In the world of content, video is king. Welcome to the We Are Slam Show where we share marketing agency insights, best practices, and ideas to help your business or brand grow. My name is Tyler Kelly. I'm the co-founder and chief strategist here at Slam Agency. We have offices in St. Louis and Miami. And here at Slam, we know that effective content is the only content that matters. You hear all over the place that content is king. And that's true, but only when it's effective. And so today, I want to share with you my tips for creating effective content. Now, if you're listening to this podcast, then you represent about 80% of our audience because 80% of our audience is listening, whether it be on Spotify, iTunes, or on another podcast network. And by the way, if you're listening on one of those networks, subscribe. But if you're not listening, then you're probably watching. And why is that? It's because that we also produce this podcast in video. Why video? Because video is the type of content that makes a huge difference. I want to share some stats with you. Including a video on a landing page can increase your conversion rate by up to 80%. After watching a video, 64% of people are more likely to buy your product online. 65% of executives will visit a marketers website after they've watched your video. 39% of executives will actually call a vendor after watching a video. And four times as many consumers would rather watch a video about a product than read about it. What does this tell you? In the world of content, video is king. Now, I know it's not perfect yet, meaning it hasn't reached its full potential, but it's definitely happening. So as a marketing director, you need to this year go all in with video. That's one of my secrets. You got to go all in with video. You have to make sure in everything that you do, there's a video component, whether it's a Zoom call, whether it's a Facebook live or a Facebook premiere. Figure out ways to incorporate video in everything that you do, knowing that you're building the foundation for content success in 2020 and beyond. Now, I also do a podcast called Innovation City. And these interviews are the perfect pieces of evergreen content, which we release on a weekly basis. And when I say evergreen content, I'm talking about like a large chunk of content, which is like the pillar, right? It's the pillar that all your other content would lead to. So in the case of Innovation City, we have a 30 minute interview. And what we do with that interview is we do audio and video, and then we break it up into chunks. We do video teasers. We pull out quotes from the interview and we create graphics with those quotes. We do promotions with the guests. What you want to do is you want to remix your content in a way that connects with the way that people use the networks where you're placing that remix content. So if it's on Instagram, if it's on IGTV or something, there's a certain way that people interact with IGTV. Number one is you have to flip your phone to see it, or you have to produce content vertically in order to watch it and it not be weird, right? So figure out a way to produce content for that medium, for that channel. On Facebook, people interact and engage with types of content differently than they would on Instagram or on Twitter. Figure out for each network, what's the format that works for your audience, and then remix your evergreen pieces of content in a way that fits for each of those networks. Don't syndicate remix. That's a big tip. If you're new to content, this word evergreen might be new to you, but it's exactly what it means. I also think I might have mentioned pillar posts. These are words that come from back in the day, like when blogging just became a thing. You'd have these two 300-word posts, that blog posts that were in effect teasers or just snippets that would lead you to bigger posts, right? The bigger posts are what the search engines wanted because that's where all the meat was, right? So you had a 1500, 2500-word evergreen or pillar post with two 300, 350-word posts that led back to that. And this is how blogging really started to gain steam is through this philosophy, through this methodology. And so here we are in the world of video, video being so huge in terms of content. Here we are, we're applying the same principles that we applied to blogging 10 years ago to video. We're remixing and we're creating an evergreen machine.  It's the type of content that doesn't, it's not necessarily dated, it doesn't get old, and it defines you as a brand. This is where you need to lend your voice and become the expert. In a previous show, we talked about consumer journey mapping. And in order to do consumer journey mapping correctly, you have to know what types of content are going to captivate, motivate, and inspire people along each of the five levels of awareness. And so if you've built this map out, then you know, at each point, at each place of awareness, this is a type of content that could be evergreen that I could place my voice in the discussion, in the conversation, and begin to build a brand that people are aware of who we are and what we do. Once you've created that list, and at that point, I want you to circle the things that really stand out and could be evergreen, and then begin to create content. Start off with the blog post that will get the ideas running. It will help you develop the content. And then from there, sit down and think about how can we make this a video?  Now, my final tip is this, advertise to your audiences. Now, this is key, and the reason it's key is because, number one, your audiences are the people that you're going after. These are the people that you want to see your content. These are the people that you're targeting. These are your segments. When I say advertise to your audiences, I want you to advertise to the people that are your potential customers, that are your customers, that you're looking to bring back in and become repeat customers. Advertise to these people. And what does this assume? It assumes that, number one, you know who your audiences are and you've segmented them and you've created audiences, whether it be in Facebook or Google, that you can actually advertise to. So I'm not talking about just like putting a video on Facebook and boosting it to everyone that likes your page because everyone that likes your page may or may not be a buyer of your product or service. So take a step back. Think about, who's my customer? Where are they online? Do I have their contact information? Can I create a custom audience? And if I have created that custom audience, what types of content can I share with them that I can advertise and pay for them to see that will captivate, motivate and inspire them? At the end of the day, people do business with brands that they like and trust. How is likeability built? It's built through this idea of familiarity and you do this by advertising to your audiences. So to wrap it up, when they say content is king, I want you to remember that only effective content is king. Go all in with video because video is where it's at and video is where it's going. Remember to remix and not syndicate. Create a machine for your evergreen post. Write it out and say these are the areas where we see ourselves becoming a thought leader and finally advertise to your audiences. This is how you can begin to create not only content for content's sake, but effective content that captivates, motivates and inspires people to action through advertising and marketing. Now, if you've enjoyed this show, do me a favor, subscribe, rate and review. If you're watching on Facebook or on another network where you can leave a comment or click a like button, do it for me. And if you're a marketing director, business owner or founder who is looking for ways to incorporate content, not just any content, but content that will move the needle, content that will have an impact, content that will make a difference, then reach out to us at We Are Slam. You can find us online at slamagency.com. Click the free consultation button. We'll be happy to help you. Thank you for tuning in and we'll see you next week.


