Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 28 February 2009

Total Synthesis of Sporolide B


K. C. Nicolaou, Y. Tang, J. Wang, Angew. Chem. Int. Ed. 2009, 48, 3449-3453.

DOI: 10.1002/anie.200900264

Sporolide B is a very challenging target, but devoid of any biological activity. Nicolaou justifies his synthesis by discussing the biosynthetic origins of the sporolides, which are potentially products of enediyne cyclisation.

Anyway, the structure is certainly interesting and perhaps the most interesting feature is the 1,4-dioxane-style bridging ring, which would be a tough disconnection. The other intriguing disconnection is about the chloro benzene ring, where Nicolaou hoped to utilise a [2+2+2] cyclisation:

The total synthesis starts with the construction of an enediyne intermediate. To get to this point, the group already performed 13 steps starting from a chiral cyclopentenone originally developed by Carl Johnson. The more interesting steps included an early palladium mediated carbonylation and later an exceptionally high-yielding Sonogashira coupling using only 2% palladium. They then used a very interesting anion formation to install the chloroacetylene, in which pretreatment of cis-dichloro ethylene with methyl lithium resulted in lithiochloroacetylene. Addition of the aldehyde resulted in an impressively clean reaction, almost completing the substrate for the [2+2+2].

The other partner was produced quicker, installing the asymmetry using a Sharpless dihydroxylation and a procedure developed by Yadav to make the chiral propargyl alcohol. Towards the end, though, I liked the usage of some well-known chemistry to provide an orthoester from the acetal protected catechol.

And now to that [2+2+2], and a regioselectivity issue, as there are two ways for the propargyl alcohol partner to approach the diyne. Nicolaou suggests that the perfect selectivity achieved results from steric (the chlorine atom) and chelation (the propargyl alcohol) control, exemplified in the scheme shown below. Very nice preparation of a tetrasubstituted benzene.

After a bit of protecting group transformations, they use an interesting approach for the macrocyclisation. To install the pyran-style bridge in a [4+2] cycloaddition, they needed an equivalent of a diene - in this case, an ortho-quinone, provided by silver oxide oxidation of the diol. Then, due to the astonishing molecular flexibility, thermolysis of the intermediate led to a reasonable yield of the desired macrocycle and recovered starting material. The selectivity of this cycloaddition is remarkable - sure, the top face of the ‘dienophile’ is restricted by the bulk of the fused cyclopentadiol, but either face of the ortho-quinone should be accessible.

The last reaction worth discussing is the oxidation of the dioxane to give the ketal. This was neatly done with a hypervalent iodine reagent, using a tenfold excess of 4-methoxybenzyl alcohol. Delivery to the desired ether is presumably controlled by the para-phenol, and leaves only a few more steps to complete the synthesis; via oxidation/reduction to correct the erroneous configuration of the cyclopentadiol, some deprotections and finally a selective epoxidation of the cyclohexadienone. This final reaction was done using a combination of t-BuOOH and DBU.

A very interesting total synthesis from the Nicolaou labs.