 Good morning and welcome back to the lecture series on Classics in Total Synthesis Part 1. So we have been discussing about total synthesis of various alkaloids and today we will talk about one very interesting pyrolyzidine alkaloid called swine-sonane. So swine-sonane is a very simple bicyclic compound and have three hydroxyl groups. 1, 2, 3. So this is a very important manasodized inhibitor and also has been examined closely as a potential anti-cancer drug. So this molecule has attracted attention of synthetic chemists because if you look at this molecule one can easily think of making from carbohydrates as starting material. So several synthetic approaches were known. What we will do today? We will talk about four short total synthesis and incidentally three of them are coming from carbohydrate starting material, okay. And this as I mentioned this is a interesting indolazirine alkaloid. There are many alkaloids belonging to this family and some of them are shown here. This is Homo-alexine and that differs if you look at swine-sonane and this one you can see there is additional CH2 OH group and also pterochemistry of this hydroxyl group you know varies. And in this case in the Alexine you have a 5-ampered, a coupled with another 5-ampered whereas in these two cases you have a pyrolyzidine coupling with a 6-ampered link, okay. And this is australine again it differs only with the ring junction here, okay. Here also the ring junction differs. And this one it is a 6-ampered ring you can call it as hydroxymethyl swine-sonane, okay. Swine-sonane is without this CH2 OH so it is hydroxymethyl swine-sonane, okay. So there are many related alkaloids and they are Potential Assoc sugar inhibitors, okay. So many of them have been used as glycosidized inhibitors and there are several synthetic groups who worked on the synthesis of such molecules. So as I said we will talk about three total synthesis starting from carbohydrates and let us start with Hashimoto's total synthesis of swine-sonane. This was published in JOC in 1985 and here the key reaction is a one-pot nucleophilic opening of epoxide by an amine followed by formation of 6-ampered lacto. So both are happening in one part. So that is the key step. So for the retrosynthetic analysis so the first disconnection was you just remove this bond. Before that that can be easily made from the corresponding lactum, okay. So once you have lactum and simply you reduce with LAH or borane you get the corresponding reduced bond. And the second disconnection is the key disconnection which I said already. It is a one-pot reaction where the amine opens the epoxide and at the same time this also attacks the ester where the OR group comes out. So in one part both the rings are formed, okay. And this can be obtained from the corresponding alpha-beta unsaturated ester and as you know once you have alpha-beta unsaturated ester that can be obtained from the corresponding aldehyde by stabilized witty, okay. This aldehyde can be obtained from this diol, okay. So now if you look at this diol, if you treat with a base, okay, so this can attack this carbon and mesolate can go out forming the alpha epoxide, okay. One can also see that the primary alcohol can attack but that will lead to the formation of our umber ring. So it is a highly selective epoxide formation where only three umber rings is formed. And this in principle can be obtained from this hydroxy amine compound. So you can remove this estonite, okay. Before that you have to mesolate the secondary alcohol. And this in principle can be obtained from mannose diacetonide. This is called d-mannose diacetonide and this can be obtained from d-mannose diacetonide in two steps. Of course the starting material is d-mannose which upon treatment with acetone and blue acid you will get d-mannose diacetonide. Now let us see how Ashimoto's group successfully completed the total synthesis of swine-sonite using this key reaction. So first the d-mannose was protected as di-astronite. And this on treatment with hydroxylamine hydrochloride form the enzyme. And so once you form the enzyme, you treat with LIH. As you know, oxymes can be completely reduced to corresponding primary amine. So that is what happened. Then that NH was protected as CBZ. So you treat with chlorobenzyloxychloride. Then so now OH is converted to the mesolate. Then selectively you can remove this acetonite in the presence of the other one, okay. This is a terminal acetonite. So more exposed and that can be selectively removed by treating with para-toluene sulfonic acid and methanol to get the diol. Then this on treatment with amberlite having OH-type. So that generates anion here and attacks