Hello and welcome to NewsClick. Today we are joined by Professor Satyajit Rath to get the most recent updates on COVID-19 and how the vaccination campaigns are progressing. Welcome Dr. Satyajit. So to start with, we want to ask you about the AstraZeneca vaccination. Recently there's been news that South Africa has returned 1 million doses of this vaccination. So because it's not very effective against the variant in South Africa, the South Africa variant as it's known. So what implications does this have even for India? Because we know that there are cases of this variant in India as well. So let's get a few facts clear before we discuss implications for India. In the first place, as we keep pointing out in our weekly updates, we should not be calling it the South African variant, we should be calling it B1351, which is what it is called, formally. So the reason why the South Africans have currently halted the AstraZeneca vaccine rollout is a small study that suggested that the B1351 variant was not terribly well protected against for mild to moderate COVID-19. That study did not test whether severe COVID-19 illness was protected against or not. It's plausible that it is, it just hasn't been tested. So those two issues, number one, that it's a limited study, it's a very small study and number two, it hasn't tested for serious illness need to be kept in mind. So even within the South African government, it seems that there are multiple voices with respect to COVID-19 vaccination policy, some people wanted to stop the deployment of the Oxford AstraZeneca vaccine, some people thought we should halt and wait for more data. And currently what seems to have happened is they've halted and are waiting for more data. And that's why, because vaccines are time bound, there is an expiry date, they've asked for current doses to be repatriated so that they can be used elsewhere. So if this is not about South Africa, I haven't decided that it doesn't work and therefore having rejected it or anything of the sort, this is much more nuanced and complex than that. Let's keep also something else in mind, which is that the South African government seems to have decided on the basis of a similarly small study and preliminary evidence that the single dose Johnson & Johnson vaccine, which properly should be called the Janssen Johnson & Johnson vaccine, since Janssen is the company that developed it, Johnson & Johnson just spent money on it, on buying IP for it. That vaccine is to be deployed. Now once again, the small study that says that that vaccine works is really small, number one. Number two, the Johnson & Johnson vaccine and the AstraZeneca vaccine are not terribly different from each other. So all of this is based on very preliminary, very modest differences in evidence. And therefore, none of us should get terribly worked up about any of these decisions. All of these are going to be interim decisions that will get revisited as more and more evidence comes along. That's background that I think is important to keep in mind. Coming to the Indian issue, since B1351 variant cases have been now detected, they are really single hand count numbers. But given that we are testing for variants in very, very limited fashion as yet, who knows how many more there are out there that we haven't detected. How widely is that going to spread? And is that going to have consequences for the success or vaccination program for bringing down the spread of transmission of COVID-19 in India and for life to come back to normal? So the issue is really variants of this sort are going to take time to establish themselves. Keep in mind that this variant seems to spread just a little bit better than the original strains. Keep also in mind that it's not that this strain is likely to have escaped vaccine-mediated protection completely. It's just that protection is not as robust as it could be. The current estimates are that there is a three-fold decrease in protection, but those are very crude estimates. With all of that, it's not that within the next few weeks we are going to be overwhelmed by this variant. So I think that it is appropriate for our current vaccination rollout to carry on. I think it's appropriate for us to keep the physical distancing rules and norms in place, both physical distancing of people from each other and mask wearing. Regardless of whether you've had COVID-19 or not, whether regardless of whether you've been vaccinated or not, these norms ought to be kept. Are we going to triumph in our fight against COVID-19? As we keep saying in this program, this is not a war, COVID-19 and SARS-CoV-2 are not evil enemies. This is a biological phenomenon. We will arrive at an equilibrium at some sort of compromise and accommodation, at which point the disease will subside to the point of not being a public health emergency. How long will that take? That depends on how well we follow physical distancing norms. It depends on all of us who have access to it, taking the vaccine shots and not giving into vaccine anxieties. It depends on our government providing vaccination, providing credible information and support, and providing the vaccine in an appropriate, credible, accessible rollout in the interests of public health, as well as providing for variant testing and variant tracking. Now, all of those are open-ended questions at the moment, so we cannot be too sanguine about this, but that's where we currently stand. And as you've been talking about variants and the effectiveness of vaccinations against these variants, we also have our own indigenously developed vaccination co-vaccine. And we recently have Dr. V. Ravi, who is the former Dean of Basic Sciences at National Institute of Mental Health and Neuroscience, who said that this co-vaccine is capable of working against all variants, all COVID-19 variants, because it's a vaccination that uses the wholly inactivated virus and not like a part of the virus, which is what other vaccinations are doing. So what do you think about this statement of his? How true is it? So Ravi is an old friend for 30 years. He's also an outstanding medical virologist, but when he says this, unless he has access to unpublished information that I am not aware of, where this claim has been actually tested, unless that is the case, I have not seen any such evidence. Currently, he is a little bit in Mungerilal mode, where he hopes that this guesswork that because you are vaccinating with a whole virus, many more antibodies will be generated, a much greater diversity of antibodies will be generated and they will stop even variant viruses from sticking to cells, whereas when you think about the other vaccines which are directed at just one part of the virus, if that part changes shape, as it does with some of these variants, then that antibody response will not protect. That's the guess he's offering. But as far as I'm aware, in the first place, that's really just a guess. There is currently no evidence for this. And in the second place, even the biology that the diversity of antibodies against a whole virus is much greater has not been properly established with evidence as far as I'm aware. Finally, to say this on the background that weeks and weeks and weeks and weeks after leadership of Bharat Biotech said, give us 15 days and we will provide you preliminary evidence of co-vaccine efficacy. We still have not seen preliminary evidence of co-vaccine efficacy, gives me a skeptical pause about accepting any of these claims about co-vaccine. I hope that Bharat Biotech is right and that efficacy data are good. I hope that Ravi is right and that it will provide a little more robust protection. But we have as yet seen no evidence and I think jumping the gun with wishful thinking is everybody's entitled to their own wishes. Finally, to wrap it up, there's one question which is still on everyone's mind that we have these vaccination campaigns, which of course we just had the UN Secretary General Antonio Gutare say, reinforced that how there is still extreme inequity in vaccine distribution. So keeping that in mind and keeping in mind all the vaccination campaigns that are ongoing, how soon can we really expect life to return to normal? Also because what does getting vaccinated mean? Does it mean you cannot transmit the disease anymore? Will it curb the pandemic? What is the future look like with this? Let's think about it this way. Again, as we've discussed on this weekly update for months now, only part of the answer to this question of yours is in the science and the technology. A large part of it is in the politics and it's in the politics not simply of capitalist profit making sector generated vaccination. Remember that all of these vaccines that are currently out there are private sector, profit making sector. But it's in addition to that, it's also over the past year become an apparent reality that conservative xenophobic political ideologies and governments across the world have taken advantage of fear generated communities, xenophobia across the world, and therefore vaccine nationalism and in fact COVID nationalism has become yet another obstruction, I would argue, to a global community collective response to the pandemic. And in the absence of a coordinated global collective community response to the pandemic, we are going to have fragmentary responses popping up. We are going to have countries pulling at cross purposes with each other. We are going to have these situations of vaccines being returned or vaccines being demanded. We have the situation that the WHO sponsored covax program to supply vaccines for underprivileged communities across the world, not having enough vaccines as yet being supplied to that those programs. In addition to that we have these variants that are inevitably going to pop up. We have extremely variable variant tracking methodologies in place across the world. And we have stigmatization as a consequence of variants that is going to be prevent travel from the UK from Brazil from South Africa identify those players those people lock them up, and so on and so forth. In this extraordinary coordination of capitalism and xenophobia. It's a little hard to make optimistic predictions about how well life for the ordinary people of the world is going to return to normal. It's certainly not going to happen, like magic over the next few months. I remind all our listeners that in the last one whole month, India has not vaccinated even one crore people. Now, we have heard brave words and I hope they are real that we are going to ramp up our vaccination capacity and so on and so forth and we are going to do better and therefore by July we are actually going to achieve 25 crore vaccinations. But I ask all of us how likely do we think that is. So under those circumstances over the next few months, let us not live in a fool's paradise of hope. Let us stay with the community norm of physical distancing and masking. Let us acknowledge that the vaccines are safe, because the evidence is that the vaccines are safe, and therefore let us not give into vaccine anxieties and take vaccine shots as and when they become available. Let us keep pressing our governments for better public health system investment, resources, vaccine rollout and variant tracking. More than that, we will meet and see. Thank you Satyajit for talking to us today on this issue. We will come back to you next week to discuss further developments. That's all the time we have for today. Keep watching.


