Hi, welcome back to history and philosophy of science and medicine. I'm matt brown today We're talking about values and disease screening and the science And decision-making behind disease disease screening in medicine. I Want to remind you about something we talked about last week having to do with inductive risk. So if you remember According to the way we talked about this last week You have if you have a hypothesis like Chemical X is safe for human consumption And that's a hypothesis that could be true or false It's also based on the evidence that you get from the the data you collect You could choose to accept or reject the hypothesis and therefore possible situations either you Accept the hypothesis and the hypothesis is true, which is great That's what you want or you reject the hypothesis and the hypothesis is false also great either way you've got the right answer but if you Accept the hypothesis, but the hypothesis is actually false you have a false positive result, right? That's a form of error Similarly, if you reject the hypothesis, but the hypothesis is actually true. That's a false negative error, right? presumably the chemical is safe or it's not to some criteria of safety and You accept or reject it or not and so use these four possibilities and two of them are forms of error Now if you have a false positive error The consequences of that could be risk to human life and health because if you accept the hypothesis that the That the chemical is safe and so you don't regulate it or ban it But it in fact is not safe then you're gonna have those risks those those consequences On the other hand if you reject the hypothesis if you if you say it's not safe And then you go ahead and regulate it or ban it then you're going to forgo the benefits of chemical x and they're going to be economic Losses to the producers of it and and so on and so forth, right? so these are the kinds of considerations that One has to weigh in order to make judgments about the evidence, right? So in designing Studies in determining what the criteria For accepting or rejecting the hypothesis is going to be you have to you have to weigh These possible consequences and the risks associated with them and set your standards accordingly That's what we talked about last time Now suppose we switch the case a little bit Our hypothesis now is not concerning some chemical safety question It's concerning of the situation of a particular patient, right? The the hypothesis in question is that patient that a patient has Condition x that's going to cause disease for example, they may have Some kind of growth of cells in their breast that is going to cause breast cancer disease We might have a test of this hypothesis Through a screening technology like screening mammography, right? And this screening test has the same structure of possible choices Either the either the condition is going to cause disease or not, right? at some at some for some criteria of disease and We can choose we can design our We can design our Screening test in various ways, but there's always going to be some probability of False positive or false negative air so false positive your tests come back comes back and says You have the disease or you have the condition that will lead to disease but you actually don't or False negative error. It says you're fine the test says you're fine, but in fact you have The disease or the conditions that are precursors to the disease, okay? Now The assumption is going to be that this test is is going to in many cases where there's a treatment available Is going to lead to certain kinds of treatment so Whenever we accept the hypothesis that the patient has the disease or has the condition that will cause disease We are presuming also that we're going to treat Treat that accordingly. There's going to be some kind of treatment decision made on the basis of that information okay, and Here again, we have the same kind of inductive risk issues, right? If you have a false positive error, then there are risks of over treatment of Stigma if the disease carries some form of social stigma of the mental distress of being told you have a disease when you in fact You don't have the disease all of these things are Consequences of a false positive error and the things we risk Based on the the the probability of a false positive error Similarly for a false negative error if we tell you you're fine, but you're not then we're risking increased morbidity and mortality, right? So these are the kinds of errors that need to be balanced in the design of of screening medical screening Techniques and technologies right so you might in the case of Cancer screening for example, you might start with an early detection test that Tries to minimize false negative errors, but has lots of false positives As long as you can follow that up in relatively short time with a second test That is that is less That may be more expensive or more difficult, but has a much lower false positive rate, right? Those are the kinds of choices there both economic Aspects to these choices as well as these sort of social ethical consequences to to human well-being at stake We should think also in the con in the context of our discussion today Not only about the the inductive risks involved in a particular screening test Which is which is definitely relevant to patient treatment and Medical decision-making we should also think about the inductive risk involved in the evidence about those screening tests So both of the articles that you read for today by Plutinska and by Koranian Fernandez Pinto look at breast cancer screening and