carbon bearing mesolate in a center fashion. So you get the epoxide. So now you have got the epoxide in place and already the nitrogen is also in place. What you should do? You have to homologate the primary alcohol. So that is done by oxidation of the primary alcohol using Collin's reagent to get the aldehyde. Then you do the stabilized metique and homologate to get the alpha-beta unsaturated ester. And this alpha-beta unsaturated ester you treat with sodium borohydride. You reduce the double bond to completely saturated ester. Then the CBZ group, okay, that is easily removed under hydrogenalysis condition. So benzene group gets cleaved, CO2 goes and then what you get is the NH2. But as soon as the NH2 is formed, then this will open the epoxide and also the NH2 attacks the ester and in one part, okay, in one part you get the bicyclic comp. So this is the first step. The NH2 attacking the epoxide to get the alcohol, then the NH that is the pyrolydine substituted pyrolydine attacking the ester to form the 6-membered lactam. So now what is left is to remove the carbonyl group of the lactam and remove the astronyne. So the sodium borohydride ethanol, you convert the lactam into corresponding amine and HClTHF, so you remove the astronyne, so you get swine sodium. So this was reported 37 years ago by Hashimoto's group and starting from De Manos and overall he took about 12 linear steps and yield was about 4% okay. The key step was a one part opening of the epoxide with a primary amine followed by lactam formation. So in one part you basically they form two rings which are present in swine sodium. The second synthesis was reported by Pearson and Hemre and this was reported in 1996 and his synthesis started from again another simple carbohydrate called De Erythrose and the key reaction involved was Sharpless asymmetric dihydroxylation and the second key reaction was reduction of azide and followed by cyclization to form the pyrrolidine ring in one part. From retrospective point of view again the first disconnection was you know introduce a carbonyl group to form the lactam because it is easy you know reducing the lactam to corresponding amine is very easy and straightforward and this type of lactam can be easily obtained by having pyrrolidine as well as carboxylic acid. So this can be obtained from this acide so this is the key reaction which I said. So what happens if you reduce this N3 to NH2 okay this NH2 what will happen it will straight away attack as soon as it is formed it will attack the 5 umber lactam and open this okay. So what will happen so the NH2 first it will attack the mesolate so it forms the 5 umber ring then that NH attacks the lactam and open the lactam so you get the corresponding 6 umber. This in fact can be obtained from this gamma delta unsaturated ester okay alpha beta gamma gamma delta unsaturated esters. If you have a gamma delta unsaturated ester and if you do a dihydroxylation particularly if you do a sharp less asymmetric dihydroxylation. So what will happen so one of them immediately will cyclize to form a 5 umber lactone and the other will be free alcohol and this gamma delta unsaturated ester or aldehyde can be easily obtained from the corresponding allylic alcohol through glycent rearrangement. So the precursor for this is this allylic alcohol so once you have this allylic alcohol this can undergo intramolecular glycent rearrangement to give the gamma delta unsaturated esters and this can be easily obtained from erythrose which is commercially available. Now let us see how this molecule was synthesized by Pearson's group so they started with de-erythrose. So you take de-erythrose and then directly protect it with acetone you will get this austenite then you treat with vinyl magnesium bromide so that will give you the corresponding diol okay. So once you have this diol then you can selectively protect the primary alcohol as Tb acetyl okay you can take this diol and treat with TBMS chloride and humidus ol you protect the primary alcohol as Tb acetyl. Now the allylic alcohol on treatment with trimethyl orthoacetate the presence of catalytic amount of propionic acid undergoes a glycent rearrangement to give the gamma delta unsaturated ester. So this is the result of glycent rearrangement okay and that goes through this intermediate. So once you have this gamma delta unsaturated ester then Sharpless asymmetric dihydroxylation gives a diol and one of the alcohol immediately attacks the ester and forming a 5 member lactone and the secondary alcohol which is formed can be easily mesylated okay. So here as you can see there are two isomers the alpha diol was obtained in 70% and beta diol which was obtained in 