Research summary
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University
Natsuhisa Oka

Synthesis of optically active cyclopentene derivatives by a novel
domino reaction
Domino reactions are useful for the efficient synthesis of complex compounds. We have discovered that thetreatment of Julia-Kocienski sulfones derived from nucleosides with bases such as DBU affords cyclopentene
nucleosides in one step via a novel domino reaction. In addition, we discovered that the same reaction in thepresence of a nucleophile such as a thiol or a thiocarboxylic acid provides cyclopentenes bearing thenucleophile in place of the nucleobase. The resulting cyclopentenes would be useful as synthetic intermediates
for biologically active carbocyclic nucleosides and cyclopentanes.

1. Oka, N.; Kanda, M.; Furuzawa, M.; Arai, W.; Ando, K. ChemRxiv 2021, DOI: 10.33774/chemrxiv-2021-j0rc0.
2. Oka, N.; Kanda, M.; Furuzawa, M.; Arai, W.; Ando, K. J. Org. Chem. 2021, 86, 16684-16698.
3. Oka, N.; Kanda, M.; Furuzawa, M.; Arai, W.; Ando, K. Curr. Protocol. Nucleic Acid Chem. 2022, 2, e398.

Stereoselective synthesis of 1,2-cis-glycosyl sulfones and theirapplication
Glycosyl sulfones are useful as synthetic intermediates for various sugar derivatives and biologically activecompounds. However, most of the previous research has used easily synthesized 1,2-trans-isomers, and little
progress has been made in the study of 1,2-cis-isomers. We developed a novel method for the synthesis of 1,2cis-glycosyl sulfones using glycosyl iodides as glycosyl donors. The resulting 1,2-cis-glycosyl sulfones wereuseful as Julia-Kocienski reagents to give exo-glycals in good yields from aldehydes. The 1,2-cis-glycosyl
sulfones derived from ribose and glucose afforded the corresponding exo-glycals with higher E-selectivity than
the 1,2-trans-isomers, and the difference was particularly large for the ribose derivatives. Thus, our study has
revealed the usefulness of 1,2-cis-glycosyl sulfones.

1.

Oka, N.; Mori, A.; Ando, K. Eur. J. Org. Chem. 2018, 6355-6362.

2.

Oka, N.; Mori, A.; Suzuki, K.; Ando, K. J. Org. Chem. 2021, 86, 657-673.

3.

Oka, N.; Suzuki, K.; Mori, A.; Ando, K. Eur. J. Org. Chem. 2021, 5922-5933.

Synthesis of nucleosides phosphorylated at their carbonyl groups
In the biosynthetic pathways of nucleic acids, there are several reactions in which the carbonyl group of a
nucleobase is activated by phosphorylation and replaced by an amino group or a sulfur atom. We developed amethod for the synthesis of carbonyl-phosphorylated inosine, an active intermediate analog, to elucidate the reaction
mechanism of the biosynthesis of adenylosuccinate. Such molecules would also be useful to develop enzymeresponsive molecules. Although the phosphorylation of nucleoside carbonyl groups is difficult to achieve using
existing methods, we have succeeded in the synthesis of O6-phosphorylinosines by using CMPT or CMMT, which
are acidic activators with low nucleophilicity, to suppress the degradation of unstable synthetic intermediates. In
addition, we succeeded in synthesizing an O2-phosphorylxanthosine derivative as a simple model compound of
adenosine monophosphorylated xanthosine monophosphate (AMP-XMP), which is known as a biosynthetic
intermediate of guanosine monophosphate and clarified its hydrolytic stability.
NCON
TBSO

OTBSO–+N
NH

N

R1O

H TfO

NOTBS

R2CMPTO
R2 P Ni-Pr2
R1O

R1 = Bn, i-Pr, Ph; R2 = H, MeTBAF

HONC

NOorHO

OR

R1O

O
R1O

12NN
H

1)
O

OR1

R , R = protecting groups2) oxidation
3) deprotectionN

R1 = Bn, i-Pr, PhO
P Ni-Pr2
PhO
CMMT

NOH

NC
2NO

H TfO
N+CMMT

N

O

N

NC+OPONHOO
HON

NHNOO

POPhO–OH

Rate of hydrolysis at pH 4.8 > 6.8 > 11.1

1.

Oka, N.; Morita, Y.; Itakura, Y.; Ando, K. Chem. Commun. 2013, 49, 11503-11505.

2.

Oka, N.; Hirabayashi, H.; Kumada, K.; Ando, K. Bioorg. Med. Chem. Lett. 2021, 54, 128439.

Chemical synthesis of archaeosine
Archaeosine is a hypermodified nucleoside found in archaeal tRNAs, and their biosynthesis and functions havebeen studied for a long time. The supply of pure archaeosine by chemical synthesis is important for promoting suchresearch, but existing methods have shortcomings, such as low synthetic yields. We have developed an efficientmethod for the synthesis of archaeosine using PreQ0-nucleoside as an intermediate. In addition, we applied thismethod to the synthesis of PreQ0-nucleoside-lysine adduct 1. Collaborative research with Prof. Yokogawa of ourDepartment has revealed that 1 is a biosynthetic intermediate of archaeosine.
ONH
H2NN

HOO
HOAcO H2NNH

NH2HOOH

O
HOOH

N

NOH

NH2HO2) H2, Pd/CAcOH

HNNHHOOHONNOHNH2NNH2OHarchaeosine
7 steps, 29% overall yieldNH2OH
1) H2O, 80 °C

+H2N

NO
HO

preQ0-nucleoside

OONH

1) NH2OH
H2O,HO2C
NC

NH2+O

NC

CO2H·DBU

2) H2, Pd/C, AcOH
EtOH H2O, 80 °C

HNH

NONHHOONN

NH2

preQ0-nucleoside
HOOH
1

1. Oka, N.; Fukuta, A.; Ando, K. Tetrahedron 2018, 74, 5709-5714.
2. Yokogawa, T.; Nomura, Y.; Yasuda, A.; Ogino, H.; Hiura, K.; Nakada, S.; Oka, N.; Ando, K.; Kawamura,T.; Hirata, A.; Hori, H.; Ohno, S. Nat. Chem. Biol. 2019, 15, 1148-1155.

Development of α-selective ribofuranosylation reaction
Ribofuranosides are found in various biologically active natural products. Some of them are potentially useful as
cosmetics, food additives, and medicines. Ribofuranosides have two stereoisomers, α- and β-ribofuranosides. While
the synthesis of β-isomers is generally easy, it is still difficult to synthesize α-ribofuranosides completelystereoselectively. We developed a novel α-selective ribofuranosylation of alcohols using a ribofuranosyl iodide 1 asa glycosyl donor. The α-selectivity is up to >99:1 for various glycosyl acceptors.

1.

Oka, N.; Kajino, R.; Takeuchi, K.; Nagakawa, H.; Ando, K. J. Org. Chem. 2014, 79, 7656-7664.