Evidence that engaging in those screenings is effective, right? So right hypothesis in this case might be that screening for condition X say breast cancer is Effective for patients in group Y say women age 40 to 50, right? if we say if our if our sort of if the hypothesis if we accept the hypothesis, right and therefore we have a policy recommendation or a medical recommendation that women 40 to 50 and in that group Should receive the screening, right? We risk all the same sort of Consequences of a false positive error over treatment stigma mental distress, etc If we do not give the if we do not recommend the screening Then there's a risk of false negative error that that has the consequences of increased morbidity and mortality and and you know, we can compare the individual level here that we were talking about before with the with the mass level so the the The judgment about effectiveness in the population right is a judgment about sort of the What's going to happen to the whole group of people that does or does not get this treatment, you know for individuals, right? There's always going to be some cases of breast cancer that are caught early and receive treatment And you know, if they get this if they get this screening their lives are going to be extended There are going to be other cases where people slip by as a false negative They're not going to get detected and they're not going to get treatment early on Similarly, they're going to be false positives. They're going to be those who suffer from over treatment Or or the mental distress that goes with over diagnosis But the question is sort of, you know stacking it all up in the in the mass, right for the whole population Is the risks are the risks associated worth it, right? Is it worthwhile for? for a person in this group to get the the screening Or are there odds of harm greater than their odds of being helped? Now there are a number of sources of uncertainty about the effectiveness of disease screening that are discussed in the readings Choice of end point, right? This this is a question of what it is. We're measuring for effectiveness Are we effect? Are we measuring survival time from detection? Say if we introduce an early detection technology Does that increase survival time? But that can be a biased end point, right? Because Others who are not detected at all Until later, you know There may it may be that you don't you don't actually extend life. You just extend the time That you know that they are going to have the disease Also, the choice of disease specific or all-cause mortality is a crucial Case of uncertainty There are some screening technologies where you can show that it makes it less likely that they're going to die from the disease That that's detected, right? But that they're also not they're not likely to live any longer So there's no no reduction in all-cause mortality That's a little bit puzzling, right?  These are population level Results not individual level results. That's puzzling but but partly it's because It's it's harder to detect reductions to all-cause mortality because there are so many more factors involved There are biases and confounds of various kinds in trial design and in the results of those trials These are these are covered in great detail in the readings. There there are various ways in which Either the researchers The statistical techniques or even the patients can be biased by the trial design There's a variety of choices in your meta-analysis and your systematic reviews that means that Even when you're aggregating a large number of trials on the same question you can come to diverging Judgments for or against the effectiveness of a screening for a particular group There are also a lot of unknowns about the disease etiology and mortality so so You know what it what causes the disease? How does the disease progress and how many people in the general population now all actually die from the disease? Are things that we may not know a lot about in many cases. We we don't know a lot about What the causes of breast cancer are what the progression of breast cancer is at a biological level? and You know for many diseases our estimates of of Who dies from those from those diseases is a little bit uncertain right based on How we decide to measure it and estimate it There's also competing and uncertain evidence concerning over diagnosis rates so what constitutes an over diagnosis we have a clear definition You know someone is over diagnosed if that they are diagnosed as having a disease but the disease is not actually going to lead to lead to real symptoms detectable symptoms Or experienceable symptoms in the life course of the patient right so for example some cancers Right can be detected quite early, but they grow so slowly that the patient dies of natural causes Long before the disease the the cancerous growth would cause any disease There's also conflict over how we measure the harms of over diagnosis, right? so not only what is the rate which People are over diagnosed, but how bad is it and we don't agree about how to measure that One of the things to keep in mind is that research funding itself is biased towards detection and treatment not prevention, right? There's a there's a kind of crass economic reason for this There is no profit in prevention, but there is profit in providing treatment, right? So it's it's natural that The the medical Companies that provide the detection Technology would be interested in this and would provide funding for it Also, you know in some cases we don't you know the the the prevention is Hard to figure out because we don't