Satori Makes Good (Steroids)

Whether it's because of the evergreen interest in Carl Djerassi, the discovery of a (new-to-me!) blog, or Percy Julian's recent Google Doodle, everything in the blogosphere seems to be coming up steroids.

Take a peek at these back-to-back OPRD articles, both from chemists at the former Satori Pharmaceuticals.

As a "cub blogger" for CENtral Science, I still remember gaping at how radically different their root-derived phytosterols were from the rest of the anti-Alzheimer's medicines. Now, almost a year to the day after Satori shut its doors, we have some insight from the team responsible, just before they scattered to the winds.*

So, that means 6.99 tons of plant waste to dispose? [rubs eyes]
OPRD, 2014 ASAP

To access their preclinical candidate, Satori scientists first needed a reliable supply of the glycosylated intermediate. Enter seven metric tons of dried black cohosh, a traditional medicine used as a pain reliever by Native American healers. A third-party vendor crushed the root and sent it to another firm, where they extracted it with ethanol, passing about 300 kg of "solids" back to Satori. Suspension in brine / DCM partitioned the desired compounds into the organic phase, which was treated with triethylamine and catalytic zirconium tetrachloride. This ejects the pesky E-ring alcohol, and the resulting compound performs a net oxidation to yield a diastereomeric mixture of ketones (above).


(Warning: I guess you haven't lived 'til you've purified 70 kg of crude, brown extract with DCM over silica...yuck!)

So, once Satori had in hand ~11 kg of compounds 1 + 2 (see right), they needed to advance the structures to their desired candidate (below) which you'll notice has a few little changes from the plant-derived drug. Gone are the acetyl group. Reduced is the ketone. Ripped apart is the sugar, making way for a morpholine.

The scientists' first-gen synthesis, an 8-step sequence, wasn't up to snuff for kilogram work. The trouble? Too many chemically similar hydroxyls, prompting some protecting group manipulation to target one or two selectively. Process work on the ethyl ether step - utilizing diethylsulfate / tert-butoxide in place of an earlier NaH / EtI mix - allowed a telescoped 5 step route, cutting out 2 silica gel columns and upgrading the final process purity to >95%.

Interestingly, the authors, ever circumspect, reflected on the limitations of their final process:

"While this reported route was sufficient to provide the kg-scale quantities of target compound for preclinical studies, we acknowledge that it has limitations that would make it impractical at the 100 kg scale."

Silica gel chromatography strikes again! Still, their candidate came through on 1 kilo, at about 30% overall yield after HCl salt formation. Not too shabby.

Update (5/30/14): Want to see how Satori chose these molecules? One of the authors (Hubbs) writes in to recommend their 2012 J. Med. Chem. optimization paper.

*According to the author lists, everyone on the team ended up in a different place: Enanta, AstraZeneca, Celgene, ETH, Genzyme, Resilientx, Sanofi.

Parsley, Sage, Rosemary and...Moringa?

I wrote this post for the #foodchem carnival, hosted at CENtral Science. Thanks again, Rachel!

Ahh, November! Chilly winds, smells of wood smoke in the air - along with the start of the NFL season - mean it must be near time to celebrate Thanksgiving. Don't know about you, but this season calls to mind three heartwarming, folksy tunes:

1. "We Gather Together," almost the banner song of the Pilgrim Hymnal.
2. "Alice's Restaurant." Yes, it's hokey and hackneyed, but darnit, it's a tradition! And #3...

Are you going to Scarborough Fair?

Parsley, Sage, Rosemary and Thyme |

Remember me to one who lives there

She once was a true love of mine.

Simon and Garfunkel, 1966 (and a bunch of Scots-men* and -ladies afore that). The haunting imagery of so many aromatic spices brings me back home: warm cardamom, sweet cinnamon, dark clove, tangy lemongrass. Certainly chemistry enough to wet your whistle: each spice carries a wealth of compounds to cure whatever ails you. Rosmarinic acid (sage, rosemary) for neuroprotection, thymol (thyme) to ward away bugs, trimyristin (nutmeg) for skin creams, or menthol (mints) to dull the pain.

Rosmarinic acid. How come all the good plant
products have Michael acceptors?
Credit: Wikimedia Commons

Speaking specially for the parsley (one of my favorites), I can tell you that its dried leaves contain more iron than just about any other spice; we verified this by thiocyanate titration in undergraduate lab. Since then, I've admitted to placing parsley on just about every food: breakfast, lunch, or dinner.

