Total Synthesis Strychnine - Step 15

Our next step in this synthesis is to perform the Dieckmann Condensation that we wanted to do previously, however, those attempts were thwarted by that N-toluenesulfonyl group.  Now that we have taken the steps to get rid of that and protect other remaining groups on the molecule we can finally complete this reaction.  Below is the scheme.

Scheme 1.  Dieckmann Condensation of our compound to form the fifth ring of strychnine.

Mechanism:
Let's first look at the general mechanism of a Dieckmann Condensation and how it differs compared to say an aldol condensation, or Knoevenagal Condensation.  I will lay out the differences in a table format, and will not explain as the differences are quite obvious.  I will however, discuss the Dieckmann Condensation after.

_______________________________________________________

Dieckmann Condensation
Molecularity: Intramolecular
Functional group: Diester
Conditions: Base
Workup: Acid
Bond formed: Carbon-Carbon (single bond) - (double bond if enol form predominates)

Scheme 2. Dieckmann Condensation mechanism.

Knoevenagel Condesation
Molecularity: Intermolecular
Functional groups reacted: Ketone/Aldehyde with CH2X2, where X=electron withdrawing group
Conditions: Base
Workup: None
Bond formed: Carbon=Carbon (double bond)

Scheme 3. Knoevenagel Condensation mechanism between benzaldehyde and dinitromethane.

Aldol Condensation
Molecularity: Intermolecular
Function groups reacted: Ketone/Aldehyde with Ketone/Aldehyde
Conditions: Base or Acid
Workup: None
Bond formed: Carbon=Carbon (double bond) - Single bond formed if stopped at aldol addition (this is done by performing reaction at low temperatures such as -78˚C)

Scheme 4. Aldol Condensation between benzil and benzaldehyde

Claisen Condensation
Molecularity: Intermolecular
Function groups reacted: Ester with ester/ketone/aldehyde
Conditions: Base
Workup: Acid
Bond formed: Carbon-Carbon (single)
Mechanism: Similar to aldol, however, rather than leaving of OH, the alkoxide leaves.
_______________________________________________________
The Chemistry:
Ok, so that's a lot of information and I think it's helpful to differentiate between the reactions.  They are all very similar, it's really just how you mix and match the groups.  Let's go back to our Dieckmann Condensation and rationalize what happens.  A few things stand out to me.

1.) The molecule has a few basic protons which I see, it's interesting that only the one by the aromatic ring reacts (red protons below).  See Scheme 5 below.

Scheme 5. Two possible reaction pathways.

It is my belief that the red pathway occurs for three reasons.  They are likely most acidic because the pyridone ring is very electron withdrawing (inductively, not through resonance).  While this is the same case for the N-acetyl group, due to the aromatization of the pyridone group, this effect is great.  Second, there are two red protons and only 1 blue proton.  Kinetically speaking, the red ones have a better chance of being deprotonated and reaction.  Third, the blue proton is a tertiary carbon and is very hindered.  The approach of this carbon to form a quaternary center will very very hindered and the blue pathway is thus rather unlikely.

One extra interesting note is that in order for this Dieckmann Condensation to occur, the blue proton must become deprotonated at some point.  This is because in the current geometry, the methyl ester on the pyrrolidine ring is facing away from the red protons and is unaccessible for attack (it may take some careful looking to see this).  Actually, epimerization (steroechemical switching) at this center must occur in order for the reaction to proceed.  Thus we can see that this proton is accessible to the basic environment, but is a poor nucleophile due to the steric encumbrance of the tertiary center.  Once this proton is deprotonated, an equilibrium exists between both isomers at this carbon, and as the favored conformation reacts, it shifts the equilibrium forward driving the reaction nearly to completion.

2.) The enol form predominates when typically the ketone form is favored.

This is odd because ketone forms are very often more stable than the enol form.  The enol dominates due to the electron inductance provided by the pyridone ring.  This effect is so strong that during the reaction, actually the sodium salt of the enol was isolated.  The molecule could actually be deprotonated in sodium bicarbonate solution (pH~7-8) which is astounding for an alcohol.

Workup:
This reaction is almost like a chemist's dream.  There is really no work up here.  The product precipitates from the solution which also helps to drive the reaction forward, as the precipitation of product keeps the concentration of product in solution low, helping to shift equilibrium to the right.  After a brief 20 minute reflux, and allowing the solution to sit in the cold overnight, the light yellow crystals could be simply filtered (how great!).  And in 88% yield, I'm sure Woodward would be high-fiving everyone in lab.  I know I would after first overcoming the problem with the N-toluenesulfonyl group, then beautifully creating the fifth ring in a simple reaction which also elegantly sets up for the next step in another high yielding reaction which I will cover next time.  Genius.

