Asymmetric Synthesis of the Lycopodium Alkaloid, Na-Acetyl-Nb-methylphlegmarine

Comins, Daniel L.; Libby, Adam H.; Al‐awar, Rima; Foti, C.

doi:10.1021/jo990192k

Cited by 67 publications

(24 citation statements)

References 17 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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“…N -Acylation of 6 with n -BuLi and phenyl chloroformate gave a quantitative yield of enantiopure carbamate 7 . Conjugate reduction of 7 can be effected with L-Selectride/BF 3• OEt 2 4c (86% yield) or more conveniently with Zn/AcOH12 to give 8 in 93% yield. Ozonolysis of the terminal alkene of 8 provided a high yield of aldehyde 9 , which on acid-mediated cyclization13 was converted efficiently to bicyclic enone 10 .…”

Section: Resultsmentioning

confidence: 99%

“…Synthesis and spectroscopic structure studies carried out by Braekman’s group7a determined the basic carbon skeleton, but it was not until the work of MacLean8 and co-workers that the relative stereochemistry of all five stereogenic centers of the phlegmarines was defined. The absolute stereochemistry of these alkaloids was established in our laboratories through the asymmetric total synthesis of (−)- N α -acetyl- N - β -methylphlegmarine ( 1d ) 4c. We report herein the total synthesis of all the known phlegmarine alkaloids 1a–d , and the N β -acetyl derivative 1e .…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Synthesis of All the Known Phlegmarine Alkaloids

et al. 2010

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The asymmetric synthesis of all four of the known natural phlegmarines and one synthetic derivative has been accomplished in 19 to 22 steps from 4-methoxy-3-(triisopropylsilyl)pyridine. Chiral N-acylpyridinium salt chemistry was used twice to set the stereocenters at the C-9 and C-2′ positions of the phlegmarine skeleton. Key reactions include the use of a mixed Grignard reagent for the second N-acylpyridinium salt addition, zinc/acetic acid reduction of a complex dihydropyridone, and a von Braun cyanogen bromide N-demethylation of a late intermediate. These syntheses confirmed the absolute stereochemistry of all the known phlegmarines.

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Asymmetric Synthesis of the Lycopodium Alkaloid, N_a-Acetyl-N_b-methylphlegmarine

Cited by 67 publications

References 17 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.

Asymmetric Synthesis of All the Known Phlegmarine Alkaloids

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