B.R.S.M. Home of Woodward Wednesdays


Schindilactone A

Here's an impressive total synthesis of schindilactone A by Tang, Chen, Yang,[1] and 14 coworkers. At 29 steps in the longest linear sequence that's comfortably fewer than two per author. Still, the route is entirely linear and it's a fairly heroic effort, as we'll see.

Work began sometime ago as the group published syntheses of the ABC (Org. Lett., 2006, 8, 107) and FGH (Org. Lett., 2005, 7,885) fragments of the slightly more complex micrandilactone A some time ago. Apparently that unique, ketal spanned, 7-8 carbocyclic system in the middle took some time to work out. I'll cover the older work on those fragments as well, as it shows the origins of some of the key steps in the schindilactone A total synthesis.

The route to the ABC chunk of micrandilactone A began with my favourite named reaction: the Diels-Alder. It turns out that the regioisomer they get is by far the major product, but in the absence of a Lewis acid the regioselectivity is reversed. This surprises me as the TiCl4 should presumably complex the more Lewis basic ester in preference to the ketone, which would favour the isomer that isn't formed. And it's not coordinating the oxygen in the diene because the reaction also gives this regiochemistry if the diene is simply isoprene. Anyway, the Diels-Alder gave the expected trans-6-5 system, which underwent epimerisation during the Grignard addition - lactonisation step. The lactone was then a-hydroxylated in the most economical way possible; using base and oxygen. This step is performed here on 3g, and later on 10g (for schindilactone A), a scale on which MoOPH,[2] oxaziridines, or even the Rubottom oxidation aren't too tempting. Reduction of the lactone to the lactol with lithium aluminium hydride set the stage for a rather clever anulation reaction using triethylphosphonoacetate to install the second ring. The cyclohexene was then converted to the ketoaldehyde by ozonolysis, quenching with dimethyl sulfide. The aldehyde was then selectively reduced to the alcohol using freshly prepared Raney Nickel under hydrogen, which didn't touch the ketone (or the benzyl ether). This alcohol was protected as the TBS ether and then treated with the organocerium reagent derived from lithium trimethylsilylacetylide. Strangely the paper text says that catalytic CeCl3 was used when the SI says that a whole equivalent was employed, and even mentions forming the organocerium and then adding this to the ketone. The newly formed propargylic alcohol was then protected as its acetate ester, which required heating for a fairly long time in toluene, presumably due to its hindered nature. Deprotection, oxidation, and methylenation of the TBS-protected alcohol gave the eneyne precursor, which, using a fairly generous spoonful of Grubbs 2nd generation catalyst, closed to give the ABC ring system.

The group's previous preparation of the micrandilactone A FGH system starts with another reaction which I like, but have never had an excuse to perform - the Pauson-Khand cyclopentenone synthesis. For me this always brings back memories of seeing P. Andrew Evans talk, and how his accent is different every time. Here, the reaction worked in excellent (80%) yield using standard conditions, with superstoichiometic Co2(CO)8, but this method was deemed too impractical and expensive for such an early step, so a catalytic process was developed. It was found that the reaction was greatly improved by the addition of tetramethylthiourea, the use of which as an additive had been previously reported by the group, and just 5 mol% Co2(CO)8 was needed.[3] Luche reduction and protection of the enone, followed by reduction (and reoxidation) of the lactone gave the g-hydroxyaldehyde. This was reacted with a threefold excess of vinyl magnesium bromide to give a 3:2 mixture of epimeric alcohols in favour of the desired compound. Although this compound did undergo the key Pd−thiourea-catalysed carbonylative annulation, the yields were poor and some interesting byproducts formed (see the paper if you like palladium chemistry). None of the desired product was formed in the absence of the thiourea ligand. Fortunately, it was found that if epoxidation of the tetra-substituted olefin was performed before the annulation step, rather than after, the yield increased to essentially quantitative. A few standard transformations gave the FGH enone, although apparently with the wrong diol stereochemistry for the natural product.

