Lecture 14: Tf/Fg/SM based strategies and its exploration

Welcome back. We are discussing several problem-based approaches of a given target molecule And we have talked that transformation-based approaches starting material based approaches and functional group-based approaches are the key core three strategies which can be combined together efficiently to solve numerous problems, as discussed in the earlier lectures Now, in continuation with the same thing, we will now try to provide you a similar problem, but you need to figure it out the target structure in very closely. So, the six-member ring is there, and in addition, you have a seven-member ring. Then, I am trying to draw 1 2 3 4. So, this is the target molecule, just try to draw the target molecule and then, this target molecule is bit complex; you have a bridge structure from here Now, in reality, the structure which was given here, it’s not a simple structure as it looks-the six-member ring. Then, you have a seven-member ring; 1 2 3 4 5 6 7. Then, you are having a five-member bridged; 1 2 3 4 5 So, now there are cyclic structures connected in a different way. Probably a topologically distinct molecule. But eventually, we will be just trying to analyze the molecule in a very straightforward retro by normal functional group-based approaches. Let us first do the very conventional retro, and then, you will realize and how this retro is so powerful The only thing if you check in the molecule, you will find that a probably an Aldol kind of transformation is useful to make this target molecule. Now, how? I will try to draw the structure. So, this is OBn; Bn is Benzyl I am writing it Bn is Benzyl; CH2 Ph it’s an abbreviated form Then, from this part, you can make a hanging Aldehyde, Aldehyde appendage. Then, you can put something like this and then, you will try to make the bridge; try to make the bridge Now we say that we are doing a disconnection here. Now, this is a Methylene compound adjacent to a carbonyl and close proximity. You have a Carbonyl or Aldehyde group. So, basically is an Aldol Reaction. It is an Aldol Transformation Now, the structural simplicity is basically until, and unless you draw the Aldol retro, it’s not visible; it sometimes means you try to make a visible or visual communication with this target molecule and then try to simplify the main target structure. Now this structure, we will write it in a simplified form If you write it, now you see the structure is basically nothing but a 6-6 molecule fused together, is not it? See the analogy; this

is the OMe; this is the fused, common fuse together, 1 2 3 4 5 6. So, the Ketone, this red color Ketone is basically this, and then, you are doing it an Aldol reaction with this Alde Hyde to this. So, this is the Aldol reaction we are doing Now this compound has been rewritten in this way. So, that is what the structure looks pretty complex. Now once it is simplified, you are quite comfortable. Now it looks quite comfortable, and then, probably, you can design a very straight forward retro based on a known starting material This starting material is known is a 1 2 3 4 5 6 7; 7 Methoxy-Beta tetralone. That was already known, and probably this is a beta-tetralone derivative, it’s a commercially also available; Beta-tetralone derivative. It could be a very good starting material. Now, what exactly you want to do it, you will be doing a successive round of alkylation to put these functional groups Now, remember you have a Methylene group here as well as here, fine. Now out of these Methylene groups, this Methylene group is most acidic because it is a Benzylic also. So now you realize that. if you start with this compound again, we will draw the parent compound, and you both the hydrogen’s you will basically be replaced by some carbon-containing electrophile, that will be given you this target. This target will then undergo Intramolecular Aldol reaction to give you the final target, is not it So, let us start the forward synthesis The 7 Methoxy-betatetralone derivatives, which you choose. As you are doing the successive round of alkylation, so, LDA 1 equivalent Now, what are the groups that need to be introduced? The first one is Benzyl …BnO-CH2Cl, this is called Benzyl Oxy Methyl Chloride or abbreviated as BOM Chloride So, the first round of alkylation, we get OBn. The second group which you need to introduce must have a CH2CHO. In principle you can use this kind of chloro acetaldehyde, is possible definitely possible, but sometimes this reagent might not be easily available; So, what you do, you can try to take another source or another electrophile, which will give you this particular functional group So, alternatively, we will be using this reagent condition, will be using LDA and Allyl Bromide; Allyl Bromide is a very cheap material, cheap starting material, and then, you will basically do another round of alkylation to get this all-carbon quaternary center here, fine Then as the situation demands, you need to do an oxidative cleavage here to remove this

