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Building Our Own Molecular Machines

Let’s talk about enzyme envy. That’s what we organic chemists experience when we stop to think about how every complex natural product in the world is synthesized so much more quickly and efficiently than we can do it. All those crazy multiple rings systems, those bizarre heterocycles, huge macrolides, and dense arrays of stereochemistry are cranked out at ambient temperature, under aqueous conditions, on a time scale of minutes to hours. Oh, and they’re made offhand, in the background, as time permits, while the cells and organisms themselves are otherwise occupied with the even more startling business of being living chemical systems. Envy? It’s more like enzyme terror, when you really think about what’s going on.

Now let’s talk about nanotechnology. Not the press-release stuff, I mean hard-core nanotech. The dream of assembling molecules and materials to order, atom by atom, has been around for some years now, and it largely remains just that: a dream. Eric Drexler and others have taken a lot of grief for maintaining that such things are possible, and to be sure, I have trouble myself with the real atomic scale this-carbon-goes-right-here level of the idea. But what about “this acetyl group goes right here?” That is, small-molecular scale versus atomic scale? That is exactly what every living cell on the planet is doing right now – that’s enzymatic chemistry, and I see no reason why we can’t get smart and capable enough to do the same sorts of things ourselves, and more.

That leads up to this new paper, which is a big (but small) example of just that sort of thing. A group from the University of Manchester reports the system shown above, which is basically a molecular-sized stereoselective synthesis machine. You put that unsaturated ester together on the left-hand side, and the first step is an olefin cross-coupling with it and acrolein dimethyl acetal. Now comes that “rotary switch” in the middle. If you treat the molecule with trifluoroacetic acid, it deprotects the acetal, and the acrolein now is set up to do a tandem nucleophile/electrophile addition under the influence of the chiral prolinol group. That reaction is done in solution, as stereoselective synthesis fans will know, but you only really get the syn isomers.

This system will give you both, and both enantiomers, depending on the reaction conditions. Depending on the conditions (time spent treating with trifluoroacetic acid, or with triethylamine afterwards), that hydrazone in the middle can go from E to Z putting the acrolein aldehyde in range of either the (S) or the (R) prolinol, at your choice. That forms a chiral iminium, whereupon you add a thiol nucleophile. The iminium is now released, and you have your choice again of whether you want the hydrazone in the middle to be E or Z. Whichever one you choose, you now form an enamine intermediate and bring in the electrophile (a highly activated Michael acceptor, 1,1 phenylsulfonylethylene). That does the second bond formation, and reduction with LAH releases the ester linkage and frees the product as a primary alcohol. You end up with two chiral centers, and you can choose which of the four diastereomers you want by moving the hydrazone switch around during the reaction sequence.

OK, we’re not all going to be making compounds like this next week – fine. This system is set up with every bias possible to make it succeed (such as a terrific thiol nucleophile and a terrific sulfonyl electrophile), and it doesn’t produce pure stereoisomers out the other end, even with that. Rather, you get ratios from about 80:20 to about 60:40 (although, to be sure, the solution methods to do this reaction don’t always do much better, and they can’t give you all four isomers under any conditions). The point is not that this is a wonderful new stereoselective reaction that we can use to make chiral products; the point is not the chiral products themselves at all. The point, of course, is that this thing has been designed to give you such chiral products, in a programmable fashion, and that it can indeed switch states on command to give them to you. It’s a machine – a very small machine, with limited inputs, but the first computer circuits were also very small machines with limited inputs, too.

The scientific and engineering challenges are similar – how to make these things work more reliably and how to scale them up to greater levels of complexity and utility. It’s going to be harder for chemistry than it was for computation, since our computers, fundamentally, are all about moving 1s and 0s around (throwing on/off switches over and over in increasingly complicated ways). That made the development of processing circuits more straightforward, as difficult as it was in reality to get all that to work. Organic synthesis has a lot more letters in its alphabet than just A and B, and its processes are a lot more irreducibly complex than binary logic is. But that just means that it’s a trickier problem, not that it’s an insoluble one.

I think this work points to one way around the difficulties: try, whenever you can, to reduce the key steps to binary ones. The heart of this molecular machine is that hydrazone, which can point in this direction or in that one, which makes all the difference. If we develop these and other spatiotemporal switches to be faster, more responsive, more reliable, and more orthogonal to other functional groups, we can adapt them (as this paper does) to do some fairly complicated chemistry by positioning our other reagents in the appropriate places. Some of these things are already out there in the literature (azo groups or other double bonds that isomerize photochemically, pH-responsive hydrogen bonding groups, and others). We can take our cues from the biochemical world, which uses both of those just-named processes, and how, and we can design new ones that no living cell has ever gotten around to. Cells, when you get down to it, build incredible synthesis machinery, but it’s bespoke stuff: it does what it does with fantastic speed and precision, but if you don’t want exactly what it does, you’re out of luck. What we’re after is are tougher, more general solutions: machines that will make whole ranges of molecules, the way we tell them do, with (ideally) the ability to be switched around to different functions as needed.

