Tag Archive | pyrrolidines

Just look at the structure of this alkaloid!

Sometimes you just have to step back and marvel at the structures that are found in nature.  Check out zamamiphidin A, a new manzamine alkaloid isolated from an Okinawan sponge by J. Kobayashi and co-workers (Organic Letters).  Heptacyclic.  Quaternary ammonium.  Massively bridged.  Well done, sponges!

Zamamiphidin A

Saturated nitrogen heterocycles by intramolecular CH amination reactions

Here’s a process that I think needs continued attention from the synthetic community:  Making saturated nitrogen heterocycles from simple N-alkylamines by intramolecular CH amination reactions.  There’s a lot of great chemistry out there for related process where there is an electron-withdrawing group attached to the nitrogen within the tether (vide infra), but let’s focus on N-alkyl groups.  With all the activity on CH functionalization chemistry in general, I hope this reaction will become routine at some point.  Let’s take a look at some recent work in this area.

The basic CH amination reaction

The Hoffmann-Löffler-Freytag reaction – An medicinal chemistry application

To exemplify the need for such a reaction, consider the compounds shown below, appearing in a recent J. Med. Chem. paper by McClure and coworkers at Pfizer.  The diazatricyclodecane (or diazaadamantane) heterocycles in the dotted boxes were proposed as conformationally restricted piperidines that might make good agonists of G-protein-coupled receptor 119.

Pfizer diazatricyclodecanes

The Pfizer group settled on a Hoffmann-Löffler-Freytag (HLF) reaction to form the heterocycle.  In their initial work, they were unable to reproduce Rassat’s route to such diazatricyclodecanes (JACS 1974), which involved heating the N-bromoamine in acid.  Switching to the N-chloroamine led to only 14% of the desired compound accompanied by 40% of an elimination product involving the N-benzyl group.

Initial HLF route

Ultimately, forgoing the protecting group was fruitful.  N-Chlorination of the primary amine shown below was followed by photolysis with a 450 W mercury lamp to provide multigram quantities of the crude cyclization product.  Acylation followed by demethylation of the other amino group provided the key diazatricyclodecane for their studies.

Final HLF route

One curious bit is the chlorination reaction:  The authors do not state how many equivalents of t-butylhypochlorite are used.  This seems rather important, since primary amines are well-known to form dichloroamines.  I’ve contacted to authors, so hopefully we’ll know soon whether they were dealing with the monochloroamine or the dichloroamine. [Update: Dr. McClure responded that 1.2 equivalents of t-BuOCl were used.]

The Pfizer compounds did not pan out, so we’ll never know if their process research wizards would be able to employ the HLF route in a scaleup setting, but I imagine it would be an uphill battle.  If photochemistry is ruled out, I imagine the “acid and heat” HLF would have to be sorted out somehow.

Now it’s easy to see why a more modern CH functionalization reaction with a catalytic transition metal would be useful, right?

Toward a practical intramolecular CH functionalization reaction

In recent work, Chen (Penn State) and Daugulis (U. Houston) and their coworkers have independently described palladium-catalyzed picolinamide-directed intramolecular CH amination reactions:

Chen + Daugulis insertions

This seems like an excellent strategy, and I look forward to seeing where this research will go.  How about metal-free, light-free, halogen-free versions?  There’s a worthy goal!

[Edit: More Chen goodness covered by See Arr Oh at Just Like Cooking: Remote alkylation directed by PA groups.]

Finally, I’d be remiss if I didn’t mention the extensive work in the literature on intramolecular aminations using nitrenoids that are substituted by strong electron-withdrawing groups (DuBois, Sanford, Davies, White, Lebel, Panek, and others, leading reference here).  It’s a bit different from what we’re talking about here, since the electron-withdrawing group ends up in the tether, making cyclic sulfamates, carbamates, and the like.