9% the alpha diol is the one which is required. So you took the TBS ether and removed the TBS group with Tbaf to get a diol and the diol upon treatment with mesyl chloride we got the dimesolate. Once you have the dimesolate the primary alcohol can undergo acetyl reaction with sodium azide. So the mesolate was removed and you replace it with N3. Now the key reaction where the N3 was hydrogenated to get NH2 and that NH2 intramolecularly attack the carbon wearing mesolate to form the 5 member pyrolyne ring followed by opening of the 5 member lactone to get the corresponding 6 member 1. So this is the first step and followed by intramolecular attack of this NH2 open this to give the 6 membered hydroxy lactone. So now what needs to be done is you have to remove the carbonyl and also remove the austenite. So that is straightforward if you treat with borane dimethyl sulfide the lactone becomes corresponding amine and then treat with dilute HCl so you get swine saline. So overall this particular synthesis reported by Pearson in 1996 started from erythrose and involved about 12 longest linear steps however the yield is quite good and they could get about 20% overall yield. The third synthesis again as I said was started from commercially available de-erythrose and this was reported by J. K. Shah but the key reactions are 1, 3 dipolar cycloaddition between an acide and a double bond. So this is an intramolecular 1, 3 dipolar cycloaddition. Then the second key reaction was highly stereoselective reduction of imine and as soon as the imine is formed imine is reduced it cyclizes to form the lactone. So the retrosynthesis again starts with a similar you know formation of the lactone as you know the lactone can be easily reduced but at the same time he also has a double bond. So this double bond one can do a hydroboration to introduce the hydroxyl group that this particular retrosynthesis involves two key reactions. One removal of the lactone to the corresponding 6-wombered piperdendering and hydroboration of the double bond to give a corresponding hydroxyl group. And this can be easily obtained from this imine just you know you just it forms enamine and then cyclises and that can be obtained from the corresponding azidoalkene. This azidoalkene undergoes an intramolecular 1, 3 dipolar cycloaddition followed by extrusion of nitrogen will give this immunocompo and this can be obtained from the corresponding lactone. So the synthesis reported by Char started with de-erythrose and this one can write like this and if you do a vitic reaction and you get this double bond and convert the primary alcohol into tosylate or mesylate because you have to convert that into a good living group then treat with sodium azide you get the corresponding acid. So when you do this SN2 reaction so normally you have to heat it around 7200 degrees so that time not only SN2 displacement took place but also it underwent an intramolecular 1, 3 dipolar cycloaddition and it did not stop there once the intramolecular dipolar cycloaddition went it underwent the extrusion of nitrogen to form this imine okay. So once you have this imine if you treat with potassium carbonate methanol you hydrolyze the ester to corresponding carboxylic acid this carboxylic acid when you reflects what happened the carboxylic acid adds to this imine to form a spiral lactone okay this spiral lactone upon further heating it undergoes a rearrangement to give this imine okay. So it is very easy it undergoes cleavage and followed by elimination and then cyclization okay. Three steps involved in this particular reaction to form this bicyclic compound now as you know what you need to do you have to remove the carbonyl group and do a hydroboration. So both are done in one part okay one when you treat with boron THF you know boron THF is known to convert lactum to corresponding amine okay and also if you have a double bond that will undergo hydroboration. So both reactions are done in one part to get this now just removal of the acetonide gives swine on it okay. So these three synthesis if you look at all the three synthesis started with chiral starting material okay two started with erythros the third one started with erythros the second one started with erythrolactone and the first one started with D malose. Here Char reported the total synthesis of swine on it in six steps and with an overall yield of 21 percent okay. The fourth synthesis was reported by Zhao and here the key reactions are Char plus asymmetric dihydroxylation and also the kinetic resolution okay. It is a kinetic resolution of farfural imine okay. So we know if you have a farfural alcohol then one can do Char plus kinetic resolution. So here