Avenaol, isolated from the allelopathic plant black oat, was the first C20 germination stimulant related to strigolactones. Structurally, it consisted of a bicyclo[4.1.0]heptanone skeleton containing a cyclopropane ring bearing three main chains projecting in the same direction (i.e. all-cis-substituted cyclopropane). Herein, we report the total synthesis of avenaol using a robust strategy involving the formation of an all-cis-substituted cyclopropane via an alkylidenecyclopropane. The key factors in the success of this total synthesis include the Rh-catalysed intramolecular cyclopropanation of an allene, an Ir-catalysed stereoselective double-bond isomerisation, and the differentiation of two hydroxymethyl groups via the regioselective formation and oxidation of a tetrahydropyran based on the reactivity of a cyclopropyl group. This strategy effectively avoids the undesired ring opening of the cyclopropane ring and the formation of a caged structure. Furthermore, this study confirms the proposed structure of avenaol, including its unique all-cis-substituted cyclopropane moiety.
Natural products containing complex three-dimensional structures represent challenging synthetic targets, and compounds of this type have consequently received considerable interest from research groups all over the world1,2,3. Notably, cage-shaped natural products have been reported to show several interesting biological activities, and numerous polycyclic terpene4,5,6,7 and alkaloid8 targets of this type have inspired synthetic chemists to develop innovative new strategies to access these compounds. Non-cage-shaped natural products that are capable of being converted to cage-shaped materials also exhibit an interesting range of biological activities, as exemplified by avenaol9, shagene A10, erythrolide A11 and arisanlactone C12 (Fig. 1a). These compounds are characterised by their bicyclo[4.1.0]heptane (avenaol, shagene A), bicyclo[3.1.0]hexane (erythrolide A), and bicyclo[6.1.0]nonane (arisanlactone C) skeletons, all of which contain a cyclopropane ring bearing three main chains projecting in the same direction (i.e. an all-cis-substituted cyclopropane). Although the synthesis of these natural products is considered to be as challenging as the synthesis of their cage-shaped counterparts, there have been very few reports to date pertaining to the synthesis of all-cis-substituted cyclopropanes. In fact, there have been no reports to date concerning the total synthesis of non-cage-shaped natural products containing an all-cis-substituted cyclopropane. Furthermore, it is envisaged that these syntheses would lead to the identification of several stereochemically interesting structures. With this in mind, we became interested in investigating the synthesis of natural products containing an all-cis-substituted cyclopropane using the non-typical strigolactone avenaol, which shows important biological activity, as a representative example.
Classics In Total Synthesis Ii Pdf 16
Herein, we report the total synthesis of avenaol based on a strategy for the construction of all-cis-substituted cyclopropanes using alkylidenecyclopropane as a key intermediate. The core structure is constructed through the Rh-catalysed intramolecular cyclopropanation of an allene, and an Ir-catalysed stereoselective double-bond isomerisation. This strategy effectively avoids the undesired ring opening of the cyclopropane ring and the formation of a caged structure. Furthermore, this study confirms the proposed structure of avenaol, including its unique all-cis-substituted cyclopropane moiety.
The main challenges associated with the synthesis of avenaol include the construction of a bicyclo[4.1.0]heptanone skeleton containing an all-cis-substituted cyclopropane, controlling the stereochemistry at the C8 position of the C ring, and the introduction of a C3 hydroxyl group on the A ring. The construction of bicyclo[4.1.0]heptanone skeletons has mainly been investigated in the context of constructing caged structures26,27,28. For non-caged structure, the direct synthesis of these systems has been limited to the 1,4-addition of a suitable anion of a trans-chloroallylphosphonamide29 or Ir-catalysed or Rh-catalysed cis-selective cyclopropanation reactions30, 31. However, preliminary work in our own group has shown that these methods are unsuitable for the synthesis of avenaol (Supplementary Fig. 1). Furthermore, cyclopropane rings bearing an electron-withdrawing group can readily undergo a ring-opening reaction32,33,34, further highlighting the difficulties of this approach. On the basis of these issues, we envisioned that the use of alkylidenecyclopropane35 as an appropriate intermediate would avoid an unwanted ring-opening reaction and the formation of a caged structure. We also envisioned that avenaol could be obtained from 2 by the dihydroxylation of its convex face and the introduction of the D ring (Fig. 2). The C ring lactone could be constructed by the diastereoselective transformation of the diol based on the reactivity of the cyclopropyl group in 3, which could be obtained by introduction of a hydroxymethyl group to the all-cis-substituted cyclopropane 4. Compound 4 could be synthesised by the intramolecular cyclopropanation of allene 6, which could be readily prepared from aldehyde 7, followed by double-bond isomerisation of alkylidenecyclopropane 5. The intramolecular cyclopropanation of an allene to form a six-membered carbocycle has not been reported, indicating that development work would be required to allow for the construction of the bicyclo[4.1.0]heptanone core.