By the way, if you’re interested in this topic, you might also look at some nice recent work by Tom Driver at UIC, who is using aryl azides as the nitrogen source for metal-catalyzed intramolecular CH aminations.  His paper is also a good entry to the literature of CH aminations in general.

A beautiful synthesis of (+)-pseudococaine

You might recall my fascination with cocaine (no, not for that reason), which culminated in a total synthesis of its enantiomer, (+)-cocaine, using our 2-azaallyl anion chemistry (Mans and Pearson, 2004, blog post here).  Davies and co-workers at Oxford have now published a short and elegant synthesis of (+)-pseudococaine, a diastereomer of natural (-)-cocaine.

The key step is a highly diastereoselective transannular iodoamination with concomitant N-debenzylation by iodide ion to produce the tropane skeleton:

It’s worth pointing out that intramolecular iodoamination reactions of simple primary and secondary amines can be problematic due to N-iodoamine formation and subsequent shenanigans, including potential post-cyclization aziridinium ion formation.  Davies’ reaction is well-behaved, since transannular iodoaminations are especially favorable, the amine is tertiary, and the product is not susceptible to aziridinium ion formation.

The cyclization precursor is made by a very nice sequence involving conjugate addition of a chiral lithium amide to an enoate with subsequent in situ trapping of the enolate by a diasteroselective aldol condensation (7% of the other aldol diastereomer is not shown).

Nice work!

Cyclodehydration of amino alcohol derivatives – Acid catalysis vs Mitsunobu

In principle, the acid-catalyzed cyclodehydration of amino alcohols is an attractive way to make saturated nitrogen heterocycles since it avoids having to make the alcohol into a leaving group such as a halide or sulfonate.  And acid is cheap.

Unfortunately, this reaction doesn’t work well for underivatized amines because the amine is converted to a non-nucleophilic ammonium salt.

Enter the Mitsunobu reaction, which works quite well with simple amino alcohols (despite their low pKa) as well as their derivatives (amides, sulfonamides, etc.)  The literature is filled with examples of such intramolecular Mitsunobu reactions.

However, if you play your cards right, acid-catalyzed cyclodehydrations can be practical and even preferred over the Mitsunobu method.  The rule of thumb is that the alcohol should be able to form a reasonable carbocation.  Park and co-workers recently published a nice example that compares these two methods in the context of 2,3-disubstituted indoline synthesis.

An attempted Mitsunobu reaction on the amido alcohol shown gave the indoline in low yield; the major product was elimination of water.  Resorting to aqueous HCl in dioxane afforded the desired indolines in good yield with a small amount of elimination.  Inversion at the secondary alcohol was observed.  Substrates with a secondary benzylic or allylic alcohol worked, whereas those with a secondary alcohol (or an electron-poor benzylic alcohol) failed.

The authors propose a rather implausible nitrogen-complexed cation intermediate and don’t speculate on the why acid catalysis beats the Mitsunobu reaction.  I suspect it’s related to leaving group ability and subtleties wherein the amide carbonyl oxygen is involved in a balancing act between assisting the departure of the leaving group by neighboring group participation (for hydronium ion) and acting as an internal acceptor of the benzylic proton in an E2-like mechanism (for oxyphosphonium ion).  Your thoughts?

The starting materials were made by a diastero- and enantioselective reaction of the sparteine-complexed dianion shown below.  While the authors don’t show it this way, I’ve taken the liberty of drawing the organolithium as internally complexed.  It is believed that the benzylic organolithium equilibrates to the most stable diasteromeric sparteine complex, which then reacts with inversion of configuration with aldehydes to give the desired secondary alcohols in good yield with high er and dr.  As a reminder, most configurationally stable organolithiums react with retention of configuration, but it’s not a certainty; there are numerous examples where inversion is observed.

In summary, if your alcohol is reasonably capable of ionization, the acid-catalyzed method is worth a shot.  Otherwise, the Mitsunobu is generally a nice way to make saturated nitrogen heterocycles.  Of course, classic chemistry involving halides and sulfonates is also viable if you don’t mind the extra work.