I will try to give you an overview of the Italian from the Italian perspective of the recovery procedure of state heads in Thailand. I will focus on the recovery procedure because I will say before, and for close to the entire structure of the Italian litigation tax litigation, we do not have a case of a charge that is competent for the legitimacy of a measure granting tax state head. I give you some ideas about our tax litigation structures. We used to think that the tax litigation could arise just to oppose to appeal an act of the administration. That's the main idea. Unless you have a decision of the revenue, you cannot vote a court in Italy. You need a decision of the court. You cannot vote the court immediately, directly. You need a decision of the administration. You need a decision. What's the effect of this structure? Very strong principle. We have a list of the decisions that could be directly appealed. We have a list, close to the list of the decisions of tax administration that could be appealed. We have an assessment of compulsory collection and so on. We have a close list of this. Due to this structure, we have no experience in Italy of direct access. We cannot have experience of direct access to a tax charge asking him to declare a measure that grants an aid to someone else. We cannot have legal, we cannot have. It is impossible. That's why I was saying for the strudel position of the Netherlands, the General Netherlands Court is interesting from this point of view. As part of the order, there is no legal scholar that proposes this. But a civil action could be initiated for a competitor in order to have a declaration from a civil judge of the measure granting an aid to a competitor. But by now in Italy we do not have, we didn't have this kind of measure. So the Italian charge, as known, dealing with the Italian tax charge, as known, dealing with the recovery act, the decision of recovery. One of the unlawfulness of the measure, national measure, is clear. It has been set by EC decision. And this is the decision of recovery. That's the main frame. That's why I call this the recovery procedure. Because we do not have any experience of declaration of unlawfulness of a single measure in Italy. Of physical state aid. At least I refer to the tax state aid, not the general state aid. Of course. As known, that's the general rule. All we know about that, I just have some light for that. That's the main frame. As general rule, the state has the duty to recover the state aid, where the European Commission issues a recovery decision. It is up to the European Commission to issue a recovery decision. It is up to the state to reinforce this decision and to recover. What happened in the state is not doing that? The Italian state doesn't recover it. Yeah, there is an infringement procedure. Yeah, there is an infringement procedure. Yeah, there is an infringement procedure started by the European Commission against the state. So as a competitor, I have to write a letter to the commissioners, playing with the state. Yeah, yeah, you better obey them. But after the overall decision, yes. Of course, the European Commission would say the state is not recovering the amount yet. Yes, of course. In this case, the single charge will be competent, because the lack of recovery could be suited as damage. I have a message for you under the recovery program. I know you have a single charge. Yes, a single charge. Up in the arm with no contractual damages, but no extra contractual damages. Yeah, serial damages. Yeah, okay. The procedures of recovery today, as like said before me, much better than me, depends on the national law. And yes, it complies with the European law and principle. To principle, principle of effectiveness and equality. Equivalence. We're not about that. I would like to give you our position in April 8th before 2012. Before 2012, there was not a clear process for the recovery of state ads in Italy. We didn't have a clear process. We didn't know how to recover. We just knew the state ads had duty to recover. But there was no procedure to recover this amount. And so, from time to time, state, our legislator, our parliament, to comply with easy decisions for recovery, passed a specific law, a specific measure, with reference to specific decisions, and with reference with specific internal measures, granting unlawful and compatible data. We had the law for recovering law for state ads running to the surgical sector. The state for the law for recovery and the law in running to the public home had come. Each decision we tend to introduce a law, and not a state. The state is that we contain the person's rules of recovery. That's the main situation in Italy. And that was, to some extent, in my experience, merged with this aspect. That was, in my opinion, to some bias or cultural bias of Italian legal tradition. We used to consider an administrative law, that the law that the administration cannot take a decision without law. Without the law, you cannot recover. To recover is an administrative power. And you cannot exercise this administrative power without a law. Without a law that authorizes the specific example. With law you mean only written law? Written law. Written in Italian law. Written in Italian law. That would be in accordance to European rules. That is a hierarchy. European decisions and frame is a higher level. You're right. In fact, that's due to the lack of European insistence that we still apply this. Well, we have to continue. We have civil law countries with very deep legal tradition. Written in Roman law. And we have administrative law, imported administrative law. Partly from France, partly from Germany. But this rule of law principle that the administration cannot act beyond the power conferred by the law. And to act, it needs a law. The administration needs a law to act. It's up to now very affluent by the Dutch courts. It is not so strange. But it should be corrected by considering the law, European law. Also European law and European decisions. The administration cannot act unless there is a law that should be intended as also European law. That's correct. But due to the rule of law, due to the presence of this deep-rooted principle in our tradition, we, for a long time, we tend to act as I described here. Each state has to be recovered as a single state to be recovered in that state. And that also, of course, that was very much the case in tax state aid. Because to a certain point of view, the tax state aid is not granted by the administration. The tax state aid is granted by the law. So to recover tax state aid, to recover tax, you need a law that allows you to do that. Because it is not the local administration that needs to do that, that's granting an aid. But this is the law, the general law, that grants an aid. And so to recover the aid, to recover this aid, we used to think in a way that we need a law, we need a specific law that allows us to tax to a certain state that has been exempted before. That's the rational behind. I'm going to give you, I think I'm going to give you the details of a single specific comma of our rules. We are very complex, but I'm going to give you the rational behind our system, and outbooks to general standards, to general frame. But I think it would be useful for you not to do a single specific act. In the lack of general standards, some principles, some ideas emerged in Italian criminal tradition. The first main idea is, who is in charge to recover the... The first idea is the authority that grants the aid, who is still in charge to recover it by issuing an order of payment. The rational behind is the same authority that has the power to grant, has the power to recover, grant aid, has the power to recover. It works, but it works for a certain grant by a mystery authority. One of the authority for taxing tax ads, one who is not the authority that grants the aid of the law, that grants the aid, but it didn't work this way. So, the other general rule that we apply in the way is most, the civil code rules were debatable. In lack of specific principles, we didn't agree with the general civil code rules, but with major exception, interest calculation, time limitation. As I said before, we have the general rule that forbids the general principle according to which the combined interest is forbidden. It's a legacy from the Roman law. The interest on the interest is forbidden in England as normal. We cannot consider the interest on the interest of debt for interest, but for civil obligation. But for state debt, we consider that the combined interest, the combined method to compute the interest was applicable in lack of specific principles. So, the time limitation. We consider five years, but the general code, the general civil code is not clear in this. In general code, the time limitation is ten years or so, ten years to be called. Major exceptions for the... Major exceptions in order to informally comply with the European rule, to give you discretion. But the legal framework was the civil code. It was a civil obligation, civil debt with major exception of trying to comply with the European law. That was the legal framework. Third, third main rule that we apply, the collection was made according to a procedure set forth for the great of the public policy. We had, and we have, in early, a specific procedure to