Strategic Young Researcher Overseas Visits Programfor Accelerating Brain Circulation 2011
“Development of Young Researchers
Based on International Joint Research
on Green Energy Systems”
Progress Report

1. Name: Tsutomu Fukuda
2. Title: Assistant Professor
3. Host Institution: Max-Planck-Institut für Kohlenforschung(Federal Republic of Germany)
4. Host Researcher: Professor Alois Fürstner
5. Duration: 10-July-2012 – 12-July-2013
6. Research Topic:
Development of an atom-economical and energy-saving methodology foreffective synthesis of highly functional chemicalcompounds
7. Overview of the Results of the Collaborative Research:
Marine natural products derived from a variety of sources have attracted considerable
attention from chemists for their unusual structures and concomitant biological activities.
Therefore, a large number of methodologies for the syntheses of them have been reported sofar.

On the other hand, the total synthesis of marine natural products possessing amacrocyclic pyrone scaffold was given exceptionally little attention despite of their uniquestructures and potent biological activities.

The aim of this research is to develop anatom-economical and energy-saving methodology for effective synthesis of highly functional
chemical compounds such as naturally occurring pyrone-type macrocycles.

Thus, we chosea marine natural product possessing a macrocyclic ring with 4-pyrone moiety as a target andattempted its total synthesis.
Recently, Professor Dr. Alois Fürstner and co-workers have found that a certain type ofmolybdenum complex effectively catalyzes the ring-closing alkyne metathesis (RCAM)
reaction.

Furthermore, they have also developed the gold-catalyzed construction of

2-pyrones from 3-oxopent-4-ynoates.

By using these reactions, the total synthesis of

2-pyrone macrocycle neurymenolide A was successfully achieved (Scheme) [W. Chaładaj etal, A. Angew. Chem. Int. Ed. 2012, 51, 6929-6933.].
OCy
Cy P AuNTf
2i-Pr

O

R3SiO

i-Pr

Ot-Bu

PhK
AcO

i-Pr
AuXPhosNTf2 (5 mol%)

OO

Mo

OSiR3

R3SiO
OSiR3
R = p-MeOC6H4-H

H

AcO

Au-catalyzed
cyclization

Mo-catalyzed
RCAMO

HOOO
O

Neurymenolide AScheme
Based on the previous results, we initially carried out the retrosynthetic analysis of the target
molecules by using molybdenum-catalyzed RCAM and gold-catalyzed pyrone synthesis as
key reactions.

As a result, it seemed that the target molecule could be synthesized from a

carboxylic acid part (fragment A) and an alcohol part (fragment B).
According to the retrosynthetic analysis, the synthesis of the fragment A was examined.
The fragment A could be synthesized from commercially available 1,7-octadiyne in fivesteps.

On the other hand, synthesis of the fragment B was rather problematic owing to itsinstability. After several attempts, we could obtain the desired fragment B by using
ring-opening reaction of epoxide, P-2 Nickel mediated semi-reduction, and Corey-Fuchs
olefination as key reactions.
Having established the synthesis of fragment A and B, we next attempted the construction of
the macrocyclic scaffold using gold and molybdenum catalyzed reactions.

Thus, fragment

A and B were coupled using conventional esterification.

Gold-catalyzed reaction of theresulting ester proceeded smoothly to produce pyrone.

Successive molybdenum catalyzed

ring closing alkyne metathesis (RCAM) afforded the macrocyclic compound in good toexcellent yield.
At present, we are still attempting to synthesize the target natural product.
will publish these results after completion of the total synthesis.

Therefore, we8. Deployment Plans for Future Collaborative Research:
We could find that molybdenum-catalyzed RCAM and gold-catalyzed pyrone synthesis areeffective method for construction of macrocyclic pyrone framework.

Thus, we will apply

the method to the synthesis of the other macrocyclic pyrone type natural products.

9. List of Collaborative Research Progress:
At present, we are still attempting to synthesize the target natural product. Therefore, we will
publish these results after completion of the total synthesis.