Asymmetric synthesis of (+)-vertine and (+)-lythrine

Chausset‐Boissarie, Laëtitia; Àrvai, Roman; Cumming, Graham R.; Guénée, Laure; Kündig, E. Peter

doi:10.1039/c2ob25880c

Cited by 20 publications

(23 citation statements)

References 68 publications

(13 reference statements)

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“…The azabicyclic skeleton of quinolizidine is a relevant structural subunit present in numerous alkaloids and can be built starting from 1 . (+)-Vertine ( 55 ) and (+)-lythrine ( 56 ) are examples of this class of natural compounds ( Figure 3 ); they are extracted from Decodon verticillatus and displayed a wide range of biological activities, such as anti-inflammatory, sedative, and antispasmodic actions; recently, was realized their total synthesis starting from 1 [ 45 ].…”

Section: A General Overview Of the Structures Of Alkaloids Synthesmentioning

confidence: 99%

Enzymatic Kinetic Resolution of 2-Piperidineethanol for the Enantioselective Targeted and Diversity Oriented Synthesis

Perdicchia

Christodoulou

Fumagalli

et al. 2015

IJMS

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2-Piperidineethanol (1) and its corresponding N-protected aldehyde (2) were used for the synthesis of several natural and synthetic compounds. The existence of a stereocenter at position 2 of the piperidine skeleton and the presence of an easily-functionalized group, such as the alcohol, set 1 as a valuable starting material for enantioselective synthesis. Herein, are presented both synthetic and enzymatic methods for the resolution of the racemic 1, as well as an overview of synthesized natural products starting from the enantiopure 1.

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Section: A General Overview Of the Structures Of Alkaloids Synthesmentioning

confidence: 99%

Enzymatic Kinetic Resolution of 2-Piperidineethanol for the Enantioselective Targeted and Diversity Oriented Synthesis

Perdicchia

Christodoulou

Fumagalli

et al. 2015

IJMS

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“…Both highly enantioenriched forms of 6 (obtained from the resolution study) were used to synthesize several alkaloids. Firstly, (-)-(S)-Cbz-protected pelletierine 17 was used to prepare naturally occurring sedridine (32) and its epimer allosedridine (8). Then the preparation of both enantiomers of the quinolizidine myrtine (33) by an olefination-intramolecular aza-Michael sequence is reported.…”

Section: Introductionmentioning

confidence: 99%

“…[7] Part of this interest stems from the fact that 6 represents a useful, functionalized building block to assemble more complex structures. [8] Coniine (7), a toxic substance from several plants famously including poison hemlock (Conium maculatum), contains an unfunctionalized n-propyl substituent. [9] It is likely that natural products like 6 are assembled biosynthetically from a Mannich-type process, therefore, unsurprisingly the 1,3-amino oxygenation pattern is frequently found in this class of compounds.…”

Section: Introductionmentioning

confidence: 99%

Strategies for the Asymmetric Construction of Pelletierine and its Use in the Synthesis of Sedridine, Myrtine, and Lasubine

Zaidan

Evans

2019

Eur J Org Chem

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Three methods for the asymmetric synthesis of both enantiomers of pelletierine 6 are reported. Bella's proline‐based Mannich process gave (R)‐ and (S)‐Cbz‐protected 6 in good yields from Δ1‐piperideine 14 and in reasonable enantiomeric excess (74–80 % ee). An intramolecular aza‐Michael, cinchona‐based, organocatalytic method is also reported. With commercially available 9‐amino quinine (24a) and quinidine (24b) catalysts, Cbz‐protected α,β‐unsaturated ketone 23 also gave (R)‐ and (S)‐Cbz‐protected 6 in good yields and enantiomeric excess (90–99 % ee). This material was used to synthesize both optically active forms of deoxyhalofuginone (26), an analogue of febrifugine which is of interest as an anti‐fibrotic agent. Finally, a resolution of racemic pelletierine using (R)‐ and (S)‐mandelic acid 27 is reported. This scalable method gave both enantiomers of Cbz‐ and Boc‐protected 6 in excellent enantiomeric excess (≥ 99 %). Both highly enantioenriched forms of 6 (obtained from the resolution study) were used to synthesize several alkaloids. Firstly, (–)‐(S)‐Cbz‐protected pelletierine 17 was used to prepare naturally occurring sedridine (32) and its epimer allosedridine (8). Then the preparation of both enantiomers of the quinolizidine myrtine (33) by an olefination‐intramolecular aza‐Michael sequence is reported. Finally, the synthesis of the epimeric quinolizidine alkaloids, lasubine I (34) and lasubine II (35), from (+)‐ and (–)‐Boc‐protected pelletierine (29) respectively, is discussed.