collect, to enforce the credit of public bodies that is used for taxes. And we used this for recovering of state debt. Taxes, state debt, and also the older state debt. Not just tax state debt. We used this. In the lack of general rules. Okay, that's the main principle we used to apply before 2012 to the recovery of the state debt. Of course, it is clear that, as I said before, the goal for tax state debt, we used to pass a law to the recovery of debt of the specific tax state debt. And this law contained also some information, some details on the procedure to recover. Because you do not understand the case that the law does not pass parliament, the law of which you say that it is necessary to enforce recovery. Because when such a law should not pass parliament, it is stated as well. Yeah, that's why we forced by the European Commission to introduce general procedures. Not specifically on the case like this. Okay, practice approach. That was a point from the Italian point of view. But the problem that we... I think, I did not write it then, but I think we didn't pass it away. Also because the state debt has the sum to be recovered as had and has very different nature. And so we are a little bit reluctant to recognize a general recovery procedure for some that has different nature. That's why the general procedure in Italy causes much more issues than we think. Now we will see this. Okay, in 2012, the parliament passed a law reorganizing, introducing, reorganizing the law, the recovery procedure. And introducing the one main general recovery procedure for each every state debt. The recovery of every state debt. It is important to say that this law is not meant to settle this problem. It was a general law. It was the financial act for 2013. But due to the oppression of the European Commission, we passed this reform, this important reform in this moment. But this law is the financial act of Italy. And you look the days, the eve of Christmas when it has been passed. Because with us it is, but a very big financial act. And in this act there are three or four articles that deal with this problem. In fact, a general recovery procedure. Of course, the law cannot be discussed in need. So that's the solution that the Italian parliament found. Consider that we have to online the European law. Just make reference to the European law. So the first passage of the law is, for the recovery of state debt, the European law should be fought. That is obvious, but for us it is not. Because the reference is domestic. We all know the supremacy of the law, particularly in the field of competition law. We all know about that. But in the light of the law, lots of time to draft a law to introduce some principles. The shortest way, the way to comply with the European law is to affirm it. The law considers that we should comply with the European law. All European law. And that's the beginning of the act of 48. You have to question the question of the European law. So what? European Commission's question of the act. It's okay, I'm scared. I'm scared. I'm scared. I'm scared. I'm scared. I'm scared. I'm scared. We all agree about that. We all agree. And you probably have a feeling that the process, your generation will be formed. We all agree about that. I'm scared. I'm scared. I'm scared. I'm scared. Okay. Perhaps, perhaps the reference is a legacy of the rule of law in our history law, as I said. I just need a law to authorize the administration. In this case, the authorization was very broad. I authorize you to follow the European rule to recover the amount to be recovered last month, we say that. That's why I tend to believe that this, the rule of law is the rationale that stands out to the Italian form of recovery, the proper recovery, the amount. Anyhow, I'll go straight. I just give you this is the translation, the translation I did from the paragraph 2 of the article 4j of difficulty procedures. This proper, this article... Those aren't this... I don't know. There's not a case you have. Sorry. Authority in charge of recovery decision. Which is the authority in charge? I liked it. The minister responsible for the matter. It implies that the persons required to pay the act to be recovered as it wishes the amounts due and that aligns the terms and conditions of payments. It's a short period. Yes. The pre-empty, the competent minister shall be responsible against these two responses. It could seem clear to the minister in charge of the matter. Minister, the pre-empty, that act that is the decision to be internal decision to be recovered. It is not clear at all. And I have to explain. I have to explain why. A global index matters as you can imagine by now. The finance minister? The finance minister... The finance minister... We are... Remember, you are in Italy. It is very complex country. Special minister of taxation. Yes, yes, yes, yes. But the minister of finance and economy... The ministry of economy and finance is not in charge to tax a single taxpayer. Okay, but which minister is in charge of the application of taxes? Not a minister, but an agency. In London, I believe it. And the agency is under... The agency... Who is the minister of finance? The minister of finance. Yeah, for tax law, for tax. But we have also taxation that is... And for it, set for by national law, but collected by local authorities. Yeah. That's for national taxes, if it is okay. You're right, if it is. But for local, it is not easy at all. Any other... This article is quite clear. The minister... The minister got this responsible for the matter. And this decree should contain three elements, at least two persons. Providing to convey the benefits of... Second, the amount due, the interest included. And third, the total interconditional pay. Remember, always according to European. So... Yeah. The decision in the process, is it... We will have hearing of the person who will pay... Of his employers, of the... That's a point. That's a point. In general state tax, I don't think so. In tax state tax, state that, it could be. Because we are trying to introduce the right to be heard in tax matters, in tax proceedings. So, according to the tax law, according to the general tax law, we are keen to introduce the right to be heard of tax payer. So, the first contact between the tax payer or the beneficiary that should be repaid the amount, is an element of the legality of the procedures. I think so. I'm not sure, I have no case law on that. There is no precise... There is no precise regulation, but I think so in tax state. As it is... I'm going to... So that means, a minister of courts can have... A look to... Yeah, you're right. That's the solution. That's the solution. I don't want to anticipate... But that's the solution forward by law. But it's a very strange solution and some scholars doubt about the constitutionality of this solution. But we arrive to this... That's the point. In practical terms, that's the reason why I mentioned that too much is very short. You have to analyze the case to make a calculation... It's very short. Above all, for tax state. It's very, very short. What's the problem with those debates? Because there's a history... Yes, yes. Above all, for tax state heads that are granted by law, there are lots of tax payers that benefited from this. And so, lots of people from practical opinion are doubtful about this. And being honest, knowing the bureaucracy, the canalizing of this, I think it is not easy to stay with that line of two months. I think so. But, of course, from practical point of view... And what happens if you can't or she can't adopt it in two months? Yeah. Is it that easy? Sorry. No, no, no. Once again, I have one for you. I don't know. But I can give you my opinion. The reason of this law. I can give you my opinion from the... Our new definition of the problem is this, or is that line is strict, or it is just a set of suggestions indicative of that. In Italy, in Italy... The rule of order. What? Okay, yeah. But to a literal point of view, it is an illegal decree of recovery. Because if you think in European legal terms, the principle of the commission should adopt a decision on recovery also within reasonable time. Reasonable time. Not strict time. But the courts have held, the European court has held, where the commission has taken an unreasonable time, it becomes illegal. Yeah, yeah. Because you have infringed the principle of... That's why... Yeah. I came to think that according... If I give you my opinion, the Italian judge could interpret this term as a strict term, but it should consider it in light of the complexity of the entire proceedings. And so, as known for easy procedure, this term should be followed, it should be respected. In case of not so easy procedure to be penalized and to be organized in the recovery, I think that this term could be enlarged. Yeah. So that was that why I... It's not clear at all. It seems clear that it was not clear. Because every weapon by public authority is different from the state. And so, we need part of the treaty in the article. In cases where the commandant authority is different from the state, the mission referred to in paragraph 2 shall be taken by the agent of the autonomous province, or the commandant of the law authority. The activities referred to in paragraph 1 shall be carried out to find the concessional in order to collect the revenue