Okay, so now we're all up to speed, let's take a look at what was published last week! Don't forget that we talking about a different target now, so the fragments above don't quite fit, although the chemistry's very similar. For schindilactone A a completely new, and quite cool synthesis of the BC rings was devised. Next came the D and E rings, and followed by the F, G and H rings, which were established using pretty much the same chemistry we've just seen. The last ring to be constructed was the A ring. Unfortunately, it's all a bit linear, but I guess 29 steps isn't too bad if you've got 14 eager coworkers.

The route started much as before, with a Diels-Alder reaction, Grignard addition and a-hydroxylation with oxygen. The new hydroxyl was protected as its TES ether, and then dibromocarbene was used perform a cyclopropanation of the silyl enol ether. Treatment of the dibromocyclopropane with silver perchlorate then caused the desired ring expansion in good yield to give the 5-7 BC system. A palladium mediated cross coupling between the vinyl bromide and the silyl ketene acetal gave the b,g-unsaturated ester in excellent yield. Grignard addition with but-3-enylmagnesium bromide to the ketone then occurred with impressive diastereoselectivity, attributed to the bulk of the nearby TES ether, and the newly formed alcohol cyclised onto the nearby ester. Although some double bond isomerisation did occur, this didn't matter as the mixture could be deprotonated with KHMDS to give a single dienolate which reacted selectively in the a-position with MoOPH.[4] The new hydroxy was protected as its benzyl ether and the lactone was then treated with vinyl magnesium bromide. RCM using Grubbs' second generation catalyst in the presence of magnesium bromide successfully formed the challenging 8 membered ring and epimerised the hemiketal to the required configuration. The F ring was then installed by conversion of the alcohol to its tetrolate followed by Pauson-Khand reaction as before.

This hexacyclic compound was then further functionalised to get to a suitable precursor for the key carbonylation reaction. Thus, the diol below was prepared, and did undergo the expected reaction, although a fairly high loading of catalyst and ligand was required. This lactone was then a-methylated, which gave the wrong diastereomer as the major product. Fortunately, deprotonation with LiTMP and then quenching with ammonium chloride solution was able to effect epimerisation to the correct product. Apparently, both methylation and protonation of the enolate occur from the bottom face. Finally, the TES ether was converted to the acetate ester, the benzyl protected group on the D-ring hydroxyl was cleaved, and the acetate was then cyclised onto the nearby lactone by treatment with LiHMDS. Dess-Martin oxidation of the allyl alcohol gave the natural product.

Apparently efforts towards an enantioselective version are ongoing. Good luck!

1. You may remember controversial first total synthesis of maoecrystal V by Yang (J. Am. Chem. Soc., 2010, 132, 16745-16746; early work in Org. Lett., 2009, 11, 4770-4773) from last year, which famously appeared to have a great deal in common with an earlier approach by Baran (Org. Lett., 2009, 11, 4474). Oh, and a former Baran postdoc was on the Yang paper. For some lively discussion see: http://totallysynthetic.com/blog/?p=2577. Aside from this, Yang's actually quite the synthetic chemist, with some interesting work on the cortistatins and pseudolaric Acid A. His website says he's also working on Solanoeclepin A. Yikes.


2. I found out just last week that there's an HMPA free edition, using everyone's favourite phosphoramide surrogate, DMPU. MoOPD, a Jim Anderson product, can be found in Synlett, 1990, 107-108.


3. I hear that Lewis bases, amine oxides (NMO and TMAO), or even photolysis can be used to accelerate the reaction by helping to open a free site for the alkene to coordinate, increasing the rate of turnover.