Moringa leaves, drawn using moringa leaves!
Credit Jenna Turner, NGM

Every decade seems to have a spice of choice for the medically inclined. Ginseng (memory loss) ruled the eighties, followed by curry powder (anticancer) in the '90s, then green tea and later pomegranate juice (antioxidants). Well, make way for a new spice on the block: moringa. According to this month's National Geographic, moringa leaves, which hail from India, may pack more nutritional punch than any of your standard spices - high in iron, calcium, potassium, even protein. I'll wait 'til I see it on menus at local restaurants, but it's always fun to speculate what the next "in" food will be.

A restful and Happy Thanksgiving to all.

*It's come to my attention in proofs and comments that the song in fact hails from Yorkshire (Northern England), meaning I've just alienated roughly 1/4 of the British Isles. My sincere apologies; perhaps next time Simon and Garfunkel reunite, they can sing Loch Lomond or something....

The Chemistry Popularity Conundrum

Last week (October 16-22) was National Chemistry Week in the US. Did you celebrate? By all rights, it could have been the biggest one yet, since we’re deep into the tenth month of the International Year of Chemistry (#IYC2011). Did you see any news specials? Did Time or Newsweek run an exposé?

Credit: time.com

Probably not, but why not? When scientists cracked the human genetic code, front pages everywhere relayed the tense horse-race between Venter’s TIGR and Collins’s Human Genome Project. Whenever physicists flip the switch at the Large Hadron Collider, the public dreams of mini-black holes and cheating Einstein’s relativity. Chemistry, however, always seems to be the black sheep of the gang; DuPont’s slogan for nearly 50 years was “Better Things for Better Living . . .Through Chemistry,” until the final portion of the tagline was dropped in the mid-‘80s.

What creates the chemistry image problem? It’s true that many of the “pure chemistry” accomplishments of the last 30 years have gone largely unnoticed: ask someone at a local restaurant about triblock copolymers, organocatalysis, brevetoxin, or dye-sensitized solar cells. Applied chemistry fares a bit better, from polymers to paints, lasers to ligands, but the public still attributes many interface discoveries to other fields – drug chemistry gets lumped into “Health and Medicine,” or water-splitting tossed in with “New Energy.”

Don't let the test-tube on the front fool you.
Credit: amazon.com

The phenomenon even reaches general science books. On a whim, I opened up National Geographic’s The Science Book (bonus tagline – Everything You Need to Know about the World and How it Works) at a book store last week. A hefty volume, coming in at 432 pp., thus you might expect the “central science” to occupy at least 30% . . . right?

Wrong. Page count: biology, ecology, and sociology – 142 pages.  Physics, math, and ‘technology’ – 111 pages. Chemistry? 26 pages.

Total.

Does this all come down to poor public relations? Biology sells itself on some big questions: origin of life, evolution, ending disease, and genetic engineering. Physics moves out onto an even wider plane: does God exist?, fundamental particles, dark energy, string theory, and black holes. Ask most people about the word chemical, however, and their connotation is tangibly negative, associating the word with poisonous, pollution, ersatz stand-ins for “genuine” flavors or fragrances, artificial, corrosive, or toxic.

Prof. David MacMillan, Princeton

Not that none have addressed the issue – just recently, David MacMillan, editor of Chemical Science and accomplished organic chemist, called for increased outreach:    

‘One major thing chemists need to work on is their ability to promote their work to other scientists and the public. This is something we are really not good at in general and if we improved, it would really open doors for us and improve society’s perception of chemistry and its impact.'

ACS attempts much the same with their Chemistry Ambassadors program, and the Interactive Periodic Table of Videos surely adds some demonstration “Wow!” factor. But the days of science-themed programs (Mr. Wizard, NOVA, How it’s Made, even the tongue-in-cheek Look Around You) seem to have waned, and Mythbusters can’t save the whole genre single-handedly. Linus Pauling, Noam Chomsky, Carl Sagan, Stephen Hawking, Steven Pinker, E.O. Wilson, and Oliver Sacks have held down much of the science PR fort, but we still haven’t found the next great chemistry “populizer.” So, what are we to do?

Can these guys hold down the science program genre forever?
Credit: dsc.discovery.com

Well, I’m not the first to tackle this question. Luckily, many have gone before me: see Dr. Free Ride’s post on Scientopia (“navel-gazing” sounds so apropos) or the CHEMisperceptions Blog Roundtable from early 2011 hosted at ScienceGeist. Start there, and glance through the situations and stories these authors present. See where you stand.