Resources Every Chemist Should Have

A brief excursion to show you all some of the tools I think that every organic chemist (or chemist) should have.  I will list some textbooks, as well as online resources that are great references.

Textbooks:

1.) Organic Chemistry - Clayden (link)
This is a wonderful textbook that for an introductory organic chemistry book, is very detailed.  By far the best text out there.  Covers a large scope of reactions in sufficient detail so that one can gain a very in depth understanding.
2.) Advanced Organic Chemistry Parts A&B - Carey (Part A) (Part B)
These should be your second books that you read on your trip to understanding organic chemistry.  Part A is a more in depth look at mechanisms, Part B looks into learning a bunch of reactions.  To extend and diversify you reaction knowledge, these books are classics.
3.) Modern Physical Organic Chemistry - Anslyn (link)
This book solidifies your understanding of why reactions happen and give you the most in depth and fundamental understanding to all sorts of reactions.  It emphasizes applying thermodynamics and kinetics to all parts of organic chemistry and helps one to use these fundamentals to explain just about everything.  This book is my all time favorite.  Extremely well written, easy to follow, and it is not riddled with equations like most physical chemistry books are.
4.) March's Advanced Organic Chemistry - March (link)
This book is really more of a general reference more than something you would actually read though.  It's filled with so many references you wouldn't believe!  If you are performing research and are looking to learn more about a particular reaction, this is where you should go.
5.) Greene's Protective Groups in Organic Chemistry - Greene (link)
Another reference book and not something to read through.  But like the title says, if you want to protect something, this is where you go.  There are some great tables in the back that show you around 50 conditions that you could apply to your protecting group, and it will tell you if it is stable or not.  Excellent reference, and another classic.
6.) The Art of Writing Reasonable Organic Reaction Mechanisms - Grossman (link)
If you want to be able to predict mechanisms or brush up on your skills to diversify what mechanisms you can describe, this is a great book.  Like the title says, you will be able to better predict what electron pushing mechanisms are most reasonable to predict what products are most likely to form.

Online Resources:

1.) NMR Chemical Shifts (link)
What a great link this is!  Shows you a wide variety of proton chemical shifts for like a bazillion functional groups with many relevant examples of each.  A gold mine if you are curious about where a new functional group should appear.  Also, clicking the home page link in the upper left hand corner takes you to the home page where you can find even more resources!
2.) pKa Table (link) and for Heterocycles (link)
Here are the pKa's of a variety of different functional compounds from where you can predict how acidic something is.  This is the broadest table I have seen and it has been very useful so far.  The second link specializes for some common heterocycles.
3.) Bond Energies (link)
If you want to get a rough idea of how favorable your reaction is, a very simple way to rationalize things are with bond energies.  This is a table that shows you how strong bonds are.  If your products contain higher bond energies, they have stronger bonds, then they are thermodynamically stable, and likely to form.
4.) Elemental Properties (link)
Here you can find any physical property you want for you molecule.  Constants such as Young's modulus, enthalpy of formation, standard entropies, heat of fusion, etc.  You name it, this site has it.

*Note: The best way to find the property you want, is to click on the element you want to learn about (for bond energies, you can click on either element in the bond) and then to look for the link on the right panel that says "Find a Property".  From here, click on the property you want.  The left column defines the property, but the right hand column shows the actual physical data.
5.) Encyclopedia of Reagents for Organic Synthesis† (link) 
This reference lists properties and common uses of tons of different reagents.  So if you are curious about why a reagent is used, or in what reactions it is used, an excellent reference.  I use it frequently in my posts.
6.) Rules for Predicting UV Absorbance (link)
If you want to predict how UV spectra change upon changes in an aromatic system, this website has the rules.  Woodward actually helped to empirically determine these rules :)
7.) What to Dry Solvents With (link)
If you need a dry solvent but are not sure of reagents that are compatible, or what is the best way to dry it, this website has a table with the popular ways to dry a wide variety of common lab chemicals.
8.) Solubilities (link1) (link2)
If you need to know the solubility of a substance, these two links are good places to look.  They give accurate information about the solubility of a substance.  The first link is most easily searched through the google doc on the first page.  The second link works best when searching by CAS number.  Excellent reference I think, and this data should be more available.
9.) Reaction Finder (link1) (link2)
If you want to know what a particular reaction is or what it involves or even if it has a name, these next two links are useful for identifying, but perhaps not for learning more about it.
10.) Journal Abbreviations (link1)
A search engine where you can search from abbreviation to the journal name, or vice versa.
11.) Functional Group References† (link)
The page hosts links to common chemistries of a variety of functional groups.  Very useful if you want to learn more about chemistry of one particular functional group.
12.) Organic Syntheses (link)
A entire collection of the detailed reaction and workup procedures for a variety of compounds.  For me, I just enjoy browsing through these from time to time to learn more about the workup procedures, and to understand what each step in the work up accomplishes.
13.) Organic Reactions† (link)
It gives great detail about the mechanism, side reactions, etc.  To fully utilize this resource, you can navigate the book from the left toolbar, where you can search by structure, title, or reaction type.
14.) Merck Index† (link)
This index is a classic.  So many properties and references of a variety of compounds including their melting points, descriptions, properties, and often solubilities as well.
15.) Reaxys† (link)
An alternative to the popular Sci-Finder reaction search, you can search a reaction or even a structure to search for actual procedures for the reaction, or procedures to synthesize a compound.  Provides references to the actual papers used, just like Sci-Finder.

