Helically Chiral Polymer Ligand, “PQXphos”

Literature Seminar
2016/9/1
KAJINO Hidetoshi (M2)

Contents
Introduction
Poly(quinoxaline-2, 3-diyl)s
Helix-inversion Mechanism
PQX-based Chiral Ligand

Chirality-Amplification SystemSummary1

Introduction

2

Helical Chiral Polymers
for Asymmetric Synthesis
Advantage of helical polymer-based chiral ligands
・ease in recovery and reusability
・large chiral environment

TrMA = triphenylmethyl methacrylate
3Chem. Rev. 2001, 101, 4013−4038

Ex. Poly(triphenylmethyl methacrylate)
PhHNPhHnNOONPoly(triphenylmethyl methacrylate(ligand)Insufficient enantioselectivity
lack of rigidity, homogeneity, etc.
4Angew. Chem. Int. Ed. 2002, 41, 1641-1647

Poly(quinoxaline-2, 3-diyl)s5

Today’s Main Topic : Poly(quinoxaline-2, 3-diyl)s

杉野目先生紹介・1993-2002 Assistant Professor
Department of Synthetic Chemistry and Biological Chemistry,
Kyoto University
・2002-2004 Associate Professor
Department of Synthetic Chemistry and Biological Chemistry,
Kyoto University
・2004-present Professor
Department of Synthetic Chemistry and Biological Chemistry,
Kyoto University

Prof. Suginome
What is PQX?
◆Features・Single-handed helical polymer
・Chirality-switchability

6

The Chain-End Control Mechanism of
the Screw-Sense Selective Polymerization=P = right hended helix, M = left handed helix

7Org. Lett., 2002, 4, 351-354

The Chain-End Control Mechanism of
the Screw-Sense Selective Polymerization

8

J. Am. Chem. Soc. 1998, 120, 11880-11893

Solvent-Dependent Switch of
Helical Main-Chain Chirality
OO

NC

1) o-TolNiCl(PMe3)2
PMe3, THF, rt, 3 h2) o-TolMgBro-TolNCOO

No-TolN40(R)-monomer
1, 1, 2-TCE = 1, 1, 2-trichloroethan

Solvent-dependent
Helix Inversion

Perfect P-Helix
In CHCl3

Perfect M-Helix
In 1, 1, 2-TCE
9Chem. Commun., 2010, 46, 4914-4916

Helix-inversion Mechanism

10Screening of Chiral Side Chains

polymerin CHCl3

in 1, 1, 2-TCE

P

M

MP◆ No correlation between helical direction
and configuration of side chainsa40

R* =b40

R* =c40

R* =OPM◆ Oxygen atom were not essential.

d40

R* =OMMe40

R* =OMP◆ Switchable polymer commonly havethe chiral center at third position.

f40

R* =OPPO

11J. Am. Chem. Soc, 2013, 135, 10104-10133

Gained Energy Difference Between P and M helix

Calculated Eh and gmax Values

PP
M
M

MM

ΔG = EhN
Perfect P-helix

g = dissymmetry factor (Δε/ε)

Perfect M-helix

The large Eh value played a central rolein the highly efficient control of the screw sense.

cf. other helical polymers : Eh = 0.005-0.06 kJ mol-1
12Angew. Chem. Int. Ed. 2015, 54, 9333-9337 J. Am. Chem. Soc, 2013, 135, 10104-10133

Relationships Between Number of Chiral Units and sePolymer 3a and 3c
Helix induction was achieved very efficiency.

Polymer 3b and 3d
Many chiral units are required tomaintain a single-handed helical main chain.
※se = gabs/gmax
3b : low solubility
13
3d : no inversion
J. Am. Chem. Soc, 2013, 135, 10104-10133

Helix induction by various solvents
improveNOON

Eh (kJ mol-1)

3a40

gmax /10-3-0.59 +2.37
(P)

OON
40

CHCl3NCHCl31, 1, 2-TCE
Eh (kJ mol-1)

gmax /10-3-0.32-2.87(M)Eh (kJ mol-1)

3h40

gmax /10-3-1.01 +2.29(P)40

1, 1, 2-TCE
Eh (kJ mol-1)

gmax /10-3-0.70-2.79(M)14

J. Am. Chem. Soc, 2013, 135, 10104-10133

Helix induction by Alkane solvents

Linear alkanes (larger molecular aspect ratio)
induced M-helical structure.
Branched or cyclic alkanes(smaller molecular aspect ratio)
induced P-helical structure.
※Molecular aspect ratio =L (major axis)/D (minor axis)
15

J. Am. Chem. Soc, 2014, 136, 15901-15904

Possible conformations
o-TolOONo-TolN40

Conformation A is favoredin CHCl3?

