B.R.S.M. When all you have is a hammer everything looks like a nail

19Jan/155

Maoecrystal V (Part 2: Zakarian/Davies)

Enantioselective Synthesis of (−)-Maoecrystal V by Enantiodetermining C−H Functionalization

Armen Zakarian, Huw M. L. Davies et al.J. Am. Chem. Soc. 2014, 136, 17738 [PDF] [SI] [AZ GROUP] [HMLD GROUP]

DOI: 10.1021/ja510573v

0 minus 1This is the second part of my coverage of the two recently published syntheses of (–)-maoecrystal V, dealing with the route completed jointly by the Davies and Zakarian groups (Part 1, featuring the Thomson group synthesis is here).

That's right, for the first time in three and a half years' blogging I find myself writing about that rarest of publications: the collaborative total synthesis. Also somewhat unusually, the two US-based groups involved in the collaboration are both headed up by professors who originally hail from outside the States.[1]

Sharp eyed readers will note that a large part of this synthesis is adapted from the Zakarian group's previously reported total synthesis of racemic maoecrystal V from back in 2013, and in fact it reuses the same intramolecular Diels–Alder key step to construct the fused furanobicyclo[2.2.2]octane ring system:

I'm reusing this scheme because it took me an extremely long time to draw.

I'm reusing this scheme because it took me an extremely long time to draw.

This well-planned cycloaddition enabled the execution of a concise and efficient diastereoselective route (24 steps @ 1.5% overall yield) that compared quite favorably with the others that had been reported at the time. The 2013 paper finished with the following paragraph (emphasis mine):

"The strategic focus on the central strained tetrahydrofuran ring resulted in an initial disassembly of the lactone ring to a polycyclic enol ether. The enol ether was constructed by an IMDA reaction of a tethered CH2=CH2 equivalent with a 2,4-cyclohexadienone fragment obtained by oxidative dearomatization of a dihydrobenzofuran intermediate. This intermediate, in turn, was prepared by an effective rhodium-catalyzed C−H functionalization reaction which can potentially be modified to access enantioenriched products using chiral rhodium catalysts."

Well it seems that Zakarian group decided to go back and realize this dream, enlisting the help of C–H activation and rhodium experts the Davies group.

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3Jan/157

Maoecrystal V (Part 1: Thomson)

Enantioselective Total Synthesis of (−)-Maoecrystal V

Regan J. Thompson et al., J. Am. Chem. Soc. 2014, 136, 17750 [PDF] [SI] [GROUP]

DOI: 10.1021/ja5109694

0 minus 1Maoecrystal V—as the advanced nature of its final letter implies—is one of a great many unusual terpinoids from the Chinese flowing plant Isodon eriocalyx.[1] It possesses a rather intricate and complex structure, a fact illustrated by the two decades that passed between its (first) isolation in 1994 and the successful determination of its structure in 2004—a long period indeed with modern spectroscopic techniques. Its dense, cage-like structure proved a tough nut to crack and another 5 years passed before the deluge of synthetic publications for this target began in 2009. The first total synthesis, reported somewhat controversially by the Yang group the following year, has only seemingly intensified the attention that it has received.

0 - Structure

Maoecrystal V exhibits a heavily modified version of the more common ent-kaurene skeleton.

Interestingly, despite the hugely varied interests and specializations of the groups involved, all five of the successful total syntheses reported to date have constructed the molecule’s prominent bicyclo[2.2.2]octane ring system using the venerable Diels–Alder reaction (often in conjunction with the similarly tried-and-true tactic of oxidative dearomatization to establish the diene). That said, the number of Diels–Alder variants employed is impressive, and you could almost imagine giving a short lecture course on the reaction using nothing but examples from synthetic studies on maoecrystal V. I’ve tried to illustrate the variety below.

All 5 total syntheses to date have used a Diels–Alder reaction to form the molecule's fused bicyclo[2.2.2]octane ring system. The reaction has also featured prominently in approaches by Baran, Trauner, Nicolaou, Chen, Movin, Sorensen and others.[2]

All 5 total syntheses to date have used a Diels–Alder reaction to form the molecule's fused bicyclo[2.2.2]octane ring system. The reaction has also featured prominently in approaches by Baran, Trauner, Nicolaou, Chen, Movin, Sorensen and others.[2]

I’ve long wanted to write something about maocrystal V total synthesis, but I’ve always been too busy around the time that people have completed it to get a blog post out reasonably close to the event. Fortunately, two back-to-back syntheses from the Zakarian and Thomson groups were published in J. Am. Chem. Soc. earlier this month and I’ve now got plenty time to write about both of them, starting with that of the Thomson group in this post.

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