The Realm of Organic Synthesis

INTRO

Below are some thoughts about the Boston ACS conference recently held.  All in all, the meeting was okay—nothing seemingly groundbreaking.  The following updates were written in real time then edited at an Irish pub at 5-Points in Atlanta a day or two later (excuse the grammar in some places as I’ve recently become addicted to Shandys—Harp and Sprite). 

UPDATE

It’s 8:00 am EST, 7:00 am back home and I’ve been up since the crack of dawn after getting ~5 h of sleep last night.  I’ll mention that it is frigid in Boston (for the month of August) relative to the 3 consecutive weeks of 100+ degree temps in the south.  It’s taken me about an hour to learn how to efficiently navigate the conference program, and with that under my belt, I’ve just finished planning out my schedule at a Starbuck’s in Downtown Crossing earlier this morning.  Interestingly enough, I’m not the only one who finds the program somewhat confusing to navigate; the two gentlemen whom I met yesterday had similar problems.  As I figure out the schedule, an event coordinator is informing the room that there are errors with respect to the scheduling info in the program.  I guess bumps in the road are fairly common for conferences.

So, what’s on the agenda today?  Some interesting methodology this afternoon, possibly a session on negotiation techniques, and a definite trip to the expo.  Though, strictly as a synthetic guy, I’m interested in seeing some of the “big dogs”—Boger, Wipf, Baran, Smith—present their recent works on peptide-based natural products.  On a much more nerdlier level (I realize it’s not a word) it’s analogous to a little kid getting to watch Curt Schilling pitch in Fenway.  Sadly, some of the guys I was hoping to see speak aren’t scheduled, though. 

Plus, I’ve been invited to a couple social events tonight to mingle with a couple professionals and “learn how the game’s played”. 

UPDATE

I caught the end of Dale Boger’s lecture on his most recent peptide-based natural product (the name escapes me, and I’m not around my event program at present) and entirety of Phil Baran’s.  (BTW, the short-sleeved shirt Baran wore at his presentation makes it look like he could bench-press a truck).  Keep your eye on his work, as I believe he will blow the field away with his future contributions to synthetic organic chemistry.  Of course, he synthesizes interesting targets but chooses to employ synthetic strategies that embrace functionality rather than masking it (i.e. making use of a hydroxyl group instead of protecting it with a silicon-based group).  This frame of thought is radically different to Corey’s concept of retrosynthetic analysis.  While I’m sure that many professors are currently approaching natural product synthesis from this standpoint, Baran appears to be the front running poster child for such a strategy. 

UPDATE

Why do research advisors change a functionality on their (or someone else’s) already successful ligand/catalyst/methodology (i.e. methyl to a ethyl), parade the results of a 2% increase in yield/ee/de/rate enhancement relative to previous iterations and then market their “achievement” as “novel”?  I’ve just finished sitting through 3 organic presentations and all of them have fallen into this classification (in some way, shape or form).  It’s like Honda unveiling a brand new black Accord that gets 460 mpg, has a killer 5.1 surround sound system, helicopter blades so you can fly to your destination if you don’t feel like driving (at least that’s what I’d want) and then a month later they market the exact same car except now it’s red.  I imagine these are the type of people who played hooky from ethics class in college just to sneak in round of Dungeons and Dragons before going to organic lab.  While I’m on the subject of morality, the idea of passing off percent composition as isolated yield in publishable results is criminal at best.  “Does your catalyst work?”  “Of course it does, we had 100% consumption of the starting material, ergo we’re entitled to a $5 million DOE grant.”  Do you know what also effectively gives you 100% consumption of your starting material?  (Earmuffs, EPA!)  Pouring your reaction vessel down the drain.  If you were to take a gc at t = 0 min, empty out the flask and take another gc at t = 5 min, you’d see that 100% of the starting material was consumed (watch some professor publish these results next week).  I’ve come across about 4 papers in the last month alone that reported results in a similar fashion (2 of which specifically used the word “novel” in the abstract).  

It’s been a few weeks since I’ve updated and with good reason.  I’ve submitted a draft of my first journal-worthy paper to the Boss about 2 weeks ago.  Despite the fact that he’ll probably demolish my text then remodel it to his liking, he claims to have actually liked what I reported.  But, with the success comes extra experiments to “make a stronger paper.”  To make a tired point, I’ve been running extra reactions while teaching a compacted summer course (along with grading duties).  As such, my writing has sadly slowed to a relative minimum; enough whining.  Oh, by the way, thank you to whomever posted a response about my phosphine tirade.  While the comment (for some reason) isn’t posted on the blog, I received notification from email, which prompted me to write a bit about good ‘ole organic.

