Study of Cyclization Reactions through Carbon-Oxygen Bond Formation Initiated by Chiral Phosphoric Acid as Enantioselective Catalyst

概要

博士論文

Study of Cyclization Reactions through Carbon-Oxygen
Bond Formation
Initiated by Chiral Phosphoric Acid as
Enantioselective Catalyst
(キラルリン酸触媒を用いた炭素－酸素結合形成を伴う環化
反応の不斉触媒化に関する研究)

Ye Haiting

令和 4 年

博士論文

要約

Chapter 1, The chiral phosphoric acid catalysts have shown superior reactivity and selectivity in various organic
reactions. This catalyst having a unique chiral pocket with acid/base dual function even though a mono-functional
catalyst, which interact with electrophile and nucleophile through hydrogen bonds. When considering a substrate having
an oxygenated reaction site, the oxygen has two lone pairs both of which would be involved in a molecular
transformation, such as protonation and reaction with an electrophile. Hence, in these transformations, possible
transition states become more complex. In my doctor course research, I studied several cyclization reactions through
C-O bond formation under the influence of chiral phosphoric acid catalyst.

Chapter 2, I have developed an enantioselective [4 + 2] cycloaddition reaction of α-fluorostyrenes with N-benzoyl
imines using a chiral phosphoric acid catalyst. The present reaction afforded enantioenriched 1,3-oxazines in good
yields with excellent diastereo- and enantioselectivities. This approach highlights the utility of the fluorine substituent
in not only providing sufficient nucleophilicity to the carbon–carbon double bond but also serving as a handle for
further manipulations of the resulting enantioenriched products. Chiral phosphoric acid interacts with the nitrogen in the
imine rather than the oxygen, and the 4+2 cycloaddition reaction has better stereospecificity, fewer transition states need
to be considered in the cyclization reaction, thus obtaining a higher stereoselectivity.

Chapter 3, I have developed a novel asymmetric protonation of fluoroalkenes by Bis-chiral phosphoric acid. More
importantly, this reaction proceeds through an unprecedented conjugated addition of vinyl ketals/asymmetric
protonation of vinyl ether sequence. We clearly study every step in this transformation. The reversible activation of
ketal is the rate-determined step, and Hammett study support positive charge build in the enantio-determined step. By
utilizing the hydrogen bond donor or metal cation as additive highly accelerate the activation of ketals, while damage to
the enantioselectivity.

Chapter 4, I have performed the kinetic optical resolution via the lactonization of 4-hydroxyl esters in the presence
of chiral phosphoric acids. At first, DFT calculations of the transition states of the reaction using 4-hydroxybutyrate as a
model revealed the reason why no selectivity was observed when the BINOL-derived catalyst was used. This result was
consistent with the experimental results. Subsequently, we achieved the intended optical resolution with moderate
selectivity by using the SPINOL-derived phosphoric acid through various experiments and calculations. Distortion
analysis of the SPINOL-derived catalyst revealed that distortion of the catalyst structure in the transition state of the
reaction has a significant effect on the selectivity of the reaction. Based on this result, we performed computational
optimization of the catalyst backbones and substituents. Ultimately, the calculation results suggested that a
Cy-SPINOL-derived catalyst would give a good s-factor in the present kinetic resolution reaction. Indeed, the reactions
in the presence of a Cy-SPINOL-derived catalyst possessing 2,6-diisprpopyl-4-mesitylpehnyl substituent was
performed in standard conditions to afford the desired product with good s-value (s = 21.3). The s-factor was greatly
improved compared with the case of the SPINOL-derived catalyst (s = 7.8). We successfully found out the effective
catalyst for the kinetic resolution reaction of methyl-4-hydroxylphenylbutyrate by optimizing and screening catalyst
structures and substituents through computational analysis of transition states. ...