know what the causes are Or there may not be preventable causes in some cases It's important. I think also to point out that early detection is not the same as prevention, right? So some some defend the importance of screening Technologies as a as a general argument in favor of preventative medicine Which is you know, no doubt important But but detecting something early And treating it early is not the same thing as preventing the disease from happening All right, it's just early intervention. It's not prevention Those aren't the same. They should be they should be you know categorized separately so You might ask based on these readings This should we not do screening magma mammography or should we not do it until you reach a certain age range and Here I think the authors and me personally don't have a specific medical recommendation to make Only to point out that though the way that this is being decided is is really fraught with these values And so there may be a need for a certain kind of Patient autonomy here or also stakeholder Consultation and consideration of a variety of perspectives before we make recommendations, right? What's clear is that the recommendations that are being made now that are in conflict with one another Are being made on the basis of somewhat different values and motivations and biases So that's what we're talking about today I look forward to hearing what you think about about this and the other issues raised by the reading so please Way in on discord I leave a comment on the video or on the discussion board And I look forward to seeing many of you in class Otherwise, I look forward to talking to you next week Bye


My name is Sam Vaknin, and I am the author of Malignan's Cell Club, Narcissism Revisit. As we all know, the narcissist lacks sympathy. He is therefore unable to meaningfully relate to other people and to truly appreciate what it is to be human. Instead, the narcissist withdraws insight into a universe populated by avatars, simple or complex representations of parents, peers, role models, authority figures and other members of his social milieu. There, inside, in his inner landscape, in this twilight zone of simulacra, he develops relationships and maintains an ongoing internal dialogue with his introjects, with his internal representations. All of us generate such representations of meaningful others and internalize these objects that we have invented. This is a process called introjection. We adopt, we assimilate, and later we manifest their traits and their attitudes. This is completely normal, it's part of personal development and growth, especially in early childhood and up to early adolescence. But the narcissist is different. He is incapable of holding an external dialogue. All his dialogues are completely internal. Even when he seems to be interacting with someone else, the narcissist is actually engaged in a self-referential discourse. To the narcissist, all other people are cardboard cutouts. They are merely two-dimensional animated cartoon characters. It does not perceive other people because of his lack of empathy as three-dimensional entities with their own needs, preferences, wishes, priorities, hopes. To him, everyone is a mere symbol. People exist only in his mind. He is startled when people deviate from the script and prove to be complex and autonomous. But this is not the narcissist's only or sole cognitive deficit. The narcissist attributes his failures and mistakes to circumstances and external causes. This propensity to blame the world for one's mishaps and misfortunes is called alloplastic defense. At the same time, the narcissist regards his successes and his achievements, some of which, of course, are completely imaginary, as proofs of his own omnipotence and omniscience. So if he fails, it's someone else's fault. If he succeeds, it's his own doing. This is known in attribution theory as defensive attribution. Conversely, the narcissist traces other people's errors and defeats to their inherent inferiority, stupidity, and weakness. Their successes, he dismisses as being in the right place at the right time, the outcome of luck and circumstances. So if they succeed, it's an accident of fate. If they fail, it's their own fault, exactly the opposite of what the narcissist attributes to himself. The narcissist thus falls prey to an exaggerated form of what is known in attribution theory as fundamental attribution error. These fallacies and the narcissist's magical thinking are not dependent on objective data, on tests of distinctiveness, consistency, and consensus. He is not rational. It's an irrational thing, raging inside him. The narcissist never questions his reflexive judgments. He never stops to ask himself, are these events distinct? Are they typical? Do they repeat themselves consistently? Are they unprecedented? What do others have to say about all this? The narcissist learns nothing, because he regards himself as born and being perfect. Even when he fails a thousand times, the narcissist still feels the victim of happenstance. Someone else has repeated outstanding accomplishments are never proof of metal or merit. People who disagree with the narcissist and try to teach him differently, to improve him, to help him, are, to his mind, biased or morons or both or people with evil intentions, because the narcissist is also paranoid and enmeshed and immersed in persecutory delusions. But the narcissist pays a dear price for these distortions of perception.  Finally, the narcissist lifts the drawbridge, vanishes into a state of mind that can best be described as borderline psychosis.