of the local authority conservative. So, it is for the local authority, not the ministry, to recall. I just remind you that we, in Italy, are a republic with the regional form of state. Each region, in Italy, and each region has a normative power, as you can expect. The regional law in Italy is law, like state law. It refers to the components. There are some matter, some field in which there is components of the region and state. And in this matter, in this field, there could be a grant by the law. And all of our... We are talking about a special region. We have some special regions. We are going to know about others. Much more. And their state is approved with the constitution. Our people, our people, our people, our people, our people, our people, our people, our people, our people, our people, our people, the regional aids are granted by the... yeah, important. And much more of the regional aids are granted by this. Yeah, much more. Third, paragraph one. In Italy, as the IO's, as the IO means income, cooperation, shall collect the amount due as a result of The following decision referred to an article 4 of the Regulation of Council <IP_ADDRESS>9. Adopted after all the date of entry into force of this law. Irrespective of the form of the aid and of the person who granted it. What is Epidalia? Epidalia is a public-organized company owned by the Italian revenue but separated company in charge to collect and enforce the public debt, the public credit and debt. But there is a problem. Up to now it doesn't exist. Epidalia does not exist. There are so many shares. I don't know. Is it going very good? Yes. Of course. It doesn't exist. It has been incorporated. It says a joke but it's true. It has been incorporated in the net in the net and revenue. That's some of the issues. I'm going to illustrate these issues. A snowman Epidalia collects sums according to the stages of collection, possibly enforcing tax related sums. Shall we consider that the reference to Epidalia is important from the Italian point of view because it is a reference not just to Epidalia, to a company. But it is a reference to a set of rules of procedure. But it is a set of rules for enforce the tax credit of the revenue. We have civil enforcement of civil credit enforcement and tax credit enforcement. And the reference made in law by Epidalia is to Epidalia as important from the Italian point of view because it is a clear reference to this set of rules. To recover the state debt, we apply the rule we use to apply for recovering of tax claim. A perspective of the nature of the site. Also for contract, for guarantees to be recovered, we use the set of rules we have for the collection of tax revenue. To enforce the collection of tax revenue. This is important from the Italian point of view. I go. So now I try to give you a number of rate of the work flow of the process of the recovery of state debt. European Commission recovery decision functions to fulfill the duty to recover of the debts. National Minister of the Cree, of the Global Authority of the Cree, has sustained the benefits of demand and the way to collect the sum. So excuse me, we don't need any more new law. See, debt is not legal. You don't. No, no, no. In fact, we don't need any more after new procedure. The Cree, no, no, no. That's not it. We have a general policy of law. We just need to make the Cree. And we need to collect. Yeah. The Italian sphere, no longer exists, Italian revenue, now up to now, acts of collection. Collect, possibly enforced, the sum from the debt. That's the main work flow of the recovery of the Italian prosecutors. As I advance the programs, I go to the... The law set for the competent judge for the litigation on the recovery cost. Competence for litigation of the cause of the recovery act is act I mean, decisions, not act legal, nobody backed. It's attributed to the deterministic judge. To Bunal and Mr. Di, Mr. Giunani. It is an exclusive competence, irrespective of the nature of the state act. Providential, benefits, tax exemption, guarantees on the free, contract disproportionate, irrespective of the nature. The sum to be recovered, the litigation on the sum to be recovered, is attributed to the attorney of the judge. Each kind of state act recovered. Included that of providential state acts. That's the point of the law. That's the point because up to 2012, we strongly believed that the charge competent for the recovery is the charge according to the nature of the sum to be recovered. For recovery of the tax exemption, we used to think that the tax charge was constant. To recover your providential relief, legal exemption, we used to think that the civil providential specialized judge. Now, the law, the charge for the improvement, and attributed it to one set, one judge, the administrative judge. There is a rationale behind it. The rationale is this. The national act that starts the whole procedure is a high-level ministry, high-level administrative act. So the charge that should be valet, that should valet this act is an administrative act. Please. Suppose the minister doesn't adopt the decree at all. So there is a clear decision from the commission, but for some reason the minister does nothing. Is it still possible in Italian law for a competitor to go to the civil court and argue on the basis that Article 108 has direct effect that should be for tax case law, for tax case, tax case, no. It could be, it would be a very good solution. But up to now, no, the answer is no, up to now. It's been tried and forbidden? We don't know, and I'm keen to think the civil judge will do this mess. Because civil judge will say this is a compliance of tax charge. And to go to the tax charge, you cannot go directly because we need an act to... Yes, you are for it. That's a good reason. That's a point. That's a point. In theory, a competitor, a civil minister, we did not experience this up to now. But in theory, that's the solution that some score proposes, some score proposes. But the competitor will do the comparison and say no more. Is there any more way to do that? Yeah. Maybe this is a new act. Yeah, yeah, yeah, yeah. Yes, you can. That's the solution. The solution may be because of the damage. The damage? No, you're right. You're right. If not the damage, at least, you as a minister, as the duty. And if you cannot exercise your duty, you are acting against me. You say that no, it's good to see the competence of the minister of duty in the process of the decision in terms of competence in tax matters. Do they have specialized policies? No, we do not have administrative jobs specialized in tax matters. We have specialized jobs, different tax jobs. They are... In this room there are some tax specialized jobs, administrative jobs. We have different jobs. Other? I would like to assume that confidence is also stated in the lack of time for the subject that comes with this... The room that is... The law states that it is attributed to the... to the... An exclusive way. In the situation that my colleague said that you want to assume the minister in order that he conforms to his duty in a special way. That's a good point. I think it is in the exclusive administration. Yes, I think it is also in the... No, not the... Because it is for the... Negative exercise of... Do not exercise... That would be an administrative court anyway. Anyway, yeah. And the way you have to... So you have to ask for exercise and power, then you have to assume the minister in order to compel it to exercise the power to recover. Before a judge, of course. That's a state that you cannot go immediately. You ask formally the minister to act in recovery to the competitor. And then if the minister is silent, you assume the minister, again, at the minister of court and at the minister of court in order to minister to issue the decree and collect the... recover the... I understand you mean, at the minister of court you call the attack of making that decree itself and you have to... No, no, no. No, no, it is not confidence. It is not confidence. In the worst-case scenario it is... the administrative judge has the power to appoint a... a functioner and giving the power to... to complete the amount and to issue the decree. Of the branch. Okay. In the worst-case scenario. I would love for you to think about how many times... Not so much time, because I didn't write to you that the administrative judge the exclusive competence is attributed to the administrative judge and the law I didn't write it, but the law stated that for... said for an application of a very speedy, speedy procedure speedy procedure for this I didn't write it, but... I believe, yeah. So it's like an expedited... expedited procedure. Okay. Which is the attitude of the national judicial control? I know. No, no, no, no. Okay, remember this. Remember this. Lots of persons in Italy lots of persons in Italy state, believe that the national judge quote said for the legitimacy of the national judges but I spoke to national judge, the national judge just the legitimacy of their court not of the nation. Clearly. National judge cannot national judge cannot control whether or not the measure is compatible or unlawful. Could Europeans say that? The EC, European Commission, has in charge of that. Any other national judge just to control one of the recovery procedures in line with European and national law