Retrosynthesis of avenaol (1). Our strategy is characterised by the use of an alkylidenecyclopropane intermediate 5, providing a robust route to the required all-cis-substituted cyclopropane, while avoiding the undesired ring opening of the cyclopropane ring and the formation of a caged structure. The numbering of the carbon atoms is consistent with that used for avenaol. PMB p-methoxybenzyl
Our synthesis began with the preparation of the cyclisation precursor 6 (Fig. 3). The treatment of known aldehyde 7 36 with 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran and BnMe3NOH37, followed by methylation and acidic treatment gave 8. The subsequent hydroalumination of 8, followed by the treatment of the resulting intermediate with iodine gave 9 38, which was converted to carboxylic acid 10a via sequential protection as a triisopropylsilyl (TIPS) ether, hydroboration and oxidation by 9-azanoradamantane N-oxyl (nor-AZADO)39. The cyclisation precursor α-diazo-β-ketonitrile 6a was synthesised by sequential β-ketonitrile formation and diazo transfer reactions40. A similar sequence was used to prepare the benzyl-protected methyl diazoketone 6b. The α-diazo-β-ketoester 6c and ketonitrile 6d were also synthesised via 10b (Supplementary Fig. 2).
104. Yet it must also be recognized that nuclear energy, biotechnology, information technology, knowledge of our DNA, and many other abilities which we have acquired, have given us tremendous power. More precisely, they have given those with the knowledge, and especially the economic resources to use them, an impressive dominance over the whole of humanity and the entire world. Never has humanity had such power over itself, yet nothing ensures that it will be used wisely, particularly when we consider how it is currently being used. We need but think of the nuclear bombs dropped in the middle of the twentieth century, or the array of technology which Nazism, Communism and other totalitarian regimes have employed to kill millions of people, to say nothing of the increasingly deadly arsenal of weapons available for modern warfare. In whose hands does all this power lie, or will it eventually end up? It is extremely risky for a small part of humanity to have it.
121. We need to develop a new synthesis capable of overcoming the false arguments of recent centuries. Christianity, in fidelity to its own identity and the rich deposit of truth which it has received from Jesus Christ, continues to reflect on these issues in fruitful dialogue with changing historical situations. In doing so, it reveals its eternal newness.[98]
Eschenmoser had discussed the ETH contributions to the A/B approach in 1968 at the 22nd Robert A. Welch Foundation conference in Houston,[7] as well as in his 1969 RSC Centenary Lecture "Roads to Corrins", published in 1970.[8] He presented the ETH photochemical A/D approach to the B12 synthesis at the 23rd IUPAC Congress in Boston in 1971.[9] The Zürich group announced the accomplishment of the synthesis of cobyric acid by the photochemical A/D-approach in two lectures delivered by PhD students Maag and Fuhrer at the Swiss Chemical Society Meeting in April 1972,[10] Eschenmoser presented a lecture "Total Synthesis of Vitamin B12: the Photochemical Route" for the first time as Wilson Baker Lecture at the University of Bristol, Bristol/UK on May 8th, 1972.[note 10]
Representative reviews of the two approaches to the chemical synthesis of vitamin B12 have been published in detail by A. H. Jackson and K. M. Smith,[45] T. Goto,[68] R. V. Stevens,[38] K. C. Nicolaou & E. G. Sorensen,[15][19] summarized by J. Mulzer & D. Riether,[69] and G. W. Craig,[14][33] besides many other publications where these epochal syntheses are discussed.[note 13]
Theoretical Domains Framework represents another approach to developing determinant frameworks. It was constructed on the basis of a synthesis of 128 constructs related to behaviour change found in 33 behaviour change theories, including many social cognitive theories [10]. The constructs are sorted into 14 theoretical domains (originally 12 domains), e.g. knowledge, skills, intentions, goals, social influences and beliefs about capabilities [66]. Theoretical Domains Framework does not specify the causal mechanisms found in the original theories, thus sharing many characteristics with determinant frameworks. 2ff7e9595c
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