So good morning and welcome back to the NPTEL lecture series on classics in total synthesis part 1. And we have been discussing total synthesis of complex natural products. And in the last lecture we talked about the total synthesis of an anti-cancer agent called TAXOL and we will continue to discuss about more complex natural products and particularly anti-cancer agents. In the 1990s when we talked about TAXOL I also mentioned there were other complex natural products which were used as anti-cancer agents. There were at least 5 naturally occurring compounds which were supposed to be you know very potent against various cancers. The one which we already discussed was TAXOL which is quite complex and the second one was elitrobin which you can see that it is quite complex in structure almost similar to TAXOL. And the third one was apothelons. Here I am showing the structure of apothelon A and there are other apothelons as well. So these are macrolite and two more natural products which were also considered to be you know very good anti-cancer agents in 90s were dictostatin and discodermalite. So these are the 5 natural products where many synthetic groups were focusing on developing new methods, new strategies for their total synthesis. Today what we will do we will focus on one of them that is elitrobin. See this structure of elitrobin if you look at it has 3 rings you can call it as A, B, C ring and you have 2 side chains one here and this was isolated in 90s from elitrobia species of marine soft corals found in Indian Ocean. And it was isolated few milligram and Pennacles group which isolated this compound proposed this structure. Of course as you know it was through various high field NMR studies they could propose the structure of elitrobin. Nevertheless it is important from synthetic point of view to synthesize this compound and to prove the absolute configuration because absolute configuration was not known that time. Then the second most important thing about this particular molecule is since this was isolated from marine soft corals as you know marine soft corals particularly if it is in very sensitive region then you cannot go back and then isolate more of them. So from that angle also if this molecule has to be made or to be made available for further medicinal and biological studies and this could be done only through synthesis. So from these 2 angles it was very important to develop good strategy and using this strategy one should be able to make not only elitrobin but also several analogs. So as I said many groups were involved in the totals synthesis of elitrobin and I will talk about 2 totals synthesis today I will talk about 1 totals synthesis reported by K.C. Niccolow and as I said this was as active as taxon and it showed high activity against various cancer cells and it worked with IC50 range of 10 to 15 nanomolar that is quite significant and the mechanism of action of elitrobin was almost like pachytaxon. So this is another reason why many groups were interested in making this molecule and also it worked against various types of cancer like breast renal ovarian and lung cancer. From the structural point of view when the synthetic chemist wants to synthesize it has 3 rings tricyclic core structure having a 6-membered ring and the middle ring is 9-membered and the right hand side ring is 5-membered. So all these 3 rings have 6 chiral centers and the middle ring 9-membered ring that is a medium size ring has 6 substitutes. So construction of 9-membered rings with 6 substitutes is quite challenging and overall in this molecule there were 10 chiral centers and out of that 4 are coming from the sugar unit and in addition to the core structure that is the tricyclic ring 6-membered, 9-membered and 5-membered ring it also has 2 side chains one at the northern hemisphere. So that is an alphabet and saturated system and the down it has an arabino system these are the 2 side chains. So a successful synthesis of eletrobin not only should address the synthesis of core structure but also an efficient synthetic route to the 2 side chains. And Nikolaou was the first one to report the total synthesis in 1997 and of course as I mentioned one of the major issue was to assign the absolute configuration of eletrobin. So he could successfully assign the absolute configuration based on the starting material which he used and then further stereochemical elaboration and the key reaction in the synthesis of epithelium was an intramolecular addition of lithium acetylite to an alpha beta unsaturated oleate okay. That was the key reaction to make the 10-membered ring and afterwards the 10-membered ring was converted into 9-5 bridge system okay. And of course it was made easy since he started with commercially available monotterpin called the Carvo and look at this structure so it is quite complex and this retro synthesis started with you know removal of this side chain first that can be attached by simple esterification likewise the other side chain this arabino pyranose can also be easily attached. So the first disconnection of eletrobin was removal of these 2 side chains and the third important connection as I said first the starting material is from carbon which has the same 6-membered ring with double bond methyl group and an isopropyl group. So it was very easy to identify the starting material and construction of B C ring is quite challenging because A ring is commercially available you have to attach the B and C ring. So he used 2-3 key reactions one as I said the intramolecular addition of the triple bond the triple bond later