Conformation D is favoredin 1, 1, 2-TCE?

Chiral side chains except for those on the central quinoxaline ring16
are omitted for clarity.
Chem. Commun., 2010, 46, 4914-4916

PQX-based Chiral Ligand

17

PQXphos Ligand

Axial chirality induced by P-helix

18

Angew. Chem. 2009, 121, 547-550

Catalytic Asymmetric Hydrosilylation of StyreneHigh reactivity and enantioselectivity
19

J. Am. Chem. Soc. 2010, 132, 7899-7901

Catalytic Asymmetric Hydrosilylation of Styrene
Random copolymer (P)-co-P(950/0/50)
・easy accessible than block copolymer

Recoverable and reusable
20

J. Am. Chem. Soc. 2010, 132, 7899-7901

Catalytic Asymmetric Hydrosilylation of Styrene

Chirality-switchable

CD spectra of (R)-P(950*/50) in chloroform (blue line)
and in a 1, 1, 2-TCE/toluene (2/1) mixture (red line)
21
J. Am. Chem. Soc. 2010, 132, 7899-7901

Catalytic Asymmetric Suzuki-Miyaura Coupling
Br

B(OH)2
P(O)(OMe 2)

MePdLnLigandMeP(O)(OMe 2)+1000mer-based random copolymer
Pure right handed helical structure
NOOproductOne of the first system
reported by Buchwald and co-workers

N~ 950o-Tol

HNMe2
PCy2R2PN(S)-KenPhos

N~ 50n(P)-(R)-PQXphos

R = 2-nap
R = Cyy. 80% ee 94%
y. 72% ee 40%(-)-(S)-productJ. Am. Chem. Soc. 2000, 122, 12051-12052

y. 95% ee 86%(+)-(R)-product22

Angew. Chem. Int. Ed. 2011, 50, 8844-8847

Catalytic Asymmetric Suzuki-Miyaura Coupling(P)-(R)-PQXphos ligand afforded (-)-(S)-compound (94% ee),
whereas (S)-KenPhos gave its enantiomer (+)-(R)-compound (86% ee).

(P)-helical PQXphos bearing R-configured side chains[(P)-(R)-PQXphos]

Because of the absence of the dimethylamino group
23

Angew. Chem. Int. Ed. 2011, 50, 8844-8847

Catalytic Asymmetric Suzuki-Miyaura Coupling24

Angew. Chem. Int. Ed. 2011, 50, 8844-8847

Chirality-Amplification System25

Chirality-Amplification System2(x/y) (random copolymer)[(x-y)/(x+y)×100] = 10% ee (55:45)
x+y = 40, 100, 200, 400, 600, 800, and 1000

※ΔGh = Eh

ΔGh value suggests that the use of monomers
with 10% ee is inefficient for the induction ofabsolute screw senses.
26

Angew. Chem. Int. Ed. 2015, 54, 9333-9337

Chirality-Amplification System2(x/y)
x+y = 1000[(x-y)/(x+y)×100] = 0.0, 1.0, 2.5, 5.0, 7.5, 10, 20, 30, 50, and 100% ee

Monomers with 30% ee were able toinduce > 97% se in the polymer backbone.

27

Angew. Chem. Int. Ed. 2015, 54, 9333-9337

Chirality-Amplification System

Polymer ligand 3 and 4 exhibited an almost absolute P-helical conformation.

28

Angew. Chem. Int. Ed. 2015, 54, 9333-9337

Chirality-Amplification System

Purely right handed helical structure
Asymmetric hydrosilylation

Asymmetric Suzuki coupling

29

Angew. Chem. Int. Ed. 2015, 54, 9333-9337

Summary30

Summary 1✔ PQX exhibits pure right- or left-handed helical sense
because of large Eh value.

ΔG = EhN
Perfect P-helix

Perfect M-helix✔ PQX shows an efficient solvent dependent helix inversion.
✔ Studies for establishing the origin of conformational change are
currently being undertaken in Suginome Lab..

