Today I will be covering the process route of Simeprevir, a leading small molecule antiviral for Hepatitis C. Developed with Jannsen Pharmaceuticals Inc., Rosenquist’s paper highlights many things with SAR and computer aided drug design, and makes a great case study for medicinal chemistry students. One thing not overly emphasized in the paper, was how they moved from a lab scale lead optimization route to a process development route. They make short references that their choices of substitute reagents made things safer in the pilot plant. Given my love for scale up, I think we should talk a little more about the clever process techniques they employed. The route is broken up into 3 Schemes, and the lead optimization route will run concurrent to the process development route to highlight differences.

Before we start let’s contextualize the lead optimization route. Methodology behind medicinal chemistry synthesis is analogous to combinatorial synthesis or large panel screening synthesis techniques. The reactions have to be ubiquitous, work across a wide range of substrates and lend themselves to facile or minimal purification. We can take away is that in order to do this synthesis we need, peptide coupling, a robust method to asymmetrically get to the trans-cylclopentanone dicarboxyllic acid, and a simple way to selectively peptide couple each carbonyl.

Scheme 1: Preparation of The Bicylic Lactone Acid

The Lead Optimization Route:

Starts with a 5 step process to get to the bycyclic lactone acid. They employ unscalable reactions such as a Diels-Alder. Reagents include sodium borohydride (pyrophorric when finely divided).  They employ a clever asymmetric esterhydrolysis using Pig Liver Esterase(PLE). We must remember that PLE isn’t a cost effective method process synthesis, and would require an investment in a pilot scale bioreactor, and the somewhat rare pilot scale biosynthesis production chemist.

The Process Development Route:

The synthesis begins from an unresolved mixture of cyclopentanone 3,4 dicarboxylic acid() cutting out ~3steps from the Lead Optimization Route. They improve, on the synthesis by performing a Raney Nickel Hydrogenation, suspending the product as triethylamine salt in water, and directly lactonizing all in one pot. They perform a kinetic resolution using cinchonidine, and report the solid has a shelf life of at least 3 years.

Part 2: Preparation of The Olefin Metathesis Partners

The Lead Optimization Route:

From the bicycliclactone, the synthesis continues with a HATU/DIPEA peptide coupling off the free acid. keeping with the straightforward and simple synthesis, they perform a LiOH/water hydrolysis to open up the lactone. With the second acid free, they peptide couple to install the cycloproyl. After setting up the metathesis partners they finish the synthesis by using a Mitsunobu to install the aryl substituent.

The Process Development Route:

The process route takes a similar approach, they opt with using 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) and N-Methyl Morpholine (NMM) to peptide couple the n-methyl hexene, citing its relative safety compared to HATU. Next, they get clever with the preparation of ring opening. The lead optimization route ties up the free carboxylic acid with a peptide coupling, remembering triphenylphosphine’s oxophillicty, you can gleam that the process route needed to tie up free hydroxyl of the acid thus prompting the careful methanolysis of the bicyclic lactone acid. The aryl moiety is installed using the Mitsunobu again, with a one pot hydrolysis of the ester, and peptide coupling we get to the identical olefin metathesis setup.

Since it’s not obvious, lets talk about the pot economy and purification methods at for the two routes.

In the lead optimization route, they peptide couple, then hydrolyze in one pot, Acid/Base extraction, peptide couple in a second flask, Acid/Base extraction again, Mitsunobu in a third flask.

The process route, peptide couples in refluxing THF, Acid/Base extracts out the cinchodine, using the organic THF layer, the directly subject it to the methanoloysis (note these extractions can be done in the same reaction flask if they use a jacketed flask). They drain the aqueous layer and extract in toluene. close to dry Toluene layer into a fresh reactor(because DIAD decomposes in water) to perform the Mitsunobu and the product is collected in crystalline form. They hydrolyze the methyl ester using LiOH in the same reactor, and drain out the Aqueous layer, and peptide couple using EEDQ.They likely use Boc anhydride in excess after Acid/Base extracting out the used EEDQ. Herein they must purify the Boc Olefin, and dilute to 0.05M to perform the infinite dilution approach in Scheme 3.

Part 3: Ring Closing Metathesis(RCM) and getting to Simperevir

Lead Optimization Route:

The RCM completes in classic conditions, everyone knows there is substantial schlenck techniques necessary with carrying out a Grubbs Hoveyda gen. 1 RCM. They hydrolyze the ethyl ester off the cycloproyl group to afford an acid ready for peptide coupling.  To activate carbonyl, they cyclize into the oxazolinone, then added the cyclopropyl sulfonamide to reopen the ring, affording Simeprevir.

Process Development Route:

Given the difficulty of getting an RCM to work on the process scale, I direct you a mini-review called Olefin metathesis on the process scale.  They made mention of the process route in Simeprevir. The Simeprevir makes an allusion with “SHD techniques”, “M1 catalyst” the unexplained Boc protection/deprotections of the RCM partners/products.

