The developed chemistry may find application for the synthesis of its other family members of Schisandraceae nortriterpenoids.
Introduction Schisandra chinensis is also known as wu wei zi in China, which translates to five-flavour berry, a description given to it because it possesses all five basic flavours of salty, sweet, sour, spicy and bitter. Records show that for over 2, years five-flavour berries have been used as sedatives and tonic agents, as well as for the treatment of rheumatic lumbago and related diseases 1 , 2.
Because S. There has been considerable progress in the discovery of bioactive triterpenoids from the Schisandraceae family over the past two decades. To date, over nortriterpenoids have been structurally characterized 1 , 2 , and some representative structures 1—6 are shown in Fig. Preliminary biological assays have indicated that some of the nortriterpenoids possess inhibitory activity toward hepatitis, tumours and HIV-1 refs 1 , 2.
Figure 1: Schisandraceae family. Full size image Natural sources of these compounds are scarce, which hampers systematic studies of their biological activities. From this research, total syntheses of schindilactone A 4 , rubriflordilactone A 5 , 6 , schilancitrilactones B and C 7 and propindilactone G 8 see 3—6 in Fig. The structures of these compounds were confirmed by X-ray crystallography.
Among the nortriterpenoids, arisandilactone A 1 is unique in that it has an oxa-bridged tricyclic carbon core, which has not been encountered in natural products before. Because of this structural feature, arisandilactone A 1 is a challenging target for total synthesis. To the best of our knowledge, no synthesis of arisandilactone A 1 has been reported to date. Natural products with unique and complex architectures are challenging in organic synthesis for an excellent review, see ref.
In this regard, biomimetic approaches for the formation of complex natural products have proven to be effective strategies in organic synthesis Among the various biomimetic reactions, Michael-type reaction can be regarded as one of the most powerful reactions in the biosynthesis of natural products Results Retrosynthetic analysis For the total synthesis of arisandilactone A 1 , construction of its strained transannular oxabicyclo[5.
Thus, from a synthetic strategy point of view, this fragment should be introduced at a late stage in the total synthesis, and preferable by a biomimetic synthesis because of its high sensitivity and instability. While conducting the model study toward the total synthesis of arisanlactone C 2 , we serendipitously found that this strained bicyclic core could be constructed via an intramolecular oxa-homo-Michael reaction Fig.
In the event, we first synthesized aldehyde 7 and then coupled with tert-butyldimethyl 3-methylfuranyl oxy silane 8 via a vinylogous Mukaiyama aldol reaction VMAR.
This was followed by a homo-Michael reaction 14 , 15 through the cleavage of its carbon—carbon bond at C13 and C16 and simultaneous formation of the five-membered F ring see Fig. Figure 2: Model study. Full size image On inspection of the structure of product 9, we found that 9 could be epimerized at its C22 and C23 stereogenic centres by treatment with 1,8-diazabicyclo[5.
This strategy has been used by Pyne and co-workers in the total synthesis of Stemona alkaloid 11S, 12R -dihydrostemofoline C from 11S, 12S -dihydrostemofoline A through intermediate B Fig. Figure 4 illustrates our proposed biomimetic total synthesis of dehydroxyl arisandilactone A. The intermediate A, in turn, could be produced from B via nucleophilic attack of the silyl ether C on the aldehyde in intermediate B via a VMAR, followed by the key intramolecular homo-Michael reaction as shown above.
Precursor aldehyde B could be prepared from lactone D via a series of functional group interconversions. Figure 4: Retrosynthetic analysis of dehydroxyl arisandilactone A 1a.
This reaction would generate D with three contiguous stereogenic centres at C13, C16 and C17, as well as a lactone fragment, which could serve as a handle to install the side chain. Diene F, in turn, could be made from ketoester G by modifying the methods applied in our total synthesis of schindilactone A.
Figure 5: Synthesis of compound LiHMDS, lithium hexamethyldisilylamide. KHMDS, potassium hexamethyldisilylamide. To synthesize bislactone 16 from enone 14, we adopted the strategy developed in our total synthesis of schindilactone A 5. The observed diastereoselectivity could be attributed to the steric bulk of the triethylsilyloxy group in substrate 14, which allows both the hydrogenation and Grignard reactions to occur at the less-hindered face see three-dimensional structure of 14 in Fig.