31

Summary 2✔ PQXphos ligand can induce high enantioselectivities
that are comparable to those obtainedby low-molecular-weight catalyst system.
✔ PQXphos ligand is easily separable, reusable.
✔ Reversible conformational change of the polymer backbone can beapplied to switch the enantioinduction.
✔ The highly enantioselective generation of both enantiomers of acatalyst from a single chiral sourse with a low ee value
has not been reported previously.

32

Appendix

33

Calculation of the value of Eh and gmax
The total energy difference between P and M helical polymers is expressed as

ΔG = -RTln([P]/[M]) … (1)Where R, T, [P], [M] are the gas constant (8.314 J K-1 mol-1), operating temperature (293.15 K), and molar
concentration of P and M helical polymers ([P]/[M]). In the case where the polymer has no conformations
containing helical reversal, ΔG is proportional to the number of chiral units N and Eh, i.e., the gained energy
difference between P and M helical per a chiral unit.
ΔG = EhN … (2)The screw-sense excess (se) is defined as
se = ([p] – [M])/([P] + [M]) … (3)Here, se is represent using Eh, N, R, and T as
se = {exp(-EhN/RT) – 1}/{exp(-EhN/RT) + 1}
= tanh(-EhN/2RT) … (4)where hyperbolic tangent function (tanh) is involved. The observed dissymmetry factor gabs is proportional to
the screw-sense excess, namely

se = gabs/gmax … (5)where gmax is the g value for the purely single-handed poly(quinoxaline-2, 3-diyl)s.
Equation 4 can be expressed using gabs and gmax asgabs = tanh(-EhN/2RT) ×gmax … (6)Nonlinear least-square fitting of gabs versus N was performed by using the Solver Functionin Microsoft Office Excel 2007. Sums of the squares of the deviation were minimized
by varying two parameters, gmax and Eh. … (7)34Asymmetric Suzuki-Miyaura cross-coupling of
1-bromo-2-naphthoates

35

Asymmetric Silaborative Cleavage of
meso-Methylenecyclopropanes

36

Asymmetric desymmetrization througharylative ring opening of 1,4-dihydro-1,4epoxynaphthalenes with arylboronic acids

37

Q&A

38

Q. 高温でも適用可能か?
A. 関連論文を見る限り高くても50℃程度での反応となっています。
らせん反転は60℃で起こるので、それ以上の温度で反応をかけると生成物のeeの低下などが生じるのかもしれません。
J. Am. Chem. Soc. 2012, 134, 11092-11095

Q. ランダムポリマーの三連子構造のミクロ構造はどうなっているのか?
A. ランダム共重合で合成されるため完全にランダムになっているはずです
キラル側鎖を持つモノマーユニットが高分子末端に来るとseが低下する傾向にあるため40mer程度の重合度の場合にはブロック共重合などでキラルモノマーが末端に来ないよう制御する必要がありますが、重合度が上がるほどキラルモノマーが末端に来る確率が下がるためランダム共重合での合成が可能になります。
J. Am. Chem. Soc. 2013, 135, 10104-10113

Q. ホスフィンが入る位置による反応への影響は?
A. ホスフィンユニットが末端に来るとエナンチオ選択性を失うようです。
ただし、ホスフィンユニットが連続してしまっても生成物の選択性に影響はないようです。
Angew. Chem. 2009, 121, 547-550

39Q. 何merくらいが反応効率が最大になる?
A. 重合度と反応収率の関係について記述された論文は見つけられませんでしたが、らせんのseは重合度が高いほど高くなるため、1000mer程度のPQXphosを使う場合が多いように感じます。
また40mer程度の重合度で配位子として使う場合には、キラルモノマーがポリマー末端にこないように制御する必要があるため、低重合度で効率よく反応を進行させたい場合には、ポリマーの重合段階で手間が増えてしまいます。
Angew. Chem. 2009, 121, 547-550

Q. P, M, seはどうやって決めているのか?
A. らせんの回転方向は、5mer程度のオリゴマーについてX線構造解析を行い、CDスペクトルの結果と対応させたようです。
seはスライド内で述べたように、実測値のgabsと計算値のgmaxとの比によって算出されます。
J. Synth. Org. Chem., Jpn. 2015 73, 1141-1155

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