To get the RCM to work they employed the Ziegler Infinite Dilution. The method hinges on the lemma of competing conversion rates between the RCM product, and oligomerization. Therein, Ziegler et. al show that if the RCM partners are added to a solution of catalyst at a rate identical to its conversion to its RCM product, there will an infinitely dilute concentration of the starting material, and thus oligomerization will be disfavored.

In Higman’s review, their paragraph on Simeprevir, they clear up that SHD techniques meant that the unexplained Boc protection served to increase the concentration at which the RCM partners could be fed into the M1 Catalyst (A specialized ligand for GH RCM) solution. After the RCM, They hydrolyze using NaOH and EtOH, isolating then activating the free carboxylic acid with EDCI in a new flask, likely affording the spiro-oxazolidinone intermediate. Then using DBU to couple the cyclopropylsulfonamide. Simeprevir was collected using a controlled crystallization.

Reflections: What can you take away from this synthesis ?

What can we learn from this synthesis, process syntheses face different issues than traditional synthetic chemists. I think Janssen’s approach embodied the principles of using safer reagents, inventing cheaper methods of enantiomer resolution, and cleverly addressing the longstanding problem of unscalable olefin metathesis. After Simeprevir many other drugs including Paritaprevir(Abbvie), and Telaprevir(Vertex) have come to market using similar process syntheses. I hope to cover them in the next few weeks.

Originally published December 12, 2018

Trost’s synthesis of Aflatoxin B₁, might be a generic synthesis showcasing The Tsuji-Trost Asymmetric Allylic Alkylation (AAA) for a facile prep of the furobenzofuran core. It was a response to the known ways of using enzymatic kinetic resolution to afford their product. This paper goes to showcase Dynamic Kinetic Asymmetric Transformation (DYKAT).

The Synthesis:

The synthesis starts with a Pechmann condensation. The 1967 synthesis also has this step. The coumarin is Iodated to make the handle for the Tsuji-Trost/Heck. The Tsuji-Trost Asymmetric Allylic Alkylaltion sets the stereocenter thus inducing asymmetry for the rest of the synthesis. While not shown in the Chemistry By Design Synthesis, there was supposed to be an intramolecular Heck Coupling. Which completes the prep of the furobenzofuran ring and sets the second stereocenter. The synthesis proceeds to form the cyclopenteneone ring by performing a Friedel-Crafts off aromatic Coumarin scaffold. I questioned here why Trost did a DIBAL-H reduction to afford the vinyl ether instead of maybe a Hydroboration and elimination. This paper talks about accessing different Aflatoxins, which differ based on chirality and substitution on that hemiketal stereocenter. After reduction, the hemiketal is acetylated with acetic anhydride and eliminated to afford (-)-Alfatoxin B₁.

Key Knowledge:

The big addition was taking a racemic γ-tert-butoxycarbonyl-2-butenolide and being able to alkylate asymmetrically. Trost talks about how there was previous work on Kinetic Asymmetric Transformation (KAT), where a chiral palladium complex would form different products depending on the chirality of the substrate. Naturally this facilitates separation of the junk product but leaves much to be desired with a cap at 50% yield. Trost shows a DYKAT where the activated palladium interconverts between from the “mis-matched” to “matched” coordination and likely is caught in transition state “valley” until the substrate is in this matched state.

Taking a look at the arguments presented for the facial interconversion mechanism, I was not impressed that they didn’t get definitive proof for their conjecture. The proposed a Ligand displacement hypothesis, and a furan aromatization. Their proof was that the yield decreased with increased palladium, which meant that the sigma complex was the favored one.

I think a better proof would have been to lock out migration by probing the change in EE with the binding of a Lewis acid. Or attempting to run the reaction in the presence of a Mukiyama silyl enol ether. Other options include, having a chiral alkyl group for the γ-acyloxybutenolide, and seeing how the enantiomeric excess changed. But I think this may not have added much to the already deep knowledge of the Tsuji-Trost reaction umbrella.

Reflections:

Thinking about the disconnects and my lack of instinct when it came to this synthesis, brings to light that I don’t have a flair for syntheses that hinge on transition metal chemistry outside the classic model systems. This synthesis reminds me that you can guess what kind of chemistry to expect, based on the difficult disconnects, the author, and the history of the class of compounds.

Originally published: November 12, 2018

Looking through my old synthesis diary I played a game where I could make a fast route to THC. I was quickly disappointed when the best I could reasonably do was 9 or 10 steps (6 after revising and reading different syntheses Trost, Evans, Pinnick’s).

1. Alpha Bromination of Orange Flavor Ether using NBS and UV light
2. MOM Protection of Olivitol
3. In-situ Grignard reagent generation + Palladated Olivetol to do a fancy Kumada Coupling.
4. Total MOM Deprotection
5. Sodium ethyl sulfate Demethylation
6. ZnBr/MgSO₄ mediated S_N

The world record:

Takes simply (+)-p-mentha-2,8-dien-1-ol and olivetol in 1% BF3*(OEt₂) and Anhydrous MgSO₄ in DCM at 273K.