† = academic access needed

Total Synthesis Strychnine - Step 13 and 14

The next steps in the synthesis involve preparing the molecule for the desired Dieckman Condensation that was expected to occur previously.  Since we have now removed the offending N-tosyl group, this should be accomplishable.  What we have done in this process, however, was also hydrolyze the esters to their carboxylic acids.  Our next goal will be to re-obtain the esters as such a condensation cannot take place with the acids.  This is because under the basic conditions required deprotonate the carboxylic acids, we form a resonance stabilized carboxylate anion which makes deprotonation of the alpha hydrogen unlikely.  To accomplish this, diazomethane is the gold standard reagent for methylation of carboxylic acids.  Additionally, we will also need to re-protect the nitrogen that previously held the N-tosyl group so it does not interfere with future steps.  While accomplishing both of these tasks may seem like a lot of work, actually these modification are quite simple and both can be accomplished in one day.  Taking a look at Scheme 1 below, here are the steps we are going to accomplish.

Scheme 1. Acetylation of the secondary nitrogen followed by methylation with diazomethane.

Overview:
Acetylation of Nitrogen
The first step is the acetylation of the secondary nitrogen.  Why must we add this group?  Well, I suppose there are two possibilities, which we will see only one of which will be relevant.  The first possibility is that if we did these two steps in reverse (that is, diazomethane first, then acetic anhydride) that we may methylate the secondary nitrogen.  Actually, this is not the case.  While diazomethane is a strong methylating agent, it is really only very active in this role once it has been activated with some sort of acid, whether it be the typical bronsted acid, or a lewis acid.  Amines, amides, and alcohols in this compound are not able to attack the diazomethane because they lack a strongly acidic functionality, and so we are not worried about these side reactions.  While one may conceive that the carboxylic acids may make the solution more acidic which could lead to side reactions, once the diazomethane is activated, it becomes so reactive that it has no time to diffuse away before reacting with the carboxylate ion.  For this reason we do not see diffusion of the activated diazomethane to other regions of the molecule.  The second possibility then, is that this amine may react with future steps in the reaction.  For instance, two steps from now we will be using tosyl chloride again, which would react with the secondary nitrogen.  It is really for this precautionary reason that we are protecting the nitrogen with acetic anhydride.  This reaction has been covered before in Step 9.

Dangers of Diazomethane
For those of you who have never heard of diazomethane, this is not a step in the reaction many of us would be comfortable with.  Why is that?  Well, diazomethane is a toxic, carcinogenic, volatile, and spontaneously explosive gas.  Wow, sign me up right?  It makes sense that for these reasons, you can't go to Sigma and buy diazomethane, it's just too unstable.  So what chemists have to do is make it.  Diazomethane like I said before is a gas, but it is soluble in ether, ethanol, and dichloromethane.  Most typically is is prepared as a dilute solution in ether for safety precautions.  Dilute solutions are less likely to explode, and ether is used because its low boiling point.  Purification of diazomethane after synthesizing it involves distillation.  The closer the boiling point of the solvent is to the diazomethane, the less concentrated the vapors are with diazomethane, which leads to a safer isolation.  So how does one actually prepare diazomethane?  Diazomethane is prepared using specialized glassware that contains no sharp points (such as ground glass joints), as these sharp points can detonate diazomethane (scary).  For this same reason, whenever you want to pipette diazomethane, you must use flame dulled pipette tips to prevent detonation as well.  Two common chemicals used as a precursor to diazomethane are diazald and MNNG.  Under basic conditions, these compound decomposes to give off diazomethane and by products.  If you are still curious about the setup and mechanisms, there is a great resource here.  Typically, however, once the diazomethane is generated, it is co-distilled into the receiving flask with the ether and some small amounts of ethanol (which is the solvent of the decomposition reaction) to create a deep yellow clear solution as shown here.  One can either distill the diazomethane/ether solution right into the reaction to use it up right away, or one can store the solution for a while in a freezer (but this is not recommended).  It's best just to use what you need, but the temptation is to make a lot of it at once so you don't have to make it again.  Lastly, when one makes diazomethane, what safety equipment should be used?  Thick gloves, goggles, lab coat, and most importantly, fume hood as well as extra protection with the use of a blast shield.  There are a lot of stories about diazomethane which you can read about here, and it more than clear why all of this is needed.