instead of alcohol it was done on NHTS okay let us see how they have done. So from retrosynthetic point of view this is the first disconnection okay. This is the first disconnection to get the corresponding trial and the trial can be obtained from this allylic alcohol by Char plus asymmetric dihydroxylation and this in principle can be obtained from the six-membered lactam and this six-membered lactam is obtained from the corresponding farfural amine okay. The tosylated amine and this is obtained from simple farfural. So this total synthesis started from farfural and then you convert that into corresponding amine by treating with para-tolyvine sulfonamide okay. It is a skip base. Then you add the lithioderivative derived from propogel alcohol, protected propogel alcohol. The mom-protected propogel alcohol if you treat with butyl lithium you get this lithium species that adds to this amine and you get this compound. Now you have a triple bond. The triple bond can be reduced to get a cis-double bond and this was done with a picture of nickel acetate and sodium borohydride to get the cis-double bond and here comes the key reaction that is kinetic resolution. So if you use diisopropyl tartarate titanium isopropoxide and tercibutyl hydroperoxide so which is normally used for Char plus asymmetric epoxidation and kinetic resolution okay. Of course you have to use molecular sieves and calcium hydride. So all these were used for the kinetic resolution. So it not only resolves but also it undergoes HMOTO-H rearrangement okay. The HMOTO-H rearrangement product is the one which he further carried out for the synthesis of swine sunny. So this is the simple kinetic resolution and this rearranged product is the one which he proceeded further for the total synthesis of swine sunny. So now once you have this compound the next step is convert this OH into OET okay. You treat with triethyl orthoformate and Lewis acid like BF3 ethyl in the presence of molecular sieves. So the OH that is aminol is converted into corresponding ether okay. Once you have this ether then sodium borohydride methanol. So sodium borohydride methanol not only can reduce the ketone but also can reduce the double bond. If you take excess sodium borohydride methanol it can do both. So that is what happened so you get the alcohol. Now the alcohol was protected as benzyl ether by treating sodium hydride and benzyl bromide. The next step is the removal of the OET group okay. So if you treat with formic acid so it forms the corresponding imenium and that imenium is reduced with sodium borohydride to form the 6-numbered Tosyl N-Tosyl Piperadine ring okay. You have a cis double bond so Sharpless Asymmetric Digit translation will give the syn diol and that is a major product. Of course he also got little bit of beta diol and he took this beta diol and then treated with paratolimine sulphonic acid in solvents like tercibutanol to remove the mom group. So basically he got the 3 hydroxyl groups now. So now what needs to be done? You have to remove this Tosyl group and cyclise at this carbon to introduce the 5-numbered ring. So the Tosyl group okay how do you remove N-Tosyl? There are many methods. He used sodium anaphthalenide so that cleave the N-Tosyl to corresponding NH. Now this on treatment with triphenylposphine and CCl4. So the triphenylposphine and CCl4 is a good reagent for converting OH2 corresponding chloride okay. So and it also is a good reagent for sometimes doing Mitsunov-like reaction okay. So here what happens? This is converted into Cl and the lone pair anhydrogen immediately attacks and it forms a corresponding 5-numbered ring. So now only one thing is left that is removal of the benzyl group. So removal of the benzyl group can be easily done but however what he did he protected this diol as the corresponding asteroid. So why he did that was this compound was already converted into swine cyanine in 2 steps. So he wanted to compare the spectral data of this compound with already reported that is why the compound which he made which is a diol and he converted that into acetonide by treating with dimethoxyacetone. So thus he completed a formal total synthesis of swine cyanine and not starting from chiral starting material. So what he has done is he has used a kinetic dynamic resolution of furfuryal amine okay followed by sharpness asymmetric diatoxylation as key reaction. The whole synthetic sequence took about 15 steps nevertheless so it was an interesting total synthesis where kinetic resolution was used as the key step okay. So with this I will stop here and then we will continue our discussion on total synthesis of some more alkaloids in the next lecture. Thank you.