T. Ross Kelly and Marc Snapper have a good commentary on this paper in the same issue of Nature.

It is commonplace to dismiss seemingly impossible ideas, such as Drexler’s molecular assemblers, out of hand, and the use of such devices in chemical synthesis might indeed never find favour. One could further argue that Kassem and colleagues’ “programmable molecular machine” is more contrived than ingenious. But given that the most recent chemistry Nobel prize was awarded for the design and synthesis of molecular machines, those who dismiss the concept of molecular assemblers should heed the lesson of Lord Kelvin’s infamous 1895 pronouncement that “heavier-than-air flying machines are impossible”.

As opposed to some other similar statements that get quotes, Kelvin apparently really did say that, as well as saying (in 1900) that he didn’t think there was anything new to be discovered in physics. Anyone who watched a bird knew that heavier-than-air flight was possible; the question was whether we could figure it out ourselves. The attempt to make molecular assemblers – which is, after all, the attempt to make our own enzymes, when we know that enzymes exist – is the same sort of problem. The molecular-machine folks (last year’s Nobel!), who care about rendering fundamental ideas and processes into molecular form, and the more traditional synthetic organic chemists, who care about what products any new reaction or machine can produce for them, can find common ground in building such things. Bring on the molecular machines!



Note: All opinions, choices of topic, etc. are strictly my own – I don’t in any way speak for my employer

15 comments on “Building Our Own Molecular Machines”

  1. Hap says:

    It’s amazing what you can do, one step at a time, though, when you have a few hundred million years to do it in, or ten billion tries a day to get it right. We don’t have those advantages – we just keep trying to show that having brains can make up for lots of time or lots of tries, though it took both of them for us to have a chance to get the brains in the first place. Step by step…

    1. kjk says:

      Look at evolution as an algorithm trying to solve a problem. The computational power humans in 2018 have access to vs what Nature had/has in terms of number of tries and how much CPU power each try would take is a single poor African vs a galaxy full of Bill Gates. It’s amazing we did anything against that kind of a disadvantage.

  2. luysii says:

    They may not be molecular machines, but one of the joys of theoretical organic chemistry is that you build molecules to test your ideas. Why else would anyone have made the cyclophanes? For another example — see

  3. anon says:

    Slightly off topic. On enzyme envy, why not embrace our enzymatic overlords? Biocatalysis, especially with secondary metabolite proteins, seems incredibly underdeveloped.

    1. sanchopanza says:

      Yep, this is very cool and a great direction for organic chemistry. But let’s keep in mind that the difference between “organocatalysis” and enzymes is rate. If this field is to progress, we need designed systems with Kcat/Km that approach 10^7. If one designs an apple picker that is almost perfect, but takes 1 year to pick 100 apples it will not impress anyone.

      1. Vampyricon says:

        I don’tvknow if it’s just because I’m not a chemist, but won’t using more of them be a solution?

        1. MrRogers says:

          If they’re too slow, then all you’ve done is take a problem in making small molecules and turn it into a problem in making proteins. The latter are typically far more expensive to make in bulk.

  4. MoMo says:

    Biocatalysis has been beat to death and in some case dug up and paraded around as live tissue. I am all for molecular machines and using enzymes but guess what? They have to work, they have to be cheap, and they have to produce something cheaper than the machines or enzymes used. We worked with the Big Dogs on this at one time, came up with chemically modified molecules that were promising anticancer agents. But when asked to scale these up the Big Dogs turned into amoebas and crawled out of sight using their pseudopods.
    Cost my company a fortune and now the Big Dogs have new jobs delivering Haggis.

  5. pete says:

    Derek, nicely thought out and written up. For a molecular biologist like me, it gives me an appreciation for what makes some chemists groove & get their feet outta bed. Ain’t evolution just YUGE ?!

  6. I’ve heard Drexler say that he did his MIT PhD thesis (which is almost identical to his 1992 book Nanosystems) not to propose a starting point, but to explore a very difficult region of the space for feasibility. IIRC it was in the same conversation that he said we should start with protein as engineering polymer – with a real cow’s horn in hand.

    Remember, Drexler didn’t start with Nanosystems, or even Engines of Creation – he started with PNAS ’81, about protein synthesis.

    It’s also worth mentioning Liao S, Seeman NC. (2004). “Translation of DNA signals into polymer assembly instructions.” Science 306(5704):2072-4
    This was a machine built of DNA, and programmed by binding DNA strands, to template the synthesis of one of four DNA product strands.

    As far as I can see, fast addressable actuators are the only thing missing to let us build molecular machines (perhaps out of Schafmeister polymers) that can be computer-controlled to make products more complicated and functional than the machine that builds them.

    1. Yes, The introduction of that paper was uncalled for.
      It reads like pro forma conformist behavior based on fear of association with advanced APM.
      Here are some more of my thoughts on that:

  7. Admin says:

    I am morbidy obese, my kids are implusive and misbehaved, and my family life and mental state are in clear decline

  8. Lloyd says:

    Welcome to the machine

    1. Some idiot says:

      Is that Lloyd or Floyd? 😉

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