she also made a set case of the other one the role of national judge to control the computing the amount the beneficiaries and so on. That's very clear. Not so clear but always always there at least in charge. They granted a final decision for the payment of a night and that leads to the surgical in the wild of the national renovation C-M-E C-M-E C-M-E C-M-E C-M-E C-M-E C-M-E C-M-E there's not the key is very big the room to copies they added lots of very big factory And they are involved also in some scandals for environmental pollution and so on. Anyway, in light of the national litigation, we see that started the investigation of the measure and eventually declared it unlawful. Consequently, we see issue also of the recordings. This amount should be recorded. So we have a formal contrast. From one side, an old, fine, binational judge, Bessie McCartney, had ordered the bailout of this son to the two kids. On the other side, the decision by the European Commission ordered the recovery or not bailed his son. That was very important. That was a very, we used to say, formal contrast. The ECJ cannot leave the boy to decide on this point. After the kidney, always the ECJ aborder gave us a clear ground decision on this point, on this context. In the kidney case, the court ECJ stated that the national administration issued the recovery order and the kidney appeal. The national judge, in terms of the recovery delivery and the passing of the decision, should the recovery decision prevail on the national fine of the season? As we know, the ECJ has the presence of the European Commission decision. In front of the rest of the court, ECJ stated, no, I don't care. I don't care about your rest of the court. I think this is very important, from the Italian view, from the Italian legal conviction. It was very revolutionary, judge, because to me, of rest of the court, is to say, rest of the court, you know, we always say, we, all in Italy, studied the gomolo, proveritate adiato. Rest of the court, rest of the court is the truth. Actually, on the law process, granted, that is... Yeah, yeah, of course. Yeah, yeah, but the problem is, we used to say... It is our relation. The value of... Yes. Yes, it is an easier to do. The value of the law and the law. Yeah, yeah, you're right. But you used to say that the certainty that granted by this, we got the principle, certainty. When you have final decision, you should buy a judge. Yes. That is the legal truth. Obviously, this opinion, in case the judge has said, has to be paid, has nothing to be said about possibility that we recommend. Yes, but the... Yeah, yeah, so we pay in your call... Realization. Yeah, yes, but we pay in your call immediately. Legalization. Legalization. Legalization. No. No, yes, it means pure nonsense. It's nonsense. No, no, no, no, no. Yeah, it could be, though, it could actually be. Do you ever think that ways are strictly that the use of the referee in the court can be so hard and so... No, it will be too easy, and that's the situation. So you pay in the court, right? The name of it is European. And so European will immediately be the problem. That's what it is. That's what it is. You are thinking about national law. That's what it was raised you to have for national law. Of course, that's because the national law in the nationalist family is the principle of European law. But the important is... Yeah, that's a good solution. We're a little bit fridgey about this issue. But the important thing is, I mean, from a leukemia case. In my, I'm short, I promise. And my point of view, from my point of view, the most important of leukemia case was that E.C.J. justified this solution, that is the prevalence, the supremacy of European law, saying that in the competition model, and say that it's part of competition law, the national authorities are still not competent. That's one of the main... What's the main argument? We cannot accept the rest of the data in national law when the national law, the national judge, the national authorities, the men say, as no part of competition law. No definite part of competition law. That's the main argument. The leukemia case is very important from the Italian point of view, because it reduced very much the room for competence for national authorities. I remind, what I reminded is obvious. The national judge, the national authorities are not in charge, they are not competent to assume, to declare the law of a nation compared to the state act. They are not. It just has to control the economic philosophy. It's up to the European Commission to investigate and to control. And in leukemia, that was the main question. Quote affirmatively, why I have to stop in front of national decision if the national authorities assume no definite power in this field, competence law, competition law. And so leukemia narrowed, narrowed to move from national law. So there is no confidence from national law, from national judge in the recovery of the best. It should be considered that in the future that the law in medicine case, that the ACJ stated, no, it is not the true definition of national charge as in no way in the state act. And what's the role of national charge in state act? I consider that the role of national charge is complementary to the role of the European Commission. What does it mean? The main confidence in the qualification of the national state act is on the EC. The national charge should act as to complement the action of the European Commission. I explain. I explain. I better explain. The national charge is confident to control the correctness of the amount to be recovered. The national charge should even control the correctness of the identification of the beneficiary of the state act. The national charge should control the lowering of the entire property of your company. Just be a company. It's not so important. But what you say now is supposed that there is a decision of the European Commission on recovery. What you said now is in the context of article 100 and 100. But there is also article 100 in it. And in that context of the third article there may be a situation that there is not yet a decision of the European Commission. In this case, the role of the national charge may be different. In this case, the national charge could assume an interim measure to correct the correct application of the European Commission. That's clear. But even where there is a final decision from the European Commission, there is a role. And this role depends on the context of the European Commission. And minus that case is very important case for me. It's very important case to this point. Briefly, Italy rendered an act to the purchaser of the rest of the contract. For the purchaser of the rest of the contract. This measure was deemed as a lawful state act because it granted an advantage in the market of the digital broadcasting to the terrestrial operator compared to the satellite digital broadcasting operators. We had two main operators on the broadcasting. One operating on satellite broadcasting and the other one on terrestrial broadcasting. Of course, this act would be the paper of the terrestrial. What was it? The rest of the contract. The rest of the contract. We are happy with that. Once again, this is another requirement to certify the rules. They only decode it in terrestrial cable. What's important from our point of view is that it is the issue, the recovery decision. But in the decision, it did not identify the beneficiaries and the overall did not identify the correct amount to be decoded. This act is directly assigned to the purchasers of the contract. But undirectly, federated the operating market operator in the terrestrial measure. That's very complicated. Very, very, very complicated. Very complicated to identify the correct amount. With the beneficiary and how much does it in terms of competition advantage, that was very complex. It was exchange of letters, informal letters from the Italian government and the European Commission that agreed in the end eventually agreed on the method of computing. But it was a very complex economic point of view. Very complex way method to compute the advantage of single... Do you have to construct a counterfactual if there are no books? Yeah. That's the position of Italy. Italy assumed that in the prices in the interest of broadcasting market was the beneficiary to the recovery, to be recovered. Italy initially agreed on a method to compute the amount of exchange of informal letters. That's it. The major company in broadcasting and the mission owned by Mr. Silvio Berlusconi, our former prime minister. That was very important point of view. In this case, whether we see the recovery decision that does not contain the beneficiary is for the national charge to identify the beneficiary or control the community by the national administration compute the proper amount to be recovered. It is not so clear, but in the end, that's the end. There is this J as the main company but the national charge have to complete and complement the work of the English. That's my opinion. Seems to me an easy way to give here from the Italian perspective.


Using PulseChase experiments with senior, it was discovered that the CAP-rich phase is the source of calcium used to build the calcite crystal. This article was authored by a soft gal, Sanjasvibin, Richard Worth, and others.