Heterocycles via alkyl-Heck-type reactions

How do you make saturated heterocycles via construction of the 3,4-C-C bond?

Erik Alexanian and co-workers at UNC have just published a nice report on the use of alkyl iodides in intramolecular Heck-type reactions, producing oxygen and nitrogen heterocycles by such a bond construction.  This is a significant result for several reasons, so let’s take a look.

A bit of background on this bond construction

You have a few basic choices as indicated in the electronic disconnection shown below, where ionic and radical chemistry are considered.

While there are examples of each, this general disconnection is usually not a first choice.  β-hetero anions are prone to β-elimination; β-hetero cations may cyclize onto the heteroatom, and β-hetero radicals… well, they involve radical chemistry.  Though having said that, β-hetero radicals are some of the best radical cyclizations out there, adding to tethered alkenes at rates higher than the benchmark 5-hexenyl radical.

The most powerful way to make this bond involves organometallic chemistry, generally involving two unsaturated sites (Heck chemistry, ring-closing metathesis, eneyne chemistry).  But what if we want one partner to be an sp3 carbon?  Specifically, what if we want to do a transition-metal-catalyzed reaction where a metal resides on the sp3 carbon?

Enter the Heck reaction

The classic Heck reaction comes to mind (hey, Nobel Prize and all), but primary organopalladium species tend to β-eliminate before they can cyclize (if there is a suitably-disposed β-hydrogen).

In 2007, Firmansjah and Fu reported intramolecular alkyl-Heck-type reactions in carbocyclic systems by tinkering with the palladium catalyst, finding that the rate of cyclization could beat out β-hydride elimination.  However, the reaction appears to be limited to primary halides and terminal alkenes.

The current work

Now, Alexanian and co-workers have shown that the alkyl-Heck reaction can be accomplished with good old tetrakis(triphenylphosphine)palladium.  Below you can see the use of a primary iodide with a tethered alkene, producing hexahydroindoles in good yield.  A variety of alkene types are tolerated. Note the use of 10 atm carbon monoxide; more on that later.

In contrast to Fu’s work, which was believed to involve a two-electron oxidative addition of the palladium(0) into the C-halogen bond, Alexanian has evidence that the UNC chemistry proceeds via one-electron chemistry.  Hence, single-electron transfer (SET) from the Pd(0) to the alkyl halide results in C-I bond cleavage to produce a β-hetero radical, which cyclizes and captures Pd(I)-iodide to give the organopalladium intermediate shown.  Normal β-hydride elimination, the last part of a classic Heck cyclization, then ensues.

It’s interesting to note that carbon monoxide is required for primary halides to work.  But secondary halides don’t need it, as shown below. [Edit – Second structure revised to correct missing oxygen.]

This is some promising work for sure, providing a nice alternative to known methods involving more classical radical conditions.  Let’s hope the Alexanian group will be able to tune the reaction a bit to make it as practical as possible; it would really fill a niche.

Happy holidays, everyone!

Hooked on heterocycles

I have a question: How did you get hooked on heterocycles?

I’ll go first:

A failed exam, cocaine, and a crusty chemist:  How I came to love heterocyclic chemistry.

I became an azaphile during my undergraduate days at UNC-Chapel Hill, a process that involved failing a final exam, becoming enraptured by the chemistry of lysergic acid, morphine, and cocaine, then being turned down for undergraduate research.  Well, initially at least.

At some point, anything with a nitrogen atom in it became fascinating, especially if the nitrogen was in a ring.  Everything else started to look… bare.

How did this happen?  I can trace it back to Professor Robert L. McKee, a “heterocyclic chemist’s heterocyclic chemist” at UNC.  He’s no longer with us, but he’s worth a tribute, as you’ll see.

You know those dreams where you’re not prepared for the final exam?