I broke out an old bottle of copper(I) chloride the other day and ever since I’ve been leaving work with scrimshawed-blue calluses (I never thought I’d actually use that word in a sentence).  It turns out that copper(I), in it’s purest form, is actually colorless and oxidizes in the presence of oxygen to a blue/green copper oxide.  Ergo, as I recently purified CuCl (dissolve in HCl then precipitate the black solution with water until white) without gloves (dumb, I know), the white material I spilled on my hands during filtration eventually oxidized throughout the day.  Surely this sort of information would be extremely useful if noted in Purification of Laboratory Chemicals, but Wikipedia actually bailed me out followed by a cross-check in the Merck Index  (As a brief aside, would anyone else like to see chemical shifts reported in PoLC?)

There’s some really interesting cuprate chemistry that I’ve uncovered in recent literature searches that’s worthy of mentioning, particularly relating to conjugate reductions (an area of recent interest).  Of course, a silent majority of copper is used in conjugate additions (soft-soft interactions to all you HSAB peeps), which includes conjugate reductions using Stryker’s reagent ([Ph3PCuH]6, as seen in Org. Lett. 2001, 3, 1901-1903) or an air-stable hydrosilylating alternative (Yun’s invention, for an example, Chem. Comm. 2005, 5181-5183).  Apart from simply preparing copper hydrides from silanes (Tet. Lett. 1997, 38, 8887-8890), enantioselective variants have crept into the literature in recent years.  Here’s an interesting, yet reasonably appropriate analogy for you: Molander is to samarium chemistry as Buchwald is to enantioselective conjugate additions (check out JACS 2003, 125, 11253-11258 or Org. Lett. 2003, 5, 2417-2420, for example).  As a fairly young and naïve grad student, it’s interesting to know that Buchwald isn’t just about C-N bond forming reactions.

Does anyone know why arylsilanes work better/faster than alkylsilanes in hydrosilylating conjugate reductions?  I’m assuming it’s due to two things: (1) the electron-donating nature of an aryl ring creates a more labile hydride thus allowing for better insertion/ligand exchange with the copper and (2) the b-silicon effect seen in alkylsilanes stabilizes the cationic nature of the silicon atom making the hydride less labile.  Comments are welcome and encouraged!

As mentioned before, there’s a wide variety of conjugate additions in the literature ranging from Mulzer’s morphine synthesis (ACIE 1996, 35, 2830-2832) to Amir Hoyveda’s recent enantioselective methodologies (Org. Lett. 2007, 9, 3187-3190).  In all of the literature I’ve encountered, very few have yet to optimize an enantioselective conjugate addition of vinyl groups, which would be unbelievably synthetically useful (ORP ALERT!!!).  Apart from conjugate reductions, Evans and Johnson hammered out methodology for enantioselective Diels-Alder reactions using catalytic amounts of copper(II) and chiral ligands at low temperatures (JACS 1998, 120, 4895-4896, for example).

The majority of these reactions (with the exception of the Diels-Alder example) seem to use an excess of reagents and therefore don’t appear to be too environmentally benign.  I recall doing a copper(I)-mediated conjugate addition only to filter off the reagent during workup.  All of that precious, expensive copper gets totally wasted.  (I’ll mention that copper sulfate will complex with pyridine to pull the base out of the organic phase if your workup is acid sensitive).  Even in some of these conjugate reductions, 2 molar equivalents are used (though, it’s been demonstrated in a variety of methodologies that the mechanism is catalytic in copper) and often there’s an excess of silanes (upwards of 4 molar equivalents).  Stryker’s is no better because of the excess of triphenylphosphine, which I imagine is a pain during workup/chromatography.  Are there any benign alternatives to what’s currently out there?  (again, ORP ALERT!)

Anyone else headed to the Boston ACS conference later this month?  I’m trying to meet up with friends and colleagues in the hope of increasing my networking.  Perhaps if I come across an interesting presentation or two I’ll create a post.  Don’t really care about Barry Bonds and his 756* homeruns.  I was ecstatic about the Blue Jays, Yanks game last night when Clemens got tossed for hitting Rios (http://www.youtube.com/watch?v=-HZtiWzgT6s).  As for my Sox, we can start hitting the panic button now…