became double bond here overall how he planned was he first may started with A ring that is A ring at 6-membered ring then he attached a 10-membered ring okay. So the 10-membered ring is the combination of B and C ring then the 10-membered ring he converted into 9 and 5 B and C ring he formed from the 10-membered ring that is how he made essentially 6, 9, 5 tricyclic ring okay. Let us see how he did this first he started with carbon and as you know the carbon has 2 double bonds one is electron rich the other one is electron deficient. So what can selectively epoxidize the electron deficient double bond in the presence of electron rich double bond by alkaline hydrogen peroxide. So alkaline hydrogen peroxide epoxidize the electron deficient double bond. So now what one has to do is to reduce the electron rich double bond so that was easily done under standard hydrogenation condition. So now you have introduced the isopropyl which is required for eluptirobene A ring okay. What is required now? Now you need to attach 2 substituents at these 2 carbons okay 2 substituents at these 2 carbons at the same time you do not want this epoxide what you want is a double bond is not it? Now we have basically we have protected the double bond as epoxide but in the long run before we go for total synthesis you need that as a double bond. So what you can do one can think about a transposition okay. So what you did before that you need to introduce a functional group here okay. So if you treat with LDA one can generate enolate and followed by conging with formaldehyde now you could introduce your functional group at this curve okay. So that is done. Now you have to protect the primary hydroxyl group that can be easily done since it is primary hydroxyl group protection was done with TBS chloride and after protection now the next job is to as I said you have to introduce a functional group here and you have to remove the epoxide okay. So what you did? You reduced the ketone you reduce the ketone with L select right stereo selectively to get alpha alcohol okay then this alpha alcohol was converted into a mesolate okay. So you got the mesolate. This idea was to cleave the epoxide okay to cleave the epoxide and bring this as an allylic alcohol okay that can be done with sodium naphthalenide and sodium naphthalenide will cleave this COMS bond then it will open up the epoxide to get allylic alcohol okay. So now if you look at this structure what one needs is you need a functional group here and the double bond should shift here and what you have is an allylic alcohol okay. This allylic alcohol if you recall some of the rearrangements you have studied allylic alcohols if you attach appropriate substituents on the alcohol then it can undergo a 3-3 sygmatropic rearrangement that is twice in rearrangement it can undergo that way the double bond will migrate and in the process you can also introduce a functional group okay. So with that idea the glycine rearrangement was done. The glycine rearrangement you treat with triethyl ortho acetate okay triethyl ortho acetate in the presence of propionic acid catalytic propionic catalytic amount of propionic acid followed by heating okay so that will give you this intermediates and this goes through this intermediate. On treatment with triethyl ortho acetate it undergoes intramolecular glycine rearrangement and that will give you this gamma delta unsaturated ester alpha, beta, gamma, delta unsaturated ester. Whenever you see a gamma delta unsaturated ester the reaction which should come to your mind is glycine rearrangement. So now you have an ester and what you need is an aldehyde so that can be easily done by reducing with diball H okay diball will reduce the ester to get the aldehyde okay. So that is a AB ring fragment okay AB ring fragment that means so now you have to attach the C ring and then make the B C ring so this fragment is made now. So what is required now you have to make the two sidechains first you have to make the sugar fragment so for that you start with Arabianus. So Arabianus when you convert that into acetate that per acetylation will give you this tetra acetate okay now if you treat with phenyl thiol in the presence of Lewis acid this anomeric acetate can be easily replaced by SPH it is a standard reaction so Lewis acid will coordinate here and then this will expel the OAC so you will get an oxonium ion then phenyl thiol will attack and you will get the SPH replacing the OAC okay. Then you can remove all the acetate in one part by treating with potassium carbonate methanol so you get the corresponding triol. If you look at this triol these two diols are cis whereas these two are trans. So cis 1 2 diol can be easily protected as astronite so that is what being done so you protect the cis 1 2 diol here and this can be written like this you know it is just 180 degree just rotate if you rotate and this is what you get why I have drawn this way was this will be useful while you convert this into chair like transition state chair like product okay the chair conformation when you want to convert this into chair conformation then this will be more useful than this so that is why I ask you to rotate it by 180 degrees okay. Now you see this is the chair conformation and the diol is protected cis diol is protected and the equatorial alcohol now you can protect it as PMB ether okay sonium hydride PMB chloride will give you the protected PMB ether then you can also remove the astronite you can remove the astronite by treating with para toluene sulphonic acid and water okay. Now both hydroxyl groups are protected