別紙41 (課程博士(英文))Date of sublnission (1nonth day, year)

フ/フ/2023

NaokiHara宮Uchi

Department ofApplied chanistw

StudentlD Number

Shinichiltsuno

D199401

and Life science

SuperⅥSors

Kazutaka shibatomi
Akihiko Matsumoto

Pplicant's name

M0王王AM入仏D FAR11ADUR RA11MAN

Abstract (Doctor)
Title ofThesis

Cinchona alkaloid dedvatives and their polymers as e缶Cient catalysts forasymmetncreactlon

Approx.80o words

Asymmetric synthesis using chiral catalysts plays an lmportant role in synthesizing
Pharmaceuticals, pesticides, and the total synthesis of natural products. Because of theirVersatile structural modifications, cinchona alkaloids and their derivatives have been widely
Used as chiral organocatalysts in various asymmetric reactions
Despite the various modifications of cinchona alkaloids, cinchona alkaloids with functionalgroups in the quinoline ring are Hmited. A nitro (N02) group has strong electron・withdrawing
Properties and shows stenc and electronic interactions with substrate molecules. The

introduction of the N02 group at the C5' position in chinchona alkaloids causes a steric
repulsion between the hydrogen bound to the C9 Position and the nitro group, thus fixing thequinucHdine ring at an angle. Due to these characteristics, the N02・modified cinchona
alkaloids at the C5' position are expected to exhibit catalytic performance different from theConventional catalysts

In this study, we investigated the synthesis of novel asymmetric organocatalysts ofquinine derivatives with the N02 group at the C5' position. The effects of the N02 group atthe C5' position on asymmetric reactions were investigated in detail.＼Ⅳe also examined thedifference in the catalytic performance due to the presence or absence of the C5'・N02 group.
For the weⅡ・understanding of the effect of the C5'・N02 group on the asymmetric reaction,
Other types of cinchona organocatalysts possessing C5'・N02 moieties were fudher
investigated.

Cinchona alkaloids have been used to design chiral polymeric organocatalysts as a
Privileged class of chirality inducers. The design of polymeric catalysts is a critical tool for
Understanding the efficient catalytic process in asymmetric transformations. Although various
Studies with low・molecular・weight urea or squaramide catalysts derived from cinchona
alkaloids have been repoded, the variation of the polymeric counterparts is sti111imited.
Cinchona urea, squaramide, or ether・modified polymeric catalysts can be synthesized by
Suitable polymerization processes under optimal reaction conditions.1n our previous repods,
We have established the polymerization of cinchona alkaloids by Yamamoto coupling
Polymerization reaction and Mizoroki‑Heck polymerization reaction. Their reactions were areliable c・c bond・forming reaction to give main・chain type polymers from cinchona alkaloid
derivatives. These main・chain chiral polymers were expected to be used successfUⅡy as chiral
Catalysts in various asymmetric reactionsChapter l provides a broad introduction of chiral catalysts, an outline of the stNcturalfeatures of cinchona alkaloids, chiral organocatalysts, polymeric organocatalysts, and tl〕ebackground of the study. The broad overviews of the several asymmetric reactions catalyzed
by low・molecular・weight and polymeric cinchona alkaloids are also included in this chapter
In chapter 2, the catalytic performance of C5'・Nitro・dihydroquinine (QI) Was
investigated in an asymmetric Michaelreaction. Ql was prepared from dihydroquinine (HQ)in 65% yield. The stNcture of Ql was confinned by nuclear magnetic resonance (NMR),
fourier transform infrared spectroscopy (FT・1R), and time・of・aight mass spectrometry(TOF、NIS).＼入le found thatthe N02 group atthe C5' position of Ql was vertica11y fixed to thequinoHne ring by x・ray crysta110graphy study.＼入1'hen Ql and HQ were applied to theasymmetric Michael addition reaction of methy1 2‑O×ocyclopentanecarboxylate andtrans・β・nitrostyrene, Ql showed high yield (96%) and high enantioselectivity (99% ee). The
ability of asymmetric induction of Ql was superior to that ofHQ in the reactionIn chapter 3, cinchona urea compounds havin83,5・diiodophenyl moieties were subjectedto Yamamoto coupHng polymerization to afford the chiral urea polymers. Both urea
homopolymers and copolymers with and without the N02 group Were SuccesS6、1ⅡySynthesized using Yamamoto coupling polymenzation. These polymers showed highactivities as heterogeneous catalysts in asymmetric Michael reactions. The catalytic activities
Were comparable to those of the corresponding monomeric catalyst in solution systems. ThePolymer without the N02 group required a shorter reaction time, whereas the polymer withtl〕e N02 group had superior enantioselectivity. Furthermore, these polymeric catalysts wereeasily recovered from their reaction mixtures due to their insolubility and could be reused
Severaltimes wlthout loss of catalytic activity

In chapter 4, chiral polymers having cinchona squaramide repeating units Were
Synthesized and applied in an aza・Michael reaction. Those polymers were synthesized using
Mizoroki・Heck polymerization. The polymer organocatalysts showed exce11ent catalytic
Perfonnance in the asymmetric aza・Michael reaction between aniline and chalcone to afford
the chira1 α一amino ketones in a highly enantioselective manner (up to >99少、o ee) underSolvent・free conditions. The insolubility of the polymer catalyst facilitated the separation of
the catalyst from the reaction mixture. The recovered polymer was reused several times
Without any loss ofits catalytic performance、In chapter 5, the Yamamoto coupling reaction was applied to the synthesis of ether・ andester・based cinchona alkaloid chiral homopolymers and copolymers. Asymmetric Michael
addition reactions with chiral organocatalysts were investigated, and these catalyticPerformances were discussed. The reactions afforded the enantioselective adducts in exce11ent
yield with 87‑89少、o ee using the ether・based copolymer in toluene at 25 ゜C, while theCorresponding low・molecular・weight catalyst exhibited poor enantioselectivity (21% ee). The
reusability of copolymer up to flve cycles was satisfactory, with tolerating exceⅡent
enantioselective adduct.

Chapter 6 represents the comprehensive summary and condusion of the thesis
Introducing the C5'・N02 group into cinchona alkaloids provided a distinctive structure,
Which might lead to superior catalytic activity and stereoselectivity. Yamamoto coupHngPolymerization was effective for the synthesis of cinchona alkaloid polymers. A newCinchona polymer was synthesized by Mizoroki・Heck polymerization. These polymenc
Catalysts showed high catalytic performance and reusability in the Michael and aza・Michael
reactlons.