Simply put, Razdan does a retro-friedel crafts using BF₃ etherate as the Lewis Acid, then has acidic conditions to drive the recombination forward. His paper’s goal was to elucidate the mechanism (mind you this was 1974) and had little stereocontrol.

These syntheses show how important starting materials and one’s ability to take advantage of simple reaction kinetics can improve the efficiency of your chemistry. Switching to Organge Flavor Ether from Terpineol saved me a step from my original route. And using olivetol instead of olivtollic acid saved me from doing a Krapcho Decarboxylation. Razdan’s Synthesis was fast because his choice of a relatively obscure monoterpene “(+)-p-mentha-2,8-dien-1-ol”. The terpene had an allyl cation equivalent eager to go through the retro Friedel-Crafts. He shows that all the coupling prep that I did was somewhat unnecessary. So for you next synthesis remember to choose your starting material wisely.

Originally published: November 8, 2018

Today’s synthesis is (+)-Psiguadial B by Sarah Reisman. I urge everyone to check it out, it is a testament to the dedication total synthesis requires. In the paper she details all the failed reaction pathways and the clever model systems that led to development of the final route.

Synthetic pathway high lights:

1. Enantioselective Wolf Rearrangment/Ketene addition using  aminoquinoline and (+)-cinchonine.
2. Hoveyda Grubbs II RCM, and then a Crabtree’s tertiary Alcohol directed double olefin reduction.
3. Copper Cat. Intrmolecular O-arylation.
4. DDQ Oxidation, and Cl’ Phenylation.

Sticking with the Reisman Group theme of transition metal methodology development, we see that this synthesis is mostly transition metal catalyzed reactions. Their key additions were the Wolf Rearrangment chemistry, where they did a simple solvent substrate screen. Their other great aaddition was the Phenylation step towards the end of the synthesis. They talk about it being unclear whether an neutral Phenyl would be a suitable candidate. They achieved a 4.8:1 dr, which is reasonable given that they only examined 3 oxidants for this reaction.

Looking into other syntheses the fastest one I found was done by Cramer in 2017. He uses Caryophyllene to do most of the heavy lifting, and touts a bio-mimetic approach. The 1 step is a multicomponent reaction that would make a great group meeting problem. Thinking about what the role of total synthesis is in chemistry; As a context to develop new synthetic techniques, I think Reisman had the more valuable synthesis. I think further exploration into the enantioselective Wolff rearrangement has a lot of merit since photochemistry, has historically been difficult to employ asymmetrically.

Originally published September 19, 2018

Every once in a while I’ll walk through a synthetsis on Chemistry By Design. Usually it’s to find a unique reaction, or to find out how a unique compound was made. Most of the time it will start with me looking at the molecule and seeing the obvious retrosynthetic points, and then walking through the synthesis to see how close I was.

The criteria in which I choose my syntheses is typically:

1. Does it have fused rings or an interesting macrocyclic structure?
2. Is the synthesis less than 20 linear steps?
3.  does it rely on a magic step that was discovered through serendipity?

Toady I will go through ent-Clavilactone.

Retrosynthetic Instinct:

1. 5-member lactonization
2. Sharpless asymmetric epoxidation -> asymmetric induction point
3. Grubbs II RCM.

The True Retro synthesis:

1. RCM
2. Oxidative Lactonization
3. 3-Component Benzyne Coupling
4. Sharpless Asymmetric Epoxidation -> asymmetric induction point

Evaluating the forward synthesis:

Barret’s Synthesis aims to form a constraint 10 member benzoquinone using RCM.  His goal was motivated to study SAR of tyrosine kinase inhibitors. His synthesis uses straightforward chemistry to get to his epoxide and the neat twist is on the 3-component Benzyne Coupling, and his lactone isomerization. He states that he employs Yamamoto’s bulky alumnium Complex [ I did not do it service in the synthesis] to isomerize his lactone. It shows robustness in being able to handle a crude mixture of diastereomers and yield a single diastereomer as a product in 80% yield. After affording his lactone and setting the stage for an olefin metathesis, he optimizes his Grubbs II RCM. The synthesis finished with CAN oxdiation of 1,4 dimethyoxybenzene installed during the 3-component benzyne coupling.

The aim to use this synthesis as jumping off point to evaluate SAR of Clavilactones leaves much to be desired. When designing a SAR your goal is make a generlized and robust synthetic route. Relying on Asymmetric Epoxidation, to set your stereochemistry, and then have it be part of your most complex moiety, makes it inflexible so heteroatom substitution.

However, he does leave optionality along the saturated chain for different alkyl substitutions as long as they agree with Gilman, Grignard Organo Lithium addition conditions.

I enjoyed this synthesis and I welcome any opinion and discussion!