as TBS ether and this SPH SPH can be removed by treating with NBS acetone and water okay so this should be converted into a good leaving group now this should be converted into a good leaving group so that when you make the core structure when you make the core structure of elutrophobene then you should be able to couple okay. So for that you treat with trichloroastronite right okay sodium hydride and trichloroastronite trial and this OH becomes OCNHCCL3 that is trichloroacetamide okay so this is the sugar fragment which we need to couple with their allylic alcohol in the bearing you will have an allylic alcohol that allylic alcohol you have to compile okay. So we have made now the sugar fragment and then AB ring fragment and the third fragment which we need is the alpha beta unsaturated carboxylic acid so this is a commercially available compound and it can be also easily prepared from the corresponding aldehyde if you have an aldehyde here okay then one can do vitic reaction to get this alpha beta unsaturated ester then hydrolyze the ester to get the corresponding acid or in situ one can also add pylyl chloride so to get this mixed anhydride okay. So now you have the side chain of the northern hemisphere and you also have the sugar fragment and you have the AB fragment what you need is you have to attach the C fragment so how one can do that is you have this aldehyde okay. So this upon treatment with ethyl vinyl ether and tertiary butyl lithium so what does it do when you have ethyl vinyl ether on treatment with tertiary butyl lithium it will pick up this photon and it will generate this lithium species okay this lithium species will add to this aldehyde and you will get the corresponding allylic alcohol okay. And this is enol ether isn't it this is still enol ether so the enol ether upon hydrolysis with acid you will get the corresponding ketone okay. Now as I said you have to make shearing also and the key reaction in the total synthesis of elutrophin by Nicolau is a intramolecular addition of lithium acetyl so that means you need to add a triple bond. So the triple bond was added in the form of acetylene magnesium bromide okay you take acetylene and then treat with you know you convert it into the corresponding Grignard this gives you the corresponding tertiary allylic alcohol. So once you have this tertiary allylic alcohol now what one can do see the TBS which is protected the primary alcohol can be cleaved with t-buffs to get the corresponding primary alcohol okay. Once you have this primary alcohol you already have a secondary alcohol and tertiary alcohol okay all the hydroxyl groups can be now protected as TSEether okay. So now you see you have 3 hydroxyl groups being protected as TSEether. Once you have this selectively one can remove the primary TSEether primary TSE is level compared to secondary and tertiary so this is easily cleaved with PPTS and methanol okay. Once you have the primary alcohol now you need to homologate okay if you see the elutrophin structure you need an allylic alcohol here you need an allylic alcohol here that means this primary alcohol should be oxidized and then homologate okay the primary alcohol should be oxidized and homologated. So what you should do you should oxidize this primary alcohol and that can be done under very mild condition so that you do not see the epimerization at the adjacent carbon. So this is done by several oxidizing agents what Niccolo has used is tetra n-propyl ammonium perutonate tetra n-propyl ammonium perutonate it is a ruthenium based reagent in short it is called as T-Puff in catalytic amine and the co-oxidant is NMO. So that oxidizes the primary alcohol to corresponding aldehyde. So once you have this aldehyde then you carry out a Novanajal condensation with this ester cyanone ethyl cyanone acetate in the presence of beta alanine ethanol you carry out a Novanajal condensation to get this alpha beta unsaturated ester which also has a cyanide which also has a cyanide. So now if you reduce this with the dye ball so you have two groups which can be reduced one is cyanide the other one is ester. So cyanide if you reduce with dye ball we know that it can be reduced to aldehyde and if you take ester and then treat with dye ball ester can be reduced to corresponding primary alcohol. So in one part he converted the cyanide into aldehyde and ester into CH2 organs and if you look at again the structure of elitrobin this is what you need in beering and what you need is you have to somehow connect this the triple bond and aldehyde if you connect it you will get a 10 membered ring okay. So here he wanted to connect this with that aldehyde before that he thought it is better to connect the side chain okay it is better to connect the side chain to the primary alcohol. So already made the sugar unit so this on treatment the TMS triflate then you can see the sugar unit was attached to the primary alcohol okay. So now all free hydroxyl groups are protected if you look at this structure all the free hydroxyl groups are protected that paves way for generating anion here and then adding to the aldehyde. So that paves way for generating anion here and adding to the aldehyde. So this is easily done by treating with lithium exomethyl disalicyde. So when you take lithium exomethyl disalicyde it generates the acetyl and under dilute condition the acetyl intramolecularly adds to the aldehyde to form the corresponding allylic alcohol okay. So now what we have done we have started with the A ring we have attached the sugar unit and we also made a joint BC ring okay. So now from the BC ring we have