I had Professor McKee for two classes, one that proved traumatic, the other enlightening, both being important to my baptism into heterocyclic chemistry.

First, the trauma.

I walked into the final exam for McKee’s second semester organic chemistry class with a strong A average and a lot of confidence.  I loved the class and had studied hard for the final.  But my confidence quickly faltered as I found out that he had made two final exams, one for those with an A average and one for everyone else.  Huh?

I sat down and looked at it, and there were all these crazy rings with nitrogen atoms sprinkled all over them, none of which I’d never seen.  And the questions were unintelligible.

I walked to the front of the room to ask what was going on, and Professor McKee told me that the “A” students were supposed to have read Chapter 10 on Nucleic Acids on their own, for the exam, which would be entirely on that topic.  I had somehow missed this announcement, despite attending every single lecture.

I sat back down and tried, but I couldn’t answer a single question.  I got maybe ten points.

My “A” became a “B”, which McKee told me was generous.

I still get sweaty thinking about this.

Nonetheless, it exposed me to purines, pyrimidines, nucleosides, and nucleic acids, prime denizens of the world of heterocyclic chemistry.

Ironically, I would end up as VP of a company that specializes in nucleic acids chemistry some twenty-five years later.

I’d like to see that exam again.

Onward to enlightenment…


With my tail between my legs, I enrolled in UNC’s advanced organic chemistry course, taught by none other than my beloved Professor McKee.

Things went much better this time.

We used Noller’s Advanced Organic Chemistry, an old textbook even back then.  I loved it because it had plenty of history and was rather descriptive in its approach.  It was also heavily slanted towards heterocyclic chemistry.

What I remember most were McKee’s lectures on the chemistry of lysergic acid, morphine, and cocaine.  These were beautiful molecules and came with such rich chemistry.  I can’t say I remember much else from the class, but that was enough; I was hooked on heterocycles.

It felt empowering to know something about the drugs that were making the rounds back then.  Even more exciting was the realization that powerful physiologically-active substances can actually be synthesized.  From scratch!

Pearson/Mans synthesis of (+)-cocaine

I remember sitting on the bed in my dorm room at UNC with a ball-and-stick molecule of cocaine, thinking, “I wonder how I might make this?”  Not because I wanted to use it or sell it, mind you; just because it was beautiful.

Fast forward to 2004, when Douglas Mans, a talented graduate student in my research group at the University of Michigan, synthesized (+)-cocaine, the enantiomer of natural (-)-cocaine.  Full circle.

Do you really want to do undergraduate research with this guy?

Sometime during this period, my budding interest in heterocyclic chemistry led me to stop by McKee’s office.  It was attached to a one-man lab, and since he was getting near retirement, he no longer had graduate students.

I was struck by the dark, archaic lab crowded with hundreds of vials of crystals, each labeled with hand-drawn structures of unique heterocycles.  I could swear there was also a retort containing some bubbling liquid.  I wanted to get in there and make something!

A few things concerned me, though.

First, he smoked a pipe.  In the lab.  Not good.

Second, he tasted all of his compounds.  Even as a neophyte, I knew this couldn’t be a good thing, and I quickly made an association between this practice and the various growths I could see on his skin.  He was old-school though, and taste was part of compound characterization.

Despite my misgivings, I asked this kindly, crusty man if I could work for him.  His response was quick:  “If you want to do research and continue on to graduate school, you need to go work for someone other than me.”

He suggested Ernest Eliel, whose area was stereochemistry, a topic I also loved.  I joined Eliel’s lab, where I managed to get some heterocyclic chemistry in:  We published the first example of neighboring group participation involving a four-membered ring sulfur intermediate, a thietane.

And we used Barry Trost’s method for making the thietane intermediates, relevant in that I ended up getting my Ph.D. with Barry at Wisconsin, working on… things with lots of nitrogens!

So, how did you get hooked on heterocycles?