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 for effective synthesis of highly
functional chemical compounds
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 biologicalactivities.

Therefore, a large number of methodologies for the syntheses of them

have been reported so far.

On the other hand, the total synthesis of marine naturalproducts possessing a macrocyclic pyrone scaffold was given exceptionally little
attention despite of their unique structures and potent biological activities.

The aimof this research is to develop an atom-economical and energy-saving methodology

Ofor effective synthesis of highly functional chemical compounds
such as naturally occurring 4-pyrone-type macrocycles.

BrThus, wechose a marine natural product 1 possessing a macrocyclic ring

OO

Brwith 4-pyrone moiety as a target and attempted its total synthesis.

1

Recently, Professor Dr. Alois Fürstner and co-workers have foundthat a certain type of molybdenum complex effectively catalyzes the ring-closing
alkyne metathesis (RCAM) reaction.

Furthermore, they have also developed thegold-catalyzed construction of 2-pyrones from 3-oxopent-4-ynoates.

By using

these reactions, the total synthesis of 2-pyrone macrocycle neurymenolide A wassuccessfully achieved [Angew. Chem. Int. Ed. 2012, 51, 6929-6933.].
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 (Scheme 1).

As a result, it seemed that the target

molecule could be synthesized from an alcohol part (fragment D) and a carboxylic
acid part (fragment E).
O1

site-selectivebromination

OOO
ring-closing alkyne
metathesis (RCAM)

OO

Br

gold(I)-catalyzed Br
cycloisomerization

OOO

BrABOOHCOHO+Br
DScheme 1EAccording to the retrosynthetic analysis, synthesis of the fragment D was examined.
After several attempts, we could obtain the desired fragment D by using ring-opening
reaction of epoxide 4, P-2 Nickel mediated semi-reduction, and copper-mediatednucleophilic substitution as key reactions (Scheme 2).
OHa2

OH
O

34OTBS
hBr
7O

OTBS

5OEEdOH

OTBS

e–g
HOOEEOTBSb, c6ORiHOBr
89 (R = TBS)
10 (R = H)

Scheme 2. (a) Ti(Oi-Pr)4 (10 mol%), (+)-diisopropyl tartrate (13 mol%), cumene hydroperoxide, CH2Cl2, MS 4 Å, –25 °C(82%); (b) TBSCl, imidazole, DMF, 0 °C → RT (90%); (c) H 2 (1 atm), Pd/C (10 mol% Pd), EtOAc (95%); (d) (i) 5, n-BuLi,THF, –78 °C; (ii) BF 3·OEt2, then 4, –78 °C (72%); (e) PPTS, MeOH, 30 °C (98%); (f) H 2 (1 atm), P2-Ni (25 mol%), EtOH(79%); (g) CBr4, PPh 3, CH2Cl2, 0 °C (91%); (h) propynylmagnesium bromide, CuI (50 mol%), THF, –15 °C → –10 °C(81%); (i) CBr4, PPh 3, toluene, 65 °C (60%); (j) HF·pyridine, THF, 0 °C (83%).

jOn the other hand, fragment E could be synthesized from commercially available
1,7-octadiyne 11 in five steps (Scheme 3).
ORb, c11 (R = H)
12 (R = TMS)aO
OMe

Od, eOH
1413

Scheme 3. (a) LiHMDS, THF, –78 °C, then TMSCl, –78 °C → RT (52%); (b) n-BuLi, THF, –78 °C, then MeI, –78 °C → RT(91%); (c) MeLi, THF, –78 °C, then ClCO2Me, –78 °C → 0 °C (86%); (d) t-BuOAc, LDA, –78 °C, then 21 (87%); (e) TFA,CH2Cl2 (99%).

Having established the synthesis of fragment D and E, we next attempted theconstruction of 1 via the macrocyclic scaffold using gold and molybdenum catalyzed
reactions (Scheme 4).
esterification.

Thus, fragment D and E were coupled using conventional

Gold-catalyzed reaction of the resulting ester proceeded smoothly toproduce 4-pyrone 17.

Successive molybdenum-catalyzed RCAM afforded themacrocyclic compound 19 in good yield.

After site-selective bromination, we havecompleted the total synthesis of 1.
OMeO
Br14CyCy P AuNTf
2OMeOOOOPh 3SiO16aOMeb

O

O

15

Mo
OSiPh3

Ph 3SiOBrOOBrc

17X

18d19 (X = H)
1 (X = Br)

Scheme 4. (a) 10, DCC, DMAP cat., CH2Cl2, 0 °C (70%); (b) 16 (3 mol%), MeCN/HOAc (4:1) (97%); (c) 18 (5 mol%), MS 5 Å, toluene (82%); (d)NBS, THF (40%).

8. Deployment Plans for Future Collaborative Research:
We could find that molybdenum-catalyzed RCAM and gold-catalyzed pyrone
synthesis are effective method for construction of macrocyclic pyrone framework.
Thus, we will apply the method to the synthesis of the other macrocyclic pyrone typenatural products.

9. List of Collaborative Research Progress:Publication(s)1.

L. Hoffmeister, T. Fukuda, G. Pototschnig, and A. Fürstner, "Total Synthesis of
an Exceptional Brominated 4-Pyrone Derivative of Algal Origin: An Exercise inGold Catalysis and Alkyne Metathesis," Chemistry - A European Journal, 21(12), 4529-4533 (2015).