別紙４－１（課程博士（英文））Date of Submission（month day，year）: March 27, 2020
Department

Applied Chemistry and Life

Student ID Number

D 169403
Supervisors

Science
Applicant’s name

SEIJI IWASAKAZUTAKA SHIBATOMIPHAN THI THANH NGA

Abstract（Doctor）
Title of Thesis

Catalytic Intramolecular Carbene Transfer Reactions into σ and π Bonds（σ 及びπ結合への触媒的分子内カルベン移動反応）

Approx. 800 words
A carbene known as an most active intermediate is complexed with a transition metal, which
afford the corresponding metal-carbene complex and catalytically insert into σ and π bonds oforganic compound. Even though there are many reports on the carbene transfer process to develop a
new approach for the synthesis of medicine and other bioactive compounds, the regio-, stereo- andchemoselective approaches are still limited and remained as a main subject in the filed of syntheticorganic chemistry. For these background, I developed an efficient catalytic intramolecular carbene
transfer reactions by using originally developed ruthenium catalyst into σ and π bonds andsuccessfully applied for the synthesis of γ-lactam ring fused aromatics (oxindoles), γ-lactone ringfused cyclopropanes, and γ-lactam ring fused seven member rings via Buchner reaction.
Although ruthenium complex is a newcomer in the field of catalytic carbene transfer reaction, it
has emerged as a useful transition metal for the carbenoid chemistry of diazo compounds, besides
copper and rhodium. And recently, we have developed a Ru(II)-Pheox complex, which is efficient forcarbene transfer reactions, in particular, asymmetric cyclopropanation, N-H insertion, C-H insertionand Si-H insertion reactions.
Therefore, driven by my interests in the catalytic asymmetric carbene transfer reaction and theefficiency displayed by the Ru(II)-Pheox catalyst, I started to explore the asymmetriccyclopropanation, C-H insertion, Buchner reactions of various diazo compounds, which arepotentially building blocks and expectant to be applied in pharmaceutical and medicinal fields .
In my thesis, Chapter 1 describes the importance of carbene transfer reactions. And a short reviewof the metal carbene intermediates in C-H insertion, asymmetric cyclopropanations, and Buchner
reaction have been also illustrated in this chapter. In addition, the applicati on of metal carbene
complexes in the synthesis of biologically-active or natural product-like compounds is alsomentioned.
Chapter 2 is for the synthesis of oxindoles. The oxindole ring is prevalent as an important scaffold
found in numerous natural products and pharmaceutically active compounds. Over the past few
decades, the emerging therapeutic potential of structural motif of oxindole has encouraged themedicinal chemists to synthesize novel oxindole derivatives. I report Ru(II)-Pheox was found to be ahighly efficient catalyst for the synthesis of oxindole derivatives in excellent yields. We developed
the efficient synthesis of oxindole derivatives via intramolecular ArC sp2 -H insertion reaction of diazoacetamides derived from the corresponding anilines by using Ru(II)-Pheox catalyst. The reaction
proceeds smoothly under mild conditions, providing the corresponding oxindole derivatives inexcellent yield (up to 99%). No other side reactions related to metal -carbene reactivity such as
dimerization, aromatic ring expansion and C sp3 -H on amide nitrogen insertion reaction wereobserved.
On the other hand, the cyclopropane subunit is also present in many biologically importantcompounds and it shows a large spectrum of biological properties. Transition me tal-catalyzed
cyclopropanation involving carbene intermediate is powerful and useful methods for constructing
important substructures of targeted molecules, and therefore they have been extensively studied forthe past couple of decades. Thus, Chapter 3 presents the development of asymmetric catalysts based

on Ru(II)-Pheox complexes, I developed a new series of Ru-Colefin(sp 2) bond-containing
organometallic complexes and successfully applied them to the catalytic asymmetric inter- andintramolecular cyclopropanations, which are carbene transfer reaction. It is noteworthy that highyields and stereoselectivity were achieved for trans-cyclopropane carboxylates even with a low
catalyst loading. Catalytic asymmetric cyclopropanations of diazoesters with olefins in the presenceof the Ru-Colefin(sp 2)-phenyloxazoline complexes (Ru-Colefin(sp 2)-Ru(II)-Pheox) proceeded smoothly
to give the corresponding optically active cyclopropanes in high yield s, with a trans/cis ratio 97/3 to>99/1 and 97% to >99% ee (trans). The enantioselectivities were affected by the geminal substituent
on the Ru-Colefin (sp 2) bond; the highest enantioselectivities were obtained when using Ru(II)-Prox
catalyst with no substituent at the germinal position of the metal.
Furthermore, medium ring-containing organic molecules, such as seven-membered rings, are also
the cornerstone of many bioactive natural compounds such as guaiane sesquiterpenes, guaianolidesesquiterpene lactones. However, there are few reports on their synthesis. Thus, the development ofan efficient method to prepare these scaffolds has attracted a significant amount of research attention.
This unique strategy toward seven-membered carbocycles has been utilized in natural productsynthesis. In Chapter 4, I report the development of an intramolecular Buchner reaction of a varietyof N-benzyl diazoamide derivatives in the presence of a chiral Ru(II) –Pheox catalyst. The aromaticrings are converted into the corresponding γ-lactam ring fused seven-membered ring system withhigh regio- and stereoselectivity. A variety of γ-lactam fused 5,7-bicyclic-heptatriene derivatives
have been prepared from diazoacetamides in up to 99% yield with high enantioselecti vely (up to 99%ee) using a chiral Ru(II)-Pheox catalyst under mild reaction conditions.
In conclusion, Chapter 5, the Ru(II)−Pheox catalyzed C-H insertion reaction and asymmetric
Buchner reaction proved to be the efficient and straightforward methods for the preparation ofoxindole and seven-membered ring which are important intermediates in the synthesis of many
biologically active compounds. Moreover, we have successfully designed and synthesized a novel
Ru-Prox type catalyst. This catalyst showed excellent reactivities and selectivities in asymmetric
cyclopropanation reactions. And it is expected to provide many further opportunities in asymmetriccatalysis.
In Chapter 6, all the experimental and analytical data as the evidence for Chapter 2 to 4 aredescribed.