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“…89 Experimental details of this work have been published in a full paper detailing the synthesis of (+)-vertine (1-166) and its epimer, (+)lythrine (1-163) ( Figure 1.3-6). 90 Various macrocyclisation strategies were attempted and the synthesis will be reviewed in greater detail in Chapter 3. Bates and co-workers reported a racemic, albeit highly diastereoselective synthesis of alkaloid 1-239 (Scheme 1.3-27).…”

Section: Scheme 13-14 Kim's Synthesis Of (-)-Lasubine IImentioning

confidence: 99%

“…The synthesis of vertine (1-166) has been reported by Kündig, both in racemic 89 and enantiomeric forms. 90…”

Section: Prior Syntheses Of Vertinementioning

confidence: 99%

Synthesis of piperidine and quinolizidine alkaloids

Nur¹

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Natural products have been, and will continue to be, an important starting point for researchers in the quest for novel treatments for today's ailments. While these molecules often have very highly potent or specialised activities, they may not be the perfect drug candidate. Medicinal chemists aim to improve their therapeutic activity and at the same 6 1-11 to give a rather low diastereomeric mixture (2.3:1) of alcohols 1-12 and 1-13 which were separable by silica gel chromatography. Acetonide cleavage of 1-12 by treatment with aqueous HCl followed by the key intramolecular cyclisation step under Mitsunobu conditions furnished pyridinium salt 1-14. Subsequent reduction with hydrogen in the presence of PtO 2 as catalyst produced a 0.8:1 mixture of diastereomers. Subsequent treatment of each diastereomer with concentrated aqueous KOH yielded (-)-lentiginosine, ent-1-1, and its 8a-epimer, 1-15. 1-epi-lentiginosine, 1-16, was also synthesised in a similar fashion. Preparation of the 1-epimer began with alcohol 1-13 and the reduction step proceeded with high yields and diastereoselectivity. Scheme 1.2-2 Fruit's synthesis of (-)-lentiginosine, analogues 1-15 and 1-16 Brandi and co-workers also used a pyridine-based strategy to synthesise racemic lentiginosine (Scheme 1.2-3). 16 Here, pyridyl alcohol 1-17 was identified as a good starting point. Brandi reasoned that the double bond present could undergo electrophilic addition and then cyclise to form the bicyclic skeleton. Bromination of pyridyl alcohol 1-17 with NBS in aqueous THF furnished pyridinium salt 1-18 diastereoselectively with a yield of 53%. Similar to Fruit's work, the pyridinium salt was reduced by hydrogenation with catalytic amounts of PtO 2 to furnish a 0.7:1 mixture of diastereomers 1-19a and 1-19b. The group demonstrated that the presence of a good leaving group i.e. bromine, enabled facile

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Asymmetric synthesis of (+)-vertine and (+)-lythrine

Cited by 20 publications

References 68 publications

Enzymatic Kinetic Resolution of 2-Piperidineethanol for the Enantioselective Targeted and Diversity Oriented Synthesis

Enzymatic Kinetic Resolution of 2-Piperidineethanol for the Enantioselective Targeted and Diversity Oriented Synthesis

Strategies for the Asymmetric Construction of Pelletierine and its Use in the Synthesis of Sedridine, Myrtine, and Lasubine

Synthesis of piperidine and quinolizidine alkaloids

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