Mechanism:
Since I had covered the acetylation previously, I will discuss only the methylation reaction.  The reaction of diazomethane with a carboxylic acid is shown below.  You will see why alcohols and amines are not acidic enough to form the activated species, so these functional groups do not react unless a lewis acid is added.  This is why the reaction is allowed to proceed in methanol as the solvent.

Figure 1. Mechanism of diazomethane with a carboxylic acid.

We can see that with the resonance structures there could be two competing sites of protonation from the carboxylic acid, the carbon or the nitrogen, both of which carry a partial negative charge.  If the terminal nitrogen is protonated, it leads to no stable product and so is likely reversible.  What drives the reaction forward is protonation at the carbon.  This creates a strongly electrophilic carbon which reacts with the poor to moderate carboxylate nucleophile.  This displaces nitrogen gas which bubbles out of the solution and drives the reaction forward.  That is what makes this reaction so efficient is that product leaves immediately after the desired reaction takes place effectively forming a sink into which more and more reactant falls into.  It also makes it easy to determine when the reaction is complete.  Just drop in diazomethane until no more gas is evolved.  At that point one knows that they have added either just enough, or a little too much.  The excess diazomethane in the solution is then destroyed using acetic acid, which undergoes the exact same methylation reaction to form methyl acetate which can be easily evaporated away.

Workup:
Acetylation
The first acetylation step involved mixing the starting material into a solution of pyridine, and slowly adding acetyl chloride.  This is slightly exothermic and so the solution is usually cooled, however, in this case it appears that it was not.  After 1h reaction, water was added, and after half an hour, then the solution was evaporated.  As to why Woodward waited the 30 minutes before evaporating is odd.  I have used pyridine once, and in my attempts to remove it, I did notice that upon letting it stir with water for a while did aid in the removal of the pyridine.  Perhaps the water helps to break up some of the pyridine salts and dissolve them establishing an equilibrium between the protonated and deprotonated pyridine.  Water also forms an azeotrope with pyridine, boiling at 92˚C which may also aid its removal.  The dried material was rinsed with ether to get rid of any oily material, possibly extra acetyl chloride or acetic acid, both of which are soluble in ether.  After this, dissolving the remaining material in hot water (remember, we have a dicarboxylic acid at this point, but the rest of the molecule is hydrophobic, thus it may take hot water to dissolve the compound) and acidifying with acid precipitated the protonated di acid as yellow crystals.

Methylation
The material from the acetylation was dissolved in methanol (which to me is surprising, as I would not expect it to be very soluble in methanol, but anyways) to which a fresh, cooled solution of diazomethane was added dropwise until no nitrogen was seen to be evolved (even Woodward practiced the use of fresh diazomethane and not storing it in the freezer).  He let the solution sit in the cold for an hour to allow complete reaction, and then added acetic acid to quench any remaining diazomethane in the solution.  One thing I would like to point out as well, is that we likely now have excess acetic acid in solution as well if we are sure to destroy any remaining diazomethane.  We use acetic acid for two reasons, one, it reacts with diazomethane to form volatile by-products, and two, it is also slightly volatile, and can be pumped off under high vacuum.  Thus, after quenching with acetic acid, the solvent was vacuumed to dryness.  Then, Woodward dissolved the residue in a small amount of ethyl acetate (a small amount because it is likely very very soluble in acetic acid).  The next steps involve adding diethyl ether, followed by cyclohexane.  Why did Woodward do this?  These are poor solvents for our compound as they are both non-polar, with cyclohexane being the most non-polar of the two.  Essentially Woodward is doing somewhat of a crude recrystallization by adding poor solvent.  This doesn't mean he adds both of that very very fast, but in fact, he likely added these slowly, likely drop-wise.  How does he know when to switch over from ether to cyclohexane?  Once no more crystals appear while adding ether, he probably switched to cyclohexane to get any last remaining product out.  So the real recrystallization mixture is really ethyl acetate/ether.  This is in fact the solvent system that Woodward used afterwards to attempt to gain a more pure product, but in fact, it was identical to the crude precipitation/recrystallization.

Next Steps:
Now our molecule is set up to perform the Dieckmann Condensation that was desired this entire time.  As we will see, this is accomplished by adding base, and allowing the condensation to take place.