹

2001

Radicals in Organic Synthesis

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Over twenty years ago, my research group became interested in free-radical cyclization chemistry because we were impressed with the efficiency of a 5-hexenyl radical cyclization which we used to prove the stereochemistry of a product derived from an N-acyliminium ion cyclization [ 1, 21. A survey of the literature suggested that, at that time, free-radical cyclizations had been well developed for the preparation of carbocyclic materials, but the use of such reactions in heterocycle synthesis was not well developed. As one can see from the wealth of information that appears in Radicals in Organic Synthesis, we were clearly mistaken in our judgement of the state of the field relative to carbocycles. Nonetheless, it was this point of view that prompted us to pursue a research program designed to develop free radical cyclization reactions for use in alkaloid synthesis. Since the onset of our program [3, 41, this field has expanded enormously. This chapter will review progress in the area with certain limitations. The major focus will be on intramolecular carbon-carbon bond-forming reactions, and the chapter will be organized largely according to the type of free radical cyclization featured in the synthesis. Intermolecular free-radical reactions and cyclizations involving carbon-heteroatom bond-forming reactions will be mentioned only in passing. Although emphasis will be placed on free radical cyclization chemistry, additional details will be described in an attempt to provide the reader with an overview of each synthesis. Whereas we recognize that the inherent value of a synthesis may lie in the methodology, there is no question that chemists judge syntheses in part by their length, and this information will therefore be provided in most instances. Finally, the focus will be on completed syntheses, and only a few model studies will be presented. a-Acylamino and a-Amino Radical CyclizationsOur own efforts began with failure. Inspired by the radical addition-atom transfercyclization-fragmentation sequence reported by Heiba (Eq. 1) [ 51, we attempted the Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi

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Tandem Radical Cyclizations Initiated with α-Carbonyl Radicals: First Total Synthesis of (+)-Paniculatine

Cited by 86 publications

References 16 publications

Development of an Enantioselective Route toward the Lycopodium Alkaloids: Total Synthesis of Lycopodine

Development of an Enantioselective Route toward the Lycopodium Alkaloids: Total Synthesis of Lycopodine

Ten New Lycopodium Alkaloids Having the Lycopodane Skeleton Isolated from Lycopodium serratum THUNB.

Radical Cyclizations in Alkaloid Synthesis

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