to really make B and C ring okay. So BC ring is 10 member ring now we have to make a 9 membered B ring and 5 membered C ring and for that what one has to do you have to reduce this triple bar and this hydroxyl group this OTS should be made as hydroxyl group and that has to attack here okay. So to do this first we need to oxidize the alcohol here. To do this we should oxidize the alcohol here. So when you treat with Desmartine pereoidinase okay Desmartine pereoidinase is a very good reagent for oxidation of allylic alcohols you know like manganese dioxide, Pdc Desmartine pereoidinase is a very good reagent for oxidation of allylic alcohol. So that gives the alpha beta unsaturated keto okay. Now when you remove the PMB group because the PMB group is little bulky so it is better to remove the PMB group by treating with 3DQ you get the free hydroxyl group then you reduce the triple bond to the double bond at the same time it is better to re-protect the hydroxyl as acetate okay. So first the secondary alcohol was protected as acetate and secondary TS group and then tertiary TS group were removed and followed by the key reaction there that is the reduction of the triple bond followed by the key reaction that is the reduction of the triple bond and when you do that with Lentil catalyst the triple bond is reduced to cis double bond okay triple bond is reduced to cis double bond. At the same time the tertiary alcohol okay it can attack the ketone intramolecularly to form the lactate okay. So now you can see the real core structure of elitrobin ABC ring everything is there what needs to be done is you need to convert the hydroxyl into methoxy and also attach the side chain okay. So these two can be done subsequently first you treat this with PPTS methanol so PPTS methanol what happens if this makes this hydroxyl as a leaving group and then the lone pair comes and then this makes that oxonium ion was attacked by methanol to form the methoxy okay oxonium ion was attacked by methoxy group that is methanol to get the methoxy group okay. So now the methoxy group is introduced the sugar unit is introduced only thing left is the attachment of side chain in the northern hemisphere okay. So already we prepared this side chain mix these two in the presence of base that gives the alpha beta unsaturated ester okay. So you have this next only one step that is to remove the TBS group there are two TBS group in the sugar unit and that can be easily removed by fluoride agent. So Tbuff treatment will remove the TBS group leading to the formation of the natural product elitrobin okay it is a very important total synthesis and it was the first total synthesis of elitrobin reported in the literature and if you look at the key reaction the key reaction is the intra-molecular addition of lithium acetylide to the aldehyde to get the 10 membered ring okay and then the hydrogenation of the triple bond to double bond followed by cyclization to form the 5 membered ring these are the two key steps in the total synthesis of elitrobin reported by K. C. Nicolau and overall this total synthesis was done in 27 longest linear steps, 27 longest linear steps it is a linear synthesis if you look at this synthesis carefully it is a linear synthesis and with an overall yield close to 1% so considering the complexity of this natural product and overall yield of 1% and starting with commercially available monotterpin carbon is really a significant and then a classical one okay so with this we will stop here and then tomorrow we will talk more about another synthesis of elitrobin and this time the synthesis was accomplished by several flagships okay thank you.


A Belfrey man was indicted this week on rape and child pornography charges. According to court documents, 26-year-old Cody West of Riverfront Road in Belfrey was charged with promoting a sexual performance by a minor, possession of child pornography, third-degree rape, and third-degree sodomy. Pike County Commonwealth's attorney Bill Sloan tells Mountain Top News that the case originated from a complaint from the parents of the alleged victim in the case. Sloan says the case illustrates the importance of parents monitoring their children's use of social media, and with whom their children associate. The victim in this case was at least 16 years of age, and generally we think that 16 years of age is the age of consent that you could consent to sex. But the legislature in the last few years, I'm not sure it's been two or three years, changed that law. If the person is 10 years old, 10 years older than the victim, in this case then the victim is not considered to be capable of consent to have sex with a person that's 10 years older if the victim is 16 or 17 years old. In this case, I think our victim is 16 years old and the defendant was 26 years old. It's really important that parents be aware of who their children are involved with, and this is a case that came to the attention of law enforcement because parents were concerned about the relationship they thought that their daughter was having with an older person, and they brought it to the attention of, eventually ended up with the electronic Crimes Branch, and through an analysis that was done on some social media networks that they were able to obtain evidence that is the basis for the promoting charge. But this all came initiated because it was a concerned parent that brought it to the attention of law enforcement. West could face up to 10 years in prison on the promoting a sexual performance by minor charge, and up to five years in prison on each of the other charges.