The relative stereochemistry of 16 was confirmed by X-ray crystallography Fig. We then investigated our proposed RCM reaction to construct the medium-sized ring-based 31 tri-substituted cyclooctene in compound 18 Fig. Considering the potential for in situ epimerization of hemiketal during the RCM reaction 5 , 32 , we treated bislactone 16 with vinyl magnesium bromide The resulting dienes, as an epimeric mixture of hemiketals, were then subjected to a RCM reaction in the presence of catalyst 17 ref.
Figure 6: Synthesis of the lactone This could be attributed to steric hindrance at the C15 hydroxyl group in Consequently, we carried out a systematic study for the synthesis of We next investigated the conditions for synthesis of the rigid and highly strained intermediate 20 from 19 via the proposed intramolecular cyclopropanation reaction.
Consequently, it was unknown whether such a rigid and highly strained intermediate could be generated. The structure of 20 was confirmed by two-dimensional NMR spectroscopy. With lactone 20 in hand, we next investigated its transformation to aldehyde As illustrated in Fig. This ketone then underwent Peterson olefination 38 by reaction with freshly produced trimethylsilyl methylmagnesium chloride in the presence of CeCl3 ref.
The structure of 21 was confirmed by X-ray crystallography. Figure 7: Synthesis of alcohol BMS, borane-dimethylsulfide complex; b. Full size image It is worthwhile to mention that when the ketone derived from the Weinreb amide was directly reacted with a Wittig reagent derived from methyltriphenylphosphonium bromide, the expected olefination proceeded.
However, epimerization occurred at C17 of the product Organic Letters , 13 20 , Lacoske, William C. Mobley, and Emmanuel A. Organic Letters , 13 17 , Sunkyu Han and Mohammad Movassaghi. Journal of the American Chemical Society , 28 , Tony K. Shing, King H. So and Wun S. Organic Letters , 11 21 , Organic Letters , 0 proofing DOI: Formal Total Synthesis of N-Methylmaysenine.
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To synthesize bislactone 16 from enone 14, we adopted the strategy developed in our total synthesis of schindilactone A 5. Joseph M. Cited By This article is cited by 60 publications.
Figure 7: Synthesis of alcohol Mohammad Movassaghi,, Diana K.
Consequently, we carried out a systematic study for the synthesis of This was followed by a homo-Michael reaction 14 , 15 through the cleavage of its carbon—carbon bond at C13 and C16 and simultaneous formation of the five-membered F ring see Fig. Organic Letters , 19 22 ,
Hunt, and, Meiliana Tjandra. Joseph M. The stereochemistry at C20 in 26 was confirmed by X-ray crystallography. Therefore, 30 was also a thermodynamically stable product, which was observed experimentally. With lactone 20 in hand, we next investigated its transformation to aldehyde
The relative stereochemistry of 16 was confirmed by X-ray crystallography Fig.
Christiane Marti and, Erick M. The Michael addition takes place at the Si-face of the alkene moiety in CP11 via transition state TS10, with a barrier of Journal of the American Chemical Society , 20 , The reaction actually proceeded through a typical VMAR followed by the proposed homo-Michael reaction.
For calculation results using other methods, see Supplementary Figs 42— Total Synthesis of Aigialomycin D. Because of this structural feature, arisandilactone A 1 is a challenging target for total synthesis.
Antimalarial and Antiplasmodial Activities of Norneolignans. The Journey of Schinortriterpenoid Total Syntheses. Figure 1: Schisandraceae family.
Mohammad Movassaghi,, Diana K. Figure Energy profiles for the homo-Michael step.
Sunkyu Han and Mohammad Movassaghi. However, 30 was not the major product because the relative free energy of TS14, which leads to the formation of CP14 was 1. Here we describe a concise and efficient asymmetric synthesis of dehydroxyl arisandilactone A—which belongs to a family of architecturally unique, highly oxygenated nortriterpenoids isolated from the medicinal plant Schisandra arisanensis. This strategy has been used by Pyne and co-workers in the total synthesis of Stemona alkaloid 11S, 12R -dihydrostemofoline C from 11S, 12S -dihydrostemofoline A through intermediate B Fig. The Journal of Organic Chemistry , 79 2 ,