So, good morning everyone and welcome back to the NPTEL lecture series on Classics in Total Synthesis Part 1. The last few lectures we have been talking about total synthesis of various alkaloids and today we will continue our discussion on the total synthesis of one more alkaloid called quinine. And the quinine has a very interesting history, the structure of quinine is this one and you can see here there is another epimer, this is called quinidine and these two alkaloids were found in the bark of synchronous and Remigia species. So, these were originally part of the high forest in anti mountains from Venezuela to Bolivia in South America, okay. These two alkaloids were found in the bark of synchronous and Remigia species and the South American natives they used to call this tree synchronous tree as cuina cuina, the bark of barks and as is the case with many natural products, South American natives they have been using this bark for the treatment of high fever and also much before the Spanish people arrived in South America as you know most of the South America was taken over by Spanish people in 16th and 17th, 16th, 17th and 18th century. Interestingly, the discovery of quinine got major focus when one of the Spanish Vizra s wife in Peru was diagnosed with malaria and she was cued by giving extracts of this synchronous tree bark, okay. So, this was a major impact of South America in the treatment of malaria in Europe. Once this news came to Europe what happened automatically the plantation of synchronous trees started in whole Europe particularly in Italy where the Rome was considered as the capital of malaria, okay. So many people were suffering from malaria and this was a big boon that the bark of synchronous tree could be used for the treatment of malaria. So, afterwards as you know people started using this extracts from the bark of synchronous tree for treatment of malaria not only in Rome, but also in other parts of Europe. However, it took 200 years to isolate the pure form of quinine, it took 200 years as I said only in 1820 two French researchers Pierre Palatier and Joseph Covento. So, they isolated the pure form of quinine and afterwards British people they wanted to plant this in their colonies. So, they succeeded in planting this in India and Sri Lanka and then Dutch people also succeeded the same by planting in Java and Indonesia. Incidentally, Java became the major hub for exporting quinine even today and quinine exhibits antipyretic, anti-malarial, analgesic and anti-inflammatory activities. And as I mentioned this is the major exporter of the cultivated bark is from Java and the cultivated bark of synchronous tree has 7 to 10 percent of this alkaloids, okay out of which 70 percent is quinine. That means it has about 5 percent quinine. If you take the bark and then cultivate it from that you can isolate 5 percent pure quinine which was exported. In fact, US imports about 70 tons of quinine every year that is a major import. The cost of quinine and quinidine differs little bit, 1 gram of quinine cost about 3 US dollars whereas 1 gram of quinidine cost about 7 US dollars. However, people were always interested in the chemical synthesis of quinine. In fact, if you look at 19th century and 20th century, one natural product which you got maximum attention next to strychnine is quinine. In 1950 French Society of Pharmacy, they announced a cash price of 4000 francs for the group which completes the chemical synthesis of quinine. However, it took much more time to come up with the synthesis of quinine in fact I would say it took about 100 more years to come up with the synthesis of quinine. If you look at the structure of quinine now you may feel that it is not structurally as complex as some of the natural products being isolated in recent years. However, one should also remember that when quinine was isolated there was no NMR, no IR, no mass spectrum. So, without all these techniques one has to prove the structure of quinine then go for the total synthesis. Obviously it must have been very, very tough job to assign the correct structure of quinine first. So, those days whenever a natural product is isolated and if they find that natural product is showing exceptional activity then they use lot of degradation studies to assign partial structures first. So, once they assign partial structures then they try to link, connect it to come up with the correct structure and always synthesis is considered as the final proof for confirming the structure of isolated natural products. So, in 1853 Pasteur actually reported that quinine is levorotativic, a year later Stucker establishes correct empirical formula then it took about 50 years in 1907 Paul Rabbe proposed the correct structure of quinine. During this period though the synthesis of quinine was not accomplished lot of efforts were focused on synthesis of pyridines and quinolines. So, much literature has gone into synthesis of pyridines and quinolines. So, there are lot of degradation studies known on quinine but in this particular slide I will talk about 4 or 5 reactions where quinine gave some important clue to assign the structure. When quinine was treated with acid, strong acid it rearranged I should say it opened this bond was cleaved to give a very interesting compound called quinotoxy. Then the same compound when it was oxidized it gave Miroquinine, Miroquinine if you look at this does not have the quinoline part. The same Miroquinine was observed when quinine was treated with dilute HCl for long time continuous exposure of quinine to dilute acid for long time converted quinine into Miroquinine. When quinine was treated with fused potassium hydroxide they could get methoxy quinoline that means this whole portion disappeared and when it was treated with nitric acid and chromic acid they could get this quinoline with a carboxylic acid here. Then they took quinine reflects with water. So they could get this methyl methoxy methyl quinoline. So these are the important degradation studies which actually gave an idea about what would be the correct structure of quinine. However, you know as you know you have to make this compound then only you can propose the correct structure. So Paul Rabi was the one who proposed the correct structure of quinine in 1907 and 11 years later he reported partial synthesis of quinine from quinotoxin. We will come to that little later and 25 years later another partial synthesis was reported by Vladimir Perlov but in 1944 was the year where Woodward reported the first formal total synthesis of quinine. This was a big news among all synthetic chemists as well as for the world. So the synthesis of quinine was considered as a major breakthrough in chemical synthesis and it took almost 70 years for the first enantioselective total synthesis of quinine which was reported by Gilbert Stock in 2001 and another 10 years it took for Jacobson to complete the total synthesis of quinine and quinidine using asymmetric catalytic reaction. However, there was some controversy about the total synthesis of quinine reported by Woodward. So there were few papers questioning the authenticity of the total synthesis of quinine reported by Woodward. So Robert Williams from Colorado University and his team they completely they just followed the same route reported by Paul Rabi and completed the total synthesis of quinine thus confirm that Woodward indeed completed the formal total synthesis of quinine. So I will come to that when I talk about total synthesis of quinine by Woodward. So the first partial synthesis of quinine as I said was reported by Paul Rabi and Kainler and how they reported was that degraded product quinotoxin they took and then treated with sodium hypopromide. So that gave that N-bromocompone okay this N-bromocompone on treatment with sodium ethoxide niethanol.  This upon treatment with aluminum powder okay this upon treatment with aluminum powder they could get about 18% of quinine which was recushed lice and then they could see you know complete you know all the data are matching with their natural quinine. So that is how in 1918 this one can call it as relay approach relay approach that means you know you start with a compound which was originally from the same natural product degraded compound then convert the same into the natural product which we already discussed when we talked about totals and substrignine by Woodward okay and this quinine not only quinine is used as anti-malarial drug afterwards there are many drugs which were which came to the market based on the quinine structure for lot of structural activity studies led to the synthesis of meffloquin, primacoin, chloracoin. Now all these drugs you can see quinoline part is same okay only this region is different okay. Then this is quinidine and this is amodioquin, this is chloracoin and this is called HCQ. So HCQ as you know it was given for the treatment of COVID recently and off late a completely new set of drugs are being used for the treatment of malaria based on this peroxy natural product called RT-mesinine. So RT-mesinine, dihydro-RT-mesinine, RT-meter, RT-sunate that is RT-mesin if you treat with succinic anhydride you get this RT-sunate then this can be given along with amodioquin for the treatment of malaria okay. Now let us see how Woodward reported the synthesis of quinine. So as I said in 19th century as well as early 20th century so people spend lot of time on the chemical synthesis of quinine and during the second world war so many soldiers died because of their non-availability of quinine okay. And that time the Polaroid company very well known and very famous company so they were using quinine for a different reason. So they were using quinine as a light sensitizer okay that is a photo company okay as a light sensitizer and Woodward has been consultant to this Polaroid company. So the Polaroid company asked him whether he can develop a good method for the synthesis of quinine so that is how the Polaroid company funded the project on the synthesis of quinine okay. So according to Woodward quinine can be made from the quinotoxin because the quinotoxin has been already converted into quinine by Paul Rebey and kindler. So he thought if he makes this then that should constitute what we call it as a formal synthesis of quinine. And this quinotoxin can