Category Archives: Chiral pool

Publication of the week, number 73, 17th April 2015

This week several publications could have aspired to be my ASAP of the week. I chose the one by Fürstner in Angewandte describing the total synthesis of 5,6-dihydrocineromycin B. A paper which is full of interesting titbits of useful information.

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This compound is one of a family of antibiotics whose activity may need to be re-evaluated, consequently there is a need for an adequate supply.  The interesting part of this structure is the (E) configured 2-methyl-but–2-en-1-ol unit, which can be encountered in quite a few of such polyketides. The synthesis of this part is an obvious candidate for some sort of RCM. This has been investigated and found to be wanting, 40% yield and 25mol% Grubbs catalyst for many hours in refluxing dichloromethane.

Reaching into his box of tricks Fürstner realised that his ring-closing alkyne metathesis could be effective in this case, provided the missing methyl group could be introduced in the correct stereochemical fashion.

Starting out from (S)-citronellene one methyl acetylene fragment was prepared in 6 steps in about 40% yield:

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Notable in this sequence are a couple of things: The reactions were done on a reasonable scale, for example starting with 15g of citronellene. The following sequence, to prepare the acetylene is also interesting and has previously been described by this group:

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Reagents: i) CCl4, PPh3, THF, reflux; ii) MeLi, [Cu(acac)2], (10 mol %), Et2O, 0 °C, 74 % (2 steps, 1.1 g scale).

The other acetylene fragment was synthesised from (R)-linalool, again in 6 steps and around 40% yield:

 furst04Here noteworthy is”…. a Carreira reaction to set the missing stereocenter while installing the alkyne handle for the envisaged macrocyclization. Although the use of propyne has little precedent, the addition worked well on a multi- gram scale. ….. the excellent outcome of the asymmetric propynylation (d.r. > 20 :1) therefore constitutes a notable distinction”.

Combination of the two alkynes by esterification followed by metathesis  at RT using a molybdenum ate complex gave the desired cycloalkyne in 92% yield:

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So now the introduction of the C-8 methyl group was examined, firstly “the silyl protecting groups were cleaved with HF·pyridine and the resulting diol treated with Bu3SnH in the presence of [Cp*RuCl2]n (5 mol %) to give the expected a-alkenylstannane, basically as a single isomer (a/b > 20 :1, E/Z > 20 :1). It is also important to note that the transannular alkene, which competes with the alkyne for coordination to the π – affine ruthenium catalyst, did not interfere with the directed trans-hydrostannation.” Fürstner has, this week, also published detailed studies on the mechanism of this reaction.

Using a varient of his previous work “Specifically, the rapid sequential addition of CuTC (copper thiophene-2-carboxylate) (1.05 equiv) and MeI (1.5 equiv) to a stirred solution of 16, [Pd(PPh3)4(5 mol %), and [Ph2PO2][NBu4(1.1 equiv) in DMF at ambient temperature gave 5,6-dihydrocineromycin (3) in excellent yield. The present synthesis is shorter and considerably more selective than any the previous ones; the data of synthetic 3 thus formed are in accord with the literature data.”

The authors do say that the order of addition and the stoichiometry is very important for the success of this Stille coupling in order to avoid protodestannation. But the side reaction does allow the preparation of a des-methyl derivative. This protodestannation is achieved under very mild conditions compared to the known methodology. The Z-olefin was also prepared by Lindlar hydrogenation of the cycloalkyne. If you treat the silyl alkyne with basic TBAF an interesting structure emerges:

       furst06                                     furst07

So another worthy notch on Fürstner’s publication tree. A nice synthesis and application of all the previous hard work. So go read.

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