one of this carbon to get an Aldehyde. So, do an original analysis; your Methoxy group will always be there; you will do a unique analysis, and then, you are getting this compound Now this compound you can, try to go back to the original retro it’s nothing but this, you try to draw it in this way and then, do an intramolecular Aldol. You can now finish it off the retro in an elegant way So, that was basically a very useful simplification So, once we have a complex structure, that is why we are always saying that the retrosynthetic pathways are so powerful. So, you have to start visually communicating with the molecule and once you try to finish the chemical logic Then you simplify the starting material or the intermediate and then, you complete the forward synthesis, and the entire event is a very pleasing exercise And next, we will be basically trying to use a similar kind of strategy would be using multiple transformation based strategies It is sometimes a transformation that you required is to be combined. A couple of transformations like 3- 4 transformations should be combined together. But until now, we have not discussed any complex structure. It is basically a simple structure where you can just play with 2- 3 functional groups or 2- 3 transformation This particular target, which we will be discussing now, we will be using 2-3 transformations together, and I am sure all the transformations have been known to you as earlier discussed Is a target molecule that contains a Phenyl ring, and here it’s having an appendage which is having a -CN; CH2OH and an isopropyl group So, this carbon is a quaternary carbon, with all carbon quaternary; the Phenyl -CN, CH2OH So, to do this, I will do a functional group addition or a functional group interconversion, which is a purely FGA based approach. To do well initially, if we found somewhere the alcohol is given in the target molecule, it means that the alcohol needs to be protected Normally, Alcohol protection, as we have not discussed, but we will do it a little bit later on. But alcohol is not a good functional group which you can keep as free because acidic hydrogen play some important role. So, alcohol-free is always not recommended; you can just protect it; the suitable protecting group. Pg stands for Protecting group; we will be talking about many protecting groups a little bit later on when you talk about functional group-based strategies in detail, Protection group Next, you will try to figure it out other FGI based approaches and then, we said that this compound could be potentially created from an Oxime, which can give you cyanide Now Oximes basically have such structure…Aldoxime means Aldehyde Oxime. Now, Aldoxime, if you treat with a dehydrating agent, namely Phosphorus pentoxide, this water will be eliminated, and you get the nitrile compound. So, what is this? This is basically a functional group interconversion Now, Aldoxime means you need to have an Aldehyde; otherwise, you won’t get Aldoxime. So, this is again a FGA or FGI to come back to the parent aldehyde CHO. This isopropyl remains similar, and this group you put it as is a

suitable protecting group. So, we are here Now, this carbon is all carbon quaternary carbon The next retro was again based on a very conventional reaction, which we discussed many times in our coursework. We said a Meinwald kind of rearrangement would give you this Aldehyde So, is a Meinwald rearrangement was used as a main transformation, Now you know the mechanism of Meinwald rearrangement, and you can basically figure it out, how this transformation takes place So, next, you need to make this epoxide, simple job. You can now just make this alcohol free, and then, if you have this kind of compound, this kind of allelic alcohol you can easily make it, this is a FGI. So the manual transformation, as we discussed earlier, you know the mechanism, you can easily formulate So, now, this primary hydroxyl group we are putting in a different way, we will be accessing this primary hydroxyl group to a Cyano group Some of the reactions we are not discussing, but we will discuss it when we talked about the forward pathway, and then, this CN will be discussing from a benzyl cyano through an intramolecular Aldol reaction. So, all are FGI, FGI based on a couple of exciting transformation So, now let us go back to the forward pathway So, the forward-path starts with very simple starting material, Benzyl Cyanide. This compound is subjected to the first LDA. The acidic compound, these hydrogen’s are acidic, and then, you react to this compound with this Aldehyde. So, Aldol reaction will take place, and we definitely get these things. It is apparent means now, go back to the retro, you will find the cyanide now, needs to convert it to the corresponding Aldehyde; you can do two different kinds of formations. You probably know Stephen’s reaction Stephen’s reaction is a very simple reaction in which you can convert a CN to an aldehyde RCN to RCHO by SnCl2. Otherwise, if you don’t like the Stephen reaction, you can simply be using a DIBAL-H, di isobutyl aluminum hydride, which will also selectively convert a cyano to the corresponding Aldehyde. The beauty is the reaction will definitely stop in the aldehyde step; usually, if you use one equivalent of DIBAL-H, it ends at the aldehyde steps; otherwise, you can use excess DIBAL-H to get the primary alcohol. Because in our synthetic experiences, synthetic exercises, we need the primary alcohols Never the less, DIBAL is very expensive. So, what you do, you put a DIBAL 1 equivalent to get the Aldehyde. Then we use a cheap reagent sodium borohydride to access this allylic alcohol. Then this allylic alcohol needs to be protected. The protecting group, you usually can use any protecting group, but I am giving you a protecting group whose name is TBDPS-Cl The structure of TBDPS-Cl is Tertiary Butyl Diphenyl Silyl Chloride. So, basically, the oxygen will be replaced by this silyl ether,