be obtained from this as well as the corresponding ester okay via a Claisen reaction okay. So you can see you can generate anion and attack here and you will get a beta keto ester and then beta keto ester decarboxylation will give quinotoxin. So now he has to make these two starting materials or key intermediates. So the first one you can draw like this okay can be made from this hydroxy pyridine okay and this for the hydroxy pyridine he started from the metahydroxybenzaldehyde. So you take metahydroxybenzaldehyde and treat with this amine okay. So this first undergoes the imine formation on the aldehyde okay. Then it undergoes an intramolecular cyclization on treatment with acid to give hydroxy isochronally. Then you do a managed reaction. So you introduce the CH2 pyridyl group at alpha to the hydroxyl group then you treat with sodium ethoxide and methanol you get this and that was converted into the corresponding methyl hydroxy isochronally okay. This on treatment with barium salt okay. So basically you deprotonate the acidic phenolic proton then you do the hydrogenation okay. When you do the hydrogenation the hydrogenation takes place at the pyridine aromatic ring okay. Then you do the next step that is high pressure hydrogenation of the phenolic aromatic ring followed by oxidation of the hydroxyl group to corresponding ketone using chromium trioxide and acidic acid. So he got a mixture of these two where this is the major product because since you are using high pressure hydrogenation and when you use hydrogenation cis product should be the major product. So that was a major product. So once you have the major product and that also was crystalline. So once it is crystalline it is easy to isolate and proceed further. So he took the crystalline compound okay and treated with sodium ethoxide and this particular reagent. So this reagent is known to introduce NO group okay known to introduce nitroso group next to the ketone. So when he did that what he got was this compound. I will come to the mechanism of this little later. Basically the idea is to convert this into a double bond okay. You need a double bond binary group is not it? Basically that idea is to get or convert this oxime into double bond. So you can see that you know see this whole thing should be a vinyl group okay. Then you reduce oxime to NH2 okay you can do with LAH or you can also do it with hydrogenation condition. Now if you treat with excess methyl iodide what will happen? It will form the corresponding quaternary salt okay. It will form the corresponding quaternary salt and this on treatment with potassium ethoxide will undergo half bond elimination to give the less substituted alkene okay. So once you have that then you treat with potassium cyanate and before that I will just give the mechanism of the introduction of the nitroso group. So you have this and treat with sodium ethoxide and NO OET you get this compound is not it? So the mechanism is first it generates enolate okay. Then upon treatment with nitroso compound the enolate that is the carbonyl attacks the nitrogen of NO to give this particular intermediate. Now what will happen? This O minus will come back and eliminate the OET. So basically as I said it is a good region to introduce the NO group okay. However next when you use sodium ethoxide because sodium ethoxide is a base which you have to use to introduce the NO group. Now the sodium ethoxide will attack the carbonyl group and this bond will break okay. This bond will break and that will give you the corresponding oxide okay. So then let us see and with this key intermediate in hand the next is you have to make this carboxylic acid as ester because for the glycine reaction you need this ester. Then treat with ethanol and HCl. So ethanol and HCl not only converted the carboxylic acid into ester but also hydrolyzed this urea derivative to corresponding NH. Now on treatment with benzyl chloride okay it is like a Scotland Bobman reaction. You benzylate the secondary amine. Then you have this ester okay this is a known compound okay. Then you do the glycine reaction. So the glycine reaction gives the beta keto ester okay. This beta keto ester can be decarboxylated with 6 normal HCl. So if you reflex it for some time you get quinotoxin okay. So this is how Woodward completed the formal synthesis of quinine because he synthesized only quinotoxin and quinotoxin has been already converted into quinine by Robbie. So this constitutes a formal total synthesis of quinine however there was some controversy. So what happened Paul Robbie when he reported the synthesis of quinine from quinotoxin he did not publish the complete experimental details. Later he published several other papers related to the synthesis of many closely related synchronous alkaloids but he never published the full experimental details of quinotoxin to quinine. So Gilbert Stark who completed the first asymmetric synthesis of quinine he had his own reservation. When this full experimental details were not known for the conversion of quinotoxin to quinine then the total synthesis of quinine reported by Woodward may not be valid is not it. So he has made after all he has made only quinotoxin he has not made quinine. He thought that since quinotoxin has been already converted into quinine by Paul Robbie he did not carry out the conversion of quinotoxin to quinine. So there were many papers and finally Robert Williams and his student from Colorado University they took upon this project repeated the same reactions reported by Paul Robbie in his paper on the conversion of quinotoxin to quinine and they could indeed get quinine in 5% yield. So that confirms the formal total synthesis of Woodward is valid. So what did William do? So William first they made the quinotoxin from quinine so they made about 30 grams of this reasonably large scale from quinine then they treated with sodium bromide followed by treatment with sodium ethoxide. These are the same conditions reported by Paul Robbie and they got the mixture of these 2 ketones. So one is quinidinome other one is quinineome. So the reduction of quinidinome will give quinine the reduction of quinidinome will give quinidin. According to Paul Robbie they used aluminium powder. So aluminium powder and then sodium ethoxide ethanol they could isolate 5% yield of quinine. So they felt that whatever aluminium powder Paul Robbie would have used may be different that is the reason why they were getting 18% yield and in 2010 our Williams they might have got the highest purity aluminium powder sometimes impurity plays a role. So they suggested that impurities present in aluminium powder used by Paul Robbie might have played a role for getting higher yield of quinine from quinineome. So what is important was this actually confirmed that conversion of quinotoxin to quinine as reported by Paul Robbie could be repeated and so the formal synthesis of quinine by Woodward is valid. So now I will quickly talk about Starks first asymmetric total synthesis of quinine and until then there was no report on asymmetric synthesis though there were many resemic synthesis known and the first key step was the SN2 substitution then this can be obtained by the reduction of the corresponding imine. This imine can be obtained from the ketone and azide. So if you do a starting a reaction the N3 you can reduce to NH2 that will automatically form a imine by reacting with the ketone and this can be redrawn like this and this can be obtained by in 2 steps by treating this combo with butylethium and adding to the aldehyde you will get an alcohol that alcohol upon oxidation you will get the ketone. So basically the major focus of this work should be on preparing this compound. So he started with this known compound and with a established chiral center one chiral center is already there. So and then he opened this 5 membered lactone with the thymethyloaluminium and diethylamine and protected the primary alcohol as Tbaseeth. Then you generate the enolate here. So by treating with LDA you generate the enolate and conge with this iodide the 2 carbon alkylation takes place this upon treatment with PPTS. So the Tbase group can be selectively cleaved once it is cleaved then it cyclizes to give the 5 membered lactone. Basically if you see what you have done is you have attached a 2 carbon unit at alpha position of this lactone okay. Then it is an ester it is a cyclic ester lactone. If you reduce with di-ball you will convert this lactone into lactol this upon enolether vitique you will get the corresponding enolether. This upon treatment with triphenylposphine dead and this triphenylposphoryl acide basically mid-snow reaction converts this OH into acide followed by hydrolysis of enolether you get the aldehyde okay. Once you have this aldehyde so this is a known compound treat with LDA. So you generate the corresponding lithium derivative add to this aldehyde you get the corresponding alcohol. So now swenoxidation will give the ketone and treatment with triphenylposphine. So triphenylposphine will form immunoposphoryl that immunoposphoryl intramolecally undergo azobitic like reaction to get the corresponding 6 membered cyclic imine. Once you have this then reduction with sodium borohydride sodium borohydride will reduce the imine to give the corresponding substituted piperdene derivative okay. So what you need to be done this TBDPS group should be removed converted into a leaving group so that the cyclization can take place. So the TBDPS was removed using HF in acetonitrile and followed by treatment with mesyl chloride the SN2 displacement take took place to give the core structure of quinine. So what is left is introduction of the hydroxyl group. So that was done by treating with LDA and in fact it is known in the literature where they have used potassium tercibutoxide followed by oxygen treatment and removal of extra hydrogen of the peroxide with dimethyl sulfide gives quinine okay. Overall if you look at this whole synthesis reported by star it involved 13 longest linear sequence with an overall yield of 18 percent. 18 percent overall yield for 13 step is really a very good very good synthesis and also this is the first asymmetric synthesis of such a complex natural product known in the literature. Thank you.


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