4. Remember - enones generally deprotonate g but react a.

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  1. These all appear to be racemic so is there any reason the syntheses of the micrandilactone fragments show the opposite enantiomer? This seems unnecessarily confusing.
    In the 2nd part of the 2nd reaction of the 2nd figure, E2O?
    The “alcohol was protected as the TBS ether and the organocerium reagent”?
    In the product of the 5th reaction the stereochemistry of the alkyne-bearing carbon seems unclear as drawn; is there a convention I’m unaware of?
    In the 6th reaction Ph3OCH3Br does not seem to be possible.
    Does the Pauson-Khand cyclopentenone synthesis convert TBS to TIPS (3rd figure 1st reaction)?
    It would be worth mentioning the epimerization of the wrong alcohol (5th reaction), particularly if it really used EtO.
    The stereochemistry of the diol in the FGH enone appears to be correct considering that the opposite enantiomer is shown. (See what I meant?)
    If the Grignard addition (5th figure, reaction 4) “occurred with impressive diastereoselectivity”, how come no stereochemistry is shown at that carbon in the product?
    Here’s where I again demonstrate my lack of knowledge of applied chemistry. Is there a good explanation anywhere of the rearrangement in the final reaction in the micrandilactone ABC fragment synthesis?
    In the 2nd part of the 2nd reaction of the 2nd figure they went directly from an ester to an aldehyde so why did they reduce then oxidize the 3rd compound in figure 3?
    The last 4 steps in this figure were obviously TBS deprotection, oxidation of that alcohol, opening of the epoxide, and… well, what was the 4th step?

    • No, there’s no reason that the’re drawn that way as they are all racemic; that’s how they were drawn in the papers. I should probably have changed that. I might redraw them if I get bored at the weekend, but don’t hold your breath.

      EtO should have been Et2O. Fixed. This makes the epimerisation pretty unremarkable as it’s just a reduction-oxidation. They don’t comment on this much, or give a yield as far as I can tell.

      The stereogenic centre bearing the alkyne is drawn that way in the paper for some reason, not by any convention I’m aware of. You can infer the stereochemistry from the eneyne product, but I’ll make it clearer.

      Ph3OCH3Br is meant to be Ph3PCH3Br. The letters are, like, right next to each other.

      Regarding the diol in the FGH enone – I see what you mean, and that is the correct compound. That does mean a few changes when they attach the other rings and do the double methylation, but the ring junctions are okay. If they’re even planning to finish that natural product by that route (they’ve had 5 years…).

      Regarding that reduction; I can’t seen an obvious reason – I guess they just found it higher yielding, or easier to do so. It’s especially odd as the first reduction you mention is with LiAlH4, a reagent which very rarely stops at the lactol stage, and the second uses DIBAL which often does, but in this case they have to reoxidise. It may have something to do with when they draw one in it’s open form and one closed, but it’s not obvious to me.

      The final step in the mystery four steps was reprotecting the primary alcohol – they weren’t able to selective remove the TBS in the presence of the TPS (although this is something I would have thought possible). Incidentally, I did make a bit of a mess of the protecting groups in this scheme, but it’s all better now.

      Finally, regarding the rearrangement mechanism – do you mean the eneyne metathesis? The mechanism of this is pretty well known (well, as well known as that of cross metathesis). See, for example the wikipedia page or the organic-chemistry.org reaction page. They’re quite common reactions. There’s another on my Top 5 reactions of May/June page, in the honourable mentions bit at the bottom (from Ready’s total synthesis of isofregenedadiol)

      Thanks for the corrections!

      • Those links clarify (the triple bond confused me) the enyne metathesis – except that they show contradictory mechanisms! (Many of the reactions used in modern synthesis didn’t exist when I learned chemistry – reading about RCM really amazed me and got me much more interested in syntheses.)
        The 2nd figure still has E2O (in the ester reduction).

        • Ah, so it does. Unfortunately I can’t fix that till I get back from holiday (without redrawing the whole thing). I hadn’t noticed the two reference contradicting each other, but I’m not sure how well known the mechanism is anyway. RCM’s an amazing transformation – I remember seeing it for the first time as a fourth year undergrad and just thinking it was magic; I guess many older chemists probably felt the same way when Grubbs started publishing the stuff. I remember a story my boss tells of an excited student running into the lab in which he was working as a postdoc waving a copy of Suzuki’s original paper on his eponymous cross coupling and how everyone gathered round in awe and incredulity. I wonder how many other reactions have caused this kind of excitement…

          I’m not sure what your situation is for literature access, but there’s a review in the current Eur. J. Org. Chem. on the use of metathesis of varying kinds in synthesis, which has a few cool examples in.

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