RESEARCH ACTIVITIESDesign and Synthesis of Chiral Organic
Molecules for Asymmetric Synthesis
Department of Life and Coordination-Complex Molecular Science
Division of Complex Catalysis
Education2000 B.S. Nagoya University
2005 Ph.D. The University of Chicago
Professional Employment
2005 Postdoctoral Fellow, Harvard University
2006 Assistant Professor, Tohoku University
2014 Associate Professor, Institute for Molecular Science
Associate Professor, The Graduate University for Advanced
Studies

MOMIYAMA, Norie
Associate Professor[momiyama@ims.ac.jp]

Keywords

MemberAssistant Professor
OHTSUKA, Naoya
Graduate Student
OISHI, Shunya
KATO, Masayuki
Technical Fellow
HARADA, Kuniko
MARUYAMA, Rio
Secretary
USHIDA, HinanoAwards
2003 The Elizabeth R. Norton Prize for Excellence in Research inChemistry, University of Chicago
2004 Abbott Laboratories Graduate Fellowship2005 Damon Runyon Cancer Research Foundation Post Doctoral
Research Fellowship2008 Thieme Chemistry Journals Award
2014 The 17th Morita Science Research Award
Central Glass Co., Ltd. Award in Organic Chemistry, Japan

Synthetic Chemistry, Molecular Catalyst, Non-Covalent Interaction

The field of molecular catalysis has been an attractive areaof research for realizing efficient and new transformations inthe synthesis of functional molecules. The design of chiralmolecular catalysts has been recognized as one of the mostvaluable strategies; therefore, a great deal of effort has been
dedicated to the developments. In general, “metals” have beenfrequently used as the activation centers, and conformationallyrigid catalyst frameworks have been preferably components
for the catalyst design. To develop a new type of molecularcatalysis, we have focused on the use of non-metal elements asactivation centers and have incorporated non-covalent interac­tions as organizing forces in the molecular design of catalysts.
This approach had not received much attention until recently.
We hope that our approach will open a new frontier in chiralorganic molecules to chiral molecular science from chiralmolecular chemistry.

Figure 1. Hydrogen bonding network in chiral bis-phosphoric acidcatalyst derived from (R)-3,3’-di(2-hydroxy-3 -arylphenyl)binaphthol.
Hydrogen bond acts as activation unit for the substrate in asymmetric
reaction space and controls atropisomeric behavior in naphthyl–phenyl axis.

Selected Publications• T. P. Yoon and E. N. Jacobsen, Science 299, 1691–1693 (2003).
• N. Momiyama and H. Yamamoto, “Brønsted Acid Catalysis ofAchiral Enamine for Regio- and Enantioselective Nitroso Aldol
Synthesis,” J. Am. Chem. Soc. 127, 1080–1081 (2005).
• N. Momiyama, T. Konno, Y. Furiya, T. Iwamoto and M. Terada,“Design of Chiral Bis-Phosphoric Acid Catalyst Derived from(R)-3,3’-Di(2-hydroxy-3-arylphenyl)binaphthol: Catalytic Enantio­
selective Diels–Alder Reaction of α,β-Unsaturated Aldehydes withAmidodienes,” J. Am. Chem. Soc. 133, 19294–19297 (2011).
• N. Momiyama, H. Tabuse, H. Noda, M. Yamanaka, T. Fujinami, K.
Yamanishi, A. Izumiseki, K. Funayama, F. Egawa, S. Okada, H.

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Adachi and M. Terada, “Molecular Design of a Chiral Brønsted
Acid with Two Different Acidic Sites: Regio-, Diastereo-, andEnantioselective Hetero-Diels–Alder Reaction of Azopyridine­carboxylate with Amidodienes Catalyzed by Chiral Carboxylic
Acid–Monophosphoric Acid,” J. Am. Chem. Soc. 138, 11353–11359 (2016).
• S. Oishi, T. Fujinami, Y. Masui, T. Suuki, M. Kato, N. Ohtsuka andN. Momiyama, “Three-Center-Four-Electron Halogen Bond Enables
Non-Metallic Complex Catalysis for Mukaiyama-Mannich-TypeReaction,” iScience 25, 105220 (2022).

Annual Review 2023

1. Design of Hydrogen Bond-Based
Molecular Catalysts
Allylation of imines with allylic metal reagents has been
one of the most valuable tools to synthesize enantioenrichedhomoallylic amines. Due to the inherent nature of allylic metal
reagent, however, regioselectivity has been a long-standing
subject in this area. To develop the synthetic reaction forenantioenriched linear homoallylic amines, we discoveredchirality transferred formal 1,3-rearrangement of ene-aldiminesin the presence of Brønsted acid, and developed it as synthetic
method for variety of enantioenriched linear homo­a llylicamines.1) Furthermore, we studied details of reaction mecha­
nism and succeeded catalytic asymmetric version of thisrearrangement.2) On the basis of our discovery, catalytic asym­
metric version of this reaction was developed.3) To the best
our knowledge, our discovery is the first example of catalytic
asymmetric methylene migration.