and you will be having this OTBDPS. So, this is your compound You can do a mCPBA mediated epoxidation here, to get the corresponding epoxide, which will be next subjected to Meinwald rearrangement So, now, you are having this epoxide, and this O, let’s say Pg, OPg. Meinwald rearrangement, this is normally you treat with a Lewis Acid It is Lewis acid So, the Lewis acid you add, I know obviously, make sure which way the carbons, the carbon-oxygen bond, will be broken down. The most stable Carbonium iron will definitely be generated, and I assume that this way, you will have this OLA thing; because it is the Benzylic thing Now, then out of this, there is hydrogen There is isopropyl; the isopropyl group is secondary. It will basically migrate, isopropyl group will migrate here, and then, once the isopropyl group migrates, let the isopropyl group migrate And then, you will get the all-carbon quaternary center. This isopropyl group will migrate, and you are having this CHO after this rearrangement takes place, which is nothing but the desired compound. We said to put the isopropyl group in the top this OPg and your Aldehyde Now, make this aldehyde oxime, Aldoxime by hydroxylamine treatment, a very standard FGI So what will you get? You get to this OPg, O Pg remains the same; your isopropyl group remains similar, and then, you get the corresponding oxime. Put a dehydrating agent may be P2O5, phosphorus pentoxide, and you will get this OPg, CN here, and your isopropyl So, now we are almost close only thing is you need to remove the Pg. Now, this Pg removal is an oxygen silicon bond. We will try to give you some more information. Now, this oxygen silicon bond is very labile under fluoride condition; because you are going to form a new silicon fluorine bond. So, this will come here, you put a R- O minus, and it will give you the silicon fluorine bond, silicon has a strong affinity towards fluorine The silicon fluorine bond energy is very high; that is why normally, if you have an oxygen silicon bond or carbon-silicon bond, the base is there to cleave is the fluoride source; basically, you can access the target molecules which is required. You will get an OH here; you get a cyano, the target molecule Now, coming to the fluoride source, what kind of fluoride source you can think of using for silicon deprotection? Fluoride source The best fluoride source, what we will be using is named as TBAF, Tetra Butyl Ammonium Fluoride, whose structure is nBu4N+F-. Normally all silicon-containing protecting group has

been cleaved in this way, say R – O – TBS stands for Tertiary Butyl dimethyl Silyl, which is equivalent to Silicon methyl this group TBDPS, which we just now talked about, which are commonly used silicon reagent; silicon protecting group R – O – TIPS, TIPS stands for Silicon Try Isopropyl Silyl. There are other silicon-containing protecting groups like R – O – TES, TES is Try Ethyl Silyl When Silicon Ethyl Ethyl Ethyl. So, all the silicon-containing protecting group can be cleaved with tetra butyl ammonium fluoride These tetra butyl ammonium fluoride basically was commercially available, TBAF solution So, you try to buy from commercial suppliers You will find that TBAF in THF solution, Tetra hydro furan solution. So, normally one molar or two molar solution is commercially available, and you can just use them in some cases, you can use HF. HF was very strongly acidic, and to minimize its acidic nature; sometimes HF was combined with Pyridine, HF Pyridine is a good reagent HF-triethylamine is a good reagent to remove the silicon-containing protecting group Simple ammonium fluoride NH4HF, ammonium bifluoride was used. Potassium fluoride sometimes was used, but potassium fluoride is very much hygroscopic, is very difficult to handle The potassium fluoride normally is not used, but you can use all these compounds. TBAF was the most widely used compound to cleave any silicon-containing oxygen silicon bonds or carbon-silicon bonds. HF Pyridine also was used. HF triethylamine, ammonium fluoride, ammonium hydrogen fluoride all are used. So, what are these set of reagents, we will be using when you talk about protecting groups in detail So, we will just continue our discussion in the next week, till then, goodbye. Have a good time