And think. Just think.

Think about how you’ll answer the dreaded “So, what do you do?” question at the next holiday party. Think about a show you wish were on TV, DVD, or radio that covered breaking-edge reactions or materials, but isn’t. Think about how you might tell such a story. Think about what types of jobs you, as a chemist, might envision working in 10, 20 years . . . if they even exist right now! Think of the reactions, equations, elements, polymers, or drugs (heh) that really ‘get you up’ in the morning.

When you’ve thought awhile, narrow down your list to one or two things you truly enjoy. Write a short blog post or a newspaper article. Send an email. Take some pictures. Tell your kids. Teach a short course. Write a book. Produce a show. Anything you can do that creates new, high-quality content to help improve the stead of science in the world will do.

Idealistic?  Sure.   

Dreamy?  You got me.

Possible?

. . . I’d like to think so.

(Note: You don’t have to start from nothing - there’s quite a few folks already working on the problem. For general chemistry blogs, start at CENtral Science. Work your way around to Chemistry Blog, Discover Magazine, SciAm Blogs, and Popular Science. Chemjobber, The Curious Wavefunction, and ChemBark help capture some of the current chemical zeitgeist, while Totally Synthetic and BRSM cover my favorite topic, chemical synthesis. For health and medicine, try In The Pipeline or The Medicine Show. Want books? Napoleon’s Buttons, The Poisoner’s Handbook, Mauve, and Uncle Tungsten are a few favorites. On a personal note, although he’s not formally a chemist, Surely You’re Joking, Mr. Feynman! and What Do You Care What Other People Think? helped me appreciate how one can use scientific curiosity to change the world.)

Come On, Allene! The Crabbé Reaction

Readers: This post was written in response to Rachel Pepling’s call for submissions to the IYC2011 Chemistry Carnival over at CENtral Science

Have you ever been in love?

Has a single, chance moment changed your outlook on life?

Did you ever have the burning desire to . . . add one little methylene group to the end of an alkyne?

I’m an organic chemist, and our emotions tend to track directly with the success of our bench work. In my third year of graduate school, I felt down in the dumps.  My methodology project had no traction; heck, I couldn’t even make the (relatively simple) allene substrates I needed in less than five steps! Such was life when, during my group meeting presentation, a voice chimed in from one of the postdocs sitting in the far corner of the room:

“I think there’s a reaction for this.  Haven’t you tried the Crabbé?”

Credit: scenicreflections.com

(At first, I stared agog, since the name made it sound like he was ordering seafood in a fancy French restaurant, so I thought he was joking, but he wasn’t!)

Turned out, there was a “chemical shortcut” to do just what I needed: the Crabbé takes a terminal alkyne under Mannich-like conditions (di-isopropylamine, formaldehyde, dioxane) – with a dash of copper (I) bromide for good measure – and adds a methylene (=CH₂) unit to form an allene (see scheme). Why make allenes, you ask?  The two alkenes in this three-carbon synthon are orthogonal (at a 90^o angle), which twists their pi-electron clouds away from one another. Thus, each olefin can react independently in reactions like metal coordination or electrophile addition.

The reaction mechanism made me scratch my head for a while, just as it did Crabbé’s researchers working at U. Missouri in the early 1980s. These chemists propose that, after the initial Mannich adduct forms, a copper atom wiggles into coordination between the amine and the alkyne. When you crank up the heat, the amine kicks out a hydride (H^-) from an isopropyl group, which then migrates to the copper. This copper hydride spins around, delivers its hydride payload to the alkyne, and kicks out an imine leaving group. 

Credit: Carl Sagan's Dance Party Blog

It’s a fairly chemoselective reaction, meaning you can use it late in the game in a synthesis (assuming your compound can survive heating in dioxane for a few hours with copper!). My favorite part? I enjoy watching the autumnal palette that evolves during the reaction, from birch-tree yellow to maple-leaf red. Different starting materials lend different shades. And, as most organic chemists will tell you, one-pot preps you can set up and forget about are the reactions we love.

Traffic Spike - Hello, New Readers!

Hello!  I see you surfing by, hopefully stopping to read a bit.  Have you come from my good buddy Chemjobber?  Perhaps one of my other writing homes, like CENtral Science or Totally Synthetic? 

Wanted to say thanks for checking out my still-forming blog.  If there's anything you'd like to share, or something you want me to cover or consider, leave a comment.

Thanks.