that strong halogen bonds are realized when “R” is highly
electronegative substituents such as perfluorinated alkyl oraryl substituents. On the basis of electrophilic feature for
halogen atom, we have examined it to develop catalysis withhalogen bond for carbon–carbon bond forming reactions.9,10,11)
We found that the three-center-four-electron halogen bond
become a new driving force for catalysis. 9) By integrating
halogen(I) (X+: I+ or Br+), the bis-pyridyl ligand NN, and a nonnucleophilic counter anion Y, we developed non-metallic com­plex catalysts, [N···X···N]Ys, that exhibited outstanding activity
and facilitated the Mukaiyama–Mannich-type reaction of Nheteroaromatics with parts-per-million-level catalyst loading.
NMR titration experiments, CSI-MS, computations, and UV-vis
spectroscopic studies suggest that the robust catalytic activity of[N···X···N]Y can be attributed to the unique ability of the 3c4e
X-bond for binding chloride: i) the covalent nature transforms
the [N···X···N]+ complexation to sp2 CH as a hydrogen-bonding
donor site, and ii) the non­c ovalent property allows for thedissociation of [N···X···N]+ for the formation of [Cl···X···Cl]−.
This study introduces the application of 3c4e X-bonds in cataly­
sis via halogen(I) complexes.

Figure 2. Asymmetric counteranion-directed catalysis via OH···O,CH···O, CH···π, π···π interactions.

Perfluorinated aryls have emerged as an exquisite class of
motifs in the design of molecular catalysts, and their electronicand steric alterations lead to notable changes in the chemicalyields and the stereoselectivities. We developed the per­fluoaryls-incorporated chiral mono-phosphoric acids as chiral
Brønsted acid catalysts that can deliver high yields and stereo­
selectivities in the reactions of imines with unactivated alkenes.
We have described the first example of a diastereo- andenantioselective [4+2] cycloaddition reaction of N-benzoyl
imines, as well as the enantioselective three-component imino–
ene reaction using aldehydes and FmocNH2.4)
We have developed (R)-3,3’-di(2-hydroxy- 3-arylphenyl)
binaphthol derived chiral bis-phosphoric acid which efficiently
catalyzed enantioselective Diels–Alder reaction of acroleins
with amidodienes.5,6) We demonstrated that two phosphoricacid groups with individually different acidities can play
distinct roles in catalyst behavior through hydrogen bonding
interactions. Therefore, we developed a Brønsted acid withtwo different acidic sites, aryl phosphinic acid-phosphoricacid.7) Furthermore, molecular design of a chiral Brønstedacid with two different acidic sites, chiral carboxylic acid–cyclic mono-phosphoric acid, was identified as a new andeffective concept in asymmetric hetero-Diels–Alder reactionof 2-azopyridinoester with amidodienes.8)

2. Design of Halogen Bond-Based
Molecular Catalysts
Halogen bonds are attractive non-covalent interactions
between terminal halogen atoms in compounds of the type
R—X (X = Cl, Br, I) and Lewis bases LBs. It has been known

Figure 3. Three-center-four-electron halogen bond enables nonmetallic complex catalysis for Mukaiyama–Mannich-type reaction.

References
1) C. Jongwohan, Y. Honda, T. Suzuki, T. Fujinami, K. Adachi and N.
Momiyama, Org. Lett. 21, 4991–4995 (2019).
2) N. Momiyama, Y. Honda, T. Suzuki and C. Jongwohan, Asian J.
Org. Chem. 10, 2205–2212 (2021). [Invitation only, special collec­
tion on the Topic of Organocatalysis]
3) N. Momiyama, A. C. Jongwohan, N. Ohtsuka, P. Chaibuth, T.
Fujinami, K. Adachi and T. Suzuki, J. Org. Chem. 87, 9399–9407(2022).
4) N. Momiyama, H. Okamoto, J. Kikuchi, T. Korenaga and M.
Terada, ACS Catal. 6, 1198–1204 (2016).
5) N. Momiyama, T. Konno, Y. Furiya, T. Iwamoto and M. Terada, J.
Am. Chem. Soc. 133, 19294–19297 (2011).
6) N. Momiyama, K. Funayama, H. Noda, M. Yamanaka, N. Akasaka,
S. Ishida, T. Iwamoto and M. Terada, ACS Catal. 6, 949–956(2016).
7) N. Momiyama, T. Narumi and M. Terada, Chem. Commun. 51,16976–16979 (2015).
8) N. Momiyama, H. Tabuse, H. Noda, M. Yamanaka, T. Fujinami, K.
Yamanishi, A. Izumiseki, K. Funayama, F. Egawa, S. Okada, H.
Adachi and M. Terada, J. Am. Chem. Soc. 138, 11353–11359 (2016).
9) N. Momiyama et al., ChemRxiv DOI: 10.26434/chemrxiv-20221ljk9-v4 (2022).
10) N. Momiyama et al., One. article under revision; six manuscripts
under preparation for submission.
11) N. Momiyama, A. Izumiseki and N. Ohtsuka, ChemPlusChem 6,
913–919 (2021). [Invitation only, special issue for ISXB-4]

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